BALOWClinical Neurophysiology of The Vestibular System

CLINICAL NEUROPHYSIOLOGY
OF THE VESTIBULAR SYSTEM

SERIES EDITOR
Sid Gilman, MD, FRCP
William J. Herdman Distinguished University Professor of Neurology
University of Michigan
Contemporary Neurology Series
53 SLEEP MEDICINE 69 PALLIATIVE CARE IN NEUROLOGY

Michael S. Aldrich, MD Raymond Voltz, MD,
54 BRAIN TUMORS James L. Bernat, MD,
Harry S. Greenberg, MD, Gian Domenico Borasio, MD,
William F. Chandler, MD, and DipPallMed,
Howard M. Sandler, MD Ian Maddocks, MD,
56 MYASTHENIA GRAVIS AND David Oliver, FRCGP,
MYASTHENIC DISORDERS and Russell K.
Andrew G. Engel, MD, Editor Portenoy, MD
57 NEUROGENETICS 70 THE NEUROLOGY OF EYE
Stefan-M. Pulst, MD, Dr. Med., Editor MOVEMENTS,
58 DISEASES OF THE SPINE AND Fourth Edition
SPINAL CORD R. John Leigh, MD, FRCP and
Thomas N. Byrne, MD, David S. Zee, MD
Edward C. Benzel, MD, and 71 PLUM AND POSNER’S DIAGNOSIS OF
Stephen G. Waxman, MD, PhD STUPOR AND COMA,
59 DIAGNOSIS AND MANAGEMENT Fourth Edition
OF PERIPHERAL NERVE Jerome B. Posner, MD,
DISORDERS Clifford B. Saper, MD, PhD,
Jerry R. Mendell, MD, John T. Kissel, MD, Nicholas D. Schiff, MD, and
and David R. Cornblath, MD Fred Plum, MD
60 THE NEUROLOGY OF VISION 72 PRINCIPLES OF DRUG THERAPY IN
Jonathan D. Trobe, MD NEUROLOGY,
61 HIV NEUROLOGY Second Edition
Bruce James Brew, MBBS, MD, FRACP Michael V. Johnston, MD and
62 ISCHEMIC CEREBROVASCULAR Robert A. Gross, MD, PhD, Editors
DISEASE 73 NEUROLOGIC COMPLICATIONS
Harold P. Adams, Jr., MD, OF CANCER,
Vladimir Hachinski, MD, and Second Edition
John W. Norris, MD Lisa M. DeAngelis, MD and
65 MIGRAINE: MANIFESTATIONS, Jerome B. Posner, MD
PATHOGENESIS, AND 74 NEUROLOGIC COMPLICATIONS
MANAGEMENT, OF CRITICAL ILLNESS,
Second Edition Third Edition
Robert A. Davidoff, MD Eelco F.M. Wijdicks, MD, PhD, FACP
67 THE CLINICAL SCIENCE 75 CLINICAL NEUROPHYSIOLOGY,
OF NEUROLOGIC THIRD EDITION
REHABILITATION, Jasper R. Daube, MD and
Second Edition Devon I Rubin, MD, Editors
Bruce H. Dobkin, MD 76 PERIPHERAL NEUROPATHIES IN
68 NEUROLOGY OF COGNITIVE AND CLINICAL PRACTICE
BEHAVIORAL DISORDERS Steven Herskovitz, MD,
Orrin Devinsky, MD and Stephen N. Scelsa, MD, and
Mark D’Esposito, MD Herbert H. Schaumburg, MD
CLINICAL NEUROPHYSIOLOGY
OF THE VESTIBULAR SYSTEM
Fourth Edition
Robert W. Baloh, MD, FAAN

Department of Neurology and Surgery (Head and Neck)
Reed Neurological Research Center
UCLA School of Medicine
Los Angeles, CA
Kevin A. Kerber, MD
Department of Neurology
University of Michigan Health Center
Ann Arbor, MI
1
2011
1
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Baloh, Robert W. (Robert William), 1942-

Clinical neurophysiology of the vestibular system / Robert W. Baloh, Kevin A. Kerber. — 4th ed.
p. ; cm. — (Contemporary neurology series ; 77)
Includes bibliographical references and index.
ISBN 978-0-19-538783-4
1. Vestibular apparatus. 2. Vestibular function tests. 3. Neurophysiology. I. Kerber, Kevin A. II. Title. III. Series:
Contemporary neurology series, 77. 0069-9446 ;
[DNLM: 1. Vestibular Diseases—physiopathology. 2. Vestibular Function Tests. 3. Vestibule, Labyrinth—physiology. W1
CO769N v.77 2011 / WV 255 B195c 2011]
QP471.B34 2011
612.8’58—dc22
2010002663
The science of medicine is a rapidly changing field. As new research and clinical experience broaden our knowledge,
changes in treatment and drug therapy occur. The author and publisher of this work have checked with sources believed
to be reliable in their efforts to provide information that is accurate and complete, and in accordance with the standards
accepted at the time of publication. However, in light of the possibility of human error or changes in the practice of
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Foreword
Even the most experienced clinical neurologist may need to take a deep breath before attempting
to obtain a clear, crisp history from a patient whose chief complaint is “dizziness”. It is no secret
that people with neurological symptoms have widely varying conceptions of the meaning of this
word. In some patients, even providing hints or clues cannot induce the patient to express precisely
the feeling experienced. It may help to suggest key words such as “off-balance”, “spinning sensa-
tion”, “light-headedness”, and “faintness”. I have actually had the experience of running through a
long series of words to help guide the patient to express his symptoms precisely when, in response
to a hint from me, the patient informed me that he meant that he lost his vision briefly! Taking a
clear, precise history in a patient such as this is absolutely essential in order to determine whether
the problem might be peripheral or central. This will help greatly in focusing the neurological
examination and determining which diagnostic studies to request and how to manage the problem.
Even when the clinician determines that the problem is either peripheral or central, the list of
neurological disorders that might be responsible can be daunting. With all this in mind, it is a plea-
sure to welcome a new contribution to this interesting and challenging field in the fourth edition of
the classic book, Clinical Neurophysiology of the Vestibular System. Dr. Robert Baloh, a senior
clinician and renowned investigator famous for his seminal work on the interface between clinical
neurology and vestibular physiology, has been an author of all of the previous volumes. He is joined
in this new version of the book by Dr. Kevin Kerber, a brilliant young clinical neurologist trained
in both neurology and in clinical vestibular neurophysiology.
This edition of the book is divided into four parts: 1. Anatomy and Physiology of the Nervous
System, 2. Evaluation of the Dizzy Patient, 3. Diagnosis and Management of Common Neurotologic
Disorders, and 4. Symptomatic Treatment of Vertigo. The current volume has been completely
reorganized and expanded to cover advances over the past decade. This book includes newly
described molecular mechanisms of peripheral and central processing within the vestibular system.
There is a lucid, clinically practical review of the key features to assess in the clinical evaluation of
the patient to determine the site of the lesion. The discussion of the differential diagnosis of dizzi-
ness is clear and complete, and I found the description of bedside tests of vestibular function to be
practical and helpful. The clinical sections have been completely updated and expanded with an
emphasis on evidence-based medicine, but the book is informative even for the clinical scenarios
that are lacking in high-level evidence. The chapter on benign paroxysmal positional vertigo con-
tains guides to the latest treatment maneuvers. This book also contains a strategy for deciding on
which drugs to use for symptomatic control of vertigo and for designing a vestibular exercise pro-
gram. This extremely valuable contribution will be useful to clinical neurologists, otolaryngologists,
physiatrists, and general and emergency medicine physicians in practice as well as residents and
fellows in these specialties. This book is also a comprehensive basic science source for professionals
and trainees in vestibular neuroscience.
Sid Gilman, MD, FRCP
William J. Herdman Distinguished
University Professor of Neurology
Director, Michigan Alzheimer’s Disease Research Center
Department of Neurology
University of Michigan
Ann Arbor, MI
vii
Preface
The purpose of this book is to provide a framework for understanding the pathophysiology of dis-
eases involving the vestibular system. The book is divided into four parts: 1. Anatomy and physiol-
ogy of the nervous system, 2. Evaluation of the dizzy patient, 3. Diagnosis and management of
common neurotologic disorders, and 4. Symptomatic treatment of vertigo. Part 1 reviews the
anatomy and physiology of the vestibular system with emphasis on clinically relevant material.
Part 2 outlines the important features in the patient’s history, examination, and laboratory evalua-
tion that determine the probable site of lesion. Part 3 covers the differential diagnostic points that
help the clinician decide on the cause and treatment of the patient’s problem. Part 4 describes the
commonly used antivertiginous and antiemetic drugs and the rationale for vestibular exercises.
This completely reorganized and expanded fourth edition covers the rapid advances that have
occurred in the basic and clinical vestibular sciences in the past 10 years. Recent breakthroughs in
our understanding of the molecular mechanisms of peripheral transduction and central processing
within the vestibular system are reviewed. We discuss the differential diagnosis of dizziness of both
vestibular and nonvestibular etiology and demonstrate bedside tests of vestibular function. Videos
showing tests and important clinical findings are available online. The chapter on the laboratory
diagnosis of vestibular dysfunction has been expanded to include videonystagmography (VNG) and
vestibular evoked myogenic potentials (VEMPs). In Part 3, the chapter on benign paroxysmal posi-
tional vertigo includes all the latest treatment maneuvers. We emphasize controlled treatment
trials whenever available. In Part 4 we provide a strategy for deciding on which drugs to use for
symptomatic control of vertigo and for designing a vestibular exercise program for patients with
different types of vestibular lesions.
We believe that this book will be useful to all physicians who treat patients complaining of dizzi-
ness. It should be particularly helpful for those in the field of family practice, internal medicine,
neurology, head and neck surgery, and neurosurgery. We hope that it will encourage students (in
both the clinical and basic sciences) to choose neurotology as their field of study, or at least help
clinicians to enjoy the evaluation and management of patients with dizziness. Finally, we hope that
the information in this book can contribute to efforts to optimize the care of patients.
K. A. K.
R. W. B.
ix
Acknowledgments
Our students and colleagues in Neurology and Head and Neck Surgery provided inspiration. We
are grateful to the chairmen of our departments, John C. Mazziotta and David J. Fink, and the
major sponsors of our research (National Institutes of Health and Agency for Healthcare Research
and Quality) for their continued support. We would also like to thank Krister Brantberg, who pro-
vided helpful suggestions for the chapter on the clinical evaluation of hearing.
xi
Contents
PART 1 ANATOMY AND PHYSIOLOGY OF THE

NERVOUS SYSTEM
1. OVERVIEW OF VESTIBULAR ANATOMY AND PHYSIOLOGY 3
PERIPHERAL VESTIBULAR RECEPTORS 4

Hair Cells • The Macules • The Cristae • Basis of Stimulus Specificity of the Inner Ear
Receptor Organs
CENTRAL VESTIBULAR PATHWAYS 11

Vestibular Nuclei
VESTIBULAR REFLEXES 12
Horizontal Canal-Ocular Reflex • Nystagmus • Translational Vestibulo-Ocular Reflexes •
The Ocular Tilt Reflex • Vestibulospinal Reflexes • Vestibulo-Autonomic Reflexes
MOTION PERCEPTION AND ORIENTATION 19

PATHOPHYSIOLOGY OF VESTIBULAR SYMPTOMS 20
CENTRAL COMPENSATION FOR VESTIBULAR LESIONS 21
SUMMARY 22
2. THE PERIPHERAL VESTIBULAR SYSTEM 25
TEMPORAL BONE 25
Tympanic Membrane • Middle Ear • Facial Nerve
INNER EAR (LABYRINTH) 29

Phylogeny • Structure • Fluid Dynamics • Fluid Chemistry • Blood Supply • Innervation •
Embryonic Development
THE HAIR CELL 39

Morphologic Characteristics • Sequence of Hair Cell Activation • Relationship between the
Direction of Force and Hair Cell Activation • Mechanism of Hair Cell Activation • Hair Cell
Influence on Afferent Nerve Activity • Signal Processing at the Hair Cell/Afferent Nerve Junction
THE INNER EAR VESTIBULAR RECEPTORS 43

Anatomy of the Semicircular Canals • Physiology of the Semicircular Canals • Anatomy of Otolith
Organs • Physiology of the Otolith Organs
xiii
xiv Contents
PRIMARY VESTIBULAR NEURONS 49

Anatomy of Primary Neurons • Physiology of Primary Neurons
EFFERENT VESTIBULAR NEURONS 56
3. THE CENTRAL VESTIBULAR SYSTEM 63
VESTIBULAR NUCLEI 63
Phylogeny • Anatomy • Neurotransmitters • Physiology
VESTIBULO-OCULAR REFLEXES 72
Overview • Rotational Vestibulo-Ocular Reflexes • Translational Vestibulo-Ocular Reflexes •
Ocular Counterrolling • Semicircular Canal-Otolith Interaction
CERVICO-OCULAR REFLEXES 86
Anatomic and Physiologic Basis • Characteristics of Neck-Induced Eye Movements
VISUAL–VESTIBULAR INTERACTION 89
Visual Tracking Eye Movements • Organization of Visually Guided Tracking Eye
Movements • Comparison of Vestibular- and Visual-Induced Eye Movements • Visuo-Vestibulo-
Ocular Connections • Model of Visual-Vestibular Interaction • Adaptive Modification of the
Vestibulo-Ocular Reflex with Vision • Cellular Basis for Visual Vestibular Interaction
VESTIBULOSPINAL REFLEXES 97
Comparison of Ocular and Spinal Vestibular Reflexes • Vestibulospinal Connections •
Cerebellar–Vestibular Interaction • Vestibulo-Collic Reflexes • Cellular Mechanisms
SUBJECTIVE VESTIBULAR SENSATION 102

Vestibulothalamocortical Connections • Response Properties of Thalamic Relay Neurons •
Response Properties of Vestibular Cortex Neurons • Functional Brain Imaging in Normal Human
Subjects • Lesions of the Vestibulocortical Pathways in Patients • Psychophysical Studies
PART 2 EVALUATION OF THE DIZZY PATIENT
4. EPIDEMIOLOGY OF DIZZINESS 121
SPECIFIC DISORDERS 123

BURDEN ON PATIENTS 124
HEALTH CARE UTILIZATION 125
SUMMARY 125
5. THE HISTORY OF THE DIZZY PATIENT 127
VERTIGO 128
Central versus Peripheral Causes • Time Course • Precipitating Factors • Associated
Symptoms • Compensation • Predisposing Factors • Family History • Diagnosis and Management
Contents xv
NEAR-FAINT DIZZINESS 132

Orthostatic Hypotension • Postural Tachycardia Syndrome (POTS) • Vasovagal
Attacks • Hyperventilation
PSYCHOPHYSIOLOGIC DIZZINESS (CHRONIC SUBJECTIVE DIZZINESS) 134

Panic Disorder • Phobic Dizziness • Chronic Anxiety • Pathophysiology • Diagnosis and
Management
DRUG-INDUCED DIZZINESS 137

HYPOGLYCEMIA 138
DISEQUILIBRIUM 138
Common Causes • Gait Disorders in Older People • Falls in Older People •
Diagnosis and Management
OCULAR DIZZINESS 140

Common Causes • Oscillopsia • Management
MULTISENSORY DIZZINESS 142

Management
PHYSIOLOGIC DIZZINESS 142

Motion Sickness • Space Sickness • Height Vertigo • Mal de Debarquement Syndrome
SUMMARY: DISTINGUISHING BETWEEN VESTIBULAR AND

NONVESTIBULAR TYPES OF DIZZINESS 144
6. BEDSIDE EXAMINATION OF THE VESTIBULAR SYSTEM 149
EXAMINATION OF THE EAR 149

Fistula Test
TESTS OF VESTIBULOSPINAL REFLEXES 151

Pastpointing • Static Posture • Walking Tests
TESTS OF VESTIBULO-OCULAR REFLEXES 153

Doll’s Eye Test (Oculocephalic Response) • Head-Thrust Test • Dynamic Visual Acuity •
Cold Caloric Test • Rotational Testing
TESTS FOR PATHOLOGIC NYSTAGMUS 156

Methods of Examination
TYPES OF PATHOLOGIC NYSTAGMUS 158

Spontaneous Nystagmus • Gaze-Evoked Nystagmus • Positional Nystagmus •
Vibration-Induced Nystagmus • Head-Shaking Nystagmus • Hyperventilation-Induced
Nystagmus
xvi Contents
OTHER OCULAR OSCILLATIONS 165

Dissociated Spontaneous Nystagmus • Voluntary Ocular Oscillations (Voluntary
Nystagmus) • Convergence Retraction Nystagmus • Saccadic Intrusions • Ocular
Bobbing • Palato-Ocular Myoclonus
OCULAR TILT REACTION 166
7. LABORATORY EXAMINATION OF THE VESTIBULAR SYSTEM 171
NYSTAGMOGRAPHY 171
Methods of Recording Eye Movements • Interpreting the Recording • Recording Pathologic
Nystagmus • Bithermal Caloric Test • Tests of Visual-Ocular Control
ROTATIONAL TESTING OF VESTIBULO-OCULAR REFLEXES 189

Relationship between Stimulus and Response • Results in Normal Subjects • Results in Patients
VISUAL-VESTIBULAR INTERACTION 204

Methodology • Results in Normal Subjects • Results in Patients
TESTS OF OTOLITH-OCULAR REFLEXES 207

Ocular Counterrolling • Eccentric Rotation • Off-Vertical Rotation • Linear Acceleration
VESTIBULOSPINAL TESTING 208

Static-Force Platforms • Moving-Platform Posturography
VESTIBULAR-EVOKED POTENTIALS 209

Brain Stem and Cortical • Vestibular Evoked Myogenic Potentials (VEMPs)
8. CLINICAL EVALUATION OF HEARING 219
TYPES OF HEARING DISORDERS 219

Conductive • Sensorineural • Central Hearing Disorders
BEDSIDE TESTS OF HEARING 220

BEHAVIORAL AUDIOMETRY 221
The Audiogram • Speech Recognition Tests • Stenger Test
IMPEDANCE AUDIOMETRY 223

TYMPANOMETRY 224
The Acoustic Reflex
AUDITORY-EVOKED RESPONSES 225

Electrocochleography • Brainstem Auditory-Evoked Response
GENERATING POTENTIALS 226

TEST METHODOLOGY 227
Contents xvii
RESULTS IN PATIENTS 227

CENTRAL AUDITORY SPEECH TESTS 228
SUMMARY OF AUDITORY TEST RESULTS 229
PART 3 DIAGNOSIS AND MANAGEMENT OF COMMON

NEUROTOLOGIC DISORDERS
9. INFECTIOUS DISEASES 233
ACUTE OTITIS MEDIA AND OTOMASTOIDITIS 233

CHRONIC MASTOIDITIS AND CHOLESTEATOMA 235

Diagnosis • Management
BACTERIAL LABYRINTHITIS 236

PETROSITIS 237
INTRACRANIAL EXTENSION OF EAR INFECTIONS 238

Routes of Spread • Meningitis • Epidural Abscess • Lateral Sinus Thrombophlebitis •
Brain Abscess • Otitic Hydrocephalus • Diagnosis • Management
MALIGNANT EXTERNAL OTITIS 241

VIRAL INFECTIONS OF THE INNER EAR 242

Clinical Syndromes • Diagnosis • Viral versus Other Causes of Peripheral Cochleovestibular
Loss • Management
SYPHILITIC INFECTIONS OF THE EAR 248

TUBERCULOSIS AND MYCOTIC INFECTIONS OF THE INNER EAR 249

Tuberculous Mastoiditis • Mycotic Mastoiditis • Basilar Meningitis
10. BENIGN POSITIONAL VERTIGO 255
HISTORICAL BACKGROUND 255

CAUSES OF BENIGN POSITIONAL VERTIGO 257
POSTERIOR CANAL VARIANT OF BENIGN POSITIONAL VERTIGO 258
Clinical Features • Pathophysiology • Diagnosis • Management
xviii Contents
OTHER VARIANTS OF BENIGN POSITIONAL VERTIGO 265

Horizontal Canal Benign Positional Vertigo • Anterior Canal Benign Positional Vertigo •
Mimics of Benign Positional Vertigo
11. ENDOLYMPHATIC HYDROPS (MENIERE’S SYNDROME) 273
BACKGROUND 273
OCCURRENCE 274
CLINICAL FEATURES 275
PATHOPHYSIOLOGY 275
ANIMAL MODELS 277
ETIOLOGY 277
Genetics • Migraine and Meniere’s Syndrome • Infection/Autoimmune
DIAGNOSIS 278
Audiometric Testing • Vestibular Testing • Imaging
MANAGEMENT 280
Medical Managment • Surgical Managment
12. MIGRAINE 287
BACKGROUND 287
CLINICAL FEATURES 288
Migraine without Aura • Migraine with Aura • Migrainous Vertigo • Basilar Migraine •
Migraine and Meniere’s Syndrome • Migraine Equivalents
PATHOPHYSIOLOGY 292
Genetics • Spreading Wave of Depression • Vasomotor Abnormalities
DIAGNOSIS 295
Migraine without Aura • Migraine with Aura • Migraine Aura without Headache • Basilar
Migraine • Migrainous Vertigo
MANAGEMENT 297
Symptomatic and Abortive Treatment • Prophylactic Treatment
13. IMMUNE-MEDIATED DISEASES 303
AUTOIMMUNE INNER EAR DISEASE 303

Background • Pathophysiology • Clinical Features • Diagnosis • Management
PARANEOPLASTIC IMMUNE DISORDERS 309

Contents xix
MULTIPLE SCLEROSIS 312

14. VASCULAR DISORDERS 319
VERTEBROBASILAR ISCHEMIA 319

Pathophysiology • Transient Ischemic Attacks (TIAs) • Stroke
Syndromes • Diagnosis • Treatment
INTRALABYRINTHINE HEMORRHAGE 332

HEMORRHAGE INTO THE BRAIN STEM AND CEREBELLUM 332

VASCULAR COMPRESSION SYNDROMES 334

Vertebrobasilar Doliochoectasia • Vascular Compression by Normal Vessels (Vestibular
Paroxysmia) • Rotational Vertebral Artery Syndrome
15. TUMORS 339
TUMORS OF THE MIDDLE EAR AND TEMPORAL BONE 339

Malignant Tumors • Glomus Body Tumors (Paragangliomas) • Diagnosis • Management
TUMORS OF THE INTERNAL AUDITORY CANAL AND CEREBELLOPONTINE

ANGLE 341
Schwannomas • Meningiomas • Epidermoid Cysts (Primary Cholesteatomas) • Cholesterol
Granulomas • Metastatic Tumors • Diagnosis • Management
BRAIN TUMORS 347

Brain Stem • Fourth Ventricle • Cerebellum • Diagnosis and Management
16. TRAUMA 353
TRAUMA TO THE TEMPORAL BONE 353

Fracture • Labyrinthine Concussion • Posttraumatic Positional
Vertigo • Diagnosis • Management
PERILYMPH FISTULA 356

Pathophysiology • Diagnosis • Management
SEMICIRCULAR CANAL DEHISCENCE SYNDROME 358

Pathophysiology • Diagnosis • Management
BRAIN TRAUMA 360

Intracranial Complications Associated with Temporal Bone Fractures • Dizziness Due to Brainstem
Trauma • Postconcussion Syndrome • Whiplash Injuries • Diagnosis • Management
xx Contents
17. TOXIC/METABOLIC DISORDERS 367
DIZZINESS AND SYSTEMIC METABOLIC DISORDERS 367

Diabetes Mellitus • Uremia • Hypothyroidism • Alcohol and Thiamine Deficiency • Management
METABOLIC DISORDERS OF THE TEMPORAL BONE 371

Otosclerosis • Paget’s Disease • Other Disorders • Diagnosis • Management
OTOTOXINS 374
Aminoglycosides • “Loop” Diuretics • Anti-inflammatory Drugs • Platinum
Compounds • Diagnosis • Management
NEUROTOXINS 377
Heavy Metals • Organic Solvents • Diagnosis • Management
18. DEVELOPMENTAL AND GENETIC DISORDERS 383
THE INNER EAR 383

Acquired Disorders • Hereditary Disorders • Pathology • Diagnosis • Management
DISORDERS OF THE CRANIAL VERTEBRAL JUNCTION 390

Basilar Impression • Bony Fusions • Atlantoaxial Dislocation • Chiari
Malformation • Syringobulbia • Diagnosis • Management
INHERITED SPINOCEREBELLAR ATAXIA SYNDROMES 393

Autosomal Dominant Spinocerebellar Ataxia Syndromes • Autosomal Recessive Spinocerebellar
Ataxia Syndromes • Episodic Ataxia and Vertigo Syndromes • Diagnosis • Management
PART 4 SYMPTOMATIC TREATMENT OF VERTIGO
19. ANTIEMETIC AND ANTIVERTIGO DRUGS 405
VESTIBULAR SUPPRESSANTS 407

How Do They Work? • How to Use Them • Indications • Precautions • What to Tell the Patient
ANTIEMETIC DRUGS 410

How Do They Work? • How to Use Them • Precautions • What to Tell the Patient
SPECIFIC DRUGS 413

Scopolamine (Transderm Sco− p) • Buclizine Hydrochloride (Bucladin-S) • Diphenhydramine
Hydrochloride (Benadryl) • Meclizine (Antivert, Bonine) • Dimenhydrinate
(Dramamine) • Promethazine Hydrochloride (Phenergan) • Betahistine (Serc) • Metaclopramide
(Reglan) • Benzquinamide Hydrochloride (Emete-con) • Trimethobenzamide Hydrochloride
(Tigan) • Diazepam (Valium) • Droperidol (Inapsine) • Diphenidol (Vontrol) • Prochlorperazine
(Compazine) • Dronabinol (Marinol)
Contents xxi
20. VESTIBULAR REHABILITATION 419
ADAPTIVE CONTROL OF NORMAL VESTIBULAR REFLEXES 420

MECHANISMS FOR COMPENSATION AFTER VESTIBULAR LOSS 420
SPECIAL CIRCUMSTANCES 421
Vestibular Loss in Children • Vestibular Loss in the Elderly • Failure of Compensation
CONTROLLED TRIALS OF VESTIBULAR EXERCISES 422

STRATEGY FOR DESIGNING VESTIBULAR EXERCISES 423
Unilateral Vestibular Lesions • Bilateral Vestibular Lesions • Central Vestibular Lesions
VESTIBULAR EXERCISES 425

FUTURE DIRECTIONS 426
APPENDIX 20-1. SAMPLE HOME EXERCISE PROGRAM 428
Head-Turning Practice • Walking Practice • Other Exercises • Dizziness Exercises
21. FUTURE DIRECTIONS 431
VIDEO LEGENDS 433
INDEX 435
PART 1
Anatomy and Physiology of the

Nervous System
Chapter 1
Overview of Vestibular Anatomy

and Physiology
PERIPHERAL VESTIBULAR RECEPTORS Translational Vestibulo-Ocular Reflexes

Hair Cells The Ocular Tilt Reflex
The Macules Vestibulospinal Reflexes
The Cristae Vestibulo-Autonomic Reflexes
Basis of Stimulus Specificity of the Inner Ear MOTION PERCEPTION AND
Receptor Organs ORIENTATION
CENTRAL VESTIBULAR PATHWAYS PATHOPHYSIOLOGY OF VESTIBULAR
Vestibular Nuclei SYMPTOMS
VESTIBULAR REFLEXES CENTRAL COMPENSATION FOR
Horizontal Canal-Ocular Reflex VESTIBULAR LESIONS
Nystagmus SUMMARY
The vestibular system like other sensory most comprehensive clinical and basic science
systems (i.e, auditory, visual, olfactory, gusta- medical textbooks.
tory, and somatosensory) serves the basic func- The vestibular system has a “behind the
tion of translating environmental information scenes” role of maintaining spatial orientation
into biological signals. However, unlike other and driving reflexes that stabilize vision and
sensory systems there is usually no conscious balance. To do this, it transforms forces associ-
awareness of it during routine activities when ated with head acceleration and gravity into
the system is functioning normally. In fact, the biological signals that travel directly to motor
inner ear vestibular receptors were not even centers for postural and ocular stability and to
recognized until the seminal work of Prosper the cortex to aid in orientation. When the sys-
Meniere in the mid 1800s.1 Meniere worked in tem functions normally, you have no awareness
a deaf-mute institute and noticed that many of of these ongoing activities. Unlike the ability to
his patients with hearing loss also had vertigo. appreciate visual, olfactory, or auditory stimuli,
Prior to Meniere, vertigo—the most common you do not appreciate the function of the ves-
symptom of vestibular dysfunction—was con- tibular system until something goes awry.
sidered a cerebral symptom, similar to epilep- This is not to say that you cannot perceive
tic seizures. The semicircular canals had been motion. The vestibular system projects to many
identified but were considered to be part of the areas of the cerebral cortex but unlike other
hearing apparatus. Meniere’s notion that ver- sensory systems there is no primary vestibular
tigo could result from damage to the inner ear cortex that only receives vestibular signals. All
was met with great scepticism. The vestibular cortical neurons that receive vestibular signals
system continues to be underappreciated in also receive other sensory signals, particularly
3
4 Clinical Neurophysiology of the Vestibular System
visual and somatosensory. It is not possible to to diagnose and treat vestibular system disorders.
determine which signal is responsible for the In this overview chapter, we provide the most
perceived motion. salient information regarding the vestibular
An acute malfunction of the vestibular system. An overview chapter is important
system causes a profound inability to function, because it rapidly and succinctly presents the
leaving one completely disabled because of essential elements that can be periodically
severe spatial disorientation, imbalance, nau- revisited. Whenever appropriate the reader is
sea, and vomiting during the most intense peri- referred to later sections where the material is
ods. These are some of the most bizarre and described in more detail.
incapacitating symptoms in all of medicine.
The patient simply cannot navigate the envi-
ronment because, to the patient, the world is
moving as though he is on an unremitting car- PERIPHERAL VESTIBULAR
nival ride. Interestingly, however, a chronic RECEPTORS
lesion—even a bilateral loss of function—leads
to relatively little disability in most patients The role of the inner ear vestibular receptors in
affected by it. In fact, many patients with a maintaining orientation has remained the same
bilateral vestibular loss probably go undiag- from the earliest organisms in the animal king-
nosed because of few or mild symptoms that dom.2 A primitive gravity-detection organ, the
either do not lead to a medical evaluation or statocyst, appeared more than 600 million years
are not recognized by physicians. As opposed ago in some bygastrulated animals such as jel-
to gradual hearing loss or visual loss, a gradual lyfish, allowing the animal to regulate its static
vestibular loss can go virtually unnoticed. position in space (see Fig. 2–5 in Chapter 2).
Vestibular symptoms pose a great deal of With the advent of modern fish (about 100 mil-
difficulty in clinical medicine. First, patients lion years ago), the vestibular labyrinth reached
suffering vestibular symptoms often have diffi- its peak of development, and relatively little
culty describing the symptoms. Many patients change has taken place since that time. The
with a vestibular disturbance will simply report basic structure of the three semicircular canals,
“dizziness”—a nonspecific term that can refer the utricle, and the saccule is similar in all
to symptoms stemming from cardiac distur- higher vertebrates. The membranous laby-
bances, a psychological disorder, medication rinths of modern fish lie in the bony chamber
side effects, or many other disturbances. Second, of the skull directly behind the orbits. In its
there is much overlap among the symptoms and subsequent evolution in amphibians, birds, and
signs of vestibular disorders, and discriminating mammals, the membranous labyrinth is com-
among vestibular lesions depends on appreciat- pletely surrounded by a bony labyrinth enclos-
ing rather subtle differences in how the eyes are ing the periotic space. This space is filled with
moving. In fact, most of the examination of the perilymphatic fluid and suspensory connective
vestibular system involves observing eye move- tissue acting as a shock absorber. The relative
ments since the vestibular structures cannot be positions of the planes of the three semicircu-
visualized at the bedside and the most recogniz- lar canals vary from species to species, although
able functions of the vestibular system are in primates they are approximately orthogonal
manifest by the vestibulo-ocular reflex. Most to each other. The shape of each semicircular
physicians can recognize nystagmus—a hall- canal also varies considerably from that of a tri-
mark movement of the eyes reflecting vestibu- angle in reptiles to an ellipse in birds to an
lar function – but most physicians do not appre- almost true circle in mammals.2
ciate that characterizing the pattern of
nystagmus can discriminate a benign disorder
from a life-threatening disorder. Physicians typ- Hair Cells
ically have little training in the basic science and
clinical evaluation of the vestibular system, and The basic element of the labyrinthine receptor
this in turn results in overuse of tests, misdiag- organs that transduces mechanical force to
nosis, and underuse of effective treatments. nerve action potentials is the hair cell. Already
The purpose of this book, then, is to provide developed in the statocysts of invertebrates,
the basic science and clinical training needed this specialized sensory cell becomes more
1 Overview of Vestibular Anatomy and Physiology 5
sophisticated in mammals.2 Transducer cells of the stereocilia increases stepwise from one
are surrounded by supporting cells in special- side to the other, and next to the tallest stereo-
ized areas in the walls of the sensory epithe- cilia a thicker, longer cilia, the kinocilia,
lium. Two types of hair cells occur in birds and protrudes from the cell’s cytoplasm through a
mammals (Fig. 1–1). Type II cells are cylindri- segment of the cell membrane lacking a cuticu-
cal, with multiple nerve terminals at their base, lar plate. The tips of the cilia are connected by
whereas type I are globular or flask shaped, tip-links that open and close mechanosensory
with a single large, chalice-like nerve terminal channels (Fig. 1–1; also see Fig. 2–12 in
surrounding the base. A bundle of nonmobile Chapter 2).3
stereocilia protrudes from the cuticular plate The adequate stimulus for hair cell activation
on the apical end of each hair cell. The height is a force acting parallel to the top of the cell,
N
TIO
IBI
INH
N
IO
AT
X CIT
E
Tip links
Cilia
Kinocilium
Shaft links
Ankle Links
Cuticular plate
Supporting cell
Mitochondria
Efferent
I II
bouton
Ribbon
Synapses
Calyx
Afferent
bouton
Figure 1–1. Schematic drawing of the two types of hair cells. Inset illustrates relationship between the direction of force
and maximum hair cell activation.
resulting in bending of the cilia (a shearing the saccule. Each cavity contains a separate
force).4 Force applied perpendicular to the cell macule.9 In the saccule, the macule is located
surface (a compressional force) is ineffective in on the medial wall in the sagittal plane; in the
stimulating the hair cell. The stimulus is maxi- utricle, the macule is mostly in the horizontal
mum when the force is directed along an axis plane next to the opening of the horizontal
that bisects the bundle of stereocilia and goes semicircular canal (Fig. 1–3C). The surfaces of
through the kinocilium (Fig. 1–1, insert). the utricular and saccular macules are covered
Deflection of the cilia toward the kinocilium by the otolithic membrane, a structure consist-
opens the mechanosensory channels at the tips ing of a mesh of fibers embedded in a gel with
causing an influx of potassium and depolariza- a superficial layer of calcium carbonate crys-
tion of the resting membrane potential.5 This tals, the otoconia (Fig. 1–3A).10 The stereocilia
opens voltage-gated calcium channels at the of the macular hair cells protrude into the oto-
base and releases neurotransmitter (mostly glu- lithic membrane. The striola, a distinctive
tamate) activating the afferent nerve terminals. curved zone running through the center,
Bending of the cilia in the opposite direction divides each macule into two parts. The hair
produces the reverse effect (closing of the cells on each side of the striola are oriented so
channels and hyperpolarization of the hair that the kinocilia are in opposite directions (as
cells). indicated by the arrows in Fig. 1–3C). In the
Much of the basic information regarding the utricle, the kinocilia face the striola, and in
physiological properties of hair cells and their the saccule, they face away from it. Because of
afferent nerves has been obtained through the the different orientation, displacement of the
study of hair cell systems in nonmammalian spe- otolithic membrane has an opposite effect on
cies. Analysis of the lateral line organs of amphib- the set of hair cells on each side of the striola.
ians and fish has been particularly informative.6 The density of the otolithic membrane over-
The organs consist of groups of hair cells, the lying the hair cells of the macules is much
neuromasts, aligned in longitudinal rows on the greater than that of the surrounding endo-
side of the animal’s body and head. A free- lymph, owing to the presence of the calcium
standing gelatinous cupula covering the cilia carbonate crystals. The weight of this mem-
transmits the force associated with water dis- brane produces a shearing force on the under-
placement into hair cell deflection, which in lying hair cells that is proportional to the sine of
turn results in change in firing rate of the affer- the angle between the line of gravitational force
ent nerve. A key observation that has been and a line perpendicular to the plane of the
confirmed in all other hair cell systems is a con- macule (Fig. 1–3B). During linear head accel-
tinuous spontaneous activity of the afferent eration tangential to the surface of the recep-
nerves.7 A small percentage of the mechano- tor, the force acting on the hair cells is the
sensory channels remains open at rest, leading result of the two forces: one in the opposite
to the spontaneous afferent nerve discharge. direction of the head displacement and the
Depolarization and hyperpolarization of the hair other in the direction of gravitational pull.
cells’ membrane potential result in modulation Recordings of afferent neuronal activity from
of this spontaneous activity (Fig. 1–2). Bending the macules of primates confirm that the utric-
of the cilia toward the kinocilium increases the ular and saccular macules are responsive to
spontaneous activity, and bending of the cilia static tilt and dynamic linear acceleration forces
away from the kinocilium results in a decrease. (see Fig. 3–6 in Chapter 3).11
The spontaneous firing rate varies among differ-
ent animal species and among different sensory
receptors. It is thought to be highest in the The Cristae
afferent neurons of the semicircular canals of
mammals (up to 90 spikes per second).8 The cristae are the receptor organs of the semi-
circular canals. The semicircular canals are
aligned to form a coordinate system.12 The hor-
The Macules izontal canal makes a 30-degree angle with the
horizontal plane, and the vertical canals make
The membranous labyrinth forms two globular 45-degree angles with the frontal plane
cavities within the vestibule: the utricle and (Fig. 1–4C). At the anterior opening of the
Kc Kc
II
I
PRIMARY AFFERENT
FIRING RATE
Efferent Afferent
nerve nerves
100 msec
Figure 1–2. Hair cell modulation of spontaneous afferent nerve firing rate. Bending of the stereocilia toward the
kinocilium depolarizes the hair cell and increases the firing rate, and bending away from the kinocilium hyperpolarizes the
hair cell and decreases the firing rate. Kc – kinocilium.
horizontal and anterior semicircular canals and The hair cells in each crista are oriented with
the inferior opening of the posterior canal, each their kinocilia in the same direction. In the
tube enlarges to form the ampulla. The crista, horizontal canal, however, the kinocilia are
the sensory epithelium composed of hair cells directed toward the utricular side of the
and supporting cells, crosses each ampulla in a ampulla, whereas in the vertical canals the
direction perpendicular to the longitudinal axis kinocilia are directed toward the canal side of
of the canal (Fig. 1–4A).9 Hair cells are located the ampulla. This difference in morphological
on the surface of the crista, with the cilia pro- polarization explains the difference in direc-
truding into the cupula, a gelatinous mass that tional sensitivity between horizontal and verti-
extends from the surface of the crista to the cal canals.13 The afferent nerve fibers of the
ceiling of the ampulla, forming a watertight horizontal canals increase their baseline firing
seal. when endolymph moves toward the utricle and
(a)
(b)
Striola Kc Static tilt Otolith
Otoconia displacement
Gelatin layer
Reticular
membrane Gravitational
force
Supporting
cells
Hair cells
sal
Dor
(c)
Saccular
macule
An
ter
ior
Striola
Utricular
macule
l
era
Lat
Figure 1–3. The macule: (a) anatomy, (b) mechanism of hair cell activation with static tilt, and (c) orientation of saccular
and utricular macules. Arrows indicate the direction that the kinocilia point toward. (Adapted from Barber HO, Stockwell
CW. Manual of Electronystagmography. CV Mosby, St. Louis, 1976.)
ampulla (ampullopetal flow), but the afferent the cupula according to the pendulum model
nerves of the vertical canals increase their base- (see Chapter 2).
line firing rate with endolymph flow away from Precise measurements of primary afferent
the ampulla (ampullofugal flow). nerve activity originating from the cristae of
Since the cupula has the same specific grav- animals during physiological rotatory stimula-
ity as the surrounding endolymph, it is not tion reveal that the change in frequency of
subject to displacement by changes in the line action potentials is approximately proportional
of gravitational force. The forces associated to the deviation of the cupula as predicted by
with angular head acceleration displace the the pendulum model.8 For example, during
cupula and bend the hair cells of the crista, sinusoidal head rotation in the plane of a semi-
however. The motion of the cupula can be lik- circular canal, a sinusoidal change in firing fre-
ened to that of a pendulum in a viscous quency is superimposed on the rather high rest-
medium.14,15 Sudden displacement of the cup- ing discharge (about 90 spikes per second in the
ula by a step change in angular velocity is fol- squirrel monkey). The peak firing rate occurs at
lowed by a gradual exponential return of the the time of maximum cupular displacement,
cupula to its baseline position (Fig. 1–5). The which occurs at the time of peak angular head
rate of return (time constant, Tc) is determined velocity. With small-amplitude sinusoidal rota-
by the ratio of the viscous drag coefficient of tion, the modulation is almost symmetrical
the endolymph to the elasticity coefficient of about the baseline firing rate. For larger
(a) Cupula (b) Cupula

displacement Relative
Ampulla
endolymph
Utricular flow
sac of
macule Angular
acceleration
Semicircular
Supporting Hair cells canal
cells
(c)
Left and
right HC
30°
Right AC
Left PC
Right PC
Left AC
Figure 1–4. The crista: (a) anatomy, (b) mechanism of hair cell activation with angular acceleration, and (c) orientation of the
semicircular canals within the head. AC, anterior canal; HC, horizontal canal; PC, posterior canal.
Slow phase velocity (deg/sec)
100
50
0
0 10 20 30 40 50
Time (seconds)
Figure 1–5. Rate of return of the cupula to its initial position after a step change in angular velocity (thin solid line) and
rate of decay in nystagmus slow phase velocity after the same step change in angular velocity (each blue dot represents a
single beat of nystagmus). Note that the nystagmus outlasts the cupular deviation (and afferent nerve activity) due to central
velocity storage.
stimulus amplitudes, the response becomes of Corti. Covering the organ of Corti and rest-
increasingly asymmetrical. The excitatory ing over the hair cells is the tectorial mem-
responses can increase to more than 400 spikes brane, a relatively rigid structure attached to
per second in proportion to stimulus magni- the wall of the cochlea. A small, acoustically
tude, whereas the growth of inhibitory response induced pressure difference across the basilar
is limited to the disappearance of spontaneous membrane causes the organ of Corti and hair
activity. This asymmetry in afferent nerve cells to vibrate at the frequency of sound. The
response partially explains the presence of a motion of the basilar membrane has a different
positive head thrust sign in patients with only effect on the outer hair cells than on the inner.
one functioning labyrinth (see Chapter 6). Outer hair cells have their cilia embedded in
the tectorial membrane and are directly stimu-
lated as the cilia are displaced in relation to the
Basis of Stimulus Specificity of the relatively fixed tectorial membrane, which acts
Inner Ear Receptor Organs as a hinge.16 In contrast, the inner hair cell
cilia are not embedded in the tectorial mem-
The inner ear receptors all work on the same brane but are instead surrounded by endo-
basic principal: activation of hair cells by an lymph. Their stimulation is produced by the
applied external force. The density of the oto- dragging viscous force of the fluid on the
lithic membrane overlying the hair cells of the cilia. Intracellular recordings in mammalian
macule is greater than that of the surrounding cochlear hair cells show a difference of phase
endolymph. The hair cell cilia are embedded in between the receptor potentials of the inner
the otolithic membrane and, when displaced, and outer hair cells as predicted by the
produce a shearing force (Ft) on the underlying difference in the coupling of the cilia to the
hair cells that is proportional to the sine of the tectorial membrane.17 The outer hair cells
angle between the line of resulting gravitational respond to position and the inner hair
vector and a line perpendicular to the plane cells respond to the velocity of the basilar
of the macule. Each macule is bisected by a membrane motion.
distinctive curved zone, the striola. Hair cells In all cases, the effective stimulus to the sen-
are oriented in opposite directions on each side sory cells is the relative displacement of the
of the striola so that displacement of the oto- cilia produced by application of mechanical
lithic membrane has an opposite effect on the force to their surroundings. Since the mechan-
set of hair cells on each side of the striola (see ical properties of the “supporting and coupling”
Fig. 1–3C). structures are different, the frequency ranges
The hair cell cilia in the cristae of the semi- at which the cilia can be moved by the applied
circular canals are embedded in the cupula, a force are different. Because of the great flexi-
jelly-like substance of the same specific gravity bility of the basilar membrane, the range of
as that of the surrounding fluids. The cupula, sound frequencies to which the hair cells in
therefore, does not exert a force on the under- the cochlea are sensitive varies from 20 to
lying crista and is not subject to displacement 20,000 Hz. In the macules, the otoconia are
by changes in the line of gravitational force. maximally displaced during constant accelera-
The forces associated with angular head accel- tions such as those associated with steady head
eration, however, do result in a displacement displacement. Owing to the characteristics of
of the cupula that stimulates the hair cells of the restraining viscoelastic forces holding the
the crista in the same way that displacement of otoliths to the macule, their motion rapidly
the otoliths stimulates the macular hair cells diminishes if the linear acceleration changes at
(Fig. 1–4B). However, in the cristae, all the a frequency >0.5 Hz.18 The semicircular canals
hair cells are oriented in the same direction in also respond maximally to constant angular
the crista surface. All hair cells are either acceleration, but they can respond to changes
excited or inhibited by motion of the fluid in in angular acceleration as high as 40 to 50 Hz.19
the canal, but the orientation is different in dif- This frequency limitation is due to the inertial
ferent semicircular canals. and viscous forces restraining the displacement
In the cochlea, the hair cells are mounted of fluid and cupula in the narrow semicircular
on the flexible basilar membrane in the organ canals.
CENTRAL VESTIBULAR PATHWAYS vertebrates.25,26 This complexity accompanies

the development of other afferent systems for
Parallel to the separation of receptor organs, the maintenance of equilibrium (vision, prop-
afferent nerve fibers differentiate into bundles rioception) and pathways for interaction of
that maintain independent identity in the inter- these systems with the vestibular system.
nal auditory canal and at the entrance to the
brain stem.20 The afferent nerve from the utricle
and horizontal and anterior semicircular canals Vestibular Nuclei
and some of the nerve fibers from the saccule
form the superior division of the vestibular The central processes of the primary vestibular
nerve; most nerve fibers from the saccule and neurons divide into an ascending and descend-
the nerve from the posterior semicircular canal ing branch after entering the brain stem at the
contribute to the inferior branch (Fig. 1–6). The inner aspect of the restiform body (see Fig. 3–1
afferent fibers from the auditory organ form a in Chapter 3). The ascending branch ends
separate nerve anterior and inferior to the ves- either in the rostral end of the vestibular nuclei
tibular nerve to innervate the organ of Corti, the or in the cerebellum, and the descending
auditory receptor organ. Together these two branch ends in the caudal vestibular nuclei.
nerves constitute the eighth cranial nerve and, None of the primary afferents cross the mid-
within them, a system of efferent fibers from line. Four distinct anatomical groups of neu-
the central nervous system (CNS) gates or mod- rons have traditionally been identified: medial,
ulates the activity of the peripheral organs.21–23 lateral, superior, and inferior nuclei (Fig. 1–7).27
Phylogenetically, this neural feedback system is Canal and otolith signals converge on most sec-
already present in gastropods, in which action ondary neurons that receive primary afferent
potentials directed from the brain to the recep- input (Fig. 1–7C). Major connections run to
tors have been recorded.24 and from the cerebellum, particularly the so-
In comparison with the vestibular sensory called vestibulocerebellum (uvula, nodulus, and
organs, central vestibular connections flocculonodular lobes) (Fig. 1–7E). The two
become progressively more complex in higher sides are connected by reciprocal commissural
Vestibular nerve
superior division
inferior division
Nerve from
anterior Scarpa’s
canal ganglion
Facial nerve
Utricular
nerve
Auditory nerve
Internal
auditory canal
Nerve from
horizontal canal
Nerve from posterior canal

Round window Cochlea
Saccular
nerves Spiral ganglion
Figure 1–6. Innervation of the labyrinth.
(A) Afferent inputs to the (B) Efferent outputs from the

vestibular nuclei vestibular nuclei
Visual inputs Thalamus/Hypothalamus Cerebellum
Hippocampus
VN Commissural VN
projections to
Vestibular nerve
contralateral Extraocular
afferent inputs
side motoneurons
Neuronal integrator
(Ncl. prepositus hypoglossi)
Proprioceptive
spinal inputs Spinal cord
(C) Labyrinthine nerve (D) Vestibular (E) Afferent and efferent

afferent projections commissural projections cerebellar projections
Flocculus Uvula / Nodulus
SVN SVN
SVN Semicircular SVN

canal/otolith
afferent MVN
MVN
nerve fibers
MVN LVN MVN
LVN LVN LVN
DVN DVN DVN

DVN
Figure 1–7. Main afferent and efferent connections of the vestibular nuclei (A and B). The vestibular nuclei (VN) receive
afferent signals related to head motion in space (A) and project to target areas involved in stabilization of gaze and posture
as well as in vegetative and cognitive functions (B). The MVN is the major relay station for vestibular signals related to gaze
and postural stabilization. A large area of the MVN receives afferent labyrinthine inputs from the semicircular canal and
otolith organs (C). The MVN is the largest source and target area for reciprocal commissural pathways (D). The MVN is the
major vestibular nucleus for signals from and to the flocculus (E). DVN, LVN, MVN, SVN, for descending, lateral, medial
and superior vestibular nucleus. (From Straka H, Vibert N, Vidal PP, Moore LE, Dutia MB. Intrinsic membrane properties
of vertebrate vestibular neurons: function, development and plasticity. Prog Neurobiol. 2005;76:349, with permission.)
pathways most of which originate in the medial therefore not simply a relay station for vestibu-
nucleus (Fig. 1–7D). Secondary vestibular neu- lar signals but rather an important sensorimo-
rons project to target areas involved in stabiliza- tor interaction center.
tion of gaze and posture, vegetative regulation,
and higher cognitive function (Fig. 1–7B).
Vestibular nucleus neurons receive afferent
visual and proprioceptive signals in addition to VESTIBULAR REFLEXES
primary vestibular signals (Fig. 1–7A).28 For
example, visual and proprioceptive signals are The basic elements of a simple vestibular reflex
organized such that movement of the visual arc are a hair cell, an afferent bipolar neuron,
surround in one direction excites and inhibits an interneuron, and an effector neuron
the same neurons that are excited and inhibited (Fig. 1–8).29 This simple three-neuron reflex
by movement of the head and neck in the arc is already developed in the phylum
opposite direction. The vestibular nucleus is Mollusca, among which the class Cephalopoda
because all parts of the nervous system are con-

nected together and no part of it is probably
ever capable of reaction without affecting and
being affected by various other parts….”31 The
maintenance of body equilibrium and posture
in everyday life is a complex function involving
multiple receptor organs and neural centers in
addition to the labyrinths. Visual and proprio-
ceptive reflexes in particular must be integrated
with vestibular reflexes to ensure postural sta-
bility. The prominent role of sensory interac-
tion in orientation can already be appreciated
Primary afferent in the behavior of gastropods. The invertebrate
Hermissenda has only rudimentary vestibular
and visual receptors, yet the two systems fully
interact to control behavior.32 Afferent signals
Interneuron
from photoreceptors in the eye and from hair
cells in the statocyst converge on interneurons
Motoneuron in the cerebroplural ganglia, which control a
putative motor neuron in each pedal ganglion.
Excitation of the motor neuron produces turn-
ing of the animal’s foot in the ipsilateral direc-
tion, consistent with the animal’s turning
behavior toward light. In humans, during most
natural head movements, gaze stabilization is
Figure 1–8. Three neuronal reflex arc. The primary affer- achieved by a combination of vestibular, neck
ent neuron carries signals generated by the hair cells to
interneurons in the brainstem which in turn activate
proprioceptive, and visual inputs; the interac-
motoneurons that initiate the motor response. tion can be synergistic or antagonistic. For
example, when the vestibular induced eye
movements lie in a direction opposite to that
has contributed to many classic anatomic and required to maintain the desired gaze position,
physiologic studies of gravitational reflexes.30 the visual reflexes override the vestibular reflex.
Vestibular reflexes have developed further in The kind of head rotation that would produce
vertebrates and mammals with the addition of compensatory eye movement in the dark does
multiple neuronal pathways.29 not do so in the light if the subject fixates on a
The terminal fibers of the afferent neuron target moving in phase with the head (Fig. 1–9).
make synaptic contact with the hair cell and In this simple example, failure to override the
transmit nerve signals to neuronal sensory pools vestibular signal leads to disorientation.
on the same side of the CNS (the vestibular
nuclei) that contain both excitatory and inhibi-
tory neurons. Besides receiving signals from Horizontal Canal-Ocular Reflex
excitatory first-order neurons from the ipsilat-
eral ear, the excitatory neurons also receive The direct pathways from the horizontal canals
signals from the inhibitory neurons of the con- to the horizontal extraocular muscles deserve
tralateral side by way of crossed neural path- particular attention, since the horizontal ves-
ways. The output of the excitatory vestibular tibulo-ocular reflex is the focus of most clinical
nuclei interneurons is transmitted to the effec- vestibular testing (Fig. 1–10).33,34 The second-
tor motor pools, which consequently reflect the ary vestibular neurons lie in the medial and lat-
activity of both ears. The effector neuron, in eral vestibular nuclei. The more medial group
turn, controls the activity in an appropriate of excitatory neurons projects to the contralat-
muscle to coordinate orienting behavior. eral abducens nucleus, while the more laterally
In 1947, Sherrington noted, “The simple located excitatory neurons (in the medial part
reflex is probably a purely abstract conception of the lateral nucleus) project to ipsilateral
Chair velocity 60°/sec

0
60°/sec
Eye movements
in the dark
15° Right
5 sec
Eye movements Left
with fixation
Figure 1–9. Eye movement induced in a normal human subject by sinusoidal angular acceleration (0.05 Hz, maximum
velocity 60°/sec) in the dark and in the light with a target moving in phase with the subject.
LR MR MR LR
IR
Oculomotor
nucleus (III) IO
SR
MR
Trochlear ATD
nucleus (IV)
MLF
Abducens
nucleus (VI)
S
L
SG
M I
Vestibular
nucleus
Figure 1–10. Direct pathways of the horizontal semicircular canal-ocular reflex. The darkened cell body indicates an
inhibitory secondary vestibular neuron. SG – Scarpa ganglion, S – superior nucleus, L – lateral nucleus, M – medial nucleus,
I – inferior (descending) nucleus, MLF – medial longitudinal fasciculus, ATD – ascending tract of Deiters, IR – inferior
rectus, IO – inferior oblique, SR – superior rectus, MR – medial rectus, LR – lateral rectus.
medial rectus motoneurons via the ascending CLOCKWISE ROTATION

tract of Deiters (ATD). The ipsilateral medial
rectus neurons also receive a strong excitatory
input via the medial longitudinal fasciculus
(MLF) from interneurons in the contralateral
abducens nucleus. These interneurons are Right Left
excited by the same secondary vestibular neu- horizontal horizontal
rons that excite the abducens motoneurons.35 canal canal
The relative contributions to the horizontal
vestibulo-ocular reflex of the ATD and MLF
excitatory pathways is not entirely clear, R+ L+
but the MLF pathway seems more important
since the eyes cannot adduct past the midline if R–
the MLF is sectioned.36 Inhibitory secondary Vestibular Vestibular
neurons in the rostral part of the medial ves- nucleus L– nucleus
tibular nucleus run directly to the ipsilateral
abducens nucleus. Contralateral medial rectus
motoneurons apparently do not receive disyn-
R+ L– R– L+
aptic inhibition from the horizontal semicircular
canals.
In addition to the direct and indirect con-
nection between secondary vestibular neurons Agonist Antagonist
motoneurons motoneurons
and oculomotor neurons, commissural connec-
tions between the two vestibular nuclei play an
important role in controlling the rotational ves-
tibulo-ocular reflex.37 Through GABAnergic
interneurons, secondary vestibular neurons Increased Decreased
on one side inhibit their counterparts of the Excitatory Inhibitory
opposite side (see Fig. 3–4 in Chapter 3). As
will be seen later, the commissural connections Figure 1–11. Organization of the horizontal semicircular
canal–ocular reflex. R – right, L – left.
are particularly important after unilateral loss
of vestibular function since they provide a
mechanism for a single labyrinth to control the Nystagmus
vestibular nuclei on both sides, thus maintain-
ing a functional vestibulo-ocular reflex.38 When the head is rotated back and forth in the
Because physiological stimuli activate both dark in the plane of the horizontal semicircular
labyrinths, the horizontal vestibulo-ocular canals, compensatory eye movements are pro-
reflex is controlled by a four-way push-pull duced, with eye velocity approximately equal
mechanism (Fig. 1–11). For example, physio- and opposite to the head velocity. This is easily
logical stimulation of the crista of the right demonstrated in lower animals such as the rab-
horizontal semicircular canal excites the left bit, who have few spontaneous eye movements
lateral rectus and the right medial rectus (Fig. 1–12A,B). If the angle of rotation is large,
and inhibits the right lateral rectus. Because such that it cannot be compensated for by the
of the symmetry between the labyrinths, the motion of the eye in the orbit, the slow com-
same receptor in the other ear simultaneously pensatory vestibular-induced eye movement is
diminishes its afferent output, thereby disfacili- interrupted by quick movements in the oppo-
tating the left medial rectus and right lateral site direction. This combination of rhythmic
rectus and disinhibiting the left lateral slow and fast eye movements is called nystag-
rectus. The end result is contraction of the left mus.39 Because of the fast components, the tra-
lateral and right medial rectus muscles and jectory of the eye motion during the slow
relaxation of the left medial and right lateral components effectively compensates for head
rectus muscles. rotation as if the eye had unlimited range
EYE MOVEMENT RECORDINGS

q = 3°
a.
ANGULAR HEAD POSITION
Rt. Lt.
4° rt.
q = 6° 1sec lt.
1 sec
b.
q = 12°
q c.
q = 24°
d.
q
Figure 1–12. Compensatory eye movements in the rabbit that are produced by sinusoidal angular acceleration of the head
(0.2 Hz) at four different peak angular displacements (θ).
of motion. If the fast components were removed vestibular nuclei to the oculomotor neurons.
from the tracings in Figure 1–12C,D and the By contrast, peripheral spontaneous nystagmus
slow components joined end to end, the result- aligns with the planes of the semicircular canals,
ing sinusoidal eye movement would be approx- producing a combination of torsional and linear
imately equal and opposite in direction to the components. After a complete unilateral
sinusoidal head movement just as in Figure peripheral vestibular loss, the nystagmus is
1–12A,B. Thus, the quick component of nys- horizontal/torsional because the vertical com-
tagmus is a strategy developed in the brain to ponents from the loss of vertical canal input
increase the functional capabilities of the cancel out.
reflex. Groups of neurons in the paramedian pon-
Spontaneous nystagmus occurs after lesions tine reticular formation (PPRF) adjacent to the
of the labyrinth, the vestibular nerve or the abducens nuclei fire in short bursts just before
central vestibulo-ocular neurons and intercon- the onset of horizontal fast components.41
necting pathways. The driving force of the Pathways interconnect neurons in the vestibu-
spontaneous nystagmus is an imbalance of tonic lar nuclei with neurons in this region of the
signals within the vestibulo-ocular pathways. PPRF, and these neurons project directly to
Damage to one labyrinth or its vestibular nerve oculomotoneurons and interneurons in the
results in spontaneous nystagmus, with the abducens nucleus. Neurons in the PPRF moni-
slow phase directed toward the damaged side; tor vestibulo-ocular signals and intermittently
the tonic input from the intact side is no longer trigger bursts of firing in the opposite direction
balanced by tonic input from the damaged side. mainly based on the eye position in the orbit.
This spontaneous nystagmus is similar to nys- During angular rotation, the fast components of
tagmus produced by physiological stimulation the initial beats of nystagmus are larger in
of the horizontal semicircular canals (Fig. 1–13; amplitude than the preceding slow components
also see Video 6–4). The direction of nystag- so that the eyes deviate in the direction of the
mus associated with lesions of the brain stem is fast components. The apparent advantage of
less predictable, depending on the location and this strategy is that the eyes are ready to follow
extent of the lesion.40 Central spontaneous new targets arriving in the field of vision and
nystagmus can be purely vertical or torsional, fixation can be maintained during the subse-
since tonic signals for vertical and torsional quent slow component. Unilateral lesions of the
eye movements run in different tracts from the PPRF impair ipsilateral rapid eye movements
PHYSIOLOGIC NYSTAGMUS SPONTANEOUS NYSTAGMUS
AC Damaged
PC Utricle
HC
Ampulla
PRIMARY
AFFERENT
FIRING RATE
100 msec
Figure 1–13. Primary afferent nerve activity associated with rotation-induced physiological nystagmus and spontaneous
nystagmus resulting from a lesion of one labyrinth. The thin straight arrows indicate the direction of the slow components;
the thick straight arrows indicate the direction of fast components; curved arrows show the direction of endolymph flow in
the horizontal semicircular canals. AC – anterior canal, PC – posterior canal, HC – horizontal canal.
(both voluntary and involuntary), and the eyes compensatory eye movement increases as the
deviate to the contralateral side of the orbit.42 target moves closer, the so-called motion paral-
Stimuli that normally would produce nystagmus lax (see Chapter 3).43,44
with ipsilateral fast components simply cause a Furthermore, unlike the rotational vestib-
tonic contralateral deviation of the eyes. ulo-ocular reflexes that stabilize images on the
entire retina, the translational vestibulo-ocular
reflexes only stabilize images on one spatial
Translational Vestibulo-Ocular location in the visual field, usually the fovea.
Reflexes Not surprisingly, there is a close functional
relationship between the translational vestib-
Natural head movements consist of a combina- ulo-ocular reflexes and the other foveal stabi-
tion of rotation and translation. For images to lizing systems, the smooth pursuit and the
remain stable on the retina, vestibular reflexes vergence systems.45
must compensate for both types of movement.
Translational movements are sensed by the
otolith organs of the inner ear, and compensa- The Ocular Tilt Reflex
tory eye movements are generated by the oto-
lith ocular reflexes. Although the rotational If a subject is tilted in the roll plane (about the
vestibulo-ocular reflexes are highly conserved nasal occipital axis), there is a reflex counter-
throughout evolution, translational reflexes rolling and skewing of the eyes to maintain gaze
develop later in frontal-eyed animals with stabilization (see Fig. 6–7 in Chapter 6). This
foveal vision. Unlike the rotational vestibulo- represents an utriculo-ocular reflex primarily
ocular reflexes where an equal and opposite mediated by excitation of the utricle of the
eye movement suffices regardless of target dis- dependent ear with synapses in the ipsilateral
tance, the translational vestibulo-ocular reflexes vestibular nucleus and in the contralateral ocul-
must be scaled to viewing distance to compen- omotor complex in the rostral brain stem.46,47
sate for the fact that the size of the required Unlike the translational vestibulo-ocular reflex,
it develops early in evolution being particularly includes reflexes arising from both the semicir-
prominent in lateral-eyed animals. It is a rudi- cular canals during angular acceleration and
mentary reflex in humans since the amount of the otolithic organs during linear acceleration.51
ocular counterrolling is only about 10% of the Most natural head movements contain both
angle of head tilt.48 Attempts to use this reflex types of acceleration, and the vestibular reflexes
as a clinical test of otolith function have been act in combination to maintain equilibrium.
largely abandoned because of the large vari- A third role of vestibular reflex activity is to
ability in normal subjects and the lack of consis- help maintain muscular tone, a role in which
tent asymmetry after unilateral lesions. both the macules50 and cristae participate.52
However, understanding the connections of The labyrinthine contribution to skeletal-
this otolith-ocular reflex is critical for localizing muscle tone can be demonstrated by the
peripheral and central lesions that cause double change in posture that follows unilateral laby-
vision due to skew deviation (see Chapter 6).47 rinthectomy in normal animals.53 Tone is
increased in the extensor muscles of the con-
tralateral extremities and decreased in the ipsi-
Vestibulospinal Reflexes lateral extensor muscles. An even more striking
demonstration of the vestibular role in mainte-
At least three major functional roles for vestibu- nance of muscle tone is the removal of
lospinal reflexes can be identified.49,50 The first decerebrate rigidity after sectioning of both
is to maintain posture, namely, the upright posi- vestibular nerves or destruction of the vestibu-
tion in relation to the earth vertical. Vestibular lar nuclei (see later discussion).54,55 The exten-
reflexes of this kind induce muscle contractions sor rigidity that results from transection of the
that produce negative geotropic movement or nervous system at the caudal end of the
forces that compensate for steady changes in mesencephalon is markedly decreased when
the direction of the force of gravity. If the pull the tonic labyrinthine input is removed.
of gravity on the body were unopposed by forces The anterior horn cells of the antigravity
developed in the muscles, the body would col- muscles (extensors of the neck, trunk, and
lapse. Reflexes in this category in humans are extremities) are under the combined excitatory
dependent on the function of the otolith organs and inhibitory influence of multiple supraspi-
but not on that of the semicircular canals. The nal neural centers (Fig. 1–14).54 At least in
second role is to produce “kinetic,” or transi- the cat, one finds two main facilitatory centers
tory, contractions of muscles for maintenance (the lateral vestibular nucleus and rostral retic-
of equilibrium during movement. This category ular formation) and four inhibitory centers
–
–
2
–
3
–
+ 5 6 –
+
+
4
–
Figure 1–14. Facilitatory (+) and inhibitory (−) pathways influencing the myotatic spinal reflex in the cat. Inhibitory path-
ways are (1) corticobulboreticular, (2) caudatospinal, (3) cerebelloreticular, and (4) reticulospinal. Facilitatory pathways are
(5) reticulospinal and (6) vestibulospinal. (From Lindsley DB, Schreiner LH, Magoun HW. An electromyographic study of
spasticity. J Neurophysiol. 1949;12: 197, with permission.)
(the pericruciate cortex, basal ganglia, cerebel- the predominant presenting symptoms of a ves-
lum, and caudal reticular formation). The bal- tibular lesion. Animal and human studies have
ance of input from these different centers shown that electrical or physiological stimula-
determines the degree of tone in the antigrav- tion of the vestibular receptors alters the activ-
ity muscles. If one removes the inhibitory influ- ity of sympathetic efferents.58,59 Neurons in the
ence of the frontal cortex and basal ganglia by caudal vestibular nuclei project to medullary
sectioning the animal’s midbrain, a characteris- regions known to participate in regulation of
tic state of contraction in the antigravity mus- blood pressure, heart rate, and breathing;
cles results—so-called decerebrate rigidity. lesions in this region abolish cardiovascular and
The extensor muscles increase their resistance respiratory responses to stimulation of vestibu-
to lengthening and the deep tendon reflexes lar afferents. Loss of vestibulocardiac and ves-
become hyperactive. As noted earlier, the ves- tibulovascular reflexes may explain the fainting
tibular system contributes largely to this and near fainting often associated with vestibu-
increased extensor tone since there is a marked lar lesions. There are also connections from the
decrease upon bilateral destruction of the laby- vestibular nuclei to the locus coeruleus, area
rinths.56 Unilateral destruction of the labyrinth postrema, and more centrally to the hypothala-
or the lateral vestibular nucleus results in an mus, amygdale, and limbic cortex that could
ipsilateral decrease in tone, indicating that the explain the motion sickness and symptoms
main excitatory input to the anterior horn cells of fear and panic that commonly accompany
arrives from the ipsilateral lateral vestibulospi- vertigo.60
nal tract.55
In a decerebrate animal with normal laby-
rinths, the intensity of the extensor tone can be
modulated in a specific way by changing the MOTION PERCEPTION AND
position of the head in space.31,49,50 The tone is ORIENTATION
maximal when the animal is in the supine posi-
tion with the angle of the mouth 45 degrees Several important clinical observations support
above horizontal and minimal when the animal the existence of a specific vestibular sensation.
is prone with the angle of the mouth 45 degrees Probably the most convincing is that patients
below horizontal. Intermediate positions of without vestibular function (either on an
rotation of the animal’s body about the trans- acquired or congenital basis) do not experience
verse or longitudinal axis result in intermediate a turning sensation when rotated in the dark if
degrees of extensor tone. If the head of the visual and tactile cues are eliminated.61 In
upright animal is tilted upward (without neck contrast, in patients with the sensation of move-
extension), extensor tone in the forelegs ment, it is not dependent on vision or associ-
increases; downward tilting of the head causes ated nystagmus, since blind subjects and
decreased extensor tone and flexion of the fore- patients with complete oculomotor paralysis
legs. Lateral tilt produces extension of the experience a spinning sensation comparable to
extremities on the opposite side. These tonic that of normal subjects when their vestibular
labyrinthine reflexes, mediated by way of the end organs are stimulated. Focal cortical lesions
otoliths, seldom occur in intact animals or can interfere with spatial orientation and the
human subjects because of the inhibitory influ- performance of three-dimensional construc-
ence of the higher cortical and subcortical cen- tion tasks, and epileptic discharges from many
ters; however, they can be demonstrated in different areas of the cortex can be associated
premature infants.57 with a subjective illusion of movement (usually
spinning). These observations imply a cerebro-
cortical representation for vestibular sensation.
Vestibulo-Autonomic Reflexes The vestibulocortical pathway via the thala-
mus is concerned with the control of body posi-
The strong connections between vestibular and tion and orientation in space (Fig. 1–15).63,64
vegetative centers are apparent based on the Thalamic and cortical units that receive ves-
prominent vegetative symptoms that accom- tibular signals are also activated by propriocep-
pany vestibular lesions. Nausea and vomiting, tion and visual stimuli. Most units respond in a
diarrhea, perfuse sweating, and fainting can be similar way to rotation in the dark, or to moving
Cerebral
cortex
IPL
PIVC
VPL
Thalamus
STG
L
Muscle
and
cutaneous M Vestibular
I nucleus
afferents
Figure 1–15. Vestibulothalamocortical projections. I, inferior nucleus; IPL, intra-parietal lobe; L, lateral nucleus; M,
medial nucleus; PIVC, parieto-insular vestibular cortex; S, superior nucleus; STG, superior temporal gyrus; VPL, nucleus
ventralisposterior lateralis.
visual fields, indicating that they play a role in concerning whether the symptoms associated
relaying information about self-motion. From a with acute unilateral labyrinthine damage was
functional point of view, the vestibulothalamo- due to irritation or paralysis of the affected
cortical projections appear to integrate vestibu- labyrinth. The subsequent discovery of the
lar, proprioceptive, and visual signals to provide continuous flow of action potentials in the
one with a “conscious awareness” of body ori- vestibular nerve at baseline led to the present
entation. Beginning at the vestibular nuclei, a concept that symptoms are usually caused
stepwise integration of body-orienting signals by an imbalance of the normal resting state
occurs, reaching its maximum at the level of activity—that is, by a unilateral decrease in
the cortex. activity.
Symptoms and signs after labyrinthine
lesions can largely be traced to asymmetric
tone or loss of function within the vestibular
PATHOPHYSIOLOGY OF reflex pathways (Table 1–1). The magnitude of
VESTIBULAR SYMPTOMS symptoms and signs depends on (1) whether
the lesion is unilateral or bilateral, (2) the
Much of our knowledge of labyrinthine func- rapidity with which the functional loss occurs,
tion was accumulated at the turn of the twenti- and (3) the extent of the lesion. In most
eth century from clinical and experimental experimental animals, simultaneous removal of
observations in humans and animals with uni- both labyrinths does not produce severe
lateral and bilateral lesions of the peripheral abnormalities, although vestibular reflex activ-
labyrinth.65–67 At that time, a controversy existed ity is lost and ocular and postural stability is
Table 1–1 Symptoms and signs after labyrinthine lesions result from asymmetric
tone and/or loss of function within vestibular reflex pathways
Pathway Asymmetric Tone Loss of Function
Vestibulo-ocular Spontaneous nystagmus Head movement dependent oscillopsia
Ocular roll & skew
Vestibulo-spinal Head tilt Imbalance worse with eyes closed
Lateropulsion
Vestibulo-autonomic Nausea, vomiting, fainting, Resistant to motion sickness
fear, anxiety
Vestibulo-cortical Illusion of movement Decreased motion perception, visual dependency
Tilt of subjective vertical
impaired. Similarly, patients who lose vesti- CENTRAL COMPENSATION FOR

bular function bilaterally (e.g., secondary VESTIBULAR LESIONS
to gentamicin treatment) usually do not com-
plain of vertigo, but they do report visual blur- In animals immediately after a labyrinthec-
ring or oscillopsia with head movements and tomy, ipsilateral secondary vestibular neurons
instability when walking at night (due to loss of lose their afferent input, become silent, and do
vestibulo-ocular and vestibulospinal reflex not respond to ipsilateral angular rotation.69–71
activity). At the same time, contralateral healthy second-
In contrast, animals and humans develop ary neurons lose their inhibitory contralateral
severe symptoms and signs following acute input, and their spontaneous activity increases
unilateral labyrinthectomy. Lower mammals in comparison to normal levels. An imbalance
are initially unable to walk and develop head in ocular and skeletal muscle tone takes place,
tilt and decreased ipsilateral muscle tone. resulting in the clinical signs of labyrinthec-
Nystagmus is prominent, with the slow compo- tomy—nystagmus and disequilibrium. A few
nent directed toward the damaged side and the days after the labyrinthectomy, the previously
fast component toward the intact side. These silent secondary neurons on the damaged side
signs abate with time but may persist for recover their spontaneous activity and begin to
months after surgery. respond to physiologic stimulation of the con-
A sudden unilateral loss of labyrinthine tralateral labyrinth, the result of their connec-
function in humans is a dramatic event.68 The tions through the commissural pathways.
patient complains of severe vertigo and nausea, Although the responses of secondary neurons
is pale and perspiring, and usually vomits on the damaged side are not as intense as those
repeatedly. The patient prefers to lie motion- on the normal side, they are qualitatively simi-
less but can walk if forced to (deviating toward lar. The recovery of sensitivity in the ipsilateral
the side of the lesion). Head and ocular tilt and secondary neurons after a labyrinthectomy
changes in extremity tone occur but less fre- parallels the time course of recovery in clinical
quently than in lower animals. A brisk, sponta- symptoms and signs.
neous nystagmus interferes with vision. These The genesis of the renewed tonic input to
symptoms and signs are temporary, and the ipsilateral secondary neurons several days after
process of compensation starts almost immedi- a complete labyrinthectomy is not entirely
ately. Within 1 week of the occurrence of known. It does not come from the healthy side,
the labyrinthine lesion, a young patient can since afferent activity on that side does not
walk without difficulty and, with fixation, can change. It probably results from changes in ion
inhibit the spontaneous nystagmus. Within 1 channels expressed in the cell membrane, from
month, most patients return to work with few, the sprouting of axons from other sources (e.g.,
if any, residual symptoms. If a patient slowly neck proprioceptive), and from up and down
loses vestibular function unilaterally over a regulation of synaptic receptors (particularly
period of months or years (e.g., with a vestibu- GABA receptors) (see Chapter 3).72–75 In ani-
lar schwannoma), symptoms and signs may be mal studies, the course of compensation is
absent. affected by exercise,76 visual experience,77 and
drugs (as a rule, stimulants accelerate and sed- avenues of research in the study of vestibular
atives slow compensation).78 If a second laby- function in health and in disease.
rinthectomy is performed after compensation
for the first occurs, the animal again develops
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to the vestibular nuclei: potential substrates for auto- 73. Vibert N, Bantikyan A, Babalian A, Serafin M,
nomic and limbic influences on vestibular responses. Mühlethaler M,Vidal PP. Post-lesional plasticity in the
Brain Res. 2004;996:126. central nervous system of the guinea-pig: a “top-down”
61. Guedry FT. Psychophysics of vestibular sensation. In: adaptation process? Neuroscience. 1999;94:1.
Kornhuber HH, ed. Handbook of Sensory Physiology, 74. Vibert N, Beraneck M, Bantikyan A, Vidal P. Vestibular
The Vestibular System, Vol VI, Part 2. New York: compensation modifies the sensitivity of vestibular
Springer-Verlag; 1974. neurones to inhibitory amino acids. NeuroReport.
62. Walsh EG. Role of the vestibular apparatus in the 2000;11:1921.
perception of motion on a parallel swing. J Physiol. 75. Beraneck M, Idoux E, Uno A, Vidal PP, Moore LE,
1961;155:506. Vibert N. Unilateral labyrinthectomy modifies the
63. Angelica DE, Shaikh AG, Green AM, Dickman JD. membrane properties of contralesional vestibular neu-
Neurons compute internal models of the physical laws rons. J Neurophysiol. 2004;92:1668.
of motion. Nature. 2004;430:560. 76. Igarashi M, Levy JK, O-Uchi T Reschke MF. Further
64. Britten KH. Mechanisms of self-motion perception. study of physical exercise and locomotor balance com-
Annu Rev Neurosci. 2008;31:389. pensation after unilateral labyrinthectomy in squirrel
65. Ewald J. Physiolgisshe Untersuchungen über das monkeys. Acta Otolaryngol (Stockh). 1981;92:101.
Endorgan des Nervus Octavus. Wiesbaden, Germany: 77. Fetter M, Zee DS, Proctor LR. Effect of lack of vision
Bergmann; 1892. and of occipital lobectomy upon recovery from unilat-
66. Bárány R. Physiologie und Pathologie des eral labyrinthectomy in rhesus monkey. J Neurophysiol.
Bogengangsapparates beim Menschen. Vienna, 1988;59:394.
Austria: Deuticke; 1907. 78. Lacom M, Xerri C. Vestibular compensation: new per-
67. Magnus R. Körperstellung. Berlin, Germany: Springer- spectives. In: Flohr H, Precht W, eds. Lesion-Induced
Verlag; 1924. Neuronal Plasticity in Sensorimotor Systems. Berlin,
68. Baloh RW. Vestibular neuritis. N Engl J Med. Germany: Springer-Verlag; 1984: 240.
2003;348:1027. 79. Bechterew W. Ergebnisse der Durchschneidung des
69. Curthoys IS. Vestibular compensation and substitu- N. acusticus, nebst Erörterung der Bedeutung der
tion. Curr Opin Neurol. 2000;13:27. semicirculären Canäle für das Körpergleichgewicht.
70. Dieringer N. Activity-related postlesional vestibular Pfuegers Arch Ges Physiol. 1883;30:312.
reorganization. Ann NY Acad Sci. 2003;1004:50. 80. Barlow JS. Inertial navigation as a basis for animal
71. Dutia MB. Mechanisms of vestibular compensation. navigation. J Theor Biol. 1964;6:76.
In: Luxon, Davies R, eds. Handbook of Vestibular 81. Gonshor A, Melvill Jones G. Extreme vestibulo-ocular
Rehabilitation. London: Whurr Press; 2005. adaptation induced by prolonged optical reversal of
72. Vibert N, Babalian A, Serafin M, Gasc JP, Mühlethaler vision. J Physiol (Lond). 1976;256:381.
M, Vidal PP. Plastic changes underlying vestibular
Chapter 2
The Peripheral Vestibular System
TEMPORAL BONE Relationship between the Direction of Force

Tympanic Membrane and Hair Cell Activation
Middle Ear Mechanism of Hair Cell Activation
Facial Nerve Hair Cell Influence on Afferent Nerve Activity
INNER EAR (LABYRINTH) Signal Processing at the Hair Cell/Afferent
Phylogeny Nerve Junction
Structure THE INNER EAR VESTIBULAR RECEPTORS
Fluid Dynamics Anatomy of the Semicircular Canals
Fluid Chemistry Physiology of the Semicircular Canals
Blood Supply Anatomy of the Otolith Organs
Innervation Physiology of the Otolith Organs
Embryonic Development PRIMARY VESTIBULAR NEURONS
THE HAIR CELL Anatomy of Primary Neurons
Morphologic Characteristics Physiology of Primary Neurons
Sequence of Hair Cell Activation EFFERENT VESTIBULAR NEURONS
TEMPORAL BONE The anatomical proximity of these major ves-

sels to the inner ear can explain pulsatile tinni-
The ear is divided into three anatomic parts: tus in a patient without vascular abnormalities.
the external, middle, and inner ear. Except A cross section of the temporal bone in
for the auricle and soft tissue portion of the Figure 2–2 illustrates the relationship between
external auditory canal, the ear is enclosed the three functional parts of the ear. Although
within the temporal bone of the skull. the external and middle ear are auditory organs
The temporal bone contributes to the base with no direct bearing on vestibular function,
and lateral wall of the skull and forms part of a knowledge of their structure, particularly
the middle and posterior fossae.1,2,3 It is divided those of the middle ear, is important for under-
into four parts: the squamous, tympanic, standing diseases involving the inner ear.4
petrous, and mastoid areas. The petrous por- For example, infection arising in the middle
tion, or pyramid, contains the sense organs of ear can spread directly through its medial
the inner ear. The seventh and eighth cranial wall (oval and round windows) into the inner
nerves enter the petrous portion through the ear, or it can enter the intracranial cavity by
internal auditory canal; the facial nerve exits via breaking through the roof of the epitympanic
the stylomastoid foramen of the mastoid por- recess. The aditus ad antrum interconnects
tion (Fig. 2–1). The internal carotid artery and the epitympanic recess with the middle ear
internal jugular vein enter the skull through the by means of air cells throughout the mastoid
temporal bone, their bony canals forming part portion of the temporal bone so that infection
of the anteroinferior wall of the middle ear. beginning in the middle ear can spread to the
25
Pore of internal
acoustic meatus t
par
am ous
Vestibulo acoustic (VIII), Squ
facial (VII) nerves
ar t
Superior, inferior
Subarcuate fossa
id p
petrosal sinuses
ar t
to
sp
as
r o u
t
M
Pe
Vestibular
aqueduct Transverse sinus
Superior bulb of
jugular vein
Internal carotid
artery Stylomastoid
foramen
Internal jugular vein
Facial (VII) nerve
Figure 2–1. Medial view of the temporal bone. (From Anson BJ, Donaldson JA. Surgical Anatomy of the Temporal Bone
and Ear. WB Saunders, Philadelphia, 1973, with permission.)
vessels and nerves passing through the temporal 0.1 mm and a diameter of 8.5 to 10 mm. It con-
bone. sists of three layers, an inner mucosal layer, a
middle fibrous layer, and an external epidermal
layer. It is attached to the tympanic ring in the
Tympanic Membrane external canal at a distance of 2 to 5 mm from
the opposite (medial) wall of the middle ear.
The ear drum, or tympanic membrane, forms a From the external canal, the tympanic mem-
partition between the external and middle ear. brane appears as a thin, semitransparent disk
The tympanic membrane has a thickness of that normally has a glistening, pearly-gray color
Integument Epitympanic recess

Facial musculature Auditory ossicles
Semicircular ducts
Squama of (in canals)
temporal bone
Endolymphatic duct
Meninges (in vestibular aqueduct)
Endolymphatic sac
Brain (in dura mater)
Perilymphatic duct
(in cochlear canaliculus)
Scala tympani
Auricle Cochlear duct
Scala vestibuli
Mucous membrane
Eustacian tube
Levator veli palatini
Cartilages
of external ear Secondary tympanic membrane
L.
C. Vestibule
INN
ES Mastoid Tympanic membrane and cavity
Mastoid air cells process
Styloid process
Figure 2–2. Cross section of the ear. (From Anson BJ, Donaldson JA. Surgical Anatomy of the Temporal Bone and Ear.
WB Saunders, Philadelphia, 1973, with permission.)
2 The Peripheral Vestibular System 27
(see Fig. 6–1 in Chapter 6). It is concave on its forming the incudomalleal articulation, a type
external surface as if under traction from the of diarthric joint. The so-called long process of
manubrium—the long process (5.8 mm) of the the incus (7 mm), directed down and anteri-
malleus. orly, is connected to the stapes, the smallest of
The mallear stria (the manubrium shining the three middle ear ossicles. The footplate of
through the tympanic membrane) passes from the stapes articulates with the walls of the ves-
slightly inferior and posterior of the center tibule at the oval window to which it is attached
(umbo) toward the superior margin of the tym- by a ring of ligaments. The dimensions of the
panic membrane. Near the superior margin, window are 1.2 by 3 mm, with a total area that
the mallear prominence is formed by the lat- is one-seventeenth that of the tympanic mem-
eral process of the malleus. From the mallear brane. Sound-induced displacements of the
prominence, two folds stretch to the tympanic tympanic membrane and its attached manu-
sulcus of the temporal bone, enclosing the tri- brium are transmitted through the medial arm
angular area of the pars flaccida, or Shrapnell’s of the assembly of middle ear bones, acting as a
membrane. lever to the inner ear; in this fashion the middle
ear functions as a mechanical transformer.
Additional amplification is produced as the
Middle Ear force applied over the surface of the tympanic
membrane is funneled into the smaller area of
The middle ear, or tympanic cavity, is a flat the oval window. The middle ear compensates
cleft with a volume of approximately 2.0 cc, for the loss of energy—approximately a 99.9%
containing three tiny bones whose main role is loss—that would occur if sound were transmit-
to provide an interface for transmitting to the ted directly from air to the fluids of the inner
inner ear the changes in atmospheric pressure ear.6
produced by sound waves (Fig. 2–3).5 The The ossicles are suspended by several liga-
manubrium is attached, like the radius of a ments and are dynamically controlled by the
circle, to the inner side of the tympanic mem- action of two muscles. The tensor tympani,
brane in a superoanterior direction. Superiorly, innervated by a branch of the trigeminal nerve,
the head of the malleus is bound to the incus, is connected by a tendon to the upper part of
Superior Posterior
malleal ligament
ligament incus
Epitympanic
recess
Lateral malleal Horizontal
ligament semicircular
canal
Tympanic membrane
pars flaccida Facial nerve
(Shrapnell’s membrane) Tendon stapedius muscle
Oval window
Tendon tensor
tympani muscle
Cochlear
Tympanic mambrane promintory
pars tensa
Round window
Fabrous
annulus Eustachian tube
Bony annulus
Figure 2–3. Cross section of the middle ear.
the manubrium. Coursing in a lateral direction (Fig. 2–4). The canal segment runs in close
from the anterior part of the medial wall of the company in an anterosuperior position with the
tympanic cavity, this muscle draws the manu- vestibular and cochlear divisions of the eighth
brium medially, tensing the tympanic mem- nerve, while in its remaining segments the
brane. The stapedius muscle, innervated by the facial nerve lies separately within a bony
facial nerve, is attached to the posterior wall of canal—the facial or fallopian canal. The laby-
the tympanic cavity and is directed anteriorly rinthine segment runs at nearly a right angle to
to anchor in the upper part of the stapes. the petrous pyramid superior to the cochlea
Contraction of these muscles leads to stiffening and vestibule to reach the geniculate ganglion.
of the middle ear system and thus less sound At the geniculate ganglion, the nerve takes a
transmitted to the inner ear (i.e., increased sharp turn posteriorly, marking the beginning
impedance) (Fig. 2–3). This is the reason that a of the tympanic segment. The horizontal tym-
lesion of the facial nerve (e.g., Bell’s palsy) can panic segment courses in a posterior direction
result in hyperacusis on the affected side. along the medial wall of the middle ear supe-
Another condition involving these muscles, rior to the oval window and inferior to the hor-
middle ear myoclonus, results in repetitive izontal semicircular canal (see Fig.2–3). At the
clicking sounds in the affected ear. sinus tympani, the nerve bends inferiorly,
The medial, or labyrinthine, wall of the mid- marking the beginning of the vertical, or mas-
dle ear is an irregular surface because of the toid, segment that continues toward the stylo-
structures bulging from the inner ear: the mastoid foramen. At this level, the facial nerve
promontory of the basal turn of the cochlea consists exclusively of motor fibers that inner-
and the prominences of the facial canal and vate the muscles of the facial expression after
horizontal semicircular canal (Fig. 2–3). coursing through connective tissue septa in the
Beneath the cochlear prominence is the mem- parotid gland. Three major groups of fibers have
brane of the cochlea or round window, which been recognized that are directed to (1) the
seals the scala tympani of the cochlea and its auricular and occipital muscles, (2) the orbicu-
fluid from the middle ear. It provides an outlet laris and muscles of mimetic facial expression,
for equilibrium of pressure in the inner ear and (3) the buccinator and buccolabial muscles.
whenever sound displaces the stapes. Without Three major branches of the facial nerve lie
this compliance, sound energy could not dis- within the temporal bone: (1) the greater
place the basilar membrane of the cochlea superficial petrosal nerve, arising from the
because the endolymph fluid is incompress- geniculate ganglion; (2) the nerve to the stape-
ible. The vestibular, or oval, window is located dius muscle, arising from the initial part of the
just above the cochlear prominence, where it is mastoid segment; and (3) the chorda tympani,
closed by the base of the stapes and the annular leaving the facial nerve approximately 5 mm
ligament. These windows between the middle above the stylomastoid foramen. The greater
and inner ear can be a route for infection or superficial petrosal nerve is composed of
toxins to spread from the middle to inner ear, (1) parasympathetic efferent fibers originating
or they can rupture, allowing perilymph to leak in the superior salivatory nucleus for innerva-
from the inner ear to the middle ear (perilymph tion of the lacrimal glands and seromucinous
fistula). glands of the nasal cavity and (2) afferent cuta-
neous sensory fibers from parts of the external
canal, tympanic membrane, and middle ear,
Facial Nerve destined for the nucleus of the solitary tract.
The nerve to the stapedius muscle and the main
The facial nerve arises at the inferior border of facial nerve trunk are motor nerves originating
the pons and proceeds to the internal auditory from the facial nucleus in the caudal pons. The
canal on the superior surface of the cochlear chorda tympani, like the greater superficial
nerve. Within the temporal bone, four portions petrosal, is a mixed nerve containing (1) para-
of the facial nerve can be classified: (1) the canal sympathetic efferent fibers from the superior
(meatal) segment (7 to 8 mm), (2) the labyrin- salivatory nucleus, destined for the sublingual
thine segment (3 to 4 mm), (3) the tympanic glands, and (2) afferent taste fibers from the
(horizontal) segment (12 to 13 mm), and (4) the anterior two-thirds of the tongue, ending in the
mastoid (vertical) segment (15 to 20 mm) nucleus of the solitary tract.
Superior
salivatory
nucleus
Internal auditory canal
Nucleus of the Labyrinthine segment

solitary tract
Greater superficial
Cochlear petrosal nerve for
nerve lacrimation
Facial nucleus Vestibular
nerve
Horizontal Geniculate ganglion

(intratympanic
Lesser superficial petrosal
segment)
nerve to parotid gland
Lower
(posterior) Nerve to
genu stapedius
muscle
Vertical
(mastoid)
segment
Chorda tympani
Stylomastoid Tongue
foramen Upper division
Lower division Submaxillary

salivary gland
(salivation)
Figure 2–4. Schematic diagram of the facial nerve within the temporal bone.
Knowledge of the structure and function of affects only the latter two (3, 4). Finally, a lesion
each division of the facial nerve allows the cli- at the stylomastoid foramen causes only ipsilat-
nician to localize disease affecting the nerve eral facial muscle weakness or paralysis. Pain is
within the temporal bone.7,8 Lesions in the another common symptom particularly with
internal auditory canal commonly involve both inflammatory disorders (e.g., Bell’s palsy) and
the seventh and eighth cranial nerves. Lesions is typically postauricular pain with a lesion
of the labyrinthine segment of the facial nerve involving the geniculate ganglion.
above the geniculate ganglion impair ipsilateral
(1) lacrimation (resulting in dry eyes and
increased tearing), (2) stapedius reflex activity
(resulting in hyperacusis), (3) taste on the ante- INNER EAR (LABYRINTH)
rior two-thirds of the tongue, and (4) facial
muscular strength. A lesion of the tympanic Phylogeny
segment central to the nerve of the stapedius
muscle affects only the latter three functions The most primitive gravity-detection organ,
(2–4) listed above, and a lesion of the mastoid the statocyst, appeared more than 600 million
segment before the origin of the chorda tympani years ago in the late Precambrian era.9–11 It is
present in some bygastrulated animals with the gravity, the particles rest their weight differen-
most developed Coelenterata, such as jellyfish, tially over cilia protruding from specialized
allowing the animal to orient itself in relation to sensory neurons in the wall of the cyst. A large
the horizon by sensing the direction of the central cilia, the kinocilia, is surrounded by
gravitational force of the earth. The statocyst is rows of smaller cilia. Tethers between the cilia
a fluid-filled invagination or sac containing a and the kinocilia open and close mechanosen-
calcareous particle, the statolith, or multiple sory channels that control the firing rate of the
particles, the statoconia, of a density greater sensory neurons, allowing the animal to regu-
than that of the fluid (Fig. 2–5a). Attracted by late its static position in space.
S
CB
N N
K
b
tl
Is
N N N
HC SN HC
Figure 2–5. a: Statocyst of the ctenophore comb jelly Pleurobrachia. Ciliary bundles (CB) of hair cells support the extracel-
lular statoliths (S). N, neurons (transverse section). (Adapted from Budelmann BU. Morphological diversity of equilibrium
receptor systems in aquatic invertebrates. In: Atema J, et al. (eds). Sensory Biology of Aquatic Animals. Springer-Verlag,
New York, 1988, with permission.) b: Hair bundle complex of a sea anemone. Supporting cells located on opposite sides
of the sensory neuron (SN) function in a manner comparable that of to hair cells (HC). Large-diameter stereocilia (Is) and
the kinocilium (K) of the sensory neuron are also shown. During deflection with a vibratory stimulus, the sensory neuron
integrates the input from the supporting cells and then signals other neurons in the nerve net. Note that when the cilia of
the hair cell bend toward the kinocilium, the tip links (tl) open ion channels that lead to excitation of the sensory neuron. By
contrast, the cilia of the hair cell to the right bend away from the kinocilium and the ion channels remain closed. (Adapted
from Watson GM, Mire P. A comparison of hair bundle mechanoreceptors in sea anemones and vertebrate systems.
Curr Top Dev Biol. 1999; 43: with permission.)
A primitive receptor organ for generating by the enmatocyst, the “stinging organelle” of
kinetic reflexes can be found on the tentacles the anemones.
of marine invertebrates, such as sea anemo- From these simple mechanotransduction
nes.12,13 A sensory neuron is coupled to two receptors to the labyrinth of higher animals, a
neighboring hair cells that act as mechanore- continuous increment in anatomic complexity
ceptors of water pressure waves in their vicinity occurs that accompanies the phylogenetic evo-
(Fig. 2–5b). Supporting cells located on oppo- lution of the taxa. Next developmentally are
site sides of the sensory neuron function in a the mechanoreceptors of mollusks (e.g., octo-
manner similar to that of hair cells. During pus, sepia), in which both types of receptors,
deflection associated with a vibration stimulus, the static otolith and the kinetic cristae recep-
the sensory neuron integrates the input from tors are seen.14–17 These new receptors, incor-
the supporting cells and signals other neurons porated in an invaginated common cavity,
in the nerve net. Note that when the cilia of the accompany the appearance of motor responses
supporting cell bend toward the kinocilium of to motion, including nystagmus.14 The statocyst
the nerve cell, the tethers (tip links) open ion cavity, previously open to the outside, is closed
channels whereas when the cilia bend away and filled by an endogenous secretion (endo-
from the kinocilium the ion channels are closed. lymph). The otolith/macula system consists of a
Among important signals are vibrations pro- rounded plate of mechanosensory cells with a
duced by minuscule prey animals. The neuron compact statolith (Fig. 2–6a). The force exerted
reaction leads to a “motor” response involving a by the statolith mass on the cilia of the mecha-
sensory cell, a surrogate vestibular nucleus, and nosensory cells depends on the magnitude and
an effector neuron. The reflex response con- direction of any applied linear acceleration
sists of the secretion of a paralyzing substance including gravity. The cristae/cupula system
(a) (b)
Figure 2–6. Drawing of the octopus statocyst showing the ovoid plate of macula cells and the crista strip which runs around
the inside of the statocyst sphere and is divided into nine segments (a). Drawing of an expanded transverse section through
one of the crista segments showing the rows of primary sensory hair cells (white), secondary sensory hair cells (light blue)
and afferent neurons (dark blue) (b). The direction of movement of the overlying cupula is shown by the arrow. Scale bar
in b = 15 micrometers. (From Williamson R, Chrachri A. A model biological neural network: the cephalopod vestibular
system. Phil Trans R Soc B. 2007;362:473, with permission.)
consists of a narrow strip of sensory epithelium the lamprey is more complex, consisting of an
winding around the inside wall of the cyst such anterior and posterior canal communicating
that it covers all three orthogonal planes. The with a bilobulated sac containing separate utric-
strip is divided into nine segments comprised ular and saccular macules (Fig. 2–7b). The pre-
of mechanosensory hair cells and afferent neu- decessor of the auditory organs appears after
rons (Fig. 2–6b). A sail-like cupula overlies the development of a membranous labyrinth
each crista segment and is deflected during that is divided into two cavities. In the inferior of
rotational movements of the animal by flow of the two cavities (the saccule), two new receptor
endolymph relative to the statocyst wall. The areas develop: the lagenar macule and the basi-
cilia of the underlying mechanosensory cells lar papilla. In crocodiles, however, these recep-
protrude into the cupula, and cupular deflec- tors are contained in a cavity separate from the
tion excites or inhibits these cells, depending saccule, while in birds the basilar papilla is a
on the direction of the cupula movement and long, uncoiled organ, the predecessor of the
the polarization of the mechanosensory cells. coiled cochlea (Fig. 2–7c).18 The basic structure
Two surviving cyclostomes, the hagfish and of the three semicircular canals—the utricle,
the lamprey, demonstrate important steps in the the saccule, and the cochlea—is similar in all
phylogenetic development of the vestibular lab- mammals (Fig. 2–7d).
yrinth. In the hagfish, a simple circular tube is
interrupted anteriorly and posteriorly by bul-
bous enlargements, the ampullae, each contain- Structure
ing a primitive crista (Fig. 2–7a). Between the
ampullae, in an intercommunicating channel, Within the petrous portion of the temporal
lies the macule communis, the forerunner of the bone, a series of hollow channels, the bony
utricular and saccular macules. The labyrinth of labyrinth, contain the auditory and vestibular
C. post. C. ant.
M. comm.
b
C. post. C. ant.
M. negl. M. utr.
M. lag. M. sacc.
c d
C. ant.
C. post. C. ant.
C. lat. M. utr.
C. post.
M. sacc. M. sacc.
M. utr.
Pap. bas.
M. lag. Cochlea
Figure 2–7. Phylogeny of the labyrinth, (a) myxine; (b) petromyzon; (c) bird; (d) mammal. C. ant., anterior canal; C.
lat., lateral or horizontal canal; C. post., posterior canal; M. comm., common macule; M. lag., lagenar macule; M. negl.,
neglector macule; M. sacc., saccular macule; M. utr., utricular macule; Pap. bas., basilar papilla. (From Wersall DJ, Bagger
Sjoback D. Morphology of the vestibular sensor organs. In: Kornhuber, HH (ed). Handbook of Sensory Physiology, Vol VI,
Part 2. Springer Verlag, New York, 1974, with permission.)
sensory organs (see Fig. 2–2). The bony laby- subarachnoid and the perilymphatic spaces.
rinth consists of an anterior cochlear part and a Infection or blood in the cerebrospinal fluid
posterior vestibular part.1 The vestibule is a (CSF) can make its way into the inner ear
central chamber (about 4 mm in diameter) through this channel (see “Fluid Dynamics”).
marked by the recesses of the utriculus and The membranous labyrinth is enclosed within
sacculus (i.e., the macules). The superior and the channels of the bony labyrinth (Fig. 2–8).
posterolateral walls contain openings for the A space containing perilymphatic fluid, a sup-
three semicircular canals, and anteriorly the portive network of connective tissue, and blood
vestibule is continuous with the scala vestibuli vessels lies between the periostium of the bony
of the snail-shaped cochlea. labyrinth and the membranous labyrinth;
Medial to the bony labyrinth is the internal the spaces within the membranous labyrinth
auditory canal, a cul-de-sac housing the sev- contain endolymphatic fluid.
enth and eighth cranial nerves and the internal
auditory artery. The aperture on the cranial
side is located at approximately the center of Fluid Dynamics
the posterior face of the pyramid of the tempo-
ral bone (see Fig. 2–1). Two other important Perilymph is thought to be a filtrate of CSF and
orifices are in this vicinity. Halfway between from blood vessels in the ear.19–21As noted pre-
the canal and the sigmoid sinus, the slit-like viously, the CSF communicates directly with
aperture of the vestibular aqueduct contains the perilymphatic space through the cochlear
the endolymphatic sac, a structure important aqueduct, a narrow channel 3 to 4 mm long
in the exchange of endolymph. The second with its inner ear opening at the base of the
opening is that of the cochlear aqueduct, at the scala tympani (Fig. 2–8). In most instances, this
same level as the auditory canal but on the infe- channel is filled with a loose net of fibrous tis-
rior side of the pyramid. The labyrinthine sue continuous with the arachnoid. The size of
opening of this channel is located in the scala the bony canal varies from individual to indi-
tympani, providing a connection between the vidual. Necropsy studies in patients who died
CEREBROSPINAL FLUID
K = 4 mEq/liter Endolymphatic sac
Na = 152 mEq/liter
Protein = 20–50 mg%
CSF
Dura mater
Anterior Cochlear aqueduct
canal Endolymphatic duct
Posterior Scala vestibuli

canal PERILYMPH
K+ = 10 mEq/liter
Na = 140 mEq/liter
Horizontal Protein = 200–400 mg%
canal Cochlear duct
Scala tympani
Saccule
ENDOLYMPH Utricle Ductus reuniens
K+ = 144 mEq/liter
Round window
Na+ = 5 mEq/liter
Protein = 126 mg%
Figure 2–8. Cross section of the inner ear.
of subarachnoid hemorrhage or meningitis both at an equal positive pressure of approxi-

have revealed free passage of leukocytes and mately 7 to 10 cm of H2O.38 When the pressure
red blood cells into the inner ear in some in the intracranial cavity or the labyrinth
patients, whereas in others the cells were increases to above normal, the pressure will
blocked from passing through the aqueduct.22,23 tend to equilibrate between the two compart-
Blood cells have also been found passing into ments.42 The round window elasticity provides
the internal auditory canal and through the a measure of protection for pressure regulation
porous canaliculi that contain the vestibular in the inner ear.43
and cochlear nerves, suggesting another route Destruction of the epithelium lining the
for CSF–perilymph communication. Probably endolymphatic sac or occlusion of the duct
the most important source of perilymph, how- results in an increase of endolymphatic volume
ever, is filtration from blood vessels within the in experimental animals.25,44 The first change is
perilymph space, since blocking the cochlear an expansion of cochlear and saccular mem-
aqueduct does not appear to affect inner ear branes, which may completely fill the perilym-
morphology or function.24,25 phatic space. The anatomic changes resulting
The main sites for the production of from this experiment are comparable to those
endolymph are the marginal cells of the stria found in the temporal bones of patients with
vascularis of the cochlea and the dark cells of Meniere’s syndrome (either idiopathic or sec-
the vestibular labyrinth.19,26,27 Endolymph pro- ondary to known inflammatory disease).
duction is tightly coupled to K+ secretion.28,29A
Na-K-Cl cotransporter expressed in the baso-
lateral membrane of marginal and dark cells Fluid Chemistry
pumps K+ into these cells to high levels.
Potassium channels at the apical surface of the The chemical compositions of the fluids filling
marginal and dark cells allow K+ accumulating the inner ear are similar to those of the extra-
in the cells to flow back into the endolymph, cellular and intracellular fluids throughout the
thus maintaining the high K+ concentration body. The endolymphatic system contains
and the generator potential. In mice, mutations intracellular-like fluids with a high potassium
in the genes that code for the Na-K-Cl cotrans- and low sodium concentration, whereas the
porter protein or the apical K+ channel proteins perilymphatic fluid resembles the extracellular
lead to a failure to produce endolymph and a fluid with a low potassium and high sodium
phenotype of deafness and imbalance.30–32 concentration.36,45 Figure 2–8 shows the
Cellular water channels, aquaporins, are essen- relationship between electrolytes and protein
tial for the fluid regulation of several organs concentration of the different fluid compart-
(e.g., kidney, lung, and brain), and aquaporins ments.21,46 The high protein content in the
1–6 are widely expressed in the inner ear but endolymphatic sac, compared with that in the
their role in labyrinthine fluid dynamics is yet rest of the endolymphatic space, is consistent
to be defined.33 with the sac’s role in the resorption of endo-
Three theories have been proposed regard- lymph. The difference in protein concentration
ing the regulation of endolymph volume. The between perilymph and CSF argues against a
longitudinal, or Guild, theory34 assumes that free communication between the compart-
endolymph is produced in the cochlea and ves- ments of these two fluids and in favor of an
tibular labyrinth and flows toward the endo- active process of perilymph production. The
lymphatic sac, where it is resorbed. The radial electrolyte composition of the endolymph is
theory assumes a local transverse and active critical for normal functioning of the sensory
diffusion process between endolymph and per- organs bathed in fluid. Rupture of the mem-
ilymph.35 The dynamic theory, a combination branous labyrinth in experimental animals
of the Guild and radial theories, assumes a causes destruction of the sensory and neural
radial ionic diffusion process and a slow longi- structures at the site of the endolymph–
tudinal bulk process.36,37 perilymph fistula.47
The pressure of the inner ear fluids has been It is possible to sample the fluid in the vesti-
shown by direct measurements to be different bule by introducing a micropipette through a
from the atmospheric pressure of the middle tiny fistula in the footplate of the stapes.48,49
ear.38–41 The perilymph and endolymph are The fluid obtained normally has the chemical
composition of perilymph given in Figure 2–8. The anterior vestibular vein drains the utri-
In 29 patients with vestibular schwannomas, cle and the ampullae of the anterior and hori-
the protein content of the perilymph was con- zontal canals; the posterior vestibular vein
sistently elevated, with an average value of drains the saccule, the ampulla of the posterior
1800 mg.49 Elevation of perilymph protein can canal, and the basal end of the cochlea
occur when the protein content of CSF is nor- (Fig. 2–9B).51,52 The confluence of these veins
mal or only slightly elevated. The electrolyte and the vein of the round window becomes the
composition of perilymph remains normal in vestibulocochlear vein. Blood from the cochlea
such patients. In patients with Meniere’s syn- is carried primarily by the common modiolar
drome, the markedly dilated sacculus or herni- vein and, when joined by the vestibulocochlear
ated cochlear duct is usually in contact with the vein, becomes the vein at the cochlear aque-
footplate, so that endolymph rather than peri- duct. This large venous channel enters a bony
lymph is obtained from tapping the vestibule. canal near the cochlear aqueduct to empty into
The chemical composition of perilymph the inferior petrosal sinus. The semicircular
obtained from other regions of the labyrinth at canals are drained by veins that pass toward the
the time of surgery is normal in patients with utricle and form the vein of the vestibular aque-
Meniere’s syndrome.49 duct, which accompanies the endolymphatic
duct and drains into the lateral venous sinus.
Blood flow (BF) from the arterioles to the
Blood Supply venules is determined by the ratio of the driv-
ing force (F) to the resistance (R) of the walls
The labyrinthine artery irrigates the membra- such that BF = F/R and the value of F is given
nous labyrinth and its neural structures and by the blood pressure difference between the
does not communicate with arteries in the otic arterioles and the venules. The value of R
capsule and the tympanic cavity.50 It usually includes the wall resistance and any outside
originates from the anteroinferior cerebellar pressure acting on the vessel walls. As in other
artery (AICA), but occasionally it arises directly organs, veins in the inner ear have lower R val-
from the basilar artery or some of its branches.51 ues than those of arterioles with intraluminar
As it enters the temporal bone, it forms pressure of 5–20 cm H2O and will collapse or
branches that irrigate the ganglion cells, nerves, expand, depending on the value of F, with
dura, and arachnoidal membranes in the inter- venules operating as effective blood reservoirs.
nal auditory canal.52 Shortly after entering the However, when the pressure outside the
inner ear, the labyrinthine artery divides into venules becomes greater than the intravenous
two main branches: the common cochlear pressure, R will increase and there will be a
artery and the anterior vestibular artery collapse of the walls, with impairment of the
(Fig. 2–9A). The common cochlear artery forms blood flow. Experimental and clinical data cor-
two branches: the posterior vestibular artery roborate the possibility of inducing ischemia
and the main cochlear artery. The latter enters and damage to the sensory cells in the auditory
the central canal of the modiolus, where it gen- and vestibular organs in combination or sepa-
erates the radiating arterioles, forming a plexus rately, either by occluding the vessels or
within the cochlea irrigating the spiral ganglion, increasing intralabyrinthine pressure.
the structures in the basilar membrane, and the The physiological and anatomical effects of
stria vascularis. The posterior vestibular artery, permanent and temporary ischemia on the
a branch from the common cochlear artery, is inner ear by occluding the internal auditory
the source of blood supply to the inferior part artery have been studied extensively in ani-
of the saccule and the ampulla of the posterior mals.53–54 Cochlear function is affected within
semicircular canal. The other primary branch 15–30 sec but can recover even after 5–10 min
of the labyrinthine artery, the anterior vestibu- of complete blood flow obstruction. If the dys-
lar branch, provides irrigation to the utricle and function is of a longer duration, the damage is
ampulla of the anterior and horizontal semicir- irreversible and associated with pathological
cular canals as well as some blood to a small inner ear changes, including sensorineural
portion of the saccule. Thus, different parts of degeneration and even new bone formation
the labyrinth can be selectively damaged by destroying the inner ear spaces. Shorter inter-
thrombotic or embolic events. vals of ischemia produce mixed functional and
(a) Basilar
artery
Anterior inferior
cerebellar artery
Labyrinthine artery Anterior
Common vestibular
cochlear artery artery
Main
cochlear
artery
Arteries
Posterior of the canals
Cochlear ramus
vestibular artery
Vestibulo-cochlear
artery
(b)
Vein of the
vestibular
Anterior aqueduct
vestibular vein
Vestibulo
Anterior cochlear
spiral vein vein
Posterior Veins of
vestibular vein the canals
Posterior Vein of the round window
spiral vein Common Vein at the
modiolar vein cochlear aqueduct
Figure 2–9. Arterial (a) and venous (b) labyrinthine circulation. (From Schuknecht HF. Pathology of the Ear. Harvard
University Press, Cambridge, 1974, with permission.)
morphological changes. Interfering with endo- the lateral end is closed by a thin bony plate,
lymph circulation (experimental hydrops), and the lamina cribrosa.57 Through tiny perfora-
thus increasing inner ear pressure, can impair tions in the lamina cribrosa, the afferent and
labyrinthine blood flow.55,56 efferent vestibular and cochlear nerve fiber
endings pass into the labyrinthine cavity to
contact the sensory organs. The lamina crib-
Innervation rosa is divided into an upper and a lower
section by the crista falciformis; each of
The medial end of the internal auditory canal these halves is in turn divided by vertical bony
opens into the cerebellopontine angle cistern; cristae into an anterior and a posterior section.
The auditory nerve, consisting of approxi- The placode invaginates into the otic pit, which
mately 30,000 fibers, occupies the anteroinfe- becomes pinched off to form the otocyst (Fig.
rior part of the internal auditory canal, and the 2–10a-c). Concurrent with the placode-otocyst
vestibular nerve, containing approximately development, the statoacousticofacial ganglion
15,000 fibers, occupies the posterior half (both forms from the neural crest at the end of the
superior and inferior parts).58 The facial nerve third week. The geniculate ganglion then
is located in the remaining anterosuperior migrates away leaving the vestibulocochlear
quadrant. ganglion next to the otocyst.
The afferent bipolar ganglion cells of the The otocyst differentiates into the endolym-
vestibular nerve (Scarpa’s ganglion) are phatic, vestibular, and cochlear ducts
arranged in two cell masses in a vertical column (Fig. 2–10d). By the fifth week, the vestibular
within the internal auditory canal—the supe- duct begins to differentiate into the three
rior group forming the superior division of the semicircular canals and the vestibule (Fig. 2–10e).
vestibular nerve and the inferior forming the Shortly after formation of the otocyst the
inferior division (see Fig. 1–6 in Chapter 1).59,60 medial part, the endolymphatic diverticulum,
The superior division innervates the cristae of separates from the utriculosaccular chamber.
the anterior and horizontal canals, the macule This chamber then differentiates into an utric-
of the utricle, and the anterosuperior part of ular chamber that gives rise to the utricle and
the saccular macule. It leaves the internal audi- semicircular canals and a saccular chamber
tory canal through the posterosuperior fossa of that gives rise to the saccule and cochlea. The
the lamina cribrosa. The inferior division inner- utricular chamber rapidly expands into three
vates the crista of the posterior canal and the diverticula, the centers of which fuse, leaving
main portion of the macule of the saccule and the spaces around the perimeter to become the
leaves the internal auditory canal through the three semicircular ducts. The superior canal
posteroinferior area of the lamina. forms first at about 6 weeks followed rapidly by
the posterior and then the horizontal canals.
One end of each canal dilates to form the
Embryonic Development ampulla and both ends remain connected to
the utricle.
Embryonic development of the inner ear The cochlear duct becomes separated from
largely mirrors the phylogenic development the saccule by a narrowing at its dorsal end to
discussed earlier.61–64 In the embryo, the mem- form the ductus reunions. The cochlear turns
branous labyrinth begins as an ectodermal begin to form by the sixth to seventh week, with
thickening, the otic placode, on each side of completion of two and one-half turns by the
the rhombencephalon (Fig. 2–10). The primi- eighth week. By the end of the fifth month, the
tive otocyst forms by invagination of the otic primitive organ of Corti has formed within
placode, which becomes the inner layer of the the cochlear duct. The vestibulocochlear gan-
membranous labyrinth. Three components glion divides into a superior portion that sends
develop through infolding of the walls of the fibers to the utricle and ampullae of the ante-
otocyst: (1) the endolymphatic duct and sac, rior and horizontal semicircular canals and into
(2) the utricle and semicircular canals, and an inferior portion that sends fibers to the sac-
(3) the saccule and cochlear duct. The walls of cule and the ampulla of the posterior semicir-
the membranous labyrinth consist of an inner cular canal. The remainder of the ganglion
layer of ectodermal origin and an outer layer of becomes the spiral ganglion of the cochlea.
mesodermal origin separated by a basement The hair cells in the sensory epithelium do
membrane. These regions of the inner layer not develop until the afferent nerve endings
subsequently develop into specialized sensory arrive. By the end of the third week a large area
organs. of specialized neuroepithelium appears. The
The timing of the development of the differ- upper part of the neuroepithelium becomes
ent inner ear structures is important to know the utricular macule and the cristae of the supe-
since developmental defects can occur at each rior and horizontal semicircular canals and the
stage of development. The inner ear begins to lower part becomes the saccular macule and
develop approximately 3 weeks after concep- the crista of the posterior semicircular canal.
tion with development of the otic placode. Vestibular hair cells showing typical synapses
(a) (b) Hindbrain

Otic
placode
Acoustico
facial Otic pit
ganglion
Dorsal
aorta
Entoderm
Mesoderm
Pharynx
Ectoderm
(c) Early phase

of otocyst Hindbrain
Differentiation
of otocyst
(otic vesicle)
Dorsal aorta
Mesenchymal
condensation
for future
ossicles
(d) Endolymphatic duct (e) Semicircular

canals
Vestibular
duct
Vestibule
Cochlear duct
Cochlea
Developing eustachian
tube
Figure 2–10. Embryological development of the ear: (a) otic placode stage, (b) otic pit stage, (c) otocyst-otic vesicle
development, (d) and (e) labyrinthine development. (Adapted from Pearson AA. The development of the ear: A manual.
American Academy of Ophthalmology and Otolaryngology, Rochester, MN, 1967.)
with nerve endings are present by 9 weeks. The from a prosensory region of the otocyst
sensory epithelium is mature in the macules by defined by the asymmetric expression of
about 15 weeks, in the cristae by about transcription factors. The Notch signaling
23 weeks, and in the organ of Corti by about pathway is key for specifying the prosensory
25 weeks. region and for determining whether a cell
The molecular mechanisms underlying the differentiates into a hair cell or a supporting
development of individual sensory organs in cell (through the process of lateral inhibition).
the inner ear have largely been worked out in The level of Notch activation determines
chicks, zebrafish, and mice.65 Differences occur whether a cell becomes a hair cell (low), sup-
between species, but certain patterns are porting cell (high) or a prosensory progenitor
common. All of the sensory organs develop cell (intermediate).
THE HAIR CELL synaptic terminals from afferent and efferent

neurons. The hair cells are surrounded by sup-
Morphologic Characteristics porting cells whose top surface is covered with
microvilli. The supporting cells extend the
In the vestibular organs of avians and mam- whole length of the sensory neuroepithelium
mals, there are two different types of hair from the basal membrane to the surface. Their
cells—type I and type II (Fig. 2–11, also see nuclei line up in a row immediately above the
Fig. 1–1 in Chapter 1). Type I hair cells are basal membrane (Fig. 2–11A,B). By contrast,
globular and are completely surrounded by a the nuclei of the hair cells are midway between
large calyx nerve terminal. The afferent fibers the basal membrane and the luminar surface.
that give rise to these nerve calices are among This pattern of nuclear organization is similar
the largest in the body, measuring more than throughout all vertebrates. Supporting cells
20 µm in diameter in some lower animals and can differentiate into new hair cells following
10 µm in humans. Efferent nerves synapse on destruction of the sensory epithelium. This was
the outside surface of the calices. Type II hair initially seen in the cochlea of quail and chicken
cells are cylindrical and receive numerous small after acoustic trauma66,67 and then in the cochlea
Figure 2–11. Mammalian hair cells. (A, B) Photomicrographs of chinchilla crista (cross section). Long arrows, type I hair
cells; open arrows, type II hair cells; arrow heads, supporting cells, curved arrows, afferent nerve fibers. B is an enlargement
of the box outlined in A. Bar, 10 µm. (C, D) Electron micrographs of type I and type II hair cells from the chinchilla. Type I
hair cells are surrounded by the chalice ending of an afferent nerve fiber, whereas type II hair cells are contacted by afferent
nerve boutons (arrows). SC, supporting cell. Bar = 1 µm.
and vestibular labyrinth of mammals after drug of the same or other cells or the extracellular
ototoxic exposure.68,69 matrix.70,71 Many of the genes and proteins
associated with mechanosensory transduction
TIP-LINKS in the vestibular organs of invertebrates and
vertebrates have been identified and some are
The tips of the cilia are connected by extracel- highly conserved, particularly those coding for
lular linkages called tip-links.70–72 These struc- proteins in the tethers.70,75 Cadherins and pro-
tures are already seen in primitive aquatic tocadherins form part of the tethers from the
animals. The basic elements of a tip link include most primitive metazoan phyla to vertebrates,
an ion channel, an interconnecting tether, and including primates. Mutations in the rare tip-
a motor protein (Fig. 2–12). The motor protein link motor protein, myosin VIIa, cause vestibu-
moves along actin filaments and is critical for lar and auditory loss in humans and flies.
adaptation to prolonged stimuli.73 Mechano- Channel genes are less conserved, and so far
sensory ion channels are already present in the gene for the putative mechanosensory
single-cell organisms where they function to channel in vertebrates has not been identified.
prevent osmotic shock as the bacterium moved The transient receptor potential (TRP) super-
from salt to fresh water.74,75 These primitive family of mechanosensory channels is critical
mechanosensory channels have an iris-like for hearing in the fruit fly and touch in the
opening that enlarges with tension acting in the nematode but not for hearing or vestibular
plane of the cell membrane. The next major function in mammals.76
development is a tether that couples the chan-
nel to intracellular or extracellular structures so
RIBBON SYNAPSE
that stretch on the tether opens the channel.
The tethers are attached to stiff elements The basal portion of the hair cells makes contact
within the cell such as microtubules or actin with afferent nerve terminals by way of ribbon
filaments or outside the cell to protruding parts synapses (see Fig. 1–1 in Chapter 1).77,78 These
structures that are remarkably efficient in con-
verting Ca2+ influx into neurotransmitter release
are only seen in the inner ear and eye.79 There are
approximately 10 to 20 synapses per hair cell, and
each synapse contains 100 to 200 synaptic vesi-
Motor proteins cles. Of these about 15 vesicles are docked
beneath the ribbon ready to release their con-
Mechanosensory tents into the extracellular space. Within each
channels receptor central hair cells of both types have more
synaptic ribbons than do peripheral hair cells. 80
Tip link
Sequence of Hair Cell Activation
Actin
Bending of the hair bundle toward the kinocil-
filaments ium opens the mechanically gated ion channels,
causing an influx of potassium. The resting
potential of the hair cells is between –50 and
–70 millivolts and as the potential rises above
–50 millivolts, voltage-gated calcium channels
at the base open, allowing an influx of calcium
ions. The calcium binds to a calcium sensor pro-
Figure 2–12. Schematic model of hair cell transduction. tein in the ribbon synapse (otoferin in cochlear
Shearing with positive deflection increases tension in tip
links, which pull open a transduction channel at each hair cells), activating the SNARE complex of
end. Myosin motors slip or climb on actin filaments to proteins releasing packets of glutamate into the
restore resting tension. An elastic gating spring likely exists synaptic cleft.77,81 AMPA receptors in the affer-
between a channel and the actin cytoskeleton. (Adapted ent nerve terminals are activated, leading to an
from Vollrath MA, Kwan KY, Corey DP. The microma-
chinery of mechanotransduction in hair cells. Ann Rev
approximate linear relationship between Ca2+
Neurosci. 2007;30:339, with permission.) influx and afferent nerve firing.82 A glutamate
transporter removes glutamate from the synap- cellular space), while the basolateral membrane
tic cleft.83 About 13% of the transduction chan- is surrounded by perilymph rich in Na+ (like the
nels are open at rest, resulting in a resting extracellular space). In the cochlea, the peri-
current flow through the hair cells and a resting lymph is at zero voltage in relation to the rest of
firing rate of the afferent nerves (see Hair Cell the extracellular space of the body, but the
Influence on Afferent Nerve Activity).84 endolymphatic space has a positive potential
(+80 mV). In the vestibular labyrinth, the posi-
tive potential is smaller (+5 to 10 mV). The
Relationship between the Direction hair-bearing surface of the cell membrane is
of Force and Hair Cell Activation morphologically different from the rest, being
thicker and more electron dense. This part of
The adequate stimulus for hair cell activation is the cell membrane is depolarized because of the
a force acting parallel to the top of the cell, equal K+ concentration outside of the cell in the
resulting in bending of the hairs (a shearing endolymph and inside of the cell. It acts as a
force).85 A force applied perpendicular to the passive resistor between the inside and outside
cell surface (a compressional force) is ineffec- of the hair cell whose value is modulated by the
tive in stimulating the hair cell.86,87 The stimulus mechanical deformation associated with the dis-
is maximal when the force is directed along an placement of the hairs (Fig. 2–13). This concept
axis that bisects the bundle of stereocilia and represents the essence of the Davis mechano-
passes through the kinocilium (see Fig. 1–1 inset electric theory of hair cell function.89–93 Because
in Chapter 1). Deflection of the hairs toward the of the electrical gradient across the luminal (top)
kinocilium decreases the resting membrane part of the membrane, a current flow exists from
potential of the sensory cells (depolarization). the endolymph to the inside of the cell and out,
Bending in the opposite direction produces the through the basolateral membrane, which is
reverse effect (hyperpolarization).88 The effect known as the “current of silence,” a resting cur-
is minimal when hair deflection is perpendicu- rent. The basic concept of the Davis theory has
lar to the axis of maximal excitation. been upheld by demonstration of transmembrane
potential changes and associated impedance
modulation during deflection of the stereocilia.
Mechanism of Hair Cell Activation Intracellular recordings from hair cells of
amphibians and mammals have expanded our
The top surface of hair cells in mammals faces knowledge of the mechanoelectric transduction
the endolymph, a fluid rich in K+ (like the intra- process.92,93 When hair cells are stimulated,
Hair cell
displacement
Hair cell
resistance
+
Endolymph
voltage
–
Hair cell
current
VIIIth nerve
activity
Figure 2–13. Mechanism of hair cell activation. Sinusoidal displacement of the stereocilia produces a sinusoidal modula-
tion or the vestibular nerve firing rate. See text for details.
there is a change in the electric current begin- In contrast to nerve action potentials, the gen-
ning at the tips and the lumen of the stereocilia erator potentials have no refractory period (fol-
to the inside of the cell. This “transduction” cur- lowing the frequency of the stimulation above
rent causes a series of additional changes in the several thousand hertz), are highly resistant to
permeability of different ion channels in the anoxia, and may remain partially active after
basolateral membrane, leading to depolariza- the animal’s death. The electric current associ-
tion of the hair cell membrane and release of ated with the generator potentials acts upon
neurotransmitters (see earlier discussion). the synaptic contacts between hair cells and
There is a diversity of ion channels expressed in nerve terminals by activating chemical trans-
the hair cells.94–96 For example, type I hair cells mitters to modulate the firing of action poten-
express a K+ channel that results in an unusually tials by the afferent neurons (Fig. 2–13).
low input resistance compared to that expressed Hair cells are not passive elements; they
by type II hair cells.97 actively participate in the mechanotransduction
Measurement, with intracellular electrodes, process.100 In particular, outer cochlear hair
of the hair cell responses to cilia deflection cells, which contain several contractile pro-
shows that the curve relating the receptors’ teins,101 vary their length under direct
potential to the stimulus has greater sensitivity electrical stimulation.102,103 This electromotility
and linearity for small signals.98,99 Larger stimuli of the outer hair cells is dependent on a protein,
exhibit saturation or nonlinearity that is greater prestin, isolated with comparative cDNA
for hyperpolarizing than for depolarizing stim- analysis of the inner and outer hair cells.104
uli, leading to smaller responses, hence lower Recombinant prestin introduced into cultured
gains for deflection away from the kinocilium kidney cells provides them with contractile
(Fig. 2–14). The voltage drop produced in the properties normally not present. Presumably,
vicinity of the hair cells by the changing current during acoustic stimulation, prestin experiences
is known as the microphonic potential, the so- an electric charge realignment that results in
called generator potential of these receptor morphological changes in the shape of the outer
organs.89 It is maximal at the tips of the hairs.91,99 hair cells, elongating during hyperpolarization
and contracting during depolarization. These
Flexion conformational changes would influence the
−10° 0 +10° displacement of the basilar membrane in a pos-
100
itive feedback configuration facilitating the
+6 physiological stimulation of inner hair cells, in
essence acting as the amplifier of the acoustic
% Full responce
Responce (mV)
+4 energy entering the ear.105 In vestibular hair

cells, the stereocilia contain actin molecules
+2 and can carry out flagella-type movement.97,106,107
The cilia length varies among hair cells and
0 location, but it is logical to expect that anatomic
differences in stereocilia will result in differ-
−2 0 ences in the process of transducing head-motion
−1.0 0 +1.0 information into neural signals. Although not
Displacement (µm) proven, it is possible that hair cells at the periph-
Figure 2–14. Intracellular voltage changes (mV) associ-
ery of the vestibular organs actively pull the
ated with displacement of cilia of a hair cell from the frog cupula or otolithic membrane to influence the
saccule. Cilia bending toward the tallest stereocilia produce response of the more centrally placed hair cells,
a positive depolarizing change whereas motion in the oppo- analogous to the effect of cochlear outer hair
site direction results in a negative hyperpolarizing change. cells on inner hair cell walls.
Note that the curve relating the receptor potential to the
degree of deflection (µm) has the greatest sensitivity and
linearity for small deflections and exhibits a saturation non-
linearity for large displacements that is greater for hyper- Hair Cell Influence on Afferent
polarizing than depolarizing stimuli. (From Hudspeth AJ, Nerve Activity
Corey DP. Sensitivity, polarity, and conductive change in
response of vertebrate hair cells to controlled mechanical
stimuli. Proc Natl Acad Sci USA. 1977; 74:2407–2411 with One of the most significant findings concerning
permission.) hair cell function was the discovery by Hoagland
in 1932 that the afferent nerves from lateral-line through both presynaptic and postsynaptic mech-
organs of fish generated continuous spontaneous anisms. The number of vesicles (both total and
activity.108 This observation has subsequently docked) at the ribbon synapse can be up and down
been confirmed in all other hair cell systems and regulated based on a number of factors, including
represents a fundamental discovery in sensory synaptic activity.78 The afferent nerve terminals
physiology. As noted earlier, baseline current express AMPA, NMDA, and GABA type B recep-
flow through the hair cells generates the sponta- tors along with a wide range of ion channels, all of
neous activity and depolarization and hyperpo- which can be up and down regulated. For exam-
larization of the hair cells’ membrane potential ple, the number of AMPA receptors (GLuR 2-4)
modulates the spontaneous activity. Bending of expressed depends on the amount of glutamate
the hairs toward the kinocilium results in an released and on NMDA receptor activity.114
increase of the spontaneous firing rate, and
bending of the hairs away from the kinocilium
results in a decrease of the firing rate.109 The
spontaneous firing rate varies in different animal THE INNER EAR VESTIBULAR
species and in different sensory receptors. It is RECEPTORS
thought to be greatest in the afferent neurons of
the semicircular canals of mammals (up to 90 The vestibular system monitors the forces asso-
spikes/sec) and lowest in some of the acoustic ciated with angular and linear accelerations of
nerve fibers innervating mammalian cochlear the head by means of five organs located within
hair cells (1 to 2 spikes/sec).110,111 Given the non- the labyrinthine cavities of the temporal bones
linear behavior of the hair cell transduction on each side of the skull.115 The saccular and
mechanism, it is not surprising that the modula- utricular macules sense linear acceleration, and
tion of the spontaneous neuronal firing rate is the cristae of the three semicircular canals
likewise nonlinear. Responses to excitatory stim- sense angular acceleration of the head.
uli are more than those to inhibitory stimuli. This
asymmetry in response is of great physiological
and clinical significance, as will be shown later. Anatomy of the Semicircular Canals
The semicircular canals are three membranous
Signal Processing at the Hair Cell/ tubes with a cross-sectional diameter of 0.4 mm;
Afferent Nerve Junction each one forms about two-thirds of a circle with
a diameter of about 6.5 mm.116 They are aligned
The hair cell is a relatively simple force transducer to form a coordinate system (see Fig. 1–4c in
mirroring the biomechanics of the forces acting Chapter 1).117,118 The plane of the horizontal
on the surrounding tissues. Yet complex signals semicircular canal with two openings on the
originate from the afferent nerves at the base. lateral wall of the utriculus makes a 30-degree
Signal processing must be interposed between angle with the horizontal plane. The other two
the hair cell and the afferent nerve to account for canals are in vertical positions almost orthogo-
the wide range of afferent nerve responses.112,113 nal to each other. The anterior canal is directed
This signal processing can be traced to at least medially and laterally over the roof of the utric-
four different processes: (1) neurotransmitters ulus, and the posterior canal is directed down-
released by the hair cells, (2) neurotransmitters ward and laterally behind the utriculus. The
released by efferent terminals, (3) adaptation at two vertical canals share a common opening on
the ribbon synapse, and (4) a diversity of receptors the posterior side of the utriculus. Precise mea-
and ion channels in the afferent terminals. surement of the planes of the canals, however,
Glutamate is the main neurotransmitter at the indicates that they are not aligned perfectly
hair cell–afferent nerve junction, but other trans- orthogonal. All angular movements stimulate at
mitters, including gamma-aminobuteric acid least two canals and often all three.
(GABA), are also released. Hair cells in different
receptors and in different locations within the CRISTA
receptors release different combinations of trans-
mitters. Acetylcholine (Ach), released by the At the anterior opening of the horizontal and
efferent system, modulates afferent nerve firing anterior canal and the inferior opening of the
posterior canal, each tube enlarges to form the Physiology of the Semicircular
ampulla. A crest-like septum, the crista, crosses Canals
each ampulla in a perpendicular direction to
the longitudinal axis of the canal (see Fig. HISTORICAL BACKGROUND
1–4a,b in Chapter 1). It rests on the bone of
the canal and consists of sensory epithelium The functional role of the semicircular canals
lying on a mound of connective tissue, where was first linked to their gross anatomic features
blood vessels and nerve fibers reach the sen- by Flourens in 1842.124 While studying the audi-
sory receptor area. In the human vestibular tory labyrinth in pigeons, he noted that opening
organ, there are approximately 23,000 hair cells a semicircular canal resulted in characteristic
(type I and type II) in the three cristae and head movements in the plane of that canal.
about 52,000 in the two macules.119,120 The Several subsequent investigators proposed that
number of neurons innervating the three cris- movement of endolymphatic fluid within the
tae is approximately 5700 and the two macules, canal was responsible for excitation of the cris-
approximately 8600, for a total of approximately tae.125–127 It was not until the studies of Ewald in
14,300 nerve fibers.121 In the chinchilla, for 1892, however, that a clear relationship was
which more accurate measurements are avail- established between the planes of the semicir-
able, the number of hair cells (type I and type cular canals, the direction of endolymph flow,
II) in the crista of the horizontal semicircular and the direction of induced eye and head
canal is about the same as the number of sup- movements.128 Exposing the membranous laby-
porting cells (about 5000 of each). In the mon- rinth of the semicircular canals of pigeons,
key crista, type I hair cells outnumber type II Ewald applied positive and negative pressure to
hair cells by almost 3:1 with the ratio being each canal membrane to cause ampullopetal
>4:1 in the central zone and <2:1 in the periph- (toward the ampulla) and ampullofugal (away
eral zone.122 In the chinchilla crista the ratio of from the ampulla) endolymph flow. Three
type I to type II hair cells is near 1:1 through- important observations, which became known
out.122 as Ewald’s laws, were (1) the eye and head
movements always occurred in the plane of the
canal being stimulated and in the direction of
endolymph flow, (2) ampullopetal endolymph
CUPULA
flow in the horizontal canal caused a greater
The cupula is composed of a mixture of response (i.e., induced movements) than did
glycoproteins and proteoglycans secreted into ampullofugal endolymph flow, and (3) ampull-
the endolymph by specialized endothelial ofugal endolymph flow in the vertical canals
cells.123 It is composed of densely packed caused a greater response than did ampullopetal
filaments 40–60 nm in diameter cross bridged endolymph flow.
by thinner filaments. Between the crista Steinhausen129 and later Dohlman130 visual-
and the cupula a subcupular meshwork is ized the movement of the cupula during endo-
composed of long branching filaments lymph flow. By injecting India ink into the
(50–70 nm in diameter) oriented parallel to semicircular canals of fish, these investigators
the main axis of the stereocilia. The subcupular demonstrated that the cupula formed a seal with
filaments are connected to the cupular the ampullary wall and moved with the endo-
filaments on one side and to the sensory lymph. Steinhausen, noticing the similarity
epithelium on the other side. The cupula between the cupular movement and that of a
extends all the way to the roof of the ampulla. pendulum in a viscous medium, proposed a
The tips of the stereocilia are tightly connected model for the description of cupular kinematics
to the subcupular meshwork and sometimes that became known as the pendulum model.
the longest stereocilia or the kinocilia Although the large movements observed by
protrudes into the cupula and is connected Steinhausen were later realized to be artifactual,
to the cupular filaments. The subcupular the basic principle has been upheld by most
meshwork may help transmit the shearing experimental131 and theoretical studies.132,133
force of the cupula to the ciliary bundle Physiologic verification of the model has
and dampen unwanted vibrations. been made by detailed study of the relationship
between angular head acceleration and the cupula–endolymph system can be obtained if
flow of action potentials in isolated ampullary the values of these coefficients are known.
nerve fibers. These studies were first conducted For natural to-and-fro head movements, the
in elasmobranchs by Lowenstein and Sand,134 magnitude of the elastic and inertial forces is
later in frogs,135,136 pigeons,137 and mam- negligible and the following simplified equation
mals,138–141 and first in primates by Goldberg describes the kinematics of the cupula system:
and Fernández.111,142,143
(t)
CΘ (t)
MΘ [2]
c h
PENDULUM MODEL
The force applied to the cupula–endolymph
The pendulum model is the most useful didac- system during angular head acceleration is
tic model for describing the physiologic prop- opposed mostly by the viscous drag of the cup-
erties of the semicircular canals and, as will be ula. Integrating Equation 2 we have
shown later, for describing the semicircular
canal-induced reflexes, especially the vestib- M
ulo-oculomotor reflexes.132,144 Θc ( ) Θ h (t) [3]
The cupula acts as the coupler between the C
force due to angular acceleration of the head Thus, the displacement of the cupula system
and the hair cells (the transducer of mechanical during natural head movements is proportional
to biological energy), leading to the production to the velocity of head motion rather than head
of action potentials in the vestibular afferent acceleration. The magnitude of the proportion-
fibers. Because of the configuration and dimen- ality constant (M/C) relating angular deviation
sions of the canals, the endolymph can move in of the cupula in degrees to the velocity of the
only one direction along the cylindrical canali- head in degrees per second has been estimated
cular cavity. According to Newton’s third prin- to be approximately 0.003 sec, based on the
ciple, when an angular acceleration [and hence physical characteristics of the canals and endo-
a force MΘ̈h(t)] is applied to the head, displace- lymph.145 Most likely, during fast head move-
ment of the cupula–endolymph system acting ments with velocities as great as 800 degrees /
as a solid mass is opposed by three restraining sec, the deviation of the cupula does not exceed
forces: (1) an elastic force [KΘc (t)] due to the 1degree of deflection.120
cupula’s spring-like properties (which is pro- Figure 2–15 illustrates the relationship
portional to the magnitude of its displacement), between the time course of head acceleration,
(2) the force due to the cupula–endolymph vis- head velocity, and cupular displacement as
cosity [CΘ̇c (t)] (whose magnitude is propor- predicted by the pendulum model for three
tional to the velocity of its displacement), and different types of angular rotation commonly
(3) an inertial force [MΘ̈c(t)] due to the fluid’s used in clinical testing. The description of cup-
mass (proportional to the acceleration of the ular displacement during constant angular
fluid–cupula complex). Cupular displacement acceleration (Fig. 2–15a) can easily be derived
can be described by the following equation, from Equation 1. At the beginning of head
which is referred to as the equation of the pen- acceleration, endolymph movement lags
dulum model of semicircular canal function: behind the displacement of the head and
thereby that of the walls of the semicircular
(t) CΘ
MΘ ( t ) KΘ ( t ) = MΘ
(t) [1] canals. After a few seconds, however, a balance
c c c h
is established between the applied and restrain-
where Θc is the angular displacement of the ing forces, and the endolymph moves simulta-
cupula–endolymph system with respect to the neously with the walls of the labyrinth. At this
wall of the canals, Θ̇c and Θ̈c are the first (veloc- time the position of the ring of fluid within the
ity) and second (acceleration) time derivatives canal and therefore the position of the cupula
of the cupular displacement, and Θ̈h is the Θc(t) differ from the initial conditions, having
angular acceleration of the head. M is the been displaced by a certain amount in the
moment of inertia; C, the moment of viscous direction of the force. The magnitude of
friction; and K, the moment of elasticity. A the displacement can easily be calculated.
complete description of the kinematics of the Once the endolymph is stationary, the cupula
a. Constant acceleration stimulus

