Infectious Diseases of Central Nervous System

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Library of Congress Cataloging-in-Publication Data
Infections of the central nervous system (Scheld)

Infections of the central nervous system / editors, W. Michael Scheld, Richard J. Whitley, Christina M. Marra. — Fourth edition.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4511-7372-7 (hardback : alk. paper)
ISBN-10: 1-4511-7372-5 (hardback : alk. paper)
I. Scheld, W. Michael, editor of compilation. II. Whitley, Richard J., editor of compilation. III. Marra, Christina M., editor of compilation. IV.
Title.
[DNLM: 1. Central Nervous System Infections. WL 301]
RC359.5
616.8—dc23
2014004822
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CONTRIBUTORS
Philipp Agyeman, MD
Research Fellow
Neuroinfection Laboratory, Institute for Infectious Diseases
University of Bern
Attending Physician
Department of Pediatrics
University of Bern
Inselspital
Bern, Switzerland
Kelly J. Baldwin, MD
Clerkship Director
Department of Neurology
Temple University, School of Medicine
Philadelphia, Pennsylvania
Associate
Geisinger Medical Center
Danville, Pennsylvania
Kyra J. Becker, MD
Professor
Department of Neurology and Neurological Surgery
University of Washington School of Medicine
Seattle, Washington
J. David Beckham, MD
Assistant Professor of Medicine and Neurology
Departments of Medicine (Infectious Diseases) and Neurology
University of Colorado School of Medicine
Aurora, Colorado
Jeana L. Benwill, MD
Assistant Professor of Medicine
The University of Texas Health Science Center at Tyler
Tyler, Texas
Sven Bergström, PhD

Professor
Department of Molecular Biology
Umeå University
Umeå, Sweden
Ari Bitnun, MD, MSc, FRCPC

Associate Professor
University of Toronto
Staff Physician
The Hospital for Sick Children
Toronto, Ontario, Canada
Itzhak Brook, MD, MSc

Professor
Georgetown University School of Medicine
Attending Physician in Infectious Diseases, Pediatrics
Georgetown University Hospital
Washington DC, Washington
Mary T. Caserta, MD
Professor
University of Rochester Medical Center School of Medicine and Dentistry
Attending Physician
Golisano Children’s Hospital
Rochester, New York
Kevin A. Cassady, MD
Associate Professor
Department of Pediatric Infectious Diseases
University of Alabama at Birmingham
Birmingham, Alabama
Matthias Cavassini
Private-Decent and Senior Lecturer
Chief of Service, Department Chair
Service of Infectious Diseases, Department of Medicine
University Hospital of Lausanne
Lausanne, Switzerland
Maxine Caws, PhD, MSc, BSc

Research Lecturer
Department of Clinical Sciences
Liverpool School of Tropical Medicine
Liverpool, United Kingdom
Head of TB Research Programme
Oxford University Clinical Research Unit
Hospital for Tropical Diseases
Ho Chi Minh City, Vietnam
Won K. Chung, MD
Post-doctoral Fellow
Department of Internal Medicine, Division of Infectious Disease
University of Texas Medical Branch
Galveston, Texas
David J. Coffey, MD
Associate Professor
Geisel School of Medicine at Dartmouth
Lebanon, New Hampshire
Jeffrey I. Cohen, MD
Chief
Laboratory of Infectious Diseases
National Institute of Allergy and Infectious Diseases, National Institutes of Health
Bethesda, Maryland
Amanda C. Cohn, MD
Medical Epidemiologist
Division of Bacterial Diseases
National Center for Immunizations and Respiratory Diseases, Centers for Disease Control and Prevention
Atlanta, Georgia
Moshe Ephros, MD
Associate Clinical Professor
Faculty of Medicine
Technion-Israel Institute of Technology
Director
Pediatric Infectious Disease Unit
Carmel Medical Center
Haifa, Israel
Jeremy Farrar, FRCP, FRCP(Ed), FMedSci, PhD, OBE

Director
Oxford University Clinical Research Unit
Wellcome Trust Major Overseas Programme
Kathleen R. Fink, MD
Assistant Professor
Department of Radiology
University of Washington
Harborview Medical Center
Seattle, Washington
Sven Forner, BA
CJD Clinical Research Team
University of California, San Francisco
UCSF Memory and Aging Center
San Francisco, California
Michael D. Geschwind, MD, PhD

Associate Professor
Michael J. Homer Chair in Neurology
Michael Giladi, MD, MSc

Associate Professor of Medicine
Sackler Faculty of Medicine
Tel Aviv University
The Infectious Disease Unit and the Bernard Pridan
Laboratory for Molecular Biology of Infectious Diseases
Tel Aviv Medical Center
Tel Aviv, Israel
Stefano Giulieri, MD
Chief Resident
Service of Infectious Diseases, Department of Medicine
University Hospital of Lausanne
Carol Glaser, MD
Chief
Encephalitis and Special Investigations Section
Division of Communicable Disease Control
California Department of Public Health
Richmond, California
Associate Clinical Professor
Department of Pediatrics, Division of Pediatric Infectious Diseases
University of California, San Franciso
John W. Gnann, Jr., MD

Professor
Department of Medicine, Division of Infectious Diseases
Medical University of South Carolina
Charleston, South Carolina
Denis Grandgirard, PhD

Senior Postdoc
Neuroinfection Laboratory
Institute for Infectious Diseases
University of Bern
Bern, Switzerland
Diane E. Griffin, MD, PhD

Professor and Alfred and Jill Sommer Chair
W. Harry Feinstone Department of Molecular Microbiology and Immunology
Johns Hopkins Bloomberg School of Public Health
Baltimore, Maryland
Paul D. Griffiths, MD, DSc

Professor of Virology
Centre for Virology
University College London Medical School
Royal Free London NHS Foundation Trust
London, United Kingdom
John J. Halperin, MD
Professor
Departments of Neurology and Medicine
Icahn School of Medicine at Mount Sinai
New York, New York
Chair
Department of Neurosciences
Overlook Medical Center
Summit, New Jersey
Barry J. Hartman, MD
Clinical Professor of Medicine
Weill Cornell Medical Center
Attending Physician
Department of Medicine
New York Presbyterian Hospital
New York, New York
Rodrigo Hasbun, MD, MPH

Associate Professor
Department of Medicine, Infectious Diseases
University of Texas Health Science Center
Attending Physician
Memorial Hermann Hospital
Houston, Texas
Dorothee Heemskerk, MSc, MD

Clinical Research Fellow
Oxford University Clinical Research Unit VN
University of Oxford
David C. Helfgott, MD
Assistant Professor of Medicine
Internal Medicine
Weill Cornell Medical College
Assistant Attending Physician
New York Presbyterian Hospital
New York, New York
Jerzy Hildebrand, MD, PhD †
Professor of Neurology
Institut Jules Bordet
Université Libre de Bruxelle
Brussels, Belgium
Marc Hildebrand, MD, PhD

Hôpitaux Iris Sud
Brussels, Belgium
Susan E. Hoover, MD, PhD

Associate Professor
Internal Medicine
University of South Dakota Sanford School of Medicine
Sanford Health
Sioux Falls, South Dakota
Jennifer L. Horan, MD, PharmD

Medical Instructor
Duke University Medical Center
Durham, North Carolina
Alan C. Jackson, MD, FRCPC

Professor
Departments of Internal Medicine (Neurology) and Medical Microbiology
University of Manitoba
Head
Section of Neurology, Internal Medicine
Health Sciences Centre
Winnipeg, Canada
David W. Kimberlin, MD
Professor of Pediatrics
Birmingham, Alabama
Louis V. Kirchhoff, MD, MPH

Professor
Departments of Internal Medicine (Infectious Diseases) and Epidemiology
University of Iowa Health Care
Staff Physician
Medical Service
Department of Veterans Affairs Medical Center
Iowa City, Iowa
Matthias Klein, MD
Attending Physician
University of Munich
Klinikum Grosshadern
Munich, Germany
Serggio C. Lanata, MD
Clinical Fellow
Stephen L. Leib, MD
Associate Professor
Neuroinfection Laboratory, Institute for Infectious Diseases
University of Bern
Bern, Switzerland
Head
Biology Division, Spiez Laboratory
Swiss Federal Office for Civil Protection
Austrasse
Spiez, Switzerland
Matthias Maiwald, MD, PhD

Adjunct Associate Professor
Department of Microbiology
National University of Singapore
Consultant in Microbiology
Department of Pathology and Laboratory Medicine
KK Women’s and Children’s Hospital
Singapore, Singapore
Carrie P. Marder, MD, PhD

Acting Instructor
University of Washington Medical Center
Seattle, Washington
James D. Marks, MD, PhD

Professor and Vice Chairman
Department of Anesthesia and Perioperative Care
Chief of Anesthesia
Department of Anesthesia and Perioperative Care
San Francisco General Hospital
Christina M. Marra, MD
Professor of Neurology
Adjunct Professor of Medicine (Infectious Diseases)
University of Washington School of Medicine
Seattle, Washington
Matthew McCarthy, MD
Fellow
Weill Cornell Medical Center
New York, New York
Tony M. McGrath, MD
Associate Professor
Department of Pediatrics, Division of Child Neurology
Attending Physician
Division of Child Neurology
Children’s of Alabama
Birmingham, Alabama
Thomas O. McPharlin, RPh

Clinical Associate Professor
University of Washington School of Pharmacy
Clinical Pharmacist
Department of Neurology and Rehabilitation Medicine
Pharmacy
Seattle, Washington
Nancy E. Messonnier, MD
Medical Epidemiologist
Division of Bacterial Diseases
National Center for Immunizations and Respiratory Diseases, Centers for Disease Control and Prevention
Atlanta, Georgia
Reto Antoine Meuli, MD, PhD

Full Professor
University of Lausanne, Faculty of Biology and Medicine
Chief of Service, Department Chair
CHUV, University Hospital of Lausanne
Augusto Miravalle, MD
Assistant Professor of Neurology
Director, Neurology Residency Training Program
University of Colorado Denver School of Medicine
Aurora, Colorado
John F. Modlin, MD
Professor of Pediatrics and Medicine
Department of Pediatrics and Medicine
Geisel School of Medicine at Dartmouth
Hanover, New Hampshire
Deputy Director for Research, Polio
Global Development
Bill & Melinda Gates Foundation
Seattle, Washington
Jose G. Montoya, MD, FACP, FIDSA

Professor
Stanford University
Attending Physician
Stanford Hospital and Clinics
Stanford, California
Shannon Moonah, MD, ScM

Clinical and Research Fellow
Division of Infectious Diseases
University of Virginia School of Medicine
Charlottesville, Virginia
Adjanie Patabendige, PhD

NC3Rs David Sainsbury Fellow
Department of Clinical Infection, Microbiology and Immunology
Institute of Infection and Global Health
University of Liverpool
John R. Perfect, MD
Professor
Duke University Medical Center
Durham, North Carolina
William A. Petri, Jr., MD, PhD

Professor and Chief
University of Virginia School of Medicine
Hans-Walter Pfister, MD
Senior Consultant
University of Munich
Senior Consultant
Klinikum Grosshadern
Munich, Germany
Douglas G. Postels, MD
Associate Professor
Michigan State University
East Lansing, Michigan
Didier Raoult, MD, PhD

Director
URMITE UMR 7278, Faculté de Médecine
Aix-Marseille Université
Chief
Fédération de Microbiologie Clinique
Hôpital de la Timone
Marseille, France
David A. Relman, MD
Thomas C. and Joan M. Merigan Professor
Departments of Medicine and Microbiology and Immunology
Stanford University School of Medicine
Stanford, California
Chief
Infectious Diseases Section
Veterans Affairs Palo Alto Health Care System
Palo Alto, California
Susan Richardson, MD, CM

Professor
Department of Laboratory Medicine and Pathobiology
University of Toronto
Head
Department of Paediatric Laboratory Medicine, Division of Microbiology
The Hospital for Sick Children
Toronto, Ontario, Canada
José R. Romero, MD
Professor
University of Arkansas for Medical Sciences
Director
Section of Infectious Diseases
Arkansas Children’s Hospital
Little Rock, Arkansas
Karen L. Roos, MD
John and Nancy Nelson Professor of Neurology
Professor of Neurological Surgery
Indiana University Health Neuroscience Center
Indianapolis, Indiana
Jeffrey P. Ross, MD
Assistant Clinical Professor
Medicine
University of New Mexico School of Medicine
Albuquerque, New Mexico
Oren Sagher, MD
William F. Chandler Collegiate Professor
Department of Neurosurgery
University of Michigan
Neurosurgery Faculty
University of Michigan Health System
Ann Arbor, Michigan
W. Michael Scheld, MD
Bayer-Gerald L. Mandell Professor of Infectious Diseases
Professor, Myles H. Thaler Center for AIDS and Human Retrovirus Research
Professor of Medicine
Clinical Professor of Neurosurgery
Director, Pfizer Initiative in International Health
University of Virginia Health System
Jose A. Serpa, MD, MS

Assistant Professor
Baylor College of Medicine
Attending Physician
Medicine
Ben Taub Hospital
Houston, Texas
Tom Solomon, MD
Director
Institute of Infection and Global Health
University of Liverpool
Honorary Consultant Neurologist
Walton Centre NHS Foundation Trust
Terrie E. Taylor, DO
University Distinguished Professor
Osteopathic Medical Specialties
Michigan State University College of Osteopathic Medicine
East Lansing, Michigan
Scientific Director
Blantyre Malaria Project
University of Malawi College of Medicine
Blantyre, Malawi
Khoi Duc Than, MD

Chief Resident
Ann Arbor, Michigan
Allan R. Tunkel, MD, PhD

Associate Dean for Medical Education
Warren Alpert Medical School of Brown University
Providence, Rhode Island
Kenneth L. Tyler, MD
Reuler-Lewin Family Professor and Chair of Neurology
Professor of Medicine & Microbiology
Departments of Neurology, Medicine, and Microbiology
University of Colorado Denver School of Medicine
Chair
University of Colorado Hospital
Aurora, Colorado
Diederik van de Beek, MD, PhD

Professor
Academic Medical Center
University of Amsterdam
Amsterdam, The Netherlands
Arun Venkatesan, MD, PhD

Assistant Professor
Johns Hopkins University School of Medicine
Director
Encephalitis Center
Johns Hopkins Hospital
Baltimore, Maryland
Richard J. Wallace, Jr.

Chairman
Department of Microbiology
Chief
Infectious Disease Section
The University of Texas Health Science Center at Tyler
Tyler, Texas
Thomas J. Walsh, MD, PhD (hon), FCCP, FAAM, FIDSA

Director
Transplantation-Oncology Infectious Diseases Program
Chief
Infectious Diseases Translational Research Laboratory
Professor of Medicine, Pediatrics, and Microbiology & Immunology
Henry Schueler Foundation Scholar
Weill Cornell Medical Center and New York Presbyterian Hospital
New York, New York
Anthony C. Wang, MD
House Officer
University of Michigan Health System
Ann Arbor, Michigan
David F. Welch, PhD, D(ABMM)

Medical Microbiologist
Department of Pathology
Medical City
Dallas, Texas
A. Clinton White, Jr., MD

Paul R. Stalnaker Distinguished Professor and Director
Infectious Disease Division, Department of Internal Medicine
University of Texas Medical Branch
Galveston, Texas
Richard J. Whitley, MD
Distinguished University Professor
Loeb Scholar in Pediatrics
Professor of Pediatrics, Microbiology, Medicine, and Neurosurgery
Birmingham, Alabama
Gary P. Wormser, MD
Departments of Microbiology and Immunology and Pharmacology
New York Medical College
Chief
Westchester Medical Center
Valhalla, New York
Joseph R. Zunt, MD, MPH

Professor
Departments of Neurology, Global Health, Medicine (Infectious Diseases), Epidemiology
Attending Neurologist
Seattle, Washington
John Zurasky, MD
Neurocritical Care Medical Director
Chair of Neurology
Providence Health and Services Oregon
Portland, Oregon
PREFACE
The first edition of Infections of the Central Nervous System was published in 1991, a comprehensive
treatise addressing all aspects of central nervous system (CNS) infections for advanced readers. In its
preface, we clearly stated our goal: to develop the gold standard reference text using the “best
information from the best authors with the best format.” Judging from the reviews that followed
publication, and from feedback that we received from colleagues, we believe that the first edition
succeeded in meeting our objectives.
The second edition of Infections of the Central Nervous System was published in 1997 with identical
goals and objectives. The same format was followed, but the 37 chapters of the first edition were
expanded to 51 chapters. Reviews and comments were again positive. The third edition, of 50 chapters,
was published in 2004, with a similar positive reception from readers. A great deal of new information
has accumulated in the past decade, and we wanted to further improve the book in other ways: hence the
fourth edition. With this explosion of new knowledge, the text has changed dramatically, but we have
retained the same editorial team. In addition, we have kept the same basic format: approximately 50
chapters divided into 10 sections.
As for previous editions, the first three chapters of the book cover the approach to diagnosis of CNS
infections, including detailed discussion of diagnostic tests. The chapters that follow provide an in-depth
discussion of individual infectious agents and the CNS diseases that they produce in humans, including
differential diagnosis, clinical symptoms and findings, abnormalities on laboratory and imaging studies,
treatment, and prevention.
Although the number of chapters is approximately the same as the third edition (51 versus 50), several
other changes are noteworthy. Every chapter has been extensively revised and updated appropriately, with
cited references through early 2014. Some, reflecting a huge amount of new information accumulated in
the past decade, have been rewritten completely with essentially the same team of authors (e.g., Chapter
23 on the “Pathogenesis and Pathophysiology of Bacterial Infections”). We have added one new chapter,
on acute encephalitis, by Glaser and Venkatesan. A discussion of the diagnostic approach to the acute
encephalitis syndrome was lacking in the last edition as well as any mention of some noninfectious
entities (e.g., anti–NMDA receptor encephalitis) literally unknown at the time. Dr. Glaser headed the
California Encephalitis Project for much of the last decade, an effort which has contributed substantially
to our current knowledge of encephalitis.
As with prior editions, we chose contributors with clinical experience as well as basic and/or clinical
investigative interests in their topic. Although many of the primary authors of the chapters of the third
edition have been retained, fully 21 of the 51 chapters of this edition employ a new author team (11
chapters have completely new author teams). In choosing these new authors, we attempted to maintain the
excellence of the prior editions while emphasizing cutting edge science and a more international
perspective. This is an outstanding group overall drawn from the disciplines of medicine, pediatrics,
infectious diseases, neurology, neurosurgery, neurointensive care, neuroradiology, virology,
epidemiology, parasitology, vaccines and prevention, and the basic neurosciences. Tables, illustrations,
and photographs have again been used liberally. In many chapters, more than 50% of the references have
been published since 2012.
We plan to further develop and refine the book through future editions. We will continue to provide a
comprehensive readable resource for all physicians who deal with infections of the CNS. We welcome
your comments.
W. Michael Scheld, MD
Richard J. Whitley, MD
Christina M. Marra, MD
ACKNOWLEDGMENTS
We thank everyone who has helped us in the preparation of this large book. Most importantly, we thank all
of the authors for their outstanding contributions, especially those who have replaced prior author teams.
As editors, we were privileged to see their work first; as students of CNS infections, we admire their
special insights and expertise. Numerous other colleagues provided helpful discussion, advice, and
criticism. We are particularly grateful to our assistants, Lisa Cook and Dunia Ritchey. The editorial staff
at Lippincott Williams & Wilkins—Julie Goolsby, acquisitions editor, and Kristina Oberle, development
editor—deserve our gratitude for ensuring completion of the project. Finally, we thank our families for
their tolerance and support during interminable hours required to bring this undertaking to closure.
PREFACE TO THE FIRST EDITION
From the brain, and from the brain only, arise our pleasures, joys, laughter and jests, as well as sorrows, pains, griefs and tears.... It is the
same thing which makes us mad or delirious, inspires us with dread or fear, whether by night or by day, brings sleeplessness, inopportune
mistakes, aimless anxieties, absent-mindedness, and acts that are contrary to habit. These things that we suffer all come from the brain,
when it is not healthy, but becomes abnormally hot, cold, moist or dry.
Hippocrates, The Sacred Disease, Section XVII
Every physician, almost, hath his favourite disease, to which he ascribes all the victories obtained over human nature. The gout, the
rheumatism, the stone, the gravel, and the consumption have all their several patrons in the faculty; and none more than the nervous fever,
or the fever on the spirits.
Henry Fielding, Tom Jones, Book II, Chapter 9
I hasten to give you a sketch of the spotted fever in this place. It made its first appearance about the beginning of January last: but the
instances were few and distant from each other, until last week. Although it had proved fatal in most instances, seven only had died
belonging to this town, previous to the 25th of February. Since that time the disorder has come upon us like a flood of mighty waters. We
have buried eight persons within the last eight days. About twelve or fifteen new cases appeared on Thursday last; many of them very
sudden and violent. This was the most melancholy and alarming day ever witnessed in this place. Seven or eight physicians were
continually engaged in the neighborhood north of the meeting house, and I believe not one half hour passed in the forenoon without
presenting a new case. Pale fear and extreme anxiety were visible in every countenance....
Reverend Festus Foster of Petersham, Massachusetts in a letter to the editor of The Worchester Spy, 6 March 1810
These vignettes concerning central nervous system (CNS) infections come down to us over a span of 25
centuries. The Reverend Foster’s graphic description of an outbreak of meningococcemia and
meningococcal meningitis in the late winter of 1810 makes it easy to understand why these infections
engendered fear among physicians and lay persons alike. Today, even with the comforts of vastly better
knowledge and treatments, CNS infections continue to pose serious problems in health care. Some CNS
infections are common, occurring either as sporadic cases or in epidemics. For example, major outbreaks
of meningococcal disease have occurred in Africa and Asia during the past few years. Furthermore,
despite the introduction of new antimicrobial agents and diagnostic techniques, the mortality associated
with some infections of the central nervous system remains high, particularly in tuberculosis,
pneumococcal, and gram-negative aerobic bacillary meningitis; rabies; tetanus; cryptococcal meningitis in
patients with acquired immunodeficiency syndrome (AIDS); and Jakob-Creutzfeldt disease. The
morbidity associated with CNS infections may be even more important than the death rate, especially in
developing countries. Neurologic sequelae, elegantly described by Hippocrates above, may deprive
survivors of hearing, intellect, or function, demeaning the quality of human life and burdening health
resources and social services.
The distinctive nature and natural history of CNS infections set them somewhat apart from the
mainstream of infectious diseases. The scope of today’s knowledge of these infections can no longer be
presented adequately within the confines of a subsection in a general textbook. Indeed, the understanding
and management of CNS infections is evolving toward a subspecialty in its own right. For these reasons,
a new major text seems justified—hence this book, devoted to a comprehensive coverage of human CNS
infections.
The work is a comprehensive treatise for the advanced reader on all aspects of CNS infections. The
book occupies a central niche between large general texts on pediatrics, medicine, neurology,
neurosurgery, and infectious diseases on the one hand, and specialized single-subject treatises on the
other. We have assembled an outstanding group of contributors, drawn from the ranks of internal
medicine, pediatrics, neurology, neurosurgery, infectious diseases, epidemiology, virology,
neuroradiology, and the basic neurosciences.
After a brief introduction that emphasizes the syndrome-oriented clinical approach to the patient with a
CNS syndrome and fever, the book is divided into parts based on microorganisms. The major CNS
pathogens (viruses, bacteria, fungi, and protozoa) receive the most attention, although rarer pathogens
such as mycoplasmas, slow viruses, and helminths are also covered in depth. In keeping with our
philosophy that advances in diagnosis, therapy, prognosis, and prevention require better understanding of
the pathogenesis and pathophysiology of these disorders, an introductory chapter on these subjects is
included in each of the major sections of the book. Within each section a syndromic approach has been
maintained whenever possible, but in many instances we felt that specific diseases required separate
coverage—for example, tetanus, neurosyphilis, and Lyme disease. In some sections we have separated
processes that primarily present as meningitis or meningoencephalitis from those that usually present as
focal CNS lesions. The book concludes with discussions on two major diagnostic modalities: (i)
evaluation of the cerebrospinal fluid and (ii) neurodiagnostic imaging by computed tomography and
magnetic resonance imaging.
In choosing the contributors, we have sought individuals with clinical experience as well as with
active basic and/or clinical investigative interests in their topic. We asked them to take a comprehensive
approach, ranging from recent advances in molecular pathogenesis to the clinical manifestations, therapy,
and prevention of CNS infections. We also established certain other ground rules. To gain a measure of
unity among the chapters, each contributor was asked to write under common subheadings: history of the
syndrome, epidemiology, etiology, pathogenesis and pathology, clinical manifestations, approach to
diagnosis, therapy, and prevention. We asked authors to provide an extensive but not exhaustive
bibliography, emphasizing classical papers and recent (1985–1991) references while limiting each
chapter total to 350 citations or fewer. We strongly encouraged the liberal use of tables, drawings, and
photographs. Although a degree of overlap between chapters is inevitable (and sometimes even
desirable) in a multiauthored volume, we have attempted to minimize redundancies as much as possible.
From its inception 3 years ago, we intended that this should be a “gold standard” reference text. We set
out to bring together the best information from the best authors in the best format. Inevitably, the size and
complexity of the field means that we will fall short in some areas. Recognizing this, we hope to develop
and improve the book through future editions. Our ambition will remain the same: to present the best
available comprehensive resource and reference text for all who deal with infections of the central
nervous system.
W. Michael Scheld
Richard J. Whitley
David T. Durack
CONTENTS
Contributors
Preface
Acknowledgments
Preface to the First Edition
PART APPROACH TO THE PATIENT AND DIAGNOSTIC EVALUATION

I ■
Chapter 1 Introduction: Approach to the Patient with Central Nervous

System Infection
Christina M. Marra, Richard J. Whitley, and W. Michael Scheld
Chapter 2 Cerebrospinal Fluid in Central Nervous System Infections

Rodrigo Hasbun
Chapter 3 Imaging of Intracranial Infections

Carrie P. Marder and Kathleen R. Fink
PART VIRAL INFECTIONS AND RELATED DISORDERS

II ■
Chapter 4 Pathogenesis and Pathophysiology of Viral Infections of the

Central Nervous System
Kevin A. Cassady and Richard J. Whitley
Chapter 5 Viral Meningitis and Aseptic Meningitis Syndrome

José R. Romero
Chapter 6 Encephalitis
Carol Glaser and Arun Venkatesan
Chapter 7 Poliomyelitis, Polio Vaccines, and the Postpoliomyelitis

Syndrome
John F. Modlin and David J. Coffey
Chapter 8 Measles and Rubella
Diane E. Griffin
Chapter 9 Herpes Simplex Virus

Richard J. Whitley
Chapter 10 Neurologic Manifestations of Varicella and Herpes Zoster

John W. Gnann, Jr. and Richard J. Whitley
Chapter 11 Cytomegalovirus
Paul D. Griffiths
Chapter 12 Epstein-Barr Virus

Susan E. Hoover, Jeffrey P. Ross, and Jeffrey I. Cohen
Chapter 13 Human Herpesvirus-6

Mary T. Caserta
Chapter 14 B Virus
Richard J. Whitley
Chapter 15 Arthropod-Borne Viral Encephalitides

Tom Solomon, Adjanie Patabendige, and Richard J. Whitley
Chapter 16 Meningitis and Encephalitis Caused by Mumps Virus

John W. Gnann, Jr.
Chapter 17 Rabies
Alan C. Jackson
Chapter 18 Human Prion Diseases

Serggio C. Lanata, Sven Forner, and Michael D. Geschwind
Chapter 19 Human Immunodeficiency Virus

Christina M. Marra
Chapter 20 Guillain-Barré Syndrome

Tony M. McGrath
Chapter 21 Acute Viral Myelitis

J. David Beckham and Kenneth L. Tyler
Chapter 22 Postinfectious Encephalomyelitis

Karen L. Roos and Augusto Miravalle
PART BACTERIAL AND MYCOPLASMAL INFECTIONS

III ■
Chapter 23 Pathogenesis and Pathophysiology of Bacterial Infections

Philipp Agyeman, Denis Grandgirard, and Stephen L. Leib
Chapter 24 Acute Bacterial Meningitis

Karen L. Roos, Allan R. Tunkel, Diederik van de Beek, and W. Michael Scheld
Chapter 25 Mycoplasmal and Ureaplasmal Infections

Ari Bitnun and Susan Richardson
Chapter 26 Bartonella Infections, Including Cat-Scratch Disease

Michael Giladi, Moshe Ephros, and David F. Welch
Chapter 27 Rickettsioses, Anaplasmoses, and Q Fever

Didier Raoult
Chapter 28 Whipple’s Disease

Matthias Maiwald and David A. Relman
Chapter 29 Tuberculous Meningitis

Dorothee Heemskerk, Jeremy Farrar, and Maxine Caws
Chapter 30 Infections Due to Nontuberculous Mycobacteria

Jeana L. Benwill and Richard J. Wallace, Jr.
Chapter 31 Brain Abscess

Matthias Klein, Hans-Walter Pfister, Allan R. Tunkel, and W. Michael Scheld
Chapter 32 Epidural Abscess

Hans-Walter Pfister, Matthias Klein, Allan R. Tunkel, and W. Michael Scheld
Chapter 33 Subdural Empyema and Suppurative Intracranial Phlebitis

Barry J. Hartman and David C. Helfgott
Chapter 34 Complications of Infective Endocarditis

Stefano Giulieri, Reto Antoine Meuli, and Matthias Cavassini
Chapter 35 Iatrogenic Infections of the Central Nervous System

Kelly J. Baldwin and Joseph R. Zunt
PART CENTRAL NERVOUS SYSTEM SYNDROMES MEDIATED BY

IV ■ BACTERIAL TOXINS
Chapter 36 Botulism
James D. Marks
Chapter 37 Tetanus
Itzhak Brook
PART SPIROCHETAL INFECTIONS

V ■
Chapter 38 Neurosyphilis
Christina M. Marra
Chapter 39 Neuroborreliosis: Nervous System Involvement with Borrelia

Species
John J. Halperin, Sven Bergström, and Gary P. Wormser
PART FUNGAL INFECTIONS

VI ■
Chapter 40 Fungal Meningitis

Jennifer L. Horan and John R. Perfect
Chapter 41 Space-Occupying Fungal Lesions

Matthew McCarthy and Thomas J. Walsh
PART PROTOZOAL AND HELMINTHIC INFECTIONS

VII ■
Chapter 42 Cerebral Malaria

Douglas G. Postels and Terrie E. Taylor
Chapter 43 Toxoplasma gondii and Toxoplasmosis

Jose G. Montoya
Chapter 44 Trypanosomiasis
Louis V. Kirchhoff
Chapter 45 Free-Living and Parasitic Amebic Infections

Shannon Moonah and William A. Petri, Jr.
Chapter 46 Helminthic Infections

Jose A. Serpa, Won K. Chung, and A. Clinton White, Jr.
PART CHRONIC MENINGITIS AND MENINGITIS OF NONINFECTIVE

VIII ■ OR UNCERTAIN ETIOLOGY
Chapter 47 Chronic Meningitis Syndrome and Meningitis of Noninfective or

Uncertain Etiology
Jerzy Hildebrand and Marc Hildebrand
PART NEUROSURGICAL MANAGEMENT

IX ■
Chapter 48 Surgical Management of Central Nervous System Infections

Anthony C. Wang, Khoi Duc Than, and Oren Sagher
Chapter 49 Critical Care of Central Nervous System Infections

John Zurasky, Thomas O. McPharlin, and Kyra J. Becker
PART PREVENTION
X ■
Chapter 50 Vaccines for Viral Diseases with Significant Central Nervous

System Manifestations
David W. Kimberlin
Chapter 51 Vaccines Against Bacterial Meningitis

Amanda C. Cohn and Nancy E. Messonnier
Index
PART I ■ APPROACH TO THE PATIENT
DIAGNOSTIC EVALUATION
CHAPTER 1 INTRODUCTION: APPROACH TO THE

PATIENT WITH CENTRAL NERVOUS SYSTEM
INFECTION
CHRISTINA M. MARRA, RICHARD J. WHITLEY, AND W. MICHAEL SCHELD
Infections of the central nervous system (CNS) are notable for their diversity. They range from common to
rare, acute to chronic, and benign to fatal. Although some are self-limited or are easily cured with modern
treatment, others are relentlessly progressive despite treatment or have no known treatment. For the many
CNS infections that are treatable, prompt diagnosis and aggressive management afford the best chance of
recovery without sequelae.
The clinical hallmarks of CNS infection are fever, headache, and alteration of mental status. Focal
neurologic signs may also be evident. Nonetheless, these four symptoms and signs are nonspecific and can
also be seen in noninfectious CNS syndromes. To narrow the differential diagnosis, other characteristics
must be evaluated. Among these, risk factors for CNS infections are particularly helpful. Physical
examination may also yield information that provides clues to the etiology of a given infection. An
approach to the diagnosis of CNS infections is shown in Figure 1.1.
RISK FACTORS FOR CENTRAL NERVOUS SYSTEM
INFECTIONS
Many infections of the CNS are geographically distributed or occur seasonally. Therefore, a thorough
travel history and consideration of the date of onset of illness can provide clues to the etiology. For
example, Lyme disease is endemic in the northeastern United States but uncommon in the southwestern
states. Similarly, transmission of arborviral encephalitides requires the presence of an insect vector, and
thus these illnesses most commonly occur in summer and fall. Certain environments facilitate acquisition
and transmission of CNS infections, as exemplified by outbreaks of meningococcal infection in military
recruits and college students. Concomitant illnesses such as HIV infection or diabetes, alcoholism, receipt
of immunosuppressant medications, or cancer chemotherapy all predispose to specific CNS infections.
Similarly, receipt of prophylactic therapies protects against individual CNS infections. For example,
primary prophylaxis against Pneumocystis jiroveci pneumonia with trimethoprim-sulfamethoxazole in
HIV-infected individuals decreases the risk of CNS toxoplasmosis.
CLUES ON PHYSICAL EXAMINATION

Physical examination in the setting of suspected CNS infection has three purposes: (a) to identify
contraindications to lumbar puncture, (b) to identify concomitant sites of infection or pathology that
provide clues to the infectious etiology, and (c) to define the site of CNS infection. Depressed level of
consciousness, focal neurologic abnormalities, or seizures may indicate a structural CNS abnormality that
poses a risk of brain or spinal cord herniation after lumbar puncture. Such findings mandate neuroimaging
before lumbar puncture. Identification of concomitant pneumonia, diarrhea, and skin or bone lesions may
offer clues to the etiology of infection. Most importantly, findings on neurologic examination allow for
identification of the most likely site or sites of infection among cerebrospinal fluid (CSF) space, brain, or
spinal cord and allow for a “syndrome recognition” approach to diagnosis, as described below.
Acute Meningitis Syndrome

The dominant features of the acute meningitis syndrome are acute onset over a few hours to a few days of
fever, headache, photophobia, stiff neck, and altered mental status. The latter may range from simple
irritability to confusion, obtundation, or coma. Vomiting may occur, especially in young children. In many
cases, there is no warning, but an acute upper respiratory tract infection may precede the onset of
meningitis by a few days. The two leading causes of acute meningitis are bacteria and viruses. The
differential diagnosis includes noninfectious conditions, such as systemic lupus erythematosus and Behçet
syndrome, or rare chemical meningitis caused by nonsteroidal antiinflammatory drugs.
Subacute or Chronic Meningitis Syndrome
In contrast to acute meningitis, subacute and chronic meningitis syndromes run their course over weeks,
months, or years. Because symptoms and signs may fluctuate, subacute or chronic meningitides may be
confused with the syndrome of recurrent acute meningitis. Although in subacute and chronic meningitis the
clinical findings of fever, headache, stiff neck, and altered mental status may resemble those of acute
meningitis, the time course is quite different. Onset is usually gradual, often without any evident
predisposing condition. Fever, though often present, tends to be lower and less hectic than in acute
meningitis. The patient with chronic meningitis is likely to be lethargic and generally debilitated, in
addition to having symptoms referable to the CNS. Focal neurologic findings are more common than in
acute meningitis, although less common than in the space-occupying syndromes.
The differential diagnosis for subacute and chronic meningitis is extensive. The most likely infectious
causes are tuberculosis; fungal infections including cryptococcosis, coccidioidomycosis, and
histoplasmosis; and spirochetal infections including syphilis and Lyme disease. Important noninfectious
conditions include sarcoidosis, systemic lupus erythematosus, systemic or primary CNS vasculitides, and
neoplastic meningitis. Establishing a specific diagnosis is challenging. Of the important treatable
conditions, cryptococcosis and syphilis usually can be diagnosed or excluded quickly on the basis of
serology or antigen detection. However, tuberculous meningitis is more difficult to diagnose or exclude,
and patients with suspected tuberculous meningitis should be treated empirically while evaluation
continues. The decision whether and when to obtain a meningeal biopsy is complex and depends on many
factors, including the unfortunate fact that in practice even this invasive “gold standard” test often does
not yield a definitive diagnosis.
Acute Encephalitis Syndrome
The acute encephalitis syndrome is characterized by inflammation of the cerebral cortex and is most
commonly caused by viruses. It shares many features with the acute meningitis syndrome. Indeed, the two
conditions often coexist as meningoencephalitis. Acute encephalitis may be either diffuse or focal. Focal
encephalitis reflects tropism of some viruses for specific locations in the CNS, such as temporal lobe
infection by herpes simplex virus type 1 (HSV-1), or the anterior horn cells in flavivirus infections, such
as West Nile. Nonviral organisms that may produce the acute encephalitis syndrome include Rickettsia,
Mycoplasma, and Bartonella species that may cause encephalitis as one component of systemic infection.
Diverse conditions, including infective endocarditis, Whipple disease, and recrudescent toxoplasmosis in
the immunocompromised host may cause diffuse or focal acute encephalitis.
Chronic Encephalitis Syndrome
The chronic encephalitis syndrome shares many features with the acute encephalitis syndrome. However,
the onset is more gradual and the course is less hectic. The clinical findings may be less dramatic or less
severe. The patient with chronic encephalitis is likely to be generally debilitated rather than acutely ill.
Chronic encephalitis evolves over weeks to months or years and relapses or recrudescences may occur.
Complications such as pressure sores, contractures, or dementia may ensue in the course of disease.
Space-Occupying Lesion Syndrome
Patients with space-occupying brain lesions have focal neurologic abnormalities referable to the location
of the lesion or lesions. These include cognitive abnormalities, weakness, sensory changes, and visual
loss. Clinical manifestations, such as headache, nausea, or vomiting, often begin intermittently, but they
progress steadily to a crisis at about the time the patient is admitted to the hospital. This crisis may
consist of (a) a focal or generalized seizure or (b) onset of obtundation progressing to coma.
When a space-occupying lesion occurs in the extramedullary space in the spinal canal, a distinctive set
of manifestations may develop in a typical sequence: first, localized back pain, often severe; second,
nerve root pain with associated alteration in reflexes and sometimes paresthesias, often described as
“shooting sensations” or “electric shocks”; third, motor weakness followed by sensory changes with
bowel or bladder dysfunction; and fourth, paralysis, often accompanied by lessening in pain. The rate of
progression from one stage to the next is unpredictable. Because the incidence and severity of neurologic
sequelae depend on the stage of the disease and the degree of neural damage sustained before
intervention, this syndrome presents an emergency that requires immediate diagnosis and treatment.
Toxin-Mediated Syndromes
Microbial toxins mediate several distinctive neurologic syndromes. The leading examples are tetanus and
botulism. Toxin-mediated conditions are the least likely to show the usual manifestations of CNS
infection, including fever, headache, disturbance of consciousness, and focal neurologic signs. For
example, botulism is characterized by absence of fever and normal consciousness in most patients.
Encephalopathy with Systemic Infection
Many systemic infections involve the CNS, for example, rickettsial diseases, infective endocarditis,
typhoid fever, malaria, and Whipple disease. Usually, the systemic manifestations of the disease dominate
the clinical picture, but sometimes the CNS findings are prominent. In a few cases, CNS symptoms are the
only features. Because this is such a large and varied group of diseases, the syndromic approach to
diagnosis is less effective. In the setting of an undiagnosed CNS infectious syndrome, an important
principle is to consider systemic infection as a possible underlying cause.
Postinfectious Syndromes
Several important CNS syndromes can develop following microbial infections. The usual sequence
begins with a common, often rather trivial, viral infection that may go unnoticed. A postinfectious
neurologic syndrome develops. Rarely, these syndromes follow routine vaccinations. Examples include
postinfectious encephalitis, postinfectious encephalomyelitis, and transverse myelitis. These reactions are
presumably mediated by an immunologic response to the etiologic microbe or to antigens revealed as a
result of the initial infection. Although rare, these syndromes can be severe or fatal.
CONCLUSION
A systematic approach to the patient with a suspected CNS infection can be undertaken. This includes
assessment of risks and a careful physical examination to assess safety of lumbar puncture, identify non-
CNS sites of infection, and define the site of CNS infection. A consideration of the different CNS
infection “syndromes” as outlined above can then be used to promptly establish a diagnosis and
implement therapy.
CHAPTER 2 CEREBROSPINAL FLUID IN CENTRAL
NERVOUS SYSTEM INFECTIONS
RODRIGO HASBUN
Infections within the central nervous system (CNS) frequently, but not always, produce changes in
cerebrospinal fluid (CSF). The changes produced may provide invaluable information about the nature of
the infectious process and, in many cases, may permit specific identification of the offending organism.
Despite the great diagnostic value of CSF analysis, however, injudicious attempts to obtain CSF (as in the
setting of increased intracranial pressure) can sometimes cause brain herniation or death, and casual
handling of the CSF obtained may render the analysis useless.
This chapter is divided into three parts. The first part reviews the anatomy of the CSF spaces, the
physiology of CSF production and reabsorption, and the effect of infection on CSF physiology and
composition. The second part discusses methods of CSF analysis in CNS infections, and the third part
summarizes the CSF analysis in specific CNS infections.
ANATOMY AND PHYSIOLOGY OF THE CEREBROSPINAL

FLUID COMPARTMENTS
The CSF is contained within two connecting compartments, the cerebral ventricles and the subarachnoid
space (1). Infectious organisms may affect both compartments, and analysis of CSF from both may reflect
changes produced by infectious or parainfectious processes within meninges, brain, or spinal cord.
The Ventricular System
The cerebral ventricular system represents, in greatly elaborated form, the remnants of the embryologic
neural tube. A single layer of neuroglial-derived cells, the ventricular ependyma, lines the ventricles; a
dense network of astrocytic foot processes backs these. The ventricular system consists of two lateral
ventricles, the third ventricle, and the fourth ventricle (Fig. 2.1). The lateral ventricles are located within
the cerebrum and consist of frontal, temporal, and occipital horns; these join at the ventricular trigone
within the parietal lobe. The third ventricle is an elongated, slitlike cavity that lies within the midbrain
and is bounded inferiorly by the hypothalamus. The fourth ventricle overlies the brainstem from the level
of the midpons to the extreme rostral end of the spinal cord. The roof of the fourth ventricle is the
cerebellum posteriorly and the superior and inferior medullary veli anteriorly. The fourth ventricle is
roughly diamond shaped and is widest at the lateral recesses, which lie between the superior and middle
cerebral peduncles.
The cerebral ventricles are connected to each other and with the subarachnoid space through a series of
small openings. Each lateral ventricle drains into the third ventricle through the foramen of Monro,
located in the inferomedial wall of the frontal horn. The third and fourth ventricles are connected by the
aqueduct of Sylvius, which extends through the midbrain. The fourth ventricle drains into the
subarachnoid space through three small openings, the foramina of Luschka and the foramen of Magendie.
The foramina of Luschka are located in the lateral recesses of the fourth ventricle and are absent in up to
20% of the population. The foramen of Magendie is located in the midline and, in most persons,
represents the major communication between the fourth ventricle and the subarachnoid space. As is
discussed later, these narrow openings are important in CNS infections because they represent the sites at
which obstruction of CSF flow may most easily occur.
The Meninges and Subarachnoid Space
The brain and spinal cord are surrounded by three layers of meninges (2). The outermost layer of the
meninges is a tough fibrous membrane, the dura mater. Within the skull, the dura forms the inner layer of
the cranial periosteum and is tightly adherent to bone. Below the foramen magnum, the dura and
periosteum diverge and are separated by a fat-filled epidural space. The middle layer of meninges, the
arachnoid, is joined to the dura by a specialized layer of fibroblasts, the dural border cell layer. The cells
of this inner dural border are devoid of collagen and have few cellular junctions, providing a cleavage
plane in which infection may develop and rapidly spread. The arachnoid covers the brain and spinal cord
loosely and extends outward along the course of cranial and spinal nerves.
The third layer of meninges, the pia mater, is continuous with the surface of the brain and spinal cord.
The pia mater also follows vessels into brain and spinal cord parenchyma and projects into the ventricles
to form the choroid plexuses. The pia mater and the ventricular ependyma merge at the foramina of
Luschka and Magendie. The CSF is contained in the subarachnoid space, enclosed between the arachnoid
and the pia. The subarachnoid space surrounds the brain and extends within the spinal canal to the level of
the second sacral vertebra. Within the skull, the subarachnoid space widens into cisterns where pia and
arachnoid are more widely separated by irregularities in the contour of the brain. The largest of these, the
cisterna magna, surrounds the brainstem and the cerebellum at the base of the skull and is occasionally
used as a source of CSF for analysis and culture. The subarachnoid space is crossed by trabecular
extensions of the arachnoid itself, by cranial nerves, by a network of small arteries, the rete mirabile, and
by numerous bridging veins, which connect the meningeal veins with the deeper intracranial venous
system (2).
The subarachnoid space is normally a closed system. Occasionally, however, congenital or
posttraumatic communications may exist between the subarachnoid space and superficial tissues and may
provide a route for single or recurrent episodes of meningitis. Congenital defects arise from incomplete
closure of the neural tube. These defects may extend for variable distances into subcutaneous tissues or to
the cutaneous surface and are most common in the upper cervical regions and over the sacrum. Their
presence may be suggested by a cutaneous dimple or a patch of hair. Traumatic communications into the
subarachnoid space are most often associated with basilar skull fractures. The most common sites of
involvement are (a) the thin layers of bone that separate the cranial cavity from the paranasal sinuses and
(b) the petrous bone, which separates the auditory canals and mastoid from the cranial cavity. In rare
instances, traumatic defects may occur over the cranial convexities or along the spinal column.
PHYSIOLOGY OF CEREBROSPINAL FLUID PRODUCTION

AND REABSORPTION
CSF is produced by the choroid plexuses of the lateral, third, and fourth ventricles and, to a lesser extent,
by extrachoroidal sites (1,3). In adults, the choroid plexus produces approximately 500 mL of CSF per
day, with 150 mL present in the ventricular system at any time. The choroid plexuses are specialized
projections of vessels and pia mater into the ventricular cavities. Each choroid plexus branches into
frondlike villi, each of which contains a capillary surrounded by loose connective tissue and a layer of
specialized ependymal cells termed choroid epithelium. Choroidal epithelial cells, in contrast to
ependymal cells elsewhere in the ventricular system, are columnar in shape and are covered on their
ventricular surfaces by a brush border of microvilli. The villous structure of the choroid plexus and the
presence of microvilli greatly increase the surface area available for secretion of CSF (1).
Formation of CSF involves both filtration and active transport (1,3). Filtration of CSF varies inversely
with serum osmolality. In experimental animals, and possibly in humans, CSF production changes 7% for
each 1% change in serum osmolality (4). Active secretion of CSF involves Na+, K+-adenosine
triphosphatase (ATPase)–mediated transport of sodium across choroidal epithelium into the ventricular
lumen, with water, chloride, and bicarbonate ions following through facilitated transport. In experimental
animals, the carbonic anhydrase inhibitor acetazolamide reduces CSF secretion by approximately 50%,
whereas furosemide and ethacrynic acid reduce CSF production by 25% to 35% (5). Simultaneous use of
both agents reduces CSF formation by 75%.
Reabsorption of CSF occurs through arachnoid villi. Most of these are located along the superior
sagittal sinus. Smaller numbers of arachnoid villi are found along other intracranial venous sinuses and
around spinal nerve roots (1). During health, the arachnoid villi along the superior sagittal sinus provide
the major site of CSF uptake. The arachnoid villi along other sinuses and surrounding spinal nerve roots
may provide alternative sites of CSF absorption following superior sagittal sinus thrombosis.
Each arachnoid villus represents an extension of the arachnoid membrane through the dura mater into
the lumen of the venous sinus and functions as a one-way valve, permitting unidirectional flow from CSF
into blood. Early work by Welch (6) demonstrated that the arachnoid villi have a critical in vitro opening
pressure of 2 to 5 cm H2O; this study also demonstrated that particles up to the size of erythrocytes readily
pass from CSF into blood, whereas particles larger than 7.5 µm are excluded. Although these early data
suggested that the arachnoid villi might provide a direct communication between CSF and blood, studies
using electron microscopy have demonstrated that arachnoid villi and venous sinuses are separated by a
layer of endothelial cells connected by tight junctions, and that movement of CSF and particulate matter
across the arachnoid villi occurs by transport within giant vesicles (7,8) (Fig. 2.2). These giant vesicles,
although they provide efficient transfer of CSF into blood under normal circumstances, can become
obstructed by bacteria and inflammatory cells during meningitis or by red blood cells (RBCs) during
subarachnoid hemorrhage (9,10).
BRAIN AND CEREBROSPINAL FLUID BARRIER SYSTEMS

The brain and CSF are contained within a series of barrier systems (1). These prevent entry of fluids,
electrolytes, and other substances from blood into CSF or brain by simple diffusion and isolate the CNS
from systemic immune responses. The blood–brain barrier (BBB) is formed by tight junctions between
endothelial cells of CNS capillaries and is further reinforced by a surrounding layer of astrocytes, whose
processes terminate in overlapping fashion on the capillary walls. In contrast, the blood–CSF barrier is
formed by the endothelial cells of the choroid plexus and the tight junctions that link them. The cells of the
pia mater, like those of choroid plexus and arachnoid capillaries, are separated by gap junctions; entry of
substances from CSF into brain is modulated by a basement membrane subjacent to the pia and by a
continuous layer of astrocytes beneath the basement membrane, forming a CSF–brain barrier.
The barrier systems that surround spinal cord and brain exclude from the CNS most of the immunologic
mechanisms that provide host defense elsewhere in the body. Normally, T cells and B cells are present in
very small numbers in CSF and only rarely in brain; immunoglobulins and complement are largely
excluded from both CSF and brain; and opsonic activity of CSF, even in the presence of meningitis, is far
less than that of serum (11–14). Therefore, both the brain and the CSF are poorly equipped to deal with
infectious agents.
The barrier systems that isolate CSF, brain, and spinal cord from blood are not static systems but,
instead, are highly dynamic in their ability to interact with and transport a wide variety of substances
(15). In addition, it is increasingly recognized that the endothelial cells and astrocytes of the BBB and the
blood–CSF barrier are important sources of cytokines (including tumor necrosis factor [TNF] and
interleukins), and that astrocytes, in addition to their abilities to regulate solute entry into brain, have the
ability to act as antigen-presenting cells (16). The release of cytokines by endothelial cells and astrocytes
in response to bacterial endotoxins and other bacterial products is fundamental in the production of
inflammation and injury during CNS infections and provides an extremely important area for early therapy
(9,17–19).
MAINTENANCE OF CEREBROSPINAL FLUID HOMEOSTASIS

The BBB and the blood–CSF barrier maintain the cellular and chemical elements of the CSF within
narrow ranges (1,3,20). Lipid-soluble substances within blood readily diffuse across choroidal
epithelium or vascular endothelium into CSF or brain (3). Passage of fluid and ionically polar substances,
however, requires mechanisms for transport and facilitated diffusion. Sodium enters CSF both by Na+,
K+-ATPase–mediated transport during secretion of CSF and by passive diffusion (20). Potassium is
secreted into CSF by active transport mechanisms and is actively removed from CSF into brain by
transport mechanisms that are believed to be located in astrocyte foot processes. Movement of calcium,
magnesium, and phosphorus into CSF and brain also occurs predominantly by active transport, and the
concentrations of these substances are relatively independent of their concentrations in serum. Chloride
and bicarbonate, like potassium, are actively secreted into and actively removed from CSF. Glucose,
amino acids, amines, and thyroid hormone enter the brain by carrier-mediated transport mechanisms
(1,15). Insulin and transferrin require receptor-mediated transport (15). Although lipids complexed to
proteins were once thought to be excluded from the CNS, it is now known that complexed lipids undergo
dissociation from their carrier proteins at the blood–brain interface and may enter the CNS without
significant exodus of protein from brain capillaries (15).
Chloride represents the major anion in CSF. Normal CSF chloride concentration is 15 to 20 mEq/L
higher than that in serum. Early workers observed that CSF chloride concentrations were lowered in
tuberculous meningitis; for many years, levels of CSF chloride were used to diagnose and follow the
course of this infection (1). It is now recognized, however, that the lowered CSF chloride concentration
observed in tuberculous meningitis is nothing more than a reflection of lowered serum chloride values
and has no diagnostic or prognostic value.
The acid–base balance of the CSF, like its electrolyte concentration, tends to remain fairly constant
despite fluctuations in systemic acid–base balance. In CSF, as opposed to plasma, however, movement of
CO2 occurs readily by diffusion, whereas movement of bicarbonate occurs more slowly by carrier-
mediated transport. The discrepancy in the rate of movement of these two substances may produce
delayed (and, at times, paradoxical) responses in CSF pH as compared to systemic pH during rapid
changes in bicarbonate concentration (1). The CSF acid–base balance is also maintained by the choroid
plexuses, which possess transport mechanisms capable of removing weak organic acids—including
antibiotics such as the penicillins, cephalosporins, and aminoglycosides—from CSF (21,22). Choroid
plexus transport of antibiotics and other weak organic acids can be blocked by probenecid.
ALTERATIONS OF CEREBROSPINAL FLUID DYNAMICS AND

PRESSURE IN CENTRAL NERVOUS SYSTEM INFECTIONS:
HYDROCEPHALUS, INTRACRANIAL HYPERTENSION, AND
BRAIN HERNIATION
Acute or chronic CNS infections may produce profound alterations in intracranial pressure (ICP) by
obstructing CSF flow or reabsorption, by behaving as space-occupying lesions, or by producing
hemorrhage or cerebral edema. These pathologic consequences of infection, acting individually or
together, may cause brain herniation and death.
Alteration of Cerebrospinal Fluid Circulation in Central Nervous System Infections
Impairment of normal CSF circulation may result in ventricular enlargement and hydrocephalus.
Interruption of CSF reabsorption produces communicating hydrocephalus with normal circulation of CSF
through the ventricular system and into the subarachnoid space. Communicating hydrocephalus is a
common complication of bacterial meningitis and, in most cases, results from obstruction of the arachnoid
villi by bacteria and white blood cells (WBCs) (9). Communicating hydrocephalus may also result from
functional occlusion of arachnoid villi during severe meningitis or by RBCs in the course of subarachnoid
hemorrhage during bland or septic subarachnoid hemorrhage (10). Thrombosis of the superior sagittal
sinus may also block CSF reabsorption and thereby produce communicating hydrocephalus. Occlusion of
a large portion of the superior sagittal sinus usually produces catastrophic, often hemorrhagic, cerebral
infarction. Involvement of the anterior third of the sinus, however, may be clinically silent except for the
development of hydrocephalus.
Obstructive hydrocephalus results from interruption of CSF flow within the ventricular system or at its
point of exit into the subarachnoid space (2). This may be the consequence of infection of the ventricular
ependyma or basilar meninges or may result from extrinsic compression of the ventricular system by
infection within brain parenchyma. Lesions producing obstructive hydrocephalus most commonly involve
the ventricular system at its narrowest points: the foramina of Luschka and Magendie, the fourth ventricle,
the aqueduct of Sylvius, and the foramina of Monro. Obstruction of the foramina of Luschka and Magendie
is characteristic of exudative basilar meningitides such as those caused by Mycobacterium tuberculosis,
Coccidioides immitis, and Cryptococcus neoformans but may also be seen in bacterial meningitis.
Hydrocephalus as a result of obliteration of the fourth ventricle is almost always extrinsic and is the result
of ventricular compression by large cerebellar mass lesions such as cerebellar abscess or hemorrhage.
Occlusion of the aqueduct of Sylvius by granulomatous ependymitis may occur as a complication of
tuberculosis, fungal infections, or sarcoidosis. Mumps virus, which replicates in ventricular ependymal
cells, has been shown to produce congenital aqueductal stenosis in experimental animals (23). Rare cases
of hydrocephalus have also been reported following mumps and with Toscana meningoencephalitis in
humans (24,25). Extrinsic compression of the aqueduct of Sylvius may be produced by abscesses or other
localized infections within the pons or midbrain. Involvement of the foramen of Monro is almost always
unilateral and is the consequence of severe brain shifts caused by abscess, focal encephalitis, or
hemorrhage. Hydrocephalus caused by the occlusion of one foramen of Monro is particularly dangerous
because the CSF trapped within the involved lateral ventricle acts as a unilateral space-occupying lesion,
greatly increasing the risk of transtentorial brain herniation.
Computerized tomography (CT) and magnetic resonance imaging (MRI) are invaluable in
demonstrating the presence of hydrocephalus and in determining its cause. Ventricular dilation is common
in the elderly and is characterized by symmetric ventricular dilation accompanied by evidence of cerebral
cortical atrophy. In contrast, hydrocephalus is defined as a frontal horn ratio (Evans index) of 0.3 or
greater in the absence of cerebral atrophy (26). Hydrocephalus that occurs from impaired CSF circulation
is accompanied by loss of cortical markings visible on CT or MRI as the brain is forced outward against
the skull and by periventricular areas of increased lucency, representing transependymal leakage of CSF.
Communicating hydrocephalus and hydrocephalus from obstruction of the foramina of Luschka and
Magendie are characterized by symmetric enlargement of all four ventricles. Hydrocephalus from
occlusion of the fourth ventricle or aqueduct of Sylvius results in loss of that structure on CT or MRI, with
dilation of the third and lateral ventricles. Hydrocephalus following compression of the foramen of
Monro is almost invariably associated with an identifiable space-occupying lesion and a prominent
midline shift. Thrombosis of the superior sagittal sinus may be difficult to detect as a cause of
communicating hydrocephalus and can be missed with the use of routine CT scanning. MRI and CT
venogram are more sensitive and are used to diagnose superior sagittal sinus (SSS) thrombosis (27).
Intracranial Hypertension and Brain Herniation
The normal mechanisms of CSF secretion and drainage maintain CSF pressure at a level less than 150
mm of CSF in most patients. Infection, however, greatly alters these homeostatic mechanisms; moreover,
death during the acute stages of intracranial CNS infections often results from extreme elevation in ICP
followed by brain herniation and respiratory arrest.
For a period of time, the intracranial contents are able to compensate in response to space-occupying
lesions before a rise in ICP occurs. This compensatory ability is termed compliance (dV/dP) and
represents the ratio of changes in volume (dV) to changes in pressure (dP). Compliance in response to
space-occupying intracranial lesions consists of several factors. These include increased rate of
reabsorption of CSF (this may be prevented in meningitis by obstruction of the arachnoid villi by cells
and exudate); displacement of CSF; reduction in the total volume of intracranial blood, predominantly by
compression of veins and venous sinuses; and plasticity of the brain itself. Compliance is extremely
limited when infection is accompanied by a rapid increase in ICP, such as during acute bacterial
meningitis or subdural empyema. In contrast, the ability of CNS compliance to compensate for increased
ICP may be extensive where space-occupying lesions develop over time (28). Once compliance is
exceeded, however, the increase in pressure in chronic lesions may occur rapidly.
The elevation in CSF pressure seen in infections and other pathologic conditions is not constant but
fluctuates considerably. This fluctuation is usually not observed during the brief period of measurement
provided by LP but becomes an important parameter to observe during monitoring of ICP. Minor variation
in pressure occurs during Cheyne-Stokes respiration and during variations in blood pressure produced by
Hering-Breuer reflexes, the inflation and deflation reflexes that help regulate the rhythmic ventilation of
the lungs. More major variations in ICP occur during plateau waves. These are abrupt elevations in ICP
(usually lasting 5 to 20 minutes) in which ICP may reach 600 to 1,300 mm of CSF (50 to 100 mm Hg)
(29,30). Plateau waves are believed to represent a consequence of disturbed cerebrovascular
autoregulation because of either abnormal sympathetic tone or cyclic changes in perfusion in which mild
hypotension is followed by cerebral vasodilation and increased cerebral blood flow (30). Although
plateau waves may be without any detectable clinical effect, they may also be associated with signs of
brainstem compression and impending herniation.
Increased pressure that exceeds intracranial compliance causes downward and backward shifting of the
cerebrum and brainstem (31). Minimal degrees of shift are well tolerated, but a more extensive shift may
cause herniation of the cingulate gyrus beneath the falx cerebri, herniation of the uncus of the temporal
lobe over the tentorium cerebelli, and ultimately, herniation of the lower brainstem and cerebellar tonsils
into the foramen magnum. Herniation of the cingulate gyrus is usually asymptomatic. Uncal herniation,
however, initially produces compression of the third cranial nerve as it passes beneath the tentorium; it
subsequently causes compression of the midbrain, with resultant coma. The aqueduct of Sylvius is often
occluded during uncal herniation, and the resultant hydrocephalus increases the mass effect already
present. Herniation of the cerebellar tonsils through the foramen magnum, with compression of medullary
respiratory centers and respiratory arrest, is often the terminal event in CNS infections. Occasionally,
space-occupying lesions within the cerebellum cause upward herniation of posterior fossa contents
through the tentorial notch (32). Extreme elevation of CSF pressure may elevate ICP above systemic
arterial perfusion pressure, producing global cerebral and brainstem infarction.
Elevation in CSF pressure, as monitored by ICP monitoring devices, may provide an indication of
prognosis in bacterial meningitis and possibly in other CNS infections. Rebaud et al. (33) found that CSF
pressures were significantly higher and cerebral perfusion pressure were significantly lower (mean
systemic arterial pressure minus ICP) in patients who died due to meningitis or encephalitis than in those
who survived. Goitein and Tamir (34) found that all pediatric patients with meningitis or encephalitis
who had a cerebral perfusion pressure more than 30 mm Hg survived, whereas those with lower
pressures died.
CEREBROSPINAL FLUID ANALYSIS IN CENTRAL NERVOUS

SYSTEM INFECTIONS
Indications for Lumbar Puncture
LP is essential in the diagnosis of bacterial, viral, or fungal meningitis and may provide valuable
information in encephalitis. LP is also used to diagnose subarachnoid hemorrhage in patients with a
negative head CT scan. The procedure is of little specific diagnostic value in the diagnosis of brain
abscess or parameningeal infections. Lumbar punctures (LPs) should not be done in patients with
impending herniation or with intracranial mass lesions with severe mass effect. Furthermore,
inappropriate LP can cause patient death or serious neurologic injury, and the procedure should never be
initiated without consideration of its potential danger to the patient.
Clinicians have relied on the meningeal signs (nuchal rigidity, Kernig sign, Brudzinski sign) for over
100 years to evaluate patients with suspected meningitis to help them decide who should undergo a LP. A
prospective study of 297 adults with suspected meningitis documented a very low sensitivity of the
Kernig sign (sensitivity, 5%), Brudzinski sign (sensitivity, 5%), and nuchal rigidity (sensitivity, 30%)
(35). The absence of the meningeal signs should not defer the performance of the LP. The decision to
perform a LP on those suspected of having meningitis is largely based on a combination of clinical signs
and symptoms at presentations. The classic triad of fever, stiff neck, and altered mental status was present
in only 44% of patients in a prospective study involving 696 patients with confirmed bacterial meningitis
(36). However, at least two of the four symptoms of headache, fever, neck stiffness, and altered mental
status were found in 95% of patients.
Major Complications of Lumbar Puncture
Role of Head Computerized Tomography Scan Before Lumbar Puncture and Risk of Brain
Herniation
It has become a routine practice to obtain a CT scan of the head prior to performing a LP in patients with
suspected meningitis. This is done to “rule out” the possibility of an intracranial mass, hydrocephalus,
edema, or any other signs of increased ICP that could theoretically place the patient at risk for cerebral
herniation after CSF removal during the LP (37). Herniation of the brain as the consequence of severe
cerebral edema or acute hydrocephalus can sometimes occur in acute bacterial meningitis and other CNS
infections. Clinically, this is manifested by altered state of consciousness, abnormalities in pupil reflexes,
and decerebrate or decorticate posturing. The incidence of herniation after LP even in patients with
papilledema is approximately 1% (37).
In order to clarify the role of a screening CT scan, a prospective study involving 301 adults with
suspected meningitis was done (38). Baseline characteristics that were associated with an abnormal
finding on head CT were age 60 years and older, immunocompromised host (i.e., HIV/AIDS,
immunosuppressive therapy, or transplantation), a history of CNS disease, a history of seizure within 1
week before presentation, and any abnormality on neurologic examination. These factors have now been
included in the Infectious Diseases Society of America guidelines to decide who should undergo CT prior
to the LP (39). The decision to obtain a brain CT scan before LP should not result in delay in instituting
antibiotic therapy because delay can increase mortality (40). It should be also noted that herniation can
occur in patients with bacterial meningitis who have a normal brain CT scan. The most reliable clinical
signs of “impending” herniation include deteriorating level of consciousness, brainstem signs, and a very
recent seizure (41).
Spinal Hematoma with Cord Compression

Case reports of LP in patients with severe disorders of blood coagulation, thrombocytopenia, or in
patients anticoagulated with heparin or Coumadin have described complications with either continued
bleeding at the site of puncture or with epidural or subdural hematomas that may compress the cauda
equina, thereby producing permanent neurologic injury (42). These complications appear to be rare. In a
study of 5,223 LPs performed, no complications were seen in 941 children with leukemia who had severe
thrombocytopenia (platelet count <50) (43).
Introduction of Infection into the Subarachnoid Space

Inadvertent LP through an area of infection overlying the spinal canal may result in seeding of the
subarachnoid space and meningitis. This is a particular risk in spinal epidural abscess or subdural
empyema but may occasionally occur in the setting of superficial or deep paraspinal infections. The
problem can be avoided by entering the subarachnoid space at a level well removed from the site of
presumed infection. Thus, in patients with known or suspected focal lumbar infection, spinal fluid should
be obtained under fluoroscopic guidance by high cervical (C2) or cisternal puncture, whereas the lumbar
route should be used in patients with suspected cervical or upper thoracic infections. Introduction of
infection into the subarachnoid space during LP in uninfected individuals has been reported in 1 out of
50,000 LPs (44). The most commonly implicated organism is Streptococcus salivarius, and this could be
potentially prevented by using a mask during the procedure (45).
Post–Lumbar Puncture Headache

The most frequent complication of LP is the post–LP headache, which can occur in 10% to 60% of
patients, more commonly in young women with a lower body mass index (BMI) and in pregnancy (46).
The diagnosis is a clinical one, and it is usually defined as a bilateral headache that worsens while sitting
up and improves lying down, develops within 7 days after a LP, and disappears within 14 days (Fig. 2.3).
It is thought that the headache is caused by a CSF leak that decreases ICP. This causes headache either by
gravitational traction on sensitive meningeal vascular coverings as a result of CSF volume depletion or
by activation of adenosine receptors as a result of decreased CSF volume, which would cause cerebral
vasodilatation and stretching of pain-sensitive cerebral structures (46).
The incidence of the post–LP headache is not associated with the volume of CSF removed, hydration,
the position of the patient (lying on their side or sitting up), or the opening pressure (47). Factors that can
be associated with a decrease in the incidence of headache are the type and size of needle, the direction
of the bevel during needle placement, the replacement of the stylet, and possibly the number of LP
attempts (47). Atraumatic needles with a blunt end are recommended by the American Academy of
Neurology to reduce the incidence of post–LP headaches (48). The “blunt” end produces a more traumatic
opening with tearing and disruption of the collagen fibers that is closed faster by an immunologic reaction
and thus associated with a decrease incidence of headache (49). Additionally, smaller needles have been
shown to decrease the incidence of the post–LP headache (46). The direction of the bevel should be
parallel to the long axis of the spine to decrease the incidence of headache. If the patient is lying on his or
her side, the bevel should face “up.” This way, the needle will separate the dural collagen fibers, which
also run along the long axis of the spine, rather than cutting them (47).
Several techniques to treat the post–LP headache exist including the instillation of a “blood patch,”
dextran, or saline into the epidural space. A “blood patch” refers to the injection of 20 to 30 mL of the
patient’s fresh blood into the epidural space. It is thought to work by closing the CSF leak by forming a
clot, and it works in about 70% to 98% of patients (47). If a blood patch does not work, 20 mL of dextran
or saline can be injected into the epidural space to raise the epidural pressure and reduce the CSF leak.
Oral or intravenous caffeine can be used because they act as a cerebral vasoconstrictor and blocks
adenosine receptors. Surgical closure of the dural gap is the last resort (46).
Less Common Complications of Lumbar Puncture

Cortical Blindness. Downward displacement of the brainstem in states of increased ICP may compress
the posterior cerebral arteries against the edge of the tentorium cerebelli, causing ischemic infarction of
the occipital lobes and cortical blindness (31). Although this complication of intracranial hypertension is
often accompanied by signs of uncal or tonsillar herniation, compression of the posterior cerebral arteries
may also occur before other signs of herniation appear. Prognosis for return of vision is poor.
Cervical Spinal Cord Infarction. Rarely, LP in the setting of bacterial meningitis may be followed within
a few hours by respiratory arrest accompanied by flaccid tetraplegia (50). A variety of mechanisms,
including hypotension and vasculitis, have been postulated as the cause of cervical cord ischemia in these
patients. In some patients, however, it is likely that displacement of the cerebellar tonsils through the
foramen magnum as the result of greatly elevated ICP compresses the anterior spinal artery or its
penetrating branches, with resultant ischemic infarction of the upper cord (50).
Technique of Lumbar Puncture
The LP was first performed by Quincke in 1891 on children suffering from headaches in hopes to relieve
their symptoms. Soon after, using CSF as a diagnostic tool became the standard way for evaluating
patients with meningitis (47). The LP is generally performed with the patient in the lateral recumbent
position in a fetal position with the knees flexed toward the chest, and the neck slightly flexed. Only this
position allows the opening pressure to be measured. The other positions include sitting the patient
upright on the edge of the bed and bending forward over a bed stand or sitting with the feet supported and
chest resting on the knees.
The spinal cord typically ends as the conus medullaris at the L1 to L2 level in adults, and in children at
the L3 to L4 level. The landmarks used are the anterior superior iliac crests, which correlate with the L4
to L5 interspace. The needle may be inserted between the L3 and L4, L4 and L5, or L5 and S1 interspace
(51). Insertion above the L3 level may puncture the conus medullaris and should not be attempted. Also,
the needle should not be inserted over a skin infection or abscess because this has the potential of
inserting bacteria into the CSF. The performer of the LP should follow a sterile technique including hand
washing, gloves, gown, and mask. After the anterior superior iliac spine is identified, the spinous process
superior to the interspace is palpated. Prior to inserting the spinal needle, local anesthetic should be
utilized, usually 2 to 3 mL of lidocaine without epinephrine deposited subcutaneously and then deeper,
allowing 1 to 2 minutes for it to take effect. The needle should be inserted 1 cm below this and directed in
a horizontal position toward the umbilicus to an approximate depth of 2 cm (51). During the LP, if bone is
encountered, the needle should be withdrawn to the subcutaneous layer and reinserted at a slightly
different angle. The needle is inserted until a “pop” is felt indicating penetration of the ligamentum flavum
and presence of the needle in the subarachnoid space. The stylet is then removed and CSF obtained. A
manometer to measure the CSF pressure should be attached in all cases if possible. If CSF is not
obtained, rotate the needle as part of the dura may be blocking the hole of the needle. If this does not
work, reinsert the stylet and advance the needle, stopping frequently to withdraw the stylet (51).
Alternative Routes of Obtaining Cerebrospinal Fluid
Cisternal, high cervical (C2), and ventricular approaches may be used to obtain CSF if a lumbar approach
is contraindicated by infection or is technically impossible (1). Cisternal puncture was initially described
in 1923, but it can cause vascular injuries (52,53). Spinal puncture at the level of the second cervical
vertebra under fluoroscopic guidance has been suggested as a less hazardous approach than cisternal
puncture, but its actual value remains unproven. Ventricular CSF may be of great diagnostic value if there
is a predominantly intraventricular infection with obstructive hydrocephalus or in the presence of a
ventriculoperitoneal shunt (54).
Routine Studies of Cerebrospinal Fluid
Studies routinely obtained at the time of LP include measurement of CSF pressure, gross examination of
the fluid for turbidity or changes in color, measurement of CSF protein and glucose concentrations, RBC
and WBC counts, Gram and/or acid-fast stains of CSF sediment, and Gram stain and bacterial culture of
the fluid. Differentiation of bacterial meningitis from viral, mycobacterial, or fungal meningitis on the
basis of CSF abnormalities is presumptive unless an organism is cultured or detected by antigen tests or
PCR. Amounts of CSF required by most laboratories for commonly obtained determinations are listed in
Table 2.1. Because clinical laboratories differ in the amounts of CSF required for individual tests,
however, the clinician must determine the amounts of CSF required by the hospital laboratory for each
intended test before performing the LP.
Cerebrospinal Fluid Pressure

CSF pressure must be measured in the lateral decubitus position with the head of the bed being flat.
Opening CSF pressure in healthy adults lies between 50 and 195 mm CSF (1). Values higher than 200 mm
are abnormal. Normal lumbar CSF pressures in neonates and premature infants are significantly lower,
with mean values of 100 mm H2O and 95 mm H2O, respectively (55). CSF pressure is not affected during
pregnancy (56). A CSF baseline pressure of greater than 250 mm H2O was associated with higher
incidence of neurologic complaints including papilledema, hearing loss, and with mortality in AIDS
patients with cryptococcal meningitis (57). Extreme elevation of CSF pressure may also herald impending
brain herniation. Occasionally, CSF pressure may be normal or even low in the setting of ongoing
tonsillar herniation. The falsely low readings obtained in this setting are believed to reflect occlusion of
the CSF space at the foramen magnum by the herniated tonsils wedged against the lower brainstem. The
possibility of complete spinal block should be kept in mind if CSF pressure falls to zero during the
procedure.
Gross Appearance of the Spinal Fluid

Once CSF is obtained, it is centrifuged down to give a supernatant. Normal CSF is colorless and clear.
Under pathologic conditions, CSF may become turbid, discolored, or both. The CSF may become turbid
as a result of entry of cells, bacteria, or fat; it can be made turbid by as few as 200 WBCs/mm3 or 400
RBCs/mm3 (1,58). CSF containing RBCs will be grossly bloody if 6,000 or more RBCs are present per
cubic millimeter, and it will be cloudy and xanthochromic or pinkish if 400 to 6,000 cells are present (1).
The yellow discoloration of the supernatant is termed xanthochromia and is often used to distinguish
between a so-called bloody tap and subarachnoid hemorrhage. Xanthochromia can be assessed visually
or by spectrophotometric methodology by scanning the CSF over a range of wavelengths. The
discoloration is from degradation products of hemoglobin from lysis of RBCs. This usually forms 2 to 4
hours after RBCs have entered the subarachnoid space (1), which is why some experts suggest waiting at
least 6 hours after the onset of headache when a subarachnoid bleed is suspected because you may get a
false-negative result (58). A “traumatic tap” should clear as the CSF is collected in serial vials but not in
all cases of subarachnoid hemorrhage. Xanthochromia resulting from lysis of RBCs is initially a result of
oxyhemoglobin. After 12 hours, the pigment represents predominantly bilirubin (1). Visual assessment of
xanthochromia can be deceitful because it may also be seen in the presence of increased amounts of
protein, in metastatic melanoma, or as a consequence of systemic hyperbilirubinemia with a bilirubin
level higher than 10 to 15 mg/dL. The most appropriate and sensitive way to assess xanthochromia is by
spectrophotometry of the CSF to detect the hemoglobin breakdown products, oxyhemoglobin and
bilirubin.
Cell Count and Differential

Enumeration and characterization of cells within spinal fluid is of crucial value in the diagnosis of CNS
infections and is valuable in following the course of illness and response to treatment (Table 2.2).
Improperly handled or counted CSF, however, can be a dangerous source of error. The cell count in CSF
tends to decrease over time and may be falsely low if measured after 30 to 60 minutes. This decrease in
cell count occurs partly because leukocytes and RBCs settle out over time if the tube of CSF is allowed to
stand. In addition, however, lysis of RBCs, polymorphonuclear (PMN) leukocytes, and to a lesser extent,
lymphocytes begins in vitro within 1 to 2 hours of the LP and may occasionally occur even more rapidly.
WBCs also adsorb to the glass or plastic walls of the tube and are not easily dislodged by agitation.
Because of these factors, the reduction in cell count that occurs over time is only partially reversible if the
tube is vigorously agitated before counting. Any CSF destined for cell counts should, thus, be handled
carefully and expeditiously. Similarly, where serial tubes must be counted to exclude a traumatic tap, the
samples must be handled in the same manner and counted at the same time by the same person.
White Blood Cell Count

Quantification of numbers of cells in CSF can be carried out manually, using a Neubauer counting
chamber, but this methodology is labor-intensive, time-consuming, technique-dependent, and prone to
variability. Although electronic cell counters are available, they can have poor reproducibility especially
if the CSF samples have low WBC counts. Novel instruments using flow cell digital imaging have
excellent correlation with manual hemacytometer method and should be the method of choice (59). The
accuracy of the cell count is open to question unless the specimen is examined immediately after the LP
has been completed. Normally, CSF contains fewer than five cells per cubic millimeter (Table 2.2). Most
of these cells are small lymphocytes (nuclear diameter about 6 to 7 µm) with scant cytoplasm. Larger
numbers of PMN leukocytes are abnormal in uncentrifuged CSF. C. neoformans is similar in size to a
small CSF lymphocyte, and nonbudding forms may be mistaken for these cells in the counting chamber,
though not in stained cytocentrifuged or otherwise concentrated samples. Neonatal CSF usually contains 8
to 9 WBCs/mm3, and up to 32 WBCs/mm3 has been reported in the absence of disease (60) (Table 2.2).
The WBC count is usually between 1,000 and 5,000/mm3 in untreated bacterial meningitis (60), and
more than 90% of patients with bacterial meningitis will have a WBC count greater than 100 cells/mm3
(61). The most common three types of viral meningitis in the United States (enterovirus, West Nile virus,
and herpes simplex virus) have a median WBC count between approximately 100 and 250 cells/mm3
(25).
Differential White Blood Cell Count

A differential count of CSF leukocytes may be obtained following concentration of CSF through a
Millipore filter, centrifugation of a volume (usually 5 mL) of CSF, concentration by sedimentation, or
cytocentrifugation. The number of neutrophils is increased in various conditions. In adults with bacterial
meningitis, neutrophils make up an average of 86.4% of cells counted, with neutrophils making up an
average of 34.2% of cells counted in aseptic meningitis (1,62). In the early stages of meningitis, this
distinction between bacterial and viral etiologies may not be clear because a neutrophilic pleocytosis
(>50% neutrophils) may accompany early viral meningitis or encephalitis (63). Up to two thirds of
enteroviral meningitis cases initially have a neutrophilic predominance (64). Within 12 to 24 hours, there
is usually a shift from a neutrophilic predominance to a lymphocytic predominance, which is why some
may suggest a repeat LP if the first LP was nonspecific (47). A lymphocytic pleocytosis is typically
observed in patients with viral meningitis, M. tuberculosis, Borrelia burgdorferi, Treponema pallidum,
or C. neoformans, as well as in neoplastic and drug-induced meningitis (63). In AIDS-associated
cryptococcal meningitis, CSF pleocytosis may be absent, a finding that is associated with a worse
prognosis. Only up to 30% of patients with AIDS-associated cryptococcal meningitis have a CSF WBC
greater than 20 with a lymphocytic predominance (57). In tuberculous meningitis, the range of CSF
pleocytosis is more commonly between 50 and 300 cells/mm3 with a lymphocytic predominance. Plasma
cells and eosinophils should not be present in normal CSF (60). Increased numbers of B cells can be seen
in neurosyphilis and could represent another diagnostic option (65). Eosinophilic meningitis can be
caused by several parasitic infections, the most common being angiostrongyliasis, gnathostomiasis,
toxocariasis, cysticercosis, schistosomiasis, baylisascariasis, and paragonimiasis (66) (Table 2.3). In
addition, however, CSF eosinophilia has been reported in a wide variety of other infectious and
noninfectious conditions (Table 2.3), so detection of eosinophils within the CSF is not pathognomonic of
parasitic infestation (66).
Red Blood Cells
The presence of RBCs in CSF may result from a traumatic LP or may indicate subarachnoid or
parenchymal hemorrhage. Grossly bloody fluid that clears visibly as CSF is collected suggests a
traumatic tap. Differentiation between a traumatic LP and subarachnoid blood as the result of intracranial
or intraspinal pathology becomes more difficult if only small numbers of RBCs are present. In such cases,
one should compare numbers of RBCs present in CSF obtained at the beginning of the LP with numbers
present in CSF obtained at the end of the procedure (e.g., one should count cells from tubes 1 or 2 and
then from tube 4). The presence of xanthochromia in samples centrifuged immediately after obtaining CSF
argues against a traumatic tap, although it must be kept in mind that lysis of RBCs in vitro in CSF obtained
during a traumatic tap will produce xanthochromia if the specimen is allowed to sit. Crenation of RBCs
may occur in vitro and has no diagnostic significance (67). Blood entering CSF during spontaneous
subarachnoid hemorrhage or as the result of a traumatic tap contains WBCs and RBCs, and thus, the CSF
leukocyte count will increase. Numbers of WBCs relative to those of RBCs in CSF after a traumatic tap
should be consistent with the leukocyte count of the peripheral blood, and the differential count of CSF
will be the same. In contrast, actual subarachnoid hemorrhage often produces pleocytosis and alteration in
the differential count. A traumatic tap in the setting of CNS infection will increase the numbers of WBCs
already present by an amount that can be calculated by comparing the ratio of RBCs to WBCs in CSF with
that seen in peripheral blood.
Cerebrospinal Fluid Glucose

Most glucose present in CSF (Table 2.2) moves across the choroid plexus and across ventricular and
subarachnoid capillaries by facilitated transport. A smaller amount of glucose enters the CSF by simple
diffusion. Glucose is removed from CSF through utilization by cells lining the ventricles and
subarachnoid space and by transport across capillaries and arachnoid villi. Entry of glucose occurs over
time, and more than 2 to 4 hours is required before serum and CSF glucose levels reach equilibrium (1).
In the absence of infection or other pathologic conditions, CSF glucose levels are a predictable reflection
of blood glucose, and the ratio of CSF to blood glucose concentrations is approximately 0.6. The CSF
glucose level, equilibrated with a normal blood glucose level of 70 to 120 mg/dL, thus ranges between 45
and 80 mg/dL (Table 2.2). Levels of glucose in ventricular fluid are 6 to 18 mg/dL higher than those in
lumbar fluid (1,68).
CNS infections may alter glucose transport across the blood–CSF barrier, resulting in a low CSF
glucose level, termed hypoglycorrhachia (1). Further reduction in CSF glucose levels may result from
glucose consumption by WBCs and organisms (1). Reduction of CSF glucose relative to blood glucose is
characteristic of meningitis caused by bacteria, mycobacteria, or fungi (69,70). The CSF glucose level is
usually normal during viral infections, but low CSF glucose levels are occasionally observed in
meningoencephalitis caused by mumps, enteroviruses, lymphocytic choriomeningitis, herpes simplex, and
herpes zoster viruses (25,71). Low CSF glucose values have also been described in CNS complications
of Mycoplasma pneumoniae infection, carcinomatous meningitis, CNS sarcoidosis, and subarachnoid
hemorrhage (72–75). During recovery from meningitis, CSF glucose levels tend to return toward normal
more rapidly than cell counts and protein levels, making CSF glucose levels an important parameter to
follow in assessing response to therapy (76,77).
Both reduction in CSF glucose values and altered ratios of CSF to blood glucose levels are used as
indicators of infection. However, the literature contains a variety of recommendations about the point at
which CSF glucose should be considered abnormally low (78); this is partly because of the prolonged
interval over which CSF glucose equilibrates with serum glucose. In general, a CSF/blood glucose ratio
less than 0.5 should be considered abnormal. In premature and full-term infants, however, the normal
CSF/blood glucose ratio is 0.74 to 0.96, and a ratio of 0.6 is usually considered abnormal (79). In severe
hyperglycemia, transport of glucose into CSF may lag, and at a blood sugar level of 700 mg/dL, the
CSF/blood glucose ratio may approach 0.4. For this reason, a ratio of 0.3 has been suggested as abnormal
in diabetics (80). Silver and Todd (78) addressed the problem of diagnostically significant
hypoglycorrhachia in a study of 181 pediatric patients with CSF glucose levels less than 50 mg/dL or a
CSF/blood glucose ratio less than 50%. Patients ranged in age from younger than 1 week to 14 years, with
an average age of 1½ years. Their series included patients with bacterial meningitis, aseptic meningitis,
subarachnoid hemorrhage, and CNS carcinomatosis but did not include patients with tuberculous or fungal
meningitis. Blood for glucose analysis was obtained 1 to 114 minutes before the LP (average interval, 30
minutes). Of 35 patients with bacterial meningitis in this series, 27 (77%) had CSF glucose levels of 20
mg/dL or less, whereas CSF glucose levels of 20 mg/dL or less were found in only 10 (7%) of 146
patients with other conditions. A CSF glucose level less than 20 mg/dL or a CSF/blood glucose ratio less
than 0.30 was highly correlated with bacterial meningitis, whereas an absolute CSF glucose value
between 20 and 50 mg/dL was nonspecific; also, a CSF/serum glucose ratio greater than 0.3 was felt to
exclude most (but not all) cases of bacterial meningitis. Additionally, Spanos, Harrell, and Durack (81)
performed a retrospective study of 422 patients with acute bacterial or viral meningitis and found that
CSF glucose levels less than 18 mg/dL (1.9 mmol/L) and a CSF/blood glucose ratio less than 0.23 were
predictors of bacterial meningitis. Furthermore, hypoglycorrhachia is associated with an adverse clinical
outcome in patients with meningitis and a negative Gram stain (82).
Cerebrospinal Fluid Protein

Protein is largely excluded from CSF by the blood–CSF barrier and, under normal conditions, reaches
CSF by pinocytotic transport across capillary endothelia (83). Total CSF protein concentration in lumbar
CSF of a healthy adult (Table 2.2) is less than 45 mg, and the CSF/serum ratio of albumin is 1:200 (1,13).
Mean values of lumbar CSF protein in healthy children and adults have ranged from 23 to 38 mg/dL, and
the extreme upper and lower concentrations have been 58 and 9 mg, respectively (1). The CSF protein
level in premature and full-term neonates may range between 20 and 170 mg/dL, with a mean of 90 mg/dL
(58) (Table 2.2). Protein concentrations in cisternal and lumbar CSF are lower, ranging from 13 to 30
mg/dL (1). Elevation of protein concentration in the setting of CNS infections results from disruption of
tight junctions between endothelial cells of venules and, to a lesser extent, other small meningeal or
parenchymal vessels (83). Elevation of CSF protein level to more than 150 mg/dL may cause the CSF to
be xanthochromic. Extreme elevation of protein (to >1.5 g/dL) may cause formation of a weblike surface
pellicle or an actual clot, as may high levels of fibrinogen (1). Levels of CSF protein may be falsely
elevated by deteriorating RBCs following subarachnoid hemorrhage or traumatic LP. The amount of
increase is roughly 1 mg/dL per 1,000 RBCs. Accurate assessment of the contribution to total CSF protein
made by RBCs requires that the cell count and protein determination be carried out on the same tube of
CSF.
Changes in the concentration of protein in CSF are the most common and least specific of CSF
alterations in disease and are seen in a wide variety of infectious and noninfectious neurologic conditions.
Thus, an elevated CSF protein level, taken alone, has little specific value in the diagnosis of CNS
infections. Elevation of CSF protein to levels more than 100 mg/dL, particularly if obtained on serial LPs,
argues against viral infection, however, and Spanos, Harrell, and Durack (81) have demonstrated that
elevation of protein to a level of 220 mg/dL (2.2 g/L) suggests bacterial meningitis. The CSF protein
levels return to normal more slowly than glucose levels and cell count during recovery from meningitis
and may remain abnormal for months after parenchymal infections. Although elevation of CSF protein is
common in CNS infections, normal protein values are occasionally seen in all types of CNS infections,
including bacterial meningitis. In children with bacterial meningitis, antibiotic administration more than
12 hours before the LP is associated with lower CSF protein and higher CSF glucose concentrations (84).
Cerebrospinal Fluid Immunoglobulins

Immunoglobulins are almost totally excluded from normal CSF. The blood/CSF ratio of immunoglobulin
G (IgG) in normal CSF is usually in the range of 500:1. Immunoglobulin M (IgM) is essentially absent
from CSF. Studies with radioiodinated IgG have demonstrated that CSF IgG in healthy individuals is
derived entirely from serum, requiring 3 to 6 days to reach equilibrium (1). Immunoglobulins enter CSF
less readily than albumin; and in health, immunoglobulin/albumin ratios in CSF are reduced relative to
those in serum. Elevation in CSF immunoglobulins may follow disruption of the BBB, allowing passage
of immunoglobulins across capillary endothelium, or may result from local antibody synthesis within the
brain. Increased levels of CSF IgG per se have little diagnostic value in CNS infections. Detection of
oligoclonal IgG bands unique to CSF and not seen in serum on gel electrophoresis provides strong
evidence for an ongoing immune response within the brain and is part of the diagnostic criteria for
multiple sclerosis (85).
Microscopic Methods for Detecting Infectious Organisms
Gram Stain
Gram stain is of crucial value in providing rapid identification of the offending organism in bacterial
meningitis, and it is fast, inexpensive, and fairly reliable (Fig. 2.4). It is usually the single most important
piece of information the clinician uses to guide initial antibiotic therapy and should be an invariable part
of the CSF evaluation. Diagnostic accuracy of a properly prepared Gram stain is a function of the number
of organisms present, the type of meningeal pathogen, and by the receipt of prior antibiotic therapy (61).
In one large study of bacterial meningitis in children, prior antibiotic exposure did not alter the sensitivity
of the Gram stain but decreased the sensitivity of the blood and CSF cultures by 18% and also altered the
CSF glucose and protein levels if administered within 12 hours of the LP (84). The sensitivity of the
Gram stain in children and adults with pneumococcal meningitis ranges between 69% and 95% and in
meningococcal meningitis between 30% and 89%. Blood cultures will be positive in 50% to 80% of
patients, and the CSF cultures will be positive between 80% and 90% of cases (86). In general, the
sensitivity of the Gram stain ranges from 50% to 90%; however, the specificity approaches 100%
(61,86). In one study, only 22 (4%) out of 567 patients with community-acquired meningitis and a
negative Gram stain had culture-proven bacterial meningitis (82).
Partially Treated Bacterial Meningitis
The diagnosis of patients that present with possible bacterial meningitis who have received antibiotics
remain a challenge to clinicians. The acridine orange stain is a fluorochrome stain that has been shown to
improve detection of bacteria in CSF specimens, especially in patients who have partially treated
bacterial meningitis (87). A more recent approach is detection of Streptococcus pneumoniae C-
polysaccharide, which is found in the cell wall and is common to all serotypes, in CSF by using rapid
immunochromatographic membrane assays (88,89). Two large, multicenter studies have shown a
sensitivity and specificity of 99% detecting S. pneumoniae even in patients who have been pretreated
with antibiotics that have negative CSF cultures (90,91).
Cerebrospinal Fluid Bacterial Culture
Choice of culture media, methods of handling, and lengths of time over which cultures are to be
maintained are thoroughly discussed in standard reviews and texts (92,93). The CSF should be submitted
to the laboratory immediately after the LP and should be placed in culture promptly to avoid loss of
fastidious organisms such as Haemophilus influenzae, Neisseria meningitidis, or anaerobes. CSF
cultured for bacteria should, at a minimum, be plated on a 5% sheep blood agar, chocolate agar, and
inoculated into an enrichment broth (93). A minimum of 2 mL (ideally 5 mL or more) should be submitted
for Gram stain and bacterial culture.
Cerebrospinal Fluid Acid-Fast Bacilli Stains and Cultures
A positive acid-fast stain for detection of M. tuberculosis is highly suggestive of tuberculous meningitis,
but positive results occur in only 10% (94). The sensitivity of the acid-fast stain depends greatly on the
skill and persistence of the examiner and the amount of fluid concentrated. In general, collecting four
serial samples and spinning of large volumes (20 mL) of CSF for 30 minutes enhances the rate of
detection by smear microscopy, but it is impractical (95). Isolating mycobacteria in culture is difficult
with detection rates for M. tuberculosis between 10.2% and 55.8% for conventional Lowenstein-Jensen
medium and from 4.3% to 48.9% for the automated commercial system BACTEC Mycobacteria Growth
Indicator Tube (MGIT) 960 (96).
Microscopic Detection of Anaplasma, Fungi, and Protozoa in Cerebrospinal Fluid
In a few cases, intracellular morulae have been detected in CSF of patients with meningitis due to
Anaplasma infection (97). Fungi, including C. neoformans, Blastomyces dermatitidis, C. immitis, and
Candida albicans, may occasionally be detected on Gram or silver stains of concentrated CSF (98). In
many cases of fungal meningitis, however, organisms are too few to be readily detectable, and negative
Gram or silver stains of CSF sediment in no way excludes the possibility of fungal infection. India ink
preparations, in which CSF sediment from 3 to 5 mL of CSF is mixed with a drop of India ink, provide a
useful means of outlining the capsule of C. neoformans (Fig. 2.5). Sensitivity of the India ink preparation
is about 60% in patients who are not infected with acquired immunodeficiency syndrome (AIDS) and
more than 75% in patients with AIDS (98). Cryptococcal antigen detection has replaced India ink
preparations in most laboratories because of its high sensitivity and specificity (99).
Wet mount preparations may be used to identify motile trophozoites in the CSF of patients with primary
amebic meningoencephalitis (100). Search for motile organisms in wet mounts may be made more
reliable by the use of phase-contrast microscopy.
C. neoformans is cultured from the CSF in approximately 72% of patients on the first LP and in more
than 90% on multiple attempts (101). Frequency of recovery of C. albicans from CSF is also high (102).
Isolation of other organisms such as Histoplasma capsulatum or Brucella species often proves difficult
(103).
In most bacterial and fungal infections, extraneural sites of possible infection should also be cultured.
Depending on the organism being sought, these sites may include blood, urine, paranasal sinuses, ears,
skin, oropharynx, sputum, bone marrow, prostate, or abscess material.
Viral Culture
Isolation of viral agents by tissue culture methods has been the traditional means of diagnosis in cases of
suspected viral meningitis or encephalitis. Newer methods of virus isolation have improved diagnostic
yield; these include the incorporation of multiple tissue culture cell lines and a combination of culture and
staining procedures (shell vial assay for early antigen detection, enzyme immunoassays, and
immunofluorescence staining). Enteroviruses can be isolated in 43% to 77% of patients, depending on the
predominant viral serotype in a particular community. In approximately half of these cases, virus will be
isolated by day 3 and in more than 80% by day 7 (104). Mumps virus and lymphocytic choriomeningitis
virus, the agents of western and eastern equine encephalitides, may also be recovered from CSF. Herpes
simplex virus (HSV) types 1 and 2 can be isolated from cases of meningitis but are rarely recovered from
CSF in cases of encephalitis. Varicella-zoster virus; cytomegalovirus; and California, St. Louis, and
Japanese encephalitis viruses are rarely recovered (105).
ADJUNCTIVE AND MOLECULAR STUDIES OF

CEREBROSPINAL FLUID IN THE DIAGNOSIS OF CENTRAL
NERVOUS SYSTEM INFECTION
The need for rapidly available accurate diagnostic information in CNS infections, the poor sensitivity of
microscopic examination of CSF sediment, and the delays inherent in obtaining results of CSF culture
have led to the development of a wide variety of rapid diagnostic tests for CNS infections. At present,
PCR methods have largely replaced tissue culture methods for enteroviruses, Herpetoviridae (herpes
simplex, herpes zoster, cytomegalovirus, Epstein-Barr virus), JC virus, and West Nile virus. West Nile
virus meningoencephalitis is diagnosed largely by serology because the virus is only rarely isolated by
tissue culture methods at the time patients present with neurologic symptoms (106).
Bacterial Infections
Lactic Acid
Elevation of lactic acid levels in CSF occurs more frequently in bacterial than in viral meningitis. A CSF
lactate cutoff value of more than 3.5 to 4.2 mmol/L provides supportive evidence for a bacterial infection
in untreated patients. Two large metaanalyses have concluded that the determination of CSF lactate level
is better than the CSF WBC, glucose, or protein in differentiating bacterial meningitis from aseptic
meningitis (sensitivity of 93% and 97% and specificity of 96% and 94%, respectively) (107,108).
C-Reactive Protein
C-reactive protein (CRP) is an acute phase reactant released from the liver in response to an
inflammatory reaction, such as meningitis. CRP is released within 6 hours of insult and peaks after 36
hours. One of the functions of CRP is to bind to phospholipid components of damaged cells or bacteria
resulting in activation of the classical complement pathway (109). Both serum and CSF CRP have been
studied as potentially useful tools for discriminating bacterial meningitis from aseptic or viral meningitis.
A large retrospective study in children showed a sensitivity of 93% and a specificity of 100% with a CRP
greater than 40 mg/L to detect bacterial meningitis (110). Furthermore, a metaanalysis showed that a CRP
level greater than 20mg/L was conveyed significantly higher odds of bacterial meningitis (odds ratio
[OR] 9.9 [4.8 to 20.8]) (111). Current literature supports the assertion that CRP may be useful, but it
should be used with caution as the sole criterion in the differentiation of bacterial versus viral meningitis
(61).
Procalcitonin
Procalcitonin (PCT) is a calcitonin propeptide synthesized by C cells of the thyroid gland and released
from leukocytes of the peripheral blood (112). It has been used as a marker of severe inflammation such
as those caused by bacterial infections, pancreatitis, burns, or trauma (113). In a prospective multicenter
trial of 151 patients with a negative Gram stain, 18 had confirmed bacterial meningitis; a serum PCT
greater than 0.5 ng/mL (sensitivity 87%, specificity 100%, positive predictive value 1.0, negative
predictive value 0.99) had better diagnostic accuracy than serum CRP, CSF leukocyte count, CSF/blood
glucose ratio, CSF protein, and the physician’s assessment (109). A metaanalysis showed that a
procalcitonin level greater than 0.5 µg/L was predictive of bacterial meningitis with an OR 434 (95%
confidence interval [CI] 57 to > 1,000) (111). Procalcitonin in the CSF may also be elevated in patients
with probable Alzheimer disease, vascular dementia, dementia with Lewy bodies, frontotemporal
dementia, and encephalitis (113).
Additional Biomarkers
Bacterial meningitis results in systemic and intrathecal inflammatory reactions that may lead to significant
morbidity and mortality. Several inflammatory markers (interleukin-1β [IL-1β], IL-6 and -12, TNF-α,
soluble triggering receptor expressed on myeloid cells-1 (sTREM1), cortisol, heparin-binding protein,
and complement factor 3 and complement B) have all been evaluated in small studies with adequate
diagnostic accuracy (61).
Detection of Bacterial Antigens

Antigen-detection tests using latex agglutination assays are available to rapidly detect meningitis caused
by H. influenzae type b, N. meningitidis serogroups A, B, C, Y, and W135, S. pneumoniae, E. coli K1,
and Streptococcus agalactiae. In general, these tests find little application; antigen-detection tests are
less sensitive than bacterial culture, offer no advantages over the Gram stain, and their diagnostic
reliability and usefulness may vary from institution to institution (114,115). Situations in which antigen-
detection tests are not likely to be helpful include cases in which the Gram stain is positive, in which the
CSF WBC count and chemistries are within normal limits, and in which the CNS infection is hospital
acquired (115).
Polymerase Chain Reaction
Molecular techniques such as polymerase chain reaction (PCR) are well suited for the diagnosis of CNS
infections because the presence of microorganisms is highly suggestive of infection. PCR has emerged as
a novel technique for identifying viral, bacterial, and mycobacterial causes of meningitis (116–119).
Although CSF makes an ideal source to examine by PCR because it is sterile and without contaminants,
the presence of inhibitors, assay contamination, and experimental conditions may sometimes alter its
diagnostic value (118). There are a variety of PCR methods used today including “multiplex” and
“nested” PCR. Multiplex PCR has the advantage of potentially detecting more than one organism in the
same PCR reaction. This is done by using two or more primer pairs, each specific for a single agent. In
nested PCR, products from the first amplification are reamplified from a second set of primers that is
nested between the first set. This essentially overcomes nonspecific amplification (i.e., assay
contaminations) and increases the sensitivity of detection.
Bacterial Polymerase Chain Reaction. The use of PCR in bacterial meningitis may serve a role in
patients previously treated with antibiotics or in the detection of difficult to culture organisms such as
Mycoplasma or Brucella. However, molecular tests are not routinely available, and Gram stain and
culture of the CSF is still the gold standard for diagnosis. Broad-range PCR amplifies the 16S ribosomal
RNA (rRNA) gene that is present in all bacterial species. Broad-range PCR and organism-specific PCR
have been used in detecting meningeal pathogens with sensitivities between 89% and 100% and
specificities of 95% to 100% (61). In a study of 409 patients with bacterial meningitis in Burkina Faso,
PCR was able to make the diagnosis in a third of patients who had negative bacterial cultures (120). The
availability, expense, and time to run these test may prove difficult, and positive results ideally should be
confirmed by species-specific PCR. Furthermore, contamination of PCR specimens may cause false-
positive results, which can be encountered by improper handling or contaminated work equipment from
previous PCR reactions.
Viral Polymerase Chain Reaction. The use of PCR is the preferred method of diagnosing patients with
suspected viral encephalitis such as those caused by HSV, enterovirus, varicella-zoster virus,
cytomegalovirus, or Epstein-Barr virus (117). This is very important in cases of suspected HSV
encephalitis that can cause significant morbidity and mortality if untreated. There are over 100 known
viruses that may infect the CNS although only a limited number of tests are available for confirmation
(117). The decision to perform molecular tests is physician-driven and is often based on the clinical
presentation. In a study of 760 adult patients presenting with meningitis and a negative Gram stain, only
44% had PCR in the CSF performed for a viral pathogen (116).
Herpes simplex virus. Herpes simplex encephalitis (HSE) is the most common cause of sporadic
encephalitis in the United States, and it is the most common cause of severe viral encephalitis (121). In
immunocompetent adults, 90% of HSE is caused by HSV-1, with the remaining 10% caused by HSV-2. In
AIDS patients, the rate of HSV-2 may be higher (122). Empirical antiviral therapy and prompt
identification are of crucial importance because of the high morbidity and mortality associated with HSE.
Early initiation of intravenous acyclovir has been shown to reduce mortality in patients with HSE (123).
The availability of PCR has now become the diagnostic modality of choice for diagnosing HSE
(117,121,123). Numerous studies have shown sensitivities greater than 90%, with specificities near
100% (117). Viral cultures are not routinely recommended because they are positive in less than 5% of
adults. Prior to PCR, the gold standard for diagnosing HSE was brain biopsy (121). A negative PCR for
HSV does not rule out HSV encephalitis but rather makes it less likely (117).
Enterovirus. Enteroviruses are one of the most common causes of aseptic meningitis in children and in
adults (71). Enterovirus PCR in the CSF has improved the detection rates compared to viral cultures, and
results can be available within 2 hours. The Gene Xpert Enterovirus PCR had a sensitivity of 97.1%
(95% CI, 84.7% to 99.9%) and a specificity of 100% (95% CI, 94.6% to 100%) for the diagnosis of
enteroviral meningitis (124). A rapid diagnosis of enteroviral meningitis could impact care by avoiding
hospitalization or empirical antibiotic therapy (71).
Mycobacterial Polymerase Chain Reaction
The diagnosis of tuberculous meningitis (TM) can be difficult because culture sensitivities are low, and
the organism may take up to 6 weeks to grow (96). PCR has received interest in hopes it may serve as a
rapid, sensitive, and specific test for TM. One of the more frequently used M. tuberculosis PCR targets is
IS61100 (125). Investigators prospectively studied 677 CSF samples in patients with clinically suspected
TM (125). All culture-positive samples (n = 136) were positive (100%) by the PCR assay. In those
patients with clinically suspected (culture negative) TM, the assay was positive in 70% (n = 541). Not all
studies have shown as good of results, with some sensitivities being reported as low as 33% (126) and as
high as 87% (127). Specificities also have a wide range from 88% to 100% (94). This discrepancy could
be due to the different types of measuring methods with the use of different targets used in the laboratories
(127).
Measurement of Adenosine Deaminase Levels in Cerebrospinal Fluid

Adenosine deaminase is an enzyme that is widely distributed in human tissues and is present in high
concentrations in lymphocytes. Elevation of CSF adenosine deaminase levels may occur in a variety of
neurologic disorders, including bacterial meningitis, brain abscess, neurobrucellosis, cryptococcal
meningitis, and CNS lymphoma. Elevated levels of lymphocyte adenosine deaminase are frequently
present in the CSF of patients with TM, and measurement of this enzyme has been used to provide
presumptive evidence of M. tuberculosis infection and to evaluate response to treatment (128,129). The
test, though both sensitive and useful, is not specific because it detects a component of host response and
does not detect a structural component of the organism itself.
Lyme Disease
The overall sensitivity and specificity of tests for diagnosis of Lyme disease are still being determined, as
is the accuracy of tests used to diagnose CNS involvement. In the United States, the Centers for Disease
Control and Prevention (CDC) recommends using a two-step process for testing serum from patients
suspected of having Lyme disease (130). Step one involves screening with a sensitive assay such as
enzyme-linked immunosorbent assay (ELISA) or immunofluorescence assay. Those samples that are
negative by such an assay are not tested further. All equivocal or positive results are subsequently
confirmed by immunoblotting (Western blot) (131). Standardized criteria for interpretation of both IgM
and IgG are outlined elsewhere (131). Antibody to B. burgdorferi may be absent early in the course of
infection, and seronegative Lyme disease, diagnosed by T-cell proliferation to Lyme disease, has been
reported (132). False-positive test results for Lyme disease may be seen in patients with infectious
mononucleosis, positive serology for syphilis, and autoimmune conditions.
In the acute form of neuroborreliosis, there is usually pronounced synthesis of IgM antibody production
(133). IgG and IgA synthesis is seen in the chronic forms of disease (133). Detection of intrathecal
antibody production is considered the most specific test for neuroborreliosis (134). However, not all
patients develop CSF antibodies. The CSF antibody production in subtle CNS disease is inconsistent and
may be lacking in patients with only peripheral nerve involvement (135). Detection of CSF antibody is
not essential for diagnosis (134,135). Accuracy and reliability of tests vary considerably between
laboratories; therefore, positive values reported by laboratories unfamiliar to the physician must be
approached with caution and, if necessary, confirmed.
There is currently not a validated PCR method commercially available (136). There are several
parameters that can have significant effects on the performance of the PCR such as sample type and
volume, extraction method (nested PCR, PCR followed by hybridization, real-time PCR), target, primers,
template DNA, and PCR chemistry (136). A metaanalysis derived from published PCR results
irrespective of methods or targets from patients with all stages of Lyme neuroborreliosis demonstrated an
overall sensitivity of 19% and a specificity of 100% (137). Other reports have indicated that PCR is no
more sensitive as a diagnostic tool than the measurement of intrathecal antibody production and overall is
less useful (138–139). PCR should not be considered a “stand alone” test, and a negative result does not
rule out neuroborreliosis. At present, molecular assays may, at most, have a limited role as adjunctive
tests in patients who are seronegative and who have a high likelihood of infection (e.g., as in the case of
the immunodeficient patient). Elevated levels of CSF CXCL13 (C-X-C motif chemokine 13) have been
described in Lyme neuroborreliosis and could serve as a diagnostic marker. Furthermore, CSF CXCL13
decreased with intravenous ceftriaxone and oral doxycycline (140). As research tools, molecular assays
may provide insight into pathogenesis and clinical course when used prospectively during the course of
illness.
Fungal and Other Infections
Fungal Infections
Detection of cryptococcal antigen in spinal fluid is the most practical diagnostic test for cryptococcal
meningitis. The test has a high degree of specificity and is positive in 83% to 98% of patients (141).
Detection of cryptococcal antigen has replaced India ink stains. Despite its sensitivity and specificity,
however, assays for cryptococcal antigen may occasionally give false-negative results in both
immunocompetent and immunocompromised patients (142). Screening for cryptococcal meningitis as a
point of care test by using the cryptococcal antigen in urine or plasma could help identify patients at high
risk sooner and possibly decrease mortality (143,144).
Complement-fixing antibodies have been reported in CSF in up to 95% of cases of meningitis caused
by C. immitis (145), although yield of detection has not been that high in all series (146). Diagnosis of
Histoplasma meningitis can be extremely difficult, especially the chronic form of the disease, which may
occur in the absence of other manifestations of disseminated infection (147,148). Detection of CSF
antibodies may be useful, but false-positive results have been reported in patients with fungal meningitis
caused by other organisms and by diffusion of serum antibodies to H. capsulatum into the CSF during
other inflammatory conditions of the meninges (149). Histoplasma polysaccharide antigen detection can
be detected in CSF, serum, or in urine. Small studies of less than 20 patients have documented
sensitivities between 38% and 71% (149,150).
Development of molecular techniques for diagnosis of fungal infections has lagged behind those assays
for detection of other pathogens. There are many reasons for this, but the most compelling is the
ubiquitous nature of fungi in the environment and the difficulties with contamination control. Initial assays
used species-specific, single-copy genes (150). More recently, investigators have evaluated the use of
highly conserved, multicopy genes that are universal to all or most fungal species (150). Such targets have
included 18S rRNA subunit genes, 28S rRNA genes, mitochondrial genes, and the intergenic transcribed
spacer (ITS) region of the rRNA gene (149,150).
Toxoplasmosis
Encephalitis is the most common presentation of toxoplasmosis in the immunocompromised patient and
most commonly results from reactivation of latent infection (151). CSF antibody titers have been used to
diagnose and follow CNS infections caused by Toxoplasma gondii in both patients with AIDS and
patients without AIDS (152,153). PCR may be useful in the absence of typical serologic or radiologic
studies and could potentially decrease the need for a brain biopsy (154,155).
Whipple Disease
Whipple disease is a systemic illness caused by Tropheryma whippelii. Illness is characterized by a
predominance of intestinal manifestations, but extraintestinal manifestations including endocarditis,
myocarditis, pericarditis, and CNS disease occur with relative frequency (156). Although cultivation of
the organism has been reported (157), diagnosis is generally made by a combination of cytologic analysis
of tissue and fluids using periodic acid–Schiff (PAS) staining to demonstrate the presence of macrophages
laden with intracellular organisms and electron microscopy (158). PCR has also been used to determine
the stage of disease and monitor response to therapy (158,159). False-positive PCR results have been
reported in asymptomatic individuals, and for this reason, PCR cannot be recommended in place of
standard diagnostic techniques (159).
Viral Infections
PCR methods have had their greatest impact in the diagnosis of viral meningitis and encephalitis and have
replaced tissue culture methods (117, 123). Additionally, before the advent of PCR, CSF antibody titers
and determination of CSF/serum antibody ratios were routinely used as methods of acute viral diagnosis.
Determination of CSF antibody titers per se has been found valuable in the diagnosis of chronic CNS
infections such as tropical spastic paraparesis or subacute sclerosing panencephalitis (160), but CSF
antibody titers alone are of limited value in most cases of acute viral encephalitis with the exception of
arboviruses such as West Nile virus where the PCR is less sensitive (117). Comparison of serum and
CSF titers of IgG and IgM antiviral antibodies has been proposed as a diagnostic test in encephalitis
caused by HSV and other agents, but the test, which is dependent on intrathecal antibody synthesis, is of
limited value at the time of presentation, and intrathecal antibody may become detectable only as virus is
cleared from the CSF compartment (161). Most patients presenting with West Nile virus infection already
have CSF IgM antibodies to the virus, making this the diagnostic method of choice (162).
Compared to viral culture (overall sensitivity, 14% to 24%), the sensitivity of PCR ranges from 75% to
100% depending on the virus (163–175). Molecular detection of viral nucleic acid sequences in CSF has
not only improved diagnosis but also has largely replaced invasive methods such as brain biopsy, has
shortened time to specific diagnosis, and particularly in enteroviral CNS infections, has proven cost-
effective through decreased use of empirical antibacterial therapy and reduction in hospital stay
(163–165). Finally, molecular assays have added greatly to our understanding of the epidemiology and
pathogenesis of these infections (125,166,167).
Other Adjunctive Tests in the Diagnosis of Central Nervous System Infections
Detection of Cytokines in Cerebrospinal Fluid

TNF, IL-1, and other cytokines have received increasing attention as mediators of the inflammatory
response during bacterial meningitis and can help distinguish between bacterial and viral meningitis
(176–180). Lopez-Cortez et al. (178) have recently demonstrated that a TNF-α level of more than 150
pg/mL and IL-1β level more than 90 pg/mL showed sensitivities of 74% and 90%, respectively, in
discriminating viral from aseptic meningitis. Pinto Junior et al. (179) found that an elevated CSF IL-8
level was higher in patients with acute bacterial meningitis compared to aseptic meningitis and controls
(100% of sensitivity and 94% of specificity). Tang et al. (180) determined the concentrations of IL-1β and
TNF-α in the CSF of 171 specimens of 144 patients whose cases were classified as follows: bacterial
meningitis (n = 23), aseptic meningitis (n = 26), and nonmeningitis (n = 95). Significantly higher serum
IL-1β and TNF-α concentrations were detected in those with bacterial meningitis than those with aseptic
meningitis or among those patients without meningitis (p <0.001). These findings, though requiring both
confirmation and amplification, suggest that analysis of TNF and other cytokines, in particular IL-1β, may
prove valuable in differentiating acute bacterial meningitis from viral meningitis and possibly in detecting
patients at particular risk of adverse outcome. Their role in guiding adjunctive therapy, such as
corticosteroids and nonsteroidal treatment of BBB injury, is also under investigation.
CHARACTERISTIC CEREBROSPINAL FLUID FINDINGS IN

MAJOR CENTRAL NERVOUS SYSTEM INFECTIONS
Bacterial Meningitis
Bacterial meningitis characteristically produces a neutrophilic pleocytosis, hypoglycorrhachia (CSF
glucose <45 mg/dL), and an elevated protein level. Numbers of PMN leukocytes may vary from a few to
many thousand and usually range between 1,000 and 10,000 cells. A predominantly (>50% of cells)
lymphocytic pleocytosis has been reported in up to 14% of patients (181), and atypical CSF profiles can
especially be seen in Listeria monocytogenes infection (182). A predominance of lymphocytes may also
be seen in neonatal gram-negative meningitis (183). Leukocytes may be absent from CSF very early in the
course of infection, in neonatal meningitis, or in severely immunocompromised patients (184).
Brain Abscess and Parameningeal Infection
Subdural empyema complicates community-acquired bacterial meningitis in 2.7% of cases and is usually
caused by S. pneumoniae in association with sinusitis or otitis (185). CSF cultures are positive in 93% of
these patients. In contrast, LP in brain abscess is not helpful and has been complicated with brain
herniation in 4 out of 296 (1.3%) of patients (186). The CSF findings are nonspecific and may include (a)
a mixed, predominantly lymphocytic pleocytosis, (b) normal glucose level, and (c) elevated protein level.
Organisms are not present unless there is accompanying meningitis, in which case CSF findings will be
those of bacterial meningitis (187–188).
Tuberculous Meningitis
Typical findings in tuberculous meningitis are (a) a pleocytosis with lymphocytic predominance, (b)
lowered glucose level, and (c) elevated protein level (94,95). In approximately 70% of patients, the cell
count is between 100 and 400 cells (95). However, as many as 1,000 to 1,200 cells may be present, and
in few patients, the CSF is acellular despite the presence of organisms, elevation in protein, and
hypoglycorrhachia. Although most cells in the CSF are lymphocytes, relative numbers of lymphocytes and
PMN leukocytes may vary from LP to LP. Protein levels are 100 to 500 mg/dL in 65% of patients and may
reach levels of 1,000 mg or more if treatment is delayed (94,95). In 25% of patients, protein levels are
normal (94). Glucose levels are 30 to 45 mg/dL in 50% of patients and may occasionally be less than 10
mg/dL. In 17% of patients, CSF glucose levels are normal (94). More recently, clinical models that
include a duration of symptoms for more than 5 days, abnormal neurologic status, a CSF to serum glucose
ratio less than 0.5, a low CSF neutrophilic percentage (<50%), and a CSF protein greater than 100 mg/dL
among others can aid clinicians distinguish between TM from bacterial meningitis but need to be
validated in other patient populations (189).
M. tuberculosis may be extremely difficult to detect on smear or to recover by culture. When
tuberculous meningitis is strongly suspected, obtaining more than 6 mL of CSF and repeating LPs can be
associated with a higher degree of positive acid-fast bacilli smears and cultures (189). PCR may provide
a rapid means of diagnosis superior to acid-fast stain (125–127).
Fungal and Other Chronic Meningitides
Initial requirements for CSF analysis in suspected fungal infections are similar to those described for
tuberculous meningitis, and the same material may be sent for both mycobacterial and fungal culture. CSF
should be submitted for cryptococcal antigen and, if the patient has a history of residence in an endemic
area such as the southwestern United States, for complement-fixing antibodies to C. immitis. Additional
samples of CSF should be submitted for serologic studies for H. capsulatum, Brucella, or other
organisms as indicated by history and occupational exposure. Serum and CSF should be frozen and held
for future serologic studies. CSF findings in fungal infections are similar to those described for
tuberculous meningitis, except that PMN leukocytes may be found less often. The number of cells present
may vary widely, and as in tuberculous meningitis, CSF may be acellular in severely
immunocompromised patients, including those with AIDS (190). An exception to this rule is seen in
infections with Mucorales, in which the extremely destructive nature of the infection may result in large
numbers of neutrophils (191). As in tuberculous meningitis, CSF glucose level may return toward normal
before changes are seen in cell count and protein.
Neurosyphilis
Suspicion of neurosyphilis is predicated on the presence of reactive serum nontreponemal tests such as
the rapid plasma reagin (RPR) or the Venereal Disease Research Laboratory (VDRL) and reactive serum
treponemal tests such as the fluorescent treponemal antibody-absorption (FTA-ABS), Treponema
pallidum particle agglutination (TPPA), or various enzyme immunoassays. A serum RPR titer 1:32 or
greater is associated with a higher probability of neurosyphilis in both HIV and non–HIV-infected
individuals; a CD4 less than 350 cells/µL is another predictor in HIV-infected patients (192). A reactive
CSF VDRL test confirms the diagnosis but it may be insensitive, and a nonreactive test does not rule out
neurosyphilis (193,194). The CSF may contain variable numbers of lymphocytes and an elevated protein
level in asymptomatic or symptomatic neurosyphilis (1). The findings are extremely variable, however,
and normal CSF cell count, protein, and glucose values do not exclude active disease (193,194). Rarely,
syphilis may present as an acute meningitis, with CSF findings similar to those of bacterial meningitis (1).
The T. pallidum PCR detection has been of value in primary syphilis, but the utility in neurosyphilis is
still under investigation (195).
Lyme Borreliosis
The CSF changes in Lyme neuroborreliosis are typically a mild lymphocytic pleocytosis, modest
elevation of protein level, normal glucose level, and may mimic viral meningitis. A clinical model named
“the rule of 7s” can help distinguish patients with Lyme meningitis from aseptic meningitis with a
sensitivity of 96%. If all the variables (<7 days of headache, <70% CSF mononuclear cells, and absence
of seventh or other cranial nerve palsy) are absent, the patient has a low risk of having Lyme meningitis
(196).
Infections Caused by Mycoplasma, Rickettsia, Ehrlichia, Anaplasma
CSF in meningoencephalitis associated with M. pneumoniae infections may be normal but has also been
characterized by a usually lymphocytic pleocytosis, elevated protein level, and mildly depressed glucose
level (72). CSF in Rocky Mountain spotted fever is usually acellular but may contain increased protein
concentration (197); typhus may be accompanied by lymphocytic pleocytosis and elevation of protein
concentration (198). Meningoencephalitis has been reported in human granulocytic anaplasmosis
(Anaplasma phagocytophilum) in approximately 1% of cases and in human monocytic ehrlichiosis
(Ehrlichia chaffensis and E. ewingii) in about 20% of cases, and it usually has a mild lymphocytic
pleocytosis (199). One study has detected Ehrlichia morulae in CSF (97).
Viral and Other Acute Meningoencephalitis
Viral meningitis produces a lymphocytic pleocytosis, usually in the range of 10 to 1,000 cells/mm3 with
mildly elevated protein and normal CSF glucose (25). PMN leukocytes may at times constitute more than
50% of the cells during the first 24 to 36 hours of the infection, and this can change in a repeat LP
(200,201) and in one series were shown to be present for several days (202). In some patients with
coxsackievirus infections of the CNS, PMN leukocytes may constitute 90% of cells at the onset of
infection, and the predominance of PMN leukocytes may persist for longer than 24 hours. There are also
reports of CSF samples with few or no cells yielding enteroviruses on culture or by PCR (203). Protein is
elevated in the range of 50 to 100 mg/dL but may sometimes be higher. Glucose is usually normal, but
depression of glucose to levels approaching those of bacterial meningitis has been reported in infections
with HSV-2, herpes zoster virus, mumps, and lymphocytic choriomeningitis virus (204,205). CSF should
be routinely sent for PCR analysis for enteroviruses, including parechoviruses and for HSV. In patients
who have vesicular rashes, a varicella-zoster virus PCR should also be sent. Both CSF and serum should
be frozen for future serologic testing.
Requirements for CSF analysis in cases of suspected viral encephalitis are similar to those for viral
meningitis, and CSF findings are often similar. PMN leukocytes may be present in large numbers in
severe encephalitides accompanied by extensive destruction of brain tissue. HSV classically produces a
hemorrhagic encephalitis. However, HSV is not unique in its ability to produce hemorrhagic necrosis of
brain, and RBCs are often not detected; thus, the presence or absence of RBCs cannot be used to
differentiate HSV encephalitis from other conditions. As in viral meningitis, CSF should be sent for PCR
and/or viral culture as appropriate, and both serum and CSF should be held for future serologic studies.
Serum or CSF should be sent for IgM and IgG antibody determination in cases of suspected West Nile or
other flavivirus encephalitis (123).
AIDS
Abnormalities of CSF in HIV infection are protean and may reflect either (a) a response to CNS invasion
by the agent itself, as in HIV-related meningitis, meningoencephalitis, and encephalopathy; (b) meningitis
or parenchymal infection by other agents; or (c) meningeal reaction to neoplastic or ischemic events
within brain or spinal cord. The response to any of these conditions is often modified by the
immunosuppressive effect of the virus (206). In HIV-infected individuals, normal findings on routine CSF
studies do not exclude infectious disease of the nervous system. The neurologic complications of HIV
infection and the approach to the patient with suspected neurologic involvement are discussed in detail
elsewhere.
Prion Diseases
Prion diseases do not elicit a cellular reaction in CSF, so the presence of a CSF pleocytosis essentially
excludes this group of diseases. Mild elevation of protein may occasionally be seen (207). In recent
years, 14-3-3 protein, S100 protein, tau protein, and neuron-specific enolase in CSF have been studied as
markers for Creutzfeldt-Jakob disease; of these, CSF tau and 14-3-3 protein has proven most valuable
when used in appropriate clinical context. CSF may contain 14-3-3 protein in other neurologic conditions,
however, and its detection is thus not specific for prion diseases (208). CSF from cases of known or
suspected Creutzfeldt-Jakob disease should be regarded as infectious and handled according to current
guidelines (208).
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CHAPTER 3 IMAGING OF INTRACRANIAL
INFECTIONS
CARRIE P. MARDER AND KATHLEEN R. FINK
Intracranial infections are usually diagnosed by clinical assessment and laboratory investigations,
particularly cerebrospinal fluid (CSF) analysis, combined with radiologic findings. Imaging plays an
important role by providing or narrowing the differential diagnosis and occasionally identifying a
particular entity that has a characteristic appearance, such as herpes simplex virus encephalitis, pyogenic
abscess, or empyema. Imaging is also crucial for identifying complications of disease and assessing
response to treatment. Finally, imaging contributes to the evaluation of opportunistic infections in
immunocompromised patients and other patients at high risk for infection.
Here, we emphasize the overall strategy for imaging intracranial infections and highlight specific
entities in which imaging findings contribute to diagnosis or management. We stress the major
complications of intracranial infections and address special considerations for immunocompromised
patients.
IMAGING STRATEGY
Patients suspected of harboring intracranial infection who present with altered mental status, seizures, or
focal neurologic deficits should emergently undergo noncontrast computed tomography (NCCT) to
exclude life-threatening conditions. In the acute setting, NCCT is the test of choice to assess for
hydrocephalus, cerebral edema, mass lesions, or hemorrhage and is often performed prior to lumbar
puncture (LP) to exclude impending brain herniation. NCCT is widely available, and the images are
rapidly acquired, making the examination well tolerated even by critically ill patients.
Clinically stable patients in whom immediately life-threatening conditions have been excluded by
NCCT often require further evaluation with contrast-enhanced magnetic resonance imaging (MRI), which
has a greater sensitivity for leptomeningitis, ventriculitis, cerebral abscess, and empyema as well as
downstream complications of infection such as infarctions. MRI lacks ionizing radiation, so it is
relatively safe to perform, but specific contraindications include pacemakers and other implanted metallic
devices or metallic foreign bodies. The risks and benefits of MRI should be weighed carefully in pregnant
patients. Studies have not proven any negative effects of MRI to the fetus, but the American College of
Radiology recommends deferring MRI until after pregnancy if possible (1). Because MRI acquisition time
is much longer than CT, MRI may not be feasible in critically ill patients who require intensive
monitoring. Additionally, if a patient is unable to lie still, motion artifact may significantly degrade the
images obtained.
Gadolinium contrast agents improve the sensitivity of MRI but are generally avoided in patients with
severe renal dysfunction and a glomerular filtration rate of less than 30 mL/min/1.73 m2 due to the risk for
nephrogenic systemic fibrosis (2). Administration of gadolinium-based contrast should be avoided in
pregnancy due to the unknown effects of exposure to free gadolinium ions on the developing fetus (1).
According to the American College of Radiology Appropriateness Criteria for headache (3), both
NCCT and contrast-enhanced MRI of the head are usually appropriate for patients presenting with new
headache and suspected meningitis or encephalitis, with the choice of test depending on local preference
and availability. When MRI is unavailable or contraindicated, contrast-enhanced CT may be a suitable
alternative. Cerebrovascular complications of infection are relatively frequent, and therefore magnetic
resonance angiography (MRA) and magnetic resonance venography (MRV), either with or without
contrast, may also be appropriate tests. Computed tomography angiography (CTA) may be performed
when there is strong suspicion for vascular disease or to further evaluate abnormalities detected by MRA.
Other advanced imaging techniques such as computed tomography perfusion (CTP) or magnetic resonance
perfusion (MRP), magnetic resonance spectroscopy (MRS), and nuclear medicine studies such as single-
photon emission computed tomography (SPECT) and 18F-fluorodeoxyglucose positron emission
tomography (FDG-PET) or PET/CT are usually only performed for problem solving after the standard
imaging evaluation has been performed.
For evaluation of a new headache in an HIV-positive or immunocompromised individual, MRI with or
without contrast is usually appropriate as the initial imaging test (ACR Appropriateness Criteria
“Headache” [3]). For an indeterminate cerebral mass in an immunocompromised patient, additional
problem-solving techniques such as FDG-PET/CT, SPECT, MRS, and MRP may be helpful to narrow the
differential diagnosis.
In neonates in whom the anterior fontanelle is patent, cranial ultrasound may be used to evaluate for
hydrocephalus, subdural and epidural collections, and parenchymal masses (4).
Uncomplicated rhinosinusitis is usually managed clinically without the need for imaging, but for
suspected intracranial or orbital complications of sinonasal disease, both NCCT and contrast-enhanced
MRI of the head, orbits, and paranasal sinuses are usually appropriate, with CT and MRI serving as
complementary examinations (ACR Appropriateness Criteria “Sinonasal Disease” [5]). Brain imaging is
critical if there is a concern for intracranial extension and is best accomplished with contrast-enhanced
MRI. If the patient is unable to tolerate gadolinium contrast, noncontrast MRI augmented with contrast-
enhanced CT of the head and sinuses is recommended. Immunocompromised patients with acute or
subacute rhinosinusitis are at high risk for developing intracranial or orbital complications, and therefore
the threshold for obtaining imaging should be lower than for immunocompetent patients.
PYOGENIC INFECTIONS
Meningitis
Meningitis refers to inflammation of the pia and arachnoid membranes. LP with CSF analysis is the test of
choice for diagnosis (6), and imaging plays an ancillary role.
Meningitis may be classified based on the pattern of involvement. Pyogenic and viral meningitis
typically involve the cerebral cortices. Granulomatous or chronic meningitis typically involves the basal
surfaces of the brain (basilar meningitis) and may be due to infectious or noninfectious causes. Pyogenic
infections may also produce a basilar pattern of meningitis.
The primary goals of imaging are to evaluate for contraindications to LP and to exclude unexpected
clinical mimics or complications. NCCT can satisfy these goals, but not all patients with suspected
meningitis require CT. Reported risk factors for an abnormal CT in patients with suspected bacterial
meningitis include age 60 years or older, immunocompromise, recent seizure, focal neurologic deficits,
and impaired consciousness (7). In the absence of these clinical indicators, CT may not be necessary.
Five percent of patients with acute bacterial meningitis suffer brain herniation, and herniation accounts
for 32% of deaths (8). A causal relationship between LP and brain herniation has not been proven, but
generally accepted imaging contraindications to LP include midline shift, effacement of the basilar
cisterns, and posterior fossa mass effect (8, 9). Clinical signs of increased intracranial pressure are also a
contraindication to LP.
Imaging is usually normal in cases of bacterial meningitis (10). Imaging findings supporting the
diagnosis include cerebral edema, inflammatory material in the subarachnoid spaces, and leptomeningeal
enhancement. Cerebral edema manifests as narrowed or compressed sulci, ventricles, and basilar
cisterns. Inflammatory material in the subarachnoid spaces manifests as hyperdense or enhancing material
on CT (Fig. 3.1A) and abnormal fluid-attenuated inversion recovery (FLAIR) signal hyperintensity (Fig.
3.1B), enhancement, or restricted diffusion (11) on MRI. Leptomeningeal enhancement manifests as thin,
linear enhancement extending along the sulci and basilar cisterns in a gyriform pattern (12).
Leptomeningeal enhancement should not be confused with pachymeningeal enhancement, which refers to
enhancement of the dura mater.
Imaging is also helpful to assess for complications of meningitis, including extensive cerebral edema
resulting in brain herniation, infarcts, hydrocephalus, extraaxial pus collections, ventriculitis, cerebritis,
and cerebral abscess.
Sterile subdural effusions occur with meningitis but, unlike infected extraaxial collections, generally
resolve spontaneously. Sterile subdural effusions may develop internal membranes or septations and
occasionally become infected, resulting in subdural empyema (SDE) (13). Subdural effusions occur more
often in children with bacterial meningitis and typically develop over the frontal and temporal lobes (13).
Sterile effusions appear similar to CSF in density or signal intensity or may be mildly proteinaceous,
resulting in slight signal hyperintensity on FLAIR compared to CSF. They may be mistaken for prominent
subarachnoid spaces, a normal finding in infants. One distinguishing feature is the finding of bridging
vessels crossing the collections, which are present in prominent subarachnoid spaces but not subdural
effusions (14).
Hydrocephalus is a potentially life-threatening complication of meningitis resulting from impaired
resorption of CSF by the arachnoid granulations or by diminished CSF outflow due to viscous material in
the ventricles or basilar cisterns. Hydrocephalus may be the only imaging finding in patients with
meningitis, particularly those with basilar meningitis (Fig. 3.2). In some cases, proteinaceous or
enhancing material may also be evident in the basilar cisterns on CT (Fig. 3.2A) or MRI (Fig. 3.2B).
Cerebritis
Cerebritis refers to focal brain inflammation due to any cause, including pyogenic infection (15). Unlike
meningitis, which is localized to the pia and arachnoid, cerebritis involves the brain parenchyma and may
occur adjacent to infected subdural or epidural collections.
Cerebritis has a nonspecific imaging appearance. CT findings include focal low attenuation (16) (Fig.
3.3A) without enhancement or with nodular or peripheral enhancement, which may resemble infarct or
mass lesion. MRI findings include hyperintensity on T2 and FLAIR (Fig. 3.3B) with variable
enhancement (Fig. 3.3C). There may be hemorrhage or restricted diffusion. MRI appearance may be
similar to that seen in status epilepticus, ischemia, or neoplasm.
If inadequately treated, cerebritis may develop into a cerebral abscess, following a well-described
progression through the stages of early cerebritis, late cerebritis, early abscess formation, and late
abscess formation (16,17) (Fig. 3.3C and D). Features suggesting the formation of an abscess within an
area of cerebritis include development of a ring-enhancing mass with restricted diffusion of the central
cystic or necrotic core. This is in contrast to the restricted diffusion that may be seen with cerebritis,
which affects the brain parenchyma itself.
Abscess
Cerebral abscess refers to a focal pus collection within brain parenchyma with a surrounding capsule
(15). Abscesses may result from direct extension of local infection or from hematogenous spread. Local
infections associated with cerebral abscesses include otomastoiditis, sinusitis, and odontogenic infections
(18). Bloodborne infections may be associated with intravenous drug use, bacterial endocarditis,
pulmonary infections, pulmonary arteriovenous malformations, congenital heart disease, and other causes
(18–21). Cerebral abscesses may also occur after trauma or neurosurgical intervention.
Abscesses from bloodborne infections tend to be multiple and located at the gray–white junction, most
commonly in the frontal lobes (18–21). Abscesses arising from local spread are often spatially related to
the primary infection. For example, a frontal abscess may develop adjacent to frontal sinusitis. In these
cases, the primary infection is usually visible on imaging.
Regardless of etiology, abscesses share common imaging features. On NCCT, abscesses appear as
hypodense masses with surrounding vasogenic edema, sometimes with a hyperdense rim corresponding to
the abscess capsule (16) (Fig. 3.4A). MRI also shows a localized mass with a T2-hyperintense necrotic
core and a markedly T2-hypointense rim surrounding the collection that corresponds to the capsule (22)
(Fig. 3.4B). The central core demonstrates markedly restricted diffusion (hyperintense on diffusion-
weighted image [DWI] sequence [Fig. 3.4C] and dark on apparent diffusion coefficient [ADC] maps).
Quantitative ADC values of the necrotic core are significantly lower for abscesses than necrotic
neoplasms (23).
On both CT and MRI, cerebral abscesses demonstrate thick smooth rim enhancement, sometimes with
thinning of the medial wall. Focal wall rupture results in formation of a daughter abscess (22) (Fig.
3.4D). In immunocompromised patients, ring enhancement may be absent and vasogenic edema may be
mild (15), requiring a high index of suspicion for diagnosis.
Complications of cerebral abscess include mass effect and brain herniation. It is important to evaluate
for intraventricular rupture of the abscess with resulting ventriculitis because this is a marker of poor
prognosis that requires aggressive treatment (21). Imaging findings indicating ventricular rupture include
layering debris in the lateral ventricles and enhancement of the ependymal lining.
The differential diagnosis of a ring-enhancing mass includes high-grade glial neoplasm, metastasis, and
less commonly, tumefactive demyelination or subacute infarction. Usually, the clinical scenario helps
distinguish these entities, but in difficult cases, MRP and MRS may be helpful.
MRP allows comparison of the cerebral blood volume of the lesion with that of contralateral normal
white matter, resulting in a measure of relative cerebral blood volume (rCBV). The enhancing component
of high-grade tumors demonstrates elevated rCBV (increased perfusion) compared to normal white
matter, whereas pyogenic abscesses demonstrate significantly reduced rCBV, which is less than that of
contralateral normal white matter (23,24). It is important to evaluate the enhancing rim of these lesions
rather than the central necrotic regions, which do not statistically differ.
MRS evaluates the presence and relative ratios of metabolites present in a region of interest.
Metabolites commonly evaluated include choline, a marker of cell membrane turnover; N-acetylaspartate
(NAA), a marker of neuronal integrity; lactate, a marker of anaerobic metabolism; and lipid, a byproduct
of necrosis. Creatine, a marker for energy metabolism, is often used as an internal control against which
other metabolite peaks are compared. In the central necrotic core of both tumors and abscesses, the
metabolite peaks of NAA, choline, and creatine are all depressed or absent (25). In brain abscesses,
additional metabolite peaks may be present, including amino acids, alanine, acetate, succinate, and
lactate/lipid (26). Although lactate and lipid may be present in necrotic tumors, the other metabolites are
more specific to abscesses (23,25,27). Treatment alters the metabolite profile of the central abscess
cavity and must be considered in the evaluation.
Ventriculitis
Ventriculitis may result from intraventricular rupture of an abscess, severe pyogenic meningitis (13), or as
a complication after ventricular drainage procedures. Imaging findings include layering debris within the
ventricles, which appears hyperdense on CT, hyperintense on FLAIR, and hypointense on T2 compared to
CSF (28). Infected ventricular debris may also show markedly restricted diffusion, similar to the central
core of an abscess. Hydrocephalus is usually present, and there may be enhancement of the ependymal
lining. Ventricular septations may develop as a late sequela of ventriculitis (28).
Subdural Empyema
SDE refers to an infected subdural collection, occurring between the dura and arachnoid membranes.
SDE is often associated with direct spread of infection from sinusitis or otitis media but also occurs as a
complication of meningitis, trauma, or neurosurgical procedures. Seeding of subdural effusions in infants
with meningitis, or seeding of subdural hematomas, also leads to SDE (29,30). Early recognition of SDE
is vital because urgent surgical decompression is usually required (31).
On CT, SDE appears as a hypo- or isodense crescentic subdural collection (Fig. 3.5A) with rim
enhancement (31), which may be subtle. On MRI, SDE appears as a proteinaceous subdural collection,
hyperintense on T1 and FLAIR relative to CSF (Fig. 3.5B). This is in contrast to a subdural effusion,
which follows CSF signal intensity on all sequences. SDEs are usually hyperintense on DWI (11) (Fig.
3.5C) and demonstrate rim enhancement (Fig. 3.5D), similar to other pus collections. Sterile subdural
effusions may demonstrate mild rim enhancement but do not typically demonstrate restricted diffusion
(32). Complications of SDE include dural venous sinus thrombosis (Fig. 3.5D), cerebral edema,
cerebritis, and cerebral abscess (Fig. 3.5B and C).
Epidural Abscess
Epidural abscesses are usually the result of direct extension of adjacent infections, particularly sinusitis
or otomastoiditis (33), but may also occur after trauma (30) or neurosurgical procedures. Infected
material collects between the dura and calvarium. Epidural abscesses may extend to involve the subdural
space and may be associated with cerebritis or cerebral abscesses.
Cranial epidural abscesses appear on NCCT as hypo- or isodense extraaxial collections in the epidural
space (33) that may contain gas (Fig. 3.6A). On MRI, epidural abscesses are T2 hyperintense and T1 iso-
or hypointense relative to brain, depending on the viscosity of the infectious material. There is usually
intense enhancement of the dura (Fig. 3.6B).
Coexistence of subdural and epidural collections is common, and differentiating them is sometimes
difficult, particularly by CT (31,34). MRI may help by allowing delineation of the thickened or enhancing
dura with respect to the collection (34). Additionally, like epidural hematomas, epidural abscesses tend
to be lentiform and can freely cross dural reflections such as the falx but are bounded by the cranial
sutures.
SPECIFIC ENTITIES
Tuberculosis
Tuberculous meningitis typically involves the basilar cisterns, which become filled with a thick
inflammatory exudate (35). NCCT findings may be subtle and hydrocephalus may be the only finding,
although isodense material in the basilar cisterns may be evident. Contrast-enhanced CT may demonstrate
enhancing material in the basilar subarachnoid spaces (36), which may involve the pachymeninges.
However, the absence of basilar meningeal enhancement should not preclude the diagnosis (37).
Additional findings that support the diagnosis include infarcts and tuberculomas (36,37). HIV patients
with tuberculous meningitis are more likely to have tuberculomas and infarcts rather than basilar
enhancement or hydrocephalus (35).
MRI is useful in the assessment for tuberculous meningitis and allows better visualization of basilar
meningeal enhancement (Fig. 3.7A), infarcts, pachymeningeal involvement, and tuberculomas than CT
(38). MRI may also show enhancement of cranial nerves.
Tuberculomas are punctate or large granulomatous lesions that have a variable appearance depending
on the extent of central caseation (39). On CT, tuberculomas may appear target-like with central
calcification surrounded by an enhancing rim. On MRI, tuberculomas may be uniformly T2 hypointense or
may appear target-like, with a T2-hyperintense core surrounded by a low T2 rim (39). Enhancement may
be solid, nodular, or ringlike.
Tuberculous abscesses are encapsulated masses containing pus and viable mycobacteria that occur
more commonly in immunocompromised patients (40). Unlike tuberculomas, tuberculous abscesses are
not primarily granulomatous (35). By imaging, differentiating a tuberculoma with central caseation from a
tuberculous abscess is difficult. Tuberculous abscesses also resemble pyogenic abscesses on
conventional imaging, with rim enhancement and a central necrotic core demonstrating restricted
diffusion. MRS may help differentiate a tuberculous abscess from pyogenic abscess or necrotic tumor.
Metabolites specifically associated with tuberculous abscesses include high lipid and lactate peaks (Fig.
3.7B). Unlike pyogenic abscesses, amino acid, succinate, acetate, and alanine peaks are absent (25,26).
Lyme Disease
Lyme neuroborreliosis refers to central nervous system (CNS) involvement of Lyme disease. Although no
specific imaging findings exist, neuroborreliosis is often included in the differential diagnosis for
nonspecific white matter lesions and may share overlapping features with multiple sclerosis. Most
patients with neuroborreliosis appear normal on MRI. When imaging abnormalities exist, leptomeningeal
enhancement and cranial nerve root enhancement may be equally as common as white matter lesions (41).
The seventh cranial nerve is most commonly involved, followed by the third and fifth cranial nerves (42).
Syphilis
Neurosyphilis presents clinically in several discrete phases, with variable imaging findings in each stage.
A high index of clinical suspicion is needed for diagnosis. Imaging may be normal or may show cerebral
atrophy, nonspecific white matter lesions, parenchymal masses, or vascular complications including
infarcts (43,44). T2/FLAIR-hyperintense lesions measuring less than 1 cm occur in the deep
periventricular and subcortical white matter (43,44).
Syphilitic gummas are granulomatous lesions of the meninges that subsequently involve brain
parenchyma or dura or both and that may contain Treponema pallidum. Gummas are hypodense on CT and
T1 hypointense and T2 hyperintense on MRI, with mass-effect, enhancement, and surrounding vasogenic
edema (44,45) (Fig. 3.8). Dural thickening indicates dural involvement. Gummas typically occur in the
cerebral hemispheres but may also appear in unexpected locations, such as the pituitary gland (45).
Meningeal syphilis may manifest as meningeal enhancement on CT or MRI. Cranial nerve enhancement
may also occur, often involving cranial nerves VII and VIII (46). Syphilitic vasculitis (meningovascular
syphilis) may affect medium and large vessels (Heubner arteritis) or small vessels (Nissl-Alzheimer
type) (46). Infarctions can complicate either type. Angiographic findings of infectious vasculitis are
discussed further later in this chapter.
Neurocysticercosis
Neurocysticercosis results from CNS invasion by the parasitic organism Taenia solium and may involve
brain parenchyma, ventricles, or subarachnoid spaces. The imaging appearance varies with location and
stage of infection.
Parenchymal neurocysticercosis can be classified into four stages from acute to chronic (47), as
summarized in Table 3.1. In the vesicular stage, a thin-walled cyst forms containing the invaginated
scolex, which may be visible on FLAIR and contrast-enhanced sequences (48). During the colloidal
vesicular stage, the cyst degenerates, becomes proteinaceous, and the scolex may disappear (Fig.
3.9A–C). The granular nodular stage occurs as the cyst retracts. Vasogenic edema lessens, although
nodular or ring enhancement persists. Differentiating the colloidal vesicular stage from the granular
nodular stage may be difficult (47). Finally, during the nodular calcified stage, edema and enhancement
subside, leaving a small calcified nodule (Fig. 3.9D). MRI is best for identifying lesions in the vesicular,
colloidal vesicular, and granular nodular stages. CT is excellent at detecting lesions in the nodular
calcified stage (47), as is MR gradient-echo sequence.
Intraventricular neurocysticercosis may occur alone or in conjunction with parenchymal
neurocysticercosis. Imaging findings include cystic lesions within the ventricles, commonly in the fourth
ventricle (47). There may be associated noncommunicating hydrocephalus. Cysts usually are thin walled
and contain CSF-like fluid, making them difficult to see on standard MRI sequences. High-resolution
heavily T2-weighted MRI sequences (MR cisternography) may help to delineate the cyst walls.
Neurocysticercosis may also involve the subarachnoid spaces, particularly the basilar cisterns, and
appears as multilobular cystic lesions (“racemose” neurocysticercosis) (Fig. 3.9E). The scolex is often
not visible.
Creutzfeldt-Jakob Disease
Creutzfeldt-Jakob disease (CJD) is a prion disease that may be sporadic, hereditary, or acquired from
exposure to infected CNS tissue. Variant CJD (vCJD) most commonly occurs after consumption of meat
from cows infected with bovine spongiform encephalopathy. Kuru occurs with cannibalism. Iatrogenic
CJD occurs with surgical exposures such as corneal transplantation. Most cases of CJD are sporadic
(sCJD) (49). The imaging appearances of sCJD and vCJD have been best described.
MRI is the preferred imaging modality (49) to support the diagnosis and exclude other etiologies.
Criteria to support the diagnosis of sCJD include DWI or FLAIR signal hyperintensity in the caudate
nucleus and putamen (Fig. 3.10A), with involvement of at least one cortical gyrus or involvement of more
than three cortical gyri (50) (Fig. 3.10B). The precentral gyrus is usually spared (51). Globus pallidus,
thalamus, and periaqueductal gray matter may be involved (49). Cortical atrophy occurs with disease
progression.
vCJD is associated with the “pulvinar sign”—symmetric FLAIR signal hyperintensity in the pulvinar
nuclei of the thalamus (52). The dorsal medial nucleus of the thalamus may also be hyperintense (“hockey
stick sign”) (49,52), as may be the tectal plate, periaqueductal gray matter, or cerebral cortex. Cortical
atrophy may occur but is usually less severe than with the sCJD.
VIRAL INFECTIONS
Viral infections of the CNS manifest variably as meningitis, encephalitis, myelitis, radiculitis,
postinfectious encephalomyelitis, or various combinations thereof. Unlike most bacterial and fungal
infections, the intracranial imaging findings in viral encephalitis may predict a specific causative
organism (Table 3.2).
Viral Meningitis
Uncomplicated viral meningitis is usually diagnosed by clinical presentation combined with CSF
evaluation. Enteroviruses are the most frequent cause (53). Imaging may be normal or may show cortical
leptomeningeal enhancement on contrast-enhanced CT or MRI (12). Viral meningitis is less likely than
bacterial, fungal, or tuberculous meningitis to produce FLAIR signal hyperintensity in the subarachnoid
space (54), but this finding is not reliable for distinguishing the entities.
Herpes Simplex Virus
Herpes simplex virus (HSV) type 1 is the most common cause of sporadic acute viral encephalitis, and
early diagnosis and treatment are critical to limit morbidity and mortality. Although all patients suspected
of having HSV encephalitis should receive prompt treatment regardless of imaging findings, it is
important to recognize the characteristic imaging features because these may precede clinical suspicion of
the disease.
Infection usually begins in the anterior and medial aspects of the temporal lobe(s) but may extend to the
lateral temporal lobes, inferior frontal lobes, insular cortex, and frontal and parietal cingulate gyri.
Findings may be unilateral or bilateral. Extension to the pons may occur through retrograde viral spread
along the trigeminal nerve (55). CT may be normal initially or may show low attenuation in the affected
regions, sometimes with associated mass effect, gyral enhancement, or petechial hemorrhage (56,57) (Fig.
3.11A). MRI is more sensitive for early disease and better demonstrates the edematous changes as
T2/FLAIR-hyperintense areas (Fig. 3.11B) with concomitant decreased T1 signal intensity (55,58). DWI
may show restricted diffusion (Fig. 3.11C), which may precede findings on other sequences (59–61).
Hemorrhages occur with disease progression and are demonstrated with high sensitivity on MRI as
petechial areas of intrinsic T1 signal hyperintensity or as susceptibility artifact on gradient-echo
sequences. Variable enhancement may also develop at this stage. Progressive encephalomalacia occurs
over several weeks, often leading to marked temporal lobe atrophy (Fig. 3.11D) with associated seizure
disorder.
The differential diagnosis includes infarct, glioma, limbic encephalitis (paraneoplastic syndrome),
Rasmussen encephalitis (chronic viral encephalitis), and other viral infections, such as arboviral
encephalitis. Bilateral abnormalities, sparing of the basal ganglia, and involvement of both medial and
lateral portions of the temporal lobes (posterior cerebral artery [PCA] and middle cerebral artery [MCA]
vascular territories) are all features that increase the specificity for HSV.
Advanced techniques are not typically required for diagnosis but may be helpful for problem solving.
Both CTP (62) and SPECT (63) show hyperperfusion of the involved areas acutely. MRS may show
decreased NAA and increased choline levels acutely, which can mimic neoplasm (64). Follow-up
conventional MRI usually distinguishes these entities however, because HSV leads to atrophy, whereas
infiltrating glioma persists or progresses (64,65).
Varicella-Zoster Virus
Neurologic manifestations of varicella-zoster virus (VZV) may occur in the setting of primary infection
(chickenpox) or reactivation (shingles). Reactivation is usually associated with immunosuppression or
normal age-related declining immunity. VZV infection is distinct among viral infections in that it causes a
vasculopathy, which may involve either small or large vessels. Small artery involvement may lead to
monocular visual loss. Large artery involvement classically leads to ischemic infarctions. Other
manifestations of vasculopathy include subarachnoid hemorrhage, aneurysm formation, and arterial
dissection (66). Parenchymal lesions in VZV infection characteristically occur at the gray–white interface
but may also occur in the cortical gray matter and deep white matter. Multiple lesions at the gray–white
interface should specifically suggest VZV vasculopathy in the right clinical setting, along with the
differential diagnosis of emboli and metastases. VZV vasculopathy may coexist with meningitis,
radiculitis, and myelitis and may occur with or without rash (66).
Arboviruses
Arthropod-borne viruses, also known as arboviruses, constitute an important cause of viral
meningoencephalitis worldwide. Examples from this diverse group include the viruses causing Eastern
equine, Western equine, Venezuelan equine, West Nile, Japanese, St. Louis, California, Murray Valley,
and tick-borne encephalitides. Affected patients may have normal MRI findings or may have signal
abnormalities on T2, FLAIR, or DWI. Classically, lesions are located in the basal ganglia and thalami
bilaterally (Fig. 3.12), and this imaging pattern should strongly suggest arboviral encephalitis in a
potentially exposed patient. The differential diagnosis includes anoxic or hypoxic encephalopathy, toxic
exposures such as carbon monoxide poisoning, metabolic disorders such as Wilson disease and
mitochondrial abnormalities, and other entities such as CJD.
The basal ganglia and thalami are classically involved in arboviral infections, but additional
nonspecific areas of involvement include the meninges, the brainstem and spinal cord, the cortical gray
matter, and the cerebral and cerebellar white matter (65,67,68). Leptomeningeal or parenchymal
enhancement is variable. Isolated substantia nigra lesions have been reported with St. Louis encephalitis
(69). Arboviral encephalitis commonly involves the mesial temporal lobes, but involvement of the basal
ganglia and thalami with relative sparing of the anterior portions of the temporal lobes help to distinguish
arboviral infections from HSV (65).
Acute Disseminated Encephalomyelitis
Acute disseminated encephalomyelitis (ADEM), also known as postinfectious or postvaccination

encephalitis, is an inflammatory autoimmune demyelinating condition that typically begins abruptly 2 to 3
weeks following a viral illness or vaccination. In contrast to multiple sclerosis, ADEM follows a
monophasic course lasting several weeks.
CT may be normal or may show nonspecific areas of low attenuation (Fig. 3.13A). Lesions may show
peripheral enhancement (70–72). MRI is more sensitive, but lesions may not be visible until several days
after the onset of symptoms (73). Like other demyelinating lesions, ADEM lesions have high T2 and
FLAIR and low T1 signal intensity. They are located most commonly in the supratentorial white matter
(Fig. 3.13B) and are often multiple, bilateral, and asymmetric, although involvement of the deep gray
structures may be symmetric (74). Lesions may be small and round or large and irregular, sometimes with
a central T2-hyperintense portion creating a “fried egg” appearance (75). Mass effect and surrounding
edema are typically absent. “Tumefactive” demyelinating lesions and rare hemorrhagic forms of ADEM
may show surrounding edema (74,75). A peripheral incomplete ring of enhancement, the “open ring” sign,
may occur in lesions that partially abut white matter and cortex (Fig. 3.13C). In this situation, only the
white matter edge enhances, a sign that is highly specific for demyelinating lesions and only rarely occurs
with neoplasms or abscesses (76,77). Other patterns of enhancement observed in ADEM include closed
ring, solid, nodular, or gyral enhancement (74,75). Patterns of signal abnormality on DWI are variable
(78,79), and single lesions may have heterogeneous signal intensity on DWI and ADC map (80).
MRS shows selective reduction of NAA initially, with normal levels of the other metabolites. NAA
returns to normal levels on follow-up imaging (81). Elevated choline and/or lactate may also be observed
(79,82) (Fig. 3.13D), resembling other demyelinating conditions and brain tumors. MRP usually reveals
hypoperfusion (Fig. 3.13E) (80), which may help to distinguish ADEM from neoplastic lesions.
ADEM lesions usually either resolve or improve on follow-up imaging, although sometimes there is
residual gliosis. Clinical resolution may precede radiographic resolution (73). A subset of patients may
have a relapsing form of the disease resembling multiple sclerosis. The terms multiphasic or recurrent
ADEM, however, should be reserved for cases in which new MRI lesions develop or recur at least 3
months after the initial demyelinating event and longer than 4 weeks after completing steroid therapy (74).
These criteria help to distinguish relapse from monophasic disease with a protracted course or an
incomplete response to treatment (83).
Supratentorial white matter lesions are most common in ADEM, but lesions may also occur in the deep
gray nuclei, infratentorial white matter, spinal cord, and optic nerves (71,83). Lesions may sometimes be
isolated to the infratentorial white matter (Fig. 3.13F).
HIV
Patients infected with HIV may have imaging findings related directly to HIV infection in the CNS or
related to opportunistic infections. Associated opportunistic infections include viral diseases such as
progressive multifocal leukoencephalopathy (PML) and cytomegalovirus (CMV) infections and fungal
infections such as Cryptococcus infection and coccidioidomycosis. Tuberculosis and syphilis are also
increasingly prevalent in HIV-infected patients.
Direct effects of HIV infection include generalized cerebral volume loss and symmetric patchy or
confluent periventricular white matter low attenuation on CT and signal hyperintensity on T2 and FLAIR
(Fig 3.14), with corresponding isointensity on T1-weighted images. There is no contrast enhancement or
mass effect (40). HIV infection may be difficult to distinguish from chronic microvascular ischemia and
age-related volume loss if comparison studies are not available. Symmetry, periventricular location, and
T1 isointensity help to distinguish imaging abnormalities due to HIV from those due to PML.
OPPORTUNISTIC INFECTIONS
Immune system compromise may affect humoral immunity (B cells) or cell-mediated immunity (T cells)
and may be due to a primary immune deficiency or may be secondary to infections such as HIV, cancers
such as leukemia, and medications such as chemotherapy and immunosuppressive agents, which are used
following bone marrow or solid organ transplantation to prevent rejection. Immunocompromised patients
are prone to frequent, severe, and long-lasting CNS infections that may be caused by opportunistic
pathogens. Neutropenic patients are particularly susceptible to bacterial and fungal infections. The most
common CNS opportunistic infections to affect immunocompromised patients are discussed below.
Progressive Multifocal Leukoencephalopathy
PML is a progressive and frequently fatal demyelinating opportunistic infection caused by the JC virus, a
ubiquitous pathogen that causes disease primarily in patients with impaired T-cell immunity. The JC virus
causes demyelination by directly infecting the myelin-producing oligodendrocytes. Most cases occur in
the setting of HIV infection, hematologic disorders, organ transplantation, and treatment with the
monoclonal antibody natalizumab for multiple sclerosis or Crohn disease. The diagnosis is established by
demonstrating JC viral DNA in the CSF by polymerase chain reaction or by immunohistochemical
analysis of brain tissue, but characteristic findings on MRI (Fig. 3.15) may first suggest the diagnosis.
PML appears as confluent areas of hypoattenuation on CT and signal abnormality on MRI within the
subcortical white matter involving arcuate or “U-fibers,” sparing the cortex. MRI shows confluent areas
of T2 and FLAIR hyperintensity with progressive hypointensity on T1-weighted images and little to no
mass effect or contrast enhancement. Scant peripheral enhancement as well as restricted diffusion is
sometimes observed at the “leading edge” of demyelination (84,85). More marked enhancement and mass
effect may be observed when PML is associated with the immune reconstitution inflammatory syndrome
(IRIS), further discussed below (86–88).
Parietooccipital lobes and corpus callosum are typically affected. Unlike multiple sclerosis,
periventricular white matter is relatively spared. Lesions are frequently multiple and asymmetric
bilaterally and become increasingly confluent with progression to new areas on follow-up imaging.
Infratentorial lesions may occur, sometimes in isolation. Cerebellar lesions often have a characteristic
crescent-shaped morphology (Fig. 3.15) (85,89,90).
Although PML lesions have a fairly characteristic appearance on conventional MRI, advanced
techniques are sometimes performed. MRS may show elevated choline and depressed NAA peaks as well
as lipid and lactate peaks (91). This spectrum of metabolites reflects the underlying demyelinating
process and resembles other demyelinating conditions such as ADEM but also resembles high-grade
neoplasms. MRP typically shows hypoperfusion in the affected areas, and SPECT and FDG-PET or
PET/CT studies show reduced metabolic activity (Fig. 3.15), helping to differentiate PML from
lymphoma or a high-grade glioma.
The imaging features of PML can resemble ADEM, but the two entities can usually be distinguished
clinically. PML occurs in immunocompromised patients and has a subacute onset and progressive course
of worsening neurologic impairment and lesion enlargement on MRI. ADEM occurs in immune competent
individuals, usually children, following a viral infection or vaccination and has an abrupt onset of
neurologic impairment followed by gradual improvement clinically and radiologically during the course
of steroid treatment.
Cytomegalovirus Infection
CMV produces two distinct types of disease, one in newborns related to in utero transmission of maternal
infection and one in immunocompromised patients. Intracranial imaging findings of congenital infection
include periventricular calcifications, migrational abnormalities, atrophy, and leukoencephalopathy
(55,65,92). In acquired CMV infections that occur in the setting of immune deficiency, the intracranial
imaging findings are nonspecific but may include findings of meningoencephalitis, ventriculitis, and/or
leukoencephalopathy (40,55,65,92,93). Rarely, acquired CMV infection manifests as a space-occupying
or peripherally enhancing mass (40,90). Extracranial imaging findings of acquired CMV infection include
chorioretinitis and polyradiculitis.
The major differential diagnosis of CMV ventriculitis in an immunocompromised patient is CNS
lymphoma. Tuberculosis, toxoplasmosis, and bacterial ventriculitis are additional considerations. The
pattern of contrast enhancement may help distinguish these entities because smooth linear enhancement
favors viral or bacterial ventriculitis, whereas nodular or mass-like enhancement favors lymphoma (94).
Involvement of the corpus callosum also suggests lymphoma but can rarely occur with toxoplasmosis
(95). Definitive diagnosis of CMV ventriculitis requires polymerase chain reaction analysis for detection
of viral DNA in the CSF. Lymphoma is usually confirmed by detection of abnormal cells in the CSF or by
biopsy.
Toxoplasmosis
Cerebral toxoplasmosis usually presents clinically due to reactivation of latent infection in

immunocompromised patients (46). Toxoplasmosis appears as one or more ring- or nodular-enhancing
masses, corresponding to abscesses. T2 signal is heterogeneous and may vary according to the stage of
abscess formation and treatment effects (96). Unlike pyogenic abscesses, there is no central restricted
diffusion (97). Ring enhancement is common. The “eccentric target sign” (Fig. 3.16) refers to an
enhancing nodule along the ring-enhancing wall of the lesion, which is highly specific, but insensitive, for
toxoplasmosis (98). Typical abscess locations include the basal ganglia, thalamus, and cerebral
hemispheres at the gray–white junction (40). MRS typically shows a large lipid and lactate peak, and
perfusion studies demonstrate decreased rCBV (98).
Differentiating toxoplasmosis from lymphoma in a patient with AIDS remains a clinical conundrum
(46). FDG-PET and thallium-201 SPECT have both been used for differentiating the two entities, but the
utility of thallium-201 SPECT is variable (99–101). DWI MRI sequence may sometimes be helpful, but
there is significant overlap of ADC values between toxoplasmosis and lymphoma (102). Serial imaging
confirming expected response to antibiotic treatment, namely, resolution of ring-enhancing lesions, may be
the most helpful in diagnosing toxoplasmosis (40).
Cryptococcus Infection
Cryptococcus CNS infection may affect immunocompetent patients but is more common in
immunocompromised patients. Neuroimaging studies may be normal or may demonstrate findings of
meningitis, meningoencephalitis, or vasculitis, better depicted with MRI than CT (103). Meningitis
findings include leptomeningeal enhancement and subarachnoid space DWI hyperintensity (11). CNS
cryptococcal infection may also manifest as parenchymal mass lesion(s) or hydrocephalus.
Cryptococcus infection often results in accumulation of gelatinous exudate, which causes dilation of the
perivascular spaces and formation of pseudocysts (Fig. 3.17). These gelatinous pseudocysts favor the
basal ganglia and may have enhancing walls, particularly in immunocompetent patients (104).
Pseudocysts are hyperintense to CSF on FLAIR due to the proteinaceous contents. Prominent perivascular
spaces without gelatinous exudate also occur, in concert with cerebral volume loss, but should
demonstrate the same signal characteristics as CSF on all sequences.
Cryptococcomas may form, which are either granulomatous lesions with few organisms or
inflammatory lesions with many organisms (40). Cryptococcomas appear as a cluster of nodules that are
non- or minimally enhancing in immunocompromised patients and enhancing in immunocompetent patients
(104). There is no central restricted diffusion, unlike pyogenic abscesses. Most occur in the basal ganglia,
thalamus, and cerebellum (40).
Coccidioidomycosis
Coccidioidal meningitis may occur in both immunocompetent and immunocompromised patients and
presents as chronic (basilar) meningitis. Associated hydrocephalus is common (105,106). Vasculitis and
infarctions may complicate the infection (107). Focal-enhancing parenchymal brain lesions may occur in
severe disease as a result of direct extension of basilar meningeal disease (105). The presence of either
hydrocephalus alone or hydrocephalus with infarction is associated with higher mortality (106).
Immune Reconstitution Inflammatory Syndrome
IRIS is a complication of highly active antiretroviral therapy (HAART) that occurs in the setting of severe
AIDS-related immunodeficiency shortly after the initiation of therapy. The syndrome is characterized by
an exaggerated inflammatory response to dead, latent, or viable organisms or self-antigens and may
coexist with a variety of opportunistic infections, most commonly JC virus and Cryptococcus (108). The
imaging findings might be confused with new or worsening opportunistic infection. The diagnosis is
usually suspected when there is paradoxical clinical deterioration with imaging findings that are atypical
for a given opportunistic infection. For example, in IRIS-PML (Fig. 3.18), there may be greater than
expected enhancement or mass effect (40,86–88,108).
CEREBROVASCULAR COMPLICATIONS OF INFECTION
Intracranial vascular complications of infections may be arterial or venous and may occur in the setting of
meningitis, head and neck infections, or systemic infections. Examples include infectious vasculitis,
venous septic thrombophlebitis, septic emboli, septic (mycotic) aneurysms, and disseminated
intravascular coagulation.
Infectious Vasculitis
Cerebral vasculitis may be primary and idiopathic, known as primary angiitis of the central nervous
system (PACNS), or may be secondary to a variety of systemic vasculitides, drugs, or infections.
Infectious causes of cerebral vasculitis are potentially treatable; therefore, patients with known or
suspected infections and new neurologic deficits warrant evaluation with brain and cerebrovascular
imaging. Vascular complications of pyogenic bacterial meningitis are common and outcomes are poor,
with a high risk for stroke and associated morbidity and mortality (109,110). Diagnosis of infectious
vasculitis is usually established by characteristic clinical and radiologic signs combined with CSF
analysis using culture, PCR, and serologic tests directed toward the most common pathogens.
Pathogens known to cause infectious cerebral vasculitis include bacteria such as Streptococcus
pneumoniae (Fig. 3.19A and B), Mycobacterium tuberculosis, and T. pallidum; viruses such as VZV
(Fig. 3.19C and D); and a variety of fungi (Fig. 3.19E and F) and parasites (66,107,111–116). Any cause
of infectious basilar meningitis can potentially lead to vasculopathy involving the cerebral vessels at the
base of the brain either by inducing vasospasm or by inciting an inflammatory reaction within the vessel
walls. In VZV vasculitis, there is productive viral infection within the media of cerebral vessel walls
(66,117). It is controversial whether other viruses such as HIV also cause cerebral vasculitis, because
opportunistic infections frequently coexist (66,115).
The vascular imaging findings of infectious vasculitis are similar to other vasculitides and include
segmental vasoconstriction creating a “beads-on-a-string” appearance, irregularities of the vessel wall,
smooth vessel narrowing, dissections, occlusions, or aneurysm formation. VZV vasculitis may show
contrast enhancement of the vessel walls, possibly reflecting the underlying productive viral infection
(114). Leptomeningeal contrast enhancement on CT or MRI is variable in basilar meningitis but, if
present, may suggest infection as the cause of vasculitis. Complications of vasculitis visible on CT or
MRI include infarcts and hemorrhages, including subarachnoid hemorrhage.
Septic Thrombophlebitis
Cerebral venous septic thrombophlebitis represents an important pathway for intracranial spread of
extracranial infections from the paranasal sinuses, mastoid air cells, orbits, and other facial structures
(118,119) and may also complicate meningitis (13). Septic thrombophlebitis can involve dural venous
sinuses, cavernous sinuses, or cortical veins. High-risk patients include those with diabetes or
immunosuppression and those presenting with coalescent mastoiditis or acute bacterial or fungal sinusitis
involving the frontal or sphenoid sinuses (119). Specific patterns of septic thrombophlebitis include
sigmoid dural venous sinus thrombosis secondary to coalescent mastoiditis, superior sagittal sinus
thrombosis secondary to frontal sinusitis, and cavernous sinus thrombophlebitis secondary to sphenoid
sinusitis or osteomyelitis (Fig. 3.20), orbital cellulitis, or other facial infections.
Imaging signs of cavernous sinus thrombosis include filling defects, diminished enhancement, or an
expanded contour of the cavernous sinus (120,121). Indirect findings may include proptosis; enlargement
of the extraocular muscles; and enlargement, nonenhancement, or filling defects within the superior
ophthalmic vein(s). Occasionally, gas bubbles are present in the cavernous sinus due to dehiscence of the
sphenoid sinus walls related to osteomyelitis. Secondary arterial complications involving the cavernous
internal carotid artery may occur, including arteritis, thrombosis (Fig. 3.20A), and aneurysm formation
(Fig. 3.20B and C).
Imaging signs of dural venous sinus thrombosis include a hyperdense venous sinus on NCCT, abnormal
flow voids on noncontrast MRI, absence of the normal flow–related signal on noncontrast MRV, and
filling defects on contrast-enhanced computed tomography venography (CTV) or MRV. Findings on
noncontrast MRI or MRV may be subtle in cases of incomplete thrombosis or following partial
recanalization. Obstructive dural venous sinus thrombosis may lead to secondary complications of venous
hypertension and venous infarction, visible on CT or MRI as vasogenic edema, parenchymal
hemorrhages, ischemic or hemorrhagic infarcts, or sometimes as isolated convexal subarachnoid
hemorrhage. Multiple infarcts or hemorrhages in a nonarterial distribution may suggest the diagnosis.
Unlike arterial infarcts, which show restricted diffusion, findings on DWI are variable in venous
infarctions.
Cortical vein thrombosis may be difficult to detect by imaging. The characteristic finding on NCCT is
the “cord sign”—a hyperdense, serpiginous cortical structure corresponding to the thrombosed vein,
which does not opacify on CTV. MRI may show abnormal susceptibility on gradient echo sequences, but
this finding is often obscured by susceptibility artifact from the adjacent calvarium. Secondary
complications related to venous hypertension are similar to those of dural venous sinus thrombosis.
Septic Emboli, Septic Aneurysms, and Disseminated Intravascular Coagulation
Infectious endocarditis, as well as systemic sepsis from any cause, can lead to intracranial complications
from septic emboli, septic (mycotic) aneurysms, or complex clotting disorders such as disseminated
intravascular coagulation (DIC). Septic emboli may lead to multiple cerebral infarctions,
microhemorrhages, and microabscesses. The imaging findings on NCCT include loss of gray–white
differentiation or hypoattenuation corresponding to acute infarcts (Fig. 3.21A). MRI may show multifocal
areas of FLAIR signal hyperintensity or restricted diffusion at the gray–white interface, often associated
with small areas of abnormal susceptibility on gradient-echo images (Fig. 3.21B). Contrast-enhanced
images characteristically reveal multiple peripherally enhancing lesions at the gray–white interface, but
this finding is sometimes absent, especially early in disease. Multifocal subarachnoid hemorrhage
isolated to the cerebral convexities is another presentation of septic emboli, possibly secondary to focal
arteritis or rupture of small vessels at the sites of embolic occlusion. Convexal subarachnoid hemorrhage
may be visible on NCCT as peripheral areas of hyperdensity within the cerebral sulci or as subarachnoid
space FLAIR signal hyperintensity on MRI.
Septic aneurysms may form in association with septic emboli or as a consequence of systemic sepsis or
spread from local head and neck infections. Rupture of a septic aneurysm may result in diffuse
subarachnoid hemorrhage indistinguishable from saccular aneurysm rupture or a more localized
presentation of subarachnoid hemorrhage confined to a sylvian fissure or a cerebral convexity. On
angiography, septic aneurysms often appear irregular in shape and arise in atypical locations, usually
more distally in the vascular tree compared to saccular aneurysms.
DIC usually occurs in the setting of systemic sepsis and may also result in multiple cerebral infarcts
and hemorrhages. Multifocal convexal subarachnoid hemorrhage is another presentation of DIC (Fig.
3.22). Infarcts and hemorrhages result from clot formation, consumption of platelets and clotting factors,
and bleeding complications in multiple organ systems. The imaging findings are nonspecific and may
share overlapping features with septic emboli.
CONCLUSION
The spectrum of imaging findings in CNS infections includes leptomeningeal enhancement, extraaxial
collections, cerebritis, encephalitis, white matter abnormalities, and enhancing lesions. The pattern of
these findings, however, may aid in diagnosis of the underlying infectious agent and sometimes predicts a
specific organism. Additionally, imaging is key in evaluating complications of CNS infections, including
hydrocephalus, brain herniation, cerebral edema, infarcts, and other vascular abnormalities.
ACKNOWLEDGMENTS
We gratefully acknowledge the contribution of some illustrative cases from Dr. Mahmoud Mossa-Basha
and Dr. James Fink from the University of Washington.
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PART II ■ VIRAL INFECTIONS AND
RELATED DISORDERS
CHAPTER 4 PATHOGENESIS AND

PATHOPHYSIOLOGY OF VIRAL INFECTIONS OF THE
CENTRAL NERVOUS SYSTEM
KEVIN A. CASSADY AND RICHARD J. WHITLEY
Viral infections of the central nervous system (CNS) occur infrequently and most often result in relatively
benign, self-limited disease. Nevertheless, CNS infections have tremendous importance because of the
potential for death and neurologic damage. The highly specialized brain tissue is exquisitely sensitive to
metabolic derangements. Injured brain tissue recovers slowly and often incompletely. Even in patients
who recover fully from viral encephalitis, months may be required for return to normal function (1). The
brain and spinal cord provide diagnostic and therapeutic obstacles. On an anatomic level, the brain is
housed in a closed skull with the spinal cord suspended within a bony columnar cage. A unique
immunologic surveillance system and the blood–brain barrier further distinguish infections of the CNS
from those involving other organ systems. Pathologic processes in the CNS have limited clinical
expressions and frequently share pathogenic mechanisms. Tumors, infections, and autoimmune processes
in the CNS often produce similar signs and symptoms (2). Clinical presentation and patient history, though
frequently suggestive of a diagnosis, remain unreliable methods for determining the specific etiology of
CNS disease (2,3). Understanding the pathogenic mechanism of a disease provides a rational basis for the
development of antiviral medications and strategies for the prevention of viral CNS infections.
The pathogenesis of viral infections is multifactorial: age, immune status, cultural practices, and
genetic makeup can influence the clinical manifestations of viral infection as readily as viral load, gene
polymorphisms, receptor preference, and cell tropism. Although asymptomatic enteroviral infection
predominates, some patients progress to viral meningitis or, rarely, fulminant encephalitis (1,4). A
detailed description of the pathogenesis of the individual viral encephalitides is beyond the scope of this
chapter. Instead, general concepts of viral infection and the pathogenic mechanisms of viral CNS infection
are reviewed and specific examples developed where applicable.
DEFINITIONS
Viruses display tissue tropism and cause illness with a characteristic temporal course. The definition of
viral CNS disease is often based on both viral tropism and disease duration. Encephalitis refers to
inflammation of parenchymal brain tissue. Acute encephalitis occurs over a relatively short period of
time (days), whereas chronic encephalitis presents over weeks to months. The temporal course of slow
infections and spongiform encephalopathies of the CNS (kuru, visna, variant Creutzfeldt-Jakob disease)
overlaps with that of the chronic encephalitides. These progressive CNS diseases are distinguished by a
long incubation period, eventually resulting in death or extreme neurologic disability over months to years
(1,5).
Viral disease in the CNS can also be classified by pathogenesis. Neurologic disease is frequently
categorized as either primary or postinfectious (1). A primary encephalitis results from direct viral
entry into the CNS that produces clinically evident cortical or brainstem dysfunction. Subsequent damage
occurs as a consequence of the host immune response, but invasion by the pathogen initiates CNS damage
(6). The parenchyma exhibits neuronophagia, and viral antigen or nucleic acids can be detected (6).
Postinfectious or parainfectious encephalitis is an acute demyelinating process temporally associated
with a systemic viral infection but without evidence of direct viral invasion in the CNS and is included as
one of the causes of acute disseminated encephalomyelitis (ADEM) (6,7). Pathologic specimens
demonstrate demyelination and perivascular aggregation of immune cells but no evidence of virus or viral
antigen, suggesting an immune-mediated etiology (1). The presence of immune cells distinguishes primary
and postinfectious encephalitis from an encephalopathy.
Inflammation occurs at multiple sites within the CNS and accounts for the myriad of clinical
descriptors of viral neurologic disease. Inflammation of the spinal cord, leptomeninges, dorsal nerve
roots, or nerves results in myelitis, meningitis, radiculitis, and neuritis, respectively. Aseptic meningitis
is frequently used to refer to a benign, self-limited, viral infection causing inflammation of the
leptomeninges (1). The term aseptic meningitis is used instead of viral meningitis because a pathogen
fails to grow in conventional culture media and reflects the historic ability to diagnose and treat only
bacterial and fungal CNS infections (6,8). This misnomer hinders epidemiologic studies, because the
definition fails to differentiate between infectious (fungal, tuberculous, viral, or other infectious
etiologies) and noninfectious causes of meningitis. Meningitis and encephalitis can represent separate
clinical entities; however, a continuum exists between these distinct forms of CNS disease (1). A change
in a patient’s clinical condition can reflect disease progression, with involvement of different regions of
the CNS making it difficult to predict the extent of CNS infection early in the clinical course. A patient
may present with meningismus and be diagnosed as having viral meningitis and then progress to
meningoencephalitis with altered consciousness and focal CNS changes (6). Epidemiologic data in many
cases provide clues to the viral etiology.
EPIDEMIOLOGY
Epidemiology studies of meningitis and encephalitis potentially underestimate the true incidence of viral
CNS infections. Even when aseptic meningitis was a reportable disease, not all patients having a
cerebrospinal fluid (CSF) pleocytosis or symptoms consistent with a viral meningitis had viral cultures or
other diagnostic studies performed. An overview is difficult, because each pathogen fills a different
ecologic niche with unique seasonal, host, and/or vector properties (1) (Tables 4.1 and 4.2). Instead, it is
useful to analyze the individual agents responsible for viral brain infections in an effort to find population
patterns and trends.
Historically, laboratory techniques for identifying neurologic infections were insensitive, invasive, and
required brain biopsy. Over the last two decades, molecular detection techniques have improved the
detection of pathogen’s nucleic acids in the CSF (8,9). Despite the improved sensitivity of these
techniques, the pathogen remains unidentified in the majority of cases of encephalitis. Depending on the
study and diagnostic methods used, investigators fail to identify an agent in the majority of presumed CNS
infections (10,11). CSF viral culture rates differ based on etiology. They can often be diagnosed only
presumptively by acute and convalescent serologic testing or isolation of virus from another location in
the body (6,12). In a retrospective review of patients who had positive bacterial CSF cultures, 1 of 20
had a concomitant virus isolated from the CSF (13,14). Historically, the definitive method for virus
detection in encephalitis was brain biopsy and viral culture (1,2). Polymerase chain reaction (PCR)
techniques and other molecular biologic methods from CSF samples have replaced culture and brain
biopsy as the standard for diagnosing encephalitis for some viruses (herpes simplex virus [HSV],
enterovirus, varicella-zoster virus [VZV], and JC virus) (8,15,16). PCR has exquisite sensitivity;
however, the technique’s sensitivity can lead to erroneous diagnosis, because PCR may detect latent or
integrated viral DNA potentially unrelated to the pathogenic process (1). The introduction and testing of
new antiviral drugs will likely provide an impetus for accurate and timely diagnosis.
Acute viral meningitis and meningoencephalitis represent most viral brain infections and frequently
occur in epidemics (1). Enteroviruses cause an estimated 60% to 90% of cases, whereas arboviruses
constitute the majority of the remaining reported cases (1,8). The Centers for Disease Control and
Prevention (CDC) received notification of approximately 7,200 to 14,500 cases of “aseptic meningitis”
annually (1). Most of these cases occurred from the late spring to autumn months, reflecting the increased
incidence of enteroviral and arboviral infections during these seasons (17,18). The incidence and etiology
of encephalitis varies based on geography, environmental factors, and frequency of exposure to vectors
responsible for viral transmission (19,20).
The CDC received 740 to 1,340 annual reports of persons with encephalitis from 1990 to 1993 (1).
Herpes simplex virus infection of the brain occurs year round without seasonal variation, affects all ages,
and constitutes most fatal cases of endemic encephalitis in the United States (21). Arboviruses, a group of
more than 500 arthropod-transmitted RNA viruses, are the leading cause of encephalitis worldwide and
in the United States (1). Arboviral infections occur in epidemics and show a seasonal predilection,
reflecting the prevalence of the transmitting vector (22). Asymptomatic infections vastly outnumber those
that are symptomatic. Patients with symptomatic infections may develop a mild, systemic febrile illness or
a viral meningitis. Encephalitis occurs in a minority of persons with arboviral infections, but the case-
fatality rate varies extremely from 5% to 70%, depending on viral etiology, age of the patient, and unique
host differences (1,23).
Japanese B encephalitis and rabies constitute most cases of encephalitis outside of North America.
Japanese B encephalitis virus, a member of the genus Flavivirus, occurs throughout Asia and causes
epidemics in China despite routine immunization for the virus (24,25). In warmer locations, the virus
occurs endemically (26). The disease typically affects children, although adults with no history of
exposure to the virus are also susceptible (27). As with the other arboviral infections, asymptomatic
infections occur more frequently than symptomatic infections. However, the disease has a high case-
fatality rate and leaves half of the survivors with a high degree of neurologic morbidity (27). Of note,
West Nile virus (WNV) encephalitis, a member of the Flavivirus family, has increased in incidence
strikingly in the United States (28). In 2002 alone, the CDC reported more than 3,989 cases and nearly
250 deaths. WNV infection declined in the United States such that between 2008 and 2011, only 712 to
1,356 cases were reported. There was an increase in cases (5,387) in the United States in 2012. Many of
the cases occurred in the Mississippi Valley and Southern and Central United States, suggesting an
evolving epidemiology for this introduced pathogen (Fig. 4.1)
(http://www.cdc.gov/ncidod/dvbid/westnile/surv&controlCaseCount12_detailed.htm). Rabies virus, a
bullet-shaped RNA virus of the family Rhabdoviridae, remains endemic around the world (29). Human
infections in the United States decreased over the last decades to one to three cases per year because of
the immunization of domesticated animals. Bat exposure is increasingly recognized as the source of
infection. Fifteen percent (685 of 4,470) of bats tested carried the rabies virus in one study analyzing risk
of bat exposure and rabies (30). In most cases, (22 of 24) there was no evidence of bite; however, in half
of the cases, direct contact (handling of the bats) was documented (31). There is experimental evidence
that bat-associated rabies virus variants transmit across the dermis and potentially through hair follicles
(29). Alternatively, bat bites may not have been recognized (1). In areas outside the United States, annual
cases of rabies encephalitis number in the thousands.
Postinfectious encephalitis, an acute demyelinating process, accounts for approximately 100 additional
cases of encephalitis reported to the CDC annually in historical studies (32,33). The disease historically
produced approximately one third of the encephalitis cases in the United States and was associated with
measles, mumps, and other exanthematous viral infections (1). Postinfectious encephalitis is now
associated with antecedent upper respiratory viral infection (noticeably with influenza virus) and
varicella in the United States (32). Measles continues to be a leading cause of postinfectious encephalitis
worldwide. In addition to the postinfectious process, patients with paraneoplastic syndrome and
autoantibodies to the N-methyl-D-aspartate (NMDA) autoantibodies have also been recently described
(34). Recent studies suggest that antigenic variation in the N-terminal domain of the NMDA receptor may
predispose these patients to the autoimmune encephalitis (35). The slow infections of the CNS and
transmissible spongiform encephalopathies (TSEs) occur sporadically worldwide (5). The prototypical
TSE is Creutzfeldt-Jakob disease (CJD); it occurs at high rates within families and has an estimated
incidence of 0.5 to 1.5 cases per million populations. In 1986, cases of a TSE in cattle, bovine
spongiform encephalopathy (BSE), were reported in the United Kingdom. In addition to affecting other
livestock throughout Europe that were fed supplements containing meat and bone meal, cross-species
transmission of BSE has been documented, leading to a ban in the use of bovine offal in fertilizers, pet
food, or other animal feed (5). Increases in atypical CJD cases coincided with the peak of BSE cases,
suggesting animal to human transmission (5). The report of atypical CJD (unique clinical and
histopathologic findings) affecting young adults (an age at which CJD rarely has been diagnosed) led to
the designation of a new disease, variant Creutzfeldt-Jakob disease (vCJD). From 1996 to 2011, there
have been 224 cases of vCJD reported, with 175 of these occurring in Ireland and Great Britain (World
Health Organization [WHO] Web site: www.who.int). The numbers have declined since the ban in the use
of bovine offal in fertilizers, pet food, or other animal feed. Active monitoring is still important, and
detection of BSE continues to be reported in North America (Fig. 4.2) (CDC BSE Web site:
http://www.cdc.gov/ncidod/dvrd/bse/).
Environmental factors influence infections of the CNS. Changes in behavior, cultural beliefs, and
modification of the environment result in changes in disease patterns and exposure to new infectious
agents. Arboviral infections will likely increase as populations encroach on wilderness habitats and flood
plains (1). Vaccination has further changed the character of viral CNS disease. In 1952, poliomyelitis
affected 57,879 Americans (1). Widespread vaccination has eradicated the disease currently from the
Western Hemisphere. As social and environmental changes occur globally, the character and prevalence
of CNS viral infections will also change. CNS infections must be examined in a geographic, cultural, and
environmental context as well as at the cellular, molecular, and genetic levels.
PATHOGENESIS
Viral Spread
Viruses use two basic pathways with fundamentally different steps to gain access to the CNS:
hematogenous and neuronal. Viruses must survive and multiply at the cellular level efficiently and in
sufficient quantity to infect the CNS. The mechanism of spread to the CNS is in large part determined by
viral factors, site of entry, and successful replication in intermediate cells (1). The local immune response
at the site of entry, the systemic immune responses, and the limited vascular access afforded by the blood–
brain barrier further reduce the opportunity for viral neurologic infections (1). Differences in host
physiology and mechanism of spread to the CNS further influence the clinical manifestations of neurologic
disease (1). For example, adults with herpes simplex encephalitis (HSE) have different presenting signs
and symptoms than newborn babies with HSV infection of the CNS. The route of viral spread and areas of
neurologic involvement differ based on the age of the patient and mechanism of exposure (36). The
subsequent neurologic damage and poor outcome, however, are similar (1). Subtle differences at the
epidemiologic, host, tissue, cellular, and genetic levels can alter this balance between viral exposure and
symptomatic infection.
Hematogenous Spread
Enteroviruses and arboviruses are prototypes for viremic spread to the CNS. Although the location of
viral entry differs for each family, both cause primary and secondary viremia prior to infecting the CNS.
Reviewing the necessary steps and the numerous barriers to hematogenous neurologic infection explains
the low incidence of symptomatic viral infection and the even lower frequency of viral neurologic
infections. A virus must first bypass or attach to and enter host epithelial cells to produce infection (37)
(Fig. 4.3). In addition, the cell must be permissive, providing an adequate environment for viral
replication. The initial steps involved in hematogenous spread of virus to the CNS consist of replication
at the local site of entry and primary viremia (1). Infection of a secondary tissue frequently ensues,
permitting secondary replication and an extensive viremia that seeds the CNS. Not all viruses follow this
sequence, and genetic factors of both virus and host influence the route of viral spread.
The cornified layers of dead skin cells provide a structural defense for the greatest potential infective
surface area of the human body. Layers of keratin protect the underlying epithelium from viral contact,
thereby decreasing the incidence of viral entry (1). Breaks in this defensive layer can result in higher
frequency of infection as well as more severe disease. Some vector-borne viruses bypass the cornified
epithelial layer by inoculation into the subepithelial layer or directly into the blood (1). The
nonkeratinized epithelial layer that constitutes the conjunctival, respiratory, oral, and nasopharyngeal
surfaces provides an ideal entry point for aerosolized viruses or pathogens transmitted by large droplets.
Parainfluenza and adenovirus, although uncommon, can cause primary encephalitis (1). More frequently,
however, the respiratory viruses are associated with postinfectious encephalitis (32). A mucous layer
composed of mucopolysaccharides, secretory immunoglobulins, and inflammatory cells provides a
mechanical, chemical, and cellular defense against pathogens (1). In the gastrointestinal and urogenital
systems, constant transit protects the mucosa. As in the respiratory mucosa, leukocytes and secretory
factors augment this mechanical defense. The enteroviruses tolerate stomach acid, bile salts, proteolytic
enzymes, and alkaline infusions to infect the host. Certain viruses (coxsackievirus A9) actually require
exposure to proteolytic enzymes in the gut before they can infect select cell types (1).
Once virus breaches the epithelial barrier and finds a permissive cell, primary replication occurs.
Virus then can spread and replicate in the lymph node, or it can bypass the node and enter the circulatory
system, where it seeds other tissues (arbovirus, enterovirus, measles virus, or varicella virus) (1). Local
immune responses are crucial in limiting systemic viral infection. The generation of a swift inflammatory
response can limit viremia and symptoms of infection. Some viruses resist phagolysosomal degradation,
allowing them to circulate and replicate within the protective sheath of a macrophage (38,39). Antigenic
changes and the sequestration of viral receptors provide additional mechanisms that enable viruses to
evade lymphocytes. For example, human rhinovirus 14, influenza virus, and poliovirus have receptors
embedded in a recess or “canyon” in the viral membrane (1). The virus is able to evade the immune
response by altering the molecules on the surface surrounding the highly conserved, immunologically
inaccessible receptor molecules lining the canyon. Other viruses have hypervariable sequences
surrounding a small, molecularly conserved binding sequence. The viral binding site may be smaller than
the antigenic sequence recognized by the immunoglobulin. Changes in the hypervariable molecules
surrounding the binding site allow the virus to evade immune responses without disrupting the fidelity of
the receptor binding site (40,41).
Primary viremia allows virus to seed distant locations of the body and frequently marks the onset of
clinical illness. Virus circulates in the vascular system attached to or within host cells such or as free
virus within the plasma (1). Viruses have limited access to the CNS via cerebral vessels and require
sufficient numbers of progeny to overcome the improbability of contact and entry into a permissive cell.
In rare circumstances, such as disseminated neonatal herpes infection, virus infects the CNS after primary
viremia. However, most infect an intermediate tissue prior to reaching the CNS. Viral genes may be as
important as host physiology in determining the route and degree of viral dissemination. For example, the
reovirus S1 gene determines the mechanism of viral spread in the host. The S1 gene codes for a capsid
hemagglutinin, σ1, that binds to neuron receptors. Serotypes with an intact σ1 gene spread to the CNS by
neuronal pathways, whereas σ1-deficient mutants gain access to the CNS via the hematogenous route
(42).
The liver and spleen provide ideal locations for secondary viral replication because of their highly
vascular structure. The high degree of parenchymal contact and large number of fixed mononuclear
macrophage cells also provide an excellent opportunity for host eradication of viremia (1). Viruses infect
tissues other than the liver and spleen, such as muscle, endothelium, and blood cells. These sites provide
an environment for viral replication in highly vascular locations that facilitate extensive viremia.
Secondary viremia produces high titers of virus in the bloodstream for prolonged periods of time,
facilitating the seeding of target organs. Viral genetics and host physiology determine the location and
extent of infection at these secondary sites (1).
Virus must localize in the vessels of the CNS before crossing the blood–brain or blood–CSF barrier, a
network of tight endothelial junctions sheathed by glial cells that regulate molecular access to the CNS
(43). The pathophysiology of viral transport from blood to brain and of viral endothelial cell tropism is
poorly understood. Virus infects endothelial cells, leaks across damaged endothelium, passively channels
through endothelium (pinocytosis or colloidal transport), or bridges the endothelium within migrating
leukocytes (1). Cell-associated and cell-free viruses can cross the endothelium and enter the parenchyma
or CSF. This bridging of the endothelium occurs in choroid plexus vessels, meningeal blood vessels, or
cerebral blood vessels (1) (Fig. 4.4). Once in the CSF, virus may remain limited to the meninges or may
enter the brain parenchyma across either ependymal cells or the pial linings.
Neuronal Spread
Rabies and HSV infection are prototypes of viral CNS infections that access brain by peripheral neuronal
spread. Historically, the peripheral neural pathway was considered the only pathway of viral neurologic
infection. Experiments with HSV and rabies virus performed in the nineteenth and early twentieth
centuries, combined with the discovery of the blood–brain barrier at the turn of the century, led most
investigators to conclude that all viral neurologic infections occurred by neuronal spread (1).
Contemporary data, however, show that the bloodstream provides the principal pathway for CNS
infections in humans. Some viruses (poliovirus and reovirus), previously thought to infect the CNS by the
hematogenous route, have been detected in peripheral neurons in experimental models (44). Viremia and
neuronal spread to the CNS can occur concurrently and are not mutually exclusive (1).
Neuronal spread occurs along peripheral or cranial nerves. The nerve shields the virus from immune
regulation and allows access to the CNS. Rabies virus classically infects by the myoneural route;
however, infection has been documented from corneal transplantations, and aerosolized entry has
occurred following spelunking in caves contaminated with infectious bat guano (29,45). These sources of
infection are infrequent and employ the same axonal mechanism of spread within the nerve, albeit from a
different location than the myoneural route.
Rabies virus replicates locally in the soft tissue following a rabid animal bite, although entry into
sensory nerves prior to soft tissue replication has also been documented (1). Protection by antibody-
mediated immune mechanisms in the soft tissue provides the only known method of preventing neurologic
disease and death (29). After primary replication, the virus enters the peripheral nerve. Experimental
evidence demonstrates acetylcholine receptor binding as the mechanism of myocyte entry (1). However,
viruses have also been documented in cells lacking these receptors. Once in the muscle, the virus buds
from the plasma membrane and may cross myoneural spindles or enter the nerve by the motor endplate.
The virus then travels by anterograde and retrograde intraaxonal transport to infect neurons in the
brainstem and limbic system. Viruses appear to cross the transsynaptic space between neurons by passive
transport rather than receptor-mediated transport. Recent evidence suggests rabies virus enters
projections in the postsynaptic neuron that extend into invaginations on the presynaptic side. These
projections pinch off and fuse with the presynaptic membrane, allowing the virus to spread along motor or
sensory neural pathways (1,45).
Paresthesias near the location of the animal bite and change in behavior follow over the next weeks.
These signs and symptoms correlate temporally with the axoplasmic transport of virus and infection of the
brainstem and hippocampal region (1). The infection spares cortical regions during this phase, allowing
animals to vacillate between periods of calm, normal activity and short episodes of rage and
disorientation (45). Eventually, the virus spreads from the diencephalic and hippocampal structure to the
remainder of the brain, killing the animal. Experimental rabies infections in animals demonstrate that the
mode of acquisition influences the neuroanatomic location of initial infection (1).
Viruses also infect the CNS through cranial nerves. The olfactory system is unique among cranial
nerves in that the neurons regenerate and have approximately a 1-month life span. The olfactory neurons
are not protected by the blood–brain barrier, theoretically providing direct neuronal access to the brain
(1). Animal studies have shown that HSV can infect the brain through the olfactory system as well as the
trigeminal nerve. Moreover, the inferomedial temporal lobe, the initial location of early HSV
encephalitis, contains direct connections with the olfactory bulb. The association of viral latency in the
trigeminal ganglia, the relative infrequency of HSE, and the confusing data regarding encephalitis from
HSV reactivation suggest that the pathogenesis is more complex than described earlier (1).
Host and Viral Factors Influencing Neurotropism
As illustrated in Tables 4.3 and 4.4, viruses exhibit differences in neurotropism (1). Strain and serotype
differences influence viral neuroinvasion and neurovirulence. For example, reovirus types 1 and 3
produce different CNS diseases in mice based on serotype differences in receptor affinities (1,42).
Escape mutant B4 of tick-borne encephalitis (TBE) virus also demonstrates viral differences in mouse
neuroinvasiveness. A single amino acid substitution (Tyr to His) in domain 2 of viral surface protein E
eliminates viral neuroinvasiveness without affecting neurovirulence (1). Receptor difference is only one
determinant of viral neurotropism. Other viral factors may influence neurotropism. For example,
enteroviruses in the same receptor family produce very different diseases. Coxsackieviruses B1 through
B5 readily produce CNS infections, whereas type B6 rarely produces neurologic infection. Viral genes
influence neurovirulence of HSV-1. Mutant HSV-1 viruses with either γ134.5 gene deletions or stop
codons inserted into the gene have a decreased ability to cause encephalitis and death following
intracerebral inoculation in mice as compared with wild type virus (46,47). Upon entering mouse
neuronal cells, these γ134.5 (−) mutants trigger the shutdown of protein synthesis and elicit interferon
signaling responses that limit efficient viral replication (48).
Host physiology is also important in determining the extent and location of viral CNS disease. Age,
sex, and genetic differences between hosts influence viral infections and clinical course. With respect to
HSV infection, host mutations in pattern recognition receptors important for type I interferon production
predispose patients to HSE (49). Host age influences the clinical manifestations and sequelae of a viral
infection (50). Differences in outcome are twofold: mature neurons resist virally induced apoptosis, and
younger patients can have more immature immune response to infection (51,52). Differences in
macrophage function can alter infections and disease. Moreover, macrophage processing capacity can
change with age in humans (1,38). Enteroviral infections exemplify the difference that host physiology
plays in determining the extent of viral disease. Enterovirus infections in children younger than 2 weeks of
age can produce a severe systemic infection, including meningitis or meningoencephalitis (53). Ten
percent of neonates with systemic enteroviral infections die, and as many as 76% are left with permanent
sequelae (1). In older children, however, enteroviral infections produce less severe disease. In addition
to age, physical activity may be another important host factor that determines the severity of infection.
Exercise and trauma have been associated with increased risk for paralytic poliomyelitis and may result
in an increased incidence of enteroviral myocarditis and aseptic meningitis (1,54). The frequency of
infections in groups frequently reflects epidemiologic differences in exposure. Increasingly, host
differences are recognized as equally important determinants of disease at the cellular and molecular
levels.
Central Nervous System Physiology
The blood–brain barrier limits chemical and environmental exposure to the CNS by a series of tight
endothelial junctions bound and maintained by glial cell foot processes. This barrier provides a
physiologic boundary between the metabolically sensitive neuronal cells and the chemical changes
outside the CNS (43). In addition, the endothelial cells and tight junctions provide a physical barrier to
most pathogens, limiting viral access to the CNS. As with most biologic systems, the blood–brain barrier
is more complex and heterogeneous than previously imagined. The blood–brain barrier was first
described during the late nineteenth and early twentieth century, when scientists noted that various dyes
administered intravenously failed to penetrate the CNS (1). In the 1960s, experiments certified that the
tight junctions between endothelial cells lining the cerebral vessels blocked the passage of small protein
molecules.
The tight junctions between endothelial cells provide a relatively impermeable layer to most polar
substances. Unique transport systems and enzymes further distinguish the CNS capillaries from blood
vessels in other organs. The asymmetric distribution of transport proteins in the endothelial cell
membrane creates a highly resistant, polarized cell layer that limits paracellular diffusion (55).
Hydrophilic substances cross the endothelial layer through receptor-mediated endocytosis or through
highly specific, saturable transport systems. Respiratory gases and lipophilic chemicals passively
penetrate the layer of tight junctions readily. The cerebral vessel endothelial cells also possess second-
messenger molecules that may regulate transmembrane permeability through receptor binding (55).
Substances produced during infection or chemicals secreted by cells, such as histamine and interleukins,
change the permeability of the blood–brain barrier, thus modulating entry of viruses and immune cells into
the CNS. Astrocytes are metabolically important support cells of mononuclear macrophage origin that
surround cerebral capillaries, induce tight junctions, and may regulate immune cell entry (1).
The brain is an immunologically “privileged” site into which immune cells do not readily enter.
Increasingly, scientists are discovering that immune cells reside in and circulate through the Virchow-
Robin space, a lymphatic channel lining the perivascular space in the brain (1) (Fig. 4.5). Moreover,
many of the fixed glial support cells and pericytes surrounding the vessels in the CNS can transform to
monocyte/macrophage antigen-presenting cells. The circulating lymphocytes act as surveillance cells,
detecting small amounts of antigen presented by the macrophages in the perivascular space and initiating
the immune response either within the Virchow-Robin space or peripherally at the lymph node. During
periods of infection, immune cells readily enter the CNS and fill the Virchow-Robin space (1) (Fig. 4.6).
The perivascular space provides a staging area where lymphocytes interact chemically and differentiate
prior to entering the neuropil. Cells in the perivascular space as well as cerebral capillary endothelial
cells are capable of regulating T-helper cell subsets in vitro and may influence the expression of the
immune response, dictating which cells enter the CNS. Different viruses may activate characteristic
lymphocyte subsets for entry into the parenchyma. In some cases, the immune response is instrumental in
the pathogenesis of CNS damage (1,51,56,57).
VIRAL REPLICATION IN THE CENTRAL NERVOUS SYSTEM

The fundamental principles of viral replication and cell-to-cell spread provide a framework for
examining the pathogenesis and clinical repercussions of neurologic infections. The clinical
manifestations and the severity of illness reflect the location and extent of viral replication in the CNS.
Once virus accesses the CNS, it must introduce its genome and transport proteins into the cytoplasm or the
nucleus of the mammalian cell. Once the viral genome has been uncoated, transcription and translation
proceed in a predictable and organized cascade of gene expression, culminating in the replication of the
viral genome. Translation of late viral genes produces structural proteins essential for the construction of
the next generation of viruses. Viral genomic material is packaged with structural proteins and exits the
cell (1) (Fig. 4.7). Viruses exploit essential cell activities such as protein synthesis, intracellular
transport, and cellular communication to enter the cell and replicate their genome. As in other biologic
systems, both divergent and convergent evolution has resulted in an array of mechanisms for successful
viral reproduction. As a result, numerous strategies exist for viral entry, gene expression, replication,
assembly, and egress (1). The relative speed and efficiency with which the virus replicates determine the
progression of infection.
Attachment and Entry
Attachment is an essential first step in viral infection. Multiple copies of proteins line the surface of a
virus. These capsid or envelope proteins create high-affinity bonds with host receptors and initiate viral
infection or a host cell response (58,59). Classically, this response involves viral entry but may include a
change in cellular metabolism or generation of immune responses by the cell. Temperature, pH, receptor
affinity, and the concentration of viral and host receptors influence the host–viral receptor interaction
similar to a receptor-ligand reaction. The cell receptor consists of proteins, lipids, and/or
oligosaccharides. Receptor binding provides close contact between virus and cell, facilitating but not
ensuring viral entry into the cell. Some viruses require specific chemical or proteolytic conditions before
entering the cell (60–62). For example, Semliki Forest virus requires the presence of cholesterol in the
cell membrane as well as a pH change in the endosome for entry (63). The presence of one type of
receptor for cell entry does not preclude other mechanisms of entry into a host cell.
Viral entry into the cell is essential. Although receptors have been identified, alternative entry
mechanisms are being identified for viruses (64). Studies determining the structure of viral glycoproteins
and host receptor interactions as well as experiments using viral recombinants and cell lines expressing
cellular receptors provide two methods used to characterize viral entry. Viruses can bind nonspecifically
to the cell surface; however, these nonspecific interactions do not produce a biologic response. Viruses
frequently target essential and/or tightly conserved host receptor domains. Some viruses appear to interact
with neurotransmitter receptors in the CNS. Experimental data indicate that rabies virus binds to
acetylcholine receptors on mouse myocytes (1). Reovirus 3 binds to the β-adrenergic receptor. Viruses
also bind to immunologic proteins on the surface of cells. Poliovirus, HSV, and measles virus bind to
receptors in the immunoglobulin superfamily (65,66). Hormone and cytokine receptors provide additional
targets for viral cell entry. Viruses can have more than one mechanism for entering a cell or different
receptors for different cell types (1). The number and distribution of receptors help determine viral tissue
tropism and the extent of viral CNS disease. Receptor prevalence is not the only determinant of viral
tissue tropism (1). Transgenic mice, for example, develop poliovirus infection only in limited tissue sites
despite the widespread expression of the receptor. Some viruses require the presence of certain genes and
transactivating factors to infect a cell. While a cell may contain a certain receptor, a permissive
environment for viral replication may not exist. The tissue, in such a case, is resistant to infection (67).
Enveloped viruses have different mechanisms than nonenveloped viruses for cell entry. Once the virus
binds to the host cell receptor domain, the virus can enter the cell by direct fusion or receptor-mediated
endocytosis. The receptor-bound virus frequently becomes encased in a clathrin-coated pit during
endocytosis. Other modes of endocytosis exist, and virus has been found in uncoated vesicles (1,68).
Fusion proteins contain hydrophobic regions and initiate the union of viral and cell membranes in some
enveloped viral infections. Nonenveloped viral entry is more enigmatic. Conformational changes or
proteolytic cleavage may expose hydrophobic regions of capsid proteins, enabling the protein capsid to
fuse with or embed in the cell membrane. The capsid then opens and releases the viral genome into the
cytoplasm. Endocytosis may provide the pH change or enzymes necessary for virus–cell fusion and
ensures that the cell is metabolically viable. Furthermore, it has been suggested that endocytosis delivers
the viral genome to the proper intracellular location from which replication occurs. Viral fusion, in most
cases, occurs before the endosome fuses with the lysosome.
Replication and Egress
Viral replication begins after uncoating and delivery of the genome to a satisfactory intracellular location
(68). Viruses replicating in the nucleus often contain nuclear targeting signals and can use existing cellular
mechanisms to enter the nucleus (1). Alternatively, viruses that replicate in the cytoplasm uncoat and
deliver the genome to the perinuclear area (68). The production of positive stranded viral messenger
RNA (mRNA) and the subsequent translation of gene products provide a unifying pathway for viral
infections (Fig. 4.8). Viruses use either host enzymes or specialized viral polymerases carried with or
encoded by the viral genome.
Host protein synthesis decreases at the start of viral protein synthesis in most viral infections. Viruses
have unique mechanisms for inhibiting protein synthesis and can interfere with the translation, transport,
ribosomal binding, or stability of host transcripts (1). With some viruses, premade proteins and
synthesized viral gene products decrease the transcription of host mRNA (69–71). Cellular transport of
mRNA out of the nucleus is inhibited late in adenovirus infections. Viral mRNA copies can outnumber
host mRNA or can be more efficiently transcribed, thus restricting access to ribosomes (1). For example,
poliovirus inactivates the host cap-binding protein. This alters the cell’s ability to modify transcripts and
results in less efficient translation of host proteins (1). Degradation of host mRNA is another mechanism
used by some HSV to inhibit host protein synthesis (71). Some viral gene factors act as repressors and
inhibit host mRNA export (70).
Viral protein translation occurs in a stereotyped progression. Early gene expression regulates the
transcription and translation of the remaining viral genome, inhibits host protein and nucleic acid
synthesis, and codes for enzymes necessary for viral nucleic acid replication (1). After viral nucleic acid
replication, late viral genes are selectively expressed and transcribe templates for capsid and structural
proteins necessary for virion assembly. Proteins synthesized from viral transcripts can undergo
posttranslational modification and glycosylation (72). Viruses contain regulatory proteins and promoter
sequences that control the differential expression of transcripts. Proteolytic modifications are made to the
structural protein following attachment of fatty acids and oligosaccharides in the Golgi apparatus (1). In
some cases, these proteolytic changes are necessary for producing infectious progeny. TBE virus, for
example, requires cleavage of a membrane-bound precursor protein (prM). The proteolytic change
produces a small, membrane-bound protein (M protein) that protects another membrane-bound protein
from conformational changes in the acidic secretory pathway. Viruses that contain the uncleaved prM
moiety lack fusion capability and are noninfectious (1).
Replication of the viral genome involves the synthesis of full-length, complementary genomic
transcripts that act as templates for replication of the viral genome. The efficiency and fidelity of genomic
replication influence the likelihood of disease. Defects in the viral genome cause abortive replication or
result in conditionally defective viruses that multiply only in the presence of cells or viruses carrying
complementary genes. The newly synthesized progeny genomes are transported to capsid structures,
where they enter viral capsid shells. Enveloped viruses bud from the cell membrane, whereas
nonenveloped viruses exit the cell by lysis (1).
Viral Spread in the Central Nervous System
Viral disease of the CNS requires cell-to-cell spread of the virus. The densely packed neuropil provides
a unique environment with limited extracellular space for viral dispersion. Viruses can spread through the
CNS in four prototypical ways: (a) sequential cellular infection, (b) movement in the extracellular space,
(c) neuronal axoplasmic transport, or (d) transit via migrating lymphocytes or glial cells. Viruses may
spread within the neural tissue using more than one mechanism. Few viruses infect the CNS by contiguous
cell-to-cell spread. Sindbis virus provides one example of a virus that spreads from ependymal cells
directly to glial and neuronal cells in experimentally infected mice (1). Viruses exhibit cell tropism,
frequently infecting one cell type more readily than another. For example, HSV-1 infects neurons early
during encephalitis but is not present in glial cells until late in the infection. Herpesvirus spreads in the
nervous system via axoplasmic transport in neurons (73,74). Electron microscopy has demonstrated
togaviruses within extracellular space in the CNS. Some viruses enter the CNS through a Trojan horse
mechanism via leukocytes (1,75).
Host Defense and Immunopathogenesis
Intrinsic and systemic antiviral defenses limit viral replication and infection (44,51,76). Viral replication
can activate enzymatic pathways that degrade viral nucleic acid transcripts. Other cells undergo
apoptosis, creating a nonviable environment for the virus (1). Interferon-mediated intrinsic antiviral
pathways within cells can retard viral penetration, uncoating, transcription, translation, and assembly,
representing an important factor of host resistance to viral infection (1,77–79). Interferons—type I
(interferon-α and interferon-β), type II (interferon-γ), and type III (interferon-λ)—are secreted by distinct
cells, bind to different receptors, and represent evolutionarily distinct molecules that limit viral
replication (44,80–84). Interferons activate a cascade of enzymes and kinases that inhibit protein
synthesis at different steps in the synthetic pathway. Interferons also modify the binding properties,
electrostatic charge, and receptor expression (major histocompatibility complex [MHC] antigen, βσ2-
microglobulin, and Fc receptor) of cellular membranes, further restricting viral access and replication
(1). These cytokines can enhance or suppress expression of immune cell subsets (82,85). Although
interferon can protect host cells from viral infection, some pathogens have developed resistance.
Furthermore, the inflammatory response in some cases causes damage to tissue and constitutes a
pathogenic mechanism for viral disease (57).
The presence of viral envelope proteins in the host cell membrane elicits an immunologic response.
The host immune response targets and destroys the infected CNS cells, thus limiting spread of the virus
but potentially compounding disease. For example, rabies virus causes metabolic derangement in the
neuron, usurps the cellular metabolic machinery, and inhibits the synthesis of cellular proteins (1). The
actual pathogenic cause of neuronal cell death is not known but may involve the synthesis of toxic
metabolites by rabies virus. The immune response changes the character of disease and the pathologic
findings. In paralytic or dumb rabies, patients have disease limited to the brainstem and demonstrate
reduced B-cell, interleukin, and cellular activity in response to rabies antigens (86,87). Patients with
furious or classic rabies generate brisk, late intracranial immune responses to rabies antigens. An
experimental model, involving immunosuppression, demonstrates that this late immune response
compounds CNS damage in infected animals (1).
In postinfectious encephalitis, the immune response is misdirected against the brain itself. There is no
evidence of direct viral damage or viral antigens in the CNS (1). Viral antigens can share homology with
host proteins, and the ensuing immune reaction can damage normal host tissue resembling virally infected
cells (7,88). Immune deregulation may cause immune-mediated demyelination. For example, most patients
with (post-Semple) rabies vaccine encephalitis have antibodies against myelin basic protein. Forty-seven
percent of people with postinfectious measles encephalitis have lymphocytes directed against myelin
basic protein, as compared with a 15% rate in nonencephalitic patients with measles (1). The pathogenic
mechanism of postinfectious encephalitis is not fully understood.
HIV infection is associated with a variety of CNS diseases. Patients can develop a
leukoencephalopathy with diffuse gliosis and loss of the cerebral white matter in addition to the
opportunistic infections and neoplasms associated with the disease (51,56,89,90). Pathologic specimens
show a multifocal accumulation of giant cells with focal cerebral necrosis. PCR in tissue samples
demonstrates large amounts of HIV nucleic acids in multinucleated giant cells. The viral structural and/or
regulatory proteins may be toxic to the CNS tissue (91). Alternatively, macrophages and T lymphocytes
may damage the brain by aberrant secretion of interleukin and tumor necrosis factor (1).
Transmissible Spongiform Encephalopathies
The TSEs produce clinical changes related to CNS dysfunction similar to the encephalitides (1). Unlike
encephalitis, the TSEs are slowly progressing noninflammatory CNS diseases with long incubation
periods involving the accumulation of an abnormal form of a normal glycoprotein, the prion protein (PrP)
(92). Sporadic CJD occurs between the ages of 50 and 70 years and is characterized by dementia,
tremors, and more rarely abnormal movements and ataxia. Unlike sporadic CJD, vCJD disease affects
young adults and adolescents and produces cerebellar ataxia and sensory involvement (dysesthesias) with
florid amyloid plaques detected in the brain on autopsy (5). Neurologic deterioration progresses
relentlessly in the case of vCJD and most patients die less than a year after onset of their neurologic
manifestations.
These encephalopathies differ in mode of transmission. Although most of the TSEs are experimentally
transmissible by direct inoculation in the CNS, this mode rarely occurs except for iatrogenic
transmissions (1). The scrapie agent spreads by contact and lateral transmission. There is no evidence for
lateral transmission in the case of BSE or vCJD, and all cases appear to have occurred following
parenteral or ingestion of affected materials. The transmissible agents remain infectious after treatments
that would normally inactivate viruses or nucleic acids (detergent formalin, ionizing radiation, nucleases).
Most of the experimental work on TSEs has involved analysis of the scrapie agent. The current working
model is that posttranslational alteration of the normally α-helical form of the PrP protein results in a
protease resistant β-pleated sheet structure that accumulates in neurons, leading to progressive
dysfunction, cell death, and subsequent astrocytosis. In studies on the scrapie agent, gastrointestinal tract
involvement with infection of abdominal lymph nodes occurs first, followed by brain involvement a year
or more later. Experimental subcutaneous inoculation in mice and goats also lead to local lymph node
involvement followed by splenic spread and then CNS involvement. The mode of transmission to the
CNS (direct vs. hematogenous) or the infectivity of body fluids at different stages of infection is not
known at this time.
The TSEs are currently only diagnosed by histologic examination, characteristic
electroencephalography (EEG), magnetic resonance imaging (MRI) changes, and the clinical context.
Most laboratory tests are of little value in the diagnosis. CSF examination shows normal values or
slightly elevated protein levels. The EEG in classic CJD reveals generalized slowing early in the disease,
punctuated by biphasic or triphasic peaks late in the disease with the onset of myoclonus. MRI changes
late in the illness reveal global atrophy with hyperintense signal from the basal ganglia (5). Fluid-
attenuated inversion recovery (FLAIR) MRI provides greater sensitivity and demonstrates signal intensity
changes in the cortex that are undetectable by T2-weighted spin-echo MRI. Histopathologic examination
of the brain using a specific antibody to the PrP-res protein confirms the disease. In addition, evidence of
gliosis, neuronal loss, and spongiform changes support the diagnosis. In cases of vCJD, characteristic
amyloid plaques (so-called florid plaques) microscopically define the disease. The florid plaques are not
seen in other TSEs and consist of flower-like amyloid deposits surrounded by vacuolar halos. The
detection of PrP-res in the tonsillar tissue by immunohistochemical staining is also strongly supportive of
vCJD diagnosis (5).
Clinical Correlates to Disease
Patients with encephalitis have clinical and laboratory evidence of parenchymal disease. Some viruses
(rabies, B virus) produce encephalitis without significant meningeal involvement; however, most patients
with encephalitis have concomitant meningitis (1). Most patients also have a prodromal illness with
myalgias, fever, and anorexia reflecting the systemic viremia. Neurologic symptoms can range from fever,
headache, and subtle neurologic deficits or change in level of consciousness to severe disease with
seizures, behavioral changes, focal neurologic deficits, and coma (93,94). Clinical manifestations reflect
the location and degree of parenchymal involvement and differ based on viral etiology. For example, HSE
infects the inferomedial frontal area of the cortex, resulting in focal seizures, personality changes, and
aphasia. These symptoms reflect the neuroanatomic location of infection with inflammation near the
internal capsule, limbic, and Broca regions (1). Paresthesias near the location of the animal bite and
change in behavior correlate temporally with the axoplasmic transport of rabies and the viral infection of
the brainstem and hippocampal region (94). Rabies has a predilection for the limbic system, producing
personality changes. The damage spares cortical regions during this phase, allowing humans to vacillate
between periods of calm, normal activity and short episodes of rage and disorientation (1). Alternatively,
Japanese encephalitis virus initially produces a systemic illness with fever, malaise, and anorexia,
followed by photophobia, vomiting, headache, and changes in brainstem function. Brainstem encephalitis
leads to difficulty with autonomic functions with increased risk for cardiac and respiratory instability,
reflecting infection of brainstem nuclei (1,95–97). Other patients have evidence of multifocal CNS
disease involving the basal ganglia, thalamus, and lower cortex and develop tremors, dystonia, and
parkinsonian symptoms.
Seizures are frequent during encephalitis. For example, approximately 40% of patients with HSE
develop seizures (1). EEG patterns include focal slowing, spiking, and paroxysmal lateralizing
epileptiform discharges. The cellular mechanisms for seizures are incompletely understood. This may
result from dysfunction of the smaller, inhibitory, γ-aminobutyric acid (GABA)–secreting neurons.
Although the seizures encountered in patients with HSE could be directly attributed to cellular
destruction, an alternative hypothesis for epileptogenesis in HSE centers on the uptake of virus in the long
projections of neurons. This uptake causes perturbations in the cellular machinery necessary for the
retention of acetylcholine within the nerve terminal. As a result, the excitatory neurotransmitter could leak
from the cell and ultimately trigger a seizure focus. In addition to this mechanism, suboptimal uptake of
acetylcholine by malfunctioning presynaptic and postsynaptic terminals can result in a relative excess of
the neurotransmitter and abnormal electric discharges. An excess of acetylcholine could also result from
the decreased synthesis of degradatory enzymes (such as acetylcholinesterase) as viral replication
proceeds. Finally, chronic seizure foci are known to be hypermetabolic during interictal periods. The first
stage of viral cellular infection is the inhibition of the cell’s homeostatic mechanisms. The crippled cell,
unable to maintain homeostasis, may be predisposed to disordered electric discharges (1).
Encephalitis, unlike meningitis, has higher mortality and complication rates. Case-fatality rates differ
based on the viral etiology and host factors. For example, within the arthropod-borne viral
encephalitides, St. Louis encephalitis virus has an overall case mortality rate of 10%. The mortality rate
is only 2% in children but increases to 20% in the elderly (1). Similarly, WNV meningoencephalitis
produces greater mortality rates in the elderly than in younger adults (98,99). Other viruses like western
equine and eastern equine encephalitis produce higher mortality and morbidity in children than in adults
(1).
The age, immune status, and viral etiology also influence the clinical manifestations of viral meningitis
(51,100). Patients with enterovirus meningitis often present with nonspecific symptoms such as fever (38°
to 40°C) of 3 to 5 days duration, malaise, and headache (8,101). Approximately 50% of patients have
nausea or vomiting. Although nuchal rigidity and photophobia are the hallmark sign and symptom for
meningitis, 33% of patients with viral meningitis have no evidence of meningismus. Fewer than 10% of
children younger than 2 years develop signs of meningeal irritation. Most of these children with
meningitis present with fever and irritability. Children may also present with seizures secondary to fever,
electrolyte disturbances, or the infection itself (1). The clinician must have a high index of suspicion for
meningitis especially in younger patients. In the immunocompromised host, enterovirus infection is both a
diagnostic quandary and a potentially life-threatening disease. Immunocompromised patients frequently
do not mount a brisk immune cell response, and therefore CSF analysis may underrepresent the extent of
CNS involvement.
Symptoms of meningitis (nuchal rigidity, headache, and photophobia) occur in approximately 11% of
men and 36% of women with primary HSV-2 genital infection (1,102–104). Examples exist of recurrent
HSV-2 meningitis (with or without genital lesions), although cases associated with primary infection are
more common (105,106). HSV meningitis may spread to the CSF by neuronal spread along the sacral
nerves. Alternatively, the virus may reach the CSF by hematogenous spread, as the virus has been cultured
from the blood buffy coat layer. VZV, cytomegalovirus, Epstein-Barr virus (EBV), and parainfluenza virus
have all been cultured or detected by PCR from the CSF of patients with meningitis (1). The three
herpesvirus infections occur more frequently in immunocompromised patients and rarely produce isolated
meningitis. Instead, these infections usually progress and involve the parenchyma.
CONCLUSION
Clinical symptoms produced by a disease have a pathophysiologic basis. An understanding of the
pathogenesis of viral CNS disease provides the physician with a framework for studying related
neurologic diseases. Moreover, the pathogenic mechanism of a viral disease provides clues toward the
development of antiviral medications and strategies for the prevention of viral CNS infections. Improved
diagnostic techniques are essential for advancing both research and therapy of viral neurologic infections.
Application of viral PCR and other molecular diagnostic techniques have already changed some of the
fundamental concepts of viral infection. Basic research in neurosciences and infectious diseases will
result in a better understanding of the host–virus interaction in the CNS. These advances have the
potential for improving the care of patients with neurologic diseases.
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1990;162(2):322–330.
CHAPTER 5 VIRAL MENINGITIS AND ASEPTIC
MENINGITIS SYNDROME
JOSÉ R. ROMERO
Viral meningitis can be characterized as a central nervous system (CNS) viral infection with signs of
meningeal irritation (neck stiffness, Kernig and/or Brudzinski signs) and cerebrospinal fluid (CSF)
pleocytosis but without neurologic dysfunction due to brain parenchymal involvement (1). It differs from
viral encephalitis where evidence of brain parenchymal dysfunction is manifested by an altered state of
consciousness, change in personality, or other objective signs of neurologic dysfunction (e.g., seizures,
cranial nerve palsies, abnormal reflexes, paralysis, etc.). Although it is common to discuss the two as
wholly separate entities, it is important to note that overlap between them (i.e., meningoencephalitis) does
occur following infection with many viral agents.
Almost 100 years ago, Wallgren (2) introduced the term “acute aseptic meningitis” to describe a short-
lived, self-limited, benign CNS syndrome characterized by the acute onset of the signs of meningeal
irritation in which examination of the CSF revealed a mononuclear pleocytosis and the absence of
bacteria on direct examination and by culture. In addition, no parameningeal process, acute/chronic
systemic infectious disease, or community infectious disease could be identified that could produce the
syndrome. With advances in diagnostic methodologies, it became evident that multiple infectious agents
(e.g., Lyme disease), inflammatory conditions, drugs, environmental agents, and so forth could cause the
syndrome.
It is estimated that in the United States, the annual number of aseptic meningitis cases is at least 75,000.
Viruses account for the overwhelming majority of cases (Table 5.1). Early reports indicated that mumps
virus, lymphocytic choriomeningitis virus (LCMV), and poliovirus (PV) were the major identifiable
causes of aseptic meningitis (3). As diagnostic techniques improved as a result of the development of cell
culture, the enteroviruses were shown to have a major role in causation of syndrome (Table 5.2) (4,5).
Nucleic acid amplification tests (NAATs) have bolstered this finding and led to the identification of novel
causes (6).
The incidence of aseptic meningitis is influenced by many factors, including effective vaccine
programs, sanitation, poverty, and regional endemic viruses (7–10). Previous significant causes of viral
meningitis such as PVs, mump virus, and LCMV are now rare or infrequent as a result of effective
vaccines, sanitation, or improved housing (3,5,8,11–13). Although many of the infectious causes of
aseptic meningitis are reportable (14), the true incidence of the syndrome is unknown due to incomplete
reporting, failure to test for specific agents, and because aseptic meningitis is not a reportable condition.
In Finland, a 14-year birth cohort study found the annual incidence of viral meningitis in children younger
than 14 years of age to be 27.8 per 100,000 (15). A more recent study from Greece documented the annual
incidence of aseptic meningitis to be 17 per 100,000 in children younger than 14 years of age (16). Two
studies from the United States give widely discrepant estimates of the incidence of aseptic meningitis. A
32-year (1950 to 1981) study from Olmsted County, Minnesota found that the adjusted incidence rate of
aseptic meningitis was 10.9 per 100,000 person-years (range 7.9 to 17.8 per 100,000) (8,13). The
Centers for Disease Control and Prevention reported that the national incidence for aseptic meningitis
ranged from 1.5 to 4.0 per 100,000 for the period spanning 1971 to 1981 (17). The lower incidence in the
latter report is most likely the result of passive surveillance and, therefore, underreporting. The incidence
of aseptic meningitis is greater in males and in children, particularly those younger than 1 year of age
(8,15,16).
ENTEROVIRUSES
Virology and Pathogenesis
The enteroviruses (EVs) are one of six genera (Enterovirus, Cardiovirus, Cosavirus, Hepatovirus,
Parechovirus, and Kobuvirus) in the Picornaviridae (pico, “small”; rna, “ribonucleic acid”; viridae,
“viruses”) family of viruses known to cause disease in humans. The original classification of the EVs,
based on evidence of human origin, pathology in animal models, patterns of replication in cell culture,
and physicochemical characteristics, identified 72 serotypes (18). This schema, although initially useful,
resulted to the misclassification of several EV and inclusion of several non-EV into the genus (19). The
development of experimental and computational methodologies for the study of the molecular biology and
genomic analysis of the EV allowed for refinement in the classification of and identification of the EVs.
Currently, identification and classification of the EVs is based on the nucleotide sequence of VP1, the
largest and most surface exposed of the viral capsid proteins containing important neutralizing epitopes
(20–23). Using this approach, the EVs have been speciated into four groups (enterovirus A to D)
containing more than 100 serotypes (Table 5.3) (24). In addition, this approach has revealed that several
of the “traditional” EV serotypes are actually strains of the same serotype or are not genetically related to
the EVs (echoviruses 22 and 23) (20,21,25–27).
The EVs are nonenveloped viruses 30 nm in diameter with a buoyant density of 1.30 to 1.34 g/cm−3 in
caesium chloride (CsCl) (19). The lack of an envelope confers to them relative environmental stability
where they can survive for days at room temperature. Infectivity can be preserved for weeks at −20°C or
with little or no loss of infectivity for years when stored at −70°C. Similarly, the lack of a lipid envelope
renders them insusceptible to ether, chloroform, and alcohol. The EVs are inactivated by heating to
greater than or equal to 50°C, chlorine, and formaldehyde.
The capsid of all EVs is composed of 60 units each of four structural or capsid proteins: VP1 to VP4,
alternatively known as 1A to 1D, arranged so as to give the virion icosahedral symmetry (28–33). Each of
proteins VP1 to VP3 is wedge-shaped and composed of an eight-stranded antiparallel β-barrel core. Each
of the stands is connected to the next by intervening loops that determine antigenicity, receptor specificity,
and confer capsid stability (34). The basic structural element of the viral capsid, the protomer, is initially
composed of the proteins VP0, VP1, and VP3 (35). Five protomers self-assemble to form a pentamer.
Twelve pentamers, in turn, assemble around a single strand of viral RNA to produce the immature virion.
The cleavage of VP0 to yield VP2 and VP4 completes the formation of the mature virion. VP1 to VP3, and
in particular VP1, have surface-exposed amino acids which determine the antigenic diversity and the
receptor specificity of the EV (20,33,36,37). VP4 is not surface exposed but shares close association with
the viral RNA and plays a vital role in release of the genome after viral attachment (38).
The surface topographies of the various EVs share a number of similarities. These include a plateau or
mesa located at the fivefold axis of symmetry formed by the union of five protomers. Surrounding this
plateau is a deep cleft or canyon into which a viral receptor inserts when the EV encounters a susceptible
host cell (36). Additionally, the host immune response to EV infection generates serotype-specific
antibodies directed to antigenic sites around the fivefold axis and canyon walls, thus blocking viral-host
receptor interaction and infection. Lastly, beneath the canyon floor exists a hydrophobic pocket containing
a lipophilic factor. This pocket has been the target for the development of anti-EV drugs that result in
altered receptor binding and viral uncoating (39,40).
The EV genome consists of single-stranded, positive (messenger)-sense RNA of approximately 7,400
nucleotides (nts) in length. The genome layout may be summarized as follows: VPg+5′UTR[1A-1B-1C-
1D/2A-2B-2C/3A-3B-3C-3D] 3′UTR-poly(A) (24,41). The 5′ end of the genome is covalently linked to a
small protein, VPg, essential for viral RNA replication. The genome is organized into a long 5′
untranslated region (5′ UTR) of approximately 740 nts that immediately precedes a single open reading
frame (ORF). The ORF measures approximately 6,630 nts and is followed by a short (approximately 70
nts) 3′ UTR and a terminal polyadenylated tail.
The 5′ UTR contains multiple regions of predicted higher order structure and highly conserved
nucleotide identity among the EV. This region of the genome contains elements essential for viral RNA
replication, translation of ORF, and, in the PVs, determinants of neurovirulence. Because of the highly
conserved nucleotide sequences within the 5′ UTR found among all the EV, it serves as the target for
NAATs for the detection of the EV now in common use (42,43).
Translation of the ORF by host cell ribosomes is accomplished in a nonconical, cap-independent
manner giving rise to a single polyprotein that is posttranslationally cleaved by viral and host proteinases
to yield 11 viral proteins (four structural and seven nonstructural) as well as several functional protein
intermediates. The ORF can be subdivided into three regions: P1 to P3. The P1 region encodes for the
four structural proteins (VP1 to VP4 or 1A to 1D) that comprise the viral capsid. These are organized 5′
to 3′ as VP4 (1A), VP2 (1B), VP3 (1C), and VP4 (1D). The P2 and P3 regions code for seven
nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D) that are essential for the viral life cycle. The
intermediate proteins play roles in viral replication.
Immediately downstream of the ORF is a short 3′ UTR followed by a terminal poly(A) tract. Similar to
the 5′ UTR, the 3′ UTR is predicted to have higher order structures and play a role in genome replication
(44).
Following binding of the EV to a host cell receptor, conformational changes in the virion result in
release of the viral genome into the cytoplasm of the host cell. The RNA genome is replicated through a
double-stranded RNA intermediate that is formed by the EV RNA-dependent RNA polymerase (3D).
Despite more than 100 years of study of the pathogenesis of EV infections, much still needs to be
learned. Most of what is known stems for the study of PV types 1 to 3 using information derived from
human disease and nonhuman primate, murine, and, most recently, transgenic (Tg) mouse models
expressing the PV receptor, PVR or CD155 (45–50). It is likely that the non-PV EVs share similar
mechanisms of pathogenesis.
The majority of the EVs are transmitted via a fecal-oral route. In addition to direct person-to-person or
fecal-oral transmission, experimental or clinical evidence exists for the transmission of the EV via
houseflies, housefly-contaminated food, water, and sewage (51–54). Bivalves have been found to
accumulate EV (55,56). However, their role in transmission has not been established. Notable exceptions
to fecal-oral transmission include coxsackievirus (CV)-A21, EV-D68, and EV-D70, which may spread
via contaminated fomites or ocular and respiratory secretions. Evidence for transplacental transmission
exists, leading to congenital infection (57–61).
Following ingestion of the EVs, infection of the cells of the nasopharynx and, more significantly, the
lower gastrointestinal (GI) tract occurs. The inherent acid-resistance of the EV favors the latter.
Replication in the lymphatic tissues of these sites (i.e., tonsils and Peyer patches) leads to shedding of the
EV from the nasopharynx for 1 to 2 weeks and from the GI tract in feces for several weeks to months (7).
Seeding of EV to the deep cervical and mesenteric lymph nodes ensues and results in their spread to the
systemic circulation via the lymphatics. This primary or minor viremia leads to seeding of various organs,
including the CNS, liver, lungs, skin, and heart. Further replication in the tissues of those organs results in
a major (secondary) viremia. If the CNS was not seeded during the initial viremic episode, spread there
may occur with the major viremia. Viremia or presence of virus in the CNS continues until the host
develops type-specific neutralizing antibodies directed to the capsid proteins, usually by day 7 to 10
postinfection. Immunoglobulin A (IgA) antibodies appear in the respiratory and GI tracts 2 to 4 weeks
after infection. Unlike other viruses, which are largely contained by cellular immune mechanisms, the EVs
are cleared from the host primarily by antibody-mediated mechanisms.
Great strides have been made in understanding the pathogenesis of EV infections at a molecular level.
The presence of an EV receptor is the primary, but not the sole, determinant for cellular infection (62). As
stated previously, PVR has been shown to be the receptor for the PVs (62) and maps to chromosome 19.
PVR is a member of the immunoglobin superfamily and functions as an adhesion molecule. It helps to
form adherens junctions and is a recognition molecule for natural killer cells. In addition to PVR, at least
11 other cell proteins have been identified as receptors or coreceptors for other EV serotypes (Table 5.2)
(63–66).
The exact identity of the cells in the upper and lower intestinal tract infected by the PVs is unknown.
However, they have been identified within the ileal wall and mesenteric nodes in human infection
(45,49,50). It is believed that the PV infect either lower GI cells expressing the PVR or use transcytosis
through microfold (M) cells in the lower GI tract to gain access to lymphoid tissue. Supporting this is the
finding of PVR on the surface of intestinal epithelium, M cells, and in the germinal centers of Peyer
patches (67). Support for the latter comes from the finding that M cells can bind and endocytose PVs
(68,69).
Why the majority of EV infections do not result in clinically apparent infection (70–73) comes for a
number of studies that suggest that replication of PV in extraneural tissues is inhibited by the host
interferon (IFN) response. PVR Tg mice that are IFN α/β receptor deficient are highly susceptible to PV
infection, and PV replication in the small intestine is enhanced (74,75). Thus, IFN responses may be
crucial in limiting the spread of EV infection.
Lastly, the mechanism of EV entry into the CNS remains unclear. Evidence for two pathways exist for
PV: transit through the blood–brain barrier (BBB) or via retrograde axonal transport. For the
development of paralytic disease in chimpanzees, viremia has been shown to be essential (76). This
finding provided initial support that the BBB may be a route to the CNS. Endothelial cells may express
EV receptors that may influence tissue susceptibility to the EV (77) and facilitate virus entry into the CNS
and other organs. Further buttressing of this hypothesis came from the finding that cultured human brain
microvascular cells can support PV replication (78,79). However, in other studies, pharmacokinetic
analysis of PV injected into Tg and non-Tg mice indicated that PV was delivered to the brain in
significantly greater amounts than would be expected from the vascular concentration (80). This suggests
that PV may enter the CNS via the BBB but without need of PVR.
Evidence in humans supports EV access to the CNS via a neural route. Individuals inadvertently
inoculated with an incompletely inactivated PV vaccine developed initial paralysis in the limb receiving
the vaccine (81). Trauma to a limb preceding PV infection has been associated with the development of
paralysis of that limb. “Provocation poliomyelitis” following intramuscular injections into an extremity of
a person incubating wild type PV or those receiving live attenuated PV vaccines has been well
documented (82,83).
Substantial evidence from nonhuman primate and murine models exists in support of EV access to the
CNS via a neural route. In monkeys, inoculation of the sciatic nerve with PV results in viral spread along
the inoculated nerve and the spinal cord (84). The initial limb to develop paralysis following
intramuscular inoculation of PV in monkeys and Tg mice is the one injected (85–87). If the sciatic nerve
of the intramuscularly inoculated lower extremity is frozen or transected, paralysis of the limb is
prevented (84,87). In Tg mice, it has been shown that in provocation PV, there appears to be induction of
retrograde axonal transport (88). PV may gain access to neurons at the level of the neuromuscular
junction.
The search for viral genomic determinants of neurotropism and neurovirulence has focused on the PVs
(89). After immunization with live, neuroattenuated vaccine (Sabin) PV strains, shedding of PV that has
recovered the ability to cause paralysis (i.e., neurovirulent revertant strains) occurs routinely.
Comparison of wild type, vaccine, and revertant PV strains has identified a 10-nucleotide region within
the 5′ UTR (nts 472 to 484 relative to PV type 3 Sabin strain) where neuroattenuating mutations are found
to cluster. Additional minor determinants of virulence are localized to amino acids encoded in the P1 and
P3 regions. The search for determinants of neurovirulence in other EV has been unsuccessful.
Histopathology
The benign nature of EV meningitis has made human pathologic data for this disease sparse. A report of a
child who died of CV-B5 myocarditis with concomitant meningitis describes inflammation of the choroid
plexus of the lateral and fourth ventricles, fibrosis of the vascular walls with focal destruction of the
ependymal lining, and fibrotic basal leptomeninges (90). Parenchymal findings were limited to moderate
symmetric dilation of the ventricles and an increase in the number and size of subependymal astrocytes.
The inflammatory reaction at the choroid plexus supports the concept of viremic spread to the CNS. An
adolescent presenting with a similar constellation of findings died of systemic CV-B3 infection (91). The
dura was grossly distended with swelling also of the pia, arachnoid, and brain parenchyma.
Microscopically, round cell infiltrates were noted in the meninges overlying the cerebellum; the brain
parenchyma was congested with increased numbers of oligodendrocytes. Lymphocytic infiltration was
most prominent around blood vessels in the cerebral white matter and in the basal ganglia, again
suggesting viremic CNS access; focal areas of necrosis and hemorrhage were also seen (91).
Epidemiology
The EVs have a ubiquitous worldwide distribution; humans are their only natural reservoir (58,92). It is
estimated that they result in more than 1 billion annual infections worldwide (22). In the United States
alone, the non-PV EVs are estimated to cause 30 to 50 million infections each year. Due to underreporting
of EV infections (93), a well-grounded estimate of the number of cases of EV meningitis that occurs each
year is not possible. However, conservative estimates place the annual number to be between 30,0000
and 75,000 cases (22,94). The EVs are responsible for 80% to 90% of identifiable causes of viral
meningitis (94–97). Wild type PV were eradicated for the West Hemisphere in 1991 (98) and are
currently endemic only in Afghanistan, Nigeria, and Pakistan (99). As such, they do not contribute to the
burden to EV in most of the world.
In regions with temperate climates, the non-PV EV exhibit marked seasonality with the majority of
infections occurring in the summer and fall (Fig. 5.1) (92,100,101). This being said, EV infections do
occur during the winter, warranting their inclusion in the diagnostic evaluation of aseptic meningitis
during that time of year (102–106). In tropical and subtropical areas, EVs occur year-round, but with
higher incidence during the rainy season.
Despite the existence of more than 100 serotypes of EV, only a limited number are responsible for the
majority of disease observed annually in each geographic region (58,93,107–110). The rank of each
serotype within the most frequently isolated EVs varies annually and geographically. In the United States,
15 serotypes accounted for approximately 80% of all EVs reported from 1970 to 2005 (in descending
order): echoviruses (E)-9, -11, -30, CV-B5, E-6, CV-B2, CV-A9, E-4, CV-B3, E-7, CV-B4, E-18, CV-B1,
E-3, and -5 (93). Some serotypes cycle with varying periodicity within a community (58,93,109,110), a
reflection of the availability of new susceptible host populations (especially children). Other serotypes
appear de novo as novel epidemic-associated viruses (111). Around the world, the serotypes most
commonly isolated from the CSF and, therefore, from cases of meningitis or meningoencephalitis, belong
to the Enterovirus B species (93,108,112,93,113,–114). In the United States, the serotypes most frequently
isolated from CSF specimens over a 36-year period, in descending order of frequency, are E-9, -11, -30,
CV-B5, E-6, CV-B2, CV-A9, E-4, CV-B4, E-7, -18, and -5 (93).
Outbreaks of EV meningitis are common. Large nation- and community-wide outbreaks involving
thousands of individuals have been well documented (115,116). Outbreaks involving more localized
venues such as neonatal units, nurseries, daycare centers, orphanages, schools, pools, camps, and sports
teams occur (53,117–122). Sequential episodes of EV meningitis involving different serotypes have been
reported to occur within a month of each other (123–125). Mixed infections involving EVs, other viruses,
or bacteria have been well described (102–130).
Children represent the overwhelming majority of cases of EV meningitis. An incidence peak among
young infants and school-aged children ages 5 to 10 years has been reported in multiple studies
(58,131–133). Occasional outbreaks of EV CNS infections occur predominantly among adults (134–136).
A possible explanation for these findings may lie in the history of the particular serotypes in the
geographic area studied. Serotypes with “endemic” patterns, those occurring with significant incidence
annually, are most likely to affect only the youngest children because of their absence of previous
exposure and immunity. Older children and adults are more likely to predominate in an outbreak of a
serotype that has not been present in a community for several years, thereby creating a reservoir of
susceptible individuals among children born since the last appearance of that serotype.
Host factors that predispose to EV meningitis, other than young age and immunodeficiency, have been
difficult to identify. A slight male-to-female predominance in the incidence ratio for EV infections has
been noted in large series. However, in a recent report, male predominance was present only among
persons younger than 20 years of age (male/female ratio 1.4:0.9) (101). This most likely represents the
larger number of females exposed to young children who are principal source of household exposure.
Infection rates are higher among persons of lower socioeconomic status, in areas of crowding, and larger
families (7).
Clinical Manifestations
The clinical manifestations of aseptic meningitis do not significantly differ among the non-PV EVs causing
the syndrome (9,137). However, clinical manifestations do vary with the age and immune status of the
patient. Meningitis or meningoencephalitis, singularly or in combination with other syndromes, are
common manifestations of symptomatic EV infection in neonates and young infants. Two large
retrospective reviews have documented that 62% of infants younger than 3 months of age with group B
coxsackievirus infections and 27% of neonates younger than 2 weeks of age with infections due to the
echoviruses had associated meningitis or meningoencephalitis (60,138). In two prospective studies,
clinical or laboratory evidence of meningitis was found in 42% to 75% of neonates with EV infection
(139,140).
Early presentation of EV infection following birth suggests transplacental, intrapartum, or immediate
postpartum acquisition of virus (60,138,139). Maternal illness (fever, symptoms of upper respiratory tract
infection, abdominal pain) has been reported to occur in 14% to 68% of infected neonates (60,138–141).
In neonates, fever (≥38.0°C) is almost universal and accompanied by any or all of the following
nonspecific signs: irritability, lethargy, poor feeding, emesis, and upper respiratory tract findings
(60,139,140,142). On physical examination, the fontanelle may be full or bulging. Signs of meningeal
irritation such as nuchal rigidity, Brudzinski, and Kernig signs are generally absent. An exanthem may be
present. If encephalitis in addition to meningitis (meningoencephalitis) is present, the neonate may present
with profound lethargy, seizures, and focal neurologic abnormalities that suggest herpes simplex virus
(HSV) infection. In some newborns, encephalohepatomyocarditis syndrome may develop in which signs
and symptoms of severe hepatitis and myocarditis are superimposed on those of meningoencephalitis
(143). Disseminated intravascular coagulation and other findings of “sepsis” result in an illness that may
be indistinguishable from that caused by overwhelming bacterial infection.
In infants and children, following an incubation period of 5 to 10 days, the onset of EV meningitis is
usually abrupt with fever (38° to 40°C), the most common presenting sign (137,143–147). The natural
history of EV meningitis is depicted in Figure 5.2. The fever pattern may be biphasic, initially appearing
in association with nonspecific constitutional signs and symptoms followed by resolution and
subsequently reappearing with the onset of meningeal signs (137,148). Headache is nearly always present
in those individuals old enough to report it. Interestingly, it may be ameliorated following the performance
of a lumbar puncture, indicating that it may be the result of increased intracranial pressure (149,150).
Photophobia is commonly reported. Infants and young children may be irritable or, less commonly,
lethargic (142). Nonspecific findings, singly or in combinations, include anorexia, exanthems, malaise,
sore throat, abdominal pain, nausea, emesis, and myalgias (144,147). In infants, the fontanelle may be full
or bulging. Less than 5% of infants younger than 3 months of age have signs of meningeal irritation (142).
However, these become more common in older patients (144,147,151,152). Seizures are noted in less
than 5% of children (142,146). Other uncommon complications include coma, increased intracranial
pressure, and inappropriate secretion of antidiuretic hormone (142,153). The duration of EV meningitis in
infants and children is generally less than 1 week.
Fewer clinical reports exist documenting the presentation of EV meningitis in adolescents and adults
(134,136,154–157). Headache is the most frequently reported symptom and is nearly uniformly present.
The severity of the headache may be such as warrant the use of narcotic analgesics in order to control the
pain (157). Photophobia, fever, signs of meningeal irritation, nausea, emesis, and neck stiffness occur in
more than 60% of cases. Other less frequently encountered signs and symptoms include myalgia,
exanthems, and abdominal pain. Full recovery takes longer in adolescents and adults and may require up
to 2.5 weeks (157).
In individuals with humoral immunodeficiencies (X-linked agammaglobulinemia, X-linked hyper IgM
syndrome, common variable immunodeficiency), EV infection may result in chronic meningitis or
meningoencephalitis that may last for years and often have a fatal outcome (158–161). In addition to the
common signs and symptoms of EV meningitis mentioned previously, neurologic manifestations include
paralysis/paresis, seizures, cognitive impairment, developmental regression, sensorineural hearing loss,
coma, dysarthria, hydrocephalus, and aphasia. Extra CNS manifestations occur singly or in combination in
a significant number of cases and include dermatomyositis, chronic hepatitis, arthritis, myocarditis, and
subacute lumbosacral polyradiculopathy. In patients who have undergone repetitive, sequential lumbar
punctures, the cell culture detection of EV in CSF has been intermittent. However, using NAATs, evidence
of their persistence in CSF has been documented (162). Treatment with antibody preparations
intravenously and intrathecally or intraventricularly has resulted in stabilization of some of these patients;
however, viral persistence has been documented during therapy (159,162,163). With the availability of
intravenous preparations of immune globulin and the early recognition of this illness, fewer patients
appear to be progressing to the classic description of this disease, and atypical neurologic presentations
have appeared. The mortality rate in patients with humoral immunodeficiencies may be as high as 50%.
The infected neonate is at greatest risk of severe morbidity and mortality when signs and symptoms
develop in the first days of life (60,138,139,164). Neonates infected with CV-B4 were found to be higher
risk of death than those infected with other EV. The short-term prognosis of young children with EV
meningitis early in life appears to be good; however, there has been some controversy over possible later
sequelae. Neurologic, cognitive, developmental, and language abnormalities have been reported in
controlled studies of long-term outcome in children with EV meningitis during infancy (165–168). In the
largest and most meticulously controlled study, however, no differences between patients and controls
could be demonstrated in any of the neurodevelopmental parameters studied (142). Less well studied are
the ultimate outcomes of aseptic meningitis cases in older children and adolescents; preliminary data
suggest possible school and learning difficulties, but control patients were not studied (169).
Laboratory Findings and Diagnosis
Salient among the laboratory analyses performed for the evaluation of EV meningitis is the evaluation of
the CSF. CSF analysis can provide initial clues as to the etiology of the clinical syndrome (Table 5.4).
Cytochemical analysis of the CSF typically shows a mild to moderate lymphocytic pleocytosis ranging
from 10 to 1,000 cells/mm3 (136,139,141,142,145,149,160). White blood cell (WBC) counts exceeding
1,000 cells/mm3 are seen occasionally (60,103,147,170). Although pleocytosis is almost always present,
EVs have been isolated by cell culture or detected by NAAT from the CSF of patients with clinical
evidence of meningitis without pleocytosis (171). This is particularly true in the young infant. If the CSF
is examined early in the course of the illness, a predominantly polymorphonuclear pleocytosis may be
observed (136,139, 142,146,149). Reexamination of the CSF several hours later will document a typical
lymphocytic pleocytosis (172–174). The progression of an initially polymorphonuclear pleocytosis to one
of a more viral meningitis mononuclear pleocytosis has also been observed with St. Louis encephalitis
virus (175). The CSF protein concentration is mildly to moderately increased, whereas the glucose
concentration is generally normal. However, hypoglycorrhachia may occur, serving to confound the
assessment by suggesting a bacterial etiology (146,147,170).
Traditionally, the diagnosis of EV meningitis has relied on isolation of the virus from CSF using cell
culture or inoculation of suckling mice (176). Although initially very useful, these techniques have
significant limitations. The sensitivity of tissue culture for EVs is only 65% to 75% (177). The titer of
EVs in the CSF of patients with aseptic meningitis may be as low as 101 to 103 TCID50 (median tissue
culture infectious dose) per milliliter of CSF. This results in slower growth than is observed with
specimens of throat or rectal origin. The time to isolation of EV from CSF ranges from 4 to 8 days (178)
using traditional cell culture—too long to be clinically useful in patient management. Using shell vial
culture, the time can be shortened to 2 to 3 days, but sensitivity may be lost (179,180). Lastly, optimum
recovery of EVs from clinical specimens requires the use of multiple cell lines, either individually or as
mixtures, in order to increase culture yield (181). Even using multiple cell lines, some EVs, in particular
the group A CVs and some of the newer EVs, fail to grow in cell culture (182). The added cost and
technical expertise required for suckling mouse inoculation makes it impractical for use in the modern
diagnostic laboratory. Serologic confirmation of EV infection is also generally impractical and not useful
in acute management of the patient.
As mentioned previously, the 5′ UTR contains regions of conserved nucleotide identity among the EVs.
These regions have been exploited for the creation of primers and probes that can be used in NAATs
capable of detecting all EVs (43). Compared to cell culture, NAAT detection of EVs in the CSF has been
shown to exhibit sensitivities that range from 86% to 100% and specificities ranging from 92% to 100%.
Furthermore, NAATs are capable of detecting EV genome in CSF samples from individuals with
syndromes clinically compatible with aseptic meningitis previously deemed negative by cell culture or
without pleocytosis (163,162,183). These assays are also able to detect EV that cannot be grown in cell
culture. Lastly, NAAT can be performed rapidly, generally in a matter of hours. The results can be made
available with sufficient speed as to have an impact on patient management, resulting in a reduction in
hospital stay, antibiotic use, and ordering of ancillary tests (184–188). A confirmatory polymerase chain
reaction (PCR) test result obtained on a patient with clinical aseptic meningitis can reassure the clinician
that no further diagnostic investigation is required. For these reasons, NAAT detection has become the
method of choice for the diagnosis of CNS EV infection. Because of the lack of sensitivity of viral culture
for detection of the EV in CSF, it should be reserved for instances when NAAT is not available.
Two caveats should be borne in mind when establishing the diagnosis of EV meningitis. Confirmation
of EV as the etiology for aseptic meningitis syndrome should rely on detection of the virus from the CSF.
As previously discussed, following EV infection viral shedding may occur from the throat and GI tract for
up to several weeks (7,92). Therefore, detection of the EV from the stool or throat of an individual with
aseptic meningitis may represent an infection that occurred weeks previously and is unrelated to the
present syndrome. Shedding from a past infection cannot be ruled out unless the virus is detected in
nonpermissive sites (i.e., CSF, blood, tissue) (189).
Lastly, rare reports of co-infections of the CSF by bacteria and EVs exist (102,126,129,130). In these
patients, the clinical and laboratory picture of bacterial meningitis dominated and the virus was isolated
incidentally. The patients were sick enough that identification of a virus before identification of the
bacterium would have been unlikely to dissuade the clinician from continued use of antibiotics. Thus, the
detection of an EV either by culture or NAAT must always be placed in the context of the patient’s
clinical picture and laboratory findings. In the clinical presentation typical of viral meningitis, co-
infection with a clinically “silent” bacterium would be extraordinarily unlikely.
Treatment and Prevention
No specific treatment exists for EV meningitis. Supportive measures include bed rest, antipyretics, and
analgesics, as indicated. Administration of parenteral fluids for individuals unable to take adequate fluids
orally, especially infants, is indicated. Seizures should be controlled with appropriate anticonvulsant
drugs.
Immune globulin preparations have been used for the treatment of newborn infants with severe disease
and immunocompromised individuals, but their efficacy is not established (61,159,190). Intravenous, as
well as intrathecal, administration may be necessary to ameliorate or prevent CNS infection in
immunocompromised patients.
The promising results from clinical trials of pleconaril (39), an antiviral that inhibits EV binding and
viral uncoating, were overshadowed by its adverse effects (40). In clinical trials, pleconaril was found to
induce cytochrome P450 3A, resulting in menstrual irregularities in women taking hormonal
contraceptives. This finding raised concerns that it might increase the metabolism of some hormonal
contraceptives and anti-HIV drugs, thereby reducing their efficacy, prompting the U.S. Food and Drug
Administration not to grant a license for its use.
The EVs are spread primarily through a lack of good hygiene. Hand washing prevents the spread of the
EVs and should be encouraged in families and institutions (191). In patients hospitalized with EV,
meningitis infection control measures using standard precautions are sufficient. Community measures for
the prevention of EV infections rely on the development and maintenance of sewage and potable water
systems. No vaccines exist for the non-PV EV. However, recent early studies suggest that it may be
possible to develop an inactivated EV-A71 vaccine that can induce neutralizing antibodies and is well
tolerated in humans (192).
PARECHOVIRUSES
The first two members of the genus human parechoviruses (HPeVs) were found in 1956 (193). However,
it was not until the turn of the century that they were accorded their own genus. Originally classified as
EVs and designated as echoviruses 22 and 23 (18) (currently designated HPeV 1 and 2, respectively), it
became evident early on that they exhibited characteristics that differed from the other members of the
genus (193,194). The development of methodologies to probe the molecular aspects of viral replication
and viral genetics confirmed that they differed substantively from the EV (25–27,195,196) and led to their
reclassification in a separate genus (24).
Morphologically, HPeVs exhibit similar characteristics as the EV: small size, lack of an envelope, a
positive sense, and single-stranded RNA genome of the length and organization consistent with that of the
EVs (6). Important differences are the lack of maturational cleavage of VP0 to yield capsid proteins VP2
and VP4. As a result, the HPeV capsid is composed of three, rather than four, proteins. Differences also
exist in the function of two nonstructural proteins. A detailed discussion of these and other differences is
beyond the scope of this chapter, and the reader is directed to a recent review (6).
The genus is currently composed of 16 serotypes (Table 5.3) (24). HPeVs have been reported
worldwide. The epidemiology of the HPeV continues to evolve as new serotypes are identified and
detection is improved using NAATs. Current data indicates that the HPeVs account for approximately 2%
of the “EV” isolated using traditional cell culture in clinical laboratories (6). HPeV1 followed by HPeV3
are the types most frequently isolated. Infection with HPeV appears to occur early in life. In the United
States, 73% of HPeV1 and 67.6% of HPeV2 isolated come from infants younger than 1 year of age. A
longitudinal study of Norwegian infants documented that the cumulative incidence of HPeV infection by
24 and 36 months of age was 86% and 94%, respectively (197).
HPeV infections exhibit a strong seasonal epidemiology. Worldwide, the peak incidence of infections
occurs during the summer and fall months (197–204). A unique biennial pattern of circulation has been
reported for HPeV3 (205–208). As with the EVs, multiple HPeV serotypes circulate within a community
at the same time. The majority of cases of HPeV meningitis occur in male infants younger than 3 months of
age. HPeV3 is the overwhelmingly dominant cause of HPeV meningitis. Considerable variation in the
annual prevalence of HPeV meningitis is observed.
Transmission of the HPeV occurs via the fecal-oral and respiratory routes. They may be shed from
these sites for weeks to months (197,201,209). The finding of HPeV in the stool of healthy, asymptomatic
infants indicates that many, if not the majority, of infections are subclinical.
Irritability is present in nearly all cases of HPeV meningitis (202,207,210). An exanthem is frequently
present. Emesis, diarrhea, and distention are reported in approximately one-quarter to half of cases.
Rhinorrhea, cough, tachypnea, apnea, and wheezing may be present. Notably, findings of increased
intracranial pressure (bulging fontanelle) or meningeal irritation (nuchal stiffness, Kernig or Brudzinski
signs) are absent. The CSF cytochemical evaluation reveals no or minimal abnormalities in WBC count
or protein and glucose concentrations in the overwhelming majority of patients (202,207,210).
Currently, NAAT is the methodology of choice for HPeV detection because of its sensitivity and ability
to detect all known HPeV types in a clinically meaningful time frame (6). Optimum diagnostic assays
target the HPeV 5′ UTR and are not type-specific. They are designed for increased sensitivity and to
broadly detect all HPeV types from clinical specimens.
The HPeV can produce cytopathic effect on appropriate cell lines (211). However, cell culture
detection is limited by those factors discussed for the EV (see previous discussion) (211,212).
ARBOVIRUSES
The arboviruses are a group of more than 500 viruses from various viral families that are transmitted by
the bite of an insect or tick (i.e., an arthropod vector) (213); hence, the derivation of their name ar–
arthropod, bo–borne, viruses. Transmission to humans (epizootic transmission) occurs by chance and is
secondary to the natural enzootic cycle involving an arthropod vector and an avian or mammalian host.
Mosquitoes serve as the vectors for the majority of clinically significant arbovirus endemic to North
America. However, Colorado tick fever virus, Powassan (POW) virus in North America, and tick-borne
encephalitis (TBE) virus in Eurasia are transmitted by ticks (214,215).
Flaviviridae
West Nile Virus

West Nile virus (WNV) was first isolated in Uganda in 1937 (216). Its incursion into the United States in
1999 (217) preceded a rapid spread throughout the contiguous continental United States as well as North
and South America (218,219). In the United States, WNV has displaced all autochthonous arboviruses as
the single major cause of CNS disease (220). WNV is a member of the Flaviviridae family of RNA
viruses, within the genus Flavivirus (221). All members of the family possess a host cell–derived lipid
envelope that is modified by the insertion of viral proteins and a positive (message)-sense, single-
stranded RNA genome.
WNV is maintained in an enzootic cycle that involves primarily avian hosts and mosquitoes (222).
Culex mosquitoes are important vectors in the United States (223). Mosquitoes are important in
transgenerational and transseasonal maintenance of the WNV enzootic cycle (224,225). WNV infections
occur during the summer months, generally from July through October in the United States, coinciding
with periods of increased activity of its vectors. However, as WNV has spread southward in the United
States, reported transmissions to humans have occurred as early as April and as late as December (223).
Transmission to humans (i.e., epizootic transmission) is incidental and, with rare exception, results in a
“dead-end” infection without subsequent human transmission. The latter has occurred through transfusion
of blood products and organ transplantation (226–229). In addition, confirmed or suspected maternal–
fetal and maternal–infant vertical transmission of WNV has been reported (230,231).
The majority of WNV infections in adults and children result in subclinical disease. Infection of
children results in asymptomatic infection or milder disease more frequently than in adults (232–236).
During one outbreak, children were 4.5 times more likely to become infected with WNV but 110 times
less likely to develop West Nile neuroinvasive disease (WNND) (237). In adults, age is the single most
significant risk factor for development of WNND (235,236,238). The incidence of severe neurologic
disease is 10 times higher in persons aged 50 to 59 years and 43 times higher in those aged 80 years or
older compared with individuals 20 years of age or younger. Other risk factors include hypertension,
diabetes mellitus, cardiovascular disease, alcohol abuse, and immunosuppression. Approximately 80% of
those infected with WNV remain asymptomatic. The majority of the remainder develops an acute, self-
limited febrile illness known as West Nile fever. It is characterized by a sudden onset of fever (38° to
40°C), accompanied by fatigue, malaise, anorexia, headache, myalgias, and weakness. Ocular pain on eye
movement has been reported. A diffuse nonpruritic, macular, papular, maculopapular, or morbilliform
exanthem and diffuse lymphadenopathy may be seen (222,235,239–241).
Less than 1% (1:140 to 320) of adults develop WNND: aseptic meningitis (WNV meningitis),
encephalitis, or poliomyelitis- like syndrome (241–245). WNND may be even rarer in children:
approximately 1:4,200 infected children according to one study (237,246). The median age of patients
with WNV meningitis is less than those with encephalitis (247). The percentage of individuals with WNV
meningitis that comprise cases of WNND varies by report. In an outbreak in Israel, 15.9% of hospitalized
patients with WNND had meningitis (233). In the United States, WNV surveillance data from 1999 to
2008 found that 33% of WNND cases reported to the Centers for Disease Control and Prevention (CDC)
were meningitis (247). Individuals 19 years of age or younger accounted for 8% of all cases of
meningitis. However, when cases of WNND in children were analyzed for nearly the same time frame,
47% of all pediatric cases were of meningitis as compared to encephalitis or meningoencephalitis, which
accounted for 37% of cases (236).
In adults and children, West Nile meningitis is clinically indistinguishable from other causes of viral
meningitis. The illness begins abruptly with fever, headache, nuchal rigidity, and meningeal signs
(222,235,244). Photo- and phonophobia may be present. The headache may be so severe as to need the
use of narcotic analgesics to control. Weakness and dyskinesias in the form of tremors, myoclonus, or
parkinsonism may occur. The outcome of West Nile meningitis is favorable, although it may take 2 to 3
weeks to fully recover.
Analysis of the CSF shows a lymphocytic pleocytosis of generally less than 500 cells/mm3 (235). If the
CSF is examined early in the course of the illness, a polymorphonuclear pleocytosis may be seen (248).
The presence of plasma cells may be indicative of WNV as the etiology (249).
The diagnosis of WNV infection relies on the detection of WNV-specific antibodies in CSF or paired
serum samples (235,250). The most sensitive and commonly used diagnostic assay is the IgM antibody-
capture enzyme-linked immunosorbent assay (MAC-ELISA). It is capable of detecting CSF IgM
antibodies 3 to 5 days into the clinical illness and 3 or more days earlier than detectable serum antibody
(251). However, a positive test should always be interpreted in the context of clinical syndrome because
the presence of WNV-specific IgM has been detected in the CSF for up to 199 days after onset of illness
(252). The finding of WNV-specific IgM in the CSF of an individual with a clinically compatible CNS
syndrome generally is considered diagnostic of WNND. If only serum is used for establishing a diagnosis,
a second convalescent serum sample, obtained 2 or more weeks later, should be collected to document a
fourfold increase in specific antibody titers using a functional assay such as neutralization or
hemagglutination inhibition (235). Because serologic cross reactions among St. Louis encephalitis virus,
WNV, and POW virus can occur, serologic testing ideally should include a battery of region-specific
arboviral antigens (253).
St. Louis Encephalitis Virus

St. Louis encephalitis virus (SLEV) was first identified in 1933 following an epidemic of encephalitis in
St. Louis, Missouri (254). Like others of the genus, it is an enveloped, positive (message)-sense, single-
stranded RNA virus (221). It is recognized as the cause of sporadic and epidemic encephalitis and
meningitis throughout the Americas. In the United States, most cases are seen from July through September
(255). In Florida, epidemics have continued into December (256). Birds are the reservoir, and four
different species of Culex mosquitoes, each with a specific geographic distribution, are the principal
vectors (257). Younger patients tend to have milder forms of SLEV-associated CNS disease (1,258).
Approximately 15% of all symptomatic cases of SLEV infection present as meningitis. The frequency of
SLEV meningitis in children is much higher: approximately 40%. In contrast, patients older than 60 years
of age rarely (5% or less) present with aseptic meningitis. No specific therapy is available.
Tick-Borne Encephalitis Virus

Tick-borne encephalitis virus (TBEV) is an important cause of meningitis in Europe. Cases in returning
travelers from Europe and China have been seen in the United States (259). The disease was first
described in Austria in 1931 (260). TBEV is endemic from Europe through far-eastern Russia, northern
China, and Japan. Three subtypes of the virus exist: European, Siberian, and Far Eastern (10,215). It is
maintained in enzootic cycles involving Ixodid ticks and wild rodents (215). Humans may be infected
through the bite of an infected tick or, less commonly, the consumption of virus-infected milk. The
majority of cases occur from March to November (10). The annual incidence of disease varies widely by
country: Latvia, Estonia, Lithuania, and southern Germany—30, 16.5, 11.2, and 2 cases per 100,000
inhabitants, respectively (10). Aseptic meningitis is seen with infection due to the European and Siberian
viral subtypes. Meningitis is more frequently seen in younger age-groups (10). Sixty-six percent of cases
in infants and children 15 years of age or younger are of meningitis. This decreases progressively with
advancing age such that for individuals 60 years of age or older, 32% or less develop meningitis.
Diagnosis of TBEV infection is established by the detection of virus-specific IgM and IgG in serum.
Vaccines for the prevention of TBEV-related disease are available in Europe and Canada and are
recommended for certain regions of the world (10,215,261). No specific therapy is available.
Other flaviviruses such as POW virus (214,262) and Japanese encephalitis virus (263,264) are far less
commonly identified as causes of meningitis.
Colorado Tick Fever Virus

Colorado tick fever (CTF) virus is an Orbivirus, a member of the family Reoviridae. Orbiviruses are
double-stranded, segmented RNA viruses. The virion is nonenveloped, with an outer diameter of 80 nm
and an inner core of 50 nm diameter. CTF virus is found mostly in western and mountainous regions of the
United States. Its tick vector is Dermacentor andersoni, also known as the Rocky Mountain wood tick
(265). After a bite by an infected tick, a 3- to 6-day incubation period follows. Hematopoietic cells,
principally erythrocytes, are the major targets, wherein viral replication and dissemination occurs (265).
A biphasic illness is characteristic but is actually observed in only half of patients (265). It consists of
initial sudden onset of high fever and headache with flulike constitutional symptoms. Hepatosplenomegaly
may occur, as well as GI symptoms. Stiff neck and other meningeal signs occur in as many as 18% of
confirmed CTF cases (266). Meningoencephalitis and encephalitis can occur but less commonly than
meningitis. The period of illness is usually brief (2 to 3 days). A peripheral leukopenia with relative
lymphocytosis is common. A lymphocyte-predominant CSF pleocytosis and elevated protein level are
typically found in patients with neurologic manifestations. Certain patients transiently improve (1 to 2
days), and then a second phase of illness of equal or greater severity follows (lasting an additional 2 to 3
days). Severe sequelae and death, though rare, have been reported. Typically, recovery is rapid and
complete within 2 weeks. Laboratory diagnosis can be made using PCR (within the first 5 days of illness)
or IgM-based serology (214). Virus may also be detected in peripheral blood smears by indirect
immunofluorescence. Paired acute and convalescent serology is useful for retrospective diagnosis.
Bunyaviridae
The California encephalitis group of viruses include five viruses in the family Bunyaviridae. Three—La
Crosse, Jamestown Canyon, and snowshoe hare—viruses have been associated with aseptic meningitis
(128,267). Numerically, La Crosse is the most clinically relevant. From 1999 to 2007, La Crosse virus
was reported from 25 states. However, 87% of cases came from 7 states: West Virginia, Ohio, North
Carolina, Tennessee, Wisconsin, Minnesota, and Illinois (255).
PARAMYXOVIRUSES
Mumps Virus
Mumps virus is a member of the genus Rubulavirus within the subfamily Paramyxoviridae (268). It is an
enveloped, pleomorphic virus possessing a single-stranded, negative-sense RNA genome. Only a single
serotype exists, although 13 genotypes have been identified (269,270). In the United States, prior to 1967
and the introduction of an effective vaccine, mumps infections are observed during the winter and spring,
with epidemics occurring approximately every 3 to 5 years (271,272). It was responsible for 2.5% to
15% of all cases of aseptic meningitis and between 17.5% and 22% of known causes of meningitis
(5,8,9,11). As a result of mumps vaccine and effective vaccination programs, mumps cases have been
reduced by 99% (273). However, mumps outbreaks continue to occur in the United States (274,275).
Mumps is transmitted via respiratory droplets. Once infection occurs, viremia is the likely means of
spread to distant target organs, including the CNS (276). Meningitis is the most common neurologic
manifestation of mumps infection (277). Mumps once was the leading identifiable cause of aseptic
meningitis. The widespread use of the attenuated live-virus vaccine in the United States has resulted in a
dramatic drop in incidence of mumps as well as its major role as a cause of meningitis (278). Neurologic
involvement is three times more common in males. More than 50% of patients with mumps parotitis have
CSF pleocytosis (277); however, most are not symptomatic of meningitis.
Clinically symptomatic meningitis occurs in up to 10% of patients with parotitis (279). Symptoms of
meningitis are reported in cases of mumps parotitis by 4 to 10 days of illness but may precede parotitis by
as much as 7 days; half or more cases of mumps meningitis may not be associated with parotitis at all
(280,281). The clinical manifestations of mumps meningitis are nonspecific and differ little from those of
EV cases. Fever is universal, usually lasting 3 days but occasionally persisting for a week (280).
Bradycardia, drowsiness, lethargy, and anemia are all reported. More significant neurologic involvement
can occur. Encephalitis is described concomitantly with meningitis in as many as 35% of cases (280) or
as few as 4% (166).
Mumps virus meningitis and meningoencephalitis are usually benign and self-limited diseases
(277,280). The prognosis for rapid and full recovery from mumps meningitis is excellent (277,280). The
occasional fatalities demonstrate pathologic findings of demyelination near blood vessels (277).
Most but not all cases of symptomatic mumps meningitis have a primarily monocytic CSF pleocytosis,
primarily mononuclear cells (277). Half of patients have 500 or fewer cells/mm3, 75% of cases have
1,000 or fewer cells/mm3, and the remainder have fewer than 5,000 cells/mm3. Exceptional cases with
more than 5,000 cells/mm3 have been reported. Pleocytosis may persist for weeks. CSF protein level has
been reported as normal in more than half of patients with mumps meningitis (280,282).
Several approaches exist for the diagnosis of mumps virus meningitis: viral isolation, documentation of
increased antibody titers between serum acute and convalescent serum samples obtained 2 to 3 weeks
apart, documentation of the presence of mumps-specific IgM antibodies, or NAAT detection of mumps
virus genome (283). Mumps virus can be detected in saliva, blood, urine, and CSF. It is present in saliva
9 days prior to and 8 days after the onset of parotitis. In urine, it is detectable for up to 2 weeks after the
onset of symptoms. Mumps-specific IgM is present in the blood within 3 to 4 days of the start of
symptoms and may persist for up to 3 months. A sole serum sample demonstrating the presence of mumps-
specific IgM obtained within 10 days of the onset of illness is sufficient to establish the diagnosis. IgG
antibodies are detectable 7 to 10 days after the start of symptoms and persist for life. Antibodies to other
paramyxoviruses may cross-react with in mumps virus in serologic assays, leading to false-positive
results.
Other Paramyxoviruses
Measles infection may be associated with pleocytosis in as many as 30% of uncomplicated cases in
normal patients, usually without signs or symptoms of meningitis (284). The parainfluenza viruses have
been associated with CNS infection (285). The dominant serotype reported has been parainfluenza virus
type 3.
ARENAVIRUSES
Lymphocytic Choriomeningitis Virus
LCMV, a member of the family Arenaviridae, is an enveloped virus with a genome consisting of two
single-stranded, ambisense RNA molecules (286). LCMV was one of the earliest and significant viruses
to be associated with aseptic meningitis in humans (3) (Table 5.2). It is now rarely identified as a cause
of CNS infection in humans. The virus is endemic in wild mice, which serve as its reservoir (287). In the
United States, the prevalence in wild mice is estimated to be 3.9% to 13.4% (287). Seroprevalence
studies in the United States suggest that the 0.4% to 5% of patients sampled in three large cities had
evidence of LCMV infection (287–289). The virus is transmitted by rodents (hamsters, guinea pigs, rats,
mice) via their saliva, urine, feces, and nasal secretions (290). Individuals who work with or own rodents
as well as those living under impoverished and nonhygienic circumstances have traditionally been at
greatest risk (291–294). Human-to-human transmission can occur through transplantation (295,296).
Approximately one third of LCMV infections are asymptomatic. Clinically manifest infections are usually
mild and of brief duration. The infection frequently results in a biphasic illness characterized by an initial
“flulike” illness with fever, headache, malaise, myalgia, anorexia, nausea, and emesis. A temporary, brief
period of improvement follows and precedes the onset of symptoms of meningitis or encephalitis
(291,292,297). Occasional severe neurologic disease (meningoencephalitis, encephalitis) has been
reported (298). The course of meningitis and recovery are often prolonged (299), but permanent
neurologic impairment is rare. CSF findings are indistinguishable from those of other viral causes of
aseptic meningitis: lymphocytic pleocytosis (up to several thousand), mildly elevated protein, and usually
normal or low glucose level. Other abnormalities include leukopenia, thrombocytopenia, elevations of
transaminase levels, and pulmonary infiltrates (297). Cell culture of CSF usually detects the presence of
LCMV. In severe disseminated infection, virus may be found in the blood, urine, and nasopharyngeal
secretions. NAAT can be used to detect viral genome in CSF. Acute and convalescent serum specimens
can be tested for raising antibody titers by enzyme immunoassays.
HUMAN HERPESVIRUSES
The majority of the human herpesviruses—HSV types 1 and 2, varicella-zoster virus (VZV) (300,301),
Epstein-Barr virus (EBV) (302,303), cytomegalovirus (CMV) (304), human herpesvirus (HHV)-6
(305–308), and HHV-7 (308)—have been associated with reports of aseptic meningitis. Numerically,
HSV-1 and HSV-2, in particular the latter, are the major causes of aseptic meningitis among this family for
viruses.
HSVs appear to account for approximately 1% to 3% of all cases of aseptic meningitis (Table 5.2).
HSV-2 and, much less commonly, HSV-1 have been associated with aseptic meningitis in patients with
primary genital herpes infection (309–311). HSV-2 meningitis following primary genital infection is more
frequently seen in women. Genital lesions may not be present at the time of symptoms of aseptic
meningitis (310). Examination of the CSF demonstrates a lymphocytic pleocytosis, elevated protein, and
normal glucose concentrations.
Recurrent benign lymphocytic meningitis (RBLM), also referred to as “Mollaret meningitis,” has been
shown to be associated primarily with HSV-2 and, much less so, HSV-1 (312–315). The prevalence of
RBLM is difficult to assess because of its intermittent presentation, and it is not a reportable condition.
However, two reports place it between 1 and 2.2 cases per 100,000 population (316,317). The syndrome
is more frequently seen in young women and consists of recurrent episodes of aseptic meningitis, lasting 2
to 5 days, which resolve spontaneously and without sequelae (318). The clinical presentation of RBLM is
typical of viral meningitis. However, approximately 50% of patients have transient neurologic
manifestations (seizures, hallucinations, diplopia, cranial nerve palsies, altered consciousness). Lesions
of genital herpes are absent. Cytochemical analysis of the CSF reveals a lymphocytic pleocytosis, mildly
elevated protein, and normal glucose concentrations (318). Detection of HSV genome is made by NAAT.
The role of antiviral therapy in the management of RBLM is debated. Administration of acyclovir has
been reported to result in rapid resolution of symptoms, and suppressive therapy using valacyclovir or
famciclovir may prevent recurrences. In individuals with HSV-2 detected from the CSF, counseling
regarding prevention of transmission of genital HSV should be undertaken (318).
VZV-related meningitis is a recognized complication of primary infection (chickenpox) and
reactivation (zoster) (300,301,319,320). Meningitis has been associated with infection due to multiple
different genotypes of the wild type strain as well the vaccine strain (Oka strain) of VZV (321) and may
be seen in immunocompetent and immunocompromised individuals. The clinical and CSF presentation is
typical of aseptic meningitis. However, in recent report, only half of patients had fever, and nearly 25%
had altered mental status or lethargy (321). In that study, all cases of meningitis occurred in children.
When meningitis complicates zoster, typical vesicular lesions restricted to dermatomal distribution are
seen. The use of NAAT has identified individuals with meningitis due to reactivation of VZV but without
skin lesions (301,321). The benign course is typical of other aseptic meningitides.
Reports of meningitis with EBV and CMV infection are far less common that those of the agents
discussed previously. Although HHV-6 and HHV-7 have been reported as causes of CNS infection,
including meningitis (305,307,308), these reports must be interpreted with caution. HHV-6 has been
shown to establish persistence in the CNS and has been found in the CSF of asymptomatic individuals
(322).
OTHER VIRAL PATHOGENS

HIV
Aseptic meningitis is known to occur as part of the clinical constellation of syndromes associated with
primary HIV infection (323–325). The symptoms and signs are typical of aseptic meningitis and resolve
rapidly. If the CSF is examined, a lymphocytic pleocytosis is present along with mildly elevated protein
and normal glucose concentrations. HIV can be detected in the CSF. Pleocytosis may also be seen in
asymptomatic HIV-infected individuals.
Occasional cases of aseptic meningitis or meningoencephalitis have been associated with adenoviruses
in normal and immunocompromised patients (326–330), influenza A and B viruses (331–333), parvovirus
(334), and rotavirus (335–337).
NONVIRAL PATHOGENS
Multiple pro- and eukaryotic pathogens (bacteria, spirochete, mycobacteria, fungi) can present with the
classic features of aseptic meningitis. The majority of these agents would not be readily detectable by
Gram stain of the CSF and may require special culture techniques to identify. As originally noted by
Wallgren (2), parameningeal foci (sinusitis, otitis, mastoiditis, trauma) can present similarly to viral
meningitis and need to be always considered in the differential diagnosis of aseptic meningitis.
Spirochetes
Lyme Disease
In areas of the United States where Lyme disease is endemic (338), CNS infection due to Borrelia
burgdorferi may be encountered in 10% to 15% of individuals infected by this spirochete (339,340). B.
burgdorferi is transmitted by Ixodes species (scapularis—Eastern United States, or pacificus—Western
United States) of ticks. Because the vector is so diminutive, a significant number of infected individuals
do not recall a tick bite. The illness is commonly seen in the spring and summer months and overlaps with
EV and arboviral causes of meningitis. Meningitis usually occurs in the early disseminated stage of
infection. The clinical manifestations are similar to viral meningitis and may occur in association with
cranial neuritis and radiculoneuritis (339–343). The majority of children have associated findings such as
facial or sixth nerve palsies, papilledema, and increased intracranial pressure of erythema migrans.
Analysis of the CSF reveals a lymphocytic/monocytic pleocytosis (<500 cells/mm3) and elevated protein
concentration. The CSF glucose concentration is usually normal but may be slightly decreased.
The diagnosis of Lyme meningitis requires documenting B. burgdorferi infection using a two-step
diagnostic approach consisting of an initial enzyme-linked immunosorbent assay (ELISA) followed by a
specific Western blot assay. In addition, the CSF should be examined for the presence of intrathecal
production of antibody to B. burgdorferi (339–341). Treatment with ceftriaxone, cefotaxime, or penicillin
G for 2 to 4 weeks is recommended (340,342,343).
Other Spirochetes
Leptospirosis is an acute systemic vasculitic disease caused by a number of spirochetes in the Leptospira
genus. Acquisition is via contact with infected animal body fluids. Although more typically noted in the
anicteric variety, meningitis is common in icteric leptospirosis (Weil disease) as well (344). The CSF
profile is indistinguishable from that caused by common viruses, except that overall, more patients
develop elevated CSF protein than patients with common viral meningitis. Aseptic meningitis is a
relatively uncommon manifestation of secondary and tertiary syphilis (345). Meningitis due to tick-borne
relapsing fever may be seen as frequently as with Lyme disease (346).
Bacterial and Fungal Causes
The majority of tuberculous CNS infections are caused by Mycobacterium tuberculosis. A small
percentage is due to bovine tuberculosis, Mycobacterium bovis. Children are particularly prone to
develop tuberculous meningitis (347). The presentation is often subacute, occurring over 1 to 3 weeks
(348). The clinical course consists of three stages. Personality change, irritability, anorexia, listlessness,
and occasional fever characterize the first stage. Second stage signs and symptoms reflect increased
intracranial pressure and cerebral ischemia: drowsiness, nuchal rigidity, cranial nerve palsies,
anisocoria, emesis, and seizures. In older children, adolescents, and adults, headache and emesis may be
the dominant features. The third stage is characterized by coma, autonomic instability, fever, and
progressive cerebral dysfunction. Chest radiograph; tuberculin skin testing; and, in older children,
adolescents, and adults, IFN gamma release assays should be performed, seeking evidence of
tuberculosis. The lumbar puncture reveals elevated opening pressure. The CSF reveals a markedly
elevated protein and decreased glucose concentrations. A lymphocytic pleocytosis of usually less than
500 cells/mm3 is seen.
CNS infections with Brucella species occur in less than 5% of systemic brucella infections (349).
Meningoencephalitis is the usual presentation. Both acute and chronic forms have been reported.
Antibiotic therapy is usually curative; however, some residual neurologic defects are the rule.
Fungal meningitis is more commonly seen in immunocompromised individuals; however, occasional
cases have been reported in immunologically normal individuals (350–355). Cryptococcus is the most
commonly recognized cause of fungal meningitis (352). Other causes include Candida, Histoplasma,
Coccidioides, Blastomyces, and Aspergillus (350,351,353–355). The clinical presentation is that of a
subacute or chronic meningitis with fever, headache, and altered consciousness. Meningismus and focal
neurologic findings are common findings. Evaluation of the CSF reveals a lymphocytic pleocytosis in
most cases (a polymorphonuclear pleocytosis may be seen in some cases) in association with an
increased protein concentration and hypoglycorrhachia. In addition to fungal culture of the CSF, evidence
of infection should sought through detection of fungal antigen, fungal wall constituents, or specific
antibodies in CSF and blood. When attempting to detect fungi through culture, it is important to use 10 to
15 mL of CSF. Evidence of fungal infection in sites outside of the CNS should also be sought.
A variety of neurologic manifestations have been reported to be associated with Mycoplasma
pneumoniae infections (356). Of these, aseptic meningitis and encephalitis are the most common.
Clinically, mycoplasmal meningitis is impossible to distinguish from viral meningitis, and as in typical
viral infection, sequelae are not observed. Diagnosis is by serology or PCR (356,357). Mycoplasma
hominis has been associated with cases of neonatal meningitis, usually in preterm infants (358).
Systemic Diseases
Kawasaki disease (KD) is an acute, self-limited vasculitis of unknown etiology affecting children. In the
United States, the estimated overall annual incidence among children younger than 5 years of age is 20
cases per 100,000 population (359). The incidence is higher among Asians and Pacific Islanders. Several
reports indicate that between 40% and 60% of children with KD have a mild (usually <100 cells/mm3)
mononuclear pleocytosis on CSF examination (360,361). The incidence appears to be highest in reports
from Japan. The CSF protein and glucose concentration are normal in the overwhelming majority of
children.
Many other systemic vasculitides (e.g., polyarteritis nodosa, temporal arteritis, Takayasu arteritis,
Wegener granulomatosis) are associated with CSF pleocytosis (362). Meningitis has been described as
the initial manifestation of systemic lupus erythematosus in several patients (363). Two percent to 4% of
patients with lupus may develop aseptic meningitis during the course of their disease (363).
Medication-Induced Aseptic Meningitis
The clinical features of medication-induced aseptic meningitis are not such that they set it apart from that
caused by infectious etiologies nor do they permit differentiation of the multiple medication causes of the
syndrome. A wide variety of medications, vaccines, or dyes, administered systemically or within the
CNS, have been associated with aseptic meningitis (364–372).
The most common class of medications associated with aseptic meningitis is nonsteroidal
antiinflammatory drugs (NSAIDs) (364). Of the nonselective and selective inhibitors of cyclooxygenase 1
and 2, ibuprofen is the most frequently associated NSAID with aseptic meningitis. Ibuprofen-associated
aseptic meningitis is frequently seen in association with systemic lupus erythematosus. The majority of
cases are reported in women. The associated pleocytosis is frequently polymorphonuclear in nature.
Antimicrobial agents have also been shown to cause aseptic meningitis (364). Leading this group of
medications are trimethoprim and penicillin (penicillin, amoxicillin, or amoxicillin-clavulanic acid).
Intravenous immunoglobulin is a well-recognized cause of aseptic meningitis (364). In pediatric clinical
trials using intravenous immunoglobulin, the incidence of aseptic meningitis ranged from 6% to 32%.
Immunomodulators such as monoclonal antibodies against CD3 or tumor necrosis factor-α are important
causes of aseptic meningitis (364,368). Vaccine strains of mumps have been the most frequently
associated (364,373). Greater than 10 mumps vaccine strains are used around the world (373). Although
the Jeryl Lynn and related vaccine strains rarely, if ever, cause aseptic meningitis, other vaccine strains
have been associated with varying incidences of this side effect (373).
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CHAPTER 6 ENCEPHALITIS
CAROL GLASER AND ARUN VENKATESAN
Encephalitis is one of the most challenging syndromes for clinicians to manage. Patients are often
critically ill, and there are many potential etiologies. Despite exhaustive testing, an etiology is only
identified in 40% to 70% of cases. Even when a cause is identified, there may be no effective treatment
(1–3). Mortality rates vary substantially across studies and range from 3% to 15% (4,5). The frequency of
sequelae, including cognitive and motor impairment as well as seizures, is also variable; some case
series report severe disability in 20% to 40% of patients (4,6,7). Not surprisingly, given the severity of
the disease as well as the complexity of diagnosis and clinical management, substantial health care costs
are associated with encephalitis.
The term encephalitis generally refers to inflammation of the brain parenchyma. However, without the
identification of a neurotropic agent or confirmation of inflammation in brain tissue, the diagnosis of
encephalitis is presumptive and based on clinical features. Clinically, patients with encephalitis often
present with fever, headache, and altered mental status. Seizures or focal neurologic deficits may also be
present. In principle, alteration in mental status distinguishes encephalitis from uncomplicated meningitis
as meningitis symptoms typically include fever, headache, and nuchal rigidity but lack global or focal
neurologic dysfunction. In practice, however, the distinction between these two entities is not always
readily apparent, and in descriptions of central nervous system (CNS) infections with mental status
changes due to agents such as enteroviruses, rabies, West Nile virus or herpesviruses, the terms
encephalitis or meningoencephalitis are often broadly applied.
In contrast to encephalitis, encephalopathy refers to any diffuse disease of the brain that results in
changes in function; the clinical hallmark of encephalopathy is an altered mental state. Many entities
including metabolic or mitochondrial dysfunction, toxins, trauma, poor nutrition, or lack of oxygen or
blood flow to the brain can lead to encephalopathy.
This chapter focuses predominantly on the immunocompetent host and pathogens in North America that
either cause encephalitis or an encephalitis-like syndrome. Moreover, many patients with encephalitis
also have meningeal inflammation, thus demonstrating the overlap of encephalitis and
meningoencephalitis. For the purposes of this chapter, the terms encephalitis and meningoencephalitis
are used interchangeably. Other regions of the CNS may be variably affected, including the spinal cord
(myelitis), nerve roots (radiculitis), and nerves (neuritis).
GENERAL: ETIOLOGIC AGENTS AND EPIDEMIOLOGY

Although the term encephalitis is often used in conjunction with a viral etiology, many other infections
and noninfectious entities can cause encephalitis or encephalitis-like symptomatology. The incidence of
encephalitis varies throughout the world and is contingent upon the population under study, the geographic
region, the availability of vaccines for some causes of encephalitis, and differences in case definitions
and surveillance activities. In tropical regions of the world, the minimum estimated incidence of
encephalitis is 6.3 per 100,000 (8). In the Western world, the incidence ranges between 0.7 and 13.8 per
100,000 (8–10). Most reports find the incidence of encephalitis higher in the pediatric age-group than in
adults. For example, a study in England of hospitalized patients with encephalitis over a 10-year period
demonstrated an overall incidence of 1.5 per 100,000 population, a rate of 2.8 per 100,000 in children,
and a rate of 8.7 per 100,000 in infants (11). Somewhat higher rates in children were reported from
Finland (8.8 per 100,000 from 1973 to 1987) (12) and in Slovenia (6.7 per 100,000 from 1979 to 1991)
(13).
The epidemiology of encephalitis is a dynamic process. In countries where vaccines are widely used
for measles, mumps, rubella, and varicella infections, the incidence of encephalitis due to these viruses
has decreased (14,15). However, there is a growing list of emerging and reemerging pathogens such as
Nipah virus, enterovirus 71, Balamuthia mandrillaris, European tick-borne encephalitis virus, Hendra
virus, Baylisascaris procyonis, and Chandipura virus that can cause encephalitis. Moreover, some agents
are now identified in previously nonendemic regions of the world. Notable is West Nile virus, which has
expanded its geographic region from Africa to North and South America, Europe, the Middle East,
Western Asia, and Australia (16). Chikungunya virus is yet another striking example of a virus that has
spread from its origin in Africa to nearly 40 countries including a number of countries adjacent to the
Indian Ocean: La Reunion Island, Madagascar, the Maldives, the Seychelles, and India. (17).
The increasing recognition of specific autoimmune causes, as discussed later in this chapter, has also
had a tremendous impact on our understanding of the epidemiology of encephalitis.
INFECTIOUS CAUSES: SPECIFIC EPIDEMIOLOGIC AND

CLINICAL FEATURES
Viruses
Many cases of viral encephalitis are either an uncommon complication of a common infection, such as a
herpesvirus or enterovirus infection, or a predictable presentation of a rare pathogen such as rabies or
lymphocytic choriomeningitis virus. The clinical manifestations of encephalitis are variable and reflect
the degree of brain involvement, host factors, and the inherent pathogenicity of the offending agent. Most
patients with encephalitis have headache and fever, followed by altered mental status. Seizures,
behavioral changes, impaired cognition, aphasia, hemiparesis, and other focal neurologic signs may be
seen. Arboviruses are often associated with global CNS dysfunction, whereas agents such as herpes
simplex encephalitis typically result in focal manifestations. Although there is significant overlap in the
clinical presentation of various agents and diagnosis can rarely be made on clinical grounds alone, the
most typical and/or characteristic features of some of the causes are highlighted in the following sections.

Herpesviruses are enveloped DNA viruses that are among the most common causes of infections in
humans. At least eight herpesvirus types are known to infect humans. Herpes simplex virus type 1 (HSV-
1) is one the most common causes of sporadic encephalitis in the world (see Chapters 9 and 10). The
epidemiology and clinical features of neonatal herpes CNS infections differ from children and adults and
are not covered in this chapter. The incidence of herpes simplex encephalitis (HSE) caused by HSV-1 is
estimated to be 4 per 1,000,000 (11,18). HSE is responsible for 10% to 20% of adult encephalitis cases
(3,19). HSE is less common in children than in adults; in a large cohort of over 300 pediatric encephalitis
patients over a 12-year period, only 5% were due to HSE. In the pediatric age-group, HSE is often a
result of a primary infection, whereas most HSE infections in adults are the result of HSV reactivation.
Importantly, the presence of herpes labialis has no diagnostic specificity for encephalitis causality but
does serve as a marker of HSV infection.
The characteristic clinical presentation for HSE includes altered mental status (97%), fever (90%), and
headache (81%) (20). Other common neurologic findings include personality change (85%), aphasia
(40%), ataxia (40%), hemiparesis (38%), cranial nerve deficits (32%), and seizures (31%) (4,21).
Children are more likely to have extratemporal involvement as manifested by clinical symptoms as well
as neuroimaging (22).
Unlike HSV-1, HSV-2 is more likely to cause disseminated encephalitis and does not generally localize
to the temporal and inferior frontal regions of the brain (23). Most neurologic CNS HSV-2 infections
present with lymphocytic meningitis. Relapsing meningitis, encephalitis, and myelitis can also occur.
HSV-1 and HSV-2 can also cause brainstem encephalitis. A recent comprehensive literature review of
HSV brainstem encephalitis identified 24 cases: 79% due to HSV-1 and 29% due to HSV-2 (24). The
most prominent features were neuro-ophthalmologic manifestations; these were seen in over 80% of
patients and included nystagmus, impaired ocular movements, anisocoria, ptosis, oscillopsia, or
spasmodic movements (24). Other cranial deficits, altered mentation, ataxia, and corticospinal tract
findings (e.g., hyperreflexia) were also described. Although not common, quadriplegia was also present
in some (19%) of the patients (24).
Both primary infections with varicella-zoster virus (VZV) and endogenous reactivation (herpes zoster)
can lead to encephalitis (25) (see Chapter 10). The most characteristic manifestation of VZV encephalitis
in children is acute cerebellar ataxia (e.g., nystagmus, dysarthria, and ataxia), which usually occurs 1
week after rash onset (26). VZV encephalitis, once a leading cause of encephalitis in children, is much
less common due to the widespread use of VZV vaccine (27).
However, VZV encephalitis is relatively common in adults, and its incidence rivals that of HSE
(28–31). The clinical presentation in adults is different than in children and includes diffuse brain
dysfunction, seizures, cranial nerve palsies, and other focal neurologic signs (4,32). The presence of a
diffuse varicella rash or a vesicular rash in a dermatome distribution can be an important clue to
diagnosing VZV encephalitis. Notably, however, as many as 44% of patients lack cutaneous findings, a
condition termed herpes sine zoster or preeruptive varicella (32–36). Although the pathophysiology of
VZV-associated encephalitis remains unclear, some cases appear to be due to a medium and large vessel
vasculopathy (25).
Epstein-Barr Virus
Epstein-Barr virus (EBV), another herpesvirus, is most often associated with “mononucleosis” but can
also cause several distinct neurologic syndromes including aseptic meningitis, Guillain-Barré syndrome,
Bell palsy, transverse myelitis, cerebellitis, and encephalitis (37,38) (see Chapter 12). Most neurologic
complications due to EBV occur during primary infection, typically in childhood. Importantly, many
patients with EBV-associated encephalitis do not have classic mononucleosis symptoms (39,40). In a case
series of 216 pediatric encephalitis patients in Canada, 21 (9.7%) were identified with EBV-associated
encephalitis (40). Of these, only one patient had classic mononucleosis symptoms; most others had a
nonspecific prodrome of fever (81%) and headache (66%) (40). Seizures occurred in almost half (48%)
(40). Some individuals with EBV-associated encephalitis experience micropsia, macropsia, and/or size
distortion. This pattern of unusual images of body and objects is referred to as the “Alice in Wonderland
syndrome” (41). There are sporadic reports in the literature that reactivation of chronic EBV infection in
adults may cause neurologic manifestations, including encephalitis (42).
Human Herpesviruses 6 and 7

Human herpesvirus-6 (HHV-6), the primary cause of roseola infantum in young children, has been
identified as the causal agent of 10% to 20% of febrile seizures and is also occasionally associated with
encephalitis (43,44) (see Chapter 13). Several studies of encephalitis in children have identified HHV-6
as a causative agent, with the incidence of HHV-6 encephalitis ranging from 1% to 11% of cases (45–49).
In one study of nine children with HHV-6 CNS infections, characteristic clinical features included fever,
gastroenteritis, rash, seizures, and ataxia (50). Another case series reported three pediatric patients with
HHV-6–associated rhombencephalitis; clinical manifestations included encephalopathy, seizures, ataxia,
and myoclonus (51). HHV-7, a recently described herpesvirus, is occasionally associated with roseola
and is typically acquired in the first few years of life. Recent studies from the United Kingdom suggest
HHV-7 may be an important cause of febrile seizures and encephalitis in young children (52).
Enteroviruses and Parechoviruses

Enteroviruses (EVs) are small, nonenveloped, single-stranded RNA picornaviruses. Similar to
herpesvirus infections, EV infections are very common, and neurologic complications, including
encephalitis, represent a rare complication of EV infection. Because EV infections occur frequently in
children, they are a leading cause of encephalitis in children and are responsible for 10% to 15% of
encephalitis cases for which an etiology is identified (53). In general, EVs cause a milder clinical illness
than many other etiologies of encephalitis. In the California Encephalitis Project, EV encephalitis patients
had less severe manifestations, including lower frequencies of coma and shorter hospitalization stays than
those due to other agents (54). CNS infections with EV-71 are an important exception to the decreased
severity of EVs (55,56). In addition to causing acute flaccid paralysis (aka polio-like syndrome), EV-71
has also been associated with a distinctive form of encephalitis initially described in Taiwan and
Malaysia (55,57). Most cases were in young children (younger than 5 years of age), with a characteristic
hand, foot, and mouth rash along with ataxia, nystagmus, myoclonus, and oculomotor palsies (55). The
predominant neurologic presentations included myoclonus (68%), vomiting (53%), and ataxia (35%)
(57). Many of the fatalities associated with EV-71 are due to pulmonary edema and hemorrhage, which
are thought to be a consequence of pronounced autonomic instability due to lesions in the medulla and
spinal cord (58,59). Sporadic outbreaks involving substantial numbers of EV-71 encephalitis cases have
been observed among young children in Europe and Asia over the past several decades (60–62).
The reclassification of former EVs, echovirus 21 and echovirus 22, resulted in the human parechovirus
(HPeV) genus. Echoviruses 21 and 22 are currently classified as HPeV-1 and HPeV-2, respectively. At
least 12 HPeV serotypes have been described to date; nearly all have been associated with encephalitis,
typically in children younger than 2 years of age (63,64). Clusters of HPeV-3 CNS infections have been
reported (65). Young children and infants with HPeV encephalitis develop fever, seizures, irritability,
feeding problems, and rash (66). The relative frequency of HPeV encephalitis is unknown, particularly
because HPeV testing has only recently become available.
Arboviruses
Arboviruses, viruses transmitted by an arthropod vector, are well-recognized causes of encephalitis. The
vast majority of neurologic illnesses seen in humans are caused by three arbovirus families: Togaviridae,
Flaviviridae, and Bunyaviridae (see Chapter 15).
West Nile virus (WNV), a flavivirus, was first detected in the Western Hemisphere in 1999 in New
York City and rapidly spread across North America from the Atlantic to the Pacific coasts and into
Mexico and Canada. It is the now the most common cause of arboviral encephalitis in the United States
(67). Most individuals infected with WNV will experience subclinical infection (70% to 80%) or febrile
illness (20% to 30%). Less than 1% of infected individuals develop West Nile neuroinvasive disease
(WNND), which includes meningitis, encephalitis, and/or acute flaccid paralysis.
WNND is more common in older individuals, with an incidence of 1.35 per 100,000 in persons 70
years of age or older compared with 0.05 per 100,000 in persons younger than 10 years of age (67). Other
risk factors for WNND include male gender, hypertension, diabetes, renal disease, and
immunosuppression (68,69). Characteristic presentations of WNND include altered mental status or
lethargy with or without movement disorders (tremors, Parkinsonism, or myoclonus). Acute flaccid
paralysis is also a feature of WNV infection and can be seen along with encephalitis or may occur in
isolation (70,71).
Although the number of WNND cases has far surpassed the number of cases due to other arboviruses in
recent years, other arboviruses in the United States cause seasonal outbreaks and sporadic cases of
neurologic disease. These include La Crosse virus (LACV), eastern equine encephalitis virus (EEEV),
Powassan virus (POWV), and St. Louis encephalitis virus (SLEV). In 2012, over 2,500 WNND cases
were recognized in the United States compared with 78 LAC cases (71 neuroinvasive), 15 EEE cases (all
neuroinvasive), 7 POW cases (all neuroinvasive), and 2 SLE cases (1 neuroinvasive) (72).
LACV, primarily found in the upper Midwestern, mid-Atlantic, and Southeastern regions of the United
States, is the second most common cause of arbovirus-associated CNS infections in the United States.
Unlike WNV, most neuroinvasive LACV cases occur in the pediatric population rather than in adults; in
2012, 86% of cases were younger than 20 years of age (73).
Outside the United States, other arboviruses predominate. Japanese encephalitis virus (JEV) is the most
common cause of mosquito-borne encephalitis worldwide. An estimated 50,000 cases of JEV clinical
disease occur annually, primarily in children younger than 10 years of age in Asia, South Asia (east of
Pakistan), and Southeast Asia (74–76).
Similar to many other arboviruses, most JEV infections are asymptomatic, with less than 1% of
infections leading to clinical disease. When symptoms occur, encephalitis is the most common
presentation. After a characteristic febrile prodrome including headache and vomiting, mental status
changes, seizures, focal neurologic deficits, and movement disorders develop. Similar to patients with
WNV, those affected by JEV can also develop acute flaccid paralysis (77).
In Europe, tick-borne encephalitis virus (TBEV), another flavivirus, is the most common cause of
arboviral encephalitis (78). It is also found in China and Japan. Analogous to WNV, neuroinvasive
disease is more common in older populations (79). Growing numbers of cases have been recognized in
recent years as a result of improvements in diagnostics and case reporting as well as increased
recreational activities in tick-infested areas (80). In Europe and Russia, there was an average of 8,755
reported cases per year from 1990 to 2007 compared to an average of 2,755 cases per year from 1976 to
1989 (81). TBEV is characterized by three different subtypes: European (TBEV-Eu), Siberian (TBEV-
Sib), and Far Eastern (TBEV-Fe). The TBEV-Eu subtype circulates predominantly in Western, Central,
Northern, and Eastern Europe; the TBEV-Sib circulates predominantly in Asian parts of Russia; and
TBEV-Fe circulates predominantly in China, Japan, and Eastern Russia. The clinical spectrum of disease
ranges from mild meningitis to severe meningoencephalitis with or without paralysis (82). In individuals
affected with the European virus subtype, the illness is often biphasic, with the first stage characterized by
fever, fatigue, general malaise, headache, and body pain. During the second phase of the illness, clinical
manifestations range from mild meningitis to severe encephalitis, with or without myelitis and paralysis.
Seizures are uncommon. The disease associated with TBEV-Fe subtype is the most severe, with a case
fatality of 20% to 40% and higher rates of neurologic sequelae compared with other subtypes (82).
Although JEV is recognized to cause more cases of encephalitis than any other mosquito-borne virus
worldwide, dengue viruses are the most prevalent arboviruses that infect humans and result in an
estimated 390 million infections every year (83). Infections with dengue typically result in dengue fever,
dengue hemorrhagic fever, and dengue shock syndrome. Unlike many of the aforementioned arboviruses,
neurologic manifestations of dengue have traditionally been considered to be the result of an
encephalopathy rather than encephalitis. However, detection of dengue viral RNA in brain tissue, virus
isolation in CSF, and the presence of dengue-specific CSF antibody suggesting intrathecal synthesis have
been described in recent studies and strongly suggest the neuroinvasive potential of dengue (84–86).
Rabies
Rabies virus is one of the oldest known infectious diseases and is considered to be the most deadly of all
infectious diseases (see Chapter 17). The number of rabies encephalitis cases in the United States has
declined dramatically from an average of 100 or more cases per year before 1940 to only 2 to 3 cases per
year (87). Although rabies is rare in the United States, an estimated 50,000 rabies cases occur annually
worldwide; most are acquired via rabid dog contact (88). In Asia, Africa, and Latin America, animal
rabies control programs and postexposure prophylaxis are limited. A recent report of 49 rabies cases in
the United States, from 1995 to 2011, identified 10 imported and 39 cases acquired in the United States;
of the cases acquired in the United States, one was associated with a raccoon strain of rabies, and the rest
were due to bat exposures. The incubation period is generally between 20 and 60 days but can range from
a few days to several years (89). Paresthesia at the site of the bite is unique to rabies and can be an
important clue to the diagnosis. Approximately 80% of human rabies cases develop the encephalitic
(“furious”) form characterized by unusual behavior, extreme agitation, hydrophobia, delirium, and
seizures. The remainder of cases develops the paralytic (“dumb”) form which is characterized by
ascending paralysis followed by confusion and coma. Patients generally have a predominance of one
form, but many affected individuals have components of both forms.
Lymphocytic Choriomeningitis Virus

Lymphocytic choriomeningitis (LCM) virus is an Old World arenavirus that can be acquired from infected
house mice, hamsters, and guinea pigs. Humans become infected with LCM virus when aerosolized
saliva, respiratory secretions, or urine from rodents or virus-contaminated dust are inhaled or possibly
ingested. Infections occur more frequently in the winter months when rodents migrate indoors (90). The
incidence of LCM is unknown but appears to have decreased substantially in the last several decades due
to improvements in housing, which have resulted in less contact between house mice and humans.
However, it is likely that cases continue to occur but are not recognized (91). LCM often results in a
biphasic illness with an initial phase of fever, anorexia, headache, muscle aches, nausea, and vomiting.
Several days later, CNS symptoms can occur with either meningitis or encephalitis. Extra-CNS
manifestations may also be present, including orchitis, parotitis, arthritis, or alopecia (92,93).
Hendra Virus
Hendra virus is a paramyxovirus first recognized in Hendra, Australia where it was associated with an
outbreak of respiratory and neurologic disease in horses and humans in 1994. The natural reservoir of the
virus is thought to be flying foxes (bats of the genus Pteropus). The virus is transmitted from bats to
horses and then transmitted to humans as a result of direct contact with infected horses. More than 60
equine and 4 human fatalities have been reported (94). The high fatality rate of this infection in horses and
people, as well as the large reservoir species, underscores the potential of this virus, and other similar
viruses, to emerge and cause outbreaks of severe illness. Human illness due to Hendra virus is
characterized by influenza-like symptoms often followed by acute encephalitis. A relapsing neurologic
syndrome has also been described in a few individuals (94).
Nipah Virus
Nipah virus, another emerging paramyxovirus, was first recognized in 1999 and associated with an
encephalitis outbreak among pig farmers in Malaysia. This virus has also caused outbreaks in Singapore,
Australia, Bangladesh, and India (95–97). Human infections can range from asymptomatic infection to
fatal encephalitis. When neurologic illness occurs, individuals often experience influenza-like illness
followed by dizziness, excess drowsiness, and altered consciousness.
Measles Virus
Measles virus infection causes acute encephalitis in approximately 1 in 1,000 cases, often resulting in
permanent brain injury (see Chapter 8). Although indigenous transmission of measles was eliminated in
the United States in 2000, it is still a common infection in much of the world. In addition to acute
encephalitis, measles is associated with subacute sclerosing panencephalitis (SSPE), an indolent,
progressive, and often fatal form of encephalitis that typically occurs 7 to 12 years after the initial
infection and usually affects children between 10 and 14 years of age (98,99). A history of prior measles
vaccination does not preclude the diagnosis of SSPE because an unrecognized measles infection may
occur at an early age prior to immunization. This is supported by molecular studies that have identified
wild type measles virus (rather than vaccine-type virus) from brain specimens of SSPE cases (100).
Early clinical features of SSPE include personality and behavior changes, lethargy, decline in school
performance, and hyperactivity. More pronounced neurologic manifestations such as aphasia, difficulty
walking, and involuntary movements (e.g., tremors, myoclonic jerks, and choreoathetosis) later ensue. In
the final stages, neurologic deterioration resulting in a vegetative state occurs in most affected patients
(99).
Bacteria
While many infectious encephalitis cases have a viral etiology, bacterial causes are important to consider
in the diagnosis either as a “mimicker” of encephalitis or as an actual cause of encephalitis. For example,
Neisseria meningitidis and Streptococcus pneumoniae do not cause encephalitis per se but can cause
clinical manifestations that are indistinguishable from encephalitis. Mental confusion, drowsiness,
convulsions, and coma are not uncommon manifestations of N. meningitidis and S. pneumoniae bacterial
meningitides (see Chapter 24).
Mycobacterium tuberculosis
Although meningitis is the most common form of neurotuberculosis, Mycobacterium tuberculosis was the
third leading cause of encephalitis in a French study where it was identified in 15% of cases (101). In
England, from 2005 to 2006, M. tuberculosis was the causative agent in 12% of encephalitis cases with
an identified cause (29). Analogously, in a multicenter study of encephalitis in Taiwan, M. tuberculosis
was the third most common cause of encephalitis in both pediatric and adult patients (31). Of 20 patients
with M. tuberculosis encephalitis referred to California Encephalitis Project (CEP) between 1998 and
2005, many had features in common with patients with viral encephalitis, including fever (75%), altered
consciousness (65%), personality change (45%), and hallucinations (16%) (102). Because the base of the
brain is often affected by M. tuberculosis, signs referable to cranial nerves are often seen along with
fever, headache, irritability, and drowsiness. Diffuse meningeal irritation may also result in impairment of
CSF resorption with accompanying hydrocephalus (see Chapter 29).
Listeria monocytogenes
Unlike S. pneumoniae and N. meningitidis that rarely cause parenchymal brain infections, Listeria
monocytogenes has tropism for the brain parenchyma itself as well as the meninges (103). The most
common CNS manifestation of listeriosis is of an isolated meningitis, but approximately 10% of patients
present with brainstem encephalitis, encephalitis, diffuse cerebritis, or abscess in cerebral cortex or
spinal cord (104). In the French study cited earlier, L. monocytogenes was the fourth most common
etiology identified (101). Reported risk factors for CNS Listeria include male gender,
immunosuppression, chronic illness, and advanced age (35,105–108). Conversely, an in-depth review of
Listeria rhombencephalitis found that it was reported primarily in healthy, nonimmunosuppressed middle-
aged adults and affected both genders equally (109). Clinically, a biphasic disease course may be seen; a
nonspecific prodrome lasting several days is typical of the first phase. The prodrome itself is similar to
many viral illnesses with fever, headache, nausea, and vomiting, but the duration of prodrome is longer in
CNS Listeria illnesses compared with viruses. The second phase is characterized by progressive
asymmetric cranial nerve palsies, cerebellar signs (e.g., ataxia or dysmetria), hemiparesis, and altered
level of consciousness (109).
Treponema pallidum
Treponema pallidum, the cause of syphilis, is yet another bacterial infection that can potentially be
confused with CNS viral etiologies. Syphilis, also known as the “great mimicker,” can be difficult to
recognize; this is particularly true for neurologic presentations. Neurologic manifestations can occur
during any stage of the infection and include meningeal syphilis, meningovascular syphilis, paretic
neurosyphilis, and tabes dorsalis (see Chapter 38).
Borrelia Species
Borrelia burgdorferi, the causative agent of Lyme disease, is primarily endemic to the eastern United
States, although reservoirs are also present in the Pacific Northwest and Midwestern states. Notably, the
geographic range is expanding. Lyme disease can affect both the peripheral and central nervous system;
CNS involvement is typically characterized by meningitis, although encephalitis can rarely occur (see
Chapter 39).
Rickettsia
Rickettsial infections can also cause encephalitis. Of the rickettsial diseases, Rocky Mountain spotted
fever (RMSF) and epidemic typhus are most commonly associated with neurologic manifestations (110).
In patients with RMSF, an intense headache along with restlessness, irritability, confusion, and delirium
often occur. General or focal neurologic impairment including vertigo, seizures, hemiparesis, and ataxia
may also be present (111). In a study of 92 children hospitalized with RMSF in the southeastern and south
central United States from 1990 through 2002, 33% had altered mental status, 18% photophobia, 17%
seizures, and 10% coma (112). Ophthalmic features including photophobia, conjunctivitis, petechiae of
the bulbar conjunctiva, exudates and retinal venous engorgement, papilledema, and ocular palsies are
frequently described (113,114). Acute temporary hearing impairment may also occur (115). Similar
neurologic complications have also been described for other rickettsial infections, although generally are
not as severe (116) (see Chapter 27).
Parasites and Free-Living Ameba
A number of parasites can cause encephalitis via direct invasion of the brain. Helminthes including
various ascaris, hookworms, Gnathostoma spinigerum, Angiostrongylus cantonensis, Spirometra spp.,
Alaria spp., and others can cause larva migrans, which refers to the prolonged migration and persistence
of helminth larvae in the tissues of humans (117,118). Larva migrans can result in visceral (VLM), ocular
(OLM), neural (NLM), and cutaneous larva migrans (CLM) based on the organ systems involved (118).
VLM and NLM are usually diseases of childhood, affecting children ages 1 to 8 years old.
B. procyonis, a common ascarid roundworm in raccoons, causes an eosinophilic encephalitis in
humans and other animals. It is most commonly identified in children and, although it is rare, often results
in a severe and fatal illness. B. procyonis occurs in raccoons in North America, Europe, and parts of Asia
(119). More than 90% of juvenile raccoons are infected in some areas of the United States (118). Humans
become infected by ingesting raccoon roundworm eggs in raccoon feces, by soil or water contaminated
with raccoon feces, or via contaminated hands. Small children are particularly vulnerable to infection
because of their propensity to place dirt and other objects in their mouths.
Other important neurotropic helminthes associated with eosinophilic encephalitis or meningitis
includes G. spinigerum and Angiostrongylus species. Gnathostomiasis, most commonly caused by the
nematode G. spinigerum, is a cause of eosinophilic myeloencephalitis. G. spinigerum is endemic in
Southeast Asia and is increasingly being recognized in Central and South America (120,121). Most cases
are associated with the ingestion of raw or undercooked fish, frogs, snakes, chickens, or ducks. The
median time from ingestion of infected food to onset of symptoms may be several weeks to several months
(122). Common early symptoms may include sporadic episodes of cutaneous larva migrans (“creeping
eruption”) with localized pain and pruritus. When CNS involvement occurs, it may result in the sudden
onset of radicular pain or headache. Paralysis of the extremities and loss of bladder control may also
occur (123). Cranial nerve abnormalities are also described. Intermittent symptoms can occur for 10 to 15
years after exposure because the larvae are long lived (124).
A. cantonensis, the rat lungworm, is the principal cause of human eosinophilic meningitis worldwide,
and although many cases are self-limiting, severe forms of the disease occur (125,126). Angiostrongylus
spp. have been reported in Louisiana and Hawaii as well as the South Pacific, Asia, Australia, and the
Caribbean (127,128). Humans become infected by ingestion of the third stage larvae in the molluscan
intermediate host (e.g., snails, crabs, freshwater prawns) or contaminated vegetables. Following
ingestion, the larvae penetrate the intestinal wall and reach the CNS via the bloodstream. Clinical illness
often consists of severe headache, photophobia, meningeal signs, hyperesthesia, and paresthesia. Coma,
paralysis of extremities, and seizures are seen in the severe forms of the disease (125,126).
Conjunctivitis, periorbital swelling, retinal hemorrhage, retinal detachment, or blindness may occur if the
eye is infected (129,130) (see Chapter 46).
Free-living ameba are ubiquitous in nature, and a few have been associated with human disease. Those
causing encephalitis are generally divided into two clinical entities: (a) primary amebic
meningoencephalitis due to Naegleria fowleri (also known as “the brain-eating ameba”), and (b)
granulomatous amebic encephalitis.
Primary amebic meningoencephalitis (PAM) is a fulminant disease occurring in children and young
adults. The disease has been reported in Australia, Europe, Asia, Africa, and North America. In the
United States, most of the cases have developed in the southern tier of the country, where warm water
conditions are more likely to be encountered. Typically, humans become infected with N. fowleri while
swimming or washing in warm, fresh water containing the ameba. Recent cases associated with the use of
“neti” pots where N. fowleri–contaminated tap water were implicated as the source of infection have also
been described (131). The onset of PAM is usually within 2 to 3 days after exposure, and symptoms
include severe headache, fever, stiff neck, nausea, vomiting, diplopia, seizures, behavioral changes, and
coma (132–135). Distortion of taste or smell may also be a clinical feature (136,137). The case fatality
rate is very high; of 111 reported cases in the United States between 1962 and 2008, only one individual
survived (131).
Two different closely related ameba cause granulomatous encephalitis: Acanthamoeba spp. and B.
mandrillaris. Acanthamoeba granulomatous encephalitis is an opportunistic, chronic disease that may
have a prodromal period of weeks to months. Predisposing factors to acanthamebiasis include steroid
treatments, autoimmune conditions, organ transplants, chemotherapy, radiation therapy, alcoholism, and
pregnancy (134,138). A small number of Acanthamoeba granulomatous encephalitis cases have been
described in immunocompetent children. Clinical features of CNS Acanthamoeba infections are variable
but typically have a subacute to chronic presentation with fever, headache, seizures, personality change,
lethargy, or confusion. Cranial nerve palsies, meningeal signs, or hemiparesis may be seen on physical
exam (138). Children infected with Acanthamoeba have exhibited headache, stiff neck, vomiting,
abnormal behavior, fever, ataxia, and tonic-clonic seizures (139–141).
When first described, B. mandrillaris was considered to be very rare, but recent reports suggest it may
be more common than previously recognized (142–145). Symptoms of Balamuthia granulomatous
encephalitis include fever, headache, vomiting, ataxia, hemiparesis, tonic-clonic seizures, cranial nerve
palsies (third and sixth cranial nerves), and diplopia (146). Otitis media has preceded the onset of
Balamuthia granulomatous encephalitis in several pediatric cases (146,147). Hydrocephalus develops in
many cases (147,148). Interestingly, two independent case reports involving Balamuthia encephalitis
patients describe associated CNS aneurysms (149,150) (see Chapter 45).
Fungi
Although fungal CNS infections do not cause encephalitis per se and often manifest as meningitis and
abscesses, some patients present with encephalitis-like symptoms. These illnesses are more common in
immunocompromised individuals, but fungal neurologic infections can be seen in immunocompetent
individuals. Important fungal causes of CNS infections in the United States include Cryptococcus
neoformans, Coccidioides immitis, Histoplasma capsulatum, and Blastomyces dermatitidis.
Cryptococcus gattii is an emerging fungal infection in the United States, particularly in the Pacific
Northwest, and has a greater tendency to affect normal hosts than Cryptococcus neoformans (151) (see
Chapter 40).
Other Agents
Hundreds of other infectious agents have been associated with encephalitis, but the frequency and
significance of many of them are unknown. This is especially true when a nonneurotropic agent is found in
a patient with encephalitis, particularly when the agent is identified outside the CNS. For example,
Mycoplasma pneumoniae is one of the most commonly diagnosed infections among children with
encephalitis (see Chapter 25). However, the significance of this association is unclear, particularly as
most of the diagnoses are based on a positive immunoglobulin M (IgM) antibody to M. pneumoniae. M.
pneumoniae is a ubiquitous pathogen, and there is a high background incidence of acute infection.
Furthermore, there are many limitations of Mycoplasma serologic testing (152). Other similar examples
of nonneurotropic agents implicated as causative agents include parvovirus B19, rotavirus, and human
metapneumovirus (153–155).
Although the association of influenza viruses and encephalitis is better documented and more accepted
than parvovirus B19, rotavirus, or human metapneumovirus, the mechanism by which influenza leads to
neurologic illness is poorly understood. Influenza-associated encephalitis (IAE) and encephalopathy is
typically characterized by a rapidly progressive neurologic illness. Cases have been described
sporadically and follow the seasonal influenza pattern, with illnesses typically occurring during winter
months in temperate climates. IAE is more common in the pediatric population than in adults. Evidence of
neuroinvasion by influenza is rarely seen; these cases are better characterized as an encephalopathy rather
than encephalitis. Many cases of IAE, especially acute necrotizing encephalopathy (ANE), have been
reported from Japan, but cases of encephalitis and encephalopathy have been reported throughout the
world, including the United States (156,157). Several case reports and case series describe neurologic
illness associated with the pandemic H1N1 influenza virus, including encephalitis/encephalopathy
(158–160).
Similarly, the neurologic illness associated with Bartonella is often an encephalopathy rather than
encephalitis. Cat-scratch disease (CSD), typically caused by Bartonella henselae, is usually a self-
limited infection associated with fever, regional lymphadenopathy, and malaise. As the name implies,
many affected individuals have contact with a cat, often a kitten. Atypical presentations can occur
especially in children and young adults and immunocompromised individuals. In a case series of 130
CSD cases in Japan, 19 (15%) had encephalopathy (161). Although lymphadenopathy is a hallmark of
CSD, it is not always present in encephalopathy cases (161). Neuroretinitis can be an associated feature
as well (162).
ACUTE DISSEMINATED ENCEPHALOMYELITIS

The incidence of acute disseminated encephalomyelitis (ADEM) is estimated to be 0.4 to 0.8 per 100,000
and it accounts for 10% to 15% of encephalitis cases in the United States (163–165). It is more common
in children than adults, and many cases of ADEM have an identifiable trigger such as a recent illness or
vaccination. Neurologic symptoms typically develop 2 to 4 weeks after the trigger with rapid progression
of symptoms (165). Prior to the widespread use of vaccine-preventable diseases in the United States,
measles and mumps were common triggers of ADEM. In regions of the world where vaccines are widely
used to prevent measles and mumps, such as the United States and Canada, upper respiratory infections
are now the most commonly identified triggers of ADEM.
ADEM affects multiple regions of the brain and spinal cord and is characterized by the rapid onset of
encephalopathy along with multifocal neurologic deficits. Up to three quarters of patients with ADEM
will have altered mental status, whereas seizures occur in 10% to 35% of patients (165). Motor deficits
(e.g., acute hemiparesis), ataxia, decreased verbal output or mutism, cranial neuropathies, and urinary
disorders are common (166). Recovery can be complete, although residual deficits can occur in up to
30% of patients.
NONINFECTIOUS ETIOLOGIES
There is growing recognition that immune-mediated conditions result in a substantial proportion of cases
of encephalitis. Anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis, a relatively newly
recognized neuronal antibody-associated encephalitis, deserves special mention because of the seemingly
high frequency of the syndrome. In the California Encephalitis Project, the frequency of anti-NMDAR
encephalitis surpasses that of any single viral entity in the pediatric population and also contributes to
cases in adulthood (167).
Clinically, anti-NMDAR encephalitis is characterized by abnormal behavior, seizures, and movement
disorders followed by decreased level of consciousness and autonomic instability and may be associated
with ovarian teratoma (168). Importantly, the development of prodromal symptoms of headache, low-
grade fever, or a nonspecific viral-like illness prior to the onset of neurologic symptoms in many patients
may initially suggest the diagnosis of an infectious, rather than autoimmune, encephalitis (168).
Another important cause of immune-mediated encephalitis is anti–voltage-gated potassium channel
(VGKC) encephalitis. Patients are typically older than 50 years of age, present with symptoms of limbic
encephalitis (memory dysfunction, behavioral changes, and seizures) and hyponatremia, and rarely have
an underlying neoplasm. Although antibodies were initially thought to recognize the VGKC receptor,
subsequent studies have demonstrated that the target of autoimmunity is usually a different antigen (i.e.,
LGI1 or CASPR2) that is tightly associated with the VGKC complex (168,169). Several other antibodies
are also associated with limbic encephalitis, including those that recognize glutamic acid decarboxylase
(GAD), AMPA receptor, and the γ-aminobutyric acid (GABAb) receptor. Intracellular onconeural
antibodies associated with paraneoplastic conditions (e.g., anti-Hu, Yo, Ma2, CV2, amphiphysin,
CRMP5, etc.) also need to be considered (170).
PATHOLOGY
Given the many different etiologies of encephalitis, the pathology is highly variable and dependent not
only on the underlying etiology but also the relative severity of the infection. The characteristic histology
of patients with viral encephalitis includes perivascular mononuclear cell inflammation, phagocytosis of
neurons, and microglial nodules. Distinctive characteristic histopathologic features are seen with some
viral infections; intranuclear inclusion bodies are sometimes seen in herpes simplex and varicella zoster,
whereas Negri bodies (eosinophilic cytoplasmic inclusions) are found within Purkinje cells and are
pathognomonic for rabies (Fig. 6.1).
EVs, parechoviruses, herpesviruses, arboviruses, and rabies have well-established neurotropic
potential where the virus directly invades the CNS and primarily affects the gray matter of the brain.
Other viruses, such as measles and rubella viruses, primarily affect the white matter of the brain by
triggering an autoimmune reaction and result in a postinfectious encephalitis (e.g., ADEM). Symptoms
indistinguishable from viral encephalitis can be seen in patients with bacterial meningitis and rickettsial
infections where associated vasculitis and elaboration of toxins can lead to CNS dysfunction. Intense
inflammatory responses to fungi, free-living ameba, and parasites can also lead to CNS dysfunction.
Organisms enter the CNS by different routes. Most enter via the bloodstream, as is the case for EVs,
HPeVs, and arboviruses as well as several bacteria, rickettsia, and fungal agents (171). Once the agent
reaches the CNS, the blood–brain barrier is penetrated via the choroid plexus or through vascular
endothelium (172).
The proposed mechanism for entry into brain of the amebae varies by organism. For example,
Balamuthia is thought to enter the CNS via a hematogenous route, with ameba entering the bloodstream
either from the lungs or from cutaneous lesions. Naegleria ameba, on the other hand, enter the nasal
passages and directly extend into the CNS by penetrating the olfactory mucosa, entering the submucosal
nervous plexus, migrating along the olfactory nerves, and traversing the cribriform plate. A distinct
mechanism of entry via axon transport resulting in intraneuronal route is used by some viruses such as
rabies and HSV-1.
Within the CNS, the pathogen often targets specific cells and, depending on the brain region affected,
variable clinical manifestations ensue (173). Agents with specific predilection to areas such as the
brainstem (e.g., EV-71 and Listeria) can cause rapid decompensation with coma or respiratory failure.
Herpes simplex encephalitis characteristically affect the temporal lobes and cause hemorrhage and
necrotizing lesions (174) (Fig. 6.2).
WNND has a predilection for the gray matter of the brainstem and spinal cord, but cerebellum,
temporal lobe, basal ganglia, and thalamus may also be affected (175). Indeed, many of the neuroinvasive
flaviviruses such as JEV, TBEV, and WNV have a predilection for specific regions of the brain, including
those regions important for motor control (thalamus, basal ganglia, brainstem, and anterior horn cells of
spinal cord) (176).
In other instances, the infectious agents do not necessarily infect neurons. Nonneuronal cells, such as
oligodendroglia, may be infected, with resultant demyelination (177). Alternatively, an infection may
cause immune changes that result in damage. EBV-associated encephalitis, for example, may be a result of
an immunologic phenomena rather than acute neuroinvasion. There is typically a 1- to 3-week delay in the
onset of neurologic symptoms after acute EBV infection (40). Further, the virus itself is often not found in
the CSF (40). In one cohort of five EBV encephalitis patients with CNS demyelination, four had
prodromal symptoms for 2 weeks or more and did not have EBV detected by polymerase chain reaction
(PCR) in CSF (40). Conversely, the development of neurologic symptoms either in the absence of, or
within a few days of prodrome onset in the presence of, EBV in the CSF is suggestive of direct invasion.
In the pediatric series cited previously, one such patient had EBV detected by PCR in brain tissue,
suggesting that direct invasion of the brain may occur in some cases.
Viruses such as influenza are well known to be associated with CNS manifestations, but the
mechanisms by which they cause neurologic signs and symptoms are not well understood. The lack of
viral detection in most IAE cases in the CNS strongly points to a different pathogenesis; a number of
potential mechanisms have been invoked, including excessive production of proinflammatory cytokines,
vascular endothelial dysfunction, and mitochondrial dysregulation (178).
As discussed earlier, Listeria may be associated either with a pure meningitis or encephalitis.
Pathologically, a suppurative reaction is seen in the meningitic form, whereas a granulomatous response
is seen in the meningoencephalitis form (104).
Rickettsial agents invade and multiply in vascular endothelial cells, leading to vasculitis both within
and outside the CNS (179,180). Vasculitis in the small vessels in the brain leads to meningeal irritation
with perivascular mononuclear infiltrates. Characteristic pathologic lesions within the CNS include
multifocal glial nodules and arteriolar microinfarctions (181).
In partially treated bacterial meningitis and in tuberculous and fungal meningitis, a chronic basilar
meningeal inflammation can cause a subarachnoid exudate, leading to obstruction of CSF reabsorption
with resultant communicating hydrocephalus and cranial nerve palsies. CNS vasculitis can also lead to
infarcts and focal neurologic deficits.
N. fowleri, a free-living ameba, causes destruction of gray matter and devastation of the olfactory bulbs
with purulent meningitis and pronounced brain edema (182). In Balamuthia and Acanthamoeba CNS
infections, a granulomatous reaction occurs with affected areas including the cerebrum, cerebellum, and
brainstem, where the amebae produce hemorrhagic necrotic lesions. Multinucleated giant cells, focal
necrosis, and hemorrhage are seen in brain histopathology. In some instances, large sheets of ameba can
be found in the perivascular areas of brain tissue (Fig. 6.3).
B. procyonis and other nematodes that invade the CNS cause damage by CNS larval migration, with
histology demonstrating inflammation and necrosis with “track”-like spaces. Pathologic findings of fatal
cases demonstrate necrosis and inflammation with eosinophils, macrophages, lymphocytes, and plasma
cells concentrated in periventricular white matter and leptomeninges in brain tissue. A characteristic of
NLM/Baylisascaris infection is a large number of eosinophils and eosinophil granules surrounding the
nematode migration track and blood vessels (183).
DIAGNOSTIC APPROACH OF PATIENTS WITH ENCEPHALITIS
Identification of a specific etiology, even if there is no available treatment, is important for counseling of
patients and families, potential postexposure prophylaxis of contacts, and other public health
interventions. Additionally, the identification of a specific agent may lead to withdrawal of unnecessary
antimicrobial agents and reduce further testing. Knowledge of limitations of testing, appropriate test
selection, and timing of sample collection is crucial to optimal diagnosis.
A thorough assessment of exposures highlighting ill contacts, occupational exposures, vector and
animal exposures, outdoor activities, and ingestions should be ascertained. Both recent (e.g., for
arbovirus) and remote (e.g., rabies, fungal) travel history are important. Any recent or current respiratory,
gastrointestinal, or rash illness should be investigated. Based on this information, specific assays can be
performed (Tables 6.1 and 6.2) (184).
A complete blood count, renal function tests, hepatic enzyme levels, and coagulation studies should be
included in the evaluation of a patient with suspected encephalitis. An initial chest radiograph should also
be performed as focal infiltrates are suggestive of certain pathogens (e.g., fungal or mycobacterial
infections) and might lead to other diagnostic studies (e.g., bronchoscopy). A thorough eye exam by an
ophthalmologist may identify a migratory nematode which would considerably narrow the differential.
Unless there is a specific contraindication, a lumbar puncture (LP) with cerebrospinal fluid (CSF)
analysis (cell count with differential analysis, glucose and protein concentrations) and a measurement of
the opening pressure should be performed (185). A simultaneous peripheral glucose should also be
measured and is particularly important in a diabetic patient because what appears to “normal” CSF
glucose might actually be low if the ratio of CSF to serum glucose is not taken into consideration (102).
The CSF sample should be analyzed promptly, particularly because neutrophils degrade within a few
hours (186). Additionally, if the CSF cell counts are performed by an automated cell counter, eosinophils
can be mistaken for neutrophils. Accurate identification of eosinophils is best done by Giemsa or Wright
stain of CSF (128). The identification of CSF oligoclonal bands, representing intrathecal antibody
synthesis, is a nonspecific finding but can be helpful in corroborating an infectious or inflammatory
etiology.
The CSF profile offers important diagnostic clues on whether a patient has an infectious or
noninfectious etiology and, within the infectious sphere, whether the cause is likely viral, bacterial,
fungal, or parasitic. The CSF profile in most viral encephalitis patients demonstrates CSF mononuclear
cell pleocytosis, with cell counts ranging from 10 to 200 mg/dL. However, several studies have shown
that pleocytosis can be absent or there may be an elevation in neutrophils early in the course. Although
many textbooks mention that polymorphonuclear leukocytes (PMNs) can predominate the first 24 hours of
viral CNS infections and suggest that a shift to mononuclear cells occurs after that time period, there have
been studies showing that PMNs may still predominate well beyond this 24-time period (187). Therefore,
a repeat LP a few days following the first LP may be useful (188,189). In viral encephalitis, the CSF
protein generally is elevated but is typically less than 100 mg/dL, whereas the glucose level is almost
always normal with a few important exceptions (e.g., LCM and mumps; Table 6.3).
As outlined earlier, viral infections can sometimes be associated with a neutrophilic predominance;
however, when a neutrophilic pleocytosis is observed, particularly in cases where CSF white blood cell
(WBC) count is more than 1,000 cells/mm3, protein more than 100 mg/dL, or CSF glucose level less than
2/3 of serum levels, a nonviral entity should be strongly considered. For most bacterial pathogens, the
CSF shows a WBC of 1,000 to 5,000 cells/mL with predominance of neutrophils (80% to 95%), glucose
less than 40 mg/dL in over half the cases, and a CSF glucose level less than 2/3 serum levels. In fungal
infections, moderate lymphocytic pleocytosis usually is found along with elevated protein and low CSF
glucose.
Eosinophils in the CSF are suggestive of a helminth infection (e.g., B. procyonis, Angiostrongylus spp.,
and G. spinigerum). Eosinophils can also be seen in patients with neurococcidiomycosis or neuro-
Mycobacterium tuberculosis. In patients with PAM, the CSF typically contains a very high CSF cell
count with a predominance of neutrophils, a slight to pronounced decrease in glucose concentration, and
an increased protein content (75 to 970 mg/dL). The amebae can sometimes be seen in wet-mount
preparations of spinal fluid (139,140,190). In patients with CNS Balamuthia infections, elevated CSF
WBC is often seen along with mild to markedly elevated protein (>1,000 mg/dL) and normal or slightly
decreased glucose.
Although brain biopsy in the setting of suspected encephalitis has become less common, examination of
brain tissue still has utility because of limitations in both molecular and serologic methods. The use of
targeted biopsy was recently demonstrated by a report of 16 patients with undiagnosed CNS illness where
brain biopsy detected bacterial abscess (6), toxoplasmosis (3), HSV (1), Aspergillus infection (2), and
M. tuberculosis infection (2). Biopsies can also be particularly helpful for the diagnosis of noninfectious
entities such as small vessel vasculitis and intravascular lymphoma (191). An autopsy should be
encouraged to determine the cause of death in patients who die with unexplained encephalitis.
In addition to studies done acutely, an extra red top serum tube should be drawn during the acute phase
of illness and held for later serologic studies. A convalescent serum should be collected 10 to 21 days
later. Similarly, extra spinal fluid should also be frozen for future testing. Specific caveats of testing are
outlined in Table 6.3 and selected agents are outlined in the following sections.
TESTING OF SELECTED ETIOLOGIES

Viral Testing
Specific studies for viral agents often employ molecular testing. Molecular testing by nucleic acid
amplification (e.g., PCR) testing provides more timely and typically more sensitive results than culture
for viral CNS infections (116,192,193). However, the limitations of these tests are often not recognized
by physicians, particularly false-negative and false-positive results as discussed in the following sections
for specific agents. Testing for intrathecal antibody synthesis of specific pathogens such as arboviruses
and herpesviruses can be useful adjunct for diagnosis, particularly in the later stages of disease (see the
following discussion).
In patients with either preceding or concurrent respiratory symptoms, a viral culture from the
respiratory tract should be performed early in the hospital course to optimize the virus recovery. When a
particular agent such as influenza or another virus is suspected but the viral culture is negative, agent-
specific PCR testing should also be performed. Similarly, if there is a history of preceding or concurrent
diarrhea, a stool culture for viral and, possibly, bacterial pathogens should be performed. In children, a
stool viral culture and/or EV PCR should be routinely performed to enhance EV detection, regardless of
the presence of diarrhea.
Herpesviruses
The diagnostic test of choice for HSE is CSF HSV-1 DNA nucleic acid (PCR) testing. If testing from the
first LP is negative and HSE is still suspected (e.g., temporal lobe involvement seen on neuroimaging), a
second LP should be performed within 24 to 48 hours as a number of studies have shown that HSV PCR
can be falsely negative, particularly early in course of illness and in the pediatric age-group (22,189). For
HSE, intrathecal antibodies can be performed as a complement to molecular testing, and this may be
particularly helpful in establishing the diagnosis later in the course. Intrathecal synthesis of HSV-specific
IgG antibodies can often be detected 10 to 14 days after the onset of illness (194).
As mentioned in the clinical and epidemiology section, the clinical spectrum of CNS infections
associated with HSV-2 often differs from HSV-1. Molecular testing of CSF for the presence of nucleic
acid is the most reliable method for diagnosis for HSV-2; intrathecal antibody testing can be used as an
adjunct as described previously for HSV-1.
Because VZV encephalitis is one of the most common causes of encephalitis in adults, VZV testing
should be performed in all adult patients, with or without skin lesions. Testing should include both CSF
VZV PCR and CSF VZV antibody (195). Although detection of VZV antibody in the CSF can be more
sensitive than PCR, intrathecal synthesis may be delayed by a week or more after onset of neurologic
symptoms (196,197). In the event of a traumatic tap, distinguishing intrathecal antibody synthesis versus
blood contamination of CSF may be accomplished by calculation of an antibody index (198).
For the diagnosis of EBV encephalitis, both serology and molecular testing is recommended (40).
Quantitative viral load may be helpful, as a high viral load supports a significant CNS infection, whereas
a low positive PCR in CSF may represent latent virus and may only be an incidental finding (199,200).
Conversely, the absence of a positive PCR in the setting of acute EBV serology does not rule out acute
infection, and a negative PCR may be a result of the timing of LP (i.e., after virus has cleared from CSF)
or may reflect a mechanism other than direct infection.
CSF PCR testing is recommended for the diagnosis of HHV-6 and HHV-7; however, the finding of a
positive CSF PCR for HHV-6 or HHV-7 is not necessarily equivalent to a diagnosis of HHV-6 or HHV-7
encephalitis. This is because HHV-6 DNA can be present in normal brain tissue and HHV-6 may be
identified in CSF as an incidental “bystander” rather than a cause of infection (201). Additionally,
chromosomal integration must be considered as a potential reason for a positive PCR in the CSF. If a
positive HHV-6 CSF PCR is obtained, an evaluation of HHV-6 in the blood should be done to distinguish
between chromosomal integration and acute infection (48).
Enteroviruses and Parechoviruses

PCR testing of both CSF and a throat specimen should be performed; if only CSF is tested, the diagnosis
may be missed. For example, in an outbreak of EV-71 in the United States, EV PCR of CSF was positive
in only 5 (31%) of 16 cases, whereas PCR testing of throat specimens were uniformly positive (202,203).
Because EVs may be shed in the stool for weeks after infection, culturing the stool for EV may increase
the diagnostic yield; for the same reason, a positive stool is suggestive, but not confirmatory, of the
diagnosis. Testing for parechoviruses should be considered in all children younger than 3 years of age
with the same range of biologic samples tested as EVs. Parechoviruses can only be detected by
parechovirus-specific PCR assays.
Arbovirus
For most arboviruses, serologic testing of CSF and serum is preferred to molecular testing because peak
viremia generally occurs prior to symptom onset (204). The diagnosis of WNV infection is typically made
via detection of IgM capture enzyme-linked immunosorbent assay (MAC-ELISA) or a fourfold or greater
change in antibody titer on paired or convalescent serum. Approximately 90% of patients with
neuroinvasive disease will have detectable CSF IgM antibody by days 8 to 10 after symptom onset (205).
However, WNV IgM may persist for prolonged periods, with detectable IgM titers persisting more than
500 days after presentation in some individuals with neuroinvasive disease (206). Furthermore, there is
serologic cross-reactivity between the flaviviruses (SLEV, dengue virus, yellow fever virus, or JEV),
such that individuals infected with, or vaccinated against, one of these agents could test positive for WNV
by IgM MAC-ELISA. Differentiation of WNV from other flaviviruses is achieved by plaque reduction
neutralization testing (PRNT) (207).
For other arboviruses, the standard method for diagnosis is similar, namely through detection of IgM or
a fourfold or greater change in antibody titer on paired acute and convalescent serum (208).
Other Viral Testing

The diagnosis of rabies should be considered in any rapidly progressing encephalitis. Antemortem testing
for rabies requires highly specialized testing in a public health laboratory using a combination of different
assays and specimen types (209). Whenever the diagnosis of rabies is entertained, consultation with
public health authorities is strongly recommended. Testing for other viruses should be performed as
suggested by exposures or travel history.
Bacterial Testing
In most instances, detection of routine bacterial pathogens via Gram stain and/or culture is fairly
straightforward. The CSF bacterial culture for L. monocytogenes, however, is relatively insensitive
compared with many other bacterial agents. Additionally, in contrast to many bacterial pathogens, the CSF
profile of CNS listeriosis patients, particularly those with rhombencephalitis, can appear normal or
similar to viral illnesses with only a mild pleocytosis, a lymphocytic predominance rather than
polynuclear predominance, and a normal to minimal protein elevation (109) (see Table 6.3).
Neurotuberculosis can also be difficult to diagnose. The sensitivity of CSF tuberculosis (TB) PCR is
very poor; reported sensitivity has been less than 25% in some studies (102). This may be because of low
bacillary load in the CSF, relatively small CSF volumes submitted for testing, or PCR inhibitors in
samples (210). Testing from both CNS and extra-CNS sites should be done for the workup of neuro-TB
(see Table 6.3).
Fungal Testing
Fungal meningoencephalitis is typically a subacute illness. Fungal culture of the CSF should be performed
in individuals with indolent symptoms, immunocompromised persons, or when the CSF findings are
suggestive (e.g., CSF lymphocytic pleocytosis, high protein, and low glucose). If a fungal etiology is
suspected, several different tests including culture, antigen test, and serology on both CNS as well as non-
CNS specimens should be done (see Table 6.3) (211).
Rickettsial Testing
Diagnostic testing is similar for most rickettsial infections. Serology is the most widely used method, and
the indirect fluorescent antibody (IFA) assay is considered the gold standard. Because serologic tests may
be negative early in the illness, detection of the rickettsial agent in blood or tissues by molecular assays
(e.g., PCR) may be useful. Confirmation of disease is best accomplished by evaluation of paired serum
specimens collected during the acute and convalescent phases of the illness for a fourfold or greater
change in antibody titer. Immunohistochemistry of patients’ tissues (e.g., brain) is another methodology
that can be used to diagnose rickettsial infection (212).
Parasitic and Free-Living Ameba Testing
The diagnosis of Baylisascaris is often suggested by a history of exposure to raccoons (or their feces),
clinical presentation, and persistent eosinophilia in the blood and spinal fluid. Serologic assays are
available at the Centers for Disease Control and Prevention (CDC). In patients with a history of travel
outside the United States with presence of CSF eosinophilia, both gnathostomiasis and Angiostrongylus
should be considered. An ELISA test has been developed but is not widely available (213). Molecular
tests for Angiostrongylus are available at the CDC.
Molecular technology is also available for the identification of Balamuthia and Acanthamoeba DNA
in tissues and CSF (CSF PCR is less sensitive than brain tissue PCR) but is largely limited to research
laboratories and the CDC.
NEUROIMAGING MODALITIES
Neuroimaging plays a crucial role in the evaluation of patients with suspected encephalitis, as it may
support the diagnosis of a specific etiology or identify alternate conditions that mimic encephalitis (Table
6.4). Routinely available studies to evaluate patients with suspected encephalitis include computed
tomography (CT) and magnetic resonance imaging (MRI). CT scanning involves the application of x-rays
to produce tomographic images, resulting in excellent delineation of bony structures; conventional MRI
uses nuclear magnetic resonance (MR) to detect hydrogen nuclei and provides good contrast between soft
tissues. Of the two, MRI is far more sensitive and specific for the evaluation of infectious encephalitis
(214–216). Conventional MRI imaging entails acquisition of various sequences that provide
complementary information. For example, T1-weighted imaging (T1W) is well suited to define structural
abnormalities; T2-weighted imaging (T2W) and fluid-attenuated inversion recovery (FLAIR) sequences
may identify areas of edema, demyelination, or inflammation; and susceptibility-weighted imaging (SWI)
is particularly useful in identifying areas of hemorrhage. T1W imaging following gadolinium
administration can identify parenchymal or meningeal regions where the blood–brain barrier has been
compromised, as occurs in active inflammation. Of particular note is diffusion-weighted imaging (DWI),
which identifies brain regions where diffusion of water is restricted and may be more sensitive than other
conventional sequences for detection of early abnormalities in encephalitis (217,218).
Several additional imaging modalities have emerged for evaluation of encephalitis. MR spectroscopy
can identify a number of metabolites, including N-acetylaspartate (NAA), choline, creatine, and lactate,
based on unique proton chemical shifts. Quantification of the ratios of these metabolites can provide
information regarding inflammation, neuronal loss, and demyelination. Both single-photon emission
computed tomography (SPECT) imaging and fluorodeoxyglucose positron emission tomography (FDG-
PET) involve detection of radioisotopes within the brain following injection into the bloodstream and can
provide information regarding metabolism. Other MR-based techniques, including magnetization transfer
and diffusion tensor imaging, as well as molecular imaging techniques that allow for the detection of
disease-specific molecules, are currently being optimized and may eventually show promise in evaluation
of patients with encephalitis (219).
Imaging of Selected Etiologies
Herpesviruses
The neuroimaging findings of encephalitis caused by HSV-1 reflect its predilection for the limbic system,
with frequent involvement of the mesial temporal and inferior frontal lobes (Fig. 6.4).
In the acute stage, HSE typically results in edema, inflammation, or hemorrhage. Although initial CT
scans are normal in up to 25% of affected individuals, greater than 90% of patients with HSE documented
by CSF PCR will have MRI abnormalities (220–223). Abnormalities on conventional MRI appear within
48 hours and include isointense or hypointense lesions on T1W images and hyperintense lesions on T2W
or FLAIR images. Changes in DWI, which may reflect the rapid accumulation of intracellular water in the
setting of impaired ion transport during acute infection, are seen even earlier (218,224,225). MRI is
superior to CT in the detection of subacute (>1 week) hemorrhage. Contrast enhancement on MRI is
typically in a cortical gyral pattern and often lags behind symptom onset (226). Extratemporal
abnormalities occur in over half of cases and may involve the cerebral hemispheres, thalamus, and
brainstem (227–229). Notably, in up to 15% of patients, extratemporal involvement may be the sole-
observed neuroimaging abnormality (229) and is more likely to occur in pediatric and
immunocompromised populations (230–232). MR spectroscopic findings have also been described,
although the clinical use of this imaging modality in the evaluation of HSE remains undefined.
Abnormalities, which typically include decreased NAA and increased choline, myoinositol, and lactate,
are thought to represent loss of neuronal integrity and necrosis with accompanying macrophage infiltration
and gliosis (233–235).
In several case series of VZV encephalitis, the most notable finding was the absence of brain imaging
abnormalities in the majority of patients. In a minority of patients, affected regions included the temporal
lobe and brainstem. A notable caveat is that many patients in these series underwent CT scanning only
(32,236). VZV vasculopathy is often associated with T2W hyperintensities in the white matter and at the
gray–white matter junctions on MRI, with evidence of either ischemia or hemorrhage (25). The most
commonly reported imaging abnormalities in EBV-associated encephalitis include multiple, diffuse
hyperintensities on T2W and FLAIR imaging, often transient and with involvement of the splenium of the
corpus callosum (237–239).
HHV-6 associated limbic encephalitis typically involves the mesial temporal lobe (hippocampus,
entorhinal cortex, and amygdala). Additional cortical and subcortical areas can be involved and may be
associated with specific clinical subtypes (240,241). Involved areas are characterized by T2W
hyperintensity and variable degrees of enhancement. In addition, increased hippocampal uptake of
glucose, suggestive of increased metabolic activity, has been detected by FDG-PET (242,243). Although
both HSE and HHV-6 limbic encephalitis are associated with mesial temporal abnormalities, a recent
study suggested that early extratemporal involvement was more likely in HSE (244). Rarely, HHV-6
infection of the CNS has been associated with a syndrome similar to ANE (51,245).
Enteroviruses
Although poliovirus has almost completely disappeared in developed countries, nonpolio EVs are an
important cause of diffuse, generalized encephalitis. In such cases, neuroimaging is typically normal.
Certain EVs, however, may result in similar clinical and radiographic manifestations as poliovirus. EV-
71, for example, is characterized by symmetric bilateral T2W hyperintensities in the dorsal brainstem,
cerebellar dentate nuclei, and anterior horns of the cervical spinal cord on MRI (246,247) (Fig. 6.5).
As in many cases of acute encephalitis, DWI appears to be more sensitive than other conventional
sequences for detection of EV-71 lesions (248). Echovirus 7-associated encephalomyelitis is also
associated with a similar topographical distribution on MRI (249). Isolated reports of unilateral and
bilateral hippocampal lesions in the setting of acute enteroviral infection have also been described
(250,251).
Arboviruses
Neuroimaging abnormalities in WNV often involve the deep gray matter, although findings are highly
variable and up to half of patients may have normal brain MRI (233,252,253). In those who develop a
flaccid paralysis, spinal cord imaging may demonstrate T2W hyperintensities in the anterior cord and
gadolinium enhancement of the cauda equina, conus medullaris, and nerve roots (252,254). Limited
studies of other arboviruses, including SLE, EEE, TBE, and Murray Valley encephalitis, suggest
involvement of the substantia nigra and other deep gray structures, and the latter three viruses may also
resemble WNV acute flaccid paralysis both clinically and radiographically (255,256). The considerable
overlap in the neuroimaging spectrum of these arboviruses prevents discrimination between these
etiologies based on imaging alone.
JEV is most commonly associated with T2W hyperintensities on MRI in the thalami, with variable
involvement of the substantia nigra, basal ganglia, brainstem, cerebellum, and cortex (257). Although the
presence of thalamic abnormalities is highly sensitive for JEV in the appropriate clinical setting, their
absence does not rule out JEV (258). Mesial temporal lobe involvement has also been reported, although
unlike herpes encephalitis, the insula and anterior portion of the temporal lobe are usually spared, while
additional thalamic lesions are typically present (259,260). In JEV cases with biphasic illness, regression
of prior lesions and the appearance of new lesions in typical areas are described (261,262). In cases of
dengue encephalopathy, focal MRI abnormalities in a number of brain areas have been found. In addition,
generalized cerebral edema has been reported and may be related to the prominent metabolic disturbances
observed in affected individuals (263).
Bilateral frontoparietal white matter lesions with restricted diffusion, suggestive of subcortical strokes,
have been reported in two cases of Chikungunya encephalitis (264). However, in another case series of
children with various CNS manifestations including encephalitis, MRI abnormalities were only rarely
observed (265).
Rabies
The often rapid clinical course of rabies encephalitis presents a challenge in obtaining neuroimaging. The
limited available data demonstrate diffuse T2W hyperintensities affecting both the deep and cortical gray
matter of the brain and spinal cord in both the paralytic and encephalitic forms of rabies (266). Although
abnormalities may also be seen in the white matter, the predominant gray matter involvement distinguishes
rabies encephalitis from ADEM. Initially nonenhancing, the gray matter lesions may demonstrate
gadolinium enhancement once the patient becomes comatose (267).
Nipah
In the acute phase, Nipah encephalitis is associated with small, punctate T2W hyperintensities in the
subcortical white matter, often restricting diffusion (268). This imaging evidence of microinfarction is
congruent with the main pathologic findings of vasculitis-associated thrombosis and presence of Nipah
virus antigen in endothelial and smooth muscle cells of blood vessels (269). For the subset of patients
who suffer from a relapse of neurologic symptoms, MRI shows patchy areas of confluent cortical
involvement on MRI and focal hypoperfusion on SPECT imaging (270).
Hendra
In contrast to Nipah virus, the closely related Hendra virus is associated predominantly with gray matter
abnormalities in the setting of meningoencephalitis. In three reported cases, T2W hyperintense lesions
involved the cortical gray matter, with relative sparing of the deep white matter tracts and cerebellum.
Cortical lesions may be confluent or multifocal, and restriction of diffusion can be seen on DWI (271).
Measles
Measles virus can cause differing CNS syndromes, including acute measles encephalitis and SSPE.
Neuroimaging in acute measles encephalitis typically demonstrates bilateral, symmetric T2W
hyperintense lesions involving the white matter and deep gray matter structures in a pattern that can
resemble ADEM (272). Cortical gyral swelling may also be present in the acute setting, and hemorrhage
may develop in gray matter areas over days to weeks (273).
The earliest stages of SSPE are often not characterized by abnormalities on conventional MRI, although
FDG-PET can demonstrate cortical hypometabolism and MR spectroscopy may show decreased NAA
levels (274). As the disease progresses, T2W hyperintensities in the subcortical and periventricular white
matter can develop, as does brain atrophy. By the late stages of SSPE, widespread changes in the cortex,
brainstem, and cerebellum can be seen (275).
Mumps
Encephalomyelitis following mumps is associated with white matter changes on brain MRI and a
longitudinally extensive myelopathy on spine imaging that may be indistinguishable from ADEM; rarely,
hemorrhagic white matter lesions have been reported (276–278).
Influenza
Neuroimaging findings in influenza-associated encephalopathy/encephalitis are diverse. MRI can be
normal or may demonstrate diffuse brain edema or symmetric involvement of the thalami (233,279,280).
Severe cases of encephalitis are characterized by T2W hyperintensities, hemorrhage, and restricted
diffusion in the thalami, basal ganglia, and cerebellum, consistent with ANE (281). Milder cases may be
associated with reversible lesions of the splenium of the corpus callosum (282). Notably, imaging
abnormalities caused by the 2009 H1N1 virus do not appear to differ significantly from other influenza
strains (283–285).
Cranial TB can present as tuberculous meningitis (TBM), tuberculomas, or abscesses—each of which
have differing neuroimaging characteristics. TBM is associated with basal meningeal enhancement, often
accompanied by hydrocephalus, strokes in the basal ganglia and internal capsule, and a focal or diffuse
pachymeningitis (286–288). Intracranial tuberculomas consisting of granulomatous tissue may have
variable appearance on T2W imaging depending on the pathologic stage of the lesion; noncaseating
tuberculomas are T2W hyperintense, whereas those with solid caseation are isointense or hypointense.
When central liquefaction ensues, tuberculomas may take on an appearance more similar to that of an
abscess. Such lesions exhibit T2W hyperintensity surrounded by a peripheral rim of hypointensity and
demonstrate peripheral rim enhancement on contrast imaging (289).
Fungal Infections
Neuroimaging findings in the setting of CNS fungal infections are often nonspecific and may be mistaken
for TBM, pyogenic abscess, or brain tumor (290,291). Fungal infections may result in basilar meningitis,
hydrocephalus, vasculitis, or abscess, and any combination of these may be present on neuroimaging. In
immunocompetent individuals, fungal abscesses are hypointense on T1W imaging and hyperintense on
T2W imaging, with a well-defined rim enhancement on postcontrast images, similar to pyogenic or
tubercular abscesses (290). Recent progress has been made in distinguishing fungal abscesses from other
abscesses. In one study, all of the fungal abscesses showed intracavitary projections directed centrally
from the wall, a finding not seen in the other abscess types. Overall, a ring-enhancing lesion with
irregular walls and nonenhancing intracavitary projections was likely to be a fungal abscess (292).
Detection of the disaccharide trehalose on MR spectroscopy may also distinguish fungal from nonfungal
abscesses (292–294).
MRI is frequently normal in the setting of cryptococcal meningitis, although evidence of a basilar
meningitis and/or hydrocephalus indistinguishable from TBM may be observed. The adjacent brain
parenchyma may also be affected, giving rise to cryptococcomas, most commonly seen in the midbrain
and basal ganglia. These lesions are of variable density on CT scan and, on MRI, are hypointense on
T1W imaging and hyperintense on T2W imaging. Contrast enhancement is variable and more commonly
seen in immunocompetent individuals. Unlike pyogenic abscesses, cryptococcomas typically do not
demonstrate restricted diffusion on DWI. MR spectroscopy demonstrates elevated lactate and decreased
NAA, choline, and creatine (26,290,295).
Imaging abnormalities in patients with CNS coccidioidomycosis may reflect strokes, granulomas, and
white matter disease, in addition to basilar meningitis and hydrocephalus. Ischemia has been reported in
over half of cases and typically results in deep cerebral infarcts seen as areas of hyperintensity on T2W
imaging. Less commonly, focal enhancing lesions in the white matter or deep grey matter representing
granulomas are observed (292,296,297).
Rhombencephalitis in the setting of L. monocytogenes infection is characterized by the presence of
multiple, small, medullary T2W hyperintensities that demonstrate rim enhancement on T1W imaging,
reflecting a combination of microabscesses and associated edema in the lower brainstem (298) (Fig. 6.6).
Borrelia Species
Acute CNS Lyme disease is associated with small T2W hyperintense and T1W isointense lesions in the
subcortical white matter, which may mimic those seen in multiple sclerosis (299). Multifocal lesions may
also be observed in the brainstem and spinal cord (300).
Treponema Pallidum
The clinical and MRI features of neurosyphilis are highly variable. The MRI of patients with clinical
encephalitis is characterized by diffuse brain atrophy, evidence of subcortical white matter infarcts, or
T2W hyperintensity in the mesial temporal lobe (301,302).
Acute Disseminated Encephalomyelitis

MRI findings in ADEM typically include multiple, asymmetrically distributed areas of T2W
hyperintensity in the subcortical and deep white matter (Fig. 6.7).
Lesions in the deep gray matter, which are characteristic of ADEM but atypical for multiple sclerosis
and other demyelinating disorders, often have a symmetric appearance. In approximately one third of
cases, the cerebral cortex is also involved. Infratentorial involvement occurs in over half of cases, with
lesions seen in the brainstem, middle cerebellar peduncles, and cerebellar white matter (303–305). The
size and morphology of lesions is highly variable, although they tend to have poorer margination as
compared to lesions in other demyelinating diseases. In most cases, lesions appear simultaneously, and all
lesions will exhibit a similar degree of contrast enhancement. Restricted diffusion may be observed on
DWI sequences in the acute stage, potentially representing swelling of myelin sheaths, myelin
vacuolation, or infiltration of inflammatory cells with concomitant free radical production (306,307).
Rare variants of ADEM include hemorrhagic, necrotizing, and relapsing forms (308).
Anti–N-Methyl-D-Aspartate Receptor Encephalitis

One third to one half of patients may have abnormalities on brain MRI. Affected areas, seen as T2W or
FLAIR hyperintensities, include the mesial temporal lobes, periventricular white matter, cortex,
cerebellum, brainstem, or basal ganglia. Notably, on follow-up, many of these abnormalities improve,
although atrophy may develop. Less than 20% of affected individuals will have evidence of contrast
enhancement (168,309).
Anti–Voltage-Gated Potassium Channel Receptor Encephalitis

The spectrum of diseases associated with antibodies to the VGKC complex has been steadily growing. In
the setting of encephalitis, the most common finding is unilateral or bilateral T2W hyperintensity in the
mesial temporal lobe (169) (Fig. 6.8).
Recent reports have suggested additional or exclusive involvement of the basal ganglia (310,311).
MANAGEMENT
Clinicians should focus first on treatable and common causes of encephalitis. Empirical treatment for
bacterial meningitis (vancomycin plus a third-generation cephalosporin) should be started because the
clinical presentation may overlap with encephalitis. Therapy with ampicillin should also be considered
when the demographics (i.e., older individuals), clinical presentation (i.e., rhombencephalitis), or CSF
profile is suggestive of Listeria infection. Antiviral therapy is generally restricted to treatment of
herpesviruses (especially HSV-1 and VZV) and the unusual instance of HIV infection (312). Therapy with
acyclovir should be started and continued until HSV-1 has been reasonably excluded as a diagnosis,
which may require testing serial CSF samples (see prior discussion). Therapy for M. tuberculosis or
fungal meningitis should be initiated when clinical and laboratory testing is compatible. If rickettsial or
Ehrlichia infections are suspected, doxycycline should be initiated empirically.
For IAE, oseltamivir may be beneficial (313). Corticosteroids or intravenous immune globulin may
also be helpful in some IAE cases to combat the proposed hyperintense cytokine response. There is no
evidence that treatment of presumed CNS Mycoplasma infection alters outcome.
In addition to directed therapy, aggressive supportive care is critical, and minimizing secondary brain
injury should be made a high priority (314). Seizures, status epilepticus, and cerebral edema are
important complications of encephalitis and encephalopathy and should be monitored closely in patients
who are not improving. An elevated CSF opening pressure may serve as a harbinger for impending
complications. Repeat neuroimaging to monitor for cerebral edema is particularly important in comatose
patients. Typical indicators of elevated intracranial pressure, such as poorly reactive dilated pupils,
decorticate or decerebrate posture, or Cushing triad (systolic hypertension, bradycardia, and shallow
respirations) are late findings. Patients should also be monitored for the syndrome of inappropriate
secretion of antidiuretic hormone (SIADH). SIADH and extrapontine myelinolysis (EPM) are important
examples by which acquired metabolic derangements can both complicate, and mimic, encephalitis (315).
Conditions that mimic infectious encephalitis should be considered, particularly if no etiology is
identified in the first week of hospitalization. Metabolic and toxic disorders causing encephalopathy and
seizures should be excluded. Anti-NMDAR encephalitis is of particular importance given its apparently
high incidence; when identified, immunotherapy and removal of the tumor, if present, have been
associated with improvement.
OUTCOME
In general, the prognosis of encephalitis is highly dependent on the underlying cause. Rabies and N.
fowleri, for instance, have an almost 100% fatality rate. Two of the most well-studied viral causes of
encephalitis are HSV-1 and EV. HSV-1 encephalitis has been reported to have a worse prognosis than EV,
with greater than 35% of patients with HSE suffering severe sequelae or death (4). Although EV
encephalitis patients often have a good outcome, EV-71 is associated with fatalities and neurologic
sequelae (58). Other viral etiologies are less well studied, with information limited to case reports and
small series. Persistent neurologic deficits after EBV encephalitis are reported to be rare (316). Influenza
has been associated with a severe type of encephalitis with high mortality particularly in Japan and
Taiwan, including several case reports of ANE (317,318). In the United States, cases appear to be less
severe with better outcomes, although further studies are needed (319).
Deaths and complications caused by arboviruses are better documented as a result of comprehensive
reporting to the CDC. WNV infections are less severe in children than in adults; children accounted for
only 4% of WNND reported to the CDC from 1999 to 2007, with 63% of cases older than 10 years of age
and only 15% younger than 4 years of age. There were only three pediatric fatalities over this time period
(1% of all cases of WNND), a case fatality rate substantially lower than for older adults (14% for adults
50 years of age or older) (320). In a study of 127 children with LACV, 12% had neurologic deficits at
discharge (321). EEE is also known to have a higher mortality (almost 30%) and potentially severe
neurologic complications.
Bacterial infections also have variable outcomes. Both L. monocytogenes and M. tuberculosis may
have relatively high morbidity and mortality (109,322). In a French encephalitis study, these two
etiologies accounted for the majority of fatalities due to encephalitis (together, 12 of 26 fatalities) (101).
On the other hand, infection with bacterial agents, such as Bartonella spp., which typically causes
encephalopathy rather than encephalitis, has an excellent outcome; over 90% of patients recover
completely without sequelae. There are limited studies reporting outcomes specifically on encephalitis of
unknown etiology. One study, however, reported significant sequelae in up to 53% of survivors
hospitalized with unknown causes of encephalitis (323).
SUMMARY
It is unfortunate that in this era of modern medicine, so little progress has been made in the field of
encephalitis. An etiology is only identified in about half of the cases and for those patients who receive a
viral diagnosis; very few specific antivirals are available for treatment. Given the significant morbidity
and mortality of this syndrome along with the financial costs of hospitalization, rehabilitation, and
sequelae, research to address gaps in our understanding of this entity are urgently needed as well as
development of effective antiviral agents.
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CHAPTER 7 POLIOMYELITIS, POLIO VACCINES, AND
THE POSTPOLIOMYELITIS SYNDROME
JOHN F. MODLIN AND DAVID J. COFFEY
Poliomyelitis is a systemic viral infection caused by any of three human poliovirus serotypes that is
characterized by acute meningitis and lytic infection of motor neurons in the brainstem and spinal cord
resulting in cranial nerve dysfunction and transient or permanent paresis of one or more extremities. In the
United States and other developed countries, poliomyelitis due to naturally occurring polioviruses has
been eliminated by routine childhood immunization. Global eradication is a major priority of the World
Health Organization (WHO) and other major partners in the Global Poliomyelitis Eradication Initiative.
A BRIEF HISTORY OF POLIOMYELITIS

Poliomyelitis has afflicted humans since antiquity (1). The first acknowledged description in English is a
biographical narrative of the acute paralysis suffered by Sir Walter Scott in the second year of his life,
circa 1772, and the first medical description is recorded in the second edition of A Treatise on Diseases
of Children, published in 1789 by Michael Underwood, a London pediatrician and obstetrician (2,3).
Major contributions to understanding the disease were made by the German orthopedist Heine, whose
1840 monograph describes the clinical features of acute poliomyelitis in young children (4), by the French
anatomist Charcot who showed that paralysis was accompanied by a loss of motor nerve cells within the
anterior horns of the cord (5), and by Karl Oskar Medin, a Swedish pediatrician who, in 1887, recorded
the natural history of poliomyelitis and developed a classification that became widely used for decades
afterwards. The eponym “Heine-Medin disease” was widely used throughout Europe and North America
during the early twentieth century.
Up to this time, only sporadic cases of poliomyelitis were recognized. The first recorded outbreaks of
poliomyelitis occurred in the mid- and late nineteenth century in northern Europe and later in North
America. Charles Caverly, a Dartmouth College trained physician, described 132 cases with 18 deaths in
the Otter Creek Valley near Rutland, Vermont, the largest outbreak known to have occurred up to that time
in North America (6). These early outbreaks heralded larger epidemics, including a countrywide
epidemic of more than 1,000 cases in Sweden in 1905 (7) and 1,200 cases in New York City in 1907 (1),
and the spread of disease throughout Europe and North America. The shift from endemic to epidemic
disease has been ascribed to the improved hygienic conditions that accompanied the increasing standards
of living in the industrialized world. In theory, extensive exposure to polioviruses during infancy in the
presence of passively acquired maternal antibody results in harmless but immunizing infections.
Conversely, infections delayed beyond infancy as a result of higher sanitary standards and reduced
opportunities for exposure are associated with an increased risk of neurotropic infection (8).
In 1908, Landsteiner and Popper (9) demonstrated that the etiologic agent of poliomyelitis was a
“filterable virus” in a series of experiments in which they induced paralysis and spinal cord lesions in a
monkey by intraperitoneal injection of neural tissue from a fatal human case; shortly thereafter, Flexner
and Lewis (10) at the Rockefeller Institute serially passed polioviruses in monkeys, fulfilling one of
Robert Koch’s postulates.
Serologic surveys in the 1930s and 1940s helped define the basis for the observed differences in the
behavior of epidemics in different locations and social conditions. Evidence of immunity was found in
80% to 100% of adults tested, with generally lower levels in children (11). In time, it was shown that the
risk of infection was universal, but children living in poor sanitary conditions acquired infection at a
much earlier age than children from higher socioeconomic backgrounds, an observation that explained the
enigmatic shift during the early twentieth century from an endemic disease involving only young infants to
an epidemic disease that also affected older children and young adults (12). Later studies conducted by
Paul and Riordan (13) in a remote Eskimo population 15 to 20 years following outbreak of poliomyelitis
showed that immunity persisted for at least two decades and perhaps for life.
The existence of more than one type of poliovirus was first inferred by Burnet and Macnamara (14) in
1931 when they demonstrated that monkeys who had recovered from infection with a strain recovered in
Melbourne subsequently developed disease when given the virulent MV strain and showed that the two
strains differed qualitatively in in vitro neutralization tests. These results were confirmed by Paul and
Trask (11) at Yale and the two virus groups were respectively designated “Lansing”-like, or “Brunhilde”-
like, the latter in reference to the name of a laboratory chimpanzee (1). A third type was predicted by the
studies of Bodian (15), at Johns Hopkins in 1949. The existence of three types, and not more, was
verified by the testing of poliovirus strains collected worldwide by a collaborative group organized by
the National Foundation for Infantile Paralysis (16).
The era of effective poliomyelitis treatment began in the 1920s with the invention of the Drinker
negative pressure ventilator or “iron lung” at the Harvard School of Public Health (17) and its
development at several Boston hospitals (18). The earliest devices were powered by vacuum cleaners
and were fitted with boat portholes for access to the body of the patient. Progress in the management of
the persistently paralyzed patient was also made during this period. The practice of rigid immobilization
of even mildly involved extremities for long periods gave way to the influential practices of Sister
Elizabeth Kenny using warm, moist packs and prolonged physical therapy (19).
In 1936, Sabin and Olitsky (20) produced the first unequivocal evidence that polioviruses could be
grown in vitro when they propagated the MV poliovirus strain in human embryonic central nervous system
(CNS) tissue, and a decade later, Enders, Weller, and Robbins (21), succeeded in growing Lansing strain
poliovirus in human embryonic tissues. This achievement is widely acknowledged as the landmark event
that opened the door to further characterization of the virus, better understanding of the pathophysiology of
poliomyelitis, and development of successful vaccines.
Building on these advances, Jonas Salk (22) developed the first successful inactivated poliovirus
vaccine (IPV), which was first administered to paralyzed patients in a home for crippled children in
Pittsburgh in 1952. In 1954 to 1955, Salk IPV was successfully tested in a monumental controlled trial
involving more than 1.8 million U.S. schoolchildren. In the meantime, several investigators were studying
live, attenuated polioviruses that could be delivered orally and induce mucosal as well as systemic
immunity (23). Live attenuated poliovirus strains were tested in humans in several countries and
ultimately, three monovalent strains developed by Sabin were licensed for use in the United States in
1961 and 1962. Over the next 2 years, more than 100 million oral poliovirus (OPV) vaccine doses were
distributed in the United States via community programs organized by health departments and medical
societies. Trivalent OPV vaccine was introduced in 1964 and remained the principal poliovirus vaccine
used in the United States until 1997.
Figure 7.1 illustrates the reported incidence of paralytic poliomyelitis cases in the United States from
1920 to 1960. A peak of 55,000 cases was reported in 1952. The introduction of IPV vaccine for general
use in 1955 and OPV vaccine in the early 1960s led to rapid and dramatic control of epidemic
poliomyelitis, and the incidence of paralytic poliomyelitis fell from 13.9 cases per 100,000 in 1954 to
less than 0.5 cases per 100,000 in 1965. By the 1970s, sustained transmission of naturally occurring
polioviruses ceased and the last case of domestically acquired poliomyelitis was reported in 1979 (Fig.
7.2). Rare cases acquired in other countries continued to be imported into the United States in the 1980s,
but control of poliomyelitis in the Western Hemisphere by 1991 resulted in virtual disappearance of
imported cases. Approximately 8 to 10 vaccine-associated paralytic poliomyelitis (VAPP) cases
following administration or transmission of OPV were observed until OPV vaccine was discontinued in
favor of IPV in 1997 (24). Since then, only very rare poliomyelitis cases attributed to imported VAPP or
to acquisition of OPV vaccine-derived polioviruses (VDPV) by immunodeficient persons have been
reported in the United States (25,26).
VIROLOGY, TRANSMISSION, PATHOPHYSIOLOGY, AND
IMMUNITY
Virology
The polioviruses are prototypical human enteroviruses (species: Enterovirus C; family Picornaviridae).
Three poliovirus serotypes are distinguished from one another by in vitro neutralization with type-
specific antisera. The icosahedral virion of approximately 27 nm in diameter is composed of a protein
capsid and an enclosed single-stranded RNA genome of approximately 7,500 bases in length. The genome
functions as a monocistronic message with a single open reading frame coding a 250 kDa polyprotein,
which is subsequently cleaved by both viral coded and cellular proteases into capsid proteins, an RNA
polymerase, proteases, and other regulatory proteins. The four capsid proteins (VP1 through VP4)
combine to form the 60 structural subunits that are assembled into the viral capsid.
Like all picornaviruses, polioviruses exhibit substantial genomic variability with up to 15% variation
within the capsid coding region for each serotype. The three Sabin OPV vaccine strains differ from their
naturally occurring parents at fewer than 0.2% of positions across the full genome (27). For all three
serotypes, analogous nucleotide substitutions in the 5′ noncoding region appear to be associated with
diminished ability to replicate in the gastrointestinal tract and with diminished neurovirulence.
Attenuating mutations also map to capsid proteins for each of the individual serotypes.
All three poliovirus serotypes share a common cell membrane receptor (poliovirus receptor [PVR]), a
67-kDa member of the immunoglobulin superfamily coded on human chromosome 19 (28,29). PVR-
transgenic mice express PVR in CNS and muscle tissue, endowing susceptibility to these tissues but not
on intestinal mucosal cells (30).
Transmission of Polioviruses
Before the introduction of poliovirus vaccines, naturally occurring polioviruses circulated in temperate
climates with a marked seasonal variation resulting in peak activity from July to October and low levels
from December to May. All three serotypes circulated concomitantly, although one or two types often
predominated within a defined community during a single season. Horizontal transmission in the
community occurred mostly among children 2 to 5 years of age, and data from virus watch studies
indicated that poliovirus transmission was strongly associated with low socioeconomic status and
household contact. Once virus was introduced into a household, 90% to 100% of susceptible persons
became infected, along with 20% to 50% of seropositive persons (31). Adults were only slightly less
likely to become infected than young children. After the introduction of OPV vaccine, the attenuated
vaccine viruses replaced the epidemiologic niche inhabited by the naturally occurring viruses. The very
low levels of person-to-person transmission of naturally occurring polioviruses during the winter and
spring months probably abetted the disappearance of naturally occurring viruses and their replacement by
OPV strains (32).
Pathophysiology
Ingested polioviruses implant in the oropharynx and small bowel and penetrate the mucosa via
specialized microfold cells (M cells) and other epithelial cells overlying submucosal lymphoid tissues
(33). In primate models, the most efficient site of viral replication is detected in Peyer patches in the
intestinal submucosa (34,35). Spread to regional lymph nodes gives rise to a transient and clinically silent
“minor” viremia during which virus spreads to systemic reticuloendothelial tissue including lymph nodes,
bone marrow, liver, and spleen (36). For most poliovirus infections, viral replication is contained at this
stage, resulting in subclinical infection. In a minority of infections, further replication of virus in
reticuloendothelial tissues leads to a “major” viremia, which coincides with the onset of fever and other
clinical symptoms (37).
The path by which polioviruses reach the CNS remains unsettled. It is well established that viremia
precedes paralysis, but the precise mechanism by which the virus breaches the blood–brain barrier is not
known (38,39). A study using transgenic mice bearing the PVR gene found that spinal cord involvement
can be blocked by sciatic nerve section after virus is injected intramuscularly (40), suggesting that virus
replication in skeletal muscle precedes transport of virus to the cord via the peripheral nerve (41,42), a
concept consistent with the myotropic nature of enteroviruses and the clinical observation of intense
myalgias preceding the onset of paralysis in affected patients.
Polioviruses are recoverable from the spinal cord for only the first several days of paralysis. The
necrotic lesions and inflammatory infiltrates (Fig. 7.3C), which are distributed within the gray matter of
the anterior horn of the spinal cord, the motor nuclei of the pons and medulla, and occasionally other
locations (Fig. 7.3A and B), may persist for months (43). The severity of clinical paralysis depends more
on the intensity of the lesions, rather than their distribution.
Immunity
Immunity to poliovirus infection is type specific; cross protection between the three serotypes is low, if it
exists at all. Reinfection with the same serotype occurs upon exposure to live poliovirus, regardless of
whether prior immunity is based on infection with naturally occurring polioviruses, infection with live,
attenuated viruses, or inactivated poliovirus vaccine administration. After household exposure to wild
type virus, 20% to 50% of naturally immune (31), 30% to 50% of OPV immune, and 90% to 100% of IPV
immune persons are reinfected, as defined by virus excretion from the gastrointestinal tract or rise in
antibody titer. Reinfections are universally asymptomatic and are rarely associated with oropharyngeal
virus excretion.
Passively acquired poliovirus antibody protects against disease, but not against infection (44).
Preexisting humoral antibody prevents or reduces oropharyngeal shedding of poliovirus upon reinfection
but has only a minor effect on fecal shedding (38,45–47). Serum-neutralizing antibodies are made in
response to natural infection and to immunization with either OPV or IPV vaccine. Antibodies made in
response to natural infection appear to persist for life (48), and it is presumed that vaccine-induced
protection is long term, if not lifelong.
Poliovirus secretory immunoglobulin A (IgA) appears in nasopharyngeal and intestinal secretions 1 to
3 weeks after natural infection or administration of OPV vaccine (49). Secretory IgA antibody persists for
at least 5 to 6 years at low levels and, unlike humoral antibody, is not boosted significantly upon
rechallenge with OPV vaccine (50). The degree of protection conferred by local IgA antibody is relative.
Upon rechallenge, high secretory IgA titers inhibit virus replication, whereas lower titers permit
replication; virus shedding is dependent on the challenge dose (46,51). Studies in the field show that
childhood recipients of OPV are often reinfected and shed OPV virus in feces despite multiple prior OPV
doses (52,53).
CLINICAL FEATURES OF POLIOMYELITIS

Acute Illness
More than 90% of naturally occurring poliovirus infections are inapparent. Acute clinical poliomyelitis is
traditionally separated into two distinct phases: the “minor illness” with an incubation period of 3 to 7
days and the “major illness” with onset of symptoms generally 9 to 12 days after exposure (54). The
minor illness, coinciding with viremia, consists of nonspecific symptoms such as fever, headache, sore
throat, anorexia, and listlessness. Overall, 4% to 8% of infected persons experience symptoms of the
minor illness, and most resolve their illness within 1 to 2 days without further symptoms.
The major illness is associated with CNS infection, which has been variously estimated to occur in
0.1% to 1.0% of all poliovirus infections (8,55). About one third of young children who develop the
major illness experience a biphasic illness with symptoms of the minor illness preceding onset of CNS
disease; adults usually develop CNS disease without the preceding minor illness (37,56). The major
illness is heralded by the abrupt onset of fever, headache, vomiting, and meningismus (Table 7.1). CSF
pleocytosis is present at this early stage. Approximately one third of cases of CNS disease are limited to
meningitis without detectable motor neuron impairment, which resolves within 5 to 10 days (i.e.,
“nonparalytic poliomyelitis”).
Muscle weakness is preceded by intense myalgias of the involved limb(s) and the axial skeleton. The
pain may be relieved by exercise; patients may pace nervously in an attempt to “work off” the pain. The
hallmark of poliomyelitis is asymmetric motor paresis, which ranges from mild weakness of a single
extremity to complete quadriplegia. Proximal limb muscles are more involved than distal, and legs are
more commonly involved than arms. The deep tendon reflexes, which were initially brisk, become absent.
The pace of development of the paresis ranges from several hours to several days; most commonly
occurring over 2 to 3 days. Cranial nerve involvement (i.e., “bulbar poliomyelitis”) occurs in 5% to 35%
of paralytic cases. Any of the motor cranial nerves can be involved, with the ninth and tenth being the
most common.
Complications
Bulbar paralysis results in dysphagia, nasal speech, dyspnea, difficulty managing secretions, anxiety, and
respiratory compromise. Involvement of respiratory and vasomotor nuclei is less common but may
portend serious complications due to hypoventilation, blood pressure lability, and cardiac arrhythmias.
Respiratory failure from paralysis of the diaphragm and intercostal muscles represents the most serious
complication of paralytic poliomyelitis. Aspiration pneumonia, pulmonary edema, myocarditis, paralytic
ileus, gastric dilation, and ileus of the bladder may also complicate acute paralytic disease.
Prognosis
Paralysis most often progresses for 1 to 3 days after onset, rarely more than a week, halting about the time
the patient becomes afebrile (57). Most patients with limb paresis experience some recovery of function
in the weeks to months after acute disease. An estimate of the eventual outcome can be made by a month
after onset when most reversible weakness will have resolved. Very little additional recovery of strength
can be expected after a period of 9 months. Residual motor deficits remain in about two thirds of initially
paralyzed patients, ranging from minor debility to permanent, flaccid paralysis.
Overall mortality for spinal poliomyelitis is about 4% to 6%. During the poliomyelitis epidemics in the
1940s and 1950s, bulbar polio caused a mortality of 20% to 60% when respiratory assistance was
required. With modern intensive care, deaths from temporary respiratory paralysis should be less
common.
Differential Diagnosis
Sporadic cases of paralytic disease due to the nonpolio enteroviruses and West Nile virus is clinically
indistinguishable from poliomyelitis. Only two nonpolio serotypes have been known to cause epidemic
disease: coxsackievirus A7 virus, which has caused small outbreaks of paralytic disease in the former
Soviet Union (58), South Africa, and Scotland (59), and enterovirus 71, which has caused large outbreaks
in Eastern Europe in the late 1970s and more recently in several countries in Southeast Asia (60–62).
Poliomyelitis must also be distinguished from other causes of acute paralysis including the Guillain-
Barré syndrome, which is associated with paralysis that is classically ascending in nature, symmetric, and
is accompanied by sensory abnormalities in approximately 80% of cases. The CSF pleocytosis that
occurs during the major illness of poliomyelitis is not characteristic of the Guillain-Barré syndrome,
which is associated with a normal CSF leukocyte count and an elevated CSF protein concentration. Other
conditions produce acute paralysis, including transverse myelitis, botulism, tick paralysis, epidural
abscess, cord tumors, and hysteria; however, each of these diseases has features that readily separate
them from acute poliomyelitis.
Risk Factors
Although it was once believed that adults are more susceptible to paralytic complications, there is
probably little correlation of age with severity of disease after the decline of maternal antibody (8,55).
Studies during outbreaks suggest that infected pregnant women have an increased risk of developing
paralytic disease (63,64). There is no evidence that either naturally occurring polioviruses (65) or
attenuated vaccine polioviruses (66) cause congenital defects.
Persons with B-cell immunodeficiency, primarily young children with X-linked immunodeficiency
syndromes, have an increased risk of CNS disease when infected with either naturally occurring or
attenuated vaccine polioviruses. These patients may develop acute paralysis or may have an atypical
course with an incubation period of several months, prolonged febrile illness, chronic meningitis, and
progressive neurologic dysfunction that includes both upper and lower motor neuron involvement
(67–70).
Strenuous exercise during the early stages of the major illness substantially increases the risk and
severity of poliomyelitis. This effect has been well documented clinically (71,72); and experimental
infections with other enteroviruses provide supportive evidence (73).
Paralytic poliomyelitis tends to localize in a limb that has been the site of a recent intramuscular
injection or injury (74–76). Observations in experimental poliomyelitis (39,40) and after the
administration of OPV vaccine (77) confirm this association but do not fully explain the mechanism of the
provoking effect. Tonsillectomy during the incubation period of poliomyelitis markedly increases the risk
of bulbar disease (78). The mechanism may be similar to the provoking effect of injections on spinal
poliomyelitis.
POSTPOLIOMYELITIS SYNDROME
As many as 20% to 30% of patients who recover from paralytic poliomyelitis experience new onset of
muscle weakness, pain, atrophy, and fatigue many years after the acute illness. With the eradication of
acute poliomyelitis, the postpolio syndrome remains the sole polio-related clinical disease encountered
by physicians in all but a few polio-endemic nations. It is expected that the postpolio syndrome will
ultimately decline in incidence and disappear as poliomyelitis is controlled around the globe.
History and Background of the Postpoliomyelitis Syndrome
In 1875, Charcot (79) described a relationship between acute poliomyelitis and late development of
motor neuron degeneration. By 1969, approximately 83 cases had been described in which motor neuron
degeneration occurred decades after acute poliomyelitis (80), although the distinction between what we
now describe as postpolio syndrome and other possible causes of late denervation, such as amyotrophic
lateral sclerosis (ALS), was not possible in many of these cases. The hypothesis was advanced that the
incidence of late motor neuron disease might increase as children affected during the epidemics of the
1950s reached middle age (81,82). Initial concern that paralytic poliomyelitis might increase the risk of
subsequent ALS was allayed by careful epidemiologic studies, suggesting that prior infection with
poliomyelitis might actually protect against the subsequent development of ALS (83). At present, it seems
clear that the etiology and natural history of the postpolio syndrome and ALS are quite different.
Postpolio syndrome is an indolent condition that rarely leads to severe disability or death (84).
Nomenclature
Although the term postpolio syndrome has sometimes been applied to all neurologic symptoms occurring
as late manifestations of poliomyelitis, most authorities reserve this designation for a disorder
characterized by new-onset muscle weakness, fatigue, and pain, associated with loss of function that
occurs years after the original acute poliomyelitis episode (85–87). Another term, postpolio progressive
muscular atrophy (PPMA) refers specifically to the weakness with or without atrophy that results from
late denervation of muscles of patients (88–91). Criteria for PPMA include a reasonable past history of
poliomyelitis with partial recovery of function and at least a decade of stabilization after recovery from
the initial illness. PPMA is then the development of progressive muscular weakness following these
antecedent criteria. It is worth noting that atrophy probably occurs in only half or fewer of the patients
who develop new weakness (92). Although the terms postpolio syndrome and PPMA are used almost
interchangeably, it should be recognized that postpolio syndrome or postpoliomyelitis sequelae may
include other symptoms such as fatigue (undoubtedly the most common of all symptoms), subjective
alterations in attention or cognition, sleep disturbance, and alterations in pain perception. Bulbar
symptoms, including dysphagia and some pulmonary disturbances, can occur and may be more common
and severe in those who had bulbar symptoms during their childhood illness.
Epidemiology and Risk Factors
Epidemiologic studies indicate that postpolio syndrome affects a substantial proportion of the 250,000 to
640,000 polio survivors estimated to live in the United States (83,86,93). A cohort study of 300 persons
living in Olmsted County, Minnesota, who had contracted paralytic poliomyelitis between 1935 and 1955
found that 32 (64%) of 50 poliomyelitis survivors had symptoms consistent with postpolio syndrome, and
in another retrospective study of Allegheny County, Pennsylvania, residents with a history of paralytic
poliomyelitis noted a prevalence of 28% (94,95). In the latter study, female gender and permanent
impairment sustained at the time of acute polio infection seemed to convey a higher risk of developing
postpolio syndrome. However, the strongest risk factor for developing postpolio syndrome was the
interval from the original paralytic disease with the incidence of postpolio syndrome peaking 30 to 34
years after the original illness. Older age at the time of presentation with postpolio syndrome has also
been identified as a risk factor (86).
Etiology
Although the precise cause of postpolio syndrome remains unknown, there is a consensus among authors
that the cause is probably related to exhaustion of motor units previously overstressed by recovery from
the acute denervation during acute polio virus infection following which terminal elements of surviving
alpha motor neurons sprout to reinnervate adjacent myofibrils. After acute poliomyelitis, fewer anterior
horn cells innervate a relatively larger number of myofibrils, thereby exaggerating the effects of the
additional, physiologic cell loss at a later date attributed to aging (92,96).
Other possible mechanisms have been considered, including immunologic events and other virus–host
interactions. Prime among these alternative theories is the conjecture that polioviruses can persist for
many years within the CNS of patients with postpolio syndrome and cause recrudescent disease by direct
viral infection or immunopathologic pathways (97). Evidence in support of this theory includes the
demonstration of oligoclonal immunoglobulin G bands (84,98) or poliovirus-specific immunoglobulin M
bands (99) in CSF, and the demonstration of poliovirus-like RNA sequences in CSF of postpolio
syndrome patients by the polymerase chain reaction (100). However, the presence of CSF oligoclonal
bands has been inconsistent across studies (101,102), and virologists debate the likelihood of infectious
virus, or even viral RNA, persisting for long periods in immunocompetent hosts.
Pathophysiology
Physical fatigue may result from damage to motor units in previously affected muscle (103–106), perhaps
associated with a change in acetylcholine receptor sensitivity and/or number. (This has a practical
ramification for anesthesiologists who may find it prudent to reduce the dose of paralytic agents for
patients with postpolio syndrome [107].) During exercise, there is decreased maximal voluntary
contraction of muscles affected by postpolio syndrome, decreased tetanic force, and delayed recovery.
Based on these and other data, Sharma et al. (106) hypothesize that muscle fatigue in postpolio syndrome
may be due to impaired activation beyond the muscle membrane at the level of excitation–contraction
coupling. Based on neuropathologic studies of patients with poliomyelitis in the 1940s and 1950s, another
hypothesis suggests that the fatigue experienced by patients with postpolio syndrome has a central origin.
These studies showed lesions in specific areas of the brain whether or not clinical symptoms of
encephalitis had occurred, including the reticular formation in the brainstem, vestibular nuclei, cerebellar
nuclei, periaqueductal gray, hypothalamic and thalamic nuclei, substantia nigra, locus ceruleus, and
median raphe nuclei (43,107,108). The reticular activating system, responsible for maintaining normal
alertness and attention, is composed of the brainstem reticular formation, posterior hypothalamus, and
thalamus. Specific injuries to these structures from poliovirus infection could cause the acute
disorientation and depression of consciousness seen in acute poliomyelitis and hypothetically could set
the stage for late-onset decompensation of arousal, attention, and subjective cognition in postpolio
syndrome (109,110). It has been suggested that T2-weighted hyperintense areas observed on brain
magnetic resonance imaging (MRI) scans could represent these areas of polio virus–induced damage
(111) (Fig. 7.4). Injury to the periaqueductal gray of the brainstem and substantia gelatinosa of the
posterior horn of the spinal cord may explain the hyperpathia that is reported by many polio survivors
(111).
Clinical Features
Fatigue, which may be the most distressing and disabling symptom, is also the most common complaint,
occurring in 91% of polio survivors in national surveys (89,96,103,112). Of these individuals, 41%
experienced work limitation and 25% had interference with self-care (111). Patients also report mental
fatigue affecting attention and concentration (103).
The most common neurologic sign of postpolio syndrome is new weakness, which may be
accompanied by atrophy and pain. Weakness occurs in those muscles previously weakened during acute
paralytic poliomyelitis or in muscles thought to be previously unaffected and may increase with exertion.
The pain may be perceived in muscles or joints and can occur in the presence or absence of weakness.
Joint pain may occur because chronic residual weakness leads to abnormal joint stresses. Scoliosis, poor
mechanics, and abnormal postures may all contribute. The degree of actual osteophytic change may be
less than one might anticipate given the amount of residual weakness. Muscle pain may result from
chronic denervation or, if residual weakness is present, merely from overuse of muscles. Secondary
myopathy with elevation of creatine kinase levels, usually of a mild degree, may occur in some patients
(95).
Postpoliomyelitis dysphagia, whether simply residual or progressive could be a consequence of bulbar
motor nerve injury. Attention to the problems of dysphagia in patients with postpolio syndrome was first
drawn by Sonies and Dalakas (113), who suggested that it was analogous to the postpolio syndrome seen
in the limbs, based on their series in which all but 1 of the 32 patients studied had some abnormality in
swallowing function. Cinefluorography can demonstrate whether there are impaired movements of the
tongue, aspiration, or pooling of material in the pyriform sinuses or valleculae. Aspiration seems to be
found only very infrequently and probably does not pose a severe risk in most instances (93,113). Other
symptoms that might be attributed to late-onset bulbar dysfunction include the sleep-disordered breathing
and chronic alveolar hypoventilation that sometimes develop in patients with postpolio syndrome (114).
Sleep-disordered breathing may include obstructive sleep apnea syndrome and may occur more
commonly in patients with postpolio syndrome who suffered insult to respiratory control centers in the
brainstem at the time of their primary infection. Pulmonary function may be further compromised if
weakness of respiratory muscles, impaired swallowing or cough mechanisms, chest wall deformity, or
poor thoracoabdominal interaction is present (115).
Electrophysiology
Conventional electromyography (EMG) demonstrates chronic denervation and occasionally reveals new
or ongoing denervation in the form of fasciculations, fibrillations, and positive sharp waves (87,91,116).
Both symptomatic and asymptomatic patients with postpolio syndrome show similar EMG findings.
Similarly, the chronic denervation and reinnervation signs (including both enlarged and polyphasic motor
unit potentials) and decreased interference patterns are seen whether or not the muscle being tested was
originally weak (91,92,117). Enlarged motor units consistent with highly increased fiber density can be
demonstrated in 90% of patients with postpolio syndrome with single-fiber EMG (90). Jitter and
neuromuscular blocking effects are also noted, which correlate with the interval since acute poliomyelitis.
Like conventional EMG, single-fiber EMG is unable to distinguish symptomatic and asymptomatic
patients with postpoliomyelitis. In contrast, macro-EMG may distinguish muscles with new weakness,
because previously increased amplitudes decline with new weakness and atrophy (90).
Although electrophysiologic studies in postpolio syndrome and PPMA have provided important
pathophysiologic information and supported the etiologic concept of overuse or accelerated aging of
overcompensated motor units, the primary clinical role for nerve conduction and EMG studies is to
exclude other causes for the patient’s complaints.
Psychologic Issues
Although the cardinal manifestations of postpolio syndrome are neither caused nor modified by
psychopathologic or personality factors, patients with postpolio syndrome may be subject to
characteristic psychologic symptoms (110,116,118). Bruno et al. (112) argue that anxiety, depression, and
compulsive behavior occur frequently in polio survivors, resulting from the experience of a disabling
disease in childhood from which recovery was achieved only by extreme effort (118). Success in
obtaining independence and in overcoming a disability was often accomplished by adopting very
compulsive behavior and demanding very high standards of themselves. One of the goals that many
individuals set was to overcome the need for assistive devices such as braces, crutches, wheelchairs, and
the like. In consequence, polio survivors achieved higher than expected life goals.
Effects of Exercise
Unfortunately, the avoidance of assistive devices at the time of acute weakness may be maladaptive in
subsequently dealing with postpolio syndrome (112). Overtaxing motor units with exercise may contribute
to irreversible damage to muscle fibers and more severe weakness (88,119,120). Patients with postpolio
syndrome may benefit from rest periods, increased sleep time, and other energy-conservation methods to
overcome fatigue (121). Compliance with appropriate intervention to correct the overuse pattern appears
to result in improvement or resolution of new weakness and fatigue (122). However, because disuse can
also enhance weakness, some moderation must be sought. Muscle strength may be improved by
nonfatiguing exercise (123). Specific protocols for high-resistance exercise to improve isokinetic and
isometric strength for patients with postpolio syndrome have been described (124,125).
POLIOVIRUS VACCINES
Inactivated Poliovirus Vaccine
IPV vaccine is prepared by inactivation of poliovirus seed strains by formalin treatment for 12 to 14 days
at 37°C, the method originally developed by Jonas Salk. However, contemporary IPV vaccines contain
higher concentrations of all three antigens compared with IPV vaccines introduced in the 1950s. Three
IPV formulations are now distributed in the United States: trivalent IPV (IPOL, Aventis Pasteur) and
trivalent IPV combined with other recommended childhood vaccines (Pediatrix, GlaxoSmithKline and
Pentacel, Sanofi Pasteur). Most available IPV vaccines are produced from wild type polioviruses grown
in monkey kidney cells and contain 40-, 8-, and 32-D antigen units, respectively, for poliovirus serotypes
1, 2, and 3. IPV formulations produced from Sabin OPV vaccine strains are under development in China
and elsewhere. The primary vaccination series for IPV vaccine in the United States consists of four doses
administered at 2 months, 4 months, 6 to 18 months, and 4 to 6 years of age (126). Since 2000, IPV
vaccine has been used exclusively in the United States for routine immunization of infants against
poliomyelitis and for all other recipients including unimmunized adults, immunodeficient persons, and
anyone requiring polio vaccine boosters to travel to poliovirus endemic regions (126).
Neutralizing antibodies are detectable to all three poliovirus types in 99% of IPV vaccine recipients
after two doses and 100% after the third dose (127,128). A large boost in antibody titer follows the third
dose (127,128). After three doses, mean titers to types 1 and 3 are higher than in OPV-immunized
children, whereas mean titers to type 2 are equivalent. Detectable antibody persists at protective levels
for at least 5 years, although mean titers decline considerably (128). Vaccine efficacy for IPV distributed
in the 1960s was estimated to be 91% and 95% for 3 and 4 doses, respectively. There are few data
regarding vaccine efficacy of the current IPV formulations. A case–control study in Senegal indicated
protection rates of 36% and 89% for recipients of one and two doses, respectively (129). The efficacy for
three doses is assumed to be higher.
IPV-immunized children develop little or no measurable secretory antibody (49). When challenged
with live polioviruses, IPV-immunized children shed the challenge virus in their feces at a higher rate,
higher titer, and for a longer period than OPV-immunized children (51), indicating a greater potential for
asymptomatic infection and transmission of circulating polioviruses to unimmunized contacts. Although
this is widely considered to be a disadvantage of IPV, there is strong evidence that widespread use of IPV
results in protection that extends to unvaccinated persons in the community in developed nations with
good sanitation (130,131). IPV vaccine may reduce community transmission of polioviruses due to
reduction of pharyngeal shedding of poliovirus in reinfected IPV vaccine recipients, which may be the
important mode of community spread (47), although there is little effect of IPV vaccine in preventing
spread within families in which fecal-oral spread may be a more important mode of transmission
(132,133).
Live, Attenuated Poliovirus Vaccine
Live, attenuated trivalent (tOPV) vaccine remains the principal vaccine used throughout the developing
world. There are different manufacturers worldwide, but most follow a common production method in
which Sabin seed strains representing each of the three poliovirus serotypes are individually grown in
monkey kidney cells and are combined for oral administration in concentrations of approximately 106.0
TCID50, 105.1 TCID50, and 105.8 TCID50 for poliovirus types 1, 2, and 3, respectively. The unequal
contribution of each type to the trivalent preparation represents a “balanced” formulation designed to
account for the more efficient replication of type 2 OPV vaccine in the gastrointestinal tract (134).
Because type 2 virus regularly interferes with replication of types 1 and 3, a primary series of three doses
are routinely administered to enhance seroconversion to all three serotypes. Under conditions of good
hygiene, seroconversion rates of 50%, 85%, and 30% to serotypes 1, 2, and 3, respectively, are achieved
following the first tOPV dose (135), and a second and third tOPV dose induce neutralizing antibodies to
all three types in 86% and 96%, respectively (127,136). Serum antibody to all three types persists in 84%
to 98% of vaccinees 5 years after primary immunization (137), although reexposure to vaccine viruses
probably aids the maintenance of antibody levels in the population. Secretory IgA poliovirus antibody
appears in oropharyngeal and duodenal secretions 1 to 3 weeks after OPV immunization (49) and persists
for at least 5 to 6 years (138). Challenge studies suggest that the intestinal immunity induced by OPV
vaccine is similar to intestinal immunity following natural infection (139).
The WHO Expanded Program on Immunization (EPI) recommends one dose of tOPV at birth, a practice
that provides an opportunity to administer at least one dose of vaccine to a child who may not present for
routine health maintenance care later, and three tOPV doses at 6, 10, and 14 weeks of age (140). Even
though passively acquired maternal antibody to polioviruses present in the infant’s circulation and in
breast milk reduces vaccine virus replication in the gastrointestinal tract and therefore blunts the immune
response in some infants, infants who receive OPV at birth are more likely to have antibody to all three
poliovirus types at 4 months of age (141). Seroconversion rates to tOPV are lower in many tropical
countries compared to seroconversion rates in developed countries (142–144). Poor responses to tOPV
have contributed to outbreaks of poliomyelitis in Oman, Israel, and Brazil despite relatively high
immunization rates existing before the appearance of epidemic disease (145–147). Although the reasons
for the lower potency of tOPV vaccine in tropical areas remain incompletely understood, concurrent
diarrheal disease at the time of immunization is an important factor (148,149).
Monovalent type 1 (mOPV1), monovalent type 3 (mOPV3), and bivalent type 1 and type 3 (bOPV)
were added to the Global Polio Eradication Program in 2006 and 2009, respectively to enhance
seroconversion rates to type 1 and type 3 OPV in the absence of the type 2 vaccine virus (150). Studies in
Egypt and South Africa have confirmed the superior immunogenicity of the monovalent vaccines
compared to tOPV in resource poor settings (151,152).
Nonimmune OPV recipients shed vaccine viruses in the feces for 1 to 6 weeks and from the oropharynx
for 1 to 3 weeks. The spread of OPV viruses to unimmunized children is an advantage in areas in which
immunization levels are low. For example, a seroprevalence study in Houston and Detroit found that 11%
to 42% of 11- to 35-month-old children possessed poliovirus neutralization antibodies, despite receiving
no prior OPV vaccine (153).
Vaccine-Associated Paralytic Poliomyelitis
The only serious adverse reaction associated with OPV is the rare occurrence of VAPP. The incidence of
VAPP has been estimated to be 2 to 4 cases per million individuals per year in countries using OPV
(154). In industrialized countries, the relative frequency of paralysis associated with the first dose in the
OPV series is about 10-fold higher than with subsequent doses, whereas in developing countries, this
ratio is lower, probably due to lower vaccine effectiveness (155). OPV virus types 3 and 2 were most
common causes of VAPP in the United States prior to discontinuation of OPV use in 2000 (155).
Approximately half of VAPP cases are recent OPV vaccinees, most of whom develop paralysis 7 to 21
days after the first feeding of OPV. A similar number of cases occur among parents, other family members,
or other household contacts that develop paralysis several weeks after the administration of OPV to a
close contact.
Persons who have transient or hereditary B-cell immunodeficiency, severe combined
immunodeficiency syndrome, or common variable immunodeficiency have an elevated risk of VAPP
(69,156). For immunodeficient VAPP patients, interval between the last OPV dose and onset of neurologic
disease is unusually long, with a typical range of 1 to 8 months, and has been documented to be as long as
7 years (70). The illness may be protracted with chronic meningitis, progressive neurologic dysfunction
suggesting involvement of both upper and lower motor neurons, progression of paralysis over several
weeks, and high mortality (67,68). Although fewer than 20% of surviving VAPP patients excrete
polioviruses for longer than 6 months (70), fecal excretion of virus has been estimated to occur for as
long as 18 years in one immunodeficient patient (157).
GLOBAL CONTROL OF POLIOMYELITIS
With some notable exceptions (158), paralytic poliomyelitis affects mostly children between the ages of 6
months and 2 years in developing countries, and most cases are caused by type 1 poliovirus. Lameness
surveys of school-aged children in more than 20 developing nations revealed lower limb paralysis
prevalence rates of 2 to 11 per 1,000 in the 1960s and 1970s, prevalence rates that equal or exceed those
of the peak epidemic years in the United States (159,160). Currently, OPV vaccine is used almost
exclusively in underdeveloped nations because of lower cost, ease of administration, enhanced mucosal
immunity, and enhancement of population immunity through transmission of vaccine viruses from
immunized children to nonimmune contacts.
Following the successful eradication of smallpox, an international conference held in Bellagio, Italy in
1983 articulated the possibility of poliomyelitis eradication based on the unique epidemiology of
poliovirus infections and the widespread availability of an inexpensive oral vaccine (tOPV) (161,162).
By 1991, the Pan American Health Organization succeeded in eradicating polio in the Americas, and in
1988, the World Health Assembly resolved to eradicate polio globally by the year 2000 (163–165). The
Global Poliomyelitis Eradication Initiative (GPEI) is a consortium of international partners led by the
WHO (159,166). The principal strategies employed by the GPEI include enhancement of routine infant
tOPV immunization, the conduct of large scale supplementary immunization activities (SIAs) targeting all
children younger than 5 years of age, surveillance for poliomyelitis cases through identification of
persons with acute flaccid paralysis (AFP), and maintenance of a global network of laboratories capable
of identification and characterization of polioviruses in fecal specimens obtained from AFP cases.
Seroconversion rates during SIAs are higher than for routine immunization (167), possibly because of
spread of OPV or because they are conducted during the dry season when diarrheal disease is less
prevalent. In the Americas, twice yearly mass campaigns were credited with rapid cessation of poliovirus
circulation and disappearance of disease (168,169).
Although there has been a reduction of more than 99% in the burden of paralytic poliomyelitis and
circulation of type 2 polioviruses ceased in 1999, the goal of complete eradication has proven to be more
difficult to attain than originally anticipated (170–172). Progress stalled in the last decade due to inability
to stop transmission in some highly endemic areas, exportation from these areas to previously polio-free
nations, social and cultural opposition to OPV immunization, civil unrest, funding gaps, and the
emergence of VDPV in areas with low OPV coverage (173,174). Eventually, many of the social, cultural,
and political barriers were addressed, and in the mid-2000s, the deployment of monovalent and bivalent
OPVs during SIAs led to improved seroconversion rates in many countries affected by low tOPV potency.
These new formulations are now credited with the eventual elimination of poliomyelitis in India and the
marked reduction in case load in some particularly challenging areas in sub-Saharan Africa (166).
Vaccine-Derived Polioviruses
One unanticipated challenge to global poliomyelitis eradication is the emergence of virulent polioviruses
derived from OPV vaccine strains among underimmunized children living in certain economically
deprived regions (175,176). A retrospective laboratory investigation demonstrated previously
unrecognized type 2 VDPV isolates that circulated in Egypt from approximately 1982 to 1993, and global
surveillance since 2000 has uncovered more than 15 subsequent VDPV outbreaks representing all three
poliovirus serotypes (177). All VDPV strains have been isolated from regions with low OPV coverage,
permitting VDPV to circulate, and all have acquired biologic properties that are indistinguishable from
naturally occurring wild type polioviruses, including neurovirulence in monkeys and transgenic mice
(178,179).
The discovery of the potential for reintroduction of virulent polioviruses into previously polio-free
areas via generation of VDPV has reinforced the necessity of maintaining high immunization levels in all
polio-free regions and has created the necessity of discontinuing the use of all live, attenuated poliovirus
vaccines once eradication of naturally occurring poliovirus disease is assured (180,181).
OUTLOOK
As of 2013, renewed commitment to eradication has reduced the number of polio-endemic nations to three
—Nigeria, Afghanistan, and Pakistan—and the annual global case count to less than 300, and there is
hope that the mission to eradicate will soon be met. The polio “endgame” now calls for replacement of
tOPV by bOPV once the threat from type 2 circulating vaccine-derived poliovirus (cVDPV) is diminished
and the ultimate discontinuation of all live OPV and a phased introduction of IPV. IPV is known to be
highly immunogenic when administered to infants and children in resource-poor settings (182–185) and
has shown promise as a supplement to OPV in similar settings (147,186–188). Furthermore, strategies are
being developed to overcome the higher costs associated with IPV production, delivery, and storage,
including development of dose reduction by intradermal injection, development of new adjuvants, and
combination of IPV with other vaccines routinely administered to infants (174).
SUMMARY
Epidemic paralytic poliomyelitis is a disease that has both appeared and disappeared during the past 120
years. Most medical practitioners in industrialized countries have never seen a case of acute
poliomyelitis but may encounter patients who are now developing the symptoms of postpolio syndrome.
The clinical, epidemiologic, and scientific foundations for the control of poliomyelitis were laid in the
first half of the twentieth century. Now, eradication has been achieved throughout the developed world by
routine immunization programs using two very effective vaccines, each of which possesses unique
advantages and disadvantages. In recent years, IPV has become the preferred vaccine for developed
countries because of the risk of rare VAPP cases associated with OPV.
Attention is now focused on the few remaining locations where polio remains endemic. Despite
setbacks, new strategies are being deployed and real progress has been made in recent years. Hopefully,
the goal of global poliomyelitis eradication will be achieved before the next edition of this text is
published. The posteradication phase will require continued surveillance, maintenance of vaccine
stockpiles for use should virulent polioviruses reemerge, and containment of laboratory stocks of
naturally occurring and attenuated polioviruses (189). The discovery of VDPV in multiple locations has
limited the options available for eventual discontinuation of polio immunization and underscored the
critical need to maintain active surveillance and high levels of immunity worldwide for many years
(180,181).
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CHAPTER 8 MEASLES AND RUBELLA
DIANE E. GRIFFIN
Measles and rubella are rash diseases of childhood that can be complicated by neurologic disease.
Measles virus (MeV)–induced neurologic disease is associated with community-acquired infection of
children, whereas the most important rubella virus (RV)–induced neurologic disease is associated with
congenital infection. For both diseases, effective and safe vaccines exist. Despite wide distribution of
measles vaccine, measles remains a frequent cause of morbidity and mortality worldwide, and even a low
incidence of measles-associated neurologic disease has a significant impact on society because of the
long-term neurologic disabilities that ensue (1). Rubella vaccine is less widely distributed, but there is an
intensifying effort to increase coverage in developing countries and reduce the worldwide incidence of
congenital rubella syndrome (CRS) (2). The World Health Organization has targeted both viruses for
elimination and potential eradication (3).
Neurologic complications may result from direct virus invasion of the central nervous system (CNS) or
from induction of an autoimmune response to CNS antigens. For measles, there are three distinct
neurologic diseases that occur either at the time of the acute disease or months to many years after
apparent recovery: acute disseminated encephalomyelitis (ADEM), measles inclusion body encephalitis
(MIBE), and subacute sclerosing panencephalitis (SSPE). Rubella causes ADEM and progressive rubella
panencephalitis (PRP) less frequently than measles but is also teratogenic and causes CRS.
BACKGROUND ON MEASLES
MeV, the etiologic agent of measles, is a member of the Morbillivirus genus of the Paramyxoviridae
family of nonsegmented, negative-stranded, enveloped RNA viruses. There are several morbilliviruses
and each has a relatively restricted host range. Nonprimate morbilliviruses cause respiratory disease in
dogs, horses, cows, goats, sheep, and marine mammals and neurologic complications are common.
Rinderpest, a disease of cattle, has recently been eradicated (4,5).
Morbilliviruses have six structural proteins (Fig. 8.1). The hemagglutinin (H) and fusion (F) are
transmembrane proteins present on the surface of the virus and infected cell. These proteins are important
for viral attachment and penetration of the target cell. The matrix (M) protein is found on the inner surface
of the membrane and interacts with the cytoplasmic tails of H and F and with the nucleocapsid for virion
assembly and budding. The nucleocapsid (N) protein surrounds and encapsidates the viral RNA to form
the helical nucleocapsid structures. The phosphoprotein (P) and large (L) polymerase protein are also
associated with the nucleocapsid and complete the viral elements necessary for RNA transcription. Two
nonstructural proteins, C and V, are encoded within the P gene and regulate the host innate response to
infection (6–12).
MeV transmission from person to person is by the respiratory route. The virus spreads from the initial
site of replication in the respiratory tract to local draining lymph nodes (13–15). Replication in lymphatic
tissue produces virus that then spreads through the blood to multiple organs including skin, lung, liver,
spleen, and lymph nodes. The viremia is cell associated with infected B cells, T cells, and monocytes in
circulation (16–18). MeV-infected leukocytes increase expression and activation of the integrins
lymphocyte function-associated antigen (LFA)-1 and very late antigen (VLA)-4 that promote adherence to
the surface of endothelial cells and this interaction is likely to facilitate the spread of infection to many
organs and tissues (19,20). In tissue, endothelial and epithelial cells are also targets for infection
(21–23).
Three cellular receptors have been identified: membrane cofactor protein or CD46 (24,25), signaling
lymphocyte activation molecule (SLAM) or CD150 (26), and nectin 4 (27,28). CD46 is a widely
distributed human complement regulatory protein expressed on all nucleated cells including the apical
surface of polarized epithelial cells. In the CNS, CD46 is expressed on choroid plexus epithelial cells, on
cerebral endothelium, and ependymal cells (29,30). SLAM/CD150 is a membrane glycoprotein expressed
on cells of the immune system including immature thymocytes, activated T and B lymphocytes, activated
monocytes, and mature dendritic cells (31,32) but is not expressed by brain parenchymal cells (29).
Nectin 4 is an adherens junction protein expressed by epithelial cells in the lungs, tonsils, and placenta
(33,34). Studies of different strains of MeV have shown that both vaccine and wild type viruses can use
CD150 and nectin 4 as a receptor. However, although most vaccine strains use CD46 efficiently, wild
type strains do not (35–37). The receptors used for neural cell infection by wild type MeV and chick cell
infection by vaccine virus (38–40) have not been identified.
Through expression of the H and F proteins on the cell surface, infected cells may fuse with nearby
cells to form syncytia or giant cells both in vitro and in the lungs and lymphoid tissues of infected patients.
However, MeV is not detectable by usual pathologic or immunocytochemical techniques in the brains of
patients dying acutely with measles (21). Studies using in situ hybridization have identified MeV infecting
cerebral capillary endothelial cells during acute fatal disease (22). In addition, electroencephalographic
(EEG) abnormalities and a cerebrospinal fluid (CSF) pleocytosis are common in acute uncomplicated
measles (41–43), suggesting the possibility that MeV infection of the CNS is common during
uncomplicated infection. However, these changes are also observed after measles immunization, so it is
not clear that they indicate virus infection of the CNS (44).
The characteristic morbilliform rash of measles is due to immune cell infiltration into sites of MeV
infection of skin epithelial cells and marks the onset of the immune response and the initiation of virus
clearance (45). It is a time of intense immune activation (46–48) which is accompanied by suppression of
skin test responses to recall antigens such as tuberculin (49,50) and decreased in vitro
lymphoproliferative responses to mitogens (51). This immune suppression contributes to an increased
susceptibility to secondary infections, the most common cause of death due to measles (52). The immune
activation accompanying measles may contribute to the neurologic complications as well.
Although clearance of infectious MeV is generally complete after the rash has resolved, clearance of
viral RNA requires many months (53,54). This continued presence of MeV RNA in lymphoid tissue and
circulating mononuclear cells may contribute to immune suppression and to development of acute and
chronic neurologic disease.
OVERVIEW OF THE NEUROLOGIC COMPLICATIONS OF

MEASLES
The neurologic complications of measles are uncommon and occur at three distinct times in relation to the
primary infection and acute disease (Fig. 8.2). ADEM usually presents within 1 to 2 weeks of the
appearance of the rash (55,56), MIBE within a few months (57,58), and SSPE several years after initial
infection (59). The age and general immune status of the individuals susceptible to these complications
are also distinct (Table 8.1). ADEM occurs in individuals who have apparently normal immune systems
and are older than 2 years at the time of primary infection (52). The incidence is 1:1,000 cases of measles
(52,60). MIBE occurs in immunosuppressed patients of any age (61–65). The incidence is approximately
1:10 cases of measles in immunocompromised children (66,67). SSPE occurs in immunologically normal
individuals who have often had measles at younger than 2 years (59,68,69). The incidence is
approximately 1:10,000 cases of measles (70).
MeV is easily demonstrable in the brains of patients with MIBE and SSPE, but not ADEM (21). The
current understanding of these three neurologic complications of measles is that ADEM is an autoimmune
demyelinating disease triggered by measles, MIBE is a progressive MeV infection of the brain in patients
unable to mount an effective immune response, and SSPE is a slowly progressive MeV infection of the
CNS that is poorly controlled by the immune system and presents clinically many years after infection.
MEASLES INCLUSION-BODY ENCEPHALITIS

History
Progressive MeV infection was reported first by Hecht (71) in 1910 as a case of giant cell pneumonia.
“Hecht pneumonia” was suspected to be a complication of measles and this hypothesis was proven in
1959 when Enders et al. (72) isolated MeV from the lungs and respiratory tract secretions of three young
children with compromised immune systems and progressive pulmonary disease. Pathologic examination
of the lungs of these children showed giant cell pneumonia. None had a history of rash or other classic
signs or symptoms of measles, but all had histories of exposure to measles in the preceding months. Giant
cells were found in other organs (e.g., liver, lymph nodes), but neurologic symptoms were not reported
and it is not clear that the brain was examined (72).
Breitfeld and colleagues (73) first reported progressive nervous system disease in 1973 as cases of
SSPE. Two young children with leukemia developed progressive neurologic disease and died
approximately 6 months after exposure to measles. At autopsy, giant cells were not present in the CNS,
but there were intranuclear and intracytoplasmic inclusions now recognized to be frequent pathologic
features of persistent MeV infection of the CNS. One also had Hecht pneumonia. Subsequently, this
neurologic disease, MIBE, was distinguished from SSPE by its time of onset in relationship to measles,
lack of inflammatory response in the brain (74), and occurrence in immunocompromised individuals.
Recently, this disease has also been described in adults who are immunocompromised due to HIV
infection (65) and after immunization with the live attenuated MeV vaccine (75).
Pathogenesis and Pathology
The rash marks the onset of the immune response with the appearance of MeV-specific antibody and
cellular immunity, and this immune response to MeV is normally effective at clearing infectious virus
from blood and tissues (53). In individuals with severe acquired or genetic defects in cellular immunity, a
rash may not appear (72,73) and MeV infection may not be controlled. These patients often develop
progressive pulmonary or neurologic disease due to unrestrained MeV replication (66,73,74).
Virus infection of the CNS is presumed to begin with infection of cerebral capillary endothelial cells or
with infiltration of infected leukocytes into the brain (20,22,76). Neurons or glial cells subsequently
become infected and virus spreads slowly within the CNS. Intranuclear and intracytoplasmic eosinophilic
inclusion bodies are seen primarily in gray matter areas (73). There is focal necrosis, and neurons often
show signs of degeneration (74). The areas of brain most frequently involved are the parietooccipital
areas, basal ganglia, and brainstem. Typically, there is little evidence of an inflammatory response to the
infection, although proliferation of astrocytes and microglia is often apparent (61,74).
On electron microscopic examination, inclusion bodies contain the microtubular structures of MeV
nucleocapsids (58,74). MeV antigens (particularly N) can be identified by immunocytochemical staining
(77). However, the H, F, and M proteins are undetectable (78) and often MeV cannot be recovered in
culture from brain tissue (61,64). Examination of viral RNA extracted from the brains of MIBE patients
has shown that messenger RNAs (mRNAs) for the envelope proteins are limited in amount and that the
virus has accumulated many mutations, particularly in the M-protein gene, similar to those found in SSPE
(see later discussion) (79,80). These mutations often preclude or severely limit productive replication
(81–83). These mutations may reflect positive selection and adaption of the virus to growth in neurons or
frequent transcription errors, including biased hypermutation due to the action of dsRNA–dependent
adenosine deaminase (84), combined with a lack of selection for replication-competent virus. Production
of infectious virus may not be important for virus replication and spread in the CNS, because neurons can
allow transsynaptic spread of viral RNA–containing nucleocapsids from cell to cell without production
of infectious virions (85–88).
MIBE usually presents 1 to 6 months after exposure to measles with progressive neurologic deterioration
in the absence of fever. Signs and symptoms include altered mental status, lethargy, slurred speech, focal
motor seizures or epilepsia partialis continua, weakness, and occasionally blindness or hearing loss
(57,62,65,77). Typically, the seizures are resistant to control by anticonvulsant medications (62). Disease
progresses over days to weeks to coma and death and may be accompanied by inappropriate secretion of
antidiuretic hormone (58,66,73).
Diagnosis
The diagnosis is often difficult because there may be no history of a rash. History of exposure to measles
or immunization in the preceding months should be sought in immunosuppressed individuals with
progressive neurologic deterioration. Brain biopsy with pathologic examination and reverse
transcriptase-polymerase chain reaction (RT-PCR) to detect MeV RNA is often necessary for definitive
diagnosis (62,65,89). At the time of presentation, there is often no detectable antibody to MeV, consistent
with the poor immune response to infection, although at later times antibody may be present in serum or
CSF (62,66,74). CSF examination is usually within normal limits, but occasionally there is a moderate
elevation in the protein concentration (62). EEG findings are usually abnormal, but nonspecific and
nondiagnostic, with diffuse slowing or periodic lateralized spike and wave activity (62,65,66,90).
Computed tomographic (CT) scan and magnetic resonance imaging (MRI) scans are often normal at the
time of presentation with later development of T2 signal abnormalities, edema, cortical atrophy, and
ventricular dilation (62,65,66).
Adequate measles immunization prior to the onset of leukemia or other immunosuppressive illness
undoubtedly prevents many cases of MIBE (57). It is difficult to discern the usefulness of postexposure
immunoglobulin prophylaxis for immunocompromised individuals. Several cases of MIBE have occurred
despite administration of immunoglobulin, but many more may have been prevented. There is no
established antiviral treatment for MIBE and essentially all cases are fatal. However, there are case
reports of neurologic improvement with prolonged intravenous ribavirin treatment (62) and slowed
disease progression with initiation of antiretroviral therapy in patients with AIDS (65).
SUBACUTE SCLEROSING PANENCEPHALITIS

History
SSPE was first described in 1933 by Dawson (91) in a 16-year-old boy with progressive neurologic
deterioration characterized by failing memory, slow and deliberate movements, and myoclonus. The
following year, he reported an additional case of this subacute inclusion body encephalitis in a 5-year-old
girl (92). Histologic examination of the brains of these patients showed inflammation with eosinophilic
intranuclear and intracytoplasmic inclusions in neurons. The disease became known as Dawson
encephalitis, and Dawson postulated that the disease was of viral etiology, but he could not transmit the
disease to experimental animals. In 1945, van Bogaert (93) described a similar condition, subacute
sclerosing leukoencephalitis with prominent white matter involvement. It was appreciated subsequently
that the same disease could involve both gray and white matter (94). In 1966, paramyxovirus-like
particles suggestive of MeV were seen on electron microscopic examination of the inclusions (95).
Reports of these virus particles were followed rapidly by observations of elevated MeV antibody in
serum and CSF, staining of the inclusions with antibody to MeV antigens and culture of MeV from brains
(96–100).
Epidemiology
SSPE is a rare (approximately 1 in 10,000) late complication of measles (68,70,101). The mean time to
onset of SSPE after measles is 6 to 10 years (59,102,103) (Fig. 8.2). Children with SSPE often have a
history of acquiring measles at an early age (59,68–70,104–107) when the immune system is immature
and maternal antibody may still be present. In most parts of the world, the disease occurs preferentially in
boys (68,104,108,109). Exposure to birds has been identified as a risk factor (69,105,108). How these
factors increase the risk of developing SSPE is unknown. There is no clustering of cases to suggest that
the virus causing the initial infection leading to SSPE is different from the virus causing uncomplicated
disease.
SSPE is the most extensively studied of the neurologic complications of measles. Nevertheless, the
pathogenesis of this rare complication remains obscure. It is not known whether infection of the nervous
system occurs at the time of primary infection and progresses slowly with clinical evidence of disease
apparent only after years or whether the infection is latent at a site outside the CNS and then spreads to
the brain. The route of virus entry into the CNS is unknown, but infection of cerebral capillary endothelial
cells is a likely possibility (76,11). Extensive sequence analysis of viral RNA from various parts of the
brain in SSPE suggests that the virus in the nervous system is clonal (111), implying that virus entered the
brain at one time and then gradually spread throughout the nervous system. This gradual spread has also
been suggested by serial MRI studies (112,113). Therefore, it is most likely that MeV enters the brain at
the time of the original acute infection or during the prolonged phase of circulating viral RNA and
subsequently spreads slowly through the CNS eventually infecting a sufficient number of cells to produce
dysfunction and clinical evidence of infection.
At the time that neurologic symptoms are recognized, the infection is extensive. Neurons and
oligodendrocytes contain nuclear and cytoplasmic viral inclusion bodies (114), antibody responses are
vigorous and evident both in serum and CSF (115,116), and there is an extensive mononuclear
inflammatory reaction in the brain (92,93,117). Gray matter is most prominently affected, but pathologic
changes are present in white matter as well (92,93). Retinitis is frequently present with MeV antigen
demonstrable in the retinal neuroepithelium. At autopsy, MeV RNA or antigen can be detected in a wide
variety of tissues (118).
Pathologic examination of the brain shows intranuclear and intracytoplasmic inclusions, in situ
hybridization shows MeV RNA, and immunocytochemical staining shows MeV antigens (110). However,
no virus is seen budding from the surface of infected cells (119). Nuclear inclusions are filled with
“smooth” nucleocapsids (114,119) consistent with the absence of the associated L and P proteins
necessary for transcription and replication of viral RNA. The cytoplasm contains replication-competent
“fuzzy” nucleocapsids that extend into neuronal processes further suggesting that virus can spread within
the CNS by cell-to-cell synaptic transmission of the ribonucleoprotein complex (85,87,88,113,120). The
observation that strains of MeV isolated from SSPE patients are more likely than standard strains of MeV
to cause neurologic disease after intracerebral inoculation into small animals and primates suggests that
the virus has adapted to growth in neural tissue.
Like MIBE, the virus present in the brain of SSPE patients is replication defective and cannot usually
be recovered from SSPE brain in a cell-free form (99,100,121). Extensive sequence analysis of viral
RNAs has shown that SSPE viruses are of the same lineage as viruses that cause acute measles but
distinguishable in the genes encoding the M, F, and H proteins (112,122–129). Studies of brain-associated
viral proteins and RNA in SSPE have revealed differences in the relative amounts of the various viral
mRNAs and proteins (127–130), in the antigenicity of viral proteins (131), and in RNA sequences coding
for viral proteins (125–127) between SSPE viruses and wild type or vaccine strains of MeV. Because the
disease cannot be studied prospectively, it is not known for certain whether these differences represent
unique features of the original infecting virus, selection for growth in the CNS, or selection for growth in
the presence of a vigorous antibody response.
In general, expression of M protein is low (130,132,133) and the mRNA encoding M extracted from
SSPE brain is mutated throughout the gene. Construction of recombinant viruses has shown that functional
M is dispensable for virus growth and spread in the CNS and may foster the formation of nuclear and
cytoplasmic inclusion bodies (83). Mutations in the H and F envelope proteins that interfere with
assembly and budding of infectious virus are also associated with persistent infection and SSPE
(123,126,127,134).
The possibility that the development of SSPE represents a defect in the immune response has led to
investigations of cellular and humoral immune responses to MeV and other antigens. In contrast to patients
with MIBE, there is often an intense perivascular mononuclear inflammatory response in brain and high
levels of antibody to MeV in serum. There is also significant production of MeV-specific antibody by
plasma cells residing in the CNS. This locally synthesized antibody appears in the CSF leading to
characteristic elevations in the level of CSF immunoglobulin much of which is MeV specific
(96,135–137). Antibody produced in the CNS derives from clones of resident antibody-secreting B cells
and is therefore of restricted heterogeneity leading to the appearance of oligoclonal immunoglobulin
bands on electrophoretic analysis of the CSF from SSPE patients (138–142). Antibodies against the N
and P proteins are particularly abundant and antibody against the M protein is particularly deficient
(132,143). Antibody to CD9, a tetraspanin protein widely expressed in the CNS, is also elevated, raising
the possibility of an autoimmune component to this progressive disease (144).
Experiments in small mammals have shown that treatment with antibody after intracerebral infection
with neuroadapted strains of MeV attenuates acute disease but increases the incidence of persistent virus
infection and subacute or chronic encephalitis (81,145). Cases of SSPE have been associated with
passive transfer of immunoglobulin and persistent infection has been induced experimentally by passive
transfer of antibody (146). Therefore, antibody may contribute to the establishment and maintenance of
persistent nervous system infection.
The mononuclear inflammatory response in the brain includes CD4 and CD8 T cells as well as
monocytes and immunoglobulin-secreting B cells (103,136,147,148). Expression of class I and class II
major histocompatibility antigens is increased in brain, and β2-microglobulin, interleukin (IL)-1, soluble
intercellular adhesion molecule (ICAM), soluble IL-2 receptor, and soluble CD8 are increased in CSF
(149,150). Thus, there is no evidence for a global defect in immune responses, although MeV induction of
interferon-γ (IFN-γ) is reduced in some individuals (151). It is likely that SSPE and MIBE are similar in
their pathogenesis, but that MeV replication and the appearance of neurologic symptoms is slowed in
SSPE by the presence of a vigorous immune response (64). However, this immune response is not able to
clear the virus once parenchymal CNS infection has been established and infection is progressive.
The age of initial MeV infection in individuals subsequently developing SSPE is often younger than 2
years. The age of onset of neurologic disease is typically between 2 and 20 years of age but has been
reported up to the age of 35 years (59,68,102,109). The onset is insidious and the diagnosis is often not
suspected early in disease (152,153). The first symptoms are likely to be deterioration in school or work
performance and changes in personality (stage I). In adults, visual impairment is often an early sign
(112,154). Alteration in mental status is followed by the onset of myoclonus, convulsions, abnormal
postures and movements, and autonomic dysfunction (stage II). Progressive neurologic deterioration is
marked by rigidity (stage III), optic atrophy, and akinetic mutism, ending in coma (stage IV) and death
months to years after onset (155–157). The course of SSPE is usually 1 to 3 years. More rapid
progression has been reported with perinatally acquired infection (102,158,159). Occasionally, with
good supportive care, patients survive for longer periods of time and remissions lasting weeks to years
with total clinical courses of 10 to 16 years have been reported (119).
Diagnosis
The diagnosis of SSPE can be made by demonstration of high levels of antibody to MeV in CSF in the
setting of a characteristic clinical picture. Typical EEG changes include a burst-suppression pattern often
most easily demonstrable during sleep (94,156,160), but this may not be present in adult-onset disease
(112). The CSF is often normal on routine analysis of pressure, protein, glucose, and cells. However, the
immunoglobulin concentration is usually elevated, oligoclonal bands are present on electrophoretic
analysis, and MeV-specific antibody is elevated (155). MeV RNA can be detected in the brain and CSF
by RT-PCR (112,161,162). CT and MRI scans are generally unhelpful. CT scans often show evidence of
loss of parenchyma with ventricular dilation and cortical, brainstem, and cerebellar atrophy accompanied
by low parenchymal attenuation (163). MRI scans tend to show hyperintense T2-weighted lesions in gray
and white matter, with white matter lesions becoming more prominent as disease progresses
(112,164–166).
Numerous therapeutic agents including bromodeoxyuridine, azaguanine, amantadine, interferon,

isoprinosine, ribavirin, and cimetidine have been used for the treatment of SSPE (162,167–170).
Evaluation of the efficacy of any of these regimens is difficult because the disease is rare, most reports
are anecdotal or uncontrolled, and the benefits at best are short term. Therefore, there is no established
treatment for this disease.
Timely measles immunization is the most effective means of prevention. The incidence of SSPE has
decreased dramatically since introduction of the live attenuated measles vaccine and there is no evidence
that the vaccine virus can cause SSPE (70,101,102,104,160,171–173).

History
In 1790, James Lucas (174), an English surgeon, described the first case of postmeasles
encephalomyelitis in a 23-year-old woman who developed paraparesis and urinary retention as the
measles rash was fading. ADEM can develop after a number of infections and is known under many
names including postinfectious and parainfectious encephalomyelitis (175). Acute hemorrhagic
leukoencephalitis or acute hemorrhagic necrotizing encephalopathy probably represents a more severe
form of the disease. In 1960, Koprowski (176) hypothesized that ADEM was an autoimmune (hyperergic)
disease based on the similarity of the pathology and clinical picture to experimental autoimmune
encephalomyelitis (EAE) and the demyelinating disease that complicates immunization with the brain-
derived Semple rabies vaccine. This remains the leading hypothesis (55), but understanding of the
pathogenesis of ADEM is incomplete.
Epidemiology
ADEM occurs worldwide and complicates many infections but is most frequent after measles (105,177).
The overall incidence of ADEM associated with measles is approximately 1 per 1,000 infections (52) but
varies with age. ADEM is more frequent in children older than 5 years of age and rare in those younger
than 2 years of age (52). It occurs equally in males and females.
ADEM occurs in close temporal association with acute measles (Fig. 8.2) at a time of an active immune
response to the infection (178). Brain pathology shows perivascular inflammation and perivenular
demyelination. During the acute phase, there is patchy swelling in the walls of small cerebral vessels and
mononuclear cell infiltration. Later, perivenous inflammation is more marked and demyelination is
evident (60,179,180).
There is little evidence for direct infection of the brain by MeV. Virus has rarely been recovered from
the brain (56,181), viral antigen is not detectable by immunocytochemical staining (21,182), and viral
RNA has not been detected by in situ hybridization (21). Furthermore, there is no evidence for a local
virus-specific intrathecal antibody response as is expected in diseases caused by direct virus infection of
the CNS (55). Therefore, there is no evidence that virus is present in the CNS at the time of neurologic
disease, but more sensitive techniques such as RT-PCR have not been applied and specimens from early
in disease have not generally been available for study. It is possible that virus in cerebral endothelial
cells plays a role in triggering the autoimmune disease or allowing access of autoreactive cells (22).
Thus, virus may no longer be detectable by the methods used at the time that tissue has been examined.
The pattern of loss of the myelin proteins, myelin-associated glycoprotein, and myelin basic protein
resembles that seen in EAE, a disease induced in animals by inoculation of myelin or myelin proteins
(182). Furthermore, immunologic studies of patients with ADEM have shown the presence of cellular
immune responses to myelin basic protein (55,181,183) and antibody to myelin proteins similar to that
seen in animals with EAE and in humans with Semple rabies vaccine-induced encephalomyelitis
(55,184–187). It is postulated that ADEM is analogous to these autoimmune diseases, but the mechanism
by which an autoimmune response to myelin proteins is induced during a systemic infection is not clear.
The timing of this complication suggests that immune activation associated with MeV infection may play a
role in induction of ADEM. Immune activation may increase presentation of self-peptides and allow the
proliferation of autoreactive clones of cells (178,188). Patients with ADEM differ from patients with
uncomplicated measles by having more marked and prolonged immunologic abnormalities. In particular,
IgE is more persistently elevated and soluble IL-2 receptor is lower in patients with ADEM (47,189). IL-
2 is one of the cytokines elevated in plasma (190), and a similar disease has been reported as a
complication of IL-2 infusion (191).
The possibility of immunologic cross reactivity between some component of myelin and a component
of MeV has been explored. Limited sequence homologies have been identified but none for which
biologic relevance has been shown (192). Studies of MeV-specific antibodies and T cells have shown no
cross reactivity with myelin basic protein or galactocerebroside (193,194).
Typically, patients recovering from measles present with an abrupt onset of renewed fever and
obtundation accompanied by neurologic signs and symptoms that can include meningismus, seizures,
altered mental status, multifocal neurologic deficits, and coma (177,180). The onset is most often between
2 and 7 days after the appearance of the rash but occasionally predates or appears up to 3 weeks after the
rash (55). The disease has a monophasic course over 10 to 20 days. Improvement is usually evident
within a few days after onset. Mortality ranges from 10% to 40% with substantial neurologic residua in
the majority of survivors (55,60,179). Prior to widespread measles immunization, ADEM was a common
cause of chronic neurologic disability.
Diagnosis
The diagnosis is apparent on clinical grounds when neurologic disease follows shortly after the rash.
Routine laboratory tests are not particularly helpful. There are no consistent abnormalities in blood or
urine. CSF may be normal or contain a modest elevation in protein and a mononuclear pleocytosis. The
EEG shows a nonspecific diffuse slowing. The CT scan may be normal, but the MRI scan usually shows
multiple foci of demyelination most likely to be seen on T2-weighted and fluid-attenuated inversion
recovery (FLAIR) images in subcortical and central white matter of the cerebral hemispheres,
cerebellum, brainstem, and spinal cord (166,177,195).
Measles vaccine is highly effective in prevention of ADEM and neurologic complications after
immunization are rare (196). Treatment is not well established. Corticosteroids are widely used, but the
benefit is not clear (177,197–199). One randomized study showed no benefit (200) and a retrospective
study found higher mortality and rates of sequelae in steroid-treated patients (201). Intravenous
immunoglobulin and plasma exchange have also been used with some reported success (177,202).
BACKGROUND ON RUBELLA
RV, the etiologic agent of the mild rash disease rubella or German measles, is the only member of the
Rubivirus genus of the Togaviridae family. Togaviruses are single-stranded, positive-sense, enveloped
RNA viruses and all, except RV, are in the Alphavirus genus and are transmitted by mosquitoes. No
related animal viruses have been recognized. RV has three structural proteins. The capsid protein
surrounds the RNA and the two envelope surface glycoproteins E1 and E2 are important for attachment
and entry. E1 induces neutralizing antibodies. Two clades and 10 genotypes are recognized (203).
Like MeV, RV is a human virus that is transmitted between individuals by respiratory droplets or
aerosol and spreads through the blood via a cell-associated viremia to skin and other organs (204). RV
can infect many types of cells, and myelin oligodendrocyte glycoprotein has recently been identified as a
cellular receptor (205). The immune response is associated with the appearance of the rash. There is
substantial evidence of immune activation, leukopenia, and immune suppression, as indicated by loss of
skin test responses to recall antigens (206,207).
The neurologic complications of postnatally acquired rubella include ADEM, which is in every way
similar to ADEM complicating measles but occurs less frequently (approximately 1:5,000 to 8,000 cases)
(208), and PRP, a disease similar to SSPE. However, the most important neurologic complications occur
when RV infection is acquired prenatally (Table 8.2).
CONGENITAL RUBELLA SYNDROME

History
The first recognition of the connection between rubella and birth defects was in 1941 when Norman
Gregg (209), an Australian ophthalmologist, noted an increase in cases of congenital cataracts, frequently
accompanied by cardiac abnormalities, in babies born after an epidemic of rubella. Subsequent studies
documented the relationship between maternal rubella early in pregnancy and multiple congenital defects
in the infants born to these mothers. The virus was isolated in 1962 and an attenuated live virus vaccine
was licensed in 1969 (210,211).
During the viremia in pregnant women, RV can infect the placenta and spread to the fetus. Fetal infection
is systemic, persistent, and teratogenic. The most significant damage occurs when infection occurs in the
first trimester of pregnancy (212) (Fig. 8.3). Spontaneous abortion is common during this period (212). In
infants who survive to term, common congenital defects include cardiac abnormalities, hearing loss, low
birth weight, and cataracts. Neurologic complications that include microcephaly, mental retardation,
retinopathy, and meningoencephalitis are common (213–215).
RV infects vessels and causes obstructive vasculopathy and CNS lesions due to ischemia (216).
Vascular lesions include focal areas of destruction of the walls of arteries and veins, pericapillary debris,
thickening and proliferation of vessel walls, and vascular constriction. Foci of parenchymal necrosis
follow the paths of damaged brain vessels and involve both white and gray matter. In addition, RV
infection of CNS cells inhibits cell division leading to microcephaly (217).
Infection is persistent and RV can be isolated from tissues, blood, CSF, and secretions for 6 to 30
months after birth, with boys clearing virus more slowly than girls (218). Failure to clear infection may
be due to the immaturity of the immune system at the time of infection (219) and is associated with a
number of RV-specific and nonspecific immune deficits. RV-specific IgM with neutralizing activity is
present, but levels of IgG are low and cellular immune responses are impaired (219–221). Peripheral
blood mononuclear cells (PBMCs) do not proliferate in response to mitogens (222) and responses to
routine immunizations are decreased compared to infants without CRS (218).
Infants at the time of birth typically show intrauterine growth retardation and frequently have
thrombocytopenia purpura, hepatomegaly, and splenomegaly. Signs of neural involvement include a
bulging anterior fontanel, lethargy, irritability, psychomotor retardation, and abnormal motor tone. Other
common manifestations of CRS are congenital heart disease, typically patent ductus arteriosus, valvular
stenosis or pulmonary artery stenosis; eye disease, most often cataracts, glaucoma, or retinopathy; and
sensorineural hearing loss (213,214). As infants with CRS mature, psychomotor retardation, behavioral
disorders, psychiatric disturbances, and autism, as well as endocrinopathies, ocular damage, and
hypertension may become apparent (223–225). Prenatal exposure to RV is also associated with
subsequent diagnosis of schizophrenia spectrum disorders, often accompanied by a progressive cognitive
decline (226,227).
Diagnosis
Subependymal cysts and hypoechogenicity indicative of calcification can be detected by cranial

ultrasonography (228,229), intraventricular and periventricular calcification is often evident on CT scans,
and parenchymal lesions are seen on MRI scans (230,231). CSF protein is typically elevated and RV can
often be isolated from CSF as well as many other tissues, nasopharyngeal secretions, and urine. RV RNA
can also be detected by RT-PCR. RV-specific IgM is usually present in serum.
Prevention and Treatment
Routine childhood, premarital, and postnatal RV immunization programs prevent maternal infection and
thus CRS (232,233). Widespread vaccination has been successful in eliminating rubella and CRS from the
Americas (234,235). However, introduction of rubella vaccine must be carefully planned to avoid
increasing the age of infection and thus the risk of CRS (236–238). When rubella is diagnosed in early
pregnancy, therapeutic abortion can be performed. Inadvertent immunization of pregnant women can result
in placental or fetal infection but rarely results in congenital abnormalities (239,240) and is not
considered an indication for therapeutic abortion.
PROGRESSIVE RUBELLA PANENCEPHALITIS

CRS is not usually progressive and virus is gradually cleared. However, in a few individuals,
progressive neurologic deterioration begins many years later. This disease, PRP, was first recognized in
1975 and is characterized by motor and mental deterioration accompanied by high levels of RV-specific
antibody in serum and CSF (241,242). The disease has also been recognized as an occasional late
complication of postnatally acquired rubella (243).
On pathologic examination, white matter is preferentially affected with mononuclear cell infiltration,
microglial nodules, astrocytosis, and amorphous vascular and perivascular deposits (244,245).
Cerebellar atrophy is common (244). Inclusion bodies are not present.
Clinical features include new onset of progressive intellectual deterioration, seizures, ataxia,
spasticity, and myoclonus (246). The diagnosis is usually made by the presence of high levels of antibody
to RV in serum and CSF and the presence of oligoclonal bands containing RV antibody in CSF (247,248).
The disease is progressive over several years and eventually fatal. No effective treatment has been
identified. Prevention requires widespread use of the live attenuated rubella vaccine.

Rubella is one of the rash diseases associated with ADEM (175,208). Symptoms typically occur abruptly
within the first week after the onset of the rash and often include headache, vomiting, meningismus, and
seizures. Neurologic abnormalities may include evidence of meningitis, transverse myelitis, radiculitis,
and optic neuritis, in addition to encephalitis (249,250). In addition to ADEM, RV-induced arteritis may
lead to cerebral infarction (249). CSF shows a moderate increase in mononuclear cells. The EEG is
abnormal. RV IgM is positive, but virus is rarely isolated from CSF or CNS samples (249,250). As with
the other neurologic complications of rubella, immunization will prevent ADEM.
ACKNOWLEDGMENTS
Studies from the author’s laboratory were supported by research grants from the National Multiple
Sclerosis Society, the National Institutes of Health (AI23047), and the Bill & Melinda Gates Foundation.
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CHAPTER 9 HERPES SIMPLEX VIRUS
RICHARD J. WHITLEY
Eight herpesviruses routinely cause human disease. The current classification of herpesviruses into
subfamilies serves the purposes of identifying evolutionary relatedness and summarizing unique
properties of each member. The three subfamilies are alpha that include herpes simplex virus 1 (HSV-1),
HSV-2, and varicella-zoster virus (VZV); beta consisting of cytomegalovirus (CMV), human herpesvirus-
6 (HHV-6) and HHV-7; and the gamma herpesviruses, Epstein-Barr virus (EBV), and Kaposi sarcoma
herpesvirus (i.e., HHV-8). One simian herpesvirus, B virus (Cryptotetia crypta), also an alpha
herpesvirus, can inadvertently infect humans, resulting in devastating central nervous system (CNS)
disease. These viruses share similar molecular and biologic characteristics, including the unique ability
to establish latency and reactivate. These agents, among the most common encountered by humans, are
common causes of CNS infections (1). Members of the alpha herpesvirus subfamily are characterized by
a very short reproductive cycle, prompt destruction of the host cell, and ability to establish latency,
usually in sensory ganglia. Both HSV-1 and HSV-2 are routine causes of CNS disease and the subject of
this chapter.
GENERAL CHARACTERISTICS OF HERPESVIRUSES

All members of the family Herpesviridae have a similar molecular structure. These viruses contain
double-stranded DNA, which is located at the central core. The DNA is surrounded by a capsid,
consisting of 262 capsomers and providing icosapentahedral symmetry to the virus. Tightly adherent to the
capsid is an amorphous tegument. Loosely surrounding the capsid is a bilayered lipid envelope. The
overall size of herpes virions varies from 120 to approximately 300 nm, depending on the virus. The
envelope consists of polyamines, lipids, and glycoproteins. The glycoproteins confer distinctive
properties to each virus, providing unique antigens to which the host is capable of responding.
Herpesvirus DNA varies in molecular weight from approximately 80 to 150 million and consists of
120,000 to 230,000 base pairs. Base composition of herpesvirus DNA varies between 31% and 75% of
guanine plus cytosine. Of all the herpesviruses, HSV-1 and HSV-2 are the most closely related, with
approximately 50% genomic homology. With the exception of HSV-1 and HSV-2, the structural and
nonstructural proteins coded by the DNA of the HHVs are not immunologically related. However, HSV-1
and HSV-2 share common types of proteins; therefore, cross-antigenic reactions do occur.
HISTORY
Infections caused by HSV have been recognized since the time of ancient Greece. Greek physicians used
the word herpes to mean creeping or crawling in reference to observable skin lesions. Likely, this word
was used to describe various skin conditions ranging from cancer to shingles and probably even fever
blisters. The Roman scholar Herodotus associated mouth ulcers and lip vesicles with fever (2). He called
this event herpes febrilis. Genital herpetic infections were described first by a physician to the French
royalty, Astruc (3).
The transmissibility of these viruses was established unequivocally by passage of virus from human lip
and genital lesions to either the cornea or the scarified skin of the rabbit (4). Goodpasture (5) further
demonstrated that material derived from the lesions of herpes labialis consistently produced encephalitis
when inoculated onto the scarified cornea of rabbits.
Since the first suggestions of herpes simplex encephalitis (HSE) by the Mathewson Commission in
1926 (6) and subsequent description of the histopathologic changes (7), HSV is reported as the most
common cause of sporadic fatal encephalitis in the United States. Intranuclear inclusion bodies consistent
with HSV infection were first demonstrated in the brain of a neonate with encephalitis (7) in 1941, as is
described later in this chapter. Virus was subsequently isolated from this brain tissue (7). The first adult
case of HSE providing similar proof of viral disease (i.e., intranuclear inclusions in brain tissue and
virus isolation) was described in 1944 (8). The most striking pathologic findings in this patient’s brain
were apparent in the left temporal lobe where perivascular cuffs of lymphocytes and numerous small
hemorrhages were found. This temporal lobe localization subsequently has been determined to be
characteristic of adult HSE, and it differs from the patchy diffuse encephalitis of neonates with HSV brain
infection.
In the mid-1960s, Nahmias and Dowdle (9) demonstrated two antigenic types of HSV. Viral typing
allowed the demonstration that HSV-1 was historically primarily responsible for infections “above the
belt” (including brain disease in adults), whereas HSV-2 was primarily responsible for infections “below
the belt” (brain disease in neonates). However, more recent studies (10,11) indicate that either virus can
infect the mouth, genital tract, or brain.
INFECTIOUS AGENT
Recent detailed reviews highlight the importance of these organisms as models of viral replication and as
pathogens for human infection (11). Our current understanding of the structure of HSV indicates that the
genome has a molecular weight of approximately 100 million. The DNA encodes about 80 polypeptides.
The DNA strands of HSV-1 and HSV-2 are colinear with reasonable but not identical matching of base
pairs. Of note, there is considerable overlap in the cross reactivity between the HSV-1 and HSV-2
glycoproteins, although uniqueness can be demonstrated, as discussed later in this chapter. Distinction
between the two viral types can be demonstrated by restriction enzyme analysis of viral DNA patterns.
This technique has been applied to epidemiologic investigations of human HSV infections, as well.
Replication of HSV is characterized by the expression of three gene classes: immediate early (alpha),
early (beta), and late (gamma), which are expressed temporally and in a rolling-circle sequence (11). A
few relevant events will be noted. There are five “immediate early” genes, one of which is necessary for
initiating viral replication. The “early” gene products include those enzymes necessary for viral
replication (such as HSV thymidine kinase), as well as the regulatory proteins. Current antiviral drugs
with selective mechanisms of action are activated at the level of early gene expression. Acyclovir is an
example of such a drug, being converted to its active monophosphate derivative by HSV thymidine kinase.
Early gene expression coincides with an irreversible shutoff of host cellular macromolecular protein
synthesis, which results in cell death. Structural proteins are usually of the late gene class. Assembly of
the virus begins in the nucleus, and the envelope is acquired as the capsid buds through the inner lamella
of the nuclear membrane, as shown in Figure 9.1. Virus is transported through the cytoskeleton to the
plasma membrane, where lysis of the cell and release of progeny virions occur. The replicative efficiency
of HSV is poor, as indicated by the ratio of infectious to noninfectious virions. With the completion of
replication, 11 glycoproteins are expressed on the plasma membrane (12).
PATHOLOGY AND PATHOGENESIS

General Observations of Pathology
The pathologic changes induced by replicating HSV are similar for both primary and recurrent infection
and for both adults and newborns but vary in the quantitative extent of cytopathology. The histopathologic
characteristics of a skin lesion induced by HSV represent a combination of virus-mediated cellular death
and associated inflammatory responses. Changes induced by viral infection include ballooning of infected
cells and the appearance of chromatin within the nuclei of cells; this is followed by degeneration of the
cellular nuclei, generally within parabasal and intermediate cells of the epithelium. Cells lose intact
plasma membranes and form multinucleated giant cells. As host defenses are mounted, an influx of
mononuclear cells can be detected in infected tissue.
Pathology of Central Nervous System Disease
HSE results in acute inflammation, congestion, and/or hemorrhage, most prominently in the temporal
lobes and usually asymmetrically in adults (13) and more diffusely in the newborn. Adjacent limbic areas
show involvement as well. The meninges overlying the temporal lobes may appear clouded or congested.
After approximately 2 weeks, these changes proceed to frank necrosis and liquefaction, as shown in
Figure 9.2.
Microscopically, involvement extends beyond areas that appear grossly abnormal. At the earliest stage,
the histologic changes are not dramatic and may be nonspecific. Congestion of capillaries and other small
vessels in the cortex and subcortical white matter is evident; other changes are also evident, including
petechiae. Vascular changes that have been reported in the area of infection include areas of hemorrhagic
necrosis and perivascular cuffing (Fig. 9.3). The perivascular cuffing becomes prominent in the second
and third weeks of infection. Glial nodules are common after the second week (14,15). The microscopic
appearance becomes dominated by evidence of necrosis and eventually inflammation; the latter is
characterized by a diffuse perivascular subarachnoid mononuclear cell infiltrate, gliosis, and satellitosis
neuronophagia (13,16). In such cases, widespread areas of hemorrhagic necrosis, mirroring the area of
infection, become most prominent. Oligodendrocytic involvement and gliosis (as well as astrocytosis) are
common, but these changes develop very late in the disease. Although found in only approximately 50%
of patients, the presence of intranuclear inclusions supports the diagnosis of viral infection, and these
inclusions are most often visible in the first week of infection. Intranuclear inclusions (Cowdry type A
inclusions) are characterized by an eosinophilic homogeneous appearance and are often surrounded by a
clear, unstained zone beyond which lies a rim of marginated chromatin, as shown in Figure 9.4.
General Observations on the Pathogenesis of Human Disease
The pathogenesis of human disease depends on intimate, personal contact of a susceptible individual
(namely, one who is seronegative) with someone excreting HSV. Virus must come in contact with mucosal
surfaces or abraded skin for infection to occur. With viral replication at the site of infection, the capsid is
transported by neurons to the dorsal root ganglia, where after another round of viral replication, latency is
established. These events have been demonstrated in a variety of animal models (17). Transport of the
virion is by retrograde axonal flow (18). In some instances, replication can lead to severe CNS infection;
however, more often, the host–virus interaction results in latency. After latency is established,
reactivation can occur, with virus shedding at mucocutaneous sites appearing as skin vesicles or mucosal
ulcers or being totally asymptomatic. Occasionally, primary infection can become systemic, affecting
other organ systems besides the CNS and the peripheral nervous system. Such circumstances include
disseminated neonatal HSV infection with multiorgan involvement, multiorgan disease of pregnancy, and
infrequently dissemination in patients undergoing immunosuppressive therapy. Multiorgan disease is
likely the consequence of viremia in a host not capable of limiting replication to mucosal surfaces.
Infection with HSV-1 is transmitted either by respiratory droplets or through direct contact (to a
susceptible individual) with infectious secretions (such as virus contained in orolabial vesicular fluid).
Acquisition of HSV-2 infection is usually the consequence of transmission via genital routes. Under these
circumstances, virus replicates in the vaginal tract or on penile skin sites, with seeding of the sacral
ganglia.
Pathogenesis of Latency
All of the herpesviruses have the ability to become latent, persist in an apparent inactive state for varying
durations, and be reactivated by a provocative stimulus, as yet unidentified (11,19), as recently reviewed.
As a biologic phenomenon, latency has been recognized since the beginning of the twentieth century
(20–26). In 1905, Cushing (27) noted that patients treated for trigeminal neuralgia (by sectioning a branch
of the trigeminal nerve) developed HSV lesions along the innervated areas of the sectioned branch, as
suggested previously by Goodpasture (28,48). Several investigators have demonstrated that
microvascular surgery of the trigeminal nerve tract for tic douloureux resulted in recurrent herpetic
lesions in more than 90% of seropositive individuals (29–32). Axonal injury and attempts at excision of
lesions have been associated with recurrences (33). Reactivation of latent virus appears to depend on an
intact anterior nerve route and peripheral nerve pathways.
Recurrences occur despite both cell-mediated and humoral immune responses and can be either
symptomatic or asymptomatic. Recurrences are spontaneous, but there have been associations with
physical or emotional stress, fever, exposure to ultraviolet light, tissue damage, and immune suppression
(25,34,35). Viral DNA can be detected in neuronal tissue in the absence of cutaneous lesions (17,36–39).
Latent virus has been retrieved from the trigeminal, sacral, and vagal ganglia of humans (20–22,36,39).
Pathogenesis of Encephalitis
The pathogenesis of HSE in children (older than 3 months) and adults is only partly understood. Both
primary and recurrent HSV infections can cause disease of the CNS. From studies performed by the
National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group
(CASG), approximately one third of the cases of HSE are the consequence of primary infection. For the
most part, the patients with primary infection are younger than 18 years. The remaining two thirds of cases
occur in the presence of preexisting antibodies, but only approximately 10% of patients have a history of
recurrent herpes labialis. Patients with preexisting antibodies are considered to have HSE as a
consequence of reactivation of HSV (40). A limited number of patients, approximately 15%, have active
herpes labialis and HSE, allowing comparison of the DNA by restriction enzyme analyses. The isolates
are usually identical; however, this is not always the case. The virus isolated from the peripheral site can
be different from that retrieved from the CNS (41). Thus, the issues of reactivation of virus directly within
the CNS, the potential for enhanced neurotropism of certain viruses, and the selective reactivation and
access of one virus by the trigeminal route or other routes to the CNS remain for further elucidation.
The route of access of virus to the CNS in primary infection is a subject of debate, especially in
humans. Studies performed more than five decades ago defined pathways for HSV access to the brain in
animals, including both the olfactory and trigeminal nerves among others (42). However, which of these
nerve tracts uniformly leads to HSV infection in the CNS of humans is not clear. The anatomic distribution
of nerves from the olfactory tract into the limbic system, along with the recovery of virus from the
temporal lobe (the site of apparent onset of HSE in the human brain), suggests that viral access to the CNS
via this route is a tenable hypothesis. Reports in the literature have found electron microscopic evidence
that suggests this has been the case in some individuals with HSE (43–45). Animal model data support the
contention that the olfactory tract provides one neurologic avenue for viral access to the CNS and causes
localization of the infection in brain regions analogous to medial temporal structures in humans (46,47).
Definitive proof of such progression in humans is lacking.
Reactivation of HSV, leading to focal HSE, is a similarly confusing problem from the standpoint of
pathogenesis. Evidence of latent virus within infected brain tissue exists (48); however, virus reactivation
at that site remains purely hypothetical. Reactivation of virus peripherally (namely, in the olfactory bulb
or the trigeminal ganglion) with subsequent neuronal transmission to the CNS has been suggested
(42,49,50). Nevertheless, a relevant observation is that with recurrent herpes labialis, whereby
reactivation of virus from the trigeminal ganglia occurs, HSE is a very uncommon event. Furthermore,
HSE does not occur more frequently in immunocompromised patients.
Host immunity plays an important, but undefined, role in the pathogenesis of HSE. Possibly, the CNS is
particularly prone to HSV infection because intraneuronal spread may shelter virus from host defense
mechanisms. HSE is no more common in the immunosuppressed host than in the normal host; however,
when it does occur, the presentation is atypical, with a subacute but progressively deteriorating course.
More recently, a host genetic deficiency has been found to play a role in recurrent HSE but certainly
does not exist in all patients (51).
EPIDEMIOLOGY
Herpes Simplex Virus, Type 1
The epidemiology of HSV infections is multifaceted. Because the focus of this book is CNS infections,
only a brief review of non-CNS HSV infections follows. The reader is referred to more complete
reviews (11). HSV infections are distributed worldwide and have been reported in both developed and
developing countries, including remote Brazilian tribes (52). Animal vectors for human HSV infections
have not been described; therefore, humans remain the sole reservoir for transmission of these viruses to
other humans during close personal contact. There is no seasonal variation in the incidence of infection.
Because infection is rarely fatal, and because these viruses become latent, more than two thirds of the
world’s population can have recurrent HSV infections and, therefore, can transmit infection during
episodes of reactivation. HSV disease ranges from mild (even indiscernible) in most patients to sporadic,
severe, and life-threatening disease in a few infants, children, and adults. Children, particularly those
younger than 5 years, are most often infected; however, primary infections can also occur in older
individuals. With clinical illness, oropharyngeal disease, namely gingivostomatitis, usually is the
manifestation. Primary infection in young adults has been associated with pharyngitis and often a
mononucleosis-like syndrome (53). Seroprevalence studies have demonstrated that acquisition of HSV-1
infection is related to socioeconomic factors, namely lower socioeconomic populations acquire infection
earlier in life than more affluent individuals. The identification of primary gingivostomatitis that was
proven to be caused by HSV infection (54,55) led to the definition of the natural history of infection,
including the appearance of neutralizing antibodies (56), absence of virus shedding in children younger
than 6 months (57), and a higher rate of occurrence among individuals of lower socioeconomic status.
Contemporary surveys document the viral shedding data, ranging from 2% to 5% (58–63).
Antibody surveys have helped clarify the epidemiology of HSV infection. Geographic location,
socioeconomic status, and age all influence the acquisition of HSV infection (54,64–66). In developing
countries, seroconversion occurs early in life. In Brazilian Indians, HSV antibodies are detectable in
more than 95% of children by the age of 15 years (67). Similarly, serologic studies performed in New
Orleans demonstrated acquisition of antibodies in more than 90% of children by the age of 15 years (68).
In developing countries, such as Uruguay, or in lower socioeconomic populations in the central United
States, the appearance of antibodies occurred at similar but lower frequencies (68–71). By 5 years of age,
approximately one third of patients had seroconverted; this frequency increased to 70% to 80% by early
adolescence.
Middle-class individuals of industrialized societies acquired infection later in life. Seroconversion
occurred during the first 5 years of life in 20% of children; there was no significant increase until the
second and third decades of life, at which time the prevalence of antibodies increased to 40% and 60%,
respectively (72,73). One study of university students demonstrated that seroconversion of susceptible
individuals occurred at an annual frequency of approximately 5% to 10% (53,74,75). In summary,
primary infection occurs very early in children of underdeveloped countries and in those of lower
socioeconomic classes; however, in developed countries and more affluent classes, primary infection is
delayed until adolescence or, perhaps, even adulthood. The frequency of direct person-to-person contact
is the major mediator of acquisition of infection.
Over the past decade, HSV-1 has been increasingly associated with primary genital herpes, reflecting a
change in the epidemiology of infection (11).
Herpes Simplex Virus, Type 2
Because HSV-2 infections are usually acquired through sexual contact, antibodies to this virus are rarely
found before the age at onset of sexual activity. Although most genital HSV infections are caused by HSV-
2, an ever-increasing proportion is attributable to HSV-1, as noted earlier, now as high as 50% of all new
primary infections (10,76–78). Approximately 1.5 million new cases of HSV-2 occur annually in the
United States (79). Genital HSV infections are not reportable in the United States (80). Current estimates
of infected individuals with genital herpes in the United States range from 40 to 60 million (76–78,81).
Women have the highest rates of infection, particularly prostitutes and others with multiple sex partners,
including those with HIV infection. The incidence of genital HSV infections in both indigent women and
those of middle and upper socioeconomic classes is significantly lower than the incidence found among
women attending sexually transmitted disease clinics (82). As with HSV-1 infections of the mouth, HSV-2
can be excreted in the absence of symptoms at the time of primary, initial, or recurrent infection (83,84).
The actual frequency of asymptomatic excretion of HSV-2 in women by culture is approximately 3% to
5% of all days, and by polymerase chain reaction (PCR) 15% to 20%. Furthermore, some individuals can
start and stop shedding multiple times during the same day (85). Its occurrence creates a silent reservoir
for transmission of infection (86,87). The appearance of HSV-2 antibodies reflects the time of exposure
or more simply the acquisition of infection and is positively correlated with the onset of sexual activity
(70,71,88). However, crowded living conditions may indirectly contribute to antibody prevalence (89). If
HSV-2 type-specific antibodies are sought in healthy women, there is a wide discrepancy in prevalence,
ranging from averages of 10% in England and Italy to 25% in the United States and 77% in Uganda
(90,91). Up to 50% to 60% of lower socioeconomic populations in the United States and elsewhere
develop antibodies to HSV-2 by adulthood. The reader is referred to a review for worldwide
seroprevalence of HSV-2 (90). Seroprevalence is a function of age, number of sexual partners, race, and
marital status (92–94).
Latent Genital Herpes Simplex Virus Infections
Latent genital infection with subsequent reactivation is the largest reservoir for transmission of HSV-2. As
with HSV-1 infection, recurrent HSV-2 infection can be either symptomatic or asymptomatic; however,
recurrence is usually associated with a shorter duration of viral shedding and fewer lesions. Several
studies have implicated a frequency of recurrence as high as 60% (88,95). The type of genital infection,
HSV-1 versus HSV-2, is predictive of the frequency of recurrence (95–97), with HSV-1 infection
recurring less frequently than HSV-2 (98,99).
HERPES SIMPLEX ENCEPHALITIS

Background
HSV infections of the CNS are among the most severe of all viral infections of the human brain. Currently,
HSE is estimated to occur in approximately 1 per 250,000 to 500,000 individuals per year. At the
University of Alabama at Birmingham, the diagnosis of HSE was proven by brain biopsy in an average of
ten patients per year, for an incidence of approximately 1 in 300,000 individuals, an incidence similar to
those in Sweden and England (100,101). With the advent of PCR, brain biopsy is no longer used. In the
United States, HSE accounts for 10% to 20% of viral infections of the CNS (102).
The economic cost of HSE is considerable, as estimated in 1983 for hospitalization alone of adults to
be more than $25 million (103). The total medical cost is considerably higher because of the long-term
care and support services required for many of the survivors.
HSE occurs throughout the year and in patients of all ages, with approximately one third of cases
occurring in patients younger than 20 years but older than 6 months and approximately one half in patients
older than 50 years (102). Caucasians account for 95% of patients with biopsy-proven disease. Both
sexes are affected equally.
The severity of disease is best determined by the outcome of patients who have received either no
therapy or an ineffective antiviral medication, such as idoxuridine or cytosine arabinoside. In such
situations, mortality is in excess of 70%; only approximately 2.5% of all patients with confirmed disease
(9.1% of survivors) returned to normal function after recovery from their illness (104–108). Because
brain biopsy with isolation of HSV from brain tissue was the method of diagnosis in these early studies, a
far broader spectrum of HSV infections of the CNS actually was thought to exist. However, with the more
recent use of PCR for diagnosis of HSE, virtually all patients have a focal neurologic disease, suggesting
a limited spectrum of disease (109).
Diagnosis
Several aspects relating to the diagnosis of HSE merit discussion: (a) the clinical presentation in regard
to the sensitivity and specificity of various clinical characteristics, (b) the historical use of brain biopsy
to establish the diagnosis, (c) conditions that mimic HSE, and (d) noninvasive means of diagnosis. Data
from the NIAID CASG compare presentation and outcome for brain biopsy–positive and brain biopsy–
negative patients (137). Of 202 patients who were evaluated for HSE because of focal neurologic
findings, HSV was isolated from brain tissue of only 113. Only three of the remaining patients had
combinations of serologic and clinical findings suggestive of HSE. These patients were subsequently
shown to have HSV DNA in their cerebrospinal fluid (CSF) by PCR.
As shown in Table 9.1, most patients with biopsy-proven HSE presented with a focal encephalopathic
process, including (a) altered mentation and decreasing levels of consciousness with focal neurologic
findings; (b) CSF pleocytosis and proteinosis; (c) the absence of bacterial and fungal pathogens in the
CSF; and (d) focal electroencephalographic (EEG), computed tomographic (CT), and/or magnetic
resonance image (MRI) findings (102,110–120). The frequency of headache and CSF pleocytosis is
higher in patients with proven HSE than in patients with diseases that mimic HSE. Nearly uniformly,
patients with HSE present with fever and personality change. Seizures, whether focal or generalized,
occur in only approximately two thirds of all patients with proven disease. Thus, the clinical findings of
HSE are nonspecific and do not allow for empirical diagnosis of disease predicated solely on clinical
presentation. Although clinical evidence of a localized temporal lobe lesion is often thought to indicate
HSE, various other diseases can mimic this condition.
Examination of the CSF is indicated in patients with altered mentation, provided it is not
contraindicated because of increased intracranial pressure. In patients with HSE, CSF findings are
nondiagnostic, being similar in patients with confirmed disease or diseases that mimic HSE. Both the CSF
white blood cell (WBC) count (lymphocytes predominance) and the CSF protein level are elevated. The
average CSF WBC count is 100 cells/µL; the protein averages approximately 100 mg/dL. Sequential
evaluation of CSF specimens from patients with HSE indicates increasing cell counts and levels of
protein. The presence of CSF red blood cells is not diagnostic for HSE. Approximately 5% to 10% of
patients have a normal CSF formula on first evaluation.
Noninvasive neurodiagnostic studies support a presumptive diagnosis of HSE. These studies have
included EEG, CT, and MRI. Focal changes of the EEG are characterized by spike and slow-wave
activity and periodic lateralized epileptiform discharges, which arise from the temporal lobe (114–118).
Early in the disease, the abnormal electric activity usually involves one temporal lobe and then spreads to
the contralateral temporal lobe as the disease evolves, usually over 7 to 10 days. The sensitivity of the
EEG is approximately 84%, but the specificity is only 32.5%. CT scans initially show low-density areas
with mass effect localized to the temporal lobe, which can progress to radiolucent and/or hemorrhagic
lesions (119,120). Bitemporal disease is common in the absence of therapy, particularly late in the
disease course (Fig. 9.5). When these neurodiagnostic tests are used in combination, the sensitivity is
enhanced; however, the specificity remains inadequate. None of these neurodiagnostic tests is uniformly
satisfactory for diagnosing HSE. MRI detects evidence of HSE earlier than CT scan (111).
A sensitive and specific means of diagnosis is the isolation of HSV from tissue obtained at brain
biopsy (121). However, PCR detection of HSV DNA in the CSF has become the diagnostic procedure of
choice. Brain biopsy is of value in confusing clinical presentations. Complications, either acute or
chronic, occur in approximately 3% of patients. Fears of potentiating acute illness (by incising the brain
in a diseased area) or of causing chronic seizure disorders have not been substantiated by follow-up
studies of patients in the NIAID CASG.
Serologic Evaluation
Several strategies using antibody production as a means of diagnosing HSE have been utilized (58).
Because most encephalitic patients are HSV seropositive at presentation, seroconversion per se is usually
not helpful because fever alone can reactivate labial herpes, resulting in antibody elevations. A fourfold
rise in serum antibody was neither sensitive nor specific enough to be useful. A fourfold or greater rise in
CSF antibody occurred significantly more often within a month after onset of disease in patients with
biopsy-proven HSE: 85% versus 29%. By 10 days after clinical presentation, however, only 50% of
brain biopsy–positive patients had a fourfold rise in CSF antibody. This test is useful only for
retrospective diagnosis. The use of a ratio of serum to CSF antibody of 20 or less did not improve
sensitivity during the first 10 days of disease.
Polymerase Chain Reaction Detection of Viral DNA
PCR detection of HSV DNA in the CSF is the diagnostic method of choice (121–127). Data from the
NIAID CASG defined the sensitivity and specificity as 94% and 98%, respectively. These CSF
specimens were obtained from patients with biopsy-proven or biopsy-negative disease. Notably, the
specificity would have been higher except that some tissue specimens were fixed in formalin, which
killed infectious virus, prior to an attempt to isolate virus. HSV DNA persisted in 80% of tested CSF
specimens for 1 week or more.
Diseases That Mimic Herpes Simplex Encephalitis
In a compilation of the NIAID CASG data, 193 (45%) of 432 patients undergoing brain biopsy for a focal
encephalopathic process had HSE (128). As shown in Table 9.2, the remaining patients were evaluated
for diseases that mimic HSE (128). Thirty-eight had disease amenable to other forms of therapy, including
brain abscess, tuberculosis, cryptococcal infection, and brain tumor. An additional 19 patients had
diseases that were indirectly treatable, and another 38 patients had an alternative diagnosis established
for which there was no current therapy, usually other viral infections. Thus, those diseases that mimic
HSV infection of the CNS and that require immediate medical intervention should be considered if the
PCR is negative for HSV DNA.
Associated Neurologic Syndromes
HSV obviously involves areas of the nervous system other than the brain. Primary and recurrent genital
herpes have been associated with neuritis localized to one extremity or even transverse myelitis. Neuritis
evident in such patients can be associated with altered sensation of the lower extremities, as well as
dysesthesias, shooting pain, and motor impairment. Urinary and fecal incontinence have been reported in
a few patients. An aseptic meningitis syndrome is also common, frequently being associated with a
Mollaret syndrome, and not without complications.
Guillain-Barré syndrome and localized dermatomal rashes associated with acute neuritis have also
been attributed to HSV infections.
Acute retinal necrosis has been reported as a long-term complication of HSE (129).
Therapy
The first antiviral drug reported as efficacious therapy of HSE was idoxuridine; however, it was soon
proven both ineffective and toxic (104). Subsequent therapeutic trials defined vidarabine as a useful
medication for the management of biopsy-proven HSE (107,108); however, it has been replaced by
acyclovir in the physician’s armamentarium. During these studies, the variables of age, disease duration,
and level of consciousness at the onset of therapy were proven major determinants of clinical outcome.
Patients younger than 30 years and with a more normal level of consciousness (lethargic as opposed to
comatose) were more likely to return to normal function than older patients, especially those who were
semicomatose or comatose (Fig. 9.6). From these data, older patients (older than 30 years), whether
comatose or semicomatose, had mortality rates that approached 70%, a figure very similar to that
encountered in the placebo recipients of the previously cited studies. If therapy is to be effective, it must
be instituted before the onset of hemorrhagic necrosis of a dominant temporal lobe and significant
deterioration of consciousness.
Acyclovir is superior to vidarabine for the treatment of HSE (166). The NIAID CASG study defined a
mortality of 55% at 6 and 18 months after the initiation of treatment for vidarabine recipients versus 19%
and 28%, respectively, for the acyclovir group (Fig. 9.7). Late deaths were not a consequence of either
persistent or reactivated HSV infection but occurred in patients who were severely impaired as a
consequence of their disease. Acyclovir decreases mortality to 19% 6 months after therapy. Importantly,
38% of patients, irrespective of age, return to normal function.
Previous studies indicated that age and level of consciousness influenced long-term outcome. A more
objective reflection of level of consciousness is the Glasgow Coma Scale (GCS). Scores that approached
normal predicted enhanced survival. When GCS score and age were assessed simultaneously (Fig. 9.8), a
GCS score of 6 or less predicted a poor therapeutic outcome, irrespective of the agent administered or of
the age of the patient (130).
Regarding morbidity for acyclovir recipients, 38% of patients were normal or with minor impairment,
9% of patients had moderate sequelae, and 53% of patients were left with severe impairment or died. No
patient entered into the NIAID trials suffered a relapse after completion of therapy. Relapse of HSE has
been reported, though not well documented, in a few patients following the administration of vidarabine
(131–133) and acyclovir (133,134). Many patients were not afebrile at the conclusion of treatment,
suggesting that a longer duration of therapy to a minimum of 14 to 21 days may be desirable.
Of acyclovir recipients, 10% experienced an increased BUN level, and 6% developed a creatinine
level in excess of 2 mg/dL. No clinical evidence of toxicity was detected. The current therapy of choice
for the management of HSE is acyclovir. This drug is administered at a dosage of 10 mg/kg every 8 hours
(30 mg/kg per day) for 14 to 21 days.
NEONATAL HERPES SIMPLEX VIRUS INFECTIONS

History
In 1941, Smith, Lennette, and Reames (7) reported the first case of HSV infection of the CNS, as noted
earlier. This case occurred in a newborn with neonatal HSE. In 1952, Zuelzer, Wolf, and Stulbery (135)
reviewed eight cases of disseminated HSV infection in neonates with involvement of most organs,
including the brain in many instances. This report was followed shortly by others indicating the
association between HSV infection of the newborn and necrotizing encephalitis, including the isolation of
HSV in cell cultures from brain tissue.
Pathology and Pathogenesis
Pathology
Although the pathology of HSE is discussed earlier in this chapter, a few characteristics appear more
commonly in the newborn. Gross examination of the brain often reveals encephalomalacia and
hydranencephaly, which are likely the consequence of extensive hemorrhagic necrosis. Porencephaly,
hydranencephaly, and multicystic lesions are often sequelae in neonates who survive for several weeks or
months following neonatal HSV infection of the brain. The microscopic appearance of the brain is
characterized by a mononuclear inflammation, necrosis, and hemorrhage.
Pathogenesis
In utero disease is likely a consequence of transplacental infection and usually involves skin, brain, eye,
liver, and adrenals. More commonly, the fetus comes in contact with infected maternal genital secretions
at the time of delivery. Viral replication in the newborn either remains limited to the portal of entry—
namely, the skin, eye, or mouth—or progresses to involve various other organs, including the brain
(resulting in encephalitis), causing life-threatening disease. Host mechanisms responsible for control of
viral replication at the site of entry are unknown. For babies with encephalitis, intraneuronal transmission
of virus provides a privileged site that may be impervious to circulating humoral and cell-mediated
defense mechanisms. Thus, transplacental maternal antibodies may be of less value in the prevention of
encephalitic forms of neonatal HSV infections. Disseminated infection is a consequence of viremia or
secondary to extensive cell-to-cell spread, as occurs with pneumonitis after aspiration of infected
secretions.
Neonatal HSE illustrates the two major pathogenic routes for virus access to the brain, namely,
hematogenous and intraneuronal. For example, hematogenous spread of virus usually occurs with
disseminated disease, and diffuse involvement of the brain ensues in 60% to 80% of patients. In contrast,
neuronal transmission probably results in the focal CNS disease encountered in babies with encephalitis
only when no distal organ involvement is documented (136).
Times of Transmission of Infection
Neonatal HSV infection is acquired at one of three times: in utero, intrapartum, or postnatally. Regardless
of the time or route of acquisition, the newborn is at risk of CNS disease. Certainly, the mother is the most
common source of infection for the first two of these routes of transmission of infection to the newborn.
Intrauterine Infection
In utero acquisition of HSV infection is becoming increasingly documented (137–139). Manifestations of
disease acquired in utero include chorioretinitis, cutaneous aplasia, hydranencephaly, and
encephalomalacia (138) (Fig. 9.9). Risk factors associated with intrauterine transmission of infection are
unknown; however, both primary and recurrent maternal infection can result in infection of the fetus in
utero. In utero infection is the consequence of either transplacental or ascending infection.
Intrapartum Infection
The most common time of transmission of infection from mother to the fetus is intrapartum. Transmission
occurs when the infant comes in contact with infected maternal genital secretions at delivery, accounting
for 85% of cases (140).
Prospective assessment of HSV excretion in the genital tract at delivery indicates that shedding can
occur in 0.5% to 1.3% of women (141). Maternal primary versus recurrent infection influences the
probability of neonatal infection, as discussed later in this chapter. With the increasing prevalence of
HSV-2 infection in the population at large, the probability of excreting HSV at delivery should increase
(142,143).
Factors that influence intrapartum acquisition of infection by the fetus include the following: (a) type of
maternal infection (primary vs. recurrent) (144), (b) maternal antibody status (145,146), (c) duration of
ruptured membranes (147), and (d) placement of a fetal scalp monitor in a woman excreting HSV
(148,149).
Primary infection is associated with (a) larger quantities of HSV replicating in the genital tract (more
than 106 viral particles/0.2 mL of tissue culture inoculum) and (b) a period of viral excretion that on
average persists for 3 weeks. In contrast, in women with recurrent genital infection, HSV is shed for an
average of only 2 to 5 days and at lower concentrations (approximately 103/0.2 mL of tissue culture
inoculum). Because of the larger quantity of virus and the longer period of viral excretion, primary
maternal infection is associated with a higher rate of transmission to the fetus—estimated between 30%
and 50% (147). Reflecting the type of maternal infection, the delivery of transplacental maternal antibody
to the fetus influences both the severity of disease in the newborn and the likelihood of fetal infection
(145,146,150). Lastly, placement of a fetal scalp monitor in women excreting virus has been shown to
lead to fetal infection. Monitor placement should be discouraged in women with a history of genital
herpes or visualized lesions.
The duration of ruptured membranes is reported to be an important indicator of risk for acquisition of
neonatal infection. Cesarean section decreases the incidence of infection in women with lesions present at
delivery (147).
Postnatal Infection
The third route of transmission is postnatal acquisition (151–158). Documented sources include the
mother (including the breast as a source of virus [151,152]), the father (labial lesions) (153,154),
nosocomial transmission (nursery personnel or other babies) (155–157), and as a consequence of the
Jewish tradition of circumcision, known as metzitzah b’peh (158).
Epidemiology of Maternal Infection
Disseminated Maternal Infection

HSV infections of pregnant women may extend beyond the usual sites of disease, the oropharynx and the
genital tract. As first reported in 1969, dissemination can occur, leading to cutaneous or visceral disease;
fortunately, this is a rare occurrence. In a limited number of cases (159–162), dissemination following
primary oropharyngeal or genital infection has led to life-threatening diseases such as (a) hepatitis with or
without thrombocytopenia, (b) leukopenia, (c) consumptive coagulopathy, and (d) encephalitis. Although
only a small number of patients have been studied, the mortality among pregnant women with
disseminated infection has been greater than 50%. Fetal deaths also occurred in more than 50% of cases,
though not necessarily associated with the death of the mother.
Localized Maternal Infection

During the first 20 weeks of gestation, primary maternal genital HSV infection is associated with an
increased frequency of spontaneous abortion (approximately 25%), stillbirth, and as noted earlier,
congenital disease, particularly hydranencephaly and chorioretinitis (138,163). Several studies have
prospectively evaluated the frequency and nature of viral shedding in pregnant women with a known
history of genital herpes. In a predominantly white middle-class population, documented recurrent
infection occurred in 84% of pregnant women (164). Moreover, asymptomatic viral shedding occurred in
at least 12% of the recurrent episodes. Viral shedding from the cervix occurred in only 0.56% of
symptomatic infections and in 0.66% of asymptomatic infections (84,165,166). For asymptomatic
pregnant women, an incidence of cervical shedding as high as 3% has been reported (167). More than
60% of women in various groups who give birth to infants with neonatal HSV infection report no
symptoms (168–170).
Incidence and Presentation of Neonatal Infection

The incidence of neonatal HSV infection is about 1 in 3,000 (0.03%) deliveries (136). Overall, two
thirds of children with neonatal HSV infection develop disease of the CNS, and the disease may remain
localized to the brain or become disseminated to involve various other organs. If untreated, newborns
with disseminated disease have a mortality of 80%, and newborns with disease limited to the CNS have a
mortality of approximately 50%.
Classification of newborns with HSV infection is mandatory for prognostic and therapeutic
considerations (163). Babies with congenital infection, by definition, must be identified within 48 hours
of birth. Those babies who are infected (either during delivery or postnatally) are divided into three
categories: (a) those with disease localized to the skin, eye, or mouth; (b) those having encephalitis with
or without skin, eye, and/or mouth involvement; and (c) those having disseminated disease involving
multiple organs, such as CNS, lung, liver, adrenals, skin, eye, and/or mouth. This chapter focuses on CNS
disease and considers prospectively acquired data obtained through the NIAID CASG. All babies,
irrespective of disease classification, should be considered at risk for CNS complications of infection.
The presentation and outcome of infection (particularly prognosis after therapy) according to category
vary significantly with regard to both mortality and morbidity.
Intrauterine Infection
Intrauterine infection is usually apparent at birth and is characterized by a triad of findings: (a) skin
vesicles and/or scarring (cuteus aplasia), (b) eye disease (chorioretinitis, optic atrophy), and (c) brain
disease (microcephaly, encephalomalacia, or hydranencephaly). Serial ultrasound examination of the
mothers of those babies infected in utero has occasionally demonstrated hydranencephaly. Retinitis alone
can be a presenting sign and should alert the pediatrician to the possibility of intrauterine HSV infection,
although HSV infection is a less common cause of chorioretinitis relative to other congenital infections.
The frequency of occurrence of intrauterine HSV infection has been estimated to range between 1 in
100,000 (0.001%) and 1 in 200,000 (0.0005%) deliveries (138).
A small group of children will have skin vesicles or eye lesions, which are present at the time of
delivery. These neonates are often born to women who have had prolonged rupture of membranes. The
babies have no other findings of invasive multiorgan involvement; specifically, there is no chorioretinitis,
encephalitis, or evidence of other diseased organs.
Disseminated Infection
Table 9.3 summarizes the classification of 297 babies with neonatal HSV infection from the NIAID
CASG. Disseminated HSV infection has the worst prognosis with regard to mortality. Children with
disseminated infection usually present to tertiary medical centers for therapy between 9 and 11 days of
life; however, signs of infection are, on average, usually present 4 to 5 days earlier.
The principal organs involved following disseminated infection are the liver, brain, and adrenals;
however, infection can involve various other organs, including the larynx, trachea, lungs, esophagus,
stomach, lower gastrointestinal tract, spleen, kidneys, pancreas, and heart. Constitutional signs and
symptoms include irritability, seizures, respiratory distress, jaundice, bleeding diatheses, and shock, in
addition to a characteristic vesicular exanthem that is often considered pathognomonic for neonatal HSV
infection.
The vesicular rash, as described later in this chapter, is particularly important in the diagnosis of HSV
infection. Notably, about 20% of children with disseminated neonatal HSV infection will not develop skin
vesicles during the course of their illness (140,171). In the absence of skin vesicles, the diagnosis
becomes exceedingly difficult because the clinical signs are often vague and nonspecific, mimicking those
of neonatal sepsis. Mortality in the absence of therapy exceeds 80%; if therapy is instituted before CNS
disease ensues, outcome is usually good. The most common cause of death in babies with disseminated
disease is either HSV pneumonitis or disseminated intravascular coagulopathy.
Evaluation of the extent of disease is imperative, as with all cases of neonatal HSV infection. The
clinical laboratory should be used to define hepatic enzyme elevation (serum alanine aminotransferase
and AST), direct hyperbilirubinemia, neutropenia, thrombocytopenia, and bleeding diatheses. Unless
contraindicated, examination of the CSF is imperative. In addition, chest roentgenograms, abdominal x-
rays, EEG, and CT or MRI of the head can be judiciously and serially employed to determine the extent of
disease. The radiographic picture of HSV lung disease is characterized by a diffuse interstitial pattern that
progresses to a hemorrhagic pneumonitis. Pneumatosis intestinalis can be detected when gastrointestinal
disease is present. Encephalitis is a common component of disseminated infection, occurring in about
75% of these newborns. Serial evaluation of the CSF and noninvasive neurodiagnostic tests, as defined
later in this chapter, will help assess the extent of brain disease.
Encephalitis
Infection of the CNS alone or in combination with disseminated disease presents with findings indicative
of encephalitis. Overall, nearly 90% of babies with brain infection caused by HSV have evidence of an
acute neurologic syndrome. Brain infection can occur in one of two fashions: either as a component of
multiorgan disseminated infection or as encephalitis only, with or without skin, eye, and mouth
involvement. Nearly one third of all babies with neonatal HSV infection have only the encephalitic
component of disease.
Clinical manifestations of these two types of encephalitis include seizures (both focal and generalized),
lethargy, irritability, tremors, poor feeding, temperature instability, bulging fontanel, and pyramidal tract
signs. Whereas babies with disseminated infection often have skin vesicles in association with brain
infection, the same is not true for babies with encephalitis alone. In this latter group, only approximately
60% have skin vesicles at any time during the disease course (140,169–171). Cultures of CSF yield virus
in 25% to 40% of all patients. Anticipated findings on CSF examination include pleocytosis and
proteinosis (as high as 500 to 1,000 mg/dL). Although a few babies with CNS infection, demonstrated by
brain biopsy, have been reported to have no abnormalities of their CSF, certainly this is very uncommon.
Serial CSF examinations provide a useful diagnostic approach because the infected newborn with brain
disease demonstrates progressive increases in its protein content. The importance of CSF examinations in
all infants is underscored by the finding that even subtle changes have been associated with significant
developmental abnormalities (172). An EEG, CT, or MRI can be very useful in defining the presence of
CNS abnormalities. A characteristic MRI scan is shown in Figure 9.10. Death occurs in 50% of babies
with localized CNS disease who are not treated, and it is usually related to involvement of the brainstem.
In the absence of antiviral therapy, with rare exceptions, survivors are left with neurologic impairment,
and the long-term prognosis after either disseminated infection or encephalitis alone is particularly poor.
Up to 50% of surviving children have some degree of psychomotor retardation, often in association with
microcephaly, hydranencephaly, porencephalic cysts, spasticity, blindness, chorioretinitis, or learning
disabilities. Whether visceral or CNS damage can be progressive after initial clearance of the viral
infection is unclear, but it is a possibility suggested by long-term assessment of children with skin, eye, or
mouth disease (140,173) and more recently by a study of a group of babies with more severe disease
(174).
Several points warrant reiteration. Clinical manifestations of disease in children with encephalitis
alone are virtually identical to those findings that occur with brain infection in disseminated cases, in
spite of the presumed differences in pathogenesis. For babies with encephalitis only, approximately 60%
develop evidence of a vesicular rash characteristic of HSV infection. Thus, a newborn with pleocytosis
and proteinosis of the CSF but without a rash can easily be misdiagnosed as having bacterial or other
viral infection unless HSV infection is carefully considered. In such circumstances, a history of genital
lesions in the mother or her sexual partner may be very important in the incrimination of HSV as a cause
of illness.
Skin, Eye, and/or Mouth Infection
Infection localized to the skin, eye, and/or mouth is associated with virtually no mortality. When infection
is localized to the skin, the presence of discrete vesicles remains the hallmark of disease. Clusters of
vesicles (Fig. 9.11) often appear initially upon the presenting part of the body that was in direct contact
with the virus during birth. With time, the rash can progress to involve other areas of the body as well.
Vesicles occur in 80% of children with skin, eye, or mouth infection. Children with disease localized to
the skin, eye, or mouth generally present at about 10 to 11 days of life. Those babies with skin lesions
invariably suffer from recurrences whether therapy is administered or not. Although death is not
associated with disease localized to the skin, eye, and/or mouth, approximately 30% of these children
eventually develop evidence of neurologic impairment in the absence of antiviral therapy, which can
result in significant neurologic morbidity (140,173).
Infections involving the eye may manifest as keratoconjunctivitis or later chorioretinitis. The eye can be
the only site of HSV involvement in the newborn. Findings include keratoconjunctivitis, microphthalmia,
or retinal dysplasia. In the presence of persistent disease and no therapy, chorioretinitis can result.
Chorioretinitis can be caused by either HSV-1 or HSV-2 (175–177). Keratoconjunctivitis, even in the
presence of therapy, can progress to chorioretinitis, cataracts, and retinal detachment. Cataracts have been
detected on long-term follow-up of proven perinatally acquired HSV infections (178).
Long-term neurologic impairment has been encountered in children whose disease appeared localized
to the skin, eye, and/or mouth. The significant findings include spastic quadriplegia, microcephaly, and
blindness. Despite normal clinical and CSF examinations at the time these children completed antiviral
therapy, neurologic impairment became apparent between 6 months and 1 year of life. In retrospect, when
CSF from these babies was subjected to PCR analysis, evidence of HSV DNA was detected in virtually
all of these children, indicating an asymptomatic infection of the CNS (179).
Diagnosis
The appropriate use of laboratory tools is essential if a diagnosis of HSV infection is to be achieved
(180). Virus isolation remains one of two definitive diagnostic methods. If skin lesions are present, a
scraping of skin vesicles should be made and transferred (in appropriate virus transport media) to a
diagnostic virology laboratory. Clinical specimens should be shipped on ice for prompt inoculation into
cell culture systems that are susceptible for the demonstration of the cytopathic effects characteristic of
HSV replication. Specimen shipping and processing should be expedited. In addition to sampling vesicle
fluid, other sites from which virus may be isolated include the CSF, stool, urine, throat, nasopharynx, and
conjunctivae. In infants with evidence of hepatitis or other gastrointestinal abnormalities, duodenal
aspirates are useful for HSV isolation. The virologic results of cultures from these anatomic sites should
be used in conjunction with clinical findings to define the extent of disease in the newborn. Typing of an
HSV isolate must be done for prognostic purposes.
Cytologic examination of cells from the maternal cervix or from the infant’s skin, mouth, conjunctivae,
or corneal lesions has a sensitivity of only approximately 60% to 70% and, therefore, should not be the
sole diagnostic determinant for infection in the newborn (11). Cellular material obtained by scraping the
periphery of the base of lesions should be smeared on a glass slide and promptly fixed in cold ethanol.
The slide can be stained according to the methods of Papanicolaou, Giemsa, or Wright before examination
by a trained cytologist. Deployment of Giemsa or, alternatively, Tzanck smears likely will not
demonstrate the presence of intranuclear inclusions. Intranuclear inclusions and multinucleated giant cells
are indicative, but not diagnostic, of HSV infection. The use of HSV monoclonal antibodies for rapid
diagnosis has gained widespread acceptance. These fluorescence studies should be performed by
laboratories experienced in the procedure.
Serologic diagnosis of HSV infection is not of great clinical value. Therapeutic decisions cannot await
the results of serologic studies. The inability to differentiate transplacentally acquired maternal
immunoglobulin G from endogenously produced antibodies makes the assessment of the neonate’s
antibody status both difficult and of little value during acute infection. Commercially available serologic
tests are now capable of distinguishing HSV-1 from HSV-2 antibodies. These assays are based on
differences in glycoprotein gG1 and gG2 (181). These are the only antibody assays that should be used.
Serial antibody assessments may be useful if a mother without a history of HSV infection has a primary
infection late in gestation and, therefore, transfers little or no antibody to the fetus.
The use of CT and MRI scans to define CNS disease is essential, even in the child who appears
normal.
Polymerase Chain Reaction to Detect Viral DNA
The other definitive diagnostic method is PCR detection of viral DNA, as discussed earlier in this chapter
(121,179,182). PCR has been applied to blood as an additional site for diagnosis that is especially useful
in babies with disseminated disease.
Prevention
Cesarean Section
Mothers with active herpetic lesions should deliver their child by cesarean section if delivery can be
achieved within 4 hours of membrane rupture (147). Cesarean section is of unproven benefit if
membranes have been ruptured for more than 4 hours. Recent data support this approach (147).
Furthermore, infection of the newborn has occurred in spite of delivery by cesarean section (183), which
was performed specifically to prevent neonatal infection.
Vaccination
Though various strategies for prevention of neonatal infection must be instituted, eventual control of HSV
infection is most likely to be achieved through vaccination, and there is considerable research under way
to design and test HSV vaccines, in spite of a recent failure to prevent HSV-2 infections (85). Several
principles should be understood. First, the efficacy of the vaccine must be sufficient to prevent
transmission of infection. It is highly unlikely that any vaccine will totally prevent infection. Second, high
titers of antibody against HSV do not protect humans from reactivation of latent infection. Third, live
virus vaccines tend to induce more potent and durable humoral and cellular immune responses than
subunit or purified glycoprotein vaccines.
Treatment
Background
Of all the perinatally acquired infections, the one most likely to be amenable to successful therapy is that
caused by HSV. Because most babies acquire infection at the time of delivery or shortly thereafter,
successful antiviral therapy should decrease mortality and improve long-term outcome. Inherent in these
presumptions is the recognition that diagnosis early after the onset of clinical illness is essential, as is the
case with perinatally acquired bacterial infections. Equally importantly, the possibility of disease
progression should encourage the early institution of therapy. Of children presenting with disease
localized to the skin, eye, and/or mouth, approximately 70% will progress to involve the CNS or result in
disseminated infection (169). When such events occur, the likelihood of an adequate outcome, even with
efficacious drugs, is not optimal because many of these children will either die or be left with significant
neurologic impairment. The following paragraphs summarize our knowledge of therapy.
First, the overall mortality rate for babies with encephalitis or disseminated infection 1 year after
treatment with high doses of acyclovir (20 mg/kg every 8 hours for 21 days) is lower than that of prior
studies of neonatal HSV infection that used lower doses, as compared in Figure 9.12 (184,185). There are
no differences in either adverse effects or laboratory toxicity.
Second, irrespective of the therapeutic modality employed, there has been a significant increase in the
number of babies who returned to normal function. This can be accounted for largely by the introduction
of therapy before the development of encephalitis or disseminated disease, as reflected by Table 9.4
(185). Of the babies entered in the trial referenced in Table 9.4, more than 48% have disease localized to
the skin, eye, and mouth (185). This represents a threefold increase in the number of babies with skin, eye,
and mouth involvement, when compared with that of previous studies and historic data (p < .001). The
change in spectrum of disease presentation is most likely related to earlier diagnosis. The number of
babies with encephalitis has remained fairly constant at approximately 30%, whereas the number of
babies with disseminated disease has decreased to 22%. Nevertheless, improved morbidity by disease
classification is unchanged for encephalitis (Fig. 9.13).
Third, available data indicate that therapy has not been initiated any earlier in the most recent neonatal
HSV studies (186) as compared to earlier studies (185). However, the mean duration of disease for all
children (irrespective of disease classification) entered into these studies was 4 to 5 days; therapy can,
therefore, be instituted even earlier in the disease course. This “window” for earlier administration of
therapy is significant if further advances in therapeutic outcome are to be achieved.
The existing database from the NIAID CASG has provided insight into those factors that influence
outcome, as summarized in Table 9.5 (187). Those factors that have a major impact on outcome include
disease classification, level of consciousness, time of initiation of therapy, virus type (Fig. 9.14), and the
virus type and frequency of skin recurrences for babies whose disease is localized to the skin, eye, and
mouth. Our understanding of these data implies that limitation of disease before there has been extensive
multiorgan involvement or disease of the CNS is associated with the best prognosis. This information
will be useful in developing therapeutic strategies and in counseling parents of children with neonatal
HSV infection.
From a laboratory perspective, a CSF that remains PCR positive at the conclusion of therapy predicts a
poor prognosis and has resulted in prolonged therapy until the viral DNA can no longer be detected at that
site.
Long-Term Therapy with Oral Acyclovir
The use of oral acyclovir therapy for prolonged periods for 6 months has recently been shown to improve
neurologic outcome in children with encephalitis such that over 60% of children with CNS disease
returned to normal function (188). This finding implies the chronic replication of HSV in the brain.
Long-Term Follow-up
Children with neonatal HSV infection require frequent and detailed long-term follow-up. Children with
CNS or disseminated disease are at risk for neurologic impairment. Management of resultant seizure
disorders is standard. Even children with skin, eye, and/or mouth disease are at risk for neurologic
impairment and must be followed carefully.
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CHAPTER 10 NEUROLOGIC MANIFESTATIONS OF
VARICELLA AND HERPES ZOSTER
JOHN W. GNANN, JR. AND RICHARD J. WHITLEY
Varicella-zoster virus (VZV) causes two clinically distinct diseases. Varicella (chickenpox), which
results from primary infection of a susceptible individual, is a common, extremely contagious, and usually
benign acute illness that occurs in epidemics and is characterized by a generalized vesicular rash. Like all
other herpesviruses, VZV establishes latency following primary infection. Reactivation of latent VZV
results in a localized cutaneous eruption termed herpes zoster or shingles, a common disorder among the
elderly. Both varicella and herpes zoster can be complicated by central nervous system (CNS)
involvement (1).
EPIDEMIOLOGY
Varicella
Humans are the only known reservoir for VZV. Primary infection occurs when a susceptible individual is
exposed to airborne virus by the respiratory route. Patients with chickenpox are contagious for about 48
hours before and 4 to 5 days after rash onset. Infection is usually acquired after exposure to another
individual with varicella but can also result from exposure to a patient with herpes zoster. Varicella is
highly infectious; attack rates of 61% to 87% have been observed following household exposure.
In the United States, varicella epidemics occur annually in the late winter and early spring, with peak
numbers of cases reported in March. Before the availability of the varicella vaccine, about 3.8 million
cases of chickenpox occurred each year in the United States (15 cases per 1,000 population), which
approximately equaled the annual birth cohort (2). Varicella was predominantly a disease of school-aged
children. About 50% to 60% of varicella cases occurred in children between 5 and 9 years of age, and
90% of cases occurred in patients younger than 15 years. Previous surveys indicated that more than 90%
of the U.S. population was VZV seropositive by age 20 years (3). Mortality estimates for varicella in
children (ages 1 to 14 years) are 1.4 per 100,000 cases and in adults 31 per 100,000 cases (4).
Introduction of the varicella vaccine in the United States in 1995 resulted in striking changes in the
epidemiology of chickenpox. By monitoring vaccine and disease activity at three sentinel sites, the
Centers for Disease Control and Prevention (CDC) showed that vaccine coverage among preschool-aged
children increased from 40% in 1997 to 70% in 1999. Between 1995 and 1999, varicella incidence
declined 80% in the surveillance areas, with the greatest decline seen in children aged 1 to 4 years (5).
Herpes Zoster
Herpes zoster occurs as a result of reactivation of latent VZV. The annualized incidence of herpes zoster
is 1.5 to 3.0 cases per 1,000 persons in the population (6,7). An incidence figure of 2.0 cases per 1,000
persons would predict about 500,000 cases of zoster annually in the United States. Expressed another
way, an individual has a 10% to 20% risk of developing herpes zoster at some point during his or her
lifetime. Increasing age is the most important risk factor for the development of herpes zoster. There is an
increase in the age-specific incidence of herpes zoster beginning at around age 55 years; individuals older
than 75 years have a zoster incidence of more than 10 cases per 1,000 person-years (7). Zoster occurs
with equal frequency in men and women, with no seasonal association. The other well-defined risk factor
for herpes zoster is altered cell-mediated immunity. Patients with neoplastic diseases, especially
lymphoproliferative malignancies and organ transplant recipients, are at very high risk for development of
herpes zoster. Approximately 15% to 30% of patients with Hodgkin disease experience herpes zoster,
compared with 2% of patients with various solid tumors (8). The disease occurs in 3% to 10% of renal
transplant recipients, 20% to 25% of cardiac transplant recipients, and 20% to 50% of allogeneic
hematopoietic stem cell transplant recipients (9). Herpes zoster is also seen with increased frequency in
persons infected with human immunodeficiency virus (HIV) and often serves as an initial marker of
disease in that population (10). A longitudinal study of a cohort of HIV-seropositive men in San Francisco
demonstrated an incidence of zoster of 29.4 cases per 1,000 person-years, compared with 2.0 cases per
1,000 person-years in a matched population of HIV-seronegative controls (11).
INFECTIOUS AGENT
VZV shares structural characteristics with other members of the family Herpesviridae. The complete
virion is approximately 180 to 200 nm in diameter. It is composed of an icosahedral nucleocapsid
measuring 90 to 95 nm in diameter, an amorphous tegument, and a lipid-containing envelope with
glycoprotein spikes (12). The VZV genome consists of a linear, double-stranded DNA molecule
containing 125,000 base pairs with guanosine-plus-cytosine content of 46% (13). The genome is
organized in a manner similar to that of other herpesviruses, having unique long (UL; 104.5 kb) and
unique short (US; 5.2 kb) regions flanked by inverted repeats. VZV encodes approximately 69
polypeptides, including seven glycoproteins.
VZV can be propagated in vitro in a limited number of continuous and discontinuous cell culture
monolayers, mostly of human or simian origin. In human embryonic lung fibroblasts, cytopathic effects
begin as a focal process with subsequent cell-to-cell spread. Approximately 8 to 10 hours after infection,
virus-specific immunofluorescence can be detected in cells adjacent to the initial focus of infection. VZV
is highly cell associated, with very limited release of infectious virions into the media.
PATHOGENESIS AND PATHOLOGY

Pathogenesis of Varicella
Varicella is transmitted via the respiratory route. Virus in airborne droplets enters the susceptible host via
mucosal surfaces of the conjunctiva, oropharynx, or upper respiratory tract. VZV undergoes an initial
round of replication, presumably in cervical lymph nodes (14). When local immune responses are
overcome, a primary viremia occurs, with widespread dissemination of VZV to the reticuloendothelial
system and possibly to epithelial cells of other organs. VZV then undergoes multiple cycles of replication,
resulting in a second viremic phase (about 1 week after the initial viremia) that is accompanied by the
onset of clinical symptoms. VZV localizes to endothelial cells of cutaneous capillaries and then extends to
epithelial cells of the epidermis, where replication results in formation of the characteristic vesicles.
Viremia and new vesicle formation continue for 3 to 5 days and then terminate when humoral and cellular
immune responses appear.
Pathology of Varicella
The cutaneous manifestations of varicella begin with hematogenous infection of the endothelial cells of
cutaneous blood vessels. VZV then begins to replicate in the skin, leading to ballooning degeneration of
epithelial cells in the prickle cell (malpighian) layer of the epidermis. Local collections of extracellular
edema fluid result in acantholysis, with elevation of the stratum corneum to form a clear vesicle.
Multinucleated giant cells are found at the base of the lesion. Infected cells contain eosinophilic
intranuclear inclusion bodies (Cowdry type A inclusions) surrounded by a clear zone. A perivascular
infiltration of mononuclear cells is seen around cutaneous vessels. The vesicular fluid becomes cloudy as
it accumulates inflammatory cells and desquamated epidermal cells. The vesicular fluid is resorbed,
resulting in drying and crusting of the lesion. Healing occurs with regeneration of the epithelial cell
layers.
Pathogenesis of Herpes Zoster
As VZV replicates in the skin during acute varicella, some virions are transported via sensory nerves to
the corresponding dorsal root ganglia (15). The virus establishes a latent infection within the ganglion,
preferentially infecting satellite cells rather than neurons (16). An alternative explanation is that VZV may
reach the ganglion by viremic spread. VZV may periodically reactivate and undergo limited replication,
but replication is suppressed by the immune response before any clinical symptoms result (17,18). The
specific immune responses that limit reactivation of VZV from the sensory ganglia are poorly understood.
The most important factor that predisposes to the development of herpes zoster appears to be decline or
suppression of VZV-specific cellular immunity. This may occur naturally with aging or be induced by
immunosuppressive illness or therapy. Following reactivation and replication in the ganglion, virus
travels along the sensory nerve to the skin, where it again replicates in epithelial cells, producing the
characteristic dermatomal vesicular rash of shingles. Unlike the lesions of varicella, in which different
stages are seen simultaneously, most zoster lesions are in the same stage of development. A limited
viremia occurs during many episodes of herpes zoster, reflected by the appearance of a few
extradermatomal vesicles.
Pathology of Herpes Zoster
Replication of VZV in the sensory ganglion results in intense inflammation, neuronal destruction, and
focal hemorrhage. Less severe inflammatory changes often occur in the adjacent ganglia. Occasionally,
inflammation and necrosis also extend to the anterior nerve root, resulting in localized motor neuropathy.
These changes are accompanied by lymphocytic pleocytosis. Movement of virus from the ganglion down
the sensory nerve to the skin produces acute inflammation of the nerve (19). Virus reaching the skin
replicates in epithelial cells of the epidermis, producing pathologic changes identical to those described
for varicella. Inflammatory changes in the sensory nerve persist for months and may result in
demyelination, wallerian degeneration, and sclerosis.
CLINICAL MANIFESTATIONS
Natural History of Varicella
Varicella is generally a benign disease in healthy children, although symptoms are often more severe in
adolescents and adults. Fewer than 5% of primary VZV infections are subclinical. Symptoms develop
after an incubation period of about 15 days (range, 10 to 20 days). A prodrome of fever, malaise,
headache, and anorexia is variably present, occurring more commonly among older children and adults
and lasting 1 to 2 days. A transient scarlatina-like rash is occasionally noted just before or coincident
with the appearance of the varicella lesions. The lesions first appear on the head, then the trunk, and
finally the extremities. The greatest concentration of lesions is on the trunk and proximal extremities. The
rash of varicella is characterized by rapid evolution of lesions over 8 to 12 hours and by successive
crops of new lesions. Consequently, lesions of all stages are present simultaneously on involved skin
surfaces. Lesions begin as pink macules that quickly become papular and evolve into fragile vesicles 1 to
4 mm in diameter surrounded by a zone of erythema. As inflammatory cells migrate into the vesicular
fluid, the lesions become pustules; these are often centrally umbilicated. The pustules become crusted and
the crusts detach after 1 to 3 weeks, usually healing without scarring. Vesicles also appear on mucosal
surfaces and rapidly evolve into shallow ulcerations. New lesion formation continues for 2 to 4 days,
accompanied by pruritus, fever (100° to 102°F), headache, malaise, and anorexia. The rash peaks on
about the fifth day, with an average lesion count of 250 to 500; fewer lesions are seen in children younger
than 5 years (20). Older children and secondary cases within a household tend to have higher lesion
counts and higher fever.
The most common complication of varicella in otherwise normal children is bacterial superinfection
(usually staphylococcal or streptococcal infection) that can occasionally progress to serious necrotizing
cellulitis (1). Varicella pneumonia is rare in children but occurs more often in adults (21). Pregnant
women with chickenpox may be at especially high risk for severe varicella pneumonia. Neonatal
varicella can occur when the mother develops chickenpox within a period of 5 days before to 2 days after
delivery. The infected neonate can develop severe disseminated varicella with a mortality of 20% to
30%. Maternal varicella occurring during the first trimester of pregnancy has been associated with
congenital abnormalities, but the risk appears low (about 1% to 2%) (1).
In immunocompromised children, varicella is a serious and potentially fatal infection. Children at
highest risk are those with acute leukemia, although children with other malignancies and those on
cytotoxic or immunosuppressive medications (including high-dose corticosteroids) can also develop
complications. Immunocompromised children may develop severe hemorrhagic or necrotic skin lesions
(purpura fulminans or hemorrhagic varicella) or severe bacterial superinfection. Persistent viremia can
result in dissemination of VZV, producing pneumonitis, hepatitis, or encephalitis. A chronic form of
varicella has been reported in HIV-infected children.
Neurologic Complications of Varicella
The incidence of CNS complications with varicella is reported to be 1 to 3 per 10,000 cases (3,21).
Because many uncomplicated cases of varicella do not come to medical attention, any calculation of the
frequency of complications is likely to be an overestimation. The CNS manifestations most frequently
associated with chickenpox are cerebellar ataxia and encephalitis (22,23). Uncommon neurologic
complications include transverse myelitis, aseptic meningitis, strokes, and Guillain-Barré syndrome (23).
Optic neuritis has been reported as a rare complication of varicella in both pediatric and adult patients,
with good visual recovery expected in most cases (24). Reye syndrome, a triad of acute hepatic failure,
encephalopathy, and hypoglycemia, was previously associated with varicella (and with other viral
infections) but is now known to be more specifically related to salicylate therapy in febrile children.
However, many cases of Reye syndrome are included in older reviews of varicella encephalitis, resulting
in misleading estimates of incidence and mortality.
Cerebellar Ataxia
Cerebellar ataxia, the most common neurologic abnormality associated with varicella, is diagnosed in
approximately 1 per 4,000 cases of chickenpox (21). Children can develop ataxia from several days
before to 2 weeks after the onset of the rash, although neurologic symptoms most often occur
simultaneously with the rash (23). Symptoms include vomiting, headache, and lethargy accompanied by
ataxia. Fever, nuchal rigidity, and nystagmus occur in about 25% of patients. Seizures are rare and suggest
a more diffuse encephalitis. In cases of ataxia presenting before the development of rash, the correct
diagnosis may not be clinically apparent unless an association is made with recent varicella exposure.
The extent of the diagnostic evaluation in patients with varicella-associated cerebellar dysfunction
should be governed by the severity of the illness and the degree of certainty of the diagnosis. In
uncomplicated cases, the clinical presentation alone is sufficient to establish the diagnosis, and no further
evaluation is necessary. In more complicated situations, a cerebrospinal fluid (CSF) examination, an
electroencephalogram (EEG), and magnetic resonance imaging (MRI) scan of the brain usually are
warranted. The CSF is frequently normal, but a moderate lymphocytic pleocytosis (<100 cells/µL) with
mildly elevated protein and normal glucose levels may occur in 20% to 30% of patients (23). The EEG
demonstrates diffuse slow-wave activity in approximately 20% of patients and normalizes as the
symptoms resolve (23). Few data are available regarding the utility of computed tomographic (CT) or
MRI scan in diagnosing varicella-associated cerebellar ataxia.
Cerebellar ataxia associated with chickenpox is self-limited, and most abnormalities completely
resolve within 1 to 3 weeks. Mortality is essentially zero, and deaths that occur are usually attributed to
the development of nonneurologic complications such as pneumonia (22,23).
The pathogenesis of this syndrome is unknown, partly because of the lack of necropsy studies in this
nonfatal illness. The two pathogenic mechanisms that have been proposed are direct viral involvement of
the cerebellum or a parainfectious, immunologically mediated demyelinating process analogous to that
seen with other viral infections. Recovery of VZV from brain or CSF by culture has not been reported in
varicella-associated cerebellar ataxia. VZV antibodies have been detected in the CSF of patients with
CNS abnormalities in association with varicella but were absent in children who had varicella but no
neurologic symptoms, perhaps reflecting intrathecal antibody production (25). Analysis of CSF using
polymerase chain reaction (PCR) revealed VZV-specific DNA in three of five children with varicella
cerebellitis (26). These observations suggest that VZV replication within the CNS does occur, but
detailed studies are lacking and the evidence for viral invasion of the cerebellum is circumstantial.
Encephalitis
A less common but more severe CNS complication of chickenpox is encephalitis or cerebritis. The
incidence of encephalitis is estimated to be 1 to 2 cases per 10,000 cases of chickenpox (3). Most cases
of encephalitis occur in children, but the incidence is highest in adults (older than 20 years) and infants
(younger than 1 year). Neurologic symptoms may occur from 2 weeks before to several weeks after the
varicella rash (most often about 1 week after), and the onset may be abrupt or gradual (22,27). Headache,
fever, vomiting, and an altered sensorium are the usual presenting symptoms (23,28). Seizures occur in
29% to 52% of patients (23). Focal neurologic abnormalities can include ataxia, hypertonia or hypotonia,
hyperreflexia or hyporeflexia, positive plantar reflexes, hemiparesis, and sensory changes (23,28).
The CSF from patients with varicella-associated cerebritis is frequently abnormal, with elevated
opening pressure, a mild to moderate lymphocytic pleocytosis (usually <100 cells/µL), elevated protein
(50 to 100 mg/dL), and normal glucose (22). The EEG is often abnormal, showing slow-wave activity
consistent with a diffuse encephalitis. Focal EEG abnormalities suggestive of epileptiform activity may
occur even without clinical seizures. In patients who do have seizures, these EEG abnormalities tend to
persist and are present in 43% of follow-up studies at 1 year. Abnormalities observed by CT in patients
with varicella encephalitis have included cerebral or cerebellar edema and areas of low attenuation
consistent with demyelination. MRI abnormalities in children with postvaricella encephalitis have
included diffuse gray and white matter lesions or bilateral basal ganglia lesions (29).
The reported mortality for varicella encephalitis has varied from 5% to 35%, although many of these
series included cases of Reye syndrome (22,23,28). The actual mortality rate for varicella cerebritis is
probably less than 10%, with complete or nearly complete recovery expected in most cases. Long-term
sequelae may be present in 10% to 20% of survivors (23). In a series of 59 cases of varicella with CNS
involvement, the mortality rate was 5% (22). Two of the three deaths were associated with pneumonia,
and 80% of the survivors were discharged from the hospital without detectable sequelae.
The role of active viral replication in the CNS in varicella encephalitis remains uncertain (30).
Postmortem studies of the brain have shown a wide range of histopathologic findings (22,23,31). Diffuse
cerebral edema is generally present. Perivascular infiltration of mononuclear cells and demyelination
have been seen in some cases, the latter suggesting a postinfectious demyelinating process. Other cases
have shown focal hemorrhagic lesions. Intranuclear viral inclusions have been observed only rarely in the
brain following varicella, usually in immunocompromised patients (31).
Transverse Myelitis
On rare occasions, varicella has been associated with an isolated weakness of the lower extremities,
sphincter dysfunction, abnormal deep tendon reflexes, and extensor-plantar reflexes (32). The CSF is
characterized by a lymphocytic pleocytosis and elevated protein level with a normal glucose level. The
completeness of recovery is variable. The pathogenesis of varicella myelitis is not known, although cases
have been published in which VZV DNA was detected in CSF by PCR, suggesting that active viral
invasion of the spinal cord may be involved (33).
Aseptic Meningitis
Aseptic meningitis has been reported as a complication of varicella (23). Meningismus without evidence
of cerebral or cerebellar dysfunction is suggestive of the diagnosis, and complete recovery is expected.
CSF findings are typical of viral meningitis, with mild lymphocytic pleocytosis, slight elevation in the
protein content, and normal glucose level. VZV has not been cultured from the CSF in this setting; PCR
would be an appropriate diagnostic test. It is probably appropriate to consider CNS involvement with
varicella as a spectrum, with aseptic meningitis the most benign manifestation and encephalitis the most
serious.
Stroke Syndromes
Arterial ischemic strokes are a well-recognized complication of herpes zoster ophthalmicus (HZO) but
can also occur after varicella (34,35). By some estimations, young children with arterial ischemic strokes
are threefold more likely than controls to have recently had varicella. In a prospective cohort study, 22
(31%) of 70 children with arterial ischemic strokes had varicella within the preceding 12 months,
compared with 9% in the healthy population (36). Children with strokes and recent varicella infection had
higher rates of basal ganglia infarction, abnormal cerebral vascular imaging, and recurrent ischemic
attacks (p < .05 for all) (36). The syndrome typically occurs in otherwise healthy, immunocompetent
children (median age, 5 years). The median interval between varicella infection and the onset of
neurologic deficits is 2 months (37). The children usually present with hemiplegia, and angiography
reveals vasculopathy of the branches of the middle cerebral artery (MCA). MRI typically demonstrates
unilateral infarctions in the MCA distribution (38,39). In one fatal case, histopathology revealed active
granulomatous arteritis of the MCA with lymphocytic inflammatory infiltrate and VZV antigens in the
smooth muscle layer (37). Patients have been treated with intravenous acyclovir and corticosteroids, but
no data from controlled studies are available to assess the efficacy of these treatments. Most children with
hemiplegia following varicella infection have good neurologic recovery (which is a much better
prognosis than that associated with strokes in adults following HZO).
Natural History of Herpes Zoster
The inflammatory changes that occur in the sensory ganglion and nerve as VZV reactivates are manifested
by pain in the corresponding dermatome. The patient may report sensations ranging from mild itching or
tingling to severe pain that precedes the appearance of the skin lesions by 1 to 5 days (or occasionally
longer). Constitutional symptoms are reported by fewer than 5% of patients during the prodromal phase.
The cutaneous eruption of herpes zoster is unilateral and does not cross the midline. The rash appears in
the skin segment innervated by a single sensory ganglion (Fig. 10.1). Overlap of lesions into adjacent
dermatomes occurs in 20% of patients. Scattered cutaneous vesicles beyond the primary or adjacent
dermatomes appear in about one third of patients with herpes zoster infection and have no prognostic
significance. Disseminated VZV infection with visceral involvement is extremely rare in
immunocompetent patients with herpes zoster infection, although occasional cases of encephalitis and
myelitis have been reported. Herpes zoster appears with increased frequency in certain dermatomes, and
this is thought to reflect the distribution of skin lesions during varicella (18). The most common sites for
herpes zoster are the thoracic dermatomes (50% of cases), followed by cervical (15%), lumbar (15%),
and sacral (5%) dermatomes (18). About 15% of zoster cases occur in cranial nerve dermatomes, with
most cases involving the first division of the trigeminal nerve (HZO). Ocular involvement can be a
serious complication of HZO. Conjunctivitis is common and benign, but more serious ocular
manifestations, such as keratitis, scleritis, and iridocyclitis, may develop in 50% to 70% of patients with
HZO (40).
Skin changes begin with an erythematous maculopapular rash, followed by the appearance of clear
vesicles. New vesicle formation typically continues for 3 to 5 days, followed by lesion pustulation and
scabbing. The extent of involvement can range from a few vesicles to a confluent eruption filling the
entire dermatome. Most lesions are crusted by day 10, but complete skin healing may require 2 to 4
weeks. Unlike varicella, herpes zoster is associated with a significant risk of skin scarring and permanent
pigmentation changes. Skin necrosis and gangrene in the involved dermatome can occur but are more
commonly encountered in immunocompromised patients.
During the acute phase of herpes zoster, most patients experience dermatomal pruritus and pain, which
can be severe. The acute neuritis is variably described as an aching, burning, or stabbing pain. Many
patients complain of headache, photophobia, and malaise, but significant fever is rare. CSF examination
(which is not routinely necessary) reveals a lymphocytic pleocytosis and increased protein concentration;
VZV can occasionally be cultured from the CSF. Although the skin usually heals in 2 to 4 weeks, pain
(postherpetic neuralgia [PHN]) persists for longer than 1 month in 20% to 70% of patients with herpes
zoster, with elderly patients experiencing the highest frequency of chronic pain. Although herpes zoster is
most common among older adults, the disease can occur in patients of any age. Immunocompetent children
and young adults with herpes zoster tend to have less extensive cutaneous eruptions, less severe pain, and
a much lower risk for chronic pain.
Patients with deficiencies in cell-mediated immunity have an increased incidence of herpes zoster and
a higher risk for complications. In immunocompromised patients, zoster causes more severe skin
involvement within the dermatome and may be accompanied by viremia with cutaneous or visceral
dissemination. Without antiviral chemotherapy, cessation of new vesicle formation does not occur until
about day 8, pustulation on day 9, and scabbing on day 18 (41). Patients with herpes zoster infection at
highest risk for dissemination are those with lymphoproliferative malignancies or those who recently
received induction chemotherapy (8,42). Without antiviral treatment, the reported incidence of cutaneous
dissemination in immunocompromised populations is 6% to 26% (43). In most patients, dissemination is
limited to the skin and does not substantially alter the prognosis. However, 10% to 50% of patients who
develop cutaneous dissemination also have evidence of visceral dissemination (such as pneumonitis,
meningoencephalitis, or hepatitis), which carries a much more serious prognosis. Even with the
availability of antiviral chemotherapy, the mortality rate for zoster with visceral dissemination is 5% to
15%, with most deaths attributable to pneumonitis (44). Visceral VZV infection occurring without any
evidence of skin lesions is uncommon. However, several patients with acquired immunodeficiency
syndrome (AIDS) and VZV myelitis or encephalitis but without clinically apparent zoster have been
reported. Another syndrome unique to the immunocompromised host is chronic cutaneous VZV infection,
sometimes associated with acyclovir-resistant virus.
Neurologic Complications of Herpes Zoster
Neurologic complications of herpes zoster can occur during the acute eruption (e.g., segmental motor
paresis) or may appear weeks to months after the herpes zoster rash has resolved (e.g., delayed
contralateral hemiparesis) (45). Neurologic complications appear more often in immunocompromised
patients, including patients with HIV infection. Several pathologically distinct syndromes have been
defined, including large and small vessel vasculopathies and ventriculitis (46). Investigators have also
described myelitis and polyradiculitis, as well as a variety of cranial and peripheral nerve palsies in
association with herpes zoster (47). The most common neurologic complication of herpes zoster is
chronic pain, or PHN, which occurs with sufficient frequency that it can be considered a part of the
natural history of the disease (48).
Encephalitis
Herpes zoster can be complicated by acute encephalitis that usually occurs a few days after the onset of
rash but has been reported from days to weeks before or after the skin eruption (49). Encephalitis has
occasionally been documented in the absence of apparent cutaneous zoster and in patients who received
appropriate antiviral therapy during the acute episode of herpes zoster (50,51). Immunocompromised
patients are clearly at increased risk for the development of encephalitis (49,52). Other markers of
increased risk for CNS involvement include zoster in a cranial nerve dermatome or the presence of
cutaneous dissemination. The mortality of herpes zoster–associated encephalitis has been reported to be
from 0% to 25%, and the true incidence is probably about 10% (49). The clinical presentation is most
often an acute or subacute delirium accompanied by few focal neurologic signs (6,49,53). Other findings
can include headache, meningismus, fever, ataxia, and seizures.
CSF examination reveals increased opening pressure, increased protein, and a lymphocytic
pleocytosis. Caution must be used in interpretation of the spinal fluid findings, because pleocytosis is also
present in about half of patients with uncomplicated herpes zoster (54). Positive VZV cultures have been
obtained from CSF in patients with zoster encephalitis, and cells containing VZV-specific antigens have
been identified in CSF. Serologic assays have revealed increased levels of VZV-specific intrathecal
antibodies (25). EEGs show diffuse abnormalities with an excess of slow-wave activity (53). Images
obtained by CT are generally nondiagnostic; published experience with MRI in this syndrome is limited.
PCR is the most sensitive diagnostic tool for zoster encephalitis. In one study of seven patients with
herpes zoster with neurologic symptoms (meningitis or encephalitis), PCR performed on CSF was
positive for VZV DNA in all cases (26). The frequency of PCR positivity in CSF from patients with
uncomplicated cutaneous herpes zoster remains to be established.
As with virtually all neurologic syndromes caused by VZV, there is controversy regarding the relative
contributions of direct viral replication and postinfectious immunopathologic changes in the pathogenesis
of herpes zoster–associated encephalitis. Histologic studies have shown demyelination with mononuclear
cell infiltrates, especially in white matter (19,55). In brain tissue from patients who died with herpes
zoster–associated encephalitis, intranuclear inclusion bodies were often evident, and viral particles have
been visualized by electron microscopy (49). Supporting the hypothesis that active viral invasion and
replication play a role, there are many anecdotal reports of rapid clinical improvement after initiation of
acyclovir therapy (52).
Chronic VZV encephalitis is seen almost exclusively in immunocompromised patients, especially
patients with AIDS with marked depletion of CD4+ lymphocytes (56). The onset of the encephalitis may
occur months after an episode of herpes zoster and 30% to 40% of these patients have no recognized
history of cutaneous VZV infection, making the diagnosis more difficult. Pathologic studies reveal
multifocal leukoencephalopathy, with lesions in the white matter near the gray–white junction, small
vessel vasculitis, and demyelination (46). The clinical presentation is usually subacute with headache,
fever, mental status changes, and seizures. Patients may have focal neurologic defects including aphasia,
hemiplegia, and visual-field cuts (57–59). MRI demonstrates plaquelike lesions in deep white matter,
changes consistent with demyelination, and late development of ischemic or hemorrhagic infarcts of
cortical and subcortical gray and white matter (60,61). CSF examination reveals mild mononuclear
pleocytosis. VZV DNA has been amplified from the CSF of patients with chronic encephalitis using PCR
(62,63). Patients often follow a clinical course of progressive deterioration and death, although anecdotal
reports have suggested some benefit from high-dose intravenous acyclovir therapy (46,64). Other VZV-
induced neurologic disorders described in patients with AIDS include multifocal leukoencephalitis (57),
ventriculitis (65), myelitis and myeloradiculitis (65,66), and focal brainstem lesions (67).
Herpes Zoster Ophthalmicus with Delayed Contralateral Hemiparesis

Hemiparesis is a rare but serious complication of herpes zoster that has been reported in
immunocompetent and immunocompromised patients (68), including both children and adults (69). The
mean interval from rash to onset of neurologic symptoms in adults is about 7 weeks, although intervals of
up to 6 months have been reported. The typical presentation is headache and hemiplegia occurring in a
patient with a history of recent HZO (70). The mortality rate is 20% to 25%. There is a high probability
of permanent neurologic sequelae among survivors (71).
CSF examination reveals mononuclear cell pleocytosis (71). Imaging studies (CT or MRI) show
changes consistent with brain infarction (72,73). Arteriography is usually diagnostic and demonstrates
inflammation, narrowing, and thrombosis of the proximal branches of the anterior cerebral artery or the
MCA (74). Rare cases of posterior circulation strokes following herpes zoster infection involving a
cervical dermatome have been reported (75). The pathogenesis of this unusual disorder is thought to be
direct VZV invasion of cerebral arteries by extension along intracranial branches of the trigeminal nerve.
This results in inflammation of the internal carotid artery or one of its branches on the side ipsilateral to
the rash. The local inflammatory response and thrombosis produce vascular occlusion or distal
embolization, resulting in infarction and contralateral hemiparesis. Pathologic studies have demonstrated
a necrotizing arteritis of large and small cerebral vessels with thrombosis in the proximal anterior
cerebral artery or the MCA (76). Although VZV has not been cultured from the areas of inflammation,
VZV-specific antigens and DNA have been demonstrated in the smooth muscle cells of the media of
affected vessels (77).
Both acyclovir (78) and corticosteroids (79) have been used in an effort to treat this syndrome,
although no therapy has been evaluated in a controlled or prospective fashion. Antiviral therapy is
warranted because of the demonstrated presence of VZV in the inflamed vessels, but benefit of therapy is
difficult to assess, because irreversible cerebral infarction has usually occurred by the time the diagnosis
is made.
Myelitis
Herpes zoster–related myelitis is thought to result from direct invasion of the spinal cord by VZV, with
unilateral motor and posterior column dysfunction evolving into paraplegia (33). The disorder most often
follows thoracic herpes zoster, with weakness developing in the same spinal cord segment as the rash.
Neurologic symptoms begin to develop an average of 12 days after the onset of the rash (80). However,
VZV myelitis in patients with no history of antecedent zoster has also been reported (81,82).
Immunocompromised patients are at increased risk for postzoster myelitis, and the syndrome is well
described in patients with AIDS (58,83). The most common initial manifestation is bladder dysfunction
(e.g., urinary retention), often accompanied by weakness of the lower extremities, asymmetric reflexes,
and sensory disturbances (80). Prognosis for recovery of neurologic function has been variable. In severe
cases, the myelopathy can progress to a partial Brown-Séquard syndrome or total cord transection. MRI
has been useful in diagnosing myelitis, with abnormal signal evident in the cord at the level of
inflammation (33,81,84–86).
Pathologic studies have demonstrated necrosis of the spinal cord, with posterior column involvement,
focal demyelination, and perivascular inflammation. The presence of intranuclear inclusion bodies and
positive immunofluorescence stains for VZV antigens in spinal cord tissue are evidence for the direct role
of the virus in this disease (80). VZV DNA has been amplified from the spinal fluid of patients with
myelitis by PCR techniques (33,81). Although there are anecdotal reports of significant neurologic
improvement with antiviral treatment, this therapeutic approach has not been studied in a prospective
fashion (33,87).
Cranial and Peripheral Nerve Palsies

Segmental motor paresis complicates about 2% to 3% of cases of dermatomal herpes zoster. Weakness,
which may be abrupt in onset, usually begins within a few days to 2 weeks after the onset of the rash. The
involved muscle groups are those whose innervation corresponds with that of the affected dermatome.
Thus, thoracic zoster may be associated with paralysis of limb or trunk muscles, while sacral zoster may
result in bladder or anal dysfunction. The peripheral motor neuropathy is caused by viral invasion and
inflammatory changes affecting motor neurons in the anterior horn. Weakness is usually transient, and 75%
to 85% of patients can expect total resolution, although a few patients experience prolonged paralysis
with muscle atrophy.
Twelve percent to thirty percent of patients with herpes zoster involving a cephalic dermatome develop
oculomotor or facial palsies. HZO can be associated with partial or complete palsies of the third, fourth,
or sixth nerve. Facial palsy (sometimes including loss of taste on the anterior two thirds of the tongue)
may accompany otic zoster (Ramsay Hunt syndrome) or zoster involving the second or third cervical
dermatomes (88,89).
Acute Retinal Necrosis

VZV-associated acute retinal necrosis (ARN) has been described in both immunocompetent and
immunocompromised persons. Since the advent of the AIDS epidemic, a more aggressive variant of this
disease (sometimes termed rapidly progressive herpetic retinal necrosis [RPHRN]) has been identified
(90,91). Visual changes are usually noted weeks to months after the antecedent herpes zoster. ARN can
follow either HZO or herpes zoster in a remote dermatome. Furthermore, retinal involvement is bilateral
in more than half of cases, suggesting that VZV reaches the CNS via hematogenous spread, possibly with
extension along nerve pathways within the anterior visual system (91). VZV retinitis presents with
multifocal necrotizing lesions, often initially involving the peripheral retina. The granular,
nonhemorrhagic lesions rapidly extend and coalesce, accompanied by relatively little intraocular
inflammation (92).
In patients with AIDS, VZV retinitis rapidly progresses to full-thickness retinal necrosis, usually with
retinal detachment, resulting in blindness in 75% to 85% of involved eyes (91). Because the involved eye
is rarely salvageable in HIV-infected patients with RPHRN, the goal is to try to prevent disease
progression in the uninvolved eye. Intravenous acyclovir alone is ineffective (92). Some experts
recommend intravenous therapy with ganciclovir or foscarnet (or a combination of the two) (93).
Anecdotal success with cidofovir or with intravitreal injections of ganciclovir has also been reported
(94). Results of antiviral therapy for VZV retinitis in HIV-infected patients, regardless of regimen, have
been disappointing.
ARN in immunocompetent patients is a less virulent disease and responds better to antiviral therapy. In
this setting, acyclovir is clearly beneficial for preserving useful vision (95). A suggested antiviral
regimen for ARN in the otherwise healthy host is intravenous acyclovir 10 to 15 mg/kg every 8 hours for
10 to 14 days, followed by oral valacyclovir 1 g three times daily for 4 to 6 weeks, although this
treatment approach has not been studied in a controlled fashion.
Postherpetic Neuralgia
PHN is the term traditionally used to describe the chronic dermatomal pain that persists after the
cutaneous eruption of herpes zoster has healed. PHN has been estimated to occur following 10% to 40%
of zoster cases; some of the variability in incidence calculations can be attributed to differing definitions
of PHN (6,18,96). Ragozzino et al. (6) reported that 9.3% of the patients with herpes zoster in their study
had PHN; of these patients, 22% (or 2% of the total study population) had pain that persisted for longer
than 12 months. The incidence (and possibly the duration) of PHN correlates directly with patient age.
Pain that persists for longer than 1 year has been noted in 4%, 22%, and 47% of patients younger than 20
years, older than 55 years, and older than 70 years of age, respectively (6,97,98). Within the affected
dermatome, patients with PHN experience a variety of sensory abnormalities (paresthesias, dysesthesias,
allodynia) and neuralgic pain of varying quality and severity. The pathogenesis of PHN is not completely
understood but apparently involves both peripheral and central mechanisms. Experimental evidence
suggests that the damaged sensory nerve develops a lowered activation threshold and superphysiologic
responses to distal stimuli. This excessive input from the peripheral sensory nerve results in
hyperexcitability of the dorsal horn, producing exaggerated central responses that are perceived as pain
(99).
Successful treatment of PHN often requires a multifaceted approach (48,100,101). Opioid analgesics
are the mainstay of therapy during the early phases of neuralgic pain. A clinical trial with oxycodone for
patients with PHN demonstrated a significant level of pain reduction (67% of those receiving oxycodone
vs. 11% receiving placebo), as measured by a visual analog scale (102). Long-acting opioid preparations
(oral or transdermal) are preferable to short-acting analgesics for management of chronic PHN. Several
randomized, controlled clinical trials have shown tricyclic antidepressants (including amitriptyline,
nortriptyline, and desipramine) to be effective in reducing the pain of PHN, either as a single agent or in
combination with other drugs (103,104). Because tricyclic antidepressants are often associated with
sedation and anticholinergic side effects, treatment should begin with a relatively low dose at bedtime,
with a gradual increase in dosage as required and tolerated. Clinical trials have shown the anticonvulsant
gabapentin to significantly reduce established PHN when used alone or in combination with other
modalities (105). For treatment of PHN, physicians should initiate gabapentin at a dose of 300 mg three
times daily and escalate as required, watching for adverse effects such as somnolence, dizziness, and
ataxia. The adverse effects of these medications can be additive (such as sedation due to opioids,
tricyclic antidepressants, and gabapentin), especially in elderly patients. Topical application of capsaicin
provides relief of PHN for some patients, but others find the local stinging and burning associated with
application of capsaicin cream to be intolerable (106). Transdermal administration of lidocaine via
patches has been shown to reduce PHN in controlled trials (107,108). Topical treatments should be used
only on intact, healed skin. In a controlled clinical trial of 277 patients with intractable PHN, intrathecal
injection of 60 mg of methylprednisolone acetate once weekly for 4 weeks resulted in significant pain
reduction (109); these promising initial results await validation.
Zoster Sine Herpete

Clinicians occasionally encounter patients who present with zoster-like neuropathic pain but never
develop the characteristic dermatomal rash (110,111). Recent detailed studies of a few patients presenting
with dermatomal pain have established that some of these cases are due to VZV reactivation. Patients
with this syndrome, termed zoster sine herpete, have rising titers of VZV-specific antibody in both serum
and CSF and have VZV DNA in CSF and peripheral blood mononuclear cells detectable by PCR
(112,113). Because there is no easy way to make the diagnosis, the incidence of zoster sine herpete is not
known. In anecdotal reports, responses to antiviral therapy have been inconsistent.
DIAGNOSIS
The appearance of varicella is quite distinctive, and in most cases, a clinical diagnosis is accurate and
reliable. The presentation of a child with mild constitutional symptoms, a diffuse vesicular rash, and no
prior history of chickenpox (or vaccination) is strongly suggestive of the diagnosis, especially during an
epidemic. Other infections that can occasionally mimic chickenpox include vesicular exanthems caused
by coxsackievirus, disseminated herpes simplex virus (HSV) infection, diffuse impetigo, or
rickettsialpox. Noninfectious cutaneous diseases that may resemble varicella include contact dermatitis
and dermatitis herpetiformis. Herpes zoster, with its characteristic dermatomal vesicular rash, is also
readily diagnosed on the basis of clinical appearance. The diagnosis may be less apparent in patients who
present with dermatomal neuralgia before the emergence of skin lesions. The skin disease that is most
commonly confused with herpes zoster is zosteriform HSV infection (usually in the sacral area), which
can closely mimic the appearance of shingles. Contact dermatitis can also occasionally resemble herpes
zoster, but it tends to cross dermatomal boundaries.
There is no asymptomatic shedding of VZV, as there is with HSV and cytomegalovirus. Therefore,
identification of VZV virions, antigens, or nucleic acids from cutaneous lesions or nonneuronal tissues is
diagnostic of active infection. VZV can be cultured by inoculation of vesicular fluid into monolayers of
human fetal diploid kidney or lung cells (114). VZV is very labile, and every effort should be made to
minimize time spent in transport and storage. Ideally, fluid should be aspirated from a clear vesicle using
a tuberculin syringe and inoculated directly into tissue culture at the bedside. Characteristic cytopathic
effects are usually seen in tissue culture within 3 to 7 days. The culture process can be accelerated by use
of centrifugation in shell vials. Identification of the isolate can be confirmed by direct immunofluorescent
staining using VZV-specific monoclonal antibodies. In general, viral culture for VZV is highly specific but
slow, insensitive, and expensive.
VZV infection can be demonstrated in infected tissue by histopathology or electron microscopy.
However, visualization of multinucleated giant cells with inclusion bodies or herpesvirus virions does
not distinguish between VZV and HSV. Direct immunofluorescence staining using fluorescein-conjugated
monoclonal antibodies to detect VZV glycoproteins in infected epithelial cells is highly sensitive and
specific (115). Specimens can also be stained with HSV-specific monoclonal antibodies to distinguish
VZV from HSV infection. This direct fluorescent antigen-detection method is rapid, simple, and more
sensitive than virus isolation (especially in late stages of infection, when virus isolation becomes more
difficult) and is especially helpful for making a rapid diagnosis when the clinical presentation is atypical.
The use of PCR to detect VZV nucleic acids in clinical specimens holds great promise, but it is used
primarily as a research tool (116,117). PCR overcomes the difficulties inherent in culturing labile VZV
and has been useful in detecting VZV DNA in CSF from patients with CNS infections (26,54,118–120). In
addition, the use of PCR makes it possible to distinguish between disease caused by wild type VZV or by
the VZV vaccine virus, which is not routinely possible by culture (121).
Serologic techniques are used to determine susceptibility of an individual to VZV infection and to
document rising antibody titers in patients with acute varicella or herpes zoster. A serologic response is
usually considered diagnostic if there is a fourfold rise in antibody titer. Serum antibodies appear several
days after the onset of varicella and peak at 2 to 3 weeks, meaning that serologic determinations usually
deliver a retrospective rather than a real-time diagnosis. Acute infection can be established by
demonstration of VZV-specific serum immunoglobulin M titers. However, antigen-detection techniques
are usually faster and more reliable. Patients with herpes zoster are VZV seropositive at the time of
disease onset, but most show a significant rise in titer during the convalescent phase. Elevated antibody
titers in CSF can support the diagnosis of VZV encephalitis (25,54,122). Most laboratories have now
adopted an enzyme-linked immunosorbent assay (ELISA) or a latex agglutination (LA) assay for VZV
serodiagnosis (114).
TREATMENT
Varicella
For most immunocompetent children, chickenpox is a disease associated with very low morbidity and
mortality and supportive care alone is sufficient. Astringent soaks and nonaspirin antipyretics improve
comfort. Trimming the fingernails closely helps prevent bacterial superinfections caused by scratching. If
bacterial cellulitis develops, antibiotics may be required. Oral acyclovir has been evaluated for treatment
of uncomplicated varicella in immunocompetent children (20,123). Acyclovir therapy, initiated within 24
hours of the onset of rash, resulted in shorter duration of fever, fewer skin lesions, and accelerated lesion
healing. Overall, oral acyclovir reduced the duration of symptomatic illness by about 24 hours. The
populations studied in these controlled trials were not sufficiently large to assess the impact of acyclovir
therapy on the incidence of varicella complications. Oral acyclovir has also been evaluated in
immunocompetent adolescents and adults (124,125). As seen in the pediatric studies, initiation of
acyclovir therapy within 24 hours of onset of rash resulted in reduction in time to cessation of new lesion
formation, reduced the number of lesions, and reduced constitutional symptoms, including fever. The dose
of oral acyclovir for chickenpox is 20 mg/kg (up to a maximum of 800 mg) five times daily for 5 to 7
days. Famciclovir and valacyclovir are likely to be at least as effective as acyclovir for chickenpox but
have not been extensively studied. Oral antiviral therapy is optional in healthy children with varicella, but
it should definitely be used in adolescents and adults because of their increased risk for more severe
illness.
Few data exist to help address the question of antiviral therapy for neurologic complications of
varicella. In general, the cerebellar ataxia syndrome is benign and self-limited, and there is no evidence
that antiviral therapy alters the natural history. Varicella encephalitis is associated with a substantial
degree of morbidity, and the availability of some specific therapy would be useful. As discussed earlier
in this chapter, there is considerable controversy regarding what role, if any, active VZV replication plays
in the pathogenesis of varicella encephalitis. However, because no other mode of therapy is available,
and because acyclovir is extremely safe and well tolerated, therapy with acyclovir in patients with
varicella encephalitis is warranted. Corticosteroids have been proposed for use in varicella encephalitis,
but there are no reliable data to support their use.
In immunocompromised children, varicella is a serious and potentially lethal infection that requires
antiviral therapy (126). Intravenous acyclovir was compared with placebo in a small population of
immunocompromised children with chickenpox (127). In this trial, the administration of acyclovir
reduced the frequency of pneumonitis from 45% to 0%. Despite the lack of data from large-scale
controlled trials, the safety and efficacy of intravenous acyclovir have led to its acceptance as the drug of
choice for varicella infection in immunocompromised patients. For treatment of serious VZV infections,
intravenous acyclovir is given at a dose of 10 mg/kg (or 500 mg/m2) every 8 hours.
Herpes Zoster
Appropriate supportive care can help make patients with herpes zoster more comfortable. The skin
lesions should be kept clean and dry to reduce the risk of bacterial superinfection. Astringent soaks (e.g.,
Domeboro solution) may be soothing. Most patients with acute herpes zoster infection have significant
pain and require therapy with opioid analgesics.
Three oral antiviral drugs are approved in the United States for treatment of herpes zoster infection in
the normal host. Oral acyclovir, initiated within 72 hours of the onset of lesions at a dose of 800 mg five
times daily, reduces the duration of viral shedding, accelerates the cessation of new lesion formation, and
accelerates the events of cutaneous healing (128–130). These clinical trials showed variable benefit from
acyclovir for reducing the duration of PHN. However, data from these studies have been reexamined in a
metaanalysis, which conclusively demonstrated that acyclovir was superior to placebo for reducing the
duration of “zoster-associated pain,” defined as pain measured from the initial onset until final resolution
(131). Oral administration of valacyclovir (a prodrug of acyclovir) as a dose of 1 g three times daily
produces plasma acyclovir levels that are approximately threefold to fivefold higher than those
achievable with acyclovir. Valacyclovir and acyclovir have been compared in a controlled trial for
treatment of herpes zoster infection in the normal host (132). The two drugs were equivalent in terms of
accelerating events of cutaneous healing; however, valacyclovir was superior in accelerating the
resolution of zoster-associated pain. When evaluated for treatment of herpes zoster in the normal host,
famciclovir (500 mg orally three times daily) was significantly superior to placebo in reducing the
duration of viral shedding, limiting the duration of new lesion formation, and accelerating the events of
cutaneous healing (133). Most importantly, famciclovir was significantly superior to placebo in reducing
the duration of PHN. A study comparing valacyclovir and famciclovir for herpes zoster showed these
drugs to be therapeutically equivalent (134). All these compounds are safe and well tolerated for short-
term administration. Patients who are most likely to benefit from antiviral therapy of herpes zoster are
those who present for medical attention within 72 hours after onset of lesions, patients with severe pain or
large lesion surface area involvement at the time of presentation, and elderly patients who are at high risk
for long-term complications, especially chronic pain (135). HZO is a special situation in which antiviral
therapy is clearly beneficial and significantly reduces the risk for ocular complications (136).
Consultation with an experienced ophthalmologist is also recommended for patients with HZO and ocular
involvement. Because of their convenience of administration, famciclovir and valacyclovir are the
preferred drugs for uncomplicated herpes zoster infection in the normal host.
Two large clinical studies have helped clarify the role of corticosteroids in herpes zoster infection
(137,138). Both studies demonstrated benefit from corticosteroids in reducing the duration of acute
neuritis, but neither study showed any reduction in the incidence or duration of PHN among steroid
recipients. Therefore, although corticosteroids (in combination with antiviral therapy) can provide some
symptomatic benefit during the early phases of herpes zoster, corticosteroids will not have an impact on
the development of PHN.
Immunocompromised patients who develop herpes zoster are at significant risk for morbidity and
mortality related to disseminated infection. Controlled trials have shown that intravenous acyclovir
substantially reduces the risk for cutaneous and visceral dissemination (44,139). In patients who are less
severely immunocompromised, it may be feasible to use an oral antiviral drug for the treatment of zoster
(140).
The role of antiviral drugs in the management of neurologic complications of herpes zoster has not been
evaluated in a controlled fashion. For those diseases in which viral replication likely plays an important
role in pathogenesis (e.g., zoster myelitis), therapy with intravenous acyclovir is recommended; this
approach is supported by benefits noted in anecdotal experience. For diseases such as delayed
contralateral hemiparesis, in which the role of active viral replication is much less clear, the value of
antiviral therapy is uncertain, but in general the potential benefits of antiviral therapy probably outweigh
any potential risks.
PREVENTION
A live, attenuated varicella vaccine containing VZVOKA strain was developed in the 1970s in Japan and
approved for use in the United States in 1995 (141). At the standard dose, the protection provided by the
vaccine against VZV disease following household exposure was approximately 70%. Any case of
chickenpox occurring among vaccinated individuals was almost invariably mild (median lesion count of
15 to 32) (142). The most common adverse event associated with the vaccine has been a mild
varicelliform rash (median lesion count of two to five), occurring in about 7% of recipients (141). The
VZV vaccine is also safe and effective in seronegative adults, although the seroconversion rate after a
single dose is lower (79% to 82%) than that seen in pediatric populations (143). The varicella vaccine
has been endorsed for routine use in children by the American Academy of Pediatrics (144).
Widespread use of the vaccine should result in a reduction in varicella and varicella-related neurologic
complications. Herpes zoster does occasionally develop in patients who have received the varicella
vaccine, and in some instances, it has been documented to be caused by the VZVOKA vaccine virus (145).
Among immunocompromised children, however, the risk of herpes zoster is lower in children who have
received the vaccine than in those who have experienced wild type varicella.
For immunocompetent children aged 12 months to 12 years, the vaccine is administered as a single
subcutaneous dose (0.5 mL containing no fewer than 1,500 plaque-forming units of VZV). Adolescents
and adults should receive two doses of vaccine 4 to 8 weeks apart. VZV vaccine is not approved in the
United States for use in immunocompromised patients, but the vaccine has been shown to be effective in
these populations, and further studies are ongoing to clarify these indications (146). An inactivated virus
vaccine is also being evaluated for use in immunocompromised patients (147). Routine administration of
a booster vaccine is not recommended, but additional long-term surveillance studies are in progress to
better define the need for a booster.
Another potential application of the VZV vaccine is to stimulate waning cell-mediated immune
responses in elderly individuals to prevent VZV reactivation and herpes zoster. An enhanced VZV-
specific cytotoxic lymphocyte response can be demonstrated in elderly seropositive individuals receiving
the VZVOKA vaccine (148). Whether this enhanced immune response will be clinically effective in the
prevention or amelioration of subsequent herpes zoster infection will be determined by a large placebo-
controlled clinical trial.
ACKNOWLEDGMENTS
This project has been funded in whole or in part with Federal funds from the National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under
Contract (N01-AI-65306, NO1-AI-15113, NO1-AI-62554, NO1-AI-30025), the General Clinical
Research Unit (RR-032), and the State of Alabama.
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CHAPTER 11 CYTOMEGALOVIRUS
PAUL D. GRIFFITHS
HISTORY
In the early years of the twentieth century, histopathologists studying stillborn infants identified the
characteristic intranuclear inclusions in fatal cases of what is now termed cytomegalic inclusion disease
(1). At first, the inclusion bodies were attributed to a new protozoal infection (2). However, in 1921
Goodpasture and Talbot (3) remarked on the similarity between these strange bodies and the intranuclear
inclusions produced in the skin lesions of varicella (4). The viral etiology of the inclusions was first
proposed by von Glahn and Pappenheimer (5) in 1925. The following year, Cole and Kuttner (6) were
able to transmit the guinea pig form of cytomegalic inclusion disease from salivary gland material passed
through a Berkefeld N filter. Later, three laboratories simultaneously reported the isolation of the
causative human virus in cell cultures: Smith (7) in 1956 from salivary glands, Rowe et al. (8) in 1956
from adenoid tissue, and Weller et al. (9) in 1957 from a liver biopsy specimen. In 1960, Weller et al.
(10) named the virus “cytomegalovirus” (CMV).
Since a characteristic feature of cytomegalic inclusion disease is global mental retardation, scientists
have known for more than 50 years the basic nature of CMV and its tropism for cells of the central
nervous system (CNS). However, whether this tropism resulted from the immature phenotype of cells
dividing to form the fetal CNS or whether CMV could also infect terminally differentiated neural cells of
adult origin was not known. Although individual cases of CMV encephalitis have been described in
patients who were immunocompromised but not infected with human immunodeficiency virus (HIV), such
cases are still the exception rather than the rule. For example, CMV encephalitis was described in a renal
transplant recipient treated with augmented immunosuppression for graft rejection (11) and in a patient
with Hodgkin disease who became demented and died of pneumonia (12). The acquired
immunodeficiency syndrome (AIDS) epidemic changed this perspective; CMV infection was found so
often at autopsy before the advent of highly active antiretroviral therapy (HAART) that it was the most
common opportunistic infection of the CNS in patients with AIDS (13). Both CMV infection and disease,
including of the CNS, have decreased dramatically in countries where HAART is readily available. This
clinical benefit is consistent with the possibility that CMV infection of the CNS was a major and often
unrecognized contributor to CNS disease. However, the clinical course of patients with AIDS is so
complex that it is not certain how much CNS disease could be attributed to the presence of CMV as
opposed to HIV, which is also neurotropic and controlled by HAART. Interestingly, CMV encephalopathy
can predominate as the cause of death in a child who acquires both CMV and HIV from its mother (14).
The aim of this chapter is to review what is known and how much remains to be defined about CMV
infection of the CNS.
INFECTIOUS AGENT
CMV has the largest genome (229 kb) of the viruses known to infect humans. More than 200 potential
open reading frames were identified in strain Ad169 (15), with an additional 22 in wild type strains (16).
Propagation in fibroblasts selects for this and other genetic changes so viruses are now maintained in the
laboratory as bacterial artificial chromosomes with approximately 165 protein-coding genes in wild type
strains (17). In addition, the genome encodes approximately 10 micro-RNAs. Recent results with
ribosome profiling suggest that the genetics of this virus may be even more complex than described so far
(18). Salient features of the molecular biology of the virus are summarized later in this chapter, with a
focus on genes important for immune control or which are the targets of antiviral chemotherapy; for
extensive details, readers are referred elsewhere (19). By international agreement, proteins encoded by
the virus are described according to their map position (20) (Fig. 11.1). For example, gpUL55, the
glycoprotein known as glycoprotein B, originates from the fifty-fifth open reading frame of the unique
long region, while ppUL82 is a tegument phosphoprotein transactivator that maps to the eighty-second
open reading frame of the unique long region.
CMV encodes several transactivators. The major immediate-early region maps to UL122/123.
Alternative splicing produces four major proteins, one of which interacts directly with TATA-binding
protein and downregulates its own promoter. This region contains upstream enhancers, is a strong
regulatory region, and is a major target of cell-mediated immunity. pUL69 is a transactivator found in the
virion. It synergizes with ppUL82 to activate the major immediate-early promoter. These two proteins
together can thus be thought of as being functionally equivalent to the α-transinducing factor of herpes
simplex virus (HSV).
A total of 11 genes are required for CMV replication (21). These proteins together provide in trans the
functions required to allow replication of the lytic origin of replication (22). Some of the functions are
directly analogous to those required by HSV, for example, DNA polymerase (UL54) and its accessory
protein (UL44), although an equivalent to the origin-binding protein has not been identified.
Structural proteins of the virus include the major capsid protein, UL86, and the minor capsid protein,
UL46. The assemblin gene complex (UL80a) includes a protein important for packaging DNA as well as
a protease. Several phosphoproteins are found in the tegument (UL32, UL83, UL82, UL99). ppUL83,
known as the lower matrix protein, is the major antigen detected in circulating leukocytes (23) and is the
second major target of the cell-mediated immune response (24).
Major envelope proteins exist on the plasma membrane as multimolecular complexes and are major
targets for humoral immune responses. Glycoprotein complex I consists of a homodimer of glycoprotein B
(gB; gp UL55). Glycoprotein complex II consists of gM (gp UL100) and gN (gp UL73). Glycoprotein
complex III consists of gH (gp UL75), gL (gp UL115), and gO (gp UL74) in fibroblasts but gH, gL, and
three proteins (pUL128, pUL130, pUL131A) encoded within the region of the genome which is deleted
upon passage in fibroblasts. This five-member complex of proteins mediates viral entry into epithelial
and endothelial cell lines (25).
CMV encodes a series of genes that interfere with immune recognition of virus-infected cells. The
product of US6 blocks the transporter associated with antigen presentation, which normally takes peptides
from the cytosol into the lumen of the endoplasmic reticulum. US3 binds to human leukocyte antigen
(HLA) heavy chains and retains them in the endoplasmic reticulum. Genes US2 and US11 take HLA
complexes from the endoplasmic reticulum and export them back into the cytosol for degradation in the
proteasome. All of these effects combine to decrease HLA display at the plasma membrane and thus
allow the virus to escape from cytotoxic T cells. However, because HLA molecules also provide non–
antigen-specific signals to natural killer (NK) cells and macrophages, their absence could trigger
destruction of the virus-infected cell via these innate immune effectors. To avoid this, CMV has additional
genes: UL18 to provide a negative signal to macrophages and UL40 to provide a negative signal to NK
cells. In addition, the proteins encoded by UL16, UL141, and UL142 block the recognition of a positive
signal for NK cells. In addition, a viral micro-RNA interferes with recognition of another of these host
defense signals. In combination, the function of these genes allows CMV to persist in the host despite
strong humoral and cell-mediated immune responses.
CMV encodes four sets of proteins that are predicted G protein–coupled receptors (US27 and US28;
UL33; UL78). UL97 is a protein kinase homolog responsible for phosphorylating ganciclovir and
acyclovir (26–28).
EPIDEMIOLOGY
Humans are the only reservoir for CMV (29). Infection is endemic worldwide and has no seasonal
variation. The prevalence of CMV infection increases directly with age, with significant variations
according to geographic, ethnic, and socioeconomic backgrounds. Antibodies of immunoglobulin G (IgG)
class against CMV can be found in approximately 60% of adults in developed countries, and virtually
100% of adults in developing countries (30). Within developed countries, acquisition of CMV infection is
increased in poor socioeconomic environments and by sexual contact. The presence of IgG antibodies
indicates that infection has occurred sometime in the past and that the virus should be presumed to be
latent. The sites of latency of CMV are not known, although myeloid dendritic cells are clearly one of
them, with reactivation of virus linked to cellular differentiation (31–33). CMV can be transmitted
iatrogenically by all organ allografts and at autopsy can be found in most tissues of the body. Thus,
whether CMV has a single site of latency or whether silent infection can become established in multiple
tissues is debatable.
Transmission of infection from one individual to another requires direct contact. Sources of virus
include saliva, blood, vaginal secretions, semen, and breast milk (34–36). Salivary excretion of virus,
particularly in association with mouthing of toys, can lead to baby-to-baby transmission in the child care
setting (37–39). Susceptible children can thus acquire CMV in the day care environment and transmit
infection to susceptible family members in the home. Transmission of CMV from an infant to his or her
seronegative mother—as well as from an infant to pregnant caretakers, with subsequent transmission to
the fetus—has been documented (40,41). Overall, in the United States, contact with young children is a
much more important source of CMV for mothers than is sexual exposure (42).
Prospective studies in the United States and Europe have established that pregnancy itself does not
increase the risk of acquiring CMV infection (43–50). Primary CMV infections during pregnancy are
generally asymptomatic (43,45–47,49–51). Among susceptible women, the risk of seroconversion during
pregnancy averages 1.7% (52). In primary CMV infection, an innate barrier prevents in utero
transmission; thus, primary maternal CMV infection leads to transmission in only about 32% of fetuses
(53). Moreover, only 12.7% of infected infants have clinical manifestations at birth (from very mild to
severe), and the risk of subsequent sequelae averages 13.5% (54). Although the rate of transmission of
virus in utero appears lower, the risk of neonatal disease with attendant sequelae appears to be higher
when the mother has acquired CMV infection during the first trimester of pregnancy (55).
Maternal immunity to CMV neither prevents virus reactivation nor controls the systemic spread of virus
that can produce congenital infection (44,48,56–60). Studies that use restriction endonuclease analysis of
viral DNA to examine the genetic relatedness between CMV strains isolated repeatedly from mother and
offspring indicate reactivation of an identical latent virus rather than reinfection with an exogenous one
(61). In other cases, there is evidence for exogenous reinfection with a different strain (62,63). In a highly
seropositive (82% of persons) urban population of low socioeconomic background in Alabama, recurrent
CMV infection produced a 1.6% (13/835 infants) rate of congenital infection, thus indicating that most
intrauterine infections in this population result from this phenomenon (49). In contrast, the infants of
immune middle-class women with a seropositivity rate of 55% had a lower rate of congenital infection
(0.19%, i.e., 10/5,242). This rate is not significantly different from that observed in Great Britain and
Sweden (44,48,57). Overall, the mothers of only 25% of babies born with congenital CMV infection in
the United States had primary infection during pregnancy (64). Although maternal immunity is imperfect,
congenital infections that result from recurrent infection are less likely to produce fetal damage than those
resulting from primary infections (49). However, the larger number of seropositive women in a
community may provide a number of infected neonates equal to those born to seroconverting mothers (65).
During pregnancy and in the immediate postpartum period, CMV can be shed at variable rates from one
or more sites (49). Rates of excretion are higher in younger, nonwhite women from lower socioeconomic
backgrounds. Most women who excrete virus during pregnancy do so as a result of recurrent infections
(reactivation or reinfection) (61). There is little correlation between CMV excretion from the cervix or in
urine during pregnancy and the subsequent birth of a congenitally infected infant (47,50,66), but the
presence of CMV in the maternal genital tract at delivery and in the breast milk after delivery is strongly
associated with intrapartum/postpartum transmission of infection to the infant (34,36). In full-term and
otherwise healthy infants, perinatal infection has little clinical importance except for a small number of
cases of interstitial pneumonia (36,67,68). However, such children are a major source of infection for
other children in the day care environment (69,70) and represent an occupational risk to child care
personnel, particularly women of childbearing age (39,71–73).
If a patient who is CMV IgG-seropositive becomes immunosuppressed, CMV reactivation is common,
being found typically in 50% of transplant recipients at some time after transplantation. The donor organ
can also transmit CMV to seronegative individuals (74) or to seropositive individuals (75), showing that
preexisting immunity to CMV does not provide protection against infection. However, preexisting
immunity does provide moderate protection against CMV replication to high levels and disease (76).
Primary CMV infection can also be acquired from blood transfusion (77).
In patients who are HIV positive, the same principles apply: CMV infection becomes increasingly
common as the immunocompromised state progresses, although formal studies of natural history have not
been performed. However, CMV disease, typically retinitis, clearly is uncommon before the CD4 count
declines to 100 × 106/L. It becomes increasingly common as such patients are followed, with typically
10% of patients developing CMV disease within 2 years of follow-up (78). Retinitis is associated with
CMV encephalitis (79). By itself, it represents approximately 85% of CMV disease in patients with
AIDS, with gastrointestinal tract infection representing approximately 10% and CMV CNS disorders only
1% of total disease. Nevertheless, presentations in the CNS (and peripheral nervous system) are being
increasingly recognized, as described later in this chapter.
ETIOLOGY
In cases of congenital CMV, one can be certain that the CNS disease is attributable to CMV, as no other
infectious agent is present and the syndrome is characteristic. The same is probably true in the case of a
female preterm infant born to an HIV-positive mother who acquired congenital CMV and HIV infection
vertically. At 5 months, the child developed AIDS and died at age 11 months of a rapidly progressive
diffuse encephalopathy. At autopsy, CMV encephalitis was seen, with occasional inclusion bodies, yet
there was no evidence for HIV infection of the brain (14).
However, the same clear-cut picture is not seen in adult patients with AIDS, who typically have
evidence for HIV involvement of the CNS, with or without CMV infection (80). A case definition for
CNS conditions attributable to HIV has been provided (81). However, it is not possible to exclude an
HIV contribution to CNS symptomatology in patients with CMV. Indeed, in vitro there are multiple ways
in which CMV and HIV could interact so that each could enhance the replication of the other; this has
been reviewed by Griffiths (82). CMV infection can also downregulate HIV (83). Other opportunistic
infections of the CNS are usually spatially distinct from CMV, with the exception of HSV type 1 (HSV-1);
superimposed CMV/HSV-1 infection has been described (84,85). Interestingly, superimposed CMV/HSV-
1 infection of the brain has also been described in a patient who does not have AIDS (86).
Cases have been described in which CMV appears to be the cause of CNS dysfunction (87–89). Until
more is known about the pathogenesis of CMV infection of the CNS, however, it is not possible to
guarantee that CMV infection is the sole cause of the CNS dysfunction in an individual patient.
Nevertheless, populations of patients with AIDS can be examined to discern patterns of clinical
syndromes, with the strong presumption that CMV is a candidate etiologic agent.
Animal experiments are not particularly helpful, because human CMV is strongly species specific and
replicates only in humans. Animal CMVs, such as murine or guinea pig CMV, can be studied; although
they are different viruses, they do have the advantage of occupying the same ecologic niche in their
species as human CMV does for humans. For example, studies of the direct intracerebral inoculation of
murine CMV into mice of different ages show that the virus has a predilection to infect developing brain
cells (90).
PATHOGENESIS
Results of preliminary studies indicate that the virulence of congenital CMV infection is not strain
dependent (61). Although only a few infants have been studied, viruses isolated from congenitally or
perinatally infected siblings were genetically identical. In two of the pairs of siblings assessed, the first-
born baby was severely affected, whereas the second-born infant was only subclinically infected (60).
Mechanisms that possibly explain some of the CNS damage associated with CMV infection include
productive CMV replication leading to destruction of individual cells (lytic infection) and indirect
damage mediated by action of components of the immune system (immunopathology).
Lytic Infections
Continuous viral replication in affected organs could explain why some infants are severely affected and
others remain free of symptoms. Longitudinal studies have demonstrated that excretion of CMV into urine
and saliva persists for years. Chronic viral replication probably also occurs at other anatomic sites that
are less accessible to virologic examinations (e.g., middle ear, brain).
The histopathologic hallmark of CMV CNS infection is the characteristic intranuclear inclusion body
(Fig. 11.2). This indicates productive infection of the cell and represents a major site of virus formation.
Such cells are likely committed to die, so CNS dysfunction could result from loss of their function.
Inclusion-bearing cells were seen in six fetuses with polymerase chain reaction (PCR)–positive amniotic
fluids that were terminated at 19 to 35 weeks because of CNS lesions seen on ultrasound examinations
(91). Meningoencephalomyelitis and micronodular encephalitis were seen in all, consistent with
bloodborne dissemination of virus. Diffuse periventricular microglial nodules were present. Inclusions
were seen in the stria vascularis, Reissner membrane, and the organ of Corti as well as in epithelial cells
of the saccule and utricule. The authors suggested that CMV may gain access to the inner ear via the highly
vascularized stria vascularis and damage the ability of this structure to maintain potassium homeostasis,
dissipate electric potentials, and support recirculation of potassium within the perilymph.
Immunopathology
Studies of CMV polypeptides immunoprecipitated by IgG antibodies indicate that symptomatically
infected infants had a delay (until 12 months of age) in the appearance of precipitating antibodies (92).
However, when a humoral immune response develops, antibodies to viral polypeptides are precipitated
in greater numbers and are maintained for longer periods. This sustained humoral immune response to
congenital CMV infection occurs in the presence of persistent viral replication, thereby creating the
potential for the formation of immune complexes (93). During the first year of life, immune complexes
circulate in a large proportion of infants with congenital infection. The molecular weight of these immune
complexes is higher in symptomatic infants than in asymptomatic infants. In a few fatal symptomatic cases,
deposition of immune complexes in renal glomeruli has been demonstrated. Another factor in disease
pathogenesis is vasculitis, which may occur in utero or after birth. Infants with congenital CMV infection
who die soon after birth usually have disseminated intravascular coagulopathy.
CMV pneumonitis in transplant recipients may be immunopathologically mediated (94). Thus, the
presence of the virus is required for the syndrome, but the clinical disease may be caused by an abnormal,
enhanced, cell-mediated immune response. Immunopathology presumably also explains the immune
recovery vitreitis, which follows successful treatment of CMV retinitis in patients with AIDS. Similarly,
it has been suggested that the demyelinating component of the disease in the peripheral nervous system
could be immunopathologically mediated (95). It is unlikely that an identical scenario pertains in the CNS
of patients with AIDS, because neurologic symptoms usually occur at profoundly low CD4 cell counts.
However, there are distinct possibilities that host cytokines, released as a result of CMV infection,
stimulated by CMV, or even encoded by CMV, could mediate extensive neural damage. For example,
CMV activates tumor necrosis factor-α and interleukin-6 (IL-6), both of which may induce HIV
expression in macrophages (96). CMV replication is also enhanced by IL-8. CMV infection induces
production of messenger RNA (mRNA) of the IL-8 receptor, while IL-8 increases CMV replication
approximately fourfold (97). pUS28 has 33% amino acid homology with the IL-8 receptor (97). Because
IL-8 stimulates production of polymorphonuclear leukocytes, this is a plausible explanation for the
increased level of polymorphonuclear leukocytes seen in the CNS in association with CMV, particularly
polyradiculopathy. The CMV genome encodes an α-chemokine (UL146) and an IL-10 homolog (UL111A)
whose function remains undefined in vivo.
PATHOLOGY
CMV reaches the brain through viremic spread. In patients with AIDS, viremia has been reported to have
both a cellular and a plasma component (98). In healthy individuals, CMV can be found by PCR in
monocytes (31). In transplant recipients, ppUL83 (pp65) antigen has been demonstrated in monocytes,
polymorphonuclear cells, or endothelial cells (23). Which, if any, of these cells are important for
disseminating CMV to the brain of patients with AIDS is not clear, but there is evidence that microglia are
derived from the peripheral blood monocyte pool (99,100). Regardless, there is evidence that CMV can
spread through the brain by two routes.
The first route involves infection of the endothelial cells of the brain, with spread to the contiguous
astrocytes in foot processes and their cognate neurons. This route of inoculation is mirrored by the
following histologic findings: (a) infection of endothelial cells in the brain, which may sometimes be
associated with vascular thrombosis. Isolated endothelial cells containing inclusion bodies may also be
seen in the spinal cord in association with a myelitis; (b) multiple foci of glial nodular encephalitis. The
glial nodules consist of multiple microglial cells and some astrocytes. In some cases, the microglial
response surrounds an inclusion-bearing cell. Other inclusion body cells may be missed in the plane of
section. In the series by Vinters et al. (85), CMV could not be found in every case of microglial nodular
encephalitis identified. Infected cells can likely be targets for microglial attack before reaching the stage
of bearing an inclusion body, because staining with monoclonal antibodies or the use of in situ
hybridization reveals many more cells to be CMV infected (101,102).
The second route of viremic spread is through the cerebrospinal fluid (CSF) following viral replication
in infected epithelial cells of the choroid plexus (Fig. 11.3). Secondary seeding of the ependymal surfaces
and internal spread produce necroses of periventricular white matter (102). This condition, necrotizing
ventricular encephalitis, may be extensive. Ependymal surfaces are replaced with CMV-infected cells,
infiltrating macrophages, inflammatory exudate, and necrotic cells with or without hemorrhage (85,101).
The histologic changes may be classified into one of five major groups: (a) nodular encephalitis, in
which widely disseminated microglial nodules, only a minority of which may contain inclusion-bearing
cells (Fig. 11.4), are seen disseminated over a wide area (103); (b) isolated inclusion-bearing cells,
which may be astrocytes (Fig. 11.5), neurons, or macrophages (104); (c) focal parenchymal necroses in
an otherwise normal neuropil, whose lesions are characterized by accumulations of macrophages with
axonal destruction and occasional inclusion-bearing cells (105); (d) ventricular encephalitis,
characterized by inflammation and necrosis involving the ependyma and subependymal glia (Fig. 11.6),
often over a wide area of the ventricular lining (106); and (e) radiculomyelitis, in which inflammatory
changes, often with a marked infiltrate of polymorphonuclear neutrophils, are seen involving the cord
(Fig. 11.7), spinal roots, and dorsal root ganglia. To some extent, the histologic changes mirror the portal
of entry of the virus into the CNS and its dissemination throughout the brain and spinal cord, as discussed
earlier.
The incidence of such findings in seven separate AIDS autopsy series is shown in Table 11.1. The
proportion of patients in whom CMV infection of the CNS was documented varied from 7.9% to 28%. In
total, 161 (15.7%) of 1,026 patients in these studies had CMV involvement of the CNS.
An increasing number of viruses are being described that produce similar clinical and pathologic
changes in patients with AIDS (107). Indeed, the clinical and pathologic features may reflect more the
route of infection and the state of the immune system than the nature of the virus.
Clinical Presentation of Congenital Infection
Symptomatic Infection
Disease in the symptomatic newborn is characterized by hepatomegaly, splenomegaly, microcephaly,
direct hyperbilirubinemia, petechiae, and thrombocytopenia (108). Intracranial calcifications and retinitis
are demonstrable with regularity. Intrauterine growth retardation is often present. Diabetes insipidus has
been reported in a few infants with congenital infection (109).
The mortality among congenitally infected infants may be attributed to hepatic dysfunction, bleeding, or
secondary bacterial infection (Table 11.2). Death after the first month of life is usually the consequence of
hepatic dysfunction; however, beyond the first year of life, death is usually the result of complications in
the neurologically handicapped child secondary to malnutrition, aspiration pneumonia, or overwhelming
infection.
The CNS defects in these children of microcephaly and intracranial calcifications are particularly
striking. The CNS lesions of two children with intracranial calcifications evaluated by computed
tomographic (CT) and magnetic resonance imaging (MRI) scans are shown in Figure 11.8. If
calcifications are present on neurodiagnostic evaluation, long-term neurologic impairment is unequivocal.
Children with head circumferences less than the fifth percentile at birth may subsequently establish a
normal brain growth pattern (110). Ocular and hearing defects are common in children with symptomatic
congenital CMV infection. The principal abnormality of the eye associated with congenital CMV infection
is retinitis, with optic atrophy being relatively uncommon (110). Retinitis in the newborn with CMV
infection will usually resolve spontaneously over the first several months of life, leaving residual,
characteristic pigmented scars. From a systematic review of the literature (54), 50% of the survivors
develop late-appearing complications, such as hearing loss, mental retardation, delay in psychomotor
development, chorioretinitis, optic atrophy, seizures, expressive language delays, learning disabilities,
and defects of dentition (48,56,108,110–115).
Of the 87.3% of infants with no clinical manifestations at birth, an average of 13.5% is at risk for the
development of similar abnormalities (54). The single most important late-appearing sequela is
sensorineural hearing loss (5% to 10% of cases), which is bilateral in nearly half of the cases and
substantial enough to interfere with learning and verbal communication. The hearing impairment may
become progressive only after the first year of life.
Sensorineural deafness is probably the most common handicap caused by congenital CMV infection, as
first identified by Medearis (114). CMV can replicate in the inner ear, as evidenced either by the
cytopathology of Reissner membrane, stria vascularis, or semicircular canals or by the presence of
disease in the organ of Corti. Hearing impairment in the child with symptomatic congenital CMV infection
can be progressive; it often becomes significant in infancy and early childhood but has been documented
to occur in some patients between 4 and 14 years of age (116). Congenital CMV is second only to genetic
defects in connexin proteins as a known cause of sensorineural hearing loss (117).
Late-onset appearance of CMV retinitis has also been documented, although previously, CMV retinitis
in the congenitally infected infant was not thought to relapse (118).
As techniques for neuroimaging improve, (119) isolated lesions may be identified by cranial ultrasound
or MRI which were not part of the original case definitions of “symptomatic” CMV infection given
earlier. A current example is lenticulostriated vasculopathy, which some investigators consider a high risk
of future sensorineural hearing loss. There is a need for an internationally agreed case definition which
takes account of changes in diagnostic practice.
Factors That Influence Disease
The type of maternal infection—that is, primary or recurrent—has a direct impact on neurologic sequelae
(Table 11.3). Any neurologic impairment occurred in 25% of children of mothers with primary infection,
as compared to 8% among offspring of women with recurrent disease. Importantly, the time to
documentation of neurologic impairment was also influenced by type of infection (120), as shown in
Figure 11.9. Among women with primary infections, those occurring in the first trimester had a greater
association with both the incidence and severity of sensorineural hearing loss and CNS sequelae (55).
However, damage was observed at all gestational ages, so the timing of maternal infection cannot explain
all of the variability seen in clinical practice.
The quantity of CSF protein is a predictor of neurologic outcome (121). Protein concentrations more
than 120 mg/dL were more commonly associated with microcephaly, abnormal hearing, and multiple
neurologic sequelae (121). Microcephaly and an abnormality detected in the neonate by CT predict future
mental retardation and motor disability (122).
Asymptomatic Infection
Most newborns with congenital CMV infection will have no symptomatology but are still at risk for
neurologic and sensorineural impairment, which usually become apparent within the first 2 years of life
(118,123–127). These observations underscore the necessity for early diagnosis and intervention in CMV
infection.
Long-Term Follow-Up and Economic Impact
Long-term follow-up is mandatory in children with congenital CMV infection because of late-onset
hearing and ocular disease. The economic significance of this disease cannot be underestimated, as
reflected by a recent report from the Institute of Medicine (128), which estimates that the present value of
the annualized health care costs of caring for individuals damaged by CMV is $4 billion (mostly driven
by congenital CMV).
Patients with Acquired Immunodeficiency Syndrome

With the exception of polyradiculopathy, CMV infection of the CNS produces no unique clinical features.
Diagnosis is often made at postmortem. Cell culture techniques were used to test for CMV in brain tissue
from 47 patients with AIDS (13). A clinicopathologic association was seen between the detection of
CMV in the CNS and an antemortem diagnosis of undiagnosed encephalopathy, consistent with, but not
proof of, an etiologic role for CMV.
Encephalitis
CMV may cause encephalitis that is clinically indistinguishable from HIV dementia and is often not
diagnosed until autopsy (129). When 14 autopsy-confirmed cases were compared with 17 controls with
HIV dementia, the median survival of the cases was shorter and they were more likely to have CMV
disease outside the CNS (129). Typically, patients have a subacute or chronic course, with cortical
dysfunction leading to confusion, lethargy, disorientation, and perhaps seizures. Brainstem lesions, if
present, may produce focal signs.
In six patients with necrotizing ventricular encephalitis, chart review revealed distinctive clinical
associations with cranial nerve defects, nystagmus, and progressive ventriculomegaly detected by serial
CT scans (130). This form of CMV encephalitis is rapidly fatal.
Polyradiculopathy
Patients present with a subacute onset of leg weakness and numbness, leading to flaccid paraparesis.
There may be preceding pain and paresthesias in the legs and perineum, and areflexia with or without
bladder dysfunction (131–133). CMV retinitis is also frequently found (131). A distinctive CSF feature is
the florid polymorphonuclear pleocytosis and low glucose concentration.
Stem Cell Transplant Patients
Encephalitis caused by CMV is emerging as a late complication in patients with severe and protracted T-
cell immunocompromise due to receipt of cord blood donation, T-cell depletion, and/or antithymocyte
globulin (134). These patients have an extensive history of treatment of recurrent episodes of CMV
viremia and often have strains of virus resistant to ganciclovir and/or foscarnet before encephalitis
develops. The mortality is high.
Rasmussen Syndrome
There is some evidence that Rasmussen syndrome, with onset in childhood following an infectious illness
and characterized by seizures and a progressive, unilateral cerebral atrophy and neurologic deficits, may
in some cases be associated with CMV infection (135,136). However, detection of latent viral infection
remains a possibility, and other investigators have not been able to confirm a pathogenic role for CMV
(137,138). An uncontrolled case series of four cases reported benefit after treatment with ganciclovir
(139).
Peripheral Nervous System Syndromes
For completeness, distinctive clinical syndromes of the peripheral nervous system that have been
associated with CMV infection are described in the following sections.
Distal Symmetric Peripheral Neuropathy

Often termed painful peripheral neuropathy, distal symmetric peripheral neuropathy has a subacute
presentation, with pain in the feet and clinical evidence of axonal atrophy (140). Some of the early
syndromes of the peripheral nervous system may be the result of abnormal immune reaction.
Mononeuritis Multiplex
Patients with mononeuritis multiplex may present with sensory and motor involvement of peripheral or
cranial nerves. Histologically, multiple peripheral nerves are involved in an inflammatory process in
which infiltrating polymorphonuclear leukocytes and necrotizing vasculitis are seen (141).
DIAGNOSIS
The differential diagnosis of the clinical syndromes caused by CMV is complex and discussed elsewhere
(140,142). Electromyography, nerve conduction studies, sural nerve biopsies, and MRI are frequently
employed.
Evaluation of urine or saliva specimens from a child with suspected congenital infection should lead to
prompt detection of CMV. Classically, this was done by cell culture but is usually performed nowadays
by PCR, which has equivalent sensitivity and specificity (143). Repeat samples of urine and saliva should
then be tested to confirm the diagnosis, because a positive saliva test can occasionally represent infected
breast milk imbibed by the baby rather than true congenital infection. A blood sample should also be
tested by PCR to detect viremia which has a moderate association with the risk of developing subsequent
sensorineural hearing loss (144).
Diagnosis of CMV CNS infection is best made by PCR. Several investigators have reported that PCR
is a method of high sensitivity and specificity for detecting CNS involvement (145–147). One exception
to this is CSF samples collected at autopsy, of which 70% were found to be PCR positive for CMV with
no clear correlation with histologic findings (148). This indicates that CSF samples must be collected
during life.
Cytospin preparations of CSF from 25 patients with AIDS have been studied and stained with
monoclonal antibodies against pUL83 (pp65). Ten CSF samples were positive for CMV with this
technique, and it was reported that the polymorphonuclear leukocytes were hypersegmented, whether or
not they stained with the monoclonal antibody (149). The same technique has also been shown to detect
CMV in 13 cases of painful peripheral neuropathy, although these cells are also found in cases of CMV
retinitis (150).
Conventional cell culture for the propagation of CMV is far too insensitive to detect the small amounts
of CMV that are found in the CSF, so this test is not recommended. Serology, either of IgG or IgM
antibodies, has no diagnostic value in the investigation of these patients.
TREATMENT
Individual neonates with CMV disease have been given ganciclovir, and inhibition of CMV has been
reported. However, ganciclovir has important potential toxicities in the neonate, including neutropenia.
The drug is also carcinogenic in animals and has a cytostatic effect on the testes. It requires intravenous
administration, which may also produce significant morbidity. To begin to study the potential safety and
toxicity of ganciclovir in neonates, Whitley et al. (151) conducted a randomized trial comparing two
doses of ganciclovir (4 mg/kg or 6 mg/kg given intravenously twice daily for 6 weeks). The higher dose
was tolerated as well as the lower dose, and so was taken forward into a randomized trial of efficacy
(152). The primary end point was the proportion of children at 6 months with improved brainstem evoked
potentials (or normal results if the baseline test result was normal). This primary end point was met in
69% of children given ganciclovir compared with 39% allocated to no treatment. In addition, the
proportion of children in whom hearing worsened was 0% in the ganciclovir arm and 42% in the no-
treatment arm. Follow-up shows that these significant changes are still present at 12 months of age. The
neurologic development of these children was worse in those not given ganciclovir (153). This benefit is
so important clinically that a 6-week course of ganciclovir should now be considered to be the standard
of care for any child born with symptomatic congenital CMV infection who would have met the entry
criteria for the trial described by Kimberlin et al. (152). The same investigators showed that the prodrug
valganciclovir could be given to newborns (154). They are conducting a randomized controlled trial
comparing 6 weeks versus 6 months of valganciclovir given to symptomatic neonates with congenital
CMV infection, and the results are awaited with interest (http://www .clinical
trials.gov/show/NCT00466817).
Three drugs are used for the systemic treatment of CMV disease: ganciclovir, foscarnet, and cidofovir.
Based on assessment of CSF levels, ganciclovir and foscarnet do not penetrate the CNS well, with
estimates from animal experiments and small studies in humans indicating that the CSF level is about one
third that found in plasma (155,156). Rather more patients have been tested for foscarnet, whose CSF
penetration appears to be between one third and one half of plasma levels in most patients (157,158). In
addition to this pharmacologic disadvantage, all drugs have toxicities, discussed in the following
paragraphs. There are no reported double-blinded, placebo-controlled trials of anti-CMV therapy in
patients with AIDS with CMV involvement of the CNS.
A case series examined the survival of two groups of AIDS patients presenting with first-episode
retinitis who had all been treated with an intraocular device that released ganciclovir. Some of the
patients were given systemic ganciclovir treatment in addition and had reduced mortality (159).
Five patients with CMV retinitis treated with maintenance levels of ganciclovir have been described in
whom abrupt preterminal changes in mental status occurred. At autopsy, fulminant CMV encephalitis was
found in all five, with prominent ependymal and periventricular necrosis (160). These cases demonstrate
that prophylaxis with ganciclovir, in the doses used for maintenance of CMV retinitis, cannot guarantee
protection against CMV encephalitis. Furthermore, one patient has been described who developed
polyradiculopathy attributed to a ganciclovir-resistant strain of CMV after receiving maintenance therapy
for 8 months following a diagnosis of CMV retinitis (161). Mathematical models of the replication
dynamics of CMV in vivo predicted that resistance should be more common than was recognized
clinically or by the use of cell cultures for detecting CMV (162). This prediction has been borne out by
clinical cohort studies reporting that 15% to 22% of transplant recipients or patients with AIDS given
long-term oral ganciclovir therapy develop CMV disease due to resistant strains (163–165).
Most patients given ganciclovir for polyradiculopathy do not have clinical improvement
(135,166,167). Some, however, appear to respond (132,135,168). Some authorities use a combination of
ganciclovir plus foscarnet (each at full dose) but again with disappointing results (169). There is no
evidence for synergy between ganciclovir and foscarnet in vivo, although these drugs can be used in
combination (each at half the normal dosage) to reduce the incidence of side effects (170).
The complications of ganciclovir include neutropenia and thrombocytopenia. The drug is poorly
bioavailable and is usually given by the intravenous route. Trials of high-dose oral ganciclovir showed
that maintenance doses can be provided orally (171). This had the advantage of freeing the patient from
daily intravenous administrations, with the associated risk of intravenous lines, but it did not overcome
the problem of subtherapeutic doses at the target organ, which facilitates the emergence of resistant strains
of CMV. More recently, the valine ester prodrug, valganciclovir, has been licensed, which provides the
same area under the time–concentration ganciclovir curve as does intravenous ganciclovir (172). It
should provide a more convenient and safer means of treating CMV, especially because intravenous lines
may predispose to bacteremias with a drug that causes neutropenia, and should reduce the incidence of
resistance.
Foscarnet is nephrotoxic and alters plasma levels of electrolytes, particularly ionized calcium, which
may precipitate seizures. The drug also causes a fixed drug eruption on genital skin. Although the
incidence of nephrotoxicity can be reduced significantly by adequate hydration, this drug remains second-
line therapy for the treatment of CMV disease. This is despite the fact that a randomized comparison of
ganciclovir and foscarnet for the treatment and maintenance of CMV retinitis in HIV-infected individuals
showed the drugs to be equipotent for treating retinitis but that foscarnet had a significant survival benefit
over ganciclovir (173). There are several possible explanations for this finding including the potential
efficacy of foscarnet in treating HIV itself (174).
Cidofovir is nephrotoxic and must not be administered if renal function is abnormal or if proteinuria is
present. The nephrotoxicity can be reduced by prehydration and administration of probenecid.
A lipid prodrug of cidofovir (CMX001) is currently undergoing clinical trial (175).
Maribavir is a drug that directly inhibits CMV UL97. There was evidence of antiviral activity in a
phase 2 study of bone marrow transplant patients where the need for preemptive therapy was the primary
end point (176). However, there was no significant benefit when the lowest dose was compared to
placebo in a phase 3 study of bone marrow transplant patients managed by preemptive therapy but where
the end point was CMV disease (177).
AiCuris 246 (Letermovir) inhibits the terminase enzyme complex of CMV (responsible for packaging
unit length DNA into virions) and is currently in clinical trial in transplant patients (178).
PREVENTION
Improved control of CMV disease of the CNS would be expected if infection could be detected at an
early stage and treatment instituted promptly. However, in the absence of natural history studies, it is not
possible to design such trials rationally. In my opinion, such trials should be organized so that intervention
studies, preferably prophylaxis of infection, can be designed. Such studies should also include
quantitative measures of CMV load to determine whether a threshold value exists above which CMV
disease becomes more likely, as has been reported for renal, liver, and marrow transplant recipients
(179–181). In transplant recipients, preemptive therapy is given when CMV viremia is detected by PCR
or antigenemia (182,183), although its relative merits compared with prophylaxis are debated (184). A
trial of preemptive therapy in patients with AIDS (ACTG protocol 5030) failed to recruit sufficient cases
because HAART became available (185).
Controlled trials of antiviral chemotherapy for the prophylaxis of CMV disease in individuals infected
with HIV have been attempted. Oral ganciclovir has been reported to reduce the rate of CMV retinitis,
whereas oral acyclovir in high doses had no effect on CMV retinitis (186,187) despite its significant
effect in preventing CMV pneumonitis in bone marrow transplant recipients (188,189). Oral valacyclovir
significantly reduced CMV disease in patients with AIDS, although the dose chosen was poorly tolerated
(190).
Because CMV disease of the CNS often occurs in patients with CMV retinitis, routine ophthalmoscopy
to detect early cases of retinitis may be helpful (although this remains to be proved), whereas treatment
modalities for CMV disease outside the CNS should include consideration of controlling CMV CNS
disease. For example, intraocular ganciclovir implants suppress CMV retinitis, but these would not be
expected to have any effect on systemic CMV infection, including dissemination to the brain. Indeed, a
randomized trial showed that addition of oral ganciclovir to an intraocular implant significantly reduced
the incidence of CMV retinitis in the contralateral eye (191).
Experimental work to produce CMV vaccines is under way. Glycoprotein B absorbs much of the
neutralizing antibody from sera and is a promising target for a prototype CMV vaccine (192–194). A
phase 2 randomized, placebo-controlled study of recombinant soluble glycoprotein B plus MF59 adjuvant
in seronegative women reported significant protection against acquiring primary CMV infection (195).
The same vaccine and adjuvant reduced the viral load parameters after transplant of a kidney or a liver
when patients were immunized while on the waiting list for transplantation (196). This finding is
consistent with that described previously for the live attenuated Towne strain of CMV, which reduced the
severity of CMV disease in those originally seronegative (197). In addition, seropositive transplant
candidates were randomized to receive the same vaccine and adjuvant or placebo with evidence of
boosted antibody levels and improved control of viral load parameters (196). Likewise, glycoprotein B
plus MF59 adjuvant given to seropositive women boosted their neutralizing antibody levels and gB
specific CD4 T cells (198).
Because virtually all patients with AIDS are CMV seropositive, such an immunotherapeutic use of
vaccine could be considered for placebo-controlled trials in individuals with relatively high CD4 cell
counts, with the objective of delaying the onset of CMV disease. Finally, work is under way to devise
techniques for adoptive transfer of immunocommitted T cells, as has been described in bone marrow
transplant recipients (199).
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CHAPTER 12 EPSTEIN-BARR VIRUS
SUSAN E. HOOVER, JEFFREY P. ROSS, AND JEFFREY I. COHEN
ETIOLOGY
Epstein-Barr virus (EBV) is a member of the herpesvirus family (1) and, like other herpesviruses,
contains a double-stranded DNA core surrounded by a nucleocapsid. A tegument layer containing several
proteins envelops the nucleocapsid, which is surrounded by an outer lipid envelope studded with viral
glycoprotein spikes.
EBV infects B lymphocytes and epithelial cells in the oropharynx (2). Infection of epithelial cells
results in lytic infection with production of virions, lysis of the cell, and release of infectious virus.
During virus replication, multiple EBV proteins are expressed including the EBV early antigens (EAs),
DNA polymerase (the target of acyclovir), viral capsid antigen (VCA), and viral glycoproteins. Infection
of B lymphocytes usually results in latent infection and immortalization of the cells in vitro, without
production of infectious virus. These latently infected cells express only the EBV-encoded RNAs (EBER-
1 and EBER-2), nuclear proteins (EBNA-1, -2, -3A, -3B, -3C, and LP), and latent membrane proteins
(LMP-1, -2A, and -2B).
EBV has a worldwide distribution, and the vast majority of adults show serologic evidence of past
infection. Primary EBV infection is usually asymptomatic or mildly symptomatic in early childhood; in
contrast, symptomatic infectious mononucleosis is more common in individuals who become infected
with EBV after the first decade of life. Transmission of EBV probably occurs most often by exposure to
saliva from asymptomatic individuals who shed the virus. Serologic studies suggest that EBV is
commonly spread among susceptible siblings within a family. EBV-associated infectious mononucleosis
has been transmitted by blood transfusion.
The incubation period for symptomatic infectious mononucleosis is 30 to 50 days. During the first few
weeks of the illness, peripheral lymphocytosis occurs, with a marked increase in T cells and natural killer
cells; many of these cells appear as “atypical lymphocytes” on the peripheral blood smear. Most of the
clinical features associated with infectious mononucleosis are manifestations of the vigorous cellular
immune responses to EBV infection rather than to direct cytotoxic effects of the virus. B cells are also
increased in number, and up to 20% may express EBV nuclear antigen during the first week of illness.
DIFFERENTIAL DIAGNOSIS
Other infectious or noninfectious diseases can produce the syndrome of infectious mononucleosis. Acute
infection with cytomegalovirus (CMV), Toxoplasma gondii, human immunodeficiency virus type 1 (HIV-
1), human herpesvirus type 6, or hepatitis viruses can result in fever, lymphadenopathy, sore throat, and
atypical lymphocytes. Acute leukemia, lymphoma, and reactions to certain drugs (e.g., phenytoin and
sulfonamides) can also produce a syndrome resembling infectious mononucleosis.
Other herpesviruses also produce neurologic symptoms similar to EBV. Infection with varicella-zoster
virus also can result in encephalitis, myelitis, or neuropathy in nonimmunocompromised persons.
Although encephalitis or radiculoneuropathy can occur in patients with CMV infection, these patients are
usually immunocompromised, and the disease is progressive. Encephalitis due to herpes simplex virus
(HSV) is usually localized to the temporal lobes.
Infectious Mononucleosis
EBV-associated infectious mononucleosis is an acute illness characterized by fever, pharyngitis,
lymphadenopathy, and mononuclear leukocytosis with atypical lymphocytes (3). Symptoms of infectious
mononucleosis commonly include sore throat, headache, and malaise in more than 50% of patients, and
myalgias, anorexia, nausea, and abdominal discomfort in 10% to 20% of individuals. Physical
examination shows lymphadenopathy, pharyngitis, and splenomegaly in most patients, whereas 10% have
hepatomegaly, jaundice, palatal enanthem, or rash. Posterior cervical lymphadenopathy is most often
noted; however, any group of lymph nodes may be involved. A pruritic maculopapular eruption develops
in nearly all patients after the administration of ampicillin. Important complications of infectious
mononucleosis include splenic rupture, autoimmune hemolytic anemia, thrombocytopenia, hepatitis,
myocarditis, airway obstruction from enlarged tonsils, and neurologic abnormalities. Neurologic
complications are cited as the leading cause of death resulting from infectious mononucleosis, followed
by secondary infection and splenic rupture. Fatalities occur in fewer than 0.03% of cases of infectious
mononucleosis.
Rare individuals infected with EBV develop a chronic active infection, persisting >6 months and
characterized by persistent adenopathy and hepatosplenomegaly and involvement of the lungs, eyes, or
nervous system with EBV-infected lymphocytes. EBV infection of patients with the X-linked
lymphoproliferative disorder results in a fatal disease characterized by lymphoid infiltration of organs,
lymphomas, and opportunistic infections. Immunocompromised patients may develop EBV-associated
lymphomas.
Neurologic Complications of Acute Epstein-Barr Virus Infection
Involvement of the nervous system in infectious mononucleosis is more common than generally
appreciated. About 50% of patients have headache on presentation. Neck stiffness without meningitis is a
common finding. In one study, about 25% of patients (43 of 162) had more than five cells per cubic
millimeter in the cerebrospinal fluid (CSF) (4). Many of these patients had no symptoms of meningitis.
Abnormal electroencephalograms (EEGs), which most often reveal diffuse slowing patterns, have also
been reported in patients with infectious mononucleosis, but without clinically significant central nervous
system (CNS) disease (4).
Significant neurologic complications of acute infectious mononucleosis are rare, occurring in fewer
than 0.5% of more than 4,300 cases of infectious mononucleosis in one review (5). Neurologic
complications, however, are an important cause of morbidity in infectious mononucleosis and have been
reported in 6% to 7% of patients hospitalized with infectious mononucleosis (6,7,7a). A study of children
admitted to the hospital with new neurologic symptoms found acute EBV infections in 4% of patients and
reactivated infections in 17% of patients (8).
CNS symptoms may occur shortly before, during, or after infectious mononucleosis or following acute
EBV infection in the absence of symptomatic infectious mononucleosis. Cases of neurologic symptoms
associated with infectious mononucleosis before the 1970s, when EBV-specific serologic tests were
developed, must be regarded with caution because a number of other infectious agents can produce the
clinical syndrome of mononucleosis. Only 1 of 14 cases of neurologic complications associated with
primary EBV infection reported by Grose et al. (9) presented with clinical infectious mononucleosis.
Similarly, only 1 of 21 children with EBV encephalitis identified prospectively at the Hospital for Sick
Children in Toronto had infectious mononucleosis; the others had nonspecific symptoms of fever and
headache (9a).
Examination of biopsy or autopsy specimens suggests that immunologic mechanisms are probably more
important in the pathogenesis of neurologic complications than active viral replication. Perivascular
lymphocytic infiltrates, which may include atypical lymphocytes, are often found in the leptomeninges,
CNS parenchyma, nerve roots, and peripheral nerves (10) (Fig. 12.1). Additional findings include
parenchymal edema and microglial proliferation (11). Inflammatory demyelinating lesions similar to those
found in multiple sclerosis or “postinfectious” encephalomyelitis or neuritis have also been described
(10,12). A report of antineuronal antibodies in the serum of a patient with EBV-associated acute
cerebellar ataxia, but not in patients with other neurologic diseases, provides support for an immune-
mediated mechanism for CNS disease (13).
These studies indicate that the pathogenesis of EBV-associated neurologic disease is different from that
of HSV CNS disease. Although viral proteins are present in the brain of patients with herpes simplex
encephalitis, brain biopsies from patients with EBV encephalitis do not show viral nucleic acids or
proteins (14). Thus, autoimmune mechanisms are probably responsible for the pathogenesis of EBV-
associated CNS disease.
Aseptic Meningitis
Aseptic meningitis is the most common neurologic complication of primary EBV infection. Patients
present with headache, malaise, stiff neck, and occasionally photophobia (15). The CSF usually shows a
mild to moderate lymphocytic pleocytosis, occasionally with atypical lymphocytes. The CSF protein
concentration is normal or mildly elevated, and the glucose concentration is usually normal (15,16).
Although the CSF opening pressure is usually normal or slightly elevated, in some patients, it is markedly
increased, and repeated lumbar puncture provides symptomatic relief (17). Aseptic meningitis associated
with EBV has a good prognosis and usually resolves without CNS sequelae.
Encephalitis
Patients having encephalitis associated with acute EBV infection may present with seizures, coma,
personality changes, distortions of perception, cerebellar ataxia, or focal brainstem or cerebral findings.
These complications usually occur 1 to 3 weeks after the onset of clinical infectious mononucleosis, but
they have occurred shortly before, during, or after other symptoms of infectious mononucleosis
(15,16,17a). Alternatively, they may be the only symptom of acute infection with EBV (6,18,19). Patients
usually present with fever and headache progressing to encephalitis over a few days. Most cases occur in
older children and young adults.
Generalized seizures, as well as coma and other signs of diffuse encephalopathy, may occur without
focal neurologic findings (5,7,15,16). Patients have presented with new onset of seizures and only later
have been found by serology to have recent EBV infection (20). EEGs in patients with diffuse
encephalopathy show generalized slowing with occasional sharp wave activity, but they may reveal
periodic discharges in patients with seizures (20).
Focal neurologic findings in EBV-associated encephalitis include localized seizures, hemiparesis, and
unilateral Babinski reflexes. In a large prospective study of encephalitis by the Collaborative Antiviral
Study Group, in which focal neurologic findings were required for entry, 2% of patients (8 of 432) were
found to have EBV encephalitis (21).
Although EBV encephalitis may involve any area of the brain, the cerebellum is commonly involved.
Numerous cases of cerebellitis, usually manifested as acute cerebellar ataxia, have been reported
(13,21a). Most patients present with abnormalities of gait. A complete recovery is usual, but severe cases
with tonsillar herniation and death have been reported (21b). Other commonly involved areas include the
basal ganglia and cerebral hemispheres, with many patients having involvement of multiple areas
(21c–21e). Several cases of increased intracranial pressure associated with ischemic lesions of the
corpus callosum have been reported, two requiring decompressive craniectomy (17a,21f,22).
Encephalitis resulting from EBV infection has been reported as a cause of acute hemiplegia in children
and young adults (23). Some patients present with a typical history of infectious mononucleosis followed
by psychosis and personality changes. Children with EBV encephalitis may present with metamorphopsia,
the so-called “Alice in Wonderland” syndrome, in which affected individuals have perceptual distortions
of personal body image, size, and spatial relationships (8,18). Movement disorders indicative of
extrapyramidal involvement have been reported. These include cogwheel rigidity and athetosis (24),
Parkinson-like syndrome (25,21d,21e), and Sydenham-type chorea (26). Brainstem encephalitis with
cranial nerve and long-tract signs (27) and the “locked-in” syndrome have been described. Acute
psychosis (28) and transient global amnesia (29) may be the only neurologic manifestation of EBV
infection. Unusual complications of EBV encephalitis include acute aqueductal stenosis (30) and the
syndrome of inappropriate antidiuretic hormone secretion (31). Reye syndrome, acute fatty degeneration
of the liver accompanied by encephalopathy, has followed primary EBV infection in a number of reported
cases (32).
Rare cases of relapsing or chronic encephalitis associated with acute EBV infection have been
reported. Tolly, Wells, and Sty (33) described a 10-year-old girl with waxing and waning neurologic
symptoms associated with EBV infection that occurred over 3 months. Magnetic resonance imaging (MRI)
showed rapidly changing CNS lesions that correlated with the fluctuating neurologic examination results
(Fig. 12.2).
Myelitis
Spinal cord lesions can accompany encephalitis and present as paraplegia, quadriplegia, or other motor
or sensory losses (5,34). The CSF shows a mononuclear pleocytosis with elevated levels of protein, but
the glucose level is often normal. Isolated transverse myelitis with sensory and motor loss in the absence
of encephalopathy has also been reported (6,9), with viral DNA being detected in the CSF (35,36). Most
cases of myelitis occur in older children and young adults and eventually resolve without residua,
although several cases in older adults have resulted in long-term sequelae such as muscle weakness and
sensory deficits (34).
Cranial and Peripheral Neuritis
Although any of the cranial nerves may be affected during EBV infection, palsies of cranial nerve VII are
most common. Numerous cases of unilateral or bilateral Bell palsy have been reported in the setting of
acute infectious mononucleosis (5,6,15). With the advent of specific EBV serologic tests, increased
numbers of cases of Bell palsy have been attributed to otherwise asymptomatic EBV infection (9). Other
forms of cranial nerve involvement include anosmia (37); Fisher syndrome, involving multiple cranial
nerves (38); bilateral sensorineural hearing loss (39); unilateral hearing loss with ipsilateral involvement
of cranial nerves V and VII (40); vestibular neuritis with oscillopsia; hypoglossal (XII) nerve palsy (41);
vocal fold paralysis due to vagal (X) nerve palsy (41); extraocular muscle palsies involving cranial
nerves III (42), IV, or VI (6); and acute optic neuritis (15,43). Other ocular complications include
papilledema, retrobulbar neuritis, chiasmic neuritis, ptosis, uveitis, episcleritis, and opsoclonus (44,45).
Among peripheral nerves that are affected during EBV infection, the brachial plexus and its branches
are most commonly involved. Brachial plexopathy in the setting of infectious mononucleosis usually
presents with shoulder pain followed by paralysis of the serratus anterior for weeks to months (7,46).
Five patients with lumbosacral radicular plexopathy and one patient with femoral neuropathy were
described who had serologic evidence of recent EBV infection (47). Acute autonomic neuropathy has
also been reported with acute EBV infection (48).
Guillain-Barré Syndrome
Guillain-Barré syndrome, or acute inflammatory demyelinating polyneuropathy, is characterized by

progressive motor weakness of more than one limb and areflexia. Guillain-Barré syndrome usually
presents several days to weeks after the onset of infectious mononucleosis, or it may present in patients
with otherwise asymptomatic EBV seroconversion. Grose et al. (9) found evidence of acute EBV
infection in 12 of 24 patients with Guillain-Barré syndrome. None of these patients had symptomatic
infectious mononucleosis before the onset of Guillain-Barré syndrome. Dowling and Cook (49) reported
that 8 of 100 patients with Guillain-Barré syndrome had an immunoglobulin M (IgM)–positive test result
for EBV, indicative of recent infection. A prospective study found evidence of acute EBV infection in only
2 of 99 patients with Guillain-Barré syndrome, with a similar frequency (2%) in age-matched controls
(50). However, the lack of association of Guillain-Barré syndrome with EBV may have been a
consequence of the older age of the patients studied, because most older individuals are already
seropositive for EBV. A case–control study from the Netherlands found evidence of acute EBV infection
in 16 (10%) of 154 patients with Guillain-Barré, compared with 1% of age-matched controls with other
neurologic diseases (51).
Epstein-Barr Virus–Associated Central Nervous System Lymphoma
EBV has been associated with CNS lymphomas in patients without any apparent immunodeficiency or,
more commonly, in patients with underlying immunodeficiencies. Although some studies of
immunologically normal individuals have demonstrated EBV DNA in up to 46% (11/24 patients) of B-
cell CNS lymphomas by in situ hybridization (52), most primary CNS B-cell lymphomas in
nonimmunocompromised persons do not contain EBV genomes.
EBV-associated CNS lymphomas have been reported in patients receiving solid organ or bone marrow
transplants and in patients with leukemia, X-linked lymphoproliferative disease, and acquired
immunodeficiency syndrome (AIDS) (53). From 10% to 25% of lymphomas in patients with heart, heart–
lung, liver, kidney, or bone marrow transplants involve the CNS and contain EBV genomes (54).
EBV has been detected in virtually 100% of CNS lymphomas in patients with AIDS (54–56). Nearly
all EBV-positive lymphomas in human immunodeficiency virus (HIV)–positive patients express the EBV
latency-associated proteins EBNA-2 and LMP-1 (57,58) (Fig. 12.3). Viral DNA is present in the
lymphoma, not in neuronal cells (55). EBV-associated CNS lymphoma in patients with AIDS occurs more
often in patients with very low CD4 cell counts. HIV patients who later developed CNS lymphomas
lacked EBV-specific CD4 T cells (58a). CNS lymphomas are more often monoclonal and lack c-Myc
translocations when compared with systemic (not involving the CNS) lymphomas in patients with AIDS.
Early studies, prior to the era of highly active antiretroviral therapy (HAART), showed that polymerase
chain reaction (PCR) detection of EBV DNA in the CSF was highly predictive for primary CNS
lymphoma in patients with AIDS. Cinque et al. (59) used EBV DNA PCR to test CSF of patients with HIV
and CNS symptoms. They found that PCR for EBV had a sensitivity of 97% (35 patients PCR positive/36
with disease), specificity of 98% (180 patients PCR negative/183 without disease), and a positive
predictive value of 90% for the diagnosis of CNS lymphoma. Antinori et al. (60) showed a sensitivity of
85% and a specificity of 100% for PCR of CSF in their evaluation of patients for CNS lymphoma. In
some patients, EBV was detected in CSF by PCR before CNS lesions were apparent on computed
tomographic (CT) or MRI scanning (59). However, more recent studies in the era of HAART indicate that
PCR alone is less specific for a diagnosis of CNS lymphoma with a positive predictive value of 30% or
less (60a,60b).
The combination of CSF EBV PCR and single-photon emission computed tomography (SPECT)
scanning has shown promise for distinguishing CNS lymphoma from cerebral toxoplasmosis and other
infections (61,62). A SPECT-to-thallium uptake ratio is calculated as the amount of thallium-201 uptake in
the lesion divided by uptake in uninvolved brain or scalp. Using SPECT scanning in HIV-infected patients
with focal brain lesions on CT or MRI, the sensitivity of a positive scan for lymphoma ranged from 86%
to 92%, and the specificity ranged from 83% to 89% (61,62). When both SPECT scanning and CSF EBV
PCR were performed, the sensitivity increased to 100% (61).
Other Neurologic Syndromes Possibly Associated with Epstein-Barr Virus
Epidemiologic data suggest an association between EBV and multiple sclerosis (MS). Eight case–control
studies found that 97% to 100% of patients with MS were seropositive for EBV, whereas only 65% to
95% of age- and sex-matched controls were seropositive (63). Compilation of these studies, involving
about 1,000 patients with MS and a similar number of controls, yielded an odds ratio for MS in EBV-
seropositive persons versus EBV-seronegative persons of 13.5 (95% confidence interval, 6.3–31.4). A
case–control study of 305 persons who developed MS and 610 matched controls found that all 10 of the
EBV-negative persons who subsequently developed MS became EBV positive before MS onset, whereas
only 10 of 28 controls who never developed MS became EBV positive (64). Although a metaanalysis
showed a 2.2-fold relative risk of MS in persons with infectious mononucleosis (65), the vast majority of
patients with MS have no history of infectious mononucleosis (66).
A nested case–control study of stored sera from more than 3 million military personnel found that
serum levels of IgG VCA or EBNA complex were proportionate to the risk of MS with an average time of
4 years between serum collection and diagnosis of MS (67). The relative risk of MS was 20 and 34 in
those with the highest level of EBV VCA and EBNA complex antibodies, respectively, compared with
those with the lowest titers of these antibodies. A follow-up study showed a similar increase in risk with
antibodies to EBV EBNA complex and EBNA-1 antibodies (68). Wandinger et al. (69) reported an
association between EBV reactivation and MS disease activity. In their study of 19 patients with MS
followed monthly for 1 year, patients with clinically documented relapses or progression of MS had more
frequent anti-EBV EA immunoglobulin A (IgA) seroconversion or detectable EBV DNA in the serum
compared with those with stable MS. Several patients have been reported who initially presented with
acute EBV encephalitis and developed new demyelinating CNS lesions over a period of years, resulting
in the diagnosis of MS (12,70). MS patients have increased T-cell responses to EBV EBNA-1 which
cross-react with myelin antigens and result in production of interferon (IFN)-γ (70a). Although one study
reported finding EBV RNA and protein in the brains from patients with MS (71), EBV RNA has generally
not been detected in MS plaques or in CSF from patients with MS, and intrathecal anti-EBV antibody
synthesis did not differ in patients with MS and other controls (72). EBV might be a cofactor for MS, or
EBV infection and MS may share a common genetic predisposition or a common immunologic
abnormality. The true role of the virus in the pathogenesis of MS is unclear. Additional studies are
needed, particularly to look at CSF for EBV DNA or RNA, oligoclonal bands specific for EBV,
intrathecal synthesis of EBV antibody, and EBV-specific T cells in patients with MS and controls.
In the mid-1980s, two small case–control studies reported elevated antibody titers to EBV EA in
patients with the chronic fatigue syndrome (73,74). These patients presented with persistent fatigue,
myalgias, and mild cognitive impairment. Other studies have shown that antibody titers to EBV EA remain
elevated in a substantial number of otherwise healthy individuals. A study of 548 patients attending a
referral clinic found no differences in the seroprevalence or mean titers of antibodies to EBV in patients
with chronic fatigue compared with healthy controls (75). Although some patients have persistent fatigue
lasting several months after acute infectious mononucleosis, at present, there is no evidence for persistent
EBV infection as a cause of the chronic fatigue syndrome.
Several patients have been reported with the new onset of depressive illness following acute infectious
mononucleosis (76). Subsequent case–control studies have yielded conflicting results (77,78). Review of
these studies indicates that EBV does not play a significant role in the pathogenesis of depression. Three
cases have been reported in which fatal subacute sclerosing panencephalitis (SSPE), which is associated
with a measles-like agent, occurred concomitantly with infectious mononucleosis (79). Whether EBV
infection or its associated immune alterations contributed to the development of SSPE in these cases is
not known.
LABORATORY AND IMAGING STUDIES

The humoral immune response to EBV infection involves both viral-specific and nonspecific antibodies
(Table 12.1). Detection of heterophile antibodies at a titer of more than 40, along with symptoms of
infectious mononucleosis and atypical lymphocytes, is diagnostic of acute EBV infection. The titer of
heterophile antibody is defined as the maximum serum dilution after absorption with guinea pig kidney
cells, which can agglutinate sheep, horse, or beef erythrocytes. The commercially available monospot test
is based on the heterophile test. False-positive results may occur in some patients with collagen-vascular
disease, lymphoma, or hepatitis; false-negative results are more common in children younger than 5 years.
Specific antibody responses directed against EBV are more reliable than heterophile antibodies in
making a diagnosis of EBV infection. Detection IgM antibodies to VCA, which are usually present for 1
to 2 months after infection, is particularly useful in the diagnosis of acute EBV infection. Immunoglobulin
G (IgG) antibodies to VCA are less helpful for diagnosis, because they persist for life. EBV EA
antibodies develop later after infection and generally are not useful for diagnosis of acute infection.
Patients with chronic active EBV infection may have elevated VCA IgG or EA antibody titers. Antibodies
to EBNAs are usually detectable 3 to 4 weeks after onset of symptoms of infectious mononucleosis and
persist for life. Seroconversion to anti-EBNA positivity is evidence for recent infection with EBV. Anti-
EBNA antibodies may be absent in immunocompromised patients.
Establishing the diagnosis of an EBV-associated neurologic syndrome relies on an appropriate clinical
neurologic diagnosis in the setting of serologic evidence of acute or rarely chronic active EBV infection
(Table 12.1). Examination of the CSF often reveals a lymphocytic pleocytosis with an elevated protein
level, particularly in EBV encephalitis; atypical lymphocytes, if present, provide a clue to diagnosis. The
CSF in Guillain-Barré syndrome typically contains increased levels of protein without a significant
pleocytosis.
EBV has rarely been cultured from the mononuclear cells obtained from the CSF of patients with
neurologic complications of EBV (80). EBV DNA has been detected by PCR of CSF or neural tissue in
patients with EBV-associated neurologic conditions (14,26,81). Imai et al. (81) studied five children with
EBV-associated neurologic conditions diagnosed by standard EBV serology. EBV DNA, but not other
herpesvirus DNA, was detected by PCR of the CSF from each case. EBV DNA became undetectable by
PCR as patients recovered from their neurologic complications. Weinberg et al. (36) performed
quantitative PCR of the CSF and demonstrated that patients with CNS lymphoma and encephalitis had
high EBV loads (104 EBV copies/mL); patients with encephalitis had higher leukocyte counts than those
with lymphoma. Two patients with myelitis had lower EBV loads (103 EBV copies/mL), but high
leukocyte counts. Reverse transcriptase PCR (RT-PCR) detected EBV lytic cycle messenger RNAs
(mRNAs) in the CSF of several patients with lymphoma or encephalitis.
EBV in the CNS declined in two patients with lymphomas that responded to treatment, and increased in
four patients with progressive disease (60). Because EBV is present in circulating lymphocytes in
asymptomatic seropositive individuals, culture or PCR of cells from the CSF of EBV-seropositive
patients with other causes of CNS inflammation is an important negative control before a causal
association with EBV can be shown. Measurement of EBV DNA is frequently used for diagnosis,
monitoring, and prevention of lymphoproliferative disease after transplant (81a).
Intrathecal production of EBV-specific antibody is considered present when the ratio of the CSF-to-
serum EBV antibody titer is greater than the ratio of the CSF-to-serum γ-globulin concentration.
Production of EBV antibody in the CSF has been demonstrated in several studies and suggests that active
virus replication may occur in the CNS (31,34,81).
CT may show changes typical of viral encephalitis or acute disseminated encephalomyelitis with low
attenuation, nonenhancing cerebral lesions that may be associated with mass effect, or edema in
progressive disease (33). MRI is considerably more sensitive and can reveal lesions, particularly on T2-
weighted images, when CT findings are normal (82) (Fig. 12.4). SPECT brain scans show lesions with
reduced uptake in patients with EBV encephalitis (18) and increased uptake in patients with EBV
lymphomas (61,62). EEGs frequently show generalized slowing with occasional bursts of activity in
patients with encephalitis.
TREATMENT AND OUTCOME
The treatment of neurologic complications associated with acute EBV infection is generally supportive
and may include anticonvulsants, judicious use of fluids (to avoid cerebral edema), and mechanical
ventilation. Corticosteroids may be required in cases of increased intracranial pressure. Steroid treatment
in cases of uncomplicated infectious mononucleosis reduces the duration of fever and sore throat but does
not reduce lymphadenopathy or splenomegaly (83). Corticosteroids have been reported to be helpful in
several anecdotes describing neurologic complications related to EBV infection (including
encephalomyelitis, cerebellar ataxia, transverse myelitis, and cranial and peripheral neuropathies)
without intracranial hypertension (24,38,47). Steroids, however, have also been associated with the new
onset of neurologic symptoms in patients with acute infectious mononucleosis (84) and with a worse
outcome in Guillain-Barré syndrome (85). The limited experience with corticosteroids for EBV-
associated CNS disease suggests that they are useful in select cases; however, their potential benefits
must be balanced against their numerous risks.
Acyclovir inhibits EBV replication in vitro; however, a metaanalysis of five clinical trials did not
show any benefit of acyclovir in the therapy of acute infectious mononucleosis (86). Although acyclovir
has been used in some cases of CNS disease associated with EBV, it probably provides little or no
benefit (87). Acyclovir might be used in conjunction with corticosteroids for select cases of EBV-
associated CNS disease in an attempt to reduce viral replication in the setting of an immunosuppressing
agent.
EBV-associated lymphomas involving the CNS in posttransplant recipients are usually treated with
cytotoxic chemotherapy and/or radiation therapy. Immunosuppression is reduced when possible. Newer
treatments include monoclonal antibodies to B-cell surface antigens (88,89), interferon-α therapy (90), or
infusion of EBV-specific cytotoxic T cells (91). The incidence of AIDS-related primary CNS lymphoma
is decreasing in the era of HAART (92). A regimen including high-dose methotrexate, corticosteroids, and
HAART is usually used for CNS lymphomas in patients with HIV. Although some patients with CNS
lymphoma who received HAART and cranial irradiation had prolonged survival compared with those
who received only cranial irradiation, insufficient data are available to verify the efficacy of HAART in
the treatment of CNS lymphoma (93).
Most patients with neurologic complications of acute EBV infection recover completely within weeks
to months; however, some have sequelae. Of 35 patients with neurologic syndromes associated with
heterophile antibody–positive infectious mononucleosis in whom outcomes were noted, 80% (28/35)
recovered completely, 14% (5/35) had neurologic residua, and 6% (2/35) died (15). Fatalities are
usually caused by respiratory arrest related to encephalitis or Guillain-Barré syndrome or occasionally to
secondary infections.
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_________________________
Disclaimer: This chapter was prepared by Drs. Hoover, Ross, and Cohen in their personal capacities. The views expressed herein do not
necessarily represent the views of the NIH, DHHS, or the federal government.
CHAPTER 13 HUMAN HERPESVIRUS-6
MARY T. CASERTA
HISTORY
Human herpesvirus-6 (HHV-6) was first isolated from six adults with acquired immunodeficiency
syndrome (AIDS) or lymphoproliferative disorders by Salahuddin et al. (1) in 1986. Limited genomic
analysis and morphologic studies suggested that the new virus was a member of the herpesvirus family
and it was named human B lymphotropic virus (HBLV) based on an apparent B-cell tropism (2). Further
experiments demonstrated the propagation of HBLV in various human cell lines, including those of T-cell,
B-cell, megakaryocytic, glial, and endothelial origin, and the designation of HHV-6 was proposed (3,4).
In 1988, Yamanishi et al. (5) were the first to report an etiologic role for HHV-6 in human disease.
They isolated HHV-6 from the peripheral blood mononuclear cells (PBMCs) of four Japanese children
with exanthem subitum (roseola infantum) and demonstrated seroconversion to HHV-6 in the patients’
convalescent sera. Since its discovery, numerous other diseases have been linked with HHV-6 in both
immunocompromised and immunocompetent hosts during primary or reactivated infection, but a clear
causal connection has not always been proven. Diseases of the central nervous system (CNS) that have
been associated with HHV-6 include encephalitis, primarily in immunocompromised hosts, seizures, and
multiple sclerosis (MS) (6). Chronic fatigue syndrome, Sjögren syndrome, and several
lymphoproliferative disorders including malignancies were all initially associated with HHV-6 but have
now been shown by further study to be unlikely due to HHV-6 infection (7–9).
The syndrome of roseola has been well known among pediatricians for generations. Most authors
credit Zahorsky (10) in 1913 with the first definite description of the illness as a common, self-limited,
febrile exanthematous disease of infancy. In 1941, Breese (11) described the epidemiologic, clinical, and
laboratory manifestations of roseola based on his experience with 100 patients. Eight years later,
Berenberg, Wright, and Janeway (12) reported convulsions as the most common complication of roseola,
occurring in up to one third of children. Kempe et al. (13) were able to document the infectious nature of
the illness in 1950 by directly transmitting disease via serum and throat washings from an infected child
to an uninfected child and to rhesus monkeys (Macaca mulatta).
EPIDEMIOLOGY
Seroprevalence
Worldwide surveys have demonstrated ubiquitous infection with HHV-6. Seroprevalence rates of more
than 80% have been reported consistently in various populations of adults by several methods (14–16).
Age-specific studies have revealed that antibody to HHV-6 is universally present in cord blood and
newborn sera at titers higher than in maternal sera, with a gradual fall in geometric mean titers and
seroprevalence noted in the first 4 months of life, corresponding to the loss of transplacental antibody
(17,18). Following this nadir, the geometric mean titers increase steadily to reach a peak at 1 year of age
(7,19,20). By 3 years of age, 100% of children have acquired serologic evidence of infection with HHV-
6. No seasonal predilection for primary HHV-6 infection has been noted in prospective studies, but small
outbreaks of roseola among infants documented by seroconversion to HHV-6 have been reported (21,22).
Seroprevalence rates remain stable throughout childhood, adolescence, and adulthood until age 40 years,
when a gradual fall in the prevalence and geometric mean titer of antibody to HHV-6 is noted (23,24).
Transmission
The pattern of widespread and rapid acquisition of HHV-6 infection in infancy without contact with
similarly ill individuals implies that the virus is spread readily from asymptomatic children and adults to
susceptible infants. HHV-6 DNA has been frequently detected via polymerase chain reaction (PCR) in
saliva and throat swabs from healthy adults and children both in cross-sectional studies and over time
(25,26). Salivary gland tissue specimens screened by in situ hybridization, immunohistochemistry (IHC),
and PCR have also been shown to contain HHV-6, suggesting that saliva may be a major mode of
transmission and that the salivary glands are a site of persistent infection (27,28). In a prospective,
longitudinal study of infants, the risk of acquiring primary HHV-6 infection in the first year of life was
greater among subjects whose parents reported saliva-sharing practices, further supporting saliva as an
important mode of transmission (29). Recently, HHV-6 DNA has been identified in a majority of nasal
mucous and olfactory tissue specimens suggesting that respiratory droplets may also be a source of viral
spread (30).
Evidence of primary HHV-6 infection in infants as young as 14 to 21 days documented by viremia and
rising antibody titers demonstrates that the protection provided by maternal antibody is incomplete and
suggests the possibility of perinatal transmission of HHV-6 (21,31). These data are consistent with
reports of HHV-6 DNA in both the blood and the cervical/vaginal samples from 12% to 25.8% of both
pregnant and nonpregnant women, implying possible sexual transmission of HHV-6 as well (32–35).
HHV-6 DNA was not detected in 120 specimens of breast milk, making breast-feeding an unlikely mode
of transmission of HHV-6 (36).
Congenital infection with HHV-6, defined as the presence of viral DNA in cord blood specimens, has
been documented in 1.19% (exact CI 1.02, 1.38) of newborns (37). Eighty-six percent of congenital
infections are due to chromosomal integration. Transplacental HHV-6 infection accounts for the remaining
14% of congenital infections (38). Chromosomal integration is unique to HHV-6 among the human
herpesviruses and has been identified in 0.85% of unselected subjects (39). In individuals with
chromosomal integration of HHV-6 (ciHHV-6), the entire viral genome is present in every nucleated cell
of the body, including the germline, and transmitted via Mendelian genetics (40). Fluorescent in situ
hybridization has demonstrated that multiple chromosomes may harbor integrated virus; however, the
viral genome is always identified at the proximal end of the telomere with one site usually identified per
family (41,42). The HHV-6 U94 gene product is thought to play a role in HHV-6 latency and in mediating
HHV-6 chromosomal integration via homologous recombination between the perfect telomere repeat
sequences (TRS) found in the direct repeat segments of the HHV-6 genome and human telomeres (43)
(Fig. 13.1).
Individuals with ciHHV-6 are notable for having persistently high HHV-6 DNA viral loads in whole
blood, serum, plasma, and hair follicle specimens, with one or more genome copies per cell (44).
Although replicating virus can be induced from cultured lymphocytes of individuals with ciHHV-6 via
treatment with histone deacetylase inhibitors, it is unknown whether the production of infectious viral
particles occurs in vivo (41). The observation that infants with transplacental HHV-6 infection have
mothers with ciHHV-6 suggests that integrated virus may be able to replicate as free virus and be
transmitted (45). No clinical manifestations have been recognized in infants with ciHHV-6 and the long-
term clinical significance of chromosomally integrated HHV-6 is unknown. Preliminary data have
demonstrated the rate of ciHHV-6 in groups of solid organ transplant patients and those with malignancies
to be approximately double that found in the general population suggesting possible pathogenic potential;
however, this has yet to be confirmed (39).
Taxonomy
Soon after the initial description of HHV-6, two groups of viruses were identified: HHV-6 variant A and
variant B (46). Both were included as members of the Roseolovirus genus in the Betaherpesvirinae
subfamily, along with HHV-7 and human cytomegalovirus (CMV) (7). The two HHV-6 variants were
found to be highly genetically related but could be distinguished by the pattern of reactivity with
monoclonal antibodies, in vitro cellular tropism, nucleotide sequence analysis, and restriction fragment
length polymorphisms (7,47,48). In North America, Europe, and Japan, HHV-6B was found in
approximately 97% of both healthy and immunocompromised hosts and in infants during primary infection
(49,50). Recent PCR data have suggested that HHV-6A is the predominant virus identified in children in
sub-Saharan Africa (51). In infants identified with ciHHV-6 in the United States, approximately one third
had HHV-6A, a frequency substantially higher than in children with primary infection (21,38). Dual
infection with HHV-6A and HHV-6B has also been documented in both adults and children. Because of
the differences noted in epidemiology, tissue tropism, genome composition, disease associations, and
possible virulence between HHV-6A and HHV-6B, the two were reclassified as separate species in the
genus Roseolovirus by the International Committee on Taxonomy of Viruses in 2012. Further clarification
of the epidemiology of HHV-6A and HHV-6B awaits the development of reliable species-specific
serologic assays (52,53).
VIRAL CHARACTERISTICS
HHV-6 contains a linear, double-stranded DNA genome of 160 to 170 kb that consists of a single unique
sequence of approximately 143 kb bounded by a single direct repeat (DR) at both termini. The complete
sequences of representative isolates of both HHV-6A and HHV-6B have been published and shown to be
approximately 90% identical at the nucleotide level (54–56). The seven conserved gene blocks shared by
all HHVs are organized in an identical fashion in HHV-6A, HHV-6B, HHV-7, and CMV, and the unique
segment of both the HHV6A and HHV-6B genomes are colinear with the long unique segment of CMV (7).
In addition, CMV, HHV-6A, HHV-6B, and HHV-7 share a unique set of genes called beta genes that are
found only in CMV, HHV-6A, HHV-6B, and HHV-7 (7).
HHV-6 displays the typical ultrastructural characteristics of the herpesvirus family. It is an enveloped
virus, approximately 160 to 200 nm in diameter, and contains an electron-dense core. The core is
surrounded by a nucleocapsid with icosahedral symmetry with a prominent tegument between the
nucleocapsid and outer lipid membrane (57) (Fig. 13.2). HHV-6 viral replication occurs in the nucleus of
the infected cell. Viral particles are initially released by exocytosis and then cell death.
Both HHV-6A and HHV-6B have the potential to encode for approximately 97 proteins including those
involved in regulatory functions, DNA replication, and structural proteins as well as several unique genes
not found in other herpesviruses. Many of these gene products have been identified and reviewed
previously and thus are not mentioned here (7,48,58). One notable exception is HHV-6 U94, a protein that
is homologous to the parvovirus adeno-associated virus type 2 (AAV-2) Rep 68/78 gene that has been
implicated in the maintenance of latency and chromosomal integration as noted earlier (59).
PATHOGENESIS
Viral Growth Characteristics and Cellular Tropism
All HHV-6 isolates can be grown in the laboratory in primary cord blood mononuclear cell cultures that
have been pretreated with phytohemagglutinin (PHA) (60). HHV-6 has also been propagated in adult
PBMCs that have been stimulated with monoclonal antibody to CD3 but not PHA (61). HHV-6 replication
in vitro is augmented by T-cell activation and enhanced in the presence of low concentrations of
interleukin-2 (IL-2), with increasing concentrations producing inhibition (62,63). Following infection,
HHV-6 reproducibly induces a cytopathic effect characterized by large refractile mononucleated or
binucleated cells with intracytoplasmic and/or intranuclear inclusions (64). Infected cells exhibit a
slightly prolonged life span in PHA-stimulated cultures compared with uninfected controls; however, lytic
infection of mononuclear cells has been the rule (65).
Santoro et al. (66) described CD46 (i.e., membrane cofactor protein) as an essential cellular receptor
for HHV-6. CD46 is also the receptor for the Edmonston strain of measles virus and other bacterial
microbes and functions as a complement regulatory protein present on the surface of all nucleated cells.
This finding is in keeping with the observation that HHV-6 can infect a broad range of cell types in vitro
including primary T cells, monocytes, natural killer (NK) cells, dendritic cells, oligodendrocytes,
microglia, and astrocytes, with infection of T-cell, B-cell, megakaryocytic, endothelial, glial, and
epithelial cell lines described (4,7,60,67–74). Variability has been noted in infectivity between HHV-6A
and HHV-6B (69). HHV-6A viruses are most efficiently propagated in the HSB2 or J-Jhan T-cell lines,
whereas HHV-6B isolates can be adapted to grow in the Molt-3 T-cell line. A viral glycoprotein complex
of gH, gL, gQ1, and gQ2 has been demonstrated to be the viral ligand for many, but not all, laboratory
isolates of HHV-6A and HHV-6B (75). Given these observations, the possibility of a second cellular
receptor that could explain the differential tropism between HHV-6A and HHV-6B has been postulated.
Ablashi et al. (60) studied the kinetics of host cell destruction in T-cell lines and reported that HHV-6A
isolates demonstrated enhanced cytopathogenicity compared with HHV-6B isolates suggesting greater
virulence of HHV-6A. Despite the broad tropism of HHV-6 noted in vitro, viral replication in
nonlymphoid cell lines appears to be substantially restricted with decreased production of infectious
virus (58,76).
A previous study of PBMCs from children with roseola suggested that HHV-6 acutely infects primarily
mature CD4+ T cells in vivo (77). However, higher viral loads and evidence of viral gene transcription
have been demonstrated in monocytes and macrophages compared with CD4+ T cells during the acute
phase of primary HHV-6 infection (78). Following primary infection, the HHV-6 genome persists in
PBMCs with evidence suggesting that a true state of viral latency is induced in cells of the myeloid
lineage including CD34+ stem cells, which may function as a reservoir of latent virus (79,80).
The neuroinvasive potential of HHV-6 has been documented in several reports by the detection of
HHV-6 DNA in 32% to 85% of brain tissue specimens from immunocompetent adults at autopsy (81–83).
Chan et al. (84) sampled areas of the cerebellum, frontal, temporal, parietal, and occipital lobes
bilaterally from 40 patients postmortem and found that 85% had one or more positive specimens.
However, there was no association between the presence of HHV-6 DNA and the location of the sample,
suggesting that HHV-6 may be widely disseminated in the human brain (84). In addition, HHV-6 DNA has
been found in gray matter and white matter samples and in primary brain tumor tissue (82,85). Primary
infection with HHV-6 identified by viral isolation from PBMCs is due almost exclusively to HHV-6B. In
contrast, HHV-6A DNA was detected in 12% to 70% of human brain tissue specimens in the studies
described previously, with up to 21% of patients harboring both HHV-6A and HHV-6B in different
regions of the brain (81,82,84,86). In vitro studies have demonstrated HHV-6A and HHV-6B infection of
primary astrocytes and oligodendroglia with the formation of multinucleated syncytia (70,87). Attempts to
infect neuronal cells have led to conflicting results but generally suggest these cells are not a significant
source of productive infection (67,68,87). Enhanced neurovirulence of HHV-6A has been suggested by
several in vitro studies examining the degree of cytopathic effect, DNA replication, induction of
apoptosis, and inhibition of cell proliferation induced by HHV-6A compared to HHV-6B in both primary
glial cells and established cell lines (67,88–91).
The clinical relevance of detecting HHV-6 DNA in cerebrospinal fluid (CSF) samples has not been
fully clarified. HHV-6 DNA has been detected in the CSF of one quarter to one half of children with
primary infection, indicating that viral DNA may be present in the CSF of a substantial number of
immunocompetent children during primary infection (92–94). In one report of young febrile children with
evidence of past HHV-6 infection, approximately 30% had detectable HHV-6 DNA present in the CSF
(92). The CSF was the only site of viral DNA detection in 29% of children, and these children were
significantly younger than those with HHV-6 DNA in both the CSF and the PBMCs, indicating that the
CNS may be a preferred site of latency in younger children (92). Typing of CSF samples revealed a
greater frequency of HHV-6A in CSF (14%) than in PBMCs (5%), also implying a greater neurotropism
of HHV-6A (50). These data imply that finding HHV-6 DNA in the CSF of normal hosts is not a rare
event. However, in a single report of bone marrow transplant (BMT) recipients, HHV-6 DNA was
identified in 22% of CSF samples from patients with symptoms of CNS dysfunction compared with only
1% of control patients with leukemia (95). Unfortunately, the cases and controls in this study were not
well matched by degree of immunosuppression. Nevertheless, these data suggest that detecting HHV-6
DNA in CSF may be a useful marker of disease in the proper clinical setting. Part of the discrepancy
between the results from studies of children with primary infection and the BMT patients may be due to
the young age of the immunocompetent children studied and the significant percentage with primary HHV-
6 infection compared to the older group of BMT patients. Given the recent identification of ciHHV-6 and
the fact that most subjects with ciHHV-6 have no symptoms referable to the integrated virus, caution
should be used in interpreting the presence of HHV-6 DNA in CSF in order to avoid misdiagnosis of
active HHV-6 infection in an individual with ciHHV-6 (39,93). Obtaining HHV-6 viral load
measurements in blood and CSF concurrently may be able to help distinguish between these different
clinical scenarios (93). Studies of healthy adults have demonstrated the presence of HHV-6 DNA in
saliva, PBMCs, urine, and vaginal secretions, with evidence of continued presence of the viral genome at
these sites over several months consistent with the broad in vitro tropism of HHV-6 (32,96–98). Despite
initial reports of isolation of HHV-6 from adult saliva, subsequent studies have shown that viral isolates
obtained from saliva are HHV-7 (99). Additionally, attempts at isolating infectious HHV-6 from healthy
subjects’ PBMCs have been generally unsuccessful. In contrast, isolates can be readily obtained from
immunocompromised hosts, demonstrating reactivation of latent HHV-6 (100). Reactivation documented
either by HHV-6 viral isolation or by quantitative DNA PCR has also been reported in immunocompetent
children with measles or dengue hemorrhagic fever and in adults with critical illness requiring intensive
care unit care or those with drug induced hypersensitivity syndrome (DIHS) or drug rash with
eosinophilia and systemic symptoms (DRESS) (101–104). The cumulative data support the concept of
active HHV-6 viral replication in mononuclear cells during primary infection, with the production of
abundant infectious particles. The virus then becomes latent or persistent in the host PBMCs, salivary
gland tissue, the genitourinary (GU) tract, and the CNS, with the detection of the HHV-6 genome in the
absence of significant amounts of infectious virus. Immune dysfunction allows for HHV-6 reactivation, as
evidenced by renewed viral isolation with subsequent disease manifestations in a subset of patients.
Immune Response
Children with primary HHV-6 infection develop an immunoglobulin M (IgM) response on day 5 of
illness, with the appearance of immunoglobulin G (IgG) at approximately 1 week (105). The IgM
response is short lived, persisting for only 2 to 3 weeks, and the IgG response lasts for extended periods.
Low level neutralizing antibody develops at approximately day 3 of illness, coincident with a falloff in
the rate of viral isolation, and peaks at 2 to 4 weeks into the illness (106,107). Although the immune
response to HHV-6 is generally sensitive and specific, IgM has also been detected in approximately 5%
of healthy adults and has been shown to be cross reactive with HHV-7, limiting the usefulness of this test
for the diagnosis of HHV-6 infection or reactivation (108). HHV-6–specific CD4+ and CD8+ T-cell
responses have also been described, supporting a role for cellular factors in the immune response to
HHV-6 (109,110).
Following infection of PBMCs, HHV-6 interacts with the immune system in several ways including
downregulation of CD3 and CD46 cell surface molecule expression, upregulation of CD4, induction and
suppression of cytokines and type I interferons, and effects on NK cell activity (107,111–114). In vitro
HHV-6 infection of dendritic cells has been described with conflicting reports on the functional outcome
of this infection (115,116). Apoptosis of T cells both in vitro and in vivo has been detected following
HHV-6 infection, as well as the previously well-described cell lysis (117,118). In addition to the immune
response generated to HHV-6, the viral genome itself encodes several factors that have immunologic
regulatory activity including two chemokine receptor homologs (U12 and U51) and two putative
chemokines (U22 and U83) (111). It has been postulated that through these proteins, HHV-6 may either
enhance viral replication in infected cells, enlarge the pool of available virus susceptible cells, or
circumvent the host immune response to infection.
Primary Infection
Roseola is an acute self-limited disease of infancy and childhood. It is characterized by the abrupt onset
of high fever lasting approximately 72 hours. The fever resolves by crisis coincident with the appearance
of a faint morbilliform rash on the neck and trunk. Associated signs are notably sparse but can include
mild injection of the pharynx, palpebral conjunctivae, or tympanic membranes and enlarged suboccipital
nodes (11).
Prospective studies have extended our knowledge of the clinical manifestations of acute HHV-6
infection beyond that of classic roseola. Hall et al. (21) identified 160 children with primary HHV-6
infection by viremia and seroconversion from a large number of children evaluated in a pediatric
emergency department. The mean age at primary HHV-6 infection was 9.4 months, with few cases
occurring before 2 months or after 25 months of age (Fig. 13.3). High fever was the most consistent
manifestation of infection. All children had an acute febrile illness, and 87% had fever of more than 39°C.
Fever persisted for 6 days or longer in 15%. Associated clinical symptoms and signs included irritability
or a toxic appearance in 72%, inflamed tympanic membranes in 46%, and upper respiratory tract signs in
41%. Children with primary HHV-6 infection were significantly more likely to exhibit these signs than
matched controls. Cough and lower respiratory tract signs were seen significantly less often in children
with primary HHV-6 infection than controls. Only 17% of children with primary HHV-6 infection
developed a rash, making it difficult to identify correctly the cause of the illness. Most children were
given a diagnosis of fever with otitis media, fever of undetermined origin, or presumed sepsis, and 13%
were hospitalized. A more recent prospective study of an outpatient cohort of infants with primary HHV-6
infection identified by HHV-6 DNA detection in saliva confirmed that over 90% of the infants had
symptoms with fever, fussiness, and rhinorrhea noted most often (119). Rash was identified in a little less
than one third of the cohort (119).
In a report from Japan of 176 children with roseola identified retrospectively, fever and rash were
noted in 98% of the patients (120). This study also detected a higher percentage of children with
gastrointestinal tract disturbances (68% with diarrhea), in addition to edematous eyelids in 30%,
erythematous papules in the pharynx in 65%, cough in 50%, and mild cervical lymphadenopathy in 31%.
The differences between these studies may be attributed in part to study design and case definition. Also,
the severity of the clinical symptoms associated with acute HHV-6 infection has been shown to be related
to the degree of viremia, which may contribute to the range of reported manifestations of primary HHV-6
infection (121).
The laboratory evaluation of children with primary HHV-6 infection is generally nonspecific and
reveals a depressed total white blood cell count, with lymphopenia noted early in the course of the
infection. C-reactive protein levels have been reported to be less than 10 mg/L in most patients (21,122).
Rarely reported complications of primary HHV-6 infection include intussusception, Kawasaki disease,
hepatitis, hemophagocytic syndrome, and fatal multisystem disease (7,123). A heterophil-negative
mononucleosis syndrome has been associated with primary HHV-6 infection in immunocompetent adults
(124). However, most reports have relied on seroconversion as evidence of HHV-6 infection, a method
that is not optimal.
Central Nervous System Complications of Primary Infection
Seizures have been reported as a complication of primary HHV-6 infection. In the study from Japan noted
earlier, 8% of the children with roseola had seizures during the febrile phase of the illness (120).
Seizures were the most common complication of primary HHV-6 infection, occurring in 13% of children
with acute infection described by Hall et al. (21) from a pediatric emergency department population. The
highest incidence of seizures was 36%, noted in children 12 to 15 months of age. This rate was
significantly greater than that of age-matched controls with other febrile illnesses. In prospective studies
of children with first time febrile seizures, primary infection with HHV-6 has been observed in 18% to
26% of the patients (125,126). However, in the study by Zerr et al. (119) noted earlier, no seizures were
recorded among 81 ambulatory children with primary HHV-6 infection. Although the exact rate of
seizures due to primary infection with HHV-6 has not been precisely defined, a review of the viral causes
of febrile seizures examined almost 1,000 published cases of primary HHV-6 infection and found seizures
to be a complication in 16.5% (127).
Clinically, no differences have been identified between children with febrile seizures associated with
primary HHV-6 infection and those with febrile seizures not associated with primary HHV-6 infection,
including the height or duration of fever or the recurrence rate of seizures in the first 24 hours (125).
Additionally, CSF analysis does not typically reveal pleocytosis or abnormal glucose or protein levels in
patients with primary HHV-6 infection. Suga et al. (128) reported a higher frequency of partial seizures,
postictal paralysis, prolonged seizures, and clustering of seizures in 19 children with primary HHV-6
infection compared with children with seizures not associated with primary HHV-6 infection, suggesting
more significant CNS pathology and implying an increased risk for the later development of epilepsy
(92,129). Early reports did suggest an increased risk of recurrent febrile seizures in children due to HHV-
6 infection, but a case–control study of children with febrile seizures associated with primary HHV-6
infection compared with children with febrile seizures not associated with primary HHV-6 infection
demonstrated a statistically significant lower rate of seizures over the following 3 years in the children
with primary HHV-6, casting doubt on this association (130). However, more recent data have suggested
a link between chronic smoldering or reactivated HHV-6 infection of the CNS and the later development
of medial temporal lobe epilepsy (MTLE) (131). One line of evidence supporting this association comes
from a prospective study of children with febrile status epilepticus (FSE), a known risk factor for the
development of MTLE that identified active HHV-6 infection in peripheral blood samples of almost one
third of the patients (132). Similar to the data from children with simple febrile seizures, the children with
FSE associated with HHV-6 did not have CSF pleocytosis or differences in peripheral white blood cell
counts from patients with FSE not associated with HHV-6. There were also no differences in the
proportion of children with EEG abnormalities or acute hippocampal changes on MRI. Seizure
characteristics between children with FSE associated with HHV-6 and those not associated with HHV-6
were similar (Table 13.1), suggesting a shared pathogenesis of FSE among different etiologies (132).
Further data supporting a link between HHV-6 and MTLE comes from a series of studies of adult and
adolescent patients undergoing epilepsy surgery. HHV-6B DNA was found in 28% to 63% of resected
temporal lobe specimens in patients with MTLE compared to zero specimens from patients with other
forms of epilepsy or 8% of specimens obtained from trauma patients (133–137). Active HHV-6
replication was identified via the detection of higher viral loads of HHV-6 in the hippocampus than the
surrounding tissue, HHV-6 protein expression via IHC, and HHV-6 messenger RNA (mRNA) production
in the hippocampus and temporal lobe tissue as well as cultured astrocytes from the resected MTLE
patient specimens (133,134,136). Loss of glutamate transporter EAAT2 protein in infected astrocytes due
to active HHV-6 infection with a resultant inability to process extracellular levels of the excitatory
neurotransmitter glutamate is one proposed mechanism of pathogenesis (131,134). Alternatively,
increased levels of expression of NFκB have been detected in hippocampus and temporal lobe specimens
from MTLE patients suggesting a role for inflammation in the development or progression of MTLE
(136).
Several older case reports have described encephalitis or encephalopathy in children with roseola
(138). Fever, depressed level of consciousness, and seizures were the prominent symptoms noted in these
patients, with normal CSF findings or mild pleocytosis with elevated protein levels. Computed
tomography (CT) was often normal at onset but progressed to reveal hypodense lesions in multiple areas
of the cerebral cortex, including the frontal, parietal, temporal, and occipital lobes, the putamen, and
internal capsule (138–140). A single report including magnetic resonance imaging (MRI) results
demonstrated multiple lesions of demyelination in the thalamus and parietooccipital deep white matter
(141). Electroencephalographic (EEG) findings were either normal or nonspecific, with most studies
remarkable only for diffuse slowing following seizures. Single photon emission CT (SPECT) performed
in one patient showed diffuse hypoperfusion of the left hemisphere that persisted for at least 50 days
(142). Although complete or near-complete recovery was noted in several cases, mortality was also
reported. More recent reports of young children with probable primary infection with HHV-6 have
described a syndrome of rhombencephalitis with progressive neurologic symptoms including ataxia and
cranial nerve deficits associated with imaging abnormalities of the brainstem and cerebellum (143,144).
Pleocytosis, HHV-6 DNA in the CSF, and elevated CSF total protein values were found with
identification of HHV-6 protein by IHC in a brain biopsy sample from a single patient (143). Other
reports from single cases of encephalitis have not identified a unique pathologic description from brain
tissue specimens and have reported inconsistent results of DNA and IHC testing suggesting a possible
immune-mediated pathogenesis (145,146). In children with primary HHV-6–associated encephalitis or
encephalopathy with or without HHV-6 DNA in the CSF, significantly greater concentrations of both
interleukin (IL)-6 and IL-8 have been identified in serum and CSF compared to values from patients with
HHV-6–associated febrile seizures or normal controls supporting this hypothesis (147–149).
Reactivation
The lifelong consequences of infection with HHV-6 are still not well known. Although HHV-6 DNA can
be detected in several body sites in adults years after primary infection, the occurrence and frequency of
reactivation, as well as the clinical relevance of reactivation, have not been completely defined. As noted
earlier, HHV-6 reactivation has been reported in children with measles or dengue hemorrhagic fever and
in seriously ill adults in an intensive care unit or with DIHS or DRESS. Evidence of reactivation as
determined by quantitative PCR of HHV-6 DNA in PBMCs in the critically ill adult patients was not
associated with any specific symptoms and did not have an impact on mortality. However, it is notable
that all but one of these patients had HHV-6A detected, which may actually have been due to ciHHV-6 and
not true viral reactivation given the apparent low prevalence of HHV-6A in the general U.S. population
(103). Reactivation of HHV-6 does occur in immunocompromised hosts of all ages and has been
associated with a range of illnesses in this population. Following hematopoietic cell transplantation
(HCT), HHV-6 reactivation documented by viral culture or quantitative PCR has been documented in
35% to 65% of patients (150,151). Several diseases including fever and rash, encephalitis, interstitial
pneumonitis, acute graft-versus-host disease, delayed engraftment or myelosuppression, CMV disease,
and increased mortality have been associated with HHV-6 reactivation in the HCT population
(48,100,152). Two of the best documented diseases linked to HHV-6 reactivation in HCT recipients are
fever with rash and encephalitis, occurring from 2 to 4 weeks after transplantation (48,100).
HHV-6 reactivation has also been associated with both direct and indirect clinical effects in
approximately 1% of solid organ transplant recipients including fever, rash, encephalitis, bone marrow
suppression, interstitial pneumonitis, gastrointestinal infections, CMV disease, fungal infections, and graft
rejection or dysfunction (153–162). Many of these reports provide conflicting results and older studies
often relied on serologic markers of reactivation. In prospective studies of HCT recipients that have
included both serology and viral culture or quantitative PCR, the serologic results did not correlate with
viral assays, suggesting caution in diagnosing reactivation of HHV-6 based on serology alone (163–165).
Encephalitis associated with HHV-6 reactivation has been reported in both immunocompetent and
immunocompromised hosts. Single case reports or small series have described disease in previously
healthy adults and children (166–173). The quality of these reports varies substantially and no clear group
of symptoms or unique clinical presentation has been identified. Clinical characteristics have included
both acute and subacute presentations, diffuse headache, altered mental status, and seizures as well as
focal neurologic signs. Variable degrees of CSF pleocytosis and protein elevations have been reported.
Imaging studies have been normal or with a range of findings including focal abnormalities in the motor
cortex, parietal lobe, temporal lobe, or white matter disease in the pons, internal capsule, and midbrain
(166–174). Outcomes have been mixed with both death and full recovery reported. One point that appears
consistent among these cases is the identification of HHV-6 DNA in CSF as the main diagnostic criteria.
Given the relatively recent recognition of ciHHV-6 and the persistent detection of HHV-6 DNA in all
body fluids associated with viral integration, it is possible that several of the earlier reports were
confounded by ciHHV-6. Alternatively, individuals with ciHHV-6 may develop encephalitis due to the
integrated virus as has been suggested in a prior report (175). The question of whether HHV-6
reactivation can cause encephalitis in immunocompetent individuals with ciHHV-6 or prior childhood
infection requires further careful study.
Encephalitis associated with HHV-6 reactivation in HCT recipients has been well defined with the
majority of reports describing a syndrome of acute limbic encephalitis also referred to as
posttransplantation acute limbic encephalitis (PALE) (176–181). In addition, HHV-6 reactivation has
been temporally associated with more common CNS symptoms including delirium during the early
posttransplant period and neurocognitive decline measured at 12 weeks after transplant, suggesting a
significant impact on the clinical course of transplantation (182).
The incidence of PALE among HCT recipients is estimated at 1.5% overall but may be as high as 28%
in patients receiving two or more cord blood stem cell transplants (176,177,179). PALE typically
develops around the time of neutrophil engraftment, usually from 2 to 6 weeks after transplantation
(176,179,181). Risk factors for the development of PALE appear to be similar to the risk factors
identified for HHV-6 reactivation in HCT and include umbilical cord blood as a donor source, human
leukocyte antigen (HLA) mismatch, time-dependent acute graft-versus-host disease, and the receipt of
corticosteroids during the first 4 weeks after transplantation (176,181,183). Hill et al. (176) have
reported that all patients who develop PALE have evidence of HHV-6 reactivation with positive DNA
detection in plasma (176). In addition, patients with PALE have been found to have significantly higher
HHV-6 viral loads measured in plasma than patients with HHV-6 reactivation without neurologic
symptoms with the peak viral load correlating with the time of development of neurologic symptoms
(176,183,184). Various plasma viral load cutoff values have been proposed as a threshold for predicting
PALE with variable sensitivity and specificity (176,183). However, not all studies have consistently
noted an association between HHV-6 viral loads and the development of disease. Betts et al. (185)
performed a prospective surveillance study for HHV-6 reactivation following HCT in 82 subjects and
measured weekly whole blood viral loads. They did not find an association between HHV-6 reactivation
and total CNS symptoms, including headache. Nor was there an association between high level viremia
(>25,000 genome copies/mL of whole blood) and CNS symptoms. Patients with HHV-6 reactivation were
more likely to have mental status changes, and it is notable that the only patient who died with neurologic
complications had the highest level of HHV-6 viremia among patients with CNS symptoms (185).
Wainwright et al. (180) were the first to describe five patients with limbic encephalitis associated with
HHV-6 reactivation. Since then, multiple reports have confirmed the typical clinical presentation of PALE
as an acute onset of altered mental status with confusion and prominent anterograde amnesia
(176,179,181,183). Fever, insomnia, hallucinations, agitation, or emotional lability have also been
described (179,186). Seizures are frequently identified either clinically or via EEG monitoring. Reported
laboratory findings include the syndrome of inappropriate antidiuretic hormone with minimally elevated
levels of CSF total protein (176,179–181). CSF pleocytosis is noted less commonly, probably due to the
marked cytopenias found posttransplantation (176,179–181). MRI studies may be normal early in the
course of disease but typically show focal nonenhancing abnormalities in the medial temporal lobe often
including edema in the hippocampus, uncus, and amygdala either unilaterally or bilaterally on T2 fluid
attenuation inversion recovery (FLAIR) images with hypermetabolism in these regions on positron
emission tomography (PET) scanning (186,187) (Fig. 13.4). Extension of abnormalities beyond the
medial temporal lobe into other limbic structures or extralimbic areas has also been described
(176,186,188). A small number of postmortem examinations have been performed with neuronal loss and
gliosis limited to the hippocampus and amygdala regions (179,180). HHV-6B DNA has been identified in
the CSF in the majority of patients with PALE and in one autopsy specimen HHV-6 protein was detected
within astrocytes and neurons in the hippocampal areas (180). A role for a direct viral effect on disease
pathogenesis is also supported by data from a small study demonstrating that the viral load of HHV-6 in
CSF of HCT patients with encephalitis was significantly greater than from children with primary infection
(149). However, similar to findings in children with primary HHV-6 infection and encephalitis or
encephalopathy, elevated levels of CSF IL-6, IL-8, and IL-10 have been identified in patients with HHV-6
reactivation and associated limbic encephalitis compared to controls suggesting neuroinflammation as one
alternative pathogenic mechanism (149).
Mortality rates reported due to HHV-6–associated PALE have varied from 0% to 50% but do not
appear to be different than mortality in the general HCT population (176–179). Differences may become
more apparent when patients with cord blood transplantation are evaluated separately (176). There does
not appear to be an association between mortality and viral load measurements in the CSF or plasma,
time to antiviral treatment, or other clinical characteristics, suggesting that although plasma viral loads
may be useful as a marker for disease development, they do not predict outcome (176–178). Morbidity is
common following PALE with approximately 40% of patients reported to make a full recovery (181).
Most patients have persistent memory difficulties that limit their day-to-day function, and symptomatic
generalized epilepsy has also been described (176–179,181).
HHV-6 infection has also been etiologically linked to MS and hypothesized to act as a “trigger” for
disease development (6,189). Studies have demonstrated a statistically significant increased detection of
HHV-6 proteins and both early and late gene mRNA in oligodendrocytes from brain specimens of patients
with MS compared to control brains and from MS plaques compared to normal-appearing white matter
(189,190). An increased frequency of detection of HHV-6 DNA in serum and PBMC samples from
patients with MS has also been described, as well as an increased percentage of patients with MS who
have positive IgM antibody assay results to protein p41/38 (191,192). This last finding is tempered by a
study that found no difference in antibody reactivity to recombinant HHV-6 p41 protein between patients
with MS and controls and suggested that previous results may have been confounded by reactivity to p38,
a cellular protein (193). However, multiple reports have continued to describe an increased frequency of
detection of HHV-6 DNA in the serum of patients with MS and a correlation between clinical disease
activity and HHV-6 DNA detection in serum as well as mRNA detection in whole blood was noted in a
group of patients with relapsing and remitting MS over time (194). Additionally, an increased prevalence
of detection of HHV-6A in serum has been reported in patients with MS, suggesting a potential
association between HHV-6A and this disorder (194). These findings are in contrast to multiple studies of
CSF, serum, PBMCs, and brain tissue including demyelinated plaques from patients with MS and controls
demonstrating no difference in the detection of HHV-6 DNA by PCR (195–198). The ability to compare
results across studies is hampered by the methodologic differences between these reports, making it
difficult to form a conclusion about the strength of the association between HHV-6 and MS.
DIAGNOSIS
The diagnosis of primary HHV-6 infection is confirmed by isolation of the virus in culture coupled with
seroconversion. Several serologic methods have been developed for the detection of antibody to HHV-6
including an indirect immunofluorescence assay (IFA), neutralization assay, immunoblot assay, and
enzyme-linked immunosorbent assay (ELISA) (199,200). Although antibody to HHV-7 limits specificity at
low titer, higher titer responses have been shown to be reliable (200). IFAs that include the measurement
of antibody avidity have also been described and have the added benefit of being able to provide an
approximate timing of primary infection (200). The IgM response to HHV-6 is short lived, cross reactive
with HHV-7, and can reappear after initial infection diminishing the use of this test in the clinical
diagnosis of primary infection or reactivation (108).
Rapid diagnostic methods for the confirmation of HHV-6 infection are not available. The detection of
HHV-6 DNA in PBMC samples does not distinguish between latent infection and active viral replication
associated with primary infection or reactivation. Secchiero et al. (201) detected HHV-6 DNA in the
serum of six of seven children with roseola, suggesting that this method was both sensitive and specific
for the timely detection of active viral replication if performed on cell-free specimens. In a separate
report of 47 plasma samples obtained from children with roseola, HHV-6 could be isolated in culture
from only 21% of the samples, implying that plasma contained infectious virus in only a minority of
patients with primary HHV-6 infection (106). This was confirmed by Achour et al. (202) in a study
demonstrating that HHV-6 DNA in cell-free specimens is primarily due to the presence of free DNA, not
viral particles, and that detection in plasma or serum correlates well with the viral load in PBMC
samples (202). However, the description of ciHHV-6 and the recognition that asymptomatic individuals
with ciHHV-6 have HHV-6 DNA detectable in all body fluids with high viral loads has limited the use of
detecting HHV-6 DNA in plasma or serum as the sole test of active viral replication. Reverse
transcriptase polymerase chain reaction (RT-PCR) assays for HHV-6 have been developed to amplify
mRNA corresponding to late structural proteins of the virus produced during lytic infection in order to
detect active replication (203,204). The performance characteristics of each of these assays compared to
viral culture varies with the population being tested, but in general, the detection of U90 and U100 mRNA
is 90% to 100% sensitive and 90% to 98% specific for primary and reactivated HHV-6 infection
(203–205). Preliminary data suggest that approximately 5% to 15% of samples of PBMCs from
individuals with ciHHV-6 are positive in the U100 RT-PCR assay slightly diminishing the discriminatory
power of this test but raising the possibility of viral protein production and or active replication of the
integrated genome (205). The measurement of HHV-6 viral loads in whole blood has been suggested as a
means of differentiating between primary infection, reactivation, and ciHHV-6 with viral loads in
individuals with ciHHV-6 often greater than 5.5 log10/mL or at least one genome equivalent per cell with
lower levels found in primary infection, reactivation, and during latency (39,206). Additionally,
individuals with ciHHV-6 will have persistently high viral load measurements in whole blood over time
with HHV-6 DNA present in all tissues including hair follicle specimens, which has been used in research
settings to identify subjects with integrated virus. From a practical standpoint, it appears as though a
combination of DNA detection in plasma coupled with whole blood quantitation may provide the best
discriminatory power to identify different types of infection with HHV-6 because both of these assays are
commercially available (39).
TREATMENT
In vitro studies have evaluated the susceptibility of HHV-6 to available antiviral agents. Varying methods
used in different experimental systems make absolute comparisons between reports difficult. In general,
however, the pattern of antiviral inhibition of HHV-6 resembles that of HCMV, with ganciclovir,
foscarnet, and cidofovir demonstrating effective in vitro activity (48,58). This pattern of antiviral
susceptibility is in agreement with the results of in vitro assays and genomic analyses that have failed to
identify a virally encoded thymidine kinase in HHV-6 and suggest that ganciclovir, foscarnet, and
cidofovir may be of use in the clinical setting, whereas acyclovir- and thymidine kinase–dependent drugs
should have little effect (207).
Randomized controlled clinical trials aimed at evaluating the effectiveness of antiviral agents in
patients with primary or reactivated HHV-6 infections are lacking, and no drug is currently licensed for
the treatment of HHV-6 infection or disease. Case reports have described the successful treatment of
HHV-6–associated encephalitis in HCT recipients using ganciclovir, foscarnet, or cidofovir, either alone
or in combination, with a suggestion of benefit in preventing CNS disease in small trials of prophylaxis
(208–213). Unfortunately, in vitro resistance of HHV-6 to each of these drugs has been identified (58).
Nevertheless, treatment of HHV-6–associated PALE is recommended with ganciclovir or foscarnet
suggested as first-line agents for a minimum of 3 weeks (100).
ACKNOWLEDGMENTS
The author is indebted to Andrew Schultz and Pam LaDuke for their expert technical assistance.
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CHAPTER 14 B VIRUS
RICHARD J. WHITLEY
HISTORY
Of the nearly 35 herpesviruses that have been isolated from nonhuman primates, only one—B virus of Old
World monkeys—is highly pathogenic for humans. In 1932, a young physician (W.B.) bitten by a monkey
developed localized erythema at the site of the animal bite. This apparently localized infection was
followed by lymphangitis, lymphadenitis, and ultimately transverse myelitis. The demise of W.B. was
ascribed to respiratory failure. Tissue specimens from W.B. were obtained by two independent research
groups. In 1933, Gay and Holden (1) reported the identification of an ultrafilterable agent that recreated in
rabbits a disease similar to that observed in W.B. This virus was recovered from the neurologic tissues of
W.B. The inoculation of this virus by either intradermal or intracranial routes was lethal in the animal
model. These investigators thought that the virus was similar to herpes simplex virus (HSV) and referred
to the isolate as W. While attempts at transmission of this virus to rhesus monkeys failed, infection of
Cebus monkeys was successful. In 1934, Sabin and Wright (2) reported the identification of a similar
filterable agent, which they identified as B virus, named W.B. They isolated virus from several neurologic
tissues as well as from peripheral organs (spleen but not lymph nodes). As with the isolate named W, B-
virus infection resulted in lethal disease when inoculated by either intradermal or intracerebral routes into
rabbits. However, the virus was avirulent when inoculated by the same routes into a variety of other
species, including mice, dogs, and guinea pigs. Furthermore, Sabin (3) recognized by immunologic
characterization of the isolate that it was related to both HSV and pseudorabies virus (3,4). At the time
when latinization of viral names was fashionable, B virus acquired the name herpes simiae. The name is
a misnomer because nonhuman primates have yielded numerous unrelated herpesviruses. According to the
present nomenclature, it is designated as the cercopithecine herpesvirus type 1. In this chapter, the virus is
designated by its common name, B virus.
B virus is indigenous to Old World monkeys (5,6), being enzootic in rhesus (Macaca mulatta) and
cynomolgus (Macaca fascicularis) monkeys, as well as in other Asiatic species of the genus Macaca.
Most reported human cases result from bites by rhesus monkeys. Since the original reports of human
herpes B-virus infections, advances in our knowledge about human disease caused by this virus have
proceeded slowly. Although B-virus infection of humans is not a common public health problem, the
diagnosis of B virus in four individuals living in Pensacola, Florida; two in Kalamazoo, Michigan; and an
animal handler at Yerkes Primate Center has refocused medical and public health attention on the
neuropathogenicity of infection (7). Approximately 50 cases have occurred, although only 26 are well
documented (7). Other cases are pending verification. Person-to-person transmission of infection from
one of the fatal cases to a relative was documented for the first time. Additionally, a case has been
identified that led to infection, but without evidence of life-threatening clinical disease (8). Lastly, ocular
inoculation of virus proved lethal (7).
INFECTIOUS AGENT
B virus was propagated on the chorioallantoic membrane of embryonated eggs in 1939 (8). Tissue culture
isolation of B virus did not occur until 1954, when it was recovered from rhesus kidney tissue used for
preparation of poliomyelitis vaccines (9). During vaccine production, suspended cell culture systems
from six kidneys elicited cytopathic effects similar to those of HSV.
Notwithstanding numerous attempts at isolation of virus from macaques, the first report of virus
isolation is that of Reissig and Melnick (10), who recovered B virus from tissue cultures of purportedly
normal rhesus monkeys. Further studies led to the realization that this virus was easily propagated in
monkey kidney and chick embryo cell lines (10, 11). B virus also multiplies well in rabbit kidney cells
and other established cell lines such as BS-C-1 (12) and LLC-RK (13). Virus is stable in tissue culture
media when stored at 4°C and viral infectivity is maintained if the culture is stored at −72°C.
Replication characteristics of B virus have been reported by several laboratories (4,10,11,14–16). The
reproductive cycle is relatively short. The virus inhibits host cell DNA and protein synthesis during the
first 4 hours after infection. Infectious virus is detectable approximately 6 hours after infection, and both
extracellular and intracellular virus levels reach a plateau approximately 24 to 36 hours after infection
and decline thereafter (10,16).
PATHOLOGY AND PATHOGENESIS

Pathology
The characteristic cytopathic effect is similar to that of HSV. Cells balloon, fuse into polykaryocytes, and
form clusters as focal areas of infection spread through the entire cell sheet. On fixation and staining,
Cowdry type A eosinophilic intranuclear inclusions are demonstrable.
Pathologic findings in humans are indicative of the target organs involved. As described later in this
chapter, there is little difference in the histopathologic findings encountered following either infection of
humans or simians.
Pathogenesis of Human Infection
Disease in humans usually results from an animal bite or scratch, although disease that is the consequence
of respiratory spread and reactivation has been reported (see later discussion). Following exposure,
replication of virus at the local site of inoculation occurs. If the skin is the primary site of inoculation,
virus replicates in the skin; this leads to erythema and calor at the initial site of involvement. A vesicular
rash may appear in association with tingling and numbness. Usually, there is evidence of local
inflammation at the site of infection with mononuclear infiltrate followed by evidence of lymphangitis and
subsequent lymphadenopathy. Although viremia has been documented in both rabbits and monkeys, this
route of pathogenesis has not been documented for humans. With lymphatic involvement, it is possible for
the virus to spread by lymphangial routes. Visceral organs that are involved, including the heart, liver,
spleen, lungs, kidneys, and adrenals, demonstrate evidence of congestion and focal hemorrhagic necrosis;
however, the degree of involvement varies from one patient to the next. A striking characteristic of human
B-virus infection is the propensity to involve the central nervous system (CNS) and likely reflects spread
via neuronal routes. Transverse myelitis is a prominent neurologic finding, with ultimate progression of
infection to the brain. B-virus infection can involve all regions of the brain without evidence of
localization to any particular region, in contrast to HSV infection of the CNS, which tends to localize in
the temporal lobe. Histopathologic findings of the brain include hemorrhagic foci, necrosis, and
inflammatory changes, as evidenced by perivascular cuffing with mononuclear infiltrates. Edema and
degeneration of motor neurons are prominent. Even with advanced disease, Cowdry type A eosinophilic
intranuclear inclusions can be found in only a few cases. In addition, gliosis and astrocytosis are late
histopathologic findings. Thus, there can be evidence of myelitis, encephalomyelitis, encephalitis, or
combinations thereof (17).
Pathogenesis of Latency in Macaques
Like other herpesviruses, B-virus infection in macaques becomes latent and can recur. As is discussed
later in this chapter, prevalence of antibodies to B virus is widespread in Old World rhesus monkeys.
Rhesus monkeys captured in the wild and shipped to primate centers develop vesicular lesions of the
oropharynx, suggesting a pattern of virus reactivation and recrudescence of lesions similar to that
encountered with HSV. Unequivocal evidence of latent B-virus infection in rhesus monkeys evolved with
the studies of the recovery of B virus in monkey kidney cell culture systems. Thus, Wood and Shimada (9)
obtained six isolates from 650 pools of monkey kidneys, suggesting that at least 1% of rhesus monkeys
contain latent virus that can be reactivated by culturing kidney cells. Virus was isolated from rhesus
tissues also by Boulter (18). B virus was recovered by cocultivation from a variety of neuronal tissues
(including gasserian ganglia, trigeminal ganglia, and dorsal root ganglia) and the spinal cord (19). Latent
virus was also isolated by cocultivation of tissues from experimentally infected rabbits (9).
As in the case of HSV infections in humans, the most prominent factor associated with reactivation of B
virus in rhesus monkeys is stress, particularly stress associated with the capture and shipping of animals
from the wild to captivity. To date, the state of viral DNA during latency or on the molecular or
biochemical events associated with the establishment and reactivation of latent virus are unknown.
EPIDEMIOLOGY OF HUMAN INFECTION

B-virus infections of humans must be considered in the context of the epidemiology of any infectious
disease, including the susceptibility of the host and quantity of virus to which they are exposed.
Importantly, the frequency of excretion of B virus in infected animals averages 2% to 3% at most; thus, if
a human is bitten by an infected animal, the probability of infection is low, albeit existent. Direct contact
with a source of virus—namely, an actively or latently infected animal (or cells obtained from an infected
animal)—is the means by which an infection is transmitted. Virus cannot penetrate intact skin; thus, a
break in the skin is required for acquisition of infection. Sites that have been documented as initially
infected in humans include wounds, the eyes, and perhaps the respiratory tract. Because it is well
established that infected animals can excrete virus in saliva, from the eyes, in vesicular fluid, and perhaps
in the stool, these must all be considered potential sources for human infection. Furthermore, as has been
well documented in the history of the development of poliomyelitis vaccine, infected cell culture tissues
can also be a source of viral infections for humans.
Person-to-person transmission of B virus has been documented (17). In this instance, the wife of an
animal worker, who subsequently died of B-virus infection of the CNS, acquired vesicular lesions of her
ring finger. She provided direct care of her husband’s vesicular lesions. Although she survived infection
without evidence of neurologic disease, the extent of disease may have been limited by early intervention
with acyclovir. Notably, individuals who developed B-virus infection had either skin-to-skin or face-to-
face contact with at least 40 other individuals during a cluster of cases in Pensacola, Florida. Although
these other individuals were under close surveillance, none developed evidence of infection. Thus, casual
contact can be excluded as a method of transmission of B-virus infection. This is particularly important
from a public health standpoint.
Nonfatal infection has not been well documented in reports of human disease. One recent animal bite
resulted in localized viral replication without systemic involvement (20). Serologic assessment of humans
for evidence of B virus as a marker of subclinical infection is confounded by cross reactivity to HSV.
MANIFESTATIONS OF CENTRAL NERVOUS SYSTEM DISEASE

Human B-virus disease is characterized by an ascending myelitis or encephalomyelitis. To date, there are
a limited number of cases of human disease caused by B virus in the literature, depending on the criteria
for case definition (7). Several cases have been cited in the literature but have not been documented.
Regardless of the exact number of cases, the total number of patients who have experienced disease is
limited. Probably thousands of animal workers have been exposed to animals excreting virus, but very
few have developed disease. As noted earlier, casual transmission is unlikely. Nevertheless, the lessons
learned regarding the clinical manifestations of disease in individuals exposed to B virus, as well as the
necessity for methods of intervention and prevention, are reinforced by the findings in these particular
patients.
Infection can occur in one of four fashions. First, infection may be asymptomatic. An animal worker
exposed to a rhesus monkey with conjunctivitis was stuck by a needle that had been used for inoculation
of this animal (20). Subsequent biopsy of the needlestick site revealed evidence of multinucleated giant
cells. B-virus DNA was detected in the biopsy specimen, but there was no evidence of clinical disease.
This form of infection may be an underreported event for individuals exposed to B virus. A second, and
more common, route of infection is by animal bite. Following a bite by a monkey excreting B virus, a
localized vesicular lesion associated with erythema and edema develops at the site of viral inoculation.
Subsequently, lymphangitis with spread to regional lymph nodes occurs, along with the development of
secondary lymphadenopathy. These early stages of disease are generally accompanied by fever, myalgia,
vomiting, abdominal cramping, meningeal irritation, and such cranial nerve signs as nystagmus and
diplopia. Neurologic symptoms develop very rapidly. Altered sensation, hyperesthesia, or paresthesia of
the limbs usually precede evidence of weakness, areflexia, and flaccid paralysis. Transverse myelitis
with urinary retention is likely to occur. With progressive involvement of the CNS, decreased levels of
consciousness, altered mentation, respiratory depression, seizures, and ultimately neurologic death ensue.
Although the incubation period for B virus has been debated, most cases have a relatively short
incubation period of approximately 3 to 5 days; however, some cases have been reported to occur as late
as 24 days after an animal bite. The onset of neurologic symptoms generally occurs 3 to 7 days after the
appearance of a vesicular rash. Time to death varies and can occur as early as within 10 to 14 days or
much later. Improvements in intensive care for critically ill patients probably have influenced these
survival data. The progression of infection is likely related to a variety of factors, including host
immunologic status quantity of neutralizing antibodies to HSV, age of the patient, site of the bite, and
quantity of virus inoculated. Prolonged incubation periods, as well as the mechanism for these prolonged
incubation periods, have not been well characterized (7).
Third, cases have been documented following exposure to infected secretions by an ocular or
respiratory route. An animal care provider was exposed to direct inoculation of saliva into the eye. In
spite of rigorous rinsing, she became infected and subsequently died (7). Two other cases illustrate the
potential for respiratory spread. Symptoms in these individuals were localized to the respiratory tract,
including coryza, cough, laryngitis, and pharyngitis. While associated with fever, these symptoms
progressed to respiratory distress, as evidenced by a radiographic evidence of interstitial pneumonitis.
One of these two patients had virus isolated from a vesicle. Subsequently, neurologic symptoms
developed, ultimately leading to death of these patients (5).
The fourth manifestation of human disease is recurrent infection. At least two patients illustrate that a
recurrent vesicular rash can occur as a consequence of B-virus infection. In one case, infection was
acquired as a consequence of person-to-person transmission. In another case, an individual developed
lesions compatible with the diagnosis of herpes zoster; however, B virus was isolated from these lesions.
Of the well-described cases of herpes B-virus infection, the majority developed encephalitis (>90%),
with a documented mortality rate of 75%. Survivors of B-virus infection of the CNS have a broad
spectrum of neurologic impairment. Of those documented in the literature before the availability of
antiviral therapy, two had mild or minimal impairment, one had moderate neurologic impairment, and the
remainder had severe impairment. The literature also documents three patients who were infected with B
virus and survived infection but did not develop encephalitis. One had severe neurologic impairment
(presentation of herpes zoster), and two appeared normal on follow-up. With the use of antiherpetic
drugs, survivors who were treated early, even if they had CNS disease, tended to survive without
significant impairment (21–23). Thus, taken together, these cases serve to emphasize the severity of B-
virus disease.
DIAGNOSIS
Clinical
The total number of cases of B-virus infection is small. The possibility of B-virus infection must be
considered in any individual having contact with Old World monkeys, particularly Asiatic Macaca
species. Because of the recent identification of person-to-person transmission, individuals having intimate
contact with workers exposed to these animals should be considered as having B-virus infection if
compatible clinical findings occur. The suspicion of B-virus infection should be reinforced in the
presence of historical evidence of direct contact with a rhesus monkey, either by bite, scratch, or
laboratory accident. In addition, some cases have been acquired by exposure to monkey tissues;
consequently, this route of transmission should not be excluded as a possibility for human infection.
Clinical evidence of disease has been defined earlier. Of particular interest to the clinician is the
presence of a vesicular rash at a bite site with ipsilateral regional lymphadenopathy. With a compatible
incubation period, the progressive appearance of neurologic symptomatology—particularly altered
sensation in the extremities, weakness, hyporeflexia or areflexia, and altered mentation—in the presence
of a wound should suggest the possibility of B-virus infection.
Virus Isolation
Recovery of virus from humans suspected of having B-virus infection must be attempted. Sources for
retrieval of virus are those indicative of the pathogenesis of disease. These include vesicles,
conjunctivae, pharyngeal swabs, and tissue biopsy material. Furthermore, retrieval of virus from the
cerebrospinal fluid (CSF) should be attempted, although the yield is very low. Specimens for virus
isolation should be processed in cell lines that are susceptible to B virus. As noted earlier in this chapter,
these include primary vervet monkey kidney, rabbit kidney cells, or established strains such as BS-C-1 or
LLC-RK-1. B virus replicates in all these cell lines, in contrast to other simian viruses, which have a
more limited spectrum of susceptible cell lines (24).
Once viral isolation has been achieved, identification of virus can be accomplished using either
molecular methods (25,26) or neutralization assays, although the latter assay is cumbersome and tedious
(5,27,28). Rapid identification of isolates is essential for purposes of intervention with appropriate
therapeutic agents (29,30).
Serologic Evaluation
Serologic determination of B-virus infection is exceedingly difficult because of its cross reactivity with
HSV. Attempts at antibody absorption are not satisfactory. The extensive cross reactions of sera to simian
viruses in the presence of HSV antibodies have made diagnosis difficult (5,31,32). Animal workers
providing care for Macaca monkeys should be serially bled for antibody determinations. Sera should be
banked for future reference. The standard serologic assays that have been employed generally use either
neutralization assays or complement fixation (33). In general, complement-fixing antibody titers to HSV
are higher in humans than in monkeys, whereas titers against B virus are higher in Macaca monkeys than
in humans. As previously mentioned, human sera contain higher levels of neutralizing antibodies to HSV
than to B virus. Furthermore, sera derived from monkeys with B-virus infection have been reported to
neutralize HSV better than they neutralize the endogenous virus. No simple test exists to distinguish
antibodies to HSV from antibodies to B virus. Nevertheless, a variety of assays for the rapid evaluation
of human antibody response are under development (29,34). The advent of these newer diagnostic assays
will be of value for prospectively evaluating patients exposed to B virus.
Polymerase Chain Reaction Detection of B-Virus DNA

Recently, a single-step polymerase chain reaction (PCR) assay has been reported to be of value for
diagnostic purposes (35). Because of the rarity of disease, field performance characteristics need to be
determined. Primate workers should carry a card that indicates symptoms of B virus and contact
information for clinical and laboratory consultation regarding B virus (Table 14.1).
CONTROL OF B-VIRUS INFECTION

As with all other infectious diseases, the principal goal is to prevent infection. Prevention has been
stressed on numerous occasions by the Centers for Disease Control and Prevention (CDC) and in reviews
published over the last 15 years (5–7,36–38). Although a vaccine is not readily available for the
prevention of B-virus infections, one is under development (37). Proper laboratory and animal breeding
and handling procedures will significantly decrease the risk of infection. A CDC Advisory Committee has
recommended procedures for control and management of infected animals and exposed animal workers
(7,37). Although the risk of acquisition of infection by B virus is extremely low, caution is indicated (37).
Guidelines for the management of macaques in captivity for research purposes include the following:
1. Macaque monkeys should be used only for research purposes and only when clearly indicated.
2. It is desirable to use macaques that are free of B-virus infection. Thus, screening for B-virus infection
before their use for research purposes is necessary. Furthermore, these animals should be maintained in
a state that will prevent acquisition of infection (5,6). Attempts are in progress to establish B-virus–
free colonies.
3. All macaques should be considered infected unless proven otherwise. This point warrants emphasis
because it encourages careful methods of handling these animals.
4. Macaque handlers should be properly attired (arm-length leather gloves, protective eyewear, and
mask) and prepared to use proper restraints or anesthetic agents, such as ketamine, before manipulating
animals.
5. Cages and equipment for housing and transport of macaques, as well as laboratory equipment with
which macaques have contact, should be thoroughly cleaned. Sharp edges can lead to wounds in the
macaques, which may ultimately be a source of infection.
6. Animal handlers, investigators, and support personnel who handle macaques should be properly
trained in the methods of animal restraint and manipulation. Every effort must be made to educate
personnel in bite prevention. Serial and prospective serologic evaluation of individuals who have
continual contact with these animals should be performed and sera specimens maintained at a
repository for future evaluation, if necessary. Knowledgeable medical personnel should be readily
available for consultation.
7. Any bite or scratch wound incurred from a macaque or as a consequence of contact with a macaque
cage should be decontaminated as quickly as possible. Cleansing with soap and water should be done
for at least 15 minutes. If an eye is involved, a sterile saline wash should be used. Cultures of both the
animal and the wound site should be obtained immediately. Follow-up evaluation of these individuals
should include clinical and serologic evaluation. If there is evidence of suspected disease, assessments
should proceed, with virus isolation and further serologic evaluation. With evidence of disease,
specific antiviral therapy should be instituted, as noted in the next section, “Prevention and Treatment.”
These recommendations have been provided as guidelines for the management of macaques in captivity
for research purposes (7,39). Variations from these guidelines can be discussed with investigators at the
CDC (Viral Exanthems and Herpesvirus Branch, Division of Viral Diseases, Centers for Disease Control
and Prevention, 404-329-1338, www.cdc.gov/ncidod/diseases/bvirus.htm).
PREVENTION AND TREATMENT

Treatment
Although vaccines have been evaluated in animal models, none has proven efficacious in humans
(17,40–42). The use of hyperimmune serum or γ-globulin has not been proven effective for the treatment
of human infections caused by B virus (43). Other investigators have demonstrated protection with
hyperimmune horse and rabbit sera for rabbit infection (44). The use of other forms of hyperimmune sera
has not been proven effective.
With the advent of antiviral therapy, nucleoside analogs have been deployed for the management of B-
virus infection of humans. Four drugs have been used experimentally: vidarabine, acyclovir, valacyclovir,
and ganciclovir. Each of these drugs has been reported to have varying activity. Studies with an
acyclovir-based medication have attracted the most attention. In cell culture systems, acyclovir is active
against B-virus infection. One milligram of acyclovir decreased the yield of virus by approximately 90%
(45). Subsequent experiments in animal models provided varying evidence of efficacy, depending on the
quantity of inoculation, delay in therapy, and duration of treatment. Overall, a beneficial effect could be
achieved in animals (45). Smith et al. (46) have demonstrated that ganciclovir is extremely active against
B virus at concentrations of 0.55 mg/mL or less. These concentrations are achievable in humans. More
recently, animal model studies have shown the efficacy of acyclovir and superiority of ganciclovir for
disease therapy (15).
The use of acyclovir and its prodrug valacyclovir for therapy of human disease has been more limited.
The literature includes several cases in which therapy instituted early in the disease course may have
slowed progression and led to a return to normal function (20). Two of these cases were reported in the
Pensacola outbreak. The value of acyclovir under such circumstances cannot be unequivocally determined
because of the small number of patients who have this disease for evaluation in controlled studies. If
acyclovir is used initially for cutaneous disease, some experts recommend a dose of 12.5 to 15.0 mg/kg
every 8 hours intravenously (IV) (7). With the availability of the prodrug of acyclovir, valacyclovir,
higher plasma levels can be achieved (45). Thus, a recommendation for valacyclovir therapy is made
because of the severity of disease and its uniformly near-fatal outcome (7). The dose is 1 g every 8 hours.
Some experts recommend ganciclovir therapy for symptomatic B-virus disease, particularly if the CNS
is involved, for a minimum of 14 days at dosages of 5 mg/kg every 12 hours IV (7). The duration of
therapy is not known but should continue until all CNS symptoms have resolved. Subsequent oral
administration of valacyclovir for suppression of latent infection is considered by many experts; however,
there are no data regarding the value of therapy for prolonged periods under such circumstances.
Furthermore, the value of valacyclovir for life is recommended by some experts.
Prophylaxis
Valacyclovir should be used for prophylaxis in patients exposed to B virus. The dosage is 1 g every 8
hours and should be continued until the results of laboratory tests are available.
FUTURE DIRECTIONS
B-virus infection in humans should not occur. The proper deployment of control procedures among animal
handlers should avoid all human infections. Regardless, the future will allow for the development of more
rapid and precise diagnostic assays and the further definition of appropriate procedures for handling
infected animals and humans at risk for infection.
ACKNOWLEDGMENTS
Original studies performed by the investigators were supported by grants from the National Institute of
Allergy and Infectious Diseases (NO1-AI-62554, NO1-AI-30025), the Division of Research Resources
(RR0023) of the National Institutes of Health, and the State of Alabama.
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CHAPTER 15 ARTHROPOD-BORNE VIRAL
ENCEPHALITIDESM
TOM SOLOMON, ADJANIE PATABENDIGE, AND RICHARD J. WHITLEY
Conventionally, viruses are placed within families and genera according to the taxonomic system, based
on morphologic, biochemical, antigenic, and genetic similarities. However, because the taxonomic system
tells us nothing about how a virus is transmitted or about the patterns of disease it causes, it is of
relatively little help to the practicing clinician. For this reason, alternative groupings that incorporate
these clinical and epidemiologic aspects are often used. One such group is the arthropod-borne viral (or
arboviral) encephalitides that includes viruses transmitted by arthropods (insect, ticks, sandflies, and
biting midges) that are important causes of central nervous system (CNS) disease in humans. Altogether,
there are more than 500 arthropod-borne viruses, or “arboviruses,” that come from four viral families
(Togaviridae, Flaviviridae, Bunyaviridae, and Reoviridae); only a relatively small number of these
viruses are responsible for human disease (Table 15.1). Within the family Togaviridae, the Alphavirus
genus contains eastern, western, and Venezuelan equine encephalitis (EEE, WEE, and VEE) viruses—
important causes of disease in horses and humans in the Americas—and chikungunya virus (CHIKV),
which caused major outbreaks associated with severe morbidity in the Indian Ocean islands and in India
during 2005 to 2007 (1). The flaviviruses (genus Flavivirus, family Flaviviridae) include Japanese
encephalitis virus (JEV), which occurs across much of southern and eastern Asia and is the most
important cause of epidemic encephalitis worldwide; West Nile virus (WNV), which has spread to cause
large encephalitis outbreaks in the United States; dengue virus (DENV), which continue to be a global
threat with over 100 million infected annually; and tick-borne encephalitis (TBE) viruses—important in
Europe and Russia. Within the family Bunyaviridae, the Bunyavirus genus includes La Crosse virus
(LACV) and other California serogroup viruses that cause encephalitis, whereas the Phlebovirus genus
includes Toscana virus (TOSV), an important emerging cause of CNS disease in southern Europe. The
Reoviridae family includes Colorado tick fever virus (CTFV) and similar members of the Coltivirus
genus that causes febrile illness and CNS disease.
Arboviruses classically cause three disease patterns in humans (Fig. 15.1): fever-arthralgia-rash
syndromes, viral hemorrhagic fevers (often associated with hepatitis), and neurologic disease, which are
the focus of this chapter. They constitute some of the most important emerging and reemerging infectious
diseases. General principles of arboviral ecology, epidemiology, and pathogenesis, as well as diagnosis,
management, and prevention of arboviral encephalitis, are discussed before the more important diseases
are considered in more detail.
ECOLOGY OF ARBOVIRUSES
A basic understanding of the ecology of arboviruses is helpful in understanding the epidemiology of
human disease. For most of the arboviruses that cause neurologic disease in humans, including many of
the flaviviruses, alphaviruses, and bunyaviruses, humans are not part of the natural cycle, being incidental
hosts (Fig. 15.2). In nature, these viruses are typically transmitted between birds or small rodents in
enzootic cycles that use mosquitoes or ticks as vectors. To be evolutionarily successful, arboviruses
require immunologically naive hosts, which is why most have evolved to use rapidly reproducing
animals. Humans are infected when they encroach upon this natural enzootic cycle and are bitten by the
vector. This may be because they live in or have entered areas where the virus circulates naturally or
because changes in ecologic or environmental circumstances have caused the virus to move closer to
areas inhabited by humans. Sometimes a different mosquito carries the virus to humans (a bridging
vector), and sometimes there is an intermediate vertebrate cycle that brings the virus closer to humans
(e.g., equines for some of the alphavirus encephalitides and swine for JEV). A large outbreak of disease
in animals is an epizootic. Whereas natural hosts have prolonged and high viremia, humans have transient
and low viremia, insufficient to transmit the virus further, and are considered “dead-end” hosts. Most
human infections are asymptomatic or result in a mild nonspecific febrile illness, but in a small
proportion, the virus enters the CNS to cause the syndrome for which the virus is known. The brief and
low viremia makes diagnosis of human infection by virus isolation or nucleic acid amplification difficult,
and for the most part, serologic tests are used. Although humans are “dead-end” hosts for most
arboviruses, some arboviruses are better adapted to replicate in humans, resulting in persistent and high
viremias, allowing for further transmission to a biting insect. Examples include VEEV, TOSV, CTFV, and
DENV. These high viremias typically cause a characteristic arboviral “fever-arthralgia-rash” syndrome in
most patients; CNS manifestations tend to be milder, for example, aseptic meningitis. Because of the high
viremias, virus isolation and polymerase chain reaction (PCR) are more successful for these viruses.
Arboviruses replicate in both the vertebrate host and the vector in an “extrinsic” cycle. Whereas
vertebrate hosts typically mount an immune response and clear the virus, the arthropod vectors are usually
infected for life. Virus is ingested by the vector with an infected blood meal, replicates in the epithelium
of the mesenteron (midgut), then disseminates to the salivary glands, where it replicates further and is
excreted with each blood meal. The virus may also be passed on from the adult mosquitoes and ticks to
their offspring, via transovarial transmission (Fig. 15.2). For ticks, virus can also be transmitted
vertically from the larval to nymph then adult stages (transtadial transmission). Vertical transmission is an
important means of overwintering (i.e., surviving the cool winter months) for some viruses, but for others,
the means of overwintering is uncertain. An exception to a “typical” arboviral cycle includes mechanical
transmission via the vector’s mouth parts. More importantly, some viruses, as well as being arthropod
borne, can also be directly transmitted between vertebrate hosts, bypassing the arthropod vector, for
example, humans can become infected with Rift Valley fever virus (RVFV) from the body fluids of
infected animals (2), TBE virus can be transmitted to humans via infected goat’s milk (3), and WNV can
be transmitted in infected blood products or transplanted organs (4).
PATHOGENESIS OF ARBOVIRAL ENCEPHALITIS

Despite the wide range of arboviruses that cause encephalitis, there are many similarities in the
pathogenesis and pathology (see Table 15.2 for an overview of the arboviral encephalitides). Much of the
data has come from rodent models of alphavirus encephalitis. Following inoculation, usually during the
bite of a blood-sucking mosquito or tick, arboviruses typically replicate in the skin and local lymph
nodes, causing a viremia, before entering the CNS (5). Langerhans cells in the skin have been implicated
as a site of replication for alphaviruses and some flaviviruses (6–8). Keratinocytes have also been shown
to be one of the initial targets for WNV replication and could be contributing to the persistence of WNV
in the skin (9). Replication in local skeletal muscle may also be important for alphaviruses. Invasion of
target organs appears to depend in part on the extent of viremia, but also on other invasive viral
characteristics (10). The two peaks of the characteristic saddleback or biphasic fever curve seen in many
arboviral infections correspond to production of interferon (IFN) and proinflammatory cytokines during
the initial viremia, and then a mononuclear inflammatory response in infected target organs (11). IFN
production is induced when viral components are detected by cytoplasmic proteins such as retinoic acid-
inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) during the unwrapping
of the viral RNA from the nucleocapsid to allow replication. In addition, cells use toll-like receptors
(TLRs) to recognize pathogen-associated molecular patterns. TLR3, TLR7, TLR8, and TLR9 are the main
viral sensors in humans. TLR7, TLR8, and TLR9 are localized in the endosomal compartments and signal
through the MyD88 adapter, leading to type 1 IFNs and inflammatory cytokine production. TLR3 is
located both on the cell surface and in endosomal compartments and induces production of type 1 IFNs
through toll/interleukin-1 (IL-1) receptor (TIR) domain-containing adapter-inducing IFN-β (TRIF)
adapter. Protein kinase R (PKR) and 2′, 5′-oligoadenylate synthetase (OAS) are two other cellular viral
sensors. Viral sensors activate IFN regulatory factors and transcriptional induction of IFNs, which then
signal through the JAK/STAT pathway leading to transcription of many interferon-stimulated genes
(ISGs). The expression of ISGs and induction of their products (e.g., RIG-I, MDA5, TLRs, OAS, PKR)
are critical for limiting replication of arboviruses. Many arboviruses encode nonstructural proteins to
counter the host immune response. The main function of these nonstructural proteins is to antagonize the
initial IFN response and is an important adaptation that has helped arboviruses to establish themselves in
numerous vertebrate hosts (12).
The mechanisms of virus entering the CNS may include infection of or transport across brain
microvascular endothelial cells that form the blood–brain barrier (BBB) and infection of olfactory
neurons or of choroid plexus epithelial cells (13–16). However, the exact mechanisms of virus entry into
the CNS across the BBB and interactions of the virus with the BBB remain incompletely understood,
despite the critical role of the BBB in preventing pathogen entry to the CNS (17–20). In animal models,
the term neuroinvasiveness is used to describe a virus’ ability to enter the nervous system following
peripheral inoculation. “Neurovirulence” describes its ability to cause damage once within the CNS (e.g.,
following invasion from the periphery or following direct intracranial inoculation). Once inside the
nervous system, the pathogenesis may involve a combination of infection and dysfunction of neurons,
caused by direct viral or indirect inflammatory damage and other mechanisms such as programmed cell
death. The immune response to alphavirus infection has been characterized in experimental animals and
includes an early innate response with type I interferon (IFN-α and IFN-β) production, followed by
specific humoral and cellular immune responses (21). Experiments with knockout mice have shown type I
IFN limits early viral replication, possibly by production of MxA protein, a large cytoplasmic guanosine
triphosphatase that prevents accumulation of viral genomic and subgenomic RNA (22). Tumor necrosis
factor-α (TNF-α) and other proinflammatory cytokines are produced, contributing to the pathogenesis
(23). Production of IFN-α and other cytokines and chemokines has been implicated in JEV in humans
(24–26).
The humoral immune response in human alphavirus and flavivirus encephalitis includes early
production of immunoglobulin M (IgM), followed by immunoglobulin G (IgG) that persists for years
(27–30). The failure of antibody production is associated with a fatal outcome in human disease (30–32).
Antibody appears to be protective by neutralization, nonneutralizing binding, and complement-mediated
lysis of infected cells (33). In animal models of alphavirus encephalitis, antibody assists with nonlytic
clearance of virally infected cells by a mechanism that appears to be synergistic with the effects of IFN-α
(34). This may be especially important for clearing virus from the CNS, where limited expression of
major histocompatibility class (MHC) antigens in mice (or human leukocyte antigen [HLA] antigens in
humans) may restrict the role of T lymphocytes. Infiltration into the CNS of antibody-producing B cells
has been demonstrated in animal models (35). Cellular immune responses to alphavirus infection include
lymphoproliferative, cytokine, and cytotoxic. In alphavirus encephalitis, there is infiltration of natural
killer cells, B cells, CD4, CD8 T cells, and macrophages. CD8 T cells may be important in virus
clearance from infected macrophages (36). Studies on humoral responses to flavivirus infection have
shown protection of mice by passive transfer of antibodies against lethal challenge by several
flaviviruses (37–39). Furthermore, B cell–deficient mice were shown to be highly susceptible to
flavivirus infection (37,40–42). In contrast, the role of T cells during flavivirus infection is less well
characterized. A few studies have shown a protective role for CD4+ T cells by enhancing antibody
production and sustaining flavivirus-specific CD8+ T-cell responses (43,44). CD8+ T cells have been
shown to be important for clearance of virus and survival of mouse models of WNV (45–48), whereas
cytotoxic T cells caused accelerated and more severe pathogenesis in mice infected with MVEV (49). In
mice infected with JEV, CD8+ T cells did not affect the outcome of the infection. Therefore, a conflicting
role for CD8+ T cells in flavivirus encephalitis is suggested (40).
PATHOLOGY OF ARBOVIRAL ENCEPHALITIS

Few data are available for CNS infections caused by coltiviruses and phleboviruses because they are
rarely fatal. Pathologic studies of fatal human encephalitis caused by alphavirus, flavivirus, and
bunyaviruses show many common findings (50–56). The leptomeninges are normal or slightly hazy, and
histologic examination shows an inflammatory infiltrate. The brain parenchyma is congested with focal
petechiae or hemorrhage. Lesions are distributed through the gray matter of the cerebral cortex, midbrain,
basal ganglia, cerebellum, brainstem, and spinal cord, providing the anatomic correlates for many of the
clinical features seen (see later discussion). Microscopically, there is perivascular cuffing, with
infiltration of mononuclear and polymorphonuclear cells into the parenchyma, as well as neuronophagia
of infected cells by glial cells. Immunohistochemical analysis of the lymphocyte populations typically
shows CD4+ and CD8+ cells, which are presumed to be cytotoxic T cells. Similar changes are seen in
animal models. Initially, there is perivascular infiltration of mononuclear cells, with a few
polymorphonuclear cells, which is accompanied by perivascular extravasation of red blood cells
(RBCs), endothelial cell swelling, and hyperplasia (57,58). This is followed by migration of lymphocytes
and monocytes toward virus-infected neurons. The inflammation is accompanied by gliosis and by
inflammatory and glial cell apoptosis (59). Demyelination is seen in encephalitis caused by some
alphaviruses but does not seem to be important in the flaviviruses (60). Although the cellular immunity
and the inflammatory response are important in most infections, some patients die from virally induced
neuronal cell death before there is evidence of a cellular immune response and inflammation.
Various processes contribute to neuronal cell death including apoptosis, cytoplasmic swelling,
vacuolation, and membrane breakdown (61). In some instances, alphaviruses are inadequately cleared
from the CNS, as illustrated by detection of viral RNA in the brains of mice long after recovery (62,63).
Chronic progressive human disease with continuing brain inflammation long after the acute disease has
been reported in some alphavirus encephalitides (64). For example, persistent symptoms such as joint and
muscle pains can last for several years post CHIKV infection (1). Chronic infection does not appear to be
important for most of the mosquito-borne flaviviruses, but there is evidence of persistent infection and
chronic inflammation for humans infected with TBEV and in animal models (65,66).
CLINICAL FEATURES OF ARBOVIRAL ENCEPHALITIS

The clinical syndrome following neurologic infection with an arbovirus depends on the site of attack. If
the meninges are involved, meningitis results; inflammation of the brain parenchyma causes encephalitis;
and damage in the spinal cord causes myelitis. The term meningoencephalomyelitis encompasses the
concept that all three components may be affected. Despite the wide range of etiologic agents, there are
many similarities in the clinical presentations of arboviral encephalitis. After a brief incubation period,
which typically is 4 to 8 days but may range from 1 to 28 days, patients develop a nonspecific flulike
illness with fever, headache, nausea, and vomiting. Often, there are upper respiratory tract symptoms,
such as cough and sore throat, or abdominal pain and diarrhea. Sometimes, a rash, conjunctival or
pharyngeal injection, or lymphadenopathy may give a clue to the diagnosis. This may be seen for the
“fever-arthralgia-rash” viruses, for example, WNV, DENV, CTF, TOSV, or VEEV. The febrile phase
usually lasts a few days and may immediately be followed by continued fever with the development of
neurologic symptoms and signs, or there may be an intervening asymptomatic period, thus giving a
“saddleback” or biphasic fever curve characteristic of some arboviral infections, such as TBE or CTF.
Neurologic disease may manifest as subtle changes in behavior, or mutism, resulting in an initial
misdiagnosis of psychiatric illness. More often though, there is a profound reduction in consciousness
level, which in children may be heralded by seizures. Seizures and status epilepticus are especially
common in children with JEV and LACV encephalitis (67,68). As well as obvious generalized tonic-
clonic seizures, subtle motor status epilepticus is being increasingly recognized. A great range of focal
neurologic signs may be seen in arboviral encephalitis, including those of upper motor neuron damage,
such as a hemiparesis, and cranial nerve signs indicative of brainstem damage. Flaccid limb weakness
due to destruction of the anterior horn cells in the spinal cord is seen in flavivirus encephalitis and EEEV.
Most flaviviruses can also cause a poliomyelitis-like flaccid paralysis that typically affects the lower
limbs for mosquito-borne flaviviruses such as JEV, WNV, and Murray Valley encephalitis (MVE), and the
upper limbs for TBE (69–71). Extrapyramidal signs are common in both alphavirus and flavivirus
encephalitis and are thought to be the clinical correlates of the basal ganglia damage evident
pathologically and radiologically, including increased tone causing generalized axial and limb rigidity, or
rigidity/spasm such as opisthotonus, and tremors of the limbs, eyelids, and tongue.
DIFFERENTIAL DIAGNOSIS OF ARBOVIRAL ENCEPHALITIS

The differential diagnosis of arboviral encephalitis is broad and includes other causes of viral
encephalitis (Table 15.3), as well as diseases that mimic viral encephalitis (Table 15.4). Certain
epidemiologic features may give a clue that a patient has an arboviral infection. For example, in parts of
Asia, epidemics of JEV occur with great predictability after the start of the rainy season. In the Americas,
the alphavirus equine encephalitides are typically associated with illness in horses. More recently, birds
falling from the sky have heralded the arrival of WNV. The age and occupation of the patient can also
point to epidemiologic risk factors. JEV tends to affect children in rural parts of Asia, recent WNV
encephalitis outbreaks have affected the elderly or patients on immunosuppressive drugs, and LACV
encephalitis tends to affect children. A recent tick bite may suggest TBE in Europe, Russia, and the Far
East, or CTF in parts of North America, though other tick-borne diseases, such as borreliosis,
ehrlichiosis, and rickettsial disease must be considered. A biphasic illness is characteristic of some
arboviral encephalitides. On examination, certain neurologic signs may suggest a patient has arboviral
encephalitis rather than encephalitis caused by herpes or other viruses. For example, in an unconscious
patient, the presence of flaccid limbs consistent with anterior horn cell damage, or the tremors, increased
tone, and rigidity spasms suggestive of basal ganglia damage may suggest an arboviral cause.
INVESTIGATION AND DIAGNOSIS OF ARBOVIRAL

ENCEPHALITIS
A mild leukocytosis is common in many arboviral encephalitides, but leukopenia with thrombocytopenia
is sometimes seen in TBE and CTF. Hyponatremia due to a syndrome of inappropriate antidiuretic
hormone (SIADH) secretion is common, and in some infections, alanine transaminase may be mildly
elevated. In Western settings, lumbar puncture is often delayed in severely ill patients until imaging has
ruled out a space-occupying lesion, or incipient brainstem herniation. In many tropical settings where
imaging is not available, lumbar punctures are performed on most encephalopathic patients who do not
have signs of brainstem damage because of the importance of excluding other treatable causes,
particularly bacterial infections (72,73). Lumbar puncture will often reveal mildly elevated cerebrospinal
fluid (CSF) opening pressures (up to 250 mm of CSF), a lymphocytic pleocytosis with a normal CSF-to-
plasma glucose ratio, and slightly elevated protein level. However, an early lumbar puncture may reveal
no cells, or a neutrophil predominance, rather than a lymphocytic CSF. A low glucose ratio has been
reported for EEEV and CTF, whereas an elevated ratio has been reported for VEEVs. Radiologic
investigations may be helpful in excluding other conditions and in highlighting changes such as the high
signal intensity seen on magnetic resonance imaging (MRI) in the thalamus and basal ganglia that
characterizes both alphavirus and flavivirus encephalitis (74). Computed tomography (CT) scans may
show low signal in the same areas or just edema. Although they do not reveal diagnostic information,
electroencephalograms (EEGs) can help identify seizures (particularly the subtle motor seizures
described earlier) and distinguish focal seizures from tremors.
For most arboviral infections of humans, viremias are so low and brief that they are undetectable by the
time a patient comes to the hospital (75) (Fig. 15.3); exceptions are the viruses for which humans are
important natural or amplifying hosts, such as DENV, VEEV, and TOSV. Virus may also sometimes be
isolated from the CSF, particularly for infections that prove fatal, or from brain tissue at either biopsy or
autopsy. The traditional method for virus isolation was inoculation into suckling mice, but this has largely
been replaced by continuous cell lines (e.g., C6/36 cells derived from Aedes albopictus mosquitoes, and
Vero cells derived from African green monkey kidney). Amplification by PCR of viral nucleic acid in the
CSF or serum tends to be more sensitive than virus isolation, particularly if real-time Taq-Man PCR is
used and has helped with diagnosis of WNV and TOSV infections, although false-positive results do
occur. Immunohistochemistry of brain tissue may demonstrate viral antigen in fatal cases, and antigen-
capture enzyme-linked immunosorbent assays (ELISAs) have been developed, but they have limited
utility.
Serologic methods to detect antiviral antibody are the mainstay of the diagnosis of arboviral infections.
The traditional techniques such as hemagglutination inhibition, complement fixation, indirect
immunofluorescence, and neutralization tests require the demonstration of a greater than fourfold rise in
antibody titer in samples taken several weeks apart and thus have practical limitations; for example, they
do not give a diagnosis acutely and are not helpful in patients who die or are lost to follow-up. However,
they do have specific research uses. For example, hemagglutinating antibodies are often broadly cross
reactive, so in a patient with an undiagnosed encephalitis, a panel of antigens can be used to indicate
whether a patient was infected with a flavivirus, an alphavirus, a bunyavirus, or other virus; this can then
be followed by more specific tests within that group. Neutralizing antibodies persist for life, so they can
be used for serologic surveys to indicate whether individuals have ever been infected with a virus. In
recent years, IgM and IgG capture ELISAs have become the most useful and widely deployed tests for
diagnosing arboviral encephalitis. Depending on the virus, typically 50% of patients have antibody on
admission to hospital, and more than 90% have antibody 1 week later, so in patients whose initial test
results are negative, the test should be repeated after 1 week (Fig. 15.3). Although they are the most useful
tests, ELISAs too have their limitations. For example, because closely related viruses have many shared
epitopes, there may be cross reactivity in IgM and IgG capture ELISAs between the viruses. This problem
can usually be overcome by testing for the related viruses in parallel, with the strongest reaction
indicating the infecting agent. However, sometimes a neutralization test, which is more specific, may be
needed. Importantly, antibody will be detected in the serum of individuals who have had recent
asymptomatic or febrile infection but no neurologic disease. Its detection in the CSF is usually taken as a
better indicator of viral replication in the CNS. Finally, some patients may make antibody late or not at
all. These patients are more likely to die and to have virus detected by another means such as isolation or
PCR.
Newer approaches for detection of flaviviruses antibody include the lateral flow assay and the
microsphere immunoassay (MIA). The lateral flow device was recently approved by the U.S Food and
Drug Administration (FDA) for the diagnosis of WNV infection in humans, which can give a result in 15
minutes (76). In MIA, an antigen is attached to encoded microbeads that will bind the target analytes
during the assay procedure. These can then be identified using a fluorescence-activated cell sorting
system (FACS). MIA is used by many laboratories in the United States for WNV diagnosis as it is highly
sensitive compared to a standard ELISA. Furthermore, one serum sample can be analyzed for reactivity to
several antigens in a single assay (77). Other approaches include high-throughput rapid
microneutralization assays, biosensor-based assays, microfluidic systems based on virus-coated magnetic
beads, and multiplex real-time RT-PCR assays (78–81).
TREATMENT OF ARBOVIRAL ENCEPHALITIS

There are no established antiviral drugs for any arboviral encephalitides. IFN-α, ribavirin, and
intravenous immunoglobulins have been given to patients with flavivirus encephalitis, based on in vitro
and animal data. However, the few clinical data available suggest that IFN-α is not effective in JEV (82).
In the West, most patients with encephalitis will be given acyclovir until herpes simplex virus type 1
(HSV-1) encephalitis has been ruled out. The management of arboviral encephalitis focuses on treating the
complications of disease, in particular hyponatremia, seizures, and increased intracranial pressure (ICP).
In most Western settings, severely ill patients will be electively ventilated and managed in intensive care
settings, allowing airway protection, seizure control, optimal assessment of fluid balance, and
hyperventilation to reduce increased ICP. However, in many of the settings in which arboviral
encephalitis occurs, this is not possible. At a minimum, patients at risk of raised ICP should be nursed at
30°C, with the neck held straight to ensure the jugular venous outflow is not impaired and with urine
output monitored and oxygen given.
Seizures are common, particularly in children with flavivirus and bunyavirus infections. In addition to
obvious tonic-clonic seizures, subtle motor seizures may be indicative of subtle motor status epilepticus
(68). An EEG is advisable, particularly in patients with twitching of a finger, lip, or eyelid. Simple or
complicated seizures should be managed according to local standard of care (83–85) (see Chapter 1
where the management of the critically ill patient with CNS infections is discussed). A few specific notes
relating to arboviral encephalitis are indicated. Attention to the etiology of increased ICP is of the greatest
importance (86,87). In many encephalopathies, if the blood pressure is well maintained, but increased
ICP is suspected, 20% mannitol (0.5 to 1.0 g/kg) is given, although the little evidence available suggests
the benefits, if any, are only short term (68,88). Steroids are sometimes given, although they were not
shown to be beneficial in JEV (89). Hypoglycemia is common in many tropical pediatric conditions (90)
and must be looked for and corrected.
PREVENTION OF ARBOVIRAL ENCEPHALITIS

A consideration of the typical arboviral ecologic cycle (Fig. 15.1) reveals points at which intervention
might be effective. These can be divided into measures to interrupt the natural cycle, measures to stop
humans being bitten by infected vectors, and measures to stop infection resulting in disease (i.e.,
vaccination). For most of the arboviruses that cause encephalitis, because the natural cycle involves small
wild birds and rodents, interrupting this cycle is not possible. However, when an intermediate or
amplifying vertebrate host brings the virus closer to humans, for example, equines for VEEV and swine
for JEV, measures can be taken. For example, vaccines that protect horses against VEE probably also
reduce the number of human cases. Immunization of swine against JEV has been practiced in Asia, though
with limited success. However, relocation of swine away from homes is probably a more effective way
of reducing transmission of JEV to humans. Surveillance of mosquitoes, dead birds, and sentinel chickens
(i.e., chickens deliberately exposed to mosquito bites) for viral infection is used in many Western settings
as an indicator of viral activity and possible impending human disease, and antimosquito measures are
then implemented. Interventions to reduce the number of circulating mosquitoes depend on the species and
the setting. Measures include removing stagnant water from swampy areas, ditches, and drains favored by
many Culex species and removing the freshwater containers (car tires, tree holes, litter) favored by Aedes
species. Larvicides can also be applied to potential breeding sites (either biologic larvicides such as
Bacillus thuringiensis variance israelensis or the chemical larvicide, metoprine). With continuing human
cases, public health authorities have practiced ground or aerosol spraying with pyrethroid formulations
that kill adult mosquitoes. Newer interventions are under development including the sterile insect
technique and the Wolbachia-based strategies to control Aedes species (91–94).
For many of these measures, evidence of beneficial impact is limited, but they demonstrate that public
health authorities are taking the situation seriously. Personal measures to reduce the chance of being bitten
by infected vectors are important. These include using repellents that contain 10% to 30% DEET (N, N-
diethyl-3-methyl benzamide) on skin and clothing, applying permethrin insecticides on clothes, and
wearing long-sleeved shirts and trouser. In areas where tick-borne viruses circulate, regular inspection of
the limbs ensures no ticks are attached. Many of the Culex vectors bite at night, and the use of
impregnated bed nets is recommended. Public education is an important part of any of these measures. For
some flaviviruses (e.g., JEV and TBEV), inactivated or live attenuated vaccines are available, although
their use is limited by cost and availability. The dramatic reduction in TBE in Austria following
widespread vaccination demonstrates feasibility. However, because most of these viruses are enzootic,
eradication by vaccinating humans is not possible. For other arboviral diseases, the sporadic nature and
low incidence mean that the vaccines would not be economically viable, even if they existed.
ALPHAVIRUSES
The alphavirus genus is one of two important genera in the family Togaviridae (named after the cloak, or
toga that envelops the viruses) (11). Whereas alphaviruses are arthropod-borne members of the other
genus, the Rubivirus genus organisms (e.g., rubella virus) are not arthropod borne and so are not
considered further here (Table 15.1). Alphaviruses cause two clinical syndromes. In Africa, Old World
alphaviruses CHIKV and o’nyong-nyong virus cause large outbreaks of fever arthralgia and rash; a
similar syndrome in which arthritis is predominant is caused by Ross River virus in Australia. In the
Americas, New World alphaviruses EEE, WEE, and VEE viruses cause outbreaks of encephalitis in
horses and humans and are the focus of this section (Table 15.2). EEE is notable for having a higher case-
fatality rate than other viruses in the group, whereas WEE is remarkable because although it has caused
large outbreaks in the past, it has now virtually disappeared as a disease of humans. Although VEEV
causes encephalitis in equines, in humans it causes a febrile disease, with only a small proportion
developing usually mild CNS disease. Two other alphaviruses, Sindbis virus and Semliki Forest virus,
have animal models of the pathogenesis of alphavirus encephalitis. Phylogenetic analyses suggest that the
alphaviruses arose in the New World with subsequent introductions into the Old World. The WEE lineage
appears to have derived as a recombinant of an ancestral EEE-like and Sindbis-like viruses (95).
Infectious Agent
Alphaviruses consist of a single strand of positive-sense RNA wrapped in a nucleocapsid and surrounded
by a glycoprotein-containing lipid membrane that is derived from host cell plasma membrane (11). The
virion is 60 to 70 nm in diameter. The 11to 12-kb RNA has a 5′ cap and a 3′ polyadenylated tail. It
consists of message-sense RNA that is directly infectious. It codes from the 5′ to the 3′ end for four
nonstructural proteins, nsP1, nsP2, nsP3, and nsP4, and five structural proteins—capsid (C), envelope 3
(E3), E2, 6K (a 6-kd protein), and E1. The nonstructural proteins are involved in replication of the viral
RNA and production of subgenomic RNA. The C protein has a conserved end with many basic amino
acids and is presumed to bind the viral genomic RNA to form the nucleocapsid. This nucleocapsid is an
icosahedron with T = 4 symmetry. The E1 and E2 glycoproteins project from the lipid membrane, forming
heterodimers that group as trimers to form 80 knobs on the virion surface (96). Alphaviruses gain entry
into cells by attaching to the cell surface and entering via the endocytic pathway to form vesicles. As the
pH level of the vesicles decreases, the E1/R2 heterodimer dissociates, revealing a highly conserved
hydrophobic sequence in E1. This is thought to act as a fusion peptide, causing viral membrane and host
cell membrane to fuse, and thus releasing the viral nucleocapsid into the host cytoplasm. Here the
nucleocapsid is uncoated of its capsid protein so that naked RNA is exposed to ribosomes for initiation of
translation as the first step of viral replication. Virus is replicated in association with the endoplasmic
reticulum and Golgi apparatus, and new virions are released by budding at the host cell surface.
Eastern Equine Encephalitis
Epidemiology
EEE virus was first isolated from the brain of a horse that died during an epizootic of equine encephalitis
in New Jersey and Virginia in 1933 (97). The first human isolate was made 5 years later. The
geographical area affected by EEE extends from Ontario and Quebec provinces in Canada, down the
eastern seaboard of the United States, and into South America as far as Argentina. To the West, the area
extends as far as Wisconsin and eastern Texas. The virus is transmitted between wading birds, passerines,
and other swamp birds by Culiseta melanura and other mosquitoes. It has also been isolated from crows
(98). These mosquitoes are strictly ornithophilic (bird biting). However, other mosquitoes that feed on
both birds and mammals serve as bridging vectors carrying the virus to horses, humans, and other
mammals (Fig. 15.2, Table 15.2). In South America, rodents and marsupials may be more important
natural hosts than birds. Outbreaks of disease have also occurred in commercial flocks of pheasants,
partridges, turkeys, and emus (99). In these circumstances, direct transmission between birds because of
preening and pecking and transmission via the fecal-oral route have also occurred. The means by which
the virus persists during the winter is not known, but persisting viremia in birds or vertical transmission
into mosquito eggs has been postulated. Cases occur year round but are more likely in the summer,
especially when associated with increased rainfall, which by creating a high water table augments the
breeding habitat of C. melanura.
EEE usually occurs as single cases and rarely as clusters that may be preceded by disease in horses.
The median annual number of cases in the United States is three (range, 1 to 14), and the reported
incidence is less than 0.1 to 0.4 per 107. Seroepidemiologic studies show that humans are only rarely
infected with the virus. Fewer than 7% of residents older than 45 years had antibody in one study (100).
Most infected patients are asymptomatic with a ratio of symptomatic to asymptomatic infections of about
1 in 30. However, the elderly and young children are more likely to develop disease.
Clinical Features
After an incubation period, which is thought to range from 3 to 10 days, patients present with a few days
of febrile prodrome and then neurologic disease. Early symptoms include headache, myalgia,
photophobia, abnormal sensations, vomiting, dizziness, and lethargy, followed by neck stiffness, a
reduced level of consciousness, and seizures. In infants, progression to coma may be more rapid,
occurring over 48 hours. On examination, a high pyrexia (>39°C) is common and one third of patients
have signs of meningismus. Clinical signs suggestive of brainstem involvement include gaze deviation,
nystagmus, and papillary abnormalities. This may be because of inflammatory lesions in the brainstem,
but uncal and subtentorial herniation have been seen at autopsy. Hemiparesis and limb spasticity suggest
upper motor neuron involvement, whereas flaccid limbs suggest involvement of lower motor neurons in
the spinal cord. Seizures may be generalized or focal. In patients who remain conscious, aphasia and
emotional lability may occur. Limb dysesthesia and flaccid paralysis have also been reported in a fully
conscious patient, suggesting myelitis may occur without brain involvement (101). Approximately one
third of patients die, but for those older than 60 years, the proportion is 50%. One third of survivors have
moderate or severe sequelae (102).
Diagnosis
Peripheral leukocytosis, with neutrophil predominance can occur. The CSF resembles that of acute
bacterial meningitis with a neutrophil pleocytosis (as high as 5,000 cells/mm3); the RBC count and
protein level are often elevated, and the glucose ratio is less than 50% in half of the patients (102,103).
CT scans show diffuse cerebral edema in most patients. On MRI, lesions that do not enhance with
gadolinium are seen in the basal ganglia, thalamus, and brainstem (102). EEGs show background and
focal slowing, as well as burst suppression. High-voltage delta waves carry a poor prognosis (103).
Virus isolation from the blood is unusual, although it has been reported for EEE early in the illness
(101). In fatal cases, virus may be isolated from brain tissue or detected by PCR or immunohistochemical
staining. In most cases, the diagnosis is made serologically by detecting antibody in the blood. Older
serologic tests such as hemagglutination inhibition, complement fixation, and neutralization tests are being
replaced by IgM capture ELISAs, which detect antibody in a single blood or CSF sample, thus providing
an earlier diagnosis.

Because there are no antiviral drugs, treatment is focused on the complications of infection, particularly
seizures and raised ICP and pneumonia. No vaccine against EEE is commercially available, although an
inactivated vaccine is used by laboratory workers and others at high risk (104). Recently, a chimeric
Sindbis (SINV)/EEEV candidates have been shown to be safe and effective against protecting mice
against EEEV (105). A similar vaccine is used to protect horses. Personal protective measures against
mosquito bites are described earlier in this chapter.
Western Equine Encephalitis
Epidemiology
The isolation of WEE virus from the brain of horses during an epizootic episode of unknown etiology in
1930 in the San Joaquin Valley of California marked the first time an arbovirus was isolated in the
territorial United States (106). Subsequently, in 1938, WEE virus was obtained from a child who
succumbed to encephalitis (107). Virus activity has been reported from western Canada, the western and
midwestern United States, and as far south as Argentina. In the western United States, WEE virus is
transmitted between passerine birds (sparrows and house finches) by Culex tarsalis mosquitoes.
Epidemic and epizootic activity occurs mainly in the summer months. Highlands J virus, which is found in
Florida, is one of several related viruses in the WEE complex that do not appear to cause disease in
humans (108).
Clinical Epidemiology
Until recently, exposure to WEE virus was common, with up to 20% of humans having antibodies in some
areas. However, a decline in the rural population and changes in land use have meant that even in areas
where the virus circulates, this figure is now less than 1% (109). The largest outbreak was in 1941, with
more than 3,000 human cases and hundreds of thousands of equine cases (110) and an estimated incidence
of 167 per 100,000 in North Dakota, but since the 1990s, there have been only a handful of reported cases
each year. The ratio of apparent to inapparent infections is estimated to be fewer than 1 in 1,000 in adults
and 1 in 60 in children.
Clinical Features
The clinical features of WEE tend to be milder than those of EEE. After an incubation period, which
ranges from 2 to 10 days, there is a nonspecific febrile prodrome before neurologic disease. Meningismus
is seen in half the patients, and although weakness and tremors are common, fewer than 10% of patients
develop coma (111). Focal signs include cranial nerve palsies, hemipareses, hyporeflexia, spasticity,
generalized rigidity, and occasionally opisthotonus. The overall case-fatality rate is approximately 4% to
10% (112), being higher among the elderly. WEE virus is more severe in infants, with rapid progression
from nonspecific illness to convulsions and coma. Transplacental infection has been reported (113). The
overall case-fatality rate is 3%, increasing to 8% for those older than 50 years (114). Neurologic
sequelae are common in young children. Parkinsonian features including cogwheel rigidity and tremors
have also been reported (115).
Diagnosis
The peripheral white blood cell count is usually normal or mildly elevated. Hyponatremia due to SIADH
has been reported. CSF opening pressures of more than 200 mm occur in two thirds of patients. CSF
white blood cell counts are usually less than 100 cells/mm3 but may range from less than 10 to 500
cells/mm3 with lymphocyte predominance, a slightly elevated protein level, and a normal glucose ratio.
CT scans have been reported as normal, but EEGs show diffuse slowing with focal delta activity in the
temporal region, which may mimic HSV-1 encephalitis (116). WEE virus is occasionally isolated from
the CSF or from diagnostic brain biopsies (117). Detection of IgM in the CSF or serum is the preferred
diagnostic test (30).

There is no specific treatment, although equine immune serum was used following laboratory exposure in
one patient (118). A nonlicensed inactivated vaccine is available for laboratory workers and others at
high risk (119). A recent study has shown the potential of an adenovirus-vectored WEEV vaccine, Ad5-
WEEV, for development into an emergency vaccine during an outbreak of WEEV (120). Furthermore, a
human adenoviral vector (Ad5-mIFNα) expressing mouse IFN-α was shown to offer 100% protection
against mice challenged with various WEEV strains (121). Surveillance and vector control measures are
practiced in some areas where the virus circulates.
Venezuelan Equine Encephalitis
Epidemiology
VEEV was first isolated from the brains of dead horses in 1938 (122), and subsequently six antigenically
related subtypes (I through VI) have been identified based on serologic cross reactivity (123). Tonate
virus is a subtype IIIB VEE complex virus that circulates in French Guiuan and has caused encephalitis
(124,125). Subtype I viruses were further subdivided serologically into IAB, IC, ID, IE, and IF. More
recent molecular genetic studies suggest a revision of some of these groups. VEEV circulates in an
enzootic sylvatic (forest) cycle (Fig. 15.2) and emerges to cause major epizootics in horses and human
epidemics every 10 to 20 years. Sylvatic VEEV is found in Central and South America, and although most
epizootics have occurred in northern South America, particularly Venezuela and surrounding countries,
they have extended as far north as Mexico and Texas (21,85,126). In its sylvatic cycle, VEEV is
transmitted between small mammals and aquatic birds mainly by Culex melanoconion mosquitoes (Table
15.2). Sporadic human cases occur when people enter the swampy and forested locations where the
viruses circulate or when bridging mosquitoes such as Aedes taeniorhynchus carry the virus to nearby
human habitats. In contrast, human epidemics occur at the same time as equine epizootics when the virus
emerges from its enzootic cycle and is transmitted between susceptible horses by Aedes, Psorophora,
Mansonia, and Deinocerites mosquito species. Some studies suggest that the E2 protein encodes
mosquito infection determinants for VEE, suggesting selection for efficient infection of epizootic mosquito
vectors may mediate VEE emergence (127). Major epizootics and epidemics of VEE have occurred every
10 to 20 years in cattle-ranching areas of Venezuela, Peru, Colombia, and Ecuador. Although epizootic
viruses (subtypes IAB and IC) were originally thought to be maintained in a separate transmission cycle
from enzootic viruses (subtypes 1D, 1E, or 1F), later studies have suggested that epizootic IC viruses
arise by mutation from sylvatic ID viruses (128–131). The 1C strains remain in the sylvatic cycle until the
ecologic factors support its emergence into the epizootic cycle. Such outbreaks occur when heavy rainfall
and flooding expand the mosquito breeding habitats and support expansion of the rodent population but
also require a large susceptible equine population. Outbreaks of VEE IAB subtype that spread to Central
America and Texas in the late 1960s and early 1970s are thought to have originated from improperly
activated equine vaccine strains, as indicated by the fact that the epizootic strains are genetically almost
identical to the vaccine strains (132).
Seroprevalence studies indicate that up to 50% of the population have antibody to VEEV in some
sylvatic areas, whereas the remainder of the population is immunologically naive until an outbreak
occurs. During the 1995 outbreak of VEE in Venezuela and Colombia, an estimated 85,000 human cases
occurred, of which 3,000 had neurologic disease and 300 were fatal (128,133). One third of the human
population seroconverted, and 8% of the equines died. Unlike most of the other arboviral encephalitides,
human viremias are sufficiently high to infect mosquitoes, suggesting humans may not always be dead-end
hosts. Isolation of virus from the pharynx of up to 40% of patients suggests direct spread between humans
is possible (134). No epidemiologic evidence of such spread has ever been demonstrated (133,134).
Clinical Features
Compared with the other alphavirus encephalitides, only a very small proportion of symptomatic VEE
infections results in severe neurologic disease. The incubation period is brief (<1 to 5 days), and most
patients then develop a febrile illness with severe headache, made worse by eye movements,
photophobia, facial flushing, conjunctival injection, myalgia, arthralgia, nausea, vomiting, and dizziness.
Pharyngeal inflammation and pain associated with cervical lymphadenopathy is common, and there may
be subcostal tenderness (133,135,136). Somnolence and tremulousness occur often. More severe
neurologic features occur in 4% to 14% of patients, particularly the young and elderly. Seizures,
particularly focal seizures, and raised ICP are common (133,137). In 5% to 10% of hospitalized patients,
cranial nerve palsies, motor weakness, paralysis, or cerebellar signs are reported. Respiratory tract
infections, including interstitial pneumonia and tracheobronchitis, are common and may result in
secondary bacterial infection. Overall, 0.2% to 1.0% of symptomatic VEE infections are fatal, but this
increases to up to 10.0% to 25.0% of those with encephalitis. Children are estimated to have ten times the
risk of neurologic disease of adults, and younger children have a greater case-fatality rate.
Diagnosis
Rather like the arboviral fever-arthralgia-rash syndromes, VEEV infection is typically associated with a
leukopenia and elevated serum aspartate amino transferase levels (135). When lumbar punctures are
performed, the CSF reveals a lymphocyte pleocytosis that may reach several hundred cells/mm3 and is
reported to be associated with an elevated CSF glucose level. As expected, given the relatively high
viremias, VEEV can be isolated from blood and pharynx up to the eighth day of illness and can be
detected by PCR (134). VEEV antibody can be detected by IgM capture ELISAs (138). A VEEV-specific
blocking ELISA that also identifies serotype-specific antibodies against VEEV in sera of humans, equids,
or rodents has been reported (139).

There is no antiviral treatment for VEE. Supportive measures include attention to seizures and increased
ICP. Equine vaccines for VEE interrupt transmission during outbreaks and prevent epizootics. An
inactivated vaccine has largely been replaced by a live vaccine (TC-83), attenuated by serial passage in
guinea pig heart cells (140). VEEV is considered a useful agent for biological warfare, because of its
potential for droplet spread and tendency to cause an incapacitating flulike illness, rather than a fatal
encephalitis, and for this reason, the vaccine was produced by the U.S. military. TC-83 is given to
laboratory workers and produces neutralizing antibodies in more than 80% of recipients; however, it is
associated with a high incidence of adverse events including fever and aseptic meningitis (37%). Most of
those who do not respond immunologically to the vaccine seroconvert when subsequently given a killed
vaccine (TC-84). An improved genetically engineered vaccine V3526 is being developed (141,142).
Another vaccine candidate in development is the recombinant, chimeric Sindbis/VEEV (SIN-83) that is
more highly attenuated than TC-83 (143,144). In addition, the use of antisense technology and humanized
monoclonal antibody has been shown to be effective against mice infected with VEEV (145,146).
Chikungunya Virus
Epidemiology
A large outbreak of a disease locally known as “Chikungunya” in the Newala district of Tanganyika (now
Tanzania) occurred in 1952 to 1953 (147). However, CHIKV may have caused outbreaks as early as
1779 as the disease was frequently mistaken with dengue (148). In the local language, Chikungunya means
“the disease that bends up the bones.” CHIKV was first isolated in 1952 from the serum of a febrile
human during this outbreak (147,149). Although initially assessed as a dengue outbreak, further
characterization of the isolates by serologic and antigenic techniques indicated that CHIKV was an
alphavirus (150). Since then, frequent outbreaks of CHIKV have been reported from many African and
Asian countries. There are three CHIKV genotypes (West African, East/Central African, and Asian) but
only one CHIKV serotype, and therefore, infection with a given genotype should result in lifelong
immunity against any genotype (151).
In Africa, CHIKV typically circulates in a sylvatic, enzootic cycle involving wild primates and forest-
dwelling mosquitoes with sporadic infection of rural human populations. The principle enzootic mosquito
vectors include Aedes furcifer-taylori (southern and western Africa), Aedes africanus (central Africa),
Aedes luteocephalus and Aedes dalzieli (Senegal), Aedes cordellieri (South Africa) and Aedes
neoafricanus. Human migration has attributed to the introduction of CHIKV to the urban setting, where
human-to-human transmission occurs through domestic and peridomestic mosquito vectors. The main
domestic vector, Aedes aegypti has been responsible for the major outbreaks of CHIKV in Comoros,
India, Kenya, Seychelles, and Singapore during the early phases of the global emergence of CHIKV
during 2004 to 2011 (151,152). However, during the later phases (2006 onward), genetic adaptation of
CHIKV to a new vector, A. albopictus led to major outbreaks in several Indian Ocean islands (Reunion
Island, Sri Lanka), India, and Southeast Asian countries (Singapore, Malaysia and Thailand) (153,154).
The Indian outbreak resulted in an estimated 1.4 million cases during 2006 to 2009, whereas an estimated
266,000 cases (258 deaths) in the Reunion Island were reported, with an overall attack rate of 34%
during 2005 to 2006 (152,155). Later studies confirmed that the epidemics in the Indian Ocean islands
and in India were associated with an amino acid substitution in the E1 envelop glycoprotein (E1-A226V)
in CHIKV, which allowed the virus to adapt for dissemination by A. albopictus. A further mutation (E2-
L210Q) has been described in the 2009 Indian outbreak, which again resulted in an increase in the
dissemination of CHIKV in A. albopictus (156). Autochthonous transmission of CHIKV has been reported
in Italy (2007) with over 250 cases and in France (2010), signaling the emergence of CHIKV in Europe
for the first time (157,158). Imported cases of CHIKV infection have now been reported in several
European countries, Australia, and the Americas (159–161).
Clinical Features
The clinical features of CHIKV infection have some similarities with dengue infection (162).
Asymptomatic CHIKV infections are rare. After an incubation period that can range from 1 to 12 (average
of 2 to 4) days, a sudden onset of high fever followed by severe arthralgia and a skin rash develops.
Almost all CHIKV patients have symmetrical polyarthralgia. The most affected joints are the fingers,
wrists, ankles, elbows, toes, and knees. The fever can reach as high as 40°C and may last up to 10 days. A
transient maculopapular and erythematous rash on the face, limbs, and torso is common and may last for 2
to 3 days. Other symptoms include myalgia, headaches, photophobia, lumbar back pain, chills, weakness,
malaise, nausea, and vomiting (151,163). The acute phase of CHIKV infection usually resolves within 1
to 2 weeks, but the arthralgia may persist for many months or years in some patients (164,165). Age and
underlying joint disorders have been shown to increase the likelihood of developing persistent arthralgia.
The case-fatality rate for CHIKV is about 0.1%, with most deaths occurring in the elderly, neonates, and
adults with an underlying disorder. Heart failure, multiple organ failure, hepatitis, and encephalitis are the
most common causes of death (163).
CHIKV has not been generally considered to be a neurotropic virus. However, reports from recent
outbreaks have given strong evidence of neurologic involvement of CHIKV. The main neurologic
manifestations of adults infected with CHIKV are encephalopathy, acute flaccid paralysis, and Guillain-
Barré syndrome (166–169). A recent study has reported that about 25% of adults admitted with atypical
CHIKV infection during the 2005 to 2006 Reunion Island had neurologic involvement (mainly
encephalitis, malaise, and meningoencephalitis) (170). Neurologic manifestations were more common in
children. The most common manifestations were encephalitis, febrile seizures, and acute
encephalopathies (171). For the first time, vertical transmission of CHIKV, from mother-to-child was
reported during the Reunion Island outbreak. Encephalopathy was the most common neurologic
manifestation among newborns infected by vertical transmission (172).
Diagnosis
A possible CHIKV case is suspected when a patient is presented with an acute onset of high fever and
severe arthralgia unexplained by other medical conditions. The case becomes probable if the patient is
living or has visited an endemic area within 15 days before onset of symptoms. The case is confirmed
when the patient test positive for one of the diagnostic laboratory tests for CHIKV (163). Diagnosis of
CHIKV is made during the acute phase of infection by detection of viral RNA in serum samples by RT-
PCR and by virus isolation. Viral RNA can be detected in samples obtained from 1 day before symptom
onset to day 7. Real-time RT-PCR assays capable of detecting a region of the nonstructural protein (nsp1)
gene or the envelope (E) gene are also used for diagnosis (173,174). For later samples, indirect
immunofluorescence and ELISA can be used to rapidly and sensitively distinguish between IgG and IgM
antibodies. CHIKV antigen can be detected in serum and CSF samples obtained 2 days after onset of
symptoms by antigen capture ELISA. Several commercial serologic assays as well as in-house ELISA
techniques have been used for CHIKV diagnosis and have been shown to accurately distinguish CHIKV
from other alphaviruses (except o’nyong-nyong virus) and flaviviruses (175–177).