100%
Stimulus
Velocity
Acceleration
0
displacement 100%
Cupula
63
37
0
T1 T1
b. Impulse stimulus
100%
Stimulus
Velocity
Acceleration
0
displacement
100%
Cupula
37
0
T1
Time
c. Sinusoidal stimulus
max Acceleration
Stimulus
max Velocity
displacement
100%
Cupula
100%
Figure 2–15. Relationship between cupular displacement and three types of angular acceleration of the head (a–c) as
predicted by the pendulum model.
velocity Θ̇c(t) and its acceleration Θ̈c(t) in The relationships embodied in Equations 3
relation to the walls are zero and, consequently, and 4 are two of the fundamental concepts of
the terms for viscous and inertial restrain- cupular function. To restate them: the maxi-
ing forces vanish in Equation 1, which now mum deviation of the cupula increases propor-
reduces to tionally to the magnitude of head velocity
(t) during sinusoidal head rotations at the frequen-
KΘ (t) MΘ
c h cies of natural head movements and to the
or magnitude of head acceleration during rotation
with constant angular acceleration.
M Cupula displacement after a constant angu-
Θc ( ) Θ h (t) [4] lar acceleration stimulus follows an exponential
K time course (Fig. 2–15a) that can be deter-
That is, the final displacement of the cupula mined by a more detailed mathematical treat-
depends on a proportionality constant and ment of Equation 1. Sixty-three percent of the
on the magnitude of the constant angular total cupular deviation, regardless of its final
acceleration. value, always takes place after a fixed delay
determined by what is known as the long time the cosine function at that instant in the cycle
constant (T1) of the system. The subsequent of motion. Since this value oscillates between
deviation of the cupula increases at the same + 1 and −1, the head velocity ranges between
rate (63% of the remainder every T1 seconds), +ωA and −ωA. These relationships are felt to
so that 95% of the final deviation will take place apply for sinusoidal rotations between 0.1 and
after approximately 3T1 sec. The magnitude of 4.0 Hz and therefore cover the range of most
the time constant depends on the viscous and natural to-and-fro head movements.118
elastic coefficients: T1 = C/K. That is, the time
the cupula takes to reach a maximum deviation
is directly proportional to the viscosity of the Anatomy of the Otolith Organs
endolymph and inversely proportional to the
elasticity of the cupula. T1 cannot be measured MACULES
directly, but it has been estimated to be
about 7 sec, based on the average response The two otolith organs consist of a sensory area
of primary afferent neurons in the squirrel (i.e., the macules) and a surface area (i.e., the
monkey.111,142,143 otolithic membrane), which are located in the
According to the pendulum model, not only middle chamber of the inner ear (i.e., the vesti-
is the initial deviation of the cupula related bule). The vestibule is oval in shape, connecting
to the constant acceleration stimulus, but after to the membranous semicircular canals via five
the stimulus is terminated the cupula returns to openings. The saccule lies on the medial wall of
the resting position with the same exponential the vestibule in a spherical recess inferior to the
time course. It was precisely the observation by utricle with which it is in contact but without
Steinhausen119 of the slow exponential-like direct connection.115 It communicates with the
return of the cupula to the resting position after endolymphatic duct (and thus the utricular
it had been deviated that led to the formulation duct) by the saccular duct and with the cochlea
of the pendulum model. by the ductus reuniens (see Fig. 2–8). The mac-
The cupular displacement following a brief ule of the saccule is a differentiated patch of
impulse of angular acceleration is given in membrane in the medial wall, is hood shaped,
Figure 2–15b. This type of angular accelera- and lies predominantly in a vertical position
tion, although the least natural, is of great value (see Fig. 1-3c in Chapter 1). The macule of the
in clinical vestibular testing. An impulse of utricle is located next to the anterior opening of
acceleration is generated by changing the the horizontal semicircular canal and lies mostly
velocity of the head (∆Θ̇h) with the maximum in a horizontal position in a recess on the anterior
acceleration possible. The maximum deviation part of the utricle. The utricle communicates by
of the cupula takes place almost immediately the utricular duct with the endolymphatic duct
and is proportional to the magnitude of the at the same level as, but by different openings
instantaneous change in head velocity from, those of the saccular duct. Thus, the
Θc(t) ≈ ∆Θ̇h. Of particular note, the cupular endolymph in the superior or utricular part of
deviation thereafter decays exponentially with the labyrinth is separated from that of the sac-
the same time constant to return to 63% of the cule and cochlea by these tiny ducts.
maximum deviation.
The sinusoidal rotation in Figure 2–15c most PRODUCTION AND MAINTENANCE OF
closely resembles natural head movements OTOCONIA
because movement in one direction is followed
by movement in the opposite direction. Most Otoconia are complex calcium carbonate
natural head movements can be broken down (CaCO3) biominerals that serve an important
into a series of sine waves with different fre- role in both normal and abnormal vestibular
quencies and amplitudes. According to function (also see Chapter 10). Otoliths is
Equation 3, the cupular displacement Θc(t) is another word for otoconia. Thousands of tiny
given by ωA cos ωt (the differential of head dis- calcium carbonate crystallites (0.1 to 25
placement A sin ωt), where ω is the radian fre- micrometers) surround a glycoprotein/proteo-
quency (2 πf) of head rotation and A is the glycan core that is bound to the underlying
angular head displacement. The head velocity amorphous gelatinous layer by fibrous proteins
at a given time t is proportional to the value of (Fig. 2–16, also see Fig. 1–3 in Chapter 1).147,148
Otoconia
Gelatinous layer
Otogelin
Subcupular meshwork
α-tectorin
β-tectorin
Otoancorin
Macula
Hair cells (hc)
tc hc Support cells (sc)
Otopetrin 1 Transitional cells (tc)
NOXA 1 sc
NOX 3
Basement membrane
Figure 2–16. Schematic representation of the utricular macule. The macule is composed of sensory hair cells (hc) and sup-
porting cells (sc); transitional cells (tc) border the edge of the macules. Directly above the macule, the otoconial membrane
is composed of the subcupular meshwork, a fibrillar structure which rings the stereociliary projections of each hair cells, and
the gelatinous membrane which is amorphous. Otoconia, CaCO3 biominerals precipitated around a proteinaceous core, are
embedded in the gelatinous membrane and maintained in place by strands of noncollagenous extracellular matrix proteins
that resemble beads on a string. Proteins that have been identified to influence the activity or structure of each of these
layers are listed on the left. (Adapted from: Hughes I, Thalmann I, Thalmann R, Ornitz DM. Mixing model systems: Using
zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development. Brain
Res. 2006;1091:58 with permission.)
Between the gelatinous layer and the sensory otoconia and may have an increased risk of
epithelium a dense reticular network of fibril- developing benign positional vertigo.153
lar proteins ring the stereocillary projections of Much of the information regarding the genes
the hair cells. In the mouse, otoconia form over and proteins critical for otoconia production
the sensory epithelium of the macules when and maintenance have been determined
core proteins (mostly Otoconin 90) coalesce through the study of mutant mice and
into distinct structures at approximately embry- zebrafish.148 Many of these animals were first
onic day 14.149 Calcification of the protein identified as having a possible vestibular disor-
structures rapidly occurs over the next few der after observing behavioral features that
embryonic days. Normal production of the might suggest inner ear dysfunction (e.g.,
otoconial membrane requires an ordered dancer, backstroke, head tilt, twirler). Knockout
sequence of events, including localized pro- models have also provided insight into impor-
duction and export of otoconial matrix proteins, tant proteins for otoconia production.
assembly of the protein core from free-floating Interestingly, despite the numerous animal
matrix proteins, and locally increasing Ca2+ and models with absent or abnormal otoconia, so
CO3– concentrations. Inhibitors of calcification far no human counterparts have been found.
in other areas prevent more generalized calcifi- Abnormal or reduced otoconia have been pro-
cation. duced in humans and experimental animals
The rapid deposition of calcium carbonate by a range of pharmacological agents, includ-
on the protein matrix requires adequate Ca2+ ing aminoglycosides, phenytoin, carbonic
and CO3– ions. The plasma membrane calcium anhydrase inhibitors, prostaglandins, and
ATPase 2 (PMCA2) is the primary calcium ethacrynic acid.154–159 It appears that mainte-
pump for maintaining endolymph Ca2+ levels nance of normal otoconia requires the mainte-
and carbonic anhydrase generates CO3–.150,151 nance of normal hair cells. Animal models that
Once formed there is normally a low rate of lose hair cells with aging also lose otoconia.148
turnover of otoconial calcium in adult mice.152 Aminoglycosides damage hair cells and lead to
Like bone, otoconia mineralization and turn- otoconial degeneration. Alteration in endolym-
over may be sensitive to hypo and hypercalce- phatic ion concentration may be the cause of
mia. Patients with osteoporosis have abnormal both hair cell and otoconial degeneration.
Physiology of the Otolith Organs The nerve fibers of the macule are activated
by linear accelerations and by changes in head
HISTORICAL BACKGROUND positions in space.160 Each neuron has a charac-
teristic functional vector that defines the axis of
Over a century ago, Mach,125 Crum-Brown,126 sensitivity for head acceleration. Individual
and Breuer127 each concluded that linear and neurons appear to be stimulated only by con-
angular acceleration must be mediated by dif- tiguous hair cells whose kinocilium is oriented
ferent end organs, and Breuer in particular pos- with the same vector of excitability, creating a
tulated the mechanism by which the otoliths sensorineural unit (see Fig. 1–3c in Chapter 1).
sense linear acceleration. As in the case of the The combined functional units from the mac-
semicircular canals, a gross anatomic feature of ules cover all possible positions of the head in
the macules—the dense, calcified otolithic three-dimensional space. However, most of
membrane—suggested the mechanisms by the units are oriented in the horizontal plane
which they sense the direction of gravitational in the utricular macule and in the vertical plane
force. The afferent neuronal activity from the in the saccular macule.160–162
macules associated with precise static and In the utricular macule, tilting of the head
dynamic linear acceleration forces has only ipsilaterally results in an increase in firing of
recently been investigated in primates.160–162 units on the medial side of the striola and a
These studies confirm that the utricular and decrease in firing of units on the lateral side of
saccular macules are responsive to static tilt and the striola. With the subject in the upright posi-
dynamic linear acceleration, resolving an earlier tion, most of the units are at baseline because
controversy as to whether the saccular macule the vector orientation of the utricular macule is
functions as an auditory or vestibular organ. orthogonal to the gravitational vector. Because
However, we also know that the sacculus can be of the curvature of the macule, some afferent
stimulated by loud sounds, which is the basis for units are sensitive to forward and backward
the vestibular evoked myogenic potentials tilting of the head.
(VEMP) test (see Chapter 7). The pattern of Since the saccular macule is oriented in the
afferent nerve response is complex, with vari- sagittal plane, the vectors of most of the func-
ous neurons exhibiting different resting activity, tional units are parallel to gravity when the
frequency response, and adaptation properties. head is in the upright position. Because of the
push–pull relationship of hair cells on either
MECHANISM OF STIMULATION side of the striola, some functional units are
excited, whereas others are inhibited. The stri-
During head displacement, the calcified otolithic ola of the saccular macule has less curvature
membrane is affected by the combined forces of than that of the utricle and therefore most
applied linear acceleration and gravity and tends of the units have an orientation in the rostro-
to move over the macule, which is mounted in caudal direction. Baseline firing of neurons
the wall of the membranous labyrinth (see innervating the saccule and macule are about
Fig. 1–3b in Chapter 1). The otolithic mem- the same.160
brane is restrained in its motion by elastic, vis-
cous, and inertial forces analogous to the forces
associated with cupular movement. De Vries146
measured the displacement of the large saccular PRIMARY VESTIBULAR NEURONS
otolithic membranes of several fish and obtained
estimates of the forces restraining the mem- Anatomy of Primary Neurons
brane to the macules. He proposed a model,
analogous to the pendulum model, that described The bipolar primary vestibular neurons of
the dynamics of otolithic membrane displace- Scarpa’s ganglia are located within the internal
ment as those of a low-pass filter. Displacements auditory canal. The ganglia is shaped like an
due to sinusoidal linear acceleration would be hourglass with a superior division, an inferior
greatest at low frequencies, including static head division, and an isthmus (see Fig. 1–6 in
tilts. At greater frequencies, the otolithic mem- Chapter 1).163 The superior division innervates
brane displacement would decrease by one-half the horizontal and anterior canals, the utricular
each time the frequency was doubled. macule, and part of the saccular macule, while
the inferior division innervates the posterior cell body diameter in several species studied
canal and the rest of the saccular macule. (Fig. 2–17). As noted earlier, small fibers
During development the vestibular ganglia (<2.5 µm) project preferentially to the periph-
elongates with the growth of the nerves and ery of the sensory epithelium, whereas larger
temporal bone, leading to the fusiform appear- ones (>4.5 µm) project to the center.
ance seen in adults. On average there are approx-
imately 25,000 neurons in the human Scarpa’s
INNERVATION OF THE CRISTAE
ganglion.164,165 Neuronal diameters vary greatly
in each division of the ganglia. The largest neu- The highly organized innervation of the crista
rons innervate type I hair cells in the center of in the chinchilla is shown in Figure 2–18.172
the cristae and macules, and the smallest neu- Underneath the sensory organ, the main nerve
rons innervate type II hair cells in the periphery divides into two smaller ones. Each of the two
of the cristae and macules. Intermediate-sized nerve branches innervates half of the crista and
neurons innervate combinations of type I and thus half of the hair cells. Within half a milli-
type II hair cells throughout the cristae and mac- meter from the sensory epithelium, each nerve
ules (dimorphic units). Immunohistochemical divides into 8 to 10 bundles of fibers that align
studies show a differential expression of calcium- in two rows, one for each slope of the crista.
binding proteins in large and small neurons.166 Among these smaller bundles, those that inner-
Only large cells show immunoreactivity (IR) vate the center of the crista have a greater pro-
for calbindin and calretinen, while all cells portion of thick fibers, whereas the bundles
show IR for parvalbumin. Large neurons also that innervate the periphery have a preponder-
show greater IR for neurofilament proteins ance of thin fibers (Fig. 2–18a, inset).
than do small neurons.167 The bundles of fibers that innervate a dis-
Detailed study of the vestibular nerve in ani- crete area of the crista travel together toward
mals and humans reveals a highly organized the nervous system and, in all probability,
arrangement of the nerve fibers originating from innervate groups of neighboring neurons in the
the different inner ear receptors and from the vestibular nuclei. There appears to be a topo-
two types of hair cells within each receptor.168–171 graphical representation of the vestibular end
There is a similar unimodal distribution of pri- organ in the central nervous system that is
mary afferent neurons with regard to axon and comparable to the topographical projection of
Diameter: Human Monkey Chinchilla

µm
< 2.5
2.5 – 4.5
> 4.5
500 600 300

Number
of fibers
0 0 0
1.0 9.0 1.0 9.0 1.0 9.0
Binwidth = 0.5 µm
Figure 2–17. Distribution of primary afferent fibers of different diameters (including myelin) within the cristae of humans,
monkeys, and chinchillas. The smallest fibers (< 2.5 µm) are concentrated in the periphery while the largest libers (> 4.5 µm)
are more numerous at the center of the cristae. Intermediate-size fibers tend to be equally distributed throughout the
cristae.
Figure 2–18. Cross sections of the superior semicircular canal nerve as it enters the crista in the chinchilla. (a) At 20 µm
below the base of the crista the nerve fiber bundles are arranged in rows and each bundle consists of 30–50 nerve fibers.
Fibers in the periphery have smaller diameters than those in the center. (b) At 400 µm below the surface of the crista. The
nerve trunk is separated into two parts by a bony septum. (c) At 600 µm below the base of the crista. The nerve bundles of
different sizes are surrounded by the fibrous perineurium to form a single nerve trunk.
different parts in the basilar membrane of the With techniques for labeling individual neu-
cochlea to the auditory nuclei. Each of the rons and fibers by intracellular injection of
afferent bundles containing fibers of different horseradish peroxidase, detailed information
diameters—thick, medium, and thin—is has been obtained in the chinchilla regarding
derived from the same restricted area of about the association of fiber diameter size with dif-
0.2 mm2 on the crista and carries information ferent nerve endings in different parts of the
about localized cupula movement. receptors. In the crista, neurons with large axon
Classical morphologists identified three diameters (2.8 ± 0.6 µm) innervate one or a few
types of nerve endings in the receptors: hair cells with caliceal endings (type I) in the
large-diameter fibers had caliceal endings, center (Fig. 2–19).174,175 Neurons with interme-
small-diameter fibers had bouton endings, and diate-size axon diameters (2.3 ± 0.6 µm) have
intermediate-size fibers had both types of ending.173 both bouton and caliceal endings and are more
Figure 2–19. Different types of primary afferent nerve endings labeled by intracellular injection of horseradish peroxidase.
Reconstructions of two calyx units with simple (a) and complex (b) endings, a dimorphic unit (c), and a bouton unit (d), all
taken from a single horizontal canal crista, are shown. The points at which the parent axons of labeled afferents enter the
sensory epithelium are indicated on a standard surface reconstruction (center). Bar = 10 µm. (From Fernandez C, et al.
The vestibular nerve of the chinchilla. 1. Peripheral innervation patterns in the horizontal and superior semicircular canals.
J Neurophysiol. 1988;60:167, with permission.)
or less evenly distributed throughout the NEUROTRANSMITTERS

crista. Neurons with small axon diameters
Glutamate is the main excitatory neurotrans-
(1.4 ± 0.4 µm) have only bouton endings and
mitter of primary afferent neurons.177
innervate multiple type II hair cells predomi-
Immunohistochemical studies in a range of
nantly in the periphery. Of a sample of 368
species, including primates, found glutamate
fibers, 40 (11.1%) were calyx units, 79 (21.5%)
immunoreactivity (IR) in all bipolar neurons
were bouton units, and 248 (67.4%) were
in the vestibular ganglia. The majority of neu-
dimorphic units. Approximately the same dis-
rons also showed a graded IR to glycine and
tribution of fibers according to diameter size is
choline acetyltransferase (ChAT) in a highly
seen in the crista of the squirrel monkey and in
overlapping neuronal population.178 Similar
humans (Fig. 2–17).
co-localization of glycine and ChAT was also
seen in afferent terminals in the end organs.
INNERVATION OF THE MACULES Glycine and acetylcholine presumably have a
co-transmitter or modulatory function.
In the macules, as in the cristae, the diameter
of the nerve fibers has a unimodal distribu-
tion.176 Fibers of large diameter with only cal-
iceal endings predominate near the striola,
Physiology of Primary Neurons
whereas the thinner fibers innervate the periph-
SPONTANEOUS FIRING RATES
ery. Fibers of intermediate diameter (dimor-
phic) are distributed evenly throughout the Just as there is a continuous spectrum in axon
macule. In the chinchilla macule, as in the diameters, primary afferent neurons have a
crista, dimorphic units outnumber caliceal units wide range of spontaneous firing rates and
by 3 to 1. Caliceal units typically innervate more dynamic properties. It has proved useful to
hair cells (10–40) than dimorphic units (5–20). divide them on the basis of the regularity of
Table 2–1 Classification of primary afferent neurons based on their spontaneous

firing rate
Firing Response Size Conduction Galvanic Epithelial zone Afferent type
regularity dynamics velocity Stimulation
Regular Tonic Small Low Less sensitive Peripheral/ Bouton/
extrastriola dimorphic
Irregular Phasic Large High More sensitive Center/striolar Calyx/
dimorphic
their spontaneous discharge rate (Table 2–1).179–181 for these electrical properties (Fig. 2–20, Table
Neurons with the most irregular baseline firing 2–2).166 In isolated rat vestibular ganglia neu-
rate (given by the coefficient of variation [CV] rons, Kv1 potassium blockers converted phasic
of the mean interspike interval) are the most firing cells to tonic firing cells, indicating
sensitive to galvanic stimulation, while neurons that Kv1 potassium channels control the firing
with the most regular baseline firing rate are patterns of irregularly discharging primary neu-
least sensitive to galvanic stimulation. As a rons.183 Blocking of calcium-activated potassium
general rule, a primary afferent’s sensitivity to channels decreased the number of spikes origi-
angular acceleration (in spikes/sec per degree/ nating from tonic primary afferent neurons.
sec2) is inversely related to the regularity of its Ca2+ binding proteins and Ca2+ channels regu-
baseline firing rate—that is, irregular units with late the activation of Ca2+-dependent potassium
high CV values have a higher sensitivity than channels and thus regulate firing frequency.166
regular units with low CV values.
Early in vivo experiments showed that regu-
AFFERENTS FROM THE CRISTAE
lar afferents have a different after-hyperpolariz-
ing potential (AHP) following each spike than As noted earlier, the primary vestibular afferent
do irregular afferents.182 More recent in vitro fibers maintain a constant baseline firing rate of
studies of isolated primary afferent neurons action potentials. Recordings from the primary
confirmed these findings and suggest that dif- afferent fibers of the cristae in mammalian and
ferential expression of ion channels accounts nonmammalian species reveal that physiologic
Table 2–2 Pattern of expression of ion channels in large and small vestibular
ganglion somata in rodents
Large neurons Small neurons
Firing regularity Irregular Regular
Spike shape Prominent AHP Brief AHP
Ca++ dependent K+ Lower total density; More dense, more blocker
channels proportionally more BK resistant current
Voltage-gated K+ channels A A
KCNQ channels KCNQ4 ?
Voltage-gated Ca++ channels HVA, LVA (T) HVA
Voltage–gated Na+ channels Nav 1.5? Nav 1.8, 1.9?
HCN channels Yes Yes
Acid-sensing ion channels More Less
AHP – afterhyperpolarizing potential; BK – class of Ca++dependent K+ channels with large single-channel conductances;
A – rapidly inactivating voltage gated K+ channels of heterogenous molecular composition; HVA – high voltage activated
Ca++ channels; LVA – low voltage activated Ca++ channels (T current); HCN – hyperpolarization-activated cyclic-
nucleotide-modulated channels. (Adapted from Eatock RA, Xue J, Kalluri R. Ion channels in mammalian vestibular
afferents may set regularity of firing. Primary afferents J Exp Biol. 2008;211:1764, with permission.)
Striola Extrastriola
Tip links
Mechanosensory
ion channels
Nav 1.5 II II
I
I I
KCNQ4
Ribbon
Sunapses *Na
K *
*
*
BK
IK
SK
A ASIC
C HCN
Na HCN Na
B HVA
LVA D
IK
HVA A
BK
Figure 2–20. Schematic showing classification of vestibular afferent neurons by terminal morphology as pure-calyx (C),
dimorphic (D) and pure-bouton (B). Trunkated fibres are efferents, arising from neurons in the brainstem. Pure-calyx
afferents exclusively innervate the centre and striola and often form complex calyces around multiple type I hair cells, as
illustrated. Pure-bouton afferents exclusively innervate the peripheral zone and extrastriola and can innervate tens of type
II hair cells. Dimorphic afferents innervate both zones, but have more compact dendritic trees in the centre and striola
than in the periphery and extrastriola (not shown). Pure-calyx afferents express calretinin, calbindin and parvalbumin;
dimorphic afferents are thought to express calbindin and parvalbumin; and pure-bouton afferents, which are the thinnest,
express only parvalbumin. Some differences in ion channel expression have been noted between large and small isolated
ganglion somata and are indicated here on the pure-calyx and pure-bouton somata and summarized in Table 2–2. Whether
dimorphic somata, which are likely to be mid-sized, have intermediate expression is not known. Asterisks indicate possible
sites of spike initiation on each afferent. Abbreviations defined in Table 2–2. (Adapted from Eatock RA, Xue J, Kalluri R.
Ion channels in mammalian vestibular afferents may set regularity of firing. Primary afferents J Exp Biol. 2008;211:1764,
with permission.)
stimulation producing endolymph flow toward nerve. The differences in the physiological
the ampulla (i.e., ampullopetal flow) in the characteristics of responses from the horizontal
horizontal semicircular canal increases the and vertical canals are the physiological basis to
baseline firing rate. Conversely, endolymph the formulation of Ewald’s second and third
flow away from the ampulla (i.e., ampullofugal laws.
flow) decreases the baseline firing rate. In the Detailed measurements of afferent nerve
vertical canals the reverse occurs: ampullopetal activity from the cristae of squirrel monkeys
endolymph flow decreases the baseline firing show that the firing rate associated with physio-
rate, and ampullofugal flow increases the firing logic rotatory stimulation follows qualitatively
rate. Considering these observations and the the prediction of the pendulum model;111 that is,
previous anatomic descriptions, it is apparent the magnitude of change in frequency of action
that endolymph displacement that deviates the potentials is proportional to the theoretic devia-
hairs of the sensory cells toward the kinocilium tion of the cupula. For example, during sinusoi-
results in increased firing of the afferent nerve, dal head rotation, the firing rate follows the time
whereas displacement away from the kinocil- course of cupular displacement shown in Figure
ium results in decreased firing of the afferent 2–15c. A sinusoidal change in firing frequency is
superimposed on a rather high resting discharge nerve terminals within the crista can be delin-
(70 to 90 spikes/sec). The peak firing rate occurs eated: (1) caliceal endings, (2) bouton endings,
at the time of the peak angular head velocity. For and (3) combined caliceal and bouton endings
sinusoidal rotation of small magnitude, the mod- (dimorphic units). All caliceal units are at the
ulation is almost symmetrical about the baseline center of the crista and have “irregular”
firing rate. For higher stimulus magnitudes, the dynamic properties, whereas bouton units are
responses become increasingly asymmetrical. in the periphery and have “regular” dynamic
For the largest magnitudes, the excitatory properties (Fig. 2–21). Dimorphic units can be
responses can increase up to 350 to 400 spikes/ either “irregular” or “regular,” with the former
sec in proportion to the stimulus magnitude, usually innervating the center of the crista and
while the growth of inhibitory response is limited the latter, the periphery. Surprisingly, the cal-
to the disappearance of spontaneous activity. iceal units at the center of the crista have a
This asymmetry in afferent nerve response to lower rotational sensitivity than that of dimor-
stimuli of large magnitude explains Ewald’s sec- phic units with similar-size axons innervating
ond and third laws because the “pneumatic ham- the same region. Possibly the lower sensitivity
mer” that he used to apply pressure to the canals of these caliceal units extends the dynamic
produced a massive stimulus.128 range of vestibular reflexes—that is, they do
When the cristae are subjected to prolonged not become saturated by the large velocity
constant acceleration, a substantial proportion active head movements. Dimorphic units
of nerve fibers undergo a slow decline in firing innervating different regions of the crista vary
rate (adaptation) rather than maintaining a in their dynamic properties, even though they
steady state as predicted in Figure 2–15a. contacted similar numbers of type I and type II
Because of adaptation, the firing rate does not hair cells. Taken together, these findings indi-
return to baseline after cessation of accelera- cate that the dynamic properties of a semicir-
tion, but rather, drops to a lower level before cular canal afferent neuron reflect the number
slowly returning to the resting level.111,138 and type of synaptic connections, and location
Similar overshooting of the baseline occurs within the crista. However, these factors alone
after stimulation with an impulse of accelera- cannot explain regularity of firing. For this one
tion. Instead of the monotonic response pre- must look to the intrinsic membrane properties
dicted by the pendulum model (Fig. 2–15b), of the primary afferent neurons as described
the afferent nerve firing pattern exhibits a earlier.
biphasic reaction with a prolonged secondary
phase that slowly returns to baseline. It is not
AFFERENTS TO THE MACULES
known whether the behavior is due to anatomic
or synaptic processes. The process is more pro- As in the crista, the neurons of the macule can
nounced in “irregular” neurons. As will be be classified according to the regularity of the
shown later, the vestibulo-ocular reflex also spontaneous firing rate.162 Recordings from
reflects this deviation from the predicted pat- neurons whose nerve endings were visualized
tern (see Fig. 7–19d). with intracellular labeling show that caliceal
How are these physiological properties related units (mostly near the striola) are irregular,
to the anatomical features of primary afferent whereas bouton units (in the periphery) are
neurons described earlier? The anatomical and regular (Table 2–1). Dimorphic units that
physiological properties of a single primary innervate the areas near the striola are more
afferent neuron can be studied by first record- irregular than those innervating the periphery.
ing the neurons’ dynamic response to angular In the chinchilla, regular units outnumber
acceleration with a micropipette and then irregular units by a ratio of 3 to 1. As in the
injecting it with a tracer to study its anatomical crista, irregular units are more sensitive and
connections. Initial studies in the bullfrog dem- have a wider frequency range of response than
onstrated that “irregular” neurons had thick, that of regular units. They adapt promptly to
rapidly conducting fibers that preferentially stimuli of constant linear acceleration (e.g.,
innervated the central ridge of the crista, while head tilt). By contrast, regular units maintain a
“regular” neurons had thin, slowly conducting constant relation between the gravity vector and
fibers that predominantly innervated the the firing rate during static tilts. As in the crista,
periphery.184 In mammals three patterns of large primary afferent neurons with an irregular
(a)
d c P
I
c
c d
I I
d d
P P
d b
(b)
Calyx
Dimorphic
Bouton
Figure 2–21. (a) Dynamic properties of afferent fibers originating in different parts of the chinchilla crista. This cross sec-
tion of the crista is divided into peripheral (P), intermediate (I), and central (C) zones. Calyx (c) fibers innervate the central
zone; bouton (b) fibers, the peripheral zone; and dimorphic (d) fibers innervate all three zones. (From Fernandez C et al.
The vestibular nerve of the chinchilla. I. Peripheral innervation pattern of the horizontal and superior semicircular canals.
J Neurophysiol. 1988;60:167–181, with permission.) (b) Locations of intraaxonally labeled fibers in the chinchilla cristae.
(Left) Units are sorted by their normalized coefficients of variation into three categories: regular (open symbols), interme-
diate (half-filled symbols), and irregular (filled symbols). (Right) Units are sorted into three categories according to their
phases with regard to head velocity for 2 Hz sinusoidal head rotation: tonic (open symbols), intermediate (half-filled sym-
bols), and phasic (filled symbols). (From Baird R et al. The vestibular nerve in the chinchilla. 11. Relation between afferent
response properties and peripheral innervation patterns in the semicircular canals. J Neurophysiol. 1988;60:182–203, with
permission.)
spontaneous firing rate have a different ion seventh nucleus, while vestibular efferent
channel profile than do small afferent neurons neurons are located near the sixth nucleus.
with a regular spontaneous firing rate.156 Although there are only about 300 vestibular
efferent neurons on each side of the brain
stem, their axons branch extensively such that
EFFERENT VESTIBULAR NEURONS in the sensory epithelium efferent boutons out-
number afferent boutons by a ratio of 3:1.187
In all vertebrates the inner ear efferent neu- Each labyrinth receives about an equal num-
rons are located in the hindbrain with cell bod- ber of efferent fibers from each side of the
ies near brachial motor nuclei within the pons brain stem. Consistent with its role as a sensory
and medulla.185,186 Typically axons separate feedback system, the efferent neurons receive
from the facial nerve and join the eighth nerve input from the ipsilateral vestibular nerve and
to innervate the different receptor organs. both vestibular nuclei.
Even though they innervate sensory epithe- Consistent with its embryological origin
lium, efferent neurons are derived from the from motor neurons acetylcholine is the princi-
motor column and share a common embryo- pal neurotransmitter of the vestibular efferent
logical origin with motor neurons. In fish and system.188 Choline acetyltransferase (ChAT)
amphibians all efferent neurons are localized immunoreactivity (IR) was found in nerve
in a single nucleus, the octavolateralis nucleus, fibers and boutons adjacent to afferent nerve
near the rostral end of the facial motor nucleus, calyces and type II hair cells in the vestibular
whereas in mammals cochlear and vestibular receptors of multiple animals including
efferent neurons are in separate nuclei. humans.189–193 GABA and the neuropeptide cal-
Cochlear efferent neurons are located near the citonin gene-related peptide (CGRP) IR was
found in a subpopulation of efferent neurons 3. Duckworth EA, Silva FE, Chandler JP, Batjer HH,
varying among species.194 Nitric oxide synthase Zhao JC. Temporal bone dissection for neurosur-
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Chapter 3
The Central Vestibular System
VESTIBULAR NUCLEI Adaptive Modification of the

Phylogeny Vestibulo-Ocular Reflext with Vision
Anatomy Cellular Basis for Visual Vestibular
Neurotransmitters Interaction
Physiology VESTIBULOSPINAL REFLEXES
VESTIBULO-OCULAR REFLEXES Comparison of Ocular and Spinal Vestibular
Overview Reflexes
Rotational Vestibulo-Ocular Reflexes Vestibulospinal Connections
Translational Vestibulo-Ocular Reflex Cerebellar–Vestibular Interaction
Ocular Counterrolling Vestibulo-Collic Reflexes
Semicircular Canal–Otolith Interaction Cellular Mechanisms
CERVICO-OCULAR REFLEXES SUBJECTIVE VESTIBULAR SENSATION
Anatomic and Physiologic Basis Vestibulothalamocortical Connections
Characteristics of Neck-Induced Eye Response Properties of Thalamic Relay
Movements Neurons
VISUAL–VESTIBULAR INTERACTION Response Properties of Vestibular Cortex
Visual Tracking Eye Movements Neurons
Organization of Visually Guided Tracking Functional Brain Imaging in Normal Human
Eye Movements Subjects
Comparison of Vestibular- and Lesions of the Vestibulocortical Pathways in
Visual-Induced Eye Movements Patients
Visuo-Vestibulo-Ocular Connections Psychophysical Studies
Model of Visual–Vestibular Interaction
VESTIBULAR NUCLEI innervate second-order neurons in four ana-

tomically distinctive groups, located on the floor
The vestibular system must integrate multiple of the fourth ventricle.1–5 Afferents from the
internal representations of head and body semicircular canals stay separate from each
movement obtained from several different sen- other, but they converge with afferents from
sory systems into a single internal coding of the macules in a specific spatial pattern.6,7
space that provides a frame of reference for Secondary vestibular neurons form a column of
encoding motor commands. Secondary vestibu- different lengths depending on the species,
lar neurons are at the center of this sensorimo- being the longest in humans (13.5 mm) and
tor transformation. They receive a multiplicity smaller in animals with evolutionarily smaller
of signals originating in the vestibular end brains—frogs (2.2 mm), chinchillas (4.0 mm),
organs. Thousands of axons of primary vestibu- and squirrel monkeys (5.0 mm). However,
lar neurons enter each side of the brain stem to not all of the neurons in these nuclei receive
63
primary afferent vestibular nerve fibers and most using intracellular labeling techniques can trace
receive input from other sensory systems and the trajectory of afferent neurons to answer this
other nuclei (Figs. 3–1 and 3–2). important question. Each fiber usually inner-
The main vestibular nuclei are the superior vates a restricted number of secondary neurons
(angular or Bechterew’s), the lateral (Deiters), in all four of the vestibular nuclei. There are
the medial (triangular nucleus of Schwalbe), clear separations of afferent fibers such that
and the descending (inferior or spinal) vestibu- specific areas in each nucleus preferentially
lar nuclei. In addition, the vestibular nuclear receive afferents from specific receptors. At the
complex includes several small groups of cells same time, secondary vestibular neurons receive
that are closely associated topographically with a converging input from different sensory organs
the main nuclei but have distinct morphologic from each ear—that is, where interactions
characteristics and anatomic connections (e.g., between the organs of the two ears take place.
the interstitial nucleus).8–10 The emerging picture is a complex one of both
There are a number of questions about the separation (channeling) and convergence of
organization and function of the vestibular afferent signals at the level of the vestibular
nuclei that are pertinent to clinical neurophysi- nuclei.
ology of the vestibular system. The amount of The biology of individual neurons in the ves-
information arriving at the vestibular nuclei tibular nuclei is an important aspect of vestibu-
from different sources reaches staggering levels. lar physiology that is just beginning to be
In primates, since afferent vestibular neurons addressed. What transmitters are released and
are characterized by their high level of sponta- what ion channels and receptors are expressed
neous activity, the nuclei receive about 100 in the different nuclei and within different
action potentials/sec/nerve fiber (see Chapter neurons in the same nucleus? How do the
2). In humans, since each vestibular nerve has characteristics of these secondary neurons
approximately 15,000 fibers, more than 1.5 million influence signals arriving from the primary
action potentials are received every second from afferents and the organization of reflexes
the vestibular organs alone. How are the signals involved in the maintenance of gaze, equilib-
that originate in different receptor organs dis- rium, and orientation? Finally, how do neurons
tributed within the vestibular nuclei? Studies in this major sensorimotor integration center
(a) (b)
Cerebellum Cerebellum
L M
AC
HC
UT
PC
SA D
1 mm
Figure 3–1. Distribution of primary vestibular afferent fibers (shaded blue areas) within the vestibular nucleus of the chin-
chilla. (a) superior vestibular nerve, (b) inferior vestibular nerve. AC, anterior canal; D, descending nucleus; HC, horizontal
canal; L, lateral nucleus; M, medial nucleus; PC, posterior canal; S, superior nucleus; SA, saccule; UT utricle.
3 The Central Vestibular System 65
SVN LVN
GAD+ GAD– Dorsal GAD+ GAD–
Lateral Medial
DVN MVN
Ventral
GAD+ GAD– GAD+ GAD–
Figure 3–2. Immunohistochemical staining of the vestibular nuclei (VN) in the chinchilla showing distribution of neurons
that are glutamic acid decarboxylase (GAD) positive and GAD negative. Shaded blue areas receive primary vestibular
afferents.
adapt to conflicting sensory perceptions that Modern fish (teleosts) have four discernible
occur in daily life or after damage to the inner vestibular nuclei, although the nuclei contain
ear or motor apparatus? relatively few cells. This basic organization of
four vestibular nuclear groups is maintained
throughout the higher vertebrates, although
Phylogeny the relative size of each nuclear group varies
from species to species (see earlier discussion).
The vestibular nuclei are one of the first In invertebrates and early vertebrates, sec-
supraspinal cell groups that differentiate them- ondary connections of the vestibular nuclei are
selves from the reticular formation.11,12 primarily vestibulospinal, in keeping with their
Lampreys have two discernible vestibular major role in maintaining body orientation.13
nuclear groups, the dorsal and ventral, com- Vestibulocerebellar connections become pro-
posed of granular and spindle-shaped cells. gressively more prominent in higher vertebrates.
The development of these “modern” vestibular abducens nucleus.18–20 It is the smaller of the
pathways accompanies the development of main nuclei with a length of 2.7 mm, contain-
increasingly complex somatic and ocular motor ing approximately 20,000 neurons.20,21 Medium-
skills. In primates, vestibulocerebellar and size neurons of about 15–30 µm in diameter
vestibulo–ocular connections form a large part predominate, with some large multipolar cells
of the central vestibular pathways, and vestibu- at the center. Most of the primary afferent pro-
lospinal connections are less prominent.13 The jections to the superior vestibular nucleus
lateral vestibular nucleus (Deiters’ nucleus), a come from the cristae of the semicircular
major source of vestibulospinal fibers, is the canals, arriving at the nucleus in the form of
most prominent nuclear group in lower mam- fascicles with a variety of fiber diameters.4
mals, whereas in human beings it is small and Large fibers terminate preferentially on the
almost confined to the vestibular root entry zone. larger neurons in the center of the nucleus.2,10,22
By comparison, the superior vestibular nucleus Fibers from the superior semicircular canal are
is barely detectable in lower vertebrates but is found medially, those from the horizontal and
prominent in humans, where it is the major posterior canals more laterally (Fig. 3–1).
source of vestibulo-ocular fibers. It extends ros- Fibers from the utricle and saccule innervate
trally from the root entry zone (at the medullo- only the periphery of the nucleus on the lateral
pontine junction) to the midpontine region.11 side.
Another major group of afferent fibers origi-
nates in the cerebellum. Those from the floc-
Anatomy culus end in the central region and those from
the fastigial nucleus, nodule, and uvula end in
PRIMARY AFFERENT ENDINGS the peripheral region.10,23 A group of fibers
from the contralateral medial and descending
The thousands of primary afferent vestibular nucleus connects the two sides.
nerve fibers arrive in the vestibular root in a Axons from the neurons in the superior ves-
specific orientation depending on their organ tibular nucleus run in the ipsilateral and con-
of origin (Fig. 3–1).1–5 After entering the brain tralateral medial longitudinal fasciculus (MLF)
stem, they divide into secondary ascending and to innervate the motor nuclei of the extrinsic
descending branches that form a clearly defined eye muscles; others project to the cerebellum
vestibular tract in all animals studied. Branches and dorsal pontine reticular formation.24,25
from fibers in the ascending tract end in the Dendrites of neurons in the periphery of the
rostral part of the vestibular nuclei or in the nucleus extend into the adjacent reticular for-
cerebellum, while branches from the descend- mation and into the principal trigeminal
ing tract course in a ventrolateral direction in nucleus. Because of the pattern of afferent and
relation to the fourth ventricle, ending in the efferent connections, the superior vestibular
caudal vestibular nuclei.1–5 nucleus is a major relay center for ocular
Individual primary afferent neurons provide reflexes mediated by the semicircular canals.
multiple branches; in the bullfrog and cat,
there is an average of 200 branches per affer-
ent fiber.14–17 As illustrated in the chinchilla LATERAL VESTIBULAR NUCLEUS
(Fig. 3–1), not all areas of the vestibular nuclei (DEITERS’ NUCLEUS)
are innervated by the labyrinthine afferents. In Beginning at the caudal end of the superior
addition, in the areas that receive primary nucleus and ending below the level of the
afferents, signals from the vestibular organs abducens nucleus, the lateral nucleus is trans-
interact with afferent fibers from other versed by the initial segments of the vestibular
systems (visual and proprioceptive) and centers tract fibers corresponding to the root entry
(especially the cerebellum).8,10 zone. In humans, the length of the lateral
nucleus is 5.6 mm. It contains approximately
SUPERIOR VESTIBULAR NUCLEUS 25,000 neurons.20,21 It is distinguished by the
presence of giant cells (30 to 60 µm) that are
The superior vestibular nucleus in humans relatively more numerous in the dorsocaudal
extends from the caudal pole of the trigeminal than in the central ventral part.8,10 No sharp
motor nucleus approximately to the level of the anatomic distinction divides these two parts of
the nucleus; in cats and chinchillas, only the Efferent connections from the medial nuclei
rostroventral part receives primary vestibular run in the descending MLF to the cervical and
afferents (the majority originating from the thoracic spinal levels by way of the medial ves-
utricular macule). The dorsocaudal part tibulospinal tract (see Fig. 3–25). From the
receives afferent fibers from the vermis rostral area (receiving afferent input from the
and fastigial nucleus of the cerebellum (see cristae), efferent fibers pass to the ascending
Fig. 3–26). Afferent components from other MLF bilaterally to reach the nuclei of the ocul-
sources (spinal and commissural fibers) are few omotor nerves.30 Other efferents are distrib-
in comparison with those from the cerebellum uted to the vestibular cerebellum, the reticular
and vestibular nerve. The lateral nucleus sends formation, and the contralateral vestibular
most of its efferent fibers to the spinal cord nuclei.18 Because of its projections in the MLF
as the ipsilateral vestibulospinal tract (see to extraocular muscles and the cervical cord,
Fig. 3–25). This projection is somatotopically the medial vestibular nucleus appears to be an
organized in that fibers to the cervicothoracic important center for coordinating eye, head,
cord originate from the rostroventral part of and neck movements.31 The prominent com-
the nucleus, while fibers to the lumbosacral missural connections are probably important
cord originate from the dorsocaudal part.26,27 for the compensatory processes following
The lateral nucleus also sends efferent fibers peripheral vestibular lesions.
bilaterally to the MLF, which connect with the
various oculomotor nuclei. Based on its fiber DESCENDING (INFERIOR) VESTIBULAR
connections, the lateral vestibular nucleus is NUCLEUS
an important station for control of vestibulospi-
nal reflexes, particularly those involving the The descending, or inferior, vestibular nucleus
forelimbs.28 is difficult to differentiate anatomically from
the adjacent medial vestibular nucleus. In
humans, it has a length of about 8 mm with
MEDIAL VESTIBULAR NUCLEUS
approximately 55,000 neurons.20,21 It consists of
The medial vestibular nucleus is located beneath small and medium-sized cells with occasional
the floor of the fourth ventricle caudal to the giant cells.4,10,18 Projections from the labyrinth
superior nucleus and medial to the descending are restricted to the lateral side, with those
(inferior) nucleus (see Fig.1–7). In humans, it is from cristae extending more to the center and
the largest nucleus (about 10 mm in length and those from the macules to the periphery (utric-
a total volume of about 30 mm3) with by far the ular being more ventral, saccular–dorsal).
greatest number of neurons (about 125,000).20,21 Cerebellar afferents from the flocculus, nod-
It consists of cells of many different sizes (12 to ule, and uvula are scattered throughout the
33 µm in diameter) and shapes that lie rela- nucleus, intermingling with the vestibular
tively close together, embedded in a fine mesh- afferents. Projections from other sources,
work of very thin fibers that course in almost all including spinal afferents, are minimal. Most
directions.8,10,18 It differs from the other nuclei of the efferent fibers from the descending
in that it does not receive large-diameter nucleus pass to the cerebellum and to the
fibers.29 Anatomic separation from the superior reticular formation.28 Numerous commissural
nucleus is not well defined. Neurons in the fibers supply the contralateral superior,
upper part of the nucleus receive afferent fibers descending, medial, and lateral nuclei.8,32 The
from the cristae of the semicircular canals as descending nucleus apparently integrates ves-
well as from the fastigial nucleus and flocculus tibular signals from the two sides with signals
of the cerebellum. Saccular and utricular affer- from the cerebellum and reticular formation.
ents project to the medial lateral section of the
nucleus.2,5,7 The caudal part receives its main INTERSTITIAL NUCLEUS OF THE
afferents from the cerebellum (the ipsilateral VESTIBULAR NERVE
and contralateral fastigial nucleus and the ipsi-
lateral nodule). Other afferent contributions Of the small groups of cells associated with
include a large projection from the contralat- the vestibular nuclei (such as groups x, f, p, m,
eral medial vestibular nucleus and a small and others), the interstitial nucleus is most
projection from the reticular formation. clearly defined.4,10 It consists of small strands of
elongated cells, some as large as the giant cells decarboxylase (GAD)—the enzyme used for
of the lateral nucleus, interspersed between synthesizing GABA—and consequently may
the root fibers of the vestibular nerve near the act as inhibitory neurons.47 The distribution of
brainstem entry zone. In the chinchilla, the neurons capable of releasing GABA (GAD+
interstitial nucleus receives numerous short neurons) among the four major vestibular
afferent collaterals from the macules of the nuclei is shown in Figure 3–2. Ninety percent
utricle (rostral) or saccule (caudal), but only a of neurons < 7 µm in diameter are GAD-
few from the cristae of the semicircular canals. positive neurons, whereas 80% of neurons
Efferent projections from the interstitial with a diameter >15 µm are GAD negative.
nucleus enter the ascending MLF and may be Overall, it appears that most large neurons
important in mediating VOR.33 are excitatory and most small neurons are
inhibitory.
Neurotransmitters
Physiology
Signal processing in the secondary vestibular
neurons depends not only on anatomical con- Vestibular signals originating in the two laby-
nectivity but also on the type of synaptic recep- rinths first interact with signals from other sen-
tors expressed and neurotransmitters released. sory systems at the neurons of the vestibular
At least eight neurotransmitters and four neu- nuclei.32 Only a fraction of the neurons receive
ropeptides are involved.34–38 Among the major direct vestibular connections and, with the
neurotransmitters, γ-aminobutyric acid (GABA), exception of the interstitial nucleus of the ves-
glutamate (glu), and glycine (gly) are believed tibular nerve, the neurons that receive primary
to be the most important in both the synaptic vestibular afferent fibers also may receive affer-
input and output.37 ents from the cervical area, the cerebellum,
All primary vestibular fibers release gluta- the reticular formation, the spinal cord,
mate, an excitatory neurotransmitter, at their and the contralateral vestibular nuclei.31,48
synapses in the vestibular nuclei.39 Glycine acts Consequently, efferent signals from the ves-
as a cotransmitter in large-diameter fibers. tibular nuclei reflect the interaction of these
Most other neural inputs to the nuclei utilize various afferent systems.49 For example, visual
terminals that express GABA immunoreactiv- signals relayed through the cerebellar flocculus
ity, which suggests that they have an inhibitory to neurons in the superior and medial vestibu-
influence upon vestibular nuclei neurons.39–41 lar nucleus modulate the activity of the VOR.50–54
The afferent excitatory action of glutamate Inputs from neck proprioceptors modulate the
on secondary vestibular neurons is mediated vestibulocollic reflexes.55 The cerebellum influ-
by both α-amino-3-hydroxy-5-methyl-4- ences the vestibulospinal reflexes by means of
isoxasoleproprionic acid (AMPA) and connections between the vermis and the lateral
N-methyl-d-aspartate (NMDA) glutamate and descending vestibular nuclei.56 Through
receptors.42–44 In situ hybridization techniques connections with the reticular substance, ves-
found that all secondary vestibular neurons tibular neuron outflow interacts with descend-
express the AMPA-selective receptor subunit ing corticobulboreticular and reticulospinal
GluR2 with the highest levels of expression in signals.57
the giant Deiters’ cells.44 GABA receptors were
found ubiquitously in the vestibular nuclei TYPES OF SECONDARY VESTIBULAR
neurons by Lopez et al.41 NEURONS
Among the second-order vestibular neurons,
most use glutamate as their excitatory37 Following stimulation of the vestibular nerve
and GABA as the inhibitory neuro- with a single brief electric pulse, two different
transmitter.36,39,40,45,46 In the chinchilla, the groups of secondary vestibular neurons have
vestibular nuclei contain approximately 40,000 been identified on the basis of field potentials
neurons—about 15,000 each in the medial and produced in areas of the brain stem receiving
descending nuclei and the rest in the remain- vestibular inputs (Fig. 3–3).58–60 This field
ing nuclei. A large percentage of these potential consists of three components: an ini-
neurons (about 60%) express glutamic acid tial positive–negative deflection from action
a b c
N1
N2
1.2 0.36 1.35

Figure 3–3. a Field potential recorded in the medial vestibular nucleus after electric stimulation of the ipsilateral ves-
tibular nerve. N1 is generated by monosynaptic activated secondary vestibular neurons and N2 by multisynaptic activated
neurons. b Response of a monosynaptic activated neuron N1 field potential is not seen because of superposition of spikes.
c Response of a multisynaptic activated neuron demonstrating spikes timed with N2 field potential. Each recording is com-
posed of about 20 superimposed traces. (Adapted from Precht W, Shimazu H. Functional connections of tonic and kinetic
vestibular neurons with primary vestibular afferents. J Neurophysiol.1965;28: 1014.)
currents in the primary vestibular fibers, a neg- The second-order vestibular neurons can be
ative deflection wave (N1) with a short latency of divided into two groups: type I neurons, which
<1.0 msec (generated by monosynaptically are excited, and type II neurons, which are
activated secondary vestibular neurons and inhibited by ipsilateral head rotations.48,54,62,63
fibers), and a delayed negative deflection (N2) Type I neurons are also excited by electrical
with a latency of about 2.5 msec (generated by stimulation of the ipsilateral vestibular nerve.
multisynaptically activated neurons and fibers) The physiological response of type I neurons is
(Fig. 3–3a). By carefully placing microelec- similar to that of primary vestibular afferents.
trodes in the vicinity of or inside secondary ves- Type II neurons respond to electrical stimula-
tibular neurons and tailoring the electric stim- tion of the contralateral vestibular nerve with
uli, it has been demonstrated that some neurons greater latency than do type I neurons to ipsilat-
produce action potentials at the time of the eral stimulation. The physiological response of
extracellular N1 wave with latencies between type II neurons is opposite that of type I neu-
0.5 and 1.0 msec (Fig. 3–3b), suggesting rons—that is, type II neuronal response is
that they receive monosynaptic input. Other qualitatively similar to the response of primary
neurons produce delayed action potentials afferent neurons innervating the contralateral ear.
(Fig. 3–3c), which suggests that they might be Among the type I neurons there are two
activated through multisynaptic connections. groups (Fig. 3–4). One group activates the
Only about 75% of neurons are activated by agonist motor neurons—for example, motor
nerve stimulation and approximately half of neurons innervating the lateral rectus of the
these are monosynaptically activated.58,60 All opposite side and the medial rectus of the ipsi-
monosynaptic connections are ipsilateral and lateral side for the horizontal semicircular canal
excitatory. Among the monosynaptically acti- reflex. These neurons are excitatory, that is,
vated neurons, about 37% respond to small GAD-negative neurons, as illustrated in Figure
electrical stimuli with very short latencies that 3–2. The second group of type I neurons inhib-
activate only the thickest, most sensitive irreg- its the antagonist muscles—for example, the
ular primary afferents.61 The rest of the neu- ipsilateral lateral rectus and the contralateral
rons respond to larger electrical currents. This medial rectus. These neurons are GAD posi-
suggests that they receive a predominant input tive. Type II neurons are activated by type I
from thinner, regular afferents. This differen- neurons from the contralateral side.62 After
tial input is at least in part reflected in the output destruction of the labyrinth, excitation of type
of the secondary neurons with vestibulospinal II neurons by stimulation of the contralateral
neurons receiving more input from irregular nerve inhibits neighboring type I neurons.
afferents and vestibulo-ocular neurons receiv- Type II neurons are GAD positive, which is con-
ing more input from regular firing afferents. sistent with their inhibitory action (Fig. 3–4).
However, it would be wrong to view secondary In summary, during physiological rotatory
vestibular neurons as narrowly tuned channels, stimulation of the horizontal semicircular
with each receiving only a single kind of pri- canals, the central vestibular neurons on one
mary afferent input.61 Most vestibular nuclei side receive ampullopetal signals (increased
neurons, even those predominantly related to firing), while the neurons on the opposite side
regular and irregular afferents, receive a broad receive ampullofugal signals (decreased firing).
range of afferent inputs. However, since excitatory type I neurons are
Right Middle Line Left
Horizontal
Semicircular
Canal
Scarpa’s
Type II
Ganglion
GAD+
Type I Type I
GAD– GAD+ Vestibular
Nucleus
Oculomotor
Neurons
Rt MR Lt MR Rt MR Lt MR
Lt LR Rt LR Lt LR Rt LR
Figure 3–4. Interrelation of type I and type II secondary vestibular neurons. Blue neurons are inhibitory and white
neurons are excitatory. LR, lateral rectus; MR, medial rectus.
connected to inhibitory type II neurons of the can only be identified as secondary vestibular
opposite side, the excitatory type I neurons neurons based on their location within the
receive a combination of stimulation from the boundaries of the known vestibular nuclei.
two ears, corresponding to the sum of the Just as with primary vestibular neurons sec-
ampullopetal (excitatory signals) from the ipsi- ondary neurons can be classified as regular
lateral side and the inverted ampullofugal (dis- (tonic) and irregular (kinetic) based on their
inhibitory) signal mediated by the type II spontaneous firing pattern.58 Spontaneous
(inhibitory) neurons (Fig. 3–4). Most of the activity is probably due to a combination of
cells in the vestibular nuclei also respond to intrinsic membrane properties of the second-
visual stimulation.64,65 The main visual input to ary vestibular neurons and excitatory and
the vestibular neurons comes from the cerebel- inhibitory input from primary afferents.68–71
lum, particularly the flocculonodular Based on an average spontaneous firing rate for
lobe.52,53,66,67 secondary vestibular neurons of about 30
spikes/sec one can estimate that about half of
the spontaneous rate is generated by intrinsic
INTRINSIC MEMBRANE PROPERTIES OF
pacemaker activity and half by spontaneous
SECONDARY NEURONS
primary afferent input since the spontaneous
In most physiological studies, secondary ves- rate is reduced to 16 spikes/sec in alert animals
tibular neurons are identified either by their that undergo bilateral labyrinthectomy.32,72
location within the know boundaries of the ves- In vitro slice preparations from the medial
tibular nuclei or by their activation by stimula- vestibular nucleus of rat and guinea pig have
tion of the eighth nerve or some of its branches. allowed a classification of secondary vestibular
Secondary neurons are most clearly identified neurons based on action potential shapes and
in whole-brain preparations where the eighth membrane properties (Table 3–1).68,73–75 Type A
nerve or nerves from individual canals or secondary neurons show a single deep after-
macules can be selectively stimulated. These phyperpolarization (AHP) after each action
preparations have been particularly useful for potential and a rectifying IA-like K+ current when
studying vestibulo-motor signal processing in released from hyperpolarization (Fig. 3–5a). By
central networks. By contrast, slice prepara- contrast, type B secondary neurons have an ini-
tions that are disconnected from most inputs tial fast AHP followed by a delayed slow AHP
and outputs have been particularly useful for and no IA-like rectification (Fig. 3–5b). Also,
studying membrane properties in individual type A neurons have wider action potentials than
neurons with the disadvantage that neurons type B neurons. Type A secondary neurons
Table 3–1 Functional classes of different secondary vestibular neurons identified in

the rodent medial vestibular nucleus
Type A Neurons Type B Neurons
After-hyperpolarization Monophasic, large amplitude Biphasic, small amplitude
A-like rectification Strong Weak
Action Potential Broad Thin
Discharge regularity Regular Irregular
Dynamic response Mostly tonic Phasic-tonic
Major afferent inputs Thin afferents; no input from Thin and thick afferents; some receive
flocculus floccular input
predominantly receive input from thin primary that the majority of type A secondary neurons
afferents, have a regular spontaneous firing rate, are GABAergic neurons, while type B neurons
and have a wide linear range, whereas type B can be either GABAergic or glutamatergic.77
neurons receive input from thick and thin affer-
ents, have an irregular spontaneous firing rate,
COMPENSATION AFTER
and have a relatively smaller linear range.32 It
LABYRINTHECTOMY
appears that type A neurons correspond to the
tonic secondary neurons and type B neurons Knowledge of the different types of secondary
correspond to kinetic neurons in the earlier vestibular neurons and their interconnecting
classification of Shimazu and Precht.58 pathways is important for understanding the
Potassium channels are critical for determin- sequence of recovery following a unilateral loss
ing resting potential, shaping action potentials, of labyrinthine function.78–80 On the basis of
and controlling discharge regularity; prelimi- connections depicted in Figure 3–4 it can be
nary studies suggest that K+ channels have anticipated that immediately after a labyrinth-
differential expression in type A and type B ectomy, the ipsilateral type I neurons lose their
secondary vestibular neurons.32,74,75 As with spontaneous activity and become unresponsive
primary vestibular neurons Ca2+-dependent K+ to ipsilateral angular rotation due to excessive
channels play a key role in shaping the AHP.76 inhibitory activity arriving via commissural
Initial studies attempting to correlate physio- pathways. At the same time, contralateral
logical properties with neurochemistry indicate healthy type I neurons lose their inhibitory
a b c
5 mV
20 mV
Contralesional side 2 ms
50 ms
Spike
Control
threshold
Ipsilesional side
Type A MVN Type B MVN
neuron neuron
Figure 3–5. Changes in spike profiles of guinea pig medial vestibular nucleus (MVN) neurons after unilateral labyrinth-
ectomy. A: typical spikes of a type A MVN neuron a with a monophasic after-hyperpolarization (AHP; arrow) and a type
B MVN neuron b with a biphasic AHP (double arrow) recorded on the contralesional side of slices taken one month
post-lesion; superposition at spike threshold of averaged spikes of type B MVN neurons at the resting membrane potential
c recorded in control slices and from the ipsi- and contralesional sides of slices taken one month after the lesion. All neurons
were identified as type B MVN neurons by the presence of the biphasic AHP at hyperpolarized membrane potentials. Note
the inverse changes in the amplitude of the AHP of spikes recorded on the two sides. (From Straka H, Vibert N, Vidal
PP, Moore LE, Dutia MB. Intrinsic membrane properties of vertebrate vestibular neurons: function, development and
plasticity. Prog Neurobiol. 2005;76:349, with permission.)
contralateral input, and their spontaneous spontaneous firing rate with tonic dynamics,
activity increases in comparison to normal whereas those on the contralesional side have a
levels.81 Contralateral type II neurons lose their more irregular spontaneous rate with phasic
inputs from deafferented excitatory type I neu- dynamics. The result is a switch from the
rons and cannot be identified electrophysiolog- balanced “push-pull” mode in the normal con-
ically. Specifically, an imbalance in the muscle dition to a state where the ipsilesional side
tone takes place, resulting in the signs of laby- provides more tonic activity in vestibular cir-
rinthectomy—spontaneous nystagmus, yaw cuits while the contralesional side provides
and roll tilt of the head, asymmetric tone in more of the dynamic responses.32
extensor muscles, and falling toward the side of After labyrinthectomy, in parallel with the
the lesion. changes in membrane properties, there is a
A few days after a labyrinthectomy, the pre- reorganization of synaptic inputs onto the deaf-
viously silent type I neurons on the damaged ferented secondary neurons, changes in synap-
side recover their spontaneous activity and tic sensitivity to neurotransmitters, and changes
begin to respond to physiologic stimulation of in vestibular neuronal networks.80,89,91,92 Similar
the contralateral labyrinth,82–84 as a result of lesion-induced plasticity is seen in other sen-
their connections with ipsilateral type II neu- sory systems and appears to be a general reac-
rons. These reactivated type I units are inhib- tion pattern to injury, the so-called distributed
ited when the type I neurons on the healthy process described by Llinas and Walton.32,93
side are excited and are disinhibited when the Triggers for the plastic changes after unilateral
contralateral type I neurons are inhibited. The labyrinthectomy are not entirely clear.
recovery of sensitivity in the ipsilateral type I Intracellular messenger systems are activated
neurons after a labyrinthectomy parallels the to initiate the gene/protein changes required
time course of or improvement in clinical for the compensation process.94 The transcrip-
symptoms and signs. Experimental studies in tion factor c-Fos is activated in secondary neu-
rodents confirm that immediately after a uni- rons on both sides and could be a trigger for
lateral labyrinthectomy there is a marked changes in expression of channel proteins and
increase in GABA release in the ipsilesional transmitter receptor subtypes.95–97 There is an
vestibular nucleus that is not prevented by increased expression of the transmembrane
bilateral flocculectomy, indicating that it is due phosphoprotein GAP-43, known to be involved
to hyperactivity of the inhibitory commissural in growth, regeneration, and remodeling of
pathway.85 With vestibular compensation and neuronal pathways.98 The neurotrophic factor
recovery of vestibular symptoms and signs, the BDNF is transiently expressed in some sec-
elevated GABA levels on the ipsilesional side ondary vestibular neurons after labyrinthec-
return toward normal levels.86 At the same time tomy and mutant mice deficient in BDNF have
there is a downregulation of GABA receptor impaired vestibular compensation.99 Increases
efficacy, decreasing the response to commis- in intracellular Ca2+ concentration seen in sec-
sural inhibitory drive. ondary vestibular neurons after labyrinthec-
The return toward normal spontaneous fir- tomy might be a link between changes in
ing in secondary neurons after labyrinthectomy genetic regulation and changes in membrane
is associated with changes in both active and and discharge properties.32
passive membrane properties.87–90 Overall the
resting membrane properties of secondary
neurons on the ipsilesional side shift toward
type A-like properties and those on the contral- VESTIBULO-OCULAR REFLEXES
esional side shift toward type B-like properties
(Fig. 3–5c). The AHP and discharge regularity Overview
of type B neurons on the ipsilesional side are
selectively augmented, while the reverse occurs All sensorimotor reflexes have a reference
on the contralateral side.91,92 These changes frame for coding spatial information.100 The
result from changes in expression of a variety vestibular receptors are fixed in the head so
of genes and proteins that determine each they have a head-centered reference frame.
cell type.32 On average, secondary neurons on They provide no information about how the
the ipsilesional side develop a more regular head moves relative to the body or how the
outside world moves relative to the head. For reliable estimate of angular velocity at very low
this the brain must rely on information from frequencies (<0.1 Hz).107,108 It was the illusion
the somatosensory and visual systems each with of tilt experienced when riding a curve in the
their own reference frame. Coordinating head, railroad line that lead Mach to postulate a “sixth
eye, and body movements requires transforma- sense” for the perception of acceleration in the
tions so that signals from the different systems head. Somatogravic and oculogravic illusions
can interact appropriately. For example, by commonly occur during airplane landings and
combining head-centered vestibular signals takeoffs due to the tilt-translation ambiguity.
with neck proprioceptive information that sig- Extravestibular signals are required to avoid
nals the static position of the head relative to these illusions.
the body, head-centered motion signals are The brain must also differentiate between
transformed into a body-centered reference self-generated and externally applied move-
frame. Whether it is necessary for the brain to ments. Primary afferents fire the same regard-
bring all sensory information into a common less of whether the movement is active or pas-
reference frame or whether separate reference sive. A common strategy for solving this
frames can be maintained even at the highest problem is the principle of reafference—a copy
level of integration is still debated.101 of the expected sensory result of a motor com-
The inner ear does provide information in a mand is subtracted from the sensory signal.109
world-reference frame generated by the gravi- This principle has been well studied in
ty-sensing otolith organs. As will be seen later, mechanosensory systems of primitive animals
the velocity storage system uses this informa- where self-generated behaviors are selectively
tion to align the low-frequency rotational VOR suppressed in central neurons.
with gravity. Angular velocity from the semicir-
cular canals is combined with gravitational
information from the otoliths into two compo- Rotational Vestibulo-Ocular
nents, one parallel to gravity and the other Reflexes
perpendicular to gravity.102,103
As noted earlier, the otolith organs detect The basic organization of the rotational VOR in
net linear acceleration but do not distinguish the horizontal plane is shown in Figure 3–4.
between translational movements and gravity, Type I secondary neurons make direct contact
the so-called tilt-translation ambiguity. One with oculomotor neurons and provide axon col-
solution to the tilt-translation ambiguity is to laterals to other secondary neurons and to the
frequency filter the otolith signals such that cerebellum (not shown).110 Commissural con-
low-frequency otolith components are inter- nections connect the two sides. These and
preted as gravitational acceleration and high- other feedback pathways form the velocity stor-
frequency components are interpreted as age system, which allows signals from different
inertial accelerations.104 Another solution is vestibular receptors and other sensory systems
convergence of canal and otolith signals begin- to interact with vestibular signals while sustain-
ning at the vestibular nuclei.105,106 Unlike pri- ing the activity in the vestibular nuclei beyond
mary afferent neurons that fire the same the time of arrival of the primary afferent
regardless of the type of linear acceleration, signal.111
many secondary neurons fire selectively for The effect of velocity storage is graphically
translational motion and are relatively silent illustrated in Figure 3–7 (see also Fig. 1–5).
during changes in head position relative to After an impulse of head acceleration, the time
gravity (Fig. 3–6). These translational sensitive constant (TCOR) of the oculomotor response is
neurons are not only found in the vestibular prolonged beyond that of the primary afferent
nuclei but also in the cerebellum, particularly response (T1) because of feedback onto the
in areas that receive primary vestibular affer- secondary vestibular neurons. Quantitatively, the
ents. The translation-only secondary neurons positive feedback loops perform the equivalent of
disappear after canal plugging, proving that a partial mathematical integration on the primary
they result from convergence of canal and afferent signal.112 The interneurons in these
otolith signals. The tilt-translation ambiguity is feedback pathways can be viewed as valves con-
not always resolved at the perceptual level, trolling the spontaneous activity and dynamic
however, because the canals do not provide a properties of the secondary vestibular neurons.
Translation only Roll tilt only Roll tilt-translation Roll tilt + translation
net accel: 0.2 g net accel: 0.2 g net accel: 0 g net accel: 0.4 g
IFR
100 sp s–1
Otolith
20 cm
afferent Htrans
Hroll 12º
IFR 100 sp s–1

Vestibular
nucleus
Htrans 20 cm
neuron
Hroll 12º
Figure 3–6. Instantaneous firing rate (IFR) from a primary otolith afferent (top) that encodes net linear acceleration, and a
central vestibular nucleus neuron (bottom) that encodes translational motion during four movement protocols: Translation
only, Tilt only, Tilt – Translation and Tilt + Translation (0.5 Hz). The stimulus (bottom) traces show sled position (Htran) and
roll tilt position (Hroll). (From Angelaki DE, Cullen KE. Vestibular system: the many facets of a multimodal sense. Annu
Rev Neurosci. 2008;31:125, with permission.)
Velocity
storage
Canal
signal Σ to EOM’s
T1 TCOR
Figure 3–7. Prolongation of the dominant time constant of the canal ocular reflex (TCOR) by velocity storage within the
feedback pathways shown in Figure 3–4. A step change in head angular velocity occurred at time 0 (vertical arrows). T1
represents the long time constant of the cupula measured from the average response of primary afferent neurons. EOM,
extra ocular muscle.
From the above-described experimental data terminals from axons of GABAergic medial ves-
and model simulations, the rotational VOR is tibular neurons, and type C boutons originating
thought to be mediated by two components: a from the vestibular commissural pathway of
rapid, or “direct,” and a slow “indirect,” or velocity storage.115
“velocity storage,” pathway.111 The three-
neuron chain that conveys neural signals from SEMICIRCULAR CANAL–OCULAR
the labyrinth to the motor neurons of the CONNECTIONS
extraocular muscles constitutes the direct path-
way. It has been modeled as a direct pathway Detailed information about the connections
because it does not substantially alter the that link vestibular receptors and different eye
dynamics of the semicircular canal responses muscles was initially obtained by recording the
transferred to the eye muscles. The indirect eye muscle response following either physiologic
VOR pathway also receives semicircular canal or electric stimulation of each receptor.116–118
input, but it has slow charge and discharge time By measuring the muscle tonus, the excitatory
constants. It holds, or “stores,” activity from the or inhibitory nature of each connection was
vestibular periphery and discharges it over a established. Table 3–2 summarizes the primary
more prolonged time span, thus the term excitatory and inhibitory connections of each
“velocity storage” and the designation “indi- semicircular canal with the muscles of both
rect” in models of the VOR. Commissural path- eyes.117 Note that each semicircular canal is
ways between the two vestibular nuclei are connected to the eye muscles in such a way
involved in both direct and indirect pathways, that stimulation of the canal nerve results in
but the fibers appear to cross at different lev- eye movement approximately in the plane of
els.113 In monkeys, an experimental midline that canal. For example, stimulation of the left
section of rostral medullary commissural fibers posterior canal nerve causes excitation of the
abolishes oculomotor and vestibular functions ipsilateral superior oblique and the contralat-
attributable to velocity storage, whereas the eral inferior rectus muscles while inhibiting the
direct VOR pathway remains intact.113 ipsilateral inferior oblique and the contralateral
Utrastructural studies after such lesions indi- superior rectus. An oblique downward move-
cate that the commissural neurons related to ment in the plane of the left posterior canal is
velocity storage are located in the lateral cres- the end result. As suggested in Chapters 1 and
cents of the rostral medial vestibular nucleus. 2, the spontaneous activity of neurons in each
Immunohistochemical staining of the neurons canal leads to a resting level of contraction at
in this portion of the medial vestibular nucleus each eye muscle from all the labyrinthine
in monkeys identified at least two types of organs and provides an important background
GABAergic neurons: neurons related to the upon which these more specific reflexes act.116
velocity storage pathway and vestibular By systematically recording responses in
interneurons.114 A variety of GABAergic bouton different vestibular and oculomotor nuclei
endings was also identified in this region of the after selective stimulation of each semicircular
medial vestibular nucleus: type A boutons cor- canal, it has been possible to trace the main
responding to Purkinje cell afferents, type B disynaptic excitatory and inhibitory pathways
Table 3–2 Connections of the Semicircular Canals with Muscles of the Eyes
Semicircular Canal Excitation Inhibition
Horizontal I–MR C–MR
C–LR I–LR
Posterior I–SO I–IO
C–IR C–SR
Anterior I–SR I–IR
C–IO C–SO
C, contralateral; I, ipsilateral; IO, inferior oblique; IR, inferior rectus; LR, lateral rectus; MR, medial rectus; SO, superior
oblique; SR, superior rectus.
connecting the semicircular canals with the activated canal (Lt HSC). This push–pull
extraocular muscles, as shown in Figure 3–8 organization provides more stability to the
and Table 3–2.117,119,120 As a general rule, reflexes and improves the dynamic linear range
excitatory connections run in the contralateral of the system. The muscles are in a constant
MLF and inhibitory connections run in the state of tension and respond to minimal
ipsilateral MLF.121 modulation of activity of the peripheral
Each muscle receives an excitatory input organs.
originating from the ampullopetally activated The connections illustrated in Table 3–2 are
canal and a disinhibiting input from the ampull- only part of the picture, however. Since the
ofugally activated canal pair on the opposite planes of the semicircular canals are not exactly
side operating in reciprocity. For example, the aligned with the planes of the three pairs of eye
right medial rectus receives an excitatory input muscles, a spatial transformation from canal to
from the right horizontal semicircular canal via muscle coordinates must occur if eye move-
the ipsilateral type I excitatory (GAD-negative) ments are to compensate for head movements.
neurons and a disinhibition input mediated In other words, it is not adequate to simply
through the contralateral type I (GAD-positive) connect afferents from a single canal to a set of
neurons (see Fig. 3–4). Consequently, during eye muscles as shown in Figure 3–8; other con-
clockwise rotation, the muscle will experience nections must also exist. Studies of labeled sec-
an increase in the excitatory input from the ondary vestibular neurons, identified as part of
ampullopetally activated canal (right horizontal the canal ocular reflex, indicate that the spatial
semicircular canal [Rt HSC]) and a decrease in transformations occur through both a conver-
the inhibitory signal from the ampullofugally gence of signals at the level of the vestibular
a b c
SO
SR MR LR
III IR
IO
IV ATD
AC MLF
S
HC L
VI D
M
PC
VN
d e f
SO SR
LR MR
IR III
IO
IV
AC
HC
VI
VN PC
Figure 3–8. Excitatory (a, b, c) and inhibitory (d, e, f) pathways between the individual semicircular canals and eye
muscles in the cat.96,97 AC, anterior canal; ATD, ascending tract of Dieters; HC, horizontal canal; III, oculomotor complex;
IO, inferior oblique; IR, inferior rectus; IV, cochlear nucleus; L, lateral nucleus; M, medial nucleus; D, descending nucleus;
LR, lateral rectus; MLF, medial longitudinal fasciculus; MR, medial rectus; PC, posterior canal; S, superior nucleus; SO,
superior oblique; SR, superior rectus; VI, abducens nucleus; VN, vestibular nuclei.
nuclei and a divergence of signals at the level of velocity (Fig. 3–9c) rather than head acceleration
the oculomotor nuclei.122,123 (Fig. 3–9b). But the normal reflex response pro-
duces a compensatory eye movement amplitude
COMPENSATORY EYE MOVEMENTS that is equal and opposite to the amplitude of the
head movement (compare a and g in Fig. 3–9).
The semicircular canal–ocular reflexes produce This eye movement results from activation of,
eye movements that compensate for head rota- among others, the abducens nerve to the left lat-
tions. Angular and sinusoidal head rotation of eral rectus muscle (Fig. 3–9f) during ampullo-
small amplitude within the frequency range of petal stimulation of the right cupula–vestibular
natural head movements (0.1 to 4.0 Hz) results nerve (Fig. 3–9d, e). However, the timing of the
in compensatory sinusoidal eye movement ampli- recorded activity in the abducens nerve lags
tudes that are 180 degrees out of phase with the behind the activity in the vestibular nerve by an
head (i.e., eye movements in the opposite direc- additional 90-degree delay. This raises a key
tion as the head movement) (as illustrated in question first asked by Skavinski and Robinson:
Fig. 1–12a, b). The various transformations what produces the phase shift (i.e., increase from
involved in this process are illustrated in 90 degrees to 180 degrees) between the firing
Figure 3–9. The natural stimulus for the semicir- rates of the vestibular nerve and abducens nerve
cular canals is head angular acceleration, as (between Fig. 3–9e and Fig. 3–9f)?124 To answer
shown in Figure 3–9b. During sinusoidal rota- this question, they introduced the concept of an
tion, at the frequencies of natural head move- oculomotor integrator, a hypothetical neural net-
ments, the viscoelastic properties of the canal– work that integrates, in a mathematical sense,
cupula complex (as defined by the pendulum velocity-coded signals, such as those originating
model in Chapter 2) produce the equivalent in the vestibular end-organ, to position-coded
of one step of mathematical integration signals required by the oculomotor neurons.
(a 90-degree phase shift) so that the vestibular Although the concept of neural integration
nerve firing rate (Fig. 3–9e) is in phase with head is now generally accepted, the specifics are
a
R
Head
position
L
+ b
Head
0
acceleration
–
+
c Head
0
velocity
–
Ap
d Right cupula
center
displacement
Af
e Right vestibular
baseline
spikes/sec
nerve firing
0
f
baseline Left abducens
nerve firing rate
0
R g
Left eye
position
L
Figure 3–9. Mechanism by which sinusoidal change in head position (a) is converted to an equal and opposite-eye position
(g). R, right; L, left; Af, ampullofugal (i.e., away from the ampulla); Ap, ampullopetal (i.e., toward the ampulla). See text
for details.
still debated. Some investigators feel it is “local- head velocity and eye velocity is in the opposite
ized” in a region of the brain stem125,126 or cere- direction so that the signals are complimentary
bellum,127 whereas others consider it a “distrib- during visualization of an earth-fixed target.
uted property” of the feedback pathways shown EH neurons also modulate their firing rate
in Figure 3–4. Mathematical models show how during both smooth pursuit and vestibular sup-
these feedback pathways, particularly those via pression but in the opposite direction of PVP
the commissural connections, can produce the neurons such that the two signals oppose each
necessary integration.128,129 other during visualization of an earth-fixed tar-
Although the VOR operates as an effective get. BT neurons do not modulate their activity
integrating angular accelerometer for frequen- during vestibular suppression, but their firing
cies >0.1 Hz, at lower frequencies the VOR is rate is strongly correlated with all types of eye
progressively less effective, which is manifest movements. Based on these features it appears
by a phase lead of eye velocity relative to head that BT neurons carry a fully transformed
velocity, reaching a maximum of 90 degrees at motor signal, whereas PVP and EH neurons
about 0.001 Hz. Velocity storage within the carry signals with intermediate features in the
central VOR feedback pathways improves the transformation of sensory input from the semi-
low-frequency gain and phase deficit of incom- circular canals to motor signals required by the
ing primary afferent signals but does not cor- oculomotor neurons.
rect it completely. As will be shown later, this The relationship between the firing rate of
low-frequency gain and phase deficit of the oculomotor neurons and the movements of the
VOR is of little functional significance, since eyes during each phase of nystagmus has been
natural head movements combine visual and studied extensively. During the production of
vestibular stimulation and the combination of an agonist slow component, the membrane
visuovestibulo-ocular responses results in potential is slowly depolarized by excitatory
essentially perfect compensation, even at postsynaptic potentials arriving via the vestibulo-
the lowest frequencies. However, the low- ocular pathways discussed in the previous
frequency phase shift does have important sections.133,134 Toward the end of the slow com-
implications for clinical testing since an increase ponent, the membrane potential rapidly
in the low-frequency phase two-standard devi- becomes hyperpolarized and the motoneuron
ations above the mean normal value is a non- abruptly terminates its discharge. This hyper-
specific sign of damage to the canal-ocular polarization is produced by inhibitory activity
reflexes (see Chapter 7). of a group of neurons different from those
In summary, the rotational VOR involves the producing the slow component.
activity of many nuclei and a countless number Figure 3–10 illustrates the firing rate of a
of neurons whose group behavior may differ single right abducens nerve fiber during sinu-
from that of the isolated units. One must keep soidal angular rotation at three different mag-
this complexity in mind when attempting to nitudes.135 The concurrent nystagmus of the
evaluate the effects of lesions on VOR activity. left eye is shown above each firing record. With
It is often impossible to interpret the results of slow components to the right, the right
vestibular tests in terms of deficits in a single abducens nerve innervates an agonist muscle,
neural pathway. and a steady increase in nerve firing occurs that
is roughly proportional to the eye displace-
NEURONAL MECHANISMS ment. Just before initiation of the fast compo-
nent in the opposite direction (to the left), the
Based on recordings from the vestibular nuclei firing of the right abducens nerve suddenly
in animals three groups of secondary vestibular decreases and, in many instances, stops com-
neurons likely provide the main premotor pletely. During the subsequent slow compo-
drive for the rotational VOR: (1) position-ves- nent, the nerve fiber remains silent until the
tibular pause (PVP) neurons, (2) eye-head eye reaches a position in the orbit that is above
(EH) neurons, and (3) burst tonic (BT) threshold for this particular abducens neuron.
neurons.130–132 PVP neurons modulate their With slow components to the left, an abrupt
firing rate during visual suppression of the increase in firing rate occurs just before
VOR and during smooth pursuit and stop firing the onset of the fast component, followed by a
during saccades. Their response to angular slow decrease during the slow components.
Whereas the change in nerve firing rate during ligaments.137 Once the new position is reached,
the slow component bears a close relationship a much lower rate of discharge produces com-
to the change in eye position, during the fast pensation for the elastic restraining force and
component a much larger increase in action maintains the new position. Although the reflex
potentials occurs per unit of time. pathways for vestibular and visually induced
Measurement of the relationship between eye movements involve different neuronal cir-
motoneuron firing rates and eye movement cuits, the motoneurons governing the extrinsic
induced by vestibular or visual stimuli has eye muscles fire in the same manner regardless
shown that the motoneurons behave the same of the original sensory input.
regardless of the nature of the stimulus.136
Almost all oculomotor neurons exhibit a thresh-
FAST COMPONENT GENERATION
old above which they increase their firing rate
roughly in proportion to the change in eye posi- As noted in Chapter 1, neurons in the parame-
tion in the orbit. A small percentage of the dian pontine reticular formation (PPRF) fire in
change in firing rate (approximately 20%) is short bursts just before the onset of horizontal
proportional to the velocity of the eye move- fast components and voluntary saccades.138–140
ment. It is as though the firing rate of the ocul- Fast eye movements, whether voluntary or
omotor neurons were designed to overcome involuntary, apparently are generated by a
the elastic and viscous forces (roughly in a ratio common neuronal mechanism.138,141 The PPRF
of 5 to 1) restraining the eye in the orbit. This is not a discrete anatomic structure but rather a
relationship can best be appreciated by exam- region that has been designated as such because
ining the rate of firing of an oculomotor neuron of its apparent functional specificity. Stimulation
associated with a visually induced refixation in the PPRF produces ipsilateral slow and rapid
saccade (Fig. 3–10d), where the goal is to move eye movements, depending on the stimulus
the eyes as rapidly as possible from one posi- variables.139,140 The latency of induced eye
tion in the orbit to another and to maintain the movements suggests that one or two synapses
new position once it is reached. During lie between the pontine neurons and the
the high-velocity saccade, the oculomotor neu- oculomotor neurons. Anatomic pathways
ron increases its firing rate to a high level to between this area of the reticular formation
compensate for the viscous drag of the eye and the eye muscle motor nuclei were
100
0
b
100
0
c
100
0
100
0
0 10 20 30
Seconds
Figure 3–10. Right abducens motoneuron activity during induced nystagmus in the cat. In each pair of traces, the top
trace represents the electrooculographic recording of eye movement and the bottom trace, the motoneuron firing fre-
quency, (a–c) The animal was rotated at the frequency of 0.1 Hz at peak velocities of 30°, 60°, and 120°/sec, respectively,
(d) Spontaneous eye movements (saccades).
first reported by Lorente de Nó110 and subse- nuclei and ipsilateral to lesions in the lateral
quently confirmed by other investigators.140 and caudal medial nuclei. The imbalance
Numerous documented anatomic pathways between inhibitory and excitatory secondary
also interconnect the vestibular nuclei with the vestibular neurons undoubtedly determines
PPRF.140,142 the direction of spontaneous nystagmus.
Lesions involving the vestibulo-ocular path-
PATTERN OF EYE MOTION ways in animals may affect either the slow or the
fast component and occasionally both phases of
Intuitively one might assume that the slow induced nystagmus. Interruption of the connec-
phases of nystagmus deviate the eyes toward tions linking the semicircular canals to the oculo-
the periphery of the orbit and the fast compo- motor neurons decreases the velocity of the slow
nents reset them back to the center. Indeed, components of induced nystagmus. Lesions
this pattern occurs in the rabbit (see Fig. 1–12 involving the peripheral vestibular structures
in Chapter 1). In animals with more developed (end organ and nerve) affect the nystagmus in
visual oculomotor function, however, the fast both eyes equally, since the central pathways are
components act as anticipatory movements symmetrically connected. A single remaining
taking the eyes toward the periphery.143 The labyrinth senses angular rotation in both direc-
fast components of the initial beats of nystag- tions and produces conjugate nystagmus in both
mus are larger than the preceding slow compo- directions. The maximum slow component veloc-
nents, and the eyes deviate in the direction of ity of induced nystagmus may be asymmetric,
the fast component (see Fig. 7–19a, b, and c in however, because of the asymmetry in afferent
Chapter 7). In humans, the exact threshold nerve firing rate produced by ampullopetal and
position for the generation of a saccade varies ampullofugal endolymph flow. Central lesions
with the velocity of the slow component of lying anywhere from the vestibular nuclei to the
nystagmus, but it is usually near the mid- oculomotor neurons often produce disconjugate
position.144 The apparent advantage of this nystagmus, since the pathways to the eye muscles
strategy is that the eyes are ready to focus on diverge beginning at the vestibular nuclei.146 A
newly arriving targets in the field of rotation, lesion of the MLF, for example, impairs slow and
and fixation can be maintained during the fast components made by the ipsilateral medial
subsequent slow component. rectus muscle but leaves normal slow and fast
components at the contralateral lateral rectus
EFFECT OF EXPERIMENTAL LESIONS (see Fig. 7–29d in Chapter 7).
The proposed role of the PPRF in the pro-
Spontaneous vestibular nystagmus is produced duction of rapid horizontal eye movements is
by lesions of the labyrinth, the vestibular supported by the results of experimental lesions
nerve, and the vestibular nuclei.118,145 A key in several species of animals. Animals with uni-
ingredient for the production of spontaneous lateral lesions of the PPRF lose all types of
nystagmus is an imbalance of tonic activity rapid ipsilateral eye movement, and the eyes
within the vestibulo-ocular pathways. If a pro- move into the contralateral hemifield.147,148
cess simultaneously removes both labyrinths, Ipsilateral voluntary saccades and quick phases
spontaneous nystagmus does not result, dem- of vestibular and optokinetic nystagmus are
onstrating that, for production of nystagmus, affected equally. Stimuli that normally would
the relative balance of input is more important produce nystagmus with ipsilateral fast compo-
than the absolute magnitude of input. nents simply cause a strong tonic contralateral
Spontaneous nystagmus produced by section- deviation of the eyes (see Fig. 7–29c in
ing of the vestibular nerve duplicates that Chapter 7). By contrast, vestibular stimuli that
resulting from labyrinthectomy. The slow com- produce contralateral fast components result in
ponent is directed toward the side of the lesion. normal nystagmus, that is, ipsilateral slow
The direction of spontaneous nystagmus asso- phases that are normal. Lesions in the pretectal
ciated with lesions of the vestibular nuclei, region have a similar effect on vertical rapid
however, is less predictable and depends on eye movements without affecting horizontal
the location and extent of the lesion. Typically, eye movements,149,150 an effect consistent with
the slow phase of nystagmus is contralateral the separate neural organization of horizontal
to lesions in the superior and rostral medial and vertical saccades.
LEVEL OF AROUSAL AND produces an eye muscle contraction that com-

HABITUATION pensates for a specific head movement with the
objective of maintaining gaze stability. Second,
Since the turn of the twentieth century, numer-
null spots do not exist in the receptive field of
ous investigators have noted a relationship
the semicircular canals because the organs
between the magnitude of induced nystagmus
in each ear form a complementary set of accel-
and the state of arousal of the animals or human
eration sensors capable of reacting to the indi-
subjects receiving vestibular stimulation.151 In
vidual components of angular acceleration
animal studies, amphetamines are routinely
associated with head movement in any direc-
used to maintain alertness. During rotational
tion in three-dimensional space. Third, each
and caloric testing in human subjects the veloc-
receptor organ simultaneously activates an
ity of the slow components of induced nystag-
excitatory and an inhibitory pathway to agonist
mus depends on the type of mental activity.152
and antagonist muscles, resulting in a push–
If subjects are instructed to relax and daydream,
pull system of control. Fourth, most natural
the velocity is less than when they are instructed
head movements activate several receptors
to perform continuous mental arithmetic (suc-
simultaneously and inputs from multiple recep-
cessive division). Although other techniques of
tors converge on secondary neurons. Fifth,
mental alerting, such as having the subject
alternate pathways complement the elemen-
report on the turning sensation or estimate the
tary disynaptic connections. These pathways
time of auditory stimuli, are also effective, men-
consist of chains of interneurons that form
tal arithmetic tasks are most effective in main-
reverberating circuits by means of which dif-
taining mental alertness. The mental task has to
ferent reflexes interact and “fine-tune” the
achieve a certain degree of complexity since
more specific end-organ reflexes. Finally, it is
simple forward-counting may not be effective
becoming evident that, because of multisen-
in maintaining the nystagmus response.151
sory interactions and neurochemical weights,
If a normal subject is continuously rotated
the strength and even the specificity of
at low sinusoidal frequencies in the dark, there
the reactions from these pathways can be
is a gradual decrease in gain and an increase in
physiologically modulated.
the phase lead of eye velocity relative to head
velocity (so-called habituation).153,154 The effect
peaks in about an hour and can persist for days.
Presumably, with habituation, there is a gradual
Translational Vestibulo-Ocular
decrease in velocity storage within the multi- Reflex
neural pathways, illustrated in Figure 3–7,
shifting the low-frequency response of the OVERVIEW
canal-ocular reflex toward that of the primary Sensory cells of each macule are oriented along
afferent signal (i.e., the VOR time constant either side of an equatorial boundary created
decreases toward that of the cupula). Since a by the striola, as shown earlier. The orientation
caloric stimulus is equivalent to a very low- of the cells in multiple directions in each mac-
frequency rotational stimulus (approx- ule is different from that in the cristae. All the
imately 0.002–0.004 Hz), habituation with sensory cells of a semicircular canal are aligned
repeated caloric testing is explained on a in the same direction and are either excited or
similar basis. Alerting techniques (including inhibited by a stimulus acting in the plane of
stimulant drugs) may work by activating the the canal. The study of the otolith-ocular
multineural feedback pathways and thereby reflexes is, therefore, more complex than that
improving the low-frequency response of the of canal–ocular reflexes and also technically
canal–ocular reflex. more difficult.155
To simplify the discussion of otolith-ocular
SUMMARY reflexes, it has been traditional to consider
the otolith organs (utriculus and sacculus
Several basic principles underlie the connec- combined) as a unitary sensor capable of resolv-
tions between the semicircular canals and eye ing all of the linear forces acting on the head
muscles. First, a receptor organ is connected into a single resultant vector force. This “uni-
to a group of motoneurons whose activity tary” three-dimensional otolith receptor is
positioned at the center of the head with the target. Similarly, with fore–aft movements,
x- and y-axes orthogonal to and the z-axis paral- vertical eye movements would impair rather
lel to the earth’s vertical axis. The receptor than improve fixation on an earth-fixed target
computes the angle (θ) between the resultant in the axis of movement.
vector force and the earth’s vertical axis and Furthermore, the translational VOR can
sends this information to the central nervous only stabilize images on one area of the retina.
system (CNS), where a compensatory eye devi- Consider the circumstances one experiences
ation is generated with the goal of maintaining when walking straight ahead. Objects in the
the eyes at normal orientation to the earth’s periphery of the visual field appear to move
vertical axis. The perfect macular reflex would faster than those on the fovea and objects move
be one that rotates the eyes at an angle in different directions based on their location
equal and opposite to θ. In the case of head within the visual field. The amplitude and
tilt in the sagittal plane, as illustrated in Figure direction of the translational VOR is designed
3–11, the efficiency or gain of the reflex can to minimize image slip on the fovea.
be represented by the relation of the angle of As noted earlier, most natural head move-
eye deviation to the angle of head tilt θ ments are composed of a combination of linear
(gain equals α/θ). and angular displacements so that the canal-
Following this simple model of otolith func- and otolith-ocular reflexes must work together
tion, one would predict that linear acceleration to ensure steady fixation. There is an important
along the occipitonasal axis (y-axis) would difference, however, between the geometry of
result in vertical eye movements and linear target displacement during angular and linear
acceleration along the interaural axis (x-axis), in accelerations. With the latter, the angle of the
torsional eye movements (just as lateral tilt required compensatory eye movement
produces ocular counterrolling). However, lin- increases as the target moves closer to the
ear acceleration in the occipitonasal axis pro- subject. A simple model of canal-otolith-ocular
duces minimal vertical eye movements, and reflex interaction during horizontal head
acceleration along the interaural axis induces movements assumes the gain of the canal-
predominantly horizontal eye movements.155,156 ocular reflex is fixed while the otolith-ocular
This is reasonable from a functional point of reflex gain increases with decreasing target
view, since the logical function of the reflex is distance.158 This simple model ignores interoc-
to augment visual pursuit during linear dis- ular spacing and the separation of the vestibu-
placement of the head (analogous to the role of lar organs from the eyes (i.e., it assumes a
the canal-ocular reflex during angular displace- central cyclopean eye), but this is not a major
ment of the head).157 Lateral head movements problem as long as the target distance is greater
require horizontal, not torsional, eye move- than a meter. With this model, if the head
ments to maintain fixation on an earth-fixed rotates with angular velocity A and translates
(a) (b) (c)
q Ft
a Fg
q
Fg Fǵ
Figure 3–11. Compensatory eye movement induced by static head tilt (b) and by linear acceleration tangential (Ft) to the
“unitary” otolith receptor (c); α = the angle of eye rotation and θ = the angle between the resultant force of gravity (Fg) and
a line orthogonal to the receptor.
with linear velocity T, then the eye angular However, electrically induced muscle responses
velocity ω = −A − KT, where K inversely depends are not as useful for determining the specific
on target distance. Studies in primates includ- connectivity as responses to semicircular canal
ing humans found that the magnitude of nerve stimulation. Because of the varied orien-
induced eye movements measured during tation of hair cells within the macules, simulta-
combined linear and angular accelerations (by neous electrical stimulation of all the nerve
varying the radius of head rotation) was depen- fibers coming from a macule produces the
dent on target location.159,160 Furthermore, the equivalent of a heterogeneous activation of dif-
adjustments for target distance occurred too ferently oriented hair cells.164 The induced eye
fast (within 10 msec) to be visually guided. movements fail to represent those seen with
naturally occurring hair cell stimulation.
Likewise, direct mechanical displacement of
OTOLITH–OCULAR CONNECTIONS
the otolithic membrane has similar
The pathways from the macules to the extraoc- limitations.165–167 As one would expect, stimula-
ular muscles are less clearly defined than those tion on each side of the striola produces oppo-
from the semicircular canals. The latency of site-directed eye movements. In the utricle, on
eye muscle activation after stimulation of the the basis of the type of eye movements observed
utricular and saccular nerves is similar to that experimentally, the macule can be divided into
recorded after semicircular canal nerve stimu- three sections: anterior, posterior, and central
lation; disynaptic pathways also exist from the (Fig. 3–12).166 Each section is divided by the
macules to the extraocular muscles.161–163 striola into two unequal parts—peripheral and
Anterior
(a)
Central Medial
Lateral
Posterior
(b)
Superior
Posterior
Anterior
Inferior
Figure 3–12. Separation of the utricular (a) and saccular (b) macules into different sections based on the eye muscles
activated by electrical stimulation of each section (as shown in Table 3–2). Arrows indicate polarity of hair cells on each side
of the striola (dark blue area).
medial. The eye muscles activated by stimula- polarity of hair cells on each side of the striola,
tion of each section are those required to convergence of input from both sides of the
produce compensatory eye movements in the striola on secondary neurons could take the
plane of the hair cells activated—that is, those place of commissural inhibition.172,173 Cross-
required to compensate for linear head move- striolar inhibition was observed in two-thirds of
ments or head tilts in that plane (Table 3–3). saccular activated and one-third of utricular
The saccular macule is much simpler in its activated secondary vestibular neurons.174,175
organization. It can be divided into a superior This cross-striolar convergence on secondary
and an inferior area (Fig. 3–12).167 As with the neurons might make it possible for one laby-
utricular macule, the eye movements produced rinth alone to generate the translational VOR.
by discrete electrical stimulation of the saccu- There is an important difference between
lar macule occur in the direction expected to the signals coded by the canal and otolith affer-
compensate for the physiological stimulus ents. Within the range of natural head
(Table 3–3). movements, otolith afferents code linear accel-
Unlike the horizontal semicircular canal that eration while canal afferents code angular
makes strong disynaptic excitatory connections velocity. An additional integration or low-pass
with the contralateral abducens motoneurons filter of the otolith signals as compared to canal
and disynaptic inhibitory connections with the signals is needed in the VOR pathways. Several
ipsilateral abducens neurons, abducens models have been developed to account for the
motoneurons and internuclear neurons receive needed extra low-pass filter.155,176,177 Otolith sig-
only weak disynaptic excitation after stimula- nals could undergo a separate neural integra-
tion of the ipsilateral utricular nerve and only tion prior to convergence on the common
trisynaptic inhibition after stimulation of the neural integrator shared with canal ocular sig-
contralateral utricular nerve.168–173 Only trisyn- nals or the otolith signals could enter the shared
aptic connections have been found between but distributed velocity-to-position integrator
the utricle and the medial rectus motoneurons. network at different sites such that signals from
Also unlike the canal activated secondary ves- the canals are only integrated once while those
tibular neurons, only about half of utricular from the otolth organs are integrated twice.
activated secondary neurons receive commis- One way to achieve the latter is to assume that
sural inhibition and almost none of the saccular both the angular and translational VOR share
activated secondary neurons receive commis- the same neural integrator pathway but have
sural inhibition. However, due to the opposite completely different direct pathways (a reason-
able assumption based on the above). The
direct pathway of the rotational VOR is strong
Table 3–3 Connections of the Utricle while that of the translational VOR is weak.
and Saccule with Muscles of the Eyes The strong rotational VOR pathway generates
a lead that can compensate for the low-pass
UTRICLE dynamics of the eye plant while the weak trans-
Lateral Medial lational VOR pathway does not generate a lead.
The low-pass filter dynamics of the eye plant,
Anterior I–SR I–IR which remains uncompensated, can provide
C–IO C–SO the second integration for the translational
Central C–MR I–MR VOR but only at high frequencies above
I–LR C–IR the dominant time constant of the eye plant
Posterior I–IO I–SO (a prediction consistent with experimental
C–SR C–IR findings).
SACCULE
Superior Inferior CHARACTERISTICS OF EYE
I–SR I–SO MOVEMENTS INDUCED BY
C–IO C–IR TRANSLATION
C, contralateral; I, ipsilateral; IO, inferior oblique, IR, Brief high-acceleration steps of the whole body
inferior rectus, LR, lateral rectus; MR, medial rectus; SO, along the interaural axis have been used to
superior oblique; SR, superior rectus. assess the function of the otolith-ocular reflex
in primates and in normal human subjects and than ideal (i.e., that required for compensatory
patients. Paige and Tomko178,179 studied the eye stabilization), implying that during most
translational VOR in squirrel monkeys and natural head movements, the angular VOR
found a short latency response that was depen- plays the major role in gaze stabilization.
dent on viewing distance. Lempert et al.180
studied humans with step accelerations of
0.24 g using a cart on wheels and recorded eye Ocular Counterrolling
movements with electrooculography. Normal
subjects have symmetrical otolith-ocular Compensatory eye movements produced by
reflexes with short latencies (<130 msec). static head tilt have been easier to measure in
Abnormalities in gain, symmetry, and latencies animals that have limited spontaneous eye
were seen in patients with bilateral loss of movement. They usually are either rotational
caloric responses, but none of these findings or torsional, depending on the direction of tilt
seemed specific for loss of the otolith-ocular and the position of the orbits in the skull. For
reflex. Crane et al.181 produced brief high- example, in rabbits and fish, lateral tilt causes a
acceleration steps (0.4 g) using a pneumatically vertically directed rotational movement, and
driven chair moving along the interaural axis forward–backward tilt causes a torsional eye
and recorded eye movement with the precise movement. These results are consistent with
scleral search coil technique. Normal subjects the compensatory movement of the eye in rela-
showed stereotyped short-latency (about tion to the earth reference coordinates. In
30 msec) otolith-ocular responses that humans, compensatory torsional movements
depended on the distance of a fixation target are produced by lateral tilt (ocular counter-
that was extinguished just before the onset of rolling), whereas vertical rotation results from
the head acceleration (Fig. 3–13). Patients with forward–backward tilt (see Fig. 3–11). Eye
bilateral loss of caloric response showed pro- movements associated with static tilt have
longed latencies and decreased gain of the been studied most extensively in the rabbit.
otolith-ocular reflex and these responses were Head tilt in the dark within a range of ± 45
minimally affected by the distance of a remem- degrees of the normal position causes a
bered visual target. In all of these studies, the compensatory eye deviation with a gain of
gain of the otolith-ocular reflex was much less approximately 0.6182; that is, the angle of eye
Normal Subject Bilateral Vestibulopathy

10 10
Head Position (cm)
Head Head
5 5
3 cm 3 cm
0 0 200 cm
Eye Position (deg)
3º 200 cm 3º
Eye 25 cm
–5 –5
Eye
25 cm
–10 –10
–100 –50 0 50 100 150 200 250 300 –100 –50 0 50 100 150 200 250 300
Time (msec)
Figure 3–13. Short-latency otolith-ocular responses to brief high-acceleration (> 0.5 g), linear displacements along the
intraaural axis in a normal subject and a patient with bilateral vestibulopathy (absent caloric responses). Subjects fixated on
a target at 25 cm and 200 cm that was extinguished just before the onset of the acceleration in total darkness. Eye move-
ments were recorded with scleral search coils. (Courtesy Crane B, Wiest G, Demer J, Departments of Ophthalmology and
Neurology, UCLA.)
rotation (α) is approximately 60% of the angle the sum of the angular and translational
of tilt (θ). In human subjects, the ocular VOR.192 This finding is consistent with the
response to tilt is much less efficient. The concept that the translational VOR functions
maximum ocular torsion for a lateral tilt of mainly in the frequency range of natural head
50 degrees is only 5 to 6 degrees (a gain of movements.
approximately 0.1).183,184 After an acute unilat- If a monkey is rotated at a constant velocity
eral lesion, there is a static ocular torsion (about about a tilted vertical axis (OVAR), the slow-
10 degrees) toward the side of the lesion185 phase velocity of induced nystagmus does not
and decreased ocular counterrolling with tilt decay to zero (as when the monkey is vertical),
toward the side of the lesion,186 but these but rather persists at a steady-state level.191,194
asymmetries disappear with compensation. If the animal is suddenly stopped, the post-
Ocular counterrolling responses may be rotatory nystagmus after OVAR shows a shift in
transiently decreased after prolonged space axis toward the GIA and is shorter than when
flight.187 the animal is stopped in the upright position.
Blocking the semicircular canals does not alter
the steady-state response during OVAR, indi-
Semicircular Canal–Otolith cating that the otoliths generate the signals
Interaction necessary for the continuous nystagmus. It has
been postulated that sequential excitation and
Two techniques have been routinely used to inhibition of the otolith hair cells by the rotat-
study the interaction of semicircular canal and ing gravity vector produces a traveling wave
otolith induced eye movements: off-center axis whose velocity is estimated centrally and then
rotation (OCAR) and off-vertical axis rotation passed on to the velocity storage integrator,
(OVAR). With both techniques the otolith which produces the continuous horizontal
component of the induced eye movement can nystagmus.195 The velocity storage system can
be studied in isolation once a constant velocity be activated by many types of stimuli (canal,
of angular rotation is achieved. otolith, vision) and through a three-dimensional
OCAR, which induces combined centripetal gravity-dependent structure; the system is
and angular acceleration, has been used exten- capable of storing information to produce eye
sively to study the interaction of the rotational movements in all planes.196–197
and translational VOR in animals.188–192 If a
monkey undergoes OCAR by rapidly accelerat-
ing to a constant angular velocity, the induced
nystagmus is similar to that seen after a compa- CERVICO-OCULAR REFLEXES
rable rotational stimulus about the z axis
but with several important differences Ocular stability during most natural head
(Fig. 3–14).193 The axis of induced eye move- movements results from a coordinated interac-
ments shifts toward the gravito-innertial accel- tion of signals originating in vestibular, visual,
eration (GIA) so that the amplitude of the and neck receptors. The compensatory nature
horizontal component decreases and torsional of neck-induced eye movements has been well
and vertical components develop. A DC offset documented in animals. In 1924 De Kleyn198
develops in the roll plane (counterrolling) and showed that if one holds an animal’s head sta-
the time constant of nystagmus decay shortens. tionary and displaces the body, a compensatory
When the canals are plugged isolating the con- eye deviation occurs that tends to preserve the
tribution of the otolith organs, nystagmus dis- relationship between gaze and the body axis.
appears and only the counterrolling remains Nonfoveated animals, such as the rabbit, exhibit
(Fig. 3–14b). Both the shift in the axis of eye clear compensatory eye deviations.199 Cervico-
velocity and the change in time constant are ocular and vestibulo-ocular reflex interaction is
quantitatively predicted by models of the spa- more difficult to study in primates because of
tial orientation properties of velocity storage.193 the dominance of voluntary and visually con-
By contrast if monkeys undergo OCAR at high trolled eye movements and because the gain of
frequencies (1–4 Hz) where there is minimal the cervico-ocular reflex is so low compared to
tilt of the GIA, only horizontal eye movements that of the vestibulo-ocular reflex. Very few
are induced and the eye movements represent investigators have quantitatively assessed eye,
a
PRE-OP M9308
ANG
VEL GIA
ANG VEL 52º
–400º/S
GIA
θ 60º
ψ 30º
φ 60º
ωX 500º/S
ωY Facing Motion
500º/S
GIA Ag
ωZ 500º/S θº
Ag
20 Sec
b
POST-OP M9308
ANG
VEL GIA
ANG VEL 52º
–400º/S
GIA
θ 60º
ψ 30º
φ 60º
ωX 100º/S
ωY 100º/S
ωZ 100º/S
20 Sec
Figure 3–14. Response to centrifugation after plugging the 6 semicircular canals. a: preoperatively, the animal had normal
horizontal eye velocity and normal counterrolling during the period of gravito-inertial acceleration (GIA) tilt (between the
arrows). b: after plugging the canals, normal counterrolling was still present during the period of GIA tilt (between the
arrows) indicating normal otolith function. No horizontal or vertical eye velocity was present. (From Wearne S, Raphan T,
Cohen B. Effects of tilt of the gravito-inertial acceleration vector on the angular vestibuloocular reflex during centrifugation.
J Neurophysiol. 1999 May;81:2175, with permission.)
head, and neck movement coordination in cervical articulations.55,201 The reflex can be
humans, and the clinical significance of lesions induced by electrically stimulating the capsules
involving the cervico-ocular reflex pathways is of the upper cervical joints, the C1 to C3 dorsal
controversial.200 roots, and the high cervical spinal cord. The
reflex is not induced by stimulating the superfi-
cial muscles or skin of the neck. Bilateral sec-
Anatomic and Physiologic Basis tioning of the high cervicodorsal roots or the
application of local anesthetic around the cer-
Animal studies have shown that the cervico- vical articulations abolishes the cervico-ocular
ocular reflex originates from nerve endings in reflexes. Unilateral interruption of the neck-
the ligaments and capsules of the upper ocular reflex pathways produces nystagmus in
rabbits, cats, and monkeys when fixation is hand, in rhesus monkey there was no modula-
inhibited, although no consistent relationship tion in EH secondary vestibular neurons with
exists between the side of dorsal root involve- passive neck rotations.208 These different find-
ment and the direction of nystagmus.202,203 As ings are consistent with the fact that squirrel
with the VOR, the eye muscles are either monkeys have a relatively robust cervico-ocular
excited or inhibited by neck stimulation, reflex compared to the rhesus monkey.208
depending on whether the muscle is agonistic
or antagonistic for the required compensatory
movement. Characteristics of Neck-Induced
Electrophysiologic experiments suggest that Eye Movements
the cervico-ocular reflexes are mediated via the
vestibular nuclei (primarily in the medial and Figure 3–15 illustrates the synergistic interac-
descending nuclei).55,204 The precise projection of neck and vestibulo-ocular reflexes.
tions of the neck afferents to each vestibular When the rabbit’s head is turned to the right
nucleus are only partially known, but it can be (clockwise about the cephalocaudal axis), the
anticipated that since the neck-induced eye eyes turn counterclockwise in the orbit because
movements compensate for displacement in the movement stimulates the horizontal semi-
the precise plane of body motion, the vestibu- circular canals and neck reflexes (Fig. 3–15b).
lar nuclei must contain a discrete topographic The direction of the eye movement is the same
representation of cervical afferents that is simi- as if the whole animal had been rotated, stimu-
lar to that of the vestibular afferents. lating only the semicircular canals (Fig. 3–15c).
Electric stimulation of the high cervicodor- The characteristics of the neck-ocular reflex
sal roots in the cat produces evoked potentials alone are evaluated by rotating the body while
in the contralateral vestibular nuclei55 followed the head is stationary (Fig. 3–15a). The same
by excitation of the abducens nucleus ipsilat- relationship between head and torso is pro-
eral to the neck stimulation and inhibition of duced as in Figure 3–15b and the eyes deviate
the contralateral abducens nucleus. In addi- in the same direction. In both instances, the
tion, stimulation of the cervicodorsal roots normal relationship between eyes and torso is
enhances the amplitude of action potentials in maintained.
the ipsilateral abducens nerve induced by con- Since the time of Bárány, rotating the body
tralateral vestibular nerve stimulation, and it with the head stationary and measuring the eye
inhibits action potentials in the contralateral movements has been considered a potential
abducens nerve induced by ipsilateral vestibu- functional test of the human neck-ocular reflex
lar nerve stimulation. Vestibulo-ocular and pathways.209–213 Several methodologic problems
cervico-ocular reflex interactions, therefore, have been encountered, however. It is difficult
result from a convergence of neck and semicir- to induce body motion and concurrently main-
cular canal afferents on secondary vestibular tain the head completely stationary so as to
neurons. avoid vestibular stimulation. As with vestibular-
The firing properties of VOR-related sec- induced eye movements, care must be taken
ondary vestibular neurons and floccular to inhibit fixation while monitoring the neck-
Purkinje cells were studied during neck rota- induced eye movement. Even if these prob-
tions in monkey.205–208 In squirrel monkey, pas- lems are overcome, the gain of the cervico-
sively moving the neck produced changes in ocular reflex in humans is very low (<0.1 for the
firing rate related to neck position and/or neck frequency range between 0.1 and 1.0 Hz).210,213
velocity in PVP and EH neurons.205,206 Floccular The gain of the cervico-ocular reflex does
Purkinje neurons were relatively insensitive to appear to increase with age, but this increase is
neck-induced eye movements, but when eye only seen at low frequencies (<0.1 Hz) and
movements were visually suppressed the firing peak velocities (<15 degrees/sec) so it is unlikely
rate of these neurons was modulated by neck that it could help compensate for VOR loss in
movements. Thus, it appears that the flocculus the frequency and velocity range of natural
plays a role in suppressing the cervico-ocular head movements. Studies in monkeys and
reflex when it would cause inappropriate move- humans after unilateral vestibular loss found
ment of a visual target on the retina (similar to no increase in cervico-ocular reflex gain, but
its role in modulating the VOR). On the other similar studies after bilateral vestibular loss
a b c
Angle of:
Head motion
qh qh
Eye motion
qe qe qe
qt
qt
Torso motion
Figure 3–15. Synergistic interaction of cervico-ocular and vestibulo-ocular reflexes. See text for details.
found an increase in cervico-ocular reflex gain. position. The optokinetic system is generally
Again, it is unclear whether this increase would considered to be a primitive form of smooth
be beneficial at the frequencies of natural head pursuit involving the whole retina instead of
movements. the fovea alone. The eye tracking motion is
periodically interrupted by corrective saccades
in the opposite direction to relocate the gaze
on new targets coming into the visual field.
VISUAL–VESTIBULAR
INTERACTION
Visual Tracking Eye Movements
Three visually controlled ocular stabilizing sys-
tems produce versional eye movements: the
OPTOKINETIC
saccadic, the smooth pursuit, and optokinetic
systems.214 In everyday life, these three systems Afoveate animals, such as rabbits, have been
interact with the vestibular system for the useful models for studying the organization of
maintenance of gaze as subjects attempt to the optokinetic reflex response. In the rabbit,
identify moving objects in space and maintain monocular stimulation results in a prominent
stability in gaze. The optokinetic is the phylo- asymmetry in response; temporonasal target
genetically older system; the other two are motion induces much greater slow-phase veloc-
related to the anatomical development of the ity than nasotemporal motion. 216,217 The peak
fovea. The saccade system responds to an error optokinetic nystagmus (OKN) slow-phase
in the direction of gaze with respect to the posi- velocity rarely exceeds 30 degrees/sec, and
tion of an object of interest by initiating a rapid there is a gradual buildup in slow-phase
eye movement (a saccade) to correct the “reti- velocity after the step onset of an optokinetic
nal position error,” bringing the object to the stimulus (over 20 to 30 sec). In foveate
fovea in the shortest possible time. The brain- animals, including humans, OKN slow-phase
stem centers for generating saccades were velocity is symmetrical and may exceed
briefly discussed earlier (for review, see 100 degrees/sec.218
Shinoda et al.215). The smooth pursuit system is Although OKN can be elicited in primates
responsible for maintaining gaze on a moving with parafoveal stimulation, the strongest
target, that is, it keeps the target within the responses are induced when the fovea is
foveal visual field. It compares the eye velocity included in the field of stimulation.219,220 A tem-
with that of the target velocity and produces poronasal preponderance occurs during mon-
a continuous match of the eye and target ocular stimulation in the first few months of life
while the fovea is immature.221,222 Also, mon- (<0.1 Hz) but progressively decreases at higher
ocular asymmetry has been observed in patients frequencies (e.g., 0.3–0.5 at 2–4 Hz).226,227
with maldeveloped foveas223 and with congeni- A slow buildup in OKN slow-phase velocity
tal or early acquired amblyopia.224 is not observed in normal humans,220 but it has
In rhesus monkeys the OKN response to a been seen in patients with lesions of the
step change in stimulus velocity has two retina,223,224 parietal lobe,228 and cerebellum.229
dynamic components (Fig. 3–16). There is a If normal subjects are instructed to follow the
rapid initial jump in slow-phase velocity (Fig stripes on an optokinetic drum, the subjects
3–16B,a) followed by a gradual rise to a steady- produce a large-amplitude, low-frequency nys-
state level (Fig. 3–16B,b).225 If the lights are tagmus (“look” OKN); if they are instructed to
turned off after the steady state is achieved, the stare straight ahead at the drum surface, they
eye velocity immediately drops to a value near produce a small-amplitude, high-frequency
that achieved after the initial rapid rise (Fig. nystagmus (“stare” OKN). In normal human
3–16B,c) from which it slowly decays as optoki- subjects the slow-phase velocity of “look” OKN
netic after-nystagmus (OKAN) (Fig. 3–16B,d). can exceed 100 degrees/sec, whereas that of
The eye velocity reached after the initial fast “stare” OKN rarely exceeds 60 degrees/sec.230
jump varies from 40% to 80% of the stimulus The OKAN responses in humans are much less
velocity; the steady-state values are almost consistent than those in monkeys; the maxi-
equal to stimulus velocities up to 60 degrees/ mum initial slow-phase velocity does not exceed
sec but progressively decrease for higher-stim- 20 degrees/sec.231,232
ulus velocities.225 Also, OKN is more irregular
at high-stimulus velocities, so that average gain SMOOTH PURSUIT
values are less than peak values. The maximum
initial velocity of OKAN varies with stimulus In foveate animals, the smooth pursuit system
velocity but can exceed 70 degrees/sec.225 With functions to stabilize a moving target on
sinusoidal optokinetic stimulation in monkeys, the fovea.233 The system operates optimally
the gain of OKN is near 1 at low frequencies for low velocities and low frequencies of
A OKN OKAN
Smooth
pursuit
velocity 30º/sec
Horizontal
EOG 30º
Drum 15 sec
160º/sec
velocity
B OKN OKAN
b c
Smooth
pursuit
velocity
a d
Figure 3–16. A Optokinetic nystagmus (OKN) and optokinetic after-nystagmus (OKAN) in response to a velocity step
of the optokinetic drum. First trace, velocity of horizontal eye movements, fast phases clipped; second trace, horizontal
eye position; third trace, velocity profile of the optokinetic drum. Upward arrow, lights on; downward arrow, lights out.
B Velocity envelope (a–d) of the slow phases of OKN and OKAN redrawn schematically from the first trace in A. (From
Waespe W, Henn V. Gaze stabilization in the primate. The interaction of the vestibulo-ocular reflex, optokinetic nystagmus
and smooth pursuit. Rev Physiol Biochem Pharmacol. 1987;106: 37, with permission.)
target motion.234,235 As the velocity and fre- direct pathway. The velocity storage element
quency increase (e.g., above 60 degrees/sec or accounts for the slow buildup in optokinetic
1 Hz in humans), the eyes continually fall nystagmus and OKAN. The direct pathway
behind and frequent corrective saccades are accounts for the initial rapid rise in OKN and
required to bring the target to the fovea. The the rapid drop after turning off the lights.
gain of smooth pursuit is not only a function of In 1936 Ter Braak242 performed a series of
target velocity but also of target acceleration.236 experiments in which he confirmed the pres-
Subjects better pursue a target with continu- ence of cortical and subcortical optokinetic
ously changing velocity if the pattern of move- pathways in several animal species. Cortical
ment is predictable (as with a sinusoidal OKN was elicited by movement of a series of
pattern).234 The stimulus for smooth pursuit relatively small objects that attracted the ani-
may be perceived target motion rather than mal’s attention (so-called active nystagmus),
actual target motion since subjects can pursue while subcortical OKN was produced by
apparent target motion in the absence of a tar- movement of the whole optical environment
get moving across the retina.237 Also, subjects (passive nystagmus). Presumably, the cortical
can pursue a stabilized retinal image eccentric pathway corresponds to the direct (pursuit)
to the fovea.238,239 Probably retinal velocity error pathway and the subcortical pathway to the
is the main driving force for smooth pursuit eye indirect (velocity storage) pathway. In animals
movements, with a lesser contribution coming without a fovea, such as the rabbit, only passive
from retinal position error and perceived target OKN can be induced, and bilateral occipital
motion.240 lobectomy produces a minimal effect on
induced OKN.243 In cats and dogs, passive and
active OKN can be induced, but only the latter
Organization of Visually Guided is abolished by bilateral occipital lobectomy.242
Tracking Eye Movements In monkeys bilateral occipital lobectomy abol-
ishes smooth pursuit and the initial rapid rise in
A simple scheme of visually guided tracking OKN (leaving the slow buildup and OKAN
eye movements based on the concepts of intact), but after a few months the animals
Cohen et al.241 is shown in Figure 3–17. Visual regain some smooth pursuit and part of the
motion information reaches the oculomotor rapid phase of OKN.244
neurons via two pathways: a direct pathway Since human subjects have poor OKAN and
with fast dynamics and an indirect pathway do not exhibit a buildup in OKN slowphase
with slower dynamics. A key feature of the velocity, the subcortical (indirect) pathway
indirect pathway is the velocity storage element must be much less prominent in humans than
shared with the VOR. Optokinetic stimulation in other animals. However, patients with occip-
activates both pathways, whereas pursuit ital infarction often have the ability to perceive
(according to Robinson112) activates only the visual motion and avoid objects when walking,
Retinal Σ
Direct to EOM’s
signal
Velocity
storage
Figure 3–17. Schematic drawing of the direct and indirect (velocity storage) visuomotor pathways. A constant velocity
optokinetic stimulus begins at the first arrow and the lights are turned off at the second arrow. The signals from the two
pathways add together to produce the characteristic slow-phase velocity envelope of OKN and OKAN (far right). EOM-
extra ocular muscle.
even though they are not consciously aware of contrast, the gain of the VOR is about 0.6 when
“seeing.”245 One such patient exhibited a slow a normal human subject is sinusoidally rotated
buildup in OKN.246 As noted earlier, patients in the dark at 0.1 Hz and a maximum velocity
with lesions of the parietal lobe and midline of 30 degrees/sec. Unlike the visuomotor sys-
cerebellum also exhibit a slow buildup in OKN; tem, however, the VOR responds with a gain
the indirect pathway is uncovered after loss of near 1 for frequencies from 1 to 4 Hz and
the direct pathway.228,229 velocities >100 degrees/sec.234,241 The reader
can test the increased efficiency of the vestibu-
lar system over the visuomotor system at high
Comparison of Vestibular- and input velocities and frequencies by a simple
Visual-Induced Eye Movements maneuver. Rapidly move your hand back and
forth with increasing velocity with your head
The schematic diagrams of the visuo-ocular stationary until your hand appears blurred.
(pursuit and optokinetic) and the vestibulo- Then hold your hand stationary and rapidly
ocular reflexes in Figure 3–18 illustrate impor- move your head back and forth at the
tant similarities and differences between the same high speed. Despite the rapid head move-
two types of reflexes. In both instances the ment, the smallest detail of the palm remains
objective of the reflex eye movement (Θ̇e) is to clear.248
match that of the stimulus velocity if the system
is functioning perfectly. In the case of the
visuomotor system, the stimulus is the target Visuo-Vestibulo-Ocular
velocity Θ̇t (or optokinetic drum velocity), while Connections
for the vestibular system it is the head velocity
Θ̇h. The eye movement takes the form of either The existence of neurons in the vestibular
smooth pursuit or nystagmus. In the latter case, nuclei whose responses reflected visual inputs
the Θ̇e response is that of the slow component represented a new concept in the organization
of the nystagmus. The target velocity and head of the vestibular reflexes. Shortly after it was
velocity must have opposite signs to produce demonstrated by Dichgans et al.249 that neu-
(Θ̇e) with the same sign. The visuomotor system rons in the vestibular nuclei of goldfish
functions as a closed-loop system with negative responded to visual inputs, similar observations
feedback to compare eye and target velocity, were made by other investigators in a variety of
whereas the VOR is an open-loop system. animals under a variety of experimental
For both systems, the gain of induced eye conditions.8,250 The need for a site for interac-
movements is dependent on the velocity and tion of vestibular and visual inputs had been
frequency of the stimulus. The visuomotor sys- recognized, but the realization that the interac-
tem is most efficient at low target velocities and tion took place within the vestibular nuclei rep-
frequencies. Normal human subjects can track resented a departure from the rules of sensory
a target moving sinusoidally at 0.1 Hz, peak specificity for the vestibular system.
velocity 30 degrees/sec, with a gain near 1.236,247 In afoveate animals, the subcortical, accessory
The gain rapidly falls off for target velocities optic system is the predominant pathway for
>100 degrees/sec and frequencies >1 Hz. By visual–vestibular interaction.59,217,251 This system
Negative Feedback Loop
⭈ Target Visuoocular Eye ⭈

Θ† Retina Θe
velocity reflex velocity
⭈ Head Semicircular Vestibuloocular ⭈

Θh Θe
velocity canals reflex
Figure 3–18. Schematic diagrams of the visuo-ocular and the vestibulo-ocular reflexes. The former is a closed-loop
negative feedback system and the latter is an open-loop system.
includes a group of nuclei at the mesodienceph- (Fig. 3–19).117 Retinal sensory information
alic border that, like the lateral geniculate reaches the inferior olives by way of the acces-
nucleus, receives direct retinal projections but, sory optic tract and the central tegmental tract
unlike the lateral geniculate, projects directly to and then the cerebellum, where they activate
the brain stem and cerebellum. The most prom- Purkinje cells in the flocculus, nodule, and
inent cell group of the accessory optic system, other adjacent areas. These parts of the cere-
the nucleus of the basal optic root, is identifi- bellum also receive primary vestibular afferent
able in all classes of vertebrates. Lázár252 found fibers and secondary vestibular fibers originat-
that optokinetic responses are abolished in frogs ing mostly in the medial and descending ves-
after destruction of the basal optic root nuclei, tibular nuclei. Outflow from the cerebellar
whereas ablation of the lateral geniculate nuclei Purkinje cells terminates at secondary vestibu-
and superior colliculi did not affect optokinetic lar neurons and neurons in the adjacent reticu-
responses. As in the rabbit, only subcortical pas- lar substance.
sive OKN can be elicited in the frog. With the development of the fovea, cortical
Electrophysiological studies in rabbits pathways become progressively more impor-
have demonstrated projections from the tant in visual–vestibular interaction. Anatomical
retina to the flocculonodular lobe of the and physiological studies in primates indicate
cerebellum via the accessory optic system.253–255 that visual signals reach the brain stem
Microelectrode recordings in the accessory for interaction with vestibular signals via a
optic nucleus of the rabbit and the cat reveal complex cascade of interconnecting pathways
units that show a strong response to a slow full- (Fig. 3–20). In contrast to the rabbit and cat,
held retinal stimulation.217,256 Temporonasal neurons in the pretectal complex of the mon-
movements of large patterns rich in texture key receive predominant input from the visual
evoke the strongest response. Neuroanatomical cortex and respond equally well to small spots
studies using horseradish peroxidase to map or large random dot patterns moving through
the connections between the accessory optic their receptive field.222,259 Furthermore, they
system and the flocculus show two separate respond in the same manner to monocular or
pathways—one direct and the other an indirect binocular stimulation—that is, they do not
pathway synapsing in the inferior olive.257,258 exhibit the temporal-nasal preponderance seen
The cerebellovestibular pathways involved in in afoveate animals. Electrical stimulation of
visual–vestibular interaction were first described the nucleus of the optic tract (NOT) in alert
by Ito on the basis of his studies in rabbits monkeys evokes horizontal nystagmus with
PU
FL
GR
OM
VN
MF
CF
VO Eye
CTT AOT
IO
Figure 3–19. Anatomic pathways of visual–vestibular interaction in the rabbit. AOT, accessory optic tract; CTT, central
tegmental tract; Fl, flocculus; GR, granule cell; IO, inferior olive; MF, mossy fiber; OM, ocular motoneuron; PU, Purkinje
cell; VO, vestibular end organ; VN, vestibular nucleus. Inhibitory neurons are dark blue. (From Ito M. The vestibulo-
cerebellar relationships: vestibulo-ocular reflex arc and flocculus. In: Naunton RF (ed). The Vestibular System. Academic
Press, New York, 1975, with permission.)
Retina
Pretectal Primary Frontal

nuclei visual eye field
AOS, NOT cortex cortex
Visual
association
cortex
MT, MST, PP
Pontine
nuclei
DLPN, RTPN
Other
Brain stem Cerebellum
nuclei FI, Ve
VN, PH, IO
Oculomotor
neurons
Figure 3–20. Schematic drawing of visual–vestibular pathways in the primate (see text for details). AOS, accessory
optic system; DLPN, dorsal lateral pontine nuclei; DMPN, dorsal medial pontine nuclei; Fl, flocculus; IO, inferior olive;
MST, medial superior temporal area; MT, middle temporal area; NOT, nucleus of the optic tract; PH, prepositus hypo-
glossi nucleus; PP, posterior parietal cortex (area 7a); Ve, vermis; VN vestibular nucleus. Dashed lines indicate probable
pathways.
a slow buildup in slow-phase velocity followed frontal eye fields (FEFs) and the supplemen-
by after-nystagmus in the same direction.260 tary eye fields (SEFs).269,270 Both regions receive
The rising time course in slow-phase velocity visual and vestibular inputs and both are criti-
is similar to the slow buildup in OKN and cal for integrating extraretinal pursuit informa-
the falling time course of the after-nystagmus tion. The FEF plays an important role in pre-
parallels that of OKAN. The striate cortex,261 dictive pursuit while the SEF is specialized for
the superior temporal sulcus (particularly the different task conditions. These cortical cen-
middle temporal [MT] and medial superior ters project to the dorsolateral pontine nucleus
temporal [MST] areas)262–266 and the posterior (DLPN) and the neighboring rostral reticularis
parietal cortex267,268 are the key cortical areas tegmenti pontes nucleus (RTPN), which are
in the monkey for processing retinal motion a primary source of afferents to the flocculus
information. The frontal cortex contains key and vermal areas VI and VII, two cerebellar
pursuit-related regions: the caudal part of the areas involved in the regulation of eye
movements.271–274 Neurons in the DLPN exhibit target and the head move, the driving stimulus
a directionally selective response to movement of to the visuomotor system is the angular
discrete spots, and large backgrounds and micro- velocity of the target relative to the head—
stimulation in the region of the DLPN cause a that is, the difference between the target
short-latency modification of the velocity of an velocity relative to space (Θ̇t) and the head
ongoing pursuit eye movement.272 angular velocity relative to space (Θ̇h). In
In the monkey, lesions of the parietotemporal the absence of head movement (Θ̇h=0), the
region,275 DLPN,272 and the flocculus276 result in eye movement response is under the control
an impairment of (1) smooth pursuit, (2) the ini- of the closed-loop visuomotor system, whereas,
tial rapid rise in OKN slow-phase velocity, and if the head is rotated in the dark, the visual sys-
(3) visual vestibular interaction, requiring the tem is inoperative and the eye movement
“direct” visuomotor pathway, for example, fixa- response is under the control of the vestibular
tion suppression of vestibular nystagmus with a system.
foveal target. By contrast, lesions of the pretec- A few general features of this model deserve
tal nuclei (nucleus of the optic tract) impair emphasis because of their relevance to clinical
OKN but not pursuit.277 Taken together, these testing. A full-field target activates both the
data suggest that the cortical and subcortical direct (pursuit) and indirect (velocity storage)
pathways illustrated in Figure 3–20 roughly cor- pathways, the latter being shared with the ves-
respond to the direct and indirect visuomotor tibular system. Optokinetic after-nystagmus
pathways of the model shown in Figure 3–17. provides the only independent measure of the
indirect pathway. In contrast, a foveal target
activates predominantly the direct pathway
Model of Visual–Vestibular (pursuit after-responses are minimal).236
Interaction Therefore, pursuit testing is almost exclusively
a measure of the direct visuomotor pathway. At
Figure 3–21 gives a simple linear interaction low-input frequencies and velocities (head or
model for the visual and vestibular oculomotor target), the gain of the direct pathway is an
systems.195 The two independent block order of magnitude higher than that of the
diagrams in Figure 3–18 have been interrelated other pathways. This explains why normal sub-
to produce a single output eye velocity (Θ̇e). jects can completely inhibit the VOR when
When the target (foveal or full field) is station- rotated with a fixation target at the low
ary, movement of the head results in an equiva- frequencies commonly used for clinical
lent movement of the target in the opposite testing (i.e., ≤0.1 Hz) (see Fig. 1–9 in
direction relative to the head. When both the Chapter 1).
Retina
Direct pathway
Θ† Σ Σ
ΣΘ
Velocity
Σ Θe
storage
Semicircular
Θh
canals
Direct pathway
Figure 3–21. Model of visual–vestibular interaction after Cohen et al.130 Θ̇h, eye velocity; Θ̇h, head velocity; Θ̇t target (foveal
or full field) velocity. See text for details.
Adaptive Modification of the restricted to a single plane. For example, if an

Vestibulo-Ocular Reflex with animal was sinusoidally rotated in one plane
(the horizontal) while the visual surround was
Vision simultaneously rotated in another plane (the
vertical), the VOR measured with horizontal
On the basis of psychophysical studies of
rotation in the dark developed a vertical
Kohler,278 Gonshor and Melvill Jones279–281
component.286 Although the site of these
began a series of experimental studies in the
induced plastic changes in the VOR remains
early 1970s that were designed to investigate
uncertain, the cerebellum appears to play a key
the potential for adaptive plasticity within the
role. Lesions of the cerebellum in a variety of
VOR. Probably the most dramatic example of
animals block adaptive plasticity of the
this plasticity was the complete reversal of the
VOR.282,283,287
VOR that occurred in normal subjects after
wearing optically reversing prisms.281 After
about 2 weeks of wearing goggles that pro-
duced continuous left–right reversal of the Cellular Basis for Visual Vestibular
visual environment, the VOR measured in the Interaction
dark adaptively changed such that the direction
of the slow and quick phases of induced nystag- As indicated above, the vestibular nucleus is a
mus was the reverse of normal. The process key visual vestibular interaction center. In early
occurred gradually over days, initially with a studies, Waespe and Henn found that nearly
drop in gain, followed by a progressive change every neuron in the vestibular nucleus of alert
in phase (although never quite reaching the monkeys that responded to horizontal rotation
desired 180-degree phase shift). After the gog- of the animal in the dark also responded to
gles were removed, the VOR gradually returned horizontal rotation of the visual
to normal somewhat faster than with the origi- surround.64,65,250,288,289 During combined visual–
nal adaptation. Subsequent studies using mag- vestibular stimulation, neurons were maximally
nifying and minifying lenses in normal excited (or inhibited) when the vestibular
humans248 and a variety of animals282–285showed and optokinetic nystagmus were in the same
that the dark-measured VOR gain could be direction—that is, the background moved in
increased and decreased, respectively, almost the opposite direction of the monkey. If the
with a machine-like precision (Fig. 3–22). optokinetic drum was mechanically coupled to
Furthermore, these adaptive changes were not the turntable so that both rotated together,
× 2.0 × 2.0
Spectacles Spectacles
on off
1.8 1st exposure
2nd exposure
3rd exposure
1.6
VOR Gain
1.4 Gain = 1.03 + 0.60 (1 – e–0.135†)
1.2
Gain = 1.02 + 0.61 (1 – e–0.023†)
1.0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6
Time (days)
Figure 3–22. Adaptive enhancement and recovery of vestibulo-ocular reflex (VOR) gain in a monkey exposed to
continuous × 2 binocular vision. The different symbols represent data from the same animal that were obtained on differ-
ent occasions. The similarity of the curves they depict emphasizes the machine-like characteristics of the adaptive process.
(From Miles FA, Eighmy BB. Long-term adaptive changes in primate vestibulo-ocular reflex: I. Behavioral observations.
J Neurophysiol. 1980;43: 1406, with permission.)
nystagmus was reduced and neuronal activity unmodifiable component by about 5 msec.
was attenuated compared to pure vestibular Although both PVPs and FTNs make direct
stimulation in the dark.288 Later studies, how- connections with oculomotor neurons, FTNs
ever, suggest that only a subgroup of secondary probably make stronger connections than
vestibular neurons are modified by visual adap- PVPs.297
tation of the vestibulo-ocular reflex, the so-
called floccular target neurons (FTNs).290–296
Although FTNs have similar properties to EH
secondary vestibular neurons, the extent of VESTIBULOSPINAL REFLEXES
overlap of these two neuronal populations is
largely unknown.155 Comparison of Ocular and Spinal
Lisberger and colleagues proposed a model Vestibular Reflexes
of visual vestibular interaction that consisted
of two parallel pathways: an unmodifiable path- It is helpful to consider the similarities and
way relayed through PVP secondary vestibular differences between the ocular and spinal ves-
neurons and a modifiable pathway relayed tibular reflexes as an introduction to the orga-
through FTN secondary vestibular neurons nization of vestibulospinal reflexes. If a rabbit
(Fig. 3–23).290,291,296–298 In addition to primary is rotated at a constant speed on a turntable
vestibular inputs, floccular Purkinje neurons and suddenly stopped (producing an impulse
receive eye velocity and retinal slip velocity sig- of acceleration to the horizontal semicircular
nals. Consistent with the model, recordings canal), a burst of ocular nystagmus results, with
from FTNs and PVPs after modification of the the slow phase being in the direction of the
gain of the VOR found large changes in the fir- rotation prior to the deceleration (in the direc-
ing rate of FTNs but only slight changes in the tion of endolymph flow). In addition, if the
firing rate of PVPs.290,296 Furthermore, both head is mobile, it deviates slowly in the same
pathways introduce a frequency-dependent direction as the slow-phase eye deviation. In
phase lag, but FTNs have a much larger phase some animals, if the stimulus is large enough,
lag than PVP neurons.291 The time delays intro- quick return movements regularly interrupt
duced by the FTN cerebellar loop are consis- the slow head deviation, resulting in head oscil-
tent with behavioral studies that found the lation (“head nystagmus”). The relationship
modifiable component of the VOR lags the between the magnitude of reflex head
Floccular complex
P
Semicircular
canal Eye velocity
Retinal slip
Eye
–
Head velocity FTN
PVP Motoneuron
Vestibular nucleus
Figure 3–23. Vestibular nuclei neurons involved in motor learning. Head velocity signals originating in the semicircular
canals are passed through the vestibular nucleus and the floccular complex to the extraocular motoneurons. Visual signals to
the floccular complex (retinal slip velocity) are transmitted to the cerebellum by both mossy and climbing fibers. Eye move-
ment signals (eye velocity) arrive at the floccular complex via mossy fibers. FTN, floccular target neurons; PVP, position-
vestibular-pause neurons; P, Purkinje cell. (From Lisberger SG. Physiologic basis for motor learning in the vestibulo-ocular
reflex. Otolaryngol Head Neck Surg. 119: 43, 1998, with permission.)
movement and nystagmus changes along the although the vestibulospinal reflexes require a
phylogenetic scale. For example, in pigeons coordinated action of synergistic and antago-
the head movement predominates, in rabbits nistic muscles to respond to postural distur-
head movement and nystagmus are equally bances, different subjects may use a different
prominent, whereas in primates nystagmus motor strategy to achieve the goal. These fac-
predominates. When present, head movement tors have made studies of the vestibulospinal
occurs in the plane of the stimulated canal; one reflexes much more difficult than studies of the
can infer a highly organized pattern of connec- vestibulo-ocular reflexes.
tions between the individual semicircular
canals and neck muscles similar to that of the
connections between the individual canals and Vestibulospinal Connections
the eye muscles.299–301
The rabbit on the turntable, if unrestrained The connections from the vestibular nuclei to
and standing on four legs, tends to fall in the the spinal cord were initially identified in cats
direction of the slow phase of eye and head using electrophysiological techniques.303–306
deviation when the table is suddenly stopped. Stimulating electrodes are placed near neurons
This falling tendency is counteracted by reflex in each subnucleus and recordings are made
activation of the antigravity muscles of the at different levels within the spinal cord and
limbs on the side toward which the rabbit is anterior horn to identify the neurons’ termina-
falling, producing an increased extensor thrust tions. Electromyograph (EMG) recordings
in those limbs. At the same time, the extensor were used to study the pattern of activated
tone of the contralateral limbs is diminished muscles. Stimulating electrodes have also been
and the rabbit maintains its balance. These placed on individual canal and otolith nerves to
extremity muscle reflexes are mediated via the determine the end organ input to each path-
semicircular canals and are always appropriate way (Fig. 3–24).307–311 Electrophysiological
to prevent falling regardless of the direction of studies in primates have largely confirmed the
the acceleration force.302 findings in the cat, and in addition labeling
The effector organs of the vestibulo-ocular studies of individual secondary vestibular neu-
reflexes are the extraocular muscles, while rons have traced their projections in the spinal
those of the vestibulospinal reflexes are the cord.301,312–315
“antigravity” muscles, the extensors of the
neck, trunk, and extremities. The organization LATERAL VESTIBULOSPINAL TRACT
of the vestibulospinal reflexes is the same as
that of the vestibulo-ocular reflexes as shown The vast majority of fibers in the lateral vestib-
in Figure 1–11 in Chapter 1. The same push– ulospinal tract originate from neurons in the
pull mechanism exists for controlling the lateral vestibular nucleus (Fig. 3–25).8 A soma-
balance between the extensor and flexor skele- totropic pattern of projections originates in the
tal muscles as for the agonist–antagonist lateral vestibular nucleus such that neurons in
extraocular muscles of the lateral and medial the rostroventral region supply the cervical
recti. A major difference between the organi- cord while neurons in the dorsocaudal region
zation of ocular and spinal reflexes is the innervate the lumbosacral cord. Neurons in the
increased complexity of the spinal muscle intermediate region supply the thoracic cord.
response compared to the eye movement In the spinal cord, the majority of fibers run
produced by an agonist and antagonist muscle ipsilaterally in the ventral half of the lateral
acting in the horizontal plane. Even a simple funicle and the lateral part of the ventral funi-
movement about an extremity joint in a two- cle (Fig. 3–25). The tract terminates through-
dimensional plane requires a complex pattern out the length of the cord, either directly on
of contraction and relaxation in numerous dendrites of anterior horn cells or on interneu-
muscles. Multiple agonist and antagonist mus- rons that project to anterior horn cells of the
cles on both sides must receive appropriate axial and proximal limb musculature.316 Some
signals to ensure a smooth coordinated of the cells of the eighth lamina send their
movement. Unfortunately, a simple recording axons to the contralateral cord, which might
technique does not exist for quantifying this account for the bilateral effects that have
complex skeletal muscle response. Furthermore, been observed after stimulation in the lateral
Projection Level and Pathway of Vestibulospinal Neurons

a Utriculus b Sacculus
80 80
Percentage (%)
Percentage (%)
60 60
40 40
C1/C2 C1/2
20 C3 20 C3
0 T1 0 T1
i-LVST MVST L3 i-LVST MVST L3
c-LVST c-LVST
c Horizontal Canal d Anterior Canal e Posterior Canal
100
Percentage (%)
Percentage (%)
Percentage (%)
80 80
80
60 60
60
40 40
40 C1/2 C1/2 C1/C2
20 C3 20 C3 20 C3
0 T1 0 T1 0 T1
i-LVST MVST L3 i-LVST L3 i-LVST MVST L3
c-LVST MVST c-LVST c-LVST
Figure 3–24. Projection level and pathway of vestibulospinal neurons originating from five different vestibular end-organs.
a Utricular nerve-activated vestibulospinal neurons. b Saccular nerve-activated vestibulospinal neurons. c Horizontal
semicircular canal nerve-activated vestibulospinal neurons. d Anterior semicircular canal nerve-activated vestibulospinal
neurons. e Posterior semicircular canal nerve-activated vestibulospinal neurons. The vertical axis in each plot indicates
the relative percentage of the sum of the neurons activated from the C1/C2 junction to the total number of vestibulospinal
neurons (100%). Note that, in (e), many of the ipsilateral-lateral vestibulospinal tract (i-LVST) neurons descended to or
caudal to the L3 segment level. (From Kushiro K, Bai R, Kitajima N, Sugita-Kitajima A, Uchino Y. Properties and axonal
trajectories of posterior semicircular canal nerve-activated vestibulospinal neurons. Exp Brain Res. 2008 Nov;191:257, with
permission.)
vestibular nucleus. There may also be some VIII, and XI of the cervical cord with the
crossed pathways. Activation of vestibulospinal unique feature that crossed axons show a high
fibers by electric stimulation in the lateral degree of collateralization throughout the cer-
nucleus produces monosynaptic excitation of vical cord, while uncrossed axons often termi-
extensor motoneurons and disynaptic inhibi- nate in a single cervical segment.301 The medial
tion of flexor motoneurons.317,318 The main pri- vestibulospinal tract receives afferent input
mary afferent input to the lateral vestibulospi- from both otolith organs and all three semicir-
nal tract is from the utricule and posterior cular canals, but the saccular input is more
semicircular canal particularly for fibers termi- prominent than the utricular input and the
nating in the lumbar cord (Fig. 3–24).307 horizontal and anterior canal input is more
prominent than the posterior canal input
(Fig. 3–24).
MEDIAL VESTIBULOSPINAL TRACT
The fibers of the medial vestibulospinal tract RETICULOSPINAL TRACT
originate mostly from neurons in the medial
vestibular nucleus and enter the spinal cord in The reticulospinal tract originates from neurons
the descending MLF (Fig. 3–25).8 The fibers in the bulbar reticular formation but is heavily
travel bilaterally in the ventral funicle as far as influenced by vestibular inputs .319 The nuclei
the midthoracic level with the vast majority reticularis gigantocellularis and pontis caudalis
ending on neurons in the cervical cord. In provide most of the long fibers passing into the
monkey, medial vestibulospinal neurons spinal cord, although most of the neurons in the
labeled with biocytin terminate in lamina VII, caudal reticular formation also contribute fibers.
S
M L
CR Dorsal
Medial Lateral
Ventral
Rostral
Medial
vestibulo- Ventral Dorsal
Lateral
spinal tract
vestibulo-
spinal tract
Caudal
C8 VII
Fibers to:
IX Cervical cord
VIII Thoracic cord
Lumbosacral cord
I-III
L7 VII VII
IX IX
VIII
Medial vestibulo- Lateral vestibulo-

spinal fibers spinal fibers
Figure 3–25. Lateral and medial vestibulospinal tracts. Topographical organization within the lateral vestibular nucleus
(upper right) and endings within the spinal cord (lower right). CR, Corpus Restiform; S, superior nucleus; M, medial
nucleus; L, lateral nucleus. (From Brodal A. Anatomical organization of cerebello-vestibulo-spinal pathways. In: De Renck
AVS, Knight J (eds). CIBA Foundation Symposium: Myotatic, Kinesthetic and Vestibular Mechanisms. Churchill, London,
1967, with permission.)
Both crossed and uncrossed fibers transverse fibers end in the reticular formation; the main
the length of the spinal cord, terminating in vestibular influence on reticulospinal outflow is
the seventh and eighth laminae of the gray mediated by way of the secondary vestibular
matter.320 Stimulation of the pontomedullary neurons. A pattern exists within the vestibu-
reticular formation in the regions where the loreticular projects such that each nucleus
long descending spinal projections originate projects to different areas of the reticular for-
results in inhibition of both extensor and flexor mation, but no detailed somatotropic organiza-
motoneurons throughout the spinal cord.321,322 tion has been identified.8
The vestibular nuclei are one of many struc-
tures that send fibers to the reticular formation.
Axonal branches and collaterals of cells in all Cerebellar–Vestibular Interaction
four main vestibular nuclei are distributed
to the pontomedullary reticular formation. The “spinal” cerebellum provides a major source
Only a small number of primary vestibular of input to neurons whose axons form the
VI
V
VII
IV VIII
++ ++
++ ++ +
++ + ++ + ++
III + + + + +
++ + ++ + + + ++ +
+ ++ + + ++ + + +
+ + + + ++
+ IX ++
II
I X
Rostral
Hook bundle fibers ++
+ ++
Fastigial nucleus
+++++
Caudal
Rostral Rostral
Lateral
+ +
++
Ventral ++ Dorsal Ventral Dorsal Ventral +++ Dorsal vestibular
++ ++
+ + nucleus
+ +
Forelimb
+ Hindlimb
Figure 3–26. Topographical organization of cerebellar vermian, fastigial nucleus, and lateral vestibular nucleus connec-
tions. Filled circles, forelimb; +, hindlimb. (From Brodal A. Anatomy of the vestibular nuclei and their connections. In:
Kornhuber HH (ed). Handbook of Sensory Physiology, Vol VI, Part I. Springer-Verlag, New York, 1974, with permission.)
lateral vestibulospinal and reticulospinal tract. functional unit for the maintenance of equilib-
A somatotopic organization of projections to rium and locomotion.
the lateral nucleus occurs in both the vermian
cortex and fastigial nuclei (Fig. 3–26).56,302,323
The caudal part of the fastigial nucleus gives Vestibulo-Collic Reflexes
rise to a bundle of fibers that cross the midline
(Russell’s hook bundle), curving around the The VCR stabilizes the head in space and pro-
brachium conjunctivum before running to the duces smooth coordinated movements to track
contralateral lateral vestibular nucleus and dor- a moving target. The head and neck represent
solateral reticular formation. In addition, direct a complex biomechanical system with a large
ipsilateral outflow passes from the fastigial eccentric mass located on top of a column of
nucleus to areas of the reticular formation cervical vertebrae.324 Although theoretically
that send long fibers to the spinal cord in the there are multiple degrees of freedom about
reticulospinal tract. The cerebellar–reticular each of the eight vertebral joints, most move-
pathways do not appear to exhibit somatotopic ments are made about a restricted set of joint
organization.56 The cerebellar vermis and fasti- axes; for example, yaw movements are mostly
gial nuclei receive input from secondary made about C1-C2 and pitch movements about
vestibular neurons, the spinal cord, and the C1-skull or C6-7-T1.
pontomedullary reticular formation. The result Both lateral and medial vestibulospinal tracts
is a close-knit vestibular–reticular–cerebellar send fibers to the cervical cord, but the medial
vestibulospinal tract is most important for SUBJECTIVE VESTIBULAR

coordinating neck-vestibular-ocular reflexes. SENSATION
As noted previously, two types of MVST
fibers have been identified based on labeling Unlike those sensory organs that respond to
studies in monkey: crossed axons with a high energy sources external to the body, the laby-
degree of collateralization throughout the cer- rinths respond to self-generated forces within
vical cord and uncrossed axons with few collat- the head. During natural head movements,
erals that target selective cervical segments.301 these forces are not under voluntary control
The former could provide tonic input to widely and therefore the vestibular responses are
distributed motor neurons to stabilize the head, more automatic than those of the other sensory
while the latter could provide canal specific modalities. For example, one can remove vision
input to motor neurons that initiate head move- simply by closing one’s eyes, whereas one can-
ments about selective vertebrae. Convergence not suppress vestibular stimuli during head
of canal and otolith input onto vestibulospinal movement. The recognition of the existence of
neurons is also important for generating the a “sixth sense” for the perception of accelera-
“spatiotemporal” convergence within the tions (motion) is a relatively late concept that
VCR.308 resulted from the imaginative experiments of
Mach in the 1870s.331 Mach observed that the
perception of motion in his different experi-
Cellular Mechanisms ments could be altered by changing the posi-
tion of the head in relation to the body, which
Recordings made from identified secondary suggested to him that the sensory organs were
vestibulospinal neurons in squirrel monkey located in the head. His findings, along with
indicate that the neurons encode the velocity the physiologic and histologic work of contem-
of externally applied head movement but not poraries such as Flourens,332 Breuer,333 and
head velocity in space during self-generated Crum-Brown,334 led him to the conclusion that
head movements.325 So-called vestibular-only the semicircular canals and the otoliths were
(VO) neurons, defined based on the lack of eye responsible for the perception of angular and
movement–related firing, show marked sup- linear acceleration, respectively.
pression of firing during active head move-
ments compared to passive movements.326–329
Furthermore, these neurons continue to fire Vestibulothalamocortical
selectively with passive movements even dur- Connections
ing a combination of active and passive move-
ments. Many of these VO neurons control the Microelectrode recordings from multiple dif-
vestibulocollic reflexes through their projec- ferent cortical regions in multiple species have
tions to the cervical spinal cord. When the goal documented trisynaptic connections between
is to make an active head movement, vestibular the cortex and the labyrinthine end organs.
drive to the reflex would cause an inappropri- The pathways from the labyrinths to the cortex
ate head movement in the direction opposite to have been dissected using electrophysiolocal
the intended goal. Logically secondary neurons recordings along with anterograde and retro-
in these reflexes should be less responsive dur- grade tracer techniques. Secondary neurons
ing active head movements. Since these are located in all four vestibular nuclei and in
neurons selectively monitor passive head move- the fastigial and anterior interposed cerebellar
ments even during active movements they can nuclei, and tertiary neurons are mainly located
selectively respond to an unexpected head in the ventroposterior thalamus (see Fig. 1–15
movement such as one that might occur while in Chapter 1).335–340 Cortical regions that receive
tripping over a curb while walking.Convergence trisynaptic vestibular inputs include the parie-
of somatosensory, neck, and vestibular signals to-insular vestibular cortex (PIVC), the soma-
on Purkinje cells in the cerebellar vermis could tosensory cortical area 3aV, the anterior tip of
provide the substrate for adaptive plasticity the intraparietal sulcus, the medial superior
within the vestibulo-spinal reflexes analogous temporal area, the ventral intraparietal area
to the role of the flocculus in the vestibulo- and the frontal eye fields and premotor/motor
ocular reflexes.330 cortex (Fig. 3–27).341–347
3a V Monkey Galvanic
c 2v (fMRI)
7 a,b
VTS
PIVC
Calorics right
(PET)
–10 +10 +20
R L
Figure 3–27. Illustration of the normal activation–deactivation pattern during unilateral vestibular stimulation in healthy
volunteers (activations in black, deactivations in blue). For comparison a schematic drawing of a monkey brain with the neu-
rophysiologically determined multisensory vestibular areas 6, 3aV, 2v, 7a, b, PIVC and VTS is given (top left). Note that the
locations of the activated areas during galvanic stimulation of the vestibular nerve (fMRI; top right) are similar in humans.
During caloric irrigation of the right ear in healthy right-handers, activations (H215O-PET) occur in temporo-parieto-insular
areas of both hemispheres, but there is a dominance of the non-dominant right hemisphere (middle: surface view of the
right and left hemispheres; bottom: transverse sections Z = –10, +10, +20 mm). Deactivations are located in areas of
the visual cortex bilaterally. (From Dieterich M, Brandt T. Functional brain imaging of peripheral and central vestibular
disorders. Brain. 2008;131:2538, with permission)
Electrophysiological and tracer studies in utricular-thalamic projections are mostly

rats and cats have found bilateral projections to ipsilateral, while posterior semicircular canal
large parts of the thalamus originating from all and saccular-thalamic projections are mostly
four vestibular subnuclei.348,349 Based on selec- contralateral.350,351 Two anatomically separate
tive nerve stimulation in cats it appears that graviceptive vestibulothalamic pathways have
been identified based on tracer studies in mon- cortex to the parieto-occiptal cortex, a portion
key and lesion studies in patients; a crossed of the retroinsular cortex, the parieto-insular
pathway running within the MLF and an vestibular cortex (PIVC), is felt to be at the
uncrossed pathway running near to or within center of the vestibular cortical network.341,342
the medial lemniscus.352 Lesions in the former About two-thirds of neurons in PIVC respond
pathway result in a combination of eye and to vestibular stimulation and almost all vestibu-
perceptual tilt, while lesions of the latter path- lar activated neurons also respond to soma-
way cause only a perceptual tilt. In monkey the tosensory and visual stimuli. Vestibular signals
vestibulothalamic projections end mostly in the to this region mostly originate from the semi-
somatosensory VPL region but some also end circular canals with only rare responses to
in VPI and VPM and even in the somatomotor steady tilt in darkness. The optimal activation
VL region.340,353 The largest number is at the of these canal-related neurons is not in the
border between VPL and VL. Different thal- planes of the semicircular canals but rather is
amic regions project to different cortical distributed through all possible spatial planes
regions. In the squirrel monkey the PIVC through the head. Neurons with the same spa-
receives its main thalamic input from the tial plane tend to cluster in subdivisions of
caudal VPL and the pulvinar, while the soma- PIVC. Furthermore, the response to optoki-
tosensory cortex (area 3aV) receives its main netic stimuli is best when the plane of the visual
input from the rostral and dorsal VPL.340,343 movement is in the optimal vestibular plane
indicating a change to a head co-ordinate frame
of reference. The gain of the vestibular and
Response Properties of Thalamic optokinetic responses is similar for low fre-
Relay Neurons quencies, but at 1 Hz the optokinetic gain is
low while the vestibular gain remains strong.
Thalamic neurons receiving vestibular input Overall the gain of PIVC neurons to angular
show a range of dynamic properties similar to acceleration is lower by a factor of four com-
neurons in the vestibular nuclei but with the pared to vestibular neurons in the vestibular
major exception that few have eye movement nuclei and in the thalamus.
sensitivity.340,353 With angular rotation most thal-
amic relay neurons show a modest phase lead
but unlike primary afferents, these neurons show Functional Brain Imaging in Normal
little additional phase lead and little drop in gain Human Subjects
at low frequencies of rotation reflecting the addi-
tion of velocity storage to the primary afferent Functional magnetic resonance imaging
signal.337,340 For translational movements (fMRI) and positron emission tomography
response phase and gain differed somewhat from (PET) studies in normal humans after galvanic
vestibular nucleus neurons, suggesting additional stimulation of the vestibular nerve or after
processing.340,353 As in vestibular nucleus neu- caloric activation of the horizontal semicircular
rons, most thalamic neurons reflected a combi- canal have largely confirmed the multiple ves-
nation of net linear acceleration originating from tibulocortical projection areas identified in ani-
otolith afferents and an estimate of gravitational mals (Fig. 3–27).347,354,355,356 As in monkey, the
acceleration derived from spatially and tempo- temporo-insular and temporo-parietal regions
rally transformed canal afferents. Although some seem to be at the center of the vestibulocortical
cells encoded just translation or net linear accel- network in humans. The degree of activation in
eration, most had intermediate properties. Most these cortical areas after vestibular stimulation
of these were more sensitive to translation than is greater in the nondominant hemisphere, in
to net acceleration. the hemisphere ipsilateral to the stimulated
ear, and in the hemisphere ipsilateral to the
slow phase of caloric nystagmus. Interestingly,
Response Properties of Vestibular there is a deactivation of visual and somatosen-
Cortex Neurons sory areas of both hemispheres after unilateral
vestibular stimulation, suggesting reciprocal
Although vestibular activity can be found in inhibitory interactions between the sensory
multiple cortical regions from the frontal systems.357 Activation of the hippocampus after
caloric stimulation is consistent with animal order of magnitude lower than the constant
studies showing connections between the ves- angular acceleration necessary to produce
tibular nuclei and hippocampal CA1 nystagmus.365 For stimulation with angular
neurons.358,359 So-called place cells in the sinusoidal rotations, the perception of motion
hippocampus encode location within the envi- corresponds to the prediction of the pendulum
ronment and are critical for normal spatial ori- model, just as the pendulum model predicts
entation and navigation. the velocity of the slow phases of nystagmus.
In accordance with this model, the threshold
for the perception of motion is approximately
Lesions of the Vestibulocortical 1 degree/sec for all frequencies within the
Pathways in Patients range of natural head movements.
Cupulometry developed by van Egmond
As discussed earlier, lesions of the vestibular and associates366 was the first quantitative test
nuclei or more peripheral vestibular structures used for assessing vestibular function on the
lead to a combination of motor and perceptual basis of subjective sensation. With this test, the
abnormalities. For example patients with infarction subject is maintained at a constant velocity
of the dorsolateral medulla (Wallenberg syn- of angular rotation and then suddenly stopped.
drome) typically have an ocular tilt response, The durations of “after-turning” sensation
spontaneous nystagmus, lateropulsion, and tilt are measured for impulses of different ampli-
of the perceived vertical. By contrast patients tude (usually 15 to 60 degrees/sec) and plotted
with lesions of the posterolateral thalamus or versus the log of impulse magnitude (to obtain
vestibular cortex have deviations of the per- the so-called cupulogram). The intercept of
ceived vertical and imbalance but without ocul- the line with the abscissa corresponds to a sub-
omotor signs. The imbalance associated with jective sensation threshold and the slope, a
thalamic infarcts has been called “thalamic time constant of after-turning sensation.
astasia,” a severe imbalance but without weak- Normative data for the subjective threshold
ness or incoordination.360 Only lesions that vary from 1 to 4 degrees/sec and the time con-
involve the posterolateral thalamus cause the stant of after-turning sensation, from 2 to
perception of tilt and imbalance. 362 14 sec.365 Studies using low-frequency sinusoi-
dal rotations have found identical phase shifts
in the subjective sensation of turning and the
Psychophysical Studies VOR in normal subjects and in patients after
unilateral labyrinthectomy.367 Furthermore, in
SEMICIRCULAR CANALS patients with unilateral vestibular loss, the
As Mach described,331 a subject rotated about duration of the subjective sensation of turning
an earth-vertical axis on a rotatory platform will during ampullofugal stimulation of the
perceive turning that is dependent on the per- remaining intact labyrinth is shorter than the
ceived “speed of turning.” The sensation that duration of the sensation of turning during
subjects qualitatively describe as “moving” to ampullopetal stimulation—similar to the asym-
the left or to the right progressively increases metry in VOR amplitude seen in these
with prolonged constant acceleration, although patients.
the turning sensation increases at a lesser rate Sinha et al.368 studied the perception of self-
than the platform velocity. Mach noted that rotation with constant velocity angular rotations
below a minimum or threshold angular accel- and found a delay of 2–5 sec before subjects
eration the subject does not perceive turning. perceived constant velocity and a plateau of
The modern era of vestibular psychophysics 9–14 sec at maximum perceived velocity before
began with attempts to correlate the threshold they perceived a decay in velocity. Since there
and magnitude of subjective sensation with the is a rapid rise and an immediate decay in nys-
magnitude of angular acceleration. Although tagmus slow-phase velocity, they concluded
considerable difference exists in reported that sensory signals from the semicircular
values, the threshold to constant angular canals must undergo additional neural process-
acceleration is in the range of 0.1 to 0.5 ing beyond the contribution of the velocity
degrees/sec2.363,364 This is approximately an storage mechanism.
OTOLITH ORGANS
vary with the changing velocity (acceleration)
Data on threshold and accuracy of estimation of the platform.365 Beginning with low ampli-
of earth visual vertical have been obtained with tudes of oscillation, the subject initially per-
static (postural) tilt experiments.369–373 The sub- ceives motion without a specific direction. This
ject is strapped to a tilt platform in darkness is followed by perception of the direction of
and asked either to estimate the deviation of linear movement and finally at higher intensi-
his head from the earth-vertical or to adjust a ties of stimulation by a perception of tilting.
luminous line on a dark field to a vertical posi- Using dynamic stimuli, estimates of the
tion. Normal subjects respond with an accuracy minimal horizontal linear acceleration that
of 2 to 4 degrees for tilt angles up to 40 degrees normal subjects can perceive range from 5 to
(accuracy falls off progressively for larger angles 15 cm/sec2.363 Interestingly, these threshold
of tilt). The subjective estimate of tilt obviously values are similar to the values obtained
depends on the gravitational force (Fg).374 If the by Mach for the perception of vertical linear
subject is asked to estimate the angle of tilt acceleration (10 to 12 cm/sec2).
under different gravitational forces, the esti- During centrifugal stimulation, normal sub-
mate will vary with Fg. For g values <1, the jects have the illusion that a horizontal small
angle of tilt is underestimated, whereas for g luminous bar is roll-tilted in the direction of
values >1, the angle of tilt is overestimated. In the resultant force by the same amount that
experiments carried out at “zero g” in parabolic they feel roll-tilted—the so-called oculogravic
aircraft flights and in orbiting spacecraft, the illusion (Fig. 3–28).377–379 Patients who undergo
subjects are unable to perceive tilt. Patients therapeutic unilateral vestibular nerve section
with unilateral vestibular lesions report a static show a marked asymmetry of this illusion: they
tilt of the visual vertical toward the side of the perceive the illusion when the resultant force is
lesion and have impaired estimation of the directed toward their intact ear, but they per-
visual vertical when tilted toward the damaged ceive a much reduced illusion (roll-tilt) when
ear compared to toward the intact ear.375–376 the force is directed toward the operated ear.
These illusionary effects are transient, disap- As with the tilt of the static visual vertical, this
pearing within several weeks of the lesion. asymmetry in the oculogravic illusion gradually
A subject undergoing linear oscillation (e.g., disappears over several weeks (presumably
on a parallel swing) reports experiencing two because of central compensation).377 Curthoys
separate types of motion: one is a sensation of et al. likened this asymmetry in otolith function
linear movement in the horizontal plane and to the asymmetry of the semicircular canal
the other is a sensation of tilt. Both sensations function seen after similar operations.378
a b c
R R
g
ω ω
Sees bar at rest Sees bar during rotation Sets bar during rotation
Figure 3–28. Oculogravic illusion experienced by normal subject seated on the arm of a centrifuge. At rest (a), the subject
perceives the bar in the gravitational (g) horizontal. (b) When the centrifuge is revolving at a constant velocity (ω), he per-
ceives himself as being roll-tilted and consequently judges that the bar has been roll-tilted in the same direction. (c) When
instructed to set the rotatable bar to the gravitational horizontal, he rotates the bar through the perceived angle of roll-tilt
(θ in Fig. 1–1). R = resultant of the centrifugal and gravitational forces. (From Curthoys IS, et al. Human otolithic function
before and after unilateral vestibular neurectomy. J Vestib Res. 1990;1: 199–209, with permission.)
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PART 2
Evaluation of the Dizzy Patient