Nonsteroidal antiinflammatory drugs are the only recommended treatment for arthralgia caused by CHIKV
infection. Ribavirin, chloroquine, and passive transfer of antibodies are other potential treatments being
investigated (163,178). Vector control remains the main method of CHIKV prevention (91,179). Several
vaccine candidates are under development. These include inactivated, whole-virus, DNA-based,
viruslike particle, and adenovirus-vectored vaccine approaches as well as a chimeric alphavirus vaccine
(105,180–183).
FLAVIVIRUSES
Infectious Agent
There are three important genera in the family Flaviviridae: the genus Hepacivirus, which includes
hepatitis C virus, the genus Pestivirus, which includes bovine viral diarrhea viruses, and the genus
Flavivirus (Table 15.1). This genus includes many important causes of arboviral encephalitis, as well as
arboviral fever-arthralgia-rash and hemorrhagic fever syndromes, such as dengue viruses and yellow
fever virus (Fig. 15.1). The genus and family are named after the Latin word for yellow (flavus).
Flaviviruses are thought to have evolved from a common ancestor as recently as 10,000 years ago and are
rapidly evolving to fill new ecologic niches (184,185). They consist of a single strand of positive-sense
RNA, wrapped in a nucleocapsid and surrounded by a glycoprotein-containing envelope. The RNA
comprises a short 58 untranslated region (UTR), a longer 38 UTR, and between them a single open
reading frame (186). This codes for a single polyprotein, which is cotranslationally and
posttranslationally cleaved by viral and host proteases into three structural proteins (core, or C,
premembrane, or PrM, and envelope, or E), and seven nonstructural (NS) proteins (NS1, NS2A, NS2B,
NS3, NS4A, NS4B, and NS5). The C protein is highly basic and combines with the RNA to form the
nucleocapsid. The PrM is closely associated with the E protein, forming a heterodimer, and is thought to
act as a “chaperone” to it, impairing its function until after virion release. Immediately before virion
release, the PrM protein is cleaved by a furin-like protease to its mature M protein form. This allows the
formation of E protein homodimers, which are thus “activated” (187). The E protein is the largest
structural protein, consisting of nearly 500 amino acids with up to two potential glycosylation sites. It is
the major target for the humoral immune response and is thought to be important in viral entry into host
cells. Studies with monoclonal antibodies and more recently with x-ray crystallography have determined
the composition of the E proteins’ three domains (188,189). Domain III is the putative receptor-binding
domain (by which virions attach to the yet-to-be-identified host cell receptor), domain II is the
dimerization domain, and domain I has a central beta barrel and is the hinge domain that links the other
two domains. Following viral attachment to the cell surface, flaviviruses enter cells by endocytosis.
Subsequent fusion of the virus’ lipid membrane with the endosome membrane allows viral RNA to
penetrate into the cytoplasm of the infected cell (186). Recent cryoelectron microscopic studies have
shown an arrangement of 90 E-protein dimers lying flat on the surface of the virion, which rearrange to
form E homodimers as the pH level decreases, exposing an internal fusion peptide and a patch of viral
membrane for fusion. Interestingly, recent studies have shown the E1 protein of alphaviruses has a striking
similarity to the flavivirus E protein, in terms of structure and function (96). Together, they have been
labeled class II fusion peptides (190).
West Nile Virus
Epidemiology
WNV was first isolated from the blood of a febrile woman in the West Nile region of northern Uganda in
1937 (191). It was soon shown to be transmitted between vertebrate hosts (especially birds) by
mosquitoes. Sporadic cases and larger outbreaks of febrile disease (West Nile fever) were reported in
Africa, the Middle East, and Asia (192). Although meningeal irritation was noted in some patients with
West Nile fever, the first cases of encephalitis due to WNV occurred when the virus was given as an
experimental (and unsuccessful) treatment for advanced cancer in 1951. The first naturally occurring West
Nile encephalitis cases were in the elderly residents of a nursing home in Israel (193). Outbreaks of
equine and human meningoencephalitis occurred in southern France during the 1960s, and a subtype of
WNV (Kunjin virus) was isolated in Australasia. Since the 1990s, the clinical epidemiology of WNV
appears to have changed with increasing frequency and severity of outbreaks, including urban disease.
These included an outbreak with nearly 400 confirmed cases in Romania in 1996, nearly 200 cases in the
Volgograd region of Russia in 1999 and more than 200 cases in Israel in 2000 (194–197). In 1999, the
virus appeared in North America for the first time, with 62 confirmed cases (198,199). It spread across
the continent during 2000 and 2001, causing a largest encephalitis outbreak in 2002, with nearly 3,000
cases and 250 deaths (75). WNV is now the leading cause of domestically acquired arboviral disease in
the United States of America and has spread throughout Canada, the Caribbean, Colombia, and Mexico
(200,201). In 2010, WNV outbreaks occurred in Greece with 262 confirmed human cases with 197 cases
of neuroinvasive WNV and in Romania with 57 cases, out of which 54 was neuroinvasive (202,203).
Another outbreak occurred in Greece in 2011 with 31 cases of neuroinvasive WNV (204).
Most human infections with WNV are asymptomatic. In the 1998 to 1999 outbreaks, approximately 1 in
5 infections resulted in West Nile fever and only about 1 in 150 developed CNS disease (194,197). Over
75% of patients infected with WNV had neuroinvasive disease (encephalitis, meningitis, or acute flaccid
paralysis) during the recent outbreak in Greece and over 94% during the Romanian outbreak (202,203). In
contrast, the proportions were much lower in earlier outbreaks in Africa (192,205). In outbreaks across
Europe and America, the risk of febrile disease and of neurologic disease increased with age, which may
in part explain the differences compared to parts of Africa. In Egypt, most of the population is infected
during childhood, and neurologic disease is rare (205). In a South African outbreak of 18,000 people of
all ages, only a single encephalitis case was reported (192).
Recent molecular phylogenetic studies show that isolates of WNV can be divided into seven lineages.
Lineage 1 has been subdivided into a further three clades: 1a, 1b, and 1c. Lineage 1b has spread to
Australasia as Kunjin virus, whereas lineages 1a and 5 are found in India, and lineage 6 in Malaysia
(206). Lineage 2 strains have mostly been found in Africa, whereas lineage 1 strains are more widely
distributed and are responsible for all the large outbreaks during 1998 to 1999 (207,208). This has led to
the suggestion that they may be more virulent, although neuroinvasive strains have been shown in both
lineages in animal models (209). However, lineage 2 was more prevalent during the recent outbreaks in
Europe (Greece, Romania, and Italy) and therefore may disperse wider in the future (210,211).
In nature, WNV is transmitted in an enzootic cycle between birds by mosquitoes. WNV infects over
300 different bird species and 50 mosquito species (1). Members of the order Passeriformes (jays,
blackbirds, finches, warblers, sparrows, and crows) appear to be important in maintenance of the virus in
nature (because of viremias); the family Corvidae (crows, blue jays) seems to be particularly susceptible
Culex mosquitos, particularly Culex pipiens, appear to be important in the enzootic cycle, although
different species may act as “bridging vectors” transmitting the virus to humans.
How WNV is introduced to new areas is not completely understood. Migratory birds are thought to be
important for the movement of WNV from Africa into southern Europe. They may have been involved in
the virus’ introduction into the United States, although imported exotic birds, a viremic human, or
inadvertently transported mosquitoes seem more likely (212). Molecular genetic evidence suggests there
was a single introduction into the United States of a strain closely related to one isolated from a goose in
Israel (207). A complex interplay of viral, avian, mosquito, human, and climatic factors may contribute to
the large outbreaks that have characterized the disease recently (Fig. 15.4). During the 2002 outbreak in
the United States, transmission also occurred via transplanted organs, infected blood products, and
possibly breast milk (213).
Clinical Features
After an incubation period, which is typically 2 to 6 days but may extend to 14 days, patients with West
Nile fever develop a sudden onset of an acute nonspecific flulike illness, characterized by high fever with
chills, malaise, headache, backache, arthralgia, myalgia, and retroorbital pain (86). Other nonspecific
features include anorexia, nausea, vomiting, diarrhea, cough, and sore throat. In epidemics of West Nile
fever, a flushed face, conjunctival injection, and generalized lymphadenopathy were common. A
maculopapular or pale roseolar rash was reported in about 50% of patients and was more common in
children. In one outbreak, 20% of patients with West Nile fever had hepatomegaly and 10% had
splenomegaly (214). Myocarditis, pancreatitis, and hepatitis occur occasionally in WNV infection.
Patients with neurologic disease due to WNV typically have a febrile prodrome lasting 1 to 7 days that
may be biphasic, before developing neurologic symptoms. Although in most cases, the prodrome is
nonspecific, 15% to 20% of patients may have features suggestive of West Nile fever, including eye pain,
facial congestion, or a rash, though less than 5% had lymphadenopathy (215). In the 1998 to 1999
outbreaks, approximately two thirds of hospitalized patients had encephalitis (with or without signs of
meningeal irritation), and one third had meningitis (194,196,199). Severe generalized muscle weakness
was a common feature in the 1999 New York outbreak and subsequent outbreaks in the United States
(199). In some patients, this affects only the limbs, but in others, respiratory and bulbar musculature are
affected, requiring ventilation. Though initially ascribed to Guillain-Barré syndrome, the weakness was
probably due to anterior horn cell damage (myelitis), as is seen in other flavivirus infections (86).
Conscious patients with a polio-like flaccid paralysis due to WNV were recognized in the 1970s and
2002 (70,216). In the recent outbreaks in Greece, 85% of patients had encephalitis/meningoencephalitis
and 12% had meningitis, followed by 3% with acute flaccid paralysis (202).
Although seizures occurred in approximately 30% of patients in the early descriptions of West Nile
encephalitis, they did not appear to be an important feature in the Romania or the New York outbreak
(199). Other neurologic features include cranial neuropathies, optic neuritis, and ataxia. Stiffness, rigidity,
spasms, and tremors associated with basal ganglia damage similar to that seen in JE (217) have also
recently been recognized in West Nile encephalitis (32).
Overall case-fatality rates for patients hospitalized with West Nile encephalitis outbreaks ranged from
4% to 14% but were higher in older patients (196,199). However, the overall case-fatality rate during the
recent Greece outbreak was much higher at 17%, increasing to nearly 35% for those older than 80 years
of age (202). Other risk factors for death include the presence of profound weakness, deep coma, failure
to produce IgM antibody, impaired immunity, and coexisting illness such as hypertension and diabetes
mellitus (199,218). Neurologic sequelae are common among survivors. In one study, half of patients
hospitalized still had a deficit at discharge and only 33% recovered fully at 1 year (219).
Diagnosis
Approximately 50% of patients have a peripheral leukocytosis, and 15% have leukopenia (199,219).
Hyponatremia sometimes occurs in encephalitic patients. Examination of the CSF typically shows a
moderate lymphocytic pleocytosis, although sometimes no cells or neutrophils may predominate. The
protein is moderately elevated and the glucose ratio is typically normal. CT scans of the brain are usually
normal. MRI may show nonspecific enhancement of the meninges or periventricular areas (199,220) or
high signal intensities on T2-weighted images in the thalamus and other basal ganglia (32). Nerve
conduction studies typically show reduced motor axonal amplitudes consistent with anterior horn cell
damage, although there may also be some slowing of conduction velocities and some changes to sensory
nerves (86,216). The differential diagnosis is broad and includes other causes of viral encephalitis (Table
15.3) and other causes of fever and reduced consciousness (Table 15.4).
Attempts at WNV isolation from serum or CSF are usually unsuccessful, because viremias are low, and
the virus has cleared by the time most patients present (Fig. 15.3). Techniques include detection of viral
antigen by ELISA or of viral nucleic acid using reverse transcriptase PCR (RT-PCR) or real-time PCR
(Taq-Man). Real-time PCR, the most sensitive of these techniques, detects only 55% of patients (221).
Newer real-time RT-PCR assays, including multiplex RT-PCR assays are more sensitive and offer rapid
detection of WNV (81,210,222). The accepted standard for diagnosing WNV infection is the detection of
IgM-specific antibodies in CSF and/or serum using IgM capture ELISAs (29). Whereas antibody is
detected in the serum of those with West Nile fever or even asymptomatic infection, IgM in the CSF is
specific for CNS infection. Half of patients have antibody on admission, and almost all have antibody by
the seventh day of admission. Those who do not are more likely to have virus isolated and are more likely
to die (32,223).
There is no established antiviral treatment for West Nile encephalitis, although IFN-α, ribavirin, and
human immune globulin have been used in some patients (196). Treatment for patients with West Nile
encephalitis is supportive. Mosquito repellents are an identified prophylaxis being particularly important
for those in “at-risk” groups, such as the elderly and the immunocompromised. There is no human vaccine
for WNV, although a crude formalin-inactivated vaccine and a recombinant plasmidic DNA vaccine has
been developed for horses (224,225). Several new vaccine candidates for human are being developed
and evaluated with some vaccines in phase I/II human trials (210,226,227).
Japanese Encephalitis
Epidemiology
Outbreaks of encephalitis have been described in Japan since the 1870s (228). The virus was first
isolated in 1935 and has been recognized across much of eastern and southern Asia since then. All of
Southeast Asia, the western Pacific region, most of the Asian subcontinent, and much of southern China is
now affected, and the virus recently reached Australia for the first time (229). An estimated 35,000 to
50,000 cases and 10,000 deaths occur annually, making JEV numerically the most important cause of
epidemic viral encephalitis worldwide (230). Approximately half the survivors have severe
neuropsychiatric sequelae, imposing a large socioeconomic burden in the areas affected. JEV is
transmitted naturally in an enzootic cycle between birds, pigs, and other vertebrate hosts by mosquitoes,
especially Culex tritaeniorhynchus, Culex gelidus, and other species that breed in rice paddies. Humans
become infected when they encroach upon this enzootic cycle. Because the virus is so ubiquitous, in rural
areas almost all humans become infected during childhood, but only a small proportion, estimated at
around 1 in 300 develop symptoms (230), which may range from a nonspecific febrile illness through to a
severe meningoencephalomyelitis. In endemic areas, most cases of JEV occur in children because by the
time they reach adulthood, almost all individuals have been exposed to the virus and will have developed
neutralizing antibodies. However, when immunologically naive adults are exposed to the virus, for
example, when the virus moves to new geographical areas or when travelers or service personnel visit
Asia, they too may develop disease (231). In northern temperate parts of Asia, JEV causes large summer
epidemics, but in southern tropical areas, disease is year round, with a peak in the summer months (232).
There are at least four genotypes of JEV across Asia; molecular phylogenetic studies suggest that the
distribution of genotypes is best explained by the virus’ origin in the Indonesia-Malaysia region and
spread from here (233–235). A recent molecular phylogenetic study has identified the Muar strain of JEV
as the fifth genotype of JEV with approximately 20% divergence from other JEV strains (236).
Furthermore, recently isolated strains from C. tritaeniorhynchus in China and from Culex
bitaeniorhynchus in Republic of Korea have been identified as genotype V, suggesting that this genotype
may be reemerging in Asia (237,238).
Clinical Features
After a 4- to 14-day incubation period, most patients develop a brief nonspecific febrile illness and then
neurologic disease, manifesting as a reduction in the level of consciousness and seizures. Seizures occur
in approximately 85% of children and 10% of adults with JEV (68,239). Multiple seizures and status
epilepticus are associated with a poor outcome. Subtle motor status epilepticus, in which the only clinical
manifestation might be the twitching of a finger or eyebrow, is important in JEV (68). Multiple
uncontrolled seizures may be associated with increased ICP and clinical signs of brainstem herniation
syndromes (68). Movement disorders are common in JEV, both in the acute stages of infection and as part
of the spectrum of neuropsychiatric sequelae. One quarter of patients showed acute manifestations in one
series (68). A characteristic parkinsonian syndrome includes masklike facies, tremors, and cogwheel
rigidity. Other movement disorders include generalized rigidity, jaw dystonias, opisthotonus,
choreoathetosis, orofacial dyskinesias (involuntary tongue protrusions), myoclonic jerks, and opsoclonus
myoclonus (68,217). These disorders are thought to be the clinical correlate of the inflammation often
seen in the basal ganglia—particularly the thalamus and substantia nigra—on MRI and at autopsy
(217,240). In some patients, intention tremors and ataxia reflect cerebellar involvement. Other focal
neurologic signs include cranial nerve palsies, upper motor neuron weakness (in 30% to 50% of
patients), and flaccid limb weakness, with reduced or absent reflexes, which is often associated with
respiratory or bulbar paralysis (241). The combination of upper and lower motor neuron damage can lead
to bizarre mixtures of clinical signs that can change hourly during the acute stages of infection. In addition
to causing flaccid weakness in comatose patients with encephalitis, JEV can cause a poliomyelitis-like
acute flaccid paralysis in fully conscious patients (69). Acute retention of urine, due to an atonic bladder,
may be an early clue that paralysis is due to a flavivirus (69). Overall, 20% to 30% of hospitalized
patients die, and half the survivors have neuropsychiatric sequelae. Poor prognostic signs include a
depressed level of consciousness, decerebrate posturing, multiple seizures, increased ICP, isolation of
virus from the CSF, and low levels of JEV-specific IgM and IgG in CSF and serum (31,68,239,242).
Other nonspecific indicators include elevated admission temperature, absent abdominal reflexes,
hyponatremia, low serum iron level, and elevated CSF white blood cell counts and protein level
(68,126,239,243,244).
Diagnosis
A peripheral polymorphonuclear leukocytosis is common. CSF examination reveals an elevated opening
pressure in 50% of patients and usually a lymphocytic pleocytosis with a normal glucose ratio and
slightly elevated protein. MRI may show high signal intensity on T2-weighted scans in the thalamus, other
basal ganglia, midbrain, brainstem, and sometimes anterior spinal cord. EEGs may reveal seizure activity,
including periodic lateralized epileptiform discharges (PLEDs) as occurs with HSV encephalitis. This is
usually on a background of slow-wave activity. Nerve conduction studies typically show reduced motor
amplitudes, consistent with damage to the lower motor neurons in the anterior horns of the spinal cord
(69,241), as is seen at autopsy (240). JEV is confirmed by IgM and IgG capture ELISAs, revealing
antibody in the serum and the CSF (27,245,246). A robust and userfriendly rapid IgM capture ELISA
(JEV Chex) has been developed with similar sensitivity as conventional ELISAs (247). Virus isolation
and PCR from serum are usually negative; they may be positive in the CSF of fatal cases and in
postmortem brain tissue (31,248).
A number of antiviral compounds against JEV have shown promise in vitro or animal models, including
nitric oxide, ribavirin, and IFN-α (249–251). IFN-α showed promise in open clinical trials (252), but in a
randomized placebo-controlled trial in Vietnamese children, it failed to make any difference to the
outcome (82). Treatment of JEV focuses on controlling the complications of infection such as seizures and
ICP. High-dose dexamethasone failed to show any benefit (89). Recent studies on mice have shown
protective effects of pentoxifylline and minocycline against JEV challenge (253–255).
Given that the vectors of JEV breed in rice paddies, vector control may seem an impossible task, but
measures that may have an impact include intermittent irrigation of the rice paddies and use of natural
larvicides, such as larvivorous fish and the plant neem (Azadirachta indica) (256). Personal protection
with insect repellents and by using mosquito netting is also recommended. However, the most effective
prevention is with vaccines. A mouse-brain–derived formalin-inactivated vaccine (JE-Vax) has been
available for many years, produced by the Japanese under the Biken label and by the Korean Green
Cross. Efficacy was demonstrated in a double-blind trial in Thailand (257), and it is used by travelers
and service personnel and in some of the wealthier Asian countries (231). Earlier crude preparations of
the vaccine were associated with adverse events, and in the early 1990s, there were reports of
hypersensitivity reactions, although the risk of serious neurologic adverse events is low, at about 1 in 1
million (258). JE-Vax is no longer manufactured and all existing stocks expired in May 2011 (259). A live
attenuated vaccine (SA14-14-2), developed by passage through primary hamster kidney cells, has been
used in China since the 1980s and was shown to be safe and efficacious (260–262). It is also relatively
cheap and has been licensed to use in Korea, Nepal, and Sri Lanka. However, regulatory approval for its
wider use has been delayed because of concerns about its production, in particular whether it meets
international “good manufacturing practice.” A new inactivated Vero cell culture–derived vaccine (IC51
or IXIARO) using the attenuated SA14-14-2 strain for adults is now approved for use in the United States,
Europe, Canada, Australia, Hong Kong, and Switzerland. Clinical trials are ongoing to determine the
safety and efficacy of this vaccine for use in children (259). Newer vaccines in clinical trials include a
chimeric vaccine (JE-CV or IMOJEV) in which the prM and E genes of JEVSA14-14-2 strain are
inserted into the genome of the yellow fever 17D “backbone” containing the yellow fever nonstructural
gene, which has been used safely for many years (226,263).
St. Louis Encephalitis
Epidemiology
Before West Nile encephalitis in New York in 1999, St. Louis encephalitis (SLE) was the most important
flavivirus in North America. Outbreaks compatible with SLE were described from the 1920s, but the
disease was first recognized in Paris, Illinois and then St. Louis and Kansas City, Missouri in the 1930s.
The virus was isolated from the brain of a fatal case in 1931 (264) and is transmitted in nature between
passeriform and columbiform birds by Culex mosquitoes. The area affected by SLE extends from Canada
through the United States to Central and South America. Strains of virus circulating in the United States
are genetically distinct from those in Central and South America, forming two major clades, within which
there are subgroups. Strains in the western United States, which are transmitted by C. tarsalis mosquitoes,
differ from those found in the east that are transmitted by C. pipiens/Culex quinquefasciatus and Culex
nigripalpus. Eastern strains are associated with greater epidemic potential, being more readily
transmitted by mosquitoes, causing higher viremias in sparrows (one of the major vertebrate hosts) and a
higher case-fatality rate in humans (265). However, between epidemics in the east, there may be long
intervals during which no cases are seen. In contrast, in the western United States, transmission is
endemic and sporadic cases are seen every year, but the case-fatality rates are lower. The incidence rates
are highest in the Ohio and Mississippi River basins and the Gulf Coast. The annual reported incidence
has fluctuated from 0.003 to 0.752 per 100,000, with a median of 35 cases reported each year (265).
However, larger numbers have occurred in some years. In 1975, the largest outbreak recorded caused
2,800 cases in 31 states, and in 1990, there were 222 cases during an epidemic in Florida. Serologic
surveys suggest that on average approximately 1 in 300 infections is symptomatic. This rises with age,
from 1 in 800 among children younger than 10 years to 1 in 85 for adults. Human immunodeficiency
virus–positive individuals appear to be at greater risk of acquiring SLE (266). More recently, an outbreak
of SLE occurred in Argentina with 47 laboratory-confirmed cases and nine deaths (267,268).
Clinical Features
After an incubation period, which is usually around 4 days but may extend to 21 days, patients present
with fever, headache, malaise, myalgias, and other nonspecific features such as diarrhea, nausea,
vomiting, cough, and sore throat. Dysuria, urgency, and incontinence are early features in some patients. In
patients younger than 20 years, about 55% have encephalitis, and 40% have meningitis, but in those older
than 60 years, more than 90% have encephalitis (269). The most common manifestation of encephalitis is
a reduced level of consciousness, which may range from mild confusion to deep coma. Tremulousness of
the eyelids, tongue, lips, and extremities is one of the most common neurologic signs. More marked
involuntary movements such as myoclonus, nystagmus, and opsoclonus are less common. About 25% of
patients have cranial nerve palsies, usually unilateral. Cerebellar ataxias are also common. Seizures
occur in children and in more severe adult cases and are a poor prognostic sign (270). Subtle motor
seizures have also been reported (271). About 17% of patients die (269), and neuropsychiatric sequelae
including emotional disturbances, forgetfulness, tremor, unsteadiness, and visual disturbances occur in
about 33% of patients.
Diagnosis
The peripheral white blood cell count is normal or slightly elevated. In some patients, microscopic
hematuria, proteinuria, and pyuria have been reported. Hyponatremia due to SIADH secretion occurs in
more than one third of patients, and alanine aminotransferase and creatinine phosphokinase levels may be
slightly elevated. One third of patients have an elevated CSF opening pressure, and there is typically a
moderate mononuclear pleocytosis, with an elevated protein level. EEGs show diffuse slowing and
occasional spike-and-wave activity, including PLEDs. The MRI may show high signal intensity in the
substantia nigra (269). The diagnosis is usually made by IgM capture ELISA or immunofluorescence, with
nearly 100% of CSF samples being positive by day 7 of illness (272). Antibody can also be measured in
the serum, but there may be problems with cross-reactive antibody in patients previously exposed to other
flaviviruses, such as dengue. Virus can sometimes be cultured from the brain tissue of fatal cases or
occasionally demonstrated by electron microscopy. Viral antigen detection and PCR results may be
positive but are not reliable for routine diagnosis.

There is no antiviral treatment; thus, care is supportive. There is no vaccine. Measures to reduce the risk
of being bitten by an infected mosquito are described earlier in this chapter.
Murray Valley Encephalitis
Epidemiology
Outbreaks of encephalitis in Australia in 1917 and 1922, labeled “Australian X” disease, or an “aberrant
form of poliomyelitis” (273), have subsequently been attributed to MVEV, which was first isolated from
the brain of a fatal case in 1951 (274). The virus has been found across parts of Australia and New
Guinea and is transmitted between herons, egrets, and other aquatic birds, by Culex annulirostris, and
other mosquitoes. The overwintering mechanism and factors responsible for the intermittent epidemics
are not known. MVEV is enzootic in the Kimberley region of Western Australia and the Northern
Territory and is thought to only reach southeastern Australia during extreme weather conditions (275).
Only about 1 in 1,000 to 1 in 2,000 infections result in disease, and the number of cases is small, 25
between 1990 and 1998. Most cases are in aboriginal children living in areas where they are exposed to
the virus, but cases have also occurred in travelers to these areas (276). More recently, the number of
MVEV cases increased (16 cases and three deaths) in endemic areas of Australia and reemerged in
southeastern Australia. This outbreak in 2011 was followed after heavy rainfall and flooding resulting in
increased numbers of C. annulirostris mosquitoes and widespread seroconversion among sentinel
chicken flocks (277).
Clinical Features, Diagnosis, and Treatment

After a brief nonspecific febrile illness, milder cases develop meningism and tremulousness, whereas in
more severe cases, there are seizures, flaccid paralysis requiring mechanical ventilation, and coma (276).
Infants may deteriorate rapidly and die within 24 hours. Approximately one fourth of hospitalized cases
die and one fourth have severe sequelae. Typically, there is a CSF pleocytosis, with mildly elevated
protein and normal glucose levels. MRI may show high signal intensities in the basal ganglia (278). Virus
has been isolated by inoculating postmortem brain tissue into chick embryos, but the diagnosis is usually
made serologically with an ELISA, hemagglutination inhibition, complement fixation, or neutralization
test. Treatment is supportive, because there is no antiviral drug. Patients with MVE have been treated
with corticosteroids but the effectiveness has not been assessed in controlled clinical studies (277). No
vaccine is available, and the low incidence of disease makes it unlikely that one will be developed.
However, recent studies in mice have shown that the live chimeric JEV vaccine offered cross protective
immunity against lethal challenge with MVEV (279).
Tick-Borne Encephalitis
Epidemiology
Descriptions of a disease compatible with TBE appeared from the 1930s, and the virus was first isolated
by Russian scientists in the Far East in 1937 (280). Three closely related subtypes of TBE virus exist,
whose names reflect the geographical areas they principally affect: European/Western, Siberian, and the
Far East. However, across this vast geographical area, the disease was given a range of different names
(central European encephalitis, Russian spring/summer encephalitis, Far East Russian encephalitis,
biphasic milk fever, Taiga encephalitis, Kumlinge disease, Fruhsommer meningoenzephalitis) before it
was realized that they are essentially the same disease. The TBE group serocomplex (recently renamed
the mammalian group of tick-borne flaviviruses) also includes Powassan virus (a rare cause of
encephalitis in Canada); louping ill virus (a very rare cause of CNS disease in the British Isles and
Scandinavia); and viruses that cause hemorrhagic disease, such as Kyasanur Forest disease virus (in
India) and Omsk hemorrhagic fever virus (in Siberia) (Fig. 15.1). TBE virus is naturally transmitted
between small rodents by hard Ixodes ticks (particularly Ixodes ricinus and Ixodes persulcatus).
Because ticks may live for months or even years, and because they can pass the virus to their offspring
transovarially and transtadially, they act as important reservoirs. Following the bite of an infected tick,
small mammals become viremic, and subsequent biting ticks then become infected. In addition to this
“classic” arboviral transmission cycle, virus may also be transmitted from tick to tick via infected
reticuloendothelial and inflammatory cells (Langerhans cells, neutrophils, monocytes, and macrophages)
in the skin of the vertebrate host without the need for the animal to become viremic (8). Adult ticks tend to
feed on larger mammals and thus infect humans walking through dense forest between spring and autumn.
Across the large geographical area where TBE occurs, the virus tends to circulate in small “natural foci”
where the vegetation, temperature, moisture, and presence of appropriate mammalian hosts supports their
existence. Humans can also become infected by drinking the unpasteurized milk or cheese of infected
goats, cows, and sheep, causing “biphasic milk fever.” There has been a dramatic increase in the number
of cases of TBE in humans following drinking TBEV-infected milk in Russia and Europe (281). The
incidence of TBE varies according to location and year (282). TBE is endemic in 27 European countries.
The endemic area spans from central and Eastern Europe to Siberia and some parts of Asia, including
China and Japan. Nearly 170,000 clinical cases of TBE have been reported in Europe and Russia
between 1990 and 1999. In Europe, there have been on average about 3,000 cases annually in the last 5
years (281). Following the collapse of the former Soviet Union and reduced use of pesticides and vaccine
against TBE, the annual incidence rose to more than 10,000 cases (3). Serologic surveys indicate that in
endemic regions, 70% to 95% of infections are subclinical.
Clinical Features
Three fourths of patients recall a tick bite, a median of 8 days (range, 4 to 28 days) before symptoms
develop (283). A couple days of headache, fatigue, and pain in the neck, shoulders, and lower back
precede the onset of high fever, nausea, and vomiting. In three fourths of patients, the illness is biphasic,
with this febrile prodrome of several days, followed by an afebrile period of about 8 days (range, 1 to 33
days) before neurologic disease develops (283,284). In the mildest form of disease—labeled the “febrile
form” by Russian clinicians—the febrile phase lasts from 1 to 5 days, sometimes with severe muscle
pains and sometimes numbness and fasciculations, before resolving with no residual deficit (3). In the
“meningeal form” of disease, there is neck stiffness and photophobia. The “meningoencephalitic form” is
characterized by a reduced level of consciousness, which may range from drowsiness and hallucination to
deep coma, focal neurologic signs, including hemiplegia, and seizures. There may also be cardiac
arrhythmias. A “poliomyelitic form” with poliomyelitis-like flaccid paralysis is common in TBE virus
infection. This usually affects the neck and upper limbs to cause pain, sometimes with periodic muscle
contractions and numbness, then upper limb weakness with winging of the scapula, wristdrop, or a
“hanged head” due to neck extensor weakness. Muscle atrophy begins after the second or third week and
persists. In contrast, some patients develop a “polyradiculoneurotic” form of disease: neuropathy occurs
1 to 2 weeks after the initial febrile phase and is associated with a recurrence of fever, but there is usually
complete recovery. Finally, in Russia, a “chronic” form of TBE has been described and is believed to be
caused only by the Siberian subtype of TBEV. In some patients, deterioration continues long after the
acute disease, postmortem examination suggests chronic inflammation, and viral RNA may be detected by
nucleic acid hybridization. Other patients are asymptomatic following the initial tick bite but present
years later with a progressive form of disease, with virus being isolated at autopsy (65). Spontaneous
regular contractions (myoclonic jerks) of the limbs are seen in about 25% of patients with all neurologic
forms of TBE disease and may persist as epilepsia partialis continua (Kozhevnikov epilepsy).
Traditionally, disease caused by the Far East subtype of TBE virus is thought to be more severe than
that caused by the European subtype, with case-fatality rates of 20% to 60% compared with 1% to 3%,
respectively. Differences in criteria for hospitalization may account for much of this apparent difference,
although differences in virulence have been found in animal models. The case-fatality rate of the Siberian
subtype appears to be similar to that of the European subtype, with neurologic sequelae reported for 30%
to 60% of survivors. Interestingly, in biphasic milk fever following oral ingestion of infected milk, TBE
virus typically causes only the “febrile form” of disease. Although there is sometimes mild meningism,
encephalitis and paralysis are not seen, and recovery is the rule (3).
Diagnosis
During the initial febrile stage, leukopenia and thrombocytopenia are common (285), but by the time
patients have neurologic disease, many have a leukocytosis (283). CSF examination usually reveals a
mild pleocytosis with elevated protein level. EEGs of patients with encephalitis show slowing with or
without focal activity (283). On MRI, abnormalities have been shown in about one fourth of patients with
encephalitis, usually in the thalamus but sometimes in the caudate, cerebellum, and brainstem. The
diagnosis is usually suspected because of the history of tick bite, although other tick-borne febrile
illnesses including borreliosis and ehrlichiosis should be considered. The diagnosis is confirmed by
detection of IgM antibodies in CSF and/or serum using an ELISA (286), although during the early viremic
phase, virus may also be cultured from the blood. PCR assay have also been shown to be useful in
detecting TBEV in the first phase of illness (287).

There is no antiviral treatment, but an anti-TBE immune globulin has been used for postexposure
prophylaxis in those bitten by ticks in areas where the virus circulates. It is licensed under the FSME-
Bulin label by Baxter in Austria, and the Encegam label by Chiron/Behringwerke in Germany. An
intramuscular dose of 0.2 mL/kg is recommended up to 4 days after the tick bite (288). Prophylaxis later
than this is not recommended because of the theoretical potential of antibody aggravating inflammation in
patients with established neurologic disease. Postexposure prophylaxis is not recommended for children.
The preparations have also been used (at 0.4 mL/kg) as short-term preexposure prophylaxis for those
about to visit areas at risk.
A formalin-inactivated vaccine based on an Austrian virus isolate (TBEV-Eu strain Neudoerfl) grown
in chick embryo cells has been commercially available in Europe since 1976. It had a relatively high rate
of side effects (fever, headache, malaise) but has been replaced by a highly purified form, prepared by
ultracentrifugation (289). This vaccine (FMSE-Immun, Baxter), which contains aluminum hydroxide as an
adjuvant, has an efficacy of about 98%. Vaccination is recommended for those living, traveling, or
working in areas at risk, as well as laboratory workers. Mass vaccination since 1981 in Austria resulted
in a marked decline in the number of TBE cases (290). Another formalin-inactivated vaccine, based on
the TBEV-Eu strain K23 (Encepur, Novartis) manufactured in Germany is also used in Europe. This
vaccine was initially withdrawn from pediatric use because of allergic reactions related to polygelin,
which was removed in 2001 (291). Children are given half the adult dose to reduce the high fever that
was observed when given the full dose (292). Two other formalin-inactivated vaccines, TBE-Moscow
vaccine (based on the Far-Eastern Sofjin strain) and EnceVir vaccine (based on the Far-Eastern 205
strain), are widely used in Russia and several Asian countries. EnceVir is not currently recommended for
pediatric use because of high rates of fever and allergic reactions observed in 2010 and 2011. These two
vaccines are produced similar to the vaccines used in Europe except the TBE-Moscow vaccine, which is
finally lyophilized. All four vaccines are produced according to the World Health Organization (WHO)
manufacturing standards (293). Live attenuated vaccines against TBEV are currently under development
(294). In 2011, the WHO published its first position paper on TBE vaccines, giving recommendation for
TBE vaccination (295).
Neurologic Dengue Disease

Epidemiology
Most patients affected by one of the four dengue viruses (dengue 1, 2, 3, and 4) present with a fever-
arthralgia-rash syndrome or a viral hemorrhagic fever (296). The cause and even existence of neurologic
manifestations of dengue has been a long-standing controversy (297–302). However, more recent studies
have given strong evidence to support neuroinvasion of DENV (303–306). Most authorities now accept
that dengue viruses can cause a nonspecific encephalopathy and occasionally encephalitis, even if the
mechanism is not yet clear (307,308). The four types of dengue virus were isolated from febrile patients
in the 1940s, and dengue is unusual among arboviruses in that humans are the main natural host, although a
sylvatic cycle exists in primates in Southeast Asia and West Africa (309). The virus is transmitted
between humans by A. aegypti and A. albopictus mosquitoes that breed in small collections of fresh water
around the home (e.g., collected in rubbish, water containers, and tires). Dengue is very widely
distributed, being found in almost every country between the tropics of Capricorn and Cancer (310).
According to the WHO, over 50 million cases of dengue occur every year. Three outbreaks of dengue
occurred during 2001 and 2011 in the United States, and the reemergence of autochthonous dengue
transmission within Europe has also been described (311,312). Neurologic disease has been reported
from virtually every country where dengue occurs (297). It is now recognized that in parts of Southeast
Asia, dengue is responsible for 1 in 20 patients admitted with a suspected CNS infection (300) and as
many as 1 in 5 of those with a clinical diagnosis of encephalitis (299).
Clinical Features
Most patients with neurologic dengue present with a reduced level of consciousness and other signs of
severe dengue infection, including the shock, vascular leakage, and hemorrhage that characterize dengue
hemorrhagic fever (DHF). They may also have metabolic disturbances such as hyponatremia and
acidosis, and in many patients, the encephalopathy is thought to be secondary to these complications.
However, in other patients with no rash, hemorrhage, or other signs of dengue fever or DHF, viral
invasion across the BBB causing encephalitis is thought to occur. In support of this is virus isolation, PCR
detection, and detection of anti-dengue IgM antibody in the CSF of some patients (300,313–315). A recent
study on 150 CSF samples from fatal cases during a dengue epidemic period in Brazil found evidence of
DENV in 41 CSF samples out of 84 dengue-positive patients (306). Clinically, these patients present with
a brief febrile illness followed by a reduction in consciousness level, which may range from lethargy,
drowsiness, and irritability to deep coma. Seizures are also common, particularly in young children
(316,317). These may be simple febrile seizures or those associated with prolonged coma. Pyramidal or
long tract signs also occur, but the extrapyramidal tremors and tone abnormalities that characterize other
arboviral encephalitides such as JEV and West Nile encephalitis (86) are less common in dengue,
although they have been described (318,319). Presentations consistent with acute disseminated
encephalomyelitis have also been described, some time after a dengue infection (320). Meningismus
occurs in up to 30% of patients, usually as part of an encephalopathic illness. Uncomplicated viral
meningitis due to dengue viruses is rare. Other neurologic manifestations include mononeuropathies,
polyradiculopathies, Guillain-Barré syndrome, and acute neuromuscular weakness due to myositis and
hypokalemia (303,307,321,322).
Diagnosis
Patients with dengue often have leukopenia and thrombocytopenia, as well as mildly elevated hepatitic
transaminases. In patients with DHF, an elevated hematocrit is found because of fluid loss from blood
vessels due to increased vascular permeability (301,323). Hyponatremia is common, particularly once
fluid resuscitation has begun. CSF examination reveals a moderate lymphocytic pleocytosis in up to 30%
of patients with neurologic disease. CT and MRI may show diffuse cerebral edema, although focal
abnormalities have also been reported (300,313,319,324). Dengue can be confirmed by isolating the virus
from serum or CSF, PCR detection, or demonstrating IgM antibodies. Because dengue is so common in
many parts of the world, and because IgM antibody may persist in the blood for up to 3 months,
confirmation of antibody or virus in the CSF provides stronger evidence that dengue was the cause of the
neurologic symptoms (307). In addition, rigorous efforts must be made to rule out other causes.

No effective drugs against dengue are available. Because patients with DHF are particularly likely to
develop shock, fluid management is critical, and detailed guidelines are available (325). No vaccines are
available yet, but several vaccine candidates are currently undergoing preclinical development and some
in clinical trials (326,327). Currently, the most advanced dengue vaccine in phase III clinical trials is
ChimeriVax, the chimeric tetravalent live vaccine (yellow fever 17D backbone) manufactured by Sanofi
Pasteur (226). Several other chimeric and live attenuated vaccines are also in clinical trials
(326,328,329). There is no important enzootic cycle, and because the disease is spread by peridomestic
mosquitoes, vector control measures can have an impact. These include educating people to remove
Aedes breeding sites, treating stored water with larvicide (e.g., temephos), or the copepod Mesocyclops
that feeds on A. aegypti larvae, covering water storage containers, and ultralow volume spraying of
organophosphorus insecticides during epidemics (330). In some settings, legislation and fines for those
who fail to remove Aedes breeding sites from the home have been effective. Personal protection with
insect repellents is also recommended. The evidence for the efficacy of these measures is variable. The
only undoubtedly effective vector control measure was the near eradication of A. aegypti from South
America, using DDT, during the yellow fever campaign of the 1950s to 1970s. Since that campaign ended,
Aedes has reinfested South America (331). Worldwide, A. aegypti continues to spread, and dengue is
increasing as a global health problem (332). In 2007, sequencing of the A. aegypti genome was completed
and has led to the development of transgenic mosquitoes that could be useful in preventing dengue
transmission to humans (333). These include development of sterile mosquitoes, interfering with mosquito
feeding and reproduction and the use of Wolbachia to infect mosquitoes (92–94).
BUNYAVIRIDAE
The Bunyaviridae family is the largest family of animal viruses, with more than 350 members. It is named
after Bunyamwera Village in Uganda where the prototype virus was isolated. The family consists of five
genera, the first two of which contain important arboviral causes of CNS disease. Within each genus of
the family, viruses are placed into serogroups according to their cross reactivity in serologic tests.
• The Orthobunyavirus genus contains the mosquito-borne LACV and other members of the California
encephalitis serogroup of viruses.
• The Phlebovirus genus includes the sandfly-borne TOSV, which is emerging as an important cause of
CNS disease in southern Europe, and RVFV, which is transmitted by mosquitoes and causes febrile,
hemorrhagic, and occasional CNS disease.
• The Nairovirus genus includes Crimean-Congo hemorrhagic fever virus, which is transmitted by ticks.
• The Hantavirus genus, whose members are not arthropod borne, includes viruses that cause hantavirus
pulmonary syndrome, and hemorrhagic fever with renal syndrome.
• The Tospovirus genus contains only plant viruses transmitted by thrips (woodworm), and no human
pathogens.
Infectious Agent
All members of the family Bunyaviridae are 90 to 120 nm in diameter and are spherical in shape, except
hantaviruses, which are either spherical or rod-shaped particles. These enveloped viruses have
glycoprotein spikes assembled from the glycoproteins Gn and Gc, and enclose three circular
nucleocapsids, containing three linear segments of single-stranded negative-sense RNA, designated L
(large), M (medium), and S (small) (334,335). These range in size from 1 to 2.2 kb for the S, 3.5 to 6 kb
for the M, and 6.3 to 12.0 kb for the L. The L segment codes for a single L protein, RNA-dependent RNA
polymerase (RdRp) protein. The M segment codes for surface glycoproteins G1 and G2, and for a
nonstructural protein NSm. The S segment codes for nucleocapsid protein N (forms the ribonucleoprotein
[RNP] complex by encapsidating the viral RNA replication products) and for a nonstructural protein NSs,
although for hantaviruses, the nonstructural proteins NSm and NSs have not been detected (335,336).
Attachment of G1 and/or G2 glycoproteins to an as yet unidentified cell receptor is thought to be the
first step in viral replication. However, some studies suggest that integrins are involved in hantavirus
attachment, and phebovirus entry into dendritic cells involves DC-SIGN (337,338). Entry into the cell by
endocytosis is followed by uncoating and release of the three nucleocapsids into the cytoplasm, possibly
mediated by pH-dependent fusion of the viral envelope and host endosomal membrane. A recent study
suggests that after clathrin-independent endocytosis, phleboviruses pass through early and late
endosomes, followed by late endosomal acidification and release of RNPs and accumulation in the Golgi
(339). Replication of viral RNA occurs via a positive-sense complementary RNA (cRNA) intermediate.
Transcription of viral RNA to messenger RNA (mRNA) is followed by translation to produce viral
proteins. For Phlebovirus and Tospovirus, the SA segment is transcribed in both positive and negative
directions (ambisense). The G1 and G2 proteins are glycosylated, and viral particles assemble by
budding into the Golgi vesicles. These are transported to the cell surface, and fusion of the cytoplasmic
vesicles with the plasma membrane results in virion release through exocytosis. Although this mechanism
of viral release applies to most viruses in the family Bunyaviridae, RVFV can also bud off directly at the
cell surface.
La Crosse and Other California Serogroup Viruses
The California serogroup viruses are the only major cause of CNS disease in the Bunyavirus.
Epidemiology
California encephalitis virus was isolated from mosquitoes by Reeves and Hammon in 1941 (340) and
was shown to be associated with three cases of encephalitis. Although the serogroup was named after this
virus, human disease is rare (341). LACV, which was isolated from the brain of a fatal encephalitis case
in 1960 (342), is the most important member of the group and was probably the most common cause of
arboviral encephalitis in the United States until the arrival of WNV. Other members of the California
serogroup include Jamestown Canyon virus, which is also a relatively common cause of CNS disease,
and snowshoe hare virus, which is not (Table 15.2). California serogroup viruses are typically
transmitted in nature between rodents by Aedes mosquitoes. LACV is transmitted between chipmunks and
squirrels by Aedes triseriatus, a forest-dwelling tree-hole breeding mosquito that breeds in rainwater
collected in artificial containers in urban settings. Evidence is accumulating that the recently introduced
mosquito species A. albopictus may be involved in the emergence of LACV infection (343). During the
winter months, the virus overwinters by vertical transmission into Aedes eggs (344). For Jamestown
Canyon virus, the white-tailed deer is thought to be an important amplifying host. In Europe and Russia,
the California encephalitis virus serogroup Tahyna virus is a cause of fever, respiratory symptoms, and
occasionally CNS disease (345,346).
Most encephalitis cases due to California serogroup viruses occur during the summer and early fall,
particularly among residents of the Mississippi and Ohio River basins (347); however, 31 states have
now reported cases, with 130 cases (116 neuroinvasive cases) reported from 14 states in 2011. Nearly
95% of patients were younger than 18 years of age (348). The recent spread of LACV to Tennessee, North
Carolina, and West Virginia has been attributed to invasive mosquitoes including A. albopictus (349). The
incidence of LACV encephalitis is estimated at up to 30 per 100,000 in endemic areas (67). Most cases
occur in children living close to wooded forests or visiting them for recreation; risk factors include the
time spent outdoors and proximity of homes to tree holes (343). Approximately 75 encephalitis cases are
reported each year. The ratio of asymptomatic to symptomatic infections is about 1,000:1, and in endemic
areas, 20% of the population is seropositive by age 60 years. Jamestown Canyon virus is distributed
across the northern United States. Encephalitis due to Jamestown Canyon virus occurs mostly in the
elderly. Seroprevalence is 4% to 10% in some areas (350).
Clinical Features
Children with LACV encephalitis typically present with fever, headache, malaise, nausea, and vomiting,
which are often accompanied by meningeal signs (67,351–353). Seizures, which often include a focal
component, occur in approximately 50% of children, one third of whom have status epilepticus. Half the
patients have altered consciousness, and 10% are comatose. Focal neurologic signs include hemiparesis,
aphasia, dysarthria, chorea, and in about 10% clinical signs of raised ICP. Poor prognostic indicators
include reduced plasma sodium level, increased body temperature, and a Glasgow Coma Scale score of
less than 13 out of 15, and possibly increased number of seizures. Although fatalities are rare,
approximately 10% of patients have sequelae at hospital discharge. About 20% of those with seizures in
the hospital develop epilepsy. Jamestown Canyon virus causes a similar clinical pattern (354).
Diagnosis
A peripheral leukocytosis is common, and although there is usually a CSF lymphocytic pleocytosis up to
600 cells/mm3, an early lymphocytic pleocytosis may be normal. CSF protein is elevated in about 30% of
patients, but the glucose level is usually normal. Low sodium level due to SIADH secretion is reported in
about 20% of patients. Diagnosis is usually serologic because attempts to isolate virus from CSF or blood
are negative, although virus has been isolated from brain tissue.

There is no antiviral treatment for California serogroup viruses, or indeed any members of the
Bunyavirus genus. A recent study investigated the safety and pharmacokinetics of intravenous ribavirin
treatment for children with LACV encephalitis, but the results did not support the use of ribavirin for
LACV encephalitis (355). Attention should focus on treating the complications of infection, particularly
hyponatremia and seizures. There is no vaccine. Preventive measures include environmental measures to
decrease breeding sites, for example, removing tree holes, tires, and litter, which provide pools of water
favored by Aedes mosquitoes for breeding.
Phleboviruses Causing Central Nervous System Disease
Most members of this genus are transmitted by phlebotomine sandflies, although RVFV, which causes
epidemics of febrile illness, and occasional hemorrhagic disease, retinitis, or neurologic disease, across
sub-Saharan Africa, is a notable exception, being transmitted principally by Culex mosquitoes.
Sandfly Fever Viruses
A febrile illness associated with sandfly bites was recognized since the early twentieth century. During
outbreaks in World War II, Albert Sabin isolated sandfly fever Sicilian virus and sandfly fever Naples
virus from U.S. troops (356). Both viruses decreased or disappeared after the 1940s in countries
performing insecticide spraying for malaria eradication. More recently, an outbreak occurred among
Greek soldiers stationed in Cyprus with 256 out of 581 soldiers infected with sandfly fever Sicilian virus
(357). In 1971, TOSV, a new virus antigenically closely related to sandfly fever Naples virus, was
isolated in Italy from the sandfly Phlebotomus perniciosus (358,359). It has since emerged as the most
important cause of pediatric CNS infections in some parts of Italy, causing up to 80% of cases during the
summer (360). Children from rural or semiurban areas are especially vulnerable. TOSV has also been
recognized in other Mediterranean countries, including Cyprus, France, Greece, Portugal, Spain, and
Turkey (361,362). In affected areas, seroprevalence levels of 10% to 25% have been found (361,363).
The virus’s natural cycle has not been fully determined. In particular, although it has been shown that the
virus replicates in sandflies and can be passed vertically to offspring via transovarial and transtadial
transmission, no natural vertebrate host has yet been identified. However, humans have sufficiently long
and high viremias to transmit sandfly viruses to biting sandflies, which contributed to some urban
outbreaks.
Clinical Features, Investigation, and Diagnosis

Aseptic meningitis is the most common presentation of TOSV, but encephalitis has also been described
(363–367). In one series, all 14 patients had neck stiffness and 3 were encephalopathic, including 1 with
repeated seizures (360). Peripheral white blood cell counts are usually normal, and the CSF shows a
lymphocytic pleocytosis with normal glucose and mildly elevated protein levels. The outcome is
generally good, with no deaths or severe sequelae reported. Enterovirus infections are high on the
differential for patients with aseptic meningitis in the summer months, and a duplex PCR has been
developed to distinguish between these infections (368). TOSV can be isolated from the serum and CSF
by inoculation into suckling mice or cell lines. Because humans have high viremias, virus isolation and
PCR from serum and CSF is often successful (369). IgM ELISAs have also been developed
(368,370,371).

There is no established antiviral treatment for TOSV infection or other CNS Phlebovirus infections,
although ribavirin may be effective in RVF (250). Widespread use of DDT was effective in controlling
sandfly fevers in the past, particularly residual spraying of internal walls in homes where sandflies rest.
Although sandflies are small enough to penetrate mosquito netting, impregnated bed nets are a deterrent,
and the application of insecticides on the skin is recommended.
Rift Valley Fever Virus
RVF virus was first isolated in 1930, during an investigation of a large epizootic of disease causing
abortion and death in sheep. Originally found in the Rift Valley of Kenya, the virus is distributed across
sub-Saharan Africa, Egypt, Saudi Arabia, and Yemen (332,372,373). Disease in animals follows the
explosive increases in mosquito populations caused by heavy rains or new irrigation projects. Humans
become infected by mosquitoes or contact with animal blood or other products. In humans, the virus
causes epidemics of febrile illness with hemorrhagic manifestations in about 1% to 2% (2). About 0.5%
to 1.0% of patients develop retinal vasculitis or encephalitis as a late sequelae 1 to 4 weeks after the
acute illness (374). Encephalitis manifests as headache, meningismus, and clouding of consciousness,
sometimes with a recrudescence of fever. In fatal cases, focal necrosis is seen pathologically, which may
be due to viral cell damage. However, the late presentation after viral clearance and development of
antibodies suggest an immunopathologic process may be responsible, possibly due to a delayed
hypersensitivity reaction (375). Because this virus is directly transmissible to humans from the body
fluids of livestock, abattoir workers in affected areas should wear protective clothing. There are no
human vaccines against phleboviruses, but vaccines are available to protect livestock against RVFV and
are the main countermeasure against eliminating the source of human infection (376).
COLTIVIRUSES
The genera of the family Reoviridae include the Rotavirus genus and three genera of arboviruses,
Orbivirus, Coltivirus, and the recently designated Seadornavirus. The orbiviruses include animal
pathogens such as bluetongue virus and African horse sickness virus, but no important human pathogens,
and so are not considered further here. The most important coltivirus is CTFV, which because of
similarities in its geographical distribution, vector and symptoms were not distinguished from the
rickettsial disease Rocky Mountain spotted fever until the 1930s. Its viral etiology was demonstrated in
the 1940s. Eyach virus is a coltivirus isolated from ticks in central Europe, where patients with CNS
disease have been shown to have antibodies against the virus (377). Banna virus was isolated from the
CSF and blood of patients with encephalitis in China (378,379). It had been classified as a coltivirus, but
following genome sequencing, it has been placed with Kadipiro virus in the new genus, Seadornavirus
(380,381).
Infectious Agent
Like other Reoviridae, coltiviruses are nonenveloped particles consisting of a double-capsid structure
with icosahedral symmetry containing double-stranded RNA. The 29-kb genomes are divided into 12
segments of double-stranded RNA (ranging from 0.3 to 3.7 thousand base pairs), which can undergo
resortment (382). Based on comparisons with other Reoviridae, each segment is thought to encode the
mRNA for a single gene product, which in the case of VP1 is thought to be the RNA-dependent RNA
polymerase.
Epidemiology
CTFV is transmitted between ground squirrels, chipmunks, and other small mammals by Dermacentor
andersoni (wood ticks). The geographical distribution of cases is limited by the distribution of the
vectors and host to mountainous areas between 4,000 and 10,000 feet in the western United States and
Canada (383). CTFV or a closely related virus may be transmitted by Dermacentor variabilis in parts of
California. Larval, nymphal, or adult ticks may be infected. The virus persists transtadially between the
maturing tick forms but is not passed transovarially (Fig. 15.2). Ticks are infected for life, which may be
up to 3 years. The vertebrate hosts usually have subclinical viremias that can last for months or even
longer in hibernating animals, possibly providing one means for viral overwintering. Whereas immature
ticks feed on small mammals, adults feed on larger mammals, deer, elk, and occasionally humans. Human
cases of CTF occur in the summer months, when the number of ticks and vertebrate hosts is increased, as
is human exposure to the ticks, because of recreational and occupational activities.
Pathogenesis and Clinical Features
CTFV infects hematopoietic cells, resulting in persisting infection of erythrocytes, leukopenia, and
thrombocytopenia (384). The relative contributions of viral cytopathology and the host immune response
in the pancytopenia is not certain (385). Because CTF is rarely fatal, there are few reports of the
pathology, but hyaline membrane disease, endothelial swelling, and focal necrosis of the brain, liver, and
spleen have been reported, similar to the changes seen in animal models (386). IFN-α levels in the
plasma are high during the first 10 days of infection. After this neutralizing antibody, titers raise, but
despite this, viremias persist in nearly half the patients (383).
Transplacental transmission has been recorded, but most patients present with a history of exposure to
ticks in an area where the virus circulates, and many will recall a tick attachment. Following 3 to 5 days
of incubation (range, 1 to 14 days), there is fever, headache, malaise, and gastrointestinal disturbances.
After 2 to 3 days, the fever may subside for a couple of days, before recurring, illustrating the biphasic or
“saddleback” fever pattern (50% of patients with CTF). There is sometimes mild conjunctivitis,
lymphadenopathy, and a faint maculopapular rash, or petechiae (383). Neurologic features include neck
stiffness, photophobia, and mildly reduced consciousness. Rarely, there is encephalitis hepatitis,
perimyocarditis, and pneumonitis. Intravascular coagulopathy has been reported; only three deaths, all in
children, are noted (387).
Diagnosis
Moderate leukopenia with a relative lymphocytosis and a “left shift” have been reported along with
thrombocytopenia, anemia, and elevated liver transaminase and creatinine phosphokinase levels (383). In
the CSF, a moderate lymphocytic pleocytosis (up to 500 cells/mm3) is described with normal or slightly
elevated protein and reduced glucose. The differential diagnosis includes other tick-borne conditions,
including Rocky Mountain spotted fever, ehrlichiosis, tularemia, and Lyme disease. The diagnosis of CTF
is confirmed by virus isolation from blood clots or red blood cells, direct immunofluorescence of blood
smears to detect antigen in erythrocytes, or antibody detection using ELISAs or neutralization assays.
There is no established antiviral treatment, although ribavirin has activity in vitro and in the mouse model
(388). Treatment is symptomatic; aspirin and other nonsteroidal antiinflammatory drugs should be
avoided because of antiplatelet effects. To avoid infection, standard methods to reduce the chances of tick
bites should be used, including wearing long-sleeved shirts and trousers, using repellents containing
DEET, and frequently inspecting for attached ticks.
ACKNOWLEDGMENTS
Some of the work on flaviviruses described in this chapter was supported by the Wellcome Trust and the
Medical Research Council of Great Britain. T.S. is a professor of Neurology. A.P. is an NC3Rs David
Sainsbury Fellow. This project has been funded in whole or in part with Federal funds from the National
Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and
Human Services, under Contract (NO1-AI-65306, NO1-AI-15113, NO1-AI-62554, NO1-AI-30025), the
General Research Unit (RR-032), and the State of Alabama.
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CHAPTER 16 MENINGITIS AND ENCEPHALITIS
CAUSED BY MUMPS VIRUS
JOHN W. GNANN, JR.
Mumps is an acute systemic human infection caused by a paramyxovirus. Mumps virus is highly
transmissible and, in unimmunized populations, causes epidemics of mumps among school-aged children.
Although salivary gland enlargement, especially parotitis, is the most readily recognized clinical
manifestation of mumps, the infection involves many other organs, including the central nervous system
(CNS). In the past, nonsuppurative parotitis was considered the sine qua non of mumps, and involvement
of any other organ system was viewed as a complication. However, studies conducted over the last 60
years have made it clear that CNS involvement during mumps occurs with such high frequency that it
should be considered a part of the natural history of the infection and not as an aberrant manifestation or
complication. Indeed, some virologists have classified mumps virus as primarily neurotropic.
The spectrum of CNS diseases associated with mumps ranges from mild aseptic meningitis, which is
very common, to fulminant and potentially fatal encephalitis, which is very rare. The literature describing
CNS involvement with mumps can be difficult to assess critically because some authors have grouped all
cases of mumps neurologic disease under the label “mumps meningoencephalitis.” Although this term is
convenient, its use obscures the fact that the clinical course and prognosis of mumps aseptic meningitis
differs markedly from that of mumps encephalitis, although there is considerable overlap between the two
syndromes. It is important for the clinician to establish whether an individual patient with mumps has
clear evidence of encephalitis because that diagnosis has important implications for management and
prognosis.
EPIDEMIOLOGY
In unvaccinated urban populations, mumps (or “epidemic parotitis”) is a disease of school-aged children
with a worldwide distribution. Mumps infrequently occurs in infants younger than 1 year of age,
presumably because of transplacentally acquired antibody. Most mumps cases occur in children between
4 and 7 years of age (1). By age 15 years, over 90% of children have antibodies against mumps virus.
Prior to the release of the live attenuated mumps vaccine in the United States in 1967, mumps was an
endemic disease with a seasonal peak of activity occurring between January and May (2). The largest
number of cases reported in the United States occurred in 1941, when the incidence of mumps was 250
cases per 100,000 population (3). In 1968, when the live attenuated vaccine was first being put to clinical
use, the incidence of mumps was 76 cases per 100,000 population. In 1985, a total of only 2,982 cases of
mumps were reported, an incidence of 1.1 cases per 100,000 population, representing a 98% decline
from the 185,691 cases reported in 1967 (4). Sporadic outbreaks of mumps in secondary schools
occurring in the United States were attributed to primary vaccine failure (5). Between 1988 and 1993,
36% of all mumps cases in the United States were in patients older than 15 years of age (6). In 1989, the
Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices
recommended that all children receive a second dose of the measles-mumps-rubella (MMR) vaccine at
the time of school entry, which reduced the rate of primary vaccine failure (4). The incidence of mumps in
the United States declined steadily after 1987; only 387 cases were reported in 1999 (7). By testing sera
from the 1999 to 2004 U.S. National Health and Nutrition Examination Survey (NHANES), the overall
age-adjusted seroprevalence of immunoglobulin G (IgG) to mumps virus was shown to be 90% (8).
However, a series of outbreaks in the United States and Canada in 2005 to 2006 reemphasized the
potential for mumps virus to cause localized epidemics even in highly vaccinated populations (9,10). In
2006, a total of 6,584 cases of mumps were reported, with a national incidence of 2.2 cases per 100,000
population (9). The U.S. outbreak was centered in the Midwest and peaked in April 2006; 34% of the
cases occurred in Iowa. The highest age-specific age rate was in persons aged 18 to 24 years (median age
22 years), many of whom were college students (11). Among the Iowa cases, 7% were unvaccinated;
14% had received one dose of MMR; 49% had received two or more doses of MMR; and 30% had
unknown vaccine status. Although some cases can be attributed to failure to vaccinate, most represented
primary (insufficient initial immune response) or secondary (waning immune response) vaccine failure
(12). These findings suggest the need for a mumps vaccine with a longer duration of protection or
modification in vaccination policy, perhaps focusing on young adults (9,13). In selected outbreaks, a third
dose of mumps vaccine has been administered for outbreak control, which appears to be a safe and
effective measure (14,15).
The importance of immunization of adolescents and young adults was emphasized by a large outbreak
(over 56,000 reported cases) of mumps in the United Kingdom in 2004 to 2005 (16,17). Many of the
cases occurred in university students who were too old to have been vaccinated in childhood but too
young to have been exposed to epidemic natural infection (18). Conversely, a large mumps outbreak
(>3,500 cases) occurred in 2009 to 2010 in New York and New Jersey, causing disease primarily among
adolescent boys attending Orthodox Jewish schools (19). Mumps transmission in this highly vaccinated
population was apparently facilitated by the close face-to-face interactions among the students. The
propensity for mumps to spread among vaccinated adolescents in schools and communal living
environments raises the question of whether a revised vaccination schedule should be considered
(20–22).
In unimmunized populations, mumps is one of the most common causes of aseptic meningitis and
encephalitis (23). In a survey conducted in Minnesota from 1950 to 1981, mumps was identified as the
cause of encephalitis in 6 of 189 cases and the cause of aseptic meningitis in 7 of 283 cases (24). In that
series, mumps was the second most common cause of both encephalitis and aseptic meningitis (behind
California virus and enteroviruses, respectively). Meyer et al. (25) reviewed 713 cases of encephalitis
and aseptic meningitis treated at U.S. military hospitals between 1953 and 1958. In those patients in
whom a specific etiology was established, mumps was identified in 91 cases, poliomyelitis in 156,
coxsackievirus B in 80, lymphocytic choriomeningitis virus in 58, and echovirus in 53. In an analysis of
191 cases of acute encephalitis occurring in adults in Finland between 1967 and 1978, mumps virus was
found to be the second most common etiologic agent (following herpes simplex virus), accounting for
6.8% of the cases (26).
The frequency with which CNS manifestations occur during acute mumps has varied tremendously
(from <1% to >70%) among published series (27,28). A more realistic estimate of the frequency of
symptomatic CNS involvement during mumps appears to be 10% to 30%. Potential causes for this
variability in reported incidence include the interest and skill of the observer, the population studied (e.g.,
schoolchildren vs. military recruits, outpatients vs. hospitalized patients), the case definitions used, and
the frequency of use of lumbar puncture for diagnosis. Symptomatic encephalitis is observed much less
frequently than aseptic meningitis, probably occurring in fewer than 0.1% of cases of acute mumps
(29–31). Cerebrospinal fluid (CSF) pleocytosis occurs in 40% to 60% of patients with acute mumps,
although only 10% to 30% of patients with mumps have clinical evidence of meningeal irritation. That is,
about half of the patients with mumps with CSF pleocytosis do not have CNS symptoms (28,32). Bang
and Bang (27) performed lumbar punctures on 371 patients with mumps parotitis and found that 235
(63%) had elevated CSF white blood cell counts; of these 235 patients, 129 showed no clinical evidence
of meningitis or encephalitis. Similarly, Finkelstein (33) found elevated CSF white blood cell counts in
16 of 40 patients (40%) with mumps parotitis; 6 of these had no clinical evidence of CNS involvement.
Clearly, mumps CNS disease can also occur in patients without evidence of parotitis; indeed, 40% to
50% of patients with mumps meningitis have no evidence of salivary gland enlargement (34,35). If we
accept that CSF pleocytosis occurring during acute mumps is indicative of CNS infection, then we must
conclude that CNS involvement during mumps is quite common and frequently asymptomatic.
Although male and female patients have the same risk for mumps parotitis, there is a distinct male
predominance (70% to 80%) with respect to development of CNS disease among children with mumps. In
virtually every published series, the ratio of boys to girls is between 3:1 and 4:1 (28,30–32,36–39). This
striking difference in the incidence of mumps CNS disease between the sexes has not been satisfactorily
explained. Among young adults with mumps and CNS involvement, the ratio of men to women is closer to
1:1 (39). The peak incidence of CNS involvement in mumps occurs at about age 7 years in both sexes
(31,39,40). Of all cases, 60% to 70% occur in children between 5 and 9 years of age (28,30,37,38,41).
Several authors have reported seasonal differences in the frequency of mumps meningoencephalitis, with
and without parotitis (34,35,40–44).
INFECTIOUS AGENT
Mumps virus is classified as a member of the family Paramyxoviridae and the genus Rubulavirus (45). In
general, members of the family Paramyxoviridae possess nonsegmented RNA genomes, bind to
neuraminic acid receptors on host cells, replicate in the cytoplasm, are inactivated by ether, and cause
respiratory infections in humans (46). Serologic testing with hemagglutination inhibition (HI) or
neutralization assays has identified only one serotype of mumps virus, although minor antigenic
differences among mumps virus isolates can be detected using panels of glycoprotein-specific monoclonal
antibodies (47). Infection can be prevented by vaccination with a single strain of mumps virus. Mumps
virus shares some serologic cross reactivity with other paramyxoviruses, especially parainfluenza
viruses, which can complicate interpretation of serodiagnostic assays (48).
Mumps virions are pleomorphic, irregularly spherical, enveloped particles with an average diameter
of about 200 nm. Glycoprotein spikes project from the outer surface of the lipid envelope, which encloses
a helical nucleocapsid composed of RNA and nucleoproteins. The mumps virus genome consists of a
linear molecule of single-stranded, negative-sense RNA approximately 15.3 kilobases in size that
encodes seven major proteins and several minor proteins. The three proteins contained in the
ribonucleoprotein complex are the nucleocapsid protein (NP), which is the major structural protein of
mumps virus, plus the phosphoprotein (P) and large (L) protein, which are thought to function as the
RNA-dependent RNA polymerase (49). Full-length transcription of the V/P gene yields the V protein
(also known as NS1), whereas RNA editing during the transcription of V/P produces the phosphoprotein
as well as the nonstructural I protein (also known as NS2) (50). The V protein blocks host antiviral
responses by inhibiting the interferon signal transduction pathway and interleukin (IL)-6 expression and
may serve as a virulence factor (51–53). The function of the I protein is not known. The envelope contains
the matrix (M) protein and the two surface glycoproteins that mediate hemagglutinin-neuraminidase (HN)
and fusion (F) activities. The HN glycoprotein is responsible for attachment of mumps virus to the
receptors on the host cell, and the F glycoprotein induces the fusion of lipid membranes necessary for
penetration of the virus nucleocapsid into the cell. In traditional complement fixation (CF) assays, HN and
NP are known as “V antigen” and “S antigen,” respectively.
The function of the membrane-associated protein encoded by the small hydrophobic (SH) gene has not
been fully defined, although it does not appear to be essential for viral replication (54). Characterization
of the genetically divergent SH region is a useful tool for distinguishing wild type and vaccine strains of
mumps virus (55). Furthermore, studies employing reverse transcriptase polymerase chain reaction (RT-
PCR) methodology have demonstrated 13 distinct viral genotypes (designated A to M) based on sequence
of the SH gene (56–58). These molecular tools will allow more precise studies of mumps transmission
and population genetics (59–62). In the Western hemisphere, genotypes A, C, D, E, and H are more
common, whereas genotypes B, F, and I predominate in Asia. Although there is only a single mumps
serotype, some investigators have found that cross-neutralization between mumps virus genotypes is
reduced (63,64). Some studies have suggested that infection with certain genotypes (e.g., C, D, H, or J)
may result in enhanced neuropathogenicity (60,65), but this observation was not confirmed by other
investigators (58).
Humans are the only known natural hosts for mumps virus, although infection can be experimentally
induced in a variety of mammalian species. In vitro, mumps virus can be cultured in many mammalian cell
lines, including primary Rhesus monkey kidney, human embryonic kidney, BSC-1, Vero, and HeLa cells,
as well as in embryonated hens’ eggs (66). In tissue culture, the cytopathic effects caused by mumps virus
appear within 3 to 6 days and are highly variable. They include development of rounded cells, formation
of eosinophilic intracytoplasmic inclusions, and fusion of cells to form giant multinucleated syncytia.
Guinea pig or chick erythrocytes will adhere to mumps virus–infected cells, a phenomenon mediated by
hemagglutinins present on the surface of infected cells. Traditionally, verification of the isolate as mumps
virus has been accomplished by a hemadsorption inhibition assay, in which mumps virus–specific
antiserum is used to block the adherence of erythrocytes to mumps-infected cells. Most laboratories now
use direct or indirect immunofluorescence methods to identify mumps virus in tissue culture (66).
Molecular methods based on PCR have also been described (67).
PATHOGENESIS AND PATHOPHYSIOLOGY
Mumps is highly contagious, although some studies have suggested that it is less contagious than varicella
or measles (68). This clinical observation may be skewed by the fact that up to 30% of all mumps
infections are subclinical and asymptomatic (69). Over 90% of adults who give negative histories for
mumps are, in fact, seropositive when tested for mumps antibodies, indicating prior subclinical infection
(70).
Mumps can be experimentally transmitted to humans by inoculation of virus onto the nasal or buccal
mucosa, suggesting that most natural infections result from droplet spread of upper respiratory secretions
from infected to susceptible individuals. Virus can be isolated from saliva for 5 to 7 days before and 5 to
8 days after the onset of clinical symptoms, meaning that an infected individual is potentially able to
transmit mumps for a period of up to 2 weeks (71,72). The average incubation period for mumps is about
18 days (range 14 to 28 days) (73,74). During this interval, primary viral replication is thought to take
place in epithelial cells of the upper respiratory tract, followed by spread of virus to regional lymph
nodes and then viremic dissemination to glandular and neural tissue (75,76).
Mumps virus is delivered to the CNS either via free plasma viremia or by infected host mononuclear
cells (77,78). Virus is thought to spread across the endothelium of the choroid plexus and to infect
choroidal epithelial cells. Replication of mumps virus then takes place in the choroidal epithelium, and
progeny virus is shed into the CSF. In support of this model is the observation that mumps virus can be
easily recovered from CSF during the early phases of mumps meningitis in humans. Additionally,
choroidal and ependymal epithelial cells containing mumps antigens can be recovered from the CSF of
patients with mumps meningoencephalitis (79). Replication of mumps virus in the choroid plexus and
ependyma (the tissue that lines the cerebral ventricles and covers the choroid plexus) has been
demonstrated in rodent (77) and primate (80) models of mumps CNS infection. When mumps encephalitis
develops, it is presumed that virus replicating in ependymal cells spreads by direct extension into neurons
within the brain parenchyma, as has been observed in the hamster model of mumps encephalitis (81).
PATHOLOGY OF MUMPS CENTRAL NERVOUS SYSTEM

INFECTION
Autopsy reports of patients who have died with acute encephalitis caused by mumps virus have been
reviewed by Donohue (82) and Schwarz et al. (83). Many of these cases occurred prior to the availability
of modern virologic or serologic methods for confirmation of the diagnosis, and some were likely caused
by pathogens other than mumps virus. Among those cases in which mumps virus was the probable cause
of the fatal encephalitis, neuropathological findings were quite variable (28,82–84). The most commonly
recorded features were diffuse edema of the brain, limited mononuclear cell infiltration of the meninges,
perivascular infiltration with mononuclear cells, glial cell proliferation, focal areas of neuronal cell
destruction, and localized demyelinization. These histologic changes were seen in the white matter of the
cerebral hemispheres and cerebellum and in the white and gray matter of the brainstem and spinal cord.
Because of the pattern of perivascular demyelinization, Donohue (82) and Schwarz et al. (83) suggested
that these findings were more suggestive of a postinfectious or parainfectious encephalopathy rather than
of tissue destruction caused directly by mumps virus. Conversely, other authors have interpreted the
findings of cellular destruction as consistent with primary mumps virus cytopathic effect (85). In most
cases of fatal mumps encephalitis that have been carefully studied, there has been histologic evidence of
both cellular destruction (suggestive of direct virus effect) and demyelinization (suggestive of an
autoimmune process). The pathogenesis of mumps encephalitis remains incompletely understood.
Investigations using the hamster model have made major contributions to our understanding of the
pathogenesis of mumps CNS disease. CNS mumps infections have been produced experimentally by the
intracerebral or intraperitoneal inoculation of newborn hamsters with a neuroadapted strain of mumps
virus (77,86). About 9 to 12 days after intracerebral inoculation with mumps virus, suckling hamsters
developed wasting, ruffled hair, and arched backs; they usually died within 24 hours. Maximum titers of
mumps virus were detected in hamster brains at 5 days, and the virus titer declined as neutralizing
antibodies appeared. The clinical symptoms occurred 3 to 5 days after the decline in virus titers and the
concurrent development of neutralizing antibody (86). During the first week after virus inoculation, the
neuropathologic appearance of the brain was characterized by intense perivascular mononuclear cell
infiltrates. During the second week, microglial cell proliferation and small areas of necrosis were
observed. Notably, no foci of demyelinization (as has been observed in human brains) were apparent.
Immunofluorescence studies of suckling hamster brains following intracerebral inoculation with mumps
virus showed that mumps virus antigens were present in endothelial cells of the choroid plexus, in
ependymal cells, and in neurons of the brainstem, hippocampus, and cerebral cortex. Most of the infected
neurons were morphologically normal, and there was little correlation between the major sites of
neuronal infection and the observed sites of perivascular inflammation (86). The histologic appearance of
mumps encephalitis in suckling hamsters is more consistent with direct virus-induced pathology than with
immunologically mediated pathologic changes. Studies using the suckling hamster model have also
demonstrated an association of mumps CNS infection with the development of stenosis of the aqueduct of
Sylvius and with granular ependymitis (87). These findings suggest a possible (but unproven) linkage
between mumps CNS infections and aqueductal stenosis in children (88,89).
The ability of mumps virus to establish chronic infections in tissue culture systems is well known
(90,91). In the hamster model, cell-associated mumps virus can be recovered from brain explant cultures
for up to 50 days after infection, well after the appearance of specific humoral immunity (77). In humans
with mumps meningoencephalitis, the persistence of leukocytes and oligoclonal mumps-specific
immunoglobulins in the CSF for months after the acute infection suggests the possibility of ongoing
antigenic stimulation from chronic mumps CNS infection (92,93). Sufficient data do not yet exist to
confirm or refute a potential for mumps virus as a cause of chronic CNS infection in humans, but chronic
infection, if it occurs at all, is uncommon (92,94).
IMMUNE RESPONSES
Specific humoral and cell-mediated immune responses develop during the course of acute mumps
infection, but the relative contributions of antibody and cellular immunity to viral clearance have not been
precisely determined. Interestingly, mumps does not often cause unusually severe or prolonged infections
in immunocompromised patients, although severe nephritis due to mumps virus has been reported in renal
transplant recipients (95).
Within 10 days of infection, mumps-specific immunoglobulin M (IgM) appears in serum and
immunoglobulin A (IgA) can be detected in saliva (96,97). Serum IgM titers begin to wane shortly after
the acute illness and are usually undetectable after 6 months (96,98). A mumps-specific IgG response is
detectable during the first week of the acute infection, peaks about 3 to 4 weeks after the onset of the
infection, and persists for decades (99). Using the CF assay, a fourfold rise in mumps-specific IgG can
usually be demonstrated within 10 to 14 days after the onset of the disease (100). Lifelong immunity
follows natural infection. Symptomatic mumps virus reinfections have been reported, but most patients
who report more than one episode of mumps probably had parotitis caused by infection with a different
pathogen (101).
Mumps-specific immunoglobulins are also detectable in CSF of patients with mumps
meningoencephalitis (102). Using a sensitive enzyme-linked immunoadsorbent assay (ELISA) method,
mumps-specific IgG was detected in almost all CSF specimens from patients with mumps meningitis, and
mumps virus IgM was detected in about 50% of patients (103). By measuring the levels of
immunoglobulin in serum and CSF and then comparing this ratio with that of an index antibody (such as
measles antibody), intrathecal synthesis of mumps-specific immunoglobulin was shown to occur during
mumps CNS infection. There was no apparent correlation between the severity of clinical disease and the
presence or absence of mumps IgM in the CSF (104). Furthermore, no correlation between the CSF
leukocyte count and the CSF mumps antibody titer was demonstrated (104). Infection (or vaccination)
with mumps virus also elicits a cell-mediated immune response (105). Peripheral blood lymphocytes that
proliferate when stimulated with mumps S and V antigens can be detected by an in vitro blastogenesis
assay following natural infection or immunization (106). Lymphocytes recovered from the CSF of patients
with mumps meningitis also proliferate when stimulated with mumps antigens (107). Human leukocyte
antigen (HLA)–restricted cytotoxic T lymphocytes (CTLs) are detectable in peripheral blood following
mumps infection or immunization and in CSF of patients with mumps CNS infection (108). Kreth et al.
(109) demonstrated that T lymphocytes from CSF and from blood from 10 children with mumps
meningitis were cytotoxic to autologous mumps virus–infected target cells. Lymphocyte-mediated toxicity
was present during the acute phase of mumps meningitis, declined over 2 to 3 weeks after the onset of
symptoms, and was no longer apparent after 50 days. Fleischer and Kreth (110) cloned mononuclear cells
directly from the CSF of a patient with mumps meningitis and demonstrated that 90% of the cells were T
lymphocytes and that 60% were CD8+ suppressor/ cytotoxic T cells. A high percentage of the T-cell
clones showed specificity for the autologous mumps virus–infected target cells. In patients with self-
limited mumps meningitis, CSF interferon disappeared within a week, whereas interferon levels remained
elevated in the CSF from those patients who had persistent CSF pleocytosis (111). These findings suggest
that the recruitment of CTLs into the CNS in mumps meningitis is highly antigen specific and that mumps-
specific CTLs could play a role in the immunopathologic changes observed in human brains after fatal
mumps encephalitis. Recent studies have also demonstrated increased levels of IL-8, IL-10, IL-12, IL-13,
and interferon (IFN)-gamma in CSF from children with mumps meningitis (112).
CLINICAL COURSE AND NATURAL HISTORY

Mumps usually begins with a short prodromal phase characterized by low-grade fever, malaise,
headache, and anorexia. Young children may initially complain of ear pain. The patient then develops the
characteristic salivary gland enlargement and tenderness (113). The parotid glands are most commonly
involved, although other salivary glands (e.g., submandibular and sublingual) may be enlarged in about
10% of cases. Parotitis may initially be unilateral, with swelling of the contralateral parotid gland
occurring 2 to 3 days later; bilateral parotitis eventually develops in over 80% of patients with
symptomatic salivary gland involvement. Painful parotid gland enlargement progresses over the course of
2 to 3 days, lifting the earlobe outward and obscuring the angle of the mandible (Fig. 16.1). The orifice of
Stensen duct is often red and edematous. Lymphatic obstruction resulting from bilateral glandular
enlargement can occasionally result in presternal edema (114). Fever and parotid gland swelling peak on
about the third day of the illness, followed by defervescence and resolution of parotid pain and swelling
within about 7 days. Long-term sequelae of parotitis are uncommon. Children with mumps are usually
isolated for about 5 days after the appearance of parotitis, although this practice is of dubious benefit to
classmates, because the virus is excreted for several days prior to the onset of clinical symptoms (115).
Epididymoorchitis is rare in boys with mumps, but it occurs in 25% of postpubertal men with mumps
infection (19,116,117). Orchitis is caused by replication of mumps virus in seminiferous tubules, with
resulting lymphocytic infiltration and edema (118–120). Orchitis is most often unilateral, but bilateral
involvement occurs in 10% to 30% of cases (121). Orchitis typically develops within 1 week after the
onset of parotitis, although orchitis can develop prior to or even in the absence of parotitis. Mumps
orchitis is characterized by marked testicular swelling and severe pain, accompanied by fever, nausea,
and headache (121–123). The pain and swelling resolve within 5 to 7 days, although residual testicular
tenderness can persist for weeks. Testicular atrophy may follow orchitis in about 35% to 50% of cases,
but sterility is an uncommon complication, even among patients with bilateral orchitis. Orchitis occurring
in vaccinated males who develop “breakthrough” mumps tends to be less clinically severe (124).
Mumps can cause inflammation of other glandular tissues, including pancreatitis (125) and thyroiditis
(126). Investigators in the 1970s proposed an epidemiologic association between mumps and juvenile
diabetes mellitus (127); however, the dramatic decline in the incidence of mumps has not been reflected
by a similar decline in the occurrence of juvenile-onset diabetes. Oophoritis and mastitis have been
reported in postpubertal women with mumps (113,128). Renal function abnormalities are common in
mumps and virus can be readily isolated from urine, but significant or permanent renal damage is rare
(129,130). Other infrequent manifestations of mumps include arthritis (131,132), myocarditis (133,134),
and thrombocytopenia (135).
Maternal mumps infection during the first trimester of pregnancy results in an increased frequency of
spontaneous abortions (136). However, no clear association between congenital malformations and
maternal mumps has been demonstrated (137). An etiologic relationship between gestational mumps and
endocardial fibroelastosis has been postulated (138). Mumps occurring during the perinatal period is
usually benign, perhaps due the partial protective effect of transplacental antibody (139).
Central Nervous System Manifestation of Mumps
CNS infection is the most common extrasalivary manifestation of mumps and may precede, accompany, or
follow the development of parotitis (35). There is no association between the severity of the parotitis and
the likelihood or severity of meningitis (27). Most frequently, CNS symptoms follow the onset of parotitis
by about 5 days (140). In a study of 41 cases of mumps encephalitis reported by Koskiniemi et al. (31),
parotitis appeared 3 to 14 days prior to CNS involvement in 15 patients, was coincident with encephalitis
in 9 patients, occurred 1 to 4 days after the onset of CNS symptoms in 2 patients, and was absent in 15
patients. In another series of 24 patients with mumps parotitis and meningoencephalitis, 11 patients had
parotitis for 6 to 21 days before the onset of the CNS symptoms, 9 patients had neurologic symptoms
preceding the parotitis by 1 to 8 days, and 4 patients had parotitis and CNS symptoms that occurred
simultaneously (42). Levitt et al. (30) noted a mean interval of 2.7 days between the onset of parotitis and
the development of CNS symptoms, but the range was wide, with parotitis developing from 20 days
before to 7 days after CNS disease. These data clearly indicate that the development of CNS disease in
mumps does not depend on prior development of parotitis. The physician examining a patient with
suspected meningoencephalitis may not exclude the possibility of mumps simply because the patient does
not have clinically apparent salivary gland involvement.
The common presenting signs and symptoms seen in patients with mumps CNS infection are
summarized in Table 16.1. The most frequently reported presentation is a triad of fever, vomiting, and
headache. Salivary gland enlargement is present in only 50% of patients with mumps CNS disease. The
fever is frequently high (39°C to 40°C) and lasts for 72 to 96 hours. The headache and vomiting may also
be quite severe and usually persist for about 48 hours (32,141). Other frequently noted clinical findings
include neck stiffness, lethargy or somnolence, and abdominal pain. Most patients with mumps with CNS
involvement have signs of meningitis (e.g., headache and nuchal rigidity), but no evidence of cortical
dysfunction. Defervescence is usually accompanied by overall clinical recovery, and the total duration of
illness in uncomplicated cases is 7 to 10 days (40,41).
The presence of seizures, pronounced changes in level of consciousness, or focal neurologic findings
are indicative of significant encephalitis (30). Koskiniemi et al. (31) reviewed 41 cases of mumps
encephalitis occurring in Helsinki, Finland between 1968 and 1980 and reported high fever (>39°) in
83%, vomiting in 88%, headaches in 71%, difficulty walking in 37%, nuchal rigidity in 27%, seizures in
24%, psychiatric disturbances in 22%, and significantly depressed levels of consciousness in 20% of
patients.
Mumps meningitis is a benign disease with essentially no risk of mortality or long-term morbidity. It is
difficult to judge accurately the true incidence of neurologic sequelae following mumps CNS disease from
published reports because of the variability of the populations studied. Patients who develop permanent
sequelae following mumps with CNS involvement are presumed to have had mumps encephalitis.
However, the mortality rate for patients with mumps encephalitis is 1.5% or less, and permanent sequelae
are rare. As with many childhood viral infections, the mortality rate for mumps appears to be substantially
higher among adults than among children. Between 1982 and 1991, 14 mumps-associated deaths were
reported in the United States, and more than half occurred in patients older than 20 years of age. Even
among patients who are profoundly encephalopathic, the probability for complete recovery is high;
sustained seizures and focal neurologic deficits (both of which are uncommon) may predict a less
favorable outcome (31). In many large series of patients with mumps CNS infection, no long-term
neurologic sequelae were identified (28,42,44,141). Ataxia, behavioral changes, and
electroencephalographic abnormalities have been noted in children in the immediate postencephalitis
period, but these usually resolve within a few weeks (42).
A wide variety of other neurologic complications have been observed following mumps encephalitis.
Among the reported sequelae are behavioral disturbances and personality changes (31,34,36,142),
seizure disorders (40,143), cranial nerve palsies (especially facial and ocular palsies) (36,144), muscle
weakness including hemiparesis (34,37), cerebellitis and ataxia (31,145), acute hydrocephalus (146), and
chronic headaches (143,147). Myelitis and polyneuritis have also been reported as sequelae of mumps
(148,149).
Sensorineural hearing loss is an uncommon but well-recognized complication of mumps that occurs
with an estimated frequency of 0.5 to 5.0/100,000 cases (143,147,150,151). In a recent survey conducted
in Japan, the incidence of hearing loss in children with mumps was reported to be much higher (7 in 7,400
cases, or approximately 1/1,000 cases) (152). Deafness may be either transient or permanent and
probably results from direct damage to the cochlea by the mumps virus (154). Rare ocular complications
of mumps include keratitis, iritis, and central retinal vein occlusion (154,155).
DIAGNOSIS AND LABORATORY FINDINGS

The presentation of a febrile child with parotitis strongly suggests the diagnosis of mumps, particularly if
the individual is known to be susceptible and has been exposed to mumps during the preceding 2 to 3
weeks. However, the reduced frequency of mumps in countries where vaccination is routine may result in
physician inexperience and reduced accuracy of clinical diagnosis (156). An atypical clinical
presentation (e.g., meningitis or orchitis without parotitis) will usually require laboratory confirmation.
Culturing for mumps virus is the definitive diagnostic test but is frequently not available and has largely
been replaced by polymerase chain reaction (PCR) assays. Testing of paired acute and convalescent sera
should demonstrate a diagnostic fourfold rise in mumps antibody titer, providing a retrospective
diagnosis. Parotitis can occasionally be caused by other viruses (e.g., Epstein-Barr, adenovirus, influenza
A, parainfluenza, coxsackievirus, lymphocytic choriomeningitis) or by bacteria (e.g., Staphylococcus
aureus) (157,158). Noninfectious causes of parotid gland enlargement include Sjögren syndrome,
sarcoidosis, thiazide ingestion, iodine sensitivity, tumor, or salivary duct obstruction (159,160). Parotid
gland enlargement has been described in patients with AIDS, especially children (161,162). A careful
physical examination should permit parotitis to be distinguished from lymphadenitis or lymphadenopathy.
When aseptic meningitis occurs in the context of parotitis, the diagnosis of mumps is usually obvious.
The cause of the meningitis may be obscured, however, if there is no accompanying salivary gland
enlargement. Mumps meningoencephalitis has been confused with nonparalytic poliomyelitis, especially
when it occurs during the summer (34). In general, the CSF leukocyte count is higher in mumps than in
poliomyelitis, and the clinical findings of neck stiffness and fever resolve more quickly in cases of mumps
than in polio (28). Lennette et al. (163) reported 11 cases of encephalitis with mild local muscle
weakness that were all clinically considered to be polio but that were serologically demonstrated to be
caused by mumps virus.
Confirmation of CNS involvement in patients with mumps is based on examination of the CSF. CSF
pleocytosis (>5 white blood cells/mm3) occurs in 40% to 60% of patients with mumps parotitis (27,32).
The spinal fluid opening pressure is normal in virtually all cases (28). The CSF white blood cell count is
usually in the range of 200 to 600 cells/mm3 (Table 16.2), although cell counts of 1,000 to 2,000
cells/mm3 are not uncommon. In the series of 45 patients with mumps meningoencephalitis reported by
Wilfert (38), the CSF white blood cell count on the initial lumbar puncture was less than 100 cells/mm3 in
13% of patients, 100 to 500 in 53%, 500 to 1,000 in 29%, and more than 1,000 cells/mm3 in 5% of
patients. The differential count of CSF leukocytes demonstrates more than 80% lymphocytes in 80% to
90% of patients (28,30,36,38). A small number of neutrophils are commonly seen, but neutrophil
predominance in the initial CSF sample occurs in fewer than 5% of patients with mumps CNS infection
(28,38,42). The CSF protein is normal in about one half the patients and moderately elevated (<100
mg/dL) in the remainder (31,38,40,41). The CSF glucose is normal in most patients, but moderate
hypoglycorrhachia (20 to 40 mg/dL) may be present in 10% to 20% of patients with mumps meningitis
(30,31,41,42). In the series reported by Wilfert (38), 14 of 45 patients had CSF glucose of less than 40
mg/dL. Marked hypoglycorrhachia (<10 mg/dL), as can be seen in pyogenic bacterial meningitis, is very
uncommon in mumps meningitis. An abnormally low CSF glucose is an unusual finding in viral meningitis
and has been reported most often in meningitis caused by mumps virus, lymphocytic choriomeningitis
virus, or herpes simplex virus.
No clear association has been established between the magnitude of the CSF pleocytosis and the
clinical course. The CSF white blood cell count may be higher in patients with parotitis and signs of
meningitis than in patients with parotitis alone (27). However, there is no correlation between the level of
CSF pleocytosis and severity of illness (40). CSF findings do not differ significantly between those
patients with meningitis only and those with mumps encephalitis (30). The magnitude of the spinal fluid
abnormalities is not predictive of the risk for long-term sequelae following mumps encephalitis (31).
Studies employing sequential lumbar punctures have demonstrated that the CSF white blood cell count
frequently increases during the first 2 to 3 days after the onset of CNS symptoms and then begins to
decline (34,38,164). Even 2 weeks after the onset of CNS symptoms, when most patients with mumps
meningoencephalitis are asymptomatic or substantially improved, the CSF white blood cell count may
still be in the range of 100 to 500 cells/mm3. Complete normalization of the spinal fluid and
disappearance of CSF pleocytosis may require several weeks (28,40,165).
Laboratory confirmation of the clinical diagnosis depends on isolation of mumps virus, nucleic acid
amplification, or demonstration of an appropriate serologic response (166). Mumps virus can be isolated
from saliva from virtually all patients with acute mumps parotitis (34). Virus can also be recovered from
the urine for up to 2 weeks after the onset of illness. Virus can be isolated from 30% to 50% of CSF
samples collected early during the course of mumps CNS infection (28,39,44). Wolontis and Björvatn
(167) attempted virus isolation from CSF specimens of 655 patients with mumps and CSF pleocytosis and
were successful in 33% of cases. Interestingly, no significant association between the magnitude of the
CSF pleocytosis and the probability of viral isolation could be demonstrated (34,167).
Widespread availability of molecular diagnostic techniques such as RT-PCR has replaced viral culture
in many settings and may eventually replace serology (67,168,169). Detection of mumps virus RNA is
diagnostic of infection; sequence analysis of the amplified SH gene can be used for molecular
epidemiologic studies. Quantitation of viral RNA is readily accomplished using real-time RT-PCR
methods (170–172). RT-PCR appears to be more sensitive than culture or immunohistochemical staining
for detection of mumps virus in CSF or oropharyngeal swabs (168,173).
A variety of assays have been developed to measure the humoral immune responses to mumps virus
infection (66). To greater or lesser degrees, all these serologic tests are limited by cross reactions
between mumps virus and other human parainfluenza viruses (48). The neutralizing antibody assay has
been considered the “gold standard” test, but it is technically demanding. The HI assay is simple and
sensitive, but reagents may not be commercially available. In the past, the most widely used serologic test
has been the CF assay, which detects antibodies directed against the V (HN) and S (nucleocapsid)
antigens. Highly sensitive ELISAs that can be readily automated have now largely replaced CF as the
preferred method for serodiagnosis (174,175). All these assays are designed to measure a fourfold
increase in mumps-specific IgG between the acute serum (collected at the time of clinical disease) and the
convalescent serum (collected 2 to 4 weeks later). Alternatively, demonstration of mumps-specific IgM
by ELISA is indicative of recent infection and is widely used for serodiagnosis of acute disease (176). An
IgM response is detectable during the first week of illness and persists for at least 6 weeks (177–179). In
cases of mumps meningoencephalitis, involvement of the CNS can be confirmed by demonstration of IgM
or elevated ratios of mumps-specific IgG in CSF (103,180). Presence of IgG by a standard serologic test
provides presumptive laboratory evidence of prior infection, but there is no universally accepted
surrogate immunologic marker of protection (181). The mumps skin test is not a reliable indicator of
immune status.
Other routine laboratory studies are not generally helpful. The average peripheral white blood cell
count in patients with mumps is 10,000 to 12,000 cells/mm3, with a differential of 30% to 40%
lymphocytes (36,40,42). Approximately 30% of patients have an elevated serum amylase, reflecting
inflammation of the salivary glands or pancreas (42). During acute mumps encephalitis, the
electroencephalogram characteristically shows moderate to severe slowing without spikes or lateralizing
signs (31,182). Little information is available regarding the utility of modern imaging methods (computed
tomography or magnetic resonance imaging) in the diagnosis and management of mumps CNS infections
(183). Scrotal ultrasonography may help with the evaluation of orchitis (184).
THERAPY
Clinical management of patients with mumps consists of conservative measures to provide symptomatic
relief and ensure adequate rest, hydration, and nutritional support. There is currently no established role
for antiviral chemotherapy or passive immunotherapy in mumps. Treatment of orchitis includes bed rest,
scrotal support, analgesics, and ice packs. In anecdotal reports, men with mumps orchitis were said to
improve and have a lower frequency of testicular atrophy after administration of interferon-α-2B, but this
therapy has not been adequately studied in a controlled fashion (121,185–188). Patients with clinical
evidence of significant CNS involvement (altered mental status, seizures, or focal neurologic findings)
require hospitalization for observation. Supportive care for patients with mumps encephalitis includes
hydration, fever control, antiemetics, and anticonvulsants as required. Lumbar puncture has been reported
to relieve the headache associated with mumps meningitis in some patients. There have been anecdotal
reports of the use of corticosteroids in patients with mumps encephalitis, but no benefits have been proven
(40). In the series of patients with mumps meningoencephalitis reported by Ritter (40), the average
duration of hospitalization was 9.1 days, with a range of 5 to 19 days.
PREVENTION
The cornerstone of mumps prevention is active immunization with the live attenuated mumps vaccine
(189,190). The U.S. Public Health Service recommends administration of the MMR vaccine by
subcutaneous injection in two doses, with the first dose given at 12 to 15 months of age and the second at
ages 4 to 6 years, prior to school entry (191). In 2011 to 2012, median coverage of children with two
doses of MMR in the United States was 94.8% (192). Clinical trials conducted during vaccine
development indicated a vaccine efficacy rate of 97% (193). However, studies conducted during more
recent mumps outbreaks have suggested that the vaccine is 80% to 90% effective in preventing clinical
mumps (26,194–198). Vaccine efficacy may be lower among household contacts (65 to 75%) (198). In
countries where universal vaccination is practiced, mumps outbreaks due to failure to vaccinate continue
to occur among immigrants and in specific groups where vaccination is not accepted (199–202).
Furthermore, large-scale mumps outbreaks in highly vaccinated populations continue to occur and can be
attributed to primary (inadequate immune response) or to secondary (waning immunity after successful
immunization) vaccine failure (19–22,203,204). Asymptomatic mumps virus infection has been
demonstrated in vaccinated children (with an attack rate of 7% to 10%) and may contribute to epidemic
spread (205). Because wild type mumps virus is always genetically distinct from vaccine-strain virus,
concerns have been raised that vaccine-induced immunity might not provide protection against some
wild-type variants (206). However, in vitro studies have shown that genetically diverse mumps virus
isolates collected during outbreaks were all effectively neutralized by sera from vaccinated children,
arguing against immune escape (207).
Administration of the live mumps vaccine is contraindicated in pregnant women (208). Vaccination is
also not recommended in persons who have received immunoglobulin therapy within the preceding 3
months (which might interfere with the immune response to the vaccine) or in persons with severe
systemic immunosuppression caused by disease or medical therapy. Mumps immunization (using MMR)
is recommended for children infected with human immunodeficiency virus (HIV) who do not have
evidence of severe immunosuppression (defined as CD4 count less than 200 lymphocytes/mm3 or CD4
less than 15% (209). Since mumps vaccine is produced in cell cultures of chick embryos and may contain
trace amounts of egg protein and neomycin, immunization is not recommended for persons with a history
of anaphylactic reactions to those substances. Desensitization protocols to permit safe administration of
the vaccine to egg-allergic children have been described (210).
Questions regarding prevention often arise when an individual with no history of mumps (typically a
male adult) is exposed to a patient with active mumps. The immune status of the exposed individual can
be determined by ELISA, although this may involve some delay (98). Mumps vaccine can be safely
administered to an individual of unknown immune status (211). However, vaccine given to a susceptible
individual after exposure to mumps may not provide protection. The vast majority of adults born in the
United States before 1957 have been naturally infected and are therefore immune, although susceptibility
rates among younger adults are higher (212).
Widespread use of the mumps vaccine has had a major impact on the incidence of mumps and mumps
meningoencephalitis (190). Through the mid-1960s, mumps was a leading cause of viral encephalitis
(213). By the mid-1980s, however, mumps had been reduced to the seventh most common cause of viral
encephalitis in the United States, accounting for only 0.5% of cases of viral encephalitis. This trend was
documented in Minnesota, where mumps was the second most common cause of encephalitis between
1950 and 1972, but where no cases of mumps CNS infection were noted in 1972 to 1981 (24). Similarly,
mumps and measles disappeared as leading causes of encephalitis in children in Finland after institution
of a nationwide MMR vaccination program in 1982 (214). Not surprisingly, the resurgence in mumps
over the last decade has been accompanied by increased numbers of cases of mumps-associated
meningitis and encephalitis.
The Jeryl Lynn strain of attenuated mumps virus used in the United States since 1967 is a very well-
tolerated vaccine, although rare instances of fever, parotitis, orchitis, or aseptic meningitis following
immunization have been reported (215). Other attenuated mumps viruses used for vaccination in various
countries include RIT 4385, Urambe Am9, Rubini, Leningrad-3, Leningrad-Zagreb, Hoshino, and Torii
strains (216). Beginning in 1988, an increased frequency of vaccine-related mumps meningitis cases
(rates as high as 1 to 3/1,000 vaccinations) was recognized in Japan (217), Canada (218), Brazil (219),
and the United Kingdom (220). These cases followed administration of an MMR vaccine containing the
Urabe Am9 strain of mumps virus. In several instances, mumps virus was recovered from the CSF (221).
A similar situation was reported from Yugoslavia following administration of the Leningrad-3 mumps
vaccine (222). The clinical presentation and CSF findings of the vaccine-related cases are similar to
those of naturally occurring mumps meningitis, with onset of symptoms about 3 weeks after vaccination.
In general, the patients with vaccine-related meningitis were not seriously ill, and long-term sequelae
have not been noted. This adverse effect of vaccination was presumed to result from inadequate
attenuation of the vaccine virus. However, nucleotide sequencing of the mumps virus HN gene from the
Urabe vaccine showed that the vaccine was actually a mixture of wild type and variant mumps viruses
with identifiable genetic differences, which appear to confer differences in neurovirulence (223,224). For
example, most isolates recovered from patients who developed postvaccination parotitis or meningitis
were wild type (Lys335) rather than variant (Glu335) virus (223). In some countries, the highly
immunogenic Urabe mumps vaccine strain was replaced by the highly attenuated Rubini strain, which
appears to provide unacceptably low levels of clinical protection (190,225). These problems have not
been recognized in the United States, where the Jeryl Lynn mumps vaccine is still used.
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CHAPTER 17 RABIES
ALAN C. JACKSON
Rabies is an acute viral infection of the central nervous system (CNS) that also involves the peripheral
nervous system both in its pathogenesis and clinical manifestations. Rabies is a zoonotic disease affecting
mammals that is usually transmitted to humans by bites from animal vectors. Rabies virus infection causes
most cases of rabies, although non–rabies virus lyssaviruses have been recognized to very rarely cause
disease with identical clinical and pathologic features, but not in the Americas. Physicians in geographic
regions where rabies is rare must consider the diagnosis based on the clinical picture alone, because
there may not be a history of an animal exposure. Rabies can nearly always be prevented after a
recognized exposure with initiation of appropriate prophylactic therapy. Once rabies develops, the
disease is almost invariably fatal with rare exceptions, and survival has usually been associated with the
administration of rabies vaccine prior to the onset of the disease.
HISTORY
Rabies has a long and colorful history going back to antiquity. Perhaps the earliest reference to rabies was
in the pre-Mosaic Eshnunna Code of Mesopotamia in about 2300 BC (1). Rabid dogs were recognized in
China centuries before the birth of Christ (2). The works of Democritus, Aristotle, Hippocrates, and
Celsus made reference to rabies in both humans and animals (3). In 100 AD, Celsus described human
rabies and used the term hydrophobia, which is derived from the Greek words meaning fear of water.
Celsus recognized that the saliva of the biting animal contained the poisonous agent, and he recommended
the practice of using caustics, burning, cupping, and also sucking the wounds of individuals bitten by
rabid dogs in order to prevent the subsequent development of rabies (3).
In the early nineteenth century, Zinke (4) demonstrated experimentally that the infectious agent causing
rabies was transmitted in the saliva by painting saliva from a rabid dog into incisions made in healthy
animals. In 1879, Galtier, who was working at a veterinary school in Lyon, France, used rabbits in his
rabies experiments and noted that it was technically much less difficult and dangerous than experiments
using dogs and cats (5). Subsequently, Louis Pasteur took up this experimental rabbit model of rabies. He
transmitted rabies virus by inoculating CNS tissues of rabid animals into the brains of other animals and
noted that sequential brain passages led to attenuation for peripheral inoculation (6). In 1885, Pasteur (7)
successfully immunized a 9-year-old boy, Joseph Meister, who had been severely bitten by a rabid dog,
with a series of inoculations of infected rabbit spinal cord tissues that had been partially inactivated after
variable periods of desiccation. Joseph Meister never developed rabies and, subsequently, many people
were immunized with nervous system vaccinations in Paris and other locations throughout the world.
In 1903, Adelchi Negri (8) described eosinophilic cytoplasmic inclusions in infected neurons, which
are now called Negri bodies. Negri bodies proved to be useful for a pathologic diagnosis of rabies. In
1958, fluorescent antibody staining was applied in order to demonstrate rabies virus antigens in tissues
(9), which became very useful for rabies diagnosis and also for early rabies pathogenesis studies in
animals performed by Richard Johnson (10) and Frederick Murphy (11,12) and their colleagues.
RABIES VIRUS
Rabies virus is in the family Rhabdoviridae and genus Lyssavirus and is a nonsegmented negative-strand
(antisense) RNA virus consisting of 11,932 nucleotides that code for five viral proteins: nucleocapsid
protein (N), matrix protein (M), phosphoprotein (P), glycoprotein (G), and large polymerase protein (L)
(13) (Fig. 17.1). Helical genomic RNA forms a ribonucleoprotein (RNP) core associated with the N, P,
and L proteins. The RNP serves as a functional template for viral transcription and replication. The G and
M proteins are associated with a lipid bilayer envelope that surrounds the RNP core. The G protein forms
spikelike projections on the surface of the viral envelope and serves as the major surface antigen of the
virus and binds viral neutralizing antibodies and is important for immunity. Rabies virus belongs to
genotype 1 of lyssaviruses, which includes wild type rabies virus strains (also called street rabies
viruses) and also laboratory-adapted strains, including vaccine strains. The non–rabies virus lyssaviruses
that have been recognized to rarely cause human disease, which is indistinguishable from rabies, include
Mokola virus (genotype 3), Duvenhage virus (genotype 4), European bat lyssavirus 1 (genotype 5),
European bat lyssavirus 2 (genotype 6), Australian bat lyssavirus (genotype 7), and Irkut virus (genotype
pending) (14).
PATHOGENESIS
Rabies virus is usually transmitted in the saliva to humans and animals via a bite, although a scratch or
abrasion with salivary contamination can also result in viral transmission. Aerosol transmission in a
laboratory accident (15,16) and in a cave containing millions of bats (17) has also been documented but
only occurs very rarely. Organ and tissue (corneal and vascular conduit) transplantation are also well-
documented causes of transmission of rabies virus in humans, which account for a total of 16 well-
documented cases (14,18,19). Much has been learned about the steps involved in rabies pathogenesis
(Fig. 17.2) from experimental studies in animals. Usually, the incubation period lasts about 20 to 90 days
after the time of the exposure (e.g., bite), although it may vary from a few days to over a year. Based on
studies in animals, the virus is thought to remain close to the site of viral entry during most of this
incubation period. After an exposure involving muscle, rabies virus is known to bind to nicotinic
acetylcholine receptors (20), which are located in the postsynaptic membrane of the neuromuscular
junction. The virus spreads across the synaptic cleft and then spreads centripetally toward the spinal cord
in motor nerve fibers of peripheral nerves by retrograde fast axonal transport (21). Bats cause more
superficial exposures with their bites involving cutaneous and subcutaneous tissues, but experimental
studies have not yet examined the detailed pathways of viral spread in animal hosts. After infecting spinal
cord neurons (e.g., ventral horn neurons), rabies virus spreads within axons of the CNS by fast axonal
transport along neuroanatomic connections. After CNS infection is established, there is centrifugal spread
of rabies virus to multiple organs along sensory and/or autonomic nerves. In rabies vectors, viral spread
to the salivary glands is important, and saliva is secreted containing infectious rabies virus, which is
important for transmission to new hosts via bite exposures. Viral spread also occurs to multiple organs,
including the skin (important for rabies diagnosis using a skin biopsy), heart (with myocarditis in some
cases), adrenal medulla, and gastrointestinal tract (22).
PATHOLOGY
Characteristic microscopic features of rabies encephalomyelitis include mild mononuclear inflammatory
changes involving the leptomeninges, perivascular regions, and the parenchyma. There are microglial
nodules called Babes nodules in the parenchyma, which were described by Babes (23), that consist of
activated microglia and monocytes. Degenerative neuronal changes are not usually prominent in rabies.
However, neuronophagia can be observed with accumulations of activated microglia/macrophages in the
process of phagocytosing degenerating or dying neurons (24). Infected neurons may contain characteristic
eosinophilic inclusions called Negri bodies (Fig. 17.3), which were described by and named after
Adelchi Negri (8,25). Electron microscopy has demonstrated that Negri bodies are composed of large
aggregates of granulofilamentous matrix material and variable numbers of viral particles (24).
EPIDEMIOLOGY
Worldwide, about 99% of human rabies cases are related to transmission from dogs related to the
presence of endemic dog rabies, particularly in Asia and Africa. Although the means of controlling dog
rabies are very well established, for a variety of economic, cultural, and political reasons, dog rabies
persists in many countries, and people in these regions are at a continued risk of transmission via dog
bites. In other countries, rabies is endemic in wildlife, and this poses the main risk for transmission of
rabies virus. Rabies virus variants can be identified with molecular techniques, including monoclonal
antibody characterization and reverse transcriptase polymerase chain reaction (RT-PCR) amplification
with sequencing. Bats are the most important wildlife rabies vectors, and in the United States, bat rabies
is present in every state except Hawaii (Fig. 17.4). Because of their small size, bat bites may not be
recognized, leaving no opportunity for initiating effective preventive measures. Patients infected by bat
rabies virus variants may not even be aware that they have had contact with bats (Table 17.1). A bat
rabies virus variant associated with silver-haired bats and tricolored bats are most frequently associated
with human rabies in the United States and Canada. A variant associated with Brazilian (Mexican) free-
tailed bats is the second most common variant associated with human rabies cases in the United States.
Although big brown and little brown bats are often found in houses and they are commonly found to be
infected with rabies virus, they are not frequently responsible for human rabies cases.
Terrestrial animals that are vectors of rabies in North America include raccoons, skunks, and foxes
(30) (Fig. 17.5). Raccoon rabies is endemic along the entire eastern coast of the United States. In the
1940s, raccoon rabies was present in Florida, and over a period of decades, it gradually spread north and
the first incursion occurred into Ontario, Canada in 1999. There are only two documented cases of human
rabies due to a raccoon rabies virus variant (19,31). Skunk rabies is present in midwestern states, the
prairie provinces of Canada, and in California. Fox rabies is now uncommon in North America because it
has been well controlled, particularly in Ontario (red fox) and Texas (gray fox), and in Europe with oral
vaccination programs. Companion animals, especially dogs and cats, are also at risk of developing rabies
transmitted from wildlife vectors, and they may then pose a danger to humans.
CLINICAL FEATURES
Typically, the incubation period from the time of the exposure until the time of the onset of clinical
disease is between 20 and 90 days but may be as short as only a few days or exceed a year. There is a
well-documented report of rabies with an incubation period as long as 6 years (32). Prodromal symptoms
in rabies are nonspecific and include fever, chills, malaise, fatigue, insomnia, anorexia, headache, anxiety,
and irritability. They may last for up to 10 days prior to the onset of neurologic symptoms. The earliest
neurologic features of rabies include paresthesias, pain, and pruritus at or close to the site of exposure,
which likely reflects infection and inflammatory changes in local sensory ganglia (e.g., dorsal root ganglia
or cranial sensory ganglia). By this time, the wound may have completely healed. There are two clinical
forms of disease in rabies: encephalitic rabies (in 80% of cases) and paralytic rabies (in 20% of cases).
The main burden of the infection in encephalitic rabies involves the brain, whereas in paralytic rabies, the
main burden likely involves the spinal cord, nerve roots, and peripheral nerves. Fever occurs in both
forms. In encephalitic rabies, there may be episodes of generalized arousal or hyperexcitability, which
are separated by lucid periods (33). Patients may have aggressive behavior, confusion, and
hallucinations. Features of autonomic dysfunction are common, and these may include hypersalivation,
piloerection (gooseflesh), sweating, priapism, and cardiac arrhythmias. Hydrophobia is a characteristic
clinical feature of encephalitic rabies and occurs more frequently with infections due to rabies virus
variants associated with dogs than with bats. Patients may initially experience pain in the throat or have
difficulty swallowing. When they attempt to swallow, they experience contractions of the diaphragm and
other inspiratory muscles, typically lasting for 5 to 15 seconds. Subsequently, this may become a
conditioned reflex and the sight, sound, or even mentioning water (or other liquids) may trigger the
spasms. Aerophobia is the occurrence of these same spasms precipitated by a draft of air on the skin.
There is progressive neurologic deterioration with worsening in the level of consciousness to coma and
the development of paralysis.
In paralytic rabies, there is early prominent weakness that usually initially involves the bitten extremity
and progresses to involve the other extremities and facial muscles. Sphincter involvement, pain, and
sensory disturbances also occur. Hydrophobia is unusual in paralytic rabies, although weakness of bulbar
and respiratory muscles also develops. Patients with paralytic rabies later develop neurologic
deterioration with progression to coma, and they typically survive longer than patients with encephalitic
rabies.
Medical complications are common in rabies patients treated aggressively in a critical care unit.
Cardiac and respiratory complications are common. Cardiac disorders include heart failure, hypotension,
a variety of arrhythmias, and cardiac arrest. Both cardiac ganglia and the myocardium may become
infected with rabies virus, and in some cases, there is an associated myocarditis (34–36). Respiratory
complications include hyperventilation, hypoxemia, respiratory depression with apnea, atelectasis, and
aspiration pneumonia (37). Hyperthermia or hypothermia may occur, likely secondary to hypothalamic
infection. Endocrine complications include inappropriate secretion of antidiuretic hormone and diabetes
insipidus (37,38). Multiple organ failure commonly occurs in patients treated aggressively in critical care
units.
The diagnosis of rabies may be difficult without a history of an animal exposure. Physicians may not ask
about animal exposures, and the patient may not recall an exposure or may not be able to provide this
information at the time of presentation. In early phases, encephalitic rabies may be misdiagnosed as a
psychiatric disorder and paralytic rabies as Guillain-Barré syndrome. Rabies hysteria is a conversion
disorder (somatoform disorder) that likely occurs as a psychologic response to the fear of developing
rabies (39). It is characterized by a shorter incubation period than rabies, aggressive behavior (not
common in humans), inability for the patient to communicate, and a long clinical course with recovery.
Other viral encephalitides may show behavioral changes with fluctuations in the level of
consciousness. Hydrophobic spasms are not observed, and the presence of brainstem signs is unusual in
conscious patients in most of the other viral encephalitides. Herpes simiae (B virus) encephalomyelitis,
which is transmitted by monkey bites, is usually associated with a shorter incubation period and recovery
may occur (40) (see Chapter 14). Tetanus has a shorter incubation period (3 to 21 days) than rabies and is
characterized by sustained muscle rigidity involving paraspinal, abdominal, masseter (trismus), laryngeal,
and respiratory muscles with superimposed brief recurrent muscle spasms (41) (see Chapter 37). In
tetanus, consciousness is preserved, there is no cerebrospinal fluid (CSF) pleocytosis, and the prognosis
is much better than in rabies. In Africa, rabies is commonly misdiagnosed as cerebral malaria (42). Anti-
N-methyl-D-aspartate receptor (anti-NMDA) encephalitis occurs in young patients (especially females)
and is characterized by behavioral changes, autonomic instability, hypoventilation, and seizures, and it
has recently been recognized that this autoimmune disease rivals viral etiologies as a cause of
encephalitis (43). Postvaccinal encephalomyelitis is an important differential diagnosis in patients
immunized with a vaccine derived from neural tissues (e.g., Semple vaccine), which is currently used in
only a few resource-poor countries. Patients with paralytic rabies may resemble the Guillain-Barré
syndrome, and the pathologic features may also be similar (44). Local symptoms at the site of the bite,
piloerection, early or persistent bladder dysfunction, and fever are all more suggestive of paralytic
rabies.
INVESTIGATIONS
Routine blood tests and computed tomography (CT) head scans are typically normal in rabies. Magnetic
resonance (MR) imaging may be normal or show signal abnormalities in the brain, spinal cord, and nerve
roots/plexuses, but these findings are not specific for rabies and the main usefulness of MR imaging is to
exclude other diagnostic possibilities (45). CSF analysis usually shows a mononuclear pleocytosis with a
cell count of less than 100 cells/µL. Serum-neutralizing anti–rabies virus antibodies may develop in
unvaccinated patients but may not appear for a week or more during the clinical course of disease, and
some patients never develop antibodies prior to death. Neutralizing anti–rabies virus antibodies may also
develop in the CSF, whereas CSF antibodies are not present in vaccinated patients who do not have
rabies encephalitis. Specific laboratory tests for confirmation of a diagnosis of rabies include a full-
thickness skin biopsy taken from the posterior region of the neck at the hairline. Rabies virus antigen may
be detected in nerve fibers around hair follicles with direct fluorescent antibody staining. A recent
advance in the laboratory diagnosis of rabies is detection of rabies virus RNA in fluids or tissues using
RT-PCR amplification. Detection of rabies virus RNA in saliva is the most useful. RT-PCR can also be
used on skin biopsies (46) and CSF but is much less sensitive on CSF. A negative laboratory test for
rabies never excludes rabies unless performed on brain tissues, and the tests may need to be repeated for
diagnostic confirmation of a rabies diagnosis. Brain tissues are only very rarely obtained by biopsy
antemortem but are routinely evaluated postmortem by direct fluorescent antibody staining and by culture
techniques.
PREVENTION OF RABIES
Rabies can be very effectively prevented after recognized exposures. Detailed guidelines that are
periodically updated are available from the Centers for Disease Control and Prevention (47) and from the
World Health Organization (48), and these documents are available on the Morbidity and Mortality
Weekly Report (http://www.cdc.gov/mmwr/) and World Health Organization (http://www.who.int/en/)
Web sites. Algorithms can be very useful in making decisions concerning postexposure rabies prophylaxis
(Fig. 17.6). The first step is to determine whether there is a real risk of rabies virus transmission, which
depends on obtaining the details of the exposure, the species of animal involved, and also on knowledge
about the local epidemiologic situation. Advice from local public health officials can be very helpful in
determining whether postexposure rabies prophylaxis measures should be initiated. Laboratory testing on
brain tissues from an animal is needed for a definitive diagnosis of rabies, which is usually performed by
an antigen detection method using the fluorescent antibody technique. If a dog, cat, or ferret remains
healthy for a 10-day period after an exposure, then a confident conclusion can be made that rabies virus
transmission did not occur during the exposure because the brainstem infection associated with the
salivary excretion of infectious virus would have progressed to overt clinical signs within the period. Of
course, unwanted animals may be tested without an observation period. Other animals must not be
observed after an exposure because there is uncertainty about the period of time for clinical disease to
develop, and this period may substantially exceed 10 days. If an animal escapes after an exposure, then it
should be considered rabid unless information from public health officials indicates that this is unlikely.
Current recommendations indicate that the physical presence of a bat may warrant postexposure
prophylaxis when a person such as a small child or sleeping adult is unable to reliably report contact that
could have resulted in a bite (47). However, in light of the low risks and high costs, recommendations for
bedroom exposures to a bat while sleeping and without known physical contact have been questioned
(49).
Postexposure rabies prophylaxis in previously unvaccinated persons includes wound cleansing and
active immunization with rabies vaccine and passive immunization with human rabies immune globulin
(HRIG). All animal bite wounds should be thoroughly cleaned with soap and water and, if available, a
virucidal agent (e.g., povidone) should be used to irrigate the wounds. In the United States, four doses of
rabies vaccine, which was recently reduced from five doses, are recommended on days 0, 3, 7, and 14
(50), and for each dose, 1.0 mL of vaccine should be given intramuscularly in the deltoid muscle. Two
rabies vaccines are currently licensed in the United States and Canada: purified chick embryo cell
vaccine (PCECV) (RabAvert) and human diploid cell vaccine (Imovax). Pregnancy is not a
contraindication for immunization. Local and mild systemic adverse effects are common. Local reactions
include pain, erythema, edema, and pruritus; systemic reactions include fever, myalgias, headache, and
nausea. Antiinflammatory medications and antipyretics may be used, but immunization should not be
discontinued. The dose of HRIG is based on weight (20 IU/kg), and HRIG should be infiltrated into and
around the wound and the remaining portion of the dose can be given intramuscularly in a different
location (e.g., gluteal muscles) than the vaccine is given. If there are multiple or extensive wounds and a
large volume of HRIG is needed for infiltration, then HRIG can be diluted as required for satisfactory
wound infiltration. HRIG should not be given later than 7 days after the first dose of rabies vaccine.
Adverse effects of HRIG include local pain and low-grade fever. If HRIG is not available, then purified
equine rabies immune globulin, which is much more readily available in some rabies-endemic countries
(e.g., Thailand), may be used in the same manner at a dose of 40 IU/kg.
In persons at risk of rabies exposures, including laboratory workers, veterinarians, and travelers to
places with endemic dog rabies (e.g., Asia and Africa), preexposure rabies immunization should be
considered. Three doses of vaccine are given on days 0, 7, and 21. When prolonged protection is needed,
booster doses of rabies vaccine can be given periodically as required based on a serum-neutralizing anti–
rabies antibody titer. After a rabies exposure in preimmunized individuals, in addition to wound
cleansing, two doses of rabies vaccine should be given on days 0 and 3 and HRIG should not be given.
THERAPY OF HUMAN RABIES

There is no effective therapy for human rabies, and the disease is virtually always fatal. In all except a
single case, survivors have received rabies vaccine prior to the onset of the clinical disease. In 2003, a
viewpoint article was published outlining the therapeutic options for consideration of an aggressive
approach for a patient with rabies (51). Young and previously healthy patients with an early clinical
diagnosis of rabies were felt to be the best potential candidates for aggressive therapy (51). Therapies
suggested for consideration include rabies vaccine, HRIG, monoclonal antibodies (for the future),
ribavirin, interferon-α, and ketamine. It was felt that a combination of therapies might improve efficacy in
situations in which specific therapies used individually had failed in the past, similar to the situation for
current therapies of a variety of infectious and other noninfectious diseases.
In 2004, a 15-year-old female who had been bitten on her finger by a bat and did not receive
postexposure prophylaxis therapy survived rabies (52). She developed typical clinical features of rabies
encephalitis about a month after the bite. On arrival at a tertiary care hospital in Milwaukee, Wisconsin,
neutralizing anti–rabies virus antibodies were detected in sera and CSF (initially at titers of 1:102 and
1:47, respectively). Nuchal skin biopsies were negative for rabies virus antigen, and rabies virus RNA
was not detected in saliva or in the skin biopsies using RT-PCR. She was intubated and put into a drug-
induced coma, which included the noncompetitive NMDA antagonist ketamine at 48 mg/kg/day as a
continuous infusion and intravenous midazolam for 7 days. A burst-suppression pattern on her
electroencephalogram was maintained, and supplemental phenobarbital was given as needed. She also
received antiviral therapy, including intravenous ribavirin and amantadine 200 mg per day administered
enterally. She improved and was discharged from hospital with neurologic deficits, and she subsequently
demonstrated further neurologic improvement (53).
This patient is the first documented rabies survivor who did not receive any rabies vaccine prior to the
onset of clinical rabies (Table 17.2). It remains uncertain if therapy with one or more specific agents
played a significant role in her favorable outcome (60). Since that time, there have been over 25 cases in
which the main components of this approach (the “Milwaukee protocol”) have been used, and the therapy
failed with fatal outcomes (61). The induction of coma per se has no established benefit for the
management of infectious diseases of the nervous system, and there is no evidence to date supporting this
approach in rabies or other viral encephalitides. Hence, therapeutic coma should not become a routine
therapy for the management of rabies. Recent experimental evidence does not support a mechanism of
excitotoxicity in a mouse model of rabies and also in rabies virus infection of cultured neurons, and there
was also a lack of efficacy of ketamine therapy in cultured neurons and in the mouse model (62). Even in
situations in which there is very strong experimental evidence of excitotoxicity in animal models,
numerous clinical trials in humans have failed to demonstrate efficacy of neuroprotective agents in stroke
(63). Hence, a neuroprotective effect of a therapy given to a single patient without a credible scientific
rationale is highly doubtful. It is likely that this patient would also have recovered with only good
supportive therapy.
Neutralizing anti–rabies virus antibodies are an important marker of an adaptive immune response that
is essential for clearance of rabies virus and recovery (64). The presence of serum-neutralizing anti–
rabies virus antibodies early in a patient’s clinical course probably occurs in less than 20% of patients
with rabies and is likely an important factor contributing to a favorable outcome in this patient. There
have been six survivors of rabies who received rabies vaccine prior to the onset of their disease and only
one without vaccine. This suggests that an early immune response is associated with a positive outcome.
Recovery of cases with atypical clinical features of rabies without the development of anti–rabies virus
neutralizing antibodies (65,66) were probably not actual cases of rabies and should not be considered
survivors. Bat rabies virus variants are probably less neurovirulent than canine virus variants or other
variants that are responsible for most human cases of rabies (67), and human rabies due to canine rabies
virus variants likely has a reduced chance of a favorable outcome than cases caused by bat rabies virus
variants. One previous survivor of rabies, who was also infected with a bat rabies virus variant received
rabies vaccine prior to the onset of disease and made an excellent neurologic recovery (54). It is unknown
if the causative bat rabies virus variant in the Milwaukee case was attenuated and had different biologic
properties than other isolated variants because there was no viral isolation in this case. However, in
rabies survivors, diagnostic laboratory tests are usually negative for rabies virus antigen and RNA in
fluids and tissues, and brain tissues have not been tested. This may reflect effective viral clearance in
which centrifugal spread of the infection to peripheral organ sites is reduced or very rapid clearance
occurs through immune-mediated mechanisms.
Pathologic data from a number of human rabies cases treated with the Milwaukee protocol indicate that
the therapy is ineffective in clearing rabies virus infection from the brain and from preventing neuronal
injury. A case from Edmonton (Canada) was treated with the Milwaukee protocol and after termination of
the therapeutic coma remained in a brain death–like state for about 4 weeks (68). At autopsy, there was
complete loss of neurons in the cerebral cortex, and positive staining for rabies virus antigen was
observed in both brainstem and cerebellar neurons, indicating a failure of clearance of the viral infection
from the brain and also failure of protection against neuronal injury and loss (68). In Germany, lung and
kidney/pancreas recipients from a rabies virus–infected donor developed rabies and were treated with
major components of the Milwaukee protocol, including intravenous midazolam, ketamine, and
phenobarbital (in one) (19). One patient died within 2 days, whereas the other survived 64 days after the
onset of clinical rabies. At autopsy, the two patients had 1.2 to 2.3 × 109 RNA copies per mg of CNS
tissue, indicating ineffective viral clearance. The long surviving patient showed viral clearance from
systemic organs and peripheral nerve. Hence, Milwaukee protocol therapy has proved ineffective in
promoting viral clearance from the CNS in rabies. It remains highly doubtful that the Milwaukee protocol
will prove to be useful in the management of human rabies. Unfortunately, promotion and repetition of this
flawed therapy has likely already impeded progress in the development of new effective therapies for
rabies. A better understanding of basic mechanisms underlying rabies pathogenesis in humans and animals
is needed, which may prove to be very helpful in the development of novel therapeutic approaches for the
management of this dreaded disease.
OTHER LYSSAVIRUS INFECTIONS

Non–rabies virus lyssaviruses may cause fatal neurologic illnesses that are clinically and pathologically
indistinguishable from rabies. Mokola virus has been isolated from shrews, although the reservoir is
unknown. In 1971, a 6-year-old girl died with Mokola virus infection (69); another case with mild illness
was more likely due to cross-contamination of specimens in the laboratory (70). The index case of
Duvenhage virus infection was transmitted by a bat and occurred in South Africa (71), and two additional
cases were recently reported (72,73). There have been two cases reported due to European bat lyssavirus
1 (74,75) and another two cases due to European bat lyssavirus 2 (76,77). In 1996, 1998, and 2013, cases
due to Australian bat lyssavirus were likely transmitted by a fruit-eating bat (flying fox) and an insect-
eating bat, respectively (78–80). In 2007, a 20-year-old female died in the Primorye Territory, which is in
the Russian Far East, due to Irkut virus, which had been previously isolated from a greater tube-nosed bat
(81).
Suggested Readings
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Jackson AC. Update on rabies. Res Rep Trop Med. 2011;2:31–43.
Jackson AC. Research advances in rabies. In: Jackson AC, ed. Advances in Virus Research. Vol 79.
London: Elsevier Academic Press; 2011.
Jackson AC. Rabies: Scientific Basis of the Disease and Its Management. 3rd ed. Oxford: Elsevier
Academic Press; 2013.
Meslin FX, Kaplan MM, Koprowski H. Laboratory Techniques in Rabies. 4th ed. Geneva: World Health
Organization; 1996.
Schnell MJ, McGettigan JP, Wirblich C, et al. The cell biology of rabies virus: using stealth to reach the
brain. Nat Rev Microbiol. 2010;8:51–61.
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Rabies Bull Europe. 2009;33:5–8.
CHAPTER 18 HUMAN PRION DISEASES
SERGGIO C. LANATA, SVEN FORNER, AND MICHAEL D. GESCHWIND
The transmissible spongiform encephalopathies (TSEs) are a group of closely related fatal
neurodegenerative diseases that affect humans and several other mammals (Tables 18.1 and 18.2). TSEs
have a few characteristics in common: (1) they are transmissible in nature and/or experimentally; (2) they
invariably lead to brain dysfunction or “encephalopathy,” which manifests clinically as cognitive,
behavioral, sensory, and/or motor dysfunction; (3) they are uniformly fatal; and (4) they currently can only
be diagnosed definitively by neuropathology (or genetically in certain cases).
TSEs are caused by prions (for “proteinaceous infectious particles”), misshapen forms of the
endogenous prion protein, in the central nervous system (1); hence, TSEs are now referred to as “prion
diseases,” which is the term that will be used for this chapter. Prion (pree-ahn) diseases are unique in
medicine in that they occur in three forms: sporadic, infectious/acquired, and genetic. All three
mechanisms occur in humans. Prions are considered infectious because they rarely can be transmitted
from person to person (iatrogenically) or even less commonly by ingestion. When they are transmitted
into, or develop in, the nervous system, they cause the conversion of normal-shaped prion proteins into an
abnormal, pathogenic conformation. This conversion process becomes exponential and leads to the
spread of prions throughout the brain, causing neuronal dysfunction and cell death and, ultimately,
neurodegeneration. Prions are intrinsically different from all other naturally occurring infectious agents,
however, in that they do not rely on nucleic acid to replicate within the host organism. Furthermore, the
presence of sporadic and heritable forms of prion disease also differentiates prions from all other
infectious agents. This chapter will focus primarily on human prion diseases, with the caveat that most of
our knowledge of the pathophysiologic mechanisms of prion disease has been obtained from animal and
cell culture studies.
SCRAPIE, KURU, AND THE DISCOVERY OF PRIONS

The history of the discovery of prions is an inspiring journey of multidisciplinary scientific collaboration
that profoundly changed our understanding of infectious and neurodegenerative diseases. This journey
began with the careful study of the prion disease called scrapie, which primarily affects sheep and goats.
Scrapie is probably the earliest described prion disease, with the first reports published in 1750, but
the disease was probably recognized as early as 1732 in Great Britain. The clinical signs of scrapie are
variable; the most frequently observed clinical signs are emaciation, repetitive head rubbing,
hyperesthesia, and pruritus. Pruritus is often severe enough to make the affected animal rub and scrape
(hence the term “scrapie”) its body against rough surfaces, leading to wool loss and skin abrasions (2).
Affected animals often become hypersensitive to outside stimuli, including noises, sudden movements, or
handling by humans, to the extent some stimuli will cause the animal to startle violently or convulse. Other
common signs include tremor and ataxia leading to impaired gait and falls. Behavioral changes are
prominent and common. A nibbling response of the mouth is often evoked by scratching the animal’s back
(“positive scratch response”). Scrapie has a long incubation period, ranging between 2 and 5 years, and
affected animals live up to 6 months after symptom onset.
Scrapie is transmissible both naturally and experimentally. The natural means of transmission is a
matter of debate, with both environmental and genetic susceptibility factors influencing transmission (3).
Experimental transmissibility of scrapie, however, was firmly demonstrated in 1936 when Cuillé and
Chelle (4) showed that healthy sheep inoculated with scrapie-infected spinal cord tissue developed the
disease. At the time, however, the infectious agent of scrapie was unknown.
Puzzled by scrapie’s long incubation period and devastating course, Bjorn Sigurdsson, an Icelandic
veterinarian, first proposed the notion of “slow viral infections” in the 1950s regarding a paralytic
encephalitis of sheep called rida (5). In his view, these neurologic diseases were caused by unknown
viruses with prolonged incubation periods (years to decades) that led to death after a short and
progressive clinical course. Sigurdsson’s ideas shed light on the etiology of many diseases that were
poorly understood at the time (6). For example, maedi, a deadly form of pneumonitis in sheep, and visna,
a slowly progressive encephalitis, were found to be caused by the same virus, now known as the maedi-
visna lentivirus (7). The suspected viral cause of scrapie, on the other hand, still remained elusive.
Concurrently, in the 1950s, D. Carleton Gajdusek, an American physician and virologist, initiated the
scientific study of a human neurologic disease known as kuru in Papua New Guinea. Papua New Guinea
is one of the most culturally diverse countries in the world, with more than 800 languages spoken among
roughly 6.3 million people segregated in different tribes. The kuru epidemic emerged in the early
twentieth century among the Fore tribe that inhabits one of the highland provinces. Kuru means to shiver
from fever or cold in the language of the Fore people (8). The disease is characterized clinically by the
insidious onset of progressive cerebellar ataxia, eventually leading to inability to walk. A typical early
feature of the disease is the presence of unusual laughter, giving rise to the phrase “the laughing death” to
describe kuru (9). In later stages, brainstem findings typically manifesting as eye movement abnormalities
and severe dysarthria are also common. Like scrapie, the incubation period for kuru is long, as long as 50
years (10), and disease duration is relatively short, usually less than 12 months.
Early anthropologic studies of the Fore people described a ritualistic form of cannibalism that
prevailed across all age groups. Fore people consumed the bodies of their deceased relatives
(endocannibalism), including those who died of kuru (11). This was done with the hope of maintaining the
spirit of the deceased within the village community. Perhaps partly for this reason, Gajdusek and his team
initially suspected an infectious, probably viral, etiology to kuru, borrowing from Sigurdsson’s concept of
slow viral infections (12). It soon became clear, however, that kuru was not a typical infectious disease,
in that victims did not exhibit fever or other clinical signs of infection, including no signs of
meningoencephalitis, no obvious cerebrospinal fluid (CSF) abnormalities, and patients did not respond to
antibiotic medications. Furthermore, autopsy studies of brains affected by kuru did not demonstrate the
inflammatory changes typically seen in many forms of nervous system infections. Additionally, it was not
transmissible to small laboratory animals and no infectious agent had been identified (8). This led
Gajdusek and others to conduct an exhaustive search of environmental factors that could explain the
transmissible and seemingly infectious nature of kuru (13,14), but none were found. The absence of an
environmental cause for kuru coupled with the well-described tribal and familial distribution of the
disease led some to believe that kuru was a genetically inherited condition (15). Large epidemiologic
studies showed that the incidence of kuru dramatically decreased among members of tribes who abolished
endocannibalism, thus pointing toward a transmissible disease mechanism rather than a genetic one (8).
A major breakthrough came when William J. Hadlow, a veterinarian pathologist, made note of the
neuropathologic similarities between kuru and scrapie and postulated that a similar infectious agent was
the cause of both diseases (16). This was an important conceptual contribution to the study of prion
diseases in general, as prior to the 1950s, the efforts to understand scrapie and kuru were disjoined (1).
This observation further motivated scientists to take on the challenge of identifying the causative agent of
these diseases.
Toward this goal, a series of careful experiments done on scrapie-infected brains demonstrated that the
scrapie agent was resistant to conditions that normally inactivated other infectious organisms like viruses
and bacteria, such as exposure to formalin (17), very high temperatures (18), and other solvents (19).
Scrapie, and presumably kuru, was beginning to show properties that distinguished it from other
infectious diseases.
Siggurdson’s and Hadlow’s hypotheses were eventually supported experimentally in 1966, when the
transmission of kuru was demonstrated by Gajdusek and colleagues (20) through the intracerebral
inoculation of diseased brain tissue in the chimpanzee. The proven transmissibility of kuru helped solidify
the natural transmissibility theory that had already been gaining momentum based on anthropologic and
epidemiologic observations: kuru was transmitted through endocannibalism (21). Furthermore,
neuropathologic similarities between kuru and Jakob-Creutzfeldt disease (JCD) had been clearly
recognized in the late 1950s (22). And the same group of investigators that demonstrated transmission of
kuru to chimpanzees also demonstrated transmission of JCD to the chimpanzee in 1968 (23). This was an
important experimental discovery, as JCD had previously been regarded as a human neurodegenerative
disease of unknown etiology. Taken together, these observations led to the introduction of the term
“transmissible spongiform encephalopathies” to highlight the many neuropathologic and clinical
characteristics shared by these three diseases.
Still, although experimental transmissibility had been proven for scrapie, kuru, and JCD, and natural
transmissibility had been shown for scrapie and kuru, the infectious substrate of these diseases remained
unknown. As mentioned earlier, the scrapie agent did not share basic biochemical and biophysical
properties with other known infectious organisms. This notion was strengthened in 1966, when Alper and
colleagues (24) showed that extracts of scrapie-infected brains retained their infective nature even after
exposure to large doses of ultraviolet light that were known to irreversibly damage the DNA and RNA
molecules, thus implying that the scrapie agent lacked nucleic acid. Later, similar studies were conducted
on tissue containing the agent responsible for kuru and JCD (25).
The idea of an infectious agent lacking nucleic acid was considered outlandish at the time. It implied
that the agent that transmitted these diseases was, at its core, unlike any other known infectious agent. This
idea captured the curiosity of neurologist Stanley Prusiner and other researchers. Through a series of
careful experiments using animal models, Prusiner confirmed that the scrapie agent indeed resists
inactivation by procedures that hydrolyze, modify, or shear nucleic acids; furthermore, Prusiner and
colleagues demonstrated that the scrapie agent was inactivated by treatments that denatured protein (26).
Based largely on this line of evidence, Prusiner postulated that a protein, which he named “prion” (pree-
ahn) for “proteinaceous infectious particle,” was the principal carrier of scrapie (27).
The discovery of prions (PrP, for “prion protein”) shattered the concept that nucleic acids are the sole
carriers of transmissible infectious disease. Alternative theories to explain the nature of the scrapie agent
were proposed for years after Prusiner’s postulate (28,29), but none of these theories has been proven
experimentally and the prion model has become widely accepted over the last two decades, supported by
a vast body of evidence.
NORMAL AND PATHOGENIC PRION PROTEINS: PrP C AND

PrP Sc
After PrP was found to be the disease-producing substrate in concentrates of scrapie-infected brain tissue
(27), the question arose whether PrP was acquired exclusively from the environment via an infectious
mechanism or if it was also produced endogenously by the diseased animal.
In 1986, for the first time, researchers were able to isolate PrP-related genomic clones in normal
hamsters using complementary DNA (cDNA) obtained from PrP messenger RNA (mRNA), thus
demonstrating that mammalian cells carry the gene responsible for encoding PrP (30). Similar
experiments were performed in mice (31) and other mammals including humans (32). The gene that
encodes PrP is known as PRNP. PRNP encodes a normal form of PrP with incompletely understood
cellular functions. The misshapen, pathogenic form of PrP, on the other hand, has unique biochemical
properties that distinguish it from its normal counterpart (as will be discussed in the following sections).
This distinction led to the current designation of “cellular PrP” (PrPC) to describe PrP in its normal form
and “scrapie PrP” (PrPSc) to describe the misfolded, pathogenic form of PrP. The terms PrPC and PrPSc
will be used accordingly in this chapter.
The Prion Protein Gene (PRNP)
The prion gene, PRNP, is located in the short arm of chromosome 20 in humans. It is composed of two
exons and one intron, and the protein-coding region is located in exon 2. PRNP encodes the 253 amino
acid PrP. A schematic of PRNP and the prion gene in other species is shown in Figure 18.1. There are
more than 30 autosomal dominant mutations of PRNP that lead to inherited forms of prion disease in
humans. These occur primarily in the form of point mutations as well as some insertion, and possibly
deletion mutations. Point mutations normally occur in the central and C-terminal portions of PrP. Insertion
mutations occur in the N-terminal end of the protein, which is normally composed of a nonapeptide
followed by four octapeptide repeats. Different mutations lead to varied familial forms of the disease
(33,34).
Historically, clinically-based studies of the heritable forms of prion disease in humans led to the
identification of three classic phenotypes: Gerstmann-Sträussler-Scheinker disease (GSS), familial
Jakob-Creutzfeldt disease (fJCD), and fatal familial insomnia (FFI). These three forms of familial JCD
were described based on clinicopathologic features, prior to the identification of PRNP. The
classification of familial (genetic) prion diseases, however, has changed with the division of familial
forms based on specific PRNP mutations. Genetic prion diseases (gPrDs) are discussed in detail in the
section, “Human Genetic Prion Diseases.”
Polymorphisms in the PRNP gene have been shown to influence prion disease susceptibility and the
clinical phenotype. The most important polymorphism in humans is at amino acid 129 of PRNP, which can
be methionine (M) or valine (V). As every person has two copies of each gene, humans can be either
MM, MV, or VV. Homozygosity (either MM or VV) at codon 129 increases susceptibility to sJCD
(35,36), for example. Likewise, in patients with gPrD, the cis codon 129 polymorphism (i.e., the codon
129 allele on the same DNA strand as the mutation) can greatly influence how a disease presents (37).
The phenotypic influence of these polymorphisms will be discussed further under the gPrDs section.
The Function of Cellular PrP
PrPC is expressed mostly in the brain, but it has also been detected in a wide variety of mammalian
tissues, including leukocytes, heart, skeletal muscle, lung, intestinal tract, spleen, and reproductive organs
(38). The role of PrPC in the nervous system remains elusive and controversial. PrPC is a cell-surface
glycoprotein that forms part of cell membrane structures known as lipid rafts (39). In the nervous system,
lipid rafts are heavily involved in cellular signal transduction pathways, including neurotrophic factor
signaling, cell adhesion and migration, axon guidance, myelin genesis, and synaptic transmission (40). It
is therefore not surprising that most of the cellular functions of PrPC that have been described over the
past two decades relate to a wide range of signal transduction pathways (41) involving molecular
interactions with multiple cellular proteins (42), some of which are vital for normal neuronal function.
For example, in mouse neuroblast brain cells, PrPC overexpression enhances cell proliferation and cell
cycle reentrance, whereas PrPC silencing slows down the cell cycle; these effects are mediated via PrPC
interactions with epidermal growth factor receptor (EGFR) in the plasma membrane (43). Similarly, PrPC
expressed in pluripotent human embryonic stem cells have been shown to induce and modulate cell cycle
dynamics and partly determine cell differentiation (44). PrPC has also been shown to be essential for
myelin maintenance, as depletion of PrPC in neurons triggers a form of chronic demyelinating neuropathy
in mice (45). PrPC has been implicated in neuroprotective and neurotoxic signaling cascades (46).
Furthermore, there is an expanding body of evidence that supports clear interactions between PrPC and
metal ions in different signaling pathways, particularly copper, zinc, and iron (47).
Despite the role of PrPC in a variety of important cellular functions (48), however, some PrPC knockout
mice have been shown to develop normally and do not have signs of neurologic disease (49), thereby
suggesting that the absence of PrPC is not a sufficient cause of neurodegeneration or neurodevelopmental
abnormalities.
Structural Differences Between PrP C and PrP Sc

All mammalian proteins are composed of a specific structure of amino acids (primary structure) that are
arranged into identifiable repeating structures held together by hydrogen bonding (secondary structure),
which in turn cause protein molecules to adopt specific three-dimensional conformations (tertiary and
quaternary structures). Via their three-dimensional structure, cellular proteins are able to interact with
each other and thereby dictate an organism’s physiology.
The primary structure of PrPC across different mammalian species is highly conserved (50) and is
nearly identical to that of PrPSc (51). PrPSc and PrPC also share important posttranslational modifications,
including the presence of two N-glycosylation sites, a single disulfide bond between cysteine residues,
and a glycosylphosphatidylinositol membrane anchor at the C-terminus (this is the site of attachment of
PrPC to the cell membrane) (52).
The biochemical and biophysical differences that exist between PrPC and PrPSc are the result of
specific posttranslational modifications that affect the secondary, tertiary, and quaternary structures of
these proteins. In this respect, the most important difference between PrPC and PrPSc relates to their
response upon exposure to detergents and proteases. PrPC is soluble in nondenaturing detergents and
degrades when exposed to proteases. PrPSc, on the other hand, forms amyloid structures (prion rods that
show the typical fluorescence birefringence of amyloids) when exposed to detergents and is highly
resistant to cellular proteases, particularly proteinase K (PK) (52). It is important to note that PrPSc is not
fully resistant to PK, however, and this will be discussed further in the following texts. The insolubility of
PrPSc to detergents, on the other hand, is universal, and this property is used in the laboratory to
accurately diagnose the presence of prion disease.
Our knowledge of the structural differences that exist between PrPSc and PrPC at an atomic level has
been obtained via careful studies on different transgenic animal models using nuclear magnetic resonance
(NMR) and infrared (IR) spectroscopy and x-ray crystal diffraction. IR spectroscopy studies have shown
that PrPC has a high alpha-helix content and virtually no beta-sheet content, whereas PrPSc is
characterized by roughly equal amounts of alpha-helices and beta-sheets (53). Alpha-helices and beta-
sheets are secondary protein structures. NMR spectroscopy studies also reveal that PrPC forms a unique
three-dimensional structure in its C-terminus, consisting of three alpha-helices bundled with two short
antiparallel beta-sheets (52), whereas the N-terminus does not arrange into a specific conformation.
These findings have been largely replicated using x-ray crystal diffraction methods (54).
Possible Mechanisms of PrP C Conversion and PrP Sc Propagation
The infectious nature of prions in animals was perhaps most influentially demonstrated by Legname and
colleagues (55) in 2004, when they inoculated fibrils of N-terminally truncated recombinant mouse PrP
made in Escherichia coli into the brains of transgenic PrP knockout mice expressing N-terminally
truncated PrP and showed that these mice developed neurologic dysfunction between 380 and 660 days
after inoculation, with neuropathologic findings consistent with prion disease. When brain extracts from
these mice were then inoculated into the brains of wild-type mice, these mice developed a prion disease.
Many other similar experiments have confirmed that prions have the ability to replicate and propagate
within the nervous system.
As stated previously, the mode of propagation of prions is unique among infectious agents, in that
prions do not appear to use nucleic acid to replicate within the host species. Instead, according to the
protein-only hypothesis of prion spread, the presence of PrPSc by itself induces endogenous PrPC to
misfold into PrPSc via the modification of the secondary and tertiary structures of PrPC in a process
referred to as template-directed misfolding. In other words, PrPSc acts as a template that guides PrPC
misfolding: one molecule of PrPSc induces the conversion of one molecule of PrPC into PrPSc, two
molecules of PrPSc induce the transformation of two new molecules of PrPC, and so PrPSc accumulates in
an exponential fashion (see Figs. 18.2 and 18.3. The progressive accumulation of pathogenic PrPSc in the
nervous system leads to the clinical manifestations and neurodegeneration seen in prion disease (1).
The exact mechanisms by which PrPSc leads to the misfolding of PrPC are yet to be determined. It has
been demonstrated experimentally that the first step in prion infectivity involves the successful cellular
uptake of PrPSc in susceptible host cells (56,57), thereby allowing the physical interaction between PrPC
and PrPSc that is required for misfolding. Although it is widely accepted that the presence of cellular PrPC
is required for the propagation of prion disease (58,59), the initial cellular uptake of PrPSc occurs without
participation of PrPC (60). Instead, several cell membrane receptors have been implicated in the initial
steps of transformation of PrPC into PrPSc. Among these, the low-density lipoprotein receptor–related
protein 1 (LRP1) might be an important player (61) as well as glycosaminoglycan (62) and laminin
receptors (63). There are likely other cellular receptors involved in this process.
Once incorporated to the host cell, PrPSc leads to PrPC misfolding within minutes. This was elegantly
demonstrated in in vitro experiments using epitope-tagged PrPC in neuroblastoma cell lines (64).
Moreover, it appears that PrPC misfolding occurs largely within the cell surface, from where PrPSc is then
endocytosed and either recycled back to the plasma membrane or deposited within the Golgi system (65).
Several biochemical and biophysical factors have been shown to facilitate the misfolding of PrPC into
PrPSc in vitro, including the presence of acidic and/or salt solutions and interactions between PrPC and
metal ions (66). The cellular mechanisms of PrPC misfolding remain elusive, however, and there is
mounting evidence suggesting that there are several different cellular structures and cofactors mediating
the transformation of PrPC to PrPSc (67,68).
SPORADIC HUMAN PRION DISEASE: JAKOB-CREUTZFELDT

DISEASE, FATAL INSOMNIA, AND VARIABLY PROTEASE-
SENSITIVE PRIONOPATHY
Sporadic Jakob-Creutzfeldt Disease
The disease that we now recognize as sporadic Jakob-Creutzfeldt disease (sJCD) clinically and
neuropathologically was first described by Alfons Maria Jakob (69,70) in the early 1920s. The single
case that his mentor Hans Gerhard Creutzfeldt (71) described in 1920, on the other hand, was neither
clinically nor neuropathologically representative of sJCD or what we now know as prion disease
(72,73). Therefore, some authors prefer the more correct eponym Jakob’s or Jakob-Creutzfeldt disease
rather than Creutzfeldt-Jakob disease (CJD) when referring to prion disease. The authors of this chapter
prefer the name Jakob-Creutzfeldt over Creutzfeldt-Jakob. Thus, the term should probably be Jakob-
Creutzfeldt disease (or even Jakob’s disease [JD]). Of note, some physicians have mistakenly thought
prion disease was due to the JC virus and incorrectly sent the JC virus PCR as a test for prion disease. In
this chapter, we use the term Jakob-Creutzfeldt disease.
Most studies have shown that about 85% of human prion diseases are sporadic, 10% to 15% are
genetic, and less than 1% is acquired. In a large prospective systematic study of human prion disease in
Europe, Australia, and Canada from 1993 to 2002, which included more than 4,400 pathology-proven
cases, the incidence of sporadic prion disease was approximately 85%, genetic was about 10%, and
acquired were about 6% (74). The larger percentage of acquired cases than many other studies is likely
due to the emergence of vJCD primarily in the United Kingdom and France during this time period (75) as
well as the emergence of human pituitary hormone cases from prior exposure in the United Kingdom,
France, and Australia (76). The incidence of sporadic human prion diseases in most populations is about
1 per million, of gPrD about 1 per 10 million, and even less for acquired prion disease (77).
Before recent advances in molecular biology were applied to study human prion disease, sJCD was
subdivided into separate phenotypes based on clinical and histopathologic characteristics. Classic
subtypes of sJCD described in the early literature include the Heidenhain variant of sJCD, characterized
by prominent early visuospatial symptomatology, sometimes leading to cortical blindness (78); the Jakob
variant or spastic pseudosclerosis, which presents with prominent frontal, pyramidal, and
extrapyramidal symptoms; and the Brownell-Oppenheimer variant, characterized by early cerebellar
dysfunction and late dementia. Other clinical variants exist in the literature.
It is now known that the clinicopathologic variability of sJCD is in part due to two factors: the
polymorphisms at codon 129 of PRNP (36) and at least two distinct “species” of PrPSc (PrPSc type 1 and
type 2). In the laboratory, the two types of PrPSc are distinguished by their mobility on Western blot
transfers after exposure to PK (Fig. 18.4) (79). Taken together, this line of evidence suggests that the
different sJCD phenotypes are an expression of interactions of the host PRNP genotype and PrPSc type,
and this notion forms the basis of our current classification of sJCD.
Large studies have been carried out comparing molecular, neuropathologic, and clinical characteristics
of sJCD subjects (80). Results of these studies prompted a classification scheme that included six
molecular subtypes based on PRNP codon 129 polymorphisms (M/M, M/V, or V/V) and PrPSc type (type
1 or 2). There is considerable overlap between classic sJCD clinical phenotypes and the clinical
phenotypes associated with each molecular subtype to the extent that five combined sJCD subtypes were
initially recognized: MM1/MV1, VV1, VV2, MV2, and MM2 cortical and MM2 thalamic (the latter of
which corresponds to sporadic fatal insomnia) (79,81). The discovery that many patients have both type 1
and type 2 prions has complicated this earlier molecular classification and expanded the subtypes of
sJCD (79,82). It is beyond the scope of this chapter to describe the clinicopathologic characteristics of
each subtype in great detail. The main characteristics of each subtype are shown in Table 18.3 (79).
The clinical presentation of sJCD in general is protean, however. Studies show that 40% to 60% of
affected individuals initially develop cognitive symptoms (83–85), generally manifesting as memory,
executive, and language dysfunction and/or confusion. Other early clinical manifestations include
cerebellar dysfunction, constitutional symptoms, and behavioral/personality changes (e.g., depression,
irritability) in around 20% of pathology-proven cases of sJCD. Furthermore, impaired vision (blurred
vision, diplopia, and visual hallucinations) has been reported as an initial complaint in 9% to 15% of
cases (84–86). Myoclonus, which is anecdotally considered to be a sensitive sign of sJCD by many
clinicians, is a late feature of the disease in up to 90% of cases (84). Other movement disorders are often
seen in patients with sJCD, either early or late in their disease course, including dystonia (fixed posturing
of a body part), choreoathetosis (slow, writhing or quick dance-like movements), parkinsonism (slowed
movements, tremor at rest, etc.), and supranuclear gaze palsy (inability to move eyes volitionally) (87).
Other rare initial manifestations of sJCD include seizures (including status epilepticus) (88); these have
been reported in some studies in up to 10% of cases, but usually later in the disease course. In our
experience, seizures are far less common than this (84,86,88). Clinically evident peripheral neuropathy
(including cranial neuropathy) is very uncommon in sJCD (89,90) but is seen more commonly in some
gPrDs (91–95).
The average age of onset of sJCD is 65 years, with a peak incidence in the 7th decade. The average
disease duration is 4 to 7 months. The great majority of patients (90%) die within 1 year of diagnosis, but
up to 5% of patients may survive for 2 or more years (36,84,96). Certain factors such as younger age at
onset, female gender, and heterozygosity at codon 129 have been associated with longer survival in sJCD
(36,77,79). Invariably, however, sJCD leads to a relatively rapidly progressive dementia (RPD)
(compared to most other neurodegenerative diseases), with varied clinical manifestations, depending on
which areas of the brain are affected by prion neurodegeneration. Regardless of pattern of prion spread,
most cases develop akinetic mutism prior to death (87). Death is usually due to aspiration pneumonia.
Brain magnetic resonance imaging (MRI) is the most sensitive and specific diagnostic test for sJCD,
with published sensitivity of approximately 91% to 96% and specificity of approximately 92% to 94%
(79,97,98). The high diagnostic sensitivity of brain MRI is largely a reflection of its ability to detect
changes very early in the disease course (98). The most sensitive MRI sequences for the diagnosis of
sJCD are diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences; indeed,
DWI has been shown to be more sensitive than fluid-attenuated inversion recovery (FLAIR)/T2
sequences abnormalities (98,99).
The radiographic hallmark of sJCD is the presence of DWI MRI hyperintensities in the neocortex,
basal ganglia, and/or thalamus, often associated with corresponding ADC map hypointensities, suggesting
restricted flow of water molecules in these regions (97), probably due to pathological changes occuring
in prion disease, particularly vacuolation (spongiform change), prion deposition, and/or gliosis (astrocyte
proliferation) (100). These MRI findings have been included in various criteria for sJCD (101), although
some criteria allow T2 or FLAIR and do not require DWI abnormalities (102), which might lead to false-
positive diagnoses (97). An example of the typical brain MRI findings seen in sJCD is shown in Figure
18.5. Three major patterns of DWI MRI hyperintensities have been identified in sJCD: neocortical and
subcortical (approximately 68% of cases), predominantly neocortical (24% to 30%), and predominantly
subcortical (mostly striatal hyperintensities, with or without thalamic involvement) (2% to 5%) (97,103)
(Fig. 18.6). Cortical hyperintensities (or cortical ribboning) can be unilateral or bilateral but typically
spares the precentral cortex (97,104). Striatal involvement often begins unilaterally, but eventually
becomes bilateral, and typically has a decreasing anterior-posterior gradient (i.e., the anterior caudate
appears more hyperintense than the posterior putamen) (97). Moreover, up to 90% of sJCD cases
demonstrate involvement of limbic and paralimbic cortical structures (i.e., insula, anterior cingulate,
hippocampus), visualized as hyperintensities and hypointensities of these regions on DWI and ADC
sequences, respectively. In our experience, isolated limbic involvement is atypical for sJCD, however,
and should alert the clinician toward alternative diagnoses (97).
Cortical ribboning is not 100% sensitive and specific for sJCD, however, as it is also seen in cases of
viral and/or autoimmune encephalitis, hypoglycemia, seizures and status epilepticus, hyperammonemic
encephalopathy, hypoxic injury, mitochondrial encephalopathy, vasculitis, and other conditions
(97,98,105). Hence, clinicians should consider these and other conditions in the presence of cortical
ribboning on brain MRI. Likewise, striatal and diencephalic DWI hyperintensities with ADC
hypointensities should not be considered pathognomonic of sJCD, as these changes have been observed in
extrapontine myelinolysis, Wilson disease, Wernicke encephalopathy, and hyperglycemia with seizures
(97,105). These DWI hyperintensities might decrease in late stages of the disease due to brain atrophy,
particularly in patients with disease duration of over 1 year (97). Despite the high sensitivity and
specificity of MRI DWI and ADC sequences for the diagnosis of sJCD in the right clinical setting, there is
evidence to suggest that radiologists often miss the diagnosis of sJCD because they fail to recognize these
changes (106,107).
Electroencephalogram
The diagnostic value of electroencephalography (EEG) has lessened to some extent due to the high
sensitivity and specificity of brain MRI for the diagnosis of sJCD (98). Still, the presence of periodic
sharp wave complexes (PSWCs), often biphasic or triphasic, occurring every 0.5 to 2 seconds (Fig. 18.7)
remains a useful finding that helps rule in sJCD in the right clinical setting (77,108). This EEG finding is
found only in about two thirds of sJCD patients, however, and is most often present late in the disease
course and may require repeated EEG testing (108). In general, compared to brain MRI, EEG probably
provides little value for diagnosis early in the disease course. Furthermore, the presence of PSWCs rarely
is seen in other neurologic conditions such as Alzheimer disease, dementia with Lewy bodies, toxic-
metabolic and anoxic encephalopathies (e.g., hepatic), progressive multifocal leukoencephalopathy, and
Hashimoto encephalopathy (109,110).
Cerebrospinal fluid
Routine CSF analysis is typically normal in sJCD, although sometimes a mild elevation in the total
protein level can be seen (typically less than 75 mg/dL). CSF pleocytosis (>10 cells/µL white blood cells
[WBCs]), an elevated immunoglobulin G (IgG) index, and/or the presence of oligoclonal bands are
unusual in sJCD and should lead the clinician to consider other conditions, particularly infectious or
autoimmune disorders (111,112).
The clinical use of several CSF biomarkers is quite controversial, with evidence showing varying
degrees of sensitivity and specificity for the diagnosis of sJCD. The 14-3-3 protein, for example, which is
one of the first CSF proteins reported to be elevated in sJCD, and initially reported to have 100%
sensitivity and 96% specificity for the diagnosis of sJCD (113), has been subsequently found to have
more limited sensitivity and specificity when studied in larger patient cohorts (114,115). A more recent
analysis in the United Kingdom showed CSF 14-3-3 protein sensitivity of 86% and specificity of 74% in
a pathologically confirmed cohort (116). Similarly, an analysis of data obtained from the U.S. National
Prion Disease Pathology Surveillance Center (NPDPSC) showed the 14-3-3 protein Western blot only
had a receiver operating characteristic area under the curve (ROC AUC) value of 0.68 (117), which is
poor considering that a test with perfect sensitivity and specificity would be 1.0. Some studies on the
clinical use of CSF 14-3-3 protein suggests it should be considered a general marker of neuronal injury
and death. Indeed, 14-3-3 protein is ubiquitously present in the intracellular compartment of brain neurons
and is released into the CSF compartment due to neuronal injury from varied causes. Thus, 14-3-3 protein
can be elevated in many non-prion neurologic conditions, such as multiple sclerosis, acute stroke,
Alzheimer disease and other neurodegenerative dementias, HIV-related neurodegeneration, seizures, and
many others (118–122). In this respect, a large multicenter European study found that the specificity of 14-
3-3 protein is lowered when used to differentiate sJCD from acute neurologic disorders (such as
vascular, inflammatory, or seizures) versus neurodegenerative dementias (82% to 87% vs. 95% to 97%
respectively). This suggests taking the differential diagnoses into consideration is important when
interpreting the test result (123). In summary, a positive 14-3-3 protein does not necessarily equate with
prion disease. Regardless, recent recommendations from the American Academy of Neurology suggest
ordering CSF 14-3-3 protein when there is a strong clinical suspicion of JCD (pretest probability of 20%
to 90%) in order to reduce diagnostic uncertainty (124).
Total-tau (t-tau), neuron-specific enolase (NSE), and the astrocytic protein S100β are also used as CSF
biomarkers for sJCD diagnosis. The sensitivity and specificity of these biomarkers varies greatly among
studies. In a large multicenter, retrospective European study (115), the combined sensitivity and
specificity of the four main sJCD biomarkers (14-3-3 protein, t-tau, NSE, and S100β) was found to be
higher than the individual sensitivity and specificity. Not all patients in this study underwent all four tests
nor were the tests performed in the same CSF samples, however; hence, this study did not permit a fair
comparison between biomarkers. Nevertheless, the study found the sensitivity and specificity of the 14-3-
3 protein to be 85% and 84%, t-tau (cutoff >1,300 pg/mL) 86% and 88%, NSE 73% and 95%, and S100β
82% and 76%, respectively (115). Other studies, however, have shown sensitivity and specificity values
higher than 90% for t-tau in sJCD (125,126), although there is still no agreement over its cutoff value
(usually higher than 1,150 pg/mL).
In reviewing all of the data, the opinion of the authors of this chapter is that among 14-3-3, t-tau and
NSE, the single best CSF biomarker is the t-tau, although NSE has somewhat higher specificity, whereas
the 14-3-3 protein is overall the least clinically useful. There probably is not sufficient data to make a
determination of the clinical utility of S100B (beta). At our center, we send all three biomarkers when
looking for evidence of rapid neuronal injury. In summary, these CSF biomarkers are likely markers of
rapid neuronal injury and do not equate with prion disease, but might be helpful in some cases, yet have
overall less diagnostic use than brain MRI (97,98). New CSF diagnostic tests, such as real-time quaking-
induced conversion reaction (RT-QuIC), that are relatively specific for prions (and not just biomarkers)
are under development (127).
Two Uncommon Forms of Sporadic Human Prion Disease: Fatal Insomnia and
Variably Protease-Sensitive Prionopathy
The MM2 thalamic form of sJCD is sometimes referred to as sporadic fatal insomnia (sFI), the least
common of the six forms of sJCD based on molecular classification (36,81). It is similar clinically and
pathologically to the rare gPrD FFI, as described under gPrDs section. It is the rarest form of sporadic
human prion disease, with approximately 31 cases reported in the literature. On average, affected patients
are 46 years old at disease onset, mean survival is 24 months (79). Clinicians should consider this form
of sporadic prion disease in patients with rapidly progressing dementia associated with sleep
abnormalities and dysautonomia. Unlike sJCD, EEG, CSF, and brain MRI investigations have not been
shown to be helpful for the diagnosis of this disorder (79). Instead, polysomnography, which shows
impaired sleep-related wave forms (such as K-complexes and spindles), and brain positron emission
tomography (PET) examinations, which consistently show thalamic hypometabolism, have proven to be
more useful diagnostic tools (79).
The variably protease-sensitive prionopathy (VPSPr) is the latest addition to the list of sporadic human
prion diseases introduced into the literature in 2008 (128). The term variably protease-sensitive
prionopathy is derived from the fact that prions extracted from brain tissue from such cases produces a
distinctive electrophoretic profile on Western blot due to sensitivity to protease digestion, which
distinguishes it from other forms of prion diseases. As most laboratory techniques for diagnosis of prion
disease (e.g., Western blot and immunohistochemistry) rely on identification of protease-resistant PrPSc,
as described previously, detecting this form of prion disease can be quite difficult (129). VPSPr has
certain distinctive clinical, molecular, and pathologic characteristics (79,129). Clinically, patients
generally present with prominent psychiatric manifestations and rapid cognitive decline (primarily
aphasia), followed by motor manifestations (ataxia and parkinsonism). Clinical presentations, however,
vary according to codon 129 genotype (79). Based on the cases identified through 2010, cases associated
with methionine homozygosity (VPSPr-129MM) seem to not have prominent psychiatric features, whereas
VPSPr-129MV and VSPr-129VV cases usually lack parkinsonism and ataxia. As is the case in sJCD
MM2-thalamic form, MRI, CSF, and EEG investigations often do not show the typical features diagnostic
for sJCD. It is not clear if VPSPr is as transmissible as other prion diseases, as the prions in VPSPr are
more sensitive to proteases and thus might be more easily degraded.
Basic Neuropathology of Human Prion Diseases

At a macroscopic level, atrophy is the only gross neuroanatomic finding in sJCD brains. Atrophy can be
mild to moderate, localized to the cerebral cortex, basal ganglia, and cerebellar regions. As in other
neurodegenerative diseases, atrophy is most pronounced in patients with a long clinical course. Unlike
what is seen in other neurodegenerative diseases, however, prominent hippocampal atrophy is usually not
seen in human prion disease (130).
Microscopically, the histopathologic hallmarks of human prion disease are the presence of neuronal
loss, astrocytic gliosis, vacuolation (or spongiform changes), and deposition of prions (PrPSc) in the brain
(Fig. 18.8) (131). These changes occur without signs of inflammation in the brain, other than those seen
typically with neuronal loss in neurodegenerative disease, such as microglia activation, astrocytosis, and
release of cytokines (132–134). The distribution of vacuolation changes seen in human prion disease vary
between cases and disease subtypes (77), although the head of the caudate nucleus is most often involved,
whereas the brainstem is relatively spared (130). More than 95% of sJCD cases show vacuolation and
the remaining cases are diagnosed by immunohistochemistry to PrPSc. PrPSc deposition in sJCD is usually
in a nonamyloid form, with frequent “synaptic” or punctate deposition in the cortex as well as
perivacuolar PrPSc deposition in brain regions containing vacuolation.
Amyloid plaques of PrPSc are very common in kuru and the gPrD GSS (see the following texts) but are
only found in about 10% or less of sJCD cases. More specifically, GSS is usually characterized by
multicentric plaques, composed of a dense core of amyloid surrounded by smaller globules of amyloid. A
different type of plaque known as “florid plaque” is commonly seen in vJCD (see the following texts); it
consists of an amyloid core surrounded by a halo of spongiform change, giving it a flower (“florid”)
appearance. This is a finding strongly suggestive for vJCD, as it is rarely seen in other prion diseases.
FFI (see the following texts), a gPrD, is characterized by severe neuronal loss and gliosis in thalamic
nuclei, whereas vacuolation and amyloid deposition are minimal or even absent (130). Small amounts of
PrPSc are usually found but often restricted to the thalamus, temporal lobe, or other regions (77).
The Differential Diagnosis of Sporadic Jakob-Creutzfeldt Disease

Because of the protean manifestations of sJCD, it is often confused with many other conditions. Table
18.4 shows the breakdown of non-prion diagnoses of patients referred to two large prion referral centers.
Many cases initially misdiagnosed as prion disease had other neurodegenerative diseases, encephalitis,
or autoimmune (antibody-mediated) encephalopathies (135–138). Among 1,106 brain autopsies from
patients referred with potential JCD to the NPDPSC, 32% (342 cases) were negative pathologically for
prion disease. Among the 304 cases with adequate tissue for diagnosis, 51% had Alzheimer disease, 12%
had vascular disease, but almost 25% had possibly treatable conditions, most commonly autoimmune,
neoplastic, or infectious conditions (139). Unfortunately, the reverse is also true in that prion diseases are
often misdiagnosed as other conditions. In our own recent study of 163 pathology-proven sJCD subjects,
patients were an average of two thirds of the way through their disease course before sJCD was
diagnosed clinically. Infections (non-prion) was the third most common misdiagnosis category; the top
two diagnostic “misdiagnosis” categories were other neurodegenerative diseases and autoimmune
encephalopathies (91). The authors of this chapter have written several papers on the workup and
evaluation of patients with RPD, including prion disease (112,140,141). Some suggested diagnostic tests
for a patient with suspected JCD or another form of RPD is shown in Figure 18.9.
ACQUIRED HUMAN PRION DISEASES: KURU, IATROGENIC
JAKOB-CREUTZFELDT DISEASE, AND VARIANT JAKOB-
CREUTZFELDT DISEASE
By far, the most efficient route of transmission of prion diseases is through direct intracerebral
inoculation, yet acquired forms of prion disease would be virtually nonexistent in nature if this were the
only mode of transmission. Indeed, similarly to viruses, bacteria, and parasites, prions have been shown
to invade host mammalian organisms via parenteral and oral routes. Oral transmission of prion disease
has been demonstrated in humans as well as several animal prion diseases (142,143). More specifically,
in humans, variant Jakob-Creutzfeldt disease (vJCD) and kuru are acquired via oral transmission
(although vJCD can also be transmitted by blood products; see the following section on vJCD). Acquired
prion diseases can also occur iatrogenically via neurosurgical manipulation with contaminated
instruments, from contaminated corneal and dura mater grafts, through EEG electrodes, and from
intramuscular injection of cadaveric-derived human pituitary hormones (144,145).
Prions Invade the Host Organism Analogously to Other Infectious Agents
A basic understanding of the mechanisms of spread of prions after oral inoculation in animal models
serves to highlight the “infectious” nature of prions. Owing to the unique biochemical and biophysical
properties of PrPSc, prions are able to resist the low pH and proteolytic environment of the upper
gastrointestinal tract. Indeed, even direct intragastric inoculation of PrPSc, in which it is exposed to the
low pH of stomach acid, leads to the development of prion disease (146). Once prions reach the small
intestine, they enter the gut-associated lymphoid tissue (GALT), accumulating in Peyer patches (147,148).
The exact mechanisms of absorption of PrPSc from the gut lumen into Peyer patches is a matter of debate
(149); there is strong evidence to suggest that microcytic cells (M cells), which are specialized cells
within follicle-associated epithelia that overlie organized mucosa-associated lymphoid tissues (MALTs),
are key players for the transportation of PrPSc across the gastrointestinal epithelium (150,151). Recent
studies also suggest M cell–independent routes of PrPSc transportation (149,152). Once inside
enterocytes, prions are transported into Peyer patches mainly by dendritic cells, which are bone marrow–
derived antigen-presenting cells (153), with macrophages also playing a somewhat unclear role in this
process (154). Accumulation of PrPSc within Peyer patches is a crucial step in allowing efficient spread
of prions from the gastrointestinal system into the central nervous system. Indeed, the absence of Peyer
patches impairs neural invasion of PrPSc in animals (155).
After PrPSc accumulates in GALT, and in Peyer patches in particular, prions infiltrate the enteric
nervous system. Evidence for direct spread from GALT to the enteric nervous system is most clearly
supported by the fact that the regions of myenteric (Auerbach) plexuses with the most robust accumulation
of PrPSc are those closest to Peyer patches harboring PrPSc (151). Clinicopathologic studies in animals
show that after entering the enteric nervous system, prions reach the brain via the autonomic peripheral
nervous system (primarily the sympathetic nervous system) and spinal cord or by direct spread into the
medulla oblongata through vagal nerve efferent fibers. In mice infected intraperitoneally with PrPSc, prion
accumulation occurred first in the splanchnic autonomic (mostly sympathetic) fibers, which served as
conduits for prion spread to the midthoracic spinal cord, from where prions ascended into the brain via
the intermediolateral cell columns (156). A similar pattern of spread has been described in a hamster
animal model (157). Furthermore, PrPSc inoculated into the sciatic (158) and optic (159) nerves of mice
leads to prion-related brain degeneration, further proof that the peripheral nervous system can serve as a
conduit for prion spread. Moreover, sympathectomy delayed or prevented neural invasion of PrPSc from
GALT. (160)
Interestingly, other experiments that probed the temporospatial spread of PrPSc using
immunohistochemical methods showed an alternative, direct route of spread from the enteric nervous
system to the medullary dorsal motor nucleus in the medulla oblongata, from where prions ascend into the
brain (161,162). Similar patterns of neural invasion of prion disease have been described in other
animals, including cattle (163). Together, these experiments suggest that the vagus nerve serves as conduit
of prion spread.
There is also experimental evidence suggesting that prions spread from GALT into more distant
lymphoid organs before reaching the central nervous system. In several animal forms of prion disease, as
well as in vJCD, the spleen and lymph nodes have been shown to be the first sites of PrPSc replication
after peripheral inoculation. This notion is supported by the fact that splenectomy delays the onset of
orally transmitted prion disease in mice (164), whereas athymia does not (165), thus indicating that the B
cell immune system plays a major role in prion disease spread, as has been shown experimentally
(166–168). Moreover, prions accumulate in the appendix of patients with vJCD before they become
symptomatic (169), and tonsil biopsy has been used to diagnose vJCD in the preclinical phases (170). As
discussed previously, PrPSc requires the presence of PrPC for infectivity (171,172). Therefore, in order
for prion disease to propagate within the lymphoid system, it must express PrPC; this has been shown
experimentally (173). Taken together, this evidence suggests that lymphoid organs influence the host’s
susceptibility to peripheral infection and serve as foci of propagation and spread to the CNS via the
hemopoietic system.
Aside from direct transmission of prions occurring from the autonomic nervous system into the central
nervous system, there is also considerable evidence to suggest that prions are carried to the brain through
the blood by crossing the blood–brain barrier (BBB). Prions can be detected in blood plasma in animals
(174), and vJCD can be transmitted via blood transfusion (175), thus suggesting that blood has the ability
to harbor and transmit disease. Furthermore, PrPC has been shown to participate in the transport of
molecules across the BBB (176), and radioactively labeled PrPC has been shown to cross the BBB in
both the brain-to-blood and blood-to-brain directions (177).
Kuru
As discussed in detail previously in the section on the historical background of prion diseases, kuru is an
acquired form of prion disease due to endocannibalism, confined to the Fore ethnic group in Papua New
Guinea. It has largely become extinct after the cessation of endocannibalism by missionaries. Due to an
incubation period as long as 50 years or greater, very rare cases are still being identified (10).
Variant Jakob-Creutzfeldt Disease
vJCD was first identified in the United Kingdom in 1995 (178) and quickly garnered global media and
epidemiologic attention due to its association with bovine spongiform encephalopathy (BSE) (mad cow
disease) and that it was affecting young persons. BSE is unique in that it is the only form of nonhuman
prion disease known to be transmissible directly to humans. It is hypothesized that BSE in bovine
populations occurred through contamination of cattle feed with scrapie-infected sheep products
(179–181). Worldwide, more than 180,000 cattle are thought to have been infected with BSE, and the vast
majority of these were in the United Kingdom (182). Due to heightened awareness and more rigorous
screening of livestock, however, the incidence of BSE has been dramatically reduced since 1992 (182).
Two new vJCD cases were identified in the United Kingdom in 2011, and to our knowledge, no new
cases of vJCD were reported in the United Kingdom in 2012 or 2013. As of November 2013, 228 cases
have been reported worldwide (183). The relationship between the number of BSE and vJCD cases over
time in the United Kingdom is shown in Figure 18.10.
Although vJCD shares many features with sJCD, the clinical presentation of vJCD differs in several
salient ways. Patients infected with vJCD are often younger, with a median age of onset around 27 years
(range 12 to 74 years) (184) and a longer median disease duration of about 14.5 months (184) than
patients with sJCD. The PRNP codon 129 polymorphism has been identified as a critical susceptibility
factor for the acquisition of vJCD, with nearly every reported case thus far having been found to be
homozygous for methionine at this location (185,186). Psychiatric symptoms are often an early, prominent
feature, occurring as long as 6 months before obvious neurologic impairments manifest. As a result, many
patients with vJCD are often initially thought to have psychiatric etiologies for their illness (184).
Sensory symptoms (dysesthesias), often painful; cerebellar signs; and involuntary movements such as
dystonia, myoclonus, and chorea often become more evident later on in the disease course (184,187).
Diagnostic test results are often also divergent with those seen in sJCD. CSF tests are often less
revealing, with lower sensitivity and specificity than they are in the differential diagnosis of sJCD (188).
Patients with vJCD rarely exhibit the classic PSWCs seen in sJCD on EEG, and if so, only in the final
stages of disease progression (189). The brain MRI hallmark of vJCD is the “pulvinar sign,” in which
bilateral hyperintensity in the pulvinar nucleus in the posterior region of the thalamus is brighter than in
the anterior putamen on T2-weighted, FLAIR, or possibly other MRI sequences (Fig. 18.11). In 85% of
patients with vJCD, the pulvinar sign is seen on their first exam (190). This is a finding rarely exhibited in
other forms of human prion disease (191), although it has been reported in sJCD (192). The literature
investigating the use of brain MRI in the differential diagnosis of vJCD has focused heavily on T2-
weighted sequences (i.e., proton density, T2 and FLAIR imaging), primarily because the preponderance
of data has been collected in the United Kingdom, where the acquisition of DWI sequences is uncommon.
Thus, the sensitivity and specificity of DWI for the pulvinar sign is not yet known.
As with other forms of non-gPrD, the definitive diagnosis of vJCD relies on neuropathologic evidence
of the presence of PrPSc in the central nervous system. In vJCD, there is typically abundant PrPSc
deposition and vacuolation in the neuropil as well as the presence of florid plaques composed of multiple
fibrillary PrP plaques surrounded by spongiform vacuoles. These are seen most commonly in the
molecular layer of the cerebellum (130). Because vJCD is acquired peripherally, PrPSc accumulation
often is identified in tonsillar tissue and other parts of the lymphoreticular system (see Fig. 18.12) (193).
Importantly from an infectious disease perspective, it was recently discovered that vJCD could also be
acquired from transfusion of vJCD-contaminated blood products (194,195). Three cases of vJCD have
been reported in patients who received (contaminated) blood transfusions prior to 1999 and developed
symptoms from 6.5 to 7.8 years after the date of implicated transfusion; all cases clinically and
neuropathologically were similar to other cases of vJCD (196). Two additional patients, both
heterozygous at codon 129 in PRPN (129MV), received contaminated blood products (nonleukodepleted
red blood cells and factor VIII, respectively) and died of nonneurologic causes but had positive prion
testing in their lymphoreticular system but without clinical signs of vJCD and without vJCD prions in
their brains; it is not known if they would have ever developed clinical vJCD (145,186). Of great concern
is that these cases show that vJCD was transmissible by blood product donation years before the donors
became symptomatic.
In order to determine the number of persons in the United Kingdom who might be harboring latent
vJCD, and be potential transmissible carriers of vJCD prions, a few studies have analyzed anonymized
U.K. appendix and/or tonsil samples. An initial large study found a prevalence of 1 per 4,000 appendices
positive for vJCD prions (197), whereas a follow-up larger study found a higher prevalence of 1 per
2,000 appendices positive, leading to assumptions that there are subclinically infected persons in the
population who might be transmissible carriers (198); their risk of either developing symptomatic vJCD
and/or passing it on to others through medical/surgical procedures or blood products is not known.
Measures were taken in the United Kingdom to prevent transmission of vJCD through blood products with
donor selection, leukodepletion of blood (WBCs carry a majority of prions in blood), and efforts toward
developing methods to detect PrP in blood (182). It is important to note that although transmission through
blood products has been reported in vJCD, there are no known cases to date of transmission from sJCD
patients through blood transfusion.
Iatrogenic Jakob-Creutzfeldt Disease
To date, with the exception of kuru, human-to-human transmission of prion disease has only occurred
iatrogenically. The first reported case of suspected iatrogenic prion disease was published in 1974 of a
55-year-old female who developed RPD beginning 18 months after receiving a corneal transplant from a
donor who later was found to have autopsy-confirmed JCD. The patient died of JCD 8 months later (199).
Multiple other cases of suspected iatrogenic Jakob-Creutzfeldt Disease (iJCD) have been reported in
the literature since the 1970s. These have been carefully reviewed by Paul Brown and colleagues up to
2012 (76,144,200). Several other vectors of transmission have been implicated in iJCD: dura mater
grafts, EEG leads, neurosurgical instrumentation, human pituitary hormone extracts, and packed red blood
cells. These modes of transmission will be reviewed briefly.
Since the original report of iJCD via corneal transplantation, only two other similar cases have been
published in the literature. The first occurred in Japan and the second case involved a German patient
(201). Neither case is very conclusive for a causal relationship, however, as the medical history of the
donor of the Japanese case is unknown and the German patient developed JCD 30 years after receiving
corneal transplants from a donor who died of JCD. Nevertheless, potential donors of any tissue, including
corneas, should be screened for dementia, particularly prion disease.
Three years after the first case of iJCD was published in 1974, Bernoulli and colleagues (202)
reported on two patients—a 23-year-old woman and a 17-year-old boy—who developed JCD within 2
years of having depth electrodes placed as part of an EEG study for epilepsy. It was later found that the
same electrodes had been previously used in a 69-year-old woman who died from JCD. Transmission
occurred despite standard sterilization procedures at the time (70% alcohol and formaldehyde vapor).
More than 2 years later, and after repeated sterilizations, the same electrodes were implanted in the cortex
of a chimpanzee: the animal became symptomatic 18 months later and subsequently died of JCD,
confirming the cases were iatrogenic (203). To date, this represents the only case of experimentally
proven iJCD. A handful of other cases of JCD have been associated with neurosurgical instrumentation,
but not proven, with a mean incubation period of 17 months (range 12 to 28 months).
By far, the most common sources of iJCD has come from cadaveric prion-contaminated growth
hormone extracts and dura mater grafts. The first published case associated with cadaveric human growth
hormone (hGH) extracts involved a 20-year-old man with congenital idiopathic hypopituitarism who had
been treated for approximately 14 years with growth hormone extracts obtained from pooled human
cadaver pituitary glands (204). He developed ataxic gait and dysarthria, followed by cerebellar
dysfunction, myoclonus, and dementia that progressed rapidly to death due to JCD. Concurrently, two
similar cases were reported to the Centers for Disease Control and Prevention (CDC): one involved a
22-year-old man with long-standing growth hormone deficiency who had been treated with cadaveric
hGH for approximately 8 years and the other case involved a 34-year-old man with congenital
hypopituitarism who had received cadaveric hGH for approximately 6 years; the former case died of
autopsy-confirmed CJD and the latter case died after a course of RPD highly suspicious for CJD (205)
(http://www.cdc.gov/mmwr/preview/mmwrhtml/00000563.htm).
The hormone extracts used to treat these patients was produced and distributed by the National
Hormone and Pituitary Program (NHPP). Approximately 10,000 U.S. patients received cadaveric hGH
through the NHPP between 1963 and early 1985 from different hGH batches derived from a pool of
approximately 16,000 cadaver pituitary glands. The average duration of therapy was 4 years. Each patient
received extracts from up to three different batches per year. Since the original reports of hGH-associated
iJCD, a total of 226 similar cases have been reported throughout the world, with most originating in
France (119 cases), in the United Kingdom (65 cases), and in the United States (29 cases). In the United
States, all reported cases have occurred in patients who received cadaveric hGH prior to 1977, before a
column chromatography step was added to the manufacturing purification process of cadaveric hGH
extracts (206). It is estimated that around 2,700 people received NHPP extracts prior to 1977, and to our
knowledge, the last case in the United States was reported in 2009. In the United Kingdom, on the other
hand, cases continue to appear at a rate of approximately 2 per year, the most recent case was reported in
2011. In France, all cases are thought to have arisen within a 20-month period between December 1983
and July 1985, when up to 50% of hormone extracts produced became contaminated due to faulty
manufacturing processes (206).
It is important to note that the vast majority of pituitary hormone–associated iJCD cases have been
associated with hormone extracts produced and distributed by the NHPP. There are at least two case
reports, however, of iJCD associated with commercially available cadaveric hGH extracts, which were
produced in different laboratories from those used to produce the NHPP-distributed hGH (207). The first
case involved a 39-year-old Austrian man who died of JCD approximately 22 years after receiving
commercial cadaveric hGH in the mid-1980s. The second case was a 33-year-old man who developed
rapid dementia approximately 26 years after the midpoint of commercial hGH treatment and died 9
months later from probable sJCD. His clinical syndrome and CSF and brain MRI findings were consistent
with JCD, but autopsy was not performed. Both patients were treated with different extracts of
commercial cadaveric hGH, but it appears that they received some extracts from the same brand in the
same year (Crescormon, by Kabi Pharmaceuticals, Sweden) (207). More than 10,000 people, mostly
outside the United States, received commercial cadaveric hGH produced by different companies. Many
details regarding sourcing and production methods of these extracts are lacking.
Incubation periods for hGH-associated iJCD range from 5 to 42 years (mean 17 years) from the
midpoint of treatment duration (206). Clinically, iJCD secondary to hGH therapy tends to produce a
clinical syndrome that is reminiscent of kuru, with prominent early cerebellar signs and late cognitive
dysfunction. Although there is not much data on MRI findings in hGH-associated iJCD, they appear to
range from isolated cerebellar involvement (208) to appearing similar to sJCD, often with deep nuclei
involvement (207).
Susceptibility to infection is influenced by the methionine/valine polymorphism at codon 129 of the
PRNP gene. Methionine homozygosity is present in 55% of affected U.S. and French individuals
(compared to 40% methionine homozygosity in the general population), whereas valine homozygosity is
far more common in the U.K. cohort. Moreover, patients who were heterozygous at codon 129 tend to
have longer incubation periods (>30 years) than normal (mean 17 years) (209).
Dura mater–associated iJCD is as common as hGH-associated iJCD worldwide. As of 2012, there are
228 reported cases of dura mater–associated JCD, and 142 of these have occurred in Japan (200,210).
The remaining cases have been reported in Argentina, Australia, Canada, and Europe. Most iJCD cases
due to dura mater graft contamination have been traced back to grafts manufactured by one German
company, which was a global provider of dura mater grafts in the 1980s (manufacturing ceased in 1987,
but patients received grafts until 1993) (200). The main reason why so many cases have been reported in
Japan relates to the high frequency of use of these grafts in Japan compared to other countries; it is
estimated that 20,000 Japanese patients received contaminated grafts annually during the 1980s, often for
non–life-threatening conditions. Other factors, however, may have contributed to the high incidence, such
as longer survival, and hence longer incubation times, among Japanese recipients (210).
In most cases the clinical and neuropathologic features of dura mater–associated iJCD appear similar
to those of sJCD (200). In Japan, however, there is evidence suggesting that dura mater–associated iJCD
may have distinctive clinical and molecular features. In Japanese patients with dura mater–associated
iJCD, two distinct phenotypes were identified: a dominant type, comprising nearly two thirds of cases,
that is pathologically and clinically nearly identical to sJCD and an atypical type with prominent plaque
formation in the brain and other atypical clinical features such as slower disease progression. Both of
these types were associated with methionine homozygosity at codon 129 of the PRNP gene. These
differences have led some investigators to postulate contamination of the dura mater grafts with different
prion strains (211). Worldwide, the mean incubation period of dura mater–associated iJCD is 12 years,
with the shortest and longest reported incubation times being 16 months and 30 years (200).
The emergence of dura mater–associated iJCD occurred almost concurrently to that of hGH-related
iJCD, and the incidence of both peaked in the mid-to-late 1990s and has steadily declined since the
institution of recombinant growth hormone extracts (growth hormone extracts and gonadotropins have
been manufactured in vitro since 1987) and synthetic dura mater grafts (77). Nevertheless, given the long
incubation times reported for both modes of transmission, it is expected that additional cases might still
occur from past exposure. Likewise, the medical community across different specialties has adopted
effective infection control measures that have decreased the risk of iJCD significantly. Patients with
suspected JCD are excluded as blood, tissue, or organ donors. Clinicians evaluating patients with
suspected JCD should always ask about any prior human pituitary hormone use, ophthalmologic surgery,
and neurosurgical procedures.
Measures to prevent iJCD vary by country and by health care institution. Our institution’s infection
control guidelines for managing suspected human prion cases are available online at
http://infectioncontrol.ucsfmedicalcenter.org/ICMANUAL2007/Section4/Sec%204.2%20Human%20Prion%
31-2012.pdf. The World Health Organization and the CDC have published iJCD prevention guidelines as
well as information on the distribution of tissue infectivity (212,213)
(http://www.who.int/csr/resources/publications/bse/whocdscsraph2003.pdf,
http://www.cdc.gov/ncidod/dvrd/cjd/qa_cjd_infection_control.htm).
HUMAN GENETIC PRION DISEASES: FAMILIAL JAKOB-

CREUTZFELDT DISEASE, GERSTMANN-STRÄUSSLER-
SCHEINKER DISEASE, AND FATAL FAMILIAL INSOMNIA
gPrDs account for approximately 10% to 15% of all cases of prion disease. They are associated with
autosomal dominant mutations in the human PrP gene, PRNP, on the short arm of chromosome 20. PRNP
mutations are of different kinds, including point mutations, insertions, truncations, and deletions
(34,214,215). There are presently more than 30 PRNP mutations associated with gPrD, all of which lead
to disease via the production of a mutant PrP molecule (PrPSc) (34,214,215). Some gPrDs have been
shown to be transmissible to laboratory animals, although most have not been tested for transmission and
a few have failed to transmit (216). Genetic forms of prion disease can be diagnosed through DNA testing
of blood in vivo or through autopsy tissue. Most known PRNP mutations have very high penetrance
(nearly 100%), yet more than 60% of patients with gPrD do not report a positive family history of prion
disease. This is likely due to a combination of factors, including misdiagnosis. Some mutations, such as
the E200K mutation, however, have reduced penetrance (217). Patients with gPrD are typically younger at
onset (approximately 40s to 60s) and have a slower and longer disease course compared to sJCD
patients, although there is great clinical variability among different mutations, in part due to other genetic
(codon 129 polymorphisms) and epigenetic factors that influence phenotypic expression (34,214).
As stated previously in the basic prion genetics section of this chapter, there are three main forms of
gPrD in humans: Gerstmann-Sträussler-Scheinker disease, familial Jakob-Creutzfeldt disease, and fatal
familial insomnia. Before discussing these three familial presentations of gPrD, it is important to mention
that all three forms were described prior to the identification of the PRNP gene, hence the description of
these diseases is primarily based on clinicopathologic observations (214). After the identification of
PRNP and its mutations, a much wider spectrum of phenotypes associated with gPrD is emerging. In a
recent study, for example, researchers identified a consistent phenotype of chronic diarrhea with
autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy
associated with a specific PRNP mutation (PRNP Y163X truncation mutation) (218). These patients begin
to develop peripheral neurologic symptoms in early adulthood, whereas cognitive decline does not occur
until their 40s or 60s, thereby suggesting that genetic forms of prion diseases can affect the peripheral
nervous system before leading to encephalopathy and dementia. Furthermore, a recent case of atypical
parkinsonism was linked to a specific mutation in the PRNP gene, the D202N mutation, that had
previously only been associated with GSS (219). Indeed, the phenotypic heterogeneity associated with
PRNP mutations is certainly not encompassed by the three classic forms of gPrD mentioned previously.
Clinical features of each gPrD can be highly variable, not only within the same mutation but also within a
single family (215). In order to help categorize gPrDs more easily, however, we will briefly discuss each
one of these forms.
Familial Jakob-Creutzfeldt Disease
For most mutations causing fJCD, the clinical presentation usually is indistinguishable to that of sJCD,
with RPD, ataxia, and other motor manifestations. More than 15 mutations have been associated with
fJCD, most are point (missense) mutations but some are insertion mutations and a deletion (34,214). The
most common fJCD mutation worldwide is E200K (214) found most commonly among Libyan Jews and
Slovakians (220). Similarly to sJCD, brain MRI is helpful for the diagnosis of fJCD, and both fJCD and
sJCD have overlapping findings on MRI. The MRI appearance of fJCD seems to vary according to
mutation type, however. For example, fJCD patients due to E200K mutation typically show symmetric,
prominent striatal hyperintensities on MRI, with less prominent cortical ribboning (221), whereas patients
with V180I mutations often shows cortical ribboning with minimal or absent basal ganglia
hyperintensities (222). An MRI of a patient with fJCD due to E200K is shown in Figure 18.13A. Also,
depending on the mutation, the EEG often shows PSWCs in fJCD, particularly in late stages. CSF
biomarkers (14-3-3 protein, NSE, t-tau) in fJCD often are elevated, but with typically lower sensitivity
than in sJCD (115).
Gerstmann-Sträussler-Scheinker Disease
Patients with GSS often become symptomatic earlier than patients with sporadic prion disease (disease
onset is typically in the 50s or younger). Clinically, GSS often manifests with the insidious onset of
movement abnormalities, including progressive ataxia or parkinsonism. Cognitive impairment is usually a
late feature, although some mutations present with early dementia and/or behavioral abnormalities.
Among all forms of human prion disease, patients with GSS are perhaps the most likely to be
misdiagnosed as having other neurodegenerative diseases or even non-neurodegenerative neurologic and
psychiatric illness. This occurs largely because GSS may have an unusually long survival compared to
other forms of prion disease (214,223,224).
There is considerable phenotypic variability in GSS within and between mutations and families
(34,225,226). There are at least 10 PRNP mutations associated with GSS, these include several missense
mutations, a stop mutation, and insertion mutations (octapeptide repeat insertions [OPRIs]). In general,
OPRI mutations with 5 or more additional octapeptide repeats (repeats of 24 base pairs) are associated
with a long duration (several years), GSS phenotype, whereas OPRI mutations with 4 or fewer repeats
may present as sJCD (34,214). An 8-octapeptide repeat insertion mutation (OPRI-8) of PRNP results in a
GSS phenotype with prominent early neuropsychiatric features, often in the late 20s, with a long disease
course of several years. These patients have ended up hospitalized in psychiatric institutions for
management of manic manifestations (223). Likewise, patients with 6-OPRI mutations may demonstrate
psychologic and/or personality changes (irritability, short temper, aggression, antisocial behavior, and
aggression) years before the onset of GSS (33). Neuropsychologic testing of these cases almost invariably
shows frontal executive impairment as well as frequent visuospatial, language, and memory impairments
(224).
EEGs of patients with GSS usually reveal slow waves, not the PSWCs seen in sJCD. Likewise, CSF
biomarkers that offer some diagnostic use in sJCD (protein 14-3-3, NSE, and t-tau) are typically not
elevated in GSS (115). Given that these CSF biomarkers are thought to be released into the CSF as a
result of rapid neuronal injury or neurodegeneration, it is possible that the slow course of GSS is
preventing the accumulation of these markers in the CSF of affected patients (121). Finally, brain MRI
investigations in patients with GSS usually do not reveal the cortical ribboning or deep nuclei
hyperintensities seen in sJCD and in other forms of prion disease, although patients with some PRNP
mutations associated with GSS do have brain MRI findings characteristic of prion disease (97). An MRI
of a GSS patient due to an F198S mutation is shown in Figure 18.13B.
Fatal Familial Insomnia
FFI is a very rare form of gPrD caused by a single PRNP point mutation, D178N, with codon 129 having
methionine (129M) on the same chromosome (cis). Curiously, patients with the D178N mutation with the
cis codon 129 being valine (129V) usually present with an sJCD clinicopathologic phenotype. Thus,
codon 129 can have a profound effect on the expression of human prion disease. The codon 129
polymorphism on the trans or normal (without the mutation) allele also affects disease presentation; for
example, FFI patients with codon 129 methionine homozygosity have shorter disease durations than those
with a trans valine at codon 129 (227). Patients with FFI usually become symptomatic in their late 40s
(48 to 49 years; range 20to 72 years), usually with severe, progressive insomnia over several months,
followed by other manifestations such as dysautonomia (e.g., tachycardia, hyperhidrosis, and
hyperpyrexia) as well as motor and cognitive manifestations appearing later in the illness. Mean survival
is about 18 months (range 7 to 33 months), which is slightly longer than most sJCD patients (34,77).
Similarly to patients with GSS, EEG investigations in patients with FFI usually show generalized
slowing, not PSWCs. Brain MRI is usually unremarkable, but fluorodeoxyglucose positron emission
tomography (FDG-PET) imaging reveals thalamic and cingulate hypometabolism, often even before
disease onset (228) CSF biomarkers in general have very low sensitivity in FFI (115).
The infectious nature of human gPrDs is not clear, but overall they appear very difficult to transmit and
the risk of transmissibility is presumed to be very low. There are no known cases of transmission of gPrD
from human to human. Because of the theoretical risk of transmission through blood products, persons
with sJCD, gPrD, or at risk for gPrD (asymptomatic either with a mutation or have not had PRNP testing)
should not donate blood products. The American Red Cross does not accept blood product donations
from blood relatives of someone who has died from JCD (http://www.redcrossblood .org/donating-
blood/eligibility-requirements/eligibility-criteria-alphabetical-listing); their presumed reasoning is that
there is a chance that the JCD patient had gPrD and thus blood relatives are at risk for also carrying a
mutation and thus being potential transmissible carriers. Realistically, if a patient with JCD does not have
a PRNP mutation, then all blood relatives are no more at risk of developing JCD than anyone else in the
population.
TRANSMISSIBILITY OF HUMAN PRION DISEASES:

EVALUATING AND CARING FOR PATIENTS
Although human prion diseases can be infectious, they are very difficult to transmit, typically requiring
direct contact with the nervous system. Most cases of human prion disease are not due to infection,
however, but occur spontaneously. As discussed in the section, “Acquired Human Prion Diseases,” the
risk of transmission through certain neuroinvasive medical procedures is not insignificant (76), and new
cases of potential transmission through neurosurgical procedures, particularly brain biopsies without
using JCD precautions (229), are still occurring. This is particularly important as all prion diseases are
uniformly fatal, and to date, no treatments or cures have been identified (230). Therefore, certain
precautions are advised when evaluating patients with prion disease (229). There is no evidence that
human prion diseases are transmitted through casual, or even intimate, contact. In recorded history, to our
knowledge, there is only one case of spouses both developing sJCD (231) given the incidence and a
person’s lifetime risk of developing prion disease (estimated to be 1 in 10,000s), one would have
expected there to be more familial nongenetic cases to occur by chance alone. This suggests that even
intimate contact is not a risk factor for human prion disease transmission. Although prion diseases are not
transmitted easily, standard universal precautions, such as using gloves when handling bodily fluids and
waste, are advised when caring for patients with suspected prion disease. More information regarding
care, management, autopsy, and burial-related issues can be found at the Creutzfeldt-Jakob Disease
Foundation (www.cjdfoundation.org) and UCSF Memory and Aging Center (http://memory.ucsf.edu) Web
sites.
CONCLUSIONS
Prion diseases are unique in medicine because of their multiple modes of occurrence from a single
protein or agent. New data suggest that the mechanisms for prion propagation in the body might be
relevant for most other neurodegenerative diseases (232). This suggests that what we learn from this rare
family of diseases might have far greater applicability in our understanding of more common conditions.
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648.
CHAPTER 19 HUMAN IMMUNODEFICIENCY VIRUS
CHRISTINA M. MARRA
HIV can directly infect the cerebrospinal fluid (CSF) and the brain. Infection of the CSF is a notable
feature of the acute retroviral syndrome, and CSF pleocytosis is common in HIV infection, particularly
among individuals with high peripheral blood CD4+ T-cell counts, detectable plasma HIV RNA, and in
those not on antiretroviral therapy (1). Infection of the brain likely is the substrate for dementia in HIV
infection. The immunodeficiency caused by HIV predisposes individuals to secondary or opportunistic
central nervous system (CNS) infections or neoplasms (Table 19.1). The incidence of dementia and most
CNS opportunistic infections has declined in the developed world with widespread use of combination
antiretroviral therapy (CART). However, although the incidence may be decreasing, the prevalence of
cognitive impairment is increasing (2–4). In addition, treatment of HIV itself may be associated with
neurologic complications. The clinical findings and treatment of CNS opportunistic infections seen in
HIV-infected individuals are covered in several chapters of this book. In particular, a detailed discussion
of cerebral toxoplasmosis is provided in Chapter 43, and neurosyphilis is covered in Chapter 38. This
chapter addresses two opportunistic infections not covered elsewhere: primary CNS lymphoma, which is
considered with infections because of its association with Epstein-Barr virus infection, and progressive
multifocal leukoencephalopathy (PML) caused by the JC virus. In addition, the most common CNS
complications associated with HIV itself are discussed, including newly recognized syndromes.
FOCAL BRAIN DISEASE

Opportunistic infections, neoplasms, and cerebrovascular disease are the most common causes of focal
findings referable to the brain in HIV-infected patients. In such individuals, the presence or absence of
contrast enhancement and mass effect on cranial neuroimaging studies helps to narrow the differential
diagnosis. Lesions associated with contrast enhancement and mass effect are most commonly due to
toxoplasmosis, primary CNS lymphoma, or tuberculoma. Lesions with minimal or no contrast
enhancement and no mass effect are most commonly due to PML.
Primary Central Nervous System Lymphoma
Etiology
Primary CNS lymphomas in HIV-infected patients are typically of B-cell origin and are classified as
diffuse large cell or immunoblastic (5). Epstein-Barr virus (EBV) is detectable in these tumors in
virtually all HIV-infected patients (5). Prolonged immune suppression and EBV-induced B-cell
stimulation likely contribute to tumor development (6).
As noted earlier, the most common causes of brain lesions associated with contrast enhancement and mass
effect are toxoplasmosis, primary CNS lymphoma, and tuberculoma. Other causes are listed in Table
19.1.
Clinical Symptoms and Findings
The presenting clinical features of HIV-associated primary CNS lymphoma include confusion, lethargy,
memory loss, hemiparesis, speech and language disorders, seizures, and cranial nerve palsies (7,8).
Laboratory and Imaging Studies
HIV-infected patients with primary CNS lymphoma typically have peripheral blood CD4+ T-cell counts
less than 50/µL (9). Brain computed tomography (CT) or magnetic resonance imaging (MRI) show ring-
or homogeneously enhancing lesion(s), often located periventricularly or in the frontal lobes, although
other locations may be seen (Fig. 19.1). These lesions may cross the midline in the corpus callosum and
may be associated with patchy nodular ventricular enhancement (10). Thallium-201 (201Tl) single-photon
emission computed tomography (SPECT) may be helpful in distinguishing between CNS infections and
primary CNS lymphoma in HIV-infected individuals. Focal areas of increased 201Tl uptake are seen in
patients with lymphoma, whereas no brain uptake is seen in patients with CNS infections such as
Toxoplasma encephalitis or tuberculoma (11,12). Delayed imaging and calculation of a retention index
increase the specificity of the test (12).
Although the diagnosis of primary CNS lymphoma can only be proven by histopathology, examination
of CSF for EBV DNA by polymerase chain reaction (PCR) may be sensitive and specific for establishing
the diagnosis (13) when it is used in the appropriate clinical setting: an HIV-infected patient with a focal
brain lesion with mass effect and enhancement. The positive predictive value of the test is highest in
patients with a low likelihood of CNS toxoplasmosis, such as those who are Toxoplasma seronegative or
who have been taking trimethoprim-sulfamethoxazole for prophylaxis against toxoplasmosis. When the
test is used more broadly in clinical settings, the positive predictive value of detection of EBV DNA in
CSF is lower (14,15).
HIV-associated primary CNS lymphomas are sensitive to radiation therapy. In a retrospective analysis
conducted before the availability of CART, median survival was about 3 to 4 months with radiation
therapy and dexamethasone and untreated survival was 3 to 4 weeks (16). Death was usually due to
opportunistic infection rather than lymphoma (7,8). Absence of opportunistic infection, younger age,
higher Karnofsky performance status, and delivery of higher biologically effective doses of radiation
were associated with longer survival (17).
More modern studies show that whole brain radiation therapy (at least 30 Gy) (18–20) and CART
(18,20,21) are associated with better survival in HIV-infected patients with primary CNS lymphoma,
often with best survival seen in those who receive both modalities. Prolonged survival has also been
reported in HIV-infected patients with primary CNS lymphoma who only received CART (22–24). Some
have suggested that whole brain radiation be reserved for patients who do not respond to antiretrovirals
to avoid the morbidity, particularly leukoencephalopathy, associated with this treatment modality.
Because of the association with EBV, some investigators have advocated combination therapy for HIV-
associated primary CNS lymphoma that targets this virus with agents such as ganciclovir or foscarnet.
Individual reports of success with these regimens can be difficult to evaluate because patients are often
also treated with radiation, CART, and immune modulators (25–30). Overall, treatment data for HIV-
associated primary CNS lymphoma are mostly from retrospective case reports and series and are limited
by selection bias. The best treatment for HIV-associated primary CNS lymphoma is not known because a
randomized trial has not been conducted, and, given the low incidence of the disorder, may never be
feasible.
Prior to the advent of CART, primary CNS lymphoma occurred in 1% to 4% of HIV-infected persons.
Since CART has become widely available, the incidence of this disorder has declined (31,32) and
survival has improved (18,33). Thus, prevention lies in antiretroviral treatment to prevent prolonged
immunosuppression.
Progressive Multifocal Leukoencephalopathy
Etiology
PML is caused by a polyoma virus called JC virus. This virus is usually acquired in childhood. It remains
latent in kidney and perhaps in brain, reactivates in the setting of immunosuppression, and infects
oligodendrocytes and less so astrocytes. Death of oligodendrocytes leads to demyelination.
The diagnosis of PML should be considered in patients with dementia, particularly if there are also focal
neurologic findings. Varicella-zoster encephalitis may cause demyelination and should also be considered
(34). Cytomegalovirus (CMV) encephalitis is sometimes accompanied by focal lesions that could mimic
PML (35). Substance abuse, particularly a form of heroin use called “chasing the dragon,” can cause
clinical and radiographic abnormalities similar to PML (36). A severe form of HIV-associated
leukoencephalopathy characterized pathologically by extensive perivascular macrophage infiltration and
demyelination and high levels of brain and CSF HIV RNA has been described (37). Patchy or confluent
white matter high signal intensity is seen on brain MRI. The syndrome occurs in patients failing CART
and is accompanied by cognitive abnormalities. Leukoencephalopathy has been described in individuals
whose HIV is successfully treated, and has been attributed both to “CNS immune reconstitution” (38–40)
and to “CNS escape” in individuals with suppressed plasma HIV RNA but detectable CSF HIV RNA
(41). The latter two diagnoses may be distinguished from PML because they may be associated with CSF
pleocytosis.
Clinical Findings
Patients with PML typically experience insidious onset of progressive neurologic deficits, most
commonly cognitive dysfunction, limb weakness, gait disturbance, coordination difficulties, and visual
loss. Headache is a complaint in about one fourth of patients. Neurologic examination shows focal
deficits, particularly hemiparesis or visual field abnormalities (42,43). Less common manifestations of
CNS JC infection include cerebellar granule cell neuronopathy (44) and JC infection of cortical
pyramidal neurons, causing an acute encephalopathy (45).
HIV-infected patients with PML typically have peripheral blood CD4+ T cells less than 200/µL, although
even before the advent of CART, about 10% of patients had CD4 counts above this threshold (43). In the
current treatment era, individuals with PML and much higher or even near-normal peripheral blood CD4+
T cell concentrations have been reported (46,47).
Brain CT in patients with PML may sometimes be normal. More often, it shows multiple, often
confluent, white matter lesions that are most commonly located in the parietooccipital regions. These
lesions are low density and have little, if any, mass effect (43). Enhancement may be seen in 10% of CT
scans and is usually faint and peripheral (43). Brain MRI shows more lesions than CT (48). In contrast to
the white matter lesions seen in HIV-associated dementia, which are visible only on T2-weighted images,
PML lesions are low intensity on T1-weighted and high intensity on T2-weighted images (Fig. 19.2);
about 15% show faint contrast enhancement (43). Contrast enhancement is more likely to be seen in the
setting of immune reconstitution (see the following discussion). In addition to the abnormalities seen on
T1- and T2-weighted MRI, restricted diffusion may be seen; additional examples of MRI abnormalities in
PML are shown in Chapter 3.
Diagnostic criteria for PML have been recently published (49). In patients with characteristic clinical
and neuroimaging findings, histologic examination or identification of JC virus DNA by PCR in CSF can
confirm the diagnosis. However, a negative PCR does not exclude the diagnosis. Individuals who develop
PML while receiving CART as well as those with higher peripheral blood CD4+ T cell concentrations
are more likely to have a negative diagnostic PCR (50).
Recent studies suggest that the current incidence of PML has declined approximately three- to fourfold
compared to before 1996, with estimates among HIV-infected individuals ranging from 0.6 to 1.3 per
1,000 person-years (51,52). Treatment with potent antiretrovirals has also resulted in significantly
improved survival in patients with PML (51–53).
Several prognostic factors have been identified in HIV-associated PML. Mass effect on MRI (54) and
brainstem and cerebellar involvement (55,56) are associated with poorer outcome. Higher peripheral
blood CD4+ T-cell count at diagnosis (48,51,57–60), PML as the AIDS-defining illness (58), lower
concentration and decline in CSF JC virus DNA concentration during antiretroviral therapy (59–64), and
the presence of JC virus-specific cytotoxic T cells in blood (65–67) are associated with improved
survival.
All HIV-infected patients with PML should be treated with CART aimed at complete suppression of
plasma HIV viremia. Whether certain types of antiretroviral regimens are more effective than others
remains a matter of debate because few prospective studies have been conducted. Two retrospective
analyses suggest that a regimen that includes a protease inhibitor may be more effective than one that does
not (68,69). Gasnault and colleagues (60) conducted a multicenter, prospective, open-label trial of an
individualized regimen of five antiretrovirals, including enfuvirtide for the first 6 months, in 28 HIV-
infected patients with PML. The 1-year survival was 75%, significantly higher than the historically
reported survival of 45% at the time the trial was planned (63,70–72). In this trial, all deaths occurred
within the first 4 months of treatment (60).
As a consequence of an immune reconstitution inflammatory syndrome (IRIS), PML may develop
(unmasking or simultaneous IRIS) or worsen (paradoxical or delayed IRIS) after beginning antiretroviral
therapy. In an observational study in Spain of 61 patients with PML, 14 (23%) developed PML IRIS, of
which 8 were unmasking IRIS and 6 paradoxical IRIS (53). In a case series and retrospective review,
PML IRIS developed 1 week to 26 months (median 7 months) after beginning antiretroviral therapy, with
a shorter latency, greater number of MRI-defined brain lesions, and poorer outcome in paradoxical
compared to unmasking IRIS (73). A retrospective case series showed that peripheral blood CD4+ T cells
& <50/µL at the time of initiating antiretroviral therapy significantly increases the risk of PML IRIS and
that the prognosis of patients with PML IRIS is no different than PML patients without IRIS (74).
Paradoxical IRIS is characterized by clinical worsening and progression of previously defined MRI
lesions or development of new lesions, often, but not always, with evidence of contrast enhancement. In
the absence of new enhancement, paradoxical IRIS can be difficult to distinguish from progressive
disease, although the onset of clinical worsening in IRIS may be more acute. Both fatal and benign
courses have been described (73,75–77) as well as individuals that do and do not respond to
immunosuppression with steroids (73,78). A single case of rapid improvement in paradoxical PML IRIS
after treatment with the CCR5 inhibitor, maraviroc, but not treatment with methylprednisolone, has been
reported (79). The authors speculated that blocking of CCR5+ leukocyte recruitment to the CNS might
have been the underlying mechanism of improvement.
No specific therapy for HIV-associated (or nonassociated) PML has been identified. Cytosine
arabinoside (Ara-C) given intravenously (IV) or intrathecally did not confer a survival benefit in a
clinical trial conducted before the availability of CART (80). A metaanalysis of cidofovir showed no
benefit beyond that of CART (72). Mefloquine showed anti-JC activity in an in vitro assay (81), but an
open-label randomized trial was stopped early because of lack of efficacy (64). Based on the observation
that the cellular receptor for JC virus is the 5-HT2A serotonin receptor (82), mirtazapine has been used
for PML treatment with anecdotal reports of success (83,84), but no clinical trial has been conducted.
HIV-infected patients with PML who survive generally have persistent neurologic deficits, although
some regain independence. In the trial by Gasnault and colleagues referenced earlier, the median modified
Rankin scale at 12 months in the 21 survivors was 3 (moderate disability). Eight patients had only slight
disability and were independent (60). In contrast, in the Swiss HIV Cohort Study, among 47 individuals
who survived more than 1 year, only 8 (17%) had clinical improvement (52). In a convenience sample of
23 HIV-infected patients with PML who survived at least 5 years, 9 remained neurologically stable, 10
had partial improvement, and 4 had marked improvement; 8 had only slight disability and lived
independently (55). In a population-based study from Denmark, 5 of 11 patients followed for 3 years
(from an original group of 47 patients) returned to their pre-PML level of function (51).
DIFFUSE CENTRAL NERVOUS SYSTEM DISEASE

HIV-Associated Neurocognitive Disorders
Cognitive impairment due to HIV infection was first characterized by Navia et al. (85) in 1986 and
termed AIDS dementia complex or ADC to emphasize a triad of cognitive, motor, and behavioral
abnormalities: (a) forgetfulness and loss of concentration; (b) apathy, social withdrawal, and irritability;
and (c) loss of balance and leg weakness. On neurologic examination, such patients typically
demonstrated slowed verbal and motor responses, reminiscent of neurologic findings in Parkinson
disease. Not every patient with ADC had all three components of the triad at onset of disease, and not all
patients with mild disease progressed to more severe disease. As will be discussed further in the
following section, with the advent of CART, the incidence of HIV-associated dementia (HAD) has
decreased, but the incidence and prevalence of less severe forms of cognitive impairment have increased.
In 2006, a working group addressed the criteria for diagnosis of HIV-associated neurocognitive disorders
(HAND) (86). These criteria are commonly referred to as the “Frascati criteria,” because the working
group met in Frascati, Italy. Three categories of impairment were established: asymptomatic
neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HAD. The diagnosis of all
three disorders is based on results of neuropsychologic (NP) tests covering at least the domains of
verbal/language, attention/working memory, abstraction/executive, memory (learning, recall), speed of
information processing, and sensory–perceptual or motor skills, in combination with an assessment of
everyday functioning. In all categories, cognitive or functional impairment cannot be explained by
delirium, opportunistic CNS disease, systemic illness, psychiatric illness, substance use, or medications
with CNS effects (Table 19.2). Although these categories were intended for research purposes, they have
become increasingly applied to clinical settings.
Epidemiology and Risks

Estimates early in the HIV epidemic suggested that at least 60% of patients with AIDS developed overt or
subclinical HAD (85,87). The proportion decreased to about 7% in the first years after antiretrovirals
became available (88,89). Several studies in the CART era show that the prevalence of HAD is low but
the prevalence of milder impairment (MND and ANI) is surprisingly high. For example, in the multicenter
U.S. CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, among 1,316 participants
without severe confounding disorders that could independently explain cognitive impairment, 2% had
dementia, 12% had MND, and 33% had ANI (90). In a study of 100 Italian patients with undetectable
plasma HIV RNA, 2% met criteria for HAD, 17% for MND, and 50% for ANI (91), and in a study of 400
French patients, 7% had HAD, 31% had MND, and 21% had ANI (92). Although symptomatic HAND
(MND and HAD) remains a risk factor for poorer survival (4), the relevance of an ANI diagnosis has
been questioned for several reasons. These include concerns that (a) normative NP data are from
nonconfounded “normal” individuals rather than background-matched controls; (b) in a normally
distributed population, 16% will score 1 SD below the norm on a given test; and (c) no published study
has demonstrated that ANI confers a risk for subsequent dementia (93,94). In addition, patients frequently
transition from mild impairment to normal cognition and vice versa despite stable CART regimens
(95,96). Whether this reflects diagnostic imprecision, practice effects or normal variation remains
undefined (97).
Low current, and in particular low nadir, CD4 is a risk factor for prevalent neurocognitive impairment
in the CART era (90,95,98,99). However, the association between HIV-related factors and incident
cognitive impairment is less clear. Although current but not nadir CD4 remained a significant predictor of
incident dementia in the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE)
cohort (100), in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) study,
neither current nor nadir CD4 or plasma HIV RNA predicted incident cognitive impairment (95). In a
population-based study of 1,320 HIV-infected patients in Canada, incident symptomatic cognitive
impairment was more common with lower nadir CD4 and plasma HIV RNA greater than 1 million
copies/mL (101). In this study and in the CASCADE study, longer estimated duration of HIV infection
conferred greater risk of incident impairment (100,101).
Etiology
HIV can be recovered from CSF (102) or brain (103) early in the course of infection, and acute
meningitis or encephalitis may be part of the acute retroviral syndrome (102,104,105). Moreover, brain
inflammation and injury is evident in primary HIV infection in some, but not all, patients (106–108). Most
experts agree that productive brain HIV infection is restricted to perivascular macrophages and less so
microglia (109). Infection of the CNS may be driven by activation of peripheral monocytes as a
consequence of microbial translocation from the gut early in infection (110). Activated monocytes are
better able to support productive HIV infection (111), and HIV DNA concentration in activated monocytes
is higher in patients with cognitive impairment than in those with normal cognition (112). Astrocytes may
be infected but do not support viral replication (113). The prevailing view is that HIV causes brain injury
and subsequent cognitive impairment via indirect mechanisms (114–116). Proposed models suggest that
HIV-infected mononuclear phagocytes release toxic viral gene products such as gp120 or tat.
Alternatively, infected brain macrophages or microglia may release cell-derived toxins such as quinolinic
acid; cytokines, including tumor necrosis factor-α (TNF-α); eicosanoids; platelet-activating factor; or
nitric oxide. This hypothesis is particularly compelling because the neuropathology of HAD is
characterized by increased numbers of activated macrophages, and the severity of dementia correlates
better with the degree of macrophage staining in brain than with the number of HIV-infected cells in brain
(117). Toxic substances released by activated macrophages may injure neurons directly, may injure
astrocytes or oligodendrocytes and interfere with their supporting functions, or may stimulate astrocytes
or oligodendrocytes to release toxic products that may augment neurotoxicity. Nonproductive HIV
infection of astrocytes may contribute to macrophage activation, a 180 augmenting neurotoxicity.
The relationship between brain HIV infection and clinically evident cognitive impairment may be
changing in the current treatment era, particularly among patients with mild impairment. A recent
pathologic study of 589 individuals with advanced disease showed no relationship between brain HIV
infection and HAND (118), and, as discussed in the following section, although detectable CSF HIV was
associated with prevalent dementia and predicted it in the pre-CART era, these associations are less
robust in the era of CART. Moreover, the relationship between lower nadir CD4 and cognitive
impairment suggests that CNS injury may have occurred in the past, and that although impairment may be
persistent, it may not reflect the effect of ongoing CNS infection, inflammation, or injury. This “legacy,”
however, might lessen cognitive reserve. As HIV-infected patients live longer, aging (119), vascular
disease (120–122), metabolic abnormalities (123), and CART toxicities (124–126) may increasingly
contribute to cognitive impairment.
Before the advent of highly active antiretroviral therapy, HAD was a disease of those with advanced
immunosuppression, and CMV encephalitis was an important alternative diagnosis to consider. In the
current treatment era, patients with HAD may present with peripheral blood CD4+ T cells more than 200
cells/µL (2,3) and CMV encephalitis is rare. The differential diagnosis includes psychiatric disease,
particularly depression; adverse effects from prescription or illicit drugs; and cerebral opportunistic
infections including toxoplasmosis, tuberculosis, cryptococcal meningitis, and neurosyphilis. Rarely, PML
may present solely with cognitive changes, but focal neurologic findings and neuroimaging almost always
distinguish patients with PML from those with HAD (127).
Clinical Symptoms and Findings
Patients with HAD generally present with subacute onset of cognitive impairment, often with complaints
of mental and physical slowness. Neurologic examination typically is remarkable for slowed verbal and
motor responses. Ataxia and hyperreflexia may also be seen. A staging system for HAD has been used to
characterize clinical severity (128,129). It is based on functional disability and ranges from normal
cognitive and motor function (stage 0), to mild impairment (stage 1) with preserved ability to perform all
but the more demanding tasks of work or daily activities, to end-stage disease (stage 4) distinguished by
rudimentary comprehension and responses. Not all patients with mild disease progress to more severe
stages.
The diagnosis of HAD is based on clinical findings and remains one of exclusion. There is no specific
test that establishes the diagnosis. However, CSF studies may be the most informative. Conventional CSF
evaluation helps exclude other disorders. Data from the Multicenter AIDS Cohort Study suggest that a
CSF β2-microglobulin concentration more than 3.8 mg/dL in a CSF specimen with a normal white blood
cell (WBC) count is specific, but not sensitive, for the diagnosis of HAD (130). In the pre-CART era,
among patients with AIDS, CSF HIV RNA levels were elevated in those with cognitive impairment
(131); they correlated with severity of dementia (132,133) and predicted incident impairment (134). In
the CART era, CSF HIV RNA does not distinguish between those with and without cognitive impairment
(135,136). However, in the clinical setting, measurement of CSF HIV RNA can be useful. A CSF
concentration higher than plasma suggests, but does not prove, that cognitive impairment is due to ongoing
CNS HIV infection and is one definition of CNS escape (see the following discussions).
Neuroimaging is useful in excluding other disorders but does not establish the diagnosis of HAD.
Cranial CT may be normal or show atrophy or patchy white matter attenuation (85). Cranial MRI is more
sensitive than CT for demonstrating white matter abnormalities and may show high T2 signal in the
periventricular regions and in the centrum semiovale that are not seen on T1-weighted sequences (Fig.
19.3). However, atrophy and focal white matter abnormalities may be seen in HIV-infected individuals
without cognitive changes (137).
Early studies showed that even zidovudine monotherapy improved cognition and survival in patients with
HAD (138,139). Studies early in the CART era showed that decline in CSF HIV RNA and improvement
in NP test performance could be seen in individuals treated with CART (140–142), and CART is also
associated with increased survival in patients with HAD (143). Improvement in cognition after starting
CART may lag behind improvement in CD4 or decline in plasma HIV RNA; in one study, improvement
peaked at 24 to 36 weeks after beginning CART (144). That CART may also play a role in preventing
development of cognitive impairment is shown by a recent study demonstrating that HIV-infected patients
who initiated CART early in the course of disease had a low prevalence of cognitive impairment that was
comparable to matched HIV-uninfected individuals (145).
In the last few years, much attention has been given to whether antiretroviral regimens with “good CNS
penetration” are more effective in decreasing CSF HIV RNA concentration and in improving cognitive
function than regimens with “poorer” penetration. Letendre and colleagues (146,147) have published two
versions of the CNS Penetration Effectiveness (CPE) rank, which estimates CNS drug penetration based
on virologic and pharmacologic data. The most recent version uses four categories (1–4), with higher
values assigned to drugs with better predicted penetration (147). The score for a given regimen is
calculated as the sum of the scores of its component drugs. Higher CPE regimens convey increased
likelihood of suppressed CSF HIV RNA (146,147). However, the relationship between regimen CPE and
improvement in cognition is less clear. Although several studies suggest that regimens with higher CPE
improve cognitive function more than regimens with lower scores, this finding is not universal (148). A
recent study suggested that the revised CPE rank is superior to the original, which might explain some, but
not all, discrepancies between different studies (149). An observational study showed that higher CPE
conveyed an increased risk of cognitive worsening in patients with advanced HIV (124), and a small
randomized trial of three CART regimens showed that although patients in the arm with the highest CPE
had greater cognitive improvement, these patients also had greater evidence of brain inflammation by
neuroimaging (150).
Shikuma and colleagues (151) have proposed a monocyte efficacy (ME) score as a means of
determining the effectiveness of an antiretroviral regimen in treating CNS HIV infection. The ME score is
defined as the summed reciprocal (× 1,000) of each agent’s median effective concentration (EC50) in a
resting macrophage acute infection model (151). The relationship between cognitive impairment and ME
score was examined in a cohort of 139 individuals on stable CART for at least 6 months; those who were
taking atazanavir or lopinavir were excluded because of lack of EC50 data. Patients whose regimens had
higher ME scores had lower odds of symptomatic cognitive impairment. Of note, the CPE rank and ME
score of individual regimens may not be congruent. For example, an “acceptable” regimen of abacavir,
lamivudine, and nevirapine yields a high CPE of 9 but a low ME of 73 (152).
Several adjunctive agents have been investigated for the treatment of HAD. Their rationale is based on
data reviewed above suggesting that neuronal damage is a downstream event triggered by release of toxic
viral gene products or inflammatory mediators from infected mononuclear cells. None have proved to be
beneficial, including nimodipine (153), CPI-1189 (an antioxidant that blocks TNF-α in animal models)
(154), selegiline (155,156), memantine (157,158), minocycline (159–161), and rivastigmine (162).
Encephalitis in the Setting of Combination Antiretroviral Therapy: Central Nervous

System Immune Reconstitution Inflammatory Syndrome, Central Nervous System
Escape, and CD8+ T-Cell Encephalitis
Just as there are reports of IRIS in patients with CNS opportunistic infections treated with CART, “CNS
IRIS” due to HIV itself has been reported after CART initiation (38–40). Typically, patients develop
diffuse or focal neurologic symptoms and signs usually accompanied by CSF pleocytosis in the absence
of an identifiable infectious agent. Such patients need to be distinguished from those with CNS escape in
the setting of apparently effective CART. These patients develop diffuse or focal neurologic symptoms
while on CART, with detectable CSF HIV RNA in the setting of suppressed peripheral viremia or with
CSF HIV RNA concentrations higher than simultaneous plasma levels (163–165). Canestri and colleagues
(166) described CNS escape in 11 patients defined as CSF HIV RNA more than 200 copies/mL with
corresponding plasma HIV RNA less than 50 copies/mL or CSF HIV RNA more than 1 log higher than
plasma. Clinical syndromes included meningitis, encephalitis, and myelitis. Based on genotypic analysis,
CSF virus was not sensitive to the CART regimen in five patients (166). Asymptomatic low-level CNS
escape with CSF HIV RNA concentrations ranging from 52 to 860 copies/mL has been described in a
small series of patients (167). Compared to patients with undetectable CSF HIV RNA, those with CNS
escape had a longer duration of CART and had experienced more treatment interruptions, raising the
question of whether CSF viral “blips,” similar to what has been described in plasma, may occur. A
review of the literature shows overlap between CNS IRIS and CNS escape. The distinguishing feature
should be detection of CSF HIV RNA, which is not seen in IRIS, but that is an integral part of the
diagnosis of CNS escape. Reports describe successful treatment of CNS IRIS with steroids, whereas
reports of successful treatment of CNS escape usually entail changes in CART based on genotypic
analysis of CSF viral sensitivity or by substitution or addition of agents thought to have good CNS drug
penetration. Of note, the pathogenesis of CNS IRIS and CNS escape may be similar. Lescure and
colleagues (168) describe 14 HIV-infected patients who were initially diagnosed with encephalitis of
unknown etiology. Two patients had CNS IRIS, two had CNS escape, one had viral rebound after
stopping CART, and six had a minor infection a few days before onset of their neurologic illness. Brain
MRI showed diffuse T2 and fluid-attenuated inversion recovery (FLAIR) signal intensities in gray and
white matter with punctate or linear gadolinium enhancement that was best seen with T1-weighted spin-
echo sequences combined with magnetization transfer. Histology showed intense perivascular infiltration
of polyclonal CD8+ lymphocytes.
SPINAL CORD DISEASE

HIV-Associated Myelopathy
Several processes can affect the spinal cord in HIV-infected patients (Table 19.3). HIV-associated
myelopathy (HAM) is likely the most common cause of spinal cord dysfunction in this population in the
U.S. Most of what we know about the disorder comes from studies conducted before the advent of CART,
and the overall incidence of the disease is now low.
Etiology
The pathogenesis of HAM, pathologically termed vacuolar myelopathy, is poorly understood. Detection
of HIV in spinal cord is not associated with presence or severity of vacuolar changes (169). Activated
macrophages can be identified in the posterior and lateral columns of spinal cords from HIV-infected
individuals with and without vacuolar myelopathy (170), and degree of myelin damage is proportional to
the number of infiltrating macrophages (171). Thus, the pathogenesis of HAM may be similar to that
proposed for HAD. Because of pathologic similarities between HAM and myelopathy associated with
vitamin B12 or cobalamin deficiency, nutritional or vitamin deficiencies have also been suggested as a
cause of HAM. In autopsy-based series, vitamin B12 levels in patients with vacuolar myelopathy are not
low (170,172). However, cobalamin is a cofactor for conversion of homocysteine to methionine, which is
subsequently converted to S-adenosylmethionine (SAM). SAM is needed for myelin formation and repair.
In a small study, CSF SAM levels were significantly lower in patients with HAM compared to HIV-
infected patients without myelopathy and normal controls (173). These results support the hypothesis that
HAM may be due to abnormalities of a B12-dependent metabolic pathway.
Differential diagnosis of myelopathy in HIV-infected patients includes extrinsic cord compression from
tumor such as lymphoma, infection, such as bacterial or mycobacterial osteomyelitis, or hemorrhage
(174). These entities usually have a rapid course and associated back pain and sensory level, which are
uncharacteristic of HAM (see the following discussion). Intrinsic cord abnormalities due to tumor or
abscess, particularly lymphoma, toxoplasmosis, or tuberculosis, should also be excluded. Human T-
lymphotropic virus (HTLV) type 1 or type 2 infection may be indistinguishable from HAM. Myelitis due
to syphilis or herpes viruses (varicella-zoster virus [VZV], herpes simplex virus [HSV], or CMV) and
nutritional disorders should also be considered (Table 19.3).
Clinical Findings
Patients with HAM complain of slowly progressive lower extremity weakness and stiffness, trouble
walking, and urinary frequency and incontinence. Men may note erectile dysfunction. HAM typically
coexists with distal sensory peripheral neuropathy, with concomitant complaints of lower extremity
numbness, pain, or dysesthesia (175). Neurologic examination shows spastic paraparesis or paraplegia;
gait dysfunction; sensory ataxia; hyperreflexia, often with absent ankle reflexes in the setting of
concomitant neuropathy; impaired vibration and position senses; extensor-plantar responses; and
sphincter dysfunction (172,175).
HAM is a diagnosis of exclusion. MRI of the spinal cord should be undertaken to exclude extrinsic or
intrinsic cord lesions. In HAM, MRI is usually normal. When abnormalities are seen, they typically
involve the thoracic spinal cord with or without involvement of the cervical cord and include atrophy or
increased intramedullary signal intensity (176,177). Abnormal tibial somatosensory-evoked potentials
with prolonged conduction time are considered by some to be diagnostic (173). Analysis of CSF is
indicated to exclude alternative diagnoses; in HAM, the CSF is typically acellular with mild to moderate
elevation in protein concentration (175). One study showed that CSF HIV-1 RNA concentrations were not
increased in patients with HAM; however, these individuals were all on stable antiretroviral therapy
(178).
There is no proven treatment for HAM. Case reports describe improvement after beginning CART
(179–182), and this is currently the therapy of choice. A controlled trial of L-methionine (183) and an
open-label study of IV immunoglobulin for HAM showed no benefit (184). The association between
advanced HIV disease and HAM suggests that earlier treatment for HIV is the best preventative strategy.
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CHAPTER 20 GUILLAIN-BARRÉ SYNDROME
TONY M. MCGRATH
Since the decline in cases of poliomyelitis, the Guillain-Barré syndrome (GBS) has emerged as the most
frequent cause of acute flaccid paralysis. The spectrum of GBS includes classical acute inflammatory
demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor sensory
axonal neuropathy (AMSAN), and variants such as Fisher syndrome (1,2). AIDP, the most common form
in the Western Hemisphere, is characterized by rapidly progressive, usually ascending, and symmetric
paralysis of the extremities, variable involvement of bulbar, facial, and ocular muscles, and loss of deep
tendon reflexes (3). Although the disorder is often preceded by a bacterial or viral illness, no evidence
presently exists to indicate that GBS is caused by direct infection of nervous tissue. Current research
implicates an autoimmune mechanism.
HISTORY
Landry is credited with the first modern description of a disorder similar to GBS. In 1859, he reported a
patient with paresthesias and subjective weakness. Unlike present definitions of GBS, objective
weakness did not occur until 1 month after symptom onset but was then severe and rapidly progressive,
leading to death 8 days later (4). Although Osler’s account in 1892 (5) of acute febrile polyneuritis was
remarkably similar to the illness we now term GBS, the development of the lumbar puncture in the late
nineteenth century permitted a more precise characterization of the disorder and its differentiation from
poliomyelitis and other neuropathies (6). In 1916, Guillain et al. (7) detailed a clinical syndrome in two
individuals characterized by motor weakness, paresthesias, areflexia with preservation of cutaneous
reflexes, and increased cerebrospinal fluid (CSF) albumin without pleocytosis (albuminocytologic
dissociation). Both recovered fully. Similar descriptions soon followed, but controversy arose regarding
diagnostic criteria.
In 1976, following an apparent increase in GBS associated with the swine flu vaccine, the National
Institute of Neurological and Communicative Disorders and Stroke (NINCDS) was directed by the
Centers for Disease Control and Prevention (CDC) and the National Institute of Allergy and Infectious
Diseases to develop clear diagnostic criteria for GBS to assist in epidemiologic studies. These criteria
(NINCDS criteria) were reported in 1978 (3) and, though intentionally somewhat restrictive, are now
generally accepted. The clinical section of this chapter contains a summary of these criteria.
EPIDEMIOLOGY
Epidemiologic studies of GBS are inherently troublesome (8). The major difficulty is the lack of
definitive diagnostic markers for GBS. Because diagnosis must rely on clinical criteria, incidence may be
over- or underestimated if criteria are too broad or stringent or if atypical variants are counted or
excluded. Also, the results of studies employing dissimilar criteria may not be comparable. A dilemma
arises in regard to whether persons with an underlying condition known to produce a neuropathy, such as
diabetes mellitus, should be included when one is attempting a survey of a pure neuropathy such as GBS.
Moreover, GBS displays a wide range of clinical severity. Because many epidemiologic studies rely on
hospital-based reporting, mild cases not requiring hospitalization could be lost. Despite these difficulties,
numerous epidemiologic investigations of GBS have been performed. Ten of these are summarized in
Table 20.1.
Incidence rates in studies using NINCDS criteria (9–14,15) range from 0.4 to 2.0 per 100,000 persons.
In the population-based Olmstead County survey (9), 15% of GBS cases were mild and did not require
hospitalization. Therefore, hospital-based studies (10,11,13,14) may underestimate the true rate by as
much as 15%. Nevertheless, incidence rates are similar among studies conducted in different decades,
ethnic groups, races, and geographic areas. These findings are consistent with the hypothesis that the
triggering agents responsible for GBS are widespread and numerous, and susceptibility is similar among
populations.
Most studies of GBS have revealed higher incidence among men (9–11,13) and no significant seasonal
differences (9,13,16). Incidence increases with advancing age beyond 40 years, commonly peaking in the
seventh and eighth decades (10,11,13,14,16,17). Autumn clustering of GBS following Campylobacter
jejuni infection has occurred (18,19).
Four epidemiologic surveys have examined the incidence of GBS in children (20–23). Two (21,23)
used NINCDS criteria, and two (20,22) used criteria outlined in Table 20.2 (24). Although children with
clinical variants of GBS were identified, they were not included in the results. Annual incidence rates of
GBS in children were lower (0.4 to 1.1 per 100,000 children) than rates obtained in the general
population (see Table 20.1). No difference in frequency between boys or girls occurred in California (20)
and Finland (22), whereas male-to-female ratios of 1.5:1 were observed in Paraguay (21) and Taiwan
(23). Although a seasonal preponderance was not apparent in three studies (20,22,23), 76% of affected
children in Paraguay (21) had onset of symptoms during the summer months.
When childhood GBS in California (20) was analyzed by age at onset, frequency was significantly
greater in 2-year-old children than among other age groups. This finding may reflect the higher incidence
of triggering infections in this age group. In Paraguay (21), a similar increase in children younger than 4
years of age was seen, but in Finland (22) and Taiwan (23), age distribution was evenly dispersed.
Antecedent Events
Clinically apparent antecedent infections occur within 28 days of onset in approximately 50% of persons
with GBS (9–14,16, 25,26). Minor upper respiratory symptoms account for about 60% of the infections,
followed by gastrointestinal ailments and nonspecific febrile illnesses. Elderly persons with GBS
experience a similar incidence of antecedent infections (27,28). However, they may be less likely to
complain of preceding gastrointestinal symptoms (27). As many as 70% of children with GBS experience
an infectious disease within 28 days of neurologic symptom onset, with nonspecific upper respiratory
illnesses being responsible in nearly 80% (20–23). Yet, gastrointestinal prodromic symptoms may vary. A
recent study found that vomiting was more common in children with AIDP compared with AMAN (28.1%
vs. 6.5%), and diarrhea was more common in AMAN compared with AIDP (32.6% vs. 12.5%) (19).
Persons with severe GBS resulting in tetraparesis and prolonged mechanical ventilation are generally no
more likely than mildly or moderately affected patients to have an antecedent infection (29–31).
Neurologic symptoms usually begin within 2 weeks after the infectious illness (9,13,16,26,27,30,31)
but may occur more acutely (31). Shorter periods between the prodromal illness and neurologic
symptoms seem to follow antecedent upper respiratory infections, but a longer delay may occur in patients
with preceding gastrointestinal symptoms (32,33). In the majority, an infectious agent responsible for the
prodromal illness is never identified.
Many viruses and bacteria (Table 20.3) have been implicated as antecedent triggering factors in GBS
(16,21,28,32–36), although many of the proposed causal agents and GBS may simply represent a chance
association. Winer et al. (26) tested the proposition in serologic studies on 100 persons with GBS and
age- and sex-matched controls. Evidence of cytomegalovirus (CMV) and C. jejuni infection was
significantly more frequent in GBS patients (11% and 14%, respectively) than among controls. Although
positive Epstein-Barr virus (EBV), parvovirus B19, and Mycoplasma pneumoniae serologies were
identified in GBS, controls demonstrated similar results. Hankey (13) obtained acute and convalescent
serum from 62 persons with GBS and found evidence of recent viral infection in 50%. Parainfluenza virus
type 3, CMV, and adenovirus titers were identified in five, six, and seven specimens, respectively,
whereas EBV, herpes simplex, herpes zoster, parainfluenza type 1 and 2, measles, coxsackie, echovirus,
coronavirus, and influenza A and B titers were each present in one or two samples. Infection with M.
pneumoniae was encountered in five. Despite these various reports, convincing evidence of causality
exists for only CMV, EBV, human immunodeficiency virus (HIV), herpes zoster, C. jejuni, and M.
pneumoniae. Measles-associated GBS may occur, but only rarely. Although variola (smallpox) and
vaccinia have been conclusively linked with GBS, the eradication of smallpox and the discontinuation of
vaccinia immunization make any association with GBS of historic interest only. However, since the
September 11, 2001 terrorist attack and the threat of bioterrorism, the expected increase in smallpox
vaccinations could lead to an increase in vaccine-related GBS.
Dowling and Cook (36) detected immunoglobulin M (IgM) antibody directed against CMV in 15% of
220 persons with GBS. Those with CMV antibodies were primarily young women (average age, 25.6
years) in whom only 80% had a clinically apparent preceding infection. CMV-associated GBS appeared
in three separate 10- to 16-week clusters over 3 years. Abnormal liver enzymes were present in 50% of
the CMV seropositive cases. Evidence of recovery was associated with a fall in CMV IgM antibody titer.
No correlation has been demonstrated between primary infection with CMV and severity or outcome of
GBS (26,33). CMV-associated GBS has occurred following transplant of a CMV-infected heart in a
CMV-negative recipient (37) and may occur with CMV reactivation after autologous bone marrow or
organ transplantation (37,38).
EBV (like CMV, a herpesvirus) infection may precede neurologic symptoms in 2% to 8% of GBS
(20,26,28). It may present as hepatitis or mononucleosis or, like CMV, may be clinically silent prior to
GBS onset. Clinical or subclinical encephalopathy may complicate EBV-associated GBS (36).
Antecedent primary herpes zoster infection may occur in 3% to 4% of children with GBS (20,23). GBS
may also develop in association with reactivated herpes zoster infection (13,25,30). In contrast, recent
herpes simplex virus infection is uncommonly identified in GBS (34). The most recently identified
herpesvirus, human herpesvirus type 6 (HHV-6), has been proposed as an etiologic agent in GBS.
Antibody against HHV-6 was demonstrated in a significantly greater number of GBS patients than among
blood donors in Italy (35).
GBS has been described early in the course of HIV infection (39–41). In 1987, HIV was the most
common infection associated with GBS at the University of Miami School of Medicine (41). In
Zimbabwe, 55% of 29 consecutive persons with GBS were HIV seropositive (39). HIV infection did not
produce a higher incidence of prodromal illness in GBS. In each seropositive individual, GBS was the
initial manifestation of HIV infection. Generalized lymphadenopathy, coincident encephalopathy, and CSF
pleocytosis were significantly more likely with HIV infection. Mean CSF white blood cell counts in HIV-
associated GBS were 14/mm3 (range of 0 to 63 cells) (39). HIV seropositivity has not been associated
with poor recovery following GBS (40,41). GBS in HIV-infected individuals is probably secondary to
disordered immune regulation characteristic of the infection.
Several mosquito-borne infections have been reported with GBS. Japanese encephalitis virus (JEV)
may be an important antecedent infection in endemic areas. JEV is the most frequently recognized cause of
mosquito-borne encephalitis and typically occurs in epidemics in endemic areas. Ravi et al. (34) detected
high titers of IgM antibody specific to JEV in serum and/or CSF in 62% (21 of 34) of consecutive cases
in southern India. None had signs of encephalitis, and all satisfied NINCDS criteria (see later discussion)
for GBS. Clinical course and outcome were similar in JEV-seropositive and -seronegative individuals.
The JEV antigen was demonstrable in the CSF of one person, and virus was isolated from CSF in another.
Pathologic examination in one autopsied case demonstrated discrete necrotic lesions at the cerebral gray–
white matter junction and demyelination of ventral and dorsal nerve roots. West Nile virus (WNV) was
reported in an individual with GBS during the 1999 outbreak in New York City (42). During the summer
of 2002, six cases of acute flaccid paralysis syndrome associated with WNV were reported in
Mississippi and Louisiana (43). The individuals, however, had asymmetric weakness and CSF
pleocytosis, suggesting a polio-like syndrome. Falciparum malaria has also been reported with GBS
(44,45). Sokrab et al. (45) reported a mortality rate of 40% in 10 individuals with acute falciparum
malaria and GBS during a seasonal exacerbation.
In 1982, Rhodes and Tattersfield (46) reported the first case of GBS following C. jejuni enteritis.
Subsequently, C. jejuni has been recognized as the most common bacterial antecedent infection in GBS.
Serotyping of C. jejuni is accomplished by examination of heat-labile antigens (Lior method) and/or heat-
stable antigens (Penner method) (47). Several Penner and Lior serotypes of C. jejuni have been isolated
from GBS patients, but Penner serotype 19 and Lior serotype 11 predominate (48–58). These serotypes
are uncommon in uncomplicated gastroenteritis (47). Winer et al. (26) and Boucquey et al. (33) found
serologic evidence of recent C. jejuni infection in approximately 14% of GBS, and Mishu et al. (18) and
Kaldor and Speed (59) reported C. jejuni infection in 37% of GBS. No history of preceding
gastrointestinal symptoms has been reported in some GBS patients with serologic evidence of recent C.
jejuni infection (33,59). The incidence of C. jejuni infection in the United States peaks from August
through October (56), whereas the peak incidence for children in Mexico is from July through September
(19). Statistically significant summer and autumn clustering of C. jejuni–associated GBS has occurred
(18).
Stool cultures after onset of GBS with C. jejuni seropositivity are often negative (33,49,52,54,59),
because C. jejuni excretion lasts an average of 16 days (60), and GBS symptoms may be delayed until 3
weeks after gastrointestinal symptoms. Appropriate antibiotic treatment of C. jejuni enteritis does not
prevent GBS (46,49).
Although Boucquey et al. (33) and Enders et al. (54) reported no association between C. jejuni
seropositivity and GBS severity or outcome, severe disease and poor prognosis in C. jejuni–associated
GBS is well recognized (26,46,59,61). In one series of 21 C. jejuni–infected persons with GBS, 90%
required mechanical ventilation (59). Severe involvement may occur because of a tendency of C. jejuni–
associated GBS to damage axons rather than myelin (62). Of 11 children in China with AMAN, 90%
demonstrated serologic evidence of recent C. jejuni infection (63). Conversely, Enders et al. (54)
reported no greater electrophysiologic evidence of axonal involvement in C. jejuni–associated GBS, and
although Vriesendorp et al. (61) demonstrated severe disease and poor recovery more commonly in C.
jejuni–seropositive GBS, electrophysiologic evidence of primary axonal involvement was not apparent.
The mechanism by which C. jejuni infection triggers GBS is now better understood. Antigenic cross
reactivity occurs between C. jejuni and components of peripheral nerves (PNs) (64,65). Host factors may
determine whether infection with C. jejuni produces GBS. Although Hillert et al. (66) found no common
human leukocyte antigen (HLA) class II antigens in GBS, and Winer et al. (67) demonstrated no
association between HLA class I antigen and GBS and only a weak association between HLA class II
antigen DR2 and severe GBS, Yuki et al. (52) reported HLA class I antigen B35 in seven Penner serotype
19 C. jejuni–associated cases of GBS. The authors concluded that the combination of HLA B35 antigen
and Penner serotype 19 C. jejuni infection could precipitate an autoimmune response culminating in GBS.
This is due to molecular mimicry between lipooligosaccharides (LOSs) of C. jejuni and gangliosides in
PNs (68). The sialyltransferase gene (cst-II) has been identified to produce ganglioside-like LOS. The
gene consists of 291 amino acids; the 51st determines its enzymatic activity. Cst-II (Thr51) produces
GM1-like and GD1a-like LOSs, whereas Cst-II (Asn51) produces GT1a-like and GD1c-like LOSs which
mimic GQ1b (69,70).
Evidence of M. pneumoniae infection has been confirmed in 1% to 5% of GBS (13,23,26,34).
Currently, it is the second most commonly identified nonviral pathogen associated with GBS. An
influenza-like syndrome may precede the onset of neurologic symptoms.
Mori et al. (71) reported elevated anti–Haemophilus influenzae antibodies in 6 of 46 (13%) Japanese
patients with GBS but none of the 49 controls. Western blot analysis performed on the H. influenzae–
positive patient’s immunoglobulin G (IgG) confirmed recognition both of lipopolysaccharides of H.
influenzae and the ganglioside, GM1 (72).
In 1998, Chiba et al. (73) detected antibodies against Helicobacter pylori in the CSF from 4 of 7
patients with GBS. In 2002, Chiba et al. (74) examined CSF from 13 patients with GBS (8 AIDP, 4
AMAN, 1 unexcitable nerve conduction) and 8 control patients. Six of the AIDP patients had a specific
IgG antibody to the VacA of H. pylori.
Rabies vaccine and the A/New Jersey/76 swine influenza vaccine (swine flu vaccine) have been
reliably linked with GBS (32). Early rabies vaccine was made of desiccated brain and spinal cord of
rabies-infected animals. Both acute demyelinating encephalomyelitis (ADEM) and GBS sometimes
followed vaccination. A proliferative lymphocytic response and antibodies to myelin basic protein
(MBP), a constituent of central and peripheral nervous system myelin, have been demonstrated in persons
with rabies vaccine–associated GBS (75). An immune response against MBP has been proposed as the
cause of ADEM and GBS in these individuals. The discontinuation of rabies vaccine prepared from
infected animal brain and spinal cord has virtually eliminated rabies vaccine–associated ADEM and
GBS.
In 1976 and 1977, an increase in GBS in the United States was temporally associated with the A/New
Jersey/76 swine influenza vaccination campaign. The original CDC study demonstrated a statistically
significant increase in the risk of developing GBS within 6 weeks of swine flu vaccine administration in
persons 18 years of age and older (76). This study has been criticized because uniform GBS diagnostic
criteria were not used, records were reviewed by nonphysician caseworkers, no standardized method of
record assessment was used, and follow-up evaluations were not performed (77). Safrenek et al. (78)
reviewed all GBS cases in Michigan and Minnesota from October 1, 1976 through January 31, 1977.
Diagnostic criteria were developed, and a neurologist reviewed all medical records blindly. Although
mistakes in the original CDC study were uncovered, these authors also demonstrated a significant
increase in the relative risk of adults developing GBS within 6 weeks of swine flu vaccine. Four
manufacturers produced the swine flu vaccine administered to the civilian population in 1976. All were
associated with an increased risk of GBS (79). GBS has not been linked to previous or subsequent
influenza vaccinations. Military personnel who received swine flu vaccine developed by the United
States military in 1976 did not experience an increased frequency of GBS (80). The factor associated
with the civilian vaccine that was responsible for the increased risk of GBS has never been determined;
however, in 2008, Nachamkin et al. showed that the 1976 swine flu vaccine contained contaminating
moieties which elicited anti-GM1 antibodies after inoculation into C3H/HeN mice. Vaccine samples from
11 unopened vaccine lots containing A/New Jersey/76 swine influenza antigen from three different
manufactures were found to induce IgG and IgM antibodies to GM1, but no to C. jejuni, after
immunization in mice. This response was also observed in both the 1991 to 1992 and 2004 to 2005
vaccines. No vaccines were found to contain bacterial DNA (81).
GBS has been reported following other vaccinations, but clear evidence of causality is lacking. Hankey
(13) recorded recent vaccination in 5% of GBS, and of 100 individuals with GBS studied by Winer et al.
(26), 6 had received a vaccination within 3 months of GBS onset. Ten vaccines were involved, and the
rate of vaccination was similar in a control population. The latter study illustrates the importance of
discovering the frequency of vaccination in the background population before assigning significance to a
case of GBS following vaccination.
Several reports of GBS following vaccination against poliomyelitis have been recorded. In 1984, an
outbreak of poliomyelitis in Finland resulted in an intensified vaccination program with oral poliovirus
vaccine (OPV) (82). Subsequently, an unexpected rise in GBS occurred, precipitating epidemiologic
surveys attempting to link OPV with GBS. Although an unexpectedly high rate of GBS occurred within 10
weeks following OPV administration, a small number of persons were involved, and an unexpectedly
high rate of GBS also occurred in the weeks prior to the vaccination program.
Five percent to ten percent of GBS cases occur following intracranial, thoracic, abdominal, and
orthopedic surgical procedures (6,13,26,29,30,33,37). This could be secondary to primary CMV
infection following blood transfusion, although many reports exist of persons who did not receive
transfusion. Other sources of iatrogenic infection associated with surgery or hospitalization could be
responsible. Possibly, the surgery itself elicits a disordered immune response culminating in GBS.
GBS may also occur during pregnancy or the postpartum period (11,13,30,32). Unlike infants of
mothers with myasthenia gravis, infants of mothers with GBS are unaffected. Whether the pregnancy or an
associated infection, such as CMV, precipitates GBS is uncertain. Clinically and pathologically typical
cases of GBS have also been associated with malignancy, especially Hodgkin and non-Hodgkin
lymphoma (13,33,83). GBS is rarely associated with other autoimmune disorders (32).
PATHOLOGY
The pathologic findings in GBS are remarkably uniform irrespective of the antecedent illness or
precipitating event. Lesions usually occur as discrete foci of abnormality and have been observed along
the entire length of PNs. Areas of preferential involvement are the nerve roots, sites of ligamentous
entrapment, and distal terminal branches (32). Kanda et al. (84) noted a relative absence of lesions in the
initial few millimeters of anterior and dorsal nerve roots. This sparing of the transitional region between
central and peripheral nervous systems (CNS and PNS) may be attributable to the marginal blood supply
in this location. The pathologic process may involve autonomic, motor, and sensory systems
simultaneously, but in individual cases, abnormalities may predominate in one. Areas of maximal
pathologic change usually parallel clinical involvement, although this association is imperfect. Generally,
motor involvement exceeds sensory changes, but in most patients, pathologic lesions do not preferentially
or more severely involve the anterior roots or motor nerves (32,84–88). In a subset of GBS patients
primarily manifesting motor dysfunction, relative sparing of dorsal roots and sensory nerves has been
noted (63,85). The pathologic hallmark of GBS is a perivenular mononuclear cell infiltrate with
segmental demyelination. In 1969, Asbury et al. described multifocal, perivenular mononuclear cell
infiltration involving motor, sensory, autonomic, and cranial nerves (85). The invading lymphocytes and
monocytes were derived from blood. Even in diffusely involved nerves, inflammatory cell concentration
was greatest around blood vessels of the endoneurium, the connective tissue surrounding individual nerve
fibers. Infiltration about vessels of the epineurium, the connective tissue sheath of the entire nerve, was
present but less commonly observed.
Small and medium-sized lymphocytes were the predominant inflammatory cells recognized early;
macrophages were the more prominent cell type in older lesions with considerable myelin destruction.
Polymorphonuclear leukocytes were infrequently observed and then only in early, extensively affected
areas, apparently in response to tissue necrosis. Plasma cells appeared in some chronic processes.
Lesions of various ages were present within specimens from individual cases. Indeed, reparative
processes were apparent in areas still presenting evidence of ongoing myelin breakdown (85).
Alterations of the myelin sheath occurred in the areas of inflammatory cell infiltration (85). Retraction
at the node of Ranvier was seen in early lesions; more advanced changes included a complete dissolution
of the myelin sheath. Myelin disintegration appears to evolve from the nodal region toward the centrally
located Schwann cell. These areas of segmental demyelination were bounded by intervals of normal-
appearing myelin. Active phagocytosis of myelin was evident. Axonal damage with resultant wallerian
degeneration was present almost exclusively in areas with extensive inflammation. Asbury et al. (85)
concluded that axonal degeneration was a secondary phenomenon induced by the severe inflammation and
demyelination.
Schwann cell proliferation was present in lesions from patients surviving longer than 2 weeks.
Although demonstrated in areas with segmental demyelination but preserved axons, Schwann cell
proliferation was most common in nerves that had undergone wallerian degeneration. The proliferating
Schwann cells were arranged in columns, forming a tube to guide the regenerating axons. Patients
surviving several months with incomplete recovery of motor function demonstrated evidence of imperfect
remyelination: myelin sheaths were thin and pale, internodes were shorter, and Schwann cell numbers
were increased (85).
Subsequent examinations have supported many of the original findings of Asbury et al., but marked
variability in the pathologic lesions of GBS is now commonly reported. These reports have described,
even in early lesions, less conspicuous or absent lymphocytic infiltrate (63,84,86–91). Treatment with
steroids or other immunomodulatory therapies may alter the degree of lymphocytic infiltration.
Immunohistochemical analysis of biopsy material has demonstrated T-cell lineage in most of the invading
lymphocytes with only a few B cells present (80,83). Although CD4+ helper/inducer and CD8+
cytotoxic/suppressor T cells are present, CD4+ cells may predominate in early lesions (88). Like Asbury
et al. (85), Hanovar et al. (86) were unable to identify the origin of the larger mononuclear cells present
in more advanced lesions.
Pathologic reports of GBS have confirmed the invariable presence of macrophages in areas of
demyelination. Electron microscopic (EM) studies have demonstrated macrophages existing as two types
(88–94). One type consists of actively phagocytic macrophages that occur in an extratubal location within
the endoneurial space and in an intratubal location beneath the Schwann cell basement membrane. Focal
lysis of the outermost myelin lamellae occurs in the areas contacted by the macrophage. The cytoplasmic
projections of the macrophage then penetrate through the myelin gaps, insinuate themselves between the
myelin lamellae, and peel away layers of myelin from the axon. These invading, actively phagocytic
macrophages express major histocompatibility complex (MHC) class II antigens (86,88,95–98).
The manner in which macrophages accomplish myelinolysis is not understood. Arstila et al. (92)
demonstrated increased acid phosphatase and acid proteinase activities in GBS lesions. These lysosomal
enzymes may be derived from macrophages. However, the macrophage processes observed in GBS
lesions are devoid of organelles, including lysosomes (90). The second type of macrophage, the foamy
macrophage, is postphagocytic, contains myelin debris and lipids, and does not express MHC class II
antigen (95). In GBS lesions, MHC class II antigen expression has also been observed on endothelial and
Schwann cells (98).
Macrophages have also been observed within the axon cylinder (63). This location might explain some
cases of axonal degeneration that apparently ensue in the absence of severe demyelination. McKhann et
al. (63) reported pathologic findings on 10 autopsies from individuals with acute flaccid paralysis in
China, a syndrome clinically indistinct from GBS. Although two of the patients had pathologic findings
similar to those described by Asbury et al. (85), five were dominated by selective involvement of motor
axons with absence of inflammation and little evidence of demyelination. Numerous macrophages were
present in the areas of axons undergoing wallerian degeneration. The macrophages were located within
both endoneurium and degenerating axons. The authors have designated this entity AMAN.
Immunoglobulin and activated complement deposits have been described in GBS nerve biopsy
specimens. Nyland et al. (96) detected activated complement C3b receptor along nerves in GBS. Positive
staining for C3 was observed along nerve fibers, and IgG and IgM were apparent in the region of the
myelin sheath. Other investigators have failed to demonstrate immunoglobulin within the myelin sheath
(88–90,94). Immunoglobulin staining of the endoneurium has occasionally been noted (89,90). Deposition
of IgM on perineurium is a normal finding (89,90). Deposits of C3d were present in the myelin sheath of a
single patient (94). In mice models of GBS, deposition of complement at the presynaptic motor nerve
terminus has been reported (99,100,101). This in turn leads to a blockage of synaptic transmission at the
neuromuscular junction (102).
Axonal degeneration in the absence of demyelination or inflammation has also been observed by
Feasby et al. (88). Macrophages were not seen within the axon cylinder, and no evidence of inflammation
or macrophage-associated demyelination was encountered. Axonal degeneration of motor and sensory
nerves was severe. Electrophysiologic studies demonstrated inexcitability of motor nerves, a pattern seen
primarily in axonal degeneration. The authors named this variant AMSAN. Prognosis for recovery is poor
with axonal degeneration, whether it is a primary event or secondary to intense inflammation and
demyelination.
PATHOGENESIS OF GUILLAIN-BARRÉ SYNDROME

The most compelling evidence for a T-cell–mediated mechanism in the pathogenesis of GBS is the finding
of T-cell infiltration in affected nerves (32,85,87,88,90,91). Another indicator of T-cell involvement is
the presence of lymphoblasts in blood during early GBS and a possible correlation between their number
and disease severity (103). Increases in HLA-DR antigen and transferrin receptor, both present with T-
cell activation, have been observed on the surface of T cells in GBS (104–108). Serum levels of
interleukin-2 (IL-2), a T-cell growth factor, and serum-soluble IL-2 receptor (sIL-2R), shed from
activated T cells, are increased in GBS (104–107). Levels are maximal at onset and decrease during
recovery. Serum levels of IL-2 do not correlate with maximal functional disability. However,
concentration of sIL-2R may predict severity (107). Activated T cells may mediate injury in GBS by (a)
stimulation of B-cell proliferation and antibody production against myelin components, (b) macrophage
recruitment, (c) activation of the complement system, or (d) direct cytotoxic damage of myelin or
Schwann cells (97).
Consistent alterations in T-cell subpopulations have not been demonstrated (104,108–110). Dahle et al.
(108) noted normal total lymphocyte counts in acute GBS but a decrease in the proportion of CD4+
helper/inducer T cells and an increase in the proportion of CD8+ cytotoxic/suppressor T cells. Within the
CD4+ population, helper/inducer cells predominated over suppressor/inducer cells, known to be
decreased in diseases of autoimmune mechanism. Winer et al. (110) demonstrated decreased numbers of
CD8+ T cells in GBS patients with serologic evidence of recent C. jejuni infection and decreased
numbers of CD4+ T cells in GBS patients with serologic evidence of recent CMV infection. Specific
activation of T cells against myelin proteins has not been consistently observed with the sera from those
with GBS. Two series (111,112) found no evidence of T-cell sensitivity to myelin P2 protein. Several
reports have demonstrated T-cell clonal proliferation against proteins P2 and P0 and their peptides
(113–115). However, similar results have been obtained in normal controls and controls with other
neurologic diseases (113,115).
Macrophage involvement in GBS is evidenced by demonstration of macrophages in affected nerves in
GBS pathologic specimens (32,85–88), electron microscopic observation of macrophage-mediated
myelin stripping and phagocytosis (89–94), and indications of macrophage activation and their possible
role as antigen presenters through the surface expression of MHC class II antigens. Neopterin is produced
by macrophages in response to T-cell activation. Serum levels of neopterin are increased in GBS and fall
as clinical involvement improves (116). In vitro, monocytes from GBS patients have demonstrated a
greater ability to generate reactive oxygen species, indicative of cytokine activation, than monocytes from
controls (104). Thus, available data indicate that macrophage activation, probably by activated T cells or
their byproducts, occurs in GBS.
MHC class II marker expression is necessary for antigen presentation. Invading, actively phagocytic
macrophages in GBS express MHC class II markers on their surface (86,88,89,95). Although MHC class
II marker has been detected on the Schwann cell surface in GBS (98), these markers have also been
observed on the Schwann cell surface in degenerative, toxic, and metabolic neuropathies (117). Tumor
necrosis factor-α (TNF-α) is a cytokine elaborated by both activated T cells and macrophages. Increased
serum levels of TNF-α occur in GBS (118). Although TNF-α may play a role in the immune-mediated
injury in GBS, recombinant TNF-α alone will not produce myelin destruction in vitro (119).
The mechanism by which activated T cells and macrophages gain access to PN is not fully understood
but apparently involves two adhesion molecules, E-selectin (ELAM-1) and intercellular adhesion
molecule-1 (ICAM-1) (97). ELAM-1 is expressed on endothelial cells activated by IL-2, TNF-α, and
endotoxin. It aids in the binding of lymphocytes, monocytes, eosinophils, and neutrophils to the blood
vessel wall. Like IL-2 receptor, ELAM-1 enters the circulation and can be measured in serum. Elevated
ELAM-1 serum levels have been observed acutely in GBS (120,121).
In recent years, the humoral immune system has been implicated in the pathogenesis of GBS because of
(a) the demonstration of immunoglobulin and complement deposition in GBS nerve biopsy specimens
(89,90,94,95), (b) the therapeutic effect of plasmapheresis and intravenous immunoglobulin (IVIG) (see
later discussion), (c) the ability of GBS sera to cause demyelination of nerve in tissue culture and
possibly in vivo, and (d) the demonstration of antibodies against PN constituents in GBS sera. Whole
serum or IgM antibody from some patients with early GBS will produce complement-dependent
demyelination of PN tissue cultures (122–124). Electron microscopic studies have disclosed damage to
cultured Schwann cells and vesicular myelin degeneration after exposure to GBS sera in the absence of
leukocytes, lymphocytes, or macrophages (122). A lesser degree of in vitro demyelination occurs in PN
tissue culture after exposure to control sera, GBS patients during recovery, or persons with other
neurologic diseases (123).
A humoral mechanism in the pathogenesis of GBS has focused on the detection of antibodies to PN
constituents, especially gangliosides and related glycolipids. Complement-fixing antibodies directed
against PN myelin are demonstrable in the sera of some persons with early GBS (120,125). Anti–PN-
myelin antibodies are highest at presentation, significantly increased over levels from normal and
diseased controls, and decrease with improving clinical symptomatology (125). Production of anti–PN-
myelin antibodies in GBS is predominantly extrathecal, although measurable amounts are present in CSF
(126). In GBS, activated complement components are detectable in serum and CSF. Anti–PN-myelin
antibodies peak prior to activated complement levels, providing evidence of an antibody-mediated
complement attack on PN myelin (127,128).
Characterization of anti–PN-myelin antibodies has disclosed increased levels of circulating antibody to
galactocerebroside (GalC) (110) and P2 protein (112). Antibody levels to these myelin constituents were
low and, in the case of P2 protein, only marginally increased over those of control sera. Koski et al. (129)
discovered anti–PN-neutral glycolipid antibodies in GBS sera. Antigenic cross reactivity was
demonstrated between this PN neutral glycolipid and Forssman antigen, a component of some viral and
bacterial cell membranes.
Gangliosides are sialylated glycosphingolipids located on mammalian cell plasma membranes.
Ganglioside function is not known precisely, but gangliosides are implicated in cell differentiation, cell–
cell interactions, and receptor functions such as binding of viruses, bacterial toxins, hormones, growth
factors, and interferons (130). IgG and IgA antibodies to GM1, GD1b, and GQ1b have been shown to
activate leukocytes, which may contribute to the pathogenesis of GBS (131). The major gangliosides of
PN are GM3 and GD3, and the major ganglioside of PN myelin is LM1. GM1, although a major
component of CNS myelin, is only a minor constituent of PN. GM1 has been localized to both nerve
plasma membrane and the myelin sheath and appears to accumulate in the paranodal region (132).
Antibody to gangliosides is present in low amounts in normal human plasma (133). In 1988, Ilyas et al.
(134) detected significantly increased levels of antibodies to the gangliosides GD1a, GD1b, and GT1b
and to two associated glycolipids in serum from patients with acute GBS compared to controls.
High IgG antibody titers against GQ1b, a minor ganglioside of PN that has been localized to the
paranodal region of human ocular motility nerves, was detected in 90% of 41 persons with Fisher
syndrome (FS) (135–137), a GBS clinical variant manifesting primarily as ophthalmoplegia and ataxia.
Anti-GQ1b antibody decreases as clinical symptoms improve and may be absent in people with mild FS
(135–137). High anti-GQ1b antibody titers have also been demonstrated in Bickerstaff brainstem
encephalitis, a syndrome that bears some clinical resemblances to FS (138), and in typical GBS with
prominent ophthalmoplegia (137). High-titer anti-GQ1b antibody is not usually detectable in typical GBS
lacking ophthalmoplegia or in normal controls (137). The pathogenetic role of anti-GQ1b antibodies in
FS is not known. Lipopolysaccharide of C. jejuni isolated from FS does cross-react with epitopes of anti-
GQ1b antibody (56).
Subsequent to the original observation of high antiganglioside antibody titers in GBS (134),
antiganglioside antibodies (AGA) have been detected in 10% to 60% of patients with GBS
(61,97,139–145). The AGA titers may correlate with GBS severity and decrease with clinical
improvement (143). Antibodies to many known gangliosides and unidentified glycolipid fractions have
been demonstrated in association with GBS, but antibody to GM1 is most frequently cited, especially in
cases with mainly motor symptoms (139,141–144,146). Both IgM and IgG antibodies to gangliosides are
present, but IgM antibodies predominate early (142). The early presence of IgG or IgA antibodies to GM1
has been associated with severe, prolonged GBS (139) and may predict poor recovery
(141,144,147–149). AGA have also been detected in individuals with hyperreflexia and impaired central
motor conduction in association with acute paralysis, acute ataxia, or chronic paralysis (150).
Anti-GM1 antibodies have been reported in up to 58% of patients with GBS showing serologic
evidence of preceding C. jejuni infection (139,149). Yuki et al. (62) described anti-GM1 antibody in
association with C. jejuni infection in severe GBS with electrophysiologic evidence of primary axonal
degeneration and poor recovery. Immunogenic cross-reactivity between GM1 and C. jejuni isolates from
GBS patients has been described (53,57). GM1 antibodies recognize a carbohydrate sequence that is
present in several gangliosides and on bacterial cell walls. GM1 gangliosides may also be important for
nerve growth factor signaling. Tanaka et al. reported that GM1 antibodies interfered with the neurotrophic
action of nerve growth factor and TrkA autophosphorylation signaling in PC12 cells, a sympathetic nerve
cell line (151). Nakatani et al. reported GM1 antibodies of patients with AMAN inhibit the current action
of Cav2.1 (P/Q-type) voltage-dependent calcium channel in Purkinje cells of rats (152).
Elevated titers to GM1 and GD1b occur in C. jejuni infection without GBS (153). However, research
now shows that elevated antibodies to GM1, GD1a, GM1b, and GalNAcGD1a occur with higher
frequency in AMAN, whereas elevated GQ1b, GT1a, GD3, and GD1b antibodies occur in the majority of
FS (154). In 32 Japanese children with GBS, Nishimoto et al. (155) reported the frequency of IgG
antibodies to gangliosides: GM1 (34%), GM1b (22%), GD1a (25%), and GalNAc-GD1a (13%). In
addition, antibodies to ganglioside complexes (GSCs) are associated with severe GBS. Patients with
GBS requiring mechanical ventilation may have antibodies to GD1a/GD1b and GD1b/GT1b complexes,
and patients with FS may have antibodies to GQ1b/GM1 and GQ1b/GD1a GSC (156,157,158,159).
GM1/GalNAc-GD1a GSC have also been reported in 10 patients with GBS (160). Other antibodies
associated with GBS have been identified (Table 20.4) (65,162–164). Immunogenic cross reactivity
between GalC and M. pneumoniae has also been described (165).
The IgG subclasses 1 and 3 predominate in IgG antibodies to both GM1 and GQ1b. These subclasses
are usually seen in immune responses to protein antigens rather than to carbohydrates such as
gangliosides. This suggests that the primary antibody response in GBS is against a protein. The antibody
simply cross-reacts with gangliosides (161). The IgG subclass may be a predictor of severity and
outcome. Jacobs et al. reported patients with only IgG1 AGA had a worse prognosis compared to patients
with both IgG1 and IgG3 AGA. This may be in part due to the longer serum half-life of IgG1 (21 days)
compared to the relative shorter half-life of IgG3 (7 days) (166).
An ad hoc committee of the NINCDS proposed diagnostic criteria for GBS in 1978 (3). These criteria,
further reaffirmed and elaborated by Asbury in 1980 (167) and Asbury and Cornblath in 1989 (168), are
summarized in the following paragraphs along with additional comments. Electrodiagnostic criteria are
discussed in the subsequent section.
The diagnosis of GBS is based on (a) progressive motor weakness of more than one extremity and (b)
areflexia, although proximal hyporeflexia with distal areflexia may be seen. Weakness may precede reflex
changes by 2 or 3 days (168) and typically spreads from the lower extremities to involve the upper
extremities, trunk, and cranial nerves (6,7). Weakness usually ascends from the thighs to the upper arms,
although hands and feet are initially involved in some cases (6). Muscle wasting may eventually occur in
50% of patients (168).
Features strongly supportive of the diagnosis include (a) rapid progression of motor weakness
reaching a plateau in 4 weeks—in one study, the average time elapsing from onset of weakness to its
maximum was 12 days, with 98% of patients reaching maximal weakness by 4 weeks (25); (b) relative
symmetry of motor weakness; (c) mild sensory symptoms. GBS is often heralded by paresthesias in the
toes and fingers (6). Sensory symptoms are eventually present in 70% of GBS patients (9,11,13).
Subjective sensory complaints commonly exceed objective sensory findings (6,11). When objective
sensory loss occurs, proprioception and vibration are primarily involved (169), presumably because the
fibers involved in their conduction are myelinated to a greater extent than are the fibers conducting
temperature, pinprick, and light touch; (d) cranial nerve involvement. Data in one study of 100
consecutive GBS patients revealed facial palsy (frequently bilateral) in 53% of patients, bulbar weakness
in 13%, and extraocular muscle palsy in 9% (169). Rarely, all brainstem reflexes may be lost simulating
brain death; (e) recovery ensues. This usually begins 2 to 4 weeks after cessation of progression but may
be delayed months (6). Little improvement is seen after 1.5 to 2 years (25,29); and (f) autonomic
dysfunction. Sympathetic and parasympathetic systems may be involved, producing cardiovascular,
gastrointestinal, urinary, pupillary, and sudomotor symptoms. Autonomic involvement is recognized in
about 20% of GBS cases, although the actual figure is probably much higher (13,20,21). Minor
cardiovascular abnormalities in GBS include sinus tachycardia and postural hypotension. Malignant
arrhythmias secondary to autonomic dysfunction remain a leading cause of death in GBS patients.
Hypertension, hypotension, and sensitivity to vasoactive drugs also occur. Urinary retention, constipation,
gastroparesis, and loss of pupillary responses are less frequent (25). Disordered sympathetic function can
produce both excessive sweating and anhidrosis (170). Impotence may persist in a few men (6).
Variant clinical features include (a) fever at the onset of neurologic symptoms; (b) severe sensory loss
with pain. Severe pain may be the presenting complaint in some GBS patients, particularly in children, in
whom the diagnosis of GBS may be difficult initially. Painful symptoms may include myalgias and
arthralgias, paresthesias and dysesthesias, meningismus, radicular and back pain, and abdominal
discomfort (9,25,171); (c) progression may continue beyond 4 weeks or show a minor relapse.
Approximately 3% to 9% of patients will have one or more relapses (9,32); (d) no significant recovery.
Complete recovery occurs in approximately 60% of patients, but mild disability persists in 30%, and
significant handicap remains in 5% to 10% (6,9,25,169). Children experience a better outcome (20–23);
(e) sphincteric dysfunction may occur; urinary retention is rare but may occur secondary to autonomic
involvement (169); and (f) CNS involvement. Although controversial, occasional GBS patients
demonstrate cerebellar ataxia, extensor plantar responses, and ill-defined sensory levels (25).
CSF findings that are strongly supportive of the diagnosis include (a) elevated CSF protein. Increases
in CSF protein concentrations are thought to arise from the severe nerve root involvement. CSF protein
elevations are usually not present until after 1 week of symptoms and peak during the nadir and early
recovery period (6,11). CSF protein concentrations may reach levels of 2 g/dL, though much lower levels
are typical (11,14,32); a CSF protein concentration greater than 2.5 g/dL should alert one to the
possibility of cord compression (6). No correlation exists between protein values and mode of onset or
progression, severity, or outcome of GBS (9,25,32). However, elevated heavy chain neurofilament (NfH),
a marker of axonal damage, may indicate a worse prognosis (172). Papilledema noted in some cases of
GBS has been attributed to impaired CSF absorption secondary to increased protein levels (13,25,169).
However, papilledema and increased intracranial pressure have been seen in GBS with normal CSF
protein, and papilledema is not consistently present in patients with extremely high protein values (32);
and (b) ten or fewer mononuclear leukocytes per cubic millimeter.
CSF variants include (a) normal CSF protein in the period 1 to 10 weeks following the onset of
neurologic symptoms—normal CSF protein values may be present in 20% of GBS patients (6,9,11,32)—
and (b) 11 to 50 mononuclear leukocytes per cubic millimeter. In the presence of HIV infection, CSF
pleocytosis in GBS is expected. Cornblath et al. (40) noted a mean of 23 cells/mm3 in nine HIV-infected
persons with GBS.
Clinical variants of GBS include (a) FS with ophthalmoplegia, ataxia, and areflexia; (b) polyneuritis
cranialis (173); (c) pharyngeal–cervical–brachial weakness (174); (d) paraparesis with areflexia (32);
(e) sensory loss with areflexia (32,168); (f) pure pandysautonomia (175); (g) pure motor weakness (32);
(h) AMAN (63); and (i) AMSAN (88). Paraparesis with areflexia can be included as a variant of GBS
only if spinal cord compression and transverse myelitis have been excluded and electrophysiologic
studies are consistent with demyelinating polyneuropathy (32). Sensory loss with areflexia is most
commonly secondary to a neuronopathy associated with malignancy, particularly small cell carcinoma of
the lung and lymphoma. Rather than a demyelinative process, dorsal roots are destroyed by intense
inflammation (32). Although pure pandysautonomia may result from an autoimmune pathogenesis similar
to that of GBS, pathologic evidence of demyelination is lacking (32,167,175). GBS with motor weakness
in the absence of subjective or objective sensory loss may occur (32). However, such patients should be
distinguished from those with AMAN (63), a syndrome clinically similar to a predominantly motor form
of GBS but pathologically and probably pathogenetically distinct. AMSAN as described by Feasby et al.
(88) is also pathologically different from GBS and should be considered a separate entity as well.
Radiologic studies are generally not helpful in the diagnosis of GBS. However, contrast-enhanced
magnetic resonance imaging may demonstrate enhancement of nerve roots.
Clinical and laboratory features that should alert one to the possibility of alternative diagnoses are (a)
conspicuous asymmetry of extremity weakness; (b) persistent bladder or bowel dysfunction or bladder
or bowel dysfunction at onset; (c) more than 50 mononuclear leukocytes/mm3 in CSF or the presence of
polymorphonuclear leukocytes in CSF; (d) protein concentration greater than 2.5 g/dL; and (e) distinct
sensory level.
The differential diagnosis of GBS includes ADEM presenting transverse myelitis, or spinal cord
compression presenting as flaccid paralysis, myasthenia gravis, diphtheritic neuropathy, vasculitic
neuropathy, lead neuropathy, and arsenic poisoning. Weakness related to enteroviral infection (including
poliovirus), botulism, and hysterical paralysis may occasionally be confused with GBS. Weakness
secondary to enteroviral infection is associated with a CSF pleocytosis and electrophysiologic evidence
of motor neuron injury. A history of prodromal constipation and poor feeding in infants or the ingestion of
contaminated food in adults, preservation of reflexes in some patients, and the presence of a presynaptic
defect on electrophysiologic studies can differentiate weakness secondary to botulism from GBS. Acute
intermittent porphyria is excluded by the absence of urinary excretion of porphobilinogen and δ-
aminolevulinic acid. The presence of cells in the CSF should alert one to the possibility of lymphomatous,
carcinomatous, or sarcoid meningitis as well as Lyme disease. Extremity and respiratory muscle
weakness mimicking GBS can occur 12 to 96 hours after organophosphate exposure (176), secondary to
blockade of nicotinic receptors by excess acetylcholine. Basilar artery occlusion and tick paralysis may
mimic MFS (6).
ELECTROPHYSIOLOGIC FEATURES
Electrophysiologic studies have significantly increased our understanding of GBS and improved
diagnostic accuracy. The symptoms and signs in GBS are attributed to abnormalities in nerve conduction.
Although the diagnostic criteria of GBS described in 1978 (3) report normal studies of nerve conduction
in up to 20% of GBS, more recent series have identified electrophysiologic abnormalities in 90% to
100% (169,177–180). Because of the multifocal nature of pathologic lesions in GBS, the likelihood of
detecting electrophysiologic abnormalities increases with the number of nerves tested (177). Generally,
three or more motor nerves should be examined (168). Early in the course of GBS, nerve conduction may
be normal or minimally abnormal. Repeat testing may be necessary in inconclusive cases. Abnormalities
in motor nerve conduction, sensory nerve conduction, mixed nerve conduction, and late motor responses
(H-reflex study and F-wave study) may occur alone or in any combination.
In 1990, Asbury and Cornblath (168) proposed electrodiagnostic criteria for demyelinating
neuropathies, including GBS. These criteria require three of the following to be present: (a) decreased
conduction velocity in two or more motor nerves; (b) conduction block or abnormal temporal dispersion
in one or more motor nerves—peroneal nerve between ankle and below fibular head, median nerve
between wrist and elbow, or ulnar nerve between wrist and below elbow; (c) prolonged terminal motor
latency (TML) in two or more motor nerves; and (d) absent F-waves or prolonged F-wave latency.
In early GBS, electrophysiologic evidence of demyelination is apparent primarily in proximal nerve
plexuses and in the distal nerve twigs (31,181,182). During the first 5 weeks, motor conduction
abnormalities are more common than sensory nerve conduction abnormalities (169,178). Slowed motor
nerve conduction is present at some point in 60% to 80% of those with GBS with maximal slowing
detected in the third week (167,168,177,180). Electrophysiologic evidence of motor nerve demyelination
(conduction block or temporal dispersion) is present in approximately 60% of GBS patients within 2
weeks of illness onset (177,179,183). Markedly slowed motor conduction velocity has been associated
with a poor long-term prognosis (169,182). In a given nerve, conduction block may be generalized, or
predominantly proximal or distal. Abnormal temporal dispersion is evident in only 20% (183). Abnormal
TML occurs in 40% of GBS (177,182) and may be present in nerves with normal motor conduction
velocity between the proximal and distal sites (31). The nadir of abnormalities of sensory conduction is
reached in the fourth week (169). The delay in sensory electrophysiologic abnormalities is felt to reflect,
in part, secondary involvement of sensory nerves related to intraneural edema accentuated by
compression at sites of anatomic vulnerability.
When the motor nerve is inexcitable, either severe distal demyelination with complete conduction
block or axonal degeneration is responsible (184,185). Inexcitable motor nerves may be present in up to
20% of GBS (182). Although some authors have reported that inexcitable motor nerves within 2 weeks of
symptom onset is uniformly associated with a poor long-term prognosis (185), Triggs et al. (184) found
complete recovery by 1 year in 50% of such individuals. Abnormal temporal dispersion with reduced
distal compound motor action potential (CMAP) is due to demyelination. Whether secondary to axonal
loss or severe distal demyelination, the absence or marked reduction (0% to 20% of the lower limit of
normal) of the distal CMAP amplitude appears to be the strongest electrophysiologic predictor of
prolonged disease and incomplete recovery following GBS (31,169,178,182,185). In those with reduced
distal CMAP amplitude, if improvement in CMAP amplitude occurs on sequential studies or if plasma
exchange is performed, better outcome results (184). In one series of 23 children in whom reduced distal
CMAP amplitude was the most common electrophysiologic abnormality, no correlation between distal
CMAP amplitude and degree of recovery following GBS was evident (179). However, the absence of a
distal CMAP abnormality early in GBS does not predict a good outcome (186).
Prolonged F-wave latency, indicating abnormal conduction in the proximal motor nerve, is the most
common electrophysiologic abnormality in GBS, occurring in approximately 90% of patients during the
course of the illness (169,177). Indeed, prolonged F-wave latency may be the only detectable
electrophysiologic abnormality in some patients (187). F-wave latency does not predict outcome.
The occurrence of spontaneous fibrillation potentials during EMG in GBS, an indication of muscle
denervation, has also been associated with incomplete recovery following GBS (188,189). It generally
appears between the second and fourth weeks after onset. In some cases, particularly in children, the
presence of fibrillation on EMG is not predictive of poor recovery (178,179).
In AMAN, sensory and motor nerve conduction velocity and TML are normal, but CMAP is reduced
and F-waves are either absent or normal. Unlike GBS with CMAP abnormalities, the outcome in AMAN
is good with only mild distal weakness and atrophy present at 1 year (63). Electrophysiologic studies in
FS differ from those in typical GBS by predominant abnormalities in sensory rather than motor nerves
(190,191).
TREATMENT
Despite recent successes of immunomodulatory therapies in GBS, meticulous nursing and medical care
remain essential. Most individuals with GBS require in-hospital observation. Patients with mild disease
may not require treatment but must be monitored closely until progression has ceased (6). Rapidly
progressive weakness, respiratory embarrassment or infection, progressive bulbar dysfunction, or
cardiovascular abnormalities warrant intensive care monitoring (6,192).
Respiratory failure occurs in approximately 20%, necessitating careful respiratory monitoring,
especially during the progressive stage of illness. Vital capacity should be measured every 4 to 6 hours,
and elective intubation should be performed when the vital capacity falls to 15 mL/kg of body weight
(6,192–195). Patients should be observed for clinical signs of respiratory fatigue such as diaphoresis,
tachycardia, and paradoxical movement of abdominal muscles during inspiration. Respiratory rate is
variable in persons with GBS and impending respiratory failure (195). Blood gas studies and oxygen
saturation are unreliable predictors of respiratory failure. Significant respiratory compromise can be
present before hypoxia and hypercarbia occur. Oropharyngeal weakness may warrant earlier intubation
(6,192). Newton-John (196) demonstrated fewer pulmonary complications with early assisted ventilation
(before the vital capacity fell below 21 mL/kg) compared to late assisted ventilation (after the vital
capacity fell below 15 mL/kg). The use of immunomodulatory therapies (see later discussion) in
ventilated GBS patients has decreased the mean time of ventilation to 16 to 24 days from 26 to 48 days
(24,197,198). Weaning from mechanical ventilation should not begin until vital capacity is greater than 7
mL/kg; extubation can be safely attempted when the vital capacity is 15 mL/kg (197).
Because of the prominence of autonomic disturbances in GBS, continuous electrocardiographic and
possibly arterial blood pressure monitoring is necessary in those requiring intensive care (6,192,193).
The majority of cardiovascular irregularities occur during peak motor weakness, but episodes during
convalescence have also been reported (170,194,199–201). Cardiovascular dysfunction in GBS include
sinus tachycardia, postural hypotension, minor ECG changes, hypertension, episodic hypotension,
bradyarrhythmia, tachyarrhythmias, and sensitivity to vasoactive drugs (188,194,199,201). Drugs
producing hypotension in GBS include phentolamine, nitroglycerin, hexamethonium, edrophonium
chloride, thiopental sodium, morphine sulfate, and furosemide. Phenylephrine, ephedrine, dopamine, and
isoproterenol have been associated with hypertension (170). Carbamazepine precipitated asystole in a
man recovering from GBS (200). Atropine and glycopyrrolate should be used cautiously in GBS because
of a risk of tachyarrhythmias. Some authors advocate insertion of a cardiac pacemaker in any patient with
a nonsinus arrhythmia (170). Vagal stimulation such as occurs with tracheal suctioning, intubation,
extubation, Valsalva, and distention of a hollow viscus may produce hypotension and bradyarrhythmias in
GBS (192,194). Severe tachyarrhythmias have been terminated with verapamil and pindolol (194).
Infection of the urinary tract or lung occurs in almost 25% of those requiring intensive care (202).
Intravenous line or generalized sepsis occurs less commonly. Chest physiotherapy and incentive
spirometry are essential to prevent sputum retention, bronchial obstruction, and segmental collapse. In
individuals requiring long-term urinary drainage, intermittent catheterization may be less problematic than
a chronic indwelling catheter (194).
Gastrointestinal hemorrhage complicates the course of 2% to 8% of those in intensive care units (194).
The best prophylaxis against gastritis is regular feeding. If feeding is not possible because of gastric
paresis, gastric emptying may be improved with metoclopramide or cisapride and isotonic, low-fat
enteral formulas, and avoidance of sedatives and narcotics. When feeding is impractical, sucralfate or
magnesium-containing antacids may provide adequate gastric bleeding prophylaxis (193). Individuals
with GBS have increased nutritional needs from hypercatabolic states and the metabolic demands of
regenerating myelin and atrophied muscles and must be closely followed (193).
Early physical and occupational therapy in GBS may aid in the prevention of joint contractures and
pressure nerve palsies and may also hasten the return of limb control, walking, and balance during the
recovery period. Frequent position changes and soft bedding are needed to prevent decubiti (192).
Subcutaneous low-dose heparin is commonly employed for prophylaxis against deep vein thrombosis
(192,194).
Successful treatment of pain and dysesthesias associated with GBS is highly individualized. Painful
symptoms are usually worse at night and may preclude intensive physiotherapy. Proper positioning and
splinting, socks or gloves, massage, and hot or cold packs can provide relief in many (171). Nonsteroidal
antiinflammatory drugs may alleviate musculoskeletal pain. Tricyclic antidepressants and carbamazepine
are popular choices for neurogenic pain but should be used cautiously in those who have cardiovascular
irregularities or urinary retention (171,200). Quinine and capsaicin or lidocaine salve have proved
beneficial (171,192). Low-dose methylprednisolone may benefit some individuals (192). Narcotic
analgesics may be required for adequate pain relief but should be used cautiously because of secondary
hypotension and risk of ileus. Some authors advocate the use of epidurally administered opioids for
severe pain (171). Transcutaneous nerve stimulation has received mixed commentary as an adjunct to
other forms of pain management (171).
Acute GBS can be a frightening experience. Severe GBS is susceptible to anxiety and depression.
Reassurance that the disorder is self-limited and that the majority of patients make a full recovery is
beneficial. Visits from individuals who recovered from GBS may also be helpful (193,194).
Individuals with GBS are at risk for hyperkalemia following succinylcholine chloride (203). Muscle
membrane changes after nerve injury result in the proliferation of cholinergic receptors. Succinylcholine
interacts with the cholinergic receptor, producing depolarization with the influx of sodium and release of
potassium. Normally, depolarization does not release enough potassium to increase serum levels.
However, after diffuse PN injury such as occurs in GBS, the increase in cholinergic receptors may cause
enough potassium release to increase serum potassium levels sufficient to produce arrhythmias and
cardiac arrest. It is not known when, if ever, succinylcholine can be safely administered to patients
recovered from GBS (203). Nondepolarizing neuromuscular blocking agents may also result in prolonged
paralysis (204).
Immune Modulation
Immune modulation has now emerged as a promising adjunct to general medical care in GBS.
Corticosteroids were used in the treatment of GBS for many years. Their use was based largely on their
antiinflammatory effects and the results of a few uncontrolled trials. Three randomized, controlled trials
showed little, if any, benefit from corticosteroids (205–207). In fact, steroids may have a detrimental
effect (205). One study comparing 21 prednisolone-treated subjects and 19 untreated individuals
demonstrated slower improvement in the treated group at 1, 3, and 12 months. Six of the treated groups
had disabling weakness compared to one control. Three relapses occurred in the treated group. A
nonrandomized study of GBS suggested that coincident administration of methylprednisolone and IVIG
was more effective than treatment with IVIG alone (208).
Plasma exchange (PE) appeared in the 1980s as a beneficial treatment for GBS (209). Enthusiasm for
its use was based on three sets of observations: (a) case reports showing improvement following PE; (b)
efficacy of PE in chronic inflammatory demyelinating polyneuropathy; and (c) reports of in vivo
demyelination by GBS sera (25). Four randomized controlled trials employing PE have been performed
(24,210,211). Because it was considered unethical to carry out sham PE, none of the trials was blinded.
These studies included 263 in the PE-treated group and 269 treated with conventional methods alone.
Only individuals who required assistance walking were included. The greatest benefit was seen in those
who began PE within 1 week of onset. PE 14 days or more after onset observed little benefit in those
treated. Duration of mechanical ventilation was significantly shorter, and time to onset of motor recovery,
independent walking, and length of hospitalization were shorter. Outcome at 6 months and 1 year was
better compared to those receiving conventional therapy. In one large series (24), a 12-year-old boy with
GBS died of inflammatory myocarditis after two PE treatments. Otherwise, no deaths in the PE-treated
group could be attributed to PE, and the number of deaths in each group was similar.
IVIG has recently proved efficacious in the treatment of GBS. IVIG is pooled human IgG from 5,000 to
10,000 blood donors. Side effects of IVIG occur in fewer than 5% of recipients and are summarized in
Table 20.5 (212). The most common adverse reactions are systemic and include nausea, vomiting,
headache, fever, chills, myalgias, tachycardia, and hypotension. These reactions are believed to be
secondary to impurities in the preparation and can usually be managed by slowing the infusion rate. Fatal
anaphylaxis may occur during IVIG administration in IgA-deficient individuals. Preparations with very
low levels of IgA should be used in IgA deficiency and in those for whom determination of IgA levels is
not possible (213). Patients with impaired renal function have rarely developed renal failure following
IVIG administration. With current preparations of immune globulin, the remaining adverse reactions listed
in Table 20.5 are extremely rare (213).
The early justification for treatment of GBS with IVIG was based on its efficacy in other immune-
mediated disorders (214). The mechanism by which IVIG exerts its effectiveness in immune-mediated
diseases such as GBS is unknown but could be related to the presence of antiidiotypic antibodies (215).
Antiidiotypic antibodies are normally circulating antibodies that bind other antibodies and serve as
immunoregulators. Treatment with IVIG exposes circulating autoantibodies to antiidiotypic antibodies in
IVIG and may result in clearance of the autoantibodies (215). Other possible beneficial effects of IVIG in
GBS include inhibition of complement-binding and cytokine secretion, blockade of antibody receptors,
reduction in autoantibody synthesis, amplification of suppressor cell activity, and inhibition of lymphocyte
proliferation (215).
Treatment of GBS with IVIG may have several therapeutic advantages over PE. It is readily available,
may be given in any hospital without delay, and can be used in those patients with cardiovascular
instability. Also, IVIG administration does not remove medications or plasma proteins as PE does and
rarely requires placement of a central venous catheter. Treatment cost is comparable to that of PE.
A randomized trial comparing IVIG and PE treatment of GBS was performed by the Dutch Guillain-
Barré Study Group (216). Individuals with typical GBS of less than 2 weeks’ duration with a clinical
motor function grade of 3 or greater (Table 20.6) (24) were included. PE of 200 to 250 mL/kg of body
weight in five sessions was performed in 73 subjects, and 400 mg of IVIG/kg body weight was
administered on five consecutive days to 74 subjects. PE was interrupted one or more times in 16% of the
PE group, primarily because of hypotension and difficulties with venous access. IVIG infusion was not
interrupted in any. Although this study did not establish superiority of IVIG over PE in GBS, it did
demonstrate equal effectiveness. IVIG treatment was significantly better in the median time of
improvement by one clinical grade (41 days in the PE group and 27 days in the IVIG group). Significantly
fewer subjects receiving IVIG required mechanical ventilation compared to the PE-treated group. In the
Dutch Guillain-Barré study, 8 of 74 (11%) patients treated with IVIG experienced a relapse of symptoms
after the treatment ended (217). Clinical deterioration following PE or IVIG may occur because early
treatment ends before natural progression has ceased or the pathogenic process is reactivated after
treatment is completed (218). Most authors advocate retreatment only if clinical grade 3 or worse is
reached. One trial found no significant differences in secondary outcome measures of PE alone compared
to PE followed by IVIG (219). No data exist to support changing treatment in those who do relapse.
The treatment of GBS in children is similar to treatment in adults. Despite the apparent effectiveness of
immunomodulatory therapies in children with GBS, meticulous nursing and medical care remain the
mainstay of therapy. Children who are too young to perform forced vital capacity measurements must be
monitored closely for signs and symptoms of impending respiratory failure.
No randomized trials have been performed to assess efficacy and safety of PE or IVIG in pediatric
GBS. A review of the literature reveals 62 children treated with PE (220–227). The children ranged in
age from 1.2 to 16 years. Grade 3 or greater disability (Table 20.6) was present in all treated children.
Mild hypotension responsive to fluid administration was the most frequent complication of PE in the 49
children for whom information was available (220,221,223,224,226,227). Systemic reactions occurred in
four children who received fresh frozen plasma as a replacement fluid. Two children displayed emotional
upset at the end of a PE session, possibly secondary to hypocalcemia (224). Only 1 of 58 reported
children began PE more than 2 weeks after symptom onset (15 days) (224). Fifty-four of the 62 reported
children (87%) receiving PE improved significantly after beginning PE; most within 1 week. Two
children responded partially, and six did not respond. One PE nonresponder improved after a single IVIG
dose of 1.5 g/kg body weight (225). Six months after onset, 29 of 33 examined children had achieved
clinical motor function 1 or 0 (220,223,224,226,227). Two of the remaining four children had no residua
at 1 and 2 years (208). These reports support the notion that PE can be safely performed in seriously ill
children with GBS and that they benefit from PE therapy.
IVIG is an attractive treatment for childhood GBS for reasons similar to those in adults. Also, central
venous access required for PE is rarely necessary in IVIG. This is particularly advantageous in infants
and small children. Sixty-seven children administered IVIG for GBS have been described
(212,225,227–233). All treated children were clinical motor function grade 3 or worse and ranged in age
from 1.7 to 16 years. IVIG was administered in doses of 400 mg/kg body weight on 5 consecutive days, 1
g/kg body weight on 2 consecutive days, or a single dose of 2 g/kg body weight. Thirty-five children were
treated within 2 weeks of symptom onset, 1 child was treated 19 (232) and 30 days (230), respectively,
after onset, and time of treatment was not available in 30 children (225,229,231). Side effects of IVIG
treatment occurred in three children. Two complained of headache during treatment, and one developed
macroscopic hematuria. Sixty-five of the 67 children (97%) demonstrated a significant response to IVIG
therapy, usually within 1 week. Improvement attributed to IVIG therapy was seen as late as 19 days (212).
One of the nonresponders began IVIG treatment on day 3 of her illness but developed respiratory failure
on day 7 and required mechanical ventilation for 28 days. She eventually recovered (227). The course of
the other nonresponder was not described, but all of the children in that series completely recovered in 4
months (229). Interestingly, both of the nonresponders received the shorter 2-day course of IVIG rather
than the 5-day course administered in the Dutch Guillain-Barré study (216).
The results obtained in these 67 IVIG-treated children with GBS are similar to results obtained in the
62 children treated with PE. The nonresponder rate in the PE-treated children was 10% versus 3% in the
IVIG-treated children. In both groups, improvement was usually evident within 1 week of beginning
therapy. Comparisons of the two treatments for time to achieve independent walking and final outcome are
not reliable because information is not available for many of the patients. One of the series compared
IVIG administration and PE in children with GBS (227). This study was not randomized or blinded, and
the attending neurologist made the treatment choice. Five children underwent PE, and 10 received 1 g of
IVIG/kg body weight on two consecutive days. All children receiving PE responded, whereas 9 of 10
children in the IVIG group responded. The PE group improved two functional grades in a mean of 48 days
versus 17 days in the IVIG group. The outcome at 6 months was similar. Although it appears that IVIG
resulted in quicker improvement, the groups were not equal. Mechanical ventilation was necessary in
60% of the PE group but in only 30% of the IVIG group. Patients in the IVIG group began treatment one
day earlier than those in the PE group, and their average age was 2 years younger. Certainly, one can
conclude from the available reports that both PE and IVIG can favorably alter the course of GBS in
nonambulatory children, but whether one treatment is superior will have to be answered by a randomized
trial.
PROGNOSIS
Despite the considerable progress made in the treatment of GBS in recent decades, the mortality rate
remains 5% to 10% (6,9,14,24,25,28,30,169). In some geographic locations, mortality as high as 21% has
been recorded (11). Causes of death directly attributable to GBS include cardiac arrest related to
dysautonomia and respiratory failure (9,14). Mortality secondary to assisted ventilation and paralysis
occurs following accidental disconnection from ventilation, pneumonia, adult respiratory distress
syndrome, septicemia, and hemorrhagic or thrombotic events.
Approximately 60% recover fully. Minor residua such as footdrop or mild distal numbness remain in
approximately 20%, and 5% to 10% will retain permanent disability (6,9,14,25,33). GBS may recur
years after the initial event in 5% of individuals (9,23). The lack of uniform recovery has prompted a
search for clinical, laboratory, and electrophysiologic features predictive of prognosis.
Most authorities agree that older age, rapid progression to quadriparesis, and need for ventilatory
assistance predict severe disease and prolonged or incomplete recovery (6). Underlying malignancy may
also be predictive of poor outcome. Treatment with PE has a beneficial effect on duration of disease and
speed of recovery but may not influence the final degree of recovery in GBS (210,211). However, the
French Cooperative Group demonstrated a significant increase in the percentage of fully recovered GBS
patients in the PE versus conventional therapy groups (71% vs. 52%). PE did not influence the incidence
of severe residual disability following GBS (234). The Dutch Guillain-Barré study found advanced age to
be the only clinical predictor of slowed or incomplete recovery (216). However, older age has not been
associated with poor outcome in several series (13,27,28,48,235). Beghi et al. (9) found an association
between age and GBS severity only in persons older than 70 years of age, and Winer et al. (169) noted
poor outcome more often in those older than 40 years of age.
In one series, 50% of GBS patients with rapid progression to quadriparesis in 2 to 5 days were
nonambulatory 2 years after onset (29). Loss of ambulation in 7 days was predictive of poor outcome in
the large multicentered trial comparing PE and conventional therapy of GBS (235). However, other series
have not related rapid progression to outcome (9). A prolonged plateau period before onset of recovery
(23 days) has also correlated with incomplete recovery (48).
The need for ventilatory support may be a negative prognostic feature in GBS (6,48,169,235), but
Hankey (13) found no difference in outcome among individuals requiring ventilation shorter or longer
than 28 days.
Laboratory features predictive of severe disease and incomplete recovery include serologic evidence
of C. jejuni infection (26,46,59,61) and the early presence of IgG or IgA AGA antibodies
(139,141,144,147–149). Other associated infections including HIV are not associated with protracted
disease. Increased CSF neuron-specific enolase or S100b protein levels were seen with longer disease
duration (236).
The most powerful predictor of severe disease and prolonged or incomplete recovery appears to be
low distal CMAP amplitude (0% to 20% of normal) (31,169,178,182,183,185,235). The appearance of
denervation on EMG is also predictive of poor outcome (188,189). The degree of conduction slowing
does not, however, correlate with maximal clinical disability or duration of disease (189).
In children, GBS may be a more benign disorder compared to adults, but they often will have severe
neuropathic pain (237). In Finland (22), 26 of 27 children recovered fully, and no deaths occurred. No
deaths were noted among 72 children diagnosed in Taiwan, and 75% recovered completely by 6 months
(23). In Paraguay, 80% achieved full recovery (21). Conflicting results have been observed with distal
CMAP amplitude in children with GBS. Children with inexcitable motor nerves or severely reduced
distal CMAP (<10% of lower limit of normal) were more likely to require ventilation and a longer time
to become ambulatory than were children with distal CMAP amplitude greater than 10% of the lower
limit of normal (31). Bradshaw and Jones (179) found no difference between children with reduced distal
CMAP amplitude and other children with GBS. All the children recovered completely.
SUMMARY AND FUTURE DIRECTIONS

GBS is a demyelinating disorder of PN occurring in all ethnic groups and geographic locations. Men and
older individuals appear to be more frequently affected. A variety of preceding events may incite GBS,
but minor infections are implicated most often. Recognition of C. jejuni infection in association with
GBS, in particular AMAN and FS, has improved our understanding of its unique pathogenesis. Both T-
cell–mediated and humoral immune responses appear to play important roles in the genesis of GBS. The
significance of the relationship between AGA and GBS has not been fully elucidated. Electrophysiology
is important in both the diagnosis and prognosis of GBS. Despite PE or IVIG treatment of GBS, 5% to
10% of affected individuals will retain permanent disability, and 5% to 10% will die. With improved
understanding of the varied causes and pathogenesis of GBS, new and disease-specific therapies should
be developed.
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study. Neuropediatrics. 2007;38:10–17.
CHAPTER 21 ACUTE VIRAL MYELITIS
J. DAVID BECKHAM AND KENNETH L. TYLER
Viral infections of the spinal cord occur as part of more extensive infection of the central nervous system
(CNS) or peripheral nervous system. When myelitis occurs in association with encephalitis or meningitis,
the resulting syndromes are referred to as encephalomyelitis or meningoencephalomyelitis. Myelitis
associated with involvement of spinal nerve roots or peripheral nerves is referred to as myeloradiculitis
or myeloradiculoneuritis. This chapter focuses on acute viral infections in which spinal cord
involvement is the dominant feature. Acute myelitis associated with rabies virus and HIV infection is
discussed elsewhere (see Chapters 17 and 19), as are cases of chronic viral myelitis due to infection with
retroviruses including HIV and human T lymphotropic viruses (HTLVs). In addition to directly infecting
and injuring the spinal cord, viruses can trigger postinfectious immune-mediated tissue injury. Spinal cord
involvement is a common but rarely dominant feature of acute disseminated encephalomyelitis (ADEM)
(see Chapter 22). Transverse myelitis (TVM) is an acute syndrome defined by the nature and extent of the
anatomic injury to the spinal cord, often associated with antecedent viral infections. Specific causes of
TVM are discussed under the individual viruses involved, and the idiopathic syndrome is briefly
reviewed at the end of this chapter.
The term myelitis means “inflammation of the spinal cord” and refers to disease of the spinal cord
caused by a direct infectious process, a postinfectious process, or another indirect mechanism of injury.
The clinical features are determined to a large degree by the location and extent of the process both in the
craniocaudal and the transverse axes of the spinal cord rather than by the inciting agent.
The clinical features of myelitis provide important clues to the anatomic location of the lesion but do
not enable myelitis to be separated from other causes of intramedullary spinal cord injury. The clinical
features of myelitis caused by different viruses overlap substantially, and identification of a specific viral
etiology typically depends on the results of laboratory tests. The characteristic features of myelitis include
variable combinations of weakness; sensory loss; and bowel, bladder, and sexual dysfunction, typically
evolving over days. Apoplectic or hyperacute (hours) evolution of symptoms is occasionally seen in viral
myelitis but is more typical of vascular spinal cord disease (1) (e.g., infarction resulting from
atherosclerosis, arteritis, emboli or hemorrhage, or even venous thrombosis [Foix-Alajouanine
syndrome]). Viral causes of chronic myelitis or myelopathy in which symptoms evolving over weeks or
months are largely limited to HIV and HTLV.
Weakness in viral myelitis may be either of the upper motor neuron type with associated spasticity,
hyperreflexia, and extensor-plantar reflexes or of the lower motor neuron type with flaccid weakness and
decreased or absent deep tendon reflexes. Lower motor neuron involvement in the absence of significant
sensory signs or symptoms is often referred to as acute flaccid paralysis or poliomyelitis-like illness,
although the latter term is best reserved for cases in which pathology is limited to the anterior horns of the
spinal cord. Involvement of motor neurons in the anterior horns or involvement of the anterior roots can
result in prominent clinical and electrophysiologic evidence of denervation, including the presence of
fasciculations and fibrillations. Sensory loss in myelitis can be radicular, dermatomal, or both. Depending
on the transverse localization of the lesion(s), either loss of position and vibration sense or loss of pain
and temperature may occur. Finding a “sensory level” below which sensory functions are lost is a classic
hallmark of spinal cord disease. Either relative or absolute sparing of sensation in sacral dermatomes
(“sacral sparing”) may occur when an intramedullary process such as viral myelitis leaves the most
peripheral fibers in the spinothalamic tract relatively unharmed.
Patients with acute onset of signs and symptoms suggestive of spinal cord dysfunction are a medical
emergency. Initial clinical and laboratory studies should be directed at trying to identify whether a
compressive lesion is present and whether it is intramedullary or extramedullary in location. An
algorithm for the immediate diagnostic approach to patients with acute myelopathy is shown in Figure
21.1(2). Table 21.1 summarizes key diagnostic tests that may be useful in evaluating a patient with
suspected acute viral myelitis. In the following sections, viral etiologies of acute myelitis are discussed
individually.
HERPESVIRUSES
Both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) can cause myelitis. HSV-2 most commonly
causes myelitis in adults and HSV-1 most commonly in children (1,3). The clinical presentation ranges
from mild forms of disease with full recovery to severe necrotizing myelitis with permanent sequelae.
Most cases are monophasic, although about 20% of patients experience recurrent episodes of myelitis, a
feature common to infection with several herpesviruses (4–7). In patients with recurrent disease, the
interval between recurrences may vary between 1 week and several months, with three or more discrete
recurrences being noted (5,7). Up to two thirds of patients with HSV myelitis have an ascending pattern of
spinal cord involvement, with the remainder having TVM (5).
Most cases of monophasic HSV myelitis are due to HSV-2 (5). Patients with HSV-2 myelitis often have
a history of genital herpes. However, in one series, only two of seven patients with HSV-2 myelitis had
known genital herpes, and lesions, when present, often preceded spinal involvement (5). Clinical features
of HSV myelitis include paresis or paralysis, more commonly involving the legs than the arms. Patients
may have either reduced and/or absent tendon reflexes or hyperreflexia with extensor-plantar responses.
Decreased sensation to pain, temperature, and touch is common and tends to be more severe in sacral
dermatomes. Patients can have decreased anal tone and urinary incontinence with overflow. HSV-2 can
also cause a lumbosacral radiculomyelitis characterized by urinary retention associated with constipation,
dull pain in the anogenital region, paresthesias, loss of sensation, or flaccid paresis of the leg muscles (8).
The most severe form of HSV myelitis is an acute necrotizing myelopathy, which occurs predominantly
in patients with underlying diseases including HIV infection (9), malignancy (10), and diabetes (11,12),
although rare cases occur in the absence of associated disease (13). All cases to date have been
associated with HSV-2. At autopsy, these patients often show areas of necrosis in the gray and white
matter of the spinal cord associated with perivascular lymphocytic cuffing. Cowdry type A inclusions are
found in neurons, viral antigen can be demonstrated by immunocytochemistry, and herpesvirus-like
particles have been seen by electron microscopy (9–13). Some cases have a prominent necrotizing
arteritis associated with myelomalacia with Cowdry A inclusion-bearing cells seen in the wall of the
anterior spinal artery (9).
In HSV myelitis, the cerebrospinal fluid (CSF) typically shows a lymphocytic pleocytosis and normal
glucose concentration. Patients with recurrent attacks may have a progressive reduction in the degree of
pleocytosis with succeeding attacks (7). Typical cell counts range between 10 and 200 cells/mm3,
although rare cases with normal cell counts have been reported (5,14). The CSF profile in patients with
acute necrotizing myelopathy may show striking pleocytosis with up to 5,750 cells and a predominance of
polymorphonuclear (PMN) leukocytes rather than lymphocytes (12). Surprisingly, some reported patients
have had no or minimal pleocytosis (9,11). The CSF protein concentration is almost invariably elevated
(range, 50 to 430 mg/dL). Oligoclonal bands were found in one of nine patients in one series (5) and have
been noted in other case reports (7,15).
HSV is only rarely cultured from CSF in patients with myelitis (15), and diagnosis depends on
demonstration of HSV DNA in CSF by polymerase chain reaction (PCR) (4–6,15–17). In one series of
nine patients, all had PCR amplifiable HSV DNA in CSF, with six cases due to HSV-2, two cases due to
HSV-1, and one case indeterminate. In this series, HSV-2 DNA was found in six of six cases with
ascending myelitis, whereas HSV-1 DNA was found in two of the three patients with nonascending TVM
(5). In an HSV CSF PCR-negative patient, a presumptive diagnosis can be made by demonstrating
intrathecal synthesis of HSV-specific antibodies (7). Antibody studies may be particularly useful in cases
in which CSF is only available late in infection (e.g., >14 days), when HSV DNA is likely to have
disappeared. Evidence of intrathecal synthesis of HSV-specific antibodies can be based on (a) the
presence in CSF of immunoglobulin M (IgM) anti-HSV antibodies (these antibodies cross the blood–
brain barrier poorly and their detection in CSF is generally indicative of intrathecal synthesis); (b) the
detection of HSV-specific oligoclonal bands present in CSF but not in serum; (c) the comparison of HSV-
specific immunoglobulin G (IgG) levels in CSF and serum with correction for blood–brain barrier leak
using either the CSF/serum albumin ratio or the ratio of antibody titers in CSF to that in serum for an
“irrelevant” virus (5,14,16,18). Basic laboratory studies usually add little to the diagnosis, although some
patients have elevations in erythrocyte sedimentation rate and C-reactive protein (6,18).
Magnetic resonance imaging (MRI) is exceedingly important for its role in both excluding other
potential diagnoses and in establishing the presence of an intramedullary process. The typical appearance
of HSV myelitis is of an intramedullary fusiform or spindle-shaped area of an increased T2-weighted
signal (5,7,14,16). The spinal cord is often enlarged or swollen in the area of the lesion. Areas of an
increased T2-weighted signal may also have T1-weighted signal hypointensity. In rare cases, areas are
both T1 and T2 hyperintense, a finding suggestive of hemorrhagic necrosis (5). Contrast (gadolinium)
enhancement may be seen in the area of the lesion and the adjacent meninges and nerve roots (6,7,16,17).
Lesions are most commonly in the upper thoracic and cervical cord (5,6) but can also involve the lower
cord including the conus medullaris and cauda equina (7,15–17).
No controlled clinical trials of antiviral therapy for HSV myelitis are available. Based on anecdotal
reports, patients should be treated with intravenous acyclovir for at least 14 days (10 mg/kg three times
per day). This can be followed by oral antiviral drugs (e.g., valacyclovir at 1 g three times per day) until
symptoms resolve. The utility of adding steroids is unproven. When given, steroids should be used only in
combination with antiviral therapy. A typical regimen involves intravenous methylprednisolone (500 to
1,000 mg per day for 3 to 5 days) followed by oral prednisone (100 mg per day) with doses tapered over
2 weeks (5,7,17).
The prognosis of HSV myelitis is extremely variable. In one series of nine patients, one third (n = 3)
made a complete recovery, and the remaining two thirds (n = 6) had residual sequelae including
paraplegia and tetraplegia (5).
Myelitis is an unusual complication of varicella-zoster virus (VZV) infection, with most cases occurring
in immunocompromised individuals (19–21). Myelitis can also occur as a complication of primary
varicella infection or chickenpox (20,22,23). In immunocompromised patients, common underlying
diseases include HIV infection (19,20,21,24,25), Hodgkin and non-Hodgkin lymphoma (19), and
immunosuppressive therapy (26,27). In a recent review of 31 cases of VZV myelitis, 55% of patients with
VZV myelitis were immunocompromised, and the majority of the remaining patients had an underlying
comorbidity such as malignancy or autoimmune disease (28). Cases of VZV myelitis in immunocompetent
patients are reported but uncommon (29). Many patients have antecedent zoster, although several cases
without rash (myelitis sine herpete) have been reported (30–32). When zoster is present, it can involve
virtually any dermatome, but myelitis is often associated with disseminated zoster in
immunocompromised patients (19). Cord dysfunction typically follows the onset of zoster with a median
of 12 days (range, 5 to 21 days), but symptoms of myelitis may follow rash by up to 3 months or myelitis
symptoms may precede the appearance of rash (19,24). Cases of TVM following zoster have also
occurred in patients who have previously received zoster vaccine (33).
Patients with zoster myelitis present with subacute onset of asymmetric leg weakness which progresses
to bilateral leg weakness with paraparesis in up to 85% of patients (19). Sensory loss is common (75%),
with involvement of pain and temperature more common than position and vibration sense. A Brown-
Séquard syndrome may occur, with posterior column signs (loss of position and vibration sense)
ipsilateral to the rash and spinothalamic tract signs (loss of pain and temperature sense) contralateral
(19). Approximately one third of patients will have a level to all sensory modalities, urinary incontinence
occurs in about 50%, and bowel incontinence can also occur. In a few cases, VZV myelitis may show a
relapsing and remitting pattern (20,25,34), a feature also seen in some cases of HSV-2 myelitis (see
earlier discussion). Atypical presentations of VZV myelitis including cases not associated with rash
(zoster sine herpete), skin lesions developing after myelopathy, or lack of correspondence of zoster
lesions to spinal cord injury level occur more frequently in immunocompromised patients (28).
In VZV myelitis, CSF shows a mononuclear pleocytosis in about 75% of patients with an increase in
PMN predominance in patients with rapid onset and severe disease (19). Recurrent episodes of CSF
PMN pleocytosis with recurrent episodes of VZV myelitis have been reported (30). CSF protein
concentration is elevated in 70%, but glucose concentration is almost always normal. It is important to
recognize that at least 50% of immunocompetent patients with a zoster rash in the absence of myelitis
have a CSF lymphocytic pleocytosis with cell counts from 5 to 1,440 cells/mm3 and exceeding 100
cells/mm3 in 30% of those with pleocytosis (35).
Approximately 25% of patients with a zoster rash will also have evidence of CSF anti-VZV IgG and
detectable VZV DNA by PCR, but CSF anti-VZV IgM is usually not detectable and the CSF VZV IgG
index is usually normal, suggesting that intrathecal synthesis of VZV-specific antibody does not occur in
uncomplicated herpes zoster reactivation (35). By contrast, patients with zoster myelitis often have a
positive CSF VZV PCR and intrathecal VZV-specific IgG synthesis, even VZV specific CSF oligoclonal
bands (36).
Patients with VZV myelitis frequently have abnormalities on spinal MRI (Fig. 21.2). These can include
diffuse swelling of the cord and areas of high T2-weighted signal with or without associated T1
hypointensity and contrast enhancement (20,22,27,32,37–39). MRI lesions in the brainstem and cervical
cord may also occur in immunocompetent patients with zoster myelitis (35).
The diagnosis of VZV myelitis is generally suspected when signs of myelitis develop following a
typical zoster eruption in an immunocompromised patient. Definitive diagnosis depends on isolation of
virus from CSF (24,31), demonstration of intrathecal synthesis of VZV-specific antibody (20,36,37,40),
or PCR amplification of VZV DNA from CSF (20,27,37,40–42). Comparative studies of the sensitivity
and specificity of these tests are lacking, although clinical experience suggests that PCR is likely to be the
most sensitive, and culture the least. Antibody and PCR test results should be viewed as complementary
rather than mutually exclusive; as in other viral infections, antibodies typically develop later than
detectable nucleic acid. The duration for which VZV DNA remains detectable in CSF following varicella
myelitis is unknown. In patients with relapsing-remitting myelitis, CSF VZV DNA may persist, as two
patients had positive CSF PCR results 8 and 11 months after onset of disease (20).
No controlled clinical trials of treatment for VZV myelitis are available. Treatment typically involves
intravenous acyclovir given alone or in combination with steroids (19,31,37,39,42–44), although the
paucity of cases and the variability in treatment regimens make efficacy difficult to access (20). In several
patients who received intravenous acyclovir after myelopathy was established, treatment seemed to be
without effect (24,39,44). By contrast, there are also reports of complete recovery in AIDS patients with
VZV myelitis following acyclovir therapy (10 mg/kg every 8 hours) for 21 to 35 days (42) and
improvement in patients treated with either acyclovir alone (20,37) or a combination of acyclovir and
high-dose steroids (31). One patient apparently responded to oral famciclovir (500 mg every 8 hours),
who had not previously responded to steroids, acyclovir, or foscarnet (37).
Pathologic studies of VZV myelitis are limited (19,25,32). In a comprehensive review of nine fatal
cases, there was extensive hemorrhagic necrosis with necrotizing vasculitis and thrombosis in the dorsal
root ganglia associated with Cowdry type A intranuclear inclusions in both ganglion and satellite cells
(19). Almost all cases had abnormalities in the posterior roots and the posterior horns of the spinal cord,
although severity varied. Inclusion bodies were seen in about 50%, and patients could have demyelination
and signs of necrotizing vasculitis and hemorrhagic spinal cord necrosis (19,32). A similar necrotizing
process with demyelination and Cowdry type A inclusions was described in an AIDS patient with chronic
zoster myelitis (25). In a recent review of five postmortem cases of VZV myelitis, tissue necrosis and
inflammatory cell infiltration were the primary findings, but other pathologic changes were noted as well,
including vasculitis, thrombosis, hemorrhagic transformation, and Cowdry type A inclusions (28).
Cytomegalovirus
Cytomegalovirus (CMV) involvement of the spinal cord either can result in a pure TVM or can produce
myeloradiculitis, or radiculomyelopathy. Most cases of CMV-associated myeloradiculopathy occur in
HIV-infected patients (45–48), and this can be the initial manifestation of AIDS (49). Myelitis can be a
complication of both adult and pediatric HIV infection (50). Although CMV myelitis is predominantly a
disease of immunocompromised individuals, there have been isolated reports of both TVM and
myeloradiculopathy in immunocompetent individuals (51–57). Isolated cases of dual infection of the cord
with both HSV and CMV have been reported in patients with AIDS (58). The incidence of CMV-
associated myeloradiculopathy has declined dramatically since the introduction of highly active
antiretroviral therapy (HAART). Myeloradiculopathy occurs with approximately equal frequency as an
isolated manifestation of CMV infection and in systemic CMV disease (59). Patients present with rapidly
progressive flaccid paralysis of the legs with hyporeflexia or areflexia (60). Urinary retention occurs in
almost all patients (60). Pain, often involving the perianal region and low back, is a common initial
symptom. Sensory loss usually involves small-fiber modalities (pain, temperature) more than vibration or
proprioception, although both can occur. The symptoms are typically progressive, although some patients
have a more indolent course.
One of the unusual features of CMV myeloradiculitis is the common occurrence of a PMN rather than a
lymphocytic CSF pleocytosis (61,62). This feature is distinctive enough that its presence in an HIV-
infected patient with myeloradiculopathy should always suggest the possibility of CMV infection (63).
Cell counts exceeding 1,000/mm3 can occur (46,64–66), although median values of 150 to 650 cells/mm3
are more typical (60,61). In addition to pleocytosis, the CSF typically shows an elevated protein
concentration. Severe hypoglycorrhachia may occur (46), although a CSF glucose concentration of less
than 50% of the coincident plasma value has been reported in only about 30% of patients (62).
Imaging studies are useful in demonstrating the location and extent of lesions. Typical findings on
spinal MRI include areas of increased T2-weighted signal within the spinal cord, associated with
enhancement of the pial lining of the cord, conus, cauda equine, and lumbosacral nerve roots on contrast-
enhanced T1-weighted images (66,67). The presence of prominent radicular enhancement in association
with myelitis occurs more often with CMV infection than in other forms of viral myelitis and may provide
a clue to the diagnosis.
Clinical electrophysiologic studies may be helpful in demonstrating the presence of radicular and
peripheral nerve involvement in association with myelitis, especially because this component of the
disease may be clinically obscured when the myelitis is severe. Both slowed conduction velocities
consistent with demyelination and reduced amplitude of motor and sensory action potentials consistent
with axonal injury occur (59,68).
PCR tests to amplify CMV DNA from CSF are the diagnostic procedure of choice (59,69–72). The
diagnostic sensitivity of CSF PCR in CMV myelitis is more than 80%, with a specificity of more than
90% (59). It is important to emphasize that CSF PCR is often positive when cultures are negative (69,72).
Quantitative PCR studies of CMV DNA in CSF suggest that extremely high DNA levels, exceeding 10
million copies of CMV DNA per milliliter of CSF can be found in patients with myeloradiculopathy
(59,69,73).
CMV may be cultured from CSF in cases of radiculomyelitis (59). The high seroprevalence rate of
anti-CMV antibodies in serum generally renders serologic studies of limited value. However, the
demonstration of specific intrathecal synthesis of anti-CMV antibodies or the presence of detectable CSF
anti-CMV IgM antibodies can be considered presumptive evidence for CNS infection.
Controlled clinical trials of antiviral therapy in CMV-associated neurologic disease are lacking, and
most reports of treatment of CMV-associated neurologic disease involve isolated cases (59,69,74,75).
Response to treatment of myeloradiculopathy is variable. Improvement or stabilization of symptoms has
followed treatment with ganciclovir, foscarnet, or a combination of the two agents (60,62,64,68,76–80).
Disease has been associated with ganciclovir-resistant strains (81,82), and this risk may be enhanced in
patients whose disease developed during ganciclovir treatment for CMV infection elsewhere. As a
general rule, the presence of myelitis is an extremely poor prognostic indicator, with one review citing
mean survival times of 5.4 ± 1.8 weeks in patients not receiving ganciclovir and 14.6 ± 9.4 weeks in
those receiving ganciclovir therapy (76).
Successful treatment is usually associated with disappearance of CMV DNA from CSF, whereas viral
DNA persists in nonresponders (74). A typical induction regimen for ganciclovir involves 14 to 21 days
of intravenous therapy with doses of 5 mg/kg every 12 hours. Intravenous foscarnet at a dose of 90 mg/kg
every 12 hours provides an acceptable alternative. Patients who fail to respond to either foscarnet or
ganciclovir alone may respond to combined therapy with the two drugs (79). A third agent, cidofovir, has
been shown to be efficacious in treatment of CMV retinitis, but experience with this agent in CMV-
associated neurologic disease is limited (83). A typical dosing regimen is 5 mg/kg intravenously every
week for 2 weeks followed by infusions of 5 mg/kg every 2 weeks. Fourteen to twenty-one days of
ganciclovir or foscarnet therapy is likely to be sufficient for immunocompetent patients. In most organ
transplant recipients, 14 to 21 days of therapy is also likely to be adequate assuming clinical and
virologic response has occurred. Maintenance therapy is usually not required for CMV myelitis in organ
transplant recipients, although maintained vigilance for recurrent disease is essential. In patients with HIV
infection, it is critical that HAART be initiated or optimized concomitantly with anti-CMV therapy. HIV-
infected patients invariably require maintenance therapy with an orally bioavailable valine ester of
ganciclovir (valganciclovir). Induction and maintenance doses of intravenous and oral ganciclovir,
intravenous foscarnet, and intravenous cidofovir require adjustment in patients with renal insufficiency.
Neutropenia is the major dose-limiting side effect with ganciclovir, and nephrotoxicity with foscarnet and
cidofovir. Nephrotoxicity can occur with ganciclovir but is less common. Neurotoxicity can occur with
ganciclovir and foscarnet and in the case of foscarnet is often related to electrolyte alterations (especially
hypocalcemia). Patients whose HIV infection responds to HAART and who consistently (>6 months)
demonstrate nondetectable HIV viral loads and CD4 cell counts of more than 100 cells/mm3 may be able
to discontinue maintenance therapy.
Few detailed pathologic studies of CMV myeloradiculitis have been performed. There is often a
prominent PMN and mononuclear cell infiltrate involving the sacral spinal cord, cauda equina, and
lumbosacral nerve roots associated with both demyelination and axonal destruction. CMV antigen is
detectable in the spinal cord and in involved roots and endothelial cell (47,59).
Human Herpesvirus-6 and Human Herpesvirus-7
Human herpesvirus type 6 (HHV-6) causes exanthema subitum (roseola infantum). Most individuals are
infected in early childhood (age 6 to 12 months). Although primary HHV-6 infection is usually benign,
there have been isolated reports of meningoencephalitis. Myelitis appears to be extremely rare in patients
with HHV-6 infection. HHV-6 neuroinvasive disease including encephalitis and/or myelitis are most
commonly reported as a complication in bone marrow transplant recipients (84,85) and occur with a
frequency of about 3% in allogeneic hematopoietic stem cell transplantation and up to 16% in patients
receiving cord blood transplantation from an unrelated donor (86). Median onset of clinical symptoms is
23 days after transplant, and limbic encephalitis is the most common presenting syndrome with or without
associated myelitis. Very rare cases of HHV-6 myelitis in immunocompetent individuals have been
reported (87). HHV-6 may also be responsible for rare cases of chronic myelitis presenting as spastic
paraparesis (88).
There is one reported case of combined encephalitis and acute flaccid paralysis in an
immunocompetent 19-year-old man infected with HHV-7 (89). The CSF had a lymphocytic pleocytosis,
an elevated protein concentration, and a normal glucose. HHV-7 DNA was amplified from CSF by PCR.
Serologic studies were also consistent with acute HHV-7 infection. Virus was not cultured from either
blood or CSF, and serum PCR studies, in contrast to those in CSF, were negative.
Epstein-Barr Virus
Neurologic complications of Epstein-Barr virus (EBV) infection have been estimated to occur in 1% to
5% of patients with severe infectious mononucleosis (90). EBV-associated neurologic disease can also
occur in the absence of, or even precede, symptoms of infectious mononucleosis (91,92). CNS and
peripheral nervous system manifestations of EBV infection include meningoencephalitis, cerebellitis,
Guillain-Barré syndrome, and TVM. The spinal cord manifestations of EBV infection are generally
considered among the more unusual neurologic complications of EBV infection, although exact data about
their frequency are not available (91–95). Many cases of EBV myelitis have occurred in apparently
immunocompetent individuals and often present as a meningoencephalomyeloradiculopathy (96,97).
Isolated reports of myelitis in immunocompromised patients, including a case in a bone marrow transplant
recipient, have appeared (98).
TVM typically develops 1 to 2 weeks after the onset of infectious mononucleosis. It is important to
recognize that the symptoms of mononucleosis may be mild (e.g., pharyngitis alone). Patients present with
flaccid weakness with absent or decreased reflexes (91,92,98–101). Most patients have a sensory level,
often associated with some radicular sensory signs and symptoms. Urinary retention is common (101).
Less typically, the acute onset of paraparesis or tetraparesis is associated with spasticity, hyperreflexia,
and extensor-plantar reflexes (91). A more indolent course in which weakness is preceded by back pain
and radicular sensory symptoms has also been reported (91). A lower motor neuron pattern of asymmetric
flaccid weakness resembling poliomyelitis can occur with absence of associated sensory or bladder
symptoms (102).
In some patients, even though myelitis is the dominant feature, associated radicular and encephalitic
symptoms coexist, and the syndrome has been referred to as encephalomyeloradiculopathy (103),
encephalomyelitis (101), meningoencephalomyelitis, meningomyeloradiculitis, and
encephaloradiculitis (96). When signs and symptoms suggesting involvement of multiple areas of the
CNS occur, they can appear concomitantly (98) or sequentially (104). One reported patient had
associated bilateral optic neuritis, suggestive of Devic disease (neuromyelitis optica [NMO]) (99).
Spinal MRI in EBV myelitis typically shows an area of increased intramedullary T2-weighted and
decreased T1-weighted signal with enhancement of the lesion and adjacent meninges after administration
of gadolinium (91,96,98,99,101). The affected area of the spinal cord may appear widened or swollen
(91,98). Nerve root enhancement has also been noted in patients with myeloradiculitis (96). A patient
who presented with a poliomyelitis-like syndrome had no abnormal intramedullary signal but did show
meningeal enhancement around the cauda equina (102). Myelitis can occur with a normal MRI scan
(93,103).
In patients with a prominent radicular component, results of clinical electrophysiologic tests may be
abnormal with prolonged F-wave latencies on electromyography (EMG) and increased spontaneous
activity consistent with denervation (100–102). Laboratory studies can provide clues to the diagnosis.
Complete blood cell count may show lymphocytosis and atypical lymphocytes (93). The presence of
significant numbers of atypical lymphocytes in blood or CSF should prompt consideration of EBV
infection but can occur with other infections (101). Older serologic tests, including the heterophil
antibody test (the Paul-Bunnell test), have been largely replaced by commercial spot and slides tests (e.g.,
Monospot test) to detect heterophil antigens. It is important to recognize that heterophil tests are often
negative in patients with EBV-associated TVM (91,92). Serologic tests measuring antibodies against
distinct virus-specific antigens, including the viral capsid antigens (VCAs), early antigens (EAs), and
Epstein-Barr nuclear antigen (EBNA), provide more sensitive and specific confirmation of diagnosis.
Serodiagnosis of EBV infection is made by demonstrating serum IgM VCA, which is generally present
acutely then declines over 1 to 3 months (99). Detection of IgM antibodies to VCA is both sensitive and
specific for diagnosis of recent EBV infection and can be found in about 90% of patients. The presence of
IgG antibodies to VCA, IgG antibodies to EA, and no antibodies to EBNA in convalescent sera provides
evidence of recent EBV infection (91,92,99). A fourfold increase in titer of anti-VCA IgG antibody
between acute and convalescent sera is also presumptive evidence of acute infection. However, IgG VCA
antibody titers are often elevated in the acute sera, and seroconversion is demonstrable only in a few
patients (about 10% to 20%). IgG VCA and EBNA antibodies can persist for life, and their presence, in
the absence of other serologic signs of acute infection, reflect past rather than active infection. In rare
cases, seroconversion may be delayed for up to 2 months after onset of illness (92), further complicating
diagnosis.
In patients with EBV myelitis, the CSF typically shows a mild lymphocytic pleocytosis (25 to 500
cells), mildly elevated protein concentration, and normal or mildly depressed glucose concentration
(91,93,98,99,101–104). EBV can be cultured from oropharyngeal washings and circulating lymphocytes
in patients with infectious mononucleosis. However, virus is only rarely isolated from CSF in patients
with neurologic disease (105), although EBV DNA has been amplified from brain tissue by PCR
(106,107). Virus may be shed by asymptomatic patients or as a result of reactivation induced during other
diseases which limits the specificity of culture. In patients with serologic evidence of systemic EBV
infection, CSF studies can assist in definitively establishing the presence of associated CNS infection.
Demonstration of EBV IgM VCA antibodies in CSF provides evidence of intrathecal antibody synthesis
and presumptive evidence of associated CNS infection (99). Sequential studies of CSF EBV-specific IgM
have only rarely been performed. In one reported case, CSF IgM was detected at 2 weeks after onset, was
equivocal at 4 weeks, and absent at 8 weeks (99). Intrathecal synthesis of IgG antibodies can be
demonstrated by measuring concomitant CSF and serum IgG VCA levels and correcting for CSF/serum
albumin ratio (96,104). Amplification of EBV DNA by PCR from CSF provides strong evidence of CNS
infection (93,96,98,101,102,104), although cases with negative CSF PCR and positive serology results
have been reported (91,103). The duration for which PCR-amplifiable EBV DNA persists in CSF is
unknown, although one immunocompromised patient treated with ganciclovir and hyperimmunoglobulin
was PCR positive after 1 month but became PCR negative at 2 months after onset of symptoms (98). A
second patient was found to have positive CSF PCRs at 1 and 4 weeks postinfection, with a negative
result at 7 weeks postinfection (108). Semiquantitative PCR can be used to evaluate EBV genome copy
numbers in different forms of EBV infection, including CNS disease, and to a more limited degree to
evaluate the effects of therapy (109,110) Genome copy number has generally been in the range of 500 to
2,000 copies/mL, although one immunocompromised patient had 100,000 copies/mL (98,110). PCR and
antibody tests should be considered complementary, with nucleic acid frequently detected acutely and
then clearing over approximately the first 2 weeks, and antibody production appearing after the first week
or two of infection.
Acyclovir inhibits EBV replication and viral shedding but does not significantly reduce clinical
symptomatology associated with uncomplicated infectious mononucleosis (90). Studies of the effects of
antiviral therapy in EBV myelitis are anecdotal, and no controlled clinical trials have been performed.
Intravenous acyclovir (10 mg/kg three times a day for 14 to 21 days) has been associated with clinical
improvement in some patients (93,101). Whereas ganciclovir is more active in cell culture against EBV
than acyclovir, only anecdotal experience exists. A 16-year-old boy who developed TVM following a
bone marrow transplantation was successfully treated with a combination of ganciclovir (10 mg/kg per
day intravenously for 4 weeks followed by 60 mg/kg per day orally for 4 weeks) and CMV
hyperimmunoglobulin (400 mg/kg three times a week for 1 month then twice weekly for an additional
month) (98). The role of steroids as adjunctive treatment in EBV infections remains controversial,
although their use has been advocated for “severe” complications of infectious mononucleosis. In one
multicenter double-blind controlled trial, the use of steroids in uncomplicated infectious mononucleosis
was without clinical benefit and increased the risk of cardiac and neurologic complications (90,111).
However, steroids, in combination with acyclovir, have been used in individual cases of EBV myelitis,
and some patients have experienced rapid improvement after their institution (91). Doses have been
extremely variable, with one typical regimen using intravenous methylprednisolone (1,000 mg every 12
hours for 7 days) followed by prednisone (60 mg per day) for an additional week followed by a tapering
dose over several months (91). Although studies are limited to isolated cases, some reports indicate that
the number of genomic copies of EBV in CSF declines with antiviral therapy (109).
Pathologic studies of fatal cases of EBV-associated myelitis are extremely limited. In some patients,
both anterior horn cell degeneration and inflammatory infiltration of nerve roots have been described
(100). Clear prognostic information is difficult to obtain because of the paucity of reported cases. Many
patients make a significant recovery, although mild residual weakness and sensory loss often persist (91).
Other patients have improved to a more modest degree, with substantial residual weakness and
hyperreflexia (92,93,96).
Herpesvirus simiae (Monkey B Virus, Cercopithecine Herpesvirus-1)
B virus is considered at length in Chapter 14 and is not further discussed here.
PICORNAVIRUSES (POLIO AND OTHER ENTEROVIRUSES)

Poliovirus infection was previously the world’s most common cause of acute flaccid paralysis. In 1988,
an estimated 350,000 cases of polio occurred worldwide in 125 countries. In 1988, the Global Polio
Eradication Initiative was launched by the World Health Organization (WHO). Thanks to an aggressive
campaign of immunization, the number of cases of wild type (non–vaccine-associated) polio has declined
by more than 99.8% worldwide. In 2013 (through 10 December), 359 cases of poliovirus have been
reported and all were due to serotype 1 viruses. The cases have occurred predominantly in countries with
ongoing civil strife and weakened governmental and public health institutions including Somalia (183),
Pakistan (74), Nigeria (50), Syria (17), Kenya (14), Afghanistan (11), Ethiopia (6), and Cameroon (4). In
1994, the WHO was able to certify the region of the Americas as “polio free,” followed by the western
Pacific region in 2000, and the European region in 2002 (www.polioeradication.org). The last known
case of indigenous wild type polio infection in the Western Hemisphere occurred in Peru in 1991 (112).
Given the reemergence of poliovirus in countries of previous eradication, the American Academy of
Pediatrics recommends continued vigilance in the United States to maintain vaccination with the
inactivated poliovirus vaccine (113). A few cases of poliomyelitis still occur in several countries in
association with the use of the live attenuated (“Sabin”) polio vaccine (114). In 2002, 13 such cases, all
from countries in Africa, were reported to the WHO. Vaccine-associated poliomyelitis can occur at a rate
of 1 in 2.7 million vaccines in either vaccinated individuals, nonimmunized, or incompletely immunized
individuals exposed to circulating vaccine strain viruses and often is associated with an undiagnosed
immune deficiency (115). A recent case of vaccine-derived poliomyelitis infection was recently
described in a 44-year-old woman with common variable immune deficiency that was infected when her
child was immunized 11.9 years earlier with type 2 vaccine-derived poliovirus (116). In some cases, low
vaccine coverage is associated with mosaic recombinant poliovirus lineages that include genetically
distinct vaccine-derived strains of poliovirus (117). An outbreak of vaccine-associated poliomyelitis
occurred in children in the Dominican Republic and Haiti in 2000/2001 and involved 21 confirmed cases,
with two fatalities (118). All the affected individuals were unvaccinated or incompletely vaccinated, with
disease being caused by a derivative of the poliovirus type 1 oral vaccine strain.
Ninety percent to ninety-five percent of patients infected during an epidemic with poliovirus remain
asymptomatic. A small percentage (4% to 8%) develop a “minor illness” lasting 1 to 4 days and
characterized by pharyngitis, gastrointestinal symptoms, fever, malaise, and headache. This corresponds
to the period during which virus is replicating in the nasopharynx and gastrointestinal tract (119). Only
approximately 1% to 2% of individuals develop neurologic signs and symptoms (“major illness”). Major
illness typically begins with fever, malaise, and headache, followed within 24 hours by signs of
meningeal irritation indistinguishable from other forms of viral meningitis. Within 2 to 5 days of onset of
meningitis, weakness appears, often associated with muscle pain and tenderness. Infection may
predominantly involve the spinal cord (spinal poliomyelitis), brainstem (bulbar poliomyelitis), or
cerebrum (polioencephalitis). Spinal poliomyelitis accounts for 66% to 75% of neurologic cases (120).
Weakness manifests as a flaccid areflexic paralysis, which is typically more severe proximally than
distally, affects the legs more severely than the arms, is asymmetric, and progresses for 3 to 5 days after
onset. Atrophy appears rapidly, usually within 5 to 7 days, and can progress over several weeks.
CSF studies show a lymphocytic pleocytosis, normal or mildly elevated protein concentration, and
normal glucose concentration (120). More than 90% of patients have 20 to 300 cells/mm3. During the first
72 hours, PMN cells may predominate, but they are subsequently replaced by lymphocytes. The results of
electrophysiologic tests are consistent with an anterior horn cell process and include reduced amplitudes
of compound muscle action potentials (CMAPs) with normal sensory amplitudes and no significant
alteration in conduction velocity beyond that explained by the degree of axonal loss. MRI studies in
classic polio have only rarely been reported but show increased T2-weighted signal in the substantia
nigra and spinal cord anterior horns and cord swelling (121,122).
The pathologic substrate of spinal poliomyelitis is injury predominantly affecting the motor neurons of
the anterior horns (120). Injury is typically more severe in the lumbar and cervical enlargements and can
extend transversely to involve the posterior and intermediate horns, intermediolateral cell column, and
even dorsal root ganglia.
Diagnosis is similar to that of other enteroviruses (EVs) and can be made based on virus isolation,
amplification of viral RNA, or serologic studies. Stool cultures have the highest yield for isolation of
virus and are often positive for weeks to months after onset of illness. Amplification of viral RNA from
CSF by reverse transcriptase PCR (RT-PCR), using the generally available “EV” probes, confirms the
presence of an “EV,” but not specifically polio. Poliovirus-specific primers for RT-PCR are available but
are not generally used by hospital diagnostic laboratories. A fourfold increase in poliovirus-specific
neutralizing or complement-fixing antibody in serum confirms diagnosis.
There is no specific treatment for spinal poliomyelitis. The experimental antiviral agent pleconaril is
unfortunately not currently available from the manufacturer (ViroPharma) but was of benefit in treatment
of two of three patients with vaccine-associated paralytic poliomyelitis in an uncontrolled open-label
study (123). Pleconaril acts by integrating into a hydrophobic pocket on the capsid of picornaviruses such
as polio and thereby inhibiting both viral uncoating and receptor binding (123). Vaccination using either
the inactivated Salk or live attenuated Sabin vaccines or a combination of both provides effective
protective immunity and has been the mainstay of the worldwide poliovirus eradication campaign.
Mortality from poliomyelitis was about 8% in the last prevaccination polio epidemics in the United
States, with deaths occurring predominantly in patients with bulbar or encephalitic forms of the disease.
Patients with spinal poliomyelitis rarely die. Most patients with weakness show some improvement
within the first several weeks after onset, with 60% of eventual recovery being achieved by 3 months and
80% by 6 months (124).
Twenty-nine percent to sixty-five percent of patients surviving paralytic poliomyelitis will
subsequently experience new onset of fatigue, weakness, and increasing muscle atrophy decades after
recovery from their initial illness, termed the postpolio syndrome (125,126). The most common
symptoms of postpolio syndrome include generalized fatigue (62% to 89%), weakness in previously
affected muscles (54% to 87%), weakness in previously unaffected muscles (33% to 77%), myalgia
(39% to 80%), and increasing atrophy (28% to 39%) (125,127). Some patients experience new
respiratory insufficiency, bulbar dysfunction, or sleep apnea (125).
The pathogenesis of postpolio syndrome remains unknown and some aspects remain controversial
(125,127). There is no known therapy for postpolio syndrome that has been shown to be of efficacy in
randomized controlled trials (128).
Nonpolio Enteroviruses
Rare cases of myelitis due to EVs other than poliovirus have been reported. Most cases have been
attributed to coxsackievirus A7, A9 (129), B1, B3, and B4 (130–133); ECHO virus types 2, 5, 11, 18, 19,
and 25 (134–139); and EV type 71 (see later discussion). Most patients have been immunocompetent,
although myelitis has been described in a patient with X-linked agammaglobulinemia (132). The clinical
syndrome can be indistinguishable from that caused by poliovirus. Most patients have asymmetric muscle
weakness, usually involving the legs. The deep tendon reflexes are diminished or absent, and muscle tone
is decreased or flaccid. Weakness can occur with dramatic suddenness, even evolving over several hours.
Sensory abnormalities are not present in classic “poliomyelitis.” In patients with TVM, the typical picture
is of a flaccid paralysis either with decreased or absent or less commonly with increased deep tendon
reflexes combined with the presence of a sensory level, urinary retention, and in some cases decreased
anal sphincter tone (129,134,135,139).
Because of their rarity, laboratory studies of patients with nonpolio EV myelitis are limited. CSF
usually shows a mild lymphocytic pleocytosis with normal or mildly elevated protein and normal glucose
concentrations (129,137), although cases with entirely normal CSF parameters occur (131,132).
Electrophysiologic studies do not distinguish between anterior horn cell disease and a motor axonopathy.
In both cases, there is evidence of denervation and reduction in amplitude of CMAPs with preserved
conduction velocities and normal sensory action potentials (132). MRI can show areas of increased T2-
weighted signal predominantly localized to the gray matter (121,131), although studies may also be
normal (129,132). In addition to abnormal intramedullary signal, some patients have cord swelling and
gadolinium enhancement of affected areas on T1-weighted images (139).
Diagnosis depends on amplification of enteroviral RNA from CSF by RT-PCR (132), isolation of virus
from CSF (129,132), or demonstration of a more than fourfold increase in specific antibody titer between
acute and convalescent sera (129,131). Isolation of virus from throat or stool provides supportive
evidence (137), but because of the potential for viral shedding for up to several months, cultures from
these sites cannot be considered definitive evidence of enteroviral CNS infection.
No controlled trials of therapy are available. As noted earlier, pleconaril, although not currently
available, was reported to be of benefit in two of three treated patients with paralytic poliomyelitis
associated with the polio vaccine (123). In one adult patient with acute flaccid paralysis due to echovirus
19, clinical and laboratory evidence of improvement occurred following combined therapy with
pleconaril and intravenous immune globulin (IVIG) (138).
PCR and in situ PCR (IS-PCR) have been used to search for evidence of enteroviral infection in
patients with amyotrophic lateral sclerosis (ALS). One study reported that 88% of patients with ALS (vs.
3% of controls) had enteroviral nucleic acid detected by IS-PCR in spinal cord specimens. The amplified
RNA had high homology with ECHO virus 7 (140). The same group reported isolating enteroviral RNA
by RT-PCR in 60% of spinal cord specimens from Japanese patients with ALS as compared to 14% of
controls. Amplification of nucleic acid from two cases indicated the sequences had high homology with
ECHO viruses 7, 9, and 30 (141). Unfortunately, these studies have not been confirmed by other
investigators. One important study using real-time RT-PCR failed to detect any ECHO sequences in 20
spinal cord and 10 motor cortex samples from patients with ALS (142). As a result, the evidence linking
enteroviral infection to ALS must be considered unconfirmed and extremely suspect.
Enterovirus-71
EV-71 is endemic worldwide and causes periodic epidemic outbreaks of both hand, foot, and mouth
disease (HFMD) and neurologic illness (143–145). The largest known outbreak to date involved 100,000
to 300,000 cases in Taiwan in 1998 (146,147). A small outbreak of 45 cases of EV-71 infection,
including 7 cases of poliomyelitis-like paralysis, occurred in the United States in 1987 (148). Overall, the
most common CNS manifestations of EV-71 include aseptic meningitis, brainstem encephalitis, and
poliomyelitis-like flaccid paralysis, with children younger than 4 years of age at higher risk for
neurologic complications. Most patients will have a 1- to 7-day prodromal illness that precedes the onset
of neurologic disease. Prodromal symptoms include rash, headache, fever, coryza, and diarrhea.
EV-71 spinal cord involvement can result in either poliomyelitis or TVM (144,145,149–152). In some
patients, spinal cord disease is combined with encephalitis (encephalomyelitis). The frequency of spinal
cord involvement has varied in different outbreaks between 1% and 21% (149,153). Sporadic cases of
EV-71 poliomyelitis-like illness can also occur (148,152).
CSF studies usually show a lymphocytic pleocytosis with normal or slightly elevated protein and
normal glucose concentrations. MRI can show areas of increased T2-weighted signal within the cord,
cord swelling, and increased signal in the ventral roots and in the conus medullaris associated with dorsal
brainstem involvement (154). In patients with poliomyelitis-like illness, increased signal can occur
predominantly in the anterior horns (147,150). Definitive diagnosis depends on isolation of virus from
CSF, amplification of viral nucleic acid from CSF by RT-PCR, or documentation of seroconversion
between acute-phase and convalescent-phase sera. Unfortunately, CSF viral cultures are only rarely
positive. In one recent series, no positive CSF cultures were found among 27 tested patients (146). The
sensitivity of CSF RT-PCR is also uncertain. Virus is isolated from throat and/or stool cultures in only
approximately 20% of patients, but EV-71 RNA can be amplified from these specimens in approximately
50% of patients, suggesting that RT-PCR is more sensitive than culture (146).
No controlled clinical trials of treatment are available. IVIG was without effect in one study (103). The
antiviral drug pleconaril, which has activity against many enteroviral strains, does not have significant
inhibitory activity against EV-71 in vitro but has not been tested clinically in EV-71 myelitis or CNS
infection. It is no longer available in the United States.
Hepatitis A
TVM is a rare complication of hepatitis A infection. All cases reported to date have been in
immunocompetent individuals, including both adults and children (57,155,156). Several patients have had
associated brainstem involvement (57,156). The usual presentation for myelitis is flaccid weakness and a
sensory level (57,155,156). CSF shows a lymphocytic pleocytosis, elevated protein concentration, and
normal glucose concentration (155). Liver function test results are abnormal and can provide an important
clue to diagnosis. MRI studies are limited, but in one report, increased T2-weighted signal was noted in
the cervical cord in association with cord swelling (155). Diagnosis depends on demonstration of
seroconversion (155).
ARBOVIRUSES
West Nile Virus
West Nile virus (WNV) is an arbovirus belonging to the Flaviviridae family and the Japanese encephalitis
(JE) virus serocomplex, a group that includes JE, St. Louis encephalitis, and Murray Valley viruses. WNV
was identified as the cause of a cluster of encephalitis cases in New York City in August, 1999 (157).
This marked the first emergence of this virus as a cause of encephalitis in the Western Hemisphere,
although major outbreaks of WNV encephalitis had occurred in Romania (1996), Russia (1999), and
Israel (2000) (158). The geographic distribution of the virus spread progressively across the United
States and now causes annual epidemic outbreaks of neuroinvasive viral infection throughout the United
States. In 2013 (through 3 December), 2,318 cases of WNV were reported to the Centers for Disease
Control and Prevention (CDC), including 1,171 cases of neuroinvasive disease and 105 deaths
(http://www.cdc.gov/westnile/statsMaps/). Serosurveys following the initial outbreak in New York
suggest that asymptomatic cases outnumber symptomatic ones by about 150:1. Symptomatic disease can
take the form of West Nile fever, aseptic meningitis, meningoencephalitis with or without weakness, or
acute flaccid paralysis. In the initial New York outbreak, 63% had encephalitis, 29% aseptic meningitis,
and 8% fever and headache alone (158). Encephalitis occurred predominantly in older individuals. One
of the striking features in encephalitis cases was the presence of weakness in 32%, flaccid paralysis in
11%, and 40% of encephalitis cases had hyporeflexia (157).
The pathogenesis of the weakness associated with WNV is multifactorial. Early reports suggested that
some patients had electrophysiologic findings consistent with Guillain-Barré syndrome (159). However,
most cases of weakness following WNV infection are secondary to a poliomyelitis-like syndrome
attributable to WNV-associated injury to anterior horn cells (160–168). Acute flaccid paralysis can vary
in extent from a single limb to tetraparesis in some cases with associated severe respiratory impairment
(160,161,169). Although WNV neuroinvasive infection is much more common in adults and in the elderly
in particular, cases of WNV poliomyelitis are also reported in children (170). Uncommon presentations
of WNV acute flaccid paralysis include isolated upper extremity brachial monoplegia or diplegia as well
as reports of delayed and recurrent limb weakness (171,172).
Patients with WNV-associated myelitis typically have a CSF lymphocytic or PMN pleocytosis with
elevated protein (75 to 234 mg/dL) and normal glucose concentrations (160–163). However, cell counts
were normal in 20% of patients in one series (160,163). When CSF pleocytosis is present, the range has
typically been between 50 and 350 cells/mm3, although counts as high as 2,600 cells/mm3 have been
reported (160). Large studies of MRI changes for WNV myelitis are not available. A recent small study of
17 patients with WNV encephalitis or meningoencephalomyelitis found that 50% of patients had an
abnormal MRI in the deep gray matter or brainstem, and two patients had increased T2 intensity in the
ventral horn of the spinal cord (173). This data is consistent with prior studies showing that 38% of MRIs
were abnormal (162), with one patient exhibiting enhancement of the cauda equina and two patients with
areas of increased T2-weighted signal within the cord as well as abnormal gradient and spin-echo
signals. Electrophysiologic studies in these cases are consistent with injury to anterior horn cells or their
axons and have shown reduced motor amplitudes, from 25% to 50% of normal, with preserved sensory
responses, conduction velocities, and distal latencies. On EMG testing, motor units are normal, but
recruitment is severely reduced (160,162,163).
Pathologic studies on patients with acute poliomyelitis-like flaccid paralysis are limited.
Histopathologic changes reported include acute parenchymal and perivascular inflammatory changes in
the spinal cord with associated loss of anterior horn cells (162,165).
Diagnosis of WNV infection depends predominantly on serology (158). In patients with fever and
neurologic manifestations, diagnosis of WNV CNS infection can be made by (a) detection of anti-WNV
IgM in CSF by capture enzyme-linked immunosorbent assay (ELISA), (b) demonstration of both IgM and
IgG antibody in a single serum sample, (c) detection of WNV RNA in CSF by RT-PCR, or (d) isolation of
virus from CSF, blood, or brain tissue. Of these methods, the CSF IgM assay is the most sensitive and
specific. CSF RT-PCR is highly specific but considerably less sensitive than serology. Serologic cross
reactions can occur with other members of the JE virus serocomplex and can often be distinguished by
performing neutralizing antibody tests. IgM antibodies in both serum and CSF can persist for 6 months or
longer, providing another potential source of confusion in endemic areas (158).
Currently no known effective treatment of WNV infection is available. Both ribavirin and interferon
alpha, alone or in combination, have been utilized in non-controlled studies. A phase I/II randomized
placebo-controlled double-blind trials to evaluate the efficacy of an Israeli IVIG preparation
(Collaborative Antiviral Study Group [CASG210]) and a phase II/III randomized, placebo-controlled,
double-blinded trial to evaluate the safety and efficacy of a humanized monoclonal antibody (MGAWN1)
were both discontinued due to low enrollment.
The prognosis of patients with West Nile flaccid paralysis or poliomyelitis is not fully understood, but
studies suggest that morbidity and mortality are substantial (174). A wide range of presentation and
degrees of limb weakness may occur. In cases of bulbar involvement and acute flaccid paralysis, the
mortality may be as high as 70% (175,176). In general, respiratory failure is associated with fatality rates
greater than 50%. Of patients who survive West Nile flaccid paralysis, most strength recovery occurs in
the first 6 to 8 months following weakness onset. However, initial severity of paralysis does not predict
strength outcome (175,176).
Japanese Encephalitis (B) Virus
JE virus is the most common cause of epidemic viral encephalitis worldwide, typically causing in excess
of 50,000 cases per year. As with other arboviruses, asymptomatic cases outnumber cases of encephalitis
by at least 100:1. The virus is endemic in many parts of Southeast Asia, China, and the Indian
subcontinent. Myelitis can occur in conjunction with encephalitis or more rarely as the predominant
clinical manifestation. Most cases of JE virus myelitis present as a poliomyelitis-like acute flaccid
paralysis, but cases of acute TVM following JE virus infection are also reported (177).
In a survey of 22 cases of acute flaccid paralysis in children occurring in a Vietnamese hospital, 12
(55%) cases were due to JE virus (178). Patients typically presented with a febrile illness followed by
acute onset of asymmetric areflexic weakness, typically involving legs more than arms. Seven of twelve
patients had associated acute urinary retention. Muscle pains in the affected limbs, back stiffness, and
nuchal rigidity were common. Respiratory tract muscle involvement leading to respiratory failure
occurred in one third of patients. Two patients had findings suggestive of associated brainstem
involvement. Objective sensory findings did not occur in this series, although two patients had sensory
symptoms. Patients typically had a CSF lymphocytic pleocytosis with normal or mildly elevated protein
concentration and normal glucose concentration. Electrophysiologic studies in patients with distal
weakness typically showed reduced amplitude of motor action potentials with normal conduction
velocities and distal latencies, although study results were often normal in patients without distal
weakness.
Diagnosis of JE virus infection depends on demonstration of anti–JE virus IgG antibodies in serum.
Detection of CSF anti–JE virus IgM is a specific marker of CNS disease, because CSF IgM antibodies do
not occur in asymptomatic individuals. CSF PCR can be performed by the CDC, and if positive also
allows for definitive diagnosis of neurologic disease.
No specific therapy for JEV myelitis is available. An effective formalin-inactivated JEV vaccine has
been available since the early 1950s. Neurologic complications following vaccination for JE virus are
rare. Three cases of myelitis associated with the formalin-inactivated killed vaccine have been reported
(179–182). These patients typically present 1 to 2 weeks after vaccination with a TVM. Typical
symptoms include paraparesis, a sensory level, and urinary retention. Weakness is usually initially flaccid
and associated with hyporeflexia or areflexia. CSF studies typically show a pleocytosis with elevated
protein concentration. One patient had a PMN predominance (950 cells/mm3, 90% PMN). Elevated CSF
myelin basic protein has been detected in several patients (180,182). MRI scan can show cord swelling,
with areas of high T2-weighted and reduced T1-weighted signal with associated gadolinium enhancement
(179,180,182). Two patients improved dramatically after intravenous or oral steroid treatment (180,182).
Tick-Borne Encephalitis Virus
Tick-borne encephalitis (TBE) virus is another member of the family Flaviviridae. Human infection can
occur either from exposure to the virus-carrying tick vector or from ingestion of raw milk or cheese from
infected goats, sheep, or cows. Illness is often biphasic, with neurologic symptoms appearing following
an acute febrile illness and defervescence followed by recurrent fever associated with possible
neurologic symptoms. Asymmetric paralysis of single or multiple limbs commonly occurs in conjunction
with meningoencephalitis, but myelitis can also occur as the predominant presentation of infection with
either Central European TBE virus or Russian spring-summer encephalitis virus. The most common
myelitic presentation is an acute flaccid paralysis resembling paralytic poliomyelitis (183–185).
Diagnosis is made by demonstration of specific IgM antibody in serum or CSF. No specific therapy is
available, although immune globulin has been utilized in non-controlled trials (186). Rare cases of
myelitis have also occurred following vaccination against TBE virus (187). Symptoms develop days to a
few weeks following immunization and usually take the form of a TVM with weakness, a sensory level,
and urinary retention. Although patients may initially have a flaccid paralysis with hyporeflexia or
areflexia, this usually evolves into a hyperreflexic spastic paralysis with extensor-plantar responses
(187). MRI has been reported to show increased T2-weighted signal within the spinal cord (187). One
patient improved following immunosuppressive therapy with cyclophosphamide (187).
ORTHOMYXOVIRUSES AND PARAMYXOVIRUSES

(INFLUENZA, MEASLES, AND MUMPS)
Myelitis has been reported as a rare complication of influenza A infection (188,189). Patients typically
present with initial respiratory symptoms and fever. Myelitis manifests as weakness usually with
depressed or absent deep tendon reflexes, although extensor-plantar responses may be present (189).
Cases of TVM associated with H1N1 infection were recently reported (190). One case of TVM was
reported following vaccination with the H1N1 live attenuated influenza vaccine; but it was unclear
whether TVM was vaccine-related or a consequence of a concomitant mycoplasma infection (191,192).
One reported case of influenza myelitis progressed to complete tetraparesis with associated dysarthria
and dysphagia (189). CSF shows a pleocytosis with elevated protein and normal glucose concentrations.
MRI of the spinal cord shows cord swelling with intramedullary increased T2- and decreased T1-
weighted signal (189). Diagnosis of influenza myelitis is based on serology. Demonstration of intrathecal
synthesis of antibody against influenza A provides strong supportive evidence for direct CNS viral
infection (193). TVM has also been reported as a complication of seasonal influenza vaccination (193).
MRI in one patient showed fusiform cord enlargement and increased intramedullary T2-weighted signal,
but no gadolinium enhancement on T1-weighted images. Recovery from vaccine-associated myelitis can
be complete.
Isolated cases of myelitis have been reported in association with both wild type rubella (164,165) and
the live attenuated vaccine strain (194), measles (195), and mumps (196).
OTHER VIRUSES
Isolated examples of myelitis caused by other viruses include lymphocytic choriomeningitis virus,
adenovirus, parvovirus B19, and hepatitis B (197–203).
TRANSVERSE MYELITIS
TVM is an anatomic diagnosis that refers to a focal inflammatory disorder of the spinal cord (“myelitis”)
that affects motor, sensory, and autonomic pathways (hence, “transverse”) (204–208). In adults, the
incidence of TVM ranges from 1.3 to 8 cases per million population with a bimodal peak in incidence at
ages 10 to 19 years and 30 to 39 years (209–213). As noted earlier, TVM can be caused by viral
infections. It can also occur after an infection or vaccination and is likely due to a postinfectious or
parainfectious immune-mediated response. The general term TVM should be reserved for those patients in
whom no specific etiology is identified. When a specific etiology is known, this is best included in the
designation (e.g., EBV TVM).
TVM may selectively involve the conus and epiconus of the spinal cord (214). A progressive
myelopathy with evidence of spinal cord necrosis with features resembling Devic disease (NMO) may
occur (215,216). “Relapsing” forms of TVM have also been described (217); distinguishing these cases
from predominantly spinal forms of relapsing-remitting multiple sclerosis is problematic. Finally, a
subset of patients with a dominant clinical picture of TVM with encephalitic and/or radicular signs and
symptoms (“encephalomyeloradiculopathy”) has been reported (218).
Patients develop weakness typically maximal in the legs with 50% progressing to complete paraplegia.
Virtually all patients have sensory signs and symptoms including paresthesias, numbness, or
radicular/bandlike dysesthesias (2). Most will have an associated sensory level. Autonomic symptoms
are variable and can include constipation, bowel or bladder incontinence, and voiding difficulties,
particularly urinary retention (2). Deficits can develop in as little as 4 hours, although in most patients,
progression occurs over days to several weeks. Patients who take more than 1 month to progress to
maximum deficit are unlikely to have TVM. Most patients will have a CSF pleocytosis, and it has been
suggested that evidence of spinal cord inflammation, as documented either by CSF pleocytosis, by
abnormal IgG index, or by gadolinium-enhancing lesions, should be part of the diagnostic criteria for
TVM (2).
Diagnosis of TVM depends on clinical features and supportive laboratory study results. In most
patients, abnormalities of central motor conduction time are more frequently encountered than abnormal
sensory evoked potentials, although both are abnormal in more than 75% of patients. Findings related to
the caudal region of the cord are typically more severe than those in the cervical region, although these
changes vary depending on clinical presentation. Spinal MRI is abnormal in approximately 90% of
patients (219–221). Common findings include an area of increased T2-weighted signal hyperintensity in
the central region of the cord, occupying two thirds or more of the cord’s cross-sectional area and often
extending for several segments (219,222). Swelling of the cord occurs in approximately 50% of patients
(219). MRI examination of the brain can be extremely helpful in identifying multifocal demyelination
suggestive of either ADEM or multiple sclerosis. CSF oligoclonal bands are also strongly suggestive of
multiple sclerosis. The presence of antibodies directed against the aquaporin-4 water channel is generally
diagnostic of NMO or NMO-like illness and are not a feature of idiopathic TVM.
There is no definitive evidence from well-designed clinical trials that an effective therapy for TVM
exists. Most studies have suffered from design flaws including lack of randomization, blinding, or
appropriate controls. In many cases, the rarity of the disorder has resulted in small sample sizes. In
several trials using historical controls or no controls, treatment with intravenous methylprednisolone
(e.g., 1 g/1.73 m2 per day for 3 to 5 days) followed by oral prednisone (1 mg/kg per day for 2 to 3 weeks)
was felt to shorten the duration of disease and improve outcome (211,223,224). However, in another
recent study using historical controls, treatment with methylprednisolone (500 mg intravenously for 5
days) did not alter outcome (225).
Predictors of prognosis in TVM have been studied (226,227). In one review of 31 patients,
approximately 50% had a good outcome (Barthel score ≥12) at 6 months. In a recent review of several
published studies (2), it was estimated that one third of patients recover with few or no sequelae, one
third have moderate sequelae, and one third severe sequelae. The most important predictors of poor
outcome were the initial severity of weakness and evidence of denervation on EMG (225,226). The
presence of detectable 14-3-3 protein in CSF is also associated with a poor outcome (228).
ACKNOWLEDGMENTS
Dr. Tyler is supported by grants from the National Institute of Neurological Disorders and Stroke
(NINDS) (NS076512), National Institute of Allergy and Infectious Diseases (NIAID) (AI01064), the
Department of Veterans Affairs (BX000963), and by the Reuler-Lewin Family Professorship of
Neurology at the University of Colorado Health Sciences Center. Dr. Beckham is supported by the NIAID
U54 AI065357 Rocky Mountain Regional Center of Excellence.
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CHAPTER 22 POSTINFECTIOUS
ENCEPHALOMYELITIS
KAREN L. ROOS AND AUGUSTO MIRAVALLE
Postinfectious encephalomyelitis is an acute monophasic disorder of the central nervous system (CNS)
that occurs within days to weeks of a viral illness or a vaccination. The antecedent viral illness is
typically either an upper respiratory tract infection or a nonspecific febrile illness. In the past, most cases
were associated with the exanthematous diseases (vaccinia, measles, varicella, and rubella) (1). Although
postinfectious encephalomyelitis has a clear temporal relationship with infection or immunization, it is
not the result of primary neural tissue invasion by an organism. Infectious agents are rarely identified or
recovered from neural tissue (2). The disease is instead an immune-mediated disease triggered by an
infectious agent or an immunization.
HISTORY
One of the earliest descriptions of postinfectious encephalitis was recorded in 1790 of a 23-year-old
woman who developed symptoms of encephalitis following smallpox (3). This was followed by reports
of several neurologic disorders following smallpox infection (4). In 1905, a case of encephalitis after the
jennerian cowpox inoculation was reported in France, and another case was observed in the London
Hospital in 1912 (5). The disease was recognized as a well-defined entity in 1922, when 11 fatalities due
to postinfectious encephalitis were reported in Great Britain (4).
Paralysis and encephalitis is a well-known complication of animal brain tissue–derived rabies
vaccine. In developed countries, these have been replaced by the use of commercial tissue culture rabies
vaccines, but animal brain tissue–derived rabies vaccines continue to be used in many areas of the world.
In 1941, Weston Hurst (6) described a syndrome with similar clinical presentation to postinfectious
encephalomyelitis but with a worse prognosis. This entity was characterized by the presence of petechial
hemorrhages around blood vessels, intense numbers of polymorphonuclear leukocytes, perivenular
demyelination, necrosis, and fibrin deposits on pathologic examination. This disease was called acute
hemorrhagic leukoencephalomyelitis (6).
On the basis of the preceding illness, postinfectious encephalomyelitis has also been called
parainfectious, postexanthematous, postvaccinal, and postinfluenzal encephalomyelitis. In reference to
the pathology, this illness is also known as acute disseminated encephalomyelitis (ADEM), perivascular
myelinoclasis, perivenous encephalitis, acute demyelinating encephalomyelitis, immune-mediated or
hyperergic encephalomyelitis, and disseminated vasculomyelinopathy (7). These terms are used
interchangeably.
ETIOLOGY
The incidence of postinfectious encephalomyelitis from different causes has been reported to be between
0.4 and 0.8 per 100,000 of population, with a median age of onset of 4.5 to 7.5 years in pediatric studies
and 33.5 years in a study of adult patients (8). The disease has a seasonal peak in winter and spring,
consistent with its putative infectious etiologies (9,10).
Although postinfectious encephalomyelitis can occur spontaneously, most often it follows a
precipitating event (Table 22.1). As stated, the major preceding event is either a viral infection or a
vaccination. Measles, varicella, rubella, mumps, and influenza A and B viruses have all been associated
with the development of postinfectious encephalomyelitis. The other major inciting event is vaccination,
particularly in cases involving enveloped viruses such as smallpox (vaccinia virus) and rabies. In
addition to viral infection and vaccination, other less common etiologies associated with postinfectious
encephalomyelitis are bacterial infections and autoimmune and hematologic disorders (5,11–33).
Viral Etiologies
Postmeasles encephalomyelitis is the most common CNS complication of measles virus infection, with an
estimated incidence of 1 to 2 in 1,000 cases of measles. The onset of symptoms of postmeasles
encephalomyelitis is variable. Typically, after the rash is fading, fever suddenly returns, associated with
headaches, vomiting, and signs of meningeal irritation. Headache is invariably an early feature and often
relieved by lumbar puncture. If the spinal cord is involved, there is backache, progressive lower
extremity weakness, and urinary retention (13).
Postinfectious encephalomyelitis as a complication of varicella virus infection is rare and occurs in
about 1 in 10,000 cases of chickenpox. The onset of symptoms is usually between 4 and 14 days after the
appearance of the rash, with sudden fever, ataxia, seizures, drowsiness, stupor, and obtundation (13).
Postinfectious encephalomyelitis is thought to occur in approximately 1 out of 5,000 children with
rubella infection. Signs and symptoms of neurologic involvement occur within the first week after the
onset of the rash. The presentation is usually very severe with convulsions and sudden loss of
consciousness. Headache and meningeal signs are also common (13).
Postinfectious encephalomyelitis has been reported in association with hepatitis C virus infection and
as a primary manifestation of human immunodeficiency virus (HIV) infection (14–16).
Vaccination
At present, less than 5% of all postinfectious encephalomyelitis cases follow immunization. Postvaccinal
encephalomyelitis has been associated with immunization for rabies, hepatitis B, influenza, Japanese B
encephalitis, diphtheria/pertussis/tetanus, measles, mumps, rubella, pneumococcus, polio, smallpox, and
varicella (Table 22.1) (34). Postvaccinal encephalomyelitis usually occurs 7 to 14 days after vaccination,
but cases have been reported as early as 1 day and as late as 23 days following vaccination (35). The risk
is usually increased directly with increasing age of primary vaccination after the first year of life (36). In
general, postvaccinal encephalomyelitis occurs more frequently in primary vaccinees than in revaccinees.
Complications in revaccinees occur in individuals who have not been vaccinated for many years, and
therefore react like primary vaccinees, or in individuals who have acquired immunodeficiency disorders
(37). During the 1947 smallpox outbreak in New York City, the reported incidence of postvaccinal
encephalomyelitis was 1 in 100,000 (35). In 1968, 5,594,000 primary smallpox vaccinations and 857,400
revaccinations were given in the United States. The overall incidence of postvaccinal encephalomyelitis
was 2.9 per 1 million primary vaccinations. None of the revaccinees developed postvaccinal
encephalomyelitis. The case-fatality rate of postvaccinal encephalomyelitis between 1959 and 1966 was
approximately 25% in the United States (38) and 30% to 50% in Europe (4,39).
The incidence of encephalitis associated with the live attenuated measles virus vaccine is thought to be
1.16 per 1,000,000 doses, with most cases occurring in the second week after immunization (19).
Postvaccinal encephalomyelitis has been associated with the poliovirus vaccine (19), the Japanese
encephalitis vaccine (20), the tetanus toxoid vaccine (21), and the recombinant hepatitis B vaccine (24).
Other Infectious Agents
Streptococcus pyogenes has been reported as a causative agent of postinfectious encephalomyelitis

associated with acute glomerulonephritis (23). Postinfectious encephalomyelitis has been reported as a
complication of Legionella pneumophila infection (24), following leptospirosis (25), typhoid fever (26),
and in the recovery phase from Rocky Mountain spotted fever (28).
A postmalaria neurologic syndrome has been described, characterized as acute onset of convulsions,
acute confusional state, dysphasia, acute psychosis, tremor, myoclonus, and ataxia in patients recovering
from Plasmodium falciparum malaria. Giemsa-stained smears of peripheral blood must be negative at the
time of symptom onset, distinguishing this syndrome from cerebral malaria, which occurs during
parasitemia. The development of the syndrome can be up to 9 weeks (median, 4 days) from eradication of
the systemic parasitemia (29). Postinfectious encephalomyelitis has been reported as a complication of
Mycoplasma pneumoniae infection (30), after autologous stem cell transplantation (31), and in
association with lupus (32) and autoimmune hemolytic anemia (33). Whether this is simply a chance
association or these diseases have a specific role in the pathogenesis is unclear.
CLINICAL PRESENTATION
The presentation of postinfectious encephalomyelitis is usually characterized by abrupt onset of
neurologic symptoms days to weeks after a viral illness or vaccination. Nevertheless, a clear preceding
infection or vaccination cannot be found in up to one third of children and half of adults presenting with
disease (8,40). In those cases, systemic symptoms, including fever (43% to 52%), headache (45% to
58%), malaise, and myalgias may occur shortly before the appearance of neurologic signs and symptoms
(41).
Because of the widespread involvement of the optic nerves, brain, and spinal cord, postinfectious
encephalomyelitis usually presents as a polysymptomatic, monophasic, multifocal neurologic
demyelinating disease. Obtundation and depressed consciousness, in addition to unilateral or bilateral
long tract signs (85%), acute hemiparesis (76%), and ataxia (59%), are the most common presentations.
Cranial nerve deficits may be present because of involvement of the corticobulbar fibers to the motor
nuclei of the cranial nerves. These signs may be associated with an altered level of consciousness ranging
from lethargy to coma (42). Focal or generalized tonic-clonic seizures and psychosis may also be part of
the initial presentation (43). Postinfectious encephalomyelitis can be distinguished clinically from acute
viral encephalitis by the predominance of subcortical white matter involvement. In contrast, viral
encephalitis usually presents with predominantly cortical features, including confusion, aphasia, and
convulsions. Other common presenting signs and symptoms are listed in Table 22.2. Interestingly,
presenting symptoms may vary in pediatric versus adult-onset postinfectious encephalomyelitis. Motor
deficits can occur in both adult and pediatric cases. However, sensory deficits and
polyradiculoneuropathies are more frequently found in adults, whereas seizures predominate in pediatric
cases.
Even though postinfectious encephalomyelitis usually displays a monophasic disease course, rare cases
of relapsing postinfectious encephalomyelitis have been described. In order to fulfill definition of
“recurrent postinfectious encephalomyelitis,” the second clinical event should occur at least 3 months
from the initial event, without involvement of new clinical areas or magnetic resonance imaging (MRI)
evidence of dissemination in time. It has also been suggested that in order to distinguish recurrent
postinfectious encephalomyelitis from multiple sclerosis (MS), the second event should not occur while
the patients is receiving steroid treatment (44). Multiphasic postinfectious encephalomyelitis is a term
that has been assigned to recurrent postinfectious encephalomyelitis cases where the second event
represents a polysymptomatic presentation with involvement of a different anatomic area. In those cases,
MRI must show new areas of involvement with complete or partial resolution of previous lesions
(10,44). Long-term clinical and imaging follow-up has shown the resolution of lesions with no long-
lasting neurologic impairments in most of these multiphasic cases (41).
There is a long-standing controversy about whether a second episode of postinfectious
encephalomyelitis should be called MS and treated accordingly. As a general rule, patients who develop
clinical evidence of dissemination in space and time along with evidence of chronic demyelination in the
CNS will likely develop MS. The classic scenario is the patient, typically a child, who is diagnosed with
postinfectious encephalomyelitis following a viral infection, recovers, and then after some time develops
recurrent symptoms with or without an antecedent viral infection. Two criteria are helpful in making the
correct diagnosis: (a) The development of new symptoms representing distinct areas of demyelination not
involved in the original episode favors the diagnosis of relapsing-remitting MS, and (b) the appearance of
new lesions on neuroimaging supports the diagnosis of MS (45). It is worth remembering that brain
lesions of MS patients usually increase in size and number during the course of the illness (41). In
addition, chronic MS lesions appear as black holes on T1-weighted images, whereas black holes are not
seen on T1-weighted images in patients with postinfectious encephalomyelitis. As patients recover from
postinfectious encephalomyelitis, there is evidence of complete or partial resolution of lesions on
neuroimaging. Oligoclonal bands should not persist in the cerebrospinal fluid (CSF) of patients with
postinfectious encephalomyelitis, but will either persist or appear over time in the CSF of patients with
MS (41).
Acute hemorrhagic leukoencephalitis is considered a hyperacute form of postinfectious
encephalomyelitis and has been reported to occur in 2% of pediatric cases (46). On physical examination,
there may be meningismus, obtundation, and lethargy, in addition to upper motor neuron signs, brainstem
findings, transverse myelitis, and cranial neuropathies. In general, maximum deficits are reached in the
first week from onset. Recovery usually starts to become clinically evident after the first week, with
complete resolution of deficits and MRI lesions within 3 months (10). Although the prognosis is in
general favorable, as high as 30% of patients require intensive care, with an estimated mortality rate of
20% (10). Despite the neuropathologic differences between postinfectious encephalomyelitis and acute
hemorrhagic leukoencephalitis, it is possible that they represent a gradient of severity of the same
pathologic process.
PATHOGENESIS
The pathology of postinfectious encephalomyelitis can be reproduced in the animal model of experimental
allergic encephalomyelitis. This is a demyelinating disorder of the CNS induced in animals by
immunization with myelin extracts, proteins, or peptides found in myelin. In an effort to reproduce in
animal models the lesions described in postvaccinal encephalomyelitis, Rivers and colleagues (47) in
1933 injected homogenates of normal rabbit brains into monkeys. After 6 months, several monkeys
developed a lymphocytic infiltration and demyelination of the CNS tissue (47).
Experimental allergic encephalomyelitis can be passively transferred to healthy animals by immune
lymphocytes (48). These activated T cells assume a novel functional phenotype after transfer into a
recipient animal that allows them to migrate to the CNS and pass through the blood–brain barrier. This
migration briefly precedes the onset of clinical experimental allergic encephalomyelitis. There is a
minimal interval of 3 days between the intravenous administration of pathogenic T cells and the onset of
clinical experimental allergic encephalomyelitis (49).
T cells can potentially react with a wide variety of molecular structures, but normally they do not react
against self-antigens. However, some encephalitogenic CD4 and CD8 T lymphocytes can be found in the
blood, thymus, and secondary lymphoid tissues of apparently healthy individuals, but through the action of
suppressive cytokines, they usually do not attack the CNS. T cells become pathogenic only if activated.
One possible scenario to explain the development of postinfectious encephalomyelitis is that an infecting
microbe expresses a peptide that is structurally similar to myelin basic protein (MBP). This epitope can
trigger the activation of self-reactive T cells by a mechanism known as molecular mimicry. Once
activated, these cells can multiply and mature into effector T cells, producing mediators and cytokines that
can react to normal self-antigens. In addition, some T cells express more than one specific antigen
receptor. One receptor type could be specific for the myelin antigen and the other for the microbial
antigen. Exposure to the microbial antigen could activate the T cell, which by virtue of its myelin-specific
alternative receptor could attack the CNS (49).
Another mechanism proposed to explain the pathogenesis of postinfectious encephalomyelitis is the
activation of self-reactive immune cells by the release of cytokines by virus-mediated death of host cells.
Penetration of these self-reactive immune cells into the brain or spinal cord leads to the characteristic
pathology of postinfectious encephalomyelitis.
The role of circulating humoral factors in the pathogenesis of postinfectious encephalomyelitis is still
unclear, but several lines of evidence suggest that antibody production by the host may aid in limiting or
preventing the disease presumably by binding to MBP and inhibiting the access of autoreactive T
lymphocytes. Prostaglandins of the E series secreted by blood monocytes and cerebral glial cells inhibit
the immune response in experimental allergic encephalomyelitis by downregulation of monocytes and T
cells and reduce the clinical and histologic abnormalities of experimental allergic encephalomyelitis in
rats (12).
DIAGNOSIS
The diagnosis of postinfectious encephalomyelitis is based on clinical history, the findings on neurologic
examination, neuroimaging abnormalities of demyelination, and CSF analysis. Several attempts have been
made to establish a series of clinical features that will increase the likelihood of the diagnosis of
postinfectious encephalomyelitis. The International Pediatric Multiple Sclerosis Study Group has
developed a series of criteria for the diagnosis of postinfectious encephalomyelitis (Table 22.3). These
criteria have been developed based on selected review of the literature and expert panel discussion. The
specificity, sensitivity, and biologic validity to the diagnosis of postinfectious encephalomyelitis when
using these guidelines have not been evaluated to date.
Due to the broad spectrum of differential diagnosis in patients presenting with a monophasic
demyelinating CNS disorder (Table 22.4), the diagnosis of postinfectious encephalomyelitis usually
requires a comprehensive, thorough investigation. The most common disorders in the differential
diagnosis are MS (both pediatric as well as adult presentation), viral encephalitis, transverse myelitis,
and neuromyelitis optica. Common symptoms of MS are listed in Table 22.5. Other disorders including
CNS infections, neurometabolic CNS disorders (including mitochondrial disorders), neurosarcoidosis,
systemic lupus erythematosus, primary CNS angiitis, NMO, anti-N-methyl-D-aspartate-receptor (anti-
NMDA) encephalitis, chronic lymphocytic inflammation with pontine perivascular enhancement
responsive to steroids (CLIPPERS), Bickerstaff encephalitis, and CNS malignancies should be
considered.
Imaging
The typical computed tomography findings are areas of disseminated hypoattenuation in the subcortical
white matter of the brain that enhance after the administration of contrast (35). They may or may not be
surrounded by edema. MRI is a useful tool to aid in the diagnosis of postinfectious encephalomyelitis. In
general, patients with postinfectious encephalomyelitis have a higher frequency of large confluent
bilateral symmetrically oriented diffuse T2/fluid-attenuated inversion recovery (FLAIR) high signal
lesions, ventral brainstem lesions, as well as the presence of monophasic pattern of enhancement (Fig.
22.1) (50). T2-weighted and FLAIR MRI scans demonstrate areas of increased signal in the subcortical
white matter, brainstem, cerebellum, and periventricular white matter (43). These may have the
appearance of large globular lesions (Fig. 22.1). Periventricular lesions are less frequently seen in
postinfectious encephalomyelitis than MS, and if present, there is usually homogeneous contrast
enhancement. The lesions are typically bilateral and asymmetric, vary in size and number, and could
enhance in a nodular, spotty, ring, or heterogeneous pattern after the administration of intravenous
gadolinium. There may be lesions in gray matter as well. Involvement of the deep gray matter may help
distinguish postinfectious encephalomyelitis from MS (43). More advanced imaging techniques, such as
magnetic resonance spectroscopy, have demonstrated elevation of lipids and reduction of the
myoinositol:creatinine ratio during the acute phase, followed by reduction in lipids and increased
myoinositol:creatinine ratios in the chronic setting (51). Fluorodeoxyglucose positron emission
tomography scans usually show marked hypometabolism in the affected areas of the brain (45).
A recent review suggested that the use of Callen MS-ADEM criteria resulted in a high sensitivity
(75%) and specificity (95%) for distinguishing MS at first attack from postinfectious encephalomyelitis
(Table 22.6) (52). The authors also concluded that these MRI-based criteria were predictive of the
diagnosis of MS versus postinfectious encephalomyelitis even in the absence of encephalopathy.
Laboratory Investigations
Given the possible similarities between postinfectious encephalomyelitis and MS, similar laboratory tests
are performed as part of the workup of both conditions. MS is classically diagnosed by multiple lesions
on MRI as well as the presence of oligoclonal IgG bands in the CSF (53). Unfortunately, in the majority of
postinfectious encephalomyelitis cases, there are minor and nonspecific changes that occur that make
diagnosis based on the standard of care laboratory testing difficult. However, there are some
distinguishing features that do differentiate this disease from patients with MS and with healthy controls.
These include elevated levels of total protein concentration (usually above 100 mg/dL) and increased cell
count (usually more than 50 cells/mm3) (54,55). It has been shown that the presence of certain cytokines,
such as tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-8, IL-10, and interferon
(IFN)-γ, are more common in postinfectious encephalomyelitis than MS (56,57). IL-17 has been reported
to be increased in the CSF and blood of MS patients (58,59); however, this is not observed in patients
with postinfectious encephalomyelitis. A study performed measuring 18 different chemokines in the blood
and CSF of patients with suspected postinfectious encephalomyelitis, MS, or healthy controls revealed a
distinct pattern of increased expression of specific chemokines in postinfectious encephalomyelitis
patients not observed in patients with MS or controls. These changes were only observed in the CSF and
not in the blood. Mean concentration of the chemokines (postinfectious encephalomyelitis, MS, healthy
controls) CXCL7 (522 +/− 115 vs. 197 +/− 37 vs. 158 +/− 53), CCL1 (28.7 +/− 6.8, 18.5 +/− 3.4, 10.0
+/− 1.7), CCL22 (75.7 +/− 38.5, 9.4 +/− 1.8, 4.3 +/− 0.8), and CCL17 (18.6 +/− 3.4, 1.8 +/− 0.6, 7.2 +/−
0.6) were distinctly higher in the CSF from postinfectious encephalomyelitis patients. Based on these
data, it may be possible to distinguish postinfectious encephalomyelitis patients from MS patients based
on increased chemokine levels and lack of IL-17. However, more concrete studies will need to be
performed to determine this. In order to facilitate the initial steps in the diagnosis of postinfectious
encephalomyelitis, we propose a list of basic CSF studies that are useful in the differential diagnosis of
postinfectious encephalomyelitis, MS, and viral encephalitis (Table 22.7).
PATHOLOGY
In rare circumstances, pathologic evaluation of involved tissue can assist in the diagnosis. Consistent with
postinfectious encephalomyelitis clinical presentation, focal, perivenous, and subependymal changes
dominate the pathologic pattern. Similar to MS, postinfectious encephalomyelitis lesions are mostly in the
white matter at the cortical–subcortical junction but may also be seen in the cerebellum, spinal cord, and
brainstem (43,60). Contrary to MS, early postinfectious encephalomyelitis involves infiltration of
adaptive immune cells, mostly T lymphocytes, followed by innate monocytic cells. Inflammatory lesions
in postinfectious encephalomyelitis spread radially outward from the vessels, whereas in MS, they border
the plaques (43). Additionally, axons in areas of demyelination are relatively preserved in postinfectious
encephalomyelitis, whereas in MS, there can be significant axonal loss. The major pathologic
distinguishing factor is irregular borders observed in postinfectious encephalomyelitis lesions, whereas
lesions from MS patients exhibit sharp distinct borders. Postinfectious encephalomyelitis is also
distinguished from acute viral encephalitis by its pathology. Postinfectious encephalomyelitis is
predominantly a disease of white matter, but gray matter may also be affected, particularly basal ganglia,
thalami, and brainstem (42). Acute viral encephalitis is predominantly a disease of gray matter. The
lesions characteristic of postinfectious encephalomyelitis are around small veins, in the cerebral white
matter, brainstem, and spinal cord, and are composed of mononuclear cells and lymphocytes. Luxol fast
blue stains that stain myelin reveal well-demarcated areas of loss of myelin. Staining for axons in the
same areas that have loss of myelin reveals that the axon cylinders are relatively preserved. The neurons
in the area show minor changes (4). The degree of the preservation of axon cylinders and the extent of the
involvement of neurons determine prognosis.
The differential diagnosis is that of inflammatory, demyelinating diseases of the CNS. These include MS,
viral encephalitis, transverse myelitis, and neuromyelitis optica (Devic syndrome) as the most common
disorders. Table 22.7 provides a list of CSF studies to determine the etiology. The leading disease in the
differential diagnosis is MS. The first attack of MS can be difficult to differentiate from postinfectious
encephalomyelitis. The specific neurologic symptoms are often very helpful in distinguishing between the
two diseases, as is the history of the onset of symptoms within 2 to 31 days of a viral illness or
vaccination. Although typical of postinfectious encephalomyelitis, a confusional state, headache, a
decreased level of consciousness, and convulsions are also quite atypical of MS. MS is more likely than
postinfectious encephalomyelitis to have a monosymptomatic presentation of optic neuritis, a brainstem
syndrome, a cerebellar syndrome, or a transverse myelitis. The presence of bilateral optic neuritis is
more suggestive of postinfectious encephalomyelitis than MS (41). Although both syndromes are
primarily demyelinating diseases, the lesions of postinfectious encephalomyelitis are larger, more
extensive, homogeneously enhance with contrast, and can involve gray matter, whereas the classic lesions
of MS are ovoid-shaped, may or may not enhance, and usually involve the periventricular white matter,
particularly the trigone and body of the lateral ventricle (41).
The Marburg variant of MS is a fulminant form of MS. Neuroimaging abnormalities may distinguish the
Marburg variant from postinfectious encephalomyelitis, but more often it is the clinical course.
The viral encephalitides that may have a similar presentation and similar neuroimaging and CSF
abnormalities to postinfectious encephalomyelitis include flavivirus infections (Japanese encephalitis
virus, St. Louis encephalitis virus, and West Nile virus), herpesvirus infections (varicella-zoster virus
[VZV], Epstein-Barr virus [EBV], herpes simplex virus [HSV], and other nonserotypable herpesviruses),
progressive multifocal leukoencephalopathy due to JC virus, and HIV encephalitis. Japanese encephalitis
virus classically infects the thalamus, brainstem, basal ganglia, substantia nigra, spinal cord, cerebral
cortex, and cerebellum. The clinical presentation is characterized by fever, vomiting, convulsions, and
coma. During the acute illness, patients may have movement disorders due to lesions in the basal ganglia
and substantia nigra or flaccid paralysis due to lesions in the spinal cord (61,62). Hyperintense lesions on
T2-weighted images in the substantia nigra and thalami can be seen in Japanese encephalitis (61,63). The
diagnosis is made by demonstrating intrathecal production of specific antibodies.
West Nile virus encephalitis presents with fever, headache, and confusion and may have associated
weakness in a “poliomyelitis-like syndrome.” The diagnosis is made by either the demonstration of West
Nile virus nucleic acid in CSF, West Nile virus immunoglobulin M (IgM) antibody in CSF, or a fourfold
increase in serum West Nile virus immunoglobulin G (IgG) antibodies between acute and convalescent
sera.
VZV encephalitis presents with headache, malaise, and confusion days to weeks after the cutaneous
eruption of zoster. The neuroimaging abnormalities of VZV encephalitis can be strikingly similar to those
of postinfectious encephalomyelitis. VZV encephalitis may manifest as spherical subcortical white matter
lesions with the typical appearance of demyelination (64).
In addition, there may be large and small ischemic and hemorrhagic infarctions of the cortical and
subcortical gray and white matter. The diagnosis is made by demonstrating either VZV DNA in CSF, VZV
IgM antibodies in CSF, or a positive CSF viral culture.
EBV may cause a meningoencephalitis during the course of mononucleosis. Following primary
infection, the virus establishes latent infection in the CNS and can reactivate, causing encephalomyelitis.
The clinical presentation includes fever, headache, focal neurologic deficits, an altered level of
consciousness, and convulsions. This is a monophasic illness with neuroimaging evidence of lesions
throughout the CNS. Diagnosis is made by demonstrating EBV DNA in CSF.
HSV-1 may reactivate from latent infection in the trigeminal ganglia and present as a brainstem
encephalitis instead of causing the classic presentation of frontoorbital and temporal lobe dysfunction.
There are also reports of HSV DNA in the CSF of patients with a clinical syndrome of encephalomyelitis
and neuroimaging evidence of multiple hyperintense lesions in the thalamus, corpus striatum, pons, and
deep white matter on T2-weighted MRI scans (65,66). The diagnosis of brainstem encephalitis or
encephalomyelitis due to HSV-1 is made by the demonstration of HSV-1 DNA in CSF by polymerase
chain reaction or by the demonstration of intrathecal production of HSV antibodies.
Progressive multifocal leukoencephalopathy is a demyelinating disease occurring in patients with
severe cellular immunosuppression caused by a reactivation of latent JC virus likely acquired during
childhood. This disease is progressive to death over the course of a few months. HIV patients and patients
receiving immunosuppressive therapies are at higher risk of developing progressive multifocal
leukoencephalopathy (PML). HIV encephalitis occurs in immunosuppressed individuals and presents with
cognitive, motor, and behavioral abnormalities. T2-weighted MRI scans show areas of increased signal
intensity in the subcortical white matter.
Subacute sclerosing panencephalitis (SSPE) is a degenerative disease of the brain due to measles
virus, which presents after a latent period of several years or more from acute measles infection (67).
This disease manifests with visual complaints, behavioral changes, and myoclonic jerks followed by
hemiparesis, cogwheel rigidity, and dementia. There are elevated antibody titers against measles virus in
CSF specimens and histopathologic evidence of extensive demyelination, glial proliferation, and neuronal
and glial intranuclear inclusions (67,68). Although initially this disease may be a consideration in the
differential diagnosis, SSPE is not a monophasic disorder, but a progressive illness.
Transverse myelitis is an inflammatory condition of the spinal cord due to a number of infectious and
autoimmune etiologies. The thoracic cord is most commonly affected. There is a progressive weakness of
lower extremities over the course of several hours to several days. Back pain may be present. Typically,
there is a sensory level and bowel and bladder dysfunction. The maximum deficit is reached by definition
within 4 weeks. Spinal MRI demonstrates swelling of the cord at the level of involvement. Devic
syndrome refers to the combination of optic neuritis and myelitis and is now more commonly referred to
as neuromyelitis optica.
Posttransplantation lymphoproliferative disease and leukoencephalopathies after chemotherapy and
radiotherapy may have neuroimaging abnormalities that resemble those of postinfectious
encephalomyelitis but are distinguished by the clinical setting in which they occur.
TREATMENT AND PREVENTION

Vaccination of infants against measles, mumps, and rubella has had a significant effect on decreasing the
incidence of postinfectious encephalomyelitis caused by these viruses. Despite the inherent risk of acute
neurologic complications following vaccination, the incidence of naturally occurring encephalomyelitis is
still greater.
Currently, the only agent with proven efficacy in the prevention of postvaccinal encephalomyelitis is
antivaccinia γ-globulin (AGG). The first clinical trial to prevent postvaccinal encephalitis was performed
in 1956. At the time of primary smallpox vaccination, 53,630 Dutch military recruits were given an
injection of 2 mL of 16% AGG, and 53,044 were given placebo. The donors of the AGG were healthy
volunteers from the Royal Netherlands Army and the Royal Netherlands Air Force who had recently been
vaccinated. Only 3 cases of postvaccinal encephalitis occurred in the treated group, compared with 13
cases in the control group (69). AGG is not effective in treating postvaccinal encephalitis once this
complication has occurred.
Therapeutic recommendations for postinfectious encephalomyelitis are complicated by the lack of
double-blind placebo-controlled clinical trials and the fact that postinfectious encephalomyelitis
improves spontaneously. Several case series suggest that early high-dose corticosteroid therapy is
beneficial (70,71). Early series used adrenocorticotropic hormone (ACTH) or dexamethasone (1 mg/kg
per day), but recent series use intravenously administered methylprednisolone in a daily dose of 1000 mg
per day for 3 to 5 days based on the experience with treating an acute exacerbation of MS. No firm
guidelines exist on whether intravenously administered methylprednisolone therapy should be followed
by an oral prednisone taper.
A randomized, sham-controlled clinical trial of plasma exchange in patients with either MS (12
patients) or other inflammatory demyelinating disease of the CNS (10 patients) was performed (72). The
10 patients with inflammatory demyelinating disease other than MS had transverse myelitis, ADEM,
neuromyelitis optica, and focal cerebral demyelinating lesions. The patients were randomly assigned to
receive either true or sham plasma exchange every other day for 2 weeks. All patients had a severe
clinical deficit and had failed to improve over a period of 2 weeks from the initiation of high-dose
intravenous corticosteroid therapy. Eight patients who were treated with true plasma exchange
experienced moderate to marked improvement at the end of the 14 days. One patient who was treated with
sham treatment had a moderate to marked improvement (72).
There are a number of case reports on the use of intravenous immune globulin (IVIG) therapy in ADEM
(73–75). The mechanism of action of IVIG is not completely understood, but IVIG contains a wide
spectrum of antibodies that have the potential to bind and neutralize pathogenic antibodies (73). These
antibodies might bind to MBP and inhibit the access of autoreactive T lymphocytes.
In the initial days of the illness, postinfectious encephalomyelitis is often not distinguishable from acute
viral encephalitis. A combination of intravenous acyclovir (10 mg/kg every 8 hours) and intravenous
methylprednisolone (1000 mg per day) can be used until a definitive diagnosis is made. The addition of
IVIG or plasma exchange may be beneficial either in the initial days of therapy or in those patients in
whom a diagnosis of postinfectious encephalomyelitis is established, and the course is progressive
despite intravenous methylprednisolone therapy.
PROGNOSIS
The mortality rate of postmeasles encephalomyelitis is 10% to 20%, and neurologic sequelae occur in
25% of survivors. The prognosis is related to age, with increasing mortality in those older than 16 years,
and with the presence and duration of coma and convulsions (13). The mortality of postvaricella
encephalomyelitis is approximately 10% (13). The mortality rate of postrubella encephalomyelitis was
high, with 20% of children dying during the first week (13). Postinfectious encephalomyelitis in children
that occurs as a complication of an upper respiratory tract infection or nonspecific febrile illness typically
has a favorable prognosis. In adults, however, there are often neurologic sequelae. As described,
prognosis is directly related to the degree of pathologic involvement of neurons and axon cylinders. To
the extent that these are affected by the inflammatory process, there are varying degrees of cognitive
deficits, movement disorders (dystonia), and spasticity. These deficits are often chronic.
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PART III ■ BACTERIAL AND MYCOPLASMAL
INFECTIONS
CHAPTER 23 PATHOGENESIS AND

PATHOPHYSIOLOGY OF BACTERIAL INFECTIONS
PHILIPP AGYEMAN, DENIS GRANDGIRARD, AND STEPHEN L. LEIB
The brain not only is a normally sterile site but also is protected from infection by specialized barriers,
including the bony skull and the WWWblood–brain barrier (BBB). Consequently, infections of the central
nervous system (CNS) in general and bacterial infections of the CNS in particular are comparatively rare.
In the United States, the incidence of bacterial meningitis decreased to 1.38 per 100,000 population in
2007 (1). The incidence of brain abscesses is not known precisely but is estimated to be approximately 1
per 100,000 population (2,3). In contrast, the incidence of severe sepsis in the United States in 2007 was
303 cases per 100,000 population (4).
To establish bacterial CNS infections, pathogens must gain access either to the subarachnoid space (in
the case of meningitis) or to the brain parenchyma (in the case of brain abscess). Many of the complex
processes involved in the transition of pathogens from outside the host into the CNS have been elucidated,
particularly for meningitis. Most cases of bacterial meningitis likely arise from bacteremia, which is
caused by invasion of the bloodstream by the pathogen after colonization of the nasopharyngeal and
intestinal mucosa. Similarly, in the pathogenesis of brain abscess, the hematogenous route is important in
a substantial number of cases. However, the mechanisms by which pathogens gain access to the site of
infection from the bloodstream likely differ substantially between meningitis and brain abscess. This is
suggested by the fact that organisms typically causing bacterial meningitis (e.g., Streptococcus
pneumoniae, Haemophilus influenzae, Neisseria meningitidis) very rarely cause brain abscess, whereas
pathogens typically found in brain abscess (e.g., aerobic and anaerobic Streptococcus species and
Staphylococcus aureus) are rarely the cause of bacterial meningitis. Further elucidation of the molecular
events leading to CNS invasion is likely to allow a better understanding for these differences.
Not all bacterial infections of the CNS are the result of bacteremia. This is most obvious when
bacterial meningitis occurs as a consequence of infection of a cerebrospinal fluid (CSF) shunt or when a
brain abscess results from breaching of the skull and meninges by trauma or a neurosurgical procedure.
Similarly, in patients in whom brain abscess or meningitis originates from a focal infection in the vicinity
of the brain (i.e., sinusitis, otitis media, dental abscess), contiguous spread rather than bacteremia
represents the likely route by which the pathogen gains access to the CNS. Again, the pathogen causing the
focal infection seems to determine whether the secondary infection is meningitis (in the case of S.
pneumoniae or H. influenzae) or brain abscess (in the case of streptococci other than S. pneumoniae),
suggesting pathogen-dependent differences in pathogenesis.
Multiple processes occur from the time a pathogen has reached the site of infection until the full
manifestations of the disease have developed. These include the induction of cytokines and chemokines,
activation of inflammatory mediators such as nitric oxide (NO), reactive oxygen species (ROS), or matrix
metalloproteinases (MMPs), recruitment of white blood cells to the site of infection, and cytotoxic events.
Many of these events have been analyzed in detail in bacterial meningitis, whereas less is known in the
case of brain abscess.
This chapter focuses on the pathogenesis of bacterial meningitis and the subsequent development of
brain damage. Aspects of the pathogenesis of brain abscess are discussed in detail in Chapter 31.
PATHOGENESIS OF BACTERIAL MENINGITIS

The development of bacterial meningitis progresses through four interconnected phases: (a) bacterial
colonization and invasion of the host with subsequent infection of the CNS, (b) bacterial multiplication
and induction of inflammation in the subarachnoid and ventricular space, (c) progression of inflammation
with associated pathophysiologic alterations, and (d) damage to the CNS (Fig. 23.1).
Bacterial Invasion of the Host and Penetration of the Blood–Brain Barrier

Figure 23.2 shows the pathogenic steps involved in the development of bacterial meningitis.
Colonization
Before a meningeal pathogen can cause invasive disease, it has to successfully colonize the host first. S.
pneumoniae, N. meningitidis, and H. influenzae type B, which most frequently cause bacterial meningitis
in humans, colonize the nasopharynx and are transmitted from person to person by the respiratory route.
On the other hand, group B Streptococcus (GBS) (Streptococcus agalactiae), Escherichia coli, and
Listeria monocytogenes, which cause meningitis at the vulnerable extremes of age and in
immunocompromised persons, colonize the gastrointestinal tract and are transmitted through the oral,
vaginal, or fecal-oral route.
Colonization of the nasopharyngeal mucosa is established by evasion of mucosal host defense
mechanisms, for example, ciliary clearance and secretory immunoglobulin A (IgA), successful
competition with other organisms in the aerobic environment of the upper respiratory tract, and adherence
to the mucosal epithelium. Specialized surface components, such as components of the polysaccharide
capsule, or pili, and the production of bacterial enzymes are crucial for the various steps necessary to
establish colonization.
The mucociliary escalator is the main mechanical defense machinery of the respiratory tract. It
constantly propels particles, including bacteria, to the outside. In order to gain access to the mucosa and
establish themselves in the respiratory tract, S. pneumoniae, N. meningitidis, and H. influenzae type B
have to overcome the mucociliary escalator. As exemplified by S. pneumoniae, there are several means
by which bacteria may avoid being trapped and flushed away by mucus. The polysaccharide capsule of S.
pneumoniae is almost exclusively negatively charged. This could increase electrostatic repulsion from
the likewise negatively charged sialic acid residues of mucus (5). Additionally, deglycosylation of mucus
by secreted exoglycosidases (e.g., neuraminidase A [NanA], beta-galactosidase B, etc.) may decrease its
viscosity and lessen entrapment (6). Furthermore, pneumolysin, a major virulence factor of S.
pneumoniae that is released by autolysis, inhibits ciliary beating (7,8). Pneumolysin has been shown to be
necessary for successful colonization of the nasopharynx (9). Ciliostasis has also been documented in H.
influenzae infection (10), whereas nasopharyngeal colonization of N. meningitidis entails cytotoxicity for
ciliated epithelial cells (11).
Besides its mechanical action, respiratory mucus also harbors several soluble antibacterial agents.
Secretory IgA antibodies inhibit microbial adherence and penetration into the mucosa. N. meningitidis, S.
pneumoniae, and H. influenzae, as well as some members of the resident oral flora, secrete highly
specific endopeptidases that cleave the heavy chain of human IgA1, including its secretory form (sIgA1),
thus separating the monomeric antigen-binding fragments (Fab) from the secondary effector functions of
the IgA1 antibody (Fc) (12). IgA1 proteases exist as three different classes of proteinases. IgA1 proteases
of H. influenzae and N. meningitidis are genetically related serine proteinases, those of S. pneumoniae
are metalloproteinases. Cleavage of IgA1 by proteases impairs specific mucosal immunity in the upper
respiratory tract, thus allowing bacteria to colonize. IgA1 proteases may also contribute to the
pathogenesis of invasive infections by leading to the coating of bacteria with Fab fragments, which mask
epitopes and thus protect them from subsequent recognition by intact immunoglobulin (13). Lysozyme is
an important component of the innate immune system and abundantly present in the saliva, airway fluid,
and lysosomal granules of neutrophils. Its muramidase activity leads to hydrolyzation of the bacterial cell
wall polymer peptidoglycan. Modification of peptidoglycan by N-deacetylation and O-acetylation and the
production of lysozyme inhibitors are bacterial strategies to fend off lysozyme action (14). The gene
coding for the enzyme responsible for N-deacetylation, peptidoglycan N-acetylglucosamine deacetylase A
(PdgA), is present in S. pneumoniae and L. monocytogenes (15). Genes encoding for peptidoglycan O-
acetyltransferases have also been found in S. pneumoniae (attenuator of drug resistance [adr]) and N.
meningitidis (peptidoglycan acetylase A [pacA] and pacB) (16). For S. pneumoniae, it has been shown
that expression of PdgA and Adr is necessary to provide lysozyme resistance and provide colonization
advantage in the mouse model (17). Finally, apolactoferrin, the iron-depleted form of lactoferrin, is
bacteriostatic or bactericidal for bacteria. The pneumococcal surface protein A (PspA) protects against
the bactericidal effect of apolactoferrin, probably by binding to the active sites of apolactoferrin (18).
Bacterial adherence to epithelial cells is mediated by adhesins on the bacterial surface binding to
epithelial cell receptors. Based on their structure, fimbrial and afimbrial adhesins can be distinguished in
meningeal pathogens. Fimbriae (or pili) are filamentous structures, first identified in Gram-negative
bacteria, that protrude from the outer cell membrane. Fimbriae are composed of several subunits that form
rodlike structures and carry a specific adhesive subunit at their tip (19,20). Fimbriae have been
associated with the early steps of adhesion mostly, but not exclusively, in Gram-negative meningeal
pathogens. Several afimbrial adhesins have been identified in all meningeal pathogens and will be
discussed with the respective pathogens.
Adherence of pneumococci to mammalian cells and pneumococcal virulence is facilitated by regulated
expression levels of the polysaccharide capsule in a process called phase variation. Capsular phase
variation of S. pneumoniae is marked by changes in colonial morphology from opaque to transparent and
correlates with differences in virulence. The transparent, less capsulated phenotype is more capable of
colonizing the nasopharynx, whereas the opaque phenotype shows increased virulence during systemic
infections (21,22). Masking of underlying adhesion molecules by the polysaccharide capsule is a possible
explanation for the inferior colonization capabilities of opaque strains. Adherence of S. pneumoniae in
itself is thought to involve binding to glycoconjugates on the surface of the respiratory epithelium,
although the exact mechanisms have not been completely elucidated (23). Recognition of these binding
sites is enhanced by cleavage of the terminal sialic acid by NanA and other glycosidases (24,25). Further
putative roles of NanA during the colonization process are its involvement in the formation of biofilm
(26) and competition with other meningeal pathogens (27). A specific function as adhesin has been shown
for the choline-binding protein A (CbpA; also called PspC or SpsA), which binds to the polymeric
immunoglobulin receptor (pIgR) on human mucosal epithelial cells and complement factor H (23).
Importance of CbpA has been demonstrated in an infant rat model where CbpA-deficient pneumococci
were significantly restricted in their ability to colonize the nasopharynx (28). CbpA is a member of the
family of choline-binding proteins. This family of proteins shares phosphorylcholine, a component of
lipoteichoic and teichoic acids, as common cell wall anchor. Interestingly, phosphorylcholine also binds
to activated platelet-activating factor receptor (PAFr) on epithelial cells and C-reactive protein (CRP)
(29). Inflammation enhances this process, as expression of PAFr on lower respiratory tract epithelial
cells, and thereby PAFr-dependent adhesion and transcytosis of S. pneumoniae, are increased by
rhinovirus, acid, fossil fuel–derived particulate matter, and cigarette smoke (30). On the other hand,
phosphorylcholine expression itself can be modulated by the pneumococcal phosphorylcholine esterase.
This may allow the bacterium to limit CRP-binding and consecutive complement activation (23).
Eventually, cell–cell adhesion molecules have been identified as important adhesion targets for viruses,
bacteria, and parasites (31). For S. pneumoniae, it has been shown that pneumococcal surface antigen A
(PsaA) attaches to E-cadherin, an adhesion receptor it shares with L. monocytogenes (32). CbpA and
PsaA are produced by virtually all clinical isolates of S. pneumoniae and contribute to their virulence
(33). It has also been shown in children that pneumococcal carriage and infection induce salivary and
serum antibodies against NanA, CbpA, and PsaA, among other pneumococcal antigens (34,35). Also,
levels of PsaA and NanA antibodies in the serum were inversely correlated to frequency of respiratory
tract infections (35).
Primary adherence of N. meningitidis depends on the binding of type 4 pili on the bacterial cell surface
to nonciliated epithelial cells. Thereby, N. meningitidis induces rearrangements of the cellular
cytoskeleton leading to protrusion of microvilli and formation of cortical plaques in epithelial cells (10).
Clusters of bacteria are then embraced by microvilli, increasing stability of the adhesion. Further physical
proximity of the bacterial and epithelial cell surfaces accompanied by the loss of fimbriae and
downregulation of capsule allows other adhesins to attach to their respective receptors (36). Most
notably, opacity-associated (Opa) proteins, a family of phase-variable outer membrane proteins of N.
meningitidis, bind to carcinoembryonic antigen-related cell adhesion molecules (CEACAM), cell
surface–expressed heparan sulfate proteoglycans, and extracellular matrix (ECM) proteins (37).
CEACAMs are further involved in the invasion process of N. meningitidis (discussed below). While
fimbriae protrude from the polysaccharide capsule, the capsule interferes with the function of other
adhesins of N. meningitidis (38,39). Downmodulation of the capsule or inducing the upregulation of
adhesion receptors (e.g., CEACAMs) are proposed mechanisms by which invasive N. meningitidis
overcome this disadvantage (38).
Although structurally different, fimbriae are also important adhesion molecules of H. influenzae (40).
They mediate adhesion to mucin, ECM, and epithelial cells (41). Besides fimbriae, the protein Hsf is a
major adhesin of H. influenzae. Hsf is anchored in the outer membrane of H. influenzae and forms fiber-
like structures on the cell surface (41). Similar to N. meningitidis, the outer membrane protein P5 of H.
influenzae binds to CEACAM-1 and intercellular adhesion molecule-1 (ICAM-1) (42,43).
E. coli and GBS are the main pathogens of neonatal meningitis but, like L. monocytogenes, may also
cause meningitis in the elderly and immunocompromised persons. Transmission from the
asymptomatically colonized mother or the environment can lead to the colonization of the intestinal tract
of the infant, the first step in the pathogenesis of neonatal E. coli and GBS meningitis. The food-borne
pathogen L. monocytogenes disproportionately affects pregnant women and is transmitted to the fetus
through the placenta (44).
Similar to N. meningitidis, adherence of E. coli to host cells depends primarily on fimbriae. For
example, the type I fimbriae in E. coli harbor the adhesive FimH subunits on their tip (45). FimH binds
mannose-containing residues on the host cell and has been implicated in the tissue tropism of pathogenic
E. coli (46). Additionally, type S fimbriae are expressed by E. coli that have been isolated in neonatal
meningitis and sepsis cases (47). Another heterogenous family of adhesins that may be assembled into
fimbriae-like structures are the Afa/Dr adhesins that have been reported to adhere to the decay-
accelerating factor (DAF) expressed on cells exposed to plasma, complement proteins, CEACAMs, and
type IV collagen (19). The expression of adhesins on E. coli differs between the different pathogenic and
nonpathogenic subtypes and likely determines the organ tropism. Accordingly, the majority of E. coli
isolates found in neonatal meningitis exhibits the capsular serotype K1 and a limited repertoire of
different O antigens (48). The reason for the neurotropism of these specific serotype combinations is not
yet completely understood, although the K1 capsule seems to be the decisive factor for meningitis
development (49).
Akin to neonatal E. coli meningitis, epidemiologic analysis of GBS in neonates with GBS meningitis
shows a predominance of the capsular serotype III and the clonal complex ST-17 (50). Recently, a novel
virulence factor has been described in bacteria belonging to the ST-17 complex. The hypervirulent GBS
adhesin is anchored to the cell wall and in vitro significantly enhances adhesion to intestinal epithelial
cells, resulting in increased colonization of the intestine in the in vivo mouse model (50). Other adhesins
involved in the attachment of GBS to the gastrointestinal epithelium primarily bind to components of the
ECM. For example, the cell surface protein SepB binds to fibronectin but also mediates cleaving of
complement factor C5a. Attachment to laminin is mediated by the adhesin Lmb, whereas the surface-
anchored protein FbsA binds to fibrinogen (51). Finally, fimbriae have also been involved in GBS
adherence and biofilm formation (52).
For adherence and internalization of L. monocytogenes at the intestinal mucosa level, the interaction of
the internalin A (InlA) with the cell-junction protein E-cadherin is paramount (53,54). E-cadherin is
normally located below the tight junction and not available as a receptor to intraluminal bacteria.
However, it has been demonstrated that E-cadherin is present on the luminal surface of mucus-secreting
goblet cells and may be temporarily accessible at the tips of intestinal villi due to constant shedding of
dead enterocytes (55,56). Whereas adherence to the intestinal epithelium is important for the pathogenesis
of L. monocytogenes in the elderly and immunocompromised persons, transmission of L. monocytogenes
to the neonate occurs via the transplacental route. Histopathologic analysis of placentas from women with
fetoplacental listeriosis and in vitro analysis indicate that L. monocytogenes targets E-cadherin on the
surface of syncytiotrophoblasts in a similar way as in the intestine (57).
Invasion of the Bloodstream

The functional integrity of the respiratory tract mucosa is critical in protecting the host from bacterial
invasion. Viral infections of the respiratory tract may lead to a decrease in ciliary function and associated
mechanical clearance of bacteria, upregulation of different host cell receptors involved in bacterial
adherence, and alteration of host immune response (58,59), and are associated with an increased risk of
invasive bacterial disease. Epidemic outbreaks of meningitis due to N. meningitidis in the sub-Saharan
“meningitis belt” coincide with the dry periods of the year, when the protective barrier of the mucous
membrane is compromised (60).
Bacteria can penetrate the mucosal barrier through or between epithelial cells, and both routes seem to
be employed depending on the pathogen. Presence of a capsule or sialylated lipooligosaccharides, factors
that are instrumental for the survival of meningeal pathogens in the bloodstream, hinders the process of
transcytosis (10,61). Most of the identified mechanisms by which these pathogens directly invade human
nasopharyngeal mucosal cells take advantage of a ubiquitous cellular endocytosis mechanisms. In
clathrin-mediated endocytosis, a ligand-receptor interaction initiates the formation of a clathrin-coated
pit, which eventually forms a vacuole that engulfs particles (62,63). Additionally, actin rearrangements
are induced and further enhance bacterial internalization. On the other hand, paracellular migration of
bacteria might be facilitated by toll-like receptor (TLR)–dependent downregulation of tight junction
components (64) or degradation of intercellular junctions mediated by bacterial enzymes or bacteria-
bound plasmin (65–68). So far, several host cell factors have been identified as targets of bacterial
invasion mechanisms.
The transmembrane receptor pIgR is necessary for transport of IgA and IgM across epithelial cells.
After binding of the immunoglobulins at the basolateral surface of the epithelial membrane, the pIgR-
immunoglobulin complex is taken up into endosomes and transported across the epithelium in vesicles to
the apical mucosal surface, where it is released into mucosal secretions (69). S. pneumoniae is capable
of exploiting this mechanism for its own transcytosis across mucosal cells. As previously mentioned,
binding of S. pneumoniae to human pIgR is mediated by CbpA. This interaction allows S. pneumoniae to
hijack the recycling pathway of pIgR from the apical to the basal cell surface by retrograde transport,
thereby facilitating transmucosal invasion of pneumococci (70,71).
The CEACAM proteins, a family of proteins involved in intercellular adhesion, have been identified as
target of adhesion molecules of N. meningitidis, H. influenzae, and E. coli (72). Of the CEACAMs that
have been associated with bacterial binding, CEACAM-1 is most widely distributed on different human
cell types. Other CEACAMs that have been shown to bind to Opa of N. meningitidis are CEACAM-3,
CEACAM-5, and CEACAM-6 (73). Interestingly, binding to CEACAM-1 does not only allow N.
meningitidis to adhere and invade epithelial cells by endocytosis (74) but may also downregulate the host
immune response on several levels (72). On the other hand, binding of N. meningitidis to CEACAM-3 on
neutrophils has been shown to enhance engulfment and killing of bacteria (73).
E-cadherin is the cell surface protein responsible for establishment of adherens junctions between
neighboring cells (31). In the intestine, the interaction of listerial protein InlA with E-cadherin leads to the
rearrangement of the actin skeleton of the host cell and ensuing engulfment of the bacteria into a vacuole
that is transported to the basolateral cell surface (56). Persistence in the vacuole until release into the
lamina propria is in contrast to intracytosolic release and replication of L. monocytogenes in other human
cells. Although interaction of InlA with E-cadherin is also involved in the invasion process of L.
monocytogenes in the placenta, additionally, binding of InlB to its host receptor Met is necessary (75).
The exact mechanisms by which E. coli K1 and GBS invade human mucosal cells have not been
elucidated. One adhesin/invasin that has been identified in E. coli K1 is the Hek outer membrane protein,
which mediates binding to proteoglycan on the epithelial cell surface (76). Additionally, a role for outer
membrane protein A (OmpA) and IbeB, better studied in BBB crossing, has been suggested (76).
Altogether, akin to other meningeal pathogens, this points to an endocytosis-like process which is enabled
by rearrangement of the epithelial cell cytoskeleton (77).
Between epithelial cells and mesenchymal cells lies the basement membrane, providing a final
mechanical barrier before the invading pathogen can disseminate throughout the host. Attachment to ECM
components is an important property of bacterial infection pathogenesis, and ECM adhesins have been
identified in most meningeal pathogens (e.g., PavA of S. pneumoniae [23], Opc of N. meningitidis [78],
fimbriae of H. influenzae [79], and ScpB of GBS [51]). To cross the basement membrane, meningeal
pathogens have devised several strategies: degradation of the basement matrix by secretion of proteolytic
enzymes, use of the host’s plasminogen-plasmin system, and possibly crossing of the basement membrane
in phagocytic cells. Hyaluronidase is an endoglycosidase that degrades hyaluronic acid, a component of
the ECM. S. pneumoniae strains demonstrate a strong correlation between hyaluronidase activity and the
capacity to induce meningitis (80). Intranasal instillation of pneumococci together with hyaluronidase was
followed by meningitis in 50% of inoculated mice, whereas mice inoculated without hyaluronidase failed
to develop meningitis (65). Plasminogen is the key proenzyme of the fibrinolytic system, which after
activation becomes the broad-spectrum protease plasmin. Although fibrin is its main substrate, plasmin
can cleave several components of the basement membrane and ECM (81). Binding of plasminogen has
been shown for N. meningitidis, S. pneumoniae, and H. influenzae (82) and enhances invasiveness of S.
pneumoniae and H. influenzae (67,83,84). Phagocytic cells targeting colonizing pathogens on the
mucosal surface move freely between the mucosal surface and the intraluminal space of the mucosal
microvasculature. This movement of phagocytic cells can be exploited by bacterial pathogens that are
able to survive in phagocytic cells (85). For L. monocytogenes, it has been shown that dendritic cells are
an important transport vehicle from the mucosa to lymphatic organs (86).
Intravascular Survival
Once in the bloodstream, meningeal pathogens are immediately attacked by the host immune defense. To
establish successful bacteremia, meningeal pathogens need to overcome the different effector systems of
the immune defense. Clearance of the classical meningeal pathogens S. pneumoniae, H. influenzae, and
N. meningitidis relies on antibody-mediated opsonization followed by activation of the complement
system. In the case of S. pneumoniae and H. influenzae, this is followed by phagocytosis and finally
intracellular killing, whereas the membrane attack complex is important for control of N. meningitidis
(87). In neonates with E. coli and GBS meningitis, immune defense relies especially on innate immunity,
with the complement system being the first line of defense. The importance of the complement system for
the clearance of meningeal pathogens is underlined by the fact that patients with impaired complement
activation (i.e., sickle cell disease, anatomical or functional asplenia, or polymorphisms in the
complement components) are predisposed to invasive pneumococcal infections, whereas patients with
deficiencies in the terminal complement components are prone to invasive infections with N. meningitidis
(88–91).
The complement system may be activated by the classical pathway, the mannose-binding lectin (MBL)
pathway, or the alternative pathway, all converging at the deposition of activated complement factor C3b
on the pathogen surface, which catalyzes the downstream effects—opsonization and phagocytosis or
bacteriolysis—of the complement system (87). The meningeal pathogens have developed several
mechanisms to evade deposition of C3b on the cell surface. The polysaccharide capsule, although
hindering adherence to the mucosal surface and entry into epithelial cells, is the primary survival factor in
the bloodstream, operating against circulating antibodies, complement-mediated bacterial killing, and
neutrophil phagocytosis (49). Accordingly, encapsulation is a shared feature of the major hematogenous
meningeal pathogens (H. influenzae, N. meningitidis, S. pneumoniae, E. coli K1, and GBS). Sialic acid,
which is present on most human cells and blocks activation of complement, is also found in the capsule of
meningeal pathogens, for example, GBS (type III), E. coli (K1), and meningococci (groups B and C).
Thereby, the polysaccharide capsule may prevent complement-mediated bacteriolysis (92). Also, in S.
pneumoniae, the capsule is thought to interfere with the activation of the classical complement pathway
by limiting binding of immunoglobulin and CRP to subcapsular antigens (93). Binding of immunoglobulin
may further be hindered by the action of IgA1 proteases. IgA1-proteases cleave IgA1 in the hinge region
and liberate monomeric Fab-a fragments, which block the access of intact immunoglobulin G (IgG) or
immunoglobulin M (IgM) to the pathogen (94). Several host defense mechanisms counteract the
antiphagocytic activity of the bacterial capsule. Most effective are antibodies against capsular
components, which permit optimal opsonization of bacteria and ensure efficient phagocytosis by
polymorphonuclear (PMN) leukocytes and macrophages. The efficacy of this mechanism is underscored
by the more than 95% decrease of H. influenzae type b meningitis after the introduction of conjugate
vaccines, which induce high anticapsular antibody titers even in young children (95).
The first step in the classical complement pathway is the association of C1-complex to antibodies
bound to the bacterial surface. The pneumococcal protein PspA has been shown to limit this step (96).
C1-complex (classical complement pathway) or MBL-associated serine protease 2 (MBL pathway) then
activate the C3-convertase C4b2a, which in turn activates C3 to C3b. As with any enzyme cascade,
activation of the complement system needs to be balanced carefully to avoid damage to host cells.
Regulators of complement activation include C4-binding protein (C4BP), factor H, and DAF, which
accelerate the dissolution of C3-convertases (97). E. coli K1, N. meningitidis, S. pneumoniae, GBS, and
H. influenzae may all inhibit the classical and MBL complement pathway by binding of C4BP (98,99).
Also, S. pneumoniae, N. meningitidis, and GBS can bind factor H and downregulate the alternative
complement pathway (100–102). In particular, meningococcal factor H–binding protein has received
considerable attention because this molecule is a key component of group B meningococcal vaccines
(103,104). The result of C3 activation is the generation of C5 convertase. C5 convertase cleaves C5 into
C5a, a strong chemoattractant and anaphylatoxin, and C5b, member of the membrane attack complex
(MAC). GBS express an endopeptidase that cleaves C5a (105). The final step of complement cascade is
the generation of the MAC, which mainly affects Gram-negative pathogens. Vitronectin regulates this last
step of the complement cascade by interfering with MAC assembly. H. influenzae and N. meningitidis
have been shown to bind vitronectin through Hsf and Opc, respectively, and thereby limit bacteriolysis
(106). Although evasion of the complement system also impedes opsonic phagocytosis, the
polysaccharide capsule of the classical meningeal pathogens additionally allows for direct evasion of
bacterial uptake and killing by professional phagocytes (107,108).
In contrast, the intracellular pathogen L. monocytogenes depends mainly on its ability to evade
intracellular killing in the phagolysosome to evade the host immune system. After uptake into the cell, L.
monocytogenes can rupture the vacuole through the action of two phospholipases and listeriolysin and
escape into the cytosol (109). Concurrently, N. meningitidis and S. pneumoniae have been shown to
escape the oxidative burst in leukocytes by guarding themselves against ROS by the production of
glutathione (110,111). Another important virulence factor of L. monocytogenes is the actin assembly–
inducing protein ActA, which catalyses polar actin assembly and autophagy escape, thereby enabling
intracellular motility and spread to adjacent cells (109). Although bacterial clearance by phagocytosis is
an important early step in listeriosis, the ability of L. monocytogenes to survive intracellularly in
macrophages allows it to travel to target organs, thereby evading innate immune mechanisms.
In summary, the intricate defense mechanisms of bacteria against the host immune system only need to
safeguard the survival of one (or a few) organism(s), which may then gain access to the subarachnoidal
space and cause meningitis (112).
Meningeal Invasion
To enable efficient neuronal signaling, the CNS is a tightly regulated space protected from its
surroundings by different barriers. The boundary to the blood is provided by the BBB, the blood–
cerebrospinal fluid barrier (BCSFB), and the arachnoid (113). The BBB is composed of brain endothelial
cells, closely connected through adherens and tight junctions; a basal membrane; astrocytic and microglial
processes; and pericytes. The close interconnection of endothelial cells, low pinocytic activity, and
specific transport mechanisms allow for a selective permeability (113). Bloodborne pathogens must cross
the BBB or the BCSFB from the bloodstream to induce bacterial meningitis. Clinical observations and
experimental studies demonstrate a relationship between the magnitude of bacteremia and the
development of meningitis for most meningeal pathogens (89,114,115). However, high bacteremia alone
is not sufficient for the development of bacterial meningitis, but expression of selective bacterial adhesion
and invasion factors is necessary (116).
Attachment to the brain microvascular endothelial cells is facilitated by receptors for meningeal
pathogens found on the endothelium in cerebral capillaries and the choroid plexus. The laminin receptor,
a cell surface protein involved in binding to ECM components, has been suggested as common adhesion
target for S. pneumoniae, N. meningitidis, and H. influenzae and also supports invasion of cytotoxic
necrotizing factor 1 (CNF1) expressing E. coli K1 (117,118). Adhesion to brain endothelial cells via the
laminin receptor is mediated by CbpA in pneumococci, outer membrane proteins PilQ and PorA in
meningococci, and the porin OmpP2 in H. influenzae (117). Further, fimbriae are important structures in
bacterial adhesion to human cells (see earlier discussion). Fimbriae are essential for binding of N.
meningitidis to brain endothelial cells (119). Binding of E. coli K1 to brain endothelial cells is also
mediated by FimH on type 1 fimbriae binding to CD48 and OmpA association with glycoproteins on the
cell surface (116). For GBS as well, several adhesins are required for binding to brain endothelial cells,
including the pilus tip adhesin PilA (120–122).
Once attachment has occurred, pathogens may employ several strategies to migrate across the BBB and
gain access to the CSF space. These include (a) transcellular traversal by transcytosis, (b) paracellular
passage by disruption of the intercellular endothelial connections or endothelial injury, and (c) invasion
within white blood cells during diapedesis. Causative organisms of bacterial meningitis have mainly been
shown to migrate into the CSF by transcellular or paracellular migration (116). However, L.
monocytogenes also accesses the CSF space inside leukocytes (123).
Direct invasion of endothelial cells by meningeal pathogens involves ligand-receptor interactions
between bacteria and host cells and rearrangement of the endothelial actin cytoskeleton, which ultimately
leads to the uptake of the pathogen in a vacuole and transcellular transport (116,124). For S. pneumoniae,
the interaction of phosphorylcholine with PAFr and expression of NanA are important for invasion of the
BBB (125). PAFr is a transmembrane receptor expressed by several different cell types across the human
body and involved in the pathogenesis of different inflammatory diseases, atherogenesis, embryo
implantation, and CNS signaling (126). PAFr is a G protein–coupled receptor and the ligand-receptor
complex can be taken up into a vacuole that either recycles back to the cell surface or fuses with
lysosomes to terminate signaling (126). Similarly, pneumococci bound to PAFr via phosphorylcholine are
taken up into vacuoles but may then avoid fusion of the vacuole with lysosomes. Instead, they are
transported to the basolateral surface of the endothelial cell and released out of the cell (127). Likewise,
IbeA and CNF1 proteins are involved in the invasion of brain endothelial cells by E. coli K1, ultimately
leading to the uptake of E. coli into a vacuole (116,128). An important aspect of transcytosis of meningeal
pathogens is the ability of bacteria to avoid fusion of the vacuole with lysosomes as demonstrated for E.
coli K1 (129).
Interaction of bacterial adhesins with ECM proteins may enhance invasion of meningeal pathogens. In
vitro evidence has been brought forward for the exploitation of the integrin receptor–mediated mechanism
of ECM protein internalization by N. meningitidis and GBS (122,130). On the other hand, for N.
meningitidis, experimental evidence indicates that the formation of cortical plaques, induced by
microcolonies on brain endothelial cells, and the ensuing reorganization of the intracellular cytoskeleton
lead to the opening of intercellular junctions followed by paracellular penetration of the BBB (119).
Receptor-mediated signaling as well as local inflammation with recruitment of leukocytes may further
modify tight junctions and allow bacteria to penetrate paracellularly (119,122).
Transcellular invasion of brain endothelial cells by L. monocytogenes is thought to be mediated by
InlA and InlB in similar fashion as in the intestine and placenta, although conflicting experimental
evidence exists (123,131). Additionally, the effective intracellular trafficking of L. monocytogenes across
the BBB in phagocytic cells has been shown in a mouse model (132,133).
In humans, invasion of the CSF by bacteria can occur independently of bacteremia. This happens
typically when focal infections occur in structures in immediate proximity to the brain (e.g., otitis media,
mastoiditis, sinusitis) or when the integrity of the skull and meninges surrounding the brain is disrupted
(e.g., malformations, trauma, neurosurgery). In a case series of 87 patients with pneumococcal meningitis,
more than half of the patients had radiologic signs of otitis or sinusitis (134), whereas in a larger
observational study, otitis and sinusitis were reported as predisposing conditions in 25% of patients
(135). In a model of pneumococcal respiratory tract infection, meningitis occurred without detectable
bacteremia, suggesting that pneumococci are able to invade the brain by bypassing the bloodstream (136).
Similarly, a galU mutant and its parent pneumococcal strain both caused meningitis following otitis media
infection in gerbils, despite the mutant’s impaired ability to disseminate to the bloodstream following
infection (136).
For L. monocytogenes, S. pneumoniae, and N. meningitidis, retrograde access to the CNS via the
neural route has also been documented (123,137,138). However, for L. monocytogenes, this mechanism
is likely only important in ruminants. These observations support the notion that meningeal pathogens can
gain access to the subarachnoid space by several routes. The relative importance of hematogenous versus
nonhematogenous routes of infection in humans is not exactly known.
Meningeal Infections Associated with Foreign Bodies

Pathogenesis of foreign body–associated meningeal infection differs in several important aspects from
bacterial meningitis described earlier. First, at the time of foreign body insertion and due to local tissue
damage, access of bacterial pathogens to the CSF space is facilitated. Second, bacteria may organize on
the foreign body in form of biofilm, thereby defying the host’s immune system and systemically
administered antimicrobials. Finally, foreign body-associated meningitis frequently brings forth only low-
grade inflammation, with fever, irritability, and shunt malfunction being the most prevalent clinical
findings (139,140). CSF shunt infections develop into clinical ventriculitis or meningitis only in
approximately 30% of patients. In patients with hydrocephalus, CSF shunts convey CSF from the lateral
cerebral ventricles to the peritoneum or right cardiac atrium or transiently to an external collection
system. Shunt infection is one of the main complications associated with CSF shunts. The reported
incidence of CSF shunt infection is in the range of 5% to 15% (141–144), with pediatric patients being
more affected than adults (143). Shunt infections occur primarily as an early postoperative event, which
manifests itself within a few days or weeks after surgery (139,142,143). Due to the close association with
the operative procedure and the prevalence of bacteria belonging to the skin flora, intraoperative
inoculation is thought to be the most likely cause of infection in early CSF shunt infection. However, late
shunt infections can occur several years after implantation, likely due to hematogenous infection or
associated with intraabdominal infection (139,143). Shunt colonization with bloodborne pathogens such
as H. influenzae or S. pneumoniae has also been found, and one study reported five cases of meningitis
due to N. meningitidis, H. influenzae, and S. pneumoniae out of a series of 289 patients with CSF shunt
followed for 10 years (145). Nevertheless, most shunt infections are caused by staphylococci, in
particular S. epidermidis, which causes half of all cases (143,144,146). The characteristic feature of CSF
shunt infection is the adherence of bacteria to the inner surface of the shunt tubing. Insertion of a CSF
shunt leads to local inflammation and deposition of ECM proteins, that is, fibronectin or fibrinogen, on the
shunt surface (147). Binding of ECM proteins via fibrinogen-binding protein (148), fibronectin-binding
protein (149), and vitronectin-binding proteins (150) enhances adherence of S. epidermidis to the shunt
surface. In an experimental model of catheter-associated infection, presence of a foreign body reduced the
number of bacteria needed to establish infection (151). Once attached to the shunt surface, S. epidermidis
rapidly organizes into a biofilm, characterized by bacteria embedded in a self-generated polysaccharide
matrix (152,153). Although shunt infection does elicit an inflammatory response in the CNS (154),
staphylococci forming a biofilm are relatively protected from the host immune defense mechanisms
(151,155,156). Additionally, bacteria organized in a biofilm have a greatly increased resistance to
systemic antimicrobial therapy. This is likely due to the diversity of metabolic states of bacteria inside the
biofilm combined with the physical protection by the extracellular polysaccharide matrix (153,157).
Penetration of most antimicrobials through the BBB does not suffice to reach the necessary concentrations
needed to kill bacteria inside a biofilm (158), therefore intraventricular administration of antibiotics and
shunt removal are frequently necessary to treat CSF shunt infection.
The pathogenesis of Gram-negative CSF shunt infection is not well understood. Retrograde infection in
which bowel perforation may lead to distal colonization of the shunt with subsequent retrograde migration
to the ventricles is frequently suggested as the most likely mechanism for Gram-negative shunt infections.
The several times higher risk of patients after cochlear implantation to develop bacterial meningitis
was first appreciated in 2002. Depending on the type of cochlear implant used, there was a 16 to 30 times
higher incidence in bacterial meningitis than in the general U.S. population (159). S. pneumoniae
accounted for 60% of the cases with known etiology (159). Incidence of bacterial meningitis in this
special population has since then decreased, but it is still at least twice as high as in the general
population (160). Cochlear implants are designed for people with profound bilateral sensorineural
deafness in whom the auditory nerves are intact but hearing aids are ineffective. In animal studies, the
insertion of an electrode array into the scala tympani reduced the number of bacteria needed to induce
meningitis in animals challenged with S. pneumoniae by the hematogenous or otogenic route, whereas
sole cochleostomy surgery did not (161). The exact impact of the foreign body in this setting has not been
elucidated. To reduce the risk of post–cochlear implantation meningitis, it is suggested that patients are
thoroughly evaluated for accompanying inner ear malformations, which may increase the risk for CSF
leaks, and completion of their vaccination status. At surgery, measures should be taken to minimize
communication between the middle and inner ear, as this is thought to be the mode of bacterial entrance in
a sizable portion of meningitis cases in patients with cochlear implant (162).
Bacterial Multiplication in the Cerebrospinal Fluid

Host defense mechanisms in the CNS are tightly regulated. Peripheral immune cells and plasma proteins
are largely excluded from the brain parenchyma by the BBB and BCSFB, and the brain parenchyma
additionally features anti-inflammatory properties. Therefore, under physiologic conditions, microglia
and astrocytes provide basic immune functions in the brain (recognition of pathogen-associated molecular
patterns [PAMPs], initiation of inflammation), whereas peripheral leukocytes cross the BBB only in low
numbers and stick to the perivascular space of CNS microvessels (163). In bacterial meningitis, the
perivascular space and the meninges are the interface where cellular recognition of PAMPs and danger-
associated molecular patterns elicits a strong inflammatory reaction and leads to the recruitment of
peripheral immune cells to the CNS (164,165). In contrast to the peripheral blood, where cellular and
soluble factors of the innate immune system are present in abundance and may act immediately on
bacterial challenge, innate immune defense in the perivascular and meningeal space needs to be scaled up
first (166,167). This delay in immune activation favors the survival of pathogens once they have reached
the CSF. Bacteria can multiply within the CSF almost as efficiently as in vitro (168), reaching titers of up
to 109 CFU/mL, spread over the entire surface of the brain and spinal cord, and extend into the Virchow-
Robins space along penetrating vessels. Interestingly, presence or absence of leukocytes in the CSF does
not affect bacterial multiplication in experimental meningitis models (169,170). In contrast, the
complement system has been found to be instrumental to the control of bacterial multiplication in the CSF,
supporting leukocyte influx, cytokine expression, and bacterial phagocytosis (171,172). Consistent with
this, negative outcome in bacterial meningitis has been associated with depletion of complement factors in
the CSF (166,173).
Gene expression analyses of S. pneumoniae have shown that, with exception of capsule genes,
classical virulence genes (i.e., encoding for pneumolysin, autolysin, and pyruvate oxidase) are
downregulated in the CSF (174–176). In contrast, upregulation of genes involved in amino acid
acquisition/synthesis and energy metabolism has been documented in S. pneumoniae growing in CSF due
to the scarcity of nutrients in the CSF (175,176).
Induction of Inflammation
Autolysis or exposure of bacteria to lytic antibiotics in the CSF leads to the release of subcapsular
components (fragments of cell wall, lipopolysaccharide, teichoic and lipoteichoic acid, peptidoglycans,
bacterial DNA, and other cytosolic factors) that trigger the inflammatory response in the subarachnoid
space. Different cells from the tissues lining the CSF (ependymal and endothelial cells, perivascular
macrophages) and brain-resident cells (mostly microglia, but also astrocytes and neuronal cells) are able
to recognize these bacterial components. Distinct and often overlapping sets of specialized extracellular
(i.e., TLRs) or intracellular (i.e., NOD-like receptors [NLR]) receptors are used by these cells to sense
the major meningeal pathogens (177–179). Genetic variations related to these receptors are associated
with negative outcome during bacterial meningitis (180–182). In response to bacterial stimuli, cells
equipped with these specialized receptors produce cytokines, chemokines, and other proinflammatory
molecules, leading to the recruitment of leukocytes to the site of infection (183,184).
Cytokines and Chemokines

A large variety of cytokines and chemokines have been detected in the brain parenchyma or the CSF
during bacterial meningitis in patients or in experimental models (185–188). The pattern of cyto-
/chemokines produced in response to the different meningeal pathogens has been shown to vary in in vitro
and in experimental infection models. These differences are presumably related to pathogen-specific
activation of pattern recognition receptors (189–192). They may contribute to the differences in outcome
observed in patients affected by the different pathogens.
Early in the course of bacterial meningitis, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and
IL-6 are released, which then trigger, often in synergy, a cascade of inflammatory mediators, including
other cytokines, chemokines, platelet-activating factor (PAF), antimicrobial peptides, prostaglandins,
MMPs, NO, and ROS. The expression of TNF-α and IL-1β is detected first in the ependyma and the
meninges and later in the parenchyma in experimental meningitis (194).
Increased CSF concentrations of TNF-α, IL-1β, IL-6, IL-8, and IL-10 are characteristic for bacterial
meningitis. These cytokines are predominantly proinflammatory with the exception of IL-10, which
downmodulates the production of TNF-α and other proinflammatory cytokines (194–196).
High concentrations of TNF-α in CSF were detected within 3 hours after injection of live H. influenzae
in an experimental meningitis model (197). Intracisternal injection of S. pneumoniae led to a peak
concentration of TNF-α in CSF approximately 12 to 24 hours after infection, with persistently elevated
levels for at least 24 hours (198,199). The sustained TNF-α activity in the CSF may be explained by
continuous stimulation by products released from bacteria in the CSF or by a positive feedback loop in
the inflammatory cascade (198). TNF-α leads to nuclear factor-κB (NF-κB) activation, which regulates
the expression of many proinflammatory genes (e.g., IL-1, TNF-α, IL-6, IL-8, macrophage inflammatory
protein-1, inducible NO synthase [iNOS], cyclooxygenase-2, ICAM-1) (200,201).
Administration of TNF-α into the CSF results in pathophysiologic changes characteristic of bacterial
meningitis, including BBB breakdown, neutrophil influx, and increase of cerebral metabolism, oxygen
consumption, and cerebral blood flow (CBF), which in part are mediated through cyclooxygenase activity
(202–207). Antibiotics cause rapid lysis of microorganisms and an associated brisk release of bacterial
cell wall products, resulting in significantly higher TNF-α concentrations in CSF shortly after initiation of
antimicrobial therapy (208,209).
The proinflammatory cytokine IL-1β is released by mononuclear phagocytes, glial cells, and
endothelial cells in the CNS. Upon recognition of intracellular pathogens, the precursors of IL-1β or IL-
18 are activated by caspase-1 in the inflammasome complex (179, 210–212). IL-1β is present in CSF
samples of patients with bacterial meningitis, and its concentration is significantly correlated with
inflammatory parameters, TNF-α concentrations, and adverse disease outcomes (213). IL-1 appears in the
CSF of rats as early as 30 minutes after intracisternal injection of H. influenzae lipooligosaccharide
(214) and 6 to 12 hours after injection of live S. pneumoniae in infant rats (199). When injected directly
into the CSF of rabbits, IL-1 triggers a meningeal inflammation without detectable TNF-α activity,
suggesting an independent mechanism of action, whereas simultaneous administration of TNF-α and IL-1
results in a synergistic increase in leukocyte influx into the CSF. TNF-α and IL-1 induce other secondary
cytokines such as IL-6, IL-8, and IL-10 (213).
IL-6 is produced by monocytes, endothelial cells, and astrocytes, essentially in response to IL-1β. IL-6
is present in the CSF during meningitis later than TNF-α and IL-1β and remains present longer than the
latter cytokines. Although IL-6 can be detected in the CSF of patients with bacterial meningitis, its
presence is not correlated with any of the indices of meningeal inflammation or with severity of disease
(215). IL-6 has a predominantly proinflammatory effect and is a potent inducer of acute-phase proteins,
fever, leukocytosis, and activation of the complement and clotting cascades (216). Some antiinflammatory
effects of IL-6 include inhibition of TNF-α and IL-1β production in vitro and induction of IL-1 receptor
antagonist (217). Accordingly, knockout mice lacking IL-6 display an increase in pleocytosis and in the
inflammatory response (218).
IL-8 (CXCL8) was the first identified member of a large family of chemokines shown to regulate the
migration of leukocyte subsets toward the CNS during bacterial meningitis (187). Similar to most
chemokines, its primary action is to activate and attract leukocytes, mainly neutrophils, to sites of
inflammation. Cells shown to produce IL-8 upon stimulation with TNF, IL-1, or bacterial products include
monocyte-macrophages, neutrophils, endothelial cells, astrocytes, microglia, and neurons. IL-8 is present
in the CSF of patients with bacterial meningitis (187) and enhances neutrophil adhesion to endothelial
cells, a prerequisite for the invasion of leukocytes into the brain. Belonging to the same chemokine
subfamily as IL-8, the concentrations of CXC5 (ENA-78) and CXCL-1 (GRO-α) increase in the CSF of
patients with bacterial meningitis, inducing neutrophil chemotaxis (119). To a lesser extent, another
subfamily of chemokines, including monocyte chemoattractant protein-1 (MCP-1, CCL2), MIP-1α
(CCL3), and MIP-1β (CCL3) is upregulated in the CSF of patients with bacterial meningitis and attracts
mononuclear leukocytes (220).
IL-10 is an antiinflammatory cytokine that inhibits the production of TNF-α, IL-1, IL-6, and IL-8 in
vitro and attenuates brain edema during meningitis. High levels of IL-10 have been found in the CSF of
patients with bacterial meningitis, and in rabbits with experimental meningitis, administration of IL-10
downmodulated subarachnoid space inflammation (221). In an experimental rat model of pneumococcal
meningitis, systemically, but not intrathecally, administered IL-10 reduced CSF pleocytosis and the
concentration of proinflammatory cytokines (222). The inflammatory responses of IL-10 gene–deficient
and wild type mice were compared in a mouse model of meningitis induced by intranasal inoculation of S.
pneumoniae. Although antibacterial defense and survival were not influenced, the absence of IL-10 was
associated with an increased immune response, as reflected by a more pronounced inflammatory
subarachnoid infiltrate and higher concentrations of proinflammatory cytokines and chemokines in brain
tissue (223). In experimental neonatal E. coli meningitis in mice, IL-10 favors the immune response by
increasing the phagocytic activity of immune cells to clear the pathogen more rapidly and reduce the
inflammatory response (224). In addition to IL-10, transforming growth factor-β (TGF-β) has also been
shown to have antiinflammatory properties in experimental meningitis by reducing cerebral edema,
intracranial pressure (ICP), and CBF (225). Conversely, by specifically blocking TGF-β signaling on
neutrophils and macrophages, neutrophil influx and bacterial clearance were increased in experimental
pneumococcal meningitis, which resulted in less secondary brain damage and improved survival (226).
Matrix Metalloproteinases and Related Proteases

The MMPs comprise endopeptidases that serve as effectors of cell migration, tissue remodeling, and
cytotoxicity by degradation of ECM components. MMPs are synthesized as inactive zymogens and can be
activated by conformational changes that disrupt a Zn2+ binding cysteine switch. MMPs not only function
as effectors of tissue remodeling but also interact with the cytokine network. Cytokines such as TNF- α,
IL-1, and IL-2 modulate the expression and regulation of MMPs. In return, MMPs and related
metalloproteinases can act as sheddases or convertases as they transform membrane-bound cytokines,
cytokine receptors, and adhesion molecules to their soluble forms. TNF-α converting enzyme
(TACE/ADAM-17) is a member of the ADAM (a disintegrin and metalloproteinase) family of membrane
proteins and is a highly efficient sheddase of TNF-α and TNF receptors. These have an integral role in the
network of MMPs and cytokines (227).
Most MMPs are expressed only on demand through the action of cytokines, eicosanoids, growth
factors, and components of infectious pathogens, among others. The most prominent of these inducers are
the proinflammatory cytokines IL-1 and TNF-α. MMP-2, in contrast to other MMPs, lacks a classic
promoter sequence and is constitutively expressed. Tissue inhibitors of metalloproteinases (TIMPs), the
specific endogenous inhibitors of MMPs, form complexes with pro- and active forms of MMPs and
inhibit the enzymatic activity. Similar to MMPs, TIMPs are also regulated by a network of different
signaling molecules (228).
MMPs appear to play a central role in the development of bacterial meningitis (e.g., breakdown of the
BBB, intrathecal production of cytokines, and accumulation of blood-derived leukocytes in the CSF)
(229,230). Levels of MMP-1, -3, -7, -8, -9, and -10 have been found to be upregulated in the CSF of
patients with bacterial meningitis, whereas TIMP-1 and TIMP-2 may be slightly upregulated.
Interestingly, in the same patients, TIMP-4 was downregulated in the CSF (231–233).
Immunohistochemical analysis of the brain tissue of patients with purulent meningoencephalitis revealed
endothelial cells and infiltrating leukocytes with an increased staining signal for MMP-9, TIMP-1, and
TIMP-2 (234). CSF levels of MMP-9 were significantly higher in those children who developed
neurologic sequelae than in those who recovered fully, thus identifying high CSF concentrations of MMP-
9 as a risk factor for the development of neuronal damage (235).
Studies in a rat model of pneumococcal meningitis documented a 100-fold to 1,000-fold transcriptional
induction of MMP-3, -8, -9, -12, -13, and -14, but not of MMP-2 and -7, in brain parenchymal tissue
(198,236). In CSF cells, messenger RNA (mRNA) of MMP-8 and -9 were 10-fold to 100-fold increased,
whereas MMP-2 and -7 remained at basal levels (198). The cortical brain damage in this experimental
model is associated with changes in MMP-9/TIMP-1 ratio and an increase in collagen degradation (237).
In experimental meningitis, treatment with MMP inhibitors led to a significant reduction of mortality and
seizure incidence and reduced the extent of cortical damage (236,238). In addition to this effect,
combined inhibition of MMP and TACE led to a reduction of hippocampal apoptosis and preserved
learning capacity of animals that recovered from bacterial meningitis (198).
Neutrophil Invasion
Neutrophil migration into the CSF is a distinctive feature of bacterial meningitis and contributes to the
deleterious effects of inflammation on the brain. In response to cytokines, chemokines, and other
chemotactic stimuli, neutrophils penetrate the microvascular basement membrane, leaving the
bloodstream to accumulate in the CSF, where they produce the profound CSF pleocytosis characteristic of
bacterial meningitis (239–241).
The entry of blood-derived neutrophils into the CSF is facilitated by a cascade of events (Fig. 23.2).
The initial step in the adhesion cascade is the tethering and rolling of leukocytes along the endothelium,
which is mainly mediated by the interaction of members of the selectin family and their glycoprotein
ligands (242,243). E-selectin and P-selectin, upregulated on the endothelial cell surface in response to
proinflammatory stimuli, bind to P-selectin glycoprotein ligand-1 and other glycosylated ligands (243).
The rapid formation and breakup of these bonds on the neutrophil surface enable the rolling motion along
the vessel wall (244). Further, the hydrodynamic drag forces close to the vessel wall induce the flattening
of the rolling neutrophil. This reduces hydrodynamic drag and increases the area where selectin-ligand
bonds may be established (245). Consequently, in mice deficient in P-selectin, partial reduction of
neutrophil influx was observed after cytokine-mediated induction of sterile meningitis, whereas mice
deficient in P-selectin and E-selectin showed almost complete inhibition of neutrophil influx in the same
experimental model (246). The polysaccharide fucoidin is a selectin blocker that inhibits leukocyte
rolling and subsequent leukocyte transendothelial migration. Treatment with fucoidin intravenously has
been shown to attenuate the pleocytosis in experimental pneumococcal meningitis (247–249). Rolling of
leukocytes along a chemotactic gradient is followed by firm adhesion to the endothelium. Halting of the
rolling motion is induced by the activation of integrins on the neutrophil surface by chemokines (e.g., IL-8,
C5a) (250). Activated leukocyte β1-and β2-integrin (i.e., LFA-1) demonstrate higher affinity to members
of the immunoglobulin-like superfamily on the endothelium, including ICAM-1 and vascular cell adhesion
molecule-1 (VCAM-1) (251). After firm adhesion to the vessel wall, neutrophils crawl, mediated by a
different β2-integrin (i.e., Mac-1), to a suitable transmigration site (252). Transgenic deletion of ICAM-1
in a mouse model of brain inflammation and trauma led to a significant reduction in the number of
granulocytes infiltrating the brain tissue (253). Also, antibody-mediated blocking of integrins or ICAM-1
was shown to decrease leukocyte influx in experimental meningitis models, confirming an important role
for these molecules in assisting leukocyte entry into inflamed neural tissue (254–256).
Finally, the transmigration of leukocytes across the BBB may occur by the paracellular or transcellular
route (243,257,258). Intracellular signaling induced by the interaction of integrins with their ligands leads
to remodeling of endothelial cell actin cytoskeleton and facilitates paracellular or transcellular migration
of leukocytes (257).
TARGETS OF DAMAGE IN MENINGITIS

Figure 23.3 shows the histopathology of experimental pneumococcal meningitis and group B
streptococcal meningitis.
Cerebral Vasculature
Very early in the pathogenesis of meningitis, the cerebral vasculature is at the center of processes that lead
to the development of meningitis and CNS damage. Processes at the level of the cerebral vasculature
include activation of endothelial cells by inflammatory mediators produced during bacteremia, disruption
of endothelial function by the traversal of meningeal pathogens and inflammatory cells from the
bloodstream into the CSF, and involvement of the vasculature by the granulocytic inflammation in the
subarachnoid space. Important consequences of these processes are the disruption of the BBB, brain
edema, loss of CBF autoregulation, and focal and global changes of CBF resulting in cerebral ischemia.
Pathology
Subarachnoid space inflammation appears as a gray-yellow to green exudate covering the base and
convexities of the brain with obvious involvement of cerebral arteries and veins. Histologic examination
shows that the exudate in acute bacterial meningitis consists predominantly of granulocytes, whereas there
is a mixture of lymphocytes, macrophages, and granulocytes in subacute to chronic forms of meningitis
(259). Infiltration of vessel walls by these inflammatory cells, often in a focal pattern, is observed.
Inflammatory alteration of the vessel wall is often associated with permanent thrombosis of the vessel
lumen and vascular occlusion (260). Vascular occlusion may also occur in absence of local inflammatory
infiltrate (261). Vascular complications have been shown to be a frequent occurrence in children and
adults with bacterial meningitis (262,263). In fatal cases of neonatal meningitis, inflammatory vasculitis
is uniformly present, possibly indicating that the cerebral vasculature of the neonate is particularly
susceptible to inflammatory damage (264). Some of the severe structural damage in the neonatal brain
following meningitis may be related to this susceptibility of the vasculature to inflammatory damage.
Disruption of the Blood–Brain Barrier

Under physiologic condition, the BBB and BCSFB act as barriers to the brain, selectively limiting the
entry of macromolecules and cells. Access of leukocytes to the CNS is therefore tightly regulated, and in
the healthy individual, only very few leukocytes transmigrate the BBB and BCSFB (163). In meningitis,
however, the permeability of these brain barriers increases as a result of functionally relevant alterations
induced by the disease process.
In this respect, enhancement of BBB permeability due to an increase in paracellular leakage has been
particularly studied. Tight junctions and the corresponding intracellular actin cytoskeleton are the most
important components of the BBB that regulate paracellular transport pathways. Remodeling of the actin
cytoskeleton, reorganization of tight junctions, and enzymatic degradation of tight junctions and basement
membrane components may all lead to increased BBB permeability (257,265). These changes are
mediated by direct damage to endothelial cells by the infecting pathogen, alterations induced by signaling
and effector molecules released during the inflammation process, and changes induced by the interaction
of inflammatory cells with the brain barriers.
In vitro cytotoxic damage to brain endothelial cells has been seen with S. pneumoniae, mainly
mediated by pneumolysin (266–268), and N. meningitidis, mainly mediated by NO (269). Pneumolysin
was also shown to lead to astrocyte cytoskeleton remodeling in vitro (270), which might also support
BBB disruption. Nevertheless, the importance of direct cytotoxic damage to the brain endothelial cells in
vivo is not known.
Different proinflammatory molecules produced by endothelial cells, circulating leukocytes, microglia,
or astrocytes may induce disruption of the BBB (271). Some of the cytokines that have been associated
with disruption of the BBB are TNF-α, IFN-γ, IL-1β, and IL-6 (218,272). Mechanisms by which
cytokines may increase permeability of endothelial tissue include rearrangement of cellular cytoskeleton
and tight junction organization, activation of metalloproteinases, and increased generation of ROS. In
vitro evidence for a direct effect of TNF-α and IFN-γ on the endothelial cytoskeleton and intercellular
tight junctions mainly stems from non-CNS endothelial models (273), whereas direct effects on brain
endothelial cells are disputed (274–276). A direct effect of IL-1β on BBB permeability via protein kinase
C theta mediated phosphorylation of zona occludens-1 has been demonstrated (277).
MMP-3 and MMP-9 are, via NF-κB upregulation, some of the main downstream effector molecules in
BBB disruption triggered by the cytokines TNF-α and IL-1β, but MMP-9 may also be activated by NO or
MMP-3 (278). MMPs may increase BBB permeability by breakdown of basement membrane and tight
junctions. Significantly increased CSF levels of MMP-8 and MMP-9 have consistently been found in
human meningitis cases (230–232,235). Further, in a rat model of meningococcal meningitis, disruption of
the BBB, increased ICP, and CSF pleocytosis were paralleled by the occurrence of MMP-9 activity in the
CSF 6 hours after bacterial challenge (229). Besides MMPs, ROS and NO have been identified in
experimental studies as key mediators in the pathophysiology of bacterial meningitis (279–282). Both
molecular mediators contribute to the development of increased ICP, BBB disruption, and CSF
leukocytosis (283). Inhibition of the biologic effects of ROS and NO by radical scavengers in
experimental meningitis prevented cerebral damage including BBB breakdown (279,282,284,285). There
are several pathways by which ROS and NO may induce BBB/BCSFB disruption. Cell membrane
dysfunction mediated by lipid peroxidation and oxidative damage to cell membrane proteins, tight
junction and cytoskeletal reorganization, and MMP activation may all contribute to BBB disruption (286).
In clinical and experimental studies, markers for lipid peroxidation were elevated in the CSF in bacterial
meningitis (287,288). Furthermore, in experimental studies, pharmacologic inhibition of lipid
peroxidation reduced ICP and cerebral edema (289), whereas pharmacologic ROS inhibition lowered the
level of peroxidation markers in the CSF (280,290). Vascular endothelial growth factor (VEGF) is also
involved in the disruption of the BBB in traumatic brain injury and multiple sclerosis (291,292).
Interestingly, experimental and clinical evidence does not support a role for VEGF in the disruption of the
BBB in bacterial meningitis (186,291,293).
Besides their chemoattractant properties, chemokines also exert a direct effect on BBB permeability.
For example, the chemokines IL-8 and MCP-1 lead to cytoskeleton rearrangements (294).
Massive neutrophil pleocytosis in the CSF space is a hallmark feature of bacterial meningitis (see
previous discussion). Both the paracellular and transcellular route are accepted for the diapedesis of
leukocytes across the BBB (257,258). The effect of neutrophils on BBB permeability may be divided in
release of effector molecules like MMP-9 and ROS and direct opening of paracellular pathways.
Downstream signaling induced by adhesion of leukocytes to ICAM-1 and VCAM induces remodeling of
the endothelial cytoskeleton and reorganization of tight junctions, ultimately increasing paracellular
permeability of the BBB (257).
As a result of the increased BBB permeability during meningitis, molecules in the blood, including
antibiotics, penetrate at increased rates into the CSF. This facilitates therapy, because the CSF/serum ratio
of antibiotic concentration is often higher than without inflammation (295). Other molecules penetrating
the BBB may, however, be harmful. It is hypothesized that the disruption of the BBB leads to alterations in
the brain’s microenvironment that contribute to neuronal demise, for example, by leading to higher
concentrations of excitatory amino acids (EAA) (see later discussion) and other potentially harmful
molecules present at high concentrations in the bloodstream.
Alterations of Cerebral Blood Flow

Bacterial meningitis is associated with marked changes in CBF. Early in the course of the disease, an
increase in blood flow is observed, whereas in advanced meningitis, CBF is reduced
(262,279,280,296–299). Focal changes in the vasculature, loss of CBF autoregulation, ICP, and systemic
hypotension may all lead to perturbation of CBF in bacterial meningitis. Cerebrovascular changes
documented in patients with vascular complications include segmental narrowing of vessels and
irregularities of vessel walls (134,300). Additionally, arterial and venous thromboses are frequently
documented (261,301). Vasculitis (301) and vasospasms (299) likely explain segmental alteration of
vessel wall diameter in meningitis, whereas a procoagulable disposition caused by the bacterial infection
may additionally explain vascular thrombosis (261). The middle and anterior cerebral arteries or the
basilar artery are frequently affected during stroke associated with bacterial meningitis (134,262).
Sequelae are most devastating when large vessels at the base of the brain are affected, resulting, for
example, in hemiparesis or quadriparesis (264,302,303).
Impairment of CBF autoregulation has been documented in bacterial meningitis, both in experimental
models and in clinical studies (279,298,299,304–308). As a result of loss of CBF autoregulation,
systemic hypotension, which may arise in patients with meningitis as a result of sepsis or severe
dehydration, cannot be compensated and may lead to cerebral ischemia. Conversely, systemic
hypertension may then augment vasogenic edema and ICP. Elevated ICP has been associated with an
increase in CBF in experimental pneumococcal meningitis (309,310). Ultimately, in the rigid framework
provided by the cranium, an excessive increase in ICP may limit CBF. Factors leading to increased ICP in
bacterial meningitis are cerebral edema (see later discussion) and increased blood volume in the brain
resulting from hyperemia or from venous congestion precipitated by thrombotic occlusion of inflamed
veins (304).
In addition to global cerebral hypoperfusion, brain regions with focal hypoperfusion caused by
vasculitis of large and small arteries traversing the inflamed subarachnoid space are frequently observed.
This form of vasculitis is thought to be mainly responsible for ischemic damage leading to permanent
neurologic sequelae (Fig. 23.3A and B) (279,303). NO plays a crucial albeit complex role in modulating
CBF during meningitis. In experimental models of bacterial meningitis, inhibition of NO formation by a
nonselective, competitive inhibitor of NOS reduced the hyperemia observed early in the disease
(279,311,312). In more advanced disease, inhibition of iNOS significantly increased the extent of
ischemia and neuronal injury in the brain (296). These studies suggest a dynamic role of NO at the level
of the cerebral vasculature during meningitis. Early in the disease, the vasodilatory effect of NO
contributes to the hyperemia induced by the subarachnoid space inflammation. Later, when CBF
progressively declines under the influence of vasoconstrictive factors (see later discussion), NO
produced in the vasculature has some protective effects against ischemia. Thus, attempts to downmodulate
NO production during meningitis are potentially dangerous, despite the evidence that NO contributes to
some of the potentially harmful changes in bacterial meningitis, such as CSF inflammation, brain edema,
and ICP (see later discussion).
ROS also play a critical role in modulating CBF during meningitis (280,289,312,313). During the early
phases of pneumococcal meningitis in rats, scavenging of O2 and of H2O2 by superoxide dismutase and
catalase prevented the development of hyperemia and increased ICP (312,313). Generation of ROS is
localized primarily to the cells of the subarachnoid and ventricular inflammation and to the cerebral
vasculature, as shown in infant rats with experimental meningitis (280). The likely cellular sources of
ROS include granulocytes, endothelial cells, and activated microglial cells. Interestingly, the cerebral
vasculature shows evidence of marked oxidative alterations during experimental pneumococcal
meningitis in infant rats, whereas oxidative damage to the brain parenchyma itself has not been yet
documented conclusively (314). The oxidative damage to the vasculature can be inhibited by treatment
with antioxidants. The same antioxidants have been shown to reduce cerebral ischemic damage in these
models and prevent the decline in CBF (280,281). These data suggest that the cerebral vasculature is
exposed to significant oxidative stress during meningitis, which in turn contributes to CBF reduction and
cerebral ischemia.
NO and ROS can chemically react and form peroxynitrite, which is a strong oxidant that exerts
cytotoxic effects (283,315). In addition, the reaction leads to the loss of the vasodilatory biologic effect of
NO. Nitrotyrosine residues on proteins as a marker for the presence of peroxynitrite were detected in the
meninges, the cortical blood vessels penetrating the subarachnoid space, and inflammatory cells in the
brains of patients with bacterial meningitis and corresponding animal models (283,316). Furthermore,
pretreatment with the peroxynitrite scavenger urate attenuated meningeal inflammation, BBB disruption,
and intracranial hypertension (316).
Endothelins, potent vasoconstrictor peptides produced in the CNS by vascular endothelial cells,
astrocytes, and neurons, are also involved in CBF dysregulation. Increased endothelin levels are found in
the CSF of patients with bacterial meningitis (317). Endothelin synthesis is triggered by cytokines, that is,
TNF-α (318–320), and inhibited by NO (321). In experimental pneumococcal meningitis, therapy with an
endothelin antagonist significantly prevented the reduction of CBF induced by the infection and
concomitantly reduced the extent of cerebral ischemia (322).
Inner Ear
Unilateral or bilateral hearing impairment is the most common neurologic sequelae following bacterial
meningitis and is found in 5% to 30% of survivors (323–326). S. pneumoniae meningitis is associated
with the highest risk of developing sensorineural hearing loss (327–330). Onset of hearing loss during
bacterial meningitis is progressive rather than abrupt and the magnitude of hearing loss is related to the
duration of untreated infection (324). Hearing loss consecutive to bacterial meningitis can be transient or
permanent. Studies in models of meningitis indicate that hearing loss is the result of direct involvement of
the inner ear by the inflammation during the acute phase of the disease. However, no close correlation
could be found between the extent of hearing loss and the magnitude of CSF pleocytosis or CSF bacterial
concentrations (324). Magnetic resonance imaging (MRI) studies in humans with meningitis have
documented inflammatory involvement of the inner ear, suggesting that the animal models reflect the
clinical situation (331). In survivors of meningitis, progressive cochlear ossification and spiral ganglion
loss is observed years after the disease (332,333).
Pathology
During the acute stage of meningitis, suppurative labyrinthitis is a common feature observed in the human
temporal bone of patients with bacterial meningitis, often accompanied by pus in the perilymphatic duct
(334). Similarly, histopathologic examination of the temporal bone from rats with bacterial meningitis
showed a dense inflammatory cell infiltrate throughout the subarachnoid space extending to the inner ear.
Studies in experimental meningitis revealed that in the earliest stages of pneumococcal infection, bacteria
and inflammatory cells are already present within the cochlea (335,336). Inflammation in the inner ear is
primarily confined to the perilymphatic space (scala tympani) (337,338). Inflammatory infiltration of the
cochlea was shown to progress via the cochlear aqueduct to the perilymphatic space and via the spiral
ligament to the endolymphatic space during experimental pneumococcal meningitis (336). During this
phase, which is characterized by high inflammation, damage to the blood–labyrinth barrier, the hair cells,
and the spiral ganglion is observed (339). Damage begins at the base of the cochlea and progresses to the
apex, corresponding to hearing loss first at high then at low frequencies. Studies in experimental
meningitis caused by E. coli and S. pneumoniae revealed that both pathogens invaded the scala tympani
and triggered the development of lesions including craters in the apical surface of inner supporting cells
and disruption of the inner hair cell stereocilia. Pneumococcal meningitis produced more pronounced
lesions and induced breaks in the junctions between inner hair cells and their adjacent supporting cells, as
well as ballooning and rupture of the apical surface of outer hair cells (340). Spiral ganglion neuronal
loss is observed later than the first signs of hair cell damage and hearing loss. In the early stage of
inflammation, hearing threshold changes are associated with nonlethal structural changes in cochlear hair
cells and are potentially reversible. Conversely, in more advanced experimental infection, irreparable
ultrastructural inner ear damage, especially the loss of spiral ganglion neuronal cells, is associated with
severe to profound deafness (335,341).The more severe cochlear lesions induced by S. pneumoniae may
explain the higher incidence of deafness after pneumococcal meningitis. Toxic effects of the meningeal
pathogen (e.g., pneumolysin from S. pneumoniae [342]) and inflammatory mediators appear to be
responsible for the cytopathic effects (340,343). In particular, the production of ROS seems to be crucial
for the pathogenesis of cochlear damage and hearing loss in bacterial meningitis (339). Inducible and
endothelial NO synthase expression and tyrosine nitration have been documented in the cochlea of rats
with pneumococcal meningitis (344). Treatment with peroxynitrite scavengers or antioxidants resulted in
reduced hearing loss and protection of spiral ganglion neuronal cells (345,346). Upon microperfusion in
cochleas, NO donors have been demonstrated to damage hair cells and supporting neuronal cells
(347,348). Furthermore, in vitro, exposure to NO causes irreversible morphologic changes in isolated
outer hair cells (349). A direct neurotoxic effect of ROS on hair cells or spiral ganglion cells seems
therefore plausible, but other possible points of action may also exist, like damage to the blood–labyrinth
barrier (339).
Damage to the cochlea and hearing loss is prevented by antioxidants or NO synthase inhibitors in
experimental studies (344–346). Similarly, strategies to limit the host inflammatory reaction by using
doxycycline (350) or non-lytic antibiotics (351) are promising adjuvant therapies reducing sensorineural
hearing loss. Conflicting results have been published concerning the use of dexamethasone in both
experimental and clinical studies. Whereas some experimental models showed an improvement in hearing
capacity by dexamethasone (352–354), others did not (355). Similarly, the beneficial use of
dexamethasone in clinical practice is inconsistent (356–360) and may differ depending on the causative
agent, the age of the patient, comorbidity, and socioeconomic factors.
Central Nervous Tissue
Neurologic Sequelae
Apart from the high mortality, bacterial meningitis often causes brain damage of both cortical and
subcortical structures. The neurologic sequelae resulting from brain damage include hearing impairment
(see previous discussion), obstructive hydrocephalus, and damage to the brain parenchyma with focal
sensorimotor deficits, mental retardation, seizure disorders, and cortical blindness. In a meta-analysis,
hearing loss was the most frequent sequelae, almost three times more frequent than seizures and motor
deficits, respectively (323). Less frequent were cognitive impairment, hydrocephalus, and visual
disturbance. Any sequelae after discharge was present in 19.9% of patients with bacterial meningitis. The
risk for a major sequelae after bacterial meningitis (i.e., cognitive deficit, bilateral hearing loss, motor
deficit, seizures, visual impairment, hydrocephalus) was at least twice as high in African and Asian
countries compared to European countries (323). Bacterial meningitis caused by S. pneumoniae has
consistently been associated with higher rates of disabilities than infection with H. influenzae or N.
meningitidis (135,323,361). Lately, behavioral and cognitive sequelae in children and adults after
bacterial meningitis have been increasingly and accurately appreciated (362–367). This is of special
concern in childhood meningitis, as it was shown that neurologic sequelae of childhood meningitis may
persist for more than 10 years, thus impairing learning during the entire time children attend school
(363,365,368,369). In adults tested 0.5 to 13.5 years after acute bacterial meningitis, 32% of 155
meningitis survivors suffered from relevant impairment of psychomotor performance, speed of cognitive
processes, and concentration and memory functions (366). Overall, these studies emphasize the
substantial neurologic damage and functional impairment resulting from bacterial meningitis in children
and adults.
Pathology
The neuropathology of bacterial meningitis includes subarachnoid space inflammation, inflammatory
involvement of the cerebral vasculature (see previous discussion), and evidence of parenchymal brain
damage. Damage to the brain parenchyma is evidenced by the presence of brain edema, including signs of
cerebral herniation (see later discussion), by areas of cerebral infarction resulting from ischemia, and by
histologic changes (370–374). The latter show loss of neurons, often in a focal pattern (Fig. 23.3A and
B), which is most prominent in patients who survive acute meningitis for several days before succumbing
to the disease. MRI performed on newborn or children affected by bacterial meningitis showed
infarctions in the frontal, temporal, and parietal lobes; the basal ganglia; and the thalamus, as well as
periventricular white matter injuries, leading to cerebral atrophy and hydrocephalus (263,375–377). In
adult patients with bacterial meningitis, the temporal lobe and the limbic system also displayed structural
changes (367). Neuronal loss is associated with a marked reaction of astrocytes and microglia (378) as
well as axonal injury (379,380). Furthermore, meningitis induced by Gram-negative bacteria is often
characterized by the development of brain abscesses (381,382).
In the dentate gyrus of the hippocampus, special forms of cell death have been observed during
meningitis (280,383,384) (Fig. 23.3D and E). The first form of injury is defined as apoptosis based on
morphologic criteria in cresyl violet–stained brain sections (condensed, fragmented nuclei) (Fig. 23.3D,
inset) and the detection of fragmented DNA (i.e., TUNEL stain) (385). Furthermore, activated caspase-3,
an effector caspase that is responsible for executing the cell death program, has been documented in
apoptotic neurons of the hippocampal dentate gyrus in experimental meningitis (384,385). The specific
role of caspase-3 in this form of neuronal apoptosis was documented in infant rats with pneumococcal
meningitis, where enzymatic caspase-3 activity was significantly increased and intracisternal
administration of the caspase-3–specific inhibitor Ac-DEVD-CHO significantly reduced apoptosis in the
hippocampus of infected animals (385). In a different approach, caspase-3 activation and hippocampal
damage was prevented by treatment with a pan-caspase inhibitor, which exhibits antiinflammatory activity
through blocking of interleukin-converting enzyme (386).
The apoptotic injury in the hippocampus is of particular significance because experimental data suggest
that it is related to learning impairment following meningitis (198,387,388). Such an association is also
supported by the observation that activated caspase-3 and morphologic evidence of apoptosis is primarily
localized to immature progenitor cells in the subgranular zone of the dentate gyrus, cells that have been
implicated in the acquisition of new memory (384,385,389). Damage to the dentate gyrus of the
hippocampus may thus represent an anatomic substrate for cognitive impairment and learning disabilities
following meningitis (198,387,388,390). As a consequence of apoptotic damage, hippocampal
neurogenesis is impaired after bacterial meningitis (391). Furthermore, hippocampal cell death
associated with inflammatory conditions results in a dysregulation of hippocampal neurogenesis, with a
transient increase in cell proliferation (392–394) and changes in the transcriptional profile in the stem
cell population of the dentate gyrus (i.e., the neurogenic niche) (395).
Confirming the findings in animal models, brain sections of 20 patients who died from bacterial
meningitis showed apoptotic neurons with immunoreactivity for precursor and active forms of caspase-3
in the dentate gyrus (396). In a study in patients surviving meningitis, volumetric measurements of the
hippocampus by MRI techniques showed unilateral and bilateral hippocampal atrophy, potentially
reflecting the apoptotic loss of neurons observed by histopathology (397). Furthermore, cell proliferation
in the hippocampus was also found to be dysregulated in human patients who succumb to bacterial
meningitis (398).
The second form of hippocampal neuronal damage is characterized morphologically by uniformly
shrunken nuclei, forming clusters of damaged cells predominantly in the lower blade of the dentate gyrus,
spanning the entire width of the dentate gyrus band (Fig. 23.3E). This form of hippocampal damage is the
preferential pattern of neuronal injury observed in experimental meningitis caused by GBS (280,384).
Criteria for classical apoptosis, such as formation of apoptotic bodies and positive staining for activated
caspase-3, as well as morphologic criteria for necrosis, for example, cell swelling, loss of cellular
structures, are absent (384). However, this form of neuronal injury may be linked to apoptosis-inducing
factor (AIF) (399,400), more reminiscent of ischemia-related neuronal damage (401). Therefore, both
forms of damage may be temporally distinct and caused by distinct mediators (402).
Brain Edema and Cerebral Herniation

The development of cerebral edema is a hallmark of the cerebral involvement during meningitis (403).
Cerebral edema may be classified as vasogenic, cytotoxic, interstitial, or osmotic (404). Cerebral edema
in bacterial meningitis may be a combination of all four forms. Vasogenic cerebral edema is primarily a
consequence of increased BBB permeability, which leads to extravasation of plasma proteins into the
brain parenchyma (see earlier discussion) and mainly affects the white matter (404). Cytotoxic edema
results from an increase in intracellular water following intracellular accumulation of osmotically
effective ions (i.e., sodium, potassium, or glutamate). Cytotoxic mechanisms include ischemia and the
effect of EAAs (404–406). Cytotoxic edema affects gray and white matter in the brain. Interstitial edema
occurs by an increased influx of CSF across the ventricular ependyma into the periventricular white
matter, either through increased CSF production (increased blood flow in the choroid plexus) or
decreased resorption secondary to increased CSF outflow resistance across the arachnoid villi system of
the sagittal sinus (407). In obstructive hydrocephalus after meningitis, chronic interstitial edema may lead
to destruction of brain tissue (408). Osmotic edema might be caused by inappropriate secretion of
antidiuretic hormone during the course of bacterial meningitis. The observed hypoosmolality of serum
results in a net influx of water into the brain (404,409).
Brain edema contributes substantially to the acute fatal outcome of bacterial meningitis (134,410,411).
The major dangers of extensive brain edema during meningitis are herniation of brain tissue and
compression of the brainstem due to increased ICP, which can cause complete cessation of cerebral
circulation. But increased ICP alone may compromise cerebral perfusion and lead to ischemia. In addition
to brain edema itself, other factors associated with bacterial meningitis can contribute to excessive
intracerebral hypertension, including the development of obstructive hydrocephalus, meningitis-
associated cerebritis, cerebral infarction, cerebral venous thrombosis, and status epilepticus (412,413).
Impaired regulation of water transport underlies the pathophysiology of brain edema. Aquaporins
(AQP) are pore-forming membrane proteins ubiquitously present in living organisms (414). AQP-1,
AQP-4, and AQP-9 have been documented in the primate brain and are involved in water homeostasis of
the brain (415). The major aquaporin in the brain, AQP-4, shows contradictory effects in several forms of
brain edema. In cytotoxic edema, AQP-4 was shown to support brain edema formation by increasing
transcellular influx of water across the BBB, whereas in vasogenic and interstitial brain edema, lack of
AQP-4 leads to more severe brain edema by limiting outflow of CSF (404,416). In a mouse model of
pneumococcal meningitis, AQP-4 was significantly upregulated and associated with increased cytotoxic
brain edema (417). AQP-4 upregulation was also found in the brain of a patient with bacterial meningitis
(418), but not in the CSF of patients with bacterial meningitis (419).
Severe brain edema results in a caudal shift of midline structures, leading to their entrapment in the
tentorial notch or foramen magnum. The most common type of brain herniation occurs when a portion of
the temporal lobe is displaced (uncal herniation), which compresses cranial nerve III, the midbrain, and
the posterior cerebral artery, leading to coma and respiratory arrest. Caudal shifts produce herniation of
the parahippocampal gyri and/or cerebellum, which occurs when part of the cerebellum is displaced
through the foramen magnum. These intracranial processes are manifested clinically in altered
consciousness and postural reflexes. Caudal displacement of the brainstem causes palsy of the third and
sixth cranial nerves. Ultimately, these changes can result in decortication or decerebration with rapid
progression to respiratory and cardiac arrest. Cerebral herniation is occasionally precipitated by lumbar
puncture in the setting of brain edema and increased ICP. The highest risk for cerebral herniation is in
patients in whom there is a focal brain lesion leading to midline shift and intracranial hypertension. In
these patients, performance of a lumbar puncture is contraindicated (420).
Factors other than brain edema and intracranial hypertension that may lead to acute death from bacterial
meningitis include extensive cerebral infarction resulting from vasculitis and coagulation disturbances
and/or circulatory failure resulting from septic shock (421).
Mediators of Cell Death in Neuronal Tissue

EAAs including glutamate have been proposed as mediators of brain damage by inducing either apoptosis
or necrosis and appear to mediate neuronal injury in a variety of brain disorders. In ischemia, the best
studied example of EAA-mediated injury, increased concentrations of EAA in the brain interstitial fluid
result from an increased release by ischemic neurons and reduced uptake by glial cells (422). Studies in
experimental models of bacterial meningitis and inference from clinical studies point to ischemia and
EAA as likely mediators of direct neuronal toxicity (378,406).
A role for EAA in mediating neuronal injury in meningitis is supported by the following evidence.
Glutamate concentrations in the CSF of patients with bacterial meningitis were significantly elevated
compared to those in patients with viral meningitis and noninflammatory neurologic diseases and
correlated with the severity of the disease as scored by the Glasgow Coma Scale (423,424). In a rabbit
model, glutamate concentrations in the brain interstitial fluid, as measured by microdialysis probes, were
significantly increased in pneumococcal meningitis (424). The source of the increased EAA
concentrations in the brain during meningitis has not been identified but may be related to BBB disruption.
Furthermore, in an infant rat model of neonatal meningitis, kynurenic acid, a nonselective inhibitor of the
neurotoxic effect of EAA, significantly attenuated brain injury, both in the cortex and in the hippocampus
(378,406). However, adjuvant treatment with dextromethorphan, a noncompetitive N-methyl-D-aspartate
(NMDA) receptor antagonist, was found to aggravate hippocampal apoptosis in the infant rat model of
pneumococcal meningitis (425). Furthermore, accumulation of endogenous kynurenic acid by combined
inhibition of kynurenine 3-hydroxylase and kynurenine kinase resulted in an aggravation of apoptotic
neuronal death in the hippocampal dentate gyrus in the same experimental model; in this case,
nicotinamide adenine dinucleotide depletion, observed as a result of the intervention, may have caused an
energy failure responsible for the increase in apoptosis (426).
Inflammatory factors such as cytokines, metalloproteinases, and ROS are produced by leukocytes,
monocytes, and microglia as a result of the host immune response. The intensity and duration of this
response are responsible for the development of neuronal damage. Reducing the intensity by the use of
anti-inflammatory corticosteroids or nonlytic antibiotics may be a therapeutic option (427). Some
pathogens have been shown to interfere with the activation-induced cell death of immune cells, possibly
prolonging in a detrimental way the extent of inflammation. For example, N. meningitidis inhibits
apoptosis in neutrophils (428) or macrophages (429). Similarly, GBS interfere with TLR-2–mediated
activation-induced cell death in macrophages and microglia (430). Therefore, modulating the lifespan of
the cells producing neurotoxic factors may be a beneficial treatment during bacterial meningitis (431).
Because neutrophils produce different presumably neurotoxic factors (cytokines, metalloproteinases,
ROS), often modulating each other, it is difficult to determine which really directly triggers neuronal cell
death (432).
The marked increase in ROS production during certain pathologic conditions, such as during acute and
chronic inflammation, ischemia/reperfusion, or trauma, can lead to oxidative cell and tissue injury. The
brain is believed to be particularly vulnerable to oxidative damage because of its high concentrations of
unsaturated fatty acids, high rate of oxygen consumption, and relatively low concentrations of antioxidants
(433). Compatible with an important role of ROS in experimental meningitis, the use of radical
scavengers prevented BBB breakdown, attenuated lipid peroxidation and ischemia in the brain
parenchyma, and protected neurons from injury in experimental meningitis models (434). Furthermore, the
neurotoxic effect of EAAs has been shown to involve ROS (435). Despite these observations, a direct
neurotoxic effect of ROS in the brain parenchyma during meningitis has been difficult to document
conclusively. In the infant rat model of pneumococcal meningitis, there was only a moderate loss of
soluble antioxidants (ascorbate, glutathione) in the brain parenchyma and CSF and no evidence for
induction of antioxidant defenses (290). Furthermore, most of the beneficial effects of ROS scavengers in
experimental meningitis are compatible with a beneficial effect primarily at the level of the cerebral
vasculature (314) (see previous discussion). In the same model, marked loss of adenosine triphosphate in
the brain parenchyma was positively correlated with the extent of neuronal injury (436). Oxidative
alterations of cerebral vasculature and subsequent reduction of CBF leading to cerebral ischemia are
plausible mechanisms for neuronal damage during meningitis.
Theoretically, NO may act as a neuroprotective or neurotoxic molecule in meningitis depending on its
redox state; in its oxidized form, it can inactivate glutamate receptors and reduce the neurotoxicity of
EAA, whereas in the reduced form, it can react with superoxide to form peroxynitrite, which can exert
cytotoxic effects by damaging DNA, lipid membranes, and proteins (437). Genetic inactivation of iNOS
results in a marked reduction of caspase-3–dependent hippocampal apoptosis in a mouse model of
pneumococcal meningitis (438). However, iNOS inhibition by aminoguanidine has been shown to
increase neuronal injury in experimental GBS meningitis (296).
MMPs, whose role in CSF inflammation, recruitment of granulocytes into the subarachnoid space, and
disruption of the BBB has been described earlier in this chapter, may also exert direct neurotoxic effects
(227) by degrading perineuronal components of the ECM, such as laminin (439,440) or the neural cell
adhesion molecule (NCAM) (441). Furthermore, the modulation of the shedding of death receptors
ligands (FasL, TNF-α) by MMPs and TIMPs can directly regulate cell death in cells that express these
ligands, including neurons (278). Given as adjuvant therapy in addition to antibiotics, MMP inhibitors
reduced the extent of cortical damage, and combined inhibition of MMP and TACE led to a reduction in
hippocampal apoptosis (198,236,238). The adjunctive therapy with MMP-TACE inhibitors also
preserved learning capacity in experimental animals after recovery from bacterial meningitis (198).
Apart from host-derived neurotoxic mediators, there is emerging evidence that bacteria may also
directly damage neurons. An example of such a direct bacterial action is the ability of pneumococci to
induce apoptosis in vitro (400). Potential neurotoxic mediators produced by S. pneumoniae include
pneumolysin and superoxide. In vitro studies revealed that pneumolysin and bacteria-derived superoxide
initiated the neuronal death cascade via damage to mitochondria and subsequent release of the
proapoptotic mitochondrial factors cytochrome c and AIF (442,443). Studies in experimental
pneumococcal meningitis in rabbits demonstrated that pneumolysin colocalized with apoptotic neurons of
the hippocampus, and infection with pneumococcal mutants unable to produce pneumolysin and
superoxide caused significantly less damage (442). Furthermore, pneumolysin was also implicated in the
mechanism of cochlear hair cell death in the rat (444). Pneumolysin was also shown to induce cell
damage in endothelial cells in vitro (267,268). Other bacterial toxins with the ability to form pores are
able to directly induce neuronal damage, such as the beta hemolysin/cytolysin of GBS (445). But not only
the presence of bacteria in the CSF but also in the blood (bacteremia) has been suggested to influence the
development of neurologic damage during bacterial meningitis (446).
ACKNOWLEDGMENTS
This work was supported in part by grant no. 138094 (to SLL) from the Swiss National Science
Foundation.
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CHAPTER 24 ACUTE BACTERIAL MENINGITIS
KAREN L. ROOS, ALLAN R. TUNKEL, DIEDERIK VAN DE BEEK, AND W. MICHAEL
SCHELD
The meningitis syndrome has been recognized for centuries. Hippocrates realized the important
intracranial consequences of otitic infection, and clear clinical descriptions of meningitis have been found
dating from the sixteenth century. However, the syndrome of epidemic meningitis with a purpuric rash was
not identified until 1805, when Viesseux wrote about an epidemic of “malignant purpuric fever”
surrounding Geneva, Switzerland, the first clinical description of meningococcemia with meningitis. The
pathologic hallmark of the condition, inflammation within the subarachnoid space (SAS), was described
in autopsy reports in the French literature the following year. Danielson and Mann (1) recorded the first
observations of meningococcemia and meningitis in the United States in 1806. Many of these early
descriptions were collated in a treatise by Elisha North of Connecticut in 1811 and summarized in
references 1 and 2. Then, as now, the disease could present dramatically in a fulminant form. The
epidemic nature of meningococcemia was frightening to physicians and lay persons alike. For example,
Dr. Samuel Woodward, of Torrington, Connecticut, wrote the following in The American Mercury,
Hartford, in 1807:
The violent symptoms were great lassitude, with universal pains in the muscles, chills; heats, if any, were of short duration; unusual
prostration of strength; delirium, with severe pain in the head; vomiting, with indescribable anxiety of stomach; eyes red and watery, and
rolled up, and the head drawn back with spasm; pulse quick, weak, and irregular; petechiae and vibices all over the body, and a
cadaverous countenance and smell; death often closed the scene in ten or fifteen hours after the first attack . . . the body, near the fatal
period, and soon after, became as spotted as an adder. . . .
Similarly, the following was written by the Reverend Festus Foster of Petersham, Massachusetts, as a
letter to the editor of The Worcester Spy, dated March 6, 1810:
I hasten to give you a sketch of the spotted fever in this place. It made its first appearance about the beginning of January last; but the
instances were few and distant from each other, until last week. Although it had proved fatal in most instances, seven only had died
belonging to this town, previous to the 25th of February. Since that time the disorder has come upon us like a flood of mighty waters. We
have buried eight persons within the last eight days. About twelve or fifteen new cases appeared on Thursday last; many of them very
sudden and violent. This was the most melancholy and alarming day ever witnessed in this place. Seven or eight physicians were
continually engaged in the neighborhood north of the meeting house, and I believe not one half hour passed in the forenoon without
presenting a new case. Pale fear and extreme anxiety were visible in every countenance. . . .
It is inconceivable that this fulminant form of meningococcemia had been previously unrecognized,
especially given the excellent clinical descriptions of rashes in the literature from the period. One must
speculate that the virulence of meningococci for humans changed in the early nineteenth century.
Meningococci were first isolated in 1887 by Anton Weichselbaum in Vienna; they were obtained from
the cerebrospinal fluid (CSF) of six patients with meningitis and were initially named Diplococcus
intracellularis meningitidis. All three of the major meningeal pathogens (Neisseria meningitidis,
Streptococcus pneumoniae, and Haemophilus influenzae) were isolated and described in the last two
decades of the nineteenth century. Quincke introduced lumbar puncture (LP) in 1891, and the major CSF
alterations associated with meningitis (pleocytosis, hypoglycorrhachia, and elevated protein
concentration) were well recognized by the turn of the century.
The treatment of bacterial meningitis in the early years of this century was dominated by methods for
removal of large volumes of CSF and/or direct instillation of substances (e.g., dyes, enzymes) into the
SAS. After early leads from European investigators, the first truly significant therapeutic modality for this
disorder on a large scale, the systemic and intrathecal administration of antimeningococcal antisera raised
in horses, was documented by Simon Flexner in 1913. Though toxic, antisera therapy reduced the
mortality of meningococcal meningitis (from approximately 80% to 30%) during World War I and for
decades thereafter. The principles of serum therapy were applied by Dr. Hattie Alexander and others to
meningitis caused by H. influenzae in the 1940s.
The approach to the patient with bacterial meningitis was profoundly altered by the advent of
antimicrobial therapy. The first successful account of the therapy of meningococcal meningitis with an
antimicrobial agent in this country was published by Schwentker et al. (3) in 1937; nine patients survived
after receiving subcutaneous and intraspinal injections of sulfanilamide, and the sole death occurred after
eradication of the organism from CSF. The introduction of penicillin and other antimicrobial agents (e.g.,
streptomycin and chloramphenicol) ushered in the modern antimicrobial era, likened to an industrial
revolution (4). These developments led to the widespread belief that serious bacterial infections were
“solved.” Despite the introduction of myriad new antimicrobial agents and the development of newer
diagnostic techniques, the mortality from meningitis caused by the three major bacterial pathogens has not
changed appreciably in the last four decades. However, the use of the third-generation cephalosporins
during the 1980s for therapy of gram-negative aerobic bacillary meningitis has substantially reduced the
mortality of this condition. Recent years have revealed an explosion of new knowledge on the
pathogenesis and pathophysiology of bacterial meningitis (see later discussion), with attendant
ramifications on the use of adjunctive therapy (e.g., corticosteroids, nonsteroidal antiinflammatory agents,
and monoclonal antibodies) for this disease.
EPIDEMIOLOGY
During 2003 to 2007, approximately 4,100 cases of bacterial meningitis occurred annually in the United
States (5), but this disease is much more common in developing countries (see later discussion). In
addition, the relative frequency with which each of the various bacterial species causes meningitis is age
related. Gram-negative bacilli (principally Escherichia coli K1), group B streptococci, other enteric
bacilli, and much less commonly, Pseudomonas species are the major causative agents during the
neonatal period. Meningitis in children and adults is primarily caused by meningococci and pneumococci,
although disease caused by aerobic gram-negative bacilli is increasing in frequency, especially in the
elderly. N. meningitidis is the only major cause of epidemics of bacterial meningitis.
The development of meningitis depends on a complex array of factors, including virulence properties
of the organisms, the carrier state, and the host’s humoral immune response. These factors differ among
the major pathogens, for which reason epidemiology, carrier state, and host immunity are considered
separately for each of the three major etiologic agents in this section.
The classification of the pathogens, putative virulence factors, and the clinical settings associated with
less prevalent agents are discussed later (see the section “Etiology,” later in this chapter).
Haemophilus influenzae
H. influenzae type b (Hib) was previously the leading cause of bacterial meningitis in the United States
but now accounts for only approximately 7% of cases (5). Meningitis caused by Hib displays an
interesting bimodal seasonal pattern in northern Europe and the northern United States, with peaks in June
and September through November (6,7).
The overall annual incidence of serious Hib disease differs between geographic locales and among
populations. Significant interannual variations in the incidence of meningitis caused by Hib have also
been reported within a single geographic area over time (8). This is an important consideration in
assessing the efficacy of Hib vaccines. Before the advent of conjugate vaccines (see later discussion), the
overall rate of Hib meningitis in the United States was approximately 60 per 100,000 children younger
than 5 years of age (9), greater than the figures from other countries in northern Europe. These incidence
rates differ markedly among age-groups (see later discussion) and in children younger than 6 years. In a
3-year nationwide prospective study on pediatric meningitis in Israel, the incidence of Hib meningitis
during the first year of life was 67.1 per 100,000, and in children younger than 5 years of age, it was 18.5
per 100,000 (10). Some studies report a higher incidence in nonwhites (7,11). For example, the incidence
rate for Hib meningitis for the total population of Washington State was 2.2, 3.4, and 13.5 per 100,000 for
whites, blacks, and Native Americans, respectively (11). In contrast, others have found no differences
between rates for blacks and whites younger than 1 year of age (12).
Before the availability of the current Hib vaccines, 1 in every 200 children developed invasive Hib
disease by 5 years of age. Meningitis caused by Hib in the first 2 months of life is rare, presumably
because of placental transfer of protective concentrations of maternal bactericidal antibody. Most cases
occur between 4 months and 2 years of age. The highest rate of illness occurs in children 6 to 17 months
of age; children older than 2 years of age have a lower incidence (6,8,9,11–17). Approximately 80% of
cases develop in unvaccinated children younger than 2 years of age in this country, but this proportion
varies by geographic locale. The proportion of cases is approximately 20% lower in this age-group in
northern European countries. These differences in age distribution may directly influence the efficacy of
candidate Hib vaccines. Nontypeable strains of H. influenzae are commonly carried in the nasopharynx of
asymptomatic individuals. Carriage of encapsulated strains (usually type b) is rare: rates are less than 5%
in children and less than 1% in adults. However, the carriage rates among household contacts of an index
case are much higher: 20% to 25% overall and more than 50% among children younger than 5 years of
age. This varies with the clinical disease. For example, carriage rates among children 5 years old are
20% and 55% for household contacts of epiglottitis and meningitis cases, respectively. This prevalence is
reflected in the increased risk for serious Hib disease among household contacts of the index case, which
is age dependent: 4% for children 2 years of age, 2% for children 2 to 3 years old, and 0.1% for children
4 to 5 years of age. The risk for Hib infection among household contacts is approximately 600-fold
greater than the age-adjusted risk for the population at large and is the basis for chemoprophylactic
strategies. Carriage is usually asymptomatic and may occur despite the presence of circulating
anticapsular antibodies or effective eradication of meningitis following antibiotic therapy. The Hib
carrier state may persist for weeks to months.
The occurrence of Hib meningitis is inversely proportional to the age-related concentration of type-
specific anticapsular antibodies (18). Finnish studies, measuring anti–polyribosylribitol phosphate (anti-
PRP) antibodies by radioimmunoassay, confirm the age-related susceptibility to systemic Hib disease:
90% of children (3 to 12 months old) had concentrations of less than 150 ng/mL, whereas adults had
higher concentrations (19). These anti-PRP antibodies, in concert with complement, are (a) opsonic and
bactericidal against Hib in vitro and (b) protective in vivo. Antibodies to Hib outer membrane proteins
(Omps) also appear protective, but only against the homologous subtype. The anti-PRP response to
infection is age related, being poor in infants; older children and adults develop higher titers. It is also
dependent on PRP concentrations and clearance rates. PRP antigenemia may persist for weeks in younger
children with Hib meningitis, delaying the antibody response. Approximately 80% of children with Hib
meningitis develop an antibody response within 3 months. The antibody response is blunted in children
with agammaglobulinemia or immunoglobulin G2 (IgG2) subclass deficiency, as well as in all children
younger than 24 months of age receiving the Hib PRP vaccine, because this polysaccharide is a poor
immunogen in this age-group (9). The age-related acquisition of protective anticapsular antibodies is too
rapid to be accounted for by the low incidence of carriage or disease caused by Hib alone. Cross-reacting
antigens from E. coli and other bacteria within the gut are postulated to serve as the primary immunogen.
Acquisition of Hib (nasopharyngeal carriage) and the concentration of circulating anticapsular antibody
are the two main factors that determine risk for disease in most patients. Some of these risk factors have
been alluded to (e.g., immunoglobulin or complement deficiency, household contacts of an index case).
Other conditions that also may be important in increasing susceptibility to invasive Hib infection include
sickle cell anemia, postsplenectomy states, CSF fistulas, chronic pulmonary infections, alcoholism, and
probably lower socioeconomic status (e.g., Eskimos and American Indians). Day care outside the home
and the presence of young siblings increases the risk for invasive disease, whereas breast-feeding is
protective. The risk is highest for children younger than 2 years of age in day care but is not apparent for
older children, is equally high for those in a family day care setting or those in a professional day care
center (mean group size, 4 and 12 children, respectively), and is significantly higher (p < .02) within the
first month of attendance, especially among younger children (20). The risk ratio doubles with each
additional sibling younger than 7 years of age and is higher in twins (20). New associations have also
suggested that the child’s previous state of health, especially a history of otitis media and/or previous
hospitalization, increases the risk for serious Hib disease. Otitis media remains significant, especially for
younger children, even after controlling for confounding variables such as day care attendance (21).
Pharyngitis and otitis media are associated with Hib meningitis in approximately one half and two thirds
of the cases, respectively.
Because of the bimodal seasonal occurrence of Hib meningitis, at least in northern latitudes, it has been
suggested that preceding viral upper respiratory tract infections predispose to the acquisition of Hib and
subsequent disease, but this issue remains controversial (22). Recent studies comparing the attack rates of
meningitis between two ethnic groups living together in one geographic area (Jews and Bedouins in the
Negev region of Israel) suggested that community-acquired bacterial meningitis is associated more
strongly with the type of morbidity most prevalent in the region at any given time (e.g., upper respiratory
tract or gastrointestinal infections) rather than any specific type of infection (23).
There has been a profound reduction (from 76% to 90%) in the incidence of invasive infections caused
by Hib in the United States, specifically in young children (24–27), attributed, in part, to the widespread
use of conjugate vaccines against Hib that were licensed for routine use in all children beginning at 2
months of age. In a study of Hib disease rates in Los Angeles County, California, Hib disease was nearly
eradicated in a fully immunized population, demonstrating the importance of promotion of widespread use
of these conjugate vaccines (28). Similar results have been observed outside the United States. In Finland,
there has been a marked decrease in the number of cases of Hib meningitis from a peak of 43 cases per
100,000 population in the late 1970s to no cases in 1991 in the greater Helsinki area (29). Similarly,
during a prospective study of bacterial meningitis in the northeast Thames region of the United Kingdom,
there was an 87% decline in the number of cases of Hib meningitis in 1993 (7 cases) compared with 1991
and 1992 (50 cases) (30). Widespread usage beginning at 2 months of age has nearly eliminated serious
invasive Hib disease in children in North America, Western Europe, Japan, and in many areas of Latin
America. Unfortunately, for reasons of cost, Hib conjugate vaccines are used sparingly in many resource-
limited settings, and Hib meningitis remains common in children in these areas. For example, Hib still
accounted for 32% of cases in children younger than 5 years of age in Bulgaria in the mid-1990s (31). In
addition, there was a report of emergence of cases in Nottingham, United Kingdom of invasive Hib
disease in those previously vaccinated against the disease (32). Several explanations were put forth to
explain this increase, most notably that the vaccination schedule in the United Kingdom was at 2, 3, and 4
months of age, and no booster dose was given (33). In areas in the developing world, declining rates of
Hib meningitis have been reported since introduction of Hib conjugate vaccines, with effectiveness
ranging from 88% to 94% (34–37).
The occurrence of meningitis caused by Hib in individuals older than 6 years of age should prompt
efforts to exclude common accompanying conditions, such as otitis media, sinusitis, epiglottitis, CSF
leaks, an immunodeficiency state, splenectomy or asplenic states, other parameningeal foci of infection,
diabetes mellitus, and alcoholism (38,39). Although the incidence in children has dramatically declined,
the incidence of invasive H. influenzae disease in adults is more complex. In one population-based study
of the epidemiology and outcome caused by typeable and nontypeable H. influenzae among adults in Utah
during 1998 to 2008, there was an increase in incidence over the study period from 0.14 per 100,000
person-years in 1998 to 1.61 per 100,000 person-years in 2008 (40); patients older than 65 years of age
accounted for 51% of the cases and 67% of the deaths.
Neisseria meningitidis
Meningococcal infections continue to pose serious problems on all continents. They are influenced by
multiple factors, including geography, season, climate, meningococcal serogroup, and population
demographics (2,41). Although worldwide in distribution, the incidence of epidemic meningococcal
meningitis and/or meningococcemia exhibits high geographic variability. The meningitis belt of sub-
Saharan Africa represents a classic endemic area (Fig. 24.1). Although meningococcal infections were
not recorded in the area until the 1880s, large outbreaks still occur regularly. Although the precise effects
of climatic conditions on the incidence of meningitis are unresolved, the belt lies within the 300- and
1,100-mm rainfall lines. At least 390,000 cases with 53,000 deaths occurred within the seven countries of
the belt in the 10-year period 1951 through 1960. The average annual incidence since 1950 has been
estimated as approximately 70 cases per 100,000 population by the World Health Organization (WHO)
(41). In 1988, more than 57,000 cases of meningococcal disease were reported from the African
continent; in 1989, the number of cases increased to more than 70,000, with more than 40,000 reported
from Ethiopia (42). Because reporting is often delayed and may be incomplete, this figure likely
underestimates the actual number of cases. More than 180,000 cases were reported by the WHO for the
regions in 1996, the highest yearly total in more than 40 years. Similarly, within a 1-month period
(October 1974), 4,865 patients with meningococcal meningitis were treated at the major infectious
diseases hospital in Sao Paulo, Brazil. The overall mean annual incidence of meningitis caused by N.
meningitidis reached 370 cases per 100,000 population in the greater Sao Paulo area in that year. The
attack rate was 517 cases per 100,000 inhabitants during a group C epidemic in Upper Volta (now
Burkina Faso) in 1979, and recent studies documented an attack rate of 400 to 450 per 100,000 children
up to 8 years of age in the Faeroe Islands (43). In contrast, the mean annual attack rate in the United States
(1975 to 1980) was approximately 1.2 per 100,000 persons but was, again, age dependent: 17.1 per
100,000 in children younger than 1 year of age, 5.2 per 100,000 in 1- to 4-year-old children, and 0.3 per
100,000 among adults. Approximately 2,500 to 3,000 cases of meningococcal infection were reported
annually in the United States between 1984 and 2003. In a multistate surveillance project conducted
between 1989 and 1991 in the United States, the average annual incidence of meningococcal disease was
1.1 per 100,000; 46% of cases occurred in children 2 years of age, and the highest age-specific incidence
was in children younger than 4 months of age (44). A similar figure of approximately 2 per 100,000
population was reported from Finland from 1976 through 1980.
The peak incidence of meningococcal meningitis in industrialized nations occurs in winter through
early spring in both epidemic and endemic periods. Similar seasonal trends may also occur in tropical
areas. For example, both the group C and group A meningococcal epidemics in the Sao Paulo area from
1971 to 1974 began in May or June, the point of transition from the rainy to the dry season. African
outbreaks occur during the dry season from December to June. Annual outbreaks in the sub-Saharan
meningitis belt tend to peak in late April and early May, when the dry desert wind (harmattan) has ceased
and temperatures are high throughout the day, and terminate abruptly with the onset of the rainy season
(41). Low humidity may alter the pharyngeal mucosal barrier, thereby predisposing it to infection.
Although the introduction of a new virulent strain into a susceptible population may contribute to the
epidemics, many other factors—including crowding, the presence of other respiratory pathogens, poor
hygiene, and poorly defined environmental features—contribute to the initiation of a meningococcal
epidemic (45).
Although meningococcal meningitis may be more prevalent in men and boys, the reports are often
skewed by the inclusion of military recruits and chronic alcoholics. Meningitis caused by N. meningitidis
is primarily a disease of children and young adults: fewer than 10% of cases occur in patients older than
45 years of age. In the United States and Finland, children younger than 5 years of age account for
approximately 55% of cases during nonepidemic conditions, whereas in Zaria, Nigeria, the peak
incidence occurs in 5- to 9-year-olds (43). Major epidemics are heralded by a “shift to the right” toward
older age-groups (i.e., adolescents instead of children), a predictive feature of epidemics in the
meningitis belt identified by prospective surveillance. Although meningococcal meningitis is unusual in
adults, 33% of sporadic meningococcal disease occurred in adults in a 5-year population-based study in
Atlanta (46). Underlying conditions such as congestive heart failure, multiple myeloma, and infection with
human immunodeficiency virus (HIV) were prevalent in adults older than 24 years of age with
meningococcal infection but unusual in the 18- to 24-year-old group.
Large-scale epidemics caused by serogroup A meningococci have occurred at 20- to 30-year intervals
throughout the world in the last and this century and continue at approximately 8- to 12-year intervals in
the African meningitis belt, where approximately 1% of the population is affected. These strains
infrequently cause disease in the United States, but serious outbreaks caused by serogroups A, B, or C
continue in many areas (Table 24.1). A predominant serogroup circulating in the African meningitis belt
since 2000 is W135, an unusual occurrence (see later discussion). Serogroups B and C now cause most
focal outbreaks and endemic disease in many areas (see the section “Etiology” later in this chapter).
N. meningitidis disease is exclusive to humans. No intermediate host, reservoir, or animal-to-human

transmission has been proved. The nasopharynx is the natural reservoir for meningococci; transmission is
facilitated by airborne droplets or close contact. The definition of “close contact” has not been clearly
elucidated but generally refers to persons who have had prolonged (8 hours or longer) contact while in
close proximity (3 feet or less to the patient) or direct exposure to the patient’s oral secretions (through
kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management) within 1
week before the onset of the patient’s symptoms until 24 hours after initiation of appropriate antimicrobial
therapy (47). Meningococcal colonization may result in an asymptomatic carrier state (which is most
common) or in endemic, hyperendemic (e.g., a meningitis belt between epidemics at 10 to 50 cases per
100,000 per year), or epidemic disease. Although there is no clear relationship between carriage rate and
overt disease, the development of the carrier state and the host immune response are, as for Hib
meningitis, important variables in the epidemiology of meningococcal infections.
Approximately 6% of the population develops nasopharyngeal colonization with N. meningitidis
yearly. Nasopharyngeal carriage rates vary with age and the population under study. The carriage rate is
markedly influenced by age: 0.5% to 1% in children 3 to 48 months old, approximately 5% in adolescents
14 to 17 years old, and 20% to 40% in young adults. Analogous to Hib, carriage rates are higher in close
contacts of an index case. Carriage rates of meningococci of approximately 40% have been documented
in close family contacts of meningococcal cases. In closed populations (e.g., military barracks during
early training), carriage rates of 20% to 60% are commonplace and may reach 90% during epidemics of
meningococcal disease. Nasopharyngeal carriage usually persists for weeks to months, similar to Hib
carriage. Spread of meningococcal disease is usually carrier mediated (i.e., not spread by case-to-case
contacts) and largely accounts for the increased risk for disease (500- to 1,000-fold above the background
endemic rate) in household contacts of an index case. The organism is often introduced into the home
environment by an adult family member, with subsequent transmission to others; infants are colonized last
of all. Although uncharacterized host and environmental factors contribute to containment of infection to
the nasopharynx (thereby preventing disseminated disease), host immunity also plays an important role.
Nevertheless, those individuals most recently colonized with meningococci appear to be at the greatest
risk for invasive disease. Secondary systemic meningococcal disease often develops within 5 days of
recognition of the index case, with 70% to 80% of secondary cases occurring within 14 days of the
primary case.
As with Hib disease, the age-specific incidence of meningococcal infection is inversely proportional to
the presence of serum bactericidal antibodies against serogroups A, B, and C. More than 50% of infants
possess bactericidal antibody at birth as a result of transplacental transfer. The specifics of the antibody
response may be responsible for the occurrence of meningococcal meningitis during the neonatal period.
The group B capsular polysaccharide is a polymer consisting of two to eight linked sialic acid residues
but is immunologically identical to the oligosaccharides of several human glycoproteins, including brain
gangliosides. Immunologic tolerance thus exists in this age-group; although IgM antibody can be induced,
the usual switch to IgG antibody production does not occur (43). Because IgM does not cross the
placenta, IgG antibody to the serogroup B polysaccharide is lacking in neonates, contributing to the
occurrence of group B meningococcal disease in this patient population. In addition, group B
meningococcal capsular antigen is identical to the capsular polysaccharides of E. coli K1 and certain
types of group B streptococci, major causes of neonatal sepsis and meningitis. The prevalence of
antimeningococcal capsular antibodies is lowest between 6 and 24 months of age, increasing to
approximately 70% by early adulthood. The inverse link between occurrence of invasive disease and
bactericidal antibody was first documented during an outbreak of serogroup C meningococcal meningitis
among army recruits in 1968 (48). In this study, the sera of only 5.6% of the recruits who developed
meningococcal disease had bactericidal activity before the onset of illness, compared with 82.2% of
control sera. Notably, 5 (38.5%) of 13 recruits without bactericidal antibody developed systemic illness
after colonization with the group C strain.
Although recovery from invasive meningococcal disease generally confers lifelong immunity against
the homologous serogroup, this is not the major immunizing process. Nasopharyngeal colonization,
particularly with serogroups B, C, or Y, may elicit the development of bactericidal activity, primarily
directed against the colonizing strain but also against heterologous organisms within 5 to 12 days of
acquisition. Colonization with nongroupable meningococci or Neisseria lactamica may elicit protective
immunity, especially in young children. N. lactamica is virtually nonpathogenic, but nasopharyngeal
carriage rates of this organism are highest (4% to 20%) in children between 3 months and 12 years of age,
whereas the age-adjusted carriage rates for N. meningitidis are only 0.5% to 2%. As with Hib, the
carriage rates of pathogenic meningococci are too low in children to account for antibody formation, and
the importance of other cross-reacting organisms has also been proposed: Bacillus pumilus for group A
polysaccharide and E. coli for group C organisms. Paradoxically, an exuberant IgA response to
meningococci may actually enhance the development of systemic disease. When a large proportion of
induced anticapsular antibodies are of the IgA class, complement-mediated immune bacteriolysis by IgM
is blocked, thus enhancing susceptibility to invasive disease. This peculiar immunologic phenomenon is
transient, lasting only a few days following asymptomatic nasopharyngeal acquisition of N. meningitidis
or closely related organisms.
In addition to antibody, an intact complement system is also a component of host defense against
invasive meningococcal disease. Studies of extreme phenotypes have identified genetic correlates of
increased susceptibility in the complement system (49). Recurrent or chronic neisserial infections have
been associated with rare isolated deficiencies of late complement components (C5, C6, C7, or C8, and
perhaps C9), occasionally in concert with failure to produce antimeningococcal antibodies. Recurrent
episodes of neisserial infections may occur in these patients without an increase in susceptibility to other
pathogens (50), and screening for complement defects is useful in patients with these syndromes.
Complement deficiency also appears to predispose to meningitis caused by nongroupable meningococci
and Neisseria-related bacteria (i.e., Moraxella and Acinetobacter species) (51). In addition, complement
deficiency or depletion of early components (C1, C3, or C4) because of an underlying disease such as
nephrotic syndrome, hepatic failure, systemic lupus erythematosus, presence of C3 nephritic factor, or
multiple myeloma may predispose to the first episode of invasive meningococcal disease. An association
between homozygous C4b deficiency (present in approximately 3% of the population) and the
development of childhood meningitis was demonstrated. Up to 30% of patients with invasive
meningococcal syndromes display decreased complement function. Properdin deficiency, or dysfunction
with normal concentrations, also predisposes to meningococcal infections; this defect is reversible by
vaccination (52). The mortality associated with meningococcal meningitis in patients with complement
component deficiencies is actually lower than the general population (3% versus 19%, respectively).
However, since invasive meningococcal infection occurs in 39% of patients with deficiency of terminal
complement components and about 6% of those with properdin deficiency, a screening test (e.g., CH50)
has been suggested (53) for all individuals with serious meningococcal disease, with further
consideration for determination of specific complement and/or properdin concentrations if documented.
Asplenic states increase the risk for serious infections by encapsulated organisms, especially Hib or S.
pneumoniae but also meningococci.
In genetic case–control studies, invasive meningococcal disease was associated with the IL1RA +
2018T → C polymorphism, with susceptibility increased in homozygous IL1RA + 2018C carriers (49).
CFH, SFTPA2, CEACAM3, and CEACAM6 polymorphisms were significantly associated with an
increased susceptibility to meningococcal disease, whereas other CEACAM6 and SFTPA2
polymorphisms showed a protective effect (49). A genome-wide association study identified variants in
the CFH region associated with host susceptibility to meningococcal disease (54). Further studies are
needed to confirm these associations before a definite conclusion can be drawn on their role because of
the limited sample size and lack of correction for multiple testing.
Although all the aforementioned factors (particularly recent colonization with a pathogenic strain in a
nonimmune host) undoubtedly contribute to the pathogenesis of meningococcal disease, the precise
determinants contributing to overt clinical illness (as opposed to the usual outcome of asymptomatic
carriage) are poorly defined. Even during epidemics, only 1 in 1,000 to 5,000 colonized patients develop
disease (43). Various predisposing factors, including crowding, lower socioeconomic status, and poor
general health, have been proposed to explain the increased incidence among blacks in the United States
and among alcoholics in Finland or Alaska (41). However, the influence of such conditions (e.g.,
overcrowding) has not been supported by studies in Nigeria. An antecedent viral infection has been
suggested as another predisposing factor, because approximately one third of meningococcal cases follow
symptoms referable to the upper respiratory tract. An outbreak of meningococcal disease followed a large
influenza epidemic in Texas in 1981, and simultaneous outbreaks of meningococcal and influenza A2
infections have been described in institutional settings. Although meningococcal pneumonia may
complicate influenza (e.g., the 1918 to 1919 pandemic), the role of viral infections in the enhancement of
meningococcal dissemination is unproved (22).
The time from nasopharyngeal acquisition to bloodstream invasion is short (usually approximately 10
days). The incubation period may also be short, because “secondary” cases commonly occur within 1 to 4
days of the index case. Once the organism is bloodborne, more than 90% of meningococcal disease is
manifested as meningitis and/or meningococcemia.
Although a single case of meningococcemia or meningitis in a college student engenders alarm,
invasive disease due to this organism is no more common in such students when compared with
nonstudent age-matched 18- to 22-year-old controls but is increased threefold in freshmen living in
dormitories, a target of some vaccine recommendations. Active or passive smoking and binge alcohol
consumption also appear to increase the risk of meningococcal disease in this age-group. The first
quadrivalent meningococcal conjugate vaccine against serogroups A, C, Y, and W135 was licensed in
January 2005 in the United States for routine use, starting at age 11 to 12 years; recent recommendations
are for one vaccine in this age-group, with a booster dose given at age 16 years (55,56). A two-dose
primary series administered 2 months apart is recommended for those age 2 to 54 years with persistent
complement component deficiency or functional or anatomic asplenia and for adolescents with HIV
infection. A two-dose primary series is also recommended for children 9 to 23 months of age at increased
risk for invasive meningococcal disease (57). Lack of a vaccine against serogroup B meningococcus is a
significant issue, although recent investigations of a multicomponent serogroup B vaccine (4CMenB)
demonstrated that this vaccine was immunogenic (58–61); 84% to 100% of infants who were
administered the vaccine developed bactericidal antibodies.
Streptococcus pneumoniae
Although pneumococcal meningitis occurs in all age-groups, pneumococci remain the most common cause
of bacterial meningitis in adults. The annual incidence of pneumococcal meningitis has remained
relatively stable in the United States for the past three decades until recently with introduction of the
heptavalent pneumococcal conjugate vaccine (see later discussion). In seven studies analyzing data from
diverse geographic areas in this country from 1959 to 1978, the annual incidence was 0.3 to 2.3 per
100,000 population, with a mean of 1.3 per 100,000. An identical infection rate of 1.3 per 100,000
persons annually was recorded from the Oklahoma City area in 1984 and extrapolated from several states
and Los Angeles County in a relatively recent (1995) national survey conducted by the Centers for
Disease Control and Prevention (CDC) (62,63); higher rates of invasive pneumococcal disease were
reported at the extremes of age (see later discussion), in men and boys, and among blacks and American
Indians as compared with whites. Nearly identical incidence figures (1.2 to 1.4/100,000 population
annually) were reported from the Göteborg, Sweden area from 1975 through 1980 (64) and from Örebro
county in Sweden (1.0/100,000 population annually) from 1981 through 1992 (65). Pneumococcal
meningitis was, again, more common in men and boys, and most cases occurred from December through
May. However, higher incidence rates have been reported from other areas. For example, surveillance
studies from 1980 to 1986 among the Alaskan native population in the Yukon-Kusko-Kurin delta region of
southwestern Alaska documented an extremely high frequency of invasive pneumococcal disease; the
annual rate for pneumococcal meningitis was 13.2 per 100,000 persons overall (66). Perhaps more
importantly, the annual incidence rate was 216 per 100,000 children younger than 2 years—18 times
higher than that reported from Sweden (64) and 36- to 37-fold greater than United States rates derived
from both passive and active surveillance (7,62,66). These rates of bacteriologically confirmed invasive
pneumococcal disease were the highest reported for any population worldwide. Although most cases of
invasive pneumococcal disease occurred during the Arctic summer, pneumococcal meningitis cases
clustered in the winter (66), as described in other reports (7).
The risk for pneumococcal meningitis is age dependent, with increased incidence rates occurring at the
extremes of age. For example, the number of cases per 100,000 persons per year in the Göteborg, Sweden
area for 1970 through 1980 were as follows: 12.0 for infants younger than 12 months old, 0.4 to 0.9 for
children and adults 2 to 39 years old, 1.2 to 1.6 for persons 40 to 70 years old, and 2.2 for those older
than 70 years of age (64). The dramatic incidence among Alaskan native children younger than 2 years of
age (216/100,000 annually) are noted earlier in this chapter. Similarly, the annual incidence rates for all
invasive pneumococcal infections (including bacteremic pneumonia) in the Oklahoma City area in 1984
were 97 per 100,000 for infants younger than 1 year of age and 87 per 100,000 for elderly adults older
than 80 years of age.
As with disease caused by the other major meningeal pathogens, pneumococcal meningitis follows
recent nasopharyngeal colonization by a virulent strain. The rate of asymptomatic carriage varies with
age, environment, geographic locale, and the presence of an upper respiratory tract infection.
Pneumococci have been isolated from the upper respiratory tract of 5% to 70% of normal adults;
approximately 25% acquire a new strain annually. Carriage rates decline with age (30% to 35% for
children ages 6 to 11 years and 18% to 19% in adults) and are higher in closed populations (e.g., 27% to
58% in schools and orphanages, 50% to 60% in closed military populations). The duration of
pneumococcal carriage varies from weeks to months and is longer in children than in adults. Most carrier
strains in the normal population are of higher numbered capsular types and only infrequently are
associated with invasive disease (see later discussion). Carriage is prolonged in individuals with low
serum antibody concentrations against the homologous capsular type before colonization. Spread of this
organism within the family unit is influenced by crowding, the season (greater in fall and winter), and the
presence of pneumococcal disease (particularly pneumonia and otitis media). The precise relationship
between pneumococcal carriage and the development of protective immunity is poorly defined. More than
50% of children develop a rise in type-specific antibody concentrations following colonization; this is
rarely observed in adults, perhaps because of the relatively high antibody concentrations already present
in adults. Nevertheless, otitis media often occurs in colonized infants despite the presence of type-
specific antibodies. Antibody concentrations generally decline with time despite persistent carriage of a
given strain (67). In addition, antibody responses to different capsular types vary considerably and are
generally poor in infants younger than 2 years of age. Specific antibody responses tend to be higher after
intermittent periods of nasopharyngeal carriage than after continuous ones. The antibody response after
pneumococcal colonization, its influence on subsequent disease, and the impact of other environmental
antigens require further study.
Studies of extreme phenotypes among patients with invasive pneumococcal disease have identified
genetic correlates of increased susceptibility in the complement system and the signalling cascade after
toll-like receptor pathways (49). Case–control studies showed that invasive pneumococcal disease was
associated with certain MBL and C3-variant genotypes (49,68).
Several factors predispose to pneumococcal meningitis (69,70):
■ Pneumonia (15% to 25% of patients)
■ Otitis media
■ Sinusitis
■ CSF fistulas, leak
■ Head injury
■ Cochlear implants with positioners
■ Alcoholism, cirrhosis
■ Sickle cell disease, thalassemia major
■ Other splenic disease
■ Wiskott-Aldrich syndrome
■ Multiple myeloma
Pneumonia coexists much more commonly with pneumococcal meningitis than with the other two major
pathogens. Acute otitis media is seen in approximately 30% of patients with pneumococcal meningitis;
acute sinusitis may also be an important antecedent event. Pneumococci are the most common cause of
recurrent meningitis in the setting of CSF leaks. Recent or remote head trauma is found in about 10% of
patients with pneumococcal meningitis. Alcoholism, cirrhosis, and spontaneous bacterial peritonitis are
underlying disorders in approximately 20% to 35% of patients with this disease. Pneumococci are the
most common cause of meningitis in children with sickle cell anemia and commonly cause meningitis in
other asplenic states or in the setting of primary or acquired immunodeficiencies (71). S. pneumoniae
causes 87% of pyogenic meningitis cases in sickle cell disease; cases in the 2- to 3-year-old group occur
at a rate of 12 per 1,000 patient-years. The risk for pneumococcal meningitis in this age-group of children
with sickle cell anemia is increased 36-fold as compared with that observed in control groups of black
children, and it is increased 314-fold over that observed in whites. Pneumococcal meningitis also occurs
with increased frequency in persons with the Wiskott-Aldrich syndrome, thalassemia major, childhood
nephrotic syndrome, multiple myeloma, and chronic lymphocytic leukemia. Defects in immunoglobulin
concentration or function, as well as poor alternative complement pathway–mediated opsonization of
pneumococci, are common in many of these disorders. Pneumococcal meningitis is approximately 450-
fold more common in patients with acquired immunodeficiency syndrome (AIDS) when compared with
the general population (71), often despite prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX)
to prevent other opportunistic infections. In one study of 352 episodes of community-acquired
pneumococcal meningitis in adults, 245 (70%) were associated with an underlying disorder and the
overall in-hospital mortality rate was 30% (72); death in patients younger than 60 years of age was more
often caused by neurologic complications; in patients 60 years or older, death was more likely secondary
to systemic complications. In children with cochlear implants with positioners who are beyond 24 months
after implantation, the incidence of bacterial meningitis was 450 cases per 100,000 person-years
compared with 0 cases in children without positioners (73); the updated overall incidence was 189 cases
per 100,000 person-years, with most cases caused by S. pneumoniae (74). Outbreaks of pneumococcal
meningitis have also been described during African outbreaks of meningococcal meningitis (75). In
children who develop second episodes of pneumococcal meningitis, screening for congenital
immunoglobulin deficiencies should be performed (53).
The rates of pneumococcal meningitis have decreased in children and adults since introduction of the
heptavalent pneumococcal conjugate vaccine (from 1.13 to 0.79 cases per 100,000 between 1998 to 1999
and 2004 to 2005), although the increase in disease caused by serotypes not in the vaccine (19A, 22F, and
35B) is concerning (76). The Advisory Committee on Immunization Practices now recommends use of the
13-valent pneumococcal conjugate vaccine (77), which not only offers protection against the serotypes in
the heptavalent vaccine (4, 6B, 9V, 14, 18C, 19F, 23F) but also protection against additional serotypes
(serotypes 1, 3, 5, 6A, 7F, 19A).
ETIOLOGY
In a review of 296 episodes of community-acquired meningitis in adults reported from the Massachusetts
General Hospital from 1962 through 1988, the most common pathogens were S. pneumoniae (37%), N.
meningitidis (13%), and L. monocytogenes (10%) (78).
The epidemiology of bacterial meningitis changed dramatically in areas that have embraced Hib
conjugate vaccines starting in the late 1980s. The influence of these vaccines from the four largest and
most recent surveys conducted in the United States (7,62,79) is shown in Table 24.2. Hib was responsible
for 45% to 48% of cases from 1978 through 1986 but only 7% of cases in a surveillance study (62)
conducted in 1995 in laboratories serving all acute-care hospitals in 22 counties from four states (>10
million population). The incidence of Hib meningitis declined from 2.9 to 0.2 per 100,000 population
from 1986 to 1995, respectively. The median age of patients with bacterial meningitis rose from 15
months to 25 years during this interval, perhaps the most dramatic change in the epidemiology of any
bacterial infection in recent decades. As a result, approximately 70% of bacterial meningitis in the United
States is due to pneumococci or meningococci. In the early pivotal trial in California, invasive (e.g.,
bacteremia and meningitis) pneumococcal disease was virtually eliminated in infants vaccinated with the
heptavalent conjugate vaccine at 2, 4, and 6 months of age. Although targeted to children, recent data
support a “herd” immunity phenomenon, similar to that experienced with Hib conjugate vaccines, leading
to a decline in pneumococcal bacteremia and/or meningitis in the population (including adults) following
introduction of conjugate pneumococcal vaccine in infancy. In another surveillance study among residents
in eight surveillance areas representing 17.4 million persons from 1998 to 2007, the impact of the
heptavalent pneumococcal conjugate vaccine was appreciated in which the incidence of meningitis
caused by vaccine serotypes decreased from 0.61 cases per 100,000 population in 1998 to 1999 to 0.05
cases per 100,000 population in 2006 to 2007, although the number of cases of bacterial meningitis
caused by nonvaccine serotypes increased by 61% (5); the mean age of all patients with meningitis
increased from 30.3 years in 1998 to 1999 to 41.9 years in 2006 to 2007. However, despite the declining
incidence of bacterial meningitis in the United States, the overall case-fatality rates did not change
significantly (15.7% in 1998 to 1999 compared with 14.3% in 2006 to 2007; p = .50).
As shown in Table 24.1, the responsible organisms for community-acquired bacterial meningitis in
adults older than 16 years of age are somewhat different, but S. pneumoniae, N. meningitidis, and L.
monocytogenes predominate. Similar recent (e.g., after 2000) surveys for resource-limited settings are
lacking and sorely needed to guide vaccine strategies in this age-group.
In the following sections, each of the major meningeal pathogens is considered, including relevant
classification schemes. In addition, the potential virulence characteristics of each organism are briefly
discussed.
Haemophilus influenzae
Haemophilus species are small, gram-negative, pleomorphic coccobacilli. They are facultative
anaerobes that grow best anaerobically with 5% to 10% CO2 on blood-enriched media. H. influenzae
requires both X factor (hematin) and V factor (nicotinamide adenine dinucleotide, nicotinamide adenine
dinucleotide phosphate, or nicotinamide nucleoside) for growth under aerobic conditions and is
nonhemolytic. Chocolate agar is most commonly employed for the initial isolation of H. influenzae.
H. influenzae strains are either encapsulated (typeable) or unencapsulated (nontypeable). Encapsulated
strains are classified into six types, designated a through f, according to specific reactions with antisera
directed against epitopes on capsular antigens. Methods for grouping include
counterimmunoelectrophoresis, latex particle agglutination of culture supernatants, immunofluorescence,
and the production of halos surrounding colonies on media containing antisera. Nearly all invasive H.
influenzae infections are caused by serotype b (Hib). The capsule is a repeating polymer of PRP, an
important virulence determinant of this organism (see later discussion). Hib also contains a
lipooligosaccharide (here, designated lipopolysaccharide [LPS] for convenience) in the outer membrane,
an additional virulence determinant. Hib strains have been further classified into subtypes based on
electrophoretic mobility differences among Omps. Although the pathogenic role of these Omps is
uncertain, subtype analysis is useful for epidemiologic studies. For example, in a survey of 256 invasive
isolates from 22 states representing a variety of clinical settings, about 70% of cases were caused by
strains of three subtypes (1H, 2L, and 3L) among the 21 Omp subtypes identified. In contrast, 84% of 80
invasive isolates studied in the Netherlands had the same Omp subtype pattern (type 1, identical to
subtype 3L in the Granoff classification system), and no strains of subtype 1H, 1L, or 2H were found.
It has been recognized, largely on the basis of multilocus enzyme electrophoretic analysis by Musser et
al. (80), that the natural populations of Hib from widely divergent geographic areas are clonal as a
consequence of infrequent recombination of chromosomal genes. For example, 32 distinct multilocus
enzyme genotypes, referred to as electrophoretic types (ETs), were apparent among 177 U.S. isolates by
analysis of 16 metabolic enzymes, but 73% of invasive disease episodes were caused by strains
belonging to only three ETs. In the largest and most comprehensive analysis (80), 2,209 encapsulated H.
influenzae strains (including 1975 Hib) from 30 countries on six continents collected over a 40-year
period were studied by multilocus electrophoresis of 17 chromosomally encoded metabolic enzymes,
Omp subtyping, and the pattern of restriction fragment length polymorphism in the cap region (the
chromosome region responsible for capsular expression). On the basis of allele profiles at the enzyme
loci, 280 distinct ETs in two phylogenetic divisions were identified: the population structure is definitely
clonal. Currently, nearly all invasive disease worldwide is caused by nine clones of Hib. One genetically
distinct clone complex occurs with considerable frequency worldwide, but marked geographic variation
occurs for other clones or clone families. Based on an extensive analysis, it appears that this distribution
of clones on an intercontinental scale is largely accounted for by the patterns of racial/ethnic composition
and historical demographic movements of the human host populations (80).
Neisseria species are non–spore-forming, nonmotile, oxidase-positive, gram-negative cocci (measuring

approximately 0.8 × 0.6 µm) that usually appear as biscuit- or kidney-shaped diplococci on smears of
infected fluids. Because other organisms (e.g., Moraxella species) are similar morphologically,
identification rests on biochemical or immunologic techniques. All Neisseria species are oxidase
positive, and sugar fermentation reactions are usually sufficient for speciation within the genus.
Gonococci ferment glucose (but not maltose or lactose) to acid, whereas meningococci ferment both
glucose and maltose to acid. N. lactamica, a related organism occasionally present in throat cultures,
ferments glucose, maltose, and lactose. Maltose-negative variants of meningococci have been isolated;
these strains may be differentiated from gonococci by fluorescent antibody tests, coagglutination tests, or
electrophoretic analysis of hexokinase isoenzymes. These strains usually acquire the ability to ferment
maltose on subculture; true maltose-negative variants are rare, but this property is genetically linked to
sulfadiazine resistance. Meningococci grow rapidly on blood, chocolate, gonococcal, or enriched
Mueller-Hinton agar in a moist, 3% to 10% CO2 environment at 35°C to 37°C. A modified Thayer-Martin
medium is employed for meningococcal isolation from contaminated sites, as in detection of the carrier
state. The transoral approach for obtaining specimens is more practical and is at least as sensitive as
older transnasal approaches for carrier detection. Because this organism is susceptible to drying and
chilling, all specimens should be inoculated promptly.
As in other gram-negative bacteria, the ultrastructural characteristics of meningococci are complex.
The surface components include capsular polysaccharide, fimbriae or pili, LPS, and Omp; several of
these structures are important virulence determinants. Meningococci are classified by serogroups based
on structural differences among capsular polysaccharides and agglutination reactions with specific
antisera, and they are further defined by serotypes based on analysis of the Omp. Capsular polysaccharide
detected by positive agglutination with reference antisera is uniformly present among invasive isolates,
but 20% to 50% or more of carrier strains are unencapsulated (nongroupable). The serogroups have
important epidemiologic and prevention-related implications. Thirteen serogroups are recognized (43),
designated as follows: A, B, C, D, H, I, K, L, X, Y, Z, 29E, and W135. Most meningococcal disease is
caused by organisms in serogroups A, B, C, and Y, although the proportion of cases caused by serogroup
W135 is increasing. Although serious outbreaks of serogroup A, B, or C disease have occurred
worldwide, most focal outbreaks and endemic disease in many countries are caused by serogroups B and
C. For example, in the United States from 1975 to 1980, the distribution of serogroups among 12,980
cases was as follows: B, 56%; C, 19%; Y, 11%; W135, 10%; and A, 3%. Similar figures were reported
for the period 1978 to 1981 (7). Serogroup W135 disease, especially among adults, has been increasing
in the United States and apparently elsewhere (e.g., Senegal) since 1981. Group B organisms, especially
B:15:P1.16, have emerged as important pathogens in northern Europe, causing serious local outbreaks
peaking in the 10- to 20-year-old group. The continued high prevalence of serogroup B meningococcal
disease has important implications because of the lack of an effective, widely available vaccine against
this serogroup. An outbreak of serogroup C disease occurred in California in 1987 (81). Serious
outbreaks caused by serogroup A continue in Nepal, Saudi Arabia, Chad, Sudan, Burkina Faso, and
elsewhere. Approximately 40,000 cases of serogroup A disease occurred in Ethiopia in the spring of
1989 (Fig. 24.1).
There have been increases in the incidence of serogroup C disease in North America to equal or
surpass the incidence of disease caused by serogroup B (42). From 1985 through 1992, a clonal
serogroup C meningococcal strain (designated ET-15 and defined by multilocus enzyme electrophoresis)
was associated with an increase in both the incidence and the mortality of meningococcal disease in
Canada (82). This and four other closely related clonal strains were also implicated in a marked increase
in outbreaks of serogroup C meningococcal disease in the United States (83). These studies suggested the
emergence of a clonal group of virulent serogroup C meningococcal strains in North America, leading to
an increase in the rate of meningococcal disease in some regions, an increased number of outbreaks, and a
higher case-fatality rate (84).
In an analysis from the United States (85), part of an active and ongoing laboratory-based population-
based surveillance for meningococcal infection from 1992 to 1996, the serogroup distribution for the
three most common isolates was as follows: C, 35%; B, 32%; and Y, 26%. Similar results were noted in
New York City through 2000 (86). In contrast, serogroup B accounted for 75% of meningococcal isolates
in Italy (87). More than 98% of cases of invasive meningococcal disease are sporadic (88). From 1998 to
2007, a total of 2,262 cases of meningococcal disease were reported to the Active Bacterial Core
surveillance sites, with an annual incidence of 0.53 cases per 100,000 population (89). The incidence
decreased from 0.92 cases per 100,000 population in 1998 to 0.33 cases per 100,000 population in 2007;
the incidence decreased to this historic low before the introduction of the quadrivalent meningococcal
conjugate vaccine. Infants younger than 1 year of age had the highest incidence (5.38 cases per 100,000
population), although the distribution of serogroups is also different in this population (serogroup B, 3.08
per 100,000 population; serogroup C, 0.53 per 100,000 population; serogroup Y, 1.50 per 100,000
population). A recent outbreak of serogroup C disease was reported in New York City among men who
have sex with men (90). During the outbreak of meningococcal disease coinciding with the Hajj
pilgrimage in March 2000, the attack rate of W135 disease was 25 cases per 100,000 pilgrims (91); all
outbreak-associated isolates of serogroup W135 were members of a single clone of the hypervirulent ET-
37 complex, which occurred as the result of expansion of a clone that had been in circulation since 1970
(92). A high incidence of serogroup X cases was reported in Niger (93), representing 51% of 1,139
confirmed cases of meningococcal meningitis in 2006; serogroup X disease also emerged in Togo and
Burkina Faso during 2006 to 2010 (94).
Serotypes within a serogroup of N. meningitidis are classified largely on analysis of Omp profiles in
the cell envelope. At least 20 serotypes are recognized (95), resulting in a classification scheme that is
useful in epidemiologic studies. Physicochemical characterization of the Omps, which might be candidate
antigens for vaccines, has led to the designation of five major classes. Class 2 and 3 proteins are the
major porins responsible for aqueous channels in the outer membrane. Class 5 proteins are surface
exposed and may have a role in virulence, but the function of class 1 and 4 proteins is poorly defined. The
serotype designation has important epidemiologic uses and may identify virulence characteristics among
meningococci. For example, serotype 2 (2a, 2b) strains are responsible for approximately 50% of
serogroup B disease (in which 15 serotypes have been described), followed by serotypes 15 and 9; in
contrast, serotypes 4 and 6 have been isolated only from carriers. Serotype 2 is also responsible for about
80% of invasive serogroup C disease and is an important marker for serogroups Y and W135 pathogenic
strains as well (95). All serogroup A meningococci, in contrast, are homogeneous with respect to Omp
and show no homology to serotypes within other serogroups. Serotype analysis has also been linked to
certain clinical characteristics (96). However, this technique is available only in research or reference
laboratories. In addition, at least eight immunotypes of meningococci, classified by differences among
LPS subtypes, are known to exist and may play a role in pathogenesis and disease expression. LPS
immunotype analysis may also be useful in the further characterization of the epidemiology of
meningococcal disease (41,43). The recent availability of monoclonal antibodies to detect variations in
Omp and/or LPS will improve the resolution of these typing systems for epidemiologic analysis.
In addition to classification by serogroup, serotype, and LPS subtype, many reports have focused on
multilocus enzyme electrophoresis for the characterization of the chromosomal genome of isolates and for
estimation of the genetic relatedness among strains (97). These studies, similar to the analysis of Hib
(80), have identified the clonal nature of N. meningitidis and have been useful for epidemiologic
purposes. For example, electrophoretic variation (defined as <17% genetic distance between isolates) in
seven metabolic enzymes and two Omp in 423 isolates of serogroup A strains recovered from 23
epidemics or outbreaks occurring in 38 countries on six continents over a 70-year period since 1915
identified 21 “clones” (designated A I-1 through A IV-4) containing 34 ETs (97). This technique has been
useful for delineating similarities and differences among isolates from cases and carriers before, during,
and after epidemics (98). It has also been useful for tracing movements of epidemic strains geographically
over time (81). For example, following an epidemic in Nepal (1983 to 1984), a single clonal complex of
serogroup A meningococci (III-1, representing 11 closely related ETs) was introduced into Saudi Arabia
in 1987 by Muslim pilgrims traveling to Mecca for the annual hajj (98). The same strain was then
introduced into sub-Saharan Africa following the hajj, causing an explosive outbreak in Chad in 1988. An
analysis of 109 isolates of serogroup B meningococci in Norway has also revealed differences among
carriers and cases (99). Although 78 ETs were identified, 91% of the cases of systemic disease in 1984
were caused by strains from the ET-5–ET-37 complex, whereas these isolates were recovered from only
7% and 9%, respectively, of healthy carriers. The most common clonal complex found among carriers
was never isolated from patients with invasive disease, suggesting a low virulence potential for these
clones. Two clones, ET-15 and ET-508, have been associated with outbreaks of meningococcal infection
in North America (82,83,100). Clonal analysis will undoubtedly continue to contribute important
information on the epidemiology of meningococcal infection, and it may prove useful in an analysis of
virulence properties. As noted earlier, serogroup W135 has been circulating, particularly among pilgrims
to Mecca during the hajj since 2000 in Africa, the Middle East, and worldwide (attack rate ≥25/100,000);
all isolates were members of a single hypervirulent ET-37 complex (91,92). This occurred through the
expansion of a clone that had been circulating since 1970. Vaccination with quadrivalent vaccine in hajj
pilgrims from several areas (e.g., North America, Western Europe) appears to have reduced transmission
of W135 meningococci to close contacts upon return (101,102).
The putative meningococcal virulence characteristics are as follows:
■ Capsular polysaccharide
■ Pili
■ IgA protease
■ LPS (endotoxin)
■ Omps
■ Outer membrane vesicles, or blebs
■ Metabolic pathways (e.g., iron)
As noted earlier, all isolates from invasive infections are encapsulated (serogroup positive), but 20%
to 90% of isolates from carriers are unencapsulated (nontypeable). The capsular polysaccharide appears
to be essential for meningococcal virulence, probably because of its antiphagocytic properties that allow
the organism to escape host phagocytic clearance mechanisms within the bloodstream and/or CSF. Pili are
protein surface appendages composed of identical pilin-repeating subunits. Pili from meningococci and
gonococci are morphologically and chemically similar. Cross-reacting antibodies bind to a short peptide
sequence (residues 69 to 94) of gonococcal pili that is essential for receptor-binding function. Fresh
meningococcal isolates from carriers and cases contain 7 to 40 pili per diplococcus. Pili are important
mediators of meningococcal adhesion to human nonciliated columnar nasopharyngeal epithelial cells, an
important early step in the development of the carrier state. Extracellular proteases that cleave the IgA1
heavy chain in the hinge region are elaborated by pathogenic Neisseria species (i.e., meningococci and
gonococci). Although the role of IgA proteases in the pathogenesis of disease is controversial, these
enzymes are produced by only a few organisms (e.g., N. meningitidis, Neisseria gonorrhoeae, H.
influenzae, S. pneumoniae, and Streptococcus sanguinis), many of which are important meningeal
pathogens and may promote invasion at the pharyngeal portal of entry. Meningococcal LPS resembles H.
influenzae LPS by a lack of the O-antigenic polysaccharide side chains found in enteric bacilli despite a
smooth phenotype and proven virulence. LPS is clearly important in the genesis of an array of the clinical
manifestations of meningococcemia and/or meningitis (see later discussion). Although the specific role
for Omp in meningococcal virulence is unclear, these organisms release substantial amounts of cell
surface material (in the form of outer membrane vesicles containing Omp and LPS) during growth in vitro
and in vivo in the absence of cell lysis, a process exacerbated by antimicrobial agents. These outer
membrane vesicles, or blebs, represent relevant vehicles for central nervous system (CNS) tissue damage
during meningococcal infection (see later discussion). Tissue invasion may also be facilitated by the
ability of meningococci to obtain iron from transferrin.
Pneumococci are non–spore-forming, nonmotile, small (approximately 0.8 µm), gram-positive

streptococci that typically appear as lancet-shaped diplococci with the tapered ends in juxtaposition in
clinical specimens. They tend to associate in pairs rather than in short chains, although the latter
morphology is facilitated by broth culture. Pneumococci are facultative anaerobes that flourish in a
variety of supplemented artificial media. Optimal growth occurs in various media supplemented with
serum or blood and glucose, at a pH level of 7.8 and a temperature of 37°C in an enriched CO2
environment. The organisms are catalase negative and relatively fastidious. Colonies on blood agar are
initially dome shaped, but they become umbilicated with time as a result of the activity of autolytic
enzymes (L-alaninemuramylamidase). Pneumococci are α-hemolytic (i.e., a greenish discoloration
surrounds colonies on blood agar), although β-hemolysis occurs under anaerobic conditions. S.
pneumoniae must be separated from other α-hemolytic streptococci in the laboratory; this is usually
accomplished with a disk susceptibility test using the unique susceptibility of pneumococci to Optochin
(ethylhydrocupreine hydrochloride). Pneumococci, but not other streptococci, are also sensitive to bile or
bile salts (e.g., 10% deoxycholate), but the bile solubility test is now rarely performed in hospital
laboratories.
Pneumococci are classified within serotypes on the basis of antigenic differences among capsular
polysaccharides. These capsular substances are complex polysaccharides that form hydrophilic gels on
the surface of the organism. At present, at least 90 serotypes have been identified, classified by two
systems of nomenclature (American and Danish). Capsular polysaccharides are identified by
agglutination; the Neufeld quellung reaction, characterized by capsular swelling and increased refraction
in the presence of antisera, also useful for identifying pneumococci in clinical specimens (e.g., CSF);
precipitation; and counterimmunoelectrophoresis. It is important to emphasize that cross reactions exist
between individual pneumococcal serotypes, as well as with other bacteria (e.g., E. coli, Klebsiella
pneumoniae, Hib, and S. sanguinis). For example, serotype 14 pneumococcal capsular polysaccharide
cross-reacts with type III group B streptococci and with certain human ABO blood group isoantigens.
Capsular polysaccharide is essential for pneumococcal virulence, and a few serotypes are associated
with most invasive infections. Encapsulated organisms (smooth colonies on agar) are virulent for humans
and experimental animals, whereas unencapsulated (rough colonies on agar) strains are avirulent.
Capsular polysaccharide enhances virulence through its antiphagocytic properties, as in Hib and
meningococci.
Of the more than 90 known pneumococcal serotypes, only a few (usually the lower number types rather
than the higher number types commonly found in the carrier state) account for most invasive
pneumococcal infections. The predominant capsular types were types 1, 2, and 3 in the preantibiotic era.
A different pattern has emerged in the past 40 years, and it differs between adults and children. A few
capsular types cause the majority of bacteremic cases among adults: types 1, 3, 4, 7, 8, 9, 12, and 14, and
less commonly types 6, 18, and 19 (these are not listed in rank order). Approximately 65% of cases are
caused by eight serotypes, although no single serotype predominates among bacteremic adults. Capsular
types 14, 6, 18, 19, 23, 1, 4, and 9 cause approximately 85% of serious infections in children, a pattern
different from that observed in adults. Perhaps more important with respect to this discussion, there is a
very strong correlation between serotypes causing pneumonia (or bacteremia) and those responsible for
pneumococcal meningitis (69). For example, 76% to 86% of blood and CSF isolates were included
among the 14 serotypes represented in the original pneumococcal vaccine. However, marked geographic
variations exist among pneumococcal serotypes causing invasive disease, and the serotype distribution
may change over time in a given locale. Furthermore, some serotypes may be more virulent than others
and associated with less favorable outcomes, including death. Older studies of pneumococcal meningitis
in the 1950s (summarized by Scheld [69]) noted an increased mortality with disease caused by serotypes
2, 8, and 12. Although type 12 caused only 2.5% of cases, it was responsible for 30.7% of the deaths.
Similarly, serotype 6 was associated with four of eight deaths in a more recent survey.
The role of other cell surface components (such as C-polysaccharide antigens, cell wall antigens, M-
or R-protein antigens) and putative toxins (such as hemolysin, neuraminidase, purpura-producing
principle) in the pathogenesis and pathophysiology of pneumococcal meningitis remains poorly defined.
Nevertheless, CSF inflammation is induced by pneumococcal cell wall and its constituents (particularly
lipoteichoic acid) but not by purified pneumococcal capsular polysaccharide (see later discussion).
Gram-Negative Bacilli
Approximately 84% of cases of neonatal meningitis and sepsis attributable to E. coli are caused by
strains bearing the K1 capsular polysaccharide antigen; this capsular type serves as a marker of
neurovirulence. In addition to the K1 capsule, multiple other potential virulence factors for blood–brain
barrier (BBB) traversal and meningitis have been documented in E. coli from phylogenetic groups A, D,
and B2 (e.g., O45:K1 and O18:K1 strains) (103).
Aerobic gram-negative bacilli have become increasingly important in patients with bacterial meningitis
(104). Beyond the neonatal period, aerobic gram-negative bacillary meningitis occurs in three major
clinical settings: head trauma (approximately 30% of cases, especially in conjunction with CSF
rhinorrhea or otorrhea); after neurosurgical procedures (approximately 50% of cases); and in association
with other conditions (approximately 20% of cases), including strongyloidiasis, gram-negative
bacteremia, ruptured brain abscess, or impairment of host defense mechanisms (e.g., steroids or AIDS).
Many of these infections are nosocomial in origin, although community-acquired gram-negative bacillary
meningitis is increasing in frequency, particularly in the elderly older than 71 years and in debilitated,
alcoholic, or diabetic adults (105–107). The most common causes of gram-negative aerobic bacillary
meningitis beyond the first month of life include Klebsiella species (about 40% of cases), E. coli (roughly
15% to 30%), and Pseudomonas aeruginosa (about 10% to 20%). In a recent study from Korea of 91
adult patients with nosocomial meningitis, Acinetobacter species accounted for 32.5% of cases (108).
Streptococcus agalactiae
Group B streptococci are the most common cause of invasive neonatal disease in the United States,
accounting for approximately 11,000 cases of meningitis and/or bacteremia yearly. The incidence of
group B streptococcal neonatal infections has remained relatively stable in this country until recently
(109). The use of antimicrobial agents (e.g., ampicillin) in pregnant women with vaginal colonization
with group B streptococci at the time of delivery has led to a decline in the incidence of neonatal invasive
group B streptococcal disease, perhaps, as suggested by one study, with an increase in ampicillin-
resistant E. coli early-onset sepsis in low-birth-weight infants (110). However, it appears to be
increasing in frequency in the developing world.
Group B streptococci are classified into six main serotypes (designated Ia, Ib/c, Ia/c, II, III, and IV)
based on the expression of type-specific capsular polysaccharide antigens and various surface proteins as
additional antigenic markers (111); additional candidate serotypes are under evaluation. Although all
serotypes have been isolated from neonates with invasive disease, type III is responsible for the vast
majority of meningeal infections, suggesting a high virulence potential and/or CNS tropism for this
serotype. The chromosomal genetic diversity of S. agalactiae was studied and the clonal nature of the
native bacterial populations was again demonstrated (112). A collection of 128 isolates representing all
six serotypes, including 44 type III isolates from invasive episodes (18 recovered from CSF), were
subjected to multilocus enzyme electrophoresis, an analysis based on electrophoretically demonstrable
allelic profiles at 11 metabolic enzyme loci, all encoded at the chromosome level. Nineteen distinct ETs
were identified in two primary phylogenetic divisions, each representing a multilocus clonal genotype. A
single ET (ET-1), comprising 40 isolates of serotype III group B streptococci, formed the first
phylogenetic division. These strains produced greater amounts of neuraminidase and were more virulent
than the other type III isolates found in several of the 18 ETs in the second division. This newly evolved
clone (ET-1) is responsible for most invasive disease episodes caused by group B streptococci type III in
the United States (112). Overall, approximately 52% of group B streptococcal meningitis cases in the
United States occur during the first month of life. In one recent review of 444 cases of neonatal bacterial
meningitis over a 7-year period, group B streptococcus was the most common etiology in early-onset
(occurring between day 0 to 4 of birth) and late-onset (occurring between day 5 and 28 of birth) disease,
responsible for 77% and 50% of cases, respectively (113). In the United States, the overall mortality rate
ranges from 7% to 27%. Survivors of group B streptococcal meningitis also have substantial long-term
morbidity (114), indicating the need for ongoing developmental follow-up and the development of
preventive strategies (see later discussion).
In addition to the common conditions of neonatal meningitis and postpartum fever and/or bacteremia in
parturient women caused by group B streptococci, these organisms also cause serious infections in adults,
including meningitis (115,116). Risk factors in adults include age older than 60 years, diabetes mellitus,
parturition, cardiac disease, collagen-vascular diseases, malignancy, alcoholism, hepatic failure, renal
failure, corticosteroid therapy, decubitus ulcers, neurogenic bladder, previous stroke, and AIDS. No
underlying illnesses were found in 43% of patients in one review (116).
L. monocytogenes remains an important cause of neonatal meningitis; the source is the genital tract or
subclinical infection of the mother. Although L. monocytogenes may cause meningitis in normal adults,
most patients are diabetic, alcoholic, elderly, or immunosuppressed. L. monocytogenes had been the
major cause of bacterial meningitis among renal transplant recipients, but this is decreasing in frequency
as a result of the use of TMP-SMX prophylaxis.
L. monocytogenes is widespread. Although clusters of nosocomial cases and focal outbreaks are
reported, most cases of human listeriosis are sporadic. The incidence of L. monocytogenes infections is
difficult to quantitate. Many countries in northern Europe have reported annual incidence figures of
approximately 2 to 3 per million. After a large (142 cases) food-borne outbreak in Los Angeles County,
California, in 1985, mandatory reporting of L. monocytogenes isolates by clinical laboratories was
instituted. During the first year of active surveillance, 94 cases of listeriosis were reported (117), for an
annual crude incidence of 11.7 per million persons, similar to figures (11.3 per million annually) reported
from France in 1984. Listeriosis is undoubtedly underreported.
Approximately one third of cases in the United States are in neonates and/or their mothers (39% in the
Los Angeles survey) (117). The proportion of perinatal infections in Europe is higher. Among the
nonperinatal cases, various risk factors for listeriosis were identified, including immunosuppression as a
documented history of steroid ingestion or chemotherapy (35% of cases, the single most important risk
factor); age older than 75 years; renal disease; cancer; alcoholism and/or cirrhosis; and AIDS.
Nevertheless, serious Listeria infections, including meningitis, remain uncommon in patients with AIDS
(118,119), but diagnosis of Listeria meningitis in anyone younger than 50 years of age should prompt
testing for HIV, if not done previously. Of the nonperinatal cases, only 2 of 57 had no definable underlying
risk factor; 21 of 57 had meningitis (117). As stated earlier, L. monocytogenes remains a distinctly
unusual cause of meningitis in developing countries. Listerial infection is most common in infants younger
than 1 month of age (up to 10% of cases), adults older than 60 years of age, alcoholics, cancer patients,
those receiving corticosteroid therapy, and immunosuppressed adults (e.g., renal transplant recipients)
(120–122). In one recent study, patients with chronic lymphocytic leukemia had a greater than 1,000-fold
risk of acquiring listeriosis (123). Other predisposing conditions include diabetes mellitus, liver disease,
chronic renal disease, collagen-vascular diseases, pregnancy, and conditions associated with iron
overload. Listeria meningitis has also been reported with use of anti–tumor necrosis factor-α (TNF-α)
agents, such as infliximab in patients with Crohn disease (124) and ulcerative colitis (125), and
etanercept in a patient with adult Still disease (126). Meningitis can also occur in immunocompetent
children and adults (127,128). In nonperinatal cases, the route of transmission is often unknown. At least
1% of normal individuals excrete the organism in their stools, but contacts of symptomatic patients have
much higher excretion rates (approximately 25%). Nevertheless, the true carriage rate, its duration, and
its relationship to invasive disease are poorly defined. Although often considered a zoonosis, most
patients do not report animal exposure. Reports have emphasized food-borne transmission of L.
monocytogenes, a route of transmission that accounts for the overwhelming majority of sporadic cases.
Many foods have been implicated, including coleslaw, Mexican-style cheese, raw vegetables, seafood,
pasteurized milk, Swiss cheese, raw hot dogs, undercooked chicken, alfalfa sprouts, cantaloupe, diced
celery, hog head cheese (a meat jelly made from hog heads and feet), and processed meats, thus pointing
to the intestinal tract as the usual portal of entry (120,122,129–134). In one outbreak, 57 cases of
listeriosis occurred in western Switzerland in association with the consumption of soft cheese (135); 40%
of these cases were meningitis and 39% were meningoencephalitis. Some studies report a higher
frequency of listeriosis in summer, opposite to the seasonal pattern seen with most other forms of
bacterial meningitis. However, the incidence of invasive listeriosis has been decreasing, likely a result of
a decrease in the prevalence of L. monocytogenes contamination of ready-to-eat food (136); this has been
associated with a decrease in nonperinatal listeriosis-associated deaths (137).
L. monocytogenes is a gram-positive, non–spore-forming, catalase-positive, aerobic rod that may be
difficult to culture on initial isolation but that, once grown, passes readily on a variety of laboratory
media. The organisms may appear coccoid on Gram stains of clinical specimens, particularly CSF, and
are often mistaken for pneumococci. More importantly, L. monocytogenes resembles diphtheroids and
may thus be dismissed as a “contaminant,” a grave error. The presence of α-hemolysis and a
characteristic tumbling motility at room temperature are used to separate L. monocytogenes from similar
diphtheroid-like organisms. A hemolytic and cytolytic toxin (listeriolysin 0) of 52 kd appears essential for
virulence; the toxin is expressed under conditions of low pH and low iron concentration and may
facilitate phagolysosomal disruption and growth within mononuclear phagocytes. At least 11 serotypes
are recognized, but more than 90% of invasive infections are caused by three serotypes: Ia, Ib, and IVb.
The rate of unfavorable outcome among adults with Listeria meningitis was recently found to increase
over a 14-year period from 27% to 61%, with the emerging L. monocytogenes serotype ST6 identified as
the main factor leading to a poorer prognosis (138).
Staphylococcus epidermidis
Coagulase-negative staphylococci are very rare causes of bacterial meningitis in children and adults,
except in the setting of an indwelling CSF shunt, where these organisms are the most prevalent pathogen.
Therefore, this group is discussed elsewhere in this volume.
Staphylococcus aureus
Meningitis caused by Staphylococcus aureus is relatively unusual; this organism was responsible for
0.8% to 8.8% of cases in various surveys (139,140). S. aureus is the second most common cause of CSF
shunt infections, accounting for 12% to 36% of cases. This organism is also frequently isolated from
patients with nosocomial meningitis and is responsible for approximately 20% of such cases. Although
secondary meningitis in the setting of infective endocarditis is an uncommon event, most of these
infections are caused by S. aureus. Other important associated conditions have been recognized, including
head trauma, neurosurgical procedures, various abscesses (cerebral, epidural, oral, abdominal), sinusitis,
osteomyelitis, decubitus ulcers, pneumonia, cellulitis, injection drug use, malignancy, and infected
intravascular grafts or shunts. Several other predisposing factors have been proposed. In a retrospective
review of 28 cases of S. aureus meningitis seen from 1972 to 1982 at three North Carolina teaching
hospitals, 22 occurred beyond the neonatal period (140). Among the adult patients (n = 20; mean age 52
years), 45% had an underlying condition (diabetes mellitus, malignancy, renal failure,
immunosuppression), 35% had had head trauma or undergone neurosurgery (ventriculoperitoneal shunt,
craniotomy), and about 20% developed meningitis in association with endocarditis or a paraspinal
infection. Mortality was high (50% in adults), especially when S. aureus meningitis complicated a distant
extracranial focus of infection (five of the six patients with purulent meningitis during active endocarditis
died) (140). The prognosis for S. aureus infections of CSF shunts is more favorable. In a review of
clinical and bacteriologic data from 61 postoperative and 43 hematogenous cases of S. aureus meningitis
from Denmark, postoperative cases had a lower mortality rate (18%) than cases resulting from
hematogenous spread (56%); hematogenous S. aureus meningitis had a higher mortality rate related to
age, presence of shock, and infections with strains of phage type 95 (141). Hospital-acquired cases are
often caused by methicillin-resistant strains (142). In one series from 1999 to 2008 (143), S. aureus
accounted for approximately 5% of cases of culture-proven bacterial meningitis in adults; since 2005,
more than 75% of all cases were caused by methicillin-resistant Staphylococcus aureus (MRSA) and
52% (11 of 21 cases) of hematogenous cases were seen in injection drug users. In a multicenter review of
86 cases of MRSA meningitis in adults (144), the infection was nosocomial in 93% of cases; in those
patients with postoperative meningitis, the most common predisposing conditions were the presence of
CSF devices, neurosurgery, CSF leaks, and head trauma.
Anaerobic Bacteria
Meningitis caused by anaerobic bacteria is rare, accounting for fewer than 1% of pyogenic cases, except
following the intraventricular rupture of a brain abscess. Anaerobic meningitis may be underrecognized
because CSF is not routinely cultured anaerobically. Enriched media and proper transport of CSF to the
laboratory, which are essential for isolation of anaerobes, are not uniformly performed. Only five cases
caused by strict anaerobes were reported among 18,642 patients analyzed by the CDC in one study (7).
Anaerobic meningitis is associated with a variety of clinical conditions, including rupture of brain
abscess or extension to the surface of the brain; chronic otitis, mastoiditis, or sinusitis; head trauma;
neurosurgical procedures (e.g., craniotomy, laminectomy); congenital dural defects; abdominal trauma or
surgery; gastrointestinal disease; head and neck cancer; suppurative pharyngitis; CSF shunts; and
immunosuppression (particularly corticosteroid administration) (145,146). Most cases arise from spread
of infection secondary to a contiguous focus of disease; anaerobic meningitis rarely complicates
bacteremia from a distant extracranial focus.
A variety of bacterial species are responsible for anaerobic meningitis. Only nine cases of Bacteroides
fragilis meningitis unaccompanied by a brain abscess had been reported in the modern era through 1987
(147). Seven occurred in premature infants or neonates (median age, 20 days), thereby complicating
congenital defects or gastrointestinal disease such as necrotizing enterocolitis (148). Meningitis caused
by Fusobacterium species, usually Fusobacterium necrophorum, generally occurs in older children
(median age, about 5 years) or adults as a complication of acute or chronic otitis media (148). A variety
of anaerobic gram-positive cocci have been isolated in a few cases, particularly peptostreptococci.
Meningitis caused by Clostridium species almost always develops following head trauma or a
neurosurgical procedure. For example, in a summary of 17 cases caused by Clostridium perfringens
(149), only 3 were not associated with CNS trauma or surgery. Although the disease course is highly
variable, some cases of clostridial meningitis are characterized by intracranial gas formation, visible on
plain skull radiographs or computed tomography (CT); CSF white blood cell (WBC) concentrations
exceeding 20,000/mm3; and death within hours of presentation. A few cases of meningitis caused by
Actinomyces species (in the absence of brain abscess formation) and Propionibacterium acnes (usually
subacute with a predominantly monocytic CSF pleocytosis) have also been reported. In approximately
one eighth of patients, the infection is mixed, with anaerobic plus aerobic or microaerophilic organisms
recovered from CSF.
Unusual Etiologic Agents
CNS infections caused by higher bacteria (e.g., Mycobacterium species, Nocardia species, Actinomyces
species), spirochetes (e.g., Treponema pallidum, Borrelia burgdorferi, Leptospira species), Brucella
species, and so on, are discussed elsewhere in this volume. A plethora of bacteria have been documented
as the cause of meningitis in isolated case reports or in small numbers of patients, including group A
streptococci usually in association with pharyngitis, otitis media, and/or sinusitis (150);
nonpneumococcal α-hemolytic streptococci such as Streptococcus mitis (151); enterococci (152,153);
Streptococcus gallolyticus; diphtheroids (although P. acnes is an important etiologic agent in patients
with CSF shunt and drain infections); N. gonorrhoeae (approximately 30 cases reported in the past 20
years); Neisseria subflava; Gardnerella vaginalis (one case report); many members of the
Enterobacteriaceae in addition to E. coli and Salmonella species; Flavobacterium meningosepticum;
Haemophilus species other than H. influenzae; and many others. Fewer than 0.5% of adult cases of
bacterial meningitis are caused by group C streptococci but may occur in humans after contact with
domestic animals (especially horses) or their unpasteurized products (154,155); however, mortality is
high, perhaps because of the unpredictable susceptibility of this organism to β-lactam agents.
Despite the frequency with which the viridans streptococci cause bacteremia, they are unusual causes
of meningitis (0.3% to 5% of culture-proven cases) (156). Streptococcus salivarius meningitis has been
reported following spinal anesthesia (157,158) and myelogram procedures (159), supporting the
importance of appropriate infection control practices (i.e., masks, proper aseptic technique, and safe
injection practice) in those who perform spinal procedures. Streptococcus suis is the most frequent cause
of bacterial meningitis in southern Vietnam and is associated with significant morbidity attributable to
hearing loss (160); the pig is the natural reservoir of this microorganism and the main source of human
infection. Risk factors for S. suis meningitis include eating “high-risk” dishes (such as undercooked pig
blood or pig intestine) popular in parts of Asia, occupational exposure to pigs, and exposures to pig or
pork in the presence of skin injuries (161).
Polymicrobial bacterial meningitis, with simultaneous recovery of two or more bacterial species from
CSF, is unusual. Mixed infections account for about 1% of bacterial meningitis cases. In a review of 34
series encompassing 11,281 cases of bacterial meningitis, 116 cases (1%) were mixed (162). This
condition appears to be evolving in the antibiotic era. Before 1950, nearly all cases occurred in children
and were caused by combinations of bacteria commonly associated with meningitis (the three major
meningeal pathogens). Since 1950, most cases have occurred in adults, with a wider spectrum of etiologic
agents, particularly gram-negative aerobic bacilli. Approximately one third of cases were nosocomially
acquired. Common predisposing conditions in the older population affected since 1950 include
contiguous foci of infection, tumors in close proximity to the neuraxis (e.g., head and neck), rectal
carcinoma, or fistulous communications with the CNS. The mortality rate is 63% for cases occurring after
1950. Several cases of meningitis caused by mixed bacterial and mycobacterial or fungal agents have also
been reported.
Simultaneous isolation of viruses and bacteria from the CSF is rare; only seven well-documented cases
were reported prior to 1988 (163). However, in a 1-year retrospective review from the Ohio State
University published in 1986, 5 (2.8%) of 176 children with CSF enteroviral isolates also had bacterial
meningitis (163). Conversely, CSF samples from 5 (4.8%) of 105 children with bacterial meningitis also
grew an enterovirus. All the patients presented in late summer at the peak of the enterovirus season, and
each case was caused by a different bacterial pathogen. Because the CSF formula was indistinguishable
from that of patients with typical bacterial meningitis, and because the clinical course and response to
therapy were similar to those of patients with typical bacterial meningitis, this condition may be
underrecognized, as CSF viral cultures are rarely performed when bacterial meningitis is the likely
diagnosis.

Despite the availability of effective antimicrobial therapy, bacterial meningitis continues to be a
potentially fatal illness. Several investigators have examined the pathogenic and pathophysiologic
mechanisms operating in meningitis, with the aim of improving the outcome of patients with this disorder.
These pathogenetic and pathophysiologic mechanisms are discussed in detail in Chapter 23 and are
detailed in a number of excellent reviews (164–174).
PATHOLOGY
Adams et al. (175) described the pathology of bacterial meningitis in 1948 based on examination of
autopsy material from patients with H. influenzae meningitis. Experimental models of bacterial
meningitis, knowledge of host defense mechanisms, and the pathophysiology of associated complications
have subsequently allowed for a more complete understanding of the pathologic processes operating in
this disorder.
Bacteria reach the meninges through one of the following pathways: (a) hematogenous dissemination
from a distant site (e.g., nasopharynx, lung, skin, and genitourinary tract); (b) spread from an adjacent
suppurative focus of infection (e.g., otitis media, sinusitis, and mastoiditis); and (c) a congenital or an
acquired structural defect (176).
Once bacteria gain access to the SAS, an inflammatory process ensues (Fig. 24.2). Neutrophils migrate
into the SAS, producing a purulent exudate. On gross examination, the exudate has a gray-yellow or
yellow-green appearance (Fig. 24.3). It is most abundant in the cisterns at the base of the brain and over
the convexities of the hemispheres in the rolandic and sylvian sulci (175) (Fig. 24.4). The tendency for
exudate to accumulate in the cisterns at the base of the brain is explained by the anatomy of the SAS,
which is deepest at the base of the brain. The various cisterns are expansions of the SAS, with the largest
of these areas lying between the cerebellum and medulla and extending downward below the foramen
magnum, the so-called cisterna magna or cerebellomedullary cistern (177). Purulent exudate
accumulates in this cistern and extends into the other basal cisterns and onto the posterior surface of the
spinal cord (Figs. 24.5 and 24.6). The exudate also extends into the arachnoidal sheaths of the cranial
nerves and into the perivascular spaces of the cortex. A small amount of exudate may be found in the
ventricular fluid and attached to the ventricular walls and choroid plexus; thus, the appearance of the
ventricular fluid is usually cloudy by the end of the first week of the infection (175).
Microscopic examination of the subarachnoid exudate in the early stages of infection demonstrates
large numbers of neutrophils and bacteria (lying either free in the exudate or within neutrophils) (Fig.
24.7) (176). The role of the neutrophil in eradicating infection at this stage is unknown. The presence of
free-living bacteria in the exudate suggests that phagocytosis by neutrophils is incomplete as a result of
deficient opsonic activity in CSF; however, low CSF leukocyte concentrations in the presence of high
CSF bacterial concentrations have been associated with a poor prognosis in both experimental and human
meningitis (178). These observations suggest that the neutrophils have a beneficial role in partial control
of the early stages of the infection. The presence of large numbers of neutrophils in the SAS and vessel
walls may, however, also be detrimental to the host, as is discussed in the previous section.
Within the first 48 to 72 hours of infection, there is evidence of inflammation in the walls of the small
and medium-sized subarachnoid arteries (Fig. 24.8). The endothelial cells swell and multiply, narrowing
the lumen. The adventitia is infiltrated by neutrophils, and neutrophils and lymphocytes form a layer
beneath the intima (Fig. 24.9). Subintimal arterial infiltration by neutrophils and lymphocytes is relatively
unique to infection of the meninges, and it may be related to the anatomy of the meningeal arteries. It is
only rarely observed in inflammatory processes in other organs (175). The adventitia of the subarachnoid
vessels, as they enter the brain parenchyma, is formed by the arachnoid membrane. As arteries and veins
enter the brain parenchyma, they carry with them a sleeve of arachnoid immediately surrounding the
vessels and a sleeve of pia mater external to this. Between these two layers lies an extension of the SAS,
known as the perivascular space or Virchow-Robin space, which is filled with CSF (177) (Fig. 24.10).
Because the vessel wall is enveloped by the arachnoid membrane, it is affected early by any inflammatory
process in the meninges. However, as shown in animal models of bacterial meningitis, the arachnoid
membrane generally remains intact.
The meningeal veins become distended and develop mural inflammation during bacterial meningitis.
There may be focal necrosis of the vessel wall, along with mural thrombus formation in the lumen of the
vein or in the dural sinus (175) (Fig. 24.11). Hemorrhagic cortical infarction is the result of cortical
venous and dural sinus thrombosis.
Toward the end of the first week of meningeal infection, there is a change in the cellular composition of
the subarachnoid exudate. Neutrophils begin to degenerate and are removed by macrophages, which are
derived from meningeal histiocytes. Lymphocytes and fibroblasts proliferate in the exudate. Microscopic
changes in the brain parenchyma may also be present. The nuclei of neurons and glial cells become
shrunken, pyknotic, and darkly staining (Fig. 24.12). Rod-shaped microglial cells and astrocytes increase
in number in the cerebral and cerebellar cortex, brainstem, and spinal cord (Fig. 24.13). Astrocytic
processes become swollen (Fig. 24.14). There is a loss of myelinated fibers in the subcortical white
matter, cerebellum, and brainstem (175). Similar morphologic changes are seen in ischemic and hypoxic
cortical injury, suggesting that ischemia and/or hypoxia may contribute to the pathologic changes from
bacterial meningitis at this stage.
Also at the end of the first week of the infection, there is infiltration of the subependymal tissues and
perivascular spaces by neutrophils and lymphocytes. The ependymal and subependymal tissues become
edematous, and cells begin to die; desquamation of the ependymal lining also occurs. Rod-shaped
microglial cells and swollen astrocytes proliferate and overgrow the remnants of the ependymal lining.
An inflammatory infiltrate in the walls of the subependymal arteries may occlude the vessel, leading to
tissue necrosis (175).
As the infection progresses, the subarachnoid exudate continues to accumulate. In some areas, it may
become several millimeters thick (Fig. 24.15). Toward the end of the second week, the exudate separates
into two layers. The outer layer, just beneath the arachnoid membrane, is composed of neutrophils and
fibrin. The inner layer, which is contiguous with the pia, is composed of lymphocytes, plasma cells, and
macrophages (175). As the subarachnoid exudate continues to accumulate, the flow of CSF may become
obstructed.
The dynamics involved in obstruction of CSF flow are as follows: the bulk of CSF is formed by the
choroid plexus in the lateral and third ventricles, and it flows through the cerebral aqueduct into the fourth
ventricle. CSF leaves the fourth ventricle through the midline foramen of Magendie and the lateral
foramina of Luschka to reach the SAS (177). When the foramina of Magendie and Luschka are blocked by
exudate, the spinal fluid cannot circulate to the convexities of the brain, where it is normally absorbed.
The flow of CSF is blocked at the level of the fourth ventricle, resulting in noncommunicating or
obstructive hydrocephalus (Fig. 24.16).
From the fourth ventricle, CSF normally flows to the SAS at the base of the brain. From here, CSF
flows up over the convexity of the hemispheres to be absorbed by the arachnoid villi in the intracranial
venous sinuses (177). The presence of a fibrinopurulent exudate in the SAS interferes with the absorption
of CSF by the arachnoid villi. This obstruction to CSF resorption resulting from inflammatory changes in
the arachnoid granulations results in communicating hydrocephalus. When the subarachnoid exudate has
been present for several weeks, there are (a) marked fibrosis of the arachnoid villi and (b) pockets of
exudate walled off by adhesions between the arachnoid membrane and dura (175). These fibrotic changes
produce further mechanical obstruction to the resorption of CSF by the arachnoid villi. The end results
are (a) transependymal movement of CSF from the ventricular system into the brain parenchyma and (b)
the development of interstitial cerebral edema.
The development of diffuse cerebral edema and increased ICP further complicates the pathologic
changes already described. Cerebral edema is defined as an increase in the volume of the brain resulting
from an increased water content (179) (Fig. 24.17). The cerebral edema in meningitis is a combination of
vasogenic, cytotoxic, and interstitial edema (170). Vasogenic edema is a result of increased permeability
of brain capillaries with the subsequent accumulation of water and protein molecules in the extracellular
space, mainly in the subcortical white matter. Cytotoxic edema is caused by an accumulation of
intracellular water and sodium with subsequent swelling of cells. Membrane polyunsaturated fatty acids
and other toxic factors released from leukocytes contribute to the development of cytotoxic edema (69).
Interstitial edema is a result of obstruction to CSF resorption, as discussed earlier in this chapter.
Cerebral edema leads to an increase in ICP, and increased ICP adversely affects cerebral perfusion
pressure (CPP), defined as the difference between the systemic mean arterial pressure (MAP) and the
ICP: CPP = MAP − ICP (180). Cerebral blood flow may be maintained at normal or near-normal levels in
the presence of increased ICP, provided that the CPP is maintained at a range of at least 50 to 60 mm Hg.
As ICP continues to rise, or if systemic arterial pressure decreases, cerebral ischemia and infarction may
result.
Experimental evidence exists for a loss of autoregulation of cerebral blood flow in bacterial meningitis
(181). This is another potential contributing factor to the development of cerebral ischemia in this
infection. Cerebral blood flow is normally constant within a range of mean systemic arterial pressure
from 50 to 150 mm Hg. When autoregulation is disturbed, systemic hypotension results in decreased
cerebral blood flow and cerebral ischemia (182).
Cerebral edema may lead to herniation of brain tissue. Herniation may compress intracerebral arteries,
leading to ischemia and infarction; it may also compress the surface of the brain against the dura, leading
to necrosis of brain tissue. Tonsillar herniation, the downward displacement of the cerebellar tonsils
through the foramen magnum, can result in apnea, hemodynamic instability, coma, and death (177,183).
The pathologic lesions described are typical of meningitis caused by bacteria, but some distinctions
among lesions caused by H. influenzae, N. meningitidis, and S. pneumoniae infection have been
observed. The subarachnoid exudate in H. influenzae meningitis is very thick and purulent, with loculated
pockets of pus in the basilar cisterns and cerebral sulci. In contrast, the exudate in pneumococcal
meningitis tends to be more extensive over the convexities of the hemispheres than in the basilar cisterns
(Fig. 24.18). In meningococcal meningitis, the pathologic changes depend on the severity and duration of
the infection. In acute fulminating meningococcemia, death may occur before pus can accumulate in the
SAS. At autopsy, severe hyperemia and swelling of cerebral tissue are evident, with petechial
hemorrhages in the gray and white matter (Fig. 24.19) and in the subependymal regions of the lateral
ventricles. A hemorrhagic ependymitis is typical of severe lethal meningococcal infection (Fig. 24.20).
The presence of pus in the SAS may be evident only by microscopic examination (183). The pathologic
changes in meningococcal meningitis of longer duration are similar to those described for meningitis
caused by pyogenic organisms in general.
Cranial and spinal nerve deficits, focal neurologic deficits, seizure disorders, and subdural effusions
are well-recognized complications of meningitis. The cranial and spinal nerve deficits are usually
transient and caused by exudate in the SAS surrounding the nerves. Focal neurologic deficits and seizure
activity arise from cortical and subcortical ischemia and infarction (bland and hemorrhagic), which are
the result of inflammation and thrombosis in arteries and veins. Subdural effusions are relatively common
in the course of bacterial meningitis in children; they are the result of an increase in the permeability of
the thin-walled capillaries and veins in the inner layer of the dura, with leakage of fluid into the subdural
space.
Bacteremia also contributes to the pathologic features of this disease. Bacteremia is present in 30% to
90% of cases of bacterial meningitis. It can be either the primary event leading to development of
meningitis or a secondary event arising from the clearance of bacteria from the SAS through the arachnoid
villi to the bloodstream. Pneumococcal cell walls activate the alternative complement pathway, with the
generation of chemotactic peptides in the systemic circulation and in CSF. The principal component of
this activity is C5a, a highly chemotactic peptide that is a stimulus for an intense CSF accumulation of
neutrophils. By this process, neutrophils also become sequestered in the pulmonary vascular bed, leading
to cardiopulmonary dysfunction, neutrophil-mediated vascular damage, and the development of the acute
respiratory distress syndrome and thereby further contributing to the morbidity and mortality of meningitis
(69).
Neonates
Clinical clues to the presence of meningitis in neonates are temperature instability (hypothermia or
hyperthermia), listlessness, high-pitched crying, fretfulness, lethargy, refusal to feed, weak suck,
irritability, jaundice, vomiting, diarrhea, or respiratory distress (184,185). Nuchal rigidity is not typically
found in the neonate. A change in the child’s affect or state of alertness is one of the most important signs
of meningitis. A bulging fontanelle (seen in one third of cases) usually occurs late during the course of
illness; seizures are observed in 40% of neonates with bacterial meningitis.
Infants and Children
The symptoms and signs of acute bacterial meningitis in infants and children depend on the age of the
child, duration of illness, and host response to infection (186); the clinical features can be subtle,
variable, nonspecific, and even absent. The initial symptoms of bacterial meningitis in infants and
children may be any of the following: fever, stiff neck, headache, lethargy, irritability, nausea, vomiting,
and photophobia (Table 24.3). In children 1 to 4 years of age, fever (94%), vomiting (82%), and nuchal
rigidity (77%) are the most common initial symptoms.
Although the symptoms are nonspecific, the combination of one or more of these symptoms with signs
of meningeal irritation should suggest the diagnosis of meningitis. The classic signs of meningeal irritation
are nuchal rigidity and Brudzinski and Kernig signs. Brudzinski actually described several signs of
meningeal irritation, including the nape-of-the-neck sign, the identical contralateral reflex sign, and a
reciprocal contralateral reflex sign, as well as others (187,188). The nape-of-the-neck sign is
Brudzinski’s best-known sign and is universally recognized today as “Brudzinski sign.” The nape-of-the-
neck sign is positive when passive flexion of the neck results in flexion of the hips and knees. The
identical contralateral reflex sign is elicited with the patient in the supine position by passively flexing the
hip and knee on one side. This sign is positive when the contralateral leg flexes with this maneuver. The
reciprocal contralateral reflex sign is positive when the leg that has flexed in response to passive flexion
of the other leg begins to extend spontaneously, resembling a “little kick.” The identical and reciprocal
contralateral reflex signs are not elicited as often as the nape-of-the-neck sign (188). The manner in which
Kernig sign is elicited and the interpretation of the results of the maneuver as it is done today are different
from those originally described by Kernig (189). The maneuver as described by Kernig was performed
with the patient in a seated position while the physician attempted to extend the knee passively. In the
presence of meningitis, knee extension was resisted so that a “contracture of the extremities” was
maintained (188,189). Today the sign is elicited with the patient in a supine position. The thigh is flexed
on the abdomen, with the knee flexed. The leg is then passively extended. When meningeal inflammation
is present, the patient resists leg extension (190). Nuchal rigidity and Brudzinski and Kernig signs are
observed in fewer than 50% of children with bacterial meningitis.
The possibility of bacterial meningitis should be considered in every child with fever, vomiting, nuchal
rigidity, and lethargy or an altered mental status. In a review of 110 cases of culture-proven bacterial
meningitis in children, fever (≥38.5°C) was the most common symptom, being present in 94% of patients.
The absence of fever, particularly hypothermia, was associated with a worse prognosis, perhaps related
to the slower rate of bacterial replication in CSF when temperatures are elevated. Apart from fever, the
most common symptoms were (a) vomiting (82%) and nuchal rigidity (77%) in 1- to 4-year-old children
and (b) headache (92%) in children ages 5 to 12 years. Vomiting and nuchal rigidity were present in 80%
of the children who were 12 months or older. Nuchal rigidity is a classic sign of meningitis but can be
absent early in the course of this illness; therefore, the absence of nuchal rigidity should not exclude the
diagnosis of bacterial meningitis (191).
In a review of 709 LPs done on children in an outpatient setting in which there was a concern for
meningitis, the CSF was abnormal in 16% (192). There were 30 cases of bacterial meningitis, 70 of viral
meningitis, and 12 of unknown etiology. Lethargy was more common in children with bacterial meningitis
than in children with viral meningitis: 50% of the children with bacterial meningitis were lethargic, and
32% of the children with viral meningitis were lethargic (p >.14). Although vomiting is a symptom of
meningeal irritation, it is a nonspecific symptom in children. Vomiting occurred in 336 children, 84 of
whom had bacterial or viral meningitis. Fever was present in every child with meningitis. The
temperature elevations were higher in bacterial meningitis than in viral meningitis; 80% of the children
with bacterial meningitis had temperatures of 38.8°C or higher. In children with viral meningitis, 40% had
temperatures of 38.8°C or greater (193). The possibility of meningitis in a child who does not or cannot
complain of headache or stiff neck and who does not have meningeal signs should be suspected when
fever accompanies changes in behavior, changes in mental status, or new onset of seizures.
In one recent review of children aged 2 months to 15 years who presented with suspected meningitis,
the classic clinical signs had limited value in establishing the diagnosis (194). Clinical examination
revealed nuchal rigidity in 65% of those with meningitis; Brudzinski and Kernig signs were elicited in
51% and 27% of those with meningitis, respectively. Therefore, physicians should have a low threshold
for LP in patients at high risk for bacterial meningitis, given the serious nature of this disease.
In a review of 1,064 cases of bacterial meningitis in infants and children, there were no signs of
meningeal irritation in 16 patients (1.5%). Eight patients were older than 2 years of age. LP was
performed because of unexplained fever associated with an altered level of consciousness, behavioral
changes, seizure activity, or petechial skin lesions. Meningitis was caused by N. meningitidis in seven
patients, H. influenzae in six, S. pneumoniae in two, and Salmonella enteritidis in one. Most patients had
a peripheral leukocytosis with a left shift. The peripheral WBC count was greater than 10,000 cells/mm3
in 12 patients and greater than 20,000 cells/mm3 in 7 patients (195). The results of this review suggest
that although meningitis may occasionally occur without meningeal signs, there will usually be other signs
or symptoms of intracranial infection and a peripheral leukocytosis.
Observational data that are useful in predicting the presence of serious illness (e.g., meningitis) in a
febrile child include the following: (a) quality of cry, (b) reaction to parent stimulation, (c) level of
consciousness, (d) color, (e) hydration, and (f) response to social stimulation. These six items were
identified as significant and independent predictors of serious illness from a list of 14 observational
items, scored by pediatricians, for 312 febrile children 24 months of age or younger (196). The quality of
the cry in a child with a serious illness was weak, moaning, or high pitched. A healthy child was either
not crying or had a strong cry with normal tone. Reaction to parental stimulation was judged based on the
parent holding the child, talking to the child, or giving the child a bottle. The child with a serious illness
did not stop crying or barely responded to stimulation by its parent. Consciousness was impaired in
children with serious illnesses. They were lethargic, stuporous, or obtunded. Sick children were
described as pale, cyanotic, or ashen. Signs of dehydration were present. The response to social
stimulation was judged according to whether the child would smile when talked to or smiled at. Sick
children did not respond to social stimulation. These six items, when used together, had a specificity of
88% and a sensitivity of 77% for the presence of serious illness. When combined with history and
physical examination, the sensitivity of the six-item model increased to 92%. If all six of the observation
items were normal in a child, the probability of that child having a serious illness was only 4.7% (196).
The possibility of meningitis in a febrile child may also be suggested by the tempo of the illness. The
presentation of meningitis in children is that of either a subacute infection or an acute fulminant illness.
Children with a subacute presentation have fever, lethargy, and nuchal rigidity that progresses over 1 to
several days and is usually preceded by an upper respiratory tract infection or otitis media (197).
Children with meningitis may also present with an illness that has been progressive over 24 to 72 hours
or a fulminant illness that develops over several hours.
Children with a more rapidly progressive illness have signs and symptoms of meningeal irritation and
increased ICP on initial presentation. CSF pressures exceeding 300 mm H2O are common in acute
bacterial meningitis, and ICPs exceeding 500 to 600 mm H2O are not unusual (197,198). Increased ICP in
bacterial meningitis in children is the consequence, in part, of vasogenic and cytotoxic cerebral edema,
altered CSF resorption, and the inappropriate secretion of antidiuretic hormone (199) (see Chapter 23).
The clinical manifestations of increased ICP include (a) an altered level of consciousness; (b) dilated,
poorly reactive or nonreactive pupils; (c) abnormalities of ocular motility; (d) pathologically brisk lower
extremity reflexes; and (e) bradycardia and hypertension, also known as Cushing reflex. The development
of elevated ICP should be anticipated and monitored in a child with bacterial meningitis. The absence of
papilledema does not exclude the presence of increased ICP. Papilledema is rarely observed early in the
course of increased ICP and is usually not evident until increased ICP has been present for at least several
hours (197,198). For this reason, the presence of papilledema at the time of the initial presentation should
raise suspicion of a focal intracranial process such as a brain abscess or other localized mass lesion, and
it is an indication for CT prior to LP.
Seizures occur in 30% to 40% of children with acute bacterial meningitis, usually during the first 3
days of illness (200). In one review of 52 cases of H. influenzae meningitis in children, seizures occurred
in 44% (23 cases) (198). There has been a long-standing controversy about whether to do an LP in febrile
children with new-onset seizures. The vast majority of children who present with a new-onset seizure
associated with fever and who have a normal neurologic examination do not have meningitis. One series
reviewed the results of LP performed on 328 children presenting with their first febrile convulsion. None
of the children had meningeal signs. Meningitis was diagnosed by LP in four children (1.2%). Three of the
children had viral meningitis, and one had H. influenzae meningitis. All four children were younger than
18 months of age. All the children in this series who were older than 18 months of age had unequivocal
signs of meningitis (201). A similar observation was made in a review of LP performed on 304 children
for evaluation of new-onset seizures associated with fever. There were 15 cases of meningitis, and in
only one case were there no meningeal signs. In that case, the child had viral meningitis and recovered
fully without treatment (202). These studies suggest that LP should not necessarily be routinely performed
in children for evaluation of simple febrile convulsions in the absence of meningeal signs.
Convulsive seizure associated with fever is a problem unique to young children. A simple febrile
seizure, as defined by the Consensus Development Meeting on Long-term Management of Febrile Seizures
(1980), occurs between ages 3 months and 5 years in association with fever and is of brief duration (<15
minutes), nonfocal, nonrepetitive, and without associated neurologic deficits. If the seizure fits this
definition and the child is awake and alert after the seizure, the yield of an LP is very low. If, however,
there are clinical signs of meningitis, an LP is indicated. If the seizure has a focal onset or there is a focal
neurologic deficit on examination, CT is indicated before LP is performed. All children with new-onset
febrile convulsions in whom LP is not performed should be reexamined 1 to 4 hours after the initial
examination to be sure that serious disease is not present (203).
The presence of a diffuse erythematous maculopapular rash may be an early manifestation of
meningococcemia or may represent a viral illness. The presence of a purpuric or petechial rash on the
trunk and lower extremities is suggestive of meningococcemia, although petechiae are sometimes seen in
echovirus type 9 meningitis, acute staphylococcal endocarditis, and rarely pneumococcal or H. influenzae
meningitis (198,204). Petechiae are found in the skin, mucous membranes, or conjunctivae, but never in
the nailbeds, of patients with meningococcemia; they usually fade in 3 or 4 days (205). Petechiae and/or
purpura occurs in 50% to 75% of children with meningococcal meningitis. Children with fulminating
meningococcal septicemia may have the Waterhouse-Friderichsen syndrome, characterized by the
following: (a) sudden onset of a febrile illness, (b) large petechial hemorrhages in the skin and mucous
membranes, (c) cardiovascular collapse, and (d) disseminated intravascular coagulation. Of all patients
with a meningococcal infection, 10% to 20% have a fulminant meningococcal septicemia (206) (Color
Figs. 24.21 to 24.26).
Focal neurologic signs, such as cranial nerve palsies with abnormalities of ocular motility,
hemiparesis, visual field defects, and ataxia, may occur early or late in the course of bacterial meningitis
in approximately 15% of children (197). Cranial nerve palsies likely develop as the nerve becomes
enveloped by exudate in the arachnoidal sheath surrounding the nerve. Alternatively, cranial nerve palsies
may be a sign of increased ICP. The presence of bilateral palsies of the sixth cranial nerve, manifested as
weakness of lateral rectus muscles, is a well-recognized sign of increased ICP.
Hemiparesis may be caused by vasculitis and cerebral infarction or may be a sign of the presence of a
large subdural effusion. Subdural effusions commonly develop in the course of bacterial meningitis in
children and are not usually associated with clinical symptomatology. Subdural effusions develop when
the infection in the adjacent SAS leads to an increase in the permeability of the thin-walled capillaries
and veins in the inner layer of the dura. The result is leakage of albumin-rich fluid into the subdural space,
usually a self-limited process. When the inflammatory process subsides, fluid formation usually ceases
and the fluid in the subdural space is resorbed (197). Some subdural effusions are, however, clinically
significant. The development of a hemiparesis or increased ICP may be the consequence of an enlarging
subdural effusion causing mass effect. The presence of a prolonged fever in a child with a subdural
effusion suggests that the effusion has become infected.
Ataxia may be the presenting sign of bacterial meningitis in a child. Ataxia is a sign of vestibular
dysfunction, and in this clinical setting, it suggests the presence of labyrinthitis. In most children, it is a
transient symptom; however, it has implications for prognosis, because auditory and vestibular
disturbances usually occur together. As such, ataxia is associated with postmeningitic hearing loss (207).
Children with meningitis may develop hyponatremia and the syndrome of inappropriate secretion of
antidiuretic hormone (SIADH) (208). The symptoms of hyponatremia and/or SIADH are lethargy, stupor,
confusion, and/or seizure activity. When the following criteria are met, the diagnosis of SIADH should be
considered: (a) serum sodium level less than 135 mEq/L, (b) serum osmolality less than 270 mOsm/L, (c)
urine osmolality greater than two times the serum osmolality, (d) urine sodium greater than 30 mEq/L, and
(e) no clinical evidence of hypovolemia or dehydration (209). SIADH is not the only cause of
hyponatremia in children with bacterial meningitis. Hyponatremia may also develop when fluid therapy is
too aggressive or as a result of the syndrome of cerebral salt casting. Regardless of the reason for
hyponatremia, the serum sodium level should be monitored frequently in every child with bacterial
meningitis. This is discussed in greater detail later in this chapter (see the section “Therapy”).
Ocular complications, including fundal abnormalities, cranial nerve palsies (see earlier discussion),
pupillary dysfunction, and corneal or conjunctival lesions, are actually quite common during the course of
bacterial meningitis in children, but only one case of transient cataract formation has been reported in
association with meningococcal meningitis.
Bacterial meningitis is at least 30-fold more common in children with cochlear implants to address
profound hearing loss than in controls (210). The major pathogen is S. pneumoniae and risk factors
include use of a positioner to improve transmission of the electrical signal by pushing the electrode
against the medial wall of the cochlea (voluntarily withdrawn from the market by the manufacturer in July
2002); and joint radiographic evidence of inner ear malformation and CSF leak. More cases occurred
within 30 days of surgery, but sporadic cases were observed 24 months after implantation (210).
Adults
The typical presentation of bacterial meningitis in an adult is that of an upper respiratory tract infection
during which a meningeal symptom, such as headache, nuchal rigidity, vomiting, or an altered level of
consciousness, develops (211) (Table 24.3). The clinical signs and symptoms of bacterial meningitis in
an adult are very similar to those in children, with a few exceptions. The most common bacterial cause of
meningitis in adults is S. pneumoniae. The clinical presentation of meningitis caused by S. pneumoniae is
somewhat different from that of meningitis caused by the meningococcus or H. influenzae. Adults with
pneumococcal meningitis usually have an altered mental status on admission and rapidly become
stuporous or comatose. In addition, recurrent seizure activity and focal neurologic deficits are more
common in the early stages of pneumococcal meningitis than in meningococcal or H. influenzae
meningitis. These and other factors may contribute to the continued high mortality rate in pneumococcal
meningitis. S. pneumoniae is associated with the highest mortality rate of the major meningeal pathogens.
For example, a mortality of 36.8% was reported from one series of 55 cases of community-acquired
pneumococcal meningitis (212). Death is more likely to occur in patients of advanced age, in the absence
of meningismus, and in the presence of pneumonia, other extraneural complications, or a prolonged
duration of illness prior to therapy (7 days). Nevertheless, it appears that most deaths occur later in the
disease course as a consequence of cardiorespiratory insufficiency (213). They are not usually caused by
early overwhelming CNS damage.
A classic description of the clinical presentation of bacterial meningitis in adults was presented by
Carpenter and Petersdorf (211) in 1962. This review includes 209 cases of bacterial meningitis: 53 cases
were caused by meningococci, 63 by pneumococci, 35 by H. influenzae, and 58 by other bacterial
organisms. A reliable history of the onset of symptoms was obtained in 134 patients. Thirty-six patients
(27%) had sudden onset of headache, confusion, lethargy, and loss of consciousness and sought
hospitalization within the first 24 hours. Only 3 of these 36 patients had symptoms of respiratory tract
infection. In contrast, 71 (53%) of the 134 patients had more slowly progressive symptoms of meningitis
for 1 to 7 days before admission. Of these, 26 patients (37%) had respiratory symptoms. In 27 (20%) of
the 134 patients, an infection in the respiratory tract developed 1 to 3 weeks before the first symptom of
meningitis. The results of physical examination for meningeal signs were recorded in 199 cases. Either
nuchal rigidity, Kernig signs, or Brudzinski signs were present in 161 patients (81%). Studies suggest that
the latter two signs are less common in adults with meningitis than previously reported (214). Level of
consciousness on admission was recorded in 191 patients (96%); only 9 (5%) patients were alert, 48
(24%) were lethargic, 44 (22%) were confused, and the remainder were obtunded or comatose (211).
Patients with meningococcal meningitis were most often alert, and those with pneumococcal meningitis
were more often obtunded.
Geiseler et al. (215) made observations of altered consciousness at presentation in bacterial
meningitis, similar to those of Carpenter and Petersdorf (211). They recorded level of consciousness at
the time of admission in 1,289 patients with community-acquired bacterial meningitis. Overall, 230
(17.8%) were alert, 672 (52.1%) were irritable or lethargic, 262 (20.3%) were stuporous or obtunded,
and 125 (9.7%) were comatose and/or convulsing (215). In adults, as in children, lethargy or an altered
mental status is the strongest indicator of bacterial meningitis.
Durand et al. (78) reviewed the charts of all cases of acute bacterial meningitis in individuals 16 years
or older at the Massachusetts General Hospital from 1962 through 1988. The most common pathogen of
community-acquired meningitis was S. pneumoniae. Ninety-five percent of patients had fever
(temperature 37.7°C) on presentation. Neck stiffness was present in 88% of patients on initial physical
examination. At the time of admission, 61 (22%) were alert, 142 (51%) were confused or lethargic, 61
(22%) were responsive only to pain, and 17 (6%) were unresponsive to all stimuli. On presentation or
during the first 24 hours, 81 (29%) had focal seizures or focal neurologic findings. The most common
predisposing factors for community-acquired meningitis were pneumonia, sinusitis, acute otitis media,
altered immune state, alcoholism, and diabetes mellitus (78).
In another review of 696 episodes of community-acquired bacterial meningitis, the triad of fever, neck
stiffness, and altered mental status was present in only 44% of episodes (216), although almost all
patients (95%) presented with at least two of four symptoms (i.e., headache, fever, stiff neck, and altered
mental status). Cerebrovascular complications may manifest at any time during the course of
pneumococcal meningitis. In an observational study of 696 patients with community-acquired bacterial
meningitis, cerebral infarction occurred in 174 (25%) episodes and was seen in 128 (36%) of 352
patients with pneumococcal meningitis (217).
Pneumonia is present on admission in 25% to 50% of adults with pneumococcal meningitis (211).
Acute and chronic otitis media are also predisposing conditions for pneumococcal meningitis. In one
series of 178 patients with pneumococcal meningitis, acute otitis media was present in 59 (33.1%) (215).
When pneumonia or otitis media is not present, the possibility of a dural sinus fistula should be
considered. S. pneumoniae is the most common causative agent in meningitis following head trauma
(basilar skull fracture) or meningitis associated with a structural defect (either congenital or traumatic in
origin) that creates a communication between the paranasal sinuses, nasopharynx, or middle ear and the
SAS (218).
In adults aged 15 to 60 years, underlying host factors may increase the risk for meningitis while
simultaneously blunting its presenting signs. Such predisposing factors include malignancy, alcoholism,
sickle cell disease, diabetes, organ transplantation, splenectomy, high-dose steroid therapy, and long-term
dialysis. In these clinical settings, the symptoms of meningitis may include altered sensorium, persistent
headache, or new-onset seizures. Fever or nuchal rigidity may not develop (219).
The occurrence of H. influenzae meningitis in an adult should prompt consideration of the presence of
(a) otitis media, (b) paranasal sinusitis, (c) other parameningeal foci of infection, (d) CSF leak from
previous head trauma, or (e) a concurrent pneumonia, pharyngitis, or immunodeficiency disease. The
clinical presentation of H. influenzae meningitis in adults is typical of bacterial meningitis and includes
headache, fever, altered mental status, and nuchal rigidity (220).
Elderly
Meningitis should be suspected in every elderly patient who is febrile and either disoriented, stuporous,
or comatose (Table 24.3). In a review of 54 cases of bacterial meningitis in the elderly, confusion was
present in 92% (12 of 13) of the patients with pneumococcal meningitis and in 78% (7 of 9) of those with
gram-negative meningitis on initial presentation. This review compared the clinical presentation of
bacterial meningitis in the elderly (patients aged 50 years and older) with that in younger patients (aged
15 to 49 years). On initial presentation, the incidence of more severe abnormalities of mental status in the
older age-group with bacterial meningitis was statistically different from that of the younger group, and
concurrent pneumonia was present more often in the older patients than in the younger group (221). In
another review of CNS infections in patients older than 65 years of age at the Mount Sinai Hospital in
New York from 1970 through 1985, 28 cases of bacterial meningitis were identified (222). Although
fever (often of low grade) was uniformly present, only 57% had meningismus and only 21% complained
of headache. Pneumococci were the most common etiologic agent, and these cases were often (58%)
accompanied by pneumonia, sinusitis, or otitis media; the overall mortality was approximately 40%.
Most elderly patients with meningitis have nuchal rigidity, that is, resistance to passive flexion of the
neck. Resistance to passive movement of the neck is a common physical finding in elderly patients
because of the presence of cervical spondylosis. It is important to be able to distinguish between the
cervical rigidity of cervical spondylosis and nuchal rigidity resulting from meningitis. In nuchal rigidity,
the neck resists flexion but can be passively rotated from side to side. In rigidity consequent to cervical
spinal disease, lateral rotation, extension, and flexion of the neck are all associated with resistance.
Similarly, hypertonicity of the neck muscles resulting from disease of basal ganglia, such as parkinsonism,
can be distinguished from true nuchal rigidity.
Specific comments should be made about the presentation of nontraumatic, spontaneous gram-negative
bacillary meningitis in the elderly or debilitated patient. In these patients, the classic signs and symptoms
of meningitis may be subtle at initial presentation. They may have only low-grade fever and altered
mental status without headache or nuchal rigidity; however, patients with spontaneous gram-negative
bacillary meningitis tend to have a rapidly progressive fulminant course associated with bacteremia,
shock, and coma (223). The elderly patient with gram-negative meningitis may rapidly become comatose
after presenting with what at first appeared to be a minor illness. Once coma develops, nuchal rigidity
may not be present, because this sign is lost during deep coma.
In a recent 30-year study of 185 patients 65 years of age and older, the diagnosis of community-
acquired bacterial meningitis was more difficult because of the absence of characteristic meningeal signs
(224); compared with adult patients younger than 65 years of age, the older patients showed greater
neurologic severity with a high number presenting with coma on admission, seizures, and hemiparesis.
Posttraumatic Meningitis
Bacterial meningitis may develop following a traumatic head injury that produces a dural fistula between
the SAS and the nasal cavity, paranasal sinuses, or middle ear. The infection may develop shortly after the
injury or may not occur until months to years later (225). Traumatic head injury is the most common cause
of recurrent meningitis in the adult (220). Conversely, congenital fistulous connections to the CNS, often
via the middle ear in association with Mondini dysplasia, are the most common underlying process in
children with recurrent bacterial meningitis (226). An immunodeficiency state may also be instrumental in
the development of this syndrome.
A dural fistula develops when the force of the injury is sufficient to fracture bone and tear the dura. The
most common site for dural fistula is in the anterior cranial fossa, in the area of the cribriform plate. Here,
the bone is very thin and the dura is tightly adherent to the bone. A fracture in this area allows CSF to leak
through torn arachnoid and dura into the nasal cavity, resulting in CSF rhinorrhea (225). There may also
be loss of the sense of smell, or anosmia. CSF rhinorrhea can be distinguished from nasal secretions by
testing the fluid for β2-transferrin.
Physical signs indicating a basilar skull fracture with the potential for development of a dural fistula
and meningitis include periorbital ecchymoses, bruising behind the ear (Battle sign), hemotympanum,
and/or blood in the external auditory canal (225).
In most patients, CSF rhinorrhea ceases spontaneously. Approximately one in four patients with CSF
rhinorrhea develops meningitis (225); the reported frequency ranges from 9% to 36%. Surgery is
indicated in patients who develop meningitis with persistent rhinorrhea. The management of meningitis
occurring in this setting and the approach to demonstration of the location of the dural fistula is discussed
later in this chapter.
Meningitis Following Neurosurgical Procedures
Meningitis complicating a neurosurgical procedure, such as a craniotomy, is usually insidious in onset and
difficult to distinguish clinically from the neurologic abnormalities expected in the postoperative period.
Although an altered level of consciousness and signs of meningeal irritation may be expected in the
postoperative period, the presence of fever or prolonged obtundation should prompt an examination of the
CSF.
Approximately 60% to 70% of all cases of meningitis complicating a neurosurgical procedure, with the
exception of a shunting procedure, are caused by gram-negative bacilli (223). The remainder is caused by
staphylococci, predominantly S. aureus. In the postneurosurgical patient, K. pneumoniae, Acinetobacter
baumannii, and E. coli are the most common infecting gram-negative organisms. Craniotomy for trauma
or for tumor represents the most common surgical procedure associated with postoperative gram-negative
bacterial meningitis (227).
Although the surgical insertion and subsequent constant presence of an indwelling ventriculoperitoneal
(VP) or ventriculoatrial (VA) shunt catheter for decompression of hydrocephalus allow bacteria to enter
the CSF space, signs of meningitis usually do not accompany these infections in the early stages. The
bacteria involved in early shunt infection gain entry to the lumen of the shunt from a contaminated wound
or from the patient’s skin surface at the time of operation (228). The initial symptoms of shunt infection
are nonspecific and include fever, nausea, vomiting, and lethargy. Fever is the most common manifestation
of shunt infection. Virtually all patients have temperatures greater than 37.8°C, and most have
temperatures of 38.8°C or more (229). Fever is often the sole manifestation of infection in patients with
VA shunts, whereas patients with infected VP shunts are more likely to present with signs of shunt
malfunction and/or signs of inflammation around the shunt reservoir or along the course of the tubing
(229,230). Signs of shunt malfunction are secondary to progressive hydrocephalus and, in children,
include enlarging cranial circumference, tense nonpulsatile fontanelle, and papilledema. Signs of shunt
malfunction may be associated with signs of meningitis. Results of examination of CSF from the lumbar
area may be negative; therefore, CSF should be obtained by aspiration from the infected shunt reservoir.
Infections of the CNS may also develop when subcutaneous CSF reservoirs, such as Ommaya and
Rickham reservoirs, are placed for therapeutic purposes. These and other types of indwelling
intraventricular catheters may lead to meningitis with coagulase-negative staphylococci, S. aureus,
Corynebacterium species, or gram-negative bacilli. Infections usually occur within the first 3 months
after insertion of the device and, as with infections of VP or VA shunts, are probably the consequence of
contamination by skin flora during implantation or subsequent use for therapeutic purposes. In these
patients, signs of meningitis are usually not present, but most will complain of fever, lethargy, headache,
or nausea and vomiting (231).
Immunosuppressed Hosts
The risk for development of bacterial meningitis in an immunocompromised patient depends on a number
of factors, such as the underlying disease and its treatment, the duration of immunosuppression, and the
type of immune abnormality (232). There are four major types of host defense abnormalities in the
immunocompromised patient: (a) defects in T-lymphocyte–macrophage function (cell-mediated
immunity); (b) defects in humoral immunity; (c) defects in the number and function of neutrophils; and (d)
loss of splenic function from surgery, disease, or radiotherapy, resulting in the inability to remove
encapsulated bacteria. Knowledge of the type of host defense abnormality is often helpful in predicting
the infecting organism (233,234).
Patients with defects in cell-mediated immunity include (a) those with lymphomas, particularly
Hodgkin disease; (b) organ transplant recipients; (c) patients treated with daily corticosteroid therapy;
and (d) patients with AIDS. These patients are most susceptible to CNS infection by microorganisms that
are intracellular parasites, the eradication of which depends on an intact T-lymphocyte–macrophage
system (233). L. monocytogenes is a causative organism of bacterial meningitis in patients with defective
cell-mediated immunity due to hematologic malignancies, organ transplantation, pregnancy, chronic
corticosteroid therapy, alcoholism, and advanced age (235). The incidence of L. monocytogenes
meningitis in HIV-infected individuals is low due to pneumocystis prophylaxis with TMP-SMX. The
clinical presentation of L. monocytogenes meningitis includes fever and headache, as well as an
increased tendency for focal neurologic deficits and seizures during the initial presentation. Meningitis
caused by this organism may also present with a clinical picture suggestive of an acute brainstem disorder
or rhombencephalitis, with signs of ataxia, cranial nerve deficits, and nystagmus (236).
Patients with defective humoral immunity are unable to mount an antibody response to bacterial
infection, and they are, therefore, unable to control infection caused by encapsulated bacteria. Patients
with this type of host defense abnormality include those with chronic lymphocytic leukemia, multiple
myeloma, or Hodgkin disease following chemotherapy and radiotherapy, among others. These patients are
at particular risk for meningitis caused by S. pneumoniae, Hib, and less commonly N. meningitidis. The
presentation of meningitis in these patients is often that of a fulminant illness resulting in death in several
hours.
Patients with splenectomy may develop (a) overwhelming bacteremia and fulminant meningitis with the
same organisms, resulting from loss of the filtering function of the splenic sinusoids in removing
encapsulated bacteria from the bloodstream, and (b) a reduced ability to produce IgM opsonizing
antibodies (233,234).
Patients with neutropenia are at particular risk for meningitis caused by P. aeruginosa and members of
the Enterobacteriaceae family (234). The clinical presentation of bacterial meningitis in patients with
neutropenia may be subtle, consisting of low-grade fever and lethargy or a change in headache pattern
(233). Signs of meningeal irritation depend on the host’s ability to mount an inflammatory response;
therefore, in the neutropenic patient they are often minimal.
Although the diagnosis of meningitis is usually made by examination of the CSF, the decision to perform
spinal fluid analysis is based on the clinical presentation. When the signs and symptoms suggest
meningitis, and the decision is made to examine the CSF, the next step is to be certain that a focal
intracranial mass lesion does not exist that may predispose to brain herniation following LP. If the history
and neurologic examination suggest a focal mass lesion, then LP should be delayed until a neuroimaging
procedure, either a cranial CT scan, without and with contrast enhancement, or a cranial magnetic
resonance imaging (MRI) scan is obtained.
LP is relatively contraindicated in the presence of a focal mass lesion because of the danger of brain
herniation. However, it has become common practice to delay LP until a CT or MRI scan has been
obtained despite the absence of focal neurologic deficits by history or examination. The time involved in
waiting for a CT or MRI scan significantly delays treatment, and delay in treatment is the most critical
factor in determining morbidity and mortality in bacterial meningitis. Therefore, if a CT or MRI scan is to
be performed, antimicrobial therapy should be initiated promptly, pending results. In the absence of an
altered level of consciousness, focal neurologic signs, and/or papilledema, an LP can be safely performed
without first obtaining a CT or MRI scan. Although CT is commonly performed before LP in adults with
suspected meningitis, the vast majority of scans are unnecessary and unlikely to reveal abnormalities, and
clinical characteristics can be used rapidly to exclude patients that are unlikely to have abnormal findings
on CT (237). Focal infectious lesions that have clinical presentations similar to those of meningitis and
that can result in significant morbidity if LP is unknowingly performed include brain abscess, subdural
empyema, and epidural abscess. The clinical presentation of each of these disorders has similarities and
distinguishing features when compared with that of meningitis.
The most common symptom of a brain abscess is a hemicranial or generalized headache, generally seen
in 70% to 75% of patients (238–242). A brain abscess presents as an expanding intracranial mass lesion
rather than as an infectious process; as such, fever is present in only 45% to 50% of patients and usually
is not prominent. More than 50% of patients have focal neurologic deficits, and one third of patients
present with new-onset focal or generalized seizure activity. The findings on neurologic examination are
related both to the site of the abscess and to the presence of raised ICP caused by an expanding mass
lesion. Hemiparesis is the most common sign of a frontoparietal lobe abscess. A disturbance of language
or behavior or an upper homonymous quadrantanopia is the sign of a temporal lobe abscess. Ataxia is the
most common sign of a cerebellar abscess. Nuchal rigidity rarely occurs until the abscess has ruptured
into the ventricle or until infection has spread to the SAS. Sudden worsening of the headache,
accompanied by new-onset meningismus, may signify rupture of the abscess into the ventricular space
(243).
Most patients with a subdural empyema initially complain of headache that is localized to the side of
the subdural infection. The headache becomes increasingly more severe and generalized, and it is
followed by an alteration in the level of consciousness. Fever, chills, and nuchal rigidity are present in
most cases. Focal neurologic deficits are present in 80% to 90% of patients, and they include hemiparesis
or hemiplegia, paralysis of horizontal gaze to the side opposite the lesion, and focal or generalized
seizures (244). The diagnosis should be considered in patients with acute bacterial sinusitis in
combination with severe intractable headache, varying degrees of altered level of consciousness, focal
neurologic deficits, and/or signs of meningeal irritation (245,246). The presentation of a posterior fossa
subdural empyema includes severe headache, vomiting, marked nuchal rigidity, cranial nerve deficits, and
pupillary abnormalities (247); cerebellar signs were elicited in only 40% of patients in one study (248).
A typical presentation of an intracranial epidural abscess is an unrelenting hemicranial headache and
fever that have developed during or after treatment for frontal sinusitis, mastoiditis, or otitis media. If the
abscess is large, mild alterations of consciousness may occur; however, focal neurologic deficits,
seizures, and signs of increased ICP do not develop until the infection has extended into the subdural
space or a deeper intraparenchymal complication has occurred (244).
The decision to delay LP until CT or MRI scan is obtained may be made when the patient does not
appear to be seriously ill or when there is uncertainty about the findings of neurologic examination.
Patients with viral meningitis usually do not appear as ill as patients with bacterial meningitis and often
have had symptoms for several days. When the history suggests a focal onset to the headache or a transient
neurologic symptom, LP is best delayed until a CT or MRI scan has been obtained.
The initial symptoms of viral meningitis are fever, headache, lethargy, myalgias, and nuchal rigidity.
There are several distinguishing clinical features of viral meningitis: (a) viral meningitis has a more
insidious onset and a slower progression than bacterial meningitis; (b) patients with viral meningitis often
complain of an incapacitating headache that is not relieved by analgesics, but they are otherwise awake
and alert; (c) the fever is usually higher in bacterial meningitis than in viral meningitis; and (d) although
generalized malaise may be present, stupor, obtundation, and coma do not occur in viral meningitis (219).
Altered level of consciousness, focal neurologic deficits, and new-onset seizure activity are symptoms
of a viral encephalitis, meningoencephalitis, or bacterial meningitis. The presentation of herpes simplex
virus (HSV) encephalitis is often subacute and on examination is characterized by (a) fever, confusion, or
a change in behavior; (b) new-onset seizure activity; and/or (c) focal neurologic deficits. A history of
hemicranial headache of several days’ duration, preceding the onset of the confusional state, is a classic
presentation of this illness. HSV has a predilection for the temporal and orbitofrontal areas; therefore, a
change in mentation or behavior is a common finding (249).
Signs and symptoms of meningitis represent the most common neurologic presentation of Lyme disease.
Patients have headache, stiff neck, low-grade fever, a unilateral or bilateral (in 25% of cases) facial
nerve palsy, or a radiculitis. The characteristic skin lesion of Lyme disease, erythema migrans (EM),
precedes the symptoms of meningitis in approximately 80% to 90% of patients. Signs and symptoms of
meningitis occur weeks to a few months after the initial infection, or they may be the first manifestation of
the disease without antecedent EM (250).
The presence of a rash with meningitis suggests meningococcemia. As has been discussed, the classic
lesions associated with fulminating meningococcal septicemia are large petechial hemorrhages in the skin
and mucous membranes. Between 50% and 75% of children with meningococcal meningitis have a
purpuric or petechial rash, principally on the trunk and lower extremities. Petechiae are found in the skin,
mucous membranes, and conjunctivae, but not in the nailbeds, in meningococcemia. Petechiae are also
sometimes seen on the trunk and extremities in echovirus type 9 meningitis, acute staphylococcal
endocarditis, and rarely pneumococcal or H. influenzae meningitis except in asplenic patients (198,204).
Petechiae may be found in the nailbeds in acute staphylococcal endocarditis. Petechial rashes should be
promptly examined microscopically in the initial evaluation of meningococcemia after aspiration or after
making a “touch preparation” on a glass slide; approximately 70% of these preparations will reveal the
organisms, usually within vacuolated neutrophils. In fulminant meningococcemia, the organisms may be
visualized in the peripheral blood smear. Although the sensitivity of this method is low, this simple test
should always be performed in suspected meningococcemia.
Headache, fever, rash, and altered mental status are symptoms of rickettsial infections (see Chapter 27)
and, as such, enter into the differential diagnosis of meningitis. A petechial rash is characteristic of Rocky
Mountain spotted fever (RMSF), which is caused by Rickettsia rickettsii. The rash of typhus is a faint
macular-papular pink rash (251). The rash of RMSF consists initially of 1- to 5-mm pink macules that are
often noted first on the wrist and ankles and then spread centrally to the chest, face, and abdomen. The
rash of RMSF usually does not involve the mucous membranes. Petechial lesions in the axillae and
around the ankles, accompanied by lesions on the palms and soles of the feet, are characteristic of RMSF,
but this classic pattern is often absent. The macules will initially blanch with pressure, but after a few
days they become fixed and turn dark red or purple. Diagnosis can be made by biopsy of the lesions and
staining of the specimen with fluorescent antibodies to R. rickettsii (252). A negative result does not
exclude RMSF, because sensitivity of this test is only 70%.
The characteristic rash caused by an enterovirus consists of erythematous macules and papules on the
face, neck, trunk, and to a lesser degree the extremities. Rarely, the rash associated with enteroviral
infection may become petechial in nature.
The rash of Lyme disease, EM, begins as a red macule or papule at the site of the tick bite. It then
expands centrifugally as an erythematous lesion with central clearing. This may be the only lesion, or the
disease may disseminate to form multiple secondary ringlike lesions. Symptoms of meningitis may
develop while the skin lesions are still present, or they may begin 1 to 6 months after the skin lesions have
resolved (250).
Noninfectious neurologic disorders that have clinical presentations similar to those of meningitis are
subarachnoid hemorrhage, neuroleptic malignant syndrome, and posterior fossa tumors. The classic
presentation of a subarachnoid hemorrhage is the sudden onset of a severe, excruciating headache, or a
sudden transient loss of consciousness followed by a severe headache. Most patients complain of
vomiting. Syncope accompanies the explosive onset of headache in about 50% of cases. Nuchal rigidity
develops within a few hours of the onset of a subarachnoid hemorrhage and is usually associated with a
change in the level of consciousness. Low-grade fever may develop within several days. When an
intracranial aneurysm ruptures into the brain parenchyma, a focal neurologic deficit is usually present. A
unilateral palsy of the third nerve, with a dilated, nonreactive pupil, is suggestive of third nerve
compression by an aneurysm at the junction of the posterior communicating artery and the internal carotid
artery. The triad of headache, neck stiffness, and vomiting should raise suspicion of a warning leak from
an aneurysm (252).
The symptoms of neuroleptic malignant syndrome (NMS) are fever, generalized “lead-pipe” rigidity
(including cervical rigidity), fluctuating level of consciousness (ranging from agitation to stupor and
coma), and autonomic instability. The latter is characterized by pallor, unstable blood pressure,
diaphoresis, tachycardia, and arrhythmias. A leukocytosis of 15,000 to 30,000 cells/mm3, with a shift to
the left, is common. Liver function abnormalities are usually seen, but the most specific laboratory
abnormality in this disorder is marked elevation in the serum creatine kinase (CK) concentration, usually
exceeding 10,000 IU/L (253).
Signs of a posterior fossa tumor are stiff neck, cranial nerve abnormalities, gait disturbance, vomiting,
cerebellar deficits, and occasionally an altered level of consciousness.
A cranial CT or MRI scan and examination of the CSF will narrow the differential diagnosis. The
possibility of the presence of increased ICP should be considered before LP. Increased ICP is an expected
complication of bacterial meningitis and is not a contraindication to LP.
The clinical signs of increased ICP are (a) a dilated, nonreactive pupil; (b) drowsiness; (c)
abnormalities of ocular motility, the most common of which are the consequence of unilateral or bilateral
palsies of the sixth cranial nerve; and (d) bradycardia and hypertension, the Cushing reflex. Pupillary
dilation is usually secondary to parenchymal midbrain distortion from either raised ICP or transtentorial
herniation. Drowsiness or stupor is often the first sign of increasing ICP and is caused by interference
with the reticular activating system in the brainstem.
If raised ICP appears likely and a focal intracranial mass lesion has been excluded by CT or MRI scan,
LP can usually be safely performed. When the decision is made to delay LP until a CT or MRI scan has
been obtained, blood cultures should be obtained and intravenous antibiotics and dexamethasone therapy
begun while awaiting results of CT or MRI scan (see later discussion). Intravenous antibiotics usually do
not sterilize the CSF in the time it takes to obtain a CT or MRI scan and spinal fluid. Blood cultures may
identify the infecting organism in 50% to 80% of cases of bacterial meningitis (although this frequency
varies with the causative organism), and they are more often positive in patients who have not received
prior treatment with oral antibiotics (189).
LABORATORY DIAGNOSIS
Cerebrospinal Fluid
The typical CSF findings of bacterial and aseptic meningitis are compared in Table 24.4.
Opening Pressure
The first step in examination of the CSF is measurement of the opening pressure with an air-water
manometer. This step is often neglected, but knowledge of the presence of raised ICP is important in
management of the patient. Normal CSF pressure, with the patient in the lateral recumbent position, is
usually defined as less than 180 mm H2O (254). However, normal opening pressure can be as high as 250
mm H2O in obese patients (255). CSF pressure should not be measured with the patient in a seated
position. If the spinal needle is inserted with the patient seated, the patient should then be moved to a
lateral recumbent position and the opening pressure recorded. Elevated CSF pressure in the range of 200
to 500 mm H2O is common in bacterial meningitis.
Appearance
Normal CSF is clear. The presence of more than 200 WBCs/mm3, more than 400 red blood cells
(RBCs)/mm3, bacteria (>105 CFU/mL), or an elevated protein concentration makes the fluid appear
cloudy or turbid. When the LP is traumatic and the initial CSF sample appears bloody, the fluid should
clear as flow continues. Xanthochromia refers to a yellow or yellow-orange color in the supernatant of
centrifuged spinal fluid; it may be used to distinguish CSF that is bloody secondary to subarachnoid
hemorrhage from CSF that is bloody as a result of a traumatic LP. When CSF is bloody secondary to
traumatic LP, the supernatant of the centrifuged fluid is clear. In subarachnoid hemorrhage, the supernatant
is xanthochromic within 2 hours after the hemorrhage. Elevated CSF protein concentrations (>150 mg/dL)
also cause xanthochromia (254,256) and are the usual reason for xanthochromia in bacterial meningitis.
Glucose
The normal CSF glucose concentration is greater than 45 mg/dL. A glucose concentration of less than 40
mg/dL occurs in approximately 58% of patients with bacterial meningitis (257). However, the CSF
glucose may be falsely low in the presence of hypoglycemia, or it may be erroneously interpreted as
normal in the presence of CNS infection when the serum glucose is elevated. An accurate interpretation of
the CSF glucose concentration is done by determining the CSF-to-serum glucose ratio. A normal CSF-to-
serum glucose ratio is about 0.6 (257). Values less than 0.31 are an indication of low CSF glucose, and
they are observed in approximately 70% of patients with bacterial meningitis (257). A decreased CSF-to-
serum glucose ratio is also consistent with fungal or tuberculous meningitis, carcinomatous meningitis,
mumps encephalitis, subarachnoid hemorrhage in 15% to 20% of patients, and several other conditions
(258).
Protein
Any process that disrupts the BBB results in an elevated CSF protein concentration. Values greater than
50 mg/dL in CSF obtained from the lumbar SAS, as well as ventricular CSF protein concentrations
greater than 15 mg/dL, are considered abnormal. When the LP is traumatic and there is blood in the CSF,
the true protein concentration is corrected by subtracting 1 mg of protein per deciliter for every 1,000
RBCs in CSF (258).
White Blood Cell Count

The CSF abnormalities characteristic of bacterial meningitis include a polymorphonuclear (PMN)
pleocytosis, a low glucose concentration, and an elevated protein concentration. The CSF should be
examined promptly after it is obtained, because WBCs in the CSF begin to disintegrate after about 90
minutes. The normal WBC count in the CSF of adults and children is 0 to 5 mononuclear cells
(lymphocytes and monocytes)/mm3; a WBC count of greater than 10 cells indicates a pathologic process
such as infection. Normal CSF does not contain PMN leukocytes; however, following centrifugation, an
occasional PMN leukocyte may be seen. It has been stressed that for the CSF to be considered normal, no
more than a single PMN leukocyte should be seen in the differential count, accompanied by a total WBC
count of less than 5 cells/mm3 (254,256). However, most CSF differential counts are now performed on
cytocentrifuged specimens in hospital laboratories. In these preparations, a few PMN leukocytes may be
seen even in the absence of disease (i.e., when minimal blood contamination is present) or in association
with a high peripheral leukocyte concentration (258).
A traumatic puncture or an intracerebral or subarachnoid hemorrhage introduces RBCs and WBCs into
the CSF. The correction factor for the WBC count in the presence of blood in the CSF is as follows: (a) If
the peripheral RBC and WBC counts are normal, then 1 WBC/700 RBCs can be subtracted from the total
WBC count in CSF; and (b) in the presence of an abnormal peripheral WBC or RBC count, the following
formula can be used (258), although valid studies on the diagnostic accuracy in meningitis are lacking:
True WBC (CSF) = Actual WBC (CSF) − WBC (Blood) × RBC (CSF)/RBC (Blood)
Generalized seizures may induce a transient CSF pleocytosis consisting predominantly of PMN
leukocytes. However, to attribute a CSF pleocytosis to seizure activity, the following criteria should be
met: (a) The fluid should be clear and colorless, (b) the opening pressure should be normal, (c) the CSF
glucose concentration should be normal, (d) the WBC count should not exceed 80 cells/mm3, (e) there
should be no meningeal signs or other evidence of infection, and (f) Gram stain results should be negative
(259). Even if these conditions are met, patients should usually be treated with antibiotics until the results
of bacterial cultures are known. There also remains the possibility that a viral encephalitis, with a
predominance of PMN leukocytes in CSF, is the cause of the seizure activity.
In large reported series of bacterial meningitis, in 90% of cases, there are greater than 100 WBCs/mm3
in the CSF, and in 65% to 70% of cases, there are greater than 1,000 WBCs/mm3 (211,215,260,261). The
differential count usually shows a predominance of PMN leukocytes. In about 10% of cases of bacterial
meningitis, there may be a predominance of lymphocytes early in the infection, especially if the total
WBC concentration is less than 1,000/mm3. In one series, 32% (13 of 41) of patients with bacterial
meningitis with a CSF WBC concentration of 1,000 cells/mm3 or less had a predominance of lymphocytes
(262). In addition, in about 20% to 75% of patients with viral meningitides, the CSF may initially have a
predominance of PMN leukocytes, with an eventual shift (over the course of several hours) to a
monocytic predominance. This has led to controversy about the necessity for repeated LP and the time
period in which a repeated LP should be obtained to demonstrate a shift in cell type. It is our feeling that a
repeated LP is usually not necessary unless there is further clinical deterioration. In the presence of a
lymphocytic pleocytosis, the results of CSF chemistries, Gram stain, and other tests (see later discussion)
suggest the diagnosis. If bacterial meningitis is suspected, even though there is a predominance of
lymphocytes, the patient should be treated with antibiotics until the results of bacterial cultures are
known.
Gram Stain and Culture

Examination of CSF by Gram stain allows for rapid, accurate identification of the infecting organism. If
the CSF is cloudy, smears should be obtained from fresh, uncentrifuged fluid for Gram stain. If the CSF is
clear, smears should be obtained from the centrifuged sediment. The Gram stain is positive in identifying
the organism in 60% to 90% of cases of bacterial meningitis (257,263). However, the probability of
detecting bacteria on a Gram-stained specimen depends on the number of organisms present. Most smears
will be positive when the CSF bacterial concentration is greater than 105 CFU/mL. Only 25% of smears
are positive when the bacterial concentration is 103 CFU/mL or less (197).
Cerebrospinal Fluid Lactate

The lactic acid concentration in CSF has been reported to be useful in differentiating between bacterial
and viral meningitis, especially in those patients who have been partially treated with antibiotics prior to
examination of the CSF, as well as in those patients with low CSF WBC concentrations. In a European
study, the lactic acid in CSF was measured in 50 patients with acute bacterial meningitis. In 46 patients
(92%), the CSF lactate concentration was 3.5 mmol/L or greater. The investigators in this study concluded
that CSF lactate was useful in the diagnosis of acute bacterial meningitis if it was 3.5 mmol/L or more
(264). Other studies have demonstrated that in most cases of acute bacterial meningitis, the CSF lactate
concentration is 3.8 mmol/L or more (254). Although the sensitivity of the CSF lactate level is high for
bacterial meningitis, its specificity is low.
In a review of the lactic acid concentrations in 493 samples of CSF from 434 adults with various CNS
conditions, the lactate concentration was greater than 35 mg/dL in 50 cases. Only 19 of the 50 cases of
infective meningitis were caused by either bacterial or viral pathogens. Although the lactic acid
concentration was elevated in most cases of bacterial meningitis in this study, the CSF samples with
elevated lactic acid concentrations had cell counts and chemistries suggestive of bacterial meningitis;
therefore, the elevated lactate concentration provided little additional information (265). In this review,
as in others, an elevated CSF lactic acid concentration was nonspecific. Other causes of elevated CSF
lactate concentrations include recurrent seizure activity, cerebral ischemia, hypocapnia, closed head
injury, neoplasms, and craniotomy (254,265). Although the source of the CSF lactate is debated, cerebral
hypoxia/ischemia, anaerobic glycolysis, vascular compromise, and metabolism of the CSF leukocytes are
all potentially important factors (266).
Additional studies have examined whether elevated CSF lactate concentrations are useful in
differentiating bacterial from nonbacterial meningitis in patients who have not received prior
antimicrobial therapy (267). Two metaanalyses, one including 25 studies with 1,692 patients (adults and
children) (268) and the other including 31 studies with 1,885 patients (269), concluded that the CSF
lactate concentration is useful in the differentiation of bacterial from aseptic meningitis. In another study
of adult patients, the CSF lactate concentration had a negative predictive value 99% and positive
predictive value 82% for bacterial meningitis when it was 3.8 mmol/L or higher (270). However, in
patients who received antimicrobial therapy prior to LP, CSF lactate concentrations had a substantially
lower sensitivity compared to those who had not been treated with antimicrobial agents (269), such that
the usefulness of CSF lactate in patients pretreated with antimicrobial therapy is probably limited.
Other Tests
The CSF concentration of several other substances also increases in the presence of bacterial meningitis,
including various enzymes (e.g., lactate dehydrogenase and creatine phosphokinase) and fibrin-
degradation products; however, the elevations are nonspecific. Tests for these compounds are rarely, if
ever, performed in hospital laboratories.
Combinations of Cerebrospinal Fluid Tests

Although many of the aforementioned tests commonly performed on CSF may suggest the diagnosis of
bacterial meningitis, none is irrefutable evidence of this disease, except a positive culture and/or positive
stains. Combinations of test results with clinical parameters may permit a more accurate assessment of the
probability of bacterial versus viral meningitis. This approach appears to have merit, as emphasized in a
retrospective review of 422 patients with acute meningitis at Duke University (271). The following CSF
parameters were individual predictors of bacterial meningitis with greater than 99% certainty: glucose
level of less than 34 mg/dL; CSF-to-blood glucose ratio less than 0.23; leukocyte counts more than
2,000/mm3 or neutrophil counts more than 1,180/mm3. Although any one of these results predicted
bacterial meningitis with high probability, none could rule it out. A multiple regression model using four
parameters (age, month of onset, CSF-to-blood glucose ratio, and CSF neutrophil concentration) proved
highly reliable in separating bacterial from viral meningitis. Although the model requires further
validation, a nomogram is included in the article and should be consulted for more precise analysis of
gram-negative cases (271).
A number of other studies have examined combinations of clinical features, with or without test results,
to develop models in an attempt to accurately predict the likelihood of bacterial meningitis compared to
other potential etiologies (most often viruses) (272). In several retrospective studies of immunocompetent
patients older than 1 month of age with acute bacterial or viral meningitis, a CSF glucose concentration
less than 34 mg/dL, a CSF-to-blood glucose ratio less than 0.23, a CSF protein concentration greater than
220 mg/dL, more than 200 leukocytes per cubic millimeter of CSF, and more than 1,180 neutrophils per
cubic millimeter of CSF were found to be individual predictors of bacterial rather than viral meningitis,
with 99% certainty or better. Many other prediction models have been developed. In a recently published
metaanalysis of bacterial meningitis score validation studies in which 5,312 patients were identified from
eight studies, 4,896 (92%) had sufficient clinical data to calculate the Bacterial Meningitis Score, which
identifies children with CSF pleocytosis who are at very low risk of bacterial meningitis (low-risk
features were negative CSF Gram stain, CSF absolute neutrophil count <1,000 cells/mm3, CSF protein
<80 mg/dL, and peripheral absolute neutrophil count <10,000 cells/mm3) (273). The combined sensitivity
was 99.3%, specificity 62.1%, and negative predictive value 99.7%, indicating that this scoring system
could be used to assist clinical decision making for the management of children with CSF pleocytosis. If
used, these models should be limited to the age cohort in which they were developed. Despite the positive
results of this metaanalysis and other studies, clinical judgment should continue to be used in decisions
about the need for administration of empirical therapy in patients with suspected bacterial meningitis
(272). Prediction models may be most useful in doubtful cases, when they can be used to suggest a
reconsideration of the diagnosis.
Partially Treated Meningitis

The effect of oral antibiotic therapy on CSF analysis was studied in two prospective studies of 281
children with Hib meningitis. Ninety-four (33%) children had been treated with more than one dose of
antibiotics within 1 week before admission. Compared with results in untreated children, the results of
CSF analysis in children pretreated with antibiotics showed significant decreases in the percentage of
neutrophils (p < .03), protein concentration (p < .001), and percentage with a positive Gram stain or
culture (p < .05). Differences in total WBC count, glucose concentration, CSF-to-serum glucose ratio, and
blood culture results were not statistically significant. When adjustment was made for duration of illness
before admission, only the difference in CSF protein concentration remained statistically significant (p <
.01) between children who were pretreated as compared with untreated children. The duration of illness
preceding admission was significantly longer in children who had been treated with antibiotics compared
with that in untreated children. These observations suggested that the natural progression of illness in the
pretreated group was less rapid than that in the untreated group and possibly accounted for the differences
in numbers of WBCs and bacteria in the pretreated group, in whom infection was less fulminant (274).
Intravenous antibiotic therapy, even for as long as several days prior to initial LP, does not markedly
alter the chemical or morphologic characteristics of the CSF in cases of bacterial meningitis (197). CSF
was examined in 68 children with acute bacterial meningitis on admission and 44 to 68 hours after
intravenous antibiotic therapy. Initial antibiotic therapy in all cases consisted of ampicillin (200 mg/kg
daily in six divided doses) in combination with chloramphenicol (100 mg/kg daily in four divided doses).
In those cases in which meningococci, pneumococci, or group A streptococci were isolated from CSF
culture, aqueous penicillin G (400,000 U/kg daily in six divided doses) was substituted. In 65 children
with meningitis caused by Hib, pneumococci, group A streptococci, and meningococci, intravenous
antibiotic therapy did not significantly alter the CSF protein, glucose, or WBC concentrations. However,
bacteria were not evident on smear and did not grow in culture from CSF obtained after intravenous
antibiotic therapy of this duration (275).
In general, bacteria should not be seen on Gram stain or grow in culture from CSF examined 24 hours
after treatment has begun with appropriate antibiotic therapy. The CSF glucose concentration approaches
normality by the third day of antibiotic therapy in 80% of patients, but it may remain low for as long as 10
days. The CSF protein concentration remains elevated for at least 10 days. The WBC count in CSF
remains elevated in more than 50% of cases after a standard 7- to 10-day course of antibiotic therapy, but
it typically decreases when compared with the value obtained prior to therapy or early in the course of
Rapid Diagnostic Tests

Several techniques have been developed for the rapid detection of bacterial antigens in the CSF, including
the latex agglutination test, the staphylococcal or other coagglutination tests, and
counterimmunoelectrophoresis, among many others (276). These techniques use serum containing
bacterial antibodies or commercially available antisera directed against the capsular polysaccharide to
detect the presence of bacterial antigens in CSF. Counterimmunoelectrophoresis requires specialized
equipment and expertise and is rarely performed in hospital laboratories. Due to unacceptably poor
sensitivity of latex agglutination for the diagnosis of bacterial meningitis in CSF samples with a negative
Gram stain (277), this test has been abandoned in most hospital laboratories and cannot be routinely
recommended, although might be considered for patients who have been pretreated with antimicrobial
therapy and when CSF Gram stain and culture results are negative, where available (278).
The limulus amebocyte lysate test can detect minute quantities of endotoxin (e.g., 10 ng/mL) in the CSF.
It is reported to have a sensitivity of 77% to 100%, with some studies reporting sensitivities of 97% to
99% for detecting gram-negative endotoxin. It has been recommended as a useful method for the detection
of gram-negative bacterial meningitis (279). It is occasionally employed in the setting of an abnormal
CSF following neurosurgery or head trauma. Nevertheless, the results of the test rarely change patient
management because physicians should employ antimicrobials with activity against gram-negative
aerobic bacilli in this clinical setting, even if the limulus lysate test result is negative.
C-Reactive Protein and Procalcitonin
The C-reactive protein (CRP) is an acute-phase reactant that, when present in concentrations greater than
100 ng/mL in CSF, is quite sensitive for differentiating bacterial from viral meningitis. The CRP response
is minimal in viral meningitis. CRP concentrations in CSF may be elevated in other CNS inflammatory or
necrotic conditions and thus are not specific for bacterial meningitis; however, when cell counts and
chemistries suggest meningitis, the CRP concentration is useful in distinguishing between bacterial
meningitis and viral meningitis (280,281). In this circumstance, a negative CSF CRP result excludes
bacterial meningitis with 99% certainty. Because CRP is produced in the liver, serum CRP may be useful
in differentiating bacterial from viral meningitis as well. A normal serum CRP has a negative predictive
value of about 99% for acute bacterial meningitis. Thus, in patients where the CSF Gram stain is negative
and the differential diagnosis is between acute bacterial (or partially treated bacterial) and viral
meningitis, a normal serum CRP concentration excludes bacterial meningitis with about 99% certainty and
these patients may be safely observed in the absence of antibacterial therapy.
A normal serum procalcitonin (another acute-phase reactant) concentration has nearly identical
predictive value to the CRP (282–284). In one study, a serum procalcitonin concentration of more than 0.2
ng/mL had a sensitivity and specificity of up to 100% in the diagnosis of bacterial meningitis (285),
although false-negative results have been reported (286). In another study, serum procalcitonin, at a cutoff
of 0.28 ng/mL, had a sensitivity of 95%, specificity of 100%, negative predictive value of 100%, and
positive predictive value of 97% in the diagnosis of bacterial meningitis (270). In patients with
meningitis in whom the CSF Gram stain is negative and analysis of other parameters is inconclusive,
serum concentrations of CRP or procalcitonin that are normal or below the limit of detection have a high
negative predictive value in the diagnosis of bacterial meningitis, so that these patients (i.e., with a
presumptive diagnosis of viral meningitis) can be carefully observed without initiation of antimicrobial
therapy (278,284).
Other Diagnostic Markers
Other markers that have been studied as markers for acute bacterial meningitis in children and adults
include CSF concentrations of cortisol, heparin-binding protein, soluble triggering receptor expressed on
myeloid cells 1, interleukin-6, interleukin-12, interleukin-1β, tumor necrosis factor-α, complement
component B, and complement component 3 (272). Most of these studies included low numbers of
patients, limiting their generalizability. In one study, heparin-binding protein had a sensitivity of 100%
and specificity of 99.2% in the differentiation of bacterial from aseptic meningitis (287).
An immunochromatographic test for detection of S. pneumoniae in CSF was found to be 100%
sensitive and specific for diagnosing pyogenic pneumococcal meningitis (288), although more studies are
needed to demonstrate the usefulness of this test in the diagnosis of pneumococcal meningitis; the overall
sensitivity of the test is 95% to 100% (289).
Polymerase chain reaction (PCR) assays that use specific bacterial primers to detect the nucleic acid of S.
pneumoniae, N. meningitidis, H. influenzae, E. coli, S. agalactiae, and L. monocytogenes in CSF are
available. These assays are reported to be highly sensitive (290–295). In clinical practice, culture results
are often reported before the results of the PCR assay are known limiting the usefulness of this assay. A
broad-range bacterial PCR that can be performed in 2 hours and that can detect small numbers of viable
and nonviable organisms in CSF has been developed. This could be useful as a screening test for
bacterial meningitis and in patients who have been treated with antimicrobial therapy in whom CSF
culture is often negative (296); in this study, the test characteristics for broad-based bacterial PCR
demonstrated a sensitivity of 100%, a specificity of 98.2%, a positive predictive value of 98.2%, and a
negative predictive value of 100%. In another study with use of a multiplex PCR assay for detection of N.
meningitidis, S. pneumoniae, and Hib, the overall specificity and positive predictive value were 100%
and the negative predictive value was 99.1% to 99.5% (297). Multiplex assays for detecting genes of
meningeal pathogens were 100% specific for detecting its target organisms or serogroups, and the lower
limit of detection was similar to that for the singleplex assays (298). In another study, the sensitivity of
broad-range PCR was higher than that of culture (59% versus 43%), whereas the specificity was 97% for
both methods of diagnosis (299). Therefore, broad-based bacterial PCR can be used to detect the most
common microorganisms in only one test and has adequate sensitivity and excellent specificity (272). The
broad-based bacterial PCR can be done within 2 hours in most industrialized countries, although they are
scarce in resource-poor countries. PCR may be particularly useful in patients with bacterial meningitis
who have received prior antimicrobial therapy and are more likely to have negative CSF cultures (300).
The sensitivity and specificity of PCR in CSF for the diagnosis of pneumococcal meningitis are 92% to
100% and 100%, respectively (289). Real-time PCR has also been used for the diagnosis of L.
monocytogenes meningoencephalitis (301). Problems with false-positive results arise when using PCR,
although further refinements in this technique may lead to its usefulness in the diagnosis of bacterial
meningitis, particularly when CSF Gram stain and cultures are negative. Another potential application of
PCR is rapid detection of the in vitro susceptibility of meningeal pathogens to specific antimicrobial
agents. In one report, a novel real-time PCR-hybridization assay was developed for the rapid detection of
penicillin susceptibility in S. pneumoniae; when applied to 24 pneumococcal DNA-positive CSF
extracts, penicillin-sensitive S. pneumoniae was detected in all instances (302). Further studies may
establish the usefulness of this rapid technique in allowing clinicians to decide on the use of specific
antimicrobial therapy in patients with bacterial meningitis (see later discussion).
Neuroimaging
In the acute stage of bacterial meningitis, the CT scan may be normal or it may demonstrate enhancement
of the meninges and ependyma with widening of the cisterns at the base of the brain and the cortical sulci,
a result of the accumulation of purulent exudate in the basal cisterns and over the convexities of the
hemispheres (303). However, the presence of these abnormalities on CT scan contributes very little to the
diagnosis of meningitis. The diagnosis is made by the clinical presentation and analysis of the CSF. The
extent of meningeal enhancement on CT also does not influence management or prognosis. The value of
CT in suspected bacterial meningitis is in the exclusion of other CNS pathologic processes and in the
investigation of the complications of this infection, including (a) prolonged fever for several days after
the initiation of antibiotic therapy, (b) fever that develops after an afebrile period during therapy
(secondary fever), (c) prolonged obtundation or coma, (d) new or recurrent seizure activity, (e) signs of
increased ICP, and (f) focal neurologic deficits.
The most common causes of prolonged fever in patients with bacterial meningitis are subdural
effusions, drug fever, and concomitant arteritis or pneumonia. In published series, 9% to 13% of patients
with Hib or with pneumococcal or meningococcal meningitis had fever for 10 days or longer after the
initiation of appropriate antibiotic therapy. In approximately 25% of these patients, the fever was
attributed to the presence of a subdural effusion. The most common causes of secondary fever are
nosocomial infections and subdural effusions (304). Although the intracranial complications of meningitis
are demonstrated well by CT scan, the results of the CT scan rarely influence the management of children
with meningitis and prolonged fever in the absence of other clinical features suggesting CNS
complications (305). In one review of 107 children with bacterial meningitis who underwent CT scan,
one or more abnormalities were found in 52% of cases (306). However, the majority of findings did not
require specific intervention.
Subdural effusions are a relatively common complication of bacterial meningitis, being reported in
20% to 50% of infants and children with meningitis. Only a small percentage is clinically significant
(307–310). In most cases, the fluid in the subdural space is sterile and is resorbed when the inflammatory
process subsides; however, when a subdural effusion is demonstrated by CT in a patient with prolonged
fever, the possibility of the development of a subdural empyema is raised. Subdural effusions are
typically low-density collections of fluid adjacent to the inner border of the skull that are hypodense to
brain and nearly isodense to spinal fluid (Fig. 24.27). They are often bilateral and may flatten and
displace the frontal horns posteriorly. When a subdural effusion becomes purulent, its density on CT scan
appears higher than that of CSF. After the administration of an intravenous contrast agent, there is
significant enhancement, when the effusion is an empyema, at the border between the extraaxial fluid
collection and the underlying cortex (Fig. 24.28). Sterile subdural effusions do not typically demonstrate
contrast enhancement of the medial border (303) (Fig. 24.29).
The possibility of raised ICP secondary to diffuse cerebral edema or obstructive or communicating
hydrocephalus should be considered in patients with a progressive or prolonged alteration of
consciousness. The CT abnormalities consistent with diffuse cerebral edema include (a) loss of
differentiation between gray matter and white matter; (b) compression of the ventricles, giving the frontal
horns a slitlike appearance; (c) loss of sulcal markings; and (d) lack of visualization of the
perimesencephalic, suprasellar, or quadrigeminal cisterns (303) (Fig. 24.30). The CT appearance of
communicating hydrocephalus is an enlargement of the entire ventricular system, including the fourth
ventricle, with periventricular lucencies surrounding the frontal horns (Fig. 24.31). The latter abnormality
represents transependymal movement of CSF from the ventricular system into the brain parenchyma as a
result of blockage in the normal CSF resorption pathways (303). The development of an obstructive
hydrocephalus secondary to blockage of CSF flow by exudate at the foramina of Magendie and Luschka
has the CT appearance of dilated lateral and third ventricles, with nonvisualization of the fourth ventricle.
The development of seizure activity and/or focal neurologic symptoms and signs during the course of
meningitis are clear-cut indications for neuroimaging. The cause of these abnormalities may be cerebritis,
brain abscess, cortical infarction, enlarging subdural effusions, or empyema. Areas of cerebritis can
easily be missed by CT scan. When they are visualized by CT, they appear as low-density lesions on the
noncontrasted scan; after contrast administration, they are surrounded by an inhomogeneous “halo.” There
may also be diffusion of contrast medium into the low-density center of an area of cerebritis. As the
abscess matures and a capsule is formed, it becomes a low-density lesion with a sharply demarcated
dense ring of contrast enhancement, surrounded by a variable hypodense region of edema (311) (see
Chapter 25).
Cortical infarctions complicating bacterial meningitis are the result of vasculitis. The CT appearance
of a cortical infarction is that of a hypodense lesion that conforms to a vascular territory. Following the
administration of contrast, cortical infarctions have a gyriform, nodular, or ring pattern of enhancement
(306) (Fig. 24.32). Hemorrhagic infarctions are characteristically associated with hyperdense areas on
noncontrasted scans (303).
MRI scanning, like CT, is useful for evaluating the complications of bacterial meningitis. Subdural
empyemas, cortical infarctions, and areas of cerebritis are more readily imaged by MRI than by CT, but in
a sick patient an MRI scan is more difficult to obtain than a CT scan. It is considerably more difficult to
manage a critically ill patient in an isolated MRI scanner suite than in the CT scanner.
The extent and degree of leptomeningeal enhancement from bacterial meningitis are well demonstrated
by MRI scan after the intravenous administration of the paramagnetic contrast agent gadolinium (Fig.
24.33). Paramagnetic contrast agents produce local alterations in magnetic environments that directly
affect the MRI signal obtained from protons. The image that is obtained after the administration of the
contrast agent visualizes this effect on proton relaxation. The contrast agent itself is not visualized. Areas
of active breakdown in the BBB are enhanced when scans are obtained after the administration of
gadolinium (312). Pathologic examination of animals with experimental bacterial meningitis demonstrated
that areas of contrast enhancement on both CT and MRI scans correlated with inflammatory cell
infiltration, and gadolinium-enhanced T1-weighted MRI scans revealed inflammatory meningeal and
ependymal lesions more effectively than did contrast-enhanced CT. Unenhanced T1- and T2-weighted
MRI scans did not detect meningeal inflammation (313).
Subdural effusions can sometimes be distinguished from subdural empyemas by their MRI appearance.
Subdural effusions are low-protein collections; therefore, they appear isointense to spinal fluid on MRI
(Fig. 24.34). Subdural empyemas are more proteinaceous and therefore appear to have higher signal
intensity than CSF on T2-weighted MRI scans (314).
MRI is superior to CT scan in visualizing a cortical infarction. Ischemia and/or infarction are common
causes of focal neurologic deficits in bacterial meningitis. On T2-weighted MRI images, areas of
infarction appear as areas of abnormal, increased signal intensity. An acute infarction is often not
visualized on CT scan within the first 24 hours unless the infarction is large or associated with edema and
mass effect. MRI is the most sensitive modality for these complications, particularly with regard to
infarction, especially when seen on diffusion-weighted imaging, and ventriculitis (315). MR angiography
and perfusion-weighted imaging may show vascular complications, including focal stenosis and
irregularity of major intracranial arteries. CT angiography is more sensitive than MR angiography for
demonstrating focal stenosis of small cerebral arteries.
INITIAL MANAGEMENT
The initial management of a patient with presumed bacterial meningitis is to obtain blood cultures, initiate
antimicrobial and dexamethasone therapy if indicated, and obtain spinal fluid analysis to determine
whether the CSF formula is consistent with that diagnosis (see earlier discussion) (278,316). Empirical
antimicrobial therapy should be initiated based on the patient’s age and underlying disease status (Table
24.5). Although no prospective data are available on the timing of administration of antimicrobial therapy
in patients with bacterial meningitis, a retrospective cohort study in patients with community-acquired
bacterial meningitis demonstrated that a delay in initiation of antimicrobial therapy after patient arrival in
the emergency department was associated with an adverse clinical outcome when the patient’s condition
advanced to a high stage of prognostic severity (317), thus supporting the assumption that treatment of
bacterial meningitis before it advances to a high level of clinical severity improves clinical outcome.
This concept has also been supported by two retrospective studies: one demonstrated a reduction in
mortality with early administration of antimicrobial therapy (318), and the other showed a benefit in terms
of neurologic outcome and survival in patients who received antimicrobial therapy before the patient’s
level of consciousness deteriorated to a score lower than 10 on the Glasgow Coma Scale (319). In
another retrospective case study, delay in administration of antimicrobial therapy was associated with
death; in the multivariate analysis, a delay of longer than 6 hours in antimicrobial administration after
presentation conferred an 8.4-fold greater risk of death (320). An additional retrospective cohort study of
286 patients with community-acquired bacterial meningitis confirmed these results, in which early and
adequate administration of antimicrobial therapy related to onset of overt signs of meningitis was
independently associated with favorable outcome (odds ratio [OR] = 11.19) (321).
Some patients should have a noncontrast CT scan of the head performed before LP to rule out the
presence of brain shift (as a result of an intracranial mass lesion or generalized brain edema) because of
the potential risk of herniation (278). However, the time involved in waiting for a CT scan significantly
delays the initiation of antimicrobial therapy, with the potential for increased morbidity and mortality in
patients with bacterial meningitis. Therefore, emergency empirical antimicrobial therapy and adjunctive
dexamethasone therapy if indicated, after obtaining blood cultures, should be initiated before sending the
patient to the CT scanner. Although CSF cultures may be sterile after the initiation of antimicrobial
therapy, pretreatment blood cultures and the CSF formula or Gram stain will provide evidence for or
against a diagnosis of bacterial meningitis. In one retrospective review of 177 patients (39 of whom had
received prior antimicrobial therapy) with CSF culture–proven bacterial meningitis (322), the
combination of blood culture and CSF Gram stain, with or without latex agglutination, identified the
causative bacterium in 92% of patients. Although some clinicians routinely order CT scans of the head
before performance of an LP in adults with suspected bacterial meningitis, this is not necessary in most
patients. In a study of 301 patients with bacterial meningitis (237), the clinical features at baseline that
were associated with an abnormal finding on CT scan of the head were an age of at least 60 years,
immunocompromised status, a history of CNS disease, a history of seizure within 1 week before
presentation, and neurologic abnormalities (an abnormal level of consciousness, an inability to answer
two consecutive questions correctly or to follow two consecutive commands, gaze palsy, abnormal visual
fields, facial palsy, arm drift, leg drift, and abnormal language). It is reasonable to proceed with LP
without CT scan of the head if the patient does not meet any of the following criteria: new-onset seizures,
an immunocompromised state, signs that are suspicious for space-occupying lesions (papilledema or
focal neurologic signs, not including cranial nerve palsy), or moderate to severe impairment of
consciousness (278,323). Although the decision to perform a CT before LP must be individualized, these
guidelines are useful in determining the patient groups that are more likely to have abnormal findings on
neuroimaging studies.
Once the infecting meningeal pathogen is isolated and susceptibility testing known, antimicrobial
therapy can be modified for optimal treatment (Tables 24.6 and 24.7) (278,316). Recommended dosages
of antimicrobial agents for children with infections of the CNS are shown in Table 24.8, and those for
adults are presented in Table 24.9. In addition, certain patients should receive adjunctive dexamethasone
therapy when presenting with suspected or proven bacterial meningitis (185,186,278,316). This is
discussed in more detail in the section “Adjunctive Therapy.”
TREATMENT
General Principles of Therapy
Bacteriologic cure of meningitis is defined as the eradication of bacteria from CSF. Effective
antimicrobial therapy of bacterial meningitis depends on attaining adequate bactericidal activity in the
CSF. Several factors, largely elucidated in experimental animal models of meningitis, determine whether
bactericidal activity is achieved, including (a) the ability of an antibiotic to penetrate the BBB, (b) the
activity of the antibiotic within purulent CSF, and (c) the rate of metabolism of an antibiotic and its rate of
clearance from CSF (324–328).
The BBB poses physiologic restrictions, allowing only highly lipid-soluble substances or substances
transported by carrier-mediated facilitated diffusion to traverse it under normal conditions (324,329). The
ability of an antibiotic to penetrate the BBB depends on several factors: (a) degree of lipid solubility, (b)
degree of ionization at physiologic pH, (c) protein binding in serum, (d) molecular size and structure of
the antibiotic, and (e) status of the BBB. The BBB acts physiologically like a lipid bilayer. In general, the
greater the lipid solubility of an antibiotic, the better its penetration into CSF. For example,
chloramphenicol is a highly lipophilic substance that easily penetrates the BBB. The β-lactam antibiotics
have poor lipid solubility, which limits their entry into CSF under normal conditions (324). The un-
ionized form of a drug possesses greater lipid solubility than the ionized form. Thus, a lesser degree of
ionization at the pH of serum and CSF increases entry of antibiotics into CSF by increasing their lipid
solubility. Penicillin G has a high degree of ionization at the pH of plasma and CSF. This, combined with
its low lipid solubility, may explain the poor penetration of penicillin G across intact meninges. The
normal plasma-to-CSF pH gradient is approximately 0.1 pH unit (330). The plasma-to-CSF pH gradient
is altered, however, by purulent meningitis. The accumulation of lactate in CSF during bacterial
meningitis decreases the pH of CSF, increases the gradient, and enhances the penetration of some
antibiotics into CSF. Conversely, as metabolic acidosis develops, the pH gradient is reversed and the
penetration of antibiotics into CSF is reduced (324).
Protein binding and molecular size limit the ability of an antibiotic to enter the CSF. Only the free non–
protein-bound portion of an antibiotic in serum can enter the CSF; therefore, highly protein-bound
antibiotics have lower CSF concentrations than antibiotics with a lower degree of protein binding, other
factors being equal. Increased binding to plasma proteins reduces the amount of antibiotic penetration into
CSF; however, it is the concentration of free antibiotic in CSF relative to its minimum bactericidal
concentration (MBC) that determines its therapeutic effectiveness (329).
Although the pharmacokinetics of an antibiotic greatly influence its ability to penetrate the BBB, the
most important factor appears to be the presence of meningeal inflammation. A moderate degree of
meningeal inflammation results in a marked increase in the penetrability of most antibiotics. In many
instances, altered BBB permeability is essential for an antibiotic to be effective in bacterial meningitis.
The morphologic alterations of the BBB observed in an adult rat model of experimental meningitis consist
of an early and sustained increase in pinocytotic vesicles with a progressive separation of intercellular
tight junctions in the cerebral microvasculature (331). These features may contribute to antimicrobial
entry into purulent CSF.
Once the antibiotic penetrates into CSF, several factors influence its ability to eradicate the infection:
(a) sufficient concentrations of free active drug must be achieved in CSF, because this form of the
antibiotic is necessary for bactericidal effect. The high protein concentrations in purulent CSF limit the
concentration of free, unbound antibiotic; (b) an antibiotic must achieve concentrations in CSF in vivo
exceeding the MBC of the infecting organism by 10- to 20-fold for optimal efficacy (173); (c) the
bactericidal activity of an antibiotic may be diminished by the coadministration of a bacteriostatic agent.
For example, chloramphenicol inhibits the bactericidal effect of aminoglycosides against gram-negative
aerobic bacilli within the CSF (332). Conversely, antimicrobial combinations may exert an enhanced,
synergistic improvement in the rate of bactericidal activity within the CSF in vivo (e.g., ampicillin plus
gentamicin versus L. monocytogenes or S. agalactiae); (d) early in the course of bacterial meningitis,
there may be very large numbers of bacteria in CSF (i.e., >108 CFU/mL). Some antibiotics—in particular
the β-lactam antibiotics—demonstrate an inoculum effect in vitro, such that the minimum inhibitory
concentration (MIC) increases dramatically as the inoculum of the test strain is increased from 105 to 107
CFU/mL under standardized in vitro conditions (324). The inoculum effect may explain the failure of
certain antibiotics in vivo, as the in vitro activity of an antibiotic is routinely determined in standard
growth media using a bacterial concentration of 105 CFU/mL (325); (e) an antibiotic must remain
physically stable in the presence of bacterial inactivating enzymes, such as β-lactamase and
chloramphenicol acetyltransferase (329).
The effectiveness of an antibiotic in eradicating bacterial meningitis is also determined by its rate of
metabolism and the activity of its metabolites. For example, cephalothin is metabolized in vivo to
desacetylcephalothin, which is less active in vitro than the parent compound (324). In contrast, the
metabolite of cefotaxime (desacetylcefotaxime) is as active in vitro as the parent compound. Antibiotics
are removed from CSF either by simple resorption through arachnoid villi or by an energy-dependent
active transport process that removes the antibiotic from the CSF to the intravascular compartment across
the epithelium of the choroid plexus. This “exit pump” is inhibited by weak organic acids, such as
salicylates and probenecid, and to some extent by meningitis itself. β-Lactam antibiotics are cleared from
the CSF by this process. The third-generation cephalosporins (e.g., ceftriaxone and cefotaxime) possess
decreased affinity (as compared with penicillin G) for the choroid plexus “exit pump,” so that they remain
in CSF for a longer time (329).
There have also been investigations to determine whether continuous infusion of antimicrobial therapy
improves outcome in patients with bacterial meningitis. In one study of 723 African children with
bacterial meningitis randomly assigned to receive bolus or continuous infusion of cefotaxime for the first
24 hours of therapy, 272 children died, but the mode of administration did not significantly affect the
proportion of children who died or were severely disabled at the time of hospital discharge (333);
children with pneumococcal meningitis given continuous cefotaxime infusion were significantly less
likely to die or have sequelae, however.
Antimicrobial Therapy for Specific Organisms
Penicillin G and ampicillin are the preferred antibiotics for the treatment of meningitis caused by N.
meningitidis (197,219,334). A 7-day course of therapy is adequate for most cases of uncomplicated
meningococcal meningitis. There are reports of strains of N. meningitidis resistant to penicillin (335).
However, β-lactamase–producing isolates are still rare (336). Penicillin-resistant strains that do not
produce β-lactamase appear, instead, to have a reduced affinity for penicillin-binding proteins (e.g., PBP-
2 and PBP-3) and have been reported from Spain, the United Kingdom, and other countries
(335,337–339). In Spain, the number of relatively penicillin-resistant meningococcal isolates reached
20% in 1989 (340). However, in the United States in 1991, MICs of penicillin of 0.125 µg/mL were noted
for only 3 of 100 isolates submitted to the CDC (341). Routine susceptibility testing of meningococcal
isolates is recommended. Meningococcal meningitis caused by the relatively penicillin-resistant strains
has, however, been successfully managed with penicillin therapy, and thus the clinical significance of this
partial resistance is unclear at present (173). Nevertheless, this situation must be carefully monitored,
because meningococci showing relative resistance to penicillin (i.e., MICs in the range of 0.1 to 1.0
µg/mL) are increasing in incidence worldwide. In Ontario, Canada, the prevalence of invasive
meningococcal disease caused by strains with decreased in vitro susceptibility to penicillin was much
higher (21.7%) in 2006 (342), although it did not change in frequency between 2000 and 2006.
Cefotaxime or ceftriaxone should be used when relatively penicillin-resistant strains of meningococci are
isolated and when a patient is allergic to penicillin (343). Because of potent in vitro activity and ease of
administration (e.g., every 12 hours and perhaps effective at every 24 hours), ceftriaxone may well be the
drug of choice for serious meningococcal infection, including meningitis. Chloramphenicol is also
generally effective and widely used in developing countries.
Initial therapy of pneumococcal meningitis includes a combination of a third- or fourth-generation
cephalosporin (either ceftriaxone, cefotaxime, or cefepime) plus vancomycin until the results of
antimicrobial susceptibility testing are known. The Clinical and Laboratory Standards Institute has
recently redefined the in vitro susceptibility breakpoints for pneumococcal isolates from patients with
meningitis as either susceptible or resistant, with intravenous penicillin breakpoints of 0.06 µg/mL or
lower and 0.12 µg/mL or greater, respectively (344). A pneumococcal isolate with an MIC for cefotaxime
or ceftriaxone of less than 0.5 µg/mL is considered susceptible, 1.0 µg/mL intermediate, and more than
2.0 µg/mL resistant (345). In the United States, approximately 34% of pneumococcal isolates are
penicillin nonsusceptible (MICs in the intermediate and resistant ranges) and approximately 14% are
resistant to ceftriaxone (346). The mechanisms by which S. pneumoniae develop resistance to β-lactam
antibiotics (penicillin and extended-spectrum cephalosporins) is through alterations of one or more
penicillin-binding proteins (347). Alterations in the penicillin-binding proteins lead to a decrease in their
affinity for β-lactam antibiotics and thus a decreased susceptibility to the antibiotic (346). In Brazil,
penicillin resistance was mainly detected in isolates of serotypes 14 (61%), 23F (16%), 6B (10%), and
19F (3%) (348). Results of recent surveillance studies in the United States show that the prevalence of
penicillin-nonsusceptible S. pneumoniae ranges from 25% to more than 50% (349); rates are as high as
60% in some parts of Latin America and as high as 80% in some countries in Asia. Factors reported to
predispose to resistance include the patient’s age (younger than 10 or older than 50 years);
immunosuppression; prolonged hospital stay; children in day care settings; infection by serotypes 14 and
23; and frequent, prolonged, or prophylactic use of antimicrobial therapy. However, penicillin
nonsusceptible strains have been isolated even when no risk factors or comorbidities are identified (350).
In view of the increasing number of strains resistant to penicillin, all CSF isolates of S. pneumoniae
should be tested for sensitivity to penicillin and the third-generation cephalosporins by in vitro
susceptibility testing. A third- or fourth-generation cephalosporin (i.e., cefotaxime or ceftriaxone or
cefepime) is recommended for strains of pneumococci resistant to penicillin (MIC ≥0.12 µg/mL) but
sensitive to the third-generation cephalosporins (MIC <1 µg/mL). For strains resistant to penicillin and
the cephalosporins, vancomycin plus a third- or fourth-generation cephalosporin is the antimicrobial
regimen of choice (351,352). The addition of rifampin or a ceftriaxone-rifampin regimen has also been
recommended by some authorities, but rifampin may demonstrate indifference or slight antagonism when
combined with β-lactam agents in standardized in vitro assays (353), although rifampin, without
bacteriolytic activity, may protect against neuronal damage (354). Although concerns have been raised
about use of vancomycin in patients with pneumococcal meningitis who are also receiving adjunctive
dexamethasone, appropriate CSF concentrations of vancomycin may be attained as long as appropriate
dosages of vancomycin are used. In a study of 14 patients, administration of intravenous vancomycin (at a
continuous infusion of 60 mg/kg per day, after a 15 mg/kg loading dose) led to mean serum and CSF
vancomycin concentrations of 25.5 µg/mL and 7.2 µg/mL, respectively (355). These data indicate that
appropriate CSF concentrations can be attained when appropriate doses are used. Trough serum
concentrations of 15 to 20 µg/mL are recommended (356). Intrathecal or intraventricular vancomycin is a
reasonable consideration in patients not responding to parenteral therapy.
Vancomycin-resistant strains of pneumococci have not been seen, but strains of S. pneumoniae tolerant
to vancomycin have been reported. Tolerance is the ability of a bacteria to survive in the presence of an
antibiotic, neither growing nor being eradicated by the antibiotic. Tolerance may be a precursor for the
development of antimicrobial resistance because it creates survivors of antibiotic therapy (357–359).
Imipenem has been utilized in the therapy of penicillin-resistant pneumococcal meningitis, although its
proconvulsant activity may limit its usefulness; meropenem, a carbapenem with less seizure proclivity
than imipenem, may be an effective alternative (360). However, in a study of 20 cefotaxime-resistant S.
pneumoniae isolates (361), 4 were of intermediate susceptibility and 13 were resistant to meropenem,
suggesting that meropenem may not be a useful alternative agent for the treatment of pneumococcal
isolates that are highly resistant to penicillin and cephalosporins. Chloramphenicol is one agent that has
been studied for the treatment of pneumococcal meningitis. However, clinical failures with
chloramphenicol have been reported in patients with penicillin-resistant isolates, probably because of the
poor bactericidal activity of chloramphenicol against these strains; 20 of 25 children had an
unsatisfactory outcome (i.e., death, serious neurologic deficit, poor clinical response) in one study (362).
Chloramphenicol resistance was also found in 27% of pneumococcal isolates in Malawi during 2004 to
2006 (363) and in 43% of isolates in Papua New Guinea (364).
Fluoroquinolones have shown efficacy in some small series or randomized trials in patients with gram-
negative meningitis. In recent years, in response to drug-resistant pneumococci in particular, newer
fluoroquinolones with improved activity against gram-positive cocci have been introduced. These agents
(e.g., gatifloxacin, moxifloxacin, gemifloxacin, and garenoxacin) penetrate well into CSF and have
produced excellent results in experimental models of multidrug-resistant pneumococcal meningitis,
including vancomycin-tolerant strains (365–370). Pharmacodynamic analysis suggests that a Cmax CSF-
to-MBC ratio of at least 5 and CSF concentrations above the MBC for the test strain for the entire dosing
interval are necessary for optimal bactericidal activity. Furthermore, newer antipneumococcal
fluoroquinolones demonstrate synergistic activity in vitro and in vivo in experimental models of
pneumococcal meningitis and combination therapy appears to prevent quinolone resistance among
pneumococci (370). A β-lactam (e.g., ceftriaxone)–potent antipneumococcal quinolone regimen is very
promising (371,372) and may well supplant the currently favored ceftriaxone (or cefotaxime or cefepime)
(373)—vancomycin in the future, pending evaluation in randomized controlled trials.
Gram-Negative Bacilli
The results of clinical trials in patients with gram-negative bacillary meningitis favor the use of a third-
(or fourth-) generation cephalosporin over conventional aminoglycoside-containing regimens
(219,223,374). Cefotaxime, ceftizoxime, ceftriaxone, and ceftazidime penetrate well into inflamed CSF
and are highly active against gram-negative enteric bacilli (223,375). Cure rates of 78% to 94% have
been achieved with the cephalosporins, compared with previous mortality rates of 40% to 90% with
predominantly aminoglycoside-containing regimens (173).
However, given the emergence of strains of gram-negative bacilli that are resistant to the third-
generation cephalosporins (376), the use of other intravenous agents, with or without intraventricular
antimicrobials, may need to be considered and several have been used in patients with meningitis caused
by aerobic gram-negative bacilli (278). In general, the aforementioned third-generation cephalosporins
appear to be equally efficacious for the treatment of gram-negative bacillary meningitis, with the
exception of meningitis caused by P. aeruginosa. Ceftazidime or cefepime is recommended when P.
aeruginosa is suspected (377). Clinical trials suggest the efficacy of ceftazidime alone for Pseudomonas
meningitis, but a combination of ceftazidime and an aminoglycoside may be used if response is delayed
(173).
Although clinical experience is scant, the fluoroquinolones have demonstrated efficacy in animal
models of gram-negative bacillary meningitis. Intravenous pefloxacin has shown good efficacy with
bacteriologic eradication from the CSF in nine of ten patients with gram-negative aerobic bacillary
meningitis failing conventional therapy in one study (378). However, the quinolones should be considered
only for gram-negative bacillary meningitis caused by multiresistant strains or in patients unresponsive to
standard therapies (379).
Although extended-spectrum penicillins (e.g., ticarcillin-clavulanate, temocillin) and aztreonam have
proved effective in the therapy of experimental models of gram-negative bacillary meningitis in animals,
their use is not recommended because the clinical experience with third-generation cephalosporins in
humans is far more extensive. Meropenem has been successfully used in patients with gram-negative
meningitis (including P. aeruginosa), and further investigations may confirm its efficacy in the therapy of
bacterial meningitis (380). The worldwide database on the use of meropenem in the therapy of bacterial
meningitis is quite extensive and encouraging, including cases of gram-negative bacillary meningitis
failing third-generation cephalosporin therapy (e.g., Enterobacter species).
For empirical treatment of Acinetobacter meningitis, intravenous meropenem with or without an
aminoglycoside administered by the intraventricular or intrathecal route has been recommended (381); if
the organism is later found to be resistant to carbapenems, colistin (usually formulated as colistimethate
sodium) or polymyxin B should be substituted for meropenem and may also need to be administered by
the intraventricular or intrathecal route (382). Intravenous colistin (5 mg/kg per day) was successfully
used to treat a patient with meningitis caused by a multidrug-resistant A. baumannii (383); intrathecal
colistin was also efficacious in other cases of meningitis caused by this same multidrug-resistant
organism (384,385) and intrathecal polymyxin E has also been used in a patient with Acinetobacter
meningitis (386). In a summary of treatment of multidrug-resistant A. baumannii, a total of 14 patients
were treated for CNS infection (ventriculitis or meningitis) with colistin given intravenously and/or either
intrathecally or intraventricularly (387); sterilization was achieved in all cases and cure in 13 of 14
cases. In the presence of meningitis, CSF concentrations of colistin were shown to be 0.5 µg/mL (34% to
67% of serum concentrations) (388). Two cases of A. baumannii meningitis were also successfully
treated with tigecycline (389).
Haemophilus influenzae type b

A third-generation cephalosporin, either cefotaxime or ceftriaxone, is recommended for the initial therapy
of H. influenzae meningitis (334). There are few differences between cefotaxime and ceftriaxone for
therapy of bacterial meningitis. Both are generally very active against the major meningeal pathogens,
rapidly sterilize CSF cultures, and are safe and effective (390). The long half-life of ceftriaxone allows
for twice-daily (or even once-daily) administration of this antibiotic. Several studies have documented
that once-daily administration of ceftriaxone is safe and efficacious for the treatment of bacterial
meningitis (336). However, this is not yet recommended as standard therapy for adults; a twice-daily dose
is preferred (173). Ceftriaxone has shown promise as once-daily therapy for completion of the therapeutic
course in the home setting in stable children with meningitis following an uncomplicated hospital stay. A
7- to 10-day course of antibiotics is generally recommended for Hib meningitis.
Despite initial enthusiasm, cefuroxime, a second-generation cephalosporin, is not recommended for the
treatment of Hib meningitis. The in vitro bactericidal activity of this drug has been shown to be inferior to
that of the third-generation cephalosporins, and there have been reports of an unusually high incidence of
positive Gram stain and cultures in CSF obtained several days into treatment. In a prospective,
multicenter study, 106 children with acute bacterial meningitis were randomly assigned to receive either
ceftriaxone or cefuroxime (391). Delayed sterilization of CSF was more common among six patients
given cefuroxime than in one patient given ceftriaxone (p = .112). When all children with positive CSF
cultures (Hib, N. meningitidis, S. pneumoniae, S. agalactiae) were included in the analysis, ceftriaxone
therapy, as compared with cefuroxime therapy, resulted in (a) more rapid sterilization of the CSF at
follow-up LP at approximately 24 hours (2% versus 12% positive cultures; p = .11); (b) less moderate to
profound sensorineural hearing loss at the 2-month follow-up examination (4% versus 17%; p < .05); and
(c) reversible biliary pseudolithiasis on serial abdominal ultrasonography (16 of 35 versus 0 of 5; p <
.001) (391). In another comparative trial, ceftriaxone also led to a more rapid clinical response as
compared with cefuroxime (392). The third-generation cephalosporins, cefotaxime and ceftriaxone, are
clearly preferable to cefuroxime in the treatment of Hib meningitis. Resistance of Hib to the third-
generation cephalosporins and fluoroquinolones in vitro has not been described (393). A combination of
chloramphenicol and ampicillin was at one time the recommended therapy for Hib meningitis. The use of
a third-generation cephalosporin, either cefotaxime or ceftriaxone, has the following advantages over
therapy with a combination of ampicillin plus chloramphenicol: (a) the need to monitor serum
chloramphenicol concentrations is eliminated; (b) the potential toxicities of chloramphenicol are avoided;
(c) the number of daily doses of antibiotics is decreased (199); (d) approximately 29% of Hib strains
causing meningitis in the United States are resistant to ampicillin, through the production of β-lactamase,
although a smaller number of strains are resistant to ampicillin because of reduced affinity for penicillin-
binding proteins. An increasing number of Hib strains are resistant to chloramphenicol, through the
production of chloramphenicol acetyltransferase (199). More than 50% of ampicillin-resistant H.
influenzae CSF isolates from Spain are also chloramphenicol resistant (394). Thus, in some countries,
Hib isolates resistant to both ampicillin and chloramphenicol are common (199). DNA coding for both the
β-lactamase enzyme and the chloramphenicol acetyltransferase enzyme can reside on plasmids, although
chromosomally mediated resistance, as, for example, to trimethoprim, has been described (395).
Therefore, any β-lactamase–positive Hib isolate should be tested for susceptibility to chloramphenicol. In
addition, therapy with the third-generation cephalosporins may result in a more rapid sterilization of the
CSF as compared with therapy with ampicillin plus chloramphenicol.
The pharmacokinetics of chloramphenicol are highly variable among individuals; therefore, serum
concentrations of this antibiotic must be monitored to ensure therapeutic concentrations while avoiding
potential toxic concentrations, especially in infants. Therapeutic serum concentrations are in the range of
15 to 25 µg/mL, obtained 60 to 120 minutes after the completion of an intravenous or oral dose.
Concentrations in excess of 30 µg/mL are associated with an increased incidence of bone marrow
suppression, and levels exceeding 50 to 80 µg/mL may depress myocardial contractility (396). The
pharmacology of chloramphenicol is altered in patients in shock or with liver disease. In either clinical
situation, excessive serum concentrations of chloramphenicol could potentially decrease cardiac
contractility. Chloramphenicol should, therefore, be avoided in patients with these conditions (396).
When chloramphenicol is used in combination with phenobarbital and phenytoin, serum concentrations
of all three drugs must be monitored. Chloramphenicol inhibits hepatic microsomal enzymes and therefore
prolongs the half-life of phenytoin in serum, resulting in toxic concentrations of phenytoin. Phenytoin,
conversely, interferes with hepatic metabolism of chloramphenicol, resulting in toxic serum
concentrations. Phenobarbital induces hepatic microsomal enzymes, increases chloramphenicol
metabolism, and decreases serum chloramphenicol concentrations. These drug interactions interfere with
the eradication of the infection as well as with the management of seizure activity (263,397).
As discussed, fluoroquinolone-resistant H. influenzae have not emerged, and these agents penetrate
well into the CSF. Trovafloxacin was compared with ceftriaxone (± vancomycin) in a multicenter,
randomized comparative trial conducted in 11 countries and enrolling children 3 months to 12 years of
age (398). The major pathogens were Hib, 39%; N. meningitidis, 32%; and S. pneumoniae, 21%. The
overall efficacy was similar in both groups (prompt CSF sterilization in 94% to 96%); fluoroquinolones
may be an excellent alternative for Hib meningitis in patients with β-lactam allergy.
Streptococcus agalactiae
Penicillin G or ampicillin or a third-generation cephalosporin has been standard therapy for neonatal
meningitis caused by group B streptococci (GBS) and is the recommended therapy for treatment of S.
agalactiae meningitis in adults (278). Additionally, the number of penicillin-resistant strains of GBS
appears to be increasing (399). Infection with strains of S. agalactiae resistant to tetracycline,
erythromycin, lincomycin, and clindamycin has been reported; therefore, the use of these penicillin
substitutes in patients with GBS infections is not recommended (399).
The therapy of GBS meningitis in patients with life-threatening penicillin allergy presents a problem. If
third-generation cephalosporins must be avoided, then vancomycin or teicoplanin may be tried, but
clinical experience is almost nonexistent.
Ampicillin is the drug of choice (often combined with gentamicin during the initial phase of treatment) for
meningitis caused by L. monocytogenes. In addition, in a recent retrospective review of patients with
listeriosis (58% with primary bacteremia and 42% with meningitis), differences in mortality were not
seen in those treated with ampicillin or with the combination of ampicillin and gentamicin. An alternative
agent in a penicillin-allergic patient is TMP-SMX, which is bactericidal against Listeria in vitro. In one
retrospective series, therapy with TMP-SMX plus ampicillin was associated with a lower failure rate
and fewer neurologic sequelae than the combination of ampicillin plus an aminoglycoside (122), although
more data are needed before this combination can be recommended. Oral therapy with TMP-SMX has
been used in some patients with Listeria meningitis and may be considered in patients who demonstrate a
rapid clinical response to intravenous therapy and in whom good adherence is expected (400). The third-
generation cephalosporins are inactive against this organism (173). Intravenous vancomycin is not
efficacious, although intraventricular vancomycin was successful in one case of recurrent L.
monocytogenes meningitis (401). Meropenem may be a useful alternative as it is highly active against
listeriae.
Staphylococci
Meningitis caused by S. aureus (MSSA) is treated with nafcillin or oxacillin (139,140,402,403).
Vancomycin is the drug of choice for methicillin-resistant staphylococci and for patients allergic to
penicillin. The CSF should be monitored during therapy, and if the spinal fluid continues to yield viable
organisms after 48 hours of intravenous treatment, then either intrathecal or intraventricular vancomycin,
20 mg once daily (in adults), can be added (402–404). The role of adjunctive rifampin therapy is unclear,
although the addition of rifampin or TMP-SMX should be considered in patients not responding to therapy
and if the organism is susceptible (144). Linezolid has been used successfully in some patients with
MRSA CNS infections (405,406). Daptomycin has been shown to have similar antibacterial activity to
vancomycin in an experimental model of MRSA meningitis (407), and daptomycin plus rifampin has been
successfully used in patients with MRSA meningitis (408–410).
Anaerobes
A combination of chloramphenicol and penicillin G has been recommended for meningitis caused by
anaerobes. Penicillin G has excellent activity against most anaerobes, with the exception of Bacteroides
fragilis. Chloramphenicol is active against most B. fragilis isolates. Analogous to the experience in
patients with brain abscess, we prefer metronidazole for the therapy of the rare cases of anaerobic
meningitis. Penicillin G should be used in addition pending culture results. Metronidazole is bactericidal
against virtually all strict anaerobic organisms and penetrates into the CSF and brain well.
Empirical Antimicrobial Therapy by Age-Group and Underlying Condition
Neonates
Enteric gram-negative bacilli, streptococci (in particular S. agalactiae), and L. monocytogenes are the
most common causative organisms of bacterial meningitis in neonates. A third-generation cephalosporin
plus ampicillin is recommended as initial therapy in this age-group.
Children
A combination of cefotaxime or ceftriaxone or cefepime and vancomycin has become the antibiotic of
choice for the initial treatment of acute meningitis in children in whom the etiologic agent has not been
identified. The empirical therapy of bacterial meningitis in children should include coverage for S.
pneumoniae, Hib, and N. meningitidis, which is provided by the third-generation cephalosporins;
vancomycin is added for pneumococcal meningitis pending in vitro susceptibility testing. The
recommended doses of these antibiotics are listed in Table 24.8.
Adults (Ages 15 to 50 Years)

S. pneumoniae and N. meningitidis are the causative organisms of approximately 85% of cases of
bacterial meningitis in otherwise healthy adults (411). Empirical therapy of meningitis in adults should,
therefore, be directed toward these organisms. Ceftriaxone (4 g per day in divided doses every 12 hours)
or cefotaxime (up to 8 to 12 g per day in divided doses every 4 to 6 hours) or cefepime (6 g per day in
divided doses every 8 hours) is effective therapy for meningitis caused by either of these organisms
(412); vancomycin should be added until the results of antimicrobial susceptibility testing are known. The
recommended doses of these antibiotics are listed in Table 24.9. All CSF isolates of pneumococci and
meningococci should be tested for penicillin or cephalosporin resistance.
Older Adults
The most common organisms causing meningitis in adults older than 50 years are S. pneumoniae and
enteric gram-negative bacilli; however, meningitis caused by Listeria and H. influenzae is increasingly
recognized. For initial therapy of meningitis in elderly patients, either ceftriaxone or cefotaxime or
cefepime plus vancomycin, in combination with ampicillin, is recommended (219,221,263). Meropenem
may be an attractive candidate for monotherapy in this age-group in the future.
Duration of Therapy
The standards for the duration of therapy of bacterial meningitis have been derived from clinical
experience rather than rigid scientific analysis (413). They are basically empirical. Although shorter
courses of therapy may be equally efficacious, we recommend the following duration of treatment as
general guidelines, not rigid standards, when the etiologic agent is known: N. meningitidis, 5 to 7 days;
H. influenzae, 7 to 10 days; S. pneumoniae, 10 to 14 days; GBS, 14 to 21 days; and gram-negative
aerobic bacilli and L. monocytogenes, 3 to 4 weeks. Nevertheless, it must be stressed that the patient’s
response, as assessed by clinical and laboratory parameters, is the most important criterion in the
decision to terminate therapy within this discretionary range. In a double-blind randomized trial of 5 or
10 days of therapy with ceftriaxone for bacterial meningitis in children beyond the neonatal period, it was
determined that ceftriaxone could be discontinued in those patients who were stable after 5 days of
treatment (414), although the uncertainties around organism-specific data (especially for S. pneumoniae)
and the need for clinical judgment at day 5 should lead to caution in reducing treatment duration (415).
Meningitis Following Trauma

S. pneumoniae is the most common cause of meningitis following traumatic head injury in association
with the formation of a dural sinus fistula (218). H. influenzae is a less common, but also important,
pathogen in this setting. A third- or fourth-generation cephalosporin plus vancomycin is recommended for
empirical treatment of meningitis in patients with closed head injury. The regimen can subsequently be
modified based on the results of CSF cultures.
Meningitis Following Neurosurgical Procedures

The most common organisms causing meningitis in the patient who has undergone a neurosurgical
procedure, with the exception of a shunting procedure, are gram-negative bacilli and staphylococci (223).
Initial therapy of meningitis in the postneurosurgical patient should be directed against gram-negative
bacilli, but also against P. aeruginosa and S. aureus (219). A third- or fourth-generation cephalosporin is
recommended for the treatment of gram-negative bacillary meningitis (223,374). Ceftazidime or cefepime
should be used. Cefepime is a fourth-generation cephalosporin that is also active against pseudomonads.
Vancomycin should be added until infection with staphylococci is excluded.
Coagulase-negative staphylococci and S. aureus are the most common pathogens causing CSF shunt
infections. Unless the organism is clearly susceptible to methicillin, vancomycin is recommended for
shunt infections caused by staphylococci (139,402,403). Therapy of methicillin-resistant staphylococcal
shunt infections should include a combination of intravenous vancomycin and either oral rifampin or
intrashunt or intraventricular vancomycin (403,416). Although cefuroxime may enter ventricular fluid in
the presence of an infected CSF shunt, the concentrations are quite variable (417). This agent is not,
therefore, recommended for shunt infections.
Immunosuppressed Hosts
As has been discussed, the risk for development of bacterial meningitis in an immunocompromised patient
depends on a number of factors, such as (a) the underlying disease and its treatment, (b) the duration of
immunosuppression, and (c) the type of immune abnormality. Knowledge of the latter helps predict the
infecting organism (233,234). Patients with defects in cell-mediated immunity are most susceptible to
CNS infections by microorganisms that are intracellular parasites, the eradication of which depends on an
intact T-lymphocyte–macrophage system. L. monocytogenes is the most common cause of bacterial
meningitis in patients with defective cell-mediated immunity (234). Patients with defective humoral
immunity are unable to mount an antibody response to a bacterial infection, and they are therefore unable
to control infection caused by encapsulated bacteria. These patients are at particular risk for meningitis
caused by S. pneumoniae, Hib, and, less commonly, N. meningitidis. Patients with neutropenia are at
particular risk for meningitis caused by P. aeruginosa and members of the Enterobacteriaceae family
(233). The choice of antibiotic for empirical treatment of bacterial meningitis in the immunosuppressed
patient should be made based on the type of immune abnormality.
Adjunctive Therapy
As is discussed in Chapter 23, the generation of bacterial cell wall components in CSF during treatment
of meningitis with antibiotics contributes to increased inflammation in the SAS (18). Bacterial cell wall
components stimulate the release of inflammatory cytokines in the CNS, such as TNF, IL-1, and
prostaglandins (173). It may be possible to reduce the inflammatory response in the SAS and thus
improve the outcome of this infection by administering antiinflammatory agents in conjunction with
antibiotics (172,418).
TNF is a macrophage-secreted hormone that is released in response to bacterial endotoxin. The
injection of small doses of purified endotoxin into healthy volunteers causes the appearance of elevated
serum concentrations of TNF within 90 minutes after the infusion, accompanied by symptoms of headache,
fever, rigors, and myalgia (419). Endogenous TNF release has been observed in patients with sepsis and
in those with meningococcemia. Damas et al. (420) detected very high serum concentrations of TNF
(mean, 701 ± 339 pg/mL; normal, 75 ± 15 pg/mL) in patients in septic shock. Waage et al. (421) found
elevated serum TNF concentrations in patients with meningococcal disease. The patients with the highest
concentrations (>0.1 ng/mL) died. Ming et al. (422) found elevated concentrations of TNF in CSF during
bacterial meningitis in both mice and humans. None of the CSF samples from patients with viral
(echovirus, coxsackievirus, or mumps virus) meningitis or other neurologic diseases (e.g., multiple
sclerosis) in this study contained measurable concentrations of TNF (422). This suggests that the presence
of TNF in CSF may be specific for bacterial meningitis (173).
TNF induces IL-1 release from endothelial cells and macrophages (423). IL-1 represents a family of
polypeptides that are both beneficial and detrimental to the host. The primary sources of IL-1 are
monocytes and macrophages, but IL-1 is also produced by brain astrocytes and microglia. IL-1 is a potent
chemoattractant for neutrophils, monocytes, B cells, and T cells; it has an important role in B-cell
proliferation and antibody production, as well as in T-cell activation (424). IL-1 may, however, also be
detrimental to the host. IL-1 released into tissue induces a proliferative response. IL-1 released by
astrocytes into brain tissue may contribute to brain gliosis and scar formation (424). IL-1 increases the
concentration of metabolites of arachidonic acid—most notably PGE2 and leukotriene B4, which are
potent mediators of inflammation (423).
Possible therapeutic approaches to decrease the harmful effects of TNF and/or IL-1 might include (a)
drugs or procedures to decrease their production, block their biologic activity, or enhance removal from
the circulation, (b) passive immunization with antibodies against TNF and IL-1, and (c) drugs that
interfere with IL-1–induced arachidonic acid metabolites. Corticosteroids are highly effective in reducing
IL-1 production in vitro and in vivo. Many of the biologic activities of IL-1 are inflammatory; aspirin,
acetaminophen, and nonsteroidal antiinflammatory agents can reduce fever, muscle PGE2 production,
leukocyte chemotaxis, and so on. Therapeutic concentrations of nonsteroidal antiinflammatory agents and
antipyretic blood levels of aspirin do not, however, reduce IL-1 production, IL-1–mediated lymphocyte
activation, or IL-1 synthesis of acute-phase proteins (424).
Passive immunization with monoclonal antibodies directed against TNF and IL-1 may be a future
therapeutic option. Beutler et al. (425) passively immunized mice with antiserum to murine TNF and
protected them from the lethal effects of gram-negative bacteremia. A major limitation, however, of
monoclonal antibody therapy for meningitis is the BBB. Even during active inflammation, the BBB is an
effective barrier of antibody penetration into the CSF. To achieve sufficient antibody concentrations
within the CSF, it would be necessary to produce serum concentrations of antibodies at least 20- to 100-
fold higher than the expected protective concentration in serum or to administer the antibody by
intrathecal injection (426).
Despite aggressive supportive care and the administration of appropriate antimicrobial agents, the
outcome for patients with fulminant meningococcemia is often poor. Serum TNF concentrations correlate
directly with outcome in this condition. Activated protein C (drotrecogin alfa activated) reduces mortality
in patients with severe sepsis (427) but has been withdrawn from the worldwide market. Plasmapheresis
has been attempted, although on an extremely limited scale, in meningococcemia and may lead to a rapid
decrease in serum TNF concentrations and/or improved mortality and morbidity (428). Despite the lack
of a controlled clinical trial, this approach definitely deserves further study.
Clinical trials suggest a beneficial effect from dexamethasone in the treatment of bacterial meningitis in
children and adults. In a prospective, randomized trial, 429 patients with bacterial meningitis were
treated with either (a) dexamethasone, ampicillin, and chloramphenicol or (b) ampicillin and
chloramphenicol only. Dexamethasone was administered intramuscularly with the first dose of antibiotic,
at a dose of 8 mg to children younger than 12 years and 12 mg to adults every 12 hours for 3 days. There
were 56 cases of Hib meningitis, 106 cases of pneumococcal meningitis, and 267 cases of meningococcal
meningitis. The case-fatality rate was significantly lowered in patients with pneumococcal meningitis
receiving dexamethasone; only 7 of 52 patients died, compared with 22 of 54 patients not receiving
dexamethasone (p < .01). Dexamethasone therapy also significantly reduced the incidence of hearing loss
in patients with pneumococcal meningitis. None of the 45 surviving patients in the dexamethasone-treated
group developed hearing loss, whereas 4 of 32 patients treated with antibiotics alone became deaf (p <
.05) (429). However, there were no significant differences between groups in time to afebrility or
improvement in CSF parameters, there was no documentation of possible adverse effects, an
extraordinarily high percentage of patients presented in a comatose state, most patients (370 of 429)
received inadequate therapy for 3 to 5 days before hospitalization, the antibiotics were administered
intramuscularly, and no differences in mortality were noted in patients with meningococcal or Hib
meningitis.
The results of a double-blind placebo-controlled trial of 200 infants and children with bacterial
meningitis demonstrated a beneficial effect of dexamethasone therapy in reducing the incidence of
sensorineural hearing loss. Patients were treated with ceftriaxone or cefuroxime, with either
dexamethasone (0.15 mg/kg every 6 hours for 4 days) or placebo. Of 84 patients in the placebo-treated
group, 13 (15.5%) had moderate or more severe bilateral hearing loss as compared with 3 (3.3%) of 92
of the dexamethasone-treated children (p < .01) (430). The beneficial effects of dexamethasone were
observed only in the children receiving concurrent cefuroxime (which may be suboptimal therapy) and not
in those treated with ceftriaxone, thus rendering interpretation difficult. Dexamethasone appeared to be of
particular benefit in children with milder cases of Hib meningitis (430).
Similar trends suggesting a beneficial effect of dexamethasone were observed in a third randomized,
placebo-controlled trial by the Dallas group for children receiving cefuroxime (431). Once again, patients
receiving dexamethasone became afebrile sooner, and the CSF glucose concentration rose more rapidly
during the first day of therapy. Although the small sample size precluded a significant result from an
analysis of hearing loss, the data combined with the data of the previous study (430) continued to reveal
an advantage for corticosteroid therapy (432). The use of cefuroxime, a suboptimal agent (see earlier
discussion) (338), in approximately 160 of 260 patients in these trials had led some investigators to
question the routine use of dexamethasone as adjunctive therapy based on the results of these clinical
trials (433). A metaanalysis of 11 randomized clinical trials (as of 1988) of dexamethasone for adjunctive
therapy confirmed benefit for H. influenzae type b meningitis, especially for hearing outcomes, and
suggested benefit for pneumococcal meningitis in children if begun with or before parenteral antibiotics
(434).
Another trial, from Costa Rica, randomized infants and children with bacterial meningitis to receive
cefotaxime with either dexamethasone or placebo (435). In this study, the dexamethasone or placebo was
administered 15 to 20 minutes before the first dose of cefotaxime in an attempt to attenuate the SAS
inflammatory response maximally. When patients were monitored for a mean of 15 months, those who had
received adjunctive dexamethasone had a significantly decreased incidence of one or more neurologic
sequelae, although there was only a trend in reduction of audiologic impairment.
A review of the medical records of 97 infants and children with pneumococcal meningitis (treated from
1984 to 1990) demonstrated a beneficial effect of dexamethasone therapy in infants and children with
fulminant meningeal infection, as defined by laboratory studies, altered level of consciousness, and the
presence of septic shock and cerebrovascular instability. They accounted for two thirds of the deaths and
had a significantly increased incidence of seizures and permanent bilateral moderate or greater hearing
loss. Of the survivors, 1 of 8 steroid-treated patients, as compared with 7 of 13 nonsteroid-treated
patients, had moderate or severe bilateral hearing loss (436). However, this was a retrospective review
and there were no data on differences in outcome with regard to specific antibiotic used.
In a prospective, placebo-controlled double-blind trial of dexamethasone (given at a dosage of 0.4
mg/kg every 12 hours for 2 days) in 115 children with acute bacterial meningitis, Hib was the infecting
organism in 30 (55%) of 55 patients in the placebo group, and in 37 (62%) of 60 patients in the
dexamethasone-treated group. N. meningitidis was the infecting organism in 12 (22%) of 55 patients in
the placebo group and in 16 (27%) of 60 patients in the dexamethasone-treated group. At follow-up
examination 3, 9, and 15 months after discharge, 3 (5%) of 60 dexamethasone-treated patients had one or
more neurologic or audiologic sequelae, compared with 9 (16%) of 55 placebo recipients (p = .065)
(437).
Other studies questioned the routine use of adjunctive dexamethasone in infants and children with
bacterial meningitis. In one trial, there were no significant reductions in audiologic and neurologic
sequelae with adjunctive dexamethasone therapy, although dexamethasone was given within 24 hours of
antimicrobial therapy (median, 11 hours) and the study was stopped prematurely because the standard of
care became early administration of dexamethasone (438). Similarly, in the second trial, adjunctive
dexamethasone was not associated with significant improvements in neurologic sequelae, developmental
outcome, or unilateral or bilateral deafness (439). Dexamethasone was given within 4 hours of the first
antimicrobial, and there was a lack of follow-up for 13% of the study population. In a very large study
from Malawi, dexamethasone again failed to improve outcome in children with bacterial meningitis, but
the evaluation of hearing loss was suboptimal and still suggested a steroid benefit (440).
The American Academy of Pediatrics recommends consideration of dexamethasone therapy in infants
and children 2 months and older with proven or suspected bacterial meningitis. A daily dose of 10 to 12
mg/m2 (0.6 mg/kg) in four divided doses is recommended for 3 to 4 days (441). Therapy for 2 days may
also be efficacious (437,442). Children should, however, be carefully monitored for potential
complications of corticosteroid use, specifically gastrointestinal hemorrhage and hyperglycemia. The
concomitant use of an intravenous H2 receptor antagonist is recommended to prevent gastrointestinal tract
bleeding. If corticosteroids are used, they should definitely be administered early, that is, before or
simultaneously with the first dose(s) of parenteral antimicrobial agents. This is particularly important,
because administration of currently available bacteriolytic agents (e.g., ceftriaxone) leads to rapid release
of free endotoxin from gram-negative organisms into CSF, with an attendant exaggeration of the host’s
inflammatory response (443).
The results of a prospective, randomized, double-blind trial of adjunctive dexamethasone therapy for
bacterial meningitis in 301 adults in five European countries over 9 years demonstrated that
dexamethasone improves the outcome in adults with acute bacterial meningitis. The benefits were most
striking in the patients with pneumococcal meningitis (444). In another clinical trial, patients with
pneumococcal meningitis who were treated with dexamethasone had a lower fatality rate than those that
were not treated with dexamethasone (429). There has been concern that dexamethasone would decrease
the penetration of vancomycin into the CSF. In a prospective study of 11 adults with community-acquired
pneumococcal meningitis that were treated with a combination of dexamethasone and vancomycin at a
dose of 15 mg/kg every 8 hours or 7.5 mg/kg every 6 hours, there were four therapeutic failures (445).
The dose of vancomycin was well below the recommended dose of 60 mg/kg per day. In a prospective
randomized clinical trial of the bactericidal activity of vancomycin against cephalosporin-resistant
pneumococci in CSF of children with acute bacterial meningitis, vancomycin in a dose of 60 mg/kg per
day penetrated reliably into the CSF when the children were treated concomitantly with dexamethasone
(0.6 mg/kg per day divided into four doses for 4 days) (446). The recommended dosage of dexamethasone
for adults is 8 to 10 mg intravenously every 8 hours for 2 to 4 days. Dexamethasone therapy should not
adversely affect the outcome of viral meningitis (447).
Many other clinical trials were undertaken to determine the effects of adjunctive dexamethasone on
outcome in patients with bacterial meningitis (173,278). On the basis of previous data, and the apparent
absence of serious adverse outcomes in adult patients who received dexamethasone, the routine use of
adjunctive dexamethasone (given concomitant with or just prior to the first dose of an antimicrobial agent
for maximal attenuation of the SAS inflammatory response) is warranted in most adults with
pneumococcal meningitis (448). A recent study demonstrated a favorable trend toward reduced rates for
death and hearing loss and no evidence that dexamethasone was harmful in patients with meningococcal
meningitis (449). Adjunctive dexamethasone should not be used in patients who have already received
antimicrobial therapy for several hours. Despite these positive benefits in terms of morbidity and
mortality, there were some concerns regarding cognitive long-term outcome in patients treated with
dexamethasone. However, a follow-up study of 87 eligible patients in which 46 were treated with
adjunctive dexamethasone and 41 with placebo, neuropsychologic evaluation showed no significant
differences between patients treated with dexamethasone or placebo (450). In an evaluation of 357
episodes of pneumococcal meningitis from 2006 to 2009 in the Netherlands since implementation of
adjunctive dexamethasone on a large scale basis, the prognosis has improved with mortality rates
decreasing from 30% to 20% (451).
Despite these positive benefits, the routine use of adjunctive dexamethasone in patients with bacterial
meningitis in the developing world has been controversial. In one randomized, double-blind, placebo-
controlled study in adolescents and adults in Vietnam with confirmed bacterial meningitis (452), patients
who received adjunctive dexamethasone experienced a significant reduction in the risk of death at 1
month (relative risk [RR], 0.43) and the risk of death or disability at 6 months (RR, 0.56); the highest
proportion of cases in this study were caused by S. suis, followed by S. pneumoniae. In contrast, in a
randomized, double-blind, placebo-controlled study from Malawi, there were no significant differences
in mortality at 40 days in the intention-to-treat analysis (56% in the dexamethasone group versus 53% in
the placebo group) or when the analysis was restricted to patients with proven pneumococcal meningitis
(53% in the dexamethasone group versus 50% in the placebo group) (453). However, in this trial, almost
90% of the patients were infected with HIV and most likely had advanced disease; delayed presentation
was also associated with a poorer outcome, although adjusting for this factor in the analysis had no effect.
These data suggest that adjunctive dexamethasone is not beneficial in resource-poor countries where a
substantial number of patients are infected with HIV (454). In a Cochrane metaanalysis of 24 studies
involving 4,041 participants, adjunctive dexamethasone did not reduce overall mortality, but there was a
trend to lower mortality in adults; corticosteroids were associated with lower rates of severe hearing
loss, any hearing loss, and neurologic sequelae, although these benefits were only seen in studies from
high-income countries (455). In a subgroup analysis based on causative microorganism, corticosteroids
reduced severe hearing loss in patients with H. influenzae meningitis and mortality in patients with S.
pneumoniae meningitis.
The use of adjunctive dexamethasone is of particular concern in patients with pneumococcal meningitis
caused by penicillin- and cephalosporin-resistant strains, in which case patients may require
antimicrobial therapy with vancomycin (173,278). A diminished CSF inflammatory response after
dexamethasone administration might significantly reduce vancomycin penetration into CSF and delay CSF
sterilization, as shown in an experimental rabbit model of penicillin-and cephalosporin-resistant
pneumococcal meningitis. This result was confirmed in another rabbit model of pneumococcal meningitis
in which significantly lower CSF vancomycin concentrations and differences in bacterial killing were
found in the dexamethasone-treated rabbits. However, CSF vancomycin penetration was not reduced by
dexamethasone in a study in children (446), and in another study in which a continuous infusion of
vancomycin was used (60 mg/kg per day), adequate CSF concentrations (7.2 µg/mL) were achieved
despite the concomitant administration of adjunctive dexamethasone (355). CSF concentrations of
ceftriaxone are not significantly altered in animals or patients treated with adjunctive dexamethasone
(456,457). In contrast, in an experimental rabbit model of cephalosporin-resistant pneumococcal
meningitis (458), concomitant use of dexamethasone with ceftriaxone resulted in higher CSF bacterial
counts and a higher number of therapeutic failures. For any patient receiving adjunctive dexamethasone
who is not improving as expected or who has a pneumococcal isolate for which the cefotaxime or
ceftriaxone minimal inhibitory concentration (MIC) is 2.0 µg/mL or greater, a repeat LP 36 to 48 hours
after initiation of antimicrobial therapy is recommended to document the sterility of CSF (278). In the
study cited earlier, only 78 (72%) of 108 CSF cultures that were positive for S. pneumoniae were
submitted for in vitro susceptibility testing, and all were susceptible to penicillin (444), a finding that is
unusual in many areas of the world. In patients with pneumococcal meningitis caused by strains that are
highly resistant to penicillin or cephalosporins, careful observation and follow-up are critical to
determine whether use of adjunctive dexamethasone is associated with adverse clinical outcome in these
patients (278,448).
In addition to corticosteroids, several other adjunctive approaches to the therapy of bacterial
meningitis may be useful (418,459). These include (a) bactericidal but nonbacteriolytic antibiotics to
reduce endotoxin and other injurious substance (e.g., outer membrane vesicle) release into CSF (a
theoretical but as yet impractical method); (b) nonsteroidal antiinflammatory agents; (c) other
prostaglandin inhibitors; (d) anti–endotoxin-binding agents; (e) monoclonal antibodies directed against
complement factor 5 (460), endotoxin, cytokines, or leukocyte–endothelium adhesion molecules; (f)
pentoxifylline; (g) cytokine antagonists; (h) nitric oxide synthase (NOS) inhibitors (i.e., aminoguanidine);
(i) thalidomide, by blocking TNF release from microglia (461); (j) osmotic dehydrating agents (e.g.,
mannitol, glycerol); (k) scavengers of peroxynitrite; and (l) inhibitors of matrix metalloproteinases
(MMPs).
Treatment of Complications
Raised Intracranial Pressure

ICP is usually increased in bacterial meningitis; therefore, this complication should be anticipated and
treated promptly. The clinical signs of increased ICP are (a) an altered level of consciousness ranging
from drowsiness to coma; (b) a dilated, poorly reactive, or nonreactive pupil; (c) abnormalities of ocular
motility; and (d) bradycardia and hypertension—the Cushing reflex. Increasing ICP may be associated
with only one or a combination of these clinical signs. Papilledema does not develop until increased ICP
has been present for several hours; therefore, the absence of papilledema should not be used to exclude
the presence of increased ICP. Increased ICP may lead to herniation. Signs of impending herniation
include (a) midposition, nonreactive pupils; (b) unequal or dilated, nonreactive pupils; (c) skew
deviation or dysconjugate eye movements; (d) decorticate or decerebrate posturing; and (e) bradycardia
and abnormal respiratory patterns.
Patients who are awake and alert can be watched clinically for signs of advancing increased ICP.
Patients who are stuporous or comatose may benefit from an ICP monitoring device.
ICP exceeding 20 mm Hg is abnormal and should be treated; however, outcome may be improved if
pressures greater than 15 mm Hg are treated. The rationale for treating the smaller elevations in pressure
is to avoid large elevations, or so-called “plateau waves,” that can lead to herniation and irreversible
brainstem injury (180,263). Plateau waves are sustained elevations in ICP that may occur spontaneously
or as the result of small increases in cerebral blood volume from hypoxia, fever, or intratracheal
suctioning. When ICP is already high, plateau waves may be reached quickly and lead to brain death
(182,263). The treatment of increased ICP is outlined in Table 24.10.
Nonetheless, in one study of 15 patients with bacterial meningitis in whom intracranial pressure was
measured (462), intracranial pressure was successfully lowered in most patients by a broad range of
measures, which consisted of sedation, steroids, normal fluid and electrolyte homeostasis, blood
transfusion, albumin infusion, decrease of MAP, treatment with a prostacyclin analog, and eventually
thiopental, ventriculostomy, and dihydroergotamine. In nonsurvivors, mean intracranial pressure was
significantly higher and CPP was markedly lower than in survivors despite treatment; however, this was
not a comparative study and the results should be interpreted with caution.
Elevating the head of the bed 30 degrees reduces the ICP. Turning the head to the side (particularly to
the left) or hyperextending the neck may trigger an increase in ICP. Intratracheal suctioning or
endotracheal intubation may increase ICP (182,263,463).
Hyperosmolar agents, such as mannitol, decrease ICP by decreasing cerebral edema. Mannitol remains
almost entirely in the extracellular intravascular space, making this compartment hyperosmolar to brain
tissue. The result is movement of water from brain tissue into the intravascular space. Mannitol can be
given either as a bolus intravenous injection of 1 g/kg over 10 to 15 minutes or in small frequent doses of
0.25 g/kg every 2 to 3 hours. A bolus injection can be repeated at 3- to 4-hour intervals to maintain the
serum osmolality between 315 and 320 mOsm/L (180,182,263,463).
Dexamethasone appears to be beneficial in reducing ICP and cerebral edema in animal models of
bacterial meningitis (464,465). However, its efficacy for reducing cerebral edema in patients with
bacterial meningitis has not been established. Steroids are known to be beneficial in reducing cerebral
edema surrounding tumors. In this situation, cerebral edema is largely vasogenic in origin. Steroids
reduce vasogenic edema by reducing the permeability of cerebral capillary endothelial cells (466). There
is experimental evidence to suggest that steroids reduce interstitial edema in meningitis (467). Cerebral
edema in meningitis is a combination of vasogenic, cytotoxic, and interstitial edema (170). The evidence
that steroids decrease vasogenic and interstitial edema suggests a role for corticosteroids in the
management of this complication, which may contribute to raised ICP.
The use of steroids to reduce cerebral edema in meningitis also has disadvantages. Steroids decrease
inflammation in the meninges. As has been discussed, a moderate degree of inflammation in the meninges
is required for the CSF penetration of many antibiotics. By reducing meningeal inflammation, the
concentration of antibiotics in CSF is reduced. This may be most important several days into treatment,
when meningeal inflammation has been reduced substantially by antibiotic treatment. Steroids should,
therefore, be discontinued within approximately 4 days of treatment (441).
High-dose barbiturate therapy is useful when other modalities have failed to control ICP. Barbiturates
decrease the cerebral metabolic demand for oxygen and thus decrease cerebral blood flow. The result is a
decrease in ICP. Pentobarbital is administered in an initial dose of 5 to 10 mg/kg at a rate of 1 mg/kg per
minute, followed by a dose of 1 to 3 mg/kg per hour. This therapy requires an intracranial monitoring
device or an electroencephalogram (EEG) to monitor cerebral activity, because the clinical examination
is severely limited by the depressive effects of barbiturate. Pentobarbital is administered until the ICP is
reduced below 20 mm Hg or until the EEG demonstrates a suppression-burst pattern. Recommended
serum concentrations of pentobarbital to reduce ICP are 20 to 40 µg/dL. A Swan-Ganz catheter should be
in place to monitor cardiac output. High-dose barbiturates are associated with significant cardiac toxicity,
including decreased cardiac output, decreased contractile force, arrhythmias, and hypotension.
Pentobarbital is the recommended barbiturate when barbiturate coma is desired, because this drug has a
relatively short half-life. The half-life of pentobarbital is 24 hours, compared with the longer half-life of
phenobarbital (5 days). The use of pentobarbital allows for a more rapid reversal of barbiturate coma
than does the use of phenobarbital. Pentobarbital coma is maintained until the ICP has been below 20 mm
Hg for 24 hours. The dosage of barbiturate is then slowly decreased to prevent a rebound increase in ICP
(263,463,468).
Seizures
Seizures occur in 30% to 40% of children with acute bacterial meningitis (200). They occur in more than
30% of adults with pneumococcal meningitis in the first few days of illness (218). In a nationwide
prospective study on adults with community-acquired bacterial meningitis, seizures occurred in 17% of
patients and were associated with severe CNS and systemic inflammation, structural CNS lesions,
pneumococcal meningitis, and predisposing conditions (469). The high associated mortality rate warrants
a low threshold for starting anticonvulsant therapy in those with clinical suspicion of a seizure. If not
managed quickly and aggressively, status epilepticus may develop. Severe or prolonged seizure activity
can produce permanent damage resulting from anoxic ischemic changes in areas of the temporal lobe,
cerebellum, and thalamus (263,468). The increased energy requirements of discharging neurons cannot be
met by cerebral blood flow during sustained seizure activity. The result is ischemic necrosis and loss of
cortical neurons (441). Status epilepticus that is continuous for 90 minutes or longer can cause permanent
neurologic sequelae.
For early termination of seizure activity, a short-acting anticonvulsant with a rapid onset of action (such
as lorazepam or diazepam) is recommended. Lorazepam is administered intravenously in 1- to 4-mg
doses in adults and in an initial dose of 0.05 mg/kg in children. Lorazepam has a duration of action three
to four times longer than that of diazepam in adults (441); 4 mg of lorazepam is therapeutically equivalent
to 10 mg of diazepam (470). Diazepam is administered in a dose of 0.25 to 0.4 mg/kg (maximum, 10 mg)
at a rate of 1 to 2 mg per minute. The 10-mg dose may be repeated up to three times at intervals of 15 to
20 minutes (471). Diazepam has a half-life of 15 minutes; therefore, the blood level decreases rapidly. A
long-acting anticonvulsant should be administered immediately after lorazepam or diazepam. The long-
acting anticonvulsant of choice in children and adults is phenytoin or fosphenytoin. Phenytoin is
administered in a dose of 18 to 20 mg/kg at a rate no faster than 50 mg per minute. Phenytoin can prolong
the QT interval or lead to hypotension. If either of these side effects is observed, the rate of
administration is decreased. Fosphenytoin is a water-soluble prodrug of phenytoin that is converted to
phenytoin by nonspecific phosphatases. Doses of fosphenytoin are expressed as phenytoin equivalents.
Infusion side effects are less common with fosphenytoin than with phenytoin (472). Fosphenytoin is
administered in a dose of 18 to 20 mg/kg at a rate no faster than 150 mg per minute. Phenytoin is very
effective in controlling convulsions without depressing consciousness or respiration (263). Intravenous
phenytoin reaches peak brain and blood concentrations within 15 minutes (473). The half-life of
phenytoin following a loading dose is approximately 36 hours (470). Serum concentrations greater than
25 µg/mL are usually necessary to terminate status epilepticus. If an 18- to 20-mg/kg dose of phenytoin
fails to control seizure activity, an additional 500 mg of phenytoin can be given. A maintenance dose of
100 mg every 6 hours (in adults) should be started after the loading dose.
If fosphenytoin fails to control seizure activity, the patient can be treated with intravenous levetiracetam
or valproic acid or intubated, mechanically ventilated, and treated with phenobarbital. For adults,
phenobarbital is administered intravenously at a rate of 100 mg per minute until seizure activity stops, or
to a loading dose of 20 mg/kg (263). The loading dose of phenobarbital in children is 20 mg/kg,
administered intravenously at a rate of 30 mg per minute (474). The most common adverse effects of
phenobarbital loading are hypotension and respiratory depression. If these complications are managed
and seizure activity continues, an additional 10 mg/kg can be given (474). The primary reason for failure
to control seizures is that anticonvulsants are administered in subtherapeutic doses or that the rate of
administration is too slow.
The combination of phenytoin and phenobarbital controls seizure activity in the vast majority of
patients. When they fail to do so, general anesthesia with pentobarbital can be tried. The dose of
pentobarbital is the same for children and adults: a loading dose of 3 to 5 mg/kg and a maintenance dose
of 1 to 2 mg/kg per hour (263,474). In the past, paraldehyde or a continuous intravenous diazepam drip
was used to treat status epilepticus; however, paraldehyde is no longer available, and a diazepam drip is
no longer recommended.
Fluid Management
Most children with bacterial meningitis are hyponatremic (serum sodium concentration <135 mEq/L)
early in the course of their illness (441). Fifty percent of children have evidence of SIADH on admission
to the hospital (208). Restriction of fluids to correct serum sodium is potentially important, because the
degree and duration of hyponatremia correlate with the development of neurologic sequelae. However, a
rigid adherence to fluid restriction, a time-honored practice in the treatment of hyponatremia in children
with bacterial meningitis, is no longer recommended because of the adverse effects of hypovolemia on
cerebral perfusion pressure. A Cochrane review on fluid therapy for acute bacterial meningitis concluded
that there is some evidence that supports maintaining intravenous fluids rather than restricting them in the
first 48 hours, in settings with high mortality rates and where patients present late. However, where
children present early and mortality rates are lower, there is insufficient evidence to guide practice.
The initial rate of intravenous fluid administration should be approximately three fourths of normal
maintenance requirements, or about 1,000 to 1,200 mL/m2 daily. A 5% dextrose solution with one-fourth
to one-half normal saline and 20 to 40 mEq/L potassium is recommended. The serum sodium
concentration and urine specific gravity should be measured every 6 to 12 hours (441). The mean duration
of hyponatremia in children with Hib meningitis in one study was 20 hours (range, 0 to 240 hours) (475).
The volume of fluids administered can be gradually increased when the serum sodium concentration rises
above 135 mEq/L. In most cases, maintenance rates (1,500 to 1,700 mL/m2 daily) will be reached by 36
to 48 hours after admission. These recommendations do not apply to the child who is admitted in shock or
who is severely dehydrated (441).
Subdural Effusion
Most subdural effusions do not need intervention and are associated with no permanent deficits (199).
Routine subdural paracentesis should be avoided. Only the rare effusion becomes an empyema or is large
enough to have a mass effect. In either instance, serial imaging of the fluid collection by CT or MRI scan
will allow for early detection of these complications. Although rare, subdural empyema must be
considered in patients with community-acquired bacterial meningitis and otitis or sinusitis, focal
neurologic deficits, or epileptic seizures. S. pneumoniae is the predominant causative organism and
neurosurgical intervention should be regarded as first-choice therapy in patients with empyema causing
midline shift and focal neurologic abnormalities or a decreased level of consciousness (476).
PREVENTION
The chemoprophylaxis and immunoprophylaxis of bacterial infections of the CNS are considered in detail
in Chapter 51.
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CHAPTER 25 MYCOPLASMAL AND UREAPLASMAL
INFECTIONS
ARI BITNUN AND SUSAN RICHARDSON
Mycoplasmas and ureaplasmas (class Mollicutes) are the smallest known bacteria (1,2). They are
adapted to life in humans, animals, insects, and plants and cannot survive free living in nature due to their
dependence on host cells for nutrients. Of the more than 200 known species, about 17 have been
associated with human mucous membrane colonization. Three—Mycoplasma pneumoniae, Mycoplasma
hominis, and Ureaplasma urealyticum/Ureaplasma parvum—account for most reports of central nervous
system (CNS) disease in humans. Rare cases of CNS disease due to other species have been reported,
most often in association with immunocompromising or other predisposing conditions (3–5).
Mycoplasmas and ureaplasmas have a cell volume less than 5% that of a typical bacillus such as
Escherichia coli and one-sixth the number of genes (about 800,000 base pairs for M. pneumoniae vs. 4.6
million base pairs for E. coli) (1,6). It is thought that they evolved from gram-positive eubacteria by a
process of degenerative evolution typified by gradual reduction in genome size (6,7). Due to the lack of a
cell wall, they are pleomorphic in shape, are highly susceptible to adverse environmental conditions, and
are resistant to β-lactam and glycopeptide antibiotics. Because they do not synthesize folic acid, they are
also resistant to the sulfonamides. Their small size allows them to pass through 0.45-µm pore filters
commonly used to filter-sterilize media. This trait, coupled with challenges in detection, has earned them
wide notoriety for contamination of continuous cell lines. The small genome size also translates into less
synthetic capacity and the need for specially enriched media for laboratory cultivation (6).
This chapter covers CNS diseases attributable to M. pneumoniae (Mp), M. hominis (Mh), and
Ureaplasma species (Uu). Because the presence of infection or disease in sites other than the nevous
system can be helpful in diagnosis, these are discussed as well. In the section on Mp, information related
to Guillain-Barré syndrome is included due to overlapping pathogenetic mechanisms. The section on
diagnosis includes some basic information on laboratory detection and collection of specimens as a
resource for interacting with the clinical laboratory.
MYCOPLASMA PNEUMONIAE
Etiology
Mp is primarily an extracellular pathogen of the respiratory tract. It was first isolated in culture from the
sputum of a patient with atypical pneumonia in 1944 (8). Initially referred to as the Eaton agent, it was
classified as a “pleuropneumonia-like organism” in 1961 and received its current taxonomic name in
1963 (9). Mp is filamentous in structure (Fig. 25.1), measuring 1 to 2 µm in diameter and 0.1 to 0.2 µm in
width. It attaches to human epithelial cells primarily by means of a highly specialized organelle that
contains a network of adhesion proteins including the P1 and P30 adhesins (1,6,10). Gliding motility
plays an important role in its ability to colonize fully differentiated mucus-producing tissues of the
respiratory tract (11,12). It is capable of invading and surviving within cells in vitro (13,14), but whether
this occurs to a meaningful extent in vivo is not known. Human-to-human transmission requires close
contact and occurs by the droplet contact route.
Epidemiology
Respiratory tract infection due to Mp is extremely common; the incidence of pneumonia is highest in
school-aged children (15,16). The proportion of pneumonia cases attributable to Mp increases from about
20% in children between 10 and 16 years of age to about 50% in young adults (17–19). Many infections,
however, are subclinical, particularly in those younger than 5 years of age (20,21). There is no particular
seasonal distribution. Epidemics occur every 3 to 7 years superimposed on low level but constant
endemicity (17).
The incidence of neurologic disease attributable to Mp has been estimated at 0.1% or less (22). Among
hospitalized patients with serologically confirmed Mp infection, the incidence is higher, between 1% and
10% (23–25). Neurologic complications are most often sporadic, but clusters of cases have been
observed during epidemics of respiratory tract disease (26,27). Children account for 50% to 70% of
those diagnosed with neurologic complications of Mp (23,28,29). Furthermore, in Europe and North
America, Mp is a leading cause of acute encephalitis in children, responsible for 5% to 13% of all cases
(23,28,29). There is no apparent sex predilection (29).
Pathogenesis of Neurologic Disease

The pathogenesis of Mp-associated neurologic disease is incompletely understood. Three broad
mechanisms have been proposed with varying levels of supportive evidence (30,31): (a) direct invasion
of the brain parenchyma; (b) autoimmunity, or other immune-mediated processes; and (c) vascular
occlusion. Neurotoxin-mediated CNS disease, as seen with Mycoplasma gallisepticum in turkeys and
Mycoplasma neurolyticum in mice (32,33), has not been demonstrated in humans with Mp-associated
neurologic disease.
Several lines of evidence support the concept of direct infection of the brain by Mp. Mp has, albeit
rarely, been cultured from or detected by various indirect microbiologic techniques at autopsy from the
brain of several fatal cases of suspected Mp neurologic disease (Fig. 25.2) (34–37). It has also been
cultured from or detected in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) of over 50
subjects, 80% of whom had meningitis, meningoencephalitis, or encephalitis (28,38–53). A
cerebrovascular vasculopathy characterized by antimycoplasmal immunostaining of endothelial cells and
electron microscopic demonstration of Mycoplasma-like structures within endothelial cells has been
observed (54,55). Finally, by analogy to other species, there is conclusive evidence from both natural and
experimental infection of rodents, turkeys, and alligators by Mycoplasma pulmonis, M. gallisepticum,
and Mycoplasma alligatoris, respectively, for the direct infection hypothesis (56–58).
Autoimmunity due to antigenic mimicry and production of antineuronal antibodies has been implicated
in the pathogenesis of Mp-associated neurologic syndromes, including postinfectious encephalitis, acute
disseminated encephalomyelitis (ADEM), transverse myelitis, and Guillain-Barré syndrome (30,31).
Glycolipid epitopes of Mp cross-react with several gangliosides, and anti-galactocerebroside antibodies
(anti-GalC) have been demonstrated in the sera of individuals with postinfectious neurologic syndromes
due to Mp (59–62). In one study, serum anti-GalC was detected in 3 of 3 individuals with postinfectious
CNS disease attributed to Mp as compared to 8 of 32 with Mp infection restricted to the respiratory tract
and 2 of 52 healthy controls (61). Among patients enrolled in several Guillain-Barré syndrome treatment
trials in Europe, 11 of 16 subjects with anti-GalC had serologic evidence of Mp infection; anti-GalC was
present not only in 78% of Mp-associated Guillain-Barré syndrome patients but also in 58% of Mp
infections without neurologic disease (63). The antigen mimicry hypothesis is further supported by the
observation that the anti-GalC activity in serum of patients with Mp-associated Guillain-Barré syndrome
is inhibited by preincubation with Mp antigens (59,60). Among subjects with Mp-associated encephalitis
in the California Encephalitis Project, anti-GalC was detected in the CSF of 50% of subjects in whom
there was neuroimaging evidence of demyelination (64). Whether anti-GalC causes disease or is an
epiphenomenon is uncertain.
With respect to Mp encephalitis, current data suggest that pathogenesis is multifactorial, involving both
direct infection and immunologically mediated processes. Several investigators have observed that Mp
DNA is detected in serum or CSF of subjects with a prodrome of less than or equal to 7 days but not in
those with a longer prodrome (28,48,49). This suggests two distinct patterns of Mp encephalitis: (a) an
early-onset syndrome caused by direct invasion and (b) a late-onset syndrome in which the presence of
the organism in the CSF or brain is not necessary to cause disease. The CSF cytokine profile of both
early- and late-onset forms of Mp encephalitis, consisting of elevated interleukin-6 (IL-6) and IL-8 and
normal interferon-γ and tumor necrosis factor-α, suggests a different pathophysiology to that associated
with other bacterial and viral pathogens (31,65). The elevated proinflammatory cytokine IL-18 in late-
onset, but not early-onset, encephalitis suggests this cytokine may play an important role in the
pathogenesis of the late-onset form of disease (31,65).
The pathogenesis of Mp-associated stroke is poorly understood (30,31). A procoagulable state has
been implicated in a minority of cases (66–70), whereas in others, a systemic or focal vasculitis appeared
to be responsible (71,72). The observation that the mean interval between the onset of respiratory illness
and stroke is about 10 days (range 3 to 21 days) is consistent with an immune-mediated process (30).
Respiratory and Spectrum of Nonneurologic Systemic Manifestations

Mp is primarily a pathogen of the respiratory tract. Clinical disease is typified by an insidious onset of
fever, headache, malaise, sore throat, and dry cough. In most, disease remains confined to the upper
respiratory tract. Progression to tracheobronchitis or pneumonia occurs in fewer than 10% of cases.
“Walking pneumonia,” the hallmark of Mp respiratory disease, derives its name from the relatively mild
clinical disposition of most of those afflicted. Rales and wheezes may occasionally be heard, but physical
examination is often unrevealing despite radiographic evidence of pneumonia. Widespread mottled,
diffuse nodular densities are characteristic (Fig. 25.3); pleural effusions occur in 5% to 20% of cases.
Although rare, fulminant—and even fatal—disease can occur.
Extrapulmonary manifestations of Mp infection have been described for almost every organ system
(1,73). Neurologic complications, followed by those affecting the skin and mucous membranes, are most
common. The prototypical dermatologic complication, erythema multiforme minor and Stevens-Johnson
syndrome, are seen most often in children and young adults (74–76); in some cases, isolated mucosal
involvement can occur (75). Myalgia, arthralgia, and polyarthropathy are relatively common; septic
arthritis is restricted primarily to those with immunocompromising conditions (77,78). Cardiac
complications include myocarditis, pericarditis, and pericardial effusion. Other extrapulmonary
complications include acute glomerulonephritis, tubulointerstitial nephritis, immunoglobulin (Ig) A
nephropathy, renal failure, autoimmune hemolytic anemia, thrombocytopenic purpura, and intravascular
coagulation (1).
Neurologic Manifestations
The clinical manifestations of Mp-associated neurologic disease are protean and generally
indistinguishable from those due to other viral and bacterial pathogens. Syndromes ascribed to Mp,
selected key clinical features, strength of the microbiologic evidence supporting the association, and
references for each are provided in Table 25.1. It is important to emphasize that for most of the neurologic
syndromes associated with Mp infection, proof of causality is lacking. The association is strongest for
encephalitis, meningitis, meningoencephalitis, ADEM, transverse myelitis, Guillain-Barré syndrome, and
acute striatal necrosis.
A history of respiratory tract infection preceding or accompanying neurologic symptoms is an important
clue to the diagnosis of Mp-associated neurologic disease. However, the absence of a respiratory illness
does not preclude Mp as a cause; between 35% and 75% of those with Mp-associated acute encephalitis
have no history of respiratory symptoms (23,28,29,40,79–81). In those with respiratory symptoms,
tracheobronchitis or pneumonia is more typical of adolescents and adults, whereas children younger than
5 years of age often have upper respiratory tract disease characterized by rhinitis, mild cough, or sore
throat. In individuals with demyelinating conditions, bilateral striatal necrosis, Bickerstaff brainstem
encephalitis, opsoclonus myoclonus syndrome, and stroke, respiratory symptoms are almost universal,
preceding neurologic symptom onset by 1 to 4 weeks.
Acute encephalitis is the most common neurologic complication attributable to Mp. Common clinical
features include fever (50% to 100%), reduced or altered consciousness (45% to 100%), symptoms or
signs of meningeal irritation (20% to 80%), seizures (40% to 60%), focal neurologic deficits (20% to
60%), and ataxia (10% to 25%) (28,40,79). A mild lymphocytic pleocytosis averaging less than 100
cells/µL or a slightly elevated CSF protein is demonstrated in 30% to 60% of cases (28,40,79,81).
Nonspecific electroencephalographic (EEG) abnormalities, such as diffuse slowing or findings indicative
of an epileptic focus, are observed in 80% to 100% of cases (28,40,79). Periodic lateralizing
epileptiform discharges (28) and extreme spindles (82) have been seen rarely. Computed tomography or
magnetic resonance imaging abnormalities suggestive of focal edema, ischemia, or inflammation are
evident in 35% to 60% of cases (Figs. 25.4 to 25.6) (28,40,81). Mp encephalitis is a severe entity with a
mortality of up to 10% (23,79,81) and residual sequelae that include cognitive impairment, seizure
disorder, or focal motor deficits in 40% to 60% of survivors (28,79,81,83). In a study of 462 children
with encephalitis, those due to Mp were seven times more likely to die or have severe neurologic
sequelae than other children in the cohort, second only to herpes simplex virus (84).
Diagnosis
Mp should be considered in the differential diagnosis of any subject presenting with one of the syndromes
associated with Mp regardless of clinical manifestations, CSF profile, and EEG and neuroimaging
findings. Current or recent upper or lower respiratory tract infection or pneumonia, whether of
undetermined cause or confirmed to be due to Mp, should raise the index of suspicion for Mp as a
possible cause. It is worth emphasizing again, however, that the absence of respiratory disease does not
preclude the diagnosis, particularly in young children. The presence of nonneurologic extrapulmonary
features compatible with Mp may also serve as a clinical clue. The presence of cold hemagglutinins, often
used as a quick screen for Mp infection, should not be relied upon due to poor sensitivity and specificity
(167).
Microbiologic diagnosis of Mp infection is based on serology and detection of the pathogen by culture
or PCR in clinical samples. Culture is of limited use and not routinely available in most clinical
laboratories due to its low sensitivity compared to PCR and because it is labor intensive, expensive, and
requires up to 3 to 12 weeks of incubation for positive results. The sensitivity of PCR (1 to 10 colony
forming units) is 100-fold higher than culture. As Mp neurologic disease can be either due to direct
infection of the brain or immunologically mediated, PCR testing or culture of both CSF and respiratory
samples is recommended. In one prospective 5-year study, Mp was detected in the CSF of 6 of 11 (54%)
children and in the respiratory tract of 5 of 11 (46%) children with probable Mp encephalitis (28). CSF
samples intended for Mp PCR should be tested or frozen promptly because the stability of Mp DNA is
adversely impacted by storage at room or refrigerator temperatures (168). An important potential
limitation of both culture and PCR is that a positive result from a respiratory sample may reflect infection
acquired as much as 3 to 7 months earlier and therefore may not be relevant to the acute illness
(15,16,169–171). For this reason, combining PCR testing with acute and convalescent serologic testing is
encouraged.
Numerous commercial serologic assays are available for the diagnosis of Mp infection (172). Most use
a crude culture extract, which contains glycolipid antigens that cross-react with other mycoplasmal,
bacterial, human, or plant antigens (173). Better performance (sensitivity and specificity) has been
observed when recombinant antigens are used or the antigen is enriched for cytadhesin protein P1,
although these assays are generally not commercially available (174,175). In the appropriate clinical
context, detection of IgM or IgA in acute sera, seroconversion from negative to positive, or a fourfold rise
in titer between acute and convalescent sera is indicative of acute infection (1,6). A negative result,
however, does not exclude Mp infection; in a study of 12 commercially available kits in a predominantly
adult population with PCR-proven Mp respiratory tract infection, anti-Mp IgM was detected in only 16%
to 42% of acute sera and 32% to 84% of convalescent sera (176). Negative serology has also been
observed in patients with culture or PCR-proven CNS disease due to Mp (28,34,38).
False-positive serologic results are also a significant concern. For a cohort of children with
encephalitis in whom the prevalence of Mp infection is about 7% (28), a false-positive serologic test rate
of approximately 50% is expected for an assay with a sensitivity of 90% and a specificity of 94% (30).
The observation that 80% of children with encephalitis and reactive Mp IgM in acute sera, in whom the
organism was not detected by PCR in either CSF or respiratory samples, had compelling evidence
implicating other pathogens as the cause of encephalitis, reinforce this observation and the downside of
relying solely on serology for diagnosis (28).
Treatment
The most appropriate therapeutic interventions for suspected or proven CNS disease due to Mp depend
largely on the pathogenesis of the syndrome in question. Key considerations are the need for antimicrobial
therapy and/or immune-modulating therapies such as corticosteroids, intravenous immune globulin
(IVIG), or plasmapheresis (177,178). Because controlled trials evaluating these treatments have not been
conducted, recommendations are based on anecdotal evidence from case reports and case series and, in
reference to immunologically mediated entities such as ADEM, transverse myelitis, and Guillain-Barré
syndrome, extrapolated from data relating to these syndromes irrespective of the infectious trigger. A
multidisciplinary care approach is important; for patients with increased intracranial pressure, urgent
neurosurgical consultation should be sought as hemicraniectomy may be lifesaving (179).
Antibiotic therapy should be considered for all patients with neurologic disease attributed to Mp,
despite the paucity of efficacy data, because of the potential for significant neurologic sequelae. It should
be noted, however, that the impact of such therapy on outcome is unknown; full recovery has been
observed with (38,39,41,44,51,52,61,83,85,86,97,100,112,155) and without (47,48,61,106) antibiotic
therapy, as has an apparent lack of response to such therapy (23,25,52,53,61,83,87,112). In adults and
children 8 years of age or older, in whom direct infection of the brain is proven or possible, antibiotics
with good in vitro and in vivo activity against Mp capable of traversing the blood–brain barrier and
achieving therapeutic levels within the CNS such as azithromycin, doxycycline, or a fluoroquinolone such
as moxifloxacin or levofloxacin are preferred (100,180–184). Chloramphenicol is another option as it
achieves excellent CSF levels (184) and has good activity against Mp, but the risk of idiosyncratic bone
marrow aplasia is of concern. For those with immunologically mediated conditions in whom the CSF
tests negative for Mp by PCR, eradication of the pathogen from the respiratory tract using erythromycin or
clarithromycin may be appropriate. In children younger than 8 years of age, doxycycline and tetracycline
should be avoided due to the risk of enamel hypoplasia and irreversible darkening of permanent teeth.
Immune-modulating therapies are frequently used in the management of demyelinating conditions.
Corticosteroids and IVIG, used alone or in combination, have been associated with temporal clinical
improvement in some (28,46,51,110–112,114,118–120,185), but not all (36,103,107,186), patients with
ADEM and transverse myelitis. IVIG is preferred in Guillain-Barré syndrome (155,156,187). Plasma
exchange is reserved for patients (with all three conditions) who fail to respond to corticosteroids or
IVIG (103,109,114).
Corticosteroids may also have a role in the treatment of Mp-associated encephalitis. In a case report
and retrospective review of severe Mp encephalitis, treatment with corticosteroids was associated with
complete or near-complete recovery in 78% of cases (101). By comparison, full recovery was evident in
only 52% of children not treated with steroids (79). A prolonged taper over several weeks may be
warranted in severe cases to prevent symptomatic relapse (101). The role of immune-modulating
therapies in less common forms of Mp neurologic disease is uncertain. Corticosteroids and IVIG,
sometimes in combination, have been associated with temporal clinical improvement in several patients
with Mp-associated bilateral striatal necrosis (124,135,136) and opsoclonus myoclonus syndrome
(145,147,148). IVIG and immune adsorption therapy have been used with apparent success in Bickerstaff
brainstem encephalitis (121,122).
OTHER MYCOPLASMA SPECIES

Mh and Uu are rare causes of CNS disease but nevertheless account for the vast majority of mycoplasmal
CNS disease not attributable to Mp. Both are commensals of the genitourinary tract. The Ureaplasma
genus contains 14 distinct serovars divided into two separate species: U. parvum (serovars 1, 3, 6, and
14) and U. urealyticum (serovars 2, 4, 5, and 7 through 13) (188). It is not known if there are any
differences between the two species with respect to pathogenicity, and at present, they can only be
differentiated by serotyping or PCR (2,189). For purposes of this review, they are considered together.
Rare case reports of CNS disease due to Mycoplasma salivarium, Mycoplasma faucium, Mycoplasma
genitalium, and Mycoplasma maculosum have been reported (3–5,190,191). A summary of the salient
features of CNS infections due to mycoplasmal species other than Mp is provided in Table 25.2.
MYCOPLASMA HOMINIS
Epidemiology
Mh colonizes the genital tract of 0% to 20% and 10% to 30% of otherwise healthy sexually active men
and women, respectively (222–224). Higher rates occur in men with urethritis and in women with
bacterial vaginosis, urethritis, or cervicitis (225,226). Between 5% and 10% of newborns are
asymptomatically colonized at the time of birth (227,228). Colonization is transient, only rarely being
detected in prepubertal children beyond 3 months of age (228). Colonization rates increase with the onset
of sexual activity (222,229,230).
Clinical Features
Mh has been associated with nongonococcal urethritis in both men and women and with bacterial
vaginosis and pelvic inflammatory disease in women. Wound infections subsequent to trauma or surgery
and septic arthritis in association with a prosthetic joint or an immunocompromised state such as
malignancy and hypogammaglobulinemia have been reported (3,192,205).
The majority of CNS infections due to Mh occur in neonates (193). Premature and term infants have
both been affected. Meningitis and meningoencephalitis are the most common entities (193–204); brain
abscess and subdural empyema also occur (207–209). Colonization of the respiratory or genitourinary
tract during the birthing process followed by hematogenous dissemination is the likely pathogenesis.
Onset of symptoms in reported cases ranged from day 1 to day 32 of life, the majority during the first 2
weeks of life (193). Clinical and laboratory features are indistinguishable from those due to other
bacterial pathogens. CSF pleocytosis, elevated CSF protein, and hypoglycorrhachia have all been
observed (193); a predominance of polymorphonuclear leukocytes is characteristic. Adverse outcome is
seen in approximately 50% of cases, death in 28%, and neurologic sequelae in 28% (193).
In older children and adults, Mh has been implicated as a cause of brain abscess subsequent to
neurosurgical procedures (192,206) and meningitis in the context of immune suppression related to cancer
chemotherapy (192). Fever and focal neurologic manifestations are typical. Mh has also been detected by
multiple 16S ribosomal DNA sequencing in polymicrobial brain abscesses (190); the significance of Mh
in pathogenesis of these brain abscesses and, by extension, the need for Mh-targeted antimicrobial therapy
is unknown.
Diagnosis
Because of the rarity of Mh CNS infection and the difficulty in culturing the organism, diagnosis requires
a high index of suspicion. It should be considered in any neonate with meningitis, encephalitis, or brain
abscess when CSF cultures are negative and there is no clinical response to standard “neonatal sepsis”
treatment, such as a combination of β-lactams (e.g., ampicillin plus cefotaxime) or a β-lactam with an
aminoglycoside.
As the organism is extremely sensitive to environmental conditions, specimens should ideally be
inoculated into appropriate transport media, such as 10B or SP4 broth, at the bedside. The preferred
culture medium is SP4 broth and agar (pH 7.5) supplemented with arginine. Mh may occasionally grow as
pinpoint translucent colonies after 2 to 3 days incubation on conventional blood or chocolate agar plates.
Failure of these colonies to enlarge and the inability to visualize organisms by Gram stain of a colony
sample should lead to consideration of mycoplasmal infection. Molecular diagnosis using PCR offers
superior sensitivity and improved turnaround time compared to culture (231,232). Serology is of no value
in diagnosis.
Treatment
Mh is usually susceptible to the tetracyclines (tetracycline, doxycycline, minocycline), chloramphenicol,

lincosamides (clindamycin), quinupristin-dalfopristin, and selectively to the fluoroquinolones (233).
Tetracyclines are considered the drugs of choice (192,193). Doxycycline has been used most extensively,
including in neonates despite the potential for bone and dental toxicity (194,196,197,199,201,208).
Chloramphenicol has been used alone or in combination with other antibiotics
(193,195,197–199,203,209); in one case, it had to be discontinued due to presumed toxicity that included
hypotension and pancytopenia (199). Several recent Mh meningitis cases have been successfully treated
with moxifloxacin or gatifloxacin (193,202,206). The in vitro efficacy of these fourth-generation
fluoroquinolones is superior to that of the older generation fluoroquinolones ciprofloxacin and
levofloxacin (193,233). Potential advantages of the fluoroquinolones include their bactericidal activity
and excellent CSF penetration (193,202,206). A 2- to 3-week course of antibiotic therapy is usually
sufficient for Mh meningitis. In those with brain abscesses, 6 weeks of such therapy should be given;
surgical drainage needs to be considered in all cases.
It is paramount that susceptibility testing be performed on all sterile site isolates of Mh due to
increasing rates of antibiotic resistance (234). For example, over a 20-year period in Germany, resistance
to tetracycline, doxycycline, and ciprofloxacin rose from 2.1% to 14.5%, 0% to 14.5%, and 0% to
15.4%, respectively (234).
UREAPLASMA SPECIES (UREAPLASMA UREALYTICUM AND