Chapter 4
Epidemiology of Dizziness
SPECIFIC DISORDERS
BURDEN ON PATIENTS
HEALTH CARE UTILIZATION
SUMMARY
Dizziness consistently ranks among the most Nearly 16,000 households were called using
common symptoms experienced by patients, random digit dialing and 52% (8318 subjects)
and it is also among the most common reasons of those contacted agreed to participate. All
that patients seek medical care.1,2 Accurate epi- subjects were asked the following question,
demiological information is important for “Did you ever experience moderate or severe
understanding the impact of a symptom or dizziness or vertigo?” Nearly 30% (29.3%, 95%
disorder on patients and on the health-care CI 27.8%–30.9%) of participants responded
system. The prevalence of disorders can be “yes” to this question (Fig. 4–1).6 Other epide-
defined and the information can also be used to miological studies have found similar preva-
identify associations with the disorder, predic- lence rates.7–9 The prevalence of dizziness was
tors of the disorder, and also links to outcomes. higher in women compared to men (35.9%,
This information informs health-care policy 95% CI 33.7%–38.3% versus 22.6%, 95% CI
and also care of individual patients. Knowledge 20.6%–24.7%, respectively).6
about prevalence is needed when a physician Next, a random subsample of participants
formulates a differential diagnosis and also reporting “yes” to the dizziness question were
helps guide the interpretation of tests and use invited to complete a detailed neurotologic
of treatments by enabling accurate assessments phone interview (response rate 87%,
of the pretest probability of a disorder. But 1003/1212). The neurotologic phone interview
obtaining accurate epidemiologic data about was validated by the authors. Of the partici-
dizziness is difficult because of ambiguity pants that experienced dizziness at some point,
regarding the term dizziness3 and also selection 24% (n = 243) reported “vestibular vertigo” as
and information bias inherent to this type of the type of dizziness. Vestibular vertigo was
research.4 For accurate estimates, required defined as either rotational vertigo, positional
elements include a valid sampling method of vertigo, or recurrent dizziness with nausea and
a large population, valid tools for classifying either oscillopsia or episodic imbalance.
participants, and a robust response rate. Rotational vertigo was defined as an illusion of
The most detailed information about dizzi- self-motion or object motion, and positional
ness in the general population comes from a vertigo was defined as vertigo or dizziness pre-
cross-sectional telephone survey of subjects cipitated by changes of head position, such as
age ≥18 years in Germany.5 A two-stage ran- lying down or turning in bed. Applying this
dom sampling method was used. The first stage information to the broader general population
was part of a general health survey in Germany. sample, the lifetime prevalence of vestibular
121
30%
Population Prevalence
20%
10%
0% s
y g
ve in
on s
em
ve in
ur or
ph es
ur sp
y^
y^
ur ov
e
†
y^ se
le in
ls s
ve
ls s
ls m
ai es
Te izz
ai g
ve t
m in
ai a
ur en
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an d
m th
ls d
nd ad
m re
i
ai pon
nd h
nd w
er ve
la e
i
la d
ot h
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w
h
e
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nd r
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Sc n
a
, F ci
tla ich
”, s i
l
m
t
t”, ,
n” o
o
rv rti ate
in ss
nd es
io ss
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at a
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, S in
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“M
“D
el te
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“V
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“U
to izz
*German National Telephone Health Survey 2003, response rate 8,318/15,996 (52%),
Neuhauser HK, et. al., Neurology 2005;65:898–904.
^Scotland mail survey, response rate 7,244/12,100 households (60%).
Hannaford PC, et. al., Family Practice 2005;22:227–233.
†
Finland mail survey, response rate 3,138/5,000 (63%).
Havia M, et. al., Otolaryngology–Head and Neck Surgery 2005;133:762–768.
Figure 4–1. Population prevalence of dizziness symptoms.
vertigo in the general population was estimated less than 1 minute in approximately half of the
to be 7.4% (95% CI, 6.5%–8.3%) (Fig. 4–2). participants (mostly positionally triggered
The remainder of the subjects reporting both- group), between 1 and 60 minutes in a quarter
ersome dizziness were classified as either a of participants, and an hour to several days in
nonvestibular type of dizziness (n = 742) or a the remaining quarter of participants. Among
dizziness that could not be classified as either subjects with vestibular vertigo, 80% reported
vestibular or nonvestibular (n = 18).6 a history of headaches and 62% met criteria for
The proportion of vestibular vertigo among migraine headaches or probable migraine
participants with moderate to severe dizziness headaches. In a multivariable regression model
increased with age, so that vestibular vertigo examining the association of vestibular vertigo
was the type of dizziness reported by 37% of with sociodemographic factors and comorbid
those age ≥60 years.5 Vestibular vertigo was conditions among patients with vestibular ver-
recurrent (at least two attacks) in 89% of sub- tigo in the last 12 months (163 subjects) com-
jects. Two-thirds of subjects who reported ves- pared with a dizzy-free comparison group
tibular vertigo experienced it within the past 12 (2816 subjects), the following factors demon-
months—a rate suggesting recall bias. Of sub- strated a significant association: Female gender
jects with rotational vertigo (as opposed to diz- (OR 3.2, 95% CI, 2.2–4.7), self-reported
ziness with nausea and either oscillopsia or depression in past year (OR 2.5, 95% CI,
imbalance), approximately half reported spon- 1.5–4.0), bothersome tinnitus in the past 7 days
taneous attacks and half reported positionally (OR 3.7, 95% CI 2.4–5.6), hypertension (OR
triggered attacks. The duration of attacks was 2.1, 95% CI 1.5–3.1), and increased blood
4 Epidemiology of Dizziness 123
Population Prevalence of Moderate or Severe Dizziness or Vertigo
None Non-vestibular dizziness or

(69.5%) undifferentiated (22.1%)
Vestibular vertigo
(7.4%)
Spontaneous rotational
vertigo (40%)
Position triggered
rotational vertigo Vestibular
(43%) dizziness*
(17%)
*Vestibular dizziness = recurrent dizziness with nausea and either oscillopsia or episodic imbalance.
From German National Telephone Health Interview Survey 2003. Neuhauser HK. Neurology. 2005;
65:898–904.
Figure 4–2. Lifetime prevalence of moderate or severe dizziness or vertigo.
lipids (OR 1.7, 95% CI, 1.2–2.4). Increasing was used. Based on responses to the phone
age and many other covariates had a significant interview, subjects were classified into benign
bivariate association with vestibular vertigo paroxysmal positional vertigo (BPPV), migrain-
but did not retain a significant association in ous vertigo, and Meniere’s disease.
the multivariable model. The association of The most common specific cause of dizzi-
migraine with dizziness could not be tested in ness was BPPV. The lifetime prevalence of
the model because a migraine history was not BPPV was estimated to be 2.4% of the general
taken in the general survey portion, so that the population. BPPV accounted for 8% (80/1003)
migraine status of the comparison group was of all subjects with a history of moderate or
not known. severe dizziness and 33% (80/243) of all sub-
jects with vestibular vertigo. In this survey
study, the criteria for BPPV classification
included (a) recurrent vestibular vertigo, (b)
SPECIFIC DISORDERS attack duration always <1 min, (c) symptoms
invariably provoked by changes of head posi-
The German epidemiological study also sought tion (specifically, lying down, turning over in
to classify subjects with dizziness into specific the supine position, reclining the head, rising
causes of dizziness.5 A structured interview up from supine position, or bending forward),
that had been validated in a specialty clinic set- and (d) symptoms not attributable to another
ting against the expert diagnosis of clinicians disorder. The prevalence of BPPV increased
with age. In subjects age 80 years or greater, only a history of coronary artery disease was
nearly 10% reported BPPV. Of those with significantly associated with migrainous ver-
BPPV, almost two-thirds reported attacks dur- tigo, but overfitting the model is a concern
ing the past year and 25% reported BPPV dur- (tested 11 independent variables, but only 30
ing the past 4 weeks. The mean age of onset outcome positive subjects).
was 49.4 ± 13.8 years. The median duration of In this study, very few subjects were classi-
the last bout of BPPV was 2 weeks (range 0.5 fied with Meniere’s disease as the cause of diz-
days to 104 weeks). One-third of subjects ziness.11 Of the 243 subjects with vestibular
reported that the episodes lasted longer than dizziness, only 4 (1.6%) met the criteria for
1 month. More than half (56%) reported Meniere’s disease. This translates to a popula-
recurrent bouts of dizziness. The type of dizzi- tion prevalence of 0.12% for Meniere’s disease.
ness was rotational vertigo in most patients The criteria for Meniere’s disease included at
(86%) with the remainder reporting the least two vertigo attacks lasting at least 20 min-
symptom as dizziness with nausea and oscillop- utes, interictal unilateral hearing loss, and at
sia rather than rotational vertigo. About half of least one cochlear symptom (i.e., tinnitus, hear-
the group also reported imbalance during ing loss, or aural fullness) during at least two
attacks. All participants reported BPPV attacks vertigo attacks.
triggered by either turning over in bed
(85%) or getting in or out of bed. In a multi-
variable logistic regression model (54 BPPV
patients, 6136 general population controls), BURDEN ON PATIENTS
age, hypertension, increased blood lipids,
stroke, and migraine were associated with Many studies show that dizziness symptoms
BPPV diagnosis, though overfitting of the and particularly vertigo and vestibular disor-
model is a concern. ders have an adverse effect on quality of life.12–22
The lifetime prevalence of migrainous ver- In the German epidemiological study, one-fifth
tigo was estimated to be 0.98% (95% CI, (18.8%) of subjects with dizziness reported an
0.70%–1.37%).10 The criteria for migrainous interruption in daily activities and 12.2%
vertigo were vestibular vertigo plus the follow- reported avoiding leaving the house because of
ing: (1) a history of migraine according to the the dizziness symptoms.6 Of working subjects
criteria of the International Headache Society, with dizziness, one-fifth (20.7%) reported
(2) at least one migrainous symptom during at taking sick leave as a result of the dizziness.
least two vertiginous attacks (i.e., migrainous The burden was greater in the subgroup with
headache, photophobia, phonophobia, or visual vestibular vertigo compared to those with
aura), and (3) symptoms not attributable to nonvestibular dizziness. More than 40% of
another disorder. Of those patients reporting those with vestibular vertigo reported an
vestibular vertigo (243), 33 (14%) were classi- interruption in daily activities. And 80% of
fied as migrainous vertigo. Two-thirds of the subjects with vestibular vertigo reported at
migrainous vertigo subjects reported spontane- least one of the following (as the result of
ous rotational vertigo and 24% reported posi- the vertigo): interruption of daily activities,
tional vertigo (overlap with BPPV was not medical consultation, or taking sick leave. The
reported). The remainder (9%) reported ves- rate was 57% in subjects with nonvestibular
tibular dizziness rather than rotational vertigo. dizziness and 63% in the overall dizziness
Headache always accompanied vertigo attacks group. Quality of life, measured by the SF-8,
in only 24%. Duration of attacks was <1 minute was reduced in both vestibular vertigo subjects
in 25%, 1–59 minutes in 44%, 1–24 hours in and nonvestibular dizziness subjects when
28%, and >24 hours in 3%. Cochlear symptoms compared to control subjects in the general
(i.e., tinnitus, aural fullness, or hearing loss) population without dizziness, adjusting for age
during vertigo attacks were reported by 12 sub- and sex.6 For BPPV subjects, 69% reported
jects (36%) with migrainous vertigo but none restricting head movements in order to avoid
had progressive hearing loss. Typical migraine attacks.23 And during episodes, 24% reported
triggers were reported in 61% of those with giving up driving a car with 18% avoiding
migrainous vertigo. In a multivariable model, leaving their home.
4 Epidemiology of Dizziness 125
HEALTH CARE UTILIZATION For patients reporting vertigo or dizziness as a

reason for visiting the emergency room, about
From the German epidemiological study, 58% 10% underwent a CT scan in 1995 and this rate
of the subjects who reported bothersome dizzi- increased by 169% to nearly 30% in 2004.
ness sought out a medical evaluation.6 This rate
was lower in the Scotland postal survey (23%).9
A previous hospitalization because of dizziness
was reported by 7% of those with dizziness.6 SUMMARY
Both medical consultations and hospital visits
were more common for subjects with vestibu- Dizziness is common among the general popu-
lar vertigo than for subjects with nonvestibular lation and leads to substantial burden on
dizziness. Most of the subjects with a medical patients and the health-care system. Dizziness
consultation reported seeing a general practi- that is vestibular in origin accounts for about a
tioner (52%), followed by a neurologist (16%) quarter of patients with dizziness symptoms,
or an otolaryngologist (14%).6 About a quarter and the most common cause of vestibular ori-
(24%) of subjects seeking a medical consulta- gin dizziness is BPPV. Migrainous vertigo also
tion saw more than one type of physician. appears to be common. Meniere’s disease, on
Subjects with BPPV had the highest rate of the other hand, was relatively uncommon in
medical consultation (78%), followed by sub- the general population and also as a proportion
jects with migrainous vertigo (67%), other ves- of vestibular origin dizziness. Most patients
tibular vertigo (67%), other nonvestibular diz- with vestibular origin dizziness present for a
ziness (61%), and orthostatic dizziness (46%).6 medical evaluation. Diagnostic tests are com-
Diagnostic tests were commonly performed monly ordered and in the United States rates
in dizziness patients but were not reported at of use of imaging studies have dramatically
the aggregate level of dizziness patients from increased. Positional testing and particle repo-
the German study. For patients with migrain- sitioning seem to be underutilized.
ous vertigo who saw a physician, most under- Though the German study is a large and
went one or more diagnostic test, including an detailed epidemiological study on dizziness and
audiogram (27%), electroencephalogram (27%), vertigo, more epidemiological studies are needed
brainstem auditory evoked potentials (21%), in other populations. Remaining needs from
cranial computed tomography (CT) or magnetic epidemiologic studies include more data from
resonance imaging (MRI) (21%), caloric test other populations and prospective longitudinal
(18%), or ultrasound of carotid or vertebral cohorts with relevant outcome measures so we
arteries (12%).10 In subjects with BPPV, most can see how processes of care impact important
also underwent diagnostic testing (77%), but patient outcomes in real-world settings.
only 27% reported diagnostic positional testing
(i.e., Dix-Hallpike testing).23 Furthermore, most
BPPV subjects who presented to a physician
received either no treatment (45%) or medica- REFERENCES
tion treatment (27%) for vertigo.23 Only 10% of
BPPV subjects who presented to a physician 1. Kroenke K, Jackson JL. Outcome in general medical
patients presenting with common symptoms: a prospec-
underwent a particle repositioning maneuver.23 tive study with a 2-week and a 3-month follow-up. Fam
Most of the repositioning maneuvers were Pract. 1998;15:398.
Brandt-Daroff exercises, rather than the most 2. Kerber KA, Meurer WJ, West BT, Fendrick AM.
effective Epley or Semont maneuvers. Dizziness presentations in U.S. emergency depart-
ments, 1995-2004. Acad Emerg Med. 2008;15:744.
Diagnostic testing among patients with dizzi- 3. Newman-Toker DE, Cannon LM, Stofferahn ME,
ness in the emergency room in the United States Rothman RE, Hsieh YH, Zee DS. Imprecision in
has been reported using the National Hospital patient reports of dizziness symptom quality: a cross-
Ambulatory Medical Care Survey (NHAMCS).2 sectional study conducted in an acute care setting.
NHMACS is an annual four-stage probability Mayo Clin Proc. 2007;82:1329.
4. Nallamothu BK, Hayward RA, Bates ER. Beyond the
sampling study where patients are selected and randomized clinical trial: the role of effectiveness stud-
medical records are reviewed. This ongoing ies in evaluating cardiovascular therapies. Circulation.
study can be used to study trends over time. 2008;118:1294.
5. Neuhauser HK, von Brevern M, Radtke A, et al. 15. Hsu LC, Hu HH, Wong WJ, Wang SJ, Luk YO, Chern
Epidemiology of vestibular vertigo: a neurotologic CM. Quality of life in elderly patients with dizziness:
survey of the general population. Neurology. 2005;65: analysis of the Short-Form Health Survey in 197
898. patients. Acta Otolaryngol. 2005;125:55.
6. Neuhauser HK, Radtke A, von Brevern M, Lezius 16. Nazareth I, Landau S, Yardley L, Luxon L. Patterns
F, Feldmann M, Lempert T. Burden of dizziness of presentations of dizziness in primary care–a cross-
and vertigo in the community. Arch Intern Med. sectional cluster analysis study. J Psychosom Res.
2008;168:2118. 2006;60:395.
7. Colledge NR, Wilson JA, Macintyre CC, MacLennan 17. Lopez-Escamez JA, Gamiz MJ, Fernandez-Perez A,
WJ. The prevalence and characteristics of dizziness in Gomez-Finana M. Long-term outcome and health-
an elderly community. Age Ageing. 1994;23:117. related quality of life in benign paroxysmal posi-
8. Havia M, Kentala E, Pyykko I. Prevalence of Meniere’s tional vertigo. Eur Arch Otorhinolaryngol. 2005;262:
disease in general population of Southern Finland. 507.
Otolaryngol Head Neck Surg. 2005;133:762. 18. Fife D, FitzGerald JE. Do patients with benign par-
9. Hannaford PC, Simpson JA, Bisset AF, Davis A, oxysmal positional vertigo receive prompt treatment?
McKerrow W, Mills R. The prevalence of ear, nose Analysis of waiting times and human and financial
and throat problems in the community: results from a costs associated with current practice. Int J Audiol.
national cross-sectional postal survey in Scotland. Fam 2005;44:50.
Pract. 2005;22:227. 19. Kinney SE, Sandridge SA, Newman CW. Long-term
10. Neuhauser HK, Radtke A, von Brevern M, et al. effects of Meniere’s disease on hearing and quality of
Migrainous vertigo: prevalence and impact on quality life. Am J Otol. 1997;18:67.
of life. Neurology. 2006;67:1028. 20. Soderman AC, Bagger-Sjoback D, Bergenius J, Langius
11. Radtke A, von Brevern M, Feldmann M, et al. A. Factors influencing quality of life in patients with
Screening for Meniere’s disease in the general popu- Meniere’s disease, identified by a multidimensional
lation - the needle in the haystack. Acta Otolaryngol. approach. Otol Neurotol. 2002;23:941.
2008;128:272. 21. Yardley L, Owen N, Nazareth I, Luxon L. Prevalence
12. Tinetti ME, Williams CS, Gill TM. Health, functional, and presentation of dizziness in a general practice
and psychological outcomes among older persons community sample of working age people. Br J Gen
with chronic dizziness. J Am Geriatr Soc. 2000;48: Pract. 1998;48:1131.
417. 22. Nazareth I, Yardley L, Owen N, Luxon L. Outcome
13. Aggarwal NT, Bennett DA, Bienias JL, Mendes de of symptoms of dizziness in a general practice com-
Leon CF, Morris MC, Evans DA. The prevalence of munity sample. Fam Pract. 1999;16:616.
dizziness and its association with functional disability 23. von Brevern M, Radtke A, Lezius F, et al. Epidemiology
in a biracial community population. J Gerontol A Biol of benign paroxysmal positional vertigo: a popula-
Sci Med Sci. 2000;55:M288. tion based study. J Neurol Neurosurg Psychiatry.
14. Grimby A, Rosenhall U. Health-related quality of 2007;78:710.
life and dizziness in old age. Gerontology. 1995;41:
286.
Chapter 5
The History of the

Dizzy Patient
VERTIGO DRUG-INDUCED DIZZINESS

Central versus Peripheral Causes HYPOGLYCEMIA
Time Course DISEQUILIBRIUM
Precipitating Factors Common Causes
Associated Symptoms Gait Disorders in Older People
Compensation Falls in Older People
Predisposing Factors Diagnosis and Management
Family History OCULAR DIZZINESS
Diagnosis and Management Common Causes
NEAR-FAINT DIZZINESS Oscillopsia
Orthostatic Hypotension Management
Postural Tachycardia Syndrome (POTS) MULTISENSORY DIZZINESS
Vasovagal Attacks Management
Hyperventilation PHYSIOLOGIC DIZZINESS
PSYCHOPHYSIOLOGIC DIZZINESS Motion Sickness
(CHRONIC SUBJECTIVE DIZZINESS) Space Sickness
Panic Disorder Height Vertigo
Phobic Dizziness Mal de Debarquement Syndrome
Chronic Anxiety SUMMARY: DISTINGUISHING BETWEEN
Pathophysiology VESTIBULAR AND NONVESTIBULAR
Diagnosis and Management TYPES OF DIZZINESS
Dizziness is a nonspecific term that patients what the patient means by dizziness. Patients
use to refer to some sort of an ill feeling. The should be encouraged to use their own words
variety of symptoms that patients label as “diz- to describe the sensation and how the sensa-
ziness” is large and includes visualized spinning tion interferes with their daily activities. Some
of the environment, other types of movement of these descriptions can be highly suggestive
of the environment (e.g., bouncing, rocking), of a lesion location or even a specific etiology,
“internal” movement sensations (i.e., move- but a patient’s description of the type of
ment sensation but no visualized movement of dizziness can also be unclear or even inconsis-
the environment), light-headedness, near-faint, tent.1 Because the dizziness description can be
unsteadiness standing or walking, disorienta- problematic, other important characteristics,
tion or confusion, or even anxiety. The initial including the circumstances, duration, associ-
task of the clinician is to obtain a description of ated symptoms, and triggers, become equally
127
Table 5–1 Mechanisms of Common Types of Dizziness

Type Mechanism
Vertigo Imbalance in tonic vestibular signals
Near-faint dizziness Diffusely decreased cerebral blood flow
Psychophysiologic Impaired central integration of sensory signals
dizziness
Hypoglycemic dizziness Inadequate brain glucose; increased circulatory catecholamines
Disequilibrium Loss of vestibulospinal, proprioceptive, cerebellar, or motor function
Ocular dizziness Visual–vestibular mismatch due to impaired vision
Multisensory dizziness Partial loss of multiple sensory system function
Physiologic dizziness Sensory conflict due to unusual combination of sensory signals
Drug-induced dizziness CNS depression, cerebellar toxicity; change in cupula’s specific gravity (alcohol)
important to detail—particularly when the patient’s spontaneous nystagmus (i.e., away

symptom is vague or mild. Because the from the side of the lesion). This illusion of
diagnostic evaluation and management differ movement occurs because the brain interprets
markedly depending on the features of the diz- the target displacement on the retina as object
ziness, it is critical that the examining physician movement rather than as eye movement. An
determine the type and characteristics of the illusion of linear movement or tilting suggests
dizziness (Table 5–1) before proceeding with isolated involvement of an otolith or its central
exhaustive diagnostic studies. connections.
Vertigo is strongly suggestive of an imbal-
ance within the vestibular system. The main
VERTIGO caveat is that a symptom is subjective and
subjective symptoms—including vertigo—can
Vertigo is an illusion of movement, usually that be inconsistent and unreliable.1 A description
of rotation, although patients occasionally of vertigo is probably a less valid indicator of
describe a sensation of linear displacement vestibular imbalance when it is mild or an
or tilt. The afferent nerves from the otoliths “internal” (i.e., no visualized movement of the
and semicircular canals of each labyrinth environment) sensation. It may also be less
maintain a balanced tonic rate of firing into the valid when the patient acknowledges vertigo
vestibular nuclei. Asymmetric involvement only after being specifically asked about it
of this baseline activity anywhere in the periph- rather than providing a spontaneous descrip-
eral and central vestibular pathways leads to tion of it.
an illusion of movement. For example, damage
to a semicircular canal or its afferent nerve
produces a sensation of angular rotation in Central versus Peripheral Causes
the plane of that canal similar to the sensation
experienced during physiologic stimulation. The symptom of vertigo does not indicate
More typically, lesions affect the afferent where in the system a vestibular imbalance
input from all the canals and otoliths of one originates. The same sensation can result from
labyrinth, producing a sensation of rotation in a lesions in such diverse locations as the inner
plane determined by the balance of afferent ear, the deep paravertebral stretch receptors of
signals from the contralateral labyrinth (usually the neck, the visual–vestibular interaction cen-
near the horizontal plane, inasmuch as the ver- ters in the brain stem and cerebellum, or in the
tical canal and otolith signals partially cancel subjective sensation pathways of the thalamus
out). If a patient with a unilateral vestibular or cortex. Distinction between peripheral and
lesion attempts to fixate on an object, it will central causes of vertigo can usually be made,
appear blurred and seem to be moving in the however, on the basis of other features in the
direction opposite that of the slow phase of the history (Table 5–2).
5 The History of the Dizzy Patient 129
Table 5–2 Differentiation between Peripheral (End-organ and Nerve) and Central
Causes of Vertigo
Nausea Imbalance Hearing Oscillopsia Neurologic Compensation
and Loss Symptoms
Vomiting
Peripheral Severe Mild Common Mild Rare Rapid
Central Moderate Severe Rare Severe Common Slow
Well-documented lesions within the vestib- vertigo interspersed with a more persistent
ular pathways sometimes produce only a non- nonspecific dizziness. An episode of vertigo
specific sensation of disorientation without a lasting minutes suggests a transient vascular
clearly defined illusion of movement. Normal ischemic attack.3 This is the typical duration of
subjects undergoing caloric stimulation (i.e., a vertigo with transient ischemia within the basi-
physiologic imbalance in the vestibular system) lar vertebral circulation. With a typical bout of
occasionally describe the experience with terms Meniere’s syndrome, the vertigo reaches a peak
such as floating or even giddiness. For these within minutes, remains severe for an hour or
reasons one must not be too restrictive in clas- two, and then gradually resolves over the next
sifying dizziness on the basis of subjective few hours.4 Vertigo gradually resolving over
description alone. several days occurs with viral vestibular neuri-
tis, labyrinthine trauma, infarction of the laby-
rinth, or any lesion that produces permanent
Time Course damage to the inner ear or vestibular nerve.5
Even with a complete unilateral loss of vestibu-
Vertigo invariably occurs in episodes, usually lar function, the vertigo will gradually resolve
abrupt in onset, followed by decreasing inten- as central compensation occurs. The onset is
sity as the inciting factor dissipates or as com- abrupt with trauma and vascular occlusion,
pensation occurs. Continuous dizziness without whereas it is typically more gradual in onset
fluctuation for long periods of time (e.g., weeks (over hours) with viral vestibular neuritis.
or longer) is not typical of vestibular disorders.
Durations associated with several of the more
common causes of vertigo are outlined in Table Precipitating Factors
5–3. Episodes lasting seconds suggest the diag-
nosis of benign positional vertigo.2 During the The events just prior to an episode of vertigo
acute phase, such patients may report a non- are important in determining the cause. Rapid
specific feeling of disorientation and imbalance head movements commonly induce vertigo
along with nausea and vomiting that lasts for because they accentuate any imbalance within
hours to days, but on careful questioning one the vestibular pathways. Even after compensa-
can identify recurrent brief attacks of positional tion has occurred, head movements or change
in position can lead to a brief sensation of ver-
tigo and disorientation. Positional vertigo is
commonly induced by turning over in bed, sit-
Table 5–3 Duration of Common ting up from a lying position, extending the
Causes of Vertigo neck to look upward (so-called top shelf ver-
tigo), or bending over and straightening up.
Seconds Benign positional vertigo
Patients with a fistula in the bony labyrinth
Minutes Vertebrobasilar insufficiency,
migraine* develop brief episodes of vertigo precipitated
Hours Meniere’s syndrome by changes in middle ear pressure (coughing,
Days Vestibular neuritis, infarction of sneezing).6 The pressure change in the middle
labyrinth ear is transferred directly to the inner ear (usu-
ally the horizontal semicircular canal) through
*Though migraine vertigo is commonly minutes in dura- the fistula. Occasionally, loud noises induce
tion, it can also last seconds, hours, or days.
transient vertigo in patients with inner ear
lesions (Tulio phenomenon). This phenome- facial numbness and weakness and ipsilateral
non can occur with a range of clinical extremity ataxia. As with vertigo, the time
syndromes, including perilymph fistula, course of an associated hearing loss can help
dehiscence of the superior semicircular canal, determine the cause. Fluctuating hearing loss
Meniere’s syndrome, congenital deafness, and and tinnitus are characteristic of Meniere’s
hypermobile stapes.7 syndrome. Patients with this disorder usually
notice a buildup of pressure in the ear just prior
to the onset of hearing loss, tinnitus, and ver-
Associated Symptoms tigo. Complete unilateral deafness and vertigo
occur with viral involvement of the labyrinth
Autonomic symptoms such as sweating, pallor, and or eighth nerve and with vascular occlusion
nausea, and vomiting commonly accompany to the inner ear. A slow, progressive unilateral
dizziness caused by vestibular lesions, but such hearing loss over months suggests the existence
symptoms are uncommon with other types of of an acoustic neuroma or other cerebellopon-
dizziness. Typically, the autonomic symptoms tine angle tumor.
are more pronounced when the vertigo has a Because of the proximity of other neuronal
peripheral origin, although there are frequent centers and fiber tracts in the brain stem
exceptions to the rule. Occasionally, vegetative and cerebellum, it is unusual to find lesions in
symptoms are the only manifestation of a these areas that produce isolated vestibular
vestibular lesion. Numerous interconnecting symptoms. Lesions of the brain stem invariably
pathways between brainstem vestibular and are associated with other cranial nerve and
autonomic centers account for this close asso- long-tract symptoms. For example, vertigo
ciation of vestibular and autonomic symptoms. caused by transient vertebrobasilar insuffi-
The site of the lesion determines the symp- ciency is associated with other brainstem and
toms that accompany vertigo (Table 5–4). In occipital lobe symptoms such as diplopia, hemi-
addition to vertigo, lesions of the labyrinth or anoptic field defects, drop attacks, weakness,
eighth nerve commonly produce auditory numbness, dysarthria, and ataxia. Lesions of
symptoms such as hearing loss, tinnitus, a sen- the cerebellum (e.g., infarction or hemorrhage)
sation of pressure or fullness in the ear, or pain may be relatively silent but are typically associ-
in the ear. Lesions of the internal auditory ated with extremity or truncal ataxia in addition
canal also produce hearing loss and tinnitus to vertigo. Hearing loss for pure tones is unusual
and may be associated with ipsilateral facial with central lesions, even in the late stages.
weakness, whereas those in the cerebellar- Vertigo can occur as part of an aura of an
pontine angle may be associated with ipsilateral epileptic seizure.8 The cortical projections of
Table 5–4 Symptoms Associated with Vertigo Due to Lesions at Different

Anatomical Locations
Inner Ear Brain stem
Hearing loss Diplopia
Tinnitus Dysarthria
Pressure Perioral numbness
Pain Extremity weakness and numbness
Internal Auditory Canal Drop attacks
Hearing loss Cerebellum
Tinnitus Imbalance
Facial weakness Incoordination
Cerebellopontine angle Temporal lobe
Hearing loss Absence spells
Tinnitus Visual (formed), olfactory or gustatory hallucinations
Facial weakness and numbness
Extremity incoordination Occipital lobe
Visual field loss
Visual hallucinations (unformed)
the vestibular system are activated by a focal are associated with dizziness due to either par-
discharge within the frontal or temporal lobes. tial involvement of all the body-orienting sys-
Such vertigo is nearly always associated tems or a decreased capacity of the central ner-
with other typical aura symptoms such as an vous system (CNS) to deal with information
abnormal taste or smell and distortion of the from these systems (a type of multisensory
visual world (hallucinations and illusions). dizziness). Some systemic disorders such as
Rarely, however, vertigo can be the only mani- vasculitis, bacterial endocarditis, and septice-
festation of an aura. In such cases, the associa- mia can selectively damage the vestibular sys-
tion with typical absence spells should lead one tem by interfering with its blood supply. Such
to the correct diagnosis. patients may develop severe vertigo and vomit-
ing typical of an acute peripheral vestibular
loss. Patients with viral vestibular neuritis fre-
Compensation quently report an upper respiratory tract illness
either within 2 or 3 weeks before or at the time
The severity of symptoms following a vestibu- of onset of vertigo. Chronic middle ear infec-
lar lesion depends on (1) the extent of the tions may lead to bacterial labyrinthitis or
lesion, (2) whether the lesion is unilateral or serous labyrinthopathy, and patients with
bilateral, and (3) the rapidity with which the bacterial meningitis may develop bacterial lab-
functional loss occurs. Patients who slowly lose yrinthitis through the direct cerebrospinal
vestibular function bilaterally (e.g., secondary fluid–perilymph connections. Patients with
to ototoxic drugs) often do not complain of ver- Meniere’s syndrome may have an attack of ver-
tigo but will report oscillopsia with head move- tigo precipitated by foods high in salt content.
ments and instability when walking (due to loss Head injury can damage the delicate laby-
of vestibulo-ocular and vestibulospinal reflexes, rinthine membranes with or without associated
respectively). If a patient slowly loses vestibu- bone fracture. Labyrinthine trauma may result
lar function on one side over a period of months in a single prolonged episode of vertigo or,
to years (e.g., with an acoustic neuroma), symp- more commonly, recurrent episodes of posi-
toms and signs may be absent. A sudden unilat- tional vertigo. The more common nonspecific
eral loss of vestibular function, by contrast, is a light-headed dizziness following head trauma
dramatic and debilitating event. Patients comis probably not related to vestibular damage,
plain of severe vertigo and nausea, are pale and inasmuch as common associated symptoms and
perspiring, and usually vomit repeatedly. They signs are absent. Surgery in or about the ear is
prefer to lie quietly in a dark room but can walk a major cause of trauma to the labyrinthine
if forced to (falling toward the side of the membranes. Vertigo not infrequently follows
lesion). A brisk spontaneous nystagmus inter- surgery confined to the middle ear. Past medi-
feres with vision. These symptoms and signs cal history should focus on past or chronic
are transient, however, and the process of medical illnesses, such as diabetes mellitus,
compensation begins almost immediately. atherosclerotic vascular disease, syphilis (con-
Within 1 week of the lesion, a young patient genital or acquired), and major allergies, that
can walk without difficulty and with fixation might predispose the patient to vestibular sys-
can inhibit the spontaneous nystagmus. Within tem damage. Viral illnesses that damage the
1 month most patients return to work with little inner ear in utero or in infancy (e.g., rubella,
if any residual symptoms. Occasionally patients mumps, rubeola) may be followed years later
will have difficulty compensating for unilateral by recurrent episodes of vertigo.10 This so-
loss of vestibular function. The presence of called delayed endolymphatic hydrops may not
migraine, anxiety, or depression seems to cor- be associated with auditory symptoms such as
relate with persistence of symptoms.9 hearing loss, tinnitus, or ear pressure because
the patient may be deaf in the damaged ear.
Predisposing Factors
Family History
The patient’s general state of health just prior
to the onset of dizziness should be carefully Common vestibular disorders with a genetic
investigated. Most severe systemic disorders predisposition include migraine, Meniere’s
syndrome, otosclerosis, neurofibromatosis, and Friedreich’s ataxia or olivopontocerebellar

spinocerebellar degeneration. Migraine can atrophy) or may occur as an isolated phenom-
present as isolated episodes of vertigo (a enon (both autosomal dominant and recessive
migraine equivalent) in some members of a inheritance). Although uncommon, the syn-
family, whereas other members have classic drome of familial periodic ataxia and vertigo
migraine headaches.11 Some varieties of “famil- (episodic ataxia type 2[EA-2]) is important to
ial Meniere’s syndrome” are likely due to recognize because it often responds dramati-
migraine. Patients with otosclerosis usually cally to acetazolamide. With this dominantly
present with a conductive hearing loss, although inherited disorder, episodes of vertigo and
sensorineural hearing loss and vertigo may ataxia recur throughout the patient’s life
result if the otic capsule becomes involved. sometimes without objective findings between
Neurofibromatosis type 1 (NF1) is manifested episodes.
by the combination of pigmented skin lesions,
multiple tumors of the spinal and cranial
nerves, tumors of the skin, and intracranial Diagnosis and Management
gliomas. Neurofibromatosis type 2 (NF2) is
commonly manifested by bilateral acoustic The reader is referred to Chapters 9–18 for
neuromas and meningiomas without periph- discussion in detail of the diagnosis and man-
eral manifestations. Any young patient (<30 agement of common causes of vertigo.
years old) with an acoustic neuroma should be
followed carefully for development of a tumor
on the opposite side (due to NF2). Central
varieties of positional vertigo are commonly NEAR-FAINT DIZZINESS
seen in patients with the inherited ataxia syn-
dromes (particularly common with spinocere- Near-faint dizziness or presyncope can best be
bellar atrophy type 6[SCA-6]).12 Positional described as the lightheaded sensation of an
vertigo and ataxia are also commonly seen with impending faint. It is often associated with a
Hippel-Lindau disease. This autosomal domi- feeling of unsteadiness or even of falling. Near-
nant disorder is characterized by hemangio- faint dizziness results from pancerebral isch-
blastomas of the cerebellar hemispheres, emia.13 Common causes are summarized in
angiomas of the retina, and cystic changes in Table 5–5. We emphasize that near-faint dizzi-
the kidney and pancreas. The diagnosis should ness is not a symptom of focal occlusive cere-
be considered in any patient with a cerebellar brovascular disease (i.e., not a symptom of
tumor or hemorrhage who manifests an ele- impending stroke).
vated hematocrit.
Congenital deformities of the inner ear may
result from abnormal genes or from abnormal Orthostatic Hypotension
development in utero. Most of the inherited
malformations of the inner ear are associated All of us have experienced light-headedness
with multiple malformations in other organs after rapidly assuming the standing position
producing a characteristic clinical profile (e.g., from the supine or sitting position. This symp-
Alport’s and Waardenburg’s syndromes). tom is transient and of little consequence. Also,
Progressive atrophy of the cochlear and ves- not uncommonly, susceptible subjects may
tibular nerves may be seen as part of a more develop presyncopal lightheadedness and may
diffuse degenerative disorder (e.g., with even faint after standing for a prolonged period
Table 5–5 Common Causes of Near-Faint Dizziness

Cause Precipitating Factors
Orthostatic hypotension Reduced blood volume, hypotensive drugs, autonomic dysfunction
Vasovagal attack Prolonged standing in hot sun, fear, severe pain, acute vertigo
Hyperventilation Anxiety, stress, panic attacks
Decreased cardiac output Arrhythmia, valvular disease, heart failure
in the hot sun. Recurrent symptoms of postural autonomic symptoms. It most commonly
hypotension, however, can usually be traced to occurs in young women (ages 20–40 years).
either reduced blood volume, the chronic use Multiple pathophysiological mechanisms have
of hypotensive drugs, or autonomic dysfunc- been associated with POTS, including periph-
tion.14,15 Nearly all of the antihypertensive drugs, eral denernation, hypovolemia, beta receptor
a large number of antidepressants and major hypersensitivity, deconditioning, and psycho-
tranquilizers, and long-term bed rest will pre- logical factors.
dispose a patient to orthostatic hypotension.
DIAGNOSIS AND MANAGEMENT
The diagnosis of POTS is made by documenting
Near-faint dizziness with orthostatic hypoten- a heart rate increase of >30 beats per minute in
sion can develop immediately on standing or a patient who develops orthostatic symptoms on
insidiously after several minutes of standing. standing. Treatment begins with a high-salt diet,
The diagnosis is made by documenting an acute copious fluids, and postural training. Some
or progressive decline in mean blood pressure patients benefit from low doses of beta-receptor
of more than 10 to 15 mmHg with a corre- antagonists or vasoconstrictors.
sponding increase in pulse rate while the
patient is in the erect position. In patients with
autonomic insufficiency the pulse rate will Vasovagal Attacks
remain unchanged despite the hypotension.
Autonomic impairment can be documented at Prior to a common faint, one experiences sen-
the bedside by taking the pulse while the supine sations of light-headedness, giddiness, nausea,
patient performs a vigorous Valsalva maneuver. and an abdominal sinking sensation. Typically
Normally, the pulse slows and the mean blood the subject is pale and there are associated
pressure increases by 10 to 30 mmHg in the signs of parasympathetic hyperactivity, includ-
immediate post-Valsalva period. Orthostatic ing piloerection and sweating. These symptoms
hypotension can often be eliminated by remov- are induced when emotions such as fear and
ing offending drugs or by correcting the causes anxiety, initiated in the forebrain limbic sys-
of blood-volume depletion. In patients with tem, activate the medullary vasodepressor cen-
autonomic insufficiency, increased salt intake ters.13,20 The consequences are a fall in heart
can increase blood volume, and elastic stock- rate and blood pressure and a decline in car-
ings can prevent pooling of blood in the lower diac output, leading to a decrease in cerebral
extremities.16,17 In severe cases the salt- blood flow. Parasympathetic hyperactivity
retaining steroid fluorocortisone can aid in accounts for the slowing of heart rate, and
expanding blood volume. Orthostatic lighthead- diminished sympathetic tone leads to vasodila-
edness is particularly common in the elderly tion. Normal cardiovascular reflexes are rein-
and in many cases may be an effect of arterio- stated if the subject lies supine or if there is loss
sclerosis (manifest by white matter hyperinten- of consciousness with a common faint.
sities on magnetic resonance imaging [MRI]) Vasodepressor light-headedness commonly
leading to reduced cerebral blood flow as occurs when a subject has fasted for a long
opposed to the typical causes of orthostatic period of time, is exposed to hot, moist weather,
hypotension. Patients with arteriosclerosis have and/or has stood for a prolonged period of time.
reduced cerebral blood flow even though blood Some individuals are clearly more susceptible to
pressure measured at the arm is normal. 18 presyncopal light-headedness and the common
faint than others, and occasionally one can find
a family history with members in several gener-
Postural Tachycardia Syndrome ations who are susceptible. Family pedigrees
(POTS) are most consistent with an autosomal dominant
transmission with incomplete penetrance but so
POTS is associated with orthostatic dizziness far no definite genetic mutation has been identi-
but without orthostatic hypotension.19 The fied.21 Vasodepressor episodes can also be pre-
pulse typically increases above 120 beats per cipitated by acute visceral pain or by a sudden
minute on standing and there are associated severe attack of vertigo. This explains the
occasional patient with an acute peripheral ves- 25 mm of mercury or less in a few minutes.
tibular lesion who will present with a history of Once this level is achieved, the subject does
syncope. In this case, it is important to obtain a not have to breathe excessively to maintain
history of severe vertigo and autonomic symp- the low PaCO2, so it is possible to be
toms preceding the loss of consciousness. chronically hypocapnic without appearing to
hyperventilate.25
The first and most important step in the evalu-
ation of a vasovagal event is to assess the risk The diagnosis rests on identifying the charac-
for a serious cause (i.e., myocardial infarction, teristic associated symptoms in the setting of
arrhythmia, stroke) or a future serious event. A anxiety and dyspnea. It is usually helpful to
clinical decision rule—the San Francisco have the patient voluntarily overbreathe to
Syncope Rule—was developed and validated reproduce his or her symptoms and to provide
for this purpose.22 The probability of a serious insight into the mechanism.23 In addition to
cause or future event (outcome at 30 days) is educating the patient, treatment must be
very low (<0.5%) when the patient has none of directed at the underlying anxiety. Behavioral
the following: history of congestive heart fail- interventions directed at dysfunctional breath-
ure, hematocrit less than 30%, abnormal ing can benefit susceptible patients.24 Long-
electrocardiogram (EKG) (new changes or term use of tranquilizers should be avoided
non-sinus rhythm), complaint of shortness of because increased tolerance and dependency
breath, or a systolic blood pressure less than commonly occur.
90 mmHg at triage.
Patients found to be a low risk for severe
causes or events can be treated symptomatically
rather than requiring an extensive evaluation. PSYCHOPHYSIOLOGIC
DIZZINESS (CHRONIC SUBJECTIVE
DIZZINESS)
Hyperventilation
A wide range of dizzy sensations are associated
Chronic anxiety with associated hyperventila- with psychiatric illnesses.26,27 Feelings of disso-
tion is a common cause of persistent near-faint ciation, as though one has left one’s own body,
dizziness.23 Patients typically describe sensa- are common. Patients use terms such as “float-
tions of light-headedness, faintness, and giddi- ing,” “swimming,” and “giddiness” to describe
ness along with other sensations described later the dizzy sensation. They may report a feeling
in the section “Psychophysiologic Dizziness.” of imbalance (commonly a rocking or falling
Associated symptoms typically include fre- sensation) or even of spinning inside the head—
quent sighing, air hunger, perioral numbness, sensations that can usually be differentiated
paresthesias of the extremities, lump in the from vertigo because they are not associated
throat, and tightness in the chest. Patients with an illusion of movement of the environ-
often report being unable to obtain the satis- ment or with nystagmus.28 Psychophysiologic
faction of a full deep breath and they will sigh dizziness may be constant or occur in attacks
frequently as though they were trying to catch and is typically associated with symptoms of
their breath. Studies in patients who hyperven- anxiety. Common associated somatic com-
tilate with medical procedures such as blood plaints include tension headache, heart palpi-
drawing or injections showed excessively deep tations, gastric distress, urinary frequency,
and irregular breathing which was associated backache, and a generalized feeling of weak-
with symptoms of dizziness and fainting.24 ness and fatigue. Attacks may be provoked by
Hyperventilation causes presyncopal light- sensory stimuli (driving on a freeway, walking
headedness by lowering the carbon dioxide on a brightly polished floor, watching a train go
content of the blood, thus producing by) or by social situations (eating in a restau-
constriction of the cerebrovasculature. In rant, shopping in a department store, attending
most subjects only a moderate increase in a reception). Symptoms often begin after a
respiratory rate can drop the PaCO2 levels to period of stress, especially after the death of a
loved one or after a patient has been through Table 5–6 Common Symptoms during
an illness, and may continue for months or Panic Attacks
years.
Shortness of breath, smothering, choking
Palpitations, accelerated heart rate
Panic Disorder Chest pain or discomfort
Sweating
Common causes of anxiety in daily life are cir- Dizziness, unsteady feeling, sensory illusions
cumstances in which one must make a decision Nausea or abdominal distress
that could have major implications for future Depersonalization or derealization
social and economic status. The symptoms Numbness or tingling sensations (paresthesias)
associated with this type of anxiety are usually Flushes (hot flashes) or chills
transitory and completely reversible.29 Anxiety Trembling or shaking
can also be associated with a number of neuro- Fear of dying
logic and psychiatric disorders. For example, Fear of going crazy or doing something
the first sign of dementia or manic depressive uncontrolled
illness can be an attack of severe anxiety with-
out obvious cause. activities to the point of becoming housebound
Panic attacks are a distinct form of anxiety for fear of having a panic attack. The multiple
that typically occur in a background of persis- symptoms of panic attacks (see Table 5–6),
tent apprehension but at times when there including dizziness, are commonly reported by
appears to be no obviously threatening circum- patients with agoraphobia. By contrast, simple
stance.30,31 Such attacks often occur when it phobias, such as fear of flying, heights, and
would be difficult for one to make a rapid exit snakes, are usually associated with generalized
(e.g., traveling in an airplane or train, driving in anxiety rather than panic episodes.
the fast lane of the freeway, shopping in a Phobic postural vertigo is characterized by a
crowded store, or waiting in a supermarket frightening feeling of dizziness with subjective
line). The condition typically builds up over 10 postural and gait instability.35 Although patients
to 15 min with progressively increasing anxiety have multiple symptoms of panic attacks, often
associated with dizziness, shortness of breath, with a steadily mounting fear of impending
sweating, flushing, trembling or shaking, heart death, they feel physically ill and the associated
palpitations, paresthesias, and a generalized symptoms of anxiety are brought out only after
feeling of weakness (Table 5–6). The dizziness appropriate questions have been asked. They
can take several forms, from a giddy, unsteady describe their dizziness as a perception of illu-
sensation to a progressing, presyncopal light- sory body motion that can occur in brief bouts
headedness. Patients may experience a tight- lasting seconds or be prolonged over hours and
ness in the chest as though the lungs cannot be days. Typically patients have a fear of falling
adequately filled. Hyperventilation and when sitting or standing, and active body move-
enhanced CO2 sensitivity are also common.32 ments provoke unpleasant illusions of body
The person may try to flee and in the future acceleration along with simultaneous illusory
avoid the situation in which the panic attack movement of a stationary environment. With
occurred. There is a clear genetic predisposi- the attack, patients experience anxiety, psycho-
tion to panic disorders, distinguishing them motor restlessness with escape reactions, a
from the more common anxieties that are a sudden desire to flee from the place where the
response to specific life situations.33 attack is provoked, aimless walking, and, if
seated, a rigid grasp of the arms of the chair.
Anticipatory anxiety leads to further attacks of
Phobic Dizziness dizziness despite the discrepancy between the
subjective fear of falling and the absence of
Agoraphobia, defined as a morbid fear and objective unsteadiness. Although some patients
avoidance of being in public places, is closely develop typical symptoms of agoraphobia, oth-
linked with anxiety disorders and panic ers are able to continue their social and work
attacks.29,34 Often agoraphobia is secondary to habits despite symptoms they feel are dominat-
panic attacks; the patient restricts outside ing their lives.34 The outlook for these patients
is good with most having improvement or even cerebrovascular vasospasm can explain the
complete resolution of symptoms.36 presyncopal light-headed sensation, it cannot
Some patients develop a profound fear of explain the many complex sensory distortions
falling in open spaces where a visuospatial such as feelings of dissociation, illusions of
reference is absent.37 Unlike the fear of public body movement, imbalance, and fear of fall-
places found with agoraphobia, patients with ing.39 Abnormalities within the autonomic ner-
space phobia fear open spaces where there is vous system may account for some of these
no “visual” support nearby. They will crawl on symptoms.40 In susceptible patients, panic
the floor to cross a room or walk close to walls attacks can be precipitated, by a large number
or hedges in streets. The average age of onset of substances, including carbon dioxide, lac-
of space phobia is later than that of agorapho- tate, caffeine, isoproterenol, yohimbine, and
bia (55 years compared with 24 years), and the benzodiazepine receptor antagonists.33 All
former is rarely associated with depression or these agents interact with the central nora-
free-floating anxiety, as typically seen with ago- drenergic neuronal system. A popular hypoth-
raphobia. Marks suggested that many of these esis is that panic attacks result from central
patients have an underlying organic disorder of dyscontrol of the locus ceruleus, leading to the
balance, because they are resistant to the expo- episodic release of catecholamines. Studies
sure treatments that are often successful with using positron-emission tomography (PET)
agoraphobics.37 A variant of space phobia (the scanning in patients with panic disorder dem-
so-called motorist’s disorientation syndrome) is onstrated an asymmetry of blood flow and oxy-
an illusion of falling to the side or that the car is gen utilization in the parahippocampal gyrus
turning to the side when driving in open spaces, (increased on the right side), 41,42 one of the
on featureless roads, or on the brows of hills.38 major projection areas of the locus ceruleus.
These abnormal sensations are typically accom- The parahippocampal region is closely interre-
panied by a panic reaction. Typical of phobias, lated with the hippocampus, a key multimodal
these patients develop avoidance behavior, sensory integrative center that receives projec-
either driving at very low speeds in restricted tions from the association areas of all sensory
areas or completely stopping driving. modalities and projects to other limbic struc-
tures and to autonomic centers in the hypo-
thalamus and brain stem. Abnormalities in the
Chronic Anxiety hypothalamic orexin/hypocretin neuronal sys-
tem may also explain the breathing and sleep
Unlike acute anxiety, chronic anxiety is often dysfunction seen with panic disorder.43
difficult to ascribe to a specific inciting factor.29
Symptoms are less intense although qualita-
tively similar to those of acute anxiety. The Diagnosis and Management
patient may complain of dizziness and giddi-
ness that persist for years, present from morn- The diagnosis of psychophysiologic dizziness
ing to night. The patient appears tense and on rests on finding the characteristic associated
edge, and there are often symptoms of associ- symptoms of acute and chronic anxiety
ated chronic depression. As with acute anxiety, discussed previously. One must keep in mind
there are typically associated somatic com- that vestibular disorders can also cause
plaints, and on examination there may be anxiety and fear of further attacks of vertigo.44,45
several physical signs of chronic tension mani- A classic vicious cycle may develop whereby
fested by a fine tremor of the extended hands, the vestibular disturbance causes anxiety,
very brisk deep tendon reflexes, chronic tachy- which in turn causes chronic dizziness that may
cardia, and pupillary dilatation. persist after the vestibular imbalance has been
compensated. A negative examination in the
face of obvious signs of acute and chronic anxi-
Pathophysiology ety will help support the presumed diagnosis
based on the history. It can sometimes be
The pathophysiologic mechanism of psy- difficult to recognize panic attacks because
chophysiologic dizziness is poorly understood. patients will focus on the somatic symptoms,
Although hyperventilation with its concomitant especially the dizziness and autonomic
symptoms, rather than the intense anxiety asso- DRUG-INDUCED DIZZINESS

ciated with the attack.
The first step in management of patients A careful history of medications is critical in
with psychophysiologic dizziness is to acknowl- evaluating any patient complaining of dizziness
edge their symptoms as “real,” due to physio- (Table 5–7). Antihypertensive and antidepres-
logic changes occurring in their bodies and that sant medications are common causes of near
the pattern of symptoms is commonly reported faint dizziness and falls in the elderly.47,48
by other patients. Patients are often convinced Ototoxic drugs such as the aminoglycosides
that they have a severe neurologic disorder and and cisplatin can cause vertigo if hair cell loss is
that the anxiety, which they have recognized, is asymmetrical, but more often they cause dis-
secondary to the physical disorder. It is impor- equilibrium and oscillopsia from bilateral sym-
tant to them that the physician understands metrical end-organ damage.49,50 Carbamazepine,
that they are suffering from “physical symp- phenytoin, primidone, and alcohol can cause
toms.” An explanation for how the release of acute reversible disequilibrium and chronic
catecholamines can produce symptoms such as irreversible disequilibrium from cerebellar
tachycardia, chest pain, paresthesias, and dizzi- dysfunction. Sedating drugs cause a nonspe-
ness may improve their acceptance and provide cific dizziness typically described as a fogginess,
the groundwork for therapeutic considerations. cloudiness, or giddiness that is presumably due
Three general classes of medications are com- to diffuse depression of the central nervous
monly used in the treatment of panic attacks: system. A number of commonly used drugs
(1) the tricyclic amines (e.g., imipramine and produce a characteristic drug intoxication syn-
desipramine), (2) benzodiazepines (e.g., alpra- drome that might be confused with other types
zolam or clonzapam), and (3) the selective of dizziness. The associated confusion, disori-
serotonin reuptake inhibitors (SSRIs) (e.g., entation, memory and cognitive deficits, gaze-
paroxetine and fluoxetine).31 The SSRIs typi- evoked nystagmus, and gait and extremity
cally have an acceptable side effect profile and ataxia indicate combined cortical and cerebel-
do not have the tolerance and dependency that lar dysfunction.51 These drugs affect multiple
occurs with benzodiazepines. These medica- neurotransmitters within the central nervous
tions should be used in conjunction with sup- system (CNS), but the cause of the drug intoxi-
portive psychotherapy. Patients with phobic cation syndrome is unknown.
dizziness may respond to cognitive behavioral The most commonly recognized syndrome is
therapy, although long-term benefit has not that associated with alcohol ingestion. A light-
been demonstrated.46 We strongly encourage headed, swimming sensation is typically associ-
patients to enter a progressive exercise ated with slowing of cognitive functions and
program with the goal of gradually improving motor responses. Gaze-evoked nystagmus with
their diminished physical fitness. It is very horizontal gaze deviation and gait ataxia are early
important that patients feel responsible for reliable signs of the syndrome. With increased
their therapy program. intoxication, gaze-evoked nystagmus occurs with
Table 5–7 Type and Mechanism of Dizziness Associated with Commonly Used
Drugs
Drug Type of Dizziness Mechanism
Aminoglycosides, cisplatin Vertigo, disequilibrium Damage to vestibular hair cells
Antiepileptic: carbamazepine, Disequilibrium, intoxication Cerebellar toxicity, CNS depression
phenytoin, primidone
Tranquilizers: barbiturates, Intoxication CNS depression
benzodiazepines, tricyclic
amines, marijuana
Antihypertensives, diuretics Near-faint Postural hypotension, reduced cere-
bral blood flow
Alcohol Intoxication, disequilibrium, CNS depression, cerebellar toxicity,
positional vertigo change in cupula-specific gravity
vertical gaze deviation, and the upper extremi- subjective vertigo. Both the vertigo and imbal-
ties are ataxic. The alcohol concentration in the ance are compensated for within a few days.
blood can be reasonably well predicted by the Patients who slowly lose vestibular function on
degree of gaze-evoked nystagmus. one side, such as with an acoustic neuroma,
The diagnosis rests on finding the character- may not experience vertigo but often describe
istic combination of symptoms and signs in a a vague feeling of imbalance and unsteadiness
patient taking one of the offending drugs. on their feet. Bilateral symmetrical vestibular
Blood levels can now be routinely obtained on loss results in a more pronounced and persis-
most of these drugs, so a specific diagnosis is tent unsteadiness, which may be incapacitating
possible. in elderly patients.53,54 The imbalance due to
loss of vestibulospinal and proprioceptive func-
tion is typically worse in the dark, when the
patient is unable to use vision to compensate
HYPOGLYCEMIA for the loss (Fig. 5–1). Patients with a severe
bilateral vestibular loss will report movement
Hypoglycemia may lead to behavioral changes, induced oscillopsia, often described as a feel-
light-headedness, lethargy, confusion, amnesia, ing of looking through the lens of a video cam-
seizures, weakness, shakiness, fatigue, and era. Patients with cerebellar lesions, on the
diaphoresis.52 It usually is a complication of other hand, show little change in their balance
insulin or sulfonylurea treatment in diabetic with and without vision (the basis for the
patients, but it may occur with insulinomas Romberg test). Disequilibrium may be the
or as a fasting or postprandial phenomenon. presenting symptom of lesions involving
Postprandial symptoms of shakiness, palpita- the motor centers of the basal ganglia and fron-
tions, fatigue, and dizziness have been termed tal lobes such as with Parkinson’s disease,
functional hypoglycemia because most such hydrocephalus, and the multiple lacunar infarct
cases are not associated with significantly syndrome.
low plasma glucose levels. The history in
patients suspected of having hypoglycemia
should focus on whether insulin or sulfonylu- Gait Disorders in Older People
reas have been taken. Diagnosis rests on mea-
suring plasma glucose, insulin, and c-peptide. The gradual loss of cells in the sensory and
c-Peptide is the connecting peptide that is motor centers of the brain with aging is usually
cleaved from proinsulin to form insulin.52 a very subtle process that parallels similar
Elevation of c-peptide and insulin suggests slight changes in memory and other cognitive
excessive endogenous insulin (such as from an functions, generally considered the normal
insulinoma). An elevated insulin level with nor- aging process.55 The gait of normal elderly
mal or suppressed c-peptide level indicates men is characterized by slight anteroflexion of
excessive exogenous insulin, since c-peptide is the upper torso with flexion of the arms
not present in pharmaceutical insulin and is in and knees, diminished arm swing, and shorter
fact suppressed by it. step length;56 the gait of older women tends to
be more narrow based, with a waddling
quality.57 When minor, these changes are not
likely to lead to a specific medical complaint.
DISEQUILIBRIUM However, a small number of older patients
develop a progressive deterioration of gait,
Common Causes beginning in the eighth and ninth decades.
Their steps shorten and the base widens until
Patients often use the term “dizziness” to their gait is reduced to a shuffle. They turn en
describe a sensation of imbalance or disequi- bloc rather than with a normal pivot, and upon
librium that occurs only when they are stand- arising they have great difficulty in initiating
ing or walking and is unrelated to an abnormal the first step. Once they begin, their arms are
head sensation. Imbalance is common with held rigidly at their sides, and they exhibit
acute unilateral peripheral vestibular lesions, a characteristic stooped posture. Walking in
but it is transient and invariably associated with tandem is impossible.
Imbalance
Unilateral
Associated Yes peripheral
with acute vestibular
vertigo lesion
No
Yes Yes Bilateral

Much worse Oscillopsia
vestibular
in dark +/– hearing loss
lesion
No No
Yes Associated numbness,

Cerebellar Incoordination
lesion of extremities weakness, bowel and
bladder dysfunction
No Yes
Slow, loss of Proprioceptive

associated loss
movement
Yes
Frontal lobe,
basal ganglia
Figure 5–1. Logic for distinguishing between different causes of imbalance.
On examination, patients are unable to relax 60, and it is greater in women than in men.
their limbs voluntarily. This phenomenon has Most falls in the elderly result from an acciden-
been described as Gegenhalten or paratonic tal slip or trip (Table 5–8). The cause can often
rigidity. Cortical release signs commonly be traced to decreased sensory input, slowing
accompany the diffuse rigidity. The patients of responses, and weakness of support.53
attribute their difficulty in walking to a lack of Medications are a common contributing fac-
confidence or a fear of falling, and, not surpris- tor.47 Falls can be directly traced to an acute
ingly, major falls frequently occur. In the late attack of dizziness in less than 10% of patients.64
stages, patients cannot walk unassisted and may This low incidence probably can be attributed
have great difficulty sitting down from a stand- to the fact that most types of dizziness, includ-
ing position. They land on the edge or side of ing attacks of vertigo, begin slowly enough to
the chair and fall off. Ultimately they are con-
fined to bed. The neuropathologic basis of this
gait disorder is poorly understood. Postmortem
Table 5–8 Common Causes of Falls in
examinations typically show diffuse cortical
Older People64
atrophy and subcortical small-vessel ischemic
changes.58–60 Cause %
Accidental (falling on stairs, slips, trips) 40–50
Falls in Older People Neurologic (drop attacks, weakness, 20–30
ataxia)
Falls in the elderly are a common source of Dizziness (orthostatic hypotension, 5–10
arrhythmia, vertigo)
morbidity and mortality.61–63 The risk of falls
Uncertain 5–10
increases linearly with age beyond the age of
allow the patient to sit down or to grab onto a exercises help slow the progression. Exercise
support to avoid falling. intervention has clearly been shown to reduce
risk and rate of falls.67 The greatest benefit of
exercise on fall rates was seen with programs
Diagnosis and Management that included challenging balance exercises
and long duration (>50 hours).68
Considering the many possible loci of dysfunc-
tion, the examination of a patient complaining
of disequilibrium must include a careful assess-
ment of gait, strength, coordination, reflexes, OCULAR DIZZINESS
and sensory function (particularly of the lower
extremities).53,55 The broad-based ataxic gait of Common Causes
cerebellar disorders is readily distinguished
from the milder gait disorders seen with ves- Many patients complain of a vague dizziness
tibular or sensory loss. Furthermore, other cer- when they first wear glasses. They describe a
ebellar signs (e.g., dysmetria, dysarthria, inten- feeling of disorientation, often accompanied by
tion tremor, pathologically impaired smooth headache. The dizziness most frequently
pursuit, and gaze-evoked nystagmus) usually accompanies correction of astigmatism but also
accompany the gait ataxia. Bilateral vestibular occurs after a change in magnification. It is
loss may or may not be associated with hearing nearly always mild and short-lived. A more per-
loss. The diagnosis rests on finding reduced sistent and distressing dizziness may occur in
vestibular function based on a positive head patients who are required to use high magnifi-
thrust test (bilateral) or decreased or absent cation or who have had a lens implant after
response to caloric and rotational stimulation cataract removal to correct severe visual loss.
(see Chapter 7). In these cases, the vestibulo-ocular reflex must
The deterioration of gait that occurs with adapt if visual objects are to be stabilized dur-
aging must be distinguished from that associ- ing head movements. This compensation pro-
ated with lesions of the cortical and subcortical cess may be slow or inadequate in elderly
motor centers.55 The shuffling, flexed, steppage patients or in subjects who require magnifica-
gait of Parkinson’s disease resembles the nor- tion so high that it is beyond the adaptive range
mal gait of older males. The diagnosis of of the vestibulo-ocular reflex.69 Multifocal
Parkinson’s disease rests on finding associated glasses may predispose to dizziness and falls in
signs, including bradykinesia, cogwheel rigid- older people.70
ity, and the characteristic “pill-rolling” tremor. Dizziness also can result from an imbalance
Apraxia of gait, characterized by slow, halting, in the extraocular muscles. After an acute ocu-
sliding steps as if the patient’s feet were adher- lar muscle paralysis, looking in the direction of
ing to the floor, is caused by bilateral frontal the paralyzed muscle causes dizziness (in addi-
lobe dysfunction. Common causes include tion to diplopia). This dizziness results from a
multiple subcortical infarcts, infiltrating mismatch between where the brain “thinks”
tumors, and hydrocephalus. These abnormali- the eye is, based on its efferent innervation,
ties are easily identified with computerized and where it actually is, based on the visual sig-
tomography (CT) and MRI. nal.71 As with other types of ocular dizziness,
With the exception of normal pressure the nervous system usually adapts to this altered
hydrocephalus, which can be dramatically spatial information and the dizziness is rarely
reversed with placement of a shunt, most gait severe or prolonged.
disorders in the elderly are not reversible.
Some can be helped by improving support with
canes or a walker. Optimizing footwear is Oscillopsia
very important.65 Tranquilizing medications
and polypharmacy should be scrupulously The optic illusion that stationary objects are
avoided, inasmuch as they can further impair moving back and forth or up and down is called
the central integration of sensory information.66 oscillopsia. It is usually a sign of vestibular,
Physical therapy programs consisting of brainstem, or cerebellar involvement, although
gait and balance training and strengthening rarely it can result from paralysis of the eye
Oscillopsia
Spontaneous
nystagmus
No Yes
Head movement Transient

Bilateral Yes induced with vertigo Yes Unilateral
peripheral
peripheral
vestibular or No No vestibular
cerebellar
lesion
lesion
Central vestibular
Visual association
or cerebellar
cortex
lesion
Figure 5–2. Logic for distinguishing between different causes of oscillopsia.
muscles or from a lesion in the visual associa- placing their hand on their chin to prevent even
tion areas in the cortex (Fig. 5–2). Oscillopsia the slightest movements associated with
can be either a constant symptom or a move- pulsatile cerebral blood flow. Patients with cer-
ment-induced symptom. Not surprisingly, con- ebellar lesions cannot suppress their vestibulo-
stant oscillopsia is associated with acquired ocular reflex with fixation. They experience a
spontaneous nystagmus. If a patient attempts brief sensation of oscillopsia after each rapid
to fixate on an object after an acute unilateral head movement, owing to a transient, unwanted
peripheral vestibular lesion, it will appear vestibular nystagmus. These patients typically
blurred and seem to be moving in the opposite have gaze-evoked nystagmus on lateral or verti-
direction of the slow phase of the spontaneous cal gaze, so they may experience oscillopsia
nystagmus. Some patients will report a flicking with both head and eye movements.
back and forth associated with the fast compo-
nent of nystagmus. The oscillopsia associated
with unilateral peripheral vestibular lesions is Management
usually transient, disappearing as the acute ver-
tigo and spontaneous nystagmus disappear. Ocular dizziness due to changes in refraction is
Patients with spontaneous nystagmus due to rarely severe and usually disappears spontane-
lesions of the central vestibular pathways report ously as the patient adjusts to the altered visual
severe persistent oscillopsia, invariably associ- environment. Patients should be encouraged to
ated with other symptoms and signs of brain- return to normal activities even though the diz-
stem dysfunction. ziness is initially worse. In the long term this will
Oscillopsia that occurs only with head move- accelerate the central compensation process. By
ment suggests some abnormality of the vestib- contrast, oscillopsia is often a severe, persistent
ulo-ocular reflexes. Patients with symmetrical symptom that can be disabling. The most both-
loss of vestibulo-ocular reflex function (e.g., ersome type is that associated with an acquired
due to ototoxic drugs) are unable to fixate on central spontaneous nystagmus (see
objects when walking because the surround- “Spontaneous Nystagmus” in Chapter 6). With
ings appear to be bouncing up and down.72 The one exception (Baclofen for periodic alternating
head oscillates in the vertical plane in the fre- nystagmus), drugs are not effective in suppress-
quency range of 2 to 3 Hz. The visual pursuit ing oscillopsia due to central spontaneous nys-
system cannot compensate for the loss of ves- tagmus.73 If the nystagmus has a clearly defined
tibular function in this frequency range. In null region, prisms fitted in glasses or eye mus-
order to see the faces of passersby, patients cle surgery can sometimes be helpful. In patients
learn to stop and hold their heads still. When with head movement–induced oscillopsia due
reading, they learn to stabilize the head by to bilateral peripheral vestibular loss, the visual
and neck ocular reflexes can compensate for the physiologic stimulation of the vestibular, visual,
loss during low-frequency head movements but or somatosensory systems. It typically results
not during high-frequency movements.74,75 from a mismatch in sensory signals, resulting in
When walking, patients learn to stop and hold a feeling of disorientation, imbalance, and veg-
their head still to see clearly. Unlike the widely etative symptoms.
available devices used to augment an impaired
auditory system, there are no current devices
that augment the vestibular system. A number Motion Sickness
of devices that aim to improve the overall bal-
ance function in patients with bilateral vestibul- Motion sickness refers to the syndrome of diz-
opathy are in the development phase or early ziness, perspiration, nausea, vomiting, increased
clinical testing phase.76–83 These devices gener- salivation, yawning, and generalized malaise
ally encode head or body movements into tactile induced by motion.85 It is usually produced
cues that are delivered to the trunk and tongue. by vestibular stimulation but also can occur
with visual stimulation (e.g., with prolonged
optokinetic stimulation). Both linear and
angular head acceleration induce motion sick-
MULTISENSORY DIZZINESS ness if applied for long periods in susceptible
subjects. Combinations of linear and angular
Occasionally, one can trace dizziness to disease acceleration or multiplanar angular accelera-
involving multiple sensory systems, particularly tions are particularly effective. Rotation about
in elderly patients and in patients with systemic the vertical axis, along with either voluntary or
disorders, such as diabetes mellitus.84 A typical involuntary nodding movements in the sagittal
combination might include peripheral neurop- plane, rapidly produce motion sickness in
athy resulting in diminished touch and proprio- nearly everybody. This movement combines
ceptive input, decreased visual acuity (cataracts, linear and angular acceleration (Coriolis
glaucoma), and impaired hearing (as in presby- effect).
cusis). In such patients an added vestibular Autonomic symptoms are usually the initial
impairment (from ototoxic drugs, for example) manifestation of motion sickness.86 Sensitive
can be devastating, making it impossible for sweat detectors can identify increased sweating
them to walk without assistance. Patients with as soon as 5 sec after onset of motion, and
multisensory dizziness may be unable to adapt grossly detectable sweating is usually apparent
to unfamiliar surroundings, such as in the before any noticeable nausea. Increased saliva-
hospital. Not infrequently, their complaint of tion and frequent swallowing movements occur
dizziness will improve when they return to early. Gastric motility is reduced and digestion
familiar surroundings at home. is impaired. Hyperventilation is almost always
present, and the resulting hypocapnia leads to
changes in blood volume with pooling in the
Management lower parts of the body, predisposing the sub-
ject to postural hypotension. Motion sickness
Treatment is directed at increasing sensory
affects the appetite so that even the sight or
input wherever possible. This might include
smell of food is distressing.
improved diabetic control, surgery for cataracts
Other symptoms of increased sensitivity may
or glaucoma, amplification for presbycusis, and
suggest a general hypersensitivity syndrome in
the use of a cane or walker to improve support
these patients. Other hypersensitivity symp-
and increase somatosensory signals. As with
toms include sensitivity to light, sound, and
other balance disorders, sedating medications
other pain syndromes, dry eyes, and irritable
should be avoided.
bowel syndrome.
Some people are sensitive to development of
motion sickness, but others are highly resistant.
PHYSIOLOGIC DIZZINESS Most will adapt to prolonged vestibular stimula-
tion, whereas some never adapt (the chronically
Physiologic dizziness refers to a group of phe- seasick ocean voyager). For unknown reasons,
nomena that occur in normal subjects with babies are highly resistant to motion sickness.
Unfortunately, there is no reliable way to Space Sickness

predict who will develop motion sickness.
Thresholds for vestibular stimulation Space sickness is a kind of motion sickness that
(rotational or caloric) and the rate of habi- is induced by active head movements in
tuation to vestibular stimulation are no differ- space.93,94 It has occurred in approximately 50%
ent in susceptible and resistant subjects.87 of the astronauts and cosmonauts who have
Patients whose labyrinths have been inacti- entered space. Most adapt within 2 to 3 days.
vated by congenital or acquired disease are Because active head movements do not elicit
resistant to motion sickness, whether induced motion sickness within the gravitational condi-
by visual or vestibular stimuli. Such patients tions on earth, the absence of gravity appears
can withstand prolonged exposure to wave to be a key factor. The leading theory at pres-
motion during a heavy storm at sea that would ent is that the symptoms are generated by a
lead to motion sickness in even the most hard- mismatch between otolith and semicircular
ened seaman. canal signals as well as between otolith and
Genetic factors clearly are important in sus- visual signals.94 On earth, the semicircular
ceptibility to motion sickness. Twin studies canals and otoliths work together, sensing the
indicate heritability for motion sickness in the angular and linear acceleration components of
range of 55% to 70%.88 Families with migraine active head movements, but in space the oto-
have increased sensitivity to developing motion liths fail to signal orientation of the head in the
sickness.89 A functional polymorphism in the absence of gravity. Thus, the afferent signals
alpha2-adrenergic receptor gene was signifi- generated by head movements in space are dif-
cantly more common in subjects susceptible to ferent from the signals expected from prior
motion sickness compared to those who were calibration on earth. The vestibular system
not sensitive to motion sickness.90 Since this must recalibrate to account for the absence of
receptor mediates central and peripheral auto- gravity; presumably this recalibration takes
nomic responses, alleles that affect the level of about 3 days. Supporting this notion, some
expression could explain the varied autonomic astronauts develop transient motion sickness
responses to provocative motion. However, when they return to earth, although it is usually
the findings need to be replicated in other of shorter duration than in space.
populations.
Motion sickness seems to result from a
visual–vestibular conflict.91 This theory is sup- Height Vertigo
ported by the fact that visual influences during
body motion have a clear effect on the develop- Height vertigo refers to the subjective sensa-
ment of motion sickness. The symptoms are tion of instability and imbalance along with a
aggravated if one sits in an enclosed cabin on a fear of falling and vegetative symptoms that
ship or in the back seat of a moving vehicle. normal subjects experience in high places.
Because the environment is moving with the More appropriate terms might be “height diz-
subject, visual–vestibular conflict occurs. The ziness” or “height sickness,” inasmuch as there
vestibular system signals movement while is usually no illusion of movement. Height ver-
the visual system signals a stationary environ- tigo occurs when the distance between the
ment. Motion sickness can be alleviated by observer and visible stationary contrasting
improving the match between visual and ves- objects in the environment becomes critically
tibular signals. This can be accomplished on a large.95 Presumably, the normal lateral and
ship by standing on deck and focusing on the fore–aft body sway sensed by the vestibular
distant horizon or on land, if possible. When system conflicts with the visual information of
riding in a car, the susceptible subject should no sway (the greater the distance between the
sit in the front seat to allow ample peripheral eyes and the nearest stationary object, the
vision of the stationary surround. Motion sick- smaller the angular displacement on the ret-
ness suppressants such as scopolamine and ina). The symptoms can be reduced by having
dimenhydrinate are effective, presumably by the subject sit or lie down to increase soma-
diminishing activity at the vestibular nucleus tosensory input or by having a nearby station-
and thereby diminishing the potential for ary object in the visual periphery, such as a
visual–vestibular conflict.85,92 railing or window frame. Some subjects develop
associated panic attacks and avoidance behav- used to describe each type of dizziness (Table
ior typical of agoraphobia. Cognitive factors 5–9). A sensation of “spinning” nearly always
such as anticipatory anxiety and overestimation indicates a vestibular disorder, particularly if it
of somatic symptoms play an important role in is moderate to severe in intensity and when the
the development of agrophobia.96 environment is seen moving (as opposed to an
“internal” sensation). Patients with nonvestibu-
lar dizziness occasionally will report a sensation
Mal de Debarquement Syndrome of spinning inside the head, but the environ-
ment remains still and they do not have nystag-
Most of us have experienced the persistent mus. Patients with vestibular lesions often liken
rocking sensation after disembarking from a the sensation to that of being “drunk” or “motion
boat, particularly after a long voyage. This usu- sick.” They describe feelings of “imbalance,” as
ally subsides gradually over a few hours and though they are “falling” or “tilting” to one side.
seldom is of major significance. Rarely, patients Illusions of motion of the environment are rare
report the persistent rocking sensation of a but illusions of self-motion are common in
boat long after returning to land (months to patients with nonvestibular dizziness. These
years).97,98 These patients often report that their patients typically use terms such as “light-
symptoms are less bothersome when they are headed,” “floating,” “rocking,” “giddy,” or
in motion such as driving, swimming, or going “swimming.” The sensation that one has left
back on a boat. The syndrome typically devel- one’s body is characteristic of psychophysiologic
ops in middle age and is more common in dizziness.
women than in men.98 Both motion-triggered Vertigo is an episodic phenomenon, whereas
and spontaneous episodes occur with the latter nonvestibular dizziness is often continuous. An
more common in patients with migraine. The exception would be presyncopal light-headed-
cause is unknown but presumably it represents ness caused by postural hypotension or cardiac
maladaptation within the central vestibular arrhythmia. Patients with psychophysiologic
pathways. dizziness often report being dizzy from morn-
ing to night without changes for months to
years at a time. Vertigo is typically aggravated
SUMMARY: DISTINGUISHING by head movements, whereas nonvestibular
dizziness is often aggravated by movement of
BETWEEN VESTIBULAR AND visual targets. Episodes of dizziness induced by
NONVESTIBULAR TYPES OF position change suggest a vestibular lesion if
DIZZINESS postural hypotension has been ruled out.
Although stress can aggravate both vestibular
Although the description alone does not distin- and nonvestibular dizziness, dizziness that is
guish between vestibular and nonvestibular reliably precipitated by stress suggests a non-
causes of dizziness, certain words are commonly vestibular cause. Finally, episodes of dizziness
Table 5–9 Distinguishing between Vestibular and Nonvestibular Types of

Dizziness
Factor Vestibular Nonvestibular
Common descriptive Spinning (environment moves), Light-headed, floating, dissociated from
terms merry-go-round, drunkenness, body, swimming, giddy, “internal” spinning
tilting, motion sickness, (environment stationary)
off-balance
Course Episodic Constant
Common precipitating Head movements, position Stress, hyperventilation, cardiac arrhythmias,
or aggravating factors change situations
Commonly associated Nausea, vomiting, unsteadiness, Paresthesias, syncope, difficulty
symptoms tinnitus, hearing loss, impaired concentrating, tension headache
vision, oscillopsia
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1995;45(suppl 5):S5.
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Chapter 6
Bedside Examination of
the Vestibular System
EXAMINATION OF THE EAR Spontaneous Nystagmus

Fistula Test Gaze-Evoked Nystagmus
TESTS OF VESTIBULOSPINAL REFLEXES Positional Nystagmus
Pastpointing Vibration-Induced Nystagmus
Static Posture Head-Shaking Nystagmus
Walking Tests Hyperventilation-Induced Nystagmus
TESTS OF VESTIBULO-OCULAR REFLEXES OTHER OCULAR OSCILLATIONS
Doll’s Eye Test (Oculocephalic Response) Dissociated Spontaneous Nystagmus
Head-Thrust Test Voluntary Ocular Oscillations (Voluntary
Dynamic Visual Acuity Nystagmus)
Cold Caloric Test Convergence Retraction Nystagmus
Rotational Testing Saccadic Intrusions
TESTS FOR PATHOLOGIC NYSTAGMUS Ocular Bobbing
Methods of Examination Palato-Ocular Myoclonus
TYPES OF PATHOLOGIC NYSTAGMUS OCULAR TILT REACTION
As noted earlier, the vestibular system works in deep within the temporal bone, and the subjec-
conjunction with the visual and somatosensory tive sensation to vestibular stimulation is ill
systems to achieve ocular and postural stability. defined. One can visualize the tympanic mem-
To examine the vestibular system adequately, brane and some structures within the middle
one must isolate it from these other sensory ear, but this generally provides no information
systems. Historically this has been a difficult about the status of the inner ear.
task at the bedside, which is why most general
textbooks only describe ways to assess the
“audio” component of the audio-vestibular sys-
tem or eighth cranial nerve. The contribution EXAMINATION OF THE EAR
of the visual system can be removed with eye
closure, but then the eye movements gener- The neurotologist should be familiar with the
ated by the vestibular system cannot be normal anatomy of the external canal and tym-
observed. There is no simple way to eliminate panic membrane (see Chapter 2), be capable
somatosensation. of removing cerumen that interferes with visu-
Unlike the visual system, in which the optic alization of the tympanic membrane, and be
nerve can be directly visualized and acuity able to recognize certain common disorders on
accurately measured, the inner ear is located inspection (Fig. 6–1). Otoscopy is performed
149
Figure 6–1. Appearance of the tympanic membrane in a normal subject (A) and in patients with a superior marginal
perforation and cholesteatoma (B), a tympanic glomus body tumor (C), and a step deformity caused by a longitudinal
temporal bone fracture (D).
with the largest speculum that fits comfortably Fistula Test

into the external canal: the pinna is gently
pulled posterior and superior to straighten the A fistula test is performed by transiently
canal. The tympanic membrane is normally increasing and decreasing the pressure in the
translucent; changes in color indicate middle external canal with a pneumatoscope.1 A posi-
ear disease (e.g., an amber color with middle tive fistula sign (a transient burst of nystagmus
ear effusions). Tympanosclerosis, the conse- and vertigo) occurs in patients with a perfo-
quence of a resolved otitis media or trauma, rated tympanic membrane and erosion of the
appears as a semicircular crescent or horse- bony labyrinth from conditions such as chronic
shoe-shaped white plaque within the tympanic infection, surgery, or trauma. The change in
membrane. It is rarely associated with hearing pressure is transmitted directly to the peri-
loss but is an important clue to past otitic lymph, compressing the membranous labyrinth
infections. The pars flaccida region, the area and stimulating the semicircular canal cristae.
superior to the lateral process of the malleus, The resulting nystagmus usually lasts from 10
should be carefully inspected for evidence of a to 20 sec. The direction of the nystagmus may
retraction pocket or attic cholesteatoma. The be toward or away from the involved ear and is
ossicles and the color of the underlying mucous often the same for both positive and negative
membrane of the middle ear can often be pressure changes.
assessed through a normal translucent tym- Lesser ocular and subjective responses may
panic membrane. Pneumatoscopy allows one occur in patients with an intact tympanic mem-
to determine the mobility of the tympanic brane. Hennebert 2 first described this sign in
membrane. Lack of mobility may indicate an patients with congenital syphilis, but it can
unsuspected perforation (usually under an occur in patients with a wide range of labyrin-
anterior overhang), fluid in the middle ear, or thine disorders. The response is a slow ocular
severe scarring of the tympanic membrane or deviation followed by a few beats of nystagmus
middle ear. even with sustained pressure. The abnormal
6 Bedside Examination of the Vestibular System 151
eye movements are in the plane of the affected TESTS OF VESTIBULOSPINAL

semicircular canal. With semicircular canal REFLEXES
dehiscence syndrome the pressure changes are
transmitted to the abnormal canal due to the As discussed in Chapter 3, the labyrinths influ-
presence of a “third window” in the bony laby- ence spinal cord motoneurons through the lat-
rinth (see Fig. 16–3 in Chapter 16). In the case eral vestibulospinal tract, the reticulospinal
of endolymphatic hydrops (idiopathic or sec- tract, and the descending medial longitudinal
ondary to infection), fibrous adhesions between fasciculus (MLF). Labyrinthine stimulation of
the medial surface of the stapedial footplate the spinal cord increases extensor tone and
and the membranous labyrinth could result in decreases flexor tone, resulting in a facilitation
displacement of endolymph when the footplate of the antigravity muscles. Both otolith and
moves.3 This sign can occasionally be elicited semicircular canal signals influence spinal cord
during routine pneumatoscopy in normal sub- anterior horn cells, but the former are more
jects. In these cases it is usually present bilater- important in maintaining posture.
ally. The mechanism by which pressure changes
in the external auditory canal result in a pres-
sure gradient across a normal vestibular recep-
tor organs is unclear. Pastpointing
Fistulas of the labyrinth can also be tested
for by inducing pressure changes by pressing Pastpointing refers to a reactive deviation of
and releasing the tragus (induces less pressure the extremities caused by an imbalance in the
changes in the external canal than pneumatos- vestibular system (Fig. 6–2). The test is per-
copy), Valsalva maneuver against closed glottis formed by having patients place their extended
(increases intracranial pressure which can be index finger on that of the examiner’s, close
transmitted to the inner ear by an intracranial their eyes, raise the extended arm and index
fistula such as superior canal dehiscence), and finger to a vertical position, and attempt to
Valsalva maneuver against pinched nostrils return the index finger to the examiner’s.
(increases pressure transmitted to the middle Consistent deviation to one side is pastpointing
ear via the Eustachian tube).4 (See Video 6–1).
Past
Pointing
2 Test Romberg Test
Tandem Walking
3
1
Figure 6–2. Bedside tests of vestibulospinal function.

Pastpointing tests represent one of the earli- importance of vestibular influences in main-
est attempts to clinically assess vestibular func- taining the Romberg position (Fig. 6–2). As
tion. In 1910, Bárány5 published a review of with pastpointing, he noted that patients with
pointing deviation and emphasized the impor- acute unilateral labyrinthine lesions swayed
tance of having patients sit with their eyes and fell toward the diseased side, that is, in the
closed to avoid confusion with other orienting direction of the slow component of nystagmus.
information. Bárány showed that caloric stimu- However, like the pastpointing test, the
lation consistently induced pastpointing in the Romberg test was found to be rather insensi-
direction of the slow component of induced tive for detecting chronic unilateral vestibular
nystagmus. Cold caloric irrigation (inhibiting impairment, and sometimes the patient would
the horizontal ampullary nerves’ spontaneous fall toward the intact ear. The so-called sharp-
firing rate) resulted in pastpointing toward the ened Romberg test is a more sensitive indica-
irrigated ear, and warm caloric irrigation tor of vestibular impairment. For this test the
induced the opposite effect. As expected, patient stands with feet aligned in the tandem
patients with acute unilateral loss of vestibular heel-to-toe position with eyes closed and arms
function past-pointed toward the damaged folded against the chest. Most normal subjects
side. Bárány and numerous others emphasized under the age of 70 can stand in this position
that repeated testing shows a large variability, for 30 sec: older normal subjects and patients
occasionally with drift in the wrong direction. with unilateral or bilateral vestibular impair-
Subsequent investigators tried to improve test ment usually cannot sustain the position.
accuracy by eliminating tactile feedback and Abnormalities on this test, however, are not
using small finger lamps that could be photo- specific to the vestibular system.
graphed, but the large variability among nor- Although lower mammals consistently
mal subjects and patients remained. develop ipsilateral hypotonia of extensor mus-
It is apparent that results from a single point- cles after labyrinthectomy, one rarely finds this
ing test can be misleading and should not be in human patients. Occasionally, slight asym-
considered clinically relevant when in isolation. metry in posture is found with the ipsilateral
Extralabyrinthine influences should be elimi- upper extremity slightly flexed and abducted
nated as much as possible by having the patient compared to the contralateral upper extremity.
seated with eyes covered and arms and index The clinically elicited deep tendon reflexes
fingers extended throughout the test. The are also unaffected by vestibular lesions.
standard finger-to-nose test will not identify Apparently, other supraspinal influences on
pastpointing, inasmuch as joint and muscle the anterior horn cells rapidly compensate for
proprioceptive signals permit accurate localiza- the loss of tonic vestibular signals.
tion even when vestibular tone is asymmetric.
Although patients with acute peripheral ves-
tibular damage usually past-point toward the Walking Tests
side of loss, compensation rapidly corrects the
pastpointing and can even produce a drift to Unterberger8 was the first to systematically
the other side. The cortical and subcortical study the tendency of vestibular stimulation or
pathways to the spinal anterior horn cells, illus- unilateral vestibular lesions to induce blind-
trated in Figure 1–14 in Chapter 1, apparently folded subjects to turn in the earth’s vertical
account for the compensation. axis when walking. The direction of turning
coincided with the direction of pastpointing
and falling (in the direction of the slow compo-
Static Posture nent of nystagmus). Fukuda9 obtained similar
results by having subjects take 50 to 100 steps
Patients with damage to the vestibular system on the same spot and recording the angle of
often suffer instability of the trunk and lower rotation as well as forward and backward move-
limbs so that they sway back and forth or even ments. Both of these tests were performed with
fall to one side. In 1846, Romberg6 noted that arms extended parallel and horizontal in front
patients with proprioceptive loss from tabes of the subject, so upper extremity deviation
dorsalis were unable to stand with feet together (pastpointing) may have added to the tendency
and eyes closed. Bárány7 first emphasized the to rotate in a given direction. Tandem gait tests
(Fig. 6–2) are widely used as part of the routine eye movements in a comatose patient is usually
neurologic examination, and most clinicians an ominous sign, indicating massive brain stem
recognize normal and abnormal performances. damage if acute drug intoxication or metabolic
When performed with eyes open, tandem walk- disorders can be ruled out.13,14
ing is primarily a test of cerebellar function, The doll’s eye test can also provide highly
because vision compensates for chronic localizing information. For example, if the test
vestibular and proprioceptive deficits. Acute results in disconjugate eye movements, then
vestibular lesions, however, typically impair one could localize the lesion to MLF, the ocul-
tandem walking, even with the eyes open. omotor neurons, or the ocular muscles (depend-
Recently, there has been an emphasis on ing on the abnormal pattern).
timed walking tests to provide a semiquantita-
tive measure of balance and risk of falling in
older patients. These tests are not specific for Head-Thrust Test
vestibular function but rather provide an over-
all measure of gait and balance. Gait speed The head-thrust test is a simple way to identify
(over a set path), timed tandem stance and a complete unilateral or bilateral loss of ves-
walking, and maximum step length (ability to tibular function at the bedside.15 The discovery
maximally step out and return to the initial of this test was a major breakthrough in the
position) have all been shown to predict the ability to examine the vestibular system at the
likelihood of falls in older people.10,11 bedside. Prior to the head-thrust test, the bed-
side assessment was mostly limited to search-
ing for surrogate signs of an acute vestibular
imbalance (i.e., nystagmus). Tests such as past-
pointing, the Unterberger test, and the doll’s
TESTS OF VESTIBULO-OCULAR eye test could be used, but these had major
REFLEXES limitations as noted previously.
The head-thrust test is used to directly assess
Doll’s Eye Test (Oculocephalic for vestibular de-afferentation and thus is anal-
Response) ogous to the test for an afferent pupillary defect
(i.e., the swinging light test). Though the affer-
The doll’s eye test involves slowly moving the ent pupillary defect was first reported around
head back and forth in the horizontal plan to 1900,16 the head-thrust test was not reported
induce reflex eye movements. In an alert until 1988.15 Despite the consensus opinion
human these eye movements result from com- among neurotologists regarding the substantial
bined visual and vestibular stimulation. value of the head-thrust test, it remains a test
Therefore, a patient with complete loss of ves- that is underappreciated and underutilized in
tibular function will have compensatory eye the general medical community.
movements on the test if the visuomotor sys- The head-thrust test is performed by grasp-
tem is intact. On the other hand, an alert human ing the patient’s head and applying brief, small-
can also use the visuomotor system (i.e., the amplitude, high-acceleration head thrusts, first
smooth pursuit system) to overcome or sup- to one side and then to the other (Fig. 6–3, See
press the vestibular eye movement in this test Video 6–2 and Video 6–3). Before the move-
that uses slow passive movements of the head. ment, the patient is instructed to fixate on the
In a comatose patient, however, the doll’s examiner’s nose. During and after the quick
eye test is a useful bedside test of the vestibulo- movements, the examiner closely watches the
ocular reflex since the pursuit system is not patient’s eye position looking specifically for
functioning.12 Conjugate compensatory eye “catch-up” saccades, which are the sign of an
movements indicate normally functioning inappropriate compensatory vestibular system
vestibulo-ocular pathways (those shown in response. If the vestibular system is intact on
Fig. 3–8 in Chapter 3). This test is a standard both sides, then movement to either side trig-
component of the coma exam and also brain gers the eye movements (the eye movements
death exam because the reflex eye movements are triggered by a reflex, the vestibulo-ocular
indicate intact function not only of the inner reflex) that keep the patient’s eyes fixated on
ear but also the brain stem. Absence of reflex the examiner’s nose. On the other hand, if a
(a) 20°
Line of Eyes remain

sight fixed on target
Fixed
target
(b) 20°
Line of Line of sight Quick saccade

sight moves back to target
with head
Fixed movement
target
Figure 6–3. The head thrust test. The head thrust test is a test of vestibular function that can be easily done during the
bedside examination. This maneuver tests the vestibulo-ocular reflex (VOR). The patient sits in front of the examiner and
the examiner holds the patient’s head steady in the midline. The patient is instructed to maintain gaze on the nose of the
examiner. The examiner then quickly turns the patients head about 10-15 degrees to one side and observes the ability of
the patient to keep the eyes locked on the examiner’s nose. If the patient’s eyes stay locked on the examiner’s nose (i.e., no
corrective saccade) (picture a), then the peripheral vestibular system is assumed to be intact. If, however, the patient’s
eyes move with the head (picture b) and then the patient makes a voluntary eye movement back to the examiner’s nose (i.e.,
corrective saccade), then this indicates a lesion of the peripheral vestibular system and not the central nervous
system. Thus, when a patient presents with the acute vestibular syndrome, the test result shown in picture A would suggest
a CNS lesion (because the VOR is intact), whereas the test result in picture B would suggest a peripheral vestibular lesion
(because the VOR is not intact).
With permission from: Edlow JA, Newman-Toker DE, Savitz SI. Lancet Neurology. 2008; 7:951–964.
vestibular lesion is present, then the movement the vestibular system at a very low acceleration.
in the direction of the lesion results in the eyes Furthermore, the caloric test, though generally
moving with the patient’s head (because the regarded as the gold standard test for a unilat-
reflex is not working to move the eyes in the eral vestibular lesion, is known to have con-
opposite direction). Thus, if a patient has a right cerning levels of false-positive results based on
vestibular lesion, then after a head thrust to the the limitations of the test and thus is not an
right, the patient’s eyes will move with the head optimal gold standard test.20
(stay in midline position), and then the patient The head-thrust test is nearly always positive
will have to make a voluntary saccade (“catch- in patients with acute vestibular neuritis
up” or “corrective” saccade) back to the exam- because the lesion is of the vestibular nerve
iner’s nose. and is typically at least a moderate to severe
The passive head movement is fast enough lesion.21,22 For this reason, the head thrust is
(high enough acceleration) that the smooth particularly valuable in the presentation of the
pursuit system cannot be used to keep the acute vestibular syndrome because a positive
patient’s eyes fixated on the examiner’s nose head-thrust test is a very strong indicator of a
(recall how the smooth pursuit system can cover lesion of the vestibular nerve (and thus the
up for vestibular impairment with the low- most common cause, vestibular neuritis). A
velocity and low-frequency movements of the negative head-thrust test in the acute vestibu-
doll’s eye test). In addition, the patient also can- lar syndrome suggests the vestibular nerve is
not initiate a voluntary saccade fast enough to intact and thus the likelihood of a a brainstem
keep the eye’s on the nose and for this reason a or cerebellar lesion increases.21,22
“catch-up” saccade is required to move the eye The head-thrust test is also particularly help-
back to the nose. Of course, if a patient can cor- ful for identifying a bilateral vestibulopathy. A
rectly predict the direction of the head move- bilateral vestibulopathy can be difficult to rec-
ment and then time the initiation of a saccade ognize based on the symptom report and gen-
accurately, then a voluntary saccade can come eral examination. As a result, many patients
very close to covering up for a vestibular lesion. likely go undiagnosed. However, a positive
In the same way that the afferent pupillary bilateral head-thrust test can clinch the diagno-
defect is mostly a test of the optic nerve func- sis at the bedside.
tion, the head-thrust test is mostly a test of the
vestibular nerve function. Intact end-organ
(e.g., labyrinthine) function is of course Dynamic Visual Acuity
required to generate the vestibulo-ocular reflex
but a disorder of the end-organ may not result The dynamic visual acuity test is performed by
in a positive test unless it is severe or complete. having the patient shake the head rapidly back
Similarly, retinal lesions, unless severe, do not and forth in the horizontal plane at approxi-
typically result in an afferent pupillary defect. mately 2 Hz while reading a Snellen visual acu-
For this reason, the head-thrust test is typically ity chart at the standard distance.23,24 Inasmuch
not positive in patients with Meniere’s disease as the smooth pursuit system functions best
unless a procedural lesion has been per- below 1 Hz and almost not at all at 2 Hz, this is
formed.17 In addition, the accuracy of the head- primarily a test of the horizontal vestibulo-
thrust test is also influenced by the severity of ocular reflex. A drop in acuity of more than one
the nerve lesion. For example, the head-thrust line on the Snellen chart suggests an abnormal
test may not be positive if the vestibular nerve vestibulo-ocular reflex. The test is most useful
lesion is only mild to moderate in severity (i.e., for identifying bilateral vestibular loss but can
resulting in approximately less than a 50% also be abnormal with unilateral vestibular loss
paresis) but is nearly always positive with and with cerebellar lesions.25,26
lesions that are moderate to severe.18,19 It is not
completely fair to gauge the value of the quali-
tative positive versus negative results of the Cold Caloric Test
head-thrust test to the quantitative results of
the caloric test. The reason is because the head Because of its ready availability, ice water
thrust is a test of the vestibular system at high (approximately 0°C) is commonly used for
acceleration, whereas the caloric test is a test of bedside caloric testing.27 Tap water can be
brought to 4°C in about 10 minutes after add- was large. Much of this variability could be
ing ice cubes. To bring the horizontal canal traced to the difficulty in manually maintaining
into the vertical plane, the patient lies in the constant velocity and then a uniform sudden
supine position with the head tilted 30 degrees deceleration. Furthermore, the vestibular
forward or in the sitting position with the head response to the initial acceleration was often
tilted 60 degrees backward (see Fig. 1–4C in not completed before deceleration began,
Chapter 1). Infusion of ice water induces a resulting in interaction between the two
burst of nystagmus with slow phase toward the responses. As with the ice water caloric testing,
side of infusion and the fast phase in the oppo- this type of qualitative testing can provide only
site direction, usually lasting from 1 to 3 min. gross information about the presence and sym-
The volume of ice water recommended for this metry of vestibular function, and thus it is not
test varies from 0.5 to 2 ml. Regardless of the felt to be as valuable as the head-thrust test.
volume used, however, it is critical that the One aspect of rotational testing that is useful at
stimulus reach the eardrum (i.e., not be injected the bedside is the fixation-suppression test.
into the canal wall or in a canal blocked by With this test the subject extends the arm rig-
cerumen). Direct visualization of the eardrum idly and attempts to fixate on the extended
is mandatory. We suggest using 1 or 2 ml of ice thumb while the entire body is rotated back and
water infused directly against the tympanic forth en bloc. Normal subjects can completely
membrane through a small rubber hose. The suppress their vestibulo-ocular reflex, keeping
ear being infused is turned upward for approx- their eyes fixed in the center of the orbits (as
imately 30 sec after the infusion to be certain shown in Fig. 1–9 in Chapter 1). Abnormal
that the water stays against the drum. In an fixation-suppression (nystagmus) indicates
alert subject, a burst of nystagmus will develop impairment of the smooth pursuit systems and
within 30 sec to 1 min after infusion and last thus is an indicator of a central lesion, often
from 1 to 3 min. In a comatose patient, only a involving the cerebellum (see “Visual-Vestibular
slow tonic deviation toward the side of stimula- Interaction” in Chapter 7).
tion is observed because the brain does not
generate the fast phases. In normal subjects,
duration and speed of induced nystagmus var-
ies greatly, but >20% asymmetry in nystagmus TESTS FOR PATHOLOGIC
duration suggests the possibility of a lesion on NYSTAGMUS
the side of the decreased response, though this
test is less valid than standard bithermal caloric Nystagmus can be defined as a nonvoluntary
testing with nystagmography (see Bithermal rhythmic oscillation of the eyes. It usually has
Caloric Test in Chapter 7). clearly defined fast and slow components alter-
In terms of the bedside vestibular evaluation nating in opposite directions. By convention,
in an alert subject, the use of the cold caloric the direction of the fast component defines the
test has largely been replaced by the head- direction of nystagmus (e.g., left-beating nys-
thrust test. tagmus indicates the fast phase is to the left).
Physiologic nystagmus refers to nystagmus that
occurs in normal subjects, whereas pathologic
Rotational Testing nystagmus implies an underlying abnormality
(Table 6–1). Spontaneous nystagmus refers to
Qualitative rotational testing of the horizontal nystagmus that occurs with the eyes in the pri-
vestibulo-ocular reflex can be performed at the mary position, without external stimulation
bedside by using a swivel chair. Bárány7 intro-
duced a rotatory test in which the chair on which Table 6–1 Types of Nystagmus
the patient was seated was manually rotated 10
times in 20 sec and then suddenly stopped with Physiologic Pathologic
the patient facing the observer. The duration of
Rotational-induced Spontaneous
postrotatory nystagmus in each direction was
Caloric induced Gaze-evoked
then measured. In normal subjects an average
Optokinetic Positional
of 22 sec was required for cessation of postrota-
End-point
tory nystagmus, but intersubject variability
such as movement of the head or surroundings. spontaneous nystagmus. While the fundus of
Gaze-evoked nystagmus is induced by changes one eye is being visualized the patient is asked
in gaze position. Nystagmus that is not present to lightly cover the other eye with one hand.
in the sitting position but is present in some Nystagmus appears as a slow drift of the retina
other head and body position is called posi- in one direction interrupted by flicking move-
tional nystagmus. This definition excludes nys- ments in the opposite direction (the direction
tagmus present in the sitting position that is of the nystagmus is reversed, inasmuch as one
modified by a change in position. is visualizing the back pole of the eye).
Alternatively, one can simply shine a penlight
in one eye while intermittently occluding the
Methods of Examination other eye.28 In some cases, simply holding a
blank sheet of paper in front of the patient’s
The clinical examination for pathologic nystag- vision and asking the patient to stare through it
mus should include a systematic study of is enough to bring out the spontaneous nystag-
changes in (1) fixation, (2) eye position, and (3) mus. When this is done, the examiner has to
head position. Omission of any of these three look at the patient’s eyes from the side.
maneuvers may lead to overlooking the pres- Occasionally, nystagmus can be seen even
ence of nystagmus or misinterpreting its type. through closed lids. This can be misleading,
Sometimes pathologic nystagmus can be trig- however, because lid-twitch movements often
gered by vibration, head shaking, or hyperven- mimic nystagmus.
tilation. The effect of change in eye position is evalu-
Spontaneous nystagmus may be present with ated by having the patient fixate on a target 30
fixation, or it may occur only when fixation is degrees to the right, left, up, and down. Because
inhibited (See Video 6–4). There are several horizontal eye deviation beyond 40 degrees
simple methods for achieving the latter at the may result in a low-amplitude, high-frequency
bedside. Frenzel glasses consist of +30 lenses torsional nystagmus in normal subjects (so-
mounted in a frame that contains a light source called end-point or end-gaze nystagmus),
on the inside so that the patient’s eyes are eas- extreme eye positions should be avoided. Each
ily visualized (Fig. 6–4). The light can be pow- eye position is held for at least 20 sec. First-
ered by a battery, making the entire system degree nystagmus refers to nystagmus that is
portable. Frenzel glasses should be used present only on gaze in the direction of the fast
only in a darkened room, because the patient component. Second-degree nystagmus is pres-
can fixate (at least partially) through the lenses ent in the midposition (primary position) and
in a lighted room. An ophthalmoscope can on gaze in the direction of the fast component,
also be used to block fixation and bring out a and third-degree nystagmus is present even on
Figure 6–4. Frenzel glasses.

Peripheral Spontaneous Symmetric Gaze-evoked
Congenital Spontaneous Downbeat Spontaneous

Figure 6–5. Method for describing the effect of eye position on nystagmus amplitude and direction. Arrows indicate direc-
tion of nystagmus (direction of fast component) in each eye position.
gaze away from the fast component. These patient shake the head back and forth in the
terms are not applicable to all varieties of nys- horizontal and vertical planes for approximately
tagmus and, therefore, can lead to confusion. A 10 cycles. For hyperventilation-induced nys-
simple description can be rapidly summarized tagmus, the patient breathes rapidly in and out
with a box diagram as illustrated in Figure 6–5. for about a minute and a half.
The size, shape, and direction of the arrows
provide information about the amplitude and
direction of the fast component of nystagmus
in each eye position. TYPES OF PATHOLOGIC
Routinely, two types of positional testing are NYSTAGMUS
used: slow and rapid. With the first, the patient
slowly moves into the supine, right lateral, and Spontaneous Nystagmus
left lateral positions. Positional nystagmus
MECHANISM
induced by slow positioning is persistent, low
in frequency, and often present only when fixa- Spontaneous nystagmus results from an imbal-
tion is inhibited. Paroxysmal positional nystag- ance of tonic signals arriving at the oculomotor
mus, however, is induced by a rapid change neurons. Because the vestibular system is the
from the erect sitting to the supine head- main source of oculomotor tonus, it is the driv-
hanging left (left Dix-Hallpike test), center, or ing force of most types of spontaneous nystag-
right position (right Dix-Hallpike test) or from mus (tonic signals arising in the pursuit and
the supine to head-right or head-left position optokinetic systems may also play a role, par-
(supine positional testing). It is initially high ticularly with congenital nystagmus).29 A ves-
frequency but rapidly dissipates within 30 sec tibular imbalance results in a constant drift of
to 1 min (see Chapter 10). the eyes in one direction (slow phase) inter-
For vibration-induced nystagmus, a hand- rupted by fast components in the opposite
held vibrator (approximately 100 Hz) is placed direction. If the imbalance results from a
on the mastoid and suboccipital bones on each peripheral vestibular lesion, patients can use
side for 10 to 15 seconds. The test for head- their pursuit system to cancel it. If it results
shaking nystagmus is performed by having the from a central vestibular lesion, their pursuit
Table 6–2 Differentiation between Spontaneous Nystagmus of Peripheral and

Central Origin
Appearance Fixation Gaze Mechanism Localization
Peripheral Combined Inhibited Unidirectional Asymmetric loss Labyrinthine
horizontal, (Alexander’s of peripheral or vestibular
torsional law) vestibular tone nerve
Central Often pure Usually May change Imbalance in central CNS, usually
vertical, little direction oculomotor tone; brain stem or
horizontal, effect usually central cerebellum
or torsional vestibular, may be
pursuit or OKN
CNS, central nervous system; OKN, optokinetic nystagmus
system usually cannot suppress it (because cen- CENTRAL SPONTANEOUS NYSTAGMUS

tral vestibular and pursuit pathways are highly
Central spontaneous nystagmus is usually
integrated; see “Visual–Vestibular Interaction”
prominent with and without fixation. It may be
in Chapter 3). The features that separate
purely vertical, horizontal, or torsional, or have
peripheral from central varieties of spontane-
some combination of torsional and linear
ous nystagmus are summarized in Table 6–2.
components (See Video Video 6–7 and Video
6–8). As with peripheral spontaneous nystag-
mus, gaze in the direction of the fast compo-
PERIPHERAL SPONTANEOUS
nent usually increases nystagmus frequency
NYSTAGMUS
and amplitude, but unlike peripheral sponta-
Lesions of the peripheral vestibular system neous nystagmus, gaze away from the direction
(labyrinth or eighth nerve) typically interrupt of the fast component will often change the
tonic afferent signals originating from all direction of the nystagmus (i.e., direction
of the receptors of one labyrinth so that the changing nystagmus). There is typically a null
resulting nystagmus has combined torsional, region several degrees off center in the direc-
horizontal, and vertical components. The hori- tion opposite that of the fast component where
zontal component dominates, because the nystagmus is minimal or absent. Gaze beyond
tonic activity from the intact vertical canals this null region results in reversal of nystagmus
and otoliths partially cancels out. Gaze in the direction. The slow phase of central spontane-
direction of the fast component increases the ous nystagmus may be linear, exponentially
frequency and amplitude, whereas gaze in increasing, or exponentially decreasing.31
the opposite direction decreases the frequency With spontaneous downbeat nystagmus the
and amplitude (Alexander’s law) (See Video 6–4, vertical amplitude increases with horizontal
Video 6–5, and Video 6–6).30 Peripheral spon- gaze deviation.32 Downward gaze also increases
taneous nystagmus is “unidirectional” meaning the amplitude in about two-thirds of cases, but
that the primary direction does not change. in the other one-third it decreases it. Upward
Thus, if the primary position nystagmus is gaze may reverse the direction to upbeat.
right-beating, then it will not change to left- Downbeat nystagmus has been produced in
beating nystagmus even on left gaze. The slow monkeys after lesions of the uvula and floccu-
phase is linear, resulting in a saw-toothed wave- lonodular lobes of the cerebellum.33 In the
form. As noted previously, peripheral sponta- human it is localizing to the cervicomedullary
neous nystagmus is strongly inhibited by junction (which includes the midline cerebel-
fixation. Unless the patient is seen within a few lar regions). Common causes of downbeat
days of the acute episode, spontaneous nystag- nystagmus include cerebellar atrophy, verte-
mus will not be present when fixation is brobasilar ischemia, multiple sclerosis, and
permitted. Arnold-Chiari malformation.34,35 The latter
produces downbeat nystagmus, presumably by nystagmus, occurs only when either eye is
pressure on the flocculonodular region of the covered, permitting monocular fixation. The
cerebellum; in some cases it may be reversed resulting nystagmus beats toward the fixating
by decompression of the foramen magnum eye. Latent congenital nystagmus is usually
region.36 Spontaneous upbeat nystagmus usu- associated with other congenital ocular defects
ally results from lesions of the dorsal central such as concomitant squint and alternating
medulla in the region of the medial vestibular hyperphoria.42
and prepositus hypoglossi nuclei.35,37 Common Several characteristic clinical features help
causes include infarction, infiltrating tumors, distinguish congenital from acquired spontane-
and multiple sclerosis. Pure torsional sponta- ous nystagmus. It is usually purely horizontal
neous nystagmus is frequently associated with and may diminish or disappear with conver-
syringomyelia and syringobulbia. A high- gence. The waveform may be pendular to saw-
frequency, small-amplitude pendular sponta- tooth shaped, with many variations in between.43
neous nystagmus is commonly seen in the Different waveforms occur in the same patient
late stages of multiple sclerosis.38 This pendular in different eye positions. Gaze in the direction
nystagmus converts to a sawtooth pattern of the fast component converts a pendular nys-
on lateral gaze to either side. Lesions involving tagmus to a jerk nystagmus; often there is a null
the vestibular nuclear region can produce region where the nystagmus is minimal. Several
a horizontal torsional nystagmus similar to different waveforms may be seen in members
that seen with peripheral lesions, but, unlike of the same family with congenital nystagmus.
the latter, the direction of nystagmus does The frequency of congenital nystagmus is
not reliably indicate the side of lesion and usually >2 beats/sec and at times reaches 5 to
the nystagmus persists with fixation because 6 beats/sec. Nystagmus of this high frequency
of damage of visual–vestibular interaction is unusual other than on a congenital basis. Of
pathways.39 course, most patients are aware that the nystag-
Central spontaneous nystagmus has gener- mus has been present since infancy.
ally been attributed to an imbalance in either The pathophysiologic mechanism of congen-
central vestibulo-ocular or smooth pursuit ital nystagmus is only partially understood.31
pathways.32 Horizontal and vertical pathways Convincing evidence exists that the slow com-
are usually separate so that lesions can component causes the target to slip from the fovea,
monly lead to pure horizontal or pure vertical and the fast component brings the target back
nystagmus. Often central spontaneous nystag- to the fovea. The slow component is not the
mus is altered by position change, suggesting result of, but the cause of, decreased vision.
that peripheral otolith input can alter the cen- Maneuvers designed to decrease the target
tral imbalance. Marti and colleagues suggested slippage (fitting glasses with prisms and extraoc-
that downbeat nystagmus results from damage ular muscle surgery) improve visual acuity.
to the inhibitory vertical gaze-velocity sensitive Patients with congenital nystagmus can make
Purkinje cells in the cerebellar flocculus.40 normal-velocity saccades, indicating that the
These neurons have spontaneous activity and extraocular muscles and orbital mechanics are
most exhibit downward on-directions. Loss of normal. The vestibular system also appears
these vertical flocculus Purkinje cells would to be normal in most of these patients.
lead to disinhibition of their brainstem target Abnormalities in smooth pursuit and optoki-
neurons and spontaneous upward drift (i.e., netic slow phases are uniformly present, but it
downbeat nystagmus). is difficult to know whether these abnormalities
are due to a superimposition of the spontane-
ous nystagmus on attempted tracking eye
CONGENITAL NYSTAGMUS
movements or to an underlying abnormality.44
Congenital spontaneous nystagmus is almost Recently mutations have been identified in two
always highly dependent on fixation, disappear- genes associated with X-linked congenital nys-
ing or decreasing with loss of fixation.41 In some tagmus: FRMD7 causing X-linked idiopathic
instances a slow nystagmus in the reverse direc- congenital nystagmus and GPR143 causing
tion occurs when fixation is inhibited. One X-linked ocular albinism and congenital nystag-
common variety, so-called latent congenital mus.45,46 Characterizing these genes and other
congenital nystagmus genes should provide from the primary position (See Video 6–9,
insight into the pathophysiological mechanism Video 6–10, and Video 6–11). The eyes drift
of these poorly understood disorders.47 back toward the center with an exponentially
decreasing wave form; corrective saccades (fast
PERIODIC ALTERNATING NYSTAGMUS components) constantly reset the desired gaze
position. Gaze-evoked nystagmus is therefore
Periodic alternating nystagmus (PAN) is a always in the direction of gaze. The site of
spontaneous nystagmus that periodically abnormality can be anywhere from the neuro-
changes direction without a change in eye or muscular junction to the multiple brain centers
head position.48 Cycle length varies between 1 controlling conjugate gaze (Table 6–3).
and 6 min, with null periods between each half Dysfunction of the oculomotor integrator (see
cycle varying from 2 to 20 sec. The nystagmus Chapter 3) may be a common mechanism for
slowly builds in intensity and reaches a peak several types of gaze-evoked nystagmus.
slow component velocity near the center of
each half cycle before slowly decreasing. This
SYMMETRIC
type of nystagmus has been reported in associ-
ation with such varied conditions as encephali- Symmetric gaze-evoked nystagmus (equal
tis, brainstem ischemia, demyelinating disease, amplitude to the left and right) is most com-
syringobulbia, syphilis, and trauma and as a monly produced by ingestion of drugs such as
congenital disorder. Unlike patients with other phenobarbital, phenytoin, alcohol, and diaze-
forms of congenital nystagmus, patients with pam. With these agents, high-frequency, small-
congenital PAN frequently complain of oscil- amplitude nystagmus (<2 degrees) is found in
lopsia because they are unable to adapt to the all directions of gaze. A rough correlation exists
constantly changing direction of nystagmus. It between nystagmus amplitude and blood drug
is usually present with fixation, although cases level.52,53 The nystagmus initially appears
have been reported in which PAN occurs only at extreme horizontal gaze positions and
with loss of fixation. moves toward the midposition with higher
Necropsy studies from three patients with drug levels. In addition to its association
acquired PAN showed diffuse brainstem with drug ingestion, symmetric gaze-evoked
involvement, with a predilection for the caudal nystagmus commonly occurs in patients with
brain stem.49 Reported cases have been associ- myasthenia gravis, multiple sclerosis, and cere-
ated with downbeat nystagmus, further sug- bellar atrophy.
gesting caudal brainstem dysfunction. The
pathophysiologic mechanism for production of
PAN is unknown. The PAN cycles can be
altered in both phase and magnitude by a ves- Table 6–3 Causes of Gaze-Evoked
tibular stimulus (rotatory or caloric), suggest- Nystagmus
ing that the PAN rhythm is not the result of an
independent central nervous system (CNS) Localization Common
pacemaker but, rather, a response pattern of Causes
the central vestibulo-ocular reflex arc.50 It is
important to recognize this unusual form of Symmetric Nonlocalizing or Drugs,
cerebellum metabolic
spontaneous nystagmus because the acquired disorders
variety is markedly diminished by baclofen, a Asymmetric Unilateral brain stem Tumor,
gamma-amino butyric acid (GABA) agonist.51 and/or cerebellum infarction
Unfortunately, congenital PAN does not Rebound Cerebellum Tumor,
respond to baclofen. infarction,
atrophy
Dissociated MLF, extraocular Multiple
Gaze-Evoked Nystagmus nerve, or muscle sclerosis,
MECHANISM myasthenia
gravis
Patients with gaze-evoked nystagmus are unable
to maintain stable conjugate eye deviation away MLF, medial longitudinal fasciculus.
ASYMMETRIC bilateral or unilateral, depending on the extent

of MLF involvement. Bilateral MLF nystag-
Asymmetric horizontal gaze-evoked nystagmus
mus is most commonly seen with demyelinat-
always indicates a structural brain lesion. When
ing disease, whereas unilateral MLF nystagmus
it is caused by a focal lesion of the brain stem or
most often accompanies vascular disease of the
cerebellum, the larger amplitude nystagmus is
brain stem.58 Patients with myasthenia gravis
usually directed toward the side of the lesion.
develop dissociated gaze-evoked nystagmus
Large cerebellopontine angle tumors com-
similar to MLF nystagmus (pseudo-MLF nys-
monly produce asymmetric gaze-evoked nys-
tagmus) because of unequal impairment of
tagmus from compression of the brain stem
neuromuscular transmission in adducting and
and cerebellum (Bruns’ nystagmus). Some
abducting muscles. Unlike MLF nystagmus,
patients with large acoustic neuromas develop
the dissociated nystagmus with myasthenia
a combination of asymmetric gaze-evoked nys-
progressively increases in amplitude as the gaze
tagmus from brainstem compression and
position is maintained.59
peripheral spontaneous nystagmus from eighth
nerve damage.54,55 Asymmetric gaze-evoked
nystagmus may be present during the recovery
from gaze paralysis (either cortical or subcorti-
Positional Nystagmus
MECHANISM
cal in origin), in which case it is large in ampli-
tude and low in frequency and present only Beginning with Bárány, positional nystagmus
in one direction of gaze (the direction of the was attributed to lesions of the otoliths and
previous gaze paralysis). their connections in the vestibular nuclei and
cerebellum, as these are the receptors that are
REBOUND sensitive to changes in the direction of grav-
ity.5,60 Subsequently, other mechanisms for the
Rebound nystagmus is a type of gaze-evoked production of positional nystagmus have been
nystagmus that either disappears or reverses identified, forcing reexamination of these tra-
direction as the lateral gaze position is held. ditional concepts. If a semicircular canal cupula
When the eyes return to the primary position, is altered so that its specific gravity no longer
another burst of nystagmus occurs in the direc- equals that of the surrounding endolymph or if
tion of the return saccade. Thus, the patient debris inappropriately enters a semicircular
may have a transient primary position nystag- canal, the canal becomes sensitive to changes
mus in either direction. Rebound nystagmus in the direction of gravity and can produce
occurs in patients with cerebellar atrophy and positional nystagmus (see Causes of Benign
focal structural lesions of the cerebellum; it is Positional Vertigo in Chapters 10 and Alcohol
the only variety of nystagmus thought to be and Thiamine Defeciency in Chapter 17).
specific for cerebellar involvement.56 Traditional classifications of positional nys-
tagmus are often confusing and can be difficult
DISSOCIATED to apply in clinical practice. Some classifica-
tions have been based on clinical observations
Dissociated, or disconjugate, gaze-evoked nys- obtained while the patient is fixating, whereas
tagmus commonly results from lesions of the others have been based on electronystagmog-
medial longitudinal fasciculus (MLF), so-called raphy (ENG) recordings with eyes closed or
internuclear ophthalmoplegia. With early MLF with eyes open in darkness. Some investigators
lesions the eyes appear to move conjugately, use slow positioning maneuvers, but others
but the abducting eye on the side opposite the employ only rapid positioning. These different
MLF lesion develops a regular small-amplitude, methods make it difficult to compare classifica-
high-frequency nystagmus in the direction of tions. Nylen60 initially described three types of
gaze. With more extensive MLF lesions, the positional nystagmus based on visual inspec-
adducting eye lags behind and develops a low- tion of nystagmus direction and regularity.
amplitude nystagmus while the abducting eye Type I, direction changing, and type II, direc-
overshoots the target and develops large- tion fixed, remained constant as long as the
amplitude nystagmus that has a characteristic position was maintained. Type III was less
peaked waveform.57 A MLF nystagmus can be clearly defined, comprising all paroxysmal
varieties of positional nystagmus and some per- combined torsional (fast component toward
sistent varieties that did not fit into types I and the undermost ear) and vertical (fast compo-
II. Numerous modifications of Nylen’s original nent toward the forehead) components (See
classification have subsequently been pro- Video 6–12 and Video 6–13). Although infre-
posed, and the definition of each type has quent bilateral cases do occur, the nystagmus is
changed. Most investigators do agree that two usually prominent only in one head-hanging
broad categories of positional nystagmus can position, and a burst of nystagmus occurs in the
be identified: paroxysmal and persistent. reverse direction when the patient moves back
to the sitting position. Another key feature is
that the patient experiences severe vertigo with
PAROXYSMAL POSITIONAL
the initial positioning, but with repeated posi-
NYSTAGMUS (POSITIONING
tioning, vertigo and nystagmus rapidly disap-
NYSTAGMUS)
pear (fatigability). This type of paroxysmal
The most common type of paroxysmal posi- positional nystagmus is specific for the
tional nystagmus is induced by a rapid change posterior canal variant of canalithiasis (see
from erect sitting to the supine head-hanging Chapter 10). Horizontal canal variants also
left or right position (Dix-Hallpike test) (Fig. exist but are less common. They are induced by
6–6). It is initially high in frequency but turning the patient’s head to the side while the
dissipates rapidly. There is a 3- to 10-sec patient lies supine.
latency before onset and the nystagmus rarely Paroxysmal positional nystagmus can also
lasts longer than 30 sec.61,62 The nystagmus has result from brainstem and cerebellar lesions.
The central type does not decrease in ampli-
tude or duration with repeated positioning,
(a)
does not have a clear latency, and usually
lasts longer than 30 sec. The direction is unpre-
dictable and may be different in each position.
It is often purely vertical with fast phase
directed downward (i.e., toward the cheeks).
The presence or absence of associated vertigo
is not a reliable differential feature. Central
paroxysmal positional nystagmus can be the
initial presenting sign of a posterior fossa
tumor such as a medulloblastoma or cerebellar
glioma.63,64 It is therefore critical to distinguish
it from the benign peripheral variety (Table
6–4).
(b)
PERSISTENT POSITIONAL NYSTAGMUS
This type of positional nystagmus remains as
long as the position is held, although it may
fluctuate in frequency and amplitude. It may
be in the same direction in all positions or
change directions in different positions.
Direction-changing and direction-fixed static
positional nystagmus are most commonly asso-
ciated with peripheral vestibular disorders,
although both occur with central lesions.65
One variety of persistent direction-changing
positional nystagmus (apogeotropic) is thought
to result from otolithic debris attached to
Figure 6–6. Method for inducing paroxysmal positional
nystagmus (Dix-Hallpike maneuver). Patient is taken rap- the cupula or lodged in the ampulla of the
idly from sitting to head-hanging right (a) or head-hanging horizontal semicircular canal (see Chapter 10).66
left (b) position. As with spontaneous nystagmus, lack of
Table 6–4 Differentiation between Peripheral and Central Paroxysmal Positional

Nystagmus
Appearance Latency Duration Fatigability Mechanism Localization
Peripheral Torsional, upbeat, or Usual < 60 sec Usual Change in Labyrinth
horizontal geotropic cupula-specific
gravity
Central Pure vertical, often Unusual > 60 sec Unusual Damage to Brain stem or
downbeat central cerebellum
otolith-ocular
pathways
suppression with fixation and signs of associ- changes activate the canal (see Fig. 16–3B and
ated brainstem dysfunction suggest a central 3C in Chapter 16).
lesion.
Head-Shaking Nystagmus
CENTRAL POSITIONAL NYSTAGMUS
Positional nystagmus can also stem from a cen- Patients with a compensated vestibular imbal-
tral lesion. The most common pattern is a per- ance due to either peripheral or central lesions
sistent downbeating nystagmus. In fact, a may develop a transient nystagmus after vigor-
persistent downbeating positional nystagmus ous head shaking.70 With unilateral peripheral
may be the most prominent examination find- vestibular lesions, the abnormal side is in the
ing in a patient with a central lesion causing direction of the slow phase. With central ves-
dizziness symptoms. Typical causes include a tibular lesions, the direction of nystagmus is
genetic cerebellar ataxia syndrome or a struc- nonlocalizing. Sometimes vertical nystagmus is
tural lesion (e.g., Chiari malformation or induced by horizontal head shaking.71 The
tumor). Central positional nystagmus does not results of vertical head shaking are more diffi-
mimic the key characteristics of BPV from the cult to interpret because some normal subjects
posterior semicircular canal but can mimic the will have transient vertical nystagmus after ver-
positional nystagmus of BPV from the horizon- tical head shaking.
tal semicircular canal.
Hyperventilation-Induced
Vibration-Induced Nystagmus Nystagmus
Vibration applied to the mastoid can often Hyperventilation can induce a near-faint dizzi-
induce a typical peripheral vestibular nystag- ness in anyone, particularly in anxious patients,
mus in patients with compensated unilateral but hyperventilation-induced nystagmus is
vestibular lesions.67,68 With vestibular neuritis less common.72 Patients with compressive
the slow phase is nearly always directed toward lesions of the vestibular nerve, such as with
the lesion side but with Meniere’s syndrome it an acoustic neuroma or cholesteatoma, or with
can be directed to either side. Vibration may demyelination of the vestibular nerve root
activate hair cells in the inner ear although the entry zone, such as with multiple sclerosis,
exact mechanism for vibration induced nystag- may develop nystagmus after hyperventilation.
mus is poorly understood. In some cases of Presumably metabolic changes associated
anterior semicircular dehiscence syndrome with hyperventilation trigger the partially
vibration over the suboccipital cranium will damaged nerve to fire inappropriately. Hyper-
induce nystagmus in the plane of the anterior ventilation-induced nystagmus has also rarely
canal.69 In this case vibration activates the ante- been associated with labyrinthitis or perilymph
rior semicircular canal just as noise or pressure fistula.
OTHER OCULAR OSCILLATIONS sets in. Several siblings in the same family may
have the ability to produce voluntary ocular
Dissociated Spontaneous oscillations. Keyes79 reported two generations
of the same family who could produce the eye
Nystagmus movements, suggesting a dominant mode of
inheritance.
Several different lesions of the posterior fossa
can result in a spontaneous nystagmus with tor-
sional, horizontal, and vertical components Convergence Retraction Nystagmus
varying in each eye. The nystagmus is usually
synchronized, however, in that the fast compo- This dramatic ocular motor disorder results from
nent occurs at exactly the same time in both lesions involving the diencephalic midbrain
eyes. Tumors, vascular disease, and demyeli- junction. When the patient attempts to make
nating disease of the brain stem produce this voluntary upward saccades or when involuntary
form of dissociated nystagmus.73 Frequently upward saccades (fast components) are induced
the eye on the side of the lesion shows the larg- by an optokinetic or vestibular stimulus, the
est amplitude oscillation. Monocular nystag- patient develops co-contraction of all extraocu-
mus results from similar posterior fossa lesions; lar muscles and the eyes rhythmically retract
this unusual form of dissociated nystagmus also and converge.80 (See Video 6–14). In other cases
has been reported with such varied entities as convergence nystagmus occurs without retrac-
congenital syphilis, meningitis, optic nerve tion, apparently because of asynchronous
glioma, cerebral trauma, unilateral amblyopia, adducting saccades.81 Convergence retraction
and high refractive error.74,75 As expected, these nystagmus is usually associated with other signs
patients are typically bothered by severe of midbrain dysfunction (impaired upward gaze,
oscillopsia. pupillary abnormalities, accommodative spasm,
Seesaw nystagmus is an unusual type of dis- retraction of the lids, and skew deviation), con-
sociated nystagmus in which one eye rhythmi- stituting the dorsal midbrain syndrome. This
cally rises and intorts and the other eye falls syndrome is most frequently produced by dys-
and extorts. It may be congenital but most germinomas of the pineal region but is also asso-
often is produced by acquired lesions near the ciated with other tumors and vascular lesions
optic chiasm, particularly those producing a involving the tectal or pretectal area.
bitemporal field defect and decreased central
visual acuity.76 Lesions associated with seesaw
nystagmus include craniopharyngiomas, syrin- Saccadic Intrusions
gobulbia, brainstem infarction, and diffuse
choroiditis; compression of the midbrain teg- Included under this category are square wave
mentum may be the common denominator.24 jerks, macrosquare wave jerks, macrosaccadic
oscillations, ocular flutter, and opsoclonus. The
common feature is that unwanted saccades dis-
Voluntary Ocular Oscillations rupt steady fixation. Square wave jerks refer to
(Voluntary Nystagmus) small-amplitude involuntary saccades that take
the eyes off the target, followed after a normal
Some normal subjects are able to produce intersaccadic interval (∼200 msec) by a correc-
rapid oscillations of the eyes at will, apparently tive saccade bringing the eyes back to the tar-
by producing rapid sequenced saccades back get. Infrequent small square wave jerks can be
and forth.77 Some cases may overlap with con- seen in normal subjects, especially the young
genital nystagmus.78 The main significance of and elderly.82 Persistent large-amplitude square
these ocular gymnastics is that they may be wave jerks (1 to 5 degrees) are abnormal
mistaken for pathologic nystagmus. High in but nonlocalizing. They are prominent with
frequency (90 to as high as 1380 cycles/min) cerebellar lesions and with progressive supra-
and low in amplitude (2 to 5 degrees), these nuclear palsy and have been reported with dif-
rapid horizontal movements cannot be main- fuse cerebral lesions, Huntington’s disease,
tained for more than 20 to 30 sec before fatigue and schizophrenia.83,84 Macrosquare wave jerks
(10 to 50 degrees) have been observed in mul- that also produce absent reflex horizontal eye
tiple sclerosis and olivopontocerebellar atro- movements, but they have also been reported
phy. Macrosaccadic oscillations are typically with posterior fossa lesions that compress the
seen in patients with saccade overshoot dysme- pons and with metabolic encephalopathy.87
tria (i.e., those with cerebellar lesions). After Inverse ocular bobbing or ocular dipping refers
refixation, patients make a series of hypermet- to a slow downward movement of the eyes fol-
ric saccades, apparently because they are lowed by a rapid return to midposition. Reverse
unable to make a small enough saccade to bring bobbing consists of a rapid deviation of the eyes
the target onto the fovea. Ocular flutter refers upward followed by a slow return to the pri-
to a burst of to-and-fro horizontal saccades mary position. These latter phenomena may be
occurring either spontaneously or after a sac- variations of ocular bobbing because all can be
cade to a target (See Video 6–15). This burst of seen in the same subject at different times.88 As
saccades lacks the characteristic delay normally with typical ocular bobbing, they are usually
present between serial saccades. Ocular flutter seen with metabolic disorders or structural
is typically seen with diffuse involvement of lesions of the pons.
brainstem-cerebellar pathways, being particu-
larly prominent in such varied disorders as
Friedreich’s ataxia, brainstem encephalitis, and Palato-Ocular Myoclonus
paraneoplastic syndromes.
The most prominent saccadic oscillations are This is a rhythmic oscillation of the eyes associ-
seen with opsoclonus.85 With this rare eye ated with synchronous oscillation of the palate.
movement disorder, the eyes are constantly An associated rhythmic oscillation of die phar-
making random conjugate saccades of unequal ynx, larynx, mouth, tongue, diaphragm, extrem-
amplitude in all directions. As with ocular ities, and intercostal muscles may also occur.89
flutter, there is typically no intersaccade inter- The eye movements are typically pendular
val. The phenomenon occurs with several oscillations that are often vertical but may have
different types of CNS disease and probably a horizontal or torsional component. The fre-
represents a mixed group of eye movement quency varies from 1 to 3/sec, and the move-
disorders. The inappropriate saccades are ments may continue with loss of fixation. Ocular
most prominent immediately before or after myoclonus often disappears during sleep even
a refixation and are only slightly affected by though the palatal movements continue.
loss of fixation. One variety of opsoclonus prob- Palato-ocular myoclonus is seen in association
ably represents a continuum with square wave with lesions disrupting the connections between
jerks and ocular flutter. Other more dramatic the cerebellar dentate nucleus, the red nucleus,
varieties of opsoclonus have been reported in and the inferior olivary nucleus (Guillain-
patients with brainstem encephalitis, as a MoDaret triangle). It most commonly accom-
remote effect of tumors (e.g., neuroblastoma), panies vascular lesions but also occurs with
and in association with toxins (e.g., the pesti- tumors and degenerative disease. When seen
cide kepone).24 These saccade disorders prob- in association with vascular lesions, it often
ably represent a release of the brainstem sac- develops months after the brainstem or cere-
cade burst neurons from supranuclear control. bellar infarction. Intravenous scopolamine has
Functional MRI showed activation of the deep been reported to abolish the ocular oscillations
cerebellar nuclei in two patients whose temporarily, but there is no good long-term
opsoclonus was markedly diminished with eye treatment.90
closure.86
Ocular Bobbing OCULAR TILT REACTION