UREAPLASMA PARVUM)
Epidemiology
Asymptomatic colonization of the genital tract occurs in 40% to 80% of sexually active women
(2,222,225); among sexually active men, approximately 25% to 50% are similarly colonized (223,225).
Approximately half of newborn infants of colonized mothers acquire the infection perinatally, the vast
majority asymptomatically (235–237). Colonization rates decline during early infancy, and in children 2
to 13 years of age, the organism can rarely be detected (228,230). As is the case with Mh, genital
colonization rates increase with onset of sexual activity (230).
Clinical Features
In adults, Uu is primarily associated with nongonococcal urethritis in men and complications of pregnancy
in women (238). Maternal urogenital colonization with Uu is associated with histologic chorioamnionitis,
stillbirth, preterm birth, and adverse neonatal outcomes including neonatal pneumonia, bronchopulmonary
dysplasia, intraventricular hemorrhage, and lower psychomotor development scores at 2 years of age
(239). High levels of the proinflammatory cytokines IL-1β, tumor necrosis factor-α, IL-6, and IL-8 in
amniotic fluid correlate with preterm premature rupture of membranes (pPROM) and isolation of Uu,
which suggests that Uu is truly pathogenic in this setting. Extragenital non-CNS infections reported rarely
in older children and adults include postoperative wound and prosthetic joint infections and systemic
infections such as septic arthritis in patients with common variable immune deficiency and other
immunocompromising conditions (3,240–243).
CNS disease due to Uu occurs primarily in premature infants (200,201,208,210–220). Meningitis is the
most common syndrome. There is one report of a brain abscess, from which both Uu and Mh were
isolated, in a 3-week-old term infant (208). An association between Uu infection and intraventricular
hemorrhage has been noted in some (201,220), but not all, studies (244). In one study, the risk of grade 3
to 4 intraventricular hemorrhage among very-low-birth-weight premature infants was fivefold higher
when Uu was detected in serum by PCR and serum IL-1β was elevated; of note, U. parvum was the only
Uu species detected in the serum of these patients (220). Despite these suggestive data, a causal link is
uncertain because very-low-birth-weight premature infants are at high risk of intraventricular hemorrhage
for many reasons irrespective of Uu colonization or infection status.
In adults, CNS disease due to Uu is exceedingly rare. The only published report was that of a 38-year-
old male who developed Uu (biovar 2) meningitis 10 weeks after renal transplantation and 4 weeks after
placement of a ventricular drain for management of increased intracranial pressure (221). He was
successfully treated with a combination of doxycycline and chloramphenicol.
Diagnosis
Unlike Mh, Uu cannot be cultured from routine bacteriologic media. Its specific transport and culture
requirements are similar to those of Mh (239). Growth usually occurs in 24 to 48 hours. Uu is
distinguished from other Mycoplasma species by its ability to hydrolyze urea. As is the case for Mh, PCR
is increasingly used in diagnosis, and serology is of no diagnostic value.
Treatment
In contrast with Mh, Uu is usually susceptible to erythromycin and other macrolides but is relatively
resistant to clindamycin (2). Macrolides are considered the treatment of choice for infections outside the
CNS, whereas the tetracyclines, chloramphenicol, or a fluoroquinolone are preferred for CNS infections.
Doxycycline and chloramphenicol exhibit excellent in vitro efficacy (233), and no treatment failures have
been reported with their use (212). The fluoroquinolones have been used less often but appeared to be
effective (210,212,245). Most cases of meningitis have been treated with erythromycin in combination
with doxycycline, chloramphenicol, or a fluoroquinolone (201,208,211–214,218,219,245,246). Persistent
CSF cultures while on erythromycin monotherapy and prompt sterilization following the addition of
doxycycline, chloramphenicol, or ciprofloxacin has been observed (212,213,218). Susceptibility testing
of sterile site isolates is required as resistance to the tetracyclines, chloramphenicol, and the
fluoroquinolones can occur (2,211,245,247).
Approximately two thirds of neonates with Uu meningitis recover despite not receiving specific
antibiotic therapy, perhaps reflecting the low virulence of the organism and containment of the infection
by the immune system (212). Nevertheless, it is recommended that symptomatic patients, in whom Uu is
isolated from the CSF, should receive targeted antibiotic therapy (2,212). A treatment duration of 2 to 3
weeks is sufficient in most cases.
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CHAPTER 26 BARTONELLA INFECTIONS, INCLUDING
CAT-SCRATCH DISEASE
MICHAEL GILADI, MOSHE EPHROS, AND DAVID F. WELCH
The bacterial genus Bartonella is named for Dr. A. L. Barton, who described the erythrocyte-adherent
Bartonella bacilliformis in 1909. It is the etiologic agent of Oroya fever, an acute bacteremic infection
characterized by sepsis and hemolysis, and of verruga peruana, principally a cutaneous nodular vascular
eruption representing chronic infection. The previously suspected link between the two conditions was
tragically confirmed in 1885 by Daniel Carrión, a medical student who injected himself with bloody
material from a verruga and subsequently died of Oroya fever. This form of bartonellosis is thus known as
Carrión disease and South American bartonellosis because it is limited to the Andean mountain regions
of Peru, Ecuador, and Colombia. It affects the local population and, rarely, travelers to these countries.
Bartonellosis garnered little attention outside its endemic zone in recent years until related bacteria, then
named Rochalimaea species, were found to be important pathogens, primarily in patients with acquired
immunodeficiency syndrome (AIDS).
TAXONOMY
The now supplanted genus Rochalimaea was formerly classified with Bartonella in the order
Rickettsiales and consisted of only two species, Rochalimaea (Rickettsia) vinsonii, the “Canadian vole
agent,” and Rochalimaea (Rickettsia) quintana, the agent of trench fever. The latter is a debilitating but
self-limited human illness so named after it affected many military personnel in World War I. Except for
sporadic outbreaks, trench fever had all but disappeared from the clinical scene in recent decades.
However, the 1990s saw the reemergence of R. quintana as a pathogen of considerable interest (1–5),
coincident with the discovery of two related species that also cause human disease, originally named
Rochalimaea henselae and Rochalimaea elizabethae (6–9).
Bartonella species are alphaproteobacteria, which also contains Afipia, Agrobacterium, and Brucella.
Unlike members of the order Rickettsiales, Bartonella species have been cultured on cell-free media.
Sequencing of 16S ribosomal RNA (rRNA) genes to determine phylogenetic relationships among these
organisms revealed high levels of relatedness between B. bacilliformis and the former Rochalimaea
species (10) and confirmed that all of them are more closely related to Brucella and Agrobacterium than
to members of the rickettsiae. Based on DNA hybridization and 16S rRNA similarity, the former
Rochalimaea species were combined with Bartonella in 1993 (11), and the members of the family
Bartonellaceae were removed from the order Rickettsiales. A further proposal was made in 1995 to
merge into the genus Bartonella a number of species of the genus Grahamella, which are
intraerythrocytic pathogens of rodents, birds, fish, and other animals (12). Recently, an increasing number
of Bartonella species have been identified and characterized. Currently, the genus Bartonella consists of
at least 27 recognized species or subspecies, of which at least 13 have been recognized as confirmed or
potential human pathogens. Others have been isolated from nonhuman wild and domestic mammals,
including rodents, cervids, and cattle, without associated identifiable human illness (13). Comparison of
phylogenetic data, inferred mainly from 16S rDNA, 16S-23S rRNA intergenic spacer, citrate synthase and
60-kd heat shock protein gene sequences have identified six evolutionary clusters within the genus
Bartonella (14). Cat-scratch disease (CSD)–causing B. henselae are classified into two serotypes,
Houston-1 and Marseille, which correspond to two genotypes based on 16S rRNA gene sequences,
genotype I and genotype II. The significance of this and other classifications with respect to pathogenesis
and clinical manifestations has not been established (15,16).
EPIDEMIOLOGY
Infections with B. bacilliformis are geographically limited to middle altitudes of the Andes mountains,
probably because of the distribution of species of the genus Lutzomyia (formerly Phlebotomus), its
sandfly vectors. B. quintana is globally distributed; there have been reports of focal, but widely
separated, outbreaks of trench fever, also known as quintan or 5-day fever. Outbreaks commonly have
been associated with conditions of poor sanitation and personal hygiene that predispose to exposure to the
human body louse Pediculus humanus, the only identified vector of B. quintana. Although B. quintana
has also been identified in the human head louse P. humanus capitis, there is no strong evidence that head
lice are vectors of this organism between human hosts (17). Nonhuman vertebrate reservoirs have not yet
been identified for either B. bacilliformis or B. quintana.
Cats bacteremic with B. henselae constitute the major reservoir of this pathogen. B. henselae has been
documented to cause bacteremia (18,19) in seemingly healthy domestic cats, including some that have
been specifically associated with bacillary angiomatosis (19) or typical CSD (18) in their human
contacts. B. henselae bacteremia has been globally reported among pet, impounded, or stray cats. Rates
of bacteremia can vary and may be as high as 89% (18–25). Other animals, particularly dogs, have been
implicated as a possible reservoir for B. henselae, but reports are anecdotal and evidence essentially
circumstantial. Fleas and ticks are arthropod vectors of B. henselae, based on epidemiologic associations
(26,27) and reports of identification of B. henselae by both culture and DNA amplification from cat-
associated fleas (18,19). Cat-to-cat transmission by infected fleas has been shown to occur (21), although
evidence of cat-to-human transmission by fleas is lacking. Like B. quintana, B. henselae infection is
globally endemic. However, regional variations in the prevalence of either B. henselae or B. quintana
may occur. Transmission to humans has been linked to cats by serologic and epidemiologic studies
(27,28), its recovery from cases of human lymphadenitis consistent with CSD (18,29), and the
identification of B. henselae DNA by polymerase chain reaction (PCR) in CSD lymphadenitis and other
affected tissues (30–33).
OVERVIEW OF CLINICAL/PATHOLOGIC MANIFESTATIONS

Oroya Fever and Verruga Peruana
Bartonella bacilliformis
Oroya fever, the bacteremic illness of primary B. bacilliformis infection, develops 2 to 14 weeks (mean 3
weeks) after inoculation by the sandfly Lutzomyia verrucarum (34). Bacteria invade blood vessel
endothelium, proliferate, and upon reentry into blood vessels replicate and destroy erythrocytes.
Microvascular thrombosis results in end-organ ischemia. In its milder form, the febrile illness often
remits in a week. When abrupt in onset, high fever, chills, diaphoresis, headache, and mental status
changes are associated with a rapidly developing severe hemolytic anemia (35–38). Lymphadenopathy,
thrombocytopenia, severe myalgia and arthralgia, and complications such as delirium, coma, dyspnea, and
angina can occur during this stage. Without antimicrobial treatment, mortality rates up to 40% to 80%
have been reported (39,40); however, a disease milder in severity and with a low (0.7%) case-fatality
rate may occur (41). Convalescence is associated with a decline of fever and disappearance of bacteria
on blood smears as well as increased susceptibility to intercurrent opportunistic infections such as
salmonellosis (42) or toxoplasmosis (43). Usually within months of acute infection, verruga peruana may
become evident. This late-stage manifestation of infection is characterized by crops of nodular skin
lesions; mucosal and internal lesions can also occur. Their histology typically contains neovascular
proliferation with occasional bacteria evident in interstitial spaces. B. bacilliformis invasion of
endothelial cells, which was described by Rocha-Lima and believed to be the etiology of cytoplasmic
inclusions, is rare (44). Verruga peruana lesions may develop at one site while receding at another. They
may persist for months to years and eventually become fibrotic with involution. Asymptomatic persistent
bacteremia with B. bacilliformis infection can occur in up to 15% of survivors of acute infection (45)
who may serve as the organism’s reservoir.
Bacteremic Illness and Endocarditis
Bartonella quintana, Bartonella henselae, and Other Bartonella Species

The natural course of trench fever includes a spectrum of self-limited clinical patterns (46). Incubation
may span days to weeks before the typical sudden onset of fever. The febrile illness may be brief (lasting
4 to 5 days), prolonged (uninterrupted for 2 to 6 weeks), or most commonly, paroxysmal (three to five
episodes, each of about 5 days). Fever may be accompanied by other nonspecific symptoms and signs
such as headache, vertigo, retroorbital pain, conjunctival injection, nystagmus, myalgia, arthralgia,
hepatosplenomegaly, rash, leukocytosis, and albuminuria. B. quintana has reemerged as a cause of
bacteremic illness (designated also as urban trench fever) in human immunodeficiency virus (HIV)–
uninfected homeless patients with chronic alcoholism (5,47,48). B. quintana was also identified in body
lice from these patients. Clinical characteristics include headache, sweats, severe leg pain, and low
platelet counts. Many bacteremic patients were afebrile and some were asymptomatic. Chronic
bacteremia, as indicated by positive blood cultures up to 78 weeks, and intermittent bacteremia were
found to occur.
B. quintana or B. henselae bacteremia in HIV-infected persons is often characterized by insidious
development of fatigue, malaise, body aches, weight loss, progressively higher and longer recurring
fevers, and sometimes headache. Hepatomegaly may occur. Although there is evidence implicating
Bartonella species in some cases of HIV-associated encephalopathy, meningoencephalitis, and
neuropsychiatric disease, lumbar puncture during acute bacteremia in HIV-infected persons can be
unrevealing (6,9). Rarely, fever without localizing symptoms or signs in association with B. henselae
bacteremia has been reported in immunocompetent patients (6,9). Aseptic meningitis concurrent with
bacteremia has been documented in an immunocompetent host (26). B. henselae bacteremia can evolve
into long-term asymptomatic persistence (26).
Both B. quintana and B. henselae are considered important pathogens of endocarditis, accounting for
approximately 3% of all patients with infective endocarditis, and a much larger proportion, up to 28%, of
patients with culture-negative endocarditis (1,4,49–51). B. elizabethae, B. vinsonii subspecies
berkhoffii, B. alsatica, and B. koehlerae have rarely been isolated from patients with endocarditis
(8,52–54). Patients with B. quintana endocarditis often have been homeless and alcoholic, whereas
patients with B. henselae endocarditis have commonly reported being in contact with a cat. The typical
clinical presentation is that of subacute bacterial endocarditis, including neurologic manifestations such
as stroke. In a retrospective study of 101 patients with Bartonella endocarditis, embolic phenomena were
reported in 43% of patients. A significant number of patients were afebrile at presentation, 12 of the 101
patients died, 2 relapsed, and 76 underwent valvular surgery (55).
Bacillary Angiomatosis and Peliosis
Bartonella quintana and Bartonella henselae

Bacillary angiomatosis (BA), also termed epithelioid angiomatosis or bacillary epithelioid
angiomatosis, is a disorder of neovascular proliferation originally described involving skin and regional
lymph nodes of HIV-infected persons (56–58). It has since been demonstrated to involve a variety of
internal organs (59–61), including the brain (62), and to occur in other immunocompromised (59,63) and
immunocompetent hosts (64–66). B. quintana infections have a predilection for causing subcutaneous and
deep soft tissue disease and lytic bone lesions, whereas B. henselae infections are associated with lymph
node disease and parenchymal peliosis of the liver and/or spleen. B. henselae and B. quintana (2,9,67)
equally cause BA of the skin, the most common manifestation of this illness. Risk factors for B. quintana
infection are low income, homelessness, and body louse infestation, whereas B. henselae infection is
associated with cat or cat fleas contact (67).
Skin lesions often arise in crops, but their timing and gross appearance can vary. They can be
remarkably similar to the lesions of verruga peruana. However, most cases of BA have been identified
outside the region of endemic B. bacilliformis. Thus, the most important differential diagnoses are Kaposi
sarcoma and pyogenic granuloma. Studies addressing the potential association between pyogenic
granuloma and Bartonella infection have resulted in conflicting results (68,69). The histologic distinction
of BA from other neovascular tumors has been clearly described (70,71).
Bacillary peliosis (BP), originally described involving the liver and sometimes spleen in HIV-infected
persons (72), has since been identified in other immunosuppressed persons and found to involve lymph
nodes as well (59,73). Involved organs contain numerous blood-filled, partially endothelial cell–lined
cystic structures and surrounding clumps of bacilli (identified by Warthin-Starry silver staining) in the
midst of inflammatory cells.
Cat-Scratch Disease
Bartonella henselae (Possibly Bartonella clarridgeiae, Bartonella quintana, and Afipia felis)
B. henselae is the major etiologic agent of CSD (18,19,28–32). B. clarridgeiae, B. quintana, and Afipia
felis have rarely been associated with CSD in humans (74–76). The various manifestations that comprise
CSD have been recognized over the past 100 years, but the syndrome per se was not really defined until
1950 (77).
In typical CSD (about 90% of cases), a cutaneous papule or pustule usually develops within a week
after an animal contact (more commonly a kitten) at a site of inoculation (usually a scratch or bite)
(78–80). Regional adenopathy (mostly involving head, neck, or upper extremity) develops in 1 to 7 weeks
(Fig. 26.1). About one third to one half of patients have fever, and about one sixth develop lymph node
suppuration. The histopathology of nodes includes a mixture of nonspecific inflammatory reactions
including granulomas and stellate necrosis. Bacilli may be demonstrable by Warthin-Starry staining.
Atypical CSD (about 10%) occurs as extranodal or complicated disease in the absence or presence of
lymphadenopathy and includes Parinaud oculoglandular syndrome, encephalopathy, neuroretinitis and
other neurologic syndromes, fever of unknown origin, hepatic and splenic abscesses, granulomatous
hepatitis, debilitating myalgia, arthritis or arthralgia (affecting mostly females older than age 20 years),
osteomyelitis and other musculoskeletal manifestations, and erythema nodosum (79,81–84). Other
manifestations and syndromes (e.g., pneumonitis, myocarditis, and thrombocytopenia) have also been
associated with CSD (85–88).
In most cases, whether typical or atypical, spontaneous resolution occurs in 2 to 4 months. The
prolonged course of CSD lymphadenopathy, which is often accompanied by fever, night sweats, weight
loss, and liver or spleen involvement, may resemble lymphoma or other malignant processes.
Consequently, this may lead to unnecessary, extensive, costly, and sometimes invasive diagnostic
procedures (89–91).
NEUROLOGIC MANIFESTATIONS OF BARTONELLA
INFECTIONS
Associated with Oroya Fever
Acute B. bacilliformis infection (Oroya fever) has long been recognized to have associated neurologic
manifestations (34). Acute onset of severe headache is usually coincident with onset of fever and
development of hemolysis. Characteristics of the meningoencephalitis that occurs in about 1 in 10 cases
include diffuse neurologic impairment that may result in seizures, hallucinations, delirium, and/or reduced
consciousness, which can progress to obtundation and coma. Diminished level of consciousness is
associated with a poorer prognosis. Meningeal findings without encephalitis also can occur and vice
versa. Less commonly, localized findings in the form of cranial or spinal nerve palsies occur, with the
latter sometimes causing a meningomyelitis with flaccid or spastic paralysis. Cerebrospinal fluid (CSF)
protein elevation and mild mononuclear leukocytosis can occur, and bacteria may be identified within
these leukocytes. Peripheral nerve palsies that occur during the later eruptive verruga stage are usually
due to granulomatous inflammatory lesions within peripheral nerves; such impediments are usually
chronic but associated with gradual resolution.
The often fatal course of Oroya fever has allowed histopathologic correlation with clinically evident
neurologic manifestations (92,93). Most of the neurologic manifestations appear to be the result of the
vascular endothelial cell damage that develops. In the leptomeninges, capillary and venous congestion
and thrombosis are common, associated with microhemorrhages, adventitial proliferation, perivascular
edema, and rarely, formation of new microvasculature. As a consequence of profound hemolytic anemia
(hemoglobin concentration ≤4 g/L has been reported in Oroya fever) and microvascular thrombosis,
resulting in ischemia, there can be subacute neuronal degeneration. Reactive glial proliferation is usually
diffuse but in some cases may be nodular. Occasionally, granuloma-like nodules composed of microglial
cells and histiocytes, named verrucomas, are found in the choroid plexus, ependyma, and brain
parenchyma. Ultimately, the meningoencephalitis associated with Carrión disease appears to be more a
consequence of the damage done to the host’s microvasculature, complicated by the associated profound
anemia, than the result of a primary neurotropic affinity on the part of B. bacilliformis.
Associated with Trench Fever and Other Manifestations of Bartonella quintana

Infection
Although trench fever is often associated with headache, specific neurologic manifestations of this form of
B. quintana infection are uncommon. Few cases of B. quintana infection with distinct central nervous
system (CNS) pathology have been described. A 19-year-old HIV-uninfected patient with
hypogammaglobulinemia presented with fever, left hemiparesis, slurred speech, urinary incontinence,
blurred vision, and behavioral changes, which developed over 2 months due to a necrotizing
granulomatous process involving the right thalamus and surrounding tissues. B. quintana was identified in
brain tissue, bone marrow, and serum specimens from this patient by PCR and nucleotide sequencing. B.
quintana DNA was also amplified from the CSF of an 8-year-old immunocompetent child with
encephalitis and axillary adenitis (94). A previously healthy 16-month-old girl was admitted to the
intensive care unit with encephalopathy complicated by Guillain-Barré syndrome and hydrocephalus,
which necessitated placement of a ventriculoperitoneal shunt. She had serologic and molecular evidence
of central nervous system infection by B. quintana (95).
Associated with Cat-Scratch Disease
The most commonly recognized neurologic manifestations associated with B. henselae infection are those
of CSD, predominantly encephalopathy and neuroretinitis. Isolated cranial and peripheral neuropathies
(e.g., facial palsy), polyneuropathy, transverse myelitis, and other manifestations uncommonly occur
(96–145). CSD vertebral osteomyelitis may rarely present with neurologic complications, including
intraspinal extension (146–150). Encephalopathy probably occurs in 2% to 4% of all recognized CSD
cases, although estimates range from 1% to 7% (115). Extrapolating from an estimated U.S. CSD case
rate of 9.3 per year per 100,000 population, 2% to 4% would represent between 500 and 1,000 annual
CSD encephalopathy cases in the United States. The California Encephalitis Project reported Bartonella
species as the causative agent in 7 (2%) of 334 patients with encephalitis, making it the most common
bacteria associated with encephalitis (151). In contrast, Bartonella cases were found neither among 203
patients with encephalitis in a multicenter prospective study from England nor among 253 patients in a
national prospective study conducted in France (152,153). However, the diagnosis of Bartonella
encephalitis in the latter study may have been underrepresented because the authors excluded survivors
hospitalized for more than 5 days because these patients were assumed to have aseptic meningitis rather
than encephalitis. Patients with encephalitis due to Bartonella species may have a fulminant presentation
but often recover fully within several days after onset and thus could have been excluded from the study
(154). Such diagnoses can easily be overlooked if the clinician fails to obtain an adequate history. With
domestic cats representing the single largest category of companion animals in the United States, the
importance of an accurate history regarding animal exposure cannot be overemphasized when evaluating a
patient with findings consistent with one of these syndromes. A common pitfall in history taking is to
inquire about a cat scratch or a cat bite rather than cat contact, as a significant proportion of CSD patients
report cat contact without injury. Though less established, one must also keep an open mind to the
possibility of transmission of B. henselae from other animals such as dogs.
CSD encephalopathy remains predominantly a clinical diagnosis, now subject to laboratory
confirmation by techniques described later in this chapter (predominantly antibody testing). Adolescents
and adults may represent a greater proportion of cases of CSD encephalopathy than they do of CSD
overall (81). Encephalitis was also reported to be more common in elderly patients (older than 60 years
of age) with CSD than in younger patients (155). The pathogenesis of CSD encephalopathy and other CNS
manifestations associated with CSD remains unclear. Whether these rare complications are attributable to
direct invasion of the CNS by B. henselae or to other mechanisms such as vasculitis or immune response
is unknown. B. henselae has been shown to infect feline microglial cells in vitro and survive
intracellularly for up to 4 weeks; however, no ultrastructural abnormalities were identified within
infected brain cells by electron microscopy (156).
In most patients, encephalopathy usually follows lymphadenopathy, by a period of days up to 2 months,
although it has also been reported to precede lymph node involvement or to occur in its absence.
Persistent generalized headache is a common part of the history, but fever is an inconsistent finding.
Patients may become restless and combative. Nearly half of patients develop seizures, which may range
from focal to generalized and from brief and self-limited to status epilepticus. Short-term anticonvulsant
therapy may be required, as may be supportive therapy in the face of obtundation or coma. Nuchal
rigidity, pathologic reflexes, or pupillary dilation may be present transiently. Neurologic deficits such as
aphasia, cranial nerve palsy, paresis, hemiplegia, and ataxia are usually self-limited, although time to
resolution may span weeks to months to as long as a year. Persistence of intellectual impairment, ataxia,
and seizures have been reported (81,112,118,125,128), as well as rare cases of death due to CSD
meningoencephalitis in two previously healthy children, aged 4 and 6 years (157,158).
Laboratory studies in the setting of CSD encephalopathy do not add specific positive diagnostic
findings to the clinical picture, but they serve to exclude other processes. CSF measurements fit no
consistent pattern, except that hypoglycorrhachia is rare. Elevation of CSF protein concentration and
pleocytosis with lymphocytic predominance occur in only about one third of patients (but not necessarily
in the same patients) (151). Peripheral blood leukocytosis occurs as well in only about one third of
patients. CSF cultures have been consistently negative.
Studies of the brain with computed tomography (CT) and/or magnetic resonance imaging (MRI) usually
show no abnormalities. Transient nonspecific abnormalities are occasionally identified, but a few cases
of persistent structural abnormalities have been reported (128,159). Electroencephalography during the
acute phase of CSD encephalopathy commonly reveals diffuse slowing, yet another nonspecific feature
that resolves with clinical recovery. Brain biopsy is usually not indicated because of the self-limited
nature of CSD encephalopathy, and thus little is known about the histologic correlates of the clinical
manifestations. At autopsy of a fatality due to CSD encephalomeningitis, there was marked cerebral
edema with no gross evidence of acute meningitis. Microscopic examination revealed multiple
granulomatous lesions, meningitis, and encephalitis. Warthin-Starry silver stain of the brain and liver
revealed pleomorphic rod-shaped bacilli consistent with B. henselae infection. Analysis of brain tissue
with PCR confirmed the presence of B. henselae DNA (157). Histologic examination of the second
fatality showed extensive diffuse perivascular lymphocytic infiltrates with microglial nodules scattered
throughout the frontal, parietal, and occipital lobes and the pons. In some foci, the nodules appeared
vaguely granulomatous (158). Biopsy of concurrent lymphadenopathy, when done, reveals features typical
of CSD.
The neuroretinitis associated with CSD (96,108,116,117, 120,121,124,129,133,160–164) has been
confirmed by serology and culture to be related to B. henselae infection. Neuroretinitis in association
with B. henselae bacteremia (96), aseptic meningitis (165), and encephalopathy (166) have been reported
in patients with CSD. Chorioretinitis and multiple hypodense areas within the spleen and liver
parenchyma have been described in a 10-year-old previously healthy boy several weeks after a cat
scratch (167). Although long-term prognosis is usually good, some individuals may develop mild
postinfectious optic neuropathy, and few may develop permanent visual disturbances. Vitrectomy is only
rarely indicated. With the refinement of techniques for identification of Bartonella infection, diagnostic
accuracy has improved, broadening the spectrum of CSD-associated retinal manifestations and identifying
new Bartonella species as possible pathogens in neuroretinitis. B. grahamii was identified by PCR
amplification and sequence analysis in the intraocular fluid of an HIV-seronegative patient with bilateral
neuroretinitis and behavioral changes, and B. elizabethae infection was diagnosed serologically in
another patient with neuroretinitis (168,169).
The typical clinical scenario of CSD neuroretinitis, a process first described as Leber idiopathic
stellate retinopathy (116,170), is that of painless, fairly sudden loss of visual acuity, usually unilaterally,
and sometimes preceded by an influenza-like syndrome or development of regional lymphadenopathy.
Neuroretinitis is characterized by papilledema often associated with macular exudates in a star formation
(Fig. 26.2). In a retrospective study among 24 patients with CSD with 35 affected eyes, isolated foci of
retinitis or choroiditis were the most common ocular manifestation identified in 83% of eyes and 83% of
patients. Optic disk swelling was the second most common finding (46% of eyes, 63% of patients),
followed by a macular star (43% of eyes, 63% of patients) and vascular-occlusive events (14% of eyes,
21% of patients). Final visual acuity was 20/25 or better in 26 (74%) of 35 eyes and was similar in both
treated and untreated patients (161). Optic disk edema associated with peripapillary serous retinal
detachment has been described as an early sign of ocular CSD. The typical macular star may or may not
follow these early manifestations (171). Other types of ocular CSD manifestations include optic neuritis,
anterior uveitis, panuveitis, vitreitis, pars planitis, focal retinal vasculitis, retinal white spot syndrome,
branch retinal arteriolar or venular occlusions, central retinal artery and vein occlusion, focal choroiditis,
vitreous and retinal hemorrhages, and a process associated with peripapillary angiomatosis (172–181).
The pathophysiology of neuroretinitis is thought to be leakage of lipid-containing exudate from capillaries
in the optic head with subsequent extension into the subretinal space and macular region. This type of
process has been recognized as a secondary phenomenon in most circumstances, occurring in association
with traumatic injuries of the eye or brain, ocular vascular disturbances, toxins, autoimmune states (e.g.,
Behçet syndrome), or a variety of infections (e.g., influenza-like syndromes, syphilis, leptospirosis,
tularemia, tuberculosis, psittacosis, endemic mycoses, and parasites). Thus, although this process can be
considered characteristic of CSD neuroretinitis, it is not pathognomonic and many other causes must be
included in the differential diagnosis.
Associated with HIV Infection

Intracerebral bacillary angiomatosis was first recognized in 1990 (62) in a man with AIDS. In 1994,
antibody and DNA amplification evidence of Bartonella infection was reported in the setting of
neurologic manifestations complicating HIV infection (182), and epidemiologic studies have confirmed
an association between the presence of serum anti-Bartonella antibodies and increased risk of
development of neuropsychologic decline or dementia over 5 years. An estimated 4% of new cases of
HIV-associated dementia or neuropsychologic decline might be ascribed to Bartonella infections and
therefore are potentially treatable with antibiotics. Subsequent small numbers of case reports have added
anecdotal evidence suggesting the potential utility of antimicrobial therapy in reversing Bartonella-
associated neuropsychiatric abnormalities.
Chronic Neurologic and Neurocognitive Manifestations
A few recent studies, originating mostly from one group of investigators, reported the detection of various
Bartonella species, including B. henselae, B. vinsonii subsp. berkhoffii, B. koehlerae, Candidatus B.
melophagi, or coinfection with more than one Bartonella spp. in blood samples, using a novel enrichment
blood culture technique, followed by PCR and DNA sequencing. Patients were apparently
immunocompetent individuals who presented with various chronic neurologic or neurocognitive
syndromes, including seizures, ataxia, memory loss, tremors, fatigue, insomnia, headache, arthralgia,
myalgia, hallucinations, and other symptoms. Many individuals had extensive arthropod and animal
exposure. It has been suggested that because the duration of illness in these patients ranged from months to
many years, these Bartonella species may induce a chronic intravascular, persistent, or relapsing
infection. More studies are needed to evaluate the role of these pathogens in patients with chronic
neurologic and neurocognitive dysfunction (183–188).
Infections Caused by Other Species
B. vinsonii subsp. arupensis was isolated from the blood of a 62-year-old cattle rancher who was
admitted to a hospital with acute onset of confusion, emotional liability, difficulty in walking, facial
numbness, slurred speech, diplopia, headache, and myalgias. He was discharged 7 days later with a
significant improvement in neurologic symptoms (189).
A case of meningitis attributed to Bartonella washoensis, isolated from a patient’s blood using routine
blood culture system, was described in a 47-year-old previously healthy woman with exposure to pet and
farm animals. Oropsylla montana fleas were implicated as the vector for disease transmission in this
case (190).
LABORATORY CONFIRMATION OF CLINICAL DIAGNOSIS

The laboratory diagnosis of Bartonella-associated diseases can be achieved through modified
conventional bacteriologic culture methods, co-culture with endothelial cells, immunoserologic or
immunocytochemical means, or DNA amplification. These approaches are described in current diagnostic
microbiology references (191). Serologic testing has become the mainstay of diagnosis, particularly when
the involved tissue is less accessible for biopsy sampling such as CSD patients with CNS infection. Early
lymph node biopsy or fine-needle aspiration (before spontaneous resolution of lymphadenitis occurs) for
histopathology, PCR, and culture should be encouraged in patients with serious complications such as
encephalitis or neuroretinitis, when CSD is a likely diagnosis and B. henselae serology is negative or
equivocal.
Detection and Identification of the Agent
Bartonella species usually do not grow under the conditions used for standard bacteriologic cultures. If
culture is attempted, freshly prepared media provide optimal recovery. Heart infusion agar with 5% to
10% defibrinated rabbit or horse blood supports better growth of most strains than chocolate or 5% sheep
blood agars. Plates sealed after 24 hours of incubation to preserve moisture content usually can be
incubated up to 30 days without notable deterioration. Even when these techniques are strictly applied,
recovery of B. henselae from lymph nodes and other specimens of patients with CSD is extremely rare.
Moderate success in the recovery of isolates has been achieved using alternate techniques (192,193). The
combination of enrichment culture and PCR amplification may optimally detect Bartonella species with
respect to sensitivity and a clinically relevant time frame, although this approach is generally not
available in the majority of clinical laboratories.
Colonies of Bartonella species are sticky, autoadherent, and of two morphologic types: (a) irregular,
raised, whitish, rough, and dry appearing or (b) smaller, circular, tan, and moist appearing. Both types are
often present in the same culture. The degree of colonial heterogeneity varies by species, with B.
henselae typically having a greater proportion of rough colonies than B. quintana. Repeated subcultures
cause most strains of B. henselae to revert to smooth cultures. Gram stain of a colony reveals small,
gram-negative, slightly curved rods (which may mimic Haemophilus, Campylobacter, or Helicobacter),
and a wet mount usually demonstrates twitching motility. B. bacilliformis and B. clarridgeiae possess
flagella, whereas B. henselae, B. elizabethae, and to lesser extent, B. quintana have twitching motility
believed due to pili. Presumptive identification of B. henselae or B. quintana can be made on the basis of
these features, plus a lengthy (>7-day) period of incubation before appearance, negative catalase and
oxidase reactions, and absence of acid production from carbohydrates.
Confirmatory identification is usually by referral to a laboratory experienced with Bartonella species.
Newer methods have been applied to identification of Bartonella species including mass spectrometry
(194), in addition to PCR-based and DNA hybridization techniques that can be used to distinguish species
and for direct detection in clinical material (30,31,90,195–199). DNA fragments of B. henselae can be
amplified from various clinical specimens including fresh lymph nodes and other tissues (including
brain), CSF, freshly aspirated pus, minute amounts of tissue obtained from lymph node fine-needle
aspiration, and paraffin-embedded material. Molecular subtyping of strains can be performed using PCR-
based sequence analysis (15) or restriction fragment length polymorphism, and repetitive extragenic
palindromic PCR.
Serology
Because culture of Bartonella species remains technically difficult with a low success rate, alternative
means of diagnosis are important. Serology is the most commonly used test for diagnosis, replacing the
skin test that was poorly standardized and carried a potential risk for transmission of infectious agents. An
immunofluorescence assay (IFA) and several enzyme immunoassays (EIAs) have been described for B.
henselae and B. quintana detection. They have been used primarily to demonstrate anti-Bartonella
antibodies in persons with CSD (28,129,200) and in some cases of HIV-associated aseptic meningitis,
encephalopathy, or neuropsychiatric disease (96,182). The IFA described by Regnery et al. (28) in 1992
generally performs well, but it was not designed for detecting immunoglobulin M (IgM) antibodies. In
studies in which this assay was performed at the U.S. Centers for Disease Control and Prevention, with
reciprocal titers of more than 64 as the cutoff value, both sensitivity (84% to 95%) and specificity (94%
to 98%) were high. It has been less consistent in studies performed in Europe (201). A high
seroprevalence of anti–B. henselae immunoglobulin G (IgG) in Europe due to exposure to non–B.
henselae species may result in inferior performance of the IFA compared with the United States. EIA
studies in some HIV-infected persons with encephalopathy or neuropsychiatric findings have
demonstrated antibodies reactive with a formalin-fixed whole bacterial cell antigen preparation of B.
henselae but have not satisfactorily demonstrated B. henselae specificity (182). An EIA using N-lauroyl-
sarcosine–insoluble outer membrane antigen from agar-grown B. henselae to test sera from 84 patients
with CSD defined by PCR (82 patients) or skin test (6 patients) determined the EIA sensitivity to be 75%
for anti–B. henselae IgG alone, 48% for IgM alone, and 85% overall when positive IgG, IgM, or both
were accepted as diagnostic. EIA specificity was 98% (200). The same EIA was used to study antibody
kinetics in patients with CSD. Anti–B. henselae IgM remained positive for 3 months or less and its
presence indicated acute disease. IgG titers also declined over time but may last for longer than 2 years.
Serologic cross reactivity is among the limitations of both IFA and EIA. Neither adequately
discriminates between anti–B. henselae and anti–B. quintana antibodies. Cross reactivity has also been
demonstrated between Bartonella and others including Coxiella burnetii and Chlamydia species. Data
regarding the clinical significance of such cross reactivity are limited, and this represents a potential
concern because all of these microorganisms are causative agents of endocarditis and may have similar
clinical presentations.
Treatment of Bartonella-Related Neurologic Manifestations
Antibiotic regimens for Bartonella infections have been determined empirically, based on clinical
experience, as well as published case reports and clinical studies, which are mostly uncontrolled with
limited follow-up (202). One of the most intriguing aspects of non–B. bacilliformis infections is the
clinical observation that antimicrobial therapy seems to have a much greater impact on
immunocompromised patients with systemic disease (e.g., patients with AIDS with bacteremia and BA)
than on immunocompetent patients with localized disease (e.g., patients with CSD with regional
lymphadenitis). This perhaps reflects the different pathologic processes involved. The recommended
therapy for acute B. bacilliformis infection, Oroya fever, is either chloramphenicol (0.5 g PO/IV four
times a day for 2 weeks) plus another antibiotic, (preferably a β-lactam), or ciprofloxacin 0.5 g twice a
day for 10 days. CNS involvement with impaired consciousness necessitates parenteral therapy. Because
of ease of administration, low cost, and observed clinical effectiveness, the initial therapy of choice for
uncomplicated bacteremia and BA caused by B. henselae or B. quintana in immunocompromised patients
is oral erythromycin (e.g., 0.5 g four times a day as stearate). Other macrolides, doxycycline (100 mg
twice daily), or other tetracyclines may serve as alternatives (67,202,203).
The role of antimicrobial therapy for CSD-associated neuroretinitis is controversial. In a small
retrospective case series, doxycycline and rifampin appeared to shorten the course of disease and hasten
visual recovery in seven patients with CSD neuroretinitis compared to historic cases. The demonstration
of B. henselae bacteremia associated with neuroretinitis adds weight to the argument for treatment with
antibiotics (96,160). There is no definite evidence of the utility of antibiotic therapy in shortening or
altering the course of CSD encephalopathy. However, because of anecdotal reports of apparent efficacy
of antimicrobials in the treatment of other manifestations of CSD, and because of the severe clinical
manifestations of this complication, antimicrobial therapy is prudent. Doxycycline with or without
addition of rifampin seems to be a reasonable choice in these cases (203). Dramatic clinical improvement
following treatment with high-dose steroids has been described in a 4-year-old previously healthy child
with CSD encephalopathy. Another 12-year-old child with CSD and brainstem encephalopathy with basal
ganglia impairment who was admitted with profound coma recovered after treatment with high-dose
methylprednisolone and antibiotics; however, because of the self-limited nature of this complication, the
role of steroids in this setting is difficult to evaluate (204,205).
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CHAPTER 27 RICKETTSIOSES, ANAPLASMOSES, AND
Q FEVER
DIDIER RAOULT
Bacteria in the order Rickettsiales are gram-negative microorganisms that grow in association with
eukaryotic cells. They do not grow in axenic media but require living hosts such as cell cultures,
embryonated eggs, or susceptible animals. With the exception of Rickettsia prowazekii, the agent of
epidemic typhus, and possibly Rickettsia felis in sub-Saharan Africa, these bacteria infect humans
incidentally as zoonoses. On the basis of molecular phylogeny, the bacteria causing rickettsial diseases
have been reclassified (Table 27.1). Rickettsioses are emerging infectious diseases, with many new
rickettsial diseases having been described in the past 15 years. Rickettsioses can be grouped as follows:
Q fever, ehrlichioses, and diseases caused by Rickettsia and Orientia species.
The genus Rickettsia is subdivided into the typhus group, containing Rickettsia typhi and R.
prowazekii, and the spotted fever group (SFG) that includes 24 species of organisms pathogenic for
humans (Table 27.1). Rickettsiae are associated with arthropods. They are mainly transmitted to humans
by bites from infected arthropods, but infections from aerosols of infected insect feces and blood
transfusions have also been described (1). Ixodid or hard ticks are the vectors of SFG rickettsiae and
have a specific geographic distribution. Mites are the vectors of Rickettsia akari (worldwide) and
Orientia tsutsugamushi (linked to Asia), lice are the vectors of R. prowazekii, and fleas are the vectors
of R. typhi and perhaps mosquitoes for Rickettsia felis (2) (Table 27.2).
The main clinical signs and symptoms of rickettsioses include fever, headache, a rash that is
maculopapular or sometimes petechial or vesicular, inoculation eschars at the site of the arthropod bite,
and local lymphadenopathies. Neurologic involvement is mainly associated with severe forms of disease
where it is part of a multiple organ dysfunction syndrome (MODS). The main pathologic mechanism in
rickettsioses is a vasculitis following infection of the vascular endothelial cells (Fig. 27.1). Apart from
the known pathogens, many other rickettsial strains have been found in arthropods, in particular ticks (1),
but their roles as human pathogens have yet to be determined.
The first name given to a rickettsial disease, typhus, is indicative of central nervous system (CNS)
involvement because it derives from τυποσ (typhos) meaning cerebral confusion. Rickettsioses are
seasonal and the arthropod host determines their epidemiology and geographic distribution. Rickettsia
species were divided into three taxonomic groups:
• The typhus group comprises R. typhi, the agent of flea-borne, murine typhus, and R. prowazekii
causing louse-borne epidemic typhus, Brill-Zinsser disease, and American sylvatic typhus linked to
flying squirrels.
• The SFG rickettsiae, which cause tick-transmitted diseases such as Rocky Mountain spotted fever
(RMSF) (caused by R. rickettsii), Mediterranean spotted fever (MSF) (Rickettsia conorii), and
African tick-bite fever (Rickettsia africae); a mite transmitted disease, rickettsialpox (R. akari); and a
spotted fever caused by R. felis that may be transmitted by fleas or mosquitoes (Tables 27.2 and 27.3).
• The scrub typhus group includes O. tsutsugamushi, a mite (chigger)-borne disease.
Coxiella burnetii, the agent of Q fever, belongs to the γ-Proteobacteria phylum. It causes a zoonosis in
many mammal species, including domestic animals and wild ungulates, and is excreted in birth products
and milk. Humans are usually infected by aerosols and may develop an acute primary infection eventually
followed by a chronic disease when predisposing factors are present. Many acute infections cause
neurologic signs; meningitis, meningoencephalitis, and Guillain-Barré syndrome have been associated
with C. burnetii.
Ehrlichioses and anaplasmoses are zoonoses (3). Ehrlichia species grow in blood cells in a
cytoplasmic vacuole, forming clusters or morulae. The bacteria in this large group are increasingly
recognized as potential human pathogens, and their current taxonomy has been changed recently to match
current phylogenic knowledge. Four genera are described, as follows: One apparently associated with a
helminth vector and named Neorickettsia contains only one human pathogen recognized in Japan and Laos
(Neorickettsia sennetsu); two are transmitted by ticks, Ehrlichia (including the three human pathogens,
Ehrlichia chaffeensis, Ehrlichia ewingii, and Ehrlichia sp. Wisconsin) and Anaplasma (with Anaplasma
phagocytophilum being the only currently identified human pathogen). The fourth genus, Wolbachia, has
one recognized species, Wolbachia pipientis, which could be associated with arthropods or nematodes.
When associated with filaria, in human filariasis, it appears to be a pathogenic factor and a treatment
target. The two most common ehrlichioses, the human monocytic ehrlichiosis (HME) caused by E.
chaffeensis and human granulocytic anaplasmosis (HGA) caused by A. phagocytophilum may cause
neurologic pathology such as meningitis or meningoencephalitis.
RICKETTSIOSES
Historical Background and Emerging Rickettsioses
Epidemic typhus was differentiated from typhoid in the sixteenth century (4) because of the existence of a
rash in the rickettsial disease. Some authors suspected an American origin for typhus because of the
American sylvatic flying squirrel reservoir. At the beginning of the twentieth century, Ch Nicolle proved
the role of lice in typhus transmission, and Ricketts (5) proved that the wood tick, Dermacentor
andersoni, was involved in the transmission of RMSF in Montana. In the Old World in 1910, Conor
reported the first cases of MSF in Tunis. The role of Rhipicephalus sanguineus was established in 1930
(2).
Recently, several new tick-borne diseases have been identified. Of the rickettsial diseases, only five
that are transmitted by ticks were known before 1991 (1), and subsequently, many new diseases have been
reported, including Astrakhan (6); Flinders Island spotted fever (7); African tick-bite fever (8); Japanese
spotted fever (9); “American Boutonneuse Fever” (Rickettsia parkeri); and, in Europe, infections caused
by Rickettsia sibirica mongolotimonae (10), Rickettsia slovaca (11), Rickettsia raoultii, Rickettsia
helvetica (12), and Rickettsia aeschlimannii (13) (Table 27.2).
New rickettsial species have frequently been found when arthropod vectors have been studied, that is,
ticks, mites, or insects (fleas, lice, etc.). For example, C. burnetii, R. africae, R. conorii caspia, R. felis,
R. sibirica mongolotimonae, R. slovaca, R. helvetica, and R. aeschlimannii were first isolated from
arthropods and later from people.
Recently, new diseases have been discovered using combinations of isolation, serologic testing, and
polymerase chain reaction (PCR) amplification. However, to definitively establish a disease, one should
obtain an isolate of the presumptive agent from clinical patients. When this is not possible, an association
of serology, immunologic detection of antigens in tissues, and PCR amplification of two different target
genes may be used to establish an etiologic relationship between a disease and an organism. Morphologic
recognition of rickettsia-like bodies by electron microscopy is of little value (14). Microorganisms found
in ticks (15) should be suspected of being human pathogens, because isolates of unknown pathogenicity
have erroneously been considered nonpathogenic for years (1).
Diseases
Rocky Mountain Spotted Fever
Epidemiology. RMSF is the most severe of the rickettsioses. It is caused by R. rickettsii and is currently
the main tick-transmitted rickettsiosis recognized in America along with R. parkeri (with R. africae in
West Indies). It was described first in the nineteenth century in the Western United States but is now
known to be prevalent in 44 states in the United States and in Central and South America (Brazil,
Argentina, Costa Rica, Columbia, and Mexico).
The main tick vectors are Dermacentor andersoni (the Rocky Mountain spotted wood tick) in Western
United States and Dermacentor variabilis (the American dog tick) in the East, the Midwest, and the
South. In Central and South America, Amblyomma cajennense is the major identified vector. The duration
of attachment is critical for infections, and transmission is unlikely when the tick feeds for less than 20
hours. The tick bite is painless and frequently goes unnoticed. The epidemiology of RMSF undergoes
yearly variations that are largely unexplained but probably mainly due to variations in tick activity and
human encounters with ticks. There are 500 to 1,000 cases annually in the United States, with 90%
reported from April to September, during late spring and summer. The disease is relatively more
prevalent in children younger than 10 years.
Clinical Manifestations. The incubation period of RMSF ranges from 2 to 14 days. Initially, patients
have a sudden onset of fever and headache, nonspecific signs with a broad list of possible differential
diagnoses. This has led to the recommendation that in areas endemic for RMSF, primary care physicians
should treat individuals presenting with unexplained fever, with or without other manifestations of RMSF,
as if they had the disease (16,17). A rash usually appears 3 to 5 days after the onset of symptoms but is not
seen in 10% of patients, especially in dark-skinned patients. It is diffuse and involves palms and soles; it
is maculopapular and can be purpuric. Skin necrosis or gangrene involving the digits or limbs may be
observed in severe cases (18). Renal failure is common in severe cases (19) and is related to acute
tubular necrosis or hypovolemia. Pulmonary manifestations of RMSF range from cough to respiratory
distress from pulmonary edema. Retinal abnormalities seen on funduscopic examination include venous
engorgement, retinal edema, hemorrhages, papilledema, and arterial occlusion.
Abnormalities in routine laboratory screens are nonspecific; the white blood cell (WBC) count is
generally normal, anemia is uncommon, but thrombocytopenia is observed in one third to one half of
patients. Hyponatremia and elevations in serum transaminases (e.g., aspartate aminotransferase [AST])
occur commonly.
Analysis of fatal cases of RMSF has shown that older age, hospitalization, and lack of treatment or
treatment with chloramphenicol are significantly correlated with death. Treatment with tetracyclines,
however, lowered the mortality rate (20). Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is a
risk factor for fulminant disease (21).
Neurologic Involvement. The frequency and the severity of neurologic abnormalities depend on the
severity of the illness (22). Neurologic complications are often the cause of death. Headache is often
severe and diffuse or bifrontal (23–28) (Table 27.4). In one study, 23% of patients had serious CNS
complications, including stupor, seizures, delirium, ataxia, focal neurologic deficits, papilledema, and
coma (19). Coma is more likely to occur in fatal cases (28). Cranial and peripheral nerve abnormalities
can occur, with hearing loss being the most common. Neck stiffness, which is common, is usually related
to neck muscle myalgia. The incidence of meningeal signs is about 20% and a diagnosis of bacterial or
viral meningitis is often considered (27) (Table 27.5). It was found that 21 (66%) of 32 patients with
RMSF who had undergone a lumbar puncture had abnormalities of the cerebrospinal fluid (CSF) and
abnormal CSF findings have now been documented in 63 patients (19). There was a pleocytosis in 38%,
the protein concentration was increased in 35%, and there was a moderate decrease in glucose
concentration in 8%. The WBC count in the CSF is rarely more than 100 cells/mm3. Usually lymphocytes
predominate.
A wide variety of focal neurologic deficits have been described including cranial nerve palsies,
aphasia, and ataxia, hemiplegia, complete paralysis, spasticity, and neurogenic bladder (29). Patients with
encephalitis may have Rocky Mountain spotless fever (30) and two patients have been described who
developed a rash only after a brain biopsy was obtained (22). Therefore, in endemic areas, doxycycline
may be added to acyclovir in the treatment of encephalitis. There is very little information on computed
tomography (CT) findings in RMSF, but low-density areas and edema have been described (29). The
electroencephalogram (EEG) usually shows diffuse cortical dysfunction, especially in comatose patients
(19).
The gross pathologic findings in RMSF involving the CNS include edema and hemorrhage (Fig. 27.2).
Microscopically, perivascular accumulations of inflammatory cells, glial nodules, and arteriolar
thrombonecrosis with small infarcts have been seen. Microorganisms are readily demonstrated in the
endothelial cells of blood vessels using either immunofluorescence (31) or immunoperoxidase techniques
(Fig. 27.3).
Residual neurologic deficits are common following RMSF. They include learning disabilities,
deafness, behavioral disturbance, depression, transverse myelitis, aphasia, and impairment of fine motor
skills (20,32–35). It was reported in one series that 1 to 8 years after recovery, 57% of patients had
neurologic abnormalities, including headaches, mild defects in intellectual functioning, and EEG
abnormalities (34).
In America, it was believed that RMSF for decades was the only tick-borne rickettsiosis, but a
discrepancy appears in the increasing number of reported cases and a lowering fatality rate (35). Because
several tick-borne SF were identified such as R. parkeri that causes a mild disease with an inoculation
eschar and a rash, R. massiliae infecting Rhipicephalus ticks has been found to cause spotted fever in
Europe, R. amblyommii has been linked to fever and rash in Southeastern United States, and a spotted
fever with inoculation eschar in California was linked to a new rickettsia (Rickettsia philipii 364D).
Finally, R. africae is prevalent in West Indies and reported in American travelers to Africa. However,
these diseases are generally mild with rare involvement of the CNS.
Other Tick-Borne Rickettsioses

Tick-transmitted rickettsioses have limited geographic distributions that are determined by their tick
vectors. In Europe, MSF is caused by R. conorii and is also known as boutonneuse fever, Marseilles
fever, Astrakhan fever, Israeli spotted fever, Indian tick typhus, or Kenyan tick typhus. It resembles
RMSF but has specific features. The disease is milder, but a fatality rate of 1.5% to 2.5% of hospitalized
patients is still found. A malignant form of the disease with purpuric rash, shock, and MODS has been
described in alcoholic, diabetic, human immunodeficiency virus (HIV)–infected, and old, or debilitated
patients. The typical clinical presentation is that of a patient with fever, a rash (which may involve the
palms and soles [Fig. 27.4]), and a “tâche noire,” that is, a black eschar at the site of the tick bites. The
“tâche noire” is found in 50% to 80% of patients. The rash is often papular, which led to one of the names
of the disease (boutonneuse fever). Israel tick-bite fever and Astrakhan fever appear milder than typical
MSF, and a “tâche noire” is often lacking.
R. slovaca and R. raoultii causes a newly described disease that appears to be common in Europe. The
tick vectors, Dermacentor marginatus and Dermacentor reticulatus, feed mainly in the cold months and
tend to attach on the scalp of people, preferring haired sites. The disease is more prevalent in children
and women, contrary to other tick-borne rickettsioses. It is rarely exanthematic, with the typical clinical
picture including an erythematous skin lesion ranging from 2 to 8 cm in diameter at the site of the tick bite
on the scalp and regional lymphadenopathy (which may be painful). Rarely, patients have fever and a
rash, and a deep postinfectious asthenia and residual alopecia at the site of the tick bite can be observed.
A case of meningoencephalitis has been reported. The occurrence of this rickettsiosis without rash may
stimulate research on other new rickettsial diseases with only localized manifestations (36). This disease
has been named successively TIBOLA (for tick-borne disease), DEBONEL (for Dermacentor-borne
eschar and lymphadenopathy) and SENLAT (scalp eschar and neck lymphadenopathy after tick bite)
(36a).
In Africa, African tick-bite fever may be the most common tick-borne rickettsiosis worldwide. It is due
to R. africae, which is transmitted by African ticks, Amblyomma hebraeum, and Amblyomma variegatum.
They usually feed on ungulates but also feed readily on human beings and cause a high prevalence of
infection in rural Africa (60% of tested patients exhibit antibodies) and in travelers. More than 50% of
patients have more than one “tâche noire” (Fig. 27.5), which are most often on the lower limbs and are
often associated with regional lymphadenopathy in the groin. The disease differs from the other milder
rickettsioses in that fever is frequently absent; a rash is present in only half of the patients with the
disease; and the rash may be vesicular (which has never been reported in confirmed MSF) in half of the
cases. An aphthous stomatitis can be associated with the disease. In Asia, Japanese spotted fever (caused
by Rickettsia japonica), Siberian tick typhus (caused by Rickettsia sibirica), and infections caused by R.
mongolotimonae comprise commonly and ropelike lymphangitis between the inoculation eschar and a
lymph node. Rickettsia australis (Queensland tick typhus) and Rickettsia honei (Flinders Island spotted
fever) cause diseases resembling MSF, but their rash can be vesicular. The neurologic involvement of the
other tick-borne spotted fevers is comparable to that of RMSF. MSF has been associated with meningitis,
meningoencephalitis, deafness, stupor, and coma (often with MODS) (37). Meningoencephalitis was
reported in two patients with Japanese spotted fever (38).
The spotted fever caused by R. felis is a new incompletely defined disease. The bacterium is found in
fleas in the United States, Peru, Europe, and Africa and in mosquitoes in Africa. It has been grown only
recently (39,40). Seven cases have been reported from Texas, Mexico, Brazil, France, and Germany. All
had fever, six of seven had a rash, and an inoculation eschar was present in some patients (39,41). A
diagnosis can be based on serology using specific R. felis antigen or PCR of blood or skin biopsies. The
most effective treatment has not been established, but the bacterium is highly susceptible to doxycycline
(42). Recently, it was reported commonly associated with fever in Kenya and Senegal where malaria is
endemic, causing as much as 6% of fevers (2a). The infection in children in Africa consists of fever and
vesicular rash and was named Yaaf (42a).
Rickettsialpox (Rickettsia akari)

Rickettsialpox was first described in New York City, where it is still prevalent (43). The recent terrorism
events (of September 11, 2001) have led physicians to pay increased attention to skin eschars (as might be
seen with anthrax) and vesicular rashes (which might be seen with smallpox), and this has led to an
increase in the cases of rickettsialpox diagnosed in New York City between 2001 and 2002 (44). R.
akari, the causal agent, is an SFG rickettsia transmitted by the bite of the mouse mite (Liponyssoides
sanguineus). Serologically, it cross-reacts with other SFG rickettsia. The prevalence of infections is
probably underestimated, although cases have also been reported from Arizona, Utah, and Ohio and a high
seroprevalence was found in intravenous drug users in Baltimore. Cases have also been diagnosed in
Russia, Ukraine, Slovenia, and Korea (1). Ten days after the mite bite, the beginning of the illness is
marked by fever, headache, and myalgia. A careful examination will reveal an inoculation eschar and
regional lymphadenopathy. Two to six days later, a rash appears consisting of 5 to 40 macular then
papular to vesicular (or even pustular) lesions. The name of the disease was derived from the latter, and it
is often mistaken for chickenpox. The disease is usually mild (1).
Epidemic Typhus
Typhus is transmitted by the human body louse, which lives in clothes and multiplies rapidly when cold
weather and lack of hygiene allow it to. Its prevalence reflects the low socioeconomic status of certain
members of a society (45) and rises during war, in poor countries in refugee camps, and in homeless
people in rich countries, including the United States and Europe. Recent reports of cases have been made
in Burundi (46), Rwanda, Russia, Peru, the United States, and Algeria (47).
Humans are the reservoirs of R. prowazekii and lice are the vectors. They are infected by ingesting R.
prowazekii in a blood meal. The organism multiplies in the gut and is released in feces (48), where R.
prowazekii can survive for weeks. Patients are infected by aerosols or by inoculation of infected feces
into the skin during scratching. Patients who recover from typhus may have latent infections and relapse
years later with stress. The relapsing form is named Brill-Zinsser disease and is associated with
bacteremia that might lead to lice becoming infected and the start of a new outbreak (1). In the United
States, the eastern flying squirrel (Glaucomys volans) and its fleas, lice, and mites can be infected. They
constitute a sylvatic reservoir and generate cases of domestic typhus (49).
Typhus begins abruptly with fever, headache, and myalgias. Coughing is also common, as is neurologic
involvement, evidenced by stupor, confusion, or coma (Figs. 27.6 to 27.8). A rash is observed in 20% to
80% of patients but may be difficult to observe in dark-skinned people. It usually starts in the axilla and
then spreads. It is usually macular but may be purpuric in severe cases. Diarrhea and jaundice are often
reported. Splenomegaly is found only infrequently. In severe cases, shock is observed and the
spontaneous fatality rate is 20% to 30%. Abnormal laboratory results might include leukopenia,
thrombocytopenia, anemia, and increased serum hepatic enzymes. The disease should be considered in
patients with high fever and confusion and in patients exposed to lice. In tropical countries, epidemic
typhus might be confused with typhoid, malaria (50), hemorrhagic fevers, and dengue. This could have
fatal consequences because the prescribed treatments for typhoid (β-lactams, co-trimoxazole, and
quinolones) are ineffective in typhus. In people with lice, it can be confused with trench fever and
relapsing fever, in which the same treatment can be prescribed (46).
Brill-Zinsser disease is the late relapsing form of typhus that is frequently undiagnosed as a rash and
recent exposure to lice are commonly not present (51). Interviewing the patient may reveal previous
exposure to lice, associated, or not, with a previous diagnosis of typhus. The disease is mild and the
prognosis is good.
Sylvatic typhus in the United States is caused by an R. prowazekii variant and is a milder disease. The
most prominent clinical features are neurologic, with meningitis being the clinical manifestation (49).
Few cases have been described and nearly all occurred in areas east of the Mississippi, where the eastern
flying squirrel is found. In these areas, cases may be observed in winter and sylvatic typhus should be
considered in patients with a rash.
Murine Typhus
Murine typhus is associated with rat and opossum fleas. Humans are infected when contaminated flea
feces are inoculated into the skin during scratching at the sites of flea bites. The disease is more prevalent
in hot and humid areas, specifically when rats proliferate. In the United States, 50 to 100 cases are
reported yearly, mainly in southern California and southern Texas. Recently, cases have been described in
Mexico, Indonesia, Southern Europe, and Africa (52,53).
The incubation period ranges from 8 to 16 days. The disease begins abruptly with fever, myalgias,
arthralgias, nausea, vomiting, and headache. A discrete rash is observed in 40% to 50% of patients, on
average, 6 days after the onset of signs. It is detected less often in dark-skinned patients. The rash usually
consists of pink macules but may become maculopapular (54). It begins in the axilla and generalizes to the
trunk but usually does not involve the face, palms, and soles. It can become purpuric in severe cases. One
third of patients have a cough and one fourth of the patients have nonspecific interstitial pneumonia
sometimes associated with pleural effusion. In severe forms, respiratory distress might require intubation
and artificial ventilation. Neurologic symptoms range from confusion and stupor to coma and seizures in
severe forms. Cerebral hemorrhages may occur. Digestive involvement can manifest as vomiting,
abdominal pain, jaundice, and in severe cases, hematemesis (52,55).
Laboratory abnormalities include leukopenia, which may be followed by leukocytosis. There might
also be thrombocytopenia and anemia, especially when hemolysis is observed (often in patients with
G6PD deficiency). A moderate increase in serum liver enzymes is common. In patients with severe
disease, hyponatremia and hypoalbuminemia are observed.
The prognosis is usually favorable, but 10% of patients require intensive care and 1% die. The
neurologic complications of murine typhus usually manifest during the second week of illness (56).
Aseptic meningitis occurs in 2% to 5% of patients (56). Meningoencephalitis, which is rare, occurs in
older patients. Such patients usually have seizures. Papilledema rarely occurs (57). The CSF WBC count
rarely exceeds 150 cells/mm3 and mononuclear cells predominate (56).
Scrub Typhus (Orientia tsutsugamushi)

Scrub typhus is transmitted by the bite of trombiculid mite larvae infected by O. tsutsugamushi. It is
prevalent in a triangle extending between northern Japan, eastern Australia, and eastern Russia, and
including the Far East, China, and the Indian subcontinent. Altogether, 1 billion people may be exposed.
Seasonality is determined by emergence of larvae. In temperate zones, it occurs mainly in autumn and to a
lesser extent in spring. O. tsutsugamushi species have a wide heterogenicity. The more common
serotypes are Kato, Karp, Gilliam, and Kawasaki (58).
The incubation period in rural or urban scrub typhus is 10 days or more. The onset of signs is usually
sudden and associated with fever, headache, and myalgias. With careful examination, an inoculation
eschar may be found at the site of the mite bite and draining lymph nodes may be tender. Generalized
lymphadenopathies and rash may be observed. The symptoms vary according to organ involvement.
Neuromeningeal symptoms are relatively common. Severe forms can occur, associated with septic shock.
The fatality rate in untreated patients is 6% to 10%. In a study of scrub typhus in Thailand, 9 (13%) of
72 patients presented with meningitis or encephalitis syndromes, or both (59). One of the nine had
cerebellitis and another had papilledema (59). Focal neurologic signs may predominate (60). The CSF
contains mainly mononuclear WBCs (59). Laboratory abnormalities may include leukopenia,
thrombocytopenia, and increased levels of hepatic enzymes. Interestingly, scrub typhus is not more severe
in HIV-infected patients and an HIV-suppressive factor appears to be produced during infection. Relapses
of the disease may occur (61,62). Diagnosis may be difficult because the clinical presentation is often
nonspecific and identifying epidemiologic factors is critical. Infectious mononucleosis is commonly
confused with scrub typhus.
Diagnostics
Serology
Serologic assays are the simplest diagnostic tests to perform (Table 27.6). The Weil-Felix test was the
first to be used and involves antigens from three Proteus strains: Proteus vulgaris OX-2, P. vulgaris OX-
19, and Proteus mirabilis OXK. It was used widely to detect rickettsioses based on serologic cross
reactions (63), but the test lacks sensitivity and specificity.
Today, the most commonly used serologic test is microimmunofluorescence (MIF). It is reliable but
does not allow differentiation of infections within the different SFG rickettsiae (64,65). The Western blot
immunoassay (63) can be used to differentiate between infections with the various SFG rickettsiae,
provided that acute-phase serum samples are used. The test detects two types of antigens, high-molecular-
weight outer membrane protein (rOmpA and rOmpB) and lipopolysaccharide-like antigen. The proteins
are species specific (63,66) and provide the basis for rickettsial serotyping (67). If serum samples are
collected very early in infection, strong homologous reactions are often observed, making a specific
diagnosis possible (68). However, because such serum samples are not always available, more specific
methods are needed. Cross-absorption studies are useful, especially if complemented by Western blotting
(68). This is particularly the case with typhus, in which in 50% of patients, serum samples have the
identical antibody titers to both R. prowazekii and R. typhi (69).
PCR-Based Detection of Rickettsiae

PCR amplification can be used to detect rickettsiae in blood, skin biopsies, skin swabbing, and
arthropods (70,71). Blood should be centrifuged and PCRs for rickettsiae should be carried out on the
leukocyte-rich buffy coat. Although heparinized blood can be used for isolation of rickettsiae into cell
culture, it is preferable to use blood collected in ethylenediaminetetraacetate (EDTA) or sodium citrate
for PCR amplification, because heparin inhibits PCR and is difficult to neutralize. PCR amplifications
must be performed before the initiation of antibiotic treatment and before antibodies become detectable.
Fresh tissues are preferred for PCRs, but paraffin-embedded tissues and even slide-fixed specimens may
be used (72). Although not always present, the tâche noire is the most useful sample to biopsy or to swab
(72a) to detect SFG rickettsiae by PCR assay (73), and using this technique, we have characterized
several species in our laboratory (10,74). PCR amplification of tâche noires or blood samples can be
very useful because they enable earlier diagnoses of infections than cell culture or serology. PCR-based
methods for the detection of rickettsiae are attractive because they not only circumvent the need for
culture but also possibly offer a more sensitive and specific alternative. Rickettsial DNA can also be
detected in ticks (75–78), fleas (40), or mosquitoes (2a) and lice (47) by PCR-based amplification
methods (79). Detection strategies based on recognition of sequences within the 16S rRNA gene (80,81)
and those encoding a 17-kd protein (82–84), citrate synthase (41,46,85), and the rOmpB (46,86) and
rOmpA (for SFG rickettsiae) (10,87) have been described. Because none of the PCR assays to date is
specific for individual rickettsial species, reaction products must be further analyzed to identify the
species detected. Approaches involving either restriction endonuclease analysis or base sequence
determination have been described.
Immunologic Detection of Rickettsiae

Skin biopsy specimens have been used in the diagnosis of rickettsioses since the early work of Woodward
et al. (88). Samples can be tested fresh or after fixation and paraffin embedding. Samples obtained at
autopsy can be tested in the same manner as skin biopsy specimens (89,90).
The use of methods incorporating specific polyclonal antibodies or monoclonal antibodies allows the
detection of rickettsiae in blood or other tissues (91). This approach enables diagnosis of infections in
patients before they seroconvert and hence early administration of specific treatment. The method can also
be used to diagnose rickettsial infections in retrospective studies using fixed tissues.
Isolation of Rickettsiae
Isolation of rickettsiae is difficult and dangerous and should be attempted only in specialized
laboratories. Rickettsiae have been isolated by several methods. Although laboratory animals, originally
guinea pigs and subsequently rats and voles, and embryonated eggs have been widely used, cell culture is
the most commonly used system for primary isolation. Tick or mammalian cell lines can be used. We have
used a microculture system to isolate rickettsiae from human blood and other sources (92–94). The shell
vial assay was adapted from a commercially available method for cytomegalovirus culture and early
antigen detection. Isolation of rickettsiae by cell culture is now performed routinely in our laboratory
from heparinized blood (leukocyte-rich buffy coat) and skin biopsies collected from patients before they
have received antibiotic therapy and from arthropods (93,94).
Treatment
Doxycycline is the main drug used to treat rickettsioses. In vitro, SFG rickettsiae are susceptible to
doxycycline, chloramphenicol, clarithromycin, ketolides, fluoroquinolones, and rifampicin (42,95).
Typhus group rickettsiae are also susceptible to erythromycin (96).
Doxycycline is the main drug used to treat RMSF, and it should be prescribed in suspected cases. It is
used in both children and adults, but not in pregnant women and allergic patients. In rickettsioses such as
MSF, murine typhus, and epidemic typhus, a single day of treatment with doxycycline (200 mg) is
effective, but this has not yet been determined for RMSF. The drug should be given orally except in
patients with gastric intolerance or coma, in whom it should be given intravenously. The usual dose is 200
mg daily in two doses. The required duration of treatment in RMSF is not yet fully determined, but
because of the lack of relapse, it can be stopped 3 days after apyrexia. In pregnant women,
chloramphenicol is the only available alternative to doxycycline, but the drug has been shown to be less
effective than doxycycline in treating RMSF (97). Failure has been reported when patients with murine
typhus or epidemic typhus were treated with quinolones (98), and the drug should be avoided in these
diseases despite its in vitro activity. Preliminary reports indicate the new macrolides such as
azithromycin and clarithromycin are effective in the treatment of children with MSF (99). Severely ill
patients should be treated in intensive care units and fluid administration should be carefully monitored.
Mechanical ventilation is used in cases of respiratory distress, and antiseizure drugs in patients with
seizures. In patients with gangrene of the extremities, amputation may be necessary. Glucocorticoids have
not proven useful.
Prevention is based on the prevention of tick, louse, and flea bites by using repellents and/or protective
garments. It is also useful to check for ticks after exposure. Careful examination of the scalp, groin, and
axilla is recommended. Ticks can be removed with forceps and the skin should be disinfected.
ANAPLASMOSES
Anaplasmataceae species comprise four genera. They multiply in their host’s blood cells, including red
blood cells (in animals Anaplasma marginale), platelets (in dogs Ehrlichia platys), monocytes (E.
chaffeensis), and neutrophils (A. phagocytophilum). Two are tick-transmitted diseases: Anaplasma and
Ehrlichia, whereas two are helminth-borne diseases: Neorickettsia and Wolbachia.
The index case of modern ehrlichioses was reported in the United States in 1987 (100). The patient
developed a fever after being bitten by a tick in Arkansas, despite receiving chloramphenicol. The patient
had, on blood smears, morulae in polymorphonuclear (PMN) cells and antibodies to Ehrlichia canis.
Since then, three human erhlichial agents have been discovered (3). The first agent of human ehrlichiosis
identified in the United States was E. chaffeensis. This infects monocytes and causes HME. The second is
A. phagocytophilum causing HGA and infects PMN. The third is E. ewingii, an agent transmitted by A.
americanum, which is prevalent in Arkansas and infects neutrophils. It cross-reacts serologically with E.
chaffeensis and infects mainly immunocompromised people. It has yet to be cultured and has been
identified in dogs and patients by PCR. A recently identified Ehrlichia sp. was detected in four patients in
Minnesota (100a) and is yet unnamed.
Human Monocytic Ehrlichiosis (Ehrlichia chaffeensis)
Epidemiology
E. chaffeensis has been isolated or identified by PCR mainly in the United States, in southeastern, south
central, mid-Atlantic States, and California. Its vector is the American tick, A. americanum (lone-star
tick) (Table 27.7), and white-tailed deer are the mammalian reservoir. Immature ticks are infected by
feeding on blood from persistently bacteremic reservoirs. E. chaffeensis is transmitted transtadially in the
tick and infects its next host (deer or human) during its next blood meal. The disease epidemiology
reflects the tick’s biology because most cases are contracted in the south of the United States, in rural
areas where the tick is most prevalent, and from April to September when the ticks are most active. In
highly endemic areas, the incidence of HME can reach 100 cases per 100,000 inhabitants. Older patients
are more susceptible to infection. Case reports from South America and Asia have been provided (100b).
Clinical Findings
The incubation period is 7 to 10 days, and tick exposure is reported by 80% of patients. Common
presenting signs are fever, headache, nausea, malaise, and anorexia. If untreated, patients may develop
severe signs and require intensive care. Digestive tract involvement is common with nausea, vomiting,
diarrhea, and abdominal pain. CNS infection manifests in many forms, from confusion to coma (101). A
rash is observed in 30% of patients, and lymphadenopathies in 25%. In severe forms, shock may be
observed with hypotension, tachycardia, respiratory distress, seizures, renal insufficiency, myocardial
failure, and coma. CNS involvement is common (3). Patients may develop confusion, photophobia, stupor,
hallucinations, and eventually seizures and coma. Changes in mental status, ataxia, blurred vision, and
cranial palsy have also been reported (101). CSF examination often reveals pleocytosis, with a
predominance of lymphocytes or neutrophils, and elevated protein levels.
Full blood cell counts typically show leukopenia, due to lymphopenia and neutropenia, and
thrombocytopenia. Coagulopathies may be observed in severe forms. Increases in AST, alanine
aminotransferase (ALT), and lactate dehydrogenase are common. The prognosis of HME improves with
early antibiotic treatment, but the fatality rate is still high, at 2.5%. In people concurrently infected with
HIV, the disease may be most severe, and in a recent study, 6 of 13 patients with coinfections died. The
diagnosis of HME should be strongly considered in patients with a history of tick exposure and
unexplained fever.
Laboratory Diagnosis
Careful examination of blood and CSF smears may help to identify typical morulae. Treatment should be
started in any suspected case. Diagnosis can be confirmed by culture, but PCR is used more commonly. A
confirmatory PCR using a second target gene is useful. Most cases are currently diagnosed serologically
by demonstrating a fourfold or greater increase in antibody titers or by seroconversion. The reference
technique is immunofluorescence antibody (IFA). A single titer of 25 is indicative of the diagnosis. There
are cross-reactive antibodies among Ehrlichia species and with A. phagocytophilum.
Treatment
Doxycycline is the recommended treatment in adults and children. Only rifampin also shows in vitro
activity, but the drug has been used only in a few pregnant patients. The treatment is given empirically for
2 weeks, or it should be continued for 3 to 5 days after fever subsides (101a).
Human Granulocytic Anaplasmosis (Anaplasma phagocytophilum)
Epidemiology
A. phagocytophilum was identified in ungulates in the 1930s as an agent causing chronic neutropenia. The
first human case was recognized in 1990 and the disease has now been reported from America and
Europe. It is transmitted by Ixodes scapularis (eastern North America), I. pacificus (western North
America), I. ricinus (Europe), and I. persulcatus (Asia). These ticks are also vectors of Lyme disease,
and the epidemiology of the diseases is similar. Concurrent infections may also occur. The temporal
distribution of the disease parallels that of nymph stage activity, with two peaks in spring and autumn.
Ticks are infected while feeding on bacteremic rodents. Deer play a major role as hosts of adult ticks and
reservoirs. In highly endemic areas in the United States, incidences of infection can reach 50 per 100,000
inhabitants per year. Men are at higher risk of infection than women or children (3).
Clinical Findings
The incubation period is around 10 days and a history of tick exposure is reported by 80% of patients.
Signs of the disease frequently begin abruptly with fever, headache, malaise, and myalgias that may be
particularly severe. Rash is found in fewer than 10% of patients. Visceral involvement may be observed
and digestive symptoms such as nausea, vomiting, and diarrhea have been reported. Neurologic symptoms
may include confusion, meningitis, and meningoencephalitis. Brachial plexopathy and demyelinating
polyneuropathy have also been reported (102–104).
The prognosis is favorable in most patients, even without specific therapy, but some patients may
develop septic shock. Most deaths are the consequence of induced immunosuppression and patients may
die of invasive aspergillosis, candidiasis, cryptococcosis, and herpes esophagitis (104a).
Laboratory findings often include thrombocytopenia with leukopenia (lymphopenia and/or
neutropenia). Increased serum transaminases are also common. A diagnosis can be made by the
observation of morulae within PMN cells in blood smears. Culture from blood is possible (Fig. 27.9)
(105), but PCR is used more commonly to identify A. phagocytophilum. Most cases are diagnosed by
serology using IFA. Treatment is similar to that of HME except that in vitro A. phagocytophilum is
susceptible to fluoroquinolones. Response to these agents has not been tested in patients.
Human Ewingii Ehrlichiosis (Ehrlichia ewingii)
Canine granulocytic ehrlichiosis, reported in the United States in 1972, is caused by the yet uncultured E.
ewingii. The bacterium has been characterized by amplification and sequencing of the 16S rRNA gene. E.
ewingii is vectored by A. americanum, which also transmits E. chaffeensis. Of 60 cases of human
ehrlichioses in Missouri in 1999, 4 were caused by E. ewingii (105); subsequently 4 other cases have
been reported by the Centers for Disease Control and Prevention (106,107). The disease is prevalent in
immunocompromised hosts (7/8), those also infected with HIV or receiving immunosuppressive drugs.
Patients, who report tick exposure, present with fever, thrombocytopenia, leukopenia, and various
symptoms including meningitis. Morulae may be seen in PMN cells in blood smears. The prognosis in
reported cases has been good and patients respond dramatically to doxycycline. Patients have antibodies
that cross-react with E. chaffeensis and PCR of blood samples has been shown to be useful in the
diagnosis of the disease. Infections with E. ewingii should be considered when ehrlichiosis is suspected
in immunocompromised patients exposed to A. americanum ticks.
Other Anaplamoses
Neorickettsia senetsu
This bacterium is associated with fish flukes and can cause fever and mononucleosis syndrome in humans
eating raw fish. First described in Japan, it has been reported since in Korea and recently in Laos (107a).
Wolbachia
Wolbachia can infect the nematode causing filariasis in humans in which they control the reproduction
rate of the worm. They cause some of the inflammatory responses of filariasis specifically at the initiation
of treatment. Doxycycline has been shown useful in the treatment of filariasis following this discovery,
which is much less toxic than other current therapies (107b).
Candidatus Neoehrlichia mikurensis

This rare disease found in Europe and Asia can cause fever in immunocompromised hosts.
Q FEVER
Q fever is a worldwide zoonosis caused by C. burnetii. Ungulates and pets are the major reservoirs. The
infection in humans is variable in severity, clinical expression, and natural course and may be acute or
chronic. C. burnetii, a gram-negative bacterium, multiplies in acidic vacuoles within the monocytes of its
host. Growing in vitro, C. burnetii becomes a deleted avirulent mutant, which is named phase II and is
useful in serologic diagnosis of acute infections (108). Coxiella organisms survive for long periods in the
environment and can be wind borne.
C. burnetii infection is incompletely eliminated after acute infection in some hosts, for example,
immunocompromised patients and those with cardiac valve lesions. C. burnetii organisms continue to
multiply despite high antibody titers and cause chronic infection. In patients with endocarditis,
interleukin-10 (an antiinflammatory cytokine) is increased and monocytes are unable to control growth of
C. burnetii (109).
Epidemiology
C. burnetii infects a wide range of animals, especially ungulates and cats, which are the most important
vectors for people who are usually infected by aerosols, or less frequently by ingesting milk products.
Interhuman spread of infections during sexual intercourse, parturition, and blood transfusions has been
reported (108). In the past few years, major outbreaks have been related to sheep and goats in the United
States and Canada (108) and a giant outbreak was observed in the Netherlands (109a). The current
geographic distribution is largely unknown. As C. burnetii is considered a potential bioterrorism agent,
diagnostic tools have been developed rapidly in the United States. Adult men are the predominant group
(110).
In several series, 60% of infected patients seroconvert without apparent disease, 38% experience self-
limiting mild disease (111), and only 2% require exhaustive diagnostic procedures and hospitalization.
Months to years after initial infection, 0.2% to 0.5% of patients develop cardiovascular infection
manifestations, usually those suffering from immunosuppression or a cardiac valve or vascular lesion
(109a,112).
Patients diagnosed with acute infections present with a variety of symptoms. Most common are isolated
prolonged fever (14%) (113), pneumonia (37%), and as the only symptom in 17%. Hepatitis is found in
60% of patients and is the only sign in 40%. Some hepatitis cases are associated with an inflammatory
syndrome and autoantibodies and may be resistant to antibiotic treatment. When liver biopsies are
performed, typical lesions are lipid vacuoles surrounded by a fibrinoid ring in the form of a doughnut
(Fig. 27.10). Patients may have a rash in 1.5% of cases. Patients may also have other cardiovascular
manifestations such as pericarditis or more rarely myocarditis (1% to 2%).
Severe headache is the most common CNS symptom. The neurologic manifestations of Q fever (Table
27.8) also include toxic confusional states, encephalitis, dementia, cerebellar symptoms, cranial nerve
palsies, psychoses, and motor and sensory neuropathies (22,114). A few cases of encephalitis,
meningoencephalitis, and encephalomyelitis have been reported late in the course of acute Q fever
(115–117). Meningoencephalitis is present in approximately 1% of patients with Q fever (118).
Seizures and coma may accompany the meningoencephalitis of Q fever. A study (114) reported an
incidence of neurologic complications among 22% of 103 patients, in which 46 had acute Q fever, 5
chronic Q fever, and 52 past infections. Six of the forty-five patients with acute Q fever had residual
neurologic impairment, weakness, blurred vision, recurrent meningismus, residual paresthesias, and
sensory loss involving the left leg (114). Behavioral disturbance, cerebellar symptoms, cranial nerve
palsies, extrapyramidal disease, and the Miller-Fisher variant of the Guillain-Barré syndrome (areflexia
and ophthalmoparesis) have been reported as complications of acute Q fever. The most common residual
disorder of Q fever meningitis is a disturbance of vision (119). In the series reported by Derrick (120), 1
(0.3%) of 273 patients examined had encephalomyelitis. In a report of neurologic involvement in acute Q
fever in 29 patients, we found 17 with meningoencephalitis or encephalitis, 8 with meningitis and
myelitis, and 4 with peripheral neuropathy (121). A review of 16 patients with Q fever
meningoencephalitis (116) revealed that 8 patients had an elevated CSF WBC level, ranging from 18 to
1,392 cells/mm3. In all but one case, mononuclear cells predominated. The EEG showed nonspecific
abnormalities in five of the six patients tested.
Post–Q fever chronic fatigue was first reported in Australia. Patients presented with prolonged fatigue,
arthralgia, myalgia, muscle fasciculation, blurred vision, sweats, and enlarged painful lymph nodes. A
case–control study was conducted more recently in the United Kingdom in 102 patients from a 1989 Q
fever outbreak, and pneumonia patients were used as controls (122). Chronic fatigue syndrome was found
more often in patients convalescing from acute Q fever. In some patients, the symptoms persisted for many
years. Thus, human C. burnetii infection may induce a persistent debilitating syndrome in convalescing
patients, as is occasionally observed in patients with chronic typhoid fever or chronic brucellosis.
However, this clinical manifestation is extremely rare in my experience in France. Whether this reflects
differences in strains or other specificities is unknown (123). In the Netherlands, many cases have been
reported since the beginning of a large outbreak; preliminary data suggest that behavioral psychotherapy
may be helpful in these cases.
Prognosis is usually favorable even without treatment, except in certain patients. In pregnant women,
with or without symptoms, Q fever compromises the pregnancy, including spontaneous abortion,
intrauterine growth retardation, oligoamnios, intrauterine fetal death (IUFD), and premature delivery
(123a,123b).
Patients with Q fever endocarditis have a very chronic infection with low-grade fever, progressive
deterioration of valve function, and progressive heart failure. Fever is intermittent and vegetations are
frequently absent with echocardiography. If not diagnosed, the disease progressively worsens and emboli
(mainly cerebral) may be observed associated with renal insufficiency, splenomegaly, and hepatomegaly.
Digital clubbing may also be observed (108).
Laboratory abnormalities include increases in hepatic enzymes and leukopenia and thrombocytopenia,
which are common. Circulating anticoagulant associated with antiphospholipid may be observed, as may
anti–smooth muscle antibodies. With endocarditis, antinuclear antibodies, microhematuria, and serum
rheumatoid factor are often found.
Diagnosis
Diagnosis is based mainly on serology. Direct detection of C. burnetii by culture, PCR, or

immunochemistry in valve, liver, or blood samples is useful, but serology by IFA is the reference method.
Two antigens (phase I and phase II) can be used in the IFAs. Acute Q fever is diagnosed when there is
seroconversion or a fourfold increase is seen to phase II antigen. A single serum sample with
immunoglobulin G (IgG) antibodies more than 200 and immunoglobulin M (IgM) more than 50 against
phase II is also diagnostic (124). In chronic Q fever, antibodies are at higher titers and directed against
both phase I and II. IgG to phase I at a titer of 800 or 1,600 is diagnostic of chronic infection, as is IgA of
more than 100.
Treatment
In vitro, several antimicrobials are bacteriostatic with minimum inhibitory concentrations compatible
with clinical use. These include co-trimoxazole, doxycycline, rifampin, fluoroquinolones, and newer
macrolides (but not erythromycin). All these compounds have been used with anecdotal success. Only
doxycycline for acute Q fever (108) and co-trimoxazole for a Q fever during pregnancy (125) have been
proven effective. None of these compounds is bactericidal in vitro, but doxycycline together with
chloroquine (which alkalinize the acidic pH of the vacuole where C. burnetii organisms multiply) is
bactericidal and has been proven the best antibiotic therapy for chronic Q fever (125a).
Treatment is straightforward in patients with acute Q fever, but when patients spontaneously resolve,
treatment is of uncertain benefit. Doxycycline, the most effective antibiotic, should be given for up to 2
weeks. The use of fluoroquinolones for patients with neurologic involvement was suggested because of
the good CSF penetration by the drugs, but this is not supported by convincing clinical data. Some patients
with hepatitis do not respond well to antimicrobial therapy because of an excessive immunologic
response. They do, however, improve rapidly with a short course of glucocorticoids (108). In pregnant
women, it has been shown that taking co-trimoxazole for the duration of pregnancy avoids unfavorable
outcomes (125).
Bactericidal drugs are necessary in patients with endocarditis (126,127). In vitro, antibiotic efficacy is
impaired by the low pH of the vacuole in which C. burnetii organisms reside. Hydroxychloroquine
increases the pH of this vacuole and restores the bactericidal effect of doxycycline. In patients with
endocarditis, the recommended treatment is the concurrent use of doxycycline (200 mg daily) and OH
chloroquine (600 mg daily, then adjusted to reach a 1-mg/mL plasma concentration). This regimen is
given for 18 to 36 months, depending on serologic responses. The major problem with this treatment is
photosensitivity and exposure to the sun should be avoided. Alternative treatment is the concurrent use of
doxycycline and ofloxacin for 3 years or more (127,128). The outcome could be favorable if there is a
four-time decrease of phase I IgG and IgA and the complete disappearance of IgM specific to phase II
antigen with no biologic or clinical sign of disease progression (125a). Serologic monitoring for at least
5 years seems appropriate given the risk of relapse.
Prevention is based on veterinary control in animals. A Q fever vaccine is available in Australia.
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CHAPTER 28 WHIPPLE’S DISEASE
MATTHIAS MAIWALD AND DAVID A. RELMAN
In a seminal autopsy report in 1907, George H. Whipple provided a thorough and articulate description of
the disease that now bears his name (1). His publication illustrated nearly all the key features that define
this clinical entity. However, there was no mention of neurologic manifestations, and no postmortem
examination of the central nervous system (CNS). More than 50 years later, the incidence and significance
of CNS involvement in Whipple’s disease began to be appreciated (2). We now know that Whipple’s
disease is a systemic disorder that typically affects the gastrointestinal tract and that the CNS is one of the
most common sites of extraintestinal involvement, along with the lymphatic system and the heart (3,4). In
addition, the CNS is the most common site of relapse after antimicrobial treatment of non-CNS disease
(5). Furthermore, it has been suggested that early CNS infection occurs in most or all patients with
Whipple’s disease, although only a subset of patients develop symptomatic or radiologically apparent
CNS disease (6).
Classical Whipple’s disease primarily affects middle-aged men and usually presents with arthralgias,
abdominal pain, fever, diarrhea, malabsorption, and weight loss (4,7–12). A fastidious bacterium,
Tropheryma whipplei, is the causal agent of the disease; it is an actinomycete (class Actinobacteria) on
the basis of molecular phylogenetic analysis (13–16). Whipple’s disease can present with protean
manifestations, especially in the setting of symptomatic CNS involvement. Thus, delays or failures in the
diagnosis of this disease are common. The prognosis of CNS Whipple’s disease is generally serious and
is worsened by delays in, or withholding of appropriate antimicrobial therapy (5,17).
This chapter focuses on the CNS aspects of Whipple’s disease. Relatively little attention is given to the
systemic (non-CNS) features of this disorder. These have been well described in a number of other
reviews (4,10,18–21). Because it is an extension of the CNS, a discussion of Whipple’s disease
involving the eye is included (see the section “Clinical Manifestations”).
ETIOLOGY
George Whipple concluded from histology and special stains that the subject of his case report suffered
from a disorder of lipid metabolism (1). Although he observed bacilliform structures in silver-stained
sections of a lymph node, he did not interpret this finding as related to the pathogenesis of the disease.
However, beginning in the 1950s and 1960s, evidence started to accumulate that Whipple’s disease is
caused by a distinct species of bacterium. First, bacteria with a characteristic uniform morphology are
consistently seen by electron microscopy in pathologically affected tissues (22–25). These organisms are
usually numerous, are recognized and phagocytosed by tissue macrophages, and undergo binary fission in
areas of pathology. Second, patients with clinical manifestations of Whipple’s disease respond to
antibacterial therapy (4,26). Third, intact bacteria disappear with clinical response to antibiotics and
reappear during clinical relapse (27). Fourth, specific bacterial DNA sequences from T. whipplei are
consistently detected in and have been shown to hybridize to areas of pathology (14,28). Finally, after
several decades of unsuccessful attempts, the bacterium was isolated in culture, first from a heart valve
specimen (29) and subsequently from other clinical specimen types, including intestinal tissue (30) and
cerebrospinal fluid (CSF) (31).
The Whipple’s disease bacterium (T. whipplei) is rod-shaped, measures about 0.2 µm by 1 to 2 µm,
and is surrounded by a 20-nm-thick cell wall. The outermost layer surrounding the bacterium consists of a
symmetric membrane that morphologically resembles those of eukaryotic origin (25). An inner electron-
dense layer within the wall reacts strongly with periodic acid–Schiff (PAS) reagent and accounts for the
PAS-positive staining pattern of the bacteria and their remnants within macrophage vacuoles. The
organism stains weakly gram positive and is not acid fast. Examples of typical morphology, when viewed
by electron microscopy, are shown in Figure 28.1 and in several references (24,25,27). Characterization
of the bacterium at the molecular level was initially achieved by broad-range 16S ribosomal DNA
(rDNA) polymerase chain reaction (PCR): a unique bacterial 16S ribosomal RNA (rRNA) gene sequence
was found directly in affected tissues (13,14). Phylogenetic analysis indicated that the bacterium belongs
to the actinomycetes (13,14); however, its relationships to the other known actinomycetes are relatively
distant (15). The name Tropheryma whipplei (initially proposed as Tropheryma whippelii) is based on
the Greek words trophe, nourishment, and eryma, barrier, because of the malabsorption in classical
Whipple’s disease and to honor George Whipple as the discoverer of the illness (14,16,32).
Cultivation of T. whipplei in the laboratory was finally successful in prolonged co-culture with human
fibroblast cells (29). In the initial culture setup, a bacterial generation time of about 18 days was
observed (29), but subsequent reports estimated the doubling time at between 28 hours and 4 days
(31,33,34). In any case, this is among the slowest growth rates ever reported for a medically relevant
bacterium. Subsequently, a cell-free culture medium was designed, consisting of tissue culture medium
supplemented with amino acids which the bacterium cannot synthesize on its own (34), and additional
strains—both in cell culture and in cell-free medium—have been cultivated from various other clinical
specimen types (35,36). Of relevance for the neurologic aspects of Whipple’s disease is the successful
isolation of T. whipplei from CSF specimens; this includes CSF from neurologically symptomatic as well
as asymptomatic patients and from a patient in the treatment-free period after prolonged antibiotic therapy
(31,37). These findings indicate that T. whipplei is viable and presumably is able to replicate in the CNS.
Nevertheless, at the present time, culture is not a suitable tool for routine diagnostic purposes in the
workup of possible Whipple’s disease.
Two T. whipplei isolates from culture, one from CSF and another from an infected heart valve, served
as the basis for genome sequencing projects (38,39). It is now established that the genome of T. whipplei
is quite small, slightly less than 1 Mbp, and bears the features of a reduced-genome organism that is
dependent on a host for synthesis of amino acids and for energy metabolism. At the same time, there is a
relative abundance of predicted surface molecules, and this includes a unique protein family, termed the
WiSP family (for T. whipplei surface proteins). The genome also possesses a number of “built-in”
mechanisms to create genetic and antigenic variation, and these are predicted to generate considerable
variability among the organism’s surface molecules. It is hypothesized that these features are linked to
immune evasion and thus to the organism’s ability to sustain a chronic infection.
The natural occurrence and reservoirs of T. whipplei are a topic of ongoing research and debate. The
first record of the bacterium’s occurrence outside diseased human tissues was provided by the detection
of specific sequences in wastewater from sewage treatment plants (40), suggesting that T. whipplei may
have an environmental reservoir and reside within polymicrobial communities. Several diagnostic PCR
studies only rarely found positive results in pathologically unaffected human tissues (41–44). However,
several other studies found T. whipplei–specific DNA sequences in saliva, gastric juice, intestinal
biopsies, and stool of asymptomatic persons (45–49), prompting debate as to the reliability and
generalizability of these findings (20,50). More recent studies have reported positivity rates of 2% to 4%
in stool and 0.2% in saliva of healthy adults and 8% in stool and 2% in saliva of sewage workers, both in
France, and the results were confirmed by a second PCR assay (48,49). Further evidence was provided
with the detection of T. whipplei in stool and saliva of asymptomatic household members of patients with
Whipple’s disease, including some of the same bacterial genotypes as in the respective patients (51). As a
consequence, it has been postulated that there is an asymptomatic carrier state with T. whipplei and that
the organism is a commensal bacterium of humans that causes Whipple’s disease only in a subset of
predisposed individuals (20,36,50).
Differences between T. whipplei strains were first detected in the 16S-23S rRNA intergenic spacer
sequence, and up to seven different spacer sequence types have been described (52–54). Subsequent
analyses found several highly variable genomic sequences (HVGS) that formed the basis for an improved
strain typing system (55); this genotyping system has been used in several epidemiologic investigations in
France and in Senegal (51,56,57). However, although some geographical differences in strain distribution
have been noticed, so far, no specific associations between different T. whipplei strains and particular
disease manifestations or carrier states have been identified (36).
EPIDEMIOLOGY
Classical Whipple’s disease with intestinal involvement is a rare entity. It has been estimated that about
20 to 30 cases of Whipple’s disease are reported each year in the literature (4) and that the total number
of published cases since Whipple’s original description is less than 2,000 (12). Available epidemiologic
data indicate that the disease almost exclusively affects Caucasians, that the mean age at diagnosis is 50 to
60 years, that there is a strong proclivity for males, and that people in the farming trades and other
outdoor professions are proportionately overrepresented (4,10–12,58). However, available incidence
estimates almost certainly underrepresent the true number of cases and tend to exclude cases with
nonclassical pathology or purely extraintestinal disease. In fact, recent reports indicate that the
involvement of T. whipplei in culture-negative endocarditis without intestinal manifestations may be more
common than would be expected from the incidence of classical Whipple’s disease, suggesting that
endocarditis might follow a different epidemiologic pattern (59,60). Other reports implicate T. whipplei
in acute transient illnesses, such as episodes of febrile illnesses in Senegal (61) and acute diarrhea in
children in France (56), although the causative role of the organism in these instances is uncertain.
Epidemiologic assessment of CNS Whipple’s disease is hampered by frequent uncertainties
surrounding the diagnosis of cases. Often, investigators diagnose CNS Whipple’s disease on the basis of
CNS clinical manifestations plus confirmed diagnosis of Whipple’s disease pathology at other anatomic
sites, typically in the small intestines or mesenteric lymph nodes. In cases with positive histopathology in
the small intestine and confirmed by either electron microscopy or a well-validated PCR test, the
diagnosis is firm (4,18,62). However, there is an increasing number of reports and case series of
presumed, isolated CNS Whipple’s disease in the absence of other organ manifestations (63–66). In a
considerable fraction of these published cases, the diagnosis has been made solely on the basis of
positive PAS staining results and/or insufficiently validated PCR tests. As discussed in the section
“Diagnosis and Differential Diagnosis” (later in this chapter), such diagnostic approaches lack the
necessary specificity to be able to confirm CNS Whipple’s disease.
Current literature suggests that the demographics of CNS Whipple’s disease are roughly similar to
those of Whipple’s disease cases involving all sites, although relevant information is limited. In the large
review by Dobbins (4), among 28 patients with CNS Whipple’s disease for whom an age is listed, the
mean is 40 years. A published series of 11 cases of CNS Whipple’s disease lists a 9:2 male:female ratio
and a mean age at onset of 49 years (67). Another review of CNS Whipple’s disease (68) provides a
mean age of 50 years and a male:female ratio of 8:2 among a group of 70 patients with predominant but
not exclusive neurologic presentation, and a mean age of 42 years and a male:female ratio of about 1:1
among a group of 21 patients with presumed isolated neurologic manifestations.
Among several published case series of systemic and/or classical intestinal Whipple’s disease, the
proportion of patients with neurologic manifestations ranges between slightly less than 10% and slightly
more than 40% (7–12). Three case series (8–10) list neurologic symptoms as the presenting symptoms—
although that does not mean sole or isolated CNS disease—in 4% of cases each. The overall incidence
and the proportion of truly isolated CNS Whipple’s disease are too rare and too small to allow for any
meaningful estimates. Patients who are symptomatic may be only a small subset of those with bacterial
infection in the CNS or with CNS pathology. This follows from two types of observations. First, a PCR-
based study (69) demonstrated positive results for T. whipplei in CSF in 7 out of 10 (70%) neurologically
asymptomatic patients at the time of diagnosis of intestinal Whipple’s disease. Second, autopsy cases
from the preantibiotic era had a high proportion of pathologic findings in the brain. Sieracki et al. (2)
described extensive CNS involvement at autopsy in two patients with Whipple’s disease who never
reported CNS symptoms. In a series of postmortem examinations on patients with Whipple’s disease
described by Enzinger and Helwig (3), 10 of 11 patients had characteristic brain lesions associated with
this disease. It has been suggested that isolated CNS manifestations as primary presentations of Whipple’s
disease may be increasing in frequency and that this may be attributed to the incidental use of antibiotics
that suppress early, presymptomatic non-CNS disease but do not penetrate well enough into the CNS to
halt progression there (70). Again, the numbers of isolated CNS cases are insufficient for a careful
analysis of this issue, and increasing disease awareness may be an alternative explanation.

The pathogenesis of Whipple’s disease and of T. whipplei infection is an evolving field. A number of
immunologic abnormalities have been identified in patients with Whipple’s disease, and these are
presumed to play a role in pathogenesis by way of increasing host susceptibility to infection. However, so
far these abnormalities are all of a quantitative nature: No clear genetic defects or dichotomous presence
or absence of any defined phenotypic markers have been described. Identified abnormalities include (a)
diminished ability of macrophages of Whipple’s disease patients to degrade intracellular microorganisms
(71–73); (b) reduced interleukin-12 production by patients’ peripheral blood monocytes upon stimulation
with bacterial antigens (74); (c) dysregulation of mononuclear cell function such that the components of a
T helper 1 (Th1) immune response are reduced and those of a T helper 2 (Th2) immune response
increased (75); (d) diminished Th1 reactivity of peripheral and duodenal CD4+ T cells upon stimulation
with specific T. whipplei antigens (76); (e) a transcriptional pattern of M2/alternatively activated
macrophages—which is associated with a Th2 immune response—as detected in duodenal tissue of one
patient with Whipple’s disease (77); (f) a lack of an inflammatory response and a predominance of an
M2/alternative activation phenotype in peripheral and duodenal macrophages, in combination with
reduced nitrite production in duodenal tissue and an impaired capacity of peripheral monocytes to
perform oxidative burst upon exposure to T. whipplei (78); and (g) a “paradoxically” higher
immunoglobulin G (IgG) antibody response against T. whipplei in asymptomatic carriers as compared to
patients, indicating a diminished serologic response to infection (79,80).
There are a few reports of secondary or opportunistic infections in patients with Whipple’s disease
(81), but apart from Giardia duodenalis infection, which has been reported in 8% and 12% of patients,
respectively, in two case series (82,83), these are not commonly observed phenomena, and humoral
immune responses against other pathogens are largely intact (4). Also, there is no significantly increased
incidence of Whipple’s disease in patients with known primary immunodeficiencies or
immunosuppressive therapies and instead only reports that immunosuppressive therapy may hasten the
onset of clinically apparent Whipple’s disease in patients with prodromal articular manifestations
(84,85). Surprisingly, one sequence-based study of the lung microbiome (i.e., the lung’s microbial content
and composition) (86) found T. whipplei DNA in HIV-infected individuals. Furthermore, in 11 of the 82
HIV-positive subjects, T. whipplei sequences dominated the microbial community (>50% of sequence
reads). The clinical significance of these findings is unclear because none of the individuals suffered from
respiratory complaints or known lung pathology, but these findings also suggest that T cell–based
immunity is important in controlling the organism.
Based on the detection of T. whipplei in acute self-limited illnesses and also in asymptomatic people, it
has been proposed that T. whipplei may be transmitted from infected hosts or the environment, possibly in
early childhood; may cause acute primary infections in some; may go on to be carried by some; and may
cause classical Whipple’s disease only in those who lack the immune response to contain the organism
(87,88). However, at this point, available data are not sufficient to be able to confirm these proposals.
Taken together, there is good evidence that immunologic factors play an important role in pathogenesis,
but the abnormalities identified so far are comparatively modest and mainly manifest as immunologic
dysregulation between a Th1 and Th2 response.
Current concepts hold that the disease process is initiated by translocation of the bacterium from the
intestinal lumen into the intestinal mucosa, possibly via invasion of intestinal epithelial cells or through
epithelial intercellular junctions, followed by crossing of the basement membrane and replication in the
intestinal lamina propria (24,89). There, the bacteria are ingested by macrophages and appear to spread
via blood vessels or via lymphatics into mesenteric lymph nodes and into the systemic circulation.
Infected blood monocytes are possible vehicles for dissemination to other organs (90). Uncertainty still
exists concerning the preferred compartment for bacterial multiplication. Earlier electron microscopic
studies indicated that most intact bacterial structures in untreated intestinal Whipple’s disease are
extracellular, just beneath the intestinal basement membrane, whereas ingested bacteria in macrophages
exist both with intact shapes and in varying stages of degradation (24,25). In situ hybridization localized
the 16S rRNA of T. whipplei (corresponding to intact bacteria) to the extracellular spaces of the intestinal
lamina propria, most concentrated underneath the basement membrane, but not in macrophages (28).
However, some investigators also report intracellular replication in a monocyte and macrophage cell
culture model and enhanced replication after addition of interleukin-16 (91).
Once T. whipplei disseminates, the brain is one of the favored sites for metastatic infection. The
mechanisms by which the bacteria cross the blood–brain barrier and infect brain parenchyma are
unknown. Entry by extracellular bacteria or by bacteria within monocytes both are possibilities. The
perivascular and subependymal distribution of macrophage nodules suggests bloodborne bacterial
dissemination. The distribution of microorganisms and histologic lesions within the CNS is relatively
widespread and therefore argues against highly localized microbial tropism. The size and multifocal
nature of the microglial nodules in CNS Whipple’s disease is compatible with neurologic deficits
described in patients. For example, microscopic lesions in the oculomasticatory segments of the midbrain
and upper pons might explain the unusual features of oculomasticatory myorhythmia (OMM) or
oculofacial-skeletal myorhythmia (OFSM), both findings that are nearly pathognomonic for CNS
Whipple’s disease (92–94). However, the degrees to which CNS manifestations are directly due to the
bacteria or to immunologic or cellular responses are not known. In cases with extensive CNS disease,
bacteria are found within neurons and in macrophages (see the next section), and neuronal loss and
reactive astrocytosis are seen during later stages of the disease process.
PATHOLOGY
In 1936, Ford and Walsh (95) described the case of a 47-year-old man who died after a 10-month history
of sleep disturbance, progressive paralysis of ocular movements, keratitis, bulbar palsies, and what
would later be called OMM (92). They did not recognize this as a case of Whipple’s disease. Notable
findings at postmortem examination included cerebral atrophy, swelling of basal ganglia, and widespread
degenerative changes of the cerebral gray matter with encephalitis, especially involving the corticobulbar
tracts. In some areas, there was neuronal cell death; other neurons were swollen with a granular bluish
purple cytoplasm. More than 50 years later, these tissues were reexamined with a variety of histologic
techniques, including the PAS stain (96). The encephalitis involved extensive mononuclear cell
infiltration of gray and white matter with perivascular cuffing, microglial proliferation, and marked
astrocytosis. Foamy macrophages formed nodules and contained PAS-positive accumulations. Some
neurons and astrocytes were PAS positive as well. These are all features that are typical of Whipple’s
disease pathology in the brain. In addition, electron microscopy confirmed the presence of bacillary
structures in the cerebral cortex as well as in retinal tissue.
Other cases of CNS involvement in Whipple’s disease have probably gone unrecognized (2,3). For
example, 3 of the 34 patients with Whipple’s disease that were reported in the literature between 1907
and 1948 had symptoms referable to the CNS at the time of death, including confusion and somnolence
(97); however, CNS Whipple’s disease was not formally discussed before 1960. The development of
PAS reagents and electron microscopy greatly facilitated this discussion. Sieracki et al. (2) were the first
to address CNS pathology in Whipple’s disease directly. Two postmortem examinations revealed
numerous and widespread periventricular, subependymal, and subcortical nodules, containing PAS-
positive sickle-form particle-containing (SPC) cells. These SPC cells corresponded to the same foamy
macrophages that had been traditionally associated with Whipple’s disease in intestinal tissues. They
noted less consistent involvement of the choroid plexus and leptomeninges. In the autopsy review by
Enzinger and Helwig (3) of Whipple’s disease 3 years later, 10 of 11 cases in which CNS tissue was
available displayed the characteristic lesions described earlier.
The gross and microscopic pathology of CNS Whipple’s disease has been summarized by a number of
investigators (98–101). In many cases, chalky yellowish white 1- to 2-mm nodules are distributed
diffusely throughout the cortical and subcortical, cerebral and cerebellar gray matter, and in
subependymal locations. They demonstrate a special predilection for temporal, periventricular, and
periaqueductal gray matter, hippocampus, hypothalamus, and basal ganglia. Less common sites include the
cerebellum and the thalamic and olivary nuclei. They tend to be perivascular. Other common gross
pathologic findings in CNS Whipple’s disease include cortical atrophy and ventricular dilation.
On microscopic examination, nodules are aggregates of primarily macrophages (microglia) that stain
strongly positive with the PAS reagents (Figs. 28.2 and 28.3). Reactive and hypertrophic astrocytes are
common at the periphery of these nodules; lymphocytes and plasma cells are uncommon. Dual staining
with PAS reagent and antibodies directed against glial fibrillary-associated protein (GFAP) indicates
astrocytes (Fig. 28.3). In cases with more extensive involvement, individual PAS-positive cells are more
diffusely distributed and may infiltrate overlying subarachnoid space (100) and white matter (Fig. 28.4).
High-power examination of PAS-stained tissue reveals intracellular and extracellular material with
variable appearance, from lacy strands to darker specks and larger irregular granules or clumps (Fig.
28.5). Occasionally, a bacilliform particle can be discerned. In areas with more substantial collections of
PAS-positive material, there tends to be neuronal loss and demyelination with vacuolization. Smaller
(microscopic) microglial nodules have been described that stain less intensely with the PAS reagents
(99). Some reports have described microinfarcts that occur most often in the frontal or occipital lobes
(100); it is hypothesized that such infarcts may be caused by small emboli released from cardiac valvular
vegetations that were found commonly in Whipple’s disease patients in earlier autopsy series (3,4). The
phagocytes associated with these infarcts are not PAS positive.
Bacilli were first seen in the brain in 1969 with electron microscopy and resembled those previously
described in non-CNS cases of Whipple’s disease (101,102). The distribution of bacteria and bacterial
remnants corresponds well with areas of PAS-positive staining. Large numbers of extracellular bacteria
can be detected within neuropil and near macrophages. Intact intracellular bacteria, as well as bacilli
undergoing various stages of degradation, are found within the widely distributed PAS-positive
macrophages (98,101,103–105). Evidence of bacillary binary fission suggests that microbial replication
does take place within the CNS (98,101). Macrophages with degraded bacilli found at the center of older
lesions stain more strongly with PAS than macrophages with intact bacilli at the periphery (99). Late
stages of bacterial degradation produce intracellular accumulations of serpiginous bacterial membranes
that create the large, homogeneous, and more strongly staining PAS-positive granules. Whipple’s disease
pathology can be focal; involvement of the brain, as with the small intestine, may be patchy (106); thus, a
negative random biopsy result does not rule out the disease (see also section “Diagnosis and Differential
Diagnosis”).
Neurologic manifestations of Whipple’s disease occur in three scenarios: (a) accompanied by intestinal
and/or other systemic disease manifestations at the time of diagnosis, particularly when the disease is
diagnosed at an advanced stage; (b) in the setting of clinical relapse after antibiotic treatment of intestinal
or other manifestations; and (c) as primary or isolated neurologic disease without other apparent
manifestations. Among these scenarios, neurologic relapse after treatment (b) is most commonly
encountered. This scenario was particularly common before the 1980s, when tetracyclines—which do not
cross the blood–brain barrier well—were typically used for treatment. In one review of 88 mostly
tetracycline-treated patients, 31 relapsed after initial treatment, and relapses in 13 patients (15% of all
patients) affected the CNS (5). CNS relapses generally have a poor prognosis, and some are refractory to
renewed antibiotic treatment (4,5,17,107). However, more recent case series (10,12,108,109) show a
much lower incidence of CNS relapses, particularly when initial intravenous induction therapy with β-
lactams and/or oral long-term treatment with trimethoprim-sulfamethoxazole (TMP-SMX)—which cross
the blood–brain barrier better than tetracyclines—have been used.
Presentation with isolated CNS Whipple’s disease is an extremely rare clinical event. However, this
may be difficult to differentiate from CNS disease combined with other systemic manifestations; for
example, a history of migratory arthralgias or chronic cough might represent extraintestinal Whipple’s
disease, but these complaints are quite nonspecific and may not be viewed as significant during the time
leading up to more prominent manifestations. Even cases with classic features of Whipple’s disease may
be missed because of the drawn-out time course of the illness. Nonetheless, there are a number of notable
reports in this context. Some reports represent primary presentation with isolated CNS Whipple’s disease
where examination of other organs yielded negative results (65,99,110,111). Several other cases
represent primary neurologic presentation where other organs were not investigated (112,113) or where
involvement of other organs was also found but was not prominent (92,96,98,114–119). A few published
cases represent CNS relapses years after initial treatment, at a time when the non-CNS findings had
become completely negative (120–122). Several combined case reports and literature reviews
specifically dedicated to primary or isolated CNS Whipple’s disease have been published (63–65); the
most recent one by Mohamed et al. (65) discusses 24 cases. However, these published cases should be
interpreted with caution, because a significant number of these diagnoses were based solely on PAS-
positive histologic findings that have not been confirmed with either electron microscopy or well-
validated PCR assays. As discussed (see “Epidemiology” and “Diagnosis and Differential Diagnosis”),
PAS-positive histologic findings are not entirely specific for Whipple’s disease. Another report (37)
summarizes 20 cases (authors’ own and cases from the literature) that are described as T. whipplei
chronic encephalitis, but the case definition used would also fit the description of primary or isolated
CNS Whipple’s disease as commonly used by other authors; similar caution concerning the certainty of
diagnoses is also indicated with this series.
Common neurologic manifestations of Whipple’s disease are dementia (or cognitive impairment),
ophthalmoplegia, myoclonus, altered level of consciousness, psychiatric abnormalities, hypothalamic
dysfunction, and ataxia (4,37,67,68,93) (Table 28.1). The first three are considered a characteristic triad
that should suggest the diagnosis of CNS Whipple’s disease, although only a minority of patients
(approximately 15%) has all three signs together (4,93). Headache is a common but nonspecific
complaint. The dementia is slowly progressive and manifest by memory impairment, confusion,
personality change, paranoia, emotional lability, and depression. Approximately 71% of patients with
CNS Whipple’s disease show signs of cognitive impairment, and nearly half of these patients also
demonstrate psychiatric disturbances (93). Patients have sometimes been misdiagnosed with Alzheimer
disease. Nearly all cases of ophthalmoplegia are supranuclear, usually in the form of vertical volitional
ophthalmoplegia with preserved involuntary extraocular movements in response to head movements.
OMM and OFSM constitute a peculiar mixture of synchronized eye movements and myoclonus that are
reported in about 20% of patients; both may be pathognomonic for CNS Whipple’s disease (see later
discussion) (93), but other forms of myoclonus can occur without eye involvement or in a dyssynchronous
fashion. In a particularly severe case of myoclonus, a patient suffered from synchronized 1-Hz jerks of the
right face, pharynx, arm, diaphragm, and calf, causing her entire body to shake (114). Segmental
myoclonus involving the facial nerve is also described in the setting of Whipple’s disease (123).
Hypothalamic signs reported in this disease include polydipsia, polyphagia, insomnia, and hypersomnia
(111,120,121,124). In their review of 28 patients, including 12 with CNS manifestations, Fleming and
colleagues (8) found headache, diplopia, depression, confusion, and other forms of altered personality to
be common at the time of presentation. A subsequent review of CNS Whipple’s disease cases from the
same institution (67) found cerebellar ataxia (6 of 11 cases, 55%) to be more common than described in
other series.
Less common clinical manifestations of CNS Whipple’s disease include aphasia, paresis, impaired
vision due to cortical lesions, seizures, dysarthria, auditory impairment, tinnitus, vertigo, trigeminal
neuralgia, hydrocephalus, and meningitis (68,93,110,116,125–128). Syndromes and pathology suggestive
of cerebrovascular stroke have been reported in patients with Whipple’s disease (129,130). In addition to
cognitive impairment, behavioral disturbances may be prominent (131). In the setting of disease relapse
with neurologic presentation, the most common clinical features are dementia, ataxia, hypothalamic
dysfunction, ophthalmoplegia, and seizures (4,5). Although uncommon, the spinal cord and peripheral
nerves may also be involved in Whipple’s disease (68,110,132,133), and although not directly affecting
the nervous system, infectious spondylodiscitis with T. whipplei (134,135) and myopathy (136) have also
been reported.
OMM was originally described by Ford and Walsh (95) in 1936 and by Van Bogaert et al. (137) in
1963, but the diagnosis of Whipple’s disease was not made until reexamination of these cases years later
(96,104). Though rare, OMM may be unique to Whipple’s disease and for this reason warrants
appreciation by clinicians. OMM is manifest by smooth convergent-divergent pendular oscillations of the
eyes with synchronous rhythmic (approximately one per second, 1 Hz) contractions of the jaw
(92,93,138,139). It can be continuous during the day, persist during sleep, and remain unaffected by
environmental stimuli (92). In one patient, it led to permanent bruxism (140). Similar clinical findings,
such as convergent nystagmus, may be related to OMM and are equally suggestive of Whipple’s disease.
In addition, OMM may be a form (or subset) of OFSM (93,141–143), which is also associated with
Whipple’s disease and is manifest by synchronous rhythmic movements of the face and extremity muscles.
It can also involve eyelids, palate, tongue, and cervical muscles and is also seen rarely in ocular
pontocerebellar atrophy.
Early observations on the natural course of untreated Whipple’s disease suggested three clinical phases
(3,7): (a) an initial prolonged phase with insidious onset, marked by arthralgias, fatigue, occasional
cough, and anemia; (b) a second phase characterized by abdominal pain, diarrhea, fever,
lymphadenopathy, and weight loss; and (c) a terminal phase marked by cachexia, congestive heart failure,
and death. In retrospect, CNS findings were often evident but unrecognized during the second phase.
Nonetheless, even today, the diagnosis of Whipple’s disease is made in some cases only after death.
Untreated CNS disease usually leads to progressive dementia, decline in level of consciousness, coma,
and death within a period of months to several years.
The eye is a site of significant and probably underappreciated involvement by Whipple’s disease
(93,116,144–149). Ocular manifestations include (a) CNS disturbances affecting the eye, as described
earlier, and including ophthalmoplegia, cranial nerve III, IV, or VI palsies, OMM/OFSM, pupillary
abnormalities, and ptosis (93); and (b) direct peripheral involvement of the eye and ocular structures,
mostly by infectious processes (147,148). The latter, in general, occurs in individuals with preexisting
evidence of gastrointestinal and/or neurologic involvement; however, a few reported cases of ocular
disease have been diagnosed without or with minimal extraocular manifestations. In one of these cases, T.
whipplei DNA was detected in the duodenal mucosa, despite normal duodenal histology (144). The most
common eye manifestations of Whipple’s disease are visual loss, uveitis, vitreitis, retinitis, optic neuritis,
and papilledema. Anterior chamber findings have included keratitis with corneal precipitates and iris
nodules. These latter findings may suggest a diagnosis of sarcoidosis. Ocular disease is usually bilateral.
Histologic or cytologic examination may reveal typical PAS-positive macrophages (SPC cells) within the
vitreous humor, lens capsule, and inner retina (116,145,149,150). Whipple’s bacilli have also been
visualized with electron microscopy, and their DNA can be detected in vitreous fluid and ocular tissues
by PCR (144,149,150). In a large series of microbiologic investigations on 1,520 anterior chamber and
vitreous fluid specimens from cases of uveitis of unknown etiology in France, infections were diagnosed
in 147 cases, and among other fastidious bacteria, possible T. whipplei infection was diagnosed by PCR
in 8 cases and definite T. whipplei infection in 2 cases (151). Thus, when investigating inflammatory eye
manifestations suspected to be due to Whipple’s disease, a combination of PAS staining and PCR may be
a useful diagnostic approach. Antimicrobial treatment usually arrests progression of ocular disease and
may lead to clinical remission (149).
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The diagnosis of CNS Whipple’s disease remains a clinical challenge, mainly because of its rarity and
because most signs and symptoms—except presumably OMM and OFSM—can also be observed in other
clinical entities. The diagnosis requires astute attention to the overall clinical history and physical
findings, and this includes CNS findings as well as other relevant details, such as joint problems, low-
grade fever, unusual skin pigmentation, changes in bowel habits, weight loss, and abdominal and
peripheral lymphadenopathy. Any diagnostic workup for possible CNS Whipple’s disease should always
include upper gastrointestinal endoscopy, including multiple (about five) small intestinal biopsies, as
well as an assessment of a patient’s lymph nodes. Results of routine laboratory studies are often
nonspecific. Anemia, hypoalbuminemia, steatorrhea, increased erythrocyte sedimentation rate and C-
reactive protein, and low serum carotene levels are relatively common in patients with Whipple’s disease
(3,4,7,8,10–12). Standard CSF analysis may be unremarkable or may display mild abnormalities such as
elevated pressure, elevated protein concentration, and mild pleocytosis (4,68,93,128). The CSF glucose
content is almost always normal. The electroencephalogram (EEG) may be unremarkable or show diffuse
slowing (65,68,115).
Neuroimaging studies have not revealed any specific or characteristic patterns for CNS Whipple’s
disease; imaging results may even be normal (10,68,93,152). Computed tomography (CT) scans may
reveal cortical atrophy and ventricular dilation; low-density, contrast-enhancing mass lesions are also
well described (105,110,126,153). Magnetic resonance imaging (MRI) probably offers greater sensitivity
than CT scanning in detecting CNS Whipple’s disease pathology (68,93). Various reports describe lesions
with increased T2-weighted signal intensity in the subcortical white matter, hypothalamus, uncus, medial
temporal lobes, and amygdala with variable degrees of enhancement (103,111,112,132,139,154) (Fig.
28.6). Adler and Galetta (139) provide gadolinium-enhanced T1-weighted images with evidence of
blood–brain barrier leakage that resolved with treatment. Positron emission tomography (PET) scanning
may also be used to detect areas of pathology with increased glucose uptake (65). Focal lesions as
detected by neuroimaging may be targeted for stereotactic brain biopsies, if this becomes necessary
(65,105,110,112,113).
Diagnostic testing includes studies based on histology, cytology, electron microscopy, and PCR.
Histology is the traditional diagnostic approach for Whipple’s disease and may reveal PAS-positive
inclusions in macrophages in intestinal, brain, and other tissues (62). Some investigators supplement
histologic examination with immunohistochemistry using T. whipplei–specific antibodies, although this
test is not widely available (37). Cytologic examination, involving PAS staining of a cytocentrifuge pellet,
is useful for CSF and vitreous fluid (69,120,149,153). When positive, cytology shows mononuclear cells
with PAS-positive inclusions, also termed sickle-form particle-containing cells (Fig. 28.7). Electron
microscopy, which has been in use since the 1960s, serves as the traditional confirmatory test for PAS-
positive histologic findings (24,25). PCR testing has been available since the 1990s; various assays have
targeted sequences such as the 16S rRNA gene, the 16S-23S rDNA intergenic spacer, and genomic
repetitive sequences (14,41,49,155–157). In recent years, most PCR assays have been transferred to a
real-time platform (44,158,159). PCR can serve as a confirmatory or supplementary test for intestinal
biopsies and as a primary or supplementary test for extraintestinal tissues or body fluids (19,21). The
possibility of serology for diagnostic purposes has been explored but has not yet reached a stage of wider
availability for routine diagnostic use (29,79,80).
In the setting of suspected CNS Whipple’s disease, a reasonable primary approach is to pursue a
diagnosis with upper gastrointestinal endoscopy and small intestinal biopsies, in combination with lumbar
puncture to obtain CSF for cytology and/or PCR testing (21). Cytologic examination requires coordination
with the receiving laboratory because CSF must be fresh (preferably <1 hour old) (69). Some
investigators have proposed PCR testing of saliva and stool for first-line screening to diagnose classical
intestinal Whipple’s disease, but this approach lacks sensitivity for extraintestinal manifestations and may
be positive in asymptomatic carriers (49). Secondary approaches should be guided by clinical judgment
and should target suspected pathologically affected sites, such as lymph nodes, ocular fluids, or brain.
Like the intestinal mucosa, brain involvement may be localized and/or patchy, and therefore brain
biopsies should be guided by neurophysiologic examination and imaging results (68,93). Apart from
positive results for standard brain histology (using the PAS stain) and electron microscopy, T. whipplei
rDNA has been amplified from brain tissue (37,65); however, the common practice of prolonged fixation
may hinder PCR-based amplification from archival specimens, and controls for the presence of
amplifiable DNA are a necessity (160). Although a rare occurrence, PCR may detect T. whipplei DNA in
histologically unaffected sites, such as the duodenal mucosa in a case of T. whipplei uveitis (144). Also,
apart from being useful for establishing a diagnosis, PCR and cytologic examination of CSF initially and
at regular intervals during treatment may be useful for staging and monitoring disease in order to detect
and respond to the threat of CNS relapses in classical and CNS Whipple’s disease (69).
Reactivity to the PAS stain is not specific for Whipple’s disease. The PAS reagent stains other
microorganisms, including a number of actinomycetes and fungi, as well as nonmicrobial glycoprotein
and some cellular debris (4,18,62). As a consequence, it is necessary to confirm PAS-positive findings by
electron microscopy (showing bacteria of the typical size and shape of T. whipplei) or by PCR. Some
investigators have indeed documented instances of PAS-positive brain histology that were not confirmed
to be due to Whipple’s disease (37,160). Two microorganisms to consider in the differential diagnosis of
PAS-positive findings are Mycobacterium avium complex and Histoplasma capsulatum, both of which
are found within macrophages and both of which may involve the brain. These organisms are particularly
relevant in the setting of HIV infection; in such instances, attempts should be made to distinguish these
organisms from T. whipplei by culture, PCR, and other staining procedures. In this context, it is relevant
that CNS and other systemic T. whipplei infections have been documented—although rarely—in patients
with AIDS (161,162), and Whipple’s disease–like syndromes can be induced by M. avium complex and
Rhodococcus equi in patients with AIDS (163,164).
Similarly, PCR testing requires attention to detail; false-positive results may arise from PCR
contamination as well as from amplification of nontarget sequences (20,165,166). When PCR results are
solely judged by agarose gel electrophoresis, bands of presumably the right size may be seen that
nevertheless do not correspond to T. whipplei DNA (M. Maiwald and D. A. Relman, unpublished
results). As a consequence, it is recommended that one employ strict anti-contamination practices and use
PCR assays that have been validated with adequate positive and negative clinical samples, that one
include adequate negative as well as inhibition controls, and confirm the identity of PCR products by
sequencing. Some investigators propose confirmation of positive results by a second PCR with a different
target sequence (157).
The differential diagnosis of CNS Whipple’s disease includes other forms of subacute or chronic
encephalopathy (e.g., Wernicke encephalopathy, heavy-metal poisoning, and storage diseases in children),
Alzheimer disease, Parkinson disease, prion diseases, cerebral vascular infarcts, CNS vasculitis,
paraneoplastic syndromes, neurosyphilis and other CNS infections, and chronic demyelinating disorders
(167). In addition, hypothalamic presentations of Whipple’s disease may resemble Kleine-Levin
syndrome (120). A history of alcoholism and a response to thiamine may help to identify Wernicke
encephalopathy. Some presentations of CNS Whipple’s disease may resemble multiple sclerosis (MS),
but supranuclear ophthalmoplegia, myoclonus, and seizures are unusual in MS. Also, MS may be
associated with myorhythmias and rarely with pendular ocular oscillations, but they are usually of a
higher frequency (4 to 5 Hz) than those seen in CNS Whipple’s disease. Isolated myorhythmias are also
sometimes seen in brainstem vascular disease and in cerebellar degeneration secondary to chronic
alcoholism. Creutzfeldt-Jakob disease and CNS Whipple’s disease share some features, including patient
age at onset, dementia, and myoclonus. Subacute sclerosing panencephalitis can also resemble CNS
Whipple’s disease; however, the former typically occurs in a younger age-group. CNS Whipple’s disease
can be distinguished from slow virus infections or prion diseases on the basis of brain pathology.
OMM and OFSM are mimicked by at least three neurologic clinical entities, although generally, they
are differentiated from other forms of pendular nystagmus by their smooth continuous nature, high
amplitude, and slow frequency. First, OFSM occurs rarely in ocular pontocerebellar atrophy. Second,
oculopalatal myoclonus can appear similar to OMM, although there are no convergent ocular oscillations
in oculopalatal myoclonus, and there is no olivary pseudohypertrophy in Whipple’s disease. Third, OMM
can be confused with convergence nystagmus of Parinaud, but the latter is episodic and is usually
provoked by attempted upward gaze (92).
TREATMENT
Therapy for Whipple’s disease has been largely guided by empirical observations and retrospective
literature reviews (5,8–10,108). Before the 1980s, when tetracyclines were commonly used for treatment,
relapse rates were high and CNS relapses occurred frequently (5). Even though recent case series show
much lower relapse rates (10,12,109), CNS relapses continue to pose a real and very serious threat to
patients. In two remarkable published cases, CNS relapse occurred 8 and 12 years, respectively, after
treatment and presumed cure of intestinal Whipple’s disease (121,122). Earlier case series showed that
patients who received initial intravenous induction therapy with penicillin and streptomycin followed by
oral maintenance therapy with tetracyclines (the “Duke regimen”) had a more favorable clinical outcome
(5). Supplemented by the fact that TMP-SMX shows better clinical outcomes than tetracycline-based
regimens (108) and even penetrates a relatively intact blood–brain barrier well, several recent
recommendations for treatment suggest initial intravenous induction therapy for 2 weeks with a β-lactam–
containing regimen (e.g., either penicillin G plus streptomycin, a third-generation cephalosporin, or a
carbapenem) followed by oral maintenance therapy with TMP-SMX for at least 1 year (19–21).
Despite the use of these induction and maintenance regimens, instances of treatment failure, including
worsening of CNS symptoms, have been observed under TMP-SMX therapy, and this includes cases of
apparently acquired TMP-SMX resistance in T. whipplei (103,108,139,168–170). Some patients with
worsening CNS symptoms have benefitted from a change in regimen or from cycles of intravenous
salvage therapy. Relevant case reports describe intravenous treatment periods with ceftriaxone (69,139);
switches to the oral third-generation cephalosporin, cefixime (103); and addition of rifampin, which is
also known for excellent CNS penetration, to the regimen (171).
In vitro studies with cultivated T. whipplei have shown that in co-culture with fibroblasts, the organism
appears susceptible to doxycycline, macrolides, penicillins, rifampin, teicoplanin, and TMP-SMX and
variably susceptible to imipenem (172); in axenic medium, the organism also appears susceptible to
ceftriaxone and vancomycin (173). Furthermore, genome analysis has suggested that T. whipplei is
inherently resistant to the trimethoprim component in TMP-SMX (174). Thus, some have proposed that
the TMP-SMX combination can be safely replaced by sulfadiazine alone (175); the latter also penetrates
the blood–brain barrier well. In vitro studies have further suggested that the combination of doxycycline
and hydroxychloroquine is bactericidal for T. whipplei, presumably because hydroxychloroquine
enhances tetracycline activity by raising the pH value of phagolysosomes (172). Encouraging initial
treatment results in patients have been reported with this regimen (19,176). As a consequence, it has been
suggested that patients with CNS involvement may benefit from treatment with doxycycline plus
hydroxychloroquine, plus either TMP-SMX or sulfadiazine (175). To improve on CNS penetration of the
tetracycline-chloroquine combination, one group (177) treated a patient with persistent infection of the
CSF using a combination of minocycline and chloroquine (minocycline has better CNS penetration than
doxycycline) and successfully eradicated T. whipplei from the CSF. A randomized clinical trial of initial
intravenous ceftriaxone followed by 1 year of oral TMP-SMX versus initial meropenem followed by 1
year of TMP-SMX in 40 patients (109) did not show any significant difference between the two regimens,
and apart from one patient with persistent T. whipplei in the CSF, there were no relapses within a median
observation period of 89 months.
Some patients may experience clinical deterioration, often accompanied by fever and other systemic
manifestations, weeks to months after initiation of treatment. In these patients, the deterioration has been
attributed to a phenomenon akin to immune reconstitution inflammatory syndrome (IRIS), as described in
patients with HIV infection (178). This phenomenon may be clinically serious. Although patients often
respond favorably to corticosteroid treatment, one patient apparently failed steroid treatment and
responded instead to thalidomide (179).
In summary, the treatment of Whipple’s disease, and its CNS manifestations in particular, remains
difficult. It is unclear how much weight should be assigned to in vitro susceptibility data. One should
continue to rely on clinical studies or case series as a major source of information on which to base
treatment decisions. Initial intravenous therapy with a β-lactam, either alone or in combination with
another agent, and subsequent extended oral treatment with drugs that penetrate well into the CNS appear
to be most effective.
PREVENTION
Whipple’s disease in its classic form is a rare disorder. Our present understanding of the risk factors for
this disease is insufficient to allow for any recommendations for preventive strategies. However, once
diagnosed, it is important to treat with prolonged courses of antibiotics that penetrate the blood–brain
barrier in order to prevent CNS relapses.
FUTURE DIRECTIONS
Although significant progress has been made in the last 10 to 20 years, a number of important questions
about the pathogenesis, clinical spectrum, diagnosis, and treatment of Whipple’s disease remain to be
answered. Further information concerning the prevalence and clinical significance of T. whipplei in
healthy carriers, in the respiratory tract of HIV-infected individuals (86), and in nonhuman reservoirs is
needed. The association of T. whipplei with acute self-limiting disease is intriguing and warrants
investigation of causality and possible clearance of the organism. Further exploration of possible
predisposing immunologic host factors for Whipple’s disease is needed, as is additional work on
pathogenetic mechanisms. The first randomized clinical trial of antibiotic treatment (109) may invite
investigators to conduct additional trials, such as with different drug combinations or treatment durations;
however, the limited number of available patients with disease will continue to pose challenges for
efforts to achieve statistical significance. Diagnostic strategies will undoubtedly be refined; in this
context, it will be interesting to see whether the “paradoxical” serologic response of patients (79,80) may
be further used for the development of a diagnostic test.
The clinical significance of T. whipplei strain diversity remains another open question; currently, there
appears to be no link between different strains and disease manifestations. The cultivation of T. whipplei
in 2000 (29) and the sequencing of its genome in 2003 (38,39) were big steps forward and provided the
basis for advanced strain typing capacities (55). With remarkable advances in DNA sequencing
technologies and capabilities, it seems clear that many more T. whipplei genome sequences will be
generated for both research and clinical purposes. These efforts will certainly facilitate further advances
in diagnostics, understanding of pathogenesis, and treatment for this unusual organism and disease.
ACKNOWLEDGMENTS
We thank Drs. Donald Regula and Lysia Forno, Department of Pathology, Stanford University School of
Medicine, Stanford, California, for histopathologic photomicroscopy.
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CHAPTER 29 TUBERCULOUS MENINGITIS
DOROTHEE HEEMSKERK, JEREMY FARRAR, AND MAXINE CAWS
Yea, I have known inflammations, Imposthumes, whelks, scirrhus Tumors growing to the Meninges, with the Skull, and other Diseases of
an evil conformation, excited in the Membranes of the Brain; by which at first for a long time, frequent headache, and most cruel, and
then afterwards a sleepy and deadly distemper hath been induced; the cause of the Disease not detected, but after Death by the
Anatomy; and indeed it is to be suspected that inveterate and pertinacious pains in the Head, which return, and daily become more
tormentive, in spight of all Remedies depend upon some such invincible Cause.
– Thomas Willis (1621–1675), from “De Anima Brutorum” (1672) (1)
HISTORY
Tuberculosis
Tuberculosis (TB) has been a part of everyday human life since ancient times. There is evidence of TB in
man dating back to 4000 BC, but the disease may have been present even earlier. Before the discovery of
the causative agent (Mycobacterium tuberculosis), TB, in its many forms, has had many different
syndromal descriptions: phthisis, consumption, scrofula, Pott disease, or others less well known such as
yaksma (Indian) and Chaky Onkay (Incan). The term “tubercle” was first used by Franciscus de la Boe,
also known as Sylvius of Leyden (1614–1672). He stated that tubercles were often seen in the lungs of
consumptives (2). He was also accredited with discovering a cleft in the brain consequently named the
sylvian fissure, which we now know to be a preferential site for exudates formed in tuberculous
meningitis (TBM).
The Origin of Tuberculous Meningitis

The earliest descriptions of intracranial TB date back to the seventeenth century. Physicians frequently
used the term “acute hydrocephalus” or “dropsy of the brain” for a condition in children of which the
etiology was unknown but presented with fever, headache, vomiting, and rapid death. Some of the
historical descriptions vividly illustrate the despair of both patient and doctor; some pathologic
descriptions were punctilious and very archetypal.
Nec minus a phlegmone et abcessu quam hujasmodi meningitis et tuberculis, cephalgiae lethales et incurabiles oriuntur
(Sometimes the headaches, fatal and incurable, follow abscesses and swellings of the envelopes of the brain, as well as placques and
tubercles of these membranes). (Willis, 1672 [1])
Willis was far ahead of his time as it was not until 150 years later that the tubercles found upon autopsy
were regarded as a distinguishing aspect of the clinical syndrome, which was only then proposed to be
tubercular meningitis.
Attempts were made to define this disease entity based on clinical and autopsy findings, but due to the
multiform presentation both clinically and pathologically, consensus was not reached until Robert Whytt
(1714 to 1766) lifted the disease out of obscurity with his treatise “Observations on the dropsy in the
brain.” He gives a detailed account of 20 patients, dividing the disease in four different stages, according
to the pulse of the patient. He emphasized that the terminology “Dropsy upon the brain” (ύδρω-κεφαλον
[hydrocephalus] επι [on] τωενχεφαλω [the brain] as described by Hippocrates [460 to 377 BC] in his De
Morbis Popularibus) is in these cases incorrect, because the accumulated fluid is not found between the
skull and the dura mater but most frequently in the ventricles. The antediluvian technique proposed by
Hippocrates to make a perforation in the upper part of the cranium to evacuate the fluid Whytt concluded
was of no use (3). This publication gave an impetus to scientists to study this condition systematically and
many contributions followed with different views on the origin of the disease. Some considered the
arachnoid the seat of the pest, others lesions in the brain parenchyma, the ventricles, until finally Penn in
1825, who thought the origin was in the pia mater, called it meningitis (1).
The term tubercular meningitis was first used in 1836 by P.H. Green in the Lancet. Green introduced
the term tubercular meningitis to describe the condition of the cerebral membranes, which were affected
by tubercular lesions in nine tenths of the cases in a series of 45 children, who at the same time had
tubercular deposits in the lungs or the abdomen. Green argued that these findings were a more essential
characteristic of the disease than the accumulation of cerebrospinal fluid (CSF) (4,5). The condition was
uniformly lethal.
Elucidating Pathogenesis
By the end of the nineteenth century, attempts were made to relieve symptoms from raised intracranial
pressure and hydrocephalus. Walter Wynter (1860 to 1945) had devised a crude technique to puncture the
lumbar subarachnoid space. He successively performed this archaic form of lumbar puncture on four
patients with TBM to relieve symptoms but with short-lived improvement (widening of the pupils and
temporary improvement of sensorium), but all four patients died (6,7). Morton (1891) describes the
clinical findings of a series of patients during illness and the pathologic findings in the brain postmortem
to further explore whether there would be a rationale for Wynter’s procedure. Although failing to clearly
associate the extent of the hydrocephalus to the observed clinical picture, he concluded:
The operation does no harm, and as the patient is already comatose no anaesthetic is required. But in any efforts we may make to
remove the more serious symptoms of tuberculous meningitis by draining the intraventricular fluid we must remember it is nearly always
only part of general tuberculosis, which may, and probably will, prove fatal in other ways, though if in this rapidly fatal meningitis we can
prolong life it may be some time longer before the general tuberculosis does its deadly work. (8)
Tuberculous meningitis remained universally fatal.
It was not Wynter but Heinrich Quincke who began to popularize the lumbar puncture for both
therapeutic and diagnostic purposes in the late nineteenth and early twentieth century. With the discovery
of M. tuberculosis by Robert Koch in 1892 and the development of x-rays by Wilhelm Roentgen in 1895,
diagnosis before death was now achievable, although effective treatment remained elusive.
The disease was still thought to develop in a manner analogous to other meningitides until a meticulous
serial autopsy study of 82 patients by Rich and McCordock (9) in 1933 provided the basis of what still
now is considered to be the establishment of pathogenesis. In guinea pigs and rabbits, Rich and
McCordock (9) could only provoke inflammation of the meninges by the direct inoculation of bacilli into
the central nervous system (CNS) and not by peripheral injection and consequent hematogenous spread. In
human autopsy studies, they described that the tubercles found in the brain were seldom of the same age as
those found in other organs and that vasculitis found in the brain was rather a process originating from the
adventitia inward, more likely to be the result of a focus within the brain rather than caused by direct
hematogenous spread of bacilli. These findings led them to form a coherent hypothesis in which they
postulated that, after inhalation of the pathogen, a short-lived bacteremia followed, during which bacilli
spread throughout the body and seeded the surface of the brain, forming small granulomas known as Rich
foci. These can exist without causing symptoms for an unknown period but may rupture; upon release of
the mycobacteria, meninges become inflamed, giving rise to a multitude of possible pathologic
tuberculous conditions in the CNS (9).
Treatment Development
The discovery of the causative pathogen was met with euphoria, as new hopes were raised of a cure.
Experimental treatment was attempted with tuberculin, originally a glycerin extract of M. tuberculosis
developed by Koch, but with catastrophic results. Other therapies raised hopes but proved ineffective,
including sanocrysin (gold therapy) (10). In 1944, the first effective antituberculous agent, streptomycin,
was discovered by Salman Waksman, a discovery for which he would win the Nobel Prize for Medicine
in 1950. By 1948, dozens of cases of successfully treated TBM with intrathecal and intramuscular
streptomycin were reported in the literature. Rich and Samuels (11) reviewed these cases while giving a
striking account of a case involving a 2-year-old boy who at the height of his disease was in a vegetative
state but within 6 months recovered with residual weakness of his left arm and minor mental impairment.
Many publications followed on successful streptomycin treatment. However, by 1950, numerous
streptomycin resistance reports appeared (12–17). Paraaminosalicylic acid (PAS) was added to the
regimen; although a weak antituberculous agent, it prevented development of resistance. With the
introduction of isoniazid (1952), a major improvement in treatment of all forms of TB was seen. It
became clear that intrathecal administration was no longer necessary. With the introduction of
pyrazinamide (1954) and rifampicin (1963), treatment regimens for all presentations of drug-susceptible
TB could be shortened to 6 to 8 months. The relative contributions of the first-line TB drugs to the
efficacy of TBM treatment were comprehensively reviewed by Donald in 2010 (18). Fifty years on these
drugs isoniazid, pyrazinamide, rifampicin, and streptomycin remain the mainstay of treatment for the vast
majority of patients with TB globally. It is difficult to think of another common infectious disease whose
treatment regimen has remained largely unchanged for over 50 years.
Vaccine Development
Despite failing to find a cure, Koch continued experimenting with tuberculin hoping to develop an
effective vaccine; however, it proved not to be effective. Clemens van Pirquet (1874 to 1929), after
observing a hypersensitivity reaction to a second inoculation with smallpox vaccine, was led to the idea
that Koch’s tuberculin might cause a similar reaction in patients previously exposed to mycobacteria.
Charles Mantoux (1877 to 1947) expanded on these ideas and developed the Mantoux diagnostic test in
1907, which is still in use today. During 1902 to 1920, Albert Calmette and his assistant Camille Guérin
developed a vaccine by serial passage of Mycobacterium bovis (which can cause TB in both cattle and
humans). After 13 years and 230 passages, the bacille Calmette-Guérin (BCG) strain was considered
attenuated and was first used as a vaccine in humans in 1921 (2).
The accomplishments in the first half of the twentieth century in diagnosis, treatment, and understanding
of pathogenesis seemed to offer the opportunity of eradication. However, the next 60 years has been
fraught with setbacks and TB remains a huge global public health problem. The first cases of AIDS came
to light in the early 1980s. Since then, it has become clear that the interaction of TB and HIV has had a
severe impact on both pandemics, while complicating the management of both diseases. HIV-infected
individuals are more susceptible to both active TB disease and all extrapulmonary forms of TB. The HIV
epidemic has therefore generated significant increases in the number of adults presenting with TBM in
high HIV prevalence areas. Drug-resistant strains of M. tuberculosis have continued to increase in
prevalence, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB, which are
now present in every region of the world. Huge advances have been made in unravelling immunology, and
genetics has deepened our understanding of the immunopathology underlying disease; however,
vaccination, diagnosis, and treatment are still reliant on antiquated techniques, which are inadequate to
control the continued pandemic.
BURDEN OF DISEASE
Tuberculosis Epidemiology
In the nineteenth century, TB was highly prevalent in Europe, with an annual incidence estimated to be
greater than 1,000 per 100,000. Mortality was high because patients were only treated with bed rest or
ineffective therapies and it is thought that over 50% of sufferers died. In the time of Robert Koch, one out
of seven Germans died of TB. In the late nineteenth and early twentieth century, incidence declined in
more developed countries due to economic development, improved living conditions, hygiene, and the
introduction of sanatoria in which patients were isolated from the general population. After the
introduction of antimycobacterial treatment, the decline in incidence and mortality accelerated. The initial
response was euphoric, and expectations to extinguish this blazing epidemic were high.
Despite the initial achievements during the twentieth century, global TB burden remains enormous.
Worldwide, approximately 2.4 billion people are infected with M. tuberculosis, of whom 10% will
develop active disease during their lifetime. People infected with HIV with latent TB are 20 to 30 times
as likely to develop active forms of TB (19).
A systematic analysis for the global burden of disease study in 2010 including mortality data from 187
countries from 1980 to 2010 ranked TB as the 10th leading cause of death globally. Of the 52.8 million
deaths of all causes globally in 2010, 1.2 million were attributable to TB (20). According to the World
Health Organization (WHO), 8.7 million new cases were reported in 2011 and an estimated 1.4 million
died (21). The Millennium Development Goals aimed to achieve a 50% reduction in prevalence and
death rates of TB relative to 1990 levels by the year 2015. According to the WHO, from 1990 to 2011, a
reduction of 41% in mortality was observed. According to the WHO, if the current trend is preserved, the
set target for 2015 will be met (21). However, this is dependent on the continued commitment of national
TB programs and policy makers. The TB epidemic is highly pluriform, with 22 developing countries
carrying more than 80% of the burden of TB. Demographic factors such as poverty, crowding, and
malnutrition play an important role, as does availability of good quality TB drugs. The impact of the HIV
pandemic is illustrated by the huge increase in the contribution of HIV/TB to cause of death patterns
among young adult men and women; by 2010, HIV/TB and injuries combined caused more than half of
deaths among men aged 20 to 39 years (20). Together with HIV, MDR and XDR TB continue to fuel the
pandemic (21). The goal to eliminate TB as a public health problem by 2050 seems quixotic without
renewed and sustained commitment from international donors and the global health community.
Burden of Tuberculosis of the Central Nervous System
The burden of extrapulmonary TB is tightly associated with the general pandemic and accounts for more
than 10% of all TB cases (21). Of these, about 5% are forms of TB in the CNS. These estimates are crude
because diagnosis of extrapulmonary TB in general and CNS TB in particular is challenging, and
according to WHO definitions, a patient who has both signs of pulmonary and extrapulmonary TB should
be classified as having pulmonary TB (21).
In endemic settings, TB is often the leading cause of childhood bacterial meningitis (22). In 2009, 7%
of all annual cases of bacterial meningitis and septicemia in the United Kingdom were caused by TB,
being the third leading cause after meningococcal and pneumococcal disease (23). With the introduction
of meningococcal C (1999) and pneumococcal (2006) vaccines in the routine immunization schedule in
the United Kingdom (and in the absence of an effective TB vaccine), TBM may well become the lead
cause.
In high TB-burden countries, young children aged 0 to 4 years are mostly affected, however, rarely,
younger than 3 months of age (24). The age range from 5 to 15 years old is often referred to as “the
favored age” as this population has the lowest rate of TB of all forms (25). In countries with a low
prevalence of TB, most cases of TBM are in adults. Commonly reported risk factors are alcoholism,
diabetes, recent corticosteroid use, malignancy, and immunosuppression (26). The advent of HIV has
dramatically changed the dynamics of the TB pandemic.
Mortality and Morbidity

Mortality among TBM cases remains high and varies depending on age, risk group (HIV), stage of disease
upon diagnosis, drug sensitivity of the infecting organism, time between onset of symptoms and initiation
of effective antibiotics, and the sophistication of health care infrastructure and facilities. Mortality in
children ranges between 10% and 20% (24,25,27,28). Neurologic sequelae are frequent and reported in
more than half of surviving children. In a retrospective survey of 554 children in South Africa, 74% of
patients suffered long-term disabilities or death (13%), including hearing or vision impairment (14% and
16% respectively), motor deficits (44%), and cognitive impairment (77%) (29).
For HIV-uninfected adult patients presenting early (stage I disease), mortality is approximately 20%
(30). Mortality increases with delayed presentation and advanced stage of disease (Table 29.1). For
patients in stage II, mortality is approximately 30% and in stage III, 55%. As in children, in adults,
permanent neurologic disability affects over half of the survivors (30). Co-infection with HIV has a major
impact on mortality. In Vietnam, mortality for the corresponding grade groups in a trial of immediate
versus delayed antiretroviral therapy (ART) for HIV-associated adult TBM was stage I, 40%; stage II,
52%; and stage III, 75% (31). In HIV-infected children in India, 6-month mortality has also been reported
to be drastically higher than in HIV-negative children (36% vs. 10%) (32). These mortality figures are a
reflection of the severe immunosuppression in these HIV-infected patients, illustrating the importance of
commitment of policymakers to invest in accessible integrated TB/HIV care.
The Influence of HIV

The HIV epidemic has undoubtedly fuelled the TB epidemic. Worldwide, an estimated 34 million people
are infected with HIV (33). An estimated one third of these patients are thought to be co-infected with M.
tuberculosis. HIV-infected patients with latent TB have a 50% lifetime risk of progressing to active forms
of TB versus HIV-negative patients with latent TB who have a 10% lifetime risk of developing disease
(34). HIV patients are more likely to develop extrapulmonary forms of TB, including TBM, and have a
higher mortality. Diagnosis of TB can be more challenging in HIV patients due to a less specific
presentation, wider differential diagnosis, and lower sensitivity of sputum smear microscopy. However,
in contrast, CSF smear is more likely to be positive in HIV-infected individuals with TBM due to higher
bacillary loads (35). Patients with low CD4 levels and smear-negative results may have atypical CSF
findings, immunologic tests are not reliable, and neuroimaging may not reveal typical lesions and includes
a wider differential diagnosis (36). Polypharmacy may prove problematic, with higher toxicity from
combined ART and antituberculous regimens and drug interactions. ART-naive patients who commence
ART treatment during their treatment of TBM may present with immune reconstitution inflammatory
syndrome (IRIS), which may be particularly detrimental if it presents intracranially (37).
Drug Resistance
WHO estimates 20% of M .tuberculosis infections worldwide are now resistant to at least one first-line
drug (38). MDR TBM is resistant to at least rifampicin and isoniazid, the two most effective first-line
agents. MDR TBM has been associated with very high mortality in both children and adults (39–41).
Drug resistance in TBM is rarely diagnosed in time to make appropriate treatment adjustments. The
difficulties of access to rapid TB drug susceptibility testing (DST) in much of the world are compounded
by the rarity of a positive isolation of M. tuberculosis from the CSF. Drug resistance prevalence among
TBM cases will generally follow similar patterns to those observed regionally for pulmonary TB.
Isoniazid resistance in the absence of concomitant rifampicin resistance is more prevalent than MDR
TB; 7% of M. tuberculosis strains globally are now resistant to isoniazid (38). Because isoniazid is the
most effective drug in decreasing the bacterial load in the first two days of anti-TB treatment, early
recognition of resistance is of great importance, particularly in TBM cases where rapid killing of bacilli
is likely to be crucial. In Vietnam, isoniazid resistance alone or combined with resistance to other drugs
was found in a third of culture-positive samples in adult HIV patients with TBM, with 4.3% MDR TBM
(40). In a cohort with predominantly HIV-negative patients, isoniazid resistance was found in 37.1% of
samples of which 21% were MDR (overall MDR rate was 5.6%) (39). Mortality from MDR TBM was
100% in the absence of available second-line therapy. In children with a culture-proven diagnosis of
TBM, MDR TB or rifampicin monoresistance was identified in 5% of cases in South Africa. Multidrug
resistance, not surprisingly, was associated with very high mortality (83%) (42).
Isoniazid resistance without rifampicin resistance also has a significant impact on mortality. An initial
analysis of a cohort of TBM patients in Vietnam failed to find a significant impact of isoniazid resistance
(+/− streptomycin resistance) on mortality (43), but a larger study in Vietnamese HIV-positive patients
showed a significant reduction in survival (adjusted hazard ratio [HR], 1.78; 95% confidence interval
[CI], 1.18 to 2.66) among patients infected with isoniazid-resistant, rifampicin-susceptible strains
compared to those with fully susceptible isolates (40). In a retrospective cohort study in the United States,
researchers also found a significant increase in risk of death associated with isoniazid resistance (odds
ratio [OR], 1.61; 95% CI, 1.08 to 2.40) (44). Among Vietnamese HIV-positive adult patients, the adjusted
hazard ratio for mortality of MDR TBM patients compared to patients with isolates susceptible to all
agents or streptomycin monoresistant was 5.21 (95% CI, 2.38 to 11.42) (Fig. 29.1).
Long-Term Disability
Very little is known about long-term outcome and disability for both children and adults. Antituberculous
chemotherapy has been unsuccessful in completely preventing long-term sequelae; in many cases,
diagnosis may be too late, but in others, significant neurologic damage occurs subsequent to initiation of
treatment. Especially in children, neurocognitive impairment can jeopardize development, education, and
quality of life and place a great burden on families, schooling, and medical systems. A recent long-term
follow-up study on a South African cohort of pediatric TBM patients who were severely ill on
presentation (stage II or III) reported only 20% of children to be functionally normal at follow-up (median
6 years after TBM treatment completion). The main areas of functional deficit were cognitive impairment
(80%), poor scholastic progress (43%), and emotional disturbance (40%). A smaller proportion of
children (25%) had evidence of motor impairment (45). In a Danish nationwide, population-based cohort
study with up to 30 years follow-up, TBM was associated with an almost twofold increased long- term
risk of dying compared to a background population (mortality risk ratio [MRR], 1.79; 95%, CI, 1.09 to
2.95). In this study, the underlying cause of long-term death was most frequently TBM itself rather than
secondary to the most commonly reported neurologic sequelae (46).
Neurologic sequelae most frequently described in adults are cognitive impairment, motor deficits,
cranial nerve palsy, and optic atrophy (47). A 5-year follow-up on Vietnamese adults with TBM who took
part in a randomized controlled trial on the effect of dexamethasone on survival could only demonstrate
an overall benefit of dexamethasone up to 2 years following treatment. Five years after treatment
completion, there was no difference in overall survival or disability outcome in both groups. In the group
receiving dexamethasone, 48.4% (vs. 52.7% in placebo group) of patients had died at 5 years (31% at 9
months), 6.8% (vs. 7.4% in the placebo group) were severely disabled, 17.2% (vs. 14.8% in placebo
group) had intermediate disability, and only 27.6% (vs. 25.1% in the placebo group) had good outcome
(48). However, the beneficial effect of dexamethasone was preserved at 5 years for patients with stage I
TBM at presentation, demonstrating that, contrary to preceding medical wisdom, patients with stage I
TBM are the group who gain the greatest benefit from corticosteroids.
Vaccination with Bacilli Calmette-Guerin and Protection Against Tuberculous

Meningitis
The controversies surrounding the protection that the BCG vaccine confers to adult pulmonary and
meningeal TB still exist. In adults, reported efficacy against all forms has ranged from as high as 80% to
0%. It is proposed that the vaccine establishes immunity by inducing effector memory T cells in the lungs
that gradually wane after 10 to 15 years rather than building a longer lasting “central memory” (49).
Various theories have been proposed for the differences observed in efficacy, including differences in the
circulating M. tuberculosis strains, BCG vaccine strains, or preimmunization exposure to environmental
mycobacteria. Nonetheless, consensus on the benefit of prevention of severe forms of childhood TB
including TBM and miliary TB is established. The vaccine is thought to be 52% to 86% protective
against developing the severe complications of childhood TB such as miliary TB and TBM (50). It has
been estimated that the 100.5 million BCG vaccinations given to infants in 2002 would have prevented
29,729 cases of TBM in children during their first 5 years of life, or 1 case for every 3,435 vaccinations,
and 11,486 cases of miliary TB, or 1 case for every 9,314 vaccinations. Based on these data, it is
considered a cost-effective intervention in Southeast Asia, Africa, and the Western Pacific, where TB
infection rate and vaccine coverage are highest (50). In BCG-vaccinated children in India who do
develop TBM, the clinical spectrum of disease does not seem to be ameliorated (51). The BCG is the
most widely used vaccination globally.
IMMUNOPATHOGENESIS
Transmission of TB occurs when a person inhales mycobacteria-laden droplet nuclei. One to five bacilli
are sufficient to cause infection. M. tuberculosis is the causative agent of almost all cases of TBM. M.
tuberculosis is an obligate aerobic, intracellular bacterium. On the cell surface, it has a waxy coating.
The high lipid content of the cell wall renders these bacilli imperceptible to the Gram stain. The
organisms are slow growing with a generation time of 15 to 20 hours, contrasting with that of some
pyogenic bacteria, such as Streptococcus pneumoniae, Neisseria meningitides, and Staphylococcus
aureus, with generation times of less than an hour. The complex antigenic structure of the cell wall
includes polysaccharides, proteins, peptides, lipids, and glycolipids with specific immunologic
properties. Other antigens are contained within the cytoplasm. These molecules determine the
characteristic immune response to tuberculous infection and its resultant pathology.
Macrophages and Granuloma Formation
In pulmonary TB, the alveolar macrophage has a central role in the initial innate immune response to M.
tuberculosis as well as in initiating the adaptive T-cell immunity. If upon recognition and ingestion of
bacteria, the macrophages fail to eradicate M. tuberculosis, T cells are recruited to the site of infection
and generate a chronic inflammation and granuloma formation in order to contain the infection (52). The
granuloma is pivotal to tuberculous disease and characterized by the formation of central necrosis of the
lesion, often referred to as caseation. In solid necrosis, mycobacterial growth is inhibited, and the
infection can be contained and can remain dormant. Granuloma with liquefied central necrosis provides
an optimal environment for extracellular mycobacteria and may rupture, allowing the spread of bacilli to
other parts of the lung, the bloodstream, or the exterior environment (53).
The onset of the adaptive immune response to M. tuberculosis is delayed compared to other infections.
This delay allows for an exponential growth of the mycobacteria before it is slowed or arrested by the
host defenses (54). For the adaptive immune response in TB, CD4+ T cells are essential. CD4+ T cells
exert their protective effect by the production of cytokines, primarily interferon-γ (IFN-γ) and tumor
necrosis factor-α (TNF-α). IFN-γ is a central protective cytokine in mycobacterial infection proposed to
protect by mediating the induction of nitric oxide synthase (NOS), enhancing the microbicidal system
within macrophages (55). TNF-α plays a key role in granuloma formation and macrophage induction and
has immunoregulatory properties (53). Other cytokines involved in mycobacterial disease control are
interleukin (IL)-1B, IL-6, IL-12, IL-15, IL-18 (proinflammatory) and IL-10, IL-4, and transforming growth
factor-β (TGF-β) (antiinflammatory) (53,56). In addition to the complex regulatory meshwork of cells and
immune mediators that control the innate and adaptive immune response, different components may be
negatively influenced by microbe-specific virulence factors. The virulence of the mycobacteria is thought
be founded in their ability to regulate macrophage chemotaxis, necrosis, and apoptosis, facilitating a
beneficial environment within the macrophage or extracellularly in the granuloma and consequently their
own proliferation and possibly also facilitating egress to other sites of infection, including the CNS (57).
Immune Response in Tuberculous Meningitis
TNF-α is thought to have a crucial but controversial role in pathogenesis of TBM. TNF-α is a
proinflammatory cytokine produced by monocytes, macrophages, and dendritic cells upon stimulation
with mycobacteria or mycobacterial products and plays an essential role in granuloma formation and
maintenance (58). Whereas in pulmonary TB, TNF-α-neutralizing drugs can lead to progression to (fatal)
disease, in TBM, an elevated production of TNF-α has been proposed to be associated with more severe
disease, but it has not been established if this is merely a marker of advanced disease or if
disproportionate TNF-α responses mediate disease progression. It is probable that protective immunity is
dependent on a delicate balance between pro- and antiinflammatory factors and that individuals with
responses at the extremities of the spectrum are both at risk of more severe disease.
In vitro infection of microglial cells (macrophages of the brain) results in the production of robust
amounts of TNF-α, IL-6, IL-1B, CCL2, CCL5, and CXCL10 (59). In rabbits infected intracisternally with
M. bovis, oral thalidomide treatment led to reduction of TNF-α levels and clinical improvement (60). In
vivo in TBM, TNF-α levels show a peak in the early phase of disease but drop soon after initiation of
treatment (61). Some researchers found an association in disease severity and CSF levels of IFN-γ and
TNF-α in both HIV-positive and HIV-negative patients (62). This was not supported in a Vietnamese
cohort, in which the only cytokine independently associated with severe disease was IL-6. HIV co-
infection was associated with attenuated levels of several immune mediators in CSF, in whom low levels
of IFN-γ did show an association with death, implying a protective role for IFN-γ. Interestingly, the
addition of dexamethasone to treatment was not associated with an attenuation of inflammatory indices but
did lead to a decreased mortality rate (61).
The brain provides a unique immunologic environment to pathogens. We know most of the
inflammatory mediators are produced locally at the site of infection. Immunologic studies usually involve
cells from peripheral blood or CSF. Compared to the infected tissue, even in pulmonary TB, low
proportions of M. tuberculosis–specific effector cells are found in the blood (63).
Central Nervous System Pathology
Unfortunately, current postmortem studies are scant (64,65) but would contribute a great deal to our
understanding of the disease. Rabbit models are thought to mimic human disease; however, immunologic
interpretation is imperfect. Murine studies are not of use in directly studying neuropathogenesis in TBM
although are widely used in understanding susceptibility and protective responses to mycobacteria (66).
Our current knowledge on pathogenesis of CNS TB is based on the hypothesis promulgated over 70 years
ago. Even though later researchers have expressed criticism (67), their view has been carried forward by
most recent experts; in short, small intracranial granulomas are formed after seeding of bacilli in the brain
during a short-lived bacteremia. These Rich foci may rupture during periods of relative
immunosuppression or other unknown stimuli, releasing mycobacteria in the subarachnoid space or
ventricular space which may give rise to the various forms of CNS TB: meningitis, tuberculoma,
tuberculous abscess, encephalitis, or spinal cord TB. Incorporating more recent pathologic data, Donald
and colleagues (68) have proposed the following classification of pathogenesis in TBM:
1. The hematogenous dissemination of bacilli from the primary complex establishes a cortical or
meningeal focus. Soon after its establishment, this proceeds to caseate and discharge its contents into
the subarachnoid space. In young children, this hematogenous dissemination is particularly likely to
take the form of miliary TB.
2. In a small minority of cases, hematogenous dissemination may establish a caseating focus in the choroid
plexus or in the walls of the ventricles from which TBM may develop.
3. Hematogenous dissemination at the time of primary infection, or later, establishes a cortical or
meningeal focus. This is initially controlled but may, at any time thereafter, undergo caseation and
discharge its contents into the subarachnoid space.
4. A caseous process extends from adjacent structures such as the vertebrae or middle ear to involve the
CNS (very rare).
As a result of this infection, a dense gelatinous fibrinocellular leptomeningeal exudate is formed.
Microscopically, this exudate contains small and large mononuclear cells, including epithelioid cells,
which also act as macrophages. The exudate typically centers around the interpeduncular fossa. When
substantial, the exudate may extend anteriorly to the suprasellar region, and it may extend through the
prepontine cistern and surround the spinal cord and cerebellum, often into the sylvian fissures. It can
envelope and compress cranial nerves and arteries. Vasculitis may develop, giving rise to ischemic
events. Hydrocephalus can develop by blockage of CSF circulation when exudates cover the choroid
plexus and the basal subarachnoid cisterns around the midbrain and pons or when tuberculoma cause
narrowing of the aqueduct and third ventricle (66,69). Exudate, vasculitis, and hydrocephalus can cause
changes in brain parenchyma. “Border-zone encephalitis” describes a tissue reaction commonly seen in
brain tissue adjacent to zones of thick adherent exudate. The brain tissue softens, showing signs of edema,
perivascular infiltration, and microglial reaction (66,70). In the following paragraphs, we will briefly
discuss other forms of CNS TB; the rest of the chapter will focus on TBM.
Tuberculoma in the Central Nervous System
CNS tuberculoma can be encountered separate from TBM, as it is estimated only 10% of patients with
tuberculoma develop meningitis (71,72). Conversely, in some radiologic studies, tuberculomas were
observed either at presentation or developed during treatment in over 60% of patients with TBM (73). In
endemic areas, tuberculoma represents the cause of up to 30% of patients presenting with intracranial
masses. Tuberculoma can be solitary or multiple, with some reporting hundreds of lesions in one patient,
dubbed “tuberculomatosis cerebri” (71). In general, tuberculomas in the context of TBM, although
depending on the location, are not associated with worse outcome and will resolve on antituberculous
treatment (74). Rarely, tuberculomas coalesce and liquefy to cause tuberculous cerebral abscess, which
may necessitate surgery (75).
Tuberculous Encephalopathy
Tuberculous encephalopathy (TBE) was first described in 1966 in Indian children who presented with
symptoms of a diffuse cerebral involvement (coma, convulsions, movement disorders) in the context of
disseminated TB but normal cerebrospinal findings (76). As there was no clear evidence of TB infection
within the brain, the authors proposed an alternative pathogenetic immune-/hypersensitivity-mediated
explanation for this syndrome, pathologically characterized by white matter, myelin loss with
commensurate axonal loss, and focal necrosis. The principal pathogenetic factor in the group of cases was
said to be an allergic cerebral edema leading to an edematous leukoencephalopathy similar to acute
disseminated encephalomyelitis (ADEM) (77). However, use of steroids for these patients had proven
ineffective. Careful review of the original publication and the literature of the following 40 years led
South African experts to reappraise this entity in 2007, concluding that the patient population joined under
the umbrella of TBE was clinically and histopathologically heterogenous. According to the authors, other
plausible factors may have caused the typical findings of TBE, including hypoxic ischemia and toxic or
drug-related complications of TB infection (78). TBE has not been reported in adults.
Tuberculosis of the Spinal Cord
Tuberculous radiculomyelitis (TBRM) has been used as a generic term to include arachnoiditis,
intramedullary tuberculoma, and spinal cord complications of TBM (79). Currently, it is thought that
TBRM may develop in alternative ways, either (1) as a primary lesion, (2) as an extension from TBM, or
(3) secondary to vertebral TB (80). Intramedullary tuberculomas are rare. The pathogenesis is parallel to
CNS TB: via bloodborne seeding of bacilli, granuloma formation follows, drainage persists into the
subarachnoid space which may lead to an inflammatory reaction in the pia-arachnoid, which may lead to
secondary meningitis (81). Clinical presentation may vary, usually presenting with symptoms of a
subacute intramedullary space-occupying lesion (82). Early recognition of this form of CNS tuberculoma
is important because early surgical intervention and decompression followed by long-term
antituberculous chemotherapy may significantly improve morbidity. Accurate diagnosis can be helped by
magnetic resonance imaging (MRI) (83).
Vascular Events
Secondary to the infection with M. tuberculosis and resultant intracerebral immunologic response, stroke
may develop. In the late nineteenth and early twentieth century, vascular involvement in TBM was
recognized and extensively studied. Still the vascular events in TBM are a pressing subject in TBM
research, because the damage caused by stroke is often irreversible and the occurrence of stroke is
associated with worse outcome (84,85).
Stroke was reported in 13% to 57% of Indian patients with TBM (85). In Vietnam, serial MRI revealed
stroke in only 9% of patients upon diagnosis, but after 60 days of treatment, 41% of patients had
developed stroke (73). This may be even more prevalent in children, with infarcts reported in 76% of
systematically scanned children in South Africa (86). Most infarcts occur in the region of the arteria
cerebri media (middle cerebral artery [MCA]), particularly in the medial lenticulostriate and
thalamoperforating vessels, causing the characteristic basal ganglia infarcts (84). It is thought that this
vascular involvement follows the distribution of the meningeal exudates, which causes local vasculitis,
particularly at the base of the brain and along the sylvian fissures. The proposed mechanisms by which the
vessels occlude resulting in ischemia are multiform. Meticulous histopathologic descriptions of the
vascular changes in TBM were published by Hektoen (87) in the late nineteenth century. He concluded
that the changes could be either explained by an endarteritis with subendothelial tubercles, proposed to be
caused by direct hematogenous invasion of bacilli in the vessel wall, or tuberculous proliferation affected
the arteries from the adventitia inward to reach the media and the intima (87). Currently, largely based on
the findings of Rich and McCordock (9), the widely accepted view is that the inflammation is spread from
outward (adventitia) in rather than reversed. Other stenosing or damaging mechanisms are thought to be
intimal proliferation, vessel wall necrosis, or vasospasms. The role of vessel thrombosis is unclear.
There is some evidence that strokes early in the course of disease are caused by vasospasms and later
strokes involve proliferative intimal disease, raising the prospect for therapeutic interventions for the
prevention of thrombotic and vasospasm-associated stroke (9,84).
The Role of Miliary Tuberculosis
Rich and McCordock (9) did not assign a role for miliary TB in the pathogenesis of TBM as the Rich foci
found in their subjects were often older than the miliary lesions, and therefore military TB was deemed to
be an incidental occurrence rather than part of the etiology. Even though this is the view carried forward
in most textbooks, some researchers claim that, particularly in children and possibly in
immunocompromised patients, the disseminated state of miliary TB increases the likelihood of the
formation of leptomeningeal granuloma (Rich foci) (68). This may well explain the frequent association
of TBM with miliary TB (Fig. 29.2). In children, the prevalence of miliary TB of the leptomeninges is
much higher than in adults. Younger children most often develop both TBM and miliary TB within 3
months of primary infection. Children with concomitant miliary TB and TBM are also significantly
younger than those with TBM only (24). The immune system of these young children and the
immunocompromised may not be robust enough to prevent an overwhelming bacteremia, exemplified by
the miliary character of disease. In these individuals, TBM may be the result of a more direct spread of
the pathogen to the meninges and subarachnoid space.
CLINICAL PRESENTATION
General Symptoms on Presentation
TBM typically presents in a subacute manner. Presenting signs, symptoms, CSF findings, and frequencies
according to the British Infection Society guidelines are shown in Table 29.2. In adults, the majority of
patients present with fever, headache, nuchal rigidity, vomiting, meningism, abnormal mental stage, and
photophobia (75,88,89). Weight loss, night sweats, lethargy, and cough have also be reported (90). The
mean duration of symptoms is typically more than 5 days. A longer duration of history is associated with
worse symptomatology on presentation.
In 1948, the British Medical Research Council first published a classification of TBM patients
according to the severity of disease (see Table 29.1). Over the years, these stage groups have been
refined and are published in different formats. In general, both adult and pediatric patients in stage I are
fully conscious and may have nonspecific symptoms; in stage II, patients will have signs of meningitis,
lethargy, or cranial nerve palsies; in stage III, TBM is accompanied by stupor, severe illness, gross
paralysis, or paresis, convulsions, and or involuntary movements (51). In clinical practice and research, it
would be more useful to have a Glasgow Coma Scale (GCS)–guided staging system. An example is
shown in Table 29.3.
Typical findings upon neurologic examination are VI cerebral nerve palsy (present in up to 40% of
patients) but also nerves III and VII are often involved (5% to 20%). Hemiparesis and paraparesis may be
present upon presentation (in 5% to 20% of patients) (75,88) but may also develop during treatment
secondary to infarction. Seizures are rarely a presenting symptom in adults, however in children are
reported in around 50% of patients (28,29).Visual disturbances, decreased vision, and diplopia may have
a variety of causes, including primary involvement of optic nerve by tuberculous lesion leading to optic
neuritis, optochiasmatic arachnoiditis (OCA), and tuberculoma in the chiasmatic region or in the optic
pathways (91). More often, visual disturbances are secondary to raised intracranial pressure or
ethambutol toxicity. A rare cause of visual loss in TBM is neuroretinitis (92). Tuberculoma can cause a
wide array of neurologic symptoms associated with space-occupying lesions depending on their location
within the CNS. Urinary retention is common which may indicate spinal cord involvement. Movement
disorders are associated with basal ganglia involvement, mostly tremor, but also chorea, ballismus, and
myoclonus have been reported (88).
The initial symptoms of TBM may be nonspecific, but within the context of prolonged symptoms, a
previous history of TB, or a chest x-ray consistent with recent or past TB infection, this history must raise
heightened suspicion with the treating physician. In many textbooks, TBM is described as chronic or
subacute meningitis; however, this terminology is unhelpful. Once a patient with TBM seeks medical care,
he or she should be treated as a medical emergency as with any other meningitis.
Children may have a more protracted and nonspecific presentation. In TB-endemic settings, it is often
the most common cause of childhood bacterial forms of meningitis (22). Prodromal symptoms include
fever, headache, anorexia, and vomiting in older children, whereas failure to thrive, poor appetite,
vomiting, and sleep disturbances are more common in younger children or infants. Cough and weakness
may also be reported (28,29).As these symptoms are nonspecific, children tend to present to the hospital
only when the clinical situation has deteriorated and they are already in the later stages of disease (29).
Similar to adults, when initial nonspecific symptoms are associated with a history of recent contact with a
case of documented TB, TBM should be suspected. A prolonged history of more than 5 days, focal
neurologic deficit, and abnormal movements have been found to be independently predictive of TBM
(27). Examination may reveal nonspecific signs of meningism, failure to thrive, and in younger children, a
bulging fontanel or increased head circumference. Funduscopy may reveal signs of papilledema or retinal
involvement. In a retrospective study of 554 South African children, 97% presented in stage II or III, with
a median duration of symptoms of 9 days. Meningeal irritation was the most frequent finding (98%).
Convulsions (47%) and mono-/para-/quadri-/hemiplegia (63%) were also frequently observed. Cranial
nerve palsies were less common (27%) than in adults, as was raised intracranial pressure (23%) (29).
The emergence of HIV has changed the epidemiology of TB and particularly the clinical outcome of
disease. HIV-infected patients are more likely to develop extrapulmonary forms of the disease. TBM is
considered an AIDS-defining condition. Research studies do not suggest that HIV greatly alters the
clinical presentation of TBM, especially in patients with higher CD4 counts; the clinical presentation may
mirror that seen in HIV-negative individuals. Patients with lower CD4 counts may have a more atypical
course of disease, with less specific and more subtle signs and wider differential diagnosis, rendering
diagnosis more challenging (36). Therefore, HIV-infected patients may present later during the course of
disease, with altered consciousness, and consequently more often in the advanced stages of disease (35).
HIV patients are more likely to have impaired cognition, generalized lymphadenopathy, and
hepatosplenomegaly (32). A retrospective study comparing clinical presentation and outcome in children
with and without HIV infection surprisingly found that HIV-uninfected children were more likely to
present with a decreased level of consciousness; this may be related to the poor immune response in
immunocompromised children. Similar to adults, HIV-infected children had a longer history of being
unwell, poorer nutritional state, more commonly had accompanying hepatosplenomegaly,
lymphadenopathy, and otorrhea (93). Despite the similarity in presentation, outcome is significantly worse
for HIV-infected adults and children with TBM.
Progression During Treatment

Paradoxical responses during antituberculous treatment are frequently reported despite appropriate
chemotherapy with susceptible bacilli. This can be encountered in all tissues but most often in the lungs,
lymph nodes, and the brain (94). In the brain, tuberculoma may develop or enlarge during treatment for
pulmonary TB, TBM, or miliary TB. Either discovered on routine brain imaging or accompanied by
worsening of symptoms, signs of a space-occupying lesion, or convulsions. This generally occurs within
1 to 4 months of starting treatment, often after initial improvement. Antituberculous therapy should be
continued; the addition of systemic corticosteroids may be considered (95). Within the context of a sound
diagnosis and microbiologic confirmation of a susceptible pathogen, paradoxical response can be
diagnosed clinically; however, incorrect diagnosis, drug resistance, and cerebral infarction may be
alternative causes of deterioration despite treatment. Early recognition of these alternative causes is
important as they warrant urgent intervention.
In TBM, vascular events are most often ischemic in nature. Vascular involvement is more frequently
seen in chronic meningitides than in treated acute bacterial forms of meningitis (96). Other infective
causes of stroke in tropical regions may include malaria, syphilis, Chagas disease, cysticercosis. Events
can go unnoticed, as they occur silently or in severely ill patients already in deep coma. The most
common signs of TBM-associated stroke are mono- or hemiplegia but also may present as lowered
consciousness, disorders of movement, seizures, cranial nerve palsies, papilledema, and decerebration
(84). Clearly, neurologic deterioration also can have its origin in a tuberculoma, cerebral edema, or
infiltrating exudate (97). Unlike hypertensive or atherothrombotic stroke, transient ischemic attacks
(TIAs) and lacunar lesions are rare in TBM (84). Patients may present with symptoms of stroke but more
often develop stroke later in the course of disease, typically during the first weeks of treatment (73,84). It
is not currently possible to predict which patients will develop stroke and it is associated with higher
mortality and morbidity. Initial imaging studies may not be sensitive enough to detect the early changes of
an ischemic event. Antithrombotic therapies such as aspirin and dipyridamole which prevent or reduce
the incidence of stroke may improve outcomes in TBM and warrant further clinical study.
DIAGNOSIS
Clinical Case Definition
Early recognition of TBM is pivotal, because prompt initiation of treatment greatly increases chances of
survival and reduces disability. However, early symptoms are nonspecific and diagnostic confirmation
has hardly improved since the early twentieth century. Ziehl-Neelsen smear for acid-fast bacilli is central
to diagnosis because it gives rapid results; however, the reported sensitivity is low. Sensitivity estimates
depend on the criteria used for gold standard and range widely from 10% to 60%. This wide variation is
likely to depend on many factors including laboratory performance, workload, technician diligence and
experience, time from taking the sample to staining in the laboratory, and volume of CSF examined.
Liquid culture of M. tuberculosis is considered the gold standard for diagnosis, but due to the slow
growing nature of mycobacteria, the time to a positive result may range from 2 to 8 weeks. This renders
the test ineffective for clinical decision making regarding treatment initiation, although a positive result
can confirm the decision to continue therapy (although a negative result should not automatically lead to
stopping) and provides an isolate for drug susceptibility evaluations. A suggestive history must raise
clinical suspicion. A clinical diagnostic algorithm based on prospective data and validated against a
second data set is available based on clinical and laboratory features (98,99). Different clinical
algorithms are published throughout the literature; those of most use are based on simple clinical and
laboratory criteria and can be used in resource-limited settings, where disease burden is highest. Table
29.4 shows an example.
In order to address the heterogeneity in clinical diagnosis among published research studies of TBM, a
consensus score-based case definition, based on expert opinion, has been published for use in the
research context, with an alternative scoring if imaging is not available. This case definition is not
intended to determine treatment decisions and may be less practical in the clinical setting. In particular, it
should not be used to exclude a diagnosis of TBM (100) (Table 29.5).
Without the context of a suggestive clinical history, TBM can mimic other chronic
meningoencephalitides. Notably, in HIV-infected patients, the chief obstacle in clinical practice is the
distinction from other chronic forms of meningitis, in particularly cryptococcal meningitis, cerebral
toxoplasmosis, cytomegalovirus encephalitis, and CNS lymphoma. Because diagnostic yield from smear
is generally low, careful exclusion of other diagnoses is imperative. As soon as suspicion is raised,
history taking and additional investigations should be directed toward the exposure to TB and ruling out
other treatable causes.
Cerebrospinal Fluid Analysis
Fundamental to diagnosis is the lumbar puncture and consequent CSF analysis. CSF pressure is raised
(>20 cm H2O) in approximately 50% of adults and 40% to 75% of children (>10 cm H2O). Typically, the
CSF is “straw” colored. The results can be equivocal. The white cell count (WCC) is generally lower
(10 to 1,000 × 106 cells/mL) than in bacterial meningitis, predominantly lymphocytic, with a low serum to
CSF glucose ratio (<50%). Lactate is usually raised, reflecting intracerebral metabolic disturbances or
ischemic processes. Raised total protein levels (>0.5 g/L) are an indication of blood–brain barrier
disruption or increased intracerebral production of immunoglobulins. In children, CSF modifications are
similar to adults; however, smear and culture are less sensitive.
In HIV-positive patients, atypical findings are encountered in a considerable proportion of patients,
which may lead to delay in diagnosis and treatment. Normal levels of lactate, glucose, protein, and WCC
are more often reported in HIV; even completely normal CSF findings can be found particularly in
patients with severe immunosuppression (CD4 count <50 cells/µL). In the context of HIV, neutrophils
often predominate in the CSF cell population (37).
Essential to the search for acid-fast bacilli is the volume of the CSF sample, the time spent on
microscopic examination, and the efficiency with which the microbiology, biochemistry, and hematology
laboratories use the precious CSF sample. Increasing the volume (to a minimum of 6 mL) and slide
examination time to a standard time (preferably 30 minutes) can improve the yield to more than 60% of
clinically diagnosed cases (101). Particularly for pediatric patients, it can be difficult to obtain large
volumes of CSF, but drawing of larger volumes should be encouraged to improve the confirmation rate,
where not contraindicated. It should be remembered that the major safety issue relates to the decision on
whether to perform a lumbar puncture; the volume of CSF then taken is of secondary consequence. Hence
having made the decision to perform a CSF, it is only ethical to then take a volume of CSF that will give a
good chance of improving the care of the patient. The CSF should be concentrated prior to examination of
the deposit, either by centrifugation or filtration (102). Direct smear examination of CSF is rarely
positive.
Chest X-Ray
The chest x-ray may reveal active or previous infection with M. tuberculosis. In children, signs of
primary infection may be noted on chest x-ray. In adults, the chest x-ray is often normal, but all typical
lesions can be found including apical scarring, calcified Ghon complex, upper lobe infiltration, and
nodular and cavitating disease. Miliary TB is frequently associated with TBM (see Fig. 29.2) found on
chest x-ray in 25% to 50% of adults and 15% to 25% of children with TBM (103,104).
Mycobacterial Culture
As for CSF smear, sensitivity of culture of M. tuberculosis from the CSF is increased by using a larger
volume of CSF, which should be concentrated prior to inoculation of the deposit wherever possible.
Previously, Lowenstein-Jensen (LJ) media and later agar media (Middlebrook 7H10, 7H11) were
recommended; however, liquid culture techniques show increased sensitivity and more rapid turnaround
times for the isolation of mycobacteria and should be used where possible. Commercial liquid culture
systems include BACTEC MGIT 960 system (Becton Dickinson Microbiology Systems, Sparks, MD) and
MB/BacT system (BioMérieux, Durham, NC) and have reduced the time to results for both isolation and
DST of mycobacteria (105). CSF cultures generally become positive between 10 and 21 days on
commercial liquid culture systems, although late positives may occur after 35 days due to the low
bacillary load (106,107).
The microscopically observed drug susceptibility (MODS) assay is a noncommercial liquid culture
technique with minimal technical requirements that can detect both mycobacteria and drug resistance
(108). In TBM, MODS culture has shown comparable sensitivity to mycobacteria growth indicator tube
(MGIT) for CSF culture, however with a median turnaround time of 6 days versus 15.5 days (106). This
study did not evaluate direct DST using MODS or MGIT. MODS is increasingly used in low-resource
countries for the diagnosis of pulmonary MDR TB; however, it is still not widely used for TBM, although
that should change. WHO has endorsed both commercial and noncommercial liquid culture systems for
TB diagnosis (109).
MDR TB is defined as M. tuberculosis with resistance to at least rifampicin and isoniazid. XDR TB is
defined as M. tuberculosis with resistance to at least isoniazid and rifampicin, any fluoroquinolone, and
at least one of three injectable second-line drugs (amikacin, capreomycin, or kanamycin). Whereas MDR
pulmonary TB can be effectively treated with second-line antituberculous drugs, evidence on effective
treatment of MDR TBM is limited to small series or single case reports and mortality is extremely high
(39). The majority of deaths from TBM occur within the first month of treatment (30,31,110). If the CSF is
culture positive for mycobacteria, molecular diagnostic tests can be used to establish resistance to
rifampicin or isoniazid (111,112). If only conventional phenotypic DST is available, the results of the
drug susceptibility test will be returned to the treating physician at the earliest after 4 to 6 weeks but more
often after at least 8 weeks of treatment. The majority of TBM patients infected with rifampicin-resistant
strains will have succumbed before the decision can be made to change to a second-line regimen; for this
reason, molecular tests for rifampicin resistance should be applied in all cases of TBM, but especially
where there is a high suspicion of MDR TBM (previous treatment history, known exposure to an MDR or
chronic TB case, HIV patient, or failure to respond to first-line therapy). Currently, there is no evidence
base to support treatment regimens for patients with MDR TBM, but the principle of TB treatment to
“never add a single drug to a failing regimen” should be applied. Experience from pulmonary TB and
pharmacokinetic data support the use of a fluoroquinolone (levofloxacin, gatifloxacin, or moxifloxacin)
(113,114). Ciprofloxacin should not be used because it is less active against M. tuberculosis; resistance
develops rapidly and may cause selection of strains resistant to more active fluoroquinolones (113).
Tuberculin Skin Testing
The Mantoux tuberculin skin test (TST) is performed by intracutaneously injecting a small dose of
purified protein derivative (PPD). After 48 to 72 hours, an induration of 15 mm or more is considered
positive in all persons (115). The value of this diagnostic test is highly dependent on the background
prevalence of TB, age of the patient, and the co-infection with HIV. Up to 10% to 15% of
immunocompetent children with culture-documented TB do not initially show TST reactivity. Sensitivity
can be decreased by host factors, such as young age, poor nutrition, immunosuppression, other viral
infections (such as measles, varicella, and influenza), recent TB infection, and disseminated TB diseases
(116). In culture-proven TBM patients in Egypt, only 19% of patients had tuberculin positivity on
admission. The yield improved when the test was repeated after 60 days, with 62% positivity (117).
Severe immunosuppression will also suppress skin test reactivity (118). False-positive TST results may
also occur in BCG-vaccinated individuals and those exposed to environmental nontuberculous
mycobacteria (116). In the United Kingdom, Heaf testing was preferred to Mantoux. It follows the same
principles as the Mantoux test, however a special “Heaf gun” with multiple small needles is used, which
is thought to be less painful in children and has an easier readout (119).
Developments in Diagnostics
Biochemical tests
Biochemical tests can detect features of the infecting organism or products of the host immune response.
Of the biochemical tests, adenosine deaminase (ADA) assays are still of interest worldwide, particularly
in low-income settings. The test is relatively cheap and easy to perform. It is an attractive candidate for
the diagnosis of TBM because it has been shown to be of value in the distinction of tuberculous pleural
effusions (120). ADA is released by T cells during cell-mediated immune response to bacilli (121). A
recent metaanalysis reviewed 10 publications on ADA for the diagnosis of TBM and concluded that the
mean values of the sensitivity and specificity of the ADA assays were respectively 79% and 91%
compared to culture as the gold standard, with an inability particularly to distinguish TBM from bacterial
meningitis (122). However, publication bias and spectrum bias in included cases may have resulted in
overestimation of diagnostic accuracy. Inclusion of inappropriate controls will result in an overestimation
of diagnostic accuracy, particularly if the test is poor at discriminating the common differential diagnoses;
raised levels may also be seen in sarcoidosis, meningeal lymphoma, subarachnoid hemorrhage, and
neurobrucellosis. Although ADA may be of use within diagnostic algorithms, the probability that a patient
has TBM with a negative result is still too high to rule out the diagnosis using ADA values. Furthermore,
in HIV-infected individuals, the test is not of use (123).
Immunoassays
Various immunoassays have been evaluated for diagnosis of TBM, with highly variable sensitivity and
specificity between studies, again commonly due to spectrum bias among controls. WHO issued the first
ever negative policy recommendation against using existing commercial serologic assays for the
diagnosis of pulmonary TB in 2011, following a systematic evaluation (124). Immunoassays may not
distinguish between acute infection and previous exposure, and cross reactivity of antibodies may further
decrease specificity. The detection of lipoarabinomannan (LAM) has been evaluated for the diagnosis of
TB and current interest is heightened since the development of a point of care lateral flow urine assay,
which has shown value in the diagnosis of pulmonary TB in HIV patients with severe immunosuppression
(CD4 <100 cells/µL) (125,126). However, this is a relatively distinct subset of patients and a CD4 assay
is first required to determine if the LAM test is applicable. LAM is a cell wall component of M.
tuberculosis, has immunoregulatory and antiinflammatory effects, and serves as a virulence factor of the
mycobacteria (127). Earlier studies on ELISA directed toward detection of IgG antibodies to LAM
antigens have reported promising sensitivity and specificity in small studies, but highly variable results
are published for different clinical populations with TB, reflecting the spectrum bias in evaluation of
serologic tests for TB. A standardized LAM antigen detection ELISA test, showing results within 2 to 3
hours (Clearview TB ELISA, Inverness Medical Innovations, Waltham, MA), has been assessed on CSF
of 150 patients in an HIV high-prevalence setting. With a disappointingly low sensitivity of 31%, but
specificity of 94%, it has the potential to be a rapid rule-in test for TBM for HIV-infected patients with
advanced immunosuppression when used in combination with a clinical prediction rule (128), but
optimized CSF smear is likely to have a higher diagnostic yield. Other immunologic tests that have been
evaluated are interferon-γ release assays (IGRA), including peripheral blood IgG ELISPOT response to
PPD, CFP-10, and ESAT-6; however, all showed poor sensitivity in patients with TBM (129,130). One of
the commercially available IGRA tests, QuantiFERON-TB Gold In-Tube test (QFT-GIT) uses enzyme-
linked immunosorbent assay (ELISA) technique to measure cell-mediated immunity in response to
proteins specific for M. tuberculosis complex. When assessed for TBM in India, the whole blood IGRA
had sensitivity of 44.4% and specificity of 62.5% for diagnosing TBM with positive predictive value
(PPV) of 72.7%. IGRA on CSF had 88% indeterminate results in TBM patients (131).
Nucleic Acid Amplification Tests

Amplification of mycobacterial DNA by polymerase chain reaction (PCR) has turned away attention from
immunologic techniques. Systematic review on commercial nucleic acid amplification tests (NAATs) for
TBM summarized the performance as having potential to rule in or confirm diagnosis (specificity 98%),
but low sensitivity (56%) precludes the use of these tests to rule out (132). NAAT should be used as an
adjunct to conventional microscopy, culture, and clinical algorithms.
The most recent advance in diagnosis is the GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA), an easy-
to-use desktop machine that simultaneously detects the presence of M. tuberculosis and rifampicin
resistance using real-time PCR, giving results within 2 hours. Risk of contamination and consequent false-
positive results is reduced by the use of sealed disposable cartridges. The rapid turnover time may lead to
an important improvement in the management of MDR TB. The test has been endorsed by the WHO in
2010 for the use in pulmonary TB (112). GeneXpert is more sensitive than smear, compared to culture. In
smear-negative, culture-positive sputum samples, detection of M. tuberculosis showed 76.9% sensitivity
and 99.0% specificity in a decentralized low-income setting. Sensitivity for rifampicin resistance was
94.4% and specificity 98.3%, regardless of HIV infection (133). These results are clearly promising and
roll out of the GeneXpert MTB/RIF test has been impressive globally
(http://who.int/tb/laboratory/mtbrifrollout/en/). The GeneXpert test has been shown to be more sensitive
than smear on extrapulmonary samples in reports combining analysis of all extrapulmonary samples with
a small number of CSF samples (134–137). In June 2013, the WHO Strategic and Technical Advisory
Group (STAG) reviewed the evidence for use of GeneXpert on extrapulmonary samples. 15 published
and 7 unpublished studies, involving 5,922 samples, were included in the review which endorsed
GeneXpert for use on extrapulmonary samples, including CSF. The report recommended “Xpert MTB/RIF
should be used in preference to conventional microscopy and culture as the initial diagnostic test in
testing cerebrospinal fluid specimens from patients presumed to have TB meningitis (strong
recommendation given the urgency of rapid diagnosis, very low quality of evidence).” Pooled sensitivity
and specificity against a clinical gold standard were estimated to be 55.6% and 98.8%, respectively
(138).
Data from 265 consecutive patients with suspected TBM presenting at Hospital for Tropical Diseases,
Ho Chi Minh City, Vietnam showed GeneXpert detected M. tuberculosis in 56.7% (n = 97/171 [95% CI,
48.9; 64.2%]) of pretreatment CSF samples of patients clinically diagnosed with TBM (specificity was
100%, n = 94/94). Detection was only marginally lower than MGIT culture at 60.8% (n = 104/171) and
similar to detection rates in CSF reported for other commercial nucleic acid amplification tests, with the
advantage that rifampicin resistance is also detected by GeneXpert (139). Three cases of rifampicin
resistance were detected and confirmed by MGIT DST. Although the numbers of MDR cases are too
small to draw robust conclusions regarding accuracy in CSF, rifampicin resistance detection by
GeneXpert MTB/RIF has been shown to be accurate in sputum samples. For MDR TBM, this test will be
of great importance, as detection of drug resistance within hours rather than days will allow research into
optimal treatment of MDR TBM. Further multicenter evaluation of this novel GeneXpert assay may lead
to significant improvement in the diagnosis and treatment of TBM in general and MDR TBM in particular.
Central Nervous System Imaging
Radiologic results can add additional evidence for diagnosis while also potentially serving as the missing
link between epidemiology, etiology, and pathophysiology, especially given the paucity of postmortem
studies. Presenting findings are pluriform and during treatment, progressive changes may appear.
Contrast-enhanced MRI is the modality of choice because it has a higher resolution over computed
tomography (CT) scanning. However, in many endemic settings, MRI is too expensive or not readily
available.
The typical initial findings are hydrocephalus, basal meningeal enhancement, and tuberculoma.
Hydrocephalus (Fig. 29.3) is the most common finding. Hydrocephalus is also seen in bacterial
meningitis, although less frequent (140). Generally, in TBM, hydrocephalus is of the communicating type
(141). Occasionally, obstructive hydrocephalus can be diagnosed by imaging, when narrowing of the
aqueduct of Sylvius is noted or when a parenchymal mass is demonstrated obstructing the flow of CSF. If
neurosurgical interventions (shunting, endoscopic third ventriculostomy) are available and contemplated,
air encephalography can be helpful in excluding patients with communicating hydrocephalus from
undergoing unnecessary procedures (142).
Basal meningeal enhancement (Fig. 29.4) in the advanced stage can, although rarely, be demonstrated
on noncontrast CT scans, when obliteration of the interpeduncular cisterns is observed. After contrast
administration, there is typically diffuse enhancement of the basal subarachnoid cisterns; occasionally,
meningeal enhancement is seen over the cerebral convexities, the sylvian fissures, and the tentorium
(143). In the early stages, CT or MRI imaging without the use of contrast may show little or no
abnormalities.
Tuberculomas (Fig. 29.5) are characteristic for TBM and can involve the parenchyma of the brain,
spinal cord, subarachnoid, and subdural or epidural space; may be multiple or solitary; and have been
reported to occur in 5% to 40% of patients presenting with TBM (74,144). The typical features on MRI
imaging depend on whether the granuloma is noncaseating, caseating with a solid center, or caseating with
a liquid center. The noncaseating tuberculoma is usually hypointense on T1-weighted images and
hyperintense on T2-weighted images and shows homogeneous enhancement after contrast administration.
The caseating tuberculoma with solid caseation looks hypointense or isointense on T1-weighted images
and isointense to hypointense on T2-weighted images, with rim enhancement on contrast administration.
Caseating granuloma with a liquid center looks hypointense on T1-weighted images and hyperintense on
T2-weighted images, with rim enhancement after contrast administration (74). On imaging, a (tubercular)
abscess may be difficult to distinguish from tubercular granulomas with a liquid center. Tuberculous
abscesses are generally more rapidly progressive, larger, have a thinner wall, and can be loculated and
irregular in shape.
During treatment, tuberculoma may develop paradoxically; however, in a prospective serial MRI study,
this phenomenon was observed in 60% of patients, suggesting that it is part of the natural course of
disease on treatment rather than being discordant (73).
Ischemic events most commonly occur during treatment rather than being a presenting sign, mostly
located in the basal ganglia (Fig. 29.6), which is in line with the severe basal infection, exudates
formation, and consequent vasculitis. In a serial MRI study, dexamethasone reduced the proportion of
patients who developed infarcts during treatment; however, the difference was not statistically significant,
possibly due to insufficient sample size (73).
Using contrast-enhanced MRI in children in Turkey, presenting findings were meningeal enhancement
(90.9%), hydrocephalus (63.6%), infarction (45.5%), tuberculomas (27.2%), cranial nerve involvement
(27.2%), and severe cortical atrophy (9.1%) (145). Retrospectively, miliary involvement of the
leptomeninges was present in a very large (88%) proportion of young South African children scanned for
TBM (146). However, rare miliary CNS involvement is also reported in some adult patients (Fig. 29.7).
This discrepancy between adults and young children may be an indication that direct hematogenous
spread to the meninges plays a larger role in the young, possibly due to immature innate and adaptive
immunity.
The same diagnostic imaging criteria apply to children with HIV infection, however cortical atrophy is
a more common finding (86) (Fig. 29.8). In adults with AIDS, radiologic findings are reported to be
similar to patients without HIV; however, the differential diagnosis will include other opportunistic
infections and primary or metastatic lymphoma of the CNS (32,37,147). Some have observed that
hydrocephalus and meningeal enhancement are a less common radiologic finding in HIV patients (36).
Infarcts, tuberculous abscess, tuberculous encephalitis, and optochiasmatic arachnoiditis on imaging have
all been associated with poor outcome.
With the advent of newer more sensitive imaging techniques, our ability to detect abnormalities will
improve. Magnetic resonance angiography (MRA) may have a role in predicting the chance of infarction
in TBM (148). 3-Tesla magnetic resonance neurography imaging may carry improved sensitivity and
ability to detect cranial nerve involvement, for example. Still, the obvious obstacles in low-resource
settings, where rapid diagnosis is needed the most, remain.
TREATMENT
The treatment of TBM may be divided into four complementary areas: specific antituberculous therapy,
adjunctive immunomodulatory therapy, anticoagulant therapy, and management of intracranial pressure. In
addition, treatment of HIV-associated TBM requires consideration of drug interactions and IRIS.
Specific Antituberculous Treatment
Treatment guidelines for TBM treatment are not uniform. In general, global guidelines recommend 9 to 12
months treatment with rifampicin, isoniazid, pyrazinamide, and streptomycin (or ethambutol) in the
intensive phase, followed by a combination of rifampicin and isoniazid in the continuation phase
(75,149–151). These treatment regimens are based on the early trials in pulmonary TB involving the
introduction of the new first-line antituberculous drugs. The drug dosages and duration of treatment
recommended for TBM are derived from pulmonary regimens and are not based on pharmacokinetic
principles. Regimens for children and adults are similar; however, for children, often higher dosages are
used (Table 29.6).
In this section, we would like to put emphasis on the statement that the CNS “should be regarded as a
unique therapeutic compartment” (152) and pharmacokinetic and pharmacodynamic data should be
considered in the construction of more effective treatment schedules. The majority of deaths from TBM
occur in the first 2 months of treatment, indicating that effective antimycobacterial killing is most critical
in the intensive phase. However, prevention of relapse and the prevention of emerging resistance are
additionally important principles of effective multidrug treatment.
The ability of the different first-line antituberculous drugs to penetrate the CSF is variable and few of
the second-line drugs are effective in reaching the brain. A summary of antimycobacterial activity and
CSF penetration of the first-line drugs used in the intensive phase is appropriate. We will also briefly
review some of the second-line agents with favorable CSF levels. Of note, little is known about the levels
of antimycobacterial drugs in the brain tissue. Drugs may need to overcome both blood–CSF barrier,
consisting of the choroid plexus and the lining epithelial cells, and the blood–brain barrier, made up of
endothelial tight junctions in capillaries and surrounding glial cells. The level of drugs in the two
compartments, CSF and brain tissue, may not be equal. A third hurdle may be the penetration and action of
drugs in the relatively anaerobic conditions within the tuberculoma.
Streptomycin and Ethambutol

The initial drug to be introduced for TBM treatment was streptomycin. This aminoglycoside must be
given intramuscularly. Streptomycin is a protein synthesis inhibitor. The minimal inhibitory concentration
(MIC) in fully susceptible clinical isolates is in the range 0.5 to 2.0 µg/mL (153). With the commonly
used dosages in adults, the early bactericidal activity (EBA; generally defined as the fall in counts per
milliliter sputum per day during the first 2 days of treatment) of streptomycin, however, is low (<0.1 log10
colony-forming unit [CFU]/mL sputum per day) (154). With a poor penetration in CSF, the contribution of
streptomycin to multidrug regimens for TBM is probably very limited. In the absence of meningeal
inflammation, penetration does not occur. However, in meningitis, the penetration can be up to 20% of
simultaneous serum levels. In the early course of disease, when blood–brain barrier disruption is
prominent, levels above the MIC may be found in CSF (3 to 16 µg/mL). However, when clinical
improvement is noted, CSF levels barely reach the MIC (0 to 1.25 to 4 µg/mL) (155). Because TBM may
reflect a general state of disseminated TB, it appears appropriate to maintain streptomycin in treatment
schedules, however at the cost of increased toxicity. For HIV patients, ethambutol should be substituted
for streptomycin because injection should be avoided when possible in HIV-infected individuals.
Ethambutol is bacteriostatic against actively growing TB bacilli by obstructing the formation of the
bacterial cell wall. Ethambutol is slightly more efficient in penetrating the CSF, with levels compared to
serum in the range of 0% to 54%. In healthy adults, despite an oral dose of 50 mg/kg which was twice the
usual therapeutic dose, and in the presence of proportionally high blood levels, ethambutol did not appear
in the CSF of healthy adults. After oral doses of 18.6 to 25 mg/kg levels, ethambutol did appear in the
CSF of patients with active meningitis (0.74 to 1.98 µg/mL) (155). Still, with an MIC of 0.5 to 2.0 µg/mL,
there may be a limited role for ethambutol in TBM treatment. Both streptomycin and ethambutol have been
shown ineffective in sterilizing sputum in pulmonary TB, so their role in TBM may be limited to
resistance prevention. It is possible that by increasing the dose of these drugs, therapeutic levels could be
achieved in the CSF, but this would come at the cost of increased toxicity.
Isoniazid
After the introduction of isoniazid, a major improvement was seen in the outcome for patients with all
grades of TBM. Isoniazid exerts its antimycobacterial activity by inhibiting the synthesis of mycolic acid
required for the mycobacterial cell wall. It is the most bactericidal TB drug and kills approximately 95%
of rapidly multiplying organisms in sputum samples within 48 hours (156). Isoniazid has the highest EBA
of the first-line TB drugs ranging from 0.4 to 0.8 log10 CFU/mL sputum per day (154). MIC in liquid
media is low: 0.02 to 0.04 µg/mL (153). A Cmax of 3 to 5 µg/mL is needed for optimal action against
sensitive M. tuberculosis and isoniazid-resistant strains with relatively low MICs (157). It has good
penetration in the CSF in both children and adults. Peak levels are reached at approximately 6 hours after
dose (155). With an oral dosage of about 9 mg/kg, isoniazid rapidly diffused into the CSF. By 4 hours,
mean CSF isoniazid concentrations measured were 3.2 µg/mL, well over the MIC and in the range of
optimal Cmax for sensitive strains (158). Isoniazid is effective in preventing resistance when used with
companion drugs. It is less efficient in eradicating slow-growing organisms. Some advocate the
administration of higher doses because resistance is increasingly abundant and higher intracerebral Cmax
may lead to killing of strains with low-level resistance, which do not carry mutations in the katG gene.
Additionally, the N-acetyltransferase-2 genotype of an individual (NAT2) influences the EBA of isoniazid
at a given dose, and faster isoniazid acetylators consistently have a lower EBA (154). Conversely, slow
acetylators may have increased susceptibility to hepatotoxicity (159).
Rifampicin
Rifampicin is a key drug in the treatment for TBM, illustrated by the high mortality in MDR TBM patients
compared to isolated isoniazid resistance. In contrast, in a review of the literature, Donald (18) found
little effect on mortality in adults after the introduction of rifampicin and pyrazinamide to the TBM
treatment schedule but a significant effect on survival in children. Still, based on the drug resistance data,
rifampicin seems to have a pivotal role in treatment; it may well be that doses in adults are not sufficient
to reach adequate levels in the CSF. An Indonesian phase 2 clinical trial, establishing the safety of high-
dose intravenous (13 mg/kg/day) rifampicin with or without (high dose) moxifloxacin, did not show
increased toxicity and moreover showed a 50% reduction in mortality for patients receiving high-dose
rifampicin (160). However promising, this trial was not powered for a clinical outcome, and the results
of a current randomized controlled trial comparing an intensified 2-month regimen of high-dose (15
mg/kg/day) oral rifampicin and levofloxacin are awaited (161).
Rifampicin inhibits bacterial RNA synthesis by inhibiting RNA polymerase. Rifampicin is highly bound
to plasma proteins, which leaves only 20% of total drug freely diffusible. This is reflected in the ability
of rifampicin to penetrate the CSF, with a CSF/plasma ratio of maximally 20% found in early TBM and
no drug detectable in CSF in the absence of meningeal inflammation (155). After an oral dosage of
approximately 11 mg/kg, serum Cmax averaging 11.5 µg/mL were obtained at 2 hours. Rifampicin
penetrated very slowly into the CSF, and concentrations only slightly in excess of its MIC against M.
tuberculosis (approximately 0.3 µg/mL) maintained throughout the period (158). In general, low serum
levels of rifampicin are reported, particularly in HIV-positive patients, in whom absorption of all TB
drugs may be impaired (162). It is suggested that rifampicin serum concentrations 2 hours post dose
between 8 and 24 µg/mL are required for optimal treatment of pulmonary TB. Serum levels below 4
µg/mL are defined as very low (163). In Indonesia, 70% of TB patients had 2-hour plasma concentrations
(Cmax) below 4 µg/mL (164). Increasing the dose of rifampicin from 10 mg/kg to 13 mg/kg led to a
disproportionate (65%) increase in plasma levels and significantly increased the proportion of patients
with rifampicin peak plasma concentrations above the reference value of 8 µg/mL (165). The EBA and
bactericidal activity of rifampicin (0.2 to 0.6 log10 CFU/mL sputum per day) may be enhanced with an
increased dose.
Pyrazinamide
The mechanism of action of pyrazinamide is not completely understood. It is known for its ability to kill
semidormant M. tuberculosis bacilli in low pH milieu that are not killed by the other TB drugs, possibly
by disrupting membrane energetics and inhibiting membrane transport function in M. tuberculosis (166).
In pulmonary TB, addition of pyrazinamide to a 6-month regimen significantly reduced relapse rate to less
than 5% (18,156). Pyrazinamide is very efficient in penetrating the CSF. Generally high levels are found
comparable to those in serum (167). The EBA in the first few days of treatment is low but at days 4 to 14
matches that of rifampicin and isoniazid and is probably also active against extracellular bacilli (18).
Because rifampicin penetration in CSF is limited and isoniazid resistance is frequent, the role of
pyrazinamide in TBM should not be underestimated.
Drug-Resistant Tuberculous Meningitis
The general principles for treating multidrug-resistant TB are as follows: (a) use at least three previously
unused drugs, one of which should be a fluoroquinolone; (b) streptomycin resistance does not confer
resistance to other aminoglycosides, therefore amikacin or kanamycin can be used; and (c) treat for at
least 18 months (168). There is no uniform guideline for treatment of drug-resistant TBM. No clinical
trials have been conducted. Our ability to diagnose drug-resistant TBM more rapidly with PCR-based
techniques will warrant an expeditious introduction of protocols for practitioners in all settings. Such
guidelines should be based on our existing pharmacokinetic and pharmacodynamic knowledge in order to
minimize toxicity and maximize efficacy. Most second-line TB drugs have limited bactericidal capacity
and do not diffuse easily to the CSF (41).
Second-Line Agents
Of the second-line drugs, fluoroquinolones are an attractive option for the treatment of TB meningitis
because of their demonstrable in vitro activity, intracellular penetration, tolerability, good bioavailability,
and ease of administration. With the exception of ciprofloxacin, the mycobactericidal activity is
comparable to that of isoniazid. The EBA of levofloxacin, gatifloxacin, and moxifloxacin in pulmonary
TB were compared to that of isoniazid by Johnson and colleagues (169). This study reported levofloxacin
to have the greatest EBA, comparable to that of isoniazid. “The EBA 0–2 of INH (0.67 log10 cfu/ml/day)
was greater than that of moxifloxacin and gatifloxacin [both 400 mg daily] (0.33 and 0.35 log10
cfu/ml/day, respectively), but not of levofloxacin 1000 mg daily (0.45 log10 cfu/ml/day)” (169). The
diffusion to the cerebral compartment is excellent. A pharmacokinetic study comparing ciprofloxacin,
levofloxacin, and gatifloxacin in patients with TBM found levofloxacin to have excellent CSF
penetration, with a ratio of area under the curve (AUC) in CSF to AUC in plasma of 75%. This compared
favorably with gatifloxacin (35%) and ciprofloxacin (14%) (170). For moxifloxacin, the penetration has
been reported to be 71% and 82% of plasma levels with doses of 800 mg and 400 mg, respectively (171).
In serum, median free AUC0–24/actual MIC90 in plasma was 180.99 for levofloxacin, 179.77 for
gatifloxacin, and 58.35 for moxifloxacin. Cmax was 15.55 µg/mL for levofloxacin, 4.51 µg/mL for
gatifloxacin, and 6.13 µg/mL for moxifloxacin (172). These pharmacokinetic data suggest that the
fluoroquinolones, levofloxacin and moxifloxacin in particular, have the potential to be highly effective
sterilizing agents in the treatment of TBM.
Of the remaining second-line drugs, only ethionamide and cycloserine have considerable ability to
diffuse to the CSF. In TBM, serum to CSF penetration ratio of 40% to 100% were reported, with peak
CSF concentrations ranging from 1.0 to 2.6 µg/mL achieved 3 hours after administration of a 250-mg dose
(155). The reported MIC was 0.25 to 0.5 µg/mL (157). Ethionamide may be a valuable drug for the
management of both susceptible and drug-resistant TBM. Ethionamide is a structural analog of isoniazid.
If isoniazid resistance is conferred by mutations in the KatG gene, these isolates may still be sensitive to
ethionamide; however, inhA mutations for isoniazid resistance confer cross-resistance to ethionamide
(173,174). Cycloserine is only moderately bactericidal and has an MIC of 25 to 75 µg/mL; however,
penetration in CSF is good (157). None of the second-line drugs have been subjected to clinical trials for
the use in TBM treatment with the exception of moxifloxacin and levofloxacin (160,161).
Of the new agents, a diarylquinoline (bedaquiline or Sirturo, previously known as TMC207) was
approved for the treatment of MDR TB by the U.S. Food and Drug Administration in December 2012. It
has a novel mode of action specifically inhibiting mycobacterial adenosine triphosphate (ATP) synthase
(175). When added to a background regimen of second-line drugs in patients with MDR pulmonary TB,
TMC207 led to more rapid sputum culture conversion and possibly prevented resistance formation in
companion drugs without adding to toxicity of the regimen (176). Its MIC against M. tuberculosis is very
low (0.06 µg/mL) (177). The EBA in the first 3 days of treatment is not optimal, but from days 4 to 7,
TMC207 induced similar reduction in CFUs to rifampicin and isoniazid over the same period (178). The
ability of this new compound to cross the blood–brain barrier has not been established yet; however, it
has favorable pharmacokinetic properties and is an attractive candidate for future studies in patients with
TBM.
In view of the severity of TBM, generally, higher toxicity of treatment may be acceptable if
accompanied by improved clinical outcomes. The most common reason for treatment interruption is
hepatotoxicity. Especially isoniazid, rifampicin, and pyrazinamide are implicated in drug-induced
hepatitis (DIH); however, when carefully monitored, gross hepatic failure can be prevented. Streptomycin
can cause oto- and nephrotoxicity, and ethambutol optic neuritis. Cardiac tachyarrhythmias are reported
for the fluoroquinolones, moxifloxacin in particular, but are very rare. Key to favorable outcome is early
initiation of effective anti-TB treatment. Clinical trials are needed to develop more effective treatment
guidelines for both drug-susceptible and resistant TBM. General management guidelines have been
published by the British Infection Society and may be helpful for clinicians to make individual treatment
decisions (Fig. 29.9) (75).
Adjunctive Treatment
Corticosteroids
Global guidelines now recommend the use of corticosteroids as an adjunct to treatment. Addition of
dexamethasone to the antibiotic regimen used in TBM has been proven to reduce mortality in TBM in both
adults and children (30,179). A Cochrane review concluded that the adjunctive use of corticosteroids
reduce the risk of death (risk ratio [RR], 0.78; 95% CI, 0.67 to 0.91; 1140 participants, 7 trials) in
patients with TBM. Data on disabling residual neurologic deficit showed that corticosteroids additionally
reduce the risk of death or disabling residual neurologic deficit (RR, 0.82; 95% CI, 0.70 to 0.97; 720
participants, 3 trials) (180). This has not been proven or refuted for HIV-positive patients. The beneficial
effect of steroids may not be homogenously distributed among different patient populations. Across the
different severity groups, the beneficial effect of dexamethasone may be more pronounced in the less
severe grades (30,48). More recently, it has been reported that the immune response can be modulated
through the leukotriene A4 hydrolase (LTA4H) gene. Indirectly, this gene regulates TNF-α levels, and
promoter polymorphisms can lead to either a hyperinflammatory state, inadequate inflammation, or an
intermediate response. Patients with TBM, who were homozygous for the LTA4H-high polymorphism
(T/T), had higher levels of TNF and high leukocytes in CSF. Among patients not receiving
glucocorticoids, mortality was highest among patients with a T/T genotype. However, these patients
showed the greatest reduction in mortality in the group treated with adjunctive dexamethasone, suggesting
that the dexamethasone may reduce excessive inflammatory response in this group. By contrast, patients
who were homozygous for the polymorphism causing low expression of LTA4H (C/C) showed increased
mortality when treated with dexamethasone, probably due to further suppression of an inadequate immune
response. The patients who were heterozygous at this locus (C/T) had the lowest mortality and the use of
dexamethasone did not appear to influence mortality in this group (181).
These results suggest that disease severity in humans can be caused either by an exaggerated or a
deficient immune response and, perhaps more importantly, that treatment with corticosteroids may only
benefit those with a certain predisposition to hyperinflammation and may be detrimental in those with
deficient immune responses. This needs prospective assessment and if proven may necessitate more
tailored use of corticosteroids according to individual genotyping or phenotyping of the immune response
in the future.
Thalidomide
Thalidomide is a drug with immunomodulatory properties through the inhibition of TNF-α (182). In
animal studies, TNF-α levels in the CSF produced during TBM were shown to correlate with the extent of
pathogenesis, although this has been difficult to replicate in humans with TBM (84). In rabbits infected
intracranially with TB, an antitubercular regimen that included thalidomide led to reduction of TNF-α
levels in CSF and prevented death (183). The same group has used a thalidomide analogue (IMiD3) for
the treatment of experimental animals infected with TBM as an adjunct to standard antituberculous
treatment. IMiD3 has comparable immunomodulatory action to thalidomide, but unlike thalidomide,
IMiD3 is not teratogenic. The additional use of IMiD3 in rabbits resulted in marked improvement in
survival, reduced CSF leukocytosis, lower levels of TNF, and attenuated inflammation of the meninges on
histologic examination. The beneficial effect on survival and severity of symptoms of IMiD3 was
markedly greater than that of thalidomide in this animal model (184).
Conversely, increases of TNF-α concentrations have been reported during thalidomide treatment,
raising more questions about the interaction between TNF-α and thalidomide. A clinical study in 15 adults
with TB, including HIV-positive and HIV-negative patients, showed a reduction in disease severity with
the use of thalidomide, which was correlated with an increase in TNF-α levels. By contrast, those
patients with poor outcome who were not designated to receive thalidomide continued to demonstrate
clinical progression of the disease and remained with low levels of TNF-α and type 1 cytokines (185).
In children with TBM, a randomized placebo controlled study of adjunctive thalidomide was stopped
early because of an increased risk of death and adverse events in the treatment arm (186). The role of
TNF-α in TB is complex and has yet to be fully elucidated. Currently, there is no role of TNF-α inhibition
in the treatment for TBM; however, the potential role for IMiD3 in the management of TBM in patients
may be a subject of future pharmacokinetic research.
Immune Reconstitution with Antiretroviral Therapy

The mortality for HIV-infected patients with TBM is alarmingly high. CD4 counts of patients with TBM
are characteristically very low (35). For these patients, the question of timing of initiation of ART is
critical. Initiation should be as early as possible to support the immune response; however, toxicity,
pharmacokinetic interactions, IRIS, and pill burden may complicate early treatment. Two recent clinical
trials on initiation of ART in HIV-associated TB showed that severely immunocompromised (CD4 <200
cells/µL) patients with (mostly pulmonary) TB may benefit from early initiation of ART with lower rates
of AIDS-defining illnesses or death, but at the cost of a higher occurrence of IRIS (187,188). In TBM,
mortality is much higher and intracranial IRIS may be detrimental (189). A randomized controlled trial in
Vietnam showed no reduction in mortality with immediate initiation of ARTs; instead, the study suggested
that it may be safer to defer the initiation of ART to 8 weeks of TBM treatment in patients with TBM, as
delayed treatment was associated with fewer adverse events (31). TBM IRIS has been reported to be a
frequent occurrence in ART-naive patients who started ART treatment 2 weeks after initiation of TBM
treatment (16/34, 47%). High CSF neutrophil counts, culture positivity, and a combination of high CSF
TNF-α and low IFN-γ concentrations on presentation was associated with development of IRIS (190).
For a more elaborate review and guideline of ART and TB drug interactions, we refer to the National
Institutes of Health (NIH) guidelines (191).
Aspirin and Dipyridamole

Stroke is associated with poor outcome in TBM. Infiltrative and proliferative vasculitis and necrotizing
vessel pathologies have been implicated in the pathogenesis. The relative contribution of thrombosis to
the development of ischemic events is unknown. Tuberculous thrombophlebitis has been described in
earlier pathologic studies (64,87). Severe pulmonary TB is characterized by impaired fibrinolysis and a
hypercoagulable state (192). In children with TBM, changes were found in procoagulation, antithrombotic
factors, fibrinolysis, platelet counts, and vascular endothelium functions, all contributing to an increased
risk of thrombosis (193). Aspirin has been subjected to clinical trials in TBM because it is antithrombotic
and possibly neuroprotective. However, a clinical trial in 146 children with TBM showed no significant
effect on either mortality or neurologic deficits with low-dose or high-dose aspirin regimens (194). One
open-label randomized study in 118 adults on the role of aspirin showed a beneficial effect on mortality
and MRI results (195). In this study, some patients selectively received corticosteroids, which may have
biased the results. Larger appropriately randomized studies are needed to establish the role of aspirin
(and dipyridamole) in the management of TBM-related ischemic events. In an intensive neurosurgical
care setting in South Africa, cerebral tissue oxygenation was monitored in two children. A decline in
oxygenation was reversed by aggressive therapy with oxygen, fluid resuscitation, inotropic support, and
blood transfusion, which possibly prevented infarction (196). More profound insights into the
pathogenesis of TBM vascular disease are necessary to guide rational therapeutic interventions.
Raised Intracranial Pressure and Hydrocephalus
Furosemide with or without acetazolamide can be used for treating communicating hydrocephalus in TBM
to decrease CSF production by the choroid plexus. Some institutions favor daily lumbar punctures with
intracranial pressure monitoring through manometry to assess the response to medical therapy. An external
ventricular drain, ventriculoperitoneal shunting, or endoscopic third ventriculostomy may be indicated for
patients not responding to conservative measures and noncommunicating hydrocephalus (197). Patients
for these procedures should be carefully selected, as the success rate depends on the correct diagnosis,
the severity of disease, and the expertise of the neurosurgical teams. Outcome is better in patients with
early intervention in the better grades (198). Some institutions use osmotic agents, such as mannitol or
hypertonic saline, however there have been no studies establishing the effectiveness in TB of the CNS.
Hyponatremia
TBM accompanied by hyponatremia is associated with a worse outcome. Mostly, it is caused by the
syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt-wasting (CSW)
syndrome. CSW is probably underdiagnosed in TBM, and the distinction between the two entities is often
difficult in endemic settings. Treatment should be directed to avoid both hypoosmolality and
hypovolemia. Fluid restriction can be detrimental and is not recommended. Generally, it is advised to
treat all hyponatremic patients cautiously with hypertonic saline with or without fludrocortisones
(197,199). Correction should be gradual in order to avoid pontine myelinolysis.
Pathogen Genetics and Virulence
M. tuberculosis strains were shown to vary in virulence in the 1960s when Mitchison et al. conducted
experimental infection of Guinea pigs with strains from South India and Britain (200,201). Many
epidemiologic in vitro and in vivo studies have since attempted to establish differences in virulence with
regard to dissemination and disease severity but no consensus has yet been established due to often
contradictory findings and the difficulty of interpretation (202,203). There is wide variation in
experimental technique in vitro or the comparative strains in both laboratory and epidemiologic studies.
Evolutionarily, TBM represents a dead end for the pathogen and therefore propensity to cause TBM is not
directly advantageous but may be a by-product of increased pulmonary virulence causing greater
transmission (204). The standard laboratory strain, H37Rv, which was the first M. tuberculosis strain
sequenced in 1997 (205), is laboratory adapted and exhibits low virulence in vitro and in animal models
in comparison with almost all clinical strains (206), therefore demonstration of increased virulence in
comparison with H37RV does not represent a “hypervirulent” strain.
Analysis of large sequence polymorphisms within the M. tuberculosis genome has defined six major
global lineages, which are largely geographically restricted within the eponymous region; Indo-Oceanic,
Euro-American, East Asian, East African-Indian, and two Mycobacterium africanum lineages. Within the
“modern” East-Asian lineage, the Beijing genotype has been defined by its characteristic spoligotype and
extensively investigated, as it has been associated with increased virulence and drug resistance in several
regions (207–212). Introduction of the Beijing genotype into some regions also resulted in rapid increases
in prevalence of this strain (212). In Vietnam, among TBM cases, it shows significant association with
HIV status, drug resistance, and multidrug resistance (213) compared with Euro-American and Indo-
Oceanic strains. HIV-negative patients infected with the Beijing-strain had shorter duration of illness
before presentation to hospital and fewer CSF leukocytes, suggesting that mycobacterial genotype may
affect disease progression and the nature of the intracerebral inflammatory response (214). Studies in
South African children have also shown an association between Beijing genotype and extrapulmonary TB
(208). A recent retrospective cohort study of TBM patients in Thailand supported the theory that the
Beijing genotype is the most pathogenic strain of M. tuberculosis and associated with TBM, whereas the
Euro-American lineage was much less commonly linked with TBM. Results showed that modern
sublineages of Beijing genotype were associated with higher CSF WCC and more severe (stage III)
disease but not with mortality rate (215). Conversely, among HIV-positive patients in Vietnam, those
infected with the modern Beijing lineage strains had lower mortality than patients infected with the
ancient Indo-Oceanic lineage (HR, 0.29; 95% CI, 0.14; 0.61) (214). This contradictory finding might be
explained by the proinflammatory properties of the modern Beijing lineages, which although detrimental
to the immunocompetent host may be conversely protective in the immunocompromised. It is known that
protective immunity in TB disease is a delicate balance of pro- and antiinflammatory cascades. However,
studies in other regions have found no association between Beijing genotype and dissemination
(216–218). Within each region, the M. tuberculosis genotypes circulating vary significantly as do the
genotyping divisions applied to analysis and therefore the pathogen populations being compared are not
identical. Wider studies synthesizing global data are required to establish definitive interpretation.
Host-Genetics
It has long been known that there is a genetic element to TB susceptibility. Of those exposed to M.
tuberculosis, approximately 10% establish an infection and, of those, 10% will develop active disease
while the remaining individuals will harbor a latent infection. Approximately 1% of active TB cases
develop into TBM. Susceptibility to the different forms of TB (latent, active, disseminated) is a complex
interplay between host genetics, pathogen genetics, and environmental factors (such as smoking,
malnutrition, comorbidities).
Protective immunity to TB depends on innate immunity and an effective TH1 response, as evidenced by
the dramatic increase in susceptibility shown by HIV-infected individuals. Many candidate genes have
been proposed to be associated with susceptibility to pulmonary TB (219–222), but fewer studies have
looked at the association between host genetics and susceptibility to severe and disseminated disease.
The toll-like (TLR) receptor pathway has been implicated in TB progression. The human TLR family has
12 members that can recognize pathogen-associated molecular patterns (PAMPs) and upon activation
initiate an innate immune response, cytokine production, and the formation of the adaptive immune
response. The TLRs known to be involved in M. tuberculosis recognition are TLR2, TLR4, TLR9, and
possibly TLR8 (223). One of the few host genetic studies to investigate susceptibility factors for TBM as
distinct from pulmonary TB showed an association between a polymorphism in the TLR2 gene (SNP
T597C) and the development of TBM and miliary TB, indicating the TLR2 pathway plays a role in the
ability to disseminate of M. tuberculosis (214). However, this polymorphism is itself synonymous, and
the causative single nucleotide polymorphism (SNP) in linkage disequilibrium has not yet been identified.
Further studies investigating the interaction between host and pathogen in TBM susceptibility have shown
that individuals with the TLR2 polymorphism are more likely to be infected with the Beijing genotype of
M. tuberculosis and that this association is strongest in those with TBM (214). Polymorphisms in the toll-
interleukin 1 receptor domain-containing adaptor protein (TIRAP) gene have also been shown to be
associated with susceptibility to TBM in Vietnam and South Africa (224,225). TIRAP is a protein further
down the TLR pathway, which mediates signals from the TLR receptors, activating macrophages and
dendritic cells.
Recently a SNP in the promoter region of the LTA4H gene has been identified to play a role in
susceptibility to mycobacteria which is discussed in more detail in the section on corticosteroid
treatment. Future research on host genetic susceptibility to TB and TBM will need to explore the potential
of genetically tailored adjunctive therapies.
CONCLUSION
CNS TB is a devastating form of TB. In resource-limited settings, it places a high burden on patients,
their families, society, and health care systems. Disease incidence is a direct reflection of the TB
epidemic and complicated by the MDR/XDR TB and HIV epidemic. The current developments in TBM
research have advanced our understanding of the disease; however, they have not led to acceptable
improvements in clinical outcomes. Early diagnosis and treatment initiation are essential to a good
outcome. The recent endorsement of the GeneXpert test for pulmonary TB may impact the management of
MDR TBM in particular, which is highly lethal, and offers the potential for improved diagnostics for
TBM. However, more robust evidence must be generated to validate the specificity for rifampicin
resistance on CSF, because withholding rifampicin from treatment regimens for sensitive strains may be
detrimental. Little is known about the optimal second-line treatment regimen for MDR TBM and this may
pose TB programs and clinicians with a problem when confronted with a rifampicin-resistant positive
result on GeneXpert, without an elaborate drug sensitivity spectrum. Both first- and second-line treatment
will need to be optimized for TBM according to the ability of antimycobacterial drugs to penetrate the
brain. Still, there is a pressing need for the development of a rapid, sensitive, point of care diagnostic that
can be used in decentralized settings. This will lead to a reduction in frequently encountered disastrous
treatment delays.
Currently, the TB drug pipeline has 10 compounds in the clinical development phase for both MDR and
drug-sensitive TB (http://www.newtbdrugs.org/pipeline.php). Because the pipeline is aimed to create
affordable, tolerable, active new antimycobacterials for pulmonary TB, CSF penetration is not
necessarily an attribute that these candidate compounds have been developed for. Assessing any new drug
that emerges from the pipeline will need to be subjected to well-designed, adequately powered clinical
trials for TBM, which are resource consuming and difficult to achieve and will require multisite
involvement. Other areas of future research for TBM treatment should include the benefit of adjunctive
drugs such as aspirin or immune-modulating drugs, which may reduce sequelae. In general, future trials
should be aimed at efficiency by using innovative trial designs, making more efficient use of existing
drugs, and by basing the trial rationale on existing pharmacokinetic/pharmacodynamic data, in particular,
the ability to penetrate the brain. Protection conferred by BCG vaccine is insufficient. The TB vaccine
pipeline has 11 vaccine candidates entered in clinical trials.
(http://www.tbvi.eu/fileadmin/user_upload/Documenten/News/TB_Vaccine_Pipeline_2011_FINAL030420
Most are preexposure vaccines aimed to prevent TB disease intended to either replace BCG
(recombinant live vaccines) or to be given after BCG prime as boosters (either protein adjuvant
formulations or recombinant viral carriers) (226). Recently, MVA85A, a booster vaccine for BCG, was
subjected to the first efficacy trial since BCG; however, it failed to prove a statistically significant effect
(227). The development of an effective vaccine has the potential to greatly influence the TB epidemic,
however requiring renewed funding incentives, appropriately structured trials, and eventually government
commitment to support vaccination strategies. It is a less popular notion, but fundamental to the control of
both the TB and HIV pandemics is the commitment of policymakers to address socioeconomic issues,
such as poverty, crowding, lack of education, failing health care infrastructure, and lack of access to
health care—factors significantly contributing to the perpetuation of these epidemics.
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CHAPTER 30 INFECTIONS DUE TO
NONTUBERCULOUS MYCOBACTERIA
JEANA L. BENWILL AND RICHARD J. WALLACE, JR.
Mycobacteria other than Mycobacterium tuberculosis have established themselves as human pathogens.
By 1960, most of the common species of nontuberculous mycobacteria (NTM) had been described,
including Mycobacterium kansasii, Mycobacterium avium, Mycobacterium intracellulare, and
Mycobacterium fortuitum (1). More than 140 species have now been recognized and characterized in the
genus Mycobacterium (2–5), more than 70 of them in the past 20 years (4,5). Much of this taxonomic
explosion relates to the use and availability of 16S ribosomal (rRNA) gene sequencing, 65 kDa heat
shock protein (hsp65), β-subunit of RNA polymerase (rpoB), and large public DNA databases (2–5).
Two general groups of NTM can be delineated on the basis of microbiologic, clinical, and
epidemiologic characteristics: the slowly growing and rapidly growing mycobacteria (RGM).
Characteristics of the species included in these groups are shown in Table 30.1 (see later discussion).
The incidence of disease due to NTM has increased substantially in the past 20 years, in part because of
better knowledge of its diseases, in part because of improved laboratory techniques, and in part because
of the pandemic of human immunodeficiency virus (HIV). The most commonly recovered species or
species complex is M. avium complex (MAC), which commonly caused disseminated disease in patients
with advanced HIV infection before the advent of effective antiretroviral therapy (ART). Among the
slowly growing mycobacteria: MAC, M. kansasii, M. genavense, M. malmoense, and M. simiae have
been identified with central nervous system (CNS) disease. In addition to the slowly growing NTM, the
RGM organisms that have been associated with CNS disease have been M. fortuitum group (primarily M.
fortuitum) and the M. abscessus complex. This chapter summarizes the epidemiology, diagnosis, and
treatment of each of the NTM reported to cause CNS disease.
GENERAL OVERVIEW
NTM are generally free-living organisms that are ubiquitous in the environment. They have been
recovered from surface water, household water and biofilms, soil, and domestic and wild animals (1–6).
Studies have demonstrated that mycobacteria easily become aerosolized from aqueous sources and that
more easily aerosolized strains also more commonly cause pulmonary infections.
During the 1950s, the ability of NTM to cause human disease became increasingly clear as a
consequence of several landmark publications. In 1959, Runyon (7) proposed a classification system that
divided human isolates of NTM into four groups on the basis of growth rates, colony morphology, and
pigmentation in the presence and absence of light. This allowed mycobacterial laboratories to more
readily identify individual species of NTM, allowing clearer characterization of distinct diseases and
syndromes associated with these organisms. In 1979, Wolinsky (1) published an exhaustive review of the
clinical and laboratory features of these organisms. This provided one of the first reference sources for
physicians to review the clinical significance of the wide variety of species grouped as NTM and the
clinical disease syndromes they produce. The number of cases of NTM disease has dramatically
increased, as has knowledge about these mycobacteria, in the more than 30 years since this publication
appeared. Subsequent major reviews that have updated newer species since the study by Wolinsky (1) in
1959 were by Wayne and Sramek (2) in 1992, Brown-Elliott and Wallace (3) in 2002, and Tortoli (4,5) in
2003 and 2006.
The frequency of disease due to the different species of NTM is unknown. By the early 1990s,
laboratories informally reported that more than 50% of evaluated mycobacterial species were NTM.
Much of this increase is related to the high incidence of disseminated MAC disease in patients with
acquired immunodeficiency syndrome (AIDS). Among 41,439 cases of AIDS reported to the Centers for
Disease Control and Prevention (CDC) from 1981 to 1987, disseminated NTM infection occurred in
5.5%, and 96% of these were due to MAC (8). As a consequence, CNS infections due to NTM have
increased in frequency.
Prior to describing NTM infections of the CNS in patients with HIV, it may be useful to briefly review
disseminated NTM infection in these patients. With the exception of rare cases that might occur by direct
extension or from trauma, infection of the CNS is likely to occur from hematogenous dissemination.
Therefore, these patients may approximate the patient population from which CNS disease arises.
Horsburgh and Selik (8) summarized the epidemiology of disseminated NTM infection in the pre-ART era
in the United States from 1981 to 1987 based on data reported to the CDC. As stated previously,
disseminated NTM infection was reported in 5.5% (2,269 cases) of patients with AIDS over this 7-year
period and 96% of these were MAC. The remaining 4% included M. kansasii (2.9%), M. gordonae
(0.6%), and M. fortuitum complex (0.3%). The number of patients with NTM disease increased in
parallel with the incidence of AIDS, and the overall proportion in the pre-ART era remained nearly
constant at 5.5%. Significant regional variations in this figure, from 3.9% to 7.8%, were noted. NTM
disease occurs primarily in patients with AIDS, generally in patients with fewer than 50 CD4+ cells/µL
(9). Patients with disseminated NTM infection had significantly shorter survival (median, 7.4 months)
than patients with AIDS without disseminated NTM infection (median, 13.3 months). Disseminated NTM
infection is diagnosed after AIDS in nearly one half (47.2%) of patients. In short, the early AIDS
epidemic has been accompanied by an epidemic of disseminated NTM disease as severely
immunocompromised patients were exposed to these ubiquitous but relatively less virulent organisms.
With the advent of ART, however, the recovery rate of MAC and other NTM in patients with AIDS has
fallen dramatically since the mid to late 1990s.
In the absence of HIV infection, on the other hand, the distribution of infections due to the different
NTM species was reported by Swiss investigators who reviewed all 513 HIV-negative patients from
whom NTM were isolated at the University of Zurich from 1983 to 1988 (9). In this study, 34 patients
were thought to have clinical disease due to these infections, 21 had pulmonary disease, 10 had soft tissue
disease, and 1 had disseminated disease. There were no instances of CNS involvement. The most
common isolates were MAC in 16 patients and M. kansasii in 9 patients. M. terrae complex, M.
fortuitum group, M. marinum, and M. malmoense were also involved.
NTM disease in children before the AIDS era was reviewed by Lincoln and Gilbert (10). In contrast to
adults, cervical lymphadenitis due to M. scrofulaceum and MAC, as well as cutaneous disease due to M.
marinum and M. ulcerans, predominated. Twelve cases of disseminated disease were reported. Six
patients were reported with definite CNS disease and one additional case was highly probable. Of these
seven patients, M. kansasii was the pathogen in three patients (one was a dual infection with M.
tuberculosis), scotochromogens were reported in two patients, and MAC in two patients. Three patients
were Asian and two patients each were from Europe and the United States. Cerebrospinal fluid (CSF)
results reported in five of seven patients were typical of mycobacterial infection, that is, lymphocytic
pleocytosis, elevated protein level, and depressed glucose levels. One definite case, however, had a
neutrophilic pleocytosis. Treatment was not detailed and four patients died. A 2-year prospective
surveillance study of children in Netherlands with NTM demonstrated that MAC was the most common
pathogen, but no disseminated or CNS disease was reported (11). Jensen et al. (12) conducted a
retrospective review of mycobacterial disease in HIV-infected children in Spain from 1997 to 2008. Of
1,307 HIV-infected children, 42 had mycobacterial disease of which 22 had NTM. Nine had disseminated
disease, but CNS involvement was not reported. Overall, a reduction of mycobacterial infection
decreased from 5.9 to 1.6 events per 1,000 HIV-infected children-year. NTM disease rates were 2.3, 3.4,
and 0.3 per 1,000 HIV-infected children-year for 1997 to 1999, 2000 to 2002, and 2003 to 2008,
respectively. The authors attribute the increase of NTM disease during the 2000 to 2003 period to
increased awareness and diagnostic consideration of NTM (12).
The review by Wolinsky (1) serves as a convenient and authoritative starting point for a discussion of
NTM infections of the CNS prior to 1979. One case each of meningitis due to M. kansasii, MAC, and M.
gordonae were described. The patient with M. kansasii was a 34-year-old woman who died of
disseminated infection. The patient with MAC was a 13-year-old boy with disseminated disease who had
MAC isolated from CSF and had granulomatous meningitis on postmortem examination. The patient with
M. gordonae infection was a hydrocephalic infant who had undergone multiple shunt procedures with
infection of the peritoneal fluid and CSF. Wolinsky (1) also mentioned one case of MAC meningitis from
his own experience. In addition, he noted two instances in which other pathogens were also present: M.
kansasii was isolated from the meninges at postmortem examination in a 2-year-old with miliary and
meningeal M. tuberculosis, and M. intracellulare was isolated from the CSF of a 46-year-old woman
with cryptococcal meningitis (a subsequent smear of the CSF for acid-fast bacilli [AFB] was positive,
but cultures were negative with the patient receiving chemotherapy). Because two pathogens were
isolated, the role of NTM in these patients’ diseases was difficult to determine.
The following sections of this chapter review the epidemiology, microbiology, and chemotherapy of the
NTM implicated in CNS disease and summarizes reported cases to date. The chapter is organized by
species of mycobacterium divided into slowly and rapidly growing species. Several case series
described more than one species. Investigators from Brooklyn, New York described 11 years of
experience at Kings County Hospital with NTM from 1980 through 1990 infections of the CNS in patients
with AIDS (13). Sixteen CSF cultures were positive for NTM. Fifteen grew MAC and one grew M.
fortuitum group. Three patients concurrently had CNS toxoplasmosis. Ten of the fifteen died during
hospitalization. Japanese workers accumulated 109 cases of NTM disease by nationwide investigation
from 1955 to 1965; 6 involved the CNS, but the NTM isolates were not speciated (14). A report from
Malaysia identified a 9-month-old admitted with meningitis and CSF from which AFB with yellow-
orange colonies were cultured from a cisternal puncture but not from a lumbar puncture (15). Wolinsky’s
view of these reports raised the important issue of acceptable criteria for the diagnosis and reporting of
CNS disease due to NTM. Given a compatible clinical situation, isolation of multiple colonies of NTM in
pure culture from repeated specimens of CNS tissue or fluid would constitute strong evidence for NTM as
a cause of the patient’s CNS disease (16). Clinical and microbiologic response to specific therapy and the
absence of other pathogens would virtually seal the diagnosis.
SLOWLY GROWING NONTUBERCULOUS MYCOBACTERIA

Mycobacterium avium Complex
Epidemiology
MAC includes ubiquitous, free-living organisms (1). MAC isolates are readily recovered from natural
reservoirs including soil and water, and organisms similar to those causing human disease have been
recovered from aerosols near natural waters. Recent environmental studies have shown that the major
reservoir for M. avium is household water and pipe biofilms but that M. intracellulare is absent and
presumably acquired from environmental exposure outside the household (17). The geographic
distribution of the organism, however, is not uniform. A survey of skin-test reactivity within the United
States to an antigen prepared from MAC was published in 1969 (18). The skin-test reagent, called PPD-B
or Battey antigen (Battey State Hospital, Rome, Georgia), was applied to approximately 275,000 naval
recruits who had lived their entire lives in a single county. Skin-test reactivity was most common among
recruits from the southeastern and Gulf Coast states. In these areas, more than 70% of individuals had
been exposed to or infected with MAC or an antigenically similar organism. MAC lung disease appears
to be relatively more prevalent in these same areas.
The incidence of MAC infections in selected groups of HIV-infected patients before the advent of
effective ART was measured by Nightingale et al. (9). They followed 1,006 patients at one institution
during a 3-year period with monthly blood cultures from the date of AIDS diagnosis and determined the
incidence of MAC bacteremia to be 21% at 1 year and 43% at 2 years (9). The incidence of MAC
bacteremia was inversely related to CD4+ lymphocyte counts, occurring in only 3% of patients with CD4+
lymphocytes of 100 to 199 cells/µL increasing progressively to 39% for patients with fewer than 10
CD4+ lymphocytes/µL.
Pathogenesis
MAC is likely to disseminate to the CNS hematogenously from a respiratory or gastrointestinal source. In
rare cases, CNS disease may occur following trauma, direct extension from an adjacent focus of infection
such as the paranasal or mastoid sinuses and with implantable foreign material (19–22).
Early experience with MAC disease in HIV-infected patients indicated that heavy bacteremia,
widespread disease, and a high tissue burden of organisms were typical. Subsequent study suggests that
these early observations focused on patients with relatively far advanced disease. Torriani et al. (23)
studied 44 patients with MAC bacteremia who eventually had complete autopsies over 5 years in
California. No tissue involvement could be identified in 30% of patients, whereas 70% of patients had
one to nine different tissue sites involved (median of four). CNS involvement was seen in one patient who
had both cerebral and spinal cord infection with MAC. The likelihood of detectable tissue involvement
increased directly in proportion to the length of survival after the first positive blood culture: 43% in
patients dying within 2 months, 72% among patients dying in 2 to 10 months, and 90% among patients
dying after 10 months. This suggested that mycobacteremia preceded disseminated MAC disease. These
workers hypothesized that mycobacteria infect a mucosal surface (gut or lung), multiply locally, and
eventually enter the bloodstream and disseminate, seeding other organs and tissues. CNS involvement is
likely to be a natural consequence of this pathogenic sequence.
Some understanding of the pathogenesis of CNS infection by MAC in immunocompromised patients is
provided by a murine model reported by Wu et al. (24). Following intravenous administration of M.
avium, numerous mycobacteria were present in macrophages within granulomatous lesions in the brain by
6 months. Interestingly, none of the mice exhibited clinical signs of meningitis or encephalitis, a finding
similar to many HIV-infected patients with CNS involvement with M. avium.
Mycobacterium avium Complex Infection of the Central Nervous System in HIV-Infected Patients
CNS disease due to MAC in HIV-infected patients has been documented through case reports, case series,
and reviews of medical records associated with laboratory isolates of MAC (Table 30.2). Interestingly,
of the five patients in the initial description of AIDS from Los Angeles (25), all five eventually developed
disseminated MAC disease and two of the five had CNS disease due to MAC (26).
Hawkins et al. (27) reported the experience of the Memorial Sloan-Kettering Cancer Center with
disseminated MAC infection in patients with AIDS from 1981 to 1984. Of 366 patients with AIDS, 67
(18.3%) were diagnosed with disseminated MAC infection. CNS involvement was not identified before
death in any of these patients. Autopsies were performed in 45 of these patients, and 12 (39%) of 31
whose brain tissue was cultured had positive cultures for MAC from brain tissue. In another report from
the same institution focusing on the neuropathology of AIDS, Snider et al. (28) described 50 patients (of
160 patients with AIDS from 1980 to 1983) who developed neurologic dysfunction. Twenty patients had
complete autopsies. MAC was cultured from the brains of two patients with disseminated MAC disease,
and AFB were seen microscopically in the brain tissue in one of these. AFB were seen in brain tissue of a
third patient with disseminated MAC disease, but cultures were negative. These patients had impaired
cognition, psychomotor retardation, fevers, sweats, anorexia, malaise, and gastrointestinal complaints.
CSF showed a mild pleocytosis (7 to 36 white blood cells [WBCs]/µL, 90% polymorphonuclear [PMN]
in one patient, and 70% lymphocytes in a second) but normal protein and glucose concentrations.
Pathologically, two had gray and white matter changes of subacute encephalitis with nodular collections
of microglial cells, without inflammatory changes and reactive astrocytosis and small foci of
demyelination in the white matter.
Levy and Bredesen (29) reviewed the neurologic manifestations of 1,286 patients with AIDS in San
Francisco, of whom 474 had diseases affecting the CNS. Included were four patients with MAC infection
of the CNS. Computed tomographic (CT) scan of the head revealed single hypodense lesions in two
cases, a single contrast-enhancing lesion in one, and no abnormalities in one. Biopsy of the contrast-
enhancing lesion revealed toxoplasmosis and lymphoma, in addition to MAC infection. In the CSF, there
was a mild pleocytosis (12 to 15 WBCs/µL) and mild elevations of protein but normal glucose values.
CSF culture grew MAC in two patients. Brain biopsy yielded MAC in one patient, and postmortem
examination identified MAC in the CNS in the fourth patient. In reviewing the published literature to that
point, the authors identified 14 cases of CNS infection with MAC. Most patients had disseminated MAC
infection before presenting with diffuse encephalitis. Meningitis, cranial neuropathy, and peripheral
neuropathy were also reported in association with MAC infection of the CNS. Survival was uniformly
poor.
In these severely immunocompromised patients, more than one opportunistic pathogen may be isolated
from the CNS especially in the era of more sensitive tests like polymerase chain reaction (PCR) assays.
Two AIDS patients were reported by Sharma et al. (32) in which one patient had altered sensorium,
fever, and meningismus who in the CSF had 20 WBCs/µL (100% lymphocytes) and mild elevation of
protein with normal glucose. CSF culture and multiplex PCR grew M. avium and M. tuberculosis. The
second patient had prior pulmonary tuberculosis (TB) and had severe headache. CSF contained 110
WBCs/µL (70% lymphocytes), 600 mg/dL protein, and glucose 63 mg/dL. Cultures of CSF were negative
for M. avium and M. tuberculosis, but multiplex PCR was positive for both species. In addition, CSF
cryptococcal antigen was positive.
At Kings County Hospital in New York, Jacob et al. (13) reviewed all positive CSF cultures for NTM
over 11 years, from 1980 to 1990. Of the 16 patients with positive cultures, 14 occurred from 1987 to
1990, 15 were MAC, and 1 was M. fortuitum group (see later discussion). Twelve patients had a
previous diagnosis of AIDS and the remaining four had at least one major risk factor for HIV infection.
All 15 patients with MAC disease had widespread dissemination, and in 3 patients, autopsies
demonstrated extensive MAC disease of CNS, bone marrow, liver, gastrointestinal tract, and lymph
nodes, but no other CNS disease.
The number of additional cases of CNS disease due to MAC over the years has declined dramatically
with better ART and the decline in cases of disseminated MAC (33–46). However, MAC involving the
CNS has been increasingly reported with immune reconstitution (41,42,44,47). Lee et al. (47) reported an
interesting case of diffuse nodules of the brain and spinal cord (Fig. 30.1) of a patient with AIDS whose
treatment for disseminated MAC had been discontinued after immune reconstitution. MAC was isolated
from blood and CSF cultures and responded well with reinitiation of MAC drug therapy. Most cases in
the literature describe one to three brain lesions, but Verma and Dhamija (45) reported a case of
disseminated M. avium-intracellulare infection in an AIDS patient with multiple brain lesions (Fig.
30.2).
Mycobacterium avium Complex Infection of the Central Nervous System Not Associated with HIV
Infection
MAC infection of the CNS has also been reported in the absence of HIV infection, both in patients with
another immunocompromising process and in patients without identifiable immunologic deficits (Table
30.3). The frequency with which this occurs is difficult to determine because it is relatively rare,
generally not reported, and no surveillance system for NTM infection exists. At Mt. Sinai Hospital in
New York, mycobacteria were recovered from CSF specimens from 21 patients between 1970 and 1983
(16). Three isolates were NTM and 19 were M. tuberculosis. Two patients had high colony counts of
MAC recovered on both inoculated slants. The third had a single colony of M. gordonae, probably a
contaminant, isolated from otherwise normal CSF. The first patient was previously healthy and presented
with meningitis clinically. Her CSF had 471 WBCs/µL (84% lymphocytes), 234 mg/dL of protein, and 41
mg/dL of glucose. Both MAC and M. tuberculosis were isolated from the CSF. The second patient had
chronic myelogenous leukemia (CML) in blast crisis and MAC was isolated in pure culture with high
colony counts on both slants.
These cases raise the critical issues of interpreting positive CSF cultures of NTM and reasonable
criteria to diagnose NTM infection of the CNS. These authors suggest that to ascribe CNS disease to
NTM, multiple colonies of the NTM should be demonstrated on repeated cultures of CSF in the absence
of other pathogens. None of these three patients met these criteria, but the high colony counts and pure
culture of MAC from the single CSF specimen of the second patient make contamination unlikely.
However, these criteria may focus too narrowly on CSF alone as a specimen source. For example,
isolation of MAC from a biopsy of brain, meninges, aspirate of a brain abscess, or from a postmortem
specimen in an appropriate clinical setting would be strong microbiologic evidence of MAC disease. In
addition, these criteria do not allow for the possibility of dual infection with NTM and another pathogen.
A case report illustrates these points (48). A 48-year-old woman presented with fever, a shift in her
leukocyte differential toward immature forms, and a posterior fossa mass lesion. A ventriculoatrial shunt
was placed and CSF from this procedure contained 32 mg/dL of glucose, 38 mg/dL of protein, and 83
WBCs/µL (all mononuclear). Two days later, CSF obtained by lumbar puncture (opening pressure 300
mm) had 14 mg/dL of glucose, 107 mg/dL of protein, and 44 WBCs/µL (75% mononuclear). India ink and
culture demonstrated Cryptococcus neoformans. The patient was treated with amphotericin B and 5-
fluorocytosine and gradually improved. After 6 weeks, CSF from the original lumbar puncture grew M.
intracellulare. Lumbar puncture was repeated and several AFB were seen on direct smear, but no further
cultures grew the organism. Isoniazid and rifampin were added to her therapeutic regimen and she
eventually recovered. She was free of relapse at a 3-year follow-up but had significant neurologic
sequelae. The role of M. intracellulare in producing disease in this patient was difficult to determine, but
based on careful evaluation of the circumstances, the authors concluded that the organism was unlikely to
be a contaminant.
Another case of MAC infection of the CNS in a previously healthy person was reported by Uldry et al.
(49). A 31-year-old woman presented with a 2-year history of progressive headaches that suddenly
became worse associated with lethargy, confusion, vomiting, and a grand mal seizure. On examination, the
patient had depressed consciousness, a stiff neck, decorticate posturing, and bilateral flexor-plantar
reflexes. CT of the head showed hydrocephalus due to compression of the fourth ventricle and meningeal
enhancement with contrast. A ventriculoatrial shunt was placed and the CSF contained 453 WBCs/µL
(80% lymphocytes). The patient was treated with isoniazid, rifampin, and pyrazinamide for TB and
steroids for sarcoidosis, but all cultures were negative. Immunologic evaluation was negative. The patient
improved clinically, and repeated immunologic parameters, HIV serology, and chest radiography
remained normal. Over the subsequent 2 years, however, the patient fluctuated clinically, the CSF profile
remained abnormal, and cultures were repeatedly negative. After 2 years, headache recurred and a left
hemiparesis developed. Repeated CT scans showed a right temporal mass with surrounding edema.
Craniotomy revealed a hemorrhagic necrotic mass, which on microscopic examination had granulomas,
multinucleated giant cells, and few AFB. The tissue grew MAC. This case is noteworthy because it
illustrates the difficulty of diagnosing and treating MAC infection of the CNS. However, an alternative
explanation is possible, based on the long duration of disease before the diagnosis of MAC. The patient
may have had an undiagnosed cause for her CNS disease initially and then developed a MAC cerebral
abscess as a consequence of chronic steroid therapy.
Additional cases of CNS infection due to MAC have been reported in the context of disseminated MAC
disease by workers at National Jewish Hospital (Denver, Colorado)—in a review of 13 cases of
disseminated MAC infection in HIV-negative patients from 1940 through 1984 (50). The criteria for
disseminated disease by which they selected cases required isolation of MAC from at least one
nonpulmonary site and microbiologic or histopathologic evidence of granulomatous disease at a second
anatomically distinct site. By this case definition, one patient with meningeal involvement was identified.
No details were provided. It is now presumed that all these patients had a genetic abnormality that
predisposed them to NTM disease.
One case of disseminated MAC infection with CNS involvement was reported by Japanese workers in
a patient with pulmonary alveolar proteinosis and CML (51). A 47-year-old woman with CML who had
been treated with busulfan for 2 years developed a recurrent cough and had an abnormal chest radiogram.
AFB smears of expectorated sputum were positive. Transbronchial lung biopsy revealed pulmonary
alveolar proteinosis. Cultures of sputum, bone marrow, and CSF grew MAC.
Four interesting cases of brain abscess mimicking spindle cell tumors have been described. Di Patre et
al. (52) reported a 50-year-old patient with systemic lupus erythematosus who presented with a dural-
based meningioma-like mass in the right frontal lobe. The mass resembled a meningioma with fascicular
arrangement of spindle cells without caseation or giant cells but by AFB stains consisted of large numbers
of AFB in histiocytes (52). A very similar case was reported by Morrison et al. (53) of a 38-year-old
man with sarcoidosis who also presented with a spindle cell pseudotumor. It had minimal necrosis but
was loaded with AFB. Arkun et al. (54) reported a 52-year-old with history of lung carcinoma, left upper
lobectomy, and radiotherapy with complex, multiloculated, ring-enchancing cystic lesion of the left
tentorium with compression of the fourth ventricule resulting in hydrocephalus. The tissue consisted of
spindle cells arranged in bands, fascicles, and ill-defined nodules with a single giant cell. Ziehl-Neelsen
and Fite staining was positive, and MAC was identified by DNA probe (54). Sadek et al. (55) described
a case with underlying sarcoidosis with headache and word-finding difficulties with a left frontal ring-
enchancing lesion. Tissue revealed multiple foci of spindle cell pseudotumor formation with large number
of AFB. Similar “pseudotumors” have been described with M. tuberculosis in immunosuppressed
patients, but these are some of the first to be described due to NTM.
Gyure et al. (56) presented the case of a patient with underlying Hodgkin disease who presented with
signs of meningoencephalitis that included seizures, confusion, nuchal rigidity, and extensor-plantar
responses. The patient died and at autopsy was found to have focal aggregates of lymphocytes,
macrophages, and AFB located predominantly in a perivascular location. Cultures of CSF and brain were
positive for MAC. Okada and Yoshioka (57) reported a case of acute disseminated encephalomyelitis
associated with meningitis in a 73-year-old female who had fever, meningism, disorientation, left eye
eversion, muscle weakness, and ataxic gait. Magnetic resonance imaging (MRI) showed multifocal and
asymmetric increased T2 signals of the white and cortical gray–white matter junction of cerebral
hemispheres, cerebellum, and brainstem. CSF contained WBCs of 1,295/µL (60% PMNs) and protein of
60 mg/dL with normal glucose. M. intracellulare was isolated from CSF by PCR. The patient was treated
with rifampicin, streptomycin, clarithromycin, and steroids with resolution of symptoms.
Immune defects involving interleukins (IL) 10 and 12 and tumor necrosis factor-α (TNF-α) and
interferon-γ (IFN-γ) are risk factors for pulmonary and disseminated NTM. Browne et al. (58) reported
adult-onset immunodeficiency in Thai and Taiwanese patients associated with autoantibodies to IFN-γ.
One hundred five patients had NTM isolated, with 52 having disseminated disease, but no details of CNS
involvement were reported. Two cases of immunodeficiency with CNS NTM involvement have been
reported. Dickerman et al. (59) reported a case of a 38-year-old male with sarcoidosis who underwent
MRI due to possible seizure activity which demonstrated right frontal, left parietal, and right cerebellar
lesions. M. avium was cultured from resected frontal and parietal lesions. Despite therapy, the cerebellar
lesion increased in size and total resection of the cerebellar mass was performed. Histopathology showed
encapsulated abscess with mixture of plasma cells, lymphocytes, and macrophages with AFB. The patient
was found to have low concentrations of IFN-γ and TNF-α. The case described by Sadek et al. (55) as
previously discussed on further analysis showed TNF-α and IL-12 defect in response to MAC antigens
but high levels of IFN-γ. These cases demonstrate the complex and fascinating IL, TNF, and IFN immune
response in NTM disease.
Laboratory
MAC is readily identified in the laboratory by acid-fast smear and culture using techniques for CSF and
tissue standardized for TB. The organisms grow well in broth medium and on Middlebrook 7H10 agar,
typically producing small, flat transparent smooth colonies on agar that often have a pale yellow color.
Their colony morphology readily distinguishes them from M. tuberculosis. Commercial nucleic acid
probes (AccuProbe, Gen-Probe, Inc.) are available that identify MAC isolates with greater than 99%
accuracy 1 day after the colonies have grown, a technique used in most laboratories. M. avium and M.
intracellulare are separate species, but their separation has no clinical value for the individual patient
with lung disease and, hence, is generally not done. Specific DNA probes that recognize only M. avium or
M. intracellulare are commercially available, however, MAC is also readily identified by high-
performance liquid chromatography (HPLC) by analysis of mycolic acid patterns, a technique used by
many large state laboratories and the CDC.
Antimicrobial susceptibility testing of NTM based on the American Thoracic Society (ATS) and the
2011 Clinical and Laboratory Standards Institute (CLSI) guidelines currently recommend reporting
primary susceptibility to only clarithromycin with secondary testing of linezolid and moxifloxacin
(60,61). It recognized that the only drug for MAC for which susceptibility testing has been shown to be
predictive of clinical outcome was clarithromycin. Studies have shown that untreated strains of MAC
were all clarithromycin susceptible, with minimum inhibitory concentrations (MICs) of less than 8 µg/mL,
whereas strains that relapsed or failed therapy had one of two mutations in the 23S rRNA gene, with
MICs generally more than 32 µg/mL. Susceptibility to other drugs such as ethambutol, rifampin, rifabutin,
streptomycin, and amikacin provided no information about clinical responses to therapy. However,
recently, Brown-Elliott et al. (62) proposed amikacin MIC breakpoints reporting 96.2% of clinical
isolates had MICs of less than 32 µg/mL and prolonged exposure correlated with development of 16S
rRNA mutation with MICs more than 64 µg/mL.
Treatment
Therapy of disease due to MAC, like susceptibility testing, is more difficult and more controversial than
that for M. tuberculosis. There have been few prospective controlled treatment trials (63–67). Treatment
of CNS disease must be extrapolated from cumulative experience and data on treatment of MAC lung
disease in HIV-negative patients and disseminated disease in patients with AIDS. Recommendations for
therapy generally follow ATS guidelines last updated in 2007 (60). The regimen recommended by the
ATS for the treatment of MAC lung disease is a three-drug regimen. The daily regimen consists of
clarithromycin (500 mg twice daily) or azithromycin (250 mg daily), rifampin (600 mg), and ethambutol
(15 mg/kg daily). The same three drugs can also be given intermittently. The doses then are clarithromycin
at 1,000 mg or azithromycin 500 mg, ethambutol at 25 mg/kg, and rifampin at 600 mg given three times
weekly (Monday, Wednesday, and Friday). Rifabutin at 150 mg can be substituted for rifampin in the daily
regimen, and at 300 mg in the three-times-weekly regimen for severe disease. Aminoglycoside therapy
with either streptomycin or amikacin is usually reserved for cavitary, extensive disease or macrolide-
resistant cases. Patients requiring long-term parenteral therapy should receive a dose of 8 to 10 mg/kg
two to three times per week.
These macrolide-based regimens appear to have good activity in the therapy of disseminated MAC
disease in patients with AIDS (68–71) and in MAC lung disease in HIV-negative patients (60,63–65).
Their usefulness and role in the therapy of MAC disease of the CNS have not been studied, but they offer
exciting potential for therapy of a very difficult disease. Treatment of MAC lung disease is continued until
cultures remain consistently negative for at least 12 months.
For the treatment of MAC in AIDS, a joint panel between the CDC, the National Institutes of Health,
and the HIV Medicine Association of the Infectious Diseases Society of America published
recommendations (72). The basic principles for therapy included the necessity of regimens containing at
least two drugs, one of which should be either clarithromycin or azithromycin. Most commonly,
ethambutol and either rifampin or rifabutin would be the second and third drugs. Clofazimine was once
considered among the possible agents to treat these infections. However, studies now show increased
mortality when this drug is used in this setting, so it should not be used for treatment of disseminated
MAC. Treatment should be continued for at least 12 months and discontinuing treatment is based on the
absence of ongoing MAC disease and appropriate and sustained immune response due to ART.
Treatment of CNS infection is complicated by the lack of therapeutic data and by the preference for
parenteral therapy in critically ill patients with altered mental status. Clarithromycin, rifampin, and
ethambutol penetrate relatively well into the CNS. With inflamed meninges, the aminoglycosides and the
newer quinolones penetrate into the CNS to a limited extent. Intrathecal therapy with aminoglycosides has
been well described in other conditions, especially meningitis due to gram-negative bacteria. At present,
the standard agents for treatment of pulmonary or disseminated MAC disease would appear to be the best
available agents for MAC CNS disease.
Mycobacterium kansasii
The major reservoir for M. kansasii is likely commercial or household water, and clinical disease
predominates along the southeastern and southern coastal states and the central plains states. Unlike other
NTM, M. kansasii has never been found in soil or natural water supplies but has been recovered
consistently from tap water in cities where M. kansasii infection is endemic. Previous studies in Texas
show that M. kansasii disease is concentrated in urban areas, supporting a possible association between
clinical disease and potable water supplies. M. kansasii infection causes pulmonary nodular disease in
patients with bronchiectasis, fibrocavitary pulmonary disease resembling TB, and, rarely, disseminated
disease in immunocompromised hosts including patients with AIDS (1,8). The most common
extrapulmonary sites are lymph nodes, bone marrow, bone, joints, and skin. Only 10 cases of CNS
disease have been described, 7 of whom occurred in patients with AIDS.
Mycobacterium kansasii Infections of the Central Nervous System

The 10 cases of CNS disease due to M. kansasii that have been reported are listed in Table 30.4. The
first description of M. kansasii disease in the CNS was reported by Wood et al. (73) in 1956 in the
context of disseminated M. kansasii infection and was just discussed. In the second report of M. kansasii
disease of the CNS in the literature (1966), both M. kansasii and M. tuberculosis were isolated from a 2-
year-old girl with meningitis (74). The patient presented with signs of meningitis and her father was
subsequently discovered to have active pulmonary TB. Lumbar puncture on two occasions had
pleocytosis (200 to 313 WBCs/µL, with a lymphocytic predominance), elevated protein level (59
mg/dL), and depressed glucose levels (22 to 27 mg/dL). The second specimen had one AFB on direct
microscopy and grew M. tuberculosis. Despite treatment with isoniazid and streptomycin, the patient
died. At autopsy, the CSF grew M. tuberculosis, but the leptomeninges grew M. kansasii in pure culture.
This highly unusual report, the first of its kind, raises the possibility of mixed infection by M. tuberculosis
and M. kansasii.
In patients with advanced HIV infection, M. kansasii often produces disseminated infection. Among
patients with AIDS reported to the CDC from 1981 to 1987, disseminated M. kansasii was reported in
0.44% of patients from areas endemic for M. kansasii and in 0.08% in patients from nonendemic areas
(8). Several retrospective studies have examined disseminated M. kansasii infection in HIV-infected
patients (75–80). In two of these reports, M. kansasii was isolated from CSF in one patient each, but few
clinical details were provided (79,80).
A report from New York reported 121 patients with AIDS of whom one had M. kansasii isolated from
the CSF (79). Symptoms included fever, weight loss, hypoadrenalism, and hematemesis. Lumbar puncture
was performed before treatment and three times over the next month because of neurologic deterioration.
All CSF specimens had normal cell counts, protein values, and glucose values, and negative cultures until
the fourth specimen grew M. kansasii several weeks after the patients’ death. Smith et al. (80) reported a
retrospective review of the pathologic features of M. kansasii in patients with AIDS during 1990 to 2001.
Twelve patients were identified with only one patient having CNS involvement. Little details were
provided, but brain biopsy revealed granulomatous inflammation with AFB and the patient recovered on
therapy.
The sixth case of M. kansasii CNS disease was reported by Shafer and Sierra (81) in 1992. They
summarized the experience with NTM (excluding MAC and M. gordonae) over a 10-year period (1981 to
1990) at Kings County Hospital in Brooklyn, New York. Seven patients had M. kansasii. Six of the seven
M. kansasii isolates were from respiratory specimens. The seventh was isolated from the CSF of a 22-
year-old HIV-infected Haitian woman who had a brain lesion visualized by contrast-enhanced CT scan
but no other details of this case were provided.
In 1992, Gordon and Blumberg (82) reported a 40-year-old woman with a 5-day history of right-sided
headaches and left-sided weakness. Physical examination disclosed fever, oral thrush, right Horner
syndrome, and gait ataxia. CD4+ lymphocyte count was 118 cells/µL. CT scan of the head revealed two
ring-enhancing lesions in the right frontal lobe and thalamus. Fine-needle aspiration of the right frontal
lobe mass revealed focal necrosis and perivascular inflammation, but no organisms were visible
microscopically. Cultures grew only M. kansasii. The patient survived 20 weeks after the initiation of
treatment.
A mass lesion with associated meningitis due to M. kansasii infection was reported from Florida in
1993 (83). A 42-year-old man with AIDS presented with 2 weeks of headaches, 1 week of confusion and
fever, and 1 day of loss of balance. CT of the head revealed a 4-cm mass in the right occipitoparietal
region, which enhanced with intravenous contrast. CSF contained no cells, no organisms microscopically,
and normal glucose level, but protein level was 690 mg/dL. Aspiration of the intracranial mass yielded
pus, which was smear positive for AFB. Blood, sputum, and CSF cultures grew M. kansasii and PCR of
the abscess aspirate was positive for M. kansasii. Treatment with isoniazid, rifampin, and ethambutol led
to resolution of symptoms and negative blood cultures within 1 month and clearing of the lesion on CT by
3 months.
Thus, disseminated M. kansasii disease occurs in a small but consistent fraction of patients with AIDS,
and CNS involvement occurs rarely. The majority of published CNS infections with M. kansasii have
occurred in HIV patients. CNS disease may be a manifestation of hematogenous spread of this
microorganism.
Laboratory
M. kansasii is seen on smear and recovered in culture by techniques designed for M. tuberculosis. It
grows readily in broth, as well as on Middlebrook 7H10 agar and Lowenstein-Jensen agar. The organism
typically produces rough large colonies that turn bright yellow with exposure to light (photochromogen).
A species-specific DNA probe for M. kansasii has been described and is commercially available
(AccuProbe, Gen-Probe, Inc.). The organism is readily identified by biochemical tests as well as by
HPLC. On acid-fast smears, M. kansasii typically appears as a large, long bacillus that has unusual
beading when stained with Ziehl-Neelsen or Kinyoun stains. This often allows an initial suspicion that
one is dealing with this organism, as opposed to M. tuberculosis.
Current 2011 CLSI recommendations for susceptibility testing of M. kansasii are for rifampin and
clarithromycin only given the concentration problems with isoniazid and to do additional testing for other
drugs such as amikacin, ethambutol, ciprofloxacin, moxifloxacin, linezolid, rifabutin, and sulfonamides
only if the isolate is rifampin resistant (61).
Treatment
Treatment of M. kansasii disease of the CNS is extrapolated from the treatment of M. kansasii lung
disease in HIV-negative patients and from the case reports summarized herein. Treatment of M. kansasii
was dramatically improved by the additions of rifampin and ethambutol to the pharmacopeia, as the
success rate for regimens containing these two drugs approach 100% (84,85). The current 2007 ATS
recommendation for treatment of pulmonary disease due to M. kansasii includes isoniazid (300 mg per
day), ethambutol (15 mg/kg per day), and rifampin (600 mg per day) for a duration that includes 12
months of negative cultures (60).
However, the British Thoracic Society reported 155 patients who were treated with ethambutol and
rifampicin (86). Sputum conversion was reported in 99.4% of patients. In addition, Griffith et al. (87)
reported 15 patients treated with standard MAC therapy three times weekly. The sputum conversion and
long-term success rates were excellent with no treatment failures or relapses, but the study was too small
to change the current ATS recommendations. Thus, clarithromycin in combination with rifampin and
ethambutol is believed to be the best regimen based on excellent in vitro activity, minimal toxicity,
clinical performance against other NTM, and anecdotal experience (78,88,89). For patients with HIV
disease on ART regimens for which rifampicins are contraindicated, a macrolide may substitute for the
rifampicin if the ART regimen cannot be adjusted (63). Tompkins and Witzig (90) retrospectively
reviewed M. kansasii infection in 137 HIV patients grouped pre-ART era and ART era. Clarithromycin-
treated patients survived a median of 8 months (2 vs. 10 months) longer compared to those treated without
clarithromycin.
In place of isoniazid, which has marginal activity, sulfamethoxazole-containing regimens have been
used successfully in the treatment of rifampin-resistant disease, but these studies antedated the availability
of clarithromycin (91,92). In a study of 40 patients, Ahn et al. (84) demonstrated that the addition of
streptomycin at 1 g twice weekly for the first 3 months to a 12-month regimen of the recommended three-
drug daily combination resulted in a long-term success rate of 97%.
Treatment for CNS disease should be based on optimal regimens for this infection at other body sites
where sufficient numbers of cases provide a more solid understanding of the chemotherapy of this
disease, combined with pharmacologic principles of the treatment of CNS infections. One additional drug
that offers potential for treatment of CNS disease due to M. kansasii is linezolid (Zyvox). All isolates of
M. kansasii have MICs of less than 4 µg/mL (peak serum levels are 15 to 20 µg/mL) (93) and the drug
has excellent CNS penetration. Because of the large number of drugs available for M. kansasii and the
cost of linezolid, there is no reported experience with other clinical forms of M. kansasii or with CNS
disease. Linezolid has proven effective for the treatment of Mycobacterium chelonae (94) and Nocardia
species (95), including patients with brain abscesses (95).
Mycobacterium simiae
This species of mycobacteria was first reported in 1965 when it was isolated from Macacus rhesus
monkeys (96). M. simiae are slow-growing organisms that may produce pigmented and nonpigmented
colonies. It has been rarely associated with human disease but has been described to cause lung disease in
the setting of structural lung disease (bronchiectasis). M. simiae is usually reported from Israel and the
southwestern United States based on clinical samples (60). The epidemiologic source of M. simiae is not
well established but has been reported in several pseudo-outbreaks in the southwestern United States
attributed to hospital water and has been recovered from tap water sources derived from large aquifers
(97). Four cases of CNS infection of M. simiae have been reported. Valero et al. (98) reported 137
clinical isolates of M. simiae in 75 patients in San Antonio, Texas over an 11-year period (1983 to 1993).
One hundred twenty-eight (93%) isolates were from respiratory sources, four blood, one skin, one urine,
one lymph node, and one bone marrow. Only one case involved the CNS, a 38-year-old man with AIDS
who presented with fever, night sweats, and falls. CT of the head revealed three brain lesions with brain
biopsy reported as B-cell lymphoma that was AFB stain positive with no granulomas. Tissue culture grew
M. simiae, but the patient refused therapy and 10 weeks after brain biopsy died.
The second case of M. simiae occurred in a 40-year-old man with AIDS who developed right
hemiparesis, progressive truncal ataxia, vertigo, and horizontal binocular diplopia with fever and weight
loss (99). MRI demonstrated multiple enhancing isointense nodular lesions at the left cerebral peduncle
and medulla involving the leptomeninges. Lumbar puncture on two occasions revealed 10 to 20
mononuclear cells/µL, glucose of 47 to 72 mg/dL, and protein of 49 to 135 mg/dL. Partial surgical
resection of the medullary lesion revealed dense proliferation of spindle cells with histiocytes,
lymphocytes, and mononuclear cells. Ziehl-Neelsen staining was AFB positive and tissue culture grew M.
simiae that was confirmed using 16S rRNA PCR gene sequencing. M. haemophilum was also isolated
from blood cultures, and the authors attribute the negative tissue culture for M. haemophilum due to lack
of hemin or ferric ammonium citrate in culture medium that is essential for its growth (61). He received
isoniazid, rifampin, pyrazinamide, ethambutol, and clarithromycin for treatment and improved with only
residual neurologic deficits. This is the fifth case of CNS NTM infection forming spindle cell
pseudotumors (52–55,99).
Balkis et al. (100) reported the third case of M. simiae in an 83-year-old HIV-negative man who
developed fever, confusion, and agitation 2 days after surgery for a right hip fracture secondary to a fall
who had complained of “feeling ill” for several weeks prior to the fall. Bilateral interstitial infiltrates
were seen on chest radiography. His level of consciousness deteriorated along with respiratory failure
requiring intubation. Brain CT scan showed small vessel ischemic disease and CSF specimen showed 1
WBC/µL, normal glucose and protein levels. Bronchoalveolar lavage was performed and 1 week later
grew M. simiae in culture. One week after lumbar puncture, CSF culture grew M. simiae. Both isolates
were identified using 16S rRNA gene sequencing. The patient developed cardiopulmonary arrest and
died. The authors contend that because cultures were recovered from two different sterile sites and no
other mycobacteria was isolated in any other culture during hospitalization, M. simiae was a true
pathogen.
The final case of M. simiae was reported in a 39-year-old with a 4-month history of fever, night
sweats, and weight loss who was diagnosed with AIDS (101). Physical exam revealed
hepatosplenomegaly, and liver biopsy showed AFB with minimal disruption of the liver tissue and was
treated empirically for TB with rifampicin, isoniazid, ethambutol, and pyrazinamide. CSF specimen
showed no WBCs, normal protein, and glucose. After hospital discharge, blood and CSF culture grew M.
simiae and antimycobacterial therapy was changed to moxifloxacin, rifabutin, ethambutol, and
azithromycin and ART was started 10 days later. Three months after ART, fever and malaise returned
with negative microbiologic workup, and immune reconstitution inflammatory syndrome was diagnosed
and resolved with steroid therapy.
M. simiae is highly drug resistant, including ethambutol and rifabutin. The best antimycobacterial drugs
are the macrolides (clarithromycin or azithromycin), trimethoprim-sulfamethoxazole (TMP-SMX),
moxifloxacin, and amikacin (102).
Mycobacterium gordonae
M. gordonae organisms are ubiquitous in the environment, but their recovery has been most closely
identified with water. M. gordonae are slow-growing, rarely pathogenic organisms that are occasionally
encountered in the microbiology laboratory and usually considered an environmental contaminant.
Weinberger et al. (103) reviewed all reported cases of disease due to M. gordonae to 1992 and identified
23 cases, of which 13 had sufficient information to be judged definite. Eight had pulmonary disease,
seven had soft tissue infection of an extremity, five had disseminated disease, three had peritonitis, and
one had corneal infection. The CNS was involved in two cases, both of whom involved CSF shunts (see
following section). In most of these patients, the infection was treated with three antimycobacterial drugs
including isoniazid, rifampin, ethambutol, and/or an aminoglycoside. Overall, 6 of 24 patients died. These
cases and all reported cases of M. gordonae infection involving the CNS were in the premacrolide era,
and no isolates were confirmed by molecular methods.
The first case was a hydrocephalic child who had two ventriculoatrial shunts placed at 18 days and 7
months of age (104). The child had an elevated CSF protein level (106 mg/dL) and increased intracranial
pressure necessitating a ventriculoperitoneal (VP) shunt. The patient underwent several shunt revisions
complicated with the development of ascites. CSF specimens grew M. gordonae, and shunt valve was
“loaded” with AFB. The meningitis and ascites resolved with shunt removal and antimycobacterial
therapy. The second case of M. gordonae meningitis occurred in a 23-year-old woman, who underwent a
VP shunt following excision of a cerebellar medulloblastoma 9 years prior, who presented with fever,
hematuria, and progressive renal insufficiency (105). Nine months before admission, she had been placed
on prednisone for presumed hypersensitivity pneumonitis and hepatitis. Cultures of lung biopsy obtained 9
months prior revealed 2+ growth of M. gordonae. CSF was tapped from the shunt and showed numerous
AFB. CSF analysis showed normal glucose and slightly elevated protein. M. gordonae were cultured
from CSF, urine, renal biopsy, and the shunt that had been removed.
Although one cannot generalize from two reported cases, it remains prudent to consider a
mycobacterial etiology in chronically febrile patients who have had shunting procedures including
infection of the shunt itself. Treatment with antimycobacterial agents and removal of the foreign body was
effective in these two cases.
Mycobacterium genavense
This species of mycobacteria was first reported by Bottger et al. (106) in 1992 who described it in 18
patients with AIDS presenting with fever, diarrhea, and marked weight loss. Two subsequent reports on
M. genavense described similar symptoms in patients with AIDS, with a 68% mortality by 12 months
(107,108).
In terms of CNS disease, two cases have been reported. Berman et al. (109) reported a 50-year-old
man with AIDS. The patient was admitted with a 1-month history of memory problems, confusion, and
episodic tremor of the right arm, as well as a 2-week history of right-sided weakness and paresthesias.
The patient had mild right-sided motor and sensory deficits and slurred speech. CT revealed cerebral
edema and a mass effect in the left parietal region. The patient was treated empirically for toxoplasmosis
with pyrimethamine and sulfadiazine but had a grand mal seizure after 1 week. MRI at that time showed a
left parietal mass abutting the dura with meningeal enhancement and a large zone of surrounding edema.
CT-guided needle biopsy revealed a patchy lymphocytic infiltrate without granuloma formation but with
clusters of AFB on Ziehl-Neelsen stain. Treatment was started with five drugs to cover M. tuberculosis
and MAC, and then was changed to clarithromycin, ciprofloxacin, and ethambutol when the organism was
identified as M. genavense. The patient did well clinically and repeat imaging demonstrated complete
resolution at 12 months.
Uchino et al. (110) reported a 50-year-old man with primary immunodeficiency who presented with
dysarthria, aphasia, and right hemiparesis. MRI revealed multiple intracranial masses in the subcortical
regions. CSF cultures were negative for NTM. Brain biopsy was perfomed, which confirmed M.
genavense infection. These reports, as well as the previous reports on M. genavense, describe significant
difficulties culturing this organism using standard techniques for mycobacteria. Identification to the
species level, in most cases, requires molecular methods.
Mycobacterium terrae Complex
The M. terrae complex initially included only M. terrae and M. nonchromogenicum. The species has
now been expanded to multiple other species, with the most common isolate being M. arupense. The M.
terrae complex are rare, slowly growing nonpigmented mycobacteria that are present in tap water
presumed to be nonpathogenic in the lung but are a recognized cause of posttraumatic tenosynovitis and
local osteomyelitis of the extremities. Two cases involving the CNS have been reported (111,112).
Woods and Washington (111) reviewed the microbiology and clinical aspects of NTM and described the
Cleveland Clinic Foundation’s experience with NTM, from 1982 to 1985. Of 140 patients with
mycobacteria isolated from clinical specimens, 93 were NTM, primarily MAC (124 specimens). M.
gordonae (75 specimens), M. kansasii (59 specimens), and M. fortuitum group (58 specimens)
accounted for most of the remainder. Whereas most of these isolates were from respiratory tract
specimens, one patient who had an acoustic neuroma removed several months previously developed
meningitis due to M. terrae complex. Details of the case were not published. Lai et al. (112) described a
65-year-old HIV-negative man who had radiotherapy for nasopharyngeal carcinoma 6 years prior to
presentation. He was admitted with a 2-month history of headache and 5-day history of fever, nausea, and
poor appetite. Physical exam revealed meningismus and CT disclosed dilated ventricles with diminished
sulci. Two lumbar punctures were performed revealing pleocytosis, 140 to 488 WBCs/µL (77% to 81%
PMNs), elevated protein of 131 to 267 mg/dL, and glucose 11 to 37 mg/dL. Microbiologic CSF analysis
showed negative Gram stain and culture, AFB stain, and cryptococcal antigen. Fever and headache
persisted, and MRI revealed leptomeningeal enhancement of the right temporal region and premedullary
areas of the brain stem. Empirical therapy for TB meningitis was initiated, but neurologic status worsened
to coma. Repeat CT demonstrated hydrocephalus necessitating external ventricular drainage. Five weeks
after CSF AFB cultures were obtained, both yielded M. nonchromogenicum.
Mycobacterium malmoense
M. malmoense is a slow-growing pigmented species first recovered in Malmo, Sweden. It can cause a
variety of diseases such as chronic pulmonary disease or cervical lymphadenitis in children. It is second
only to MAC in many areas of northern Europe as a cause of NTM disease and is rarely seen in the United
States. Two cases with CNS disease have been reported. Florakis et al. (113) described a patient with
chronic mastoiditis who was found to have pituitary insufficiency secondary to mycobacterial infection
due to M. malmoense. The disease was proven by surgical biopsy and 16S rRNA gene sequencing. The
second case was a 49-year-old woman with a 6-month history of deteriorating vision, anorexia, anxiety,
and poor memory with a change in behavior manifested as disinhibition and aggression (114). Physical
exam revealed poor cognitive performance, bilateral papilledema, and general hyperreflexia and extensor
plantar reflexes. CSF analysis revealed pleocytosis, 37 WBCs/µL (monocytes), elevated protein of 949
mg/dL, and 1:3 CSF:serum glucose ratio with negative AFB stain. MRI demonstrated periventricular
white matter changes and enhancement in the basal ganglia. CSF culture grew M. malmoense and M.
interjectum based on the Hain PCR method. Empirical therapy with rifampicin, isoniazid, ethambutol,
and pyrazinamide with steroids was initiated. Over the next 3 months, the clinical course worsened with
development of myoclonus, vision loss, sleep–wake cycle disturbance, and agitation. Repeat CSF
analysis revealed elevated protein of 541 mg/dL and bilateral optic atrophy by funduscopic examination.
MRI demonstrated development of secondary white matter changes (Fig. 30.3). After 8 weeks of
treatment, encephalopathy improved, enabling the patient to be discharged home. Specific
antimycobacterial therapy was not described further.
Mycobacterium triplex
M. triplex is a rare slowly growing nonpigmented species. Most clinical cases have had underlying
immune deficiencies, especially advanced HIV disease. Zeller et al. (115) described a 41-year-old man
from Nigeria with AIDS with positive cultures of blood, sputum, and ascitic fluid with the organism
shown to be related to M. triplex by partial 16S rRNA gene sequencing. The patient developed signs of
left hemiballism-hemichorea. An MRI showed a lesion in the subthalamic lesion. Cultures of CSF also
grew M. triplex. The patient initially responded to antimycobacterial therapy but did poor clinically and
died 5 months after the start of the therapy.
Thus, it appears that less commonly encountered species of mycobacteria also cause CNS disease on
occasion. Diagnosis of mycobacterial disease of the CNS requires, ideally, that the involved tissue be
examined microbiologically for AFB and histopathologically specifically for mycobacteria and chronic
(often granulomatous) inflammation. Treatment of CNS disease due to these organisms must be based on
published findings and clinical experience, largely in other organs, as well as principles of
pharmacotherapy of CNS disease.
Transverse Myelopathy and Radiculomyelopathy

One study described two cases of transverse myelopathy and radiculomyelopathy associated with
pulmonary disease due to M. kansasii and M. malmoense (116). The fact that only one such report exists
suggests it is a rare event with NTM.
RAPIDLY GROWING NONTUBERCULOUS MYCOBACTERIA

RGM include four clinically relevant species, including M. fortuitum, M. mucogenicum, M. chelonae,
and the M. abscessus complex. The proper taxonomy and nomenclature of M. abscessus complex that
now includes M. abscessus (sensu stricto), M. massiliense, and M. bolletti will be a continual and
dynamic process as more detailed genomic sequencing occurs. The RGM are generally considered
environmental saprophytes widely distributed in nature, including tap water (1,60).
Mycobacterium fortuitum
The M. fortuitum group includes a variety of species that include M. fortuitum, M. porcinum, M.
senegalense, M. mageritense, M. peregrinum, and M. houstonense. M. fortuitum was originally
described as a cause of a postinjection site abscess and principally causes primary skin and soft tissue
infections, surgical wound infections, and central venous catheter–related infections (117). Rarely, other
infections such as pulmonary disease, prosthetic valve endocarditis, and cervical lymphadenitis can
occur.
The relative frequency of CNS infection due to the M. fortuitum group is unknown but is probably rare.
Most cases were reported before the recognition of the earlier noted new species, which require
molecular methods for identification. Hence, all early isolates are listed as M. fortuitum group unless
clearly delineated from these other species by molecular methods. Reported experience with this disease
is summarized in Table 30.5. It has been associated with spinal catheters, ventricular shunts, and
mastoiditis. Indirect information in this regard can be gleaned from reported cases such as the 1983 report
by Wallace et al. (117). During a 4-year period, these workers were involved in the care of 125 patients
with disease due to RGM. One of these patients had M. fortuitum meningitis.
Hand and Sanford (118) reported the first case of a CNS infection due to the M. fortuitum group. They
described an 8-year-old boy with 12 days of fever, stiff neck, back and leg pain, lethargy, and disturbed
gait. Eight days before admission, a lumbar puncture revealed 3,025 WBCs/µL (74% PMN cells), 237
mg/dL of protein, and 51 mg/dL of glucose. Smears and cultures were negative, and the boy was
diagnosed with aseptic meningitis. On admission, the boy was febrile and had a stiff neck. Repeated
lumbar puncture was essentially unchanged. On the sixth hospital day, however, attempted lumbar
puncture yielded frank pus. Myelography revealed a complete block to contrast material at T12. At
surgery, a cauda equina abscess was drained and an Ommaya reservoir was placed. Cultures of the pus
obtained at attempted lumbar puncture and the material from surgery grew an M. fortuitum group, which
was resistant to all antibiotics tested. Multiple subsequent cultures of CSF and reservoir grew M.
fortuitum group and the reservoir was eventually removed. The organism based on in vitro susceptibility
testing was only sensitive to oxacillin and kanamycin, and the patient was treated with these antibiotics
for 25 days. Six months after discharge, the patient was ambulating without crutches but with persistent
gait disturbance.
Four cases of M. fortuitum group CNS infection have been reported occurring after surgical
procedures (20,21,119,120). Meningitis developed in a 19-year-old woman following lumbar discectomy
(119). CSF was sampled repeatedly over a 10-month period. Two initial cultures of CSF were positive
for M. fortuitum group and eight subsequent cultures during a 10-month period were negative with the
patient on treatment. CSF leukocyte counts ranged from approximately 100 to 800 cells/µL, peaking 1
month after presentation. Débridement of the infected site revealed granulomatous reaction with AFB in
the bony tissue. Treatment was primarily with doxycycline, amikacin, and capreomycin once the identity
of the organism was established. The next case involved a 57-year-old woman who developed recurrent
fever and headache for 1 year following surgery for meningioma (120). Repeated CSF analysis was
indicative of bacterial meningitis with negative microbiologic cultures. One year after surgery, repeat
CSF culture grew M. fortuitum group, which was treated with clarithromycin and levofloxacin.
Symptoms and CSF analysis improved on therapy.
The remaining two cases involved children. A 9-year-old female underwent tympanomastoidectomy
and 1 month later developed a mastoid fluid collection (20). Fluid collection was drained and culture
grew M. fortuitum group with subsequent development of osteomyelitis of the right temporal bone with
meningeal enhancement by MRI. Lumbar puncture was negative for organisms. The patient underwent a
modified radical mastoidectomy and histopathology revealed granulomas with central necrosis, chronic
inflammation with lymphocytes, and AFB stain negative. Tissue sent to the CDC for culture and
susceptibilities identified M. fortuitum/M. peregrinum group with reported sensitivity to doxycycline and
meropenem. The patient was treated with doxycycline and meropenem and 1 month later developed fever,
headache, and back pain. MRI demonstrated a subdural fluid collection in the cerebellopontine angle that
was surgically excised. Histopathology revealed inflammatory tissue and negative stain for AFB. Quinn
and Steele (21) reported a 12-year-old male with Arnold Chiari type I malformation diagnosed at 8 years
of age who underwent posterior cranial fossa decompression with dural grafting. Fever and severe
headaches followed immediately after surgery with CSF showing lymphocytosis with negative bacterial
and fungal cultures. Two weeks postoperatively, he developed a CSF leak requiring surgical revision, but
fever and headaches continued, in addition to nausea, vomiting, and photophobia. Three weeks
postoperatively, he developed personality changes that progressed to deteriorating mental status and 5
weeks postoperatively, CT demonstrated obstructive hydrocephalus. Ventriculostomy with subsequent VP
shunt placement was performed. CSF obtained during ventriculostomy demonstrated AFB and he was
empirically treated for TB. When AFB was identified as M. fortuitum group, antimycobacterial therapy
was changed to amikacin, cefoxitin, and clarithromycin. The VP was not removed due to the patient being
shunt dependent. Over the next 2 months, fevers, decreased appetite, and abdominal pain with VP
obstruction requiring multiple revision and externalization of the shunt occurred. Ventricular and
peritoneal fluid grew M. fortuitum group several times. Up to this point, the patient had received 2
months of cefoxitin, 4 months of amikacin and clarithromycin, 1 month of ciprofloxacin, and 3 weeks of
meropenem. Based on in vitro susceptibility, he was continued on ciprofloxacin, clarithromycin, and
TMP-SMX with minimal planned therapy of 6 months. However, subsequent chest CT demonstrated
multiple pulmonary nodules, and CSF grew M. fortuitum group. The authors concluded that the VP shunt
seeded the vasculature resulting in pulmonary infection. Antimycobacterial therapy was changed to
linezolid, azithromycin, amikacin, ciprofloxacin, and TMP-SMX with clinical improvement. After 12
months from initial presentation, the shunt was obstructed again and CSF remained culture positive for M.
fortuitum group. Intraventricular injection of amikacin (4 mg) and linezolid (1 mg) were initiated due to
failed oral and intravenous therapy. Based on new in vitro susceptibility, antimycobacterial therapy with
ciprofloxacin, TMP-SMX, and twice-weekly intraventricular amikacin and linezolid was initiated with
subsequent sterile CSF cultures.
Two additional cases involving ventricular shunts have been reported. Chan et al. (121) described a
60-year-old woman in which a ventriculoatrial shunt was inserted for obstructive hydrocephalus from
spontaneous cerebellar hematoma. At the time of shunt placement, the CSF was normal except for the
presence of blood. From the time of shunt placement, however, the patient had persistent fever. Routine
studies of the CSF were normal except for a “slightly elevated” protein level. AFB smears, however,
were positive and cultures grew M. fortuitum group. The CSF studies were repeated and the results were
the same. The only drugs to which the organism was susceptible in vitro were amikacin and ofloxacin.
Treatment with these antibiotics was ineffective, and the patient deteriorated until the shunt was removed.
Intraventricular amikacin (20 mg on alternate days) was initiated through a Rickham reservoir. After 1
week of intraventricular plus systemic therapy, the patient defervesced. Smears and cultures of the CSF
became negative after 3 weeks of this therapy, and therapy was continued for 10 weeks. The other case
involved a VP shunt for hydrocephalus (122). Two additional reports involving an epidural spinal
catheter and intrathecal drug delivery device have been described (22,123).
Two cases of M. fortuitum group meningitis followed local penetrating trauma. In 1984, Santamaria-
Jauregui et al. (124) reported a 16-year-old boy who developed relapsing M. fortuitum group meningitis
following a motor vehicle accident. A minor skin wound in the right sacral region from the accident
necessitated excision and drainage 3 days later. Two weeks later, the boy developed fever, headache, and
a stiff neck. Lumbar puncture revealed cloudy CSF with 1,085 WBC (80% neutrophils) with normal
biochemistry and negative microbiologic analysis. Radiographic studies were negative including head CT
scan and myelography. The patient was treated with two courses of multidrug antibacterial therapy but
relapsed both times when the drugs were discontinued. Repeated lumbar puncture after the second relapse
showed the CSF contained 2,100 WBCs/µL (75% neutrophils), 100 mg/dL of protein, and 45 mg/dL of
glucose. The patient developed signs of meningitis and repeated CSF examination showed 1,200 WBCs
(75% PMN), glucose level of 10 mg/dL, and protein level of 1.5 g/dL. CSF from both relapses grew M.
fortuitum group. The original sacral wound became fluctuant and pus from the wound grew M. fortuitum
group. An abscess and fistula that reached the sacrum were surgically excised and drained and a piece of
glass was found in the débrided tissue. However, the fistula could not be demonstrated to communicate
with the spinal canal. M. fortuitum group was isolated from the débrided tissue and glass fragment.
Treatment with isoniazid and trimethoprim-sulfamethoxazole produced clinical improvement and
normalization of the CSF. Wallace et al. (125) reported a similar case that also followed a motor vehicle
accident and recovered after prolonged antibiotic therapy and multiple surgeries.
Dalovisio et al. (126) reported 10 patients with disease due to M. fortuitum group and M. chelonae.
One was a 10-year-old boy with chronic otitis media. A CT scan of the head showed a right
cerebellopontine angle mass. At surgery, the patient had a subdural empyema and abscess, which grew M.
fortuitum group. The patient was treated with erythromycin, isoniazid, and kanamycin for 2 weeks
without success. Clinical deterioration led to reexploration of the posterior fossa but only partial
resection of the abscess due to extensive disease. Subsequent treatment with doxycycline and ethionamide
for several months did not resolve the fever, and after 8 months, he developed obstructive hydrocephalus
requiring VP shunt placement. A culture obtained at that time grew M. fortuitum group susceptible to
amikacin. The patient was treated with amikacin with gradual improvement, and all signs of the infection
eventually cleared; however, the patient developed permanent partial hearing loss from the amikacin. The
authors concluded that aggressive surgical débridement and treatment with antibacterial drugs based on in
vitro susceptibility results (often including amikacin and doxycycline) were critical components of
successful therapy.
Two patients with AIDS developed M. fortuitum group meningitis with no precipitating cause
(13,127). Both were 28-year-old men with far advanced HIV disease presenting with clinical meningitis.
One patient was lost to follow-up (13) and one patient died with proof of the meningitis at autopsy (127).
Saritsiri et al. (128) reviewed NTM infection of 103 patients in a Thai hospital. Seventy-one patients
were HIV-infected and only two cases involved the CNS. Both patients were HIV negative, had
hydrocephalus, and M. fortuitum group was isolated from the CSF.
Kell et al. (129) reported M. fortuitum group CNS infection in a 33-year-old HIV-negative patient with
recurrent double vision, paresthesia, and vertigo for 2 years following an appendectomy. MRI
demonstrated multiple-enhancing leptomeningeal and intraparenchymal lesions in the cervical spinal cord
and brainstem. CSF contained 100 WBC/µL (lymphocytes), CSF/serum glucose ratio of 0.4, total protein
of 2,500 mg/dL, and positive AFB stain. However, microbiologic cultures and PCR were repeatedly
negative. The authors assumed infection was due to slowly growing NTM, and antimycobacterial therapy
was initiated with clarithromycin, ethambutol, and rifabutin. The patient improved until several months
later when Lhermitte phenomenon, neck stiffness, recurrent hiccups, and unsteady gait developed. MRI
demonstrated increased numbers of lesions disseminated in the basilar cisterns, subarachnoidal space of
the vermis, and meninges and lumbar puncture “proved disease progression.” Therapy was changed to
ethambutol, isoniazid, and levofloxacin with improved symptoms. Two months later, this patient
developed cranial nerve palsies and MRI revealed hydrocephalus requiring VP shunt and therapy was
changed to rifampicin, ethambutol, isoniazid, and levofloxacin for 1 month without improvement. Open
biopsy (approximately 1 year after initial presentation) of a meningeal lesion at C5/C6 demonstrated
caseating granulomas with negative Ziehl-Neelsen stain for AFB. Tissue by PCR analysis identified M.
fortuitum group. Tissue culture remained negative (on chemotherapy). Amikacin and meropenem were
started when M. fortuitum group was identified, and later, tigecycline was added and amikacin was
stopped. The patient had improved at 18 months and therapy was continued.
The remaining two reported cases of M. fortuitum group CNS infection included a patient with fatal
prosthetic valve endocarditis with secondary meningitis (130). A study from Hyderabad, India reviewed
50 cases of brain abscesses that were diagnosed by CT scan and confirmed surgically in all cases (131).
One specimen grew M. fortuitum group but no other microorganisms. No other details of this case were
published.
Laboratory
RGM are the most difficult of the NTM to be recognized by standard staining and culture techniques used
for M. tuberculosis. The organisms do not always stain well with the Ziehl-Neelsen or Kinyoun method
and may not be recognized readily with the fluorochrome method. For example, it is not uncommon to see
a sputum sample that is AFB smear negative but with a heavy growth of an RGM species such as M.
abscessus, suggesting that the organisms did not stain. Though not pertinent to CSF specimens, RGM are
also highly susceptible to the decontamination procedures that are used to remove other bacteria from
specimens. Hence, quantitation of the amount of RGM organisms present by smear or culture can be
difficult and should be assessed carefully. Separation of M. fortuitum from the M. chelonae and M.
abscessus group is done fairly readily in the laboratory if molecular methods are used (132).
M. fortuitum is the more drug susceptible of the RGM group, and essentially all isolates are
susceptible or intermediate in vitro to achievable serum levels of amikacin, imipenem, sulfonamides, and
fluoroquinolones, and approximately 50% are susceptible to doxycycline and cefoxitin (102). Most
isolates are susceptible to linezolid (133), an oxazolidinone that has excellent CNS penetration with high
serum and CSF levels (95). Macrolide therapy for the RGM group is complicated by inducible
erythromycin ribosomal methylase (erm) gene that confers resistant by methylating an adenine in the
peptidyltransferase regions of the 23S rRNA (102). Erm gene sequencing and extended incubation with
clarithromycin of the mycobacteria for 14 days, compared to routine 3-day incubation, will detect
inducible resistance.
Treatment
In general, patients with serious M. fortuitum group disease are given parenteral therapy with amikacin
plus cefoxitin or imipenem combined with one or more oral agents and then are treated with oral agents
alone. For most diseases, the total duration of therapy has been 6 months. Success rates with M. fortuitum
group skin and soft tissue infections and in lung disease are quite high. Wallace et al. (125) prospectively
studied treatment outcomes of 76 patients with extrapulmonary disease due to M. fortuitum group who
were treated on the basis of in vitro drug susceptibility results once these became available. Thirty-three
patients had extensive or serious disease requiring inpatient combination chemotherapy and surgical
débridement (31 patients). Almost all patients were treated successfully despite that these studies
antedated the availability of clarithromycin, the fluorinated quinolones, and imipenem. No single regimen
for M. fortuitum group CNS disease has been established. Multiple drugs would appear to have potential;
and three to four drugs should probably be used, at least initially.
Mycobacterium chelonae
M. chelonae was previously grouped as the M. chelonae/abscessus complex and M. abscessus was not
officially recognized as a separate species until 1992. Thus, literature prior to that date makes the
nomenclature difficult to interpret. M. chelonae causes predominately skin, soft tissue, and bone infection
and rarely pulmonary disease. M. chelonae is more likely to cause disseminated cutaneous disease
compared to the M. fortuitum group (117,134,135). Wound infections and abscesses are generally the
consequence of trauma, surgery, or immunosuppression.
Wallace et al. (134) characterized clinical disease due to 100 isolates of M. chelonae associated with
extrapulmonary disease. No case involved CNS disease. One case of M. chelonae CNS infection has
been reported involving a 39-year-old man who developed a spontaneous extradural abscess with
associated psoas abscess due to M. chelonae who recovered after multiple surgeries and prolonged
antibiotic therapy over a 33-month period (136).
M. chelonae organisms are more susceptible based on in vitro susceptibility to tobramycin than to
amikacin, and it is the preferred aminoglycoside for this species. Macrolide therapy, either with
clarithromycin or azithromycin, is an option for treatment because M. chelonae does not possess an erm
gene. M. chelonae are uniformly resistant to cefoxitin, and approximately 60% of isolates are susceptible
to imipenem; however, susceptibility testing with imipenem is problematic due to lack of reproducibility
(102). Linezolid penetrates into the CNS, and approximately 50% of isolates are susceptible (102).
Mycobacterium abscessus Complex
The M. abscessus complex includes M. abscessus (sensu stricto), M. massiliense, and M. bolletti. The
proper taxonomy surrounding these closely related RGM is currently in debate. M. abscessus (sensu
stricto) is predominately isolated in the southeastern United States and has similar endemic geographic
distribution as MAC. It is the predominate RGM causing pulmonary disease (approximately 80%) and
similar to MAC is usually superimposed on preexisting lung disease, especially bronchiectasis. The
natural epidemiology and pathogenicity of M. massiliense and M. bolletti is less known.
Eleven cases of CNS disease with M. abscessus complex have been reported. Maniu et al. (137)
described a 59-year-old woman with a stab wound to the neck 6 months before her admission with
meningitis. Despite multiple antibiotics that included clarithromycin, the patient died of her disease. A
27-year-old man with secondary pulmonary alveolar proteinosis associated with myelodysplastic
syndrome developed a subcutaneous abscess and meningitis after video-assisted thoracic surgery (138).
The patient died of graft versus host disease and M. abscessus complex sepsis after transplantation.
Liebeskind et al. (139) described a 35-year-old man with 5 months of fever, fatigue, night sweats,
anorexia, jaundice, and difficulty concentrating found to have M. abscessus complex bacteremia with a
vegetation of the posterior leaflet of the mitral valve. Lumbar puncture revealed 80 WBC/µL, glucose 41
mg/dL, and total protein 88 mg/dL. Punctate lesions of the left basal ganglia, right thalamus, and diploic
space of the right parietal bone were seen on MRI. Ciprofloxacin, amikacin, and meropenem for
antimycobacterial therapy was started. On hospital day 18, CSF cultures from admission grew M.
abscessus complex and therapy based on in vitro susceptibilities was switched to clarithromycin,
imipenem, and amikacin. During hospitalization, the patient had intermittent tonic-clonic seizures and on
day 44 had a seizure; repeat MRI revealed left frontoparietal hemorrhage and subsequently developed
brain herniation and respiratory distress on day 69 and died. Autopsy demonstrated disseminated
granulomas with AFB in meninges and subcortical structures.
Talati et al. (140) reported a 28-year-old woman with left eye enucleation and ocular prosthesis
placement after trauma 10 years previously. The patient underwent prosthesis replacement due to failure
and within 1 year developed extrusion of the implant with purulent drainage. The prosthesis was removed
and surgical cultures grew M. abscessus complex. The patient was placed on clarithromycin and
presented several months later with headache, meningismus, and nausea. MRI revealed enhancement of
the left orbit, inferior portion of the left cavernous sinus, and infratemporal fossa. CSF analysis showed
pleocytosis, 411 WBC/µL, glucose 30 mg/dL, and total protein 111 mg/dL with negative bacterial and
fungal cultures. The patient was treated with amikacin and meropenem for 2 weeks followed by cefoxitin
monotherapy for 6 weeks. Fever and headaches persisted, and an Ommaya reservoir was placed for
intraventricular amikacin therapy and cefoxitin was changed to tigecycline. After 1 month of therapy,
seizures developed and MRI demonstrated a cerebral abscess surrounding the Ommaya reservoir,
prompting shunt removal. At that time, therapy was changed to cefoxitin and tigecycline. At this point, the
patient had received 4 months of intravenous antibiotic therapy with persistent symptoms. Repeat CSF
analysis revealed 450 WBC/µL (82% PMN) and total protein 548 mg/dL. Repeat MRI (Fig. 30.4)
demonstrated basilar meningitis, resolving brain abscess, and multiple microabscesses. CSF cultures
grew M. abscessus complex. The patient was treated with a variety of antibiotics including amikacin,
tigecycline, linezolid, meropenem, moxifloxacin, and co-trimoxazole and received approximately 21
months of therapy with marked improvement of her symptoms and functional status.
Lee et al. (141) reviewed 15 patients with CNS NTM infection in a Taiwanese hospital from 2000 to
2010. M. abscessus complex was identified in 8 patients, MAC in 6 patients, and M. kansasii in 1
patient. The MAC and M. kansasii patients were not described in detail. Six out of the 8 patients with M.
abscessus complex had preserved isolates that were analyzed using 23S rRNA and erm (41) PCR gene
sequencing. All six isolates were determined to be M. massiliense. Underlying disease identified 2
patients to have otomastoiditis, 1 patient chronic otitis media, and 4 patients steroid use. Five patients
developed infection postneurosurgery, and 2 patients had disseminated disease. Clarithromycin-based
therapy combined with imipenem, amikacin, levofloxacin, and moxifloxacin were the most common
regimens with treatment courses ranging from 4 months to 1 year. Five patients died.
Treatment
M. abscessus (sensu stricto) is the most drug-resistant organism of the RGM which makes treatment
difficult. Most isolates are susceptible to amikacin. Approximately 50% are sensitive to linezolid and
imipenem based on in vitro susceptibilities (102). Seventy percent are susceptible to cefoxitin, and
commonly, tigecycline therapy is used, but there are no established breakpoints. M. abscessus (sensu
stricto) has a functional erm gene in contrast to M. massiliense and M. bolletti causing macrolide-based
therapy a rare exception. In contrast, M. massiliense and M. bolletti lack a functional erm gene, and
macrolide-based therapy is the main treatment. These organisms otherwise have similar in vitro
susceptibilities as M. abscessus (sensu stricto) (102). No single regimen has been established for CNS
infection with M. abscessus (sensu stricto), M. massiliense, or M. bolletti.
Mycobacterium mucogenicum
M. mucogenicum, formerly known as a “Mycobacterium chelonae–like organism,” is an RGM common

in tap water. It has been associated with outbreaks linked to water contamination and central venous
catheter infections remain the most common clinical infection due to this organism. Four cases of CNS
infection due to M. mucogenicum have been reported. Wallace et al. (142) reviewed 87 isolates of which
20 (23%) were determined to be clinically significant. Only two cases involved the CNS with limited
clinical data. The one case with clinical disease occurred in an AIDS patient who had a lumbar puncture
3 weeks prior for an unrelated reason. M. mucogenicum was isolated from multiple CSF cultures that
were also AFB smear positive. Two fatal cases of M. mucogenicum were reported by Adékambi et al.
(143). The first patient was a 23-year-old man with 2-week history of headache, vertigo, and neck pain
who presented with fever. A CSF specimen revealed 24 WBC/µL (26% PMN), normal glucose and
protein levels, and negative Ziehl-Neelsen stain. The patient died 3 days after admission. Microbiologic
analysis was negative except for positive CSF PCR analysis yielding M. mucogenicum using 16S rRNA
and rpoB gene sequencing. CSF culture confirmed M. mucogenicum. The second case was an 82-year-
old man with diabetes and chronic renal failure with femoral vascular graft who was admitted for fever,
cough, and confusion. Chest radiography demonstrated alveolar pneumonia. CSF analysis demonstrated
no WBCs, normal glucose level, and elevated protein level of 67 mg/dL. CT scan showed extensive
cerebral thrombophlebitis. The patient died 6 days after admission with multiorgan failure. Similar to the
first patient, extensive microbiologic analysis only yielded a positive CSF PCR product of M.
mucogenicum identified by 16S rRNA and rpoB gene sequencing, which was confirmed with CSF
culture.
The final case reported of M. mucogenicum CNS infection was similar to the previous two cases and
was also fatal (144). A 42-year-old man presented with 3-week history of headache, fever, chills,
dizziness, and myalgias. Physical exam demonstrated neck tenderness and mild sixth cranial nerve palsy.
CT revealed a hypodense cystic area on the posterior aspect of right internal capsule. Lumbar puncture
showed “leukocytosis with monocytic predominance 84%,” glucose 27 mg/dL, and protein of 457 mg/dL.
Over 6 days, neurologic status worsened and repeat CT demonstrated sudden dilatation of the lateral and
third ventricules. On day 7, the patient had no spontaneous respirations and corneal or gag reflexes with
fixed, dilated pupils. Electroencephalogram yielded an isoelectric line and death occurred on day 9.
Microbiologic analysis was negative. Autopsy revealed a brain with extensive, diffuse lymphoplasmatic
leptomeningeal infiltrates with multinucleated giants cells, noncaseating granulomas, and necrosis. DNA
was extracted from 35 different parts of the encephalon and 2 samples from the temporal lobe by PCR,
rpoB, and restriction fragment length polymorphism yielded M. mucogenicum. The authors conclude that
M. mucogenicum was not a contaminant because the water in the autopsy room was used as a negative
control and only 2 out of 35 samples of brain tissue isolated M. mucogenicum.
Mycobacterium neoaurum
M. neoaurum is a RGM rarely associated with human infection. One case of CNS involvement has been
reported (145). A 63-year-old HIV-negative woman with rheumatoid arthritis who had a stroke 10 months
previously presented with rapidly functional decline over 2 months and died. Autopsy revealed multiple
bilateral infarcts of the cortices, pons, thalamus, middle temporal gyrus, and putamen. Infarcts were
associated with a thick exudate characterized by granulomatous inflammation with caseation necrosis and
foreign body–type giant cells. Ziehl-Neelsen stain was negative. PCR on brain tissue identified M.
mucogenicum by 16S rDNA gene sequencing.
Mycobacterium tokaiense
Kondo et al. (146) reported a 36-year-old man found to have a pituitary stalk lesion who underwent
complete surgical resection. Histologic examination revealed caseous necrosis, multinucleated giant cells
with negative Ziehl-Neelsen staining with cultures. M. tokaiense was identified by 16S rDNA gene
sequencing.
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CHAPTER 31 BRAIN ABSCESS
MATTHIAS KLEIN, HANS-WALTER PFISTER, ALLAN R. TUNKEL, AND W. MICHAEL
SCHELD
DEFINITION
Brain abscess is a focal intracerebral infection that begins as a localized area of cerebritis and develops
into a collection of pus surrounded by a well-vascularized capsule. It continues to be a diagnostic and
therapeutic challenge to the clinician.
HISTORY
The first reference to a brain abscess is attributed to Hippocrates in the fifth century BC (1). He described
a syndrome of purulent otorrhea and fever associated with cerebral symptoms and stressed that the
chances of survival depended on the external draining of purulent material: “Chills, pain, and fever
throughout the head, especially in the ear, temples, and bregma. . . . If anyone moves him, he vomits
copiously and easily. . . . If, in this patient, a watery discharge breaks out through the nostrils or ears, it
runs out mixed with pus, and he recovers; if not, he usually dies in seven days.” The Corpus
Hippocraticum even advocated surgical therapy: “Then incise the head at the bregma; bore right through
to the brain, and heal the wound as you would one made by sawing.” The first documented successful
drainage of a brain abscess (of otitic origin) is attributed to the French surgeon S.F. Morand in 1752 (2).
In 1872, the army surgeon J. F. Weeds reported on the successful drainage of a traumatic frontal brain
abscess and reviewed the American and European medical literature (2). Of 214 cases of brain abscess
on record, only 4 cases resulted in recovery. Weeds noted that “not a single case recovered without the
abscess being opened and its contents evacuated, either by nature or by the knife of the surgeon.” In 1893,
Sir William MacEwen published his famous monograph Pyogenic Infective Diseases of the Brain and
Spinal Cord (2). Nineteen patients operated on for a cerebral or cerebellar abscess were reported in that
work; eighteen of these recovered and only one patient died. This publication established MacEwen as
the “father” of modern brain abscess management. Diagnostic delay was the major obstacle in the success
of therapeutic intervention, as Victor Horsley put it in 1888, “These cases are fortunately simple, perhaps
the simplest, examples of intracranial surgery, but there remains yet the method of diagnosis” (3). In the
twentieth century, refined surgical techniques, introduction of antibiotics, and finally the advent of
computed tomography (CT) have contributed to a significant improvement in the mortality and morbidity
rates associated with brain abscess (e.g., 4% mortality from 1981 to 1986 in a study by Mampalam and
Rosenblum [4]). Among the major problems in the twenty-first century are postoperative intracranial
infections due to antimicrobial-resistant bacteria and growing numbers of immunosuppressed patients
who have an increased risk of developing a brain abscess, mostly due to “atypical” pathogens such as
fungi, and excessive mortality rates of up to 97% (5,6). Further progress in the therapy of brain abscess is
therefore necessary.
EPIDEMIOLOGY
The incidence of brain abscess is estimated at 0.3 to 1.3 cases per 100,000 people per year (7,8) with a
male-to-female ratio of 2:1 to 4:1 (4,9,10). One important factor in the incidence of brain abscess (as is
true for most infectious diseases) seems to be the general health status of the population: In a study on 973
patients from South Africa with brain abscess from 1983 to 2002, the incidence dropped by 50% from
1983 to 2002, mainly due to improvements of socioeconomic standards and increased availability of
primary health care services (9). In the total population, the incidence of brain abscess is relatively low;
however, the risk is markedly elevated in certain patient groups (Table 31.1).
ETIOLOGY
In the preantibiotic era, analysis of intracranial pus revealed Staphylococcus aureus in 25% to 30% of
patients, streptococci in 30%, coliforms in 12%, and no growth in approximately 50% (11,12). With
proper attention to techniques, the role of anaerobic agents in brain abscess has become apparent. In one
earlier study (13), 14 of 18 abscesses grew anaerobes on culture—predominantly streptococci in 66%,
with Bacteroides species in 60%. Series from the United Kingdom have stressed the role of anaerobic
bacteria in brain abscesses, especially of otitic origin (11,12). The results of seven studies (in adults and
children) demonstrate a particularly important role for streptococci, Enterobacteriaceae (in particular
Proteus species), and Bacteroides species (Table 31.2). The organisms and their frequency of isolation in
exclusively pediatric-based series of brain abscess are similar to these figures except in the neonatal
setting: In a large study on neonatal brain abscess, Proteus mirabilis was identified in 27 (90%) of 30
cases, Escherichia coli in two, and Serratia marcescens in another newborn (14).
The location of a given brain abscess or its predisposing cause often suggests the most likely etiologic
agents (Table 31.3).
Bacteria
The streptococci represent a diverse group of organisms; however, those most frequently isolated in
patients with brain abscess belong to the Streptococcus milleri group (Streptococcus anginosus,
Streptococcus constellatus, Streptococcus intermedius), which has a recognized predilection for causing
focal suppurative disease (15–17). Streptococci from this group are often microaerophilic. Streptococcus
pneumoniae, despite being the leading cause of bacterial meningitis in adults, is only rarely cultured from
patients with brain abscesses (18).
S. aureus is the most common cause of traumatic and postoperative brain abscesses, often isolated in
pure culture (9). After craniotomy, S. aureus accounted for almost 50% and Staph. epidermidis for 5% of
intracranial infections in a large prospective study of 2,944 patients (19) and the proportion of
methicillin-resistant Staph. aureus (MRSA) was very high (41%). In a recent study from Argentina,
MRSA was even identified in 10% of 80 patients with brain abscess (15).
Enterococcus faecalis has been reported as a rare cause of otogenic, metastatic (e.g., due to
endocarditis), meningitis-associated, and neonatal brain abscess (20–22). Peptostreptococci, which are a
common oropharyngeal flora, have been occasionally found in odontogenic, otorhinogenic, postoperative,
and metastatic (e.g., following esophageal dilation) brain abscess (20,23).
Enterobacteriaceae are usually found in mixed cultures. Proteus species are the most commonly
isolated organism; they exhibit a particular association with otogenic disease (17,24,25) and neonatal
brain abscess (26). Brain abscesses due to Proteus species have also been reported after neurosurgical
procedures (27). E. coli is sometimes found in otogenic or metastatic brain abscesses (28). It is also a
cause of neonatal brain abscesses (29). In two studies from Taiwan (30,31), Klebsiella species (mostly
Klebsiella pneumoniae, less often Klebsiella oxytoca) were common (some with a gas-forming
appearance) in patients with debilitating diseases (in particular, diabetes mellitus). Citrobacter species,
especially Citrobacter diversus, are often implicated in brain abscesses that arise as a complication of
neonatal meningitis (32,33), but they are very rare in adults with brain abscesses (34). Salmonella (S.
typhi, S. typhimurium, and S. enteritidis of group B, C, or D) brain abscess is also uncommon (35). This
disease is most likely to occur in adults with certain predisposing factors like meningitis, tumor, ischemia,
trauma, intracranial hematoma, and human immunodeficiency virus (HIV) infection (36–38). Enterobacter
species, though another rare cause of brain abscess (39), must be considered in postoperative cases (27).
Serratia marcescens is another rare cause of neonatal brain abscess (40,41). In adults, only few cases
with opportunistic S. marcescens brain abscess are reported (42,43). In general, Enterobacteriaceae must
be taken into account especially in postoperative deep brain infections (9,19,35).
Aggregatibacter aphrophilus and Aggregatibacter paraphrophilus are most often isolated in brain
abscesses due to Haemophilus species (16,17,44,45). Brain abscess secondary to H. influenzae is rare
(46). Eikenella corrodens, which belongs to the oropharyngeal flora, has been occasionally detected in
particular in otorhinogenic or odontogenic brain abscess (47,48). Pasteurella multocida brain abscess
has been reported as a rare complication of animal scratches or bites (49–51). Actinobacillus
actinomycetemcomitans is sometimes encountered in polymicrobial odontogenic brain abscesses, often
in conjunction with Actinomyces infection (52,53).
Pseudomonas aeruginosa is mainly associated with otogenic brain abscess but has also been detected
as a postoperative, posttraumatic, or as a hematogenous complication (9,20,35,54). Anaerobes are
significant causative pathogens of brain abscess, often found in mixed culture (16,35). Bacteroides and
Fusobacterium species are most frequently isolated. Brain abscesses due to Clostridium species
(typically with a gas-forming appearance) may develop in particular after penetrating head trauma with
soil or fecal contamination of the wound. Clostridium infections must also be considered postoperatively
(55). In particular, cases due to Clostridium welchii, Clostridium perfringens, Clostridium septicum,
Clostridium tertium, and Clostridium bifermentans have been reported (56–58). Propionibacterium
acnes has also gained attention as a cause of postoperative and posttraumatic brain abscess, being
reported to occur up to 10 years after surgery (59–61). Few cases of a brain abscess due to
corynebacteria have been reported (62–64). Actinomyces species are anaerobic human commensals of
low pathogenicity, which have been repeatedly recovered from brain abscesses (65). Two thirds of the
patients with central nervous system (CNS) actinomycosis have an obvious primary site of infection
distant from the CNS, most commonly the lung or cervicofacial region. When no obvious source is
apparent, occult dental infection is often suspected (66).
Especially in immunocompromised hosts with brain abscess, Listeria monocytogenes or Nocardia
species can be found as causative pathogens (more than 90% of patients with listerial brain abscess and
34% with nocardial brain abscess are immunocompromised [9,30,35,67]). N. asteroides was isolated in
98% of nocardial brain abscesses; single cases were due to N. farcinica and N. caviae (67). N.
asteroides infections of the brain often had evidence of a pulmonary portal of entry (38% of cases).
Bacillus cereus (68,69), Rhodococcus equi (70,71), and Gordona terrae (72) are other recognized
pathogens of brain abscess in immunocompromised hosts. In approximately 5% to 10% of cases of
meningitis due to Mycobacterium tuberculosis, tuberculous granulomas (tuberculomas) can be found
(73,74); they usually resolve with medical therapy. When the caseous core of a tuberculoma liquefies, a
tuberculous abscess results; tuberculous brain abscesses are usually larger and less common than
tuberculomas, may be multiloculated, and often have greater mass effect and edema (73). Depending on
the prevalence of tuberculosis, a considerable proportion of focal intracranial infections may be due to
M. tuberculosis (9,30), reaching 56% in a Saudi Arabian study (75). In addition to M. tuberculosis, other
mycobacteria were observed to cause focal CNS lesions; these include Mycobacterium bovis (bacille
Calmette-Guérin) in an immunocompromised child (76), Mycobacterium kansasii in patients with
acquired immunodeficiency syndrome (AIDS) (77), and Mycobacterium avium complex in patients with
and without AIDS (78).
Yeasts and Fungi
Fungi have assumed an increasing role as the etiologic agents of focal intracranial infections. Many
pathogenic fungi, such as Cryptococcus neoformans, Candida species, Sporothrix schenckii, Aspergillus
species, and Zygomycetes species are ubiquitous (79). Others are geographically restricted, such as
Coccidioides immitis (southwest United States, northern Mexico, and Argentina), Histoplasma
capsulatum (greater Mississippi Valley, along the U.S.–Mexico border, in multiple regions of Central and
South America, and in scattered areas around the world), and Blastomyces dermatitidis (midwestern and
mideastern United States, along the St. Lawrence River, and in certain countries in Africa, the Middle
East, and India). Most cases occur in immunocompromised patients, and mortality remains high.
Cerebral aspergillosis occurs in 10% to 20% of all cases of invasive aspergillosis (Fig. 31.1) and only
rarely is the brain the sole site of infection (80). Without therapy, mortality is high, but survival rates of up
to 31% are reported in patients receiving voriconazole therapy (81,82). Among the most important risk
factors for invasive aspergillosis are immunosuppressive therapy (including high-dose steroids),
hematologic malignancies, solid-organ and bone marrow transplantation, and HIV infection (80,83). A
report of brain abscesses in bone marrow transplant recipients observed that 33 (58%) of 62 cases were
due to Aspergillus species (mostly Aspergillus fumigatus, with a few cases of Aspergillus flavus and
Aspergillus terreus) (6). Fungi of the Zygomycetes (formerly Phycomycetes) class can also invade the
CNS. Rhino-(orbital-)cerebral mucormycosis usually affects immunocompromised patients, in particular
patients with diabetes mellitus, hematologic malignancies, or stem-cell and solid organ transplantation
(84–86). Isolated cerebral mucormycosis has been observed mostly in injection drug users with or
without AIDS (87), but also in patients with hematologic malignancies (88) or pharmacologic
immunosuppression (89). Candidiasis is the fungal infection most often observed at autopsy to be
involving the CNS (90). Cases of diffuse cerebritis with miliary microabscesses, large parenchymal
abscesses, meningitis, and cerebrovascular complications have been described (90). Risk factors for the
development of CNS candidiasis are immunosuppression, treatment with antibiotics or corticosteroids,
intravascular catheters, recent abdominal surgery, prematurity (in neonates), recent neurosurgery or
cerebrospinal fluid (CSF) diversion, and injection drug abuse (90). Cryptococcus neoformans usually
causes meningitis when it invades the CNS, but mass lesions due to this organism have been observed.
Neuroradiologic studies have shown cryptococcoma (granuloma) in 11% of patients with cryptococcal
meningitis studied by CT (91) and in 50% of patients studied by magnetic resonance imaging (MRI) (92).
Scedosporium apiospermum (formerly known as Allescheria boydii, Pseudallescheria boydii, and

Petriellidium boydii) has received increased attention as a potential cause of CNS infection (93). In
addition to immunosuppression, near drowning in polluted water and rarely direct inoculation (orbital
trauma, lumbar puncture) were reported as predisposing conditions (94,95). Cladosporium trichoides
(Xylohypha bantianum, Cladosporium bantianum) is the most common cause of cerebral
phaeohyphomycosis, accounting for 28 of 53 reviewed cases (96).
Protozoa and Helminths
Various protozoa and helminths may cause brain abscesses, with their incidence varying with geographic
location. Toxoplasmosis is one of the most common parasitic infections of the brain, particularly in the
setting of AIDS (97) (see later discussion) but also in patients after bone marrow transplantation (98,99).
Entamoeba histolytica infections rarely involve the brain (100). The lesions are usually multiple and are
most often associated with another focal site of infection, usually hepatic. Free-living amebas (Naegleria
species, Acanthamoeba species, and Balamuthia species) are preferentially neurotropic (101,102). CNS
infection with Naegleria fowleri typically presents as acute fulminant meningoencephalitis (primary
amebic meningoencephalitis) in immunocompetent children and adults after exposure to polluted water
(water-related sport activities in the tropical and subtropical climates) (102). Balamuthia mandrillaris
and Acanthamoeba species cause granulomatous amebic encephalitis, which has a subacute or chronic
course and is usually seen in immunocompromised individuals (in particular, in patients with AIDS)
(102,103). Amebic CNS infections are usually fatal.
Neurocysticercosis (due to Taenia solium larvae) is the most common parasitic infection of the human
nervous system (104–107). It is endemic in many parts of the world, particularly Latin America, Africa,
and Asia, and still relatively common in Portugal, Spain, and Eastern European countries. In many
developed countries with high rates of immigration from endemic areas, neurocysticercosis is an
imported disease (107,108). Cysticercosis is probably the single most important cause of acquired
epilepsy in the developing world (109). Focal brain lesions in neurocysticercosis usually present as
(solid-enhancing) granulomas, calcified nodules, or (ring-enhancing) cystic lesions with or without a
scolex (109). Other helminthic infections that occasionally lead to focal intracranial lesions include
schistosomiasis (110), echinococcosis (111), paragonimiasis (112), trichinosis (113), sparganosis (114),
and infections due to Angiostrongylus cantonensis (115) or Strongyloides stercoralis (116).
PATHOGENESIS
Brain abscesses occur most commonly in association with one of three distinct clinical settings: (a) a
contiguous focus of infection, (b) cranial trauma or neurosurgical procedures, or (c) hematogenous spread
from a distant focus. No predisposing factors are recognized in approximately 10% to 25% of reported
cases (Table 31.4).
Contiguous Infectious Foci
Most patients with brain abscess demonstrate a contiguous focus of infection, usually sinusitis or otitis.
Otitis/Mastoiditis
The incidence of otogenic brain abscess (Tables 31.1 and 31.4) seems to decrease in developed
countries. However, in areas where otitis media continues to be neglected or where therapy is delayed,
intracranial complications of this process still present a particularly serious threat (117). Chronic otitis
media and/or mastoiditis leads to intracranial extension much more often than acute disease. In particular,
cholesteatoma is a common associated finding in otogenic brain abscesses, being found in 38% to 98% of
patients (24,25). Most otogenic brain abscesses are solitary lesions. The majority of otogenic brain
abscesses (55% to 75%) are located in the temporal lobe (24,25). The cerebellum is the next most
commonly affected area (20% to 30%), and it has been observed that approximately 90% of cerebellar
abscesses are secondary to otogenic infections (118). Otogenic intracranial suppuration most often
develops in patients younger than 30 years and shows a male predominance (24,25).
Sinusitis
Sinugenic brain abscesses are almost exclusively located in the frontal lobe (Fig. 31.2), reflecting the
distribution of the associated sinusitis (119–121). Most cases are in the setting of frontoethmoidal disease
followed by maxillary disease (122). Sphenoid sinusitis, despite its relative rarity (approximately 3% of
all sinusitis cases), has a relatively high rate of intracranial complications (123). Intracranial suppuration
secondary to sinusitis predominates in men in their second or third decade of life (119,120).
Dental Infection
Dental infections have less often been documented as a predisposing cause of a brain abscess in the past
(Table 31.4), but a recent study indicated an important role for dental infection as a source of brain
abscess in up to 12% of patients (16). Given the frequency of dental infections, however, intracranial
complications of this process are rare. The site of an associated brain abscess is most commonly the
frontal lobe, but temporal lobe localization can also occur by direct extension. A large majority of
intracranial infections in this setting follow a recent tooth extraction or dental manipulation. Bacteremia
has been observed in 100% of patients after dental extraction, in 70% after dental scaling, in 55% after
third molar surgery, and in 20% after endodontic treatment (124). Another study reported that 9% of
children with extensive tooth decay were bacteremic before treatment (125). Hygiene procedures such as
brushing of the teeth increased the prevalence of bacteremia to 40%, and anesthetic and surgical
procedures increased it to 97%. In both studies, the bacteria isolated from the blood were mostly
facultative species indigenous to dental plaque, in particular viridans streptococci (124,125). Many cases
of cryptogenic brain abscess are believed to be secondary to asymptomatic dental foci of infection.
Facial and Scalp Infections
Facial and scalp infections were reported in 1% to 4% of patients with brain abscess (126,127). Septic
thrombosis of the cavernous sinus is a possible link, and Staph. aureus is the most common pathogen in
this setting (128).
Meningitis
Brain abscess rarely complicates bacterial meningitis; however, it should be strongly considered as an
associated possibility in the neonate with purulent meningitis, particularly when meningitis is due to
gram-negative organisms (29). The vast majority of neonatal brain abscesses that complicate meningitis
are due to P. mirabilis or C. diversus. Neonatal meningitis due to Enterobacter species or Serratia
species is also often complicated by brain abscesses (39,40). Although P. mirabilis is a rare cause of
neonatal meningitis, 27 of 30 neonatal brain abscesses diagnosed over a 12-year period were due to this
organism (14). Additionally, abscess formation has been associated with more than 70% of cases of C.
diversus meningitis in the infant (129). The increased propensity for these two organisms to cause a brain
abscess is incompletely understood (130,131).
Cranial Trauma and Neurosurgical Procedures
Penetrating Cranial Injury

The risk of a brain abscess is increased in the setting of a penetrating cranial injury. Combat series
reported a risk of 3% to 4.2% of developing a brain abscess after missile or fragment injuries (Table
31.1). Risk factors were extensive brain injury, coma, trajectory through an air sinus, wound infections,
CSF fistula, inadequate initial débridement, retained (bone or metallic) fragments, and incomplete dural
closure. Several series have noted the role of head trauma as the cause of brain abscess in civilians. Thus,
head trauma was reported as an underlying cause of brain abscess in 3% to 11% of patients in most series
(4,28,132,133). Whereas the incidence of brain trauma as the cause for cerebral abscess formation
declined in a study from the United Kingdom (16), it was found to be the most common cause (33%) for
brain abscess in 973 patients from South Africa (9), reflecting the incidence of brain trauma (due to
accidents or violence) in a society. Various types of cranial trauma have been implicated, including
compound depressed skull fractures (133,134), dog bites (135), injuries due to rooster pecking (136), and
cranial penetration with lawn darts, pencil tips, or paint brushes (137,138). Several cases of brain
abscess as a complication of cervical traction with tongs or halo fixation have been described (139,140).
Associated pin-site cellulitis is usually observed.
Craniotomy
Brain abscess after neurosurgery is common (Fig. 31.3). In a series of 2,944 patients who underwent
neurosurgery, neurosurgical site infections developed in 117 (4%) (19). Forty-four patients (1.5%) had
incisional infections (30 with scalp infections and 14 with bone flap osteitis), and seventy-three (2.5%)
had deep wound infections (meningitis in 56 and mass lesions in 17 patients). Given the high number of
neurosurgical operations at certain centers, it was reported among the most frequent causes for brain
abscess in some series (16,141). Risk factors for deep wound infections were a Glasgow Coma Scale
score of less than 10 on admission, total hair removal, emergency surgery, CSF drainage, CSF leakage,
and early subsequent operations. Interestingly, wound contamination, surgical duration, and the absence of
antimicrobial prophylaxis were not significant risk factors for deep wound infections (19). The authors,
therefore, hypothesized that the risk of contaminating CSF or brain parenchyma begins during surgery but
persists in the postoperative period if a CSF drainage or leakage is present. This hypothesis was
supported by a predominance of hospital-acquired antibiotic-resistant bacteria in deep wound infections.
Hematogenous Spread
Hematogenous brain abscesses often share the following characteristics: (a) a distant focus of infection,
most often within the chest; (b) location in the distribution of the middle cerebral artery (Fig. 31.4), (c)
initial location at the gray matter–white matter junction, (d) poor encapsulation, and (e) high mortality.
These abscesses are more often multiple and multiloculated as compared with those that have an origin
from a contiguous focus of infection. Thirty-seven percent to 50% of multiple brain abscesses were of
hematogenous origin in several studies (142–144), whereas metastatic spread accounted only for 17% to
34% of all brain abscesses (Table 31.4).
Pulmonary Infections
Pyogenic lung diseases, especially lung abscess and bronchiectasis, accounted for 7% to 18% of total
brain abscess cases in four studies (4,9,122,127). Underlying chronic pulmonary diseases such as cystic
fibrosis, however, are surprisingly infrequently complicated by a brain abscess (145). When observed, it
most often occurs in older adolescents or adults (146). The organisms cultured from the sputum only
occasionally matched those cultured from the brain abscess and in some patients, associated sinus disease
was found. These observations suggest that the lung is not necessarily the source of brain abscess in
patients with cystic fibrosis and that contiguous spread of infection should also be considered.
Endocarditis
Brain abscess occurs in 5% to 7% of patients in the setting of bacterial endocarditis (Table 31.1)
(147,148), despite the presence of persistent bacteremia (see Chapter 34). The highest incidence of brain
abscess (5.4%) was reported in infective endocarditis of the left-sided valves due to Staph. aureus
(148). The development of a brain abscess depends on the level and duration of the bacteremia, the
virulence of the organism, and the occurrence of preceding emboli. A greater incidence of brain abscess
or meningitis is observed in cases of acute, rather than subacute bacterial endocarditis (Fig. 31.5).
Right-to-Left Shunt
Abnormal venous-arterial channels which increase the risk of developing a brain abscess probably
because of septic microemboli that can escape the pulmonary capillary filter (right-to-left shunt) include
pulmonary arteriovenous malformations (AVMs), congenital cardiac defects, patent ductus arteriosus, and
patent foramen ovale (PFO) (149,150). Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber
disease) is complicated by brain abscess, with striking regularity (151). Approximately 25% of patients
with this condition have pulmonary AVMs and 70% of the patients with pulmonary AVMs have hereditary
hemorrhagic telangiectasia (152). The incidence of brain abscess seems to increase with the number of
pulmonary AVMs (Table 31.1). Clinical findings, such as cyanosis, clubbing, polycythemia, and
hypoxemia, may be absent (asymptomatic AVMs). The diagnostic workup of patients with brain abscess
should therefore include a search for pulmonary AVMs (153). Congenital cyanotic heart disease (CCHD)
was found in 0% to 10% of patients with brain abscess (122,154). Some pediatric series suggest that
CCHD is the most common cause of brain abscess in children (150,155). In many studies, 50% or more of
all brain abscesses were attributed to CCHD in this age-group (155–160), and in two large series of
brain abscess in those with cyanotic heart disease, more than 50% of patients were younger than 10 years
of age (161,162). Tetralogy of Fallot is consistently the most commonly cited defect (161,162).
Transposition of the great arteries, double outlet right ventricle, single ventricle, tricuspid atresia, Ebstein
disease, and Eisenmenger complex were the next most frequently observed disorders in the largest series
(161). Several reports showed PFO in patients with brain abscesses (163). However, the prevalence of
PFO in adults is high (20% to 35%). Therefore, a population study will be necessary to document
whether the prevalence of PFO is higher in patients with brain abscess with a presumed spread from a
distant infectious focus than in the general population.
Other Foci of Metastatic Spread
Other distant foci of infection may be associated with brain abscess and have included wound and skin
infections, osteomyelitis, pelvic infection, cholecystitis, and other forms of intraabdominal sepsis. Brain
abscess has also been described as an unusual complication of esophageal dilation of caustic strictures
and endoscopic ligation of varices (164,165). Brain abscess in these cases is probably due to bacteria of
the oropharyngeal flora that entered into the circulation through lesions of the mucous membrane.
Transient bacteremia develops in up to 100% of cases of esophageal dilation (mostly due to viridans
streptococci, Staph. aureus, and Staph. epidermidis) and in up to 50% of cases involving sclerotherapy
(mostly due to Pseudomonas species and α-hemolytic streptococci) (164,166).
Location
In approximate decreasing order of frequency, a solitary abscess may involve the following brain regions:
frontal, temporal, parietal, and occipital lobes and cerebellum (Table 31.5). This distribution reflects the
associated, often contiguous, focus of infection (Table 31.3). Intrasellar, brainstem, basal ganglia, and
thalamic abscesses are rare.
Pituitary Abscesses
Pituitary abscess is caused either by hematogenous seeding of the pituitary gland or by direct extension of
an adjacent infection, such as meningitis, sphenoid sinusitis, cavernous sinus thrombophlebitis, or a
contaminated CSF fistula (167). Besides infection by pyogenic bacteria, pituitary infections have been
caused by Treponema pallidum, M. tuberculosis, Entamoeba histolytica, and a variety of fungi,
including Histoplasma capsulatum, Blastomyces dermatitidis, Sporothrix schenckii, Candida species,
and Aspergillus species (167,168).
Brainstem Abscesses
Brainstem abscesses (Fig. 31.6) often arise from hematogenous spread or, less frequently, in association
with a contiguous infection, such as otitis (169,170). Brainstem abscesses have a relatively poor
prognosis. This is primarily because their anatomic location can lead to catastrophic neurologic
complications and often preclude definitive drainage. Brainstem abscesses tend to elongate in the
brainstem rather than expand laterally (170). Therefore, the clinical findings can be confusing.
Abscesses in the Thalamus and Basal Ganglia

Inflammatory lesions (especially when solitary) of the thalamus and basal ganglia are also somewhat
unusual (Table 31.5). Most often they are hematogenous (171) and they are frequently associated with
hydrocephalus, most likely due to close proximity to the ventricles (172).
General Pathogenetic Considerations
The final common pathway for brain abscess development in the preceding conditions appears to require
a compromised area of brain. Experimental data suggest that infection is extremely difficult to establish in
normal brain tissue (173). Brain abscess may develop from a contiguous infection via direct extension
through areas of associated osteitis or osteomyelitis and retrograde thrombophlebitic spread via diploic
or emissary veins into the intracranial compartment. Additional possibilities in the case of otogenic
infection include spread through preexisting channels (the internal auditory canal, cochlear, and vestibular
aqueducts) or between temporal suture lines. Hematogenous dissemination is occasionally implicated
with contiguous foci, particularly in cases of sinus or odontogenic origin. None of these hypotheses
explains the relative rarity of intracranial infection with sinusitis or otitis, how bacteria traverse an intact
dura, or what determines the form of intracranial complication that eventually evolves (e.g., meningitis,
epidural abscess, subdural empyema, or brain abscess) in the individual with the same predisposing
condition.
The development of a brain abscess in the setting of neonatal meningitis deserves special comment.
The pathogenesis appears to follow the initiation of a necrotizing vasculitis (particularly in the small
penetrating vessels), leading to subsequent hemorrhagic necrosis and liquefaction of the subcortical white
matter, an area highly susceptible to changes in cerebral perfusion (174). Others disagree with this
formulation, contending that the evidence favors an initial ventriculitis followed by ependymal disruption
and subsequent direct extension of the infection into the brain parenchyma. Similar findings have been
noted in an infant rat model of Citrobacter diversus meningitis and brain abscess (175) and support the
latter hypothesis.
In hematogenous cases, the polycythemia and systemic hypoxia observed in CCHD and hereditary
hemorrhagic telangiectasia increase blood viscosity, with an associated reduction in brain capillary flow,
perhaps leading to microinfarction and reduced tissue oxygenation in the brain. Septic microemboli that
escape the pulmonary capillary filter through right-to-left shunts during bacteremic episodes might then
seed already compromised brain tissue. This hypothesis is in good agreement with the development of
abscesses in focal brain damage due to, for example, brain tumor, hemorrhage, or ischemia. In 1997, a
review reported 15 cases of abscess formation in brain neoplasms (176). Six of the brain abscesses
developed in a meningioma, glioma, or craniopharyngioma and were associated with bacteremia due to
Salmonella typhi, Staph. aureus, Bacteroides oralis, or E. coli (most of the other abscesses developed in
pituitary tumors or craniopharyngiomas and were attributed to contiguous spread from an adjacent
infected sinus). It was proposed that tumor-associated blood–brain barrier breaching favored the
development of hematogenous brain abscesses as eight such cases of abscess development at the site of an
intracerebral hemorrhage were reported (21). A similar mechanism has been proposed for the
observation of brain abscess formation in ischemic brain tissue (177,178) and after endovascular
treatments of cerebral aneurysms, AVMs, or dural arteriovenous fistulas (38,179,180).
The immune response that is elicited to combat the invading pathogen is an essential part of abscess
formation as it also destroys surrounding normal brain tissue (181). This is suggested by the finding that
lesions of the brain are much greater than the area of bacterial growth in experimental brain abscesses
(182,183). The most extensive work on the pathogenesis of brain abscess has been performed in a mouse
model of S. aureus brain abscess. S. aureus has been shown to activate parenchymal microglia and
astrocytes (in a toll-like receptor 2 [TLR2], TLR4, and MyD88-dependent fashion [184,185]). In turn,
they produce a variety of cytokines and chemokines such as interleukin-1β, tumor necrosis factor-α (TNF-
α), and macrophage inflammatory protein-2 (MIP-2) (186–189) that attract peripheral inflammatory cells.
If the initial immune response is unable to clear the infection (which can be related to the presence of
bacterial virulence factors such as α-toxins in S. aureus–related brain abscess or the result of an
insufficient immune responses), a continuing inflammatory response is initiated and upheld. Among the
stimuli for such an ongoing inflammation are bacterial toxins (pathogen-associated molecular patterns
[PAMPs]) and endogenous agents that are set free as a consequence of tissue damage (damage-associated
molecular patterns [DAMPs]) and stimulate the immune response (189,190). As a consequence, the
development of a chronic disruption of the blood–brain barrier and final abscess formation is found.
These experimental findings support the idea that an intervention with both antiinfective and
antiinflammatory compounds might be an effective strategy to minimize damage to brain parenchyma in
brain abscess (181).
PATHOLOGY
Histopathologic Stages of Brain Abscess Development
The evolution of a brain abscess includes four histopathologic stages (191). This staging process,
described in animal models of brain abscess, correlates well with human brain abscess evolution (192).
The first stage is an early cerebritis (days 1 to 3 following intracerebral inoculation in animals), which
progresses to a perivascular inflammatory response surrounding the developing necrotic center by the
third day. Profound edema in the surrounding white matter develops concurrently (Fig. 31.7).
In the second stage of late cerebritis (days 4 to 9), development of a well-formed necrotic center
reaches its maximum size. Additionally, fibroblasts appear, setting the stage for capsule formation and a
marked increase in neovascularity at the periphery of the necrotic zone. These newly formed capillaries
often lack tight junctions and leak proteinaceous fluid. Surrounding this is the beginning of a reactive
astrocyte response, along with persistent white matter edema.
The third stage, early capsule formation (days 10 to 13), is characterized by a slight decrease in the
size of the necrotic center (Fig. 31.8). At this point, there is a well-developed layer of fibroblasts, with
significantly more reticulin deposition on the cortical side than on the ventricular side of the lesion.
Outside this developing capsule is a region of persistent cerebritis and neovascularity, with a further
increase in reactive astrocytes.
These processes continue in the fourth and final stage, late capsule formation (day 14 and later). The
capsule continues to thicken, with an abundance of reactive collagen present by the third week.
Some studies have criticized the preceding model’s utility in describing a uniform mode of brain
abscess evolution (193). These authors, using the same dog model and inoculum, could not detect viable
organisms in the brain lesions after 3 days and, in all animals, the lesions spontaneously resolved. Further
work is necessary to reconcile this debate. Nonetheless, a brain abscess model in rats supports the
previously mentioned histologic progression (194). Two other experimental models of brain abscess
using organisms other than α-hemolytic streptococci also indicate that this view of abscess evolution is
either overly stereotyped or affected by inadequate growth of the microorganisms. In a model of
Bacteroides fragilis (inoculated with Staph. epidermidis) brain abscess (195), the same stages of
evolution were observed; however, the early and late capsule stages could not be differentiated, because
of a delay in encapsulation when compared to abscesses following streptococcal challenge. These
abscesses enlarged more quickly, were prone to early ventricular rupture (25%), and exhibited
incomplete encapsulation. This suggests the extreme virulence of B. fragilis, an important pathogen in
brain abscess, in brain tissue when part of a mixed infection. In an experimental model using S. aureus
(196), there were quantitative and qualitative differences in abscess evolution when compared with
inoculation of α-streptococci. S. aureus inoculation resulted in larger lesions, earlier ependymitis, and
delayed progress toward healing, with longer periods required for the infection to reach a stable size. The
same approximate stages were present, but their separation was also not as distinct as previously
described. The white matter appeared more susceptible to destruction than the gray matter, and the spread
of infection was centrifugal, rather than along particular white matter tracts. In contradistinction, a model
of E. coli brain abscess exhibited expansion of the abscess along white matter tracts (197). In addition,
results from the S. aureus experimental model raised some questions regarding the previously held
assumption that the capsule serves to contain infection. The abscess reached its maximum size in the late
cerebritis stage, before any significant capsule formation had taken place, suggesting that the host was
able to contain the infection before capsule formation. Also, even in the late capsule stage, inflammation,
necrosis, and edema extended well beyond the well-formed capsule.
Two observations regarding encapsulation deserve special attention: (a) capsule formation is usually
more complete on the cortical side of the abscess than on the ventricular side (191), and (b) encapsulation
is less extensive in abscesses resulting from hematogenous spread than in those arising from a contiguous
focus of infection (198). The preferential deposition of collagen on the outer edge of the abscess is
thought to be due to the better vascularization of the gray matter (197). This discrepancy probably
explains the propensity for abscesses to rupture medially rather than into the subarachnoid space.
Similarly, cerebral ischemia from a septic embolus might impede optimal collagen formation (198).
Therefore, brain abscess formation is a continuum from cerebritis to a collagen-encapsulated necrotic
focus; however, its maturity is dependent on many factors, including local oxygen concentration, the
offending organism, and the host’s immune response.
Signs and Symptoms
The clinical manifestations of a brain abscess (Table 31.6) can vary greatly among patients. Additionally,
symptoms from the primary site of infection (i.e., otitis, sinusitis, or distant suppurative foci) may
predominate. The evolution of symptoms of a brain abscess may range from indolent to fulminant; the
average duration of symptoms until hospital admission is 11 to 12 days (range, hours to several weeks)
(122,132). The classic triad of fever, headache, and a focal neurologic deficit is present in less than 50%
of patients. In most patients, the prominent clinical manifestations of brain abscess are due to an
expanding intracerebral mass rather than infection; neurologic signs, such as headache and hemiparesis,
predominate in patients with multiloculated brain abscess as compared with patients with uniloculated
brain abscess (199). The clinical presentation of patients with cerebellar abscesses is different, because
signs of raised intracranial pressure (ICP) (e.g., headache, vomiting, and papilledema, >90%), fever
(90%), meningismus (>70%), and depressed consciousness (>50%) are particularly common (118,200).
Cerebellar signs are present in 25% to 50% of patients, whereas hemipareses are evident in only 10% of
patients. The clinical presentation of frontal lobe abscesses is often dominated by headache, drowsiness,
inattention, and a generalized deterioration in mental function. Hemiparesis with unilateral motor signs
and a motor speech disorder are the most common focal findings. A temporal lobe abscess may present
with early ipsilateral headache. If the abscess is in the dominant hemisphere, an aphasia or dysphasia may
be present. An upper homonymous hemianopia may also be demonstrated and may be the only sign of a
right temporal lobe abscess. Intrasellar abscesses often simulate a pituitary tumor, presenting with
headache (>90%), abnormal pituitary function (>50%), and visual field defects (50%) (167). The clinical
presentation of brainstem abscess is usually a rapidly progressing neurologic deficit involving cranial
nerves and long tracts.
Because of their nonspecific presentation and frequent lack of fever, brain abscesses can be confused with
several other processes. The major differential diagnoses of a brain abscess include primary
(glioblastoma) or metastatic malignancies of the CNS (Figs. 31.9 and 31.10). Furthermore, differential
diagnoses may include other infectious diseases, including viral encephalitis (especially due to herpes
simplex virus), subdural empyema and epidural abscess, or mycotic aneurysms in the setting of infective
endocarditis. Cerebral venous sinus thrombosis, cerebral infarction, resolving hematoma, arterial
infarction in the stage of luxury perfusion, AVM, neurosarcoidosis, and tumefactive multiple sclerosis may
also be confused with a brain abscess, both symptomatically and occasionally radiographically (201). In
patients with AIDS, the most common cause of intracranial mass lesions is toxoplasmosis; the most
important differential diagnosis is primary CNS lymphoma, followed by brain abscesses due to pathogens
other than Toxoplasma (Table 31.3), metastatic tumors, and cerebrovascular disease (202).
APPROACH TO A DIAGNOSIS
Laboratory Investigations
Examination of the blood is rarely helpful in the diagnosis of a brain abscess (Table 31.7). The serum C-
reactive protein (CRP) values are more commonly elevated than the blood leukocyte counts or erythrocyte
sedimentation rate (ESR). However, up to 23% of patients in previous studies had a normal CRP serum
concentration. Blood cultures are infrequently positive (about 10%) at the time of presentation. However,
blood cultures were reported to be positive in 86% of patients with listerial brain abscesses (203).
Lumbar puncture is also of very limited value for the diagnosis, most often reveals nonspecific CSF
alterations, and carries a considerable risk of cerebral herniation; therefore, it should not be performed in
patients with a space-occupying brain abscess. Cerebral herniation developed immediately after lumbar
puncture in 2.1% of patients (mean, range 0% to 4.2%) (126,127,132,204,205), and neurologic
deterioration was observed in 13.5% of 193 patients with brain abscess who received a lumbar puncture
(9). Positive CSF cultures, however, were reported in only 6% of patients (mean, range 0% to 10%)
(4,122,127,132), unless there has been a rupture of abscesses into the ventricles or subarachnoid space,
in which case up to 20% may be positive (122). The CSF cell count can range from 0 to more than
100,000 cells/µL, the protein level from normal to more than 500 mg/dL, and CSF glucose concentration
can be normal or severely depressed (122,132).
Neuroimaging Studies
Neuroimaging is the most important first step in establishing the diagnosis of brain abscess. Cranial CT
(Table 31.7, Figs. 31.11 to 31.14) and in particular MRI (Table 31.7, Figs. 31.2, 31.3, 31.5, and 31.15 to
31.17) are very sensitive neuroimaging modalities for the detection of brain abscesses and yield precise
anatomic information. However, this is not paralleled by an equivalent specificity; a similar appearance
is occasionally seen with other cystic brain lesions, in particular neoplasms (201). Cranial CT is widely
available and often facilitates early detection of brain abscess. For the detection of a brain abscess, the
CT must be performed with intravenous contrast administration. During early brain abscess, a
nonenhancing hypodensity is usually found. However, it has to be kept in mind that in the earlier phases of
brain abscess, CT may show only low attenuation abnormalities with mass effect (Fig. 31.11) or even fail
to detect a lesion at all (Fig. 31.14). This is especially true in brainstem abscesses. During later stages,
when blood–brain barrier breaching progresses, contrast enhancement and finally a thick ring-enhancing
lesion is found on CT, representing the development of an inflammatory capsule (Figs. 31.12 and 31.13).
During later stages, the contrast-enhancing ring becomes thinner. Features thought to discriminate
abscesses from malignant tumors (thinner, more regular contrast-enhancing rim and homogeneous
enhancement of the capsule after infusion of contrast medium) do not always permit a precise diagnosis.
The value of MRI in differentiating brain abscess from other cystic lesions of the brain, such as tumor,
has increased in the past years. Compared to CT, MRI is more sensitive in the detection of early
cerebritis and small satellite lesions. Furthermore, MRI allows estimation of the degree of central
necrosis, ring enhancement, and surrounding cerebral edema more accurately than CT. MRI is also better
suited for the detection of brain abscess in the brainstem. In contrast to tumors, increased signal in
diffusion-weighted imaging (DWI) at reduced apparent diffusion coefficient (ADC) values are found in
brain abscesses (Figs. 31.9 and 31.10) (206–209). In a study of 147 cystic lesions of the brain in 115
patients, the sensitivity and specificity of DWI for the differentiation of brain abscesses from non-
abscesses were 96% each (208). This does not hold true for all cases of cerebral toxoplasmosis where
MRI, and especially DWI, findings differ depending on the stage of the disease (Fig. 31.17) (210).
Although less readily available, an increased fractional anisotropy (FA) was found in the cavity of
abscesses using diffusion tensor imaging (DTI), allowing discrimination of abscesses from tumors (211).
Using magnetic resonance (MR) spectroscopy, resonances for acetate, lactate, alanine, succinate, and
pyruvate as well as valine, leucine, and isoleucine were found elevated in brain abscess but not in tumors
(212,213). Recent studies suggest an additional role of perfusion-weighted MR measurements (of the
peripheral regions of cystic lesions of the brain) to distinguish brain abscess from tumor (214). Possibly,
a combination of MR spectroscopy, DTI, and perfusion-weighted MR might be helpful to further increase
specificity of MR in diagnosing brain abscess in the future.
Biopsy
The most important diagnostic measure in the establishment of the diagnosis of brain abscess is histologic
and microbiologic assessment of tissue from the suspicious lesion. This not only allows differentiation
between tumor and abscess but also identification of the causative pathogen. Thus, a specimen obtained
from biopsy of cystic lesions should (a) be sent for histologic evaluation and (b) be evaluated by Gram
stain and aerobic, anaerobic, mycobacterial, and fungal cultures (Fig. 31.18). Furthermore, staining for
mycobacteria, Nocardia, and fungi should be performed. In recent studies, 16S ribosomal DNA
polymerase chain reaction amplification was shown to increase the number of bacterial species isolated
from brain abscesses (215–217), but further data are needed to determine its use in identification of
important causative pathogens in patients with brain abscess. Identification of the causative organism(s) is
especially crucial for further therapy (see the following discussion).
TREATMENT
Treatment of brain abscess is based on the following principles: (a) surgical therapy of brain abscess, (b)
antibiotic therapy, and (c) surgical therapy of the primary infectious focus. Therefore, optimal medical
care of brain abscess requires the cooperation between an infectious disease specialist, neurologist,
neuroradiologist, neurosurgeon, microbiologist, and sometimes an ear, nose, and throat specialist,
surgeon, dentist, or maxillary surgeon. Cranial CT or MRI allows a precise localization of the abscess or,
when multiple abscesses are present, identification of the lesion that is most suited for stereotactic
aspiration. In addition, sources of infection (e.g., otitis or sinusitis) can be detected. Randomized
controlled studies of therapies for brain abscess do not exist. Treatment recommendations are, therefore,
based on retrospective analyses and clinical experience. Although doubted by some authors (132), some
major series have demonstrated that the administration of preoperative antibiotics reduces the yield of
positive cultures (4,218). However, antimicrobial therapy can be withheld until surgery only if the
operation can be performed within a short time (hours) and the abscess does not show a significant mass
effect (risk of herniation). The risks of stereotactic aspiration are probably less than the risks of incorrect
diagnosis and choice of antibiotics; therefore, the decision to use empirical therapy alone should be made
with great caution.
Surgical Therapy
The timing of surgery and type of surgical procedure selected remain controversial and prospective
studies are lacking. Usually, aspiration or excision is used. Retrospective series failed to detect any
significant difference in mortality (or functional neurologic outcome) between patients treated by
aspiration or excision (4,28,218,219). Nevertheless, the type of care (stereotactic aspiration plus medical
treatment vs. operation plus medical treatment vs. medical treatment alone) in these studies was often not
based on clear and explicit data. However, there is consensus that bacterial brain abscess should be
treated by surgery if larger than 2.5 cm and causing significant mass effect. However, it remains unclear
what type of operation should be favored. Interestingly, outcome was more associated with clinical
presentation and the speed of operation rather than the type of operation (14,132,220). The choice of
surgical treatment should, therefore, depend on the patient’s clinical status, the location and accessibility
of the abscess(es), the techniques available, and the surgeon’s expertise.
Stereotactic Aspiration
Because stereotactic aspiration causes less tissue damage than excision, CT (or MRI)-guided stereotactic
aspiration through a burr hole is usually considered the method of choice in patients with brain abscess
(Fig. 31.18). Stereotactic aspiration is particularly valuable for deep-seated abscesses (brainstem,
cerebellum, and basal ganglia), multiple abscesses, and abscesses in critical locations (Figs. 31.6 and
31.19), where high precision is necessary (221–223). In addition, patients who are poor candidates for
general anesthesia might better be treated by aspiration rather than operation. With large superficial
abscesses of the cerebral hemispheres, CT-guided “freehand” burr-hole aspiration may be performed as
an emergency measure (in those with impending cerebral herniation). It requires less preparation but is
less precise than stereotactic aspiration.
Compared with excision, the disadvantage of aspiration is that repeated aspirations or even excision
may become necessary. Another considerable risk is intracranial bleeding; therefore, abnormal results of
clotting studies or thrombocytopenia are particular contraindications for burr-hole aspiration and must be
corrected.
Excision
Open craniotomy and total excision of the abscess may become necessary in all lesions that fail to
respond to repeated aspirations and medical therapy (Fig. 31.20). Excision is also necessary in brain
abscesses secondary to foreign bodies, and some authors advocate that abscesses exhibiting gas by CT or
on plain film should also be completely excised, because an open craniotomy will allow for the detection
and treatment of an extracranial communication (224). Furthermore, patients with abscesses in the
posterior cranial fossa are often preferably treated by excision (223,225,226). Patients with posttraumatic
or postoperative brain abscess have also been considered candidates for excision by most authorities
(222,225).
Medical Therapy
Antibiotic therapy, usually in combination with surgery, is important in the management of brain abscess.
Because the chance to detect the causative pathogen from specimens collected during aspiration or
excision of the abscess decreases in a time-dependent manner after antibiotic therapy has been started,
immediate surgery followed by empirical antibiotic therapy is recommended. However, if surgery is
delayed, empirical antibiotic therapy needs to be started before surgery. Despite a lack of data, medical
therapy alone might be an option in certain situations. However, by not performing surgery, confirmation
of the diagnosis and identification of the causative pathogen is important to be able to select the correct
antimicrobial therapy. In consequence, only few patients are treated by medical therapy alone; for
example, only 19 of 973 patients received nonsurgical treatment in a study from South Africa (9). In
retrospective case series, candidates that seemed suitable for antibiotic therapy alone were patients with
small abscesses (<2.5 cm), in good clinical condition (Glasgow Coma Scale >12), and in whom the
etiology of the abscess was established (170,227). Medical therapy alone can also be considered in
patients with a lesion in the cerebritis stage (which are much more likely to respond to antibiotic therapy
alone because of lack of a capsule) or surgically inaccessible abscesses (in particular brainstem
abscesses) (170). These patients should be treated with high-dose broad-spectrum intravenous antibiotics
for at least 6 to 8 weeks and perhaps longer. If the patient shows neurologic deterioration or serial CT
scans show that the abscess does not decrease in size within several weeks or even grows, a surgical
procedure should be reconsidered to confirm the diagnosis, collect material for culture, and remove as
much pus as possible (220,228).
Suitable Antimicrobial Agents

Randomized controlled studies that compared the efficacy of different antibiotic regimens are lacking in
patients with brain abscess. Antibiotics used for the treatment of brain abscess should be administered
intravenously, be active against the pathogens that have been identified as causative agents of the abscess
or are likely in a given clinical scenario, penetrate into the abscess fluid (and into the site of the
underlying infection) in adequate concentrations, and have bactericidal activity (220). Additional
therapeutic concerns include the effect of the abscess environment on the activity of the antibiotic and the
possibility of negative drug interactions when multiple agents are administered. In 32 patients with brain
abscess, penicillin G was detectable consistently if the dose exceeded 24 million units daily (in adults)
(229). Fusidic acid entered the brain abscess readily, but concentrations of various cephalosporins and
cloxacillin were low. Metronidazole attains high concentrations in brain abscess pus (230), often
exceeding serum concentrations after a dose of 400 to 800 mg every 8 hours. Because of these results and
the bactericidal activity of metronidazole against strict anaerobes, this agent is an important component of
antimicrobial regimens for brain abscesses. Vancomycin attained acceptable concentrations (for aerobic
streptococci and staphylococci) in the single brain abscess studied (231). Cefotaxime, ceftazidime,
ceftriaxone, and ampicillin/sulbactam were shown to be efficient in the treatment or to have an adequate
penetration into brain abscesses (232–236). Imipenem/cilastatin has also been demonstrated to penetrate
at sufficient levels into brain abscess pus and to be effective (237–240). However, because of the
reported neurotoxicity (increased incidence of seizures) of imipenem, meropenem is preferred; a
successful outcome using this agent in the treatment of a brain abscess due to a multidrug-resistant
Enterobacter cloacae was shown (241). In the search for newer antibiotics, linezolid has been shown to
be a promising agent for the treatment of CNS infections, having good penetration into the CSF (242,243).
Quinolones, which have been used with success, should be used with caution in the treatment of cerebral
abscesses, because they can also lower seizure thresholds (244).
Empirical Antimicrobial Therapy

The antimicrobial regimens commonly recommended for the therapy of brain abscess are empirical and
reflect the considerations already noted, as well as the in vitro activity of the component agent(s) against
the usual pathogens. No controlled trials on the relative efficacy of various regimens have been
performed. Interpretation of the success or failure of a given regimen is further confused by the various
surgical procedures, which may be used concomitantly.
In patients with community-acquired brain abscesses (Tables 31.8 and 31.9), third-generation
cephalosporins, such as ceftriaxone or cefotaxime, which are directed against streptococci and a broad
range of gram-negative bacteria are preferred for first-line empirical therapy. In addition, coverage of
anaerobes (e.g., by metronidazole) and staphylococci (e.g., by flucloxacillin, nafcillin, or vancomycin)
should be considered in appropriate circumstances. If meropenem is used, the addition of metronidazole
is not necessary because meropenem is active against anaerobic bacteria itself. Patients with otogenic
brain abscesses should be treated initially with ceftazidime or cefepime, because these cephalosporins
are also effective against Pseudomonas aeruginosa (Table 31.8).
Because patients with posttraumatic brain abscess or nosocomial brain abscess are at risk for infection
with MRSA and multiresistant Enterobacteriaceae, meropenem or cefepime plus vancomycin is the
recommended empirical treatment in such cases (Table 31.8). Bone marrow, stem cell, and solid organ
transplant recipients with brain abscesses often require initial polypragmatic therapy including
meropenem, vancomycin, voriconazole, and anti-Toxoplasma therapy to treat a wide variety of potential
infectious pathogens. In all cases, the empirical treatment should be modified or extended, if laboratory,
clinical, or radiologic findings are suggestive of a specific pathogen. After culture results are obtained,
therapy needs to be modified according to the identified pathogen(s) and in vitro susceptibility testing.
The usual treatment of choice for CNS candidiasis is the combination of intravenous liposomal
amphotericin B and oral flucytosine (90,245). Cryptococcal CNS disease, best studied in patients with
cryptococcal meningitis, is usually treated with a combination therapy consisting of liposomal
amphotericin B and flucytosine (induction therapy). After 2 weeks, consolidation therapy with
fluconazole (400 mg per day) should be given for an additional 8 to 10 weeks. Then, immunosuppressed
patients should receive fluconazole (200 to 400 mg per day) for an additional 6 to 12 months
(suppression) (246). In HIV-positive patients, suppressive therapy is continued until CD4 cells are
maintained above 150 to 200 cells/µL for more than 6 months in patients on antiretroviral therapy. CNS
coccidioidomycosis should be treated with fluconazole or, alternatively, itraconazole (247), and patients
with CNS blastomycosis should be treated with liposomal amphotericin B (248). CNS histoplasmosis
should be treated initially with amphotericin B for 3 months, then with itraconazole for 12 months (249).
In the treatment of cerebral mucormycosis, amphotericin B is the only antifungal agent with proven in vivo
activity (250). Actinomycosis of the CNS is often treated with high-dose intravenous penicillin for 2 to 6
weeks, followed by oral therapy with amoxicillin, ampicillin, or penicillin V for 6 to 12 months.
Doxycycline, erythromycin, and clindamycin can be given alternatively according to sensitivity test
results.
Instillation of antibiotics into the abscess cavity during aspiration has been employed, but the efficacy
of this practice has never been established. Antibiotics given in this manner may diffuse into surrounding
brain tissue in high concentrations, causing seizures. It should, therefore, be used with caution and is not
recommended.
Management of Nocardial Brain Abscesses

A study of 131 patients with nocardial brain abscesses (67) recommended that (a) if an extraneural
nocardial infection (present in 70% of patients) is documented in a clinically stable immunocompetent
patients with a brain abscess less than 2 cm in diameter, empirical treatment with trimethoprim-
sulfamethoxazole should be given (possible alternatives are meropenem, ceftriaxone, ampicillin,
linezolid, vancomycin, or amikacin) and (b) if the patient deteriorates clinically, or if the abscess does not
decrease in size within 4 weeks, stereotactic aspiration should be performed to confirm the diagnosis and
to decompress the lesion. However, several recent reviews challenged this view and recommended that
an open or stereotactic biopsy should be performed early in the patient’s course, because it facilitates an
early and accurate diagnosis (251–253). Another series of 11 patients confirmed that aspiration is an
effective treatment of nocardial brain abscesses with considerable mass effect (254). Nine of these
patients were treated only with aspiration and long-term chemotherapy (intravenous chemotherapy for 4 to
6 weeks and subsequent oral drug therapy for 6 to 12 months; nine patients were treated with
trimethoprim-sulfamethoxazole) and two patients underwent craniotomy and lesion excision. Four of the
nine patients needed only one aspiration, three patients needed two aspirations, and three or four
aspirations were necessary in one patient each. There were no fatalities in this series.
Management of Cerebral Aspergillosis

A prospective unblinded study on 277 patients with invasive aspergillosis showed that voriconazole
therapy was associated with a lower mortality than amphotericin B during the first 12 weeks of treatment
but the number of patients with cerebral aspergillosis was low (n = 5 in each treatment group) (82).
Nevertheless, in a retrospective study of 81 patients with cerebral aspergillosis, treatment with
voriconazole was associated with a complete or partial response in 35% of patients (81). In comparison,
cerebral aspergillosis was reported to be fatal in more than 90% of patients despite therapy with
amphothericin B. Thus, voriconazole is recommended as the treatment of choice for cerebral
aspergillosis. Furthermore, multifactorial analysis revealed that additional neurosurgical treatment such
as craniotomy, abscess resection, abscess drainage, or shunting/placement of an Ommaya reservoir were
associated with improved outcome (81). To date, whether excision or aspiration is the better treatment for
cerebral aspergillosis is not clear. However, an early diagnostic stereotactic aspiration, if feasible, is
warranted in cases of suspected cerebral aspergillosis (80,255).
Management of Brain Abscess in Patients with AIDS

The following procedures have been proposed for the evaluation and treatment of intracranial lesions in
patients with AIDS (202): (a) empirical treatment for toxoplasmosis should be instituted in all cases
(pyrimethamine plus sulfadiazine or pyrimethamine plus clindamycin), except when a single intracranial
mass lesion accompanies negative serology for toxoplasmosis; and (b) a stereotactic biopsy is indicated
if serology is negative or the patient deteriorates clinically or radiologically during antitoxoplasmic
therapy, although large lesions may require immediate surgical decompression. In HIV-infected children,
proceeding directly to stereotactic biopsy may be considered, because toxoplasmosis is rare in this
patient population.
Management of Patients with Multiple Abscesses

For patients with multiple brain abscesses, it has been recommended that all abscesses larger than 2.5 cm
in diameter or with significant mass effect should be stereotactically aspirated (or excised) (220,221). If
the abscesses are all smaller than 2.5 cm in diameter, the largest and/or most accessible lesion should be
aspirated for diagnostic purposes. In the case of enlargement of an abscess after a 2-week interval or a
failure of an abscess to diminish in size after 3 to 4 weeks of antibiotics, further surgical drainage is
recommended.
Duration of Antimicrobial Therapy and Follow-up

In general, the appropriate duration of antimicrobial therapy for brain abscess is not completely clear, but
duration of antibiotic therapy for shorter than 4 weeks are not reported. Usually, 4 to 8 weeks of
intravenous therapy is reported suitable, provided that the pathogens are susceptible, a clear clinical and
radiographic response is observed, and the treatment is well tolerated by the patient. Some favor an
additional 2 to 4 weeks, others a several months course of oral antimicrobial therapy to prevent relapse.
However, clinical evidence for that recommendation is lacking. Drugs used for oral treatment include
trimethoprim-sulfamethoxazole, amoxicillin/clavulanic acid, moxifloxacin, linezolid, and rifampin (220),
although rifampin should not be used as single-agent therapy. Follow-up should include clinical
examinations and serial CT scans or MRI to document resolution of the abscess (Fig. 31.19). However,
even a cured brain abscess may continue to exhibit areas of contrast enhancement on neuroimaging for
several months after completion of successful therapy (256). Follow-up DWI might be of help in
assessing treatment responses in brain abscess in the future (257).
Corticosteroids
The use of corticosteroids in brain abscess is problematic because it might interfere with the CNS
penetration of antibiotics (258). In summary, there is no data favoring a routine use of steroids in the
treatment of brain abscess. Adjunctive therapy with corticosteroids should, therefore, be restricted to
patients with a progressive neurologic deterioration or impending cerebral herniation and radiologic
evidence that the abscess is causing significant cerebral edema and mass effect. Furthermore, in patients
with abscesses in areas where edema might quickly become critical (cerebellum), the use of
corticosteroids should be considered. Whenever corticosteroids are used, a rather quick reduction of
dosage is recommended once the patient has had a clinical response.
TREATMENT OF COMPLICATIONS
The most important complications of brain abscesses are (a) seizures, (b) obstructive hydrocephalus, (c)
intraventricular rupture of the abscess resulting in ventriculitis and/or meningitis, and (d) brain edema.
Seizures
On admission, seizures are reported in up to 34% of patients with brain abscess (9,16,32,259). Acute
seizures should be terminated with administration of intravenous benzodiazepines, such as lorazepam or
midazolam, or by intravenous fosphenytoin. For the prevention of further seizures, carbamazepine and
fosphenytoin are recommended; in addition to phenytoin, valproate and levetiracetam are available for
intravenous administration. Patients without seizures but with epileptic discharges on the
electroencephalogram (EEG) should also be treated with antiepileptic drugs. Interestingly, a reduced
frequency of seizures in brain abscess was reported in patients treated with aspiration in comparison to
those treated with excision, but studies were retrospective (260). The prophylactic treatment of patients
without EEG abnormalities, however, still is a matter of debate, and there are no conclusive studies of
seizure prophylaxis in patients with brain abscess. For brain abscesses, some authors propose seizure
prophylaxis for all patients with a duration of at least 1 year (190,227). Others recommend reevaluation
of initially treated patients by neurologic and EEG examination several weeks after treatment of the
abscess is initiated and withdrawal of the medication if no seizures occurred and EEG does not show
signs typical for epilepsy (261). In patients with EEG abnormalities that are indicating epileptic activity,
however, the treatment should be continued.
Obstructive Hydrocephalus
Unilateral or bilateral external ventricular drainage (in cases with obstruction at the foramen of Monro,
especially in cases with basal ganglia or thalamic abscess [171]) may become necessary in brain
abscesses complicated by obstructive hydrocephalus. Placement of an external ventricular drain is
especially important in patients with abscess formation in the posterior cranial fossa. In a series of 77
patients with cerebellar abscesses, hydrocephalus was diagnosed in 79.2% (118). In these patients,
hydrocephalus was found to be a significant adverse prognostic factor. With a policy of aggressive CSF
diversion (immediate ventricular drainage in any patient with a cerebellar abscess and an overt or
incipient hydrocephalus, even in patients that were fully conscious), the authors were able to reduce the
mortality from 29% to 11.6% (118). Besides acute hydrocephalus, persistent disturbances of CSF
circulation are common in patients with brain abscess: 10 of 20 survivors of intraventricular rupture of
brain abscesses in the study by Takeshita et al. (262) required permanent CSF shunting.
Ventricular Rupture
The encapsulation of a brain abscess often is more complete on the cortical than on the ventricular side
(191). Thus, brain abscesses are more likely to rupture into the ventricles rather than laterally into the
subarachnoid space (262). Intraventricular rupture of brain abscesses affects approximately 15% to 25%
of patients with brain abscess (127,262,263) and results in ventriculitis, meningitis, and disturbances of
the CSF circulation, causing an additional increase of ICP. Accordingly, intraventricular rupture of brain
abscess is associated with an unfavorable outcome (127,263). Because intraventricular rupture of brain
abscesses often affects drainage of CSF, placement of external ventricular drains (sometimes even
bilaterally) might be necessary in such patients.
Brain Edema
The edema around the abscess cavity is usually very pronounced; it may be greater in volume than the
abscess itself (201). To reduce the surrounding edema, corticosteroids are frequently recommended.
Controlled prospective studies on adjunctive therapy with corticosteroids for brain abscesses have not
been performed. Retrospective studies failed to show a beneficial effect of corticosteroids on outcome
(122,132). However, the analysis is complicated because corticosteroids are given mostly to severely
obtunded and comatose patients who are known to have a dismal prognosis (4,218). The use of
corticosteroids should be restricted to patients with a progressive neurologic deterioration or impending
cerebral herniation and radiologic evidence that the abscess is causing significant cerebral edema and
mass effect. Prolonged use of corticosteroids cannot be recommended in view of animal experimental
findings of delayed capsule formation and reduced bacterial clearance. Therefore, high-dose
corticosteroid therapy (e.g., intravenous dexamethasone at 8 mg every 8 hours) should be given when
necessary and should then be tapered off over a few days after the patient’s condition has stabilized.
Severe brain edema and impending cerebral herniation may necessitate further measures to reduce the
increased ICP, such as osmotherapy (e.g., mannitol), sedation, and moderate hyperventilation.
Meningitis
A brain abscess can rarely complicate bacterial meningitis and vice versa; also, both can develop from
contiguous or hematogenous spread from an extradural focus. The association of brain abscess and
meningitis is particularly common in neonates. In older children and adults with brain abscess, meningitis
is probably the result of rupture of the abscess into the ventricles or into the subarachnoid space in most
cases. Meningitis is also more common in patients with a brain abscess due to L. monocytogenes: 38% of
these patients were reported to have positive CSF cultures (203).
Lumbar puncture should not be performed in patients with a proven brain abscess. However, one
should be aware of meningitis as a complication of brain abscess, because meningitis-associated systemic
and CNS complications (such as vascular complications) may contribute to an adverse outcome. For the
management of acute bacterial meningitis and its complications, see Chapter 24.
Hyponatremia
Like other intracranial diseases, a brain abscess can be complicated by hyponatremia; its incidence in
patients with brain abscess, however, is unknown. Two different syndromes causing hyponatremia are
particularly important, the syndrome of inappropriate antidiuretic hormone secretion (SIADHS) and that
of cerebral salt wasting (CSW). SIADHS is characterized by water retention, leading to dilutional
hyponatremia. By comparison, CSW is due to primary natriuresis, leading to hypovolemia and sodium
deficit. SIADHS should be treated by volume restriction; the treatment of CSW consists of sodium and
water replacement (264).
Hemorrhage
Bleeding into the abscess cavity, the surrounding brain parenchyma, into the ventricular system, or the
subarachnoid space has been reported as a rare complication of brain abscesses (265–267). It may lead
to a stroke-like presentation and the neuroradiologic diagnosis of the brain abscess may be confused by a
hemorrhage. The underlying mechanism is not clear. However, the bleeding seems likely to occur from
newly formed fragile blood vessels in the wall of the abscess cavity. There are no specific
recommendations for the treatment of hemorrhage associated with brain abscess.
PROGNOSIS
Mortality
The mortality of brain abscess was 40% to 80% in the preantibiotic era with a decline in numbers after
the introduction of penicillin (268). An adverse prognosis previously was associated with (a) delayed or
missed diagnosis, (b) poor localization, (c) multiple, deep, or multiloculated lesions, (d) ventricular
rupture, (e) coma on admission, (f) fungal etiology, and (g) inappropriate antibiotics. Additional negative
factors often cited are extremes of age, large abscesses, presence of metastatic abscesses, and rapidly
progressive disease (4,132,218,262,269). Since the introduction of CT scanning, the mortality has
decreased substantially (4,16,270). Thus, in recent studies, the mortality of brain abscess was between
10% and 19% (9,15–17,30). Easier detection of underlying conditions (e.g., sinusitis or osseous
dehiscence), monitoring of the therapeutic progress, and recognition of complications by CT and MRI
have probably contributed to the improved prognosis. Furthermore, CT-guided stereotactic aspiration has
greatly improved in particular the treatment of deep-seated and brainstem abscesses.
Seizures
Among the long-term complications of brain abscess, seizures have been particularly well studied. Older
follow-up studies showed a prevalence of 50% (mean, range 34% to 72%) (269,271–273). However,
most of the patients included in these studies had been treated in the pre-CT era and the figures might be
lower today. By comparison, studies in the CT era (though with fewer patients and much shorter follow-
up) reported seizures in 12% of the survivors (mean, range 10% to 16%) (4,132,234). Seizures were
reported to have manifested within 1 year after discharge in 86% (269), within 2 years in 78% (272), or
in 41% within 1 year and in 76% of patients within 4 years (273); however, intervals of more than 10
years have also been observed. Also, the amount of spike and sharp waves on EEG showed a marked
increase during the first 4 years both in patients with and in those without seizures (273). Neither seizures
nor EEG abnormalities before treatment of the abscess are predictive for a later epilepsy (269). Seizures
are common following frontal, parietal, or temporal abscesses, but they are rare after abscesses located in
the cerebellum or the occipital lobe (272,273). The impact of the surgical method on the frequency of
seizures is not clear. After burr-hole aspiration alone compared with craniotomy and total excision of the
abscess, some authors observed a reduced frequency of seizures (272,274), but others did not (4,273).
Other Sequelae
PROPHYLAXIS OF BRAIN ABSCESS

Prophylactic measures that may be relevant to neurologists, neurosurgeons, and infectious disease
specialists are in particular antibiotic prophylaxis after penetrating craniocerebral injuries or craniotomy
and the secondary prevention in patients with pulmonary AVMs, cyanotic heart disease, and AIDS. For
penetrating craniocerebral injuries, recommendations exist that broad-spectrum antibiotic prophylaxis
should be given as soon as possible after the injury and be continued for 5 days postoperatively
(débridement of the scalp wound and of the intracranial injury as far as it is feasible without further
neural damage) (277).
A metaanalysis of the efficacy of prophylactic antibiotics for craniotomy reported a near fourfold
reduction of the wound infection rate (superficial and deep wound infections were included as wound
infections) by antibiotic prophylaxis (278). A large study on 6,243 patients with craniotomy noted a
reduction of incision infection through introduction of antibiotic prophylaxis from 8.4% to 4.6% (279).
A retrospective analysis of patients with diffuse pulmonary AVMs suggested that a combination of
antibiotic prophylaxis for procedures associated with bacteremia and occlusion (transcatheter
embolotherapy) of the larger AVMs is effective in preventing brain abscess (280). For patients with
CCHD, corrective surgery should be considered; patients with uncorrected cyanotic congenital heart
disease should be administered antibiotic prophylaxis for procedures associated with bacteremia.
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CHAPTER 32 EPIDURAL ABSCESS
HANS-WALTER PFISTER, MATTHIAS KLEIN, ALLAN R. TUNKEL, AND W. MICHAEL
SCHELD
SPINAL EPIDURAL ABSCESS

First described by the Italian anatomist Morgagni in the eighteenth century, a spinal epidural abscess is a
suppurative infection in the space around the spinal cord located between the dura mater and the vertebral
periosteum (1). It is both a medical and a surgical emergency, requiring prompt and accurate diagnosis
and treatment to prevent irreversible spinal cord dysfunction, paralysis, and death.
Epidemiology
Although spinal epidural infections are uncommon, recent studies suggest that the incidence of this
infection is increasing (2). Although incidence rates of spinal epidural abscesses have not been calculated
from population-based data, estimates from recent case series noted an increase from 0.2 to 1.2 cases per
10,000 admissions in the mid-1970s (3) to significantly higher incidence rates of up to 1.96 (4), 2.8 (5),
or 11.31 cases (6) per 10,000 admissions to large tertiary care centers in the 1980s and early 1990s. The
reasons for the increasing incidence of epidural spinal infections seem to be an aging population,
increased use of spinal procedures, and a rising rate of injection drug use (4–7). However, a change in
referral patterns or a greater recognition (more widespread use of magnetic resonance imaging [MRI])
must also be considered.
Approximately 70% of patients with spinal epidural abscess are between 31 and 70 years of age, with
no obvious predilection for any given decade (1). The youngest patient in the literature was 10 days of
age and the oldest was 87 years of age (1). Almost all large case series observed a preference for the
male gender, with an average male-to-female ratio of 1.0:0.56 (1). The reasons for this male
predominance are not apparent. However, some risk factors associated with spinal epidural abscesses are
more common in males, such as alcohol abuse, injection drug usage, and trauma (1).
Pathogenesis and Pathophysiology
Below the foramen magnum, the epidural space extends the length of the spine. It is composed of two
compartments: (a) a true space posterior and lateral to the spinal cord containing a cushioning layer of fat
embedded with penetrating arteries and an extensive venous plexus, and (b) a potential anterior space
where the dura adheres to the posterior surface of the vertebral body (8,9) (Fig. 32.1). The epidural space
is circumferential around the spinal cord distal to the second sacral segment, the terminal point of its
anterior attachment. Given these anatomic considerations, it is not surprising that spinal epidural
abscesses are located posteriorly in most cases (3,5).
In addition to the boundary imposed by the anterior attachment to the vertebral canal, the dimensions of
the epidural space vary from segment to segment. In the cervical region where the epidural space is
smallest, epidural abscesses occur less often than in the thoracic or lumbar regions (Table 32.1). In recent
years, the increasing use of spinal interventions for pain management has caused a relative increase of
lumbar epidural abscesses (2,10). A recent series of 40 cases reported that 11 of 16 patients who were
injection drug users had epidural abscesses in the cervical region (6). It was postulated that this may
reflect the venous and lymphatic drainage of the upper extremity. Whereas the rich circulation ensures
ample blood supply to the spinal cord, it may also act as a conduit along which infection may spread.
Infection tracking along these pathways is the likely explanation for the longitudinal extension of spinal
epidural abscesses that usually affect multiple adjacent spinal segments. On average, 3.3 ± 2.7 (mean ±
standard deviation [SD]) spinal cord segments were reported to be involved in five clinical studies with
133 patients (11,12,14–16); however, infections of the entire length of the spinal epidural space have
been reported (panspinal infection) (3,7,17). Of note, spinal epidural abscesses can also be found at
noncontiguous sites, such as the cervical and lumbar spinal cord (18).
Source of Infection
Infection may be introduced into the epidural space by direct extension from a contiguous infection (about
1/3 of cases) or by hematogenous seeding from a remote site (about half of cases); in the remaining cases,
the source of infection is not identified (7) (Table 32.2). Contiguous infections include (1) vertebral
osteomyelitis/discitis; retropharyngeal, perinephric, paraspinal, or psoas abscesses; decubitus ulcers; and
persistent dermal sinus tracts (Fig. 32.2). Local invasion from superficial infections can also occur
following penetrating injuries, including prior surgery or spinal procedures including placement of
catheters or stimulators; epidural drug injections; paravertebral injections; computed tomography (CT)–
guided needle biopsy; and, very rarely, lumbar puncture (1). Metastatic seeding may result from any
bacteremic infection. Skin and soft tissue infections are typically found, but sources have also included
endocarditis and infected intravascular catheters, respiratory tract infection, urinary tract infection, dental
abscesses, abdominal infections, and complications from gastrointestinal surgery (1). In contrast to spinal
epidural abscesses in adults (Fig. 32.3), adjacent vertebral osteomyelitis is distinctly uncommon in
children with this infection; thus, most spinal epidural abscesses in children have been attributed to
hematogenous seeding from a distant focus (21).
One possible explanation for the development of an epidural abscess after a recent or remote trauma
including prior spinal surgery is that a small hematoma or area of damaged tissue may provide a fertile
area for subsequent hematogenous seeding (22). Whether antecedent trauma is indeed a true risk factor for
the subsequent development of a spinal epidural abscess or whether patient recall bias has influenced this
history has not been systematically examined. Of course, spinal trauma may also contribute to the
development of an infection by creating a site of entry for microorganisms into the epidural space
(disruption of anatomic barriers).
The reported risk of an epidural abscess after epidural catheterization varies widely in the literature.
Prolonged use of epidural catheters, significant comorbidity, older age, injection drug use, and diabetes
mellitus contribute to the rate of infection (2). A retrospective analysis of 505,000 extradural blocks in
obstetric practice (84% for relief of pain in labor and 16% for cesarean sections) reported only a single
case of an epidural abscess (23). Another mostly retrospective study estimated the risk at approximately 1
per 5,000 catheters (24). A recent prospective study identified nine patients with epidural abscess after
17,372 epidural catheters (1 per 1,930 catheters), with a mean catheterization time of 11 days (25).
Immunocompromise and longer duration of catheterization were associated with an increased risk of an
epidural abscess in that study: only one of the nine patients had no complicating disease (four had
malignancies, two had diabetes mellitus, one had multiple trauma, and one had chronic obstructive airway
disease); furthermore, all patients with abscess had epidural catheters in situ for 3 days or longer. This is
best illustrated by the relatively high risk of long-term epidural treatment of chronic pain (mostly patients
with cancer), which was complicated by an epidural abscess in 3%, 4%, or even 12% of patients in three
recent studies (13,26,27). In another study, none of 1,062 patients who had epidural anesthesia for a
period of less than 14 days developed a serious infectious spinal complication (28).
Underlying medical conditions that have been associated with spinal epidural abscesses include
degenerative joint disease, diabetes mellitus, injection drug use, alcoholism and cirrhosis, malignancy,
renal failure and hemodialysis (29–31), pregnancy, ulcerative colitis and Crohn disease (both
immunosuppressive treatment and enteroepidural fistulas may be relevant), systemic lupus erythematosus,
chronic granulomatous disease, corticosteroid therapy, and acquired immunodeficiency syndrome (1).
Compared with the damage produced by spinal tumors and cysts, the damage produced by bacterial
spinal epidural abscesses is often out of proportion to the size of the inflammatory mass, that is, the lesion
of the spinal cord can be more extensive than can be accounted for by mechanical effects of compression
alone (3). This important feature may be attributed to many factors including thrombosis and
thrombophlebitis of veins draining the spinal cord with resultant edema and venous infarction (3);
compression of the arterial supply to adjacent cord segments with local ischemia and infarction; focal
areas of vasculitis induced by the adjacent inflammatory mass; or bacterial exotoxin production,
especially by Staphylococcus aureus.
Still, a rabbit model of spinal epidural abscess has demonstrated that the damage to the spinal cord is
more consistent with mechanical compression than with ischemia or infarction (32,33). This model, using
a clinical isolate of Staph. aureus, also demonstrated many of the pathologic features seen clinically in
spinal epidural abscesses: preservation of gray matter, white matter edema, vacuolization, liquefaction,
myelin degeneration, and axonal swelling. This pattern is consistent with compressive damage, as spinal
cord ischemia is typically characterized by necrosis of the gray matter and relative preservation of the
white matter (33). Furthermore, the posterior spinal arteries and the anterior spinal artery were patent
microangiographically in paraplegic animals with minimal and moderate cord compression and even in
some cases of large epidural abscesses with severe degrees of compression (32). Dorsal and anterior
spinal veins and the anterior epidural venous plexus were also patent in animals with minimal or
moderate compression. Only in rabbits with severe cord compression, the dorsal spinal vein and the
perforating arterioles were occluded ipsilaterally to the abscess. With profound compression, all blood
flow was noted to cease. The authors, therefore, concluded that the initial neurologic deficit results from
compression and that vascular compromise (as a result of compression and probably not due to vasculitis
or thrombosis) is an important factor in the final pathogenesis of spinal epidural abscess. Although these
rabbit experiments (32,33) suggested a primary role for mechanical compression, other animal models
favored an additive adverse effect of compression and ischemia on neurologic function (7).
Microbiology
A microbiologic diagnosis is usually made from blood and/or intraoperative cultures. Polymicrobial
spinal epidural abscesses are a rarity, blood cultures are positive in about 60% of the patients (7), and
pathogens identified by blood culture are almost always identical with the infectious agents cultured from
abscess pus. This situation is, therefore, completely different from that in patients with brain abscesses. In
the latter, blood cultures are positive in only about 10% of patients, and even if the blood cultures are
positive, they do not allow for firm conclusions on the microbial spectrum of the brain abscess because
brain abscess pus often grows mixed cultures (see Chapter 31). The microbial spectrum of spinal
epidural abscesses also differs greatly from that of brain abscesses, as Staph. aureus (Fig. 32.4) is the
most common etiologic agent in children and adults (responsible for about two thirds of spinal epidural
abscesses). Coagulase-positive and negative (mostly Staph. epidermidis) staphylococci cause
approximately 70% of spinal epidural abscesses (note that in some studies, up to 15% of the isolates
were methicillin-resistant Staphylococcus species [34] with a frequency up to 40% in some studies
[7,35]). The remaining 30% of cases are caused by a wide spectrum of infectious agents (Table 32.3).
Most streptococcal spinal epidural abscesses are due to viridans streptococci and Streptococcus
pneumoniae (1,45). Escherichia coli is responsible for most infections due to Enterobacteriaceae. Much
less frequently Proteus, Enterobacter, Salmonella, Serratia, Citrobacter, and Klebsiella species have
been reported (1). Spinal epidural infections due to Pseudomonas aeruginosa are relatively uncommon
but require particular attention because of this pathogen’s resistance to many antibiotics. Anaerobes, such
as Bacteroides, Peptostreptococcus, or Fusobacterium species are also an uncommon cause of spinal
epidural abscesses. Spinal epidural abscess is rarely caused by agents of actinomycosis or nocardiosis
(1,46). The incidence of mycobacterial epidural infections (Fig. 32.5) varies greatly geographically.
Although they are very rare, for example, in studies from North America or Western Europe,
mycobacteria were responsible for 8 (28%) of 29 cases of spinal epidural abscesses in a series from
Taiwan (19) and 19 (53%) of 36 cases in a Turkish investigation (47).
Fungal etiologies of spinal epidural abscesses include Aspergillus species (48,49), Candida species
(50), Blastomyces dermatitidis (51), Coccidioides immitis (52), Cryptococcus neoformans (53),
mucormycosis (54), Sporothrix schenckii (14), and Pseudallescheria boydii (55). Recently, an outbreak
of fungal meningitis after epidural or paraspinal glucocorticoid injection with contaminated
methylprednisolone has been described (48,49). The outbreak is ongoing and involves multiple states.
Clinical data from 66 patients showed that 47 (71%) had meningitis alone, 11 (17%) suffered from cauda
equina syndrome or focal infection nearby the injection site (4 of whom had documented epidural
abscess) with or without meningitis, and 8 (12%) had posterior circulation stroke (with or without
meningitis). The median time from the last epidural glucocorticoid injection to symptom onset was 18
days. Eight patients (12%) died, and 7 of them had stroke. A total of 22 patients had laboratory
confirmation of fungal infection, either Exserohilum rostratum infection (21 patients) or Aspergillus
fumigatus infection (1 patient) (49).
Parasitic causes of epidural abscesses have also been reported, including Echinococcus (56), guinea
worm (Dracunculus medinensis) (57), and Schistosoma mansoni (58).
The microbiology of spinal epidural abscesses in children does not differ substantially from that in
adults. In 2001, a review of the literature summarized 34 cases of childhood spinal epidural abscesses
(21): Staph. aureus was cultured in 21 patients (62%), streptococci in 2 (6%, S. agalactiae in one and
viridans streptococci in another), Salmonella enteritidis in 2 (6%), E. coli in 1 (3%), Pseudomonas
aeruginosa in 1 (3%), Mycobacterium bovis in 1 (3%), Candida tropicalis in 1 (3%), and Aspergillus
flavus in 1 (3%). Multiple organisms were isolated in one patient and no organisms were isolated in three
children (9%).
The initial clinical signs and symptoms of a spinal epidural abscess, characteristically including fever,
back pain, and malaise, may be subtle. A spinal epidural abscess is often not suspected on admission. The
most common initial misdiagnoses are meningitis, intervertebral disc prolapse, vertebral osteomyelitis,
lumbar degenerative joint disease, spinal neoplasm, transverse myelitis, spinal ischemia, and urinary tract
infection (1). The duration of symptoms is variable; they may be present for just a few days or up to
several months before the patient presents for evaluation (4,59).
The four-stage clinical progression of a spinal epidural abscess was first described by Rankin and
Flothow (60) more than 50 years ago. In addition to fever and malaise, the first localizing symptoms are
backache and focal vertebral pain and tenderness on examination. This is followed by “root pain”
manifested by radiculopathy and/or paresthesias, which often may be described as “electric shocks.”
Spinal cord dysfunction, the third stage, is characterized by motor and sensory deficits or by bladder or
bowel dysfunction. This is followed by the final stage of complete paralysis (Table 32.4).
Although early symptoms of backache may be indolent and persist for weeks or months, back pain
usually progresses to root pain within 3 to 4 days followed by early signs of spinal cord dysfunction
within the subsequent 4 to 5 days. The neurologic deficits at this stage are usually reversible; however,
rapid surgical intervention at this point may be crucial because progression to complete paralysis may
occur within a few hours regardless of the chronicity of the process up to this point.
Specific neurologic signs depend on the level of spinal cord involvement and is another factor that
influences the differential diagnosis at the time of presentation.
The presentation of a spinal epidural abscess has historically been described as “acute” (symptoms
persisting for <2 weeks at the time of presentation) or “chronic” (symptoms for >2 weeks at the time of
presentation) (3,5). The rate of progression of the initial stages may suggest the route of infection: acute
presentations often represent hematogenous seeding and rapid expansion of the inflammatory mass,
whereas chronic presentations are more likely the result of a gradually expanding contiguous infection.
Although the prognostic significance of distinguishing acute from chronic spinal epidural abscesses has
recently been questioned, patients with acute presentations may have higher peripheral leukocyte
concentrations (mean values ranging from 12,300 to 16,700 cells/µL [3–5]) and higher temperatures when
compared to those of patients with long-standing symptoms who may have only mild elevations in these
two parameters (mean peripheral leukocyte concentrations ranging from 7,100 to 11,900 cells/µL). Other
authors, however, reported similar peripheral leukocyte concentrations in acute and chronic cases (6). In
both presentations, the erythrocyte sedimentation rate (ESR) is generally elevated (>25 to 30 mm per
hour); however, the magnitude of the ESR is not a reliable clinical clue as to the chronicity of the
infection (5,6). Serial ESR measurements showed good correlation between resolution of clinical signs
and decreases in ESR (34). Regardless of the clinical course, the average peripheral leukocyte
concentrations were 15,700 cells/µL in 218 patients from the literature (range, 1,500 to 42,000 cells/µL)
and the average ESR was 77 mm (range, 2 to 150 mm) in 117 patients from the literature (1). Recent
studies have also reported elevated serum C-reactive protein (CRP) levels in patients with spinal
epidural abscesses, 15.0 ± 9.5 mg/dl in one study (20). Serum CRP levels were also shown to respond
more quickly to therapeutic interventions than, for example, the ESR (61). Similarly, a persistent strong
elevation of the CRP value after 8 days postsurgery was shown to be associated with a poor outcome
(20). Blood cultures will be positive on average in 72% of patients (mean, range 64% to 82% in three
recent studies [4,16,59]).
Cerebrospinal fluid (CSF) examination is typically that of a parameningeal focus of infection with
elevated protein levels and increased leukocytes. The CSF leukocytes may be a mixture of
polymorphonuclear leukocytes and mononuclear cells or predominantly polymorphonuclear leukocytes in
most patients (3,59). The CSF leukocyte count was 40 cells/µL (median, range 0 to 27,000 cells/µL) in
one study (59) and 60 cells/µL (mean, range 0 to 820 cells/µL) in another report (3). Extremely elevated
leukocyte counts in the CSF may indicate that the spinal needle has entered a lumbar epidural abscess
(3,59). CSF protein values are elevated in approximately 90% of patients (59). Markedly elevated CSF
protein levels (>350 mg/dL) are often predictive of a complete block of the spinal canal; however, an
elevated protein level of lesser magnitude is found in patients with spinal block in nearly two thirds of
cases (5). CSF glucose concentrations were reported to be decreased (<50 mg/dL) in more than half of
the cases (59). Except when there is concomitant meningitis, CSF Gram stains rarely demonstrate
organisms, and spinal fluid cultures are positive in only 15% of patients (mean, range 7% to 25%
[4,5,59,62]), also similar to other parameningeal infections. Most authors recommend against performing
a lumbar puncture in patients with an adjacent spinal epidural abscess because of the possibility of
inducing meningitis or subdural infection if the needle traverses the epidural space or the potential risk of
neurologic deterioration if performed below the spinal block (59). Perhaps the principal reason not to
perform lumbar puncture is the meager information that this test provides. The CSF alterations are
nonspecific and when CSF cultures are positive, so usually are the blood cultures (59).
At the time of surgery, findings may range from frank pus to granulomatous tissue. Whereas acute cases
are more likely to have purulent material, this correlation was not found consistently in other case series
(4,63). Overall, intraoperative cultures have the greatest chance of yielding a microbiologic diagnosis; on
average 86% of all cases have positive cultures (mean, range 82% to 90% [3–5,16,19,59]). However,
when a patient has been receiving antibiotics for more than 1 week before culture, diagnostic cultures are
unlikely to be positive (5).
Signs of fever and back pain should raise suspicion of a spinal epidural abscess, especially when spinal
tenderness or radicular signs are demonstrated on physical examination. However, these signs and
symptoms may not always be present and lack specificity for this diagnosis. About half of the patients
with spinal epidural abscess are initially misdiagnosed (7), particularly when patients present in early
clinical stages (3–5,59,62). One review documented that spinal epidural abscesses took significantly
longer to diagnose in patients when it was not included among the differential diagnoses at admission: 6.6
days versus 1.9 days (59). The main differential diagnoses include intervertebral disc prolapse, spinal
tumors, transverse myelitis, epidural hematoma, vertebral osteomyelitis, spinal subdural or
intramedullary abscess, spinal arteriovenous malformation, and spinal arterial ischemia. The clinical
picture of spinal epidural abscess can also be mimicked by acute spinal cord dysfunction due to myelitis
during bacterial meningitis (64).
Approach to Diagnosis
The imaging method of choice for diagnosis of spinal epidural abscess is contrast-enhanced MRI
(65–70). However, availability, contraindications (e.g., heart pacemaker), or insufficient cooperation of
the patient sometimes requires the use of the other methods, such as (postmyelography) CT. Plain films of
the spine will not directly visualize the spinal epidural abscess but may demonstrate certain findings that
can be an indication of the presence of infection in the spinal canal (66,67). These findings include
intervertebral disc space narrowing in discitis and loss of definition or destruction of both the inferior
cortical margin of one vertebral body and the superior cortical margin of the contiguous vertebral body in
osteomyelitis. Rarefaction and loss of bony trabeculae can also be seen. In advanced or rapidly
progressive cases, vertebral body collapse (or dissolution) and gibbus formation may be seen on plain
films. In general, osteomyelitis most commonly occurs in the lumbar spine, and the bodies of the vertebrae
are affected more often than the posterior elements. Helpful ancillary plain film findings include a mass
effect or displacement of the larynx in a retropharyngeal abscess or scoliosis and displacement of bowel
loops in a lumbar paraspinal abscess. Normal plain films do not exclude the presence of a spinal epidural
abscess, particularly in acute presentations. In this setting, additional radiographic examinations are
almost always needed for further evaluation. Similar to plain films, bone scans often provide clinically
not useful information that may be misleading in this setting.
Myelography, which will not directly visualize a spinal epidural abscess, will demonstrate the
associated mass effect on the spinal cord, thecal sac, or nerve roots. A spinal epidural abscess can result
in a complete extradural obstructive block to the flow of water-soluble contrast. However, in patients
with a prominent ventral epidural space in the lower lumbar spine due to abundant epidural fat, an
epidural abscess may not be detected on myelography if it causes indentation or obliteration of the
epidural fat without indenting the opacified thecal sac.
Both CT and MRI can directly visualize an epidural inflammatory mass (65–68,70). As is true in the
neuroimaging of many diseases of the brain and spinal canal, MRI has proven superior to CT for
evaluation of patients with epidural abscesses. MRI obviates the need for myelography and CT in most
cases. The advantages of MRI include its ability to image long segments of the spinal canal in multiple
planes (Figs. 32.6 and 32.7), thereby enabling precise delineation of all loculations of inflammatory
tissue; its ability to image all compartments around the spinal canal into which an inflammatory process
might extend; its ability to directly visualize the neural elements with high-contrast resolution without the
need for intrathecal contrast; its noninvasiveness, which is a particular advantage over myelography,
because of the desire to avoid inadvertent puncture of the abscess or iatrogenic spread of infection from
the epidural to the subarachnoid space following introduction of a needle into the spinal canal.
Furthermore, with MRI, patient follow-up is facilitated and assessment of response to therapy is readily
performed. The ability of MRI to distinguish active inflammatory tissue from chronic granulation tissue is
further enhanced by intravenous administration of gadolinium. MRI demonstrates epidural inflammatory
disease to be a soft tissue mass, which compared to the spinal cord is isointense on T1-weighted images
and hyperintense on T2-weighted images. Diffusion-weighted imaging may show a signal abnormality
within the spinal abscess (70,71). The extradural location of disease and the associated mass effect on the
thecal sac, spinal cord, or cauda equina are generally readily appreciated on MRI, as is the extradural
location of disease and the associated mass effect on the thecal sac. The presence of concomitant
paraspinal abscesses is easily identified (Fig. 32.8). In the presence of discitis, a characteristic finding on
MRI is abnormal high signal intensity in the disc on T2-weighted images (Fig. 32.9). This is in
contradistinction to degenerative disc disease, which demonstrates low signal intensity. Vertebral
osteomyelitis is seen as low signal intensity on T1-weighted images in the involved marrow cavity, with
high signal intensity on T2-weighted images. These osseous changes are usually observed in conjunction
with inflammatory disease of the subjacent intervertebral disc as described.
Treatment
A spinal epidural abscess is a neurosurgical emergency. The neurologic deterioration to severe spinal
cord dysfunction can occur in just a few hours, making the diagnosis and treatment imperative (Fig.
32.10). The initial treatment usually consists of decompressive surgery and drainage of the abscess,
eradication of the primary underlying infectious focus (if detectable), and parenteral antibiotic therapy.
Posterior epidural abscesses are usually treated by decompressive laminectomy, removal of pus or
granulation tissue, and postoperative irrigation with sterile saline through extradural drains for several
days. Percutaneous, CT-guided needle aspiration might be a rational alternative to surgical
decompression in selected patients with posteriorly located abscesses, which extend across multiple
spinal segments, exhibit minimal cord compression, and demonstrate stable neurologic examination
results with minimal or no neurologic deficits (72). For the treatment of anterior epidural abscesses, an
anterior approach may be necessary. Adjacent sources of infection should also be cured surgically (e.g.,
vertebrectomy for severe osteomyelitis with vertebral body destruction).
Parenteral antibiotic therapy should be directed against the etiologic agents most likely to be involved:
Staph. aureus, coagulase-negative staphylococci, streptococci, and gram-negative rods. A combination of
a third-generation cephalosporin (e.g., ceftriaxone) with another antimicrobial showing
antistaphylococcal activity (e.g., nafcillin) is recommended (for dosages, see Table 32.5). If methicillin-
resistant staphylococci are suspected or isolated, vancomycin should be used. Linezolid or daptomycin
may become alternative antibiotic agents to cover methicillin-resistant staphylococci in the therapy of an
epidural spinal abscess; however, clinical experience with these agents in this disease is limited. A
nosocomial spinal epidural abscess may be initially treated with meropenem or cefepime plus
vancomycin. When the etiologic agent has been identified in cultures, the antibiotic regimen should be
modified according to the antibiogram. Minimum treatment duration of 4 to 6 weeks is usually
recommended; this period should be extended to 6 to 8 weeks or more if osteomyelitis is present.
The administration of corticosteroids (e.g., intravenous dexamethasone) is controversial. Their benefit

has not been proven and controlled studies do not exist. They may be beneficial in reducing local edema
in patients with progressive neurologic compromise who are awaiting surgical decompression (7).
Nonsurgical management using antibiotic therapy alone may be considered in selected patients without
significant neurologic deficit, with complete paralysis for more than 3 days, and in patients refusing
surgery, with panspinal infection or in poor medical condition with a high surgical risk. Identification of
the causative pathogen may be attempted by CT-guided needle aspiration in conservatively treated
patients with negative blood cultures and with posteriorly located abscesses. Conservatively treated
patients without significant neurologic deficit need close neurologic monitoring in a hospital with
facilities for emergency decompressive surgery. Retrospective analyses suggest that the outcome is
comparable to that of surgically treated patients, if these guidelines are followed (11,16,73,74). In the
future, MRI criteria may also be helpful when selecting patients for conservative treatment. A recent study
(75) suggested that a good outcome was associated with abscesses shorter than 3 cm cephalocaudally,
less than 50% narrowing of the sagittal diameter of the spinal canal, and homogenous contrast
enhancement (suggestive of phlegmonous or granulomatous tissue, opposed to the peripheral enhancement
of a frank abscess containing pus). The authors, therefore, suggested that only patients fulfilling at least
two of these criteria should be treated conservatively. However, definite conclusions can be drawn only
from controlled studies, which are still lacking and are unlikely to be performed.
In patients with tuberculous spinal epidural abscess (Fig. 32.5), antituberculous chemotherapy (usually
with four agents pending susceptibility testing) has diminished the need for surgical intervention except
when stabilization of the spine is required. Because bony changes may progress radiographically for an
average of 4 months following the initiation of chemotherapy, it has been emphasized that clinical
parameters rather than radiographic changes should be followed to monitor therapy during the early stages
of treatment. However, if neurologic signs and symptoms develop, decompression of a tuberculous spinal
epidural abscess may be required to prevent permanent neurologic deficits (76). (For the recommended
antituberculous chemotherapy, see Chapter 29.)
Prognosis
The outcome of a spinal epidural abscess seems to be directly related to several independent variables
(Table 32.6). When the diagnosis is made early in the course of their illness and before the development
of significant neurologic deficit, patients fare better than when a delay in diagnosis has occurred (1).
Complete recovery with the return of full neurologic function is most likely to occur in patients without a
neurologic deficit at the time of diagnosis and treatment or when neurologic signs are present for less than
24 hours (3). All large case series of the literature have shown that more severe preoperative neurologic
deficits are generally associated with a worse prognosis (1,19,20). If weakness or paralysis exists for
more than 36 to 48 hours, complete recovery is less likely (1). In some series, patients with cervical or
cervicothoracic epidural abscesses had more profound sequelae than those with lumbar, lumbosacral, or
sacral abscesses (16,74). Other parameters such as older age, underlying disease, septicemia, and higher
degree of thecal sac compression were also associated with an adverse outcome in several studies
(1,5,12,16,74).
INTRACRANIAL EPIDURAL ABSCESS
Epidemiology
The true incidence of intracranial epidural abscesses is not known. In one hospital-based series, it was
the third most common localized intracranial infection, following brain abscesses and subdural empyemas
(77), and in a recent South African series of 82 patients, epidural abscess accounted for 1.8% of all
intracranial infections (78). Intracranial epidural abscesses have been reported in a wide age range, from
1 month to 71 years of age (77–79). In contrast to recent studies from developing countries and earlier
studies from the developed world in which intracranial epidural abscesses were principally sequelae of
sinusitis, mastoiditis, and otitis media, recent case series from developed countries document that they are
more likely to complicate neurosurgical procedures because up to 2% of craniotomies may be
complicated by this infection (78,80).
Pathogenesis and Pathophysiology
Above the foramen magnum the dura is essentially the adherent inner lining of the skull. Here the epidural
space represents only a potential space, which is created when it is violated by an encroaching mass
(tumor, adjacent infection, or hematoma) or as a result of trauma. As a consequence, infections of the
intracranial epidural space primarily result from the extension of contiguous infections, in particular,
sinusitis (Fig. 32.11) and otitis/mastoiditis (81–84). Other common risk factors for intracranial epidural
abscesses are recent transnasal, transmastoid, or intracranial surgical procedures (Figs. 32.12 and 32.13);
posttraumatic infection; congenital osseous defects of the anterior cranial fossa that facilitate
communication between the epidural space and the paranasal sinuses; and, rarely, dental infection
(78,84,85). The abscess expands as the pressure generated by the growing inflammatory mass dissects the
dura away from the skull. As a result, an intracranial epidural abscess is a slowly growing mass, the
property that accounts for its insidious clinical presentation. Intracranial abscesses rarely dissect beyond
the base of the skull because there the dura is even more tightly fixed.
Microbiology
The etiology of intracranial epidural abscesses is frequently polymicrobial with the most common
organisms including anaerobic gram-positive cocci, Staphylococcus species, Streptococcus species (in
particular Streptococcus anginosus), and anaerobic gram-negative bacilli (84). Anaerobic bacteria are
cultured from many sinus-associated intracranial epidural abscesses. Streptococci and staphylococci
(including Staphylococcus epidermidis and methicillin-resistant Staphylococcus aureus) are the leading
pathogens in postoperative epidural abscess (78,84).
Other organisms isolated from localized intracranial epidural abscesses include Peptostreptococcus
species, Salmonella species, Klebsiella species, Proteus species, E. coli, Providencia species,
Citrobacter species, Serratia marcescens, Proteus mirabilis, Haemophilus influenzae, Eikenella
corrodens, Bacteroides species, Propionibacterium acnes, Enterobacter cloacae, Mycobacterium
tuberculosis, Aspergillus fumigatus, Pseudallescheria boydii, and Rhizopus species (mucormycosis)
(55,80,84,86–88).
The slow-growing intracranial epidural abscess may cause few symptoms other than fever, localized skull
tenderness, dull headache, nausea, vomiting, and lethargy (79). Papilledema may develop with increasing
intracranial pressure. When cranial osteomyelitis is present, edema and cellulitis of the face and scalp
also may develop. Thus, although attention is focused on the primary process such as sinusitis, cellulitis,
skull fracture, or a recent neurosurgical or otorhinologic procedure, a developing intracranial abscess
may remain undetected. A recent paper on 82 patients with cranial epidural abscess reported that the
prominent clinical features were fever (57%), frontal subgaleal abscess (Pott puffy tumor, 46%),
periorbital edema (40%), headache (37%), meningismus (35%), and seizures (11%) (78). In 23 cases of
postoperative epidural abscess, the most common sign was wound infection (95.7%), followed by
encephalopathy (44.7%), fever (34.8%), and headache (17.4%) (80). Symptoms may be present for
several weeks or months before the diagnosis is made (78).
Depending on the location of the abscess, focal neurologic signs may develop as a result of continued
expansion of the inflammatory mass. However, in the aforementioned series of 82 patients, focal
neurologic signs were present in only 4.9% of patients (78). Involvement of the apex of the petrous
temporal bone and cranial nerves V and VI may lead to unilateral facial pain and lateral rectus weakness
(Gradenigo syndrome) (89). Although the gradually expanding intracranial abscess may remain localized,
more often the dura cannot contain the expanding epidural abscess. This may result from the development
of thrombosis of the valveless emissary veins that run between the skull and meninges or it may result
from direct penetration through the necrotic dura. When this occurs, the intracranial epidural abscess may
be complicated by subdural empyema, brain abscess, or meningitis. The process may be further
complicated by venous sinus thrombosis, which, though uncommon, is a serious complication (90).
Because the uncomplicated epidural abscess grows slowly, it is often the striking manifestations of the
complications—meningismus, seizures, changing mental status, or coma—that may be the first indication
of an intracranial process.
Approach to Diagnosis
In contrast to spinal epidural abscess, in an intracranial epidural abscess, a microbiologic etiology is

established far more reliably from intraoperative cultures than from blood cultures (80). Diagnosis is
made by contrast-enhanced CT or MRI. CT can detect a low-attenuation extraaxial mass (84). Contrast
CT in epidural abscesses reveals a thick medial rim enhancement, which represents inflamed displaced
dura (Fig. 32.12). The degree of rim enhancement is usually thicker and more irregular in an epidural
abscess than in subdural empyema. Calvarial osteomyelitis, subgaleal or subperiosteal abscesses, and
frontal sinus inflammatory disease are typically associated with intracranial epidural abscesses. Large
epidural abscesses can cause mass effect on the underlying brain (Fig. 32.14); however, in
contradistinction to the clinically more significant subdural empyema, an intracranial epidural abscess
rarely demonstrates parenchymal abnormalities on CT (Fig. 32.12C). As noted, it is important to
appreciate that an intracranial epidural abscess often coexists with a subdural empyema, so presence of
the former should prompt a careful search for the latter.
Patients with postoperative and posttraumatic extraaxial abscesses often present months to years
following surgery or head trauma, respectively (80). These patients may have signs of local wound
infection, but they generally show neither systemic signs of infection nor neurologic changes. Patients with
postoperative and posttraumatic abscesses usually have underlying structural brain lesions that may lead
to the persistence or the reaccumulation of these collections. Postoperative abscesses occupy the cavity
created by the craniotomy defect, whereas posttraumatic abscesses are often an iatrogenic complication of
evacuation of a preexisting subdural or epidural hematoma. Both postoperative and posttraumatic
abscesses are visualized as hypodense extraaxial collections with medial rim enhancement on CT. Edema
and mass effect on the underlying brain are usually minimal and parenchymal abnormalities are rare (91).
The indolent clinical course and the relatively benign radiographic findings are due to the presence of a
discrete limiting membrane from prior surgery or trauma, which serves to shield the underlying cerebral
cortex. Abscesses in these two clinical circumstances can be very difficult, if not impossible, to
differentiate from noninfected sterile effusions or chronic extraaxial hematomas. A change in density of
these collections on serial CT scans, associated with subtle mass effect on adjacent brain, may be the first
indication of an intracranial infection.
The morphology of posttraumatic intracranial epidural abscesses on MRI corresponds to that seen on
CT—that is, lentiform or crescentic collections overlying a cerebral convexity and/or in the
interhemispheric fissure (Fig. 32.15). MRI offers several advantages over CT in the evaluation of patients
with intracranial epidural abscesses. Specifically, in otorhinologically induced abscesses, MRI can
accurately identify and delineate the collections (including small loculations) early in the stage of disease,
when the findings on CT can be subtle (92). This ability of MRI is attributable to the inherent high degree
of contrast between the purulent collections and the subjacent calvaria, brain, and CSF, combined with the
absence of streak artifacts from bone. The diagnosis of an intracranial epidural abscess can be confirmed
by diffusion-weighted imaging restriction (Figs. 32.13 and 32.15) (84,93). In postoperative and
posttraumatic abscesses, MRI can readily differentiate these collections from sterile effusions and chronic
extraaxial hematomas based on signal-intensity differences, a distinction that is usually subtle or
undetectable on CT. Intracranial abscesses are usually mildly hyperintense to CSF on T1-weighted
images and more markedly hyperintense to CSF on T2-weighted images (Figs. 32.5C and 32.6). In
contrast, sterile effusions are isointense to CSF (92,94). Posttraumatic abscesses are hypointense on both
T1-weighted and T2-weighted images in contrast to most chronic hematomas (94).
Lumbar punctures contribute little to the diagnosis of epidural abscess, because the CSF findings are
nonspecific, cultures are usually negative, and there is a considerable risk of neurologic deterioration
following lumbar puncture because of transtentorial or foraminal herniation (78). A lumbar puncture
should, therefore, not be performed in patients with suspected or proven epidural abscess.
Treatment
Therapy consists of surgical drainage of the epidural abscess (formal craniotomy or drainage through burr
holes or an extended craniectomy), surgical therapy of underlying infections, and medical therapy. The
medical therapy is that of brain abscess (see Chapter 31). In brief, empirical antibiotic therapy should
usually include a third-generation cephalosporin (e.g., ceftriaxone) and metronidazole in cases of
community-acquired epidural abscesses. Postoperative or posttraumatic epidural cranial abscesses can
be treated empirically with a combination of vancomycin and meropenem. After culture results, the
therapy should be modified according to the antibiogram.
The surgical therapy of an intracranial epidural abscess is primarily aimed at drainage of the collection
to prevent further accumulation and neurologic damage while obtaining material for culture. Burr holes
may suffice, but craniotomy or craniectomy may be required, particularly if overlying bone is involved.
Nathoo et al. (78) reported that they could adequately drain the purulent material in their series of 82
patients using burr holes (21 of 70 patients treated surgically) or limited craniectomies (39 of 70
patients), because the extradural pus collections were usually liquid and never loculated.
Prognosis
The combination of medical and surgical management of uncomplicated intracranial epidural abscesses
has generally resulted in favorable outcomes. In a recent series of postoperative infections, the 18% 5-
year case-fatality rate was attributed primarily to comorbidities rather than the intracranial infectious
process (80). In the aforementioned South African series of 82 patients, 78 patients recovered completely,
3 had a moderate disability, and 1 died (mortality rate, 1.2%) (78). However, similar to spinal epidural
abscesses, delays in diagnosis may result in irreversible neurologic deficits, as prognosis is inversely
related to the degree of encephalopathy at initial presentation.
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CHAPTER 33 SUBDURAL EMPYEMA AND
SUPPURATIVE INTRACRANIAL PHLEBITIS
BARRY J. HARTMAN AND DAVID C. HELFGOTT
CRANIAL SUBDURAL EMPYEMA

Empyema is an important form of intracranial suppuration, accounting for 15% to 25% of pyogenic
intracranial infections (1–3,97). It represents an infectious process that occupies the space between the
dura mater and arachnoid surrounding the brain. Left undiagnosed and untreated, subdural empyema is
rapidly fatal, so early recognition is critical. In older children and adults, subdural empyema is most often
a complication of otorhinologic infection (1,4–19,98). Subdural empyema may also occur as a result of
head trauma or surgery, osteomyelitis of the skull, or bacteremic spread from a distant focus of infection.
In infants, leptomeningitis is the most common predisposing cause of subdural empyema (11,20,21,97).
Males predominate over females, and about 70% of patients are in their second or third decade of life
(3–5,7–10,12,13,15,22–26). Patients will present with fever and headache in more than 90% of cases and
many will have associated neurologic abnormalities (1,3–9,12,13, 15–19,21,23,24,26–30,99,100,101).
The diagnosis of subdural empyema is confirmed using computed tomography (CT) or magnetic
resonance imaging (MRI) scanning techniques. However, a strong clinical suspicion despite the lack of
evidence for subdural empyema on scans warrants more invasive investigation. Definitive therapy
consists of surgical drainage and systemic antibiotics, yet mortality remains as high as 40% in some
series (14,21). Spinal subdural empyema also has been described; however, it is quite rare, with fewer
than 150 cases reported in the literature (31,102). This condition is addressed briefly later in the chapter.
Suppurative intracranial phlebitis is a serious complication of cranial and facial infections and results in
thrombosis of the major dural venous sinuses. This is discussed at the end of this chapter.
Historical Perspective
The first comprehensive clinicopathologic descriptions of subdural empyema as a distinct entity were
published in the 1940s, although the first definitive report of subdural empyema dates back to 1861
(32,33). This initial report was followed by several more around the turn of the century, with a
compilation of 44 cases by Blegvad (32) in 1910. Early names for this disease included “pachymeningitis
interna,” “purulent pachymeningitis,” “pia-arachnoid abscess,” “phlegmonous meningitis,” and “subdural
abscess,” but these were rejected by Kubik and Adams in favor of “subdural empyema” (8,32).
Interestingly, early publications reported a preponderance of subdural empyema secondary to otogenic
infections (32). However, because of the compilation of 42 confirmed cases resulting from frontal
sinusitis by Courville (33), it has become clear that paranasal sinusitis is the most important causative
factor in the development of subdural empyema in older children and adults. During the past 50 years,
much has changed in the areas of therapy and diagnosis of subdural empyema. Before the development of
antibiotics, subdural empyema was almost always fatal (32,33). Antibiotics, improved diagnosis, and
newer surgical techniques have combined to lower the mortality rate to 10% to 40%
(1,4,5,7–15,21,22,24,28,29). Physicians depended on their clinical skills and plain roentgenograms of the
sinuses and skull to direct their attention to the possibility of intracranial suppuration, until the
development of cerebral angiography in the early 1960s, which proved an extremely sensitive method of
detecting a subdural collection (13,34). The emergence of CT in the 1970s provided a noninvasive rapid
means of visualizing the cranial contents; its reliability, safety, and ease of operation made it the first
choice for diagnosis of suspected subdural empyema (2,10,26,35). Recently, MRI has proven even more
sensitive than CT (36).
Pathogenesis and Anatomic Considerations

The clinical features of subdural empyema are easily understood if one considers the anatomy of the
subdural space with respect to its surrounding structures (Fig. 33.1). The subdural space is normally a
potential space rather than an actual space because the dura mater follows the contours of the skull and
lies adjacent to the arachnoid and pia mater (37). The ability to form an actual space with fluid collection
is greater around the convexities of the cerebral hemispheres where the brain does not approximate the
skull as closely as it does around the basal areas (15,22,33).
Posteriorly, the tentorium cerebelli is a reflection of dura separating the cerebellum from the cerebral
cortex (38). It is an effective barrier to the passage of subdural collection infratentorially, except at its
free anterior margin where fluid may seep into the subdural space of the posterior fossa. Only about 10%
of subdural empyemas are infratentorial (15,39,40). Medially, the falx cerebri is a reflection of dura
extending the length of the cerebrum that separates the cerebral hemispheres (38). Subdural fluid that
accumulates between the falx and the arachnoid are known as parasagittal, interhemispheric, or
parafalcine subdural empyemas and are usually secondary to surface subdural collections but rarely may
be primary (41–43). A subdural empyema may communicate with the contralateral side via the inferior
free margin of the falx.
It therefore follows that infections or trauma of the head are the usual causes of subdural empyema.
Table 33.1 reviews the conditions predisposing to subdural empyema in series reported during the past
two decades (excluding series of only infants). Paranasal sinusitis overwhelmingly predominates as the
precipitating factor for the development of subdural empyema (101). The sinusitis almost always involves
a frontal sinus, often with other sinuses affected as well. The incidence of subdural empyema following
frontal sinusitis is 1% to 2% (45). The frontal and sphenoid sinuses are intimately associated with the
dura mater, separated from the dura only by a thin plate of bone.
These sinuses communicate with the maxillary and ethmoid sinuses, which are more anteriorly placed.
Because of its position, the frontal sinus is almost always involved in paranasal sinus infection that
spreads to the subdural space. In addition, the growing posterior wall of the frontal sinus during puberty
has been offered as a possible explanation for the striking age susceptibility for the development of
subdural empyema (7,26,46).
Two modes of extension have been proposed for the spread of infection from a frontal sinus to the
subdural space: direct and indirect (33). Direct extension involves erosion of the posterior bony wall of
the frontal sinus by infection, with further erosion of the underlying dura mater (33). In teenagers
primarily, frontal bone osteomyelitis with subperiosteal abscesses (a Pott puffy tumor) can extend directly
into the subdural space (47,103). The more likely route is indirect, with extension of infection and
associated thrombophlebitis through the mucosal veins of the sinus to the emissary veins that link the
facial and dural venous systems (15,33,48). From the dural sinuses, the infection establishes itself in the
subdural space at the frontal pole and may spread posteriorly over the convexity, medially into the
interhemispheric region, and contralaterally. This extension may create significant pressure on a large
area of underlying brain tissue (15,22,49). As stated previously, it is unusual but possible for the
empyema to spread infratentorially (15). Further retrograde thrombophlebitis often occurs, involving the
valveless, deeper veins of the cerebrum, which in turn may lead to necrosis and infection of brain tissue
(10,13,32,33). Subdural empyema secondary to an otogenic source of infection differs only in the site at
which pus enters the subdural space. The tympanic cavity is bounded superiorly by the tegmen tympani, a
thin plate of bone forming part of the temporal bone of the skull separating the tympanic cavity from the
brain (37). Perforating veins pass through this plate of bone to communicate with the superior petrosal
venous sinus of the dura (37). In addition, mastoid air cells within the temporal bone surrounding the
middle ear communicate with the tympanic cavity and may lie very close to the posterior cranial fossa
separated from the dura by slivers of bone (37). Otitis or mastoiditis may, therefore, extend directly into
the subdural space via erosion of the tegmen tympani or bone adjacent to the air cells and dura mater or
spread infection indirectly by way of a progressive thrombophlebitis of the perforating veins (27,32).
Because the venous sinuses into which the veins from the middle ear and mastoid bone drain are within or
beneath the tentorium (38), otogenic infection may result in posterior fossa subdural empyema (27). As
opposed to subdural empyema secondary to frontal sinusitis, otitis-induced subdural empyema is initially
localized posteriorly or on the tentorium (50). Hematogenous spread of bacteria to the subdural space
from a distant site of infection is an uncommon cause of subdural empyema, accounting for fewer than 5%
of all cases in most series (Table 33.1). Several reports describe the development of subdural empyema
via hematogenous spread to a preexisting subdural hematoma (51,52). Subdural empyema is a rare
complication following cranial surgery; in one series, subdural empyema occurred in slightly more than 1
in 1,000 craniotomies (53). In a large series of 16,540 craniotomy procedures from 1997 to 2007, only
0.5% had intracranial infection (only 7 cases were pure subdural infections) (104).
In adults, the extension of a subdural empyema from acute purulent meningitis is very unusual. Although
there is a subarachnoid inflammatory exudate, the arachnoid is fairly impermeable to the bacterial process
occurring adjacent to it (22). Bacterial meningitis in adults is a very unusual cause of subdural empyema,
occurring in less than 1% of cases (21,105). However, in infants, meningitis is an important predisposing
condition for the development of a subdural empyema (11,20,21,97,100). Subdural empyema occurs in
about 2% of infants with bacterial meningitis (54). The pathogenesis is presumably infection of an
initially sterile subdural effusion (13,20,21). Such sterile effusions are variably reported as occurring in
up to 60% of infants with meningitis (13,20,97).
Clinical Features
A high clinical suspicion and rapid diagnosis of subdural empyema are critical for a successful outcome.
Certainly, an adult with a recent history of sinusitis and a new presentation suggestive of central nervous
system (CNS) infection warrants an investigation to exclude subdural empyema. However, in some cases,
the antecedent infection is subtle enough to be unrecognized. In others, the concurrent complication of
sinusitis with a subdural empyema delays the diagnosis of the latter because symptoms are attributed to
the sinusitis. In other cases, the subdural empyema is not suspected because the precipitating cause for the
subdural empyema is unknown or arises from a distant focus of infection. Although the clinical
presentation may vary, there are key clinical features of subdural empyema that if present should result in
its inclusion in one’s initial differential diagnosis. The sex and age distributions of patients with subdural
empyema are striking. There is an overrepresentation of men reported in series of patients (mostly adults)
with subdural empyema published during the last two decades. In those that report only children, males
also predominate. However, in infants, this sex discrepancy may not be so marked
(3–5,7–10,12,13,15,16,18,19,22–26,54,99,100,106). Figure 33.2 displays the age distribution of patients
reported in series of consecutive patients with subdural empyema. It is clear that most cases occur during
the second and third decades of life. As stated earlier, the significant growth of the frontal sinus during
puberty has been proposed as an explanation for the uneven age distribution (7,26,46). However,
confirmatory analyses comparing patients’ sex, age, and source of infection have not been reported.
The clinical features of adults with subdural empyema are presented in Table 33.2. Generally, patients
have a nonspecific illness for a few days to a few weeks before presentation to the hospital acutely ill
(1,5,12,13). However, if the infection is a result of head trauma or surgery, the symptoms may be milder
and present more subacutely (10,23,55,56,104). The most common symptoms and signs are headache,
fever, neurologic deficit, and stiff neck. Vomiting and malaise are often reported as well (8,15). Seizures,
papilledema, and altered level of consciousness ranging from drowsiness and disorientation to coma also
occur frequently. These neurologic changes may be presenting signs or, as is often the case, may develop
during the course of the illness (6,7,15,28).
Diffuse neurologic signs such as altered level of consciousness, papilledema, and generalized seizures
are a result of increased intracranial pressure (ICP) (33,57). Focal neurologic abnormalities such as
hemiparesis, jacksonian seizures, dysphasia, and cranial neuropathies may be secondary to local pressure
on the underlying cortex by the subdural process (21,27,32,33,41,49,58) and may be precipitated by
cortical venous thrombosis with accompanying brain inflammation and infarction (21,22,57). Such focal
neurologic signs may help to localize the empyema. This is particularly true in cases of infratentorial
subdural empyema that occurs infrequently, but that is easily suspected if cerebellar signs such as ataxia
and nystagmus are present (27). Interhemispheric (parasagittal, parafalcine) subdural empyema, usually
associated with disease over the convexities but uncommonly occurring alone (43), characteristically
produces contralateral leg symptoms, including weakness and focal seizures (41,43,49,58). As the
interhemispheric suppuration extends backward over the tentorium and below the occipital lobes,
homonymous hemianopia may result (49,58). Subdural empyema overlying one or both convexities yields
the most nonspecific neurologic signs. Clues to the involved areas can be (a) contralateral paresis or
seizures, (b) aphasia or dysphasia associated with left-sided infection, or (c) cranial neuropathies
(32,33,49). The clinical signs of subdural empyema in infants are similar to those in adults. In addition, a
bulging anterior fontanelle is a common finding in infants (11,20,54).
The cardinal features of headache, fever, stiff neck, and neurologic signs are not specific for subdural
empyema. The differential diagnosis also includes brain abscess, epidural abscess, meningitis,
meningoencephalitis, subdural hematoma, and intracerebral thrombophlebitis (21,48). Of these, the
presence of focal neurologic signs makes meningitis much less likely. The presence of nuchal rigidity is
unusual in brain abscess and subdural hematoma. Unfortunately, clinical grounds alone do not allow the
exclusion of most of these possibilities. Therefore, more specific testing should be undertaken as soon as
the diagnosis of subdural empyema is suspected.
Diagnostic Studies
Routine studies such as blood tests and plain roentgenograms are of very little value in patients with
suspected subdural empyema. Most patients are found to have a peripheral blood leukocytosis
(3,11,13,27,30,33). Plain films of the skull are not useful except to demonstrate a sinusitis or mastoiditis
or to show widened sutures in infants (21). In infants, cranial ultrasonography can detect a subdural
collection and may differentiate a reactive effusion from a subdural empyema (107). Before the
development of CT, cerebral arteriography, with a diagnostic accuracy of 80% to 90%, was the
procedure of choice to diagnose subdural empyema (13,15,21,27). Although nearly perfect for the
detection of hemispheric and parafalcine subdural collections, the sensitivity of carotid angiograms for
posterior fossa subdural empyema was not as great (27). Presently, the safety, ease of application, and
reliability of CT and MRI make them the modalities of choice to diagnose subdural empyema.
Computed Tomography and Magnetic Resonance Imaging

The radiologic evaluation of patients with subdural and epidural empyemas has been revolutionized by
the advent of CT in 1972 and MRI in 1984. The introduction of CT has had a major impact on the
management and prognosis of subdural and epidural empyemas because CT allows (in a noninvasive
manner) earlier and more accurate detection, delineation, and characterization of these extraaxial
(extraparenchymal) inflammatory lesions and their associated intraaxial (parenchymal) sequelae when
compared to carotid arteriography (10). In addition, CT provides an important adjunct to standard clinical
parameters in the assessment of the adequacy of patient response to therapy. The CT, findings during the
early stages of development of a subdural empyema may be subtle and easily overlooked (10).
Noncontrast CT scans typically demonstrate a crescentic hypodense collection over one or both cerebral
convexities and/or around the interhemispheric tissue (Fig. 33.3A). Contrast-enhanced CT increases the
conspicuity of the collections that represent active inflammatory disease either in the leptomeninges or in
the subjacent cerebral cortex (Fig. 33.3B).
Thick, irregular enhancement of the falx in association with a spindle-shaped collection is seen in
interhemispheric subdural empyemas (43) (Fig. 33.4). Parenchymal changes at this early stage include
thickening and hyperdensity of the underlying cortical gray matter and hypodensity of the white matter on
noncontrast CT images; these changes indicate the presence of edema, hyperemia, and ischemia (10).
Additionally, gyral enhancement subjacent to an extraaxial empyema on contrast CT scans is a common
finding, indicative of meningitis, cerebritis, and/or venous thrombosis (Fig. 33.3B). Extensive mass effect
on the ipsilateral cerebral hemisphere that is out of proportion to the small size of the extraaxial
collection is invariably present, and it is manifested as ventricular compression, sulcal effacement, and
midline shift. It is important to examine the paranasal sinuses, middle ear cavity, and orbits for the
presence of inflammation, which may reflect the origin and extent of the intracranial abnormalities (26,29)
(Figs. 33.5 and 33.6A).
Unrecognized and untreated, the subdural empyema rapidly grows and develops loculations and the
parenchymal abnormalities progress to cortical infarction and abscess formation. MRI is proving to have
a greater sensitivity and specificity in the workup of patients with an extraaxial empyema; this is
attributed to several inherent advantages of MRI over CT (36,59,60). MRI uses several standard pulse
sequences referred to as “T1 weighted,” “proton-density weighted,” and “T2 weighted” (61). T1-
weighted images emphasize contrast between the brain and cerebrospinal fluid (CSF), and proton-
density–weighted and T2-weighted images emphasize contrast between brain and pathologic processes
(61) (Fig. 33.6B and C).
MRI has been found to have six inherent advantages over CT. First, MRI permits excellent
visualization of superficial brain anatomy, precise localization of extraaxial empyemas (Fig. 33.4C), and
more definitive separation of extraaxial collections from their associated intraaxial complications such as
edema, cerebritis, and venous thrombosis, which are more readily visualized on MRI than on CT (36,62).
Second, streak artifacts from the bony calvaria, which are particularly problematic on CT, are not
limitations on MRI. Third, MRI is superior to CT in differentiating noninfected subdural effusions and
hygromas from infected empyemas. As with other proteinaceous fluids, the T1- and T2-weighted values
of purulent collections are smaller than those of CSF. These collections are, therefore, mildly
hyperintense to CSF on T1-weighted images and markedly hyperintense to CSF on T2-weighted images
(36). Fourth, the unprecedented sensitivity of MRI to subtle changes in tissue water content is uniquely
suited to the goal of early detection of the parenchymal abnormalities that can occur secondary to a
subdural empyema. Fifth, MRI is more specific than CT in differentiating a subdural from an epidural
empyema (36,63). A hypodense medial rim, representing inflamed displaced dura, is seen on MRI of an
epidural empyema but not on that of a subdural empyema. Finally, the delineation of extraaxial
inflammatory disease, leptomeningeal disease, and parenchymal abnormalities is improved with the use
of the MRI contrast agent, gadolinium diethylenetriamine pentaacetic acid (64), and diffusion-weighted
imaging (108,109).
CT and MRI play a role in the follow-up of patients with extraaxial empyemas (10,36,59). Residual or
recurrent collections that may necessitate reexploration are particularly prone to occur in the parafalcine
or subtemporal regions. These locations are well imaged on MRI because of its ability to obtain direct
coronal sections of the brain. Long-term follow-up CT or MRI examinations frequently demonstrate
cortical atrophy adjacent to a previous extraaxial empyema.
Lumbar Puncture
Lumbar puncture is often performed in patients who are subsequently diagnosed with subdural empyema,
but it is neither sensitive nor specific for this disease. Recovery of a causative organism in the CSF is
rare, except in infants in whom meningitis preceded the development of the subdural empyema
(11,20,21,54). The CSF formula in children and adults with subdural empyema is unpredictable, as shown
in Table 33.3. Typically, the white blood cell (WBC) count is elevated; however, many series report
patients with zero to five CSF leukocytes per cubic milliliter (13,25,26,29,30). The differential cell count
on the CSF is highly variable: although a polymorphonuclear pleocytosis is more common, the
mononuclear cell predominates in close to 40% of patients. A normal protein concentration suggests the
absence of a subdural empyema because there is an inflammatory response by the arachnoid to the
overlying subdural process. However, because the arachnoid is generally impermeable to the infectious
agent, CSF Gram stain and culture almost never demonstrate the bacterial cause of the subdural empyema
and are, therefore, not helpful in choosing antibiotic therapy.
In addition to providing no valuable diagnostic information, lumbar puncture is a potentially dangerous

procedure in patients with signs of increased ICP (66). Several deaths from cerebral herniation have been
reported in patients with subdural empyema shortly after undergoing lumbar puncture (13,25,26,40,44).
Certainly, patients with papilledema or a focal neurologic abnormality or patients with suspected
increased ICP should not undergo a lumbar puncture.
Bacteriology
The microbiologic etiology of subdural empyema is established by Gram stain and culture of evacuated
pus from the subdural space. Unfortunately, cultures of subdural pus are sterile in about one third of
patients (25) because patients are almost always receiving antibiotics preoperatively. It has been
suggested that the high number of negative cultures is also related to the lack of proper handling and
culture for anaerobes (25). In one study in which paranasal sinus cultures and subdural cultures were
compared, three of the four sinus isolates did not correlate with the subdural isolates (26). Blood cultures
may provide additional diagnostic information in about 10% of cases in which the subdural fluid is sterile
(11,21,26). The organisms cultured most often from subdural infections are aerobic and anaerobic
streptococci. Staphylococci are cultured less often, followed by aerobic gram-negative bacilli and
nonstreptococcal anaerobes (Table 33.4). In most patients, a single organism is responsible for subdural
empyema. However, several series have included cases in which multiple organisms have been cultured
(3,5,7,16,17,19,21,22,25,27).
Generally, the causative organism is predictable based on the anatomic focus from which the infection
originated (3,5,8,13,45,55,56,100). Otorhinogenic subdural empyemas are most often due to aerobic and
anaerobic streptococci and are less often due to coagulase-positive staphylococci and other anaerobes.
Infections secondary to head trauma, surgery, or an indwelling foreign device are most often caused by
coagulase-positive and coagulase-negative staphylococci and gram-negative bacilli. Four cases of
postneurosurgical subdural empyema caused by Propionibacterium acnes, a gram-positive anaerobic
bacillus, were reported often occurring several weeks after the surgical procedure (67,68).
Subdural empyemas originating from distant foci of infection are caused by a variety of organisms. In
infants with leptomeningitis, subdural empyema is caused by the same organism responsible for the
meningitis, usually Streptococcus pneumoniae or Haemophilus influenzae (21,54). Many organisms
other than those mentioned have been reported to cause subdural empyema. These include Salmonella
species (69,70), Campylobacter fetus (52), Serratia marcescens (71), Neisseria meningitidis (72,73),
Pasteurella multocida (52,74), Actinomyces israelii, and Actinobacillus actinomycetemcomitans (new
genus name—Aggregatibacter) (75). In the Far East, a greater percentage of bacterial pathogens are
gram-negative aerobes (Enterobacteriaceae), particularly Klebsiella pneumoniae (110).
Treatment and Outcome
The clinical suspicion of subdural empyema requires the immediate institution of parenteral antibiotic
therapy. Antibiotics should be chosen based on the suspected source of the infection and on the organisms
known to commonly cause subdural empyema. Although no prospective comparisons of antibiotic
regimens for subdural empyema have been conducted, an acceptable empirical therapy includes a β-
lactamase–stable penicillin, a third-generation cephalosporin, and metronidazole. Depending on the
prevalence of methicillin-resistant Staphylococcus aureus or the likelihood of coagulase-negative
staphylococci, vancomycin may be used in place of the β-lactamase–stable penicillin. Although there is
no consensus, some advocate irrigation of the subdural space with antibiotics (2,8,9,12,14,49). No
current data support a specific duration of antibiotic therapy; however, most patients are treated for 3 to 4
weeks after drainage (21). Empirical therapy for seizure prophylaxis has been advocated (8,13,28,45),
and steroids and mannitol have been used successfully to decrease ICP in individual cases (5,13,24).
Although anecdotal cases have been successfully treated with antibiotics alone (76,77), surgical
drainage of a subdural empyema is imperative. Disagreement exists, however, over the optimal mode of
surgery. The comparative efficacy of multiple burr holes versus craniotomy is complicated by clinical
factors that may contribute to outcome. Several parameters have been suggested to be important in
predicting patient mortality, including age of patient (12), source of infection (12), microbiology (12),
time from presentation to surgery (13), management of the primary source of infection (1), extent of
spread of empyema (4), level of consciousness at presentation (1,4,7–9,12,27), and surgical technique
(4,5,7–9,12,14,22,24,27). Analysis of the few reviews that correlate the primary source of infection with
ultimate outcome suggest that subdural empyema secondary to paranasal sinusitis is associated with less
overall mortality compared to other primary sources of infection (1,3,12–14,18). However, level of
consciousness at presentation and surgical technique have correlated better with outcome in several
studies. Table 33.5 compares patient mortality with level of consciousness at presentation. Those patients
presenting awake and alert (grade I) have the greatest chance of survival and those presenting
unresponsive to pain (grade IV) are least likely to survive. Patients who are drowsy and disoriented
(grade II) or responsive only to painful stimuli (grade III) have intermediate survival statistics. Of the
survivors, decreased level of consciousness at presentation correlates with more severe neurologic
sequelae (4,7,8).
Several groups have advocated craniotomy over burr-hole drainage, citing increased survival in the
group treated by craniotomy (4,5,7–9,12,14,22,24,27,44) (Table 33.6). The advantage of craniotomy is
considered to be related to the greater ease of evacuating pus from a larger area. Few investigators,
however, have considered the level of patients’ consciousness when evaluating mortality of the surgical
groups. In several studies in which both the level of consciousness and the mode of surgery are
established, it is notable that patients with grades III and IV coma were more likely to undergo burr-hole
drainage (5,7,22,27). In fact, Mauser et al. (4) report a higher death rate in the craniotomy group when
patients presenting with grades III and IV consciousness are considered but lower mortality in the
craniotomy group among patients with grades I and II consciousness. Hence, the increased survival with
craniotomy may be related, in part, to its more frequent use in a patient population starting with a better
prognosis. A study by Nathoo et al. (44) of 699 patients with subdural empyema reported improved
mortality rates using craniotomy rather than burr holes or limited craniectomy regardless of severity of
disease. However, a good outcome was achieved in 71% of those undergoing burr-hole drainage and
86% undergoing craniotomy. Nathoo et al. (44) suggest that craniotomy provides the best decompression
of the brain and the most complete evacuation of pus. The optimal treatment for all patients remains
unclear; however, regardless of the initial surgical approach (multiple burr holes vs. craniotomy), several
studies report a number of patients requiring reoperation (4,7,9,98). Several studies have documented
increased reoperation rates in those patients treated with burr holes compared to craniotomy, with one
study having a reoperation rate of 50% with burr holes compared to only 20% in the craniotomy group
(4,98).
The overall mortality of subdural empyema and the extent of neurologic sequelae reported in survivors
are summarized in Table 33.7. In the past, mortality rates averaged 11% to 12% and morbidity rates were
17% to 45% (98). Some recent studies with aggressive antibiotic and surgical approaches have reduced
the mortality to less than 5% and morbidity to less than 13% (98). The potential extent of neuroanatomic
sequelae is illustrated by necropsy studies (33). Venous sinus thrombosis is a common finding in patients
with subdural empyema because the route of infection to the subdural space is generally via these venous
sinuses. As a result of the absence of valves in the venous system of the brain, thrombophlebitis may
extend to the cortical and subcortical veins of the cerebrum. Thrombosis of these vessels results in venous
stasis and subsequent congestion and softening of adjacent brain tissue. Brain infarction and necrosis (Fig.
33.7), with or without abscess formation, may ensue. Therefore, clinical neurologic sequelae may be a
consequence of brain abscess or brain infarction secondary to increased ICP or venous thrombosis. More
than 10% of patients with subdural empyema develop venous sinus thrombosis or brain abscess
(13,33,45).
SPINAL SUBDURAL EMPYEMA
Spinal subdural empyema is a rare condition, with fewer than 80 cases previously reported in the
literature, with most reports from the Western Hemisphere in patients in their sixth and seventh decade of
life. In 2013, Sandler et al. (112) reported 11 cases of spinal subdural empyema in children throughout the
world and reviewed 73 additional cases. The median age was 6.5 years with 38% of cases younger than
3 years of age and 15% younger than 1 year of age. Most of the children were male (2:1 ratio) and 53%
were associated with spinal congenital abnormalities. Fifty-six percent of cases lived in the Eastern
Hemisphere with only 17% from the United States.
In adults, signs and symptoms include fever, back pain, and subsequent signs of spinal cord
compression (78–80). It can be distinguished from spinal epidural abscess by the absence of tenderness to
palpation in most cases of spinal subdural empyema (78,79,81,102). In children, however, spinal
tenderness is more common (112). Therefore, in children, the clinical presentation may be difficult to
differentiate from acute transverse myelitis. Spinal subdural empyema most commonly occurs in the
thoracolumbar spine, although subdural infection of the cervical spine has been reported
(31,80,82–85,112).
Spinal subdural empyema most often arises as a result of hematogenous spread of infection to the spinal
subdural space, with S. aureus being the most common etiologic agent (78,102). Other reported pathogens
include streptococci (31,86), coagulase-negative staphylococci (79,87), and gram-negative bacilli
(78,80). Occasionally, this may arise from local trauma or surgical procedures including incidental dural
tears (113,114) and even acupuncture (115). In a series of childhood spinal subdural empyema, the most
common pathogens were Mycobacterium tuberculosis and Echinococcus granulosis (112).
Diagnosis is best accomplished by MRI with gadolinium with decreased signal on T1 and increased
signal on T2. Fat-suppressive techniques with MRI help define the subdural space (112). Metrizamide-
enhanced spinal CT can be used in areas where MRI is not available or is contraindicated. Treatment
consists of empirical antibiotic therapy initially directed against S. aureus, streptococci, and gram-
negative enteric bacilli, in association with laminectomy for drainage of the empyema. Antibiotics can
then be adjusted based on specific culture results for a duration of 2 to 4 weeks.
SUPPURATIVE INTRACRANIAL PHLEBITIS

Infections within the sinuses or facial structures can lead to intracranial complications that include
subdural empyema, cerebral abscesses, epidural abscesses, meningitis, and less commonly suppurative
intracranial phlebitis of the dural veins. Suppurative phlebitis can occur as a primary complication or as a
secondary complication to other intracranial infections such as subdural empyema (Table 33.8).
Pathogenesis
Infection usually spreads to the dura via venous drainage from the sinuses (91), middle ear, face, or scalp.
Within the dura mater are seven paired venous sinuses and five unpaired sinuses, all of which are spaces
between two layers of dura. They collect blood from the veins of the brain, skull, and face, and they
empty into the internal jugular veins (38). Emissary (perforating) veins allow the passage of blood from
the larger veins of the face and scalp into the dural venous sinuses, serving as a potential communication
for more superficial infection of the head with the venous system of the brain (37). The venous system of
the head and brain is valveless, allowing retrograde spread of thrombophlebitis from infected venous
sinuses into dural and cortical venous channels (21,37,116).
Suppurative intracranial phlebitis can lead to infarction or brain inflammation (21,22,57) with
subsequent neurologic sequelae such as seizures, hemiparesis, or cranial neuropathies.
Cavernous sinus thrombosis is more commonly associated with ethmoid and sphenoid disease, whereas
occasionally, ophthalmic vein thrombophlebitis may extend posteriorly to cause cavernous sinus
thrombosis (91).
Clinical Features
Most patients present with headache and fever associated with a toxic appearance and leukocytosis.
Increased ICP and papilledema are present in 53% to 65% of cases of cavernous and lateral sinus
thrombosis but less commonly with superior sagittal thrombosis (88,89). Focal neurologic findings
involve cranial nerves primarily based on the location of some cranial nerves to the venous sinuses.
Cranial nerves III, IV, and VI controlling the extraocular muscles are primarily involved with cavernous
sinus thrombosis as they pass through or near the inflamed cavernous sinuses (89). Lateral sinus
thrombosis is most often associated with unilateral sixth nerve palsy. On rare occasions, the ophthalmic
and maxillary branches of the trigeminal nerve (V1 and V2, respectively) are involved with cavernous
sinus thrombosis and less commonly with lateral sinus thrombosis. Hemiparesis may occur in up to 61%
of patients with superior sagittal sinus thrombosis due to cerebral infarcts (88).
Microbiology and Pathogenesis
S. aureus is the most common bacterial pathogen, occurring in more than 60% to 70% of cases of
cavernous sinus thrombosis (88–90). Other gram-positive bacteria such as streptococcal species and
pneumococci also can be associated with acute suppurative intracranial phlebitis. In septic lateral sinus
thrombosis, gram-negative bacteria such as Proteus mirabilis and Escherichia coli as well as anaerobes
such as Bacteroides fragilis and anaerobic streptococci may play a larger role due to the pathogens
involved in chronic otitis media, which is often its predisposing condition (88). Immunosuppression and
hematologic malignancies may be associated with fungal infections such as mucormycosis (92). A study
from Pakistan and the Middle East reviewed 109 cases of cerebral venous thrombosis of which 20 (18%)
had infectious causes ranging from tuberculous meningitis, rhino-orbital fungal infection, bacterial
meningitis, mastoiditis, malignant otitis, and others (117).
Diagnosis
High-resolution contrast-enhanced CT scans with fine cuts through the suspected areas have been used
most extensively over the years. However, MRI has now become the modality of choice for diagnosing
suppurative intracranial phlebitis, particularly cavernous sinus thrombosis, using thin-section coronal
images as well as magnetic resonance angiography (MRA) and magnetic resonance venography (MRV)
(91,93,117–120). In a recent review of cerebral venous thromboses (118), the advantages and
disadvantages of CT and MRI modalities are discussed. Although the exact sensitivity and specificity for
MRI techniques are unknown, it is estimated that CT/computed tomography venography (CTV) shows
95% sensitivity and 91% specificity and that MRI/MRV is equal or better than CT/CTV (118). In cases
where MRI is not available or contraindicated, CT techniques are fairly accurate.
Cerebral angiography and venography are used only rarely (121) since the advent of CT and MRI.
Lumbar puncture with CSF evaluation always is abnormal with neutrophilic pleocytosis and elevated
pressure but is generally not diagnostic and may pose some risk in patients with severely elevated ICP.
Treatment
All intracranial suppurative infections require the use of appropriate high-dose antibiotics with good
penetration of the blood–brain barrier. Appropriate surgical intervention to drain the sinuses or subdural
collections is usually mandatory. In addition, anticoagulants may be added to the regimen for cavernous
and sinus thrombosis using heparin or low-molecular-weight heparin followed by warfarin for a 6-week
course or until the thrombus resolves radiographically (119). The use of anticoagulants, however, is
controversial because of the risk of bleeding from carotid artery rupture or cerebral venous infarction
(94). Direct thrombolytic therapy has been used for refractory cerebral sinus thrombosis, but its use in
septic sinus thrombosis is not clear and may be hazardous (95).
Prognosis
Antibiotics have markedly reduced the morbidity and mortality of suppurative intracranial phlebitis.
However, mortality remains as high as 78% for superior sagittal thrombosis, 30% for cavernous sinus
thrombosis, and only 0% to 12% for lateral sinus thrombosis (88,96). Permanent neurologic sequelae
result in 25% to 100% of those patients who survive and are most likely to occur in those with the most
severe disease and those with superior sagittal sinus thrombosis.
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2006;26:S5–S18.
CHAPTER 34 COMPLICATIONS OF INFECTIVE
ENDOCARDITIS
STEFANO GIULIERI, RETO ANTOINE MEULI, AND MATTHIAS CAVASSINI
Central nervous system (CNS) complications of infective endocarditis (IE) occur in about 30% of
patients, with the highest incidence among patients referred to tertiary care centers and intensive care
units, as well as patients with mitral valve endocarditis and IE due to virulent microorganisms (e.g.,
Staphylococcus aureus, gram-negative bacilli, fungi). Ischemic stroke accounts for up to two thirds of
CNS complications, followed by intracranial hemorrhage, meningitis, brain abscess, intracranial
infectious aneurysm (ICIA), and encephalopathy. Embolization of infected vegetations is the main
pathogenetic mechanism. Imaging (both computed tomography [CT] and magnetic resonance imaging
[MRI], coupled with noninvasive angiography) plays a pivotal role in the diagnosis of CNS
complications. Optimal management includes early institution of antimicrobial treatment, which has the
highest impact on the risk of further emboli. Anticoagulation should be cautiously continued in patients
with established cardiac indications (e.g., prosthetic valve). In the presence of an established indication,
patients with IE and ischemic stroke should undergo cardiac surgery without delay, whereas it should be
postponed for at least 4 weeks in case of intracerebral hematoma. Unruptured ICIA may be managed
medically with radiologic follow-up, whereas enlarging or ruptured ICIA should be treated surgically or
by an endovascular approach. Despite improvement in the management, patients with CNS complications
generally carry a worse prognosis compared to patients without neurologic complications.
HISTORY
Infective endocarditis (IE) was probably recognized as early as 1646 by Rivière, but the full clinical
spectrum of “malignant endocarditis” was first comprehensively described by Sir William Osler (1) in
his Gulstonian lectures at the Royal College of Physicians in London in 1885. He not only described “the
different modes of onset, and the extraordinary diversity of symptoms which may arise,” but carefully
analyzed the pathophysiology of distant complications, particularly of central nervous system (CNS)
manifestations such as meningitis: “The meningeal complications of endocarditis have not received much
attention, considering the frequency with which it has occurred . . . somewhat over 12 per cent” (1). He
also related IE and mycotic aneurysms to a common infectious etiology and later emphasized the central
importance of blood cultures in diagnosis (2).
EPIDEMIOLOGY
In developed countries, the reported incidence of IE is 3 to 7 per 100,000 per year (3–6). This rate has
remained fairly constant over time (7). Incidence of IE increases sharply with age, with a peak of 15
episodes per 100,000 per year in patients older than 70 years (4,8). The male:female ratio is 2:1. In-
hospital and 6-month mortality in recent series are 15% to 20% and 25%, respectively (9). These
apparently stable overall rates of incidence and mortality mask the continually evolving spectrum of IE
and the contrasts that exist between various types of IE. For instance, subacute IE due to viridans
streptococci has an early mortality rate of only 5% to 10%, whereas acute prosthetic valve endocarditis
(PVE) in an elderly patient with congestive heart failure can be fatal in up to 70% of patients. The overall
figures reflect shifting frequency of predisposing factors. In developed countries, the decreasing
prevalence of chronic rheumatic heart disease is counterbalanced by an increased number of patients with
prosthetic valves and intravascular devices, injection drug use, and elderly patients with degenerative
heart disease (10). The mean age of patients presenting with IE has increased, from 34 to 43 years in the
early antibiotic period to 52 to 55 years more recently, and has even passed 60 years in some reports
(3,11,12).
PREDISPOSING FACTORS
Degenerative valve disease has replaced rheumatic heart disease as the main underlying condition in
patients with IE (10). Degenerative valvular disease with calcified atheromatous deposits is associated
with IE in a proportion of cases that increases with age and may be a predisposing factor in up to 50% of
the IE cases in elderly patients (13). Mitral valve prolapse (MVP) associated with valve dysfunction is
another recognized risk factor for IE, found in 10% to 30% of patients (14). In a case–control study, the
risk of IE was eight times higher among patients with MVP (15), but, given the high incidence of MVP
(5%) in the general population, the absolute risk per patient is low, estimated to be 0.0175% per year
(14).
Although it remains a common predisposing condition in developing countries, rheumatic heart disease
is associated with IE in less than 5% of cases in the Western countries (16). Congenital lesions are found
in 6% to 20% of cases (17), mostly ventricular septal defect, bicuspid aortic valve, patent ductus
arteriosus, and tetralogy of Fallot. A bicuspid aortic valve is an important factor in elderly persons in
whom it may be present in up to 20% of IE cases; this is probably because of associated valvular
sclerosis and abnormalities of blood flow (18).
Prosthetic valves account for 7% to 25% of the cases of IE and the annual incidence of IE in patients
with prosthetic valves is approximately 1% (19). In-hospital mortality rate ranges from 20% to 30% (20).
IE related to hospitalization and ambulatory invasive treatments (health care associated) now accounts
for one third of cases (21). The proportion of IE associated with other intracardiac devices such as
pacemakers or implantable cardioverter-defibrillators was 6.4% in the ICE-PCS (22). Nosocomial
bacteremias (mainly Staphylococcus aureus) represents as many as 25% of the cases in certain series
(23,24). IE is reported in 2% to 6% of patients undergoing long-term hemodialysis (25). Intravenous drug
users (IVDUs) are at high risk for IE. Moreover, 20% to 40% of IVDUs suffering from IE have
preexisting cardiac lesions, often caused by previous infection (26).
PATHOGENESIS
Certain lesions of the endothelium of the valve or heart cavities can easily be infected should a
bacteremia occur. This has been shown in animal models: An intravascular polyethylene catheter placed
across the aortic or the tricuspid valve will induce the deposition of platelets and fibrin and lead to the
formation of nonbacterial thrombotic endocarditis (NBTE) (27). Many factors can induce endothelial
lesions, which promote the formation of NBTE. The most important are valvular organic lesions with
associated perturbations of blood flow and prosthetic valves. Even microscopic lesions are prone to
infection by circulating bacteria (28), so not surprisingly, up to 50% of patients with IE have no known
predisposing heart condition at the time of diagnosis (29). Transient asymptomatic bacteremias occur
frequently, often following minor mucosal trauma induced by daily domestic activities such as chewing or
tooth brushing. Bacteremia may also be triggered by various iatrogenic procedures. Among the many
bacterial species that can be recovered during transient bacteremias, streptococci account for most IE
cases, probably because of the frequency with which they enter the bloodstream and the adherence
properties of their surfaces.
Circulating bacteria readily attach to NBTE. The attachment process is probably mediated on the host
side by receptor-like structures such as fibronectin, fibrinogen, laminin, or collagen, which interact with
the surface of bacteria (8). Platelets also play a role in these initial events (30,31). On the microbial side,
only bacteria with the ability to adhere to valvular lesions can produce IE. Gram-positive cocci (e.g.,
staphylococci, streptococci) adhere more strongly than enterobacteria to heart valves (32).
Once microorganisms have attached to NBTE, they start to multiply and stimulate further deposition of
fibrin and platelets through the activation of tissue factors or procoagulant activity. This thrombotic
process buries some bacterial colonies deep within the vegetation where they are protected from
circulating neutrophils. This has led to the concept of the vegetation as an area of “localized
agranulocytosis.” Bacteria deeply seated in the vegetation are metabolically inactive and thus resistant to
the action of some antibiotics. Furthermore, some antibiotics do not fully penetrate into the vegetation.
This combination of factors favors the bacteria and helps explain why cure of endocarditis requires the
prolonged administration of bactericidal antibiotics.
Because the infected vegetation is located within the bloodstream, persistent bacteremia is a hallmark
of bacterial endocarditis, permitting the diagnosis through blood cultures in most patients. Moreover,
further deposition of platelets, fibrin, and circulating bacteria will compensate for the fragmentation,
embolism, and/or resorption of the vegetation by the inflammatory response, in a delicate and complex
balance. IE also induces immunologic responses that contribute to some clinical manifestations of IE such
as glomerulonephritis or vasculitis (30).
ETIOLOGIC AGENTS
The list of microorganisms that can cause IE includes most human pathogenic bacteria, as well as
rickettsiae, Bartonella, chlamydiae, and fungi (19). However, gram-positive cocci predominate. The
pattern of distribution of these etiologic agents differs profoundly according to underlying risk factors, the
valve type (native vs. prosthetic), and geography (33).
Native Valve Endocarditis
S. aureus is now as common as streptococci as a causative pathogen of native valve endocarditis (NVE)
in developed countries (6). In the International Collaboration on Endocarditis-Prospective Cohort Study
(ICE-PCS), S. aureus and streptococci both accounted for 32% of 1,881 cases of definite NVE (16). The
increase in frequency of S. aureus IE is explained by several invasive medical procedures associated
with S. aureus bacteremia (e.g., hemodialysis, long-term intravenous catheters) (24). The clinical course
of S. aureus IE is usually acute and complicated. In-hospital mortality rate was 22% in a recent
prospective study (24). Coagulase-negative staphylococci rarely cause NVE but appear to be increasing
in frequency and can pursue an aggressive clinical course (34). Special attention has been drawn to
Staphylococcus lugdunensis, being commonly associated with valve destruction (35).
In a recent French series of 497 patients with definite IE (79% with NVE), streptococci, although less
frequent compared to a previous study (4), were still the most common cause of IE and were responsible
for 48% of cases (6). The viridans group (e.g., Streptococcus sanguis, Streptococcus oralis,
Streptococcus mutans, and Streptococcus mitis) accounts for at least two thirds of these cases. The
clinical course is generally subacute and an underlying cardiac condition is often present. Streptococcus
milleri, an occasional cause of IE, has a peculiar propensity to cause distant abscesses and local
perivalvular invasion (36). Streptococcus bovis group (including S. gallolyticus subsp. gallolyticus, S.
gallolyticus subsp. pasterianus, and S. infantarius subsp. coli) accounts for up to 20% of streptococcal
IE (37) and is often associated with neoplasms of the gut, of which it may be the first manifestation
(38,39). Streptococcus pneumoniae and streptococci of the Lancefield groups A, B, C, G may also
occasionally cause endocarditis (40,41). Enterococci account for 10% of all IE (42); these strains are
particularly resistant to the bactericidal activity of antibiotics. Older people are usually affected and
outcome can be fatal in approximately 16% of patients (42).
Numerous other bacteria are well known but uncommon causes of NVE, for example, Coxiella
burnetii, Brucella, and bacteria of the “HACEK” group (Haemophilus species, Actinobacillus
actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella species) (43).
Actinobacillus actinomycetemcomitans has now been reclassified as Aggregatibacter
actinomycetemcomitans (44). Bartonella is an unusual cause of endocarditis in homeless people (45).
Prosthetic Valve Endocarditis
PVE cases with onset within 2 months after surgery are called early PVE (46). Early PVE cases are
presumably related to intraoperative contamination. S. aureus is responsible for 35% of early PVE cases;
coagulase-negative staphylococci are found in 17% of cases. The frequency of gram-negative bacilli
(10% to 20%), diphtheroids (0% to 3%), and fungi (5% to 10%) is higher in PVE than in NVE (47), and
they are usually isolated in early PVE.
Cases occurring 2 months or more after surgery are called late PVE and are largely community
acquired. As compared to early PVE, streptococci are more common and are responsible for
approximately 20% of late PVE cases (46).
Intravenous Drug Users

S. aureus accounts for more than 50% of IVDU cases probably because of its high frequency on the skin
in local infections at the injection site (cellulitis, abscesses, suppurative thrombophlebitis) and on drug
paraphernalia (48). In some regions, methicillin-resistant S. aureus (MRSA) have been responsible for IE
among IVDUs. Several other bacterial species such as Pseudomonas aeruginosa, enterococci, and
Serratia species or fungi are all more common in addicts than in the general population (49). In 40% to
70% of the cases, the tricuspid valve is affected (50). Right-sided IE among IVDUs has a mortality rate of
less than 10% (48).
Culture-Negative Infective Endocarditis
Patients with a clinical presentation suggestive of IE but with negative blood cultures account for 5% to
10% of the cases (8). The most common cause for culture-negative IE is prior administration of
antibiotics. In the absence of prior antibiotic administration and with appropriate blood culture media,
most bacteria will eventually grow but may require repeated blood culture and prolonged incubation
periods (51). Some microorganisms, such as Aspergillus species, C. burnetii, Legionella species
(usually Legionella pneumophila), or Tropheryma whippelii, cannot be recovered from the blood, so
diagnosis relies on other methods such as tissue culture, in situ hybridization, polymerase chain reaction
(52), or special serologic tests (53). By applying a standardized diagnostic algorithm, Fournier et al. (33)
were able to identify an etiologic agent among 476 out of 759 (63%) patients referred for blood culture–
negative IE. C. burnetii (229 cases) and Bartonella sp. (86 cases) were the most common etiologic
agents. A noninfectious origin of culture-negative IE (e.g., marantic endocarditis, systemic lupus
erythematosus) was diagnosed in 19 patients.
The signs and symptoms of IE are extremely variable because of the diversity of the etiologic agents and
the various organs involved. Clinical presentation may range from a chronic disease with unspecific
systemic symptoms to acute life-threatening sepsis. Fever with a heart murmur is the most common
clinical presentation; it may be the only clue to the diagnosis, especially early during the course of the
disease and with microorganisms of low virulence. In a prospective study of 109 episodes of IE, fever
was present in 98% of cases (54). A new murmur and skin lesions were found in 59% and 32%,
respectively. Splenomegaly and musculoskeletal manifestations were present in 16% (54). Congestive
heart failure complicates one third of episodes in recent studies (4,16,54). Distant complications such as
major emboli, lumbar pain, or rupture of a infectious aneurysm may be the first presenting manifestations
of IE. All the various clinical manifestations of IE arise from one or more of four main mechanisms:
bacteremia, embolization (55), immunologic manifestations (56), and local complications (57).
DIAGNOSIS
The diagnosis of IE requires the integration of clinical, microbiologic, and echocardiographic data.
Hematologic abnormalities are frequently observed: Anemia, leukocytosis, and thrombocytopenia are
present in 66%, 50%, and 18% of cases, respectively. Urinalysis shows abnormalities in 30% or more of
patients, mainly evidence of proteinuria or microscopic hematuria, one third of patients has elevated
creatinine (54). Circulating immune complexes may be detected, but they are nondiagnostic (56).
Repeated electrocardiography can reveal new atrioventricular block, particularly in the setting of aortic
valve endocarditis, suggesting perivalvular invasion (58).
The Duke criteria combine predisposing factors to IE, the blood culture isolate or histologic
examination, and echocardiographic findings (59). Based on the number of major and minor criteria, any
case of suspected IE is classified as “definite,” “possible,” or “rejected” IE. These criteria have been
primarily developed for research purpose, but they can help integrate diagnostic findings (Table 34.1)
Echocardiography has proven to be a valuable diagnostic tool in patients with suspected IE.
Transesophageal echocardiography (TEE) has substantially better ability to detect vegetations,
perivalvular extension, and myocardial abscesses than transthoracic echocardiography (TTE). TTE has a
sensitivity of 40% to 63% for detecting vegetations in NVE (60). TEE increases the sensitivity for
detecting vegetations in NVE to more than 90% (61). TEE is particularly useful in PVE, with which
vegetations are detected in more than 80% of the cases compared with less than 30% with TTE. A
negative TEE has a negative predictive value for IE of 86% to 97%.

Once the diagnosis of IE has been made, antibiotic treatment should be started promptly to eradicate the
infecting microorganisms as soon as possible. It is well established that a prolonged course of antibiotics
is needed for cure even if the microorganisms are highly sensitive to the drug used. The antibiotic agent
must be bactericidal and should be selected according to in vitro susceptibility test results and the
experience gathered from experimental and clinical studies (10,62). Surgery has an important role in the
management of IE, as an optimal therapeutic approach requires operative intervention during the course of
medical treatment in almost 50% of patients with IE (63). In the ICE-PCS, the rate of surgical intervention
(48%) was comparable among patients with NVE and PVE (16). Nearly all patients with fungal
endocarditis require combined surgical and medical treatment (64). Hemodynamic deterioration, local
complications, and uncontrolled infection are the major indications for surgery (10,65). Although the need
for surgery in patients presenting with hemodynamic deterioration and uncontrolled infection is widely
recognized (66), it remains controversial whether surgery is indicated for prevention of systemic
embolism. In a randomized study from Korea, patients at high risk for systemic embolism (i.e., with
severe valvular regurgitation and large vegetations) had significantly less systemic embolic events if
operated early during the course of disease (67). Figure 34.1 summarizes current indications for valve
surgery in patients with IE. Other interventions that should be considered in patients with IE are the
removal of intravascular devices (e.g., pacemakers, intracardiac cardioverter defibrillators, central
venous catheters) (68), and the drainage of extracardiac infections (e.g., septic arthritis).
Attempted prevention of IE is aimed at patients with known underlying predisposing factors who
undergo a procedure that may result in bacteremia. Possible portals of entry, such as oral and dental
lesions or urinary or gastrointestinal tract pathology, should be sought and treated if necessary.
Recommendations for use of prophylactic antibiotics have been updated, and indications for prophylaxis
have been considerably restricted to four high-risk conditions: prosthetic cardiac valve, history of
previous IE, some forms of congenital heart disease (CHD) (e.g., unrepaired CHD), and heart
transplantation recipients with valvulopathy (69).
CENTRAL NERVOUS SYSTEM COMPLICATIONS OF

INFECTIVE ENDOCARDITIS
Among the various manifestations of IE, neurologic complications are particularly important for three
main reasons: They occur often, they may be the first or the predominant manifestation of the disease, and
they are a leading cause of death and complications due to IE (70).
Incidence
The reported overall incidence of CNS complications of IE varies greatly. In most series, the incidence of
CNS involvement during the course of IE ranges between 20% and 40%, with an average of 30%. The
incidence has not changed much over time, despite wide differences in the diagnostic criteria employed in
various studies and many evolutionary changes that have occurred in the natural history of IE over the past
60 years. Among 743 patients pooled from seven series published before the advent of antibiotics, 176
(24%) were noted to have neurologic manifestations (1,71–76). Among 1,622 patients from eight studies
reported between 1947 and 1978, 457 (28%) had such complications (77–85). Among 1,329 episodes of
IE from seven series published between 1981 and 1993, 437 (33%) were accompanied by neurologic
manifestations (11,86–93). And among 2,162 episodes of IE from eight series published between 1996
and 2007, 512 (24%) were complicated by neurologic events (70,94–101). Recent studies may indicate a
lower rate of neurologic complications: The incidence of stroke in a French cohort of 390 patients and in
the ICE-PCS was 18% and 17%, respectively (4,16). However, data on other neurologic complications
were not reported. Finally, among 513 patients presenting with complicated native-valve IE, focal
neurologic findings, and altered mental status were described in 18% and 16%, respectively (9).
Incidence of asymptomatic CNS events is much higher. By systematically using resonance imaging of
the brain, Snygg-Martin et al. (102) identified cerebrovascular complications in 65% of patients; about
half of them were asymptomatic. In another study of systematic brain imaging in IE, radiologic evidence
of brain embolism was detected in 80% of patient, whereas 25% had clinical stroke (103).
Factors Influencing the Incidence of Central Nervous System Complications
The reported incidence is understandably higher in studies devoted primarily to the neurologic aspects of
IE and in studies based on autopsies, because brain damage often causes or contributes to death in IE
(11,78,79). In one autopsy series of 69 cases of IE, cerebral emboli were found in up to two thirds of the
young adults and in 46% of the total cases (104). Frequency of CNS complications also tends to be higher
in series gathered from referral centers (105) or specialized units. For example, among 198 patients with
IE hospitalized in 33 intensive care units (ICUs) in France, 108 (55%) presented with neurologic
complications (106). In contrast, the rate of CNS complications was only 22% in a series of IE observed
in a large community hospital (11). This referral bias would alter not only the number but also the type
and severity of the complications because referral is often precipitated by CNS involvement. On the other
hand, in a series gathered from six hospitals of different types (university, private, and Veterans), the
frequency of CNS complications was very similar (92).
Age and Sex

In many studies of adults with IE, the age of the patients did not appear to greatly influence the overall
frequency of CNS complications. In a recent series, however, major neurologic events were recorded in
22%, 28%, and 34% of patients younger than 40 years, 40 to 60 years, and older than 60 years,
respectively. In elderly patients, neurologic manifestations tend to be more common as a presenting
clinical sign of IE (107); as many as one fourth to one third of them may present with neurologic signs
(86), compared with 5% to 17% in the general population. If disorientation is included as a neurologic
finding, the figure can be as high as 45%. Neurologic complications in children reported in five series
ranged from 15% to 32% (108). Because major neurologic events are uncommon in children or young
adults, everyone should recall the dictum, “In hemiplegia in young adults or children, always think of
infective endocarditis.”
Generally, the sex distribution of the patients with or without neurologic complications appears to be
similar in both sexes (83).
Location of Vegetations in the Heart

Neurologic complications are a hallmark of left-sided valvular abnormalities. This association was noted
as early as 1852, before IE was recognized as a clinical entity (109). The incidence of neurologic
complications is markedly lower in isolated right-sided IE. In a series of 40 IVDUs with tricuspid IE due
to S. aureus, none presented with cerebral manifestations, whereas 2 of 5 of those with left-sided
involvement had cerebral septic emboli (110). Of 97 episodes of IE in drug addicts, none of the nine
major CNS events that were present on initial evaluation occurred in the 32 cases that involved the right
side of the heart (111), although the infection was caused by highly virulent organisms such as S. aureus.
CNS complications were observed in 54 (41%) of 133 patients with aortic and/or mitral valve
involvement and in only 4 (12%) of 33 of those with tricuspid IE (92). When neurologic manifestations
occur in right-sided IE, they present as meningitis, cerebral abscesses, or encephalopathy, rather than as
strokes, and are most often related to virulent pathogens such as S. aureus or S. pneumoniae (112).
Systemic embolization is rare in right-sided IE but does occasionally occur either from septic thrombi
arising in the pulmonary veins or via paradoxical embolization through a patent foramen ovale, which is
present in 18% of the normal population.
Mitral valve endocarditis is associated with a higher rate of neurologic complications
(83,106,113,114). For example, in a recent French study of 198 patients with IE, mitral valve involvement
was independently associated with neurologic complications (OR 1.54, CI 1.07 to 2.21) (106). A study
from Duke University including 707 patients with IE found a twofold risk of stroke among patients with
mitral valve endocarditis as compared to aortic valve endocarditis (114). This association was not
reported by older studies (115), probably because of small size (88).
Neurologic complications in the context of PVE are of special concern because of the threat of
superimposed intracerebral hemorrhage, which might be caused or promoted by anticoagulation. Most
published data are derived from PVE complicating mechanical prosthetic valves. The overall incidence
of focal neurologic events associated with PVE varies from 11% to 44% (46,116–122), which is
considerably higher than the overall thromboembolic rate of 1% to 4% per year observed for
anticoagulated patients with uninfected prosthetic valves (123).
Studies comparing the incidence of CNS complications between NVE and PVE have given conflicting
results. In one study, 11 (13%) of 82 patients with NVE, compared to 6 (33%) of 18 with PVE, presented
with such complications (117); however, another study reported 40 (35%) of 113 for patients with NVE
and 24 (39%) of 62 for those with PVE (88). Other series did not report any statistically significant
difference regarding the number of NVE and PVE CNS complications (46,98,124).
It is unclear whether the incidence of embolic events is affected by the time of onset of PVE in relation
to the placement of the prosthetic valve. In one study, CNS embolic episodes were reported in 0% to 11%
of patients with early onset PVE and in 23% to 28% of those with late-onset PVE (120). The higher rate
in late-onset PVE was confirmed in another study in which peripheral manifestations occurred in 10% of
early onset PVE cases, compared to 34% in late-onset PVE cases (125). However, in a recent
prospective study of 78 cases of PVE, the rate of CNS complications did not differ between early and late
PVE (126).
The incidence of CNS complications in PVE is influenced by anticoagulant therapy. In patients
insufficiently anticoagulated, CNS complication rates of 38% to 71% were noted, compared to only 8%
to 10% in patients on appropriate anticoagulant therapy (116,119). In one series of 61 patients, there was
no difference in the rate of embolism or risk of bleeding between patients receiving no anticoagulation or
subtherapeutic doses and those who were adequately anticoagulated (121). When anticoagulated patients
develop neurologic complications, they are at high risk for major hemorrhage (83,120,127).
The type of prosthetic valve may influence the rate of CNS manifestations. Of 33 patients with
bioprosthetic valve infection gathered from three studies, 4 (12%) had neurologic events (117,120,121), a
figure lower than that with mechanical valves. However, in another study of 62 patients with PVE, there
was no statistical difference when the type of prosthetic valve involved was compared among patients
with and without neurologic complications (88).
In summary, patients with PVE do not appear to be at a much higher risk for CNS complications than
patients with NVE, provided that anticoagulation is maintained and carefully controlled for complications
associated with mechanical valves. However, those presenting a CNS complication are particularly
threatened by the possibility of a massive cerebral hemorrhage (83,116,120).
Microbiology
An important factor in determining the rate, type, and severity of the neurologic complications is the
nature of the microorganism causing the IE. This may account for some of the differences in the incidence
noted between the various studies (Fig. 34.2). In series that have correlated the incidence of neurologic
complications with the infectious agent causing IE, the frequency of CNS involvement ranged from 53%
to 71% for S. aureus and was significantly higher than that observed with some other bacteria,
particularly group D and non–group D streptococci, which ranged from 25% to 47% (83,88,92,97,113).
Some species of bacteria other than S. aureus, such as Enterobacteriaceae or anaerobic bacteria, have
been associated with a high rate of neurologic complications (83,128). Moreover, certain microorganisms
are prone to a high rate of certain types of neurologic involvement. For example, although S. pneumoniae
has become rare in IE, causing only 1% to 3% of cases (129), in these few cases, associated
pneumococcal meningitis is common, being found in 40% to 60% (130,131). Purulent complications are
also frequently encountered with S. aureus IE, either as meningitis or as brain abscess. Certain bacteria
such as the Haemophilus species, members of the genus Abiotrophia (formerly nutritionally variant
streptococci), or fastidious organisms have been associated with large emboli; these emboli may occlude
major vessels including cerebral arteries. In patients with culture-negative IE, major embolic phenomena,
including those to the brain, were noted twice as often as in patients with culture-positive IE. Cases due
to Candida spp. are also associated with large vegetations and a high rate of embolic phenomena
(132,133). Of 27 patients with IE caused by Aspergillus species, a total of 14 neurologic manifestations
secondary to emboli were recorded in 11 (41%) patients (134). In contrast, the rate of CNS complications
in IE caused by some other bacteria, such as viridans streptococci or coagulase-negative staphylococci,
appears to be lower. Of 128 patients with IE due to the latter bacteria, only 15 (12%) developed stroke
(34).
Intravenous Drug Abuse

In IVDUs, as in all patients with IE, the frequency of cerebral manifestations is dependent on the side of
the heart involved. Therefore, the reported incidence of neurologic complications will depend on the
proportion of patients with exclusively right-sided involvement. Isolated right-sided involvement in IE
has been reported in 9% to 72% in series of endocarditis in addicts (50,135). In a study comparing the
clinical manifestations of S. aureus IE in addicts and nonaddicts, neurologic involvement was found in
51% of the nonaddicts, compared to only 9% of the addicts (110). Although neurologic complications
were not categorized according to the side of the heart involved, 76% of the addicts had only tricuspid
valve involvement, contrasted to 9% in the nonaddict population, indicating that the side involved plays
an important role in the occurrence of neurologic complications (110). The frequency of neurologic
complications in IVDUs with left-sided endocarditis appears to be higher than that in the nonaddict
population, ranging from 45% to 58% (136). The higher complication rate may partly be due to the failure
of some of the addicts to undergo a full course of antibiotics, or it may be due in part to a different pattern
of etiologic agents.
Pathogenesis of Central Nervous System Complications
Neurologic complications of IE can arise through several mechanisms, as follows: occlusion of cerebral
arteries by emboli, infected or not, derived from endocardial vegetations; infection of the meninges of the
brain or of the walls of cerebral arteries by septic emboli or bacteremia; and microbial toxic effects or
immune-mediated injuries. These events may result in various secondary lesions, including bland or
hemorrhagic infarcts; intracerebral, subarachnoid, or subdural hemorrhages; focal expanding lesions such
as abscesses or infectious aneurysms; and brain dysfunction due to one or multiple factors.
When embolization is the ultimate cause of the neurologic involvement, the lesions either may affect a
single vessel and give focal signs or may affect multiple vessels and produce multifocal signs. Depending
on whether ischemia is reversed before permanent changes occur, the clinical picture may be that of a
transient ischemic attack (TIA) (137) or of a longer lasting obstruction resulting in brain damage. Because
emboli of untreated or partially treated IE contain bacteria, the lesions produced may be ischemic,
inflammatory, suppurative, or mixed. This may result in septic or aseptic meningitis, brain abscesses,
microabscesses, or meningoencephalitis. If the wall of an artery or its vasa vasorum is involved, a
infectious aneurysm may develop. Arterial rupture can occur in the absence of a detectable intracranial
infectious aneurysm (ICIA) (88,138–140). Critical factors that may determine whether a septic embolus
results in a bland infarct, a hemorrhagic infarct, a infectious aneurysm, or an abscess include the site
where the embolus lodges, the virulence and number of the microorganisms, and importantly, the delay
between the event and the initiation of antibiotic therapy.
Multiple other factors can cause or contribute to the neurologic manifestations of IE such as hypoxia,
metabolic disturbances, drug toxicity, and toxic phenomena secondary to the systemic infection. Immune
injury to small arteries is also likely to be involved (141), and proliferative endarteritis in the absence of
local infection or embolization has been described.
In patients with tricuspid valve endocarditis, the sustained bacteremia rarely results in intracranial
hemorrhage (ICH), even when due to virulent organisms, supporting the hypothesis that embolic fragments
are a required factor in the pathogenesis of bleeding (138).
Clinical Presentation
Neurologic manifestations of IE constitute the presenting symptoms of IE in 16% to 23% of the cases
(83,97,113). When a neurologic event is the presenting symptom, approximately two thirds are due to
major cerebral emboli. The remaining third are divided among other manifestations including seizures,
meningismus, subarachnoid, intracerebral, or subdural hemorrhage, personality change, visual
disturbances, or weakness of the extremities (83,97).
Interestingly, the mean duration of prodromal symptoms prior to diagnosis was found to be similar in
patients with and in those without neurologic complications (88).
Neurologic complications occur after the initiation of antibiotic treatment in 30% of patients (88). In
most of these, the neurologic events tend to occur soon after treatment has begun, usually within the first 2
weeks (88). However, cerebral emboli or rupture of ICIA rarely occurs from several months to up to 2
years after the completion of successful treatment. More than one complication is often observed in a
given patient; thus, a total of 160 neurologic manifestations were recorded among 84 patients studied by
Pruitt et al. (83). The neurologic complications of IE are numerous (Tables 34.2 and 34.3) and can mimic
many neurologic diseases of other etiologies.
Stroke is the most common presentation and accounts for one half to two thirds of the neurologic
manifestations (83,88,97,106,138). Most of these cases are due to cerebral emboli with infarction, but
some are also due to intracerebral hemorrhage or even abscesses.
Meningitis, either septic or aseptic, is found in fewer than 10% of patients, with neurologic
complications reported in most general reviews, although a rate as high as 37% has been reported (89).
Meningeal symptoms or signs were encountered in 35 (42%) of 84 patients with neurologic complications
reported by Pruitt et al. (83).
Decreased level of consciousness can be seen in association with embolism or hemorrhage. This can
also occur without any specific identifiable cause, in which case nonspecific terms such as toxic
encephalopathy or acute brain syndrome are often used (142). In one study of 63 patients with CNS
complications of IE, 13% had a diffuse encephalopathy (i.e., alteration of the level of consciousness
without focal brain lesions or meningitis) (101). These cases may be caused by various and often
combined neurologic and nonneurologic mechanisms, such as microabscesses, microemboli, hypoxia,
metabolic disturbances, bacterial toxins, or drug toxicity. The patients may present with symptoms of
varying severity including impaired concentration, irritability, drowsiness, vertigo, or lethargy.
Seizures occur in 1.5% to 15% of the patients with neurologic manifestations (83,88). Among 141
children with IE, seizures were the most common neurologic manifestation, occurring in 10%. When
seizures occur, they are often part of the presenting complex of symptoms (83). Generalized seizures
occurred as the only neurologic symptom in 4 of 110 patients with CNS complications of IE (143). Three
of these four patients also had focal components to the seizure activity. Focal seizures are usually the
consequence of cerebral infarction. Generalized seizures can be the result of any of the organic lesions
complicating IE and may be associated with other predisposing factors, such as hypoxia, metabolic
disorders, or drug toxicity, especially when renal failure is present (83).
Mild, intermittent, diffuse headache is a common complaint in IE, occurring in 20% to 43% of the
patients (87,144). However, severe or localized headache is found in only about 3% of patients with IE
(92,144); this may be the initial symptom leading to the diagnosis of IE (145) or may indicate a disastrous
complication. Indeed, 3 of 14 patients with IE and severe headache in one series (143), as well as 4 of 7
patients in another study (144), had ICIAs. Conversely, six of eight patients with ICIA in the latter study
had severe localized headache, which should, therefore, prompt further investigation. This is also
suggested by another study, in which 8 of 58 patients with IE complained of headache; a neurologic
complication occurred in 7 of these 8 (87).
A wide variety of psychiatric abnormalities from minor personality changes to major psychiatric
syndromes have been described in association with IE. This might be more common in elderly patients in
whom confusion may be a presenting feature in up to 32% (96) or in patients with other underlying
diseases, such as drug abuse or alcoholism (107). These psychiatric abnormalities may be caused by the
same mechanisms that caused the toxic encephalopathy or they may only be reactive to the conditions
surrounding the diagnosis of IE. In these cases, the neurologic examination and the cerebrospinal fluid
(CSF) might be entirely normal, and fever and a cardiac murmur may be the only clue to the diagnosis of
IE.
Various dyskinesias have been described, the most common being tremor, parkinsonism, ataxia, and
myoclonus (146). Cases of chorea in the absence of evidence of rheumatic activity have been described
(146).
Visual disturbance is a common manifestation of IE and may be due to retinal emboli or involvement of
the peripheral or central pathways of cranial nerves II, III, IV, and VI. This may result in impairment in
eye movements and varying degrees of visual loss (146,147). Iridocyclitis and panophthalmitis have also
been described, especially in drug addicts. Other cranial nerve disorders can occur and pseudobulbar
palsy has been described.
Abnormalities seen on funduscopic examination have been reported in 10% to 25% of patients with IE
(86) and they have been observed in 35% of those with neurologic complications (143). These lesions
are nonspecific. Papilledema was observed in 9 of 39 patients examined in a series of 110 cases of IE
with CNS complications (143). It was probably related to various degrees of intracranial hypertension
due to space-occupying lesions (148). Retinal hemorrhages are found in 10% to 25% of IE cases. They
are thought to be the consequence of small emboli. Those with a white center are described as Roth spots,
which occur in 2% to 9% of IE cases (149). They are probably due to a hypersensitivity reaction and not
embolic. Microscopically, they consist of lymphocytes surrounded by edema and hemorrhage in the nerve
fiber layer of the retina (150). In candidemia with or without associated endocarditis, funduscopic
examination may reveal multiple white, cotton-like, circumscribed exudates with filamentous borders
located in the chorioretina and extending into the vitreous cavity. They may initially be confused with
Roth spots, but they may proceed to vitreous abscess and endophthalmitis (151).
Spinal cord involvement, mainly in relation with ischemic lesions but also secondary to extramedullary
compression by metastatic abscesses, can be observed and may result in girdle pain and paraplegia.
Peripheral nerve involvement as a result of embolic or immunologic lesions may account for cases of
localized pain or mononeuropathy (152,153).
Diagnostic Procedures
Imaging Studies
CT scan is of utmost importance for the diagnosis and management of CNS disorders associated with IE
(88,154). Of 51 CT scans performed in 64 patients with neurologic complications of IE, 25 (39%) were
abnormal. Focal lesions were discovered in 5 patients who presented with encephalopathy or headache
but no focal deficits (88).
Brain MRI findings in IE play a major role in the diagnosis of multiple ischemic or hemorrhagic
strokes, brain abscesses, and infectious aneurysms (Fig. 34.3)(155,156). MRI is very useful for the
diagnosis of encephalopathy due to multiple microinfarcts and microabscesses that cannot be visualized
by CT scan (155). MRI is more sensitive than the CT scan for most lesions including microhemorrhage.
Magnetic resonance angiography (MRA) offers a noninvasive diagnostic method for intracranial
aneurysms. Nevertheless, four-vessel cerebral angiography remains the method of reference (157).
Diffusion-weighted imaging (DWI) allows the detection of ischemic lesions within minutes of symptom
onset (158). DWI may be useful in differentiating cardioembolic stroke patterns originating from IE or
NBTE (159). Patients with NBTE embolic events have multiple, widely distributed, small and large
strokes, whereas patients with IE-associated embolic events exhibit a panoply of stroke patterns (159).
Asymptomatic lesions are frequently found among patients with IE, if MRI is systematically applied.
For example, radiologic evidence of cerebral emboli can be shown among 65% to 80% of patients with
IE, half of these lesions are asymptomatic (102,103). The clinical significance of asymptomatic emboli is
unclear (160), and routine screening of patients with IE is not recommended. Asymptomatic microbleeds
(i.e., cerebral microhemorrhages detected by T2 sequences) were identified among 57% of patients with
IE in a French study (161). Given the strong association with IE in the case-control study (OR 6.12, CI
2.09 to 17.94), the authors suggest that this might be a new diagnostic criterion of IE. In a study of 26
patients with IE who underwent T2-weighted MRI, cerebral microbleeds were found in 14 patients
(54%) and were strongly associated with subsequent ICH (162).
A French prospective study evaluated the impact of cerebral MRI on the management of IE. Among 130
patients, cerebral lesions were found in 82% and included ischemic lesions (52%), microbleeds (58%),
and asymptomatic aneurysm (8%) (163). The systematic use of imaging modified the diagnostic or
therapeutic management in 28% of patients. However, the authors did not study the impact of imaging on
clinical outcome.
Cerebrospinal Fluid Examination

Despite similar rates of neurologic complications, the percentage of patients undergoing a lumbar
puncture (LP) varied from 32% to 82% in four large series (83,88,92,145), with the most recent studies
reporting the lowest rates. This is probably related to the recent availability of CT scan, which obviates
the necessity for invasive procedures in many patients. Hence, there has been a decreasing number of LPs
performed to investigate focal deficits in more recent studies (97).
The largest and most detailed study on CSF parameters in patients with neurologic complications of IE
is from the Massachusetts General Hospital (83). CSF examination was performed in 69 (82%) of 84
patients. Neither the clinical setting nor any of the neurologic events were associated with a specific CSF
formula, except for finding a purulent CSF more often in patients with meningeal signs. However, there
was a good correlation between the CSF findings and the nature of the infecting microorganisms in that
virulent bacteria such as S. aureus, enteric gram-negative bacilli, and S. pneumoniae were frequently
associated with purulent CSF, whereas relatively avirulent bacteria such as viridans streptococci were
usually associated with a normal or aseptic CSF. Positive culture of the CSF was found in only 11 of
these 69 patients, and these were always associated with neutrophils in the CSF. There were eight cases
of S. aureus and one case each of S. pneumoniae, Proteus mirabilis, and viridans streptococcal
meningitis. The findings of this series are similar to those of other studies (88,92,143). Occasionally, a
CSF analysis with an aseptic pattern will yield a pathogen such as a viridans streptococcus (164).
Beside diagnosis of meningitis, LP has little role in the diagnostic workup of IE. The clinical features
and careful interpretation of the CT scan or MRI studies are better guides to patient management than the
CSF findings alone (165).
Outcome
The overall mortality of patients with IE has decreased over the past 30 years, probably due to improved
management (e.g., more widespread use of echocardiography, access to surgery, interdisciplinary care)
(166). However, the mortality of patients with IE and neurologic complications has not changed
appreciably, ranging from 34% to 74% (29,83,95,101), although some studies report rates as low as 20%
(88,97). A mortality rate of 58% has been reported in patients with neurologic complications IE referred
to the ICU (106). CNS complications were associated with higher mortality in several studies
(24,83,92,101,145). For example, stroke was independently associated with in-hospital mortality (OR
3.67, CI 1.94 to 6.94) among patients with S. aureus endocarditis in the ICE-PCS (24). However, in a
study of patients with IE admitted to the ICU, mortality was similar among patients with and without
neurologic complications (106), whereas Glasgow Coma Scale (GCS) score less than 10 was a strong
predictor of mortality. This suggests that severity of neurologic complications might be a more
appropriate predictor of mortality than the occurrence of CNS complications per se, as confirmed by a
study of 513 patients with complicated IE, where abnormal mental status at baseline was independently
associated with 6-month mortality (9). Surgical treatment of IE does not appear to increase the CNS-
related mortality of IE; among 55 patients with neurologic complications of IE, mortality did not differ
between surgically and medically treated patients (97). In patients with PVE, the overall mortality was
affected by the presence of neurologic complications in some studies (46,70) but not in others (167).
When only major cerebral events are considered, they are found to be the direct cause and often the
only cause of death in more than 50% of fatal cases, both in NVE and in PVE. In many cases, the cause of
death is multifactorial. Neurologic complications were found to be directly responsible for 8% to 20% of
the deaths in patients with NVE (29,83) and for 10% to 40% in those with PVE (117). In a recent series
of 55 cases, the mortality among patients with neurologic complications was not different between those
with NVE and PVE (23% and 25%), and there was no difference in mortality between the episodes
caused by various microorganisms (97).
The type of microorganism appears to play an important role in the outcome of patients with IE and
neurologic complications, with S. aureus, Enterobacteriaceae, and fungi being associated with a higher
mortality (83,88). Obviously, some neurologic complications such as major emboli, ICH, or purulent
meningitis are associated with higher mortality rates than the less severe manifestations. Sequelae have
been noted in up to 34% of patients with neurologic complications who survived (87).
Cerebral Emboli
Incidence
Emboli arising from the heart are responsible for 30% of strokes occurring in the general population
(168–170). Emboli secondary to IE account for fewer than 1% of these episodes (171). The rate of CNS
embolism due to IE is higher in autopsy series; for example, IE was found in 69 (1.5%) of 4,558
autopsies but was present in 32 (25%) of the 126 patients with cardiogenic cerebral emboli (104).
Occlusion of cerebral arteries by emboli is the most common neurologic complication of IE,
comprising approximately half of the CNS complications (Table 34.3). Among 2,781 patients of the ICE-
PCS, stroke complicated IE in 17% of cases (16). Lower incidence (9.6%) was reported in a recent study
that used more stringent diagnostic criteria for stroke and the Duke criteria for IE (114). Stroke was
present in up to 40% of patients with IE admitted to the ICU (106).
Approximately half the patients who present with major or minor cerebral embolism have clinically
identifiable emboli to other organs as well (83). In contrast, evidence of systemic emboli was found in
only 2% of unselected patients with stroke (172). In patients with IE and systemic emboli, cerebral
emboli were found in 40% to 69% (83,154). It has been observed that the incidence of cerebral emboli
associated with IE of the mitral valve was higher than when the aortic valve was involved despite a
similar rate of peripheral emboli elsewhere (83,114,173). Except for the rare occurrence of paradoxical
embolism, emboli are usually associated with lesions on the left side of the heart. In recent studies that
compared NVE with PVE, no significant difference in the incidence of cerebral emboli was noted
(46,88,97).
Pathogenesis
Most emboli related to IE are a result of dislodgment or disruption of cardiac vegetations into fragments,
followed by lodgment of these fragments into peripheral vessels of various diameters, depending on size.
Occasionally, emboli may be related to other concurrent disorders such as atrial arrhythmias. Vegetations
are the result of complex interactions between various host components including serum, fibrin, platelets,
fibroblasts, and inflammatory cells, as well as microbial factors including growth rate, adhesion, and
production of extracellular proteases. These interactions influence the growth of the vegetation and the
frequency of embolic episodes (174). Experimentally, the proteolytic capacity of the infecting organism
was shown to influence the size of the vegetations and the course of the disease. In rabbits with IE
induced by one of ten different strains of Enterococcus faecalis, proteolytic strains caused smaller
vegetations with a soft and friable appearance, as well as an increased frequency of renal emboli, when
compared to nonproteolytic strains (175). In humans, IE due to virulent microorganisms, particularly S.
aureus, is associated with an increased frequency of systemic and cerebral emboli as compared to less
virulent bacteria such as viridans streptococci. In a study of 52 patients with PVE, the calculated rate of
stroke during uncontrolled infection ranged from 1% per day for nonvirulent streptococci to 9% per day
for S. aureus (121). Pathologic examination provides some explanation for this difference: The
vegetations of IE due to virulent bacteria are friable with little histologic evidence of healing, whereas in
subacute disease, lesions progress more slowly with evidence of fibrotic reaction and early healing
(176). In addition, certain microorganisms have been noted to produce large and mobile vegetations and
are associated with an increased propensity to be complicated by major systemic and cerebral embolism.
This has been described in IE due to microorganisms such as Haemophilus species or other slow-
growing fastidious gram-negative rods, Abiotrophia, group B β-hemolytic streptococci, and fungi
(Candida and Aspergillus species) (177,178). Occlusion of vessels by fragments of vegetations results in
various degrees of ischemia and infarction depending on the vessels involved and the collateral blood
flow. In addition, emboli occurring before the initiation or completion of successful antibiotic treatment
may contain microorganisms capable of producing secondary infectious complications, such as abscesses
of various sizes, meningitis, arteritis, or infectious aneurysms. In about 20% of the cerebrovascular
episodes, hemorrhagic complications are observed (145). They may be due to the infarction itself or the
erosion of the artery by the bacteria present in the emboli, with or without formation of a detectable
infectious aneurysm (138). Concomitant anticoagulation appears to increase the risk of developing major
hemorrhages at the sites of infarction (83,92,127,138). However, in patients with PVE, withholding
anticoagulation has resulted in high rates of thromboembolism, and adequate anticoagulation has been
shown to reduce the incidence of major CNS events (116).
As previously mentioned, macroscopic and microscopic cerebral emboli have been observed with
greater frequency in patients with mitral valve infection as opposed to those with aortic valve
involvement in most studies (55,83,106,179). Pathologic examination of operative or autopsy material
shows that vegetations are not always found in patients who had an embolic episode; of 76 valves
examined, a valvular vegetation was found in only 57% of patients with neurologic complications.
Moreover, vegetations were found in 61% of the patients without CNS complications (88).
Cerebral embolism associated with IE may present with protean clinical manifestations. Important
determinants of the symptomatology are the number, location, and size of the emboli. Some patients may
present with embolic occlusion of a single major cerebral artery, with symptomatology related to the
territory involved. Other patients may have multiple microemboli with more diverse clinical
presentations. In many patients, these two forms of emboli coexist (83,101).
By combining CT and clinical criteria, Hart et al. (154) found that 62% of 37 ischemic events involved
the cortex or the cerebellar hemispheres, 16% were exclusively subcortical, 11% involved the retina, and
11% were in an uncertain location. Most infarcts were either small (58%) or moderately sized (33%). All
three large hemispheric infarcts occurred in patients with S. aureus endocarditis (154).
Major cerebral embolism was the presenting symptom or first overt manifestation of IE in 22 (10%) of
218 patients (83) and in 12 (14%) of 86 patients (113) in two large series. The majority of the cerebral
emboli occur before the initiation of antibiotic treatment or during the first 2 weeks of therapy
(55,83,97,154,173,179–181). Among 109 episodes of stroke observed in 496 patients with IE, 31 (28%)
occurred after the initiation of antibiotic treatment; the median time interval from onset of antibiotic
treatment to the development of neurologic complications was 4 days, with a range of 1 to 21 days (179).
In another study, 87% of ischemic events occurred either at the time of diagnosis (74%) or within 48
hours thereafter (13%) (154). Among the 25 initial ischemic events, 56% were simple and unifocal, 28%
were multifocal, and 16% were associated with toxic encephalopathy. Embolization after the completion
of successful antibiotic treatment is uncommon (55), but it has been described and can occur up to 2 years
later (83). Recurrences of emboli events are rare. In one study of 55 neurologic events among 218
patients with IE, only one recurrent episode of cerebral embolism was reported (97). In another series of
64 patients with neurologic complications of IE, two recurrent embolic events occurred before initiation
of antibiotic treatment (88).
More than 90% of large cerebral emboli affect the middle cerebral arteries and their branches, leading
mainly to contralateral hemiparesis and/or hemisensory deficits. This localization may also produce
parietal lobe signs including sensory loss, neglect, dyspraxia, hemianopia, and when the dominant
hemisphere is involved, aphasia. Occlusion of anterior or posterior cerebral arteries may also produce
similar symptoms, especially those involving the lower extremities. Posterior cerebral artery occlusion
may produce homonymous hemianopia. The vertebrobasilar system was affected in 6 of 10 and 4 of 84
patients with CNS complications of IE in two series (83,143). Emboli affecting the vascular supply of the
spinal cord or peripheral nerves may also occur (182).
TIAs are occasionally noted, sometimes as the presenting manifestation of IE. Such episodes were
recorded in 15 (27%) of 55 patients with strokes associated with IE (143). Among 25 episodes of
ischemic strokes reported in a study by Hart et al. (139), 3 were TIAs, all causing amaurosis fugax. In a
patient with a TIA, the presence of fever or any other nonspecific signs of infection should raise the
possibility of IE. Some of these patients may present with fluctuating neurologic signs, presumably from
emboli that disintegrate after initial lodgment; autopsy may reveal multiple small or microscopic infarcts
(137).
Multiple cerebral microemboli are common, causing about one third of all ischemic events (154). Of
45 patients autopsied because of a fatal neurologic complication, 38 had major embolism, but 23 were
found to also have microscopic cerebral infarcts, presumably due to embolic occlusion of small vessels.
Six also had microabscesses. These findings correlated with seizures or fluctuating neurologic signs in
four patients and were clinically silent in four others. In 14 patients, multiple microscopic infarcts
manifested as an altered level of consciousness not adequately explained by other abnormalities (83).
Thus, encephalopathy among patients with IE, may partly be explained by multiple microemboli, resulting
in multifocal microinfarcts, sometimes associated with cerebritis or microabscesses (145).
Microabscesses were found in 6 of 23 patients with multiple microinfarcts at autopsy (83), demonstrating
that a continuum exists between the ischemic cerebrovascular lesions and overtly infected CNS lesions
complicating IE (145).
In summary, emboli may cause a wide variety of CNS symptoms and signs, ranging from hemiplegia to
diffuse and fluctuating neurologic dysfunction, depending on their size, location, and number. Most emboli
affect the middle cerebral artery and occur before or soon after the initiation of therapy.
Diagnostic Procedures
Cerebral CT scan and MRI are the most useful diagnostic procedures when emboli are suspected. They
are helpful both in the differential diagnosis and in the distinction between nonhemorrhagic and
hemorrhagic infarcts (Fig. 34.4). When acute hemorrhage is suspected, CT scan is preferred. MRI and
MRA also provide a baseline in monitoring for the development of ICIA, which may arise at the site of a
previous embolus. Follow-up imaging studies are also indicated when the secondary formation of an
abscess is suspected.
The effects of the performance of cerebral angiography on survival were investigated and the authors
concluded that it should not be routinely performed (183). A study comparing CT scan and angiography
suggests that ICIA is unlikely to be present when the CT scan is normal (184). Because MRA is
noninvasive, repeated studies with this technique would be more feasible than traditional angiography.
The relatively new CT technique called CT angiography (CTA) allows the assessment of cerebral
aneurysms of the circle of Willis with accuracy comparable to MRA (185). To our knowledge, there are
no CTA studies focusing on ICIA. However, according to the available data, CTA could be a valuable
diagnostic option and can be easily obtained at the same time as conventional CT.
As discussed earlier, LP is seldom helpful when IE is already suspected. A CSF leukocytosis may be
the first hint suggesting the possibility of IE in certain patients with stroke, particularly if predisposing
factors for endocarditis are present. However, this benefit is not sufficient to justify routine CSF
examination in unselected patients with stroke because the yield might not be greater than 0.25% (186).
Moreover, normal CSF values do not exclude CNS emboli originating from IE.
To exclude hemorrhagic transformation of a cerebral infarct, high-quality CT is a better procedure than
CSF examination. Some patients with such a complication on CT may have normal CSF or CSF
containing only a few red blood cells (RBCs). Furthermore, a few RBCs are often present in the CSF in
nonhemorrhagic infarcts due to traumatic taps.
Echocardiography has a pivotal role for the diagnosis of IE in patients presenting with stroke. Its value
in assessing the degree of valvular change and the status of left ventricular function is well established
(60). The role of this technique in predicting the risk of embolization is more controversial. Some reports
suggest that in patients with IE, vegetations detected by precordial echocardiography are associated with
a higher risk of embolization (187,188). However, no significant difference in the overall incidence of
embolism was found in a study of 77 patients, in which chart compilation and echocardiography readings
were performed by separate investigators who had no knowledge of each other’s findings (189).
Therefore, in some patients presenting with neurologic complications, it is possible that vegetations were
not seen because embolization had already occurred before echocardiography, a well-documented
possibility. Steckelberg et al. (55) found that detection of vegetations on two-dimensional
echocardiography was not associated with a significantly higher risk for embolus, with the exception of
patients with viridans streptococcal infection.
The vegetation size is a better predictor of systemic embolism (173,179,190–192). Thuny et al. (192)
performed multivariate analysis of a study including 384 patients with IE and identified vegetation size
larger than 10 mm, as well as vegetation mobility and infection by S. aureus and S. bovis as independent
predictors of new embolic events after initiation of antibiotic therapy. In a study that employed both TTE
and TEE, patients with large vegetations (>10 mm) had a significantly higher incidence of embolic events
(47%) than those with small or no vegetations (19%) (193). Because an embolic event may reduce the
size of vegetations, the analysis was repeated after exclusion of patients who had echocardiography after
an embolic episode; the rate of new embolism was 36% in patients with large vegetations compared to
6% in those with small vegetations, a difference that was also significant. Patients with large vegetations
of the mitral valve were at a significantly higher risk of embolism (193). Anterior as compared to
posterior mitral leaflet vegetation was associated with an increased risk of embolization (194).
In conclusion, most studies suggest that vegetations seen on echocardiography, especially those larger
than 10 mm, are associated with a higher risk of embolism. However, many patients with vegetations even
of large size do not manifest clinically detectable emboli, and vegetations may persist on
echocardiography after successful medical therapy.
Specific Management
Medical Treatment
For management of patients with IE and cerebral emboli, several aspects should be considered, namely,
the primary prevention of embolization, the prevention of subsequent episodes, the optimal therapeutic
strategy for already established lesions, and the detection of secondary complications (Fig. 34.5).
Efforts should be directed at adequate control of arterial blood pressure and provision of supportive
care. Patients should be carefully followed clinically for the occurrence of secondary hemorrhages and
repeated CT should be performed promptly if the patient’s condition deteriorates.
Prompt initiation of antibiotic treatment has a tremendous impact on the incidence of stroke in IE. In an
analysis of the ICE-PCS including 1,437 patients, rate of stroke decreased from 4.82/1,000 patients-days
during the first week of antibiotic treatment to 1.71/1,000 patients-days during the second week (195).
There is no specific antithrombotic therapy for embolic strokes in the patient with IE. This differs from
noninfectious embolic cerebral infarction, which can be treated by thrombolysis in selected cases
(196,197). Thrombolysis has been attempted anecdotally (198), sometimes because IE was not suspected
at stroke diagnosis (199), but it is unlikely to be of equal value in the patient with IE given the different
pathogenesis of vessel occlusion and the relatively high risk of ICH complication of this procedure in an
infectious setting (200).
The proper use of anticoagulants has given rise to much controversy. Soon after the advent of
sulfonamides in the 1930s and antibiotics in the 1940s, simultaneous treatment with heparin was tried
with the idea that prevention of further deposition of platelet-fibrin thrombi on infected valves might favor
antibiotic penetration and possibly prevent further emboli (201). It soon became apparent that antibiotics
alone were able to cure IE and that there was no evidence that anticoagulants were a useful adjunct to
antibiotic therapy (201). Moreover, cerebral hemorrhages were observed with a distressing frequency in
anticoagulated patients and major emboli were not prevented (201). The antibiotic therapy of that time
may have been inferior to currently recommended regimens. In the series of Pruitt et al. (83), seven
patients with cerebral emboli were subjected to anticoagulation before or within 24 hours of
embolization. Three of them (43%) developed major ICHs at the sites of infarction. In contrast, ICH was
observed in only 10 (4.7%) of 211 patients not treated with anticoagulants (83). In another older study, 30
patients (29 with prosthetic valves) who were initially anticoagulated were analyzed. Among the 20
whose anticoagulation was continued, 7 developed a stroke, 6 being bland infarcts, and 1 a hematoma;
anticoagulation was continued in 4 of them without further complications. In contrast, only one stroke was
observed in the ten patients in whom anticoagulation was stopped (88). This deleterious effect of
anticoagulants is also supported by experimental evidence. In an animal model of septic CNS embolism,
anticoagulation was associated with an increased risk of hemorrhage (202). In experimental endocarditis,
animals simultaneously treated with antibiotics and anticoagulants had a worse outcome than those who
received antibiotics only (203). Therefore, routine use of anticoagulants is generally not recommended in
the course of NVE because clinical and experimental data indicate that the rate of hemorrhagic CNS
complications is high and because there is no proven benefit with regard to the course of the disease (10).
However, in a Swedish study of 587 NVE episodes, cerebrovascular complications were significantly
less frequent among patients on warfarin (6% vs. 26%), and the risk of hemorrhage was not increased
among these patients (204). Among 332 patients with endocarditis in the series of Delahaye et al. (124),
cerebrovascular accidents were significantly more common among anticoagulated patients (19/94 vs.
19/238), but the mortality rate in patients who had a cerebrovascular event was similar (124). This
indicates that, although NVE is not an indication to start anticoagulation, antithrombotic treatment should
not be withheld when there is an established previous indication (e.g., mitral valve disease and atrial
fibrillation) and that anticoagulation with heparin should be maintained whenever a brain infarct is
present unless it is large and/or hemorrhagic (124,205).
The issue of anticoagulant therapy in patients with PVE should be considered separately. With the
exception of those patients with bioprostheses and in normal sinus rhythm, patients with prosthetic valves
are at constant risk of thromboembolism, an important reason not to interrupt anticoagulant therapy.
Patients who develop PVE are at high risk of presenting both thromboembolic and hemorrhagic
complications and the indication for the maintenance or interruption of the anticoagulation therapy should
be carefully balanced. In patients with PVE who were not anticoagulated, the incidence of CNS
thromboembolic phenomena has ranged from approximately 50% to 71% (116). An incidence of CNS
hemorrhage as high as 36% has been reported in a series of patients with PVE treated with anticoagulants
(117). In the study of Wilson et al. (116) comparing patients with PVE receiving or not receiving
anticoagulants, major CNS complications occurred in 3 (8%) of 38 patients who received adequate
anticoagulant therapy as compared to 10 (71%) of 14 of those who received either inadequate or no
anticoagulation. Mortality was 47% among the patients with adequate anticoagulation, not significantly
different from 57% among those without. Among the patients treated adequately with anticoagulants, three
deaths occurred; all were due to the CNS injury, but only one was attributed directly to the anticoagulant
therapy. Among the patients without adequate anticoagulation, eight deaths were recorded, and CNS
complications were thought to be the primary cause of death in five of them. Three of these patients were
found to have massive intracerebral bleeding caused by thromboembolism (116). A recent Spanish study
highlights the higher hemorrhagic risk associated with anticoagulation among patients with PVE due to S.
aureus (127). In that study, six episodes of cerebral hemorrhage occurred in 21 patients with S. aureus
PVE (90% of whom where anticoagulated), as compared to only one episode in 35 patients with S.
aureus NVE.
Based on these varying data, most authors suggest that closely monitored anticoagulant therapy should
be cautiously continued in patients with IE involving mechanical prosthetic valves (19,116,120).
Although coumarin drugs are generally used, favorable experience with heparin has been reported (119).
If the patient develops a CNS complication, the use of anticoagulants should be temporarily discontinued;
in addition, the patient should be evaluated for evidence of ICH. If there is no evidence of hemorrhage or
hemorrhagic infarct, carefully controlled anticoagulation with heparin may be reinstituted (10,116).
Because of the critical role played by the platelet-fibrin thrombus in the formation of the vegetations
(206), antiplatelet agents may have a role in preventing subsequent embolization, as suggested by
experimental models (207). In a randomized trial of aspirin at a dose of 325 mg/day, which included 115
patients with IE, patients treated with aspirin had similar rate of embolic events as compared to patients
on placebo (208). By contrast, in a retrospective cohort study of 600 patients with IE, incidence of
systemic embolism was significantly reduced among patients treated with antiplatelet therapy before
diagnosis of IE (OR 0.36, CI 0.19 to 0.68), suggesting that chronic antiplatelet therapy during the early
phase of IE may have an impact on the risk of embolism (209). However, another recent study was not
able to confirm the positive effect of previous antiplatelet therapy on cerebrovascular events in patients
with IE (210). Taken together, these data do not support the routine use of antiplatelet agents in IE.
Cardiac Surgery
The role of cardiac surgery in the prevention of embolism in IE is ill defined, although current
recommendations mention systemic embolism, if vegetations have been visualized by echocardiography,
as an indication for valve replacement (10,62,65).
Thus, many patients with large vegetations may actually be operated on for a combination of
indications. The natural course of patients with large vegetations is difficult to assess because patients
may undergo surgery before a potential embolic event. Further prospective data are required before
management decisions can be based solely on the presence of echocardiographically detectable
vegetations or on their dimensions. Given the operative risk and the postoperative complications of
prosthetic valves, it seems reasonable not to operate on a patient solely because of the presence of a large
vegetation seen on echocardiogram. This point of view might change with the advent of homografts and
conservative surgery for valve repair, which carries less long-term risk than prosthetic valves.
The need for valve replacement in patients who have sustained a single embolic event and/or who have
large vegetation demonstrated by echocardiography remains controversial. Embolic stroke is uncommon
after the first 2 weeks of antibiotic therapy (97,101,179,195,199) and recurrent emboli are uncommon in
patients who survive a first embolic episode and who are receiving appropriate antibiotics (83,88,179).
When late embolic events after a cure of an episode of NVE are reported, they seem to be best explained
by factors other than the past episode of IE (83). Thus, if surgery is considered solely for prevention of
systemic embolism, it should be performed during the first days of antibiotic therapy. The impact on early
surgery on the incidence of systemic emboli was highlighted by a recent randomized study from Korea
(67). Seventy-six patients with NVE, severe mitral or aortic valve disease, and a vegetation larger than
10 mm were randomized to early surgery within 48 hours after randomization or surgery according to
current guidelines. No embolic event occurred among patients assigned to early surgery, as compared to
eight patients (21%) assigned to conventional treatment (67). However, among operated patients, rate of
valve replacement with a mechanical valve was higher in the early-surgery group. Thus, early surgery
seems to prevent systemic embolism (including stroke), but at the price of long-term anticoagulation
(211).
Patients undergoing open heart surgery after a recent CNS complication pose a difficult management
problem. There is always a risk that cardiopulmonary bypass and heparinization may exacerbate the
recent neurologic injury by promoting hemorrhagic transformation (91,212). On the other hand, delay in
surgery can have serious hemodynamic and CNS consequences, depending on the circumstances:
Worsening neurologic symptoms can result from hypotension, hypoxemia, low cardiac output, and renal
failure. Moreover, further embolization may occur, especially with microorganisms such as S. aureus,
gram-negative bacilli, or fungi. Recent data indicate that the risk of surgery among patients with stroke is
lower than previously estimated (Table 34.4). In one study, 65 patients with IE who underwent open heart
surgery a few days following embolic stroke or TIA were analyzed (199). No significant difference in
perioperative and long-term mortality was found between patients with and without preoperative stroke.
However, patients with stroke associated with other neurologic complications (i.e., meningitis, abscess,
or hemorrhage) had higher perioperative mortality as compared to patients with noncomplicated stroke
(39% vs. 8%). Seventy percent of survivors had a full neurologic recovery (199). In another study of 109
patients with IE complicated by cerebrovascular events, valvular surgery was performed in 58% of cases
early after the event (179). Postoperative neurologic deterioration was observed in only four patients
(6%). Moreover, operated patients had a higher survival than patients treated conservatively (179). A
large series of 198 patients undergoing cardiac surgery for IE after stroke was published by the ICE-PCS
group (213). This study confirmed that early surgery (i.e., <7 days) was not associated with higher in-
hospital mortality.
Thus, when there is an established indication for valvular surgery, the presence of an ischemic stroke
does not appear to justify postponement of the procedure. However, because anticoagulation may
precipitate hemorrhagic transformation of cerebral infarcts if administered during the first few hours after
the episode (214), it would appear reasonable to postpone the operation for a few days if feasible. In a
study of 33 patients with CNS complications of IE undergoing surgery, 2 developed fatal neurologic
deterioration when surgery was performed within 5 days after the cerebral embolic event (91).
Outcome
Stroke increases the mortality of IE. For example, in the study by Thuny et al. (179), stroke was an
independent predictor of death with a hazard ratio of 1.6. In another study of 68 patients with IE
complicated by stroke, in-hospital mortality and 1-year mortality were 35% and 52%, respectively (114).
Stroke was also associated with higher in-hospital mortality among patients with PVE (46) and S. aureus
IE (24) in the ICE-PCS.
Mortality is particularly high in the case of hemorrhagic transformation, because it may occur in
patients who are anticoagulated at the time of the embolic episode (83,88,116). In one study, middle
cerebral artery stroke (both partial and complete) was associated with poorer neurologic recovery (199).
In conclusion, cerebral emboli are one of the major complications of IE. Emboli may cause further
intracranial complications such as meningitis, abscesses, hemorrhages, and infectious aneurysms. To
detect these secondary complications, CT scan and possibly angiography should be performed at
appropriate intervals after an embolic episode. For these complications to be detected, investigations are
best carried out 7 to 10 days after the embolic event. Although large vegetations seen on
echocardiography seem to be associated with an increased risk of emboli, the precise role of valvular
surgery for this indication is not yet determined, although recent data may indicate a benefit of early
surgery for the prevention of systemic embolism. In patients with PVE, anticoagulation should not be
stopped but may be interrupted briefly and, in any case, must be carefully monitored.
Intracranial Hemorrhage
Epidemiology
ICH occurs in 2% to 14% of cases of IE (Table 34.3) and represents 7% to 25% of neurologic
complications. In selected populations of patients with IE, such as those hospitalized in an ICU, the
incidence is higher. For example, it was 27% in the study by Sonneville et al. (106). The hemorrhage
usually diffuses into the cerebral substance or into the subarachnoid space. Rarely, the subdural space
may also be involved.
ICH complicating IE may be the result of different mechanisms. ICH have often been attributed to
ruptured ICIA even when no aneurysms were demonstrable (83). In addition to ruptured ICIA, it has
recently been recognized that ICH in IE can also result from the septic erosion of the arterial wall without
a well-delineated aneurysm (138). Moreover, hemorrhagic transformation of ischemic brain infarcts can
also result in ICH, particularly in anticoagulated patients (83,127,214). One study reported a 29% rate of
ICH among patients with IE due to S. aureus and anticoagulated because of a prosthetic valve (83).
The proportion of ICH attributable to each of these mechanisms varies among studies. Of the 17
patients with ICH studied by Hart et al. (138), 4 presented a hemorrhagic infarct and 13 had a primary
hemorrhage that could be attributed to a ruptured ICIA in only 2 patients and to a necrotic arteritis in 4
cases. In five other patients, an ICIA was excluded by arteriography or autopsy, and the exact cause of
ICH could not be determined. In four other studies, the proportion of ICH due to ICIA ranged from 11% to
50% (83,97,106,113). Thus, less than one half of ICHs in IE are attributable to ruptured ICIA. Septic
necrosis of the arterial wall and hemorrhagic transformation of cerebral infarcts each accounts for the
other cases (83,138). Whatever mechanism is involved in the pathogenesis of ICH, the prognosis is poor
with a mortality of 35% to 87% (113,138).
Intracranial Hemorrhage Due to Cerebral Emboli

Aseptic cardioembolic strokes may undergo spontaneous hemorrhagic transformation even in the absence
of anticoagulation; pathologic examination reveals that this occurs to some degree in the majority of the
episodes. This results from multifocal extravasations of confluent petechiae and is usually not associated
with recognized clinical worsening. About 5% of the patients with embolic stroke who are not receiving
anticoagulants have hemorrhagic infarcts visible on initial early CT scan with an additional 10% to 20%
developing late, usually asymptomatic, hemorrhagic transformation (214). Hemorrhagic transformation of
ischemic infarcts caused by septic emboli appears to be the most common mechanism leading to lethal
intracerebral hemorrhage in patients with IE (139). The likelihood of developing spontaneous
hemorrhagic transformation appears to be directly related to infarct size (215). Although exact figures are
not available, hemorrhagic transformation occurred in 17% of cerebral infarcts associated with NVE in
one study (114) and in 8% to 36% of those with PVE (120).
Intracranial Hemorrhage Due to Acute Necrotizing Arteritis or Intracranial Infectious Aneurysm

The spectrum of arterial injury leading to ICH can range from acute, pyogenic necrosis to large, aseptic
aneurysms that may rupture weeks to months after bacteriologic cure. The extremes of this continuum
appear to represent different clinical syndromes, although the term infectious (mycotic) aneurysm has
usually been applied to both processes (138). For the purpose of clarity, true ICIAs are considered
separately in this chapter (see later discussion).
Septic emboli appear to be necessary for the occurrence of septic arteritis and ICH, although clinically
recognized embolism precedes ICH in only a fraction of the patients. Sustained bacteremia in tricuspid
valve IE, even with virulent bacteria, does not result in ICH, indicating an important role for embolic
fragments in pathogenesis (138).
Most ICHs due to acute erosive arteritis tend to occur early in the course of the disease and are often
already present on admission. They are more likely to occur in S. aureus IE (113,138), although this
microorganism can also be associated with the development of true ICIA at a later stage (83,139). Most
of these patients have an acute form of IE of only a few days’ duration and present with severe and
rapidly evolving neurologic signs that are related to the site of the intracerebral or subarachnoid
hemorrhage (138). ICH may be the presenting manifestation of IE (138). Some patients have a preceding
episode of clinical embolus or TIA (137,138). For example, 4 of 12 patients with IE and TIA
subsequently sustained a fatal ICH (137). The precise sequence of events leading to ICH was
demonstrated in a patient who died from a massive subarachnoid hemorrhage secondary to an erosive
arteritis that developed at the site of a septic embolus visualized both at autopsy and on an arteriogram
performed a few days before death (216).
Imaging by CT scan, CTA, MRI, and MRA (>24 hours after the acute event) plays a central role in the
evaluation and management of these patients (Figs. 34.6 and 34.7). Conventional arteriography is still the
technique of choice in cases of hemorrhage, because it allows the precise location of the arterial rupture
and the visualization of associated ICIA and of the anatomy of the intracranial vessels. This may be
particularly helpful in patients for whom surgery is considered. Surgical treatment is difficult, requiring
sacrifice of the involved artery, sometimes with microvascular pedicle/bypass surgery, because there is
not a well-delineated aneurysmal neck that can be readily clipped (138).
Intracranial Infectious Aneurysm
The term infectious (mycotic) aneurysm refers to localized dilation of an arterial wall due to an infective
arteritis. This can be caused by almost any microorganism, so the term does not indicate fungal infection.
To obviate the confusion with aneurysms of true fungal etiology, some authors have recently suggested that
all types of aneurysms due to an infectious agent be grouped under the title of “infectious aneurysms”
(217).
Incidence
ICIAs are uncommon. Although they represented 12% to 32% of all intracranial aneurysms before the
advent of antibiotics, they appear to constitute only 2.6% to 6.4% in more recent series. More than 80%
of all ICIAs occur as a complication of IE (218). In a review of 85 cases of documented ICIA reported
from 1954 to 1977, 72 (85%) were due to IE (218). In patients with IE, the incidence of recognized ICIA
ranges from 2% to 5% (83,88,106). As it has been documented that some patients with IE develop
intracranial aneurysms that remain asymptomatic and undergo healing under appropriate antibiotic therapy
(157,219,220), the true incidence of infectious aneurysm certainly exceeds the number of cases
diagnosed. This is also suggested by a study in which systematic CT scan and four-vessel angiography
were performed in patients with endocarditis and neurologic manifestations: 11 (31%) of 35 were found
to have ICIA (184).
Multiple aneurysms have been documented in about 25% of the patients with ICIA (157), but the true
figure is unknown because only a few of the reported patients have had full angiography analysis to show
all the intracranial vessels (220). In the study just mentioned, 5 of 11 patients had multiple ICIAs (184). In
another series, 17 patients had a total of 28 ICIAs (219). Multiple ICIAs may not occur simultaneously
(218). Although it is conceivable that ICIAs and infectious aneurysms located elsewhere may develop in
the same patient, it was not found in the one study that specifically investigated this possibility (83).
ICIAs can occur at any age. Most reported cases of ICIA linked to IE were observed in patients with
native valve infection, but ICIAs also occur in those with PVE.
Pathogenesis
ICIAs may develop by different mechanisms. When they occur in the context of IE, they result from septic
embolization to the vasa vasorum or to the intraluminal space of the vessel itself. Early observations of
infectious aneurysms indicated that the inflammation affected the adventitia first and then spread inward.
In experimental studies, ICIAs could be produced in dogs by the injection in the carotid arteries of
silicone rubber emboli coated with bacteria (221). Pathology showed aneurysmal dilation of the portion
of the vessel immediately adjacent to the emboli; microscopically, the vasa vasorum were packed with
inflammatory cells and the inflammatory response started first on the adventitial surface, penetrated the
muscularis layer, and in ruptured aneurysms, destroyed the internal elastic membrane and the intima
(221). However, peripheral arteries, which are frequently involved in ICIAs, are devoid of vasa
vasorum, in which case it seems that bacteria may reach the adventitia via direct penetration through the
wall. Moreover, ICIAs sometimes develop at the site of a previously documented embolic occlusion.
Thus, both microembolization of vasa vasorum and direct penetration through the wall of the arteries
appear to be possible routes of infection resulting in the formation of infectious aneurysms. The arterial
wall may rupture at various stages of dilation, depending on the severity of the necrosis, which in turn is
presumably related to the virulence of the infectious agent. Restoration of the blood flow through the
damaged segment by recanalization of the initial septic embolus may contribute to subsequent rupture by
increasing the intravascular pressure. Interestingly, treatment with an antibiotic to which the bacteria were
sensitive did not prevent the development of an aneurysm but did prevent early rupture in experimental
dogs (221). This parallels observations in humans who develop ICIAs while on appropriate antibiotic
therapy (220).
Infected emboli, not just circulating bacteria, appear to be necessary for the formation of ICIAs, as
suggested by the rarity of this complication in association with bacteremias caused by right-sided IE.
Besides septic emboli, other pathogenic mechanisms may sometimes play a role in the occurrence of
ICIA. ICIAs may result from a thrombophlebitis of the cavernous sinus (218). Rarely, ICIAs may be of
extravascular origin and may be secondary to penetrating head trauma, otitis media, or tuberculous,
syphilitic, fungal, or purulent meningitis (218,222). Superinfection of congenital aneurysm during the
course of IE or during transient bacteremia has also been reported. This usually involves the vessels of
the circle of Willis in elderly individuals.
The microbiologic spectrum of ICIAs of intravascular origin reflects that of IE. Viridans streptococci
as well as S. aureus account for the vast majority of cases responsible for 89% of those with positive
blood cultures during the period 1954 to 1977, reviewed by Bohmfalk et al. (218). The rest of the cases
are due to various microorganisms such as Corynebacterium species, P. aeruginosa, bacteria of the
HACEK group, or other bacteria. A similar distribution was found in a series of 17 patients (219).
Among ten narcotic addicts with P. aeruginosa endocarditis, two had cerebral infectious aneurysms. In
some patients, no organisms can be recovered from the blood, as a result of antibiotic treatment. In earlier
days, pneumococci were also found and syphilitic aneurysms accounted for 5% of all intracranial
aneurysms before the advent of antibiotics. S. aureus appears to be the most common offender in ICIAs
associated with thrombophlebitis of the cavernous sinus. ICIAs have been associated with bacterial
meningitis due to S. pneumoniae, N. meningitidis, M. tuberculosis, and other less common causes of
meningitis (223,224). True fungal ICIAs have been described as the result of either a concomitant IE or
direct or hematogenous spread from sinusitis. Most of them were caused by Aspergillus species. Cases
associated with Candida species have also been described (222).
Pathology
Infectious aneurysm complicating IE may occur in any artery and at any location. The proportion of
infectious aneurysms that are located in the CNS ranges from 15% to 54%. After the aorta, the brain is a
leading location (144).
ICIAs are usually small and may be saccular or fusiform. Most are peripheral to the first bifurcation of
a major cerebral artery; they involve the middle cerebral artery and its branches in more than 75% of the
patients (219). This contrasts with congenital aneurysms, which are usually located near the circle of
Willis. Vessel branching points are often affected, probably because these sites favor the impaction of
emboli (144). This has been clearly documented in some cases by serial angiography showing the
formation of an ICIA at the site of a previous embolus.
Histologically, infectious aneurysms are characterized by destruction of the normal architecture of the
arterial wall, focal areas of necrosis, and infiltration by inflammatory cells. Strictly speaking, infectious
aneurysms are pseudoaneurysms, because they result from destruction of the muscular layer. In acute
lesions, polymorphonuclear cells are predominant and microabscesses are not uncommon. Organisms may
be seen or cultured from the lesions but in many cases cannot be found, having been already eliminated
from the focus of active inflammation by host defenses or by antibiotics. In more chronic lesions, or when
rupture has not occurred, polymorphonuclear cells are mixed with lymphocytes and plasma cells in
fibroblastic granulation tissue. The fibrotic reaction may contribute to the resistance of the wall and
prevent rupture. Adhesions may form between the arachnoid and the brain in the region of the ICIA. With
rupture of the aneurysm, these adhesions may prevent free escape of the blood into the subarachnoid
space. Bleeding, therefore, tends to occur into the brain substance or into the subdural space.
Most ICIAs occur in patients with IE. In many reported cases, ICIA is described as presenting with a
sudden, often fatal subarachnoid or intracerebral hemorrhage without recognized warning signs (218).
Among 58 patients with ICIA reviewed by Bohmfalk et al. (218), 33 already presented with major
neurologic manifestations on admission, which were due to a subarachnoid hemorrhage in 19 cases.
Some authors have called attention to the fact that neurologic warning signs are often present before
rupture occurs. For example, the presence of severe, localized headache in a patient with IE should raise
the suspicion of an ICIA. Among 213 patients with IE seen at the Mayo Clinic from 1975 to 1979, 7
complained of severe localized headache and 4 had a proven ICIA; the other 3 also had an ICH, but ICIA
could not be demonstrated (144). Focal neurologic events, such as seizures, ischemic deficits, or cranial
nerve abnormalities, may often precede the development and the rupture of ICIA and should be regarded
as serious warning signs, prompting further investigation (218,225). In a retrospective study of 25 patients
with ICIAs, 40% of whom were associated with IE, headache was the most common symptom at
admission, (86%) followed by fever (67%), vomiting (50%), ocular palsy (25%), and seizures (21%)
(226). In 16 patients with ruptured ICIA reported by Pruitt et al. (83), 8 had a history suggesting
embolization prior to the hemorrhage. At angiography, an occluded vessel was often found in association
with the aneurysm. Among 81 cases of ICIA reviewed by Ojemann and Crowell (217), 65 were reported
in enough detail to determine the initial neurologic event that led to angiography. This was a definite or
probable hemorrhage in 42, an infarction in 16, an infarction followed by a hemorrhage in 5, and
headache without hemorrhage in 2. The occurrence of a TIA may also precede subsequent rupture of an
ICIA (137,225).
Although premonitory signs or symptoms may precede a catastrophic hemorrhage only by a few hours,
the delay is generally of several days. Some aneurysms may leak slowly before rupture and produce a
mild meningeal irritation; the CSF is sterile but shows an initial neutrophilic reaction and moderate
numbers of RBCs (144,219). Overall, hemorrhage was documented by LP, surgery, or autopsies in 65%
of the cases of ICIA gathered from the literature by Bohmfalk et al. (218). In approximately half of the
cases, hemorrhage occurred before hospitalization. When rupture of ICIA occurs, it almost always causes
either a subarachnoid or an intracerebral hemorrhage (218), but subdural hematomas have also been
described. In some cases, ICIA may present as a space-occupying lesion or may be accompanied by a
cerebral abscess (219). Finally and importantly, it has been documented that ICIAs may remain totally
asymptomatic and resolve with antibiotic therapy alone (220,227).
ICIAs may become symptomatic or may even develop after appropriate antibiotic therapy for IE has
been initiated (144,219) or completed (228). Delays from several months up to 2 years have been
reported (138), and a high level of suspicion should be maintained in patients with a history of IE. Cases
of ruptured ICIA during the postoperative period of cardiac valve replacement for IE have been reported
and full systemic anticoagulation may constitute an aggravating factor (78).
Diagnosis
Because some ICIAs may benefit from surgical treatment, it is of utmost importance to maintain a high
level of suspicion for ICIA in patients with active or treated IE who develop neurologic manifestations
and to initiate appropriate diagnostic procedures.
Diagnosis of ICIA may be difficult to establish. According to a retrospective study of 25 patients,
characteristics strongly associated with ICIAs were presence of a predisposing infection, specific
radiologic features (e.g., multiplicity, distal location, fusiform shape), and other features such as younger
age and fever (229).
MRI combined with MRA constitutes a major advance in the evaluation of cerebral aneurysms,
especially when bleeding has not occurred. It is likely that the favorable diagnostic experience
accumulated with noninfectious aneurysms will also apply to ICIA. This technique had a sensitivity of
100% and a specificity of 94% for intracranial aneurysms greater than 2 mm in diameter (230). In another
prospective study, 5 mm appeared to be the critical size for detection of aneurysm with MRA (231).
CT scan with and without contrast enhancement is still the diagnostic procedure of choice when acute
intracerebral or subarachnoid hemorrhage is suspected. In a systematic study comparing CT scan and
conventional angiography in 34 patients with IE and neurologic manifestations, no infectious aneurysm
was detected in the 14 patients with normal CT scans, whereas 11 cases with one or more ICIAs were
diagnosed at angiography in the 20 patients who had abnormal CT scans (184). This suggests that ICIA is
unlikely to be present when the CT scan is normal. Helical CTA is a noninvasive volumetric imaging
technique. A recent prospective study concluded that CTA and MRA were of equal value for the detection
of noninfectious intracranial aneurysms (185). In this study, the sensitivity of both techniques was
excellent for aneurysms larger than 5 mm but decreased for smaller aneurysms, the latter being detected
with higher sensitivity by regular angiography.
Digital substraction angiography remains the radiologic gold standard for the diagnosis of ICIAs. If
hemorrhage is confirmed, and intervention is contemplated, it is the method of choice to pinpoint the
location of the aneurysm and its relationship to the parent vessel (232). Because multiple aneurysms are
common, examination of all four vessels is recommended.
To summarize, patients with focal CNS signs or with localized or severe headache should have an MRI
and/or a CT scan, with contrast enhancement. CT scan is preferred if acute hemorrhage is suspected and
can be combined with CTA. When patients with proven or suspected IE are referred to CT or MRI, CTA
or MRA should be part of the examination, covering as much as possible the distal branches of the sylvian
artery where most of the ICIA are located. In the presence of hematoma or subarachnoid hemorrhage and
negative MRA or CTA, four-vessel conventional angiography is still the method of choice (184).
In patients in whom evidence of ICIA is the first manifestation of their illness, all efforts should be
made to identify the exact underlying disease and to isolate the causative microorganism by blood and
other pertinent cultures.
Specific Management
Suggested principles for management of patients with IE with proven or suspected ICIA are outlined in
Figures 34.5 and 34.8. They are based on the suggestions of several groups and take into account the
recent developments of diagnostic procedures and the endovascular therapeutic approach
(144,218,219,233).
Optimal treatment of ICIA is based on small series and expert opinion (157). Part of the challenge in
the treatment of these patients is derived from the choice of multiple treatment modalities, which currently
consists of medical (antibiotics), endovascular (clot, glue, coils), and surgical therapies. Moreover,
outcome with medical treatment alone is variable and unpredictable. Among 27 patients reviewed by
Ojemann and Crowell (217) in whom follow-up angiography was performed during antibiotic therapy,
complete disappearance of the lesions was observed in 8 patients (30%) and there was a decrease in size
in five patients (19%). The lesions were unchanged in four patients (15%) and larger in six patients
(22%). In four patients, a new ICIA was found (217). For a long time, it was believed that most ICIAs
would rupture if not resected (144). Although the natural history of ICIAs treated with appropriate
antibiotics is not known precisely, it has become increasingly apparent that a certain proportion of
unruptured ICIAs may resolve with medical treatment alone (219,220,233,234) (Fig. 34.9)
Thus, the most important aspect in the therapeutic approach to ICIAs is whether a rupture has occurred.
By reviewing existing studies, Peters et al. (157) found that mortality among patients with unruptured
ICIAs was very low, with no difference between patients treated with antibiotics alone and those treated
with surgery. By contrast, outcome among patients with ruptured aneurysm was poor. Antibiotic therapy
alone was associated with a mortality of 20% to 100% in this group, indicating that surgery or
endovascular therapy should be attempted (157). Based on these figures, most authors favor a
conservative approach in the management of patients with unruptured ICIA (157,220,233). However,
some authors recommend surgical excision whenever possible (232), due to the unpredictable course of
untreated ICIAs.
Chun et al. (233) proposed an algorithm for the assessment and treatment of patients with ICIA. Factors
that guide the decisions are the general condition of the patient, aneurysm location, aneurysm rupture,
hematomas with increased intracranial pressure (ICP), and the eloquence of brain tissue supplied by the
parent artery. Eloquence is determined on the basis of radiographic anatomic features and, if needed,
functional testing with amobarbital on a conscious patient. This technique consists of infusing amobarbital
into the vessel that needs to be occluded and to evaluate clinically the neurologic deficit the patient would
experience if the neuroradiologist proceeded with the occlusion of the artery harboring the ICIA (235).
The size of the ICIA does not appear very helpful in deciding whether to operate immediately; some small
ICIAs may rupture, whereas even large ones (>7 mm) may regress or even disappear under appropriate
antibiotic therapy (220).
Medical Treatment
Antimicrobial therapy should be initiated as soon as possible in all situations. Although few data exist for
ICIA, it is generally accepted that the regimen should be chosen according to the same principles and
guidelines used for patients with IE; however, it has been recommended empirically that the duration of
antibiotic treatment be extended to 6 to 8 weeks, even if the ICIA is resected surgically (236). Supportive
measures such as control of the arterial pressure by antihypertensive agents, steroids, and avoidance of
anticoagulation should be carefully considered.
Most authors agree that unruptured and stable ICIAs can be treated with medical treatment alone
(157,220,233). Close clinical and radiologic follow-up has been advocated for unruptured ICIAs
(157,217). Nowadays, MRA or CTA is probably preferable rather than conventional angiography for the
follow-up of ICIAs. How often these investigations should be repeated has not been established, but an
interval of 7 to 14 days appears reasonable. The patient should be monitored very closely for the
development of any symptoms or signs suggestive of an increase in size, a leak, or an imminent rupture.
Some authors also recommend surgery if the ICIA is still present at the end of antibiotic therapy (220).
However, ICIAs may continue to regress after antibiotic therapy has been completed and complete
resolution may take as long as 1 year (Fig. 34.9). Thus, if an ICIA has substantially decreased in size at
the end of the antibiotic treatment but is still present, one may elect not to operate immediately but to
continue to follow the patient with sequential CT and MRI.
Surgery
The primary goals of surgery are to eliminate the ICIA without further compromising cerebral function, to
evacuate any associated hematoma, and to reduce ICP (233). Patients with infectious aneurysms are
usually treated surgically if the aneurysm has ruptured and an intraparenchymal hematoma is producing a
mass effect or increased ICP. Recent advances in image-guided surgical techniques have enhanced the
ability of the neurosurgeon to opt for the best surgical treatment of the affected vessel (237–239).
Surgical treatment of ruptured ICIAs includes clipping, ligation, or excision (240). In some patients, the
fibrotic process generated by the infection is sufficiently advanced to allow successful aneurysm clipping
without sacrifice of the parent vessel. In other patients, the parent vessel may already be occluded by the
embolus, which was presumably responsible for the formation of the ICIA, and therefore, ligation of the
parent artery and excision of the ICIA may be performed. When surgical treatment is required for
aneurysms located on proximal arteries or on important peripheral arteries, extracranial–intracranial
bypass has been successfully attempted (241). It is important to take into consideration that administration
of antibiotics during a certain period before surgery may facilitate resolution of arteritis with subsequent
development of fibrosis in the wall of the aneurysm and the parent vessels. The lesion could then be
handled more safely at surgery.
Endovascular Approach
Endovascular repair of ICIAs is less invasive than surgery and may be of interest before valve
replacement. Small cerebral vessels can be cannulated and studied using small tracker wires. Various
materials can be injected to occlude the vessel (242). The goal of this technique is to exclude the
aneurysm from the circulation. A perioperative amobarbital test may help predict the vascular territory
supplied by the parent artery prior to occlusion (243). Endovascular approaches have been used
successfully to embolize aneurysmal vessels (242–246). Advantages of this endovascular approach
include safety of the procedure, accessibility to distal aneurysms, and endovascular occlusion with
minimal aneurysmal manipulation and low risk of rerupture. However, based on a metaanalysis of small
series and case reports, endovascular treatment appeared more likely to imply parent artery sacrifice than
surgical treatment (233). Therefore, a surgical approach is preferable for aneurysms located on eloquent
parent arteries. Moreover, the development of stereotactic angiographic guidance for localization of distal
ICIA allows the clipping of distal aneurysms using a minimally invasive procedure (237,247).
Special Issues
Few data are available to guide optimal timing of cardiac surgery in patients with IE complicated by
ICIAs (Table 34.5). In a review of 34 patients with IE complicated by acute neurologic events who
underwent valve replacement, three had a ruptured and four an unruptured ICIA (248). All patients with
ruptured ICIAs underwent clipping before cardiac surgery. All patients with unruptured ICIAs had an
uneventful postoperative course, whereas one patient with ruptured ICIA died after valve replacement.
Thus, unruptured ICIAs do not seem to be associated with worse outcome after cardiac surgery and there
is no indication for preoperative angiography (183). By contrast, ruptured ICIAs should undergo repair
before cardiac surgery (240). According to recent case reports, cardiac surgery can be performed a few
days after endovascular repair (246), thus this technique should be preferred if subsequent valve
replacement is planned. Cardiac surgery should be postponed for at least 4 weeks in the presence of
intracerebral hematoma (10).
Multiple aneurysms present a complex problem. It seems appropriate to analyze each individual case
along the same guidelines as for a single ICIA. If one or more of the aneurysms enlarge or bleed, prompt
surgical excision should be attempted. The excision of the other aneurysms during the same operation will
depend on their accessibility (217,234). Multiple aneurysms can be treated by endovascular techniques in
one session and this may represent an important advantage over a surgical approach (233,242).
Outcome
The mortality of recognized ICIA is high. Among the 85 cases reviewed by Bohmfalk et al. (218), the
figures for patients hospitalized for IE before neurologic symptoms occurred show a mortality of 80% for
aneurysms that ruptured and of 30% if the aneurysm remained intact. The overall mortality was 46%.
Metastatic Infections
Infection of the CNS secondary to IE may present as meningitis, meningoencephalitis, cerebral

microabscesses or macroabscesses, parameningeal abscesses, or infectious arteritis.
Meningitis
In the context of IE, the term meningitis is used to cover various conditions, ranging from full-blown
bacterial infection with positive CSF cultures to sterile inflammatory reactions to infection, ischemia, or
hemorrhage. Before the advent of antibiotics, meningitis was one of the more common neurologic
complications of IE, accounting for up to two thirds of CNS complications in some studies (76). In more
recent reviews of IE, meningitis was recorded in 2% to 15% of patients with IE, accounting for 15% to
40% of CNS manifestations of IE (83,97,101). The great variability of these percentages is partly due to
the fact that some authors include all meningeal reactions whatever the underlying process, whereas
others restrict the diagnosis to cases with positive CSF cultures. Moreover, the lower rate of meningitis in
recent series may be related to a decrease in LPs because of improved cerebral imaging. Referral bias
and a changing spectrum of IE may also account for some differences. For example, patients admitted to
the ICU have higher rate of neurologic complications including meningitis: In a recent series of 198
patients, 41 (21%) were reported to have meningitis or meningeal reaction (106).
Although meningitis may be the presenting symptom of IE (83,249), IE is an uncommon cause of
bacterial meningitis in general accounting for 3% in a large series (250). Microorganisms recovered in
these cases are either Staphylococcus aureus or Streptococcus pneumoniae (251), but other pathogens
(e.g., Streptococcus agalactiae, viridans streptococci, enterococci, gram-negative bacilli) are also found.
When meningitis is due to bacterial species that do not normally cause primary meningitis, the proportion
of cases associated with IE is higher (83,249). In a recent series of nine patients with community-
acquired Staphylococcus aureus meningitis, endocarditis was found in five (252). Outcome was very
poor with a mortality of 67%, while two of three survivors presented neurologic sequelae. In another
study, IE was present in one quarter of 28 patients with community-acquired Staphylococcus aureus
meningitis. Mortality was 43% (253). In pneumococcal endocarditis, meningitis has been recorded in
40% to 60% of the patients (130,131). Austrian syndrome was first described in 1956 and represents the
triad of Streptococcus pneumoniae pneumonia, endocarditis, and meningitis (254). Although chronic
alcoholism is thought to be a risk factor, in a review of 31 published case reports of Austrian syndrome,
only 38% were alcoholics (254).
Brain Abscess
Brain abscesses associated with IE are uncommon, especially in subacute cases. In a series of 218
patients with IE, 8 (3.6%) developed abscesses (83). In other large series, rates of 1% to 8.6% were
recorded (88,92,97,101,143). In patients hospitalized in the ICU, the rate was 7% (106). In an autopsy
study, cerebral abscesses were documented in 30% of cases (255). In large series of brain abscesses, IE
is not a common cause. Among 314 patients with brain abscess collected from six series, 13 (4%) had IE
(256,257). This reveals that IE should be suspected in the presence of brain abscess when there is no
other obvious source. This suspicion must be particularly high when multiple abscesses are present (Fig.
34.10). Thus, IE was responsible for 2 of 5 patients who presented with multiple abscesses in a series of
41 patients with brain abscesses observed in our institution from 1977 to 1989 (257).
Obviously, the incidence of brain abscesses associated with IE will depend on the imaging techniques
used and on whether the study included pathologic examination. In a series of patients with IE from the
Massachusetts General Hospital, 9 of 218 had evidence of brain abscess, all cases of which were
diagnosed at autopsy (83). In eight of the patients, the abscesses were less than 1 cm3 in size, not
sufficient to create a mass effect. In six of these eight patients, multiple microscopic abscesses were
present, usually in association with microabscesses in other organs. These patients also had multiple
microscopic infarcts, demonstrating the interrelationship between vascular and infectious complications
of IE. Seven of the eight patients had acute IE, four cases of which were due to S. aureus, and one had
subacute IE due to viridans streptococci. Only one patient in this series had a large abscess, which was
probably caused by the direct extension from S. aureus otitis media and mastoiditis, not by bacterial
seeding from the bloodstream (83).
Because areas of cerebritis or cerebral abscesses of small size often resolve with appropriate
antibiotic therapy alone (257), it is likely that the true incidence of these lesions is underestimated, even
in recent studies that have benefited from CT. Thus, among 64 patients with neurologic complications of
IE, abscesses were diagnosed in only 2 of the 51 patients who had a head CT scan (88). It is noteworthy
that among these 51 patients, 15 presented with encephalopathy, a clinical presentation often associated
with multiple microabscesses and/or microinfarcts (145). Likewise, 11 of these 51 had a focal deficit
with a normal CT scan and some may have had undetected cerebritis (88). This suggests that small
abscesses or foci of cerebritis may be below the level of detection of the CT scan. MRI has been shown
to be superior to CT in the detection of early cerebritis. Patients with IE and “toxic” encephalopathy were
described who had a normal CT scan but an MRI scan showing multiple lesions suggesting
microembolization and/or microabscesses. For example, in prospective study of 130 patients who
underwent systematic cerebral MRI, abscesses were found in 8 (6%) (163). Reports of abnormalities
seen on MRI but undetected by CT have also included small infarcts. Thus, it is obvious that cerebritis,
cerebral microinfarcts, and microabscesses associated with IE will be diagnosed with increased
frequency if MRI is performed, especially in patients with toxic encephalopathy or focal deficit with a
normal CT scan (163).
Pathogenesis
Clinical signs of meningitis may be associated with multiplication of the causative microorganism in the
subarachnoid space or may be a reflection of various parameningeal lesions, such as brain
microabscesses and macroabscesses, septic or nonseptic cerebral microemboli or macroemboli, leaking
infectious aneurysms, subarachnoid hemorrhage, or immune-mediated arteritis. Several of these
mechanisms can occur simultaneously or sequentially (83). Except for the immunologic arterial lesions,
all these complications ultimately relate to embolization of infected material to cerebral or meningeal
vessels. Critical factors that may determine whether a septic embolus results in a simple infarct, a
infectious aneurysm, meningitis, cerebritis, an abscess, or a combination of these lesions include the size
of the embolus, the site in which the embolus lodges, the virulence of the microorganism, and the defenses
of the host, including the timing and adequacy of antibacterial therapy. As already mentioned, neurologic
complications are characteristic of left-sided IE, indicating that emboli play a major role in the
pathogenesis of cerebral manifestations including meningitis and abscesses (83). Although these emboli
may be clinically silent, the development of macroscopic brain abscess 1 to 3 weeks after a contralateral
hemiplegic stroke due to embolism has been well documented (113). However, with certain bacteria,
meningitis can occur in the context of isolated right-sided IE, indicating that the mere presence of certain
bacteria in the blood can cause meningeal seeding. This has been described with S. pneumoniae, not
surprising given the well-known propensity of this organism to cause hematogenous meningitis. In right-
sided S. aureus IE, meningitis has also been described, but it occurred in only 2 of 53 of such episodes.
The CSF showed an “aseptic” formula. When S. aureus bacteremia is caused by IE, the incidence of CNS
involvement is higher (29% to 54%) than in the absence of endocardial involvement (3% to 10%). In a
recent study of 81 episodes of S. aureus IE, 22 neurologic complications were recorded. All but one
occurred in the 42 patients with left-sided involvement; there were five brain abscesses and two cases of
meningitis (110).
Thus, the occurrence of CNS infectious complications of IE depends on two major factors, as follows:
the virulence characteristics of the microorganism and the side of the heart involved. The fact that right-
sided and left-sided IE are both characterized by persistent bacteremia but are very much different with
respect to the incidence of CNS infectious complications suggests that emboli associated with bacteria
are more capable of disrupting the normal blood–brain barrier (BBB).
There is a continuum in the clinical presentation of meningitis, meningoencephalitis, and microscopic and
macroscopic brain abscesses. Patients may display a typical clinical presentation of primary meningitis.
Meningoencephalitis characterized by confusion, decreased level of consciousness, stiff neck, and
headache associated with normal or slightly abnormal CSF (minimal pleocytosis, normal glucose
concentration, normal or slightly elevated protein concentration, and sterile culture) has been termed
acute brain syndrome, acute encephalopathy, or toxic encephalopathy (142). Psychiatric manifestations
may predominate, including personality change, disorientation, drowsiness, irritability, or even
hallucinations. This may account for the frequent presence of confusion in elderly patients with IE in the
absence of fever or metabolic abnormalities. This presentation is related to multiple microemboli and
microinfarcts with or without microabscesses (83).
The clinical presentation of brain abscesses depends on the stage, size, number, and location of the
lesions (258,259). This may result in clinical manifestations of a focal deficit, a space-occupying lesion,
toxic encephalopathy, or meningitis. The triad of fever, headache, and focal neurologic signs is found in
less than 50% of cases (260).The accompanying meningitis will usually be sterile unless the abscess
ruptures into the subarachnoid space. Headache, confusion, increased ICP, and focal signs, often
developing slowly over several days, are noted with large abscesses (261).
Parameningeal abscess (i.e., cerebral or spinal epidural abscess, spondylodiscitis) is another
metastatic infection of IE that may cause neurologic manifestations. Back pain may be a symptom of IE in
up to 43% of patients (262), whereas spondylodiscitis complicates 15% to 20% of cases (263,264).
Conversely, IE is reported as the source of infection for vertebral osteomyelitis in up to 30% of patients
(265). By contrast, epidural abscess was found to be associated with IE in only 3% of cases (266).
Management
The treatment of IE-associated meningitis and brain abscess is covered by the antibiotic regimens
recommended for the underlying IE, provided that high doses of bactericidal antibiotics that cross the
BBB are used. Among drugs commonly used for the treatment of IE, penicillins, third-generation
cephalosporins and meropenem should be favored because they were shown to achieve bactericidal
concentrations in the CSF, provided the highest intravenous dose is used (267).
Drainage of brain abscesses is only indicated if antibiotic treatment alone is expected to fail, as
microbial etiology is usually already established by blood cultures. Most patients have small and multiple
microabscesses and surgery is generally neither feasible nor desirable. However, a large abscess can be
refractory to antibiotic treatment alone. Two centimeters appears to be the critical diameter above which
surgery is strongly indicated (268). In patients with cerebritis, early therapy alone may also be curative,
but surgery should be considered in case of neurologic deterioration (269). For CNS suppurative
complications of IE, it is generally recommended that the duration of antimicrobial therapy be extended to
6 to 8 weeks (83).
Spinal Cord Lesions
Lesions of the spinal cord may be due to external compression by a parameningeal abscess or may be the
consequence of emboli to the vascular supply. Despite the frequency of embolic phenomena in IE, there
have been only rare case reports of embolic infarction of the spinal cord and no cases are reported in the
major series of IE.
Cranial and Peripheral Nerve Lesions
In two large series of patients with neurologic manifestations of IE, mononeuropathies were reported in 5
of 110 and 5 of 84 patients (83,143). Five of these patients were reported in detail. Viridans streptococci
were the responsible microorganisms in all five. All had an elevated erythrocyte sedimentation rate
(ESR). In four patients, neuropathy was the initial manifestation of IE. Three had concomitant involvement
of multiple nerves, emphasizing the need to consider IE in the differential diagnosis of mononeuritis
multiplex (270). All patients improved after treatment, and only two of the eight nerves involved
presented minimal residual deficit. Because of the temporal and spatial association with cutaneous
emboli, embolic occlusion of the vasa vasorum was the postulated physiopathologic mechanism
(152,271). Immune-complex–mediated vasculitis in the peripheral nerves is another possible mechanism.
Peripheral neuropathy has been rarely reported as a complication of S. aureus endocarditis and
meningitis (272) and as critical illness polyneuropathy (273).
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CHAPTER 35 IATROGENIC INFECTIONS OF THE
CENTRAL NERVOUS SYSTEM
KELLY J. BALDWIN AND JOSEPH R. ZUNT
Iatrogenic infection of the central nervous system (CNS) can occur as a complication of surgery to the
cranium, brain, or, less frequently, dural puncture. There is significant morbidity and mortality associated
with postneurosurgical-related CNS infections. Early recognition and treatment is crucial to reduce
adverse outcomes and long-term complications. This chapter describes the epidemiology, differential
diagnosis, clinical presentation, workup, and treatment of iatrogenic CNS infection. Special
considerations regarding neurosurgical devices and surgery-related prion disease are also reviewed.
INFECTION ASSOCIATED WITH NEUROSURGICAL DEVICES

Etiology
Coagulase-negative staphylococci (CoNS), Staphylococcus aureus, gram-negative bacilli, and
Propionibacterium acnes are the most common organisms causing infection associated with placement of
a neurosurgical device (1,2). Tables 35.1 and 35.2 summarize the risks for CNS infection and etiologic
agents associated with ventriculoperitoneal (VP) shunt and external ventricular drains (EVD) (1–33).
Diagnosis of device-related infection can be complicated by the ability of some organisms to produce
biofilms, often referred to as “slime,” resulting in false-negative cultures. S. aureus and certain CoNS,
such as Staphylococcus epidermidis, are able to form biofilm. First recognized in 1972, biofilms are
complex communities of bacteria that enter a dormant mode to survive. They induce enhanced adherence
of bacteria to shunt material, thus decreasing susceptibility to both diagnosis and antibiotic therapy
(34–36). The presence of foreign material, such as a shunt catheter, can also diminish the host immune
system’s ability to adhere to and phagocytose bacteria (37).
S. aureus is the organism most commonly isolated in shunt infection of children (38). Although gram-
positive organisms are the most common cause of early postsurgical infection, gram-negative organisms
can produce delayed infection (18). Neisseria gonorrhoeae has been reported in a fetus with a
ventriculoamniotic shunt who developed ventriculitis (39).
Fungal meningitis, particularly due to Candida spp., is a rare complication of device-related
infections; however, it is associated with significant morbidity and mortality. Candidal infection should
be suspected in patients with neurologic deterioration in the setting of device placement, especially if
there is an antecedent history of bacterial infection (40). In one study, fungal infection accounted for 17%
of shunt infections in premature babies undergoing VP shunt placement for treatment of hydrocephalus;
fungi isolated included Candida albicans, Candida parapsilosis, Candida tropicalis, and Torulopsis
glabrata (41).
The four most common mechanisms for acquisition of shunt infection include (a) contamination at the
time of surgery, (b) direct extension of skin infection at the surgical site, (c) transmission of infection from
the distal catheter tip, and (d) hematogenous spread of infection from other sites (42).
Potential complication of VP shunt placement include mechanical malfunction, occlusion of the distal
outflow catheter in the abdomen, intracranial migration, displacement or malfunction of the proximal
inflow catheter or valve, and shunt infection. Over 50% of shunts malfunction within 10 to 12 years of
placement, and the ratio of shunt revisions to primary shunt placement approaches 3:1 (43–45). As many
symptoms associated with shunt infection, such as headache, drowsiness, and vomiting, are similar to
those caused by shunt malfunction, blockage, or breakage (46), it is often difficult to distinguish between
infection and malfunction, particularly when cerebrospinal fluid (CSF) cultures are negative and CSF
parameters are normal. More than half (62%) of shunt infections manifest within the first month of
placement, with most patients presenting with fever (78%), nuchal rigidity (45%), or local sign of
infection, characterized by erythema, local pain, swelling, or purulent discharge (49%) (2). In addition,
over 80% of patients have a CSF leukocytosis with elevated lactate.
Clinical Symptoms and Signs
Symptoms of shunt infection or malfunction typically result from increased intracranial pressure and can
include headache, nausea, vomiting, and altered mental status. Symptoms of shunt infection usually
develop within the first month, and nearly all occur within 6 months of device placement (47). Regardless
of shunt type, over 80% of patients with shunt infection will develop fever. Drowsiness may be the best
clinical predictor of shunt malfunction, followed by headache and vomiting (44). Due to containment of
most infections within the ventricles, only one third of patients with VP shunt infection develop signs of
meningeal irritation, whereas the majority of patients with lumboperitoneal shunt infection develop
meningeal irritation, due to direct extension of infection within the CSF space to the meninges (48).
Atypical symptoms may include seizure, cranial nerve palsy, hemiparesis, visual deficit, and rigidity
(44,49–51). Erythema, pain, swelling, or wound drainage may be present over the valve, cranial incision
site, or distal outflow catheter (2). Accumulation of fluid along the shunt tract or at the operative site,
although highly correlated with CNS infection, occurs in less than 10% of patients with VP shunt infection
(3). Infection at the distal catheter site typically produces an inflammation of surrounding tissues,
followed by decreased absorption of CSF, then formation of CSF-filled cysts or loculations (52). Patients
with an infected distal catheter in the peritoneal space may develop symptoms of peritonitis, appendicitis,
or perforated viscus (53,54).
In children, VP shunt infection is usually preceded by fever, irritability, or shunt malfunction (56).
Among children who undergo initial shunt insertion after 2 months of age, absence of irritability, nausea,
vomiting, and headache are strong predictors for the absence of shunt failure or infection (57).
Neuroimaging should be obtained in all patients in whom shunt infection is suspected. Neuroimaging
should be followed by CSF examination to evaluate for suspected shunt infection. CSF can be obtained
from the shunt reservoir or via lumbar puncture. Bacterial and fungal culture of CSF, in addition to blood
culture, should be obtained from all patients with suspected shunt infection; in the setting of suspected
shunt infection, CSF culture is positive in up to 66% of patients (2). Culture of CSF obtained from the
shunt is more likely to identify the causative organism than culture of CSF obtained by lumbar or
ventricular tap (14,58,59). Administration of antibiotics prior to obtaining CSF culture reduces the
likelihood of obtaining a positive culture; one study noted a decline in positive CSF cultures from 97% to
53% (59).
A positive CSF Gram stain and culture is considered the gold standard for diagnosis of shunt infection.
CSF analysis in shunt infections typically reveals a leukocyte count of greater than 5 × 106 cells/mm3;
however, cell count can be normal in up to 20% of patients with shunt infection (2). Most experts agree
that more than 100 white blood cells (WBC)/mm3 is strongly suggestive of infection (60–62). The
presence of leukocytosis with a predominance of polymorphonuclear leukocytes (PMN) is typical for
shunt infection and should elicit initiation of antimicrobial treatment. In children, eosinophilia (defined as
≥8% eosinophils of total CSF WBC), in the absence of peripheral eosinophilia or parasitic infection, was
associated with increased risk of shunt infection and higher number of shunt revisions (63). Other studies
have reported eosinophilia without infection (64). A recent study correlated the initial CSF WBC count
with organism type. Gram-negative organisms were associated with a higher WBC count, with early peak
and higher percentage of PMNs. Propionibacterium acnes produced a lower percentage of PMNs, lower
WBC count, and higher percentage of eosinophils. As Propionibacterium spp. grow slowly, CSF culture
should be held for at least 14 days before a negative report is considered final. Shunt infection typically
follows a pattern of initial PMN predominance followed by a later peak of lymphocytes, monocytes, and
eosinophils. With successful treatment, an elevated cell count should normalize (1). CSF lactate levels
are higher than 1.9 mmol/L in over 80% of patients with infection (2). Neither shunt infection nor shunt
malfunction is significantly associated with increased CSF protein concentration (65).
Neuroimaging
In general, a multimodality approach is used during the radiologic evaluation of suspected shunt infection
or malfunction: plain radiography, computed tomography (CT), magnetic resonance imaging (MRI), and
CSF flow study each providing valuable information (66). Neuroimaging is most useful when
postoperative images are available for comparison. Either CT or MRI can determine if hydrocephalus,
enhancement, or fluid loculation is present. An increase in ventricular size is observed in up to 66% to
84% of patients with shunt infection or shunt malfunction. Figure 35.1 demonstrates acute hydrocephalus.
An unenhanced CT can provide information regarding ventricular size, shunt location, and the type and
integrity of shunt components. When traditional neuroimaging is nondiagnostic, shunt injection or
radionuclide scans (shuntograms) can provide an assessment of shunt function. The combination of CT
and shuntogram, compared to CT alone, increases the sensitivity for diagnosing shunt malfunction (67).
MRI using single-shot fast spin echo (SSFSE) is as sensitive as CT for diagnosing shunt malfunction and
does not expose children to radiation. MRI requires reevaluation of the valve setting following the MRI
as the magnetic field can affect the valve setting. MRI may also reveal evidence of ventriculitis not seen
with CT imaging, such as irregular ventricular enhancement (68). Figure 35.2 demonstrates acute
ventriculitis and meningitis in a postneurosurgical patient. At the distal outflow end of the shunt, formation
of an abdominal pseudocyst has been reported (69). Distal shunt malfunction can also produce cerebral
edema (70). In addition, focal displacement of the dorsal midbrain, visualized by MRI, has been
described with shunt infection due to P. acnes (71). Ultrasound has been used as a tool to diagnose
neonatal ventriculitis associated with VP shunt; typical findings include increased echogenicity of
ventricular fluid in a fine homogeneous pattern or with strandlike material and coarse particles (72).
When shunt infection is suspected, antibiotics should be started after initial CSF and blood cultures are
obtained and then adjusted according to antibiotic sensitivity of any identified pathogen(s); in most
patients, the etiologic pathogen will be S. epidermidis or S. aureus. A combination of vancomycin with a
third-generation cephalosporin will cover the majority of pathogens causing shunt infection. Doses and
recommended administration schedules can be found in Table 35.3 (73,74). Side effects of vancomycin
include ototoxicity and nephrotoxicity, which can be limited through careful monitoring of serum
vancomycin levels. There have been reports of increasing rates of β-lactam antibiotic-resistant CoNS
(15).
Some experts recommend intrathecal administration of vancomycin in patients with gram-positive

organisms or of gentamicin when CSF culture reveals infection with Pseudomonas spp. or enteric
coliforms (73,15). Intrathecal amikacin has successfully eradicated shunt infection due to Mycobacterium
fortuitum (75). Successful treatment of fungal shunt infection usually requires shunt removal and
administration of systemic amphotericin C; intrathecal administration should be considered for patients
who do not respond to systemic therapy (41).
Systemic antibiotics, with or without concomitant administration through the infected device, are not as
effective as administration of antibiotics plus removal of the infected device. Most experts recommend
externalizing the infected shunt or replacing the infected shunt with an EVD, administering antibiotics until
CSF is sterilized, and then removing the drain and placing a new shunt (76). Recurrent shunt infection
following treatment and replacement of an infected shunt occurs in 17% to 52% of patients (77,78).
In general, the literature supports early removal of infected shunt hardware in combination with
antibiotics as the treatment of choice for all but the exceptional patient with a shunt-associated infection.
Prevention
Prevention of shunt infection starts with good sterile technique and a neurosurgeon with extensive
experience. A recent meta-analysis of prophylactic systemic antibiotics identified 21 eligible trials and
supported the use of periprocedural prophylactic antibiotics for placement of VP and ventriculoatrial
shunts. The analysis revealed a lower percentage of shunt infections in patients receiving antibiotics prior
to and up to 24 hours after surgery (79). These results were not confirmed by two randomized placebo-
controlled trials of EVD placement and systemic prophylactic antibiotics (80).
Two new catheter types that have reduced CNS infection include antibiotic and silver-impregnated
devices. In vitro studies suggest catheters impregnated with clindamycin and rifampin reduce catheter
colonization without inducing antibiotic resistance (81). In a rodent model, rifampin-impregnated
catheters prevented colonization by S. epidermidis and S. aureus, whereas nonimpregnated catheters
developed colonization with either organism (82). Antibiotic-impregnated shunts have also shown
promising results in reducing infection rates. In a recent systematic review of adults and children,
antibiotic-impregnated shunts were significantly associated with a lower incidence of shunt infection
(3.3% vs. 7.2%) (10). A recent prospective randomized controlled trial of EVD catheters impregnated
with clindamycin and rifampin compared to standard catheters did not reveal reduction in EVD infections,
but infections were uncommon in both patient groups (11). A prior prospective randomized study reported
that positive CSF cultures were seven times less common in patients receiving antibiotic-impregnated
EVDs (83). The discrepancy between these two studies may be due to the very low baseline infection rate
of the most recent trial (2.8% in the standard cohort) resulting in a failure to demonstrate a benefit of the
antibiotic-impregnated EVD. In the Zabramski et al. (83) study, 80% of patients underwent EVD
placement in the critical care unit, resulting in higher initial infection rates in the standard catheter group.
Similarly, a single institution study found infection rates decreased from 15% to 5% with the use of
antibiotic-impregnated catheters (84). Development of antimicrobial resistance has thus far not been
increasingly reported in patients receiving these coated catheters. Several studies evaluating the use of
silver-impregnated devices, including the SILVER (Silver-Impregnated Line Versus EVD Randomized
trial), demonstrated a significant reduction in CNS infections (21% in patients with standard EVD vs.
12.3% in patients with silver-impregnated EVD) and provided class I evidence that silver-impregnated
catheters reduced CNS infection. Silver catheters may thus be an alternative to antibiotic-impregnated
catheters, as silver is both safe and effective for preventing CNS infection (85).
Specific Device Considerations
Ventriculoperitoneal Shunt
Ventricular shunts, first introduced in 1952, are inserted to relieve increased intracranial pressure
associated with hydrocephalus; shunts may also be used to deliver medication or intermittently monitor
and reduce intracranial pressure (86). Ventricular shunts consist of a proximal ventricular catheter, an
optional access reservoir, a valve to regulate flow, and a distal outflow catheter draining into the
peritoneum, atrium, or pleural space. The most commonly used shunt is the VP shunt. The diagnosis of
shunt infection can be based on the laboratory and clinical criteria presented in Tables 35.4 and 35.5
(27,87).
The incidence of shunt infection reported in the literature varies widely from 1% to 39% (88). Children
may be at higher risk for developing shunt infection due to longer hospitalization, relative
immunodeficiency, and more prominent skin colonization of adherent bacteria (11,34). Factors associated
with increased risk of shunt infection include postoperative CSF leak, prematurity, nonsterile technique,
use of a three-piece shunt system, implantation by a less-experienced neurosurgeon, placement of a shunt
revision, and previous shunt infection (6,45,89).
External Ventricular Drain

EVD catheters have been used since the 1960s for the management of acutely elevated ICP. EVDs are
often an essential component in the initial management of subarachnoid hemorrhage, intraventricular
hemorrhage, head trauma, and obstructive hydrocephalus. Ventriculitis and bacterial meningitis following
EVD placement occur with an average incidence of 9% (90). Risk factors for EVD infection include prior
history of shunt infection, craniotomy, systemic infection, CNS trauma with cranial fracture,
intraventricular hemorrhage, high frequency of device access for sampling CSF, catheter leakage, and
prolonged duration of implantation (22,27,91,92). A recent study reported no difference in the incidence
of ventriculitis based on age, gender, or mean EVD duration; there was a significant decrease in the
incidence of ventriculitis from 17% to 11% with decreased sampling from daily to once every 3 days
(93). Another recent study reported a significant decrease in the development of bacterial ventriculitis
associated with shorter duration of EVD placement (20 days vs. 12 days), suggesting that earlier removal
is preferential (25).
Lumbar Drain
Lumbar drains are most often placed to treat communicating hydrocephalus following subarachnoid
hemorrhage or CSF leak or as a diagnostic procedure for normal pressure hydrocephalus. Hydrocephalus
complicates the clinical recovery of 20% to 31% of patients after subarachnoid hemorrhage, 40% of
whom will improve within 1 day without intervention (94,95). The incidence of meningitis following
lumbar drain placement varies from 0% to 25.6% and is highest in patients with subarachnoid or
intraventricular hemorrhage (96–98). Meningitis following lumbar drain placement typically occurs
within 24 hours of drain placement. Although CSF WBC count of 11 cells/mm3 or more was not a risk for
development of meningitis, the majority of patients who developed meningitis typically had an increasing
CSF WBC count in the days preceding diagnosis (96).
Intracranial Pressure Monitors

An intracranial pressure (ICP) monitor provides a quantitative measure of ICP and cerebral perfusion
pressure when physical examination alone may not reliably predict neurologic deterioration, such as
following open or closed head injury or neurosurgery. An ICP monitor may be placed within the subdural
space, parenchyma, or ventricle. Complications associated with ICP monitor placement include
hemorrhage and infection. CNS infection occurs in 2.9% to 10.3% of patients with ICP monitors. Risk
factors for infection include placement in patients with open head injury or hemorrhage, intraventricular
monitor placement, presence of CSF leak, concurrent infection outside the CNS, and presence of
monitoring device for longer than 5 days (99–101). The use of prophylactic antibiotics for ICP monitor
placement or use is controversial. Although initial studies suggested prophylactic antibiotics did not
reduce the incidence of CNS infection, other studies have demonstrated a benefit (18,99). A prospective
review of prophylactic nafcillin reported that 8% of patients with ventriculostomy systems and 0% of
patients with ICP monitors developed CNS infection. However, the majority of infections that occurred
were due to gram-positive organisms, many of which were nafcillin resistant. Patients with infection were
more likely to be younger and had longer duration of ventriculostomy placement. No specific neurologic
diagnosis, presence of intraventricular hemorrhage, or Glasgow Coma Scale (GCS) at time of admission
was predictive of development of CNS infection (102). Unlike increased rates of CNS infection
complicating shunts placed by less-experienced surgeons, CNS infection rates following insertion of
subdural or parenchymal ICP monitor are similar, regardless of whether a neurosurgeon, general surgeon,
or midlevel practitioner performs the procedure (103,104).
Deep Brain Stimulators

Deep brain stimulation is an effective treatment for a variety of movement disorders, including Parkinson
disease, dystonia, and essential tremor. The determination of infectious complication rates are difficult
due to low patient numbers, limited reporting, and lack of standardized protocols. The prevalence of
infectious complications varies from 0% to 15% (105–108). A recent study analyzing postoperative
complications of infection, wound dehiscence, and erosion identified 1.24% of patients with atraumatic
device-related infection and/or dehiscence within 12 months after implantation, nine of whom required
additional surgery after antibiotic failure (109). Two other recent large series reported incidences of
4.5% and 4.2% for hardware-related infection within the first 6 months, all requiring further surgical
intervention. Age, diagnosis, surgeon experience, placement of leads in stages, and length of surgery were
not associated with increased risk for developing infection. Pediatric patients and poor hygiene were risk
factors for infection (110,111). The management of hardware-related infections has not been standardized.
Many groups have reported that infection of any part of a device requires removal of all hardware
regardless of concomitant antibiotic treatment. Partial hardware removal may be an option if infection is
identified early and aggressive antibiotic treatment is administered (111,112).
Ommaya Reservoirs
Ommaya reservoirs were first introduced in the 1960s for the management of fungal meningitis. More
recently, these reservoirs have become a popular device for the treatment of leptomeningeal
carcinomatosis, pain, and chronic or recurrent CNS infection. The instillation of drugs directly into the
CNS is facilitated via the Ommaya reservoir; as the injected drugs are distributed over the entire
subarachnoid space, higher and more consistent concentrations can be attained (113). Complications of
Ommaya reservoir placement include malfunction, infection, hemorrhage, migration of the canula,
leukoencephalopathy, focal neurologic deficits, and seizures. Asymptomatic bacterial infection occurs in
about 8% of patients. Symptomatic bacterial infection rates vary widely from 7% to 50% (114). A large
retrospective review of 106 patients with Ommaya reservoirs reported a technical complication rate of
10%, including one death due to misplacement of the catheter, two mild intraventricular hemorrhages, and
five malfunctioning reservoirs; three required craniotomies (one for subdural hematoma and two for
subdural hygroma). Bacterial infection affected 15% of patients. Staphylococcus epidermidis and other
CoNS were the organisms most frequently isolated. There was a significantly higher rate of infection in
patients whose reservoir was punctured more than 20 times, compared to patients accessed on fewer
occasions. Ten of 61 patients with lymphoproliferative diseases had reservoir-related infections,
compared to only 3 of 44 patients with other diagnoses (115). Infection may be treated with a combination
of intravenous and intra-reservoir antibiotics without the need for device removal (116). Some studies
reported eventual device removal in up to 25% of patients due to persistent infection despite antibiotic
treatment (115,117).
CRANIOTOMY
Potential CNS infection following craniotomy includes meningitis, bone flap infection, epidural or brain
abscess, and subdural empyema. Infectious or chemical (also called aseptic) meningitis can complicate
any neurosurgical procedure. Infectious meningitis complicates less than 5% of craniotomies but is more
common in patients who undergo repeat resection surgery for recurrent glioma or a neurosurgical
procedure that traverses an area of high bacterial colonization, such as the paranasal sinuses (118–120).
Both bacterial and chemical meningitis are characterized by fever, neck stiffness, and headache and have
been reported following craniotomy, suboccipital craniotomy, and posterior fossa surgery in children. By
definition, chemical meningitis requires negative CSF Gram stain and culture, as well as recovery of the
patient without administration of antibiotics (121,122).
Etiology
The etiology of chemical meningitis in postneurosurgical patients is not completely understood; one
hypothesis suggests meningeal inflammation results from release of red blood cells or other material
during surgery. Experimental injection of saline, air, casein, or blood into the subarachnoid space
produced symptoms of meningitis and a neutrophilic pleocytosis, the latter persisting 3 to 4 weeks (123).
Infectious meningitis is usually introduced by direct contamination from surrounding skin or sinuses,
typically the same gram-positive organisms, such as Staphylococcus spp., causing shunt infection (42).
Differentiating between infectious and chemical meningitis can be difficult; aside from identifying an
organism in CSF by Gram stain or culture, no single assay or clinical symptom or sign can predict the
presence of infectious meningitis with certainty.
Most experts believe that bacterial and chemical meningitis can produce similar clinical and CSF
findings.
CSF leak and focal neurologic deficits were reported in patients with bacterial meningitis, and the
levels of peripheral WBC, CSF WBC, and PMNs were higher in patients with bacterial meningitis (124).
Factors increasing the risk for postoperative infection in patients undergoing neurosurgery include surgery
for tumor resection (especially gliomas), transsphenoidal surgery, CSF leak, and concomitant infection
outside the nervous system. A study of 70 patients with meningitis following a neurosurgical procedure
reported a CSF WBC count of more than 7,500/mL and glucose level of less than 10 mg/dL only in
patients with bacterial meningitis (125). In patients with bacterial meningitis following craniotomy,
elevation of CSF lactate level of 4 mmol/L or more was a sensitive and specific predictor for bacterial
meningitis (126); such elevations result from a combination of bacterial growth, anaerobic metabolism,
and release of lactate by neurons and glial cells affected by meningitis-induced brain edema (127,128).
Clinical Symptoms
In a study of 70 patients who developed infectious meningitis following craniotomy, paranasal or spinal
surgery, fever (temperature ≥39.4°C), and wound drainage (purulent or nonpurulent) were associated with
bacterial rather than chemical meningitis. Transient unconsciousness showed a trend toward significant
association with bacterial meningitis, but headache and neck stiffness did not occur more frequently in
patients with bacterial meningitis. Another useful analysis demonstrated that loss of consciousness, focal
neurologic deficits, and seizures occurred exclusively in patients with bacterial meningitis and not in
patients with aseptic meningitis (125).
All patients with suspected meningitis should have blood and CSF samples sent for Gram stain and
culture, in addition to routine CSF studies. Although identification of an organism on CSF Gram stain is
sufficient for diagnosing infectious meningitis, up to 70% of patients with positive CSF culture will have
a negative Gram stain (129). CSF lactate is a quick assay and when 4 mmol/L or more is both sensitive
and specific for bacterial meningitis in the postoperative neurosurgical patient (130). Neuroimaging
should not be used to differentiate between chemical and infectious meningitis as inflammation and
contrast enhancement occur in up to 80% of postcraniotomy patients without CNS infection (131).
Unfortunately, it is usually not possible to rapidly distinguish between chemical and infectious meningitis
in the postoperative neurosurgical patient. Empirical antibiotics with activity against skin flora,
especially S. aureus, α- and β-hemolytic streptococci, and gram-negative aerobic bacilli, should be
administered to postoperative neurosurgery patients with clinical or laboratory evidence of meningitis,
especially when CSF WBC is greater than 7,500 cells/µL, CSF lactate level is 4 mmol/L or more, or
temperature is 39.4°C or higher. If the patient did not receive antibiotics prior to lumbar puncture and the
CSF culture remains negative after 2 to 3 days, antibiotics can be discontinued (132). See section on shunt
infection for recommended antibiotics and dosing schedule. In a study of children who underwent
posterior fossa surgery, initiation of dexamethasone therapy immediately following surgery decreased the
prevalence of chemical meningitis from 70% to 30.5% and was not associated with an increased risk for
DURAL PUNCTURE
Potential complications of lumbar puncture (LP) include post-LP headache, meningitis, cranial
neuropathy, subdural or epidural bleeding, nerve root irritation, low back pain, and herniation of the brain
or spinal cord (134). Meningitis can also complicate dural puncture performed for spinal anesthesia,
myelography, or therapeutic purposes (135–137).
Although LP can potentially introduce infection into the CNS, the incidence of this complication is low;
less than 100 cases of meningitis complicating LP have been reported over the past 50 years (138,139). In
one study, only one case of meningitis occurred in 5,000 patients who underwent spinal or epidural
anesthesia (136). Of the reported cases of meningitis complicating dural puncture, only three deaths have
been reported, suggesting meningitis occurring in this setting may be recognized and treated earlier, may
be less severe than community-acquired meningitis (which has a mortality rate between 3% and 29%), or
may be caused by less virulent organisms (140,141). Some patient populations with increased risk of
bacteremia, such as women in labor and immunocompromised patients, may have an increased risk for
iatrogenic meningitis following dural puncture (136).
Not enough data are available to determine if LP performed on a bacteremic patient increases the risk
of meningitis (142). In one study, no statistically significant difference in incidence of meningitis was
noted between patients who did or did not receive an LP during bacteremia, suggesting infection was not
introduced by dural puncture or contaminated blood introduced with the spinal needle through the
puncture site (143). However, a study of 40 bacteremic rats found meningitis occurred only in rats that
underwent dural puncture; rats who received one dose of antibiotics prior to dural puncture did not
develop meningitis (144). A study of animals injected intravenously with bacteria prior to LP
demonstrated that meningitis occurred only in animals that received an LP (145).
Etiology
Although no study has demonstrated introduction of skin flora directly through an LP needle, clusters of
meningitis cases occurring after LP or epidural catheter placement performed by the same operator
suggest organisms may be introduced through disruption of sterile technique (146–148). Droplet
transmission as a cause of iatrogenic meningitis is supported by a study that used PCR assays to match
isolates of Streptococcus salivarius from a patient who developed meningitis following LP with isolates
from a throat swab of the neurologist who performed the LP (149). An alternative hypothesis for entry of
bacteria into the CSF during dural puncture is an increase in blood–brain barrier permeability induced by
decreased pressure following removal of CSF (150).
As with any dura-disrupting procedure, iatrogenic CNS infection complicating dural puncture is most
often caused by normal skin flora, the most common of which are normal commensal flora of the upper
respiratory tract and mouth, such as the α- and β-hemolytic streptococci. Culture of skin surrounding LP
sites have detected streptococci and other bacteria, consistent with the hypothesis that patients who
develop post–dural puncture meningitis acquire the organism from skin flora introduced with the spinal
needle (151). Culture of spinal needles immediately after dural puncture revealed bacterial contamination
in 17.9% of the needles, mostly by coagulase-negative staphylococci (87.5%) (152). The most frequently
identified species of α-hemolytic streptococci from patients with iatrogenic meningitis include S.
salivarius, Streptococcus mitis, and Streptococcus sanguis (153). Outside the setting of post–dural
puncture meningitis, α-hemolytic streptococci (e.g., S. salivarius, S. mitis, S. sanguis, Streptococcus
intermedius, Streptococcus faecalis, and Streptococcus bovis) have been isolated from patients with
meningitis and concomitant brain abscess, while β-hemolytic streptococci (groups A, B, C, and G, or
Streptococcus agalactiae, Streptococcus durans, Streptococcus pyogenes, Streptococcus zymogenes)
have been isolated from patients with meningitis and underlying endocarditis (154). Meningitis caused by
α-hemolytic streptococci most often follows a procedure requiring prolonged dural penetration, such as
spinal anesthesia or myelography, but is uncommon after a short procedure, such as LP (155). The
majority of epidural abscesses following temporary epidural catheters are caused by Staphylococcus
aureus (156).
Clinical Symptoms
Symptoms of iatrogenic meningitis are similar to those occurring with nosocomial meningitis and may
include headache, neck pain or stiffness, and, less frequently, mental status change; symptoms typically
develop within the first day after dural puncture (145). Epidural abscess after placement of a temporary
epidural catheter typically occurs within 5 days of placement, and the majority of patients develop fever,
low back pain, and neurologic deficits; in one study, 11 of 22 (50%) patients developed sensory deficits
in the lower limbs, 9 of 22 (41%) patients developed weakness or paralysis of the legs, and 8 of 22
(36%) developed bladder dysfunction (158). Meningismus occurred in only 4 of 22 (18%) patients.

Diagnosis of iatrogenic meningitis following dural puncture can be problematic; CSF WBC count may
increase during infection, chemical meningitis, or trauma. An early study of CSF from patients who
underwent spinal anesthesia, but who did not develop meningitis, noted pleocytosis in 65% of patients at
24 hours, 30% at 48 hours, and 18% at 72 hours; the highest cell count in this study was 1,950 cells/mm3
(157). Distinguishing between an infectious or noninfectious etiology of meningitis should be based on
CSF examination and culture. As opposed to the positive Gram stain rate of 60% to 71% encountered in
patients with community-acquired meningitis, Gram stain is positive in only 42% of patients with
iatrogenic bacterial meningitis (158–160).

There are many indications for dural puncture, and the incidence of CNS infection following dural
puncture is low. Adherence to sterile technique reduces the risk of introducing infectious agents into the
subarachnoid, arachnoid, or epidural spaces (161). Although proper sterile technique can reduce
introduction of skin flora into the spinal canal, performance of dural puncture through an infected lumbar
area increases the risk of introducing a bacterial pathogen and should be avoided; an alternative is to use
cisternal puncture under fluoroscopic guidance.
If prolonged presence of a catheter within the epidural space is anticipated, surgical masks may reduce
the introduction of α-hemolytic streptococci. In addition, some experts recommend wearing surgical
masks during dural puncture if the operator anticipates prolonged talking; studies have isolated oral flora,
such as α-hemolytic streptococci, from the majority of agar plates placed 30 cm from subjects who spoke
while not wearing surgical masks but not from any plates near subjects who spoke while wearing surgical
masks (162).
Treatment of iatrogenic meningitis associated with dural puncture should be guided by the sensitivities
of the suspected etiologic agent. Less than half of the α- or β-hemolytic streptococci causing iatrogenic
meningitis are highly susceptible to penicillin therapy; the majority demonstrate intermediate or high
resistance. Among antibiotic-resistant species, S. mitis most often has the highest level of resistance. In
addition, 15% to 20% of α-hemolytic streptococci are resistant to ceftriaxone (163), implying that an
alternate antibiotic, such as vancomycin, should be administered in addition to ceftriaxone when
iatrogenic meningitis is suspected.
NEUROSURGICAL-RELATED PRION DISEASE

Creutzfeldt-Jakob disease (CJD) is a rare, fatal neurodegenerative disease that occurs due to the
transformation of normal prion protein (PrPc) into an abnormal form (PrPSc). This transformation
produces a protein structure that is resistant to proteolytic digestion. Replication of the abnormal protein
leads to accumulation of toxic protein derivatives such as amyloid and pathologic changes resulting in
extensive spongiform changes throughout the brain.
Sporadic CJD is the most common form of prion disease, occurring in about one case per million
people worldwide. This form has an unknown etiology and affects patients 60 to 80 years of age. Patients
present with a rapidly progressive dementia, with death typically occurring within 6 months. Inheritable
forms of CJD are associated with mutations in the prion protein gene (PRNP), as well as Gerstmann-
Sträussler-Scheinker disease and fatal familial insomnia. There are two acquired forms of CJD: variant
and iatrogenic. The variant form is typically transmitted through exposure to bovine spongiform
encephalopathy or less commonly from sheep and affected deer. This type tends to affect a younger
population in the third decade of life with duration of about 1 year (164).
The majority of iatrogenic CJD transmission has been associated with the use of growth hormone or
transplanted dura. These tissues came mainly from infected cadavers. Cases associated with contaminated
neurosurgical equipment, corneal transplantation, intracranial electroencephalogram (EEG) leads,
gonadotrophic hormone, and transmission via blood transfusion have also been described (164). Cases
associated with blood transfusions are controversial due to small sample sizes and long incubation times
(165). The incubation period can be years to decades. Once the identification of iatrogenic CJD was
made, prompt education, disinfection methods, and blood screening have nearly eradicated the disease
(166).
CONCLUSION
Iatrogenic CNS infections are uncommon but important complications in patients following neurosurgical
device implantation such as VP shunt, external ventricular drainage, or lumbar drain placement. Infection
occurs less commonly following craniotomy or dural puncture. The majority of pathogens identified in
patients with such CNS infections are commensal organisms of the skin or oropharynx, particularly gram-
positive organisms. Identification of the responsible pathogen, as well as differentiation from aseptic
sequelae of neurosurgical procedures, typically requires a combination of physical examination,
neuroimaging, and CSF examination. Empirical treatment of suspected CNS infection should include
antibiotics with activity against pathogenic organisms most commonly encountered.
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PART IV ■ CENTRAL NERVOUS SYSTEM
SYNDROMES MEDIATED BY BACTERIAL TOXINS
CHAPTER 36 BOTULISM
JAMES D. MARKS
Botulism is a rare but life-threatening disease caused by spore-forming bacteria of the Clostridium genus,
including Clostridium botulinum, Clostridium baratii, and Clostridium butyricum (1). The disease
results from bacterial secretion of botulinum neurotoxin (BoNT), the most poisonous substance known
(2). Approximately 7 pg of pure neurotoxin is the median lethal dose (lethal to 50% of the test group)
(LD50) for a mouse, and it has been estimated that the human LD50 is approximately 0.09 to 0.15 µg
intravenously, 0.7 to 0.9 µg inhalationally, and 70 µg orally (3–6).
Botulism is characterized by prolonged paralysis, which if not immediately fatal requires prolonged
hospitalization in an intensive care unit and mechanical ventilation. The potent paralytic abilities of the
neurotoxin have also resulted in its development as a biowarfare and biothreat agent (7), as well as a
medicine to treat a range of overactive muscle conditions including cervical dystonias, cerebral palsy,
posttraumatic brain injury, and poststroke spasticity (8). The toxin is also used cosmetically, for example,
to treat wrinkles (9).
Clostridial organisms produce eight neurotoxins that differ significantly from each other in their amino
acid sequences, resulting in the elicitation of different antibody responses. The different antibody
responses allow the neurotoxins to be classified into different serotypes; antibodies that recognize one
serotype do not recognize other serotypes. Of eight neurotoxin serotypes (A, B, C, D, E, F, G, and H)
(10–12), five (A, B, E, F, and H) cause naturally occurring human botulism (7,12).
Naturally occurring botulism can result from ingestion of preformed toxin (food botulism) or from toxin
produced in situ due to wound infection (wound botulism) or colonization of the gastrointestinal tract
(infant or intestinal botulism). Botulism can also occur in exposed laboratory workers or from an
overdose of therapeutic neurotoxin. In addition, the BoNTs are classified by the Centers for Disease
Control and Prevention (CDC) as one of the six highest risk threat agents for bioterrorism, because of
their extreme potency and lethality, ease of production and transport, and need for prolonged intensive
care (7). Intoxication can occur via oral ingestion of toxin or inhalation of aerosolized toxin (13,14).
Although only five of the neurotoxin serotypes cause natural human disease, aerosolized neurotoxin
serotypes C, D, and G produce botulism in primates by the inhalation route (13) and would most likely
also affect humans. Thus, any one of the eight neurotoxin serotypes can be used as a biothreat agent.
Because of the severity of illness and the potential for outbreaks, both food-borne and biothreat botulism
are public health emergencies.
ETIOLOGY
History and Types of Botulism
Each type of human botulism (food-borne, wound, infant, intestinal, inadvertent, or bioterror) is
associated with different epidemiology and pathogenetic mechanisms. The name of the disease is derived
from the Latin botulus (sausage), a food responsible for many early outbreaks of botulism. “Sausage
poisoning” was recognized in Europe as early at the eighteenth century (15), with van Ermengem clearly
describing the bacteriologic and toxicologic basis of the disease in 1897 in an outbreak in Belgium
resulting from inadequately cured ham (16). The first recognized case of botulism in the United States
occurred in 1899 and was caused by a beef tamale (15). Food botulism was the most common form of
botulism in the United States prior to 1980.
Infant (or intestinal) botulism was first described in 1976 by two groups (17,18) and is now the most
frequently reported type of botulism in the United States
(http://www.cdc.gov/nationalsurveillance/PDFs/Botulism_CSTE_2011.pdf). Wound botulism was first
described in the United States in 1951, with initial cases primarily due to traumatic wounds of the
extremities (19). More recently, the incidence of this form of botulism has increased and has been
associated with injection drug users injecting black tar heroin (20). An adult variant of infant botulism,
varyingly called botulinal autointoxication, hidden, adult intestinal, or adult infectious botulism, was
first described in 1979 (21,22). Inadvertent botulism results from unintentional exposure and typically
occurs in laboratory workers (23) and in patients receiving therapeutic BoNT (24). Although successful
use of neurotoxin as a bioterror agent has not occurred, the Japanese cult Aum Shinryko unsuccessfully
released BoNT on at least three occasions (7).
Clostridial Bacteriology
C. botulinum can be classified into at least four genetically and phenotypically diverse groups (I through
IV) (25,26). Although these groups are different enough to be classified as separate species, they have all
been classified as C. botulinum because they share the common feature of neurotoxin production. The
organisms in group I are referred to as proteolytic and the organisms in group II as nonproteolytic, based
on their ability to digest complex proteins. All serotype A strains are group I, serotype B and F can be
produced by either group, and serotype E is produced by group II strains. Serotypes C and D are both
produced by group III organisms. Type C is found in avian species, occurring in domestic flocks and
massive outbreaks in wild waterfowl (27–29). Type C also occurs in other animals such as dogs, mink,
and cattle. Type D outbreaks are rare and associated with cattle (30). A single human outbreak of type C
and type D food botulism have been reported (31,32). Group IV was created to accommodate an organism
isolated from a soil sample in Argentina that produces a unique neurotoxin (type G) that causes a flaccid
paralysis in mice (33,34). No human cases of type G botulism have been reported, although it has been
isolated from autopsy specimens (35). Recently, the name Clostridium argentinense has been proposed
for group IV clostridia (36). Two additional clostridial species, C. butyricum and C. baratii produce
neurotoxins E (37,38) and F (39,40), respectively. Finally, rare stains of clostridia have been reported
that cause human clinical disease and secrete more than one toxin, for example, A and B (Ab), A and F
(Af), B and F (Bf), B and A (Ba), and B and H (Bh) (12,26,41–44).
Neurotoxin Structure and Function
The protein neurotoxin is secreted as a single polypeptide chain of approximately 150 kDa, which is
nicked by proteases to form a 100-kDa heavy chain and a 50-kDa light chain connected by a single
disulfide bond. The sequences of the genes encoding neurotoxin serotypes A (45–47), B (48,49), C (50),
D (51), E (52), F (53,54), and G (55) have been determined. Although these toxins differ by as much as
65% at the amino acid level (Table 36.1), it is likely that they share the same general protein structure
(11). Significant sequence variability has also been observed within toxin serotypes, the so-called
subserotypes (45,47–49,56–58). The most diverse subserotypes are those for serotype A (up to 16%
different at the amino acid level) and serotype F (up to 36% different at the amino acid level) (57,58).
Such changes account for the reported differences in the ability of monoclonal and polyclonal antibodies
to bind and neutralize BoNTs from different strains (56,59–62).
The x-ray crystal structures of types A, B, and E neurotoxins have been solved at high resolution (Fig.
36.1) (63–66). The structural studies, combined with functional studies, provide clear insight into how the
BoNTs interfere with normal release of the neurotransmitter acetylcholine resulting in flaccid paralysis
(Fig. 36.2). The C-terminal portion of the heavy chain (HC) comprises the receptor binding domain,
which binds to cellular receptors on presynaptic neurons, resulting in toxin endocytosis (67,68) (Figs.
36.2A and B). Specific cellular receptors have been identified for the BoNTs, with cellular binding and
entry requiring two co-receptors, a protein and a sialoganglioside such as GD1b or GT1b (68–71) (Fig.
36.3). The binding domain consists structurally of an N-terminal subdomain (HCN) consisting of a jelly
roll motif and a C-terminal subdomain (HCC) consisting of a β-trefoil motif. The HCC of the binding
domain comprises the protein receptor-binding site as well as the ganglioside-binding site (63) (Fig.
36.3). In BoNT/A, B, E, F, and G, ganglioside binding occurs in a conserved binding pocket in the HCC
(Fig. 36.3) (65,72,73). BoNT/C and BoNT/D have two ganglioside-binding sites, one of which is located
in the conserved binding pocket used by the other BoNTs. After ganglioside binding, a second binding
event occurs to one of several synaptosomal proteins. BoNT/A, BoNT/D, BoNT/E, and BoNT/F bind
synaptic vesicle 2 (SV2), whereas BoNT/B and BoNT/G bind synaptotagmin-1 and -2 respectively
(64,74–79).
The N-terminal portion of the heavy chain (HN) (Fig. 36.1) comprises the translocation domain, which
consists of alpha helices and is involved in pore formation. It is hypothesized that the lower pH level of
the endosome induces a conformational change in this domain, which creates a pore allowing the light
chain to escape the endosome (Fig. 36.2). The light chain (Fig. 36.1) is a zinc endopeptidase that,
depending on serotype, cleaves different members of the soluble N-ethylmaleimide–sensitive factor
attachment protein receptor (SNARE) family of proteins, resulting in blockade of neuromuscular
transmission (80,81) (Fig. 36.2). The SNAREs are essential for normal fusion of the synaptic vesicle and
acetylcholine release (Fig. 36.2). Toxin serotypes A and E cleave distinct sites within SNAP-25
(synaptosomal-associated protein of 25 kDa) (81–84), serotypes B, D, F, and G cleave distinct sites
within vesicle-associated membrane protein (VAMP, also known as synaptobrevin) (80,81,85–88) and
serotype C cleaves syntaxin and SNAP-25 (Fig. 36.2B) (89,90). These three SNARE proteins (syntaxin,
SNAP-25, and synaptobrevin) interact to form a four-helix coiled coil in a step that precedes synaptic
fusion (91) (Fig. 36.2). Cleavage of any one of these proteins blocks fusion and acetylcholine release
leading to a flaccid paralysis.
BoNTs are secreted from clostridial species as progenitor toxin complexes (PTCs) ranging in size up
to 900 kDa (92,93). These complexes consist of the neurotoxin and a number of proteins collectively
called neurotoxin-associated proteins (NAPs). The NAPs include three proteins classified as
hemagglutinins (HA70, HA17, and HA33) (94,95), because of their ability to agglutinate red blood cells,
and other proteins termed nontoxin nonhemagglutinins (NTNH) (53,96). Recently, the x-ray crystal
structure of NTNH complexed to BoNT/A was solved showing that NTNH has the same general structure
as BoNT/A, packs tightly against BoNT/A in a manner like a “handshake,” and protects it from low pH
denaturation and proteolysis in the gastrointestinal (GI) tract (Fig. 36.4) (97–99). The structure of a 760-
kDa PTC has recently been solved showing a bimodular structure that the authors liken to an Apollo lunar
module (Fig. 36.4). The “ascent stage” is a 280-kDa complex of BoNT/A and NTNH that protects BoNT
from GI destruction, and the “descent stage” is a 470-kDa module composed of HA17, HA33, and HA70
that mediates absorption of BoNT by binding to host carbohydrate receptors in the GI tract (100,101).
Botulism is underdiagnosed and often misdiagnosed, often as Guillain-Barré or Miller-Fisher syndrome,
myasthenia gravis, poliomyelitis, intoxications, or disease of the central nervous system (CNS) (Table
36.2) (7,102). Common and uncommon misdiagnoses are listed in Table 36.2, along with features that
distinguish botulism from these diseases. Common signs and symptoms of botulism are listed in Table
36.3 and discussed further in the section on clinical diagnosis. Botulism is much more likely to be
associated with outbreaks (cluster of cases) than other diseases with which it may be confused. This fact
emphasizes the importance of prompt reporting of suspected botulism cases to the public health
department. Botulism differs from other flaccid paralyses in (a) its prominent cranial nerve involvement
disproportionate to weakness below the neck, (b) the symmetry of the weakness, and (c) the absence of
sensory changes, although approximately 14% of patients report paresthesias (Table 36.3).
EPIDEMIOLOGY
In the most recent report from 2011 of the types of U.S. botulism cases, the CDC documented a total of
140 confirmed cases of botulism; 73% of cases were infant botulism, 20% food-borne, 13% wound, and
4% of unknown etiology (http://www.cdc.gov/nationalsurveillance/PDFs/Botulism_CSTE_2011.pdf).
Food-Borne Botulism
Food-borne botulism is usually associated with ingestion of preformed toxin in home canned products,
most frequently foods low in acid such as vegetables, fish or marine mammals, condiments, and meat
products. Fruits are rarely involved, because of their high natural acidity. Outbreaks have also been
reported from commercially prepared products (103,104) and from food prepared in restaurants
(105,106). In the United States, the incidence of food-borne botulism is highest in Alaska, where the
vehicle is typically native Alaskan foods consisting of fermented or salted fish or marine mammal
products (107). In other countries, different types of foods predominate (108,109). In Germany, Italy,
France, and Poland, meats such as home-cured hams are the most frequently implicated foods. In Canada,
Japan, and Scandinavia, outbreaks are usually associated with fish products.
Food-borne botulism usually occurs in outbreaks where multiple individuals ingest contaminated food.
From 1899 to 1996, 921 outbreaks of food-borne botulism were reported to the CDC, with a relatively
constant incidence of approximately 9.5 outbreaks per year, with an average of 2.5 cases per outbreak (1).
The largest number of cases in a single food-borne outbreak was 59. From 1899 to 1996, 2,368 cases of
food-borne botulism were reported; of these, 1,281 were reported between 1899 and 1949, and 1,087
were reported from 1950 to 1996. Between 1899 and 1949, the case-fatality ratio was approximately
60%. Since 1950, the mortality rate has decreased significantly to approximately 5.7% between 1990 and
1996. This decrease is attributed to improvements in respiratory intensive care and early administration
of antitoxin.
Food-borne botulism is typically caused by type A, B, and E neurotoxins. Of the 1,087 cases of food-
borne botulism reported between 1950 and 1996, the toxin type could be determined for 786; of these,
52% were type A, 22% were type B, 25% were type E, and less than 1% were type F (1). Type A
botulism is most common west of the Mississippi River, type B is most common east of the Mississippi,
and type E botulism predominates in Alaska (1,110). This distribution corresponds to the distribution of
C. botulinum spores in the soil (111–114). Three outbreaks of type F botulism have been reported in the
United States, with one of these due to home-prepared venison jerky (1). In 2011, 70% of the 20 reported
food-borne botulism cases were of type A, 25% type E, and 5% type F
(http://www.cdc.gov/nationalsurveillance/PDFs/Botulism_CSTE_2011.pdf).
Improvements in food-processing techniques have significantly reduced, but not eliminated, food-borne
outbreaks from commercially prepared foods. Those that do occur are associated with inadequate
pasteurization or breaks in the refrigeration chain (115). Outbreaks from home canning still occur and can
best be prevented by adhering to the recommended canning techniques. C. botulinum spores are not killed
by heating at 100°C, so pressure cooking is essential. BoNT, unlike spores, is heat labile and can be
destroyed by heating to 80°C (176°F). Thus, thoroughly heating home-canned foods before eating them
can reduce the risk of botulism.
Infant Botulism
Infant botulism was first reported in 1976 (17,18) but likely existed as a clinical entity before this date
(116). This form of botulism is now the most frequent type of botulism in the United States. Infant
botulism is distinct from food-borne botulism, being caused by the colonization (infection) of the
intestines with clostridial strains and the subsequent in situ production of toxin, rather than the ingestion of
preformed toxin. Between 1976 and 1996, 1,442 cases were reported to the CDC (1). The mean age at
onset was 13 weeks, with a range of 1 to 63 weeks, and males and females were equally affected. The
incidence of infant botulism has been essentially stable since 1980, with an average annual incidence of
approximately 1.9 per 100,000 live births. Since 1976, the highest incidence of infant botulism has been
in Delaware, Hawaii, Utah, and California, with almost half of reported cases from California. Reasons
for the geographic variation are unknown.
Infant botulism has been reported from at least 14 countries worldwide including Argentina, Australia,
Japan, Canada, Italy, the United Kingdom, Chile, the former Czechoslovakia, France, Spain, Switzerland,
Sweden, and Taiwan (117; S.S. Arnon, personal communication, May, 2013). In the United States in 2011,
40% of the 102 reported infant botulism cases were type A, 60% were type B, and one case resulted from
infection with a bivalent Ba strain. There have been rare reports of infant botulism caused by other
serotypes and strains, including one case in Japan caused by type C toxin (118), multiple cases in the
United States caused by C. baratii–producing type F toxin (26,39), and multiple cases in Italy caused by
C. butyricum–producing type E toxin (37,38). Cases have also occurred due to production of multiple
toxins; infant botulism cases have been reported from the United States and the United Kingdom where
both types B and F are produced (Bf) (26,42) and from the United States where types B and A are
produced (Ba) (41,43).
The primary source for clostridial spores is the environment. Clustering of some cases of infant
botulism has been reported in the eastern United States and in small towns and rural areas of the western
United States (119–122). In approximately 20% of cases, there was a history of honey ingestion prior to
the development of botulism, and spores of the same type could be cultured from the honey (119,123,124).
Infants with botulism are more likely to have been breast-fed (124–127), which in experimental models
can alter the fecal flora differently than formula feeding and increase susceptibility to C. botulinum
colonization (128).
A tentative link exists between infant botulism and some cases of sudden infant death syndrome (SIDS).
C. botulinum spores could be found in 5% of 211 necropsy specimens from SIDS cases in California,
with toxin detected in 2 of 10 culture-positive cases (129,130). Toxin or clostridial organisms have been
reported in a number of SIDS cases from Switzerland (131), Italy (132), and Germany (133), but not from
Australia (134). Thus, infant botulism may account for a small percentage of SIDS cases, perhaps
especially in North America and Europe.
Wound Botulism
Wound botulism, first described in 1951, is a rare disease caused by the growth of C. botulinum in
contaminated wounds with in situ toxin production. Through 1985, 33 cases of wound botulism were
reported in the United States; 25 of these cases were laboratory confirmed, with 17 cases type A and 7
cases type B (1). One case was a mixture of type A and B. Eighty-one percent of the cases occurred in
males with a mean age of 21 years. Wounds were typically deep with necrotic areas and associated
compound fractures. The median incubation period in trauma cases was 7 days, with a range of 4 to 21
days (135). Since 1980, most cases of wound botulism have occurred in users of illicit drugs. In these
individuals, infection is associated with either drug injection or chronic cocaine sniffing with nasal or
sinus involvement (136). From 1986 to 1996, 78 cases of wound botulism were reported in the United
States, most linked to injection of “black tar” heroin (1). Sixty-six cases were type A, nine were type B,
and the remainder of unknown type. The median age of the patients was 38 years and 60% were men. In
2011, all of the 13 reported wound botulism cases were type A and 11 of the 13 patients were injection
drug users.
Child or Adult Botulism from Intestinal Colonization
Isolated cases of botulism in adults without a clear food-borne etiology have been reported to the CDC
since 1978. These cases appear to be caused by colonization of the GI tract by C. botulinum or C. baratii
with in vivo toxin production as occurs for infant botulism (21,137). In some cases, patients had a history
of GI surgery or inflammatory bowel disease, which may have predisposed them to colonization (22).
Inadvertent or Intentional Botulism
A single incidence of botulism in three laboratory workers has been reported in the literature, which
resulted from the inhalation of powdered BoNT (23). Inadvertent botulism can also occur when large
doses of medicinal BoNT are injected for therapeutic indications (24,138). As the market for medicinal
BoNT has increased, counterfeit BoNTs (139) and highly potent amounts of BoNTs intended for research
purposes have made their way into clinical use, increasing the risk for overdose and the development of
botulism (140).
Botulinum toxin has already been released as a bioterror agent, albeit unsuccessfully, by the Japanese
cult Aum Shinryko (7). Both Iraq and the former Soviet Union produced BoNT for use as weapons
(141,142). Iraq produced 19,000 L of concentrated BoNT, of which 10,000 L were weaponized in missile
warheads or bombs (141,143). Exposure of even a small number of civilians to BoNT would overwhelm
the health care delivery system of any metropolitan center. Treatment of botulism requires prolonged
intensive care unit (ICU) hospitalization and mechanical ventilation. With the downsizing and closing of
hospitals, most ICUs run at 80% to 100% occupancy. In San Francisco, for example, there are
approximately 210 ICU beds, with an average occupancy rate of greater than 90%. As few as 30 cases of
botulism would fill all empty ICU beds and occupy them for up to 6 weeks. This would eliminate
availability of ICU beds for postoperative patients requiring ICU care, such as organ transplantation,
neurosurgery, cardiac surgery, and traumatic injuries. Patients requiring such operations would represent
“collateral damage,” with necessary surgery postponed or transferred to outlying hospitals. Major
civilian exposure to BoNT would have catastrophic effects. One study estimated that aerosol exposure of
100,000 individuals to toxin, as could occur with an aerosol release over a metropolitan area, would
result in 50,000 cases with 30,000 fatalities (144). Such exposure would result in 4.2 million hospital
days and an estimated cost of $8.6 billion. In this study, the most important factors reducing mortality and
cost were early availability of antitoxin and mechanical ventilation (144). Such treatment could reduce
deaths by 25,000 and costs by $8.0 billion.
The intentional release of botulism is most likely to be associated with the outbreak of a large number
of cases of flaccid paralysis with prominent bulbar palsies. Other features may include an outbreak with
an unusual toxin type (C, D, F, or G), an outbreak with common geographic features but without a common
dietary exposure, or multiple simultaneous outbreaks with no common source. The incubation period for
intentional botulism is unknown but is likely related to the route of exposure and amount of toxin
administered. For oral exposure to toxin, one may obtain some idea of the incubation period from the
food-borne botulism literature (see earlier discussion). It is difficult to know precisely the incubation
period for aerosol exposure to botulinum toxin due to the paucity of data. In one study, monkeys exhibited
signs of intoxication 12 to 80 hours after aerosol exposure with 4 to 7 monkey LD50s (4). The incubation
period for the three known cases of human botulism via the inhalation route was 72 hours (23).
CLINICAL HISTORY, SYMPTOMS, AND FINDINGS OF

BOTULISM
The diagnosis of botulism is made clinically, with laboratory findings and confirmation not usually
immediately available. The clinical syndrome of botulism is dominated by neurologic signs and symptoms
resulting from blockade of cholinergic neurotransmission (102,127,135). Patients with botulism usually
present with acute onset of weakness in muscles innervated by the cranial nerves, leading to diplopia,
dysphonia, dysphagia, and dysarthria (Table 36.2). In mild cases, no other symptoms may develop. In
more severe cases, symmetric weakness progresses in a descending manner, leading frequently to
paralysis. If the illness is severe enough, the respiratory muscles are involved leading to ventilatory
failure and death unless intubation and mechanical ventilation are instituted. In one series, intubation was
required in 67% of type A botulism, 52% of type B botulism, and 39% of type E botulism (145). Patients
may also have evidence of autonomic dysfunction including dry mouth, blurred vision, orthostatic
hypotension, urinary retention, and constipation. Sensory abnormalities are usually absent, because only
motor and autonomic nerves are affected. Similarly, mental function is usually not affected.
Paralysis from botulism can be quite long lasting. Mechanical ventilation may be required for 2 to 8
weeks with food-borne botulism, and paralysis lasting as long as 7 months has been reported (102).
Symptoms of cranial nerve dysfunction and mild autonomic dysfunction may persist for more than a year
(146–148). In infants, hospital stay averages 1 month, with serotype A causing longer lasting disease (5.4
weeks average hospitalization) than serotype B (3.8 weeks average hospitalization) (149). There is
experimental evidence that neurotoxin catalytic activity persists at the nerve terminal for days to more
than a month, especially for serotypes A, B, and C, and that recovery initially results from the sprouting of
new neuromuscular connections (150,151).
Food-borne botulism has an incubation period of 6 hours to 10 days (152), with most cases developing
evidence of disease between 18 and 72 hours after ingestion of contaminated food (102,145). GI
symptoms are common with food-borne botulism, including abdominal pain, nausea, vomiting, and
diarrhea. The GI symptoms may result from ingestion of other bacteria or their toxins. Death occurs in 5%
to 10% of patients with food-borne botulism; early deaths result from failure to recognize the disease, and
late deaths from complications of long-term mechanical ventilation and ICU care (102).
Infant botulism is initially characterized by constipation, which may precede the development of
neurologic symptoms by 1 to 3 weeks, followed by lethargy, poor feeding, and increasing weakness.
Other early symptoms include decreased suckling and crying, and neck and peripheral weakness. Because
infants are not able to complain, mild symptoms may be missed, leading to a clinical presentation
associated with a sudden onset of severe paralysis progressing rapidly to respiratory failure. Treatment
with aminoglycoside antibiotics may promote or worsen neuromuscular weakness in infant botulism (153)
and is associated with an increased need for mechanical ventilation. The mortality rate for treated infant
botulism is less than 2% and in one large series was 0% (149).
Wound botulism presents similarly to food-borne botulism, but without the GI symptoms or signs. There
is a history of a wound infection and usually injection or intranasal drug use. Inadvertent botulism occurs
in laboratory workers who work with toxin or in patients who have been treated with medicinal BoNT.
Bioterror release of toxin must be considered in any outbreak of botulism.
LABORATORY FINDINGS
The diagnosis of botulism should be based on the history and physical findings because routine laboratory
tests are not particularly helpful in confirming the clinical suspicion of botulism and specific confirmation
takes days. The complete blood count, electrolyte panel, renal and liver function tests, urinalysis, and
electrocardiogram will all be normal unless complications have occurred. The cerebrospinal fluid (CSF)
is typically normal in botulism, whereas the CSF protein is usually elevated in Guillain-Barré syndrome.
The Tensilon test is usually, but not always (152), normal in botulism and may be helpful in distinguishing
botulism from myasthenia gravis. The computed tomographic (CT) scan of the head is also normal in
botulism and can be used to rule out stroke or other intracranial diseases.
Patients with botulism have normal motor nerve conduction velocities and distal latencies. The
electromyogram (EMG), however, may be helpful in the diagnosis of botulism and in distinguishing it
from other neuromuscular diseases such as myasthenia gravis and Guillain-Barré syndrome (154–157). In
botulism, the EMG of involved muscle groups reveals decreased amplitude of the muscle action potential
and facilitation during rapid repetitive or posttetanic stimulation, as can also be seen in patients with
Eaton-Lambert syndrome.
Specific laboratory confirmation requires demonstration of toxin in the blood or GI tract and, in the
case of food-borne, infant, or wound botulism, culture of clostridial species from stool or wounds (158).
Currently, testing for the presence of toxin is available only at the CDC and approximately 20 state and
municipal public health laboratories (1). The most sensitive assays for neurotoxin are the mouse bioassay
and the use of mass spectrometry. The mouse bioassay is performed by injecting mice intraperitoneally
with the toxin-containing sample (serum, stool, food extract, etc.) plus or minus polyclonal and type-
specific antitoxin. The mice are observed for 4 days for the development of botulism, with the mice
usually dying from botulism within 6 to 96 hours. Protection by simultaneous administration of antitoxin
enables determination of serotype. The mouse bioassay can detect as little as 7 pg of toxin (5), the mouse
LD50. Alternatively, mass spectrometry can be used for highly sensitive BoNT detection. BoNT is
captured out of complex matrices such as blood or stool on antibody-coated beads and then incubated
with substrate for the toxin catalytic domain. Substrate cleavage can be detected and quantitated with
sensitivities equal to or better than the mouse bioassay (159–162). Such mass spectrometry assays are
used alongside the mouse bioassay at the CDC and are likely to be rolled out to the Laboratory Response
Network. Higher throughput in vitro tests to detect BoNT, especially variants of enzyme-linked
immunosorbent assays (ELISA), are under development but have not been validated (163–165) and have
sensitivities generally less than that of the mouse bioassay.
Simultaneously with collection of blood for serologic studies, stool or wound fluid can be cultured for
the presence of clostridial species in the cases of botulism occurring via the oral or wound route.
Unfortunately, current laboratory tests have not been particularly sensitive for the diagnosis of botulism.
Clostridial cultures were positive for 51% of stool specimens collected from 309 patients with clinically
suspected botulism (145). Toxin testing was positive in only 37% of sera and 23% of stool specimens. At
least one laboratory test was positive in 65% of patients (145). Collecting samples early in the course of
disease increases the likelihood of positive results. However, large outbreaks have occurred in which no
specimens or a low percentage of specimens gave positive results (166). It can also take days for cultures
or toxin testing results to be available. An alternative means of diagnosis is detection of bacteria or toxin
in source material, such as contaminated food. Because toxin prepared by terrorists is likely to be crude
and unpurified, it is possible that clostridial nucleic acids may be present on bioterror toxin preparations,
which could be amplified by polymerase chain reaction for analysis. Cultures and nucleic acid testing
would allow more specific classification of the precise Clostridial strain utilized. Because specific
therapy with antitoxin must be administered as rapidly as possible to be effective (see later discussion)
(167), specific antitoxin therapy must be based on the clinical diagnosis prior to laboratory confirmation.
TREATMENT
Treatment of botulism includes (a) early administration of botulinum antitoxin to prevent progression of
moderate illness or reduce the duration of mechanical ventilation in patients with rapidly progressive
severe botulism; (b) close monitoring of respiratory function (vital capacity and maximal inspiratory
force [MIF]) (168); and (c) intensive care for patients with significant paralysis and evidence of
respiratory insufficiency or failure. Vital capacity (VC) should be measured as soon as the diagnosis is
suspected and followed closely. In one study, 10 of 11 patients requiring mechanical ventilation had VCs
less than 30% of predicted value (169). Patients with VC less than 10 mL/kg should be monitored in an
ICU for progression of respiratory failure requiring mechanical ventilation (170). Patients requiring
mechanical ventilation obviously merit ICU care.
Treatment with antitoxin is the mainstay of therapy. In the United States, more than 80% of adults are
treated with antitoxin. Antitoxin is most effective when administered early in the course of disease and
prior to the development of respiratory failure (167). Once the toxin had entered the nerve terminal,
antitoxin cannot bind and neutralize it (10). Thus, antitoxin only works on circulating toxin. However,
antitoxin will remove any toxin remaining in the bloodstream as well as toxin that may continue to be
absorbed from the gut or respiratory tract, thus preventing further intoxication. In infant botulism, antitoxin
administered as late as 4 to 7 days after the clinical appearance of symptoms reduced morbidity, such as
length of stay (171). Thus, there is rationale for administering antitoxin even a week after the appearance
of symptoms. Antitoxin is immunoglobulin harvested from hyperimmunized horses (horse or equine
antitoxin) from which the Fc portion has been enzymatically removed (despeciation) to reduce the
incidence of side effects such as serum sickness and hypersensitivity reactions. The current licensed
equine antitoxin is heptavalent, having activity against serotypes A, B, C, D, E, F, and G (172,173). The
CDC should be contacted for information regarding these products. Efforts are underway to generate
human monoclonal antibodies that could replace equine antitoxin therapy (174–177).
Equine antitoxins are foreign proteins, and despite despeciation, there is a risk of hypersensitivity
reactions. For previous generations of equine antitoxin, the rate of these reactions was as high as 9% and
included serum sickness and anaphylaxis (178). The latest generation heptavalent botulism antitoxin
(HBAT) appears to be safer, with only one severe reaction (cardiac arrest) reported in the first 228
patients treated
(http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/Licens
There was one mild case of serum sickness, and it is recommended that patients be monitored for this and
other types of delayed hypersensitivity reaction for up to 21 days. Antitoxin can be obtained via the CDC
by contacting the local health department. A single 20-mL dose of antitoxin is recommended. The amount
of antitoxin in one 20-mL vial administered intravenously is enough to neutralize toxin amounts many
times in excess of those observed in patients with botulism. Antitoxin is diluted 1:10 in 0.9% saline and
administered slowly by the intravenous route. To minimize allergic reactions, the infusion rate should be
0.5 mL/min for the first 30 minutes and then 1 mL/min for the next 30 minutes, followed by a rate of 2
mL/min for the remainder of the infusion. Clinicians should review the package insert with public health
authorities before using antitoxin.
A second issue with equine antitoxins is that due to despeciation (removal of the Fc portion of the IgG),
HBAT has a very short serum half-life that varies depending on the serotype, ranging from 7.3 hours for
type E to 34 hours for type B. The half-life for type A is only 8.6 hours, and type F is 14 hours. As a
result, it is possible for the initial dose to be cleared from the circulation while BoNT is still being
absorbed systemically, for example, from the GI tract. This has led to relapse (rebound) botulism after
treatment with HBAT (61). Patients should be monitored for relapse and consideration given to redosing,
recognizing the potential for allergic reactions to the equine product.
Equine antitoxin is rarely administered to infants with botulism because of the risk of lifelong
hypersensitivity to equine antigens (117). In addition, there is some evidence that anaphylaxis may be
more severe in infants given equine antitoxin. As an alternative, human immunoglobulin prepared from
volunteers immunized with the investigational botulinum toxoid vaccine has been developed. This U.S.
Food and Drug Administration (FDA)–approved product, termed botulism immune globulin (BIG-IV),
has been evaluated in a prospective randomized trial in infant botulism. Infants with the clinical diagnosis
of botulism were randomized to receive either nonimmune human globulin or BIG-IV. Compared to
nonimmune globulin, BIG-IV significantly reduced the duration and cost of hospitalization, and the
duration of mechanical ventilation and tube feedings (149). This benefit appeared to accrue even in
patients treated as late as 5 to 7 days after the onset of symptoms as well as in those with ongoing toxin
production or slow clearance of toxin from the blood (S.S. Arnon, personal communication, May, 2013).
BIG-IV is available for treatment of infant botulism from the Infant Botulism Treatment and Prevention
Program (IBTPP; http://www.cdph.ca.gov/programs/ibtpp/Pages/default.aspx) of the California
Department of Public Health (CDPH) at 510-231-7600.
Botulism is a reportable disease, and suspected cases should be reported immediately to the hospital
epidemiologist or infection control practitioner as well as the local and state health departments. The
phone number of the health department can usually be found in the phone directory under government
listings or via the Internet at http://www.cdc.gov. If local or state health departments are not reachable,
the CDC can be contacted directly at 800-CDC-INFO (800-232-4636).
With respect to prevention, the risk of food-borne botulism can be reduced by adhering to proper
procedures for home canning, which are available from the U.S. Department of Agriculture Web site. The
risk of wound botulism can be reduced by avoiding the injection or inhalation of illicit drugs. Infant
younger than 12 months should not be fed honey to reduce the risk of infant botulism. For laboratory
workers who might be exposed to large amounts of botulinum toxin, an investigational pentavalent
(serotypes A, B, C, D, and E) toxoid used to be available from the CDC for immunization (179). This
product has been removed from clinical use by the CDC due to the severity of injection reactions and lack
of efficacy. A recombinant vaccine based on the toxin-binding domain for serotypes A and B is under
development (180).
ACKNOWLEDGMENTS
This work was partially supported by NIAID grants U01 AI075443, R01AI104579, R21 AI101539, U54
AI065359 and HHS contract HHSN272201100031C.
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CHAPTER 37 TETANUS
ITZHAK BROOK
Tetanus is a serious but preventable nervous system disorder caused by the toxin produced by
Clostridium tetani. Although the disease is rare in the industrial nations, it is still rampant in the
developing world. The isolations of the causative organism and its toxin were cornerstones in the history
of microbiology. Tetanus was one of the first bacterial conditions to be prevented by immunization,
representing a triumph in the application of research and public health measures.
Tetanus is an intoxication manifested mainly by neuromuscular dysfunction expressed as muscle spasms
and caused by tetanal exotoxin (tetanospasmin). Tetanus can present in one of four clinical forms:
generalized, local, cephalic, and neonatal. The goals of treatment are interruption of the production of
toxin, neutralization of the unbound toxin, controlling muscle spasms, management of autonomic
dysfunction, and appropriate supportive management. Active immunization with tetanus toxoid is the most
effective mean of protection.
HISTORICAL ASPECTS
Ancient physicians recognized the relationship between wounds and a disease producing spasticity,
violent movements, and death. Case 7 in the Edwin Smith Surgical Papyrus discusses a patient with a
penetrating skull wound who experiences trismus and nuchal rigidity (1). These findings were well
known to the Egyptian physician who used them to help formulate the prognosis. This is commonly
accepted as the earliest recorded description of tetanus. Hippocrates described the disorder clearly; and
his relative contemporary Aretaeus observed that these manifestations were “apt to supervene on the
wound of a membrane, or of muscles, or of punctured nerves, when, for the most part, the patients die; for,
‘spasm from a wound is fatal’” (2). Galen noted that cutting a nerve in tetanus stopped the movement but
paralyzed the innervated part.
The ensuing millennia saw some refinements in clinical observation. John of Arderne (1307 to 1380),
often thought to be the first English surgeon-author, described a case of tetanus in which trismus (“taken
with the cramp on his cheeks”) began 11 days after a gardening injury. In the eighteenth century, tetanus
was thought to be a consequence of nerve injury. However, the spasms of generalized tetanus were
frequently confused with the convulsions of epilepsy. Sir Charles Bell, a noted illustrator and a surgeon,
included a patient with tetanus infection in his 1824 text (3) (Fig. 37.1).
Neonatal tetanus (NT) was called the “7-day disease” in the Americas and was known as the “9-day
fits” in Dublin. In 1846, Sims proposed the “congestive” theory of neonatal tetanus. He thought that this
condition resulted from placing infants on their backs, which compressed the occiput and occluded the
veins of the medulla. Beumer determined that the umbilicus was the portal of entry for NT in 1887.
The clinical advances of the nineteenth century culminated in this description by Sir William Gowers
(4):
Tetanus is a disease of the nervous system characterized by persistent tonic spasm, with violent brief exacerbations. The spasm almost
always commences in the muscles of the neck and jaw, causing closure of the jaws (trismus, lockjaw), and involves the muscles of the
trunk more than those of the limbs. It is always acute in onset, and a very large proportion of those who are attacked die.
Gowers, and many of his contemporaries, felt that nontraumatic tetanus accounted for up to 20% of
cases; he blamed these on a sudden chill or a frightening episode. Although he recognized the similarity
between tetanus and strychnine poisoning, he disparaged the notion of pathophysiologic similarity. In one
of his few failures of insight, Gowers dismissed Nicolaier’s first report of a strychnine-like toxin isolated
from anaerobic soil bacteria (5). Six years later, Behring and Kitasato (6) proved that immunization with
an inactivated derivative of this bacterial extract prevented tetanus.
Effective therapeutic suggestions for established tetanus also date from the nineteenth century. In 1829,
Ceroli described the use of morphine as a treatment for tetanus. Based on the observations of Claude
Bernard, curare was employed with some rare successes (and some dramatic failures) in France (7),
Germany (8), the United States, and England. The lessons in long-term mechanical ventilation learned
during the poliomyelitis epidemics of the 1950s finally made treatment with neuromuscular blockade
feasible. Hutchinson and Jackson (9) of the National Hospital at Queen Square discussed the use of ether
in tetanus in 1861. Meltzer and Auer (10) employed magnesium salts to treat tetanus patients at the dawn
of the twentieth century. Gowers (4) gave the following description of autonomic dysfunction in tetanus in
1888: “The pulse is increased in frequency, especially during the paroxysms, and is often very small.
There is some reason to believe that the small size of the pulse is due to generalized vasomotor spasm.”
However, widespread recognition of the hypersympathetic state did not occur until the prolongation of
survival of tetanus patients made possible by ventilatory management.
EPIDEMIOLOGY
Risks for acquired tetanus include infected wounds, infected surgical sites (include contaminated sutures,
dressings, or plaster), burns and abscesses contaminated by C. tetani, animal-related injuries (bites and
wounds), lack of active immunization against C. tetani, umbilical stump infections (tetanus neonatorum)
when mud or feces are applied to the umbilical stump, and puerperal infections when nonsanitized
instruments are used (11).
C. tetani has a worldwide distribution and has been recovered from diverse sites, including soil, feces,
house dust, and contaminated heroin. It is one of the most common fatal infectious diseases throughout the
world and in developing countries; it is an important cause of neonatal death. Natural immunity in
communities that are not immunized is about 30% and increases with age (12). The attack rate and age-
related mortality rate after the neonatal period is higher in males.
The illness is frequent in countries or in ethnic groups who are less likely to be immunized. In the
United States, inadequate tetanus protection in rural elderly individuals was more common as compared
to the entire population (13). Tetanus is still a major cause of mortality in those areas of the world with
inappropriate hygiene and immunization programs. In 2006, an estimated 290,000 people worldwide died
of tetanus, most of them in Asia, Africa, and South America (14).
Published mortality figures underestimate the number of deaths but probably represent the most reliable
data for much of the world. In the United States, reported cases per 100,000 populations fell from 0.28 in
1955 to 0.02 in 2001 (15). Reported mortality has declined from about 65% in the 1940s to about 20% in
the 1990s, reflecting improvements in critical care. During 2001 to 2008, a total of 233 cases were
reported in the USA, and the case-fatality rate was 13.2% among the 197 cases with known outcomes.
Average annual incidence during that period was 0.10 per 1 million population overall and 0.23 among
persons aged 65 years and older (Fig. 37.2). Case fatality was higher among persons older than age 65
years, diabetics, and among unvaccinated persons or those not up-to-date with vaccination (16). An
average of 29 cases was reported each year (range: 19 to 40).
Sutter et al. (17) concluded that only 40% of cases are reported to the Centers for Disease Control and
Prevention (CDC), 60% are reported to the National Center for Health Statistics, and almost 25% are
reported to neither. As the disease becomes less common, more cases are likely to elude recognition,
causing an artifactual decline in incidence. Most reported cases occur in patients older than 60 years (18),
confirming that waning immunity is a serious problem in this population. Table 37.1 summarizes
conditions before onset of tetanus among 130 reported U.S. cases (19).
About three fourth of cases of tetanus in the United States follow injuries. Infected wounds (both
traumatic and surgical), abscesses, surgical wounds, major trauma, parenteral drug abuse, and animal-
related injuries account for about 25% of the tetanus-associated injuries; about 20% of wounds are due to
unknown causes, and in 5%, no source can be found (16).
In the developed world, about 25% of tetanus cases stem from occupational accidents, most frequently
agricultural or sylvan. Immigrants to the United States were more than three times less likely to have been
immunized than native New Yorkers in one study (20).
NT accounts for about half of all cases worldwide and has a 90% mortality (11). NT is rare in the
United States. This is due to the efficacy of the intensive immunization program. Unhygienic childbirth,
nonmedical abortion practices, inadequate immunization of mothers, and the lack of care of penetrating
wounds explain most cases of neonatal and adult tetanus in the developing world. Furthermore, climate
and soil pH in the tropics may contribute to the increased prevalence of C. tetani and its availability to
contaminate wounds (11).
A recent estimate of worldwide causes of child mortality between 2000 and 2010 found that NT
decreased from 146,000 to 58,000 at 9.5% per year (11). The incidence of NT and factors associated
with NT mortality was evaluated in 416 cases seen in a district in rural Pakistan between 1993 and 2003.
The overall case-fatality rate (CFR) for NT was 30.1% and fell from 42% in 1993 to 29% in 2003 (p =
0.377). NT incidence decreased from 0.90 per 1,000 livebirths (LB) in 1994 to 0.18 per 1,000 LB in
2003. Multivariable analysis showed that age at admission of 8 days or less with or without low birth
weight was the strongest predictor of mortality. The rate of decline of NT incidence and case fatality was
attributable to routine and supplementary immunization activities (21).
A study of neonatal mortality in Bangladesh revealed that tetanus caused 112 of 330 deaths (22). There
is great geographic variability in incidence of and mortality from the neonatal form of the disease, with an
inverse relationship between the extent of maternal immunization and incidence. In 1999, the World
Health Organization (WHO) reported that Somalia had the highest reported rate, with 16.49 neonatal
tetanus deaths per 1,000 livebirths (23). Poor prognostic factors include age younger than 10 days on
admission, symptom duration of less than 5 days on admission, risus sardonicus, and fever (24). About
30% of neonatal tetanus cases occur in babies born to mothers who have already had at least one affected
child; this dramatizes the failure to immunize mothers as a major contributor to this condition, because
these women are known to lack immunity (25). Immunization programs are clearly effective in decreasing
the mortality attributable to neonatal tetanus. Interestingly, tetanus appears to be rare at high altitudes (26).
ETIOLOGY
C. tetani (Fig. 37.3) is a slender, obligatively anaerobic bacillus measuring 0.5 to 1.7 µm by 2.1 to 18.1
µm (27). Usually classified as gram positive, it may stain variably, especially in tissues or in older
cultures (28). Most strains are sluggishly motile and have abundant peritrichous flagellae during growth
(Fig. 37.4). The mature organism loses its flagellae (Fig. 37.5) and forms a spherical terminal spore (29),
producing a profile like that of a squash racket (Fig. 37.6). The spores resist extremes of temperature and
moisture and are stable at ambient oxygen tension; in addition, they survive indefinitely. They are viable
after exposure to ethanol, phenol, and formalin, but they are killed by iodine, glutaraldehyde, or hydrogen
peroxide. Strains vary in resistance; exposure to 100°C for 4 hours or autoclaving at 121°C and 103 kPa
(15 psi) for 15 minutes is necessary to ensure sterility. They can survive in soil for years and can be found
in house dust, soil, salt, and fresh water (30).
Spores can be isolated from the feces of many animals and in small numbers are ubiquitous in soil and
on carpets. Hence, any breach in skin defenses (e.g., wounds, burns, animal or human bites, or even insect
bites) may result in inoculation. Injuries that favor growth conditions for anaerobic bacteria may lead to
the development of tetanus. Tetanus-prone wounds include those contaminated with dirt, feces, or saliva;
punctures (including the use of unsterile needles, or injections through unprepared skin); scratches, bites,
missile wounds; burns; frostbite; avulsions; and crush injuries. Penetrating ocular injuries are considered
tetanus prone based on experimental evidence, whereas nonperforating injuries are not (31). Sometimes,
no clear portal of entry can be ascertained. Unusual infection sources include the alimentary tract, tonsils,
ear lesions, and contaminated vaccines, sera, and catgut (32,33). Fatal tetanus has occurred in a patient
with Stevens-Johnson syndrome. Other unusual sources of tetanus have been described (34). The
importance of these observations lies not in their rarity, but in the much higher mortality rate associated
with unusual portals of entry. This probably reflects a longer delay in considering the diagnosis. Between
7% and 21% of tetanus cases are cryptogenic (35).
In culture, growth occurs best at 37°C. C. tetani grows on several media if oxygen is excluded. When
cultured on a solid medium such as blood agar, the organisms usually form a thin film over the entire
surface (“swarming growth”). Routine anaerobic isolation techniques are sufficient if the tissue sample is
rapidly placed in an anaerobic transport system. Clinical decisions should not be based on culture results,
because (a) cultures are commonly negative in patients with tetanus, (b) isolation of the organism is of no
consequence in an immune host, and (c) routine bacteriologic studies will not indicate whether a strain of
C. tetani carries the plasmid required for toxin production.
The spores germinate when introduced into a wound and proliferate if the redox potential of the tissue
is low. During growth, C. tetani produces two exotoxins: tetanospasmin (TS) and tetanolysin. The
potential role of tetanolysin in human tetanus is unclear; at worst, it may damage otherwise viable tissue
in the vicinity of an infected wound, lowering the redox potential and promoting the growth of anaerobic
organisms. Tetanolysin can disrupt cell membranes, apparently by more than one mechanism. Although
systemic administration of tetanolysin in animals produces electrocardiographic abnormalities and
disseminated intravascular coagulation, the relevance of these findings to clinical tetanus in humans is
uncertain.
TS, the substance commonly called tetanus toxin, is synthesized as a single 151-kd, 1,315–amino-acid
polypeptide chain (36) (Fig. 37.7). The genetic information for this molecule resides on a single large
plasmid (37) (Fig. 37.8). Strains of C. tetani lacking this plasmid are not toxigenic and do not cause
clinical tetanus. The native molecule has little or no activity but becomes potent when nicked at serine-
458 by a bacterial protease (38). This produces one heavy (100-kd) chain and one light (50-kd) chain,
connected by a disulfide bridge. This bridge, as well as another one on the heavy chain, is required for
the activity of the toxin. These chains or their fragments affect different phases of toxin binding, cell entry,
and toxicity. T cells commonly produce an immune response against two particular amino-acid sequences
from the amphipathic alpha-helical portion of the molecule. The three-dimensional structure of TS has
been determined (39) (Fig. 37.9). The genomic sequence of the bacterial chromosome and the plasmid is
now available (40).
Investigators have described several enzymatic digestion products of TS (Fig. 37.10), but their clinical
relevance is uncertain. Now that the toxin molecule has been sequenced, reference to the specific amino
acids of a fragment is preferred (41). The more commonly investigated fragments are those derived from
papain treatment, which cleaves the heavy chain at lysine-865, about 50 kd from the carboxy-terminal end
(the C fragment) (42). The light chain and the amino-terminal end, still linked by the disulfide bridge, are
variously called the B fragment or the A-B fragment. Attachment and internalization of TS into its target
neurons is mediated by the heavy chain (43) or its C fragment (44), whereas the light chain is responsible
for inhibiting transmitter release (45,46). The C fragment may also be responsible for the transsynaptic
transport of the toxin (46). However, some disagreement remains about these distinctions.
The manifestations of tetanus result from the propensity of TS to inhibit neurotransmitter release by a
presynaptic terminal (47). This is a three-step process (Fig. 37.11): binding to the presynaptic membrane,
translation of the toxin to the active site, and induction of paralysis. Because TS avidly binds to
gangliosides, these molecules were proposed as being the “receptors,” but several lines of evidence
suggest that this binding is nonspecific (48). Other evidence implicates a nonganglioside receptor (49),
but it has not been characterized. Similarly, the process by which the toxin breaches the cell membrane is
not well understood. TS enters the neuron from the extracellular space via noncoated vesicles (50);
Pelkmans and Helenius (51) stress the endocytosis of TS via caveolae, as is also the case for cholera
toxin and some nonenveloped viruses. The discovery that bafilomycin A1 prevents the action of TS on
cultured spinal cord neurons (52) implies that the toxin enters the cytoplasm in an acidic vacuole,
analogous to that described for diphtheria toxin (53). Other clostridial neurotoxins appear to share this
entry system. The internalization of TS is protease sensitive and appears to require glycosyl-
phosphatidylinositol–anchored proteins, which are present in the vicinity of synaptic release site (54).
The binding sites may differ biochemically in the central nervous system (CNS) and the peripheral
nervous system (55).
Once inside the presynaptic terminal, TS exerts a local effect to inhibit transmitter release for several
weeks. Although the synaptosomal content of γ-aminobutyric acid (GABA) is not altered in epileptogenic
cortical foci induced by TS, the GABA release evoked by depolarization remains decreased for at least 3
weeks (56). Thus, inhibitory failure is due not to a decrease in available GABA, but to the inability of the
presynaptic neuron to release the transmitter it contains.
In contrast to the lack of understanding of binding mechanisms, research in presynaptic function (much
of it dependent on TS and other clostridial neurotoxins as tools for dissecting the molecular steps
involved) paints an elegant and coherent picture of the mechanism by which these toxins prevent
transmitter release (57).
The release of synaptic vesicles by an action potential is initiated by an abrupt rise in the intracellular
free Ca2+ concentration, mediated by voltage-dependent calcium channels (Fig. 37.12). This increase in
free Ca2+ triggers an interaction between synaptotagmin (in the vesicle membrane) and syntaxin (on the
presynaptic cell membrane), clamping the vesicle to the presynaptic membrane. Synaptobrevin (also
referred to as vesicle-associated membrane protein [VAMP] [58]) also binds to syntaxin and appears to
dock the vesicle to the membrane at the proper location for fusion. There are different isoforms of
synaptobrevin within neurons; a protein termed cellubrevin performs a similar function in nonneuronal
secretory cells (59). Synaptophysin, the third major component of this mechanism, probably forms the
fusion pore that allows release of the vesicle contents into the synaptic cleft (60).
Clostridial neurotoxins inhibit vesicle release by cleaving peptide bonds in these proteins (59). Each
toxin has a specific locus of activity (61). TS, along with botulinum neurotoxins B, D, F, and G, cleaves
synaptobrevin (62). TS and botulinum neurotoxin B may share the same cleavage site on synaptobrevin.
The toxins affect only the free proteins; once they have complexed to cause transmitter release, they are
not subject to attack (63). Synaptobrevin and synaptotagmin cleavage also occurs normally, as an effect of
an endogenous protease, and they are probably involved in organelle recycling (64). The endogenous
protease does not appear homologous to the clostridial toxins.
From the medical standpoint, one of the most important properties of intraneuronal TS is its propensity
to travel via the retrograde transport system back to the cell body, which allows access to various other
neurons (65) (Fig. 37.13). This process extends from the periphery into the spinal cord as well across
several orders of synaptically connected neurons in the brain. The particular clinical manifestations of
tetanus depend on the classes and locations of the affected cells, as discussed in the section “Pathogenesis
and Pathophysiology,” later in this chapter.
Tetanus is traditionally classified into four clinical types: generalized, local, cephalic, and neonatal.
These distinctions are useful diagnostically but do not reflect toxicologic differences. Rather, they reflect
variations in the site of toxin action.
Although a portal of entry can usually be determined, the lack of a defined wound does not exclude
tetanus. Similarly, bacterial stains and cultures of wounds are of no consequence in its diagnosis or
management. A “protective” titer of antitetanus antibody may help exclude the diagnosis, but only in
retrospect. This is an area of controversy.
The temporal development of symptoms in each form of tetanus is of great prognostic significance. The
incubation period extends from the time of spore inoculation to the first symptom, and the period of onset
marks the time from that first symptom to the first reflex spasm (i.e., a spasm produced in response to
sensory stimulation, as opposed to an apparently spontaneous spasm). In a study of 176 patients from
Brazil, the incubation period for patients with severe disease (N = 116) was 8.3 ± 4.7 days, whereas that
for patients with moderate and mild disease severity (N = 60) was 11.0 ± 6.7 days. The corresponding
periods of onset were 1.9 ± 1.5 days and 3.2 ± 1.9 days, respectively (66). Regardless of the clinical type
of tetanus, shorter incubation and onset periods indicate a poorer prognosis.
A general assessment of the disease severity can be predictor of the outcome and can assist in
determining the timing and need for airway protection. The portal of entry is another important prognostic
factor, with burns, head and neck infections, umbilical stumps, surgical procedures, compound fractures,
septic abortions, and intramuscular injections all associated with lesser chances for recovery. Injection
drug users, especially those injecting narcotics and heroin, appear to develop particularly severe tetanus
(67). Tetanus following the intramuscular injection of quinine, used in some third-world countries for
malaria treatment, has an unusually high mortality rate and develops very quickly (68). This probably
reflects the very acidic milieu produced by quinine injection. Fever and tachycardia, if reflecting
autonomic dysfunction rather than wound infection, are similarly poor prognostic signs (69). The outcome
is also influenced by age and comorbidity.
Several authors have developed rating systems for severity and prognosis (70–72), summarized in
Table 37.2. The modified Ablett scale is frequently used for making decisions regarding tracheostomy,
which is performed on moderate or severely affected patients (73).
Generalized Tetanus
This is the most common form of clinical tetanus. It may occur after relatively minor injuries. Patients
generally have tonic contraction of their skeletal muscles and intermittent intense muscular spasms. Tonic
and periodic spasmic muscular contractions account for the classic clinical findings: opisthotonus, stiff
neck, risus sardonicus (sardonic smile) (Fig. 37.14), a boardlike rigid abdomen, periods of apnea caused
by viselike contraction of the thoracic muscles and/or glottal or pharyngeal muscle, and dysphagia.
The onset can be insidious; however, the typical initial findings of trismus, or lockjaw, due to
parapharyngeal and masseter muscles spasms is observed in about half of cases (32,33). Patients manifest
tonic contraction of their skeletal muscles and intermittent intense muscular spasms. These may be
triggered by sensory stimuli such as loud noises, contact, or light. Tonic and periodic spasms are
responsible for most of the clinical findings of tetanus. Trismus is caused by rigidity of the masseter
muscles, producing inability to open the mouth (see Fig. 37.14); its course can be followed by measuring
the distance between the upper and the lower teeth with the mouth maximally open. Trismus is the most
common presenting sign, although back or shoulder stiffness may have been present for hours. The most
common complaints are pain, swallowing difficulty, and unilateral or bilateral stiffness of the neck and
other muscle groups, such as those of the thorax or abdomen (74). Persistent trismus accounts for “risus
sardonicus,” which is the classic finding of tetanus (see Fig. 37.14). Risus sardonicus is often a subtle
finding that may best be diagnosed by the family or friends of the patient. Physicians can diagnose risus
sardonicus by comparison with photographs or in retrospect.
As the illness progresses, more muscle groups get involved. One of the most significant findings occur
with spasm of the paraspinal musculature, resulting in severe opisthotonos (see Fig. 37.1), where in young
infants, the soles of the feet may touch their head. The typical generalized spasm resembles decorticate
posturing, consisting of “a sudden burst of tonic contraction of muscle groups causing opisthotonos,
flexion and adduction of the arms, clenching of the fists on the thorax, and extension of the lower
extremities” (75). Although the spasms may be confused with posturing or epileptic seizures, they do not
produce loss of consciousness and are extremely painful. The tetanic contractions progress further for
several more days, with recruitment of additional muscle groups and significant aggravation of symptoms.
Painful spasms and contraction can also contort and distort the patient’s posture. All voluntary muscles
may be affected, and the disease can involve the larynx, which can be fatal. Fractures of vertebrae or
other bones and hemorrhage into muscles can also take place. Even minor stimuli including light, drafts,
noises or voices, and light touch may trigger reflex spasms. Because patients remain conscious throughout
these spasms, anxiety and pain further complicate management and can contribute to the severity of
disease.
Symptoms of autonomic overactivity are generally manifested in the early phases as irritability,
restlessness, sweating, and tachycardia. In later phases of illness, profuse sweating, cardiac arrhythmias,
labile hypertension or hypotension, and fever are commonly present (76–78). Episodes of bradycardia
and hypotension can lead to cardiac arrest. Cardiac arrest has also been attributed to myocardial damage
caused by the high catecholamine level (79) and toxic damage to the brainstem (80). Fever can be due to
the sympathetic overactivity or superinfections, such as pneumonia (81). Cardiovascular instability due to
spasms and inadequate sedation need to be excluded. Cardiovascular complications are managed in the
intensive care setting, where ventilatory support and therapeutic paralysis are available. Spasms and
cardiovascular complications occur most commonly during the first week and resolve slowly during the
ensuing 2 to 4 weeks.
Respiratory compromise is the most serious early problem in generalized tetanus. Upper airway
obstruction is common during spasms. The diaphragm and abdominal musculature are often involved, and
they can produce apnea in inadequately treated patients in spite of mechanical ventilation. The
neuromuscular junction (NMJ) effects of the toxin may produce diaphragmatic paralysis or bilateral vocal
cord paralysis (82). Severity may continue to increase for 10 to 14 days after diagnosis, reflecting the
transport time of intraneuronal toxin into the CNS. Recovery then begins, usually requiring about 4 weeks.
This period probably reflects the time needed for synthesis and transport of presynaptic constituents. In
the absence of antitoxin, disease persists as long as TS is produced. The total amount of toxin produced is
so small that it is inadequate to prompt an immune response; therefore, patients with newly diagnosed
tetanus must be actively immunized to prevent recurrence. Recurrent tetanus is well documented if this is
not done (83).
Local Tetanus
This is an unusual presentation of tetanus that occurs when circulating antitoxin prevents general spread of
the toxin but is insufficient to stop local uptake at a wound site (75,84). This causes mild, prolonged,
steady without progression, and painful muscle contraction in the wounds’ region, which can last for
several weeks to months, with subsequent complete spontaneous resolution. Localized tetanus may be
unrecognized or mistaken for pain-induced muscle spasms. Neuromuscular transmission may be affected
locally, producing weakness in addition to rigidity. Partial immunity to TS may contribute to the
development of local tetanus by decreasing the hematogenous spread of toxin (85). More commonly,
however, local tetanus is the harbinger of the generalized form, unless treated.
Cephalic Tetanus
This condition is a rare manifestation of tetanus that involves only the cranial nerves after C. tetani enters
wound(s) or chronic infection(s) in the head and neck. Although any of the cranial nerves may be affected,
singly or in combination, cranial nerve VII is most frequently involved, but involvement of cranial nerves
VI, III, IV, and XII may also occur. Patients may present with confusing clinical findings including facial
paresis, dysphagia, trismus, and other focal cranial neuropathies. Cephalic tetanus may precede
generalized disease, and isolated cephalic tetanus can occur and follows a chronology similar to
generalized disease.
Although most series suggest a poor prognosis, a large report from India described mild cases
associated with chronic otitis media (86). This may represent colonization of the infected tissue with C.
tetani and subsequently the production of toxin. Of 22 patients in one series with otogenic tetanus, 17 had
acute otitis media (87). A coexisting aerobic infection was diagnosed in 85%, most commonly with
Staphylococcus aureus. Rarely, extraocular movements are affected in patients with tetanus, causing
“ophthalmoplegic tetanus” (88) or supranuclear oculomotor palsies (89). Horner syndrome has been
reported as a presenting feature (90).
Neonatal Tetanus
This is a generalized form of the disease that often develops in infants delivered to mothers who have not
been immunized. This is because passively transferred maternal antibody is protective. The lack of
immunization of mothers and the birth practices in developing countries that include lack of aseptic
techniques in managing the umbilical stump and application of mud, clarified butter, or feces to the
umbilical stump increase the risk of acquiring this illness and are responsible for a large proportion of
cases (91). Five factors are involved with NT: (a) the length of the stump (longer seems safer), (b) the
care with which the cord is ligated, (c) the cleanliness of the instruments and dressings, (d) the
cleanliness of the environment and of the patient’s and mother’s clothing, and (e) the application of mud,
feces, or unclean material on the stump (92).
This form of tetanus usually occurs in infants within 14 days of birth and generally manifests initially
by inability to suck, and then by tetanic spasms and rigidity producing the typical opisthotonic posture,
and trismus (Fig. 37.15). The hypersympathetic state occurs commonly in these infants, and the mortality
rate is high, with infants dying of complications such as CNS hemorrhage, pneumonia, pulmonary
hemorrhage, and laryngeal spasms with asphyxia. One study found that 33% of infants with tetanus were
also bacteremic, mostly with coliforms or S. aureus, most commonly from an infected umbilical cord
stump (93). Developmental delay is common in survivors (94,95).
A Turkish study implicated unhygienic home deliveries in more than 90% of NT cases (94). A recent
study in Pakistan showed that delivery onto soil compared to a clean surface resulted in a 3.2-fold
increase in the odds ratio (OR) of death from NT (95). Other statistically significant risks included
paternal illiteracy (OR = 3.2) and having sheep at home (OR = 2.0). Soil as a delivery surface accounted
for 64% of the neonatal deaths. Although these concerns are important, active maternal immunization—or
passive immunization of the mother before delivery and of the child at birth—would eliminate the
disease.

After introduction into tissues, C. tetani spores convert to vegetative forms, multiply, and produce TS. In
numerous instances, there is no associated inflammation or apparent local infection. At the site of entry,
the toxin enters the peripheral nerve and reaches the CNS through the nerves (25,84,96).
The actions of TS predominantly involve three components of the nervous system: central motor
control, autonomic function, and the NMJ (76). The central effects have been studied most intensively, and
they provide paradigms for understanding the toxin’s effects on other nervous system components.
Central Motor Control Effects

To express its toxic potential, TS must gain access to its target neurons. The toxin appears to enter the
nervous system predominantly through the NMJ of alpha motor neurons. Some toxin enters sensory and
autonomic neurons, but the amount appears small and its contribution to symptoms is uncertain. It then
moves, via the retrograde transport system, to the cell body (57). This system, consisting of microtubules
and transport proteins, is normally used to bring signal molecules and exhausted presynaptic components
back to the cell for processing. The heavy chain or the C fragment of the toxin is necessary for retrograde
transport. TS also spreads hematogenously from its site of production, but it still must enter via neurons
(97). Toxin already in transit within the neuron is inaccessible to antitoxin, which partly explains the
progression of the disease for several days after treatment. The intrathecal administration of human
tetanus immune globulin (HTIG) is an attempt to circumvent this by allowing access to TS moving across
synapses in the CNS (see the section “Immunotherapy,” later in this chapter).
Once transported to the spinal cord or the brainstem, the toxin then migrates transsynaptically into
presynaptic inhibitory cells (98), which use either glycine or GABA as transmitters (Fig. 37.16). The
glycinergic cells are most important in the spinal cord, whereas the GABAergic cells are responsible for
decreasing inhibition from the brainstem (99). By preventing glycine or GABA release, TS denies the
alpha motor neuron its most essential inhibitory transmitters. This raises its resting firing rate, causing
muscle rigidity. Moreover, the normal inhibition of other motor neurons during movements of a particular
motor group depends on these inhibitory transmitters, as does the termination of reflexive contractions.
Deprived of this inhibition, the motor system responds to an afferent stimulus with the intense, sustained
contraction of a wide range of muscles that characterizes the tetanic spasm.
There may be some differences in the predominant effects of local and generalized tetanus regarding the
loci of inhibition. Following intravenous injection, TS appears to affect supraspinal (i.e., GABAergic)
inhibitory mechanisms exclusively, whereas local tetanus likely has more effect on the spinal glycinergic
systems. Because the human disease is caused by spore inoculation rather than toxin administration,
clinical generalized tetanus represents a variable combination of these mechanisms. In addition to the loss
of inhibitory systems, excitatory transmission is also disrupted (100). This may partially explain the
weakness associated with local tetanus.
Histologic abnormalities have been reported in the brainstem nuclei in fatal cases (101), but the
significance of these changes is unknown. They most likely reflect terminal hypoxia and autonomic
dysfunction. Reversible chromatolysis of motor neurons occurs in experimental tetanus when markedly
suprathreshold doses of toxin are employed. Whether this is simply a manifestation of hypermetabolism or
reflects another pathophysiologic process is unresolved.
Once transported into the CNS, the toxin continues its rostral movement by retrograde transport
(97,102). This implies that structures above the brainstem could be affected by TS; however, there is no
evidence that this occurs in the natural history of tetanus. It is likely that generalized tetanus does involve
some vertical movement of toxin within the neuraxis, but the widespread manifestations in this form are
mostly due to the hematogenous dissemination of toxin to NMJs throughout the body. TS does inhibit the
evoked release of norepinephrine (103), acetylcholine (104), serotonin (105), and enkephalin (106) from
brain tissue in vitro. TS is also epileptogenic, producing depolarizing shifts when added to CNS tissue in
culture and partial seizures when injected intracerebrally. These acute seizures are associated with
diminished extracellular GABA levels (107). However, the abnormal electrical activity outlasts the
period of GABAA inhibition, indicating long-lasting reorganization of synaptic function (108).
Autonomic Nervous System Effects
Before modern intensive care, most patients with severe tetanus died quickly from ventilatory failure
(109). Although autonomic involvement was mentioned in 1954, the first major report of this aspect of
tetanus appeared in 1968 (74). The latter group described “a characteristic syndrome whose features
include sustained but labile hypertension and tachycardia, irregularities of cardiac rhythm, peripheral
vascular constriction, profuse sweating, pyrexia, increased carbon dioxide output, increased urinary
catecholamine excretion, and, in some cases, the development of hypotension.” Although these signs are
usually present toward the end of the first week, they may develop during the second (110). Most are
associated with elevated catecholamine levels.
An elevated plasma epinephrine and norepinephrine concentration (74,111) and 24-hour urine
catecholamine excretions (112) were reported in patients with tetanus. These manifestations resemble the
effects of a pheochromocytoma; a similar cardiomyopathy is seen in both conditions (78).
Udwadia et al. (113) performed invasive hemodynamic monitoring of 27 patients with severe tetanus.
The major finding was a hypersympathetic state, with tachycardia (mean, 131 beats per minute) and
increased cardiac (5.48 liters per minute) and stroke volume (43.1 mL/m2) indexes. A total of 19 patients
experienced episodes of sustained tachycardia (>150 beats per minute); 17 had hypertension of varying
degree, whereas 8 experienced alternating hypertension and hypotension, and 5 had episodic hypotension
only. Seven patients had paroxysmal supraventricular tachycardia, and three had brief runs of ventricular
tachycardia. Despite the difficulties experienced by their patients, the mortality rate was 6.25%.
TS disinhibits sympathetic reflexes at the spinal level, implying that the hyperadrenergic findings are
not dependent on hypothalamic or brainstem dysfunction (114). Parr et al. (115) later showed that
cutaneous stimulation of animals with local tetanus increased firing rates in renal sympathetic nerves.
Conversely, the development of inappropriate antidiuretic hormone secretion supports hypothalamic
involvement (116).
The identification of TS as a Zn2+-dependent peptidase (117) leads to a new hypothesis to explain the
hypertension seen in tetanus patients. Captopril, an inhibitor of Zn2+-dependent proteases, antagonizes the
effect of TS on synaptobrevin and allows exocytosis to proceed normally (118). Antibodies directed
against the Zn2+-binding domain of TS restore exocytosis in chromaffin cell cultures over 4 days (119);
however, this model differs substantially from the synapse, so such rapid restoration of function would not
be anticipated in clinical disease; chelation of Zn2+ by ethylenediaminetetraacetate (EDTA) and other
chelators is also effective in experimental systems (120). Nonetheless, these results suggest that TS might,
in addition to its other effects, have an angiotensin-converting enzyme (ACE)–like effect, and a
component of the hypertension in patients with tetanus may be related to excess angiotensin-II effects
rather than catecholamine effects.
Clinical evidence suggests some disruption of parasympathetic function as well. Bradycardia is
occasionally noted as is hypotension (121) without previous evidence of increased sympathetic tone
(122). Although both of these findings can be reproduced by injection of TS into a rat’s third ventricle
(123), a more peripheral mechanism appears likely in human tetanus.
Neuromuscular Junction Effects
Because the central effects of TS are so dramatic, the peripheral disorder it produces received scant
clinical attention until 1977. Investigators showed denervation changes in the muscle closest to the site of
the injury that introduced C. tetani, which reflected failure of neuromuscular transmission (124).
Experimental studies by Harvey (125) established the presence of neuromuscular blockade 40 years
earlier. Single-fiber electromyography (EMG) confirmed a presynaptic defect of acetylcholine release
qualitatively similar to that of botulism (126). The NMJ may be permanently disabled by TS; return of
function requires sprouting of the terminal end to produce new synapses (124).
APPROACH TO DIAGNOSIS
Tetanus can be diagnosed only clinically. Generalized and cephalic tetanus are easily recognized if one
thinks of the disease. Localized tetanus is more difficult to detect early. The neonatal form is less easily
recognized on initial presentation, but it rapidly becomes obvious. Laboratory assistance is confined to
the exclusion of other diagnoses and to the determination of immunity. Tetanus can follow an incubation
period from 3 to 14 days after an injury.
EMG studies may be useful by showing evidence of denervation, reinnervation, and increased
excitability of the motor neuron pool (127). The EMG differential diagnosis of tetanus has been reviewed
(128). Blood counts are normal or slightly elevated; CSF measures are normal; and electroencephalogram
(EEG) and EMG are normal and nonspecifically abnormal, respectively. Gram stains of wounds may
reveal the characteristic gram-positive bacilli with terminal spores in as many as one third of tetanus
patients. Even though a positive wound culture can support the clinical diagnosis, a positive culture in the
absence of symptoms does not indicate that clinical tetanus will develop.
The spatula test is a simple test that can be diagnostic (129). The posterior pharyngeal wall is touched
by a spatula, which induces a reflex contraction of the masseters in the presence of tetanus.
Gowers (4), again, provided an unequaled clinical description in 1888:
The first symptom is usually a sense of stiffness in the neck or jaw, sometimes difficulty in swallowing, or stiffness of the tongue. . . . In
the course of a few hours, or at most a day or two, the difficulty in separating the jaws becomes greater, and is clearly due to increasing
rigidity of the masseters. With this there is also more stiffness in the neck, and the head is slightly bent backward from the preponderance
of spasm in the extensor muscles. As the rigidity in the neck increases, it passes down the spinal muscles. . . . The legs may also become
extended and rigid, but the arms are little affected.
A few patients have atypical features on presentation. The lack of an easily identified portal of entry,
discussed earlier, does not exclude the diagnosis but makes prognostication more difficult because the
incubation period cannot be determined. These patients should be carefully examined for signs of
parenteral drug abuse, otitis, or rectal or vaginal instrumentation. Recent injections or minor surgical
procedures may be uncovered by questioning. Lesions of the gastrointestinal tract are occasionally
implicated, especially among inhabitants of rural areas among whom the carriage rate of C. tetani may be
20-fold higher than that of urban dwellers (130).
Although many disorders have small areas of overlap with tetanus, strychnine intoxication is the only true
mimic (131). Strychnine is a component of some rodenticides. This drug is a direct antagonist at the
glycine receptor. Lack of abdominal rigidity between spasms may be more common with strychnine than
with tetanus, and trismus may be absent in the former; otherwise, the clinical presentations are similar.
For this reason, biochemical analyses of serum and urine for strychnine should be performed in suspected
tetanus cases, and tetanus should be considered even when strychnine poisoning is likely. The initial
symptomatic management of both conditions relies on benzodiazepines, but their subsequent treatments
and complications differ substantially. Many other glycine and GABA antagonists have been exploited as
experimental convulsant agents; although human poisoning has not been reported, conditions resembling
tetanus may be expected.
Dystonic reactions to dopamine blockade usually involve torticollis, and oculogyric crises are
common. Neither of these phenomena is part of tetanus, and reflex spasms are not seen. A rapid response
to anticholinergic agents (benztropine, 1 to 2 mg; or diphenhydramine, 50 mg) and subsequent toxicologic
studies help confirm the diagnosis of dystonic reaction. A trial of anticholinergic agents is reasonable in
suspected tetanus if the diagnosis is in doubt. There are anecdotal reports of transient improvement in the
symptoms of tetanus after anticholinergic drug administration, perhaps reflecting a sedative effect (132).
A report of opisthotonic posturing and risus sardonicus in a patient suffering from an amphetamine
overdose is difficult to reconcile with the expected effects of amphetamines but reminds us of the need to
keep an open mind in differential diagnosis (133).
The nuchal rigidity of meningitis may resemble the neck stiffness of tetanus, but the other manifestations
of each disorder should resolve any confusion. The cerebrospinal fluid is normal in tetanus. The other
infection that may raise a question of tetanus is an alveolar ridge abscess producing trismus. Oral pain
and tenderness is not characteristic of tetanus; the patient with a dental disorder will not display spasms
or rigidity. However, various dental infections may produce tetanus (134), and temporomandibular joint
dislocation may be a symptom of the disease (135). Verma et al. (136) described a single case of
unilateral trismus resulting from a tuberculoma of the brainstem.
Patients experiencing generalized convulsive status epilepticus may at first appear to have tetanic
spasms, but the loss of consciousness and evolutionary movements of the former should quickly resolve
any question.
Tetany precipitated by hypocalcemia or alkalosis will be accompanied by Chvostek and Trousseau
signs. In contrast to tetanus, tetany involves the extremities more than the axial musculature.
Progressive fluctuating muscular rigidity (the “stiff person” syndrome) has been likened to a chronic
form of tetanus (137). This idiopathic syndrome has an insidious onset, usually has minimal cranial nerve
involvement, lacks trismus, and is relieved during sleep. Current evidence links this disorder to
autoantibodies against GABAergic neurons (138).
Local tetanus is rarely confused with other disorders; the major problem is failure to consider the
diagnosis. It has been confused with transverse myelitis (139).
“Pseudotetanus” has been used in the past to describe a broad variety of disorders (140) and may be
due to malingering or a conversion disorder (141). In the former, the patient’s posture may be complex or
inconsistent; rigidity is lacking or feigned, the patient is distractible, and some secondary gain is
identified. Preexisting psychologic problems may also complicate the diagnosis and management of
tetanus (142).
Determination of Immunity
Tetanus Toxoid Adsorbed, for intramuscular use, is a sterile suspension of alum-precipitated (aluminum
potassium sulfate) toxoid in an isotonic sodium chloride solution containing sodium phosphate buffer to
control pH. When properly administered and maintained, immunization with tetanus toxoid is highly
effective, with an estimated failure rate of less than 4 per 100 million persons in those who are
immunocompetent (143). Therefore, a confirmed history of active immunization almost eliminates tetanus
as a diagnosis. This includes both an acceptable initial series and a booster within 10 years.
Human antibody against tetanus toxoid is predominantly in subclass immunoglobulin G1 (IgG1); there
is a moderate amount of IgG3 and IgG4, and minimal IgG2 (144). The serum concentration of antitetanus
antibodies can be measured by immunoassay or hemagglutination, but the results are seldom available in
time to influence initial diagnosis and management. The results are quantitated in international units (IU)
of antitoxin by reference to an arbitrary international standard, which has achieved international
agreement (145). The development of a rapid test holds promise not only for the exclusion of tetanus but
also for decisions regarding antitoxin administration (see the section “Therapy,” later in this chapter)
(146).
In most epidemiologic studies, a level of 0.01 IU/mL is accepted as protective, based on one study in
guinea pigs reported in 1937 (147). This level prevented death in the animals, but a few developed
tetanus with concentrations between 0.1 and 0.5 IU/mL, from which they recovered. Nonetheless, cases of
human tetanus have been reported with titers as high as 0.16 IU/mL (148–150). In one study of 64 tetanus
patients, 24 had detectable antitoxin levels, and 10 had levels greater than 0.01 IU/mL (151). The severity
of tetanus tended to be less in the patients with higher antibody levels, but six of the ten required
tracheostomy and mechanical ventilation. In a study of 20 cases of NT in Nigeria, the disease developed
in six infants whose mothers had been immunized; the mean antitetanus IgG concentration in these babies
was 0.70 IU/mL, with a range of 0.16 to 2.83 (152). The authors speculated that the toxin load in neonatal
tetanus may be greater than that in other forms of tetanus, suggesting that the antibody concentration needs
to be higher to be protective.
A population-based study, employing 0.15 IU/mL as the threshold for immunity, confirmed that antibody
levels wane with aging (153). Individuals with histories of military service, higher educational
attainment, and incomes exceeding the poverty level were more likely to have protective antibody titers.
Women and members of several minority groups were less likely to have protective titers (Fig. 37.17),
presumably because of failure to receive initial or booster vaccinations. An accompanying editorial
reinforced the responsibility of physicians to maintain their patients’ immunity to tetanus (154). A more
recent analysis confirms that failure to maintain tetanus immunity is an ongoing problem (155).
Disparity among studies regarding the level of protective antibody may reflect the insensitivity of the
test systems to antibodies that are actually protective. In a bioassay, a mixture of several different
monoclonal antibodies was necessary for protection; the most active single clone (that against the amino-
terminal end of the heavy chain) was 100-fold less active than a polyclonal antiserum (156). A level of
0.5 IU/mL in the commercially available immunoassays should probably be set as the cutoff for protection
until these questions are resolved (157). Studies characterizing the domains of the toxin molecule that
must be recognized for protection by antibody (158) suggest that assays that measure protective antibody
rather than total antibody may be on the horizon.
THERAPY
Appropriate treatment based on the clinical diagnosis is warranted even without specific confirmatory
laboratory tests (Table 37.3). A patient with generalized tetanus requires the best possible intensive care.
In this disease, the patient may become completely dependent on mechanical ventilation and the most
effective pharmacotherapy yet stand a good chance of walking out of the hospital without deficits.
An analysis of 335 consecutive tetanus patients treated before the organization of an intensive care unit
(ICU), compared with 306 consecutive patients managed after development of the ICU, revealed a
decrease in mortality from 44% to 15% (159). The major improvement came from prevention of deaths
resulting from acute respiratory failure. A recent study from Brazil showed a comparable decrease in
mortality and in other complications with the introduction of an aggressive critical care protocol (160).
However, CFR of tetanus has remained consistently high (43%) between 1996 and 2005 at a Nigerian
tertiary hospital (161). Factors that were significantly associated with high mortality included older age,
age older than 40 years, incubation period of less than 7 days, and higher degree of sedation with
diazepam.
Table 37.3 presents a time-based protocol that we have found effective in generalized tetanus. Some of
the more important or controversial aspects are discussed here. In local tetanus, a similar approach can
be adjusted for the patient’s symptoms. Autonomic management in neonatal tetanus has not been studied,
but it would likely be similar to that in older children and adults.
As the population at risk for tetanus becomes older, it becomes more important to recognize that elderly
patients without serious chronic disease can survive generalized tetanus and its intensive therapy and
return to their premorbid state. This is true even for those 80 years and older when aggressive treatment is
started early in the course of the disease (162).
Portal of Entry
In most cases, the wound responsible for tetanus is still visible on presentation. However, in up to a third
of the patients, there is no evidence of recent wound, the injury may be too trivial, or the portal of entry
may be unusual (i.e., skin, dental or ear infection, septic abortion, or intramuscular injection). If there is a
surgical indication, débridement under local anesthesia should be performed after spasms are controlled
by benzodiazepines. There is no apparent benefit of débridement for tetanus itself. If no portal of entry is
apparent, the patient should be carefully examined for ear infection, uterine disease, rectal pathology, and
foreign bodies. Foreign bodies should be removed and wounds irrigated well and left open. Local
antibiotic or instillation of HTIG is not indicated. Débridement of the umbilical stump is not
recommended in NT.
Immunotherapy
Immunotherapy includes treatment to neutralize TS and active immunization to prevent recurrent tetanus
(see later discussion). Specific therapy with intramuscular HTIG is aimed at neutralizing the circulating
toxin before it binds to neuronal cell membranes. This should be given as soon as the diagnosis of tetanus
is considered. Neutralization of TS that has not yet entered the nervous system will shorten the course of
the disease and may reduce its severity. Early administration of antitoxin may prevent spread of the toxin
within the CNS. The recommended dosage of HTIG ranges from 500 to 3,000 units. Although a dosage
recommendation based on body weight is not available, it is reasonable to give a newborn a smaller
dose, for example, a single vial of HTIG (250 units).
A retrospective study in which a group of patients who received the higher dose was compared to a
later group receiving the lower dose suggested that the 500-IU dose was adequate (163). Blake et al.
(164) also showed that a dose of 500 IU is as effective as the commonly recommended 3,000 to 5,000-IU
dose. The smaller amount can be given as a single intramuscular injection. Because each injection is a
potent stimulus for tetanic spasms, this is not a trivial point. In areas where HTIG is not available, equine
antitetanus serum is used after testing for hypersensitivity and, if necessary, desensitization.
Once the toxin has entered the motor neuron, it is no longer available for neutralization by the antibody.
Intrathecal administration may make specific immunoglobulin available where the toxin diffuses out of the
motor neuron into other CNS structures. Gupta et al. (163) showed 250 units of intrathecal HTIG to be
superior to 1,000 units administered intramuscularly. However, a subsequent study in NT failed to show
any advantage for intrathecal treatment (165). A metaanalysis showed no benefit of intrathecal
administration of HTIG (166). Because TS is irreversibly bound to tissues, only unbound toxin can be
neutralized. Further research in this area may yet bear fruit (167). The HTIG preparations currently
available in the United States are not licensed for intrathecal use, and they contain potentially neurotoxic
preservatives.
Lee and Lederman (168) proposed that intravenous immune globulin (IVIG) would be a useful
alternative to intramuscular HTIG. However, there is wide variation in antitetanus antibody content in
commercial preparations of IVIG (168). One might reserve this treatment for patients in whom
intramuscular injections are contraindicated, and then only if the product being used is known to have
anti-TS activity (168). In countries where HTIG is not readily available, equine antitoxin is used in doses
of 1,500 to 3,000 units intramuscularly or intravenously to achieve the minimal protective serum
concentration of 0.1 IU/mL. However, patients should be tested for equine antitoxin hypersensitivity prior
to its administration.
Patients should receive active immunization with a total of three doses of tetanus toxoid spaced at least
2 weeks apart because tetanus infection does not confer immunity following recovery from acute illness
(169). Subsequent boosters with tetanus doses in the form of tetanus toxoid–containing vaccine should be
given at 10-year intervals throughout life.
Corticosteroids
In 1954, Lewis et al. (170) attempted to show that steroids would diminish tetanus mortality. A group of
ten patients treated with oral cortisone (in a dose “that appeared to be just sufficient to counteract or
prevent a rise in the temperature”) experienced 60% survival; the 20 historical controls had only 15%
survival. However, a group of five patients receiving intramuscular hydrocortisone all died. The question
was later addressed by Paydas et al. (171); they found a trend toward a significant improvement in
survival in 32 patients randomized to 40 mg of daily prednisolone when compared with 31 patients
receiving placebo. Another group found that betamethasone (8 mg every 8 hours for 10 days) decreased
the need for tracheostomy and mechanical ventilation in treated patients compared to double-blind
controls (172). The mechanism by which steroid treatment might improve survival in tetanus is obscure,
and despite these promising studies, its use should still be considered experimental.
Airway Control and Ventilation
Because the upper airway is often occluded during tetanic spasms, it must be protected rapidly and
effectively preferably before spasms start. An endotracheal tube may be passed under sedation and
neuromuscular blockade. A soft small-bore feeding tube should be placed concurrently. Because the
endotracheal tube itself is a strong stimulus for spasms, some recommend that tracheostomy should be
performed within 24 hours of diagnosis in patients predicted to develop mild to moderate tetanus (173).
Early tracheostomy is often needed because of the likelihood of prolonged mechanical ventilation.
Tracheostomy allows for better tracheal suctioning and pulmonary toilet and prevent laryngospasm, which
greatly increases the mortality rate of the disease. It can also prevent aspiration and enable feeding. The
patient may not require mechanical ventilation once the airway is secure and treatment has begun.
Because pneumonia and pneumothorax occur commonly and produce fatalities, scrupulous pulmonary
hygiene and ventilatory management are required (174). TS can inhibit macrophage function, but the
relevance of this deficit to infectious complications is unknown (175).
Supportive Care
Transfer to ICU must be urgently done before spasms start. The goals of supportive care include
prevention and management of nosocomial infection, decubitus ulcers, gastrointestinal hemorrhage,
thromboembolic disease, and tracheal stenosis.
Patients with severe tetanus require prolonged immobility, much of which is during mechanical
ventilation and which may last for weeks. Patients should be managed in an intensive care setting of a
tertiary care center whenever possible. In one study, the length of ICU care ranged from 33 to 40 days
(176). The patients must be managed by experienced caregivers skilled in ventilatory support and
maintenance of cardiovascular stability. Minimizing external stimuli and maintaining intravenous
hydration may be sufficient in the initial days of the illness. Prevention of thromboembolism can be
attained with heparin, low-molecular-weight heparin, or other anticoagulants, and should be given early.
Attention must be paid to skin care. Physical therapy should be initiated as soon as spasms have abated.
Antibiotic Management
In vitro, C. tetani is sensitive to metronidazole, penicillins, cephalosporins, imipenem, macrolides, and

tetracycline. However, the utility of antibiotic therapy for what is essentially an intoxication has often
been questioned. Penicillin, which is effective against most Clostridium spp., is no longer recommended
for tetanus because it is a GABA antagonist and can aggravate the spasms of tetanus and diminish
benzodiazepine efficacy (177). Furthermore, it can be inactivated by β-lactamase–producing
polymicrobial flora that may also be present in the wound (178). High doses of penicillin might also lead
to colonization of patients with resistant organisms, increasing morbidity from nosocomial infection.
Two studies compared intramuscular penicillin and oral metronidazole therapy for generalized tetanus.
No placebo-controlled studies are available. The first study found less mortality in the metronidazole
group as compared to the penicillin group (177). No difference in mortality was found in the second
study, but patients receiving metronidazole required fewer muscle relaxants and sedatives (179).
Alternative antimicrobials include clindamycin, tetracycline, and vancomycin.
Antispasticity Agents
Extensive muscle spasms can cause respiratory failure, aspiration, and lead to generalized exhaustion.
Provocation of muscle spasms can be reduced by placing the patient in a dark and quiet room. This is
especially important where the availability of neuromuscular blocking agents may be limited.
The benzodiazepines (diazepam, lorazepam, or midazolam) are the best agents available for the relief
of spasms and rigidity. These agents’ mode of action is through GABAA antagonism, and they are
therefore able to indirectly antagonize the effect of the toxin on inhibitory neurons (180), but they do not
restore the glycinergic inhibition. Diazepam has received the greatest use, but lorazepam may be
preferable because of its longer duration of action. The pharmacokinetics of these agents have not been
studied at the exceptional doses and durations employed in treating tetanus. Doses in excess of 500 mg of
diazepam (or 200 mg of lorazepam) may be required daily (181). Prolonged use can produce lactic
acidosis, hypertriglyceridemia, and pancreatic dysfunction. Because such large doses, given
intravenously, contain enough propylene and polyethylene glycol to rarely induce metabolic acidosis
(182), administration of diazepam or lorazepam through a feeding tube should begin as soon as possible.
Because midazolam does not require glycols for solubility, it may become the agent of choice.
Benzodiazepine doses should be reduced gradually over a period of at least 14 days to avoid withdrawal
signs. Diazepam has been shown to be useful in NT as well (183).
Continuous intrathecal administration of baclofen (a GABAB agonist) may diminish the need for
sedation and ventilatory support by controlling spasms and rigidity and may shorten hospitalization (184).
Intermittent intrathecal injections have also been employed successfully (185). In several patients,
baclofen was used without the need for artificial ventilation (185–187). This approach holds promise in
regions where tetanus is relatively common, but it should probably not be considered a standard treatment
in the more developed countries. Dantrolene, a direct muscle relaxant, may also be valuable in selected
cases (188). It does not appear to have advantages over other therapeutic modalities, however.
Although barbiturates and neuroleptics have been employed for sedation of tetanus patients, they are
inferior agents for this indication and are best avoided. Propofol, a nonbarbiturate sedative, may prove to
be a useful adjunct because of its short duration of action (189,190). However, because it lacks GABA
agonist activity in the motor system, it should not be used as a single agent.
A prospective study of magnesium as an antispasticity agent suggests that this ion may have substantial
efficacy both for control of spasms and for prevention of autonomic dysfunction (191). Spasms were
controlled in most patients at a serum magnesium concentration of 4 to 8 mEq/L (2 to 4 mmol/L). Attempts
to raise the concentration in two patients who did not respond resulted in hypotension and bradycardia.
If spasms are not adequately controlled by GABAergic agents, neuromuscular blocking agents are used.
Neuromuscular blockade can be achieved with curariform drugs. The agents used most often are
pancuronium and vecuronium. Pancuronium is a long-acting agent and may worsen autonomic instability
because it is an inhibitor of catecholamine reuptake. Vecuronium is intermediate acting and is less likely
to cause autonomic problems (192). However, because it is short acting, it is given as continuous infusion
to provide adequate effects. The intervals between maintenance doses may be adjusted by the
administration of smaller or larger doses. Patients who undergo therapeutic paralysis must be sedated to
avoid anxiety and ideally monitored by EEG to confirm unconsciousness. The patient should be sedated to
the point that the EEG background is slow and there is minimal reactivity to sensory stimuli.
Atracurium has also been recommended (193), but this drug is probably best avoided in tetanus
patients because of its potentially epileptogenic metabolite laudanosine (194).
Administration of these agents requires close monitoring to avoid or recognize complications. Their
administration should be stopped periodically (at least once a day) to assess the patient’s condition. In
addition to clinical observation, neurophysiologic monitoring to ensure optimal dosing of the NMJ
blocking agent is employed (e.g., no muscle contraction in response to train-of-four stimulation) (195).
Therapy for Autonomic Dysfunction
Suppression of excessive catecholamine release that induces the autonomic dysfunction can control the
dysautonomia. Combined α- and β-adrenergic blockade with labetalol is the treatment of choice for the
hypersympathetic state in tetanus (195). Isolated β-adrenergic blockade leaves the α-adrenergic
vasoconstrictor response unopposed, and it should generally not be used. Beta blockade alone (i.e., with
propranolol) should be avoided because of the danger of sudden death (196). Buchanan et al. (196)
described a child with tetanus who died after propranolol administration, probably from myocardial
failure in the setting of a catecholamine-induced myocarditis. However, the short-acting β-blocking agent
esmolol may be useful (197); phentolamine should be available at the bedside in case esmolol elicits a
hypertensive response (198). Esmolol has been used successfully to control severe tachycardia (>200
beats per minute, associated with arterial desaturation) in a case of NT (199). Clonidine may be a useful
alternative (200), although its efficacy has been questioned (201).
Morphine sulfate is commonly used to control autonomic dysfunction as well as to induce sedation. It
acts centrally by reducing sympathetic tone in the heart and the vascular system, inducing hypotension and
bradycardia. It functions also as an adjunct to deep sedation and controls cardiac instability without
cardiac compromise (202,203). Morphine is often effective, especially when used in concert with
clonidine. Other agents available for the treatment of various autonomic events are atropine, clonidine,
and epidural bupivacaine.
Magnesium should be part of the routine therapy for tetanus. It is a vasodilator by direct action and
through inhibition of catecholamine-induced vasoconstriction. It also reduces catecholamine release from
the adrenal medulla (204) and adrenergic nerve ending (205). Of the drugs used to produce adrenergic
blockade and suppress autonomic hyperactivity in tetanus, only magnesium sulfate was evaluated in a
randomized clinical trial (206) and in clinical series for the management of autonomic dysfunction and as
adjunctive treatment for controlling spasms (191–210). In a randomized, double-blind study of 256
patients, magnesium sulfate infusion (loading dose 40 mg/kg over 30 minutes, followed by continuous
infusion of either 2 g per hour for patients >45 kg or 1.5 g per hour for patients ≤45 kg) was compared to
placebo (206). Magnesium sulfate significantly reduced the need for other drugs to control muscle spasms
and patients were 4.7 times (95% CI, 1.4 to 15.9) less likely to require verapamil to treat cardiovascular
instability than those in the placebo group.
Epidural anesthesia is also effective, perhaps by decreasing adrenal stimulation (210). Excessive
parasympathetic function occurs rarely. If bradycardia or asystole is encountered, a pacemaker should be
considered (211).
Nutrition
Maintenance of adequate nutrition and hydration is of outmost importance. Parenteral nutrition is usually
required. Adequate nutritional support can minimize weight loss, maintain electrolyte balance, and
prevent or improve management of arrhythmias. The nutritional requirements of tetanus patients may be
extraordinarily high because of both their muscular activity and their excessive autonomic activity. The
protein and calories required to maintain a positive nitrogen balance may exceed the maximum tolerable
daily volume of enteral formulas (212). If gastric emptying is impaired, central venous nutrition may be
necessary. Excretory functions must be monitored closely for urinary retention or serious constipation.
COMPLICATIONS OF TETANUS
Potential complications of tetanus include those due to direct effect of the toxin (e.g., laryngeal and
phrenic nerves palsy, cardiomyopathy) and those that are secondary to spasms (e.g., respiratory
compromise causing hypoxic cerebral injury, rhabdomyolysis causing acute renal failure, myositis
ossificans, and vertebral compression fractured) as well as the psychologic impact.
Pulmonary aspiration and breathing or swallowing complications are treated by intubation,
tracheostomy, constant suctioning, and care in an ICU. Early removal of tracheostomy can prevent tracheal
stenosis. Skin care can prevent and treat skin conditions such as decubitus ulcers. Parenteral nutrition and
enteral feeding deals with nutritional problems; prophylaxis of thromboembolism with heparin, low-
molecular-weight heparin, or other anticoagulants can treat thromboembolic disease. Prophylactic
treatment with sucralfate or acid blockers may avert gastrointestinal hemorrhage. Infection control
measures are necessary to prevent nosocomial infection.
In the past, respiratory dysfunction was the most feared result of tetanus and was the major cause of
death. The neuropathologic consequences of hypoxia (in concert with hyperthermia) probably accounted
for earlier reports of brainstem neuronal destruction in this disease (101). However, the CNS and
systemic consequences of hypoxia continue to occur, because of either delayed or inadequate treatment of
respiratory problems (213). Cardiovascular consequences of autonomic instability, including
cardiomyopathy, are still seen and may be less amenable to secondary prevention.
In the series of Vieira and Brauner (66) from 1993, the most common complications in patients with
severe tetanus were respiratory and urinary tract infections related to the use of mechanical ventilation
and indwelling catheters. The increased survival associated with the use of intensive care made
autonomic hyperactivity the major cause of death. Other complications in this series included cardiac
arrhythmias, pneumothoraxes, and atelectasis. Renal failure was uncommon, but special care was taken to
ensure adequate hydration.
Phrenic and laryngeal neuropathies as a consequence of tetanus may occur (83,85). Other
mononeuropathies probably also occur. As in any sedated or paralyzed patient, care must be taken to
prevent common peroneal nerve compression at the fibular head, which produces footdrop.
Rhabdomyolysis, which may lead to acute renal failure (214), is very common in generalized tetanus. If
the serum creatine kinase level exceeds 5,000 U/L or myoglobin is detected in the urine, hydration with
normal saline and urinary alkalinization with sodium bicarbonate should be considered. Rarely, acute
renal failure requiring dialysis may occur (215). Myositis ossificans circumscripta is a long-term
complication of severe muscular hyperactivity, coupled with hematoma formation and anoxia. Vertebral
compression fractures are common, especially in older patients. In a study from Finland, 13 of 20 tetanus
survivors had subsequent rheumatologic disorders, predominantly hyperostoses at sites of tendon
insertion and osteoarthritis of the elbows (216). About 40% of patients have psychologic aftereffects, and
25% feel that their health has permanently worsened in some manner after recovery from tetanus (213).
Other late sequelae include mild developmental delay in children (217).
PREVENTION
Local wound care, including surgical debridement, is essential. Foreign bodies should be removed and
wounds irrigated well and left open. Excision of necrotic tissue may be required, but excision of the
umbilical stump is no longer recommended in cases of NT.
In the immunocompetent host, tetanus is an “inexcusable disease” (218). Active immunization with
tetanus toxoid is one of the most effective preventive measures in medicine, and passive immunization
may be performed at the time of any tetanus-prone wound. Preventing one case of tetanus saves enough
health care expense to immunize several thousand people (219). The WHO, in concert with the United
Nations Children’s Fund (UNICEF) and the United Nations Population Fund (UNFPA), set 2005 as the
target date for the elimination of maternal and neonatal tetanus (defined as fewer than one case per
thousand livebirths in every district of every country) (220). Zimbabwe and Namibia have recently
achieved this goal (221,222). Although progress continues to be made, according to UNICEF, by
November 2012, 31 countries have not reached maternal and neonatal tetanus elimination status
(http://www.who.int/immunization_monitoring/diseases/MNTE_initiative/en/index.html).
Prophylactic Active Immunization
Active immunization with tetanus toxoid is the most effective mean of protection from the illness (223).A
series of three intramuscular injections of tetanus toxoid (10 lyophilized units [Lf]; 0.5 mL) provides
almost complete immunity to tetanus for at least 5 years. Other forms of toxoid are less immunogenic and
should be avoided (224,225). In the United States, five doses of tetanus, diphtheria, and pertussis
vaccines are recommended between 6 weeks and 7 years, and a booster dose is recommended starting at
age 11 years (226). The vaccine to be used varies with age: children younger than 7 years should receive
combined diphtheria-tetanus-pertussis vaccine; if pertussis vaccine is considered to be contraindicated,
diphtheria-tetanus–adsorbed vaccine for pediatric use should be employed (226). In those older than 7
years, tetanus-diphtheria vaccine is recommended. Because of the increase in pertussis cases in the
United States, the CDC and the American Academy of Pediatrics recommended in 2011 the use of tetanus
toxoid–reduced diphtheria toxoid-acellular pertussis (Tdap) vaccine (226). This included a
recommendation for off-label use of Tdap in children aged 7 through 10 years who are not fully
vaccinated against pertussis (226). The complete series must be given; 30% of a group of elderly patients
had inadequate antibody levels 4 years after a series of two injections (all who received three injections
were protected) (227). Routine boosters are given every 10 years; giving them more frequently may
increase the risk of an adverse reaction (228). This 10-year period has never been proven, and one study
suggested that reimmunization may not be required this often (229). With the increasing interest in health
care cost control, some analysts suggest that the routine decennial booster be replaced by a single booster
at age 65 years (230). The authors recommended adopting this practice, despite their demonstration that
the decennial strategy would be more effective, because the single booster approach was predicted to
cost $4,527 per year of life saved, compared to $143,138 for the decennial regimen. Although this type of
analysis deserves serious attention, we believe that clinicians would be well advised to let this debate
play out before adopting this recommendation. The analyses involved many assumptions, such as that of
protection at an antibody concentration of 0.01 IU/mL, which is probably incorrect; used inadequate
estimates for tetanus incidence and for the costs associated with the care of tetanus patients; and omitted
consideration of lost productivity for patients dying of the disease. As others have pointed out, eliminating
decennial boosters also places the population at risk of a resurgence of diphtheria, as has occurred in
Eastern Europe (231).
In the United Kingdom, the Department of Health states that boosters beyond five doses of adsorbed
toxoid “are not recommended, other than at the time of tetanus prone injury, since they have been shown to
be unnecessary and can cause considerable local reactions” (232). Others in the United Kingdom have
tempered this recommendation because of concern regarding waning immunity in the elderly (233). The
contention that further boosters are “unnecessary” remains to be studied adequately.
Substantial progress has been made in the effort to eliminate neonatal tetanus in the developing world,
with a nearly 50% decrease in the number of reported cases between 1989 and 1993 (234). Although the
reported cases are only a small fraction of the actual number, the reporting conditions have been
relatively stable over this period, so the decrease is likely to be real. NT decreased from 0.146 million
(uncertainty range [UR] 0.068 to 0.590) to 0.058 million (UR 0.020 to 0.276) at 9.5% (UR 0.9 to 17.8%)
per year between 2000 and 2010 (11). In 1993, the WHO still estimated 515,000 deaths attributable to
neonatal tetanus. The number was reduced to less than a third of a million by 2010 (11). In a novel
approach, one group administered a single 250-Lf dose of tetanus toxoid to unimmunized third-trimester
primigravid women and showed that both mothers and babies developed protective antibody titers (235).
Although TS does not cross the placenta, it appears that small amounts of tetanus toxoid can; 78% of
infants born to recently immunized mothers in one study showed immunoglobulin M (IgM) cord blood
antibody responses to tetanus toxoid, although none developed an IgG response as maternal antibody
waned (236). Topical antimicrobial treatment of the umbilical stump represents a novel approach that
appears even more effective in preventing neonatal tetanus than either hand washing by the birth
attendants or maternal immunization (237).
Immunization of patients before surgery is rarely considered, but case reports of tetanus following
surgical procedures (summarized by Singh et al. [238]) raise the possibility that this should be
considered, at least in cases in which antibiotic prophylaxis for other indications is not employed.
In a small number of patients with humoral immunodeficiencies, the prescribed toxoid regimen did not
produce immunity (239). Although antitetanus antibody is usually of the IgG1 subclass, three of six
children with isolated IgG2 deficiency demonstrated poor responses to tetanus toxoid (240). This may
also be true of some patients infected with human immunodeficiency virus (HIV) (241). However, a study
in Denmark showed that all of a cohort of 78 HIV-infected men had antitetanus antibody concentrations
exceeding 0.01 IU/mL; most had concentrations more than 0.1 IU/mL (242). The peripheral blood CD4+
cell concentration did not appear to affect the antibody titer. Similarly, in a study of children who were
HIV seropositive at birth, all who received three doses of tetanus toxoid achieved the 0.1 IU/mL antibody
concentration previously deemed protective (243). However, children infected with HIV developed
lower antibody concentrations than those who became HIV seronegative. Although limited in vitro
evidence suggests that tetanus toxoid immunization may provoke HIV activation (244), there is no clinical
evidence to suggest that patients with HIV infection should not receive tetanus toxoid when indicated.
However, loss of response to soluble antigens like tetanus toxoid is one of the first immunologic
consequences of HIV infection (245), suggesting that HIV-infected patients may not become immune after
toxoid administration.
Acute leukemias produce a deficit in antibody concentrations to tetanus toxoid (246), and patients who
undergo bone marrow transplantation lose their preexisting antitetanus immunity. This occurs by the fourth
posttransplant month in patients with allogeneic transplants who develop graft-versus-host disease
(GVHD), by the eighth month in similar patients without GVHD, and by the twentieth month in patients
undergoing autologous transplantations (247). A series of three reimmunizations beginning 9 to 12 months
posttransplantation will restore immunity (248). This appears to be the same for patients undergoing stem
cell transplantation (249). In renal transplant recipients, in contrast, immunosuppression (at least with
mycophenolate) does not appear to impair in vitro measures of antitetanus immunity (250).
Extremely premature infants (born before the twenty-ninth week of gestation and weighing <1 kg at
birth) make presumably adequate responses to a primary immunization series against diphtheria,
pertussis, and tetanus begun at the chronologic age of 2 months (251). Therefore, routine immunizations
against these three diseases should not be delayed on the basis of prematurity.
Administration of the Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine
in the same syringe as the diphtheria-tetanus-pertussis vaccine does not appear to impair antibody
responses (252).
Whenever a question of immunity to TS exists (whether it is due to failure of immunization or an
underlying disorder of immunity), passive immunization with HTIG is indicated after tetanus-prone
injuries unless immunity to TS has been serologically demonstrated recently.
Immunization following Injury
All patients who last received tetanus toxoid more than 10 years before any injury that brings them to
medical attention or who do not recall the date of their last immunization should receive active
immunization with tetanus toxoid–containing vaccine. If their wounds are considered tetanus prone, they
should be immunized if it has been more than 5 years since their last immunization. Patients in whom the
prior immunization history is incomplete or unknown should receive a full series of three monthly
injections.
Administration of a single booster dose of tetanus toxoid does not produce a rapid anamnestic response
in patients who are more than 10 years from their last immunization (253). A tetanus-prone wound in a
patient with an incomplete or uncertain initial immunization history should prompt passive immunization
with HTIG (250 units, intramuscularly). HTIG should also be considered for those whose immune status
is in question.
The standard recommendation of 250 units of HTIG has been questioned, based on the need to achieve
antibody concentrations higher than 0.01 IU/mL. A dose of 500 units (or 8 IU/kg in children) is necessary
to achieve an antibody concentration of 0.1 IU/mL (254).
Most authors suggest that HTIG and tetanus toxoid may be given at the same time as long as different
sites are employed. A study of this question concluded that simultaneous administration impaired the
immune response to tetanus toxoid in patients with low prevaccination antibody concentrations (it was
still adequate; however, its long-term stability is uncertain) (255). Whether such patients should receive
another dose of tetanus toxoid in 4 weeks is uncertain.
Adverse Reactions to Tetanus Toxoid
A mild degree of local tenderness and edema is common after tetanus toxoid booster injections, and fever
is occasionally noted. Rare anaphylactoid responses and delayed hypersensitivity to the preservative
thiomersal were documented in a large survey (256). Peripheral neuropathic complications (257), which
may resemble the Guillain-Barré syndrome (258) or may be relapsing (259), have been the subject of
case reports. CNS reactions have been reported rarely (260). In most of these reports, patients received
more than one vaccine or had other confounding events such as injury, which make assignment of the
apparent adverse event to a single cause difficult.
Doses of tetanus toxoid lower than the usually recommended 7.5 to 10.0 Lf (i.e., 0.75, 1.9, and 2.5 Lf)
will produce an adequate anamnestic response at 1 month in patients who have had an adequate primary
immunization series (261). In a study of 102 patients, there was no difference in the rate of adverse
reactions among patients receiving different doses, but the sample size had inadequate power to detect
such differences reliably.
ACKNOWLEDGMENTS
The author gratefully acknowledges Tomas P. Bleck and Janette Salles Brauner who wrote this chapter for
the previous edition of this book.
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PART V ■ SPIROCHETAL INFECTIONS
CHAPTER 38 NEUROSYPHILIS
CHRISTINA M. MARRA
ETIOLOGY
Syphilis is caused by the bacterium Treponema pallidum subspecies pallidum, a pathogenic treponeme
that cannot be cultured in vitro. The ability of this organism to invade the central nervous system (CNS)
was carefully documented by investigators in the early 1900s who showed that cerebrospinal fluid (CSF)
abnormalities such as mononuclear pleocytosis, elevated protein and globulin concentrations, and
reactive CSF Wassermann test (the predecessor of the Venereal Disease Research Laboratory [VDRL]
and the rapid plasma reagin [RPR] tests) were common findings in primary and secondary syphilis. In
most of these studies, CSF was examined 6 months after at least one course of arsphenamine, the then-
used syphilis therapy, because of concern that lumbar puncture could infect a previously sterile fluid with
T. pallidum (1). Despite this delay in obtaining CSF and the potential effect of nonpenicillin treatment on
the CSF formula, several studies showed that 10% to 20% of patients with primary and 30% to 70% of
patients with secondary syphilis had CSF abnormalities. These abnormalities were more common in
seropositive primary than seronegative primary syphilis, and reactive CSF Wassermann tests were more
common with longer duration of infection (2–5). Additionally, T. pallidum could be identified in CSF
from patients with early syphilis. For example, Chesney and Kemp (6) recovered T. pallidum from CSF
by rabbit inoculation in 5 (15%) of 34 patients with untreated secondary syphilis who had no other CSF
abnormality.
Modern investigations confirm the high likelihood of neuroinvasion by T. pallidum in early syphilis. In
a study of 40 individuals with untreated primary and secondary syphilis by Lukehart and coworkers (7),
16 (40%) subjects had CSF pleocytosis, 8 (20%) had a reactive CSF-VDRL, and 12 (30%) had T.
pallidum identified in CSF by rabbit inoculation. In a study that included 145 individuals with untreated
primary, secondary, and early latent syphilis by Rolfs and coworkers (8), 44 (30%) of 145 subjects had
CSF pleocytosis, 44 (30%) of 144 had a reactive CSF-VDRL, and 32 (24%) of 131 had T. pallidum
identified in CSF by rabbit inoculation or polymerase chain reaction (PCR). In a more recent study of 326
patients with early and late syphilis, including individuals who had been treated for syphilis before CSF
collection, T. pallidum was detected in CSF by reverse transcriptase PCR in 26 (8%) patients (9).
Detection was significantly more likely in patients with early syphilis, in those with serum RPR titers
greater than or equal to 1:32, and in CSF samples that were VDRL-reactive or had higher white blood
cell (WBC) counts (9).
Many early authors distinguished between CNS invasion and involvement by T. pallidum. They
believed that the nervous system was invaded in most patients early in the course of infection, but that this
was transient in many instances. Ravaut is credited with the statement that CSF abnormalities clear by the
end of the secondary stage of syphilis in 70% of individuals (10). Those who do not clear CNS organisms
were deemed to have CNS involvement as indicated by persistent CSF abnormalities, and these patients
were at risk for symptomatic neurosyphilis (see later discussion). When the results of cross-sectional
studies are pooled, the proportion with CSF abnormalities is lower in patients with late compared to
early syphilis. However, not all studies of CSF abnormalities in syphilis supported the concept of
spontaneous clearance. Wile and Marshall (11) showed that CSF pleocytosis was seen in 211 (28%) of
744 patients with primary and secondary syphilis and in 163 (29%) of 568 patients with latent syphilis.
Moreover, the proportion of individuals with reactive CSF Wassermann tests was slightly higher in those
with latent syphilis (20% vs. 28%). On the other hand, Hahn et al. (12) showed that in 290 patients with
asymptomatic neurosyphilis (abnormal CSF findings but no neurologic abnormalities) who were treated
with unspecified agents and had a known duration of infection, those who had syphilis for less time were
more likely to normalize their CSF abnormalities. Specifically, CSF became normal in 54 (57%) of 94
individuals with syphilis for less than 2 years compared to 70 (36%) of 196 with syphilis for 2 years or
more. The confounding factor in this analysis is that those with a less abnormal CSF profile, most notably
a nonreactive CSF Wassermann test, were also more likely to normalize, and we know from the data
outlined earlier that CSF Wassermann tests were more likely to be positive in later syphilis.
Regardless of whether CSF abnormalities clear spontaneously in some individuals, several studies in
the preantibiotic era showed that the more abnormal the CSF profile in any stage of syphilis, the greater
the risk of symptomatic neurosyphilis. For example, Moore and Hopkins (13) followed 123 individuals
with CSF abnormalities due to syphilis for an average of 7 years; 55 patients had early and 68 had late
syphilis and all were neurologically asymptomatic. Nineteen patients, 7 (13%) with early and 12 (21%)
with late syphilis, developed clinically definite neurosyphilis, most often dementia. The patients with the
most abnormal CSF were the most likely to develop symptomatic neurosyphilis despite nonpenicillin
therapy. Hahn and coworkers (12) reviewed the records of 533 patients with asymptomatic neurosyphilis
who had undergone at least two CSF examinations over periods ranging from 6 months to more than 10
years. Using life-table analysis, they demonstrated that progression to symptomatic neurosyphilis was five
times more likely in those in whom CSF was unchanged or worse on repeat examination, compared to
those in whom CSF normalized or improved. They concluded that 20% of individuals with asymptomatic
neurosyphilis would develop symptomatic neurosyphilis over a 10-year period.
Conversely, a normal CSF examination suggested that symptomatic neurosyphilis would not develop.
For example, Moore and Kemp (14) followed 54 patients who had a normal CSF examination after 6
months of nonpenicillin treatment for early syphilis. Subsequent examinations were usually performed 2
years later and were abnormal in only three patients; all three had evidence of reinfection or recurrence.
Similarly, Hopkins (15) conducted 2- to 10-year follow-up on 161 patients with primary and 244 patients
with latent syphilis who had a normal CSF at their first evaluation; 61 individuals with early and 61 with
latent syphilis underwent repeat CSF examination. Only two patients (both with early syphilis) developed
CSF abnormalities and both had evidence for relapse or reinfection. Overall, development of unequivocal
neurosyphilis was uncommon and occurred in 10 (3%) of the 405 patients. O’Leary and coworkers
examined the records of 5,293 patients who had undergone at least one CSF evaluation and had been
followed for at least 2 years (16). Although actual numbers are not provided, these authors concluded that
a normal CSF profile after 6 months of treatment indicated that the CSF would remain normal so as long
as the blood Wasserman test remained nonreactive.
These data show that T. pallidum infects the CNS early in the course of disease in some but not all
patients. Whether this is a consequence of differences in the host or of differences in neuroinvasive
capacity of different T. pallidum strains is not known. Some data support the latter hypothesis. In their
classic text on syphilis, Stokes et al. (10) cited experiments that showed that passage of T. pallidum in
mouse brain rendered the organism more neurotropic in rabbits. In addition, they described several case
reports of clinically identical forms of neurosyphilis developing in multiple sexual partners of a single
individual, presumably due to transmission of a highly neurotropic strain. In the rabbit model, we have
shown that T. pallidum strains vary in their ability to invade and infect the CSF after intravenous
inoculation (17). Moreover, in an analysis of T. pallidum strain types in 83 patients with syphilis in
Seattle, Washington, one type (14d/f) was significantly more common in patients with neurosyphilis
defined as a reactive CSF-VDRL, CSF pleocytosis, or both abnormalities (18). Invasion is the substrate
of subsequent symptomatic neurosyphilis and, in the preantibiotic era, the CSF profile in any stage of
syphilis predicted the risk of symptomatic disease. As stated by Wile and Stokes (3), “The fate of every
syphilitic, however, with regard to the incidence of cerebrospinal lues, whether this occurs early or late
in the course of the disease, is in all probability determined in the first months of infection.” Our
interpretation of these data in the current era must take into account the lower likelihood of CSF
abnormalities after antibiotic treatment of uncomplicated (nonneurologic) syphilis (19–21) and the
influence of concomitant HIV infection on the risk and course of neurosyphilis. Both issues are addressed
in subsequent sections of this chapter.
The neurologic manifestations of syphilis are protean. Neurosyphilis should be considered in the
differential diagnosis of any patient with acute aseptic meningitis, chronic meningitis, stroke involving the
brain or spinal cord, transverse myelitis, chronic myelopathy, and dementia. Because they may share
common neuroimaging findings, meningovascular or parenchymal syphilis should be considered in all
patients in whom herpes encephalitis is a diagnostic consideration.
CLINICAL SYMPTOMS AND FINDINGS

Neurosyphilis has been traditionally considered a late or “tertiary” manifestation of syphilis. In reality,
asymptomatic or symptomatic neurosyphilis can occur at any time after infection. However, the forms of
disease that are characterized by meningeal inflammation (asymptomatic, meningeal, and
meningovascular) are most common in the first months to years after infection and are included under the
category of “early neurosyphilis,” whereas parenchymal forms of neurosyphilis (general paresis and tabes
dorsalis) most commonly occur years or decades after infection and are categorized as the forms of “late
neurosyphilis” (Fig. 38.1). Ocular and otologic disease occur early and late in the course of syphilis,
often, but not always, in combination with meningitis. These syndromes are considered separately in the
following section.
ASYMPTOMATIC NEUROSYPHILIS
Asymptomatic neurosyphilis is diagnosed in a patient with serologic or clinical evidence of syphilis, CSF
abnormalities due to T. pallidum infection, including pleocytosis, elevated protein and reactive CSF-
VDRL, and no neurologic symptoms or signs. Asymptomatic neurosyphilis may occur very early in
infection, even in patients with concomitant primary syphilis. Pleocytosis generally precedes
development of reactive CSF-VDRL. Patients with asymptomatic neurosyphilis are at risk of progression
to symptomatic forms of disease and about 20% of such individuals developed symptomatic neurosyphilis
in the preantibiotic era (12). Thus, patients with asymptomatic neurosyphilis are treated to prevent
progression to symptomatic disease.
SYMPTOMATIC NEUROSYPHILIS
Meningitis
Symptomatic syphilitic meningitis is indistinguishable from other causes of aseptic meningitis. Clinical
findings include meningeal signs, nausea, and vomiting. Papilledema, convulsions, confusion, focal
findings, and cranial nerve (CN) abnormalities, particularly involving CN VIII, VII, and II, were common
in a large series of patients reported by Merritt and Moore (22) in 1935. Syphilitic meningitis was rare in
the preantibiotic era, affecting less than 0.5% of individuals with syphilis (23) and was more commonly
seen in patients who had been inadequately or incompletely treated for early syphilis (1,3,24). In Merritt
and Moore’s (22) series, syphilitic meningitis most commonly occurred within a year of infection (range,
2 months to 26 years) and 7.5% of patients had secondary syphilis at the time that meningitis was
diagnosed. Syphilitic meningitis is more common in the antibiotic era than it was in Merritt and Moore’s
time (25).
Syphilitic meningitis may uncommonly affect the spinal cord, where it manifests as meningomyelitis or
hyperplastic pachymeningitis. Adams and Merritt (26) described 15 cases of meningomyelitis and one
case of hyperplastic meningitis among 2,231 syphilis cases seen at Boston City Hospital. Symptoms and
signs in these patients included back pain, sensory loss, incontinence, leg weakness, and muscle atrophy.
Occasional cases of syphilitic meningomyelitis (27–33), polyradiculopathy (34–38), and amyotrophy (39)
are reported in modern times.
Localized syphilitic meningitis can produce one or more circumscribed masses of granulation tissue
called gumma (26,40–44). Histopathologically, these consist of parenchymal and perivascular infiltration
of lymphocytes and plasma cells with occlusive endarteritis and areas of necrosis (45–47). Gummas have
been mistakenly deemed “tertiary” or late manifestations of neurosyphilis, but in reality, these can be seen
early or late in the course of disease. These most commonly arise from the pia mater, especially over the
convexities (48). Less commonly, parenchymal gumma may be seen without concomitant pial
involvement. These may invade the substance of the brain and spinal cord (49) and may be mistaken for
tumors, including meningioma, schwannoma, glioma, and lymphoma (50–54). CSF analysis often shows
pleocytosis and a reactive CSF-VDRL but may be normal (48,55). Spirochetal organisms have been
identified by histology (54–56), and T. pallidum has been amplified from resected gumma (46,56,57)
(Fig. 38.2).
Ocular Syphilis
Ocular syphilis can befall any patient with syphilis, including those with normal immunity, and is seen in
all stages of disease. Any part of the eye can be involved in T. pallidum infection. Ocular findings may be
seen in patients with and without concomitant syphilitic meningitis; concomitant ocular disease and
meningitis may be particularly common in patients also infected with HIV (58). Ocular manifestations
include optic neuritis (59–61), which causes visual loss, and perineuritis (62–67) in which inflammation
is localized to the optic nerve sheath and spares the nerve itself. Examination shows papilledema,
generally normal visual acuity, except for an enlarged blind spot, and normal CSF pressure. Anterior
uveitis affects the anterior uveal tract, which includes the iris and ciliary body. Symptoms include eye
pain, redness, and photophobia. Asymptomatic involvement of the anterior chamber of the eye has been
described in as many as one half of patients with secondary syphilis (68); a more recent case report of
asymptomatic bilateral anterior uveitis in an HIV-infected man with secondary syphilis underscores this
point (69).
Posterior uveitis is more common than anterior uveitis (70); a systematic review of ocular syphilis in
HIV-infected patients showed that this form of ocular syphilis was more common in HIV-infected
individuals with CD4+ T cells less than 200/µL (71). However, ocular syphilis, including posterior
uveitis, is described in HIV-infected patients with well-controlled HIV infection on antiretroviral therapy
(72,73). Posterior uveitis can involve the choroid, retina, and retinal pigment epithelium. Patients are
described with chorioretinitis, neuroretinitis, retinal vasculitis, and retinal detachment, and syphilis
should be considered in all patients with a diagnosis of acute retinal necrosis syndrome. Posterior uveitis
is usually not painful, can be asymptomatic, or can cause severe visual loss. Visual outcome is generally
good (74–79). A retrospective study of ocular syphilis in 35 eyes from 19 patients showed that poorer
visual acuity at presentation and HIV infection predicted a poorer visual outcome, defined as acuity
worse than 20/200 (70). Moore and Gieske (80) published a large series of patients with syphilitic
uveitis in 1931 and showed that, like syphilitic meningitis, syphilitic uveitis occurred more commonly in
patients who were inadequately treated for early syphilis. In this setting, uveitis was more often
associated with meningitis. Worsening of unsuspected ocular syphilis has been observed after oral
administration of prednisone (81) and after intravitreal administration of triamcinolone acetonide
(82–84). T. pallidum has been identified by PCR in aqueous and vitreous fluid in patients with ocular
syphilis (85–87).
Otologic Syphilis
Otosyphilis can occur in early and late syphilis. Hearing loss can be unilateral or bilateral, and it is often
asymmetrical. Onset may be sudden or insidious, and speech discrimination may be preferentially
affected (88). The symptoms and signs may mimic those of Meniere disease with episodic hearing loss,
tinnitus, and vertigo (89). Hearing loss in otosyphilis may be seen in the presence or absence of syphilitic
meningitis. The pathophysiology of hearing loss in meningitis is likely inflammation of the auditory (CN
VIII) nerve within the subarachnoid space or a “meningo-neuro-labyrinthitis” from spread of CSF
infection to the perilymph via the cochlear aqueduct (90). In the absence of meningitis, the
pathophysiology is more likely to be obliterative vasculitis and osteitis of the cochleovestibular system
and temporal bone with the end result being resorptive osteitis and productive periostitis with
replacement by fat, marrow, or new bone (90–93). Meningo-neuro-labyrinthitis likely progresses to
periostitis, but T. pallidum may also disseminate directly from blood to the inner ear, particularly the
perilymph, without involvement of the CSF. Historically, compared to those with shorter duration of
hearing loss, patients with longer duration of hearing loss due to syphilis were less likely to respond to
otosyphilis treatment; this likely remains true today (94). This difference may reflect the underlying
pathophysiology: in late disease, the cochleovestibular system is irreversibly damaged, arguing for
identification of patients with otosyphilis as early in the disease course as is possible.
Meningovascular Syphilis
Syphilitic meningitis may cause arteritis affecting small (Nissl-Alzheimer endarteritis) or medium and
large vessels (Heubner arteritis), the latter with adventitial inflammation and fibrosis, medial thinning,
and intimal fibroblastic proliferation (95). Thrombosis and ischemia or infarction involving the brain or
spinal cord can occur. Intracranial aneurysms (96,97), intraparenchymal hemorrhage (98), and carotid
dissection have been uncommonly reported (99). Merritt and coworkers (40) described a series of 42
patients with meningovascular syphilis affecting the brain. These patients represented 3% of syphilis
cases seen at their institution and were selected from a possible 250 individuals after excluding
atherosclerotic cerebrovascular disease, cerebral embolism, other forms of neurosyphilis, and other
nonsyphilitic neurologic diseases. Most patients were 30 to 50 years old, and meningovascular syphilis
developed within months to years after infection, with an average of 7 years (23,40). Stroke in the
distribution of the middle cerebral artery was the most common clinical finding, with hemiparesis,
hemiplegia, or aphasia. Many patients experienced prodromal symptoms, such as headache, dizziness, and
personality changes for days or weeks before the onset of stroke. In clinical practice, patients with
meningovascular syphilis often have cognitive impairment and may even be frankly demented (100–108).
The timing of onset after primary syphilis (early) and the presence of focal examination and imaging
findings may help distinguish patients with meningovascular neurosyphilis from those with parenchymal
neurosyphilis or general paresis, but sometimes the distinction can be difficult. As is the case with
symptomatic meningitis, meningovascular syphilis is likely a relatively more common manifestation of
symptomatic neurosyphilis today than it was in the preantibiotic era (25,109,110). Although uncommon,
meningovascular syphilis can be seen in patients with nonreactive serum nontreponemal tests, but
treponemal tests should be reactive to support the diagnosis (111). Recombinant tissue plasminogen
activator has been used successfully in meningovascular syphilis (95,112).
Meningovascular syphilis involving the spinal cord is less common than involvement of brain. Adams
and Merritt (26) described 16 cases of spinal meningovascular syphilis seen among 2,231 syphilis
patients. As a result of thrombosis of spinal vessels, patients develop acute onset of transverse myelitis
characterized by paraplegia, sensory level, usually in the thoracic region, and loss of sphincter control.
Such cases continue to be reported in the modern era (27,113–117).
Parenchymal Neurosyphilis
In the preantibiotic era, the parenchymal or late forms of neurosyphilis were more common than the
meningeal or early forms. Clinical experience suggests that the opposite is true today. Wolters (118)
compared the spectrum of disease in 518 cases of neurosyphilis collected between 1930 and 1940 to 121
cases collected between 1970 and 1984 from the same neurologic clinic of the Academic Hospital of the
University of Amsterdam. He found that parenchymal disease occurred in two thirds of the symptomatic
individuals in 1930 to 1940, but that the proportions of symptomatic meningeal and parenchymal disease
were equal in 1970 to 1984. The observation that late neurosyphilis is less common than early
neurosyphilis is most striking in patients also infected with HIV. This finding may simply be due to the
fact that syphilis is so commonly seen in HIV-infected individuals due to epidemiologic factors (see later
discussion), or that, at least early in the HIV epidemic, HIV-infected patients did not live long enough to
develop late neurosyphilis. Alternatively, therapy for early (nonneurologic) syphilis may be particularly
ineffective in individuals also infected with HIV and may predispose them to develop early neurosyphilis.
This issue is discussed in the section “Neurosyphilis and HIV” later in this chapter. Several authors have
speculated that the shift in clinical presentation of neurosyphilis from late to early disease is due to
inadvertent treatment with antibiotics prescribed for unrelated conditions. This contention is supported by
observations collected in the preantibiotic era noted earlier that partial or incomplete therapy predisposes
individuals infected with T. pallidum to develop the early forms of neurosyphilis, including meningitis,
meningovasculitis, and ocular disease (1,3,24,80). Arguing against this hypothesis, in 2004, Timmermans
and Carr (108) reported the clinical spectrum of neurosyphilis in 161 patients in South Africa,
approximately 6% of whom were HIV-infected. These individuals had poor access to health care and
were unlikely to have received “incidental” antibiotics, yet the proportion with tabes dorsalis (2 [1%] of
161) was much lower than reported in the preantibiotic era.
Syphilitic Dementia: General Paresis
General paresis, also known as general paralysis of the insane or dementia paralytica, was estimated by
Merritt and coworkers (40) to develop in 5% of cases of syphilis. In their experience, it was most
commonly seen in individuals 35 to 50 years of age and occurred from 5 to 25 years after primary
infection (40). In a series by Hahn and coworkers (119), most patients with general paresis had been
infected for 10 to 24 years (range 2 to more than 30 years), and in a series reported by Dewhurst (120),
duration of infection was 4 to 15 years with a mean of 10.5 years.
Merritt et al. (40) stated that the clinical manifestations of general paresis mimic “every type of mental
disorder” (p. 194). Early in the course of this chronic, progressive, dementing illness, patients are
forgetful and have personality changes. With time, they may develop psychiatric symptoms, such as mania,
depression, or psychosis. However, most patients simply experience worsening of deficits in memory and
judgment progressing to frank dementia. In its latest stages, patients become immobile and incontinent and
may have seizures. The most frequent neurologic examination findings are pupillary abnormalities; facial
and limb hypotonia; intention tremors of the face, tongue, and hands that can cause dysarthria and
handwriting abnormalities; and reflex abnormalities. Early in the course of disease, the neurologic
examination can be normal. The average survival after diagnosis in Merritt and coworkers’ (40)
experience was 2.5 years. Intercurrent infection was the most common cause of death in the preantibiotic
era. With the availability of antibiotics for syphilis and other infections, as well as better supportive care,
survival is longer.
Cases of syphilitic dementia continue to be reported in the modern era, generally characterized by
rapidly progressive dementia with or without psychiatric features (121,122). A retrospective series of
116 patients with general paresis diagnosed in three Chinese hospitals identified dementia, personality
change, abnormal behavior, and emotional problems as the most common findings (123). As noted earlier,
there is clinical overlap between syphilitic dementia and meningovascular disease (124,125). Patients
with syphilitic dementia may show background slowing on electroencephalogram (EEG), periodic
lateralized epileptiform discharges (PLEDS) or epileptiform discharges (123,124,126). In the large
Chinese series discussed earlier, seizures were seen in 16% of patients with syphilitic dementia. Of note,
neurosyphilis was not suspected initially in 36% of patients in that series (123). A smaller series from
China compared performance on comprehensive neuropsychological testing in 12 patients with mild
syphilitic dementia to 24 patients with mild Alzheimer disease matched with regard to age, education, and
Mini Mental State scores (127). The two groups had very similar patterns of impairment.
Tabes Dorsalis
Tabes dorsalis or locomotor ataxia was the most common form of neurosyphilis described in the
preantibiotic era. Merritt and coworkers (40) established the diagnosis of tabes in 9% of 2,231 patients
with syphilis seen in the outpatient department of the Boston City Hospital. Tabes was typically seen in
patients between 44 and 60 years of age, and onset ranged from 3 to 47 years after primary infection, with
an average of 21 years (40).
The most common symptoms of tabes are pupillary abnormalities, optic atrophy, lancinating pains,
sensory changes, progressive ataxia, and bowel and bladder dysfunction. Pupillary abnormalities were
described in 94% of cases reported by Merritt and coworkers (40). They defined the Argyll Robertson
pupil as a small pupil that does not respond to light but does contract normally to accommodation–
convergence, dilates imperfectly to mydriatics, and does not dilate in response to painful stimuli. Using
this rather stringent definition, 48% of patients with tabes had Argyll Robertson pupils (40). Optic
atrophy was seen in 16% of Merritt and coworkers’ series (40). The clinical findings in optic atrophy
include gradual decrease in visual acuity with constriction of the peripheral visual fields and central
scotomata on examination. Untreated, this disorder progresses to complete blindness over months to years
(128). Lightning or lancinating pains, seen in 75% of 150 cases of tabes collected by Merritt and
coworkers (40), are sudden, brief stabs of pain that may affect the legs, back, arms, and face. They may
last for minutes to days and occur unpredictably, sometimes separated by long remissions. Visceral crises
occurred in 10% to 15% of patients with tabes (40). The most common type was the gastric crisis,
characterized by recurrent attacks of severe epigastric pain, nausea, and vomiting. Early sensory changes
include paresthesias or hyperesthesias in radicular distributions. Later, pain, vibration, and tactile
sensation become impaired, and reflexes are lost. Sensory ataxia, usually involving the lower more than
the upper extremities, was a feature in 42% of Merritt and coworkers’ patients (40). Bladder dysfunction
may occur early with urinary retention and overflow incontinence. A similar process affects the bowel,
although fecal incontinence is unusual. As noted earlier, tabes is now an uncommon form of neurosyphilis,
but cases continue to be described (129–131).
Congenital Neurosyphilis
As in adults, T. pallidum may invade the CNS in infants exposed to the organism in utero or at birth. For
example, T. pallidum was identified by rabbit inoculation in CSF from 19 (13%) of 148 infants born to
mothers with syphilis (132). The manifestations and clinical course of congenital neurosyphilis parallel
that of acquired disease, and early and late forms of symptomatic neurosyphilis have similar latent
periods. Thus, congenital meningeal neurosyphilis is seen in infancy and meningovascular disease in the
first few years of life. Parenchymal disease usually has its onset around puberty or in early adulthood
(40).
LABORATORY AND IMAGING STUDIES

Cerebrospinal Fluid
The diagnosis of symptomatic neurosyphilis is based on clinical evidence and is supported by CSF
abnormalities, particularly pleocytosis and reactive CSF-VDRL. As noted earlier, the diagnosis of
asymptomatic neurosyphilis is based on the presence of CSF abnormalities alone. CSF WBC
concentration in neurosyphilis is generally greater than 10 cells/µL with a lymphocytic predominance
(Table 38.1). Higher cell counts are seen in early compared to late neurosyphilis. For example, in an
examination of CSF from 100 patients with tabes dorsalis, Merritt and coworkers (40) found that 50%
had less than 5 WBC/µL. Mild elevations in CSF protein, ranging between 45 and 200 mg/dL are also
common, again with higher values in early compared to late neurosyphilis. The CSF-VDRL is considered
to be the gold standard test for diagnosis of neurosyphilis. However, depending on the diagnostic criteria
chosen, the CSF-VDRL may be reactive in 0% to 100% of individuals with neurosyphilis; the generally
accepted sensitivity is 30% to 70%. The CSF-VDRL test is very specific. False-positive results may be
seen when the CSF is visibly blood tinged (133,134) and rarely in the absence of blood contamination
(135). Thus, a reactive CSF-VDRL establishes the diagnosis of neurosyphilis, but a nonreactive test does
not exclude the diagnosis.
The CSF-VDRL test is not available in some parts of the world, and the test method is technically
cumbersome. Larsen and colleagues (136) suggested that the CSF-RPR and CSF-toluidine red unheated
serum test (TRUST), two alternative nontreponemal tests that are less logistically complicated to perform
than the CSF-VDRL, should not be used to diagnose neurosyphilis because of false-positive results.
However, two more recent studies suggested that the CSF-RPR (137) or CSF-TRUST (138) could be
suitable alternatives to the CSF-VDRL, reporting sensitivities of 75% and 95% and specificities of 99%
and 100% for laboratory-defined neurosyphilis. We examined the diagnostic performance of the CSF-
RPR compared to the CSF-VDRL. Although the CSF-RPR was significantly more specific for the
diagnosis of symptomatic neurosyphilis, compared to the CSF-VDRL, the CSF-RPR was negative in 36%
of CSF-VDRL-reactive samples (139). A large study from China examined concordance of CSF-VDRL
and CSF-TRUST and found that qualitative results were the same 97% of the time. However, of 204 CSF-
VDRL reactive samples, 22 (11%) were CSF-TRUST nonreactive (140). Thus, the problem of low
diagnostic sensitivity of the CSF-VDRL is likely greater for alternative CSF nontreponemal tests.
In contrast to the CSF-VDRL, several studies have shown that CSF treponemal antibody tests, such as
the CSF fluorescent treponemal antibody-absorption (FTA-ABS) or the CSF-Treponema pallidum
particle agglutination assay (TPPA), are sensitive but not specific for the diagnosis of neurosyphilis
(141–146). As noted in a systemic review of such work, the sensitivity of these tests is highest when the
diagnosis of neurosyphilis is based on CSF-VDRL reactivity (147). Thus, nonreactive CSF treponemal
antibody tests exclude the diagnosis of asymptomatic neurosyphilis with a high degree of certainty, but a
negative result is less able to exclude symptomatic neurosyphilis. Sera from patients with reactive CSF
treponemal antibody tests have higher treponemal antibody titers than sera from those with nonreactive
CSF treponemal tests, suggesting that reactive CSF treponemal tests may simply be a surrogate for higher
serum antibody concentration (141,148). However, one study suggested that a CSF-Treponema pallidum
hemagglutination (TPHA) test titer greater than 1:320 (the TPHA is an alternative treponemal test that is
not available in the United States) was sensitive and specific for the diagnosis of neurosyphilis (149),
suggesting that there may be a CSF treponemal antibody concentration above which intrathecal antibody
production is more likely.
T. pallidum may be identified in CSF by inoculation into rabbits (150). However, rabbit inoculation is
too cumbersome and expensive to be clinically useful. PCR or RT-PCR can be used to detect T. pallidum
in CSF with a limit of detection similar to that of rabbit inoculation (9,151). T. pallidum can be detected
in CSF from 25% to 30% of patients with early syphilis; detection is much less likely in late syphilis
(7–9). In our experience, T. pallidum is most often detectable in samples with reactive CSF-VDRL or
CSF pleocytosis, limiting its usefulness in neurosyphilis diagnosis (9).
The proportion of CSF lymphocytes that are B cells (145), and the CSF concentration of
chemoattractant chemokine (C-X-C motif) ligand 13 (CXCL13), a B-cell chemoattractant, are elevated in
patients with neurosyphilis compared to patients with uncomplicated syphilis (152,153). Although these
tests show promise for improving neurosyphilis diagnosis, particularly in patients infected with HIV
(152), they are not in routine clinical use. A study in HIV-uninfected patients that included 12 with late
neurosyphilis, 17 with uncomplicated syphilis, and 14 normal controls showed that a CSF total tau
protein concentration higher than 300 pg/mL, a cutoff that has been used to diagnose Alzheimer disease,
had a diagnostic sensitivity of 83% and a diagnostic specificity of 94% (154). The diagnostic
performance in HIV-infected individuals or in those with early neurosyphilis is not known, and these
results remain to be replicated.
Several studies have examined predictors of abnormal CSF in neurologically asymptomatic and
symptomatic patients with syphilis. The odds of neurosyphilis are higher when serum RPR titers are
greater than or equal to 1:32 (approximately 11-fold in HIV-uninfected and sixfold in HIV-infected
patients, regardless of syphilis stage or previous syphilis treatment [9]), and in HIV-infected individuals,
when peripheral blood CD4+ T cells are less than or equal to 350 cells/µL (9,155,156). Also, HIV-
infected patients with syphilis who are taking antiretrovirals may be at lower risk of neurosyphilis than
those who are not taking them (157). A small, retrospective study suggested that high plasma HIV RNA
concentration increased the risk of neurosyphilis among individuals with peripheral blood CD4+ T cells
greater than 350 cells/µL (158).
As noted earlier, asymptomatic neurosyphilis is defined solely by CSF abnormalities, and, in the
preantibiotic era, neurologically asymptomatic patients with syphilis of any stage who had the most
abnormal CSF measures were at highest risk for developing symptomatic neurosyphilis. This observation
prompted universal lumbar puncture (LP) in all stages of syphilis. The subsequent observation that CSF
abnormalities were uncommon in patients with early syphilis who were treated with penicillin
(19–21,159) led to recommendations to reserve the procedure for neurologically asymptomatic patients
with late syphilis. With the advent of HIV, the appreciation that benzathine penicillin G (BPG) used to
treat uncomplicated syphilis does not achieve treponemicidal penicillin levels in the CSF (160), and
concerns regarding neurorelapse in this patient population (see later discussion), the issue of which
patients with syphilis should undergo LP again arose and has remained an area of ongoing controversy. A
panel of experts convened by the Centers for Disease Control and Prevention (CDC) has provided
guidelines for LP in syphilis. Although they have consistently recommended LP for patients with
neurologic, ocular, or otologic symptoms and signs, and for patients who have failed treatment for
uncomplicated syphilis, over the years, changes have been made, sometimes in the absence of new data.
For example, in the 2002 guidelines, LP was recommended for all HIV-infected patients with late latent
syphilis or syphilis of unknown duration (161). The 2006 guidelines additionally indicated that some
experts recommended LP when the serum RPR titer was greater than or equal to 1:32 or when the
peripheral blood CD4+ T cells were less than or equal to 350 cells/µL (162). In the 2010 version of the
guidelines, however, the recommendation for LP in HIV-infected patients with late syphilis or syphilis of
unknown duration was removed. In addition, consideration of LP in HIV-infected patients with high serum
RPR titer or low CD4 was rescinded, stating, “Unless neurologic symptoms are present, CSF examination
in this setting has not been associated with improved clinical outcomes” (163). This language is repeated
in the 2013 Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults
and adolescents (http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf). In contrast, the 2008
European Guidelines on the Management of Syphilis (164) state that LP is indicated for HIV-infected
patients with syphilis, especially those who have serum RPR titers greater than 1:32 or peripheral blood
CD4+ T cells less than 350 cells/µL; a footnote adds “not obligatory, but may be indicated in late latent
syphilis or syphilis of unknown duration or in treatment failure,” perhaps underscoring the lack of
consensus regarding this issue. There are no modern day clinical outcome data to guide decisions
regarding which HIV-infected or HIV-uninfected patients with syphilis should undergo LP. The safest or
most conservative approach is to perform LP in patients with high serum RPR titers or low peripheral
blood CD4+ T-cell concentrations. However, the magnitude of averted morbidity in terms of preventing
symptomatic neurologic, ocular, or otologic disease of this approach is unknown. Suggested
recommendations for LP in patients with syphilis are shown in Figure 38.3A and B.
Neuroimaging
Neuroimaging in patients with asymptomatic neurosyphilis is usually normal (165). Neuroimaging in

syphilitic meningitis involving brain or spinal cord may show enhancement of meninges, spinal fluid,
cranial nerves, or spinal roots (35, 166–169). Enhancement of the cochlea (likely early) (169,170) and
lucency within the otic capsule and ossicular chain (late) (93) may be seen in syphilitic hearing loss.
Cerebral gummas are low intensity on T1-weighted MR sequences, isointense or high intensity on T2-
weighted sequences, enhance homogenously, sometimes with a nodular component and often with a dural
tail, and have associated edema (42,48,49,165,171,172) (Fig. 38.2). They can sometimes have the
appearance of nodular basilar meningitis (44). One report described restricted diffusion in the region of
cortical enhancement and the dural tail (172).
Brain computed tomographic (CT) and magnetic resonance (MR) scans in meningovascular syphilis
show one or more areas of infarction (102,165,168,173,174); infarctions in multiple vascular
distributions are often seen with diffuse vasculitis (175,176). Catheter, CT, or MR angiographic findings
in meningovascular neurosyphilis include segmental arterial narrowing, focal narrowing and dilation, or
“beading,” and occlusion, which may sometimes mimic vasospasm (97,100,177–179).
Meningitis or meningovasculitis affecting the spinal cord may show intramedullary high signal on T2-
weighted images; enhancement may or may not be seen on T1-weighted images after administration of
contrast material (30,32,117,180,181). Rare cases of syrinx in association with meningeal syphilis have
been reported (31,33).
Brain MR in patients with syphilitic dementia may show cerebral or cortical atrophy with
ventriculomegaly, focal or diffuse white matter changes, and low signal intensity on T2-weighted
sequences in the globus pallidus, putamen, caudate head, and thalamus (124,125,168,182). In one study of
20 patients with neurosyphilis defined by CSF abnormalities and psychiatric symptoms and signs,
measures of brain atrophy on MR were significantly worse in patients with lower scores on the Mini
Mental State (125). Medial temporal lobe atrophy may be particularly common (127) and hippocampal
atrophy on MR mimicking Alzheimer disease has been reported (183). A study of seven patients with
syphilitic dementia showed that the three with medial temporal lobe atrophy had poorer outcome after
treatment than the four patients who did not have this finding; of note, those with temporal lobe atrophy
also had atrophy of the frontal lobes and dilation of the ventricles out of proportion to the overall degree
of atrophy (184).
Several reports of meningovascular or parenchymal neurosyphilis with high signal on T2-weighted MR
sequences mimicking herpes encephalitis have been published (101,103–106, 126,168,185,186). In most,
but not all, instances, patients had seizures or PLEDS, which could explain the abnormal imaging
findings. In one report, biopsy of the affected temporal lobe showed astrocytosis and scant plasma cell
infiltration with detection of T. pallidum DNA by PCR (187).
Spinal cord MR in patients with tabes dorsalis may show increased intramedullary T2 signal,
particularly in the posterior columns and cord atrophy (35,131,168).
Evoked Potentials
In tabes dorsalis, motor and sensory nerve conductions are normal. Somatosensory evoked potentials
elicited from the median nerve are normal, whereas those elicited by stimulation of the tibial nerve show
abnormalities consistent with dysfunction of the caudal dorsal roots and posterior columns (35,188–190).