Ocular bobbing consists of abrupt, nonrhyth- If a subject is tilted in the frontal plane (about
mic, conjugate, downward jerks of the eyes, the nasal occipital axis), the head reflexively
followed by slow return to midposition.31 The tilts and the eyes counter-roll and skew toward
abnormal movements are classically seen in the opposite side. The functional role of this
comatose patients with intrinsic pontine lesions reflex in visual stabilization during natural body
Right
labyrinth and
pontomedullary
Right ponto-
mesencephalic
Figure 6–7. Ocular tilt responses associated with lesions at different locations within the peripheral and central vestibular
pathways. The ocular tilt reaction consists of a head tilt toward the side of the lower eye, a skew deviation with one eye
higher than the other, and counterroll (torsion) of both eyes, with the top poles rolling toward the side of the lower eye. The
ipsilateral eye is down with lesions of the labyrinth and pontomedtillary regions but it is up with lesions in the pontomes-
encephalic region.
movements is minimal, however, as the magni- Lesions in these regions would, of course,
tude of the compensatory head tilt and ocular result in an ocular tilt reaction in the opposite
counter-rolling is only about 10% of angular direction (Fig. 6–7). Paroxysmal tonic ocular
displacement of the head. The ocular tilt reac- tilt reactions have been reported in patients
tion is principally a labyrinthine reflex; it is with multiple sclerosis and in a patient with a
independent of the position of the head, rela- focal brainstem abscess.94,95 Such patients may
tive to the body (indicating that neck position is respond to carbamazepine or baclofen.
not important). The ocular tilt reaction can be
elicited by electrical stimulation of the rostral
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Chapter 7
Laboratory Examination of the

Vestibular System
NYSTAGMOGRAPHY Results in Normal Subjects

Methods of Recording Eye Movements Results in Patients
Interpreting the Recording TESTS OF OTOLITH–OCULAR REFLEXES
Recording Pathologic Nystagmus Ocular Counterrolling
Bithermal Caloric Test Eccentric Rotation
Tests of Visual–Ocular Control Off-Vertical Rotation
ROTATIONAL TESTING OF Linear Acceleration
VESTIBULO-OCULAR REFLEXES VESTIBULOSPINAL TESTING
Relationship between Stimulus and Response Static-Force Platforms
Results in Normal Subjects Moving-Platform Posturography
Results in Patients VESTIBULAR-EVOKED POTENTIALS
VISUAL–VESTIBULAR INTERACTION Brain Stem and Cortical
Methodology Vestibular Evoked Myogenic Potentials (VEMPs)
NYSTAGMOGRAPHY available system used for nystagmography

(Fig. 7–1).2,3 The potential difference between
Nystagmography is a method for recording the cornea and retina, known as the corneal–
nystagmus, although it can be used for record- retinal potential, acts as an electric dipole, ori-
ing any type of eye movement. One can quan- ented in the direction of the long axis of the eye.
tify the slow-component velocity, frequency, In relation to a remote location, an electrode
and amplitude of spontaneous or induced nys- placed in the vicinity of the eye becomes more
tagmus, and the changes in these measure- positive when the eye rotates toward it and less
ments brought about by loss of fixation (with positive when it rotates away from it. Recordings
eyes open in darkness).1 In addition, visually are usually made with a three-electrode system,
controlled eye movements (saccades, smooth using differential amplifiers. Two of the (active)
pursuit, and optokinetic nystagmus) can be electrodes are placed on each side of the eye,
recorded and quantitatively assessed. and the reference (ground) electrode is placed
somewhere remote from the eye. The two
active electrodes measure a potential change of
Methods of Recording equal amplitude but opposite direction. The
Eye Movements difference in potential between these elec-
trodes is amplified and then transferred to a
Electrooculography (or electronystagmogra- recording device for a graphical representation.
phy, ENG) is the simplest and still most readily Because the differential amplifiers monitor the
171
Center Right Gaze Left Gaze

– – –
Electrodes + +
+
Amplifier
Pen
Recorder
Figure 7–1. Electronystagmography. Electrode placement (top); Method for recording eye movements (bottom). See text
for details.
difference in voltage between the two active algorithms are then used to determine horizon-
electrodes, remote electrical signals (electro- tal, vertical, and even torsional eye position.
cardiographic or electroencephalographic, for Magnetic search coils are another method of
example) arrive at the electrodes with approxi- recording eye movements. This technique uses
mately equal amplitude and phase and are a contact lens embedded with two coils of wire,
canceled out. one that senses horizontal and vertical move-
Infrared video recording of eye movements ments, and the other that senses torsional
(videonystagmography, VNG) is a newer, more movements. When the subject sits in a mag-
flexible eye movement recording system that is netic field, voltages are induced in these search
gradually replacing ENG in many clinical labo- coils that can be used to measure eye position.
ratories (Fig. 7–2).4 The infrared cameras used The magnetic search coil technique is the gold
are fitted into various types of goggles, which standard technique for measuring eye move-
are then placed around the patient’s head. With ments because it allows measurement of eye
some goggles, the cameras are placed directly rotations around all threes axes with high
in front of the eyes, which is fine for recording sensitivity and low noise.
eye movements in dark conditions (i.e., caloric Each eye movement recording system has
and positional tests). To allow patients to better advantages and disadvantages. ENG is rela-
track targets (e.g., during saccade and smooth tively inexpensive, easily administered, nonin-
pursuit testing), other goggles were designed vasive, does not interfere with vision, and does
with the cameras mounted on top (thus out of not require head restraint. Furthermore, it is
the patient’s line of vision) and a reflective glass reasonably accurate even for the large-
is used so that the eyes can be recorded. The amplitude horizontal eye movements that are
infrared video camera is interfaced with a digi- encountered during routine ENG testing. The
tal computer. At regular intervals, images are disadvantages of ENG include the inability to
stored by the computer for subsequent data measure torsional eye movements and rela-
analysis. Specialized digital signal–processing tively inaccurate measurement of vertical eye
7 Laboratory Examination of the Vestibular System 173
Video Cameras
Video Cameras
Reflective lenses
Right Eye Left Eye
5 10 15
Figure 7–2. Videonystagmography. Two different examples of goggle systems, one with cameras mounted in front of the
eyes and the other with cameras mounted on top of the goggles and out of the patient’s line of vision (top); example of
appearance of video-recorded eyes (middle); example of videonystagmography caloric tracing and smooth pursuit tracing
(bottom).
movements, interference of eye blink artifacts, simply strapped on. Usually the computer finds
poor signal-to-noise ratio, and dependence on and calibrates the eyes in less than a minute.
lighting conditions in the test room.5,6 Infrared With ENG, calibrations must be repeated fre-
video recordings have the advantage of accu- quently throughout the test battery, since the
rately recording horizontal, vertical, and torsional corneal–retinal potential fluctuates, particu-
eye movements.4 In addition to providing a larly if the lights are turned on and off. In
digitized paper recording, there is a video addition, with the video system there is no
recording that can be reviewed when there are interference from extraneous electrical signals
questions about the paper recording, and it can from in- or outside the body. Disadvantages of
also be used for teaching purposes. With video the video systems include possible obstruction
recordings there is a much faster setup time, as of vision by the video cameras, difficulty wear-
the goggles containing the video cameras are ing eyeglasses, difficulty in keeping the camera
system fixed on the forehead, and difficulty by a top technician. Finally, the clinician inter-
with the digital tracking system in some patients preting the test must be familiar with these and
with poor contrast between the pupil and iris. other nuances of the test.
Eye blinks can interfere with the video record-
ing systems, but VNG can be used to monitor
eyelid dynamic disorders.7 The main disadvan- Interpreting the Recording
tage of the magnetic search coil technique is
that it requires the use of a thick contact lens, By convention, for horizontal recordings, eye
which can cause discomfort for the patient or movements to the right are displayed so that
rarely corneal abrasion. Accordingly the mag- they produce upward pen deflection and those
netic search coil technique is generally only to the left produce downward pen deflection.
used in research laboratories. For vertical recordings, upward and downward
With newer versions of VNG systems with eye movements produce upward and downward
high-frequency sampling rates, the degree of deflections, respectively. For torsional eye
precision now rivals that of the magnetic search movements, clockwise eye movements produce
coil technique,8 so such systems are being upward pen deflections while counterclockwise
incorporated into more research laboratories. eye movements produce downward pen deflec-
Although increased precision of VNG and the tion. Figure 7–3 illustrates the relationship
magnetic search coil technique is a clear advan- between components of a typical beat of hori-
tage over ENG in research studies,9 it remains zontal nystagmus. Values chosen for each
uncertain whether these advantages over ENG component are those commonly seen with spon-
enhance clinical diagnostic capabilities or can taneous vestibular nystagmus recorded in the
result in better patient outcomes. dark. The fast component moves to the left, so
Ultimately, the performance of any of these by convention the nystagmus is to the left (i.e.,
techniques to record eye movements depends “left-beating”). A 10-degree fast component
substantially on practical factors like the skills would have an average velocity (a/fd; a = ampli-
of the technician performing the test, the coop- tude, fd = fast duration) of approximately
eration of the patient, and the expertise of the 100 degrees/sec. The slow-component velocity
clinician interpreting the test. If the test is not (a/sd; a = amplitude, sd = slow duration) is usu-
properly set up or instructions are not effec- ally much slower—in this case, 10 degrees/sec.
tively communicated to the patient, then the It is approximately the product of the amplitude
results will be largely questionable. For the times frequency as long as the fast duration is
caloric test, the ear canals often need to be small compared with the slow duration. Although
cleaned, the irrigation tube must be appropri- the magnitude of each nystagmus measurement
ately positioned, and the temperature of the shown in Figure 7–2 can be calculated directly
water monitored. These are not difficult tasks, from the paper recording, such a procedure is
but appropriate training, experience, and care tedious and therefore subject to error. Digital
are required. There are many patient factors computers are ideally suited for making such
(e.g., decreased alertness from sedating medi- measurements. Using a programmed algorithm,
cines, apathy, or severe nausea) that could computers can calculate the amplitude, dura-
result in an invalid test even when performed tion, and velocity of each of the slow and fast
R sc fc
a 10°
L
sd fd
1 sec
f= 1 a vsc ≈ a·f if sd >> fd

sd + fd vsc = sd
Figure 7–3. Single beat of nystagmus recorded with electronystagmography. a, amplitude; f, frequency; fc, fast component;
fd, fast duration; sc, slow component; sd, slow duration, vsc, velocity of slow component.
components. Plots of the nystagmus slow- is illustrated with the ENG recordings in
component velocity versus time are particularly Figure 7–4. The patient was tested 3 days after
useful for quantifying the magnitude of induced and again 2 weeks after a left labyrinthectomy.
nystagmus (as will be shown later). On the initial recording, nystagmus was pres-
Nystagmography can be used to evaluate any ent even while fixating on a target, although it
type of eye movement disorder, and the testing was more prominent without fixation. On the
procedure should be flexible enough to deal subsequent recording, nystagmus occurred
with any abnormality encountered. It is useful, only when the lights were turned off. This
however, to have a standard test battery that pattern is typical of an acute peripheral vestib-
will at least screen all areas of potential abnor- ulopathy of any cause. The nystagmus is exag-
mality (Table 7–1). In most clinical laborato- gerated with gaze in the direction of the fast
ries, the test battery includes (1) recording for component (Alexander’s law). As a general
pathologic nystagmus, (2) the bithermal caloric rule, nystagmus with fixation (nystagmus seen
test, and (3) tests of visual–ocular control. on routine neurologic examination) disappears
within 1 to 2 weeks after the occurrence of an
acute peripheral vestibular lesion. By contrast,
Recording Pathologic Nystagmus spontaneous nystagmus can be recorded in the
dark for as long as 5 to 10 years after an acute
The same systematic search for pathologic nys- peripheral vestibular lesion. In some patients,
tagmus outlined in the previous chapter should the spontaneous nystagmus emerges only with
be conducted during the nystagmography mental alerting tasks (e.g., when performing
examination. Recording with eyes open in serial 7 subtractions from 100).12 Changes in
darkness is more effective than using Frenzel head position with respect to gravity may alter
glasses for identifying peripheral spontaneous the direction and magnitude of peripheral
and positional nystagmus. Approximately 20% spontaneous nystagmus.
of normal subjects have a low-velocity sponta- Eye movement recordings can help differ-
neous nystagmus (i.e., <4 degrees/sec) and as entiate congenital and central varieties of spon-
many as 75% have a low-velocity positional taneous nystagmus from peripheral varieties.
nystagmus when tested with eyes open in Spontaneous downbeating nystagmus is a com-
darkness.10,11 Apparently the vestibular system mon central nystagmus pattern. The downbeat
is unable to stabilize the position of the eyes nystagmus shown in Figure 7–5a increases in
when visual signals are removed. frequency and amplitude with downward gaze,
but it reversed direction with upward gaze.
Loss of fixation did not change the nystagmus
SPONTANEOUS NYSTAGMUS
frequency or amplitude (Fig. 7–5b). The spon-
The effect of change in ocular position and taneous vertical nystagmus was superimposed
fixation on peripheral spontaneous nystagmus on attempted vertical pursuit (Fig. 7–5c).
Table 7–1 Standard Nystagmography Test Battery

Recording for Pathologic Nystagmus
Fixation at midposition
Fixation inhibited with eyes open in darkness (constant mental alerting)
Gaze held 30° right, left, up, and down
Rapid and slow positional changes
Bithermal Caloric Test
30°C and 44°C water infused into each ear, eyes open in darkness, constant mental alerting, allow at least
5 min between each infusion
Visual Tracking Tests
Saccades: 5°–40°, target can be series of dots or lights
Smooth pursuit: target velocity 20°–40°/sec
Optokinetic nystagmus: stripe velocity 20°–40°/sec
Optokinetic after-nystagmus: lights turned off after 1 min constant velocity optokinetic nystagmus in each direction
3 Days Post 14 Days Post

Labyrinthectomy Labyrinthectomy
30° right 30° right
10°
15° right 5 sec

Center
Center 30° left
Lights out
30° right
15° left
Center
30° left
Lights out
Center 30° left
Figure 7–4. Peripheral spontaneous nystagmus (bitemporal horizontal ENG recording) taken 3 days and 14 days after the
patient underwent a left labyrinthectomy. By 14 days, the nystagmus disappeared when in the light with fixation but was
still prominent in the dark when fixation was inhibited.
The waveform of the congenital nystagmus linear, producing a sawtooth pattern, whereas
illustrated in Figure 7–6a changed in different the slow component with congenital nystagmus
horizontal gaze positions (from pendular to usually increases exponentially.13
near sawtooth). When fixation was inhibited by
darkness, the nystagmus almost disappeared
GAZE-EVOKED NYSTAGMUS
(Fig. 7–6b). Horizontal smooth pursuit was
markedly impaired in both directions (Fig. The most common type of gaze-evoked nystagmus
7–6c). By comparison, peripheral spontaneous (drug-induced) has approximately equal ampli-
nystagmus does not change direction with tude in all directions of gaze. A large-amplitude,
change in gaze position, does increase with asymmetric gaze-evoked nystagmus is often seen
loss of fixation, and usually does not impair with lesions of the cerebellar-pontine (CP) angle
smooth pursuit. The slow component with (so-called Bruns’ nystagmus).14 The lesion is usu-
acquired spontaneous nystagmus is typically ally on the side of the large-amplitude nystagmus.
(a) (b)
30° up Lights off
15° up
5 sec
(c)
Center
Pursuit down 10°
15° down
Pursuit up
Figure 7–5. Spontaneous downbeat nystagmus (monocular vertical ENG recordings). (a) Nystagmus increased on down-
ward gaze and changed direction on upward gaze. (b) Loss of fixation had little effect. (c) Nystagmus was superimposed on
attempted vertical pursuit.
(a) (b)
Lights on
Lights off
30° right
15° right
5 sec
Center
15° left (c)
10°
Pursuit right Pursuit left
30° left
Figure 7–6. Congenital nystagmus (bitemporal horizontal ENG recordings), (a) Waveform changed in different gaze posi-
tions, (b) Nystagmus decreased with loss of fixation, (c) Nystagmus was superimposed on attempted horizontal pursuit.
Rebound gaze-evoked nystagmus decays as the As suggested earlier, persistent low velocity
lateral gaze position is held (Fig. 7–7, upper positional nystagmus is a common finding on
trace) and recurs transiently after returning to nystagmography even in control subjects when
the primary position, with fast components recordings are made with eyes open in dark-
occurring in the direction of the return saccade ness. An average slow-phase velocity that
(Fig. 7–7, lower trace).15 exceeds 4 degrees/sec is considered abnormal,
but nonlocalizing. Both direction-fixed and
POSITIONAL NYSTAGMUS direction-changing static positional nystagmus
occur with peripheral and central vestibular
Although benign paroxysmal positional nystag- lesions.18 Lack of suppression of the nystagmus
mus can be readily identified on routine physi- with fixation indicates a central lesion.
cal examination, recording the nystagmus
documents its stereotyped profile. For this rea-
son, we include the Dix-Hallpike positioning Bithermal Caloric Test
test as part of our nystagmography examina-
tion; the technician also observes the nystag- MECHANISM OF STIMULATION
mus while it is being recorded. Dix-Hallpike
positioning can also be used to identify central Robert Barany received the Nobel Prize for
positional nystagmus, which is typically down- proposing the mechanism of caloric stimula-
beating. VNG is ideal for documenting vertical tion of the vestibular system. The test uses a
and torsional positional nystagmus patterns nonphysiologic stimulus (water or air) to induce
since the video recording can be reviewed. endolymphatic flow in the semicircular canals
(Fig. 7–8).16 If ENG is used with only horizon- by creating a temperature gradient from one
tal electrodes, then vertical or torsional side of the canal to the other (Fig. 7–9).19,20
nystagmus could be missed.17 Irrigation of the external auditory canal with
Center 15°
Left 30°
Center
5 sec
Figure 7–7. Rebound nystagmus (horizontal bitemporal ENG recording). Nystagmus decays as the lateral gaze position is
held and recurs on return to the primary position. The reverse occurred with gaze to the right.
20
Torsional
10
0
–10
Eye Position (deg) –20
20
Vertical
10
0
–10
–20
20 Horizontal
10
0
–10
–20
5 10 15 20 25
Time (seconds)
Figure 7–8. Three-dimensional recording of benign paroxysmal positional nystagmus. Scleral search coil in right eye.
Positive values indicate clockwise (as seen from the subject), up and right. Vertical lines indicate start and end of positioning
maneuver. (Courtesy Michael Fetter, Tübingen, Germany).
water or air that is below or above body tem- same test is repeated with the patient lying on
perature transfers a temperature gradient from the abdomen, so that the horizontal canal is
the external auditory canal to the inner ear by reversed in the vertical plane (i.e., the direction
conduction. The horizontal semicircular canal of the gravity vector with relation to the head is
develops the largest temperature gradient reversed), the direction of nystagmus induced
because it lies closest to the source of tempera- by warm and cold stimulation is reversed.
ture change. Because the vertical canals are Monkeys that have had their horizontal
relatively remote from the external ear, caloric semicircular canals blocked with paraffin still
stimulation of the vertical canals is unreliable. have caloric-induced nystagmus, although
The endolymph circulates because of the dif-
ference in its specific gravity on the two sides of Ampullopetal deviation
the canal when the semicircular canal being of cupula
investigated is in the vertical plane. Caloric Ampulla
testing of horizontal semicircular canal func- Middle
tion is usually performed with the patient in ear
.
the supine position, with head tilted 30 degrees mp t 44°C Water
Utricle Te dien
up (placing the horizontal semicircular canals gra a External
in the vertical plane; see Fig. 1–4c). With the b canal
Crista
warm caloric stimulus illustrated in Figure 7–9,
the column of endolymph nearest the middle 37°C c
ear rises because of its decreased density. This
causes the cupula to deviate toward the utricle Horizontal
(ampullopetal flow) and produces horizontal semicircular Gravity
vector 44°C
nystagmus with the fast component directed canal
toward the stimulated ear. A cold stimulus pro- Temp.
duces the opposite effect on the endolymph
column, causing ampullofugal endolymph 37°C
flow and nystagmus directed away from the c b a
stimulated ear. These induced eye movements Distance from external canal
can be remembered with the mneumontic Figure 7–9. Mechanism of caloric stimulation of the
COWS—cold opposite, warm same. If the horizontal semicircular canal (see text for details).
lesser in magnitude than prior to surgery.21 increased responses due to a shortening of the
Presumably, the spontaneous afferent nerve conduction pathway. A thickened temporal
activity increases and decreases because of bone, by contrast, would produce the opposite
heating and cooling of the afferent nerve, effect, because of decreased bone heat con-
respectively. Consistent with this interpreta- ductivity. Some of these factors no doubt
tion, the caloric-induced nystagmus in canal- underlie the large variability of caloric responses
blocked animals does not reverse direction measured in normal subjects and explain the
when the gravity vector is reversed.21 This occasional unexpected increase or decrease in
mechanism could also explain the unexpected caloric response found in patients with tempo-
finding of caloric-induced nystagmus in space, ral bone disease. The caloric response can also
outside of earth’s gravity.22 Other mechanisms, be attenuated by small or narrow external audi-
including differential pressure effects from the tory canals, or cerumen build-up within the
temperature gradient and central otolith–canal external canal.
interactions, have also been proposed to
account for caloric responses in space.23 From
TEST METHODOLOGY
a clinical point of view, however, gravity is the
main driving force for the caloric response. With the bithermal caloric test introduced by
The response can be effectively shut off (in Fitzgerald and Hallpike,27 each ear is irrigated
instances in which the patient becomes for a fixed duration (30 to 40 sec) with a con-
extremely uncomfortable) simply by having the stant flow rate of water that is 7° below body
patient sit up and tilt the head about 30 degrees temperature (30°C) and 7° above body tem-
downward so that the horizontal canals are in perature (44°C). One must wait a minimum of
the horizontal plane.24 5 min from the end of one response to the next
The caloric test is the most widely used clin- stimulus to avoid additive effects. The major
ical test of the vestibulo-ocular reflex (VOR) advantages of this test methodology are
for two major reasons: (1) each labyrinth can (1) both ampullopetal and ampullofugal endo-
be stimulated individually and (2) the stimulus lymph flow are serially induced in each
is easy to apply without requiring complex horizontal semicircular canal, (2) the caloric
equipment. Several limitations of the test must stimulus is highly reproducible from patient to
be appreciated if one is to assess the results patient, and (3) the test is tolerated by most
properly, however. The slow-component veloc- patients. The major limitation is the need for
ity and duration of caloric-induced nystagmus constant temperature baths and plumbing to
are dependent not only on the relationship maintain continuous circulation of water
between the temperature gradient vector and through the infusion hose. Patients with
the gravity vector but also on the blood flow to migraine may have an increased chance of hav-
the skin, presence of fluid in the middle ear ing a migraine headache after caloric testing.28
chamber, the physical distance between the The magnitude of caloric-induced nystag-
tympanic membrane and the horizontal canal mus is highly dependent on the degree of fixa-
(longer distance leads to less temperature tion permitted during the test procedure. Four
transfer), and heat conductivity of the temporal different fixation conditions have been used for
bone.25,26 If local blood flow to the skin is caloric testing: (1) eyes open, fixating; (2) eyes
decreased (from vasoconstriction due to pain open, Frenzel glasses; (3) eyes open, total dark-
or to anxiety), the maximum slow-component ness; and (4) eyes closed. Without eye move-
velocity of the response decreases (from ment recording devices, obviously only the first
decreased heat conductivity through skin), but two conditions can be used. Comparison of
its duration is prolonged (from delayed heat these four conditions in normal subjects shows
transfer). Patients with infection or fluid in the a consistently lower coefficient of variation
middle ear and mastoid air cells may have an (standard deviation/mean) for response mea-
increased caloric response (increased maxi- surements when the test is performed with
mum slow component velocity) because the eyes open, either behind Frenzel glasses or in
fluid can increase heat conductivity from the total darkness.29
external ear to the inner ear. Similarly, patients When caloric testing is performed with
who have undergone mastoid surgery and fixation (as initially described by Fitzgerald
reconstruction of their middle ear may have and Hallpike), two separate systems are being
evaluated: the VOR and the smooth pursuit each infusion, using a stopwatch. Prior to the
system (see Visual–Vestibular Interaction, development of eye movement recordings, this
Chapter 3). Some normal subjects are very was the only way to quantify the bithermal
good at suppressing caloric-induced nystagmus caloric test. Using nystagmography, however, it
with fixation29; others are not. Patients with is possible to record multiple response mea-
impaired smooth pursuit (such as patients with surements accurately. Figure 7–10 illustrates
cerebellar atrophy) may show no difference in an ENG recording of a normal caloric response.
caloric-induced nystagmus with or without The subject was supine, the head elevated 30
fixation.30 When measured with fixation the degrees, and the eyes open behind Frenzel
responses in these patients will appear hyper- glasses in a darkened room. Two hundred fifty
active when compared with those of subjects milliliters of 44°C water was infused into the
with a normal smooth pursuit system. Eye clo- left ear during the 40 sec marked on the figure,
sure and the associated upward deviation of the resulting in ampullopetal endolymph flow in
eyes can lead to suppression of both spontane- the left horizontal semicircular canal, producing
ous and induced nystagmus.29 It can also alter left-beating horizontal nystagmus. The nystag-
the nystagmus waveform, making it more diffi- mus began just before the end of stimulation,
cult to quantify with nystagmography. Patients reached a peak approximately 60 sec post stim-
with central nervous system (CNS) lesions ulus, and then slowly decayed over the next
often have a horizontal deviation of the eyes on minute. Next to the ENG tracing, nystagmus
closure, which can also change the waveform of slow-component velocity, slow-component
induced nystagmus.31 To avoid these uncontrol- amplitude, and frequency are plotted versus
lable variables, caloric testing should be per- time. Each measurement demonstrates beat-
formed with eyes open (either in the dark or to-beat variability, but the velocity of the slow
behind opaque goggles). For a brief period components shows the least variability.
during the test, fixation can be permitted to Furthermore, a decrease in slow-component
evaluate the nystagmus suppressing functional velocity is the most sensitive indicator of
status of the smooth pursuit system.32 vestibular damage.
As suggested earlier, the absolute magnitude
NORMATIVE DATA of caloric response depends on several physical
factors unique to each subject that are unre-
The response to caloric stimulation can be lated to actual semicircular canal function (e.g.,
assessed in several ways. The simplest method blood flow to the skin, fluid in the middle ear,
is to measure the duration of nystagmus after the physical distance between the tympanic
(a) (b)
44° Caloric infusion
Slow Comp. Vel.
30
(deg/sec)
20
10
5 sec 15° 0
Slow Comp. Ampl.
(c) (d)
20 8
(beats/sec)
Frequency
6
(deg)
10 4
2
0 0
0 30 60 90 120 0 30 60 90 120
Seconds
Figure 7–10. Caloric response produced by infusion of 250 ml of 44°C water into the left ear of a normal subject.
(a) Bitemporal electronystagmographic recording. Horizontal bar indicates duration of infusion. Plots are of slow-
component velocity (b), slow-component amplitude (c), and frequency (d) versus time, generated by a digital computer.
membrane and the horizontal canal, and heat ( )−( )

conductivity of the temporal bone). The maxi- × 100 [2]
R30° L 44° + R 44° L30°
mum slow-component velocity (MSCV) after a
caloric stimulus can be as low as 5 degrees/sec
and as high as 75 degrees/sec and still be within compares the MSCV of nystagmus to the right
the 95% confidence interval for normal with that of nystagmus to the left in the same
subjects.33 Because of this large intersubject subject. Dividing by the total response normal-
variability, intrasubject measurements are izes the measurements to remove the large
more useful clinically (Fig. 7–11). The vestibu- variability in absolute magnitude of normal
lar paresis formula caloric responses.
A caloric fixation suppression index is
( )−( ) obtained by having the patient fixate on a target
× 100 [1] during the middle of the response. Because the
R30° R 44° + L30° L 44°
slow-component velocity of caloric-induced
nystagmus is constantly changing, it is impor-
compares the MSCV of right-sided (R) tant that the fixation period occur near the time
responses with that of left-sided (L) responses, of maximum response to obtain the best esti-
and the directional preponderance formula mate of fixation suppression. The fixation
suppression index is defined as (MSCV with
fixation ÷ MSCV without fixation) × 100. With
each of these formulas, the result is reported as
a percentage of the total response.
In our laboratory, a vestibular paresis is
Nystagmus to R defined as >25% asymmetry between left-and
H2O °C
Nystagmus to L right-sided responses, and a directional pre-
Ear ponderance as >30% asymmetry between left-
30° L and right-beating nystagmus, and a fixation
R
suppression index >70% is abnormal. These
Normal values are comparable to those reported by
L
44° other investigators (many use >30% asymmetry
to define a vestibular paresis), but it must be
R emphasized that each laboratory should estab-
Slow component velocity
L lish its own normal range because of the many

30°
R methodologic variables discussed earlier.
Left
vestibular
L RESULTS IN PATIENTS
paresis
44°
R
Table 7–2 summarizes the abnormalities found
in caloric testing, their meaning in terms of
L location of lesion, and the mechanism by which
30° each abnormality is produced.
Right R
directional
L
preponderance Peripheral Lesions
44°
R Assuming acceptable test conditions and per-
(40 sec) 1 2 3 formance (e.g., experienced technician, coop-
Time (min) erating patient, clean and symmetric external
Duration auditory canals), the finding of a significant ves-
of irrigation tibular paresis with bithermal caloric stimula-
Figure 7–11. Normal and two common patterns of abnor- tion suggests damage to the vestibular system
mal response to bithermal caloric testing. With a vestibu- that can be located anywhere from the end
lar paresis, the responses to cold (30°C) and warm (44°C) organ to the vestibular nerve root entry zone in
water are decreased on the same side. With a directional
preponderance, the responses to warm water on one side the brain stem. By far, the most common cause
and cold water on the opposite side are decreased. of a caloric vestibular paresis is unilateral
Table 7–2 Interpreting the Results of Bithermal Caloric Testing

Result Location of Lesion Mechanism
Vestibular paresis Labyrinth, VIII nerve Decreased peripheral sensitivity
Directional preponderance Not localizing Tonic bias in vestibular system
Hyperactive responses Cerebellum Loss of inhibitory influence on vestibular nuclei
Dysrhythmia Cerebellum Loss of inhibitory influence on pontine nuclei
Impaired fixation suppression CNS pursuit pathways Interruption of visual signals on way to
oculomotor neurons
Perverted nystagmus Fourth ventricular region Disruption of vestibular commissural fibers
peripheral vestibular disease. For the central of the nerve fibers to transmit action potentials.
vestibular system to be the source, the lesion However, end-organ lesions involving the cup-
would need to involve the eighth nerve root ula and hair cells should affect both the MSCV
entry zone. In animal studies focal lesions in and duration of the responses. Unfortunately,
different vestibular nuclei did not produce a this turns out not to be a reliable way of differ-
vestibular paresis. This is not to say that a cen- entiating end-organ from eighth nerve lesions.
tral lesion cannot cause a vestibular paresis, but Lesions involving the eighth nerve can reduce
to simply say that a central lesion is much less the duration of nystagmus, whereas end-organ
likely. A recent study reported that 43% lesions (particularly in the early stages)
(10 out of 23) of patients with stroke (defined frequently result only in decreased MSCV (the
as a relevant lesion with restricted diffusion on duration of response remains unaffected). The
magnetic resonance imaging [MRI]) causing magnitude of loss is of some help in differentiat-
acute vertigo who underwent caloric testing ing nerve from end-organ lesions. A complete
had a vestibular paresis of >25%.34 In 22% or nearly complete unilateral paralysis is more
(5 out of 23) of these stroke patients the ves- commonly associated with nerve lesions than
tibular paresis was severe (>75%). Because with end-organ labyrinthine lesions.
peripheral causes of vestibular paresis are The vestibular paresis and directional pre-
much more common than central causes, the ponderance formulas are of little use in evaluat-
likelihood of a central cause is low particularly ing patients with bilateral peripheral vestibular
when there are no other central ocular motor lesions, because caloric responses are symmet-
abnormalities (e.g., bi-directional gaze evoked rically depressed. Because of the wide range of
nystagmus) or other brainstem signs. normal values for MSCV, the patient’s value
A directional preponderance on caloric testing may decrease severalfold before falling below
occurs with peripheral end-organ and eighth the normal range. For example, a patient may
nerve lesions and with CNS lesions (from brain have a MSCV of 7 degrees/sec for each side,
stem to cortex).30 It indicates an imbalance in the values that are typically within the normal range.
vestibular system and is usually associated with However, if that patient has other features indi-
spontaneous nystagmus: the velocity of the slow cating a bilateral vestibulopathy, then it can be
components of the spontaneous nystagmus adds assumed that the MSCV would have been sub-
to that of the caloric-induced nystagmus in the stantially higher if it was tested prior to the pre-
same direction and subtracts from that of the sentation. Baseline and serial measurements in
caloric-induced nystagmus in the opposite direc- the same patient are needed if one hopes to
tion.35 Occasionally, a directional preponderance identify early bilateral vestibular impairment,
will occur in patients without spontaneous nys- such as that produced by ototoxic drugs.
tagmus; most of these patients have peripheral
lesions, although about 5% have central lesions.36
Central Lesions
The need to distinguish between end-organ
and eighth nerve lesions is a common clinical As suggested earlier, patients with CNS lesions
problem. Partial lesions of the eighth nerve may exhibit a vestibular paresis on caloric test-
should not, in theory, affect the duration of ing if the lesion involves the root entry zone of
induced nystagmus, as it is related to the time the vestibular nerve.34 The most common neu-
course of cupular deflection and not to the ability rologic disorders associated with this finding
are multiple sclerosis, lateral brainstem infarc- section, rotatory stimuli are better suited than
tion, and infiltrating gliomas. Each disease caloric stimuli for examining the pattern of
nearly always produces other brainstem signs, induced nystagmus.
so the finding of a vestibular paresis is not likely Vertical or oblique nystagmus produced by
to be misinterpreted as a sign of a peripheral caloric stimulation of the horizontal semicircu-
vestibular disorder if the complete clinical pic- lar canals is called perverted nystagmus. Normal
ture is carefully considered. A careful assess- subjects commonly exhibit a small vertical
ment is needed because central abnormalities component on nystagmography recordings of
could be subtle such as central oculomotor caloricinduced nystagmus, but vertical compo-
abnormalities (e.g., bi-directional gaze-evoked nents larger than the horizontal components
nystagmus). In rare cases, a massive brainstem are clearly abnormal.41 Perverted nystagmus
infarction or diffusely infiltrating glioma leads with caloric stimulation has been reported with
to bilateral decreased caloric responses. both peripheral and central lesions, the latter
Lesions of the cerebellum can lead to usually being in the region of the floor of the
increased caloric responses, possibly because fourth ventricle (near the vestibular nuclei).42
of loss of the normal inhibitory influence of the Perverted caloric nystagmus occurs in rhesus
cerebellum on the vestibular nuclei. Because monkeys after unilateral focal lesions occur in
of the wide range of normal caloric responses, the rostral medial vestibular nucleus. Warm
however, it is unusual for any of the responses caloric stimulation on the intact side produces
to exceed the upper normal range. Patients downward nystagmus, and cold stimulation
with the cerebellar atrophy syndromes demon- produces upward diagonal nystagmus. These
strate a wide range of caloric responses.37 Those findings are probably due to a disturbance of
with Friedreich’s ataxia often have bilaterally the commissural fibers between the vestibular
decreased responses because of associated nuclei.
atrophy of the vestibular nerve and ganglia,
whereas those with a dominantly inherited spi-
nocerebellar ataxia (SCA) syndrome could have Tests of Visual–Ocular Control
decreased, normal, or even increased responses,
depending on which areas of the medulla and The central vestibulo-ocular connections are
pons are involved. Increased caloric responses, highly integrated with the visual-ocular stabi-
when they do occur, are usually found in lizing pathways, and both systems share the
patients with clinically pure cerebellar atrophy final common pathway of the oculomotor neu-
(e.g., SCA-6, see Chapter 18). Bilaterally rons (see Comparison of Vestibular- and Visual-
reduced caloric responses are common in Induced Eye Movements in Chapter 3). If the
SCA-1 and SCA-3.38–40 efferent limb of the VOR arc is damaged, visu-
An abnormal fixation suppression index on ally controlled eye movements are also abnor-
caloric testing typically occurs with lesions mal; but if the afferent limb of the reflex is
involving the smooth pursuit system (from the damaged, visually controlled eye movements
parietal-occipital cortex to the pons and cere- are usually normal. Because eye movement–
bellum). Lesions of the midline cerebellum recording techniques used for quantifying the
produce the most profound impairment of fixa- VOR can also be used to quantify visually con-
tion suppression. When asymmetric, pursuit trolled eye movements, an important “bonus”
deficits in one direction correlate with suppres- of information is obtained with little increased
sion deficits in the opposite direction. effort. Table 7–3 summarizes the types of sac-
Dysrhythmia refers to a marked beat-to-beat cade, smooth pursuit, and optokinetic abnor-
variability in caloric-induced nystagmus ampli- malities commonly associated with focal lesions
tude without any change in the slow-component of the nervous system.
velocity profile. The cerebellum is important
for controlling the amplitude of nystagmus fast
components, and loss of this control with cere- SACCADIC EYE MOVEMENTS
bellar lesions may lead to a disorganized Methods of Testing and Results in
nystagmus pattern. Unfortunately, from a diag- Normal Subjects
nostic point of view, caloric dysrhythmia also
occurs in normal subjects when they are tired One can induce saccadic eye movements with a
and inattentive. As will be shown in the next series of dots or lights separated by known
Table 7–3 Summary of Visual Ocular Control Abnormalities Produced by Focal

Neurologic Lesions
Location of Lesion Saccades Smooth Pursuit and OKN
Slow Phase
Cerebellopontine angle Ipsilateral dysmetriaa Progressive ipsilateral impairment
Diffuse cerebellar Bilateral dysmetria Bilateral impairment
Intrinsic brain stem Marked slowing, increased delay time Ipsilateral or contralateral impairment
Basal ganglia Mild slowing, hypometria,b increased Bilateral impairment
delay time
Frontoparietal cortex Difficulty inhibiting reflex saccades Ipsilateral impairment
a
Under- and overshoots.
b
Undershoots only.
OKN, optokinetic nystagmus.
angular degrees, or with a dot of light generated Computer algorithms have been developed
on a screen and moved through a series of step- to rapidly quantify these saccade parameters.43
wise jumps of different amplitudes.43 The ENG Saccades are easily identified on the basis of
recording in Figure 7–12A illustrates the high their characteristic velocity profile. The rela-
speed and accuracy of saccadic eye movements tionship between peak velocity and amplitude
induced in a normal subject by a target moving (the so-called main sequence) is nonlinear,
in steps of random amplitude. Normal subjects with decreasing peak velocities occurring at
consistently undershoot the target for jumps higher amplitudes (Fig. 7–12B). For example,
larger than 20 degrees, requiring a small cor- the average peak velocity for a 15 degrees sac-
rective saccade to achieve the final position. cade is 400 degrees/sec, whereas that for a 30
Overshoots of the target are rare. A character- degrees saccade is 550 degrees/sec. Saccade
istic delay time of approximately 200 msec accuracy is defined as the ratio of the saccade
occurs between each target jump and induced amplitude divided by the target displacement
saccade. amplitude times 100. The mean saccade accuracy
Right eye
Left eye 15°

R
5 sec
L
Target
Left eye Right eye

800
600
deg/sec
400
200
0
40 20 0 20 40 40 20 0 20 40
Amplitude (deg)
Figure 7–12. Saccadic eye movements induced in a normal subject by a target moving in steps of random amplitude
(3°–36°) and changing intervals between jumps (0.5–2.5 sec). (top) Monocular horizontal electronystagmographic record-
ings. (bottom) Computer-generated plots of peak velocity versus amplitude for entire sequence (dotted lines represent
normal mean ± standard deviation).
for normal subjects on the random saccade test of the pretectum or paramedian pontine retic-
is 88%. Overshooting of the target rarely occurs ular formation produces selective slowing of
in normal subjects. The mean delay time on vertical and horizontal saccades, respec-
the same test is 186 msec.44 tively.56,57 Lesions of one paramedian pontine
center produce ipsilateral saccade slowing. The
pretectal centers for upward and downward
Results in Patients
saccades are separate (downward ventral dor-
Slowing of saccadic eye movements can occur sal to the upward center) but are so close
with lesions anywhere in the diffuse central together that lesions usually involve both.
pathways involved in generating saccades. The Destruction of the pretectal and pontine supra-
most pronounced slowing occurs with lesions nuclear saccade centers results in complete
of the pretectal and paramedian pontine gaze absence of saccadic eye movements (voluntary
centers, the oculomotor neurons, and the and involuntary). Patients with such a dysfunc-
extraocular muscles. Lesions involving these tion produce only a slow tonic deviation of the
pathways impair both voluntary and involun- eyes with vestibular or optokinetic stimuli
tary saccades. Damage to the oculomotor because of the absence of fast components
neurons, oculomotor nerves, and extraocular (see Fig. 7–29c).57
muscles causes a slowing of saccades when the Impaired saccade accuracy is most com-
paretic muscle is the agonist required to gener- monly seen with cerebellar disorders.58,59
ate the sudden force necessary to move the Overshooting of the target (saccade overshoot
globe rapidly. Saccade slowing identified on dysmetria) is most apparent, as overshoots
eye movement recording can occur before rarely occur in normal subjects (See Video
clinical examination reveals the presence of 7–1). The velocity of these inaccurate saccades
strabismus.45,46 Recordings have been particu- is normal unless the brain stem is also involved.
larly helpful for identifying early lesions of the Of the cerebellar atrophy syndromes, saccade
medial longitudinal fasciculus (MLF), mani- dysmetria is most prominent with Friedreich’s
fested by slowing of adducting saccades made ataxia.60,61 Monocular overshoots in the abduct-
by the medial rectus on the side of the lesion ing eye are characteristic of MLF lesions (see
(Fig. 7–13).47,48 A characteristic saccade abnor- Fig. 7–13). Disorders of the cortical and sub-
mality is seen with myasthenia gravis. Saccades cortical supranuclear centers also affect the
begin with normal velocity, but within a short accuracy of saccades.62,63 Patients with
time the transmitters at the myoneural junc- Parkinson’s disease exhibit delayed saccade
tion are depleted, and the remainder of the reaction time and hypometria of voluntary sac-
saccade is markedly slow.49 In some patients cades. Complete removal of one hemisphere
with severe oculomotor dysfunction, only brief or the presence of a large frontal parietal lesion
bursts of oculomotor firing are possible before results in hypometria of horizontal saccades
a complete block occurs. This results in the made in the contralateral direction.64 Vertical
unusual situation in which a patient with almost saccades are unaffected. Animals with lesions
complete absence of sustained eye movements of the frontal eye fields may have normal-
can have small-amplitude, high-velocity sacca- appearing saccade metrics but have difficulty
des followed by a quick return to the primary inhibiting reflex saccades.65 Patients with lesions
position (so-called ocular quiver). These sac- of the frontal cortex and basal ganglia have sim-
cade abnormalities are usually rapidly reversed ilar difficulties.66,67 This can be demonstrated
with intravenous Tensilon.50 with the antisaccade test, in which a fixation tar-
Reversible saccade slowing is produced by get is illuminated in the periphery and the
fatigue and by ingestion of alcohol or tranquil- patient is instructed to make a saccade in the
izers.51–53 This results from impaired synaptic exact opposite direction. Normal subjects can
transmission through the multineuronal net- reliably perform this task, but patients with
works needed to generate the high-frequency lesions involving cortical and subcortical presac-
firing for horizontal and vertical saccades. cade structures often make unwanted saccades
Patients with Huntington’s disease and pro- to the fixation target before refixating in the
gressive supranuclear palsy develop slowing of desired location.
saccades, apparently due to diffuse degenera- Patients with acquired and congenital oculo-
tion of supranuclear pathways.54,55 Focal disease motor apraxia68 and ataxia telangiectasia69
Right eye
Left eye
15°
R
5 sec L
Target
Left eye Right eye

800
deg/sec
600
400
200
0
40 20 0 20 40 40 20 0 20 40
Amplitude (deg)
Figure 7–13. Saccadic eye movements in a patient with bilateral medial longitudinal fasciculus lesion caused by multiple
sclerosis. Recordings are as in Figure 7–12. Adducting saccades are markedly slow; abducting saccades have normal velocity
but overshoot the target.
exhibit prolonged reaction time for the initia- the eye is determined by using precise targets
tion of voluntary saccades and use a series of and eye movement recording. A pendulum
hypometric saccades to produce refixations. hanging from the ceiling or a metronome pro-
Nystagmus fast components (involuntary sac- vides an inexpensive reproducible sinusoidally
cades) are also abnormal, such that the eyes moving target. Precise control of the target can
deviate in the direction of the slow component be achieved over a series of velocities by pro-
rather than in the direction of the fast compo- jecting a dot onto a screen with a motor-con-
nent. To compensate for impaired voluntary trolled device. Figure 7–14b illustrates an ENG
saccades, these patients often use head recording of horizontal smooth pursuit in a
thrusts to perform refixation. Because their normal subject as he follows a sinusoidally
VOR is intact, the head thrusts produce con- moving dot on a white screen (0.3 Hz, maxi-
troversive deviation of the eyes, necessitating mum amplitude 18 degrees). The accuracy of
an overshoot of the head thrusts to obtain fixa- smooth pursuit can be quantified by repeatedly
tion. Fixation is then maintained as the head is sampling eye and target velocity and plotting
slowly returned on line with the target. The site the two velocities against each other (see
of the anatomic defect that produces these Fig. 7–14d). A computer algorithm makes the
abnormalities in voluntary saccades is unknown. comparison between eye and target velocity
after saccade waveforms have been removed.70
The slope of this eye target velocity relation-
SMOOTH PURSUIT ship (in this case, 0.95) represents the gain of
Methods of Testing and Results in the smooth pursuit system. The mean gain
Normal Subjects determined from similar plots in 25 normal
young subjects was 0.95 ± 0.07. Older normal
Examining physicians can test smooth pursuit subjects (>70 years of age) show marked vari-
eye movements by slowly moving their finger ability in pursuit ability, and therefore pursuit
or a pencil back and forth and asking the patient testing must be interpreted with caution in
to follow it as well as possible. The target should older patients.71 Also, smooth pursuit gain
be moved as smoothly as possible and the decreases with both increasing frequency and
movement should not be too fast (about 1/2 increasing velocity of the target. Each labora-
cycle/sec is an ideal rate). A more exact rela- tory must establish normative data for its stan-
tionship between the velocity of the target and dard test protocol.
(a) (d) 48
32
16 Target
15°
16 32 48 velocity
(deg/sec
5 sec R
(b)
L
15° (e)
Target
(c) velocity
16 32 48
16
15° (deg/sec
32
48
Eye velocity
(deg/sec)
Figure 7–14. Smooth pursuit of a target (a) moving with a sinusoidal waveform in a normal subject (b) and a patient
with cerebellar atrophy (c). Bitemporal horizontal recording. Eye velocity is plotted against target velocity (both sampled
10 times/sec) after saccades have been removed for the normal subject (d) and patient (e).
Results in Patients disease54,76 (Parkinson’s disease and Huntington’s

disease), or diffuse cerebellar disease37,58 consis-
Patients with impaired smooth pursuit require
tently have bilaterally impaired smooth pursuit
frequent corrective saccades to keep up with the
eye movements. Focal disease of one cerebellar
target, producing so-called cogwheel, or sacca-
hemisphere or one side of the brain stem usu-
dic, pursuit (see Fig. 7–14c). As expected, the
ally produces ipsilateral impairment of smooth
gain (given by the slope of the eye velocity–target
pursuit, although large cerebellar pontine angle
velocity plot) of the smooth pursuit system is
tumors are frequently associated with bilater-
markedly decreased in such patients (see
ally impaired smooth pursuit.14 Focal cortical
Fig. 7–14e). It must be emphasized, however,
lesions in the parietooccipital region impair
that normal subjects may intermix saccades with
ipsilateral smooth pursuit (Fig. 7–15a).77,78
smooth pursuit movements, particularly if they
are inattentive or fatigued, or if the target velocity
exceeds the limit of their smooth pursuit system.72 OPTOKINETIC NYSTAGMUS
Therefore, quantitative analysis of intersaccadic Methods of Testing and Results in
eye velocity is a more reliable way of assessing the Normal Subjects
accuracy of smooth pursuit than simply observ-
ing the frequency of superimposed saccades. The simplest optokinetic stimulus is a striped
Abnormalities of smooth pursuit are of lim- cloth that can be moved across the patient’s
ited localizing value, as they occur with disor- visual field in each direction. While the patient
ders throughout the CNS. Acute lesions of the stares at the cloth, the amplitude of induced
peripheral labyrinth or vestibular nerve tran- nystagmus in each direction is compared. This
siently impair smooth pursuit contralateral to type of test permits identification of absent or
the lesion when the eyes are moving against the markedly asymmetric optokinetic nystagmus
slow component of spontaneous nystagmus.73 (OKN). The test sensitivity is improved by
This asymmetry in smooth pursuit disappears using an optokinetic stimulus of known velocity
within a few weeks despite the continued pres- and recording the induced nystagmus. Figure
ence of spontaneous nystagmus in darkness. 7–16 shows such a recording of OKN induced
Just as tranquilizing drugs, alcohol, and fatigue by a striped drum completely surrounding a
affect saccadic eye movements, they also impair subject and moving at a constant velocity of
smooth pursuit eye movements.74 Barbiturates 30 degrees/sec. At the arrow, the lights were
may impair smooth pursuit before affecting sac- turned off and optokinetic after-nystagmus
cadic eye movements, which suggests an (OKAN) was recorded. A plot of slow-
increased sensitivity of the smooth pursuit component velocity is provided beneath the
system. Patients with diffuse cortical disease75 tracing. Typically, the OKN slow-component
(degenerative or vascular), basal ganglia velocity approaches that of the drum velocity as
(a)
Target 15º
position
R
15º
Patient 1 1 sec
L
Patient 2
(b)
60º/sec
Drum
velocity
15º 60º/sec
0º/sec
Patient 1
15º 1 sec R
L
Patient 2
15º
Figure 7–15. Right monocular recordings of horizontal smooth pursuit (a) and optokinetic nystagmus (OKN) (b) from two
patients with left parietal lobe lesions.77 In A the patients tracked a laser dot moving in a sinusoidal fashion (left: 0.2 Hz, peak
velocity 22.5°/sec; right: 0.4 Hz, peak velocity 45°/sec). In B a surrounding optokinetic drum moved in a sinusoidal pattern
(0.05 Hz, peak velocity 60°/sec). Pursuit and OKN slow phases to the left were markedly impaired.
long as the drum velocity does not exceed 30 to velocity (after the initial rapid dropoff) and the
40 degrees/sec. As with smooth pursuit gain, mean OKAN duration in 20 normal subjects
the gain of OKN (slow-component velocity/ after 1 min of 30 degrees/sec optokinetic stim-
drum velocity) drops off with increasing fre- ulation was 6.3 degrees/sec ± 4.5 degrees/sec
quency and drum velocities in normal subjects and 23.75 sec ± 23.1 sec, respectively.79
(Fig. 7–17).79 The OKAN velocity is more vari-
able than OKN velocity even in young normal Results in Patients
subjects. There is a rapid exponential dropoff
followed by a gradual decay, as shown in As a general rule, abnormalities of optokinetic
Figure 7–16. The mean OKAN slow-component slow components parallel abnormalities in
a
Lights out
15º
b
5 sec
SCV (deg/sec)
30
20
10
0
55 60 0 5 10
Time (sec)
Figure 7–16. Optokinetic nystagmus (OKN) induced by a surrounding striped drum moving at a constant velocity of
30°/sec. At the arrow the lights were turned off, and optokinetic after-nystagmus (OKAN) was recorded. a Bitemporal
electronystagmographic recording. b Plot of slow-phase velocity (SCV) versus time.
70
60
Slow Phase Eye Velocity (deg/sec)

50
40
30
20
10
0 10 20 30 40 50 60 70
Optokinetic Drum Velocity (deg/sec)
Figure 7–17. Normal mean ± 1 standard deviation for horizontal optokinetic nystagmus slow-phase velocity at different
drum velocities. ο, ramp acceleration from 0° to 70°/sec in 1 min; , constant velocity for 30 sec; ∆, sinusoidal (0.05 Hz).
smooth pursuit, and abnormalities of fast saccades produce OKN, the waveform is
components correlate with abnormalities of rounded, and the amplitude and slow-
voluntary saccades.79 Symmetrically decreased component velocity are decreased. The delayed
slow-component velocity is produced by dif- ending of the impaired fast component sub-
fuse disease of the cortex, diencephalon, brain tracts from the initial part of the slow compo-
stem, and cerebellum.37,54,58,62,75 As with smooth nent in the opposite direction. The many causes
pursuit, focal lateralized disease of the parietal of saccade slowing were outlined in detail in
occipital region, brain stem, and cerebellum the previous section.
result in impaired OKN when the stimulus Abnormalities of OKAN are typically seen
moves toward the damaged side (see with peripheral vestibular lesions.81 Unilateral
Fig. 7–15b).77,78 Lesions of the occipital lobe, lesions result in asymmetric OKAN (present only
although associated with a hemianoptic visual in the direction of the spontaneous nystagmus),
field defect, are not associated with impaired whereas bilateral lesions (e.g., due to ototoxic
smooth pursuit or OKN, presumably because drugs) result in diminished or absent OKAN in
each parietal lobe receives oculomotor signals both directions.79
from both occipital lobes. Some patients with
severely impaired smooth pursuit exhibit a
gradual buildup in OKN slow-component
velocity.80 This is a feature of OKN normally ROTATIONAL TESTING OF
seen in afoveate animals that have only a sub- VESTIBULO-OCULAR REFLEXES
cortical OKN system (see Chapter 3).
Presumably, in normal humans the cortical The determination of which vestibular subor-
pursuit system dominates the subcortical OKN gans are stimulated by rotation of the head
system, so normal OKN exhibits features of requires knowledge of three factors: (1) the
normal pursuit. When the cortical pursuit sys- axis of rotation, (2) the orientation of the skull
tem is lesioned, however, the remaining OKN (and thus the labyrinth) with respect to the
may exhibit features of the subcortical system. rotation, and (3) the orientation of the rotation
Patients who are unable to produce saccadic with respect to gravity (Fig. 7–18). Currently,
eye movements produce only a slow tonic devi- rotational tests of the vestibulo-ocular reflexes
ation of the eyes in the direction of an optoki- concentrate on the horizontal semicircular
netic stimulus. Although patients with slow canal ocular reflex (yaw, z-axis rotation) because
z-axis
Roll
Pitch
y-axis
x-axis
Yaw
Off-center rotation Off-vertical rotation

Figure 7–18. Definitions of different axes and orientations for rotational testing.
it is the easiest reflex to stimulate and record. Rotational testing of the horizontal semicir-
Rotational tests of the vertical semicircular cular canal offers several advantages over
canals and otoliths are still in the developmen- caloric testing. Multiple graded stimuli can be
tal stage and are not generally available in most applied in a relatively short period of time, and
clinical settings (Table 7–4). the testing is usually well tolerated by patients.
Table 7–4 Vestibular Tests and the Suborgans They Stimulate

Test Horizontal Canals Vertical Canals Otoliths
Conventional rotational chair +
Upright pitch rotation + +
Onside pitch rotation +
Static ocular counterrolling +
Dynamic ocular counterrolling + +
Eccentric rotation + +
Off-vertical rotation + +
Linear track +
Parallel swing +
Unlike caloric testing, a rotational stimulus to can be accurately monitored. Figure 7–19 illus-
the semicircular canals is unrelated to physical trates the nystagmus responses of a normal
features of the external ear or temporal bone, subject to three common types of angular
so a more exact relationship between stimulus acceleration used in clinical laboratories. The
and response is possible. However, rotational subject was rotated in the z-axis with the eyes
stimuli affect both labyrinths simultaneously, open in complete darkness while he performed
in contrast to the selective stimulation of one continuous mental arithmetic to maintain alert-
labyrinth possible with caloric testing. ness. Each stimulus produced a peak angular
According to the pendulum model intro- chair velocity of 120 degrees/sec.
duced in Chapter 2, the slow-component veloc- As with caloric testing, maximum slow-
ity of rotational-induced nystagmus should be component velocity is the response measure-
proportional to the deviation of the cupula, ment most useful for quantifying testing. The
which, in turn, is proportional to the intensity coefficient of variation (standard deviation
of stimulation. As will be demonstrated in the divided by the mean) for maximum slow-
following sections, this model’s applicability to component velocity after a rotational stimulus
different forms of rotational stimulation pro- is about one-half the coefficient of variation
vides a rational approach to the evaluation of after a caloric.82 Even with this increased preci-
clinical rotational testing. sion, however, there is still large variation in the
rotational responses of normal subjects. Factors
such as stress, fatigue, level of mental alertness,
Relationship between Stimulus and and habituation all contribute to the variability
Response (see Chapter 3). Complete darkness is needed
so that the patient cannot fixate on a target.
The slow-component velocity profiles
PASSIVE WHOLE-BODY YAW
(Fig. 7–19d–f) for each stimulus can be pre-
ROTATION
dicted by the pendulum model discussed in
With standard rotational chairs, the angular Chapter 2. Note the similarity between these
acceleration in the z-axis can be precisely con- profiles and the time course of cupula devia-
trolled and multiple response measurements tion illustrated in Figure 2–15. An important
a Chair velocity d
60
120
60 40
0 20
Slow component velocity (deg/sec)
0
EOG 10 20 30 40 50
60 80 100
0
10 sec 15º
b Chair velocity 5
80 e
120
0 40
120 0
40 10 20 30 40 50
EOG 15º 80
10 sec
c Chair velocity 30 f
120
60
20
0 10
EOG 0
10 sec 15º
0 10 20 30 40 50
Seconds
Figure 7–19. Nystagmus recording (a–c) and slow-component velocity profile (d–f) with three types of angular accel-
eration, each resulting in a maximum velocity of 120°/sec. With the impulse stimulus (a) the change in velocity occurs
in < 1 sec, with an acceleration of 140°/sec2. The sinusoidal stimulus (b) has a frequency of 0.05 Hz (20 sec/cycle) and
a maximum acceleration of 38°/sec2. The constant acceleration stimulus (c) is 4°/sec2 for 30 sec (horizontal bitemporal
electrooculorgraphic [EOG] recordings).
feature not addressed by the simple pendulum in all three axes—yaw, pitch, and roll. Although
model is the adaptation phenomena (see expensive rotational devices are available for
Chapter 2). The step response best illustrates passively rotating the whole body at high accel-
the effect of adaptation on induced nystagmus. erations in all three planes, the tests can also be
Instead of slowly returning to the baseline as performed with passive head-on-body rotation
would be predicted by the pendulum model, by manually moving the head with small-
the velocity of the slow component reverses amplitude thrusts in all three planes (as is done
direction and then slowly returns to the base- with the bedside head-thrust test).87 The eye
line (as shown in Fig. 7–19a, d). Reversals of movement recording system must be precise
this type consistently occur in normal subjects enough to measure the small-amplitude, high-
when the step change in angular velocity is >100 velocity eye movements that are induced. The
degrees/sec.83 scleral search coil technique is a sensitive eye
Two types of measurements are typically movement recording system that has been used
used to quantify the response to these tradi- to record these types of eye movements in
tional rotational stimuli: a magnitude (gain) research laboratories. With this system, the sub-
and a timing (time constant or phase shift) ject is seated within a set of external reference
measurement. The gain is defined as the peak magnetic field generator coils and wears a con-
slow-phase eye velocity divided by the peak tact lens that contains tiny “receiving” coils to
stimulus (chair) velocity. The time constant of record horizontal, vertical, and torsional eye posi-
the step response is defined as the time required tion.88 Similar coils can be attached to the head to
for the response to decay to 1/e or to 37% of accurately measure head position. VNG systems
the maximum value. For a sinusoidal test, the that are tightly coupled to the head to prevent
phase is typically measured by comparing the slippage are just becoming available.89 ENG is
time of the maximum head velocity (measured not sensitive enough and, of course, it can only
by chair velocity) with the time of the maxi- accurately record horizontal eye movements.
mum slow-phase eye velocity. Consistent with The unique advantage of the high-acceleration
models of the canal-ocular reflex, the maximum test is that one can measure gain in the time
slow-phase eye velocity leads the maximum domain early after the onset of the stimulus.
head velocity at low frequencies of sinusoidal Early gain measurements (<50 msec after the
rotation in normal subjects. The time constant stimulus) reflect an almost pure vestibulo-
(TCOR) of the canal-ocular reflex measured after ocular response, since visual and other modula-
a step change in angular velocity is inversely tory central influences occur later in the
related to the phase lead (θ) at low frequencies response. Another unique advantage of the
of sinusoidal rotation by84 high-acceleration test is that it is more sensitive
than traditional low-acceleration testing for
1 identifying the difference between ampullopetal
TCOR = [3]
and ampullofugal responses when there is a uni-
w q
lateral loss of function (see later discussion).
where ω = 2πF.
ACTIVE HEAD ROTATION
(AUTOROTATION)
HIGH-ACCELERATION
SMALL-AMPLITUDE ROTATION Active head-only rotational testing is a method
for assessing the VOR that can potentially be
Brief high-acceleration impulses provide a performed at the bedside or in the clinic with
unique assessment of the VOR not available inexpensive, transportable equipment.90–92
with traditional stimuli.85,86 Accelerations >2000 Patients are taught to move their head back
degrees/sec2 are typically applied for <200 msec, and forth in a sinusoidal pattern, typically in
leading to a head position change of 10 to 15 the range of 0.5 to 3 or 4 Hz. The test can theo-
degrees. By contrast, most commercially avail- retically be performed in all three axes, although
able motorized chairs have a weight-dependent subjects find it easiest to rotate their head in
peak acceleration <150 degrees /sec2. Because the yaw axis. To date, eye movements have
only a small amplitude of head displacement is mostly been recorded with ENG, but with this
produced, the head accelerations can be applied system only horizontal eye movements can be
accurately recorded. Auditory cueing is typically line fitted to the data. The normal mean gain
used to instruct the patient to perform the head and TCOR values calculated from similar plots
rotations but somatosensory cues may provide in 20 normal subjects were 0.63 ± 0.18 and
an even better training stimulus.93 The test can 12.2 ± 3.6 sec, respectively.84 These values are
be performed either at discrete sinusoidal fre- relatively stable over a wide range of step
quencies or by a sweep of frequencies, although changes in velocity (0 to 250 degrees/sec), but
the latter stimulus may be more difficult to both show a gradual decrease with larger-
train. Gain and phase measurements can be magnitude impulses (>120 degrees/sec).82,83
made after frequency analysis of the data; this The variance associated with measurements
analysis is similar to that performed with pas- comparing clockwise and counterclockwise
sive whole-body rotation. Of course, at these responses in the same subject is less than the
higher frequencies, no nystagmus is recorded variance in response between subjects. A nor-
and the sensitivity of the eye movement record- malized difference formula, [(clockwise −
ing system becomes more important. A major counterclockwise) ÷ (clock wise + counter-
advantage of the autorotation test is that it pro- clockwise)] × 100, is analogous to the directional
vides a measurement of gain for the VOR in preponderance formula used with caloric test-
the frequency range (>1 Hz) in which it nor- ing. Greater than 20% asymmetry on this nor-
mally functions.94 Disadvantages include the malized difference formula is considered
following: patients may have difficulty perform- abnormal in our laboratory.
ing the movements,92 responses may vary with
practice,92 poor test-retest inter-individual Sinusoidal Changes in Angular Velocity
repeatability,95 and extravestibular influences
such as preprogrammed compensatory eye With sinusoidal rotational testing, the gain of
movements and neck-ocular responses can the canal-ocular reflex can be measured at mul-
help compensate for vestibular loss.96,97 tiple discrete frequencies after the subject has
attained a steady-state response. It usually pro-
vides a more accurate assessment of gain than is
Results in Normal Subjects obtained with the step test. The main disadvan-
tage is the more time that it takes to test a broad
PASSIVE WHOLE-BODY YAW frequency range. Also, unlike the step test,
ROTATION sinusoidal testing measures only a single time
constant (the low-frequency phase lead reflects
Step Changes in Angular Velocity the average time constant in both directions).
The main advantage of the step stimulus is that Two standard computer plots generated dur-
it provides a rapid assessment of the gain and ing sinusoidal rotational testing in a normal sub-
the time constant of the canal-ocular reflex in ject are shown in Figure 7–21a. The subject was
each direction. Because the stimulus is brief, rotated at 0.05 Hz (peak velocity 60 degrees/
however, if subjects are not maximally alert or if sec) with eyes open in the dark while perform-
they attempt to suppress the response, the ini- ing continuous mental alerting tasks. As with the
tial peak will be blunted and the estimate of step data shown in Figure 7–20, each dot repre-
gain, inaccurate. For this reason, several mea- sents the average slow-component velocity over
surements should be averaged in each direc- a 25-msec interval. The gain (peak slow-compo-
tion. The results of a typical response to a step nent velocity/peak chair velocity) in each direc-
change in velocity in a normal subject are shown tion can be read directly from these plots, or an
in Figure 7–20a. Slow-component velocity (log- average gain can be calculated by performing a
arithmic scale) is plotted versus time; each dot frequency analysis (Fourier analysis) on the
represents the average slow-component veloc- data. From this analysis, one obtains the gain, dc
ity over a 25-msec interval. Fast components bias, and phase relationship between the funda-
have been removed. The gain (peak slow-com- mental of the slow-component velocity and the
ponent velocity/peak chair velocity) can be read chair velocity.70 If the slow-component velocity
directly from these plots. The time constant data are symmetrical (as in normal subjects), the
(TCOR) represents the time required for the phase can be read directly from these plots by
slow-component velocity to fall to 37% of its comparing the time of the maximum or the zero
peak value given by the slope of a regression eye velocity with that of the chair velocity.
(a) CW CCW
130
90 Gain = 0.78 Gain = 0.75
TCOR = 12.0 TCOR = 14.1
50
SCV
10
0 10 20 30 0 10 20 30
(b) CW CCW
130
90 Gain = 0.50 Gain = 0.95
TCOR = 5.2 TCOR = 11.2
50
SCV
10
0 10 20 30 0 10 20 30
Time (seconds)
Figure 7–20. Plots of nystagmus slow-component velocity (SCV) (log scale) versus time after a step change in angular
velocity (100°/sec acceleration 140°/sec2) in a normal subject (a) and a patient with an acute right peripheral vestibular
lesion (b). Gain is peak SCV divided by change in chair velocity. TCOR is the slope of a regression line best fit to the data.
CCW, counter clockwise; CW, clockwise, (see text for details).
However, if the responses are asymmetric (as in a rapid visual assessment of dc bias and
Fig. 7–21b), an accurate assessment of phase facilitates measurement of an average gain
can be obtained with a Fourier analysis of the in each direction (i.e., the slope of the line
data. The plot of slow-component velocity ver- in each direction). As with step-rotational
sus stimulus velocity (Fig. 7–21, right) provides stimuli, >20% asymmetry on the standard
(a) Gain = 0.58 Gain R = 0.64

80 Phase = 8 L = 0.54
DCBias = 1.2 DCBias = 0
40
Slow Component Velocity (deg/sec)
0 Normal
–40
–80
(b) Gain = 0.54

80 Phase = 25 Gain R = 0.72
DCBias = 12.8 L = 0.37
DCBias = 9
40
0 Patient
–40
–80
0 20 40 80 40 0 –40 –80
Time (sec) Stimulus Velocity (deg/sec)
Figure 7–21. Plots of nystagmus slow-component velocity versus time (left) and versus chair velocity (right) during sinu-
soidal angular rotation (0.05 Hz, 60°/sec peak velocity) in a normal subject (a) and a patient with an acute right peripheral
vestibular lesion (b) (same patient as in Fig. 6–20). The gain, phase (lead) and dc bias (+ rightward bias) were determined
from frequency analysis (Fourier analysis) of the data.
directional preponderance formula is consid- in Figure 7–23.87 The impulses are passive,
ered abnormal for all frequencies and ampli- unpredictable, low-amplitude (10–20 degrees),
tudes of stimulation. high-acceleration 3000 to 4000 degrees/s2)
The gain and phase of the canal-ocular reflex head rotations (head thrusts) in yaw, pitch, and
vary with frequency in normal subjects roll with the subject sitting upright. Head and
(Fig. 7–22),84 which is consistent with the pen- eye position and velocity are almost equal and
dulum model. Normal subjects exhibit an opposite (gain near 1.0) for yaw and pitch
approximate 45-degree phase lead of eye veloc- impulses, so there is relatively little change in
ity relative to chair velocity at 0.01 Hz, but this gaze position. By contrast, the compensatory
phase lead is near zero by 0.2 Hz. eye movement in the roll plane has a gain of
about 0.8, so there is a gaze instability in this
HIGH-ACCELERATION, plane. This difference in normal gain in the
LOW-AMPLITUDE ROTATION three planes of rotation can be more readily
seen in plots of eye velocity versus head veloc-
Typical responses to a high-acceleration impulse ity shown in Figure 7–24 (top traces). In the
in all three planes in a normal subject are shown yaw and pitch planes, the slope is near 1.0
1.0
Gain
0.1
0.05
80
70
60
50
40
Phase
30
20
10
–10
0.01 0.1 1.0
Frequency (Hz)
Figure 7–22. Plots of the gain and phase (mean ± 1 standard deviation) of the horizontal canal-ocular reflex as a function
of frequency in 10 normal subjects (ο), 20 patients with compensated unilateral vestibular lesions ( ), and 22 patients with
bilateral peripheral vestibular lesions (∆). All subjects were tested with mental alerting in the dark. The unilateral patients
had absent caloric response on one side; the bilateral patients had symmetrically decreased response to caloric stimulation.85
The peak velocities at different frequencies were 0.0125 Hz, 100°/sec; 0.05 and 0.2 Hz, 60°/sec; 0.4 and 0.8 Hz 30°/sec.
Yaw Pitch Roll

0.1 Head
| 5º Eye
Position (RV) Gaze
0.0
Onset
–0.1
–0.2
125
Velocity (º/sec)
–125
–250 Right Up CCW
0 100 200 0 100 200 0 100 200

Time (ms)
Figure 7–23. Head, gaze and eye positions and velocities in normal subjects during a yaw-right, pitch-up, and a roll-
counterclockwise (GCW) head thrust. The eye signals are inverted for illustration. The arrows indicate the onset of head
movement. Note the gaze instability with roll thrusts. (From Au ST et al. Head impulses reveal loss of individual semicircu-
lar canal function. J Vestib Res. 1999;9:173–180, with permission.)
(gain near 1.0), whereas the slope is about 0.8

Results in Patients
in the roll planes.
UNILATERAL PERIPHERAL LESIONS
ACTIVE HEAD ROTATION Patients who suddenly lose vestibular function

on one side have asymmetric responses to rota-
Most normal subjects can produce near-perfect tional stimuli because of (1) a dc bias resulting
compensatory eye movements in the frequency from spontaneous nystagmus and (2) the differ-
range of 1 to 4 Hz with active sinusoidal head ence in response to ampullopetal and ampull-
movements (Fig. 7–25).96 When the scleral ofugal stimulation of the remaining intact
search coil technique is used to record eye labyrinth.84 These features are readily seen in
movements in the horizontal and vertical passive yaw rotation data shown in Figures
planes, the gain measurements are close to 1.0 7–20b and 7–21b. The patient was tested shortly
and phase changes are near zero over this wide after the acute onset of vertigo due to a right
frequency range (Fig. 7–26). Interestingly, peripheral vestibular lesion (probable viral neu-
the VOR gain from active head rotations is rolabyrinthitis). At the time of testing, he exhib-
consistently higher than the gain from passive ited a spontaneous left-beating nystagmus (eyes
head rotations in this frequency range in open in the dark) with an average slow-phase
normal subjects (Fig. 7–26). Normative data velocity of 10 degrees/sec. This spontaneous
from studies using ENG to record eye move- nystagmus added to rotational-induced nystag-
ments have been more variable. Some investi- mus in the same direction and subtracted from
gators have found gains in excess of 1.1 in that in the opposite direction. The effects of
the high-frequency range and others have this dc bias and of the asymmetry in response to
reported poor test–retest reliability of the gain ampullopetal and ampullofugal stimulation of
measurements.95,97,98 Vertical gain and phase the intact labyrinth are best illustrated in the
measurements are particularly unreliable plot of eye velocity versus stimulus velocity
with ENG, with a wide range of normative val- from sinusoidal rotation (see Fig. 7–21b, right
ues being reported. In our experience this test side). The dc bias (the eye velocity at the point
is overused and overinterpreted. of Y-intercept) is equivalent to the average
YAW PITCH ROLL

200 Z Y X
Normal
100
0
Z Y X
–100
–200
200 Z Y X
LuPCO
100
0
Z Y X
–100
–200
200
Eye Velocity (deg/sec)
LuSD Z Y X
100
0
Z Y X
–100
–200
200 LuVD Z Y X
100
0
Z Y X
–100
–200
200 bVD Z Y X
100
0
Z Y X
–100
Right Left Up Down CW
–200 CCW
–200 –100 0 100 200 –200 –100 0 100 200 –200 –100 0 100 200
Head Velocity (deg/sec)
Figure 7–24. Eye velocity as a function of head velocity during roll, pitch, and yaw head thrusts in a normal subject and
in four patients with the following conditions: after left unilateral posterior canal occlusion (LuPCO); after left unilateral
deafferentation of the superior branch of the vestibular nerve (LuSD); after left unilateral vestibular deafferentation
(LuVD); and after bilateral vestibular deafferentation (bVD). The ten trials in each direction are displayed. CCW, counter-
clockwise; CW, clockwise. (From Au ST et al. Head impulses reveal loss of individual semicircular canal function. J Vestib
Res. 1999;9:173–180, with permission.)
slow-phase velocity of the spontaneous nystag- With compensation, the dc bias gradually
mus. The gain (slope) of the response with disappears and the gain asymmetry between
ampullopetal stimulation of the intact labyrinth ampullopetal and ampullofugal stimula-
is twice that with ampullofugal stimulation. tion decreases but does not disappear.99,100
(a)
100
50
–50 G = 1.04
(c) 100
–100
80
0 1.0 2.0 3.0 4.0 5.0 6.0
60

(b) 40
100
Head Velocity (deg/sec)
20
50 0
–20
0 –40
–60
–50
–80
–100 –100
0 1.0 2.0 3.0 4.0 5.0 6.0 –100 –50 0 50 100
Time (sec) Head Velocity (deg/sec)
Figure 7–25. Eye movements recorded with a scleral search coil during self-generated (active) head oscillations in the
pitch plane. (a) head velocity, (b) Eye velocity data are fitted to sinusoids (solid curves) for those cycles meeting the statisti-
cal criterion for acceptance, while cycles rejected due to artifacts are indicated by horizontal bars. (c) The graph plots phase-
corrected eye velocity against head velocity; the slope corresponds to gain (G). The two flanking lines indicate boundaries of
the region in which data points were accepted for analysis. (From Demer JL et al. Visual–vestibular interaction in humans
during active and passive, vertical head movement. J Vestib Res. 1993;3:101, with permission.)
It remains most pronounced after high-intensity asymmetries associated with unilateral vestibu-
stimuli. These dynamic asymmetries in the lar lesions.101,102
canal-ocular reflexes can best be determined in By performing high-acceleration, small-
the laboratory by using high-acceleration, amplitude head thrusts in all three planes, one
small-amplitude impulses or high-frequency, can assess the function of the three pairs of
high-acceleration sinusoidal rotations.86,87,101,102 semicircular canals (Fig. 7–24).86,87 For exam-
Brief high-acceleration head thrusts in normal ple, a patient who underwent blockage of the
subjects result in little gaze instability, whereas left posterior semicircular canal for treatment
in patients with a unilateral vestibular loss, of benign paroxysmal positional vertigo showed
accelerations toward the side of the lesion a prominent decrease in VOR gain during
produce a prominent gaze shift in that upward pitch and counterclockwise roll head
direction because of the lack of a compensatory thrusts (Fig. 7–24, LuPCO). A patient with
VOR response (Fig. 7–27a). This same involvement of all three semicircular canals on
gaze deviation phenomenon can be seen the left side showed a prominent decrease in
with high-frequency sinusoidal rotation; the VOR gain with horizontal head thrusts to the
deviation is most prominent at the highest fre- left and approximate symmetrical decrease in
quencies when the head rotates toward the gain with up-and-down pitch movements and a
lesion side (Fig. 7–27b). Interestingly, this gaze prominent decrease in gain with counterclock-
deviation during ipsilesional rapid head wise roll (Fig. 7–24, LuVD). Thus, directional
movements is greater with passive rotation deficits in response to ipsilesional head thrusts
than with active head rotations, suggesting that allows one to identify the individual semicircu-
with active rotations patients are able to lar canal lesions. The abnormalities are best
compensate partially for the lack of a compen- identified by measuring VOR gain close to peak
satory VOR response. It follows that passive head velocity, where the disinhibition input
head rotations at high accelerations are from the intact side approaches saturation
best suited for identifying the dynamic values. Recall that inhibition is produced by
1.75
1.50
1.25
VOR Gain
1.00
0.75
0.50
0.0 1.0 2.0 3.0 4.0
5
Active VOR
4
Passive VOR
3
2
Phase - deg
1
0
–1
–2
–3
–4
–5
0.0 1.0 2.0 3.0 4.0
Frequency - Hz
Figure 7–26. Vestibulo-ocular reflex (VOR) gain and phase from nine normal subjects tested at multiple single frequen-
cies during passive and active head rotations in the pitch plane. Gain was greater during active head rotations than during
passive rotations in the mid-frequency range. Phase was near zero for both types of rotation.
ampullofugal stimulation of the horizontal are observed. However, with a unilateral loss of
semicircular canals and ampullopetal stimula- vestibular function, aberrant torsional eye
tion of the vertical canals. In addition to the movements are generated during up-and-down
dynamic asymmetries in VOR responses in the head thrusts. These aberrant torsional eye
planes of the three sets of semicircular canals, movements could contribute to sensations of
patients with unilateral peripheral vestibular tilt often reported by patients with unilateral
lesions develop anomalous (out of the plane of vestibular lesions.102
rotation) eye movements that contribute to gaze Patients with compensated unilateral periph-
instability and to complaints of oscillopsia.102 eral vestibular lesions show a characteristic
For example, vertical head thrusts in the pitch pattern of decreased gain and increased phase
plane result in anomalous torsional eye move- lead at low frequencies of sinusoidal z-axis rota-
ments due to loss of the normally balanced ver- tion (see Fig. 7–22).103 These changes appear to
tical canal inputs (Fig. 7–28). Normally the ver- be fixed in that they can be observed as long as
tical canals on each side generate a torsional 10 years after an acute unilateral peripheral
component that is perfectly balanced with pitch vestibular loss.100 Their functional implications
rotation so that no torsional eye movements are minimal, however, as the visuomotor system
a Control Patient
R
Gaze
L
R
Head
L
10 10
250 ms 250 ms
b R
Gaze
L
R
Head
L
Active
5
500 ms
R
Gaze
L
R
Head
L
Passive
Figure 7–27. Gaze stability during horizontal head rotations in the light in a normal subject and in a patient with right
peripheral vestibular loss (after a nerve section). a The head is passively moved in quick steps (thrusts) to the right and
left. Gaze is stable in the control whereas in the patient there are prominent gaze shifts to the right with head thrusts to
the right. b Active and passive sinusoidal rotations of the patient’s head show the same gaze instability with movements to
the right, but the gaze instability is much greater with passive than with active (self-generated) movements. (From Foster
CA et al. Defects of gaze stability in multiple axes following unilateral vestibular lesions. Exp Brain Res. 1997;116:501, with
permission).
can compensate for the loss of vestibular func- identified earlier. Furthermore, artifactually
tion in the low-frequency range. decreased caloric responses occasionally occur
in patients with angular, narrow external canals
BILATERAL PERIPHERAL LESIONS or with thickened temporal bones. Because the
intensity of rotational stimuli is unrelated to
Rotational stimuli are ideally suited for testing these physical features, rotational-induced nys-
patients with bilateral peripheral vestibular tagmus is normal in such patients. Frequently
lesions because both labyrinths are stimulated patients with absent response to bithermal
simultaneously and the degree of remaining caloric stimulation have decreased but record-
function is accurately quantified.84,86,104,105 able rotational-induced nystagmus, particularly
Because the variance associated with normal at higher frequencies of sinusoidal rotation
rotational responses is less than that associated (see later discussion). The ability to identify
with caloric responses, diminished function is remaining vestibular function—even if
a Head Head
moving moving
up down
∗ ∗ ∗
CW Torsional gaze
| 10º
CCW position
Torsional gaze
| 100º/s
velocity
Torsional fast phase
up Vertical head
| 10º
position
down
| 400º/s Vertical head

velocity
1 sec
b Head movement Involuntary torsional

upward begins movement
| 10º Torsional gaze

Slow phase position
CW
| 50º/s Torsional gaze
CCW velocity
| 10º Torsional head

position
CW Torsional head
| 50º/s
CCW velocity
1 sec No torsional head

movement has occured
Figure 7–28. Aberrant torsional eye movements induced by self-generated, vertical head thrusts in a patient with a
left-sided peripheral vestibular loss. a Clockwise (CW) torsional eye movements are more prominent during upward
(first arrow) than downward (second arrow) head movement. Gaze deviations were corrected with torsional quick phases
(asterisks). b There are no torsional head movements during these vertical head thrusts to account for the torsional eye
movement responses. CCW, counterclockwise. (From Foster CA et al. Defects of gaze stability in multiple axes following
unilateral vestibular lesions. Exp Brain Res. 1997;116:501, with permission.)
minimal—is an important advantage of rota- gain of rotational-induced nystagmus. Lesions

tional testing, particularly when the physician involving the nerve root entry zone and vestib-
is contemplating ablative surgery or monitor- ular nuclei may produce responses indistin-
ing the effects of ototoxic drugs. By using pre- guishable from those produced by peripheral
cisely graded rotational stimuli on a serial basis, vestibular lesions. The spectrum of abnormali-
ototoxic effects are recognized earlier than by ties associated with central lesions, however, is
using the less-precise caloric stimulus. much more diverse than a simple decrease in
Patients with bilateral peripheral vestibular the gain. The gain may be increased in some
loss show the same pattern of low-frequency patients with cerebellar lesions.108 The highly
gain and phase deficits on sinusoidal testing organized pattern of the nystagmus produced
(only more pronounced) observed in patients in normal subjects may be disorganized, result-
with compensated unilateral peripheral vestibu- ing in so-called dysrhythmic nystagmus. If the
lar lesions (see Fig. 7–22).106 Rarely, patients production of fast components is impaired, the
may have no response to rotation at frequencies nystagmus waveform is distorted or there may
below 0.05 Hz and yet have normal responses at be only a slow tonic deviation of eyes from side
higher frequencies.84 These findings have to side. In this case, high-acceleration impulses
important clinical implications with regard to or high-frequency sinusoidal rotation are the
testing patients with suspected bilateral periph- only stimuli that can be used to measure VOR
eral vestibular disease. Given that the results of gain. Finally, central lesions often interfere
the bithermal caloric test reflect the results of with the integration of visual and vestibular sig-
low-frequency sinusoidal stimulation, the nals, producing abnormalities on tests of visual–
absence of caloric response does not indicate an vestibular interaction (see later discussion).
absence of vestibular function. In fact, a patient Low-frequency sinusoidal rotational stimuli
could have absent caloric response yet normal are ideally suited for studying the pattern of
response to traditional rotational testing at induced nystagmus. Figure 7–29 illustrates the
higher frequencies (up to 1 Hz). However, high- responses to sinusoidal rotation (eyes open in
acceleration, small-amplitude head thrusts can darkness) in (a) a normal subject, (b) a patient
be very sensitive for identifying bilateral periph- with cerebellar atrophy, (c) a patient with a left
eral vestibular loss, particularly if one focuses on pontine lesion (astrocytoma), and (d) a patient
the first 100 msec after the impulse.107 Central with a bilateral lesion of the medial longitudi-
compensation mechanisms cannot make up for nal fasciculus (MLF). In the normal subject
the loss of peripheral vestibular function in this the eyes alternately deviate in the direction of
time domain. Interestingly, patients who show the fast component for each half-cycle of
minimal or no early VOR response after high- induced nystagmus. As discussed in Chapter 3,
acceleration head thrusts can have reasonably the eye position in the orbit for initiation of fast
good responses during sinusoidal head rotation components is near the midline. Fast compo-
at higher frequencies.107 These nonvestibular nents (saccades) are generated in the parame-
oculomotor responses are presumably gener- dian pontine reticular formation, and the
ated by using whatever residual vestibular func- cerebellum controls the amplitude of both vol-
tion remains and other sensory clues that are untary and involuntary saccades. In the patient
available. These nonvestibular compensatory with cerebellar atrophy (Fig. 7–29b), the nys-
eye movements are most pronounced with tagmus pattern is disorganized with fast com-
active head rotations, presumably because the ponents occurring in random fashion, causing
patient can use information generated by the marked beat-to-beat variability in amplitude.
volitional head movements to improve the com- This type of abnormality has been termed dys-
pensatory eye movements. This must be kept in rhythmia and is commonly found in patients
mind, however, when using autorotational tests with all varieties of cerebellar lesions. Patients
to screen for bilateral vestibular loss. with dysrhythmic vestibular nystagmus also
demonstrate dysmetria of voluntary saccades.
The patient with a left pontine lesion (see
CENTRAL VESTIBULAR LESIONS
Fig. 7–29c) could not produce voluntary or
As with lesions of the peripheral vestibular involuntary saccades (fast components) to the
structures, lesions of the central VOR pathways left, so during the half-cycle that normally
can lead to a decrease or an asymmetry in the produces left-beating nystagmus, the eyes
Chair velocity
60º/sec
0º/sec
60º/sec
(a) Right eye
15º
(b) Right eye

15º
(c) Right eye

15º
(d) Right eye
15º
R
Left eye
L
15º
5 sec
Figure 7–29. Electronystagmographic recordings of nystagmus response to sinusoidal rotation at 0.05 Hz, peak velocity
60°/sec in a normal subject (a) and in patients with cerebellar atrophy (b), left pontine glioma (c), and bilateral medial
longitudinal fasciculus lesions caused by multiple sclerosis (d).
tonically deviated to the right. In patients with however, are normal because the abducting mus-
bilateral pontine lesions, the eyes tonically cles (abducens nuclei) receive their innervation
deviate to the right and left with each half-cycle for fast components directly from the parame-
of rotation because of the complete absence of dian pontine reticular formation with no involve-
fast components.57 One might mistakenly inter- ment of the MLF. Frequently, the abducting fast
pret this as a decreased or absent vestibular components are actually too large. The oculomo-
response. tor control centers attempt to overcome the block
In the patient with a bilateral MLF lesion at the MLF by increasing the innervation sent
(Fig. 7–29d), there is a dissociation in fast compo- from the paramedian pontine region to the ocul-
nents between the two eyes. When either paretic omotor neurons.109,110 Because (according to
adducting eye is required to make a fast compo- Herring’s law) this increased innervation is sent
nent, the nystagmus beats are rounded because equally to both medial and lateral rectus oculo-
of a decrease in the frequency of action potentials motor neurons, the difference in amplitude
arriving at the medial rectus motor neurons via between adducting and abducting fast compo-
the damaged MLF. Abducting fast components, nents is further magnified.
VISUAL–VESTIBULAR visual–vestibular interaction is typically tested

INTERACTION by rotating the subject either sinusoidally or with
a step change in velocity while (1) the surround-
The model introduced in Chapter 3 (Fig. 3–21) ing optokinetic drum is stationary (visualvestib-
represented two general types of visual–vestibular ulo-ocular reflex [VisVOR], a synergistic
interaction: one mediated via the “direct” (pur- interaction of the visual and vestibular systems)
suit) pathway and the other via the indirect or (2) the drum and chair are coupled so that
(velocity storage) pathway. Because the direct they move together (fixation suppression of the
pathway is dominant in humans, clinical tests vestibulo-ocular reflex [VOR-FIX], an antago-
have focused on pursuit–VOR interaction. In nistic interaction between the visual and
rare patients with selective lesions of the direct vestibular systems).111 Fixation suppression can
pathway, it is possible to demonstrate visual– also be tested by rotating the subject in the dark
vestibular interaction mediated via the indirect with a single fixation light attached to the chair.
velocity storage pathway (see later discussion).
Results in Normal Subjects
Methodology Typical responses of a normal subject to low-
frequency sinusoidal (0.05 Hz) optokinetic
Since the visual tracking systems function best at (OKN), vestibular (VOR), and visual-vestibular
low frequencies and low velocities, visual– (VisVOR and VOR-FIX) stimulation are shown
vestibular interaction is most prominent at low in Figure 7–30 (left). In each case, the peak
frequencies and low velocities. In the laboratory, stimulus velocity is 60 degrees/sec. At this low
Normal Subject Right Peripheral Bilateral Peripheral
40
Right
0 OKN
Left
–40
40
Slow Phase Velocity (deg/sec)
0 VOR
–40
40
0 VisVOR
–40
40
0 VOR-FIX
–40
0 10 20 30 0 10 20 30 0 10 20 30
Time (sec)
Figure 7–30. Plots of slow-phase velocity versus time from a low-frequency visual–vestibular test battery (see text for
details) in a normal subject (left), a patient who underwent a right labyrinthectomy (center), and a patient with bilateral
vestibulopathy secondary to ototoxic drugs (right) (0.05 Hz, peak velocity 60°/sec). OKN, optokinetic nystagmus; VisVOR,
visual-vestibulo-ocular reflex; VOR, vestibulo-ocular reflex; VOR-FIX, fixation suppression of VOR. (From Baloh RW, et al.
Quantitative vestibular testing. Otolaryngol Head Neck Surg. 1984;92:1,45, with permission.)
frequency and peak velocity, the normal sub- (see Fig. 7–30, center and right). Even with a
ject has a VisVOR gain of 1.0 (i.e., the slow- complete loss of vestibular function, the visuo-
phase eye velocity is equal and opposite to the motor system can provide good ocular stability.
head velocity) and a VOR-FIX gain of 0 (i.e., At high frequencies and velocities, however,
the subject is able to completely suppress the the VisVOR gain decreases if the VOR gain
VOR with fixation). The mean gain ± standard decreases.112
deviation for similar sinusoidal testing in 20 Three abnormal patterns of visual–vestibular
normal subjects is as follows: OKN 0.83 ± 0.13; interaction seen on low-frequency sinusoidal
VOR 0.50 ± 0.15; Vis-VOR 0.99 ± 0.05; VOR- testing in patients with central lesions are
FIX 0.03 ± 0.02. At high frequencies (>1 Hz) shown in Figure 7–31.111 Patients with lesions
and velocities (>50 degrees/sec), the OKN (and involving the vestibular nucleus region (e.g.,
pursuit) gain decreases (e.g., see Fig. 7–17). Wallenberg’s syndrome) exhibit prominent ocul-
Above 2 Hz, the VisVOR and VOR-FIX gain omotor abnormalities (see Stroke Syndromes,
are approximately the same as the VOR gain Chapter 14). With eyes open in the sitting posi-
(near 1.0). tion, there is a tonic pulling of the eyes toward
the side of the lesion, resulting in spontaneous
nystagmus with the fast phase toward the intact
Results in Patients side. With eyes closed or with eyes open in
darkness, the spontaneous nystagmus may
Patients with peripheral vestibular lesions have change direction. The responses illustrated in
decreased and/or asymmetric VOR gain, but Figure 7–31 (left) are from a 32-year-old man
visual–vestibular responses are usually normal who had the acute onset of vertigo, nausea,
at low stimulus frequencies and velocities vomiting, dysphagia, and falling to the left.
Left Lateral Bilateral Left Parietal

Medullary Vestibulocerebellum Lobe
40
0 OKN
–40
40
0 VOR
–40
40
0 VisVOR
–40
40
0 VOR-FIX
–40
0 10 20 30 0 10 20 30 0 10 20 30
Time (sec)
Figure 7–31. Plots of slow-phase velocity versus time from a low-frequency visual–vestibular test battery in a patient with
infarction of the left lateral medullary region (left), a patient with midline cerebellar atrophy (center), and a patient with
a glioma in the deep parietal lobe on the left side (right) (0.05 Hz, peak velocity 60°/sec). OKN, optokinetic nystagmus;
VisVOR, visual-vestibulo-ocular reflex; VOR, vestibulo-ocular reflex; VOR-FIX, fixation suppression of VOR. (From Baloh
RW, et al. Quantitative vestibular testing. Otolaryngol Head Neck Surg. 1984;92:145, with permission.)
On neurologic examination, he exhibited spon- As noted earlier, in patients with minimal or

taneous nystagmus to the right while fixating, no sinusoidal VOR, VisVOR, and VOR-FIX,
and to the left in the dark. He also presented responses are almost identical (e.g., Fig. 7–31,
with ipsilateral facial hypalgesia, Horner’s syn- center). These patients may show evidence of
drome, and extremity ataxia, and contralateral visual–vestibular interaction with impulse stim-
extremity hypalgesia. The OKN and VOR uli, however. The patient with cerebellar atro-
responses were asymmetric but in opposite phy, whose data are shown in Figure 7–32, had
directions, consistent with the changing direc- absent pursuit and sinusoidal OKN but exhib-
tion of the patient’s spontaneous nystagmus ited a gradual buildup in OKN after a step onset
from light to dark. Despite the decreased OKN in drum velocity. The gain (initial peak eye veloc-
gain, the VisVOR gain was normal in both ity/peak stimulus velocity) of the step responses
directions. Fixation suppression of VOR slow was the same regardless of whether the patient
phases toward the side of the lesion was received (1) a VisVOR stimulus (i.e., a step
impaired. A similar pattern of abnormalities from 0 to 60 degrees/sec in the light with a
was found in six other patients with infarction
in the lateral medulla.113 100
Patients with lesions involving the vestibulo-
cerebellum are unable to modify vestibular 40
responses with vision.114 This is illustrated by 20
the patient data shown in Figure 7–31 (center),
10 VOR
in which the VOR, VisVOR, and VOR-FIX
gains are approximately the same (nearly 1.0)
and the OKN gain is markedly decreased in
both directions. This patient was a 31-year-old
woman who complained only of unsteadiness 0
and oscillopsia. The results of neurologic exam- 100

ination were normal except for spontaneous
40
downbeat nystagmus and truncal ataxia.
Computerized tomography (CT) and magnetic 20
resonance (MR) scanning documented atrophy 10 VOR-FIX
of the midline cerebellum.
Lesions of the visuomotor pathways from
the parieto-occipital cortex to the pons
(i.e., those shown in Fig. 3–23) lead to impaired 0
smooth pursuit and optokinetic slow phases 100
toward the side of the lesion.77 The abnormal
visual-ocular control does not impair VOR 40
responses but does alter visual–vestibular inter- 20
action. Typical responses to the four sinusoidal
10 VisVOR
rotational test conditions in a patient with a
deep parietal lobe lesion are shown in Figure
7–31 (right). This 21-year-old man developed
bitemporal headaches and slowly progressive
right facial and upper-extremity weakness. An 0
0 20 40
angiogram identified a tumor blush in the left Time (sec)
parietal region. A left parietal brain biopsy
revealed a grade II astrocytoma. The OKN gain Figure 7–32. Vestibulo-ocular reflex (VOR), fixation sup-
pression of VOR (VOR-FIX), and visual-VOR (VisVOR)
was normal to the right and markedly decreased responses to step rotational stimuli (0° to 60°/sec, 140°/sec2
to the left. The VOR gain was normal in both acceleration) in a patient with cerebellar atrophy. The log
directions, but the patient was unable to inhibit of slow-phase eye velocity is plotted against time. For the
VOR slow phases to the right with fixation (i.e., VOR the chair was stopped in the dark, for the VOR-FIX
the chair was stopped in the light, and for the VisVOR the
the VOR-FIX gain was increased to the right). chair was maintained at a constant velocity in the light with
The VisVOR gain was slightly asymmetric, with a stationary surround. (From Baloh RW, et al. Late cortical
lower gain to the left than to the right. cerebellar atrophy. Brain. 1986;109:159, with permission.)
fixed surround), (2) a VOR-FIX stimulus (i.e., roll to the side of the lesion results in less coun-
stopping the rotating chair in the light with a terrolling than roll away from the side of the
fixed surround), or (3) a VOR stimulus (i.e., start- lesion.117,118 With some types of central lesions
ing or stopping the chair in darkness). However, one can see a roll rather than a counterroll
the rate of decay in slow-phase velocity (i.e., the response (i.e., the eyes rotate in the direction
time constant) was prolonged after a VisVOR of head tilt).119,120 However, the responses are
stimulus and shortened after a VOR-FIX stimu- too variable to be a reliable test for identifying
lus, compared with the VOR stimulus. Thus, one the side of a unilateral lesion.
type of visual–vestibular interaction (that medi-
ated via the velocity storage pathway) was pre-
served in a patient with absent smooth pursuit. Eccentric Rotation
In summary, in addition to tests of the VOR,
rotational testing includes tests of visual– Eccentric (off-center) rotation is delivered by
vestibular interaction. Lesions of the periph- seating a subject upright in a conventional rota-
eral vestibular system typically impair only the tional chair such that the head is away from the
VOR, whereas lesions of the CNS impair OKN axis of rotation as if the head were placed at the
and visual–vestibular interaction. The pattern end of the arm of a centrifuge (see Fig. 7–18).
of abnormal response can help localize lesions During angular acceleration with the head
within the central pathways. eccentric, the labyrinth is exposed to both rota-
tional and linear (tangential and centrifugal)
acceleration, and thus both the otolith organs
and the horizontal semicircular canals are stim-
TESTS OF OTOLITH–OCULAR ulated. Once a constant angular velocity is
REFLEXES achieved, however, only the otoliths are stimu-
lated. The net linear acceleration delivered to
Ocular Counterrolling the subject is the vector summation of the lin-
ear acceleration produced by the movement
The otolith-ocular reflex produces torsional eye itself and the linear acceleration produced by
movements during static head tilts. Rotating the gravity (See Fig. 1-3b). The advantages of
head toward the right shoulder causes the eyes eccentric rotation are that conventional rota-
to counterrotate to the left (see Chapter 3). tional chairs (with minor modifications) and
Such rotation of the head in the coronal plane is EOG methods can be used for this test.
called roll, and the counterrotation of the eyes is With sinusoidal angular acceleration the dif-
called ocular counterrolling.115,116 Dynamic roll ference between eye movements induced with
movements also stimulate the vertical semicir- the head at the center of rotation and those with
cular canals because of the angular acceleration the head eccentric is the contribution of the oto-
of the movement, so when using roll stimulation lith organs.121–123 An even simpler test of otolith
a distinction should be made between static and function is to have the subject estimate the sub-
dynamic ocular counterrolling. jective vertical (with a vertical light bar) during
The clinical use of ocular counterrolling has constant velocity eccentric rotation.124,125 Unlike
been hampered by difficulties both in stimulus other tests of subjective vestibular sensation,
delivery and in the measurement of response. the sensation of tilt experienced during eccen-
In order to rotate someone in the coronal plane, tric rotation appears to be highly reproducible.
the subject must be securely fastened to a cum- Patients who have undergone a unilateral ves-
bersome device. In addition, the amount of tibular neurectomy experience less of a sensa-
torsional eye movement produced by a static tion of tilt when the lesioned ear is outermost.124
tilt in the coronal plane is relatively small. For The deficit is maximum in the first postopera-
example, if the head is tilted 45 degrees, tive week but persists for at least 24 weeks.126
the eyes counterroll only about 7 degrees.
Electrooculography is insensitive to this type of
movement, so video recording or the magnetic Off-Vertical Rotation
scleral search coil must be employed.
Unilateral peripheral vestibular lesions can pro- Off-vertical rotation is performed by seating
duce asymmetries in static ocular counterrolling; the subject in a conventional rotational chair
and then tilting the entire apparatus, including Furthermore, the asymmetry in the linear VOR
the chair and subject (see Fig. 7–18).127,128 In gain after an acute unilateral vestibular lesion
this way, as the subject rotates, the head is con- disappears within a few months.137
tinually changing its orientation with respect to
gravity. In the extreme case, in which the chair
is tipped completely on its side (earth-
horizontal axis, or so-called barbecue rotation), VESTIBULOSPINAL TESTING
the subject is rotated from supine to lateral to
prone to lateral, and so on.129,130 Once a con- Current tests of vestibular function concen-
stant velocity is achieved, only the otolith trate on the vestibulo-ocular system: the
organs are stimulated (because the canals vestibulospinal system has been relatively
respond only to angular acceleration). neglected. A major reason for this neglect is
A major advantage of this type of otolith test that it is difficult to assess the role of the ves-
is that a conventional rotatory chair can be used tibulospinal system in isolation of the other
if the angle of inclination is kept small. Subjects sensory systems.
can be placed into or moved from the appara-
tus easily, and conventional EOG can record
the eye movements because they are largely Static-Force Platforms
horizontal. A disadvantage is that the stimulus
often produces nausea. Off-vertical constant The simplest method of recording human pos-
velocity rotation in normal subjects induces tural sway employs a force plate. There are sev-
two horizontal eye movement components: a eral devices of this type, each designed with
bias and a modulation component.129,130 In the basic idea of recording the position of a
patients with unilateral peripheral vestibular subject’s center of mass during upright stance.
lesions, the bias component is diminished when In fact, these devices measure the position of
the patient rotates toward the involved ear the center of pressure (COP), which is a good
while the modulation component remains estimate of the position of the center of mass if
unchanged.131 the body is moving slowly. The COP is mea-
sured with force transducers in the force plate
and then differentiated to give instantaneous
Linear Acceleration sway velocity (Fig. 7–33).138 The major limita-
tion of such devices relates to two factors:
Another technique that has been used to study (1) the nervous system uses a combination of
the otolith ocular reflex in the research labora- sensory modalities during the maintenance of
tory is to deliver a linear acceleration on a lin- upright stance, and (2) static force plates do
ear track or a parallel swing.132–135 As with not yield controlled stimulus–response mea-
eccentric rotation, the otolith organs sense the sures of vestibulospinal function and thus must
net linear acceleration—that is, the vector rely on spontaneous movements of the body.
summation of the linear acceleration induced This latter consideration is analogous to mak-
by the device itself and that due to gravity. For ing assessments of the vestibulo-ocular system
the relatively simple case in which the subject by simply monitoring eye position in the
is placed on the device facing the side as if absence of vestibular stimulation. The mea-
looking out the side window of an automobile surement of postural sway might be useful as a
moving forward, a consistent horizontal eye screening test for imbalance, but the informa-
movement (the linear VOR) can be recorded. tion it provides is nonspecific and probably not
For other head orientations vertical or torsional helpful for identifying vestibular lesions.138–140
eye movements are induced, requiring eye
movement recording techniques such as a
magnetic scleral search coil or video system. Moving-Platform Posturography
Although patients with complete unilateral and
bilateral vestibular loss consistently show a Moving-force platforms have been designed to
diminished linear VOR gain compared to overcome the limitations of static-force plat-
controls,134,136,137 the test is not sensitive for forms discussed above by (1) controlling the
identifying partial loss of vestibular function. relative contributions of the visual, somatosensory,
Eyes open Eyes closed Eyes open Eyes closed

COPAP (mm)
80 80
0 0
–80 –80
SAP (mm/s)
400 400
0 0
–400 –400
0 5 10 0 5 10 0 5 10 0 5 10
Time (sec)
Figure 7–33. Examples of posturography raw data from a static and dynamic test in an older subject with eyes open
and closed. Upper traces, sway position (center of pressure [COP]) in the anterior–posterior (AP) directions; lower traces,
sway velocity in the anterior–posterior ( AP) directions.
and vestibular inputs that are normally used to signals have been effectively removed.140,143,144
maintain upright posture; and (2) incorporat- However, preliminary reports that moving-
ing stimulus–response measurements. By cou- platform posturography can identify sites of
pling the platform to the sway of the subject, it lesion or specific vestibular disorders have not
is possible to maintain the angle between the been confirmed. Dynamic posturography is not
foot and the lower leg at a constant value, a diagnostic test but rather a method to quan-
thereby reducing a major source of somatosen- tify balance dysfunction under different sen-
sory input to the postural control system.141 sory conditions (Fig. 7–34).145,146 It may be
A similar effect can be achieved by having helpful for identifying people at risk for falling,
the subject stand on a thick foam rubber pad. although it is not clear if it is better at this than
If the subject simultaneously closes the eyes or a careful clinical assessment.147 Posturography
if the movement of the visual enclosure is cou- may also be helpful in distinguishing between
pled to body sway, the subject is also deprived organic and function balance disorders.148
of visual information about postural sway. In
this way, the influence of the labyrinth on
upright posture via the vestibulospinal system
can be studied in a more or less isolated fash- VESTIBULAR-EVOKED POTENTIALS
ion.142 The disadvantage of this technique is
that during postural sway many of the subor- Brain Stem and Cortical
gans of the vestibular labyrinth are simultane-
ously stimulated, including the vertical semicir- The ability to record a human brainstem vestib-
cular canals and the otolith organs bilaterally. ular-evoked potential has obvious merits, as it
For this reason, moving-platform studies are would provide an objective measure of periph-
incapable of providing an assessment of the eral vestibular function that would be indepen-
individual suborgans of the vestibular labyrinth. dent of either the oculomotor or postural
In addition, these devices do not assess the control systems. Despite the fact that short
subject’s strategy in moving other body parts latency sensory-evoked potentials using auditory,
and joints. Not surprisingly, patients with bilat- visual, and somatosensory inputs have been
eral peripheral vestibular loss perform poorly developed and are in routine clinical use, vestibu-
on these tests when visual and somatosensory lar-evoked potentials are not routinely available.
AP ML AP ML AP ML AP ML
160 160 160 160
Sway Sway Sway Sway Sway Sway Sway Sway
120 120 120 120

Eyes
80 80 80 80 Open
40
Sway Velocity (mm/sec)
40 40 40
0 0 0 0
160 160 160 160
120 120 120 120
80 80 80 Eyes
80
Closed
40 40 40 40
0 0 0 0
Static Foam AP-Tilt ML-Tilt
Young controls
Older controls
Older patients
Figure 7–34. Mean sway velocity (vertical bar = 1 standard deviation) in young (black bars) and older (gray bars) controls
and older patients with imbalance (striped bars) for the four standard posturography test conditions. AP, anterior–posterior;
ML, medial–lateral. In the two graphs to left, the platform was still; in the two graphs to the right, the platform tilted up and
down sinusidally about a central axis (0.10 Hz, 4° peak amplitude) (see Fig. 6–33).
One reason for this lack of development is clinical vestibular laboratory. Pulsed galvanic
related to the difficulty of delivering a vestibu- stimulation over the mastoid can induce a syn-
lar stimulus that is capable of triggering a coor- chronized volley within the vestibular-cochlear
dinated volley of neural activity, a requirement nerve, but this stimulus is also uncomfortable
for eliciting a measurable evoked potential.149 and could even lead to potential nerve damage.
The vestibular equivalent of an auditory click,
visual flash, or somatosensory prick is a brief,
abrupt, high-intensity rotational impulse with Vestibular Evoked Myogenic
an angular acceleration in the range of 7000 Potentials (VEMPs)
degrees/sec2.
Prior research regarding human vestibular- MECHANISM OF STIMULATION
evoked potentials has focused upon recording
long-latency cortical potentials rather than Vestibular evoked myogenic potentials were
brainstem–evoked potentials.150,151 The results first recorded in the 1960s, but it wasn’t until
of these studies are conflicting. It is still unclear the 1990s that the clinical application of this
whether the recorded potentials are specific technique was appreciated.152–154 Animal stud-
for the vestibular stimulus. Short-latency ves- ies show that both air and bone conducted
tibular-evoked potentials have been induced in sound activates otolith afferents (utricular and
animals and in humans149 using brief, high- saccular) but rarely semicircular canal
acceleration head displacements, but because afferents.155 Consistent with this observation it
of the complex methodology required and the was shown that sound-evoked potentials
potential discomfort to the patients, this type recorded from electrodes over the sterno-
of testing will not likely become available in the cleidomastoid muscle in patients persisted
despite profound sensorineural hearing loss consistent potentials appear to be obtained

but disappeared after vestibular nerve sec- from electrodes placed beneath the eyes and
tion.156 The motor neurons of cervical flexor on the cheeks while the subject is instructed to
muscles receive inhibitory input from the sac- look upward.162 The stimuli (e.g., tone burst)
cule and intramuscular recordings in the ster- can then be introduced and the response
nocleidomastoid muscle show that the initial recorded. Since oVEMPs are smaller in ampli-
positivity of the VEMP is produced by an inhi- tude than cVEMPs, more averaging may be
bition of the underlying motor units.157,158 Based needed.
on this data there is a general consensus that
cervical VEMPs (cVEMPs) are saccular and NORMATIVE DATA
inferior vestibular nerve dependent. More
recently it has been shown that VEMPs can The typical cVEMP consists of a positive/
also be recorded from electrodes placed near negative wave labeled p13 and n23 based on the
the eyes (ocular VEMPs or oVEMPs).159 These approximate latency and polarity (Fig. 7–35).163
potentials are not due to eye movement or cVEMP amplitude is linearly related with back-
electro-oculographic potentials. Since the vast ground muscular tension, so the p13-n23
majority of otolith ocular connections originate amplitude should be divided by the mean value
from the utricle, oVEMPs could be useful for of the rectified EMG. The response is much
assessing utricular function.160 Consistent with larger in the ear ipsilateral to the stimulus and
this premise patients with vestibular neuritis is larger for tone bursts than for clicks
(which typically involves just the superior divi- (Fig. 7–35). Since the responses depend on
sion of the vestibular nerve) were found to normal sound transmission through the middle
often have normal cVEMPs but absent ear, patients with middle ear disease such as
oVEMPs.161 otosclerosis may have absent responses. Of
particular importance, the p13-n23 amplitude
of cVEMPs decreases with age so the test is
TEST METHODOLOGY
less useful in older patients.163 Each laboratory
For recording cVEMPs electrodes are placed should establish normative data, but in our lab-
over the most prominent part of the sterno- oratory greater than 50% amplitude asymme-
cleidomastoid muscles and reference elec- try and absolute amplitude values below 100
trodes are placed on the clavicles. The record- microvolts are considered abnormal. We do
ings must be made when the sternocleidomastoid not routinely use latency measurements.
muscles are contracting. The simplest way to Normative data have not been established
achieve this is to have the subject raise their for oVEMPs, but when the recording elec-
head while lying supine. Many different stimuli trodes are placed beneath the eyes, contralat-
have been used, including air- and bone-con- eral responses are much larger than ipsilateral
ducted sounds, skull taps, and galvanic current, responses (i.e., the reflex is crossed). This is
but the most commonly used stimulus in our consistent with the crossed utriculo-ocular
laboratory is an air-conducted high-intensity pathway.
(100 to 130 dB SPL) low-frequency tone burst
with a center frequency of about 500 Hz
RESULTS IN PATIENTS
(2 msec rise/fall time, 2 msec plateau). Since
the myogenic evoked potentials are large in Since cVEMPs reflect activity originating in the
amplitude, usually more than 100 microvolts) saccule and carried in the inferior vestibular
only a small number need be averaged. nerve, vestibular lesions that damage the saccule
Typically three stimulation sequences (rate of and/or inferior vestibular cause abnormal
four per second) are given, each consisting of cVEMPs. About 50% of patients with Meniere’s
64 tone bursts. To correct for interindividual/ syndrome have a decreased or absent cVEMP on
interside/intertest variations in tonic muscle the involved side when tested between
contraction, a separate channel is used to obtain attacks.164,165 Furthermore, cVEMPs can be used
a numerical value for background muscle to monitor the effect of intratympanic gentamicin
tension (rectified EMG). injection for treatment of Meniere’s syndrome.166
Standard methodology has not been devel- cVEMPs are abnormal in about 55%–80% of
oped for recording oVEMPs, but the most patients with vestibular schwannomas.165,167,168
Right Ear Right Ear

500 Hz toneburst, 130 dB peSPL click, 100 dB HL
n23
n23
Right
SCM
p13
p13
Left
SCM
100 µV 100 µV
20 msec 20 msec
Figure 7–35. Vestibular evoked myogenic potentials (VEMPs) recorded from the right and the left sternocleidomas-
toid (SCM) in response to sound stimulation to the right ear in a healthy individual. Sound stimuli were either 500 Hz
tonebursts with an intensity of 130 dB peSPL or 100 dB HL clicks. The vertical dashed lines shows stimulus onset (the 20
millisecondsec prestimulus recordings were used for measuring background muscular tension). Although there are typical
positive-negative VEMPs on the side ipsilateral to the sound stimulation, there is only a weak inverted response on the con-
tralateral side. Note that VEMPs in response to tone bursts have longer latencies compared with those in response to clicks
and amplitudes in response to tonebursts are larger than those in response to clicks. (From Brantberg K. Vestibular evoked
myogenic potentials (VEMPs): usefulness in clinical neurotology. Semin Neurol. 2009;29:541 with permission.)
Stim Right (affected ear) Stim Left (healthy ear)

Right SCM Left SCM
n23
130 SPL
n23
p13
p13
5 ms 100 µv
100 SPL n23
p13
Figure 7–36. Vestibular evoked myogenic potentials (VEMPs) illustrate the typical hyperactive response and reduced
threshold in a patient with superior semicircular canal dehiscence syndrome on the right side. Active electrodes were
placed over the superior part of the sternocleidomastoid muscle (SCM), and the reference electrodes were placed near the
mid-portion of the clavicle. High-intensity (100 to 130 dB sound pressure level [SPL]), low-frequency (500-Hz tone bursts,
2-ms rise/fall time, and 2-ms plateau) sounds were presented monaurally via TDH-49P headphones. Three stimulation
sequences (rate of four per second) were given, each consisting of 64 tone bursts. The mean curves are shown below the
three repetitions for each stimulus.
This is comparable to the rate of abnormal caloric 9. Schmid-Priscoveanu A, Allum JH. Infrared and video
responses. Theoretically the test should reflect oculography – alternatives to electrooculography?
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Chapter 8
Clinical Evaluation of Hearing
TYPES OF HEARING DISORDERS TYMPANOMETRY

Conductive The Acoustic Reflex
Sensorineural AUDITORY-EVOKED RESPONSES
Central Hearing Disorders Electrocochleography
BEDSIDE TESTS OF HEARING Brainstem Auditory-Evoked Response
BEHAVIORAL AUDIOMETRY GENERATING POTENTIALS
The Audiogram TEST METHODOLOGY
Speech Recognition Tests RESULTS IN PATIENTS
Stenger Test CENTRAL AUDITORY SPEECH TESTS
IMPEDANCE AUDIOMETRY SUMMARY OF AUDITORY TEST RESULTS
TYPES OF HEARING DISORDERS The most common serious cause of conductive

hearing loss is inflammation of the middle ear,
Hearing disorders can be classified as conduc- or otitis media. Either infected (suppurative oti-
tive, sensorineural, and central, based on the tis) or noninfected (serous otitis) fluid accumu-
anatomic site of lesion. A battery of audiologi- lates in the middle ear, impairing the conduc-
cal tests can help localize the lesion within the tion of airborne sound. Otosclerosis produces
anatomical pathways.1,2 progressive conductive hearing loss by immobi-
lizing the stapes with new bone growth in front
of and below the oval window. Other causes of
Conductive conductive hearing loss include large tympanic
membrane perforations, trauma, congenital
Conductive hearing loss results from lesions malformations of the external and middle ears,
involving the external or middle ear. The and tumors of the temporal bone.
tympanic membrane and ossicles act as a trans-
former amplifying airborne sound and effi-
ciently transferring it to the inner ear fluid (see Sensorineural
“Middle Ear” in Chapter 2). If this normal
pathway is obstructed, transmission may occur Sensorineural hearing loss results from lesions
across the skin and through the bones of the of the cochlea and/or the auditory division of
skull (bone conduction), but at the cost of con- the eighth cranial nerve.3 The spiral cochlea
siderable energy loss. mechanically analyzes the frequency content of
The most common cause of conductive hear- sound. For high-frequency tones, only sensory
ing loss is impacted cerumen in the external cells in the basal turn are activated, whereas for
auditory canal. This benign condition is often low-frequency tone maximum stimulation
first noticed after bathing or swimming, when occurs at the apex, even though all or nearly all
water closes the remaining tiny passageway. sensory cells are activated with loud sounds.
219
Therefore, with lesions of the cochlea and its Central Hearing Disorders
afferent nerve, hearing levels for different fre-
quencies are often unequal, and the timing Central hearing disorders result from lesions of
(phase) relationship between different fre- the central auditory pathways: the cochlear and
quencies may be altered. Patients with sen- dorsal olivary nuclear complexes, inferior col-
sorineural hearing loss often have difficulty liculi, medial geniculate bodies, and auditory
hearing speech that is mixed with background cortex in the temporal lobes and their intercon-
noise and may be annoyed by loud speech. necting afferent and efferent fiber tracts. As a
Distortion of sound is common with sen- rule, patients with central lesions do not have
sorineural hearing loss. A pure tone may impaired hearing levels for pure tones, and
be heard as noisy, rough, or buzzing, or it they understand speech if it is clearly spoken in
may be distorted so that it sounds like a a quiet environment. If the listener’s task is
complex mixture of tones. Binaural diplacusis made more difficult with the introduction of
occurs when the two ears are affected unequally background or competing messages, perfor-
so that the same frequency has a different mance deteriorates in patients with central
pitch in each ear; that is, the patient hears lesions more than in normal subjects. Lesions
different sounds in each ear. Monaural dipla- involving the nerve root entry zone or cochlear
cusis occurs when two tones or a tone and noise nucleus can result in unilateral hearing loss for
are heard simultaneously in one ear. With pure tones (e.g., demyelination or infarction of
recruitment there is an abnormally rapid the lateral pontomedullary region). Because at
growth in the sensation of loudness as the least 50% of afferent nerve fibers cross central
intensity of a sound is increased so that faint or to the cochlear nucleus, this is the most central
moderate sounds cannot be heard, whereas structure in which a lesion can result in a uni-
there is little or no change in the loudness of lateral hearing loss.
loud sounds.
Sudden unilateral deafness is a common syn-
drome with ill-defined pathophysiology.4
Probably most cases are due to viral infections BEDSIDE TESTS OF HEARING
involving either the cochlea or auditory nerve.5
Viral infections can be part of a systemic viral A quick test for hearing loss in the speech range
illness such as measles, mumps, and infectious is to observe the response to spoken commands
mononucleosis or an isolated infection of the at different intensities (whisper, conversation,
labyrinth or eighth nerve without systemic shouting).6 The examiner stands behind the
symptoms. Mumps is a particularly common patient to prevent lip reading and occludes and
cause of unilateral hearing loss in school-aged masks the non-test ear by moving a finger back
children. Other common causes of acute uni- and forth in the patient’s external ear canal.
lateral hearing loss are head trauma and vascu- Finger rubs at different intensities and dis-
lar occlusive disease. tances from the ear have been shown in a rigor-
Relapsing unilateral sensorineural hearing ous study to be a rapid, reliable, and valid
loss associated with tinnitus, ear fullness, and screening test for hearing loss in the frequency
vertigo is typical of Meniere’s syndrome. range of speech.7 If a patient can hear a faint
Ototoxic drugs produce a bilateral subacute finger rub stimulus at a distance of 70 cm
hearing loss, and acoustic neuromas (vestibular (approximately one arm’s length) from one ear,
schwannomas) characteristically produce a then a hearing loss on that side—as defined by
slowly progressive unilateral sensorineural a gold standard audiogram threshold of >25 dB
hearing loss. The chronic progressive bilateral at 1000, 2000, and 4000 Hz—is highly unlikely.
hearing loss associated with advancing age is On the other hand, if a patient cannot hear a
called presbycusis. It may include conductive strong finger rub stimulus at 70 cm, then a hear-
and central dysfunction, but the most consis- ing loss on that side is highly likely.7 Tuning fork
tent effect of aging is on the sensory cells and tests permit a rough assessment of the hearing
neurons of the cochlea.5 Genetic disorders level for pure tones of known frequency.
account for the majority of cases of sensorineu- Clinicians can use their own hearing level as a
ral hearing loss in children (see “Hereditary reference standard. The Rinne test compares
Disorders” in Chapter 18). the patient’s hearing by air conduction with that
8 Clinical Evaluation of Hearing 221
by bone conduction. The fork (256 or 512 Hz) The Audiogram

is first held against the mastoid process until the
sound fades. It is then placed 1 inch from the Pure tones are defined by their frequency and
ear. Normal subjects can hear the fork longer their intensity. To quantify the magnitude of
by air than by bone conduction. If bone con- hearing loss, normal hearing levels have been
duction is greater than air conduction, a con- established. These levels approximate the inten-
ductive hearing loss is suggested. The Weber sity of the faintest sounds that can be heard by
test compares the patient’s hearing by bone normal ears. A patient’s hearing level (HL) is
conduction in the two ears. The fork is placed at the difference in decibel (dB) between the
the center of the forehead or on a central inci- faintest pure tone that the patient can hear and
sor and the patient is asked where he or she the normal reference level given by the stan-
hears the tone. Normal subjects hear it in the dard, where 0 dB HL is the sound pressure level
center of the head, patients with unilateral con- (SPL) at which listeners with normal hearing
ductive loss hear it on the affected side, and are able to perceive the signal 50% of the time.
patients with unilateral sensorineural loss hear Brief-duration tones at selected frequencies are
it on the side opposite the loss. Though these presented by earphones (air conduction) and a
tuning fork tests can be useful in some clinical vibrator pressed against the mastoid portion of
settings, they are not considered to be reliable the temporal bone (bone conduction). The
or valid screening tests.6 results of air and bone conduction testing are
plotted on a graph from which the magnitude of
the sensitivity loss (in dB) as a function of fre-
BEHAVIORAL AUDIOMETRY quency is determined (Fig. 8–1). A simple way
to summarize the severity of hearing loss is to
Audiometry typically consists of a battery of calculate the pure tone average (PTA) = the
tests, the differential results of which provide average hearing level at 500, 1000, and 2000
site-of-lesion information.1 It typically begins Hz. For example, if the hearing level is 40 dB,
with pure-tone threshold testing to compare a 50 dB, and 60 dB at 500, 1000, and 2000 Hz,
subject’s hearing sensitivity to norms at selected respectively, then the PTA is 50 dB, considered
frequencies (the audiogram). a moderate hearing loss (Table 8–1).
Frequency in Hz
125 250 500 1000 2000 4000 8000 125 250 500 1000 2000 4000 8000
Hearing level in dB re ANSI, 1969
0 0
10 10
20 20
30 30
40 40
50 50
60 60
70 70
80 80
90 90
100 100
110 110
Air Bone (with masking)

Right
ear
Left
ear
Figure 8–1. Pure-tone audiogram: left ear, normal; right ear, conductive hearing loss due to otosclerosis.
Table 8–1 Severity of hearing loss bone conduction. There is a <5 dB attenuation
based on the pure tone average (PTA) between the two ears for a bone conduction
receiver placed on any part of the skull. Therefore,
Normal 0-25 dB a nonhearing ear may appear to have nearly nor-
Mild Hearing Loss 26-40 dB mal hearing via bone conduction if the normal
Moderate Hearing Loss 41-55 dB ear is not properly masked. The best masking
Moderate Severe Hearing Loss 56-70 dB sound for pure tones is a narrow band of white
Severe Hearing Loss 71-90 dB noise centered about the pure tone being tested.
Profound Hearing Loss >90 dB Lesions producing sensorineural hearing loss
impair both air and bone conduction, often
PTA = Average of hearing levels at 500, 1000 and
2000 Hz.
with changing pure tone levels at different fre-
quencies. Although the audiogram does not
provide specific diagnostic information to iden-
With a conductive hearing loss, air conduction tify the site of lesion, certain patterns suggest
is impaired while bone conduction remains nor- specific diagnoses. Typical audiograms seen in
mal (i.e., an air-bone gap on the audiogram, Fig. patients with four common causes of sen-
8–1, right ear). Measurement of bone conduc- sorineural hearing loss are shown in Figure 8–2.
tion requires careful masking of the nontest ear. None of these patterns is pathognomonic of a
Masking involves introducing airborne noise into given disorder, but they occur often enough to
the nontest ear to eliminate cross-hearing via be of diagnostic value.
Frequency in Hz
A 125 250 500 1000 2000 4000 8000 B 125 250 500 1000 2000 4000 8000
0 0
10 10
20 20
30 30
40 40
50 50
60 60
Hearing level in dB re ANSI, 1969
70 70
80 80
90 90
100 100
110 110
C 125 250 500 1000 2000 4000 8000 D 125 250 500 1000 2000 4000 8000
0 0
10 10
20 20
30 30
40 40
50 50
60 60
70 70
80 80
90 90
100 100
110 110
Figure 8–2. Audiograms illustrating four common patterns of sensorineural hearing loss. (A) Notched pattern of noise-
induced hearing loss. (B) Downward sloping pattern of presbycusis. (C) Low-frequency trough of Meniere’s syndrome. (D)
V-pattern of congenital hearing loss.
Speech Recognition Tests suspect ears. The signals are turned on together
and the patient is asked to respond as long as
Two categories of tests are used to determine the tone is on. As long as the tone is below the
the patient’s ability to hear and understand actual threshold in the suspect ear, the patient
speech: (1) the speech reception threshold and will hear the sound in the other ear and respond.
(2) speech discrimination. If the tone in the suspect ear is then increased
The speech reception threshold (SRT) is the above its true threshold, the patient will either
intensity at which the patient can correctly fail to respond or show confusion, being
repeat 50% of highly familiar two-syllable unaware of the sound in the good ear and not
words (e.g., airplane, cowboy, sidewalk). The wanting the examiner to know that he hears the
SRT is an estimate of the minimum level sound in the suspect ear. A patient with true
of conversation that a person can hear. It unilateral loss will of course only hear the sound
provides a check on the validity of the pure- presented in the good ear and quickly respond.
tone audiogram, as it should agree (±5 dB) Although screening tests are usually done at
with an average of the two best pure-tone one intensity, a more complete test can be
thresholds in the speech range (500 to 2000 done at multiple intensities or using the same
Hz). It is not a test of discrimination, but it procedure with spondee words. Of course, the
does provide information about a patient’s abil- Stenger test works only with a unilateral loss, as
ity to recognize and respond to speech. a minimum 20 dB threshold difference is
Occasionally, a patient who is profoundly deaf required at the test frequency.10
or aphasic cannot repeat words. In such cases a
speech detection threshold (SDT) is obtained
by having the patient respond to a speech
signal. IMPEDANCE AUDIOMETRY
The speech discrimination test is a measure
of the patient’s ability to understand speech Impedance may be defined as the resistance of
when it is presented at a level that is easily a given system to the flow of energy. Acoustic
heard. For this test, the patient is usually pre- impedance refers to the resistance of the mid-
sented with 50 phonetically balanced monosyl- dle ear system to the passage of sound. Its
labic words at a comfortable listening level reciprocal, acoustic compliance, refers to the
(typically 35 to 40 dB above the SRT). Each ease of sound transmission through the middle
word is presented with a carrier phrase, such as ear system. In simplified terms, acoustic imped-
“you will say _______” or “say the word ______” ance is related to the elasticity and stiffness of
The test is scored as a percentage of the correct the middle ear conduction system. Acoustic
responses (e.g., 49 out of 50 correct = 98% impedance measurements are based on the
speech discrimination). In patients with eighth principle that energy that is not absorbed by
nerve lesions, speech discrimination can be the ear is reflected.11 By measuring the differ-
severely reduced even when pure-tone levels ence between the intensity of a sound going
are normal or near normal, whereas in patients into the external auditory canal and that
with cochlear lesions, discrimination tends to reflected from the tympanic membrane, one
be proportional to the magnitude of hearing can estimate the impedance (or compliance) of
loss.8 the middle ear system.
Acoustic impedance measurements are
made by a probe tip hermetically inserted into
Stenger Test the ear canal. The probe tip contains three
openings: (1) one for air pressure generation
The Stenger test is helpful for determining and measurement, (2) one for probe tone gen-
whether a patient is deliberately exaggerating eration, and (3) one for pickup of sound waves
or feigning a hearing loss.9 It is based on the reflected off the tympanic membrane. A sche-
psychophysical observation that a tone pre- matic drawing of the impedance measurement
sented to both ears in the same phase at differ- system is shown in Figure 8–3. With this sys-
ent intensities above threshold is perceived tem the difference between generated and
only in the ear with better hearing. Tones are reflected sound is systematically measured at
presented simultaneously to both good and different external ear pressure levels.
Probe tone generation

Loudspeaker
Sound
generator
220 Hz
Intensity
Air pressure knob
generation and
measurement
Manometer
Air
pump
Compliance change
meter
Probe
Rectifier AMP
SPL & compliance Microphone

sensing & (sound reflecting off
DC source measurement
(18 V) tympanic membrane to
microphone pickup)
Figure 8–3. Schematic drawing of acoustic impedance measuring system (see text for details). SPL, sound pressure level.
(From Goodhill V. Ear Diseases, Deafness and Dizziness. Harper & Row, Hagerstown, 1979, with permission.)
TYMPANOMETRY A restricted tympanogram implies normal mid-

dle ear pressure and limited compliance relative
Tympanometry is a method for evaluating to normal mobility. It is typically seen in
changes in acoustic impedance by producing advanced cases of otosclerosis, lateral fixation of
systematic changes in air pressure in the exter- the ossicular chain, tympanic membrane fibro-
nal ear canal. A plot of compliance change ver- sis, and middle ear tympanosclerosis. A hyper-
sus air pressure (the tympanogram) is made by mobile tympanogram indicates a flaccid tym-
first introducing a positive pressure into the panic membrane. It occurs with ossicular chain
external canal (usually equivalent to +200 mm discontinuity and with partial atrophy of the
of water) and then decreasing the pressure to tympanic membrane. A flat tympanogram
approximately −200 mm of water (although the means that there is little or no change in
negative range can be extended to −600 mm of middle ear compliance when ear pressure is
water). As the pressure is changed, compliance varied in the external ear canal. This pattern is
will change if the conduction system is normal. more commonly seen with secratory otitis media
The shape of the normal tympanogram resem- but can also be seen with congenital malforma-
bles a teepee (Fig. 8–4). The peak of the tions of the middle ear and occlusion of the
teepee represents the point of maximum com- external ear canal by cerumen, epithelium, and
pliance at which the air pressure in the middle foreign bodies. Finally, with a retracted tym-
ear equals the air pressure in the external audi- panogram, the maximum compliance occurs at
tory canal. Tympanometry can provide useful negative pressures greater than −100 mm of
information about (1) mobility of the tympanic water. It implies a negative middle ear pressure
membrane, (2) perforations of the tympanic with a retracted tympanic membrane. This pat-
membrane, (3) pressure within the middle ear, tern is most commonly seen with poor
and (4) patency and dynamic function of the Eustachian tube function.
eustachian tubes. Artifactual responses can
result from inappropriate placement of the
probe (against the canal wall or into impacted The Acoustic Reflex
cerumen) or from an inadequate seal.
Four characteristic abnormal tympanographic The acoustic reflex refers to contraction of the
patterns should be recognized (see Fig. 8–4).12 stapedius muscle in response to a loud sound.
A B
5
0
Compliance change
C D
5
5
–300 –100 0 +100 +300 –300 –100 0 +100 +300
Air pressure, mm H2O
Figure 8–4. Four characteristic abnormal tympanograms. (A) Restricted. (B) Hypermobile. (C) Flat. (D) Retracted. Blue
area, normal range.
It is measured by monitoring the change in level <60 dB above the auditory pure-tone
acoustic impedance in response to a loud sound threshold. This is another form of abnormal
introduced into either ear. The stapedius mus- loudness growth or recruitment. A cochlear
cle contracts bilaterally, regardless of which ear hearing loss must be severe before the acoustic
is stimulated. Contraction of the stapedius reflex is lost. An absent reflex is rarely associated
muscle produces stiffening of the tympanic with a cochlear hearing loss <50 dB, and only
membrane and thus an increase in acoustic when the hearing loss exceeds 85 dB is the reflex
impedance. This results in an attenuation of absent in 50% of patients. By contrast, patients
sound transmitted to the cochlea by about 10 with eighth nerve lesions often have either nor-
dB. In a normal subject the acoustic reflex will mal hearing or only mildly impaired hearing
be observed when a pure-tone signal is pre- (<20 dB), yet they have an abnormal acoustic
sented between 70 and 90 dB above hearing reflex. The reflex may be absent, exhibit an ele-
level (median value 82 dB), and when a white vated threshold, or exhibit abnormal decay.
noise stimulus is presented at 65 dB above Reflex decay is present if the amplitude
hearing level. decreases to one-half of its original size within
Patients with conductive hearing loss often 10 sec of tonal stimulation. However, the test
have an absent acoustic reflex because the lesion has not been proven to be a highly accurate test
prevents a change in compliance with stapedius for discriminating between these causes, or
muscle contraction. An air bone gap as small as even identifying an eighth nerve lesion.32
5 dB may obscure the acoustic reflex. Acoustic
reflex testing is particularly useful for identify-
ing a false or so-called intralabyrinthine conduc-
tive hearing loss (see Semicircular Canal AUDITORY-EVOKED RESPONSES
Dehiscence Syndrome, Chapter 16). A normal
acoustic reflex in a patient with an apparent con- The advent of averaging by computer made it
ductive hearing loss suggests the likelihood of possible to collect and analyze a variety of
superior semicircular dehiscence. The acoustic evoked electrical potentials from the auditory
reflex can also be useful for identifying the site system.14,15 Repetitive sounds are delivered to
of lesion for different types of sensorineural the external ear and an “averaged” series of
hearing loss. With cochlear lesions the acoustic specific brain wave potentials are recorded
reflex often can be demonstrated at a sensation with disk electrodes for up to 500 msec after
signal onset. The latencies (relative to signal Electrocochleography

onset) of each of the potentials are used as the
most reliable means by which generator sources Up to the present, this technique has been
for the potentials are identified. Electrical most useful for identifying cochlear responses
events in the cochlea (so-called electrococh- in infants or in very young children who are
leography) can best be monitored by an elec- unable to cooperate with behavioral testing.20 A
trode inside the external canal or from a tran- rough estimate of the cochlear response at
stympanic electrode on the cochlear multiple frequencies and intensities can be
promontory.16,17 A series of waves in the first obtained. Of course, the presence of these
5 msec after the stimulus reflects the cochlear responses does not indicate that the subject
microphonics and the compound cochlear actually “hears”; rather, it documents that
action potential (Fig. 8–5).18 Other evoked electrical activity is being generated within
potentials from the auditory nerve and central the cochlea. The presence of cochlear
nervous system (CNS) can be recorded with microphonics and summating potentials (see
differential scalp electrodes.19 One electrode is Fig. 8–5) in the absence of a compound action
placed at the vertex (the positive electrode) potential suggests a denervated cochlea.
and another on the earlobe or mastoid (the Electrocochleography is useful in conjunction
negative electrode) ipsilateral to the acoustic with brainstem auditory-evoked responses
stimulation. A third electrode (contralateral (BAER) in adults when one is attempting to
mastoid or earlobe) serves as the ground. identify whether a hearing loss is cochlear or
Acoustic signals are presented via earphones, retrocochlear. The presence of a normal elec-
or bone vibrator and responses are amplified, trocochleogram in a patient with an absent
filtered, and averaged. The early (0 to 10 msec) BAER suggests an auditory neuropathy.21
evoked responses reflect the far-field represen- Absence of both can occur with either cochlear
tation of electrical events generated at points or retrocochlear lesions. Electrocochleography
from the periphery (eighth nerve action poten- is also used to assess the likelihood of Meniere’s
tial) to the level of the brain stem. The five to syndrome, though it is not a very accurate test
seven waves in the first 10 msec are referred (see Chapter 11).
to as the brainstem–evoked response. The mid-
dle latency responses (12 to 50 msec) have
received less systematic study but probably Brainstem Auditory-Evoked
reflect electrical activity in the upper brain Response
stem and in the primary and nearby secondary
auditory projection areas. The late evoked As noted above, the BAER reflects the far-field
responses (50 to 300 msec) reflect cortical representation of electrical events occurring in
electrical activity. the eighth nerve and brain stem.15 It is highly
reproducible in a given subject, and the latency
of the various waves shows little variation
N1 among normal subjects.22 With rare exceptions,
Stimulus
the BAER is not affected by inattention to the
stimulus, alterations in the level of conscious-
CM
ness, or drugs. For this reason it can be used to
N2 test the integrity of the peripheral and brain-
stem auditory pathways in patients who cannot
cooperate with subjective auditory testing
(e.g., infants, comatose patients).23
0 1 2 3 4 5
msec
Figure 8–5. Electrical response of the cochlea to a tone GENERATING POTENTIALS
burst. An electrode near the round window records the
cochlear microphonic potential (CM) and a compound
action potential (N1 and N2). (Adapted from Sohmer H, A schematic drawing of a BAER and the
Feinmesser M. Electrocochleography in clinical audiologi- neural centers that are thought to generate
cal diagnosis. Arch Otorhinolaryngol (Berl). 1974;206:91.) each component of the response is shown
Milliseconds
0 1 2 3 4 5 6 7 8 9 10
60 dBHL 1.9 3.0 4.1 5.2 7.6 9.2

5.9
5.8
Cz+
IV
V
III
II
0.1 µV units
VII
I
VI
Central Lateral
acoustic n. lemniscus
Cz– Cochlea, Cochlear Inferior Medial Auditory
acoustic n. nucleus, colliculus geniculate radiations
terminals Superior
olivary complex
Figure 8–6. Normal brain stem auditory evoked response evoked by clicks of 60 dB HL (60 dB above normal hearing
threshold) at a rate of 10/sec. Normal mean latencies for waves I through VII are shown on the time scale (the intermedi-
ate latency, 5.8 msec, between waves IV and V, is the mean peak latency of a fused wave IV/V when present). The neural
centers thought to be responsible for generating each wave are shown at the bottom. (Adapted from Stockard JJ, Stockard
JE, Sharbrough FW. Detection and localization of occult lesions with brain stem auditory responses. Mayo Clin Proc.
1977;52:761.)
in Figure 8–6.31 Wave I (average latency 1.9 This signal produces a spectrally diffused
msec) results from activation of the eighth acoustic stimulus, with most of the energy con-
nerve terminals within the cochlea, whereas centrated in the high frequencies (around 1–4K
wave II (average latency 3.0 msec) results from Hz with most of the commercially available
activation of the central portions of the eighth speakers). The absolute latency of the BAER
nerve. The remainder of the waves are gener- waves is dependent on the intensity of the click
ated by the brainstem auditory nuclei and path- stimulus. The BAERs to unfiltered clicks pre-
ways.24,25 Although a useful working tool, this sented at various intensity levels from a normal
schematic electroanatomic correlation is an subject are shown in Figure 8–7. Wave V is
oversimplification. Clearly, each vertex-positive most robust, often being identifiable at only
and vertex-negative potential after wave I 10–20 dB above hearing level. At 60 dB above
reflects simultaneous activity in multiple brain- hearing level, all waves are identifiable. Such
stem loci. The more caudal generators, such as latency intensity functions provide a basis for
the eighth nerve, cochlear nuclei, and superior estimating the degree of hearing loss in patients
olivary complex, contribute to the response who cannot cooperate with standard pure-tone
beyond waves II and III. By the time waves VI behavioral testing.26 Because of this latency-
and VII appear, the summation of potentials intensity relationship, however, BAERs must
from the different neural centers is so complex be interpreted with caution in patients with
that the concept of single principle contribu- severe conductive or cochlear hearing loss
tors to individual waves no longer applies. (particularly if it involves high frequencies).
TEST METHODOLOGY RESULTS IN PATIENTS