There has never been a large study of currently recommended (163) penicillin regimens for the treatment
of neurosyphilis. These regimens are based on the observation that intravenous (IV) crystalline penicillin
G in doses from 5 to 24 million units (MU) per day achieves treponemicidal CSF levels (160,191,192).
Similarly, most (but not all) reports document treponemicidal CSF penicillin levels after intramuscular
procaine penicillin, 2.4 MU per day, with oral probenecid (193–195). The CDC recommends high-dose
IV penicillin G as the first-line therapy for neurosyphilis; IM procaine penicillin with oral probenecid is
an alternative in adults, but not children (163) (Table 38.2). Ocular and otosyphilis are treated as for
neurosyphilis; steroids are sometimes recommended as an adjunctive therapy.
Case reports in HIV-uninfected and HIV-infected individuals with early and late neurosyphilis and
ocular syphilis (28,196–198), and a small study in HIV-infected patients with early neurosyphilis (199)
suggest that ceftriaxone, 1 to 2 g IV every day, may be an acceptable alternative to penicillin. Based on
CSF drug concentrations and pharmacologic properties, doxycycline may be an effective alternative oral
treatment for neurosyphilis. The European (164) and United Kingdom (200) syphilis guidelines
recommend doxycycline 200 mg orally twice daily for 28 days as an alternative neurosyphilis treatment
regimen. The European guidelines reserve this regimen for patients who are allergic to penicillin or who
refuse parenteral therapy. Although such recommendations acknowledge that the evidence for the efficacy
of doxycycline for neurosyphilis is weak (164,201), case reports describe instances of treatment success
(202). The CDC guidelines do not recommend doxycycline as an alternative treatment for neurosyphilis.
Rather, they recommend penicillin desensitization for penicillin-allergic patients with neurosyphilis in
whom ceftriaxone is not an option (163).
The success of neurosyphilis therapy is judged by resolution or stabilization of clinical abnormalities
and by resolution of CSF abnormalities. Clinical abnormalities are more likely to resolve when there has
not been structural CNS damage. Patients with syphilitic meningitis can be expected to recover
completely, although if they have concomitant ocular or otologic injury, deficits may persist. Complete
resolution is the rule after antibiotic therapy for intracranial gumma; these lesions may also resolve after
steroid therapy alone (48), but this is not recommended as it will not treat the underlying infection.
Patients with meningovascular syphilis will likely resolve meningeal symptoms and signs but will be left
with residual stroke symptoms and signs. Similarly, treatment of patients with paresis or tabes will arrest
disease progression but is unlikely to reverse dementia or sensory ataxia.
The CDC guidelines state that CSF WBC count should decline at 6 months and all CSF abnormalities
should resolve by 2 years after treatment (163). Careful follow-up after neurosyphilis therapy is
mandatory for all patients. We recommend that CSF be reexamined 3 months after therapy, rather than 6
months, to decrease patient loss to follow-up and because the median time for normalization of CSF
WBC, CSF-VDRL, and serum RPR was approximately 4 months in our prospective study of 59
individuals with neurosyphilis (203). In our experience, CSF protein concentration is slow to normalize
and may remain elevated even with other objective evidence of treatment success (203,204), thus we do
not base a decision to re-treat solely on failure of CSF protein concentration to normalize. Thus, if CSF
WBC count is normal and the CSF-VDRL is nonreactive at 3 months, no further LPs are required. For
those with persistent CSF abnormalities at 3 months after therapy (excluding elevated protein
concentration), CSF should be reexamined at 6 months after therapy and every 6 months thereafter until
CSF WBC and CSF-VDRL normalize. Failure of the CSF WBC count to decrease 6 months after therapy
or failure of CSF-VDRL to decline fourfold (or to nonreactive if the initial titer is <1:2) 1 year after
therapy are indications for retreatment. Serum RPR or VDRL tests should be obtained at 3, 6, and 12
months after therapy and every 3 to 6 months thereafter until they are nonreactive. Failure of the serum
RPR or VDRL to decline fourfold (or to nonreactive if the initial titer is <1:2) at 1 year after therapy is an
indication for retreatment.
Because some patients may be reluctant to undergo follow-up LPs after neurosyphilis therapy, we
examined whether normalization of serum RPR, defined as a fourfold decline in titer or reversion to
nonreactive, could predict normalization of clinical and CSF abnormalities in 110 patients treated for
asymptomatic syphilitic meningitis, symptomatic syphilitic meningitis, or syphilitic eye disease (204).
Normalization of serum RPR predicted normalization of CSF abnormalities (except CSF protein) and
clinical abnormalities with a high degree of certainty. However, using the serum RPR criterion (and
excluding CSF protein), 12% of individuals were misclassified as treatment successes. Among HIV-
infected individuals, misclassification was most common in those not taking antiretrovirals.
Prevention of neurosyphilis rests on first preventing syphilis. As discussed earlier, LP in syphilis
patients at highest risk for neurosyphilis (based on serum RPR titer and HIV-associated disease factors)
and treatment of those with CSF abnormalities consistent with asymptomatic neurosyphilis will prevent
progression to symptomatic disease. However, the magnitude of averted morbidity of this approach is
currently undefined.
NEUROSYPHILIS AND HIV

In the developed world, syphilis is most common in individuals who are at risk for or infected with HIV,
including children and adolescents. Patients who have both HIV and syphilis may be more likely to fail
therapy for early syphilis and to develop early neurosyphilis. Although some have argued that
neurosyphilis has a more rapid or aggressive course in HIV-infected compared to uninfected individuals,
careful review of the preantibiotic literature suggests that this is not the case. However, neurosyphilis may
be more difficult to diagnose in the setting of concomitant HIV and HIV-infected patients may be more
likely to fail therapy for neurosyphilis.
Epidemiology of Syphilis and Neurosyphilis in HIV-Infected Individuals
In 2000, the rate of infectious syphilis in the United States was the lowest since reporting began in 1941.
However, since 2001, the number of cases of syphilis in the United States has increased steadily. Between
2001 and 2011, the rates of primary and secondary syphilis more than doubled (205); similar increases
have been seen in Europe (206). In the last two decades, there has been a remarkable resurgence of
syphilis in China. Syphilis is now among the top five reportable communicable diseases in many regions
in China, with an estimated rate of 25 per 100,000 in 2009 (207). In 2011, 72% of primary and secondary
syphilis cases reported to the CDC occurred in men who have sex with men (MSM) (205). HIV is
particularly common in MSM with syphilis (206,208,209). In the U.S. STD Surveillance Network, of
MSM with primary and secondary syphilis, a median of 40% were infected with HIV (205).
Neurosyphilis is not a reportable disease, and thus it is harder to estimate its incidence or prevalence
in HIV-infected people. The CDC conducted a retrospective study of definite or probable symptomatic
early neurosyphilis in HIV-infected MSM in four U.S. cities from January 2002 to June 2004 (210). Forty-
nine patients were identified: 34 had cranial nerve dysfunction (25 ocular dysfunction, 6 auditory
dysfunction, 1 had both abnormalities and 2 had other cranial nerve abnormalities); 6 had symptomatic
meningitis; 2 had strokes; and 7 had headache, altered mental status, or both abnormalities. The estimated
risk of symptomatic neurosyphilis in the study population was 1.7%. Taylor and colleagues (211)
retrospectively reviewed 109 cases of neurosyphilis identified by chart review of patients reported with
syphilis in Los Angeles between 2001 and 2004 who received a diagnosis of neurosyphilis or had CSF
findings consistent with neurosyphilis. Overall, the highest proportion of syphilis cases with
neurosyphilis was seen among those with secondary syphilis (1.9%). Among HIV-infected patients with
early syphilis, the incidence of neurosyphilis was 2.1%, which was higher than the 0.6% estimate in HIV-
uninfected individuals. As is the case with the CDC study (210), this study suffers from ascertainment
bias in that patients underwent neurosyphilis evaluation at the discretion of the treating provider and
therefore cases were likely missed.
Neurorelapse
Cases of asymptomatic and early symptomatic neurosyphilis or syphilitic ocular disease in HIV-infected
individuals were reported early in the HIV epidemic (58,212–219). Many of these patients had been
previously treated for early syphilis with appropriate doses of intramuscular BPG, suggesting that they
experienced neurologic or ocular relapse (212). Of note, in the CDC study described earlier, 9 (18%) of
the 49 individuals with symptomatic early neurosyphilis had received recommended BPG treatment for
early syphilis before developing symptomatic neurosyphilis (210). In addition to neurorelapse presenting
as neurologic or ocular disease, it may also present as otologic syphilis (220).
As described earlier, in the preantibiotic era, syphilitic meningitis, meningovasculitis, and uveitis were
most commonly seen in patients who were inadequately treated for early syphilis. Merritt and Moore
(22,24) argued that incomplete or inadequate therapy was sufficient to eradicate peripheral T. pallidum,
but not sufficient to kill organisms that had invaded the CNS or the eye. Nonetheless, this treatment led to
an appropriate attenuation of the immune response. The organisms remaining in the CNS or eye were then
free to multiply and produce neurologic or ocular disease. A parallel has been made to the HIV-infected
patient treated with benzathine penicillin for early syphilis (212). This treatment does not clear T.
pallidum from the CNS, the eye, or the inner ear (7,221). Because of impaired cell-mediated immunity,
the HIV-infected patient would not be able to eradicate persistent organisms and would thus be more
likely to suffer relapse with neurologic, ocular, or otologic disease. As noted earlier, HIV-infected
patients with low peripheral blood CD4+ T-cell concentrations or who are not taking antiretrovirals are at
increased risk for neurosyphilis (9,156,157). In addition, among HIV-infected patients with neurosyphilis,
peripheral blood CD4+ T cell concentrations are lower in those with symptomatic compared to
asymptomatic disease (211,222). Taken together, these findings support the contention that HIV-induced
immunosuppression may impair clearance of CNS T. pallidum.
Diagnosis of Neurosyphilis in HIV-Infected Individuals
Because the CSF-VDRL may be nonreactive in neurosyphilis, the diagnosis of neurosyphilis in an HIV-
infected person may need to be based solely on identification of CSF pleocytosis. CSF pleocytosis in
neurosyphilis is generally mild. As did many experts in the early 1900s, Moore and Hopkins (13) deemed
a CSF WBC greater than 10 cells/µL to be consistent with neurosyphilis, even if the CSF Wassermann test
was not reactive. Mild CSF pleocytosis is also common in HIV-infected individuals, particularly in those
who are relatively immunocompetent. For example, Marshall and coworkers (223) showed that 15.6% of
CSF samples from 649 HIV-infected individuals had greater than 10 WBC/µL with progressive decline in
CSF WBC count with more advanced stages of disease. Because HIV can cause mild mononuclear CSF
pleocytosis, we have used a cutoff of greater than 20 WBCs/µL as diagnostic of neurosyphilis in HIV-
infected individuals (9); a lower cutoff has been used by others (157) and is appropriate when the
peripheral blood CD4+ T cell concentration is low or patients are on antiretrovirals (ARVs), because
these lower the risk of HIV-related CSF pleocytosis (224).
Neurosyphilis Treatment Failure in HIV
HIV-infected individuals may be more likely than HIV-uninfected patients to fail neurosyphilis therapy
based on clinical and serologic criteria as well as on failure to normalize CSF abnormalities
(157,203,210,225–228). In a prospective analysis of 13 HIV-uninfected and 46 HIV-infected patients with
neurosyphilis, those who were HIV-infected were 2.5 times less likely to normalize CSF-VDRL after
therapy (203). Among the HIV-infected subjects, those with peripheral blood CD4+ T cells less than or
equal to 200 cells/µL were 3.3 times less likely to normalize CSF-VDRL (203). These data again lend
support to the contention that HIV-induced immunosuppression may impair clearance of CNS T. pallidum
and indicate that follow-up after treatment for neurosyphilis in HIV-infected individuals should be
particularly diligent.
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CHAPTER 39 NEUROBORRELIOSIS: NERVOUS
SYSTEM INVOLVEMENT WITH BORRELIA SPECIES
JOHN J. HALPERIN, SVEN BERGSTRÖM, AND GARY P. WORMSER
Relapsing fever and Lyme disease, infections most commonly acquired through bites of hematophagous
arthropods, are caused by spirochetes in the genus Borrelia. Both can involve the nervous system;
meningitis and cranial neuritis occur commonly. Relapsing fevers may cause more severe manifestations,
leading in extreme cases to brain microhemorrhages and focal central nervous system (CNS) damage.
Focal CNS involvement is quite rare in Lyme borreliosis; the details of its pathophysiologic mechanisms,
although clearly inflammatory, remain to be elucidated.
RELAPSING FEVER
There are approximately 20 different borrelial species capable of causing relapsing fever (Fig. 39.1), an
illness characterized by recurrent, several-day bouts of fever separated by periods of relative well-being.
The episodic nature of this infection is due to sequential evasion of the host’s adaptive immunologic
responses. In untreated patients, up to 10 to 15 recurrences may develop, although usually, the number is 1
to 3.
Epidemiology, Vectors, Agents, and Reservoirs
Borrelia recurrentis, for which the vector is the human body louse, Pediculosis humanus, is the only
known species of relapsing fever Borrelia not vectored by ticks. This form of relapsing fever, referred to
as louse-borne relapsing fever (LBRF), occurs in Africa (Fig. 39.2). Rather than being transmitted by an
arthropod bite like other Borrelia, B. recurrentis infection occurs when scratching abraded skin
inoculates organisms either from louse excrement or from lice crushed in the process of scratching (1,2).
LBRF is the most severe form of relapsing fever, and in untreated patients, mortality rates may exceed
40%. There is no animal reservoir for B. recurrentis; epidemic transmission typically occurs when body
lice spread extensively in badly overcrowded conditions such as in refugee camps resulting from war or
famine. As the only relapsing fever that causes epidemics, LBRF is sometimes referred to as epidemic
relapsing fever.
All other species of relapsing fever Borrelia are transmitted by tick bites. The resultant illness is
referred to as endemic relapsing fever or tick-borne relapsing fever (TBRF). Soft-bodied Argasidae
ticks transmit the vast majority of cases of TBRF. Transmission occurs within minutes of tick attachment
as relapsing fever Borrelia persist in the tick salivary glands from which they are rapidly inoculated into
a host. Most patients have no recollection of a tick bite because it is painless, typically occurs at night,
and the blood meal is completed within 15 to 90 minutes (3).
Borrelia miyamotoi differs from other relapsing fever Borrelia in that it is transmitted by hard ticks in
the Ixodes persulcatus family (Ixodidae). B. miyamotoi, first isolated in Japan from the hard tick I.
persulcatus (4), has been found (5,6) in all Ixodes tick species that are epidemiologically important for
transmission of Lyme disease, including I. ricinus and I. scapularis; the latter tick species frequently feed
on humans.
B. miyamotoi infections are just being recognized as a cause of infection in the United States, where I.
scapularis is the likely vector (7,8). Most cases of B. miyamotoi infection reported to date have not
caused periodic fevers nor has B. miyamotoi been detected by examination of peripheral blood smears in
the six infected patients for whom this diagnostic test was performed (9). B. miyamotoi infection has
caused chronic meningoencephalitis in immunocompromised patients (8).
TBRF occurs nearly worldwide (Fig. 39.2). In North America, these infections occur primarily in the
West and Southwest (Fig. 39.3) (3), where Borrelia hermsii, transmitted by the Ornithodoros hermsi tick,
is the most common cause, followed by B. turicatae and B. parkeri. O. hermsi ticks are found in
coniferous forests at altitudes of 1,500 to 8,000 feet (10). Consequently, in the United States, TBRF
occurs primarily in the Rocky Mountain states, with infections acquired most commonly in rustic rodent-
infested cabins. B. parkeri and B. turicatae infect ticks with corresponding names O. parkeri and O.
turicata, which are found across a somewhat broader geography at lower altitudes, primarily in caves or
burrows (3). In Eurasia, TBRF is most commonly caused by Borrelia persica but also by Borrelia
caucasica and Borrelia latyschewii (11,12). In sub-Saharan Africa (Fig. 39.4), Borrelia duttonii
(transmitted by Ornithodoros moubata) is the most common cause of TBRF (3). In rural sections of West
Africa, Borrelia crocidurae is a prominent cause of infection, responsible for 5% to 25% of all febrile
illnesses, depending on the year and location (13).
TBRF ecology varies among species. Most TBRF Borrelia infections are zoonoses, but no animal
reservoir has been identified for B. duttonii, which is closely related genetically to B. recurrentis
(1,3,14,15). For other species, the principal reservoirs are rodents, and other small animals. Infected
Ornithodoros ticks may survive without a blood meal for more than a decade. That, along with the
possibility of transovarial transmission of relapsing fever Borrelia in the tick vector (3), suggests that
ticks themselves may potentially serve as reservoirs.
Although vector-borne transmission is by far the most common means of transmission of relapsing
fever Borrelia, infection has also been transmitted through blood transfusion, sharing of needles among
intravenous drug users, laboratory accidents, and transplacentally (3,12).
General Clinical Features and Pathogenesis
Symptom severity varies widely in patients infected with relapsing fever Borrelia (16); some remain
completely asymptomatic, whereas others become critically ill. The hallmark of relapsing fever is
periodic fevers. Approximately 7 days after inoculation, patients develop the sudden onset of chills and
fever, typically between 38.7° and 41°C (Fig. 39.5), frequently with rigors, headache, fatigue, altered
sensorium, arthralgias, and myalgias (16). Some patients develop a cough, nausea, vomiting, diarrhea,
icterus, a maculopapular or petechial truncal skin rash, neurologic and ocular involvement, pneumonia,
myocarditis, acute respiratory distress syndrome, abdominal pain, hepatosplenomegaly, icterus, hepatic
failure, and splenic rupture (3). Ocular manifestations of TBRF include iritis, iridocyclitis, and
choroiditis (17). In contrast to TBRF, eye involvement occurs rarely if ever in LBRF(17).
The most common causes of death are myocarditis, cerebral hemorrhage, and liver failure. Relapsing
fever in pregnancy can result in miscarriage in one third of cases (12,18,19). B. duttonii infection is often
associated with low birth weight, preterm delivery, spontaneous abortion, and perinatal death (20–25).
The number of inoculated bacteria required to cause infection can be quite low. In mice, a single
bacterium may be sufficient to establish infection (1). Once relapsing fever Borrelia enter the blood, they
multiply to large numbers, potentially reaching concentrations of 106 to 108 organisms per milliliter, at
which point symptoms appear. Symptoms resolve spontaneously within about 3 days (range 1 to 9 days),
as bactericidal T-cell independent immunoglobulin (Ig) M antibodies (26) damage the borrelial outer
membrane, resulting in clearance of spirochetes from the blood. Both B-cell receptor and toll-like
receptor signaling are involved in the development of this rapid T-cell independent antibody response
(27,28). Neither phagocytic cells nor complement activation play an essential role in spirochete
clearance; relapsing fever Borrelia are able to inactivate the complement cascade (26,29). Fever recurs
in 7 or more days (range typically 3 to 10 days) with the emergence of an antigenically different strain of
Borrelia, resistant to the bactericidal activity of the previously produced antibodies.
These antigenically different strains arise from alteration in the expression of the variable major
surface lipoprotein, Vmp, through genetic rearrangement whereby silent genes move into an expression
locus (3,30,31). This antigenic variation is not random; certain Vmps are more likely than others to be
expressed in early infection (32), perhaps explaining why some neurologic and ophthalmologic
manifestations usually do not occur during the first bout of fever (see the following discussion). Aside
from the change in Vmp, the new strain of Borrelia is otherwise identical to the original infecting strain
(30,31,33). In theory, at least 25 antigenically distinct serotypes can be generated from a single bacterium
(27). Emergence of each successive serotype is associated with a fever relapse. Recurrences may be
shorter in duration and associated with less intense symptoms and fewer spirochetes in the blood,
especially for LBRF. In experimental animals, different serotypes not only confer antibody resistance but
also appear to vary in their capacity to cause brain infection (34,35). This may, at least in part, be
explained by different serotypes’ varying ability to bind and cross the brain microvascular endothelium
(33).
Laboratory Findings
In patients with relapsing fever, the white blood cell count, erythrocyte sedimentation rate, and liver
function tests are usually elevated. Anemia and thrombocytopenia are common (1,3), and although usually
mild, the thrombocytopenia can be severe, potentially resulting in bleeding complications. One possible
mechanism proposed for the development of thrombocytopenia, suggested by animal models (36,37), is
through binding of Borrelia to the outer surface of platelets, a phenomenon that may also play a role in
eradicating relapsing fever Borrelia from the blood. Certain species of relapsing fever Borrelia—such as
B. crocidurae, B. duttonii, and B. hispanica—bind to erythrocytes, causing erythrocyte rosetting, which
may contribute to the development of anemia (1,12,38). The resulting aggregates of bacteria and red
blood cells may also disrupt the microcirculation, resulting in hemorrhage, reduced blood flow, hypoxia,
and cell death (1,12,38,39).
The most commonly reported neurologic manifestations are meningeal symptoms, meningitis, and facial
nerve palsy.Delirium (encephalopathy) is also common. In severe cases, CNS microhemorrhages, focal
abnormalities, seizures, and coma can occur. The frequency of neurologic involvement depends on the
infecting species of relapsing Borrelia. B. duttonii, B. crocidurae, and B. turicatae are the TBRF species
most likely to cause neurologic complications (17), particularly meningitis and facial nerve palsy.
Facial nerve palsy, although frequent, does not typically appear during the first febrile episode. It
usually resolves within 2 months with or without antibiotic therapy (17). Ocular involvement is unilateral
in two thirds of cases and, like facial nerve palsy, almost never occurs during the first febrile episode.
Although there are reports of other cranial nerve palsies, optic neuritis, radicular symptoms,
neuropsychiatric abnormalities, and other findings, no large population-based studies are available to
provide clear data regarding the frequency of most of these disorders or even compelling evidence of a
causal relationship.
Microscopically, meninges and brain may show perivascular infiltrates composed of monocytes,
lymphocytes, and plasma cells (17). Cerebral edema and subarachnoid and parenchymal brain
hemorrhage may occur in fatal cases of LBRF. In experimental animals, cerebral microgliosis is a
prominent feature (33,40,41). Both meningitis and meningismus occur frequently in TBRF. In LBRF,
although as many as 50% of patients develop meningismus, far fewer have actual meningitis (as
confirmed by cerebrospinal fluid [CSF] examination) (17). In experimentally infected rodents, some
strains of relapsing fever Borrelia can cause persistent brain infection (15) that can be cleared
successfully with ceftriaxone treatment (42). Persistent brain infection in untreated humans, however, has
not been documented.
The CSF white cell count is typically elevated in relapsing fever patients with CNS involvement. CSF
examination demonstrates a mononuclear-predominant pleocytosis with cell counts in the hundreds/mm3
and protein concentration of up to several hundred mg%. CSF glucose is typically normal. Organisms
have been detected in CSF in a minority of cases by microscopic examination, culture, or animal
inoculation. In fatal cases of TBRF, spirochetes have been detected histologically in perivascular areas of
brain cortex (17). Testing for the production of intrathecal antibodies to Borrelia has not been established
to be a useful diagnostic test in relapsing fever (32).
Diagnosis
During febrile episodes, there may be up to 108 spirochetes per milliliter of blood; none are detectable
during afebrile periods. As a result, extracellular spirochetes may be directly visualized in blood
obtained during a febrile episode, either on Giemsa (Fig. 39.6) or Wright-stained blood smears or by
dark-field or phase-contrast microscopy of plasma wet mounts. The sensitivity of these techniques is 70%
or less, but this can be increased using fluorescent microscopy of acridine orange–stained smears or by
examination of buffy coat smears.
Detection of relapsing fever borrelial DNA by PCR appears to be more sensitive than detection by
blood smear but is only offered by a few laboratories. Serologic assays including enzyme-linked
immunosorbent assays (ELISAs) or immunofluorescence assays (IFAs), followed by supplemental
immunoblots using antigens from particular species of relapsing fever Borrelia, are available from a few
laboratories but only for some borrelial species. Relapsing fever and Lyme disease patients often produce
cross-reactive antibodies given the similarity of flagellin and other antigens. A specific serologic assay
for relapsing fever Borrelia infections uses the surface protein glycerophosphodiester phosphodiesterase
(GlpQ) as the antigen (3). Because this protein is not present in Lyme Borrelia, Lyme disease patients
will be seronegative using this assay. Other testing modalities with even more limited availability include
culture and animal inoculation.
Treatment
TBRF is treated with a 5- to 10-day course of oral tetracycline, doxycycline, erythromycin, penicillin,
amoxicillin, or chloramphenicol (3). The preferred therapy for LBRF is a single oral dose of tetracycline
or erythromycin, although some authorities favor extending treatment to 7 days (1). Meningitis or
encephalitis is treated with intravenous penicillin G, ceftriaxone, or cefotaxime for at least 14 days.
A Jarisch-Herxheimer reaction, thought to result from the rapid killing of relapsing fever Borrelia by
antibiotics with the sudden release of lipoproteins, occurs frequently in the first few hours following
initial treatment. The resultant induction of cytokines such as tumor necrosis factor-α (TNF-α),
interleukin-6 and -8 (IL-6, IL-8), and other chemical mediators causes rigors, leukopenia, fever, and
hypotension, signs similar to those of a classic endotoxin reaction (1,3). Because of the potential severity
of such reactions, patients should be kept under observation for approximately 2 hours after initiating
antibiotic therapy. This is an “all or nothing” reaction, occurs in more than 50% of patients, and usually
resolves spontaneously within 12 to 24 hours. However, cardiovascular collapse may occur, with a
fatality rate of about 5% (43,44). Several studies have suggested that the choice of antibiotic affects the
severity, but such data are inconclusive. Treatment with anti–TNF-α agents prior to antibiotics may
reduce the severity of the reaction but is not used clinically at this time (45).
When tick bites and/or tick exposure has occurred with ticks at high risk for transmitting relapsing
fever Borrelia, a 5-day course of doxycycline chemoprophylaxis during the infection’s incubation period
is highly effective in prevention of TBRF (46).
LYME DISEASE
Lyme disease is caused by a group of related spirochetes—Borrelia burgdorferi sensu lato or Lyme
Borrelia. Lyme disease is the most commonly reported vector-borne infectious disease in the United
States and is also of public health importance in numerous countries with temperate climates in Eurasia
(47). The term “Lyme disease” was coined in the mid-1970s, with the recognition of a cluster of cases of
what appeared to be juvenile rheumatoid arthritis (48) in Lyme, Connecticut. Europeans, however, have
been familiar with this disorder since the early twentieth century (49) and have been treating it
successfully with antibiotics since the 1950s, three decades before the isolation of the causative organism
(50). The history of European versus United States Lyme disease has resulted in the perception that these
infections behave quite differently. However, they actually share more similarities than differences,
making the century of clinical experience with European neurologic Lyme disease informative for our
understanding of this aspect of Lyme disease in the United States.
Epidemiology, Vectors, Agents, and Reservoirs of Lyme Borrelia
In North America, the only species of Lyme Borrelia known to cause human disease is B. burgdorferi
sensu stricto (which will be referred to as B. burgdorferi). In Europe, at least five species of Lyme
Borrelia can cause disease, of which B. afzelii, B. garinii, and B. burgdorferi are the most common.
Because of this species diversity, the range of clinical manifestations appears to be greater in Europe than
in North America (47). In Europe, B. garinii is the species of Lyme Borrelia most closely associated with
neurologic manifestations (47).
Lyme Borrelia is transmitted during feeding by Ixodes species ticks (Fig. 39.7). Only after ingested
blood triggers spirochete proliferation and migration to the tick’s salivary glands can infection be
transmitted. A feeding period of more than 36 hours is usually needed for transmission of B. burgdorferi
by I. scapularis or I. pacificus ticks, whereas in experimental animals, transmission of B. afzelii by I.
ricinus can occur in under 24 hours (47,51–54). The main vertebrate reservoirs for Lyme Borrelia are
mice, other small mammals, and some species of birds.
In the United States, about 30,000 cases of Lyme disease are identified by the Centers for Disease
Control and Prevention (CDC) annually; cases occur predominantly in the northeast, middle/south
Atlantic, and north central states (Fig. 39.8). In Europe and Asia, with an estimated 85,000 cases per year
(accurate numbers are difficult to obtain as this is not a reportable disease in many European countries),
infection occurs broadly across temperate central regions (55).
General Clinical Features and Pathogenesis

Lyme Borrelia resides in the midgut of unfed Ixodes ticks. When an infected tick takes a blood meal, the
spirochetes present there increase in number and undergo phenotypic changes, including the expression of
a particular outer surface protein, OspC, which allows them to disseminate within the tick and enter its
salivary glands (47). This process takes several days and explains why transmission occurs only after a
delay. Expression of OspC plays an essential part in the establishment of infection in a mammalian host,
although the mechanism by which this occurs is unknown (56,57).
During feeding, the infected tick deposits spirochetes into the skin at the bite site. This may lead to the
development of a type of bacterial cellulitis, referred to as erythema migrans (EM; Fig. 39.9), at that
location. Lyme Borrelia may disseminate from that site to other locations in the body: through the blood or
perhaps through tissue planes. The risk of hematogenous dissemination by B. burgdorferi is dependent on
the strain of Borrelia (58).
Infection elicits innate and adaptive immune responses, resulting in both macrophage- and antibody-
mediated killing of Lyme Borrelia. Despite a robust humoral and cellular immunologic response,
however, infection with Lyme Borrelia can persist. Persistence is due in part to the spirochete’s ability to
downregulate expression of particular immunogenic surface-exposed proteins, including OspC, and to
alter by recombination the antigenic properties of another surface lipoprotein known as variable major
protein-like sequence expressed (VlsE) (30,47). Lyme Borrelia may bind to various components of the
extracellular matrix, which may also contribute to persistence (59). Localized infection is typically
manifested by a single EM skin lesion. In early disseminated disease, there may be two or more EM skin
lesions or an objective manifestation of neurologic or cardiac Lyme disease. The most frequently
described manifestation of late Lyme disease in the United States is a mono- or pauciarticular arthritis.
Most patients develop EM between June and August (60). The seasonal distribution of extracutaneous
manifestations of Lyme disease is less pronounced because the time from infection to onset of these
manifestations is longer than it is for EM. Generally, the clinical features of Lyme disease are similar in
children and in adults. However, acrodermatitis chronica atrophicans (a late skin manifestation seen
primarily in Europe) is typically not seen in children (47).
Laboratory Findings
Patients with Lyme disease have a normal white blood cell count, hematocrit, and platelet count, unless
there is coinfection with Anaplasma phagocytophilum, Babesia microti, or a tick-borne encephalitis
virus (47). Slightly raised liver function tests can be seen in up to one third of patients with early
disseminated Lyme borreliosis, especially in those with EM. Erythrocyte sedimentation rates may be
slightly to moderately elevated. In patients with Lyme meningitis, CSF typically shows a pleocytosis with
more than 90% lymphocytes, a slightly raised protein level, and a normal glucose level.
Nervous system involvement, first described in 1922 in France (49), most commonly includes any or all
elements of a clinical triad—lymphocytic meningitis, cranial neuritis, and painful radiculitis—often
referred to in the European literature as Garin-Bujadoux-Bannwarth syndrome. This tends to occur
relatively early in infection, and an EM skin lesion may still be present. Therefore, in patients with
suspected neurologic Lyme disease, a complete skin examination should be done to look for EM skin
lesions to help confirm the diagnosis (61).
Clinically, the symptoms associated with meningitis vary in severity. Comparative studies suggest that
the onset is typically a little less acute than in viral meningitis, with symptoms evolving over a day or two
rather than a few hours (62,63). In contrast to patients with Lyme meningitis, individuals with summertime
viral meningitis, typically due to enteroviral infections, rarely develop cranial neuropathies. Another
group of agents, tick-borne encephalitis viruses, seen in Eurasia but rarely in North America, can
similarly cause a typical viral meningitis but can also lead to a more severe meningoencephalomyelitis
that is particularly likely to cause segmental spinal cord involvement.
Of the patients who develop a cranial neuropathy, about 80% have facial nerve paralysis, and in one
quarter of these patients, the facial palsy is bilateral (64). Other cranial neuropathies may include cranial
nerves III, IV, or VI, which innervate the extraocular muscles (causing diplopia), the trigeminal nerve
(causing paresthesias or numbness), or the vestibuloacoustic nerve (causing hearing loss or vertigo).
Reports of involvement of the lower four cranial nerves are at best anecdotal. Although the eye itself can
be involved in Lyme disease (similar to the eye involvement in relapsing fever), optic neuritis
specifically is very rare, if it occurs at all (65).
The neurologic disorder that figured prominently in the 1922 case report, but is still underrecognized,
is referred to as painful radiculitis (49,66). Patients develop severe, burning neuropathic type pain, often
radicular in distribution but not uncommonly involving more than one dermatome, usually with
corresponding sensory, motor, and reflex changes. Pain is typically worse at night. When involving truncal
dermatomes, pain can be mistaken for visceral disease. Limb symptoms can precisely mimic those of a
mechanical radiculopathy. The diagnosis should be considered in individuals with typical radicular
symptoms without an antecedent injury, especially in those with negative imaging. Although CSF
pleocytosis is not always present, when found, it should lead to consideration of this diagnosis in tick-
exposed individuals. Some patients develop other forms of mononeuropathy multiplex, including more
typical peripheral mononeuropathies or even plexopathies.
Parenchymal CNS infection is quite rare (67). Occasional patients with Lyme radiculitis may have
evidence—clinically or by imaging—of involvement of the spinal cord at the affected nerve root level.
Very rarely, patients develop parenchymal brain inflammation, a focal encephalitis (68–70).
At the other end of the spectrum, some individuals with milder but more prolonged untreated Lyme
disease (something rarely seen now) may develop more indolent and disseminated peripheral nerve
involvement (71,72). Not surprisingly, neurophysiologic studies indicate that this polyneuropathy is
similarly due to a confluent mononeuropathy multiplex, the same basic pathophysiologic process seen in
Garin-Bujadoux-Bannwarth syndrome. Although the mechanism responsible for this disorder is unknown,
one could conjecture that these patients have a smaller spirochete load, infection with an antigenically
different strain, or a different immunologic response to the infection. This manifestation of neurologic
Lyme disease is now recognized rarely in the United States. Although not specifically described in
European patients, a neurophysiologically similar disorder occurs in patients with acrodermatitis
chronica atrophicans—patients in whom this primarily involves the limb affected with the skin lesion
(73).
Over the years, possible associations between Lyme disease and a variety of serious neurologic
disorders have been proposed.
Demyelinating disease: In the 1980s and 1990s, numerous reports, primarily from Europe, described
patients with progressive inflammatory disorders of the brain and spinal cord (67–70). Far fewer
reports have appeared in recent years. Whether this phenomenon was due to inadequacies of earlier
serologic diagnostic tools, or to a change in the presentations of the illness as earlier recognition and
treatment became widespread, is unclear (74). Regardless, it is now remarkably uncommon to see
patients with Lyme disease presenting like multiple sclerosis.
Motor neuron disease: Several reports of patients (75,76) with what appeared to be motor neuron
disease, serologic evidence of Lyme disease, and improvement following antimicrobial therapy led to
an epidemiologic study demonstrating an excessive prevalence of antibodies to B. burgdorferi among
amyotrophic lateral sclerosis (ALS) patients in a Lyme disease–endemic area compared both to ALS
populations elsewhere and to a variety of other controls (77). No satisfactory explanation for this
observation has ever been provided. However, the lack of treatment responsiveness among these
patients, and the failure to replicate the observation elsewhere, suggest it was a chance observation.
Cerebral vasculitis: A number of isolated reports has described patients thought to have cerebral
vasculitis attributable to Lyme disease (78–83). In some studies, vasculitis was inferred from the
presence of areas of brain damage on magnetic resonance imaging (MRI) in the absence of vascular
imaging. In others, the support for the diagnosis of Lyme disease did not meet current serologic criteria.
Given that Lyme disease does not cause vasculitis in other organ systems, and the paucity of evidence
in the cases that have been reported, this disorder seems unlikely.
Alzheimer disease, Parkinson, neuropsychiatric disorders: Numerous case reports have purported to
show relationships between these disorders (84–87) and Lyme disease. No systematic data have ever
indicated such an association; therefore, these linkages appear unlikely.
LYME ENCEPHALOPATHY
An entity that has caused tremendous confusion is the disorder termed “Lyme encephalopathy.” Originally
described in individuals with symptoms of long-standing untreated Lyme disease (e.g., arthritis) (88–90),
it rapidly became clear that few, if any, of these patients had objective evidence of CNS infection (91).
Rather, this appeared to be an example of the encephalopathy or delirium seen in the context of
innumerable other systemic infections and inflammatory states (pneumonia, urinary tract infections,
influenza, active rheumatoid arthritis, etc.).
Initial interest in studying this as a possible model of encephalopathy in inflammatory states was
widely misinterpreted in three critical ways. First, many assumed that this constituted evidence of either
brain infection or of another neuropathologic state, something for which there is no scientific support.
Second, some assumed that this disorder was specific to Lyme disease, despite it clearly being just one
example of a state commonly occurring in a wide range of situations ranging from systemic illness to
depression, sleep deprivation, and innumerable other conditions. Most problematic has been the notion
that this encephalopathy is not only common but also often persists after antibiotic treatment, a state
sometimes referred to as post–Lyme disease syndrome. Moreover, patients with similar symptoms, but no
other evidence of Lyme disease—clinically or by laboratory studies—are sometimes, nevertheless,
assumed to have Lyme disease and treated with antibiotics for extended periods of time. Because
symptoms that are not related to infection with Lyme Borrelia would not be expected to respond to
treatment for Lyme disease, treatment unresponsiveness in this group has contributed greatly to the
widespread mistaken belief that Lyme disease does not respond to antimicrobial therapy.
Efforts to support the diagnosis of “Lyme encephalopathy” with brain single-photon emission computed
tomography (SPECT) scanning—a technique so unreliable that it never even gained acceptance in the
diagnosis of stroke, the purpose for which it was first developed—have only added to the confusion. This
has all contributed tremendously to patient anxiety about Lyme disease. Clearly, the notion of a brain-
damaging infection is terrifying to most people.
Studies of the general U.S. population, using well-validated self-reporting questionnaires, indicate that
as many as 2% of the general population without Lyme Borrelia infection may experience the symptom
complex attributed to “Lyme encephalopathy”—severe fatigue, cognitive slowing, and other nonspecific
symptoms—at any given time (92). In contrast, identifying patients with “post–Lyme disease syndrome”
for clinical trials has been remarkably difficult. One of the most systematic efforts (93), led by a group
very well connected to Lyme disease patient advocacy groups throughout the country, recruited for 4 1/3
years and was able to enroll only 37 patients who appeared to have had Lyme disease previously and had
persisting cognitive symptoms.
Pathogenesis of Neurologic Manifestations
Given the variety of clinical disorders associated with Lyme neuroborreliosis, it is likely that more than
one mechanism is involved. Lyme meningitis can be attributed to B. burgdorferi infection within or in
close proximity to the subarachnoid space because organisms can be detected in some patients’ CSF and
because antibiotic treatment leads to rapid recovery. As challenging as it is to find organisms in Lyme
meningitis, this is virtually impossible with most other neurologic manifestations of Lyme disease.
Peripheral nerve involvement, although highly variable in clinical presentation, seems to be uniformly
attributable to a mononeuropathy multiplex, a mechanism typically associated with vasculopathic
processes (e.g., vasculitis, diabetic microvascular changes). Neurophysiologic studies in patients with
Lyme disease (71), and in experimentally infected animals, suggest this pathophysiology, whether the
patient presents with facial nerve palsy, radicular symptoms, focal mononeuropathies, or “stocking glove”
type distal symptoms (71). The few available nerve biopsies from patients (94–96), as well as nerve
biopsies from experimentally infected rhesus macaques (97), consistently demonstrate perivascular
inflammatory infiltrates, without evidence of vessel wall necrosis (which would be required to diagnose
a vasculitis) or other vasculopathic changes (Fig. 39.10). None of the histopathologic studies in humans
has demonstrated either intact spirochetes or even their antigens in the biopsied nerves.
Although there is evidence that the CNS may be invaded early in the course of Lyme disease (Fig.
39.11) (98–100), parenchymal brain involvement occurs very rarely in humans. The few human autopsy
reports thought to reflect brain involvement have described primarily nonspecific changes such as glial
proliferation and lymphocytic infiltrates (101). A few studies have identified spirochetes in patients
thought to have parenchymal brain involvement. One study identified large areas of inflammation in brain
tissue thought to be due to this infection and found B. burgdorferi DNA by PCR testing of tissue from
involved areas (102), a finding that has never been replicated. The inability to demonstrate spirochetes in
most cases has led to numerous studies exploring potential roles of the immune response, either by virtue
of inadvertent cross reactivity or effect amplification by immunomodulators. Studies have shown that
antibodies to B. burgdorferi flagellin cross-react with a heat shock protein (HSP60) present in peripheral
nerve and can affect neuroblastoma cell neuritogenesis in vitro (103). Both B. burgdorferi bacteria
themselves, and antibodies to B. burgdorferi, may also potentially interact with various myelin-
associated glycoproteins (98,104). The most persuasive argument against a pathogenetic role for
molecular mimicry, though, is the fact that the humoral response to B. burgdorferi usually persists for an
extended period of time following successful antibiotic treatment, yet the neurologic disorders rapidly
resolve.
Alternatively, the cytokine response to Lyme Borrelia infection could provide a more plausible
explanation. Unlike antibodies, the level of these molecules does rise and fall rapidly with the presence
of infecting microorganisms. Equally importantly, some cytokines can affect nervous system function
(105,106) providing a potential mechanism. Over the years, a number of molecules have been
investigated. CXCL13 is produced by brain glia and dorsal root ganglia early in infection and serves to
attract B lymphocytes that then produce specific antibodies (107,108). Although there has been no
evidence that this particular cytokine affects nervous system function, it may serve as a helpful marker of
disease activity. Indirect evidence has suggested a possible role of interferon-γ (IFN-γ) (106) and
interferon-α (IFN-α) (109); however, direct proof of an effect has been lacking. In an in vitro brain slice
model (rhesus), brain oligodendroglia and astrocytes exposed to B. burgdorferi exhibited apoptosis, and
glial transcription of genes for many inflammatory immunomodulators was altered (108,110). However,
how this directly relates to neuroborreliosis remains to be elucidated.
In summary, despite numerous tantalizing suggestions regarding potential mechanisms underlying
neuroborreliosis, this remains a topic in need of additional studies.
Diagnosis
EM usually has a distinctive enough appearance to allow a clinical diagnosis in the absence of a
supporting laboratory test. Serologic assays for antibodies to Lyme Borrelia are negative at this stage in
at least 50% of cases and thus should be obtained only in atypical cases and then in conjunction with
convalescent phase serologic testing after 2 to 6 weeks (111).
For non-EM presentations of Lyme borreliosis, including neurologic Lyme disease, the mainstay of
laboratory diagnosis is two-tier serologic testing in which the first-tier test is usually an ELISA. If the
ELISA is reactive (positive or borderline), then separate IgM and IgG immunoblots are done on the same
serum sample (112). If symptoms have persisted for at least 4 weeks, then the IgG immunoblot should be
positive. Untreated patients who remain seronegative despite symptoms persisting for more than 6 weeks
are unlikely to have illness attributable to Lyme borreliosis.
Omission of the first-tier ELISA or interpretation of the immunoblot with criteria that are not evidence
based will potentially decrease specificity and possibly result in misdiagnosis (47). In addition, in
clinical practice, there are often false-positive IgM immunoblot test results because of overreading of
weak bands by some commercial laboratories (113).
As with most infections, patients with Lyme disease often continue to produce a specific immune
response long after apparent microbiologic cure. Hence, a positive serology cannot be used to judge
treatment efficacy or to establish proof of a current active infection.
Testing for anti-Borrelia antibodies that are produced locally in the CNS (i.e., intrathecal synthesis of
specific antibodies) is a mainstay of the diagnosis of Lyme neuroborreliosis in Europe (114,115), where it
is believed to be present in 70% to 90% of patients with acute neuroborreliosis and more than 90% of
those with more long-standing infection (116). In the past, some European patients were found to have
antibody in the CSF before they developed a positive serum serology (117). This observation has not
been replicated with currently recommended serologic techniques. Importantly, intrathecal synthesis of
antibodies can persist for months to years after successful antibiotic treatment and therefore cannot serve
as a test for cure (118). (CSF cell counts and protein concentration can be more useful to gauge active
infection, however.) Because there is no “gold standard” diagnostic tool for CNS infection, it is difficult
to determine the test’s sensitivity; in American patients, estimates have ranged from 46% in individuals
with more chronic symptoms (69) to 87% in those with acute Lyme meningitis (91). Finally, it is
important to appreciate that the presence of intrathecal antibody to Lyme Borrelia is a marker of CNS
infection specifically. In patients with neuroborreliosis limited to the peripheral nervous system (PNS),
with encephalopathy due solely to systemic inflammation, or with no suggestion of nervous system
involvement, there is no reason to expect that intrathecally produced antibodies to Lyme Borrelia will be
present.
Cultures for Lyme Borrelia are not routinely done to diagnose Lyme disease. Such testing is
unnecessary for patients with EM and too insensitive for patients with extracutaneous manifestations of
Lyme disease. The positivity rate of PCR in CSF tends to be low in neurologic Lyme disease, being only
about 5% in a recent study of children from the United States (119). A negative PCR result on CSF
certainly does not exclude neurologic Lyme disease. PCR on blood or urine samples, tests designed to
detect B. burgdorferi antigens in urine, tests for T-lymphocyte recognition of Borrelia antigens (as a
measure of a cellular immune response to Lyme Borrelia), measurement of the number of CD57 natural
killer cells, and use of live microscopy on blood to search for spirochetes have not been demonstrated to
be reliable and are not recommended (111).
Treatment
In Europe and the United States, parenteral antibiotic therapy had been the preferred treatment for
neurologic Lyme disease, especially for meningitis and radiculitis. Studies done in Europe, however,
have provided convincing evidence that a 14-day course of oral doxycycline is as effective as ceftriaxone
for most of the manifestations of neurologic Lyme disease (120). Although no systematic studies on this
issue have been done in the United States, there is a growing favorable clinical experience with
doxycycline. Other oral antibiotics such as amoxicillin have been used successfully to treat patients with
uncomplicated seventh nerve palsy, but efficacy data for such drugs are limited. Seventh nerve palsy will
resolve at the same rate with or without antibiotic treatment (121). Thus, one of the main reasons to treat
such patients is to prevent the development of later complications, especially Lyme arthritis in the United
States (122). At this point, it is reasonable in our judgment to reserve parenteral treatment—with at least
a 14-day course of ceftriaxone, cefotaxime, or penicillin G—for patients with parenchymal CNS disease
(both because of a lack of evidence of efficacy of oral regimens and out of an abundance of caution),
patients who continue to have active disease following treatment with oral regimens, and for those rare
patients who present acutely very ill.
There has been considerable uncertainty about the best approach for initiating antibiotic therapy for
patients with meningitis or cranial or peripheral nerve involvement suspected but not yet proven to be due
to Lyme disease. If an EM skin lesion is present, antimicrobial treatment, typically with oral doxycycline,
can be started immediately. Because most patients with meningitis, cranial neuritis, and other disorders
do not have Lyme disease, and because no clinical features reliably identify the subset of these patients
who have Lyme disease, laboratory confirmation is essential before planning definitive treatment. If there
are sound epidemiologic reasons to think the patient might have been exposed to B. burgdorferi–infected
ticks, if test results can be obtained within 24 to 48 hours, and if there are no contraindications to several
days of empirical treatment with oral doxycycline, then this can be started pending test results. On the
other hand, the likelihood of disease progression during the 1 to 2 days required to obtain test results is
small, making deferred treatment an equally valid option. Notably, if the patient presents with facial nerve
palsy and is seen within the first 72 hours of symptoms, oral corticosteroids (typically prednisolone 50 to
60 mg per day [or equivalent]) for 5 days followed by a rapid taper (123) should be started immediately
as such therapy has been shown to improve outcomes in Bell palsy, the most common cause of seventh
nerve palsy in the general population (123). In this setting, concurrent initiation of empirical oral
doxycycline is reasonable, pending test results, although there is no evidence that brief courses of steroids
make neuroborreliosis more difficult to treat.
Outcome
Lyme disease is a curable bacterial infection. Appropriate antimicrobial therapy should stop both disease
progression and the development of any new manifestations of the infection. As in many bacterial
infections, some symptoms may resolve slowly following treatment, particularly nonspecific ones such as
fatigue, malaise, arthralgias, and perceived cognitive and memory difficulty. If, prior to treatment, a
patient has developed evidence of tissue damage—synovitis in patients with rheumatologic disease;
facial nerve, nerve root, or other focal peripheral nerve damage in those with PNS disease—tissue repair
may be slow and sometimes incomplete if sufficiently severe in the first place. Focal inflammatory CNS
disease, initially described in a substantial number of European patients in the 1980s and 1990s but only
rarely since then, can respond very well to antimicrobial therapy. As in PNS disease, however, symptoms
improve with treatment, but if there has been irreparable damage to the brain or spinal cord, some residua
would be expected.
CONCLUSION
Borrelia infections, both relapsing fevers and Lyme disease, can affect the nervous system. Meningitis—
is probably the most common phenomenon in both groups of diseases. Focal and multifocal nervous
system involvement can occur, but the frequency, severity, and mechanisms probably vary with the
specific spirochete species. In relapsing fever, brain involvement probably is due to an ischemic and
hemorrhagic vasculopathy. In Lyme disease, both PNS and CNS involvement tends to be much more focal;
although it is presumed to occur on the basis of either local brain infection, multifocal vasculopathic
changes secondary to the infection, and/or the immune response to the organism, much remains to be
learned about the pathophysiology.
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PART VI ■ FUNGAL INFECTIONS
CHAPTER 40 FUNGAL MENINGITIS

JENNIFER L. HORAN AND JOHN R. PERFECT
Fungi provide humankind with many benefits. We use them to make staples such as bread, cheese, and
beer. We harness them to produce antibiotics and proteins and manipulate them to study eukaryotic
genetics and molecular biology. However, certain fungi can conversely cause major problems for humans.
Some plant fungi inflict serious damage on crops and ornamentals, and primary fungal pathogens such as
Cryptococcus, Histoplasma, and Blastomyces can infect humans, causing both local and disseminated
disease. Opportunistic fungal pathogens such as Aspergillus and Candida pose a serious threat to the
enlarging pool of immunocompromised hosts, including neonates, postsurgical patients, those with
malignancies and HIV infection, and those undergoing solid organ or hematopoietic stem cell transplants.
Many of these primary and secondary fungal pathogens can invade the central nervous system (CNS). This
chapter reviews the pathogenesis and management of these mycoses producing meningeal disease.
The brain and the subarachnoid surrounding space constitute an immunologically sequestered site. This
site is located inside anatomic and functional barriers that may exclude or modify certain immune
responses. Some patients with a CNS fungal infection have no apparent immune defects or underlying
diseases, but most have some predisposing factor or flaw in their immune responses, allowing invasion
by these relatively nonvirulent fungi. Host defenses are normally very effective in excluding fungi from
the CNS, but certain conditions can lead to failure of these defenses. Some are obvious, such as direct
inoculation of organisms into the brain following head injuries, but others are more subtle. Certain drugs
increase the frequency of CNS fungal infections; for example, neutropenia resulting from cancer
chemotherapy can predispose to CNS candidiasis and aspergillosis, and corticosteroids, often employed
in organ transplantation, predispose to cryptococcal meningitis. Infection with HIV allows invasion of the
CNS by fungi such as Cryptococcus neoformans and Histoplasma capsulatum. Finally, there are other
underlying medical conditions such as diabetes, pregnancy, malignancies, freshwater near drownings, and
iron chelation therapy that suppress normal immune responses in various ways, favoring invasion by
fungi. In addition to their role in pathogenesis, the patients’ immune responses and underlying diseases are
the main factors that determine outcome of CNS fungal infections.
A plethora of different fungal species can infect the CNS and produce meningitis. For example, the
following common environmental fungi rarely cause meningitis in humans: Alternaria (1), Rhodotorula
(2–4), Acremonium (5), Dreschlera (6), Malassezia (7), Scedosporium (8,9), Arthrographis (10),
Blastoschizomyces (11,12), Paecilomyces (13,14), Aureobasidium (15), Clavispora (16), Ustilago (17),
Exophiala (Wangiella) (18), and Exserohilum (19,20). Such cases are interesting but rare and generally
have some specific historical feature, which explains their infection in the CNS. For example, outbreaks
of fungal meningitis in 2002 with Exophiala (Wangiella) dermatitidis and more recently in 2012 with
Exserohilum rostratum were associated with contamination of compounded corticosteroids with resultant
severe complications (18,19,21). On the other hand, most cases of fungal CNS infections are caused by
only a few important species, which can be classified into two groups. First, all the primary fungal
pathogens of humans can cause CNS infections. This group includes C. neoformans (22,23),
Coccidioides immitis (24–26), Blastomyces dermatitidis (27,28), Paracoccidioides brasiliensis
(29,30), Sporothrix schenckii (31,32), H. capsulatum (33,34), Pseudallescheria boydii (Scedosporium
apiospermum) (35,36), and the dematiaceous fungi (37–39). The second group is considered
opportunists, which take advantage of significant immune defects in the host. This group includes Candida
species (40–42), Aspergillus species (43–45), mucormycosis (46,47), and Trichosporon species (48,49).
Some overlap occurs between these fungal groups and their risk factors. This chapter discusses the
pathogenesis and treatment of CNS infections caused by the leading fungal pathogens.
MAJOR FUNGAL PATHOGENS

Cryptococcus neoformans
C. neoformans, an encapsulated basidiomycetous yeast, represents one of the most common CNS
pathogens encountered in clinical practice today. The first report of human cryptococcosis was published
more than 100 years ago by Busse and Busckhe; approximately a decade later, it was identified as the
cause of human meningitis (50). A review of the incidence of systemic mycoses by selected hospitals in
the United States showed an increase in the number of reported infections, including cryptococcosis,
during the 1960s and 1970s (51). In the 1980s, a further dramatic increase in the number of cases of
cryptococcosis in the United States and certain African countries occurred, directly related to the rising
prevalence of HIV infection. Rates of cryptococcosis in non–HIV-infected individuals approach one case
per 100,000 population and are comparable to incidence rates of meningococcal meningitis (52). During
the AIDS epidemic before highly active antiretroviral therapy (HAART) in the United States, cities such
as Atlanta, Georgia were reporting annual rates of cryptococcosis as high as 66 cases per 1,000 persons
with AIDS (53). During the era of HAART, this figure of disease has been reduced (54) but not
eliminated, and without HAART, the high infection rates persist and the natural history of untreated
infection can still be traced (55). By 2009, the Centers for Disease Control and Prevention estimated that
worldwide, there are 1 million new cases of cryptococcosis per year with over 600,000 deaths, making it
the most common invasive fungal infection in the world today (56). A group in which infection is
increasingly recognized is those undergoing transplantation. In the solid organ transplant population,
Cryptococcus is the third most common fungal pathogen, accounting for 8% of invasive fungal infections
prospectively identified in the Transplant-Associated Infection Surveillance Network database from
March 2001 to March 2006 (57).
Epidemiology
C. neoformans is distributed worldwide. This yeast is found in bird excreta, soil, and animals and can
even colonize humans. Although nomenclature remains in debate, C. neoformans can be divided into two
varieties and species. Recent molecular studies support at least eight genotypes and some have named the
whole group as the cryptococcal complex (58). The two varieties include C. neoformans var.
neoformans, which represent strains with the serotype D polysaccharide capsule and are primarily found
in Europe and the United States. The most common variety is C. neoformans var. grubii with a serotype A
polysaccharide capsule and includes most isolates from patients with or without HIV worldwide. The
second species is C. gattii, which includes polysaccharide capsular serotypes B and C. This species is
predominantly found in clinical infections from Australia, Southeast Asia, and Central Africa; however,
an infection outbreak with C. gattii more recently has emerged in Vancouver, Canada and the Pacific
Northwestern United States (59,60). This new epidemiology may reflect climatic changes or the
development of more virulent strains. C. gattii is more likely to cause disease in immunocompetent hosts
and furthermore to invade the brain parenchyma, causing cryptococcomas and complications of
hydrocephalus than C. neoformans (61–63). C. gattii has been geographically associated with flowering
trees such as eucalyptus and firs; this ecologic niche has been translated into the regional distribution of
human cases. However, in the more recent Vancouver outbreak, it was associated with other deciduous
trees such as oaks, thus expanding its ecologic niche, although the cause of this environmental shift is
uncertain.
Pathogenesis
Most initial infections with Cryptococcus occur through inhalation of small yeast or reproductive spores
(e.g., basidiospores) from the environment. Once in the host, cryptococci develop large polysaccharide
capsules that strongly resist phagocytosis and release polysaccharide antigen, which has effects on host
immunity. Capsule production by the yeast is stimulated by physiologic concentrations of carbon dioxide
in serum and in low iron concentrations that are found in the lung (64). Capsular regulation is an exquisite
adaptation favoring yeast survival in mammalian hosts. Next, the inflammatory reaction to inhaled
cryptococci produces a primary lung–lymph node complex (65), which usually limits spread of the
organism from this site. Most pulmonary infections are asymptomatic, but a clinically apparent pneumonia
can occur on initial infection. This pneumonia is of variable severity, often resolving slowly over weeks
or months with or without treatment (66). Some patients develop focal or nodular pulmonary lesions, but
severely immunocompromised patients may develop diffuse interstitial pneumonitis. Cryptococci can
remain dormant in the lung or lymph nodes for long periods after infection and then reactivate when host
responses become weakened. C. neoformans infection spreads from the lung and intrathoracic lymph
nodes to circulate in the blood, especially in immunocompromised hosts. Dissemination can occur during
the primary infection or during reactivation of infection years later. If distant infection occurs, the site
most likely to be involved is the CNS.
The remarkable predilection of this encapsulated yeast to infect the subarachnoid space may indicate
the existence of a receptor on brain endothelial cells for a ligand on the yeast (67,68) and at least one
receptor (CD44) and ligand (hyaluronic acid) interaction has been identified (69,70). Phenotypic
characteristics that appear to be associated with invasion of the CNS are melanin production, presence of
a polysaccharide capsule, and ability to thrive at mammalian body temperatures (71–75). All three
phenotypes have been linked with CNS invasion and host mortality using powerful genetic tools. Melanin
is produced via a pathway that uses a unique laccase enzyme (71). Mutants that lack this laccase are
avirulent in murine models (72–74) and only rarely cause meningitis in humans. Substrates for laccase
include certain diphenolic compounds including norepinephrine and other catecholamines, which are
highly concentrated in the CNS, a characteristic that might partially explain the tropism of C. neoformans
for this site. Diphenolic compounds do not provide substrate for growth of C. neoformans (72) but do
provide substrate for production of melanin, which can protect certain microorganisms from lysis after
exposure to host defense cells; melanin may act as an antioxidant, protecting the organisms from oxidative
damage (73,74). It has also been shown that melanin is produced in vivo by this yeast.
Capsule production protects the yeast from host defenses, especially phagocytosis (71,75). A series of
genetic studies have shown that acapsular or hypocapsular mutants are less virulent in mice. A well-
known acapsular mutant, strain 602, and site-directed hypocapsular mutants do not produce a progressive
meningitis in immunosuppressed rabbits when introduced intracisternally. However, virulence is not
determined simply by the presence or absence of a capsule. An encapsulated clone was isolated from a
virulent wild type strain of C. neoformans that did not respond normally to physiologic carbon dioxide
concentrations by increasing production of polysaccharide capsular material and it had also lost its ability
to establish infection in the subarachnoid space of rabbits (64). Therefore, both the presence of capsule
and regulation of its production are likely important factors for establishing infection for this yeast within
the CNS.
C. neoformans is one of the few species of cryptococci adapted for growth in human body
temperatures; genetic studies have demonstrated the importance of this phenotype for CNS invasion (71).
Several genetic loci are now associated with growth at high temperature in C. neoformans such as
signaling genes like calcineurin, RAS (a small G protein), and the stress sugar trehalose (76,77). Mutants
that are unable to grow at 37°C are unable to establish infection in the CNS of animals. Further studies
are needed to dissect the mechanisms by which this phenotypic characteristic of elevated temperature
growth confers virulence.
Recent advances in research on C. neoformans, including gene disruption strategies, global expression
profiling techniques, and the completed genome sequence, will make this yeast an important model for
studying molecular mechanisms of fungal virulence. The C. neoformans genes involved in melanin
synthesis (78), capsule production (75), and urease and phospholipase production (79,80) have been
identified and found to be part of the virulence composite. In fact, urease production of cryptococcus has
specifically been shown to impact entry of yeasts across the blood–brain barrier. It has also been shown
that intact purine, methionine, and mannose metabolic pathways are essential for survival in the host. For
example, if the ADE2 protein (phosphoribosyl-aminoimidazole carboxylase) is not functional, C.
neoformans is rapidly eliminated from the CNS, even in an immunosuppressed host (81). Furthermore,
recent work has begun to identify the genetic control for the yeasts’ survival in CSF (82). Means to
identify CNS-specific gene expressions by C. neoformans in experimental animals have been developed
(83) and studies to correlate gene expression in the cerebrospinal fluid (CSF) with survival of the yeast
have been attempted (84). These molecular methods, such as transcriptional profiling with microarrays or
RNA sequencing from yeast cells at the CNS site of infection, will reveal further unique mechanisms of
fungal pathogenesis that could form the basis for the development of antifungal drugs or vaccines. The
molecular understandings of this yeast have dramatically increased over the last decade (85).
Host resistance to cryptococcosis depends primarily on intact cell-mediated immunity (86–94). It
appears that a functioning T helper subset 1 (Th1) cell response is important to eradication. Therefore,
most cases of cryptococcal meningitis occur in patients with conditions that weaken this system: AIDS,
reticuloendothelial malignancies, sarcoidosis, organ transplantation, collagen-vascular diseases,
corticosteroid therapy, and idiopathic CD4 lymphocytopenia. Lymphocyte functions in some respect are
impaired in most patients with disseminated cryptococcosis, and certain cell-mediated immune defects
can persist after infection has apparently been eliminated (95). Animal studies have shown the potential
importance of natural killer (NK) cells in eliminating the initial infection (87). Anticryptococcal activity
of NK cells is impaired in patients with HIV infection but can be restored by cytokines such as
interleukin-12 (IL-12) (86). In animals, cytotoxic lymphocytes can transfer protection (88), and
suppressor cells have been shown to proliferate in response to cryptococcal infection (89). Activated
macrophages become potently fungistatic for C. neoformans; this activity can be enhanced in vitro by
macrophage colony-stimulating factor, and this cytokine increases the anticryptococcal activity of
fluconazole in vitro (90). Macrophage function is probably an important factor in the host’s response to
cryptococcosis. For example, in the subarachnoid space of rabbits, the development of activated
macrophages correlated with the killing of this yeast at the CNS site (91). There are two clinical
observations that suggest that recombinant γ-interferon (a major TH1 cytokine and activator of
macrophages) may help eliminate the yeast in the CNS (96,97). The high susceptibility of patients with
AIDS vividly illustrates the essential role of CD4 lymphocytes in preventing the occurrence of
disseminated cryptococcosis and the recurrence of infection after treatment. The use of HAART with its
immune reconstitution ability is now widespread such that the incidence of cryptococcosis has dropped.
Moreover, antifungal treatment regimens are no longer considered lifelong if there is immune
reconstitution. However, in less-developed countries with limited access to HAART, cryptococcal
infection remains substantial. In animals, depletion of CD4 cells facilitates dissemination of infection
from lung to the CNS (92,93), and in humans with HIV infection, the chance of cryptococcal meningitis
goes up dramatically as CD4 cell counts decrease to less than 100 cells/µL. Finally, genetic defects in the
cell-mediated immune systems of beige, nude, and severe combined immunodeficient (SCID) mice
enhance their susceptibility to C. neoformans infection (94,98).
Humoral immunity also appears to play a substantial role in host defenses against cryptococcosis. Both
immunoglobulin G (IgG) and C3b bind to (and within) the capsule, enhancing phagocytosis. An intact
complement system may be important to prevent dissemination from lung to the CNS (99). The role of
antibody in this infection has received considerable study, with mixed results (100,101). Antibody-
dependent killing of C. neoformans by human peripheral blood mononuclear cells has been documented
(102,103), and measurable titers of serum antibody to C. neoformans were associated with a more
favorable outcome (104). However, passive immunization conferred little protection against yeast
challenge (101). In a rabbit model of cryptococcal meningitis, immunization with capsule did not protect
against subarachnoid challenge with yeasts despite significant serum antibody titers (105). However, the
use of specific monoclonal antibodies has prolonged survival of mice and reduced the tissue yeast cell
concentration even within the CNS (106–108). These studies emphasize the importance of particular
immunoglobulin subtypes in the protective response. Examination of the local immune response in the
subarachnoid space has detected specific anticryptococcal immunoglobulins in the CSF of patients with
resolution of their cryptococcal meningitis (109,110). Also, in rabbits with cryptococcal meningitis, there
is rapid local production of immunoglobulin in the CSF following infection; this appearance of local
antibody correlates temporally with the elimination of viable yeasts at this site. This specific antibody
production is halted if the animals receive large doses of corticosteroids or cyclosporine during infection
(111). It seems certain that humoral factors play an important role in host defenses against C. neoformans.
However, the rarity of cryptococcal meningitis in patients with either congenital or acquired deficiencies
in antibody or complement production argues that humoral immunity is still less important than the
cellular arm of immunity (112).
Two main factors contribute to the prominence of C. neoformans as the most common fungal pathogen
to produce meningitis: corticosteroid therapy and HIV infection. Excess corticosteroids produce a variety
of immune defects that greatly increase the hosts’ risk for disseminated cryptococcosis. Either endogenous
overproduction of corticosteroid or exogenous treatments with these corticosteroids can place the patient
at risk (113). Rabbits, which are normally resistant to experimental cryptococcosis, are rendered highly
susceptible by corticosteroid treatment (114). It is primarily an infection of the subarachnoid space, with
occasional yeasts seen in the brain parenchyma. The normal rabbit develops a brisk inflammatory
response in the meninges, whereas animals immunosuppressed by cortisone have few host cells but
masses of yeasts. These findings are similar to those seen in patients with AIDS or those receiving high-
dose corticosteroids. The rabbit model has allowed examination of many local immune CSF factors. The
single most striking finding is the CSF leukopenia caused by corticosteroids. The number of
polymorphonuclear (PMN) cells and mononuclear cells, including T and B lymphocytes and
macrophages, that migrate into the CSF of corticosteroid-treated rabbits inoculated with cryptococci is
far lower than that in untreated controls. Both the number of yeasts and the reduction of inflammatory cell
numbers in CSF are closely related to the dose of corticosteroid administered (114). The CSF leukopenia
caused by corticosteroids is partially explained by the inhibition of chemotactic factors produced locally
in the subarachnoid space (115). Experimental cryptococcal meningitis in these corticosteroid-treated
rabbits shows many similarities to CNS cryptococcosis in patients with AIDS: low CSF cell counts, large
burden of organisms, high antigen titers, and high mortality. In contrast, treatment with another powerful
suppressor of cellular immunity, cyclosporine, also predisposes rabbits to cryptococcal meningitis
without inducing the severe CSF leukopenia seen in corticosteroid-treated animals (116) and without
demonstrating its known antifungal activity (117).
The second major factor for the increasing incidence of cryptococcal meningitis is HIV infection
(22,118–120). The profound progressive loss of CD4+ (helper) cells in HIV-infected patients directly
correlates with the risk or appearance of cryptococcal meningitis, with most cases occurring once CD4
cell counts fall below 100 cells/µL. Many of these patients with advanced HIV infection will present with
a large burden of yeast in the CSF (106 to 108 CFU/mL), high polysaccharide antigen titers (>1:1,024),
and low CSF leukocyte counts (<20 cells/µL). Most patients with advanced HIV with cryptococcal
meningitis present with fewer than 20 leukocytes/mm3 in CSF and some with almost no inflammatory
cells but massive numbers of yeast. This lack of an inflammatory response at the site of infection indicates
both defective immunity and a poor prognosis. Although the successful immune response of the
immunocompetent host has many components, both corticosteroid-treated rabbits and patients with
advanced HIV demonstrate that adequate numbers of host cells in the subarachnoid space are necessary
for recovery from this persistent infection.
Despite availability of active antifungal agents, treatment of cryptococcosis often fails in
immunosuppressed hosts. Better outcomes will likely require further understanding of local CNS host
factors, leading eventually to specific or nonspecific treatments that enhance the immune response. Little
information on the role of biologic response modifiers at the site of CNS infection with this yeast exists,
although several cytokines (colony-stimulating factors, IL-2, interferon-γ [IFN-γ], IL-12) have had a
positive influence on C. neoformans and host–cell interactions (121–123). Manipulations of the immune
system using modulators such as interleukins, granulocyte colony-stimulating factor, granulocyte-
macrophage colony-stimulating factor, tumor necrosis factor, or IFN-γ to improve cell function or
recruitment of cells to the site of infection might improve results of treatment in immunocompromised
hosts and/or shorten the duration of therapy required for cure. A randomized trial of two doses of IFN-γ
for cryptococcal meningitis did appear to clear the CSF of yeasts faster and was overall well tolerated
(96). Another controlled trial to assess effects of adjunctive IFN-γ on clearance of infection in HIV-
positive patients with cryptococcal meningitis evaluated two versus six doses of IFN-γ added to standard
therapy with amphotericin B and flucytosine. The authors found that both IFN-γ regimens were associated
with faster clearance of infection without a significant increase in adverse effects or immune
reconstitution syndrome (97). Currently, the Infectious Diseases Society of America (IDSA)
recommendations for the management of cryptococcal infection are to consider adjunctive IFN-γ in
patients with refractory rather than primary disease (124). However, further study is necessary to
delineate the optimal dose and duration as well as the appropriate host for this adjunctive therapy before
definitive recommendations can be made to provide it routinely as primary therapy in meningitis.
Coccidioides
Coccidioides is a highly infectious dimorphic fungus that normally inhabits dry, slightly acidic soil. This
limits its ecologic distribution to certain areas in the southwestern United States and parts of Mexico and
Central and South America. However, because of frequent travel into and out of these areas, the human
infection, coccidioidomycosis, is often seen by clinicians outside the natural geographic boundaries of the
organism. There are two primary species of Coccidioides, C. immitis and the “non-California” species
Coccidioides posadasii, which are clinically indistinct but differ in their overall distribution (26,125).
An increase in the incidence of Coccidioides infection has been noted in areas such as California and
Arizona. This increase is likely related to both population expansion in these endemic areas as well as an
ever increasing at-risk population of immunocompromised hosts including organ transplant recipients and
patients with underlying hematologic and oncologic malignancies requiring chemotherapy. Infection
begins with inhalation of arthroconidia, which can establish a primary pulmonary infection. Most such
patients remain asymptomatic; overall, fewer than 1% of primary infections disseminate outside the
respiratory tract. In cases of extrapulmonary disease, the CNS is frequently involved, often without other
body sites involved clinically. Entry into the CNS and development of symptoms typically occurs within
the first several months after the primary pulmonary infection (26). However, in the immunocompromised
host, infection may occur significantly later. Before the advent of antifungal treatment, long-term survival
was better in patients with coccidioidal meningitis as the sole site of extrapulmonary dissemination
compared to those with multiple organ involvement, including meningitis (126).
Certain individuals appear to be at increased risk for disseminated infection inclusive of CNS
involvement. It occurs more frequently in adults but can occur in children and affects men more commonly
than women. However, in pregnant women, particularly during the later stages of pregnancy, direct
stimulatory effects of specific hormones on the fungus can result in more severe and disseminated
infection. African Americans and Filipinos and possibly other ethnic groups including Hispanics may be
at increased risk of coccidioidal infection with multiple potential contributing factors, including specific
human leukocyte antigen (HLA) and ABO blood group types. Finally, cellular immune deficiencies are
associated with increased risk of dissemination and meningitis (127–129). An intact cell-mediated
immunity is important in resistance to coccidioidal meningitis with a robust Th1 host response and not a
conversion to the less effective T helper subtype 2 (Th2) cell response (130). For example, the
development of a positive skin-test result after primary infection, which suggests an appropriate response
to infection and dissemination, is unusual in patients with meningitis. This is supported by observations of
increased rates of disseminated disease including meningitis in individuals with AIDS as well as those
receiving immunosuppressants, such as corticosteroids and anti-tumor necrosis factor (TNF) agents in the
setting of solid organ transplant, malignancy, and autoimmune diseases (131–136).
There are several additional noteworthy characteristics of coccidioidal meningitis. A chronic
mononuclear cellular response is usually found in the CSF. Coccidioides is unique among the major
fungal CNS pathogens in causing eosinophilic meningitis with approximately 70% of patients
demonstrating CSF eosinophilia that in a significant portion of patients is greater than 10 cells/mm3. The
mechanism and pathologic significance of this cellular response remains uncertain but likely reflects a
Th2 response, which is ineffective in eliminating the fungus from the CNS (137). In addition, patients with
coccidioidomycosis are at increased risk of severe complications from CNS involvement including
obstructive or communicating hydrocephalus and vasculitis and long-term persistence of disease despite
treatment (26).
Histoplasma capsulatum
H. capsulatum is the most common of the endemic mycoses in the United States and resides in the soils of
the Ohio and central Mississippi Valleys and along the Appalachian Mountains, but infection does occur
outside these regions. Infection begins after inhalation of spores. The high prevalence of positive skin-test
results in patients living in certain endemic areas who have no history of histoplasmosis indicates that the
primary pulmonary infection is usually asymptomatic and similar to primary infection by C. neoformans.
Dissemination from the lungs is rare. However, when dissemination does occur, autopsy studies have
shown rates of CNS involvement as high as 29% (138). A 15-year retrospective evaluation of 111 cases
of systemic histoplasmosis from a large academic center found CNS involvement in 17% of patients (33).
Manifestations include meningitis or meningoencephalitis, spinal and parenchymal lesions, or stroke
syndromes (34).
Development of progressive disseminated histoplasmosis including involvement of the CNS suggests
that cell-mediated immune defenses are impaired. This is demonstrated by the occurrence of disseminated
disease in a large number of patients with underlying immunosuppression such as HIV/AIDS, hematologic
and oncologic malignancies, organ transplant recipients, and particularly in those receiving
immunosuppressive therapies such as corticosteroids and anti-TNF agents (33,139–141). Similar to that
with C. neoformans in patients with underlying HIV, H. capsulatum infection most often reactivates and
disseminates with CD4 cell counts lower than 100 cells/µL. When this occurs, the CNS is a prime site for
fungal invasion. In one dramatic patient with Histoplasma meningitis, an abundance of suppressor T cells
was found in the CSF and appeared to aid the establishment of this localized infection (142). Full
understanding of the pathogenesis and natural history of this infection will require delineation of how
CD4 cells and activated macrophages act together to eliminate or suppress H. capsulatum at the
pulmonary site of initial infection and protect the CNS.
Blastomyces dermatitidis
B. dermatitidis is a dimorphic fungus that is endemic in parts of the United States; from the lower
Mississippi Valley up to the north central states and into the mid-Atlantic states. As with the other
dimorphic fungi, primary infection is presumed to result from inhalation of spores from a source in soil.
However, it has been difficult to locate the natural habitat of this fungus in the environment; only
occasionally has it been found in nature.
Disseminated blastomycosis is characterized by suppurative granulomatous lesions primarily of lung,
skin, bone, or genitourinary system. This fungus invades the CNS in 6% to 33% of patients when
dissemination occurs (143,144). Infection in the CNS can include meningitis as well as parenchymal and
spinal cord involvement with abscess formation. In some cases, the CNS inflammatory response can show
a prominent PMN response, suggesting bacterial meningitis (145). Most patients with CNS blastomycosis
have infection documented at other body sites with isolated CNS involvement less commonly reported.
For instance, a retrospective review of 22 patients with CNS blastomycosis found isolated CNS disease
in 22.7% of patients (27). In addition, CNS blastomycoma (a granulomatous mass lesion), which had
previously been thought to only rarely coexist with meningitis (143), was found in 18% of patients (27).
Age, sex, and ethnicity do not appear to have a direct relation to disease severity (146). However, cell-
mediated immunity is important in protection from infection as best illustrated by disseminated disease
inclusive of CNS infection in patients with AIDS and those receiving immunosuppressants such as
corticosteroids or anti-TNF agents similar to the other endemic fungi previously discussed
(27,28,147–149). It is likely that in severely immunosuppressed patients, B. dermatitidis disseminates to
distant body sites soon after a primary pulmonary infection. Invasion of the CNS may occur as a late
complication of systemic infection; meningitis or blastomycomas should always be considered in patients
with neurologic symptoms who previously had experienced blastomycosis (150).
Paracoccidioides brasiliensis
P. brasiliensis is a dimorphic fungus with distribution limited to subtropical areas of Central and South
America. It can be associated with acute, subacute, and chronic infections (151). Similar to most
dimorphic fungi, the lung is the primary site of infection. CNS involvement occurs most frequently in the
chronic form of infection and typically involves granulomatous parenchymal lesions with or without an
associated meningitis (29,30,152). When the CNS becomes involved, most patients already have widely
disseminated disease. Rarely, infection involves the CNS alone and in this scenario likely represents
reactivation of a dormant focus from a primary infection (152). As with other endemic fungi, the cellular
immune system is important in control of disease, and yet CNS infections generally occur in apparently
immunologically intact hosts. However, severe immunosuppression associated with AIDS likely results in
more disseminated and CNS infections (153–156).
Sporothrix schenckii
Sporotrichosis is caused by S. schenckii, a fungus with worldwide distribution. The fungus is found in
soil or plant material such as sphagnum moss. It primarily enters the body via a traumatic inoculation,
such as a prick from a rose thorn. Sporotrichosis generally presents as an infection of the skin and
subcutaneous lymphatics; pulmonary disease following inhalation of spores is uncommon. Dissemination
beyond focal lesions in skin or lung is rare, but joints can occasionally become infected, and over 20
cases of Sporothrix meningitis have been reported (157). Specific risk factors for invasion of Sporothrix
infection into the CNS are not known. However, certain patients may be more predisposed to undergo
dissemination from a local infection—for example, patients with lymphoma, alcohol abuse, or organ
transplant recipients receiving immunosuppressive therapy (158–161). Sporothrix meningitis has also
been described in patients with HIV and AIDS (31,32,157,162,163).
Phaeohyphomycoses
Phaeohyphomycosis refers to a group of mycoses resulting from infection with one of a heterogeneous
group of fungal species that form dematiaceous yeastlike cells, pseudohyphae, septated hyphae, or any
combination of these forms. In most cases, infections are limited to local disease, without dissemination.
The dematiaceous fungi contain prominent amounts of melanin in their cell walls contributing to their
pathogenicity and the light or dark brown color that is frequently seen in culture or histopathology (164).
There are several organisms within the order Chaetothyriales more commonly associated with cerebral
phaeohyphomycosis, namely Cladophialophora bantiana (also known as Xylohypha bantianum,
Cladosporium bantianum, Cladosporium trichoides) (38,165), Exophiala dermatitidis (also known as
Wangiella dermatitidis) (21) and Rhinocladiella mackenziei (also known as Ramichloridium
mackenziei and Ramichloridium obovoideum) (39,166). However, multiple other dematiaceous fungi
have been associated with CNS disease, including the large outbreak in 2012 associated primarily with
Exserohilum rostratum (19,20,167). C. bantiana has a remarkable predilection for CNS involvement and
is the pathogen most commonly associated with CNS phaeohyphomycosis. Cerebral lesions may present
as single, multilocular, or multiple abscesses. The histology of these CNS infections is similar to that seen
in the subcutaneous form of infection, with a marked inflammatory reaction and necrosis. These
dematiaceous fungi cause CNS infections in both normal and immunocompromised hosts. Infections with
Exophiala dermatitidis and Exserohilum rostratum have drawn attention secondary to outbreaks in the
United States related to injectable contaminated steroids. An outbreak in 2002 was associated with
Exophiala dermatitidis wherein four cases of meningitis were identified related to contamination of
steroids injected epidurally for pain management (21). The patients developed chronic meningitis,
presenting with headache, altered mental status, and neurologic findings approximately 1 to 3 months after
injection. Exserohilum rostratum has been associated with a larger outbreak discovered in September
2012 associated with contaminated lots of methylprednisolone acetate from a single compounding
pharmacy in Massachusetts (19,20,167,168). At the time of this writing, 395 cases of fungal meningitis,
stroke deemed secondary to fungal meningitis, or parameningeal infections (e.g., epidural abscess,
arachnoiditis with cauda equine syndromes) as well as 9 joint infections have been reported (169).
Although the pathogen identified in the index case was Aspergillus fumigatus, the majority of the cases to
date have been associated with Exserohilum rostratum and one additional case was reported with
Cladosporium spp. The majority of cases of CNS infection have presented within 1 to 4 weeks after an
epidural injection. Signs and symptoms have included headache, neck stiffness, back pain, malaise, and
weakness as well as posterior circulation strokes. After the initial meningitis presentations, the outbreak
began to focus on parameningeal sites and complications at these sites. Recommendations for management
and prophylaxis in the affected patients continue to evolve with identification of additional cases, and the
history of this outbreak will define the natural progression of directly injected black mold paravertebrally
in a corticosteroid solution.
Hyalohyphomycoses
Hyalohyphomycosis describes infections caused by the hyaline molds, a large group of septate molds that
present as colorless or lightly pigmented hyphae in tissue. There are numerous molds in this group,
including Aspergillus, Scedosporium, and Fusarium species. S. apiospermum (the teleomorph or sexual
reproductive form is P. boydii) is the most prominent species of this group with respect to CNS
infections. It has a worldwide distribution in soil and contaminated water and is a leading cause of
mycetoma (a chronic subcutaneous fungal infection of the skin and soft tissue) but causes meningitis
occasionally (170,171). Although factors that predispose to CNS invasion are not well defined,
immunosuppressants such as corticosteroids may be a risk factor, and meningitis and brain abscesses
associated with S. apiospermum have been noted in immunocompromised hosts including solid organ and
hematopoietic stem cell transplant recipients (170–172). Another unique potential risk factor for this CNS
infection is freshwater immersion (8,173). Several cases of near drowning have resulted in pneumonia
and meningitis caused by S. apiospermum, presumably from aspiration of contaminated water. Pneumonia
may serve as a nidus of infection that then allows dissemination to the CNS, although direct extension
through the cribriform plate might also occur. Fusarium species have also been found to cause
disseminated infection in severely immunocompromised hosts, particularly in neutropenic patients.
However, even with disseminated infection, Fusarium species rarely invade the CNS (174–176).
The four groups of microorganisms discussed in the following sections are considered opportunistic
invaders of the CNS, because the vast majority of cases occur in immunocompromised hosts.
Candida Species
Candida species are part of the normal human flora. They rarely cause CNS disease unless host defenses
have been impaired. Many factors encourage spread of Candida into the blood and potentially into the
CNS. These include prematurity, broad-spectrum antibiotic therapy, hyperalimentation, malignancy,
indwelling catheters, treatment with corticosteroids, neutropenia, abdominal surgery, diabetes, thermal
injuries, and parenteral drug abuse (177–180). In the past, Candida infections were considered the most
common fungal CNS infection, based on necropsy studies (181). With the AIDS epidemic and the reduced
duration of neutropenia associated with the use of biologic growth factors such as granulocyte colony-
stimulating factor and granulocyte-macrophage colony-stimulating factor, C. neoformans has replaced
Candida as the most common CNS mycosis.
Candida species are susceptible to both the oxidative and nonoxidative antimicrobial mechanisms of
professional phagocytes. Therefore, neutropenia is a major risk factor for invasive Candida infections
(181). The importance of the host response has been further emphasized by reports of Candida meningitis
in patients with myeloperoxidase deficiency (182,183), chronic granulomatous disease of childhood
(184,185), and even chronic mucocutaneous candidiasis (186). White blood cell defects should be
considered in any case of spontaneously occurring Candida meningitis (184,185). Candida meningitis or
brain abscess has been reported in patients with SCID (187) and in those with advanced HIV (40).
Candida can involve the brain and subarachnoid space by direct extension via trauma (188),
ventriculostomy placement, or ventricular shunts, particularly if antibacterials have previously been used
(41,189). It has also been associated with the use of BCNU (bischloroethylnitrosourea) polymer wafers
implanted for local therapy of CNS malignancies (190,191). In neurosurgical cases, documenting
persistent cultures and meningitis is extremely important because not all positive candidal cultures from
CNS drains and catheters represent disease (192). In premature infants and neonates, meningitis is the
most common form of Candida CNS infection. In a series of 106 cases of systemic candidiasis in
neonates, meningitis was seen in 22% and emphasizes that Candida can easily breech the immature
blood–brain barrier (42). Infections in neonates can be associated with normal CSF profiles requiring a
high index of suspicion. Moreover, invasive candidiasis inclusive of meningitis has been associated with
neurodevelopmental delays such that early diagnosis and effective therapy is imperative. It can also occur
in older children (193,194). In adults, Candida infection of the CNS, which is most common in cancer
patients with neutropenia, often presents with brain abscesses rather than meningitis. Candida meningitis
may present with acute symptoms or a chronic neutrophilic meningitis (195). Although Candida albicans
is the most common species isolated from cases of Candida meningitis, it has been reported with other
species including Candida tropicalis (196,197), Candida glabrata (198), Candida lusitaniae (199), and
Candida parapsilosis (200).
Aspergillus Species
Aspergillus fumigatus, Aspergillus terreus, and Aspergillus flavus most commonly cause CNS infections
in humans. In the severely immunosuppressed host, even the relatively nonpathogenic Aspergillus
nidulans can cause CNS infection (201). These infections develop by direct extension from the paranasal
sinuses, or following head trauma, surgery, and lumbar puncture, or via hematogenous spread in the
immunocompromised host, particularly those with prolonged neutropenia and graft-versus-host disease
(GVHD). The risk for disseminated aspergillosis and subsequent brain involvement increases with the
duration of neutropenia and the aggressiveness of treating GVHD (202). Among 14 cases of CNS
aspergillosis identified in a cohort of allogeneic stem cell transplant patients, all but one patient was
receiving high-dose corticosteroids for GVHD and over half of the patients concomitantly received
antithymocyte globulin (ATG) (43). CNS infection with Aspergillus has also been reported in patients
with advanced HIV (44,203).
The pathology of CNS aspergillosis can be divided into three forms: infarction, granuloma, and
meningitis. Invasion of the brain parenchyma with formation of abscesses or infarcts is a more common
clinical presentation for these fungi than a meningitis syndrome. In a review of 93 cases of Aspergillus
meningitis, approximately 60% of patients were seemingly immunocompetent, with meningoencephalitis
occurring in approximately one fourth of cases and evidence of arachnoiditis or ventriculitis seen in an
additional 5% (45). Aspergillus may also invade the CNS via local involvement of the vertebrae and
direct extension into the subarachnoid space (184). This pathway to CNS involvement occurs most
commonly in patients with chronic granulomatous disease of childhood. Although alveolar macrophages
play a role in limiting initial infection of the lungs with this ubiquitous fungus, the PMN leukocyte is likely
the crucial host defense against CNS invasion. The molecular virulence attributes of this mold for CNS
extension remain to be fully discovered but a basic molecular understanding of this mold’s virulence is
improving (204). Host factors such as phagocytosis or complement inhibitors may also assist CNS tissue
invasion (205,206).
Mucormycosis
The genus Rhizopus is responsible for the majority of infections within this group. The angioinvasive
nature of these fungi, similar to that of Aspergillus species, results in a presentation with symptoms of
cerebrovascular occlusion with infarction. The ubiquitous molds of this class cause CNS infection in
immunocompromised hosts primarily by direct extension or hematogenous spread (46,207). Patients with
diabetes, those given immunosuppressive therapy, intravenous drug users, and those with an underlying
malignancy are at increased risk of this CNS mycosis. Patients who have become acidotic, especially
from diabetic ketoacidosis, are at risk for invasive mucormycosis of the nasal area and sinuses, which can
spread through tissue planes and vessels into the CNS and the vascular system. Some cases of
disseminated mucormycosis, including brain involvement, have occurred in patients receiving chelation
therapy with deferoxamine (208). It is suspected that these fungi, under low iron conditions, use this iron
chelator as a siderophore to abrogate the antifungal activity of transferrin. Patients who are intravenous
drug abusers may directly inject contaminated material into the venous system with occasional
dissemination to the CNS. In one of the most comprehensive retrospective evaluations of 929 cases of
invasive mucormycosis, CNS infection was seen in 30% of patients. Rhinocerebral infections
predominated in this series (69%) and were the primary CNS infection in diabetics. Intravenous drug
abuse accounted for the majority of localized cerebral infections (47).
Trichosporonosis
Infections with Trichosporon species generally involve superficial skin or hair shafts. However, with the
increasing number of immunocompromised hosts, disseminated infections with CNS involvement due to
Trichosporon beigelii (48,209,210), T. asahii (49,211), and Blastoschizomyces capitatus (11,12) have
been reported.
CLINICAL MANIFESTATIONS OF FUNGAL MENINGITIS

The clinical presentation of fungal meningitis is less stereotyped than that of bacterial meningitis. Patients
often present with the chronic meningitis syndrome, defined as meningitis that fails to improve or
progresses over at least 4 weeks of observation (212). Clinical findings are often nonspecific. The patient
may present with general debility or failure to thrive. Likely manifestations include some combination of
fever, headache, lethargy, confusion, nausea, vomiting, stiff neck, or neurologic deficits. Often, only one
or two of these cardinal manifestations will be initially present. Patients may present with nothing more
than a subacute dementia. Raised intracranial pressure and its symptoms can develop acutely or
chronically during the progression of the disease. Cranial nerve palsies and seizures may also be
observed.
The time course of illness is an important consideration in the diagnosis of fungal meningitis. A few
cases present as acute meningitis, many are subacute, and some are chronic. Symptoms often fluctuate
over time, giving the illusion of improvement, but this is not maintained. Occasionally, fungal meningitis
causes symptoms persisting for years (213–215). Careful evaluation of the natural history and meticulous
repeated observations and CSF studies may be required before the diagnosis can be confirmed. However,
severely immunocompromised patients such as those receiving high-dose corticosteroids or those with
advanced HIV infection can develop severe symptoms and signs of cryptococcal meningitis within only a
few days and progress to death over several weeks without treatment (55).
Fungal meningitis is always a primary consideration in the differential diagnosis of a patient with the
chronic meningitis syndrome, but many other infectious and noninfectious conditions must be considered,
especially tuberculous or carcinomatous meningitis (216). Tuberculous meningitis usually produces a
more rapid deterioration to death compared to fungal meningitis in immunocompetent hosts.
DIAGNOSIS OF FUNGAL MENINGITIS

The CSF findings in fungal meningitis have been well studied (217). Most cases have a mononuclear
pleocytosis ranging from 20 to 500 cells/mm3. The proportion of PMN leukocytes is variable, usually
well below 50%. In a few cases, PMN leukocytes predominate; this occurs more commonly in meningitis
caused by fungi such as Aspergillus, Scedosporium Blastomyces, or the agents of mucormycosis. Chronic
neutrophilic meningitis caused by fungi is well described (218). Eosinophilic meningitis suggests the
possibility of infection by C. immitis. In severely immunocompromised patients, especially those with
AIDS or those receiving high-dose corticosteroids, very low (<20 cells/mm3) or even normal CSF
leukocyte counts may be found during cases of active cryptococcal meningitis. This syndrome is precisely
mimicked by experimental cryptococcal meningitis in rabbits treated with cortisone and represents a poor
prognostic indicator (114). CSF protein concentrations generally are elevated. If very high protein
concentrations (e.g, higher than 1 g/dL) are found, a subarachnoid CSF block is likely present. The CSF
glucose concentrations in fungal meningitis often are reduced but may be normal. A fungal brain abscess
may present with normal CSF parameters or with a mild pleocytosis and elevated protein concentration,
but CSF glucose concentration is usually normal.
Of the various fungal pathogens producing meningitis, cryptococci are the easiest to diagnose by CSF
examination. Encapsulated yeasts can be identified by mixing CSF with India ink on a slide for direct
microscopic examination. The yeast cells measure 4 to 6 µm in diameter, with a capsule ranging from 1 to
30 µm wide; budding may be prominent, with a narrow base (point of attachment) between parent and
daughter cells. A careful India ink examination of CSF is positive in more than half the cases of
cryptococcal meningitis. In patients with AIDS, the yield is even higher (80%). In some patients with
AIDS, the CSF contains far more yeast than leukocytes. Initial quantitative viable yeast concentrations
from patients with cryptococcal meningitis reveal a range from 103 to 107 CFU of yeasts per milliliter of
CSF and India ink examination becomes routinely positive when concentrations reach 105 CFU/mL. In
fact, quantitative CSF yeast counts can be used for prognosis, impact of treatment regimens, and outcomes
(219). This simple test is generally used in clinical research studies but may become more integrated into
clinical practice strategies.
Conclusive proof of a fungal CNS infection is provided by growth and identification of the organism in
brain tissue or CSF. The best-studied cause of fungal meningitis, C. neoformans, in the past yielded
positive CSF cultures in approximately 75% of patients. However, more than 90% of severely
immunosuppressed patients will have positive CSF cultures at presentation. Unfortunately, CSF cultures
are not always positive. For example, Blastomyces meningitis rarely yields positive CSF cultures, and
even at autopsy, it is difficult to grow H. capsulatum from the subarachnoid space even in patients
without therapy. To improve the diagnostic yield by culture, large volumes of CSF (10 to 30 mL) should
be sent for culture when fungal meningitis is considered likely but the routine CSF culture was negative.
Specimens should be centrifuged and placed on appropriate culture media or passed through a filter
before culture. A cytologic examination of cells spun down from CSF may occasionally reveal a fungus.
When brain parenchyma is involved, a methenamine silver stain of a direct aspirate or biopsy may be
extremely helpful. For example, mucormycosis may be seen on histologic or cytologic preparations even
though the direct culture of the specimen is negative. When cultures are positive, Candida species can be
quickly identified in the laboratory. C. neoformans is identified in most patients within 3 to 10 days. The
dimorphic fungi (e.g., Blastomyces, Histoplasma, or Coccidioides) may require several weeks for
identification. Lysis–centrifugation culture methods for blood isolation of yeasts may be helpful in some
patients who have systemic infection in association with meningitis. Blood cultures usually are negative
during fungal meningitis, except for Candida in neonates and Cryptococcus and Histoplasma in patients
with AIDS.
Fungal meningitis commonly involves the base of the brain more prominently than the spinal cord; thus,
cisternal CSF may yield organisms when lumbar fluid is negative (220). It is important to emphasize that
in puzzling cases of chronic meningitis, repeated examinations of lumbar CSF or cisternal or ventricular
fluid may be needed before a diagnosis is established. Stereotactic brain biopsies with culture and
histologic examination of the aspirate have been particularly successful in identifying infection with
organisms such as Aspergillus (221) and dematiaceous fungi (37).
Although a positive culture is the gold standard for diagnosing a fungal CNS infection, additional
diagnostic tests are often used in combination with cultures, particularly when cultures remain negative.
Serologic tests are important in the diagnosis of some forms of fungal meningitis, especially cryptococcal
infection. Evaluation of CSF samples with both latex agglutination and enzyme-linked immunosorbent
assay (ELISA) testing for the cryptococcal polysaccharide antigen has shown sensitivity and specificity
ranging from 93% to 100% and 93% to 98%, respectively (222). False-positive test results may occur if
surface condensation from agar plates contaminates the assay slide (223). False-positive test results also
can be associated with other infections, for example, in disseminated Trichosporon beigelii infection
(224) or paravertebral bacterial infections (225). Detection of this antigen in CSF establishes infection of
the subarachnoid space, because the large polysaccharide molecules do not diffuse into CSF from serum.
The polysaccharide antigen test may be positive early in the infection, even when the culture is negative.
Titers of 1:8 or greater are usually observed, but any titer can be significant if proper controls are
performed and the clinical condition is consistent (226). Cryptococcal polysaccharide antigen may also
be found in the serum. In normal hosts with cryptococcal meningitis, serum titers are negative or lower
than those found in the CSF. In the most severely immunocompromised patients, especially patients with
AIDS with disseminated disease, serum antigen test results are usually positive. In such cases, the serum
titer often is very high, even exceeding the titer in CSF. Therefore, serum cryptococcal antigen detection is
moderately effective as a screening test for possible CNS infection in HIV-infected patients. If a patient
whose clinical presentation does not seem compatible with cryptococcal meningitis proves to have a
positive CSF cryptococcal antigen test, it should be repeated before a diagnosis is made and treatment is
started, especially if the titer is very low. False-negative test results are uncommon and in most cases
occur due to an early infection with a low burden of organisms in the CSF and with prolonged infection
will turn positive. Repeated negative antigen titers over 1 month or longer virtually rule out the diagnosis
of cryptococcal meningitis. Alternatively, a false-negative test result can represent a prozone phenomenon
resulting from antigen excess, but in this case, cultures are routinely positive. The more recent addition of
a lateral flow assay (LFA) for the detection of the cryptococcal antigen is a major advance in
cryptococcal diagnostics (227,228). This assay has been shown to be an inexpensive, easy, rapid, and
reliable means of diagnosing HIV-associated cryptococcal infection via sampling of blood, CSF, or urine.
Particularly in low-resource settings where invasive testing such as lumbar puncture may be delayed or
even absent (227), this cheap, low-tech test could be used to screen high-risk HIV patients in the clinic
and positive tests could be evaluated with lumbar puncture if symptomatic or treated with azoles for
asymptomatic antigenemia (229). Unfortunately, the cryptococcal polysaccharide antigen test is less useful
in assessing the patient’s response to treatment. It is reassuring if antigen titers fall or become negative
during therapy when compared with previous CSF specimens tested by the same method. However,
reliable guidelines for sequential antigen titers to measure success or failure of treatment cannot be given.
On the other hand, a high antigen titer (≥1:1,024) suggests a high burden of organisms and a worse
prognosis. Cryptococcal antibody titers are not presently useful in clinical practice. However, the
quantification of CSF yeast counts in cryptococcal meningoencephalitis, developed initially as a research
tool in experimental animal models (114), has also been used for monitoring response to differing
treatment regimens in human cryptococcal meningoencephalitis (230–232). Using serial quantitative CSF
yeast counts, early fungicidal activity (EFA), defined as the calculated drop in log CFU per day, can be
determined to compare the rapidity of killing of antifungal regimens. This monitoring tool could become
the standard care of patients with cryptococcal meningoencephalitis. For example, EFA values calculated
from the CSF at day 0 and days 5 to 7 of therapy of 0.4 log10 or greater in patients clinically responding to
therapy would then prompt conversion to fluconazole, whereas low EFA values would support a more
prolonged up-front course of dual polyene combination therapy.
As positive cultures are often not seen with coccidioidal meningitis, the diagnosis is generally made
with serologic testing using methods such as immunodiffusion and complement-fixing antibodies (CFAs).
Serum CFA titers higher than 1:32 to 1:64 strongly suggest disseminated disease. However, patients with
coccidioidal meningitis may have low serum CFA titers when other body sites are not involved. In
patients with meningitis, CFAs are present in CSF from at least 70% of patients when infection is initially
diagnosed and from almost all patients as the infection progresses. If the patient does not have meningitis,
CFAs are usually absent in unconcentrated CSF, even in the presence of high serum CFA titers associated
with extraneural disease. Occasionally, CFAs are positive in CSF in the absence of meningitis when a
parameningeal coccidioidal lesion abuts the dura mater. The CSF CFA titer parallels the course of
meningeal disease and can be used along with other CSF parameters (e.g., white blood cell [WBC],
protein, glucose) to follow response to treatment (25). Patients who relapse after initial response to
therapy generally develop CSF pleocytosis or abnormal protein or glucose concentrations before
detectable return of CSF antibody.
Detection of specific antibodies in the CSF has also been used for diagnosis of CNS infection due to
Histoplasma (233), Sporothrix (234), and mucormycosis (235). Because CSF culture positivity has been
reported as low as 26% in patients with Histoplasma meningitis, use of additional testing in the CSF to
aid in the diagnosis such as antibody and antigen detection is essential, particularly when infection is
isolated to the CNS (140). Detection of antibodies to Histoplasma by both complement fixation and
radioimmune assays has been used for diagnosis (233). The sensitivity of antibody testing is typically
much higher than culture with reported values of 80% to 89% (140,233). However, the specificity is
lower given cross reactions with other fungal pathogens such as Cryptococcus and Coccidioides.
Histoplasma antibodies can also be found in CSF when the blood–brain barrier is abnormal during
meningitis caused by other pathogens if patients have preexisting antibody in serum. Histoplasma
polysaccharide antigen has been detected in the CSF of approximately 40% of patients with Histoplasma
meningitis in one series (236), with even higher rates of detection in the CSF (67%) in disseminated
infection in patients with AIDS (139). It has been useful in the rapid diagnosis of this infection in
immunocompromised hosts, in whom antibody tests are less useful, and in culture-negative cases.
Diagnosis of Sporothrix meningitis is extremely difficult. Delays of up to 6 to 7 months from initial
symptoms often occur when cultures are used as the basis for diagnosis. A latex agglutination test and
enzyme immunoassay for Sporothrix antibodies in CSF have been successful in confirming this rare
infection (234). When a titer of 1:8 or greater was used, there was no cross reaction with other pathogens.
These serologic tests for fungal antibodies and antigens should always be considered in the diagnostic
approach to difficult cases of chronic meningitis.
Several other potentially useful serologic tests for fungi have not yet been formally studied in the CSF.
Aspergillus is often diagnosed on basis of evidence of invasive disease in non-CNS sites alongside
findings consistent with CNS involvement (238). However, the Aspergillus galactomannan antigen has
been detected in the CSF in patients with presumed CNS infection and may be useful in high-risk patients
(238–240). Evaluation of the CSF for the Candida cell wall component, mannan, has been used in cases
of CNS candidiasis caused by C. albicans (241); however, Candida antibody and antigen tests have not
been sufficiently evaluated in the diagnosis of invasive candidiasis. The most advanced serologic assay
for disseminated candidiasis, the β-glucan test, has not been evaluated formally in CSF specimens in
humans; however, experimental data in nonneutropenic rabbit models of Candida meningoencephalitis
found it more sensitive than quantitative CSF cultures (242). Several other techniques could prove useful
for the diagnosis of fungal meningitis. One novel method is detection of yeasts by identifying their
metabolic products, such as mannitol. Increased mannitol concentrations have been found in the CSF of
animals with experimental cryptococcal meningitis (243). However, Liappis et al. (244) found elevated
mannitol CSF concentrations in HIV-positive patients both with and without Cryptococcus meningitis,
suggesting limited diagnostic use. Although not specific for fungal meningitis, CSF lactic acid
concentrations are generally elevated during infection (245). Finally, polymerase chain reaction (PCR)
can be used to detect fungal DNA in CSF during meningitis and possibly to monitor treatment
(239,246–248). PCR has great potential for the diagnosis of all infectious causes of meningitis but needs
further validation regarding sensitivity and specificity for fungal pathogens at this site.
TREATMENT OF FUNGAL MENINGITIS

The management of fungal meningitis is considered in this chapter from the perspectives of (a) a review
of some relevant features of the main antifungal drugs, (b) treatment (Table 40.1) and prognosis of
specific fungal infections, and (c) prevention.
Antifungal Drugs
Polyenes
Amphotericin B has been used for more than 40 years to treat various forms of fungal meningitis. The
degree of success achieved, although less than ideal, has been remarkable because amphotericin B
concentrations in the CSF during treatment are generally low or even unmeasurable (249,250). This
observation suggests either that the drug accumulates in brain and meninges rather than in CSF or that it
enhances the host’s immune responses. Amphotericin B has some known immunostimulatory effects.
Because amphotericin B concentrations in the subarachnoid space after intravenous administration are so
low, some clinicians have used intrathecal administration, via subcutaneous reservoirs or by direct
injection into the cisternal or lumbar space, to achieve higher concentrations (251,252). For example,
intrathecal doses of amphotericin B deoxycholate of 0.25 to 0.5 mg per day have been used to suppress
coccidioidal meningitis or to treat severe cases of cryptococcal meningitis, but this practice carries
certain risks. Side effects include arachnoiditis, vasculitis, and secondary bacterial infections of
subcutaneous reservoirs used to administer intrathecal amphotericin B (253). Intrathecal drug should be a
“last-resort” strategy.
The lipid products of amphotericin B have been used in the treatment of CNS infections with multiple
fungal pathogens including Cryptococcus, Aspergillus and non-Aspergillus hyaline molds, Candida,
endemic mycoses, and dematiaceous molds. Liposomal amphotericin B (AmBisome) at high doses such
as 3 to 6 mg/kg/day or more appears to be an excellent alternative to conventional amphotericin B
deoxycholate (254,255). In animal experiments, it has been suggested that liposomal amphotericin B
might be more effective than amphotericin B deoxycholate and other lipid products of amphotericin B for
CNS infections (256). Whether one polyene preparation is better than another for treatment of humans
with fungal meningitis remains unclear, but lipid products are getting more use in CNS fungal infections
because of their better tolerability compared to amphotericin B deoxycholate.
The primary side effects with systemic amphotericin B are nephrotoxicity and associated electrolyte
imbalances (e.g., hypocalcemia, hypophosphatemia, hypomagnesemia, and hypokalemia). Infusion-related
adverse effects include fevers, chills, rigors, and gastrointestinal distress (e.g., nausea and vomiting). The
administration of normal saline both pre- and post-amphotericin B infusion may reduce the associated
nephrotoxicity, and infusion-related adverse effects may be minimized via premedication with
antipyretics, antihistamines, and corticosteroids. The lipid products of amphotericin B are associated
with less nephrotoxicity and are often used first-line, particularly in patients with underlying renal disease
or who are receiving nephrotoxic therapies (e.g., transplant recipients receiving concomitant calcineurin
inhibitors). Therapeutic drug monitoring of amphotericin B is not used in clinical practice. The most
notable consideration in the context of drug–drug interactions as alluded earlier is the concomitant
administration of nephrotoxic medications.
Flucytosine
Flucytosine has been used effectively to treat CNS fungal infections caused by Candida and
Cryptococcus species and some dematiaceous fungi. This drug penetrates well into CSF, achieving
concentrations approaching 75% of simultaneous serum concentrations. Despite its excellent
pharmacokinetics in the CNS, flucytosine should not be given alone for treatment of CNS fungal
infections. Treatment failures for both meningitis and brain abscesses have occurred because of the
development of in vitro and in vivo resistance during single-drug therapy (257,258). Therefore,
flucytosine is used in combination with other agents for the treatment of CNS infections. The use of
flucytosine in combination with amphotericin B has been associated with more rapid clearance of
Cryptococcus from the CSF as well as reduced rates of relapse (230). Flucytosine and fluconazole
combination regimens have also been used for cryptococcal meningitis (232,259,260).
Flucytosine has numerous associated toxicities, perhaps most notable are its hematologic toxicities and
hepatotoxicities. Close monitoring of complete blood counts for emergence of cytopenias as well as
hepatic and renal function on therapy is required. Dose adjustment of flucytosine is required in patients
with underlying renal dysfunction to further reduce the potential for toxicities. The other primary adverse
effects are gastrointestinal including nausea, vomiting, and diarrhea. Therapeutic drug monitoring is
recommended with flucytosine both to ensure target concentrations are achieved and to avoid potential
toxicities associated with supratherapeutic exposure. Flucytosine-associated myelosuppression does not
appear to be greater in patients with poor bone marrow reserves before treatment (261), but if prompt and
reliable therapeutic drug monitoring cannot be achieved, then frequent evaluation of blood counts is
essential. Both bone marrow suppression and hepatoxicity correlate with peak serum flucytosine levels of
more than 100 µg/mL (261,262). At minimum, patients should have serum flucytosine concentrations
measured when therapy is planned for more than 1 to 2 weeks and repeated if renal function declines. For
cryptococcal infections, specific recommendations for therapeutic drug monitoring include obtaining a 2-
hour postdose serum concentration of flucytosine on days 3 to 5 of therapy with a target concentration of
30 to 80 µg/mL (124). Important drug–drug considerations include coadministration of flucytosine with
other nephrotoxic or myelosuppressive agents.
Azoles
Historically, the azoles used for fungal CNS infections included the imidazoles, such as ketoconazole and
miconazole, as well as the triazoles fluconazole and itraconazole (263–267). However, the imidazoles
and even itraconazole are seldom used for most CNS infections. Fluconazole and the newer second-
generation triazoles, namely voriconazole and posaconazole, now predominate.
Fluconazole, the first triazole introduced, is a broad-spectrum compound that has been used to treat
meningitis associated with multiple fungal pathogens. It possesses excellent pharmacokinetic properties
for treatment of CNS infections and has few side effects. The drug passes easily across the blood–CSF
barrier and has a long half-life in this CNS compartment in humans (268,269) and animals (270,271).
Macrophages may enhance the anticryptococcal activity of fluconazole (90). This convenient agent has
been used successfully in the treatment of cryptococcal meningitis in animals (271) and humans (272). It
is now widely used for therapy of cryptococcosis and coccidioidomycosis (273–276). Because
fluconazole appears to achieve CSF sterilization more slowly compared to an amphotericin B–containing
regimen, many favor its use in cryptococcal meningitis only after initial induction therapy. In resource-
limited settings such as sub-Saharan Africa where patients often receive fluconazole monotherapy for
CNS cryptococcal infections, preliminary data using abbreviated 5-day courses of amphotericin B in
combination with high-dose fluconazole (e.g., 1,200 mg daily for 2 weeks followed by 800 mg daily)
suggest rapid clearance of infection with overall acceptable tolerability (277). Further randomized
controlled trials aimed at defining the safest and most effective regimen to reduce mortality in this setting
are needed. In vitro data may help guide outcome of cryptococcal meningitis treatment with fluconazole
(266, 278). For instance, strains with minimum inhibitory concentration of 16 µg/mL and higher may be
resistant to fluconazole treatment for meningitis. Fluconazole, even at high doses used in CNS infections,
is typically well tolerated. Gastrointestinal side effects are generally mild, but all azoles, including
fluconazole, can be associated with hepatotoxicity such that hepatic profiles must be monitored on
therapy. Therapeutic drug monitoring with fluconazole is not advised given its predictable and consistent
bioavailability. As fluconazole is both metabolized by and is an inhibitor of the cytochrome P450
enzymatic system, the majority of drug interactions are mediated therein. The list of interactions is
extensive and beyond the scope of this chapter, but examples of drugs whose metabolism may be inhibited
(with resultant supratherapeutic concentrations) include warfarin and the calcineurin inhibitors,
tacrolimus and cyclosporine, such that close monitoring with concomitant therapy is necessary. Drug
interactions are additionally mediated via fluconazole’s effect on enzymes involved in glucuronidation
and is a consideration with coadministration of drugs such as zidovudine and carbamazepine (279).
Itraconazole is a less commonly used triazole with broad-spectrum in vitro inhibitory activity, which
includes Aspergillus species that are resistant to other azoles (267,280). Despite limited penetration into
CSF (270), it has been successfully used in the treatment of meningitis due to Cryptococcus,
Blastomyces, Coccidioides, and Histoplasma. Its apparently paradoxical effectiveness in treatment of
CNS infections may be related to potent antifungal activity and lipophilicity, which allows avid binding to
host cells (281). Itraconazole could be transported directly to the site of infection by immune cells
recruited to infiltrate infected tissues in the CNS. It has better activity than fluconazole against
histoplasmosis but due to the poor CNS penetration is recommended as step-down therapy following
initial treatment with liposomal amphotericin (282,283). It is less effective than fluconazole when used
early in the management of cryptococcal meningitis and therefore ranks behind fluconazole as an agent for
the induction phase management of cryptococcal meningitis (124). Gastrointestinal side effects associated
with itraconazole are typically more significant that that with fluconazole. They are contributed to by the
solubilizing excipient, hydroxypropyl-β-cyclodextrin, used in the oral solution formulation. In addition,
itraconazole has been associated with negative inotropic effects with resultant heart failure (284).
Therapeutic drug monitoring with itraconazole is advised to ensure that adequate concentrations are
achieved when treating serious infections. Factors related to drug absorption contribute to the large
interpatient variability in concentrations achieved and are most notable with the oral capsule formulation.
Unlike other azoles, itraconazole therapeutic drug monitoring requires measurement of both the parent
drug and the active metabolite, hydroxyitraconazole. High-performance liquid chromatography (HPLC)
assays are able to differentiate between the two components; however, bioassays do not (285,286). IDSA
guidelines for the treatment of histoplasmosis advise obtaining concentrations at steady state with a goal
of additive concentrations of itraconazole plus hydroxyitraconazole greater or equal to 1.0 µg/mL when
measured by HPLC (283).
Voriconazole is a second-generation extended-spectrum triazole that has broad-spectrum antifungal
activity against yeasts and molds. It has become the drug of choice for certain mold infections such as
Aspergillus, Fusarium, Scedosporium, and dematiaceous fungi (287–290). It has also been the drug of
choice in the 2002 Exophiala dermatitidis and 2012 Exserohilum rostratum meningitis outbreaks
associated with contaminated steroids (168). It is available in both oral and intravenous formulations.
Pharmacokinetic data from early clinical cases in the 2012 Exserohilum rostratum outbreak suggest that
CSF concentrations approximate 50% of that seen in the serum (291) and others have similarly reported
high levels of voriconazole in the CSF and brain tissue (292). Good penetration into the CSF and thus far
favorable clinical experience make voriconazole a major drug for the management of CNS fungal
infections. Adverse effects associated with voriconazole include gastrointestinal (e.g., nausea, vomiting,
diarrhea and hepatotoxicity), visual (e.g., photopsia and hallucinations), and dermatologic (e.g., skin rash)
manifestations. Other effects increasingly reported with long-term use include squamous cell cancers of
the skin (293) and periostitis (294). As with other azoles, QTc prolongation, particularly when used with
other QTc-prolonging drugs, can also be seen with voriconazole. Nonlinear pharmacokinetics and
extensive and variable metabolism by the cytochrome P450 enzyme system contribute to large inter- and
intrapatient variability reported in serum voriconazole concentrations (295). Because of these features, as
well as potential pharmacokinetic interactions with concomitantly administered therapies, therapeutic
drug monitoring of voriconazole is recommended. In the recent outbreak of fungal meningitis with
Exserohilum rostratum, the CDC recommended steady state trough voriconazole serum concentrations of
2 to 5 µg/mL with weekly monitoring acutely, during the first 4 to 6 weeks of therapy, to ensure that
patients remain within the “therapeutic” range (296). Voriconazole is an inhibitor of and metabolized by
the cytochrome P450 system such that interactions with other drugs that are substrates, inhibitors, or
inducers via the cytochrome P450 system are common and important considerations. Of particular
mention, concomitant administration of rifampin, a potent inducer of the cytochrome P450 system, should
be avoided all together due to potential for marked reduction in voriconazole serum concentrations and
resultant antifungal efficacy (297).
Posaconazole is the most recently approved second-generation extended-spectrum azole with activity
against multiple fungal pathogens affecting the CNS, including Candida, Aspergillus, mucormycosis,
Cryptococcus, Scedosporium, and endemic fungi. Its application in CNS fungal infections is limited
largely to case reports and series and it is often employed as salvage therapy in those with refractory
disease. Despite low concentrations in the CSF in experimental rabbit models of cryptococcal meningitis,
efficacy was similar to that of fluconazole-treated rabbits akin to previous findings described with
itraconazole in experimental models (298). Posaconazole was combined with amphotericin B in an
experimental murine model of cryptococcal meningitis with significant reductions in brain tissue
cryptococcal burden (299). It was also efficacious in a series of patients with HIV and cryptococcal
meningitis (300). Pitisuttithum et al. (301) reported on 39 cases of CNS fungal infections in patients either
intolerant or refractory to standard therapy who received posaconazole as their fungal treatment.
Cryptococcus meningitis was most common (29 of 39 cases); however, infections with Aspergillus,
Scedosporium, Coccidioides, Histoplasma, Apophysomyces elegans, Basidiomycetes, and
Ramichloridium mackenziei were also treated. Successful outcomes occurred in 48% of patients with
cryptococcal meningitis and 50% of patients with noncryptococcal CNS fungal infections despite the
majority of cases representing refractory disease, suggesting a role for posaconazole in severe and
refractory infections and the need for further studies (301). Unlike voriconazole, posaconazole
demonstrates in vivo and in vitro activity against mucormycosis and has been used both in combination
with amphotericin B and as second-line therapy for CNS infections with mucormycosis (302).
Posaconazole is typically well tolerated, although gastrointestinal side effects, including hepatotoxicity,
can occur. Skin rash and photosensitivity as well as QTc prolongation are also potential adverse effects
of posaconazole therapy. Data continue to emerge supporting an exposure–response relationship with
posaconazole such that therapeutic drug monitoring has become more customary. However, unlike
voriconazole, a clear correlation between posaconazole serum concentrations and toxicity does not exist
(303–305). Owing to a multitude of factors including posaconazole’s poor solubility and absorption, drug
interactions, and variable inter- and intrapatient serum concentrations, the authors recommend
posaconazole therapeutic drug monitoring. However, the most effective serum concentration for the
management of invasive fungal infections remains unclear and no formal guidelines exist. For the
management of invasive fungal infections (including but not specific to CNS infections), some have
proposed a steady state serum trough concentration of at least 700 ng/mL, with further adjustment to 1,250
ng/mL in those not responding to therapy (303). To optimize absorption and resultant concentrations
achieved, recommendations include administration with food (particularly high-fat meals and/or nutrition
supplements) and an acidic beverage. Proton pump inhibitors should also be avoided given the marked
decrease in posaconazole absorption associated with concomitant therapy. Posaconazole is an inhibitor of
the cytochrome P450 enzymatic system such that it can affect other substrates of this system, such as
cyclosporine and tacrolimus, warranting close therapeutic drug monitoring of these agents with
concomitant posaconazole therapy. Drug interactions with agents such as rifampin and phenytoin are also
substantial such that concomitant use should be avoided (306).
Echinocandins
The echinocandins, including caspofungin, micafungin, and anidulafungin, have attractive features for the
management of invasive candidiasis. Caspofungin is perhaps the most studied agent as it was the first in
the class, although data continue to emerge with the other echinocandins. CNS penetration by the
echinocandins is generally poor. However, a critical reevaluation of CNS penetration of echinocandins in
the treatment of hematogenous Candida meningoencephalitis in neonates is ongoing given the lack of
present good therapeutic options and the potential devastating short- and long-term consequences of
infection in this population (307,308). Echinocandins have activity against Aspergillus, and limited
experience demonstrates variable activity in CNS aspergillosis. Echinocandins may have mold activity
only if they potentiate the activity of an azole or polyene. They have no clinical activity against C.
neoformans and are not considered therapeutic agents for the treatment of the endemic fungi. The
echinocandins are generally the best tolerated of the antifungal drug classes. Adverse effects are
uncommon but include hepatotoxicity, which is typically mild, and infusion-related reactions. Drug
interactions are also less common with this antifungal class as they do not interact with either the
cytochrome P450 enzyme system or P-glycoprotein. Although efficacy is correlated with achieving
optimal peak to MIC ratios, therapeutic drug monitoring is not routinely performed or recommended
(284).
Combinations of Antifungal Drugs

Combination therapy for CNS fungal infections offers the potential of improved efficacy with less toxicity
by permitting use of lower doses of the components. Amphotericin B plus flucytosine has proven
successful in the treatment of cryptococcal meningitis and has become first-line therapy for initial
(induction phase) management of cryptococcal meningitis (124,230,309,310). A retrospective review
suggests that this combination may also be effective for Candida meningitis (311) and consideration of
combination therapy is recommended in the IDSA Candida treatment guidelines (312). Patient-specific
considerations including tolerability of flucytosine as well as isolate susceptibility must be considered.
Rifampin has been added to amphotericin B in vitro to potentiate the activity of the polyene against yeasts
(313). However, a small open-label, prospective, randomized controlled trial for the treatment of
cryptococcal meningitis in patients with AIDS in a resource-limited setting compared initial treatment
with amphotericin B alone (0.7 mg/kg/day) to that of amphotericin B plus rifampin (600 mg per day) for 2
weeks followed by fluconazole for 8 weeks and found no significant advantage in the group receiving
combination therapy (314). The combination of amphotericin B with various azoles has produced
variable in vitro and in vivo results. In vivo results for the treatment of cryptococcal meningitis in animal
models suggest that additive effects exist (315) and human studies of polyenes plus azole compounds for
fungal meningitis have never shown worsening of outcomes. A randomized, open-label, phase II trial in
cryptococcal meningitis in patients with HIV assessed the efficacy and safety of amphotericin B
deoxycholate (0.7 mg/kg/day) alone versus amphotericin B deoxycholate (0.7 mg/kg/day) in combination
with fluconazole at low (400 mg per day) and high (800 mg per day) daily doses as initial therapy and
found the primary composite efficacy endpoint of CSF conversion to negative culture results, stable
neurologic function, and survival at day 14 was greatest in the high-dose (fluconazole 800 mg per day)
combination arm (316). However, the azole-polyene combination is still an alternative regimen compared
to the preferred flucytosine-polyene combination.
Flucytosine-fluconazole is another potentially active combination that has been studied in cryptococcal
meningitis. The azole compound might prevent development of resistance to flucytosine. Some azoles
such as fluconazole achieve high CSF levels, similar to flucytosine. Multiple studies evaluating
fluconazole alone versus combination flucytosine-fluconazole suggest that the combination is more
effective than fluconazole monotherapy, particularly when higher doses of fluconazole are used
(232,259,260,317). A combination of two azoles (miconazole and ketoconazole) has been used
successfully in Pseudoallescheria boydii meningitis (318). Studies in animal models suggest an
additional benefit of combination therapy with amphotericin B plus voriconazole in CNS Aspergillus
infection; however, voriconazole remains the present treatment of choice for CNS disease (319,320).
Combination therapy with voriconazole and liposomal amphotericin B has been recommended in severe
or nonresponding cases of Aspergillus and Exserohilum spp. meningitis in the 2012 outbreak associated
with contaminated steroid injections. Assessment of the need for combination therapy outside of
cryptococcal and perhaps Candida meningitis will likely need to continue on a case-by-case basis until
more evidence is available.
Treatment of Common Forms of Fungal Meningitis
The following section describes specific antifungal treatment regimens for several of the more common
fungi causing meningitis.
Cryptococcal Meningitis
Although an occasional patient has survived for many years (321), untreated cryptococcal meningitis is
uniformly fatal. Introduction of amphotericin B produced cures in more than 50% of patients with
cryptococcal meningitis (322), but at the expense of considerable drug-related toxicity during months of
treatment. Because the combination of amphotericin B plus flucytosine had potent in vitro activity, trials
were conducted to determine whether reduced doses of amphotericin B administered with flucytosine
would be as effective as amphotericin B alone. A large collaborative trial comparing amphotericin B
deoxycholate, 0.4 mg/kg/day alone for 10 weeks, with amphotericin B deoxycholate, 0.3 mg/kg/day, plus
flucytosine, 150 mg/kg/day for 6 weeks, found the overall outcomes to be similar (323). However, the
drug combination routinely sterilized the CSF within 2 weeks and allowed treatment duration to be
shortened to 6 weeks. A follow-up study showed that approximately 85% of a select group of patients
were cured or improved with this regimen for cryptococcal meningitis (324). A 4-week combination
regimen was found to be successful for those patients with no underlying diseases and good prognostic
indicators at the beginning and end of therapy (324). Amphotericin B deoxycholate nephrotoxicity was
reduced at the low dose of 0.3 mg/kg/day that was used in this combined regimen, but flucytosine toxicity
for the bone marrow, liver, and gastrointestinal tract was troublesome. Thus, the combination may be
criticized on the grounds that it substituted flucytosine toxicity for amphotericin B deoxycholate toxicity.
In several large studies of cryptococcal meningitis, including patients with AIDS, between 30% and 50%
of patients experienced some side effects attributable to flucytosine, with approximately half occurring in
the first 2 weeks of therapy. The combination therapy of amphotericin B and flucytosine demonstrates not
only an advantage in its fungicidal properties at the CNS site of infection but this property also translates
into a survival benefit compared to amphotericin B monotherapy (325).
Fluconazole has been evaluated for primary treatment of cryptococcal meningitis (272,326–328).
Clinical trials have shown that it takes longer to sterilize the CSF with this triazole than with treatments
inclusive of amphotericin B (273,330). This finding supports previous results in the rabbit model
(271,315). In addition, Saag et al. (272) found more failures during the first few weeks of treatment with
fluconazole monotherapy when compared to combination therapy with amphotericin B and flucytosine.
However, the outcome after 1 year for cryptococcal meningitis in patients with AIDS was similar with
either regimen. Based on overall inferior experience with fluconazole monotherapy, the IDSA guidelines
for the treatment of cryptococcal infection do not recommend it in the induction phase for patients with
HIV (124). However, in resource-limited settings where it is often the only available treatment option,
high-dose (e.g., 1,200 to 2,000 mg/day) monotherapy should be used (317). It should be emphasized that
most of the studies with fluconazole were performed in HIV-infected patients who generally have a high
burden of organisms, sometimes more than 106 CFU/mL of CSF. The value of fluconazole or other
triazoles for initial therapy of patients with a lower burden of organisms or different underlying diseases
is less established.
The most common strategy today for the management of patients with HIV infection (and adopted for
non–HIV-infected patients) with cryptococcal meningitis reflects a large comparative study by van der
Horst et al (310). This regimen employs initial induction therapy with amphotericin B deoxycholate at 0.7
mg/kg/day with flucytosine at 100 mg/kg/day for 2 weeks, and then switching to consolidation therapy
with fluconazole at a dose of 400 to 800 mg per day for 8 weeks. A follow-up CSF analysis and culture
should be obtained at the conclusion of the 2-week induction with consideration for extension of induction
therapy in those patients either worsening or lacking clinical improvement, with persistently elevated
intracranial pressures, or with persistently positive CSF cultures (124). Flucytosine-fluconazole is
another alternative combination therapy used in patients with HIV. Although it is inferior to amphotericin
B plus flucytosine, it may be a consideration in resource-limited settings. Studies evaluating fluconazole
alone versus combination flucytosine-fluconazole suggest that the combination is more effective,
particularly when higher doses of fluconazole are used (232,259,260,317). Initial data from phase II
clinical trials additionally support potential benefit of amphotericin B and high-dose fluconazole
combination therapy in settings where access to flucytosine is limited as discussed in the previous section
on combination antifungal therapy (316).
Historically, following induction and consolidation therapy, patients with HIV were then given 200 mg
per day of fluconazole as indefinite suppressive (maintenance) therapy because of high relapse rates
(329). This regimen was very successful in patients with HIV (310), and further positive experiences
were seen in HIV-uninfected patients (330,331). However, with the advent of potent antiviral therapy,
multiple studies have assessed the feasibility of cessation of maintenance therapy following successful
treatment of cryptococcal meningitis and immune reconstitution (332–335). On the basis of these studies,
it is recommended that discontinuation of maintenance therapy be considered in patients who have
completed induction therapy, received a minimum of 12 months of antifungal therapy, are free of evidence
of infection, and successfully maintained on antiretroviral therapy with a CD4 cell count greater than 100
cells/µL and a low or undetectable plasma HIV RNA for at least 3 months. In addition, experts advocate
monitoring of serum cryptococcal antigen and CD4 counts once maintenance therapy is discontinued, with
consideration for reinitiation of therapy in patients whose CD4 counts fall below 100 cells/µL or serum
cryptococcal antigen titer increases (124). The optimal duration of treatment for HIV-uninfected patients
remains uncertain, so the regimen must be individualized. However, in solid organ transplant recipients,
current guidelines recommend continuation of suppressive therapy with fluconazole for at least 6 to 12
months to minimize relapse (124).
Other therapeutic interventions may be required in certain patients. Intraventricular amphotericin B has
been used successfully in cases with a poor prognosis, but side effects must be considered. The
development of hydrocephalus may require placement of a ventriculoperitoneal shunt (336). Shunts that
become infected with cryptococci (337) are generally placed before there is consideration of
cryptococcal meningitis and will probably need to be removed and replaced. With prior antifungal drug
therapy, in most cases, infection is controlled so a shunt does not need to be removed even when placed
with active infection (338).
Cryptococcomas in the brain parenchyma are much less common than meningeal disease and occur
more commonly with C. gattii infections (62). In cases in which the lesions are small and multiple,
antifungal chemotherapy alone is generally successful, although typically extended durations of both
induction (e.g., at least 6 weeks) and consolidation and maintenance therapy (e.g., 6 to 18 months) are
used. Sometimes, these CNS lesions enlarge on computed tomography or magnetic resonance imaging
scans during therapy before receding. This reflects not failure but inflammation. Large cryptococcomas
(>3 cm) located in surgically accessible areas may be considered for surgical removal (339). In patients
with advanced HIV, a ring-enhancing brain lesion in the presence of cryptococcal meningitis may
represent a simultaneous infection with another organism such as Toxoplasma gondii or noninfectious
etiologies such as CNS lymphoma rather than a cryptococcoma.
Cryptococcal meningitis during pregnancy should be managed similarly to other cases; however, both
flucytosine and fluconazole are category C drugs in pregnancy. Although no cases of congenital
cryptococcosis have been described, both amphotericin B and flucytosine cross the blood–placenta
barrier and could theoretically impact congenital infections.
A major factor influencing the treatment of cryptococcal meningitis is the degree of host
immunosuppression. The most common troublesome iatrogenic factor in patients with cryptococcal
meningitis is concomitant corticosteroid administration. In patients with cryptococcal meningitis who
must receive corticosteroids, the dose should be reduced as far as the underlying disease permits. A
reasonable goal for most patients is to reduce the dose of corticosteroids to the equivalent of 20 mg of
prednisone per day or less whenever feasible.
Evaluation of patients with cryptococcal meningitis in the 1950s to 1970s, before the emergence of
HIV, noted the following to be associated with failure of therapy: (a) positive initial CSF India ink test
results, (b) high initial CSF opening pressures, (c) low initial CSF leukocyte counts (<20 cells/mm3), (d)
cryptococci isolated from extraneural sites, (e) absent anticryptococcal antibody, (f) initial CSF or serum
cryptococcal antigen titer of 1:32 or more, (g) corticosteroid therapy, or (h) lymphoreticular malignancy
(104). In the HIV era, pretreatment factors identified as poor prognostic indicators in HIV-positive
patients presenting with cryptococcal meningitis included (1) abnormal mental status, (2) high CSF
cryptococcal antigen titers (e.g., >1:1,024), and (3) a CSF WBC of less than 20 cells/mm3 (272). As
previously discussed, one of the initial goals of treatment is CSF sterilization within 2 weeks. Failure to
sterilize CSF at this point predicts treatment failure in patients with underlying HIV, and three factors in
HIV-positive patients that may identify those less likely to have rapid sterilization include (a) high CSF
antigen titers (≥1:1,024), (b) low serum albumin concentrations, and (c) low CD4 cell counts (<50 cells/
µL) (340). Similar to the HIV population, positive CSF cultures at 2 weeks of therapy have been
associated with poor outcomes, including increased 180-day mortality, in the organ transplant population
(331). A factor significantly associated with negative CSF cultures at the 2-week mark in organ transplant
recipients include higher WBC counts in the CSF, again emphasizing the importance of the underlying
immune status of the host. However, the CSF cryptococcal antigen titer has not correlated with either CSF
sterilization or treatment outcomes in organ transplant recipients. Relapse rates in both the HIV-positive
and organ transplant population have been reduced with use of fluconazole maintenance therapy as
previously discussed. In the HIV-positive population, rates of relapse have been reduced from as high as
60% to 7.6 per 100 person-years with the institution of maintenance fluconazole therapy and potent
antiretroviral therapy (341). Singh et al. (331) reported relapse rates of only 1.3% in 79 evaluable solid
organ transplant recipients receiving maintenance fluconazole therapy compared to rates of 18% in a
literature review in transplant patients in whom suppressive therapy was discontinued.
Perhaps the single most significant factor in determining the outcome of infection is the patient’s
underlying disease. Accordingly, with the institution of potent combination antiretroviral therapy, there
has been a substantial improvement in the long-term outcomes in HIV patients with cryptococcal infection
with reported mortality rates of 63.8 versus 15.3 per 100 person-years in the time periods before and
after institution of antiretroviral therapy (341). Survival outcomes are worse in patients with underlying
malignancy when compared to those with underlying HIV (342). In other populations, such as the solid
organ transplant population, mortality rates nearing 50% with CNS cryptococcal infection have been
reported (331).
Two other areas of cryptococcal meningitis management merit consideration and further study. First,
unexpected deaths or loss of vision during the first 1 to 2 weeks of treatment have occurred in some
patients with advanced HIV and cryptococcal meningitis. These patients deteriorated suddenly; some
manifested dramatic increases in intracranial pressure (343). Patients with high CSF opening pressures
(>250 mm H2O) have a poor prognosis (344,345). The pathophysiology of this catastrophic event during
initial therapy remains imprecise. The cause of deterioration appears to be some perturbation or reaction
to treatment among the large burden of yeasts in the brain and CSF in the early phases of treatment.
Possibly, mannitol or polysaccharide antigen released by these yeasts could increase intracranial pressure
via osmotic effects, or the mass of agglutinated-killed yeasts could obstruct CSF outflow through the
arachnoid villi. Presently, the IDSA guidelines recommend that opening pressures be measured on initial
CSF evaluation. If CSF pressure is greater than or equal to 25 cm H2O with symptoms (e.g., headache,
altered sensorium, focal neurologic deficits), then relief by lumbar drainage via daily lumbar punctures,
temporary percutaneous lumbar drains, or ventriculostomy should be performed depending on the degree
and persistence of elevation and until CSF pressures and symptoms are adequately controlled (124). In a
retrospective examination, the use of corticosteroids did not show a benefit (344), but cerebral edema
still likely plays some role in the syndrome.
A second complication of treatment that has been described in populations including HIV-infected
patients receiving HAART, organ transplantation, and pregnancy is immune reconstitution syndrome
(346). After starting HAART, immune reconstitution can produce active inflammation at the site of
infection (347–349), causing new neurologic symptoms (350). This may result in the diagnosis of
previously unrecognized CNS cryptococcal infection or paradoxical worsening of existing infection
following initiation of antifungal therapy and HAART. Immune reconstitution syndrome can occur within
days to months after starting HAART; thus, the best time for starting HAART after beginning antifungal
therapy for cryptococcal meningitis remains unclear. The 2010 IDSA clinical practice guidelines for
cryptococcal infection recommend initiation of HAART 2 to 10 weeks after the start of antifungal therapy
(124). The 2013 Cochrane metaanalysis of two randomized controlled trials evaluating the timing of
initiation of antiretroviral therapy in cryptococcal meningitis reported no difference in clinical or
immunologic outcomes with early (<4 weeks) versus late (≥4 weeks) initiation of HAART following
antifungal therapy. Based on the limited available evidence, the authors concluded that sustained clinical
response to therapy be demonstrated before initiation of antiretroviral therapy (351). In the organ
transplant population, Singh and colleagues (352) described an immune reconstitution syndrome–like
presentation in patients with cryptococcal infection occurring a median of 5.5 weeks following institution
of antifungal therapy. Immune reconstitution syndrome occurred significantly more commonly in patients
whose immunosuppression consisted of triple-drug therapy inclusive of tacrolimus, mycophenolate
mofetil, and prednisone and was felt to result from both institution of antifungal therapy and rapid
reduction in immunosuppression with a shift from a Th2 to Th1 inflammatory response (352). Furthermore,
in the renal transplant population, the development of immune reconstitution syndrome in the context of
cryptococcal infection was associated with an increased risk of allograft loss (353). Patients developing
immune reconstitution syndrome may benefit from some immune modulation with corticosteroids or other
antiinflammatory drugs (348). The IDSA guidelines recommend administration of 0.5 to 1.0 mg/kg/day of
prednisone equivalent in HIV-infected patients with severe immune reconstitution syndrome–related
manifestations (124).
Coccidioidal Meningitis
Historically, the “gold standard” therapy for coccidioidal meningitis was amphotericin B using both the
intrathecal and intravenous route. However, with the advent of triazole therapies including itraconazole,
fluconazole, and more recently, the extended-spectrum azoles voriconazole and posaconazole, the
management of disease has changed substantially. The true benefit of intrathecal amphotericin B is the
potential for cure given its fungicidal activity, as compared to the fungistatic activity of the triazoles,
which require lifelong administration to prevent relapse of disease. Intrathecal amphotericin B is
typically initiated with small doses of 0.01 mg per day and gradually increased as tolerated up to 0.5 to 1
mg per day. Complications of intrathecal therapy include radicular pain or paresthesias, myelopathy,
headaches, and bacterial superinfection, particularly if a reservoir is used to administer intraventricular
therapy. Intravenous amphotericin B deoxycholate was historically combined with intrathecal therapy;
however, more recent animal studies suggest that liposomal and lipid-complexed preparations offer
additional benefit in the management of disease through higher doses and less toxicity (354,355). Early
success with triazole therapy was most prominently reported with itraconazole and fluconazole
(356–359). Galgiani et al. (358) performed a noncomparative prospective trial of fluconazole at a dose of
400 mg daily in patients with coccidioidal meningitis and demonstrated clinical response in 88% and
70% of patients with and without previous treatment for their meningitis, respectively, contributing to
transition to fluconazole as standard therapy for coccidioidal meningitis.
Formal recommendations based on available data and expert opinion currently exist for the
management of coccidioidal meningitis (24). Fluconazole is now considered the first-line agent, with
dosing ranging from 400 to 1,200 mg daily. In addition, some treating physicians use intrathecal
amphotericin B up front, whereas others reserve this therapy for patients not responding appropriately to
initial fluconazole therapy. More recent reports of success using voriconazole or posaconazole in patients
not responding to standard therapy suggest a potential beneficial effect of these agents as well (360–362).
The CSF leukocyte concentrations have been used to monitor response to therapy with a goal of 10
cells/mm3 or less with normal CSF glucose concentrations for at least 1 year. A lowering of the CSF
antibody titer also is considered a good prognostic sign. Vigilance for development of hydrocephalus or
bacterial superinfection (in the situation of intrathecal amphotericin B administration) must be maintained
throughout therapy. Vasculitis and associated infarction are significant potential complications and some
experts argue for corticosteroid administration up front, although this remains a debated management
decision. Given the high frequency of relapse and fungistatic activity of triazoles against
coccidioidomycoses, patients with meningitis should remain on indefinite suppressive therapy (363).
Factors portending an unfavorable outcome are (a) hydrocephalus, (b) an underlying disease, and (c)
nonwhite race. On the other hand, low or absent CFA titers in CSF at the end of therapy suggest a
favorable outcome (25).
Candida Meningitis
Unlike cryptococcal and coccidioidal meningitis, a few spontaneous cures of Candida meningitis may
occur. Therefore, comparison of the efficacy of different treatments is more difficult for this form of
fungal meningitis. Nevertheless, clinical experience with amphotericin B and flucytosine suggests that the
prognosis for Candida meningitis is much improved by treatment. Amphotericin B is the primary
therapeutic agent because of experience. The combination of amphotericin B with flucytosine is attractive;
as synergistic activity against Candida in vitro is observed, flucytosine reaches high concentrations in
CSF and appears to be effective. Review of the literature suggests that this combination provides a good
cure rate (311) and consideration of combination therapy is recommended in the IDSA Candida treatment
guidelines (312). Although the guidelines recommend the lipid formulations of amphotericin B for
Candida meningitis, amphotericin B deoxycholate is also routinely used in neonates given the familiarity
and established use in this patient population (42). Today, the mortality of Candida meningitis has been
reduced to approximately 10% to 20%. Fluconazole has also been successful in many cases but is
typically reserved for step-down therapy following amphotericin B with or without flucytosine (312).
Currently, the echinocandins are not recommended for Candida meningitis. However, evaluation of both
anidulafungin and micafungin in experimental rabbit models of candidiasis show that administration in
higher doses than currently approved results in increased microbiologic effect in brain tissue (307,308).
Further study is necessary to fully understand the pharmacokinetic and pharmacodynamic properties and
overall safety and efficacy of higher doses of echinocandins in Candida meningitis. Prognostic factors for
patients with Candida meningitis are less well studied, but some have been found to be associated with a
poor prognosis, such as the following: (a) greater than 2 weeks of symptoms before diagnosis and
treatment, (b) CSF glucose concentrations less than 35 mg/100 mL, and (c) development of intracranial
hypertension and focal neurologic deficits (177). It should also be emphasized that although amphotericin
B is very successful in clearing neonatal Candida meningitis, children may be left with permanent
neurologic deficits (366). Systemic candidal infections inclusive of meningitis in extremely low-birth-
weight infants (e.g., <1,000 g) has been associated with significant long-term neurodevelopmental delays
(365,366).
Histoplasma Meningitis
The clinical presentations of CNS histoplasmosis range from intraparenchymal histoplasmosis to
meningitis with or without evidence of dissemination to other sites. With the advent of HIV, the frequency
of disseminated histoplasmosis in association with meningitis increased. Guidelines for treatment are
based on retrospective reports from small series of patients and expert opinion from those managing
patients in endemic areas (34).
Therapy was historically with amphotericin B deoxycholate; however, given the improved side effect
profile, increased CNS penetration, and clinical superiority shown with liposomal amphotericin B, this
has become the initial drug of choice. There is additional data supporting the use of triazole therapy,
particularly itraconazole and fluconazole in the acute management of meningitis; however, presently, this
is deferred to the maintenance stage of therapy. Typically, therapy is initiated with liposomal
amphotericin B at a dose of 3 to 5 mg/kg/day and continued for a total dose of 175 mg/kg. In patients
responding appropriately to this therapy, transition can be made to itraconazole (200 mg twice daily) or,
alternatively, high-dose fluconazole (e.g., 800 mg per day) for a minimum of 1 year of total therapy
(34,283).
Patients need routine follow-up of CSF studies at a minimum after the first month of therapy and when
transitioned from a polyene to a triazole. In addition, therapeutic drug monitoring in those patients
receiving itraconazole therapy is imperative to ensure adequate serum concentrations are achieved.
Decisions regarding extending therapy beyond 1 year should be based on the clinical status of the patient
including the degree of continued immunosuppression and/or immune reconstitution as well as
documentation of complete normalization of CSF abnormalities. Those patients unable to demonstrate
adequate immune reconstitution at the 1-year transition point of therapy should be continued on indefinite
triazole therapy. Additional consideration to the timing of shunt placement in those developing
hydrocephalus is important to ensure colonization of the shunt does not further complicate management
decisions long-term (34). Patients with concomitant histoplasmomas should be treated as described for
patients with meningitis using systemic antifungal therapy. Surgical excision is rarely indicated although
may be required for large intraparenchymal lesions failing to respond to therapy. Reports of infections
responding to both voriconazole (367) and posaconazole (368) suggest potential benefit.
Treatment of Other Fungi
Studies on treatment regimens for Blastomyces and Sporothrix meningitis are limited because these CNS
infections are rare. Some cases have been cured with amphotericin B, which remains the recommended
primary agent followed by step-down to azole therapy (27,369). Aspergillus infections of the CNS are
very difficult to eradicate. High doses of amphotericin B have rarely been successful in arresting the
infection. Voriconazole is now considered first-line therapy for Aspergillus meningitis (370). A
retrospective evaluation of 81 cases of CNS aspergillosis treated with voriconazole found complete and
partial response in 35% (371), far better than that reported with amphotericin B (372). Voriconazole was
effectively used in the management of 5 cases of Exophiala dermatitidis meningitis related to the 2002
outbreak of contaminated compounded steroid preparations (21). Moreover, high-dose intravenous
voriconazole with or without liposomal amphotericin B has been recommended by the CDC as the initial
antifungal therapy in the 2012 outbreak of Exserohilum rostratum meningitis associated with
contaminated steroids (168). In a review of 107 cases of Scedosporium infection using voriconazole as
primary or salvage therapy, 20% of cases involved the CNS with an overall successful response in 43%
(373).
Surgical Measures
Meningeal or brain biopsy is occasionally indicated for diagnosis of fungal meningitis when other means
have failed. In such cases, it is usually best to obtain a biopsy from the basal meninges for culture and
histology. Even a meningeal biopsy will fail to provide the diagnosis in some cases of fungal meningitis.
The most important contribution of the neurosurgeon to the management of fungal CNS infection is
placement of a ventricular drain or shunt for management of acute or chronic increased intracranial
pressure, a common complication. Fungal infections of CSF shunts inserted for treatment of
hydrocephalus and chronic meningitis prior to therapy are uncommon (374). If Candida or cryptococcal
meningitis develops in a patient with a shunt in place, eradication of infection is most likely to be
achieved by removing the shunt and treating with antifungal agents and then replacing the shunt (337,375).
However, there is at least one report of cryptococcal meningitis in a patient with an indwelling
ventricular shunt successfully treated with systemic antifungal therapy alone (338).
The management of fungal brain abscesses is not well standardized (376). Blastomyces and
Histoplasma abscesses have been successfully removed surgically, with concomitant amphotericin B
treatment. As noted earlier, it has been suggested that size and location are criteria for operative
intervention for cryptococcomas. In patients with mucormycosis or Aspergillus infection invading the
vessels of the brain with resulting infarction, direct surgical removal of infarcted tissue should be
considered if lesions are accessible. Some fungal brain abscesses have been successfully managed with
stereotactic aspiration for diagnosis and systemic amphotericin B treatment (221). Dematiaceous fungi
that cause brain abscesses are surgically removed or debulked as primary therapy for cure along with
antifungal agents (377,378). In patients with AIDS with fungal meningitis and parenchymal lesions, more
than one CNS infection or concomitant tumor may be present.
Intracranial mycotic aneurysms are rare complications of CNS fungal infection. Aneurysms have been
described in association with mucormycosis, Aspergillus, Coccidioides, and Candida infections
(379–381). Aneurysms associated with fungi tend to involve proximal intracranial vessels, particularly
the large arteries at the base of the brain. Surgical treatment is warranted if discrete intracranial
aneurysms bleed, cause significant mass effect, or enlarge despite optimal medical therapy.
PREVENTION OF FUNGAL MENINGITIS

When high-risk populations can be identified, vaccines or antifungal prophylaxis might be effective.
Cryptococcal vaccines have been developed (382–384), but human trials have not been conducted.
Intensive work continues on developing a coccidioidal vaccine for those in the endemic areas (385) as
well as vaccines for other ubiquitous fungal pathogens such as Aspergillus (386). Several studies have
shown that administration of fluconazole for 1 year or more can reduce the number of cryptococcal
meningitis cases in HIV-infected patients (387,388). However, prophylaxis in high-risk patients (e.g.,
those with CD4 counts ≤50 cells/µL) is not presently recommended in areas with ready access to HAART
for a multitude of reasons, including the overall low frequency of infection, impact of HAART, cost of
therapy, and potential for the emergence of fluconazole resistance (124). Patients at high risk for
cryptococcal meningitis based on a reactive cryptococcal antigen test may benefit from prophylaxis from
fluconazole to prevent meningitis in settings with limited access to antiretroviral therapy (227,389).
Pretransplant screening for coccidioidomycosis in patients in or from an endemic area is essential given
the risk of severe, often disseminated disease posttransplantation. Azole prophylaxis is recommended in
those with positive pretransplant serologies and/or a history of coccidioidal infection (390,391).
However, prophylaxis is not routinely recommended in patients with HIV (24,392). Optimal use of
prophylaxis against histoplasmosis in patients with underlying malignancy, undergoing organ
transplantation, and with HIV is less clear, but formal recommendations by the IDSA do exist to guide
preventative management decisions (283).
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CHAPTER 41 SPACE-OCCUPYING FUNGAL LESIONS
MATTHEW MCCARTHY AND THOMAS J. WALSH
HISTORICAL BACKGROUND
The first description of fungal infection of the brain is credited to Paltauf (1), who reported a case of
cerebral mucormycosis in 1885. For many years thereafter, scattered case reports constituted the entire
literature on these infections. A review in 1933 reported 24 cases of mycotic central nervous system
(CNS) infections collected over 25 years (2). Nineteen of the twenty-four patients had “torulosis”
(cryptococcosis). At least half of these were limited to the meninges; however, several patients had true
abscesses. In a review of more than 15,000 consecutive autopsies from 1919 to 1955, fewer than ten
fungal infections of the CNS were identified (3). In 1967, Fetter et al. (4) summarized all reported cases
of CNS mycotic infection, which by that date was still a rare clinical entity. Meningitis was grouped with
abscesses, and Cryptococcus neoformans was by far the most common etiologic species (4).
EPIDEMIOLOGIC TRENDS
Since that time, the number of intracranial fungal infections diagnosed has markedly increased. Some of
this increase is due to improvements in our ability to diagnose intracranial diseases (5); however, more
important are the increases in solid organ, bone marrow, and stem cell transplantations with T-cell
depleting treatment regimens (e.g., fludarabine or alemtuzumab) placing patients at the highest risk (6); the
therapeutic use of dose-intensive cytotoxic chemotherapy and broad-spectrum antibacterial agents in
hematologic malignancies and autoimmune diseases; and the acquired immunodeficiency syndrome
(AIDS) epidemic.
A review from two tertiary care medical centers reported 57 cases of fungal meningitis or brain
abscess collected over a 30-year period, including 27 cases (44%) caused by Candida species, 16 cases
(28%) caused by Aspergillus species, and 14 (23%) caused by Cryptococcus neoformans (7). A review
from the experience at the Fred Hutchinson Cancer Research Center of brain abscess among bone marrow
transplant recipients found that 57 (92%) of 62 cases of brain abscess diagnosed from 1984 to 1992 were
due to fungi; Aspergillus species (33 cases) and Candida species (19 cases) predominated. Survival in
this series was dismal, with only one patient surviving more than 1 month (8). Kleinschmidt-DeMasters
(9) published a 20-year retrospective series on CNS septated fungi infections, where 42 of 45 CNS cases
were due to Aspergillus species. The three remaining cases were due to Pseudallescheria boydii,
Chaetomium species, and Scedosporium inflatum (9).
Dematiaceous fungi constitute a less common but emerging group of fungal pathogens occurring
increasingly in immunocompromised hosts. There are some that have known neurotropism, including
Cladophialophora bantiana, Exophiala (Wangiella) dermatitidis, Dactylaria (Ochroconis)
gallopavum, Chaetomium atrobrunneum, Bipolaris spicifera, Bipolaris hawaiiensis, Rhinocladiella
species, Curvularia species, and Fonsecaea pedrosoi (10).
APPROACHES TO DIAGNOSIS
The clinical setting and presentation may allow a specific fungal species to be anticipated (11). A logistic
regression model demonstrated a high predictive value of host factors and clinical manifestations in
distinguishing infections due to Aspergillus species, Candida species, and C. neoformans. However, the
diagnosis of fungal brain abscess is often not suspected, even in patients at risk. Hence, many cases may
go undiagnosed or are discovered at autopsy. Frequently, the presenting signs and symptoms do not allow
a clinical distinction between fungal abscess, bacterial abscess, or tumor. Spinal fluid results are usually
nonspecifically abnormal, and computed tomographic (CT) and magnetic resonance imaging (MRI) scans,
though quite sensitive, seldom show changes specific for fungi.
There are two distinct patterns of CNS fungal infection. In patients whose disease arises by direct
extension from the paranasal sinuses, eye, or middle ear, a single abscess or a few abscesses may form
(12) (Fig. 41.1). These lesions usually occur in the frontal or temporal lobes. The second pattern is
associated with hematogenous infection with or without endocarditis: multiple small abscesses and
microabscesses are seen, often at the junction of the gray and white matter. Focal involvement of the
meninges overlying the area of abscess is sometimes found. The progression of this type of infection is
usually brisk. True mycotic aneurysms may form and actually rupture with the potential for infarction,
hemorrhage, or empyema formation depending on the location.
Definitive diagnosis almost invariably requires biopsy of a lesion, with prompt inspection of the
specimen by Gram stain, potassium hydroxide (KOH) wet mount preparation, calcofluor white stain,
appropriate cultures, and histology (Gomori methenamine silver stain and periodic acid–Schiff stain) of
the lesion. Although not yet commercially available, polymerase chain reaction (PCR) will likely be used
in the future to aid in the diagnosis of space-occupying fungal lesions. Even with appropriate biopsy
specimens, the diagnosis of fungal infection is often difficult. A member of the order Murolates is often
seen on biopsied tissue yet fails to grow in culture. Conversely, sometimes a fungal isolate such as
Candida albicans that was not seen on KOH wet mount preparation or on histopathology will grow from
cerebrospinal fluid (CSF), tissue, or swabs cultured in the microbiology laboratory. Because brain
biopsies are highly invasive, may lead to neurologic deficits, and are often not feasible, a diagnosis of a
fungal CNS space-occupying mass is more often made by inference by recovery of the pathogen from a
pulmonary or sinus source in a patient with a CNS lesion that is radiologically compatible with CNS
mycosis. Immunodiagnostic assays may be helpful in diagnosis. An example is the routine use of
cryptococcal antigen detection in serum or CSF in establishing the diagnosis of CNS cryptococcosis,
although false positives may occur in the setting of infections due to the fungus Trichosporon asahii (13)
or the bacterial genera Stomatococcus (now named Rothia) (14).
Serologic tests for several other fungal infections such as histoplasmosis, coccidioidomycosis, and
blastomycosis are also available, although their utility in the diagnosis of CNS infection is less well
standardized. A sandwich enzyme-linked immunosorbent assay (ELISA) for detecting Aspergillus
galactomannan is approved for use on serum and bronchoalveolar lavage (BAL) fluid. Galactomannan has
been detected in the CSF of patients with invasive aspergillosis (15); however, its value in the clinical
diagnosis of CNS aspergillosis requires further evaluation. Increasingly, the serum (1→3)-β-D-glucan
assay, which detects (1→3)-β-D-glucan, a cell wall component of Candida spp., Aspergillus spp., and
many other fungi, is used for the detection of invasive fungal infections. Recent laboratory and clinical
studies demonstrate the use of CSF (1→3)-β-D-glucan in detection of hematogenous Candida
meningoencephalitis (HCME) (16).
Substantial progress has been made by the Antifungal Subcommittee of the National Committee for
Clinical Laboratory Standards (NCCLS) in developing reproducible methods for susceptibility testing for
yeasts and filamentous fungi (17,18). Given the critically ill nature of the affected patients and the
increasing occurrence of breakthrough infections associated with acquired resistance mechanisms,
antifungal susceptibility testing is now recognized as a useful tool in optimizing treatment of invasive
fungal infections (19).
Definitive therapy for a CNS fungal lesion is usually a combination of surgical resection and antifungal
chemotherapy (20). The arsenal against fungal infections of the CNS includes four general categories: (a)
polyenes (amphotericin B in various formulations), (b) triazole (fluconazole, isavuconazole, itraconazole,
voriconazole, pramiconazole, and posaconazole), (c) echinocandins (caspofungin, micafungin,
anidulafungin), and (d) the pyrimidine analogue flucytosine.
Lipid formulation of amphotericin B remains the standard treatment for many severe, invasive fungal
infections, including fungi of the order Mucorales. However, it is often reserved for patients with severe,
life-threatening infections due to the systemic toxicities associated with its intravenous use. Voriconazole
is the drug of choice for invasive aspergillosis (21). For cases refractory to voriconazole, a lipid
formulation of amphotericin B is recommended as monotherapy. Itraconazole may also be effective in
CNS aspergillosis, but its use is eclipsed by voriconazole and is considered a second-line treatment (22).
Caspofungin has been approved by the U.S. Food and Drug Administration (FDA) as salvage therapy for
the treatment of invasive aspergillosis in patients who cannot tolerate or who are refractory to standard
therapy (23). The optimum duration of therapy is unknown. However, a reasonable approach is to treat
until resolution or sustained stabilization of all lesions, although there are no strict criteria regarding size,
edema, or imaging characteristics such as a ring enhancement. If the patient remains immunosuppressed,
then antifungal therapy should be continued throughout the period of immunosuppression. Premature
discontinuation of antifungal therapy may lead to recrudescence of infection.
Fungi may be classified as yeasts or molds (filamentous fungi). Some yeasts are classified as
dimorphic (e.g., Histoplasma capsulatum, Blastomyces dermatitidis). Filamentous fungi may be
classified as hyaline (e.g., Aspergillus or Mucorales) or pigmented (e.g., C. bantiana). The nomenclature
and taxonomic rules of medical mycology are evolving and a detailed discussion is beyond the scope of
this chapter. Table 41.1 shows a comparison of pathogenic fungi involved in CNS infections.
HYALINE MOLDS
Hyaline molds are ubiquitous organisms found in soil, water, and decaying vegetation. The two major
groups that are pathogenic to humans are the genus Aspergillus and members of the order Mucorales.
Morphologically, these organisms exist as hyphae both at room temperature and at 37°C. Patients at risk
of infection include those treated with corticosteroids and other immunosuppressive agents, those
receiving long courses of broad-spectrum antibiotics, and those with prolonged episodes of neutropenia
as well as patients with AIDS (24). Poorly controlled diabetic patients with metabolic acidosis and
deferoxamine therapy are at particular risk of mucormycosis. Many infections of the CNS caused by
filamentous fungi occur by direct extension from an ongoing paranasal sinus infection, causing the
rhinocerebral syndrome. CNS fungal infections in otherwise immunocompetent hosts are often due to
hematogenous spread of the infection in association with intravenous drug use with or without
concomitant endocarditis. The predominant features of CNS infections caused by filamentous fungi are
summarized in Table 41.2.
Aspergillus Species
History
Aspergillus was first described in 1729 by Micheli, a priest. Its name derives from its similarity when
viewed microscopically to the aspergillum, which is a perforated globe used to sprinkle holy water in
churches. The first report of cerebral aspergillosis appeared in 1897 (25), describing a 37-year-old man
who developed aspergillosis of the sphenoid sinus that extended posteriorly to involve the optic chiasm
and internal carotid artery. Until the advent of immunosuppressive therapy, involvement of the CNS
(frontal or temporal lobes) was almost invariably a complication of sinusitis. However, hematologic
dissemination, usually in patients with severe immunosuppression or intravenous drug use, has become
more common (26,27). Dissemination usually occurs from a primary lung or gastrointestinal tract
infection (28).
Mycology and Epidemiology

The genus Aspergillus accommodates an asexual fungus that produces chains of conidia or columns
radiating from a central structure. The hyphae develop vesicles, which crown the organism with phialides
that produce conidia. The phialides or sterigmata are produced in either one or two series. The conidia (2
to 5 µm in diameter) are disposed in chains, become deciduous, and readily airborne when mature.
Aspergillus species are ubiquitous molds found in soil, water, decaying vegetation, or any location
with organic debris (29). We inhale the spores on a regular basis but fungal disease is uncommon (30).
Many species of the genus are found in a wide variety of substrata, including various food products,
cotton, and forage foods. The major pathogen of this genus, A. fumigatus, is found in soil, but it is most
abundantly found in self-heating compost, because it grows well at temperatures up to 55°C. Although
aspergillosis is usually acquired by inhalation of conidia, airborne conidia may infect tissue exposed
during surgery (31). Aspergillus spores may also infect susceptible patients by contaminated hospital
supplies. Because invasive aspergillosis most frequently occurs among severely immunocompromised
patients, neutropenic patients who have an underlying hematologic malignancy, patients receiving solid
organ (27–32), bone marrow, or stem cell transplants (8), the presence of Aspergillus spores in the
hospital air has important epidemiologic implications. The use of high-efficiency particulate air (HEPA)
filters reduces the number of airborne aspergilli (33). Aspergillus species may also be propagated from
the hospital water distribution system (34).
More than 200 species of Aspergillus have been described; species identification had long been based
on morphology, but it is now recognized that comparative sequence-based methods can offer better
resolution of species within this genus. Furthermore, species are increasingly reported as a “species
complex,” (e.g., A. fumigatus species complex) (35). At least nine species cause CNS abscess, including
A. fumigatus, which account for most human infections (36,37). CNS aspergillosis is associated with a
very poor prognosis (38) and may be preceded by organ rejection, requiring an increase in dosage of
immunosuppressive agents (39).
In patients with acute leukemia who become neutropenic and in hematopoietic stem cell transplant
(HSCT) recipients, an increased incidence of invasive mold infections—in particular, invasive
aspergillosis—has occurred. As a result, the first choice for antifungal therapy has evolved from less
broad-spectrum agents covering Candida spp. predominantly to ones that are active against Aspergillus
and other molds (40).
Aspergillus is the second or third most common genus among fungi causing intracranial infection in
most series. A report from Memorial Sloan-Kettering Cancer Center reviewed all patients with
microbiologically proven CNS infection from 1955 to 1971 and reported that 18% of brain abscesses
were caused by Aspergillus species (41). Cases of intracranial aspergillosis occur worldwide, with no
apparent sex, age, or racial differences. Most reported cases occur in adults, although the disease may
occur in children or even in neonates (42). Other associations include diabetes mellitus, recent
craniotomy (43), hepatic disease, Cushing syndrome, alcoholic liver disease (44), chronic corticosteroid
therapy, pulmonary tuberculosis, bronchopulmonary aspergillosis (45–47), and intravenous drug use (27).
Up to 56% of patients with Aspergillus endocarditis may have clinical evidence of emboli to the brain
(48).

Because the ubiquitous airborne conidia of Aspergillus species are continually inhaled, the respiratory
tract is the usual site of primary infection. Intracranial seeding occurs during dissemination, from direct
inoculation at surgery (49) or with trauma, or else by direct extension from the paranasal sinuses or eye
(2,25,50) (Fig. 41.1). Infection of the ethmoid sinuses may result in cavernous sinus thrombosis as the
result of invasion of the draining veins. This latter route resembles the rhinocerebral form of
mucormycosis, but occasionally it may present as an indolent disease with symptoms lasting for years
(51).
Sinocranial aspergillosis accounted for a significant proportion of histologically proven cases of CNS
aspergillosis in southern India (52). By comparison, aspergillosis of the nose and paranasal sinuses
commonly involves the orbit and brain in the immunocompromised host. This infection has been reported
in adults with underlying malignancy (53), in adults with HIV infection (54), and in children (55).
The brain is the second or third most commonly involved organ in patients with aspergillosis (56).
Concurrent intracranial involvement is seen in 13% to 16% of patients with pulmonary aspergillosis. Of
patients with disseminated aspergillosis, brain involvement is found in 40% to 60% of cases (36,56).
Angioinvasion, a feature common to other pathogenic filamentous fungi, is frequently seen in
Aspergillus species infection. Histopathologic examination of involved brain tissue reveals hyphal
angioinvasion with thrombosis in small and large vessels. Infarct and hemorrhage are usually present.
Focal involvement of meninges overlaying an area of brain abscess is sometimes found. The predilection
to angioinvasion also predisposes to formation of true mycotic aneurysms (57).
Focal neurologic deficits from stroke or mass effect are the most common clinical manifestation in
patients with CNS aspergillosis. Headache, mild encephalopathy, seizures, and fever may also occur.
Signs of meningeal irritation are uncommon (41,58). Patients with temporal or occipital lobe involvement
may develop visual field defects. Evidence of Aspergillus infection involving other organs is common.
Diagnosis
CNS aspergillosis should be high in the differential diagnosis for an immunosuppressed patient with a
focal brain lesion or for a persistently neutropenic patient with pulmonary infiltrates who develops focal
neurologic deficits or focal seizures. Recovery of Aspergillus from pulmonary lesions by BAL or fine-
needle aspirate should be pursued when possible. Improved diagnostic methods continue to evolve with
diagnostic imaging and non–culture-based systems for antigen detection which can obviate the need for an
invasive procedure (30). CT scanning of the lungs and sinuses may reveal infiltrates or opacities,
respectively. The earliest sign of invasive aspergillosis on CT is a nodule (59); a characteristic “halo”
sign consisting of a pulmonary nodular density surrounded by ground glass opacity may be evident in
neutropenic patients (60). Less specific infiltrates, such as bronchopneumonia or wedge-shaped opacities,
are also seen. MRI may be more sensitive than CT scanning in detection of pulmonary infiltrates due to
aspergillosis (61). The serum enzyme immunoassay (EIA) test for detection of galactomannan has a
sensitivity ranging from approximately 61% to 71% (62).
These diagnostic modalities complement microbiologic detection of Aspergillus species in diagnosis
of invasive aspergillosis. A patient with a “halo” sign and positive galactomannan EIA may be considered
to have invasive pulmonary aspergillosis. Such a patient with CNS manifestations, such as focal
neurologic deficits and compatible CT or MRI neuroradiology findings (see the following text), may also
be assumed to have CNS aspergillosis. Galactomannan also may be found in the CSF of patients with
CNS aspergillosis (15), although the test has not been approved for use on CSF samples. CSF evaluation
may be helpful in cases of CNS aspergillosis. Elevated opening pressure, decreased glucose and elevated
protein concentrations, and pleocytosis with no specific formula may be found in CSF. The CSF may also
be normal (4). CT and MRI scans are important diagnostic tools in the detection of CNS aspergillosis
(61,63) (Figs. 41.2 and 41.3). Imaging allows earlier diagnosis and therefore earlier treatment, leading to
improved survival (5). Ring enhancement is usually not prominent in neutropenic patients (11). Often
several lesions are found, yet not all of them may be clinically apparent. The finding of a cerebral
infarction or hemorrhage on imaging of a patient with known risks for invasive aspergillosis should
suggest the diagnosis. Direct examination of brain tissue (biopsy or aspiration) and CSF culture are the
only means to secure the diagnosis antemortem, but CSF culture is very rarely positive. Reinwald et al.
(62) recently demonstrated proof of concept that PCR of CSF was useful in diagnosis of CNS
aspergillosis in high-risk patients. The use of PCR for diagnosis of CNS aspergillosis, although
promising, is not readily available in most clinical microbiology laboratories.
Treatment and Prognosis

Definitive therapy for a lesion of CNS aspergillosis is a combination of surgical resection/stereotactic
drainage and antifungal chemotherapy (20). Given superior activity of voriconazole in the treatment of
invasive aspergillosis and its activity in CNS aspergillosis in adult and pediatric patients, voriconazole is
the treatment of choice (21). We recommend therapeutic drug monitoring for CNS infection given the
severity of disease and its poor prognosis, although it should be noted that there is no consensus regarding
monitoring. For cases refractory to voriconazole, a lipid formulation of amphotericin B is recommended.
The echinocandin caspofungin is approved by the FDA as salvage therapy for invasive aspergillosis.
The optimum duration of therapy is unknown. However, therapy with antifungals should be continued
until resolution of all lesions is achieved. Once the patient has had an invasive fungal infection, antifungal
therapy should be continued throughout the period of immunosuppression. Premature discontinuation of
antifungal therapy may lead to recrudescence of infection. When possible, immunosuppressive therapy
should be reduced or discontinued.
Given that most invasive aspergillosis, and therefore CNS aspergilloma, is usually seen in an
immunocompromised host, a reasonable prevention strategy includes the use of HEPA filters, confinement
of demolition and construction work areas in hospitals where there may be highly immunosuppressed
individuals, and perhaps the prophylactic use of antifungal agents in highly selected (high risk)
individuals. Preventing delayed acquired aspergillosis outside the hospital setting is more difficult.
Mucorales
History
As fungal molecular systematics continue to evolve, so, too, does fungal taxonomy. The term zygomycosis
was formerly used to embrace infections caused by both Mucorales and Entomophthorales. Mucorales
was the largest order of the Zygomycete fungi and responsible for most human infection and has been
recently reclassified into the subphylum Mucoromycotina of the Glomeromycota phylum of the kingdom
Fungi (64). This taxonomic restructuring has made mucormycosis the preferred term when referring to
infection by fungi in the order Mucorales and has made zygomycosis and phycomycosis increasingly
obsolete. For historical purposes, however, these terms may be used for continuity with older literature.
CNS mucormycosis was first described in 1885 in a man with multiple brain abscesses who died with
widely disseminated infection (1). In 1943, the description of three cases established the classic triad that
characterizes many cases of rhinocerebral mucormycosis: diabetes mellitus with ketoacidosis,
nasoorbital necrotizing infection, and meningoencephalitis (65).
Mucormycosis is perhaps the most aggressive invasive fungal infection of humans. Early cases were
uniformly fatal. The first survivor, reported in 1955, was a 14-year-old girl with diabetes who was
treated successfully by rigid control of her diabetes and administration of systemic iodides (66). The
efficacy of amphotericin B was demonstrated in 1958, and a new era of antifungal therapy began (67).
During the past five decades, survival rates for mucormycosis have improved (68). Many excellent
reviews have been published, all stressing the need for early diagnosis and prompt therapy (69).

Members of the order Mucorales are found abundantly in decaying vegetables, seeds and fruits, compost
piles, manure, and soil (69). They release large numbers of spores that readily become airborne;
transmission occurs by inhalation of aerosolized spores, ingestion of contaminated foodstuffs, or through
cutaneous exposure (70). The order Mucorales includes the family Mucoraceae, Cunninghamellaceae,
Saksenaeaceae, and Syncephalastraceae. The family Mucoraceae includes the pathogenic genera
Rhizopus, Mucor, Lichtheimia (formerly Absidia), and Rhizomucor. Brain abscesses have also been
caused by members of the family Cunninghamellaceae (71) and the family Saksenaeaceae (72). CNS
infections from organisms of the order Mucorales have been reported worldwide and in patients of all
ages, with Rhizopus oryzae the most common etiologic agent (73).
Males are most frequently affected. Risk factors for the development of mucormycosis are diabetes,
supraphysiologic doses of corticosteroids, neutropenia, stem cell and solid organ transplantation, AIDS,
deferoxamine therapy, and iron overload conditions (74).
Rhizopus organisms have an enzyme, ketone reductase, which allows them to flourish in a high-
glucose, acidic environment. Serum from healthy individuals inhibits growth of Rhizopus, whereas serum
from individuals in diabetic ketoacidosis stimulates growth (75). Thus, poorly controlled diabetes
mellitus type I carries a greater risk for rhinocerebral mucormycosis than type II diabetes. The underlying
disease influences the portal of entry, and poorly controlled hyperglycemia with metabolic acidosis is the
major condition underlying mucormycosis originating in the paranasal sinuses. Pulmonary mucormycosis
is more commonly seen in patients with hematologic malignancy, lymphoma, severe neutropenia, or a
history of deferoxamine therapy.
The most common clinical presentation of mucormycosis is rhino-orbital-cerebral infection, likely
from introduction of spores into the paranasal sinuses. Hyperglycemia, usually with an associated
metabolic acidosis, is the most common underlying condition (74). A review of 179 cases of rhino-
orbital-cerebral mucormycosis found that 126 (70%) of the patients had diabetes mellitus, and most
presented in ketoacidosis (76). Infection may also occur in the setting of neutropenia, or corticosteroid
therapy, but seldom in normal hosts. Disseminated mucormycosis with secondary CNS infection seldom
occurs due to diabetes mellitus alone. Cases of slowly progressive infection in patients without apparent
underlying diabetes mellitus have been described (77). Other patients who are acidemic from profound
systemic illnesses such as sepsis, severe dehydration, severe chronic diarrhea, chronic renal failure, or
inherited disorders of metabolism with acidosis also may develop mucormycosis (76,78,79).
Patients with neutropenia or corticosteroid therapy in the course of hematologic malignancy are more
likely to develop pulmonary or disseminated mucormycosis. In these patients, CNS involvement is more
likely to develop via hematogenous dissemination (80). In disseminated disease, either multiple or
solitary mass lesions may be found in the CNS. Isolated brain abscess in the absence of demonstrable
disease elsewhere has been described (80). Renal transplant recipients are also at risk of developing
rhinocerebral mucormycosis (81). CNS mucormycosis may rarely occur after neurosurgery or direct
trauma possibly due to direct inoculation (82).
Deferoxamine (DFO) chelation treatment for iron or aluminum overload is a well-recognized risk
factor for disseminated or rhinocerebral zygomycosis (83). Van Cutsem and Boelaert (84) hypothesized
that the rapid progression of experimentally induced zygomycosis in healthy guinea pigs after
administration of DFO, Fe3+ citrate, or both was mediated through the in vivo formation of the iron
chelate of DFO, feroxamine, for which fungi may have a receptor. Therefore, DFO could function as a
siderophore, providing iron to promote growth and sporulation of Rhizopus strains (84). This hypothesis
has been supported by in vitro studies (84). Iron overload states without chelation therapy may also be a
risk factor for the development of zygomycosis (85). Rickerts et al. (86) have shown that in patients with
hematologic malignancies, risk factors for mucormycosis were prolonged neutropenia, relapse of the
underlying disease, prior use of steroids, and development of diabetes mellitus. It has since been shown
that patients with diabetic ketoacidosis have elevated concentrations of free iron in their serum, which
supports the growth of R. oryzae in an acidic, but not at an alkaline, environment (87).
In contrast, the oral iron-chelating agent, deferasirox, showed a possible benefit when used to treat
mucormycosis in murine models. The combination of liposomal amphotericin B (LAmB) and deferasirox
iron chelation therapy synergistically improved survival in diabetic mice with mucormycosis (88).
However, a recent multicentered, placebo-controlled, double-blinded clinical trial involving 20 patients
with proven or probable mucormycosis that randomized patients to receive treatment with LAmB plus
deferasirox or LAmB plus placebo found that patients treated with deferasirox had a higher mortality rate
at 90 days (89).

Mucorales have a strong propensity for invasion of arteries, causing thrombosis and infarction. The
infection may involve all structures along its path, including the orbit, eye, bone, and brain tissue.
Sporangiospores of Mucorales colonize the epithelium of the sinus mucosa. In the setting of metabolic
acidosis, neutropenia, or corticosteroid therapy, the hyphae of germinating sporangiospores may invade
the basal membrane and penetrate subepithelial vessels, resulting in regional ischemia and infarction.
Involvement of the ethmoid sinuses allows hyphae to extend through the lamina papyracea and into the
periorbital space, thus threatening the eye, extraocular muscles, and posterior apical structures such as the
optic nerve. The venous drainage of the ethmoid sinuses extends to the cavernous sinuses. Thus,
mucormycosis of the ethmoid sinus carries a high risk of cavernous sinus thrombosis. The sphenoid
sinuses also bear an increased risk of direct extension to the laterally situated cavernous sinuses (90).
Hyphae may also penetrate rapidly through the ethmoidal and frontal sinuses to directly invade the dura,
pia mater, arachnoid, and cerebral hemispheres. Infection of the maxillary sinuses has a substantially
lower tendency to involve the CNS.
Within the lungs, the pulmonary alveolar macrophages serve as the principal line of host defense
against sporangiospores. On the other hand, neutrophils serve as primary defense against hyphae of
Zygomycetes. During neutropenia, hyphae invade pulmonary vessels to cause infarction and to
disseminate to the CNS.
Advanced rhinocerebral mucormycosis is characterized by an enlarging area of black mucosal or facial
necrosis along the medial aspect of the orbit, near the nose. Any unusual complaint referable to the eyes
or sinuses in a patient with immunodeficiency or diabetes mellitus should alert the treating physician to
the possibility of rhinocerebral mucormycosis. The complaints may include headache, facial pain,
diplopia, lacrimation, or nasal stuffiness or discharge. Patients may present with newly diagnosed
diabetes mellitus and concurrent zygomycosis. A diabetic patient presenting in a hyperglycemic
ketoacidotic coma who does not awaken upon correction of metabolic imbalance should be suspected of
having mucormycosis. Rhinocerebral mucormycosis may initially appear as a nasal ulcer, either
hyperemic from early inflammation or blackened from ischemic necrosis. Nasal discharge and facial
swelling followed by exophthalmos may ensue as the infection begins to spread posteriorly to involve the
orbit. Cranial nerve abnormalities are common. Impairment of cranial nerves III, IV, V with its first and
second branches, and VI may be the initial manifestation of cavernous sinus thrombosis. Blindness may
occur as a result of vascular compromise rather than as a result of direct invasion of the eye or optic
nerve (91). Development of focal neurologic deficits—including hemiparesis, seizure, or monocular
blindness—suggests far-advanced disease that has extended intracranially and carries an ominous
prognosis. Patients with hematologic neoplasm who develop abscess during hematogenous seeding may
have symptoms referable to the infected area of brain or may be without specific localizing signs (80). A
review of 22 cases of nonrhinocerebral brain abscess caused by the Mucorales reported fever, headache,
or focal neurologic signs to be present in more than half of the patients (92).
Diagnosis
A definitive diagnosis in a patient with suspected zygomycosis requires biopsy of infected tissue. Because
cultures may be negative, recognition of the characteristic hyphal morphology is important. Establishing a
definitive diagnosis of zygomycosis is of paramount importance, as amphotericin B is the only reliable
agent for treatment of this infection. Recovery of Mucorales from CSF is exceedingly rare. The CSF is
usually nonspecifically abnormal, although patients with normal parameters have been reported (93).
Elevated opening pressure, elevated protein concentration, and pleocytosis with at least 50%
polymorphonuclear cells are the most common abnormalities. Glucose concentration is usually normal.
One report of patients with hematologic neoplasms described red blood cells in the CSF of infected
patients (80). CT and MRI scanning are important adjuncts to staging of infection and monitoring the
course of therapy. Sinus opacification, bony erosions, and obliteration of deep fascia planes may be found
in rhinocerebral zygomycosis (94). Confirmation of a clinical diagnosis can be made by swabbing,
scraping, or biopsying an involved area. A nasal or palatal ulcer specimen, “black pus” from a surgically
drained sinus, or tissue from a brain biopsy may reveal, on KOH wet mount preparation or calcofluor, the
typical ribbon-like, broad nonseptated hyphae. PCR-based techniques on histologic specimens appear
promising for establishing the diagnosis of mucormycosis but remain investigational (95).

Successful treatment of rhinocerebral zygomycosis is dependent on three cardinal principles: (a) surgical
resection of the infected tissue, (b) reversal of underlying metabolic or immunologic impairments, and (c)
administration of amphotericin B. Although amphotericin B may be effective in isolated cases of renal
zygomycosis (96), it is seldom curative in treatment of cerebral zygomycosis (97). A lipid formulation of
amphotericin B (LFAB) at 5 mg/kg per day or amphotericin deoxycholate at 1 mg/kg per day
intravenously is used until there is clinical and radiologic evidence of resolution and correction of any
metabolic or hematologic abnormalities that may have predisposed the patient to this infection. Because
of the difficulties in administering amphotericin deoxycholate for prolonged periods, an LFAB is
recommended for primary therapy. Intrathecal amphotericin B is fraught with severe neurotoxicity.
Moreover, intrathecal amphotericin B does not penetrate substantially beyond the meningeal surfaces into
the brain parenchyma. High intravenous doses of 5 mg/kg per day of LFAB or amphotericin deoxycholate
delivers drug more reliably to brain tissue (98).
The echinocandins have no in vitro activity against the agents of mucormycosis (99). R. oryzae,
however, expresses the target enzyme for echinocandins, suggesting that these agents may one day have
clinical use (100). Small, retrospective analyses have not established a role for combination therapy;
larger trials are needed to determine if combination therapy is indeed beneficial (101,102).
Posaconazole is a broad-spectrum triazole with activity against filamentous fungal pathogens. In an
animal model, Sun et al. (103) showed that posaconazole at doses of 15 and 30 mg/kg significantly
lowered counts of three isolates in tissue. Its possible clinical efficacy was shown in a salvage study that
enrolled 91 patients who had failed or could not tolerate standard therapy (104). Posaconazole may have
a role for treatment of mucormycosis refractory to standard therapy as well as for oral step-down therapy
in patients who have responded to an LFAB. As the minimum inhibitory concentrations (MICs) of R.
oryzae tend to be elevated beyond commonly achievable serum concentrations, more studies are needed
to define the role of posaconazole in treatment of the most common cause of CNS mucormycosis.
Outcome from mucormycosis varies as a function of the underlying condition, site of infection, and use
of antifungal therapy. Even with aggressive therapy, overall mortality from rhino-orbital-cerebral
mucormycosis ranges from 25% to 62% (74).
Pseudallescheria boydii (Scedosporium apiospermum)
P. boydii is the most common cause of mycetoma in North America. Mycetoma (Madura foot) is a local,
chronic, slowly progressive, painless destructive infection that starts in the subcutaneous tissue, spreading
to contiguous structures. The organism is introduced into the subcutaneous tissue by minor trauma, often
associated with handling plant debris or soil. The extremities are the most common sites of initial
infection. The defining characteristic of this entity is the presence of grains that form in the tissue and
drain from sinus tracts. P. boydii was first reported to cause brain abscess in 1965 (105). Infections
caused by P. boydii and Scedosporium apiospermum have been reviewed extensively elsewhere (106).

P. boydii, formerly called Petriellidium boydii or Allescheria boydii, is a common mold readily isolated
from soil. It also may be cultured from polluted water, sewage sludge, and the manure of poultry and
cattle. The association between near drowning and subsequent illness from P. boydii may derive from the
pathogen’s presence in contaminated water and manure (106). It forms septate hyphae with rare branching
and may be impossible to distinguish from Aspergillus species when examined in tissue. P. boydii grows
rapidly on Sabouraud agar and produces floccose colonies that are dark gray to brownish gray. The
colonies tend to become more lightly colored during maintenance on agar media. Isolates that fail to
produce cleistothecium are identified as S. apiospermum, formerly called Monosporium apiospermum,
the asexual form of the fungus. Immunocompromise predisposes to this infection, but brain abscess caused
by P. boydii can occur in normal hosts (107). There is no evident age, race, or sex-related predilection for
this infection.

P. boydii may enter the CNS in at least four ways: by direct entry from trauma (108), by hematogenous
dissemination from a pulmonary route, including aspiration into lungs, especially implicated in near-
drowning victims (106), via an intravenous catheter (109), and via direct extension from infected sinuses
(110).
Like other molds, P. boydii has a predilection to angioinvasion. From the initial area of angiitis, the
process extends centrifugally and forms an abscess. An active granulomatous response with encapsulation
is often seen. In approximately one half of reported cases, no sites of P. boydii infection other than the
CNS were found (106).
In the immunocompromised host, infection with P. boydii occurs in the same clinical settings as for
Aspergillus infections: patients with hematologic malignancies and those receiving immunosuppressive
agents, including cyclophosphamide, azathioprine, and corticosteroids. Signs and symptoms of a space-
occupying lesion—including headache, fever, and focal neurologic deficits—suggest the presence of
Patients who develop P. boydii infection after an episode of near drowning tend to develop clinical
signs and symptoms 15 to 30 days later (106). Often they will have endured a previous episode of
bacteremia, diagnosed and treated after hospital admission. Metastatic skin lesions may herald the
fungemia. P. boydii has been isolated from these papular lesions (106).
Diagnosis
CSF abnormalities are nonspecific. Mild to moderate elevations in protein and decreases in glucose
concentration occur, together with a moderate to marked pleocytosis with a preponderance of
polymorphonuclear leukocytes. A CT scan of the head may show the abscess at any stage of development,
beginning as nonspecific edema and progressing to a well-circumscribed abscess. Single or multiple
lesions may be found.
A certain diagnosis can be made only on aspiration and culture of the abscess. P. boydii has been
successfully cultured from blood of patients with endocarditis (106) but not from blood of those with
brain abscess. A serologic test to measure antibody has aided in diagnosis in at least one patient (111).
The β-D glucan assay is approved by the FDA for use in the serum of patients with suspected deep-seated
mycoses and fungemia, including Aspergillus, Candida, Fusarium, Trichosporon, and Acremonium (112).
The diagnostic accuracy of this test for P. boydii is not yet known.

Several patients have survived infection with P. boydii, although the mortality rate remains quite high.
Survival may be better in patients with single rather than multiple lesions (106). Surgical drainage of the
abscess remains the cornerstone of effective therapy, although antifungal therapy may play an increasing
role. P. boydii shows in vitro resistance to amphotericin B; however, it is usually quite sensitive to
voriconazole (105), and a large retrospective study supports its use as the treatment of choice (113).
Other Molds
Dematiaceous Fungi
Dematiaceous fungi are a group of ubiquitous organisms that are characterized by the presence of pale
brown to dark melanin-like pigment in the cell wall. These organisms are common plant pathogens.
Clinical entities associated with dematiaceous fungi are chromoblastomycosis and black-grained
mycetoma. In humans, they cause various skin disorders, including tinea nigra, keratitis, and Madura foot.
Very rarely, they may cause systemic illness; among these, cerebral abscess is a common manifestation.
The taxonomy of this group of organisms continues to change. Similarly, pathogens previously named
Helminthosporium or Drechslera were reclassified as Bipolaris or Exserohilum. To add further to the
confusion, the terms phaeohyphomycosis and chromoblastomycosis or chromomycosis, which originally
had referred to specific groups of dematiaceous fungi, are now used interchangeably. Attempts have been
made to redefine the terms, using chromoblastomycosis to refer to chronic localized skin infections
occurring in normal hosts and reserving phaeohyphomycosis to refer to systemic disease, including
infection of the CNS (114).
In some reported cases, a pathogen identified on KOH wet mount preparation or Gram stain was not
successfully cultured. Generally, because species of dematiaceous fungi share a similar morphology,
authors have attributed these cases to C. bantiana, possibly further increasing its apparent prevalence as
the main intracranial pathogen among the dematiaceous fungi.
Cladophialophora bantiana (Cladosporium Species)

History. The first descriptions of cases of cerebral cladosporiosis are credited to Pedroso and Banti in
1911 (115). Some uncertainty exists concerning exactly which species they described. The first North
American case was reported in 1952 (116). Two reviews address the worldwide experience in diagnosis
and treatment of brain abscess due to this organism (117,118).
Mycology. Several species of Cladophialophora have been identified. C. bantiana is a ubiquitous,

brown (or olive), septated, branching hyphal fungus with elliptical unicellular conidia. Long strands may
consist of up to 30 conidia. C. bantiana is identifiable on KOH wet mount preparation. In culture, it is
gray-brown on the light-exposed side and black on the underside of the culture plate. The fungus grows
well at 42°C.
Epidemiology. Cases of intracranial C. bantiana infection have been reported worldwide. Men account
for more than 65% of the cases. There is no predisposition by age or race. A case in an infant has been
reported (119). Almost all cases have been community acquired (120). At least one case of abscess in an
immunocompromised host has been reported (120); most others have occurred in immunocompetent
individuals, although at least three had a prior history of invasive nocardiosis (118).
Pathogenesis and pathology. The neurotropism of C. bantiana has been commented on by numerous
authors (121,122). Multiplicity of CNS lesions in some cases supports the concept that spread to the CNS
takes place by a hematogenous route (121,122). There have been occasional reports of CNS infection in
which the fungus was isolated from systemic sites, including skin, lung, ear, and paranasal sinus (119).
Most patients are healthy before the development of infection. C. bantiana is now recognized as an
emergent pathogen, particularly among immunocompromised hosts (122). Of the two major reactions to
the infection, meningitis and brain abscess, the latter is most common.
Clinical manifestations. The symptoms and signs of infection are largely nonspecific and are a reflection
of mass effects, including headache and papilledema. Localizing signs vary greatly and are the result of
tissue destruction. The duration of symptoms varies, ranging from weeks (subacute) to as long as 5 years
(chronic) (119). Most patients have weeks to months of slowly developing complaints typical of a space-
occupying lesion, including headache, seizure, or localizing neurologic signs. One case of mycotic
aneurysm has been reported, although the patient had already undergone craniotomy and extensive
neurosurgery (123).
Diagnosis. There are no initial clinical or laboratory features that yield a preoperative etiologic
diagnosis as CSF and CT findings are not specific to C. bantiana abscess. Multiple abscesses and
multiloculated abscesses are common. The definitive diagnosis can be made only by biopsy and culture of
the abscess. KOH wet mount preparation of the specimen will usually be sufficient to identify the
organism as a dematiaceous fungus. Final identification requires positive culture.
Therapy. C. bantiana brain abscess has a high mortality (124). Patients who have survived had easily
resectable encapsulated masses, whereas those who died had poorly demarcated abscess borders or
multiple lesions. To date, there is no clearly effective antifungal therapy. Flucytosine (100 to 150 mg/kg
daily given orally in four divided doses, adjusted for serum and CSF flucytosine levels) has shown some
promise (125). C. bantiana is resistant to amphotericin B in vitro, although several reported survivors
have received this drug in addition to flucytosine and surgery (125). Successful therapy often requires
more than 1 year of treatment. At least one patient with C. bantiana cerebral abscess has been
successfully treated with voriconazole (126).
Other Dematiaceous Fungi. Other dematiaceous fungi with pathogenic potential for humans due to their
neurotropism besides C. bantiana (127,128) are the hyphomycetous fungi E. (Wangiella) dermatitidis
(129) and Ochroconis gallopavum (Dactylaria gallopava) (130), the Ascomycetes C. atrobrunneum
(131), B. spicifera (132), B. hawaiiensis (133), Rhinocladiella atrovirens (134), Curvularia pallescens
(135), and Fonsecaea pedrosoi (136). Voriconazole and/or LAmB in conjunction with neurosurgical
consultation when appropriate are currently recommended for initial management.
The advent of molecular techniques contributes to the current revolution in medical mycology. New
technology allows us to classify and reclassify old and new pathogens. Another example of this
continuous renaming is the genus Drechslera (including Drechslera hawaiiensis, Drechslera spicifera,
and Drechslera halodes), which was reclassified in the genus Bipolaris or genus Exserohilum. Several
cases of cerebral abscess caused by these organisms have been described, with all but one occurring in
immunocompetent hosts (137). Invasive pulmonary disease is usually seen in immunocompromised hosts
(138).
Drechslera and Bipolaris species resemble Aspergillus species in certain clinical respects, despite
their lack of taxonomic relationship. They all may cause disseminated disease in immunocompromised
hosts that is characterized by diffuse hyphal vasculitis; they may cause sinusitis in immunocompetent
hosts; and they can be associated with allergic bronchopulmonary disease (138).
Treatment with aggressive surgical débridement and intravenous amphotericin B (0.6 to 1.0 mg/kg
daily) with or without flucytosine (100 to 150 mg/kg daily given orally in four divided doses) has cured
some patients.
Several intracranial abscesses due to Curvularia species, including lunata and pallescens, have been
reported, many in patients with concurrent pneumonitis (139). Most have occurred in normal hosts; one
patient had an unexplained T-cell defect (140). The lone survivor received 12.2 g of intravenous
amphotericin B (140). Neither ketoconazole nor flucytosine was beneficial in this patient.
Cases of brain abscess caused by Fonsecaea pedrosoi (Phialophora pedrosoi), Wangiella
(Exophiala) dermatitidis, Dactylaria constricta, and Ramichloridium obovoideum (mackenziei) have
been reported (141,142). All occurred in apparently normal hosts (except that one patient had a short-
bowel syndrome), and all patients died within weeks despite aggressive surgical and medical therapy.
The primary site of infection may have been pulmonary. Differentiation of F. pedrosoi from the genera
Rhinocladiella and Ramichloridium was made after careful testing, but confusion among these genera
may exist.
A case of brain abscess due to Scopulariopsis brumptii occurred in a hog farmer who had received a
liver transplant (143). Scopulariopsis can be isolated from buildings where pigs are confined, suggesting
possible occupational exposure. This patient had developed a nonhealing thigh wound, which may have
been the portal of entry. A rapidly fatal case of Scopulariopsis cerebral infection in a 33-year-old
immunocompetent male has also been reported (144). As Scopulariopsis brevicaulis may be resistant to
all available antifungal agents, surgical resection, and reversal of immunosuppression may be the only
recourses for successful treatment.
Miscellaneous Fungi
Emerging Fungi
Dermatophytes. At least one case of brain abscess due to Trichosporon cutaneum has been reported
(145). The patient was a 39-year-old woman with untreated adenocarcinoma of the lung metastatic to
brain. At autopsy, the brain disclosed multiple lesions consisting of metastatic tumor with yeastlike
organisms seen at the periphery. Cultures grew T. cutaneum. The infection appeared limited to the CNS.
T. cutaneum typically causes white piedra of hair and occasional nail infections. It is found in soil and
may be a normal colonist of human skin.
A few cases of intracranial infection with Trichophyton species have been reported (146). In one case,
a man with a possible T-cell immune defect developed invasive Trichophyton mentagrophytes. After
more than 5 years of chronic invasive disease, he died of widely disseminated fungal infection, including
One patient with disseminated Microsporum audouinii had intracranial involvement (147). Treatment
with amphotericin B and plasma infusions cleared the infection. Rhinosporidium seeberi, a fungus of
uncertain classification (148), is endemic to India.
Hyaline Septate Molds

Trichoderma species. Trichoderma species, another filamentous fungus species considered a saprophytic
organism, only rarely pathogenic in humans, has emerged as another causal agent of brain abscess. A
brain abscess due to Trichoderma longibrachiatum in a pediatric leukemic patient is described (149).
Surgical resection of a cerebral abscess has been a successful treatment of this infection; however,
recovery from immunosuppression appears to be an essential factor for an adequate response of this
organism to antifungal therapy.
Fusarium species. Fusarium species are hyaline molds, with emerging pathogenic potential, causing lung
and disseminated disease in immunocompromised patients. In some institutions, fusariosis has emerged as
the second most common filamentous fungal pathogen after Aspergillus. This fungal pathogen has a
characteristic canoe-shaped macroconidia. Fusarium solani, Fusarium oxysporum, and Fusarium
moniliforme are the most common species of this ubiquitous mold.
In the immunocompromised patient, risk factors predisposing to invasive fungal disease are principally
prolonged neutropenia followed by corticosteroid therapy. This organism is highly angioinvasive and
leads to hemorrhagic infarction in pancytopenic hosts. It has been involved in brain abscess (150). Ports
of entry of this organism are respiratory tract, sinuses, vascular catheters, and paronychia in neutropenic
patients (151).
Paecilomyces species. Paecilomyces species are hyaline molds that cause deep infections in
immunocompromised hosts. The ports of entry of this pathogen are the respiratory tract and the skin.
Paecilomyces has also been involved in brain abscess (152). Fungemia may be observed with
disseminated infection due to Paecilomyces species. The work of Liu et al. (153) has explained the basis
of positive blood cultures (fungemia) in infections with these fungi. In tissue, Fusarium and Paecilomyces
produce not only hyphae but also adventitious structures consistent with microconidia that can easily
disseminate through the bloodstream. Such structures are not observed in tissue sections of invasive
aspergillosis, with the exception of that due to Aspergillus terreus. This species of Aspergillus has a
distinct capacity to elaborate lateral conidia.
The treatment of disseminated fusariosis is unclear due to the lack of clinical trials and because
susceptibilities within the genus are highly variable. Larger series have noted high mortality and
morbidity in excess of 80% (154,155) with higher mortality rates in persistently immunosuppressed
patients, particularly those who remain neutropenic. Immunocompromised patients with invasive
fusariosis require aggressive antifungal therapy. For initial therapy, we suggest combination therapy with
an LFAB and voriconazole, particularly in cases of severe immunosuppression or severe disease.
Adjuvant therapeutic options to voriconazole may be granulocyte transfusions from granulocyte colony-
stimulating factor–stimulated donors.
INFECTIONS CAUSED BY YEASTS

Candida
The history of candidiasis dates back to the fourth century BC when Hippocrates, in his book Epidemics,
described oral aphtha (thrush) in two patients with severe underlying disease (156). A brain abscess
caused by Candida species was first reported in 1895 (156), but it was not until 1943 that Candida was
successfully cultured from a cerebral lesion (156). Candida remained a relatively uncommon CNS
pathogen until the 1960s, when use of chemotherapeutic agents, glucocorticoids, and intravenous drugs
rendered increasing numbers of patients susceptible to opportunistic infections. A 1978 review of 9,000
autopsies disclosed that Candida had surpassed Cryptococcus as the most common CNS fungal pathogen
(157). Patients who develop CNS infections with Candida are usually immunosuppressed (HIV,
leukemia) (158), although the condition has also been documented in premature neonates (158) and after
neurosurgical instrumentation (159).
Mycology
Candida species are small (4 to 6 µm), ovoid (blastospores) yeast cells. Both sexual and asexual forms
exist. Candida organisms reproduce by budding. In tissue, Candida may exist as yeasts or as
pseudohyphae. Only Candida albicans is germ-tube positive. The genus Candida encompasses more than
350 species (160), although fewer than 10 are of clinical relevance. C. albicans is the most common
species involved in systemic candidiasis and is also the most common species responsible for
neurocandidiasis (161); however, CNS infection with non-albicans species (Candida parapsilosis and
Candida tropicalis) has been observed with increasing frequency at some centers (162).
Epidemiology and Ecology

C. albicans organisms have been recovered from soil, hospital environments, inanimate objects, and
food; Candida species are rarely laboratory contaminants. The organisms are normal commensals of
humans and are commonly found on skin, throughout the entire gastrointestinal tract, expectorated sputum,
in the female genital tract, and in urine of patients with indwelling Foley catheters. There is high
incidence of carriage on the skin of health care workers. Although most Candida infections are of
endogenous origin, human-to-human transmission is possible. There is evidence of growing nosocomial
acquisition of Candida infections. C. albicans previously accounted for approximately 90% of the cases
of candidal brain abscess, but intracranial infection has also been described with C. tropicalis, Candida
guilliermondii, Candida stellatoidea, and C. parapsilosis (4) and are becoming more common
pathogens. Non-albicans species are associated with a higher frequency of resistance to antifungal agents
and increased mortality (163). Rarely Candida meningitis has been described in an otherwise normal host
(164). There is an increased incidence of both disseminated candidiasis and CNS involvement in the
newborn, especially premature infants (165). Pediatric cases accounted for 29% of cases of CNS
infection in one series (166).
Pathogenesis and Pathologic Findings

The pathophysiology of Candida CNS involvement varies with the clinical setting. Invasive candidiasis
occurs only in patients with some form of immunodeficiency or immunocompromise. When systemic
candidiasis (candidemia) is prolonged, it can seed the CNS and induce diffuse encephalopathy with
diminished consciousness in which the predominant lesions are microabscesses. Microabscesses (<3
mm) are typically found in the union of the gray and white matter and they are widely spread in the CNS.
However, the basal ganglia and the cerebellum are the most frequently affected sites (167). These
microabscesses are foci of necrosis surrounded by polymorphonuclear leukocytes or noncaseating
granuloma with giant cells that contain the yeast or hyphae. Cerebral macroabscesses produced by
Candida species are unusual and have been reported in apparently immunocompetent (166) and
immunocompromised patients (168). Abscesses can be single (166) or multiple (169). They usually
locate in the parietooccipital area, and only exceptionally, in the cerebellum (170). Vascular invasion
resulting from Candida endocarditis can produce cerebral mycotic aneurysms that can rupture and
produce subarachnoid hemorrhage or subdural empyema (168). Mycotic aneurysms caused by C. albicans
and C. parapsilosis have been described (57,171). Meningitis allows for earlier diagnosis. Candida
meningitis can be found together with disseminated microabscesses or alone as chronic meningitis with
dense exudates at the base of the brain and brainstem.
Other risk factors for CNS candidiasis are parenteral nutrition and neutropenia. The catheter-
associated transient candidemia is an especially important risk factor for the immunocompromised
patient. Neurocandidiasis in AIDS, even though uncommon, may present in the form of an abscess or
meningitis (172). In one series of 42 patients with CNS candidal infections, 27 (64%) had meningitis
only; the remaining 15 (36%) had abscesses (166).
Any patient predisposed to develop disseminated candidiasis, including newborns, those with
immunodeficiencies, and those on immunosuppressive agents, may develop intracranial candidiasis.
Nonspecific symptoms, such as confusion, drowsiness, or stupor, may be the only indication of CNS
infection. However, fever and classic meningeal signs such as nuchal rigidity, headache, and photophobia,
which are unusual in other intracranial mycoses, may be found in candidiasis of the CNS (173). Focal
neurologic deficits corresponding to involved areas of the brain may be seen in patients with large
abscesses. Clinically they behave like a cerebral mass lesion, with seizures, focal neurologic signs (e.g.,
aphasia, hemiparesis, and visual field defects), and progressive increases in intracranial pressure.
Diagnosis
The diagnosis is still most often made at autopsy. However, premorbid diagnoses have been made from
biopsies, and rarely, the organism has been recovered from CSF. In the absence of meningeal
involvement, a positive CSF culture is rare unless parenchymal involvement develops subjacent to the
subarachnoid space. Recovery of Candida from other sites should suggest the possibility of dissemination
and possible CNS involvement. Radiologic diagnosis of candidal brain abscesses has been described,
although there are no features typical of Candida infection (170).

Successful treatment of CNS fungal infections in immunocompromised patients is related to two major
factors: (a) the cause of immunosuppression and (b) the possibilities of withdrawal of
immunosuppression. Removal of infected intravascular catheters or infected CSF devices that could
perpetuate candidiasis is very important. With the increasing incidence of non–C. albicans spp., the use
of fluconazole as first-line initial therapy for invasive candidiasis has waned due to reduced
susceptibility of the yeasts to this drug. Unfortunately, resistance to even the newer echinocandin class of
antifungals is now also being observed (40). The treatment of choice for CNS candidiasis in adults is
LFAB (3 to 5 mg/kg IV once daily) with or without flucytosine (100 mg/kg per day). Amphotericin B is
used because of its fungicidal activity against almost all Candida species, even though drug levels in the
CSF and brain are low and flucytosine is added because of its excellent CSF penetration and anticandidal
activity (174). For neonates, amphotericin B deoxycholate, 1 mg/kg IV once daily, is recommended with
flucytosine (158). This treatment should be constantly monitored with regular serum levels of flucytosine
to prevent myelotoxicity. The duration of treatment is at least several weeks or until resolution of the CNS
mass by neuroimaging and clinical improvement. Shorter courses of therapy are associated with a high
relapse rate. Fluconazole is a well-tolerated drug and has excellent penetration to the CSF; however,
treatment outcomes have varied with the use of fluconazole alone or in combination with flucytosine
(162). Fluconazole is recognized as a useful agent for step-down therapy after the initial course of
amphotericin B with or without flucytosine in patients infected with fluconazole-susceptible Candida
species.
Cryptococcus neoformans
In 1861, Zenker reported the first case of a man dying from a fungal infection involving the CNS, and it is
probable that the organism was C. neoformans (173). The first reports of intracerebral cryptococcoma
appeared in the early 1900s, although some dispute still exists concerning the identity of the reported
organisms (175). Outdated terminology includes Torulopsis histolytica and European blastomycosis. C.
neoformans, the principal pathogenic member of the genus, was the most common fungal infection of the
CNS (4) until the 1970s, when autopsy studies established that Candida species had become more
prevalent as a CNS pathogen (157). After the onset of the HIV epidemic, cryptococcal CNS infections
again lead all the rest.
Mycology
Cryptococcus is a ubiquitous encapsulated yeast, taxonomically related to Candida. It reproduces rapidly
by budding and grows well on Sabouraud agar. The capsule, which is well visualized in India ink
suspensions, is of variable size. The physiologic stimulus to capsule enlargement is the relatively high
carbon dioxide tension found in lungs and mammalian tissues. It is found in soil and occurs in high
concentrations in the feces of pigeons and chickens, although it does not appear to cause disease in these
animals. It has also been recovered from the skin and respiratory tract of healthy people and in patients
with various bronchopulmonary diseases (176). C. neoformans and C. gattii are the two major species of
the genus Cryptococcus considered to be pathogenic in humans. C. neoformans is primarily an
opportunistic pathogen while C. gattii infection tends to occur in immunocompetent hosts, although
infection can be seen in immunocompromised hosts as well. Both C. neoformans and C. gattii have a
propensity to cause pulmonary and CNS disease. C. gattii was once thought to be geographically
restricted to tropical and subtropical climates; however, an outbreak of C. gattii infection occurred in
Vancouver Island, British Columbia beginning in 1999 and cases continue to occur throughout the United
States (177).
Epidemiology
C. neoformans has been recovered from soil contaminated with avian excreta, especially pigeon
droppings, and from decaying foods, fruits, vegetables, and dust, whereas C. gattii has been cultured from
eucalyptus trees as well as Douglas fir, alder, and Garry oak but not from avian excreta (178). C.
neoformans and C. gattii can be subclassified into four serotypes and two species with two varieties.
The serotypes are based on capsular agglutination reactions and are designated A, B, C, or D (serotype A
and D were previously classified under the species neoformans) (179).
Unlike many other fungal diseases of the CNS, which occur equally in men and women, cryptococcal
infection is more common in men (180). This observation is valid for both cryptococcal meningitis and
cryptococcoma. The reasons are unknown, although occupational exposure to soil may be partially
responsible. C. neoformans typically causes opportunistic infection in patients with cellular immune
deficiencies. Life-threatening cryptococcal disease can occur in apparently normal individuals, but such
cases are relatively rare. Conditions that predispose to impaired cellular immunity and are associated
with an increased risk of cryptococcosis are those patients with advanced HIV infection (181),
lymphoproliferative disorders (182), steroid therapy (183), and organ transplantation (184).
Cryptococcosis has also been associated with hyperimmunoglobulin M syndrome in children (185). The
most common predisposing factor to cryptococcosis in non–HIV-infected patients is currently
supraphysiologic doses of corticosteroids (183). In a multicenter retrospective study of 157 cases of CNS
cryptococcosis in HIV-negative patients, 30% had no apparent underlying condition (186).
After a dramatic rise until the early 1990s, the prevalence of C. neoformans in HIV-infected patients
began to decline with the introduction of effective antiretroviral therapy and the use of fluconazole for
primary treatment and chronic suppression of oral candidiasis in patients with AIDS. C. neoformans
infection is most prevalent in areas of the world where the high cost of highly active antiretroviral therapy
and the complicated health system logistics (Africa, Thailand, India) have precluded its wide use. By
comparison, the number of cases of this infection has declined in Europe and the United States.
C. gattii infection tends to occur in immunocompetent hosts, primarily manifesting with pulmonary and
CNS involvement. Immunologic containment of infection by the immune response may be responsible for
a higher incidence of cryptococcoma due to C. gattii than to C. neoformans. Thus, CNS infections due to
C. gattii are associated with more neurologic complications requiring surgery and prolonged therapy as
compared to infections due to C. neoformans (187).
Pathophysiology and Pathology

Cryptococcus usually enters the body through the respiratory tract. Dehydrated yeast cells or
basidiospores (<5 to 10 µm) are sufficiently small for inhalation and alveolar deposition. Direct
inoculation of the skin has been postulated as an alternative route of infection for C. neoformans (176).
Clinical and experimental evidence indicates that cryptococcosis is usually a reactivation of a dormant
infection (188).
The macrophage is generally considered the central effector cell against C. neoformans. It ingests and
kills the yeast and releases proinflammatory cytokines (e.g., interleukin-12). T-cells are believed to
contribute to host defense by providing cytokines (e.g., interferon) that activate macrophage fungicidal
activity and promote the transformation of alveolar macrophages into giant cells capable of ingesting
large encapsulated yeast cells.
There is also evidence that humoral immunity contributes to protection against C. neoformans infection
(189).
Once established in the lungs, C. neoformans may spread to intrathoracic lymph nodes and then
hematogenously disseminate to seed the meninges, in similar fashion to Mycobacterium tuberculosis. It is
not known why this organism has a special tropism for the CNS or why most patients with CNS
involvement develop meningitis but only a few develop cryptococcomas. An Australian retrospective
study identified 118 cases of cerebral cryptococcosis and has found that a worse prognosis was
associated with infections due to the gattii variety (190).
The brain, including the meninges, is by far the most common organ affected in symptomatic
cryptococcosis. The term meningoencephalitis is more appropriate than meningitis because the brain
parenchyma is almost always involved. On gross inspection, a cryptococcoma in the brain may have a
honeycomb or soapsuds appearance. One review described four appearances of cryptococcoma: a well-
circumscribed pseudocystic lesion (9%); a gelatinous mass composed mostly of cryptococci, with scant
inflammatory response (24%); a fibrogranulomatous lesion consisting chiefly of fibrous reaction, with
rare cryptococci (15%); and a mixed type (43%). Nine percent of lesions could not be classified (191).
Cryptococcoma has a wide range of potential presentations. Reviews of cases of cryptococcal meningitis
estimate the concurrent existence of cryptococcoma to be 4% to 8% (190). Most patients with
cryptococcal meningitis present with signs and symptoms of subacute meningitis or meningoencephalitis.
Among presenting complaints, the most common is headache (73%). Multiple other symptoms—including
fatigue, fever, seizures, confusion or other altered mental state, visual disturbances, or unsteady gait—
occur variably; each of these symptoms is reported in less than one third of patients. As many as 18% of
patients have no complaints referable to the CNS (191). Up to 5% of patients have been incidentally
discovered at autopsy. Neurologic examination may demonstrate a focal deficit or may be normal.
Diagnosis
Cryptococcal disease can be diagnosed more readily than most other systemic fungal illnesses, for three
reasons: the yeast cells can often be seen in CSF; the routine use of latex agglutination test for the
detection of cryptococcal capsular antigen, which is both highly sensitive and specific (≥90%); and the
yeast is relatively easy to grow from the CSF specimens (192). A rare false-positive result occurs when
there is a cross-reactive antigen, such as the polysaccharide of Trichosporon beigelii or another
microorganism in the specimen. False-negative test results may be caused by low titers, early infection,
presence of immune complexes, prozone effect of high titers, or poorly encapsulated strains with low
production of polysaccharide. The antigen-detection system has its most clinical experience with CSF and
serum specimens, but it has been used in urine or BAL fluid. The CSF may be completely normal, but
usually there is often an elevated opening pressure. Almost 70% of AIDS patients with cryptococcal
meningoencephalitis have opening pressures greater than 200 mm H2O on the initial lumbar puncture
(193). The sensitivity and specificity of the cryptococcal capsular antigen test in the CSF of patients with
cryptococcal meningoencephalitis both exceed 90%; however, absence of cryptococcal antigen in CSF
has been reported (194). A patient with a granuloma seen on chest x-ray and one or several mass lesions
on head CT should be suspected of having cryptococcoma.
Surgical excision was the mainstay of therapy until the 1970s. Amphotericin B therapy transformed
cryptococcal meningitis from a uniformly fatal infection to one that is curable. Today, treatment consists
of antifungal therapy, management of elevated intracranial pressure, and reducing immunosuppressive
therapy. Guidelines for the treatment of cryptococcosis including CNS cryptococcoma have been
published (195).
Dimorphic Yeasts
The pathogenic dimorphic yeasts that cause endemic systemic mycoses are Blastomyces dermatitidis, H.
capsulatum and Histoplasma duboisii, Coccidioides immitis, Coccidioides posadasii, and
Paracoccidioides brasiliensis. In the environment, they all form mycelia with hyaline, branching, septate
hyphae. The conidia or hyphae of B. dermatitidis, P. brasiliensis, and H. capsulatum convert to budding
yeast cells in tissue or on enriched media at 37°C in the laboratory. C. immitis and C. posadasii produce
spherules in tissue or in vitro under appropriate conditions. Temperature is a critical variable in the
induction of dimorphism in these fungi. This contrasts with the hyphal fungi, which cause vasculitis and
infarction with resultant cerebritis or brain abscess, although Coccidioides may have vasculopathic
effects (196). The presentation of intracranial infection with one of the dimorphic yeasts may be
subclinical and is often similar to that of tuberculous meningitis. Occasionally, multiple microgranulomas
may be seen, presumably from miliary seeding from a primary lung focus. Chronic meningitis may also
give rise to asymptomatic local cerebritis in the subjacent parenchyma. True abscesses have rarely been
described with dimorphic yeasts, either in normal or in abnormal hosts.
Blastomyces dermatitidis

The first cases of B. dermatitidis infection of the brain were reported in the early twentieth century (197).
A 1939 review found only 16 cases of blastomycosis with CNS involvement, many of which were limited
to the meninges (197). Spinal cord compression due to epidural granuloma may be more commonly seen
with blastomycosis.
Once known as North American blastomycosis or Gilchrist disease, B. dermatitidis infection is now
known to occur worldwide. Its environmental niche is probably the soil, but attempts to define its natural
habitat have been unsuccessful. The absence of a reliable skin test has limited attempts to delineate the
prevalence of blastomycosis. Blastomycetes generally infect healthy individuals but occasionally may
occur in patients with lymphoma who are receiving corticosteroid therapy or may coexist with
tuberculosis or histoplasmosis (173). In the United States, it is endemic in the Ohio and Mississippi River
Valleys, North Carolina, and the north central part of the country. Several small epidemics have been
reported in Wisconsin, North Carolina, and other locations. Most cases occur in middle-aged people, the
male-to-female ratio is 9:1, and there is no evidence of a racial predilection.

Fungal spores enter the body via the respiratory tract and may cause subclinical infection or a subacute
pneumonitis. Certain patients may then develop disseminated disease, during which seeding of the CNS
may occur. Skin lesions from presumed dissemination are found in 50%. Occasionally infection of the
skin may go on to cause systemic disease. Other frequently involved organs include lung, bone, and
prostate. The rate of CNS blastomycosis may be higher in patients with AIDS (198). CNS involvement
may also take the form of an intracranial abscess or granuloma, spinal epidural granulomas or abscess, or
a combination of disease forms. Microscopically, an abscess may have a fibrous capsule circumscribing
necrotic tissue, inflammatory cells, and yeasts. Multinucleated giant cells are usually present;
microabscesses with caseous necrosis may also be seen, mimicking tuberculosis (4).
Most patients with CNS blastomycosis exhibit evidence of pulmonary disease; cough is the most
commonly encountered presenting symptom (199). A brain abscess may cause increased intracranial
pressure with or without localizing signs (4). Some patients are asymptomatic. The site of CNS
involvement correlates with specific neurologic deficits.
Diagnosis
CSF culture is rarely positive, even in cases of B. dermatitidis meningitis. In cases of abscess, opening
pressure may be elevated and the CSF formula may be nonspecifically abnormal, and CT scan may show
isodense or slightly hyperdense lesions with surrounding edema and uniform enhancement after contrast
administration. The appearance of the lesion can easily be confused with a brain tumor. Serology is not a
useful tool in diagnosis owing to the high degree of cross reactivity shared by the endemic mycoses; a
definitive diagnosis of blastomycosis can be made only by isolation of the organism.
Treatment
CNS infection should be treated with a liposomal formulation of amphotericin B for 4 to 6 weeks
followed by an oral azole for at least 12 months. Voriconazole has good CNS and CSF penetration and
excellent activity against B. dermatitidis and is suggested for step-down therapy. A review of the
treatment of blastomycosis, including CNS involvement and infection in the immunocompromised host,
has been published (199).
Histoplasma capsulatum
Although histoplasmosis remains the most common systemic fungal infection in North America,
development of a CNS abscess continues to be exceptionally rare. Several reviews have been published
(200,201).
Mycology
H. capsulatum is a member of the class Ascomycetes and has a heterothallic form designated Ajellomyces
capsulatum. H. capsulatum and H. duboisii are the causative agents for American and African
histoplasmosis, respectively. No cases of brain abscess caused by H. duboisii have been described. The
organism requires vitamins, including thiamine, and biotin, iron, and cysteine or cystine for growth. There
are two types of conidia: a macroconidia (8 to 15 µm in diameter) and a microconidia (2 to 5 µm in
diameter). The latter type is believed to be the infective phase because of their size and ease of access to
the terminal alveoli. Histoplasma organisms have been isolated from the soil in endemic areas and are
highly concentrated in bird excreta and bat guano.
Epidemiology
H. capsulatum has been detected in many areas of the world. The most highly endemic area is the U.S.
Ohio and Mississippi River valleys. It is also endemic along the Appalachian Mountains and in North
Carolina and Virginia (173). Serosurveys have revealed that most adults in endemic areas have been
infected. There is a bimodal incidence of disseminated disease; about half of the cases occur in infants
and children younger than 3 years of age, and half occur in people older than 40 years of age. The male-
to-female ratio is approximately 5:1 among disseminated cases and patients with intracranial
histoplasmomas. The increased incidence in men is likely due to occupational exposures (200). No racial
predisposition is apparent.

Infection is established by inhalation of airborne spores. Once present in the lung, the infection may
hematogenously disseminate and establish a focus in the CNS. One case of probable postsurgical
inoculation has been reported (202). Of the reported cases of intracranial histoplasmoma, more than one
third have occurred in immunocompromised patients. CNS involvement in histoplasmosis, including
meningitis, is seen in up to 7.6% of all cases and in 24% of patients with disseminated disease (203). In a
histoplasmoma, giant cells and other inflammatory cells surround an area of necrosis, often caseous.
Histiocytes within the abscess contain H. capsulatum. After conidia settle in the alveoli and bind to the
CD11/CD18 family of integrins, they are taken up by neutrophils and macrophages (204) and transported
to local draining lymph nodes and ultimately reach organs of the reticuloendothelial system. The yeast
grows rapidly inside the resting macrophages. Macrophages are the principal effector cells in host
resistance to this fungus. Alkalinization of the phagolysosome is important in intracellular survival of this
yeast.
Histoplasmosis of the CNS presents as a chronic indolent meningitis, mass lesion, or cerebritis. Among
these, chronic meningitis is the most common. Dissemination of H. capsulatum infection is usually seen in
the immunosuppressed individual (205). All reported cases of CNS histoplasmoma have presented with
neurologic findings, including seizure, hemiparesis, altered mental status, and ataxia (200).
Histoplasmomas may be associated with meningitis but are often independently present. Constitutional
signs of disseminated histoplasmosis, including fever, weight loss, and malaise, are often present, which
when combined with a lesion seen on CT scan may mistakenly give the picture of metastatic carcinoma.
CSF pleocytosis is common in histoplasmoma, but not hypoglycorrhachia. Spinal cord histoplasmoma is
another even rarer presentation of CNS histoplasmosis (206).
Diagnosis
The only certain way to make the diagnosis is with biopsy. However, rapid diagnosis is often achieved by
antigen determination. The assay identifies a polysaccharide antigen in either urine or serum and can be
detected in the urine of approximately 75% of nonimmunocompromised and 95% of immunocompromised
patients (207). Isolation of H. capsulatum from the bone marrow, a lymph node, or an oropharyngeal
ulcer in an individual with evidence of a brain abscess should strongly suggest H. capsulatum as the
etiologic agent of the intracranial lesion. CT scan and MRI findings are not specific. Intracranial lesions
may show ring enhancement and surrounding edema indistinguishable from tumor. Antigen detection has
been applied to CSF samples in cases of meningitis, but its clinical use has not been established.
Treatment
Treatment for Histoplasma meningitis is difficult because of the poor penetration of most antifungal
agents into the CSF. For intracranial histoplasmosis, we suggest AmBisome (5 mg/kg daily for 4 to 6
weeks followed by itraconazole (400 to 600 mg orally daily) for at least 1 year; some recommend
lifelong oral therapy given the risk of relapse. Guidelines for the treatment of CNS histoplasmosis have
been published (208).
Coccidioides immitis
All isolates within the genus Coccidioides were formerly designated C. immitis. However, based on
DNA sequence analysis, two distinct species (C. immitis and C. posadasii) have been identified (209).
The spectrums of diseases caused by the two species are identical and laboratories do not routinely
identify the species. Coccidioides is found primarily in the southwestern United States (particularly
Arizona and the San Joaquin Valley) as well as Central and South America. It is found in soil and enters
the body through the respiratory tract, causing (in most patients) a self-limited respiratory illness. Rarely,
it may disseminate and infect other organ systems, including the CNS. One study reported scattered
parenchymal granulomas in 1 of 31 autopsied patients (210). In another study, 1 of 7 patients with AIDS
and disseminated disease had intracranial granulomas (211), but CNS coccidioidomycosis is still rare in
AIDS.
The diagnosis has been made only by recovering the organism from tissue. However, most cases are
presumptively diagnosed through identifying anticoccidioidal antibodies in the CSF. CT and MRI findings
are typical for abscess but are not specific for C. immitis. Treatment with an azole is recommended (212).
Given the potentially fatal risk of relapse, patients who respond to azole therapy should continue lifelong
treatment.
Paracoccidioides brasiliensis
CNS involvement by P. brasiliensis, also called South American blastomycosis, has been well
documented in South America (4). A prospective study of 173 cases of paracoccidioidomycosis in Brazil
found that 24 (13.9%) had CNS involvement (213).
Young adults and men are infected more frequently. Immunocompromised hosts are not clearly at higher
risk for dissemination. Reports of dissemination in patients with AIDS are appearing, but incidence rates
are comparable to those of the immunologically normal population. It was once held that the primary site
of infection was direct inoculation into the nasopharynx or oropharynx (4). However, current evidence
favors a more typical route of primary respiratory tract infection with potential dissemination (214).
Following inhalation, P. brasiliensis typically causes asymptomatic pulmonary infection. Dissemination
of infection to the reticuloendothelial system results in lymphadenopathy, hepatosplenomegaly, or bone
marrow dysfunction (215). Cases of intracranial abscess without evidence of other organ involvement
have been reported (214). P. brasiliensis can cause miliary granulomas throughout the meninges and brain
parenchyma. Arteritis may occur (214). Symptoms develop from basilar meningitis or according to the
anatomic location of the abscess (214). Headache, dizziness, fever, and other signs of increased
intracranial pressure may be present. Organisms are rarely seen or cultured from CSF or tissue. Several
serologic tests are available, including quantitative immunodiffusion, complement fixation, ELISA, and
counterimmunoelectrophoresis; cross reactivity with H. capsulatum has been observed (216). CT scan of
the head may show cystic lesions suggestive of an abscess.
For patient with CNS involvement, treatment with trimethoprim-sulfamethoxazole (TMP-SMX) or
amphotericin B (0.6 to 1.0 mg/kg daily) is suggested. Patients treated intravenously can be switched to an
oral agent once significant improvement in the clinical condition has been observed (217).
Sporothrix schenckii
Sporothrix schenckii, the causative agent of sporotrichosis, rarely causes intracranial disease (218). As
with many infections, co-infection with HIV predisposes to invasive, atypical, or disseminated
manifestations of sporotrichosis. A case series of 21 HIV-positive patients with culture-positive
sporotrichosis in Brazil revealed that the most frequent clinical presentations of sporotrichosis were the
lymphocutaneous and disseminated forms (7 patients each, 33%). In the disseminated forms,
manifestations involved the skin in 6, mucosa (nasal, oral, or conjunctival) in 4, bone in 2, and meninges
in 2 (219).
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PART VII ■ PROTOZOAL AND
HELMINTHIC INFECTIONS
CHAPTER 42 CEREBRAL MALARIA

DOUGLAS G. POSTELS AND TERRIE E. TAYLOR
Malaria is arguably the most important parasitic disease affecting mankind. Around the world,
approximately 3 billion people are at risk of malaria infection (Fig. 42.1). Annually, there are about 219
million cases and nearly 1 million deaths (1). The term “complicated malaria” includes several clinical
syndromes: cerebral malaria, severe anemia, respiratory distress/acidosis, and multiorgan system failure.
Patients with complicated malaria are at risk of dying from their disease, whereas those with
uncomplicated malaria generally recover. Cerebral malaria, a clinical syndrome defined as an otherwise
unexplained coma in a patient with malaria parasitemia, is responsible for the majority of the deaths from
malaria. Although African children and Asian adults are the most common demographic groups affected
by cerebral symptoms, 80% of cerebral malaria cases and 90% of deaths are in sub-Saharan Africa.
Universally fatal if untreated, with optimal care the mortality rate is 15% to 25%. Clinically, African
children with complicated malaria have a largely “cerebral” illness, with rapid onset of coma and
seizures. In addition to signs of central nervous system dysfunction, adult patients with complicated
malaria frequently have renal, hepatic, and respiratory failures. Within this chapter, the section on clinical
findings in pediatric patients with cerebral malaria expands on the neurologic, hematologic, and
metabolic abnormalities seen frequently in children. The section on clinical findings in adults with
cerebral malaria describes in depth the non–central nervous system organ dysfunction that is more
common in older patients. This dichotomy is not mutually exclusive. Adults, by definition, must have signs
of central nervous system dysfunction to be diagnosed with cerebral malaria. Infrequently, children
manifest concomitant non–central nervous system organ dysfunction. In both age groups, multiorgan
system involvement carries a poor prognosis.
Death rates in both children and adults with cerebral malaria are high, although the immediate cause of
death is more likely to be from non–central nervous system sources in adults compared to children. One
third of pediatric cerebral malaria survivors have neurologic sequelae (2,3). Epilepsy, cognitive
impairment, behavioral disorders, and neurologic deficits including motor, sensory, and language
impairments, are frequent sequelae in children but are thought to occur less often in adult cerebral malaria
survivors.
Due to its impact, efforts to decrease malaria disease burden continue. Preventing infection with
insecticide-impregnated bed nets and enhanced mosquito control are currently funded by both
governmental and nongovernmental organizations. Although malaria incidence and prevalence are
decreasing in some parts of the world, worldwide elimination remains a distant goal. Research on
malaria vaccines is ongoing, and studies to identify effective adjunctive therapy strategies for patients
with cerebral malaria continue. Reducing rates of death and neurologic disability due to cerebral malaria
will likely only succeed when the incidence of malaria infection is dramatically decreased and more
effective treatment strategies are developed.
EPIDEMIOLOGY
In areas like sub-Saharan Africa where malaria transmission occurs regularly and there is a predictable
incidence of illness and prevalence of infection, early infectious challenges produce repeated clinical
episodes of uncomplicated and complicated malaria, and malaria transmission is deemed “stable.” A
state of partial immunity (termed “premunition”) is quickly acquired in young children who survive their
earliest few infections. Individuals with partial immunity can be infected with malaria without becoming
symptomatic. Even if symptoms ensue, they are the fever, chills, and malaise associated with
uncomplicated malaria. Although premunition does not protect against the development of symptomatic
malarial disease, it does protect against its severe complications including cerebral malaria. Comatose
individuals with asymptomatic parasitemia complicate the clinical diagnosis of cerebral malaria (see
“Diagnosis” section).
In geographical contexts where transmission is low and varies from year to year (e.g., Asia), infectious
challenges in early life are less common, premunition develops slowly if at all, and patients with
asymptomatic parasitemia are rare. Adolescents and adults are more likely to be non-immune and are
therefore at greater risk of developing severe malarial disease, including cerebral malaria, if they are
infected.
In areas of high transmission, as the intensity of transmission drops, the burden of disease (including
severe disease) shifts to older age groups (4,5). At moderate intensities, the overall incidence of malaria
does not decrease dramatically, but the proportion of patients with cerebral symptoms rises. Therefore,
the risk (incidence rate in the population) of cerebral malaria may initially increase as the transmission
intensity decreases (4). In areas of low transmission intensity, clinical malaria becomes less common.
The proportion of total malaria patients with cerebral symptoms remains elevated (compared with areas
with high transmission), but the population risk of cerebral malaria falls (6).
This has significant public health implications. In Africa, current prevention strategies are focused on
the two population groups at highest risk of death: children younger than 5 years old and pregnant women.
When control programs (see “Prevention Strategies” section) are eventually successful in decreasing
transmission intensity, the burden of cerebral malaria will likely shift to older, currently untargeted age
groups (4). Before eventually falling, transient increases in mortality rates may be seen (7). Longitudinal
studies in coastal Kenya have shown that as transmission intensity falls (either naturally or through
intervention programs), the risk of cerebral malaria rises for approximately 10 years before eventually
decreasing (6).
Seasonality of transmission also influences the age of presentation of patients with severe symptoms
(5). If average annual intensity is held constant, geographic areas with marked seasonality to their
transmission patterns have a higher average age of cerebral malaria patients than areas with year-round
transmission. This is assumed to occur because those living in areas where exposure to the parasite is
restricted to only part of the year acquire partial immunity more slowly than those exposed year-round.
PATHOGENESIS
Although the clinical condition is termed “cerebral” malaria, the parasite itself does not enter the brain
parenchyma. Rather, several pathophysiologic processes likely interact in the cerebral vasculature or
systemically to induce coma and produce the frequent outcomes of death and neurologic disability.
Despite intense research, the pathogenesis of cerebral malaria remains incompletely understood. Most
hypotheses are based on tissue samples gathered at autopsy, but it is important to recognize that
mechanisms associated with coma may differ from those associated with death. The most important
feature is likely to be the element of the parasite life cycle that distinguishes Plasmodium falciparum (and
Plasmodium knowlesi, most recently) from the other three species infecting humans: sequestration of
parasitized erythrocytes in the body’s microvasculature, including in the brain. Although sequestration is
necessary, it is not sufficient to produce coma. Other pathophysiologic processes undoubtedly interact
locally to produce coma and other signs of neurologic impairment. The most important of these may be
cytokine abnormalities in the blood and abnormalities of the blood–brain barrier.
In fatal cases of cerebral malaria, the brain is typically swollen and discolored. A histologic hallmark
is cerebral vessels densely packed with parasitized erythrocytes. Fluorescein angiograms in retinal
vessels (see “Malarial Retinopathy” section later in this chapter) that are filled with parasitized
erythrocytes reveal impaired perfusion. It is likely that similarly affected areas of the brain are subjected
to hypoxia, local hypoglycemia, and inflammation.
Life Cycle
Although five Plasmodium species (falciparum, vivax, knowlesi, ovale, and malariae) can infect
humans, P. falciparum causes almost all cases of severe disease, including cerebral malaria. P. vivax and
P. knowlesi are uncommon causes of cerebral malaria, and most of these cases are identified in Asia. The
bite of the Anopheles mosquito transmits the parasite to the human host; sporozoites in the mosquito
salivary glands are inoculated into the host’s blood stream (Fig. 42.2). In minutes, these sporozoites
invade hepatocytes. A first cycle of asexual reproduction occurs in the liver over 11 to 12 days in P.
falciparum and P. vivax. The prepatent period (the time from sporozoite inoculation until erythrocyte-
stage parasites are detected in the blood) in P. knowlesi is unknown. Within the hepatocytes, the parasite
divides repeatedly, producing thousands of merozoites; the infected human is asymptomatic during this
phase of extraerythrocytic replication. Ultimately, infected hepatocytes asynchronously rupture, releasing
merozoites into the circulation. Circulating merozoites quickly infect red blood cells. Once inside the
erythrocyte, the parasite is freely mobile. This early erythrocyte stage is known as a “ring,” reflecting its
microscopic similarity to a signet ring. Hemoglobin degradation produces the amino acids used for
protein synthesis required for a second cycle of asexual reproduction. The potentially toxic heme moieties
are eventually incorporated into hemozoin (also called “malaria pigment”) that is visible approximately
halfway through the 48-hour cycle of intraerythrocytic asexual reproduction. Once pigment is visible, the
parasitized red cells are known as trophozoites.
In the erythrocyte, one infecting merozoite will generate 16 to 32 daughter merozoites. Once these are
visible, the red cell is called a schizont. Erythrocyte schizonts rupture, releasing daughter merozoites.
These circulate briefly before infecting new red cells. At the moment of schizont rupture, a number of
pyrogens are released. These are the source of the periodic fevers associated with malaria infection, but
because erythrocyte schizont rupture is rarely entirely synchronous, regular periodic temperature spikes
are not commonly observed.
Infected erythrocytes undergo substantial morphologic changes over the course of the 48-hour cycle of
erythrocyte asexual replication. Parasite-encoded proteins appear on the erythrocyte surface, and cell
membrane deformability decreases. P. falciparum–infected red cells avoid splenic clearance by using the
new parasite-encoded surface proteins to adhere to endothelial cells in capillaries and postcapillary
venules throughout the body. This phenomenon is termed “sequestration.” The hemodynamic and
inflammatory effects of sequestration are discussed in detail in the following section.
The life cycle is completed when, in response to a number of different stimuli, some parasites divert
from intraerythrocytic multiplication and become male or female gametocytes. When these gametocytes
are ingested by a female Anopheles seeking a blood meal, the sexual replication cycle ensues, beginning
in the insect’s midgut and culminating in its salivary glands.
Sequestration
Sequestration removes parasitized red blood cells from the circulating blood by erythrocyte–endothelial
interaction and adhesion. It is mediated by parasite-encoded proteins that are expressed on the red cell
surface with an affinity to ligands on endothelial cells.
Twelve to 15 hours after erythrocyte invasion, the red blood cell membrane develops numerous
knoblike projections studded with a parasite-encoded protein termed PfEMP1 (Plasmodium falciparum
erythrocyte membrane protein 1) (8). Key PfEMP1 proteins are encoded by var genes (9,10). There are
approximately 60 var genes per parasite genome, and their expression is controlled, at least in part,
epigenetically. Only one var variant is expressed at a time (11).
Host endothelial cell receptors for PfEMP1 include CD36 (12), ICAM-1 (13), VAR2CSA (in placenta)
(14,15), and EPCR (endothelial cell protein C receptor) (16). The interaction of infected red cells with
endothelial cells in capillaries and postcapillary venules may lead to microvascular obstruction (17) and
endothelial cell activation (18). When a sequestered erythrocyte schizont ruptures, locally released heme
and hemoglobin may deplete nitric oxide, further exacerbating endothelial cell dysfunction (19).
Sequestration occurs throughout the human body, and the most heavily parasitized organs include the gut,
brain, heart, lung, and subcutaneous fat. Sequestration is a feature of P. falciparum infection. P. knowlesi
infection can also lead to erythrocyte sequestration, but P. vivax–, P. ovale–, and P. malariae–infected
erythrocytes do not sequester (20,21).
Although attractive as an explanation for the coma in patients with cerebral malaria, sequestration
alone is not sufficient to produce a change in level of consciousness (22). The overall body burden of
parasitemia may be the primary determinant of disease. Histidine-rich protein 2 (HRP-2) is a parasite
protein released largely at the time of schizont rupture. Its qualitative detection is the basis of many
widely used malaria rapid diagnostic tests. It can also be measured quantitatively and may represent a
measure of total body parasite burden (23). Quantitative measures of HRP-2 reveal greater disease
severity in those with higher serum HRP-2 concentrations (24,25).
In fatal cerebral malaria cases, sequestration is histologically demonstrated by packing of both infected
and uninfected erythrocytes into cerebral blood vessels. Infected red cells lose their biconcavity, become
spherical, and are less deformable than those that are not parasitized. Sequestered red cells remain
adherent to vascular endothelium until they eventually rupture, disturbing laminar blood flow. Uninfected
erythrocytes must squeeze through narrowed vascular spaces leading to the formation of clumps of
infected and uninfected erythrocytes, termed “rosettes”. By reducing the velocity of blood flow through
cerebral vasculature, rosettes may worsen sequestration (26). Laminar blood flow may also be disrupted
by infected erythrocyte–platelet interactions, termed “platelet-mediated clumping.”
Inflammation
Levels of cytokines, soluble mediators of inflammation, are elevated in the blood of both children and
adults with severe malaria. However, studies assaying serum levels of specific cytokines have shown
mixed results. Concentrations of both proinflammatory cytokines (such as interleukin 6) and
antiinflammatory mediators (interleukin 10) may be elevated (27). Increased concentrations of other
known proinflammatory mediators (tumor necrosis factor-α [TNF-α] and interleukins 1, 8, and 12) have
not been consistently demonstrated in the serum of patients with cerebral malaria (28). Within the brain
parenchyma itself, the reality may be very different. Proinflammatory cytokines were found to be in higher
concentrations in the brains of children dying of cerebral malaria compared to controls (29). Locally
produced TNF-α has been postulated as a central mediator of the coma in cerebral malaria (30), with
origin from macrophages (recruited in response to sequestered or ruptured erythrocytes attached to
vascular endothelium) and from microglia within the brain parenchyma. It is unlikely that circulating
TNF-α is uniquely responsible for the coma in cerebral malaria. Studies of adjunctive anti–TNF-α
antibodies in children with cerebral malaria show a decrease in circulating levels of the cytokine but no
corresponding decrease in length of coma, compared to controls treated with standard antimalarials (28).
It has been hypothesized that cytokines act by upregulating inducible nitric oxide synthase (iNOS) in
brain endothelium, leading to increased local production of active nitric oxide. Locally produced nitric
oxide may diffuse into the parenchyma, disrupting normal neurotransmission (31,32). This hypothesis is
attractive because nitric oxide diffuses readily across the blood–brain barrier and rapidly and reversibly
interrupts consciousness. Studies correlating disease severity (usually death) and iNOS activity have been
mixed. Research on iNOS activity in children dying of cerebral malaria has shown that both increases
(33) and decreases (34) in enzyme activity increase the risk of death. Cytokine-iNOS interactions may be
important, and further research is necessary to elucidate upregulation or downregulation mechanisms and
how these influence depth of coma and mortality risk.
Increased Intracranial Pressure
In African children with cerebral malaria, cerebral edema and increased intracranial pressure are
common. This can be demonstrated radiographically (35) (Fig. 42.3) and on clinical examination by the
signs of papilledema and syndromes of central or uncal herniation. Children with cerebral malaria who
have papilledema have a relative risk of death 4.5 times higher than in children without this clinical
finding (36). In Asia, where cerebral malaria is more commonly a disease of adults, increased
intracranial pressure is infrequently documented either radiologically or clinically.
The underlying pathophysiology of the raised intracranial pressure is unclear. Neuropathologic studies
provide evidence of endothelial cell activation and blood–brain barrier breakdown (18). In fatal cases,
increased brain volume is common, and vasogenic edema as the result of blood–brain barrier breakdown
may be a contributor. Perivascular ring hemorrhages are present, especially in the cerebral white matter
and the gray and white matter of the cerebellum (Fig. 42.4). Over time, these resolve and are replaced by
Dürck granulomas with a central area of neuronal necrosis and surrounding reactive gliosis (37). The
sequestered erythrocyte mass itself may result in increased brain volume. If venous drainage were
impeded by parasite sequestration in capillaries and postcapillary venules, vascular congestion could
ensue, exacerbating other pathophysiologic processes contributing to coma and death.
Other potential contributors to increased intracranial pressure include cytotoxic edema, vascular
congestion, and hyperemia associated with the heightened brain metabolic demands due to fever, anemia,
convulsions, and hypoglycemia.
DIAGNOSIS
Clinical Diagnosis
Although the clinical case definition of cerebral malaria has high sensitivity, its specificity is low. This is
due to high community rates of asymptomatic parasitemia, especially in the geographic areas with high
transmission intensity where cerebral malaria is the most common. Asymptomatic carriage of malaria may
occur in up to half of the population (6). Therefore, patients who fall into coma due to an underlying
nonmalarial etiology (e.g., viral encephalitis, postinfectious conditions, or intoxication) but have an
incidental parasitemia will be misdiagnosed as having Plasmodium sp. as the cause of their acute illness
and coma. This false-positive rate is likely quite high. In one series, 23% of patients who fulfilled the
clinical case definition of cerebral malaria, died, and went to autopsy did not have sequestered
parasitized erythrocytes in cerebral vasculature (38). Fortunately, comatose parasitemic children with
malarial versus nonmalarial coma etiologies can be differentiated by the presence or absence of a
malarial retinopathy (39–41).
Malarial Retinopathy
In 1993, malarial retinopathy was described (41) and in subsequent years it has been well characterized
(39,40,42). The retina has three main abnormalities: whitening, changes in vessel color, and hemorrhages
(Fig. 42.5). The first two are unique to malaria. Retinal whitening is best seen around the macula or
peripherally and represents areas of impaired perfusion (43). Orange or white vessel segments
(predominantly venules) are areas of intravascular sequestration (44). Intraerythrocytic parasites digest
the host cell hemoglobin producing focal stretches of pale erythrocytes, creating vessel segments that
appear orange or white by ophthalmoscopy. Retinal hemorrhages are often white-centered and are similar
in appearance to those seen in other clinical conditions (e.g., hypertension, anoxia, HIV). However, in a
comatose parasitemic patient, they are considered evidence of malarial retinopathy. Hemorrhages are
usually between retinal layers but can extend to the preretinal space. Papilledema may also be present. As
an isolated finding, papilledema is not considered evidence of malarial retinopathy, but when seen in
conjunction with one or more of the other retinal findings, its presence worsens prognosis (45). Patients
with more severe malarial retinopathy have a higher risk of death (36). Interestingly, the plasma
concentration of HRP-2 (a putative marker of total body parasite burden) can distinguish children who are
retinopathy positive from those who lack malarial retinopathy (25).
Retinal angiography in children with malarial retinopathy has shown areas of central and peripheral
nonperfusion (46). In those who recover, sequential retinal angiograms demonstrate reperfusion in areas
previously without flow. Visual impairment is uncommon in retinopathy-positive cerebral malaria
survivors (36).
Retinal abnormalities can be detected by both indirect and direct ophthalmoscopy. Their presence is
95% sensitive and 90% specific in identifying those children who have histologic evidence of
sequestration of parasitized erythrocytes in cerebral vessels at autopsy (38) and meet the clinical
diagnostic criteria for cerebral malaria. Patients with clinically defined cerebral malaria who lack
malarial retinopathy are more likely to have a nonmalarial cause of coma. It is important in the
retinopathy-negative group to assiduously pursue other nonmalarial coma etiologies. Using a more
stringent clinical case definition that includes the presence or absence of malarial retinopathy (as detected
by an individual trained in its recognition) may improve clinical care as well as the efficiency of research
studies. Combining comatose parasitemic patients with pathologically confirmed cerebral malaria
(retinopathy positive) and those with other origins for their coma (retinopathy negative) in older research
may have led to nondifferential misclassification and significant underpowering of clinical studies.
Malarial retinopathy is less well characterized in adults. Retinal hemorrhages are seen in 15% of
patients and increase mortality risk (47). Vessel color changes are less common than in children. Studies
with good clinical–pathologic correlation are lacking.
Clinical Manifestations in Children
In endemic areas of sub-Saharan Africa, cerebral malaria is most common and severe in children between
ages 6 months and 5 years old (48). In geographic areas of high transmission intensity, severe malarial
complications (including cerebral malaria) are uncommon after age 10 years. The disease prodrome
consists of nonspecific signs and symptoms including fever, anorexia, cough, and vomiting, usually lasting
1 to 3 days. The child often rapidly falls into coma or has a seizure and does not awaken afterward.
Coma and Other Neurologic Findings

In pediatric patients, depth of coma can be measured by the Blantyre Coma Scale (BCS) (Table 42.1). A
BCS less than or equal to 2 is required for the clinical diagnosis of cerebral malaria. On examination,
brainstem dysfunction may be evident with pupillary abnormalities, absent corneal reflexes, and irregular
breathing patterns (49). Seizures, both clinical and subclinical, are common. Partial or generalized
seizures are present in 40% to 60% or patients (50). These may be subtle and extremely difficult to
detect, even by experienced examiners. Nystagmoid eye movements, conjugate eye deviation, breathing
abnormalities, and other autonomias may be ictal phenomena. Early identification and treatment of
seizures may improve rates of mortality and morbidity; clinical trials are ongoing to investigate this
possibility.
Without treatment, cerebral malaria is likely to be universally fatal. In successfully treated patients,
coma often resolves as rapidly as it appeared, often within 24 hours. Longer coma duration should alert
the clinician to the possibility of misdiagnosis, especially in care settings where determination of malarial
retinopathy status is not possible. Severe anemia, nonconvulsive seizures, metabolic derangements, and
concomitant bacterial infections are all treatable reasons for prolonged coma.
Non–Central Nervous System Abnormalities

Fever. Before coma onset, malarial fevers are generally associated with other systemic symptoms
(malaise, headache, abdominal pain, nausea, and vomiting). Fevers are often irregular and are commonly
followed by diaphoresis, often profound, and chills with shivering and shaking. As previously noted,
cyclical fevers with a regular periodicity are uncommon, most likely because the proximate cause of fever
(release of pyrogens at the time of schizont rupture) is the result of an asynchronous infection in most
human hosts.
Hematologic Abnormalities. Hemolysis is an inevitable outcome of malaria infection, but the anemia that
occurs is often out of proportion to the percentage of parasitized red cells in the circulating blood. This
may be explained, at least in part, by the fact that a substantial proportion of the infected red cell mass is
sequestered in the microvasculature, inaccessible by current diagnostic techniques. Uninfected red cells
also hemolyze during the course of malaria infection and are removed by accelerated splenic clearance,
but the underlying mechanisms remain unknown (51,52). Effective antimalarial treatment with full
resolution of peripheral parasitemia is a prerequisite for hematologic recovery. A brisk reticulocytosis is
generally observed 7 to 14 days after starting treatment.
Thrombocytopenia is often profound. Its presence may be useful in differentiating whether an acute
illness is malarial (53). Febrile nonmalarial illnesses in children rarely lead to thrombocytopenia.
Metabolic Disturbances. Hypoglycemia and acidosis are both independent predictors of poor outcome in
patients with cerebral malaria (54,55). When hypoglycemia is identified before treatment, it is generally
the result of impaired hepatic gluconeogenesis or increased tissue glucose consumption secondary to poor
perfusion as a result of erythrocyte sequestration in multiple organ systems. Point-of-care testing for
whole blood glucose is useful in managing patients with cerebral malaria to identify those with
hypoglycemia, as glucose levels may fall after treatment initiation. Pretreatment hypoglycemia is very
common (56), and if rapid assessment of glucose is unavailable, a pretreatment dose of 50% dextrose (1
mL/kg) should be presumptively administered to comatose individuals. Posttreatment hypoglycemia may
be the result of overly rapid infusions of intravenous quinine (see “Treatment” section) (57).
Impaired peripheral perfusion contributes to metabolic acidosis. Hypovolemia may also be present, but
fluid boluses should be used cautiously in African children with impaired perfusion but who are not in
shock (58,59).
Although acute respiratory distress syndrome (ARDS) and acute renal failure are not unknown in
pediatric patients with cerebral malaria, their incidence is much lower than in adults with cerebral
malaria. An elevated blood urea nitrogen is an independent risk factor for death in children with cerebral
malaria (60). Elevations may be due to prerenal azotemia, renal failure, or both.
Electroencephalographic Changes
Electroencephalography (EEG) is almost always abnormal in cerebral malaria. Early in disease,
generalized symmetrical or asymmetrical slowing is common (61). Focal slowing is also a common EEG
feature in pediatric patients. Clinical and subclinical seizures may be primary generalized but more often
are partial with or without secondary generalization. Status epilepticus (clinically manifest or
subclinical) occurs in up to 28% of patients (49). Acute seizures increase the risk for both mortality (50)
and long-term neurologic disability in survivors (62).
Radiologic Features
Constrained by a lack of resources on the continent, in Africa there have been few studies of
neuroimaging in children with cerebral malaria. Both referral and selection biases have likely hampered
an accurate description of the full range of neuroradiologic findings, with only the children who are the
least or most ill undergoing neuroimaging. Computed tomography (CT) images of retinopathy-positive
children with prolonged coma reveal supratentorial and infratentorial edema (63).
Recent descriptions of brain magnetic resonance imaging (MRI) findings in retinopathy-positive
children reveal increased brain volume and increased T2 signal and abnormal diffusion-weighted imaging
in both cortex and deep gray matter (35). White matter signal abnormalities are also common (Fig. 42.3).
Outcomes
With optimal medical care, the mortality rate in pediatric cerebral malaria is 15% to 25% (64). In
children, the case fatality rate of complicated malaria increases with young age and transmission intensity
(65).
Until somewhat recently, neurologic sequelae in children surviving cerebral malaria were thought to be
both transient and uncommon. Recent epidemiologic studies have revealed that both these descriptors are
likely incorrect. In African children, neurologic abnormalities in survivors are common. In cohort studies,
children surviving cerebral malaria had an approximately 60 fold higher odds of an adverse neurologic
outcome compared to unexposed controls (2,3). This high risk of poor outcome is true for both
retinopathy-positive (2) and negative (3) cerebral malaria survivors. Impairments involve several areas:
motor abnormalities, cognition, behavior, and epilepsy. These neurologic sequelae, some with delayed
onset after hospital discharge, may persist for years.
Major motor impairments are common, seen in almost 25% of survivors (2). Manifestations include
spasticity, ataxia, cortical blindness, and language difficulties. Cognitive impairments lie in four domains:
attention, memory, language, and executive function. They are present in approximately 11% of survivors
(2). Prevalence figures may be artificially low due to the relative unavailability of culturally appropriate
and validated testing instruments that have only recently been defined. Additionally, the paucity of
personnel trained to perform standardized testing (e.g., neuropsychologists) may have led to prevalence
underestimates. Epilepsy is usually localization related and may not become manifest until many months
after hospital discharge.
Clinical Findings in Adults
In geographic areas of lower transmission intensity such as South and Southeast Asia, cerebral malaria is
more common in adolescents and adults. In addition to epidemiologic differences, the condition differs
from that seen in younger children with respect to clinical presentation, radiographic abnormalities, and
prognosis. In most adults who develop cerebral malaria, initial symptoms include those of uncomplicated
malaria: malaise, headache, myalgias, anorexia, and fever. Other symptoms include backache, dizziness,
postural hypotension, dry cough, and gastrointestinal symptoms including vomiting and diarrhea.
Nonimmune adults appear severely ill with signs of shock. Commonly there is anemia, mild jaundice, and
moderate hepatosplenomegaly.
Compared to cerebral malaria in children, disease in adults is a multisystem disorder with a higher
incidence of non– central nervous system major organ dysfunction. Acute renal failure, severe jaundice,
pulmonary edema, and ARDS, rarely seen in children, are more common disease manifestations in adult
patients. As with children, adults with cerebral malaria should be managed in an intensive care unit or its
local equivalent. The majority of deaths occur within the first 48 hours after admission, underlying the
importance of intense, early medical care (66).
Coma and Other Neurologic Findings

In adults, coma usually develops after several days of fever and other nonspecific symptoms
indistinguishable from those of uncomplicated malaria. The prodrome may last up to 7 days before
gradual coma onset. In adults, the depth of coma is most commonly measured using the Glasgow Coma
Scale (Table 42.1). A score less than or equal to 9 is required for the diagnosis of cerebral malaria. As in
younger children, signs of both brainstem and cerebral hemisphere dysfunction are often present (67).
Generalized convulsions are more common than partial seizures. They are present in about 20% of
adult patients (67). Seizures may be a manifestation of primary central nervous system dysfunction or a
marker of other metabolic abnormalities including hypoglycemia or renal failure.
Non–Central Nervous System Abnormalities

Renal Disease. Malaria acute renal failure (MARF) is associated with adult cerebral malaria (68). It is a
common complication in those living in areas of low or unstable transmission but is rare in geographic
contexts where transmission is intense and nonseasonal. In Southeast Asia, the incidence in children is
approximately 5% (69), whereas estimates in adult patients range from 13% to 30% (70,71). Renal
failure is typically oliguric but is rarely anuric. It may be present on admission or develop after a latent
period during antimalarial treatment (72). The blood pressure remains within the normal range. If MARF
presents fulminantly, it is often associated with other end-organ dysfunction, especially hepatic.
Metabolic acidosis is often present, and the patient may be jaundiced and hypocoagulable. Urinalysis
reveals proteinuria without cells.
Patients who present subacutely with oliguria and a slow rise in serum creatinine have a better
prognosis than those presenting with fulminant renal failure. If untreated, the mortality rate is over 70%
(73), and most patients die of pulmonary edema. Using dialysis in conjunction with antimalarials
dramatically decreases mortality and renal morbidity rates. Indications for dialysis include electrolyte
abnormalities (particularly hyperkalemia), volume overload, or effusions in the pleura or pericardium.
Blackwater fever is the passage of dark (red, brown, or black) urine due to massive hemolysis. Acute
tubular necrosis or myoglobinuria may be present. The condition is usually transient, not associated with
renal impairment, needs no treatment, and resolves without sequelae. In severe cases, MARF may
develop. In Europeans and Asians resident in Africa in the first half of the twentieth century, the mortality
rate of blackwater fever was 20% to 30% (74). The reason for the change in prognosis over the last
hundred years is unknown.
Pulmonary. Patients with uncomplicated malaria may have a dry cough, tachypnea (secondary to pyrexia
and anemia), and mildly reduced pulmonary diffusion capacity, likely secondary to sequestration of
parasitized erythrocytes in the pulmonary vasculature. Mild interstitial and alveolar edema is common.
World Health Organization (WHO) clinical criteria for severe falciparum malaria include “respiratory
distress,” usually manifested by nasal flaring, intercostal retractions with inspiration, and deep
(Kussmaul) breathing. Respiratory distress may be a marker of respiratory compensation for metabolic
acidosis but is also seen with the common comorbidities of pneumonia, acute lung injury (ALI)/ARDS,
pulmonary edema, and severe anemia. Because metabolic acidosis is an independent risk factor for death
in patients with malaria, the surrogate clinical signs of respiratory distress and increased respiratory rate
can be used to identify patients at high risk for mortality. When metabolic acidosis cannot be measured
due to resource limitations, patients with respiratory distress should be treated with the highest levels of
intensive care available.
ALI/ARDS symptoms may be present at disease presentation or 48 to 72 hours after beginning
treatment when parasitemia is falling. Tachypnea is the usual first sign. Respiratory distress may start
abruptly and progress within hours, leading rapidly to death. Signs include tachypnea, sweating, cyanosis,
labored breathing, and frothy sputum. Examination reveals inspiratory crepitations and expiratory
wheezes.
Treatment for ALI/ARDS in patients both with and without cerebral malaria is mechanical ventilation.
Although mortality rates in severe malaria cases with ARDS who are not ventilated are extremely high
(80% to 100%), even with this therapeutic modality there is a threefold higher risk of mortality in adult
patients with cerebral malaria who develop ALI/ARDS, compared to those without pulmonary symptoms
(75).
Hepatic. The liver is often palpable in adults with cerebral malaria. Both transaminases and functional
tests of hepatic function (albumin, prothrombin time) may be abnormal. There is no specific therapy for
cerebral malaria–related hepatic dysfunction.
Metabolic Disturbances
Common electrolyte abnormalities include hyponatremia (a potential contributor to neurologic
dysfunction), hypocalcemia, and hypophosphatemia. The creatinine concentration will be increased if
there is renal dysfunction. An elevated creatine kinase concentration suggests rhabdomyolysis.
Abnormalities of bilirubin, albumin, and hepatic transaminases may indicate hepatic dysfunction. As in
children, the blood glucose concentration should be frequently monitored. Measurement of arterial blood
gases, pH, and serum bicarbonate will detect respiratory failure and metabolic acidosis.
Electroencephalographic Changes
In adults with cerebral malaria, clinical seizures are less common than in children (67). The EEG usually
reveals diffuse slowing (76), and no changes that modify prognosis have been described in the medical
literature.
Laboratory Features
Urine should be tested for blood and myoglobin. Microscopic examination may reveal evidence of
glomerulonephritis. Anemia and thrombocytopenia are common.
Radiologic Features
Systematic studies of neuroimaging in adult cerebral malaria have not been published. In published case
reports and case series, MRI abnormalities have included focal or diffuse signal changes in the centrum
semiovale (77), corpus callosum (78), thalamus (78), and insula (79). Central pontine myelinolysis and
cerebellar demyelination or infarction have been reported (80). One series revealed a high proportion of
patients with hemorrhagic infarctions of the thalamus (81) and suggested that a diagnosis of cerebral
malaria should be considered in any patient with this radiologic pattern who had recently traveled to a
malaria-endemic area. Likely all of these reports suffer from selection bias, with patients having the most
or least severe clinical courses being imaged.
Studies of small numbers of Indian adults have shown good correlation of abnormalities on CT scan,
depth of coma, and mortality (82). These findings have not been reproduced in Thailand (83).
Outcomes
Mortality in adults with cerebral malaria is 10% to 40% (84). Depth of coma and severity of metabolic
acidosis at hospital presentation are the most important independent risk factors for death (85). Others
include high circulating parasite densities, elevated serum bilirubin, and the proportion of total circulating
parasites that are pigmented (86). Compared to cinchona alkaloids, artemisinin derivatives decrease
death rates from all forms of malaria, including adult cerebral malaria (87) (see “Treatment” section).
The prevalence of neurologic sequelae following adult cerebral malaria is unclear. Cohort studies,
similar to those carried out in pediatric cerebral malaria survivors, have not been published for
adolescent or adult patients. Epilepsy and major cognitive and motor sequelae, seen so commonly in
pediatric survivors, are thought to be less common in adults (88). The prevalence of mild or moderate
cognitive abnormalities in adult cerebral malaria survivors is unknown, primarily due to a lack of long-
term follow-up studies (89). In one case series, neuropsychological testing performed 6 to 12 months after
disease recovery revealed higher rates of impairments in verbal learning and abstract reasoning in adult
cerebral malaria survivors compared to nonaffected community controls (90). In another case report,
abnormalities of verbal and visual recall memory tasks were present (89).
Acute disseminated encephalomyelitis (ADEM), Guillain-Barré syndrome (91), and delayed onset
cerebellar ataxia (92) are all postinfectious syndromes associated with malaria. A rare postmalaria
neurologic syndrome (PMNS) that develops in adults who have recovered from cerebral malaria has been
described (93,94). This postinfectious encephalopathy may present up to 60 days after recovery from
severe malarial disease. Manifestations include disorientation, inattention, tremor, psychosis, ataxia,
perseveration, and aphasia (94). Low-grade cerebrospinal fluid (CSF) lymphocytosis with an elevated
protein is common, and the EEG is diffusely slow, consistent with encephalopathy. MRI reveals
multifocal abnormal areas of T2 white matter hyperintensity (94), raising the possibility that PMNS is a
form of ADEM. The use of mefloquine during the acute malarial illness has been associated with the
development of PMNS (93). Therefore, after patients complete intravenous therapy for cerebral malaria
with artesunate or quinine, they should be switched to an artemisinin-based combination therapy (ACT)
which does not contain mefloquine (see “Treatment” section).
Mild PMNS lasts 2 to 14 days and does not require treatment. For more severe cases, case reports
suggest that corticosteroids may be beneficial (95). Due to the rarity of PMNS, controlled trials of
therapeutic interventions have not been performed. Delayed onset cerebellar ataxia is generally self-
limited and does not require treatment.
CEREBRAL MALARIA IN SPECIAL GROUPS

Cerebral Malaria During Pregnancy
Cerebral malaria is more common in pregnant women compared to those who are not pregnant. When
complicated malaria occurs in a pregnant woman, she is at higher risk of renal failure, hepatic failure,
hypoglycemia, hypotension, and death, compared to a woman who is not pregnant (96). Severe malaria is
more common in the second and third trimesters than earlier in pregnancy. In endemic areas, symptomatic
malaria infection is a significant contributor to maternal morbidity and mortality. Over one third of
maternal deaths during pregnancy and in the first 6 weeks after delivery have been attributed to malaria
(97). Malaria during pregnancy increases the risk of intrauterine growth retardation, fetal loss, and low
birth weight, presumed secondary to sequestration of erythrocytes in the placenta with resulting placental
insufficiency.
Optimally, antimalarial prophylaxis should be given throughout pregnancy to prevent both complicated
(including cerebral) and uncomplicated disease (see Prevention Strategies” section) (98). Intermittent
preventive treatment during pregnancy (IPTp), the administration of a curative dose of an antimalarial
(usually sulfadoxine-pyrimethamine) two to three times during pregnancy whether or not the woman is
infected, is used in high malaria transmission settings (99). Although IPTp improves fetal outcome, it has
not been proven to decrease a pregnant woman’s risk of developing cerebral malaria.
Non-falciparum Cerebral Malaria
In contrast to P. falciparum, P. vivax can invade only immature red cells, including reticulocytes, leading
to lower total body parasite burdens. This species has not demonstrated sequestration in vivo, but brain,
placenta and lung in vitro models demonstrate attachment of P. vivax–infected erythrocytes to tissue
antigens, albeit to a much lesser degree than is seen with P. falciparum (100). The two species may co-
infect, and when a patient with P. vivax is diagnosed with cerebral malaria, the infection is often
presumed to be mixed (101). Although case reports of isolated P. vivax infection (with concomitant
polymerase chain reaction testing for P. falciparum) reveal that this species can cause cerebral malaria
(102,103), coma as a manifestation of severe malaria is much less common with P. vivax compared to
infection with P. falciparum (103,104).
There is a single published report of a fatal case of P. knowlesi infection (20). The patient presented in
shock but was not initially comatose. Decreased level of consciousness ensued and the patient died.
Autopsy revealed sequestration of parasitized erythrocytes in brain, heart, and kidney.
TREATMENT
Once cerebral malaria is diagnosed, treatment should begin immediately. The mainstays of therapy
include supportive care, antimalarials, and early detection and treatment of complications. Patients should
be managed in the highest level of care available, preferably an intensive care unit.
Supportive Care and Management of Complications
General and Supportive Care

At presentation, serum glucose should be checked immediately and corrected as needed. Repeated
monitoring of glucose is necessary as hypoglycemia often recurs, particularly in those receiving cinchona
alkaloids (see “Antimalarials” section). Intravenous fluids are administered to correct hypovolemia or
shock and for maintenance therapy. Bolus intravenous fluids are not indicated for African children unless
they are hypotensive and at risk of imminent death from circulatory collapse (58). Antipyretics should be
administered, and repeated doses may be required throughout hospital admission.
Cerebral Malaria and Bacterial Co-Infection

If the patient is clinically able to undergo the procedure, lumbar puncture should be performed to rule out
bacterial meningitis. The opening pressure is often elevated in children but is more likely to be under
normal pressure in adults. In cerebral malaria, the CSF shows little cellular response. Elevated numbers
of white blood cells should alert the clinician to the possibility of concomitant bacterial meningitis (105).
In cerebral malaria the CSF-to-serum glucose ratio is normal. The protein concentration may be mildly
elevated, reaching as high as 150 mg/dL.
Patients fulfilling diagnostic criteria for cerebral malaria have a 7% risk of simultaneous bacteremia
(106), but adjunctive antibiotics do not decrease mortality risk.
Anemia
Anemia is a major cause of morbidity and mortality in sub-Saharan Africa, especially among children in
areas of high malaria transmission. A majority of these children already have mild to moderate anemia,
predisposing them to severe anemia (defined as a hemoglobin <5 g/dL or hematocrit/packed cell volume
[PCV] <15%) during acute malaria. Physical findings (pallor) should be confirmed by determination of
hemoglobin or hematocrit/PCV in whole blood. Children with severe anemia have a high risk of mortality
that extends beyond the period of hospitalization and are therefore often transfused (49). In children with
nonsevere anemia, the decision to transfuse becomes less straightforward. Although transfusion may
shorten hospital stay and lower the risk of mortality, it has potential risks including circulatory overload,
transfusion reactions, and infection with HIV and hepatitis. A Cochrane review that evaluated routine
blood transfusion for patients with malaria and hematocrits between 12% and 17% showed no significant
difference in the risk of death or adverse outcome between children who were transfused and those who
were not (107). The WHO recommends that red blood cell transfusion be administered only if anemia is
associated with incipient or established cardiac failure (1).
Seizures
Standard anticonvulsant regimens for cerebral malaria have not been developed. The agents used most
frequently (benzodiazepines, phenobarbital, phenytoin) reflect the drugs most commonly available in the
countries where malaria is endemic. Seizure treatment algorithms often begin with benzodiazepines, most
commonly diazepam, clonazepam, or lorazepam. All are rapidly acting, inexpensive, and may be
administered intravenously or rectally. Diazepam administered intravenously achieves therapeutic levels
within 5 minutes. Although there is significant pharmacokinetic variability with rectal diazepam
administration, this route is crucial in low-resource settings where intravenous access is often not
feasible (108). Benzodiazepines are associated with cardiorespiratory depression (especially when
combined with barbiturates such as phenobarbital), and repetitive administration or continuous infusions
are inadvisable without inotropic or ventilator support. For patients with acute seizures refractory to
benzodiazepines or in whom a maintenance anticonvulsant is required, intravenous phenobarbital or
phenytoin are most commonly used in resource-limited settings. Phenytoin cannot be given
intramuscularly due to the high risk of muscle necrosis and erratic absorption.
Active surveillance for seizures is warranted due to the high rates of both clinical and subclinical
seizures in patients with cerebral malaria. If EEG is available, continuous monitoring is ideal. Even if
this is not feasible, periodic EEG recordings should be performed even in those without clinical seizures.
Obviously, in health care settings without EEG availability, subclinical seizures may go undetected and
untreated.
Because seizures are commonly present in affected African children, use of prophylactic adjunctive
anticonvulsants has been considered. A placebo-controlled study of a single intramuscular dose of
phenobarbital (20 mg/kg) given at the time of diagnosis of cerebral malaria showed a higher mortality
rate in the active treatment arm (109). In a separate study, fosphenytoin or phenytoin administered to
achieve standard anticonvulsant blood levels were not effective in decreasing seizure frequency in
pediatric cerebral malaria (110). A clinical trial of enteral levetiracetam as adjunctive therapy in
pediatric cerebral malaria is ongoing.
Antimalarials
After diagnosis, antimalarial therapy must begin rapidly. Currently, the two most common classes of
antimalarials used are cinchona alkaloids (quinine or quinidine) and derivatives of artemisinin
(artesunate, artemether, etc.) (Table 42.2). With both drug classes, a parenteral loading dose should be
given. Parenteral antimalarial agents should be administered for a minimum of 24 hours, even if the
patient can tolerate oral therapy earlier.
Quinine and quinidine are cinchona alkaloids derived from the bark of the cinchona tree indigenous to
the Andes. The bark was introduced into Europe as a fever cure in the seventeenth century. Cinchona
alkaloids act only on later stages of parasite development. Even though they have more side effects than
artemisinin derivatives, they are still used in many countries as the antimalarial of choice or necessity.
Quinine is available orally, but both quinine and quinidine can be administered parenterally.
Hypoglycemia is common with either agent as both increase endogenous insulin secretion. Because
quinidine may cause cardiac dysrhythmias, patients should have continuous electrocardiographic
monitoring during infusions.
Artemisinin and its related pharmacologically active compounds (artesunate, artemether,
dihydroartesunate) are derived from wormwood, used for centuries in China as therapy for fever. In the
1970s, the active compound was identified. These drugs kill parasites in all stages of their life cycle.
With activity during a wider spectrum of the parasite life cycle, artemisinins clear parasites more rapidly
than cinchona alkaloids. Unfortunately, when used as monotherapy or in subtherapeutic doses, the short
half-life artemisinin compounds may induce the emergence of drug resistance, demonstrated by delayed
parasite clearance after drug administration (111). This was first seen on the Thai–Cambodian border but
has now been detected in Cambodia, Myanmar, Vietnam, and Thailand (1). Therefore, in order to thwart
the development of resistance, oral artemisinin derivatives should be combined with longer acting partner
drugs. The most frequent combinations are with mefloquine, amodiaquine, or lume fantrine. These ACTs
are now the treatment of choice for all forms of malaria (87,112). This policy has been endorsed by the
WHO (1). In mid-2010, intravenous artesunate was U.S. Food and Drug Administration (FDA) approved
and is now available through the Centers for Disease Control and Prevention (113).
Artemisinin derivatives are generally thought to be superior to cinchona alkaloids for the treatment of
severe malaria and many experts suggest they should be preferentially administered when available (87).
A study of artesunate versus quinine in African children with severe malaria (including but not confined to
cerebral malaria) showed a significant decrease in mortality in those treated with artesunate (112). A
Cochrane review comparing artesunate with quinine therapy in Asian adults with cerebral malaria found
significant improvements in mortality in those treated with artesunate (114). Rates of abnormal neurologic
outcome were unaffected by choice of treatment.
Intravenous antimalarials are given as single agents for 24 hours or until patients regain consciousness,
whichever is more; treatment is then completed with a full course (usually 3 days) of an ACT.
When a pregnant woman develops cerebral malaria, she should be treated with artemisinin compounds
at full dose. After consciousness returns, a full course of artemether-lumefantrine or atovaquone-proguanil
is indicated. Antimalarial treatment failure is more likely in women who are pregnant compared to those
who are not (115).
The initial intravenous antimalarial treatment of P. vivax, P. knowlesi, and P. falciparum severe
malarias is identical (116). When a patient with P. vivax cerebral malaria has retained consciousness and
an ACT is chosen, artesunate + sulfadoxine–pyrimethamine is less effective than other choices.
Primaquine should be given to all patients to prevent relapse, although it is contraindicated in pregnancy
or in those with known severe variants of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Adjuvant Therapies
In an effort to improve mortality rates and decrease abnormal neurologic outcomes, a number of agents
have been studied as adjuncts to standard antimalarials. Adjuncts have been chosen on the basis of
disease pathophysiology or to preemptively treat common complications of the condition. Thus far, there
have been no adjunctive therapy trials that have resulted in decreased rates of mortality or morbidity in
survivors. Medications tested include corticosteroids, osmotic diuretics, iron chelators, N-acetylcysteine
(which increases deformability of malaria-infected erythrocytes in vitro), exchange transfusion,
pentoxifylline (an anti–TNF-α agent), anti–TNF-α monoclonal antibodies, agents that induce macrophage-
mediated phagocytosis of P. falciparum, cyclosporine A, and low-molecular-weight dextran (117).
Neither anticoagulation with heparin nor antiplatelet therapy with aspirin is indicated (118). It is likely
that due to the imprecision of clinically case-defined cerebral malaria, many of these studies were
underpowered. In addition, many studies had design flaws, making conclusions drawn from their results
problematic (119).
PREVENTION STRATEGIES
Primary prevention strategies have lain in three main areas: bed nets, chemoprophylaxis, and vaccine
development.
Bed Nets
Currently, insecticide-treated bed nets are the most widely used prevention strategy for those living in
malaria-endemic areas. Anopheles mosquitoes usually bite outside and at night. Remaining indoors or
under a bed net at these times decreases malaria risk. Insecticide-impregnated nets are superior to
unimpregnated ones. Even with intermittent washing, impregnated nets provide protection for about 1 year
(120). The WHO estimates that 53% of all households in sub-Saharan Africa have a bed net and that 33%
of the population sleeps under them (1).
Chemoprophylaxis
Chemoprophylaxis is indicated in special population groups in areas of high transmission, particularly

pregnant women and children. Intermittent preventive therapy (IPT) is a strategy where antimalarial
therapy is given at regular intervals independent of the presence of parasitemia.
Chemoprophylaxis with sulfadoxine-pyrimethamine should be administered to all pregnant women
living in malaria-endemic areas throughout gestation. This improves rates of fetal loss (98) but not low
birth weight (121). Strategies for use of IPTp include provision of antimalarials to all pregnant women at
regular intervals (during standard prenatal visits) or only to those with asymptomatic parasitemia (99).
The WHO currently recommends IPTp at each scheduled prenatal visit after the first trimester (1).
Intermittent preventive therapy in infants (IPTi) usually involves doses of sulfadoxine-pyrimethamine at
routine intervals determined by immunization schedules. In a metaanalysis of six trials of IPTi using
sulfadoxine-pyrimethamine, the intervention decreased malaria episodes by 30%, anemia by 21%,
malaria hospital admissions by 38%, and overall hospital admissions by 23% (122). However, a
randomized clinical trial of IPTi using survival as an outcome showed no benefit (123). The WHO
currently recommends IPTi for infants in moderate-to-high transmission areas where resistance to
sulfadoxine-pyrimethamine is low (1). IPT can also be extended beyond infancy to childhood (intermittent
preventive therapy in children [IPTc]). IPTc regimens are currently only recommended in areas where
transmission is highly seasonal. Children are administered oral antimalarials every month or every other
month for the duration of the malaria transmission season. In a metaanalysis combining seven randomized
controlled trials of this strategy, IPTc (now called seasonal malaria chemoprevention or SMC) prevented
74% of clinical malaria episodes (124). Although there was a trend toward a decrease in mortality among
the group receiving SMC, study power was insufficient to reach statistical significance. At this time, the
WHO recommends SMC for children aged 3 to 59 months living in areas where disease transmission is
intense but seasonal (1). Although drug resistance is a concern, a logistic impediment lies in the lack of a
structured setting for delivery because medications would be administered outside the standard vaccine
schedule. Single time point mass treatment of entire populations at risk has been attempted with little
success (125).
Vaccine
The search for a completely effective malaria vaccine has so far been unsuccessful, although intense
efforts continue. There are over 25 distinct antigens and vaccine formulations that have progressed to
phase I evaluation (126). The candidate furthest along the developmental pathway is RTS,S/AS01. The
antigenic target is the CSP (chimeric circumsporozoite protein) expressed on sporozoites. Phase II trials
showed a 38% efficacy against severe disease. A large multicentered phase III trial is underway, and
early results show a 50% reduction in clinical malaria episodes in the vaccinated group (127). Although
these levels of protection would not be acceptable with many other pathogens, this is a significant
accomplishment and could serve as one element in a multipronged malaria control approach. Other
possible avenues for improvement in vaccine efficacy include a multiantigen vaccine, prime/boost
delivery, and exploration of new adjuvants (128). A vaccine against P. vivax is in earlier stages of
development. If a state of premunition can be induced in young children, the incidence rate of cerebral
malaria in vaccine recipients may fall.
CONCLUSIONS
Malaria continues to be a major cause of mortality and morbidity in endemic countries, and cerebral
malaria is one of the most dreaded complications of infection. Despite intensive research into disease
pathophysiology, mortality and morbidity rates remain high. Adjuvant interventions to modify parasitized
erythrocyte sequestration, cytokine abnormalities, and changes in blood–brain barrier permeability have
thus far yielded negative results. Nevertheless, clinical trials targeting these processes and their clinical
consequences should continue, hopefully with designs of adequate study power to ascertain treatment
effects.
Physical and cognitive rehabilitation of cerebral malaria survivors is in its infancy, but resources for
such care are becoming increasingly available in the areas where malaria is most prevalent. The
development of prevention strategies, especially the wide distribution of bed nets and an effective
malaria vaccine, may also be important to decrease rates of mortality and morbidity from this common
condition.
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CHAPTER 43 TOXOPLASMA GONDII AND
TOXOPLASMOSIS
JOSE G. MONTOYA
Toxoplasma gondii is an intracellular parasite of worldwide distribution infecting one third of the human
population (1). The parasite has a notable tropism for the central nervous system (CNS) and maintains a
highly clonal population structure in nature (2,3). Based on genotyping studies of mostly European and
American strains, three main clonal lineages have been reported in animals and humans (types I, II, and
III) (4–8). A fourth clonal lineage (type IV) has been recently proposed to circulate in the United States
(9). In addition, atypical strains that do not fall in these four categories have also been reported as
capable of causing disease in humans (10).
Type III strains are common in animals, whereas types I, II, or atypical strains are more commonly
linked to human toxoplasmosis. Type II strains are more often associated with lower virulence in animal
models of toxoplasmosis and less aggressive clinical manifestations in humans, whereas types I, III, and
atypical strains are more often associated with worse outcomes in animal and human infections (11).
In Europe, mostly type II strains are observed, whereas in South America, type II strains are rarely
found and atypical strains (in addition to type I and III) tend to predominate. In South America, infection
with atypical strains has been associated with eye, pulmonary, and CNS infections in immunocompetent
individuals (12,13). In North America, types II, I/III, IV, and atypical strains have been reported. In North
America, atypical strains have also been associated with more severe ocular and congenital disease
(10,14).
The infectious forms of T. gondii include the tachyzoite, the tissue cyst (containing bradyzoites), and the
oocyst (containing sporozoites). The definitive host belongs to the Felidae family (e.g., cats); humans and
other animals are only intermediate hosts (15). Humans can acquire the parasite by the oral route (e.g.,
ingesting food or water containing tissue cysts or oocysts), vertical transmission (i.e., tachyzoites from the
acutely infected mother traversing the placenta), organ transplantation (i.e., tissue cysts contained in the
allograft from an infected donor), or laboratory accident (e.g., in an experimental setting dealing with
tachyzoites, tissue cysts, or oocysts) (16).
The tachyzoite is semilunar in shape, measures 2 to 3 µm wide and 5 to 7 µm long, and is responsible
for the clinical manifestations observed in patients with toxoplasmosis during primary infection or
reactivation (15,17). The tissue cyst measures up to 100 µm in diameter; it is responsible for the chronic
infection (i.e., establishes latency in organs such as the brain, eye, heart, skeletal muscle, liver, and
kidney) and for transmission via the ingestion of undercooked meat (17). Bradyzoites, crescent in shape
and usually measuring 7 by 1.5 µm, can reactivate with the advent of significant immunosuppression and
cause significant morbidity and mortality as they are transformed into tachyzoites (17). Oocysts are shed
in soil and water by felids, measure 10 to 12 µm in diameter in the unsporulated form, and are
responsible for the transmission to patients via inadvertent oral ingestion of infected cat feces;
contaminated water, vegetables, or food; and contact with contaminated soil, for example, while
gardening (17,18). Novel routes of transmission to humans have been recently described in the United
States such as ingestion of raw shellfish (including oysters, mussels, and clams) (19). Transmission does
not occur by direct contact with an infected person. Airborne transmission is unlikely (17).
EPIDEMIOLOGY
Acute infection can be asymptomatic and has been documented in individuals without history of
conventional epidemiologic risk factors for acute toxoplasmosis (e.g., cat ownership or consumption of
undercooked meat). Clinicians should not exclude the possibility of toxoplasmosis in patients who do not
recall symptoms associated with acute infection or in patients who do not own cats or eat undercooked
meat. Up to 50% of infected individuals do not have an epidemiologic history consistent with exposure to
the parasite. Moreover, in addition to ingestion of undercooked meat containing tissue cysts, food or
untreated water may be contaminated with oocysts (18).
Although primary infection is asymptomatic in most individuals, symptomatic patients with the acute
infection can present with the following symptoms or syndromes, alone or in various combinations: fever,
lymphadenopathy, headache, myalgias, arthralgias, sore throat, stiff neck, nausea, diarrhea, abdominal
pain, anorexia, skin rash, confusion, earache, eye pain, general malaise, fatigue, chorioretinitis, hepatitis,
myositis, or myocarditis. Disseminated disease, pneumonia, and even death have been observed in
immunocompetent individuals infected with T. gondii in Latin America (12,13,20).
Following acute infection, a well-orchestrated immune response will transform the primary infection
into a chronic (or latent) stage that lasts for the life of the host. Chronic infection with T. gondii in
immunocompetent individuals has been traditionally viewed as asymptomatic. However, several
investigators have suggested that chronic infection may be associated with a higher frequency of
behavioral changes, traffic accidents, suicide, schizophrenia, or bipolar disorder (21,22). Significant T-
cell–mediated immunodeficiency as observed in patients with AIDS, organ transplants, or those taking
certain immunosuppressive drugs can result in clinically significant reactivation of the parasite in the
CNS, eye, lungs, peripheral blood, heart, and skeletal muscle of chronically infected patients. The
parasite can also cause significant disease in these patients when a seronegative transplant candidate
acquires infection through the oral route or via the transplanted allograft (23).
Prevalence of chronic infection increases with age and varies highly between geographic locales and
even within subpopulations of the same locale (24). The overall age-adjusted seroprevalence in the
United States has been reported at 10%, but it may be as high as 30% in the Northeast region and higher
among certain ethnic groups (25). In France, the estimated seroprevalence is 44%, whereas in South
America and Africa, it can vary widely from 10% to 80% (26). It is important for each community to
perform their own studies on the seroprevalence of the parasite because local climate, geographic factors,
and hygienic and alimentary habits uniquely influence these rates.
The development of toxoplasmic encephalitis (TE) in immunocompromised patients depends on the
prevalence of the infection in the general population, degree of immunosuppression, and genetics of host
and parasite. Patients with hematopoietic stem cell, bone marrow, or cord blood transplants; with AIDS;
or those receiving immunosuppressive drugs affecting cell-mediated immunity develop TE by reactivation
of their latent infection. In contrast, solid organ transplants can develop TE through the transplanted organ
when a seronegative recipient (R−) receives an organ from a seropositive donor (D+). However,
seropositive (R+) solid organ recipients can also reactivate their latent infection under
immunosuppression. Of note, in recent reports, patients with chronic lymphoproliferative disorders or
taking immunosuppressive drugs affecting B-cell–mediated immunity have also been found at risk for TE
by reactivation of their latent infection (27,28). The risk of developing TE by reactivation appears to be
also influenced by the genetics of the host and parasite. Studies in mice suggesting that genetic factors in
the host contribute to the development and severity of TE (29–31) and the fact that not all HIV-infected
patients with positive T. gondii serologic findings develop TE suggested the possibility that genetic
factors may also play a role in the vulnerability of immunosuppressed patients to develop CNS
toxoplasmosis (32). The major histocompatibility complex (MHC) class II gene DQ3 (HLA-DQ3) has
been significantly associated with the development of TE in North American Caucasian AIDS patients,
whereas HLA-DQ1 was found to be marginally protective (32). HLA-DQ3 has also been significantly
associated with the development of hydrocephalus in children with congenital toxoplasmosis (33). As
noted earlier, parasite genetics appear to be an additional factor to predispose for TE because infection
with atypical strains in South America has been associated with CNS infections in immunocompetent
individuals (12,13).
Early studies indicated that 20% to 47% of T. gondii–seropositive AIDS patients ultimately developed
TE in the absence of appropriate antitoxoplasma prophylaxis and highly active antiretroviral therapy (34).
Following the introduction of effective antitoxoplasma prophylaxis and anti-HIV treatments, the risk of
toxoplasmosis significantly decreased. The incidence in the United States of AIDS-associated TE
declined from 2.1 per 100 person-years (PY) in 1992 to 0.7 per 100 PY in 1997 (35). However, TE
remains as the most common cause of space-occupying brain lesions in HIV-infected patients whose CD4
counts are less than 200 cells/mm3 and are not taking effective antitoxoplasma prophylaxis and
antiretroviral therapy (36). TE has been reported as an AIDS-presenting illness in patients who were not
aware of their diagnosis of HIV infection (37).
Rarely, TE can occur among HIV-infected patients with CD4+ counts more than 200 cells/mm3 without
brain-occupying lesions (i.e., diffuse encephalitis) or in seronegative patients. Brain biopsy or
amplification of T. gondii DNA in cerebrospinal fluid (CSF) by the polymerase chain reaction (PCR)
should be attempted in these patients in order to confirm the diagnosis of TE. If the diagnosis is confirmed
among seronegative patients, they were likely recently infected by oral ingestion, reactivated their latent
infection but were unable to produce detectable Toxoplasma antibodies, or were tested with serologic
assays with low analytical sensitivity.
TE in immunocompetent individuals is rare but has been documented in the literature, and it is probably
an underrecognized entity in these patients (38,39). In tropical areas of South America, life-threatening
toxoplasmosis in immunocompetent patients has been associated with atypical strains of the parasite
(13,40). TE should be included in the differential diagnosis of travelers returning from these areas and
presenting with encephalitis of unknown etiology.
The CNS is one of the prominent sites of infection in infants congenitally infected with T. gondii. The
parasite can cause severe TE (including hydrocephalus, brain parenchymal lesions, and calcifications)
and chorioretinitis in infected infants. Congenital TE is rarely observed in countries (e.g., France) where
infants are born to mothers who are screened and receive treatment for toxoplasmosis during gestation
(41). In contrast, TE is relatively frequent in infected infants born to mothers who do not receive this
benefit. In a recent study from the United States, severe TE was diagnosed in congenitally infected infants
whose mothers had not received antitoxoplasma treatment during gestation. Brain calcifications were seen
in 94 (79.6%) of 118 and hydrocephalus was present in 67 (67.7%) of 99 infected infants who have been
referred to a national reference laboratory for laboratory confirmation of their diagnosis of congenital
toxoplasmosis (42).
Reactivation in Immunosuppressed Patients
Toxoplasmosis should be suspected in any immunocompromised patient with encephalitis (with or
without focal brain lesions), seizures, pneumonia, chorioretinitis, fever of unknown origin, myocarditis,
polymyositis, or hepatitis because several major hospitals have encountered patients who died of
disseminated toxoplasmosis that was only diagnosed at autopsy (43–53). The CNS is often recognized as
the only and most common site for reactivation of toxoplasmosis in immunocompromised patients.
However, other organs can be concomitantly involved, including lungs, eye, heart, and adrenal glands.
Moreover, reactivation in these patients can also occur in extraneural sites in the absence of TE or
manifested only as fever of unknown origin. Multiple areas of the brain are usually affected, but there is a
preference of the parasite for the gray matter on histologic examination and for the basal ganglia in brain
imaging studies. TE has a wide spectrum of clinical manifestations, including alteration of mental status,
seizures, motor weakness, sensory abnormalities, cerebellar dysfunction, meningismus, movement
disorders, and neuropsychiatric manifestations. The typical presentation is subacute onset of focal
neurologic abnormalities seen in 58% to 89% of patients (54–57). It should be noted that patients with or
without brain space-occupying lesions may have nonfocal exams. In fact, altered mental status, manifested
by confusion, lethargy, delusional behavior, frank psychosis, global cognitive impairment, anomia, or
coma, may be present initially in as many as 60% of patients (54,56,58). Seizures are the reason for
seeking medical attention in approximately one third of AIDS patients with TE (54,56,58,59). Focal
neurologic deficits are evident on neurologic examination in approximately 60% of patients
(54,56,58,59). Hemiparesis is the most common focal neurologic finding. Additional focal findings
include visual field loss, cranial nerve palsies, aphasia, ataxia, dysmetria, hemichorea-hemiballismus,
tremor, parkinsonism, akathisia, or focal dystonia. In addition, involvement of the spinal cord with T.
gondii has been described with cases of transverse myelitis and conus medullaris syndrome (60).
Ventriculitis accompanied by hydrocephalus may also be seen (61).
A diffuse form of encephalitis, without space-occupying lesions in imaging studies, usually with a
rapidly fatal clinical course, has been reported (62,63). Although rare, T. gondii should always be
entertained as a possible etiologic agent in any patient with unexplained encephalitis or
meningoencephalitis, with or without space-occupying lesions in brain (64).
Extracerebral sites of Toxoplasma reactivation in immunocompromised patients can cause significant
morbidity and mortality and present with (40%) or without (60%) concomitant TE (65). TE must be ruled
out by brain imaging studies even in the absence of obvious CNS symptoms in any immunocompromised
patient with extracerebral toxoplasmosis. The prevalence of extracerebral toxoplasmosis in AIDS
patients has been estimated at 1.5% to 2.0% and usually occurs when their CD4 counts of less than 100
cells/mm3 (mean: 57 cells/mm3) (65). Among patients with extracerebral toxoplasmosis, the sites of
involvement include the eyes (50% of patients); lung (26%); disseminated (at least two extracerebral
visceral sites) (11.5%); peripheral blood (acute febrile syndrome with isolated positive parasitemia)
(3%); heart (3%); bone marrow (3%); bladder (1%); and isolated cases of rhinopharynx, skin, liver,
lymph nodes, conus medullaris, and pericardium (65). In addition, skeletal muscle and pancreatic
involvement were always associated with other extracerebral toxoplasmosis sites (65). Toxoplasmosis
can occasionally present as septic shock in patients with TE, with or without involvement of
extracerebral sites (66). Toxoplasmic pneumonitis is greatly underdiagnosed because clinicians do not
readily consider T. gondii among the etiologic agents of pneumonia. The most common clinical syndrome
of toxoplasmic pneumonia is prolonged febrile illness with cough, hypoxemia, and dyspnea that is
clinically indistinguishable from Pneumocystis jiroveci pneumonia (PCP) infection. Like PCP,
toxoplasmic pneumonia most often results in bilateral ground glass opacities on chest computed
tomography (CT) (no contrast is required) and can result in acute respiratory distress syndrome (67).
Toxoplasma reactivation in immunosuppressed patients can also manifest as fever and sepsis-like
syndrome with hypotension, disseminated intravascular coagulation, elevated lactate dehydrogenase, and
pulmonary infiltrates. This syndrome may not be associated with clinical or radiologic evidence of TE
(66).
Toxoplasmic chorioretinitis occurs relatively infrequently in AIDS patients (when compared with the
incidence of cytomegalovirus retinitis) (68). Floaters and loss of visual acuity are common complaints
and may be accompanied by ocular pain. In AIDS patients, funduscopic examination typically reveals
findings consistent with necrotizing retinochoroiditis. The lesions are yellow-white areas of retinitis with
fluffy borders; ocular lesions are usually located away from areas of preexisting scars. Vitreal
inflammation may vary from mild localized vitreal haze to severe vitreous inflammation. Vasculitis and
hemorrhage are uncommon. These findings suggest that the pathogenesis of these lesions may be
secondary to hematogenous seeding rather than local reactivation of previous foci of infection in the
retina. The presence of concurrent TE in AIDS patients with ocular toxoplasmosis has varied from 29%
to 63% (68). Features of toxoplasmic retinochoroiditis commonly observed in the immunocompetent host
(e.g., areas of inflammation stemming from brown-greenish scars with a light in the fog appearance) may
be absent in patients with AIDS.
Primary Infection in Immunocompetent Patients
Symptoms and signs suggestive of encephalitis, meningoencephalitis, or focal brain lesions have been
reported in immunocompetent individuals with TE (13,38–40). Severe headache, neck pain, and
meningismus are common complaints.
Congenital Disease
Vertical transmission can occur in pregnant women who acquire primary Toxoplasma infection during
gestation or in severely immunosuppressed women who reactivate chronic Toxoplasma infection during
gestation (e.g., pregnant women with AIDS who develop TE). It has also been described in women who
acquire the infection shortly before conception (e.g., within 3 months of initiation of pregnancy).
The CNS is one of the main sites of infection in congenital toxoplasmosis. Clinical manifestations of
CNS involvement by T. gondii in the fetus include hydrocephalus and brain calcifications. Clinical
manifestations in the infant include chorioretinitis, strabismus, blindness, seizures, encephalitis, abnormal
cephalic perimeter (microcephaly or hydrocephalus), and psychomotor or mental retardation. Intracranial
calcifications or hydrocephalus are visible on brain imaging studies. Children can continue suffering the
chronic sequelae of the congenital disease. However, children and adults may become symptomatic for
the first time during this phase of their lives, primarily in the form of reactivation of the congenitally
acquired chorioretinitis.
DIAGNOSIS
At present, the definitive diagnosis of TE can be accomplished by (a) amplification of T. gondii DNA
from CSF (e.g., PCR), (b) visualization of the tachyzoite form in CSF or CNS tissue (e.g., Wright-Giemsa
or hematoxylin-eosin stains), (c) visualization of tissue cysts surrounded by inflammatory cells in CNS
tissue, or (d) isolation of the parasite from CSF. Toxoplasma IgG and IgM testing in CSF is not useful and
should be abandoned as a diagnostic aid. If CSF is available in limited amount (as it is usually the case),
PCR is the preferred diagnostic method. Other diagnostic aids used toward supporting the diagnosis of
TE include detection of Toxoplasma-specific immunoglobulins (typically immunoglobulin [Ig] G and
IgM) in serum, brain imaging studies, response to Toxoplasma-specific empiric treatment (e.g.,
pyrimethamine/sulfadiazine/folinic acid), and isolation of the parasite from body fluids. In most cases of
TE, CSF general examination is normal or may reveal mild pleocytosis (predominantly lymphocytes and
monocytes) and an elevated protein level, whereas the glucose content usually is normal.

Toxoplasma PCR testing in CSF for the detection of parasite DNA is highly specific (69,70). A positive
test result in CSF (without concerns of laboratory contamination) establishes the diagnosis of TE in any
clinical setting. This is not the case for PCR of brain/spinal cord tissue because T. gondii cysts can
persist in these tissues for the life of the host and a positive test result may be indicative of latent infection
rather than toxoplasmosis by reactivation. PCR can also be helpful to support the diagnosis of TE when
other body fluids are used in immunosuppressed patients (e.g., peripheral blood, bronchoalveolar lavage,
vitreous fluid, aqueous humor, and possibly urine). In addition to TE, examination of the CSF by PCR can
also aid in the diagnosis of JC virus (JCV)–associated progressive multifocal leukoencephalopathy
(PML), Epstein-Barr virus (EBV)–associated CNS lymphoma, and cytomegalovirus (CMV) ventriculitis.
During gestation, a positive PCR test result in amniotic fluid is diagnostic of congenital TE in a fetus
whose imaging studies (fetal ultrasound or MRI) have revealed hydrocephalus or brain calcifications
(Fig. 43.1). Of note, attempts to perform prenatal diagnosis of congenital infection using PCR in amniotic
fluid of pregnant women dually infected with HIV and T. gondii had been hampered by the fact that
amniocentesis was contraindicated in HIV-infected mothers because of the potential of transmission of
HIV to the fetus during the procedure (71). However, in a recent study by Mandelbrot et al. (72), the risk
of maternal to child transmission of HIV by amniocentesis was negligible in mothers taking antiretroviral
therapy (ART). Thus, in HIV-positive women who acquired their primary T. gondii infection during
gestation or in women with AIDS who develop TE, amniocentesis to investigate whether fetal infection
has occurred is indicated assuming that these women are taking their ART and their HIV viral load is
undetectable (72).
Serologic Tests in Serum
All patients in whom TE is suspected should be tested for Toxoplasma IgG and IgM in serum. In patients
with Toxoplasma IgG– and IgM–negative test results and capable of producing normal levels of IgG and
IgM, the diagnosis of TE should be attempted by tissue biopsy or CSF PCR because these serologic test
results are suggesting absence of Toxoplasma infection. Rare cases of TE have been documented in
seronegative immunosuppressed patients.
Toxoplasma-positive IgG/negative IgM test results support but do not establish the diagnosis of TE.
Any Toxoplasma-positive IgM test result suggestive of an acute infection should undergo confirmatory
testing at a reference laboratory (e.g., in the United States, at the Palo Alto Medical Foundation
Toxoplasma Serology Laboratory [PAMF-TSL]; Palo Alto, CA; http://www.pamf.org/serology/;
telephone number [650] 853-4828; e-mail [email protected]) because positive IgM test results in serum
can be observed in 40% to 60% of chronically infected individuals (73). Confirmatory tests for positive
IgM results include IgG avidity, differential agglutination test, and Toxoplasma IgA and IgE antibodies
(74). A confirmed diagnosis of acute infection is highly suggestive that recent CNS symptoms in a given
patient are due to TE.
In infants suspected of congenital TE, the diagnostic yield of serum Toxoplasma-specific IgG, IgM, and
IgA in combination is superior when compared to the performance of either test alone (42).
Brain Imaging Studies
Imaging studies of the brain and spinal cord are essential for diagnosis and management of patients with
suspected or confirmed TE. Typically, multiple, bilateral, hypodense, enhancing mass lesions are found
on CT scan. Lesions have a predilection for, but are not limited to, the basal ganglia and hemispheric
corticomedullary junction. A significant degree of enhancement is usually present on CT scan. Abscesses
may, however, fail to enhance or be solitary and located anywhere in the brain. Magnetic resonance
imaging (MRI) (Figure 43.1C) is more sensitive than CT scan for detection of brain lesions of TE. Focal
lesions may be missed by CT scan and be apparent by MRI (75,76). Degree of enhancement both on CT
and MRI appears to correlate with the patient’s CD4 count; enhancement may be absent or mild with
counts below 50 cells/mm3, but enhancement progressively increases with increasing levels of peripheral
blood CD4 cells (77). Radiologic findings on MRI or CT scans are not pathognomonic of TE. Primary
CNS lymphoma cannot be distinguished from TE solely on the basis of neuroradiologic criteria (both can
present as contrast-enhancing lesions with mass effect). However, a single lesion, subependymal location,
and crossing of the corpus callosum suggest the possibility of lymphoma.
In congenitally infected infants, ultrasound can also be used to detect brain calcifications and
hydrocephalus (Figure 43.1A). However, the sensitivity of ultrasonography remains inferior to that of CT
and MRI (Figure 43.1B) scans in these patients
Response to Empirical Therapy as Additional Diagnostic Criteria
In AIDS patients, empirical treatment for TE is justified without further diagnostic efforts if the patient
meets each of the following criteria: (a) Toxoplasma IgG seropositive, (b) CD4 is below 200 cells/mm3,
(c) multiple ring-enhancing lesions on brain MRI, and (d) not taking appropriate antitoxoplasma
prophylaxis. In this clinical scenario, an optimal response to antitoxoplasma therapy further supports the
diagnosis of TE in AIDS patients. Inadequate clinical response to antitoxoplasma treatment, defined as
less than 50% improvement in the patient’s neurologic exam by day 7 of treatment, should question the
diagnosis of TE and prompt a lumbar puncture, if safe and feasible, for examination of the CSF for
Toxoplasma PCR or a brain biopsy. The potential morbidity associated with obtaining a brain biopsy to
establish or refute the diagnosis of TE is less than that from an erroneous diagnosis. Thus, a brain biopsy
should be strongly considered in cases where the likelihood of TE is low and only after the possibility of
performing a lumbar puncture for Toxoplasma PCR testing has been considered. The likelihood of TE is
low in T. gondii–seronegative AIDS patients, those with CD4 counts greater than 200 cells/mm3, single
space-occupying lesions in brain MRI, and those taking effective antitoxoplasma prophylaxis. Response
to empirical therapy should not be used as additional diagnostic criteria in non–AIDS-immunosuppressed
patients even in the presence of multiple ring-enhancing lesions because other etiologies are usually more
common in those patients.
Histopathology
Definitive diagnosis of TE may require demonstration of the organism on histopathologic examination of

brain tissue obtained at biopsy (78). Open or excisional biopsy may provide a higher yield when
compared to needle biopsy. A mature inflammatory reaction with gliosis and microglial nodule formation
or severe focal or generalized necrotizing encephalitis may be present. Perivascular and intimal
inflammatory cell infiltrates can lead to fibrosis and necrosis. Hemorrhage or thrombosis can be present,
accounting for many of the focal neurologic signs and symptoms. The presence of tachyzoites or numerous
tissue cysts surrounded by a significant inflammatory reaction by hematoxylin and eosin (H&E) is
diagnostic of TE. Parasites can be observed better by the use of T. gondii–specific immunoperoxidase
stain. Wright-Giemsa–stained smears or touch preparations can also be made from tissue obtained at
surgery in an attempt to make the diagnosis of TE immediately. Similarly, Wright-Giemsa stain of a
cytocentrifuge preparation of CSF may reveal the presence of tachyzoites, but it is best to use this
preparation for PCR.
Isolations Studies
Isolation of T. gondii from CSF is diagnostic of TE. Attempts to isolate the parasite can be performed at
reference laboratories (e.g., PAMF-TSL in the United States), but positive results may not be evident for 6
days to 6 weeks following inoculation of mice or tissue cultures. Isolation studies should not be attempted
from CSF unless a reference laboratory has made the determination that no additional CSF is required for
Toxoplasma PCR. Toxoplasma gondii has been isolated from peripheral blood and bronchoalveolar
lavage fluid in patients with AIDS; these results are diagnostic of pulmonary and disseminated
toxoplasmosis, respectively, and should be considered highly suggestive of TE (79–82).
Diagnostic possibilities of focal brain lesions in HIV-infected patients include TE, primary CNS
lymphoma, PML, fungal abscesses, mycobacterial or cytomegaloviral disease, and Kaposi sarcoma.
Because therapy is available for most of these disorders, brain biopsy for histopathologic diagnosis in
AIDS patients with low likelihood of having TE (see previous discussion) may be necessary for
successful management of the patient. As stated earlier, brain biopsy should be considered in all non–
AIDS-immunosuppressed patients with focal brain lesions.
The characteristic appearance of PML on neuroimaging studies often facilitates differentiation of this
disorder from other causes of intracerebral mass lesions.
MANAGEMENT
General Principles
As noted earlier, empirical antitoxoplasma therapy as a means of TE diagnosis is appropriate for AIDS
patients at high risk for TE. This approach is less appropriate for non–AIDS-immunosuppressed patients
or immunocompetent patients because etiologies other than TE are more common. Most of the studies
evaluating the efficacy of antitoxoplasma treatments for TE have focused on AIDS patients. Limited data
suggest that similar recommendations and principles to those described here for AIDS patients (with the
exception of when to use empirical treatment as the sole strategy for initial management) can be
reasonably applied to non–AIDS-immunosuppressed patients. For immunocompetent patients with TE,
treatment regimens are the same, but lower doses are usually used (Table 43.1).
PCR of CSF or brain biopsy is recommended in HIV-infected patients who do not improve clinically
within 7 to 10 days of initiation of empiric antitoxoplasma therapy (56,83). Patients should start to
improve their neurologic exam by day 3 of appropriate therapy, and 90% of patients with TE have
improved their neurologic exam by at least 50% by day 14 (56). However, the incidence of TE in AIDS
patients has decreased in recent years due to the introduction of primary anti–T. gondii prophylaxis and
ART. In contrast, the frequency of CNS lymphoma has increased in patients with focal brain lesions.
Thus, empiric anti–T. gondii therapy for patients with focal brain lesions but low likelihood of TE based
on the features outlined earlier may expose them to potentially unnecessary and toxic regimens. Although
empirical TE treatment may be initiated in such individuals, an aggressive concomitant diagnostic workup
should also be undertaken.
Diffuse TE should be considered in any Toxoplasma–seropositive patient who presents with
progressive and unexplained encephalitis and without focal brain lesions by MRI. An urgent trial of
empiric anti–T. gondii treatment is strongly recommended in this setting.
Follow-up brain imaging studies by the same modality as originally selected should be performed 2 to
4 weeks after initiation of therapy in patients who demonstrate a satisfactory clinical response (or earlier
if response is poor). Lesions should diminish in size, number, and in the intensity of the contrast
enhancement. Although the time to resolution of lesions may vary from 20 days to 6 months or longer, the
vast majority of patients who respond clinically will also reveal radiologic improvement. Improvement
of abnormalities as seen on MRI in response to specific therapy also varies with the location and
complexity of the lesions. Persistent enhancement on CT scans or MRI following antitoxoplasma
treatment has been associated with a higher incidence of subsequent relapse (56).
Corticosteroids should be considered in patients with severe intracranial hypertension triggered by
mass effect from focal lesions or diffuse TE. The use of adjuvant corticosteroids does not appear to
negatively impact response rates and time to response in AIDS patients with TE when compared to the
use of antitoxoplasma therapy alone. However, adjuvant corticosteroids may confound clinical
assessment of benefit of an antitoxoplasma treatment because lymphoma may significantly improve in
response to corticosteroids. At present, AIDS patients with TE should only receive corticosteroids if
clearly indicated (e.g., severe cerebral edema) and be limited to, if possible, no more than 2 weeks. The
administration of anticonvulsant agents should be determined by the neurologic consultant managing the
patient.
It is important to distinguish between two phases in the treatment of TE in immunosuppressed patients:
primary and maintenance therapy. Primary therapy refers to the administration of effective antitoxoplasma
treatment during the acute stage of the disease (usually prescribed for at least 6 weeks). Maintenance
therapy refers to the administration of adequate antitoxoplasma treatment following appropriate clinical
and neurologic improvements and for the duration of the immunosuppression that led to onset of the
patient’s TE in the first place.
Primary Therapy
Pyrimethamine is the most active agent against T. gondii and should always be used in combination with a
second active drug. It is standard practice to administer the combination of pyrimethamine plus
sulfadiazine or pyrimethamine plus clindamycin (Table 43.1). Prospective, randomized clinical trials
have established the equivalence of pyrimethamine plus sulfadiazine and pyrimethamine plus clindamycin
during primary therapy (84). Several small studies have also established that trimethoprim-
sulfamethoxazole (TMP-SMX) may be used for primary therapy (85–87). A small study suggested that the
combination of atovaquone (administered orally as a suspension) plus either pyrimethamine or
sulfadiazine as primary therapy had response rates (75% and 82%, respectively) similar to those reported
with pyrimethamine plus sulfadiazine (approximately 75%) (88). Thus, atovaquone-pyrimethamine can be
used as an alternative treatment for patients intolerant to sulfonamides and atovaquone-sulfadiazine for
patients who are intolerant to pyrimethamine. However, significant variations in the absorption of
atovaquone among patients are a serious clinical challenge and may hamper the efficacy of the regimen.
Early use of effective ART is central to the treatment of TE in AIDS patients. Although Toxoplasmosis-
related immune reconstitution inflammatory syndrome (IRIS) has been reported rarely (89), prompt
institution of ART is warranted in AIDS patients with TE.
Primary therapy should be extended for at least 6 weeks, assuming that the patient experiences clinical
and radiologic improvement. Longer treatment durations should be considered in patients with incomplete
clinical or radiologic responses. Of note, changes in Toxoplasma-specific IgG titters are not useful for
monitoring response to treatment.
Maintenance Therapy (Secondary Prophylaxis)
Maintenance therapy is recommended as long as factors for immunosuppression that led to the
development of TE remain present and can be discontinued once these factors are no longer present for at
least 6 months to 1 year. This principle is best illustrated in AIDS patients; once the CD4 T-lymphocyte
count has increased to more than 200/mm3 and the HIV viral load has been nondetectable for 6 months or
longer, maintenance therapy can be safely discontinued in clinically stable patients. The relapse rate of
TE in patients who are not receiving effective antiretroviral (ARV) and maintenance therapy for
toxoplasmosis can be as high as 50% to 80% at 12 months (90). The CT scans or MR images of patients
who relapse often demonstrate mass lesions in the same location as at initial presentation. Thus, it is
essential that AIDS patients who complete a primary course of therapy and who have had a favorable
clinical and radiologic response to therapy for TE receive lifelong anti–T. gondii agents unless they
experience ARV-induced immune reconstitution (e.g., CD4 T-lymphocyte count >200/mm3 and
nondetectable HIV viral load for 6 months or longer).
Following successful primary therapy, the same drugs are used for maintenance therapy but usually at
half doses (Table 43.1). Pyrimethamine plus sulfadiazine combination has the lower rates of relapse when
compared to other regimens (90). Patients on maintenance therapy with pyrimethamine-sulfadiazine do not
require further prophylaxis for P. jiroveci. Relapse rates with pyrimethamine plus clindamycin have been
reported to be relatively high (e.g., 22%) (90). Whether the high relapse rate was due to the low dose of
clindamycin (1.2 g/day) used remains to be determined. In addition, it is important to be aware that
pyrimethamine-clindamycin does not prevent PCP. Pyrimethamine-sulfadoxine (Fansidar) administered as
one tablet twice weekly has been reported to be effective as maintenance therapy (91). Atovaquone may
be an alternative for secondary prophylaxis in patients with intolerance to standard therapy or for whom
such therapy failed.
Considerations During Pregnancy and Congenitally Infected Infant

Pregnant women who are co-infected with HIV and T. gondii and who have progressed to AIDS are at
risk of reactivating their T. gondii infection, developing severe toxoplasmosis (e.g., TE, toxoplasmic
pneumonia), or transmitting the parasite to the fetus. Pregnant HIV-positive women should receive the
same treatment for TE as nonpregnant adults), including pyrimethamine plus sulfadiazine plus folinic acid;
this drug combination is thought to also prevent transmission of T. gondii to the fetus and treats affected
fetuses.
For the prevention of TE, Toxoplasma-seropositive pregnant women whose CD4 cell count is below
200 cells/mm3 should receive TMP-SMX (80 mg trimethoprim and 400 mg sulfamethoxazole in a single-
strength tablet, one tablet per day) as used for the prevention of Pneumocystis pneumonia in such patients;
this regimen is also intended to prevent transmission of the parasite to their offspring. Trimethoprim can
increase the risk of kernicterus and should be avoided in the late third trimester. For Toxoplasma-
seropositive pregnant women whose CD4 cell count is above 200 cells/mm3, spiramycin, a macrolide
reported to decrease the frequency of vertical transmission in HIV-negative women, is suggested for the
duration of the pregnancy.
As in HIV-uninfected women, primary Toxoplasma infection acquired during gestation in HIV-positive
Toxoplasma-seronegative women can result in the transplacental transmission of Toxoplasma. At present,
data are insufficient to define the effectiveness of treatment intended to prevent vertical transmission of T.
gondii in HIV-infected women. However, the same recommendations given to HIV-negative pregnant
women should apply to HIV-positive women who acquired their primary Toxoplasma infection during
gestation (71).
In several observational studies, prenatal and postnatal treatment of the congenitally infected infant has
been associated with lower frequencies of mother-to-child transmission rates and clinical manifestations
in the infected offspring (26,41,42,92–104). TE (particularly hydrocephalus) is one of the three major
clinical manifestations (the other two include chorioretinitis and brain calcifications) that have been
significantly impacted by the benefit of prenatal and postnatal treatment of the congenitally infected infant
(42,92,97,99,104). Between 1999 and 2006, several observational studies were published casting doubt
on the potential beneficial effect of prenatal treatment on vertical transmission rates and clinical
manifestations in the infected fetus/newborn (105–110). However, it became clear that findings from these
studies were biased by their small sample sizes of the untreated subjects in the comparator group and
exclusion of fetuses and infants who have died and had developed severe neurologic sequelae as a result
of congenital toxoplasmosis. Although no randomized clinical trials have ever been performed in this
subject, observational studies published before 1999 and after 2006 are highly consistent with a clinical
benefit of prenatal treatment (26,41,42,92–104). For the treatment of congenitally infected infants with
TE, see Table 43.2 and Remington et al. (26).
PREVENTION
Primary Prophylaxis
Serologic testing for T. gondii antibodies will identify immunosuppressed patients at risk for reactivation
of infection (Toxoplasma IgG positive/Toxoplasma IgM negative) from those at risk for acquisition of
infection (Toxoplasma IgG negative/Toxoplasma IgM negative). All immunosuppressed patients who are
seronegative for T. gondii antibodies should be instructed on how to prevent exposure to the parasite
(Table 43.3). Seropositive patients should be offered primary prophylaxis. Numerous studies have
reported the efficacy of TMP-SMX, atovaquone, pyrimethamine-dapsone, or pyrimethamine-sulfadoxine
in the primary prevention of TE in HIV-infected patients previously infected with Toxoplasma (111). The
high mortality rates associated with toxoplasmosis in AIDS patients strongly support the use of
prophylaxis in HIV-infected patients with CD4 T-lymphocyte counts of less than 200/mm3. It is important
to emphasize that the threshold of 200/mm3 suggested in this chapter is different than the current threshold
of 100/mm3 suggested by Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-
Infected Adults and Adolescents (111). We suggest choosing 200/mm3 as the threshold for primary
prophylaxis initiation for two reasons. All of the North American studies demonstrating the efficacy of
this intervention for the prevention of toxoplasmosis were performed in studies aimed at PCP prophylaxis
in which the threshold for intervention was 200/mm3. Additionally, more aggressive T. gondii strains are
present in North America and South America than in Europe, raising the possibility that reactivation may
occur in North and South American patients at earlier stages of immunosuppression (112). Although no
studies have directly addressed criteria for restarting prophylaxis, it would be prudent to reinitiate
primary and secondary prophylaxis in patients whose CD4 T-lymphocyte count decrease to less than
200/mm3. Despite the availability of effective antimicrobial regimens for primary prophylaxis and
treatment, toxoplasmosis in AIDS patients is associated with high mortality rates after the diagnosis of TE
if ART is not initiated (54,113,114).
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CHAPTER 44 TRYPANOSOMIASIS
LOUIS V. KIRCHHOFF
Trypanosomes are single-celled protozoan parasites that have an amazingly broad distribution in nature.
The diversity and wide geographic range of the animals infected by trypanosomes make one wonder if
they do not impart a survival advantage to the species that harbor them. Trypanosomes are found in both
warm- and cold-blooded vertebrates and also in a large number of invertebrates that often act as vectors.
Simply stated, if an animal has blood or a bloodlike substance, there is a good chance that it is a host for
trypanosomes. Trypanosomes were first observed in 1841 by Gabriel Valentin, who saw the motile
organisms while examining blood from a trout under a microscope. Two years later, David Gruby saw
trypanosomes in the blood of a toad and noted their undulating membranes. They were first seen in
mammalian blood by Timothy Lewis, who observed them while studying rats. Infection with
trypanosomes in human blood was noted for the first time in an English boat captain traveling on the
Gambia River in the early years of the twentieth century. That species was later named Trypanosoma
gambiense (1). Shortly thereafter, the Brazilian physician Carlos Chagas described the cycling of
trypanosomes between the insect (triatomine or kissing bug) vectors and wild mammals and ultimately
found the organisms in an ill child. He named the parasite Trypanosoma cruzi, after his mentor Oswaldo
Cruz, and appropriately, the illness became known as Chagas disease or American trypanosomiasis (2).
Although there are many members of the genus Trypanosoma, only T. cruzi and two African trypanosome
subspecies, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, are capable of
causing disease in humans. There are only two situations in which T. cruzi causes disease of the central
nervous system (CNS). The first is the uncommon occurrence of meningoencephalitis during the acute
phase of Chagas disease, which occurs most often in children. The second is cerebral reactivation of
chronic T. cruzi infection in immunosuppressed patients, particularly in persons infected with the human
immunodeficiency virus (HIV). In contrast, in patients with human African trypanosomiasis (HAT),
caused by T. brucei rhodesiense and T. brucei gambiense, CNS disease is the most important clinical
problem.
AMERICAN TRYPANOSOMIASIS
Life Cycle and Mechanisms of Transmission
T. cruzi has a complex life cycle that involves insect vectors and mammalian hosts (Fig. 44.1). The
vectors, often called kissing bugs or triatomines (3) (Fig. 44.2), become infected when they take a blood
meal from mammals that have parasites circulating in their blood (Fig. 44.3). The organisms then multiply
extracellularly in the midgut of the insect, and eventually, parasite forms infective for mammals are
discharged with the feces at the time of a subsequent blood meal. Transmission to a second mammalian
host occurs when mucous membranes, breaks in the skin, or conjunctivas are contaminated with insect
feces containing infective forms. The parasites can adhere to and penetrate various cell types in the new
host and having done so multiply intracellularly. When the infected cell is overwhelmed by the
multiplying parasites, it ruptures, releasing the organisms that then invade adjacent tissues and spread via
the lymphatics and bloodstream to distant sites, where they go through further cycles of intracellular
multiplication. As the parasites cycle asynchronously in this manner, lifelong parasitemias infective for
vectors are maintained. T. cruzi can also be transmitted by transfusion of blood donated by persons who
chronically harbor the parasite (4,5), from mother to fetus (6,7), and in laboratory accidents (1,8).
Epidemiology
Historically, Chagas disease has been a public health problem throughout Latin America, with the
exception of the Caribbean nations. The Pan American Health Organization (PAHO) estimates that 8
million persons are chronically infected with T. cruzi and that 12,000 people die of the illness each year
(9,10). Most persons who harbor the parasite chronically are unaware that they are infected, and only
10% to 30% will ever develop the manifestations of chronic clinical Chagas disease (11). The economic
burden of Chagas disease is enormous, and its total annual cost in all endemic countries is estimated to be
more than U.S. $8 billion (12). Considered from a global perspective, Chagas disease constitutes the third
largest tropical disease burden, after malaria and schistosomiasis.
Despite the enormous social and economic burdens that result from the high overall prevalence of T.
cruzi infection, the situation regarding current incidence rates of transmission is markedly brighter. In
1991, the countries of the Southern Cone of South America (Bolivia, Chile, Uruguay, Paraguay, Argentina,
and Brazil) initiated an ambitious program aimed at interrupting the transmission of T. cruzi, called the
Southern Cone Initiative (SCI) (13). Vector control through spraying of insecticides and housing
improvement, education of persons at risk, and serologic screening of donated blood are the core
elements of the program. During the first 8 years of the SCI, U.S. $340 million was invested in these
efforts and a striking level of success was achieved. Ongoing surveillance shows clearly that transmission
has been interrupted in vast areas of several endemic countries. Major reductions in T. cruzi prevalence
rates in younger age-groups and a gradual decrease among persons who present for blood donation stand
as clear evidence of the success of the initiative (14). Uruguay was certified free of transmission in 1997,
Chile followed 2 years later, and Brazil was certified transmission-free in 2006. Moreover, during the
past decade, programs similar to the SCI have been implemented in the Andean countries and in the
nations of Central America, and major progress is being made in these efforts.
The epidemiology of T. cruzi infection in Mexico merits special mention because it has been studied
less intensively there than in other endemic countries and because roughly 17 million persons born in
Mexico now live in the United States (15). In a national survey among Mexican blood donors done in the
mid-1990s, a 1.5% overall prevalence rate of T. cruzi infection was found, with the highest rates in the
states of Hidalgo (2.8%), Tlaxcala (1.9%), and Puebla (1.8%) (16). In a study of T. cruzi infection among
blood donors in the states of Jalisco and neighboring Nayarit, Kirchhoff et al. (5) found an overall
prevalence rate of 0.8%. Importantly, four of nine recipients of blood products from T. cruzi–infected
donors were found to be infected with the parasite. Clearly, serologic testing of blood donors in Jalisco
and Nayarit should be performed, and the epidemiologic evidence available from other regions suggests
that testing of blood donors throughout Mexico is appropriate. Unfortunately, at present, Mexico is the
only one of the 22 Chagas-endemic countries that does not have a universal blood donor screening
program for Chagas disease.
Even though the sylvatic cycle of T. cruzi is present in large areas of the western and southern United
States, only seven cases of autochthonous transmission to humans here have been described (17). In
addition, screening of U.S. blood donors for Chagas disease, which began in 2007 and to date has
involved the testing of more than 40 million units, has only turned up 17 donors who appear to have
acquired T. cruzi infection in the United States (18). In the past three decades, about 15 laboratory-
acquired and imported cases of acute Chagas disease have been reported to the Centers for Disease
Control and Prevention (CDC) but only one in the latter group occurred in a returning tourist (19).
However, three instances of tourists returning to Europe from Latin America with acute T. cruzi infection
have been described as well as a similar case in Canada (20).
The number of persons living in the United States with chronic T. cruzi infections, however, has
increased markedly in recent decades. More than 23 million persons born in endemic countries currently
reside in the United States, and it is noteworthy that almost all of the 6 million non-Mexican immigrants
from Chagas disease–endemic nations now living here were born in countries where the prevalence of
Chagas disease is higher than it is in Mexico. The CDC recently estimated that 300,000 persons with
chronic T. cruzi infection currently reside in the United States (21). Before donor screening was
implemented, seven cases of transfusion transmission of T. cruzi had been reported in the United States
and Canada (22), and two additional instances were found in trace-back studies done after screening
started (23). The confirmed rate of T. cruzi infection found in blood donors since the implementation of
screening in 2007 has been about 1 in 13,300 (24). Transplantation of organs obtained from three
chronically infected Latin American immigrants caused five cases of acute Chagas disease, one of which
was fatal (25). Regarding congenital transmission, a reasonable estimate would put the number of infants
born in the United States each year with congenital Chagas disease at 63 to 315, but only one such infant
has been described (26). Several factors likely underlie the lack of additional reports of congenital
transmission in the United States, but the low level of knowledge about Chagas disease among caregivers
certainly plays a major role (27).
Diagnosis
Because there are no specific epidemiologic or clinical markers of Chagas disease, a definitive diagnosis
of the illness must be made by laboratory studies. In acute disease, the diagnosis is parasitologic and the
highly motile parasites often can be found by microscopic examination of wet preparations of blood or
buffy coat. Parasites also can sometimes be found in the pellets of spun cerebrospinal fluid (CSF) (28).
Polymerase chain reaction (PCR)–based assays are sensitive and specific in acute Chagas disease, but
they are not used widely because of their complexity and because they are not available commercially
(29,30). Hemoculture, which requires a special medium, is rarely useful for diagnosing acute Chagas
disease because it is not widely available, requires several weeks to complete, and may have a
sensitivity of only 50% to 70% even in the best of hands. In terms of making a specific diagnosis in
patients with T. cruzi infection who may have cerebral involvement, my view is that brain biopsy is
unlikely to be diagnostic if a careful search in blood and other fluids is negative.
Chronic Chagas disease is usually diagnosed by detecting specific immunoglobulin G (IgG) antibodies
that bind to T. cruzi antigens. At present, at least two dozen serologic assays for Chagas disease are
available commercially (31), and they are used widely for screening donated blood and clinical testing in
the endemic countries and other areas to which at-risk persons have emigrated. As with all assays, the
sensitivities and specificities are less than 100%, and false-positive results typically occur with
specimens from patients with leishmaniasis, malaria, syphilis, and other parasitic and autoimmune
diseases. World Health Organization (WHO) recommends that samples be tested in two assays based on
different methodologies before diagnostic decisions are made (32).
Two tests have been approved by the U.S. Food and Drug Administration (FDA) for clinical testing in
the United States (Chagas Kit, Hemagen Diagnostics, Inc., Columbia, MD; Chagatest Recombinante,
Laboratorios Wiener, Rosario, Argentina). The Abbott ARCHITECT Chagas assay (33), which is an
accurate chemiluminescence assay based on a mixture of four hybrid recombinant proteins, is not cleared
in the United States but is approved and used widely for both donor and clinical testing in the majority of
the Chagas-endemic countries. The Abbott PRISM Chagas assay (34), an automated chemiluminescence
assay based on the same recombinant proteins employed in the ARCHITECT Chagas, and the Ortho T.
cruzi ELISA Test System (Ortho-Clinical Diagnostics, Raritan, NJ), a parasite lysate-based enzyme-
linked immunosorbent assay (ELISA) (35), are FDA-approved for donor testing and are currently used to
screen the U.S. blood supply. A Clinical Laboratories Improvement Act (CLIA)–approved radioimmune
precipitation assay (Chagas RIPA) (31,36) is employed for confirmatory testing of donated units that are
repeat positive in the Abbott PRISM Chagas assay or the Ortho T. cruzi ELISA Test System and is
available in my laboratory for testing research and clinical samples as well. Lastly, the Abbott ESA
Chagas (enzyme strip assay), also based on the group of recombinant antigens used in the ARCHITECT
Chagas assay, has been approved by the FDA for confirmatory testing of screen-positive donor samples
(37). Unfortunately, PCR-based assays have not demonstrated consistently high levels of sensitivity that
would justify their use for confirmatory testing of screen-positive donor samples (30).
Pathology and Clinical Manifestations
Acute and Indeterminate Phases of Chagas Disease

A chagoma, which is an erythematous and indurated lesion at the site where the parasite entered the host
10 to 14 days earlier, can be the first sign of acute T. cruzi infection (38). If the organisms enter through a
conjunctiva, the patient may develop unilateral painless periorbital edema, which is called Romaña sign
(Fig. 44.4). In any case, local histologic changes include intracellular parasitism of myocytes and various
other cells, lymphocytic infiltration, interstitial edema, and reactive hyperplasia of adjacent lymph nodes.
Spread of the parasites from the site of initial multiplication may be accompanied by fever and malaise,
as well as edema of the face and lower extremities, hepatosplenomegaly, and widespread
lymphadenopathy. Some patients with acute Chagas disease develop morbilliform rashes called
schizotrypanides. Muscles can become heavily parasitized, and clinically significant myocarditis occurs
in a small percentage of patients, occasionally resulting in fatal congestive heart failure (39,40) (Fig.
44.5). On histologic examination of cardiac tissue of such patients, patchy areas of infected cells are
present, as are intense infiltration of mononuclear cells and necrosis. The pathognomic pseudocysts also
often observed are aggregates of T. cruzi amastigotes inside cardiomyocytes. Nonspecific
electrocardiographic (EKG) abnormalities may be present, but the life-threatening dysrhythmias that often
are part of chronic cardiac Chagas disease usually do not occur.
Patients with acute Chagas disease can also have CNS involvement, which was first described by
Carlos Chagas (2). How often the parasites actually invade the CNS in acutely infected patients is not
known, but in general, neurologic findings are uncommon. It is noteworthy that in one study, parasites
were found in the CSF of 8 of 11 patients examined, but none had neurologic symptoms (28).
Meningoencephalitis is a rare occurrence in acute Chagas disease, and it is associated with a poor
prognosis (41). It usually occurs in the first few months of life. At a cellular level, focal presence of
parasites accompanied by mononuclear cell infiltration has been described in all anatomic areas of the
brain. Most of the parasites are inside macrophages and glial cells, and parasitized neurons are rare. The
clinical manifestations of meningoencephalitis in patients with acute T. cruzi infection are
indistinguishable from those associated with other infectious agents that similarly affect the CNS.
Seizures occur commonly in variable patterns, and spasticity and hyperreflexia are often present.
The signs and symptoms of acute Chagas disease resolve spontaneously in 4 to 8 weeks in almost all
patients, and they then enter the indeterminate phase of the T. cruzi infection. This phase is characterized
by lifelong subpatent parasitemias, a lack of symptoms, and generally detectable antibodies to T. cruzi
antigens.
Chronic Chagas Heart Disease

Fortunately, only 10% to 30% of persons with long-standing T. cruzi infections ever develop symptomatic
chronic Chagas disease. Signs and symptoms typically first appear years or even decades after initial
infection. Cardiac problems are the most common result of long-term T. cruzi infection, and during the
past decade or so, convincing evidence has accumulated indicating that the persistence of parasites in
heart muscle stimulates a chronic inflammatory process that leads to organ dysfunction and, in many
cases, death (42,43). The inflammatory process can lead to various cardiac rhythm disturbances,
including atrial fibrillation and atrial bradyarrhythmias; premature ventricular contractions; bundle–
branch blocks, often of the right bundle; and complete atrioventricular block. These abnormalities can
cause dizziness and syncope, and sudden death is common (44). Fibrosis, cardiomyopathy, and
biventricular dilation can also develop, resulting in congestive heart failure, clot formation, and strokes
(Fig. 44.6).
Heart transplantation is an option in persons with severe Chagas heart disease, and well more than 100
T. cruzi–infected patients have had this procedure in Brazil and the United States (45,46). Not
surprisingly, T. cruzi has been found in endomyocardial biopsies of transplant recipients, thus raising the
specter of early destruction of the new hearts by invasion of parasites. Somewhat surprisingly, however,
long-term survival is greater in patients with Chagas disease who have undergone cardiac transplantation
than in patients transplanted for heart diseases of other etiologies. It is also noteworthy that patients who
have had transplants for Chagas heart disease often develop skin lesions containing high numbers of
intracellular parasites. It is interesting to note that neither cerebral abscesses nor encephalitis due to T.
cruzi reactivation has been noted in patients with Chagas disease after heart transplantation, although this
commonly occurs in HIV-infected patients in whom chronic T. cruzi infection reactivates.
Chronic Gastrointestinal Chagas Disease (Megadisease)

The gastrointestinal (GI) tract is the second organ system most frequently affected in patients with chronic
T. cruzi infection. Symptoms caused by megaesophagus are the most typical clinical manifestations of
megadisease, although problems related to megacolon are common as well. Patients with megaesophagus
have complaints similar to those of idiopathic achalasia such as dysphagia, odynophagia, cough,
regurgitation, and chest pain (47,48). Hypersalivation and parotid gland hypertrophy have been observed
as well. Aspiration can occur, and repeated episodes of aspiration pneumonitis are common in patients
with severe, untreated, esophageal dysfunction. Malnutrition can combine with pneumonitis to cause death
in patients with megaesophagus, although this is not common today.
Patients with megacolon usually complain of abdominal pain and chronic constipation. Patients with
advanced megacolon can go for weeks between bowel movements, and acute obstruction, sometimes
associated with volvulus, can result in perforation, septicemia, and death (49).
Trypanosoma cruzi Infection, Immunosuppression, and HIV

When patients with chronic T. cruzi infections become immunosuppressed, reactivation can sometimes
occur in a manner and with a severity not seen in immunocompetent persons (50–53). In general,
reactivation occurs in a few patients with chronic T. cruzi infection who become immunosuppressed, but
the precise incidence is not known. Immunosuppression is the only clinical context in which brain
abscesses and encephalitis occur in persons with chronic T. cruzi infections. Several reports of
reactivation after kidney transplantation have appeared, and in rare cases, CNS abscesses were involved
(54–56). In terms of organ donors with chronic T. cruzi infection, all otherwise acceptable organs should
be considered for transplantation, with the exception of the heart and segments of the GI tract. After
transplantation, however, patients receiving such organs should be monitored closely for acute Chagas
disease with guidance from CDC staff.
Reactivation of T. cruzi infections and associated CNS mass lesions or encephalitis has been reported
in patients who become immunosuppressed in the course of other illnesses. In one patient, a tumor-like
cerebral lesion due to T. cruzi was discovered at the same time chronic lymphocytic leukemia was
diagnosed (57). Much more common, however, is the occurrence of T. cruzi reactivation in persons co-
infected with T. cruzi and HIV, dozens of whom have been described (58–60). A large proportion of these
patients developed CNS mass lesions due to T. cruzi (Fig. 44.7), which as noted simply do not occur in
immunocompetent persons with chronic Chagas disease. Myocarditis also has been noted to occur
commonly in dually infected persons in whom T. cruzi reactivates.
Treatment
In general, the two drugs available for treating patients with T. cruzi infection are unsatisfactory from
several perspectives (61). The first of these, the nitrofuran derivative nifurtimox (Lampit, Bayer 2502),
has been in use for more than four decades. In acute and congenital Chagas disease, nifurtimox reduces the
duration and severity of the illness and decreases mortality. Unfortunately, it results in parasitologic cure
only in approximately 70% of acutely infected patients. Therapy with nifurtimox should be initiated as
early as possible in cases of acute or congenital Chagas disease. A large percentage of patients treated
with nifurtimox experience bothersome side effects (62). GI complaints include anorexia, nausea,
vomiting, abdominal pain, and weight loss. Possible neurologic problems include insomnia, restlessness,
twitching, and paresthesias. These symptoms generally disappear when the dosage is reduced or treatment
is stopped. In the United States, nifurtimox is only available from the CDC Drug Service.
Benznidazole (Rochagan, Roche 7-1051), a nitroimidazole derivative, is the second drug used to treat
Chagas disease (63). Its efficacy is similar to that of nifurtimox. Considerable experience has
accumulated with the use of benznidazole to treat babies with congenital T. cruzi infections during the
first year of life. Cure rates are thought to be close to 100% in these patients. Side effects of benznidazole
include granulocytopenia, peripheral neuropathy, and rash (64,65). Benznidazole is viewed as the drug of
choice by most specialists in Latin America, where it is used widely. It also must be obtained from the
CDC Drug Service for use in the United States. The regimens of nifurtimox and benznidazole used to treat
patients with CNS Chagas disease are the same as those used in persons with other forms of T. cruzi
infection.
Regarding which groups of T. cruzi–infected persons should be given specific therapy, the consensus of
experts is that babies with congenital Chagas disease, all persons with acute T. cruzi infection, and
chronically infected children up to 18 years old should receive specific treatment. Clinical trial data
indicate clearly that a large proportion of patients in these groups who are given treatment are cured
parasitologically (66–68). The question of whether persons in the indeterminate or chronic symptomatic
phases of Chagas disease should be given nifurtimox or benznidazole has been debated for decades. This
is a difficult question because these two drugs have to be taken for 2 to 4 months, often cause bothersome
side effects, and in persons with long-standing T. cruzi infections may have parasitologic cure rates of
only about 10% (69–71). In addition, there is no convincing evidence from properly controlled trials that
full courses of either of the drugs improves long-term outcomes in patients with chronic infection (72).
The issue is further complicated by the lack of sensitive and specific tools for determining if treated
patients are cured parasitologically. A panel of experts assembled at the CDC in 2006 suggested that
therapy be offered to persons aged 19 to 50 years with long-standing indeterminate phase infections (68).
A major randomized controlled trial currently is being performed in Colombia, Brazil, and Argentina (the
BENEFIT Multicentric Trial) to assess clinical outcomes in patients treated with benznidazole (73).
HUMAN AFRICAN TRYPANOSOMIASIS (SLEEPING

SICKNESS)
Life Cycle and Mechanisms of Transmission
As noted earlier, HAT is caused by the two trypanosome subspecies T. brucei rhodesiense and T. brucei
gambiense, which cause East African and West African trypanosomiases, respectively but are
indistinguishable morphologically (Figs. 44.8 and 44.9). These organisms are members of the T. brucei
complex and are transmitted by several species of tsetse flies that belong to the genus Glossina (74,75),
which are found only in Africa. Tsetse flies of both sexes become infected with trypanosomes when they
ingest blood from infected mammalian hosts. The ingested organisms go through a developmental cycle in
the GI tract of the insects and then migrate to the salivary glands. The cycle of transmission is completed
when infective forms are inoculated with saliva of the insect during a subsequent blood meal and begin
multiplying in the new host, eventually invading the bloodstream and other extracellular spaces (Fig.
44.10). Essentially all transmission of African trypanosomes among both domestic and wild animals, as
well as to humans, occurs in this cyclic manner. Mechanical transmission by vectors may occur, but it is
not thought to be important. Transmission by blood transfusion and congenital transmission in humans are
extremely rare (76,77). Laboratory accidents resulting in infection with African trypanosomes have been
reported (8).
Three fundamental biologic differences between the trypanosomes that cause sleeping sickness and T.
cruzi are their capacity to multiply in the bloodstream and in other extracellular spaces of their
mammalian hosts, the lack of an intracellular phase, and their evasion of immune destruction by
undergoing antigenic variation, which is a process through which they periodically change their surface
coat of glycoproteins. The parasites survive indefinitely in an individual host because just as antibody-
based mechanisms are specifically poised to eliminate them, a population of organisms having an
antigenically different surface coat arises (Fig. 44.11). The intricate and fascinating molecular
mechanisms that control this process have been studied intensively (78–80).
Epidemiology
HAT, which is only found south of the Sahara, was a much more important problem in the past than it is
today (81). Major epidemics killed hundreds of thousands of people in the beginning of the twentieth
century and between 1920 and 1948. The colonial powers invested heavily in the control of
trypanosomiasis, and as a result, there was a period during which the disease was almost eliminated.
Unfortunately, nonetheless, in the decades after independence, because of persistent poverty and civil
strife in many regions, control programs were neglected and trypanosomiasis underwent a resurgence,
peaking in the late 1990s. Uganda, Angola, the Democratic Republic of Congo, and South Sudan were
particularly affected, and today, 85% of reported cases occur in these four countries. During the past 15
years, however, coordinated efforts of the WHO, the governments of the affected countries, and
nongovernmental organizations have led to effective control in many areas, and overall, the numbers of
reported cases is back down to the low point reached in the early 1960s. In 2009, less than 10,000 new
cases were reported to WHO. In 2009, a panel of experts convened by WHO to review the status of
trypanosomiasis developed a vision for its elimination (82,83). Although underreporting continues to be a
significant problem, there is no doubt that the level of control achieved to date is impressive (84–90).
East and West African HAT are distinct entities (Fig. 44.12). Epidemiologic and clinical features that
distinguish the two diseases are presented in Table 44.1. The species of tsetse flies that transmit T. brucei
gambiense inhabit wooded areas along rivers in tropical rain forests in Central and West Africa. Even
though these insects feed on various mammals, infected humans apparently constitute the only major
reservoir of this subspecies of the parasite. Transmission often occurs around water holes, especially in
the dry season as people seek water where the density of tsetse flies and mammals on which the vectors
feed are concentrated. Because of this pattern of transmission, West African sleeping sickness is primarily
a problem among people who live in rural areas, and tourists rarely get infected with T. brucei
gambiense. In contrast to persons with East African trypanosomiasis, those with West African disease
often are asymptomatic for long periods, and this fact may underlie the persistence of the parasite in
populations between epidemics.
T. brucei rhodesiense, on the other hand, is transmitted by different species of tsetse flies, which are
found in woodland and savanna areas of East and Central Africa. In contrast to T. brucei gambiense, the
principal reservoirs of T. brucei rhodesiense are not humans but wild animals, principally antelope such
as hartebeest and bush buck. These reservoirs are trypanotolerant and generally are not sickened by the
parasites. Cattle can serve as reservoirs as well but usually die of the infection if not treated. People get
infected with T. brucei rhodesiense only incidentally when they venture into areas where infected vectors
and wild mammals are present. Game wardens and others who work in such areas are at particular risk,
and tourists who come to see game in parks occasionally become infected. Most of the patients with HAT
seen in the United States have been infected with T. brucei rhodesiense, and some have had CNS
involvement (91–94). Because the natural cycle of transmission does not exist outside of Africa, the
occurrence of secondary cases in the United States is not a possibility.
Diagnosis
Systemic HAT without CNS involvement is referred to as stage I disease and is also called the
hemolymphatic stage. The hallmark of stage II disease is invasion of the CNS. Clinical and
epidemiologic information can suggest the diagnosis of sleeping sickness, and a high index of suspicion
should be maintained with patients who have been in endemic areas. Nonetheless, numerous other
illnesses can cause signs and symptoms similar to those that characterize stages I and II HAT, and thus the
diagnosis of African trypanosomiasis requires demonstration of the parasite (95–97). The organisms can
be sought in a variety of sites. If a chancre is present (see following texts), fluid should be expressed and
studied microscopically, both as a wet preparation and after Giemsa staining. Material obtained by
aspiration of enlarged lymph nodes can be examined similarly. Lymphadenopathy is more common in
patients infected with T. brucei gambiense, but even in these persons, the procedure may have to be done
repeatedly before parasites are found. Organisms can also be found by examining wet preparations of
blood and thin and thick smears stained with Giemsa. The likelihood of finding organisms in blood is
higher in stage I disease and in patients infected with T. brucei rhodesiense. Examination of buffy coat
from 10 to 15 mL of anticoagulated blood by these methods yields positive results in some infected
patients. Miniature anion exchange columns that capture red cells but not trypanosomes can also be used
to detect parasites (98), and other creative approaches to parasite detection are being developed (99).
Extensive efforts have focused on the development of PCR-based assays for detecting African
trypanosomes, and numerous articles have appeared describing this work (100). In general, PCR-based
assays can have high levels of both specificity and sensitivity, but the lack of necessary human and
technical resources in most areas of active transmission makes field implementation difficult. Loop-
mediated isothermal amplification (LAMP) of DNA methodology also has been applied to the
development of assays for HAT diagnosis, but it also will need additional work before it can be used
widely under field conditions (101–104).
CSF should be examined in all patients suspected of having sleeping sickness (105). Increased opening
pressure and cell count and elevated immunoglobulin M (IgM) and total protein levels are abnormalities
that can appear in CSF. Moreover, trypanosomes can sometimes be seen in the cell pellet of centrifuged
CSF (106). In a patient in whom trypanosomes have been found in samples obtained from other sites, any
CSF abnormality must be taken as evidence of stage II CNS disease. As indicated later in this chapter, the
treatment of stage II trypanosomiasis is different from that given to patients with stage I, hemolymphatic
disease.
Accurate diagnostic staging of HAT is critically important because treatment for stage II disease can be
far more toxic than that used for stage I illness. In a patient in whom the parasite has been found in a site
other than the CNS, the WHO criteria for stage II disease are CSF white blood cell (WBC) greater than 5
cells/µL or the presence of trypanosomes in the CSF. The former criterion is controversial, however, and
some experts have suggested that a WBC greater than 10 cells/µL be taken as the indicator of stage II
disease (95). This controversy has prompted a search for other biomarkers indicative of stage II disease,
but to date, none of the parameters investigated have gained widespread use, primarily because there is
no gold standard for stage II disease that can serve as a benchmark against which the accuracy of new
methods can be gauged (107–110).
Bone marrow aspiration is an alternative approach that can be tried for detecting trypanosomes in
patients suspected of having sleeping sickness. Material obtained by this procedure can be examined
microscopically, and it can be inoculated into specialized culture medium, as can CSF, blood, or lymph
node aspirates (111). Agglutination tests for trypanosomes performed on cards on serum samples (card
agglutination test for trypanosomiasis [CATT]) (95,97,112) are available commercially and are easy to
use in the field. These card assays are the cornerstone of epidemiologic studies and screening populations
at risk, but confirmatory parasitologic studies must be done on screen-positive persons prior to deciding
on treatment.
The pathogenesis of HAT is complex and many aspects of it are poorly understood (105,113,114). An
inflammatory lesion called a trypanosomal chancre may appear at the site of inoculation a week or so
after the bite of an infected vector. A febrile illness then develops as the parasites multiply locally and
disseminate through the lymphatics and bloodstream. In this stage, widespread lymphadenopathy and
splenomegaly reflect marked lymphocytic and histiocytic proliferation and invasion of morular cells,
which are large plasmacytes that may produce parasite-specific IgM (115). Endarteritis, with
perivascular infiltration of both parasites and lymphocytes, may develop in the spleen and lymph nodes.
Patients infected with T. brucei rhodesiense often develop pancarditis during stage I disease (116–118).
The conduction system can be involved as well (119–122).
Anemia, thrombocytopenia, and moderate leukocytosis characterize stage I HAT. High levels of
immunoglobulins, consisting mainly of polyclonal IgM, are a constant feature and persist throughout the
illness. Heterophil, anti-DNA, and antigalactocerebroside antibodies are often present, as is rheumatoid
factor. High levels of antigen–antibody complexes are generally present, but their role in pathogenesis is
not clear.
In stage II, invasion of the CNS by trypanosomes can result in meningoencephalitis or meningomyelitis
(123–125). There is patchy involvement of various areas of the brain, consisting of intense mononuclear
cell infiltration, edema, hemorrhages, and granulomatous lesions (Fig. 44.13). Thrombosis associated
with endarteritis is often present. CSF abnormalities include increased opening pressure, elevated protein
concentration, and pleocytosis. In addition, trypanosomes frequently are identified microscopically in the
CSF.
The trypanosomal chancre may be painful. Systemic spread of the parasites that occurs in stage I disease
is accompanied by fevers that do not follow a predictable pattern as in malaria. Frequently, periods of
high temperatures lasting several days are separated by days without fever. As noted, lymphadenopathy is
prominent in West African HAT but not in patients with East African HAT. The nodes are discrete,
movable, nontender, and rubbery. Enlarged cervical nodes frequently develop, and they are called
Winterbottom sign when located in the posterior cervical triangle. Transient edema is common during
stage I disease and can occur in the face as well as in the feet, hands, and other periarticular areas.
Pruritus also is common, and an irregular circinate rash is often present. The rash is located on the thighs,
buttocks, trunk, and shoulders and typically consists of erythematous areas 5 to 10 cm in diameter with
clear centers (126). Less constant findings include tachycardia, malaise, headache, arthralgias, edema,
hepatosplenomegaly, and weight loss.
Invasion of the CNS is characterized by the gradual development of various neurologic manifestations
and progressive CSF abnormalities. This process becomes evident weeks to months after initial infection
with T. brucei rhodesiense and may appear years later in the case of T. brucei gambiense. Headache is
common, as are mental status changes and sleep disturbances. Slowly, a picture of daytime somnolence
develops (thus the term sleeping sickness), accompanied in some patients by insomnia and restlessness at
night (Fig. 44.14). A loss of spontaneity accompanies a listless gaze and progressive indifference, and
speech may become halting and indistinct. Extrapyramidal signs may include fasciculations, choreiform
movements, and tremors. Affected patients are often ataxic and may appear to have Parkinson disease
with a shuffling gait and rigidity. Without specific treatment, progressive neurologic dysfunction ends in
coma and death.
The most striking difference between the West African and East African trypanosomiases is that the
latter tends to follow a much more acute course. In infected tourists, who generally have East African
disease, systemic symptoms may appear before the trip ends or shortly after returning home. In some
patients with rhodesiense disease, death may result from arrhythmias and congestive heart failure even
before a clinical picture of CNS involvement develops. In general, without treatment, East African HAT
leads to death in a matter of weeks to months, often without a clear distinction between the hemolymphatic
and CNS stages, whereas West African HAT can smolder for many months or even years.
Treatment
Treatment of HAT is complex, and currently recommended protocols recently have been reviewed in
detail (Table 44.2) (124,127). The drugs used are suramin, pentamidine, melarsoprol, eflornithine
(difluoromethylornithine), and, most recently, nifurtimox. In the United States, with the exception of
pentamidine, these drugs can be obtained only from the CDC. Therapy for HAT must be individualized on
the basis of the infecting organism (T. brucei gambiense or T. brucei rhodesiense), the presence or
absence of CNS disease, side effects, and, occasionally, even resistance (128,129).
Suramin is the drug of choice for stage I East African HAT, but it does not penetrate the CNS and thus
cannot be used for stage II disease. It can cause serious adverse effects, however, and must be
administered under the close supervision of a physician. A test dose should be given, as approximately 1
patient in 20,000 has an immediate and potentially fatal reaction to the drug involving vomiting, shock,
and seizures. Less threatening side effects include fever, photophobia, pruritus, arthralgias, and rashes.
Renal damage is the most common major adverse effect of suramin, and serial urinalyses to look for
proteinuria should be done during treatment. Suramin should not be given to patients with renal
insufficiency.
Eflornithine is highly effective for both stage I and CNS forms of West African trypanosomiasis. In the
trials on which the FDA based its approval, eflornithine cured more than 90% of 600 patients with stage
II disease. Adverse reactions include diarrhea, thrombocytopenia, anemia, hearing loss, and seizures. The
high dosage and the length of intravenous treatment required are disadvantages that make widespread use
of this drug problematic, thus leaving pentamidine as a better choice for stage I West African HAT. For
stage II West African HAT, moreover, recent trials of nifurtimox in combination with eflornithine
(nifurtimox-eflornithine combined therapy or NECT) have shown this regimen to be safe, effective, less
complicated to administer, and less expensive (130,131). The degree to which HIV coinfection affects the
course of HAT and the efficacy of NECT and other treatment approaches is not known and merits
additional investigation (132,133).
Pentamidine is the alternative drug for stage I East African HAT, although some T. brucei rhodesiense
infections are resistant. Common side effects include nausea, vomiting, tachycardia, and hypotension.
These reactions are usually transient and resolve when administration is discontinued. Other problems
associated with therapy include neutropenia, rashes, nephrotoxicity, abnormal liver function test results,
hypoglycemia, and sterile abscesses. Pentamidine must be given intravenously or intramuscularly.
The drug of choice for East African HAT with CNS involvement is the arsenical melarsoprol
(134–137). Melarsoprol cures both stages of the disease, but because of its relatively high toxicity, it
should only be used in patients with stage I disease in whom suramin or pentamidine was ineffective or
could not be tolerated. The currently recommended “short course” of melarsoprol was shown to be
noninferior to the previous treatment course for rhodesiense disease (138,139), which was given over
several weeks and was more toxic. The most important side effects of melarsoprol involve the CNS, and
a substantial proportion of patients treated with melarsoprol develop reactive encephalopathy. The
concomitant administration of prednisolone has been shown to reduce the risk of this immune-mediated
phenomenon and its associated mortality (140). Clinical indicators of reactive encephalopathy include
high fever, tremor, headache, seizures, impaired speech, and finally coma and death. Treatment with
melarsoprol should be discontinued at the first sign of encephalopathy, and it may be restarted with
smaller doses a few days after the signs and symptoms have resolved.
Several other side effects are associated with melarsoprol treatment. Extravasation can cause intense
local reactions, and vomiting as well as abdominal pain are commonly observed. Jarisch-Herxheimer–
type reactions have been reported, as have abnormal liver function tests, nephrotoxicity, and myocardial
damage. If a patient with West African CNS disease cannot tolerate eflornithine, the short course of
melarsoprol mentioned earlier should be given. This compressed regimen for stage II West African HAT
has been shown in a randomized trial to be equally effective and no more toxic than the traditional
regimen outlined previously (138).
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CHAPTER 45 FREE-LIVING AND PARASITIC AMEBIC
INFECTIONS
SHANNON MOONAH AND WILLIAM A. PETRI, JR.
Central nervous system (CNS) infection with free-living and parasitic amebae is rare but life threatening.
Three separate clinical syndromes occur from infection with free-living amebae (1). Primary amebic
meningoencephalitis is due to infection with Naegleria fowleri and occurs almost exclusively in
previously healthy children and young adults following exposure to freshwater. Pathologic examination of
brain tissues is consistent with infection via direct invasion of the brain from the olfactory nerves (2–11)
(Table 45.1). Granulomatous amebic encephalitis is due to hematogenous or direct infection of the brain
with Acanthamoeba species (including Acanthamoeba castellani, Acanthamoeba polyphaga,
Acanthamoeba culbertsoni, Acanthamoeba palestinensis, Acanthamoeba astronyxis, Acanthamoeba
hatchetti, and Acanthamoeba rhysodes) (12,13) or Balamuthia mandrillaris (formerly misidentified as
leptomyxid amebae) (14–27). Although granulomatous amebic encephalitis due to Acanthamoeba has
been observed predominantly in patients with known immunodeficiencies, B. mandrillaris infection has
also been observed in nonimmunocompromised individuals (Table 45.2). Acanthamoeba keratitis is seen
predominantly in individuals who wear contact lenses and is not discussed further in this chapter (28,29).
Brain abscess is a rare complication of Entamoeba histolytica infection, an otherwise common infectious
disease in the developing world. E. histolytica brain abscess is most commonly seen in association with
E. histolytica hepatic and/or lung abscess (30–40) (Table 45.3). As opposed to infection with the
parasitic ameba E. histolytica, infection with free-living amebae is not linked to fecally contaminated
food or water and is therefore no more common in developing nations than in the industrialized West.
Encephalitis may also be caused by ameba belonging to the genus Sappinia. Only one case of amebic
encephalitis due to Sappinia pedata infection has been reported (41,42).
ORGANISMS AND EPIDEMIOLOGY
N. fowleri is the only recognized pathogenic species of Naegleria. Trophozoites of N. fowleri are 10 to
30 µm in diameter and the nucleus has a prominent central dense nucleolus (Fig. 45.1A and B). The
trophozoites can transform into a flagellated form (seen in vitro upon transfer to distilled water). The cyst
form of the parasite is an approximately 9-µm diameter sphere with two pores in the cyst wall that serve
as an egress point for the trophozoite upon excystation. N. fowleri have been isolated from freshwater
lake and river water and soil in all parts of the world (3). Warm temperatures appear to favor their
growth; for example, in Florida, it is not uncommon to isolate N. fowleri from freshwater lakes and
streams. Most cases of N. fowleri infection have occurred in the summertime, and in the winter, the
organism is identified in lake and river sediments. The cyst form of the parasite is stable for months in the
environment but is not found in human tissues. It is estimated that in Florida, there are more than 100
million exposures to the parasite for every case of primary amebic meningoencephalitis (3). In fact most
adults in the United States appear to have been exposed to the parasite as evidenced by the presence of
serum antibodies against N. fowleri. The factors leading to N. fowleri infection in only a tiny minority of
exposed individuals is unknown. Primary amebic meningoencephalitis has been reported in the central
and southern United States, Central America, Europe, Japan, Africa, Australia, and New Zealand.
Outbreaks have been linked to common environmental exposures (2,6,10).
Acanthamoeba species consist of cyst and trophozoite stages, with the trophozoites approximately 14
to 40 µm in diameter and cysts with diameters of 12 to 16 µm (Fig. 45.1C and D). Both cysts and
trophozoites can be observed in infected brain. The nucleus has a central nucleolus similar in appearance
to that of Naegleria. Acanthamoeba species have also been isolated from soil, water, and air from
diverse geographic locations (1,12,13). In contrast to N. fowleri, Acanthamoeba may be spread through
the air. For example, 2% of nasopharyngeal swabs from healthy individuals were culture positive for
Acanthamoeba species in one study. Again, it is common to find antibodies against Acanthamoeba in
healthy individuals, although almost all cases of granulomatous amebic encephalitis due to Acanthamoeba
species have been observed in immunocompromised individuals (1,12,13). The cause of
immunosuppression has included HIV/AIDS, renal and bone marrow transplantation, cancer
chemotherapy, steroid therapy, diabetes mellitus, and liver disease.
B. mandrillaris trophozoites have an average size of 30 µm with cysts of 15 µm and therefore can be
distinguished from Acanthamoeba only by hematoxylin-eosin stains using specific antisera (1,20,26). It is
an inhabitant of soil and freshwater with the highest concentration of organisms observed in freshwater in
the spring and fall. Unique to B. mandrillaris is that it can cause CNS infection in both healthy and
immunocompromised individuals (14–17,19–21,25,26).
E. histolytica trophozoites have an average diameter of 15 to 30 µm, and the 10-µm quadrinucleate
cysts of the parasite have never been found in brain. E. histolytica infection is estimated to occur in
hundreds of millions of people annually (30,31). With the use of modern diagnostic tests, the burden of
amebic disease is becoming better appreciated. In Dhaka, Bangladesh, preschool-aged children had a
2.2% frequency of amebic dysentery during 3 years of prospective community observation (32). In Hue
City, Vietnam, an incidence of amebic liver abscess of 21 cases per 100,000 inhabitants was observed
(33). In the United States where fecal-oral transmission is unusual, amebiasis is most commonly seen in
immigrants from and travelers to developing countries. Brain abscess is seen usually in association with
an amebic liver or lung abscess (32–40). Amebic liver abscess in turn is predominantly (but not
exclusively) a disease of young men (30,31), leaving one to have the highest suspicion for an E.
histolytica brain abscess in a male patient with hepatic abscess, risk factors of E. histolytica infection,
and CNS signs or symptoms.
PATHOLOGY
N. fowleri appears to enter the CNS after disrupting the olfactory mucosa. It produces a diffuse
meningoencephalitis with purulent leptomeningitis. Cortical edema and hemorrhage with cerebellar or
uncal herniation are observed. The olfactory bulbs are commonly hemorrhagic or necrotic and
trophozoites can be observed in the olfactory nerves and in the perivascular spaces and adventitia of
arterioles and midsize arteries. A neutrophilic myocarditis has been observed in some cases (2,5,6,8).
Trophozoites of N. fowleri can be observed in wet preparations of cerebrospinal fluid (CSF) but are
commonly misidentified as monocytes.
Granulomatous amebic encephalitis due to Acanthamoeba species usually presents with focal
neurologic deficits in immunocompromised individuals. Cerebral edema resulting in bilateral cerebellar
or uncal herniation occasionally occurs. Areas of cortical involvement include the cerebellum, midbrain,
and brainstem (12,13). Histologically, the lesions spare the leptomeninges and contain necrotizing
granulomas with amebic cysts and trophozoites. Multinucleated giant cells may be seen within the
granulomas. Occasionally in immunodeficient individuals, the granulomatous reaction may not be present.
The parasites are observed most often in a perivascular location. Identification of Acanthamoeba in the
skin (Fig. 45.2), lung, adrenals, and lymph nodes of patients with CNS infection suggests hematogenous
dissemination of infection to the brain.
B. mandrillaris infection of the CNS results in a subacute or chronic granulomatous
meningoencephalitis that can closely resemble the pathologic lesions of Acanthamoeba infection (Figs.
45.3 to 45.6). Both immunocompromised and normal individuals can be infected. A chronic inflammatory
process is observed in the CNS that includes lymphocytes, mononuclear cells, and giant and plasma cells.
Granulomas may be absent, and parasites (cysts and trophozoites) are observed in a perivascular location
(Figs. 45.5 and 45.6). Angiitis and hemorrhagic necrosis of the meninges and brain tissue have been
observed.
In most cases, brain lesions due to E. histolytica infection are multiple and are most common in the
basal ganglia, followed by the frontal and occipital lobes. Lesions vary widely in size from 2 mm to 5 cm
and are associated with a polymorphonuclear infiltrate that may also be present in the CSF. Hemorrhage
may be observed at the junction of the gray and white matter (35–40) (Fig. 45.7).
Primary amebic meningoencephalitis is an almost uniformly fatal infection of previously healthy children
(2,5,7). A history of exposure to freshwater lakes, ponds, or streams in the week preceding the illness is
obtained in most cases, with an average incubation period of 2 to 5 days. The first symptom may be a
change in taste or smell. This is followed by the abrupt onset of fever, nausea, vomiting, or anorexia.
Meningismus is present in more than 85% of patients and two thirds have alterations in mental status at
the time of admission. Progression to coma and death occurs without the development of focal neurologic
signs in most patients, usually within a week of illness onset (2,5,7).
Granulomatous amebic encephalitis due to Acanthamoeba species is a subacute or chronic illness of
the immunocompromised and debilitated. Its onset is insidious, with presenting signs and symptoms
including altered mental status, seizures, fever, headache, hemiparesis, meningismus, visual disturbances,
and ataxia. Underlying illnesses include HIV/AIDS, liver and renal disease, solid organ transplants,
neoplasm, steroid therapy, pregnancy, and diabetes mellitus (4). The average time from onset of CNS
symptoms to death is a month. Acanthamoeba also causes ulcerative or nodular skin lesions on the trunk
or extremities that may develop over a period of weeks to months and may occur at the time of or before
the development of CNS symptoms or signs. The average time from onset of CNS symptoms to death is 1
month.
B. mandrillaris can cause CNS infection in both immunocompetent and immunodeficient individuals
(14,16–21,25,26). Otherwise the clinical presentation is similar to that of CNS Acanthamoeba infection.
Skin involvement with Balamuthia frequently involves the face, including papulonodular, erythematous,
plate-like lesions that are painless and begin most frequently on the nose. Hydrocephalus has been
reported as a complication.
E. histolytica brain abscess is almost always seen in an individual who also has an amebic liver
abscess and occasionally an amebic lung abscess. Thus, abdominal pain, dyspnea, pleural effusion,
anorexia, and weight loss commonly accompany the neurologic findings of headache, meningismus,
seizure, and altered mental status (36–40). Patients with amebic abscess are commonly males younger
than 50 years who have immigrated from or traveled to an endemic developing country.
DIAGNOSIS
Primary amebic meningoencephalitis should be included in the differential diagnosis of children and
young adults with meningoencephalitis, especially in patients with a recent history of freshwater
exposure. The CSF pressure is elevated, with hemorrhagic CSF, elevated white blood cell count, and a
neutrophilic predominance. If no bacteria are demonstrated in a purulent CSF, then it is important to
examine the CSF for amebic trophozoites, which can be accomplished by preparing a wet mount of fresh
CSF (1,7–9). Fixation of CSF for Gram strain disrupts the trophozoites, making diagnosis difficult or
impossible. Motile trophozoites have been observed in most CSF specimens from patients with primary
amebic meningoencephalitis but are frequently misidentified as white blood cells. Modern diagnostic
approaches using polymerase chain reaction (PCR), monoclonal antibodies, and DNA probes have also
been applied to diagnosis. N. fowleri can be successfully cultured from CSF and brain biopsies;
therefore, the microbiology lab should be informed about suspected cases so that appropriate processing
of specimens can be carried out.
Granulomatous amebic encephalitis due to Acanthamoeba species or B. mandrillaris is diagnosed by
brain biopsy. Amebae have never been observed in CSF. CSF findings are nonspecific but include
elevated protein and decreased glucose concentration. Lumbar puncture is contraindicated if the patient is
at risk of herniation. Computed tomographic and magnetic resonance imaging (Figs. 45.3 and 45.4) show
single or more often multiple enhancing mass lesions that are most commonly found in the anterior cortex
and subcortical white matter, with only rare involvement of the cerebellum and brainstem
(12–14,16–18,21). Skin lesions should be biopsied and examined for Acanthamoeba species in patients
suspected of having granulomatous amebic encephalitis. Morphologically, Acanthamoeba species and B.
mandrillaris appear similar, and specific antisera is necessary to distinguish them by
immunohistochemistry. Culture has successfully been used to isolate Acanthamoeba species and B.
mandrillaris from fresh (not frozen or fixed) brain biopsy materials (1). A multiplex real-time PCR assay
has been developed for the simultaneous detection of Acanthamoeba spp., B. mandrillaris, and N.
fowleri. The assay facilitates rapid detection with a turn-around time of 5 hours. This allows for an early
diagnosis and therefore prompt initiation of therapy (43).
The diagnosis of E. histolytica brain abscess has classically been made by the identification of E.
histolytica trophozoites by periodic acid–Schiff stain in the periphery of abscesses (36–40,44). Most
patients will have detectable serum antibodies against the parasite at the time of diagnosis. The use of
immunoperoxidase staining of tissue sections with specific E. histolytica antibodies is helpful in the
diagnosis of colonic amebiasis and could potentially be applied to cerebral amebiasis (45). The
sensitivity and specificity of modern diagnostic tests for intestinal infection, such as detection of E.
histolytica–specific antigen or DNA, for the diagnosis of brain infection are unknown.
TREATMENT
The only patients known to have survived primary amebic meningoencephalitis received amphotericin B,
but the overall mortality remains greater than 95%. A few survivors received rifampin in addition to
amphotericin, and some experts, therefore, recommend combination therapy with these two agents
(46,47). Other agents used have included miconazole, rifampin, and sulfisoxazole (7,11). In two recent
cases, both patients recovered after treatment with a combination of amphotericin B, rifampin, and
fluconazole (48,49).
The optimal treatment of granulomatous amebic encephalitis is unknown. Different species and strains
have different in vitro drug sensitivities. In general, diamidines such as propamidine, pentamidine, and
dibromopropamidine are active against Acanthamoeba species (12,13). In vitro susceptibility to
ketoconazole, paromomycin, 5-flucytosine, and amphotericin B has been observed. The combination of
hyperbaric oxygen therapy and multiple antimicrobial agents (pentamidine, fluconazole, metronidazole,
trimethoprim-sulfamethoxazole, and miltefosine) was successful in one patient (50). For B. mandrillaris,
in vitro sensitivity has been demonstrated for pentamidine, ketoconazole, paromomycin, 5-flucytosine,
amphotericin B, and phenothiazine derivatives (24,27,51). A recent report described two patients who
survived following treatment with flucytosine, pentamidine, fluconazole, sulfadiazine, a macrolide
antibiotic (azithromycin or clarithromycin), and phenothiazine derivatives (51).
E. histolytica brain abscess in the past has almost always been fatal. In the absence of any data, but in
light of the seriousness of this infection, a combination of aspiration and drainage of the brain abscess
combined with antiamebic drug therapy is prudent. The nitroimidazole metronidazole is the mainstay of
therapy for invasive amebiasis (52–55). E. histolytica persists in the intestine in many nitroimidazole-
treated patients. Therefore, intestinal infection should be eradicated by following nitroimidazole treatment
with paromomycin or the second-line agent diloxanide furoate (52–55).
In one reported case of amebic encephalitis due to Sappinia pedata infection, the patient was
successfully treated with a combination of azithromycin, pentamidine, itraconazole, and flucytosine
(41,42).
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CHAPTER 46 HELMINTHIC INFECTIONS
JOSE A. SERPA, WON K. CHUNG, AND A. CLINTON WHITE, JR.
The helminths include a broad range of organisms that are common human parasites. There are three
major groups of helminths: the nematodes (or roundworms, phylum Nematoda), the trematodes (or
flatworms or flukes, phylum Platyhelminthes, subphylum Trematoda), and the cestodes (tapeworms,
phylum Platyhelminthes, subphylum Cestoda). Numerous members of each group cause human central
nervous system (CNS) infection (Table 46.1). Helminths are part of the animal kingdom and are
eukaryotic multicellular organisms with well-developed organs including reproductive and digestive
tracts (nematodes and trematodes) or digestive surface (cestodes). Helminths are often large enough to be
visible to the human eye. They are extracellular parasites. The host response to helminths is dominated by
mechanisms aimed at extracellular organisms, resulting in the development of eosinophilia.
Most helminths have complex life cycles, with different morphologic forms and often involving
multiple hosts. Most reproduce primarily by sexual reproduction. The host in which sexual reproduction
occurs is termed the definitive host. The host in the life cycle in which no or only asexual reproduction
occurs is termed the intermediate host. In many cases, humans are a dead-end host and not part of the
parasite life cycle. In that case, humans are termed an incidental host.
CENTRAL NERVOUS SYSTEM DISEASE CAUSED BY

CESTODES
Neurocysticercosis
Taenia solium is a cestode parasite with a wide distribution globally (1–3). The parasite has two forms:
an intestinal tapeworm, found only in human hosts, and the cystic larval form, termed the cysticercus,
which is typically found in pigs. Humans can also be host to the cysticercus. Cysticercus infection of the
CNS is termed neurocysticercosis (NCC), which is now recognized as a common cause of neurologic
disease worldwide (1–3).
Epidemiology
The endemic regions for T. solium infection include most areas of the world where pigs are raised
including Latin America, sub-Saharan Africa, India, Southeast Asia, China, Indonesia, and other regions
less well characterized such as New Guinea and Eastern Europe (1–3). However, the burden of disease
was not recognized until the availability of neuroimaging studies in the early 1980s resulted in
identification of NCC as a common neurologic problem among immigrants to the United States and other
developed countries and later among residents of endemic areas. Review of studies from endemic areas
around the world document NCC in approximately 30% of patients with seizures (3). Several studies
have documented a high prevalence of infection throughout Latin America (4,5) with estimates ranging
between 15% and 38%. Similar studies have also demonstrated NCC in a high proportion of African
patients with seizures, with the disease prevalent throughout the region (6,7). The prevalence of seizures
due to NCC in sub-Saharan Africa has been estimated at 1.7 to 24.8 per 1,000 persons.
When computed tomographic (CT) scans were initially used in adults with new-onset seizures in India,
most patients were noted to have abnormalities, including single calcifications or single enhancing
lesions. In a series of 991 patients with symptomatic localization-related seizures in south India, 40% of
patients were found to have either active NCC, calcifications on CT scan consistent with prior
cysticercosis, or single enhancing CT lesions, consistent with cysticercal granulomas (8). These findings
were confirmed in a study of children with seizures regardless of features of localization and in a study
from northern India (9,10). The single enhancing CT lesions were initially attributed to tuberculosis or to
the effects of seizures. However, when excisional biopsies were performed on these patients, nearly all
showed histopathologic evidence of cysticercosis (11). More than half of 401 patients presenting with a
single enhancing lesion were subsequently proven to have NCC (12). As mentioned earlier, NCC is also
prevalent in other parts of Asia including Indonesia, Southeast Asia, China, and Korea (13). Recent data
suggest an average prevalence of T. solium infection in China of 0.11% (range, 0.05% to 15%); which
translates to about 1.26 million cases of taeniasis and 3 to 6 million cases of cysticercosis. In the United
States, estimates range from 0.2 to 0.6 cases of NCC per 100,000 general population and 1.5 to 5.8 cases
per 100,000 Hispanics (14).
Parasitology
The T. solium life cycle requires two hosts and two major forms of the parasite (Fig. 46.1). The cysticerci
are found primarily in muscle of the pig, the intermediate host. Humans are the host for the intestinal
tapeworm form. Humans become infected with the tapeworm form (taeniasis) by ingesting undercooked
pork infested with T. solium cysticerci. After ingestion, the scolex (or head) evaginates and attaches to the
small intestines by means of hooks and suckers (Fig. 46.2). Proglottids (segments) develop from the base
of the scolex. As new segments arise at the base of the scolex, the older proglottids form a chain that can
reach a length of up to 30 feet, with the larger more mature proglottids at the distal end. The mature
proglottids are off-white, opaque, and approximately 1 cm wide, 1 to 2 cm long, and 1 to 3 mm thick. The
proglottids are hermaphroditic and mate with themselves to produce ova. The ova or proglottids are shed
intermittently in the stool. Most tapeworm carriers note few or no symptoms other than possibly noting
proglottids in the stool. Excretion is intermittent, so stool examinations for the ova or parasites are usually
negative.
Porcine cysticercosis is endemic in regions where pigs consume human fecal material. Pigs, when
raised under these conditions, ingest the ova or proglottids from the tapeworm carrier. In the intestines,
the eggs hatch, release the invasive larvae (also termed oncospheres), which penetrate the intestinal
mucosa using hooklets and excretory proteases, enter the bloodstream, migrate to the tissues, and mature
into cysticerci. In the muscle, the cysticerci appear as thin-walled, translucent, oval cysts, approximately
1 cm in diameter. The invaginated scolex is found as a 1- to 2-mm opaque nodule attached to one side of
the wall.
Human cysticercosis occurs when people ingest ova shed by a tapeworm carrier. As in pigs, the eggs
hatch in the intestine, enter the bloodstream, migrate to the tissues, including muscle, brain, and eye, and
mature into cysticerci. Most epidemiologic studies suggest that close personal contact with or perhaps
food preparation by a tapeworm carrier is associated with NCC. The tapeworm carriers can also be
infected themselves, probably by the fecal-oral route, but cysticercosis is not acquired directly from pork.
This is illustrated by an outbreak that occurred in an Orthodox Jewish community in New York City
(15,16). In all the exposed households, there was a history of employment of live-in housekeepers who
had recently emigrated from Latin American countries. Examination of six housekeepers revealed an
active taeniasis in one and a positive serologic test result in another. There have been a total of 78
autochthonous cases of cysticercosis reported in the United States between 1954 and 2005 (17). A
confirmed or presumptive source of infection was identified among household members or close personal
contacts of 16 (21%) case patients.