The standard stimulus for eliciting a BAER is a In practice, only waves I, III, and V are used to
click caused by a very short (<1 msec) pulse. define response abnormalities. Waves II, IV,
V IV - V
IV Right ear II III
I III dB SL I
200 nV II
VI 70
50
30 0 2 4 6 8 10
Left ear I IV - V
10 III
0 5 10 15
msec
Figure 8–7. Brain stem auditory evoked responses in a
normal subject that are induced by clicks at varying inten-
sity levels (10 to 70 dB sensation level [SL]). 0 2 4 6 8 10
Time in msec
VI, and VII are sufficiently variable in the nor- Figure 8–8. Brain stem auditory evoked responses in a
mal population to preclude their routine use in patient with a left acoustic neuroma. Dashed lines indicate
defining response abnormalities on the basis of repeat test. Wave I occurs at normal latency on both sides,
but the I–III and I–V intervals are prolonged on the left
a single recording. Often waves IV and V fuse side.
into a single complex, which is designated as
wave IV/V. Because wave I disappears before
wave IV/V with decreasing stimulus intensity more cautious interpretation, as there may be
(e.g., see Fig. 8–7), the absence of wave IV/V in other explanations for the lack of response
the presence of wave I suggests a retrocochlear (technical or otologic problems).
lesion. The absence of all waves, on the other In patients suspected of having MS who
hand, often reflects a peripheral lesion (con- present with lesions outside of the brain stem
ductive or cochlear) or a technical problem.27 If (e.g., optic nerve or spinal cord), an abnormal
peak I occurs at normal latency, then prolonga- BAER supports the likely diagnosis (the impor-
tion of the I–III or I–IV/V interval suggests a tant second lesion).27,30 Obviously, if the initial
lesion of the eighth nerve or brain stem. lesion involves the brain stem, the finding of an
In clinical neurotology BAERs have been abnormal BAER provides little additional
used mostly in (1) evaluating the cause and information. In the past brainstem auditory-
reversibility of coma, (2) assessing the likeli- evoked responses were used to screen for ves-
hood of multiple sclerosis (MS), and (3) tibular schwannomas but with the improved
assessing the likelihood of a structural lesion resolution and reduction in costs of MR imag-
involving the eighth nerve (e.g., vestibular ing the BAER can no longer be recommended
schwannomas) (Fig. 8–8).25 Because BAERs for primary screening for these tumors (see
are relatively resistant to metabolic insults, they Chapter 15).32
can help differentiate between metabolic and
structural causes of brainstem dysfunction. The
presence of an intact BAER in a patient with
global brainstem dysfunction on neurologic CENTRAL AUDITORY SPEECH
examination suggests the possibility of a meta- TESTS
bolic, reversible cause of coma. The absence of
waves III and/or V in the presence of wave I, Patients with lesions of the central auditory
however, suggests widespread structural dam- pathways usually have normal pure-tone
age of the brainstem and implies a poor prog- hearing levels. Routine speech tests are also
nosis.28,29 The complete absence of a BAER usually normal because speech contains a great
may have a similar poor prognosis but requires deal of redundancy. Within the central auditory
pathways, redundancy is enhanced by the mul- central lesions rarely produce such hearing
tiple crossings and interactions. One of the few loss (Table 8–2). Conductive and sensorineu-
diagnostically useful central audiologic findings ral loss can usually be differentiated with an
is the reduced ability of patients with temporal audiogram based on the finding of an air-
lobe lesions to discriminate speech in the ear bone gap with the former and a characteris-
contralateral to the lesion when the task is tic frequency intensity profile with the latter.
complicated by distorting the speech.33 The causes of a conductive hearing loss can
Apparently, by making the speech less redun- be differentiated with tympanometry. There
dant, heavier demands are placed on the inte- are several test results that help distinguish
grating, synthesizing function of the auditory between a cochlear and retrocochlear sen-
cortex. sorineural hearing loss. Speech discrimina-
There are several varieties of central audition is relatively preserved with a cochlear
tory speech tests currently in use, each involv- loss, whereas it is impaired early and dispro-
ing methods of presenting distorted speech. portionately to any pure tone loss with a
Portions of the frequency spectrum of speech sensorineural loss. Loudness recruitment is
can be filtered, the speech can be time com- commonly seen with a cochlear loss, whereas
pressed, it can be presented at very low intensi- tone decay is a common feature of a sen-
ties, and the speech can be interrupted at sorineural loss. Abnormalities of the
irregular intervals. Dichotic stimulation stapedius reflex and BAER provide an
involves presenting two different messages to objective differentiation between cochlear
each ear.34 Both monosyllabic and spondee and retrocochlear lesions. With cochlear
words can be used. As with distorted speech hearing loss these measurements remain
tests, when a temporal lobe lesion exists, the normal unless the loss is profound. On the
ear contralateral to the lesion performs poorer other hand, the stapedius reflex and BAER
than the ear ipsilateral to the lesion. are usually abnormal with only mild to
moderate hearing loss due to retrocochlear
damage. Central hearing disorders may
SUMMARY OF AUDITORY TEST show abnormalities of the late waves of the
RESULTS BAER or of cortical-evoked responses or in
discriminating speech when the task is com-
Hearing loss for pure tones is typically plicated by distorting the content of the
divided into conductive and sensorineural; speech.
Table 8–2 Summary of Auditory Test Results with Lesions at Different Locations
SENSORINEURAL
Test Conductive Cochlea Nerve Central
Speech Normal Relatively Abnormal early Normal
discrimination preserved
Tympanometry Abn: restricted, Normal Normal Normal
hypermobile, flat
Stapedius reflex Absent Normal Absent or decay Normal
BAER Normal Normal Absent, delayed Delayed
I–III, I–V III–V
Special tests — Loudness Tone decay Dichotic
recruitment listening,
alter-
nating
speech,
filtered
speech
Abn, abnormal.
REFERENCES 19. Møller AR, Janetta PJ. Neural generators of the audi-
tory brainstem response. In: Jacobson JT, ed. The
Auditory Brainstem Response. Boston: College-Hill
1. Katz J, Medwetsky L, Burkard RF, et al. eds. Handbook Press; 1985.
of Clinical Audiology. 6th ed. Baltimore: Lippincott 20. Northern JL, Downs MP. Hearing in Children.
Williams & Wilkins; 2009. Baltimore: Williams & Wilkins; 1978.
2. Kileny PR, Zwolan TA. Diagnostic and rehabilitative 21. Vlastarakos PV, Nikolopoulos TP, Tavoulari E,
audiology. In: Cummings CW, Flint PW, Haughey BH, Papacharalambous G, Korres S. Auditory neuropathy:
et al. eds. Otolaryngology Head and Neck Surgery. 4th endocochlear lesion or temporal processing impair-
ed. St Louis, MO: CV Mosby; 2005. ment? Implications for diagnosis and management.
3. Arts HA. Sensorineural hearing loss: Evaluation and Int J Pediatr Otorhinolaryngol. 2008;72(8):1135.
management in adults. In: Cummings CW, Flint 22. Musiek FE, Kibbe-Michal K, Ceurkink NA, et al. ABR
PW, Haughey BH, et al. eds. Otolaryngology Head results inpatients with posterior fossa tumors and nor-
and Neck Surgery. 4th ed. St Louis, MO: CV Mosby; mal pure tone hearing. Otolaryngol Head Neck Surg.
2005. 1986;94:568.
4. Rauch SD. Idiopathic sudden sensorineural hearing 23. Wilkinson AR, Jiang ZD. Brainstem auditory evoked
loss. N Engl J Med. 2008;359:833. response in neonatal neurology. Semin Fetal Neonatal
5. Schuknecht HL. Pathology of the Ear. 2nd ed. Med. 2006;11(6):444.
Philadelphia: Lea & Febiger; 1993. 24. Møller AR, Janetta PJ, Møller MB. Neural generators
6. Bagai A, Thavendiranathan P, Detsky AS. Does of brain stem evoked potentials. Results from human
this patient have hearing impairment? JAMA. intracranial recordings. Ann Otol Rhinol Laryngol.
2006;295:416. 1981;90:591.
7. Torres-Russotto D, Landau WM, Harding GW, 25. Walsh P, Kane N, Butler S. The clinical role of
Bohne BA, Sun K, Sinatra PM. Calibrated finger rub evoked potentials. J Neurol Neurosurg Psychiatry.
auditory screening test (CALFRAST). Neurology. 2005;76(suppl 2):ii,16.
2009;72(18):1595. 26. Don M, Eggermont JJ, Brachmann DE. Reconstruction
8. Jerger J, Jerger S. Diagnostic significance of PB word of the audiogram using brain stem responses and
functions. Arch Otolaryngol. 1971;93:573. high-pass noise masking. Ann Otol Rhinol Laryngol.
9. Durmaz A, Karahatay S, Satar B, Birkent H, Hidir 1979;88(suppl 57):1.
Y. Efficiency of Stenger test in confirming pro- 27. Coats AC. Human auditory nerve action potentials
found, unilateral pseudohypacusis. J Laryngol Otol. and brain stem evoked responses. Arch Otolaryngol.
2009;123(8):840. 1978;104:799.
10. Kintsler DP, Phelan JG, Lavender RB. Efficiency of 28. Coldie WD, Chiappa KH, Young RR, Brooks EB.
the Stenger and speech Stenger tests in functional Brain stem auditory and short somatosensory evoked
hearing loss. Audiology. 1972;11:187. responses in brain death. Neurology. 1981;31:248.
11. Jerger J, Jerger S, Maulden L. Studies in impedance 29. Hall JW, Mackey-Hargadine JR, Kim EE. Auditory
audiometry. I. Normal and S-N ears. Arch Otolaryngol. brain stem response in determination of brain death.
1972;96:513. Arch Otolaryngol. 1985;111:613.
12. Liden G, PedersonJL, Bjorkman G. Tympanometry. 30. Paludetti G, Ottaviani F, Gallai V, et al. Auditory brain
Arch Otolaryngol. 1970;92:248. stem responses (ABR) in multiple sclerosis. Scand
13. Jerger J, Anthon L, Jerqer S, et al. Studies in imped- Audiol. 1985;14:27.
ance audiometry. III. Middle ear disorders. Arch 31. Stockard JJ, Stockard JE, Sharbrough FW. Brain stem
Otolaryngol. 1974;99:165. auditory evoked potentials in neurology: methodology,
14. Kileny PR, Young KE, Niparko JK. Acoustic and elec- interpretation, and clinical application. In: Aminoff
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RK, Brackmann DE, eds. Neurotology. St. Louis, MO: York: Churchill Livingstone; 1986.
CV Mosby; 1993. 32. Fortnum H, O’Neill C, Taylor R, et al. The role of
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Brainstem auditory evoked potentials–a review suspected acoustic neuroma: a systematic review of
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17. Margolis RH, Rieks D, Fournier EM, Levine SE. 34. Denes H, Cariezel F. Dichotic listening in crossed
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121:44.
18. Sohmer H, Feinmesser M. Electrocochleography in
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(Berl). 1974;206:91.
PART 3

of Common Neurotologic
Disorders
Chapter 9
Infectious Diseases
ACUTE OTITIS MEDIA AND Otitic Hydrocephalus

OTOMASTOIDITIS Diagnosis
Diagnosis and Management Management
CHRONIC MASTOIDITIS AND MALIGNANT EXTERNAL OTITIS
CHOLESTEATOMA Diagnosis
Diagnosis Management
Management VIRAL INFECTIONS OF THE INNER EAR
BACTERIAL LABYRINTHITIS Clinical Syndromes
Diagnosis Diagnosis
Management Viral versus Other Causes of Peripheral
PETROSITIS Cochleovestibular Loss
Management SYPHILITIC INFECTIONS OF THE EAR
INTRACRANIAL EXTENSION OF EAR Diagnosis
INFECTIONS Management
Routes of Spread TUBERCULOSIS AND MYCOTIC
Meningitis INFECTIONS OF THE INNER EAR
Epidural Abscess Tuberculous Mastoiditis
Lateral Sinus Thrombophlebitis Mycotic Mastoiditis
Brain Abscess Basilar Meningitis
Bacterial infections involving the audio-vestibular of infectious process involving the audio-
structures result from the spread of an infec- vestibular system.
tion from another region of the body, typically In this chapter we discuss infectious diseases
the middle ear or the meninges. As with most that can involve the audio-vestibular system.
bacterial infectious disorders, the advent of
antibiotics substantially changed the preva-
lence and scope of complications from infec-
tious diseases. Prior to antibiotics, it was ACUTE OTITIS MEDIA AND
not uncommon for the common variety of OTOMASTOIDITIS
middle ear infection, otitis media, to evolve
into a chronic infection that eventually eroded Infection of the middle ear (otitis media) is the
into the inner ear. However, with antibiotics it most common disease treated with antibiotics
is now quite rare for this to occur. Thus, at this in the United States. Because the air cavity of
point viral infections—or at least presumed the middle ear is in direct communication with
viral infections—are the most common type the mastoid air cells, infection can spread
233
Upper respiratory
tract infection
Acute
tubotympanitis
Secretory Acute Acute

otitis media otitis media otomastoiditis
Polypoid
granuloma
Chronic
otomastoiditis
Perilymph
Labyrinthitis
fistula
Cholesteatoma
Figure 9–1. Patterns of progression of middle ear infections.
throughout the pneumatized parts of the tem- patients with acute otitis media managed
poral bone (see Fig. 2–2). Typical patterns of initially with observation rather than antibiot-
progression of middle ear infections are sum- ics.5 The majority of patients who develop mas-
marized in Figure 9–1. The most common toiditis are receiving antibiotic therapy for
complication of otitis media is mastoiditis.1 acute otitis media, so antibiotics are not a safe-
Eighty percent of children between the ages guard against developing acute mastoiditis.
of 1 and 6 years have at least one bout of acute
otitis media.2 The symptoms typically include
unilateral otalgia, fever, and hearing loss. Diagnosis and Management
Vertigo is not a common symptom since the
infection in uncomplicated cases is restricted The diagnosis of acute otitis media rests on find-
to the middle ear. The peak incidence occurs ing the characteristic changes in the tympanic
during the first year of life, reaching an inci- membrane in a patient complaining of acute
dence rate of almost 50% and then gradually otalgia and hearing loss. The most common
decreasing to an incidence rate of <10% beyond organisms associated with acute otitis media
age 6.3 With acute otitis media, there is a worldwide are Streptococcus pneumoniae,
middle-ear effusion that can be determined by Hemophilus influenza, Moraxella catarrhalis,
the appearance of the tympanic membrane and group A Streptococcus.6 Once the clinical
(i.e., fullness or bulging of the membrane along diagnosis is made, the patient can either be
with cloudiness or redness), pneumatic otos- managed with observation and conservative
copy, or tympanometry. Spontaneous perfora- management when the case is uncomplicated
tion can occur, allowing the purulent effusion (mild otalgia and fever <39°C) or with antibi-
to drain into the external ear (i.e., otorrhea). otic therapy, typically amoxicillin.5 An observa-
Following resolution of the acute infection, a tion period is reasonable because in some cases
serous or mucinous effusion can persist for the cause will be viral rather than bacterial and
months (i.e., chronic otitis media with effusion). because randomized placebo-controlled trials
Persistent pain and swelling behind the ear may have shown that most patients do well even
indicate mastioditis.4 However, the incidence without antibiotics.5,7 If there is clinical wors-
of mastoiditis is very low (< 1%) even among ening or no improvement in 48 to 72 hours,
9 Infectious Diseases 235
then antibiotics should be initiated. If the simple pressure necrosis. Ultra-structural stud-
infection fails to resolve within a few days of ies in humans and experimental studies in ani-
antibiotic therapy, then the antibiotic is typi- mals suggest that the bone resorption is caused
cally changed to amoxicillin-clavulante. If acute primarily by activation of multinucleated osteo-
otitis media persists, then a myringotomy can clasts in the bone.10 Ultimately, a cholestea-
be performed to obtain a sample of the fluid for toma may erode through the temporal bone
culture and also to treat otalgia. The antibiotics into the intracranial cavity, producing central
are then adjusted on the basis of the results of nervous system (CNS) symptoms and signs.
culture. Signs of acute mastoiditis include pos- Cholesteatomas themselves are prone to
tauricular swelling, erythema, tenderness, and recurrent infection, because they contain kera-
protrusion of the auricle. The causative organ- tin debris enclosed in a tissue space. The bacte-
isms in acute mastoiditis are often different ria seen with chronic cholesteatomas are dif-
from those causing acute otitis media. Since ferent from those seen with acute otitic
potential drug-resistant staphylococcus and infections, with the most common aerobe being
pneumococcus infections are common with Pseudomonas aeruginosa, followed by
mastoiditis, obtaining a specimen for culture is Staphylococcus aureus.11 The most common
important for directing antibiotic treatment.8 anaerobes are Proteus and bacteroides. When
acutely infected, cholesteatomas can rapidly
cause bone destruction. With chronic mastoidi-
tis and cholesteatoma formation, a fistula may
CHRONIC MASTOIDITIS AND develop in the bony labyrinth, producing an
CHOLESTEATOMA artificial communication between the peri-
lymph and the middle ear.12 The fistula can be
Chronic mastoiditis results from an untreated caused by either progressive rarefying osteitis
or nonresponsive acute mastoiditis or otitis or erosion by the cholesteatoma. Patients with
media.2,3 Pathology is characterized by thick- a perilymph fistula experience severe episodes
ened edematous mucosa with obliteration of of vertigo when they sneeze or cough because
the mastoid air cell lumen, perivascular fibro- the sudden change of pressure in the middle
sis, and osteitis. Chronic obstruction of the ear is transmitted directly to the inner ear.
mastoid antrum leads to irreversible changes in
the mucosa and bone of the mastoid. Polypoid
granulomas composed of hyperplastic mucosa Diagnosis
may fill the mastoid antrum, extend into
the middle ear, and extrude through a tym- Patients with chronic mastoiditis typically pres-
panic membrane perforation into the external ent with painless purulent otorrhea. Otoscopic
auditory canal. examination of the tympanic membrane may
Another consequence of chronic otitis media reveal evidence of a perforation, particularly in
is a cholesteatoma, which is a collection of ker- the pars flaccida region, and a cholesteatoma or
atinized squamous epithelium that can invade granuloma may be visible in the epitympanic
the middle ear and other pneumatized areas of region of the middle ear. The otoscopic appear-
the temporal bone through the tympanic mem- ance of a cholesteatoma can be quite variable.
brane.9 The term cholesteatoma is a misnomer The typical attic retraction cholesteatoma
because it does not contain cholesterol and is appears as a “pearly tumor” in the posterior
not a neoplasm. Cholesteatomas usually superior portion of the tympanic membrane.
develop in the epitympanic space of the middle In other cases, a cholesteatoma develops at the
ear following a perforation in the pars flaccida margin of a perforation and migrates into the
region of the tympanic membrane (see Fig. middle ear. Cholesteatomas sometimes appear
6–1B). From here they extend posteriorly into behind or within an intact tympanic membrane
the antrum, into the central mastoid tract, or (so-called primary cholesteatomas). Rarely, a
inferiorly into the middle ear to erode the ossi- cholesteatoma is not seen otoscopically but is
cles and bony labyrinth, producing a mixed discovered at the time of mastoid surgery. A
conductive sensorineural hearing loss and ver- perilymph fistula can be identified on examina-
tigo. The mechanism by which a cholesteatoma tion by transiently changing the pressure in the
erodes bone is not entirely clear, but it is not a external canal using a pneumatic bulb attached
Figure 9–2. Computed tomography scan of the temporal bone in a patient with a cholesteatoma eroding the wall of the
horizontal semicircular canal (A) and the facial canal (B). Arrows point toward area of bony erosion. FC, facial canal; HC,
horizontal semicircular canal; IAC, internal auditory canal; V, vestibule.
to the otoscope (see Chapter 6). With a positive BACTERIAL LABYRINTHITIS

fistula test the patient develops vertigo and
nystagmus lasting 10 to 20 sec. The nystagmus Labyrinthitis refers to an inflammatory process
can be in either direction but usually is in the of the labyrinth. Bacterial infections initially
same direction with both positive and negative affect the otic capsule from which they extend
pressure. Computed tomography (CT) scan- into the perilymphatic space and ultimately
ning of the temporal bone may reveal a non- involve the membranous labyrinth. There are
pneumatized or poorly pneumatized mastoid, two types of labyrinthitis associated with acute
haziness of air spaces, or bony erosion from a and chronic bacterial infections of the tempo-
cholesteatoma or osteitis (Fig. 9–2). One can ral bone: (1) serous or toxic labyrinthitis, in
also identify erosion of the bony wall of the which bacterial toxins or chemical products
horizontal semicircular canal or the facial invade the inner ear; and (2) suppurative laby-
canal. rinthitis, in which bacteria invade the inner ear.
The former often leads to only subtle symptoms
such as an insidious high-frequency sensorineu-
Management ral hearing loss, whereas the latter typically
leads to a profound combined auditory and
Initial management is directed at medical treat- vestibular loss with little or no recovery.
ment of the chronic infection.3,13 Chronic oto- Serous labyrinthitis is a common complica-
mastoiditis that is unresponsive to medical tion of acute or chronic middle ear infections.
management requires surgical eradication of With acute otitis media, small molecules such
all diseased tissue. A complete transcortical as bacterial toxins or inflammatory mediators
mastoidectomy is performed with attention to such as cytokines and nitric oxide rapidly dif-
establishing good communication from the fuse through the round window into the scala
mastoid into the middle ear space. A bony fis- tympani.14 Acute and chronic inflammatory
tula requires microsurgical removal of the cells also infiltrate the round window, and a
lesion and closure with either perichondrium fine serofibrinous precipitate forms just medial
or fascia. Damage to the ossicular chain can to the round window membrane. The toxins
usually be repaired. and inflammatory mediators may penetrate the
basilar membrane and invade the endolymph a much more fulminant course, with both audi-
at the basal turn of the cochlea. Such changes tory and vestibular loss. Intermediate clinical
could explain the high incidence of high- pictures are not uncommon, however, and it
frequency sensorineural hearing loss in patients may be impossible to differentiate between a
with chronic otitis media.15 A more rapid onset toxic and suppurative labyrinthitis on the basis
of serous labyrinthitis results in a more com- of the symptoms alone. Bacterial labyrinthitis
plete sensorineural hearing loss along with ves- should be considered in any patient with acute
tibular symptoms, including episodic vertigo or chronic ear infection or meningitis who
and unsteadiness.16 develops a sudden or progressive sensorineural
The most common port of entry of bacteria hearing loss and vestibular symptoms. A posi-
into the inner ear (i.e. suppurative labyrinthi- tive fistula test suggests that the chronic inner
tis) is from the spinal fluid in patients with ear infection has eroded into the horizontal
meningitis (which may or may not be a compli- semicircular canal.
cation of middle ear infection).17 Children with
bacterial meningitis are particularly susceptible
to developing suppurative labyrinthitis with Management
residual severe hearing loss occurring in about
11%.18 The prevalence of residual vestibulopa- Management of labyrinthitis is directed at the
thy has not been well defined. Patients with associated infection of the middle ear, mastoid,
bacterial meningitis develop labyrinthitis when and, if present, meninges. Any patient with
bacteria enter the perilymphatic space by way acute or chronic bacterial ear disease associ-
of the cochlear aqueduct or internal auditory ated with sudden or rapidly progressive inner
canal. Meningogenic bacterial labyrinthitis is ear symptoms should be hospitalized and the
usually bilateral, whereas direct invasion from primary source (typically otitis media or men-
a chronic otitic infection is almost always uni- ingitis) should be identified. The appropriate
lateral. The most common route for a direct course of antibiotics should then be started.13 If
bacterial invasion of the labyrinth is via a mastoiditis occurs, then surgical intervention to
horizontal semicircular canal fistula from a eradicate the middle ear and mastoid infection
cholesteatoma. Endolymphatic hydrops can be is often required after a few days of antibiotic
a sequela of both serous and suppurative treatment. If bacterial meningitis is diagnosed,
labyrinthitis.19 then corticosteroids as adjuvant therapy can
reduce the incidence of long-term hearing
loss.18,20 In a rat model of meningitis-associated
Diagnosis hearing loss, antioxidant therapy plus antibiot-
ics was more effective in preventing hearing
Acute suppurative labyrinthitis has become loss than antibiotics alone.21 If the labyrinthitis
relatively rare since the introduction of antibi- and meningitis are secondary to chronic ear
otics because patients at high risk of develop- infection, a labyrinthectomy might be indicated
ing it (e.g., those with meningitis or severe if the meningitis fails to respond to adequate
middle ear infections) are typically started on medical treatment. A resistant or recurrent
treatment early in the course of the infection meningitis may result from unrecognized
before extension to the inner ear occurs. posterior fossa epidural abscesses with dural
Symptoms to indicate involvement of the inner perforation or from congenital direct commu-
ear include the sudden onset of severe vertigo, nications with the cerebrospinal fluid (CSF).
nausea, vomiting, and unilateral or bilateral
hearing loss. The diagnosis of bacterial labyrin-
thitis in association with acute or chronic ear
infections is based on finding the characteristic PETROSITIS
symptoms and signs of inner ear dysfunction.
As noted earlier, serous labyrinthitis most com- Infections involving the perilabyrinthine bone
monly produces a slowly progressive, insidious may extend into the apical regions of the
high-frequency sensorineural hearing loss, petrous bone, producing petrositis. Although
which may be discovered only with audiomet- only about 30% of petrous bones are pneuma-
ric testing. Suppurative labyrinthitis produces tized into the petrous apex, when infection
does spread into this region, management can INTRACRANIAL EXTENSION OF

be difficult because drainage is more restricted EAR INFECTIONS
and the proximity of the apical air cells to dip-
loic spaces predisposes to osteomyelitis.13,22 Extension of infection from the temporal bone
Because of these problems, petrositis is com- into the cranial cavity demands rapid diagnosis
monly associated with both bacterial labyrin- and effective therapy to prevent permanent
thitis and with intracranial extension of the neurologic sequelae or death. Complications
infection. can result directly from either acute otitis
media and mastoiditis or with chronic otomas-
toiditis and bone destruction. In a patient with
Diagnosis an otitic infection who is febrile and continues
to complain of severe ear and mastoid pain or
The main symptom of an indolent infection in headache despite appropriate antibiotic ther-
the petrous bone is a deep, boring pain. With apy, intracranial extension of the infection
infection in the perilabyrinthine region, pain is should be considered. Localized neurologic
often referred to the occipital, parietal, or signs frequently do not develop until late in the
temporal regions. With infection confined to disease process, and the diagnosis should be
the petrous apex, pain is referred to the considered before focal signs develop.
deep retro-orbital area. In 1904, Gradenigo Although the incidence of morbidity and
described a classic triad associated with mortality with CNS complications of ear infec-
lesions of the petrous apex: (1) deep retro- tions has markedly decreased since the antibi-
orbital pain, (2) paralysis of the ipsilateral lat- otic era, these disorders have not disappeared
eral rectus muscle from involvement of the and still remain a major problem in the twenty-
abducens nerve as it crosses the petrous bone, first century. In a recent review of 3364 patients
and (3) otitic infection with purulent discharge with bacterial otitis media admitted to a ter-
from the ear.23 The syndrome may be associ- tiary referral university hospital, 422 (12.5%)
ated with vertigo and hearing loss, either from presented with complications (extracranial/
a concomitant bacterial labyrinthitis or from intracranial ratio 1:1).1 Mastoiditis was the most
involvement of the eighth nerve in its bony common extracranial complication and lateral
canal. Radiologic evidence for infection of the sinus thrombophlebitis the most common
petrous apex can be difficult to establish even intracranial complication. In those with com-
with high-resolution CT and magnetic reso- plications the mortality rate was 1.4% and the
nance imaging (MRI). The difficultly with morbidity rate 3.8%.
radiologic diagnosis is that abnormalities in
this region can be missed, and fluid accumula-
tion in the petrous apex can be a benign Routes of Spread
finding even earning the label “leave alone
lesions.”24–26 Infection within the temporal bone can reach
the intracranial space via three routes: (1) direct
extension, (2) hematogenous spread, and
Management (3) thrombophlebitis. Extracranial subpe-
riosteal abscesses, intracranial extradural
Management is usually a combined medical– abscesses, and sigmoid sinus thrombophlebitis
surgical approach. After appropriate antibiotic almost always result from a direct extension
therapy, the mucosal and bone infection must of the temporal bone infection. Subdural
be removed. Surgically, one usually begins with and brain abscesses may also result from
a radical mastoidectomy and dissection along direct extension along the soft tissue planes
the cell tracts to the petrous bone. Osteomyelitis through the petromastoid canal to the poste-
of the petrous apex and cranial base can be life rior fossa or along the petrosquamous suture
threatening. The surgical goal is to remove the line to the middle fossa. There is a rich network
maximum amount of infected temporal bone of veins in and around the temporal bone, and
while preserving the seventh and eighth cranial these veins directly communicate with extra-
nerves and the labyrinth.27 cranial, intracranial, and cranial diploic veins.
Thrombophlebitis of any of these veins may Lateral Sinus Thrombophlebitis

spread to the others, resulting in osteomyelitis
of the calvaria or brain abscess at some distance Of the three dural sinuses intimately connected
from the temporal bone. Meningitis, particu- with the temporal bone, the lateral sinus is
larly in young children, typically results from most commonly affected by acute or chronic
hematogenous dissemination. The frequent temporal bone infection.31 Inflammation in the
association between acute otitis media, pneu- extradural space adjacent to the lateral sinus
monia, and meningitis is probably due to the causes a local phlebitis and formation of a
fact that all three diseases result from a sys- mural thrombus. The thrombus enlarges within
temic bacterial infection that has entered via the lumen of the vessel and may occlude it or
the upper respiratory tract. Chronic bacterial become infected. A bland or infected throm-
otomastoiditis produces meningitis by direct bus may propagate in either direction and
extension through bone and dura or through become organized. When infected, septic
the inner ear via a labyrinthine fistula produced emboli are released into the bloodstream, caus-
by a cholesteatoma. ing septicemia and its systemic manifestations
(i.e., fever, chills). When the cerebral veins are
involved, the patient may develop focal or gen-
Meningitis eralized seizures.
Meningitis secondary to ear disease is primarily

a disease of infants with acute otitis media.28 As Brain Abscess
a general rule, the bacteria causing the menin-
gitis are similar to those causing the acute ear Although the overall incidence of otitic brain
infection. With chronic ear infections and abscesses has decreased due to early treatment
cholesteatoma, however, multiple microorgan- with antibiotics, atypical brain abscesses in
isms may be involved in the meningitis. immunocompromised patients are becoming
Recurrent meningitis associated with middle more common.32 As noted earlier, brain
ear infections suggests a CSF fistula, with abscesses associated with ear infections pre-
S. pneumoniae being the most common organ- dominantly originate from venous throm-
ism responsible.29 bophlebitis rather than direct extension through
the dura mater.33 The temporal lobe is most
commonly involved, followed by the cerebel-
lum. Both aerobic and anaerobic organisms are
Epidural Abscess found in pure or mixed cultures within brain
abscesses. Multiple organisms are found in
A potential intracranial complication of chronic more than half of the cases.34 Surprisingly,
otitic infections is extradural abscess, a although H. influenza and Pseudomonas spe-
collection of purulent fluid between the dura cies are common organisms with ear infections,
mater and bone of the middle or posterior they are rare with brain abscesses.
fossa.19,29 The dura mater is usually an effective Neurologic signs associated with temporal
barrier, and the infection remains localized lobe abscess are often subtle, particularly in an
outside the nervous system. Extradural immunocompromised patient or if the patient
abscesses are frequently asymptomatic and are has received inadequate antibiotic therapy.35
discovered incidentally on CT or during mas- An upper-quadrant hemianopia can result from
toidectomies for acute or chronic disease.30 involvement of the optic radiations on either
Extradural abscesses in the middle fossa may side, and when the abscess is in the dominant
become large and compress the temporal lobe, hemisphere, speech may be abnormal. Usually
whereas abscesses in the posterior fossa remain some weakness of the contralateral face and
small because of the tight attachments of the arm occurs, but gross paralysis is rare. The
dura. The initial symptoms of fever, severe signs of a cerebellar abscess are usually more
headache, and vomiting without focal neuro- prominent. The patient complains of severe
logic signs can create a diagnostic and thera- neck stiffness and holds the head rigid in a
peutic dilemma. tilted position. Neurologic examination reveals
ataxia, dysrhythmia, and dysmetria of the ipsi- brain edema resulted from thrombosis of the
lateral extremities, and the gait is markedly superior sagittal sinus, leading to impaired CSF
ataxic—if the patient is able to walk at all. resorption. More recent MRI studies show that
Asymmetric gaze-evoked nystagmus is usually thrombosis of the lateral venous sinus alone
present with larger amplitude directed toward can impede venous draining and produce a
the side of the abscess. As the disease pro- rise in CSF pressure.37 Complications include
gresses, the speech becomes thick and slurred chronic headaches and visual loss due to optic
and swallowing difficulty develops. nerve compression.38
Otitic Hydrocephalus Diagnosis

In 1931, Symonds36 coined the term otitic An intracranial complication of an otitic infec-
hydrocephalus to describe the syndrome of tion should be considered in any patient with
increased intracranial pressure without evi- a known ear infection who continues to com-
dence of meningitis or brain abscess in patients plain of severe pain and headache despite
with chronic ear infections (i.e., pseudotumor appropriate antibiotic therapy (Fig. 9–3). The
cerebri). Symonds later hypothesized that the presence of fever, neck rigidity, and a positive
History
Persistent pain and drainage

despite appropriate antibiotics
Examination
Persistent fever and neck stiffness

Meningismus
Focal neurologic signs
Mastoiditis
Positive Cholesteatoma
CT scan with Petrositis
contrast Abscess
Venous thrombosis
Negative
Small epidural or
MRI Positive subdural effusion
MRV Cerebritis
Venous thrombosis
Negative
Positive Meningitis
LP Epidural effusion
Cerebritis
Negative
Continued
observation
Figure 9–3. Algorithm for the diagnosis of intracranial complications of ear infections. CT, computerized tomography; LP,
lumbar puncture; MRI, magnetic resonance imaging; MRV, magnetic resonance venography.
Kernig’s or Brudzinski’s sign supports the ini- MALIGNANT EXTERNAL OTITIS

tial impression. As noted earlier, focal neuro-
logic signs develop late in the course, even with Otitis externa, usually a benign disorder, can
localized brain abscesses, so one must have a lead to a debilitating disease called malignant
high degree of suspicion based on the clinical external otitis in elderly diabetic patients.40,41 It
presentation. After a detailed history and a typically begins with a nonspecific infection of
careful physical examination, a CT scan with the external canal, resulting in complaints of
contrast is the initial diagnostic test. The CT pain, drainage, and fullness of the ear. The pain
scan will show bone erosion, collections of pus becomes severe and continuous as the infec-
within the intracranial cavity, and can identify tion spreads to contiguous soft tissues and adja-
thrombosis of the venous sinuses.13 It can miss cent bony structures. The invading organism is
small collections of extradural or subdural pus almost always P. aeruginosa. The organism
and early stages of brain abscess formation, invades the junction of the cartilaginous and
however, which might be identified with MRI. osseous portions of the external auditory canal
Venous thrombosis is best identified by MRI and spreads to the temporo-occipital bones.
with venography (MRV).31 If a mass lesion has The most common neurologic sequela is
been ruled out, a lumbar puncture is performed involvement of the facial nerve in the fallopian
for analysis of the CSF. The characteristic canal or at the stylomastoid foramen.42
profile of bacterial meningitis (pleocytosis, Occasionally, multiple cranial nerves are com-
decreased glucose, and increased protein) is pressed extradurally, and in rare cases, the
readily identified. More subtle changes (mono- infection spreads across the dura to produce a
cytic pleocytosis and mildly increased protein) purulent meningitis.
can be seen with collections of pus in the epi-
dural spaces or with brain abscess. The finding
of increased intracranial pressure without a Diagnosis
structural lesion suggests the possibility of a
sinus thrombosis. Diagnosis rests on finding the characteristic
granulation tissue in the external canal along
with a positive culture for P. aeruginosa (Fig.
Management 9–4). A CT scan of the temporal bone may
reveal (1) a soft tissue mass in the external
Treatment of the intracranial complications canal, (2) clouding of the mastoid air cells, (3)
secondary to ear infections is directed along sequestra of the bony canal, (4) erosion of bony
two lines: (1) eradication of the infection with structures at the base of the skull, and (5) soft
appropriate antibiotics and (2) establishing tissue masses within the parapharynx and
adequate drainage and excision of infected tis- nasopharynx.43 Initial findings on CT can often
sue when necessary.13 Complications due to predict the likely clinical course.44 An MRI is
acute otitis media are usually effectively con- useful on follow-up to identify soft tissue evo-
trolled by a myringotomy and adequate paren- lution and meningeal enhancement.45
teral antibiotics. Complications associated with
bone destruction from chronic otitis media and
mastoiditis usually require some type of Management
mastoidectomy along with parenteral antibiot-
ics. As a general rule, when there is a collection Initial local treatment consists of removal of all
of pus within the intracranial cavity, treatment accumulated debris and granulation tissue
is directed first to reduce intracranial from the external canal and instillation of a
pressure—usually by evacuating the empyema. gentamicin wick (gentamicin sulfate drops on
Appropriate management of meningitis con- 1/2-inch gauze packing) in the external canal.
sists of first identifying the offending organism, This, along with strict control of the underlying
beginning appropriate intravenous antibiotics, diabetes, can be sufficient treatment in some
and periodic monitoring of the progress by patients with early stages of disease. In patients
lumbar puncture.39 Otitic hydrocephales typi- with more advanced disease, including bony
cally requires long-term CSF drainage with a erosion, or in those who fail to respond promptly
ventriculoperitoneal shunt.38 to this initial therapy, a bone scan is indicated
External otitis with extuberant combination of auditory and vestibular symp-

tissue in a diabetic patient toms. They may be part of a systemic viral illness
such as measles, mumps, and infectious mono-
nucleosis, or more commonly it is an isolated
infection of the labyrinth and/or eighth nerve
Biopsy and culture without systemic involvement. In the latter case,
the infecting agent is rarely identified, but an iso-
lated viral infection of the inner ear is presumed
based on the typical self-limited clinical course
and prior pathologic evidence to support the link
Malignant external otitis
between the sudden onset of hearing loss and/or
vertigo and a viral infection.46 Similar assump-
Bone erosion, tions about a viral etiology are made with idio-
Computed abscesses pathic facial nerve palsy (i.e., Bell’s palsy), which
tomography (CT) is also a typically self-limited cranial neuritis.
Of the thousands of infants born deaf every
No bone
year, about 20% of cases are thought to be the
erosion
result of congenital viral infections.47 CMV
Initial therapy: infections are most common.48 In adults, two
• Debridement relatively common presumed viral disorders
• Gentamicin wick are vestibular neuritis and sudden sensorineu-
• Strict control of diabetes ral hearing loss (SSNHL) or “sudden deaf-
ness.”49,50 Despite this strong suspicion of a
Persistence
viral origin for these common neurotologic
syndromes, proof of a viral pathophysiology in
individual cases is rare. Epidemiologic evi-
Bone scan
dence supports a viral cause in most patients
with either sudden deafness or acute prolonged
Osteitis, vertigo. A large percentage of such patients
osteomyelitis
report an upper respiratory tract illness within
Initial therapy plus: 1 to 2 weeks prior to the onset of symptoms.
• Parenteral antibiotics Both syndromes occur in epidemics, may affect
• Surgery (sequestrectomy, several members of the same family, and erupt
drain abscesses) more commonly in the spring and early
• Continue until local summer.51–53A list of the viruses that have been
disease clears
clinically associated with cases of deafness and/
Figure 9–4. Algorithm for the management of malignant or vertigo is given in Table 9–1.54 In most cases,
external otitis. (Adapted from Smith PG, Lucente FE. however, proof that these viruses caused the
External ear: Infections. In: Cummings CW, Fredrickson symptoms is circumstantial.
JM, Harker LA, Krause CJ and Schuller DE (eds).
Otolaryngology—Head and Neck Surgery, CV Mosby,
St. Louis, 1986, with permission.)
to assess the possibility of osteitis or osteomy- Table 9–1 Viruses Clinically Associated
elitis. If positive, the patient will require long- with Hearing Loss and/or Vertigo
term parenteral antibiotic therapy dependent
Cytomegalovirus Hepatitis
on the microbial findings and local cleansing
Rubella Adenovirus
and debridement, as required (Fig. 9–4).
Mumps Influenza
Rubeola Parainfluenza
Varicella-zoster Poliomyelitis
VIRAL INFECTIONS OF THE Herpes simplex Coxsackie
INNER EAR Epstein-Barr Lymphocytic
choriomeningitis
Viral infections of the inner ear can present with Variola Yellow fever
sudden deafness, acute vertigo, or with some Adapted from Davis and Johnson.54
Figure 9–5. Pathologie findings in a patient with vestibular neuritis. Sections through comparable areas of Scarpa’s ganglia
on the normal side (A) and the side with absent caloric response (B) stained with toluidine blue. Only a few small neurons
remain in B (bar = 100 µm). (From Baloh RW et al. Vestibular neuritis: clinical pathological correlation. Otolaryngol Head
Neck Surg. 1996;114:586–592, with permission.)
Possibly, the most convincing evidence for Clinical Syndromes

a viral cause of these auditory and vestibular
syndromes comes from the temporal bone HERPES ZOSTER OTICUS
studies of Schuknecht and colleagues.46,52,55
These and other investigators have reported A clear example of a viral syndrome involving
pathologic evidence for isolated viral the eighth nerve is herpes zoster oticus (also
involvement of the cochlea and auditory known as the Ramsay Hunt syndrome).59
nerve in patients with sudden deafness and Presumably, the zoster virus remains dormant
of the vestibular end organs and vestibular in the ganglia associated with the seventh and
nerve in patients with isolated sudden vertigo eighth nerves and is reactivated during a period
(Fig. 9–5).56,57 The atrophy of the nerves and of lowered immunity. The patient initially
end organs is identical to that associated with develops a deep burning pain in the ear
well-documented viral disorders (such as followed a few days later by vesicular eruption
mumps or measles).58 In all of these cases the in the external auditory canal and concha.
vasculature was intact; there was no evidence At some time after the onset of pain, either
of a vascular cause for the sudden deafness or before or after the vesicular eruption, the
vertigo. patient may develop hearing loss, vertigo, and
facial weakness. About half have cochleoves- hybridization methods. Presumably, LAT
tibular symptoms and facial paralysis and half codes for a protein that blocks the replication
have just facial paralysis.60 The pathologic find- cycle of the latent virus at some early point so
ings in patients with herpes zoster oticus con- that the infected cells are not damaged and are
sist of perivascular, perineural, and intraneural able to maintain the latent state. Since reactiva-
round cell infiltration in the seventh nerve and tion of a latent HSV-1 infection in the genicu-
in both divisions of the eighth nerve.61 late ganglion is thought to be a common cause
of Bell’s palsy,71 reactivation of a latent HSV-1
infection in Scarpa’s ganglia might be the cause
VESTIBULAR NEURITIS
of vestibular neuritis. HSV-1 has been identi-
Vestibular neuritis is typically manifested by fied in Scarpa’s ganglia72,73and in the vestibular
the gradual onset of vertigo, nausea, and vomit- labyrinth74 of autopsied adults without a prior
ing over several hours.62 Occasionally patients history of vertigo, but there is still no conclu-
have prodromal dizzy spells for a day or so sive proof that reactivation of latent HSV-1
before onset.63 The symptoms usually reach a virus is the cause of vestibular neuritis.
peak within 24 hr and then gradually resolve A unique feature with most cases of vestibu-
over several weeks. During the first day there is lar neuritis is selective damage to the superior
severe truncal unsteadiness and imbalance to part of the vestibular labyrinth with sparing of
the point that falling toward the affected side the inferior part. Since the posterior semicircu-
when trying to walk is common.64 Patients also lar canal remains functional, patients often
often report difficulty focusing because of the develop benign paroxysmal positional vertigo
spontaneous nystagmus. In most patients as a sequela even though they have no remain-
the course is self-limited with complete func- ing horizontal or anterior semicircular canal
tional recovery within 3 months.65 There are function. Rotational studies with measurement
important exceptions to this rule, however. of three-dimensional eye movements in
Occasionally patients—particularly the patients with vestibular neuritis indicates that
elderly—will have intractable dizziness that the posterior semicircular canal is typically
persists for years.66 Recurrences are relatively spared even though anterior and horizontal
rare.67 A small percentage of these patients will semicircular canal function is absent.75,76 How
have multiple recurrent episodes of vertigo the presumed viral etiology can lead to selec-
leading to a profound bilateral vestibulopathy tive involvement of the superior vestibular
(so-called bilateral sequential vestibular neuri- labyrinth is unknown. There is an anastamosis
tis).68 The episodic vertigo is eventually replaced between the facial nerve and the superior ves-
by persistent disequilibrium and oscillopsia. tibular nerve, but HSV-1 is found equally in
Experimental studies in animals have shown the superior and inferior vestibular ganglia.77
that several viruses will selectively infect the A few cases have been reported in which selec-
vestibular nerve and labyrinth.54,69 Furthermore, tive involvement of the inferior division of the
differential susceptibility to viral infection and vestibular nerve appeared to be the cause.73,78,79
antigen expression has been observed in differ- In these cases, the caloric responses were
ent cell types within the inner ear.70 Herpes normal (indicating normal horizontal canal
simplex virus type 1 (HSV-1) can produce function, and thus intact superior vestibular
selective involvement of the vestibular nerve nerve) but the VEMP response—a method to
and labyrinth when inoculated into the ear of a measure the function of the saccule and thus
guinea pig.69 The HSV is a DNA-containing inferior vestibular nerve—was abnormal, or an
virus that establishes a latent infection in neu- impulse test in the plane of the posterior canal
rons by incorporating part of its DNA into the was abnormal.76,78,79 The clinical presentation
nucleus of the neuron. Although the molecular of inferior vestibular neuritis remains ill-
mechanisms involved in the establishment and defined, however. Though one would expect a
maintenance of latency and reactivation from spontaneous downbeating and torsional nys-
the latent state are only partially understood, tagmus in the acute phase, none of the reports
part of the HSV genome, called LAT for claiming a diagnosis of inferior vestibular
latency-associated transcript, can be identified neuritis describe this pattern of nystagmus.76,78,79
in latently infected cells using molecular In fact, most reported cases of inferior vestibular
neuritis report no nystagmus at all, even in skin scrapings from maculopapular lesions.
the acute phase and even after provocative Although the herpetic external otitis is self-
tests.76,78,79 In addition, some of the cases limiting, the seventh and eighth nerve damage
reported are very nonspecific presentations is often profound and nonreversible. An MRI
rather than the typical sudden and constant with contrast will often show diffuse enhance-
acute vestibular syndrome presentation.78 ment of the seventh and eighth cranial
nerves.89,90
The diagnosis of vestibular neuritis or sud-
SUDDEN SENSORINEURAL HEARING den deafness rests on finding the characteristic
LOSS (SUDDEN DEAFNESS) clinical presentation and audio-vestibular sys-
Although the term sudden deafness is com- tem examination findings in the absence of
monly used, the hearing loss due to viral infec- neurologic symptoms and signs (See Video 6–2,
tion usually comes on over several hours and Video 6–3, Video 6–4, Video 6–5, and Video
may even extend over several days.46,80 The loss 6–6). Routine otologic examination is usually
is usually unilateral, often profound, and may unremarkable, and CT scanning of the tempo-
be permanent, although it reverses at least par- ral bone reveals only a normal-appearing bony
tially in most cases. It returns to normal in labyrinth. Occasionally, the eighth nerve or
more than 50% of patients (with or without membranous labyrinth will be enhanced after
treatment).81 Prognosis is best when the hear- contrast on MRI, but this only indicates inflam-
ing loss is mild and begins to recover within mation of unknown cause. Serologic studies
2 weeks. Severe hearing loss (>90 dB), advanced can demonstrate that a virus infected the
age, and presence of vertigo are poor prognos- patient, but they do not prove that the infec-
tic factors. Tinnitus and fullness in the involved tious agent caused the inner ear damage.
ear are common.82 Furthermore, isolation of an infectious agent
As with vestibular neuritis a viral cause is from the nasopharynx or other tissue other
likely with most cases of sudden deafness, than the membranous labyrinth does not prove
although it is rare that a viral cause can be a causal relationship between the virus and the
proven in an individual case.83 Several viruses inner ear disease. Although a few viruses have
will selectively infect the cochlea and spiral been cultured directly from perilymph samples
ganglia in animal models.84,85 Latent HSV1 has in infected ears, this is not a practical method
been identified in the spiral ganglia of autop- for routine diagnosis of viral infections of the
sied adults without a history of hearing loss85 so inner ear.54
like vestibular neuritis reactivation of a latent Vestibular neuritis presents with signs of
herpes infection may be a cause of sudden both canal and otolith dysfunction.91,92 Nearly
deafness. all have a unilateral caloric paresis, a positive
head-thrust sign, and tilt of the subjective visual
vertical. Between 30% to 50% have a decreased
vestibular evoked myogenic potential (VEMP)
Diagnosis on presentation. Otolith-related test abnormal-
ities improve more rapidly than canal-related
The diagnosis of Herpes zoster oticus rests on abnormalities, and patients with a persistently
finding the characteristic cutaneous eruptions positive head-thrust sign at follow-up are more
about the auricle and external ear canal. A spe- likely to continue to complain of dizziness than
cific diagnosis can be made using either direct patients in whom the head-thrust sign returns
fluorescent antigen assay (DFA) or polymerase to normal.92 Patients with vestibular neuritis
chain reaction (PCR). For DFA testing, a vesi- may have hearing loss in the ultrahigh-
cle should be unroofed and then the base of frequency range, which suggests that the audi-
the lesion rubbed with a cotton-tipped swab. tory end organ may be involved to a minor
The swab is then rubbed on a glass slide and degree even though it is clinically silent.93,94
sent for DFA testing.86 For PCR testing, either With sudden deafness the hearing loss tends to
vesicular fluid can be collected or material be most prominent in the high frequencies, a
from the swab can be used.87,88 PCR can also finding consistent with neuropathologic studies
be performed using saliva, CSF, or crusts or demonstrating the greatest degree of damage
in the basilar turn of the cochlea.80 Brainstem minimal recovery. Serous labyrinthitis may
auditory-evoked (BAER) studies are usually produce only a high-frequency sensorineural
normal, consistent with a cochlear site of hearing loss if the toxic products remain con-
pathology. Vestibular abnormalities have been fined to the basilar region of the cochlea.
identified on electronystagmography (ENG) in Syphilitic labyrinthitis might initially be con-
patients with sudden deafness but without fused with viral neurolabyrinthitis, but the for-
associated vestibular symptoms.95 mer leads to recurrent episodes of vertigo and
hearing loss, usually progressing to severe bilat-
eral dysfunction over a period of months.
Viral versus Other Causes of Unlike the gradual onset of symptoms over
Peripheral Cochleovestibular Loss hours with viral syndromes, infarction of the
labyrinth results in a sudden profound loss of
Viral infections of the inner ear must be dif- auditory and vestibular function—often in a
ferentiated from other forms of labyrinthitis setting of prior episodes of transient ischemia
(bacterial and syphilitic) and from acute laby- within the vertebrobasilar system (see Chapter
rinthine ischemia and from perilymph fistula 14). Infarction of the labyrinth, lateral brain
(Table 9–2). As noted earlier, bacterial labyrin- stem, or cerebellum should be considered a
thitis is typically associated with acute and potential cause in patients who present with
chronic otomastoiditis, which should be easily acute onset vertigo and imbalance. The proba-
identified on examination of the ear and with bility of having a vascular etiology drops sub-
CT of the temporal bone, or meningitis. stantially when the symptoms are isolated
Suppurative labyrinthitis invariably results in audio-vestibular symptoms,96 and it becomes
a fulminate profound loss of both auditory remarkably low when the key examination fea-
and vestibular function, usually with only tures also suggest a peripheral etiology.64
Table 9–2 Differential Diagnosis of Acute Peripheral Vestibulopathy

History Examination Laboratory
Viral Developing over hours, resolving Normal except for ENG: caloric hypoexcitability
neurolaby- over days, prior flu-like illness signs of acute Audio: may show ultrahigh-
rinthitis unilateral vestibular frequency loss
loss
Bacterial Abrupt onset, associated hearing Signs of otitis media ENG: absent caloric response
labyrinthitis loss, prior ear infections or meningitis Audio: profound sensorineural
hearing loss
CSF: pleocytosis
Syphilitic Recurrent episodes, associated May be stigmata of ENG: caloric hypoexcitability
labyrinthitis tinnitus and hearing loss, prior congenital syphilis, Audio: low-frequency loss
congenital or acquired syphilis rarely associated Serology: positive FTA-ABS
signs of CSF: usually normal
neurosyphilis
Labyrinthine Abrupt onset, usually associated May be signs of brain ENG: absent caloric response
ischemia neurologic symptoms, prior stem or cerebellar Audio: profound sensorineural
vascular disease infarction hearing loss
Neuroimaging: may show brain
infarction
Perilymph Abrupt onset associated with Positive fistula test, ENG: caloric hypoexcitability
fistula head trauma, barotrauma, or may be chronic Audio: usually sensorineural loss
sudden strain during heavy otitis with tympanic CT of temporal bone may show
lifting, coughing, or sneezing; membrane erosion from cholesteatoma
chronic otomastoiditis with perforation
cholesteatoma
CSF, cerebrospinal fluid; CT, computed tomography; ENG, electronystagmography; FTA-ABS, fluorescent treponemal
antibody absorption (test).
The key examination features that suggest a vascular or nonviral infectious cause, the
vestibular nerve localization include a unidirec- patient’s symptoms should be managed as a pre-
tional spontaneous nystagmus and a correspond- sumed viral neurolabyrinthitis. Symptomatic
ing positive head-thrust test. Red flags that raise treatment with antivertiginous and antiemetic
the suspicion for a vascular etiology include any medications are useful to treat acute vertigo
other neurologic symptoms or signs, severe with nausea and vomiting (see Chapter 19).
truncal ataxia (unable to sit unassisted), and a Vestibular physical therapy is appropriate for
clinical history indicating high risk for stroke.64 patients with acute vestibular neuritis, though
Like viral infections of the inner ear, peri- most of the randomized trials of vestibular phys-
lymph fistulae can present with hearing loss, ical therapy were conducted in patients with
vertigo, or a combination of auditory and ves- surgical lesions or groups of mixed or vaguely
tibular symptoms. With the latter, however, stated etiologies99 (see Chapter 20). Steroids
the onset is usually abrupt, and there is nearly have been recommended for their anti-
always a precipitating event, such as head inflammatory effect based on a few controlled
trauma, barotrauma, or a sudden strain during studies.100–104 One large randomized placebo-
heavy lifting, coughing, or sneezing. Perilymph controlled trial of oral corticosteroids and valcy-
fistulae are particularly common in patients clovir (2 by 2 factorial design) found that on
who have undergone stapedectomy for otoscle- average patients treated with corticosteroids
rosis. Most perilymph fistulae are self-limited, within 3 days of onset had a superior improve-
so it is presumed that the fistulae heal. ment in vestibular recovery as measured by
Indications for exploratory surgery include the surrogate outcome of caloric response at
ongoing symptoms suspicious for a perilymph 12 months compared to placebo.102 Valcyclovir
fistulae (episodes induced by coughing or did not demonstrate an average beneficial effect.
sneezing) and/or a positive fistula test (see However, it is not known if corticosteroids
Chapter 16). improve functional outcome since functional
outcome was not assessed in this trial and many
patients with a chronic caloric asymmetry are
Management asymptomatic. High doses of prednisone or
methylprednisone are given for 3 days to a week
During the acute stages of herpes zoster oticus, and then rapidly tapered. A course of corticoste-
warm, moist compresses applied locally can riods is also generally recommended for patients
provide symptomatic relief, although often sys- with sudden deafness though adequate trials are
temic analgesics are required. Based on treat- lacking.105,106 Interest has increased in the use of
ment of zoster infections in other parts of the intratympanic (IT) corticosteroids injection in
body a combination of high-dose corticoster- sudden sensorineural hearing loss, particularly
oids (e.g., prednisione 60 mg/d with taper over when used as a “salvage” therapy following failed
10–14 days) and antiviral drugs (e.g., valacycol- oral treatment,107,108 but large and rigorous trials
vir 1 g three times a day for 7–10 days) are are still necessary to establish the effect.
typically used for treatment.97 However, there Numerous so-called vasodilating regimens have
remains uncertainty because of a lack of ade- been proposed, but they would have little effect
quate trials98 in Ramsay Hunt syndrome and on the presumed viral pathophysiology. Although
also because the beneficial effects of corticos- many patients with vestibular neuritis are left
teroids and antivirals in the most common her- with a permanent loss of vestibular function (as
pes zoster disorder (i.e., shingles) is the time to documented by serial caloric examinations), the
pain recovery and time to skin lesion healing, CNS is able to adapt to the vestibular loss, and
without evidence of a beneficial long-term out- residual symptoms are usually minimal once the
come.97 In Ramsay Hunt syndrome the most compensation has occurred (see Chapter 20).
important outcomes are facial nerve recovery Although antiviral agents such as cytosine
and recovery of audio-vestibular function. arabinase and acyclovir have been used for
The management of patients who present treating systemic viral illnesses in children, it is
with an isolated episode of auditory and vestibu- unclear whether the hearing loss that is often
lar loss is controversial because the pathophysi- associated with disorders such as cytomegalovi-
ology is often uncertain. As suggested earlier, rus and rubella infections is altered by such
unless there is convincing evidence to suspect a treatment.55
SYPHILITIC INFECTIONS OF incidence in the fifth and sixth decades. The

THE EAR congenital variety is often associated with other
stigmata of congenital syphilis, such as intersti-
Involvement of the eighth nerve and/or laby- tial keratitis, Hutchinson’s teeth, saddle nose,
rinth can be an early or late manifestation of frontal bossing, and rhagades. Of these associ-
both congenital and acquired syphilis. About ated signs, interstitial keratitis is by far the most
one in three patients with congenital syphilis common, occurring in approximately 90% of
develops otologic manifestations. Although the patients.114 Pathologic changes in the labyrinth
number of new cases of congenital syphilis pro- are similar in the congenital and acquired vari-
gressively declined from 1930 to 1968, the inci- ety, consisting of inflammatory infiltration of
dence of new cases appears to have stabilized the membranous labyrinth and osteitis of all
since 1968. From 1981 through 1989, the over- three layers of the otic capsule.19 A combination
all incidence of syphilis in the United States of hydrops of the membranous labyrinth and
increased by 34%.109 More recently the inci- atrophy of the cochlear and vestibular end
dence of syphilis is again on the rise due to organs resembles the pathologic findings in
widespread human immunodeficiency virus idiopathic Meniere’s syndrome.
(HIV) infections.110 Syphilitic infections pro- The natural history of syphilitic labyrinthitis
duce auditory and vestibular symptoms by two is a slow, relentless progression to profound or
different pathophysiologic mechanisms: (1) total bilateral loss of vestibular and auditory
meningitis with involvement of the eighth function.115,116 This progression is marked by
nerve and (2) osteitis of the temporal bone with episodes of sudden deafness and vertigo and
associated labyrinthitis.111,112 The former typi- fluctuation in the magnitude of hearing loss
cally occurs as an early manifestation of and tinnitus.
acquired syphilis, whereas the latter occurs as a
late manifestation of both congenital and
acquired syphilis. With early congenital syphi- Diagnosis
lis there may be a lymphocytic infiltration of
both the membranous labyrinth and eighth Infants with congenital syphilis exhibit a pro-
nerve, leading to profound bilateral deafness. found bilateral sensorineural hearing loss along
Spirochetes have been demonstrated in tem- with extensive damage to multiple organs
poral bones obtained at autopsy in such (Table 9–3). The hearing loss associated with
patients. With early acquired syphilis, the pre- early acquired syphilis may be the only mani-
dominant pathologic finding is basilar meningi- festation of a basilar meningitis, or it may be
tis affecting the eighth nerve, particularly the associated with headaches, stiff neck, and mul-
auditory branch. The hearing loss typically tiple neurologic findings. The rash of second-
occurs with the rash and lymphadenopathy of ary syphilis may precede or accompany the
secondary syphilis. It is usually abrupt in onset, onset of hearing loss. A CSF examination is
tends to be bilateral, and is rapidly progressive. invariably abnormal with a pleocytosis and ele-
Vestibular symptoms are often absent. Patients vated protein.112 The CSF venereal disease
demonstrate symptoms and signs of meningi- research laboratory (VDRL) test may or may
tis, including headache, stiff neck, cranial nerve not be positive.
palsies, and optic neuritis. With late syphilis The diagnosis of syphilitic labyrinthitis as a
most patients have a combination of hearing late manifestation of either congenital or
loss, tinnitus, and vertigo.113 acquired syphilis is based on the finding of a
Both congenital and acquired syphilitic infec- positive serum fluorescent treponemal anti-
tions produce temporal bone osteitis and laby- body absorption (FTA-ABS) test in a patient
rinthitis as a late manifestation. The congenital with the typical clinical history of fluctuating
variety is approximately three times as common hearing loss and vertigo (see Table 9–3).117 The
as the acquired variety.114 The time of onset of serum VDRL is positive in only about 75% of
congenital syphilitic labyrinthitis is anywhere cases, making it an unreliable test for syphilitic
from the first to seventh decades, with the peak labyrinthitis.114 As noted earlier, patients with
incidence in the fourth and filth decades, congenital syphilitic labyrinthitis often have
whereas acquired syphilitic labyrinthitis rarely associated stigmata of congenital syphilis,
occurs before the fourth decade and has a peak whereas patients with the acquired variety may
Table 9–3 Differential Features of Different Otologic Manifestations of Syphilis

EARLY LATE
Congenital Acquired Congenital Acquired
Pathophysiology Inflammation of Meningitis with Temporal bone osteitis and petrositis
membranous labyrinth involvement of with secondary degeneration of
and eighth nerve eighth nerve membranous labyrinth leading to
endolymphatic hydrops
Hearing loss Congenital deafness Abrupt onset, Begins unilateral, fluctuating, progresses
bilateral, to bilateral over months; associated
progressive tinnitus and ear pressure
Vertigo No Infrequent Episodic (hours) with fluctuating
hearing loss
Age of peak At birth 20–30 years 30–50 years 40–60 years
incidence
Associated Infection involving Rash of Interstitial keratitis, Other
features multiple organs secondary other stigmata of features
syphilis congenital syphilis of tertiary
syphilis
Cerebrospinal Usually abnormal (pleocytosis, elevated Usually normal Usually
fluid protein, VDRL ±) normal
Treatment IV aqueous penicillin, 20 million U/day × IM benzathine penicillin, 2.4 million
2 weeks U, weekly × 3 months; prednisone
30–60 mg qod, 3–6 months, slow
tapering
IM, intramuscular; IV, intravenous; VDRL, venereal disease research laboratory (test).
have other clinical symptoms and signs of ter- (2.4 million units) given weekly for 6 weeks to
tiary syphilis. The CSF examination is usually 3 months. Along with the penicillin, predni-
normal in both the congenital and acquired sone, beginning at a dose of 60 mg/day on an
varieties of syphilitic labyrinthitis.113 alternate day regimen, is given for 3 months,
followed by a slow tapering. If symptoms recur
during the tapering, a more long-term mainte-
Management nance dosage of prednisone may be required.
Most patients can be expected to stabilize or
Penicillin is still the treatment of choice for the improve on this therapeutic regimen.115
otologic manifestations of syphilis, although
the optimal regimen for each variety remains
uncertain.116 Because CSF infection accompa-
nies the early manifestations of both congenital TUBERCULOSIS AND MYCOTIC
and acquired syphilis, high-dose intravenous INFECTIONS OF THE INNER EAR
penicillin seems appropriate. Prognosis follow-
ing treatment is poor in the early congenital Tuberculous Mastoiditis
form, but it is excellent in the early acquired
variety. Complete recovery of both hearing The tuberculosis pandemic along with the
and vestibular function usually occurs with the development of resistant strains has become a
latter.112 global public health problem.118 Tuberculous
For the late manifestations of both congeni- mastoiditis accompanies both pulmonary and
tal and acquired syphilitic labyrinthitis, the nonpulmonary infections, presumably because
combination of steroids and penicillin appears of hematogenous spread. In contrast to bacte-
to be superior to penicillin alone.115,116 Numerous rial infections, tuberculosis of the temporal
penicillin regimens have been used, with bone runs an indolent course and usually pro-
the most popular being benzathine penicillin duces little pain.119 The classical presentation is
multiple perforations of the tympanic mem- characteristic CSF profile of lymphocytic

brane, ear discharge, and progressive hearing pleocytosis, elevated protein, and decreased
loss. The foul-smelling otorrhea, when cul- glucose. Often, there are associated systemic
tured, typically shows nonspecific mixed organ- symptoms and signs, including multiple
isms. It may mimic chronic otomastoiditis with pulmonary lesions. Mycobacterium tuberculosis
cholesteatoma formation because there is often may be seen on acid-fast smears and cultured
tympanic membrane perforation and promi- from the CSF. The diagnosis of fungal menin-
nent granulomatous tissue. A CT scan of the gitis relies on identifying the appropriate anti-
temporal bone shows an irregular, punched- gen in the CSF.
out lesion resembling a cholesteatoma.
Tuberculosis mastoiditis can usually be differ-
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Effectiveness of intratympanic dexamethasone injection
Chapter 10
Benign Positional Vertigo
HISTORICAL BACKGROUND Diagnosis

CAUSES OF BENIGN POSITIONAL Management
VERTIGO OTHER VARIANTS OF BENIGN
POSTERIOR CANAL VARIANT OF BENIGN POSITIONAL VERTIGO
POSITIONAL VERTIGO Horizontal Canal Benign Positional Vertigo
Clinical Features Anterior Canal Benign Positional Vertigo
Pathophysiology Mimics of Benign Positional Vertigo
Benign positional vertigo (BPV), also called maneuver and clearly defined the clinical
benign positioning vertigo and benign paroxys- syndrome.2 Bárány speculated that the parox-
mal positional vertigo, is a common inner ear ysmal positional nystagmus was caused by a
disorder resulting from abnormal stimulation lesion of the otolith organs, as it was induced by
of the semicircular canals (usually the poste- a change in head position relative to gravity.
rior). The direction of the provocative move- Dix and Hallpike came to a similar conclusion
ment and the appearance of the induced eye after reviewing the clinical features of 100
movements (nystagmus) identify the involved patients with BPV and identifying unilateral
canal(s). The abnormal stimulation is due to degeneration of the utricular macule at
the presence of detached otoconia (canaliths) necropsy in a typical case.
moving in the canal endolymph under the In 1961, Schuknecht reviewed the temporal
influence of gravity. In order for positional ver- bone specimens from three patients who had
tigo to occur, two events must happen: (1) oto- been reported to have BPV and was struck by
conia must be dislodged from the utricular the remarkable similarity of the pathologic
macule, and (2) the head must be held in a changes.3 Each had a selective degeneration of
critical position that allows the otoconia to the superior part of the labyrinth, including the
enter a semicircular canal. BPV is not a disease; superior branch of the vestibular nerve, the
rather, it is a syndrome that can have multiple utricle, and the crista of the horizontal and
causes of the detached otoconia. anterior semicircular canals. He concluded
that in each case the damage to the labyrinth
resulted from occlusion of the anterior vestibu-
lar artery, the branch of the internal auditory
HISTORICAL BACKGROUND artery that supplies these organs. Schuknecht
felt that the paroxysmal positional nystagmus
The basic features of BPV and the associated that occurred in these cases must have origi-
paroxysmal positional nystagmus were first nated from the posterior semicircular canal
described in a single patient by Bárány in since it was the only peripheral sensory organ
1921,1 but it was not until 1952 that Dix and capable of generating nystagmus that was
Hallpike described the provocative positioning still functioning. He did not feel that the intact
255
saccular macule was capable of generating In 1969, Schuknecht found basophilic depos-
nystagmus. its on the cupulae of the posterior semicircular
With this hypothesis in mind, Schuknecht canals in two patients who manifested isolated
attempted to produce paroxysmal positional BPV without any other ear symptoms prior to
nystagmus in four cats by cutting off the blood death from unrelated disease (Fig. 10–1).4 The
supply in the left anterior vestibular artery.3 deposits were present on the side that was
Each animal developed the expected acute undermost when the paroxysmal positional
vestibular syndrome with horizontal nystagmus nystagmus was induced. These findings sup-
and imbalance in the immediate postoperative ported his earlier hypothesis and, even though
period. These symptoms gradually subsided he observed particles in the canal in addition to
over several days. One of the animals, however, those attached to the cupula, he coined the
developed typical benign paroxysmal positional term cupulolithiasis.
nystagmus 3 months after the operation, which The cupulolithiasis theory of Schuknecht
persisted until termination of the experiments gained general acceptance, but there were fea-
at 7 months. Schuknecht theorized that loose tures of the characteristic paroxysmal positional
otoconia from the degenerating utricular mac- nystagmus that were not adequately explained—
ule came in contact with the cupula of the pos- the transient duration and the fatigability
terior semicircular canal, causing it to move in with repeated positioning. If the particles are
the plane of the canal after position changes. adherent to the cupula, transient duration and
A Deposit Normal cupula

on cupula
Left Right
B
Macule
of the
utricle
Superior division
Saccule
Deposit on the cupula

Inferior division of the posterior
semicircular canal
Figure 10–1. Basophilic deposits on the cupula in benign positional vertigo. A Histopathological section through the crista
of the posterior semicircular canals of a patient who exhibited typical benign paroxysmal positional nystagmus in the head-
hanging left position prior to death from unrelated causes. Attached to the cupula is a granular, basophilic staining deposit.
B Drawing illustrating relationship between the macule of the utricle and the ampulla of the posterior semicircular canal
when the head is erect. (From Schuknecht HF. Pathology of the Ear. Harvard University Press, Cambridge, 1993, with
permission.)
10 Benign Positional Vertigo 257
fatigability would not be expected. In his initial into the utricle with appropriate positional
report,3 Schuknecht suggested that the otoco- changes. In a case series report in 1992, he
nial debris might dislodge from the cupula and reported that a simple particle repositioning
float away, allowing the cupula to return to its maneuver cured most patients with BPV.7
normal position, and that the particles might Later, randomized placebo-controlled (sham
become dispersed within the endolymph with positional maneuvers) trials confirmed the
repeated positionings. However, when his sub- treatment effect of what has become known as
sequent postmortem studies showed that the the Epley maneuver.8
otolithic debris was firmly attached to the cup- At about the same time of Epley’s original
ula of the posterior semicircular canal, he felt reports, Parnes and McClure described a sur-
that these possibilities were less likely.4 gical procedure for blocking the posterior
In the late 1970s, McClure began to experi- semicircular canal with a bony plug that was
ment with mechanical models of the inner ear highly effective in curing intractable cases
to see if these problems could be resolved. His of BPV.9 During the process of exposing
simple model consisted of a water bottle repre- the membranous labyrinth of the posterior
senting the utricular chamber and two attached semicircular canal for the plugging operation,
rounded tubes representing the posterior and Parnes and McClure observed a chalky
anterior semicircular canals. He placed mer- white substance within the endolymph of
cury in the canals to represent the otoconial the posterior semicircular canal. Their obser-
debris and noted that repeated positional vation supported the canalithiasis model pro-
changes from sitting to head-hanging position posed by Hall et al.5 and was consistent with
caused the mercury to enter the utricle. He the success of Epley’s particle repositioning
recognized that freely floating debris in the maneuver.
posterior semicircular canal could readily
explain both the paroxysmal nature of the nys-
tagmus and the fatigability. In 1979, along with
Hall and Ruby5, McClure published his model CAUSES OF BENIGN POSITIONAL
and suggested that benign paroxysmal posi- VERTIGO
tional nystagmus could be divided into two
types: type A, a nonfatigable form caused by The first event that must happen for BPV to
debris adherent to the cupula (i.e., cupulo- occur is that otoconia must be free floating in
lithiasis), and type B, a more common fatigable the utricule. However, in most cases, there is
form caused by free-floating particles in the no easily explainable reason for why the otoco-
endolymph, canalithiasis. This work served as nia are released. The attacks of positionally
the theoretical basis for the subsequent use of triggered vertigo are not typically preceded
positional exercises and positional maneuvers by a specific event. However, the prevalence
to treat BPV. of the disorder dramatically increases with
Epley did not distinguish between cupulo- increasing age so that release of the otoconia
lithiasis and canalithiasis but rather suggested could be an effect of the aging process.
that debris was both attached to the cupula and Osteopenia and osteoporosis are also more
free floating in the canal in most cases of BPV.6 common in patients with idiopathic BPV
He recognized that debris moving within the than in controls, suggesting that abnormal
narrow semicircular canal would be much calcium metabolism is an important etiological
more effective in deviating the cupula than an factor.10–12 Both osteopenia and BPV are
equal amount of debris floating within the more common in women and older people.
ampulla next to the cupula. He saw the analogy In osteopenic rats, otoconia have decreased
of the bolus of particles acting as a piston mov- density and increased size compared to con-
ing within the narrow confines of the semicir- trols so the otoconia may be more easily
cular canal, which, according to Pascal’s dislodged.13 Furthermore, degeneration of
formula, would lead to a magnified force acting otoconia is seen in older rats regardless of
on the cupula. Epley argued that if this bolus of osteopenia.14
debris could move so easily with position Another important association with BPV is
change, it should be possible to move it around migraine. Migraine is more common in
and out of the posterior semicircular canal and patients with idiopathic BPV than in controls
particularly in patients under the age of 50.15,16 is secondary to prolonged positioning with the
The reason for this association is not clear, but head back in people who already have free-
it is possible that migranous vasospasm could floating debris in the vestibule. Positioning for
lead to dislodged otoconia. dental and radiological procedures is another
Head trauma is the most common identifi- common precipitating factor for BPV.23,24
able cause for dislodging otoconia. The most Interestingly BPV occurs more commonly on
common cause of head trauma is motor vehicle the right side compared to the left, possibly
accidents followed by common falls.17 BPV because people tend to sleep more on the right
after head trauma tends to be more severe and side than the left.25,26
more protracted than BPV from other causes.
Infection and ischemia of the inner ear are the
next most common causes for free-floating oto-
conia. In animal models, brief periods of isch- POSTERIOR CANAL VARIANT OF
emia result in prominent release of otoconia BENIGN POSITIONAL VERTIGO
from the utricular macule (see Anatomy of
Otolith Organs, Chapter 2). Nearly half of Clinical Features
patients with vestibular neuritis have BPV as a
sequela (see Chapter 9). Vigorous exercise By far the most common variety of BPV is that
such as aerobics, mountain biking, and swim- associated with debris in the posterior semicir-
ming are associated with recurrent BPV.18–20 cular canal (PC-BPV).27 Patients develop brief
Presumably repeated abrupt accelerations can episodes of vertigo and nystagmus (usually last-
dislodge otoconia. Surgeries involving drilling ing <30 sec) with position change: typically
of the temporal bone such as with cochlear when turning over in bed, getting in and out of
implants can dislodge otoconia and predespose bed, bending over and straightening up, or
to BPV.21 extending the neck to look up.28 (See Video
The second event that must happen for BPV 6–12 and Video 6–13) Importantly, the vertigo
to occur is the otoconial debris must enter a of BPV is triggered by certain position changes.
semicircular canal. Free-floating otoconia in Any patient with vertigo will report worsening
the utricle are not believed to cause symptoms. of the vertigo in certain positions, but patients
It is only when the otoconia enter a semicircu- with BPV will report that the vertigo is
lar canal that symptoms occur. Because of its triggered by the position change. “Top shelf
position in the head the posterior semicircular vertigo,” in which a patient experiences an
canal is most vulnerable. Loose otoconia in the episode of vertigo while reaching for something
utricle will fall into the posterior semicircular on a high shelf, is nearly always due to PC-
canal and become trapped if the head is held BPV. Since the most common provocative
backward below the horizontal plane for a few movements for inducing PC-BPV occur in
minutes. This explains why BPV often first bed or when getting in and out of bed,
occurs after situations such as going to a hair- patients report that the vertigo is severe in
dresser, a dentist, or fixing a leaky kitchen sink. the morning and tends to disappear once
People with certain occupations, such as auto they are up. The common report of having
mechanics and plumbers, are particularly attacks mostly in the morning may also be
prone to developing recurrent BPV. It is not because the particles have had a chance to
too farfetched to assume that otoconial debris accumulate in one part of the canal while the
is floating freely within the endolymph in nearly patient is lying still sleeping. Turning the head
everyone, particularly older people.22 It is just a from side to side while erect does not induce
matter of whether the head is held in the criti- nystagmus because this movement does not
cal position long enough for the particles to stimulate the posterior semicircular canal.
drop into the posterior semicircular canal. Often after a flurry of episodes, patients com-
Benign positional vertigo commonly occurs plain of more prolonged nonspecific dizziness
after surgical procedures regardless of the (a motion-sick sensation) that may last hours or
nature or location of the surgery. Initially this even persist throughout the day. Vertigo can
was thought to result from some metabolic awaken the patient; presumably, positional ver-
changes associated with the trauma of surgery tigo occurs when they turn over while sleeping,
or from the anesthesia, but more likely the BPV and some patients experience severe nausea
and vomiting, which can be even more bother- Table 10–1 Diagnoses in 240 Patients
some than the vertigo. with Benign Paroxysmal Positional
As the name implies, BPV is a benign disor- Vertigo28
der meaning that it is not progressive and in
most cases will eventually remit spontane- Idiopathic 118
ously.29 However, spontaneous remission can Post-traumatic 43
take months or longer, and there are some Viral neurolabyrinthitis 37
patients who report having symptoms for Basilar vertebral insufficiency 11
many years and are only cured after a canalith Meniere’s disease 5
repositioning maneuver. In a longitudinal Postsurgery (general) 5
cohort study of patients who presented to an Postsurgery (ear) 5
Otolaryngology clinic, the mean time to symp- Ototoxicity 4
tom resolution was 39 days with a wide Luetic labyrinthitis 2
standard deviation of 47 days.29 In a population- Chronic otomastoiditis 2
based telephone survey study, patients with Other 8
BPV reported a mean symptom duration of
2 weeks (range 0.5 days to 104 weeks), with
about one-third reporting symptoms more than postviral (Table 10–1). Patients with the for-
1 month.30,31 The duration of symptoms in con- mer had the onset of BPV within 3 days of well-
trol groups of randomized trials was generally documented head trauma. Patients in the viral
more than 1 month for about 80% of the group reported a prior episode of acute vertigo
patients.32 The “benign” label also cannot be gradually resolving over 1 to 2 weeks. In 25 of
mistaken to mean that the symptoms are trivial. 37 postviral patients, there was an associated
Patients with BPV have an increased incidence sudden hearing loss that improved as vertigo
of falls, depression, and impairment of daily subsided, although most patients were left with
activities.33–35 During periods of symptomatic a residual unilateral sensorineural hearing loss.
BPV, 24% of patients reported giving up driv- The associated hearing loss suggests that the
ing a car and 18% avoided leaving their home.31 viral process targeted the labyrinth (i.e., “laby-
Also reflecting the burden of BPV on patients, rinthitis”) rather than the more common tar-
in the population-based study nearly 80% of get, the vestibular nerve (i.e., “vestibular neuri-
BPV patients reported a visit to a medical doc- tis”). Episodes of BPV can begin as soon as 1
tor.31 More than half of patients with PC-BPV week and long as 8 years after the acute viral
have at least one recurrence after a remis- syndrome. Most patients reported a cold or flu-
sion.15,27,31 In some patients, bouts of PC-BPV like illness within 2 weeks of the acute vertigi-
are intermixed with variable periods of remis- nous episode. Eleven patients reported typical
sion over many years. symptoms of vertebrobasilar insufficiency (in
In their initial description of the syndrome addition to vertigo) prior to the onset of BPV.
in 1952, Dix and Hallpike found evidence of In these cases, the BPV could have resulted
ear disease in approximately two-thirds of their from ischemic damage to the labyrinth. It is
100 patients with BPV.2 When the ear disease important to recognize that these episodes of
was unilateral, the nystagmus was usually positional vertigo in such patients do not indi-
induced when the abnormal ear was under- cate recurrent vascular ischemia.
most. Subsequent reports confirmed the benign Females outnumbered males by a ratio of
nature of the disorder but suggested that most 1.6:1, combining all diagnostic categories. This
cases were unassociated with identifiable ratio was approximately 2:1 if only the idio-
lesions.28,36,37 Despite its common occurrence, pathic and miscellaneous groups were consid-
there have been relatively few reports of large ered. Other investigators have reported an
series of patients with BPV. even higher female-to-male preponderance
We reviewed the clinical features of 240 with idiopathic BPV.37 The age of onset peaked
cases of BPV, each with a typical clinical his- in the sixth decade in the idiopathic group, in
tory and the stereotyped paroxysmal positional the fourth and fifth decades in the postviral
nystagmus.28 The mean age of onset was group, and was evenly distributed over the sec-
54 years (range 11 to 84 years). The two largest ond to sixth decades in the posttraumatic
diagnostic categories were posttraumatic and group.
Pathophysiology vertigo and nystagmus are brief in duration

because once the clot reaches its lowest posi-
As noted earlier, the most likely explanation for tion in the canal with respect to the earth’s sur-
PC-BPV is canalithiasis involving the posterior face, the cupula returns to its primary position
semicircular canal.7,38,39 With the patient sitting with its usual time constant determined pri-
upright, a clot of calcium carbonate crystals marily by cupular elasticity. The typical latency
forms at the most dependent portion of the of about 5 seconds before onset of nystagmus is
posterior canal (Fig. 10–2A). Movement of the explained by the delay in setting the clot into
head back and to the side in the plane of that motion. It also explains why slow positioning
posterior canal (such as with the standard does not induce vertigo or nystagmus, as the
positioning test) causes the clot to move in an clot would move slowly along the undermost
ampullofugal direction, producing ampullofu- wall of the canal without producing a plunger
gal displacement of the cupula due to the effect.
“plunger” effect of the clot moving within the Probably the most convincing argument for
narrow canal (Fig. 10–2B). Fatigability with the canalithiasis theory is the dramatic response
repeated positioning is explained by dispersion of PC-BPV to positional maneuvers designed to
of particles from the clot, making the plunger move the clot around the posterior semicircular
less effective. Reactivation of the positional canal into the utricle.7,27 By rotating the subject
vertigo after prolonged bed rest is also explained about the plane of the posterior canal, the clot
as the particles reform into a clot. The induced moves from a position next to the cupula, as
A B C
Anterior
Utricle Posterior
Horizontal Anterior
Horizontal
Horizontal
Posterior Anterior
Posterior
Clot
D E
Anterior
Posterior
Horizontal
Horizontal
Endolymphatic
Anterior duct
Posterior
Figure 10–2. Pathophysiology of the posterior canal variant of benign positional vertigo. In the sitting position (A) the clot
of calcium carbonate crystals lies at the bottom-most position within the posterior canal. Movement to the head-hanging
position (B) causes the clot to move away from the cupula, producing an excitatory burst of activity in the ampullary nerve
from the posterior canal (ampullofugal displacement of the cupula). Rolling across to the opposite side in the plane of
the posterior canal (C and D) causes the clot to enter the common crus of the posterior and anterior semicircular canals.
Finally, when the patient sits up (E) and the clot falls into the utricle. (Adapted from Epley JM. The canalith reposition-
ing procedure: For treatment of benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg. 1992;107:199, with
permission).
shown in Figure 10–2A, into the utricle as otherwise typical BPV and nystagmus who do
shown in Figure 10–2E. It is of particular note not show fatigue with repeated positioning.
that when the patient is moved from the initial There is usually a latency from the time the
head-hanging position (which induced the nys- head-hanging position is achieved to the onset of
tagmus) to the opposite head-hanging position positioning nystagmus but, as with fatigability, it
(with the abnormal ear up), an identical burst is not an absolute feature. The presence of posi-
of positioning nystagmus often occurs, in both tioning nystagmus correlates with the clinical
cases with the upper pole of the eye beating symptoms. Unless the patient is tested during a
toward the abnormal ear. This phenomenon is period when he or she is having acute episodes
readily explained by following the movement of of vertigo, the positioning nystagmus may not be
the clot around the posterior semicircular canal, observed. Patients with BPV may have negative
which in each case produces ampullofugal dis- positional testing if the particles are dispersed
placement of the posterior canal cupula. If the within the canal rather than coalescent as a clot.
debris were attached to the cupula as suggested With the development of particle reposition-
by the cupulolithiasis theory, one would expect ing maneuvers designed to remove debris from
the nystagmus to change direction in the oppo- the posterior semicircular canal, treating the
site head-hanging position. patients with these maneuvers also serves to
confirm the diagnosis.27 Once the typical posi-
tioning nystagmus is induced, we proceed with
Diagnosis a positional maneuver to cure the condition
(see later discussion). If the positioning nystag-
The diagnosis of PC-BPV rests on finding the mus and symptoms are gone after completing
characteristic paroxysmal positional nystagmus the maneuver, the diagnosis was correct.
in a patient with a typical history of positional Since BPV can generally be diagnosed and
vertigo. The nystagmus is induced by rapidly cured at the time of the office visit, ancillary
moving the patient from the sitting to head- testing is rarely indicated. Laboratory tests are
hanging position as originally described by Dix generally not helpful for the diagnosis of BPV.
and Hallpike (see Fig. 6–6 in Chapter 6). It is Patients with recurrent BPV might be screened
important to prepare the patient in advance by for osteopenia, although it is unproven whether
explaining that the goal is to induce positional correcting osteopenia decreases the likelihood
vertigo and that the patient must cooperate by of recurrent BPV. ENG and VNG are not help-
keeping the eyes open and avoid blinking as ful since there is usually a minimal horizontal
much as possible. The typical nystagmus has tor- component to record and the prominent tor-
sional and vertical components. The eyes beat sional component cannot easily be recorded.
upward (toward the forehead) with the upper VNG allows one to actually view the nystagmus
poles beating toward the ground (thus an upbeat- so that the torsional component can be appre-
torsional nystagmus is seen).40,41 The vertical ciated, but the pattern of nystagmus is readily
component is larger in the contralateral eye and identifiable at the bedside without the need for
the torsional component is larger in the ipsilat- VNG. The characteristic nystagmus is easily
eral eye, consistent with the known excitatory observed visually even if the patient attempts
connections from the posterior semicircular to fixate (i.e., there is no need for Frenzel lenses
canal to the eye muscles (see Fig. 3–8c in or infrared video recordings). MRI of the brain
Chapter 3). A reverse nystagmus (downbeat and is not indicated, but high resolution MRI of the
torsional) of lesser magnitude usually occurs if inner ear might be informative for visualizing
the patient is brought directly back up from the the otoconia debris and canal structure in very
head-hanging position to the sitting position, rare atypical or refractory cases.42,43
a finding which is also highly supportive of
free-floating particles in the canal because sit-
ting up reverses the movement of the particles Management
in the canal, thus triggering nystagmus in the
reverse direction. The nystagmus triggered in Once BPV is diagnosed, a simple explanation
the head-hanging position fatigues (decreases of the nature of the disorder and its favorable
with repeated positioning) in more than 90% of prognosis can help relieve the patient’s anxiety.
patients, but there are occasional patients with Because of the dramatic nature of the episodes
of vertigo, many patients believe that they have sion.31 The likelihood of a recurrence should be
a life-threatening disorder such as a tumor or explained to patients so they are not unduly
stroke, and they need to be reassured that they frightened if it occurs.
have a benign inner ear disorder. It is impor- We typically perform a particle repositioning
tant to be aware, however, that although it is a maneuver designed to liberate the clot from
benign disorder, recurrences are common. the posterior semicircular canal immediately
Episodes of positional vertigo typically occur in after the diagnosis is confirmed with the
flurries and about half of the patients will have Dix-Hallpike positioning test. We use a
at least one exacerbation after an initial remis- modified Epley maneuver, shown in Fig. 10–3.
Figure 10–3. Modified Eply maneuver for treating the posterior canal variant of benign positional vertigo. After turning
the head toward the affected side (right side in this case) the patient moves from a sitting to head hanging position (The
Dix-Hallpike test, 1–2); once the nystagmus and vertigo have subsided the patient rolls across to the opposite side, nose
facing the ground, all in one motion (2–4); finally after about 30 seconds the patient returns to the sitting position (4–5).
(From Fife TD et al. Quality Standards Subcommittee, American Academy of Neurology. Practice parameter: therapies
for benign paroxysmal positional vertigo (an evidence-based review): report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology. 2008;70:2067 with permission).
3
2
Figure 10–4. Modified Seymont maneuver for treating the posterior canal variant of benign positional vertigo. After turn-
ing the head toward the unaffected side (left side in this case) the patient moves from a sitting to right lateral position (1–2);
while maintaining the head in the same position the patient moves across to the opposite lateral position, in the plane of
the right posterior canal (2–3); after vertigo and nystagmus subsides the patient returns to the sitting position. (From Fife
TD et al. Quality Standards Subcommittee, American Academy of Neurology. Practice parameter: therapies for benign
paroxysmal positional vertigo (an evidence-based review): report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology. 2008;70:2067 with permission).
(See Video 10–1) The Semont maneuver 10%–20% of patients in the control groups with
(Fig. 10–4) may be equally effective, although outcomes measured from 1 day to 1 month.
there have been fewer controlled studies These effect sizes translate into a “number
using this maneuver.32 The key feature of the needed to treat” (NNT) of 1.43 to 2.44. The
particle repositioning maneuvers is to move NNT is a statistical measure that indicates the
the patient in the plane of the posterior number of patients that had to have treatment
semicircular canal to allow the clot of debris to achieve the beneficial outcome in one
to rotate around the canal and enter the patient. Thus, approximately two patients with
utricle. BPV require treatment with the Epley maneu-
The Epley maneuver is among the most ver to eliminate the symptoms in one patient;
efficacious interventions in all of clinical this is among the largest effect sizes achievable
medicine. The maneuver has been tested in in clinical medicine, and it is particularly
numerous randomized placebo (i.e., sham pro- impressive considering that the outcome used
cedures) controlled trials. Trial quality has been was elimination of symptoms (i.e., cure of
rigorously scrutinized independently by the symptoms) as opposed to only an improvement
Cochrane Collaboration,8 the American in symptoms.
Academy of Neurology Quality Standards Despite the large effect size of the Epley
Subcommittee,32 a multidisciplinary guideline maneuver for BPV, the maneuver appears to
development panel chosen by the American be substantially underutilized in routine prac-
Academy of Otolaryngology–Head and Neck tice. Of patients with BPV who presented to a
Surgery Foundation,44 and other independent physician, only 27% reported undergoing diag-
groups.45,46 The summary results of all the valid nostic positional testing (i.e., the Dix-Hallpike
randomized controlled trials indicate that the test) and only 10% underwent a particle repo-
Epley maneuver has a large effect size in sitioning maneuver of any type.31
treating patients with BPV. In these studies, It is doubtful that physicians are just instruct-
61%–80% of patients treated with the maneu- ing patients to avoid provocative positions and
ver had resolution of BPV compared with only await spontaneous resolution because about
75% of patients with BPV who present to a at the bifurcation of the common crus to the
physician end up having at least one diagnostic posterior and anterior canals.7 Repeating the
test ordered, including imaging studies, ves- particle repositioning with vibration applied to
tibular tests, an audiogram, and blood tests.31,47 the skull (i.e., mastoid region of affected side)
Although most patients are cured after a will usually break up the “canalith jam” and
single particle repositioning maneuver, the cure the BPV.
cure rate is improved by repeating the proce- What happens to the particles once they
dure until no vertigo or nystagmus occurs in enter the utricle? When the otoconia are sepa-
any position. Occasionally a patient will develop rated from the gelatinous layer of the otolith
severe nausea and have to be rescheduled and membrane, they can dissolve in the endolymph
premedicated with a vestibular suppressant fluid, be taken up into the membrane by the
drug. Although not routinely recommended, process of phagocytosis, or simply remain free
occasionally, vibration applied to the mastoid floating within the endolymph. The calcium
region is useful if, rather than a burst of nystag- concentration of the endolymph seems to be
mus with position change, the patient develops critical for determining whether the otolithic
a slow, persistent nystagmus, suggesting that debris will dissolve.50 Otolith debris may not be
the otolithic debris is stuck to the wall of the cleared in patients who have recurrent attacks
semicircular canal or to the cupula and not of BPV. As noted earlier, osteopenia and osteo-
freely moving. A sign that the modified Epley porosis are more common in patients with
maneuver is going to be successful is the pro- recurrent BPV than in patients with de novo
duction of a second identical burst of positional BPV.12
nystagmus when the patient is moved from the After performing a particle repositioning
initial head-hanging position across to the maneuver, we recommend that patients avoid
opposite head-hanging position.48 This indi- all extreme head-back positions such as those
cates that the particles are moving along in the mentioned earlier. Other restrictions, such as
canal in the correct direction toward the utri- having the patient sleep propped up for a few
cle. If, on the other hand, a burst of nystagmus nights or wearing a cervical neck collar, do not
in the reverse direction occurs when moving improve the outcome.51Antivertiginous medi-
from one head-hanging position to the other, cations such as meclizine or promethazine have
the particles are most likely moving in the relatively little use in the management of
wrong direction back toward the cupula, a sign patients with BPV because the acute attacks
that the particle repositioning maneuver will are not suppressed by these drugs; moreover,
be unsuccessful. When this occurs, the patient the particle repositioning maneuver is much
most likely elevated the head while rolling over more effective in controlling the condition. For
from the head-hanging position to the other the very rare patient with prolonged refractory
side because this can cause the particles to BPV, one might still consider a surgical proce-
move back in the opposite direction because of dure such as the singular neurectomy or the
gravity. It is critical that the head stay down canal plugging procedure.9,52,53 The main com-
during this phase of the positioning maneuver. plication of these procedures is a sensorineural
When returning to the sitting position at the hearing loss, which may occur in as many as
end of the particle repositioning maneuver, 10% of patients.
patients may have a brief but severe burst of Patients who have multiple recurrences of
vertigo (falling sensation) as late as 30 min after BPV can be taught to perform the particle
assuming the position.49 This delayed vertigo in repositioning maneuver on their own.55,56 We
the sitting position presumably occurs as the regularly give our patients a diagram for per-
bolus of otolithic debris drops out of the forming the maneuver on a bed at home (e.g.,
common crus of the posterior and anterior Figs. 10–3 and 10–4). One study compared the
semicircular canals into the utricle. Rarely, efficacy of self-treatment with a modified Epley
patients will develop a persistent vertigo and maneuver and a modified Semont maneuver
nystagmus after returning to the sitting posi- and found that the response rate was signifi-
tion. This phenomenon might result from a cantly greater with the modified Epley maneu-
jamming of the otolithic debris (a canalith jam) ver.56 Although minor complications such
when migrating from a wider to narrower seg- as those described earlier can occur, none of
ment, such as from the ampulla to the canal or them is serious and most are cured by simply
repeating the maneuver. Patients can pre- these variants can become attached to the
sedate themselves and often they feel more cupula, producing true cupulolithiasis.
comfortable performing the maneuver on their It is also possible for otoconia to enter
own in the controlled environment of their multiple canals at once, particularly after head
bedroom. Vibration applied to the mastoid is trauma,60 which leads to more challenging
rarely required,57 but a simple neck massage approach to repositioning.
vibrator can be used if one is available. Of Lastly, these other variants of BPV can be
course, one key point that cannot be ignored is produced after performing the particle reposi-
that the particle repositioning maneuver (i.e., tioning maneuver for the typical posterior canal
Epley maneuver or Semont maneuver) only variant. For example, as the debris is moved
works for treating PC-BPV. It is of no use for from the posterior semicircular canal, it can
treating other causes of vertigo. enter the anterior canal from the common crus
or it can enter the horizontal canal after it falls
into the utricle (Fig. 10–5).
OTHER VARIANTS OF BENIGN

POSITIONAL VERTIGO Horizontal Canal Benign Positional
Vertigo
As noted earlier, the most common type of BPV
occurs when otoconial debris are within the The clinical history of horizontal canal BPV is
posterior semicircular canal, probably because similar to that of the posterior canal variant,
this is the canal in which it is most easily trapped. although there are important differences.61–63
However, the otoconia can enter either one of With both syndromes, positional vertigo com-
the other canals and patients do present clini- monly occurs in bed, particularly when patients
cally with BPV from these canals. After poste- turn over from one side to the other. Patients
rior canal BPV, the next most common variant with PC-BPV, however, develop vertigo when
is horizontal canal BPV. Anterior canal BPV is getting in and out of bed and when bending
much less common. The clinician must also add down and straightening up or extending the
a bit more caution when making the diagnosis head backward to look up. In contrast, patients
of either the horizontal or anterior canal vari- with horizontal canal BPV develop vertigo pri-
ants of BPV because the patterns of nystagmus marily when turning over in bed or when turn-
seen with these variants can be similar to pat- ing the head to the side when lying back in an
terns of positional nystagmus caused by lesions easy chair. Occasionally, patients with horizon-
in the central nervous system.58,59 This is differ- tal canal BPV experience episodes of vertigo
ent than the clinical scenario with posterior when turning the head to the side while sitting
canal BPV because the characteristic pattern of or walking. Remissions and exacerbations com-
nystagmus in posterior canal BPV (i.e., a burst monly occur with both types of BPV, but
of upbeat, torsional nystagmus lasting <30 sec- exacerbations are typically shorter in duration
onds, and then having the nystagmus convert to with the horizontal canal variant than with the
downbeat torsional nystagmus if the patient is posterior canal variant, 29,64 though recurrences
brought directly back up to the sitting position) may be more common in the horizontal canal
is not a pattern expected or ever reported to be variant.54 With horizontal canal BPV, patients
caused by a central lesion. For the PC-BPV can develop two patterns of positionally trig-
variant, further adding to the confidence in the gered nystagmus (i.e., “geotropic” or “apogeo-
bedside diagnosis is the fact it is readily cured tropic”) depending on whether the canaliths
at the bedside. On the other hand, horizontal are in the anterior segment or the posterior
canal BPV can at times be difficult to make an segment of the horizontal canal.
immediate impact at the bedside.
The horizontal and anterior canal variants
GEOTROPIC NYSTAGMUS
have clinical syndromes that resolve on average
more quickly than the posterior canal variant,29 When the canaliths are in the posterior seg-
likely because the debris in these canals more ment (or “long arm”) of the horizontal canal,
readily falls back out based on the anatomy. patients will develop a paroxysmal, horizontal
Although, in rare cases the otolithic debris in direction–changing nystagmus that beats
Anterior canal clot moves to the bottom of the canal in the

ampulla lateral position, returning to the supine posi-
Horizontal tion results in a movement of the clot back to
Horizontal canal canal
ampulla
its original position and a burst of nystagmus in
the opposite direction. Furthermore, rotation
of the head to the opposite side causes the clot
to move in the opposite direction and produces
ampullofugal displacement of the cupula and
Utricle geotropic nystagmus.
Unlike PC-BPV, the horizontal canal variant
Saccule has only minimal latency and no fatigability. With
PC-BPV, latency is explained by a delay in move-
Vestibule ment of the calcium carbonate clot and fatigabil-
Posterior
canal Debris
ity by dispersion of the calcium carbonate
particles with repeated positioning. There may
Figure 10–5. Drawing of the vestibular labyrinth showing be a viscous plug or gel in the horizontal canal,
the proposed path of debris as it moves out of the posterior
semicircular canal and into the anterior or horizontal canal rather than a clot of calcium carbonate crystals,
(dashed line and arrows). which could explain the lack of fatigability.61
APOGEOTROPIC NYSTAGMUS
toward the ground (so-called geotropic nystag-
mus) when the head is turned to the side while The second pattern of nystagmus that occurs
they are lying supine (the nystagmus will also with otoconia in the horizontal canal is the
be triggered by a body roll to the side). Thus, “apogeotropic” (i.e., away from the ground)
when the head is turned to the left side, a left- pattern that is caused by otoconia in the ante-
beating nystagmus is triggered. Then, when rior segment of the canal.66 This again can
the head is turned toward the right side, a result from otoconia adherent to the cupula
right-beating nystagmus is triggered. The nys- (cupulolithiasis) or free floating in the anterior
tagmus lasts about a minute. Though it occurs segment of the canal (canalithitiasis). When
with the head to either side, it is nearly always patients have otoconia in these regions of the
stronger on one side (the abnormal side). The horizontal canal, a head turn to the left side
debris enters the canal side of the horizontal while lying supine triggers a right-beating (thus
semicircular canal when the patient lies supine. away from the ground, “apogeotropic”) nystag-
When the head is rapidly turned to the abnor- mus. Turning the head to the right side will
mal side, the mass is accelerated downward in trigger a left-beating nystagmus. The dynamics
the canal. The deceleration that occurs once of the buildup and decay of nystagmus depends
the lateral position is reached would normally on whether the debris is free floating or
rapidly return the cupula to the center position attached to the cupula and the dynamics of the
and there would be no post-positioning nystag- horizontal VOR. When the debris is attached
mus. Because of the continued effect of gravity to the cupula, the stimulus is constant accelera-
on the freely floating clot, however, it contin- tion, which causes a gradual buildup of slow-
ues to move downward in the canal toward the phase velocity determined by the dominant
ampulla until it reaches the bottom of the canal time constant, defined as the time it requires
in that lateral position. Movement of the clot for the response to reach 63% of maximum. An
within the canal results in an ampullopetal average time constant of the horizontal VOR in
deviation of the cupula and a burst of nystag- normal subjects is in the range of 12–20 sec.
mus beating toward the ground. When the clot The gradual decay in slow-phase velocity after
stops moving, the cupula returns to the primary reaching a peak response can be explained on
position, with the normal time constant. The the basis of central VOR adaptation.
longer duration of horizontal canal variant BPV
compared to the posterior canal variant is TREATMENT OF HORIZONTAL BPV
explained by the longer time constant of the
horizontal vestibulo-ocular reflex (VOR) than Unlike treatment for the posterior canal variant,
that of the vertical VOR.65 Once the free-floating there are no high-level randomized controlled
2
4
5 7
Figure 10–6. Maneuver for treating the horizontal canal variant of benign positional vertigo. While lying supine with
the head turned toward the affected ear (right side in this case) the patient rolls across toward the unaffected side (1–3);
the patient then continues the roll by moving through the prone position to the right lateral position (3–5); finally the
patient returns to the sitting position (6–7). (From Fife TD et al. Quality Standards Subcommittee, American Academy of
Neurology. Practice parameter: therapies for benign paroxysmal positional vertigo (an evidence-based review): report of the
Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2008;70:2067 with permission).
trials of positional treatments for the horizontal “barbeque” maneuver, the patient is rotated in
canal variant.32 However, there are several the plane of the horizontal canal.67–69 The
different positional treatments that suggest patient starts in the supine position and is rolled
efficacy in cohort and case series designs. In 90 degrees to the normal side (the side with
general, it is easier to treat HC-BPV when the lesser nystagmus), then in 90-degree steps to
otoconia are in the posterior segment (render- prone, to the abnormal side, and back to the
ing geotropic positional nystagmus) because the supine. Another maneuver gaining acceptance
particles are closer to the exit of the canal to is the Gufoni maneuver. With the Gufoni
the utricle and because they are less likely to maneuver70 the patient is rapidly moved from
be adherent to the cupula. In fact, when the the sitting position (feet forward) to a head lat-
patient is identified as having apogeotropic nys- eral position (normal ear down). The head is
tagmus, the first goal in repositioning is gener- held in this position for about 2 minutes until
ally to move the otoconia from the anterior the geotropic nystagmus disappears. The head
segment to the posterior segment, thus convert- is then quickly turned to the side, nose down
ing the apogeotropic nystagmus to a geotropic toward the ground. After 2 minutes the
nystagmus. patient returns to the starting position. (See
For patients with geotropic pattern of nys- Video 10–2) Finally, the “forced prolonged
tagmus, one commonly used maneuver is the position” is another option. With the “forced
“barbeque” maneuver (Fig. 10–6). With the prolonged position” the patient is instructed
to sleep overnight with the normal ear down,71 ampullary segments of both anterior canals
which allows the otoconia to naturally fall out point downward in the head-hanging positions.
of the affected canal. The forced prolonged The direction of the torsional component of
position is typically selected if the other maneu- the positioning nystagmus indicates which ear
vers are not effective or if the patient is not is the origin of the nystagmus.76,77 If the upper
tolerating the other maneuvers. pole of the eye beats away from the ground
When the pattern of nystagmus is apogeo- toward the uppermost ear, then it originates
tropic, performing the barbeque maneuver from the anterior canal of the uppermost ear. If
toward the affected side can convert the nys- it beats toward the ground, then it originates
tagmus to geotropic.72 The Gufoni maneuvers from the anterior canal of the undermost ear.
can also do this.73 Once the nystagmus is con- The standard particle repositioning maneuver
verted, the typical treatments for geotropic can used for treating PC-BPV on the same side is
be used. More than half of patients with apo- also successful for treating the anterior canal
geotropic BPV were cured by having them lie variant of BPV.76
on the side of weakest nystagmus for 2 nights.74
Barbaque rotation and the Gufoni maneuver
(toward the side with weaker nystagmus) can Mimics of Benign Positional Vertigo
also get the debris to move from the anterior
to posterior arm and out of the horizontal BPV is by far the most common cause of brief
canal.72,73 recurrent attacks of positional vertigo. But it is
important to know that any patient with con-
stant or prolonged vertigo will report worsening
Anterior Canal Benign Positional of the symptom with certain position changes.
Vertigo For example, if a patient has vestibular neuritis
and presents with severe and constant vertigo,
Rarely patients with a typical history of BPV, the patient will typically report feeling much
particularly after head trauma, exhibit a tor- better lying still and much worse with any
sional downbeat nystagmus rather than the movement. This history is frequently misinter-
usual torsional upbeat nystagmus on the preted as a positional vertigo syndrome.
standard Dix-Hallpike positional test.28,75,76 It is also important to know that positionally
The positioning nystagmus otherwise has all of triggered nystagmus can be a central nervous
the typical features of posterior canal BPV— system finding. The most common pattern of a
the most important of these features is the brief central positional nystagmus is a persistent
duration, since persistent downbeat nystagmus downbeating nystagmus, which can be misin-
is a central nervous system sign. With the stan- terpreted as nystagmus from anterior canal
dard Dix-Hallpike test, turning the head to the BPV.58 The next most common central pattern
right and lowering the patient into the head- of positional nystagmus is a horizontal
hanging right position activates the right poste- direction changing nystagmus, which can be
rior semicircular canal and the left anterior identical to the patterns of nystagmus seen
semicircular canal. Since the ampullae are on with horizontal canal BPV.59 Thus, when man-
the opposite ends of these two vertical canals, aging a patient with findings suggestive of
this positional change results in ampullofugal either anterior or horizontal canal BPV but
movement (excitation) of endolymph in the when the patient is not able to be effectively
posterior semicircular canal and ampullopetal treated over a reasonable time frame or if there
movement (inhibition) of the endolymph in the are any important inconsistencies, then a cen-
contralateral anterior canal. Thus, if there were tral lesion should be considered. The most
debris in the anterior canal of the contralateral common central lesions that mimic anterior
ear, it would be driven back toward the cupula and horizontal canal BPV are Chiari malforma-
rather than away from the cupula, as occurs in tions, tumors or other structural lesions involv-
the posterior semicircular canal. Once the ing the cerebellum or peri-forth ventricular
final position is reached, however, debris within regions, or neurodegenerative disorders involv-
the canal would move downward away ing the cerebellum (i.e., spinocerebellar ataxia
from the cupula of the anterior canal since the syndromes).
Fortunately, the pattern of nystagmus seen 16. Uneri A. Migraine and benign paroxysmal positional
with PC-BPV is not a pattern at all typical of vertigo: an outcome study of 476 patients. Ear Nose
Throat J. 2004;83(12):814.
a central lesion. To our knowledge there 17. Gordon CR, Levite R, Joffe V, Gadoth N. Is post-
has been no convincing report of a central traumatic benign paroxysmal positional vertigo
lesion causing all the characteristic features of different from the idiopathic form? Arch Neurol.
PC-BPV (i.e., a burst of upbeat torsional nys- 2004;61(10):1590.
18. Giacomini PG, Ferraro S, Di Girolamo S, Villanova
tagmus in the head-hanging position with the I, Ottaviani F. Benign paroxysmal positional vertigo
duration of nystagmus being less than 30 sec- after intense physical activity: a report of nine cases.
onds). Any reports that suggest this occurrence Eur Arch Otorhinolaryngol. 2009;266(11):1831.
are much more likely to be an example of a 19. Vibert D, Redfield RC, Häusler R. Benign paroxysmal
common disorder (i.e., PC-BPV) co-occurring positional vertigo in mountain bikers. Ann Otol Rhinol
Laryngol. 2007;116(12):887.
with a rare central lesion. 20. Aksoy S, Sennaro lu L. Benign paroxysmal positional
vertigo in swimmers. Kulak Burun Bogaz Ihtis Derg.
2007;17(6):307.
21. Viccaro M, Mancini P, La Gamma R, De Seta E,
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WW. Anterior canal benign paroxysmal positional
Chapter 11
Endolymphatic Hydrops (Meniere’s

Syndrome)
BACKGROUND Infection/Autoimmune
OCCURRENCE DIAGNOSIS
CLINICAL FEATURES Audiometric Testing
PATHOPHYSIOLOGY Vestibular Testing
ANIMAL MODELS Imaging
ETIOLOGY MANAGEMENT
Genetics Medical Management
Migraine and Meniere’s Syndrome Surgical Management
BACKGROUND researchers independently reported hydrops of

the inner ear in autopsy specimens from patients
When Prosper Meniere described a series of with the typical symptom triad of modern-day
patients with hearing loss and vertigo in 1861, Meniere’s disease.3,4 However, because of
he was not attempting to define a disease but Meniere’s description of the young girl’s
rather to convince his medical colleagues that autopsy in his classical paper, the concept that
vertigo could be a symptom of damage to the Meniere’s disease was caused by hemorrhage
inner ear.1,2 Prior to this time, vertigo was con- into the inner ear persisted well into the twen-
sidered to be a cerebral symptom and was tieth century. Meniere was not suggesting that
lumped together with epileptic seizures and the patients he described with episodic vertigo
stroke under the rubric of “apoplectiform cere- and fluctuating hearing loss had the same dis-
bral congestion,” a condition thought to result ease as the young girl with sudden deafness and
from overfilling of blood vessels in the brain.2 vertigo. He was simply trying to make the point
To support his argument, Meniere described that vertigo and hearing loss commonly occur
the autopsy findings in a young girl who died 5 together with inner ear disease.
days after experiencing the sudden onset of The clinical profile of Meniere’s disease
hearing loss and vertigo. Meniere observed a evolved over the years from a nonspecific
red plastic material, in the child’s inner ear, a description of just about any combination of
bloody exudate filling the semicircular canals. hearing loss and vertigo to a characteristic clin-
In retrospect, this likely represented a case of ical triad of fluctuating hearing loss, tinnitus,
acute leukemia with hemorrhage into the inner and vertigo. Once a characteristic pathology—
ear. It provided convincing evidence that dam- endolymphatic hydrops—was discovered in
age to the semicircular canals of the inner ear the late 1930s,3,4 the next question was whether
could cause vertigo. It would take almost patients with the typical clinical profile
another century before English and Japanese consistently showed this pathology. As more
273
and more pathological specimens have been all races and is recognized in all countries.
reported, the answer to this question is, usually Kitahara et al.16 found that black Americans
but not always.5–8 Complicating matters fur- were affected only about half as often as white
ther, endolymphatic hydrops can be found Americans. Although some studies have found
in ears from patients without the typical symp- a female preponderance among Meniere’s
toms of Meniere’s disease and, occasionally, patients, others have not, and the slight differ-
even in patients without ear symptoms.8–10 ences that have been reported can probably be
Furthermore, it has become apparent that attributed to patient selection. A Swedish study
Meniere’s syndrome and the characteristic of 356 patients with advanced Meniere’s syn-
inner ear pathology can be produced by several drome found a preponderance of males over
different etiologies, including infections (syph- females,17 whereas a Japanese study found a
ilitic, bacterial, and viral) and after traumatic slight female preponderance.18
and metabolic injuries to the inner ear. Some There is general agreement that Meniere’s
suggest using the term Meniere’s syndrome to syndrome is a disease of middle age.19 The
describe the broad spectrum of disorders with mean age of onset is remarkably consistent
the characteristic clinical triad regardless of around the age of 40, with the mean age at
cause, while restricting the use of Meniere’s diagnosis being closer to 50. Meniere’s syn-
disease to describe only those cases without an drome can occur in children, but it is rare.
identifiable cause (idiopathic). However, as we Initial audiograms in children often show a
will see, there are undoubtedly multiple etiolo- high-frequency hearing loss rather than the
gies for the idiopathic group so that the separa- low-frequency loss seen in adults.20 In the
tion between Meniere’s syndrome and material from the Mayo Clinic study, no
Meniere’s disease is arbitrary and likely to patients with Meniere’s syndrome were under
change constantly. For this reason, we prefer the age of 15 years.11
the general term Meniere’s syndrome to There is a good deal of confusion and con-
describe the classical clinical profile of fluctuat- troversy regarding when and how often
ing hearing loss, tinnitus, and vertigo. When a Meniere’s syndrome becomes bilateral.
cause can be determined, it can be described Thomas and Harrison21 followed 610 cases of
as Meniere’s syndrome due to infection or Meniere’s syndrome and noted that those cases
autoimmune disease, for example, and if no that were destined to become bilateral invari-
cause can be found, Meniere’s syndrome of ably developed within 5 years of presentation.
unknown cause. In contrast, Friberg and colleagues22 monitored
161 patients with repeated examinations and
noted an almost linear increase in the number
of bilateral cases from only a few percent at
OCCURRENCE onset to almost 50% in those who had been fol-
lowed for as long as 30 years. In another study
It is difficult to obtain accurate measures of the with long-term follow-up, Kitahara et al.23
prevalence and incidence of Meniere’s syn- reported development of bilateral involvement
drome because of problems with a definitive in 41% of cases. In the Mayo Clinic study,
diagnosis and patient selection. In 1984, about a third of patients developed bilateral
Wladislavosky-Wasserman et al.11 reviewed the involvement.11 Complicating matters further,
data of the Mayo Clinic in Rochester, the contralateral ear may show audiometric
Minnesota, and estimated a prevalence of 218 changes without overt symptoms.24,25
per 100,000 and an incidence of 15 per 100,000. A major problem in interpreting all of these
In 2005, Shojaku et al.12 reported an average studies on the epidemiology of Meniere’s syn-
annual prevalence and incidence of 34.5 and drome is the lack of uniform criteria for diag-
5.0, respectively, per 100,000 population in the nosis and the likelihood that many different
Nishikubiki district of Japan. Figures for the etiologies are being included in the patient
incidence of Meniere’s syndrome in European groups being studied. For example, it is possi-
countries varies from a low of 4 per 100,000 in ble that certain causes of Meniere’s syndrome
Finland13 to as high as 157 per 100,000 in might be more prevalent in one sex than the
Britain.14 A recent study from Germany found other, have a different racial distribution, and
a population prevalence of 0.12%.15 It affects be more likely to become bilateral. Until there
11 Endolymphatic Hydrops (Meniere’s Syndrome) 275
are diagnostic markers that identify specific Meniere’s syndrome experience abrupt epi-
categories of Meniere’s syndrome, it will be sodes of falling to the ground without loss of
very difficult to obtain accurate statistics consciousness or associated neurologic symp-
regarding the epidemiology of the disease. toms. These episodes have been called otolithic
catastrophes by Tumarkin30 because of his sus-
picion that they represented acute stimulation
of the otoliths from the hydrops. Patients often
CLINICAL FEATURES report feeling as though they were pushed to
the ground by some external force.31 These epi-
Typically, an attack of Meniere’s syndrome sodes can be confused with drop attacks seen
begins with a sensation of fullness and pressure with vertebrobasilar insufficiency and may
along with decreased hearing and tinnitus in suggest an inaccurate diagnosis in a patient
one ear. Vertigo rapidly follows, reaching a with otherwise typical symptoms and signs of
maximum intensity within minutes and then Meniere’s syndrome.32
slowly subsides over the next several hours. With delayed endolymphatic hydrops, the
The patient is usually left with a sense of patient reports a long history of hearing loss,
unsteadiness and dizziness for days after the often since early childhood, followed years
acute vertiginous episode. In the early stages later by typical symptoms and signs of endo-
the hearing loss is completely reversible, but in lymphatic hydrops.33,34 The hydrops can develop
later stages a residual hearing loss remains. in either ear. When it develops in the ear with
Tinnitus may persist between episodes but longstanding hearing loss, the vertigo attacks
usually increases in intensity immediately may not be accompanied by fluctuating hear-
before or during the acute episode. It is typi- ing loss and tinnitus, confusing the diagnosis.
cally described as a roaring sound (the sound of Schuknecht34 speculated that the initial hear-
the ocean or a hollow seashell sound). After ing loss results from a viral infection that also
vomiting the patient prefers to lie in bed produces subclinical damage to the resorptive
without eating until the acute symptoms pass. mechanism (in either ear). Hydrops develops
Such episodes occur at irregular intervals for years later as the balance between endolymph
years, with periods of remission unpredictably secretion and resorption is disrupted. Delayed
intermixed.26,27 Eventually, severe permanent hydrops might also result from an autoimmune
hearing loss develops and the episodic nature process triggered by antigens released from
spontaneously disappears (“burnt-out phase”).7 the previously damaged inner ear or from
However, some patients can continue to be genetic causes of unilateral hearing loss.35,36
bothered by severe dizziness even after a
20-year disease history.28
Variations from this classic picture are com-
mon, particularly in the early stages of the PATHOPHYSIOLOGY
disease process, but the diagnosis remains
uncertain unless the combination of fluctuating As indicated earlier, the principal pathologic
hearing loss and vertigo occurs. Isolated epi- finding in patients with Meniere’s syndrome is
sodes of vertigo or hearing loss often precede an increase in the volume of endolymph associ-
the characteristic combination of symptoms by ated with distension of the entire endolym-
months or even years. Although so-called ves- phatic system (Fig. 11–1).3,4,7 The membranous
tibular Meniere’s and cochlear Meniere’s have labyrinth progressively dilates until the saccu-
been proposed as variations of the classic syn- lar wall makes contact with the stapes footplate
drome, clinical–pathologic correlation of iso- and the cochlear duct occupies the entire
lated vestibular and auditory disorders with vestibular scala. The cochlear and vestibular
selective endolymphatic hydrops of the vestib- end organs and nerves show modest pathologic
ular and auditory labyrinth is lacking. A small changes. Interestingly, even the contralateral
percentage of patients with sudden deafness— ears show significantly more damage than the
particularly if there is associated vertigo—will inner ears of controls.37 Membranous labyrinth
later develop typical symptoms of Meniere’s herniations and ruptures are common, the
syndrome, so-called delayed endolymphatic latter frequently involving Reissner’s mem-
hyrdrops.29 Some patients with well-documented brane and the walls of the sacculus, utriculus,
Figure 11–1. Dilated membranous labyrinth in Meniere’s syndrome. The drawing was made from a three-dimensional
model developed from serial sections of the ear of a patient with Meniere’s syndrome. (Adapted from Schuknecht HF.
Pathology of the Ear. Lea & Febiger, Philadelphia, 1993, with permission.)
and ampullae. Occasionally, a rupture is fol- Another possible explanation for the epi-
lowed by complete collapse of the membra- sodes of hearing loss and vertigo is ruptures in
nous labyrinth. the membranes separating endolymph from
Although the pathologic changes in Meniere’s perilymph, producing a sudden increase in
syndrome have been well described, the mech- potassium concentration in the latter.7 If the
anism for its fluctuating symptoms and signs perilymph space of animals is infused with a
are still not completely understood. Some of potassium solution, the bioelectric activity of
the fluctuating symptoms with Meniere’s syn- the labyrinthine receptors is inhibited.41 When
drome probably result from mechanical the artificial infusate is stopped, potassium is
deformation of the end organ, which is revers- slowly cleared from the perilymph, and laby-
ible as the endolymphatic pressure decreases. rinthine function returns to normal in 2 to 3 hr
The characteristic hearing loss can be explained (the typical duration of a Meniere’s attack).
by increased pressure at the apex of the cochlear However, the stereotyped episodes of vertigo,
duct leading to displacement of the basilar tinnitus, and low-frequency hearing loss would
membrane and altered auditory thresholds.38,39 be difficult to explain on the basis of random
The dramatic sudden falling attacks initially ruptures in the membranous labyrinth.
described by Tumarkin are likely due to sud- As discussed in Chapter 2, there are conflict-
den deformation or displacement of one of the ing theories regarding the mechanisms in regu-
otolith organs.30,31 In addition to mechanical lating endolymph volume.42 The longitudinal
effects on the sensorineural elements of the flow theory, initially proposed by Guild, holds
inner ear, increases in endolymphatic pressure that endolymph is secreted by the stria vascu-
can cause symptoms by altering blood flow to laris in the cochlea and dark cells in the ves-
the inner ear.39 Experimental and clinical data tibular labyrinth, and the endolymph gradually
support the notion that pressure changes in the flows toward the endolymphatic duct and sac
inner ear can induce ischemia that either tran- where it is resorbed. The radial theory assumes
siently or permanently damages the sensory a local transverse and active diffusion process
cells in the auditory and vestibular organs.40 between endolymph and perilymph through-
Furthermore, hydrops can affect the neural out the labyrinth. Finally, the dynamic theory
regulation of inner ear blood flow. Hypoxic is a combination of the two, whereby endo-
changes within the ear could lead to changes in lymph volume is determined by both a radial
chemistry and resting potentials, which could ionic diffusion and a slow longitudinal bulk
explain reversible episodes of auditory and ves- process. Endolymphatic hydrops could result
tibular dysfunction. Prolonged ischemia would from an increase in production or a decrease in
lead to permanent damage to the sensorineural the resorption of endolymphatic fluid. An
elements.40 increased production of endolymph could
result from an increase in active transport of toxin into the inner ear55 and long-term admin-
cations (sodium, potassium, and calcium) with istration of alderosterone or vasopressin.56,57 A
their anionic pair (chloride) as well as water problem with all of these animal models is that
into the endolymph to maintain osmolality and they produce hydrops and hearing loss but no
electroneutrality.39 Since the stria vascularis of attacks of vertigo. Thus, they may be producing
the cochlea and the dark cells of the vestibular the interictal phase of Meniere’s syndrome but
labyrinth are the sites of maximum ion trans- not the ictal phase. Recently, Takumada et al.
port and maximum energy consumption, they produced a mouse model with episodic vestib-
are likely candidates for the site of overproduc- ular dysfunction by using a combination of
tion of endolymph resulting in hydrops. The intratympanic injections of lipopolysaccharides
adrenal hormone aldosterone controls the level and intraperitoneal injections of aldersterone.53
of membrane-bound Na/K ATPase of the stria Intratympanic injections of epinephrine caused
vascularis and dark cells.43–45 And, in turn, it episodes of vestibular dysfunction in these ani-
controls secretion of potassium ions and endo- mals but not in controls or in animals that just
lymph production. Increased aldosterone lev- received lipopolysaccharides or aldosterone.
els induced by diet or stress could be a trigger This suggests that an additional “stressor” is
for inducing Meniere’s attacks.42 The vasopres- required to trigger episodes of vestibular dys-
sin–aquaporin 2 system is also important for function with endolymphatic hydrops.
water homeostasis in the inner ear just as it is in
the kidney.46,47 Plasma vasopressin levels are
elevated during Meniere’s attacks48 and vaso-
pressin type 2 receptors are up-regulated in ETIOLOGY
surgical specimens of inner ears from patients
with Meniere’s syndrome.49 Whether this sys- Genetics
tem is involved in the pathogenesis of Meniere’s
syndrome is yet to be determined. As noted earlier, the incidence of Meniere’s
Movement of solutes along the scala media syndrome varies between populations in differ-
toward the endolymphatic duct and sac has ent continents, suggesting that genetic factors
been shown to be an extremely slow process.42 may be important in the pathophysiology.
While the bulk flow of water and ions across Between 5% to 15% of patients with Meniere’s
the endolymphatic sac is minimal, the sac has syndrome report a first-degree relative with
been shown to be important in the extraction Meniere’s syndrome.58,59 Morrison et al.
of debris and breakdown of macromolecules as reported 46 families from the United Kingdom
well as secretion of macrophages and immune with at least two affected family members (27
cells. Lesions that obstruct the endolymphatic families with two affected members, 12 fami-
duct or sac can cause typical symptoms of lies with three affected members, 6 families
Meniere’s syndrome.50 with four affected members, and 1 family with
five affected members).58 The mode of trans-
mission was most consistent with autosomal
dominant with reduced penetrance. Frykholm
ANIMAL MODELS et al.60 reported a large Finnish family with
Meniere’s syndrome in five generations. A
Endolymphatic hydrops can be reliably pro- genome-wide linkage scan of the family identi-
duced in animals by either decreasing endo- fied five candidate regions with a lod score
lymph absorption or increasing secretion. Since greater than one. Two additional Finnish fami-
the initial studies in guinea pig by Kimura and lies with autosomal dominant Meniere’s syn-
Schuknecht,51 endolymphatic hydrops has been drome were analyzed for linkage to these
produced in several animal species by surgical regions and a cumulative lod score of 3.5 was
obliteration of the endolymphatic duct and obtained for a single region on chromosome
sac.52,53 Injecting foreign substances such as 12p.61 Two of the three families shared a
lipopolysaccharides into the middle ear can 1.7 Mb haplotype in the region, suggesting a
also produce hydrops possibly by inducing common ancestral origin. However, so far no
endolymphatic sac dysfunction.54 Over- mutations have been found on chromosome
production models include injecting cholera 12p. Since mutations in the COCH gene can
produce a syndrome that is similar to Meniere’s typical pathological features of endolymphatic

syndrome, two groups screened the COCH hydrops.70 Bacterial endotoxins placed on the
gene for mutations in patients with Meniere’s middle ear of chinchillas permeate the round
syndrome but found no mutations.62,63 Single window and cause inflammatory cell recruit-
nucleotide polymorphism (SNP) analysis of ment, strial swelling, and sensory cell degen-
candidate genes found associations between eration.71 Overt or subclinical viral infections
Meniere’s syndrome and variants in the could damage the resorptive mechanisms of
potassium channel genes KCNE1 and KCNE364 the inner ear, leading to an eventual decom-
and host cell factor C1 gene,65 but these find- pensation in the balance between secretion
ings have not been replicated in other patient and absorption of endolymph.7,72 Infections in
populations. utero may lead to developmental hypoplasia of
the endolymphatic duct and sac predisposing
to later development of Meniere’s syndrome.
Migraine and Meniere’s Syndrome Autoimmune injury to the endolymphatic sac
may play an important role in the pathogenesis
Speculation on an association between migraine of Meniere’s syndrome.73 The endolymphatic
and Meniere’s syndrome dates back to the ini- sac is the only site that contains immuno-
tial description by Meniere.1,2 Numerous stud- competent cells in the inner ear and is capable
ies have found an increased prevalence of of mounting an active immune response if
migraine in patients with Meniere’s syndrome appropriately stimulated.
compared to controls.66,67 Whether migraine
mimics Meniere’s syndrome or causes
Meniere’s syndrome is yet to be determined.
Since there is a major genetic component to DIAGNOSIS
migraine, the small percentage of patients with
familial Meniere’s syndrome could have an Audiometric Testing
inherited migraine/Meniere’s syndrome.68 We
compared the clinical features of patients with The key to the diagnosis of Meniere’s syndrome
Meniere’s syndrome and migraine with those is to document fluctuating hearing levels in a
who had Meniere’s syndrome alone.69 Age of patient with the characteristic clinical history.
onset was earlier and bilateral symptoms and A shift of more than 10 to 15 dB at two differ-
signs were significantly more common in ent frequencies is required.74 In the early
migraine/Meniere’s syndrome compared with stages, the sensorineural hearing loss typically
Meniere’s syndrome alone. Forty percent of affects only the low frequencies (low-frequency
patients with migraine/Meniere’s syndrome had trough) (Fig. 11–2). This is followed by a
a family history of episodic vertigo compared to “peaked pattern” with a prominent low-
2% of patients with Meniere’s syndrome alone. frequency hearing loss, best hearing at 2000 Hz,
Inherited metabolic abnormalities shared by and a fall-off again in the higher frequencies.75,76
brain and inner ear could explain the combina- The fluctuation in hearing levels is usually most
tion of brain and ear symptoms in patients with prominent in the low frequencies. Speech dis-
migraine/Meniere’s syndrome. crimination is relatively preserved and recruit-
ment often occurs consistent with a cochlear
site of dysfunction. Brainstem auditory-evoked
Infection/Autoimmune response (BAER) and stapedius reflex mea-
surements are typically normal. Otoacoustic
Bacterial, viral, and syphilitic infections can emissions are often abnormal in patients with
lead to endolymphatic hydrops and typical Meniere’s syndrome, particularly as the disease
symptoms and signs of Meniere’s syndrome. evolves.77 If the hearing loss is >30 or 40 dB at
The hydrops presumably results from damage a given frequency, then the otoacoustic emis-
to the fluid resorption mechanism due to sions are absent at that frequency, consistent
inflammation and scarring of the endolym- with a cochlear origin for the hearing loss.
phatic duct and sac. Paparella and Djalitian Smaller amplitude otoacoustic emissions in the
found that 75 of 194 temporal bones from opposite “normal ear” may be an early indica-
patients with a history of otitis media showed tor of bilateral involvement.78
125 250 500 1000 2000 4000 8000 125 250 500 1000 2000 4000 8000
0 0
10 10
20 20
30 30
40 40
6/1976 8/1978
50 50
SRT - 20 dB SRT - 35 dB
60 Discrim - 100% 60 Discrim - 85%
70 70
Hearing level in dB
80 80
90 90
100 100
110 110
0 0
10 10
20 20
30 30
40 40
12/1980 4/1984
50 50
SRT - 50 dB SRT - 90 dB
60 Discrim - 58% 60 Discrim - 0%
70 70
80 80
90 90
100 100
110 110
125 250 500 1000 2000 4000 8000 125 250 500 1000 2000 4000 8000
Frequency (Hz)
Figure 11–2. Series of audiograms from a patient with Meniere’s disease. This patient’s hearing loss was initially fluctuant.
With time, the loss became permanent and progressive. SRT, speech reception threshold.
Electrocochleography (ECoG) is a clinical an abnormal ECoG is not very sensitive for

test that was developed to aid in the diagnosis Meniere’s syndrome. About a third of patients
of Meniere’s syndrome, and the test has also with definite Meniere’s syndrome have normal
added insights about the underlying pathophys- ECoGs.80 An elevated SP/AP ratio is helpful for
iological process.79 With ECoG, the cochlear identifying patients with sudden low frequency
microphonic (CM), summating potential (SP), hearing loss who will go on to develop Meniere’s
and the eighth nerve compound action poten- syndrome.29,81 Overall, ECoG is not widely
tial (AP) are measured in response to brief used as a clinical tool because it has not proved
acoustic stimulation (clicks, tone pips, and tone to be a valid tool for discriminating endolym-
bursts) (see Fig. 8–5 in Chapter 8). Summating phatic hydrops from other causes of recurrent
potential is superimposed on CM during dizziness at the time of clinical uncertainty.
steady-state pure-tone stimulation such as with Many patients with Meniere’s syndrome
a tone burst. It can be positive or negative note that their symptoms fluctuate with the
depending on the frequency and intensity of amount of fluid intake. Dehydration of
the pure tone. The AP is the synchronized the patient, most commonly achieved with
response of the auditory nerve to the transient the glycerol test, can transiently reverse the
acoustic stimulation. In patients with Meniere’s low-frequency hearing loss in many patients
syndrome, the SP/AP ratio (amplitude or area with Meniere’s syndrome (particularly those
under the curve) is often increased, largely who are experiencing fluctuating hearing
because of an increase in SP. Large SPs are loss).75 This test has not received general
rarely seen with other types of sensorineural acceptance, however, because some patients
hearing loss, so the finding is relatively specific (<10%) will develop severe headaches with or
for Meniere’s syndrome.75 On the other hand, without nausea and vomiting during the testing.
Other dehydrating agents such as urea, furo- Imaging

semide, or mannitol have fewer adverse effects,
but they are also less effective in elevating Radiologic studies of the temporal bones in
plasma osmolality. A minimum increase in patients with Meniere’s syndrome may show
osmolality of 10 millios-moles/kg is necessary narrowing of the endolymphatic duct or
for a valid test. The test is typically conducted decreased pneumatization of the temporal
with an oral dosage of glycerol of 1.5 ml/kg bone.87 However, these features are also seen
body weight in the fasting state together with in normal subjects and therefore are of limited
an equal volume of water and a flavoring agent. value in the diagnosis of Meniere’s syndrome.
The maximum dehydration occurs about On computed tomography (CT) scan, the
90 min after the glycerol is ingested, which is endolymphatic duct and sac may be more dif-
the best time to check for a change in hearing ficult to visualize in patients with Meniere’s
on audiometry. One must monitor blood osmo- syndrome than in controls, but this is not a reli-
lality since, even with this standard dosage, able enough finding to be of diagnostic value.
between 10% and 15% of patients will not Contrast enhancement of the endolymphatic
reach the critical change in osmolality. A posi- duct and sac on magnetic resonance imaging
tive glycerol test requires a 15 dB pure-tone (MRI) has been reported in a few patients with
change and/or a 15% discrimination gain. A Meniere’s syndrome, but again, this is not a
small percentage of patients actually have a consistent finding.88 MRI (3T) of endolymph
worsening of hearing after glycerol, possibly and perilymph after intratympanic administra-
because of glycerol entering the scala media tion of gadolinium is a promising although
and attracting fluid and thereby increasing the invasive technique for identifying endolym-
degree of hydrops. phatic hydrops.88–90
Vestibular Testing
MANAGEMENT
Electronystagmography may reveal a periph-
eral spontaneous nystagmus and either a ves- Medical Management
tibular paresis or directional preponderance on
caloric testing. The degree of caloric paresis SYMPTOMATIC TREATMENT OF ACUTE
increases with the duration of disease, eventu- SPELLS
ally stabilizing at approximately 50% of the
normal functional level. In one study, after Because the cause of Meniere’s syndrome
7 years of follow-up, 65% of patients had a is usually unknown, treatment is empiric.
reduced response, rising to 75% after 20 years.82 Medical management consists of symptomatic
A complete loss of caloric responses is unusual treatment of the acute spells (Table 11–1,
with Meniere’s syndrome. Both VEMP and also see Table 19–2 in Chapter 19) and
head-thrust tests can be abnormal with long-term prophylaxis with salt restriction
Meniere’s syndrome, but abnormalities on and diuretics. Phenergan at 25 to 50 mg, orally
these tests are less frequent than caloric abnor- or via suppository, is usually effective for
malities.83,84 It is more typical that the head- relieving the acute vertigo, nausea, and vomit-
thrust test is normal with Meniere’s syndrome ing. It should be taken as soon as possible, pref-
unless a destructive procedural has been per- erably during the prodrome if there are reli-
formed.85 During an acute attack of Meniere’s able warning symptoms. Intravenous diazepam
syndrome, the nystagmus may be directed or droperidol may be required for severe
toward the involved ear, but this “wrong- attacks with repeated vomiting. Meclizine is
direction nystagmus” may be a reversal phe- often adequate for milder attacks. Antiemetics
nomena due to central compensation, since if such as prochlorperazine (Compazine) are
the episodes are monitored from the begin- sometimes useful if nausea and vomiting are
ning, they typically begin with nystagmus in the severe. Hearing can be improved with aids
opposite direction (i.e., fast component toward that can be manually adjusted as hearing
the good ear).86 fluctuates.91
Table 11–1 Dosage and Effects of Commonly Used Antivertiginous Medications

Class Drug Dosage Sedation Anti- Dryness Extra-
emetic of Mucous pyramidal
Actions Membranes Symptoms
Anticholinergic Scopolamine0.6 mg orally + + +++ −
q4–6 h or
0.5 mg
transdermally
q3d
Monoamingergic Amphetamine 5 or 10 mg − + + +
orally q4–6h
Ephedrine 25 mg orally − + + –
q4–6h
Antihistamine Meclizine 25 mg orally + + + −
(Antivert) q4–6h
Dimenhydrinate 25 mg orally + + + −
(Dramamine) q4–6h
Promethazine 25–50 mg orally ++ ++ + −
(Phenergan) or IM q4–6h
or 25–100 mg
suppository
q8h
Phenothiazine Prochlorperazine 5 or 10 mg orally + +++ + +++
(Compazine) or IM q6h or
25 mg
suppository
q12h
Benzodiazepine Diazepam 5 or 10 mg orally, +++ + − −
(Valium) IM, or IV
q4–6h
IM, intramuscularly; IV, intravenously.
PROPHYLAXIS
patients. We have seen patients who had had
No high-level evidence has demonstrated an severe disabling episodes on a weekly basis
average beneficial effect of medical interven- have prolonged remissions (years) on a low-salt
tions for Meniere’s disease. The main problem diet. Other patients show little or no improve-
is that there is a lack of high-quality randomized ment, possibly reflecting the multifactorial
trials rather than negative results from adequate pathogenesis of Meniere’s syndrome, though
trials. Importantly, there are several options for differences in adherence to the diet or placebo
medical management that are very reasonable effects are also possible explanations. Since
to try even though high-level evidence is lack- there are no common risks associated with a
ing, because these treatments have a very low low-salt diet (other than inconvenience to the
risk of harm to patients and also very low cost. patient), we recommend salt restriction as the
One of the first options to consider is an first step in any patient felt to have Meniere’s
aggressive low-salt diet. The mechanism by syndrome. An adequate trial of a low-salt diet is
which a low-salt diet may decrease the fre- restricting the salt to about 1 to 2 g/day for a
quency and severity of attacks with Meniere’s minimum of 2 to 3 months, which is not an easy
syndrome is unclear, but there is some empiric task. If a good response is obtained, then the
evidence for its efficacy.92,93 Though no average level of salt intake can be gradually increased
beneficial effect has been demonstrated by while symptoms and signs are carefully moni-
randomized controlled trials,94 a low-salt diet tored. Fluid and food intake should be regu-
seems to have a dramatic effect in some larly distributed throughout the day, and binges
(particularly foods with high sugar and/or salt fibrous tissue. Revision operations and tempo-
content) should be avoided. Occasionally, ral bone studies in patients who have had shunts
patients will notice that certain foods (e.g., implanted have shown fibrous encapsulation of
alcohol, coffee, chocolate) may precipitate shunt devices. Not surprisingly, there are con-
attacks. Diuretics (e.g., hydrochlorothiazide, flicting reports regarding the clinical efficacy of
50 mg two times a day) may provide additional these surgical shunt procedures.101,102
benefit in some patients, although there also
have been no adequately controlled studies to PRESSURE PULSE TREATMENT
demonstrate an average beneficial effect.95
When attacks reliably occur at the time of the Recently a minimally invasive device was intro-
menstrual period, a diuretic can be started 4–5 duced for the treatment of Meniere’s disease.
days before menses and discontinued after The device, called the Meniett device, uses a
menses. Acetazolamide is a carbonic anhydrase pulse generator to provide positive pressure
inhibitor that has long been used to lower ocu- into the ear canal. A tympanostomy tube is
lar pressure with glaucoma. Some patients on required so that the pressure is transferred into
acetazolamide report an improvement in symp- the middle ear. The idea for this sort of treat-
toms. How it potentially works in Meniere’s ment was based on observation that changes in
syndrome is unknown, although it may decrease ambient pressure improve Meniere’s disease
endolymph production. Acetazolamide is also symptoms103; however, the mechanism by
known to decrease cerebrospinal fluid (CSF) which the external pressure works to reduce
secretion and was shown to decrease the vertigo attacks is not clear. One theory is that
osmotic pressure of the inner ear in experi- the intermittent pressure could decrease endo-
mental endolymphatic hydrops in guinea pigs.96 lymphatic fluid volume by forcing outflow into
An average trial dose of acetazolamide for the endolymphatic sac. A randomized con-
treating Meniere’s syndrome is 250 mg twice a trolled trial of the Meniett device found a ben-
day.97 Prophylactic use of betahistine has also eficial effect in patients who had at least two
been reported to decrease the frequency of vertigo attacks per month for the 2 months
Meniere’s attacks in an open, nonmasked prior to enrollment.104 The results indicate that
trial,98 but as with other medical treatment the control group had vertigo attacks on 13% of
options adequate trial data are lacking.99 the days over the 4 months, whereas the treat-
ment group had vertigo attacks on 7% of the
days (p = 0.048). However, all of the benefit of
Surgical Management the device was seen in the first 3 months
because in the fourth month the frequency of
SHUNTS vertigo attacks in the control group dropped
down to that of the treatment group. The
Two different types of surgery have been used authors of a longer term follow-up study of the
for treating Meniere’s syndrome: endolym- device argue that there is a beneficial effect out
phatic shunts and destructive procedures. to 2 years, but this study was uncontrolled, had
Although shunts are logical, based on the pre- a high dropout rate, and also problems with
sumed pathophysiology of Meniere’s syndrome, compliance with the device.105 As a result, pres-
several factors limit the probability of achieving sure pulse treatment may have an important
a functional shunt with this disorder.100 The impact in reducing the frequency of vertigo
most popular shunt procedure at the present attacks, but the effect appears to be moderate
time is used to drain the endolymphatic sac to and also limited to only several months. This is
the mastoid cavity. A major conceptual prob- a common theme in Meniere’s disease treat-
lem with this procedure is that pathologic stud- ment since the natural history of the disorder is
ies of temporal bones in patients with Meniere’s that vertigo episodes decrease in frequency
syndrome show evidence of blockage of the over time.
endolymphatic pathways proximal to the endo-
lymphatic sac. Furthermore, Schuknecht91
DESTRUCTIVE PROCEDURES
pointed out that any drain device that is
implanted in the endolymphatic sac will almost The rationale for destroying the labyrinth in
certainly become rapidly encapsulated in treatment of Meniere’s syndrome is that the
nervous system is better able to compensate with some deficiencies in the design or report-
for complete loss of vestibular function than ing of the trial.
for partial loss that is fluctuating in degree. The two main types of destructive surgery
Ablative procedures can be a particularly good are labyrinthectomy and vestibular nerve sec-
option in patients with unilateral involvement tion. Labyrinthectomy is useful only when
who have no functional hearing on the dam- there is no functional hearing on the damaged
aged side. This is because a unilateral severe side since any remaining hearing cannot be
hearing loss is the most valid indicator of the spared with this procedure. The purpose of a
affected side and also because one of the most labyrinthectomy is to remove the neural epi-
concerning risks of the procedure (i.e., hearing thelium of the vestibular end organs.110
loss) is no longer a factor. Obviously, ablative Sectioning the vestibular nerve, or vestibular
procedures should not be considered if the neurectomy, has the advantage of preserving
abnormal side is not well defined or if an impor- hearing in patients with salvageable residual
tant level of uncertainty still exists about the cochlear function, but the risks of complication
cause of the vertigo attacks. Severe vertigo is are greater than with labyrinthectomy.111 Again,
expected during the immediate posttreatment adequate randomized clinical trials of either of
period, but most patients who follow a struc- these procedures are lacking. Though dramatic
tured vestibular exercise program can return to and immediate reductions in the frequency of
normal activity within 1 to 3 months (see vertigo attacks have been demonstrated in case
Chapter 20).106 Ablative procedures generally series reports,112 the patients selected for these
should be avoided in elderly patients because procedures are generally at the severe stages of
the elderly have great difficulty adjusting to the the disorder and thus may not be far off from
vestibular imbalance. the late stage of the disorder when the fre-
A chemical labyrinthectomy can be achieved quency of the vertigo attacks drops substantially
by introducing an ototoxic drug into the middle based on the natural history of the disorder. As
ear, where it will be absorbed into the inner ear a result, it may be that destructive surgical pro-
via the round window or the angular ligament cedures improve the time to remission of ver-
of the round window.107 Initially, streptomycin tigo attacks but not the long-term outcome.
was used, but more recently gentamicin has
been the drug of choice. The advantages of this
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22. Friberg U, Stahle J, Svedberg A. The natural course of nosine triphosphatase activity in the absence of adre-
Meniere’s disease. Acta Otolaryngol Suppl (Stockh). nocorticosteroids. Arch Otolaryngol Head Neck Surg.
1984;406:72. 1989;115:817.
23. Kitahara M, Kitano H, Suzuku M. Meniere’s disease 44. Juhn SK, Ikeda K, Morizono T, Murphy M.
with bilateral fluctuant hearing loss. In: Kitahara M, Pathophysiology of inner ear fluid imbalance. Acta
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24. Perez R, Chen JM, Nedzelski JM. The status of the dium, high-potassium dietary intake on cochlear lateral
contralateral ear in established unilateral Menière’s wall Na+, K + -ATPase. Eur Arch Otorhinolaryngol.
disease. Laryngoscope. 2004;114(8):1373. 1994;251:6.
25. Takumida M, Kakigi A, Takeda T, Anniko M. 46. Ishiyama G, López IA, Ishiyama A. Aquaporins and
Ménière’s disease: a long-term follow-up study of Meniere’s disease. Curr Opin Otolaryngol Head Neck
bilateral hearing levels. Acta Otolaryngol. 2006;126(9): Surg. 2006;14(5):332.
921. 47. Takeda T, Taguchi D. Aquaporins as potential drug
26. Eggermont JJ, Schmidt PH. Meniere’s disease: a long- targets for Meniere’s disease and its related diseases.
term follow-up study of hearing loss. Ann Otol Rhinol Handb Exp Pharmacol. 2009;(190):171.
Laryngol. 1985;94:1. 48. Aoki M, Asai M, Nishihori T, Mizuta K, Ito Y, Ando
27. Perez-Garrigues H, Lopez-Escamez JA, Perez P, K. The relevance of an elevation in the plasma vaso-
et al. Time course of episodes of definitive vertigo in pressin levels to the pathogenesis of Meniere’s attack.
Meniere’s disease. Arch Otolaryngol Head Neck Surg. J Neuroendocrinol. 2007;19(11):901.
2008;134(11):1149. 49. Kitahara T, Doi K, Maekawa C, et al. Meniere’s attacks
28. Havia M, Kentala E. Progression of symptoms of diz- occur in the inner ear with excessive vasopressin type-2
ziness in Ménière’s disease. Arch Otolaryngol Head receptors. J Neuroendocrinol. 2008;20(12):1295.
Neck Surg. 2004;130(4):431. 50. Cmejrek RC, Megerian CA. Obstructing lesions of the
29. Junicho M, Aso S, Fujisaka M, Watanabe Y. Prognosis endolymphatic sac and duct mimicking Ménière’s dis-
of low-tone sudden deafness—does it inevitably ease. Ear Nose Throat J. 2004;83(11):753.
51. Kimura RS, Schuknecht H. Membranous hydrops in 69. Cha YH, Brodsky J, Ishiyama G, Sabatti C, Baloh RW.
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1965;27:343. 70. Paparella MM, Djalilian HR. Etiology, pathophysiol-
52. Kimura RS. Animal models of endolymphatic hydrops. ogy of symptoms, and pathogenesis of Meniere’s dis-
Am J Otolaryngol. 1982;3:447. ease. Otolaryngol Clin N Am. 2002;35:529.
53. Takumida M, Akagi N, Anniko M. A new animal 71. Lim DJ, Kawauchi H, DeMaria TF. Role of middle
model for Ménière’s disease. Acta Otolaryngol. ear endotoxin in inner ear inflammatory response and
2008;128(3):263. hydrops: long-term study. Ann Otol Rhinol Laryngol.
54. Takumida M, Anniko M, Popa R. Possible involvement 1990;99:33.
of free radicals in lipopolysaccharide-induced labyrin- 72. Welling DB, Daniels RL. Viral etiology in Meniere’s
thitis in the guinea pig: a morphological and functional disease. In: Harris JP, ed. Meniere’s Disease.
investigation. ORL J Otorhinolaryngol Relat Spec. The Hague, Netherlands: Kugler Publications; 1999.
1998;60:246. 73. Tomiyama S. Development of endolymphatic hydrops
55. Feldman AM, Brusilow SW. Effects of cholera following immune response in the endolymphatic
toxin on cochlear endolymph production: model for sac of the guinea pig. Acta Otolaryngol (Stockh).
endolymphatic hydrops. Proc Natl Acad Sci USA. 2004;124:1145.
1976;73:1761. 74. Academy of Otolaryngology Head and Neck Surgery.
56. Dunnebier EA, Segenhout JM, Wit HP, Albers Meniere’s disease: criteria for diagnosis and evalua-
FWJ. Two-phase endolymphatic hydrops: a new tion of therapy for reporting. AAO-HNS Bulletin. July
dynamic guinea pig model. Acta Otolaryngol (Stockh). 1985.
1997;117:13. 75. Morrison AW. Diagnostic and laboratory evaluation of
57. Takeda T, Takeda S, Kitano H, Okada T, Kakigi A. Meniere’s disease. In: Harris JP, ed. Meniere’s Disease.
Endolymphatic hydrops induced by chronic adminis- The Hague, Netherlands: Kugler Publications; 1999.
tration of vasopressin. Hear Res. 2000;140:1. 76. Savastano M, Guerrieri V, Marioni G. Evolution of
58. Morrison AW, Bailey ME, Morrison GA. Familial audiometric pattern in Meniere’s disease: long-term
Ménière’s disease: clinical and genetic aspects. survey of 380 cases evaluated according to the 1995
J Laryngol Otol. 2009;123(1):29. guidelines of the American Academy of Otolaryngology-
59. Klockars T, Kentala E. Inheritance of Meniere’s dis- Head and Neck Surgery. J Otolaryngol. 2006;35(1):
ease in the Finnish population. Arch Otolaryngol 26.
Head Neck Surg. 2007;133(1):73. 77. Lonsbury-Martin BL, Martin GK. Clinical utility of
60. Frykholm C, Larsen HC, Dahl N, Klar J, Rask- distortion product otoacoustic emissions. Ear Hear.
Andersen H, Friberg U. Familial Ménière’s disease in 1990;11:90.
five generations. Otol Neurotol. 2006;27(5):681. 78. Harris FP, Probst R. Transiently evoked otoacoustic
61. Klar J, Frykholm C, Friberg U, Dahl N. A Meniere’s emissions in patients with Meniere’s disease. Acta
disease gene linked to chromosome 12p12.3. Am J Otolaryngol (Stockh). 1992;112:36.
Med Genet B Neuropsychiatr Genet. 2006;141B(5): 79. Ferraro JA, Ruth RA. Clinical electrocochleography.
463. Hear J. 1985;38:51.
62. Usami S, Takahashi K, Yuge I, et al. Mutations in 80. Kim HH, Kumar A, Battista RA, Wiet RJ.
the COCH gene are a frequent cause of autosomal Electrocochleography in patients with Meniere’s dis-
dominant progressive cochleo-vestibular dysfunc- ease. Am J Otolaryngol. 2005;26(2):128.
tion, but not of Meniere’s disease. Eur J Hum Genet. 81. Fushiki H, Junicho M, Aso S, Watanabe Y. Recurrence
2003;11(10):744. rate of idiopathic sudden low-tone sensorineural hear-
63. Sanchez E, López-Escámez JA, López-Nevot MA, ing loss without vertigo: a long-term follow-up study.
López-Nevot A, Cortes R, Martin J. Absence of Otol Neurotol. 2009;30(3):295.
COCH mutations in patients with Meniere disease. 82. Hulshof JH, Baarsma EA. Follow-up vestibular
Eur J Hum Genet. 2004;12(1):75. examinations in Meniere’s disease. Acta Otolaryngol
64. Doi K, Sato T, Kuramasu T, et al. Ménière’s disease (Stockh). 1981;92:397.
is associated with single nucleotide polymorphisms 83. Osei-Lah V, Ceranic B, Luxon LM. Clinical value
in the human potassium channel genes, KCNE1 of tone burst vestibular evoked myogenic potentials
and KCNE3. ORL J Otorhinolaryngol Relat Spec. at threshold in acute and stable Ménière’s disease.
2005;67(5):289. J Laryngol Otol. 2008;122(5):452.
65. Vrabec JT, Liu L, Li B, Leal SM. Sequence variants in 84. Park HJ, Migliaccio AA, Della Santina CC, Minor LB,
host cell factor C1 are associated with Ménière’s dis- Carey JP. Search-coil head-thrust and caloric tests
ease. Otol Neurotol. 2008;29(4):561. in Ménière’s disease. Acta Otolaryngol. 2005;125(8):
66. Baloh RW, Andrews JC. Migraine and Meniere’s dis- 852.
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Netherlands: Kugler Publications; 1998. vertigo in Meniere’s disease: vestibular signs that spec-
67. Ibekwe TS, Fasunla JA, Ibekwe PU, Obasikene GC, ify completion of therapy. Am J Otol. 1999;20:209.
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observed concomitant occurrences. J Natl Med Assoc. 1727.
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68. Cha YH, Kane MJ, Baloh RW. Familial clustering of computerized tomography of the vestibular aque-
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Neurotol. 2008;29(1):93. 1984;93:547.
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1999. 102. Ress BD, Harris JP. Endolymphatic sac surgery.
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91. McNeill C, McMahon CM, Newall P, Kalantzis SA. Meniett clinical trial: long-term follow-up. Arch
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2008;19(5):430. ing after sudden loss of vestibular functions. ORL J
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1981;90:142. by intratympanic gentamicin in patients with unilat-
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Evidence. 2006;15:797. blind, placebo-controlled, randomized clinical trial.
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disease or syndrome. Cochrane Database Sys Rev. 109. Postema RJ, Kingma CM, Wit HP, Albers FW, Van
2006;3:CD003599. Der Laan BF. Intratympanic gentamicin therapy
96. Shinkawa H, Kimura RS. Effect of diuretics on for control of vertigo in unilateral Menire’s disease:
endolymphatic hydrops. Acta Otolaryngol (Stockh). a prospective, double-blind, randomized, placebo-
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97. Brookes GB, Booth JB. Oral acetazolamide in 876.
Meniere’s disease. J Laryngol Otol. 1984;98:1087. 110. Glasscock ME, Davis ME, Hughes GB, Jackson
98. Strupp M, Hupert D, Frenzel C, et al. Long-term pro- GG. Labyrinthectomy versus middle fossa vestibular
phylactic treatment of attacks of vertigo in Menière’s nerve section in Meniere’s disease. Ann Otol Rhinol
disease—comparison of a high with a low dosage Laryngol. 1980;89:318.
of betahistine in an open trial. Acta Otolaryngol. 111. Silverstein H, Arruda J, Rosenberg S. Vestibular
2008;128(5):520. neurectomy. In: Harris JP, ed. Meniere’s Disease.
99. James AL, Burton MJ. Betahistone for Meniere’s The Hague, Netherlands: Kugler Publications; 1999.
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controlled? Ann Otol Rhinol Laryngol. 1986;95:36. Neck Surg. 1991;104:88.
Chapter 12
Migraine
BACKGROUND Vasomotor Abnormalities

CLINICAL FEATURES DIAGNOSIS
Migraine without Aura Migraine without Aura
Migraine with Aura Migraine with Aura
Migrainous Vertigo Migraine Aura without Headache
Basilar Migraine Basilar Migraine
Migraine and Meniere’s Syndrome Migrainous Vertigo
Migraine Equivalents MANAGEMENT
PATHOPHYSIOLOGY Symptomatic and Abortive Treatment
Genetics Prophylactic Treatment
Spreading Wave of Depression
BACKGROUND of Meniere’s syndrome, benign positional ver-

tigo, and even vestibular neuritis.
Migraine is a complex multigenetic disorder The association of migraine and dizziness
that renders one susceptible to vascular and extends back to the nineteenth century when
chemical changes in the brain that can lead to Livening noted their connection in his classic
many different symptoms.1 The hallmark fea- book On Megrim: Sick Headaches and Some
ture of the disorder is severe attacks of head- Allied Health Disorders.2 However, only in
aches. However, migraine is also characterized recent years has vertigo been recognized as a
by many other features, including dizziness, common migraine symptom. So-called migrain-
visual phenomenon, hypersensitivities to sen- ous vertigo or migraine-associated vertigo (ver-
sory stimuli, nausea, paresthesias, and even tigo caused by migraine) affects about 1% of the
frank focal weakness in some cases. general population and about 10% of patients
Dizziness symptoms are among the most seen in dizziness clinics and in migraine clinics.3
common symptoms reported by migraineurs. The vertigo attacks can occur during the head-
In some cases, the dizziness symptom is best ache, but most often the attacks occur during
characterized as a sensitivity to motion, a symp- headache-free intervals.4 Although the clinical
tom that most patients with migraine are sus- association between migraine and dizziness is
ceptible to throughout their lives. Other times, well documented, it is difficult to prove a causal
patients use “dizziness” to label a vague and relationship between migraine and dizziness or,
nonspecific symptom such as disorientation or for that matter, between migraine and any of
difficulty focusing on a task. However, the diz- the other transient symptoms that accompany
ziness of migraine can also be true and severe it. For example, scintillating scotoma is a well-
room-spinning vertigo. Migraine, in fact, is the known accompaniment of migraine and is uni-
great mimicker of all causes of vertigo because versally accepted as a migrainous phenomenon,
symptoms of it can closely resemble the attacks yet its pathophysiologic link with headache is
287
still unknown after hundreds of years of clinical The headache begins as the aura diminishes,
association. The nonspecific, highly varied usually reaching its peak in about an hour and
nature of dizziness makes the relationship then gradually subsiding over the next 4 to
between migraine and dizziness even more dif- 8 hours. Nausea and vomiting typically accom-
ficult to characterize. Recent advances in our pany the onset of the head pain.
understanding of the genetics and pathophysiol- The migraine aura consists of transient neu-
ogy of migraine provide new hope for improved rologic dysfunction, often with visual distur-
understanding of the link between patients with bances, but also commonly includes prominent
periodic headaches and dizziness.5 vertigo or somatosensory symptoms. Both posi-
tive and negative visual phenomena occur. The
latter include complete blindness, hemianopsia
or quadrantanopsia, tunnel vision, altitudinal
CLINICAL FEATURES defects, monocular blindness, or one or more
scotomata. Positive phenomena are more com-
Migraine without Aura mon and may consist of stars, sparkling lights,
unformed flashes of light (photopsia), geomet-
Migraine without aura can probably best be ric patterns, or a jagged, sparkling zig-zag
described as a “sick headache.” Vague pro- (teichopsia or fortification spectra). Although
dromal symptoms precede it, but aura phe- usually black and white, the visual phenomena
nomena are absent. The headache, unilateral can be in color. The positive and negative visual
or bilateral, builds slowly in intensity and may phenomena are combined in the so-called scin-
go on for several days. Nausea, vomiting, diar- tillating scotoma. Patients describe a hole in
rhea, chills, and prostration can all accompany their vision with a sparkling border. The sco-
the headache. Nonspecific dizziness is a com- toma will begin in one hemifield but gradually
mon complaint, and patients frequently report enlarge and move across to involve the other
visual blurring and a sense of unsteadiness dur- hemifield, with the leading edge being a zig-
ing the entire headache phase. Vertigo can zag of sparkling lights.9
occur before, during, or entirely separate from Somatosensory symptoms, particularly par-
the episodes of headache.4,6 esthesias, are another common aura manifesta-
There is still debate as to whether migraine tion. Numbness, tingling, or both may affect
without aura and migraine with aura are dis- the hands, lower face, or half of the body. A
tinct syndromes, different manifestations of the characteristic feature of migrainous paresthe-
same disorder, or part of a continuum. Patients sias is a migration of the numbness as it gradu-
can have both types of headaches (with and ally spreads over the face or extremity, some-
without aura), and not infrequently, both types times migrating from face to extremity on the
of migraine run in the same family (see later same side or sometimes crossing over to the
discussion). The headache phases of both types face and extremity on the opposite side. In a
of migraine are almost identical, and the same small percentage of patients, the paresthesias
treatments are usually effective in controlling will simultaneously appear in multiple sites or
both types of migraine. Conversely, certain epi- be localized to a small area such as a single digit,
demiological characteristics, overall familial lip, or cheek. When focal neurologic symptoms
aggregation, and varying pathophysiologic find- such as hemianopsia or unilateral paresthesias
ings suggest the possibility that these two types occur in an aura, they usually occur on the side
of migraine represent separate entities.7,8 opposite that of the headache. Only about 12%
of patients with migraine regularly experience
aura with their headache, but as many as two-
Migraine with Aura thirds have occasional attacks with aura.13
The aura with migraine typically precedes the

onset of a severe, throbbing, unilateral head- Migrainous Vertigo
ache. The aura symptoms slowly progress
over several minutes, last 15 to 60 minutes, and Overall, episodic vertigo occurs in about 25%
then gradually abate. In a small percentage of unselected migraine patients.11 The vertigo
of patients, however, onset is more abrupt. attacks can occur during the headache, but
12 Migraine 289
most often the attacks occur during the head- Table 12–1 Most Common Symptoms
ache-free interval. Only about a quarter of in 49 Patients with Basilar Migraine
patients reliably experience headaches with
their vertigo.10 Migrainous vertigo can be spon- Symptom Cases (%)
taneous or positional and attacks typically last
from minutes to days.10,12 If examined during Headache (usually occipital) 96
an attack patients may show spontaneous or Nausea 83
positional nystagmus (either in isolation or in Vomiting 71
combination) and the nystagmus can have Vertigo 63
either central or peripheral features.13 Gait ataxia 63
Complicating matters further, benign posi- Paresthesias (usually bilateral) 61
tional vertigo is more common in patients with Dysarthria 57
Weakness (usually bilateral) 55
migraine than in the general population (see
Tinnitus 26
Chapter 10).14 Migrainous positional vertigo
Impaired hearing 20
can be differentiated from benign positional
Double vision 16
vertigo by (1) short-duration symptomatic epi-
sodes, (2) migrainous symptoms during epi-
sodes, and (3) atypical positional nystagmus.15 the posterior fossa (Table 12–1).23,24 The aura
Auditory symptoms are generally considered consists of posterior fossa symptoms such as
to be less common than the vestibular symp- vertigo, ataxia, dysarthria, and tinnitus along
toms of migraine. Phonophobia is probably the with visual phenomena consistent with ischemia
most common auditory symptom associated in the distribution of the posterior cerebral
with migraine, occurring at some time in more arteries. Motor and sensory symptoms, such as
than two-thirds of patients, usually in associa- circumoral or extremity paresthesias, weakness,
tion with headache.16 Most patients with and drop attacks, are occasionally seen as well.
migrainous vertigo have normal audiometric When vertigo occurs it usually has an abrupt
findings.17 Several investigators have identified onset and lasts 5 to 60 minutes. The headache
fluctuating low-frequency hearing levels in following the aura is usually unilateral occipital
patients with migraine, which are typical or frontal, but it can occur anywhere, especially
of those seen in patients with Meniere’s in children.
syndrome.16,18,19 These episodes are most com- Basilar migraine affects about 10% of patients
monly seen in young women around the time suffering from migraine with aura.24 One must
of their menstrual period and are usually com- be alert for the possibility of basilar migraine in
pletely reversible. In the case of Meniere’s syn- any patient presenting with transient vertigo
drome, a progressive loss of hearing is required. and other posterior fossa symptoms.25 In some
Migraine has also been identified as the cause individuals, the headache is not severe and is
of sudden hearing loss that persists.20,21 Such adequately managed by aspirin, sleep, or mild
patients report the abrupt onset of a profound analgesics and sedatives. Some of these patients
hearing loss and may show some gradual are unaware that migraine is the cause of their
improvement, but they are often left with a headaches and are much more concerned
severe unilateral sensorineural hearing loss. about the aura. If vertigo is prominent, the
Some patients with sudden hearing loss report patient may not mention the headache, think-
a prior history of fluctuating hearing in the ing it is unimportant. Similarly, other transient
same ear and many develop persistent tinnitus. manifestations may be given less importance
Hearing loss and tinnitus can also be symptoms than that given the vertigo. Such patients may
of migrainous infarction.22 be misdiagnosed as having a peripheral labyrin-
thine disease if the physician is not alert to the
possibility of basilar migraine.
Basilar Migraine
Basilar migraine is a subtype of migraine with Migraine and Meniere’s Syndrome
aura characterized by recurrent headaches, usu-
ally localized to the occipital region, preceded Speculation on a relationship between migraine
by multiple neurological symptoms localized to and Meniere’s syndrome dates back to the initial
description of the syndrome by Prosper Meniere to the endolymphatic duct and/or sac, resulting
in 1861.26 He noted that both conditions com- in impaired fluid circulation and the eventual
monly manifested episodes of vertigo, fluctuat- development of hydrops. One would then
ing hearing levels, and recurrent vomiting. expect a gradual progression of the disease typ-
Although many subsequent authors have also ical of Meniere’s syndrome of any cause.
speculated on the relation between migraine
and Meniere’s disease, there is still no generally
accepted mechanism to explain the connec- Migraine Equivalents
tion.27–29 Diagnostic criteria have been estab-
lished for both migraine and Meniere’s disease, BENIGN PAROXYSMAL VERTIGO OF
but some of the criteria overlap. For example, CHILDHOOD
the key diagnostic feature for Meniere’s
syndrome is a fluctuating, low-frequency Basser36 described an episodic disorder in chil-
sensorineural hearing loss that many clinicians dren under the age of 4 years that he called
consider pathognomonic for Meniere’s syn- benign paroxysmal vertigo. A completely nor-
drome. As noted earlier, however, fluctuating mal child suddenly becomes frightened, cries
low-frequency hearing loss can occur in patients out, clings to the parent, or staggers as though
with migraine. Although headache is the most drunk, and exhibits pallor, diaphoresis, and
common symptom of migraine, visual aura or often vomiting. Symptoms are accentuated by
episodes of vertigo can occur without headache. head movements, and sometimes nystagmus
Therefore, even when using strict diagnostic cri- and torticollis are observed. Some children
teria, it may not always be possible to separate report a true spinning sensation, but most have
the two conditions on clinical grounds alone. difficulty describing what they are experienc-
Although most authors agree that there is an ing. The spells typically last for several minutes.
increased prevalence of migraine in patients Afterward, the child is immediately normal
with Meniere’s syndrome compared with the and can resume playing as though nothing has
general population, the overall percentage of happened.
Meniere’s patients with migraine varies from Vertigo spells typically begin before the age
study to study.30 A recent study that used cur- of 4 years and occur up to several times a
rent criteria for the diagnosis of migraine and month. After several years, they decrease in
Meniere’s syndrome found a lifetime preva- number and often gradually disappear. Many
lence of migraine (with or without aura) of 56% children have no further spells after the age of
in patients with Meniere’s syndrome compared 7 or 8. The cause of benign paroxysmal vertigo
to 25% in controls.31 Furthermore, 45% of of childhood is unknown, although most have a
patients with Meniere’s syndrome experienced positive family history of vertigo or migraine.37
at least one migrainous symptom (headache, Follow-up studies of patients with typical
photophobia, aura) with their Meniere’s benign paroxysmal vertigo during childhood
attacks. Genetic factors are likely important for show that nearly all patients eventually develop
both disorders since migraine and Meniere’s other features typical of migraine.38,39
syndrome tend to cluster in families.32 In three
sets of twins in these families one twin had
VESTIBULAR MENIERE’S SYNDROME
migraine and Meniere’s syndrome while the
other twin had migraine and migrainous ver- In their initial recommendations on criteria for
tigo (without auditory symptoms). the diagnosis of Meniere’s disease, the
Numerous studies have documented that American Academy of Ophthalmology and
migraine can lead to permanent auditory Otolaryngology Committee on Hearing and
and vestibular deficits.4,33–35 Since Meniere’s Equilibrium defined vestibular Meniere’s syn-
syndrome can develop in an ear previously drome as recurrent attacks of vertigo without
damaged by infection or trauma, another associated auditory symptoms. It was assumed
explanation for the association between that most of these patients would progress to
migraine and Meniere’s syndrome is the devel- manifest all of the symptoms of classical
opment of endolymphatic hydrops in an ear Meniere’s syndrome. However, because there
previously damaged by migraine. For example, are so many causes for recurrent episodic ver-
the vasospasm could lead to ischemic damage tigo other than Meniere’s syndrome, more
12 Migraine 291
recently the American Academy of Otolaryn- common with migraine, including precipitation
gology Head and Neck Surgery Committee on by alcohol, lack of sleep, emotional stress, and
Hearing and Equilibrium recommended dis- a female preponderance.
carding the term vestibular Meniere’s disease. We studied the families of 24 adults who
Rassekh and Harker28 followed up 38 patients presented to our clinic with benign recurrent
with a diagnosis of vestibular Meniere’s syn- vertigo and who reported a family history of
drome using a standard questionnaire. similar attacks of vertigo.42 All probands under-
Seventeen of the 38 no longer fulfilled the cri- went diagnostic evaluation to exclude identifi-
teria for the diagnosis of vestibular Meniere’s able causes of recurrent vertigo and they
syndrome at follow-up. Of these, eight went on completed a standardized medical question-
to develop unilateral Meniere’s syndrome and naire pertaining to episodic vertigo and the fea-
seven became asymptomatic. Of the 21 patients tures of migraine. This questionnaire was also
who continued to meet the criteria for vestibu- sent to all relatives of the probands who agreed
lar Meniere’s syndrome, 17 (81%) had migraine to participate. Of 220 relatives who returned
headaches. Overall, this study suggests that questionnaires, 37% reported BRV and 50%
only a small percentage of patients who present met the diagnostic criteria for migraine (Table
with recurrent episodes of vertigo typical of 12–2). By contrast, only one of 43 (2%) unre-
vestibular Meniere’s syndrome go on to develop lated spouses reported BRV and 10 of 43 (23%)
the classical symptom triad of Meniere’s syn- met the diagnostic criteria for migraine. More
drome, whereas the majority are associated than two-thirds of relatives with BRV met
with migraine. the diagnostic criteria for migraine and the
majority reported that they had a typical
migraine headache with at least some of their
BENIGN RECURRENT VERTIGO OF
episodes of vertigo. Both benign recurrent
ADULTHOOD
vertigo and migraine showed a female prepon-
Slater40 and Moretti et al.41 described patients derance (more than 2 to 1). Familial benign
who, between the ages of 7 and 55 years, began recurrent vertigo appears to be a migraine syn-
to experience repeated episodes of vertigo, drome, probably inherited in an autosomal
nausea, vomiting, and diaphoresis. The attacks dominant fashion with decreased penetrance
often occurred on awakening in the morning, in men.
being particularly common around menses in
women. Duration varied from a few minutes to OTHER MIGRAINOUS PHENOMENA
as long as 3 to 4 days, with the vertigo becom-
ing primarily positional toward the end of the In young children the manifestations of
spell. Nearly all patients were asymptomatic migraine are protean, and headache is not
between spells. During episodes, there were always present.43 Migraine equivalents may
no auditory symptoms, specifically no hearing appear as cyclic vomiting, attacks of abdominal
loss, tinnitus, or ear pressure or fullness. Most pain, or even ophthalmoplegia. As the child
patients either had migraine themselves or a matures, these nonspecific and other puzzling
strong family history of migraine. Furthermore, symptoms may cease and be supplanted by
the episodes of vertigo had several features in more typical paroxysmal head pain.
Table 12–2 Incidence of Vertigo and Migraine in Probands, First Degree Relatives
(Parents, Siblings, Children), All Relatives, and Unrelated Spouses
Totala Benign recurrent vertigo Migraine Both
Probands 24 24 (100%) 20 (83%) 20 (83%)
First degree relatives 111 44 (40%) 51 (46%) 31 (28%)
All relatives 220 82 (37%) 110 (50%) 59 (27%)
Unrelated spouses 43 1 (2%) 10 (23%) 0 (0%)
a
Those who returned questionnaires. (From Oh AK, Lee H, Jen JC, Corona S, Jacobson KM, Baloh RW. Familial benign
recurrent vertigo. Am J Med Genet. 2001;100:287 with permission.)
Symptoms of migraine equivalents can also with migraine headaches was significantly
begin in adulthood. Isolated episodes of scintil- greater than in controls. The incidence of a
lating scotomas are not uncommon after the positive family history varied from approxi-
age of 40. Fisher44 reported 60 patients with mately 40% to 90% compared with approxi-
what he called “transient migrainous accompa- mately 5% to 20% in controls. The percentage
niments,” which were attacks of paresthesias, of positive family histories tended to be greater
aphasia, dysarthria, paresis, and diplopia with in those studies in which family members were
or without the visual manifestations of migraine. individually interviewed than in studies that
None of these patients had headache. Normal relied on questionnaires or on the recall of the
angiography, long-term follow-up, and, in a proband. Studies in monozygotic and dizygotic
few cases, necropsy, suggested a migrainous twins have also supported a strong genetic
syndrome despite the absence of associated component for migraine, particularly for
headaches. migraine with aura. Also, the fact that the prev-
alence of migraine in African and Asian popu-
lations is lower than in European and North
American populations favors a major genetic
PATHOPHYSIOLOGY component. Studies of migrainous vertigo show
the same familial aggregation seen in other
Genetics migraine syndromes.48–50
Although it is clear that some varieties of RARE MIGRAINE SYNDROMES WITH

migraine are inherited, it is not clear whether KNOWN GENETIC CAUSES
migraine is a single syndrome or a variety of
syndromes, some of which are inherited and The recent identification of the genes for sev-
some of which are not.45 The situation is analo- eral rare subtypes of migraine may provide the
gous to the epilepsy syndromes. Some seizure first true molecular insight into migraine
syndromes are inherited and genetic factors pathophysiology. Within families with these
are important for most types of epilepsy, but relatively rare syndromes, some members will
anyone can have a seizure with adequate prov- have only MO or MA, suggesting that these
ocation. Similarly, several inherited syndromes more common migraine syndromes may have a
are associated with migraine headache, and similar pathophysiologic mechanism.
genetic factors are important in determining Familial hemiplegic migraine (FHM) is an
the threshold for migraine headaches, but autosomal dominant disease characterized by
structural lesions such as vascular malforma- headache attacks preceded by or accompanied
tions and vasculopathies can trigger migraine by episodes of hemiplegia, sometimes lasting
headaches in anyone. Genotype heterogeneity days.51 Within reported families with FHM,
has already been established for several some affected members have interictal nystag-
migraine syndromes. These syndromes are mus, ataxia, essential tremor, and seizures. MA
defined based on the presence of hemiplegic and episodes of hemiplegia may alternate
episodes or other aura symptoms that accom- within individuals and co-occur within families.
pany migraine headaches. Within such fami- Based on this observation, Russell and Olesen52
lies, however, some members may have only concluded that the pathophysiology and etiol-
migraine headaches, indicating that there is ogy of FHM and other more common uncom-
also phenotypic heterogeneity. Not surpris- plicated migraine variants may be similar. By
ingly, since headache is the least specific symp- contrast, after comparing clinical features of
tom of the different migraine syndromes, the patients with MA and patients with FHM,
genetic basis for migraine without aura has Thomsen et al.53 concluded that hemiplegic
been more difficult to establish. migraine is a separate entity from MA. Haan
Numerous studies over the years have docu- et al.54 suggested the FHM may be a hereditary
mented familial aggregation of migraine, and form of basilar migraine. They studied aura
some neurologists have suggested that a posi- symptoms in 83 patients from six unrelated
tive family history should be part of the diag- families with FHM and found that 55 of the
nostic criteria.46,47 In nearly all studies, the inci- patients reported symptoms that met the
dence of a positive family history in patients International Headache Society (IHS) criteria
12 Migraine 293
for basilar migraine. Consistent with this inter- MA inherited in an autosomal dominant
pretation, angiography performed during an fashion found linkage to the 19p and 1q loci
FHM attack showed spasm of the basilar of these two genes.64,65 However, Kim et al.66
artery. and Wieser et al.67 could not find mutations
So far, mutations in two genes have been in CACNA1A in patients with these common
identified in FHM: CACNA1A55 and ATP1A2.56 migraine syndromes. Jen et al.62 screened
Both of these genes code for the transmem- 50 probands from families with migraine
brane component of a neuronal ion channel. (7 basilar migraine, 25 MO, 18 MA) and
Although there is overlap in clinical features, did not find any mutation in either CACNA1A
most families with FHM due to mutations in or ATP1A2. Based on this preliminary
CACNA1A have progressive ataxia and interic- data, it does not appear that CACNA1A or
tal nystagmus,55,57 while the families reported ATP1A2 is important for the common migraine
with mutations in ATP1A2 had associated epi- syndromes.
leptic seizures.56 All of the mutations in One way to explain the heterogeneity of
CACNA1A associated with FHM have been migraine syndromes is to postulate a group of
missense mutations.57 Nonsense mutations in defects in genes that code for a family of pro-
the same gene produce a related disorder, epi- teins with similar properties and functions. The
sodic ataxia type 2 (EA-2), which is also associ- family of ion channels is appealing because
ated with migraine headaches.55,58 In some many of the migraine syndromes share the
families there can be an overlap between epi- clinical features of known inherited ion
sodes of hemiplegia and episodes of ataxia.59 In channel disorders (Table 12–3). A defective
families with mutations in either FHM gene, ion channel could explain the local buildup
some members can have just MO or MA as the of extracellular potassium that initiates the
only manifestation.56,57 spreading wave of depression in migraine (see
Some families with FHM are not linked to later discussion). Since ion channels in the
either the CACNA1A locus on chromosome inner ear are critical for maintaining the
19p or the ATP1A2 locus on chromosome 1q.60 potassium-rich endolymph and neuronal
Terwindt et al.61 screened the CACNA1A gene excitability, a defective ion channel shared
for mutations in 27 patients with sporadic by the brain and inner ear could lead to
hemiplegic migraine and found only two muta- a reversible hair cell depolarization and
tions (one patient had ataxia and interictal nys- auditory and vestibular symptoms. Further-
tagmus, while the other had no cerebellar more, many of the well-known triggers for
signs). Jen et al.62 screened 19 patients with migraine symptoms, including stress and
hemiplegic migraine (8 familial and 11 spo- menstruation, could result from hormonal
radic) for mutations in CACNA1A and ATP1A2 influences on the defective ion channels.
and found only a single mutation in CACNA1A Finally prophylactic drugs such as beta
in one of the sporadic cases (who also had cer- blockers, calcium channel blockers, aceta-
ebellar ataxia). Of the approximately 40 FHM zolamide, and tricyclic amines might work by
families with identified mutations in CACNA1A, stabilizing abnormal ion channels. Acetazol-
about half had the T666M mutation. Most of amide may work in episodic ataxia type 2 by
the patients with the T666M mutation also changing cerebellar pH and stabilizing calcium
have symptoms and signs of cerebellar ataxia, channels.68
although there is a broad clinical spectrum.63
Likely mutations in several other genes will be
identified, particularly in cases of sporadic
hemiplegic migraine. Table 12–3 Clinical features shared by
known inherited ion channel disorders
CANDIDATE GENES FOR COMMON Autosomal dominant inheritance
MIGRAINE SYNDROMES Reduced penetrance
Periodic symptoms
Within families with known mutations in
Episodes triggered by stress, exercise
CACNA1A or ATP1A2, some members have
May have no interictal findings
just MO or MA. Furthermore, linkage studies
Response to acetazolamide
performed in a few large families with MO or
Spreading Wave of Depression without aura.74,75 Single-photon emission com-

puted tomography (SPECT) and other tech-
Probably the most characteristic of migraine niques for measuring cerebral blood flow have
symptoms is the classic visual aura. It typically shown areas of regional hypoperfusion, not
begins with a small scintillating scotoma that only during migraine attacks but also in the
gradually enlarges over 20 to 30 minutes. There interictal phase.76 These changes were found in
is convincing evidence that the visual aura is migraine without visual aura, with visual aura,
secondary to a spreading wave of cortical and with episodes of hemiplegia. Acetazolamide
depression beginning at the occipital pole, reversed these interictal areas of hypoperfu-
which gradually spreads across the cortex sion in all three classes of migraine patients.
before stopping at the central sulcus.69 Although How does the spreading wave of depression
decreased cerebral perfusion is associated with and associated increase in extracellular potas-
the spreading wave of depression, it is probably sium lead to a typical migraine headache?
a secondary phenomenon rather than a primary Trigeminal nerve fibers surrounding pial arter-
process.70 The spreading wave of cortical ies on the ventral surface of the brain could be
depression is associated with a marked accu- depolarized by the high potassium concentra-
mulation of extracellular potassium that must tion.77 This in turn would lead to the release of
be cleared before neural activity can return to neurotransmitters such as substance P and cal-
normal. Although the exact mechanism for the citonin gene–related peptide (CGRP) by both
spreading wave of depression is not known, orthodromic and antidromic conduction. The
most agree that the initial event is local buildup result is an increase in vascular permeability,
of potassium in the extracellular space. dilatation of cerebral vessels, and a local inflam-
Nearby synaptic terminals then depolarize matory response further activating pain-
in response to the high extracellular potassium, provoking fibers of the trigeminal vascular sys-
and both excitatory and inhibitory neurotrans- tem. Thus, the headache of migraine could be
mitters are released. This release in turn leads a secondary phenomenon, the end result of a
to the opening of subsynaptic channels, result- local increase in extracellular potassium con-
ing in further ionic exchange between the centration. Many of the drugs used for prophy-
intracellular and extracellular fluids. During lactic treatment of migraine have been shown
the spreading wave of depression, neurons are to suppress the cortical spreading wave of
completely silent for approximately 1 minute depression in an animal model of migraine.78
and they then slowly recover their predepres-
sion level of firing. The rate of movement of
the spreading wave of depression across the Vasomotor Abnormalities
visual cortex (measured with functional mag-
netic resonance imaging [MRI]) nicely corre- Vasomotor abnormalities have long been con-
lated with the rate of enlargement of the sidered in the pathophysiology of migraine
scintillating scotoma observed by patients.71 symptoms. Vasodilatation of extracranial ves-
A spreading wave of cortical depression was sels accompanies the typical migraine head-
observed on positron emission tomography ache. Vasospasm occurs in some intracranial
(PET) in a patient having a typical migraine vessels with migraine, although there is contro-
headache without aura.72 versy regarding its role in the production of
Consistent with a basic neuronal defect, symptoms. Although vasospasm is associated
patients with migraine have cortical abnormali- with the classical migraine visual aura, most
ties not only during their attacks but also in likely, vasospasm results from a metabolic
the interictal period. Paroxysmal slowing on defect slowly spreading across the cerebral
interictal electroencephalographs (EEG) is cortex and is secondary to hypometabolism.
commonly seen in migraine, and the classical Vasospasm is more likely a cause of retinal
association of migraine and epilepsy is well migraine.79 Some patients experience episodes
documented.73 Interestingly, identical paroxys- of monocular blindness, and when examined
mal slowing on EEG is seen in patients with during these episodes there is vasospasm
EA-2. Magnetic resonance spectroscopy shows of retinal arteries. Furthermore, such
decreased interictal energy metabolism in patients respond to antispasmodic agents.80,81
the cortex of patients with migraine with or Sudden episodes of hearing loss and/or vertigo
12 Migraine 295
associated with migraine could be explained by lesions reflect ischemia which could be related
the vasospasm of the cochlear and/or vestibular to vasospasm.
branches of internal auditory artery.
It is interesting to note that MRI studies in
migraine patients found an increased preva-
lence of small white matter hyperintensities, DIAGNOSIS
particularly involving the cerebellum and brain
stem, compared to non-migraine control sub- The diagnosis of migraine is relatively easy
jects.82–84 (Fig. 12–1).Though these are nonspe- when headaches are the major feature and
cific findings, a leading hypothesis is that these there is a strong family history. In patients in
Figure 12–1. Cerebellar lesions in patients with migraine from the CAMERA study. Corresponding magnetic resonance
T2-weighted (left) and fluid-attenuated inversion-recovery images (right) showing cerebellar infarct-like lesions (arrows) in
four representative cases. (Kruit et al. Brain. 2005;128:2068-2077, with permission)
whom headache is less prominent or in patients in children and has been recommended for
with migraine equivalents, the diagnosis can be inclusion as another minor criterion for the
missed if one is unaware of the diversity of this diagnosis.87
syndrome.
Migraine with Aura

Migraine without Aura
The IHS Headache Classification Committee
The criteria for the diagnosis of migraine with- defined migraine with aura as “an idiopathic
out aura, established by the IHS, are summa- recurring disorder manifesting with attacks of
rized in Table 12–4.85 The patient must have neurological symptoms unequivocally localiz-
had at least five headache attacks that meet the able to cerebral cortex or brain stem, usually
criteria and other causes of headache must be gradually developed over 5 to 20 min and usu-
ruled out. If they meet all but one criteria they ally lasting less than 60 min.”85 Visual symp-
are designated as probable migraine. No labo- toms, including the classic scintillating scotoma
ratory or radiological findings are specific for and fortification spectra, are the most com-
migraine. The physical and neurological exami- monly recognized aura phenomena, but
nations are normal and serve primarily to somatosensory and vestibular symptoms are
exclude other causes of headache. A classic probably equally common.
migraine attack typically has five phases: a
prodrome (e.g, depression, cognitive dysfunc-
tion, food craving), aura (e.g, visual, sensory, or Migraine Aura without Headache
motor phenomena), headache (usually unilat-
eral and throbbing), resolution (when pain Although less common, migraine aura without
wanes), and recovery.86 None of these phases is headache is of particular interest from a
obligatory for the migraine diagnosis, however. neurotologic point of view. The occurrence of
Symptoms (severity, duration, nature of pro- migraine aura without headache has been rec-
drome or aura) also vary substantially between ognized for many years, although this contin-
individuals. Thus, the diagnosis of migraine is ues to be a difficult concept for both patients
based on a combination of sequentially occur- and physicians to deal with. Some patients will
ring symptoms in paroxysmal attacks. Motion have isolated aura symptoms at one point in
sickness is often the first symptom of migraine their life and typical migraine headaches at
another point. In some patients the aura symp-
toms occur alone on occasion and with typical
Table 12–4 Diagnostic Criteria for headaches on other occasions. Some have only
Migraine without Aura aura symptoms and never experience a head-
A. At least five attacks fulfilling B–D
ache. Terms such as migraine equivalent and
B. Headache lasts 4–72 hr (untreated)
migraine accompaniment have been used to
C. Headache has at least two of the following describe these isolated aura symptoms, but a
features: diagnosis is difficult to arrive at without the
Unilateral
presence of typical headaches at some time
during the course.
Pulsating
Moderate or severe (inhibits or prohibits
daily activities)
Aggravated by walking, stairs, or similar
Basilar Migraine
physical activities
D. During headache at least one of the follow- In 1961, Bickerstaff described a subset of
ing: migraine with aura characterized by a combi-
Nausea and vomiting nation of symptoms that he felt reflected isch-
Photophobia and phonophobia emia within the distribution of the basilar
E. Other causes of headache have been ruled artery.88 Most of Bickerstaff’s patients were
out adolescent girls, but subsequent reports have
confirmed that basilar migraine can occur in
Source: Adapted from International Headache Society.85
both sexes at any age. Vertigo, tinnitus, and
12 Migraine 297
decreased hearing are common symptoms with Table 12–5 Common Factors that
basilar migraine and could confound the dif- Trigger Migraine Symptoms
ferential diagnosis between basilar migraine
and Meniere’s syndrome since these same Stress, emotional upset
symptoms are characteristic of the latter dis- Hormones: menstruation, oral contraceptives,
ease. The IHS criteria for the diagnosis of basi- pregnancy
lar migraine require an aura that contains two Sleep deprivation
or more of the symptoms listed in Table 12–1.85 Food: red wines, fermented cheeses, chocolate,
Patients with isolated episodes of vertigo do coffee
not meet the criteria for basilar migraine. Eating disorders: fasting, binges
Migrainous Vertigo of migraine symptoms in many patients. The

general lifestyle factors that are important
The IHS currently does not have criteria for include stress management, good quality sleep,
the diagnosis of migrainous vertigo. However, awareness of food-related factors, and cardio-
Neuhauser and Lempert have suggested crite- vascular exercise. As a general rule, migraineurs
ria that are becoming generally accepted.3,6 have fewer symptoms when following a regi-
The criteria include the following: (1) recur- mented schedule to ensure all of these factors
rent vertigo attacks, (2) migraine according to are adequately addressed. These factors are
IHS criteria, (3) migrainous symptoms during perhaps more important for the management
at least two vertiginous attacks (headache, pho- of migrainous vertigo than for migraine head-
tophobia, phonophobia, or aura symptoms), aches because there are no good trials of the
and (4) vertigo cannot be attributed to another effect of abortive or prophylactic medication
disorder. Patients who meet criteria 1, 2, and 4, treatment for migrainous vertigo, whereas
but not 3 are considered probable migrainous there are adequate trials demonstrating the
vertigo. Using these criteria in a screen of the efficacy of medicines to manage migraine
general population in Germany, Neuhauser headaches. Although we presume similar
et al.10 concluded that migrainous vertigo is mechanisms cause headaches and vertigo, we
underdiagnosed and has considerable personal cannot presume the same benefit of these
and health-care impact. medications.
Symptomatic and Abortive

MANAGEMENT Treatment
Treatment of migraine can be divided into Symptomatic and abortive treatment for
three general categories: symptomatic, abor- migrainous symptoms largely depends on
tive, and prophylactic. Some drugs are useful which symptoms the patient is most bothered
in ameliorating the symptoms of the acute by. Headache symptoms, by far, have the most
attack, others can abort an attack if taken just research to support the use of medicines, and
after the onset, and still others are effective in society guidelines have been published. 89 The
reducing the frequency and severity of attacks treatments available for acute attacks of
or eliminating their occurrence entirely. migraine headaches include serontonin recep-
Before embarking on drug treatment of tor agonsists (i.e, triptans), antiemetics, analge-
migraine, it is important to recognize that there sics, and combination preparations.
are many common triggers for migraine symp- Clinical trials of abortive therapies for head-
toms (Table 12–5). It is often helpful to have aches have also demonstrated that the medi-
the patient keep a log of his or her migraine cines can reduce other symptoms of migraine
attacks, noting any possible triggers that might attacks, including hypersensitivities (photopho-
be regularly associated with the attacks. Though bia and phonophobia) and nausea. 90 However,
rigorous clinical trials are lacking, knowledge no good clinical trial data exist to support the
of triggers and focusing on general lifestyle fac- effect of abortive therapies for migraine
tors can go a long way in reducing the burden vertigo. Only one randomized controlled trial
has been published on the treatment of Prophylactic Treatment

migrainous vertigo with a triptan medication,
but this trial had substantial limitations mainly Many studies of prophylactic treatments have
stemming from the very few subjects enrolled.91 demonstrated an average improvement in
In this trial, 3 out of 8 patients randomized to headache severity and frequency in patients
zolmitriptan met the endpoint of vertigo symp- with migraine headaches89 (Table 12–6). But,
tom improvement at 2 hours, compared with 2 as with abortive and symptomatic treatments,
out of 9 patients taking placebo. Thus, the no good trials of prophylactic agents have been
number of participants was much too small to conducted to measure the effect on vertigo
make any conclusions about the effect of zol- attacks in a population of patients with migraine
mitriptan. vertigo. As a result, we do not know whether
Symptomatic treatment of the vertigo attacks migraine prophylactic medications are benefi-
has also not been well studied specifically in cial in patients with migraine vertigo.
migraine vertigo. As a result, migraine vertigo A general sentiment exists in clinical care
is managed symptomatically the same way that that migraine prophylactic medicines can be
vertigo in general is managed. Antivertiginous effective in reducing the frequency and
and antiemetic medications are useful in reduc- severity of migraine vertigo attacks, but this
ing the severity of the symptom (see Tables sentiment is based on anecdotes and observa-
19–2 and 19–3 in Chapter 19). Promethazine tional studies. In the absence of data from rig-
at 25 or 50 mg, orally or via suppository, is par- orous clinical trials, it is a large—and poten-
ticularly effective for the relief of both vertigo tially dangerous—leap to assume that a therapy
and nausea. Drugs in this class also have a sed- is effective.
ative effect, which is probably one of the main All of the prophylactic treatment studies in
reasons for a positive effect in patients with migraine vertigo have profound shortcomings.
severe vertigo. However, the sedating effect In fact, no control groups were even used in
typically limits the use of these medicines for any of the prophylactic treatment studies iden-
less severe attacks. The decrease in gastric tified in a recent review on migraine vertigo.92
motility that occurs during migraine attacks Not using control groups is a major shortcom-
can decrease the absorption of oral drugs as ing because of the natural tendency for symp-
well as contribute to the nausea and vomiting. toms such as vertigo attacks to improve over
Metoclopramide (Reglan) promotes normal time in the absence of any treatment. In fact,
gastric motility and may improve absorption of close to 50% (9 out of 19) of the patients expe-
oral drugs. rienced spontaneous remission (i.e, no attack
Table 12–6 Common Drugs for Treating Migraine

Class Actions Sample Drugs
Serotonergic 5HT1 agonist Sumatriptan
5HT2 antagonist Dihydroxyergotamine
5HT reuptake inhibitor Methysergide, amitriptyline,
fluoxetine
Dopaminergic DRD2 antagonist, ion channel stabilization Prochlorperazine,a metoclopramidea
Beta blockers 5HT2 antagonist Propranolol, atenolol
Calcium channel Ion channel stabilization, neuronal Flunarizine, nimodipine
blockers protection, DRD2 antagonist
Non-steroidal Prostaglandin suppression, neurogenic Aspirin, naproxen, ibuprofen
anti-inflammatory inflammation
Anticonvulsants Ion channel stabilization, neuronal Valproate, gabapentine, topiramate
inhibition
Carbonic anhydrase Ion channel stabilization Acetazolamide
inhibitors
a
Can be used for both symptomatic and prophylactic treatment.
12 Migraine 299
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24. Kirchmann M, Thomsen LL, Olesen J. Basilar-type
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Chapter 13
Immune-Mediated Diseases
AUTOIMMUNE INNER EAR DISEASE Diagnosis

Background Management
Pathophysiology MULTIPLE SCLEROSIS
Clinical Features Background
Diagnosis Pathophysiology
Management Clinical Features
PARANEOPLASTIC IMMUNE DISORDERS Diagnosis
Background Management
Pathophysiology
Clinical Features
The immune system is implicated in many neu-

rologic diseases. There are some primary AUTOIMMUNE INNER EAR
immune-based neurologic diseases, such as DISEASE
multiple sclerosis and myasthenia gravis, and
also many secondary immune-based diseases, Background
including paraneoplastic syndromes. In pri-
mary immune-mediated diseases the cause is The endolymphatic sac is the key structure for
typically not known, but genetic and environ- immunoregulation within the inner ear.1 Ultra-
mental factors undoubtedly play a role. On the structural studies have identified lymphocytes
other hand, in secondary immune-based dis- and macrophages within the endolymphatic sac
eases a known inciting event occurs, typically and a surrounding network of lymphatic vessels
an infection, cancer, or environmental stimu- containing these mononuclear cells.2 Injection of
lus, in the setting of genetic susceptibility. exogenous antigens into the inner ear of a guinea
Immune-mediated disorders are important to pig is as effective for initiating systemic immunity
identify because in many cases effective thera- as intraperitoneal injection. When an antigen is
pies are available. In the absence of adequate placed into the inner ear of animals that have
therapeutic trials, identifying an immune been immunized against the antigen, immuno-
response can at least direct therapeutic competent cells infiltrate the ear and there is local
approaches for what can otherwise be severely production of antibody.3,4 The inner ear is dam-
disabling deficits. aged during the immune response, even though
In this chapter, we focus on the immune- the antigen is not expressed in the inner ear.
mediated syndromes that can involve the Surgical ablation of the endolymphatic sac or
peripheral audio-vestibular system and also the blockade of the endolymphatic duct markedly
central vestibular system. curtails the immunological response and inner
303
ear damage.5 Lymphocytes engaged in the average beneficial effect of a cytotoxic agent
immune response within the inner ear are (methotrexate) in one large randomized clinical
recruited from the circulation, presumably via trial.16 Autoantibodies have been identified in
the spiral modiolar vein. With this secondary some patients, but, as in the case of the animal
immune response, there is activation of models, it is unclear whether the antibodies are
spiral modiolar vein endothelium, release of involved in the pathogenesis or are simply an
cytokines such as interleukin-2, and up-regulation epiphenomenon (see later discussion).
of adhesion molecule expression.6
The inner ear is also capable of mounting an
immune response against one of its own anti- Pathophysiology
gens. Several groups have immunized mice,
rats, and guinea pigs with specific inner ear A wide range of multisystem autoimmune dis-
antigens and produced inner ear damage.7–11 orders can involve the inner ear (Table 13–1).
The histopathology of the inner ear in these ani- With these disorders, there appears to be an
mals shows degenerative changes with mono- episodic breakdown in immunologic tolerance
nuclear cell infiltration. Antibodies directed to self-molecules. These autoimmune diseases
against several different inner ear proteins have are thought to result from a defect in a cell sur-
been identified in these animals, but so far, pas- face protein on T cells required for the intra-
sive transfer of injury with these antibodies has thymic death of autoreactive T lymphocytes.
not been produced. Sensitized lymphocytes, The defective protein prevents negative selec-
however, can produce inner ear damage and tion of autoreactive T cells so that there are
sensorineural hearing loss after passive transfer excessive numbers of circulating autoreactive
to other animals.11–13 Although there are still T cells. In a mouse model with this T cell
many unanswered questions regarding these surface protein defect (the MRL mouse),
animal models of immune-mediated inner ear cochlear damage occurs in the early stages of
damage and how they translate to humans, they the systemic illness.17,18
clearly show that the inner ear can be damaged There are three major mechanisms by which
either directly by attack on inner ear proteins or an immune-mediated disease can damage the
indirectly by a general immune response against inner ear: (1) deposition of antigen antibody
an irrelevant antigen. immune complexes in the tissue; (2) autoanti-
In 1958 Lehnhardt14 was the first to suggest bodies directed against inner ear antigens; and
that bilateral deafness might be caused by anti- (3) infiltration and destruction of inner ear
cochlear antibodies. In 1979, McCabe described tissue by specific cytotoxic T cells. A wide range
the clinical syndrome of autoimmune inner ear of non-organ-specific autoimmune disorders
disease.15 He reported a series of patients with presumably damages the inner ear via the first
rapidly progressive bilateral sensorineural hear- mechanism.16 Temporal bone specimens from
ing loss often associated with vertigo or imbal- patients with polyarteritis nodosa, systemic
ance. There was histopathologic evidence com-
patible with vasculitis in a temporal bone biopsy
from one patient and evidence of cell-mediated Table 13–1 Systemic Immunologic
immune responses to inner ear membranous Disorders that Involve the Inner Ear15
tissue from several other patients. The most
convincing evidence of immune-mediated Vasculitis Syndromes
damage, however, was the response to corticos- Polyarteritis nodosa
teroids and cytotoxic drug therapy. Wegener’s granulomatosis
Subsequently, there have been numerous simi- Bechet’s syndrome
lar case reports of patients with this clinical Cogan’s syndrome
profile who often show good response to immu- Connective Tissue Diseases
nosuppression with corticosteroids and other Systemic lupus erythematosus
cytotoxic agents. However, the effect of corti- Sjögren’s syndrome
costeroids was variable in an open-label study Rheumatoid arthritis
Vogt-Koyanagi-Harada syndrome
(about 58% [67/116] of those enrolled met the
Relapsing polychondritis
criteria for improved hearing after initiating
Ulcerative Colitis
corticosteroid treatment), and there was no
13 Immune-Mediated Diseases 305
lupus erythematosus, and Wegener’s granulo- pig inner ear tissue, and it is not even organ
matosis show evidence of small vessel vasculitis specific, since it is present in many other tis-
with inflammation and ischemic changes. sues. There is now convincing evidence that
Endolymphatic hydrops has been found in the antigen recognized by these antibodies is
some specimens, possibly secondary to the heat-shock protein 70 (HSP-70), a highly con-
inflammatory changes. Cogan’s syndrome,19 served molecule that is up-regulated during
which is characterized by interstitial keratitis times of stress.28,29 Whether HSP-70 located in
and inner ear involvement, may blur the dis- the inner ear is the target of these antibodies or
tinction between organ-specific and non– simply shares an epitope with the true target
organ-specific inner ear immune-mediated dis- antigen is unknown. However, the level of
ease.20,21 Lunardi et al.22 used pooled IgG these anti-HSP-70 antibodies correlates both
immunoglobulins from patients with Cogan’s with the activity of disease and the steroid
syndrome to screen a random peptide library responsiveness of the disease.29 The HSPs are
to identify disease-relevant autoantigens. They ubiquitous in all normal cells and are desig-
found an immunodominant peptide with a nated as chaperone proteins because of their
sequence similar to the cell-density enhanced role in aiding protein folding. Since they are
protein tyrosine phosphatase-1 (DEP-1/ up-regulated in response to injury or stress,
CD148) that is expressed on the sensory epi- antibodies directed against them may be a sec-
thelia of the inner ear and on endothelial cells. ondary phenomenon unrelated to the underly-
Antibodies directed against the “Cogan pep- ing cause of injury.30
tide” were able to transfer the disease to other Numerous investigators have shown that
animals and mice or rabbits immunized with serum from some patients with immune-medi-
the Cogan’s peptide or a different peptide from ated inner ear disease contains antibodies
DEP-1/CD148; the animals developed hearing directed against specific inner ear structures,
loss and interstitial keratitis. Furthermore, using immunofluorescence.31 However, there
antibodies against the Cogan peptide cross- has been no consistent pattern of staining and
reacted with a structural protein of the reovirus no specific cellular or subcellular structure
type III, suggesting the possibility of molecular consistently stained. Disher and colleagues30
mimicry as a disease mechanism. About 50% of noted that patient sera containing antibodies
patients with Cogan’s syndrome report an directed against the 68 kDa protein produced a
upper respiratory infection prior to the onset of characteristic punctate “wine glass” staining
disease. pattern of the supporting cells in the guinea pig
Central to the notion of an organ-specific organ of Corti. Such a staining pattern was
immune disease is that antibodies or immune never seen with control sera. These authors
cells are directed at a specific inner ear antigen. concluded that, because of the localized stain-
Numerous clinical studies have examined cel- ing pattern, it was unlikely that HSP-70 was
lular and humoral immune reactivity to a vari- the primary target of these autoantibodies.
ety of inner ear tissues from humans and ani- Baek et al.32 found that patients with autoim-
mals with immune-mediated inner ear disease.23 mune inner ear disease had a high frequency of
Cellular immune assays using lymphocyte circulating T cells producing interferon gamma
migration inhibition and lymphocyte transfor- or IL-5 in response to recombinant cochlin, the
mation have produced some positive findings, most abundant inner ear protein. Patients also
but these assays are technically demanding and showed significantly elevated cochlin-specific
are not very sensitive.24 Detection of serum serum antibody titers compared to controls or
antibodies directed at inner ear antigens is a patients with other causes of hearing loss.
much simpler procedure and thus has potential Cochlin expression is largely confined to the
to lead to a clinically useful laboratory test. inner ear and mutations in the COCH gene
Many patients with the typical syndrome of that codes for cochlin causes progressive
idiopathic bilateral progressive sensorineural cochlear and vestibular pathology.
hearing loss first described by McCabe have So far there have been only a few histopatho-
antibodies in their serum that bind a 68 kDa logic studies of temporal bone specimens from
protein on Western blot analysis.25–27 This patients with inner ear-specific immunologic
68 kDa protein is not species specific, since it is disease. Schuknecht33 reported infiltration of
detectable using human, bovine, and guinea lymphocytes, plasma cells, and macrophages in
unilateral and progressive bilateral sensorineu-

ral hearing loss have been well documented
with SLE.34,35 In a case series of female SLE
patients, 57.5% (23/40) had impaired hearing,
particularly in the low frequencies.36 In some
cases, fluctuating low-frequency hearing loss
along with episodic vertigo suggests the
diagnosis of endolymphatic hydrops. The most
consistent inner ear pathology is a vasculitis,
presumably caused by deposition of circulating
immune complexes in the walls of blood ves-
sels.37 In theory at least, the inner ear—just like
A the kidney—is a prime target in SLE because
there are antigenic similarities between the stria
vascularis and the glomerular basement mem-
brane and both structures show deposits of
immune complexes.38
Polyarteritis nodosa (PN) is a necrotizing
vasculitis of small muscular arteries that com-
monly involves the inner ear; hearing loss is
occasionally the initial symptom.24,39 Patients
can have hearing loss for several years before
the systemic features of polyarteritis become
evident. Obliterative vasculitis of the labyrin-
thine artery can result in ischemic necrosis of
the entire labyrinth. Wegener’s granulomatosis
B is another vasculitic syndrome characterized by
Figure 13–1. Spiral modiolar vein of patient with auto- necrotizing granulomas primarily within the
immune inner ear disease showing perivascular round cell upper respiratory tract, lung parenchyma, and
infiltration (A) and new bone formation (B) in an area of kidneys. Although both acute and chronic sen-
intense inflammation (Courtesy, Harold F Schuknecht
MD). sorineural hearing loss occur with Wegener’s
granulomatosis, a conductive hearing loss due
to otitis media is a more common finding.40
the endolymphatic and perilymphatic spaces
Behçet’s disease is a rare vasculitic syndrome
and within the tympanic lamellae and spiral
characterized by aphthous ulcers, genital
ligaments (Fig. 13–1). Osteoneogenesis and
ulcers, and iritis or uveitis. Auditory and ves-
fibrous tissue were present in the scala tympani
tibular symptoms due to inner ear involvement
adjacent to the round window and dense bone
are common at any time during the course.41 A
formation surrounded the spiral modiolar vein
small percentage of patients with Sjogren’s
and modiolus. There were also focal mononu-
syndrome have a progressive bilateral hearing
clear infiltrates in the cochlear and vestibular
loss presumably secondary to infiltration of the
nerve trunks. Although hydrops was also pres-
inner ear by autoreactive T cells.42
ent, the pathology was distinct from that of typ-
As noted earlier, Cogan’s syndrome is typi-
ical Meniere’s disease. These findings are also
fied by audiovestibular symptoms and recur-
typical of those observed in experimental ani-
rent nonsyphilitic interstitial keratitis.19–21
mals undergoing chronic antigen stimulation.
Initially, the clinical picture is indistinguishable
from Meniere’s syndrome with episodic vertigo
and fluctuating hearing loss, but the course is
Clinical Features more fulminant, typically rapidly leading to
deafness if untreated. Although the disorder
SYSTEMIC IMMUNE-MEDIATED
can begin with either eye or ear involvement,
DISEASES WITH INVOLVEMENT OF THE
both organs are usually involved within 1 year
INNER EAR
of onset. Cogan’s syndrome has features of
Systemic lupus erythematosus (SLE) is the pro- both non–organ-specific and organ-specific
totypical immune complex disease. Both sudden immune-mediated disease. In most cases, there
is evidence of a systemic vasculitis with deposi- levels did not correlate with clinical activity and
tion of immune complexes. Some patients will 3 of these patients treated with immunosup-
develop a systemic illness resembling polyar- pressive therapy showed no benefit.
teritis nodosa. In most, however, only the ear Deutschlander et al.48 found antilabyrinthine
and eye are involved. or nervous tissue-specific serum antibodies in
Inner ear involvement occurs in about 50% 12 patients with bilateral vestibulopathy and
of patients with relapsing polychondritis.24 This normal hearing, but only a few showed any
rare condition is characterized by recurrent response to immunosuppression treatment and
episodes of inflammatory necrosis of cartilage.43 it was unclear whether the response was spon-
Conductive hearing loss is also common taneous or due to medication.
because of swelling and degeneration of carti- About 20% of patients with idiopathic pro-
lage in the middle ear.44 Autoantibodies gressive bilateral sensorineural hearing loss
directed against collagen type 2 and type 9 and who meet the diagnostic criteria for immune-
other cartilage components have been identi- mediated inner ear disease have a combination
fied with this disorder, but it is unclear whether of fluctuating and progressive sensorineural
the inner ear damage is due to vasculitis or to hearing loss and episodic vertigo that meets the
these collagen autoantibodies. strict diagnostic criteria for Meniere’s syn-
drome.29 About a third of patients with typical
AUTOIMMUNE INNER EAR DISEASE Meniere’s syndrome have been shown to have
the anti–HSP-70 antibodies that are character-
The typical presentation of immune-mediated istic of immune-mediated inner ear disease.49
inner ear disease is a rapidly progressive bilat- This suggests the possibility that a subset of
eral sensorineural hearing loss that extends patients in both diagnostic categories have a
beyond the arbitrary 72 hr typical of sudden common pathophysiology.
sensorineural hearing loss.15,45 Moscicki and
colleagues26 defined the following criteria for
the disorder: (1) bilateral sensorineural hearing Diagnosis
threshold of ≥30 dB at any frequency, and
(2) evidence of progression in at least one ear AUDIOVESTIBULAR TESTING
on two serial audiograms performed ≥3 months
apart (progression being defined as a threshold Serial audiograms performed every few months
loss of ≥15 dB at one frequency or 10 dB at two are necessary to confirm the presence of, and
or more consecutive frequencies). Fluctuating response to treatment for, bilateral progressive
hearing loss qualifies if there is also progression sensorineural hearing loss.50 There is no char-
as defined by the criteria. Most investigators acteristic pattern of hearing loss with immune-
have found a female preponderance, although mediated inner ear disease in which both
others have not.29,46 Immune-mediated inner up-sloping and down-sloping or even flat pat-
ear disease typically begins in the 30s and 40s, terns occur. Occasionally, speech discrimina-
although there is a wide range of age of onset tion is affected to a greater extent than hearing
from childhood into the eighth decade. thresholds, although, in this case, one should
Vestibular symptoms typically occur in about consider a search for retrocochlear disease,
50% of patients. Most commonly, there are such as that associated with multiple sclerosis
episodes of vertigo with or without episodes of (MS) or a vestibular schwannoma. Unilateral
fluctuating hearing loss. Occasionally, patients or bilateral decrease in caloric function will
show just a deterioration in balance due to often correlate with the severity of hearing loss.
bilateral progressive vestibular loss, which A subset of patients will have severe auditory
can be identified at the bedside with the involvement without any evidence of vestibular
head-thrust test. Whether a subset of patients dysfunction.
has just bilateral vestibular loss without Routine serologic tests are recommended in
hearing loss is unclear, although to date, no patients with idiopathic bilateral progressive
convincing patients with this syndrome have sensorineural hearing loss to evaluate for find-
been reported. Arbusow et al.47 found autoanti- ings suggestive of systemic immune-mediated
bodies directed at inner ear antigens in 8 of disease. The typical regimen would include a
12 patients with idiopathic bilateral vestibul- complete blood count with differential white
opathy and normal hearing, but autoantibody count, erythrocyte sedimentation rate (ESR),
antinuclear antibody (ANA), rheumatoid fac- randomized clinical trials of steroid treatment
tor, and C3 and C4 complement levels. of immune-mediated inner ear disease.
Magnetic resonance imaging (MRI) with con- Because a short course of corticosteroids is
trast is not likely to be useful in the absence of associated with relatively few adverse effects
accompanying brainstem dysfunction, but it and the medicine is inexpensive and widely
may show enhancement of the membranous available,57,58 most practitioners recommend a
labyrinth during active stages of the disease.51 therapeutic trial of prednisone in the range of
A wide range of antigen-specific laboratory 1 mg/kg/day for 4 weeks, followed by tapering.
tests have been recommended for the diagno- Some patients will show an immediate response
sis of immune-mediated inner ear disease, but within hours to days of treatment, although
to date, none of these tests are universally avail- many do not show improvement until later in
able or have been demonstrated to be useful the course of treatment. Shorter courses of
clinically. In his original description in 1979, treatment might lead to relapse.29 Hearing is
McCabe15 reported that 6 of 18 patients with typically tested at the initiation of therapy and
immune-mediated inner ear disease had a pos- at the end of the 4 weeks of high-dose steroids.
itive migration inhibition test, using inner ear If the threshold has improved by ≥15 dB at one
proteins for the antigenic stimulus. Hughes frequency or 10 dB at two or more frequencies,
and colleagues52 at the Cleveland Clinic devel- the diagnosis of immune-mediated inner ear
oped a lymphocyte transformation test, also disease is confirmed and the patient is consid-
using inner ear proteins, and found abnormal ered a steroid responder. Patients who do not
results in about a quarter of patents with show a response after a month are tapered off
immune-mediated inner ear disease. Berger the steroid over the next 12 days. Patients who
and colleagues53 used type 2 collagen in a lym- respond to the initial month of therapy con-
phocyte transformation test and reported a tinue on the full dosage until their audiogram
50% positive rate in patients with immune- shows that hearing levels have reached a pla-
mediated inner ear disease versus a 6% posi- teau. The steroids are then slowly tapered over
tive rate in controls. These cellular immune about 8 weeks and a smaller maintenance dose
assays are probably too technically demanding is continued for at least 6 months. Relapses are
for routine use in the clinical laboratory.54 more common in patients who are treated for
Between one-third and two-thirds of patients less than 6 months compared to those treated
with immune-mediated inner ear disease have for 6 months or longer.29 Up to two-thirds of
anti–HSP-70 antibodies,23,28,29 but these anti- patients who meet the diagnostic criteria for
bodies can also be seen in normal subjects.55 autoimmune inner ear disease respond initially
The presence of anti-HSP-70 antibodies seems to steroids, but only about 15% continue to
to be correlated with disease activity and with respond after 3 years. 16,50,57
steroid responsiveness.25 Rauch estimated that Long-term corticosteroid treatment can lead
a positive test indicated as much as a 75% to major side effects, including gastritis and
chance of steroid responsiveness, whereas a ulcers, labile blood pressures, altered blood
negative test indicated a chance of response of sugar metabolism and diabetes, mood changes,
<20%.25 However, controlled studies are sleep disorders, accelerated cataract formation,
needed to confirm these observations, and it is cushingoid habitus, and ischemic bone necro-
unlikely that clinicians would withhold a trial of sis. All of these side effects tend to be more
corticosteroids unless the test could identify pronounced with long-term use; the risk dur-
patients with a probability of improved recov- ing the initial 30-day high-dose steroids with
ery very close to zero. rapid taper is relatively low.58 Despite these
major long-term risks, corticosteroid therapy
continues to be the mainstay for empiric treat-
Management ment of immune-mediated inner ear disease.
Methotrexate and cyclophosphamide have
The mainstay of treatment of immune- been used as an alternative to systemic corti-
mediated inner ear disease is immune suppres- costeroids, in combination with corticosteroids,
sion with high-dose corticosteroids.24,29,56 or as an alternative to steroids in patients with
Unfortunately, there have been no prospective unacceptable side effects.24,29 Most experience
has been with methotrexate using a low-dose Pathophysiology

protocol. An initial dosage of 7.5 mg/week (3
doses of 2.5 mg) is given for 2 weeks and, if Paraneoplastic syndromes result from an
there is not major toxicity, the dosage is dou- immune-based attack on the nervous system,
bled to 15 mg/week.29 This dosage is continued usually against neurons.61 Presumably, the
for 6 to 8 weeks and then, as with steroids, dis- tumor expresses antigens that are also expressed
continued in nonresponders and carried on for by neurons. The immune system recognizes
about 6 months in responders. The main toxic- the proteins expressed by the tumor as foreign
ity associated with methotrexate includes and mounts an immune attack to control tumor
myelosuppression, oral ulceration, gastrointes- growth. In many cases, the immune response is
tinal ulcers, and hepatic fibrosis. This latter so effective that the tumor remains small and
severe complication is usually only seen when may not be detectable. The immune response
methotrexate is given for more than a year. In a consists of both an antibody and cytotoxic T
randomized placebo-controlled trial, metho- cell response. In paraneoplastic syndromes
trexate did not demonstrate an average benefi- affecting the brain, inflammatory infiltrates of
cial effect compared to placebo for maintaining T cells and plasma cells occur in both the ner-
hearing improvement achieved with predni- vous system and in the tumor. The same anti-
sone (60 mg/day for 1 month followed by bodies are found in the brain and the tumor.
18-week taper).16 In a pilot placebo-controlled Different antibodies occur with different
study, the immunomodulatory drug etanercept tumors and clinical syndromes (Table 13–2).61
was no better than placebo for treating autoim- These antibodies are directed against a num-
mune inner ear disease.59 ber of onconeural antigens, all important in
neuronal function. In many cases the antibod-
ies associated with paraneoplastic syndromes
have been used as probes to immunohis-
PARANEOPLASTIC IMMUNE tochemically localize the antigen in the nervous
DISORDERS system and to clone the gene from complimen-
tary DNA expression libraries of genes that
Background code for the onconeural antigens.61 Many of
the genes associated with these antigens appear
Remote effects of cancer on the brain were to be important in early neuronal development
first described at the end of the nineteenth and in the regulation of gene expression.
century, but case reports were largely anec- The characteristic pathologic findings with
dotal and, because similar syndromes occur paraneoplastic syndromes are perivascular
without cancer, many investigators questioned cuffing by lymphocytes, activation of microglia
the cause-and-effect relationship. Cancer can with the formation of microglial nodules, and
have remote effects on the nervous system, selective loss of neurons. The process is pre-
from the cortex to cranial and peripheral dominantly, although not exclusively, confined
nerves, including the audiovestibular nerves. to gray matter. Immunoglobulin G (IgG), nor-
Whether there is a selective cochleovestibular mally absent from the brain, can be found not
paraneoplastic syndrome is unclear, but only within the neuropil but also within neu-
involvement of audiovestibular structures is rons. These antibodies found in the brain are
common with paraneoplastic encephalomyeli- directed against specific onconeural antigens
tis. Many cancers have been associated with that are expressed within the tumor in the same
paraneoplastic effects, but small-cell carcinoma patient.
of the lung is most common. In the majority of
cases the underlying cancer is undetectable at
the time the neurological symptoms present, so Clinical Features
the diagnosis can be difficult.60 The discovery
of antineuronal antibodies not only provides a CEREBELLAR DEGENERATION
diagnosis for the neurotologic symptoms but The clinical symptoms and signs of patients with
also may direct the search for a specific cancer paraneoplastic cerebellar degeneration are
type. similar to those of patients with other diffuse
Table 13–2 Antineuronal Antibody Paraneoplastic Disorders

Antibody Associated Syndrome Brain Antigen Onconeuronal
Cancer Antigen
Anti-Hu SCLC and Encephalomyelitis, All neuronal nuclei, HuD, HuC,
neuroblastoma sensory neuropathy 35–40 kDa Hel-Nl
Anti-Yo Gynecologic and Cerebellar ataxia Cytoplasm Purkinje CDR34, CDR62-1,
breast cells, 34 and 62 kDa CDR62-2
Anti-Ri Breast, Cerebellar ataxia, Neuronal nuclei CNS, NOVA1, NOVA2
gynecologic, opsoclonus 55 and 80 kDa
and SCLC
Antiamphiphysin Breast Stiff-person, Synaptic vesicles, Amphiphysin
encephalomyelitis 128 kDa
Anti-Ma Multiple Cerebellar ataxia, Neuronal nuclei and Mai, Ma2
brain stem cytoplasm, 37 and
dysfunction 40 kDa
Anti-Ta Testicular Limbic encephalitis, Neuronal nuclei and Ma2
brain stem cytoplasm, 40 kDa
dysfunction
Anti-Tr Hodgkin’s Cerebellar ataxia Cytoplasm neurons, Unknown
lymphoma Purkinje cells, spiny
dendrites
Anti-CV2 SCLC and others Encephalomyelitis, Glia (subset), 66 kDa POP66
cerebellar ataxia
Anti-GAD Multiple Stiff-person, Glutamic acid Unknown
Cerebellar ataxia decarboxylase
Anti-VGKC Multiple Encephalomyelitis Voltage gated potassium Unknown
channels
CNS, central nervous system; SCLC, small cell lung cancer.
Source: Data modified from Dalmau and Posner.61
cerebellar lesions. The trunk and extremities associated with anti-Yo, anti-Hu, and anti-Tr
are ataxic and the speech is usually slurred. The antibodies. 63
course is subacute but can be fulminant. Often
intractable nausea and vomiting occur early.
OPSOCLONUS
Most patients are nonambulatory within 2-4
months from the onset of symptoms.62 Less A dramatic neurophthalmologic paraneoplastic
commonly patients can remain ambulatory syndrome is the opsoclonus-myoclonus syn-
throughout the course.62 After about 6 months drome.66 This disorder is characterized by cha-
the symptoms generally stabilize. 63 All types of otic conjugate eye movements in all directions,
spontaneous nystagmus are seen, but downbeat along with myoclonus of the trunk and limbs. It
nystagmus is most specific for cerebeller involve- is usually seen in children with neuroblastoma,
ment.64,65 Gaze-evoked and rebound nystagmus although it also occurs in adults with occult
are also common. Eye movement recordings malignancies in the lung, ovaries, uterus, and
document impairment of smooth pursuit, opto- breast. With opsoclonus, conjugate saccades
kinetic nystagmus, and fixation-suppression of occur continuously in all directions, often with
vestibular nystagmus. Saccades may be dysmet- torsional components.65 Eye movement record-
ric, but peak velocity remains normal. Vestibular ings document that the saccades have normal
responses are normal or hyperactive. peak velocity for their amplitude.
Patients with anti-Ri antibodies may have a
less severe course (less likely to have nystag- ENCEPHALOMYELITIS
mus and more likely to be ambulatory) and also
a better outcome when compared to patients Paraneoplastic encephalomyelitis can present
with paraneoplastic cerebellar degeneration with a wide range of central and peripheral
nervous system symptoms and signs.67 The optimal method to search for a primary
Involvement of the limbic system in the medial malignancy is not clearly defined and can vary
temporal lobes results in a combination of per- from patient to patient depending on the clini-
sonality change and memory deficits. Brain cal scenario and available resources. In addi-
stem involvement can lead to prominent ver- tion, the ultimate value of the tests used to
tigo, nausea, and vomiting, with involvement of search for a malignancy (i.e., how having the
oculomotor pathways causing strabismus and tests impacts meaningful patient outcomes)
nystagmus. Cranial and peripheral nerves are has not been defined. In most cases, the initial
also commonly involved, leading to a combina- imaging test is a whole-body computed tomog-
tion of central and peripheral signs. Often raphy (CT) scan. If no mass is identified or if
peripheral sensory nerves are involved to a uncertainty about the etiology of an identified
much greater extent than motor nerves. Cases mass exists (e.g., benign pulmonary nodule ver-
have been reported with a combination of sus lung cancer), then fluoro-2-deoxy-glucose
encephalomyelitis and inner ear involvement, (FDG) positron emission tomography (PET)
also possibly secondary to a paraneoplastic scan is typically the next step. In some cases, it
immune-based mechanism, but so far no anti- may be reasonable to order a CT scan and PET
bodies directed at the specific inner ear anti- scan simultaneously.71 The studies of body
gens have been identified.68,69 imaging to search for cancers in paraneoplastic
presentations are all small cases series (10–80
patients) and have demonstrated concerning
Diagnosis false-positive rates (typically infection or
inflammation on PET scans, benign nodules on
Although the role of the antibodies listed in CT scans) and also false-negative rates (partic-
Table 13–2 in the pathogenesis of the different ularly for small gynecologic cancers on CT
paraneoplastic syndromes is still unclear, iden- scans, and slow-growing or very small tumors
tification of these specific antibodies in the on PET scans).71 False-positive and false-nega-
clinical laboratory can help lead to a diagno- tive results may stem from suboptimal validity
sis.61 Any patient with subacute cerebellar of the tests for malignancy in these presenta-
degeneration should be examined carefully for tions or from suboptimal reliability (e.g., inter-
an occult malignancy. Antineuronal antibodies observer agreement) of the interpretation of
are identified in about 50% of patients with test results.
paraneoplastic cerebellar degeneration. The Even if an antibody is not detected in the
most specific antibody is the anti–Purkinje cell serum, imaging studies of the body may still
antibody found in women with gynecological identify an occult neoplasm in patients with the
tumors (the anti-Yo antibody).70 With immuno- symptom complex suggestive of a paraneoplas-
histochemical staining, this antibody binds to tic disorder.72 However, the false-positive rate
the Purkinje cell cytoplasm, producing a char- of imaging studies is likely to be higher in the
acteristic “ring of pearls” on microscopic exam- absence of a positive antibody test.
ination of the cerebellum. It is so specific for Neuroimaging studies in patients with
gynecological tumors that surgical exploration paraneoplastic cerebellar degeneration are
of the pelvis is indicated in any woman with the usually normal early in the course, although
antibody, even without an obvious malignancy, occasionally there can be mild cerebellar atro-
regardless of the outcome of other diagnostic phy. Cerebrospinal fluid (CSF) examination
studies. A subgroup of adults with opsoclonus may show a mild pleocytosis and elevated
and cerebellar ataxia (primarily truncal) has an gamma globulin synthesis or may be completely
antineuronal antibody called anti-Ri. Nearly all normal.60
of these patients have cancer of the breast. The
antineuronal nuclear antibody (anti-Hu) is
most commonly associated with small-cell lung Management
cancer and either a sensory neuropathy and/or
encephalomyelitis. The first goal is to identify and remove the under-
If an antibody is detected, then the next lying cancer. Although infrequent, there are case
step is to search for the primary malignancy. reports of dramatic clinical improvement after
resection of the tumor. Regardless, the best onset usually in the third and fourth decades of
chance to stabilize symptoms is when the cancer life.76 The key to the diagnosis is finding dis-
can be effectively treated.63,73 Most patients reach seminated signs of CNS dysfunction mani-
a “burnt-out” or plateau stage within 6 months fested in an alternating remitting and exacer-
where they remain with a moderate to severe bating course. Although the cause is still not
neurologic deficit.63 We have followed a woman definitely known, the characteristic findings at
with paraneoplastic cerebellar degeneration for pathology, the similarity with known autoim-
more than 25 years after a fallopian tube cancer mune animal models, and the response to
was removed. Exploratory surgery was initiated immunomodulatory and immunosuppressive
after anti-Purkinje antibodies (anti-Yo) were iden- therapies all suggest that the disorder is auto-
tified in her serum. Despite complete removal of immune in nature. Auditory and vestibular
the tumor and tumor markers returning to nor- symptoms are common in patients with MS
mal, her clinical examinations remain relatively and not infrequently they are the presenting
unchanged. She continues to have severe ataxia of symptoms.77–79
the trunk and extremities, although her nausea
and vomiting have markedly diminished.
Plasmapheresis and immunosuppression are Pathophysiology
frequently tried but only rarely associated with
an improvement.62,63 In occasional cases, par- The demyelination in MS is confined to CNS
ticularly in patients with opsoclonus, dramatic myelin—the myelin produced by oligodendro-
improvement has been reported.65 However, gliocytes. Peripheral nerve myelin produced by
unlike the cerebellar symptoms and signs Schwann cells is minimally affected. Because
associated with paraneoplastic cerebellar both peripheral and cranial nerves contain
degeneration, spontaneous remissions are CNS myelin at their root entry zones, a demy-
more common with paraneoplastic opsoclonus. elinated plaque involving the root entry zone
Exacerbations can occur months after remis- may produce signs of peripheral nerve dysfunc-
sion. Clonazepam has been reported to improve tion. Next to the first and second cranial nerves,
opsoclonus in some adults,74 but many do not the eighth cranial nerve has the largest propor-
respond to this medication. tion of CNS myelin, perhaps making it particu-
Rituximab has increased interest as a poten- larly susceptible to the effects of MS.80 Plaques
tial treatment for the paraneoplastic neurologic involving the vestibular and auditory root entry
symptoms because beneficial effects have zones can explain the frequent finding of uni-
been presumed in individual patients.75 lateral caloric hypoexcitability and hearing loss
However, any effect has generally been small. in patients with MS.79,81,82 In typical demyeli-
Furthermore, one must also consider that the nated plaques, most of the myelin sheaths are
natural history of paraneoplastic disorders is a destroyed and those that remain become swol-
symptomatic plateau which could easily be len and fragmented. The axis cylinders and
misinterpreted as a treatment effect. There are neurons are relatively spared so that conduc-
ongoing early-phase trials of medication treat- tion of nerve impulses still occurs but at a
ments in paraneoplastic syndromes, including decreased frequency and rate. Whether the
tacrolimus (Clinicaltrials.gov identifier remissions and exacerbations of symptoms and
NCT00378326) and rituximab in pediatric signs are related to repair of demyelinated
patients with opsoclonus-myoclonus syndrome regions or changes in the physiology of nerve
(Clinicaltrials.gov identifier NCT00244361). conduction unrelated to demyelination is cur-
rently debated. It has been repeatedly shown,
however, that there is a poor correlation
between the clinical symptoms experienced
MULTIPLE SCLEROSIS during life and the pathologic findings at
necropsy.
Background The initial areas of demyelination seem to be
dependent on T cell infiltration into the CNS.83
Multiple sclerosis (MS) is a demyelinating dis- However, as the lesions expand, other mecha-
ease of the central nervous system (CNS) with nisms may come into play, including activation
of CNS glial and microglial cells. In the animal Diagnosis

model for MS, autoimmune allergic encephalo-
myelitis sensitization to myelin proteins such as The findings on examination in a patient with
myelin basic protein (MBP) leads to an infiltra- MS are as diverse as the symptoms. In most
tion of the CNS by activated T cells that start long-standing cases, there are signs of involve-
the demyelinating process. There is a clear ment of the pyramidal tracts (hyperreflexia,
genetic component to developing MS that may extensor plantar responses), cerebellum (inten-
be related both to factors in the immune system tion tremor, ataxia, slurred speech), sensory
and in target CNS antigens.84 In vitro, oligoden- tracts (impaired vibratory and position sense),
drogliocytes express major histocompatibility and visual pathways (decreased visual acuity
complex (MHC) class 1 molecules and are sus- and pallor of the optic disc). The finding of dis-
ceptible to CD8 (positive plus) T cell–mediated sociated nystagmus on lateral gaze or acquired
cytotoxicity. Oligodendrogliocyte-specific anti- spontaneous pendular nystagmus is particularly
bodies can be identified in MS lesions and could helpful in the diagnosis of MS because these
induce injury by a complement-dependent are common with MS and are relatively unusual
mechanism. Oligodendrogliocytes are also sus- in other disease processes.89,90 All varieties of
ceptible to injury mediated by nonspecific positional nystagmus can be seen with MS and
immune cell mechanisms, such as through the caloric examination is abnormal in about a
cytokines. quarter of patients.91 Pure-tone hearing levels,
when abnormal, have no characteristic pattern
with MS. Special audiometric studies (speech
Clinical Features discrimination, tone decay, acoustic reflex)
indicate a neural site for the lesion. Brainstem
Although many symptoms occur with MS, cer- auditory-evoked responses (BAER) can be
tain ones deserve emphasis because of their used to detect subclinical lesions in MS, even
consistent appearance. Blurring or loss of vision when hearing is normal (see Chapter 8).92
caused by demyelination of the optic nerve Vestibular evoked myogenic potentials
(retrobulbar or optic neuritis) is an initial (VEMPs) are abnormal in about a third of
symptom of MS in about 20% of patients. patients with MS.93,94 This is the only vestibular
Diplopia, weakness, numbness, and ataxia test able to detect dysfunction within central
also occur early in the disease process. Vertigo vestibular pathways (see Chapter 7).
is the initial symptom in about 5% of patients No specific laboratory test for MS exists, but
and is reported some time during the disease abnormalities in the CSF can be identified in
in as many as 50%.76 Hearing loss occurs in about 80% to 90% of patients at some time in
about 10% of patients. No apparent relation- the disease course. These findings include
ship exists between the severity or duration of elevated gamma globulin, increased gamma
MS and the hearing loss; auditory impairment globulin synthesis, oligoclonal banding of
may be part of the initial episode or may occur gamma globulin, and elevated MBP.
more than 10 years after the onset.79,85,86 The Unfortunately, none of these findings are spe-
hearing loss can be acute (hours to a few days), cific for MS. Magnetic resonance imaging is
subacute (over months), or insidious in onset. currently the gold standard for identifying
Partial or complete remission after onset of demyelinating lesions with MS (Fig. 13–2). T2-
hearing loss is common. A typical bout of ver- weighted and FLAIR images will show charac-
tigo associated with MS lasts from hours to teristic white matter plaques in about 95% of
days, although positional vertigo lasting patients with MS, although similar lesions are
seconds is also common. Multiple sclerosis sometimes seen in patients without the clinical
can mimic vestibular neuritis, benign positional criteria for the diagnosis of MS.95,96
vertigo, and sudden deafness.82,86,87 Benign
positional vertigo is common even in patients
with MS, so this treatable cause of positional Management
vertigo should always be considered even
in patients with a clear central disorder such Steroids and adrenocorticotropic hormone may
as MS.88 hasten the remission of symptoms and signs
Figure 13–2. Magnetic resonance image demonstrates typical multiple sclerosis white matter lesions including ovoid
peri-ventricular and juxta-cortical lesions.
after an acute exacerbation with MS, but no if the presentation does not suggest a paraneo-
evidence indicates that these drugs alter the plastic disorder or MS. The case for an immune-
natural history.97,98 Immune modulation with based attack can be supported by serum
interferon-beta (IFN-β) and glatiramer acetate autoantibodies that have been associated with
have been shown to decrease the frequency subacute ataxia presentations or by CSF stud-
and severity of exacerbations with MS, although ies indicating an immune-based response.
it is still unclear which of these drugs is best.99,100 Serum autoantibodies not associated with a
Side effects tend to be more prominent with cancer have been found in patients with subacute
IFN-β and include flu-like syndromes, tachy- cerebellar ataxia presentations. In these situa-
cardia, headache, myalgias, and gastrointestinal tions, it is presumed that the antibodies
disorders. Neurological toxicity includes gen- developed spontaneously or in response to a
eral fatigue along with behavioral and cognitive noncancerous antigen and are attacking the cer-
changes. These latter symptoms may impair ebellum. Though the causal relationship is tenu-
quality of life and result in treatment discon- ous, the case that these antibodies are involved in
tinuation. Autoantibodies often develop in the immune-based attack is typically supported
patients on chronic IFN-β treatment and these by CSF pleocytosis, oligoclonal bands, increased
antibodies may not only interfere with treat- IgG index, and at times even immunohistochem-
ment but may also be associated with systemic istry. The main problem with the argument that
autoimmune symptoms in rare cases.101 the specific autoantibodies are causing the ataxia
is that most of the identified antibodies also occur
OTHER IMMUNE-MEDIATED in the general population. This is different than
DISORDERS the paraneoplastic autoantibodies, which are
extremely rare to find outside of the specific neu-
If a patient presents with subacute or fulminate rologic presentations.
progressive cerebellar ataxia, then an immune- Probably the most widely reported, biologi-
mediated disorder should be considered even cally plausible, and thus convincing evidence of a
specific antibody association with a nonparaneo- REFERENCES

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Chapter 14
Vascular Disorders
VERTEBROBASILAR ISCHEMIA HEMORRHAGE INTO THE BRAIN STEM

Pathophysiology AND CEREBELLUM
Transient Ischemic Attacks (TIAs) Diagnosis and Management
Stroke Syndromes VASCULAR COMPRESSION SYNDROMES
Diagnosis Vertebrobasilar Dolichoectasia
Treatment Vascular Compression by Normal Vessels
INTRALABYRINTHINE HEMORRHAGE (Vestibular Paroxysmia)
Diagnosis and Management Rotational Vertebral Artery Syndrome
VERTEBROBASILAR ISCHEMIA emboli, and penetrating small-vessel disease.1

Other less common causes include dissection,
Pathophysiology fibromuscular displasia, arteritis, polycythemia,
thromboangiitis obliterans, and hypercoagula-
As discussed in Chapter 2, the vascular supply to tion syndromes. In rare cases, occlusion or
the labyrinth, eighth nerve, brain stem, and cer- stenosis of the subclavian or innominate arter-
ebellum arises from a common source: the verte- ies just proximal to the origin of the vertebral
brobasilar circulation. The vestibular system is artery results in the so-called subclavian steal
subject to two general categories of vascular isch- syndrome. In this syndrome, VBI results from
emia: (1) hypoperfusion in the vertebrobasilar siphoning of blood down the vertebral artery
system, in which case multiple areas (both periph- from the basilar system to supply the upper
eral and central) become simultaneously isch- extremity. Occasionally, episodes of VBI are
emic, or (2) hypoperfusion in the distribution of a precipitated by postural hypotension, Stokes-
single smaller feeding vessel, in which case there Adams attacks, or mechanical compression
is a circumscribed area of ischemia. In the former from cervical spondylosis. Cervical spondylosis
case the site of origin of hypoperfusion can be is extremely common in the elderly, but docu-
anywhere from the heart and major vessels in the mented cases of mechanical compression of
chest and neck to the basilar artery, whereas in the vertebral arteries by neck turning or exten-
the latter case an occlusion is usually situated near sion are rare (see later discussion).
the origin or, less frequently, in the smaller feed- Vertigo is the most common symptom of
ing vessel itself. These two categories of ischemia VBI, but it is not always clear which structure
are not mutually exclusive, however; a patient or combination of structures is ischemic.2
with small-vessel disease may be as asymptomatic When vertigo is accompanied by other symp-
because of collateral circulation, but an added toms of brainstem ischemia (e.g., slurred
hypoperfusion in the vertebrobasilar system can speech or a brainstem pattern of motor/sensory
lead to focal ischemia and or infarction. symptoms), one can reasonably assume that
The most common causes of vertebrobasilar the vertigo is the result of ischemia of the
ischemia (VBI) are large-artery atherosclerosis, vestibular nuclei in the lateral medulla or the
319
complex system of vestibular pathways in the Often these brainstem syndromes occur with-
brain stem. Similarly, if the vertigo is accompa- out associated cerebellar infarction because of
nied by typical symptoms of cerebellar the anastomotic channels between the cerebel-
dysfunction, it likely results from ischemia lar arteries. Isolated cerebellar infarction in the
to the cerebellum. Isolated episodes of distribution of the superior, anterior inferior,
vertigo are more difficult to explain on this or posterior inferior cerebellar arteries usually
basis, however. The anatomy of the vasculature indicates an embolic source.13,14 Emboli typi-
to the brain stem does not explain selective cally migrate to the most distal arterial branch—
ischemia to the vestibular nucleus with sparing in this case, the cerebellar branches. Patchy
of surrounding structures. Even if the vestibu- areas of infarction in the cerebellum occurring
lar nuclear neurons are more sensitive to isch- at the junctions of the three major arteries may
emia than surrounding structures, one would indicate hypoperfusion within the entire poste-
expect only a relative difference in sensitivity, rior circulation, resulting in “watershed infarc-
not a complete sparing of surrounding struc- tions.”15,16 These types of infarctions can also be
tures. On the other hand, ischemia to the cer- seen with diffuse vasospasm associated with
ebellum, particularly to the vestibulocerebel- basilar migraine.
lum, could result in selective vertigo and
imbalance and might mimic a peripheral ves-
tibular disorder.3
Isolated episodes of vertigo can also result Transient Ischemic Attacks (TIAs)
from transient ischemia to the vestibular laby-
rinth.4 Because the labyrinthine circulation is Transient ischemia within the vertebrobasilar
an end circulation with minimal collaterals system is a common cause of episodic vertigo
from the otic capsule, the labyrinth is especially in older patients. It is typically abrupt in onset,
vulnerable to ischemia. Possibly, because of usually lasting several minutes, and is fre-
the small caliber of the anterior vestibular quently associated with nausea and vomiting.
artery (see Fig. 2–9 in Chapter 2) and the gen- In their classical description of TIAs within the
eral lack of collateralization, the superior part vertebrobasilar circulation, Williams and
of the vestibular labyrinth is selectively vulner- Wilson17 reported that vertigo was the initial
able to ischemia.5 One would expect ischemia symptom in 48% of patients. Invariably, the
to the labyrinth to be accompanied by hearing vertigo is associated with symptoms resulting
loss, but patients may simply be unaware of a from ischemia in the remaining territory sup-
transient, mild, unilateral hearing loss when it plied by the posterior circulation (those listed
is accompanied by a severe attack of vertigo.7 in Table 14–1). Next to vertigo, visual symp-
Infarction in the distribution of the posterior toms are most common. Associated symptoms
inferior cerebellar artery (PICA) or the ante- occur in episodes, either in combination with
rior inferior cerebellar artery (AICA) is invari- the vertigo or in isolation.
ably associated with severe vertigo, nausea, and Fisher’s classic paper on this topic18 is
vomiting. The full-blown syndromes are easily remembered for emphasizing that episodes of
recognized on the basis of the highly localized vertigo without other neurologic symptoms is
neurologic signs,3,6 but there might be more strongly suggestive of a disorder other than
difficulty localizing the lesion to these distribu- VBI. However, among his cases of VBI, he
tions in the case of a partial syndrome. Infarction described several patients who manifested
in the lateral medullary region in the distribu- isolated episodes of vertigo at some time
tion of PICA is usually associated with throm- during their course. Fields and Weibel19
bosis of the ipsilateral vertebral artery proximal also described several patients with isolated
to the take-off of PICA.1,8 Traumatic dissection episodes of vertigo and VBI. We reviewed
of the distal vertebral artery is a common cause the clinical findings of 42 patients who pre-
of lateral medullary infarction in younger sented to our neurotology clinic with vertigo
patients.9–11 Infarction in the lateral pontomed- due to VBI in 1989.4 The diagnosis was based
ullary distribution of the AICA is usually on their having at least some episodes with a
associated with occlusive disease of the distal characteristic combination of symptoms (those
vertebral artery and proximal basilar artery.7,12 listed in Table 14–1). There was a surprisingly
14 Vascular Disorders 321
Table 14–1 Frequency of Symptoms Stroke Syndromes

Associated with Vertigo in 42 Patients
with Vertebrobasilar Insufficiency LABYRINTHINE INFARCTION
Occlusion of the internal auditory artery leads
Symptom Patients
to a sudden profound loss of both auditory
Visual (diplopia, visual illusions and 29 and vestibular function. Hearing loss is usually
hallucinations, field defects, etc.) permanent, and a vestibular imbalance
Drop attacks 14 remains, although symptoms of dizziness and
Unsteadiness, incoordination 9 imbalance gradually improve with central
Extremity weakness 9 compensation. Pathological studies in such
Confusion 7 patients show widespread necrosis of the inner
Headache 6 ear tissues with subsequent proliferation
Hearing loss 6 of fibrous tissue and new bone formation.24
Loss of consciousness 4 Most documented cases have been associated
Extremity numbness 4 with ischemia in the distribution of the
Dysarthria 4 AICA, accompanied by infarction of the brain
Tinnitus 4 stem and/or cerebellum.25 Not infrequently,
Perioral numbness 2 infarction of the labyrinth is preceded by epi-
Source: Data from Grad and Baloh.4 sodes of transient ischemia within the verte-
brobasilar system, in some cases, manifested by
isolated episodes of vertigo.7 The diagnosis
high incidence of isolated episodes of vertigo in should be considered in patients with impor-
these patients; 62% had at least one isolated tant risk factors for stroke who present with
episode of vertigo and, in 19%, their TIAs sudden onset of unilateral deafness and
began with an isolated episode of vertigo. These vertigo, particularly if there is a history of
patients with isolated episodes of vertigo TIA, stroke, or known atherosclerotic vascular
also reported the same vertiginous sensation disease.
in combination with other symptoms at The role of vascular occlusion in producing
other times, which suggests that the vertigo sudden one-sided deafness without associated
was indeed due to transient ischemia with vertigo is unclear. There is little reason to sus-
the posterior circulation. Subsequently, there pect that unilateral deafness in a young, healthy
have been many other reports emphasizing patient is caused by vascular disease. As noted
that isolated attacks of vertigo can be the in Chapter 9, most of these cases are probably
only manifestation of a TIA within the verte- due to isolated viral infections. However, the
brobasilar system.20–22 As suggested earlier, it sudden onset of deafness without associated
is still unclear whether these isolated episodes vertigo or brainstem signs in a patient with
of vertigo originate from the brain or inner known vascular disease or a hypercoagulation
ear. As a general rule, vertigo may be an syndrome should raise the suspicion for
isolated initial symptom of VBI or may occur ischemia within the distribution of the com-
in isolation intermixed with more typical mon cochlear artery or one of its branches (see
episodes, but VBI becomes extremely Fig. 2–9 in Chapter 2).25 Sudden deafness
unlikely whenever recurrent episodes date (reversible or permanent) has been reported
back more than 3 months and are unaccompa- in patients with fat emboli,26 thromboangiitis
nied by other focal neurologic symptoms.1 obliterans,27 and macroglobulinemia.29 Athero-
However exceptions even to this more gener- sclerotic disease is also associated with
ous rule do occur. In fact, we reported a patient sudden deafness, but pathological confirmation
having hundreds of attacks of vertigo and uni- of the site of vascular occlusion is often
lateral tinnitus over a 2-year period who was lacking.28 Examination of the cochlea at
found to have a severe stenosis of the basilar necropsy in such patients reveals a loss of the
artery just proximal to AICA.23 A stent was organ of Corti and degeneration of the stria
placed to open the stenosis and resulted in vascularis, spiral ligament, and distal cochlear
resolution of the attacks. nerve fibers (findings similar to those seen in
animals that have had their labyrinthine artery cochlear artery, it may be spared even though
occluded).24 the superior part of the vestibular labyrinth is
Ischemia that is confined to the anterior ves- completely infarcted.5,32
tibular artery distribution (see Fig. 2–9 in
Chapter 2) can result in transient episodes of LATERAL MEDULLARY INFARCTION
vertigo (lasting minutes) or a prolonged
attack (lasting days) due to infarction of the The zone of infarction producing the lateral
vestibular labyrinth.5,22 The former may be medullary syndrome (Wallenberg’s syndrome)
associated with hyperviscosity syndromes such consists of a wedge of the dorsal lateral medulla
as hyperlipidemia, polycythemia, macroglobu- just lateral to the olive (Fig. 14–1). Although
linemia, and sickle cell anemia.30,31 The clinical the syndrome is commonly known as that of
picture of infarction in the distribution of the the PICA, as noted earlier, it usually results
anterior vestibular artery is that of the acute from occlusion of the ipsilateral vertebral
vestibular syndrome (i.e., sudden, severe artery, and only rarely from occlusion of the
vertigo without hearing loss or brainstem PICA. In young patients, dissection of the ver-
symptoms),2 and as such cannot be distin- tebral artery is a common cause, particularly if
guished from vestibular neuritis. After recover- there is a history of trauma or neck manipula-
ing from the acute manifestations, patients tion.11,33–36 Symptoms may come on right at the
may develop episodes of typical benign time of the trauma or neck manipulation or
positional vertigo months or years later. The they may be delayed for several days. Major
positional vertigo presumably results from symptoms include vertigo, nausea, vomiting,
ischemic necrosis of the utricular macule, intractable hiccups, severe imbalance, ipsilat-
causing a release of otoconia that make their eral facial numbness and weakness, diplopia,
way into the long arm of the posterior semicir- dysphagia, and dysphonia. A dissection is typi-
cular canal. Since the posterior semicircular cally accompanied by occipital headache or
canal is supplied by a branch of the common neck pain.36 Lesions involving the mid-level of
Dorsal efferent tract of nerve X

Nucleus solitarius
Med. vestibular nucleus
Inf. vestibular nucleus
Lat. cuneate nucleus
Restiform body
Nucleus and root

Nucleus of of nerve V
nerve XII
Vent. spinocerebellar
Nucleus ambiguus tract
Root of nerve X
Medial
longitudinal
fasciculus
Lat. spinothalamic tract
Second ascending tract

of nerve V
Inferior olive
Pyramid
Medial lemniscus
Figure 14–1. Cross-section of the medulla illustrating the zone of infarction with Wallenberg’s syndrome (blue area).
Table 14–2 Mechanism of Symptoms and Signs Commonly Seen with Infarction in
the Distribution of Posterior Inferior and Anterior Inferior Cerebellar Arteries
Symptoms and Signs Structures Involved with PICA Structures Involved with
Infarct AICA Infarct
Vertigo, nystagmus Vestibular nuclei, posterior inferior Labyrinth, vestibular nerve,
cerebellum flocculus
Tinnitus, hearing loss None Cochlea, auditory nerve,
cochlear nucleus
Gait and limb ataxia Ventral spinocerebellar tract, posterior Middle cerebellar peduncle,
inferior cerebellum anterior inferior cerebellum
Dysphagia, decreased gag Vagal nuclei and nerve None
Facial hemianesthesia Fifth nerve and nucleus Fifth nerve and nucleus
Facial paralysis Seventh nerve Seventh nerve
Crossed hemisensory loss Spinothalamic tract Spinothalamic tract
Horner’s syndrome Descending sympathetic fibers Descending sympathetic fibers
AICA, anterior inferior cerebellar artery; PICA, posterior inferior cerebellar artery.
the lateral medulla produce a characteristic affects the oculomotor system, causing exces-
combination of symptoms, including vertigo, sively large voluntary and involuntary saccades
nausea, vomiting, hiccups, and dysphagia.37 directed toward the side of the lesion, whereas
Neurological examination identifies multiple saccades away from the lesion side are abnor-
signs localizing to the lateral medulla (Table mally small.43,44
14–2). The spontaneous nystagmus is typically
horizontal-torsional with an increase in the
horizontal component on gaze toward the side LATERAL PONTOMEDULLARY
of the lesion and often a change in the direc- INFARCTION
tion of the horizontal component with gaze
away from the side of the lesion. Patients also Ischemia in the distribution of the AICA
may exhibit a transient ocular tilt reaction (ipsi- usually results in infarction of the dorsolateral
lateral head tilt, skew deviation, and ocular tor- pontomedullary region and the middle
sion, upper pole of the eye rotated toward the cerebellar peduncle (Fig. 14–2).6,7 As noted
side of the lesion) that is associated with a devi- earlier, because the labyrinthine artery arises
ation of the subjective visual-vertical in the from the AICA in most cases, infarction of the
direction of the head tilt.38 Even with their membranous labyrinth is a common accompa-
heads fixed in the true vertical, they perceive it niment. Severe vertigo, nausea, and vomiting
as tilted opposite the direction of the tilt reac- may be the initial and most prominent symp-
tion. This phenomenon results from involve- toms. The key difference between the lateral
ment of the otolith-ocular pathways at the level medullary syndrome and the lateral pontomed-
of the vestibular nucleus.39 Two distinct pat- ullary syndrome is that the latter is typically
terns of otolith dysfunction are seen depending associated with a profound unilateral or bilat-
on whether the cerebellar nodulus is involved. eral hearing loss that can be the result of infarc-
If the nodulus is infarcted, there is ocular tor- tion of the labyrinth, eighth nerve, or even the
sion and skew deviation with falling and tilt of eighth nerve root entry zone into the brain
the subjective visual vertical to the contrale- stem. Sudden unilateral or bilateral hearing
sional side. If the nodulus is spared, falling and loss and vertigo can be the initial or sole mani-
tilt of the subjective visual vertical is ipsilateral festation of AICA infarction.45,46 Neurological
without ocular torsion and skew deviation.40 examination typically reveals a profound
Patients with Wallenberg’s syndrome often unilateral hearing loss, unilateral facial paraly-
suffer a prominent motor disturbance that sis, cerebellar ataxia, and ipsilateral loss of pain
causes them to deviate toward the side of the and temperature sensation on the face due to
lesion as if being pulled by a strong external involvement of the trigeminal nucleus and
force.41,42 This so-called lateropulsion also tract, and a contralateral decrease in pain and
A PCA B
SCA 4th
ventricle V
MCP
VIII
IAA VI
AICA 2
1B
1A
1 3
PICA PICA-AICA
anastamosis VIII Flocculus
VA
C D
AICA
2
IAA ASC
AVA Flocculus
CCA
Saccule 1
HSC
3
PSC
Paraflocculus Nodulus
Cochlea
Figure 14–2. A Classical anterior inferior cerebellar artery (AICA) anatomy with AICA and posterior inferior cerebellar
artery (PICA) of equal dominance. Numbers refer to the three zones of AICA supply shown in B, C, and D. Zone 1 is sup-
plied by the recurrent penetrating arteries (RPA) off AICA, zone 2 by the internal auditory artery (IAA), and zone 3 by
the terminal cerebellar branches of AICA. B Zones 1A and 1B represent the arterial supply to the rostral pons supplied
by a premeatal and postmeatal RPA. The cross-hatched area represents the root entry zone of the facial and vestibuloco-
chlear nerves. C Zone 2 represents the arterial supply to the inner ear. D Zone 3 is the part of the cerebellum supplied by
AICA. ASC, anterior semicircular canal; AVA, anterior vestibular artery; CCA, common cochlear artery; HSC, horizontal
semicircular canal; MCP, middle cerebellar peduncle; PCA, posterior cerebral artery; PSC, posterior semicircular canal;
SCA, superior cerebellar artery; VA, vertebral artery; V, spinal trigeminal tract and nucleus; VI, abducens nucleus; VII,
facial nerve; VIII, vestibulocochlear nerve.
temperature sensation on the body due to CEREBELLAR INFARCTION

involvement of the crossed spinothalamic tract
Acute cerebellar infarction may present with
(Table 14–2).
prominent vertigo, vomiting, and ataxia;
Branches of the AICA supplying the ventro-
because typical lateral brainstem signs are not
lateral pons have few anastomoses with adja-
present, a mistaken diagnosis of an acute
cent vessels. By contrast, the root entry zones
peripheral labyrinthine disorder might be
of the seventh and eighth cranial nerves have a
made.3,47,48 We do not know the true proportion
rich network of anastomotic vessels arising
of patients with isolated vertigo who harbor an
from the lateral medullary artery, AICA, and
ischemic stroke because there is no large series
the inferior lateral pontine artery. Thus, occlu-
of such patients who all receive magnetic reso-
sion of the AICA reliably causes infarction of
nance imaging (MRI) with diffusion weight
the lateral pons and middle cerebellar pedun-
sequences. One of the first studies to attempt
cle, but because of collateral vessels, the root
to address this issue found that 25% (6 out
entry zone of the seventh and eighth nerves is
of 24) of patients with risk factors for stroke
often spared.7
who present to an emergency medical setting vestibular nuclei.51 In addition to supplying

with isolated severe vertigo, nystagmus, and the anterior inferior surface of the cerebellum,
postural instability had an infarction of the the AICA also supplies the flocculus and para-
inferior cerebellum, but diffusion-weighted flocculus, structures known to be critical for
images were not available at the time so the visual–vestibular interaction (see Fig. 14–2D).
acuity of the infarction could not be deter- Patients with infarction in the distribution of
mined.49 A more recent study using MRI with the superior cerebellar artery typically do not
diffusion-weighted imaging found that 75% present with vertigo or nystagmus but rather
(25/33) of patients with the acute vestibular severe ataxia and dysarthria.50,52 There are
syndrome had a causative stroke, most involv- reports though of rather mild imbalance (able
ing the cerebellum.50 However, this study only to stand and walk unassisted, but not able to
included patients with at least one stroke risk walk in tandem) from a superior cerebellar
factor and also excluded patients with a recent stroke.50
viral illness, so that the population was at higher
risk of stroke etiology than the general popula-
tion of patients with acute vertigo.50 The key Diagnosis
features suggesting a cerebellar infarction
include prominent cerebellar signs, particu- CLINICAL EXAMINATION
larly severe truncal ataxia (i.e., inability to sit or
stand without assistance), and direction-chang- Vertebrobasilar ischemia can usually be diag-
ing gaze-evoked nystagmus (See Video 6–9). nosed with a careful history and examination.
Patients with peripheral vestibular disorders As discussed earlier, TIAs within the posterior
will have imbalance, even to the point of falling circulation typically present with the character-
when trying to walk during the acute phase, istic symptoms, even though occasionally, diz-
but they can sit unassisted and can typically ziness or vertigo occurs in isolation. Transient
stand unassisted.38,50 Nystagmus, in patients ischemic attacks typically come on abruptly,
with an acute peripheral vestibular disorder, without an apparent precipitating factor, last
does not change direction with changes in gaze for a few minutes, and then end abruptly, usu-
(See Video 6–4, Video 6–5, and Video 6–6). ally with minimal or no residual symptoms. The
Spontaneous down-beating nystagmus localizes abrupt spontaneous (nonpositional) onset and
the lesion to the caudal midline cerebellum minutes’ duration are not typical of any of the
(See Video 6–7). common inner ear disorders. The acute stroke
There are three major cerebellar arteries: syndromes within the posterior circulation are
posterior inferior, anterior inferior, and supe- usually easily identified on the basis of their
rior (Figs. 14–2A and 14–3A). After supplying characteristic combination of neurological
branches to the brain stem, each of these arter- symptoms and signs (Table 14–3). Although
ies supplies the part of the cerebellum cerebellar infarcts can masquerade as a more
indicated by its name. Typically, there are benign inner ear disorder, through a careful
prominent anastomoses between these three examination one should be able to identify pro-
cerebellar arteries on the cerebellar surface, so found truncal ataxia and a direction-changing
that occlusion near the take-off results only in gaze-evoked nystagmus, which do not occur
brainstem infarction with sparing of the cere- with inner ear lesions. The suspicion for a
bellum. There are also common anatomical cerebellar infarction also increases if uni-
variants, the most common being anterior infe- directional nystagmus is found but the head-
rior cerebellar dominance on one side and pos- thrust sign is negative.38,50,58 The history can
terior inferior cerebellar dominance on the provide risk factors for atherosclerosis, includ-
opposite side. The PICA typically has two ing a history of coronary artery disease, hyper-
major cerebellar branches—a medial branch tension, diabetes mellitus or hyperlipidemia,
and a lateral branch—with the former supply- and a family history of early-onset atheroscle-
ing midline structures, including the vermis. rosis. In young patients without obvious vascu-
Infarction in the territory of the medial lar risk factors, the history should focus on the
branch of PICA can mimic an acute peripheral possibility of trauma (including neck manipula-
vestibulopathy probably by interrupting tion) and other systemic illnesses that might
nodulouvular inhibitory projections to the predispose to hypercoagulation.
A Medial branch
of SCA
1
Lateral branch
of SCA
Superior 2
cerebellar
(SCA)
3
Basilar (BA)
5
Anterior inferior
6
cerebellar (AICA)
Vertical (VA) Lateral branch

Medial of PICA
Posterior inferior branch
cerebellar (PICA) of PICA
1 2 3
AICA
LSCA MSCA LSCA MSCA LSCA

MSCA
MPICA
4 5 6
AICA
AICA
LPICA
LSCA
LSCA MPICA MPICA
MSCA MPICA
Figure 14–3. A Branches of the three main cerebellar arteries. B Magnetic resonance imaging horizontal axial sections
from rostral to caudal (1 to 6) showing territory supplied by each branch. L, lateral; M, medial.
BRAIN IMAGING
the cerebellar hemispheres. Specific stroke
Magnetic resonance imaging is the procedure syndromes, such as the lateral medullary and
of choice for viewing brain structures supplied lateral pontomedullary syndromes, are all eas-
by the vertebrobasilar system.1,59,61 An MRI is ily identified with MRI (Figs. 14–4 and 14–5).
usually normal in patients with TIAs within the The typical appearance is a T2 and FLAIR
posterior circulation, although occasionally intense lesion within the brain stem in the
such patients show evidence of old, silent distribution of either the posterior inferior
infarcts, particularly in the occipital poles or or the anterior inferior cerebellar arteries.
Table 14–3 Differentiating among Common Acute Vertigo Syndromes

Syndrome Spontaneous Gait Other Possible Signs
Nystagmus
Acute peripheral Unidirectional, beats Falls toward lesion Unilateral hearing loss
vestibulopathy toward intact side side but can walk
Cerebellar infarction Usually changes Severe ataxia, may Scanning speech, extremity
direction with gaze not be able to sit incoordination
or stand
Lateral medullary Usually changes Falls toward lesion Decreased gag reflex, ipsifacial
infarction direction with gaze side, may not be numbness, ipsi-incoordination,
able to walk ipsi-Horner’s syndrome,
hypophonia
ipsi, ipsilateral.
Diffusion-weighted images (DWIs) may show not enhance with contrast. The territories sup-
abnormalities in the first few hours after the plied by the different cerebellar artery branches
acute stroke syndrome that will not show up on are shown in Figure 14–3B. The sensitivity of
T2-weighted MRI scans for several hours.60 computed tomography (CT) scan for acute
However, even DWIs can give false-negative infarction is extremely low, meaning that a neg-
images in the first 24–48 hours after infarc- ative result does not alter the probability of
tion.38,50,61–63 Typically, areas of infarction do infarction in a meaningful way.61 CT scans can
Figure 14–4. Magnetic resonance images showing infarction in the lateral medulla (PICA territory) (A) and in the pontine
cerebellar peduncle (AICA territory) (B). T2-weighted axial sections.
Figure 14–5. Posterior inferior cerebellar artery (PICA) acute strokes. A variety of PICA infarctions are seen from four
different patients. Arrows point to the region of infarction. A, shows a small discrete acute stroke on a diffusion weighted
image (DWI) sequence; B, shows a large PICA stroke on a DWI sequence; C, show a midline PICA infarction on a fluid-
attenuated inversion-recovery sequence; and D, shows a very small acute stroke on DWI.
be useful in monitoring for swelling in the in the aortic arch. Amarenco and colleagues64
posterior fossa once the diagnosis of infarction identified echogenic masses in the aortic arch
has been made. on TEE in 6 of 12 patients with posterior circu-
Deciding which patients with acute pro- lation infarcts of unknown cause. Ultrasound
longed vertigo should be considered for an studies of the neck (duplex scanning and
MRI can be difficult. However the probability Doppler) can identify an occlusion of the ver-
of an infarction is extremely low when there is tebral arteries within their bony canal that may
unidirectional horizontal nystagmus, a corre- be a source of artery-to-artery emboli within
sponding positive head-thrust test, and no the posterior circulation.65 Through transcra-
other neurologic signs or symptoms. Red flags nial doppler (TCD) imaging, one can assess the
for a stroke include any pattern of nystagmus intracranial vertebral arteries, but TCD is less
other than unidirectional horizontal nystagmus, accurate for identifying lesions in the basilar
normal head-thrust test (indicating the periph- artery. TCD is not useful for assessing small
eral vestibular system is intact), inability to sit branches of the vertebrobasilar system. More
unassisted, and substantial risk factors for than any of the other ultrasound studies, TCD
stroke. Red flags for transient ischemic attacks reliability is highly dependent on the skill of
include new onset spontaneous episodes last- the performing technician.
ing minutes and a crescendo pattern.
ANGIOGRAPHY
ULTRASOUND
Magnetic resonance angiography (MRA) is the
Ultrasound studies of the heart and great ves- procedure of choice for assessing the verte-
sels are used to search for an embolic source in brobasilar circulation.1,59 Overall, there is a
patients with TIAs or stroke of presumed good correlation between MRA and conven-
embolic origin.1 Echocardiography is used to tional angiography, although MRA is relatively
search for mural thrombi and can also detect limited for evaluating smaller branches within
cardiac septal defects that allow direct commu- the vertebrobasilar system. Depending on ana-
nication between the left and right heart tomical variations and the positioning of the
chambers. Transesophageal echocardiography subject, the distal vertebral artery–basilar
(TEE) is useful for identifying embolic sources artery junction may be difficult to visualize
adequately. The neuroradiologist should be migraine headaches are at greater risk for
alerted in advance when it is important to visu- developing vasospasm.
alize these structures so that the technician can
properly position the patient. High-quality CT
angiography (CTA) is also a method for imag- Treatment
ing the posterior circulation and can be used in
place of MRA, particularly if MR is contraindi- TRANSIENT ISCHEMIC ATTACKS
cated (e.g., patient with pacemaker).1 CTA is
particularly useful for evaluating patients with The urgency regarding any TIA is that 10%–15%
suspected basilar artery occlusion because CTA of patients diagnosed with this transient event
takes substantially less time than MRA. will suffer a completed stroke within 3 months,
Conventional contrast angiography is reserved and half of these occur within the first 48
for patients in whom the pathophysiology hours.66,67 It is not clear whether the risk of
remains unclear after MRA or CT angiography stroke is higher or lower for posterior circula-
(Figs. 14–6 and 14–7). tion TIAs compared with anterior circulation
The main risk of conventional angiography is TIAs.69 As a way to estimate the risk of future
a TIA or infarction within the distribution of stroke in individual TIA patients, the ABCD2
the injected vessel. The mechanism is usually score was developed and validated.67 To deter-
vasospasm, although pieces of atherosclerotic mine the ABCD2 score, patients presenting
plaque may be dislodged, resulting in a shower with TIA are assigned points for the following
of emboli. Less common complications include five factors: age ≥60 years; blood pressure
an allergic reaction, a localized hemorrhage, ≥140/90 mmHg; clinical features of unilateral
or, rarely, infection at the site where the cath- weakness or speech impairment; duration ≥60
eter enters the artery. Patients with a history of minutes or 10–59 minutes; and diabetes.
Figure 14–6. (A) Conventional cerebral angiogram in a patient with recurrent episodes of vertigo due to vertebrobasi-
lar insufficiency. Magnetic resonance angiography showed an absent left vertebral artery but it was unclear whether this
represented a normal variant or occlusion. Right vertebral artery injection (anterior posterior view). Arrowheads show nar-
rowing of the right vertebral artery and the left vertebral stump (the left vertebral artery is blocked). Hollow arrows show
basilar artery narrowing. The long thin arrows point to the anterior inferior cerebellar arteries. (B) Schematic diagram of
the anterior posterior view of the vertebrobasilar system shown in the angiogram. AICA, anterior inferior cerebellar artery;
PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery. (From Fife TD,
Baloh RW, Duckwiler GR. Isolated dizziness in vertebrobasilar insufficiency: clinical features, angiography, and follow up.
J. Stroke Cerebrovasc Dis 4:4, 1994, with permission.)
Figure 14–7. Conventional angiogram of a patient with recurrent vertigo attacks and basilar stenosis. (A) Pre-stent angio-
gram (lateral view), demonstrating basilar artery stenosis proximal to the anterior inferior cerebellar arteries (arrow head)
and right vertebral artery occlusion (arrow). (B) Corresponding post-stent angiogram showing the treated vessel after
angioplasty and stenting. (Kerber KA, et al. Neurology. 2005;65:962).
Based on the number of points, the risk of source is suspected based on finding an
stroke at 90 days can be determined. However, intracardiac clot or severe dilated cardiomyo-
the validity of this risk assessment tool in poste- pathy.68 There is uncertainty about the use of
rior circulation TIA is not clear. As with all diz- anticoagulants versus antiplatelet agents in the
ziness, vertigo, and imbalance presentations, management of patients having recurrent ver-
there are likely to be problems with the reli- tebrobasilar artery ischemic events.
ability of the diagnostic classification particu- Retrospective studies have suggested warfarin
larly in TIA populations from claims databases may have efficacy in patients with vertebrobasi-
or large cohort studies such as those used to lar disease.70–72 However, in the Warfarin ver-
derive and validate the ABCD2 score.67 sus Aspirin in Symptomatic Intracranial Disease
Consensus guidelines for the evaluation and (WASID) trial, warfarin therapy did not reduce
management of TIA have been published.66,68 the risk of stroke even in the subgroup with
The first step includes initiating an antiplatelet stenosis of the posterior circulation.73
agent and other steps to control risk factors for Furthermore, the WASID trial was stopped
stroke.68 Noninvasive imaging of the head and prematurely because warfarin was associated
neck vessels is recommended to search for a with significantly higher rates of adverse events
critical stenosis. However, this is less relevant (i.e., increased death, major hemorrhage, and
in posterior circulation stroke because there myocardial infarction or sudden death). A sub-
are no good trials to support use of surgical group analysis of the Ticlopidine Aspirin Stroke
approaches to vessel stenosis in the posterior Study (TASS) found that patients classified as
circulation, whereas there is high-level evi- having vertebrobasilar symptom TIAs had a
dence to support the use of surgical procedures lower risk of stroke on ticlopidine compared to
for patients with symptomatic carotid stenosis. aspirin,74 but this finding has not been repli-
Echocardiography is used to search for a car- cated and ticlopidine is rarely used because of
diac embolic source, which is particularly com- the potential for adverse effects.
mon in posterior circulation events. Transient vertigo episodes can be a warning
Anticoagulation is recommended over anti- sign of impending basilar artery occlusion—
platelet agents in patients with atrial fibrillation particularly when new in onset, increasing
or a prosthetic heart valve.68 Anticoagulation frequency and in patients with significant
can also be considered when a cardioembolic stroke risk factors, or when other neurologic
features (particularly motor weakness or speech to even up to 24 hours is because the prognosis
disturbance) are reported.78–80 If a severe pos- of basilar occlusion is so poor. One recent small
terior circulation stenosis (≥50%) is identified, randomized trial found that patients receiving
endovascular therapies become a management intra-arterial thrombolysis had a good outcome
option (Fig. 14–7). But randomized trials are in 4 of 8 patients receiving thrombolysis com-
lacking for the use of endovascular therapies in pared with only 1 of 8 patients in the control
treating patients with vertebrobasilar stenosis. group.86 A systematic review of published case
Nonetheless, these procedures hold promise in series of basilar artery occlusion treated with
the management of patients with recurrent thrombolysis (either intravenous or intra-
posterior circulation TIAs or stroke. The Phase arterial) found that an outcome of death or
I trials of stenting suggest a high technical suc- dependency was more than 75% among 420
cess rate (>95%) with a low periprocedural rate patients, and it did not differ on the adminis-
of complications (about 6%).75–77 Re-stenosis tration route.87 Recanalization was achieved
rates have varied from 7.5% to 35% at 6 months. more frequently with intra-arterial thromboly-
Hopefully some of the important questions sis (225 of 344; 65%) than with intravenous
about the use of endovascular treatments will thrombolysis (40 of 76; 53%), but death and
be answered by a large 60-site randomized dependency rates did not differ. Only 24% of
controlled trial of stenting in intracranial steno- patients with intra-artertial thrombolysis and
sis, the Stenting and Aggressive Medical 22% with intravenous thrombolysis had a good
Management for Preventing Recurrent stroke outcome (e.g., modified Rankin score ≤ 2,
in Intracranial Stenosis (SAMMPRIS) trial meaning slight disability but able to walk unas-
(ClinicalTrials.gov Identifier: NCT00576693). sisted and able to care for self without assis-
tance). Without recanalization the likelihood of
a good outcome was only 2%. A similar rate
INFARCTION
(68%) of a poor outcome (death or depen-
Randomized controlled studies and consensus dency) was also found in a large international
guideline statements support the use of intra- registry study of basilar artery occlusion, and
venous thrombolytic therapy for acute ischemic no statistically significant superiority was found
stroke patients when used less than 3 hours for any treatment strategy.88 Factors associated
from stroke onset.82,83 More recent findings with a better outcome include recanalization,
from a large randomized trial indicate the ben- treatment within 8 hours of symptom onset,
efits of IV thrombolytics outweigh the risks for and a Glasgow Coma Scale score ≥9 at presen-
up to 4.5 hours from symptom onset.84 Patients tation (generally meaning not comatose).85,87,88
with posterior circulation stroke, however, Importantly, patients with radiographic evi-
were less likely to be enrolled in these acute dence of brainstem infarction have been
stroke trials, with about 5% of the patients in excluded from many of the studies reporting
the original thrombolytic trial having a poste- on the effects of thrombolytic treatment in
rior circulation stroke.85 In subsequent trials, basilar occlusion.87
patients with posterior circulation stroke have After a latent interval of several days, some
either been excluded or were likely to be patients with cerebellar infarction may develop
underrepresented.85 The reasons for this are progressive brainstem dysfunction due to com-
largely because posterior circulation stroke is pression by the swollen cerebellum or due to
less common than anterior circulation stroke the production of hydrocephalus.53,54 A large
and also because it can be more difficult to dis- infarction in the cerebellar distribution of the
criminate between patients with posterior cir- PICA poses the greatest risk for brainstem
culation stroke and patients with stroke-mimics compression. Surgical management should be
such as peripheral vestibular disorders or even a consideration in these cases because relent-
nonspecific symptom presentations. less progression to quadriplegia, coma, and
The time window for the thrombolytic treat- death can ensue.55–57 However, uncertainty
ment of stroke is generally extended when exists about the timing and selection of patients
basilar artery occlusion is identified, though for surgical management.56,57
this remains a controversial topic because of Management of labyrinthine infarction is pri-
the lack of large randomized controlled data. marily symptomatic. Antivertiginous medica-
The main reason that the window is extended tions can help relieve the acute vertigo and
nausea. Vestibular rehabilitation exercises with audiometric and electronystagmography

should be started as soon as the patient is able to tests) are profound and usually permanent.
cooperate. The clinical course for patients sur- MRI may reveal findings suggestive of intral-
viving a brainstem or cerebellar infarction is abyrinthine hemorrhage, including increased
typically that of gradual but incomplete recov- signal on precontrast T1 sequences and also
ery. Vertigo may persist for months because of increased signal on T2 or fluid-attenuated
damage to central structures important for com- inversion recovery (FLAIR) sequences.
pensation. Many patients complain of disabling However, these imaging findings could also
oscillopsia due to spontaneous nystagmus and indicate increased protein concentration rather
damaged central vestibular and cerebellar path- than hemorrhage. A more advanced FLAIR
ways. Antivertiginous medications are less effec- sequence, three-dimensional (3D) FLAIR,
tive for controlling vertigo than with peripheral might be a more sensitive test for identifying
vestibular lesions and vestibular rehabilitation hemorrhage or increased protein content in
exercises are often of minimal benefit. One the inner ear but requires more detailed study
exception to this overall generally poor progno- to determine the reliability and validity of the
sis is the recovery seen in young patients with test.95,96 Management consists of symptomatic
lateral medullary infarction due to vertebral treatment of the vertigo (see Chapter 19) and
artery dissection. Many of these patients have a correcting an underlying bleeding diathesis
complete return to normal and the great major- when possible.
ity have only minimal residual dysfunction.
HEMORRHAGE INTO THE BRAIN

INTRALABYRINTHINE STEM AND CEREBELLUM
HEMORRHAGE
Spontaneous intraparenchymal hemorrhage
Intralabyrinthine hemorrhage can be associ- into the brain stem or cerebellum produces a
ated with multiple systemic disorders, includ- dramatic clinical syndrome frequently pro-
ing leukemia, vasculitis, and cocaine abuse.24,91–93 gressing to loss of consciousness and death.97,98
Sudden deafness due to intrlabyrinthine The cause of hemorrhage is hypertensive vas-
hemorrhage is common in patients with endo- cular disease in approximately two-thirds of
lymphatic sac tumors associated with von patients. Anticoagulation therapy, cryptic arte-
Hippel-Lindau disease.94 A small percentage of riovenous malformations, and bleeding diathe-
patients with idiopathic sudden deafness show sis are also important etiologic factors, whether
MRI features of intralabyrinthine hemor- alone or in combination with hypertension.
rhage.95 Pathologic examination of the inner Cerebellar hemorrhage can be a remote effect
ear reveals hemorrhage into the perilymphatic of spinal or supratentorial surgery associated
space with smaller focal hemorrhages in the with drainage of large volumes of CSF.99
endolymphatic space.24 The vestibular and Vertigo may be an initial symptom with brain
cochlear end organs, although morphologically stem hemorrhage, but it is never an isolated
intact, are rendered nonfunctional, apparently symptom and is usually only fleeting as the
from altered fluid chemistry. A similar condi- patient rapidly plunges into coma. Hemorrhage
tion may follow from a blow to the head with- into the pons typically results in a rapid onset of
out the occurrence of a bony fracture (so-called coma, flaccid quadriplegia, loss of horizontal
labyrinthine concussion). eye movements, pinpoint reactive pupils, and
ocular bobbing.48 Hemorrhage into the medulla
is associated with rapid cardiorespiratory
Diagnosis and Management failure and death.
Because of its potential reversibility, cere-
Diagnosis of intralabyrinthine hemorrhage bellar hemorrhage deserves particular empha-
is based on finding a sudden auditory and sis.98 The initial symptoms of acute cerebellar
vestibular loss in a patient with an underlying hemorrhage are vertigo, nausea, vomiting,
predisposing condition (see earlier discussion). headache, and inability to stand or walk. As
Hearing loss and vestibular loss (documented with cerebellar infarction, these symptoms
might be confused with an acute peripheral Diagnosis and Management

vestibular lesion. Unlike the latter, however,
examination in the initial period usually reveals The diagnosis of hemorrhage into the brain
nuchal rigidity, prominent cerebellar signs, stem and cerebellum has been revolutionized
ipsilateral facial paralysis, and ipsilateral gaze with the introduction of CT and MR scanning.
paralysis. Pupils are often small bilaterally but Computed tomography is usually superior to
reactive. Approximately 50% of patients lose MR for identifying intraparenchymal blood
consciousness within 24 hr of the initial symp- (Fig. 14–8). An imaging study is recommended
toms, and 75% become comatose within 1 in any patient presenting with the acute onset
week of onset.101 The condition is often fatal of vertigo not meeting criteria for a peripheral
unless surgical decompression is performed.102 vestibular disorder and who also exhibits
Midline cerebellar hemorrhage is particularly prominent ataxia, either of the trunk and or
difficult to diagnose because it produces bilat- extremities.
eral signs and generally runs a more fulminant As indicated earlier, hemorrhage into the cere-
course than a lateralized hemorrhage. Such bellum is often fatal unless surgical decompression
patients have profound ataxia, usually being is performed.103 The earlier the syndrome is recog-
unable to stand—a finding not associated with nized, the more likely the surgery will be success-
benign peripheral vestibular lesions. ful. Once the patient is comatose, almost none
Figure 14–8. Computed tomography scan showing hydrocephalus (A) secondary to a cerebellar hemorrhage (arrows) (B).
survive. Small hemorrhages into the brain stem degeneration of the vascular wall. Probably
and cerebellum may spontaneously resolve. both factors can lead to the production of ver-
tebrobasilar dolichoectasia, but often there is a
more generalized vascular ectasia of cerebral
vessels, suggesting a more diffuse arterial
VASCULAR COMPRESSION defect. Transient ischemic attacks associated
SYNDROMES with vertebrobasilar dolichoectasia are treated
like other causes of TIAs. The role of percuta-
Vertebrobasilar Dolichoectasia neous transluminal angioplasty and stenting in
symptomatic dolichoectasia is not clear.81
Dolichoectasia refers to an enlargement and
elongation of the basilar artery (Fig. 14–9). It is
a common finding on MR images of the brain Vascular Compression by Normal
and on cerebral angiography, typically unasso- Vessels (Vestibular Paroxysmia)
ciated with any clinical symptoms. However,
there are reports suggesting that vertebrobasi- There is controversy as to whether audioves-
lar dolichoectasia can be implicated in neuro- tibular symptoms can result from compression
logic symptoms, both by compression of the of the eighth cranial nerves by normal arteries.
brain stem and cranial nerves or by producing Jannetta et al.109 reported improvement in
TIAs.104–106 In some cases, both compression patients with “disabling positional vertigo” after
and ischemia coexist in the same patient. surgically removing vascular loops that were
Patients with vertebrobasilar dolichoectasia compressing the eighth cranial nerve near the
can have evidence of both peripheral and cen- root entry zone. However, the clinical syn-
tral vestibular dysfunction, most commonly drome was ill defined and there were no
due to compression of the vestibular nerves.107 specific diagnostic tests prior to surgical explo-
The pathophysiology for cerebral ischemia is ration of the posterior fossa. Furthermore,
uncertain, but obstruction by atheromata, vascular loops, particularly loops of the AICA,
intraluminal thrombi, or artery-to-artery emboli are common in the cerebellopontine angle
have been proposed.108 Distortion of small in normal subjects without symptoms.
branches of the basilar artery due to elongation Brandt and Dieterich111 described a syndrome
and tortuosity and hemodynamic factors related characterized by brief episodes of vertigo—
to reduction in flow velocity in the enlarged vestibular paroxysmia—which they attributed
basilar artery may also contribute to the isch- to neurovascular compression of the eighth
emia. There is still debate as to whether verte- cranial nerve. Some patients had associated
brobasilar dolichoectasia represents a congeni- auditory symptoms and signs, whereas others
tal anomaly or is the result of atherosclerotic did not. Episodes could occur spontaneously
Figure 14–9. Vertebro-basilar dolichoectasia. Magnetic resonance images show an ectatic vertebrobasilar artery. Arrows
point to the artery. The large and tortuous artery can be seen lateral to the medulla (A), and then compressing the cerebellar
peduncle and pons (B and C), before coursing back to the midline (D).
or after head turns or position change. A 3. Lee H, Sohn SI, Cho YW, Lee SR, Ahn BH, Park
more recent follow-up study of 32 patients with BR, Baloh RW. Cerebellar infarction presenting iso-
lated vertigo: frequency and vascular topographical
vestibular paroxysmia found that most patterns. Neurology. 2006;67(7):1178.
responded to either carbamazepine (mean 4. Grad A, Baloh RW. Vertigo of vascular origin: clinical
dose 568 mg/day) or oxcarbazepine (mean and electronystagmographic features in 84 cases. Arch
dose 870 mg/day).112 Patients with vestibular Neurol. 1989;46:281.
5. Lee H, Kim HJ, Koo JW, Kim JS. Superior divisional
paroxysmia may also respond to low-dose vestibular paresis in anterior inferior cerebellar artery
gabapentin.110 infarction. J Neurol Sci. 2009;285:250.
6. Lee H, Kim JS, Chung E, et al. Infarction of the terri-
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Syndrome 2274.
8. Fisher CM, Karnes WE, Kubik CS. Lateral med-
Although rare, vertebrobasilar ischemia can be ullary infarction–the pattern of vascular occlusion.
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becomes compressed by an osteophyte, usually Japan. Radiat Med. 1996;14:241.
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Chapter 15
Tumors
TUMORS OF THE MIDDLE EAR AND Epidermoid Cysts (Primary Cholesteatomas)

TEMPORAL BONE Cholesterol Granulomas
Malignant Tumors Metastatic Tumors
Glomus Body Tumors (Paragangliomas) Diagnosis
Management BRAIN TUMORS
TUMORS OF THE INTERNAL AUDITORY Brain Stem
CANAL AND CEREBELLOPONTINE Fourth Ventricle
ANGLE Cerebellum
Schwannomas Diagnosis and Management
Meningiomas
TUMORS OF THE MIDDLE EAR Malignant Tumors