Despite the fact cysticerci reach their final size in a few weeks, there is a period of several years between
infection and onset of symptoms (18,19). Thus, the presence of the parasites in the CNS does not explain
symptoms. Autopsy studies of individuals in whom cysticerci were an incidental finding demonstrate
viable cysticerci in brain that appear similar to the viable cysticerci from pig muscle (20) (Fig. 46.3A
and B). By contrast, autopsies of patients with cysticercosis with seizures demonstrate a prominent
inflammatory infiltrate. Studies have elaborated a number of molecular mechanisms used by the parasites
to suppress the host inflammatory and immune responses (21). Similarly, our group has demonstrated that
parasite granulomas—not the parasite itself—are the cause of seizures in an animal model. Thus, seizures
likely result from the host response rather than from the parasitic infection per se (22). After months to
years, the cysticerci lose their ability to control the host response. The cysticerci become infiltrated and
surrounded by host inflammatory cells composed primarily of mononuclear cells, with variable numbers
of eosinophils and neutrophils, and pass through a series of stages of inflammation (23,24). This response
is associated with elaboration of substance P and type 1 cytokines such as interleukin-12 (IL-12),
interferon-γ (IFN-γ), and IL-2 (25,26). Recent findings indicate that substance P (SP) is a critical
mediator of seizures in NCC, and this may be prevented with SP-receptor antagonists (27). The walls of
the cysticercus degrade. The cyst cavity is invaded by inflammatory cells (colloid stage). As the host
response progresses, fibrosis encompasses the cysticercus with collapse of the cyst cavity (granular
nodular stage). Eventually, the parasite is replaced by progressive fibrosis, which may calcify (calcific
stage). This stage may have a minimal lymphocytic infiltrate but may also become more inflamed if the
granulomas break down.
Findings similar to these pathologic stages have been noted on neuroimaging studies (28,29). Invasion
of the CNS and early development of the cysticercus may present as an area of focal edema or
enhancement. The viable cysticercus appears as a cystic area that is isodense with cerebrospinal fluid
(CSF) (Fig. 46.4A). The cyst wall has the same density as brain parenchyma and lacks surrounding edema
or contrast enhancement. As the cysticercus becomes inflamed, the density of the cyst wall increases and
may enhance with contrast (Fig. 46.4B and C). Associated edema or enhancement is noted in the brain
parenchyma. The cyst fluid increases in density. As the cysticercus becomes fibrotic or collapses,
neuroimaging studies reveal an area of focal enhancement, suggestive of a granuloma. Finally, the calcific
stage is defined by the appearance of a focal area of calcification, typically several millimeters in
diameter (Fig. 46.4C). Recent studies have demonstrated edema and contrast enhancement associated
with symptomatic calcified lesions (30,31). This likely results from breakdown of the calcified
granulomas, triggering host inflammation.
Cysticerci can also be found in the cerebral ventricles and typically float within the CSF (Fig. 46.4A).
However, cysticerci in the ventricles can cause hydrocephalus, primarily by mechanical obstruction of
CSF flow (32). In most cases, the obstruction is caused by viable cysticerci (33). When the cysticerci
become inflamed, the ependymitis and accompanying astrocytosis cause the cysticercus to adhere to the
walls of the ventricles or block CSF flow directly (especially in the aqueduct of Sylvius).
Cysticerci in the basilar cisterns are associated with a form of NCC termed subarachnoid
cysticercosis. Some of the cysticerci within the subarachnoid space may enlarge and occasionally lose the
scolex (Figs. 46.3 and 46.4C). The cysticerci without a scolex were termed racemose. The term
racemose cysticercosis was used to describe subarachnoid disease. Because the clinical presentation,
pathogenesis, and treatment are the same, whether the scolex is present or not, the term racemose may not
be ideal. Furthermore, many of the so-called racemose cysticerci actually contain hooks, evidence that
they previously contained a scolex.
Subarachnoid NCC is characterized by a prominent basilar arachnoiditis (34). Patients may have
meningeal signs, communicating hydrocephalus, or vasculitis. The communicating hydrocephalus is
presumed to be caused by CSF outflow obstruction or blocked ventricular outflow (32). The
accompanying vasculitis may present as lacunar infarctions, or occasionally, erosion into larger vessels
may cause large vessel strokes (35,36).
Cysticerci within the subarachnoid space can grow to sizes larger than the 1 to 2 cm typical of
parenchymal cysticerci (Fig. 46.4C). These giant cysticerci may expand to sizes up to 10 cm in diameter
and can cause mass effects (37). The mass effects are especially prominent when the cysticerci are
inflamed either from spontaneous degeneration or after drug treatment.
Classification and Clinical Manifestations

The clinical manifestations of NCC depend on the number and location of the cysticerci, as well as the
associated host response. Clinical classifications are usually based on neuroimaging (38–40). The most
common scheme separates NCC into parenchymal and extraparenchymal. Extraparenchymal NCC is
subdivided into ventricular and subarachnoid (including spinal). Experts agree that the term inactive NCC
be used to describe cases in which there is no longer evidence of either a viable or a degenerating
parasite. CT scans may reveal one or more calcifications, typically 2 to 10 mm in diameter. These
correspond to the calcific stage described pathologically. Often, these lesions are symptomatic causing
recurrent seizures associated with contrast enhancement (perilesional edema) (30,41–44). Some patients
may also present with hydrocephalus without evidence of cysts. These patients have had prior
arachnoiditis or granular ependymitis resulting in obstruction of CSF flow (e.g., aqueductal stenosis) or
CSF outflow obstruction.
Symptomatic parenchymal infection typically results from the host inflammatory response and carries a
favorable prognosis. Extraparenchymal disease tends to have a worse prognosis, with associated
hydrocephalus (usually requiring surgical therapy), and can be fatal if not properly managed (45,46).
Parenchymal Neurocysticercosis. Parenchymal infection is the most common form of disease, and in
most series, the majority of cases are inflamed cystic lesions. By contrast, noninflamed cysts rarely cause
symptoms. For example, Garcia and Del Brutto (47) have described a group of patients with numerous,
noninflamed cysticerci but few, if any, symptoms. Thus, symptomatic infection likely occurs when the
cysticercus can no longer control the host inflammatory and immune responses. Neuroimaging studies
reveal round cysts, typically 4 to 20 mm in diameter. The cyst fluid is often isodense with CSF. In viable
cysticerci, the cyst wall is thin (<1 mm thick) and is usually not visible. If seen, the scolex appears as a
round or tubular mass 1 to 3 mm long on the side of the cyst wall. The inflamed cyst wall becomes denser
and may display contrast enhancement of the wall (ring enhancement), cyst fluid, or surrounding tissues.
There is often edema surrounding the cysticercus, especially on T2-weighted magnetic resonance imaging
(MRI) scans. Later stage cysticerci appear as focal areas of enhancement or granulomas. The number of
cysticerci varies from one to several thousand. However, in areas where most patients with new-onset
seizures undergo CT scanning (e.g., India and the United States), most cases of parenchymal NCC have
only a single cyst (48–50).
A subgroup of patients with active parenchyma disease present with diffuse cerebral edema and a
clinical presentation resembling encephalitis (51). This form, termed cysticercal encephalitis, is more
common in children than adults. Cysticercal encephalitis results from an inflammatory reaction to large
numbers of cysticerci in the brain parenchyma. The accompanying inflammatory response causes diffuse
cerebral edema.
Ventricular Neurocysticercosis. In some series, 5% to 30% of patients with NCC had cysticerci in the
ventricles (1,40,50). These cysticerci can obstruct CSF flow causing hydrocephalus. The cysticerci are
found in any of the ventricles. Older series noted most of the ventricular cysticerci in the fourth ventricle,
but this may have reflected more severe disease when the cysticerci are in that location. In most cases, the
cysticerci cause symptoms while still viable (33). Because viable cysticerci have thin walls with cyst
fluid isodense with CSF, they may be difficult to detect by CT scanning, which usually only shows
evidence of obstructive hydrocephalus or distortion of the shapes of the involved ventricle. The cysticerci
are frequently visible on MRI (52,53). However, the findings are subtle and can be missed unless an
expert familiar with cysticercosis reviews the scan. These patients may also have parenchymal cysticerci.
Subarachnoid Neurocysticercosis. When patients have cysticerci in the gyri of the cerebral convexities,
the radiologic appearance, clinical presentation, and pathogenesis overlap with active parenchymal NCC.
However, the cysts may be slightly larger and are more likely to persist after antiparasitic chemotherapy.
With cysticerci in the fissures (especially the sylvian fissure), the cysticerci can enlarge to several
centimeters in diameter, termed giant cysticerci (37). Isolated cysticerci in the fissures carry a similar
prognosis to parenchymal cysts with symptoms resulting from parenchymal inflammation. In some
patients, however, the cysts may enlarge to the point of causing mass effects or midline shift. Most of the
time, giant cysticerci are accompanied by cysticerci in the parenchyma or basilar cisterns. The giant
cysticerci are readily visualized by CT or MRI, but the accompanying cysticerci in the basilar cisterns
may not be seen on CT or MRI. Cysticercosis of the basilar cisterns carries a grave prognosis. Most
patients are infected with numerous cysticerci that fill the basilar cisterns. Cisternal cysticercosis is
characterized by arachnoiditis, which may be seen as focal or diffuse meningeal enhancement or
vasculitis with strokes (34,36). Patients often develop communicating hydrocephalus. The spinal
subarachnoid space is commonly involved in patients with basal subarachnoid NCC (54).
Spinal Neurocysticercosis. Only a small percentage of patients with NCC have recognized spinal
involvement (1,40). Most cases of spinal NCC result from cysticerci in the subarachnoid space (45).
Initially, the cysticerci are free floating, and they may move between levels. When the cysticerci
degenerate, they eventually become fixed at one level. The accompanying inflammation may cause cord
compression from mass effect with obstruction of flow on myelogram. Cysticerci are rarely
intramedullary and may cause symptoms or signs from mass effect or accompanying inflammation.
Other Forms of Cysticercosis. Cysticercosis can involve the eye, with either intravitreal or subretinal
cysticerci (55). Cysticerci may involve the muscles. Only rarely do they cause more than minor
symptoms. Cysticerci can involve the subcutaneous tissues, where they present as a palpable cystic lesion
that is often confused with a sebaceous cyst.
Mixed Forms. Clinical cases, especially those involving large numbers of cysticerci, often include more
than one of the aforementioned forms. The pathogenesis and presentation may reflect each location. For
example, patients who present with seizures will usually have parenchymal cysticerci. However, some
also have cysticerci in the basilar cisterns that can progress to hydrocephalus later if not properly
managed.
The most common clinical manifestation of NCC is seizures (56–58) (Table 46.2). The seizures may be
either focal, focal with secondary generalization, or generalized (56,57,59). Most patients with seizures
have evidence of parenchymal cysticerci with associated edema or enhancement, corresponding to the
colloid or granular nodular stages. Electroencephalographic (EEG) studies for patients with active
disease may reveal focal abnormalities. The seizures are usually easily controlled and often resolve as
the inflammation subsides (57).
Some patients have seizures from calcified parenchymal NCC (60). The calcified lesions are thought to
represent scarring from prior active infection (calcific stage). In spite of the presentation with seizures,
few will have focal abnormalities on EEG studies. Patients who develop calcifications are more likely to
have recurrence of seizures if anticonvulsants are withdrawn (61,62). Thus, patients with calcifications
are classified as having remote symptomatic seizures (i.e., epilepsy) (56,57). They usually require
continuous treatment with antiepileptic therapy. Recent MRI studies have documented that some patients
with NCC and seizures have calcified lesions with associated enhancement (30,41,43,60,63). There is no
evidence that these lesions are associated with viable parasites. Instead, the enhancement may result from
breakdown of the calcified granulomas, with antigen release resulting in restimulation of host
inflammation (63).
Headaches are common among patients with NCC and may be seen with parenchymal, ventricular, or
cisternal NCC. Headaches may be hemicranial or bilateral (64,65). The headaches can be confused with
uncomplicated migraines or tension headaches. The pathogenesis is also variable. In some cases,
headache is the initial symptom of raised intracranial pressure (ICP). The strong association of
parenchymal NCC with migraine-like headaches suggests vascular involvement (64). Headaches may also
reflect vasculitis associated with cisternal cysticercosis.
Patients may also present with symptoms or signs of raised ICP. Symptoms may include nausea or
vomiting, altered mental status, visual changes, or dizziness. In adults, raised ICP usually results from
obstructive hydrocephalus from cysticerci obstructing CSF flow in the ventricles. Patients with numerous
cysticerci in the basilar cisterns can also present with communicating hydrocephalus. Some pediatric
patients present with large numbers of inflamed cysticerci, causing cerebral edema (51,66). These
patients with cysticercal encephalitis may have altered mental status, raised ICP, or seizures.
Neurocognitive defects and decreases in quality of life have been described with cysticercosis (67,68).
Infected children are thought to suffer from learning disabilities (69). There also appears to be an
association of cysticercosis with depression and perhaps psychosis (70). By contrast, acute alterations of
mental status usually reflect ongoing seizures or hydrocephalus. In our experience, altered mental status
that does not resolve after a brief postictal period usually results from hydrocephalus.
Less common manifestations include spinal cysticerci, which can present with radicular symptoms or
myelopathy, ocular disease with visual changes, subcutaneous nodules, which may be confused with
sebaceous cysts, and muscular disease presenting as a myopathy.
Diagnosis
Because the symptoms of NCC are similar to those of several other diseases and the parasite material is
not readily accessible, diagnosis has proven problematic (71). A consensus panel proposed diagnostic
criteria based on neuroimaging studies, serologic tests, clinical history, and exposure (71). Patients with
either an absolute criterion or two major criteria alone with two minor or epidemiologic criteria were
considered to have a definite diagnosis. One major criterion plus two other criteria or two minor criteria
plus exposure were considered to establish a probable diagnosis (Table 46.3).
Demonstration of T. solium infection in biopsy or autopsy material makes a conclusive diagnosis but is
rarely available. Parasites may be visualized directly when there is ocular involvement (55).
Neuroimaging studies may reveal a cystic lesion with an associated scolex (demonstrated as a 1- to 3-mm
mural nodule) (Fig. 46.4A and B). This is thought to be pathognomonic for cysticercosis, although this has
never been rigorously tested (53,72). All of the aforementioned criteria were considered absolute and
diagnostic of NCC by Del Brutto et al. (71).
Neuroimaging studies that do not reveal a scolex, although suggestive of NCC, are usually not
diagnostic. Neuroimaging studies highly suggestive of NCC were considered major diagnostic criteria.
These included cystic lesions, single or multiple ringlike or nodular enhancing lesions, and typical
parenchymal brain calcifications. Parenchymal cysts are typically round and 5 to 20 mm in diameter (Fig.
46.4B). They are usually found in the cerebral cortex or the basal ganglia. Cysts in the subarachnoid
space are often larger, attaining a diameter of up to 60 mm. They may be either round or lobulated.
Cysticerci may also be located in the cerebral ventricles. Ring-enhancing or nodular enhancing lesions
are also highly suggestive of NCC. However, a number of other diseases including tuberculomas, brain
abscesses, and tumors can cause similar lesions. Cysticercal lesions are usually smaller than 20 mm in
diameter and rarely cause midline shift (12). Parenchymal brain calcifications are a common CT finding
in NCC. In cysticercosis, the calcifications tend to be solid, dense, supratentorial, and 2 to 10 mm in
diameter, and in the absence of evidence of other illnesses should be considered as highly suggestive of
NCC. Thus, characteristic calcifications are highly suggestive of NCC (71).
Which imaging modality to use depends on a number of factors. CT scanning is more sensitive than
MRI at detecting intracerebral calcifications (53,72). By contrast, MRI is much better at detecting
cysticerci in the CSF (e.g., ventricular or cisternal cysticercosis) (52,53,73,74). MRI may also reveal the
scolex, which is usually not visible on CT scans (75). Either method is adequate for imaging
intraparenchymal cysticerci or hydrocephalus.
Clinical criteria have not generally proved helpful in making a diagnosis. Rajshekhar and Chandy (12)
identified combined clinical and radiologic criteria for cysticercosis for patients who presented with
seizures and single enhancing lesions. The constellation of a single, round enhancing lesion less than 20
mm in diameter with no midline shift in patients without increased ICP, focal neurologic deficits, or
evidence of systemic disease was highly suggestive of NCC. In a cohort of more than 400 patients with a
single enhancing lesion, the criteria were about 99% sensitive and specific for NCC in an endemic
population. The diagnosis is further supported by resolution of the lesion spontaneously or after
anticysticercal therapy or by precipitation of symptoms by antiparasitic drugs (76). Thus, the consensus
panel felt that satisfying these criteria was a major diagnostic criterion (71).
Serologic tests have been examined as additional diagnostic criteria. Antibody-detection assays that
employ crude antigen have proven problematic in cysticercosis because of cross reactions to other
common parasites and nonspecific binding of antibody by the parasite. Tsang et al. (77) at the Centers for
Disease Control and Prevention (CDC) developed an immunoblot assay employing semipurified
membrane antigens (termed the enzyme-linked immunotransfer blot [EITB]). Binding to any one of seven
bands is considered positive. This EITB assay was initially reported to be 98% sensitive and 100%
specific for cysticercosis (77). Subsequent studies have confirmed nearly 100% specificity, but the
sensitivity is limited in patients with either a single lesion or only calcified lesions (5,78–80). Thus,
detection of antibody by the EITB assay is another major diagnostic criterion (71). Other serologic tests
are less accurate and are generally not considered major diagnostic criteria. However, studies mostly
published since the consensus conference suggest that assays to detect parasite antigens may prove to be
important diagnostic studies (81–87) in serum, CSF, and even urine. A number of antigen-detection tests
are being developed.
Minor criteria include lesions compatible with NCC, but less suggestive. These include isolated
basilar meningitis, hydrocephalus, or filling defects in the spinal subarachnoid space without discrete
cysticerci. Each of these may be the only neuroradiologic finding in NCC. However, the radiographic
picture is not distinct, with similar findings observed in other diseases. Clinical symptoms of seizures or
hydrocephalus, though present in most symptomatic cases, can also be caused by other diseases. Thus, the
clinical pattern is also a minor criterion. Finally, evidence of cysticercosis outside the CNS
(subcutaneous nodules demonstrated to be due to T. solium, cigar-shaped muscle calcifications) is not
diagnostic of NCC and hence is only a minor criterion. Epidemiologic criteria include residence or
prolonged visits to endemic areas or contact with a tapeworm carrier.
Management
Symptomatic therapy, antiparasitic drugs, antiinflammatory drugs, and surgical therapy are all important in
the management of different forms of NCC. Their use should be guided by knowledge of the pathogenesis
of different forms of disease. Thus, treatment of NCC should be individualized based on the clinical
presentation, the number, location, and viability of cysticerci, and the host response.
Symptomatic Therapy. Symptomatic therapy plays a critical role in the management of NCC. Seizures
should be treated with anticonvulsant drugs and are generally easily controlled (57,59,88). Most
published experience is with phenytoin and carbamazepine, but other agents such as levetiracetam and
oxcarbazepine are likely effective. Among patients in whom neuroimaging studies normalize and seizures
are controlled, antiepileptic treatment can often be tapered off (56,57,59). However, the presence of
residual calcifications is a marker for a high risk of recurrent seizures and an indication for continued
treatment (61).
Hydrocephalus should generally be treated surgically. If obstruction is due to parasites in the lateral or
third ventricles, primary endoscopic removal may be both symptomatic and definitive therapy.
Obstructive hydrocephalus can be treated acutely by CSF diversion procedures such as
ventriculoperitoneal shunting. In the past, there was a high rate of shunt failure, partly because of
aspiration of the cysticerci into the shunt. Recent studies have demonstrated that antiparasitic drugs or
treatment with corticosteroids decreases the rate of shunt failure (1,33,89).
Antiinflammatory Drugs. Corticosteroids are frequently used in NCC to control inflammation. The main
indications for corticosteroid use are for forms of the disease in which the host response causes life-
threatening reactions. These include cysticercal encephalitis, subarachnoid NCC, and spinal
intramedullary NCC. Meningitis, vasculitis with stroke, and communicating hydrocephalus can result from
the host inflammatory response and accompanying arachnoiditis in subarachnoid NCC. Chronic
antiinflammatory therapy is a key component of treatment in these cases. Steroids are also used along with
antiparasitic drugs to treat parenchymal NCC to prevent the inflammatory reaction when the parasites die.
Methotrexate is increasingly being used as a steroid-sparing agent when antiinflammatory therapy needs
to be prolonged (90).
Antiparasitic Drugs. Considerable controversy has existed on the role of antiparasitic drugs in the
treatment of NCC. Prior to the use of CT and MRI scanning, diagnosis of NCC was difficult. Thus, the
spectrum of cases diagnosed tended to be weighted toward more severe disease. Two developments led
to a dramatic change in the prognosis. First, the development and dissemination of CT and subsequently
MRI scanning led to more widespread diagnosis of milder cases. Secondly, praziquantel and later
albendazole were recognized as antiparasitic agents that could kill the parasites. In Latin America, initial
uncontrolled trials of antiparasitic drugs were accompanied by resolution of neuroimaging abnormalities
and improved prognosis (91). It was generally assumed that the improvements were a consequence of
drug effects. By contrast, in the United States, neuroimaging studies were readily available, but because
of regulatory hurdles, antiparasitic drugs were available only later. Thus, U.S. clinicians recognized that
many cases of NCC resolved spontaneously without antiparasitic therapy (88). By contrast, when
antiparasitic drugs became available, there were reports of worsening symptoms with treatment (92). The
first randomized controlled trials were published in the 1990s (93). A metaanalysis of randomized
clinical trials evaluating the use of antiparasitics in cystic parenchymal or subarachnoid convexity lesions
demonstrated a slightly higher likelihood of radiologic resolution with antiparasitics. Antiparasitics also
seemed to be associated with higher resolution of enhancing lesions, although this difference did not reach
statistical significance. In addition, antiparasitics were associated with a reduction in seizure recurrence
in patients with enhancing lesions (94–96).
Praziquantel was the first antiparasitic drug reported to be effective in NCC. It has been widely
available since the early 1980s. Praziquantel is absorbed well after oral administration, but with
extensive first-pass metabolism. Metabolism is induced by antiepileptic drugs (carbamazepine, phenytoin,
and probably phenobarbital) and corticosteroids (97,98). This induction can be inhibited by cimetidine
(e.g., 400 mg orally three times a day), which may increase efficacy when praziquantel is coadministered
with anticonvulsants or corticosteroids (99–102). Dose-ranging studies have shown greater effects at
doses of 50 mg/kg day in three daily doses for 14 days. Subsequent studies demonstrated that doses as
high as 100 mg/kg per day could be given safely (103). Studies with praziquantel in parenchymal NCC
given in three doses of 25 mg/kg separated by only 2 hours suggest similar efficacy as with longer courses
of therapy (102,104,105).
Adverse reactions to praziquantel in NCC mainly include worsening neurologic function (e.g.,
headaches, dizziness, seizures, and increased ICP) thought to be caused by the host inflammatory response
to the dying parasite. Based on these observations, some observers recommend use of corticosteroids
along with antiparasitic drugs (92), but routine use of corticosteroids may decrease efficacy.
Albendazole is a benzimidazole anthelminthic agent with broad-spectrum activity versus most
nematodes and cestodes. Albendazole is given is a dose of 15 mg/kg per day in two daily doses. Side
effects include minor gastrointestinal (GI) side effects and neurologic effects similar to those described
for praziquantel. Imaging studies demonstrated resolution of parenchymal cysticerci as good or better than
those noted with praziquantel (106,107). Controlled trials in parenchymal NCC showed no difference in
neuroradiologic resolution with treatment for 7 days versus longer courses (107–109). Albendazole was
subsequently studied in cases of extraparenchymal disease and was associated with improvement
(37,110–114). However, none of these trials was controlled. The only randomized controlled trial that
included evaluation of extraparenchymal lesions showed higher resolution with albendazole, but this was
not statistically significant (115).
Recent studies have employed albendazole in combination with praziquantel. Animal studies suggest
that the combination is synergistic (116). Pharmacologic studies have demonstrated higher levels of
albendazole sulfoxide (117). A small, randomized trial of combination therapy in single enhancing lesions
noted slightly more rapid resolution, but this was not statistically significant. Two trials of combination
therapy suggest enhanced parasiticidal activity, but these trials have not yet been published.
Antiparasitic drugs are not recommended in patients with calcified parenchymal lesions, because there
are no signs of viable parasites. These patients typically present with seizures. Seizures are clustered
near the time of diagnosis, but they may recur years later (56,57,61). Thus, these patients may require
chronic antiepileptic therapy. If patients maintain therapeutic levels of the drugs, the risk of recurrent
seizures is very low (59). Some patients will have contrast enhancement or edema on imaging studies
(30,41,63). Whether they would benefit from antiinflammatory treatment is unclear. Some patients have
hydrocephalus related to scarring from prior infection (e.g., aqueductal stenosis) (118). In this case,
hydrocephalus can be corrected by ventriculoperitoneal shunting without the need for antiparasitic drugs.
Parenchymal Neurocysticercosis. Patients with cystic parenchymal lesions are usually asymptomatic. In
most symptomatic cases, neuroimaging studies demonstrate evidence of edema or contrast enhancement.
Thus, in most cases, symptoms are associated with transitional parasites that are in early stages of
degeneration. Neuroimaging studies will typically normalize within 1 to 2 years regardless of whether the
patients receive antiparasitic drugs (88,119–123). Thus, seizures tend to cluster near the time of
presentation (57). On the other hand, seizures are more common while there is residual parasite material
present (57) and most studies demonstrate more rapid radiographic normalization with antiparasitic
therapy (120). Accordingly, antiparasitics have shown to decrease the rate of seizure recurrence in
patients with parenchymal NCC. Although there is no consensus, most experts also agree that the
prognosis for patients with a single inflamed lesion is generally favorable with only symptomatic therapy
(88,93,119,124). Many experts think that the prognosis is worse when there are multiple lesions (93,119).
Such patients are more likely to have noninflamed viable parasites, and resolution may not be
synchronized. Thus, experts are more likely to recommend antiparasitic drugs (47,93,119). In cases with
numerous inflamed lesions with associated diffuse cerebral edema (cysticercal encephalitis),
antiparasitic drugs are contraindicated (93). Instead, the management of cerebral edema with high-dose
corticosteroids (e.g., dexamethasone) or in some cases, mannitol is of utmost importance.
Ventricular Neurocysticercosis. Ventricular NCC usually presents with hydrocephalus. Management

should focus on reversing hydrocephalus, reducing the risk for recurrence, and minimizing treatment-
associated morbidity (106). The traditional treatment is with emergent surgical removal of the cysticercus
from the ventricle. Because open brain surgery is associated with significant morbidity, alternative
approaches have been tried. Recent studies have demonstrated that cysticerci can usually be removed by
endoscopic surgery (125–131). Cysticerci in the lateral and third ventricles can be removed with rigid
endoscopes and the fourth ventricle can be approached with flexible endoscopes. When possible, this is
considered the preferred treatment for ventricular cysticerci (93).
Some patients require emergent CSF diversion by placement of a ventriculoperitoneal shunt. In older
series, up to 75% of patients with shunts developed shunt failure requiring revision or replacement.
Recent studies have demonstrated that shunt revision is infrequently required among patients who are also
treated with antiparasitic drugs (33,48,113, 114,132). Similarly, corticosteroids may decrease the risk of
shunt obstruction (89).
Subarachnoid Neurocysticercosis and Giant Cysticerci. NCC with involvement of the basilar cisterns
is a rare form of NCC associated with a poor prognosis. In one series of patients with this form of NCC,
those treated with only CSF diversion had a 90% fatality rate at 10 years (133). Complications include
mass effect, communicating hydrocephalus, vasculitis with stroke, and basilar meningitis (34,118).
No controlled trials have been performed on the management of subarachnoid NCC. However, recent
case series employing antiparasitic drugs, corticosteroids, and shunting for hydrocephalus have
demonstrated a markedly improved prognosis compared to earlier studies (37,45,111,112). A large
observational study that investigated medical treatment of patients with giant cysts in the sylvian fissure
documented good responses to repeated courses of antiparasitics (37). Thus, most experts consider
subarachnoid NCC a clear indication for more intensive antiparasitic therapy. This may take the form of
prolonged treatment or repeated courses of albendazole, higher doses of albendazole, or combinations of
praziquantel with albendazole.
Other Forms of Neurocysticercosis. NCC in the spine can be located in the subarachnoid space or can
be intramedullary. Because of the risks of paralysis from cord swelling, intramedullary infection is
usually approached surgically (93). Spinal subarachnoid cysticerci may respond to antiparasitic drugs
(45). Ocular disease may also respond to antiparasitic treatment, but the standard therapy is still surgical
removal (93).
Prevention
Transmission of T. solium in developed countries has been largely eliminated by meat inspection,
improved sanitation, and better animal husbandry. Human infection with adult tapeworms can also be
prevented by destruction, freezing, or adequate cooking of infected (measly) pork. Treatment of the
tapeworm carrier might result in elimination of the disease. However, detection of tapeworm carriers has
been problematic. Mass chemotherapy of humans has been tried with limited short-term success as a field
intervention. Development of an effective animal vaccine against cysticercosis may provide the best
potential tool toward the eradication of the disease. A recombinant vaccine has been developed for
Taenia ovis that can provide nearly complete protection. This vaccine is commercially available in
several countries. T. solium antigens have been cloned, and initial study results suggest vaccines based on
these proteins may be protective (134). The optimal control measure for cysticercosis may require mass
chemotherapy of tapeworm carriers with praziquantel or niclosamide, treatment of pigs with oxfendazole,
and vaccination (135).
Echinococcus
Human infection with the different echinococcal species is termed hydatid disease (136–139). The word
hydatid refers to the fluid-filled larval forms found in the intermediate hosts (hydatid is derived from a
Latin hydatis, or drop of water). Echinococcus granulosus and related species cause cystic hydatid
disease, which is characterized by cystic lesions found mainly in the liver or lungs. Isolated brain lesions
or second lesions in the brain occur in less than 5% of patients. Echinococcus multilocularis causes
alveolar hydatid disease, characterized by tumor-like collections of vesicular parasites in the liver.
Isolated lesions in the brain are very rare, but metastatic lesions from the liver to the brain may occur.
Echinococcus vogeli and Echinococcus oligarthrus cause polycystic hydatid disease, a rare cause of
visceral organ infection noted only in Latin America. CNS involvement has not been described.
The Parasites, Life Cycles, and Epidemiology

E. granulosus has two obligate mammalian hosts (136–139). The dog and other canines are the main
definitive host containing the tapeworm form. The tapeworms are 2 to 5 mm in length and contain only
three to four proglottids. The normal intermediate hosts are ruminants, which are infected when eating
material contaminated with ova passed in the feces of the canines. In the intermediate host, the eggs hatch
and release the invasive larva (termed the oncosphere), which then penetrates the intestine and migrates
to the tissues, primarily the liver. The larva develops into a large cystic lesion containing an external
laminar membrane, a germinal layer (the brood capsule), and a central fluid layer. Within the cyst fluid
are numerous protoscolexes, which form from the brood capsule (Fig. 46.5). When ingested by the
definitive host, the protoscolexes develop into tapeworms. If the cyst ruptures, however, the
protoscolexes can develop into additional hydatid cysts. A number of separate life cycles have been noted
for what was previously assumed to be a single species (140). However, recent molecular evidence
suggests that there may be separate species infecting sheep, cattle, horses, and perhaps camels. The sheep
strains appear to be most pathogenic for humans, hence the association between human disease and sheep
raising. E. granulosus has a wide geographic distribution. Highly endemic areas include countries
surrounding the Mediterranean Sea, the Middle East, East Africa, parts of Russia, and many countries in
South America. Locally acquired cases are occasionally noted in Australia, New Zealand, North
America, China, and South Asia.
E. multilocularis is mainly found in alpine and arctic zones. Foxes and wolves are the main definitive
hosts. However, domestic dogs can also be infected. The normal intermediate hosts are rodents. Cases are
increasing in Central Europe. Endemic areas also include Russia, parts of China, Canada, and Alaska. In
contrast to E. granulosus, the parasite develops as multiple adjacent vesicles, usually without internal
protoscolexes. However, the vesicles may bud and may spread as metastatic lesions.
Pathology and Pathogenesis

Humans are infected by ingesting the ova shed by dogs or other canines. After hatching in the intestine, the
invasive larva (or oncosphere) is released, attaches to and penetrates the intestine, and spreads
hematogenously (136–140). In the case of E. granulosus, approximately 70% of the parasites develop in
the liver. Another one third develops in the lung. Less common sites include bone, pelvis, spleen, and the
CNS. The echinococcal cysts slowly expand and generally remain asymptomatic until symptoms result
from their expanding size or their space-occupying effect. Because years may elapse before cysts enlarge
sufficiently to cause symptoms, cysts may be discovered incidentally on routine x-ray or ultrasound
studies.
E. multilocularis characteristically presents as a slowly growing hepatic tumor, with progressive
destruction of the liver and extension into vital structures (138,141). Patients commonly complain of right
upper quadrant and epigastric pain, and obstructive jaundice may be apparent. The liver lesions
metastasize to brain or lung.
Patients with hepatic echinococcosis who are symptomatic most often present with abdominal pain or a
palpable mass in the right upper quadrant. Rupture or leakage from a hydatid cyst may produce fever,
pruritus, urticaria, eosinophilia, or anaphylaxis. CNS disease typically presents as a mass lesion. In this
case, the slowly enlarging lesion may cause headaches, seizures, or focal neurologic abnormalities
(137,142–145).
Diagnosis
Diagnosis is primarily made by imaging studies. In the case of E. granulosus, CT or MRI scans of brain
typically demonstrate a spherical cystic lesion with smooth borders (144,146) (Fig. 46.6). The cyst wall
may or may not be visible. Daughter cysts within the main cyst and degenerative forms are occasionally
visualized by MRI. When the internal images from the protoscolexes (or “hydatid sand”) are seen, the
image can be diagnostic. Midline shift and distortion of the ventricles are common. Lesions are usually
not inflamed and thus do not have surrounding edema or enhancement. Cysts may be found outside of the
CNS, which suggests that the CNS lesion is also due to hydatid disease. The CT appearance of E.
multilocularis is less distinct. It may present as an ill-defined mass lesion. Most cases will also have
evidence of liver involvement.
In doubtful cases, serologic assays can be diagnostic. Enzyme-linked immunosorbent assay (ELISA) or
indirect hemagglutination assays are readily available and can be confirmed by immunoblot assays.
However, the sensitivity is not optimal for extrahepatic disease. For E. multilocularis, the EM2 ELISA
with purified antigen is the confirmation test.
Treatment
The treatment of choice for CNS hydatid disease is surgical removal. In the case of E. granulosus, care
must be taken not to rupture the cyst with resultant spread of the protoscolexes (Fig. 46.7). Complications
can include recurrent disease and death (147,148). This is more readily accomplished if the diagnosis is
made before surgery. Antiparasitic drugs, particularly albendazole, are routinely recommended before
surgery in hepatic cases (138,149). Although the role of chemotherapy in CNS disease is not clear, data
suggest that adjuvant chemotherapy for CNS disease is associated with an improved outcome (143). The
practice of aspirating the cyst and injecting scolicidal agents is no longer recommended because of the
increased risk of spillage of the protoscolexes. Drapes and potentially contaminated surfaces should be
covered with hypertonic saline.
In the case of E. multilocularis, CNS involvement is often a manifestation of advanced disease (141).
Few cases of alveolar hydatid disease can be cured with surgery alone, so chemotherapy is now routinely
recommended postoperatively (149). In patients in whom the lesion is completely resected, albendazole
is recommended for 2 years after surgery. In other patients, albendazole should be continued indefinitely.
There are also reports of treatment of cerebral disease with radiosurgery plus albendazole (150).
Prevention
Peridomestic transmission of E. granulosus is linked to canine infection, which can be prevented by not
feeding dogs on viscera of ruminants. People should also limit exposure to material potentially
contaminated by dog feces. The vaccine has already been developed and licensed in New Zealand. E.
multilocularis may be acquired from foxes or other animals. Care should be taken to avoid exposure to
material potentially contaminated by feces (e.g., wearing gloves when gardening).
Sparganosis
Sparganosis, caused by Spirometra mansoni, Spirometra ranarum, and Spirometra erinaei, is a parasitic
infection caused by the migratory larvae of these tapeworms. The adult tapeworm parasitizes the
intestines of domestic and wild carnivores, such as dogs and cats. The intermediate hosts are usually
frogs or snakes. Humans are an incidental host.
Epidemiology
Sparganosis infections occur worldwide but are most commonly reported in China, Korea, Japan, and
Southeast Asia (24,151–157). Most cases have a history of eating frogs or snakes (152,153,155). Topical
application of frog or snake poultices is also an important risk factor. Less than 70 cases have been
reported from the United States. The most common species causing human infections in the Western
Hemisphere is Spirometra mansonoides. In the Far East, the most common species is S. ranarum
followed by S. mansoni and S. erinaei (24).
Parasitology
Adult tapeworms (measuring 3 to 40 cm in length) are found in the small intestines of domestic and wild
carnivores (24). Eggs are shed in the animal’s feces into freshwater. Two intermediate hosts are involved
in the sparganosis infection cycle. The first includes an aquatic copepod crustacean, Cyclops, where the
procercoid larva develops. A second host, such as frogs, snakes, mammals, and birds, can ingest these
infected copepods. The procercoid larva develops into a motile form, called the sparganum, in the
second intermediate host’s GI tract. From the GI tract, the sparganum is able to attach to the mucosa,
penetrate the intestinal wall, and migrate into various tissues. The life cycle of Spirometra species is
completed when domestic or wild carnivores eat the infected tissues of the second intermediate host.
Humans serve as accidental secondary intermediate hosts when ingesting polluted freshwater containing
Cyclops; eating raw or inadequately cooked infected tissues of secondary intermediate hosts, such as
frogs, fish, and snakes; or by the direct application of infected tissues to the eye or an open wound as in
traditional medicines (24).
The spargana are off-white, motile, ribbon-shaped larvae with a broad evaginated anterior end (future
scolex) that can protrude and retract (24,158) (Fig. 46.8). This protruding and retracting motion helps it
traverse the host’s tissues. When the larvae reach the host tissues, they will either remain coiled or can
become elongated. Nodules (2 to 3 cm) are then formed in the subcutaneous tissues and superficial
muscles and less commonly the abdominal cavity, perirenal fat, breast, scrotum, ureter, lymphatics, orbit,
and the CNS. These nodules can be tender, inflamed, painful, or pruritic. Larva can be dissected out of
fibroadipose tissue in extracted nodules. When the parasites die, a strong inflammatory reaction is
elicited, leading to an abscess containing the Spirometra larvae.
This organism rarely enters the brain parenchyma, ventricular system, or spinal canal. Cerebral
sparganosis usually involves the cerebral hemispheres, with occasional extension to the external and
internal capsules and basal ganglia (158–162). White matter degeneration occurs, probably caused by
migration of the surviving larvae along the fiber tracts. The cerebellum, brainstem, and spinal cord are
less commonly involved. In the CNS, the larva is surrounded by a collagenous capsule, granulomatous
layer of inflammatory cells, and the formation of new capillaries. Degenerated worms develop into
punctate calcifications.
A rare and lethal form of sparganosis, termed proliferative sparganosis, has been described in Japan
in which spargana proliferate in tissues and throughout the body, ultimately leading to death (24,163).
Clinical Manifestations of Central Nervous System Sparganosis

CNS involvement with sparganosis occurs in variable proportions of cases (152,153,155,159). CNS
involvement may be subacute or chronic. The most common neurologic manifestations included seizures,
hemiparesis, and headache (152,159). When the migrating worms penetrate the ventricles, they can lead
to intraventricular hematomas and obstructive hydrocephalus. Cerebral sparganosis can result in
vasculitis leading to cerebral hemorrhage or infarction.
Diagnosis
Sparganosis should be suspected in patients from endemic areas with a history of eating frogs, fish, or
snakes, or characteristic findings on imaging studies (159–162). Serodiagnostic tests for sparganum-
specific immunoglobulin G (IgG) in either serum or CSF can help support the diagnosis but are not
widely available. An ELISA developed in Korea was reported to have a sensitivity of 80% to 85%
(151). Definitive diagnosis is made by the finding of a live worm or a lesion consisting of the remains of
a sparganum. Stereotactic biopsy has also been used in making the diagnosis (164).
CNS imaging by CT or MRI may show characteristic slightly hypointensity on T1 images and
hyperintense on T2 (151,159–161,165). The CT triad of white matter hypodensity with adjacent
ventricular dilation, irregular or nodular enhancing lesion, and small punctate calcifications is specific
for cerebral sparganosis, occurring in most patients (151,160). Movement of nodules or serpiginous
tubular tracts, as shown by repeated CT or MRI of the head, represents larval migration in the brain
(159,165). This may occur in one third of patients. MRI is less sensitive than CT for detecting small
punctate calcifications. However, MRI is more sensitive in detecting inflammatory changes, degenerated
white matter, thickening of the meninges, and nodular and subcortical lesions. Intracerebral petechial
hemorrhage or hematoma may also be seen. These lesions represent capillary or venous injury from the
migrating worm. MRI may show linear or curvilinear contrast-enhancing lesions, conforming to the shape
of the worm. Cerebral sparganosis can be confused with primary or metastatic malignancies and
granulomatous diseases.
Treatment
Treatment consists of surgical removal of nodules for patients with migrating nodules or lesions or
worsening of CT findings (Fig. 46.8) (151,159,164). Whether patients with nonmigrating nodules, lesions,
or calcifications should undergo surgical removal of lesions is not clear. Medical therapy with
praziquantel (50 mg/kg per day for 14 days) can kill the parasites and might provide benefit for patients
with surgically inaccessible CNS sparganosis (141). When patients have seizures, antiepileptic drugs
should be given. Whether there are any benefits to administering antiepileptic drugs to asymptomatic
patients is not known.
Prevention
Individuals who live in or are traveling to endemic areas should avoid ingestion of frogs, fish, snakes,
and contaminated water.
CENTRAL NERVOUS SYSTEM DISEASES CAUSED BY

NEMATODES
Angiostrongyliasis
Angiostrongylus cantonensis, the rat lungworm, is responsible for most human cases of eosinophilic
meningitis and meningoencephalitis. This parasite is found in many Pacific islands and in Southeast Asia,
but has recently spread to Hawaii, the Caribbean, and the Gulf of Mexico (157,166–172). The mortality
rate of A. cantonensis in human eosinophilic meningitis is low, but fatalities do occur. Human CNS
infections with this nematode are characterized by headache, paresthesias, and CSF leukocytosis with
striking eosinophilia. The related species Angiostrongylus costaricensis causes eosinophilic
gastroenteritis.
Epidemiology
Angiostrongyliasis occurs worldwide. The disease was first described in rats in 1933, and the first human
case was described in 1944 (166,167). Initial reports came from Southeast Asia (Thailand, Malaysia,
Vietnam, Indonesia, and southern China) (166,167,173,174). Subsequent cases have been noted from the
Pacific Islands, Egypt, the Caribbean, and Brazil (166,167,170,175). In the United States,
angiostrongyliasis is endemic in Hawaii and has been reported along the Gulf coast (171,172). The wide
geographic spread of infection is attributed to rats that are carried on ships. Increasing transcontinental
travel, influx of refugees, and importation of food from Southeast Asian countries are thought to be
factors. The endemic focus in the Caribbean likely represents spread from Asia (175).
Parasitology
The definitive hosts for A. cantonensis are rats (Fig. 46.9). The adult worm (2 to 3 cm long) lives and
deposits eggs in the pulmonary arteries of rats and other rodents (176). The eggs reach the lung and hatch
into first-stage larvae in the terminal branches of the pulmonary arteries. The larvae then migrate up the
rat’s trachea to reach the pharynx. The rat swallows the larvae, allowing access to the GI tract and
subsequent passage in the feces.
Intermediate hosts are mollusks such as freshwater snails and slugs, which may be exposed to infected
rat feces. Within mollusks, larvae proliferate, molt two times, and mature into second- and third-stage
larvae. Humans can be infected after ingestion of infected mollusks or paratenic hosts, such as frogs,
freshwater prawns, crabs, fish, and planaria. A less common path of infection is ingestion of contaminated
vegetables, water, or fruit juice containing third-stage larvae (Fig. 46.9). When the infective larva is
ingested, it penetrates the intestinal wall and reaches the bloodstream. Infective larvae may die in the
meningeal vessels or gain access to the CNS and eyes by tissue migration. In humans, the third-stage
larvae may migrate through the brain parenchyma and molt a third time into a fourth-stage larvae where
they ultimately die. In rats, but not humans, the fourth-stage larvae can again invade the venous system and
return to the right side of the heart and colonize the pulmonary artery where they become sexually mature.

Pathologic studies show relatively small worm tracks (0.1 to 2.0 mm in size) and microcavities in the
brain and spinal cord; edema with dilated meningeal vessels and diffuse subarachnoid hemorrhages;
leptomeningitis with perivascular inflammatory cells in white matter; and abscesses containing
inflammatory cells, parasitic worms, and debris in the meninges, brain tissue, and sometimes in blood
vessels or perivascular spaces (169,174,176–178). The small worm tracks and lack of tissue destruction
likely explain the low mortality, clinical severity, and neurologic sequelae in patients with
angiostrongyliasis.
Clinical Manifestations of Central Nervous System Angiostrongyliasis

CNS manifestations typically begin 1 to 35 days after ingestion of snails, contaminated vegetables, or
exposure to infected rat urine. The symptoms can persist up to 10 weeks (166,
168–170,173,174,179–181). Nearly all patients report headache, often associated with photophobia.
Most will demonstrate neck pain or nuchal rigidity, nausea or vomiting, and paresthesias or hyperesthesia.
Fever, if present, tends to be modest. High fever, older age, and longer duration of fever are associated
with Angiostrongylus encephalitis, which carries a poor prognosis (180). Focal findings including
cranial nerve palsies, focal weakness, and hyporeflexia are rare except with encephalitis. Neurologic
symptoms are related to larval migration and local host reactions. Ocular involvement may result in
conjunctivitis, retinal hemorrhage, retinal detachment, or blindness.
Diagnosis
Mild peripheral blood eosinophilia is usually seen. CSF studies typically show a variable leukocytosis
(median 455 cells, range 0 to 1,660), with a predominance of lymphocytes but with some eosinophils
(median 16%) (170,173,181,182). Most will have increased protein concentration and a normal glucose
concentration. Unlike with NCC and gnathostomiasis, which are the other causes of eosinophilic
meningitis, CT or MRI scans of the brain are usually normal or lacking focal findings (with just meningeal
enhancement, cerebral edema, or enlarged ventricles) (182–185). Less common findings on MRI include
T1-hypointense/T2-hyperintense tracks and nodular enhancement. Definitive diagnosis made by isolating
larvae from brain (at biopsy or autopsy) or the CSF is rarely possible (173,182). In most patients, the
diagnosis is made by detection of specific antibody (169,170,181,186,187). An immunoblot assay is the
main test used in the United States. Antibody binding to a 31-kd antigen is considered diagnostic. A
variety of molecular methods are in development including polymerase chain reaction (PCR), loop-
mediated isothermal amplification (LAMP), and immunoPCR (188–191).
Treatment
Angiostrongylus infections are self-limited with good prognosis and low mortality
(166,169,170,173,174,181,182). Resolution of clinical symptoms takes about 1 to 2 weeks, with
occasional chronic symptoms and long-term neurologic sequelae. Corticosteroids (e.g., prednisone at 60
mg per day for 2 weeks) significantly hastens symptomatic improvement (166, 169,182,192–194).
Symptomatic therapy may also include analgesics and interval removal of CSF. Treatment with
antiparasitic drugs has been tried, including albendazole. In several small controlled trials, there was no
clear proof of benefit, but trends suggested a better response with dual therapy (166,168,
169,182,192,195).
Prevention
Travelers to endemic areas (including Southeast Asia and the Caribbean) should avoid ingestion of raw
or cooked snails and unwashed raw leafy vegetables. Contact with infected rats should also be avoided in
endemic areas.
Gnathostomiasis
Gnathostomiasis, most commonly caused by Gnathostoma spinigerum, is a human zoonotic disease

caused by migrating immature worms (157,158,168,169,196–199). Three other species of Gnathostoma
are known to cause human diseases: Gnathostoma hispidum, Gnathostoma nipponicum, and
Gnathostoma doloresi. These worms are parasites of mammalian carnivores, especially dogs and cats.
Humans are infected after ingestion of raw or pickled freshwater fish.
Epidemiology
Although gnathostomiasis is endemic worldwide, the most common areas include Southeast Asia, Japan,
Central America, Ecuador, Peru, and Mexico (157,169,197,199–201). Neurognathostomiasis is largely
confined to Thailand and Southeast Asia (197). Most cases have been associated with eating raw fish,
frogs, snakes, and raw or undercooked ducks or chickens.
Parasitology
Gnathostoma worms parasitize the gastric mucosa of mammalian carnivores (pigs, cats, dogs, and wild
animals) (Fig. 46.10) (157,158,168,169,196–200). The head of these worms (2 to 3 cm long) penetrates
the gastric mucosa of these animals while the tails protrude into the lumen of the stomach and release
eggs. The eggs then traverse the entire intestinal system and pass with feces into freshwater, where they
can hatch and mature into small first-stage larva. The larvae are then ingested by freshwater crustacean
copepods (genus Cyclops) where they undergo further maturation into second-stage larvae.
Secondary intermediate hosts such as fish, frogs, snakes, and eels ingest Cyclops containing second-
stage larvae, which encyst in the host tissues and develop into third-stage larvae. When infected,
secondary intermediate hosts are eaten by definitive hosts (pigs, cats, dogs, and wild animals), and larvae
penetrate the host’s stomach wall and develop into adult parasites before migrating to the gut to complete
their life cycle. In humans, however, larvae do not find their way back to the gastric mucosa but continue
migrating through tissues and organs. Ducks, chickens, pigs, and other species that ingest secondary
intermediate hosts may also develop infections with third-stage larvae in tissues and organs, which may
be as infective to humans. Drinking water contaminated with second-stage larvae in Cyclops may also
cause human gnathostomiasis.

The adult worm is 1 to 2 cm long with a retractable head carrying four circumferential rows of spines
(158,196,197,199). The anterior half of the worm body also carries rows of spines directed toward its
tail to assist in migration through tissues. Inflammation, hemorrhage, and necrosis result along the tracks
of Gnathostoma migration. Hemolysin, hyaluronidase, and acetylcholine-like substances are released in
response to the larvae migration through tissues. Transient painful, pruritic, edematous, creeping
eruptions, or abscesses develop in various tissues and vessels through which worms migrate.
When infected tissues containing Gnathostoma cysts are ingested, digestive enzymes from the stomach
free the larvae. The larvae then penetrate the gastric mucosa and travel to the circulation of the liver and
lungs before reaching skeletal muscles, subcutaneous tissues, and CNS.
Clinical Manifestations of Central Nervous System Gnathostomiasis

The invasive Gnathostoma larva readily penetrates tissues and is able to access any area of the CNS.
Second-stage larvae from the gastric mucosa can invade the lumbar, thoracic, cervical, and cranial nerve
roots through the spinal foramina, allowing entrance into the spinal canal and cord, causing sudden onset
of excruciating radiculopathy (157,169,174,197–199). The classic features of cerebral gnathostomiasis
include sudden onset of extreme severe radicular pain and/or headache followed by paralysis of the
extremities and/or the cranial nerves with migration signs. The radiculopathy may resolve over 1 to 5
days as the larvae continue to migrate cephalad into the brain parenchyma where they can leave tracks of
hemorrhage and necrosis. The larvae are long lived, and intermittent symptoms can occur for 10 to 15
years. Manifestations of CNS invasion included (in order of decreasing frequency) meningitis, multiple
cranial nerve palsies, encephalitis, subarachnoid or intracerebral hemorrhage, transverse myelitis,
radiculitis, optic nerve lesion, radiculomyelitis or radiculomyelitis terminating with encephalitis, and
transient obstructive hydrocephalus (157,168,197,202). When the worm migrates along the spinal cord,
hemiplegia, paraplegia, and monoplegia may occur. When the eye is involved, anterior uveitis, holes in
the iris, subretinal hemorrhages, vitreous haze, and secondary glaucoma can occur (203–205).
Other symptoms experienced by infected patients with gnathostomiasis include nausea and vomiting,
pruritus, urticaria, and upper abdominal discomfort or pain within 1 to 2 days of ingesting larvae. Once
the larvae enter the stomach and penetrate the gastric mucosa, they can migrate to subcutaneous tissues for
1 to 2 months causing intermittent migratory erythema, pruritus, warmth, and swelling. The edema may
resolve over 1 to 2 weeks but may recur at 2- to 6-week intervals characterized by marked peripheral
blood eosinophilia. The characteristic skin lesion is a localized or migratory “creeping eruption” or
swelling of the subcutaneous skin (cutaneous larva migrans) and various visceral organs (visceral larva
migrans). Occasionally, breaks in the surface of the skin occur, facilitating removal, and diagnosis. The
most commonly affected areas are the head, trunk, upper limbs, and thighs.
Up to 25% of cases with CNS involvement are fatal (168,174,197,198). Human death occurs with
direct extensive involvement of vital centers of the brainstem, intracranial hemorrhage, or complications
such as pneumonia or sepsis. Of survivors, two thirds have no neurologic sequelae, and the remaining
third of patients had residual paresis, nerve root lesions, and cranial nerve lesions. Multiple cranial nerve
palsies is a poor prognostic sign.
Diagnosis
Definitive diagnosis is made when the worm is identified in biopsies of infected tissues or by removal of
the parasite from areas of broken skin. ELISA tests have been developed to look for antigen and antibody
associated with Gnathostoma but are not widely available (206–208). Immunoblot assays containing
specific G. spinigerum antigen have been developed to support the diagnosis of human gnathostomiasis.
Patients may have marked systemic eosinophilia (168,169,197,199). Those with CNS invasion may have
elevated CSF pressure (median opening pressure, 200 mm Hg [range, 90 to 350 mm Hg]), with CSF
findings including a leukocytosis with a median white blood cell count of 920 cells/mm3 (110 to 3,000),
eosinophilia of 54% (range, 15 to 90), elevated protein concentration at 0.80 mg/L (0.43 to 1.80), and a
normal glucose level 0.51 mg/L (0.18 to 1.00) (168,169,197,199). Larvae have not been isolated in the
CSF. CNS imaging studies are nonspecific but often reveal hemorrhage or myelitis (168,185,209,210).
Treatment
The treatment of symptomatic CNS gnathostomiasis is not clearly defined. Surgical removal or
antiparasitic therapy has been tried in cutaneous and ocular disease (169,197,199,211, 212). Albendazole
at 400 mg twice a day for 21 days or ivermectin at 0.2 mg/kg daily for 2 days is more than 93% effective
in treating dermal and subcutaneous involvement with gnathostomiasis. However, relapses are common
(213). No treatment studies have been done on patients with CNS involvement with gnathostomiasis, but a
trial of albendazole or ivermectin might be tried in an attempt to decrease long-term sequelae. Surgical
removal of larvae from the brain and eye is technically challenging. The worms are extremely small and
may be difficult to find because they migrate rapidly through tissues. Patients with radiculopathy may
benefit from analgesia and those with inflammation and edema may benefit from systemic steroids.
Prevention
Prevention of gnathostomiasis includes avoidance and proper cooking of foods contaminated with
Gnathostoma cysts or larvae, such as fish, snakes, and poultry in endemic areas. Drinking potentially
contaminated water should also be avoided.
Trichinosis
Trichinosis, classically caused by Trichinella spiralis, causes disease when humans ingest undercooked
meat (especially pork) containing Trichinella cysts (214,215). Several other species of Trichinella cause
human infection, including Trichinella pseudospiralis, Trichinella nativa, Trichinella nelsoni,
Trichinella murreli, and Trichinella britovi.
Epidemiology
Trichinosis occurs worldwide, but is most commonly diagnosed in Europe (215–217). Since the
implementation of effective sanitary and public health measures, the incidence of trichinosis has been
dramatically reduced. Only a total of 66 cases of trichinosis were reported to CDC from 2002 to 2007
(218). Although trichinosis from domestic food supplies has been decreasing for many years, resurgence
has occurred in cases derived from the consumption of wild game meat, especially bear. In Europe, meats
of horses and wild boars have played a significant role during outbreaks (215,217,219). Trichinosis has
reemerged as an important clinical problem in parts of Europe.
Parasitology
When mammals ingest infected skeletal muscles containing Trichinella cysts, gastric acid and pepsin free
the larvae, which are then able to complete their life cycle by colonizing the duodenum and jejunum
where they mature into adult worms. The female adult (2.2 mm long and 60 to 95 µm in diameter) and
male adult worm (half the size of the female) colonize and reproduce in the intestinal crypts and mucous
layer lining the duodenum and jejunum. Within the body cavity of the female adult, eggs are fertilized and
develop into motile larvae (100 to 160 µm in length and 6 to 60 µm in width), which are released and are
able to cross the bowel wall into the lymphatics. Each adult worm has a life span of 3 to 5 weeks. In that
time span, the female adult worm is able to produce 1,000 to 5,000 larvae.
These motile larvae are able to gain access to the bloodstream, passing into the right side of the heart,
the lungs, and into the arterial circulation. Larvae can cause inflammatory reactions in any organ where
they encyst. However, they are only able to further develop in skeletal muscle. An eosinophilic
inflammatory reaction, maturation into cysts, and subsequent dormancy for several years can occur in
skeletal muscle, especially the masseter and diaphragm.
Humans acquire trichinosis by ingestion of infected undercooked pork or other meats contaminated
with Trichinella cysts (215,216). Pigs are primarily infected when they ingest infected rats and other
rodents. Other animals such as birds (T. pseudospiralis), wild boars, polar bears (T. nativa), dogs,
walruses, cows, whales, other herbivores, and carnivores (T. nelsoni, T. britovi) become infected when
they feed on infected animal flesh. Horse meat is an increasing source of infection in Europe.

The migration of larvae in tissues elicits an eosinophilic inflammatory response (215,220,221). When
skeletal muscle invasion occurs, a sarcolemma surrounds the larvae, creating an appearance of a
basophilic halo around the larvae. Mononuclear cells and polymorphonuclear leukocytes are stimulated
and surround the sarcolemma, creating a granuloma containing Langerhans giant cells and eosinophils.
Inflammation generally subsides over 3 months as the larvae encystment is completed. These cysts may
eventually calcify over a period of months to years.
Pathologic studies demonstrate few if any parasites within the brain (215,220,221). Focal areas of
infarction may be seen. Punctate parenchymal hemorrhages, granulomas, and calcifications may be seen.
The perivascular and Virchow-Robin space may become edematous, dilated, thrombosed, and ruptured
with hemorrhage within small vessels. However, the CSF is usually without an inflammatory reaction.
Clinical Manifestations of Central Nervous System Trichinosis

Most infections with trichinosis are asymptomatic. Symptoms may develop 2 to 10 days after ingestion of
infected pork or meat. The severity of symptoms is associated with the number of ingested larval
parasites. Patients may present with fever, headaches, conjunctivitis, subconjunctival hemorrhages,
petechiae, periorbital or facial edema, abdominal cramps, vomiting, diarrhea, peripheral edema, rashes,
or myalgias (215,216,218,222,223). Once larval tissue migration begins, high fevers (38°C to 40°C) and
intense myalgias can develop, especially with involvement of the extraocular and jaw muscles. The
muscles are often firm and tender from inflammation and edema.
Severe manifestations of trichinosis may occur with cardiac (myocarditis), pulmonary (pneumonitis),
and CNS involvement (214,222,224,225). Symptomatic CNS involvement occurs only in a small
proportion of patients. Symptoms develop in the third week after infection with Trichinella. Although
disease could be caused by larval invasion or encystment, most of the neurologic disease is thought to be
due to vascular complications of hypereosinophilia. The neurologic findings in these patients include
encephalitis, delirium, hyporeactive or absent deep tendon reflexes, findings suggesting meningitis,
polyneuritis with motor weakness in the extremities, seizures, monoplegia, hemiplegia, paraplegia,
cranial nerve palsies, and organic psychoses.
Diagnosis
With CNS involvement, CSF eosinophilia or larvae are found only in 8% to 28% of patients. CT or MRI
scans of the brain often demonstrate cerebral infarction (162,214). They may show multiple small (a few
millimeters in size), contrast-enhancing nodular or ring lesions and focal calcifications. Most patients
with CNS trichinosis (90%) have marked peripheral blood eosinophilia. When muscle involvement
occurs, there are elevated serum concentrations of creatine phosphokinase and lactic dehydrogenase.
Antibody tests may help aid in the diagnosis of trichinosis. Indirect immunofluorescence, bentonite
flocculation, IgM, IgG, and IgE ELISAs have sensitivities in the 75% to 85% range (215,226–228). These
test results become positive 2 to 4 weeks after initial infection. Antigen-detection and PCR assays have
also been developed but are not widely available. Definitive diagnosis is made by muscle biopsy
revealing Trichinella cysts by microscopy.
Treatment
Corticosteroids can decrease the amount of inflammation and edema in patients with severe symptoms
involving the CNS, cardiac, or pulmonary systems. Thus, most patients with CNS involvement should be
treated with steroids (214,229–231). The antiparasitic treatment for trichinosis includes albendazole (400
mg two times daily for 8 to 14 days) or mebendazole (400 to 1,200 mg per day in two to three doses for
10 to 14 days) (214,229,230,232–234).
Prevention
Individuals should avoid ingestion of raw or undercooked meat of animals that are known hosts of
Trichinella species.
Strongyloidiasis
Strongyloidiasis, caused by Strongyloides stercoralis, causes disease when infective larvae penetrate the
skin. The adult female worms live in the wall of the duodenum, but larvae can reinvade the host causing
cutaneous, GI, pulmonary, and neurologic disease.
Epidemiology
Strongyloides infection has a global distribution with areas of high prevalence in most developing
countries as well as economically depressed areas of Europe and the United States (235,236).
Parasitology
The Strongyloides species have both free-living and parasitic life cycles. In the parasitic cycle, filariform
larvae are highly motile (up to 10 cm per hour) and are able to penetrate the skin by both mechanical and
enzymatic factors with collagenolytic and elastase activity. After penetrating the skin, the larvae travel
into the lymphatic system, gain access to the venous system, and are transported to the pulmonary vessels
(237,238). The larvae invade the alveoli, migrate up the bronchial tree, and then are swallowed. In the
small bowel, the filariform larvae molt twice to become adult female worms. Hermaphroditic female
adult worms colonize the intestinal wall of the duodenum and upper jejunum where they can produce 40
eggs daily. Eggs develop into rhabditiform larvae in the bowel wall, which enter the lumen. Rhabditiform
larvae are passed in the stool. Most rhabditiform larvae are not infective until they pass outside the body
and spend days to weeks in the soil where they transform into infective larvae. However, some of the
rhabditiform larvae mature into filariform larvae before they are expelled in the feces. These invasive
forms can then reinfect the host (termed autoinfection). The parasites may reinvade through the rectum or
intestinal wall (internal autoinfection) or perirectal skin (external autoinfection). In hyperinfection,
reinvasion may take place in the intestines (237). Because of this efficient life cycle, S. stercoralis
infection can persist within a human host for decades after leaving an endemic area (239,240).
In the free-living cycle, the rhabditiform larvae mature in moist soil into filariform infective larvae.
Then, after molting two to four times, they become free-living adult males and females. The free-living
adults mate and produce eggs from which rhabditiform and then filariform larvae develop.

Chronic strongyloidiasis occurs because of autoinfection and can last for many years. This process is
usually controlled with limited numbers of organisms produced. However, autoinfection can also lead to
a high parasite burden, termed the hyperinfection syndrome (238,241–243). Hyperinfection is most
commonly associated with corticosteroid treatment. Hyperinfection is also associated with underlying
diseases, especially human T lymphotrophic virus type 1 (HTLV-1) infection, but also renal failure,
alcoholism, malnutrition, and chemotherapy. Hyperinfection likely results from defective host antibody,
eosinophil, and neutrophil responses (235,244). The high burden of larvae in the hyperinfection syndrome
leads to dissemination with multisystem involvement including the intestines, lungs, CNS, liver,
peritoneal cavity, and adrenals (237,238,241,242,245,246). Mobile larvae are able to carry enteric
bacteria during migration, and polymicrobial bacteremia or meningitis can ensue (241,247). Intestinal
stasis, achlorhydria, and constipation may also predispose the patient to dissemination of Strongyloides.
Clinical Manifestations of Central Nervous System Strongyloidiasis

Most Strongyloides infections are asymptomatic or associated with only minor GI or dermatologic
symptoms (248,249). Dermatologic findings include larva currens, a rapidly moving intermittent
serpiginous, itchy skin eruption, and chronic urticaria commonly found on the buttock and waist areas. GI
symptoms include nausea, bloating, pain, diarrhea, and malabsorption. Disseminated Strongyloides
should be suspected in patients with fever, abdominal pain and distention, cough, diffuse pneumonia,
diarrhea, or polymicrobial bacteremia. Disseminated strongyloidiasis may cause shock, pulmonary and
neurologic complications, and sepsis.
Cerebral strongyloidiasis occurs either by direct larval invasion or by larval-induced enteric
bacteremia with subsequent pyogenic meningitis. CNS involvement by infective larvae may also cause
small blood vessel infarction with associated inflammatory infiltrates, granulomatous ependymitis, brain
edema, demyelinization, microvacuolation, and focal hemorrhage with necrosis (242,245,247,250).
Patients present with acute or subacute meningitis, abscess, cerebritis, cerebral vasculitis, or chronic
meningoencephalitis. CNS findings include headache, altered mental status, meningismus, focal or
generalized seizures, cranial nerve palsies, and motor weakness. The most common presentation is
bacterial meningitis, most commonly due to enteric organisms, including gram-negative organisms and
streptococci (247).
Diagnosis
During the chronic stages of strongyloidiasis, peripheral eosinophilia is common. However, eosinophilia
is unusual in the hyperinfection syndrome. Cerebral abscess may be visualized on CT scans of the brain
(251), but imaging studies are not typically abnormal and are not diagnostic. Definitive diagnosis depends
on identification of larvae (rhabditiform and occasionally filariform). These should be sought by
microscopic examination of stool, sputum (disseminated strongyloidiasis), and duodenal fluid via
aspiration or an enteric string test (252–254). Examination of serial samples increases the yield of
identifying larvae. Occasionally, larvae can be identified from bacterial cultures, in which tracks of
bacterial colonies trace the larval migration on culture plates. Larvae are occasionally found in CSF and
in the brain and meninges from biopsies or autopsy (255). Serologic assays for IgG antibodies to
Strongyloides are available, and an enzyme immunoassay is available from the CDC (256).
Treatment
Strongyloidiasis has traditionally been treated with thiabendazole (25 mg/kg orally twice daily). This
regimen has been used for patients with CNS Strongyloides infection (242,246). Treatment must be
continued until consecutive stool samples are free of larvae for several days (238). Ivermectin (200 µg/kg
per day given on 2 consecutive days and repeated in 2 weeks in compromised hosts) is now the treatment
of choice for infection outside of the CNS (257–260). Efficacy is similar to thiabendazole with fewer
side effects. However, there are few data on its use in CNS infection. Albendazole is a less effective
alternative therapy. Ideally, patients taking immunosuppressive drugs should discontinue the agent or
reduce the dose as much as possible.
Prevention
Those exposed to soil in endemic areas should wear protective footwear. Those who are living in
endemic areas or who have traveled to such areas should have the possibility of strongyloidiasis
evaluated before initiation of immunosuppressive therapy.
Toxocariasis
Toxocara species are intestinal ascarid nematodes of dogs and cats. Toxocariasis is a common and
important cause of larva migrans syndrome worldwide, especially in developing countries (261).
Toxocara was first described in 1952 as a parasite that caused hepatomegaly and eosinophilia in
children. Toxocara canis and Toxocara cati live as adult worms in the intestines of dogs and cats,
respectively. Most human infections are caused by T. canis. More than 90% of puppies are infected
within the first week of life. This highly adapted nematode infects dogs by transplacental and
transmammary migration of larvae from bitch to puppy. Dogs are also infected by the oral route with
ingestion of larvae in vomitus or of embryonated eggs in contaminated soil. These routes are also similar
for larvae in infected cats, except no placental transfer of larvae has been observed. Toxocara eggs can
be found in up to 30% of soil samples (262). The egg is the infective stage for humans. Once the egg is
ingested and hatches, the larva (350 to 450 µm by 16 to 20 µm) can migrate through various tissues.
Epidemiology
More than half of all U.S. households have dogs or cats. The intimate association between children,
especially 18 months to 3 years of age, and dogs and cats leads to environmental contamination with
infective eggs and human infections with Toxocara species (261–263). Most infected children with
toxocariasis have had a dog in the house or yard within 1 year of developing illness. Pica is an important
risk factor in children 1 to 6 years of age (264). The seroprevalence by ELISA varies by age and by
region. Seroprevalence of Toxocara antibody is much higher in young children than older individuals
(265). Serosurvey results suggest widespread infection, with 6.4% of individuals seropositive in the
United States, 3.6% in Japan, 51% in Taiwan, and 83% in Saint Lucia (263). Many new infections are
asymptomatic, which suggests that Toxocara larva migrans is underrecognized and underreported.
Parasitology
Toxocara species are large (8 to 18 cm) and heavy-bodied nematodes. The adult stage of these parasites
resides in the host’s small intestine, with a life span averaging 4 months. The female Toxocara are able to
produce 200,000 eggs per day. The fertilized eggs require a minimum of 14 to 21 days to develop into
larvae. However, most larvae can remain dormant for months to years in humid soil. The larvae are
unable to survive in direct sunlight and dry soil.

Humans are infected when they ingest Toxocara eggs or infective-stage larvae in contaminated soil.
Consumption of raw or undercooked meat of paratenic animals can also result in transmission (261,266).
Raw liver seems to be particularly infective in this setting (266,267). The disease produced in humans by
Toxocara is known as visceral larva migrans (VLM). This term was used to describe the prolonged
migration and persistence of larvae in infected hosts. The eggs of this nematode hatch and produce larvae
in the proximal small intestine. The larvae then penetrate the small intestinal mucosa and migrate to
various tissues, most commonly the liver and lung, then into the systemic circulation. Other sites infected
include the eye, which can cause blindness known as ocular larva migrans (OLM) (268–270), heart, and
the brain (271–273).
The migration of larvae to various tissues causes pathologic and immunologic responses eliciting
granulomatous inflammation with associated eosinophilia (272,273). The rapid migration of the larvae of
Toxocara through tissue causes tissue necrosis along the route with minimal inflammation (272). The
larvae are able to survive and protect themselves from the host’s immunologic response by producing and
shedding surface excretory-secretory antigens. Once migration stops, necrosis and hemorrhage develop in
the surrounding tissues with infiltration of various inflammatory cells such as polymorphonuclear
leukocytes, eosinophils, histiocytes, and lymphocytes. Collagenous capsules are formed around the larvae
and larvae tracks by 1 month. Chronic infections with Toxocara cause infiltration of cells, leading to a
delayed hypersensitivity reaction to larval proteins. A granuloma with a core of multinucleated cells and
leukocytes is then formed.
Granulomatous responses limiting larval migration may be less likely to occur in the CNS as compared
to other sites (272). Similar to migration through other tissues, larvae leave tracks of necrosis with
infiltrates of inflammatory cells when infecting the brain. In contrast to other sites of infection, however,
the larvae continue to accumulate progressively in the brain, likely because of decreased inflammatory
and other systemic immunologic responses from the host (274). Few pathologic descriptions of CNS
Toxocara infections have been described (272), but case reports describe live larvae in the biopsy of the
infected brain.
Clinical Manifestations of Central Nervous System Toxocariasis

Most infections with Toxocara are asymptomatic (272,273,275). The symptoms of VLM are dependent on
the numbers of eggs or larvae ingested, frequency of reinfection, which tissues are infected, and the host
inflammatory and immunologic responses. VLM, most often infecting children at the average age of 2
years, is manifested by symptoms of fever, sore throat, cough, wheezing, cervical adenitis,
lymphadenopathy, pulmonary infiltrate or pneumonia, abdominal pain, anorexia, nausea, vomiting,
hepatomegaly, limb pains, lethargy, sleep, and behavior disturbances (272).
The average age of patients with OLM is older (8 years) (269,270). Disease typically involves only
one eye. Patients can develop visual loss, strabismus, and eye pain as larvae can cause severe exudative
endophthalmitis with retinal detachment, posterior and peripheral retinochoroiditis, optic papillitis, and
uveitis (269,270). Funduscopic examination may reveal raised, unilateral, whitish or gray solitary
posterior pole or peripheral granulomatous lesions.
OLM is associated with lower numbers of ingested Toxocara, whereas VLM is associated with an
increased number of ingested larvae (261). When the number of ingested larvae is increased even further,
OLM can develop concurrently with VLM. Concurrent infection is associated with more severe
symptoms. Toxocara serum antibody titers are lower in individuals with OLM compared to those with
VLM. Neurologic manifestations of toxocariasis have been reported in up to 28% of infected patients.
Symptoms and signs include encephalopathy, meningoencephalitis, transverse myelitis, psychiatric
disturbances, focal or generalized seizures, epilepsy, and death (272). Several studies have identified an
association of antibody to T. canis and seizures, particularly focal seizures (262,264,276,277). At
present, however, whether this association is causal or merely a marker for another infection spread by
the oral route is not clear.
Diagnosis
Patients with marked or persistent eosinophilia should be evaluated for VLM and OLM by specific
serologic tests. Some cases may not develop marked eosinophilia. Imaging studies by ultrasound, CT, or
MRI may show the migratory tracks or granulomas of Toxocara larvae in various tissues, but they are
usually normal.
In a patient with clinical signs and a history of geophagia and exposure to dogs or cats, it may be
helpful to order Toxocara serologic tests. The most useful serologic test uses excretory-secretory antigens
from infective-stage larvae in an ELISA (278,279). Although an elevated ELISA titer in an infected
patient supports the diagnosis of Toxocara VLM and OLM, definitive diagnosis relies on identifying
characteristic larvae in biopsies of the infected tissue. A positive Toxocara ELISA titer does not
distinguish between a recent and prior infection because titers may be elevated for years after initial
infection. Seroprevalence studies have shown that 1% to 10% of asymptomatic children may have
positive ELISA titers to Toxocara (263). Although nonspecific, other clinical and laboratory findings may
include leukocytosis, hypergammaglobulinemia, and blood group isohemagglutinins in individuals with
VLM. MRI abnormalities, including T2-hyperintense lesions primarily in the white matter and basilar
enhancement, have also been reported in CNS disease (280–282). In cases of spinal cord involvement,
MRI may reveal nontumorous myelopathy mimicking transverse myelitis, single or multiple T2-
hyperintense lesions with focal nodular enhancement on posterior or posterolateral segments of the spinal
cord, short segmental involvement, and migration of lesions (283).
Treatment
Asymptomatic toxocariasis does not require anthelminthic treatment. Most of these patients will have
spontaneous resolution of their eosinophilia and ELISA titers will decline without adverse sequelae
(284). In patients with symptomatic toxocariasis, the treatment is primarily supportive. To suppress the
inflammatory response in ocular, pulmonary, myocardial, or CNS involvement, systemic corticosteroid
therapy (e.g., prednisone, 30 to 60 mg per day by mouth for 2 to 4 weeks) and intraocular corticosteroids
with eye involvement may be warranted (273,277,285). The indications for use of anthelminthic therapy
have not been clearly defined (273,275,285). Albendazole (15 mg/kg per day orally for 5 to 15 days) is
the treatment of choice. Mebendazole (20 to 25 mg/kg per day orally), diethylcarbamazine (50 to 150 mg
by mouth three times a day for 1 to 3 weeks), and thiabendazole (25 to 50 mg/kg per day by mouth for 1 to
3 weeks) have also been used (285). In OLM, anthelminthic drugs have not been shown to have any
benefits in addition to corticosteroid therapy. Laser photocoagulation has been shown to be an effective
way of destroying migrating larva detected by funduscopic examination. Chronic (>8 weeks) OLM
requires corticosteroids for the treatment of exacerbations, relapse, and progression of ocular disease.
Surgical intervention such as pars plana vitrectomy and scleral buckling are common ophthalmologic
procedures used to manage intraocular fibrous adhesions, retinal traction and detachment, retrolental
plaques, and chronic vitreal inflammation.
Prevention
Increased education, timely deworming of pets, emphasis on careful personal hygiene in pet owners,
preventing children from playing in and eating contaminated soil, and avoiding ingestion of raw meat and
liver of animals will minimize the development of Toxocara infections.
Baylisascaris procyonis
The raccoon ascarid Baylisascaris procyonis has recently been recognized as an important cause of
visceral, ocular, and neural larva migrans syndromes (NLM) in the United States (286–289). Infection
usually occurs in children or mentally retarded adults with variable onset of neurologic deterioration.
Exposure occurs mainly at raccoon latrines, where large numbers of infective eggs may be accidentally
ingested. CT and MRI scans often reveal atrophy and may reveal periventricular and deep white matter
changes (287,290,291). Definitive diagnosis requires demonstration of the parasite in biopsy material.
Serologic tests have also been described. Treatment with corticosteroids and albendazole has been
attempted with some improvement. However, long-term outcomes have generally been poor.

Humans are accidental intermediate hosts for B. procyonis. Infection follows the ingestion of B.
procyonis eggs containing infective second-stage larva. B. procyonis undergo aggressive tissue migration
that includes the CNS and eyes. Continued larval growth and migration following entry of even a few B.
procyonis larvae into the CNS may have potentially severe consequences. Animal and limited human
autopsy data suggest that B. procyonis hatch in the small intestine, penetrate the bowel mucosa, and pass
presumably via the portal circulation, through the liver and along vascular channels to the lungs
(292,293). In the lungs, B. procyonis larvae rupture pulmonary capillaries, enter pulmonary veins, return
to the left side of the heart, and gain access to the systemic circulation. Larvae most likely access the
brain by penetrating cerebral blood vessels. On autopsies, the brain was the most severely affected organ.
Massive larval invasion of the CNS is characteristic, with estimates of more than 3,200 larvae being
isolated from the brain of a single case (292). Macroscopic findings included marked swelling and
softening of the brain, leptomeningeal congestion and thickening, and evidence of cerebellar herniation.
Histologic findings for acute fatal cases demonstrate necrosis and inflammation with numerous
macrophages, eosinophils, lymphocytes, and occasional plasma cells concentrated in cerebral
periventricular white matter and leptomeninges. Large numbers of eosinophils and eosinophilic granules
and deposits of extracellular eosinophilic material (the Splendore-Hoeppli phenomenon) are present
around necrotic migration tracks and cerebral blood vessels (292,293). Immunofluorescence studies
suggest that eosinophilic material surrounding migration tracks, larvae, and perivascular area consists of
eosinophil major basic protein arising from eosinophil degranulation (294). Subacute cases of NLM
demonstrate well-defined granulomata, composed of relatively few intact eosinophils surrounded by a
chronic fibrotic reaction, and the absence of the acute inflammatory reaction (293).
Clinical Manifestations of Central Nervous System Baylisascaris

The majority of human patients with B. procyonis neural larva migrans present with an acute fulminant
eosinophilic meningoencephalitis (286,288,292,293,295). Early features include low-grade fever, ataxia,
increasing lethargy, somnolence, and periods of increased irritability. Over time, there is regression and
loss of developmental milestones, progression to extensor posturing, increasing spasticity with hemi- or
quadriparesis, and ocular or cranial nerve involvement. Seizures occur commonly and may be difficult to
control. Neurologic status may deteriorate rapidly to stupor, coma, and death. To date, all survivors have
been left in a persistent vegetative state or with severe residual deficits. Most infants and children with
clinical visceral larva migrans and neural larva migrans also have evidence of ocular disease. Visual
impairment or blindness results from widespread larval migration, with destruction of the visual cortex,
or from larval migration within the eye itself (293,296).
Diagnosis
In the absence of a brain biopsy, the diagnosis of B. procyonis NLM is dependent on serology.
Demonstration of anti-B. procyonis antibodies in serum and CSF, particularly in the setting of a
compatible clinical case and epidemiologic history, is the mainstay of diagnosis. ELISA using larval
excretory-secretory antigens is available in United States (291). A diagnosis of ocular baylisascariasis is
supported by characteristic chorioretinal lesions, and especially by observation of a larva in the eye
(286,296).
Treatment
The prognosis is grave with or without treatment. The majority of cases have been treated with
anthelminthics and corticosteroids without intact survivors. The role of prophylactic anthelminthic
treatment for asymptomatic children is unclear but could be potentially beneficial (297). Given the
potentially devastating sequela of untreated infection or late treatment and the availability of well-
tolerated anthelminthics, prophylaxis appears warranted in select cases with documented exposure to
infected raccoons, raccoon feces, or contaminated environments (291,297). Systemic corticosteroids
could be beneficial and have been used in the majority of B. procyonis NLM cases.
Prevention
Most cases of B. procyonis infection are preventable by relatively simple measures. Education of the
public regarding the potential dangers of contact with raccoons or their feces is the most important
preventive step. Young infants and toddlers, particularly those with pica or geophagia, should be kept
away from potentially contaminated areas.
Lagochilascariasis
Lagochilascaris minor and other species are found in opossums, raccoons, ocelots, dogs, and cats. Cases
of human infection include abscesses of the neck, tonsils, mastoid, nasal sinus, and lesions of the lung,
cervical and sacral spine, and subcutaneous tissues (298). Lagochilascariasis has rarely been reported in
Brazil and other countries in Latin America. Lagochilascariasis is most commonly seen in individuals
who live in or close to forested areas and in rural areas and individuals of the lowest socioeconomic
status.
Parasitology, Pathogenesis, and Pathology

Little is known about the life cycle of Lagochilascaris. Wild rodents can act as intermediate hosts or
paratenic hosts of Lagochilascaris minor. An autoinfecting cycle may occur in felines, which also serve
as definitive hosts. Humans are infected when they ingest infected rodents (299).
Clinical Manifestations of Central Nervous System Lagochilascariasis

The clinical manifestation of Lagochilascaris may vary from mild to severe symptoms. L. minor lesions
in animals and humans characteristically result in tumors and fistulas with cutaneous and subcutaneous
abscesses localized in the cervical region and surrounding tissues (300). Cases have reported parasite
lesions of mastoids, jaw, tonsils, maxillary and paranasal sinuses, middle ear, pharynx, deep pharyngeal
space, ocular globe, and meninges (300,301). One report of a fatal case of encephalopathy with
lagochilascariasis minor has been described (298). The patient had signs of headache and meningismus.
His physical examination was significant for papilledema, hemiparesis, and mental deterioration, which
progressed to coma then death. Laboratory findings showed mild eosinophilia, increased erythrocyte
sedimentation rate, and increased protein concentration in CSF. A later lumbar puncture showed
progressive increases in CSF white and red blood cell counts. CT scan of the brain showed areas of
hemorrhage and infarction. Numerous larvae and adult worms were identified in the brain at autopsy.
Diagnosis
Definitive diagnosis of human infection is made by biopsy and findings of adult worms in the involved
tissues.
Treatment
There is no proven therapy for lagochilascariasis. Two case reports described successful treatment with
ivermectin (302,303). Thiabendazole, mebendazole, and levamisole have been tried with varying success
(300,301,304–306).
Prevention
Prevention likely consists of careful observation of proper hygiene, including hand washing and use of
clean water and sanitation.
CENTRAL NERVOUS SYSTEM DISEASES CAUSED BY

TREMATODES
Schistosomiasis
Schistosomiasis, depending on the region of the world, is caused by Schistosoma japonicum,
Schistosoma mansoni, and Schistosoma hematobium. Two minor species (Schistosoma mekongi and
Schistosoma intercalatum) can also cause human infection in circumscribed foci in Southeast Asia and
Africa, respectively. Human contact with water is necessary for infection by schistosomes.
Epidemiology
Schistosomiasis affects more than 200 million people worldwide (307,308). S. japonicum is found
mainly in China, the Philippines, and Southeast Asia. S. mansoni is found in Africa, Southwest Asia, the
Caribbean, the Middle East, and part of South America. S. hematobium is found in Africa, the Middle
East, and Southwest Asia. No nonhuman reservoirs have been found for S. mansoni and S. hematobium,
although these species are rarely found in other hosts. Domestic animals are important reservoirs for S.
japonicum.
Parasitology
Humans are the definitive hosts. When the parasite eggs are passed into freshwater, they can release
ciliated miracidia, which swim and penetrate freshwater snails (307,308). Once inside the snail, the
miracidium is able to mature into a mother sporocyst, which can produce motile daughter sporocysts that
target the snail’s hepatic and gonadal tissues. The daughter sporocysts develop into cercariae within the
snail’s hepatic and gonadal tissues, migrate to the vascular sinuses, and exit through the mantle. Humans,
particularly children and adolescents, become infected when released motile cercariae attach to and
penetrate skin. The cercariae shed their forked tail and develop into the schistosomula, which migrates to
the heart, lung, and the liver. From the liver, each Schistosoma species is able to migrate to its preferred
sites and to its residence in venules. Nevertheless, the parasites occasionally migrate to other sites.
The adult worms of Schistosoma live in the human vasculature. S. mansoni lives in the inferior
mesenteric veins draining the large intestine, S. hematobium lives in the venous plexus surrounding the
bladder and in the rectal venules, and S. japonicum lives in the superior mesenteric veins draining the
small intestine. After the adult worms mate in the blood vessels, the female worm (7 to 20 mm) travels
against the flow of the blood to reach the vessels surrounding the intestine or bladder. There, she releases
hundreds to thousands of eggs in the small venules of the portal (S. mansoni and S. japonicum) and
periportal (S. hematobium) systems. The eggs may attach to the venule endothelium and migrate through
tissues to reach the intestine or bladder. Both eggs in the small venules and those attached to the
endothelium elicit a granulomatous inflammatory reaction, which facilitates migration of the eggs into the
lumen and excretion in feces or urine.

Early in the course of infection, adult worms may localize in the spinal cord vasculature or cerebral
vessels (307–309). More commonly and later in the course of infection, CNS schistosomiasis results from
ectopic deposition of the parasite eggs. In heavy infection, the ova are able to reach the CNS by
retrograde flow from the iliac veins and inferior vena cava by the valveless venous plexus of Batson
(307,308). Eggs reach the brain and spinal cord by embolization from this vertebral venous plexus.
Cerebral schistosomiasis is thought to be more common with S. japonicum because S. japonicum
releases small eggs, which are able to reach the brain. The eggs of S. mansoni are larger, containing a
lateral spine, and are found more commonly in the spinal cord. The eggs of S. hematobium are of
intermediate size and are found more commonly in the brain parenchyma compared to S. mansoni but less
commonly than S. japonicum. The different schistosomal species affect different regions of the CNS. S.
japonicum affects the brain, and S. hematobium and S. mansoni more commonly affect the spinal cord
(307,308).
Schistosome eggs have been identified in leptomeninges; parietal, occipital, and temporal lobes; basal
ganglia; hippocampus; brainstem; cerebellum; choroid plexus; and spinal cord. Eggs that localize to the
brain or spinal cord may cause inflammation with perivascular infiltration of lymphocytes, eosinophils,
and macrophages, focal and diffuse vasculitis, microinfarction, or granuloma formation (307,308,310).
Granulomas are less commonly seen in the brain and in chronic infection. This may reflect modulation of
the granulomatous response in late infection.
Schistosome infection consists of three phases (307,308). The first stage is cercarial dermatitis, where
cercariae penetrate the skin eliciting an acute inflammatory reaction. This may result in a transient rash at
the site of penetration. The second stage is termed acute schistosomiasis (or Katayama fever). It begins at
the time the adult worms begin to lay eggs, 2 to 8 weeks after the initial infection. Acute disease is now
recognized with all Schistosoma species. This stage is due to immune complexes formed in reaction to
schistosomal antigens. Clinical manifestations include fever, abdominal pain, diarrhea,
hepatosplenomegaly, muscle pains, and urticaria with peripheral blood eosinophilia. The third stage is
chronic schistosomiasis, which may involve many organ systems including the hepatosplenic, intestinal,
urinary, cardiopulmonary, and CNS. All species except S. hematobium may cause colonic polyposis and
bloody diarrhea. S. hematobium is associated with cystitis and ureteritis with hematuria, which can
progress to bladder cancer. S. mansoni, S japonicum, and S. mekongi are associated with portal
hypertension with hematemesis, splenomegaly, and pulmonary hypertension. The chronic states occur
because of the inflammatory, granulomatous, and fibrotic reactions to antigens in schistosome eggs.
Involvement of the CNS occurs in about 1% to 2% of patients, but most patients do not have neurologic
symptoms (307–309). Neurologic symptoms include mental confusion, meningitis, encephalitis, headache,
vertigo, seizures, coma, visual changes, optic neuritis, papilledema, hemiplegia, opisthotonos, and
tremors. Schistosomal myelopathy, characterized by lumbar pain (often radicular), followed by muscle
weakness, sensory deficits, and loss of sphincter control, most commonly involves the conus medullaris
from intramedullary granuloma. Other spinal cord involvement includes multiple nodules on the spinal
cord, cord compression, and cord necrosis and less likely involvement of the cauda equina and thoracic
portion of the spinal cord. Involvement of the spinal cord can cause flaccid paraplegia, sphincter
dysfunction, areflexia, spasticity, sensory deficit, radiculopathy, back pain, and transverse myelitis
(310,311). Additional CNS syndromes include cerebellar and vestibular syndromes, tumor-like mass
lesions, cerebral edema, and intracerebral and subarachnoid hemorrhage.
Diagnosis
Peripheral blood eosinophilia may occur, but other general laboratory studies are not particularly helpful.
The CSF may show pleocytosis typically with lymphocyte predominance. Eosinophils are present only in
a few patients. Protein concentrations are increased, glucose concentrations are normal, and ICP may be
increased (307,308). CSF from patients with schistosomal myelopathy may be xanthochromic.
CT and MRI scans of the brain may show cerebral edema or atrophy. Many patients present with large
granulomas, which can cause focal lucencies, enhancing lesions, tumor-like lesions, or intracerebral
hematomas (307–309,312). Some patients will display a characteristic central linear enhancement
surrounded by multiple enhancing punctate nodules (313,314) (Fig. 46.11). This treelike pattern is thought
to be highly suggestive of schistosomiasis. Myelography with CT may show schistosomiasis involvement
with intramedullary cord swelling and partial or complete spinal cord block (310,311,315). MRI scan
may reveal a nodular surface to the lesion (315).
Definitive diagnosis is made by identification of the characteristic ova in stool (S. mansoni and S.
japonicum) or urine (S. hematobium) (316). Because eggs are intermittently passed, repeated
examinations increase the yield of detection. Centrifugation and examination of urine sediment can also
aid in isolating eggs. Rectal biopsy may be a more sensitive way to detect the ova. Ova are not found in
the CSF. Although demonstration of ova in biopsies is possible, it is preferable to make the diagnosis
with less invasive tests. Serologic tests using egg or other parasite-derived antigens are available to
support the diagnosis of schistosomiasis. An ELISA using adult worm microsomal antigens is available at
the CDC and is more than 99% specific for Schistosoma infection and more than 95% sensitive for S.
mansoni and S. haematobium (317,318). However, the sensitivity is poor for S. japonicum infection.
Species-specific immunoblot assays are also available using adult microsomal antigens. Antigen-
detection assays have also been developed but are not readily available in the United States (319).
Treatment
Medical therapy for cerebral schistosomiasis of all species is with praziquantel (60 mg/kg orally in three
divided doses over a single day) (320). Patients who have schistosomiasis myelopathy can be treated at a
lower dose of praziquantel (40 mg/kg in two divided doses over 1 day) (307,308,321). Although no data
are available, corticosteroids are often given to reduce the edema associated with myelopathy and
cerebral lesions.
Surgical therapy is an important adjunctive therapy in patients who have tumor-like masses (322).
Laminectomy has been used in some patients with schistosomal myelopathy and still may be required in
the case of acute paraplegia. With recent improvement in prompt diagnosis plus treatment with
corticosteroids and praziquantel, surgical therapy is now less frequently required (307,308,321).
Prevention
Prevention of schistosomiasis includes avoiding contact with freshwater in endemic regions. Cercaria can
be eliminated by chlorination or allowing water to stand for at least 24 hours before contact.
Paragonimiasis
Paragonimiasis is caused by trematode parasites of the genus Paragonimus. Initially, most cases were
attributed to the species, Paragonimus westermani (307,308,321), which is also called the oriental lung
fluke. However, recent molecular data have demonstrated that there are over 40 species in the genus and
at least 8 Paragonimus species cause human infection (323–326).
Epidemiology
The first case of cerebral paragonimiasis was reported in Japan in 1887 in a man who had a chronic
cough and hemoptysis and developed seizures that subsequently led to coma and death. Postmortem
examination revealed adult flukes in cystic lesions in the right frontal and occipital lobes. Paragonimiasis
is endemic in Southeast Asia, Korea, Japan, and China. Other foci include Africa (Cameroon and
Nigeria), the west coasts of Central and South America, and central North America.
Parasitology
P. westermani causes classical pulmonary disease in China and Korea. A second species, P. skrjabina is
associated with extrapulmonary disease including cerebral infections. P. heterophyes is the main species
in Southeast Asia and India. P. africanus is endemic in Cameroon and Nigeria. In Latin America,
Paragonimus mexicanus causes both classical and atypical infections. Paragonimus kellicotti has been
associated with human infections in the United States. The reservoirs for paragonimiasis are tigers, other
felines, pigs, dogs, foxes, opossums, humans, and other mammals. Adult worms reside in cysts of the
host’s lungs. The hermaphroditic adults produce eggs, which are coughed up and excreted unembryonated
in the sputum or the feces. When the eggs reach freshwater, they become embryonated and release
miracidia. The miracidia penetrate snails, which serve as first intermediate hosts, and then develop into
cercariae. The cercariae are released into water and are then ingested by freshwater crayfish and crabs
where they encyst and become metacercariae. Humans and other animals are then infected when
freshwater crayfish and crabs containing metacercariae are ingested. The metacercariae excyst in the
small intestines. The larvae penetrate the bowel wall, migrate into the peritoneal cavity, through the
diaphragm, and into the lungs.

The most common extrapulmonary site of paragonimiasis is the brain. The adult worm (7 to 12 mm by 4 to
6 mm) reaches the CNS through the jugular foramen and causes arachnoiditis, granulomas, or abscesses
(327,328). Lesions are most common in the temporal and occipital lobes and less commonly in the frontal
and parietal lobes. Abscess cavities, containing giant cell granulomas and Charcot-Leyden crystals, are
often formed. The wall of the cavity is composed of highly vascular glial mesenchymal capsules with
numerous inflammatory cells.
Clinical Manifestations of Paragonimiasis
Most patients with paragonimiasis are asymptomatic or have mild symptoms. Pulmonary symptoms
include chronic cough with rusty sputum, intermittent hemoptysis, or pleurisy. Extrapulmonary symptoms
include abdominal pain, diarrhea, fever, urticaria, and hepatosplenomegaly.
The frequency of cerebral disease varies markedly by species, from less than 1% for most species to
31% of P. skrjabini cases (328). The main clinical syndromes for cerebral paragonimiasis are epilepsy,
hemiplegia or other mass lesion, aphasia, and headache (327). The most common neurologic symptom
with paragonimiasis is epilepsy, which occurs in up to 80% of patients with neurologic disease. Some
patients have symptoms of meningitis, but the symptoms are usually mild and self-limiting, but they may
be recurrent and chronic. Chronic infections may persist for 20 years. Basilar meningitis can involve the
optic nerves, causing visual disturbances and optic atrophy. Therefore, it is important to perform an
ophthalmologic examination.
Diagnosis
General laboratory tests are usually not helpful, although patients often have peripheral blood
eosinophilia. With pulmonary involvement, 70% may have multiple nodular lesions, fibrosis, cavities, or
calcifications by chest x-ray. With CNS involvement, lumbar puncture usually reveals CSF pleocytosis
with increased eosinophils, low glucose concentration (50%), and increased protein concentration. Skull
roentgenograms may reveal intracranial calcium deposits, characteristically described as “soap bubble”
calcifications (157,162). CT scans of the brain may show soap bubble calcification, cerebral atrophy,
solitary ringlike lesions or irregular enhancing lesions, localized hemorrhage with or without enhancing
lesions and poorly defined nonhemorrhagic nonenhancing lesions, and ventricular dilation. The most
characteristic imaging finding is a conglomerate of ring-enhancing grapelike cysts with surrounding
edema in one cerebral hemisphere that may be evident on CT or MRI scan. MRI scans may also show
edema and inflammatory changes.
Definitive diagnosis requires demonstration of the parasites or their ova. With pulmonary disease, ova
are often present in sputum or stool. However, ova are not typically excreted in isolated CNS infection.
Ova or parasites may be identified in operative specimens from CNS lesions.
Serologic tests are an important adjunct to diagnosis. Although serum antibody may not distinguish
acute from past infection in endemic areas, positive serologic test results are predictive of disease in a
low prevalence area. ELISA and immunoblot assays are available from the CDC. Reaction with an 8-kd
band by immunoblot is 96% sensitive and more than 99% specific for paragonimiasis (283). Complement
fixation tests and skin tests are available in some countries. Antigen-detection assays are also being
developed.
Treatment
Treatment of cerebral paragonimiasis may involve surgical or medical therapy. Hydrocephalus requires
surgical removal of cysts and relief of the hydrocephalus (327). Medical therapy with praziquantel (25
mg/kg three times per day for 2 to 3 days) is highly effective in pulmonary disease (327). However,
response rates in neurologic infections are only available from retrospective studies. Corticosteroids may
be added to praziquantel to reduce the inflammatory changes occurring with treatment. Acute disease
responds well to treatment. In contrast, the prognosis of chronic CNS disease, even with treatment, is
poorer.
Prevention
Prevention of paragonimiasis infections is achieved by avoiding ingestion of infected water or foods in
endemic areas.
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PART VIII ■ CHRONIC MENINGITIS AND
MENINGITIS OF NONINFECTIVE OR
UNCERTAIN ETIOLOGY
CHAPTER 47 CHRONIC MENINGITIS SYNDROME

AND MENINGITIS OF NONINFECTIVE OR UNCERTAIN
ETIOLOGY
JERZY HILDEBRAND† AND MARC HILDEBRAND
Chronic meningitis has been defined as a predominantly leptomeningeal disease with clinical and
cerebrospinal fluid (CSF) inflammatory changes persisting for 1 month or longer (1,2). However, this
simple definition may be difficult to apply prospectively if a patient’s evaluation is performed within 4
weeks of disease onset. Only primary leptomeningeal diseases are reviewed in this chapter. However, in
most chronic meningitis, the pathologic process is not confined to only this anatomic compartment.
Parenchymal and vascular brain lesions are commonly associated with meningeal diseases. On the other
hand, clinical manifestations and CSF changes due to primary parenchymal lesions such as brain abscess,
encephalitis, or subdural and extradural empyema may produce a chronic meningeal reaction.
Infection, tumor, systemic disease, and toxic reaction may cause chronic meningitis (Table 47.1).
Importantly, the distinction between acute and chronic meningitis is primarily based on the clinical
presentation and duration of CSF inflammatory changes, and agents causing predominantly chronic or
subacute meningitis may have an acute presentation associated with initial CSF polymorphonuclear
pleocytosis.
Clinical features of central nervous system (CNS) infection depend not only on the “seed” but also on
the “soil.” Immune state, age, and prior exposure and immunization influence the incidence, severity, and
rate of progression of leptomeningeal infections.
This chapter also includes discussion of the main causes of recurrent meningitis, although in most
patients, each bout has an acute presentation.
CLINICAL APPROACH
Chronic meningitis is less common than acute meningitis. A retrospective survey performed in New
Zealand between 1967 and 1983 in a population without risk factors identified 83 cases of chronic
meningitis (1). During the same period, acute bacterial and viral meningitides were diagnosed in 1,000
patients. In chronic diseases, the causative agent was identified in 55 patients (66%) and the most
common causes were tuberculosis (60%), carcinoma (13%), and Cryptococcus neoformans (11%). This
distribution is probably fairly representative of most Western countries. But the epidemiology of chronic
meningitis shows striking differences in geographic distribution, which are specific for each disease.
These differences require that clinical history should include, in addition to personal infectious and
noninfectious diseases, patient’s geographic and ethnic origin, prolonged stays or recent visits to foreign
countries, and professional and family exposure to infections.
The onset of the first manifestations of the meningeal disease such as headache and mild cognitive and
behavioral changes must be carefully recorded. In chronic meningitis, the onset of clinical signs is more
subtle and progressive and their course more protracted than in acute meningeal disease. Several weeks
or months may elapse from initial manifestation to diagnosis. The chronic signs of meningeal irritation
may be mild or even absent, especially in noninfectious chronic meningitis, immunosuppressed patients,
elderly, alcoholics, and in individuals who underwent a neurosurgical procedure. Fever, when present, is
usually less than 39°C. Cranial nerve palsies are common in diseases affecting the basilar meninges such
as tuberculosis, sarcoidosis, leptomeningeal metastases, and fungal infections. However, neurologic
features alone rarely suggest the correct diagnosis. Valuable clues may be gained from systemic
examination, which should include funduscopic examination; inspection of the entire skin, mouth, and anal
orifice; and a search for liver, spleen, lymph node, and joint abnormality.
Most radiologic investigations are dictated by the working hypothesis. However, all patients should
undergo a contrast-enhanced brain magnetic resonance image (MRI) scan or computed tomographic (CT)
scan and CT scan chest examination. In patients with signs of intracranial hypertension, brain imaging
should be performed before the lumbar puncture. In most chronic meningitis, a T1-weighted MRI scan
with contrast will demonstrate leptomeningeal contrast enhancement and associated brain lesions such as
ischemic or hemorrhagic strokes, abscesses, granulomas, leptomeningeal and brain metastases, or
hydrocephalus or a combination of these findings. CSF examination is essential for the diagnosis of
chronic meningitis. Total and differential cell count, glucose, and protein orient the workup, but the
definite diagnosis is provided by the following:
1. Direct identification of the infectious agent or neoplastic cells
2. Culture on aerobic, anaerobic (Actinomyces, Brucella), Löwenstein (mycobacteria), and Sabouraud
(fungi) media
3. The identification of specific antigens, DNA sequence (genetic amplification by polymerase chain
reaction [PCR]), and intrathecal synthesis of specific antibodies
Specific CSF characteristics and diagnostic procedures are reviewed separately for each pathology.
Analysis and culture of biologic fluid such as blood, urine, sputum, and stool may help identify the
infectious agent. Tissue examination including meningeal biopsy is helpful in the diagnosis of not only
noninfectious diseases but also infectious granulomas.
INFECTIOUS MENINGITIDES
Immunosuppression favors the occurrence of chronic meningitis and many meningeal infections are
caused by opportunistic agents. However, most microbial organisms are not exclusively opportunistic;
several organisms may cause infection in both immunosuppressed and immunocompetent patients.
We first describe chronic meningitis in the immunocompetent population and indicate in a separate
section the infectious causes and clinical characteristics of chronic meningitides in main
immunosuppression states, particularly AIDS and cancer.
Tuberculous Meningitis
Tuberculous meningitis is caused by Mycobacterium tuberculosis hominis and very seldom by

Mycobacterium bovis. Thus, humans are the main reservoir and history of pulmonary tuberculosis in the
household and in other close contacts is a helpful element in the diagnosis of the disease. After a
substantial and steady decline, the incidence of tuberculosis is increasing even in countries where
vaccination with Calmette-Guérin bacille is routinely performed. This increase is due to the AIDS
epidemic, increased prevalence of drug-resistant mycobacteria, new endogenous pockets of poverty, and
immigration from countries where the incidence of the disease is high. In Western countries, meningitis is
the most common neurologic manifestation of tuberculosis (3). In other parts of the world, parenchymal
tuberculomas are common and figure prominently in the differential diagnosis of tumor-like lesions. In the
United States, 5% to 10% of tuberculous patients present with meningitis (4) and 4,000 cases of
tuberculous meningitis are diagnosed each year. In France, tuberculous meningitis represents 1% of all
bacterial meningeal infections and only 0.7% of tuberculous individuals develop meningitis (5). In
countries where the incidence of tuberculosis remains high, meningitis mainly occurs in children and is
associated with an active systemic, primarily pulmonary, disease. However, in countries where the
incidence of the disease is low, tuberculous meningitis tends to occur mainly in adults (6) and is often the
only active manifestation of the disease, resulting from the seeding of mycobacteria from an old focus of
leptomeningeal infection.
Tuberculous meningitis usually has a subacute onset. The duration of the prodromal stage, consisting of
apathy, anorexia, malaise, headaches, and behavioral changes, is 2 to 3 weeks. Sometimes, a few months
may elapse before the definitive diagnosis is made (7). Signs of meningeal irritation may be missing,
particularly in children (8). The temperature is often moderate. The infection predominates in the
subarachnoid space adjacent to optic chiasma, basilar artery, and ependyma, thus explaining the frequency
of cranial nerve palsies (mainly of the sixth, third, fourth, and seventh pair) and hydrocephalus. In
untreated patients, focal neurologic deficits, stupor, and coma with or without seizures characterize late
stages of the disease. Treatment delay is strongly associated with poor outcome, and tuberculous
meningitis remains a substantial cause of morbidity and mortality in both children and adults (9). The
diagnostic procedure includes the examination of eye fundus, which may show papilledema and choroid
tubercles, general physical examination, and chest imaging. Brain MRI scans will demonstrate
leptomeningeal gadolinium enhancement in more than 80% of patients, associated tuberculomas in 10% to
20% of U.S. patients, and possible hydrocephalus or ischemic brain lesions. CNS vasculitis secondary to
tuberculous meningitis develops in 30% to 70% of patients (10). Skin reactivity to purified protein
derivative (PPD) indicates a recent infection by M. tuberculosis in previously negative individuals, but a
negative reaction does not exclude the diagnosis because the patient may be anergic. The test should then
be repeated after a 2-week antituberculous treatment period. Conversely, latent tuberculosis may produce
a positive tuberculin reaction.
Lumbar puncture is the cornerstone examination. Typical CSF contains tens to hundreds of white blood
cells per cubic millimeter, predominantly lymphocytes, but polymorphonuclear cells may reach 80% early
in the course of the illness. Protein level usually ranges from 100 to 500 mg/dL. Glucose concentration is
decreased in up to 85% of the patients, but levels less than 15 mg/dL are unusual.
Bacilli demonstration by Ziehl-Neelsen stain is diagnostic but often negative because of the paucity of
the organisms in the CSF. Repeated CSF examination may increase the yield. M. tuberculosis replicates
slowly and culture on appropriate medium requires several weeks (11), but new automated methods on
liquid media have significantly reduced the growth interval (12). Detection of mycobacterial DNA is a
much faster procedure. The use of nested DNA amplification has considerably increased the specificity
and the sensitivity of the PCR (13), and PCR is used increasingly worldwide. But even today, a negative
PCR does not exclude the diagnosis of tuberculous meningitis. Because the definite diagnosis of
meningeal tuberculosis may be either difficult or delayed, prompt therapy should be initiated as soon as
the disease is suspected. Response to antituberculous treatment confirms the diagnosis.
Other investigations that demonstrate extraneural tuberculosis favor the tuberculous nature of
meningitis. These examinations include direct staining and culture of sputum, gastric juice, blood, urine,
and stool. In selected patients, biopsy of the bone marrow and liver may be contributive.
Lyme or Bannwarth Disease
Lyme disease is caused by Borrelia burgdorferi (14), a spirochete transmitted to humans by ixodic ticks
either directly (walks in the woods) or through animal’s infected ticks (e.g., horses and stags). Lyme
disease is characterized by a seasonal occurrence with peak prevalence in late summer and early fall. The
disease is common in Europe, Asia, and North America, with an estimated incidence of 50,000 cases per
year in Europe (15) and more than 20,000 in the United States, mainly in the northeastern area, northern
Midwest, northern California, and Oregon (16).
In 40% of patients, there is a history of erythema migrans, an annular erythematous lesion, which is the
cardinal initial manifestation (stage 1). A comparison between 119 U.S. patients and 85 patients observed
in Slovenia indicates that other manifestations seen during stage 1 demonstrate marked geographic
differences. Several symptoms and signs are more common in the United States: fatigue (55% vs. 33%),
myalgia (44% vs. 21%), neck rigidity (38% vs. 8%), enlarged lymph nodes (38% vs. 9%), and
temperature of 37.8°C or higher (15% vs. 1%) (17). Benign cutaneous lymphocytoma is less common in
the United States, whereas recurrent arthritis and cardiac lesions are less common in Europe. These
differences could be related to different species: B. burgdorferi stricto sensu in the United States and
Borrelia garinii or Borrelia afzelii in Europe.
Weeks to months after the first manifestations, about 15% of untreated patients progress to stage 2,
which is characterized, from the neurologic point of view, by chronic meningitis and involvement of
spinal roots and peripheral nerves. The facial nerve is most commonly involved and isolated facial palsy
may be due to Lyme disease, especially in children (18). Meningitis is fluctuant, causing mild to moderate
headache, nausea, and photophobia and/or painful myeloradiculitis. Stiff neck is found in fewer than 20%
of patients and elevated temperature in about 10% only.
The diagnosis of meningeal infection is based on CSF examination, which typically shows less than
200 cells/mm3, which are predominantly mononuclear, moderately increased protein level with frequent
(about 60%) oligoclonal immunoglobulin G (IgG) bands, and normal glucose level. Years after the
primary infection, a few patients may develop encephalopathy, polyradiculopathy, and/or peripheral
neuropathy (stage 3). At this stage, CSF examination may show no abnormalities, particularly in patients
in whom the disease is confined to peripheral neuropathy (19).
The diagnosis of neuroborreliosis is based on the demonstration of increased levels of specific
immunoglobulins (by enzyme-linked immunosorbent assay [ELISA] and Western blot analysis) in the
serum and the CSF. Immunoglobulin M (IgM) antibodies are first detected at 3 to 4 weeks after infection
(peak, 6 to 8 weeks) and IgG at 8 to 12 weeks (peak, 6 months). Thus, these test results may be negative
during stage 1 (20) and possibly in early occurring meningeal infection, but their sensitivity is close to
100% for IgG in chronic infection. Conversely, specific intrathecal antibodies may be produced years
after a successful treatment of neuroborreliosis. Several retrospective and one recent prospective study
(21) indicate that elevated CSF levels of CXCL13, a B-cell chemokine, can help diagnose clinically
atypical or early neuroborreliosis and distinguish active from extinguished infection. The culture of the
spirochete from CSF is seldom successful, and the sensitivity of PCR performed on CSF is around 50%
(22,23), limiting its clinical use.
Neurosyphilis
Syphilis is caused by Treponema pallidum, a sexually transmitted spirochete. Transmission through blood
and placenta (congenital syphilis) is rare. Today, especially in the developed world, outbreaks of syphilis
are related to AIDS, in part because patients infected with HIV are less likely to respond to conventional-
dose therapy of syphilis and in part because neurosyphilis is more difficult to diagnose in HIV-infected
individuals. Around 10% of HIV-infected patients have active syphilis infection or serologic evidence of
latent syphilis (24) and about 1.5% has asymptomatic or symptomatic neurosyphilis (25).
Meningeal invasion by T. pallidum occurs in 10% to 40% of all patients with syphilis, mainly in the
early stages of the disease. More than 95% of meningeal infections are diagnosed during the first 2 years
following primary infection (secondary syphilis). After that period, patients with normal CSF are unlikely
to develop any form of neurosyphilis. About two thirds of meningeal and meningovascular syphilis remain
asymptomatic (26). Clinical manifestations include (27) acute or subacute “viral-like” aseptic meningitis
with malaise, fever, and headache. Neurologic signs include stiff neck, cranial nerve palsies, especially
of the seventh and eighth nerve, but any cranial nerve may be involved. Lesions of spinal roots are less
common. A vascular inflammatory reaction may cause symptomatic ischemic brain strokes and rarely
spinal cord lesions (28).
Optic examination may show papillary edema and chorioretinitis; however, vision is usually
preserved. Occasionally, systemic examination may disclose lymphadenopathies. Even untreated,
meningeal syphilis usually subsides and is followed by a period of latent disease. Years later, some
patients will develop parenchymal CNS manifestations, which may be viewed as a consequence of
persisting chronic meningitis. Even before the AIDS era, the use of antibiotics increased the relative
proportion of meningovascular syphilis and made parenchymal forms (e.g., dementia or general paresis
and tabes dorsalis) less common.
The CSF changes are usually more prominent in symptomatic than in asymptomatic meningitis. Normal
CSF makes syphilitic meningitis questionable, even when clinical data favor this diagnosis. In
meningovascular syphilis occurring in immunocompetent patients, the CSF analysis is always abnormal. It
is characterized by dozens to several hundreds of cells, predominantly lymphocytes; elevation of protein
(around 100 mg/dL) with oligoclonal IgG bands in about 60% of patients; and normal or slightly
depressed glucose level.
The definite diagnosis is based on serologic test results. CSF Venereal Disease Research Laboratory
(VDRL) test is highly specific; false-positive reactions are rare and may be due to blood contamination.
In syphilitic meningitis, VDRL test sensitivity reaches 90%, but in HIV-infected patients with
neurosyphilis, the test may be negative in up to 70% (29).
Fluorescent treponemal antibody-absorption (FTA-ABS) test in the CSF is even more sensitive (30)
but less specific than VDRL (31), with a rate of 30% of false-positive reactions making it an interesting
test to rule out neurosyphilis, but not to confirm it. The diagnosis of neurosyphilis is therefore based on
clinical data, CSF changes, and reactive CSF VDRL test results. PCR determination in the CSF is not
superior to CSF serologic test for establishing the diagnosis of active neurosyphilis (32,33).
Brucellosis (Undulant Fever)
Brucella is a gram-negative organism transmitted to humans by domestic animals. In Europe, the disease
is predominantly seen in Mediterranean countries. However, it also occurs in Arabian Peninsula, India,
Mexico, and South America. Brucellosis occurs preferentially in individuals in close contact with cattle
or who ingest unpasteurized dairy products. Systemic manifestations follow an undulant course including
fever, sweats, malaise, and headache, which are present in 50% of patients. Clinical signs include
lymphadenopathy and hepatosplenomegaly. In about one fifth of patients, these early manifestations are
followed by chronic infection, which may involve joints, lungs, kidneys, and other organs. Neurologic
manifestations occur in a few patients and include chronic meningitis or meningoencephalitis that may be
accompanied by cranial nerve palsy and optic neuritis (34).
CSF changes closely resemble those of tuberculous meningitis with tens to several hundreds of white
blood cells, moderately to greatly increased protein level, and low glucose level in at least 50% of
patients.
Clinical diagnosis is confirmed by serologic (CSF Brucella agglutinating antibodies) tests or PCR
assay, which showed a sensitivity of 97% and a specificity of 94% in one study of focal complications of
brucellosis, including five patients with neurobrucellosis (35). Nevertheless, PCR sensitivity and
specificity must still be fully validated before it can be used in routine laboratory testing (36). Direct
identification by Gram stain of the organism in the CSF is difficult, and CSF cultures are seldom positive
for the organism (37).
Other Bacterial Meningitides
Meningitis caused by Listeria monocytogenes often occurs in immunocompromised and debilitated (renal
failure with dialysis or transplantation, cancer, diabetes, and alcoholism) patients, in infants, but also in
individuals without predisposing factors. The infection is transmitted through contaminated food such as
unpasteurized milk and cheese. Like other bacteria, L. monocytogenes may cause acute purulent
meningitis. Occasionally, brainstem lesions (rhombencephalitis) are prominent findings. However, in
other patients, Listeria may mimic tuberculous meningitis by CSF changes including mononuclear cell
predominance and low glucose level. The diagnosis is made by direct CSF staining and culture. Blood
culture is contributive in up to 75% of patients because septicemia is common. Pretreatment with
antibiotics may jeopardize bacteria identification in patients with persisting CSF changes. These changes
are usually characterized by a persistent polymorphonuclear predominance (38).
Neurologic disorders occur in 20% to 40% of patients with infective endocarditis. These disorders are
more common in left-sided endocarditis, which produces mostly embolic ischemic or hemorrhagic
strokes, than in right-sided lesion in which encephalitis and septic or aseptic meningeal reaction may
occur. Endocarditis-associated meningitis may be either acute and purulent or more chronic (low-grade
meningitic infection). The most common infectious agents are Staphylococcus aureus and Streptococcus
pneumonia, and CSF cultures are positive in up to 25% of patients (39).
The spirochete causing leptospirosis (Leptospira interrogans) is transmitted to humans by domestic
(cats, dogs) and wild (rats) animals. Aseptic viral-like meningitis may be part of this widespread disease
(40). CSF reaction is predominantly mononuclear, but unlike in most viral meningitides, protein levels
often exceed 100 mg/dL. The diagnosis is based on the presence of antibodies in the CSF, which may not
be detected in the early stage of the disease.
Subacute or chronic meningitis may complicate intraventricular shunts or reservoirs. Coagulase-
negative and aureus staphylococci and Propionibacterium acnes are the most common agents (41).
Nocardia asteroides complex, a gram-negative bacterium, is found in soil and vegetables and is
contracted by inhalation. N. asteroides complex is often misclassified as a fungus because of its
filamentous and branching morphology. Most CNS infections occur in immunosuppressed patients and
consist of brain abscess. Subacute or chronic meningitis is rare (42).
Fungal Meningitis
Cryptococcus neoformans and Cryptococcus gattii

Cryptococcosis is the most common mycotic infection of the CNS. About 50% of the cases occur in
immunosuppressed patients, and over three quarters of cryptococcal CNS infections occurs in sub-
Saharan Africa. C. neoformans is a ubiquitous yeast. Bird manure is the main reservoir for human
infection, and the respiratory tract is the usual portal of entry. Systemic infection (pneumopathy and
cutaneous rash) may go unnoticed, and the clinical presentation is often dominated by subacute or chronic
meningitis, the most common neurologic presentation (43). It often resembles tuberculous meningitis by
clinical features (e.g., meningism, fever, and altered mentation) and CSF abnormalities (lymphocytic
pleocytosis and low glucose), but the course is usually slower. In HIV-infected patients, leukocyte count
is usually inferior to 20 cells/mm3, whereas there are lots of organisms in the CSF. Large parenchymal
granulomas, which are rarely seen in AIDS patients, cause expanding lesions with intracranial
hypertension and papilledema in up to 20% of patients. Such lesions may be demonstrated by contrast-
enhanced CT or MRI. The most commonly involved cranial nerves are the second and the eighth.
Cryptococcus gattii, traditionally found in tropical and subtropical geographic regions and previously
characterized in the aboriginal Australian population (44), has been extensively described since an
outbreak occurring in 1999 in British Columbia, Canada, and expanding to the U.S. Pacific Northwest.
Since then to 2007, 218 cases were described in British Columbia (45). Most patients were
immunocompetent, and none of them was HIV positive. Prominent clinical features were pulmonary
syndrome with 90% of patients, when CNS involvement accounted for only 18%. Ten percent had both
respiratory and CNS syndromes. The difference in clinical presentation with C. neoformans may be due
to strain or host characteristics.
Conventional diagnostic tools include direct examination by India ink stain in the CSF, cultures on
Sabouraud medium, and detection of cryptococcal antigen on both serum and CSF by using latex
agglutination or enzyme immunoassay, which is the most sensitive, specific, and rapid test. To better
respond to the need in resource-limited countries, a lateral flow immunoassay for antigen detection has
been developed and shows equivalent results compared to the tests described earlier (46).
Other Fungal Meningitides

Several fungal infections including histoplasmosis, blastomycosis, and coccidioidomycosis infect
predominantly healthy hosts. However, chronically ill and immunologically compromised individuals are
more susceptible than healthy persons, particularly to histoplasmosis and coccidioidomycosis. All three
diseases are endemic in North, Central, and South America and are caused by inhalation or implantation
of spores. The main presentation of the neurologic lesions observed in these fungal infections is acute or
chronic meningitis, which may be associated with signs of encephalitis caused by parenchymal
granulomas.
In histoplasmosis, CSF examination shows an increased number (usually <300 cell/µL) of
lymphocytes, plasmatocytes, and Histoplasma-containing macrophages; elevated protein; and often
decreased glucose.
In coccidioidomycosis, CSF changes may mimic tuberculous meningitis by mononuclear pleocytosis
and low glucose level (47), but in about one half of the cases, CSF is characterized by eosinophilia.
In blastomycosis (48), CSF pleocytosis may reach up to 3,000 cells, either with lymphocytes or
polymorphonuclear cell predominance, elevated protein up to several hundreds per 100 mL, and normal
or decreased glucose. CSF smear reveals the organism in about 50% of patients, and definitive diagnosis
requires isolation of the organism. CSF culture is positive in a minority of patients, and CSF antigen
detection may be useful.
For Histoplasma or coccidioidomycosis, CSF antibody titers are useful diagnostic tests that are
positive in 40% and 70% of patients, respectively (49,50). Negative results are mainly found in
immunosuppressed patients.
Other fungal infections are predominantly opportunistic and infect debilitated, immunologically
compromised, and neutropenic persons.
Candida species are ubiquitous yeast (fungi composed of filaments). Candida albicans is normal
constituent of human bacterial flora but may become pathogenic in patients treated with antibiotics,
corticosteroids, or other immunosuppressors and in diabetics. C. albicans causes CNS lesions mainly
during the late stage of the disseminated infection. Neurologic lesions, which often remain asymptomatic
(51), include microabscess (often too small to be seen on CT or MRI scan) and chronic meningitis (52),
which may be the only manifestation of the disease. Cranial nerve palsies and papilledema are common.
CSF pleocytosis with lymphocyte predominance may reach several hundreds of cells per microliter;
glucose is depressed in 60% of cases. The frequency of C. albicans recovery from CSF culture is high.
Aspergillosis and mucormycosis cause predominantly parenchymal ischemic lesions, granulomas, and
abscesses, with occasional CSF changes. Symptomatic isolated meningitis is rare (53,54).
Aspergillus fumigatus, the most common pathogenic Aspergillus, is a ubiquitous airborne mold, usually
acquired by inhalation. Ninety-three episodes of meningitis have been published since 1973 and are
reviewed in a recent publication (55). This clinical entity is found in both immunocompetent and
immunosuppressed patients. Mortality rate is around 90%. CSF shows pleocytosis of hundreds to
thousands of cells, either with polymorphonuclear or lymphocytic predominance, low glucose level, and
elevated protein. Fungal culture requires large amount of CSF and is only positive in one third of the
sample. Currently, galactomannan antigen determination in the CSF is the best diagnostic tool with a
sensitivity above 85%, based on the cutoff index of 0.5.
The most common presentation of mucormycosis is the rhinocerebral form of the disease. CNS
invasion by direct extension from paranasal sinuses is favored by surgery or trauma. Hematogenous or
lymphatic spread occurs mainly in immunosuppressed patients, particularly those with prolonged
neutropenia, and in uremic or diabetic patients. The extension of the infection to the orbit and the CNS
causes cranial nerve palsy (third, fourth, and sixth nerve), focal neurologic deficits, and seizures. Isolated
CNS involvement has been reported in drug addicts and HIV-infected patients (56). CSF changes are
nonspecific, and diagnostic confirmation is based on the examination of the infected tissue.
Viral Meningitis
Most chronic (slow) viruses produce encephalopathies such as subacute sclerosing panencephalitis
(defective measles virus) or multifocal leukoencephalopathy (JC polyomavirus) with or without
meningeal reaction. Chronic predominantly meningeal abnormalities due to viruses have been
occasionally reported in lymphocytic choriomeningitis (57), mumps (58), or enteroviral infection in
agammaglobulinemic children (59).
Parasitic Meningitides
CNS cysticercosis is a common cause of chronic meningitis in Mexico, South America, China, India, and
in immigrants from these countries (60). The infection by Taenia solium tapeworm is acquired by
ingestion of ova-contaminated food. Seizures, mainly caused by parenchymal cysts, are common and may
be the revealing sign of neurocysticercosis. Manifestations of meningitis, caused by leptomeningeal cysts,
range from mild headache to chronic meningism with hydrocephalus (61). Spinal subarachnoid
dissemination, which may remain asymptomatic, is common in patients with basal subarachnoid
neurocysticercosis, and these lesions may be demonstrated by spinal MRI (62). CSF changes are
correlated with the severity of meningism. Predominantly mononuclear pleocytosis may reach several
hundreds of cells per microliter and may include eosinophils in 50% of patients (63). CSF protein is
elevated and glucose level is decreased.
The diagnosis is based on neuroimaging and on serum and CSF-specific antibodies (64). Serum and
CSF HP10 antigen detection is a new useful and economic tool for diagnosis and monitoring treatment
efficacy for neurocysticercosis that involved subarachnoid space at the base of the brain (65,66).
Human infection by Angiostrongylus cantonensis, a nematode, usually results from ingestion of raw
seafood. The main endemic area is Southeast Asia, but occasional cases have been observed in Hawaii
and southern United States. Angiostrongylosis is the leading cause of acute meningitis and
encephalomeningitis in the endemic zone, but subacute and chronic presentations have been reported (67).
CSF is characterized by an eosinophilic reaction, often combined with blood eosinophilia. The diagnosis
is confirmed by serologic tests.
CNS infection by Toxoplasma gondii, mainly seen in patients with AIDS, mostly causes multiple brain
abscesses and is considered later in this chapter. In normal hosts, acquired toxoplasmosis remains most
often asymptomatic and signs of meningeal irritation are rare. CSF changes are characterized by
moderately elevated protein level and mononuclear pleocytosis. The parasite may be demonstrated in
centrifuged CSF sediment by Giemsa staining. A PCR test has been developed for early diagnosis (68).
Recurrent Meningitides
Recurrent meningitides differ from chronic diseases by their etiology and predominantly acute clinical
presentation, but occasionally, when the interval between consecutive bouts is short, they may mimic
chronic meningitis because of persisting CSF changes.
Mollaret Meningitis
Sixteen years after he made his first observation, Pierre Mollaret (69) reported a rare syndrome
characterized by recurrent, febrile (≥39°C), fulminant meningitis with severe headache, myalgia, and
possible epileptic seizures. Most patients presenting with the syndrome are young adults without any
underlying pathology. The disease resolves spontaneously within 48 hours, recurs with variable frequency
during months to years, but leaves no sequelae.
CSF examination reveals mixed pleocytosis, mild protein increase, and large mononuclear very fragile
cells called endothelial by morphologic analogy. Using PCR, most cases of Mollaret meningitis have
been attributed to herpes simplex virus 2 (HSV-2) (70,71).
Chronic Meningitis in Immunosuppressed Patients

Infectious agents causing chronic meningitis in immunosuppressed patients differ statistically from those
found in immunocompetent population. In addition, the immune status may modify the clinical expression
and the CSF changes. HIV infection is the most common cause of immunosuppression worldwide, and
HIV serology should be performed in every patient with chronic meningitis. Other causes of compromised
immunity include the use of corticosteroids and other immunosuppressive drugs, organ graft,
malignancies, particularly lymphomas and leukemias, and congenital agammaglobulinemia.
Chronic Meningitis in Patients with Acquired Immunodeficiency Syndrome

HIV infection is responsible for a wide variety of neurologic complications from the primary HIV
infection to the late stages of the disease. The spectrum of these complications has changed from the
beginning of the epidemic where opportunistic infections, peripheral neuropathies, and central
involvement due to HIV itself with the so-called AIDS dementia complex were the prominent clinical
features to more focus, today, on understanding, diagnosing, and managing HIV-associated neurocognitive
disorders. This change in interest is a consequence of the dramatic reduction in opportunistic infections
since the introduction of combination antiretroviral therapy (cART) and the awareness of more subtle
impairment in a population with greatly increased life expectancy. Nevertheless, chronic meningitis
remains a significant cause of neurologic complication in the HIV-infected population from the developing
world and is mainly due to opportunistic infections, which may be multiple in 17% of cases (72). Most
opportunistic CNS infections have a subacute onset with nonspecific symptoms and signs. Neuroimaging,
preferably by MRI, should be performed before lumbar puncture to rule out space-occupying lesions and
other contraindications to lumbar puncture.
HIV invades the CNS during the very first days after infection and is mostly asymptomatic. Less than
10% of seroconverters will develop acute lymphocytic meningitis or rarely acute meningoencephalitis
(73). CSF shows a mild lymphocytic pleocytosis, normal glucose, and normal or slightly elevated protein,
which may remain during the course of chronic HIV infection and make the interpretation of CSF
characteristics somewhat difficult (e.g., for neurosyphilis).
The two major causes of chronic meningitis in the HIV-infected population are cryptococcal and
tuberculous meningitis, which are both serious with a high morbidity and mortality rate. The incidence of
cryptococcal meningitis has, though, significantly decreased and varies from 0.04% to 12% per year, with
the highest median incidence in sub-Saharan Africa with 3.2% and around 720,000 cases, which account
for three quarters of all cases. By contrast, it has become extremely rare in developed countries, with a
median incidence lower than 0.1% per year (74). These data reflect the use of cART which, despite a
significant improvement in the last decade, is still not available to all patients who need it in the
developing world.
This opportunistic infection develops when immunosuppression is profound (CD4 cell count <100
cells/mm3). The clinical spectrum ranges from a subacute meningeal syndrome to minor signs such as
recurrent fever or headache. The latter presentation may go undiagnosed and rarely be complicated by
cerebral infarction and the development of focal neurologic deficits. Rarely, the presentation can be
fulminant with a coma leading to a rapid death. In AIDS-related cryptococcosis, the CSF often shows
little inflammatory reaction, but severe hypoglycorrhachia and high opening pressure are frequent,
probably because of a large burden of fungi that consumes glucose in the CSF and blocks its passage
across arachnoid villi (75). Parenchymal granuloma, also called cryptococcoma, is rare in AIDS.
The incidence of tuberculous meningitis among HIV-infected individuals depends on both tuberculosis
and HIV prevalence. According to the 2011 World Health Organization (WHO) data (76), only 960 HIV-
infected individuals developed tuberculosis in the United States versus 330,000 in South Africa.
In a secondary level hospital in Cape Town, South Africa, between March and August 2009,
tuberculous meningitis was diagnosed in 82 (47 definite and 35 probable) out of 211 HIV-infected
patients with meningitis, where cryptococcal meningitis was the second more common diagnosis with 48
episodes (77).
In a survey performed in Spain, the incidence of tuberculous meningitis was fivefold higher in AIDS
(10%) than in HIV-negative tuberculous population (78). Studies comparing the characteristics of
tuberculous meningitis between HIV-positive and HIV-negative patients failed to show significant
differences in clinical presentation, CSF changes, and outcome (78–80). However, CSF cell count may be
normal in up to 21.4% of patients (78,80–82), and CD4 cell count less than 200 cells/mm3 has been
associated with increased mortality. Given the high mortality rate in tuberculous meningitis and the risk of
immune reconstitution inflammatory syndrome in the severely immunosuppressed population, early
initiation of cART has been questioned, but has not been supported (83), unlike for the pulmonary
tuberculosis–HIV co-infection (84).
Other opportunistic agents produce mainly diffuse or multifocal encephalitis with nonspecific
secondary meningeal changes. However, symptomatic chronic meningitis may occur in a minority of
patients in illnesses such as Toxoplasma encephalitis (TE), CMV, and VZV CNS infections and are
described in the following discussion.
Toxoplasma encephalitis is the most common opportunistic infection of the CNS in AIDS. T. gondii, a
ubiquitous intracellular protozoan parasite, is widely distributed in the human population. Its reservoir
includes birds and others animals, but the definitive host is the cat family. TE is a reactivation of a latent
CNS infection and its incidence is correlated with the seroprevalence of toxoplasmosis and the severity
of immunodeficiency (CD4 cell count <100 cells/mm3 in 80% to 90% of patients). However,
seronegativity for T. gondii, although uncommon, does not exclude TE diagnosis (85). TE is characterized
by brain abscesses causing fever, headache, abnormal consciousness, focal deficit, and seizures.
Meningeal syndrome occurs in about 10% of the patients (85,86). The diagnosis is based on the presence
of one or, more often, multiple ring-shaped lesions on delayed contrast-enhanced brain CT or MRI scan,
the latter of which is far more sensitive, revealing lesions smaller than 1 cm in diameter. A lumbar
puncture is not routinely performed because CSF changes are not specific, and the PCR amplification is
insensitive. In addition, lumbar puncture may be hazardous in patients with multiple abscesses. The main
differential diagnoses are intracerebral tuberculoma or primary central nervous system lymphoma
(PCNSL), which has become rare since the use of cART. It should be considered when antitoxoplasmosis
treatment fails. CSF PCR amplification for Epstein-Barr virus DNA is positive in up to 80% of cases of
AIDS-related PCNSL.
Cytomegalovirus (CMV) is an important opportunistic pathogen and causes serious CNS
complications in end-stage AIDS patients. Seventy-five percent to ninety-eight percent of AIDS patients
are co-infected by CMV. Before the ART era, the 2-year probability of developing clinical CMV disease
for patients with CD4 cell counts less than 100 cells/mm3 was 21.4%. Two major neurologic
presentations were reported (87,88): subacute diffuse encephalitis and acute ventriculitis with
involvement of cranial nerves. Meningeal signs are absent in both conditions and CSF changes are minor
in the diffuse encephalitis. In CMV ventriculitis, however, neutrophilic pleocytosis with more than 500
cells/mm3 and low CSF glucose are present in all patients. Despite the use of cART and the combination
of ganciclovir and Foscavir, the mortality rate remains high in patients with CNS infection due to CMV.
Varicella-zoster virus (VZV) causes a typical vesicular rash involving one or more dermatomes or
acute retinal necrosis through the reactivation of a latent infection. Concomitant neurologic lesions
include encephalitis, myelitis, polyradiculitis, and occasionally subacute meningitis (89). VZV PCR
amplification in the CSF is a specific and sensitive diagnostic method. However, concomitant
opportunistic CNS infection may trigger a subclinical reactivation of VZV (90) and a positive VZV PCR
does not rule out a concomitant infection.
Syphilis and HIV infection are closely related. The HIV seroprevalence among patients with primary
syphilis in the United States is 15.7% (91). Conversely, syphilis seroprevalence among the HIV
population may be as high as 37.2% in some selected population (92), and about 1.5% of AIDS patients
will develop neurosyphilis. HIV infection may alter the interpretation of syphilis serologic tests and the
response to treatment. Definitive diagnosis of neurosyphilis in AIDS patients is challenging because the
CSF VDRL test, one of the most important tests in the diagnosis, may be nonreactive. In a series (93) of
39 AIDS patients with neurosyphilis (5 asymptomatic, 23 meningitis, and 11 meningovascular
neurosyphilis), CSF VDLR was available in 37 and positive in only 30. The authors of the review felt
that the actual incidence of negative serologic test results in the CSF is probably higher due to the
tendency to report only unarguable cases. Furthermore, CSF abnormalities can be caused by HIV itself in
individuals who do not have neurosyphilis.
Several reports have described clinical and laboratory-defined (94) treatment failures in HIV-infected
patients with neurosyphilis. Nevertheless, patients on cART who normalized their serum rapid plasma
reagin (RPR) titers were 4 times more likely to normalize CSF white blood cell count and 13 times more
likely to have resolved symptoms compared to patients not receiving cART (95), advocating the use of
cART in patients with neurosyphilis. Also, the use of cART before syphilis infection reduced the risk of
developing asymptomatic and symptomatic (67% of cases) neurosyphilis by 65% in a cohort of 180
patients who experienced 231 episodes of syphilis (96). In this study as in previous ones, other risk
factors for neurosyphilis were CD4 cell count of less than 350 cells/mm3 and/or serum RPR titers more
than 1:32.
Chronic Meningitis in Cancer Patients

Infectious diseases are common in cancer patients. They are favored by abnormalities of host defense,
including the following:
a. Lymphocyte and phagocyte defects caused by anticancer chemotherapy, corticosteroids, and underlying
malignancy, mainly leukemia and lymphomas
b. Abnormal immunoglobulins in chronic lymphocytic leukemia and lymphomas
c. Neutropenia related to chemotherapy or to acute leukemia
d. Splenectomy
However, infections limited to CNS are relatively uncommon. In 1974, their incidence at the Memorial
Sloan-Kettering Cancer Center was approximately only 0.05% (97) of admitted patients. They occur
mainly after surgical procedures including placement of Ommaya reservoir and ventriculoperitoneal
shunts, in leukemic or lymphoma patients, and after bone marrow or stem cell transplantation. Their
clinical features include meningitis and meningoencephalitis, which may present as acute fulminant
disease or indolent chronic infection. The main culprits are L. monocytogenes, S. pneumoniae (in
splenectomy), and C. neoformans.
NEOPLASTIC MENINGITIDES
The clinical presentation of neoplastic leptomeningitis reflects a widespread multifocal involvement of
CNS and peripheral nervous system and includes any combination of the following symptoms and signs:
raised intracranial pressure, cognitive and behavioral disorders, epileptic seizures, meningism, cranial
nerve palsies, and spinal root palsies (98–101). Meningism, however, is often absent or less prominent
than in infectious meningitides. These multiple and progressive, often asymmetric neurologic deficits
suggest a neoplastic nature of a subacute meningitis.
Leptomeningeal metastases occur in four main categories of malignant diseases: solid tumors,
leukemias, non-Hodgkin lymphomas, and primary brain tumors. Primary involvement of leptomeninges
(e.g., without evidence of a systemic or CNS tumor) by glioma (102), lymphoma (103), primary
neuroectodermal tumor (PNET) (104) or melanoma cells (105) is very rare.
1. Symptomatic meningeal carcinomatosis is observed in up to 8% of patients with systemic solid tumors.
The main primaries are breast and lung carcinoma and melanoma (98–101). In about 90% of patients,
the diagnosis of the primary malignancy precedes that of meningeal metastases, but carcinomatous
meningitis may be the presenting manifestation of a malignant disease, and in such patients, the
diagnosis of carcinomatous meningitis may be difficult to establish.
2. Meningeal leukemia occurs primarily in acute leukemias of childhood. Diagnosis is based on the
presence of blasts in the CSF. In lymphoblastic leukemia, the incidence of leptomeningeal involvement
was around 30% before prophylactic therapy (106) and still reaches 5% to 10% despite prophylaxis
(107). In myeloblastic acute leukemia, CNS involvement is less common. Around 1% of patients have
CNS involvement at the time of diagnosis, and recurrence will occur in 2.5% of patients relapsing from
their leukemia (108).
3. Up to 20% of patients with non-Hodgkin lymphoma develop meningeal metastases. Risk factors include
high histologic grade and clinical stage.
4. In primary brain tumors, meningeal cerebrospinal seeds mainly occur in childhood. They are found in
more than 30% of medulloblastomas, 10% to 20% of pineal and supratentorial germinomas, and 10%
of anaplastic ependymomas. In adults, cerebrospinal invasion is considered to be rare in gliomas
(≤3%), although the incidence may be higher (109). It tends to be correlated with high grade; however,
even in grade 1 pilocytic astrocytoma, leptomeningeal spread may occur (110). In primary CNS
lymphomas, meninges are involved in more than 20% of patients (111).
The diagnosis of neoplastic leptomeningitis is based on the demonstration of neoplastic cells in the
CSF. Repeating lumbar puncture and examining large samples (>5 mL) of CSF increases the percentage of
positive results. Malignant cells are found in 50% of patients after a first lumbar puncture and in 80%
after a third one. The recognition of malignant cells may be difficult in lymphoma where the
monoclonality (usually of B type) may be masked by a T-cell type of reaction. The identification of glial
neoplastic cells may also be difficult and immunocytochemical staining of glial fibrillary proteins may
help identify such cells. Other CSF changes seen in carcinomatous leptomeningitis include high protein
level, often contrasting with a moderate increase of reactive monocytes, and low glucose levels
sometimes close to zero. A discrepancy between high protein levels and moderate increases of reactive
mononuclear cells favor the diagnosis of leptomeningeal carcinomatosis. High CSF and serum
concentrations of α-fetoprotein or β-chorionic gonadotropin are markers of non–germ cell tumors. Other
changes such as increased CSF concentrations of β-glucuronidase, lactate dehydrogenase isoenzyme, β2–
microglobulin, and vascular endothelial growth factor (VEGF) (112) are common in leptomeningeal
metastases but lack specificity and are of limited practical use. Elevated CSF concentrations of
carcinoembryonic antigen (CEA) in patients with lung or gastrointestinal cancer, of cancer antigen (CA)
125 in ovary, and of CA 15-3 in breast cancer favor carcinomatous meningitis (113).
Contrast-enhanced brain MRI demonstrates leptomeningeal involvement in nearly 70% of patients (Fig.
47.1A) and may often show concomitant parenchymal metastases. In carcinomatous meningitis,
leptomeningeal enhancement is usually patchy, contrasting with more diffuse and uniform enhancement
seen in infectious meningitis. In addition, spinal meninges are often involved (Fig. 47.1B). In an
appropriate clinical setting, typical MRI changes are increasingly accepted as evidence of neoplastic
meningitis, even if malignant cells cannot be demonstrated in the CSF.
SYSTEMIC DISEASES
Sarcoidosis
Sarcoidosis is a worldwide systemic disease of unknown cause. The disease is characterized by
noncaseating (nonnecrotic) granulomas containing macrophages, epithelioid cells, and multinucleated
giant cells. The lesions primarily involve the lung (70%), skin (30%), and lymphatic glands (25%).
Peripheral or central neurologic lesions, or both, occur in 5% to 15% of patients (114,115). Neurologic
symptoms and signs result in a wide range of clinical presentations which may be the presenting and
occasionally the only detectable manifestation of the disease (116). Leptomeninges are a primary site for
neurosarcoidosis, but most meningeal involvements remain asymptomatic, producing only radiologic and
CSF changes. Headache and cranial nerve deficits including the optic nerve are the most common
manifestations of a predominantly basal chronic granulomatous meningitis that may also cause diabetes
insipidus.
Characteristic CSF changes include predominantly lymphocytic pleocytosis usually less than 50
cells/mm3, moderately increased protein level (<200 mg/dL), and normal glucose in at least 80% of
patients. Oligoclonal IgG bands have been reported (117) but are unusual (116).
MRI may demonstrate contrast-enhanced leptomeningeal and/or parenchymal lesions. T2-weighted
hyperintense periventricular signals may resemble multiple sclerosis lesions (118). Hydrocephalus,
related to basal meningeal lesions or to intracranial sinus thrombosis, is seen in 6% to 30% of patients
(119).
The diagnosis, based on clinical and radiologic features, is confirmed by biopsy of accessible lesions.
Biopsy yield of clinically unaffected tissues including salivary glands is less productive. The sensitivity
of other laboratory investigations such as Kveim test or estimation of CSF angiotensin-converting enzyme
(ACE) is about 50%, and both tests are progressively abandoned.
Vogt-Koyanagi-Harada Syndrome
Vogt-Koyanagi-Harada syndrome is a relatively rare disease of unknown etiology that has a predilection
for Hispanics and Asian and American Indians. The syndrome is characterized by uveitis, retinal
hemorrhage and detachment, and skin and hair depigmentation. Meningeal symptoms and signs (headache
and somnolence) and focal neurologic deficits (deafness, ocular palsy, hemiplegia, or transverse myelitis)
were noted in 61% of patients in one series (120). They are usually acute but may be chronic and may
either precede or follow the ocular inflammation (121). The CSF examination shows moderate,
predominantly lymphocytic, pleocytosis and usually normal protein and glucose levels. The diagnosis is
based on clinical criteria, which were revised in 2009 (122). There is no established therapy, but some
observations suggest that corticosteroids may be valuable.
Collagen-Vascular Diseases
Collagen-vascular diseases usually combine visceral disorders, rash, and arthritis related to inflammatory
lesions of blood vessels. Neurologic disorders are common (123). Symptomatic or asymptomatic
leptomeningeal reaction occurs in several syndromes such as Sjögren syndrome, Behçet disease, lupus
erythematosus, and primary granulomatous CNS angiitis.
Immunologic mechanisms seem to play an important role in the pathogenesis of some of these diseases.
Corticosteroids and other immunosuppressive drugs may improve or stabilize neurologic deficits seen in
these disorders. However, treatment evaluation is complicated by the tendency of the neurologic
syndromes to remit and relapse spontaneously. Today the optimal dose, the duration of corticosteroid
administration, and the indication of drugs such as cyclophosphamide, azathioprine, methotrexate, or
mycophenolate mofetil have not been standardized.
Sjögren Syndrome
Sjögren syndrome is a common chronic inflammatory disease associated with human leucocyte antigen
(HLA) DRw52 subtype. Its prevalence is about 1%, and the syndrome affects predominantly women older
than 50 years. Primary Sjögren syndrome corresponds to a combination of xerophthalmia (dry eyes) and
xerostomia (dry mouth). Secondary Sjögren syndrome also includes a rheumatic disease. At least 20% of
patients (124) have neurologic lesions. The most common complication is a predominantly sensory
peripheral neuropathy. Aseptic, often recurrent, meningitis is uncommon. CSF is characterized by
pleocytosis made of polymorphonuclear cells and lymphocytes. Oligoclonal IgG bands have been
reported, particularly in patients with CNS lesions (125).
The diagnosis is based on Shirmer test (xerophthalmia), minor salivary gland biopsy (oral component)
(126), and SS-A (anti-Ro) and SS-B (anti-La) antibodies directed to ribonucleoproteins, which are found
in about 50% of patients (127).
Behçet Disease
Behçet disease, an illness of unknown cause, is relatively common in Japan and the Mediterranean area. It
is most often seen in young men and is associated with HLA-B51 antigen. The disease is characterized by
relapsing uveitis, retinal vasculitis, and genital and oral ulcers, but it also involves the cardiovascular,
pulmonary, gastrointestinal, and nervous systems (128–131). CNS is involved in up to 20% of patients but
is seldom the presenting feature. Subacute or chronic, usually febrile, relapsing meningoencephalitis and
cerebral thrombophlebitis are the most common manifestations of neuro-Behçet generating multiform
neurologic deficits. Isolated meningitis is rare (131). CSF pleocytosis is predominantly lymphocytic but
in some patients may mimic bacterial meningitis by high percentage of neutrophils. Protein increases are
moderate and CSF glucose levels are normal. CSF oligoclonal IgG bands may be found. Nonspecific MRI
abnormalities predominate in the basal ganglia, brainstem, and white matter. The latter may simulate
multiple sclerosis or sarcoidosis. There is no single diagnostic test, and histologic changes are not
characteristic. The diagnosis is based on clinical criteria (132).
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a multiorgan disease that preferentially affects young women.
Cerebral lupus occurs in 25% to 50% of the patients, causing psychosis, seizures, and dementia. Vascular
hyalinization, endothelial proliferation, and perivascular inflammation involves arterioles and small
arteries. Large-vessel stroke is uncommon (133). Chronic aseptic meningitis related to immunologic
damage caused by SLE is probably very rare. In a cohort (134) of 1,411 lupus patients from Mexico
followed for 18 years, 25 episodes of meningitis were described in 23 patients (1.68%). An infectious
cause could be found in 15 of them (5 tuberculous, 5 Listeria, 3 cryptococcal, 1 pneumococcal, and 1
Kingella meningitis), but for the other 10 patients, viral meningitis cannot be excluded as CSF viral PCR
were not done. Patients with infectious meningitis had more exposure to immunosuppressive drugs, and 3
of them died from their meningitis. Aseptic meningitis due to SLE itself is possible but questionable and
should only be considered after all other infectious causes have been excluded.
Primary Granulomatous Central Nervous System Angiitis
Primary granulomatous CNS angiitis is restricted to the CNS and is characterized by granulomatous
changes that include mononucleated giant cells and involve mostly leptomeningeal vessels. Headache of
progressive severity, the prominent clinical manifestation, may be combined with manifestations of
encephalopathy including mental and personality changes and focal signs such as seizures and
hemiparesis. Chronic meningitis has been observed (135,136). Signs of systemic inflammation common in
other vasculitides are absent. CSF changes include mononuclear pleocytosis, increased protein level, and
normal glucose concentration. CSF IgG bands have not been reported. There is no diagnostic laboratory
test. The diagnosis is confirmed by leptomeningeal and brain biopsy (137), which is recommended before
initiating long-term immunosuppressive treatment. Angiography demonstrates arterial nonspecific beading
in few patients (137).
TOXIC MENINGEAL REACTION

Meningeal reaction to chemicals (e.g., anticancer drugs, antibiotics, analgesics, or contrast dyes) may
follow CSF or systemic administration and has an acute presentation. Chemical meningitis is commonly
observed after intrathecal or intraventricular administration of anticancer drugs, mainly methotrexate and
cytarabine (138,139). The onset of meningism is usually acute and shortly follows CSF administration of
the foreign product. However, repeated injections are often necessary and may generate persistent clinical
features and CSF changes.
In patients treated with intrathecal chemotherapy, meningeal toxic reaction may be mistaken for the
manifestations of the underlying leptomeningeal metastatic disease and thus be underestimated. For
example, in a recent study including lymphoma patients treated prophylactically with slow-release
formulation of cytarabine, toxic meningoradiculitis was observed in 28% of patients (140).
Toxic meningitis may produce fever, and the main differential diagnosis is iatrogenic infectious
meningitis caused by lumbar puncture.
Chemical meningitis also occurs in ruptured pituitary tumor and in ruptured epidermoid cyst or
craniopharyngioma. In patients with undiagnosed neoplasm, the recognition of this complication may be
difficult.
Meningitis caused by systemic drug administration is rare. The occurrence is mostly based on case
reports, and some may be due to the underlying disease for which the drug was administrated. The most
commonly involved agents are nonsteroidal antiinflammatory drugs, trimethoprim (141), and penicillins.
Other molecules include carbamazepine (142), lamotrigine (143), isoniazid (144), and immunoglobulins
(145). Likewise, for intrathecally administered drugs, the clinical symptoms and signs are mostly acute
and self-limiting after drug withdrawal.
The CSF reaction is characterized by predominantly polymorphonuclear pleocytosis, with tens to
thousands of cells per cubic millimeter, mild increase in protein level, and normal glucose concentrations.
Despite substantial progress in the identification of infectious agents and the diagnosis of systemic
immune and malignant diseases, the etiology of chronic meningitis is still often either delayed or remains
undetermined. The two diagnostic algorithms (Figs. 47.2 and 47.3) may indicate the most likely etiology
in immunocompetent and immunosuppressed patients. Clearly, these algorithms have their limitations. The
distinction between agents causing chronic meningitis in the two populations is arbitrary. The incidence of
several diseases included in the differential diagnosis of chronic meningitis in immunocompetent patients
such as those with tuberculosis, histoplasmosis, or coccidioidomycosis is increased in
immunosuppressed and debilitated patients. Conversely, all opportunistic agents considered in Figure
47.3 are occasionally pathogenic in the general population. In addition, not all cases of chronic meningitis
reviewed in this chapter appear in the algorithms; for example, diseases such as nocardiosis,
aspergillosis, mucormycosis, and toxoplasmosis, which cause intraparenchymal more often than
meningeal lesions, have been omitted.
Empirical treatment is sometimes indicated in patients in a series of clinical conditions with
progressive neurologic deficits. In such patients, the therapeutic bet is based on criteria summarized in
Table 47.2.
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_________________________
† Deceased
PART IX ■ NEUROSURGICAL MANAGEMENT
CHAPTER 48 SURGICAL MANAGEMENT OF

CENTRAL NERVOUS SYSTEM INFECTIONS
ANTHONY C. WANG, KHOI DUC THAN, AND OREN SAGHER
Neurosurgeons play an important role in the diagnosis and treatment of central nervous system (CNS)
infections. Before the introduction of antibiotics, the treatment of CNS infections was the exclusive realm
of the surgeon, as most treatable infections were abscesses. With the development of antibiotics and
increasingly sophisticated noninvasive diagnostic methods, the spectrum of treatable CNS infections has
expanded rapidly, and the role of the neurosurgeon has changed. Medical intervention has become the
treatment mainstay for most CNS infections. Diagnosis of most infectious processes can now be made on
the basis of radiologic appearance, serologic markers, and specific culturing techniques. Nevertheless, a
number of CNS infections continue to mandate neurosurgical intervention for diagnosis and/or
management. In this chapter, we discuss the neurosurgical aspects of the management of CNS infections.
The pathophysiology, microbiology, and medical management of these infections are discussed in other
chapters, and this effort is not duplicated in this chapter. Rather, specific attention is paid to issues
relevant to neurosurgical intervention.
HISTORY
Long before the discovery of microbes, the introduction of antisera, or the development of antibiotics,
infections were routinely managed by various surgical procedures. One of the first descriptions of the
surgical treatment of abscesses is found in the Edwin Smith Papyrus (roughly 2500 BC) (1); surgical
drainage has continued to be a mainstay of abscess treatment to this day.
It is unclear when the general practice of surgical abscess drainage was applied to cranial infections.
Possibly trephination of the skull, a practice dating back to antiquity, was performed in some cases for
drainage of cranial abscess (2). However, the first description of surgical treatment for a CNS infection
does not appear until the seventeenth century. Prince Rupert of the Rhine Palatinate, a nephew of King
Charles I of England, underwent trephination of the skull for drainage of an epidural abscess in 1667 (3).
This procedure was apparently successful, and the Prince lived for 27 additional years. The first
successful treatment of an intracerebral abscess was recorded by the French surgeon, Morand, in 1772;
following the opening of a mastoid abscess, he opened the dura and resected the capsule of an
intracerebral abscess with his finger (4). More than a century later, the Scottish surgeon, Sir William
Macewen, reported on a series of patients with a variety of CNS infections, including meningitis, epidural
abscess, and brain abscess (5). Macewen, considered one of the founders of modern neurosurgery, made
many important observations on the pathogenesis and natural history of CNS infections. His operative
technique for the treatment of brain abscesses consisted of drainage of the abscess cavity, gentle irrigation
with a dilute antiseptic solution (boric acid or phenol), and placement of an external drain. Without the
aid of antibiotics, computed tomography (CT), or modern anesthetic techniques, he reported an astounding
95% success rate for surgical drainage of brain abscesses and a 100% success rate for epidural
abscesses so treated. His results have served as a benchmark for other treatments to this day.
BACTERIAL BRAIN ABSCESS

A brain abscess is a focal suppurative process affecting the brain parenchyma and is the most common
CNS infection requiring neurosurgical intervention. Although the incidence of brain abscesses overall is
generally quite low (0.4 to 1.1 per 100,000 population per year) (6,7), they comprise up to 8% of all
intracranial lesions in some parts of the world (8), approximately 1,500 to 2,500 cases arising yearly in
the United States (9).
Pathogenesis
Brain abscesses form as a result of either contiguous invasion of infection or hematogenous spread from a
distant infection. Their most common etiology is local transmission from the ear, nose, or an adjacent air
sinus, accounting for 40% to 50% of all cases (10). Vigilance has improved worldwide, and rates of
abscess formation complicating otitis have begun to fall (11). Hematogenous spread of a distant infection
typically arises from the lungs or heart valves and is slightly less common, accounting for approximately
one third of cases (12). In children, meningitis is more likely to incite the development of brain abscess
than in adults (13). Because contiguous spread frequently leads to the formation of a single, often large
brain abscess (14), most patients present with symptoms of mass effect. Multiple small abscesses are
more frequently the result of hematogenous spread of distant infection.
Predisposing Factors
The relationship between chronic ear or paranasal sinus infection and the development of brain abscess is
well documented (15–19), as are cases of cardiovascular anomalies (20–23). Source control and
treatment of predisposing factors are as important in the management of brain abscess as the treatment of
the abscess itself. Consequently, surgical drainage and débridement of infected air sinuses are important
steps in the prevention of the intracranial complications of such infections, which include brain abscess as
well as epidural abscess, meningitis, subdural empyema, and septic venous sinus thrombosis.
Pathology
The development of brain abscess following an infectious event proceeds through several well-defined
stages (24). Acute cerebritis at the site of organism inoculation is followed by the development of a
collagenous capsule as the host attempts to contain and eradicate the infection. The capsule that forms
around the localized region of cerebritis is not of uniform thickness. Evidence from animal studies (25) as
well as clinical data (24,26) suggest that capsule thickness is maximal at the superficial aspect of the
abscess and minimal or incomplete at its deep margin. This asymmetric finding likely correlates with the
tendency of untreated abscesses to migrate toward the ventricle (25).
Thus, an untreated abscess is likely to eventually rupture its contents into the ventricular system (Fig.
48.1), a potentially catastrophic complication, having a mortality rate of up to 90% (15,27–29).
Aggressive medical management demonstrates some efficacy in this setting, lowering mortality to
approximately 40% (30). Nevertheless, prompt administration of antibiotics and consideration of surgical
drainage are extremely important for those abscesses located in the periventricular region, as early
intervention may prevent intraventricular rupture. In addition, care should be taken during surgical
treatment of a periventricular abscess in order to avoid spillage of purulent material into the ventricular
system.
The abscess capsule serves to contain the infectious process. In isolating the infectious process,
however, capsule formation also creates within it an inflammatory fluid collection poorly permeable to
host defenses and antibiotic penetration (31). A large abscess can also reduce regional blood flow by
exerting mechanical pressure on the surrounding brain, thereby compromising host defenses. In addition,
some organisms produce collagenase or hyaluronidase, which may lead to disruption of the capsule and
further spread of the infection (32). Finally, the chemical environment within an abscess may inhibit the
action of systemic antibiotics, even if antibiotic levels are sufficient within the abscess cavity (33).
Abscess formation, therefore, restricts the infectious process in the brain but may impede its resolution.
Microbiology
Brain abscesses are most commonly formed by multiple aerobic and anaerobic bacteria and typically
reflect the bacterial profiles of the source infections from which they are derived. Isolation of organisms
from the blood may be indicative of the bacteria within a brain abscess propagated by hematogenous
spread, but in the more common ear- or sinus-derived brain abscesses, blood cultures are often negative
or misleading. Cerebrospinal fluid (CSF) cultures obtained by lumbar puncture may be positive in 10% to
20% of brain abscesses, but the potential for exacerbating cerebral herniation in the setting of intracranial
hypertension precludes this from being a universal diagnostic option (34). Sinus cultures may give a more
reliable indication of adjacent brain abscess bacteriology and can be used to guide antibiotic treatment
should direct aspiration of the brain abscess be undesirable. With the advent of less invasive
neurosurgical techniques and accompanying lower morbidity, direct aspiration of the abscess must be
considered a first step in determining the microbiology of the lesion.
Clinical Features
The possibility of a brain abscess should be considered in any patient who presents with signs or
symptoms of an intracranial mass lesion. Because the infectious process is usually localized and
encapsulated at presentation, symptoms are usually a result of the expanding mass within the brain.
Consequently, patients typically present with headaches (70% to 97%), focal neurologic deficits (50% to
60%), depressed sensorium (50% to 65%), and nausea and vomiting (50%) (17,18,28,35). Meningeal
signs are found in 25% of cases and may indicate concurrent meningitis. Systemic signs such as fever are
highly unreliable and may be absent in up to 55% of cases (15,17,18,27). The tempo of symptom
progression is highly variable and may occur in a stepwise manner (36). Therefore, vigilance is still the
most important tool in the diagnostic armamentarium of the physician.
Radiology of Brain Abscesses
The typical description of a bacterial brain abscess on CT or magnetic resonance imaging (MRI) is that of
a circumscribed lesion that restricts diffusion, is encapsulated by a uniformly contrast-enhancing rim, and
is accompanied by surrounding vasogenic edema (Fig. 48.2). The appearance of the enhancing rim,
however, is variable in that it is often asymmetric (classically thinner on the deep surface nearest the
ventricle) and may be altered by incomplete encapsulation. The use of corticosteroids may delay capsule
formation and suppress contrast enhancement. Abscesses with a somewhat more heterogeneous or nodular
rim can be mistaken for neoplasms. The distinction between cerebritis and encapsulated abscess may also
be difficult to make, even with advanced imaging. During the cerebritis stage of abscess formation, ring
enhancement may be absent or incomplete. The extent of surrounding edema is highly variable and is not a
reliable radiologic feature. Uncommonly, brain abscesses may spontaneously bleed, presenting as an
intracerebral hemorrhage (37).
Surgery of brain abscess has been revolutionized by the development of cross-sectional imaging
modalities. CT and MRI have allowed the surgeon not only to assess the size and location of an abscess
but also to gain information on its stage of maturity, the existence of other abscesses, and the presence of
loculation within the lesion. Although serial imaging provides detailed information on the response to
treatment, imaging findings typically lag behind clinical response to treatment, so some patients will
exhibit persistent brain edema and contrast enhancement following aspiration of a brain abscess. For
example, Rosenblum et al. (38) reported several cases that underwent medical treatment only and found
that the size of an abscess may not change for more than 2 weeks after the institution of eventually
successful therapy. On average, it took 10 weeks before the abscesses resolved on CT. Abnormal
enhancement may persist for months or years following the successful treatment of brain abscess (Fig.
48.3) (39,40), reflecting mild breakdown of the blood–brain barrier and not residual infection. Serial
imaging, therefore, is a useful tool in the management of brain abscess, although it is prone to lag behind
clinical improvement and cannot be relied on as the sole measure of treatment efficacy.
MRI has become the preferred modality in the assessment of brain abscess. The sensitivity of MRI is
superior to that of CT in detecting small or multiple abscesses. MRI scanning renders superior images of
the posterior fossa and may be better than CT at disclosing abscesses in this and other locations (Fig.
48.4). In addition, MRI is more sensitive in distinguishing cerebritis from necrosis (41). Diffusion-
weighted imaging can aid in distinguishing abscesses from neoplasms (42,43), and MR spectroscopy has
been used to differentiate likely bacterial etiologies of abscesses (44). Thus, MRI is the preferred
imaging modality in the assessment of intracranial infections.
Surgical Therapy
Surgical treatment of brain abscess is guided by its clinical presentation. For example, multiple small
abscesses—which are often metastatic—may not present with signs of focal brain compression. Surgical
intervention in such cases is more a matter of diagnosis than treatment. In these cases, surgical drainage is
aimed at the most accessible lesion in order to reduce operative morbidity. Large abscesses producing
focal neurologic deficit are treated surgically regardless of their location (45). Surgical treatment is
required from both therapeutic and diagnostic standpoints in the latter instance. In either situation,
however, surgical intervention is a matter of some urgency and should ideally be performed before
administration of antibiotics, although the diagnostic yield from samples obtained on antibiotics is
adequate to justify cultures obtained within 3 days of initiation of antibiotics (46).
The location of a brain abscess also will direct the need for any secondary means of treatment. Lesions
located in the cerebellum, for example, may compress CSF pathways and thereby lead to dangerously
high intracranial pressure. These lesions may carry a mortality rate of 20% to 50% (47), even with the
advent of intracranial imaging and appropriate surgical drainage. The current recommendations are to
drain these abscesses through a posterior fossa craniotomy as well as perform CSF diversion through an
external ventricular drain in patients with any radiologic signs of hydrocephalus. A study of 77 patients
treated with or without CSF diversion demonstrated a reduction in mortality from 29% to 11% in patients
who received a prophylactic CSF diversion procedure at the time of admission, even when these patients
did not yet have clinical signs of hydrocephalus (47).
Mechanical drainage of an abscess improves the effectiveness of antibiotic therapy. Several studies
have indicated that the contents of a brain abscess confer resistance to antibiotics (31,33,48). Smith and
Wood (31) demonstrated that phagocytes within mature abscesses were ineffective despite adequate
antibiotic levels. In 1973, Black et al. (33) aspirated brain abscesses in patients undergoing systemic
antibiotic treatment and showed that several antibiotics were unable to inhibit organism growth despite
adequate levels. A more recent study suggested that intracavitary antibiotic levels were higher in those
abscesses that underwent prior drainage (49). Surgical drainage of brain abscess, therefore, plays a
crucial role in both its diagnosis and treatment.
Over the last two centuries, a number of surgical techniques have been devised to treat brain abscess.
These techniques range from the tube-drainage methods of the past to modern image-guided, minimally
invasive approaches. For purposes of this discussion, the surgical techniques for abscess treatment are
described in a historical context.
Tube Drainage
Tube drainage is the oldest known surgical treatment for brain abscess. The technique involves entry into
the abscess cavity with a needle, followed by placement of a tube into the cavity for postoperative
drainage (Fig. 48.5). Tube drainage of brain abscess offers the advantage of allowing spontaneous
drainage of the abscess contents and decompression of the surrounding brain. This technique also
minimizes trauma to the brain. However, tube drainage is often complicated by obstruction of the tube and
occasional perforation of the deep wall of the abscess by the tube, and the reported mortality with this
technique is high (30% to 45%) (50–52). Tube drainage is now employed much less frequently, except
when used in conjunction with more recent aspiration methods.
Marsupialization
Another early method of brain abscess treatment was marsupialization of the abscess. Described in 1924
by King (53), this technique involved creating a broad opening of the cortex over the abscess and packing
the cavity with gauze (Fig. 48.6). The gauze was then gradually removed as the infection resolved. The
purported advantages of this method were that it prevented the accumulation of inspissated debris and the
formation of secondary pockets. This method was used by a number of neurosurgeons and reported in
various small series (a total of 123 patients in 13 series reviewed) with an average mortality rate of 23%
(54). The technique has not gained wide use, as it involves the sacrifice of potentially functional brain
regions overlying the abscess cavity and a persistent CSF leak until the abscess cavity is clean and
closed.
Migration Technique
One particularly innovative approach to the treatment of brain abscess is the “migration technique”
described by Kahn in 1937 (55). He noted that when a craniectomy was performed for the relief of
increased intracranial pressure, brain abscesses tended to migrate toward the cranial opening. Based on
this observation, he devised a two-stage technique composed of a decompressive craniectomy followed
by a second procedure 3 to 4 days later for either excision or drainage of the abscess (Fig. 48.7). Kahn
(56) also injected radiopaque dye into abscess cavities in order to follow their progress by skull x-rays.
The migration technique is of historic interest and has not been reported by other neurosurgeons since its
initial description. Of note, a similar technique was also commonly used for spinal cord ependymomas.
Excision
The two surgical techniques that continue to be used routinely in the treatment of brain abscess are
excision and aspiration. Excision, the older of the two techniques, was first described by Krönlein in
1910 in a case where an abscess was mistaken for a brain tumor (57). The total extirpation of abscesses
subsequently gained considerable popularity, with over 1,500 patients reported in 48 series (54). The
excision of brain abscess relies on the existence of a collagenous capsule around the mature cavity and
takes advantage of the clear plane of dissection that this capsule provides (Fig. 48.8). The main advantage
of this method is that it achieves complete removal of the infectious process and immediate relief from the
mass effect the abscess exerts.
In the 80 years since its initial description, several prerequisites for excision of an abscess have
emerged. First, the abscess should reside in a surgically accessible region. Second, the lesion should be
excised in the chronic stage, so that a well-developed capsule separates the abscess from the surrounding
brain. Third, the integrity of the capsule should be maintained in order to avoid spillage of its contents
and possible spread of the infection. Last, intraoperative entry into the ventricular system should be
avoided. Many proponents of total excision have reported zero mortality, but a comprehensive literature
review suggests that the mortality of this technique is near 20% (54). Fungal abscesses, which tend to be
more invasive and less encapsulated than their bacterial counterparts, usually do not lend themselves
readily to surgical excision. These abscesses also carry a much worse prognosis, with high mortality
rates (58).
Aspiration
Aspiration of a brain abscess was described by Mayfield and Spurling in 1937 (59), but the treatment has
its roots in the older practice of simple tapping, which was advocated by Walter Dandy in 1926 (60). The
guiding principle of abscess aspiration is that simple evacuation and decompression of abscess contents
is sufficient, with antimicrobial therapy, to allow natural resolution of the infectious process. Aspiration
can usually be performed via a burr-hole opening, reducing trauma to the surrounding brain (Fig. 48.9).
The main advantages of this technique are that it can be performed with relatively low morbidity and that
lesions in eloquent brain or deep lesions can be drained. Its principal disadvantage is that it does not
remove the infection but simply decompresses the cavity. Therefore, abscess reaccumulation is a regular
occurrence following aspiration, and repeat aspiration or excision must be performed in 50% to 70% of
cases (28,61).
Loculations within abscesses also present a potential difficulty, as adequate decompression via needle
aspiration may prove impossible in these cases. Brain abscesses caused by Nocardia asteroides are
particularly likely to be multiloculated and may not be successfully treated by aspiration; one recent
series suggests that, in the case of Nocardia, craniotomy with abscess excision must be performed to
effect a cure (62). Another potential complication of abscess aspiration relates to disruption of the
capsule by the aspiration needle, which may result in parenchymal hemorrhage or leakage of abscess
contents (63–65). Despite these potential problems, aspiration of abscesses remains the treatment of
choice in cases of multiple abscesses, in cases of deep-seated lesions, or in abscesses located within
eloquent brain.
The aspiration of brain abscesses gained considerable popularity before the development of CT
scanning or stereotactic techniques, but the technique was traditionally performed on patients who were
more seriously ill than those offered excision. Consequently, the mortality of abscess aspiration before the
introduction of CT was approximately 45% (302 deaths in 670 patients from 31 series), compared to a
mortality of 19% with primary excision in the same time period (259 deaths in 1,333 patients from 43
series) (54). Since 1990, the mortality of abscess aspiration is 6.6% compared to 12.7% for primary
excision (66). A more recent study found no difference between patients who underwent burr-hole
drainage versus open craniotomy in terms of reoperation rate, hospital length of stay, duration of
antibiotic treatment, and discharge and long-term functional outcome (67). This suggests that burr-hole
aspiration of abscesses is an effective first-line treatment.
Image Guidance
Since the introduction of cross-sectional imaging and the refinement of stereotactic techniques, however,
aspiration has become much more commonly and safely performed. Stereotaxis consists of assigning
three-dimensional coordinates to any point within the brain and uses these coordinates to guide the
surgical approach (68–70). Stereotactic techniques have traditionally required affixing a coordinate frame
to the skull before radiologic imaging, but frameless stereotactic techniques are now prevalent (71–75).
The precision of this technique, which is better than 1 to 2 mm in frame-based and frameless stereotactic
systems, has led stereotactic aspiration to be used in cases of small abscesses or in abscesses within deep
or eloquent brain (76–79). Mortality rates for patients treated in this fashion fell to 0% to 21% with the
introduction of stereotaxis (63,64,74,77,78,80–93). One risk of stereotactic needle aspiration is the
development of a hematoma that cannot be primarily controlled. This risk of stereotactic needle
placement for all pathologies ranges from 1% to 4%, with an approximate mortality rate of 0.5% to 2%
(94,95). The incidence of postoperative hematoma may be increased in immunocompromised patients
(95–98), perhaps because more of the lesions are due to toxoplasma or lymphoma.
Intraoperative ultrasonography is an image-guided operative technique that does not require the use of a
stereotactic instrument. Sonography allows the surgeon to view a brain abscess with excellent detail
through intact dura (Fig. 48.10). The additional benefit of ultrasonography is its ability to yield images in
real time, guiding the surgical approach and allowing the surgeon to adjust the planned approach as
needed (99).
Antibiotic Irrigation
The use of intracavitary antibiotic irrigation has been reported in a number of series (100–102).
Proponents suggest that irrigation of the abscess with antibiotic solution raises antibiotic levels and
reduces the bacterial load, allowing the infectious process to resolve more quickly (102). This notion,
however, remains unproven. Local administration of antibiotics is not routinely used because intravenous
antibiotics used for brain abscess treatment penetrate the brain and abscess capsule, achieving therapeutic
intracavitary levels (49). The placement of an indwelling intracavitary catheter is not without risk and can
result in bleeding within the abscess cavity (64). One scenario in which antibiotic irrigation may prove
helpful is the case of rupture of a brain abscess into the ventricle (29,103,104).
Nonsurgical Therapy
Surgery is the initial treatment of choice for most brain abscesses. Surgery confirms the diagnosis of brain
abscess, allows direct identification of the causative organisms, and decompresses the abscess cavity.
Nevertheless, selected patients may be treated by empirical medical therapy alone. Nonoperative
management of brain abscess was initially reported by Heineman et al. in 1971 (105). In that series, six
patients with abscesses were successfully treated with antibiotics alone; however, the lesions were in the
cerebritis stage. The first report of an encapsulated abscess cured by medical therapy alone was
published by Chow et al. in 1975 (106). In a 1986 review of nonsurgical series, Rosenblum et al. (10)
found a total of 50 patients with mature abscesses so treated, with a success rate of 74% and a mortality
rate of 4%. Based on their experience and review of the literature, Rosenblum et al. (38) recommended
that nonoperative treatment of brain abscess be reserved for patients with known systemic or adjacent
infection whose abscesses are smaller than 1.5 cm or for patients with uncontrollable bleeding diatheses.
However, with the increased availability of accurate stereotactic techniques, it is now possible to
approach abscesses smaller than 1.5 cm with accuracy, resulting in minimal morbidity. In a review of 16
patients with multiple brain abscesses, all patients with small abscesses underwent stereotactic aspiration
for diagnostic purposes; the only death in the series occurred in a patient who suffered transtentorial
herniation preoperatively (88). These encouraging results suggest that even the most conservative
treatment for abscess should involve surgery to identify the organism(s) and drain the mass rather than
empirical medical therapy without an accurate bacteriologic diagnosis.
PITUITARY ABSCESS
Infection of the pituitary gland is a rare but potentially fatal disease. Roughly 200 cases of pituitary
abscess have been reported in the literature, with an estimated incidence of 0.38% to 0.69% (107–111).
The pathogenesis of this lesion is not entirely clear. Traditionally, pituitary abscess was thought to arise
by direct extension from an infected sphenoid sinus or as a complication of a sellar CSF leak (111–115).
Other cases have been reported following resection of pituitary adenomas and occasionally within tumors
that had not undergone surgical resection (116,117). It has also been suggested that many pituitary
abscesses are not infectious at all but merely the result of necrosis within pituitary neoplasms (108).
The diagnosis of pituitary abscess is elusive and is most often made at operation for a presumed
pituitary adenoma (112–114,116). Often pituitary abscess manifests itself in a manner identical to other
intrasellar mass lesions, with headache, visual disturbances, and signs and symptoms of hypopituitarism.
Preoperative diagnosis in such cases is particularly difficult. When pituitary abscess develops in the
setting of sphenoid sinusitis, the diagnosis may be more apparent. Signs of CNS infection, such as fever
and meningeal signs (114–117), are often absent in patients with pituitary abscess (107,111). Radiologic
examination is often nonspecific. Plain x-rays may demonstrate sphenoid sinusitis or an eroded sella
turcica, whereas cranial CT scans often show only a mass in the sellar region. In some instances,
however, CT or MRI scanning may demonstrate ring-enhancing lesions consistent with abscess within the
pituitary fossa or sella turcica (Fig. 48.11) and can show restricted diffusion (118). However, imaging
characteristics attributed to pituitary abscess are inconsistent, and the presence of prior pituitary surgery
or known pituitary tumor may complicate the diagnosis of abscess even in the face of such radiologic
changes.
The treatment of pituitary abscess is a matter of some urgency. The tempo of symptom progression is
unpredictable, and patients with long-standing symptoms of pituitary dysfunction may suddenly deteriorate
(114,116,119). Rapid neurologic decline may be caused by endocrine failure, rupture of the abscess into
the subarachnoid space, or spasm of the internal carotid artery within the cavernous sinus (120). Sudden
visual loss may ensue if the abscess expands rapidly and compresses the optic pathways (112–114).
Treatment of pituitary abscess consists of antibiotics, endocrine support, and surgery. As is the case in
other types of brain abscess, surgical decompression and broad-spectrum antibiotics are of primary
importance in the initial management of pituitary abscess. In a series of 24 pituitary abscess cases seen at
one institution, 58% had tissue Gram stains or cultures positive for a causative organism (111), whereas
only 5 of 30 (17%) were positive in another series (110). Most of the offending organisms were gram-
positive cocci, although Neisseria, Clostridium, Micrococcus, and Citrobacter species were also
represented. In addition, cultures from some patients grew more than one organism. Because pituitary
abscess commonly causes endocrine failure, hormone replacement therapy is paramount. Hormone
replacement should be tailored to the needs of each patient and usually includes stress doses of
hydrocortisone (e.g., 100 mg every 6 hours intravenously) (116). Close monitoring of electrolytes and
fluid balance is also necessary, as some degree of diabetes insipidus is common (117,121). Hormone
function is unlikely to return to normal following treatment (27%), and abscess can recur as well (110).
Surgery for pituitary abscess is similar to that for other pituitary lesions and usually consists of a
transsphenoidal approach with drainage and débridement of purulent debris (107,111,116). The
transsphenoidal approach allows drainage of the abscess and decompression of the optic structures with
minimal morbidity. If the diagnosis of pituitary abscess is entertained preoperatively, or if the contents of
the sella appear purulent intraoperatively, tissue is sent both for pathologic examination and for
microbiologic analysis. Every attempt is made to avoid entry into the subarachnoid space, and some
authors caution against an overly vigorous removal of the abscess capsule for fear of creating a CSF
fistula (115). Drainage of the abscess may also be performed through a craniotomy, although this is less
desirable, as it necessarily involves exposure of CSF to the contents of the abscess.
BACTERIAL SUBDURAL EMPYEMA

Subdural empyemas are relatively uncommon infections characterized by a purulent collection in the
subdural space. The name “subdural empyema” was coined by Kubik and Adams (122) in 1943, although
various other names have been associated with this type of infection, including pachymeningitis interna,
circumscript meningitis, phlegmonous meningitis, and purulent pachymeningitis (123). Subdural
empyemas account for approximately 10% to 20% of suppurative intracranial processes (124) and carry a
mortality rate as high as 55% (125), although with advances in imaging and surgical techniques, most
series now report mortality rates less than 20% (126,127). Subdural empyema may occur as a
complication of meningitis or of skull fractures and neurosurgical procedures such as craniotomies and
burr-hole drainage of chronic subdural hematomas (128,129). However, in most series, infections
originating in the paranasal sinuses account for the majority of subdural empyemas (126,130–132).
Subdural empyema may be acute or subacute. Rapid clinical progression is characteristic of acute
subdural empyema. Typically, patients present with a febrile illness followed by rapid, often catastrophic
neurologic decline. Symptoms are primarily related to cortical inflammation, edema, vasculitis, and
venous thrombosis (133). Headache is almost universal in conscious patients and is followed by signs of
increased intracranial pressure, such as disturbances in consciousness and vomiting. Herniation can
occur. Nathoo et al. (134) noted seizures in only 14.7% of patients. Subacute subdural empyemas, in
contrast, often present with a history of headache and low-grade fever in the absence of profound
neurologic compromise, and in fact, these patients may exhibit only minimal changes on neurologic
examination (135).
Subdural empyemas spread along the subdural spaces and are not well encapsulated, as are
parenchymal abscesses. Pus tends to track along the falx cerebri as well as over the cerebral convexity
(Fig. 48.12); this is in contrast to sterile subdural fluid collections (i.e., hematomas, hygromas), which
have a predilection for the convexity rather than the interhemispheric region. Purulent fluid collections in
the subdural space can also be fairly unimpressive in size when compared to clinically significant sterile
collections. CT scans may disclose abnormal enhancement of the meninges around the subdural space as
well as evidence of brain edema or hemorrhage caused by cortical inflammation and venous thrombosis.
Often, however, radiologic imaging belies the clinical picture. Because the mass effect of these
collections tends to be more diffuse than that exerted by encapsulated parenchymal abscesses, it is not as
readily apparent on CT scanning. Similarly, brain inflammation and swelling may be diffuse, resulting in
an unimpressive radiologic picture. MRI with gadolinium contrast is more sensitive than CT scanning in
demonstrating small subdural empyemas or enhancement around the purulent collection (136–139) (Fig.
48.13) and can also be helpful in differentiating between empyema and effusion (135). Lumbar puncture
for CSF analysis and culture rarely provides useful information in patients with subdural empyemas and
carries with it a risk of exacerbating herniation. In one reported series, 3 of 280 patients referred for
treatment of subdural empyema died as a result of lumbar puncture, whereas another 33 sustained
neurologic deterioration (127). When CSF is collected, it often shows only nonspecific, low-grade
pleocytosis with a normal glucose and protein. CSF cultures are expected to be negative in cases of
nonmeningitic empyema (126,135). Because of the risk of lumbar puncture in the setting of subdural
empyema, patients presenting with fever, neurologic alteration, and purulent nasal or aural discharge
should always undergo cranial imaging prior to lumbar puncture, even in the absence of focal neurologic
abnormalities (127).
Treatment relies on a twofold approach using surgical intervention and intravenous antibiotics.
Evacuation of the purulent collection within the subdural space allows culture and identification of the
causative organisms, reduces the cortical irritation, and relieves the associated mass effect. In a study of
90 patients with subdural empyema, more than 65% of cultures taken intraoperatively identified causative
organisms (126), including streptococci, staphylococci, and gram-negative bacilli. The prevalence of
streptococci is greatest in subdural empyema arising from sinus spread (140,141). Broad-spectrum
antibiotics should be started as early as possible in subdural empyema patients, with tailoring of the
antibiotic regimen once organism sensitivity has been identified. The duration of antibiotic administration
is open to debate, although most authors recommend a 3-week course of intravenous antibiotics followed
by at least a 3-week course of oral antibiotics if suitable options exist (126,127,141).
Prompt surgical intervention plays an integral role in the successful treatment of subdural empyema.
Delay in diagnosis and treatment has been shown to affect the outcome of subdural empyema adversely
(132). In addition to identification of the causative organisms, evacuation of the purulent collection within
the subdural space reduces cortical irritation and relieves the associated mass effect. Although little
disagreement exists about the need to perform surgery on these lesions, considerable controversy exists
regarding the choice of surgical approach. Both burr-hole drainage and craniotomy have been advocated
for the treatment of subdural empyemas (126,131,140–143). Advocates of burr-hole drainage point out
that CT scanning allows the precise placement of burr holes and adequate removal of the purulent
collection without the complications of a craniotomy in a swollen, irritated brain (Fig. 48.14). In
addition, the potential for infection of the cranial bone flap may necessitate not replacing it after
craniotomy, resulting in a cranial defect until the infection resolves. On the other hand, proponents of
craniotomy suggest that burr-hole evacuation, with or without catheter lavage, may not adequately drain
collections that may be loculated, thick, and tenacious. Moreover, with the burr-hole approach, there may
be a greater need for multiple operations. In 1993, Bok and Peter (126) analyzed a series of 90 patients,
most of whom underwent burr-hole evacuation of subdural empyemas. The mortality rate was 4%
following burr-hole evacuation and 5% after craniotomy or burr holes with concurrent craniectomy. They
concluded that given the propensity for these cases to be performed by junior staff under acute conditions,
CT-guided burr-hole drainage was the easiest and safest choice for management. In a series of 65 patients,
Banerjee et al. (144) found a 23% rate of reoperation required after burr-hole evacuation compared with
10% after craniotomy. Nathoo et al. (127) retrospectively analyzed a series of 699 patients treated over
the period 1983 to 1997. The mortality rate was significantly higher for patients who received no surgery
(28%) or burr holes only (23.3%) compared to those who received burr holes with craniectomy (11.5%)
or craniotomy alone (8.4%). They concluded that craniotomy was the treatment of choice in most patients,
with burr-hole drainage reserved only for infants with meningitis-related subdural empyema. It should be
noted that the retrospective nature of this study placed it at risk of selection bias, and detailed
preoperative comparison between the groups was not undertaken. It is also unclear how the choice of
surgery was undertaken on a case-by-case basis.
Direct comparison of the two techniques is fraught with difficulties, as the less aggressive burr-hole
surgery is often performed on sicker patients and therefore may appear to carry a higher morbidity.
Overall, mortality associated with burr holes is generally comparable to the mortality with craniectomy
(Table 48.1). The choice of procedure often reflects the preferences of individual centers rather than a
prospective analysis of outcomes.
The role of intraoperative placement of drainage catheters is likewise unknown; when used, however,
the operative surgeon must be aware that the swollen brain is friable and can be easily damaged by such
drainage catheters (127). Finally, in patients who develop subdural empyema as a consequence of
infection of the paranasal sinuses or mastoid air cells, definitive surgical therapy should include
débridement of such sources of infection.
CRANIAL BACTERIAL EPIDURAL ABSCESS

Cranial epidural abscesses are infections localized to the potential space between the calvaria and the
dura. They are most often related to frontal sinusitis or to a previous surgical procedure, although they
have been associated with many of the risk factors for brain abscess (141,145). These lesions are less
common than subdural empyemas, representing only 1% to 2% of intracranial infections. By and large,
epidural abscess is more indolent in its presentation than infection in the subdural space, as the degree of
cerebral irritation is far less severe. However, epidural infections may extend into the subdural or
subarachnoid spaces or into the brain itself (146). Patients typically present with complaints of fever,
nuchal rigidity, and periorbital or perinasal swelling. The initial diagnostic test should be neuroimaging
with either CT or MRI, ideally with contrast and fine cuts through the paranasal and mastoid sinuses
(141). MRI may allow for greater determination of the extent of infection, especially in tissue adjacent to
bone. As with subdural empyemas, lumbar puncture should be considered with reservation, given the risk
of neurologic deterioration and low diagnostic yield.
Definitive management of cranial epidural abscess is surgical evacuation and intravenous, often
followed by oral, antibiotic therapy; recommended treatments vary widely based on the source of
infection, organism, and response to therapy. In cases of postneurosurgical epidural abscess, concurrent
osteomyelitis of the overlying bone flap must be assumed. In such cases, surgery should include removal
of the infected bone flap as well as evacuation of pus within the epidural space; the presumptive organism
is methicillin-resistant Staphylococcus aureus until culture and sensitivities can be obtained.
Staphylococcus epidermidis, Escherichia coli, and anaerobic bacilli are also common. Salvage of bone
flaps in postcraniotomy epidural abscess is feasible (147).
The treatment of epidural abscess associated with sinusitis is somewhat more controversial than the
treatment of postneurosurgical infection. Both burr hole and craniotomy have been advocated for
evacuation of epidural collections. Advocates of burr-hole evacuation point out that this method
adequately removes the purulent collection without creating a devitalized bone flap over the infected
space. On the other hand, proponents of craniotomy suggest that this method allows for complete removal
of the infected fluid collection and the ability to treat any underlying subdural spread of infection. There is
little evidence to support the superiority of either approach. The decision regarding which technique is
used often falls to the preference of the individual surgeon. In all cases, however, the potential need for
repeat surgery for source control should be considered. The outcome following surgical evacuation and
antibiotic therapy is generally favorable, with most patients (>95%) experiencing good outcomes
(135,141). As is the case in patients with subdural empyema, definitive surgical therapy also includes
débridement for source control.
The propensity of cranial epidural abscess to be associated with subdural empyema has prompted
some to advocate routine subdural exploration during evacuation (148). However, the likelihood that such
a maneuver could seed a previously sterile subdural space is worrisome. Subdural exploration is
advocated by other authors only in cases in which there is clinical or radiographic evidence of subdural
spread (141,145).
Some authors have suggested that surgery to drain extradural pus can be avoided in neurologically
intact patients with small fluid collections (141). These patients were treated with intravenous antibiotics
and followed closely for any signs of worsening neurologic status or infection such as increased white
blood cell count or erythrocyte sedimentation rate. The authors stress that such treatment should only be
used in patients who have had a surgical eradication of the primary source of infection. This treatment is
not fully accepted (135) and should only be attempted in patients who are available for close observation.
CALVARIAL OSTEOMYELITIS
Osteomyelitis of the calvaria most commonly occurs as a result of trauma, either incidental or operative.
Surgical management must be tailored as each case demands, and a detailed discussion regarding these
options is beyond the scope of this chapter. Calvarial osteomyelitis also occurs spontaneously from
hematogenous dissemination, which is treated adequately with antibiotic administration in the vast
majority of cases. Finally, calvarial osteomyelitis may occur as a result of invasion from adjacent
structures. Osteomyelitis of the skull base frequently occurs as a direct extension from otitis, sinusitis,
mastoiditis, or dental sources. Although many of these cases are also adequately managed with antibiotic
administration, advanced stage of presentation and intracranial involvement in these cases can necessitate
operative intervention.
In particular, calvarial osteomyelitis resulting in subgaleal abscess and intracranial extension (Fig.
48.15) may require urgent surgical management. Pott puffy tumor, first described by Sir Percivall Pott in
1760 (149), is most commonly found in adolescents and is defined by frontal osteomyelitis with adjacent
subgaleal abscess (150). It is most commonly suspected to arise from adjacent frontal sinusitis, although
similar infectious processes have been reported in areas of the skull not contiguous with any sinus
(151–153). The subgaleal abscess causes a soft raised mass—hence the moniker, “puffy tumor.”
Intracranial extension can lead to meningitis, epidural abscess, subdural empyema, cerebral abscess, and
thrombophlebitis of the superficial cortical veins. Venous sinus thrombosis is theorized to occur by septic
emboli in the diploic veins that drain from the frontal sinus to the dural venous sinuses (149). Devastating
venous infarcts are a major source of morbidity in cases of Pott puffy tumor, and thus, all cases suspected
of progressing to intracranial extension warrant urgent evaluation for operative intervention. Although the
frequency of cases has seemingly plummeted with the introduction of antibiotics and cross-sectional
imaging (154), surgery remains the primary treatment modality in addition to antibiotic therapy (155) in
this relatively rare presentation.
NEUROCYSTICERCOSIS
Cysticercosis is a common parasitic disease caused by infection with the larval form of pork tapeworm,
Taenia solium. It is endemic in many parts of the world, including Africa, Eastern Europe, Central and
South America, and Mexico (156). Because of the migration of people from endemic areas to the United
States, cysticercosis is being reported with increasing frequency, such that it is listed as one of the
neglected parasitic infections targeted by the Centers for Disease Control and Prevention (157–160).
Depending on the extent of CNS involvement with cysticerci, neurocysticercosis may cause high
mortality. This mortality rate has declined as better treatments have been defined, from 20% to 100% in
the 1960s (161,162) to 0.9% to 18.5% in more recent reviews (163,164).
The larvae of T. solium (cysticerci) have a marked predilection for neural tissue and readily invade the
brain, subarachnoid space, and ventricles. Invasion of the CNS in cysticercosis is extremely common,
occurring in 60% to 90% of all cases (165,166). The propensity for brain involvement in cysticercosis
makes neurocysticercosis the most common parasitic disease of the CNS (167). In rare instances, the
larvae can invade the spinal cord, causing intramedullary cysticercosis, which manifests with paraparesis
or tetraparesis (168).
Cysticerci typically develop in muscles, subcutaneously, and adjacent to the CNS. Cysticerci can
involve the spinal cord, eye, subarachnoid space, ventricular CSF space, or the brain parenchyma.
Typical cysticerci are small (<2 cm), round, thin-walled cysts found in the brain parenchyma or CSF
spaces and initially provoke only minor inflammation. Intraventricular cysticerci can obstruct the CSF
outflow tract, and hydrocephalus is a fairly common presentation of the disease. Racemose
neurocysticercosis refers to a large, actively growing form of the disease in which grapelike clusters of
cysts form in the basal subarachnoid cisterns or ventricles. The racemose form is poorly tolerated and
causes intense inflammation with resultant seizures, intracranial hypertension, and hydrocephalus due to
the size of the cysts and the accompanying inflammatory response.
Parenchymal cysts are usually multiple and may present with symptoms ranging from seizures to
hemiparesis, movement disorders, visual loss, or brainstem dysfunction. Focal or generalized seizures are
the most common symptom of parenchymal neurocysticercosis and may be present in up to 92% of cases
(158,159,166,169–172). In children, parenchymal involvement may be diffuse and cause a clinical
picture of acute encephalitis with cerebral edema (173,174).
Invasion of the ventricular system with cysticerci occurs relatively rarely. Cysts within the ventricles
tend to be free floating and do not usually adhere to the ependymal lining. Both free-floating cysts and
pedunculated cysts, which project into the ventricles, cause symptoms by obstructing midline CSF
pathways. The episodic nature of the CSF obstruction may give rise to intermittent, severe headaches,
drop attacks, or sudden death related to the sharp rise in intracranial pressure caused by obstruction.
Hydrocephalus may or may not accompany such intermittent obstruction.
Cysts are found in the subarachnoid space in approximately 27% to 56% of cases (165). Typical cysts
have a predilection for the dorsolateral subarachnoid space, usually do not present with significant
symptoms, and rarely require surgical intervention. However, racemose neurocysticercosis, which has a
predilection for the basal subarachnoid cisterns, causes symptoms of a chronic meningitis or, if CSF
pathways are sufficiently blocked, hydrocephalus. In some cases, cranial nerves and cerebral arteries may
be entrapped by the inflammatory process, giving rise to a clinical picture similar to meningeal
carcinomatosis or vasculitis (159,166,171,172,175–177). This vasculitis may lead to the development of
aneurysms within the cerebrovascular system through local inflammation of the arterial wall (175).
Racemose involvement of the basal cisterns carries the worst prognosis (161,162).
The symptoms of neurocysticercosis are related to the size and location of the cysticercus cysts. Cysts
within the brain parenchyma present in a manner similar to brain abscesses, with symptoms of increased
intracranial pressure and seizures. Subarachnoid spread of the disease causes meningitis and
communicating hydrocephalus. Those cysts that are located in the ventricular system frequently lodge at
the foramen of Monro or aqueduct of Sylvius, causing obstructive hydrocephalus. These cysts may
degenerate during the final stage of development, leading to a hyperintense T1-weighted lesion that can
mimic the appearance of colloid cysts within the ventricular system (178).
The diagnosis of neurocysticercosis is generally made by clinical, serologic, and radiographic criteria.
Because of the variety of possible presenting symptoms and physical examination findings, a diagnostic
algorithm has been proposed that divides patients into “definitive” or “probable” cases on the basis of
imaging, histopathology, serologic assays, response to antihelminthic therapy, and epidemiologic criteria
(179). Subcutaneous nodules or visualization of subretinal parasites from systemic cysticercosis may be
present on physical examination. An ophthalmologic examination is imperative in all suspected cases, as
cysts in the vitreous humor may result in blindness if ruptured. Both serum and CSF markers for
cysticercosis may reveal antibodies to T. solium antigens. A detailed discussion of the diagnostic tests
available for neurocysticercosis is found elsewhere in this book. However, several caveats bear mention
in this discussion. First, physical findings are inconstant in neurocysticercosis (179). Second, the
existence of antibodies, especially serum antibodies, is not entirely specific (179). Third, CSF antibodies
may be absent in up to 15% to 30% of cases of neurocysticercosis, particularly when lesions are
restricted to parenchyma (159,166,168,180). Taken together, the presence of serum antibodies and
compatible radiographic lesions in a patient from an endemic area is sufficient for the diagnosis of
neurocysticercosis. The absence of such correlative findings, however, mandates surgical intervention in
order to establish the diagnosis, because the only definitive test for neurocysticercosis is histopathologic
proof.
Effective antihelminthic medications for the treatment of neurocysticercosis have quickly become the
primary mode of management. Both albendazole and praziquantel have significantly reduced the need for
surgery in the treatment of the CNS manifestations of neurocysticercosis (165,167,181–183). The use of
steroids in addition to an antihelminthic agent has been shown to improve prognosis (184–187).
Nevertheless, the need for surgery in this disease persists. Medical treatment often elicits a massive
inflammatory response, one that can require operative intervention. Surgery remains the treatment of
choice for patients with hydrocephalus secondary to subarachnoid or intraventricular cysts or for
treatment of symptomatic mass effect (188). In endemic areas, neurocysticercosis accounts for as much as
11% of all neurosurgical procedures (189).
Single parenchymal cysts can be a diagnostic dilemma, as serologic markers are frequently negative in
this setting. Single cysts that are located in surgically accessible regions can be safely excised with
excellent results (Fig. 48.16A). When a single cyst is asymptomatic or seizures are well controlled,
surgery may be avoided in favor of medical treatment. Most cysticerci will die within 5 to 7 years of their
arrival in the brain (159); treatment with albendazole or praziquantel accelerates this process.
Multiple parenchymal lesions are not generally amenable to surgery because the disease is too diffuse.
In children, a frequent form of the disease is characterized by multiple cysts and severe intracranial
hypertension. In these cases, decompressive craniectomy or internal decompression may be performed as
a life-saving measure (188). Despite the use of decompressive procedures, this form of
neurocysticercosis has a poor prognosis (190).
Intraventricular cysts that cause obstruction of midline CSF pathways require surgical intervention
(Fig. 48.16B). In these cases, the preferred surgical procedure is extirpation of the often free-floating
cysts. Most often, these cysts lodge at the foramen of Monro, in the aqueduct of Sylvius, or in the fourth
ventricle and can be safely extirpated either by open neurosurgical procedures or through endoscopic
techniques. Of note, cyst rupture is a frequent result of removal but does not appear to predispose to
ventriculitis, as long as the ventricular system is well flushed prior to closure (191). CSF diversion
procedures are less effective in relieving the hydrocephalus caused by intraventricular cysts than that
caused by subarachnoid seeding, as intraventricular cysts can lead to poor communication between the
various ventricular chambers. In cases that do require CSF shunting, treatment with antihelminthic
postprocedure leads to a significant reduction in shunt failure (192).
Involvement of the basal subarachnoid cisterns with neurocysticercosis often causes hydrocephalus. In
these cases, the extensive meningeal involvement and arachnoiditis caused by the cysts make surgical
exposure difficult. Nevertheless, large subarachnoid cysts causing brain or brainstem compression should
be surgically removed (158,193). Treating the hydrocephalus with a CSF shunt in this setting is also
difficult, as both inflammatory debris and encysted parasites may obstruct the shunt tubing (191).
Morbidity from such shunt-related complications is common, and some neurosurgeons have advocated
third ventriculostomy for the treatment of obstructive hydrocephalus at the time of endoscopic cyst
removal (191). In cases of basal subarachnoid infection, treatment with antihelminthic agents is
mandatory, as the disease is often too diffuse for surgery to offer any more than a palliative option.
MYCOTIC ANEURYSMS
The term “mycotic aneurysm” was coined by Sir William Osler in 1885 in reference to the mushroom-like
morphology of an aneurysmal dilation in the aorta of a patient with infective endocarditis (194). The term
is now commonly used to describe infectious arterial aneurysms in general, although these infectious
aneurysms rarely occur as a result of fungal infection (195). Cerebral mycotic aneurysms occur in 2% to
10% of cases of bacterial endocarditis (196). A septic embolus lodges in the arterial wall of a small
vessel, disrupting its integrity and resulting in aneurysmal enlargement of the vessel. Emboli demonstrate
a tendency toward lodging in preexisting atherosclerotic plaques and areas of turbulent flow (197). The
morphology of mycotic aneurysms is characterized by friable fusiform dilations that are prone to
spontaneous rupture leading to intracranial hemorrhage (Fig. 48.17). Approximately 5% of patients with
infective endocarditis develop an intracranial hemorrhage from a ruptured mycotic aneurysm; in some
cases, a ruptured aneurysm is the first clinical manifestation of infective endocarditis (198,199). The
rupture of a mycotic aneurysm is frequently a catastrophic event and is associated with a high rate of
mortality (195).
Cerebral angiography is a very sensitive diagnostic tool for detecting mycotic aneurysms. The
evolution of mycotic aneurysms is a dynamic process, and aneurysms may enlarge, shrink, or disappear
within a short period of time (195,200,201). Serial angiography often shows this variable natural history
(Fig. 48.18). Less invasive vascular studies such as CT angiography and magnetic resonance (MR)
angiography have been used as well (202), but adequate sensitivity of these studies for the identification
of such small, distal aneurysms has yet to be proven. In addition to providing important information on the
location, size, and morphology of a ruptured aneurysm, angiography often discloses other unruptured
mycotic aneurysms (203). Cerebral angiography should be performed if mycotic aneurysm is suspected. It
has also been suggested that cerebral embolic phenomena in the setting of known infection be investigated
by cerebral angiography, as these symptoms may represent a prodrome to aneurysmal rupture (204).
The risk factors for aneurysmal rupture remain unclear, and no randomized, prospective trials to inform
treatment yet exist (196,203,205,206). In a recent review of 20 cases from one institution, Chun et al.
(200) suggest a treatment strategy guide that incorporates medical antibiotic management, cerebral
angiography, and endovascular or surgical intervention. Medical management alone consisted of a
minimum 6-week course of appropriate antibiotics and was reserved only for patients with unruptured
mycotic aneurysms. These patients were followed with serial angiography to assess for aneurysm
progression and to determine the need for invasive intervention (200). Endovascular treatment was used
in patients without an acute need for operative decompression and in aneurysms that did not involve
eloquent cortex, whereas surgical treatment was mandated for all patients who had aneurysms in eloquent
cortex or in those patients who had acute signs of increased intracranial pressure or expanding hematoma.
Because mycotic aneurysms are often necrotic or fusiform in shape, the standard neurosurgical
approach using clip ligation of the aneurysm neck with preservation of the parent artery is often not
possible (206,207). Rather, surgery of mycotic aneurysms usually involves resection of the aneurysmal
segment of the affected artery or parent vessel sacrifice. The use of bypass grafting of the distal arterial
segment has been advocated by some authors in order to preserve blood flow to the affected cortex (208).
However, bypass grafts are technically difficult and, in the setting of disseminated intravascular infection,
are prone to disruption and embolism. The surgical approach to mycotic aneurysms is also complicated
by their predominant location in the distal cerebral vasculature. This difficulty can sometimes be
circumvented by using stereotactic guidance techniques for aneurysm localization (200,206,209).
Endovascular techniques have proven useful in the management of mycotic aneurysms. The mainstay of
endovascular treatment of mycotic aneurysms remains parent artery sacrifice. Endovascular obliteration
of mycotic aneurysms with stents, balloons, glue, or thrombogenic coils has been attempted, although the
potential risks of this approach, such as perforation of the necrotic aneurysm wall, are considerable
(210,211). The natural history of mycotic aneurysm formation involves disruption of the internal elastic
lamina and inflammatory infiltration of the media and adventitia. Thus, these mycotic aneurysms resemble
pseudoaneurysms and aneurysms that occur as a result of transmural angiitis, more than they do true
aneurysms (212). As such, the risk of intraprocedural rupture is extraordinarily high.
Other authors have recommended a more aggressive approach, including surgical excision of mycotic
aneurysms whenever possible (213), whereas still others have recommended surgery in the case of
previously ruptured or enlarging mycotic aneurysms. These latter recommendations are extrapolated from
the natural history of congenital cerebral aneurysms, which suggest that these aneurysms are at higher risk
of hemorrhage (206,207). Because mycotic aneurysms are rare and their natural history is variable, a
uniform set of indications for surgical intervention has not been established. A clinical decision must
therefore be made in each case, based on the condition of the patient, the location of the aneurysm, and the
apparent response to appropriate medical therapy.
SPINE INFECTIONS
Infections of the spine are often classified anatomically, using terms such as osteomyelitis, diskitis, or
epidural abscess. However, most pyogenic spine infections affect multiple structures (214). Spine
infections most typically involve bacteria, particularly gram positives, and the most common organism is
S. aureus (215). Inoculation occurs via arterial blood flow, retrograde flow through Batson vertebral
venous plexus, or by direct invasion, whether from an adjacent infectious source or from a contaminated
external source (such as a surgeon). Diagnosis is typically made by MRI, when the finding of back pain or
neurologic deficit indicates this study. Enhancement of the vertebrae and paravertebral tissues is typical
of spine infection, and destruction of the vertebral endplates and disk spaces suggests osteomyelitis rather
than malignancy (Fig. 48.19). Spinal deformity frequently occurs with osteomyelitis as well.
Several atypical pathogens cause osteomyelitis, including fungi and mycobacteria. Many of these
organisms first involve the lung, including Mycobacterium tuberculosis, Aspergillus, Cryptococcus, and
Coccidioides. Many of these are liable to occur in the setting of immunosuppression, and correction of
this immunocompromised state as well as initiation of antifungal medications are the mainstay of
treatment. Surgical decompression and débridement is an option in cases demonstrating neurologic
decline and is frequently required in cases of candidiasis (216), aspergillosis (217), and
coccidioidomycosis (218).
The pathophysiology of spinal osteomyelitis caused by M. tuberculosis, known as Pott disease (Fig.
48.20), is characterized by slow growth, propensity for an oxygen-rich environment, and the absence of
proteolytic enzymes. Tuberculous osteomyelitis is quite different from pyogenic spine infections in that it
follows an indolent course over months to years and demonstrates a less painful evolution than the
pyogenic infections. Serum markers for inflammation may remain normal, even when an abscess already
exists. Imaging features typical of spinal tuberculosis infection include relative preservation of the
intervertebral disks due to the lack of proteolytic enzymes, spread along the anterior longitudinal
ligament, involvement of the psoas muscles, clumping of the lumbosacral nerve roots, and granulomatous
accumulation in the basal cisterns (219). Calcification within a psoas abscess is commonly considered to
be diagnostic for tuberculosis. Surgical intervention is reserved primarily for deformity correction and
spinal cord decompression, and thus the timing of surgery is highly variable. In the absence of spinal cord
compression, surgery for deformity correction is typically performed after completion of antibiotic
therapy.
Culture and speciation is a critical part of the diagnostic process, and although blood cultures are
easily and quickly obtained, sampling of infected tissue is often required via image-guided needle
aspiration or, in rare cases, open biopsy. Biopsy cultures are typically obtained for suspected cases of
polymicrobial osteomyelitis or in cases of negative blood cultures, where they can improve the diagnostic
yield from an estimated 58% to 77% (220). Little data exist to suggest an advantage of open biopsy over
image-guided needle biopsy. The impact of antibiotic administration prior to obtaining biopsy specimens
on culture results remains a controversial topic. Small studies have shown both damaging effects and little
effect on the diagnostic yield of needle biopsy performed after antibiotics have been initiated (221,222).
The role for surgery in cases of spine infection largely revolves around the question of neurologic
deficit. A progressive neurologic deficit should trigger consideration for urgent surgical intervention,
regardless of whether an epidural abscess or acute kyphotic deformity is readily visible on imaging.
However, no definitive study yet exists to prove the benefit of urgent operative decompression in spine
infections, and there is at least a small amount of debate about the issue, particularly in the case of spinal
epidural abscess, as discussed in the following section.
SPINAL EPIDURAL ABSCESS

Suppuration in the spinal epidural space is an infrequent but potentially devastating condition, one that has
traditionally been considered a neurosurgical emergency. Spinal epidural abscesses were first described
by Morgagni in 1769 (223). They were most frequently identified on postmortem examination until the
1930s (224). A number of series have been published since then, outlining the pathogenesis and treatment
of these rather uncommon infections (225–233).
Spinal epidural abscess typically arises either by hematogenous spread or by direct extension. Known
risk factors for spinal epidural abscess include intravenous drug abuse, diabetes mellitus, dialysis-
dependent renal failure, immunosuppression, alcoholism, and trauma. Hematogenous spread accounts for
up to 63% of cases and may be associated with skin abscesses (223,226,230), infected vascular catheters,
pneumonia, or otitis media (232). Direct extension from adjacent osteomyelitis accounts for up to 38% of
cases (226). Contiguous spread of infection from retropharyngeal, psoas, and pulmonary abscesses have
also been reported to cause infection in the spinal epidural space. Finally, spinal epidural abscesses have
been reported as rare complications of surgical procedures and epidural anesthesia (234–239). Most
spinal epidural abscesses are caused by S. aureus (Fig. 48.21), although the number of infections caused
by gram-negative aerobes and M. tuberculosis is significant (223,226,230). Atypical organisms that
cause meningitis, osteomyelitis, and diskitis are also prone to cause epidural abscess, most famously, the
fungus Exserohilum rostratum involved in the 2012 outbreak of infections in patients who received
contaminated methylprednisolone (Fig. 48.22).
Symptoms and signs of spinal epidural abscess include back pain and fever, followed by radicular pain
and paraparesis or tetraparesis. Patients may also have symptoms that mimic bacterial meningitis such as
headache and neck stiffness. Symptoms may vary from indolent to rapidly progressive. Rapid progression
is associated with poor outcome (227,230). Other poor prognostic factors at admission include
paraplegia, location of the abscess in the cervicothoracic region, and elevated peripheral blood white
blood cell count (232).
The management of a spinal epidural abscess has traditionally consisted of decompressive
laminectomy and débridement of the inflammatory tissue, followed by long courses of intravenous and
oral antibiotics (145,223,227). In the past, the spinal wound was commonly packed open and allowed to
close by granulation (239). More recently, however, primary closure of wounds has been advocated, as
this approach reduces the length of hospital stay and discomfort to the patient (145,223,227). Because
many epidural abscesses involve long segments of the spinal column, decompressive laminectomies are
performed at multiple levels, if necessary. For example, in a review of 188 patients from seven studies,
laminectomies were performed at an average of four spinal levels (range, 1 to 26 levels) (227). This
degree of spinal decompression, especially in children, raises the possibility of long-term spinal
instability or deformity. Some authors have advocated a more limited exposure in children in order to
minimize loss of structural stability (240,241); laminoplasty, as opposed to laminectomy, might contribute
to this goal of preserving alignment and stability, although data to support this claim are limited.
Epidural abscesses arising from vertebral osteomyelitis (usually those in the cervical or thoracic
region) are primarily ventral to the thecal sac and may be difficult to approach through a standard
laminectomy. In such cases, an anterior or anterolateral approach has been advocated in order to remove
the infected bone and adequately decompress the spinal canal. Anterior spinal procedures involve bone–
autograft fusion of one or more vertebral bodies and are more technically complicated than the traditional
laminectomy approach. The use of metal plates or screws, a standard adjunct in most anterior spinal
fusions, is controversial in the setting of osteomyelitis and epidural abscess (242). Immediate
stabilization in anterior fusions is therefore often achieved using rigid external bracing.
An alternative surgical approach to treatment of spinal epidural abscess is percutaneous drainage of the
abscess, with or without image guidance (243–245). The difficulty with percutaneous drainage lies
primarily in the consistency of the inflammatory tissue within the spinal canal; in more than 50% of cases,
the spinal epidural abscess is composed of granulation tissue rather than liquid pus (223). Nonetheless, in
cases that involve multiple spinal levels, some authors advocate the use of CT-guided percutaneous
drainage as a means of avoiding extensive decompression and the risk of spinal instability.
Several studies have suggested that certain patients, primarily those with positive cultures and without
neurologic deficits, may be treated without surgery (244,246–250). The uncertainty over which patients
can be safely treated without surgery, however, has prevented this approach from gaining wide
acceptance. In one report, several patients who were being treated medically with appropriate antibiotics
deteriorated suddenly and irreversibly before surgical decompression (251). In addition, whether
nonoperative treatment requires a longer course of antibiotics is unclear (223).
Potential for neurologic recovery with these different treatment modalities is also uncertain. The single
most important prognostic factor for functional recovery is neurologic deficit at the time of
decompression. Although there is no definitive comparison of surgical versus medical therapy for the
acute presentation of spinal epidural abscesses, it is widely accepted that immediate operative
decompression is preferable to conservative management as a means to preserve neurologic function.
Although overall paralysis rates have traditionally been reported to be quite high (21% to 39%)
(252–254), the potential for recovery of function after spinal epidural abscess appears to be better than
after traumatic spinal cord injury (255).
CENTRAL NERVOUS SYSTEM INFECTIONS IN THE

IMMUNOCOMPROMISED PATIENT
Immunocompromised patients are susceptible to infections not usually seen in the general population.
Patients with impaired immunity present with CNS infections caused by organisms such as gram-negative
bacteria, fungi, and parasites. The management of CNS infections in this group of patients presents the
clinician with a unique set of difficulties. The list of opportunistic infections that occur in
immunocompromised patients is lengthy, and a detailed discussion of rarely encountered infections is
beyond the scope of this chapter. Because the immune system of these patients is compromised, infections
are difficult to eradicate and tend to spread aggressively despite maximal therapy. Although medical
therapy is the cornerstone of treatment for all such infections, surgery plays an important role in their
management.
Fungal Infection
Aspergillus species are the most common cause of fungal brain abscess in immunosuppressed patients
(58,256) but are rare in otherwise healthy individuals (257). Aspergillus fumigatus, the most common
Aspergillus species isolated from abscesses, has a propensity for CNS invasion (20,258–260). Any CNS
involvement is predominantly parenchymal, although meningitis or vasculitis may also occur (261). The
angioinvasive nature of the fungus may result in multifocal hemorrhagic lesions or vascular thrombosis
with infarction. Brain abscess caused by Aspergillus species is extremely difficult to treat. The fungal
infection tends to be highly invasive and poorly encapsulated (Fig. 48.23) (98,101). Patients susceptible
to this type of infection have a poor immune response and are likely to have serious systemic illnesses
concurrent with the abscess.
A number of other fungal agents, such as certain Candida species, Cryptococcus neoformans (Fig.
48.24), Cryptococcus gattii, Coccidioides immitis (Fig. 48.25), and certain members of the order
Mucorales, may cause abscesses that require surgical intervention. The mainstay of treatment involves
antibiotics, such as voriconazole, posaconazole, amphotericin B, anidulafungin, or caspofungin; surgical
aspiration alone is ineffective and rarely successful in cases without a well-formed capsule. However,
when the abscess is located in noneloquent regions of the brain, some authors favor an aggressive
resection that includes a margin of uninvolved tissue (262,263); a few successful outcomes have been
reported with this approach. Intracavitary or intraventricular administration of amphotericin B is also
reported in treating fungal brain abscesses with some success (101,264–267). Although intrathecal
injection of amphotericin B circumvents the penetration difficulties of intravenous administration of this
medication, its efficacy remains unstudied. In addition, the neurotoxic effects of intracranially
administered amphotericin B, such as seizures, psychosis, quadriparesis, and leukoencephalopathy, may
limit the usefulness of this approach (268).
Rhinocerebral Mucormycosis
Cerebral involvement by fungus from the order Mucorales was described over 100 years ago and more
commonly include the genera Rhizopus, Mucor, and Rhizomucor (269). Termed “rhinocerebral
mucormycosis” (RCM) because of its propensity to involve the paranasal sinuses as well as the brain
(Fig. 48.26), this infection was universally considered fatal until 1955. RCM begins when a susceptible
patient inhales the airborne spores of the ubiquitous molds of Mucoraceae and establishes the infection in
the nasal mucosa or palate. Direct invasion into the paranasal sinuses, skull base, or frontal lobes causes
CNS symptoms such as headache, cranial nerve dysfunction, motor or sensory deficits, or altered mental
status. With the introduction of amphotericin B and aggressive surgical treatment, survival rates have
climbed steadily since then, reaching 40% to 80% (270–273). Mortality is highly dependent on the degree
of intracranial extension, which conveys a dismal outcome (274,275).
RCM is most commonly associated with diabetic ketoacidosis, hematopoietic malignancy, and
immunosuppression (276). In the United States, the incidence of RCM is declining in the overall
population; a novel hypothesis attributes the decline to increased use of statins (277). Statins induce
apoptosis in certain species of Mucorales (278). Diabetic patients are at risk of RCM because of the
impaired neutrophilic activity that results from long-standing disease. A similar mechanism is present in
patients treated with immunosuppressive medications. The susceptibility of AIDS patients to Mucor
species is not a direct function of T-cell suppression but rather occurs in the setting of neutropenia
(279,280).
Brain abscess caused by Mucor may occur by direct extension (e.g., through the cribriform plate) or by
hematogenous spread. Mucor has an affinity for the internal elastic lamina of arteries, and vascular
thrombosis is a well-known complication of RCM (281). Thrombosis of vessels in the paranasal sinuses
may result in facial necrosis, a disfiguring and often fatal complication of RCM. Involvement of the
orbital apex and cavernous sinus is common, resulting in ophthalmoplegia, proptosis, and visual loss
(Fig. 48.27) (274,282). Thrombosis of the internal carotid artery in the cavernous sinus may also occur,
with devastating consequences (283,284).
The key to successful treatment of RCM begins with rapid diagnosis. Diagnosis can be definitively
established by histopathology and culture of biopsy of the affected area, and biopsy is typically
accessible through the nasal passage in the outpatient setting. Polymerase chain reaction (PCR) techniques
have also been used for the diagnosis of Mucor infection (279,285).
Once the diagnosis of Mucor has been made, débridement of infected sinuses is mandatory. Surgical
drainage and débridement of the Mucor abscess is the rule, because antibiotic therapy is rarely effective
in the setting of the vascular thrombosis that often accompanies this disease process. Débridement has
classically been achieved through an open procedure, although endoscopic sinus drainage may also be
effective (286,287). Orbital exenteration has been advocated for cases in which the infection has spread
to the orbital apex in an effort to prevent the extension of infection into the cavernous sinus (283,288).
Because the base of the frontal lobe is most often involved, an aggressive surgical approach is usually
well tolerated, allowing débridement of the anterior skull base, which is often necrotic (288). When the
infection has destroyed the anterior skull base, a combined surgical approach is often necessary, with
neurosurgical débridement of the infected intracranial contents as well as a débridement of the infected
sinuses and skull base, followed by reconstruction of the cranial base in order to prevent CSF leak.
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J Clin Neurosci. 2009;16:1567–1571.
CHAPTER 49 CRITICAL CARE OF CENTRAL
NERVOUS SYSTEM INFECTIONS
JOHN ZURASKY, THOMAS O. MCPHARLIN, AND KYRA J. BECKER
Persons with infections of the central nervous system (CNS) are at risk for developing serious medical
and neurologic complications related to their infection and often require a level of care that can only be
delivered in an intensive care environment. Despite advances in care, infections of the CNS are still
associated with significant morbidity and mortality. For broad ranges of medical and surgical disease,
studies suggest that outcome from critical illness is improved when care is delivered by practitioners
with specialized training and expertise in the condition being treated; these findings also extend to the
treatment of patients with neurologic illnesses like stroke, intracranial hemorrhage (ICH), and
subarachnoid hemorrhage (SAH) (1–5). Specific studies to assess the benefit of specialized care by
neurointensivists in patients with CNS infections have not been done, but a benefit for this patient
population also seems likely because the secondary response of the brain to injury is usually stereotyped
and independent of the initial insult. Principles of the medical and neurologic management of CNS injury
can therefore be generalized across broad populations of patients with different pathologic processes
affecting the CNS.
STROKE AS A COMPLICATION OF MENINGITIS

Thrombosis of the vessels due to vascular inflammation leads to stroke in up to 25% of patients with
bacterial meningitis and appears to be more common in pneumococcal meningitis than meningitis due to
other bacteria (6–8). Curiously, lower cerebrospinal fluid (CSF) white blood cell counts appear to be
prediction of infarction (7,8). Deep infarction due to inflammation of the lenticulostriate vessels is a
common sequela of cryptococcal and tuberculous meningitis; stroke is seen in approximately 30% of
patients with tuberculous meningitis (9,10). Patients with cryptococcal meningitis may also develop
significant intracranial hypertension (11). Aspergillus is an angioinvasive fungus that can predispose to
both ischemic and hemorrhagic strokes (12). Stroke is also seen in patients with cerebral toxoplasmosis,
zoster vasculitis, and a variety of other more rare infections (13).
GENERAL PRINCIPLES GUIDING NEUROLOGIC CRITICAL

CARE
Among the key principles that guide the care of the brain-injured patients are the relationships between
cerebral blood flow (CBF), intracranial pressure (ICP), and mean arterial blood pressure (MABP); an
understanding of the physiologic processes that regulate these variables is crucial for providing care to
patients with neurologic illness. The CBF is determined by the cerebral perfusion pressure (CPP) and the
cerebrovascular resistance (CVR). The CPP represents the difference between the MABP and the ICP.
CBF = CPP ÷ CVR
CPP = MABP − ICP
In cortical gray matter, the CBF is maintained constant at 50 mL/100 g of tissue per minute and is
independent of the CPP (and hence MABP) over a broad range of values because of changes in the CVR,
a process known as cerebral autoregulation (14). In normotensive individuals, autoregulation is lost
when the MABP exceeds 150 mm Hg (15). Loss of cerebral autoregulation due to increased blood
pressure is referred to as hypertensive encephalopathy. The ability to adequately regulate CBF is
similarly lost in normotensive individuals when the MABP drops below 50 mm Hg (16). At MABPs less
than 50 mm Hg, CBF decreases, and ischemia ensues. Under usual circumstances in a normotensive
(120/80 mm Hg) individual, the CPP is approximately 83 mm Hg (assuming an MABP of 93 mm Hg and
an ICP of 10 mm Hg). Thus, if the ICP increases to 50 mm Hg and MABP does not change, the CPP will
become dangerously low (CPP = 93 mm Hg [MAPB] − 50 mm Hg [ICP] = 43 mm Hg) and cerebral
ischemia will result. Perhaps more importantly, the ability to regulate CBF is lost in the injured brain
(17,18); the CBF therefore becomes passively dependent on the CPP (and thus the MABP).
Another key principle that guides care of the neurologically ill patient is the pressure–volume
relationship of the intracranial cavity. According to the Monro-Kellie doctrine, the skull is nondistensible
and the contents of the intracranial cavity (brain, blood, and CSF) are noncompressible; any increase in
the volume of one of the components of the intracranial cavity will lead to displacement of another, an
increase in ICP, or a combination of the two (19). As a general rule, the brain accounts for approximately
80% of the intracranial contents and the CSF accounts for another 10%. Intravascular blood (blood within
the arterial and venous circulation) comprises the remaining 10% of the intracranial contents. The ICP
will therefore increase if there is an increase in the volume of CSF (hydrocephalus), intravascular blood
(hypertensive encephalopathy, hyperemia, or cerebral vein thrombosis), extravascular blood (ICH), or
interstitial fluid (edema). Each of these situations can occur in persons with infections of the CNS, and the
guiding principles for treatment will be discussed.
HYDOCEPHALUS
High levels of protein and pleocytosis characterize the CSF that accompanies an infection of the brain.
Both the elevated protein and the white blood cells impair CSF reabsorption through the arachnoid
granulations and may lead to communicating hydrocephalus. In addition, pathogens themselves, especially
Cryptococcus, may obstruct the arachnoid granulations. In patients with intracranial hypertension due to
communicating hydrocephalus, the ICP can be lowered through serial lumbar punctures with drainage of
high volumes of CSF; in some instances, a lumbar drain may be placed. If the flow of CSF through the
third ventricle or the aqueduct of Sylvius is impaired (i.e., noncommunicating hydrocephalus), lumbar
puncture is contraindicated and external ventricular drainage may be necessary. Even after successful
treatment of acute bacterial or fungal meningitis, hydrocephalus may persist. For patients with
communicating hydrocephalus, a finite number of lumbar punctures may be all that is needed to control the
ICP. In some individuals with persistent communicating hydrocephalus and in all of those with persistent
noncommunicating hydrocephalus, continuous extracranial shunting of CSF with a ventriculoperitoneal
shunt (VPS) may be required. Whenever possible, placement of a VPS should be delayed until the CSF
protein and cell count return to normal.
CEREBRAL VEIN THROMBOSIS

If the venous outflow of blood from the brain is impaired, there will be an increase in the volume of
intravascular blood within the intracranial cavity because arterial inflow continues. Headache is the most
common presenting feature of cerebral vein thrombosis (CVT), but given that headache is also seen
routinely in persons with meningitis, this clinical feature is of little diagnostic value in the patient with
CNS infection. When thrombosis occurs in the large draining veins of the brain, such as the sagittal or
sigmoid sinus, increased ICP, venous infarction, hemorrhage, and seizures may occur. With the advent of
modern antibiotic therapy, infections are no longer a common cause of CVT, but the possibility of CVT
should still be considered in patients with meningitis, especially those who develop extensive cerebral
infarction that does not respect a defined arterial territory. The one clinical situation in which CVT still
occurs with some frequency is in mastoiditis where the transverse and sigmoid sinuses are particularly
prone to thrombosis (Fig. 49.1). Thus, in patients who present with infections of the inner ear and mastoid
sinuses, vigilance for CVT must be maintained.
The diagnosis of CVT is now made most reliably by magnetic resonance venography (MRV) or
computed tomography venography (CTV). Either MRI or computed tomography (CT) done with contrast
may be diagnostic in sagittal sinus thrombosis because the contrast will not opacify the torcular herophili
and thus reveals what is referred to as an “empty delta sign” on axial imaging. Noncontrast CT and MRI
may also show clot within the sagittal sinus or other large veins. Gradient-echo (GRE) sequences on MRI
may also reveal clot within the large veins and sinuses. In rare cases, conventional intraarterial
angiography may still be needed to diagnose CVT. Systemic anticoagulation is generally the treatment of
choice for CVT, even in patients with hemorrhagic infarcts (20,21). Endovascular clot retrieval and local
thrombolysis have been used to treat patients with extensive CVT, but the use of these interventions
remains unclear (21).
EDEMA
Independent of the mechanism of injury, an inflammatory response occurs within the brain as a result of
that injury and contributes to it. In persons with infections of the CNS, however, the inflammatory
response is generally the primary cause of brain injury. Inflammation represents the first or innate
response of the immune system to infection or a breach of the body’s normal protective barriers. The
inflammatory response in the brain is similar to that in other tissues, but the consequences can be much
different. With inflammation, there is increased blood flow and compromise of the vascular integrity
(blood–brain barrier [BBB]), leading to extravasation of fluid into the brain tissue as well as an influx of
leukocytes into that tissue. Activated leukocytes release a number of biologically active compounds,
including cytokines and toxic oxygen metabolites, that further compromise the integrity of the
vasculature/BBB. These substances may also be neurotoxic. As a consequence of BBB breakdown and
loss of microvascular integrity, cerebral edema occurs. Increasing cerebral edema leads to increasing
ICP, and if severe enough, herniation and death. In meningitis, the infectious process, and therefore the
inflammatory response, affects the meninges and underlying brain diffusely. Cerebral edema and the
increase in ICP are therefore globally distributed without significant compartmentalization; thus, if
herniation occurs, it is usually characterized by a central downward herniation of the brain through the
tentorial incisure and foramen magnum. In herpes simplex encephalitis, however, because the temporal
lobes are preferentially involved, uncal or transtentorial herniation is common. Patients with focal mass
lesions, such as abscesses, are also prone to compartmental shifts and transtentorial herniation.
TREATMENT OF INTRACRANIAL HYPERTENSION

Intracranial hypertension contributes significantly to both the morbidity and mortality of patients with
CNS infections (22–25). There is, however, no evidence to show that ICP monitoring translates into
clinical benefit in these patients. Thus, clinical judgment must substitute for an evidence-based approach
to therapy in patients with complicated CNS infections. If an ICP monitor is in place, the ICP, and hence
CPP, are known. Knowledge of the ICP, however, should never replace for the neurologic examination. In
patients with processes affecting their temporal lobes, for instance, uncal herniation can occur in spite of
a normal ICP.
In patients at risk for herniation due either global or local increases in ICP, several simple measures
may be taken in the intensive care unit (ICU) to help decrease ICP. First, the head of the bed should be
elevated approximately 30 degrees above the horizontal plane to enhance cerebral venous outflow
through the jugular veins. Second, ventilation should be optimized to maintain a normal arterial content of
CO2 (PaCO2). Hypoventilation results in retention of CO2, which leads to an increase in CBF and
therefore cerebral blood volume (CBV); an increase in CBV translates into an increase in ICP if
compensatory mechanisms fail. Within the physiologic range, an increase in PaCO2 of 1 mm Hg leads to
approximately a 4% increase in CBF and a 1% to 2% increase in CBV (26). Similarly, a 1 mm Hg
decrease in PaCO2 leads to approximately a 4% decrease in CBF and a 1% to 2% decrease in CBV. In
patients at risk of imminent death from herniation, hyperventilation may therefore be life saving because it
will decrease the CBV and thus the ICP, but it does this at the expense of CBF. Clinical studies suggest
that hyperventilation is detrimental and hypocapnia should be avoided or normalized as soon as possible
(27,28).
In patients with CNS injury of any type, including infectious insults, hyponatremia is common. The
relative contribution of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion and
cerebral salt wasting (CSW) to hyponatremia in patients with brain injury is debated. To make a
diagnosis of SIADH, patients must be either hypervolemic or euvolemic; for a diagnosis of CSW, patients
should be relatively hypovolemic and have evidence of excess sodium in their urine. Irrespective of the
cause of hyponatremia, the situation can be particularly dangerous in patients with brain injury. Sodium is
the primary determinant of plasma osmolality, as illustrated by this equation:
plasma osmolality (mOsm/kg) = 2 [Na+] + ([glucose] 4 18) + ([urea] 4 2.8)
The plasma osmolality determines the osmotic pressure or the force per unit area that must be applied
to prevent water movement from an area of low solute concentration to an area of high solute
concentration (osmosis). If the osmolality, and hence osmotic pressure, of plasma increases, it prevents
the movement of water into the injured tissue with a lower osmolality. Further, if the osmolality (and
hence osmotic pressure) of the injured tissue is lower than that of plasma, water will move from the brain
into the more concentrated plasma, thereby dehydrating the brain and lowering ICP. Based on this
equation, it is obvious that even small changes in plasma [Na+] can have profound effects on the plasma
osmolality, and thus ICP. Plasma sodium should therefore be normalized in persons with cerebral edema,
which is most easily accomplished by the administration of isotonic fluids. In instances of life-threatening
cerebral edema, the plasma sodium can even be increased by administration of hypertonic fluids such as
3% saline. The osmolality of commonly used fluids is shown in Table 49.1. Given the large amounts of
fluids required for administration of antibiotics to critically ill patients, in some instances, it may be
advantageous to have the pharmacy mix intravenous medications in normal saline when possible. Because
most patients in the ICU will receive nutrition in the form of tube feeding, choosing an alimental formula
with minimal free water will also help to prevent hyponatremia.
Normalization of plasma [Na+] is important for patients with CNS mass lesions and for patients with
cerebral edema. Hyponatremia, and hence low plasma osmolality, allows for the movement of water from
plasma into brain, exacerbating cerebral edema and increasing ICP. In patients with life-threatening
cerebral edema, more extreme measures may be undertaken. Traditional osmotherapy is that of mannitol,
and intermittent dosing of mannitol can have profound effects (Fig. 49.1C and D). For treatment of acute
herniation, the standard dose of mannitol is 1 g/kg as a single bolus. Intermittent bolus dosing at doses of
0.25 g/kg to 0.50 g/kg also is used. Administration of hypertonic saline, either continuously or as a bolus,
can also be used to drive the plasma [Na+], and thus the plasma osmolality, to abnormally high values to
treat life-threatening cerebral edema. A prolonged increase in plasma osmolality results in the creation of
idiogenic osmoles in the brain to alleviate the osmotic stress. Rapid normalization of plasma osmolality
can thus result in “rebound edema.” It is thus important to normalize plasma osmolality over the course of
several days to prevent the movement of water from plasma into brain tissue containing high
concentrations of these idiogenic osmoles.
In patients with cerebral edema that is refractory to medical therapy, decompressive hemicraniectomy
may be life saving. Decompressive hemicraniectomy allows for normalization of the ICP and pressure
gradients within the intracranial cavity and thereby prevents herniation. Blood flow through the pial
vessels may be compromised by increased ICP; a decompressive surgery will therefore improve blood
flow and may lessen ischemic brain injury. Decompressive hemicraniectomy has been used to treat
medically intractable intracranial hypertension in patients with meningoencephalitis (29–32).
GENERAL INTENSIVE CARE UNIT CARE

Blood Pressure
In patients with pneumococcal meningitis, concomitant sepsis is common. Meningitis caused by other
bacterial pathogens may also be accompanied by bacteremia and, potentially, septic physiology. If
significant hypotension is present, the CBF may become compromised, especially if the ICP is elevated.
Care must therefore be taken to ensure that patients are euvolemic. As a rule, a MABP of at least 90 mm
Hg should be maintained to ensure adequate CBF, using intravenous fluids and vasopressors as needed. In
persons with marked cerebral edema, the MABP needs to be even higher to ensure that the CPP is
sufficient to maintain CBF. Despite the lack of clinical evidence, ICP monitoring may be useful in patients
with diffuse cerebral edema to ensure that CPP is adequate.
Glucose
Dexamethasone administration is beneficial in the treatment of meningitis, but this benefit has only been
proven in the developed world for patients infected with Streptococcus pneumoniae (33). Hyperglycemia
is common in persons stressed with serious medical illness and perhaps even more common in persons
with brain injury; administration of dexamethasone will only increase the incidence and severity of
hyperglycemia. Experimental studies show that hyperglycemia exacerbates brain injury, and observational
studies show an association between hyperglycemia and increased morbidity and mortality following
ischemic stroke, hemorrhagic stroke, subarachnoid hemorrhage, head trauma, and cardiac arrest (34–38).
Whether or not normalization of glucose improves outcome in patients with brain injury, and patients with
CNS infections in particular, is unknown. There is no consistent evidence that intensive insulin therapy
improves outcome in critically ill patients, but the data are clear that intensive insulin therapy increases
the risk of hypoglycemia and death (39–41). The only specific recommendations about glucose
management that can be made in critically ill patients with brain injury—be it ischemic, traumatic, or
infectious—are to avoid hypoglycemia and the extremes of hyperglycemia.
Fever
Fever is a classic component of the immune response, and hyperthermia augments the function of immune
cells (42). The consequences of the immune response in the CNS, however, may be deleterious, as
already discussed. Furthermore, fever is associated with increased ICP, and even mild elevations in body
temperature predict poor outcome from brain injury (43). There is laboratory evidence of benefit for
hypothermia in almost all forms of brain injury, and hypothermia is an effective treatment for elevated ICP
(44). The clinical benefits of hypothermia, however, are only proven in the setting of cardiac arrest
(45,46). Because induction of hypothermia is difficult and hypothermia may suppress the beneficial as
well as the detrimental aspects of the immune response, hypothermia cannot yet be recommended as
routine adjunctive therapy for patients with CNS infections. Aggressive maintenance of normothermia,
however, should be strived for in these patients.
Delirium
Delirium is defined as fluctuation in the level and content of consciousness. Up to 80% of mechanically
ventilated patients will develop delirium while in the ICU (47); the incidence of delirium in critically ill
patients with infections of the CNS is likely higher. Patients who experience delirium have increased
lengths of stay, increased rates of admission to long-term care facilities, and long-term impairment in
cognitive function abilities (47,48). Further, delirium is associated with increased mortality (47,49).
Delirium, by definition, is related to a medical condition or side effects from medications. Prevention
of delirium may be difficult in patients with CNS infections, where the brain is directly impacted by the
pathogenic organisms, seizures are common, metabolic perturbations (like hyponatremia) are frequent,
and sepsis may occur. These conditions in and of themselves can cause delirium, as can many of the drugs
used to treat the conditions (i.e., antibiotics, anticonvulsants, sedative/hypnotic medications). Delirium is
more common with advancing age, infection, metabolic acidosis, use of sedatives and analgesics, and
uremia; the most important risk factors, however, are the presence of coma at the time of initial admission
to the ICU (drug induced or other organic) and having an underlying neurologic diagnosis (50). To prevent
delirium, aggressive correction of underlying medical conditions is paramount as is minimizing
polypharmacy. In a single study, prophylactic haloperidol did not prevent delirium but did reduce the
duration of delirium (51). The use of dexmedetomidine, as opposed to other sedatives, may be associated
with less risk of delirium, but its use is limited by bradycardia and hypotension (52).
Patients should be screened for delirium routinely using a validated scale such as the Confusion
Assessment Method for Intensive Care Unit (CAM-ICU), the Intensive Care Delirium Screening Checklist
(ICDSC), the Richmond Agitation-Sedation Scale (RASS), or the Riker Sedation-Agitation Scale (SAS)
(53,54). Once delirium occurs, the mainstay of pharmacologic therapy is the use of antipsychotics
(55,56). Haloperidol is the most commonly used antipsychotic, but other antipsychotic agents, such as
quetiapine and risperidone, may also be used. The major dose-limiting side effect of haloperidol is
prolongation of the QT interval, which can lead to torsades de pointes; patients treated with high doses
intravenous haloperidol should thus have daily electrocardiograms (ECGs). Nonpharmacologic therapies
include early mobilization and physical therapy, which has been shown to shorten the duration of delirium
and improve outcomes (57). For sedated and mechanically ventilated patients, daily trials of awakening
and spontaneous breathing should also be undertaken (58).
SEIZURES IN THE INTENSIVE CARE UNIT

Anything that irritates the cortex of the brain, including inflammation of pial vessels or cortical infarction,
may precipitate seizures. Seizures often occur in persons with meningitis and are even more common in
persons with encephalitis (23). In addition to the underlying infectious process that precipitates seizures,
hyponatremia, which is common in persons with CNS infections, will further lower the seizure threshold
in an already irritable brain. Moreover, many antibiotics used for the treatment of CNS infections may
also lower the seizure threshold (59). The risk of antibiotic-associated seizures is increased in patients
with CNS pathology, renal insufficiency, and in those who inadvertently receive excessive doses of the
antibiotic (59). Independent of seizures, some antibiotics may also cause encephalopathy; the risk factors
for encephalopathy are similar to those for seizures. Table 49.2 provides a list of CNS toxicity associated
with antibiotics. A review of all medications should therefore be performed daily in the ICU. Drugs with
potential to cause seizures should be used with caution in patients at risk for convulsions and should be
discontinued in patients who are actively seizing or at high risk for seizing.
The approach to treating seizures in persons with infections of the CNS is identical to that of persons
without infection, with the exception of the added need to treat the underlying infection with the
appropriate antibiotic, antifungal, or antiviral agents. The diagnosis of seizures is easy to make in patients
who convulse, but nonconvulsive seizures are difficult to diagnose without the aid of electrodiagnostic
tests. Nonconvulsive seizures are common in critically ill patients and a high index of suspicion for
subclinical seizures must be maintained (60). An electroencephalogram (EEG) should be thus performed
in any patient with an altered level of consciousness where the possibility of seizures exists. If electrical
seizures are detected, EEG monitoring should be continued as treatment is initiated in order to monitor the
response to that treatment.
Single seizures may be treated with any of the currently available antiepileptic medications. Drugs that
can be given intravenously, such as phenytoin, fosphenytoin, levetiracetam, valproate sodium, lacosamide,
and benzodiazepines, are preferable for the treatment of seizures in the ICU setting. If the seizures are
prolonged or recurrent, immediate measures should be taken to control them. Status epilepticus is defined
as a single seizure lasting more than 5 minutes or two or more seizures between which the patient does
not return to baseline consciousness (61). Seizures occur in 17% to 25% of persons with bacterial
meningitis (62,63) and are more common in patients with encephalitis (64,65). Although CNS infections
account for a minority of cases of status epilepticus in the adult population, status is common in these
patients and requires that appropriate care be delivered (66). An algorithm for the treatment of status
epilepticus in adults is presented in Figure 49.2 and is synthesized from the Neurocritical Care Society’s
Guidelines for the Evaluation and Management of Status Epilepticus (67). Most patients with status
epilepticus will need to be intubated and mechanically ventilated to ensure that the airway is protected
and that oxygenation and ventilation are adequate in the face of ongoing seizures and sedating
anticonvulsant drugs. Further, most drugs used to treat seizures will cause a degree of hypotension, as
does ongoing seizures (and septic physiology); aggressive support of blood pressure is thus often needed
early during the treatment of status epilepticus. Neuromuscular blockade used during intubation may
abolish the motor manifestations of the seizures, but it will not affect the ongoing electrical activity of the
brain. In patients with nonconvulsive status epilepticus, the examination does not reliably indicate the
presence or absence of seizures. Continuous EEG monitoring must therefore be performed in patients with
refractory status epilepticus so that anticonvulsants can be titrated to electrical activity (generally burst
suppression). There is consensus among experts that convulsive status epilepticus leads to brain injury,
but there are diverging opinions about the long-term dangers of nonconvulsive status epilepticus (68). The
aggressiveness of therapy in patients with nonconvulsive status epilepticus must therefore be weighed
against potential iatrogenic complications.
Benzodiazepines are rapidly acting drugs with potent anticonvulsant effects due to their potentiation of
γ-aminobutyric acid (GABA) activity; benzodiazepines are generally used as the initial treatment for
status epilepticus. The recently published Rapid Anticonvulsant Medications Prior to Arrival Trial
(RAMPART) confirms the strategy for rapid treatment of status epilepticus (69). Initial emergent therapy
in the ICU setting can be achieved with a variety of different benzodiazepines, although lorazepam is
generally the preferred therapy as it has a longer anticonvulsant half-life in the brain than diazepam (70).
In adults, intravenous lorazepam is generally given in 2-mg doses until the seizures are controlled or until
a maximum dose of 0.1 mg/kg is reached. Based on the results of RAMPART, intramuscular midazolam is
also a viable option for emergent treatment of status epilepticus. Because benzodiazepines are short-
acting drugs, intravenous administration of a longer acting anticonvulsant is generally recommended as
soon as possible (urgent control therapy). Drugs such as phenytoin or fosphenytoin have long been
considered first-line therapy, but other options are now available (see Fig. 49.2). In the critically ill
patient where metabolism may be altered and nutrition inadequate, free drug concentrations are more
useful to follow and more predictive of toxicity than total (free and bound) drug concentrations. The
optimal plasma concentration of any anticonvulsant is one that controls seizures without producing side
effects. In general practice, the goal for phenytoin (or fosphenytoin) in the ICU patient should be a total
concentration of approximately 20 mg/dL or a free concentration of 2 mg/dL. For drugs like levetiracetam
and lacosamide, however, plasma concentrations are not readily available, and dosing is based on
guidelines and clinical judgment.
The goal of therapy in status epilepticus is to have definitive control of seizures within 60 minutes.
Patients with refractory status epilepticus are those who continue to seize despite treatment with an
emergent therapy (i.e., benzodiazepines) and urgent control therapy (with anticonvulsants used for long-
term therapy). For these patients, additional therapy is needed. Among the multiple drugs that can be used
for the treatment of refractory status epilepticus, the greatest experience is with the barbiturates.
Pentobarbital, thiopental, and phenobarbital are all options for the treatment of status epilepticus. The
half-lives of these drugs vary greatly and may help to determine which is used. The half-life of
phenobarbital is approximately 90 to 120 hours, meaning that administration of this agent generally
commits the patient to a prolonged ICU stay. The half-life of pentobarbital is approximately 15 to 48
hours and that of thiopental is 6 to 46 hours. The dose of barbiturates can be increased as needed to
control seizures, but dosing is often limited by hypotension. At very high doses, barbiturates impair the
function of cilia and neutrophils and thus predispose to pneumonia and other infections (71).
Gastroparesis is also common with high-dose barbiturate therapy and often necessitates the institution of
parenteral nutrition. Because of the relatively long half-life of the barbiturates, as well as their side
effects, alternative drugs with anticonvulsant activity are often preferred. These alternative drugs include
midazolam and propofol, which are also given as continuous intravenous infusions (see Fig. 49.2). The
short half-lives of these drugs allow for better titration to response, and once the decision is made to stop
therapy, the drugs are relatively rapidly cleared from the system. In patients who receive prolonged
therapy with either drug, however, the effective half-lives may be significantly prolonged and days may
be required to fully eliminate the drugs from the system. Propofol use is also associated with hypotension,
which may prevent achieving a dose adequate to control seizures. Propofol infusion syndrome (metabolic
acidosis, cardiac failure, renal failure, rhabdomyolysis, and hypertriglyceridemia) can complicate high-
dose (>4 to 5 mg/kg/hr) and prolonged (>48 hours) use. There are no randomized controlled trials
supporting the efficacy of one-drug therapy over another for the treatment of refractory status epilepticus,
so drug choice is usually empirical. For patients who continue to experience seizures despite the above
measures, case reports describe successful treatment with ketamine, lidocaine, high-dose magnesium,
hypothermia, and electroconvulsive therapy.
IATROGENIC INFECTIONS
Invasive instrumentation is inherent in caring for critically ill patients. Medical devices used for
physiologic monitoring that are unique to the neurologic ICU include ICP monitors, external ventricular
drains, lumbar drains, and jugular bulb catheters. These indwelling catheters violate the protective
barriers of the body and serve as a route of pathogen entry into either the CNS or bloodstream. The
diagnosis and management of iatrogenic infections in the neurologic ICU are discussed in detail in
Chapter 48.
SYSTEMIC NEUROLOGIC COMPLICATIONS IN CRITICALLY

ILL PATIENTS
Critically ill patients, such as those with bacterial meningitis and concomitant bacteremia, are at risk of
developing critical illness polyneuropathy (CIP) and critical illness myopathy (CIM). CIP and CIM may
occur independently or as overlapping disorders; the presentations are that of diffuse weakness and
failure to wean from the ventilator. CIM is more common than CIP and may have a better prognosis
(72,73). The development of either CIP or CIM is associated with a prolonged mechanical ventilation,
increased length of stay, and increased morbidity and mortality. A complete review of CIP and CIM is
provided by Latronico and Bolton (74). Identified risk factors for CIP and CIM are multiorgan failure,
sepsis, and the systemic inflammatory response syndrome (SIRS). Additional risk factors may include
hyperglycemia, prolonged vasopressor support, parenteral nutrition, prolonged mechanical ventilation,
and renal failure.
Definitive diagnosis of CIP and CIM requires clinical suspicion as well as electrodiagnostic studies; in
some instances, muscle biopsy may be necessary. In CIP, electrical studies reveal a reduction in the
amplitude of compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs)
with normal (or mildly reduced) nerve conduction velocities (i.e., findings consistent with an axonal
neuropathy). Both motor neurons and sensory neurons are affected. Denervation, characterized by
fibrillation potentials and positive sharp waves, is often seen as well. Nerve involvement, both clinically
and electrophysiologically, is greatest distally; cranial nerves are generally spared. Histologic evaluation
of the muscles in patients with CIP shows acute denervation with atrophy of both type 1 and type 2 fibers.
CIM is a primary myopathy (as opposed to a muscle disorder related to denervation, as seen in CIP).
CIM is distinguished from CIP by an increase in the duration of CMAPs and the presence of normal
SNAPs. Further, reduced muscle excitability and myopathic motor units are seen on direct needle
electromyography. Histologic evaluation of the muscles in patients with CIM most commonly shows
necrosis and loss of thick filaments.
There are data that suggest aggressive insulin therapy may prevent CIP and CIM, but the use of insulin
is associated with significant hypoglycemia (75). Aggressive insulin therapy therefore cannot be
recommended, but it seems reasonable to control extreme hyperglycemia. It also seems prudent to provide
aggressive nutritional support to patients with CIP and CIM and to mobilize these patients early, although
definitive data do not yet exist to support these interventions.
SUMMARY
Patients with infections of the CNS are at risk for a number of serious medical and neurologic
complications. Chief among these complications are cerebral edema with intracranial hypertension,
seizures, neuropathy, and myopathy. Aggressive and appropriate care within the ICU setting can minimize
these complications and improve the chance of a good outcome.
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PART X ■ PREVENTION
CHAPTER 50 VACCINES FOR VIRAL DISEASES WITH

SIGNIFICANT CENTRAL NERVOUS SYSTEM
MANIFESTATIONS
DAVID W. KIMBERLIN
Prevention of disease through deliberate exposure of susceptible human hosts to infectious agents of
decreased virulence dates back a millennium. The pace of discovery and technological advances of
vaccination development, however, have accelerated dramatically over the past 60 years, with the number
of diseases for which vaccines are routinely used in prevention now approaching two dozen. This chapter
focuses on vaccines that protect against viral infections that have significant central nervous system
(CNS) manifestations, including measles, mumps, poliomyelitis, rabies, and Japanese B encephalitis.
Given the scope of this textbook, discussion of each of these diseases is limited to neurologic
manifestations of each wild type disease, followed by a comprehensive review of vaccine prevention.
MEASLES
Neurologic Manifestations of Measles
Central Nervous System Involvement During Acute Disease
First described at the end of the eighteenth century (1), measles encephalitis causes the greatest morbidity
and mortality of all the complications of measles infection. Symptoms of encephalitis begin within 8 days
of the onset of illness, most often during the exanthem period (2,3). Presenting symptoms include seizures
(56%), lethargy (46%), coma (28%), and irritability (26%) (3). Analysis of cerebrospinal fluid (CSF)
usually yields a mild pleocytosis with a slightly elevated protein level and normal glucose concentration
(3,4). The CSF can be completely lacking in signs of inflammation in cases of measles encephalitis (3).
A Centers for Disease Control and Prevention (CDC) study of reported cases of measles
encephalopathy in the United States between 1962 and 1979 revealed a 15% mortality rate associated
with this complication (5). The investigators found that 25% of survivors of measles encephalopathy had
severe sequelae, including mental retardation, seizures, severe behavioral disorders, deafness,
hemiplegia, and paraplegia. There were 0.73 cases of encephalitis per 1,000 estimated total cases of
measles, and the death rate due to measles encephalitis was 1 per 10,000 reported cases of measles.
Other investigators have reported neurologic sequelae in as many as 50% to 60% of cases of measles
encephalopathy (2).
The mechanism by which measles virus causes encephalitis is incompletely understood. Neurologic
involvement may entail direct viral-induced cellular damage; alternatively, an autoimmune-mediated
process of tissue damage is possible. Some investigators have successfully identified viral RNA or
antigens in the CNS of affected patients (4,6), whereas others have been unable to demonstrate a direct
viral involvement (7–10). Both mechanisms may contribute to the pathology present in measles
encephalitis.
Immunocompromised patients may develop an unusual form of acute progressive encephalitis, formerly
known as measles inclusion body encephalitis (MIBE). Following an incubation period lasting from 5
weeks to 6 months, illness often initially manifests with seizure activity. Hemiplegia, slurred speech,
stupor, coma, and hypertonia can develop. This disorder is usually fatal, with death occurring within 1
week to 2 months following the onset of neurologic findings (11,12). It is often associated with
malignancies of the lymphatic or reticuloendothelial systems (e.g., leukemia or lymphoma) (13). Electron-
microscopic studies of brain specimens from these patients demonstrate nucleocapsid structures in the
cytoplasm of infected cells; however, the viral budding that can be seen in acutely infected cells is not
present (13). Infectious virus has been isolated infrequently from these patients (14).
Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a rare degenerative neurologic disease that occurs years
after measles infection. The disease was first described clinically in the 1930s (15). Since its initial
description, it has undergone many name changes, including “lethargic encephalitis with inclusions,”
“subacute inclusion body encephalitis” (15), and “subacute sclerosing leukoencephalitis” (16,17). The
term SSPE was coined in 1950 by Greenfield (16) to stress that both the white and the gray areas of the
brain are affected.
SSPE clinically is very similar to MIBE. However, the asymptomatic period following the acute
measles infection is much longer in SSPE. Additionally, whereas SSPE patients often mount a strong
immune response to most measles virus proteins (with the exception of the M protein), MIBE patients
have a diminished antibody response to measles virus antigens (13,18,19).
Patients afflicted with SSPE are usually children or young adults. Reported patient ages range from 1 to
35 years old, with an average age at onset of about 9 years (20–22). There is a 2.3:1 male-to-female
prevalence ratio (20). More than half of all cases occur in patients who had their typical measles
infection when they were younger than 2 years of age (20–22). Prior to widespread measles immunization
in the United States, there was a higher prevalence in whites and among rural populations, and a higher
prevalence in the southeastern portion of the United States (20). Worldwide annual incidence figures have
been estimated at 1 case per million persons per year (21,22); in the United States, there are 0.35 cases
per million persons per year (20). For every 100,000 cases of measles that occur naturally worldwide,
there are 0.6 to 2.2 cases of SSPE (20,23–25).
At initial presentation, patients with SSPE demonstrate subtle changes in mental status, followed by
delirium, dementia, myoclonus, motor incoordination, seizures, and visual and speech impairment;
disease then progresses to stupor, mutism, coma, and death (21,22,26–28). Clinical staging of SSPE was
established by Jabbour (29), as follows:
1. Stage 1 manifests as cerebral changes and lasts 1 to 2 months.
2. Stage 2 involves worsening convulsions and lasts 2 to 3 months.
3. Patients in the third stage (coma and opisthotonus) exhibit worsening neurologic status over 1 to 4
months.
4. The final stage of SSPE involves autonomic dysfunction and lasts from months to years.
Pathologic evaluation of the brains of patients with SSPE invariably reveals gray matter involvement,
occasionally with extensive white matter sclerosis. Intranuclear and intracytoplasmic inclusion bodies are
seen in the affected neurons. These “Cowdry inclusion bodies” have been shown to contain measles virus
(30).
The diagnosis of SSPE often can be made on the basis of information obtained on the clinical and
laboratory evaluation. The typical electroencephalographic (EEG) pattern of SSPE consists of periodic
bilateral bursts of high-voltage activity every 3 to 20 seconds with background suppression (27).
Computed tomography (CT) scan reveals atrophy involving the cerebrum, cerebellum, and brainstem; in
addition, diffuse white matter involvement can be seen, as can involvement of the thalamic and lentiform
nuclei. The correlation between the clinical staging and magnetic resonance imaging (MRI) usually is
poor (31), although diffusion-weighted MRI has been used to differentiate between stages of SSPE
(32,33). The CSF protein is elevated because of the presence of oligoclonal immunoglobulin G (IgG)
directed against measles antigens (13,18).
Although the specific pathogenic mechanisms in SSPE have yet to be elucidated, numerous reports have
detected measles virus in brain biopsy specimens from patients with SSPE (13,18,30,34–37). Intranuclear
and cytoplasmic inclusion bodies can be detected in neurons, astrocytes, and oligodendrocytes;
additionally, nucleocapsid particles can be visualized in these inclusion bodies by electron microscopy
(17,38–40). In contrast to electron microscopy of infected cells from patients with acute measles
infection, nucleocapsids are not visualized assembling or budding out from the cell surface in specimens
from patients with SSPE. Investigators have speculated that a block in the formation of competent viral
particles may exist in patients with SSPE (41). In support of this hypothesis, cell-free extracts of brain
tissue from patients with SSPE are not infectious for susceptible cells in tissue culture as assayed by
cytopathic effect, hemagglutination, and fluorescent staining. When brain tissue is co-cultivated with
tissue culture cells (e.g., HeLa cells and Hep II cells), infection of the tissue culture cells occurs,
indicating that the block is reversed by the presence of nonneural cell types (30).
Analysis of brain tissue specimens from patients with SSPE using monoclonal antibodies directed
against the six measles virus proteins revealed that whereas all the proteins are found in the various brain
tissue samples, all six proteins were never found simultaneously in a single tissue specimen. In other
words, one protein would be missing in one sample and another would be missing in a different sample
(13,18,34,37,42,43). In contrast, all six proteins can be demonstrated simultaneously in cells infected
with measles virus in tissue culture. Investigators have occasionally described more than one profile of
proteins present in different areas of the same brain specimen (43). Of the six viral proteins, M protein is
present least often. Of note, M protein is involved in viral assembly and budding. Analysis of messenger
RNA (mRNA) from SSPE specimens has revealed a high mutation rate in all of the viral proteins
(43–46). Although these mutations are not seen in viruses isolated during acute infections, they are thought
to occur with the same regularity as in SSPE but are simply selected against in the acute infection.
Selection pressures in nondividing neural tissues may be less than those in actively dividing tissues, and
such differences may permit viruses with defects to survive (46). In fact, viruses with “defects” that
prevent them from acutely lysing neuronal cells may actually have a selective advantage, in that they
remain “hidden” from the immune system when they reside solely within the cells (43).
Reports have been published suggesting that inosiplex (isoprinosine) (47), inosiplex plus interferon-β
(48), inosiplex plus interferon-α plus lamivudine (49), intraventricular ribavirin (50), interferon-β
monotherapy (51), and interferon-α monotherapy (52) may be effective in slowing the progression of
SSPE. However, these studies have not been controlled. One international multicenter controlled study
compared oral inosiplex with oral inosiplex plus intraventricular interferon-α, and found that neither
group was superior but that higher proportions of both treatment groups stabilized or improved (34% and
35%, respectively) compared to the spontaneous remission rates of 5% to 10% reported in the literature,
suggesting that treatment was superior to no treatment (53).
Measles vaccination programs provide the best means by which the incidence of SSPE can be reduced.
The risk of SSPE in vaccinated children (0.5 to 1.1 cases per million per year) is less than that in children
who have had natural measles infection (5.2 to 9.7 cases per million per year) (20). In addition, the
incidence of SSPE has fallen dramatically since the initiation of vaccination programs, suggesting that the
vaccine is protective.
VACCINATION AGAINST MEASLES

History
The progenitor measles strain for most of the current vaccines in use worldwide was isolated from a
patient named David Edmonston. Within 9 years of this initial viral isolation, two measles vaccines were
licensed for use in the United States in 1963. From 1963 to 1968, an estimated 1.8 million doses of a
formalin-inactivated, alum-precipitated measles vaccine were administered to 600,000 to 900,000
persons in the United States (54). The short-lived immunity conferred by this vaccine and the propensity
of patients to develop atypical measles infections led to the cessation of its use after 5 years (55). The
second measles vaccine licensed in 1963 was the attenuated, live-virus Edmonston B vaccine. In use from
1963 to 1975, 18.9 million doses of this vaccine were administered in the United States (26,28). Although
the protection conferred by this live-virus vaccine was superior to that of the killed vaccine, side effects
such as fever and rash were very common. Although simultaneous administration of small doses of
immune globulin decreased the occurrence of such reactions, the Edmonston B vaccine was eventually
replaced by additionally attenuated live-virus vaccines with fewer side effects.
Several further attenuated strains of measles virus have been derived from the original Edmonston
strain. These vaccines confer good protection against natural disease while causing fewer side effects,
thereby eliminating the need for the simultaneous administration of immune globulin. The Schwarz strain
was administered in the United States from 1965 through 1976, and it is still used in most parts of the
world. The Moraten (more attenuated Enders) strain has been licensed for use in the United States since
1968, with more than 165 million doses having been administered since that time (56,57). The Moraten
vaccine is the only measles vaccine licensed for use in the United States. Combination vaccines that
include mumps, rubella, and measles (the measles-mumps-rubella [MMR] vaccine) and mumps, rubella,
measles, and varicella (MMRV vaccine) have been available since 1971 and 2005, respectively.
Monovalent measles vaccine has been withdrawn from the U.S. market, leaving MMR and MMRV as the
only measles-containing vaccines available in this country. Vaccines using other strains of measles virus
are widely used throughout the world and are usually comparable to the Moraten vaccine available in the
United States (58).
Measles Vaccination Today
The dramatic decrease in cases of measles since the licensure of the measles vaccine is a testament to its
success. The incidence of measles has decreased more than 99% since the introduction of measles
vaccine in the United States in 1963 (59). The last major resurgence of measles in the United States
occurred from 1989 to 1991, during which time the incidence of measles increased sixfold to ninefold
over the median annual incidence earlier in the 1980s, with 120 reported measles-related deaths (57,60).
At the peak of the epidemic in 1990, the incidence of measles among children younger than 5 years of age
was 15-fold higher than the median annual incidence reported from 1981 through 1988 (57). This measles
resurgence was primarily a consequence of the failure to vaccinate preschool-aged children according to
the recommended immunization schedule (61). With the implementation of the two-dose measles
vaccination schedule discussed later in this chapter, the incidence of measles in the United States has
decreased to a record low, with only 86 cases being reported in 2000 (62) and a reported incidence of
less than 1 case per million since 1998 (63), culminating in the elimination of endemic transmission being
declared in 2000 (64). After the elimination of measles was achieved, a number of outbreaks of limited
size occurred as a result of importation into primarily unvaccinated populations; these outbreaks have not
extended to the highly two-dose vaccinated populations (65). Each year since 2000, an average of 60
people in the United States are reported to have measles. In 2011, the number of reported cases was
higher than usual, with 222 people developing the disease. Nearly 40% of these people acquired measles
in other countries, including countries in Europe and Asia, and then brought it to the United States and
spread it to others, resulting in 17 measles outbreaks in various U.S. communities (66).
A notable recent development in the worldwide effort to prevent measles infection involved high-titer
live attenuated measles vaccine. Several studies in the late 1980s found that high-titer (>104.7 log10
infectious units) Edmonston-Zagreb live attenuated measles virus vaccine induced serologic response
rates among young infants that were comparable to the response rates following standard titer vaccines
administered at 9 months of age (67–71). However, higher than expected mortality rates later in infancy
among recipients of these high-titer vaccines have been reported in areas where mortality rates from
measles are high among children younger than 9 months (72–74). Of note, these deaths were due to
common childhood illnesses, not measles infection (73,74). Investigators initially hypothesized that in a
manner similar to natural measles infection, immune suppression induced by the high-titer vaccine
predisposes these infants to severe life-threatening infections with common childhood pathogens (75–78),
but more recent analyses suggest that the sequence of other vaccines administered concomitantly with
high-titer Edmonston-Zagreb measles vaccine, rather than the high-titer vaccine itself, accounts for the
increased female mortality in these trials (79). These high-titer vaccines were never licensed in the
United States and are no longer in use in foreign countries (58). Importantly, increased mortality rates
have not been noted among recipients of standard-dose measles vaccine, including standard dose
Edmonston-Zagreb vaccine. Studies of standard dose Edmonston-Zagreb vaccine given at 4.5 months and
9 months of age suggest that early measles immunization has beneficial nonspecific effects on children’s
survival, particularly for girls and for children who have not received neonatal vitamin A (80).
Vaccine Recommendations
Prior to 1989, the measles elimination strategy called for administration of one dose of measles vaccine
at 15 months of age. Because of the increase in measles cases among adolescents and young adults, both
the CDC Advisory Committee on Immunization Practices (ACIP) and the American Academy of
Pediatrics (AAP) Committee on Infectious Diseases recommended in 1989 that a routine two-dose
measles vaccination schedule be adopted (58,81). The rationale behind such a recommendation is that the
two-dose schedule may successfully protect those patients who failed to respond adequately to a single
dose of measles vaccine (primary vaccine failures); in addition, patients who missed their single-dose
immunization are more likely to be detected and vaccinated under a two-dose vaccination program. Table
50.1 lists the current recommendations for measles vaccination.
Adverse Reactions to Measles Vaccine
Between 5% and 15% of measles vaccine recipients develop fever with a temperature of 39.4°C or
higher between 5 and 11 days postvaccination, presumably as a reaction to replication of the live
attenuated virus and usually without additional symptoms. About 5% of all recipients of measles vaccine
develop a transient rash. True encephalitis or encephalopathy occurs in vaccine recipients at a rate equal
to or lower than that seen in unvaccinated or baseline populations (<1 case per million doses of vaccine),
and such neurologic sequelae have not been causally associated with vaccine administration (56).
Postvaccination seizures have been reported in children, coinciding with the occurrence of fever (“febrile
seizures”). Among 12- to 23-month-old recipients of MMR and varicella vaccines administered
concurrently but at separate sites, 3 to 4 febrile seizures occur per 10,000 children vaccinated; for
children of the same age range receiving MMRV, 7 to 9 febrile seizures occur per 10,000 children
receiving MMRV (82). Thus, one additional febrile seizure is expected to occur per approximately 2,300
to 2,600 children 12 through 23 months old vaccinated with MMRV, when compared with separate MMR
and varicella vaccine administration. The period of risk for febrile seizures is from 5 through 12 days
following receipt of the vaccine(s). No increased risk of febrile seizures is seen among patients 4 to 6
years of age receiving MMR, MMRV, or monovalent varicella vaccines. Febrile seizures do not
predispose to epilepsy or neurodevelopmental delays later in life and are not associated with long-term
health impairment. The AAP recommends that either MMR and varicella vaccines separately or MMRV
vaccine be used for the first dose of measles, mumps, rubella, and varicella vaccines administered at 12
through 47 months of age (82). Transient thrombocytopenia has been reported following administration of
the MMR vaccine (83).
Allergic reactions to the vaccine occur only very rarely. The vaccine virus is grown in avian embryos,
so trace amounts of egg proteins may be present in the final product. Patients who have demonstrated
prior severe egg allergies or who have a history suspicious for egg allergy may be screened by skin
testing with the vaccine prior to its use (84–87). Of the hundreds of millions of doses given in the United
States, only five incidences of anaphylactoid reactions with associated respiratory problems have been
reported (88).
As with naturally occurring infection, measles vaccination is associated with a transient impairment of
cell-mediated immunity, as demonstrated by a blunted cutaneous delayed hypersensitivity reaction to
administered antigens (e.g., purified protein derivative of tuberculin). Although not thought to be
clinically significant, it should be considered before skin testing these patients, should skin testing be
indicated. This response can last as long as 4 to 6 weeks postvaccination (58).
Isolation of vaccine virus from human blood postvaccination has not been reported. Thus, viremia
either does not occur in this setting or is present only transiently and at very low levels. No cases of
person-to-person transmission of the vaccine strains have been reported, and there is no evidence of
shedding of vaccine virus (26,28).
In the late 1990s, allegations arose suggesting that the MMR vaccine causes autism (89,90). The
hypothesis of such a causal effect was based on an uncontrolled case report study (89). Subsequently,
extensive data evaluating this hypothesis have consistently failed to prove such an association (91–96),
leading the Institute of Medicine (IOM) Immunization Safety Review Committee (ISRC) to conclude in a
detailed report that multiple studies indicate that there is no scientific basis to support this hypothesis
(97). The original paper asserting such an association was retracted when financial conflicts of interest
by the primary author were discovered and his license to practice medicine in the United Kingdom was
revoked. Similarly, evidence does not support the suggestion that MMR vaccine or wild type measles
infection is associated with inflammatory bowel disease or Crohn disease (92,96,98–101).
Vaccine Contraindications
Although no cases of in utero infection due to a vaccine strain of measles virus have been reported,
pregnant women or those who may become pregnant within 3 months should not receive measles vaccine,
thus avoiding the theoretical risk of fetal infection with the vaccine virus (56).
Endogenous interferon induced during a severe febrile illness has the potential to interfere with the
immune responses to vaccination. As such, vaccination of patients with severe febrile illnesses should be
deferred pending resolution of the intercurrent illness. However, mild febrile illnesses should not delay
immunization. A personal or family (i.e., sibling or parent) history of seizure is a precaution, but not a
contraindication, for use of MMRV vaccine due to the slight increase in risk of febrile seizures described
previously.
In general, patients with severe immunodeficiencies should not be immunized with live-virus vaccines.
Exceptions to this recommendation include asymptomatic human immunodeficiency virus (HIV)–infected
children and those with symptomatic infection who are not severely immunocompromised, in whom
measles immunization (given as MMR vaccine) is recommended because the risk of severe sequelae
(including death) from measles infection is high (58,88,102). Severely immunocompromised HIV-infected
infants, children, adolescents, and young adults, as defined by low CD4+ T-lymphocyte counts or
percentage of total lymphocytes, should not receive measles virus–containing vaccine because vaccine-
related pneumonitis has been reported (103,104).
Worldwide Measles Elimination
Since the institution of vaccination programs in Canada, China, the United Kingdom, and the United
States, the incidence of measles has decreased markedly (105–107). In addition, the incidence of SSPE
has decreased in the United Kingdom since vaccination regimens were implemented (107), and the
incidence of measles encephalitis in the United States has declined (105). Because humans are the only
known reservoir for measles virus, worldwide eradication is possible.
To eliminate measles, a sufficient number of the world’s population must be seroprotected. When
enough people are immune to infection, the virus will no longer be able to infect the number of
susceptible hosts required for its continued spread. Mathematical models based on viral infectivity
suggest that no less than 94% of the world’s population must be immune to measles infection to eliminate
the virus. Because the available vaccines are not completely effective in eliciting a protective response,
approximately 97% to 98% of the world’s population must be vaccinated to produce a population that is
94% protected (26,28). In 1980, before the use of measles vaccine was widespread, an estimated 2.6
million deaths due to measles occurred worldwide (108). With worldwide focus, global mortality
attributed to measles has decreased from 733,000 in 2000 to 164,000 in 2008 (109). With the financial
and technical support of the Measles Initiative international partnership, all countries except India have
achieved the 2010 global goal of reducing measles mortality by 90% (109). Measles elimination has been
sustained in the World Health Organization (WHO) Region of the Americas since 2002. Although global
challenges remain, including a resurgence of measles in sub-Saharan Africa and to a lesser degree in
Europe, these encouraging developments led the WHO in 2008 to evaluate the feasibility of the global
eradication of measles. A Global Consultation on the Feasibility of Measles Eradication convened in
2010 and concluded that measles can and should be eradicated and that global eradication by 2020 is
feasible (110). A thorough assessment of the current challenges and opportunities was published as a
supplement to the Journal of Infectious Diseases in July 2011 (Volume 204, Supplement 1).
MUMPS
Neurologic Manifestations of Mumps
Meningeal viral involvement occurs in about half of all cases of mumps infection, with or without clinical
signs of meningismus (111–114). Reports concerning the frequency of CNS involvement in mumps
infection date back to the beginning of the twentieth century. In 1902, Monod performed lumbar punctures
on eight children with mumps; despite the lack of symptoms suggesting CNS involvement, six of the eight
patients had elevated CSF white blood cell (WBC) counts (112,115). Additional studies confirmed the
association between mumps and abnormal CSF indices. In the winter of 1937, CSF was obtained from 40
children admitted to Willard Parker Hospital in New York with the diagnosis of mumps (114). Sixteen
(40%) of the forty specimens had elevations in CSF leukocyte counts and protein concentrations. Six of
these sixteen children had no CNS symptoms, whereas ten had symptoms ranging from mild to severe,
including drowsiness, nuchal rigidity, seizures, severe headache, and coma. All recovered without
sequelae. In a larger study performed in 1943, 235 (63%) of 372 patients with mumps parotitis had CSF
leukocytosis (111). And during an outbreak on an army base in 1948, 26 (34%) of 77 adults who
contracted mumps had elevated CSF WBC counts, although only 9 patients had CNS symptoms (111).
Although laboratory evidence of CNS inflammation is present in a large proportion of patients with
mumps, clinically apparent meningoencephalitis occurs only rarely, on the order of 2 to 8 cases per 1,000
cases of mumps (116,117). Although CNS manifestations can begin more than a week after the onset of
parotitis, initial symptoms precede or coincide with parotid swelling in about two thirds of all cases
(113,114,118–121). Virus can be isolated from the CSF in the latter instances (122) and histology shows
neuronal breakdown (119,123), suggesting that active viral replication results in the symptomatology and
pathologic injury noted in early-onset cases. In late-onset “secondary” or “postinfectious” cases of CNS
involvement (112,124,125), neuronal injury and CNS inflammation may be caused indirectly, perhaps
through autoimmune mechanisms. In late-onset cases, perivascular leukocytic infiltration and
demyelination are present on histologic examination of the brain (119,123,124).
Patients with clinically apparent meningitis or meningoencephalitis typically have a moderate elevation
of the CSF WBC count (from 500 to 1,000 cells/mm3) with a lymphocyte predominance. The CSF protein
level is usually normal or mildly elevated, and CSF glucose concentration is normal.
Although studies vary with regard to estimates of sequelae following mumps meningitis or
meningoencephalitis, adverse neurologic outcomes probably occur in fewer than 1% of cases with CNS
symptoms (125–128). Ataxia, flaccid paralysis, incontinence, and behavioral changes have all been
described in patients with residual neurologic findings (120–122,129). Fatal cases have been reported
after mumps meningoencephalitis (119,124).
VACCINATION AGAINST MUMPS

History
A formalin-inactivated mumps vaccine was first tested in 1950, but it had a low protective efficacy
against clinical mumps among susceptible persons (130–132). In addition, protection conveyed by this
killed vaccine persisted for less than 1 year, necessitating reimmunization. As a result of these
shortcomings, the vaccine was discontinued in 1976 (130,132). The attenuated mumps strain used in the
vaccine currently licensed in the United States was derived from a child named Jeryl Lynn; this strain was
attenuated by serial passage through embryonated eggs by Maurice Hilleman, Jeryl Lynn’s father. Over his
career, he developed or substantially improved more than 25 vaccines, including 9 of the 14 now
routinely recommended for children, saving literally millions of lives (133). In the first 20 years
following the 1967 licensure of mumps vaccine in the United States, an excess of 80 million doses of the
Jeryl Lynn strain of attenuated mumps virus vaccine were administered (130,132,134). After
implementation of the one-dose mumps vaccine recommendation in 1977, the incidence of mumps in the
United States declined from an incidence of 50 to 251 per 100,000 in the prevaccine era to 2 per 100,000
in 1988. After implementation of the two-dose MMR vaccine recommendation in 1989 for measles
control, mumps further declined to extremely low levels, with an incidence of 0.1 per 100,000 by 1999.
From 2000 to 2005, there were fewer than 300 reported cases per year (incidence of 0.1 per 100,000),
representing a greater than 99% reduction in disease incidence since the prevaccine era. Since 2006,
though, a series of large-scale mumps outbreaks have occurred. These outbreaks have occurred in
communities with high intensities of person-to-person exposure, such as colleges and religious groups.
The effectiveness of MMR vaccine to prevent mumps has been estimated at medians of 78% (range: 49%
to 91%) for one dose and 88% (range: 66% to 95%) for two doses (135). In response to these outbreaks,
third doses of MMR vaccine have been administered. A small study demonstrated an anamnestic response
following a third MMR dose within 7 to 10 days after vaccination (136). Two efficacy studies of use of a
third dose of MMR to stem a mumps outbreak have been published (137,138). However, in both, the
intervention with a third dose of vaccine occurred after the peak of the outbreak. Both also had small
numbers of cases postintervention, and for these reasons, the results have limited generalizability.
Administration of a third MMR dose in an outbreak setting appears to be safe (139). As of early 2013,
available data are insufficient to recommend for or against the use of a third dose of MMR vaccine for
mumps outbreak control. Because control measures for mumps are limited, the ability to offer a third dose
of MMR vaccine might be a tool that could be used in an attempt to limit the extent of mumps outbreaks,
particularly in high-risk settings.
Following vaccination with the Jeryl Lynn strain, the frequency of such postvaccination CNS
complications as neuritis, encephalitis, and deafness is no higher than in unvaccinated populations
(130,132,140). However, aseptic meningitis as a complication of vaccination with the Urabe Am9 strain
of attenuated mumps virus has been widely reported (141–144). This complication occurs 14 to 28 days
postvaccination, with an estimated incidence of 1 case in 11,000 to 14,000 doses (143,144). Importantly,
the Jeryl Lynn strain mumps vaccine, which is the mumps component of the MMR vaccine, is not
associated with cases of aseptic meningitis (145). The meningitis associated with the Urabe Am9 strain is
usually mild, resolving without sequelae (141). Although the Urabe strain has a higher efficacy than the
Jeryl Lynn vaccine (146), this increased risk of vaccine-associated complications has resulted in its
withdrawal from the market in many countries (142).
No cases of person-to-person spread of the Jeryl Lynn mumps vaccine strain have been reported (147).
However, at least one case of transmission of the Urabe mumps virus following immunization has been
documented (148).
Two doses of mumps vaccine are recommended for children in the United States. MMR and MMRV are
both options for mumps vaccine administration, but monovalent mumps vaccine no longer is available in
the United States. The first dose of MMR or MMRV vaccine should be given routinely to children at 12
through 15 months of age, with a second dose of MMR or MMRV vaccine administered at 4 through 6
years of age. The second dose of MMR or MMRV vaccine may be administered before 4 years of age,
provided at least 28 days have elapsed since the first dose and the interval between varicella vaccine
doses is at least 90 days.
Acceptable evidence of mumps immunity include the following: (a) documentation of age-appropriate
vaccination with a live mumps virus–containing vaccine, which is one dose for preschool-aged children,
two doses for school-aged children (grades K to 12), and one dose for adults not at high risk; (b)
laboratory evidence of immunity; (c) laboratory confirmation of disease; or (d) born before 1957 (149).
Because it is a live attenuated vaccine, mumps vaccination should be deferred in pregnant women or
women who plan to conceive within 28 days. MMR and MMRV vaccines are produced in chicken
embryo cell culture and do not contain significant amounts of egg white (ovalbumin) cross-reacting
proteins. Children with egg allergy are at low risk of anaphylactic reactions to MMR or MMRV vaccine.
Skin testing of children for egg allergy is not predictive of reactions to MMR or MMRV vaccine and is
not required before administering MMR vaccine. Live mumps vaccine should be given at least 2 weeks
before or at least 3 to 11 months after administration of immune globulin, depending on the dose of
immune globulin administered. Patients with immunodeficiency diseases and those receiving
immunosuppressive therapy or who are otherwise immunocompromised should not receive mumps
vaccine. An exception to this is the patient with HIV infection who is not severely immunocompromised
(i.e., for persons aged 5 years or younger: must have CD4 percentages ≥15% for ≥6 months; for persons
aged older than 5 years: must have CD4 percentages ≥15% and CD4 ≥200 lymphocytes/mm3 for ≥6
months), in whom MMR vaccine should be given for the measles protection it conveys. Children with
minor illnesses with or without fever, such as upper respiratory tract infections, may be immunized. Fever
is not a contraindication to immunization. However, if other manifestations suggest a more serious illness,
the child should not be immunized until recovered.
Mumps vaccination is followed by a lag of up to a few weeks before antibodies are detectable. As a
result, vaccination will not protect susceptible persons recently exposed to mumps virus (131). No data
exist to support the use of immune globulin in exposed susceptible persons in either preventing or
ameliorating disease (130,132,150,151).
JAPANESE ENCEPHALITIS VIRUS

Neurologic Manifestations of Japanese Encephalitis Virus
Although only a small proportion of patients infected with Japanese encephalitis (JE) virus will be
symptomatic, these patients very often will be severely affected and can suffer permanent CNS damage or
death. Inoculation occurs with the bite of an infected mosquito. During the following 4- to 14-day
incubation period, most persons clear the infection and have no further signs of illness. Those patients
who fail to eliminate the virus, however, enter the prodromal stage of illness. This period lasts 2 to 3
days, during which time patients suffer headache, anorexia, nausea, vomiting, and abdominal pain. Low-
grade fever and CNS changes ranging from mild disorientation to frank psychosis can also occur during
the prodromal stage (152,153).
The acute stage of symptomatic JE virus infection lasts 3 to 7 days. High fever often signals the onset of
the acute stage. Seizures occur in about 20% of children during the acute stage, but convulsions develop
only rarely in adults. Rapid fluctuations in CNS signs can manifest as hyperreflexia followed quickly by
hyporeflexia. Alterations in mental status may produce confusion, disorientation, delirium, or coma.
Meningismus, diarrhea, oliguria, and bradycardia can occur during this period. CSF examination reveals
an elevated protein concentration and a moderate pleocytosis with between 100 and 1,000 cells/mm3; the
polymorphonuclear predominance that occurs early is followed by a shift to a lymphocyte predominance.
Fatal cases progress to coma and death within 10 days of the onset of the acute stage (152,153). Mortality
rates range from 20% to 30%.
Patients who survive the acute stage subsequently enter the subacute stage followed by the convalescent
stage. The former lasts from the second to the fourth week and is marked by gradual improvement in
mental status. During this subacute period, complications such as pneumonia, pressure ulcers, and urinary
tract infections are common. Motor deficits such as spastic paralysis, fasciculation, and extrapyramidal
tract abnormalities may develop. The final stage of symptomatic JE virus infection, the convalescent
stage, lasts from the fourth to the seventh week. Resolution of the neurologic deficits occurs slowly, if at
all. From 30% to 50% of survivors are left with permanent sequelae, including mental retardation,
emotional instability, personality disturbances, and motor and speech abnormalities (152–156). Children
and elderly adults are more likely to develop encephalitis during JE virus infection than young adults and
middle-aged persons (157). The neurologic sequelae following JE virus are age dependent; permanent
impairment is much more common in patients younger than 10 years at the time of onset of disease, and
infants experience more severe sequelae than older children (152,153).
Infection with JE virus in early pregnancy increases the risk of stillbirth in swine (158). In humans, JE
virus has been isolated from brain, liver, and placenta of the products of spontaneous abortion following
acquisition of JE virus infection in early pregnancy (158). In addition, cases in which neurologic
symptoms occur in newborns following first-trimester maternal JE virus infection have been reported
(158).
How much of the pathology that occurs in cases of JE virus is due to direct viral replication in the CNS
and how much damage is caused by the host immune response to the virus is not clear. Intracerebral
inoculation of JE virus into spider monkeys produces no overt symptoms unless they are given
immunosuppressive agents before infection (159). In immunocompetent monkeys, mild gray matter
destruction is seen on histologic examination of the brain and spinal cord. Immunosuppressed monkeys,
on the other hand, develop severe to overwhelming lesions that produce much neural damage that
manifests as severe flaccid paralysis. These findings suggest direct damage of the neurons due to viral
replication rather than an immune-mediated process. Clinical correlates also are more consistent with
direct viral damage, because most deaths occur during the acute phase when virus can still be cultured
from the CSF and brain tissue (155). Histologic examination of human brain tissue from fatal cases
reveals severe destruction of the gray matter throughout the brain; tissue damage is especially pronounced
in the regions of the basal ganglia, the floor of the fourth ventricle, the cerebellum, and the cerebral
cortex. In addition, the spinal cords of such persons are usually diffusely involved (160).
Infection with JE virus is thought to convey lifelong immunity, although waning protection may leave
the elderly at risk for reinfection (153,157,161). Prior infection with dengue confers a degree of
protection against JE virus, presumably through cross-reacting antibodies (162,163). Minor antigenic drift
among wild type JE virus strains has been noted across both time and geographic regions (164,165).
The diagnosis of JE virus is usually made on the basis of serology (152,153). Although laboratory
isolation of JE virus from brain specimens in fatal cases is possible, the virus has only rarely been
isolated from blood and CSF (166). It is difficult to detect viral antigens in specimens of CSF or serum,
although they can be identified by complement fixation following viral growth in tissue culture (152,153).
The differential diagnosis for JE virus includes leptospirosis, enteroviral disease, mumps
meningoencephalitis, herpes encephalitis, rabies, dengue, bacterial meningitis, cysticercosis, Reye
syndrome, neoplasia, toxins, and the postinfectious encephalitides (152,153).
Because of the high prevalence of asymptomatic JE virus infection in some areas, certain populations
have high proportions of individuals with JE virus IgG seropositivity. As a result, the diagnosis of acute
JE virus infection in patients from endemic regions frequently requires the demonstration of anti–JE virus
immunoglobulin M (IgM) antibodies. Simultaneous CSF and serum IgM titers are useful in diagnosing JE
virus; patients with acute JE virus have high anti-JE virus IgM titers in the CSF, with CSF titers usually
exceeding those in the serum (152,153,156,167). In contrast, CSF anti-JE virus IgM is undetectable or
low and serum anti-JE virus IgM is high in cases of acute asymptomatic JE virus infection (167). The
CSF IgM titers are prognostic as a high CSF IgM titer equates with a higher survival rate than those who
do not mount a strong CSF immune response (168).
In cases of JE virus, therapy consists solely of supportive measures. Although human immune globulin
prevents death in experimentally infected animals (169), it has not proven beneficial in the management of
human disease. Such passive immunization would probably have to be administered early in infection
(before the onset of neurologic symptoms) to be beneficial (152,153).
VACCINATION AGAINST JAPANESE ENCEPHALITIS VIRUS

Three types of killed JE virus vaccines are commercially available. An inactivated vaccine prepared
from JE virus grown in mouse brains is manufactured in Japan and Korea; a killed vaccine from virus
grown in hamster kidney cells in tissue culture is prepared in China (170); and an inactivated Vero cell
culture–derived JE vaccine is manufactured by the Austrian company Intercell. The administration of two
doses of the vaccine prepared from mouse brain given 1 month apart results in seroconversion rates of
90% to 100%. The protective efficacy of this vaccine is 80% (170). In comparison, the vaccine prepared
in hamster kidney cells has an estimated protective efficacy of 95% (170). For the Vero cell culture–
derived vaccine, protective concentrations of neutralizing antibodies were achieved in 58% to 83% of
recipients 12 months after a first dose of vaccine and in 100% of recipients 28 days after receipt of a
booster dose given at 15 months after the first dose of the primary immunization; neutralizing antibody
titers persist for at least 1 year. Side effects of all three vaccines occur in fewer than 1% of recipients and
include fever, headache, local pain, swelling, and fatigue; allergic reactions are noted in fewer than
0.02% of vaccinees (152,153).
In China, live attenuated JE virus vaccines have been developed and tested in humans (152,153) and
have demonstrated efficacy (171,172) but are not available outside of China. New-generation JE virus
vaccines that use attenuated vaccinia vectors expressing viral proteins of JE virus have shown promise in
animals (173–175).
The incidence of JE virus infection has decreased markedly in Japan since 1966. This decline is
largely due to the widespread vaccination of children. In addition, insect-control measures have
decreased the mosquito population, thus limiting the vector required for transmission of JE virus to
humans (154). Efforts to limit the reservoir for JE virus have focused on vaccination of domesticated
animals. Live attenuated vaccines have been used in swine because killed vaccines do not confer
immunity in this species (152,153).
The first JE virus vaccine licensed for use in the United States was a JE virus inactivated vaccine (JE-
VAX) derived from infected mouse brains by the Japanese company Biken (Osaka, Japan), which was
licensed by the U.S. Food and Drug Administration (FDA) in December 1992 and distributed in the
United States by Sanofi Pasteur (176). However, production of JE-VAX was discontinued in 2003, and
stockpiles were depleted in 2011. Recognizing this, the inactivated Vero cell–derived vaccine (IXIARO)
was licensed by the U.S. FDA in March 2009 for use in adults 17 years of age or older, and in May 2013
for use in children 2 months through 16 years of age; it is distributed by Novartis Vaccines in the United
States.
In addition to childhood immunizations for persons who live in endemic regions, vaccination against JE
virus is recommended for travelers who plan to spend a month or longer in endemic areas during the JE
virus transmission season (170,177). JE virus vaccine should be considered for short-term travelers to
endemic areas during the JE virus transmission season if they will travel outside of an urban area and
their activities will increase the risk of JE virus exposure. JE virus vaccine is not recommended for short-
term travelers whose visit will be restricted to urban areas or times outside of a well-defined JE virus
transmission season. The dosage and administration is 0.25 mL per dose for children 2 months through 2
years of age, and 0.5 mL per dose for children ≥ 3 years of age and adults. The primary series consists of
two doses administered 28 days apart.
POLIO
Neurologic Manifestations of Polio
Nervous System Involvement During Acute Disease
Polioviruses cause three recognizable forms of disease: paralysis, aseptic meningitis, and minor febrile
illness. However, most infected individuals will demonstrate no evidence of illness. The clinical and
subclinical manifestations of poliovirus infection are depicted graphically in Figure 50.1.
The possible clinical courses of polio are best understood in terms of the pathogenesis of infection
(178,179). After viral implantation in the gastrointestinal tract, poliovirus replicates in local lymphatic
glands such as the tonsils and Peyer patches. This replication leads to a low-level viremia, during which
other lymphatic tissues and brown fat are seeded. The clinical accompaniment of this primary viremia is
the minor illness (e.g., fever, malaise, headache, and sore throat). The minor illness usually constitutes an
abortive poliomyelitis infection. Symptoms are frequently so mild that patients do not seek medical
attention.
In patients whose infection does not end with the minor illness, a secondary viremia occurs 7 to 14
days after the initial infection; symptoms of CNS involvement are contemporaneous with the secondary
viremia (180,181). In some patients, the CNS involvement manifests only as aseptic meningitis, with
meningeal signs, fever, headache, and vomiting; these symptoms resolve within a week. Other patients,
however, develop a flaccid paralysis in addition to systemic symptoms. The paralysis, which results from
the death of infected neurons, is often asymmetric and variable in location and degree. Progression of the
paralysis ceases with resolution of the fever (182). Neurologic recovery is quite variable, but most
improvement usually occurs within the first 6 months after the infection (183,184).
The frequency of each of these forms of illness is dependent both on the virulence of the poliovirus
strain involved and on the age of the infected host. Illness in adults is more likely to result in paralysis
than is infection in children. Aseptic meningitis occurs in 1% to 2% of cases of poliovirus infection, and
only 0.1% to 2% of infected individuals develop paralysis (182). Thus, paralytic poliomyelitis is the
uncommon result of the viremia that usually accompanies a gastrointestinal tract infection with one of the
three polioviruses. However, the paralytic rate is quite variable from one outbreak to another (182).
When paralysis occurs, approximately 10% of affected patients die and more than half will be left with
permanent neurologic impairment (185).
Postpoliomyelitis Syndrome Manifesting Long After Recovery From Acute Disease

Individuals who have recovered from paralytic polio earlier in life can experience the onset of new
muscle weakness and muscle wasting (186,187). The postpoliomyelitis syndrome affects 20% to 30% of
previously paralyzed polio victims, usually appearing about 30 years following the acute polio illness.
This condition does not appear to be caused by persistence of viral infection but by the decrease of
anterior horn cells that occurs normally with aging (188,189). No cure is available (190).
VACCINATION AGAINST POLIO

History
Attempts at poliovirus vaccine development in the pre–tissue culture era were at best disappointing and at
worst disastrous. Human trials in 1936 using both “inactivated” (191) and “attenuated” (192) poliovirus
from monkey spinal cords produced paralysis in some vaccine recipients. The development of poliovirus
propagation in tissue culture in 1949, however, revitalized efforts to produce an immunogenic human
polio vaccine. Work toward this goal proceeded in several laboratories, although it was Jonas Salk and
colleagues whose efforts ultimately were most promising. By 1954, safety and immunogenicity studies of
a formalin-inactivated poliovirus (IPV) vaccine developed by Salk had been performed in animals and
humans (193–196). An enormous placebo-controlled clinical trial in 1954 involving 1,829,916 children
demonstrated the efficacy of this inactivated vaccine in protecting against poliomyelitis (197), resulting in
licensure in the United States in 1955.
An unfortunate event in the history of poliovirus vaccination was the “Cutter incident” (198–200). The
occurrence of paralytic disease among IPV vaccine recipients in the spring of 1955 led to the discovery
that several lots of the vaccine manufactured by Cutter contained residual amounts of noninactivated
virus. Before the situation could be rectified, 260 cases of poliomyelitis were attributed to the Cutter
vaccine; of these cases, 192 resulted in paralytic disease. Of note, this deeply regrettable episode did not
have a negative impact on the American public’s confidence in poliovirus vaccination (201,202), likely
because of the continued and very visible threat of wild type disease, which was still occurring regularly
in the mid-1950s.
Although work proceeded on the development of inactivated vaccines, other groups of investigators
were pursuing attenuation of live polioviruses. As early as 1950, studies by Koprowski et al. (203) found
that administration of attenuated vaccine conferred immunity to polio. In addition to Koprowski et al.,
both Cox (204) and Sabin (205) were developing live attenuated poliovirus vaccines in the early 1950s.
Of these three groups, Cox and Koprowski were working with similar viral strains, while Sabin had
isolated a different group of viral mutants (201,202). Extensive field trials began with the Sabin virus in
1958 in the former Soviet Union and other Eastern European countries; by 1960, roughly 100 million
individuals in these areas had received the Sabin vaccine with favorable results (206,207). Largely
because of these trials, the Sabin live attenuated poliovirus vaccine was licensed for use in the United
States in 1960.
Inactivated Polio Vaccine
Introduction of IPV vaccine to the United States in 1955 produced a marked decrease in the incidence of
poliomyelitis, with paralytic disease decreasing by more than 90% within 6 years (208,209). Despite this
resounding early success, the inactivated form of poliovirus vaccine did have weaknesses. To elicit an
adequate immune response, three doses of vaccine were necessary. Even with such a schedule, the
vaccine failed to protect 100% of recipients and it appeared that booster inoculations would be needed at
regular intervals. Perhaps most significantly, primate experiments and observations in human families
showed that IPV vaccine did not block replication of the virus in the intestines and therefore could not be
expected to eradicate polio (210,211).
Within a few years of the introduction of live attenuated poliovirus vaccine to the U.S. market, use of
the IPV vaccine decreased markedly as the new live-virus vaccine gained favor. The perceived
advantages of the live-virus vaccine over the IPV vaccine included the following (212):
1. Superior immunogenicity
2. Lower cost
3. Ease of administration
4. Induction of herd immunity
5. Generation of mucosal immunity in the gastrointestinal tract
Preferential use of the live attenuated poliovirus vaccine eventually resulted in it being the only
vaccine available in the United States between 1973 and 1978 (188,189). During the 1980s, however,
technological advances led to development of an enhanced potency IPV vaccine, which was licensed for
use in the United States in 1988. The enhanced-potency IPV vaccine is immunogenic and protective after
two doses, prevents pharyngeal excretion of poliovirus, and, to a degree, may even reduce excretion of
poliovirus from the intestines. During the 1990s, these developments led to renewed interest in adding the
IPV vaccine to routine vaccination schedules in the United States. A driving force for this renewed
interest was the desire to reduce the number of cases of vaccine-associated paralytic poliomyelitis, as
discussed later in this chapter. The AAP now recommends a four-dose all-IPV vaccine schedule for
routine immunization of all infants and children in the United States (213,214). The first two doses should
be given at 2-month intervals beginning at 2 months of age (minimum age of 6 weeks), and a third dose is
recommended at 6 to 18 months of age. The final dose of IPV vaccine should be given at 4 years of age or
older regardless of the number of previous doses; a fourth dose is not necessary if the third dose was
given at 4 years of age or older and a minimum of 6 months after the second dose.
Oral Polio Vaccine
Although oral poliovirus (OPV) vaccine is no longer available in the United States, its use in the ongoing
global effort at polio eradication warrants its discussion here. OPV vaccine protects by two mechanisms.
As it induces antibody, there is a barrier to the passage of virulent poliovirus from the intestine to the
brain. In this respect, it is not different from IPV vaccine. In addition, OPV vaccine induces local
antibody responses mediated through secretory immunoglobulin A (IgA) that block the replication of
virulent poliovirus if the vaccinee is subsequently exposed (215). This effect offers the advantage of
preventing the spread of wild virus through vaccinated communities and it is argued that the freedom of
the United States from wild poliovirus was achieved as a result of the OPV-induced herd immunity (216).
Another advantage claimed for OPV vaccine is that because it may spread from vaccinee to contact by the
fecal-oral route, there is an augmentation of the public health effect.
The OPV vaccine contains a mixture of three attenuated polioviruses: the LS-c 2ab type 1 strain, the P-
712 type 2 strain, and the Leon 12ab type 3 strain (217). These strains have each proven to be highly
attenuated when inoculated intrathalamically and intraspinally into monkeys. In addition, they have certain
in vitro markers that correlate with attenuation. A single dose of OPV contains 100,000 to 1,000,000
tissue culture infectious doses of each of the three attenuated viral types. However, various manufacturers
use differing ratios of the three components in an effort to reduce viral interference and thus improve the
immune response to vaccination (183,184). When given as a trivalent vaccine, each strain competes with
the others for replication in susceptible cells. The large amounts of virus used in OPV vaccine ensure that
each vaccine type will have a chance to replicate in the intestine and produce local and systemic immune
responses.
Adverse Reactions to Poliovirus Vaccine
IPV vaccine contains trace amounts of neomycin and streptomycin. As such, hypersensitivity reactions
following the administration of IPV vaccine are possible if persons are allergic to these compounds. No
serious adverse events have been reported with the use of the available IPV product, however.
Cases of paralysis following administration of OPV vaccine occur very rarely. Known as vaccine-
associated paralytic poliomyelitis (VAPP), administration of 6.8 million doses of OPV in the United
States resulted in one case of paralytic disease in immunocompetent vaccine recipients before the
establishment of an all-IPV polio immunization schedule (218). Similarly, one case of paralytic disease
among contacts of vaccinees occurred with every 6.4 million doses of OPV given (218). The greatest risk
of paralysis is with the administration of the first OPV dose (218), following which there is a 1 in
750,000 doses chance of paralysis in a vaccinee or contact. These cases are due predominantly to the type
3 strain, less often to the type 2 strain, and rarely to type 1 (219). Immunodeficient individuals are
particularly at risk for vaccine-associated poliomyelitis, perhaps because the viruses replicate for longer
periods in immunodeficient hosts. As such, OPV vaccination is contraindicated in immunodeficient
individuals or in their close contacts.
Vaccine Contraindications
Poliovirus immunization should be avoided during pregnancy for theoretical reasons only. OPV
vaccination is contraindicated in patients with immunodeficiencies and in immunocompetent patients who
have household contacts with immunodeficiency states, including HIV-infected persons. Breast-feeding or
the presence of diarrhea does not contraindicate the administration of either IPV or OPV vaccine.
Worldwide Poliovirus Elimination
The worldwide elimination of poliovirus is achingly within reach. Tremendous progress has been made,
with the eradication of poliomyelitis from the Americas in 1994 (220), from the Western Pacific in 2000
(221), and from Europe in 2002 (222). From the initiation of the global poliomyelitis eradication
initiative in 1988 through 2012, the number of countries where polio is endemic decreased from 125 to 3
(Nigeria, Afghanistan, and Pakistan). The number of reported polio cases decreased by more than 99%,
from an estimated 350,000 to fewer than 1,300 in 2010 (223). Wild type 2 poliovirus has not been
detected worldwide since October 1999. Three regions of the world are certified polio free—the
Americas, Europe, and the Western Pacific. In January 2012, India celebrated its 1-year anniversary since
their last reported polio case and has been declared polio free. Current challenges to global polio
eradication efforts include strongly held suspicions of Western governments and initiatives in the three
countries where polio remains endemic. An outbreak of VAPP on the island of Hispaniola illustrates the
ongoing need for vigilance with vaccination programs (224,225). Vaccine strains can circulate for years
within a region before causing paralytic disease (226). All of these challenges have led to a redoubling of
effort on the part of international organizations and governments to take the final push to achieve
eradication. Use of a bivalent OPV vaccine that contains serotype 1 and 3 but not the now-eradicated
serotype 2 is being considered, as is a follow-up vaccination program using IPV vaccine instead of OPV
vaccine (Table 50.2) as part of the final effort to rid the world of polio once and for all.
RABIES
Neurologic Manifestations of Rabies
Rabies is perhaps the only infectious disease that is virtually 100% fatal to those infected. Although a few
human survivors of rabies have been reported (227–229) and some animals give serologic evidence of
having survived rabies (230), the bat is the only animal that seems to be able to live with the virus.
Following a bite from a rabid animal, the virus replicates first in myocytes at the wound site, remaining
there for variable periods. Low-level viral replication probably occurs in the muscle cells, with
subsequent release of extracellular virus; such virus can be neutralized if exogenous antibody is provided.
At this stage of infection, the amount of virus present is insufficient to induce an endogenous immune
response. At an ill-defined time following the initial bite, rabies virus attaches to acetylcholine receptors
at the neuromuscular junction, an event expedited in highly innervated sites. Once the virus has penetrated
the nerve endings, passive movement to the neuronal body is probably inevitable. In the body of the
neuron, the virus replicates and rapidly spreads to other cells within the CNS.
The clinical presentation of rabies is justly described as terrifying. In the early stages, the patient
frequently is able to fully understand what is happening. The incubation period is quite variable, but onset
of symptoms usually occurs 1 to 2 months after exposure (231). The illness begins with a prodrome, in
which pain or paresthesia at the site of the bite is combined with manifestations of anxiety and irritability.
After 2 to 10 days of prodromal symptoms, frank neurologic signs develop, including hyperactivity,
nuchal rigidity, and disorientation. These symptoms usually progress to paralysis and hydrophobia (acute
pharyngeal and laryngeal spasms at the sight of water); the latter symptom represents an exaggerated
respiratory tract reflex (232,233). Even with good supportive care, death ensues within several days or,
at the most, several weeks.
The neuropathology of rabies is the result of neuronal destruction and glial infiltration in the
hippocampus, thalamus, basal ganglia, pons, and medulla. If present, pathognomonic Negri bodies are
collections of viral nucleocapsid in the cytoplasm of neurons (234).
VACCINATION AGAINST RABIES

History
Though never submitted to a double-blind, placebo-controlled trial, rabies vaccines are judged to be
effective by comparison to historical controls. The likelihood of viral transmission following exposure to
a proven rabid animal varies with the type of animal and with such circumstantial factors as the amount of
virus inoculated and the severity of the bite.
The first rabies vaccines consisted of inactivated rabies virus grown in the brains of such animals as
sheep or rabbits. With the development of these vaccines, physicians had the ability to reliably intervene
in rabies disease progression for the first time in history. Nevertheless, these vaccines had numerous
disadvantages. Because of their low antigen content, repeated inoculations of large volumes of vaccine
were required. In addition, the myelin present in the inoculum often resulted in neurologic reactions
among vaccine recipients. As a consequence of these weaknesses, the search for better vaccines
continued. Duck eggs (235) and neonatal mouse brains (236) were used to grow rabies virus, from which
safer vaccines were produced. Immunogenicity of these preparations, however, was still low (237).
Continuing efforts to create a vaccine with improved safety and efficacy resulted in development of
techniques for growth of the rabies virus in human diploid cell lines; virus grown in such cells was then
concentrated and inactivated, providing an abundant source of antigen for the preparation of vaccine
(human diploid cell vaccine [HDCV], Imovax, Sanofi Pasteur) (238). HDCV has now become the
standard comparator for newer rabies vaccines for preexposure and postexposure immunoprophylaxis
(239). In the absence of controlled comparative data, it is impossible to prove with certainty that one
vaccine is more protective than another. Nevertheless, the speed and degree of antibody response,
together with the accumulated observations of patient outcomes with vaccination, argue that HDCV is
more potent than the previous vaccines grown in duck eggs or neonatal mouse brains (240–243). Two
additional tissue culture vaccines are also licensed for use in the United States for prophylaxis: RVA
(rabies vaccine adsorbed), produced in rhesus diploid cells; and PCEC (purified chick embryo cell,
RabAvert, Novartis), which was approved for use in the United States in 1997 (244). However, only
HDCV and PCEC are available for use in this country.
HDCV can be administered intramuscularly or intradermally. Intramuscular administration should always

be used for postexposure prophylaxis in developed countries because it provides the highest antibody
responses (245). However, intradermal administration requires less vaccine and is therefore cheaper, for
which reason it is often used in developing countries. For preexposure vaccination, either route of
administration is acceptable. As with other killed virus vaccines, the timing and volume of doses are
important to ensure an adequate immune response (246,247). Because virus-neutralizing antibody
responses in adults who received vaccine in the gluteal area sometimes have been less than in those who
were injected in the deltoid muscle, the deltoid site always should be used except in infants and young
children, in whom the anterolateral thigh is the appropriate site.
The objective of postexposure vaccination is to deliver a large antigenic load during the first week.
However, human rabies vaccine supply has been tenuous since 2007, necessitating consideration of a
shorter immunization series compared to the traditional five-dose regimen. Although no direct
postexposure prophylaxis studies have compared four doses of vaccine to five doses, all healthy
individuals in clinical trials of rabies vaccines develop detectable rabies virus–neutralizing antibodies by
day 14 and no significant differences have been documented between a four- versus five-dose rabies
vaccine schedule in the relative amount of neutralizing antibodies produced. Studies using four doses of
vaccine, when given in a regimen that included rabies immune globulin, yield equivalent outcomes. In the
United States, no failure of human postexposure prophylaxis was identified during the past 30 years.
Outside of the United States, rabies has occurred in human patients who had no prophylaxis, substantial
delays in initiation of prophylaxis, or significant deviations from the recommended prophylaxis schedule,
but no failures have been attributable to an absence of the fifth and last vaccine dose on day 28 (248).
Therefore, beginning in 2009, the recommended postexposure vaccination course for healthy individuals
has employed four doses of either HDCV or PCEC. A 1.0-mL dose of vaccine is given intramuscularly in
the deltoid area or anterolateral aspect of the thigh on the first day of postexposure prophylaxis (day 0)
and repeated doses are given on days 3, 7, and 14 after the first dose, for a total of four doses (249).
Ideally, an immunization series should be initiated and completed with one vaccine product unless serious
allergic reactions occur. The volume of the dose is not decreased for children. For people with altered
immunocompetence, five doses of the vaccine are recommended (days 0, 3, and 7, followed by two
boosters on days 14 and 28) (244,250).
In the case of preexposure vaccination, a three-dose series is used with inoculations given on days 0, 7,
and 21 or 28 (250). The first two doses prime the immune system and the third stimulates a secondary
response providing immunologic memory.
HDCV has an excellent record of success in preventing rabies. Series have been reported in which
humans were bitten by proven rabid animals, vaccinated, and then followed for documentation of their
outcome. In this way, impressive data have been collected on Iranians exposed to rabid dogs and wolves
(242), Americans exposed to rabid skunks and raccoons (241), and Europeans exposed to rabid foxes
(251). Nevertheless, HDCV vaccine failures have been reported (252,253). In such cases, an error in
management (e.g., omission of antiserum) has usually occurred. Of note, cases of vaccination failure tend
to have shorter incubation periods, possibly due to deleterious components of a nonprotective immune
response (254,255).
Rabies Immune Globulin
Passive immunization is used in the postexposure management of patients to provide antibody protection
during the 1-week window of time between the bite and the vaccine recipient’s active antibody
production. The only clinical efficacy trial of combined vaccine and antiserum was performed in Iran,
where 18 villagers were bitten by the same rabid wolf (256). In this report, the antisera used was an
equine product. Although 3 of 5 patients given standard vaccine alone died of rabies, only 1 of 13
recipients of both vaccine and antiserum experienced a fatal outcome. Though effective, 40% of adults
developed serum sickness. Because of this side effect, equine rabies antiserum is not used in the United
States (257). Nevertheless, equine rabies immune globulin (ERIG) has been developed, which is less
expensive and much less allergenic (258). It often is used outside of the United States at a dose of 40
IU/kg.
To avoid the risk of serum sickness, immune globulin collected from volunteers immunized with HDCV
is available in a standardized concentration of 150 IU/mL (257). This human rabies immune globulin
(HRIG) is the preferred product for passive immunization in the postexposure period (258,259). It should
be administered as soon as possible after the exposure, at a dose of 20 IU/kg body weight. As much of the
dose as possible should be used to infiltrate locally around the wound(s) in an attempt to neutralize any
extracellular virus that may be present in nonneural cells. All patients should receive HRIG in addition to
vaccine unless they have been previously immunized with HDCV, RVA, or PCEC (or another rabies
vaccine if they have had documentation of serum rabies antibody in the past) (250).
Adverse Reactions to Rabies Vaccine
Historically, the chief concern with regard to reactions to rabies vaccine was neuroparalytic reactions.
Early rabies vaccines that contained nervous tissue in addition to inactivated rabies virus caused such
reactions in approximately 1 in 1,600 vaccinees (sheep brain) to 1 in 8,000 vaccinees (suckling mouse
brain) (260,261). It is noteworthy that such reactions have not been seen to date with HDCV, the RVA, or
the PCEC vaccines. Several cases of Guillain-Barré syndrome have followed administration of HDCV
(262,263) but are not thought to be causally related.
Less significant complications include local reactions at the site of infection in about 25% of HDCV
recipients and mild systemic reactions (including headache and nausea) in 20% of vaccinees (239,241).
In addition, allergic reactions characterized by urticaria, arthralgia, and angioedema have followed
HDCV, mainly after boosters. This type of reaction occurs in about 1 in 1,000 primary vaccinees but in 6
in 100 of those receiving boosters of HDCV (264). The allergic reaction appears to be caused by β-
propiolactone–induced modification of the human albumin present in the vaccine, which renders it more
capable of forming immune complexes (237,265). About 10% of reactions are anaphylactic, but
fortunately none has been fatal. Similar allergic reactions with primary or booster doses of PCEC have
been reported.
In view of the importance of rabies immunization, there are no contraindications to vaccination. Should
a patient develop a severe allergic reaction to HDCV, the PCEC vaccine can be substituted and given on
the same schedule (or vice versa) (250).
Decisions to Vaccinate
In making a decision regarding whether to vaccinate against rabies, the physician must take into account a
number of factors, including the species of animal involved, the circumstances of the attack, whether the
skin was broken, the status of animal rabies in that geographic area, and whether the biting animal had
been vaccinated or is under surveillance (250,257). Table 50.3 outlines recommendations regarding
postexposure rabies prophylaxis. The advice of experts should be sought in making such decisions.
Fortunately, the low rate of adverse reactions to HDCV or PCEC makes the decision much less agonizing
than it was in the past.
Worldwide Rabies Elimination
Human rabies is the product of rabies in domestic animals or in wild animals. The reservoir in wild
animals may impinge on humans either directly (when there is contact—e.g., with a rabid skunk) or
indirectly (when wild species bite domestic animals with which humans have contact—e.g., when a bat
bites a cow). Thus, elimination of rabies depends on how well rabies can be controlled in animals.
Certain island countries, such as the United Kingdom and Australia, have eliminated rabies through
quarantine and through the absence of native sylvatic rabies. In other vast areas, such as Asia and Africa,
trapping and killing stray dogs and cats would drastically reduce the numbers of rabid pets, but religious
ideas sometimes prevent that from happening (266).
The development of a recombinant rabies vaccine shows great promise in limiting disease in
susceptible animal populations. Recombinant virus is immunogenic and protective when given to animals
by parenteral, intradermal, or oral routes (267). When placed in baits, it is eaten by wild animals such as
skunks, foxes, and raccoons, resulting in their immunization (268). Successful programs to control fox
rabies in parts of Europe (269) and Canada (270) have relied on this approach. Similar promising results
are being obtained in the United States for controlling rabies in raccoons and coyotes (271–276).
Elimination of rabies in domestic animals, together with control in wild mammalian species, could reduce
human rabies to a rare disease in developing countries and could virtually eliminate it in affluent
countries. The technologies to accomplish this end may now be available.
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CHAPTER 51 VACCINES AGAINST BACTERIAL
MENINGITIS
AMANDA C. COHN AND NANCY E. MESSONNIER
Three major pathogens—Haemophilus influenzae type b (HIB), Neisseria meningitidis

(meningococcus), and Strep tococcus pneumoniae (pneumococcus)—cause the majority of bacterial
meningitis cases in the United States and globally each year (1). Prior to implementation of vaccines
targeting these causes of meningitis, these three agents constituted more than 75% of all cases of bacterial
meningitis in most studies and 90% of bacterial meningitis in children (2–4). Current vaccines have
virtually eliminated HIB meningitis and drastically reduced the burden of pneumococcal and
meningococcal meningitis.
HAEMOPHILUS INFLUENZAE TYPE B

Before the introduction of effective vaccines, HIB was the leading cause of bacterial meningitis in
children younger than 5 years in the United States. Approximately 120,000 cases of HIB meningitis and
7,500 cases of other invasive HIB infections occurred each year, and 1 in 200 children developed
invasive HIB disease by 5 years of age (5,6). In Europe, Latin America, and Africa, annual rates of HIB
disease varied from 20 to 60 per 100,000 children younger than 5 years prior to introduction of HIB
vaccines (4,7,8). The case-fatality proportion for HIB was 2% to 5%, and 15% to 30% of survivors of
meningitis had hearing impairment or other neurologic sequelae (5). In some developing countries, case-
fatality ratios of 40% have been reported (9).
In industrialized countries, HIB most commonly presented as meningitis; in the United States before
widespread vaccination, 60% to 70% of invasive disease due to HIB was associated with meningitis.
Epiglottitis and bacteremia without focus were the next most common presentations (10). In contrast, in
developing countries, the primary manifestation of HIB disease is lower respiratory tract infection. HIB
infection may account for 5% to 8% of all pneumonia in children in these areas (11). In the developing
world prior to implementation of HIB vaccines, H. influenzae infection (including all serotypes and
nontypeable strains) was estimated to cause 482,000 pneumonia-related deaths each year among children
younger than 5 years (12).
In the absence of vaccination, the highest rates of HIB disease occur in children younger than 2 years,
but within that age-group, rates vary (10). In many European countries and in the general U.S. population,
only 5% to 15% of cases occur before 6 months of age (10). In Native Americans and children in many
developing countries, 30% to 40% of cases occur before 6 months of age (4,13). In addition to age, risk
of HIB in the United States was increased among Alaskan natives and Navajo and Apache Indians, which
may be because of host factors, including genetic susceptibility, as well as environmental factors. Blacks
and Hispanics were also at higher risk, which was thought to be caused by nongenetic risk factors, such as
low socioeconomic status, crowding, and large family size (10).
Microbiology, Immunology, and Pathogenesis
H. influenzae are gram-negative coccobacilli that are divided into unencapsulated (nontypeable) and
encapsulated strains. The encapsulated strains are further classified into serotypes a through f, based on
the antigenic characteristics of their polysaccharide capsules.
Humans are the only known biologically important reservoirs of H. influenzae, which is transmitted
through direct or indirect exchange of oropharyngeal secretions. After introduction into the oropharynx, H.
influenzae can establish colonization, cause lower respiratory tract infection, or invade through the nasal
mucosa to enter the bloodstream.
The remarkably successful HIB conjugate vaccines developed in the 1980s originated from
investigations begun in the 1930s. Pittman (14) and others showed that although six types of
polysaccharide (types a through f) make up the capsules of invasive strains of H. influenzae, virulence
was especially associated with type b, later characterized as polyribosyl-ribitol-phosphate (PRP). Also
in the 1930s, it was shown that serum bactericidal antibodies directed against the capsular
polysaccharide were protective. Infants and children lacked these antibodies and hence were prone to the
disease, in contrast to older age-groups in whom HIB infection was rare. In the 1940s, absorption with
purified type b polysaccharide was shown to remove the protective activity from rabbit hyperimmune
serum (15), but it was not until the 1970s that anticapsular antibodies were proven capable of preventing
disease (7).
Haemophilus influenzae Type B Polysaccharide Vaccines
In the 1970s, the ease of isolating and purifying PRP from the bacterial capsule prompted researchers to
try it as a vaccine. The first trials in adults were encouraging; PRP was safe and elicited a good antibody
response in adult vaccinees (16). The results in children, however, were disappointing because PRP is a
T-cell–independent antigen and is poorly immunogenic in infants and young children. Among children 18
to 71 months of age in Finland, one dose of PRP vaccine was effective, but it was ineffective in infants 3
to 17 months of age (7). The conclusion from this trial was that 60% of all invasive HIB infections in
Finland might be preventable by routine vaccination when children reached the age of 18 months. Based
on the Finnish data, in 1985, the United States approved PRP vaccines for children 18 to 59 months of
age. During the following 5 years, more than 10 million doses were administered (17), and the vaccines
proved very safe with no serious adverse reactions reported (18).
However, reports of vaccine failures soon appeared and postlicensure case–control studies raised
questions about the efficacy of HIB polysaccharide vaccines in clinical practice. In five of eight studies,
estimated vaccine efficacy rates ranged from 41% to 88%, but three studies estimated that efficacy was
less than 0% (19). There has not been a full explanation for these variations. Although a vaccine that
prevented even half of invasive HIB disease may have been useful, these vaccines were clearly
suboptimal, especially among children younger than 18 months, who were at greatest risk of disease.
Vaccination studies using PRP also showed that this vaccine did not prime for immunologic memory or
prime cells for subsequent booster response to additional doses (20), a problem in infants who do not
respond well to polysaccharide antigens. However, these PRP vaccine studies were useful precursors for
the development of next-generation vaccines.
Haemophilus influenzae Type B Conjugate Vaccines
Conjugate vaccines opened a new era in the prevention of HIB meningitis and other HIB diseases.
Persons immunized with a conjugate vaccine develop higher concentrations of anti-PRP antibodies, and
these vaccines are immunogenic in young children and induce a rapid booster response in persons who
are reexposed to the antigen. Although major differences exist in the physicochemical structure and
properties of the available HIB conjugate vaccines, the basic principle is the same for all HIB conjugate
vaccines. Each conjugate vaccine consists of a carrier protein covalently conjugated to PRP or parts of
the PRP molecule with or without a linker, converting PRP from a T-cell–independent antigen to a T-cell–
dependent antigen. The HIB vaccines represented the first application of this important concept for the
production of vaccines, which was subsequently applied to N. meningitidis and S. pneumoniae.
Immunogenicity and Safety

Not surprisingly, given the differences between the various HIB conjugate vaccines, the immunogenicity
of these vaccines differs. In general PRP-D (diphtheria toxoid conjugate), HbOC (nontoxic variant of
diphtheria toxoid conjugate), PRP-OMP (meningococcal outer membrane protein conjugate), and PRP-T
(tetanus toxoid conjugate) behave similarly, each requiring two or three doses to reach substantial
antibody levels (21). Data from the Finnish PRP efficacy trial was analyzed to provide estimates that an
anti-PRP antibody concentration of 0.15 µg/mL obtained 1 month after vaccination was associated with
short-term protection and that a postimmunization peak of 1.0 µg/mL indicated protection for up to 1 year
(22). In one of the few studies in which three doses of all four preparations were administered in a
double-blind and randomized fashion, more than 90% of vaccines exceeded the mean PRP antibody
concentration of 0.15 µg/mL after vaccination with PRP-T, HbOC, or PRP-OMP at 1 month after
vaccination, whereas only 58% of vaccinees exceeded this level after vaccination with PRP-D. A
concentration of 1.0 µg/mL was reached by 83% of PRP-T vaccinees, 75% of HbOC vaccinees, 55% of
PRP-OMP vaccinees, and 29% of PRP-D vaccines (21). Recipients of PRP-OMP, in contrast to
recipients of PRP-D, HbOC, and PRP-T, developed high antibody concentrations after the first dose, even
in 2-month-old infants. Administration of a second dose recruits a small percentage of additional
responders, but a third dose adds little (23). However, PRP-OMP vaccination does not lead to as high a
peak in antibody concentration after a full course, as is achieved after vaccination with HbOC or PRP-T
vaccines (23). Antibody levels decrease over time after administration of the primary series of each HIB
conjugate vaccine. Because a person immunized with a conjugate vaccine should respond with a rapid
anamnestic antibody production, even though serum antibodies are no longer detectable, the boost
response may protect the individual on exposure.
These vaccines have been used widely since 1990, and adverse reactions are generally uncommon. The
most common reactions are local irritation, erythema, and pain, which have been reported in 5% to 30%
of recipients and usually resolve within 12 to 24 hours. Systemic reactions such as fever and irritability
are uncommon (24,25).
Efficacy and Impact

In the United States, following demonstration of their superior immunogenicity compared with HIB
polysaccharide vaccines, three HIB conjugate vaccines were licensed between 1987 and 1989, and in
April 1990, universal vaccination of children beginning at 15 months of age with PRP-D, HbOC, or PRP-
OMP was recommended by the Advisory Committee on Immunization Practices (ACIP). In October 1990,
following prospective studies showing good efficacy in infants, universal immunization of infants starting
at 2 months of age with an HIB conjugate vaccine was recommended by ACIP (26,27). PRP-T is given as
a three-dose primary series at 2, 4, and 6 months, with a booster dose at 12 to 15 months. PRP-OMP is
given as a two-dose primary series at 2 and 4 months, with a booster dose at 12 to 15 months. These
vaccines can be used interchangeably, but if PRP-T is used for either of the first two doses, a three-dose
primary series should be used. HIB conjugate vaccines not only are immunogenic and efficacious, but they
also reduce nasopharyngeal carriage of HIB among vaccinated children, decreasing transmission of H.
influenzae and resulting in herd immunity (13,28,29). This important benefit is probably due to the high
concentration of antipolysaccharide antibody, induced by exposure to the organism or bacteria exhibiting
cross-reactive antigenicity, which results in transudation of immunoglobulin G (IgG) antibodies through
the mucosal membranes. Vaccination does not seem to alter nasopharyngeal carriage rates of the other
types of Haemophilus strains or pneumococci. Some studies suggest that the ability of HIB conjugate
vaccines to reduce carriage may wane over time (29), but at least one study has shown persistent
reduction in HIB carriage among children vaccinated as infants who had reached 4 to 5 years of age (30).
No other bacterial vaccine has had such widespread success over such a short period. Large-scale
vaccinations were first launched in Finland in 1986; within 5 years, HIB meningitis and most other
invasive HIB diseases were virtually eliminated (Fig. 51.1) (31). This remarkable decline in incidence
occurred despite that during the first 2 years, 1986 and 1987, 50% of infants were vaccinated with PRP-
D, the vaccine with the lowest immunogenic potential (21). In the United States, HIB disease decreased
dramatically between 1988 and 1990, with increasing use of HIB conjugate vaccines, even among
children younger than 1 year in whom vaccine was not being used (17). In 1997, the proportion of infants
who had received HIB vaccine by age 7 months was only 61% (32), but rates of disease in children
younger than 5 years decreased 99% because of the unexpected benefit of herd immunity (32). In the
United States, HIB infection remains uncommon, with the highest incidence among Native Americans
(33). However, 30 to 50 cases occur each year among infants younger than 6 months who have not
completed the two- or three-dose primary series of HIB vaccination and among unvaccinated or
undervaccinated children; primary or secondary vaccination occurs less frequently than failure to
vaccinate.
Not only has use of HIB conjugate vaccines reduced disease in children, but HIB disease in persons
older than 5 years has also decreased, which has been attributed to the reduction of nasopharyngeal
carriage and transmission of HIB in infants and children (31). The unexpected, dramatic impact of HIB
conjugate vaccines on carriage raised concern that lowered nasopharyngeal competition from HIB would
result in increased disease due to other serotypes and nontypeable H. influenzae, which are more
common in adults than young children and are thought to be less virulent. Although the reduction in HIB
disease increased the proportion of H. influenzae infection caused by other serotypes, widespread
increases in disease caused by other serotypes of H. influenzae have not been reported (34). However, in
Alaska, among individuals 10 years and older, infection with other H. influenzae serotypes increased
from 0.5 per 100,000 persons per year (1980 to 1990) to 1.1 per 100,000 persons per year (1991 to
1996) (35). However, this rate has stabilized with no further increases since that time.
Control of Haemophilus influenzae Type B Infection
Close contacts of patients with HIB have higher rates of nasopharyngeal colonization with HIB. In
susceptible individuals, invasive disease may follow colonization. Studies in the 1970s demonstrated that
the risk of secondary disease was elevated among children who are household contacts of an index case
and daycare center contacts (36,37). In the 1980s, chemoprophylaxis with rifampin was recommended to
prevent secondary disease among close contacts. Because widespread use of HIB conjugate vaccines has
decreased the number of individuals susceptible to invasive HIB disease, chemoprophylaxis is now
indicated only if all contacts younger than 4 years are not fully vaccinated against HIB disease (27).
Most industrialized countries have now successfully implemented routine childhood immunization with
HIB conjugate vaccines, with near elimination of HIB disease, a public health success story. In several
countries in Europe, including Finland, instead of three doses, only two doses are administered primarily
at 4 and 6 months of age with a booster at 14 to 18 months. This policy has proven successful; the
incidence of HIB disease in Finland declined dramatically from 1988 to 1990. Germany, Switzerland,
Austria, and Ireland have followed the same policy with similar favorable results. The United Kingdom
chose another protocol in which no booster is administered, based on the finding that antibody
concentrations persisted long after an accelerated vaccination schedule. Three doses of HIB conjugate
vaccine were given at 2, 3, and 4 months of age (38). However, based on slowly increasing rates of HIB
disease in children who did not receive a dose of HIB vaccine after age 12 months, in 2003, the United
Kingdom added an HIB booster dose at age 12 months.
In the United States, previously unvaccinated infants aged 2 to 6 months receive three doses of PRP-T
administered 2 months apart or two doses of PRP-OMP, followed by a booster immunization at age 12 to
15 months, at least 2 months after the last vaccination (27). HbOC is no longer manufactured. In general,
vaccines from different manufacturers that protect against the same disease may be administered
interchangeably in sequential doses in the immunization series for an individual patient (39). If PRP-OMP
is combined with PRP-T, the recommended number of doses to complete the series is determined by the
PRP-T product, not by the PRP-OMP vaccine. Among rural Alaskan native children, a change from PRP-
OMP to HbOC in early 1996 was accompanied by an increase in HIB disease and in nasopharyngeal
carriage of HIB, raising concern that use of HbOC vaccine left partially vaccinated children susceptible
to ongoing HIB transmission that had not been eliminated by PRP-OMP (40).
Despite the availability of HIB conjugate vaccines since the 1980s and the virtual elimination of HIB in
most i ndustrialized countries, HIB vaccine has only recently been introduced in developing countries
where the burden of HIB morbidity and mortality is considerably higher. Prior to 2002, only 2 of 51
countries with an infant mortality rate more than 70 per 1,000 livebirths were routinely vaccinating
against HIB—the Gambia and Bolivia. The major obstacles to the introduction of HIB conjugate vaccine
into developing countries have been cost and the unrecognized burden of HIB disease. In 2000, the Global
Alliance for Vaccines and Immunization (GAVI) and the affiliated Vaccine Fund have provided funding for
the poorest countries to obtain HIB vaccine (www.vaccinealliance.org/home/index.php). However,
uptake was slow due in part to a lack of understanding of the full burden of HIB disease in these
countries. In 2006, World Health Organization (WHO) recommended that HIB vaccines should be
included in every national immunization program. By 2009, 60 low-income countries had introduced HIB
vaccines with GAVI support, preventing an estimated 430,000 future deaths (41). A 2008 study estimated
that, within 4 years of GAVI support helping Uganda to introduce HIB vaccine into the national
vaccination programme (June 2002), the incidence of HIB meningitis declined by 85%, and by the
following year, the number of cases fell to nearly zero (42). The impact of HIB vaccine introduction has
also been demonstrated in other GAVI-eligible countries including Kenya, Malawi, and Senegal (43–45).
With 160 countries having introduced in 2009, still only 55% of the world’s children have access to
vaccine, mostly due to delays in a few large countries (41). Although significant progress has been made
in the number of children globally who have access to HIB vaccine, continuous efforts are still needed to
improve its global coverage.
NEISSERIA MENINGITIDIS
N. meningitidis or meningococcal disease, first reported centuries ago, remains an important cause of
disease globally (46). Two main forms of meningococcal disease exist, meningococcal sepsis and
meningitis, which may occur separately or together. The third most common clinical presentation is
meningococcal pneumonia, occurring in 5% to 15% of patients (47,48). Approximately 10% of patients
with meningococcal disease die despite optimal medical care, and meningococcemia, a fulminant form of
sepsis, can cause death within a few hours (49). In addition, 11% to 19% of survivors have long-term
sequelae including hearing loss, mental retardation, and loss of limbs (50,51). In industrialized countries,
the overall incidence of meningococcal disease is relatively low at 0.5 to 3 cases per 100,000 per year;
however, meningococcal disease is unique among causes of bacterial meningitis because it causes both
endemic disease and epidemics. Because of the high case-fatality rate, substantial sequelae, and
propensity to cause epidemics, vaccination is a major focus of meningococcal disease prevention.
Outside of the meningitis belt of sub-Saharan Africa, infants have the highest risk of meningococcal
disease. Rates of disease decrease after infancy and then increase in adolescence and young adulthood.
Although rates decrease after early adulthood, a substantial number of cases occur among adults 23 to 64
years of age (48). Rates increase again in the elderly (48). In addition to age, other individual risk factors
for meningococcal disease include underlying immune deficiencies, such as asplenia, properdin
deficiency, and a deficiency of terminal complement components (52,53). Crowding, low socioeconomic
status, active or passive exposure to tobacco smoke, and concurrent upper respiratory tract infections
increase the risk of meningococcal disease (54–56).
Organism characteristics also modulate the risk of disease. Meningococci associated with invasive
disease elaborate a capsule. Meningococci can be divided into 12 serogroups based on their different
capsular polysaccharides. Globally, more than 90% of cases are caused by the serogroups A, B, and C
(57–60). In most European and many Latin American countries, serogroups B and C caused the majority
of disease prior to vaccination with serogroup C conjugate vaccines, and serogroup A causes the majority
of disease in Africa and Asia (57). In the United States, serogroup Y emerged in the 1990s as a
substantial cause of meningococcal disease, but a significant increase has not been reported by other
countries (47). Serogroups A, B, C, Y, W, and X are all capable of causing outbreaks, most
characteristically serogroup A. Although epidemics of serogroup A meningococcal disease were common
in industrialized countries a century ago, serogroup A epidemics now occur primarily in the African
“meningitis belt,” a region of savannah that extends from Ethiopia in the east to Senegal in the west
(61,62). In this region, endemic rates of disease are several times higher than in industrialized countries;
in addition, major epidemics occur every 8 to 12 years, with incidence rates as high as 1% of the
population, causing tremendous disruption to the already strained public health infrastructure (59). In
2000, the first documented epidemic of serogroup W occurred among pilgrims to the hajj in Saudi Arabia,
and in 2002, the first major epidemic of serogroup W occurred in Burkina Faso (63). Since that time,
serogroup W has remained in the meningitis belt and has been the cause of several outbreaks but does not
tend to cause the explosive epidemics that are common with serogroup C disease.
In recent years, meningococcal conjugate vaccines have had a dramatic impact on the global burden of
meningococcal disease. Meningococcal disease has a wide age distribution, and an effective vaccination
program must address the risk of disease in infants as well as older children and adolescents.
Immunology and Pathogenesis
The human nasopharynx is the only natural reservoir of N. meningitidis, most of which are nonpathogenic
and carried asymptomatically in 5% to 10% of adults (64,65). In less than 1% of those colonized, N.
meningitidis penetrate the mucosa to gain access to the bloodstream and cause systemic disease (66).
In 1913, Flexner (67) demonstrated the efficacy of antimeningococcal serum in reducing mortality due
to N. meningitidis, providing evidence of the importance of humoral immunity in protection. Except for
serogroup B, the primary host defense against meningococci is circulating antibody against the capsular
polysaccharide, as in HIB disease. In the neonatal period, natural resistance is due to the transplacental
passage of IgG antibodies, which wane during the first 6 months of life; bactericidal antibodies are
present in fewer than 25% of infants aged 6 to 23 months (68,69). As individuals develop
antimeningococcal antibodies, their susceptibility to meningococcal disease decreases, which is further
evidence of the role of humoral immunity. Nasopharyngeal colonization with meningococci and
nonpathogenic Neisseria, such as Neisseria lactamica, a common commensal organism in infants and
children, partially accounts for this immunizing process. However, a parallel rise in specific anti-A or
anti-C capsular polysaccharide antibodies measured by radioimmunoassay cannot be explained solely by
carriage of nonpathogenic Neisseria species, which do not express capsule (70,71). Therefore, natural
immunization through unrelated but serologically cross-reactive bacteria, such as Escherichia coli K1,
itself a major cause of neonatal meningitis, is likely (72).
History of Meningococcal Vaccines
The history of attempted immunization against meningococcal disease, originally known as cerebrospinal
fever, is long. Whole-cell and autolysate vaccines were used well before the natural history and
pathogenesis of the disease were fully understood. The correlation between susceptibility to disease and
the absence of circulating bactericidal antibodies was not documented until 60 years later (69).
Vaccination trials were carried out in the Sudan in 1915 and among U.S. and British troops during the
cerebrospinal meningitis epidemics of World War I (61,73).
In the 1940s, encouraged by studies with pneumococcal polysaccharides in which a good seroresponse
was achieved, the capsular polysaccharide of group A meningococci was purified using the same methods
as for pneumococci and tested the product in human volunteers. The results were disappointing, and the
study was neglected for two decades, until it was determined that the polysaccharide used was quite
small, a potential cause of the poor immunogenicity. When Gotschlich, Liu, and Arenstein (73) modified
the purification method, immunogenic preparations were obtained from both A and C strains, opening the
way for a new generation of vaccines.
Meningococcal Polysaccharide Vaccines
By 1969, Gotschlich, Goldschneider, and Artenstein (74) demonstrated the immunogenicity of serogroup
C vaccine in adults, and subsequent studies confirmed that immunogenicity was serogroup specific, so
serogroup A vaccine does not protect against serogroup C. Because of the specificity of these vaccines,
bivalent (A, C), trivalent (A, C, W), and quadrivalent vaccines (A, C, Y, W) have been developed
(75,76). Prior to development of conjugate vaccines, bivalent and quadrivalent meningococcal
polysaccharide vaccines were extensively used in mass vaccination programs and in the military. These
vaccines are well tolerated with generally mild adverse events, most commonly pain and redness at the
injection site lasting for 1 to 2 days. Transient fever occurs in 2% to 5% of vaccines, more commonly in
infants (77). Severe adverse reactions, including systemic allergic reactions and anaphylaxis, are rare
(77). Studies of vaccination during pregnancy have not documented adverse events among pregnant
women or newborns (78,79).
Immunogenicity and Efficacy

Serogroup A and C meningococcal polysaccharide vaccines have consistently been found to have good
immunogenicity and clinical efficacy in adults and children older than 5 years. Routine vaccination of
military recruits in the United States has virtually eliminated meningococcal outbreaks in the military
(80). In Italy, introduction of polysaccharide vaccines decreased rates of serogroup C meningococcal
disease; vaccine efficacy was estimated as 90% (81). Similarly high efficacy has been demonstrated in
community outbreaks of serogroup C meningococcal disease in Canada, Brazil, and the United States
(82,83). For serogroup A, controlled trials and case–control studies have demonstrated efficacy rates of
85% to 90% after a single dose (70,84). Meningococcal polysaccharide vaccines have been shown to be
effective in controlling meningococcal outbreaks in industrialized countries and Africa (82,83,85).
Serogroup Y and W polysaccharides are safe and immunogenic in older children and adults; although
clinical protection has not been documented, vaccination with these polysaccharides induces bactericidal
antibodies (76,86).
Meningococcal polysaccharide vaccines do have some important limitations. The serogroup C
polysaccharide does not induce good antibody response before 18 to 24 months of age (87). In healthy
adult military personnel, anticapsular antibodies and bactericidal activity decrease substantially during
the 2 years after vaccination but in some cases persisted for up to 10 years after immunization (88). In
children 2 to 6 years of age at the time of vaccination, antibody levels decline consistently over 1 to 4
years (87). In infants immunized before 1 year of age, antibody levels decline to baseline after 3 to 5
months (77). In both children and adults, a significant response to a booster dose has not been observed.
Although reduced clinical efficacy has not been demonstrated among individuals who have received
multiple doses, studies have raised the question of immunologic tolerance to the serogroup C
polysaccharide vaccine (89,90). Finally, polysaccharide vaccines do not completely protect from
acquisition of nasopharyngeal carriage, and therefore, they do not provide long-term herd immunity.
Conjugate Meningococcal Vaccines
As with HIB and pneumococcal conjugate vaccines, serogroups A, C, Y, and W have been chemically
conjugated to carrier proteins. Meningococcal conjugate vaccines induce a T-cell–dependent response
that improves the immune response, especially in infants. Because rates of meningococcal disease are
relatively low, clinical trials of vaccine efficacy are difficult; meningococcal conjugate vaccines have
been licensed based on immunogenicity and safety data (Table 51.1).
Serogroup C Conjugate Vaccines
Meningococcal serogroup C (MCC) vaccines were introduced in the United Kingdom in 1999 in response
to high rates of serogroup C disease caused by a virulent clone. After a mass vaccination campaign
targeting ages 1 to 17 years, MCC was introduced into the routine infant immunization schedule. The
current schedule is doses at age 3 and 4 months with a booster dose at 12 to 13 months. Canada and
several countries in Europe have single-dose MCC recommendations in toddlers or multidose MCC
schedules in infants.
The safety and immunogenicity of the three different MCC vaccines in children and adults have been
demonstrated in several studies, and there are no substantial differences in effectiveness between the
vaccine types (91–93). Ninety-eight percent of infants develop protective bactericidal antibody titers,
following a three-dose series at 2, 3, and 4 months of age. Similar immune responses are seen following a
two-dose series at 3 and 5 months as well as a single dose in older children and adults. Vaccine
effectiveness in adolescents was 93% and sustained up to 4 years after the catchup vaccination (94).
Although effectiveness was high (83%) in those receiving catchup immunization after 5 months of age, it
was lower among those vaccinated in infancy (66%) (94,95).
Antibody persistence has been followed closely after MCC vaccination in the United Kingdom, and
waning immunity is demonstrated, especially in infants and young children. In the absence of a booster
dose, only 8% to 12% of children completing a three-dose series in infancy had protective immunity at
age 4 years (96). Among children primed at ages ranging from 2 months to 6 years, only 25% had
protective titers greater than or equal to 8 at 1 year (97). Waning immunity among adolescents vaccinated
with MCC is much less pronounced. In two studies of adolescents vaccinated at age 10 years, 62% to
75% of adolescents vaccinated maintained protective antibody titers 3 to 6 years following vaccination
(98,99). These studies suggest that immune maturation may play an important role in duration of
protection.
Conjugate vaccine programs also have potential to provide indirect protection through herd immunity.
Two years after introduction of MCC vaccine in the United Kingdom, serogroup C carriage was reduced
by 67% (100). The proportion of nongroupable isolates increased (10.05% versus 11.2%, p = .071), but
there was no significant change in carriage of N. meningitidis expressing other disease-associated
serogroups (100). Attack rates among unvaccinated children in the United Kingdom also declined by 67%
in the 4 years following vaccine introduction (94,95,101,102). Between 1998 and 2009, the incidence of
serogroup C disease in persons older than 25 years dropped from 0.55 per 100,000 persons to 0.02 per
100,000 persons; and the number of cases in infants younger than 3 months of age dropped from 13 in
1998 to 1 in 2009 (102). These effects were seen despite a declining seroprevalence of protective
antibodies among vaccination cohorts as early as 18 months after the last scheduled dose of vaccine,
suggesting sustained protection due to herd immunity despite absence of protective antibodies in
individuals.
Quadrivalent (Serogroups A, C, W, and Y) and Bivalent (Serogroups C and Y)

Meningococcal Vaccines
In the United States, there are three licensed meningococcal conjugate vaccines: quadrivalent
meningococcal conjugate vaccine (MenACWY) conjugated to diphtheria toxoid (MenACWYD)
(Menactra, Sanofi Pasteur); MenACWY conjugated to CRM197, which is a nontoxic mutant diphtheria
toxin (MenACWYCRM) (Menveo, Novartis); and bivalent meningococcal conjugate vaccine combined
with HIB vaccine, conjugated to tetanus toxoid (HibMenCYTT) (MenHibrix, GlaxoSmithKline).
MenACWYD is licensed as a single dose for persons ages 2 to 55 years and as a two-dose series for
children 9 to 23 months. MenACWYCRM is licensed as a single dose for persons ages 2 to 55 years and a
four-dose series in infants (103,104). HibMenCYTT, approved in 2012, is licensed as a four-dose series
for infants aged 2 to 18 months. These vaccines all protect against serogroups C and Y, which cause
approximately two thirds of cases in the United States. MenACWYD and MenACWYCRM also protect
against serogroups A and W. Because of the frequency of meningococcal disease caused by serogroup Y
in the United States, conjugate vaccines that do not contain serogroup Y are not licensed in the United
States. Currently, adolescents are recommended to be vaccinated at ages 11 to 12 years with a booster
dose at age 16 years; other persons at increased risk for meningococcal disease are recommended to be
vaccinated as well. Routine immunization of infants in the United States is not recommended because
currently licensed vaccines do not include serogroup B and because of a historically low burden of
disease (107).
The duration of protection following vaccination with quadrivalent meningococcal conjugate vaccines
remains an important subject of evaluation. Studies among adolescent recipients of MenACWYD and
MenACWYCRM demonstrate significant declines in antibody levels over 5 years, which provides
corroborating evidence for the observed decline in effectiveness discussed earlier. After a single dose of
MenACWYD, the proportion of adolescents with protective antibodies was as low as 30% to 54% 3
years after vaccination (105). At 5 years postvaccination with MenACWYCRM, 34% (serogroup A) to
84% (serogroup W) maintained protective levels of antibody (106). Antibodies waned even faster in
infants ages 9 to 23 months who received a two-dose series of MenACWYD (107). However, infants
vaccinated with four doses of HibMenCY demonstrate better antibody persistence. Five years after the
fourth dose, 82% and 69% of children immunized as infants had protective levels of antibody for
serogroups C and Y, respectively (108). Estimates from a large ongoing case–control study evaluating one
of the two MenACWY vaccines, MenACWYD, in the United States suggest high vaccine effectiveness
early after vaccination, but 2 to 5 years after vaccination, vaccine effectiveness wanes to 50% to 60%.
Waning immunity was the primary rationale for adding a booster dose for adolescents at age 16 years.
Serogroup A Conjugate Vaccine
To address the devastating epidemics of serogroup A meningococcal (MenA) disease that occur in the
meningitis belt of sub-Saharan Africa (Fig. 51.2), a MenA tetanus toxoid conjugate vaccine, called
MenAfriVac (PsA-TT), was developed specifically for this region by a collaborative partnership, the
Meningitis Vaccine Project. The goal of this project was to ensure a vaccine that would be available in
the region that countries could afford to implement. In 2010, PsA-TT was licensed in 1- to 29-year-olds
and in 2011 was prequalified by WHO for use in Africa. This is the first large-scale introduction of a
meningococcal conjugate vaccine in Africa. At 40 cents per dose, the vaccine is priced so that mass
vaccination of all 1- to 29-year-olds is affordable for the region.
By the end of 2013, over 150 million persons were vaccinated in the meningitis belt with PsA-TT and
plans are in place for mass vaccination campaigns to occur in other meningitis belt countries by 2016
(Fig. 51.3). Early data suggest that the vaccine has potential to eliminate serogroup A epidemics in
Africa. Burkina Faso, the first country to vaccinate nationwide, achieved over 94% coverage during
campaigns in late 2010 (109). In the first year after PsA-TT vaccination in Burkina Faso, the incidence of
meningitis fell by 99.8% and there were no cases of serogroup A meningococcal disease among
vaccinated persons (110). Furthermore, 1 year after the PsA-TT campaign, there were no carriers of
serogroup A N. meningitidis in more than 5,000 persons sampled (111). However, it is possible that the
impact may not be the same in countries that implement PsA-TT vaccine in phases or do not achieve high
vaccine coverage rates in all regions. In addition, 1 year after MenA vaccine implementation in Burkina
Faso, the rates of serogroup W disease are increasing and serogroup X continues to cause disease in the
meningitis belt (http://www.meningvax.org/files/BulletinMeningite2012_S49_52.pdf). Continued
laboratory surveillance is necessary to evaluate long-term vaccine effectiveness and to monitor disease
caused by serogroups that are not covered by PsA-TT.
Although the initial vaccination campaigns in the meningitis belt have been an enormous public health
accomplishment, plans to vaccinate new birth cohorts will be critical to maintain population protection.
Strategies include adding PsA-TT into the expanded program for immunization schedules (EPI) at 9
months or having periodic campaigns targeting young children. Currently, immunogenicity and safety
studies are being conducted to license PsA-TT in infants aged younger than 1 year old.
Serogroup B Meningococcal Vaccines
Vaccines against serogroup B meningococci are challenging because the native capsular polysaccharide
of B, a homopolymer of a two- to eight-linked sialic acid, is not sufficiently immunogenic in humans
(112). Even following a natural infection with serogroup B meningococcus, antibodies produced against
capsular polysaccharide consist primarily of IgM, with low avidity and poor bactericidal activity with
human complement (113). The group B polysaccharide capsule is identical in structure to polysialic acid
(N-CAM) present in fetal neural tissue, likely accounting for its failure to induce immunity (114).
Strategies for vaccines against serogroup B have primarily focused on noncapsular antigens. Outer
membrane protein (Omp) vaccines produced from outbreak-causing strains have been safe, immunogenic,
and efficacious among children and adults and have been used to control outbreaks in South America and
Scandinavia (115–117). However, Omp vaccines have not been reliably effective in young children
(118). Because serogroup B outbreaks are due to strains of a single serosubtype and generally last 10 to
20 years, development of “designer” vaccines have been prepared to specifically target an outbreak strain
(119). This strategy requires extensive international coordination, funding, and political will to rapidly
detect the outbreak strain; to develop, test, license, and produce the vaccine; and to mount a mass
immunization strategy. However, this approach was successfully used to control a serogroup B outbreak
in New Zealand that was ongoing for more than 10 years (56).
Although serogroup B does cause outbreaks, it is probably the most common cause of sporadic
meningococcal disease, especially since introduction of conjugate vaccines for serogroup C. Unlike
outbreaks, the Omps of strains causing sporadic disease are diverse, with geographic and possibly
temporal variations. Therefore, multivalent vaccines would be needed to protect against multiple
serosubtypes. At least 20 Omp serosubtypes would need to be included in a multivalent vaccine to protect
against 80% of strains causing disease in the United States (120,121). Because of the potential limitations
of these vaccines, alternative approaches to identify immunogenic antigens have been pursued, including
vaccines against other Omps and against alternative subcapsular antigens. There are two serogroup B
vaccines that have potential to prevent a substantial proportion of serogroup B disease (122,123). The
multicomponent serogroup B vaccine licensed in Europe in January 2013, 4CMenB (Bexsero), contains
three novel antigens—factor H-binding protein (fHbp), neisserial adhesion A (NadA), and Neisseria
heparin-binding antigen (NHBA). These antigens were combined with outer membrane vesicle (OMV)
from the New Zealand epidemic strain NZ98/254. 4CMenB was recommended for licensure by the
European Medicines Agency’s Committee for Medicinal Products for Human Use in November 2012. The
second bivalent serogroup B vaccine, FHB2, contains two fHbp variants, one from each family. These
antigens have been demonstrated to be important for survival of N. meningitidis. For example, fHbp
binds human factor H, an inhibitor of the alternative complement pathway, and allows the organism to
evade the human innate immune system. Therefore, antibodies to fHbp are bactericidal and presumed to
be protective against N. meningitidis. These antigens are present in N. meningitidis independent of
serogroup and therefore could potentially also provide protection against other serogroups.
These vaccines have been shown to be immunogenic against target strains chosen to determine the
immunogenicity of each vaccine component. However, these target strains may not be representative of
disease-causing strains, which vary by country. Although 4CMenB has now been licensed, it has not been
implemented routinely in any country at this time, and therefore, no data on vaccine effectiveness data are
currently available. For these vaccines to have a substantial impact on disease burden, they will need to
be immunogenic and safe in young infants, protect against a high proportion of serogroup B strains, and
provide long-term protection. Second, it is unknown whether the vaccines will have an impact on
nasopharyngeal carriage, an important attribute of meningococcal conjugate vaccines.
Control of Meningococcal Disease
Close contacts of patients infected with meningococcal disease have an elevated risk for contracting
disease. The attack rate for household contacts of a patient with meningococcal disease is 500 to 800
times greater than that for the general population (107). Therefore, in most industrialized countries,
antimicrobial chemoprophylaxis is the primary means for prevention of secondary cases of
meningococcal disease. Because of the effectiveness of this intervention, secondary cases in
industrialized countries are rare (48). Mass chemoprophylaxis programs are not recommended to control
large outbreaks because of the multiple sources of exposure, prolonged risk, logistic problems, and high
cost. These same problems hinder the usefulness of this strategy in developing countries. Therefore,
prevention of meningococcal disease has primarily focused on vaccination.
Several countries in Europe and Latin America have routine serogroup C vaccination recommendations
for infants and toddlers. The United States is the only country currently with a quadrivalent conjugate
vaccination strategy targeting adolescents and high-risk groups (Table 51.2). In some countries,
vaccination of close contacts of an index case, including household contacts and day care contacts, is
recommended (http://www.hpa.org.uk/webc/hpawebfile/hpaweb_C/1317140499501). Meningococcal
conjugate and polysaccharide vaccines are used for control of outbreaks in both industrialized and
developing countries. The decision about when to initiate a vaccination campaign and who to vaccinate is
complicated. Vaccination campaigns are expensive and logistically difficult, involving a large
commitment of resources. In the United States, the ACIP recommends that vaccination be considered when
three or more confirmed or probable serogroup C meningococcal disease cases occur within a 3-month
time interval, with a primary attack rate of at least 10 cases per 100,000 population (107).
Rapid introduction of conjugate vaccines in countries with a high burden of meningococcal disease is
the key strategy for control of global meningococcal disease. Meningococci have the ability to exchange
the genetic material responsible for capsule production and therefore switch serogroup (124); this may
become an important mechanism of virulence with the widespread use of vaccines that provide
serogroup-specific protection. The emergence of serogroup Y in the United States in the 1990s and
serogroup W in Saudi Arabia and Burkina Faso also illustrates the potential danger of relying on
serogroup-specific vaccines. Optimal vaccines to control meningococcal disease should be simple,
inexpensive, and easy to deliver and may incorporate common antigens that will be equally effective
against all serogroups.
STREPTOCOCCUS PNEUMONIAE (PNEUMOCOCCUS)

S. pneumoniae causes more than 800,000 childhood deaths a year worldwide (125). The number of
deaths in adults is likely even greater (126). Most of these deaths are from pneumococcal pneumonia, as
S. pneumoniae is the leading cause of pneumonia mortality in all age-groups. However, pneumococcal
meningitis also causes a significant burden of mortality worldwide.
S. pneumoniae is a leading cause of bacterial meningitis in the United States, occurring at a rate of 1.09
per 100,000 population in 1998 to 1999, declining to 0.81 per 100,000 population in 2006 to 2007 (Table
51.3) (1). S. pneumoniae is the leading cause of bacterial meningitis among children aged 1 to 23 months
and adults older than 18 years; in neonates and children aged 2 to 18 years, it is the third and second most
common cause. Prior to introduction of pneumococcal conjugate vaccines, the rates were highest among
neonates (15.7 per 100,000), children aged 1 to 23 months (6.6 per 100,000), and those 60 years and
older (1.9 per 100,000) (3,127). Rates of pneumococcal meningitis were similar among children in other
developed countries, with rates per 100,000 children younger than 2 years being 4.7 in Finland, 10.5 in
Australia, and 11.1 in Israel (127–129). The rate of pneumococcal meningitis is severalfold higher in
developing countries and special populations in developed countries. The rate of pneumococcal
meningitis among children younger than 2 years was 84 per 100,000 among Alaskan natives prior to
routine pneumococcal vaccination (130) and among African infants has been shown to be more than 90
per 100,000 (131,132). Moreover, pneumococcus was found to be the leading bacterial cause of
meningitis among neonates in a study in four developing countries (133). Pneumococcal meningitis rates
among adults are also more than fivefold higher in developing than in developed countries. Outbreaks of
pneumococcal disease are uncommon but may occur in closed populations, such as nursing homes,
childcare centers, or other institutions. However, large outbreaks of meningitis caused by serotype 1 have
been reported from the African meningitis belt (134).
Overall, pneumococcal meningitis has a higher case-fatality proportion than other types of bacterial
meningitis but varies by age (1). Only 1% of cases of invasive pneumococcal disease among children
younger than 2 years were fatal compared with 20% among patients older than 60 years (135); case-
fatality proportions for pneumococcal meningitis tend to be higher. Although following a similar trend, in
developing countries, the case-fatality proportion for pneumococcal meningitis may exceed 30% (136). A
significant percentage of survivors have permanent neurologic sequelae. Four studies showed an average
incidence of 32% of neurologic sequelae (137), although this figure may be as high as 50% with more
refined hearing tests (138).
The percentage of pneumococcal isolates that are resistant to antibiotics is increasing, although the rate
of resistant organisms did decline after introduction of PCV7 for the vaccine serotypes (139,140).
Treatment failures in cases of meningitis caused by pneumococci resistant to β-lactam antibiotics have led
to recommendations to add vancomycin in cases in which penicillin-resistant pneumococcal meningitis is
suspected (141). The rise of antibiotic-resistant pneumococci further emphasizes the importance of
expanding use of pneumococcal conjugate vaccines globally.
Serotype Distribution
There are over 90 serotypes of pneumococci, which are distinguished by variations in the polysaccharide
capsule. These serotypes are further subdivided into 46 serogroups; serotypes within the same serogroup
may have cross-reactive immunity (142). A collection of 3,644 pneumococcal blood isolates from 10
hospitals throughout the United States in the 1960s and 1970s revealed that 90% of cases were caused by
the 23 most common types, with only 6 types accounting for more than half of the cases (143). The
serotype distribution is even narrower in children, where prior to vaccination, almost 90% of invasive
pneumococcal infections are caused by seven serotypes targeted in the seven-valent pneumococcal
conjugate vaccine (4, 6, 9, 14, 18, 19, and 23). These serogroups cause a lower percentage of disease in
other parts of the world, accounting for approximately 75% in Europe, 70% in Africa, and 45% in Asia
(144). In many developing countries, serotypes 1 and 5, which were not covered by the first
pneumococcal conjugate vaccines, account for more than 20% of pneumococcal meningitis cases (144).
Pneumococcal Polysaccharide Vaccine
This was the first of the polysaccharide vaccines. As early as 1911, whole-cell pneumococcal vaccines
were tested among gold miners of South Africa. The finding that an immune response could be elicited by
purified capsular polysaccharides in the 1930s led to the development of a hexavalent pneumococcal
polysaccharide vaccine in the 1940s, which was not widely used before its withdrawal from the market
(145,146). In 1977, a 14-valent vaccine containing 50 µg of each capsular polysaccharide was licensed
in the United States, which was superseded by a 23-valent vaccine containing 25 µg of each
polysaccharide in 1983. The serotypes in this vaccine were chosen by the epidemiology of the disease in
the United States, as they cause 85% to 90% of invasive infections (147).
Pneumococcal polysaccharide vaccine (PPV) is generally considered safe and effective. More than
80% of healthy young adults respond with a twofold rise in type-specific antibody after vaccination
(148). Groups for whom PPV is recommended by the ACIP, such as the elderly and those with underlying
chronic diseases, also have an immunologic response to PPV, although the levels achieved may be
diminished (149,150). Antibody levels remain elevated for at least 5 years in most individuals without
functional or anatomic asplenia (151). Of note, PPV is poorly immunogenic in children younger than 2
years to most important serotypes (152).
Several retrospective studies using case–control and indirect cohort methodologies have shown
vaccine effectiveness against pneumococcal bacteremia or invasive disease ranging from 48% to 81%
(130,153–155), with only one study failing to show efficacy (156). PPV effectiveness is limited in
children younger than 2 years and in immunocompromised persons. It fails to reduce nasopharyngeal
carriage, the main portal of entry of pneumococcus into the body (157,158). Pneumococcal carriage rates
are much higher in children than adults and may explain in part their higher rates of disease. There are no
data to suggest that PPV has a protective effect against pneumococcal meningitis in children, and its poor
immunogenicity would suggest otherwise. Therefore, PPV is not widely used among children in
developed and developing countries. The ACIP has recommended that PPV be given one time to
immunocompetent persons 65 years or older (150). PPV is recommended for persons 2 to 64 years of age
with certain underlying diseases that increase the risk for pneumococcal disease, including
immunocompromised persons. A single revaccination is recommended for adults with asplenia or
immunocompromised status for 5 or more years after the first dose (150).
Pneumococcal Conjugate Vaccines
As mentioned, PPV has poor efficacy in the group with the highest rates of pneumococcal disease—
children younger than the age of 2 years. A seven-valent pneumococcal conjugate vaccine (PCV7), in
which serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F are conjugated to a nontoxic variant of diphtheria toxin,
CRM197, was licensed in the United States in 2000. These seven serotypes were shown to cause 80% of
invasive disease among children younger than 5 years in the United States (159). However, these seven
serotypes account for a lower percentage of disease in developing countries. In 2010, a 13-valent
pneumococcal conjugate vaccine (PCV13) was introduced, adding serotypes 1, 3, 5, 6A, 19A, and 7F,
and replaced PCV7. In other countries, a 10-valent pneumococcal conjugate vaccine is licensed (PCV10)
which includes all serotypes in PCV7 and serotypes 1, 5, and 7F. Each polysaccharide is conjugated to a
carrier protein, either protein D (an Omp from nontypable H. influenzae), tetanus toxoid, or diphtheria
toxoid. These vaccines increase overall coverage of pneumococcal serotypes causing disease globally.
Safety and Immunogenicity

Pneumococcal conjugate vaccines (PCVs) are generally considered safe and have been found to be highly
immunogenic among infants (160). The immune response of PCV7 has been shown to be even greater
among South African children, with more than 92% of children having sufficient antibody concentrations
to all serotypes after three doses of PCV7 (161). PCV13 was shown to be safe and immunogenic for the
seven serotypes in PCV7 as well as the six additional serotypes (162–164).
Efficacy
In a randomized trial of PCV7 that enrolled 37,868 infants at Northern California Kaiser Permanente, the
efficacy of the vaccine against invasive pneumococcal disease caused by vaccine serotypes in an intent-
to-treat analysis was 93.9% (95% confidence interval [CI], 79.6% to 98.5%) (165). In another large,
randomized controlled trial of PCV (nine-valent formulation) in Soweto, South Africa, PCV had an
efficacy of 72.1% (95% CI, 46.1% to 86.6%) against invasive disease caused by vaccine serotypes in an
intent-to-treat analysis (166). The efficacy in HIV-negative children was 83% (95% CI, 39% to 97%) and
in HIV-positive children was 65% (95% CI, 24% to 86%). PCV7 has been shown to reduce
nasopharyngeal carriage of vaccine serotypes (167–169). However, several of these studies have shown
that there is a concomitant increase in carriage of nonvaccine types (167,169). Similarly, PCV7 has been
shown to decrease the incidence of otitis media caused by vaccine serotypes (efficacy, 57%; 95% CI,
44% to 67%), although there was a trend toward an increased number of episodes caused by nonvaccine
serotypes (efficacy, –33%; 95% CI, –80–1%) (170).
Population-based surveillance data from the United States show strong evidence of the impact that
PCV7 has had on invasive pneumococcal disease, including meningitis, since its introduction in early
2000 (171–175). Between 1998 and 1999 and in 2001, the rate of all invasive pneumococcal disease
declined by 59% (95% CI, 54% to 63%) among children younger than 5 years. The incidence of
meningitis from S. pneumoniae PCV7 serotypes changed by −92% overall (95% CI, −93 to −91), from
0.61 cases per 100,000 population (95% CI, 0.48 to 0.64) in 1998 to 1999 to 0.05 cases per 100,000
population (95% CI, 0.03 to 0.07) in 2006 to 2007. However, the incidence of bacterial meningitis from
non-PCV7 serotypes increased by 61% (95% CI, 54 to 69), from 0.48 cases per 100,000 population
(95% CI, 0.45 to 0.60) in 1998 to 1999 to 0.77 cases per 100,000 population (95% CI, 0.67 to 0.84) in
2006 to 2007 (1). There was also evidence of indirect protection, a significant decrease in the rates of
invasive pneumococcal disease, and meningitis was seen among groups that did not receive PCV7
(1,175).
Prevention of Pneumococcal Meningitis

In the United States, ACIP recommends use of PCV13 for (a) all children aged 2 to 59 months and (b)
children aged 60 to 71 months with underlying medical conditions that increase their risk for
pneumococcal disease or complications, such as sickle cell disease (SCD), anatomic and functional
asplenia, immunocompromising conditions such as hematologic malignancies and immunosuppressive
therapies, renal failure, diabetes mellitus, and chronic cardiac and pulmonary diseases. ACIP
recommends that children and adults aged 6 years and older who have not received PCV13 and are at
increased risk for invasive pneumococcal disease (IPD) because of anatomic or functional asplenia
(including SCD), HIV infection, cochlear implant, cerebrospinal fluid (CSF) leak, or other
immunocompromising conditions receive a single PCV13 dose first, followed 8 weeks or later by a dose
of PPSV23. A second PPSV23 dose is recommended 5 years after the first PPSV23 dose for children with
anatomic or functional asplenia (including SCD), HIV infection, or other immunocompromising
conditions. For those children and adults at high risk who have received a prior dose of PPSV23, they
should be given a PCV13 dose 1 year or later after the last PPSV23 dose was received. All persons
should be vaccinated with PPSV23 at age 65 years. Those who received PPSV23 before age 65 years for
any indication should receive another dose of the vaccine at age 65 years or later if at least 5 years have
passed since their previous dose. Those who receive PPSV23 at or after age 65 years should receive only
a single dose.
WHO recommends the inclusion of PCVs in childhood immunization programs worldwide. Countries
with high childhood mortality (i.e., under 5 mortality rate of >50 deaths per 1,000 births) should prioritize
the introduction of PCVs. Through the GAVI advanced market commitment, PCVs are being made
available to GAVI-supported countries at a cost of approximately $3.50 a dose, a greater than 90%
reduction in price compared to the PCVs available in the United States and Europe. This approach was
developed to reduce the gap in time between developed and developing countries’ introduction of new
vaccines and the recognition that low-income countries have the highest burden of pneumococcal disease.
The goal is to introduce PCVs to more than 45 GAVI-eligible countries by 2015.
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33. B

Infectious Diseases of Central Nervous System

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Acquisitions Editor: Julie Goolsby

Senior Product Development Editor: Kristina Oberle

Copyright © 2014 Wolters Kluwer Health

© 2004 by Lippincott Williams & Wilkins

Library of Congress Cataloging-in-Publication Data

Infections of the central nervous system (Scheld)

Sven Bergström, PhD

Ari Bitnun, MD, MSc, FRCPC

Itzhak Brook, MD, MSc

Maxine Caws, PhD, MSc, BSc

Jeremy Farrar, FRCP, FRCP(Ed), FMedSci, PhD, OBE

Michael D. Geschwind, MD, PhD

Michael Giladi, MD, MSc

John W. Gnann, Jr., MD

Denis Grandgirard, PhD

Diane E. Griffin, MD, PhD

Paul D. Griffiths, MD, DSc

Rodrigo Hasbun, MD, MPH

Dorothee Heemskerk, MSc, MD

Marc Hildebrand, MD, PhD

Susan E. Hoover, MD, PhD

Jennifer L. Horan, MD, PharmD

Alan C. Jackson, MD, FRCPC

Louis V. Kirchhoff, MD, MPH

Matthias Maiwald, MD, PhD

Carrie P. Marder, MD, PhD

James D. Marks, MD, PhD

Thomas O. McPharlin, RPh

Reto Antoine Meuli, MD, PhD

Jose G. Montoya, MD, FACP, FIDSA

Shannon Moonah, MD, ScM

Adjanie Patabendige, PhD

William A. Petri, Jr., MD, PhD

Didier Raoult, MD, PhD

Susan Richardson, MD, CM

Jose A. Serpa, MD, MS

Khoi Duc Than, MD

Allan R. Tunkel, MD, PhD

Diederik van de Beek, MD, PhD

Arun Venkatesan, MD, PhD

Richard J. Wallace, Jr.

Thomas J. Walsh, MD, PhD (hon), FCCP, FAAM, FIDSA

David F. Welch, PhD, D(ABMM)

A. Clinton White, Jr., MD

Joseph R. Zunt, MD, MPH

PART APPROACH TO THE PATIENT AND DIAGNOSTIC EVALUATION

Chapter 1 Introduction: Approach to the Patient with Central Nervous

Chapter 2 Cerebrospinal Fluid in Central Nervous System Infections

Chapter 3 Imaging of Intracranial Infections

PART VIRAL INFECTIONS AND RELATED DISORDERS

Chapter 4 Pathogenesis and Pathophysiology of Viral Infections of the

Chapter 5 Viral Meningitis and Aseptic Meningitis Syndrome

Chapter 7 Poliomyelitis, Polio Vaccines, and the Postpoliomyelitis

Chapter 9 Herpes Simplex Virus

Chapter 10 Neurologic Manifestations of Varicella and Herpes Zoster

Chapter 12 Epstein-Barr Virus

Chapter 13 Human Herpesvirus-6

Chapter 15 Arthropod-Borne Viral Encephalitides

Chapter 16 Meningitis and Encephalitis Caused by Mumps Virus