AND TEMPORAL BONE
Squamous cell carcinoma is the most frequent
A wide variety of benign and malignant tumors histologic type of malignant tumor involving
involve the middle ear and temporal bone.1 the middle ear and mastoid.2,3 It typically arises
Tumors involving the middle ear produce from epidermal cells of the auricle, external
symptoms of fullness or conductive hearing auditory canal, or the middle ear and mastoid.
loss early, whereas tumors in the temporal The prognosis is good for tumors confined to
bone outside the middle ear can become the auricle and external canal but not for those
quite large without producing symptoms. invading the middle ear and mastoid. The latter
The tumor may not become apparent until are frequently associated with prominent ear
it erodes into the external auditory canal symptoms that include vertigo, hearing loss,
(producing a conductive hearing loss) or pain, otorrhea, mastoid swelling, and facial
through the mastoid cortex into the skin. paralysis. Squamous cell carcinomas often begin
Anterior extension into the cavernous in an ear with previous otologic disease, partic-
sinus produces ophthalmoplegia from involve- ularly chronic suppurative otitis media with a
ment of the third, fourth, and sixth nerves. mastoid cavity. Other, less common, tumors
Malignant tumors in this region tend to spread originating in the external auditory canal and
locally to the regional lymph nodes; distant middle ear include adenoid cystic carcinoma,
metastasis is unusual. Ultimately, the tumor basal cell carcinoma, mucoepidermoid carci-
can be seen in the nasopharynx, middle ear, or noma, and ceruminoma. In general, these
neck. tumors are less malignant but occasionally will
339
be locally invasive. Adenoid cystic carcinoma glomus vagale (along the course of the vagus
arises from glandular tissue of the external canal nerve). Glomus vagale and jugulare tumors
and middle ear; it typically has severe pain as an often involve the labyrinth and cranial nerves,
early symptom and may be associated with dis- whereas glomus tympanicum tumors usually
tant metastasis. produce only local symptoms such as conductive
Generally, carcinomas occur in an elderly age hearing loss, pulsatile tinnitus, and rhinorrhea
group, whereas sarcomas occur in the young. because of the tumor bulk in the middle ear.
Both osteogenic sarcoma and chondrosarcoma Invasion of the labyrinth is an uncommon but
occur as primary tumors of the temporal bone, serious prognostic sign and is often associated
running fulminant courses in older children and with extension to the petrous apex and into the
young adults. Rhabdomyosarcoma is the most middle and posterior cranial fossae. The jugu-
common middle ear malignant tumor in the lar foramen syndrome consisting of ninth,
young, typically occurring in children under the tenth, and eleventh nerve involvement occurs
age of 5.4 The initial symptom is often facial with glomus jugulare and vagale tumors.
paralysis, which may be misdiagnosed as idio- Involvement of the twelfth nerve is an ominous
pathic Bell’s palsy. In later stages, the tumor sign, indicating destruction of the jugular fora-
extends beyond the middle ear to involve the men with tumor extension into the hypoglossal
petrous apex and may invade the posterior or canal and usually into the posterior fossa.
middle cranial fossi. Rhabdomyosarcoma should
be considered in any infant presenting with
idiopathic facial paralysis. Diagnosis
Metastatic involvement of the temporal bone
is common with several different tumor types Tumors of the middle ear space and temporal
but, because of the enchondral layers’ resis- bone can often be identified on careful physical
tance, neoplasms rarely invade the bony laby- examination. A malignant tumor may be visible
rinth.5 The most common sites of origin for after it has eroded into the external auditory
metastatic tumors in order of frequency are canal or through the mastoid cortex into the
breast, kidney, lung, stomach, larynx, prostate, skin. Nearby lymph nodes are often enlarged.
and thyroid gland.6 Metastatic tumors from the A biopsy of these lesions should lead to the cor-
breast and prostate commonly incite new bone rect histologic diagnosis. Glomus body tumors
formation. are often visible through the tympanic mem-
brane (see Fig. 6–1C). If not all the borders are
visible, the tumor may be either a large glomus
Glomus Body Tumors tympanicum tumor or a much larger glomus
(Paragangliomas) jugulare tumor that has extended from the jug-
ular bulb into the middle ear. If cranial nerve
Glomus tumors are the most common tumor of deficits are present, the tumor is most likely a
the middle ear, and next to schwannomas they glomus jugulare type.
are the most common tumor of the temporal Although the presence of a tumor involving
bone.7 Glomus tumors arise in the glomera of the middle ear or temporal bone can often be
the chemoreceptor system, which may be identified on physical examination, computer-
found along the vagus nerve, glossopharyngeal ized tomography (CT) and magnetic resonance
nerve, Jacobson’s nerve (tympanic branch of (MR) scanning are used to assess the extent of
the ninth nerve), and the nerve of Arnold the tumor. Computed tomography is the diag-
(postauricular branch of the tenth nerve). Most nostic procedure of choice for determining
are hamartomas with tissue components found bony involvement, and MR is most useful for
in the normal glomus body.8 Genetic factors determining the soft tissue extent. Contrast
are likely important in pathogenesis, and in should be used with either procedure to visual-
some families glomus tumors are inherited in ize vascular elements.10 Magnetic resonance
an autosomal dominant fashion with genomic angiography (MRA) is particularly useful for
imprinting (the gene only results in tumors if defining the features of a glomus body
inherited from the father).9 The most common tumor.11,12 Individuals in families with glomus
tumor sites are the glomus jugulare (jugular tumors should be screened after age 16 to
bulb), glomus tympanicum (middle ear), and detect early asymptomatic tumors.9
15 Tumors 341
Management In later stages of progression, involvement of

the sixth, ninth, and tenth nerves may give
Malignant tumors confined to the ear and rise to diplopia, dysphonia, and dysphagia.
external auditory canal can often be surgically Compression of the brain and cerebellum
resected with minimal cosmetic and functional results in ipsilateral gaze dysfunction and dys-
disability.13 Much more extensive surgical metria of the extremities.
procedures with greater cosmetic and func- In a series of over 2000 tumors of the CP
tional disabilities are required for tumors angle, 92% were vestibular schwannomas
invading the middle ear and mastoid, and (acoustic neuromas); 3%, meningiomas; 2.5%,
often only subtotal resection is possible. Most epidermoid cysts; and 1%, facial nerve
patients are treated with postsurgical radiation, schwannomas.17
but the long-term prognosis in these patients
is poor.
Although some small glomus tympanicum Schwannomas
tumors, when the borders are clearly demar-
cated, can be removed via the external auditory Tumors arising from the sheaths of the cranial
canal, more extensive procedures are usually and peripheral nerves have been called neuro-
required for these tumors. Glomus jugulare mas, neurilemmomas, and neurofibromas, but
and vagale tumors are much more difficult to convincing evidence that most represent pro-
remove because they are highly vascular and liferation of the sheath-producing schwann
closely interrelated with key neural and vascu- cells makes schwannoma a more appropriate
lar structures.7,14 A “wait-and-see” policy has term.6 These tumors comprise about 5% of
been recommended for most of these intracranial neoplasms and are by far the most
tumors.12,15 Radiation therapy may be useful for common tumor found in the temporal bone.
management of tumor recurrences and for They arise from the vestibular nerve in more
unresectable lesions.16 than 90% of cases, and much less frequently
from the facial, acoustic, or trigeminal nerves.
The general term acoustic neuroma, therefore,
is inappropriate on two accounts. Mostly,
TUMORS OF THE INTERNAL schwannomas are circumscribed and encapsu-
AUDITORY CANAL AND lated, encroaching on and displacing neural
CEREBELLOPONTINE ANGLE structures as they grow, without direct invasion
of tissue. Vascularity is variable, but they are
Tumors arising in the narrow confines of the usually less vascular than meningiomas.
internal auditory canal typically produce a Vestibular schwannomas typically arise at the
gradual compression of the seventh and eighth myelin–glial junction near the porous acousti-
cranial nerves. Sensorineural hearing loss, tin- cus, producing symptoms by exerting pressure
nitus, and facial paresis insidiously evolve on surrounding neurovascular structures.
usually over months to years. Vertigo is uncom- Infrequently, the tumor arises from the vestib-
mon with such lesions because the nervous ular nerve terminals near or in the end organ,
system is able to adapt to the gradual loss of in which case end-organ destruction occurs, or
vestibular function. Lesions within the cerebel- it may arise from the nerve after it leaves the
lopontine (CP) angle produce a similar, slowly canal in the angle, in which case it can be rela-
progressive compression of the seventh and tively large before producing symptoms and
eighth cranial nerves, although if the tumor signs. Intralabyrinthine schwannomas typically
arises in the angle, it can grow to a much larger begin in the cochlea and later spread to the
size before critical compression occurs. Most vestibular labyrinth.18 Schwannomas usually
often, tumors begin in the internal auditory grow very slowly but occasionally hemorrhage
canal and grow outward into the CP angle, into the tumor; cyst formation or associated
inasmuch as it is the path of least resistance. edema produces clinical evidence of more
Next to the seventh and eighth nerves, the fifth rapid growth. Malignant schwannomas are
nerve is most commonly involved with CP-angle rare; approximately half of them occur with
tumors, causing ipsilateral facial numbness. neurofibromatosis type II.
Schwannomas are usually encapsulated and may also produce increased intracranial pres-
grow at a very slow rate. On histological exami- sure from obstruction of cerebrospinal fluid
nation, they are typically composed of two (CSF) outflow, resulting in severe headaches
different tissues—Antoni type A and Antoni and vomiting.
type B. Antoni type A is compact and cellular
with elongated spindle cells forming palisades.
FACIAL NERVE SCHWANNOMAS
By contrast, Antoni type B is loose and much
less cellular. Most schwannomas are predomi- Facial nerve schwannomas typically present
nantly Antoni type A with some focal areas of with a slowly progressive facial paralysis devel-
type B tissue. Larger tumors often become cys- oping over months to years—although rare
tic because of necrosis and degeneration within cases with sudden onset of paralysis, fluctuat-
the tumor. ing paresis, and facial tic have been reported.
Hearing loss from compression of the cochlear
VESTIBULAR SCHWANNOMAS nerve in the internal auditory canal is the sec-
(ACOUSTIC NEUROMA) ond most common presenting symptom. When
the tumor is confined to the internal auditory
The incidence of vestibular schwannomas has canal, differentiating vestibular from facial
been estimated at about 1 per 100,000 person/ nerve schwannomas is impossible prior to
years.19,20 Although several studies identified an surgery.26 Conductive hearing loss can occur
increasing incidence over the past 25 years, this when the tumor arises in the middle ear, where
increase can probably be attributed to easier it can disrupt the ossicular chain. In these cases,
access to magnetic resonance imaging (MRI) the tumor mass may be visible behind the pos-
particularly in elderly patients, in whom small terior superior tympanic membrane.
intracanalicular tumors predominate.21 To
date, there is no conclusive evidence that cel- BILATERAL VESTIBULAR
lular phone use leads to an increased incidence SCHWANNOMAS AND
of vestibular schwannomas.22 By far the most NEUROFIBROMATOSIS TYPE 2
common symptom associated with a vestibular
schwannoma is a slowly progressive unilateral Neurofibromatosis type 2 (NF2) is an auto-
hearing loss.23 Occasionally, patients will expe- somal dominantly inherited syndrome charac-
rience fluctuating or sudden hearing loss, terized by the development of bilateral
apparently from compression of the labyrin- vestibular schwannomas; schwannomas of other
thine vasculature. Often patients will complain cranial, spinal, and cutaneous nerves; and men-
of an inability to understand speech when using ingiomas involving cranial and spinal nerves.27
the telephone even before they are aware of a It occurs in about one in 25,000 live births and
loss of hearing. Unilateral tinnitus is the next is nearly 100% penetrant by age 60. About half
most common symptom. True vertigo occurs in are due to de novo mutations. Since about 10%
<20% of patients, although about half will com- to 20% of patients with NF2 present with a
plain of some mild impairment of balance.24 unilateral vestibular schwannoma, treatment of
When vertigo is reported in acoustic neuroma these patients should be based on the knowl-
patients, it can sometimes be difficult to deter- edge that they will eventually develop a ves-
mine whether the tumor is the cause of the tibular schwannoma on the opposite side (Table
symptom because bothersome dizziness symp- 15–1). The key features that suggest the diag-
toms, including vertigo, are common symptoms nosis of NF2 in a patient with a unilateral ves-
in the general population.25 At the bedside a tibular schwannoma are a family history of NF2
positive head-thrust test can be seen if the or at least two other neural tumors, particularly
tumor is causing sufficient dysfunction. Next to meningiomas.28
the auditory nerve, the most commonly involved The NF2 gene is a tumor-suppressor gene
cranial nerves (by compression) are the seventh located on chromosome 22q.29 It codes for the
and fifth, producing facial weakness and numb- protein schwannomin/merlin (S/M) that inter-
ness, respectively. Involvement of the sixth, acts with the extracellular matrix to regulate
ninth, tenth, eleventh, and twelfth nerves cell cycle processes.30,31 A wide range of muta-
occurs only in the late stages of disease with tions in the NF2 gene have been described,
massive tumors. Large vestibular schwannomas from small and large deletions to missense and
15 Tumors 343
Table 15–1 Average Risk per Decade of Patients Presenting with Vestibular
Schwannoma Having Neurofibromatosis Type 2
Age (years) NF2 (%) NF2 UVS at Diagnosis (%) NF2 with no FH and no Other
NF2 Features (%)
10–19 33 (22–50) 6 (2.6–9) 1 (0.3–1.4)
20–29 15 (8–22) 2.7 (0.9–4) 0.45 (0.1–0.6)
30–39 5 (3–8) 0.9 (0.3–1.4) 0.15 (0.03–2.2)
40–49 2 (1–3) 0.36 (0.1–0.54) 0.06 (0.01–0.08)
50–59 1 (0.5–1.5) 0.18 (0.06–0.27) 0.03 (0.007–0.05)
FH, family history; NF2, neurofibromatosis type 2; UVS, unilateral vestibular schwannoma.
(From Evans DGR, et al. Probability of bilateral disease in people presenting with unilateral vestibular schwannoma.
J Neurol Neurosurg Psychiatry. 1999;66:764–767, with permission.)
nonsense mutations. Only about half of the angle.32,33 Meningiomas arise from arachnoid
patients who meet the diagnostic criteria for fibroblasts, usually in the posterior aspect of
NF2 have identifiable mutations in the NF2 the petrous pyramid near the sigmoid and pet-
gene in peripheral blood, probably because of rosal sinuses. They displace cranial nerves and
somatic mosaicism with the NF2 mutation compress the brain stem and cerebellum but
being present in only a proportion of somatic do not invade brain tissue. In the posterior
cells. A mutation that is present in an insuffi- fossa, the lobulated variety is more common
cient proportion of cells to detect in lympho- than the flat (enplaque) type. Meningiomas in
cyte DNA may still be found as an identical the CP angle are frequently calcified and
mutation in all tumors from that patient. induce osteoblastic reaction in adjacent bone.
Sporadic schwannomas lack normal S/M Because these tumors usually arise outside of
protein either due to a spontaneous mutation the internal auditory canal, they often become
in the NF2 gene or activation of a protease very large before producing symptoms and
cascade that leads to ineffective S/M.31 signs. As with schwannomas, the most common
Of patients with a vestibular schwannoma, symptoms are auditory—hearing loss and tin-
about 5% have NF2 and of patients with NF2, nitus. Large tumors compress the brain stem
about 15% are likely to present initially with a and cerebellum and stretch the fifth and sev-
unilateral tumor.28 Therefore, <1% of patients enth cranial nerves, producing facial numbness
who present with a unilateral vestibular schwan- and weakness. In the rare cases that originate
noma will go on to develop a tumor on the other in the internal auditory canal, symptoms and
side. The likelihood of developing the second signs are identical to schwannomas.34
bilateral tumor in a patient presenting with a
unilateral vestibular schwannoma decreases
with age so that a patient presenting with a uni- Epidermoid Cysts (Primary
lateral vestibular schwannoma between the Cholesteatomas)
ages of 10 and 20 without a family history or
other features of NF2 has about a 1% chance of Epidermoid cysts arise from congenital epithe-
developing bilateral tumors. In contrast, a lial inclusion rests in the area of the petrous
patient presenting with a unilateral vestibular apex.35,36 They slowly enlarge to fill the CP
schwannoma after the age of 30 without a fam- angle, stretching nearby cranial nerves and
ily history or other features of NF2 has less than eventually compressing the brain stem and
a 0.1% chance of developing bilateral tumors.28 cerebellum. Because these cysts are slow grow-
ing, the symptoms do not become manifest
until the second to fourth decade of life. As
Meningiomas with other CP-angle tumors, involvement of
the eighth nerve is a common early feature,
Meningiomas comprise about 14% of intracra- but unlike other tumors in this area, hemifacial
nial tumors and after schwannomas are the spasm is a frequent early distinguishing
most common primary tumor of the CP feature.
Cholesterol Granulomas In those cases in which the neurologic exam-

ination is nonlocalizing (other than audioves-
Cholesterol granulomas arise in the pneuma- tibular deficits), the first diagnostic test should
tized spaces of the temporal bone when a small be an audiogram. If a progressing unilateral
hemorrhage into the air cells causes a foreign sensorineural hearing loss is documented, then
body reaction and progressive granuloma for- one would proceed directly to an MRI with
mation.36,37 The lesion within the temporal contrast because there is an important likeli-
bone expands and can produce compression of hood of an expanding lesion. If the audiogram
the structures in the CP angle. As with other is normal or if there is a unilateral sensorineu-
CP-angle lesions, eighth nerve involvement is ral hearing loss of unknown duration, then one
most common, with hearing loss being the most can consider a brainstem auditory-evoked
frequent presenting symptom. This is an impor- response (BAER). For some time, BAER was a
tant lesion to recognize because the surgical widely used test in the workup for acoustic
management is quite different from that of neuroma. Early small studies in patients with
other CP-angle tumors (see later discussion). known vestibular schwannomas reported
BAER to be abnormal in 85% to 95% of the
patients (see Fig. 8–8 in Chapter 8).39,40
However, currently the role and the value of
Metastatic Tumors BAER is uncertain because more recent stud-
ies (including systematic reviews of studies)
The internal auditory canal is a frequent site of
show that when BAER results are compared
metastatic tumor growth.5 From this site, tumor
with MRI, the sensitivity and specificity of
cells destroy the seventh and eighth nerves and
BAER ranges widely with values, indicating it
extend into the inner ear or into the CP angle.
can be very accurate to values indicating a high
The rapid onset of hearing loss and vertigo, fol-
risk for false-positive and false-negative
lowed by other signs of cranial nerve compres-
results.42 BAER is most sensitive when tumors
sion and brainstem dysfunction, suggests the
are ≥1 cm, though false-positive rates remain a
likelihood of a malignant tumor rather than
concern.42 If the BAER is used and the results
the more common benign CP-angle tumors.
are normal, then the patient should be followed
The lung and breast are the most common sites
with at least one repeat audiogram in 6 months.
for the primary neoplasm.6
Whether further repeat studies are necessary,
should the second audiogram be normal,
depends on whether the patient notes a subjec-
Diagnosis tive progression of either the hearing loss or
tinnitus. If the BAER is abnormal, then one
By far the most common presentation of a would proceed directly to an MRI with con-
CP-angle tumor is a slowly progressive unilat- trast with emphasis on the internal auditory
eral sensorineural hearing loss (Fig. 15–1). canal and CP angles.
Unilateral tinnitus is the next most common Magnetic resonance imaging with contrast is
symptom, with vertigo being an infrequent the imaging procedure of choice for identifying
symptom. The neurologic examination should a vestibular schwannoma (Fig. 15–2).42 It can
focus on the involved and nearby cranial identify small tumors a few millimeters in
nerves—including the vestibular component of diameter that would be missed without con-
cranial nerve eight (nystagmus and the head trast.41,42 MRI can also result in false-positive
thrust test) and the fifth and seventh nerves. If and false-negative results as well.42 The
there are findings localizing to the internal dilemma is often deciding which patients with
auditory canal or CP angle, one would proceed audio-vestibular symptoms or signs should
directly to neuroimaging, beginning with an have an MRI to evaluate for a tumor. Studies
MRI. The sudden onset of vertigo and unilat- on symptoms with acoustic neuroma demon-
eral hearing loss can occasionally be seen with strate the wide variability in symptoms and that
benign tumors, but a malignant tumor should these tumors are even incidental findings on an
also be considered whenever a mass is identi- imaging study done for other purposes in a
fied and the symptoms are abrupt in onset or patient with no audiovestibular symptoms.42
rapidly progressive.5,38 One study used the prevalence of symptoms in
15 Tumors 345
History
Unilateral hearing
loss or tinnitus
Neurologic
Focal findings
examination
Normal
Audiogram
Repeat in
6 months
Unilateral Unilateral
Normal sensorineural, sensorineural,
unknown duration progressing
MRI
Normal Abnormal
Typical
Atypical tumor
schwannoma
Meningioma,
CT epidermoid cyst,
cholesterol granuloma
Figure 15–1. Algorithm for diagnosis of tumors of the cerebellopontine angle. CT, computerized tomography; MRI,
magnetic resonance imaging.
the general population and the prevalence of calcification within tumors. Meningiomas are
vestibular schwannomas (or any CP angle mass) usually more dense than vestibular schwanno-
to estimate that approximately 2500 MRI stud- mas on CT. With contrast infusion they appear
ies would need to be performed to detect one very dense and homogeneous, a feature that
vestibular schwannoma in patients with non- differentiates them from schwannomas.32
specific dizziness.43 Among patients with dizzi- There may be calcification within the tumor,
ness and subjectively normal hearing, 9307 and the nearby temporal bone may be thick-
MRI scans would be need to be performed to ened. Epidermoid cysts also have a characteris-
identify one vestibular schwannoma. Using tic profile on CT; they are less dense than brain
more stringent criteria of patients with dizzi- and do not enhance after intravenous contrast
ness and asymmetric hearing loss (defined as material. They have an irregular scalloped
asymmetry of ≥15dB at two or more pure-tone surface contour and are usually eccentric to the
frequencies), it would take 638 MRI scans to opening of the internal auditory canal.
diagnose one vestibular schwannoma. Cholesterol granulomas appear as a punched-
Computed tomography scanning is most out lesion in the temporal bone with a central
useful for identifying bony erosion and/or density the same as that of brain and with a rim
Figure 15–2. Vestibular schwannoma (acoustic neuroma). Pre-contrast (A) and postcontrast (B) magnetic resonance
images show that no lesion is seen on the precontrast image (A), but the small schwannoma is clearly seen on the postcon-
trast image.
of enhancement after contrast infusion.36 The also should not wait too long to intervene in a
lesions are smooth walled and the contralateral growing tumor since the chance of surgical
petrous bone is always well pneumatized. On complications increases with increasing size of
MRI they give a high-intensity signal in both the tumor. There are no large randomized con-
T1-and T2-weighted images.36,44 trolled trials of surgical versus conservative
management of vestibular schwannoma, and
there are also no validated predictive models to
Management assess the likelihood of future problems from
an untreated vestibular schwannoma in an
Vestibular schwannomas are generally very individual patient.
slow-growing tumors. Over time, there is the There is a recent trend toward more conser-
chance that if left untreated the hearing loss vative management of patients with vestibular
would become severe, which is important schwannomas since clinical outcomes appear
because substantial unilateral hearing loss is no different in patients who fail conservative
associated with disability, including difficulty management versus those who receive primary
hearing on the affected side, in noisy environ- treatment without conservative manage-
ments, sounds at a distance, and difficulty judgment.47–49 Patients with an intracanalicular or
ing the direction of sound.45,46 But there is also small (≤2 cm) CP angle vestibular schwannoma
a very reasonable chance that the tumor will can be followed with serial MRIs without treat-
not grow or may even regress over time. In ment. This approach is particularly recom-
fact, systematic reviews have found that about mended for older patients, asymptomatic
50% of tumors do not demonstrate growth and patients with “incidental” tumors,50 and patients
about 6% show regression.42 There is the pos- with underlying medical problems at increased
sibility that surgical treatment could protect risk for surgery. Large tumors (generally con-
one against future hearing loss and also reduce sidered >2 cm) are more likely to grow than
the chance for other deficits from the tumor, small tumors, but there are no reliable clinical
but the surgery itself could lead to hearing loss, indicators to predict growth. Surgical or
facial paralysis, or the many other complica- radiation treatment may lead to total unilateral
tions that can arise from surgery in general. No hearing loss, whereas patients treated
one would want to subject a patient whose conservatively often show no change in hearing
tumor will not grow to the surgical risk. But we even after years of follow-up.47 If the tumor
15 Tumors 347
demonstrates initial growth (>2 mm/year), then of most tumors, long-term follow-up is
there is increased risk that it will continue to still lacking. Stereotaxic radiosurgery is
grow; however, about 40% of tumors with ini- ideal for managing vestibular schwannomas
tial growth will not demonstrate future growth. associated with NF2, since eventually the
In patients managed conservatively, an initial tumors will be bilateral. Subach et al.57 were
follow-up MRI is recommended at 6 months, able to preserve hearing in about half of the
then annually for 2 years, then 2 years later and patients with vestibular schwannomas and NF2
then every 5 years.49 treated with radiosurgery. In addition, normal
There are three general surgical approaches facial nerve function was preserved in most
to the CP angle: (1) translabyrinthine, (2) sub- patients.
occipital, and (3) middle fossa.23,51 The trans- Cholesterol granulomas involving the
labyrinthine approach destroys the labyrinth petrous apex can often be managed without
but often allows complete removal of the tumor surgery, particularly when the symptoms are
without endangering other nearby neural struc- stable or improving.58 When symptoms are
tures, particularly the facial nerve. This would progressive, however, a transmastoid extra-
be the procedure of choice for a patient with dural approach with simple drainage into the
severe hearing loss and a tumor under 3 cm in mastoid sinus or middle ear can be accom-
size. With the suboccipital and middle fossa plished with low morbidity. Cholesterol granu-
approaches, residual hearing can be saved, as lomas do not need to be resected. Solid tumors
the labyrinth is not destroyed during the surgi- involving the petrous apex, however, do require
cal procedure. With the introduction of the surgery for removal, usually via a middle fossa
modern operating microscope, preservation of or infratemporal fossa approach.59
hearing is now a distinct possibility with either
of these procedures.52 Traditionally, the suboc-
cipital approach has been performed by neuro-
surgeons, whereas the middle fossa approach BRAIN TUMORS
was developed by otologic surgeons. The mid-
dle fossa approach is more likely to save hear- Brain Stem
ing and avoid damage to the facial nerve when
the tumor is <3 cm in size. For tumors >3 cm Gliomas of the brain stem usually grow slowly
in diameter, a combined translabyrinthine sub- and infiltrate the brainstem nuclei and fiber
occipital approach is commonly used. This tracts, producing multiple symptoms and signs.
procedure allows the surgeon to reduce the Although brainstem gliomas are five to ten
size of the tumor from behind by working times more common in children than in adults,
between the tumor capsule and the brain stem. they still make up approximately 1% of adult
Furthermore, large tumors are often adjacent intracranial tumors.60,61 The neurologic symp-
to or attached to the basilar artery; with the toms and signs of childhood brainstem gliomas
combined approach the surgeon can dissect do not differ in essence from those of adults.
the artery from the tumor capsule under direct The typical history is that of relentless progres-
vision. As many as 10% of patients with vestib- sive involvement of one brainstem center after
ular schwannomas will have tumor recurrence another, often ending with destruction of the
after surgery mainly due to regrowth of microf- vital cardiorespiratory centers of the medulla.
ragments left in the operative field along the Vestibular and cochlear symptoms and signs
course of the facial nerve or at the surface of are common (occurring in approximately 50%
the pons.53 of cases), the brainstem origin of which is usu-
Stereotaxic radiosurgery using ionizing radi- ally obvious because of the multiple associated
ation provides another alternative for manag- findings. Tumors originating in the pons or
ing vestibular schwannomas, particularly midbrain usually cause long tract signs, cranial
smaller tumors confined to the internal audi- nerve deficits, and ataxia. Spontaneous,
tory canal.54,55 Radiosurgery provides a better gaze-evoked, and central paroxysmal positional
chance of preserving hearing, is more cost nystagmus all occur, and impairment of sac-
effective, and has less impact on patient’s activ- cade and pursuit eye movements further sug-
ities of daily living than traditional surgery.56 gests an intrinsic brainstem disorder. Although
Although radiosurgery reliably stops the growth less common, gliomas originating in the
medulla may present with recurrent vertigo Grand67 reported two cases of medulloblastoma
and vomiting. in which paroxysmal positional nystagmus was
Cerebral cavernous malformations (CCM; the initial abnormal neurologic sign. Other
cavernomas) are common vascular malforma- fourth ventricular tumors that produce similar
tions of the brain that occur as a sporadic or as clinical pictures include ependymomas, papil-
a familial autosomal dominant disorder. So far, lomas, teratomas, epidermoid cysts, and, in
mutations in three genes have been identified endemic areas, cysticercosis.
in families with cavernomas: CCA1/KRIT1,
CCA2/MGC4607, and CCA3/PDCD10.62 A
small percentage will bleed and can produce Cerebellum
dramatic symptoms and signs, particularly
when the cavernoma is located in the brain The most common cerebellar tumor in adults
stem. Bleeding into a cavernoma near the ves- is metastasis, whereas in children the most
tibular nuclei or outflow tracts to the oculomo- common tumor is an astrocytoma. A metastatic
tor nuclei can produce episodes of vertigo and cerebellar tumor can be the initial sign of a
nystagmus. Patients are often thought to have distant tumor, or it can occur many years
either an infarct or primary hemorrhage prior after treatment of a primary cancer.68 The
to identifying the characteristic vascular mal- location of the tumor in the cerebellum is the
formation on MRI.63 Patients can have primary key to determining the nature and severity
position upbeat nystagmus, downbeat nystag- of symptoms and signs. A tumor in the cerebel-
mus, and central types of positional nystagmus lar hemisphere can grow large with relatively
associated with cavernomas of the brain stem. few symptoms, whereas a tumor near the
Brainstem metastasis also commonly leads to a midline will usually lead to early symptoms
dramatic clinical syndrome that may mimic a and signs due to either brainstem compression
stroke or a primary hemorrhage. Hemorrhage or CSF obstruction. In children, gliomas
into the metastatic tumor may account for the can infiltrate a large part of the cerebellum,
sudden symptoms and signs. As with other being relatively silent until they become
metastatic brain tumors, the most common pri- large enough to obstruct CSF circulation or
mary sites are lung and breast. compress the brain stem.69 The characteristic
symptoms include new-onset severe headache,
position-provoked vertigo and vomiting, and
Fourth Ventricle gait imbalance. Most patients will develop
papilledema from increased intracranial pres-
Many tumors arising in the fourth ventricular sure. As with medulloblastoma, occasionally
region compress the vestibular nuclei and pro- positional vertigo can be the initial symptom of
duce vestibular symptoms. Medulloblastomas, a cerebellar tumor.70 Other tumors of the cer-
occurring primarily in children and adoles- ebellum that can produce identical symptoms
cents, are rapidly growing, highly cellular and signs include teratomas, hemangiomas,
tumors that arise in the posterior midline or and hemangioblastomas.
vermis of the cerebellum and invade the fourth
ventricle and adjacent cerebellar hemi-
spheres.64,65 Vertigo and disequilibrium are Diagnosis and Management
common initial complaints. Headaches and
vomiting also occur early from an obstructive Magnetic resonance imaging is the diagnostic
hydrocephalus and associated increased intrac- procedure of choice for identifying brainstem
ranial pressure. An attack of headache, vertigo, and cerebellar tumors71 (Fig. 15–3). Gliomas of
vomiting, and visual loss may result from a the posterior fossa are particularly difficult to
change in head position, producing transient identify with non-contrast CT because they are
CSF obstruction (Bruns’ symptom). In Nylen’s often isodense; the only evidence for a lesion is
classic study66 of patients with subtentorial enlargement of the brain stem or compression
tumors, 17 of 27 patients with medulloblastoma of the fourth ventricle (the tumor shown in
demonstrated positional nystagmus, and in two Fig. 15–3 was not seen on CT scanning). Magnetic
cases it was the only focal neurologic sign. resonance imaging, however, can reliably identify
15 Tumors 349
Figure 15–3. Magnetic resonance scans (T2 weighted) showing a brain stem glioma (arrows) involving the root entry zone
of the right eighth nerve. (A) Transverse section. (B) Coronal section.
both brainstem and cerebellar gliomas as well as young patient who presents with minimal defi-
the other tumor types mentioned earlier. In some cits at the time of diagnosis. Radiation to the
cases, CT scanning can complement MRI by brain stem or cerebellum can produce late
identifying calcification and helping differentiate radiation damage that is slowly progressive and
between tumor and associated edema. If an MRI unresponsive to treatment.71,73
scan is not possible, then a CT scan with contrast
is also an accurate test for identifying a tumor in
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Chapter 16
Trauma
TRAUMA TO THE TEMPORAL BONE Pathophysiology

Fracture Diagnosis
Labyrinthine Concussion Management
Posttraumatic Positional Vertigo BRAIN TRAUMA
Diagnosis Intracranial Complications Associated with
Management Temporal Bone Fractures
PERILYMPH FISTULA Dizziness Due to Brainstem Trauma
Pathophysiology Postconcussion Syndrome
Diagnosis Whiplash Injuries
Management Diagnosis
SEMICIRCULAR CANAL DEHISCENCE Management
SYNDROME
TRAUMA TO THE TEMPORAL Although temporal bone fractures have been

BONE classified as longitudinal and transverse, mod-
ern high-resolution computed tomography
(CT) scanning shows that most fractures are
Fracture actually oblique.4,5 The fracture line typically
extends anteriomedially to the skull base, mak-
Fractures of the temporal bone most com-
ing its way through the weakest places in the
monly result from direct lateral blunt trauma to
skull base but avoiding the compact bone of
the skull in the parietal region of the head.1,2
the otic capsule surrounding the labyrinth.
Traffic accidents are by far the most common
Transient or persistent facial paralysis occurs in
cause.3 Because the otic capsule surrounding
about two-thirds of patients.3 Conductive hear-
the inner ear is very dense bone, the fracture
ing loss due to ossicular chain dislocation occurs
usually courses around it to involve the major
in more than half, but sensorineural hearing
foramina in the skull base, the most common
loss occurs in less than 20%. Overall, the audi-
being that of the carotid artery and the jugular
tory system is more vulnerable to temporal
bulb. Fractures commonly occur near the root
bone fracture than the vestibular system.
of the external auditory canal and run parallel
along the petrous apex, extending anteriorly to
the foramen lacerum and the carotid artery. Labyrinthine Concussion
They may also extend into the temporal man-
dibular joint region. Ecchymosis in the mastoid Auditory and vestibular symptoms (either
region (Battle’s sign) occurs when the fracture isolated or in combination) can follow blows
line extends into the mastoid. to the head that do not result in temporal
353
bone fracture. The absence of associated brain- usually enters the long arm of the posterior
stem symptoms and signs and the usual rapid semicircular canal, where it moves under the
improvement in symptoms following injury influence of gravity to trigger bouts of vertigo
support a peripheral localization for the lesion. and nystagmus. Benign positional vertigo after
The pathology is presumably microscopic hem- head trauma can be delayed since not only does
orrhages in the membranous labyrinth.6 the otoconial debris have to be free floating,
Although protected by a bony capsule, the del- but patients must get their head in a critical
icate labyrinthine membranes are susceptible position so that the debris can enter the long
to blunt trauma. Of 57 cases of labyrinthine arm of the posterior semicircular canal (back
damage due to blunt head trauma reported by and to the side). Patients may be unconscious
Davey,7 51% resulted from blows to the occipi- or be heavily medicated for multiple injuries,
tal region; 26%, to the frontal region; and 23%, so they may only recognize the positional ver-
to other areas. tigo once they begin to recover and are able to
Sudden deafness following a blow to the make the critical positional changes that will
head without associated vestibular symptoms is trigger vertigo. Benign positional vertigo occurs
often partially or completely reversible.8 It is after nearly half of head injuries associated with
probably caused by intense acoustic stimula- temporal bone fractures.13 Bilateral involve-
tion from pressure waves created by the blow, ment and multiple recurrences are more com-
which are transmitted through the bone to the mon in posttraumatic positional vertigo than
cochlea just as pressure waves are transmitted from other causes of positional vertigo.11,14
from air through the conduction mechanism.9
Supporting this suggestion is the observation
that the pathologic changes in the cochlea pro- Diagnosis
duced by experimental head blows in animals
are similar to those produced by intense air- Signs of a temporal bone fracture can often be
borne sound stimuli.10 These changes consist of identified on physical examination.2 If the
degeneration of hair cells and cochlear neurons fracture line transverses the tympanic annulus,
in the middle turns of the cochlea. Pure-tone the tympanic membrane is lacerated, produc-
hearing loss is usually most pronounced at 4000 ing a step-like deformity in the external
and 8000 Hz. auditory canal (see Fig. 6–1D in Chapter 6).
Cerebrospinal and hemorrhagic otorrhea are
common, and the combination of laceration of
Posttraumatic Positional Vertigo the tympanic membrane, ossicular damage,
and hemotympanum produces a conductive
Benign positional vertigo is a common sequela hearing loss. If the fracture line passes through
after any kind of head injury. The most com- the vestibule of the inner ear, the membranous
mon cause of head trauma is motor vehicle labyrinth may be torn and the vestibular and
accidents followed by common falls.11 Otoconia cochlear nerves lacerated, producing complete
are dislodged from the otolithic membrane and loss of vestibular and cochlear function. Vertigo,
typically enter the posterior semicircular canal, nausea, and vomiting are prominent for several
where they move under the influence of gravity days after the fracture, typical of any acute
and trigger episodes of vertigo. Animal studies peripheral vestibular lesion. The facial nerve
have shown that otoconia are easily dislodged may also be lacerated and loss of function may
from the otolithic membrane with high accel- be permanent unless surgical repair is insti-
erations. Karl Wittmaack performed a series of tuted. Examination of the ear can reveal hemo-
experiments on guinea pigs in Germany in the tympanum, but bleeding from the ear occurs
1930s, showing that the otolithic membrane infrequently because the tympanic membrane
could be denuded of otoconia with centrifugal remains intact. Cerebrospinal fluid (CSF) may
accelerations.12 He also noted that these ani- fill the middle ear and drain through the eusta-
mals with free-floating otoconia in their laby- chian tube into the nasopharynx. Meningitis is
rinth developed positional nystagmus, which a late complication of all types of temporal
he attributed to loading of the posterior semi- bone fractures.
circular canal cupula. As described in Chapter The diagnosis of labyrinthine concussion
10, we now know that the otoconial debris rests on the finding of acute vertigo and/or
16 Trauma 355
hearing loss after a blow to the head that did Management

not produce a fracture. In most cases, the
blow to the head is associated with a loss of There is no treatment for sensorineural hear-
consciousness (brain concussion). The diagno- ing loss secondary to temporary bone trauma
sis of posttraumatic benign positional vertigo unless there is evidence for a perilymphatic fis-
rests on finding the characteristic torsional tula (discussed later). If on the basis of audio-
vertical nystagmus after performing the metric testing and tympanometric studies a
Dix-Hallpike positioning test (see Fig. 6–6 in conductive hearing loss is identified, surgical
Chapter 6). intervention may lead to restoration of normal
High-resolution CT scanning with bone hearing. Separation of the incudostapedial joint
windows is the radiologic procedure of choice with or without dislocation of the body of the
for evaluating trauma to the temporal bone incus from the articulation with the malleus
and skull base.2 With CT scanning, one is head is the most common type of ossicular dis-
able to identify fracture lines throughout location seen with temporal bone injury.15 The
the base of the skull (Fig. 16–1). Magnetic surgeon can usually deal with these problems
resonance (MR) scanning can be of some use through a transcanal route under local anesthe-
for identifying soft tissue lesions but is of little sia using a tympanomeatal flap.
use for identifying fractures. Once the patient Damage to the vestibular apparatus results
stabilizes, a systematic evaluation of the audi- in acute symptoms, with gradual improvement
tory, vestibular, and facial nerves should be as central compensation occurs. Symptomatic
undertaken. treatment of vertigo is helpful initially, and the
Figure 16–1. Computed tomography scan of the temporal bone showing longitudinal and transverse fractures in the same
patient. The longitudinal fracture (arrowheads) crosses the middle ear, disrupting the ossicular chain, and the transverse
fracture (white arrow) enters the vestibule, damaging the membranous labyrinth. C, cochlea; ER, epitympanic recess; IAC,
internal auditory canal; IMJ, incudomalleal joint; V, vestibule.
patient is encouraged to begin vestibular exer- typically associated with a change in pressure
cises as soon as possible to accelerate the such as occurs with coughing, sneezing, or
compensation process (see Chapter 20). straining.19 The symptoms and signs are remark-
Posttraumatic positional vertigo responds to ably variable; a perilymph fistula should be con-
the particle-repositioning maneuver in a man- sidered in the differential diagnosis of sudden
ner similar to that of other varieties of benign hearing loss, recurrent vestibulopathy (particu-
positional vertigo (see Figs. 10–3 and 10–4 in larly with associated hearing loss), Meniere’s
Chapter 10). Persistent fluctuating audioves- syndrome, congenital sensorineural hearing loss,
tibular symptoms may indicate the presence of posttraumatic hearing loss and vertigo, and sta-
a perilymphatic fistula and necessitate explora- pedectomy failure (Fig. 16–2).20
tion of the middle ear (see later discussion).
The decision regarding surgical intervention in
patients with facial nerve injury secondary to History
temporal bone trauma is often difficult.2,16
As suggested earlier, most fractures do not
interrupt the continuity of the facial nerve. In
these cases, it is appropriate to observe the Sudden onset hearing loss, tinnitus,
facial weakness closely with regular follow-up vertigo associate with:
from the time of the accident. If function does • Head trauma
• Barotrauma
not return within 4 to 6 months, surgical inter- • Cough, sneeze,
vention is probably indicated.17 As a general straining, exercise
rule, regeneration of a damaged but uninter- • Cholesteatoma
rupted nerve occurs at a rate of about 1 mm a • Post-stapedectomy
• Congenital malformation
day. There is marked variability in this rate,
however; some patients show evidence of con-
tinued improvement for a year or longer after
injury. In cases of transverse fracture of the Examination
temporal bone with associated severe auditory
and vestibular loss, the likelihood of mechani-
cal disruption of the facial nerve is great, so the
decision regarding surgical intervention is eas- • Hearing loss – conductive or sensorineural
ier. In these cases, translabyrinthine decom- • Positive fistula test
• ENG – Spontaneous nystagmus, caloric
pression and repair of the facial nerve may be hypoexcitability
achieved because there is already a total loss of
auditory and vestibular function. Some cases of
severe blunt head injury may result in a tear
of the facial nerve at the root entry zone into Management
the brain stem. These patients invariably have
a prolonged period of unconsciousness at the
time of the accident, and there are nearly
always associated symptoms and signs of brain- Bed rest, elevate head,
stem injury. Obviously, there is little prospect antivertiginous medication,
avoid straining
for recovery of facial nerve function with this
type of lesion.
Recurrent symptoms
PERILYMPH FISTULA
A perilymph fistula results when there is a break
in the bony labyrinth or the oval or round win- Explore middle ear
dows, allowing perilymph to leak out.18 The most
common symptoms associated with a perilymph Figure 16–2. Algorithm for diagnosis and management of
fistula are vertigo, tinnitus, and hearing loss, a perilymph fistula. ENG, electronystagmography.
16 Trauma 357
The cause of a fistula is obvious when there leak, which may either deflect the cupula of
is a disruption of the otic capsule or a tear in one of the semicircular canals or create a shear
the bony labyrinth associated with trauma, sur- force on one of the maculae.18 More persistent
gery, or infection; spontaneous fistulae are dizziness may be the result of permanent
more difficult to explain.19 A sudden negative damage to the vestibular sensory receptors.
or positive pressure change in the middle
ear from violent nose blowing, sneezing, or
barotraumas could lead to rupture of the round Diagnosis
window. Flying with a common cold and poor
middle ear equalization should be avoided.21 A The classical presentation of an acute peri-
sudden increase in cerebrospinal fluid (CSF) lymph fistula is a sudden audible pop in the ear
pressure associated with lifting, straining, immediately followed by hearing loss, vertigo,
coughing, or vigorous activity leads to a change and tinnitus, which occur in the setting of
in CSF pressure that is transmitted to the inner trauma or substantial pressure change (e.g.,
ear via the cochlear aqueduct and/or internal decent on airplane, sneeze, etc.). The key to
auditory canal (see Chapter 2). A direct force the diagnosis is to identify the characteristic
through the auditory canal that damages the precipitating factors listed in Figure 16–2.
ossicular chain may rupture the oval window, Nonspecific imbalance and disequilibrium
producing a large perilymph fistula.22,23 aggravated by quick head movements or sud-
Perilymph fistulae may also be associated with den turning may result from chronic perilymph
developmental abnormalities of the middle or fistulae. Patients report aggravation of these
inner ear (e.g., Mondini malformation, defects symptoms in certain head positions, preferring
in the stapes footplate, malformations of the to sleep on one side rather than on the other to
stapedial arch). Recurrent meningitis can result avoid an ill-defined uncomfortable “dizzy” sen-
from a congenital perilymph fistula.24 sation. The latter feature might suggest benign
positional vertigo, but such patients do not
show the characteristic torsional vertical parox-
Pathophysiology ysmal positional nystagmus. Occasionally, peri-
lymph fistulae are discovered during middle
How leakage of perilymph leads to fluctuating ear exploration for other reasons in a patient
vestibular and auditory symptoms is unclear. with auditory or vestibular symptoms.
Removal of the round window in animals has Unfortunately, there is no pathognomonic
little effect on cochlear electrical potentials,25 test for a perilymphatic fistula. A positive fistula
and the perilymphatic space is routinely test (see Chapter 6) is suggestive but not spe-
entered during stapedectomy surgery, usually cific. False negatives are common, and false
without sequelae. The cochleosacculotomy positives occur with Meniere’s syndrome and
operation for Meniere’s syndrome produces after stapedectomy. Furthermore, dizziness and
a round-window membrane puncture, yet imbalance are occasionally reported by normal
the incidence of postoperative sensorineural subjects when the air pressure is changed in the
hearing loss is less than 25%.26 Although the external auditory canal during routine pneuma-
sensorineural hearing loss associated with peri- toscopy. Auditory examination may identify
lymph fistulae is usually not reversible, patients either a conductive or sensorineural hearing
have occasionally been reported with dramatic loss, and a unilateral caloric hypoexcitability
recovery of hearing as long as 10 years after the may appear on electronystagmography (ENG);
onset of hearing loss.27 Obviously, such patients these findings are not unique to a perilymph fis-
could not have had irreversible damage of their tula. Even when the middle ear is explored at
sensory epithelium. Presumably, the perilymph the time of surgery, serum or local anesthetic
fistula leads to aberrant or inefficient transmis- introduced into the middle ear may be mistak-
sion of mechanical energy within the cochlea. enly identified as leaking perilymph. Mini-
Vestibular symptoms are even more difficult endoscopes allow the surgeon to explore the
to explain on the basis of perilymph fistulae. middle ear under more natural conditions, but
How would such a leakage lead to stimulation this technique has not proved to be sensitive or
of the vestibular receptors? Pressure changes specific for perilymph fistula.28 Fluid identified
presumably displace fluid toward the site of the in the middle ear can be analyzed for substances
found in CSF and perilymph but not in serum perilymph fistula, where perilymph leaks from
(e.g., beta 2 transferrin, prostaglandin D syn- the inner ear, dehiscence of the bony capsule sur-
thase).29,30 It is hoped that these newer diagnos- rounding the semicircular canals results in inap-
tic studies will enable the surgeon to identify propriate activation of the affected canal when
perilymph fistula before surgery. Computed pressure waves enter the inner ear. Episodes of
tomography scanning of the temporal bone can vertigo can be triggered by sound (Tullio phe-
identify erosion of the otic capsule by infection nomenen) or positive or negative pressure
or tumor (see Fig. 9–2 in Chapter 9). changes in the ear or CSF.33 Eye movement
recordings during the episodes of vertigo show
bursts of nystagmus in the plane of the affected
Management semicircular canal. The anterior (superior) canal
is most frequently involved since normally there
The great majority of perilymph fistulae heal is only a thin plate of bone separating the apex of
spontaneously without intervention. For this the canal from the middle fossa. In some patients
reason, most authors advocate conservative the bone is so thin it cannot be seen on CT (on
management with an initial period of bed rest, either side). Presumably this thin bony plate can
sedation, head elevation, and measures to be fractured by minor trauma. Typically infec-
decrease straining. The one exception to this tiom or cholesteotoma are associated with poste-
conservative approach might be acute barotrau- rior or horizontal canal involvement.34,35
mas in which immediate exploration has been Vertigo attacks may occur after loud noise,
advocated,31 but randomized controlled trials exertion, straining, coughing, or sneezing.
are lacking. Persistent auditory and vestibular Exposure to continuous loud noise can cause
symptoms after the classical presentation of a prolonged nonspecific dizziness.33,36 Sudden
perilymph fistula are indications for explora- drop attacks can occur even without vertigo.37
tion of the middle ear after an initial trial of The most common auditory symptoms are auto-
conservative management. The rate of occur- phony of voice and sensation of blocking in the
rence of spontaneous fistulae continues to be a ear.36 Bone conduction is increased and air con-
controversial issue. Endoscopic studies indi- duction decreased, leading to the characteristic
cate a much lower incidence than has been air/bone gap on audiometry. Vibration any-
generally reported in the literature.32 The peri- where in the body can often be heard in the
lymph leak may become apparent only when affected ear. Patients may hear their pulse or
the patient is placed in the Trendelenburg even their eye movements. This clinical presen-
position, after performing a Valsalva maneuver, tation can mimic middle ear disease and patients
after jugular vein compression, or with manip- may undergo inappropriate middle ear surgery.
ulation of the ossicular chain.
The goal of surgery is to stabilize the hearing
loss and relieve vestibular symptoms. The middle Pathophysiology
ear is typically entered through a posterior tym-
panotomy.20 Most often the fistula is in the area The symptoms and signs of semicircular canal
of the oval window. Most surgeons will patch the dehiscence can be explained by the presence of a
oval window region with perichondrium or fascia pathological “third window.”33,34 The inner ear
and cover the graft with gelatin sponge (Gelfoam). fluid compartments are normally completely sur-
Recurrence of symptoms after repair occurs in at rounded by the bone of the otic capsule. Since the
least 10% of cases; rarely, intractable symptoms inner ear fluids are incompressible, an inward dis-
will necessitate destructive surgery with laby- placement of the stapes at the oval window is
rinthectomy or nerve section. accompanied by an outward displacement of the
round window. This fluid flow produces a pres-
sure gradient along the length of the basilar mem-
SEMICIRCULAR CANAL brane. The presence of a third window allows a
DEHISCENCE SYNDROME portion of the sound energy to be shunted away
from the cochlea, activating the affected semicir-
Normally there is a bony capsule completely cular canal and resulting in loss of hearing sensitiv-
surrounding the semicircular canals. Dehiscence ity to air-conducted sound. Any positive or negative
of this bony capsule can cause a wide range of pressure change in the external ear canal or CSF
vestibular and auditory symptoms. Unlike a can activate the affected canal (Fig. 16–3).38
16 Trauma 359
A
Endolymphatic sac
CSF
Dura mater
Cochlear aqueduct
Superior canal Endolymphatic duct
Posterior Scala vestibuli
canal
Perilymph
Horizontal
canal Cochlear duct
Scala tympani
Saccule
Endolymph
Utricle Rounded window
Oval
window
B C D
Figure 16–3. Mechanism of symptoms and signs with superior semicircular canal dehiscence syndrome. (A) Schematic
drawing of inner ear. There are normally two windows in the bony capsule—the oval window (filled by the stapes foot plate)
and the round window. A third window in the bony wall of the superior semicircular canal leads to vertigo and nystagmus
with loud sounds or pressure changes in the middle ear or CSF (B and C). If the window is large enough, the superior semi-
circular canal can be blocked (D). See text for details. (From Baloh RW. Superior semicircular canal dehiscence syndrome:
Leaks and squeaks can make you dizzy. Neurology. 2004;62:684 with permission).
Bone-conducted hearing normally results pressure in the external ear canal or a Valsalva
because of higher impedance at the round win- maneuver against a closed glottis (taking a deep
dow compared to the oval window.34 A patho- breath and bearing down) results in an inhibi-
logical third window on the vestibular (oval tory ampullopetal displacement of the cupula
window) side of the cochlear partition lowers of the superior canal, producing torsional
the impedance on the vestibular side (round downbeat nystagmus (see Fig. 16–3B).38
window), increasing the cochlear response to Vibration applied to the suboccipital cranium
bone conduction. Thus, the air/bone gap typi- may also trigger nystagmus.39 Nine out of ten
cally seen with semicircular canal dehiscence is patients have an air/bone gap (conductive hear-
due to a combination of decreased air conduc- ing loss) on audiometric testing (Fig. 16–4A,B).
tion and increased bone conduction. Many of these show bone-conduction thresh-
olds less than 0 dB at 250 and 500 Hz. Key
findings that separate canal dehiscence from
Diagnosis middle ear causes of conductive hearing loss
are a normal acoustic reflex and a hyperactive
The diagnosis of semicircular canal dehiscence VEMP (decreased threshold). These reflexes
rests on finding the characteristic symptoms are usually absent with middle ear causes of
and signs (Table 16–1) in a patient with dehis- conductive hearing loss.36,40,41 High-resolution
cence of a semicircular canal on CT of the tem- CT with thin cuts reformatted in the planes of
poral bone. Loud noise or pressure changes in the semicircular canals identifies areas of dehis-
the ear or CSF may trigger brief bursts of cence (Fig. 16–4C,D).33,42,43 False positives are
nystagmus in the plane of the affected canal. not uncommon, however, so the report of
For the most common superior canal syn- dehiscence alone without clear clinical symp-
drome, positive pressure in the external ear toms and signs does not make the diagnosis.44
canal or a Valsalva maneuver against pinched
nostrils (forcing air into the middle ear through
the eustachian tube) causes inward displace- Management
ment of the stapes and excitatory ampullofugal
displacement of the cupula of the superior Conservative management is a valid option and
semicircular canal, producing an upbeating one that many patients select, since patients can
torsional vertical nystagmus in the plane of the learn to avoid symptom triggers and the most
canal (see Fig. 16–3A). Conversely, negative common symptoms are brief and transient.
Several different surgical procedures have been
Table 16–1 Symptoms and signs used to treat semicircular canal dehiscence, but
of dehiscence of the superior randomized controlled trials and studies with
semicircular canal long-term follow-up are lacking. For the supe-
rior semicircular canal syndrome, initially a
Symptoms Signs middle fossa approach was used to resurface
the canal but delayed hearing loss occurred in
Sound-induced Sound-induced
several patients.33,45 Subsequently plugging or
vertigo—“Tullio nystagmus, eye
phenomenon” movement, head tilt capping the canal produced overall better
Pressure-induced Pressure-induced results.46,47 More recently a transmastoid
vertigo—coughing, nystagmus, eye approach was reported to be as effective as the
blowing nose, movement, head tilt middle fossa approach without the need for a
straining prolonged hospital admission.48 Vestibular
Hyperacusis to bone- Conductive hearing nerve section and occlusion of the round win-
conducted sound— loss dow are other options for refractory cases.49
hear pulse, eye
movements
Chronic disequilibrium Increased vestibular-
evoked myogenic BRAIN TRAUMA
potentials
Oscillopsia Decreased VOR gain in The most common mechanism of brain injury
plane of superior canal with blunt head trauma is movement and
16 Trauma 361
A Right ear Left ear

250 500 1k 2k 4k 8k 250 500 1k 2k 4k 8k
0
20
40
60
Hearing level in dB
80
100
B 250 500 1k 2k 4k 8k 250 500 1k 2k 4k 8k
0
20
40
60
80
100
Frequency in Hz
Figure 16–4. Audiograms from 2 patients with superior semicircular canal dehiscence syndrome (A) and (B) show a
low-frequency air-bone gap on the affected side. High-resolution CT images of the temporal bones (C) and (D) show
dehiscence of the superior semicircular canal on the affected side. Arrows point to where there is normally a thin bony roof
to the superior canal. (From Brantberg K, Ishiyama A, Baloh RW. Drop attacks secondary to superior canal dehiscence
syndrome. Neurology. 2005;64:2126 with permission).
deformation of the brain within the skull. When brain damage. Usually the loss of conscious-
the rapidly moving head is suddenly stopped, ness lasts for only a few minutes, although
the viscoelastic brain continues to move and residual symptoms may last for months to years
may rotate in the skull around the axis of the (see later discussion). The mechanism for such
brain stem. The internal shearing and stress a brief loss of consciousness and rapid recovery
forces traumatize neurons and disrupt axons is unknown. Often the terms concussion and
and blood vessels. The latter may cause multi- mild traumatic brain injury are used inter-
focal petechial hemorrhages or even massive changeably.50
intracerebral hemorrhage. The term concus- Most patients who suffer concussion proba-
sion refers to a brief loss of consciousness after bly have some injury to brain cells, but nearly
head trauma unassociated with focal neuro- all rapidly regain function within minutes of
logic signs or radiologic evidence of structural the injury. They can usually remember the
events up to a few moments before the injury These patients do not produce saccades, so a
and have little or no retrograde amnesia. The “normal” response is a conjugate tonic devia-
blow itself is rarely recalled, and there is invari- tion of the eyes toward the side of a cold stimu-
ably a brief period of memory loss following lus or away from the side of a warm stimulus.
the injury (posttraumatic amnesia). The dura- Absence of this tonic deviation affirms that the
tion of postconcussion symptoms and signs var- brainstem vestibulo-ocular reflex pathways
ies with the intensity of the blow and the degree have been damaged, assuming that the eighth
of brain deformity.51 nerve and end organs are intact. Unilateral loss
of tonic deviation or nonconjugate deviation
indicates focal involvement of the reflex path-
Intracranial Complications ways. The absence of caloric responses after an
Associated with Temporal Bone acute head injury is a poor prognostic sign.54
Fractures
In most cases of temporal bone fracture, brain Postconcussion Syndrome
injuries overshadow injuries to the labyrinth or
eighth nerve. In a series of 43 patients treated The postconcussion syndrome has long been the
for temporal bone fractures at Temple center of medical–legal controversy.55–57
University in Philadelphia over 3 years, 19 Symptoms include dizziness, headache (usually
patients (44%) required an open neurosurgical diffuse), increased irritability, insomnia, forget-
procedure.52 Subarachnoid hemorrhage, sub- fulness, mental obtuseness, and loss of initia-
dural hemorrhage, and cerebral edema were tive—all of which occur after a concussion.
the most common brain findings. Four patients Because of the ill-defined nature of these symp-
died (all due to neurological causes) and seven toms, it is difficult to localize the site of lesion
required institutional care after discharge. and the patient is frequently diagnosed as being
Most patients had a prior history of significant psychoneurotic (compensation neurosis). The
alcohol or drug use. dizziness associated with the postconcussion
syndrome is nearly always nonspecific; patients
use terms such as swimming, light-headed, float-
Dizziness Due to Brainstem Trauma ing, rocking, and disoriented to describe the
sensations they feel. If vertigo is present, an addi-
Brainstem injury from blunt head trauma is not tional labyrinthine lesion should be suspected.
a common cause of isolated auditory and ves- Rutherford and colleagues58 followed 145
tibular symptoms. Severe head blows may pro- patients with concussion from minor head inju-
duce hemorrhage or infarction in the brain ries to assess the type and frequency of symp-
stem, but these pathologic changes are invari- toms and to evaluate whether the symptoms
ably associated with alteration in the level of correlated with the severity of injury, associ-
consciousness and multiple neurologic signs. ated neurologic signs, or other circumstances
In their classic study, Mitchell and Adams53 related to the injury. Concussion was defined
sectioned the brain stem in 100 cases of fatal as a period of amnesia—no matter how brief—
blunt head injury. Only 18 patients showed no caused by a blow to the head. All of the patients
evidence of increased intracranial pressure, were released from the hospital after a brief
and of these, only 7 had abnormalities in the observation. Table 16–2 lists the symptoms and
brain stem attributable to the primary impact. their frequency of occurrence reported by the
In these seven patients, other areas of the brain 145 patients 6 weeks after the concussion.
were damaged, suggesting to the authors that Approximately one-half were symptom-free,
so-called primary brainstem injury does not but the other half complained of one or more
exist but, rather, is one aspect of diffuse brain symptoms. In those patients with multiple
damage. As a general rule, isolated episodes of symptoms, no consistent pattern was found
vertigo occurring after brain trauma should not to support the concept of a postconcussion
be attributed to brainstem injury. syndrome. A significant correlation existed
Caloric examination can be particularly help- between the presence of multiple symptoms
ful in evaluating the brainstem status in patients at 6 weeks and the occurrence of positive
who are comatose from blunt head injuries. neurologic signs and symptoms within 24 hr of
16 Trauma 363
Table 16–2 Symptoms Reported usually disappears as the swelling and pain sub-
6 Weeks after Concussion in 145 side. The occasional finding of unilateral caloric
Patients58 hypoexcitability is likely due to associated laby-
rinthine trauma.
Symptom n (%) From the known anatomic substrate for
neck–vestibular interaction (see Chapter 3), it
Headache 36 24.8 is unlikely that lesions involving only soft tis-
Anxiety 28 19.3 sues of the neck could produce vertigo and dis-
Insomnia 22 15.2 equilibrium. The major neck afferent input to
Dizziness 21 14.5 the vestibular nuclei arises from the paraverte-
Irritability 13 9.0 bral joints and capsules, with relatively minor
Fatigue 13 9.0 input from the paravertebral muscles. The
Loss of concentration 12 8.3 skin and superficial muscles do not appear to
Loss of memory 12 8.3
provide any input to the vestibular system. In
Hearing defect 10 6.9
addition, the relative contribution of neck affer-
Sensitivity to alcohol 9 6.2
ent input to the vestibular nuclei is small com-
Depression 8 5.5
pared with the direct labyrinthine and indirect
Visual defect 7 4.8
visual signals transmitted via other brainstem
Anosmia 4 2.8
nuclei and the cerebellum. Lesions involving
Epilepsy 3 2.1
Diplopia 2 1.4
the neck afferents in primates are rapidly com-
Other 16 11.0
pensated, and therefore prolonged dizziness
No symptoms 71 49.0
after neck injuries of any type would be diffi-
cult to explain on the basis of damage to the
neck afferent input to the vestibular nuclei.
the concussion. Postconcussion symptoms were
more frequent in women and in patients who
blamed their employers or large impersonal Diagnosis
organizations for their accidents. The authors
concluded that both organic and psychosomatic Persistent dizziness after a blunt head injury
factors were involved in the pathogenesis of often poses a difficult diagnostic dilemma
postconcussion symptoms. Although modern (Table 16–3). The diagnosis of postconcussion
neuropsychiatric and electrophysiologic stud- syndrome rests on finding the characteristic
ies can identify subtle brain abnormalities in symptoms in the absence of focal neurologic
most patients with postconcussion syndrome, findings. A careful neurotologic examination
the type and degree of abnormality do not cor- should identify most specific syndromes that
relate with the severity of symptoms, and psy- require individualized treatment. Examination
chosocial factors continue to be important in of the ear may reveal evidence of a temporal
long-term prognosis.57,59 bone fracture or perilymph fistula, positional
testing may reveal benign paroxysmal posi-
tional nystagmus, and neurologic examination
Whiplash Injuries may identify signs of brainstem damage.
Standard audiometric, brainstem auditory-
A perplexing problem because of the frequency evoked response (BAER), and ENG testing
of occurrence and the medical–legal ramifica- methods are useful to assess the functional sta-
tions is the role of soft-tissue injuries of the tus of the auditory and vestibular systems and
neck in producing dizziness and disequilib- thus can be used to document intact physiolog-
rium.60,61 Patients often describe the dizziness ical and quantifiable laboratory measures
in nonspecific terms such as lightheaded, swim- of the audio-vestibular system, though false-
ming, off-balance, floating, and rocking; as with positive and false-negative results are not
psychophysiologic dizziness, they may describe uncommon. Neuroimaging is usually helpful
a sensation of spinning inside the head unas- only when there are focal findings on the neu-
sociated with an illusion of movement or with rologic examination.
spontaneous nystagmus. The dizziness may last Computed tomography scanning is most
for months or years after the injury, although it useful for evaluating the base of the skull and
Table 16–3 Differential Diagnosis of Persistent Dizziness after Head Trauma

Diagnosis Dizziness Exam Laboratory
Benign positional Brief episodes, position Fatigable positional Normal
vertigo induced nystagmus
Labyrinthine Severe initially, gradual Peripheral Caloric vestibular paresis,
concussion improvement spontaneous unilateral hearing loss
nystagmus
Perilymph fistula Fluctuating, induced by Positive fistula test Caloric vestibular paresis,
coughing, sneezing, unilateral hearing loss
straining
Brain stem Severe, associated brain Focal neurologic signs MR scan shows focal lesions
contusion stem symptoms
Postconcussion Continuous, associated Normal Normal
syndrome headaches, irritability, etc.
for identifying blood in the subarachnoid or transient period, but prolonged use should be
subdural space and within the brain paren- avoided as dependency is common. Endogenous
chyma in the acute setting. Magnetic resonance depression is a common sequela after brain
scanning is best for identifying brain contusion injury, and antidepressant medications (e.g., tri-
and edema. cyclic amines, selective serotonin reuptake
inhibitors [SSRIs]) may be helpful in severe
cases. Although recovery is the rule, some
Management patients will have persistent symptoms for years
after a concussion. Although there is a positive
Management of traumatic brain injuries has correlation between the severity of head injury
become increasingly sophisticated with the and the length of postconcussion symptoms, one
development of electronic and chemical moni- cannot reliably judge the prognosis for recovery
toring devices and advances in critical care based on the nature of the head injury.
medicine. So far, however, clinical trials of Soft-tissue injuries of the neck are usually
neuroprotective drugs have been largely unsuc- associated with focal muscle tenderness and
cessful.62 Acute surgical intervention is usually spasm. Initial management consists of rest and
aimed at relieving intracranial pressure most immobilization with a soft collar to allow the
commonly associated with hemorrhage. The muscle contusions to heal. Once serious prob-
degree of recovery after a closed head injury lems have been ruled out, the patient should
typically depends on the severity of the injury. be reassured that there is no evidence of neu-
As a general rule, the major part of the recov- rologic damage and that the symptoms nearly
ery occurs within the first 6 months. Physical always spontaneously disappear. As in patients
rehabilitation should begin as soon as practical with postconcussion syndrome, it is important
after the acute effects of the head injury have to begin a gradual exercise program as the
subsided. It is important that the patients and acute soft-tissue injuries heal. Heat and mas-
their families are counseled regarding the sage along with judicious use of pharmacologic
expected rate of recovery and whether perma- muscle relaxation provide relief of the muscle
nent deficits are expected. spasm, which may come and go for weeks to
Treatment of the postconcussion syndrome months. Active range-of-motion exercises per-
begins by providing the patient with reassurance formed on a regular basis provide the best
that there is no evidence of structural damage, long-term relief of muscle spasm. Patients
that the symptoms are not unusual after head should be encouraged to sleep with a single flat
injury, and that they nearly always resolve over pillow and avoid long periods of hyperflexion of
time. The patient should be encouraged to the neck. In our experience, the nonspecific
return to a normal exercise level gradually, even dizziness associated with whiplash injuries
though initially the dizziness and other symp- improves as the local symptoms of muscle
toms may be aggravated.63 Tranquilizers such as spasm and stiffness subside (assuming the
diazepam and alprazolam can be useful for a medicolegal aspects can be resolved).
16 Trauma 365
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45. Peterson EC, Lazar DA, Nemecek AN, Duckert L, injury: a review of the post-concussive syndrome.
Rostomily R. Superior semicircular canal dehiscence J Clin Exp Neuropsychiatry. 1986;8:323.
syndrome: successful treatment with repair of the mid- 57. Mickeviciene D, Schrader H, Obelieniene D, et al. A
dle fossa floor: technical case report. Neurosurgery. controlled prospective inception cohort study on the
2008;63(6):E1207. post-concussion syndrome outside the medicolegal
46. Crane BT, Minor LB, Carey JP. Superior canal context. Eur J Neurol. 2004;11(6):411.
dehiscence plugging reduces dizziness handicap. 58. Rutherford WH, Merrett JD, McDonald JR. Sequelae
Laryngoscope. 2008;118(10):1809. of concussion caused by minor head injuries. Lancet.
47. Vlastarakos PV, Proikas K, Tavoulari E, Kikidis D, 1977;1:1.
Maragoudakis P, Nikolopoulos TP. Efficacy assess- 59. Fenton GW. The postconcussional syndrome reap-
ment and complications of surgical management praised. Clin Electroencephalogr. 1996;27:174.
for superior semicircular canal dehiscence: a meta- 60. Partheni M, Constantoyannis C, Ferrari R, Nikiforidis
analysis of published interventional studies. Eur Arch G, Voulgaris S, Papadakis N. A prospective cohort
Otorhinolaryngol. 2009;266(2):177. study of the outcome of acute whiplash injury in
48. Deschenes GR, Hsu DP, Megerian CA. Outpatient Greece. Clin Exp Rheumatol. 2000;18(1):67.
repair of superior semicircular canal dehiscence via 61. Rowlands RG, Campbell IK, Kenyon GS. Otological
the transmastoid approach. Laryngoscope. ePub ahead and vestibular symptoms in patients with low grade
of print, June 24, 2009. (Quebec grades one and two) whiplash injury.
49. Silverstein H, Van Ess MJ. Complete round window J Laryngol Otol. 2009;123(2):182.
niche occlusion for superior semicircular canal dehis- 62. Xiong Y, Mahmood A, Chopp M. Emerging treat-
cence syndrome: a minimally invasive approach. Ear ments for traumatic brain injury. Expert Opin Emerg
Nose Throat J. 2009;88(8):1042. Drugs. 2009;14(1):67.
50. Bigler ED. Neuropsychology and clinical neurosci- 63. Willer B, Leddy JJ. Management of concussion and
ence of persistent post-concussive syndrome. J Int post-concussion syndrome. Curr Treat Options
Neuropsychol Soc. 2008;14(1):1. Neurol. 2006;8(5):415.
Chapter 17
Toxic/Metabolic Disorders
DIZZINESS AND SYSTEMIC METABOLIC Management

DISORDERS OTOTOXINS
Diabetes Mellitus Aminoglycosides
Uremia “Loop” Diuretics
Hypothyroidism Anti-inflammatory Drugs
Alcohol and Thiamine Deficiency Platinum Compounds
Management Diagnosis
METABOLIC DISORDERS OF THE Management
TEMPORAL BONE NEUROTOXINS
Otosclerosis Heavy Metals
Paget’s Disease Organic Solvents
Other Disorders Diagnosis
DIZZINESS AND SYSTEMIC diffuse central nervous system (CNS) connec-

METABOLIC DISORDERS tions. The most common finding in the labyrinth
at necropsy in patients with diabetes mellitus is
Diabetes Mellitus a thickening of the capillary walls, which is most
prominent in the vascular stria of the cochlea,
Auditory and vestibular symptoms and signs are where it may account for the progressive, bilat-
common in patients with diabetes mellitus, but eral high-frequency hearing loss characteristic
convincing evidence does not exist for a specific of the disease.7 Similar changes are found in the
type of diabetic lesion of the inner ear or eighth vestibular end organs; these, along with degen-
nerve.1–5 In those diabetic patients with audiove- eration of vestibular nerve and ganglion, could
stibular dysfunction whose temporal bones and explain complaints of chronic disequilibrium
nervous systems have been studied at necropsy, and dizziness in diabetic patients.8
pathologic changes can be explained on the basis Sudden onset of hearing loss and/or vertigo
of associated vascular disease.6–8 Three types of in patients with diabetes mellitus can result
vascular changes occur with diabetes mellitus: from occlusion of the vessels to the labyrinth or
(1) microangiopathy with thickening of the base- the eighth nerve. The prevalence of diabetes
ment membrane of small vessels, (2) arterioscle- mellitus was significantly higher in patients
rotic narrowing of small arteries and arterioles, with idiopathic sudden sensorineural hearing
and (3) atherosclerotic narrowing of the large loss compared with age- and sex-matched con-
arteries. These vascular changes may damage trols.9 Cranial nerve mononeuropathies are a
the auditory and vestibular system from the well-known clinical phenomenon associated
peripheral end organs and eighth nerve to their with diabetes mellitus; they are most likely due
367
to arteriosclerotic occlusion of arterioles sup- tissue of the maculae and cristae in seven of
plying the cranial nerve. Atherosclerosis of the eight patients. The source of these abnor-
larger vessels predisposes the patient to tran- mal deposits is unknown. Chronic dialysis is
sient vertebrobasilar insufficiency and to spe- also associated with several neurological syn-
cific occlusive syndromes, such as the anterior dromes, including the disequilibrium syn-
vestibular artery syndrome and the lateral med- drome, subdural hematoma, and Wernicke’s
ullary syndrome (see Chapter 14). Postural encephalopathy.14
hypotension is a common cause of presyncopal
light-headedness in patients with diabetic
mellitus.10 Hypothyroidism
A symmetrical, mild to moderate sensorineural
Uremia hearing loss is commonly associated with spo-
radic, nonendemic hypothyroidism.15,16 Vertigo
Multiple causes of auditory and vestibular may also occur in hypothyroid patients,
symptoms can be identified in patients with although there is no vertiginous syndrome that
chronic renal disease. The same pathologic is characteristic of this disorder. Some investi-
process can affect both the kidneys and the gators have found a high incidence of hypothy-
labyrinths, as seen in Alport’s syndrome (hered- roidism in patients with idiopathic Meniere’s
itary nephritis and deafness; see Chapter 18), syndrome but others have not.17,18 Thyroid hor-
diabetes mellitus, and Fabry’s disease. Immu- mone is critical for the normal development of
nosuppressive treatment either of the primary both the auditory and vestibular systems.
renal disorder or to avoid transplant rejection Congenital hypothyroidism in rats leads to loss
predisposes the patient to otologic infections, of auditory and vestibular function, and replace-
often with exotic or saprophytic organisms.11 ment hormone in the early stages of postnatal
Patients with renal disease are particularly vul- development prevents the loss of function.19
nerable to the ototoxic effects of aminoglyco- Similarly, there appears to be a critical thera-
side antibiotics and loop diuretics because of peutic window for preventing hearing loss in
their inability to clear these substances from children with congenital hypothyroidism.20
the blood; ototoxicity is probably the most com- Auditory and vestibular abnormalities have also
mon cause of auditory and vestibular symptoms been documented in animals who have been
in uremic patients (see “Ototoxins”). made hypothyroid.21 However, these abnor-
Hyponatremia causes reversible hearing loss malities typically do not recover after hormone
and tinnitus in patients undergoing chronic replacement.
hemodialysis. There is a high degree of correla-
tion between the hearing loss and serum sodium
levels, irrespective of the blood urea level.12 Alcohol and Thiamine Deficiency
The hearing loss can be corrected in most
patients by returning the serum sodium level to ACUTE TOXIC EFFECTS OF ALCOHOL
normal. Patients undergoing chronic hemodi-
alysis and those receiving kidney transplants Acute alcohol intoxication is regularly associ-
often experience ill-defined fluctuating ated with unsteadiness of gait, slurring of
auditory and vestibular symptoms. Oda and speech, and, occasionally, vertigo. The gait
colleagues13 performed necropsy studies on ataxia and slurring of speech suggest cerebellar
temporal bones of eight patients with chronic dysfunction, but an additional vestibular com-
uremia who had undergone long-term hemodi- ponent may be involved. In animal studies,
alysis therapy (24 to 546 treatments). At alcohol selectively interferes with synaptic
least one kidney transplant was performed transmission within the vestibular nuclei.22
in seven of the eight patients. Vestibular Vestibular function testing with rotational
symptoms occurred in five patients and audi- stimulation in patients with alcohol intoxication
tory symptoms in three—all symptoms began has shown normal vestibulo-ocular reflex
after the start of hemodialysis. Abnormal con- gain in the dark, but impaired fixation suppres-
cretions were found in the vascular stria of the sion of vestibular nystagmus consistent with
cochlea and in the subepithelial connective cerebellar dysfunction.23,24 Slowing of saccades
17 Toxic/Metabolic Disorders 369
Right lateral position

10
Slow phase velocity

(deg/sec)
0
800
10
Left lateral position
Right-beating nystagmus
0.1
Left-beating nystagmus
Blood alcohol
(percent)
0.05
0
0 400 800
Time (minutes)
Figure 17–1. Direction-changing positional nystagmus after a normal subject ingested 150 ml of whiskey. Nystagmus
initially beat toward the ground (undermost ear) in both lateral positions, but as the blood alcohol level decreased, the
nystagmus beat away from the ground in both lateral positions.
and smooth pursuit is consistently found in nystagmus (primary phase) are given H3O, the
subjects after only moderate alcohol nystagmus disappears. Alcohol and heavy-
ingestion.25–27 Gaze-evoked nystagmus is a reli- water direction-changing positional nystagmus
able sign of intoxication, the magnitude of are likely due to a different rate of diffusion of
which is highly correlated with the blood alcohol and heavy water into the cupula and
alcohol concentration.28 the surrounding endolymph.30 In the primary
Positional vertigo is another well-documented phase of alcohol positional nystagmus, alcohol
effect of alcohol on the vestibular system rapidly diffuses into the base of the cupula
(Fig. 17–1).29 Within 30 min after ingesting a because of the latter’s proximity to blood capil-
moderate amount of alcohol (e.g., 150 ml of laries while it slowly diffuses into the endo-
whiskey), the subject develops a direction- lymph. The cupula then has a lower specific
changing static positional nystagmus often gravity than that of the endolymph and acts as
associated with vertigo. The positional nystag- a gravity-sensing organ, maintaining a slight
mus beats to the right in the right lateral posi- deflection as long as the position is held. After
tion, to the left in the left lateral position, and is approximately 3 hr, the endolymph and cupula
inhibited by fixation. The primary phase of the have approximately the same alcohol concen-
positional nystagmus reaches its peak in about tration, and the positional nystagmus disap-
2 hr, at approximately the time of peak blood pears. As the blood alcohol level falls, the
alcohol level (near 0.1% for the earlier exam- reverse situation occurs, with the cupula being
ple). Four to 5 hr after alcohol ingestion, when heavier than the surrounding endolymph, and
the blood alcohol level is below 0.01%, posi- the secondary phase of positional nystagmus
tional nystagmus is still present, but now it is occurs.
right-beating in the left lateral position and Three-dimensional recordings of alcohol
left-beating in the right lateral position (sec- positional nystagmus showed that the buoyancy
ondary phase). The positional nystagmus can mechanism accounts for only part of the
last up to 12 hr, at which time alcohol cannot observed nystagmus.31 After consuming alco-
be detected in the blood. hol, subjects were positioned so that the hori-
Direction-changing positional nystagmus in zontal canals were earth-vertical and then
the reverse direction of primary alcohol posi- rotated in the plane of the horizontal canals
tional nystagmus can be produced by giving about an earth-horizontal axis to either 45
subjects heavy water—H3O.30 When subjects degrees or 90 degrees, right or left ear down.
with alcohol direction-changing positional Spatial analysis of the recorded eye movements
showed that in addition to the positional nys- involving arterioles and capillaries on the arte-
tagmus attributed to the buoyancy of all six rial side.41 The medial vestibular nucleus is
cupulae, there was a vertical offset (slow phase most commonly involved, but the other nuclei
down in all subjects) independent of the sub- are also involved in between 30% and 50% of
ject’s orientation in space. This offset was cases.32 The changes in the vestibular nuclei
thought to be due to toxic effects of the alcohol are relatively mild, however, compared with
on central vestibulo-ocular reflex pathways. the frank necrosis and demyelination occurring
in other areas. In the cerebellum, Purkinje cell
loss is most prominent.42 Apparently, most of
WERNICKE’S ENCEPHALOPATHY
the clinical findings (including impaired ves-
This is a common clinical syndrome caused by tibular function) are secondary to thiamine-
thiamine deficiency. In the past it was almost dependent enzyme loss in the brain stem and
exclusively associated with alcoholism but now is cerebellum, and only after prolonged and/or
commonly recognized with other causes of mal- repeated episodes of deficiency do irreversible
nutrition, including cancer, and its treatments structural changes occur.
and bariatric surgery.32–34 It is characterized by
the subacute onset of confusion, ophthalmople- CEREBELLAR DEGENERATION
gia, and ataxia of stance and gait. Dizziness and
vertigo are not common complaints. Hearing In 1959, Victor and associates43 reported a dra-
loss is a rare presenting symptom.35 The truncal matic clinical syndrome in 50 alcoholics that
ataxia is often dramatic, with the patient being was manifested by severe truncal ataxia with
unable to take even a few steps without sup- relative sparing of the upper extremities. On
port, and yet standard cerebellar function test- clinical examination, all patients exhibited
ing with finger-to-nose and heel-knee-shin is severe ataxia of stance and gait, with instability
often normal or minimally impaired. The ataxia of the trunk while standing and severe incoor-
is increased with eye closure or darkness. These dination on the heel-knee-shin test. On neuro-
findings suggest a combination of midline cer- pathologic examination, atrophy was remark-
ebellar and either proprioceptive or vestibular ably localized to the superior cerebellar vermis,
impairment. Caloric responses can be dimin- paramedian superior cerebellar hemispheres,
ished or absent.36,37 Magnetic resonance and the flocculi. Subsequent pathological stud-
imaging (MRI) of the brain typically shows ies have confirmed these findings,44 and neu-
symmetrical fluid-attenuated inversion recov- roimaging studies have documented shrinkage
ery imaging (FLAIR) hyperintensities in the of the cerebellum, particularly the superior
thalami, mamillary bodies, tectal plate, and vermis in chronic alcoholics (Fig. 17–2).45,46
periaquaductal area.38 The cerebellar damage is most likely due to
Experimental studies in thiamine-deficient malnutrition rather than direct alcohol toxicity,
rats39 and monkeys40 showed that the earliest as similar cellular changes have been seen in
pathologic changes originate in the vestibular malnourished nonalcoholics47 and some of the
nuclei, particularly in the lateral nucleus. The symptoms and signs seen with acute cerebellar
nerve terminals and axons degenerate without degeneration can be reversed with massive
evidence of damage to the neuronal parikaria. doses of thiamine.48 Still, ethanol may have
Neurologic signs appear even before these direct toxic effects on the cerebellum or pro-
early pathologic changes. Loss of transketolase mote the toxic effects of thiamine deficiency.49
activity (a thiamine-dependent enzyme) in the
lateral pontine tegmentum, including the lat-
eral vestibular nuclei, correlates better with the Management
onset of clinical signs. Injection of thiamine
promptly restores transketolase activity and There is no specific treatment for the neuroto-
improves clinical signs. logic manifestations of diabetes mellitus.
Pathologic changes are seen in the vestibular Presumably the likelihood of vascular occlu-
nuclei of patients with thiamine deficiency sion (small and large vessel) decreases with
studied at necropsy. Vascular changes include good control of blood glucose levels.49 Although
endothelial swelling in small arteries and veins it has been suggested that auditory and vestib-
and fibrinoid degeneration and hemorrhage ular dysfunctions occur in the prediabetic state,
Figure 17–2. Magnetic resonance image of the brain in a patient with alcoholic cerebellar degeneration showing atrophy
of the superior vermis (arrow). T1-weighted sagittal section.
as with the retinal and renal changes, there ventricular dilation seen on imaging of the cer-
have been no controlled studies to support this ebellum are partially reversible with abstinence
supposition. The single most important aspect from alcohol.52 Proton magnetic resonance
in preventing auditory and vestibular dysfunc- spectography showed increases in the concen-
tions in patients with uremia is to avoid the use tration of choline-containing compounds within
of potential ototoxic drugs. Careful manage- the superior cerebellar vermis in chronic alco-
ment of electrolytes in patients undergoing holics after 3 to 4 weeks of abstinence, followed
chronic renal dialysis will prevent fluctuating by a reduction in these compounds with
auditory and vestibular symptoms. The bilat- relapse.53
eral sensorineural hearing loss associated with
acquired hypothyroidism improves in a small
percentage of patients after thyroid hormone
replacement.15 METABOLIC DISORDERS OF THE
With Wernicke’s encephalopathy the oph- TEMPORAL BONE
thalmoplegia, confusion, and ataxia usually
respond rapidly to thiamine replacement.32,40 Otosclerosis
Some patients are left with a chronic memory
disorder (Korsakoff’s syndrome) as well as mild Otosclerosis is a metabolic disease of the bony
ataxia due to midline cerebellar degeneration. labyrinth that usually manifests itself by immo-
In patients receiving thiamine replacement, bilizing the stapes and thereby producing a
vestibular function as measured by serial caloric conductive hearing loss.54,55 The disease, how-
testing slowly returns toward normal over sev- ever, can less commonly involve the entire otic
eral weeks, although in some cases recovery is capsule and be associated with sensorineural
asymmetric and incomplete. As suggested ear- hearing loss and vestibular symptoms. Seventy
lier, alcoholic cerebellar degeneration may also percent of patients with clinical otosclerosis
respond to thiamine replacement. Some note hearing loss between the ages of 11 and
patients with alcoholic cerebellar degeneration 30. The disorder is most common in whites
who stop drinking exhibit a significant and (prevalence about 0.2%–1%), is infrequent in
sometimes dramatic decrease in body sway as blacks, and is almost nonexistent in Asians and
measured with posturography, compared with American Indians.56 A positive family history
patients who continued drinking.51 This for otosclerosis is reported in between 50% and
improvement after abstinence from alcohol 70% of cases. Otosclerosis is genetically hetero-
may result from central plastic changes or from geneous with rare autosomal dominant forms,
recovery of function where structural damage but the majority are due to an interaction
was not complete. The cortical shrinkage and between genetic and environmental factors.57
So far in families with autosomal dominant around blood vessels, and its replacement by
transmission at least seven monogenic chromo- cellular fibrous connective tissue.55,61,62 With
somal loci have been reported but no genetic time, immature basophilic bone is produced in
mutations identified. Three susceptibility the resorption space; after several cycles of
alleles have been identified and replicated in resorption and new bone formation a mature
case control association studies: TGFB1, BMP2, acidophilic bone with a laminated matrix is
and BMP4. All three are part of the transform- produced. Bilateral involvement is usual, but
ing growth factor-beta pathway.57 about a fourth of cases are unilateral. Areas of
Although otosclerosis is primarily a disorder predilection for otosclerotic foci include the
of the auditory system, vestibular symptoms oval window region, the round window niche,
and signs are more common than generally the anterior wall of the internal auditory canal,
appreciated. In one study,58 46% of 500 patients and within the stapedial footplate (Fig. 17–3).
with nonsurgically treated otosclerosis com- Although conductive hearing loss is the hall-
plained of vestibular symptoms. The most mark of otosclerosis, a combined conductive–
common symptoms were recurrent attacks of sensorineural hearing loss pattern is frequent.
vertigo (26%) and postural imbalance (22%). The sensorineural component is perhaps
Those patients with more severe sensorineural caused by foci of otosclerosis next to the spiral
hearing loss were more likely to have vestibular ligament of the cochlea, producing atrophy of
complaints. Abnormalities on vestibular func- the spiral ligament. About 10% of patients with
tion testing have been found in as many as 50% otosclerosis eventually develop a profound sen-
of patients tested, with the most common sorineural hearing loss across all frequencies.63
abnormality being unilateral hypoexcitability to The mechanism for the production of dizzi-
caloric stimulation.59,60 The vestibular abnor- ness in patients with otosclerosis is poorly under-
malities are more common in patients with stood. Direct mechanical deformation of the
greater sensorineural hearing loss, but they are labyrinth or biochemical abnormalities of inner
not necessarily seen in the poorer hearing ear. ear fluids are likely possibilities. Endolymphatic
The basic pathologic process of otosclerosis hydrops has been identified in a few temporal
is a resorption of normal bone, particularly bones with multiple foci of otosclerosis.64
Figure 17–3. Histopathological section showing an otosclerotic lesion involving the bony labyrinth at the anterior margin
of the oval window (small arrow) and the entire footplate of the stapes (larger arrow). The patient exhibited a combined
conductive–sensorineural hearing loss. (Courtesy Harold Schuknecht, Boston, MA.)
Sando and colleagues65 studied four temporal imperfecta,73 fibrous dysplasia,74 and osteopet-
bones of two patients with otosclerosis who rosis.75 The clinical presentation of these
complained of prominent vestibular symptoms disorders is often indistinguishable from that of
and found otosclerotic foci in opposition to the otosclerosis and of Paget’s disease.
superior vestibular nerve in each patient.
Vestibular nerve degeneration distal to these
foci was also present, and three of the four Diagnosis
temporal bones exhibited a marked degenera-
tion of the sensory epithelium of the cristae of The diagnosis of otosclerosis is based on find-
the lateral semicircular canals. ing a conductive hearing loss in a patient with
the clinical picture outlined earlier. A flat tym-
panogram with maximum compliance near
Paget’s Disease zero pressure is characteristic (see Fig. 8–4C in
Chapter 8). As the disease progresses, a mixed
Paget’s disease is a metabolic disorder of bone conductive, sensorineural hearing loss is com-
marked by pronounced osteoclastic resorption mon. About 10% of patients exhibit hyperemia
of old, fully calcified bone and deposition of new of the promontory mucosa of the middle ear,
osteoid layers that calcify normally.66–68 It usually visible through the tympanic membrane
becomes clinically manifest in the sixth decade, (Schwartze’s sign). Computed tomography
affecting men four times more commonly than (CT) may show changes in the otic capsule
women. The clinical picture varies from the (ranging from a small dehiscence in the nor-
classic one of an enlarged skull, progressive mal, crisp outline of the capsule to entire loss
kyphosis, and short stature to the more common of anatomic details), but these changes are not
restricted forms confined to the skull, spine, pel- specific for otosclerosis, as they are also found
vis, and femur. Hearing loss is a common symp- in osteogenesis imperfecta, fibrous dysplasia,
tom, initially described by Paget in his early and even some normal subjects. CT bone den-
reports and subsequently studied in detail by sity measurements at the fissula antefenestram
numerous investigators.69,70 A progressive com- may be useful for the diagnosis and as an indi-
bined sensorineural and conducting hearing loss cator of disease progression.76
is usually found. The vestibular labyrinth may The diagnosis of Paget’s disease rests on
also be progressively destroyed, resulting in finding the characteristic roentgenographic
unsteadiness of gait and, in rare cases, episodic findings of increased density of bone with loss
vertigo. In the late stages, complete destruction of the normal architecture, mingled with areas
of the bony labyrinth may occur with invasion of of decreased bone density.66 The skull is
the inner ears, fractures, and degeneration of enlarged, with indistinct margins giving a
the membranous labyrinth. “cotton wool” appearance. High-resolution CT
Genetic factors play an important role in the scans of the temporal bone typically reveal poor
pathogenesis of Paget’s disease, and so far definition of the cortical margins of the inner
mutations have been identified in four differ- ear and internal auditory canals.
ent genes.71,72 By far the most common is
SQSTM1, a gene that codes for a scaffold pro-
tein in the nuclear factor KappaB signaling Management
pathway. There is a mutation hot spot at the
UBA domain of SQSTM1 with P392L being by In small observational studies, sodium fluoride
far the most common mutation. Environmental has been associated with reduced progression
factors must explain the varied clinical expres- of otosclerosis.77,78 A single controlled study
sion within families with the mutation. from Denmark and France documented both
biochemical and audiometric changes in a
treated group of patients with otosclerosis com-
Other Disorders pared with a control group.79 At 6 months, 7%
(3/43) of treated patients had progressive hear-
Other less common metabolic disorders of ing loss (>10 dB increase from baseline in pure-
the temporal bone that are associated with tone average) whereas 25% (13/52) of the
hearing loss and dizziness include osteogenesis control patients had progressive hearing loss.
This study has some methodological limitations Table 17–1 Relative Vestibular and
(nearly a 10% dropout rate) and the results have Auditory Ototoxicities of Commonly
not been replicated. The usual dosage is 40 to Used Aminoglycosides
50 mg sodium fluoride per day, given most con-
veniently as Florical (8.5 mg sodium fluoride Vestibular Auditory
and 364 mg calcium carbonate per capsule)
plus 500 mg of vitamin D daily. The calcium Streptomycin +++ +
and vitamin D prevent secondary hyperpara- Gentamicin +++ +
thyroidism from developing. Side effects occur Tobramycin ++ ++
in as many as 20% of patients, with the most Kanamycin + +++
common being gastrointestinal upset and mus- Amikacin + +++
culoskeletal pain. Whether sodium fluoride can Dibekacin + +
reverse the vestibular abnormalities associated Netilmicin + +
Sisomicin + +
with otosclerosis is not known.
Surgical treatment of otosclerosis is directed
at improving the conductive hearing loss. Many produce both auditory and vestibular damage,
different operations have been developed, and streptomycin and gentamicin are relatively spe-
most have a high success rate. Although data cific for the vestibular system, whereas kanamy-
on the results of surgical therapy in patients cin, tobramycin, and amikacin produce more
with vestibular symptoms are not available, damage to the auditory system.81,82 The newer
there is little reason to expect improvement in aminoglycosides sisomicin, dibekacin, and
such patients. In fact, surgical therapy may netilmicin are overall less ototoxic than the older
aggravate the vestibular symptoms. Smyth80 aminoglycosides.83 Although high blood levels
detected decreased caloric responses 3 months and long durations of treatment are most likely
postoperatively in 30% of 26 ears with normal to produce ototoxicity, some susceptible patients
values preoperatively. may develop ototoxicity after a brief low-dose
Bisphosphonate reduces bone turnover, and course (see later discussion). The majority of
it has been shown to clear radiological lesions patients with gentamicin vestibulotoxicity
and restore normal histology in patients with receive a total dose within the generally accepted
Paget’s disease.71 Long-term follow-up on safe range,84 and serum peak-and-trough gen-
disease progression is lacking. tamicin levels do not correlate with develop-
ment of vestibulotoxicity.85 Also, both vestibular
and cochlear toxicity have been observed with
ototopic aminoglycoside ear drops.86
OTOTOXINS The pharmacologic and biochemical charac-
teristics are similar for all of the aminoglyco-
Patients who receive ototoxic drugs are often side antibiotics.87,88 They are excreted almost
bedridden and suffer from multiple symptoms of exclusively by glomerular filtration; they are
systemic illness, so additional symptoms of audi- not metabolized. Patients with renal impair-
tory and vestibular dysfunction may be easily ment cannot excrete the drugs, so the amino-
overlooked. Vestibular symptoms are particularly glycosides accumulate in the blood and inner
difficult to identify in this setting. Only after the ear tissues. The ototoxicity of the aminoglyco-
patient begins to recover do the devastating sides has been shown convincingly to be due to
effects of vestibular loss become apparent. By hair cell damage in the inner ear. Unlike peni-
this time, the damage is irreversible. The examin- cillin and other common antibiotics, aminogly-
ing physician must be keenly aware of the poten- cosides are concentrated in the perilymph and
tial auditory and vestibular toxicity of any drug endolymph. The earliest effect of the vestibu-
that is used, if ototoxicity is to be prevented. lotoxic compounds, such as streptomycin and
gentamicin, is a selective destruction of type I
hair cells in the crista. Later, type II hair cells
Aminoglycosides are destroyed, but the supporting cells remain
unaffected. With the cochleotoxic agents, such
The commonly used aminoglycosides are listed as kanamycin and amikacin, there is first a
in Table 17–1. Although each of these drugs can selective destruction of the outer hair cells in
the basal turn of the cochlea, followed by total darkened room. Head movement–induced
hair cell loss throughout the cochlea as the dos- oscillopsia is also common. The head-thrust
age and duration of treatment are increased. test can be used at the bedside to identify ves-
Consistent with these pathologic changes, the tibular impairment. Serial caloric and rotational
sensorineural hearing loss caused by the amin- examinations document a progressive bilateral
oglycosides usually begins in the high frequen- loss of vestibular responsiveness. Because of
cies and progresses to a flat 60 to 70 dB loss their highly selective effect on the vestibular
across all frequencies. Degeneration of neu- endorgan, streptomycin and gentamicin are
rons may occur years after the loss of inner and used to produce a chemical vestibulectomy in
outer hair cells that is caused by the aminogly- patients with episodic vertigo from Meniere’s
cosides. Even after treatment is terminated, syndrome (see Chapter 11).
some of the aminoglycosides (dihydrostrepto-
mycin, gentamicin, and tobramycin in particu-
lar) have been shown to produce continued “Loop” Diuretics
damage to the sensory structures of the organ
of Corti. The two main ototoxic diuretics, furosemide
The mechanism by which aminoglycosides and ethacrynic acid, act by inhibiting active
damage hair cells is only partially under- resorption of chloride in the loop of Henle,
stood.82,83,88 Several studies suggest that amino- thereby preventing the renal resorption of
glycosides may interfere with mitochondrial sodium that passively follows chloride. The
energy metabolism by binding to the mitochon- mechanism of their ototoxic effect is not com-
drial membrane and increasing membrane pletely known, although these drugs clearly
permeability. Aminoglycosides have also been influence ion channels in the kidney and in the
shown to reversibly block calcium-sensitive cochlear duct.94 They inhibit the Na-K-2Cl-
potassium channels, increase free-radical forma- cotransporter in the marginal and dark cells of
tion, and have an excitotoxic effect on cochlear the stria vascularis, resulting in a reduction in
N-methyl-d-aspartate (NMDA) receptors.89,90 the endolymphatic potential and endolym-
With the discovery of increased sensitivity to phatic K+ concentration. The ototoxic effects
ototoxicity in families with mutations in the of the loop diuretics appear to be primarily
mitochondrial gene for the 12S ribosomal ribo- confined to the cochlea, although vertigo has
nucleic acid (rRNA), the possibility was raised been rarely reported. About 6% of patients
that even normal human mitochondrial rRNA receiving furosemide develop a temporary
may be affected by the aminoglycosides.91,92 hearing loss that is nearly always reversible.
Interestingly, the region on the 12S rRNA that The newer loop-inhibiting diuretics, bume-
is mutated in families with ototoxin susceptibil- tanide and piretanide, appear to have a much
ity is morphologically similar to the area of bac- lower rate of cochleotoxic effects in both ani-
terial rRNA to which aminoglycosides bind in mal and human studies.95,96 Loop diuretics may
the course of their bacterial cytoaction. This enhance aminoglycoside ototoxicity.97
mechanism could not explain the vestibular
loss associated with gentamicin and streptomy-
cin, however, since families with the predispos- Anti-inflammatory Drugs
ing mutations in the 12S rRNA gene have
hearing loss but normal vestibular function.93 Anti-inflammatory drugs known to be associ-
Furthermore, no mutations with confirmed ated with ototoxicity include salicylates, non-
pathogenicity were identified in the 12S rRNA steroidal anti-inflammatory drugs (NSAIDs),
gene in 66 patients with aminoglycoside ves- and quinine.98 Salicylates and NSAIDs are
tibulotoxicity or in 15 patients with idiopathic among the most commonly used drugs for
bilateral vestibulopathy.92 inflammation, fever, and pain. Quinine, origi-
As noted earlier, vestibular symptoms and nally an antimalarial drug with properties simi-
signs due to aminoglycoside toxicity are often lar to those of the salicylates, is commonly used
subtle. Although some patients complain of for treating nocturnal leg cramps. The main
vertigo (presumably due to asymmetric involve- ototoxic effect of these drugs is a reversible,
ment of the vestibular system), most complain mild to moderate flat or high-frequency
of an unsteady gait, particularly at night or in a hearing loss along with a high-pitched tinnitus.
The salicylates have been studied most exten- This is particularly important in a patient who
sively and reliably produce hearing loss and tin- is seriously ill and confined to bed or in any
nitus when the plasma salicylate level approaches patient who has renal impairment, particularly
0.35 mg/ml.99 There is almost a linear relation- renal failure. Bedside audiometric assessment
ship between serum unbound salicylate con- is available in most hospitals; bedridden
centration and ototoxic symptoms, although the patients can be tested with reproducible audi-
threshold level for symptoms varies from patient tory stimuli. Although less satisfactory than
to patient. These ototoxins cause a transient conventional testing in a soundproof room,
dysfunction of outer hair cells documented by earphones help exclude ambient noise. Because
both ultrastructural and electrophysiological the hearing loss due to ototoxic drugs usually
studies. There is no evidence that the vestibular begins in the high-frequency range, a screen of
system is affected. All symptoms and signs are the high frequencies can be used to predict
typically rapidly reversible after cessation of the future low-frequency loss. By contrast, quanti-
drug ingestion (usually within 24 hr). tative bedside vestibular testing (i.e., caloric
and rotational testing) is not available in most
hospitals so that the clinical examination is crit-
Platinum Compounds ical for identifying early vestibular loss (see
tests of vestibulo-ocular reflexes, Chapter 6).
Cis-platinum and carboplatin are the two most The head-thrust test can be performed even in
commonly used ototoxic chemotherapeutic critically ill patients and has consistently been
agents. Both are associated with auditory shown to be a sensitive test for vestibulo-
toxicity, although carboplatin is less toxic than toxicity.104,105 Whenever possible the Romberg
cis-platinum.88,100 By way of comparison, the and tandem walking tests should be used to
incidence of aminoglycoside ototoxicity is about assess balance function. Ambulatory patients
10%, whereas the incidence of cis-platinum can undergo quantitative caloric and rotational
ototoxicity is in the range of 50%. Tinnitus and testing. Rotational testing is ideally suited for
hearing loss are extremely common. Typically, identifying early vestibular ototoxic effects,
the tinnitus is transient, lasting from a few because the normal response variability is
hours to up to a week after therapy. The hear- much less than that seen with caloric testing
ing loss is usually bilateral, beginning in the (see Chapter 7). The earliest changes are short-
high frequencies and progressing to involve all ening of the dominant time constant and
frequencies; it may not appear until several decreased gain at the lowest and highest
days after treatment. The hearing loss usually frequencies.104
has some degree of reversibility, although when
it is severe and involves all frequencies it is
often permanent. The critical cumulative oto- Management
toxic dose of cis-platinum has been reported to
be in the range of 3 to 4 mg/kg of body weight.101 The key to the management of the ototoxicity is
The ototoxic effects can be decreased by using prevention. Kidney function should be mea-
slow infusions and dividing the doses over sev- sured prior to beginning any potentially oto-
eral months.102 The vestibular system is toxic drug. Patients in high-risk groups (Table
relatively spared by these chemotherapeutic 17–2) should be monitored with periodic audi-
ototoxins.103 Morphologic studies in animals tory and vestibular testing. All patients should
that have been given cis-platinum show hair be questioned on a regular basis to identify
cell damage similar to that seen with the amin- early symptoms of auditory or vestibular loss.
oglycosides. Free radical formation in the kidney When the earliest effects of ototoxicity are
and ear have been implicated in the pathogen- identified, the drug should be stopped. Usually
esis of toxicity with both compounds.94 other drugs can be used that have less ototoxic
potential.
Based on the hypothesis that aminoglycoside
Diagnosis ototoxicity results from iron chelation and free-
radical formation, use of iron chelators and
The clinician must be constantly on the alert radical scavengers was shown to prevent ototox-
for the early symptoms of ototoxic drugs. icity in guinea pigs.106 At the same time, these
Table 17–2 Major Risk Factors for Drug read a sign) and gait unsteadiness (always have
Ototoxicity a light on throughout the night) are useful,
along with an active exercise program to force
Impaired renal function central compensation (see Chapter 20).
High serum levels Younger patients often will return to nearly
Prior use of ototoxic drugs normal activity over a period of years, but
Course > 14 days elderly patients are rarely able to compensate
Preexisting sensorineural hearing loss fully for the vestibular loss.
Age > 65 years
NEUROTOXINS
drugs have no effect on serum levels of the
aminoglycosides nor on its antibacterial effi- Heavy Metals
cacy. Assuming that the ototoxic effects of the
aminoglycosides are at least in part due to exci- Both lead and mercury intoxication are known
totoxic activation of cochlear NMDA receptors, to produce auditory and vestibular symptoms,
Segal et al.90 showed that NMDA antagonists but the pathophysiologic mechanisms of these
protected animals from aminoglycoside ototox- symptoms is poorly understood. In adults,
icity. Antioxidants may prevent both the free- acute lead poisoning typically leads to a motor
radical formation and the excitotoxic effects on neuropathy, whereas in children encephalopa-
the NMDA receptors.107 A double-blind pla- thy is more prominent. Chronic lead absorp-
cebo-controlled study in China found that aspi- tion can lead to more subtle symptoms and
rin (an antioxidant) given in combination with signs, including nonspecific dizziness, imbal-
gentamicin was significantly more effective than ance, and cognitive deficits. Rats exposed to
placebo with gentamicin in preventing hearing chronic low concentrations of lead acetate in
loss.108,109 At 5–7 weeks after being treated with their drinking water showed abnormalities in
intravenous gentamicin for an acute infection, postrotatory nystagmus in the absence of
3% (3/89) of patients treated with 3 g of aspirin clinical signs of lead intoxication.111 Segmental
per day had ototoxicity (defined as hearing loss demyelination and axonal degeneration of the
of >15 dB from baseline at both 6 and 8 kHz) eighth nerve were identified in guinea pigs
compared to 13% (14/106) of the control group. given weekly intraperitoneal injections of 1%
In another controlled study the antioxidant lead acetate solution for 7 weeks.112 The end
N-acetylcysteine (NAC) significantly decreased organs and ganglion cells showed no visible
the incidence of hearing loss in hemodialysis morphologic changes. By contrast, adult
patients receiving gentamicin for dialysis cathe- squirrel monkeys that were chronically poi-
ter-related bacteremia.110 In this study at soned with lead showed minimal changes in
6 weeks after gentamicin, 25% (5/20) patients the auditory and vestibular systems, both on
treated with NAC had ototoxicity (defined as clinical and histologic examination.113 The dif-
>20 dB loss at any frequency or >10 dB loss at ference in findings may be due to the well-
any two adjacent frequencies) compared to known decreased susceptibility of the adult
60% (12/20) of the control group. Neither of nervous system to lead toxicity. Hearing
these studies assessed vestibular or balance loss and vertigo have occasionally been reported
function as an outcome, despite the fact that in isolated cases of childhood and adult lead
gentamicin is more toxic to the vestibular sys- poisoning, but no detailed study has been
tem than to the auditory system. undertaken of auditory and vestibular function
As with other vestibular disorders, manage- in a large population of lead-poisoned
ment of patients with permanent bilateral ves- patients.
tibular loss due to ototoxins should be directed Two large patient populations with organic
at retraining the nervous system to use other mercury poisoning have undergone detailed
sensory signals to replace the lost vestibular neurotologic examination in Japan. Mizukoshi
signals. Practical suggestions on how to avoid and colleagues114 studied 144 patients with
head movement–induced oscillopsia (stopping organic mercury poisoning acquired from eat-
and holding the head still when attempting to ing contaminated fish caught in the Aganagawa
River in Niigata. Impaired hearing was found and the ability to suppress the vestibular-ocular
in 50% of patients and 67% complained of reflex with fixation.124 Auditory and vestibular
dizziness and unsteadiness of gait. Episodes of function testing in workers exposed to organic
vertigo were reported in 10%. Audiological solvents identified a variety of nonspecific
examination revealed sensorineural hearing abnormalities, compared to controls, most
loss usually consistent with a cochlear origin in being consistent with dysfunction within cen-
the early stages and with a retrocochlear origin tral auditory and vestibular pathways.125,126
in later stages. Spontaneous vestibular nystag- However, these auditory–vestibular deficits
mus was present in 27%, 17% had gaze paretic found in workers with organic solvent exposure
nystagmus, and 65% had positional nystagmus. do not correlate with the degree of exposure or
Results of caloric testing were reported to be with the severity of symptoms. The effects of
abnormal in 46% of cases, with a directional organic solvents on hearing may be synergistic
preponderance being the most consistent find- with exposure to noise and other chemicals in
ing. Unfortunately, normative data were not the work environment.
included for comparison and, therefore, the
frequent occurrence of abnormalities on nys-
tagmography must be interpreted with caution. Diagnosis
Similar findings on neurotologic examination
were reported in patients who acquired Auditory and vestibular symptoms and signs
mercury poisoning from seafood caught in due to neurotoxins are typically part of a more
Minamata Bay.115 generalized encephalopathic syndrome, with
The site of vestibular and auditory dysfunction some unique features being associated with
in mercury-poisoned patients is unclear. Oral each of the different neurotoxins. Heavy metal
administration of methyl mercury to rats rapidly intoxication leads to multisystem involvement
leads to accumulation of mercury in the brain with clear neurologic findings. With acute
stem, particularly in the ventral cochlear nucleus exposure, blood levels typically correlate with
and the superior vestibular nucleus.116 Mercury the severity of exposure and the severity of
intoxication in guinea pigs resulted in changes in symptoms and signs. However, with chronic
the labyrinth and cerebellum.117,118 Necropsy exposure, heavy metals are bound to bone and
studies have not been performed on the tempo- other hard tissues so that blood levels do not
ral bones and eighth nerves from patients dying reflect the level of the body burden. Past expo-
of mercury intoxication. Examination of the sure may be identified in hair and nail samples
brain in such patients reveals a selective sensitiv- or by mobilizing bone stores with chelating
ity of the granule cell layer of the neocerebellum, agents. A 24-hr urine collection after exposure
but cases of demyelination of the subcortical and to a chelating agent provides a good means of
brainstem white matter and peripheral nerves assessment of body heavy-metal burden. There
have also been reported.119,120 is no good way of assessing past exposure to
organic solvents other than taking a careful
history regarding types of exposure.
Organic Solvents
Acute intoxication with organic solvents leads Management
to a well-described toxic encephalopathy mani-
fested by symptoms of confusion, dizziness and The first step in managing exposure to neuro-
imbalance, nausea, and generalized weakness. toxins is to remove the exposure. With acute
Whether a chronic toxic encephalopathy devel- intoxication to heavy metals, residual symp-
ops from chronic low-level exposure to organic toms and signs are common, even with aggres-
solvents is a more controversial issue.121,122 sive treatment. Chelating agents can be used to
Some workers with long-term occupational decrease the body burden of heavy metals, but
exposure to organic solvents may become intol- neurologic damage is often irreversible. The
erant even to low air concentrations so that they chelating agents must be used with caution
are no longer able to work in the industry.123 since they pull heavy metals from hard tissue
Studies in animals show direct effects of organic into the blood, which can lead to further
solvents on both vestibulo-ocular reflex gain neurologic damage.
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90. Segal JA, Harris BD, Kustova Y, Basile A, Skolnick 2006;354:1856.
P. Aminoglycoside neurotoxicity involves NMDA 110. Feldman L, Efrati S, Eviatar E, et al. Gentamicin-
receptor activation. Brain Res. 1999;815:270. induced ototoxicity in hemodialysis patients is
91. Casano RA, Johnson DF, Bykhovskaya Y, et al. ameliorated by N-acetylcysteine. Kidney Int.
Inherited susceptibility to aminoglycoside ototoxicity: 2007;72(3):359.
genetic heterogeneity and clinical implications. Am J 111. Mameli O, Caria MA, Melis F, et al. Neurotoxic
Otolaryngol. 1999;20:151. effect of lead at low concentrations. Brain Res Bull.
92. Elstner M, Schmidt C, Zingler VC, et al. 2001;55(2):269.
Mitochondrial 12S rRNA susceptibility mutations 112. Gozdzik-Zolnierkiewicz T, Moszynki B. VIIIth nerve
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2008;377(2):379. 113. Wilpizeski D. Effects of lead on the vestibular system:
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an inherited nuclear mutation or aminoglycosides. pounds. ORL J Otorhinolanyngol Relat Spec.
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J Otolaryngol. 1994;23:151. brain disturbance by methyhnercury poisoning,
101. Hayes DM, Cvitkovic E, Golbey RB, et al. High focusing on the long-term effect on brain weight.
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102. Schaefer SD, Post JD, Close LG, Wright CG. cits in the equilibrium system relevant to the clinical
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122. Herpin G, Gargouri I, Gauchard GC, et al. Effect 125. MorataTC, Nylen P, Johnson AC, Dunn DE.
of chronic and subchronic organic solvents exposure Auditory and vestibular functions after a single
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179. 126. Niklasson M, Arlinger S, Ledin T, et al. Audio-
123. Gyntelberg F, Vesterhauge S, Fog P, Isager H, logical disturbances caused by long-term exposure to
Zillstorff K. Acquired tolerance to organic solvents industrial solvents. Relation to the diagnosis of toxic
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124. Tham R, Bunnfors I, Eriksson B, et al. Vestibuloocular
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Pharmacol Toxicol (Copenh). 1984;54:58.
Chapter 18
Developmental and Genetic

Disorders
THE INNER EAR Syringobulbia

Acquired Disorders Diagnosis
Hereditary Disorders Management
Pathology INHERITED SPINOCEREBELLAR ATAXIA
Diagnosis SYNDROMES
Management Autosomal Dominant Spinocerebellar
DISORDERS OF THE CRANIAL VERTEBRAL Ataxia Syndromes
JUNCTION Autosomal Recessive Spinocerebellar
Basilar Impression Ataxia Syndromes
Bony Fusions Episodic Ataxia and Vertigo Syndromes
Atlantoaxial Dislocation Diagnosis
Chiari Malformation Management
THE INNER EAR number of children with congenital hearing

loss, it seems likely that a large number of
Permanent hearing loss occurs in about 1 to 3 children also have congenital vestibular loss.
out of every 1000 live births.1–3 In high-risk A consequence of congenital vestibular loss
neonates, the prevalence is much higher, in the is that babies have difficulty learning to crawl
range of 1 in 50 live births. Although <10% of and walk. Walking is often delayed to 15 to 18
infants are treated in neonatal intensive care months or later and the children are often con-
units, these newborns account for more than sidered clumsy. They typically will participate
half of all cases of early-onset sensorineural in all children’s games and activities, although
hearing loss.1,4 they will not perform well in tasks that require
Congenital deafness is usually recognized quick turns or excellent balance (for example,
during infancy, but a congenital vestibular gymnastics). As they get older and develop
impairment is not, because the manifestations good muscle control, their walking and running
are more subtle. Children with a vestibular appear normal as long as they have good vision.
impairment typically learn to use other sensory However, if they begin to lose vision, the bal-
information to compensate for vestibular loss ance problems become more and more notice-
and thus appear to be asymptomatic and often able, even becoming profound if a visual loss
test normal on standard assessments. Congenital becomes severe.
deafness has therefore received extensive Congenital disorders of the inner ear can be
study, whereas congenital vestibular loss has divided into two major categories: acquired
been relatively neglected. Given the large and hereditary. Acquired disorders result from
383
development of a normal fertilized egg, and in childhood.10,11 Most infants with CMV-
hereditary disorders result from abnormal related hearing loss have no other symptoms
genes or epigenetic factors.5 A large number of or signs of CMV infection. Meningitis is another
studies have looked at the relative frequency of common cause of unilateral or bilateral
hereditary and acquired hearing loss and most auditory and vestibular loss in the postnatal
have found that each category accounts for period.4,6
about 30% to 40% of cases, with the remaining The fetal alcohol syndrome is commonly
20% to 40% of cases being due to unknown associated with developmental abnormalities of
cause. It must be kept in mind, however, that the inner ear and other craniofacial struc-
these studies were all conducted before the tures.12,13 Hearing loss, which can be traced to
recent rapid advances in the identification of conductive, sensorineural, and central patholo-
genetic causes of hearing loss, so no doubt gies, contributes to delayed speech and language
future studies will find a higher frequency of development. Postural imbalance results form
hereditary hearing loss. both vestibular and cerebellar dysfunction.
Acquired Disorders Hereditary Disorders

Currently, most cases of acquired severe INHERITED SYNDROMES
hearing loss are associated with the perinatal
complex of premature delivery, anoxia, and Although it is beyond the scope of this mono-
hyperbilirubinemia.1,4,6 A gestation <32 weeks, graph to review all of the hereditary syndromes
birth weight <1500 g, prolonged mechanical that may produce sensorineural deafness and
ventilation for >10 days, and an Apgar score vestibular loss, a few common disorders deserve
after 5 or 10 min ≤ 6 are all significant risk fac- mention (Table 18–1). About 3% to 6% of con-
tors for developing permanent hearing loss. genitally deaf children have Usher’s syndrome,
Hyperbilirubinemia at a level exceeding the which is the leading cause of the combination of
indication for exchange transfusion is another deafness and blindness.14,15 Usher’s syndrome
major risk factor. Also, premature infants often was initially divided into three types on the basis
receive potential ototoxic medications includ- of clinical features, with type 1 showing the
ing but not limited to aminoglycosides.6 most severe early-onset auditory and vestibular
Pre-, peri-, or postnatal infections with toxo- loss. Patients with type 2 Usher’s syndrome are
plasmosis, herpes, cytomegalovirus, and rubella born hard of hearing with a sloping sensorineural
can all lead to permanent inner ear damage hearing loss, but vestibular function is normal.
with hearing loss and vestibular loss. The inci- Type 3 is characterized by later-onset progres-
dence of congenital rubella and associated sive hearing loss with some moderate loss of
inner ear damage has markedly decreased since vestibular function. Visual loss due to retinitis
vaccines have been widely used.7–9 Infants pigmentosa begins in infancy or early childhood
born to mothers who acquire rubella in the first with type 1 but can be delayed until the teenage
trimester of pregnancy may have multiple con- years with types 2 and 3. To date, seven differ-
genital defects, including cataracts, patent duc- ent genetic loci have been linked to families
tus arteriosus, microcephaly, dental defects, with the clinical syndrome of Usher’s type 1
and generally impaired growth and develop- while only a single genetic locus has been linked
ment. Hearing loss is more common than ves- to types 2 and 3 (for review see reference 16).
tibular loss (apparently because of the longer The protein products of the genes associated
critical developmental period). Although less with all three Usher types are critical for devel-
common, the infant’s fully developed inner ear opment and maintenance of the inner ear ste-
can be damaged by a maternal rubella infec- reocilia and kinocilia.16 Usher type I proteins
tion in the last two trimesters. Congenital cyto- cadherin 23 and protocadherin 15 are struc-
megalovirus (CMV) infections are the leading tural components of the tip links (see Fig. 2-12
cause of acquired hearing loss in developed in Chapter 2), while Usher type II proteins are
countries. In the United States at least 1000 key components of the ankle link molecular
infants/year have hearing loss at birth due to complex. The actin-based motor protein myo-
CMV and another 3000–4000 have hearing loss sin VIIA (Usher syndrome type 1B) is probably
18 Developmental and Genetic Disorders 385
Table 18–1 Genetic Syndromes with Audiovestibular Loss

Syndrome Mode of Unique Clinical Features Gene(s) Gene Product
Inheritance (Chromosome)
Usher 1B Recessive Retinitis pigmentosa MYO7A (11q) Myosin VIIa
Waardenberg Dominant White forelock, high nasal PAX3 (2q) Developmental
type 1 root, hyperplastic eye brows, protein
lateral displacement of medial
canthi, heterochromia iridis
+
Jervell-Lange- Dominant Cardiac arrhythmias KCNE1 (21q) K channel
Nielson (Long
Q-T syndrome)
Pendred Recessive Thyroid goiter PDS (7q) Pendrin
(enlarged
vestibular
aqueduct)
Alport’s X-linked Interstitial nephritis COL4A5 (Xq) Collagen
Dominant COL4A4 (2q)
Dominant COL4A3 (2q)
the general transporter of the Usher proteins potassium concentration in the endolymph
to their intended destination in the stereocilia. required for endocochlear potentials (see
In the retina, Usher proteins have been local- Chapter 2).20–22 This is an important syndrome
ized to the cilia that connect the metabolically to recognize since children are at risk for sud-
active inner segment to the photosensitive den infant death syndrome (from arrhythmias).
outer segment of the photoreceptor cell.17 Pendred syndrome is an autosomal recessive
The Dutch ophthalmologist Waardenberg disorder characterized by the combination of
described a syndrome characterized by con- congenital deafness and goiter (usually devel-
genital hearing loss, white forelock (i.e., white oping in early puberty).23 It constitutes about
hair that falls on the forehead), unusual eye 5% of all cases of childhood deafness. The
color, and dystopia canthorum.18,19 The syn- inner ear is often malformed with a “Mondini-
drome has subsequently been expanded to like” malformation, including an abnormal
include four subtypes, with type 1 representing cochlea and an enlarged internal auditory canal
Waardenburg’s initial families. With this syn- and vestibular aqueduct. The degree of thyroid
drome, vestibular function is usually impaired dysfunction is variable. The gene for Pendred’s
bilaterally and computed tomography (CT) syndrome, SLC26A4, codes for a chloride-
studies of the temporal bone may reveal bony iodide transporter (pendrin) critical for both
abnormalities of the inner ear. The gene for inner ear and thyroid function.24 Mutations in
Waardenburg’s syndrome type 1 and type 3 is SLC26A4 can also lead to a nonsyndromic
PAX-3, one of several genes that are important autosomal recessive hearing loss associated
for controlling development of the face and with an enlarged vestibular aqueduct (see later
inner ear. Other Waardenberg genes include discussion).25,26
MITF and SNA12 (type 2); and EDNRB, EDN, Alport’s syndrome has a combination of kid-
and SOX10 (type 4).19 ney and inner ear involvement.19,27 Hereditary
The Jervell and Lange-Nielsen syndrome nephritis (previously known as Bright’s disease)
(also known as the long Q-T syndrome) is can have onset from childhood into adulthood
characterized by recessive congenital audiove- and is the reason for about 2% of kidney trans-
stibular loss and cardiac defects. The genes plants in this country. A bilateral progressive
for this syndrome (KCNQ1 and KCNE1) code sensorineural hearing loss developing after
for potassium channels that allow potassium the first decade is usually mild to moderate,
accumulating in the marginal cells to flow back although in rare patients the loss can be
into the endolymph, maintaining the high profound. Decreased vestibular responses have
also been identified in some patients.27 expression is just beginning to be investigated.

Mutations responsible for Alport’s syndrome As a general rule recessively inherited deafness
have been found in three different collagen is prelingual (e.g., present prior to language
genes, the most common being inherited in an development) while dominantly inherited deaf-
X-linked fashion (see Table 18–1).19,28 ness is postlingual (e.g, develops after language
development). Vestibular loss occurs with
NONSYNDROMIC AUDIOVESTIBULAR many mutations, but most have not been ade-
LOSS quately evaluated. A better understanding of
how mutations in these genes cause audioves-
Most childhood deafness occurs in isolation tibular loss will lead not only to improved diag-
without any other organ involvement and, as nostic tests but also to improved understanding
noted earlier, most of these cases are thought of pathophysiology and ultimately to the devel-
to be inherited.19,29 Of those with inherited opment of more effective treatments.
hearing loss, the great majority are inherited in
an autosomal recessive fashion. The number of
Recessively Inherited Hearing Loss
genes associated with nonsyndromic inherited
hearing loss is expanding at a rapid rate (Table DFNB1 accounts for about two-thirds of
18–2). To date, there are more than 60 genetic Caucasians with recessively inherited hearing
loci linked to inherited hearing loss in different loss.31 It was initially linked to the long arm
families. Many of the affected genes have of chromosome 13 in several large families.
already been identified and the rest will no The causative gene GJB2 codes for con-
doubt be identified within the next few years.30 nexin-26, a component of a large family of pro-
Interestingly, different mutations in the same teins involved in gap junctions that are critical
gene can lead to well-described syndromes or for transport of ions between cells in the inner
to nonsyndromic hearing loss with either a ear.32,33 A frame-shift mutation in GJB2
recessive or dominant pattern of inheritance (35delG) was found in most patients with
(compare Tables 18–1 and 18–2). Correlation DFNB1. This mutation has a carrier frequency
between the type of mutation and clinical of approximately 1 in 25 people in the
Table 18–2 Genes Associated with Nonsyndromic Hearing Loss

Disorder Gene Protein Location Vestibular
(Chromosome) Lossa
Dominant
DFNA1 Diaphanous (5q) Diaphanous protein Hair cells No
+
DFNA2 KCNQ4 (5q) K channel Hair cells No
DFNA3 GJB2 (13q) Connexin 26 Gap junctions No
DFNA8/12 TECTA (11q) Tectorin Tectorial membrane No
DFNA9 COCH (14q) Secreted protein Extracellular matrix Yes
DFNA11 MYO7A (11q) Myosin VIIa Hair cells Yes
DFNA15 POU4F3 (5q) Transcription factor Inner ear Yes
Recessive
DFNB1 GJB2 (13q) Connexin 26 Gap junctions No
DFNB2 MYO7A (11q) Myosin VIIa Hair cells Yes
DFNB3 MYO15 (17p) Myosin XV Hair cells No
DFNB4 PDS (7q) Pendrin Inner ear Yes
DFNB21 TECTA (11q) Tectorin Tectorial membrane No
X-linked
DFN3 POV3F4 (Xq) Transcription factor Inner ear Yes
a
Based on human or animal studies.
Source: Data from www.boystown.org/hhirr.
Mediterranean area and causes deafness in at Depending on the type of mutation, several
least 1 in 2500 newborns in that area.34 Of genes can produce either a recessive or domi-
52 sequential probands with congenital sen- nant disorder (for example, GJB2, MYO7A,
sorineural hearing loss referred for genetic and tectorin) (Table 18–2). As a rule, the domi-
analysis in the Midwest of the United States, nantly inherited sensorineural hearing loss dis-
22 (42%) were found to have mutations orders have a later onset (e.g., postlingual) and
in GJB2. The 35delG mutation was found in are less severe than the recessively inherited
29 of the 41 mutant alleles.37 Analysis of 560 disorders. Some of them may even present
controls for the carrier rate was determined to later in life and be part of what is generally con-
be 3%. sidered presbycusis.
A wide range of auditory phenotypes has DFNA9 is of particular clinical interest
been associated with recessively inherited because of the late onset of progressive bilat-
mutations in GJB2. In most, the deafness is eral auditory and vestibular loss.38 Hearing loss
congenital and nonprogressive. The typical is typically noted in the fifth decade with an
audiogram is flat with a 50 to 60 dB loss. annual progression of about 3 dB eventually
However, the hearing loss can be progressive leading to profound bilateral hearing loss.
and asymmetric with a sloping downward pat- There is a similar progression in vestibular loss,
tern.33 So far, only a few patients with the with a complete loss occurring in most patients
35delG mutation in GJB2 have been tested for by the sixth decade. Some patients will show
vestibular function and no abnormalities have fluctuating hearing loss and episodic vertigo
been found. suggestive of Meniere’s syndrome.39 A low-
Another recessively inherited hearing loss frequency hearing loss pattern can also be rem-
syndrome deserves comment because its com- iniscent of Meniere’s syndrome. Vestibular
bination of auditory and vestibular symptoms involvement is common although often clini-
can mimic acquired disorders such as Meniere’s cally silent.36
syndrome and perilymph fistula. As noted ear- The gene for DFNA9, COCH, located on
lier, mutations in the SLC26A4 can result in 14q codes for a protein that is secreted into the
Pendred’s syndrome, characterized by a com- extracellular matrix of the inner ear.40 The
bination of thyroid and inner ear dysfunction. mechanism by which mutations in this gene
Other mutations in the same gene can result in lead to the delayed onset of progressive audio-
just audiovestibular symptoms associated with vestibular loss is still unknown. Postmortem
an enlarged vestibular aqueduct on imaging.25,35 studies of temporal bones from patients with
The clinical picture is that of a childhood-onset DFNA9 showed an acidophilic mucopolysac-
bilateral sensorineural hearing loss that fluctu- charide-containing ground substance in the
ates in severity, with episodic worsening being cochleas, macules, and cristae as well as some
triggered by head trauma or by coughing and degeneration of vestibular and cochlear
sneezing. Vertigo spells can also be triggered sensorineural elements.37,41 These deposits
by the same factors and there can be a gradual occurred in sites similar to those where COCH
progressive deterioration in both auditory and gene expression was seen in the normal
vestibular function. The vertigo and vestibular inner ear.
dysfunction can be delayed into adulthood,
even though the hearing loss was present since
childhood. Most of the mutations causing this Maternally Inherited Mitochondrial
syndrome have been missense mutations, Disorders
although deletions and insertions with frame
shifts have also been found. Each mitochondrion contains 2 to 10 mito-
chondrial chromosomes, so each cell contains
Dominantly Inherited Hearing Loss thousands of mitochondrial chromosomes.
Each of these mitochondrial DNA molecules
Although less common than recessively is double stranded and forms a closed circle,
inherited hearing loss, dominantly inherited and replication and transcription occur within
hearing loss is more easy to recognize because the mitochondrion. Mitochondrial DNA
multiple generations are typically involved.19,29 encodes 13 messenger RNA genes, 2 ribosomal
RNA genes, and 22 organ-specific transfer Inherited Vestibular Loss with Normal
RNA genes. The 13 messenger RNAs are Hearing
translated on mitochondrion-specific ribo-
Some patients presenting with a bilateral vestib-
somes with a mitochondrion-specific genetic
ular loss do not have hearing loss, and the clinical
code into 13 proteins. These mitochondrial-
picture does not indicate a structural lesion,
generated proteins interact with about 60
immune mediated disorder, or other etiology. In
nuclear encoded proteins to form the five
these presentations the most likely cause is an
enzyme complexes required for oxidative
inherited vestibulopathy. In contrast to the many
phosphorylation. Mutations in mitochondrial
genetic causes of hearing loss, only a few familial
DNA lead to both syndromic and nonsyndro-
bilateral vestibulopathy families have been
mic deafness.19,42 Hearing loss with mitochon-
described.48–50 As mentioned earlier, this dispar-
drial DNA mutations is typically delayed into
ity is likely explained by difficulty in recognizing
adulthood, and there is often a great deal
the symptoms and signs of a bilateral vestibul-
of variability in the degree of hearing loss
opathy and because quantitative rotational ves-
among different family members. The charac-
tibular function testing is not widely available. In
teristic maternal transmission suggests the pos-
addition, many patients with a bilateral vestibul-
sibility of a mitochondrial DNA mutation.
opathy may not present to a physician if they
An A-to-G transition mutation at nucleotide
have achieved an acceptable level of compensa-
3243 in the mitochondrial gene for the leucine
tion or substitution. Patients with inherited bilat-
transfer RNA can produce a range of clinical
eral vestibulopathy typically have recurrent
syndromes, including mitochondrial encepha-
attacks of isolated vertigo and a high prevalence
lomyelopathy with lactic acidosis and stroke-
of migraine headaches.48 Age of onset ranges
like episodes (MELAS) and a combination of
from the first to sixth decade. Vertigo attacks are
diabetes mellitus and hearing loss.43,44 This
often brief in duration (seconds to minutes).
mutation was found in 2% to 6% of diabetic
Progression of peripheral vestibular function loss
patients in Japan and in 3 out of 5 patients with
will eventually cause imbalance and oscillopsia,
diabetes and deafness.45 Twenty-seven of
typically by the fifth decade. The bedside head-
44 patients with diabetes and the nucleotide
thrust test may show bilateral corrective saccades
3243 mutation also had hearing loss. None
when vestibulopathy is severe enough; otherwise
of these cases had the other typical neurologic
the rotational chair test is used to identify these
features of MELAS. In 37 adult patients
patients. As the vestibulopathy becomes more
identified with 3243A>G in Finland, first clini-
severe, attacks of vertigo become less frequent
cal manifestations appearing in childhood
and eventually cease. Linkage analysis performed
included sensorineural hearing loss, delayed
in four families with familial bilateral vestibulop-
maturation, migraine, learning difficulties,
athy maps to a chromosomal locus on 6q.49 This
and exercise intolerance.46 A homoplasmic
region does not overlap any known autosomal-
mutation at nucleotide 1555 in the mitochon-
dominant deafness or migraine syndromes. One
drial 12S RNA gene can produce a nonsyndro-
additional familial bilateral vestibulopathy family
mic deafness and an increased susceptibility
did not link to the region on chromosome 6, thus
to aminoglycoside-induced deafness in
supporting genetic heterogeneity. A candidate
different families.47 Investigation of these
gene, OPRM1, in the region of interest on chro-
families showed that mitochondrial mutations
mosome 6 was sequenced in probands, but no
might lead to disease only in the presence of
mutations were found.49 A survey of gene expres-
a specific nuclear genotype or some environ-
sion within the vestibular labyrinth would
mental factor. Mitochondrial DNA mutations
enhance the ability to identify genetic causes of
presumably lead to hearing loss by interfering
familial bilateral vestibulopathy.
with the high energy requirements of the
inner ear. Interestingly, although the 12S
RNA gene mutations result in increased Pathology
susceptibility to aminoglycoside-induce hear-
ing loss, vestibular loss does not occur (see The first pathologic study of an inner ear con-
Chapter 17). genital malformation was described by Mondini
Figure 18–1. Computed tomography scan of the temporal bones showing a Mondini malformation on the right side. Only
the basal turn of the cochlea is fully developed (arrow). Cochlea on the left is normal.
in 1791. The Mondini malformation consists recessive mode of inheritance. Even with the
of subtotal development of the osseous and well-defined syndromes, variability in gene
membranous labyrinth with only the basal turn penetrance can complicate the clinical picture.
of the cochlea being completely formed For example, with Waardenburg’s syndrome,
(Fig. 18–1).51,52 The endolymphatic duct sys- penetrance for deafness is only 20%. Thus,
tem is dilated and the vestibular labyrinth is although this dominant disorder is passed to
underdeveloped. This deformity occurs with 50%, only 20% of the 50% will be deaf. For
many different syndromes, both hereditary and nonsyndromic audiovestibular loss, allelism
acquired, and is invariably associated with some and modifier genes are important for pheno-
(and often complete) loss of auditory and ves- type expression.55 In the initial assessment of
tibular function. Cochleosaccular dysgenesis any patient with early-onset hearing loss, one
initially described by Scheibe consists of dys- should obtain a detailed family history and
plasia of the pars inferior (cochlea and saccule) search for other family members with possible
with a fully developed bony labyrinth and hearing loss, vestibular loss, or other features
normal pars superior (semicircular canals and characteristic of the syndrome.56
utricle).53 The Scheibe deformity has classically
been associated with congenital rubella, LABORATORY TESTS
accounting for the relative sparing of vestibular
function in many of these children. A rare Identification of hearing loss or vestibular loss
deformity characterized by complete failure of in an infant requires objective measurements,
development of the inner ear (Michel’s defor- as behavioral testing is usually impractical.
mity) is associated total loss of auditory and Brainstem auditory-evoked responses (BAERs)
vestibular function. This deformity has been reflect the electrical activity of the auditory
found in several patients with thalidomide pathways in the brain stem and therefore pro-
anomalies of the ear.54 vide an objective measure of whether the end
organ and peripheral nerve generate signals to
transmit through the brainstem pathways.57
Diagnosis One must keep in mind, however, that the
presence of BAER does not mean that
As noted earlier, although inherited loss of the infant is able to discriminate sounds.
auditory and/or vestibular function may be part Measurement of otoacoustic emissions pro-
of a well-described multiorgan syndrome, most vides an objective measurement of outer hair
cases occur in isolation with an autosomal cell function. Vestibular evoked myogenic
potentials (VEMPs) provide a rapid objective and learning abilities. Congenital vestibular loss
measure of vestibular function in infants.58 might explain delayed developmental milestones
Rotational testing can be performed on infants and early problems with coordination. It is also
by rotating the child on the mother’s lap while critical to identify such patients since they need
eye movements are recorded with electro- or to be counseled about the dangers of drowning
videonystagmography. Caloric testing is more when diving into deep water. Infants with sib-
difficult to perform but also can be obtained in lings or parents with known hereditary deafness
most infants.58 should be screened for hearing loss. Genetic
Most genetic disorders of the inner ear do counseling is an important part of management
not affect the otic capsule and therefore the in these families. Many but not all are candidates
inner ear appears normal both on high-resolu- for cochlear implants.61
tion CT scans and on magnetic resonance imag-
ing (MRI). Malformations are readily identified
both with CT and MR scans of the temporal
bone.59 An enlarged vestibular aqueduct in a DISORDERS OF THE CRANIAL
patient with auditory and vestibular symptoms VERTEBRAL JUNCTION
suggests the likelihood of a mutation in
SLC26A3. In patients with fetal alcohol syn- Cranial vertebral junction disorders are often
drome, MRI will often show abnormal develop- congenital disorders and many have familial
ment of the cerebellar vermis (lobules I–V).60 patterns of inheritance. Patients with disorders
of the cranial vertebral junction present with a
range of brainstem and lower cranial nerve
GENETIC TESTING
symptoms, including tinnitus, vertigo, hearing
At the present time, the only genetic test for loss, pharyngeal dysfunction, hoarseness, or
congenital hearing loss that is widely available even airway obstruction. The basic pathophysi-
is for the 35delG mutation in GJB2. Since the ologic mechanism for these symptoms is com-
carrier rate for this recessive deafness-causing pression of the nervous system at the upper
mutation is approximately 3%, screening for spinal cord and medulla. The rostrocaudal
the mutation could lead to an early diagnosis in extent of the compression is variable, and the
a large percentage of patients with recessively impingement can be ventral, dorsal, or (rarely)
inherited deafness. None of the other muta- both. A second, less common, cause of symp-
tions in GJB2 or in any of the other genes toms is vascular insufficiency due to angulation,
associated with either recessively or dominantly stretching, or extrinsic compression of the
inherited deafness occur with a frequency anterior spinal or vertebral arteries.
rate high enough to warrant routine screening.
However, specific genes can be selected
for based on the following: (1) a characteristic Basilar Impression
clinical syndrome (e.g., Usher syndrome
type IB, MYO7A), (2) recognizable imaging Basilar impression is an upward indentation or
features (e.g., enlarged vestibular aquaduct, invagination of the ridged cervical spine
SLC26A3); (3) recognizable audioprofile (e.g., into the normally convex skull base.62
DFNA6, WFS1); or (4) prominent vestibular The odontoid projects intracranially to
symptoms (e.g., DFNA9, COCH).30 In the compress the ventral aspect of the medulla: the
future, with rapidly developing technology, cerebellum is compressed posteriorly by
“gene chips” will be available to screen a large the first and second cervical vertebrae.
number of mutations in several genes at the Disorders known to cause basilar impression
same time. include Paget’s disease, rheumatoid arthritis,
osteomalacia, osteogenesis imperfecta, cretin-
ism, and rickets.63 The term platybasia has
Management been used synonymously with basilar impres-
sion by some authors. Technically, it is not a
Congenital hearing loss is obviously important to measure of basilar impression and although the
identify as early as possible because of the rami- two often coexist, platybasia by itself causes no
fications regarding early language development symptoms.
Bony Fusions that normally secures the odontoid against the

anterior aspect of the arch of the atlas may
Assimilation of the atlas (also called occipital- weaken because of this repeated strain, and the
ization of the atlas) is a bony union between resultant laxity allows the odontoid to move
the first cervical vertebra and the skull.64 The posterior into the lumen of the foramen mag-
amount of union varies, but motion between num. Flexion or extension of the neck may then
the two structures does not occur. As a result, produce symptoms, depending on whether the
the odontoid impinges on the effective predominant neural compression is anterior
anterior-posterior diameter of the foramen. from the odontoid or posterior from the poste-
Frequently, there is associated fusion of the rior arch of C1. When the atlas or congenital
axis to the third cervical vertebra. Many differ- cervical fusion has been assimilated, the
ent varieties of cervicovertebral fusion have transverse odontoid ligament is sometimes
been reported. Klippel and Feil initially hypoplastic, which makes laxity and atlantoaxial
described a patient with only four cervical ver- dislocation even more likely. Atlantoaxial insta-
tebrae that were fused into a single column of bility is also known to be associated with a
bone. These anatomic features were associated number of congenital and acquired disease
with a clinical triad of short neck, low hair line, processes. It occurs in 18% to 30% of individu-
and limitation of neck movements. Although als with Down’s syndrome and is frequently
partial coalescence of two or more cervical ver- seen with spondyloepiphyseal dysplasia,
tebrae occurs in many patients, few develop Hurler’s syndrome, Morquio’s syndrome, and
the syndrome originally described by Klippel in achondroplastic dwarfs.70,71 Of patients with
and Feil. Probably fusion of cervical vertebrae rheumatoid arthritis, 25% have atlantoaxial
should be called congenital cervical synostosis instability secondary to destruction of normal
and the term Klippel-Feil should be used to stabilizing mechanisms by inflammatory rheu-
describe only typical clinical syndromes associ- matoid tissue in the synovial membrane.72
ated with either complete fusion of the cervical Similarly, ligamentous laxity can result from
spine or reduction in the number of cervical inflammatory conditions affecting retropharyn-
vertebrae.65 Most cases of Klippel-Feil syn- geal soft tissue or cervical bony structures, such
drome are sporadic, but both dominant and as tuberculosis (or other bacterial) osteitis,
recessive inheritance has been described. retropharyngeal abscess, or lymphadenitis.
Recently mutations in bone morphogenetic
protein 13 (BMP13) have been associated with
numerous skeletal and developmental defects, Chiari Malformation
including spinal fusion.66 Associated develop-
mental anomalies such as split cervical spinal In 1895, Chiari described a congenital malfor-
cord and cleft palate are common.67 Hearing mation of the hindbrain in which the brain stem
loss is common.68 The temporal bone of one and cerebellum were elongated downward into
such patient showed a vestigial inner ear hav- the cervical canal. Most frequently, the defor-
ing a rudimentary cystic cavity for a cochlea mity manifests itself in the first few months of
and only one semicircular canal incompletely life and is associated with hydrocephalus and
formed.69 The inner ear abnormalities with other nervous system malformations (Chiari
Klippel-Feil syndrome may be unilateral or type II malformation). Less frequent but more
bilateral and may be evident on high-resolution important to the neurotologist are those cases
CT scans of the temporal bone. in which the onset of symptoms and signs is
delayed until adult life (Chiari type I malforma-
tion). These cases often present with subtle
Atlantoaxial Dislocation neurotologic symptoms and signs and are usu-
ally not associated with other developmental
During flexion and extension of the neck, con- defects.73–75 The most common neurologic
genital fusion of the occiput to the atlas symptom is slowly progressive unsteadiness of
increases the strain on the structures that nor- gait, which the patient frequently describes as
mally restrict the motion of the atlas on the dizziness. Vertigo (particularly positional
axis, especially if there is fusion of other cervi- vertigo), tinnitus, hearing loss, and recurrent
cal vertebrae as well.70 The transverse ligament facial paresis occur in a small percentage
of patients.75,76 Some patients have fluctuating associated morphologic abnormalities of the

hearing loss and vertigo suggestive of Meniere’s neck, such as low hairline, short neck, abnor-
syndrome.74 Abnormalities on the neurologic mal head position, limitation of motion, and
exam are generally required before considering painful torticollis. Accentuation of symptoms
low-lying cerebellar tonsils to be a pathological by coughing, straining, or change in neck posi-
finding. On neurologic examination the patient tion is common. Clinical manifestations of cervi-
is ataxic, suggesting midline cerebellar involve- comedullary compression are usually relentless
ment. Pathologic nystagmus is nearly always and severe, progressing over months to years.
present. Spontaneous and positional downbeat Occipital pain with radiation toward the vertex
nystagmus are particularly common, but other is a common presenting symptom. Other symp-
forms of central spontaneous nystagmus and toms can be related to brainstem and cranial
rebound nystagmus also occur. Oscillopsia is nerve dysfunction from compression.
nearly always associated with the spontaneous The diagnosis of basilar impression is con-
nystagmus. Dysphagia, hoarseness, and dysar- firmed when lateral radiographs of the skull
thria result from stretching of the lower cranial demonstrate that the tip of the odontoid either
nerves, and obstructive hydrocephalus results extends above Chamberlain’s line (a line drawn
from occlusion of the basilar cisterns. Some from the posterior edge of the hard palate to
patients experience episodes of dizziness or the posterior lip of the foramen magnum) or
even syncope triggered by coughing or sneez- projects posterior to Wackenheim’s clivus–
ing. The Chiari type 1 malformation is a devel- canal line.70 With assimilation of the atlas or
opmental disorder of para-axial mesoderm atlantoaxial dislocation, the critical assessment
leading to underdevelopment of the posterior is whether the abnormality is reducible and the
cranial fossa and overcrowding of the normally direction of encroachment on the cervical
developed hindbrain.73 Although usually spo- medullary junction. High-resolution CT scan-
radic, both autosomal dominant and recessive ning is performed in the frontal and lateral pro-
families have been described. jections with the patient’s head in both neutral
and extended positions (with the attending
neurosurgeon supervising the procedure).78
Syringobulbia Magnetic resonance imaging is the procedure
of choice for assessing the degree of soft tissue
Syrinx formation in the medulla (syringobul- compression and for identifying Chiari malfor-
bia) damages any of the lower cranial nerve mations and syrinx formation.73,57 Midline
nuclei but most often involves the twelfth saggital sections are ideal for identifying the
nuclei and the descending tract and nucleus of level of the cerebellar tonsils (Fig. 18–2) and
the fifth nerve, producing atrophy and fascicu- syrinx formation in the medulla and high
lations of the tongue and loss of pain and tem- cervical cord. Vertical descent of the brain due
perature sensation on one or both sides of the to a cerebrospinal (CSF) leak can mimic a
face. Dysphonia and dysphagia are also preva- Chiari malformation, but usually there is an
lent because of the damage to the ninth and associated dural enhancement on MRI after
tenth nuclei. As with Chiari malformation, contrast.80
pathologic nystagmus is a common finding in
nearly all reported series, and occasionally it is
the only abnormal neurologic sign.77 A pure Management
torsional nystagmus either in the primary posi-
tion or on lateral gaze is particularly character- A series of operations have been developed to
istic of syringobulbia. Any adult presenting correct bony deformities at the craniovertebral
with oscillopsia and central spontaneous nys- junction, to eliminate the cervical medullary
tagmus should be suspected of having either compression, and to prevent its recurrence.
syringobulbia or a Chiari type I malformation. They are designed to reduce the odontoid from
its cranial position, to remove any bony liga-
mentous or inflammatory soft tissue compres-
Diagnosis sion of the cervicomedullary junction, and
to fix the skull to the cervicovertebral column
Patients with congenital abnormalities of in the reduced position when necessary.
the craniovertebral junction often exhibit In patients with Chiari type I malformations,
Figure 18–2. Chiari type I malformation. Magnetic resonance image shows a Chiari type I malformation. Arrow points to
the tip of the cerebellar tonsils.
suboccipital decompression of the foramen atypical ataxia syndromes associated with hear-
magnum region can stop the progression and ing loss and abnormal vestibular function have
occasionally lead to improvement in neurologic been reported.86–88 Clinically, however, cere-
symptoms and signs.73,81,83 Special emphasis bellar findings usually overshadow the loss of
should be given to patients with rheumatoid vestibular function; patients present with ataxia
arthritis because up to 25% of them have sig- and incoordination. In most, the symptoms are
nificant cranial vertebral abnormalities. In a slowly progressive, although in some they are
series of 45 patients surgically treated for cervi- episodic. Head movement–induced oscillopsia
cal medullary compression secondary to rheu- and dizziness are common, usually because of
matoid arthritis and cranial settling, there were the patient’s inability to suppress the vestibulo-
no operative deaths and no infections.83 All the ocular reflex with fixation, but in some cases,
patients improved to a functional class two also because of bilateral vestibular loss. Often,
grades above the preoperative level, and some only after performing caloric or rotational test-
improvement in cranial nerve function occurred ing is the loss of vestibular function identified.
in patients who had preoperative deficits. Vertigo is usually not present because the
vestibular loss occurs gradually in a bilateral
symmetrical fashion, but vertigo is a common
feature of several of the episodic ataxia syn-
INHERITED SPINOCEREBELLAR dromes. Many types of pathological nystagmus
ATAXIA SYNDROMES are encountered, including gaze-evoked, cen-
tral spontaneous (particularly upbeat and
Early classifications of the inherited spinocer- downbeat), rebound, and central paroxysmal
ebellar ataxias (SCAs) were based on a confus- positional. Bedside and laboratory assessment
ing array of eponyms and clinical–pathological of eye movements can be helpful in identifying
terms (e.g., Marie ataxia, Holmes ataxia, olivo- the phenotype prior to genetic testing (see later
pontocerebellar ataxia, parenchymal cerebellar discussion).
ataxia, etc.). With the rapid advances in genetic
analysis at the turn of the century, classifica-
tions based on phenotypic descriptions have Autosomal Dominant
been replaced with a classification based on the Spinocerebellar Ataxia Syndromes
genotype.84 The prevalence of inherited SCA
in the general population has not been well About a third of the inherited SCA syndromes
studied, although it is probably no more than 1 are inherited in an autosomal dominant
to 5 per 100,000 in unselected populations. In fashion. Classification of the autosomal domi-
some isolated populations, however, the preva- nant SCA syndromes has long been a source of
lence can be as high as 20 to 25 per 100,000.85 confusion and controversy. Harding89 sepa-
Auditory and vestibular symptoms and signs rated these disorders into types 1 through 3.
occur with several of the hereditary SCA syn- The most common, type 1, manifested ataxia,
dromes. In addition, isolated families with pyramidal and extrapyramidal signs, and
Table 18–3 Mutations associated with some common Spinocerebellar Ataxias

Classification Chromosomal Mutational Mechanisms Characteristic Features
Location
a
SCA-1 6q CAG: nl 16–37, abnl 39–81 Dysphagia, pyramidal signs,
vibratory loss
SCA-2 12q CAG: nl 15–32, abnl 34–64 Slow saccades, loss of reflexes,
dementia
SCA-3/MJD 14q CAG: nl 12–40, abnl 66–84 Pyramidal and extrapyramidal
signs, peripheral motorsensory
neuropathy
SCA-5 11cent Coding mutations in beta-III Relatively benign course,
spectrin pyramidal signs in early onset
SCA-6 19p CAG: nl 4–19, abnl 21–29 Predominant cerebellar signs
SCA-7 3p CAG: nl 7–17, abnl 38–130 Retinal degeneration
SCA-8 13q CTG: nl < 50, abnl 80–250 Predominant cerebellar syndrome
SCA-10 22q ATTCT: nl<280, abnl 850–4,500 Predominant cerebellar syndrome
with epilepsy
a
There are longer normal SCA-1 alleles, but they carry a CAT interruption.
Number of repeats, nl-normal, abnl-abnormal
ophthalmoplegia. Type 2 was similar to type 1 All of the SCA syndromes share the main
but also included retinal degeneration, while clinical features of gait ataxia, dysarthria,
type 3 was a relatively pure cerebellar syn- dysphagia, dysmetria, and intention tremor
drome. This classification has been shown to be due to involvement of the afferent and efferent
genetically heterogeneous, composed of a vari- cerebellar pathways.95 Involvement of other
ety of distinct SCA subtypes (Table 18–3).67 structures, including brain stem and spinal
To date, 28 autosomal dominant SCA syn- cord, basal ganglia, peripheral nerves, optic
dromes have been linked to chromosomal loci, nerve and retina, and cerebrum, occurs in indi-
and 17 causative genes have been identified.90 vidual syndromes. Disorders of oculomotor
Spinocerebellar ataxia types 1, 2, 3, and 6 are control are common with all of the SCA syn-
by far the most common of the SCA syndromes, dromes, and the particular pattern can help
accounting for more than half of all cases.91 define the phenotype (Table 18–4).96 The ves-
Each of these disorders is caused by an tibular-ocular reflex gain is typically decreased
expanded CAG triplet repeat in the open read- in SCA-3, presumably because of involvement
ing frame of the gene, leading to an expanded of brainstem vestibulo-ocular reflex pathways.
polyglutamine tract in the predicted protein.92,93 Slowing of both voluntary and involuntary sac-
The size range of the repeat expansion for each cades is prominent with SCA-1, SCA-2, and
is roughly similar, with less than about 30 SCA-7, so that even though the vestibulo-
repeats being asymptomatic and more than ocular reflex remains intact, vestibular nystag-
about 40 being symptomatic. The size of the mus may not be generated and vestibular test-
repeat correlates with disease severity and age ing results in a slow deviation of the eyes and
of onset. Repeat expansion constitutes the pinning in an extreme lateral position because
molecular basis of anticipation, which typically of the absence of fast components.
occurs with paternal transmission. With each
generation, the disease tends to come on ear-
lier and be more severe. Spinocerebellar ataxia Autosomal Recessive
type 6 is the lone exception to this rule, having Spinocerebellar Ataxia Syndromes
a smaller stable repeat expansion, although
disease severity is correlated with the length of Friedreich’s ataxia (FA) is by far the most com-
the expansion.94 mon of the hereditary ataxias, accounting for
Table 18–4 Summary of Type and Degree of Horizontal Eye Movement

Abnormalities with Different Spinocerebellar Ataxia Syndromes
Saccade Velocity Pursuit/OKN Gain VOR Gain VOR-Fix Gain
SCA-1 Moderate Moderate Normal Moderate
SCA-2 Severe Mild Normal Mild
SCA-3 Mild Moderate Moderate Mild
SCA-6 Normal Severe Normal Severe
SCA-7 Severe Severe Mild Severe
OKN, optokinetic nystagmus; VOR, vestibular-ocular reflex; VOR-Fix, fixation suppression of VOR.
Source: Adapted from Buttner et al.96
the majority of the recessively inherited neurological degeneration seen with FA results
ataxias.97–99 Its prevalence of about 2 per from free-radical toxicity due to mitochondrial
100,000 equals nearly that of all of the domi- damage. Selective cell vulnerability may be due
nant ataxia syndromes combined. It was first to the levels of respiratory activity (which is
described by Nicholas Friedreich in 1863.100 high in the brain and heart) and to levels of iron
He emphasized the progressive ataxia, sensory metabolism.
loss, and muscle weakness often associated Both auditory and vestibular loss commonly
with scoliosis, foot deformity, and heart dis- occur with FA, particularly in the later stages of
ease. The currently accepted clinical criteria the disease.105,106 Two sisters with FA showed
include (1) autosomal recessive inheritance, extensive degeneration of the neurons of the
(2) onset before age 25 years, (3) progressive eighth nerve (both auditory and vestibular),
limb and gait ataxia, (4) distal loss of position with preservation of the peripheral receptor
and vibration sense, and (5) absent tendon organs.107 These changes correlated with the
reflexes in the legs. Cardiomyopathy, kyphosco- clinical findings of progressive bilateral deaf-
liosis, pes cavus, optic atrophy, hearing and ness and caloric hypoexcitability for several
vestibular loss, and diabetes mellitus occur in years prior to death. Oculomotor testing typi-
some patients. With the discovery of the gene cally shows prominent saccade dysmetria and
for FA, it has become clear that the disease can ocular flutter superimposed on voluntary and
show remarkable clinical variability, sometimes involuntary eye movements.105,108
even within the same family.99,101 Age of onset, As with the other trinucleide repeat syn-
presence or absence of deep tendon reflexes, dromes, larger expansions are correlated with
and presence or absence of associated features earlier disease onset and more rapid progres-
can all be variable according to the type of sion.103 The best correlation is seen with the
genetic defect. size of the smaller allele, indicating that smaller
Friedreich’s ataxia results from a large expan- expansions are consistent with some residual
sion of a GAA repeat in intron 1 of the gene function. The frequencies of cardiomyopathy,
frataxin.102,103 This gene has 5 exons spread over flexor plantar responses, and skeletal deformi-
40,000 base pairs encoding a 210 amino acid ties all increase with increasing GAA repeat
protein designated frataxin. Most patients have number.103
the expanded GAA repeat in both alleles, but Several FA-like syndromes can result from
some have an expanded GAA repeat in one metabolic disorders that lead to vitamin E defi-
allele and a point mutation in the other, and ciency. Mutations in the alpha-tocopherol
rare patients have point mutations in both transfer protein (α-TTP) on chromosome 8q
alleles. Frataxin is a mitochondrial protein that and mutations in the microsomal triglyceride
is important in iron metabolism.104 Yeast organ- transfer protein (MTP) on chromosome 4q
isms deficient in the frataxin homologue accu- result in vitamin E deficiency and a clinical
mulate iron in mitochondria and have increased syndrome similar to FA.99,109 These syndromes
sensitivity to oxidative stress. From this are important to recognize because they can be
observation, it has been suggested that the treated with vitamin E replacement.
Refsum’s syndrome is characterized by a A large variety of missense mutations in KCNA1

combination of retinitis pigmentosa, bilateral have been found in families with EA-1 with no
sensorineural hearing loss, cerebellar ataxia, mutation being predominant.
and peripheral neuropathy. Patients with
Refsum’s disease have an elevated serum phy-
EPISODIC ATAXIA TYPE 2
tanic acid, the result of a defect in lipid alpha
oxidase.110 The disorder typically begins in the Episodic ataxia type 2 (EA-2) is characterized
first decade, is slowly progressive, and like FA by more prolonged episodes of ataxia (lasting
can be associated with cardiac conduction hours) and interictal nystagmus.119 Often the
defects and cardiomyopathy. Refsum’s syn- episodes of ataxia are associated with vertigo
drome results from missense mutations in the and nausea and vomiting. The ataxia can be
phytanoyl-CoA hydroxylase (PAHX) gene confined to just the trunk or may involve the
located on chromosome 10.111 upper extremities as well. The interictal nys-
Several recessively inherited ataxia syn- tagmus can be gaze-evoked, rebound, or spon-
dromes are associated with oculomotor apraxia: taneous vertical (particularly downbeat). Some
ataxia telangectasia, ATM gene; ataxia with patients develop a slowly progressive ataxia
oculomotor apraxia I, APTX gene; ataxia with later in life. The gene for EA-2 is a calcium
oculomotor apraxia II, SETX gene.112–114 channel gene, CACNA1A, located on chromo-
Children with these disorders have impaired some 19p.120 Missense mutations in CACNA1A
voluntary and reflexive saccades so that vestib- typically lead to a variety of familial hemiplegic
ular stimulation causes a slow deviation of the migraine, whereas nonsense mutations result
eyes without corrective fast components. in EA-2.
Refixations are made with head thrusts rather
than saccades. How these genes that are pri-
EPISODIC ATAXIA TYPES 3–7
marily involved in DNA repair lead to ataxia
and oculomotor apraxia is poorly understood. At least five other autosomal dominant EA syn-
dromes have been described in one or two
families.116 Genetic analysis ruled out linkage
Episodic Ataxia and Vertigo to the EA1 and EA2 loci, and two additional
Syndromes genes have been identified: EA-5, CACNB4,
another calcium channel gene and EA-6,
The episodic ataxias are a group of rare disor- SLC1A3, a glutamate transporter gene.121,122
ders characterized by attacks of generalized All of the genes identified so far with autosomal
ataxia with normal or near-normal neurologic dominant episodic ataxia code for ion channels
function in between.115,116 The attacks typically or transporters. Similar genes are good candi-
begin in early childhood or early adulthood. dates for other EA syndromes and for the more
Although a large number of recessive and common episodic vertigo syndromes, including
X-linked causes of episodic ataxia are known, migrainous vertigo.
most cases are autosomal dominant. The genes
for several dominant forms of episodic ataxia
have recently been discovered; this may pro- Diagnosis
vide insight into the pathophysiology of other
episodic vertigo and ataxia syndromes.116 The first step in the diagnosis of one of the
inherited SCA syndromes is to recognize the
phenotype. This will define the diagnostic
EPISODIC ATAXIA TYPE 1
workup and the type of DNA testing.95,99 The
Episodic ataxia type 1 (EA-1) is characterized clinical examination will indicate whether
by brief episodes of ataxia (minutes) and the phenotype is a pure cerebellar syndrome
interictal myokymia.117 The myokymia (muscle or whether there are combined brainstem,
rippling) is typically most evident in the eyelids cerebellar, and spinal cord findings. Most
and fingers. In some cases it can only be identi- patients with an inherited disorder will have
fied with electromyography. The gene for EA-1 a positive family history. It must be kept in
is a voltage-gated potassium channel gene mind, however, that a negative family history
(KCNA1) located on chromosome 12q.118 based on the patient’s report can be deceptive.
Often families are too small to be informative identified. The genes can be sequenced, but
or critical members cannot be evaluated or this is expensive especially for a large gene such
have died early. as CACNA1A.
Neuroimaging studies, particularly MRI of
the brain and upper cervical cord, can help
confirm which anatomical structures are Management
involved. Of the common dominant SCA
syndromes, SCA-1, -2, -3, and -7 show com- With a few exceptions, management of patients
bined cerebellar and brainstem atrophy at least with inherited ataxia is symptomatic. Patients
by the mid to late stages, whereas SCA-6 shows are encouraged to use a cane or walker to
a selective cerebellar atrophy, which is most improve sensory input and to avoid falls.
prominent in the vermis.123 With FA, the Regular physical therapy to maintain range of
cerebellum is typically spared, but the spinal motion for all joints is critical to avoid painful
cord is atrophic. Cerebellar vermian atrophy contractures. A special diet low in long-chain
is also seen with EA-2 (Fig. 18–3)124 but not fatty acids can be effective in controlling the
with EA-1. progression of symptoms and signs in patients
Specific DNA tests are now available for all with Refsum’s syndrome.110 Acetazolamide
of the trinucleotide repeat syndromes. The (Diamox) is remarkably effective for relieving
battery of tests can be ordered on any patient the episodic symptoms in patients with EA-2
with a dominantly inherited SCA syndrome. and, to a lesser degree, in patients with EA-1.115
The GAA expansion with FA should be consid- Acetazolamide is not very effective in patients
ered in just about any patient with a recessively with other EA syndromes. Acetazolamide pre-
inherited ataxia syndrome. Unfortunately at sumably works by altering the pH within the
the present time, none of the missense muta- cerebellum, thus stabilizing the mutated ion
tions, either in the frataxin gene or in the epi- channels. One typically begins with a low dos-
sodic ataxia genes, can be routinely ordered age (125 mg/day) and then works up to an aver-
since no single dominant missense mutation age effective dosage of between 500 and
has been identified. However, as in the case 750 mg/day. Most patients will experience par-
with the many missense mutations causing esthesias of the extremities after taking the
nonsyndromic hearing loss, “gene chips” should drug, but these symptoms typically decrease
be available in the near future to screen for the over time. The main long-term side effect is
large number of mutations that have been the development of kidney stones, which may
Figure 18–3. Magnetic resonance image of brain in a patient with episodic ataxia type II (EA-2) showing atrophy of the
cerebellar vermis. T1-weighted sagittal section.
markedly decrease if the patient regularly 10. Smith RJH, Bale JF, White KR. Sensorineural hearing
drinks citrus juices. Patients with SCA-6 who loss in children. Lancet. 2005;365:879.
11. Colugnati FA, Staras SA, Dollard SC, Cannon MJ.
have episodic features may also respond to Incidence of cytomegalovirus infection among the
acetazolamide.125 It is unknown whether the general population and pregnant women in the United
long-term slowly progressive ataxia is affected States. BMC Infect Dis. 2007;7:71.
by the regular use of acetazolamide. A thera- 12. Church MW, Abel EL. Fetal alcohol syndrome.
Hearing, speech, language, and vestibular disorders.
peutic trial of acetazolamide should be consid- Obstet Gynecol Clin North Am. 1998;25:85.
ered in any patient with early-onset episodic 13. Roebuck TM, Simmons RW, Mattson SN, Riley
vertigo and/or ataxia who has a family history of EP. Prenatal exposure to alcohol affects the ability
similar episodes. to maintain postural balance. Alcohol Clin Exp Res.
Although identifying the genes responsible 1998;22:252.
14. Kumar A, Fishman G, Torok N. Vestibular and audi-
for the other SCA syndromes is the first step in tory function in Usher’s syndrome. Ann Otol Rhinol
finding effective treatment, at present no Laryngol. 1984;93:600.
effective treatment exists. Therefore, genetic 15. Nikolopoulos TP, Lioumi D, Stamataki S, O’Donoghue
counseling is critical for patients both GM. Evidence-based overview of ophthalmic disorders
in deaf children: a literature update. Otol Neurotol.
before and after genetic tests are ordered.123 2006;27(2 suppl 1):S1.
Presymptomatic testing should probably be 16. Saihan Z, Webster AR, Luxon L, Bitner-Glindzicz
restricted to adults, as informed decision mak- M. Update on Usher syndrome.Curr Opin Neurol.
ing and psychological counseling can be more 2009;22(1):19.
effectively employed and the risk of stigmatiza- 17. Maerker T, van Wijk E, Overlack N, et al. A novel
Usher protein network at the periciliary reload-
tion is lessened. ing point between molecular transport machineries
in vertebrate photoreceptor cells. Hum Mol Genet.
2008;17:71.
18. Newton VE. Clinical features of the Waardenburg
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PART 4
Symptomatic Treatment
of Vertigo
Chapter 19
Antiemetic and Antivertigo Drugs
VESTIBULAR SUPPRESSANTS Diphenhydramine Hydrochloride (Benadryl)

How Do They Work? Meclizine (Antivert, Bonine)
How to Use Them Dimenhydrinate (Dramamine)
Indications Promethazine Hydrochloride (Phenergan)
Precautions Betahistine (Serc)
What to Tell the Patient Metoclopramide (Reglan)
ANTIEMETIC DRUGS Benzquinamide Hydrochloride (Emete-con)
How Do They Work? Trimethobenzamide Hydrochloride (Tigan)
How to Use Them Diazepam (Valium)
Precautions Droperidol (Inapsine)
What to Tell the Patient Diphenidol (Vontrol)
SPECIFIC DRUGS Prochlorperazine (Compazine)
Scopolamine (Transderm Scop) Dronabinol (Marinol)
Buclizine Hydrochloride (Bucladin-S)
Vertigo is an unpleasant sensation that is underlying disease, the expected course of the
frequently accompanied by nausea and vomiting. disease, and the patient’s need for mobility
These symptoms can result from a variety of during recovery.
diseases affecting the vestibular system (see Two general classes of drugs are used to
Chapters 9–18). The best therapy is to elimi- treat vertigo, nausea, and vomiting: vestibular
nate vertigo with specific treatment of the suppressants and antiemetics.1 Vestibular sup-
underlying disease. However, in cases in which pressants treat a variety of symptoms associ-
the disease is not readily treatable, when treat- ated with vestibular illness, usually reducing
ment must be continued for a long period the sensation of vertigo and associated nausea
before improvement occurs or when vertigo is and vomiting. Antiemetics are more selective
prolonged and severe, there is a need for symp- in action; they are used primarily to reduce
tomatic therapy. nausea and vomiting associated with many
The ideal symptomatic medication should illnesses and can also be used in combination
suppress the sensation of vertigo, help restore with vestibular suppressants for treating
normal balance, and prevent vomiting. There vertigo.
should be minimal side effects, and the treat- The main types of vestibular suppressants
ment should not impede the normal process of include antihistamines, anticholinergics, and
recovery from the vestibular lesion. At the benzodiazepines, although a variety of other
present time, there is no medication available drugs have also been used (Table 19–1).
that would meet these objectives. In the Abundant empirical evidence demonstrates
absence of the ideal drug, the choice of thera- the efficacy of these medications in the treat-
pies should take into account the patient’s ment of vertigo. Although the exact mechanism
405
406
Table 19–1 Main Actions of Commonly Used Antivertiginous and Antiemetic Drugs
Clinical Neurophysiology of the Vestibular System

Class Drug Histamine Acetylcholine Dopamine Serotonin GABA Agonist Opiate Agonist
Antagonist Antagonist Antagonist Antagonist
Antihistamine Diphenhydramine + +
Meclizine + +
Cyclizine + +
Buclizine + +
Promethazine + + +
Anticholinergic Scopolamine +
Benzamide Trimethobenzamide + +
derivative
Benzquinamide + +
Metoclopramide + + +
Phenothiazine Chlorpromazine + +
Perphenazine + +
Prochlorperazine + +
Butyrophenone Droperidol + +
Antiserotonergic Ondansetron +
Benzodiazepine Diazepam +
Lorazepam +
Cannabinoid Dronabinol +
Other Diphenidol + +
Domperidone + +
19 Antiemetic and Antivertigo Drugs 407
Cortex
(Cannabinoids)
(Benzodiazepines)
Chemoreceptor
trigger zone
(Antidopaminergics)
G.I. tract Emetic center Vestibular nuclei

(Antiseritonergics) (Antihistamines) (Antihistamines)
(Anticholinergics) (Anticholinergics)
(Benzodiazepines)
(Antidopaminergics?)
Figure 19–1. Schematic drawing of the major inputs to the emetic center and probable site of action of different classes
of drugs. G.I., gastrointestinal.
of action of many of these drugs is unclear, that block or otherwise modulate excitatory
most appear to act at the level of the neu- amino acid receptors has been limited. Possibly
rotransmitters involved in propagation of because of the widespread distribution of excit-
impulses from primary to secondary vestibular atory amino acid receptors in the central ner-
neurons and in maintenance of tone in the ves- vous system (CNS), therapeutic benefits that
tibular nuclei. Antiemetic drugs are directed could be derived from systemic administration
against the areas of the nervous system control- of antagonists of the excitatory amino acid
ling vomiting (Fig. 19–1).2 This system of neu- receptor are offset by generalized side effects.
rons contains central components (loosely
described as the emetic center) and peripheral
components in the gastrointestinal tract.3 How Do They Work?
Although the exact pathways mediating vestib-
ular-induced vomiting are not completely As noted earlier, vestibular suppressants are
known, patients who have a baseline sensitivity thought to work by depressing transmission of
to motion (i.e., low threshold for developing vestibular signals through the vestibular nuclei
nausea and vomiting) are often more affected to the emetic center and other brainstem auto-
by nausea and vomiting in the setting of a ves- nomic centers. As shown in Table 19–1, these
tibular disorder.4 Many of the vestibular drugs typically have multiple actions. The
suppressants also have antiemetic action and transmitters that they affect are not specific to
vice versa, and many of the antiemetic drugs the vestibular system but are present through-
produce vestibular suppression. out the CNS. This may account for the many
associated side effects. Acetylcholine is an
excitatory neurotransmitter in the vestibular
system; muscarinic receptors in the vestibular
VESTIBULAR SUPPRESSANTS nuclei are the presumed site of action for anti-
cholinergic vestibular suppressants.6,7 A major
The study and understanding of neurotrans- histaminergic system projects to the vestibular
mitters within the vestibular nuclei is in its nuclei and brainstem autonomic centers.8,9 All
infancy (see Chapter 3). New information on three histamine receptors are expressed in the
the neurotransmitters will lead to new and bet- vestibular nuclei and in the vestibular
ter vestibular suppressants and a better under- periphery.10,11,12 H1and H2 receptors are post-
standing of how vestibular suppressants work. synaptic, while H3 receptors are presynaptic.
For example, substantial evidence shows that Most antihistamines used in the treatment of
the main neurotransmitter between primary vertigo are H1 blockers, but they also have anti-
and secondary vestibular neurons is an excit- cholinergic actions. The benzodiazepines are
atory amino acid, either glutamate or aspartate, agonists of γ-aminobutyric acid (GABA), which
acting on kainate receptors.5,6 Despite this is the primary inhibitory neurotransmitter for
information, the therapeutic potential of drugs vestibular neurons.13 Furthermore, H3 receptors
modulate GABAergic transmission in the ves- many different causes, but regardless of the
tibular nuclei.14 Dopamine receptors have also cause, central compensation will occur and the
been identified within the vestibular nucleus patient will recover. Vestibular suppressants can
complex,15 but it is unclear whether antidop- impair the process of central compensation.17,18
aminergic drugs have a direct effect on the Patients are often extremely vertiginous with
vestibular nuclei or affect other centers that severe nausea and vomiting for the first few days
influence the vestibular nuclei. Finally, sero- after the vestibular lesion, and it is appropriate
tonergic neurons in the dorsal raphe nucleus to use strong vestibular suppressants in that
project directly to the vestibular nuclei.16 time frame. However, as soon as the vomiting
ceases, vestibular suppressants should be with-
drawn gradually to allow compensation.
How to Use Them The commonly used antihistamine vestibular
suppressants require 20 to 30 min to initiate
Vestibular suppressants can be used acutely to action, reach a peak plasma level in 1 to 2 hr, and
treat a discrete attack or chronically as prophy- have a half-life of about 8 hr. Therefore, dosing
laxis against future attacks. To decrease the can be as infrequent as twice a day. Transdermal
risks of unacceptable side effects, the choice of scopolamine is programmed to deliver through
drug and administration must be determined the systemic circulation 0.5 mg of scopolamine
by the underlying vestibular problem. Acute at a constant rate each day over the 3-day life-
severe attacks of vertigo accompanied by severe time of the system. When used as a prophylaxis
nausea and vomiting are the most distressing for motion sickness, the patch should be in place
form of vestibular illness. Vestibular suppres- several hours before exposure to motion.
sants are useful only for attacks that last long
enough for the drug to reach an effective blood
level before the attack ends. This limits acute Indications
therapy to attacks lasting at least an hour.
Because maximum vestibular suppression may The less sedating drugs are milder vestibular
not be reached for 2 or more hours after dos- suppressants than the more sedating drugs
ing, treatment is most useful for attacks that (Table 19–2). The less sedating medications,
last several hours. In general, the stronger sup- such as scopolamine and meclizine, are partic-
pressants are more sedating and should be ularly useful for treating chronic recurrent
reserved for acute treatment. Brief vertigo attacks of vertigo during which the patient is
spells, such as those associated with benign attempting to carry on normal activities, includ-
positional vertigo or vertebrobasilar insuffi- ing work. The more sedating medications, such
ciency, cannot be controlled by ingestion of a as promethazine, the benzodiazepines, and
suppressant at the time of the attack. droperidol, are particularly effective for an
Chronic prophylactic treatment with vestib- acute severe attack of vertigo, nausea, and
ular suppressants should be avoided because of vomiting when the patient desires sedation
potential problems with tolerance and depen- and rest. For similar reasons, the less sedating
dency. Withdraw symptoms such as motion medications are used in the prophylaxis of
sensitivity and nausea commonly occur and motion sickness.
may be misinterpreted as due to the underly-
ing disorder. The need to control vertigo must
be weighed against the need for the patient to Precautions
maintain full mobility and function. Patients
who complain of almost continuous weeks to Because drowsiness and disorientation can
months of dizziness should not be managed occur with all of these drugs, patients should
with vestibular suppressants. Such a complaint be warned about engaging in tasks requiring
suggests a diagnosis other than a specific ves- mental alertness. All medications with anticho-
tibular disorder. Vestibular suppressants are linergic properties should be used with caution
not useful in treating chronic dizziness of nonin patients with glaucoma, pyloric obstruction,
vestibular origin. or urinary bladder neck obstruction and who
A sudden loss of peripheral vestibular func- are suspected of having intestinal obstruction.
tion on one side is a common disorder with These drugs should be used with caution in
Table 19–2 Indications for Use of Common Vestibular Suppressants
LESS SEDATING MORE SEDATING
Type of Scopolamine Meclizine Cyclizine Buclizine Diphenhydramine Promethazine Diazepam Lorazepam Droperidol
Vertigo
Acute periph- + + + +
eral vertigo
Chronic + + + + + +
19
recurrent
peripheral
Antiemetic and Antivertigo Drugs

vertigo
Central + + +
vertigo
Prevent + + + + + +
motion
sickness
409
patients using CNS depressant drugs or con- safe to use during pregnancy.21 An increased
suming alcohol because the additive effects on risk of congenital malformations associated
the CNS may cause adverse reactions. As noted with diazepam during the first trimester of
earlier, withdrawal symptoms can occur after pregnancy has been suggested in several stud-
discontinuing any of these medications but are ies. Small doses of benzodiazepines may be
particularly prominent with the benzodiaz- safe later in pregnancy.21 Diazepam is excreted
epines and scopolamine.19 These symptoms in breast milk and, because neonates metabo-
include dizziness, nausea and vomiting, lize diazepam more slowly than adults, accu-
headaches, and disturbances of equilibrium, all mulation of the drug and its metabolites to
of which may be similar to the symptoms toxic levels is possible.
that initially triggered the use of the drug.
Withdrawal symptoms, of course, are most
likely to occur in patients who have been on What to Tell the Patient
the medication for many days. Abrupt with-
drawal of the benzodiazepines can lead to gen- These medications are used to suppress vertigo
eralized seizures. Addiction-prone individuals and the commonly associated nausea and vom-
should be under careful surveillance while iting. They treat the symptoms but do not
receiving benzodiazepines because of the pre- address the underlying cause of the vertigo. It
disposition of such patients to habituation and is not a good idea to use vestibular suppressants
dependence. on a chronic basis because they can interfere
Because of the multiple effects of each of with the brain’s ability to compensate for the
these drugs, possible drug interactions should underlying problem. These medications typi-
always be considered before use. The drugs cally are sedating, so at least initially they
with anticholinergic properties and the benzo- should not be used when performing activities
diazepines are contraindicated in patients with that require a high level of alertness, such as
glaucoma unless they are receiving appropriate driving, operating machinery, or performing
therapy. The antihistamines should not be used athletic activities. Patients should not take
in patients with asthma, emphysema, chronic other drugs without discussing it with the
pulmonary disease, or difficulty in urinating doctor. Avoid excessive alcohol consumption
because of an enlarged prostate. The benzodi- since the effects could be additive.
azepines are generally not recommended for
children younger than 6 months. Transdermal
scopolamine should not be used in children
because it is unknown whether the amount of ANTIEMETIC DRUGS
scopolamine released will produce serious
adverse effects in children. Extra caution The antiemetic drugs are used to suppress nau-
should be taken when treating elderly patients sea and vomiting regardless of the cause. They
because of a higher risk of drug-related prob- can be used with vestibular suppressants when
lems or toxic effects.20 Medicines with no or treating vertigo, nausea, and vomiting due to
fewer anticholinergic properties (e.g., prochlo- vestibular lesions or they can be used in isola-
rperazine) are favored over medicines with tion when treating nausea and vomiting due to
more anticholinergic properties (e.g, promet- other causes. These drugs are directed at the
hazine). Short-acting sedating medicines (e.g., areas of the nervous system controlling
lorazepam) at low doses are favored over long- vomiting (Fig. 19–1). Dopamine, histamine,
acting sedating medicines (e.g., diazepam). acetylcholine, and serotonin are all neurotrans-
Because of its potential for producing memory mitters believed to act on these sites to produce
loss, hallucinations, and alterations in mental vomiting.22 The emetic center is not a discrete
status, scopolamine should be used with localized area in the brain. The final process
extreme caution in older people. involved in emesis is coordinated in the reticu-
All of these drugs should be used with cau- lar formation of the brain stem, but input is
tion in patients with renal or hepatic impair- received from numerous areas of the brain
ment because of their multiple actions, stem and cortex.23 The chemoreceptor trigger
particularly their anticholinergic properties. zone, located in the area postrema, is a major
Meclizine and dimenhydrinate are considered relay in triggering emesis.
How Do They Work? drugs in the NK-1 receptor agonist class.27

The benzodiazepines, as a single agent, are
Many antiemetics act by suppressing activity in of limited use for treating nausea and vomiting,
the reticular formation or area postrema. but they can be used in combination with
Others suppress major centers feeding into the other antiemetic drugs because of their action
chemoreceptor trigger zone or the emesis cen- on the central emetic centers and their ability
ter. Still others suppress activity in visceral to reduce akathisia and anxiety.31 Of the
afferents running from the gastrointestinal to vestibular suppressants, promethazine and
the emetic center. Each of the antiemetic drugs droperidol are the most effective antiemetic
probably have multiple sites of action within drugs.32
the CNS (Fig. 19–1). The cannabinoids and Domperidone is chemically unrelated to the
benzodiazepines are thought to work at the butrophenones, phenothiazines, or metoclopr-
level of the cerebral cortex, controlling input to amide; however, it shares pharmacologic prop-
the brainstem vomiting center.24 The antidop- erties with these agents. In the medulla, the
aminergics block input to the emetic center drug produces a direct blocking effect of
from the chemoreceptor trigger zone located dopamine receptors in the chemoreceptor trig-
in the area postrema.25 Serotonin antagonists, ger zone. Like metoclopramide and haloperi-
particularly antagonists to the 5-HT3 receptors, dol, domperidone is a peripheral dopamine
block the activity of visceral afferents that run antagonist; however, it does not cross the
from the gut to the emetic center and the area blood–brain barrier and produce CNS effects.
postrema.26 Newer 5-HT3 receptor antagonists
and Neurkinin-1 (NK-1) antagonists work
centrally although the exact mechanism of Precautions
action is unclear. Finally, antihistamines and
anticholinergics appear to work directly on the Extrapyramidal symptoms and signs occur with
emetic center. use of phenothiazines and butyrophenones,
and they may be confused with CNS signs of
undiagnosed primary disease responsible for
How to Use Them the vomiting.33 Tardive dyskinesia, a syndrome
consisting of potentially irreversible involun-
The indications for using any of the common tary dyskinetic movements, also commonly
antiemetic drugs are summarized in Table occurs with using these drugs. The risk of
19–3. The antihistamines, anticholinergics, and developing the syndrome and the likelihood
benzodiazepines are most effective when treat- that it will become irreversible are believed to
ing nausea and vomiting associated with vestib- increase as duration of treatment and total
ular lesions; the cannabinoids, antidopaminer- cumulative dose administered to the patient
gics, and antiserotonergics are most useful in increase. Potentially fatal symptoms often
treating nausea and vomiting associated with referred to as neuroleptic malignant syndrome
surgery, chemotherapy, and radiation treat- have been associated with phenothiazines and
ment. Through its antidopaminergic and antise- butyrophenones.34 Alcohol should be avoided
rotonergic actions, metoclopramide suppresses with all of these drugs because of possible addi-
the central chemoreceptor trigger zone and tive side effects. Because of the multiple effects
diminishes the activities of visceral afférents in of each of these drugs, possible drug interac-
the gut;28 it is particularly effective for treating tions should always be considered before use.
postoperative nausea and vomiting and in com- The antidopaminergic antiemetic drugs
bination with other agents for treatment of should be used with great caution in children
postirradiation and chemotherapy-induced nausea because there is a high incidence of extrapyra-
and vomiting.29 Ondansetron is a well-tolerated midal side effects in children. Although the
selective blocker of 5-HT3 that has been effec- incidence of extrapyramidal side effects is less
tive for treating chemotherapy-induced nausea than 1%–2% in adults, it can be as high as 25%
and vomiting.30 Palonosetron is a newer 5HT3 in children.35,36 These reactions frequently
receptor antagonist with a higher binding develop during the first few days of treatment.
affinity and longer half-life than ondansetron.27 Sometimes the drugs can be restarted at a
Aprepitant and casopitant are new antinausea lower dose once the acute reaction subsides.
Domperidone
+
Dephenidol
+
Dronabinol
+
+
Ondansetron
+
+
+
Droperidol
+
+
Prochlorperazine
+
+
+
+
Perphenazine
+
+
Chlorpromazine
+
+
Table 19–3 Indications for Use of Common Antiemetic Drugs
Metoclopramide
+
+
+
Benzoquinamide
+
Trimethobenzamide
+
Promethazine
+
+
Scopolamine
+
+
Chemotherapy induced
Vestibular induced
Type of Nausea
Radiation induced
and Vomiting
Postoperative
Older patients are particularly prone to the preventing motion sickness, the system should
sedating and extrapyramidal side effects of the be applied about 8 to 12 hr before exposure
antidopaminergic antiemetic drugs. to motion. The scopolamine transdermal
Chlorpromazine should be administered system should be used with great caution
cautiously to persons with hepatic disease in older people because they are particularly
because patients with a history of hepatic susceptible to the CNS side effects, such as
encephalopathy from cirrhosis may have an memory loss, delusions, and hallucinations.
increased sensitivity to the CNS effects of Drug withdrawal symptoms, including
chlorpromazine. Most of the antidopaminergic dizziness, nausea, vomiting, headaches, and
drugs are excreted at least in part by the disturbances of equilibrium, can occur
kidneys and therefore should be used with cau- after discontinuation of the transdermal sys-
tion in patients with renal failure. Most of these tem, particularly if it has been used for several
drugs have not been assessed adequately weeks.19 Sometimes these withdrawal symp-
regarding their safety during pregnancy, and toms are confused with the symptoms that ini-
therefore use during pregnancy must be tiated the use of the transdermal scopolamine
weighed against possible hazards to mother system.
and child.
Buclizine Hydrochloride
What to Tell the Patient (Bucladin-S)
These drugs are used to suppress nausea and Buclizine hydrochloride is a vestibular sup-
vomiting but do not treat the underlying cause. pressant and antiemetic agent that is useful
Patients should understand the symptoms of for treating vertigo due to vestibular lesions
extrapyramidal side effects and with tardive and for preventing motion sickness. It is a
dyskinesia so that they can report them to the piperazine-type antihistamine with anticho-
physician immediately if any become evident. linergic properties. Like the other antihista-
If a child shows any type of unusual behavior or mine anticholinergic drugs, sedation and dry-
excessive excitement, the drug should be with- ness of the mucous membranes are the most
held and the symptoms should be immediately common side effects. The tablets can be taken
reported to the physician. As with all of these without swallowing water by placing the tablet
medications, adults should not drive or operate under the tongue and allowing it to dissolve.
machinery until the full effects of drug are real- This route of administration can be useful
ized. Sedation may range from mild drowsiness when the patient is having severe nausea and
to severe sleepiness. vomiting.
SPECIFIC DRUGS Diphenhydramine Hydrochloride

(Benadryl)
Scopolamine (Transderm Scō p)
Diphenhydramine hydrochloride is a vestibu-
Scopolamine transdermal system is an anticho- lar suppressant and antiemetic agent with mod-
linergic agent classified as a belladonna alka- erate sedating properties. It is an ethanolamine
loid that is most useful for prevention of nausea antihistamine that is also an anticholinergic
and vomiting associated with motion sickness. agent. It is most useful for treating mild to
Because of its short half-life in plasma and moderate episodes of vertigo and for preven-
dose-dependent side affects, oral or parenteral tion of motion sickness. The most common side
administration is of limited use. The transder- effects are dryness of the nose, throat, and
mal system of scopolamine is programmed mouth and moderate sedation. Diphen-
to deliver 0.5 mg at a constant rate (5 µg/hour) hydramine is often effective for treating the
to the systemic circulation over a 3-day lifetime extrapyramidal side effects that occur with the
of the system.37 To be most effective in antidopaminergic drugs.38
Meclizine (Antivert, Bonine) particularly useful for treating severe vertigo

with recurrent nausea and vomiting. It is an
Meclizine is a vestibular suppressant and anti- antidopaminergic agent and also has antihista-
emetic agent that is less sedating than most of minic and anticholinergic properties. As an
the other vestibular suppressant drugs.39 It is a antihistamine, it acts by competitive antago-
piperazine-type antihistamine that also has nism but does not block release of histamine; it
anticholinergic properties. Peak effect is not antagonizes in varying degrees most pharmaco-
reached until 7 to 9 hr after ingestion. It is par- logic effects of histamine.41 Although infre-
ticularly useful for treating mild to moderate quent, extrapyramidal symptoms can occur
episodes of vertigo and for suppressing motion secondary to promethazine, and occasionally
sickness. It should be taken several hours such symptoms can be confused for CNS signs
before exposure to motion to be effective in of an undiagnosed primary disease. Pro-
preventing motion sickness. Because it has a methazine can be very sedating, particularly in
very low risk of teratogenicity, it can be useful older people, and it should not be used in
for treating nausea and vomiting during patients with a history of sleep apnea. It can be
pregnancy. As with the other antihistaminic more effective with less sedation by combining
anticholinergic agents, the main side effects it with 25 mg of ephedrine.42 Because of its
are dryness of the mucous membranes and excellent antiemetic action, it can be combined
mild sedation. with other vestibular suppressants that have
fewer antiemetic properties, such as scopol-
amine and the benzodiazepines.
Dimenhydrinate (Dramamine)
Dimenhydrinate is a vestibular suppressant
Betahistine (Serc)
and antiemetic agent that is primarily used for
Betahistine is an H3 receptor antagonist that
preventing motion sickness. Like other drugs
has long been used for treating vertigo particu-
in this class, it has antihistaminic and anticho-
larly vertigo associated with Meniere’s syn-
linergic activity and the main side effects are
drome.43–45 Betahistine was briefly approved by
dryness of mucous membranes and mild to
the Food and Drug Administration (FDA) for
moderate sedation. The sedation associated
use in the United States about 40 years ago, but
with dimenhydrinate and other H1 blockers
subsequently approval was withdrawn due
can be reduced or avoided by using slow-
to lack of evidence for efficacy. It is still avail-
release formulations.40 Patients over age 65
able in Europe and Canada and can be
may have a stronger reaction and require
obtained through compounding pharmacies
smaller doses. Dimenhydrinate should be used
in the United States. Curiously, by blocking
with caution in patients with cardiovascular or
presynaptic H3 receptors, betahistine causes an
respiratory disease and in patients with convul-
increased release of histamine and activation of
sive disorders. For prevention of motion sick-
H1 receptors (the opposite effect of antihista-
ness, the first dose should be given 30 min
minic vestibular suppressants). However, by
before exposure to motion. Since dimenhydri-
blocking H3 receptors in the vestibular periph-
nate may cause drowsiness or impair judgment
ery, betahistine may decrease spontaneous
and coordination, patients should be warned
afferent activity.10,46
not to operate any machinery or drive a vehicle
because of the sedative effect. They should
avoid alcohol and drink plenty of fluids for dry Metoclopramide (Reglan)
mouth and to prevent constipation.
Metoclopramide is an antiemetic medication
that appears to work both centrally on the
Promethazine Hydrochloride chemoreceptor trigger zone and peripherally
(Phenergan) on the gastrointestinal tract.47 It has antidop-
aminergic and anticholinergic properties
Promethazine hydrochloride is a potent ves- and thus has the potential side effects of
tibular suppressant and antiemetic drug that is extrapyramidal symptoms and dryness of the
mucous membranes. Its gastrointestinal effects to rapidly suppress acute severe vertigo, but the
are mediated through blockage of serotonin intravenous route must be used with extreme
receptors; blocking activity originates in vis- caution particularly in patients with limited pul-
ceral afferents running from the gastrointesti- monary reserve, because of the possibility of
nal tract to the emetic center. Metoclopramide producing apnea or cardiac arrest. Abrupt with-
is an antiemetic agent useful for treating many drawal of diazepam may be associated with
causes of nausea and vomiting. It also can be prominent withdrawal symptoms, including sei-
used in combination with vestibular suppres- zures. Patients should be warned about the
sants and other antiemetic drugs.19 It can be simultaneous use of alcohol or other CNS
administered orally or by injection with onset depressant drugs because of the additive effect.
of action within the first hour (the half-life is 5
to 8 hr).
Droperidol (Inapsine)
Benzquinamide Hydrochloride Droperidol is a butyrophenone derivative that

(Emete-con) has prominent antiemetic effects. The onset of
action is within 30 min after injection; thera-
Benzquinamide hydrochloride is a short-acting peutic levels persist 2 to 4 hr and vestibular
non–amine-depleting benzamide derivative, suppression can be demonstrated for as long as
chemically unrelated to the phenothiazines and 24 hr.50 Like the phenothiazines, its mode of
other antiemetic drugs. It has antihistaminic action is blockage of dopaminergic transmis-
and anticholinergic properties, but the mecha- sion in the chemoreceptor trigger zone.35 It can
nism of action of its antiemetic properties is produce marked tranquilization and sedation
unknown. It is most useful for treating mild, and therefore should be used with great cau-
persistent nausea but has sedating properties tion in older people. The drug also produces a
like all of the other antiemetic drugs. A sudden mild α-adrenergic blockade. Hypotension, pos-
increase in blood pressure and transient sibly associated with hypovolemia, and extrapy-
arrhythmia has been reported following intra- ramidal effects should be watched for. The
venous administration of benzquinamide. FDA placed a black box warning on the use of
droperidol because of the possibility of induc-
ing fatal cardiac arrhythmias due to prolonga-
tion of the QT interval.32
Trimethobenzamide Hydrochloride
(Tigan)
Diphenidol (Vontrol)
Trimethobenzamide hydrochloride is a benz-
amide derivative that has antihistaminic and Diphenidol is a piperidinebutanol compound
anticholinergic properties. This drug is an anti- that has antiemetic properties but is chemically
emetic agent that is suitable for mild to moder- unrelated to the other antiemetic drugs.
ate nausea and vomiting. It can produce Diphenidol does have weak peripheral antich-
drowsiness and may be additive with other olinergic effects and therefore can have the
sedating medications. Extrapyramidal side usual side effects associated with these agents.
effects can also occur. Because of its potential for producing halluci-
nations, confusion, and disorientation, it should
be used with caution in older patients, particu-
Diazepam (Valium) larly those who are hospitalized. The mode of
action of its antiemetic effect is unknown.
Diazepam is a benzodiazepine agent that is a
vestibular suppressant and has antianxiety and
sedative effects.48 It may also help control nau- Prochlorperazine (Compazine)
sea associated with vertigo and motion sick-
ness.49 Diazepam is a GABA agonist that Prochlorperazine is an antidopaminergic agent
decreases transmission of signals through the that is a piperazine-type phenothiazine. Like
vestibular nucleus. It can be given intravenously the other phenothiazines, it works directly on
the chemoreceptor trigger zone by blocking of the vestibular afferents. Brain Res. 2005;1064
dopaminergic transmission. Antihistaminic (1-2):1.
11. Zhang J, Han XH, Li HZ, Zhu JN, Wang JJ. Histamine
effects have been shown during chronic treat- excites rat lateral vestibular nuclear neurons through
ment, and it is an α-adrenergic blocker.36 activation of post-synaptic H2 receptors. Neurosci
Antiemetic effects are maximal 2 to 4 hr after Lett. 2008;448(1):15.
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tors are expressed in mouse and frog semicircular
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effects, and a low incidence of anticholinergic systems in the vestibular nucleus and their contri-
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14. Bergquist F, Ruthven A, Ludwig M, Dutia MB.
performance.51 Histaminergic and glycinergic modulation of GABA
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gency department: is it safe? J Emerg Med. 2003;24(4): (1-3):63.
441. 45. Brandt T, Zwergal A, Strupp M. Medical treatment
33. Rodgers C. Extrapyramidal effects of antiemetics pre- of vestibular disorders.Expert Opin Pharmacother.
senting as psychiatric illness. Gen Hosp Psychiatry. 2009;10(10):1537.
1992;14:192. 46. Tritto S, Botta L, Zampini V, Zucca G, Valli P, Masetto
34. Leopold NA. Prolonged metoclopramide-induced S. Calyx and dimorphic neurons of mouse Scarpa’s
dyskinetic reaction. Neurology. 1984;34:238. ganglion express histamine H3 receptors. BMC
35. Ferrando SJ, Eisendrath SJ. Adverse neuropsychi- Neurosci. 2009;10:70.
atric effects of dopamine antagonist medications. 47. Talley NJ. 5-Hydroxytryptamine agonists and antago-
Psychosomatics. 1991;32:426. nists in the modulation of gastrointestinal motility and
36. Isah AO, Rawlins MD, Bateman DN. Clinical phar- sensation: clinical implications. Aliment Pharmacol
macology of prochlorperazine in healthy young males. Ther. 1992;6:273.
Br J Clin Pharmacol. 1991;32:677. 48. Takeno K, Shimogori H, Takemoto T, et al. The
37. Renner UD, Oertel R, Kirch W. Pharmacokinetics systemic application of diazepam facilitates the reac-
and pharmacodynamics in clinical use of scopolamine. quisition of a well-balanced vestibular function in a
Ther Drug Monit. 2005;27(5):655. unilateral vestibular re-input model with intracochlear
38. Baker FM, Cook P. Compazine complications: a tetrodotoxin infusion using an osmotic pump. Brain
review. JAMA. 1981;73:409. Res. 2006;1096(1):113.
39. Manning C, Scandale L, Manning EJ, Gengo FM. 49. McClure JA, Lycett P, Baskerville JC. Diazepam as an
Central nervous system effects of meclizine and antimotion sickness drug. J Otolaryngol. 1982;11:253.
dimenhydrinate: evidence of acute tolerance to anti- 50. Baldwin RL. Droperidol in the treatment of vertigo.
histamines. J Clin Pharmacol. 1992;32:996. South Med J. 1983;76:1271.
40. Seibel K, Schaffler K, Reitmeir P, Golly I. A ran- 51. Shupak A, Gordon CR. Motion sickness: advances in
domised, placebo-controlled study comparing two pathogenesis, prediction, prevention, and treatment.
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Chapter 20
Vestibular Rehabilitation
ADAPTIVE CONTROL OF NORMAL Unilateral Vestibular Lesions

VESTIBULAR REFLEXES Bilateral Vestibular Lesions
MECHANISMS FOR COMPENSATION Central Vestibular Lesions
AFTER VESTIBULAR LOSS VESTIBULAR EXERCISES
SPECIAL CIRCUMSTANCES FUTURE DIRECTIONS
Vestibular Loss in Children APPENDIX 20–1
Vestibular Loss in the Elderly SAMPLE HOME EXERCISE PROGRAM
Failure of Compensation Head-Turning Practice
CONTROLLED TRIALS OF VESTIBULAR Walking Practice
EXERCISES Other Exercises
STRATEGY FOR DESIGNING VESTIBULAR Dizziness Exercises
EXERCISES
When the vestibular system has been perma- kept in the light compensated faster than those
nently damaged, the initial state of imbalance kept in darkness.4,5 Compensation was acceler-
at the level of the brainstem nuclei results in ated in cats by stimulant drugs (amphetamine)
acute vertigo (see Pathophysiology of vestibu- and slowed by sedating drugs (diazepam,
lar symptoms in Chapter 1). Gradually, the dimenhydrinate), with the authors postulating
patient adapts to this imbalance through a pro- that the effect of the stimulating drugs was due
cess of compensation that requires intact vision to increased physical activity levels.6 For these
and depth perception, normal proprioception reasons, vestibular exercise programs probably
in the neck and limbs, and intact sensation in should be instituted as soon as possible after an
the lower extremities. Central pathways are injury to the vestibular system has been identi-
also integral to compensation, and damage to fied, and the use of sedating drugs should be
these areas results in less effective recovery. limited to the acute stage.
Clinicians have long been aware that vestib- In addition to producing the subjective sen-
ular compensation occurs more rapidly and is sation of vertigo, vestibular lesions interfere
more complete if the patient begins exercising with reflexes controlling eye movements dur-
as soon as possible after a vestibular lesion.1,2 ing active head motion and with postural right-
Controlled studies in primates have supported ing reflexes.7,8 This interference can result in
this general clinical observation. Baboons oscillopsia caused by head movements and a
whose hind limbs were restrained by plaster tendency to veer or fall when walking. These
casts after a unilateral vestibular lesion showed symptoms and the associated dizziness can be
markedly delayed recovery of balance com- improved by active exercises designed to speed
pared with lesioned animals that had been compensation. Many of the exercises will result
allowed normal motor exploration.3 Visual in dizziness. This sensation is a necessary
experience is also necessary; lesioned animals stimulus for compensation; antivertiginous
419
medications should be avoided during this Adaptive changes in vestibular reflexes are
period to allow the compensation process to typically context specific.12,13 Experimental
occur. studies in animals and humans have shown that
Although there is a consensus that vestibular adaptive changes in the angular VOR induced
rehabilitation is helpful for patients with ves- by head rotation can be gated in and out
tibular lesions,9,10 few physical therapists depending upon the static orientation of the
receive training in vestibular rehabilitation head, even though the pattern of semicircular
during their formal education.11 Most learn canal activation is the same. Therefore, physi-
about vestibular rehabilitation at short continu- cal therapy programs that are attempting to
ing education courses or from colleagues. promote adaptation—so-called adaptation
Standards need to be established and thera- exercises—should be used in a natural setting
pists need to be educated about the vestibular where the compensated vestibular reflexes will
system. be used. Cognitive factors also play an impor-
tant role in vestibular adaptation, even to the
point that mental exercises may be able to sub-
stitute for actual movements in the adaptation
ADAPTIVE CONTROL OF NORMAL process. For example, imagined fixed or mov-
VESTIBULAR REFLEXES ing visual targets can have the same effect in
modifying VOR gain as real targets. By going
Adaptive control of vestibular reflexes is con- through their routines in their minds, such as a
stantly occurring in all of us. A common professional golfer analyzing his or her swing,
example is the adjustment in the gain of the professional athletes can adapt a motor
vestibulo-ocular reflex (VOR) that occurs in behavior without actually performing the motor
normal people when they wear magnifying act. Thus, psychological factors such as motiva-
lenses in glasses. In order to maintain clear tion, attention, effort, and interest play a part
vision during head movements, the gain of the in any therapy program aimed at vestibular
VOR must be rapidly adjusted up and down as rehabilitation.
they take the glasses on and off. In the labora- Vestibular adaptation typically has a charac-
tory, subjects show even more dramatic changes teristic time course both for acquisition and
in the VOR gain when they wear more powerful loss (see Fig. 3–22 in Chapter 3).16 In order to
magnifying or minifying lenses.12,13 An extreme maintain adaptation, one requires continued
example is the reversal in VOR direction that exposure to sensory inputs for the continued
occurs in animals and humans who wear revers- elaboration of the adapted response. Central
ing prisms for several days.14,15 These gain pathways are key in maintaining adaptation, so
adjustments occur within central VOR path- obviously lesions within these pathways can
ways since there is no change in peripheral sen- lead to loss of adaptation. Adaptive capabilities
sory input. In subjects taking their glasses on seem to decline with normal aging, which may
and off, the adjustment in gain occurs immedi- in part explain why vestibular compensation
ately before there is any sensory conflict as tends to be slower in older people.7,17 In addi-
though the brain has two separate gain settings tion, older patients who lose vestibular func-
that can be turned on and off like a switch. An tion may also have an impaired somatosensory
example of this presetting of gain within the or visual system and thus be less able to com-
vestibulospinal reflex occurs when a normal pensate for the loss of vestibular function.
subject briefly loses balance when stepping
onto an escalator that is unexpectedly out of
service. The brain has preprogrammed a change
in posture to compensate for the impending MECHANISMS FOR
movement of the escalator, so that a correction COMPENSATION AFTER
for movement is automatically made even VESTIBULAR LOSS
though no actual motion is experienced when
the subject steps onto the stationary surface. Common mechanisms used for recovery after
This ability of central pathways to preprogram loss of labyrinthine function are summarized in
motor responses plays an important role in Table 20–1. In patients with partial peripheral
compensation after loss of vestibular reflexes. vestibular lesions, the gain of the vestibulo-ocular
20 Vestibular Rehabilitation 421
Table 20–1 Mechanisms for slow phases and decreasing saccade size in
Compensation after Loss of Vestibular anticipation of head movement.
Function Patients with vestibular lesions will com-
monly alter their behavior to avoid excessive
Adjust gain centrally demands on the compromised vestibular
Use other sensory inputs reflexes.23 They may walk slower, widen their
Use other motor responses base, and avoid head movements to decrease
Anticipate intended motor behavior symptoms of dizziness and imbalance. Although
Change movement strategy these changes in movement strategies may
Adjust central perception initially decrease symptoms, they may be
counterproductive in the long run since they
prevent the brain from receiving sensory sig-
nals needed in the compensation process.
and vestibulospinal reflexes can be adjusted to The brain has the ability to adjust central
help compensate for the peripheral loss. For perception of movement that occurs in patients
example, after a unilateral peripheral lesion, the after vestibular lesions. For example, the oscil-
gain asymmetry is gradually adjusted and the lopsia that occurs after bilateral vestibular loss
dominant time constant is shortened to help becomes less and less many years after the
maintain the gain in the high-frequency range.18 lesion. Patients usually have no problem driv-
The input from one normally functioning remaining or carrying on other routine activities.24
ing labyrinth is enough to drive most of the vestib- Patients with central vestibular lesions and
ulo-ocular and vestibulospinal responses over a long-standing spontaneous nystagmus also
wide functional range. There are limitations to report decreasing oscillopsia over time.
these central adjustments in gain, however, and In summary, the vestibular compensation
there must be enough residual peripheral func- process after a vestibular lesion is a fragile and
tion to allow the adaptive mechanisms to act. Also, dynamic process. It requires complex senso-
these gain adjustments only work within a certain rimotor integrations within the brain, involving
range of movements, so that compensation is not many different pathways. Intercurrent illness,
possible for high acceleration head thrusts (the injury, and excessive medication or alcohol use
basis of the bedside head-thrust test).19 may lead to temporary reemergence of long-
Substitution with other sensory inputs and compensated symptoms from a prior vestibular
alternative motor responses is commonly used lesion. The compensation process is generally
in the compensation process after vestibular slower and less complete in older patients, par-
lesions. Substitution exercises are used to ticularly if they have comorbidities resulting in
enhance these other inputs. For example, input additional defects in sensory inputs from other
from cervical muscle proprioceptors can be modalities as occurs with peripheral neuropathy
used to help generate compensatory eye move- or impaired vision.
ments in patients with labyrinthine damage.
Studies in patients with bilateral labyrinthine
disease show that the cervical–ocular and opto-
kinetic reflexes have increased gains compared SPECIAL CIRCUMSTANCES
to normal subjects.20,21 Subjects also can substi-
tute alternative motor responses in lieu of the Vestibular Loss in Children
vestibular compensatory responses. For exam-
ple, small anticompensatory saccades can be As a general rule, the vestibular compensation
substituted for vestibular slow phases to help process is more robust in children than in adults.
stabilize gaze during head rotation. However, this is not to say that children do not
Patients with labyrinthine lesions develop show significant deficits from early-onset
strategies that use prediction or anticipation of vestibular loss. In children who are born with
intended motor behavior to substitute for ves- vestibular loss or who lose vestibular function
tibular reflexes.22 For example, patients who within the first year, motor milestones are seri-
have lost labyrinthine function learn to prevent ously delayed during the first 2 or 3 years of
gaze overshoot during combined eye and head life.25 However, during the preschool age, most
movements by preprogramming compensatory children achieve standard landmarks of motor
development such as head control, independent central findings on electronystagmography

walking, and running. By the time they enter were all significantly associated with this poor
elementary school (about 6 years of age), most outcome. In another study 29 of 142 patients
have standard motor skills that would not be (20%) continued to have significant dizziness
outside of the normal range. Many can swim after they underwent surgical procedures to
even under water and maintain good balance section the vestibular nerve for a variety of ves-
even with eyes closed. These remarkable motor tibular disorders.30 Possible reasons for the
skills in the context of severe vestibular loss pre- persistent dizziness were incomplete vestibular
sumably depend on compensatory input from nerve section, poor central nervous system
visual, somatosensory, and proprioceptive senses (CNS) compensation, new vestibular disease in
and the maturation of motor systems in the cer- the opposite ear, and the presence of other
ebellum, basal ganglia, and motor cortex. CNS diseases. A prospective study of 60
patients with vestibular neuritis found that only
34 (57%) reported complete relief from sub-
Vestibular Loss in the Elderly jective symptoms at long-term follow-up.31 A
common theme in these and other studies is
Vestibular compensation is more difficult and that older patients with evidence of CNS dis-
less complete in older patients than in young ease have the highest likelihood for persistent
adults.26,27 All of the compensatory mechanisms dizziness (failure of compensation) after an
outlined in Table 20–1 may be diminished in acute vestibular lesion.
older people. Other sensory inputs such as
somatosensory and visual sense are typically
diminished so they are less able to compensate
for the loss of vestibular sense. Their ability to CONTROLLED TRIALS OF
substitute other motor responses for vestibular VESTIBULAR EXERCISES
responses is also limited because of slowing of
all motor responses due to aging; both periph- Most early studies of vestibular exercises in the
eral and central mechanisms are affected. The treatment of patients with acute and chronic
severity of age-related white matter abnormali- vestibular lesions were not controlled and
ties correlates with the severity of gait and focused on improvement in vestibular symp-
motor abnormalities.28,29 Overall cognitive toms, so it is difficult to separate the benefit of
decline that occurs with normal aging may the vestibular exercises from other nonspecific
interfere with their ability to anticipate intended effects. Several recent randomized controlled
motor behavior and adjust central perception. studies found that vestibular rehabilitation
Changing movement strategy may be one of exercises improve the functional outcome after
the few remaining options, so they may adopt a unilateral vestibular loss.32–36 A systematic
sedentary lifestyle that may further interfere review of the literature by The Cochrane
with the compensation process. Collaboration concluded that there is moder-
ate to strong evidence from high-quality ran-
domized trials supporting safety and efficacy of
Failure of Compensation vestibular rehabilitation for unilateral periph-
eral vestibular dysfunction.9,10
A small percentage of patients continue to Importantly most of the vestibular rehabilita-
complain of persistent dizziness and imbalance tion trials were conducted in the population of
months to years after an acute peripheral ves- patients with surgical lesions or groups of mixed
tibular lesion. The cause of this lack of com- or vaguely stated etiologies. Very few studies
pensation and whether it could be prevented have been performed in the population of
by a vestibular compensation exercise program patients with vestibular neuritis. This difference
are largely unknown. In one study 31% of 210 in the etiology of the peripheral deficit is impor-
patients continued to complain of disequilib- tant because many patients with vestibular neu-
rium more than 3 months after the surgical ritis will have spontaneous return of vestibular
removal of an acoustic neuroma.26 Age >55.5 function as the viral-inflammatory process
years, female gender, constant preoperative resolves. On the other hand, patients with a
disequilibrium present for >3.5 months, and fixed and complete surgical lesion will not have
return of function. For this reason, the effects Table 20–2 Unilateral Peripheral
of rehabilitation found in patients with surgical Vestibular Lesions
lesions or other fixed deficits may not be gener-
alizable to patients with vestibular neuritis. Goal Force compensation, rebalance,
One study in vestibular neuritis patients adaptation
found that the sway as measured by posturoga- Sample Fixate targets, track targets; rapid
phy was significantly improved in patients exercises head movements when sitting,
treated with an intense vestibular therapy pro- then walking; walk in dark, on
gram compared to controls.32 However, the uneven surface
randomization procedure was violated in this Expect Complete recovery, minimal subtle
study because 43 of the original 82 randomized deficits
patients were excluded because they showed a
partial or complete caloric response recovery
on day 30. Other outcomes including ocular (Table 20–2). A near-complete recovery of nor-
torsion and subjective visual vertical were not mal abilities can be expected, although specific
significantly different between the groups. The deficits will remain.
intervention in this study involved physical
therapists treating the study group for 5–7 days GAZE STABILITY
in the hospital, which is likely to be more intense
therapy than is practical in routine care. Because of the unilateral loss of the VOR in the
A second trial in a vestibular neuritis popula- acute patient, there is spontaneous nystagmus
tion did not use a placebo group.37 Instead this that results in a complete loss of gaze stability.
trial compared a program of home training This can be complicated by diplopia as part of
(e.g., oral and written vestibular therapy the ocular tilt reaction. These acute severe
instruction) to the same program of home visual symptoms resolve gradually over the first
training but also with additional physical ther- several days to a week as the remaining vestib-
apy sessions (i.e., three 40-minute supervised ular labyrinth restores VOR function or if the
sessions during the first week and then one ses- function of the lesioned side recovers. As this
sion per week for 9 weeks). No differences occurs, gaze stability improves but may not
were seen in any of the subjective outcomes return to normal. Quick movements toward
(i.e., rating of vertigo or imbalance) or objec- the side of the lesion can result in a sense of
tive outcomes (i.e., caloric testing, Romberg oscillopsia and dizziness. In some patients,
test, one-leg stance, and tandem walking) at these symptoms will remain permanent.
any of the follow-up intervals (1 week, 10 Treatment involves maintaining full neck
weeks, or 6 months). mobility to allow increased input from neck
Customized vestibular rehabilitation pro- proprioceptors during head turns and ocular
grams appear to be superior to general instruc- fixation practice while at rest and at low and
tions that simply emphasize the need for high head accelerations in both the vertical and
exposure to movement in patients after surgery horizontal planes.
for an acoustic neuroma.35 For patients who are
to undergo unilateral ablative surgery, begin- BALANCE
ning vestibular exercises a few weeks before
the surgery and continuing after surgery may Before compensation occurs, otolith input is
speed up recovery.38 asymmetric. This results in a perceptual illu-
sion that the environment is tilted. There is a
tendency to veer toward the side of the lesion
when walking. Because of an increased depen-
STRATEGY FOR DESIGNING dence on visual input, falls can occur if lighting
VESTIBULAR EXERCISES is poor or if the eyes are closed. This visual
dependence is complicated in the acute situa-
Unilateral Vestibular Lesions tion by the presence of spontaneous nystagmus
and skew diplopia. After the acute nystagmus
Persons with unilateral vestibular lesions demon- and skew deviation disappear within a few days,
strate a series of deficits requiring compensation balance improves but there are still deficits,
particularly when visual and proprioceptive cervical-ocular reflex to provide help with com-
inputs are reduced or conflicting—for example, pensatory eye movements. Slow head oscilla-
when climbing stairs in darkness. Treatment tions can be used to strengthen pursuit abilities
includes maintaining or improving ankle during head movements, and saccade exercises
strength and mobility. One strategy is to use (looking back and forth between targets) may
supportive high-top shoes to increase ankle- help optimize the voluntary use of fast eye
cutaneous input. Using shoes with firm soles is movements. Ultimately, some patients learn
recommended over shoes with heavy cushion- that to obtain maximum visual acuity, they
ing. As patients continue to improve, they must hold the head still.
should begin walking and balancing exercises One small randomized trial of vestibular
with eyes closed or in the dark. exercises assessed the efficacy of the exercises
on improvement of dynamic visual acuity (e.g.,
visual acuity under movement) and subjective
Bilateral Vestibular Lesions intensity of oscillopsia in patients with bilateral
vestibulopathy.39 The exercises used as the
Very few randomized studies have tested ves- intervention in this study were “adaptation”
tibular therapy interventions in patients with a exercises (i.e., focusing on a target during head
bilateral vestibulopathy. Persons with bilateral movements while the target is either stationary
vestibular loss demonstrate a series of perma- or moving) and balance exercises. The investi-
nent deficits that require compensation (Table gators chose to remove two out of seven con-
20–3). Some compensation involves strength- trol subjects after randomization because one
ening of existing reflexes such as the cervical- subject was moving her head during the pla-
ocular reflex and smooth pursuit, while the cebo exercises and the other had better-
remainder requires trained behaviors such as than-expected improvement in dynamic visual
substituting centrally programmed eye move- acuity. The study found that the intervention
ments for the lost VOR.39 group did improve dynamic visual acuity per-
formance, while the placebo group did not.
Although one would think improvement in
GAZE STABILITY
dynamic visual acuity would lead to less
Because of the absence of the VOR, head symptomatic oscillopsia, this study found that
movements that are of sufficient velocity to the change in dynamic visual acuity did not
exceed the smooth pursuit system (>1 Hz) correlate with change in subjective ratings of
result in retinal slip, which leads to symptom- oscillopsia.
atic oscillopsia. Treatment strategies center on
attempting to substitute other sensory input BALANCE
systems for the vestibular loss. Exercises are
used to maintain full neck mobility to allow the In the absence of peripheral vestibular input,
postural control relies upon the ankle and step-
ping strategies. Loss of the vestibulospinal
reflex leads to an increased dependence on
Table 20–3 Bilateral Peripheral ankle proprioception and cutaneous sensation
Vestibular Lesions from the feet and ankles to provide balance.
These other senses are used to substitute for
Goal Substitute other sensory the vestibular loss. Such patients are also visu-
information to replace ally dependent, but there are limitations to
vestibular their compensation because of the associated
Sample Track targets with and oscillopsia. Deficits become apparent when
exercises without head movement they are exposed to poor support surfaces (soft
Learn to hold head still to or shifting surfaces, narrow support base), par-
read ticularly if visual inputs are misleading.
Walk on foam and uneven Treatment strategies for balance include main-
surfaces with vision
taining or improving ankle strength and mobil-
Expect Mild to moderate persistent
ity, increasing cutaneous input in the lower
limitations
extremities (e.g., use of supportive high-top
shoes, shoes with firm soles), gait and balance vestibular lesions; thus, patients are at a much
exercises, and stressing the importance of solid higher risk of falling. Physical therapy should be
footing and good lighting at all times. aimed at maintaining strength, particularly in
the lower extremities, and instructing the patient
on using proper support such as a cane or a
Central Vestibular Lesions walker. Regular walking (with support) is
encouraged because it maintains strength and
Recovery from central vestibular lesions is typ- mobility, but there are no adequate randomized
ically much slower than recovery from periph- studies to indicate the benefit of a vestibular
eral vestibular lesions (Table 20–4). No doubt rehabilitation program in central disorders.
this can be traced to the fact that structures
involved in the recovery process are themselves
damaged. The cerebellum is a key structure for
compensation and patients with cerebellar VESTIBULAR EXERCISES
lesions improve the least with vestibular
rehabilitation.40 Vestibular exercises should begin as soon as the
acute stage of nausea and vomiting has ended
and the underlying disease process is subsid-
GAZE STABILITY ing. Many of the exercises will result in dizzi-
Patients with central vestibular lesions often ness. This sensation is a necessary stimulus for
will have spontaneous nystagmus that persists compensation; antivertiginous medications
for months to years. Although the oscillopsia should be avoided as much as possible during
associated with this spontaneous nystagmus this period to maximize the beneficial effect.
may decrease over years, it rarely completely Exercises should be done at least twice daily
disappears. Often there is a null region where for several minutes but may be done as often as
the nystagmus is less, or maybe even absent, so the patient can tolerate (see Appendix 20–1 for
patients can learn to hold their eyes near the sample exercises that can be given to the
null region when best visual acuity is critical patient).
(for example, when reading). If a null point is While nystagmus is present, adaptation exer-
present, then the use of an eyeglass prism or cises should begin with the patient attempting
ocular surgery may be beneficial. There are no to focus the eyes and to move and hold them in
data to suggest that either head or eye exercises the direction that provokes the most dizziness.
will decrease the magnitude of the eye move- Once the nystagmus diminishes to the point
ment or the subjective oscillopsia. In some that a target can be “held” visually in all direc-
cases, such exercises seem to aggravate the tions, the patient should begin eye and head
problem by causing nausea and even vomiting. coordination exercises. A useful exercise
involves staring at a visual target while oscillat-
ing the head from side to side or up and down.
BALANCE The speed of the head movements can be grad-
Central balance disorders tend to be much more ually increased, as long as the target can be
severe than those associated with peripheral kept in good focus. Target changes using com-
bined eye and head movements to jump quickly
back and forth between widely separated visual
Table 20–4 Central Vestibular Lesions targets are also useful. Blinking during these
fast head turns can help reduce symptoms of
Goal Suppress nausea, dizziness, dizziness or blurring of vision.
diminish oscillopsia, diplopia, Gait and balance exercises should begin by
help compensation having the patient try to stand and walk while
Sample Fixate near and far, different nystagmus is still present. It may be necessary
exercises gaze positions to walk in contact with a wall or to use an
Walk touching wall, up and assistant in the early stages. Slow, supported
down slopes turns should be made initially. As improvement
Expect Moderate to severe limitations, occurs, head movements should be added
particularly in older people while standing and walking—at first slow
side-to-side or up-and-down movements, then acceleration in the planes of the semicircular

fast head turns in all directions. Learning to canals and provides a pulse-frequency modula-
combine fast head turns with brief eye closure tion of the ampullary nerve from each canal.
or blinks during walking turns can increase sta- When such a devise was implanted in chinchil-
bility and decrease dizziness. las whose vestibular system was ablated with
Compensation can require as long as 2 to 6 gentimicin, partly compensatory vestibulo-
months. Dizziness that persists beyond this ocular responses were recorded in multiple
time indicates either the presence of an ongo- planes.44 However, current spread beyond the
ing, recurrent vestibular illness or poor com- electrode’s targeted nerve branch was a major
pensation. The patient’s history should be problem. No doubt progress will be made in
reviewed, and any vestibular suppressants the design of the acceleration sensor and elec-
should be discontinued. Evidence of central trodes and in surgical techniques for implant-
involvement or impairment of vision, proprio- ing the devises.
ception, or sensation should be evaluated. If all
areas are normal, no evidence of active disease
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been developed and implanted in mammals, ocular reflex adapt? In: Baloh RW, Halmagyi GM, eds.
Disorders of the Vestibular System. New York: Oxford
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1995;5:67,22. apy on recovery after acute unilateral vestibular loss: a
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APPENDIX 20–1. SAMPLE HOME 15 feet. Touch the wall with your hand and
EXERCISE PROGRAM keep it in contact with the wall as you walk
along it. When you reach the other end, turn
around and go back, using the other hand.
Head-Turning Practice Once you are able to walk in both directions
along the wall without bumping into it or need-
These exercises can be performed while sitting
ing to use your hand for support, start walking
in a chair. They should be repeated several
close to the wall with your hands at your side.
times at each session, and they can be practiced
Your goal is to walk in a straight line down the
as many times as you wish during the day.
middle of the hall or room without needing to
Sessions should be done at least twice daily, as
use your hands or the wall for balance.
a minimum. Gradually increase how long and
how often you perform these exercises.
WALKING TURNS
FIXATION PRACTICE Pick a wall several feet in front of you and place
a piece of tape or other target in the middle of
Select a target directly in front of you. While it at eye level. Walk toward the target. When
looking at the target, slowly turn your head you reach the wall, keep your head and eyes
from side to side. Try to keep the target from locked in place on the target as you start to turn
moving or jiggling as you turn. Repeat this, with your shoulders and body. When you can
using up-and-down head movements. If you no longer turn without moving your head, close
can keep the target perfectly still while you your eyes and rapidly turn your head, opening
move, practice doing the head turns a bit your eyes as soon as the turn is completed.
faster. Walk in a straight line away from the wall.
Extend your hand out in front of you and use Repeat, turning in the other direction.
your thumb as a target. Move your arm back
and forth, and follow your thumb with your
eyes. Next, combine head and target move- OUTDOOR WALKS
ments. For example, while moving your arm to Go for walks daily, beginning with a 5-min walk
the left, move your head to the right, all the and increasing by at least 5 min every day until
time keeping your eyes on your thumb. Go you are walking for 30 min. Try to walk at a
back and forth. normal pace. Turn your head from side to side
to look at the scenery, closing your eyes or
TARGET CHANGES blinking to reduce dizziness.
Select two targets, one off to your left, the other
off to your right, and far enough apart so that Other Exercises
you have to turn your head to look from one to
the other. Look at one target; then, as fast as Spend as much time as you wish doing these
you can, close or blink your eyes and turn your exercises. Aim for at least 5 min each day.
head to look at the other. Go back and forth
between the two targets as quickly as possible.
READING PRACTICE
Read anything that you like. If needed, you can
Walking Practice balance your head on your hand to keep the
words steady as you read. Try to keep the
You should try to spend at least 30 min a day letters in focus while you read.
practicing your walking. The more time you
spend, the quicker you will adjust. ROCKING CHAIR EXERCISES
Slowly rock in a rocking chair while you watch
GUIDED WALKING
TV, or pick a target and try to keep focused on
Stand next to a wall in a long hallway or a length it as you rock. As you improve, rock faster. Turn
of wall that you can walk along for at least your head to one side and pick something to
focus on as you rock; then practice rocking with than normal. Use the target practice exercises
your head turned to the other side. listed earlier. At least twice a day, do the fixa-
tion practice exercise, but turn your head
RIDING IN CARS quickly to make yourself feel as dizzy as possi-
ble. The more you repeat this, the quicker your
Whenever you have the opportunity, ride as a dizziness will go away. If dizziness occurs even
passenger in a car. While the car is in motion, with the eyes closed, you will need to practice
slowly turn your head from one side to the turning your head with eyes closed—slowly at
other with eyes closed, then with eyes open. first, and gradually increasing the speed until
Have the driver accelerate or slow down you become used to the dizziness.
periodically. It is normal to feel unusual sensa-
tions of motion at first, but these diminish with
EYE MOVEMENT DIZZINESS
practice.
Use this exercise if dizziness occurs when you
move your eyes, even when your head is held
Dizziness Exercises perfectly still. Lie down with your eyes closed.
Slowly rotate them around as far to the sides,
These exercises can be done as often as you up, and down as you can. If you feel increased
wish, to keep dizziness under control. dizziness in one particular direction, try to keep
your eyes turned in that direction as you count
HEAD MOVEMENT DIZZINESS to 10. Then open your eyes and try to focus on
something. As soon as the dizziness decreases
If dizziness occurs only when your head (a few seconds), close your eyes and again turn
is turned, check to see if it goes away when them in the most unpleasant direction. Keep
you turn your head with your eyes closed. If repeating this exercise until the dizziness is
it does, try to blink or close your eyes while decreased.
you turn your head, and turn your head faster
Chapter 21
Future Directions
When the first edition of this book was written vestibular synapses? What ion channels are
in the late 1970s, there was great excitement expressed in the peripheral and central vestib-
regarding the potential for engineering models ular pathways, and how do these ion channels
to describe vestibular function in normal sub- explain the observed physiology? What changes
jects and patients. Steinhausen’s pendulum occur at the molecular level after damage to
model of semicircular canal function was shown peripheral and central vestibular structures? In
to reliably predict the flow of action potentials this fourth edition, answers to these questions
in isolated ampullary nerves in several mam- are beginning to be addressed, but we are still
mals, including primates. A simple first-order in the early stages of understanding. Future
approximation of this linear model remarkably scientific discoveries will no doubt improve our
predicted vestibulo-ocular responses in normal understanding of the vestibular system in
subjects and provided a framework for inter- health and disease. A better understanding of
preting abnormal responses in patients. These this intricate system will hopefully lead to the
models consisted of “black boxes” represented future ability to modulate it or even to substi-
by transfer functions that described the rela- tute for it—advances that could enhance the
tionship between the input and output. Little care of patients with vestibular disorders.
was known about what actually went on in Meaningful scientific progress requires
these black boxes. David A. Robinson, one of translating basic science discoveries into inter-
the pioneers in oculomotor modeling, warned ventions that improve our well-being—a step
that “Block diagrams of oculomotor organiza- that hinges on rigorous clinical studies. A poster
tion serve as a compact description of system child for scientific progress in the field of clini-
behavior but seldom have much bearing on the cal neurophysiology of the vestibular system is
way in which the real system, composed of benign positional vertigo (BPV). BPV is now a
nerve and muscle, actually operates. The models well-defined entity, and we have a solid under-
thus do not contribute much to the neurophys- standing of the underlying pathophysiology of
iology (or neurology) of eye movements and the disorder. The diagnostic tests for it are reli-
incur the danger of suggesting that there actu- able and valid. A hypothesis introduced in the
ally are segregated portions of the nervous 1960s led to the development and refinement
system which perform differentiation, integra- of a treatment, and an early case series in the
tion and other operations indicated in the boxes 1980s suggested its usefulness. Numerous ran-
of the diagrams.”1 But progress in understand- domized clinical trials followed over the past
ing basic cellular and molecular mechanisms 20 years, and the efficacy of the treatment was
awaited technical advances in cell and solidly established by several independent
molecular biology. As technical advances have systematic reviews of the clinical trials. As a
occurred, we can now focus on these black result, clinical practice guidelines have been
boxes. How do the mechanosensory channels published within the past year.
and the ribbon synapses in hair cells work? As noted previously, some future advances
What transmitters are released and what recep- will require new scientific discovery, but others
tors are expressed at peripheral and central will require determining ways to optimize the
431
use of services already available. Which of our considered the intervention and patients are
vestibular patients will meaningfully benefit randomized to have it. When considered at the
from the interventions we direct them toward aggregate level of utilization, the routine use of
and which will be harmed by them? Randomized tests prior to these later phase assessments may
controlled trials are the gold standard method result in more unintended consequences (e.g.,
to study the efficacy of any intervention, yet inconvenience to the patient, adverse events,
other than a few examples adequate trials are adverse emotional effects of false-positive
lacking in many areas important for the man- results, and excess costs) than meaningful
agement and treatment of our patients. Beyond benefit to the patient.
randomized trials, we also need research that More research to define the clinical value of
defines the effectiveness of our interventions in bedside information (i.e., medical history and
the real world and that helps us better identify examination findings) may help in deciding
the patients most likely to benefit from what which patients are likely to benefit from tests
we have to offer. or therapies and which are not. For example,
Our clinical tests need later phase diagnostic the head-thrust test seems to be an exception-
test research to better define their value. Many ally effective way to assess the likelihood of
sophisticated tests have been developed to stroke in patients with acute vestibular syn-
make laboratory measurements of the vestibu- drome presentations, but what is the reliability
lar system. Most of these tests have been of the test in these circumstances (particularly
refined for optimal performance. Others are among frontline clinicians who do not regularly
still in the early development phases. These use it) and would it perform better than a
tools play an essential role in research studies. validated scale of stroke risk factors?
Clinically, some of these tests have proven to Finally, we need to understand why one of
be very good discriminators of vestibular the most efficacious and simple interventions
pathology, but others have not, particularly in all of clinical medicine—particle reposition-
when used in certain populations such as the ing for BPV—is substantially underutilized. In
elderly or patients with mild or early-stage dis- fact, patients with BPV are more likely to
orders. Most have not undergone rigorous receive a brain imaging study than to be cured
assessment of the reliability (reproducibility) of with repositioning. Many disorders are desper-
the test or the test interpretation outside of ately in need of the discovery of a cure, but
expert centers. Furthermore, later phase diag- BPV already has one. What good are efforts to
nostic test research has not been performed discover new treatments if they ultimately go
with most of these tests. The validity of these unused or misused? Is the underutilization a
tests for important endpoints (imaging find- matter of “clinical inertia” or could underuti-
ings, clinician consensus diagnosis, future diag- lization stem from other factors, such as policy
nosis or outcome) has not been assessed in disincentives?
populations of patients having important levels
of clinical uncertainty. Finally, none of the tests
has been subjected to the gold standard deter- REFERENCE
minant of the clinical value of a diagnostic test.
The gold standard is to assess whether the 1. Robinson DA. Models of oculomotor neural organiza-
patients who receive the test have better future tion. In: Bach Y, Rita P, Collins C, Hyde J, eds. The
meaningful outcomes than patients who do not Control of Eye Movements. New York: Academic
receive the test. In these designs, the test is Press;1971:519.
Video Legends*
Video 6-1. The past pointing test This recording was made on the first day of a
vestibular neuritis presentation.
With eyes closed, the patient is instructed to
lift his arm off the target and then bring the
finger back down in the same spot. The patient Video 6-5. Spontaneous nystagmus
in the video consistently misses the target to
the right side, which is the affected side. Note The patient has spontaneous left-beating nystag-
that the patient in this video is the same patient mus. The patient was videotaped on the second
in Video 6-5. day of a vestibular neuritis, and thus the velocity
of the nystagmus is less than seen in Video 6-4.
Video 6-2. The head thrust test

Video 6-6. Second
The patient’s eye stays fixed on the target after degree nystagmus
quick, small amplitude movements of the
patient’s head to the left, which is consistent The nystagmus velocity increased when the
with an intact vestibular ocular reflex on the left patient looks to the left. The nystagmus stops
side (i.e., negative head thrust test). However, when the patient looks to the on right gaze.
after head movements to the patient’s right side, Note that the patient in this video is the same
the patient’s eyes move off the target and then a patient in Video 6-5.
re-fixation (corrective) saccade is required to
bring the eyes back to the target, which is consis-
tent with a positive head thrust test on the right Video 6-7. Spontaneous
side indicating de-afferentation or a lesion of the
right vestibular system. Note that the patient in
down-beating nystagmus
this video is the same patient in Video 6-5.
In primary position, the patient has persistent
small amplitude down-beating nystagmus.
Video 6-3. The head thrust test
Note that after quick, small amplitude move- Video 6-8. Spontaneous up-
ments of the patient’s head to the right side, beating nystagmus
the patient needs to make a corrective saccade
to bring the eyes back to the target (i.e., a posi- In primary position, the patient has persistent
tive head thrust test). But, the eyes stay on tar- small amplitude up-beating nystagmus.
get after the head thrust test to left side (i.e., a
negative head thrust test). This video is partic-
ularly helpful for demonstration purposes Video 6-9. Gaze-evoked nystagmus
because the voluntary corrective saccade to the (multi-directional)
right side is delayed on the first test.
In a patient presenting with acute vertigo and
imbalance Note the prominent left-beating
Video 6-4. Spontaneous nystagmus nystagmus in left gaze. Next, note that the
patient clearly also develops right- and down-
Patient with high velocity spontaneous left beating nystagmus on right gaze. Because the
beating nystagmus which increases velocity nystagmus changes direction, this is a central
when the patient looks to the left side and then pattern even though the velocity is greater in
stops when the patient looks to the right side. one direction.
433
434 Video Legends
Video 6-10. Gaze-evoked that there is no pause between the individual

nystagmus and impaired saccades.
smooth pursuit
The patient develops right beating nystagmus
Video 7-1. Saccade dysmetria
when the patient looks to the right side and
The patient is being instructed to look back
left-beating nystagmus when looking to the
and forth from one target to another. With
left side. Also note the impairment of smooth
each saccade eye movement, the patient over-
pursuit (i.e., saccadic pursuit) as the patient
shoots the target then has to make another sac-
follows a target back and forth.
cade back to the target.
Video 6-11. Gaze-evoked Video 10-1. Epley Maneuver

downbeating nystagmus for right posterior canal benign
On gaze to either side, the patient develops positional vertigo
down-beating nystagmus.
First, the patient’s head is turned to the right
side. Next, the patient is rapidly brought down
Video 6-12. Benign positional to the right head hanging position (i.e., the right
Dix-Hallpike test). The clinician observes for
vertigo, posterior canal the typical burst of upbeat and torsional nystag-
mus (see Video 6-7). Next the patient’s head is
The patient was just placed in the right head-
turned toward the left and the patient rolls over
hanging position (i.e., right Dix-Hallpike posi-
onto the left side, making certain not to allow
tion). After a brief delay, a burst of upbeat and
the patient to lift the head up. At the end of this
torsional nystagmus is seen. The duration of
position, the patient is lying on the left side with
the nystagmus is about 12 seconds.
the face turned so the patient is looking at the
ground. This position is maintained for about
30 seconds. Then, the patient is rapidly brought
Video 6-13. Benign positional back up to the sitting position.
vertigo, posterior canal,
testing using goggles
Video 10-2. The Gufoni maneuver
Video goggles were used in this video. The for patients with left horizontal
patient is placed in the left Dix-Hallpike posi-
tion and a burst of upbeat torsional nystagmus
canal benign positional vertigo
is seen.
From the seated position, the patient is quickly
placed in the right decubitus position. This
position is maintained for approximately 10-20
Video 6-14. Convergence retraction seconds. Next, the patient’s head is turned so
nystagmus that the patient is looking into the table. This
position is maintained for approximately 20-30
The patient has spontaneous convergence nys- seconds, then the patient is quickly brought
tagmus. Also note that the patient has impaired back up to sitting position.
upgaze.
Video 6-15. Ocular flutter

*
Spontaneous bursts of back and forth horizon- Videos can be found at the following website:
tal saccades consistent with ocular flutter. Note www.oup.com/us/cns/vestibular
Index
Abducens nerve, 77, 78, 88, 238 Alpha2-adrenergic receptor gene, 143
Aberrant torsional eye movements, 199, 201f Alpha-tocopherol transfer protein (α-TTP), 395
Ablative procedures, for Meniere’s syndrome, 283 Alport’s syndrome, 368, 385–86, 385t
Abscess Alprazolam, for postconcussion syndrome, 364
brain, 239–40 American Academy of Ophthalmology, 290
epidural, 239 Amikacin, 374t
Acetazolamide (Diamox) Aminoglycosides, 374–75
for episodic ataxia type 2, 132, 397 dizziness caused by, 137
for familial periodic ataxia, 132 vestibular and auditory ototoxicities of, 374t
for ion channel disorder, 293 Amitriptyline, for migraine, 298t
for Meniere’s syndrome, 282 Amoxicillin, for acute otitis media, 235
for migraine, 294, 298t, 299 Amphetamine
for spinocerebellar ataxia, 398 for Meniere’s syndrome, 281t
Acetylcholine (Ach), 43 vestibular rehabilitation, 419
Acoustic compliance, 223 Amphotericin, mycotic
Acoustic impedance, 223, 224f mastoiditis, 250
Acoustic reflex, 224–25 Ampulla
Acquired disorders, 384 anatomy of, 9f, 17f
Acquired hearing loss, 384 Ampullofugal endolymph flow, 8, 44, 54, 69, 70, 76, 77,
Acquired syphilitic labyrinthitis, 248 77f, 80, 105, 178, 179, 192, 196, 197, 199, 260, 260f,
Actin, vestibular hair cell 261, 266, 268, 360
electromotility and, 40, 40f Ampullopetal endolymph flow, 8, 44, 54, 69, 70, 76, 77,
Actinomycosis, 250 77f, 80, 105, 178–80, 178f, 192, 196, 197, 199, 266, 268,
Active head rotation, 192–93, 198f 360
Acyclovir Angiography, for vertebrobasilar ischemia, 328–29
for sudden sensorineural hearing loss, 247 Angular velocity, 193
for viral infection, 247 sinusoidal changes in, 193–95
Adenoid cystic carcinoma, 339, 340 step changes in, 193
Aditus ad antrum, 25 Ankle links, 5f
Adrenocorticotropic hormone (ACTH), for multiple Anterior canal benign positional vertigo, 265, 268
sclerosis, 313 Anterior inferior cerebellar artery (AICA), 35, 36f, 320,
Adults 329f
benign recurrent vertigo of, 291, 291t anatomy of, 324, 324f, 326f
brain stem gliomas in, 347 internal auditory artery, 324f
cerebeller tumors in, 348 and lateral medullaty infarction
Chiari type I malformation in, 391 symptoms and signs in, 323t
dizziness in, 226 recurrent penetrating arteries, 324f
inner ear viral infections in, 242 terminal cerebellar branches, 324f
malignant tumors in, 340 Anterior spiral vein, 36f
metastatic cerebellar tumors, 348 Anterior vestibular artery, 35, 36f
maternally inherited mitochondrial disorders in, 388 Anterior vestibular vein, 35, 36f
neurologic disorders in, 274 Antiamphiphysin antibody, 310t
opsoclonus in, 310 Antibiotics
otoconia mineralization and turnover, 48 for acute otitis media, 235–36
sudden deafness in, 245 for bacterial labyrinthitis, 237
syringobulbia in, 392 Antibodies, associated with
toxic/metabolic disorders in, 377 cerebrellar ataxia, 315
vestibular neuritis in, 244 Anticoagulants, for transient ischemic attacks, 330
Afferent nerve activity, hair cell influence on, 42–43 Anti-CV2 antibody, 310t
Agoraphobia, 135 Antidopaminergic drugs, for nausea and vomiting
Alcohol, 161 associated with vertigo, 406t, 411
acute toxic effects of, 368–70, 369f Antiemetic drugs, 410–13
and thiamine deficiency, 368–70 instructions to patients, 413
acute alcohol intoxication, 368 for Meniere’s syndrome, 280, 281t
cerebellar degeneration, 370, 371f precautions, 411, 413
Wernicke’s encephalopathy, 370 usage of, 411
Alexander’s law, 175 indications for use, 412t
435
436 Index
Anti-GAD antibody, 310t for brain trauma, 363

Antigen-specific laboratory testing, in autoimmune inner impedance, 223, 224f
ear disease, 308 for Meniere’s syndrome, 278–80, 279f
Anti-glutamic acid decarboxylase (anti-GAD), 315 Audiovestibular loss. See also Hearing loss
Anti-Hu antibody, 310t, 311 genetic syndromes with, 384–86, 385t
Antihypertensive drugs, dizziness caused by, 137 nonsyndromic, 386–88, 386t
Anti-inflammatory drugs, ototoxicity of, 375–76 dominantly inherited hearing loss, 386t, 387
Anti-Ma antibody, 310t inherited vestibular loss with normal hearing, 388
Antiplatelet agents, for stroke prevention, 330 maternally inherited mitochondrial disorders, 387–88
Anti-Ri antibody, 310t, 311 recessively inherited hearing loss, 386–87, 386t
Antisaccade test, 185 Audio vestibular system
Antiserotonergic drugs, for nausea and vomiting infectious diseases of, 233
associated with vertigo, 406t, 411 Audiovestibular testing, for
Anti-Ta antibody, 310t autoimmune inner ear
Anti-Tr antibody, 310t disease, 307–8
Antivertigo drugs, 406t, 413–16 Auditory-evoked responses, 225–26, 226f
for Meniere’s syndrome, 281t brainstem auditory-evoked response, 226
Anti-VGKC antibody, 310t electrocochleography, 226
Antiviral agents, for sudden sensorineural hearing loss, 247 Auditory nerve, 11f, 37
Anti-Yo antibody, 310t, 311 Aura
Antoni type A schwannoma, 342 migraine with, 288, 296
Antoni type B schwannoma, 342 migraine without, 288, 296, 296t
Antrum, 235 Autoimmune injury, and Meniere’s syndrome, 278
Anxiety, 135 Autoimmune inner ear disease, 303–9
chronic, 136 background, 303–4
Apogeotropic nystagmus, 267 clinical features of, 306–7
Apoplectiform cerebral congestion, 273 systemic immune-mediated diseases, 306–7
Apraxia diagnosis of
of gait, 140 audiovestibular testing, 307–8
oculomotor, 185, 396 management of, 308–9
Aprepitant, for nausea and vomiting, 411 pathophysiology of, 304–6
APTX, 396 Autosomal dominant spinocerebellar ataxia syn-
Aquaporins, 34 dromes, 393–94
Arabinase, for sudden sensorineural hearing loss, 247 horizontal eye movement abnormalities
Arnold-Chiari malformation, 160 with, 394, 395t
Arnold nerve, glomus tumors in, 340 Autosomal recessive spinocerebellar ataxia syn-
Arousal, 81 dromes, 394–96
Ascending tract of Deiters (ATD), 15
Aspirin
for hearing loss, 377 Baclofen and periodic alternating nystagmus, 161
for migraine, 298t Bacterial labyrinthitis, 236–37, 246
for transient ischemic attacks, 330 definition of, 236
Assimilation of the atlas, 391 diagnosis of, 237
Astrocytoma, 348 management of, 237
Asymmetric gaze-evoked nystagmus, 162 symptoms of, 237
Ataxia types of, 236
autosomal dominant spinocerebellar, 393–94, 395t Bacteroides, 235
autosomal recessive spinocerebellar, 394–96 Barany, Robert, 177
cerebellar, and multiple sclerosis, 314–15 Barbeque” maneuver, for geotropic nystagmus, 267, 267f
episodic, and vertigo syndromes, 396 Barbiturates
Friedreich’s, 394–95 dizziness caused by, 137t
inherited spinocerebellar, 393–98 Basal cell carcinoma, 339
spinocerebellar, 183, 393, 398 Basal ganglia, lesions of, 138, 139f, 184t
telangiectasia, 185 Basilar impression, 390
Atenolol, for migraine, 298t diagnosis of, 392
Atherosclerosis, 368 Basilar meningitis, 250
Atlantoaxial dislocation, 391 Basilar migraine, 289
ATM, 396 diagnosis of, 296–97
ATP1A2 gene, and familial hemiplegic migraine, 293 symptoms of, 289, 289t
Audiogram, 221–22, 222f Battle’s sign, 353
for cerebellopontine angle tumors, 344 Bechterew’s nucleus. See Superior vestibular nucleus
Audiometry, 221–23 Bedside examination
behavioral, 221 of hearing, 131–32, 131f, 220–21
audiogram, 221–22, 221f, 222f, 222t of vestibular system, 149–67
speech recognition tests, 223 Behavioral audiometry, 221–23, 221f, 222f, 222t
Stenger test, 223 Behavioral therapy, for phobiac dizziness, 137
Index 437
Benign paroxysmal positional nystagmus, 178f Brain stem contusion, 364t

Benign paroxysmal positional vertigo. See Benign Brain stem hemorrhage, vertigo and, 332
positional vertigo (BPV) Brain trauma
Benign positional vertigo (BPV), 123–24, 255–69, 256f, 354 diagnosis of, 363–64
anterior canal benign positional vertigo, 268 dizziness due to brainstem trauma, 362
background, 255–57 management of, 364
causes of, 257–58 postconcussion syndrome, 362–63
of childhood, 290 temporal bone fractures, intracranial
diagnosis of, 259t complications, 362
horizontal canal benign positional vertigo, 265–68 whiplash injuries, 363
mimics of, 268–69 Brain tumor, 347–49
persistent, 268 diagnosis and management of, 348–49
posterior canal variant of, 258–65 Bright’s disease, 385
pathophysiology, 260–61 Bruns’ nystagmus, 162, 348
posttraumatic, 354 Buclizine hydrochloride (Bucladin-s), 406t, 409t
Benign positional vertigo, 364t for preventing motion sickness, 413
Benign recurrent vertigo of adulthood, 291, 291t for vertigo due to vestibular lesions, 413
Benzathine penicillin, for syphilitic inections, 249 Burst tonic (BT) neurons, 78
Benzodiazepines, 137, 405, 407, 412t Butyrophenones, extrapyramidal side effects of, 411
for nausea and vomiting associated with vertigo, 408,
410, 411
Benzquinamide hydrochloride (Emete-con), 406t CACNA1A gene, 396
for mild, persistent nausea, 415 and familial hemiplegic migraine, 293
for nausea and vomiting associated with vertigo, 412t CACNB4, 396
Beta blockers Calcium channel blockers, for ion channel disorder, 293
for ion channel disorder, 293 Caloric fixation suppression index, 181
for migraine, 299 Caloric testing, 390
Betahistine (Serc), 406t bithermal, 177–83, 180f, 181f, 182t
for Meniere’s syndrome, 282 in central lesions, 182–83
for vertigo associated with Meniere’s syndrome, 414 mechanism of
Bilateral peripheral lesions, 200–202 stimulation, 177–79, 178f
Bilateral sequential vestibular neuritis, 244 methodology for, 179–80
Bilateral vestibular lesions, 424–25, 424t normative data, 180–81
balance, 424–25 in peripheral lesions, 181–82
gaze stability, 424 cold, 155–56
Bilateral vestibular schwannomas, 342–43 habituation with, 81
Binaural diplacusis, 220 Canalithiasis, 257
Biopsy, for brainstem and cerebellar tumors, 349 Canalithiasis theory, 163, 257, 260
Bird, labyrinth of, 32f Canalith jam, 264
Bithermal caloric test, 177–83, 180f, 181f, 182t Canal-ocular reflex, 193, 195f
in central lesions, 182–83 Canal segment, of facial nerve, 28
mechanism of stimulation, 177–79, 178f Cannabinoids, for nausea and vomiting associated with
methodology for, 179–80 vertigo, 406t, 411
normative data, 180–81 Carbamazepine
in peripheral lesions, 181–82 dizziness caused by, 137
Bleeding diathesis, 332 for vestibular paroxysmia, 335
Blood supply, in inner ear, 35–36 Carboplatin, ototoxicity of, 376
BMP2, 372 Carcinoma
BMP4, 372 adenoid cystic, 339, 340
Bone morphogenetic protein 13 (BMP13), 391 basal cell, 339
Bony fusions, 391 mucoepidermoid, 339
Brain abscess, 239–40 squamous cell, 339
Brain-derived neurotrophic factor (BDNF), 72, 426 Cardiac output, impaired, near-faint dizziness, 133
Brain imaging, for vertebrobasilar ischemia, 326–28 Casopitant, for nausea and vomiting, 411
Brain stem CCA1/KRIT1, 348
and cortex, 209–10 CCA2/MGC4607, 348
-evoked response, 226 CCA3/PDCD10, 348
gliomas of, 347–48 Cellular mechanisms, 102
hemorrhage, 332–33 Center of pressure (COP), 208, 209f
trauma, dizziness due to, 362 Central auditory speech tests, 228–29
Brainstem auditory-evoked response (BAER), 226, 227f, Central compensation for vestibular lesions, 21–22
228f, 389 Central hearing disorders, 220
in acoustic neuroma, 344 Central lesions, 182–83
in brain trauma, 363 Central positional nystagmus, 164
in multiple sclerosis, 313 vs peripheral positional nystagmus, 164t
in whiplash injuries, 363 Central processor, in orientation, 22
438 Index
Central spontaneous nystagmus, 159–60 benign paroxysmal vertigo of, 290

vs peripheral spontaneous nystagmus, 159t brain stem gliomas in, 347
Central vestibular cerebellar tumors in, 348
compensation, 21–22 congenital hearing loss in, 384, 385
Central vestibular lesions, 202–3, 425, 425t with congenital hypothyroidism, 368
balance, 425 dizziness in, 226
gaze stability, 425 hypothyroidism in, 368
Central vestibular pathways, vestibular nuclei, 11–12 medulloblastomas in, 348
Central vestibular system, 63 Meniere’s syndrome in, 274
cervico-ocular reflexes, 87–89 migraine without aura in, 296
subjective vestibular opsoclonus in, 310
sensation, 102–7 rhabdomyosarcoma in, 340
vestibular nuclei, 65–72 sensorineural hearing loss in, 220
vestibulo-ocular reflexes, 72–86 and suppurative labyrinthitis, 237
vestibulospinal reflexes, 97–102 toxic/metabolic disorders in, 377
visual–vestibular interaction, 89–97 vestibular loss in, 421–22
Cerebellar arteries, branches of, 325, 326f Chlorpromazine, 406t
Cerebellar ataxia, and multiple sclerosis, 314–15 for hepatic disease, 413
Cerebellar–vestibular interaction, 100–101, 101f for nausea and vomiting associated with vertigo, 412t
Cerebellopontine angle Cholesteatoma, 235–36, 236f
lesions of, 184t definition of, 235
vertigo in, 130t diagnosis of, 235–36, 236f
surgical approaches to, 347 management of, 236
tumors of, 341–47 Cholesterol granulomas, 344
brainstem auditory-evoked responses in, 344 Choline acetyltransferase (ChAT), 52, 56
diagnostic algorithm of, 345f Chorda tympani, 28
management of, 346–47 Chromosome 12p, and Meniere’s syndrome, 277
Cerebellopontine angle cistern, 36 Chronic anxiety, 136
Cerebellopontine angle tumors, diagnosis of, 345f Chronic subjective dizziness. See Psychophysiologic
Cerebellum, 64f dizziness
degeneration of Cilia, of hair cell, 5, 5f, 6. 42f
in alcoholism, 370, 371f Cisplatin, dizziness caused by, 137
paraneoplastic, 309–10 Cis-platinum, ototoxicity of, 376
hemorrhage into, 332–34, 333f Clavulante, for acute otitis media, 235
infarction of, 324–25 Clonazepam, for opsoclonus, 312
lesions of Coccidioidomycosis, 250
caloric testing in, 182t, 183 COCH gene mutation, hearing loss associated with, 387
disequilibrium in, 138, 139f Cochlea, 11f
rotational testing in, 156, 202 Cochlear aqueduct, 33–35, 33f, 36f, 237, 357, 359f
smooth pursuit and, 187 Cochlear hearing loss, 225, 227, 229
Cerebellum, lesions of, 183 Cochleosaccular dysgenesis, 389
Cerebral cavernous malformations (CCM), 348 Cochrane Collaboration, The, 422
Cerebral edema, after temporal bone fracture, 362 Cogan’s syndrome, with inner ear involvement, 305
Cerebrospinal fluid (CSF), 33, 311, 354, 357 Cogwheel pursuit, 187
Cerumen, impacted, 149, 156, 179, 219, 224 Cold caloric test, 155–56
Ceruminoma, 339 Comatose patient
Cervical synostosis, congenital, 391 caloric testing of, 156
Cervical VEMPs (cVEMPs), 211–13 reflex eye movements in, 153
Cervicodorsal roots, stimulation of, 87, 88 Common cochlear artery, 35, 36f
Cervicomedullary compression, 392 Compensatory eye movements, 77–78, 77f
Cervico-ocular reflexes¸421 Computed tomography angiography (CTA)
anatomic and physiologic basis, 87–88 for vertebrobasilar ischemia, 329
neck-induced eye movements, characteristics of, 88–89 Computerized tomography (CT), 206
and vestibulo-ocular, synergistic interaction of, 88, 89f for atlantoaxial dislocation, 392
Cervicovertebral fusion, 391 for brain stem and cerebellum hemorrhage, 333, 333f
Chiari malformation, 391–92 for brain stem gliomas, 349
type 1, 392, 393f for brain trauma, 363–64
diagnosis of, 392 for cerebellopontine angle tumors, 344
management of, 392–93, 393f for inner ear abnormalities with Klippel-Feil
Children syndrome, 391
acute otitis media in, 234 for inner ear genetic disorders, 390
astrocytoma in, 348 for internal auditory canal and cerebellopontine angle
autosomal recessive spinocerebellar ataxia syndromes tumors, 345
in, 396 for Meniere’s syndrome, 280
bacterial meningitis in, 237 for middle ear and temporal bone tumors, 340
basilar migraine in, 289 for otosclerosis, 373
Index 439
for semicircular canal dehiscence syndrome, 361f Decerebrate rigidity, 19

for temporal bone trauma, 355, 355f Deep tendon reflex, 19, 36, 152, 395
of temporal bones Deiters’ nucleus. See Lateral vestibular nucleus
with Mondini malformation, 389, 389f Delayed endolymphatic hyrdrops, 275
with cholesteatoma, 236f Demonstrated positional nystagmus, 348
for vertebrobasilar Demyelination, in multiple sclerosis, 312–13
ischemia, 327–28 Dephenidol, for nausea and vomiting associated with
for whiplash injuries, 363 vertigo
Concussion Descending (inferior) vestibular nucleus, 67
definition of, 361, 362 Destructive procedures, 282–83
labyrinthine, 353–54, 355t Developmental disorders, 383–98
symptoms after, 363t Diabetes mellitus, 367–68
Conductive hearing loss, 219 presyncopal light-headedness and, 368
Congenital cervical synostosis, 391 vascular changes with, 367
Congenital cytomegalovirus (CMV), and acquired hearing Diazepam (Valium), 161, 406t, 409t, 410
loss, 384 for Meniere’s syndrome, 280, 281t
Congenital nystagmus, 177f for nausea associated with vertigo and motion
Congenital spontaneous nystagmus, 160–61 sickness, 415
Congenital syphilitic labyrinthitis, 248 for postconcussion syndrome, 364
Conventional contrast angiography, 329 vestibular rehabilitation, 419
for recurrent vertigo attacks, 329–30f Dibekacin, ototoxicity of, 374t
Conventional rotational chair, 190t Diffuse cerebellarIntrinsic brain stem, lesions of, 184t
Convergence retraction nystagmus, 165 Dihydroxyergotamine, for migraine, 298t
Corneal–retinal potential, definition of, 171 Dimenhydrinate (Dramamine), 406t
Cortical spreading depression, 294 for Meniere’s syndrome, 281t
Corticosteroids for nausea and vomiting, 414
for autoimmune inner ear disease, 308 during pregnancy, 410
for bacterial labyrinthitis, 237 side effects of, 414
for herpes zoster oticus, 247 vestibular rehabilitation, 419
for sudden sensorineural hearing loss, 247 Dimorphic afferents, 54f
Counterrolling, definition of, 207 Dimorphic unit, 52, 55
Cows (cold opposite, warm state), 178 Diphenhydramine hydrochloride (Benadryl), 406t, 409t
Cranial nerve for mild to moderate episodes of vertigo, 413
mononeuropathies, 367 for motion sickness, 413
Cranial vertebral junction disorders, 390–93 side effects of, 413
atlantoaxial dislocation, 391 Diphenidol (Vontrol), 406t, 415
basilar impression, 390 for nausea and vomiting associated with vertigo, 412t
bony fusions, 391 Direct fluorescent antigen assay (DFA), for herpes zoster
Chiari malformation, 391–92 oticus, 245
diagnosis of, 392 Directional preponderance
management of, 392–93 with caloric stimulation, 182t
syringobulbia, 392 formula for, 181
Cristae, 6–10, 9f, 43–44 Disequilibrium
cupula system, 31–32 common causes, 138, 139f
innervation of, 50–52 diagnosis and management of, 140
properties of afferent nerve fibers in, 56f falls in older people, 139–40
Crocodile, labyrinth of, 32 gait disorders in older people, 138–39
Cupula, 7, 8, 9f, 10, 44 Dissociated/disconjugate gaze-evoked nystagmus, 162
displacement of, 45–47 Dissociated-spontaneous nystagmus, 165
Cupula Dix-Hallpike positioning test, 158, 163, 177, 262, 268
anatomy of, 7, 9f, 17f for benign positional vertigo, 355
Cupulolithiasis, 256, 257 Dizziness, 127. See also Disequilibrium, Vertigo
Cupulometry test, 105 after whiplash injuries, 363–64
Current of silence,” 41 disequilibrium, 138–40
Cuticular plate drug-induced, 137–38, 137t
anatomy of, 5, 5f due to brainstem trauma, 362, 364t
Cyclizine, 406t, 409t epidemiology of, 121–25
Cyclophosphamide, for immune-mediated inner burden on patients, 124
ear disease, 308 health-care utilization, 125
Cyst, epidermoid, of cerebellopontine angle, 343 population prevalence of, 122f
Cytosine, for sudden sensorineural hearing loss, 247 specific disorders, 123–24
Cytosine arabinase, for viral infection, 247 exercises for, 425–26
falls in older people due to, 139–40, 139t
head trauma induced, 257–58, 259t
Davis mechanoelectric theory, of hair cell function, 41 hypoglycemia, 138
Deafness. See Audiovestibular loss; Hearing loss lifetime prevalence of, 123f
440 Index
Dizziness (Cont.) routes of spread in, 238–39

mechanisms of, 128t mycotic, 250
and migraine, 287 syphilitic, 248–49, 249f
multisensory, 142 Eccentric head rotation, 207
near-faint, 132–34 advantages of, 207
causes of, 132t Ecchymosis in temporal bone fracture, 353
with hyperventilation, 134 Echocardiography, for vertebrobasilar ischemia, 328
with impaired cardiac EDN, 385
output, 133 EDNRB, 385
with orthostatic Edrophorium test, in pseudo medial longitudinal fascicle
hypotension, 132–33 nystagmus, 162
with vasovagal attacks, 133–34 Efferent vestibular neurons, 56–57
ocular, 140–42, 141f Eighth nerve lesions, 182
phobic, 135 Electrocochleography (ECoG), 226, 226f, 279
physiologic, 142–44 for Meniere’s syndrome, 279
psychophysiologic, 134–37, 135t Electrode systems for
and systemic metabolic disorders, 367–71 electroculography, 171–72, 172f
alcohol and thiamine deficiency, 368–70 Electronystagmography (ENG), 162, 171, 172f, 174f
diabetes mellitus, 367–68 for brain trauma, 363
hypothyroidism, 368 for perilymph fistula, 357
management of, 370–71 test battery, 175t
uremia, 368 for whiplash injuries, 363
vertigo, 128–32 Electrooculography, 85, 171
vestibular and nonvestibular types, 144–45, 144t for ocular counterrolling, 207
DNA mutations, mitochondrial, 388 Encephalomyelitis
Dolichoectasia, definition of, 334 in paraneoplastic immune disorders, 310–11
Doll’s eye test, 153 Endolymph, 34
Dominantly inherited hearing loss, 386t, 387 volume, regulation of, 34
Domperidone, 406t, 411, 412t Endolymphatic duct and sac, 37
indications for use, 412t Endolymphatic hydrops. See Meniere’s syndrome
for nausea and vomiting associated with vertigo, 408, Endolymphatic sac, 26f, 33, 33f, 34, 277, 282, 303, 359f
411, 412t autoimmune injury to, 278
Doppler imaging, 328 tumors, 332
Dorsolateral pontine nucleus, in visual-vestibular Endolymphatic sac, 303
interaction, 94–95, 94f Endolymphatic shunts, 282
Down’s syndrome, 391 End-organ lesions, 182
Downbeat nystagmus, 159, 175 ENG. See Electronystagmography
causes of, 159–60 EOG. See Electrooculography
Dronabinol (Marinol), 406t Ephedrine, for Meniere’s syndrome, 281t
extracted from Cannabis sativa, 416 Epidermoid cysts of cerebellopontine angle, 343, 345
for nausea and vomiting associated with vertigo, 412t Epidural abscess, secondary to ear infection, 239
Droperidol (Inapsine), 406t, 409t, 411, 415 Episodic ataxia and vertigo syndromes, 396
indications for use, 412t type 1, 396
for Meniere’s syndrome, 280 type 2, 396
for nausea and vomiting associated with vertigo, 408, 412t types 3–7, 396
Drug-induced dizziness, 137–38, 137t Episodic ataxia type 1 (EA-1), 396
Drug intoxication syndrome, 137 Episodic ataxia type 2 (EA-2), 396, 397f
Drug ototoxicity, risk factors for, 377t Episodic ataxia type 5 (EA-5), 396
Dynamic ocular counterrolling, 190t Episodic ataxia type 6 (EA-6), 396
Dynamic theory of endolymph volume, 34, 276 Episodic vertigo, and transient ischemic attacks
Dynamic visual acuity test, 155 (TIAs), 320–21
Dysrhythmia Epitympanic recess, 25
with caloric stimulation, 182t Epley maneuver, 257, 263f
Dysrhythmic nystagmus, 183, 184t, 202 for posterior canal variant of benign positional
vertigo, 262f, 263, 264
Equilibrium
Ear. See also Inner ear; Middle ear loss of. See Disequilibrium
cross section of, 26f maintenance of, vestibular reflexes in, 13
embryological development of, 38f Etanercept, for immune-mediated inner ear disease, 309
examination of, 149–50, 150f Ethacrynic acid, ototoxicity of, 375
fistula test, 150–51 Eustachian tube
Ear drum. See Tympanic membrane abnormalities of, in otitis media, 234
Ear infection, 233–50 Evoked potentials, vestibular, laboratory evaluation
intracranial extension of, 238–41 of, 209–10, 210f
diagnosis of, 240–41, 240f Evoked responses, auditory. See Auditory evoked
management of, 241 responses; Brain stem auditory evoked responsees
Index 441
Ewald’s laws, 44–45, 54 Fourth ventricle

Exercise, after vestibular loss, 422–26. See also Vestibular lesions of, 183
exercises tumors of, 348
Experimental lesions, effect of, 80 Fracture of temporal bone, 353
External otitis intracranial complications associated with, 362
herpetic, 245 Frataxin gene mutation, 395, 397
malignant, 241 Free-floating otoconia, and benign positional vertigo, 258
Eye-head (EH) neurons, 78 Frenzel glasses, 157f
Eye motion, pattern of, 77f, 80 Friedreich’s ataxia (FA), 394–95
Eye movements FRMD7, 160
characteristics of, 82f, 84–85, 85f Frontal lobe, lesions of, 138, 139f
compensatory, 77–78, 77f, 82f Frontoparietal cortex, lesions
neck-induced, characteristics of, 88–89 of, 184t
off-center axis rotation, 86 Functional brain imaging, in normal human sub-
off-vertical axis rotation, 86 jects, 104–5
recording methods, 171–74 Functional hypoglycemia, 138
electrooculography, 171–72, 172 Functional magnetic resonance imaging (fMRI), in
infrared video recording, 172 normal human subjects, 104
magnetic search coils, 172
saccadic, 184, 184f, 186f
by sinusoidal angular Gabapentin
acceleration, 14f, 16f for migraine, 298t
vestibular-induced, 92 for vestibular paroxysmia, 335
visual-induced, 92 Gait
visual tracking, 89–91 apraxia of, 140
visually guided tracking, 91–92 and balance exercises, 425
Eye velocity versus head velocity, 197f disorders, in older people, 138–39
Gait tests, 151f, 152–53
Gamma-amino butyric acid (GABA), 43, 161
Facial nerve, 11f, 26f, 28–29 Gastropod, orientation in, 11, 13
schwannomas, 342 Gaze-evoked nystagmus, 161–62, 176–77
Falls, in older people, 139–40, 139t asymmetric, 162
Familial bilateral causes, 161t
vestibulopathy, 388 dissociated, 162
Familial hemiplegic migraine (FHM), 292–93 mechanism, 161
genetic factors of, 293 rebound, 162
Familial periodic ataxia and vertigo, 132, 396 symmetric, 161
Fast component generation, 79–80 Gaze stability
Fastigial nucleus, 101–2, 101f bilateral vestibular lesions, 424
Fatigue central vestibular lesions, 423
saccadic abnormalities in, 185 during horizontal head rotations, 200f
smooth pursuit abnormalities in, 187 unilateral vestibular lesions, 423
Fetal alcohol syndrome, inner ear disorders in, 384, Gegenhalten, 139
390 Gelatin layer, 8f
Fibrous dysplasia of temporal bone, 373 Gene chips, 390, 397
First-degree nystagmus, 157 Generator potential, 34, 42
Fish Genetic disorders, 383–98
vestibular labyrinth of, 30, 30f with audiovestibular loss, 384–86, 385t
vestibular nuclei of, 65 Genetics
Fistula, Perilymph. See Perilymph fistula and Meniere’s syndrome, 277–78
Fistula test, 150 and migraine, 292–93
Fixation, caloric testing with, 179–80 Genetic testing, for congenital hearing loss, 390
Fixation exercise, 423, 429 Genetic testing
Fixation suppression index, 181 in congenital inner ear disorders, 390
Flat tympanogram, 224 in spinocerebellar ataxia, 393
Floccular target neurons (FTNs), 97 Gentamicin, 374t
Florical, for otosclerosis, 374 for hearing loss, 377
Fluid-attenuated inversion recovery (FLAIR), 313, 326, for Meniere’s syndrome, 283
332 Geotropic nystagmus, 265–67
for Wernicke’s encephalopathy, 370 GJB2 gene mutation, hearing loss associated with, 386,
Flunarizine, for migraine, 298t 387, 390
Fluorescent treponemal antibody absorption (FTA-ABS) Glatiramer acetate, for multiple sclerosis, 314
test, 248 Glioma
Fluoxetine, for migraine, 298t of brain stem, 347–48
Forced prolonged position” of cerebellum, 348
for geotropic nystagmus, 267–68 Glomus body tumors (paragangliomas), 340
442 Index
Glossopharyngeal nerve, glomus tumors in, 340 Head trauma

Glutamate, 43, 52 brain stem injury in, 362
Gluten-free diet, 315 dizziness after, 362, 364t
Glycerol test, in Meniere’s syndrome, 279–80 loss of consciousness after, 361
Glycine, 52 positional vertigo after, 257
GPR143, 160 postconcussion syndrome after, 362–63, 363t
Gravity-detection organs, 4 Head-turning exercises, 428
phylogeny of, 29 Hearing, clinical evaluation of
Greater superficial petrosal nerve, 28, 29f auditory-evoked responses, 225
Group A Streptococcus, 234 brainstem auditory-evoked response, 226
Gufoni maneuver, for geotropic nystagmus, 267 electrocochleography, 226
Guild theory, of endolymph volume, 34 bedside tests, 220–21
behavioral audiometry, 221
audiogram, 221–22
Habituation, nystagmus and 81 speech recognition tests, 223
Hair cell, 4–6, 39–43 Stenger test, 223
activation central auditory speech tests, 228–29
and direction of force, relationship between, 41 impedance audiometry, 223, 224f
mechanism of, 41–42, 41f potentials, generating, 226–27
sequence of, 40–41 results in patients, 227–28
afferent nerve activity, influence on, 42–43 test methodology, 227
cilia, 5, 6 tympanometry, 224
in cochlea, 10 acoustic reflex, 224–25
definition, 4 Hearing disorders, types of, 219–20
deflection, 6 central hearing disorders, 220
depolarization, 6, 7f conductive, 219
function, Davis mechanoelectric theory of, 41 sensorineural, 219–20
hair cell/afferent nerve junction, signal processing Hearing level (HL), 221
at, 43 Hearing loss. See also Audiovestibular loss
hyperpolarization, 6, 7f acoustic reflex testing in, 224–25
in mammals, 39, 39f acquired, 384
morphologic characteristics, 39–40 audiogram in, 221–22, 221f
types, 39 auditory-evoked responses in, 225–26, 226f
transduction, model for, 40f auditory tests in, summary of, 229, 229t
types, 5–6, 5f bedside testing for, 220
Haloperidol, for nausea and vomiting associated with behavioral audiometry in, 221–23
vertigo, 408, 411 brainstem auditory-evoked responses in, 225–26
Head acceleration central, 220
angular, cupula displacement during, 9f, 10, 45–47, 46f central auditory speech tests for, 228–29
linear conductive, 219
eye movements produced by, 77, 77f hereditary, 384–88, 385t, 386t
ololith displacement during, 6 impedance audiometry in, 223, 224f
Headache sensorineural, 219–20
migraine, after caloric testing, 179 in autoimmune inner ear disease, 304–7, 306f
migraine aura without, 297 in Meniere’s syndrome, 357
in basilar migraine, 296–97 patterns of, 222f
Head injury, 131 sudden, 245–46
benign positional vertigo, 354 severity of, 222t
fracture, 353 speech recognition tests for, 223
labyrinthine concussion, 353–54 Stranger test for, 223
Head movement tympanometry in, 224, 225f
dizziness associated with, exercise for, 140 viruses associated with, 242t
force associated with, 3 Heat-shock protein 70 (HSP-70), 305
oscillopsia with, 21t, 141, 141f Heel-knee-shin test, 370
in space, 143 Height vertigo, 143–44
Head rotarion. See also Rotational testing Hemodialysis, 368, 377
active (autorotation), 192–93 Hemophilus influenza, 234, 239
compensatory eye movements associated with, 15, 16f, Hemorrhage
77, 77f into brain stem and cerebellum, 332–34
eccentric (off-center), 190f, 190t, 207 diagnosis and management of, 333–34
high-acceleration small-amplitude, 192 intracerebral, 361
off-vertical, 190f, 190t, 207–8 intralabyrinthine, 332
Head-shaking nystagmus, 164 Hennebert’s sign, 150
Head-thrust test, 153, 154f Hereditary disorders, 384–88
Head tilt, compensatory eye movement associated inherited syndromes, 384–86, 385t
with, 82, 82t nonsyndromic audiovestibular loss, 386–88, 386t
Index 443
Hereditary nephritis. See Bright’s disease Infectious diseases, 233–50

Heredity, and Meniere’s syndrome, 277–78 Inferior vestibular nucleus. See Descending (inferior)
Herpes simplex virus type 1 (HSV-1), 244, 267 vestibular nucleus
Herpes zoster oticus, 243–44 Infrared video recording, of eye movements, 172, 173,
diagnosis of, 245 173f
Herring’s law, 203 Inheritance. See Heredity
High-acceleration test, advantage of, 192 Inherited bilateral vestibulopathy, 388
Hindbrain, 38f Inherited spinocerebellar ataxia syndromes, 393–98
congenital malformation of, 391, 392 autosomal dominant, 393–94
efferent vestibular neurons in, 56 autosomal recessive, 394–96
Home exercise program, 428–29 episodic ataxia and vertigo syndromes, 396
Horizontal canal benign positional vertigo, 265–68, 267f episodic ataxia type 1, 396
apogeotropic nystagmus, 267 episodic ataxia type 2, 396
geotropic nystagmus, 265–67 episodic ataxia types 3–7, 396
treatment of, 267–68, 267f diagnosis of, 396–97
Horizontal canal-ocular reflex, 13–15, 14–15f gene location, 394t
Horizontal eye movement abnormalities management of, 397–98
with autosomal dominant spinocerebellar ataxia Inherited vestibular loss with normal hearing, 388
syndromes, 394, 395t patients with, 388
type and degree of, 395t Inner ear, 359f, 383–90
Huntington’s disease, 185 acquired disorders, 384
Hurler’s syndrome, 391 blood supply, 35–36
Hydrocephalus, otitic, 240, 241 cross-section of, 33f
Hyperactive responses diagnosis of, 389–90
with caloric stimulation, 182t genetic testing, 390
Hyperbilirubinemia, 384 laboratory tests, 389–90
Hypermobile tympanogram, 224 embryonic development, 37–38
Hyperventilation fluid chemistry, 34–35
near-faint dizziness with, 134 fluid dynamics, 33–34
nystagmus due to, 164 hereditary disorders, 384–88
Hypoglycemia inherited syndromes, 384–86, 385t
dizziness due to, 138 nonsyndromic audiovestibular loss, 386–88, 386t
functional, 138 innervation, 11f, 36–37
Hyponatremia, 368 management of, 390
Hypotension mycotic infections of, 249–50
orthostatic, 132–33 pathology, 388–89
postural, 368 phylogeny, 29–32, 32f
Hypothyroidism, 368 receptor organs, stimulus specificity of, 10
structure, 32–33, 33f
systemic immune-mediated diseases of, 304t, 306–7
Ibuprofen¸for migraine, 298t viral infections of, 242–47, 242t
Imbalance. See Disequilibrium clinical syndromes, 243–45
Immune assays, in autoimmune inner ear disease, 305 diagnosis of, 245–46
Immune-based therapy, for multiple sclerosis, 315 management of, 247
Immune disorders, paraneoplastic, 309–12 versus other causes of peripheral cochleovestibular
antineuronal antibodies in, 309, 310f loss, 246–47
clinical features of, 309–11 Inner ear vestibular receptors, 43–49
diagnosis of, 311 otolith organs
management of, 311–12 anatomy of, 47–48
pathophysiology of, 309 physiology of, 49
Immune-mediated disorders, 303–15, 314–15 semicircular canals
Immunohistochemical staining, of vestibular nuclei, 65f anatomy of, 43–44
Immunosuppression, for paraneoplastic immune physiology of, 44–47
disorders, 312 Innervation
Impaired fixation suppression of cristae, 50–52
with caloric stimulation, 182t of inner ear, 36–37
Impaired saccade accuracy, 185 of macules, 52
Impedance audiometry, 223, 224f Instantaneous firing rate (IFR), 74f
Incudomalleal articulation, 27 Interferon-beta, for multiple sclerosis, 314
Incus, 27, 27f, 355 Internal auditory artery, occlusion of, 35, 321, 324f
Infarction Internal auditory canal, 11f, 25, 36–37
cerebellar, 324–25, 327f lesions of, 29, 29f, 130, 130t
diagnosis of, 325, 327–29 tumors of, 341–47
lateral medullary, 322–23, 322f, 323t diagnosis of, 344–46, 345t, 346f
lateral pontomedullary, 323–24, 324f management of, 346–47
treatment for, 331–32 Internal auditory canal tumors, 341–47
444 Index
Internuclear ophthalmoplegia, 162 Labyrinthectomy, 21, 22

Interstitial keratitis, and syphilic infections, 248 compensation after, 71–72
Interstitial nucleus, of vestibular nerve, 67–68 for Meniere’s syndrome, 283
Intracranial complications of ear infections, 238–41 spontaneous nystagmus after, 16, 17f
brain abscess, 239–40 Labyrinthine artery, 35, 36f
diagnosis of, 240–41 Labyrinthine circulation, 36f
algorithm for, 240f Labyrinthine concussion, 332, 353–54
epidural abscess, 239 causes of, 354
lateral sinus thrombophlebitis, 239 diagnosis of, 354–55
meningitis, 239 Labyrinthine fluid dynamics, 34
otitic hydrocephalus, 240 Labyrinthine infarction, 321–22
routes of spread, 238–39 Labyrinthine ischemia, 36, 246–47
management of, 241 Labyrinthine lesions, Symptoms and signs after, 20–21,
Intralabyrinthine conductive hearing loss, 225 21t
Intralabyrinthine hemorrhage, 332 Labyrinthine stimulation, 151
diagnosis and management of, 332 Labyrinthine trauma, 131
Intrinsic brain stem, lesions of, 184t Labyrinthitis
Intrinsic membrane properties, of secondary vestibular definition of, 236
neurons, 70–71 bacterial, 131, 236–37, 246
Inverse ocular bobbing, 166 hyperventilation-induced nystagmus associated
Ion channel with, 164
differential expression of, 53 serous or toxic, 236–37, 246
disorders, 293, 293t suppurative, 236, 237, 246
expression pattern in rodent ganglion somata, 53t syphilitic, 246, 246t
Iron chelators, for prevention of aminoglycoside viral, 196
ototoxicity, 376 Lamina cribrosa, 36
Lamprey
labyrinth of, 32
Jacobson’s nerve, glomus tumors in, 340 vestibular nuclei of, 65
Jellyfish Latency associated transcript, 244
labyrinth of, 30 Lateral medullary infarction, 167, 322–23, 322f
statocyst of, 4 Lateral pontomedullary infarction, 323–24
Jervell and Lange-Nielsen syndrome, 385, 385t Lateral sinus thrombophlebitis, 239
Jugular foramen syndrome, 340 Lateral vestibular nucleus, 66–67
Lateral vestibulospinal tract, 98–99, 100f
Lateropulsion, 323
K+ secretion, 34 Lead intoxication, 377
Kanamycin, ototoxicity of, 374t Leukemia, intralabyrinthine hemorrhage in, 332
KCNA1, 396 Light-headedness, 132, 133
KCNE1, 385 presyncopal, diabetes mellitus and, 368
KCNQ1, 385 Linear acceleration, 208
Kinocilia, 5, 5f, 6, 7, 7f Linear track, 190t
Klippel-Feil syndrome, 391 Locus cerruleus, 136
inner ear abnormalities with, 391 Longitudinal fracture of temporal bone, 353, 355f
Korsakoff’s syndrome, 371 Longitudinal theory, 34
Longitudinal theory, of endolymph volume, 34
Long process of the incus, 27
Laboratory examination, of vestibular system, 171–213 Long process of the malleus, 27
nystagmography, 171–89 Long Q-T syndrome. See Jervell and Lange-Nielsen
otolith–ocular reflexes, 207–8 syndrome
vestibular-evoked potentials, 209–13 Loop diuretics, 375
vestibulo-ocular reflexes, 189–203 ototoxic effects of, 375
vestibulospinal testing, 208–9 Loose otoconia
visual–vestibular interaction, 204–7 and benign positional vertigo, 258
Labyrinth Lorazepam, 406t, 409t
blood supply to, 35–36, 36f Low-frequency sinusoidal test, in patients with central
bony, 4, 32–33, 129, 150, 151, 235, 245, 340, 356, 357, lesions, 205f
371, 372f, 373 Low-salt diet, for Meniere’s syndrome, 281
embryonic development of, 37–38, 38f
hemorrhage into, 332
ischemia of, 35 Macrosaccadic oscillations, 166
fluid chemistry of, 34–35 Macrosquare wave jerks, 165–66
fluid dynamics of, 33–34 Macules
innervation of, 36–37 afferents to, 55–56
phylogeny, 29–32, 30–32f anatomy of, 6, 8f, 47
structure of, 32–33, 33f baseline firing rate of, nerve endings and, 49
Index 445
innervation of, 52 Medial vestibulospinal tract, 99, 100f

mechanism of stimulation of, 49 Medulloblastomas, 348
nerve fiber diameter in, 50 Meniere, Prosper, 3, 273
Magnetic resonance angiography (MRA), 340 Meniere’s syndrome, 124, 130, 273–83, 368, 387, 391
for middle ear and temporal bone tumors, 340 animal models, 277
for vertebrobasilar ischemia, 328–29, 329f background, 273–74
Magnetic resonance imaging (MRI), 206 bilateral, 274
for brain stem and cerebellum hemorrhage, 333 clinical features of, 275
for brain stem gliomas, 348–49, 349f diagnosis of, 278–80
for brain trauma, 364 audiometric testing, 278–80, 279f
of cerebellar artery branches, 326 imaging, 280
for cerebellopontine angle tumors, 344 vestibular testing, 280
for Chiari malformation, 392 dilated membranous labyrinth in, 276f
for episodic ataxia type II, 397t electrocochleography in, 279
for internal auditory canal and cerebellopontine angle electronystagmography in, 280
tumors, 344 epidemiology of, 274-275
for inner ear genetic disorders, 390 etiology of, 277–78
for intralabyrinthine hemorrhage, 332 genetics, 277–78
for lateral medullary infarction, 327f infection/autoimmune injury, 278
for lateral pontomedullary infarction, 327f migraine, 278
for Meniere’s syndrome, 280 hearing loss in, 275, 278–79
for middle ear and temporal bone tumors, 340 glycerol test in, 279-280
for multiple sclerosis, 313, 314f idiopathic, 274
for temporal bone trauma, 355 occurrence, 274–75
for vertebrobasilar ischemia, 326–28 medical management of, 280–82, 281t
for Wernicke’s prophylaxis, 281–82
encephalopathy, 370 symptomatic treatment of acute spells, 280
Magnetic search coils, 172 and migraine, 278, 289–90
Main cochlear artery, 35, 36f pathophysiology of, 275–77, 276f
Mal de debarquement syndrome, 144 surgical management of, 282–83
Malignant external otitis, 241–42 destructive procedures, 282–83
algorithm for, 242f pressure pulse treatment, 282
definition of, 241 shunts, 282
diagnosis of, 241 symptoms of, 278
management of, 241–42 and syphilic infections, 248
algorithm for, 242f tinnitus in, 275
Malignant tumors, 339–40 vertigo in, 129, 129t, 275
Mallear prominence, 27 Meniett device, for Meniere’s syndrome, 282
Mallear stria, 27 Meningiomas, 342, 343
Mammal, labyrinth of, 32f Meningitis, 239
Manubrium, 27, 28 basilar, 250
Marijuana, 137 congenital inner ear disorders in, 248
Mastoidectomy labyrinthitis associated with, 248
for chronic mastoiditis, 236 secondary to ear infection, 239
for petrositis, 238 syphilitic ear infection in, 248
Mastoiditis and acquired hearing loss, 384
chronic mastoiditis, 235–36 Meningogenic bacterial
otomastoiditis, 233–35 labyrinthitis, 237
Mastoid portion of temporal bone, 25, 221 Mercury intoxication, 378
Mastoid portion of temporal bone, 25, 26f Metabolic disorders367–78
Maternally inherited mitochondrial disorders, 387–88 systemic, 367–71
Maximum slow-component velocity (MSCV), 181, 191 of temporal bone, 371–74
Mean sway velocity, 210f Metals, heavy, neurotoxicity of, 377–78
Mechanoelectric theory, of hair cell function, 41 Metastatic cerebellar tumors, 348
Mechanosensory ion channels, 40 Metastatic tumors, 344, 348
Meclizine (antivert, bonine), 406t, 409t Methotrexate
for benign positional vertigo, 264 for immune-mediated inner ear disease, 308–9
for Meniere’s syndrome, 280, 281t Methylprednisone, for SSNHL, 247
for mild to moderate episodes of vertigo, 414 Methysergide, for migraine, 298t
for nausea and vomiting during pregnancy, 410, 414 Metoclopramide (Reglan), 298, 406t, 414–15
side effects of, 414 indications for use, 412t
for suppressing motion for migraine, 298, 298t
sickness, 408, 414 for nausea and vomiting associated with vertigo, 411,
Medial longitudinal fasciculus (MLF), 15, 66, 67, 151, 415
162, 185 Michel’s deformity, 389
Medial vestibular nucleus, 67 Microphonic potential, definition of, 42
446 Index
Microsomal triglyceride transfer protein (MTP), 395 Motion sickness, 409t

Midbrain definition of, 142
glioma of, 347 genetic factors in, 143
stimulation of, ocular tilt reaction and, 166–67, 167f symptoms of, 142
Middle cerebellar peduncle, infarction of, 323 Motorists’s disorientation syndrome, 136
Middle ear, 27–28 Moving-platform posturography, 208–9, 210f
cross-section of, 27f Mucoepidermoid carcinoma, 339
inflammation of. See Otitis media Multiple sclerosis, 312–15
tumors of, 339–41 background, 312
Middle fossa approach clinical features of, 313
for cerebellopontine angle tumors, 347 diagnosis of, 313
for semicircular canal dehiscence syndrome, 360 management of, 313–14
Midline cerebellar hemorrhage, 333 pathophysiology of, 312–13
Migraine, 122, 132, 287–99 symptoms of, 313
auditory symptoms with, 289 Multisensory dizziness, management of, 142
with aura, 288 Muscular tone, maintenance of, 18
definition of, 296 Myasthenia gravis
diagnosis of, 296 gaze-evoked nystagmus in, 161
scintillating scotoma, 288 saccadic abnormalities in, 185
symptoms of, 288 Mycobacterium tuberculosis, 250
without aura, 288 Mycotic mastoiditis, 250
diagnosis of, 296, 296t Myelin basic protein (MBP), 313
aura without headache, 296 Myokymia, in episodic ataxia type 1, 396
attack, phases of, 296 Myxine, labyrinth of, 32f
background, 287–88 N-acetylcysteine (NAC), 377
and benign positional vertigo, 257 Na-K-Cl cotransporter, in endolymph production, 34
clinical features of, 288, 292 Naproxen
basilar migraine, 289 for migraine, 298t
and meniere’s syndrome, 289–90 National Hospital Ambulatory Medical Care Survey
migraine equivalents, 290–92 (NHAMCS), 125
migraine with aura, 288 Nausea, 405
migraine without aura, 288 antidopaminergic drugs for, 406t, 411
migrainous vertigo, 288–89 antiemetic drugs for, 410–13, 412t
common drugs for treating, 298t vestibular suppressants for, 407–10
definition of, 287 Near-faint dizziness, 132
drugs for treating, 298t causes of, 132t
diagnosis of, 295–97 hyperventilation, 134
incidence of, 291t orthostatic hypotension, 132–33
management of, 297–99 postural tachycardia syndrome (POTS), 133
symptomatic and abortive treatment, 298 vasovagal attacks, 133–34
prophylactic treatment, 298–99
and Meniere’s syndrome, 278
pathophysiology of, 292–95 Neck, soft tissue injury to, 363, 364
genetics, 292–93 Neck-induced eye movements, characteristics of, 88–89.
spreading wave of depression, 294 See also Eye movements
vasomotor abnormalities, 294–95, 295f Neck-vestibular interaction, 363
symptoms, factors triggering, 297t Neighboring rostral reticularis tegmenti pontes nucleus
Migraine aura without headache, 296 (RTPN), 94
Migraine equivalent, 296 Nephritis, hereditary, in Alport’s symdrom, 368
Migrainous positional vertigo vs benign positional Nervous system, immune-based attack on, 309, 314
vertigo, 289 Netilmicin, totoxicity of, 374t
Migrainous vertigo, 124, 125, 288–89, 297 Neurilemmomas, 341
criteria for, 297 Neurkinin-1 (NK-1), 411
Mild traumatic brain injury, 361 Neurofibromas, 341
MITF gene, 385 Neurofibromatosis type 1 (NF1), vertigo in, 132
Mitochondria, anatomy of, 5f Neurofibromatosis type 2 (NF2), vertigo in, 132, 342–43, 343t
Mitochondrial DNA, mutations in, 388 Neuroleptic malignant syndrome, 411
Mitochondrial encephalomyelopathy with lactic acidosis Neuromas, 341
and stroke-like episodes (MELAS), 388 acoustic, 341, 342
Mollusk, mechanoreceptors of, 31 Neuronal mechanisms, 78–79, 79f
Monaural diplacusis, 220 Neuronal reflex arc, 13t
Mondini malformation, 388, 389, 389f Neurotoxins, 377–78
Monocular nystagmus, 165 diagnosis of, 378
Moraxella catarrhalis, 234 heavy metals, 377–78
Morquio’s syndrome, 391 management of, 378
Motion perception and orientation, 19–20 organic solvents, 378
Index 447
Neurotransmitters, 52 Ocular and spinal vestibular reflexes, comparison

of vestibular nuclei, 68 of, 97–98
NF2 gene, 342–43 Ocular bobbing, 166
Nimodipine, for migraine, 298t Ocular counterrolling, 85–86, 207
Nitric oxide synthase (NOS), 57 Ocular dipping, 166
N-methyl -d-aspartate (NMDA), 43, 68, 375 Ocular dizziness
antagonists, for prevention of aminoglycoside causes of, 140
ototoxicity, 377 management of, 141–42
Nonsteroidal anti-inflammatory drugs (NSAIDs), oscillopsia, 140–41
ototoxicity of, 375 Ocular flutter, 166
Nonsyndromic audiovestibular loss, 386–88, 386t. Ocular oscillations, 165
See also Audiovestibular loss convergence retraction nystagmus, 165
dominantly inherited hearing loss, 386t, 387 dissociated spontaneous nystagmus, 165
inherited vestibular loss with normal hearing, 388 ocular bobbing, 166
maternally inherited mitochondrial palato-ocular myoclonus, 166
disorders, 387–88 saccadic intrusions, 165–66
recessively inherited hearing loss, 386–87, 386t voluntary ocular oscillations, 165
Notch signaling, 38 Ocular-otholith-canal reflex interaction, model of, 82
Nucleus of optic tract, 93, 93f Ocular tilt reaction
Number needed to treat” (NNT), 263 bedside examinations of, 166–67, 167f
Nylen, 162 in lateral medullary infarction, 323
Nystagmography, 171 Ocular tilt reflex, 17–18
bithermal caloric test, 177–83 Oculocephalic reflex, 153
eye movements recording methods, 171–74 Oculogravic illusion, 106, 106f
interpreting the recording, 174–75 Oculomotor apraxia, 185, 396
pathologic nystagmus, recording, 175–77 Oculomotor integrator, 77
visual–ocular control, tests of, 183–89 Off-center axis rotation (OCAR), 86
Nystagmus, 15–17, 158f Off-vertical axis rotation (OVAR), 86
asymmetric gaze-evoked, 162 Off-vertical head rotation, 207–8
Bruns,’ 162 advantages of, 208
central origin spontaneous, 159 disadvantages of, 208
central positional, 164 Ondansetron, 406t, 412t
congenital spontaneous, 160–61 for chemotherapy-induced nausea and vomiting, 411
convergence retraction, 165 indications for use, 412t
definition of, 15, 156 Onside pitch rotation, 190t
dissociated, 162, 165 Ophthalmoscope, for nystagmus testing, 157
downbeat, 159 OPRM1 gene, 388
first-degree, 157 Opsoclonus-myoclonus syndrome, 166
gaze-evoked, 161–62 in paraneoplastic immune disorders, 310
head-shaking, 164 Optokinetic after-nystagmus (OKAN), 90f, 91
hyperventilation-induced, 164 abnormalities of, in peripheral lesions, 188, 188f
optokinetic, 89–90, 90f velocity of, 187, 187f
after-nystagmus, 90f, 91 Optokinetic nystagmus (OKN), 89–92, 90f, 91f, 187–89,
paroxysmal positional, 163, 163f 188f, 189f
pathologic, 156–57, 158 abnormalities of, in peripheral lesions, 188, 188f
periodic alternating nystagmus (PAN), 161 cortical (active), 91
peripheral positional, 164t high-frequency (stare), 90
peripheral spontaneous, 159 interaction with smooth pursuit, 91
persistent positional, 163–64 low-frequency (look), 90
physiologic, 156 methods of testing and results in normal
positional, 162–64 subjects, 187–88
rebound, 162 in parieto-occipital lesions, 206
recording, 191f slow-phase velocity of, 89, 90
second-degree, 157 subcortical (passive), 91
seesaw, 165 results in patients, 188–89
spontaneous, 158–61 Optokinetic reflex, 421
vestibular, 80 Optokinetic system, 89
symmetric gaze-evoked, 161 Optokinetic system, 89–90
third-degree, 157–58 Organic solvents, neurotoxicity of, 378
types of, 156t Orientation, 19–20
vibration-induced, 164 central processor in, 22
voluntary, 165 vestibular sensations during, 104–5
Orthostatic hypotension, 132–33
Oscillopsia, 141f
Occipitalization of the atlas. See Assimilation of the atlas head movement–induced, 393
Occipital lobe, lesions of, 130, 130t definition of, 140
448 Index
Ossicles Oval window

anatomy of, 27 dimensions of, 27
assessment of, 150 rupture of, 357
Osteogenesis imperfecta, 373 Oxcarbazepine
Osteogenic sarcoma, of temporal bone, 340 vestibular paroxysmia, 335
Osteopenia, and benign positional vertigo, 257
Osteopetrosis, 373
and benign positional vertigo, 257 Paget’s disease, 373
Otalgia, in otitis media, 234 Palato-ocular myoclonus, 166
Otholith-ocular canal reflex interaction, model Palonosetron
of, 82 for chemotherapy-induced nausea and vomiting, 411
Otitic hydrocephalus, 240 Panic attacks, 135
Otitis externa medications for, 137
herpetic, 245 symptoms of, 135t
malignant, 241 Parallel swing, 190t
Otitis media, 131 eye movements produced
acute, 233–35 by, 106
diagnosis and management of, 234–35 Paramedian pontine reticular formation (PPRF), 16–17,
hearing loss, 234 79–80
labyrinthitis and, 236–37 role of, 80
progression patterns, 234f Paraneoplastic immune disorders, 309–12
serous, 234 antineuronal antibodies, 309, 310t
Otoacoustic emissions, in congenital inner ear background, 309
disorders, 389 clinical features of, 309–11
Otoconia cerebellar degeneration, 309–10
anatomy of, 8f, 47–48, 48f encephalomyelitis, 310–11
production and maintenance of, 47–48 opsoclonus, 310
Otocyst, 37, 38f diagnosis of, 311
Otolaryngology Committee on Hearing and management of, 311–12
Equilibrium, 290 pathophysiology of, 309
Otolithic catastrophes, 275 Paratonic rigidity, 139
Otolithic membrane, 6, 10 Paresthesia, migrainous, 288
Otolith–ocular reflxes Parieto-insular vestibular cortex (PIVC), 102, 104
eye movements with, 83–84, 83f, 84t Parietooccipital region, lesions of, 187
laboratory examination of, 207–8 Parkinson’s disease
Otolith organs, 106–7, 106f diagnosis of, 140
anatomy of, 47–48 saccadic abnormalities in, 187
macules, 47 Paroxetine, for panic attacks, 137
production and maintenance of, 47–48 Paroxysmal positional
physiology of, 49 nystagmus, 163, 163f
historical background, 49 peripheral vs central, 164t
stimulation mechanism, 49 Particle repositioning maneuver
Otologic manifestations of syphilis, features of, 249t for posterior canal variant of benign positional
Otomastoiditis, 233–35 vertigo, 264, 265f
diagnosis and management of, 234–35 for posttraumatic positional vertigo, 356
Otorrhea Passive whole-body yaw rotation, 191–92, 193–95
in otomastoiditis, 250 Pastpointing test, 151–52
in tuberculous mastoiditis, 250 Pathologic nystagmus, 156–57, 158
Otosclerosis, 371–73 gaze-evoked nystagmus, 161–62
hearing loss in, 219 head-shaking nystagmus, 164
pathologic process of, 372, 372f hyperventilation-induced nystagmus, 164
surgery for, 374 methods of examination, 157–58
vertigo in, 132 positional nystagmus, 162–64
Otoscopy, 149–50 recording, 175–77
Ototoxins, 374–77 gaze-evoked nystagmus, 176–77
aminoglycosides, 374–75, 374t positional nystagmus, 177
anti-inflammatory drugs, 375–76 spontaneous nystagmus, 175–76, 176f
diagnosis of, 376 spontaneous nystagmus, 158–61
dizziness caused by, 137 vibration-induced nystagmus, 164
hearing loss due to, 220 Pathophysiology of vestibular symptoms, 20–21
“loop” diuretics, 375 PAX-3, 385
management of, 376–77 Pendred (enlarged vestibular aqueduct) syndrome, 385,
for Meniere’s syndrome, 283 385t, 387
platinum compounds, 376 Pendrin gene mutation, hearing loss associated
risk factors for, 377t with, 385
in uremic patients, 368 Pendulum model, 44, 45–46, 46f
Index 449
Penicillin Petrous bone

plus prednisone, 249 anatomy of, 25, 26f
plus steroids, 249 infection of, 237, 238
for syphilitic inections, 249 Phenergan, for Meniere’s syndrome, 280
Perilymph, 33–34 Phenobarbital, 161
Perilymphatic fluid, 33 Phenothiazines, extrapyramidal side effects of, 411
chemistry of, 34 Phenytoin, 161
Perilymph fistula, 247, 364t, 387 dizziness caused by, 137
algorithm for diagnosis and management of, 356f Phobic dizziness, 135
diagnosis of, 357–58 Phylogeny, 65–66
management of, 358 Physical rehabilitation, for brain injury, 364
pathophysiology of, 357 Physiologic dizziness
symptoms of, 356 height vertigo, 143–44
Periodic alternating nystagmus (PAN), 161 mal de debarquement syndrome, 144
Periodic ataxia and vertigo, 132 motion sickness, 142–43
Peripheral lesions, 181–82 space sickness, 143
Peripheral positional nystagmus, 164 Physiologic nystagmus, 17f, 156
vs central positional nystagmus, 164t Phytanoyl-CoA hydroxylase (PAHX), 396
Peripheral spontaneous nystagmus, 159, 176f Pill-rolling” tremor, 140
vs central origin spontaneous nystagmus, 159t Plasma membrane calcium ATPase 2 (PMCA2), 48
Peripheral vestibular receptors, 4–10 Plasmapheresis, for paraneoplastic immune
cristae, 6–10 disorders, 312
hair cells, 4–6 Platinum compounds, ototoxicity of, 376
inner ear receptor organs, 10 Platybasia. See Basilar impression
macules, 6 Pneumatoscopy, 150
Peripheral vestibular system, 25 Polyarteritis nodosa, with inner ear involvement, 304, 306
efferent vestibular neurons, 56–57 Polychondritis, relapsing, 307
hair cell, 39–43 Polymerase chain reaction (PCR), for herpes zoster
activation oticus, 245
sequence of, 40–41 Pons
and direction of force, relationship between, 41 glioma of, 347
mechanism of, 41–42 Pontomedullary reticular formation, stimulation of, 100
afferent nerve activity, influence on, 42–43 Positional nystagmus, 162–64, 177
hair cell/afferent nerve junction, signal processing at, 43 central, 164
morphologic characteristics, 39–40 classification of, 162
inner ear definition of, 157
blood supply, 35–36 mechanism, 162–63
embryonic development, 37–38 paroxysmal, 163
fluid chemistry, 34–35 horizontal canal, 265–68
fluid dynamics, 33–34 peripheral versus central, 164t
innervation, 36–37 persistent, 163–64
phylogeny, 29–32, 32f Positional vertigo, benign, 255–69
structure, 32–33, 33f Position-vestibular pause (PVP) neurons, 78
inner ear vestibular receptors, 43 Positron-emission tomography (PET), 136, 311
otolith organs, 47–49 in normal human subjects, 104
semicircular canals, 43–47 Postconcussion syndrome, 362–63, 364t
primary vestibular neurons, 49–56 Posterior canal variant of BPV (PC-BPV), 258–65
anatomy, 49–52 clinical features of, 258–59, 259t
physiology, 52–56 diagnosis of, 261
temporal bone, 25–29, 26f management of, 261–65
facial nerve, 28–29 pathophysiology of, 260–61, 260f
middle ear, 27–28 Posterior cerebellar artery (PCA), 329f
tympanic membrane, 26–27 Posterior inferior cerebellar artery (PICA), 320, 324f,
Perphenazine, 406t 326f, 327f, 328f, 329f
for nausea and vomiting associated with vertigo, 412t acute strokes, 328f
Persistent dizziness and lateral medullaty infarction
after brain trauma, differential diagnosis, 363, 364t symptoms and signs, 323t
reasons for, 422 Posterior spiral vein, 36f
Persistent positional nystagmus, 163–64 Posterior vestibular artery, 35, 36f
Perverted nystagmus Posterior vestibular artery, 35, 36f
with caloric stimulation, 182t Posttraumatic positional vertigo, 354
definition of, 183 diagnosis of, 355
Petromyzon, labyrinth of, 32f Postural tachycardia syndrome (POTS), 133
Petrositis, 237–38 Postural vertigo, phobic, 135
diagnosis of, 238 Posture
management of, 238 static, test of, 152
450 Index
Posturography, 209f Push-pull mechanism, 15

static-force platforms, 208
moving-platform, 208–9
Potassium, in pathogenesis of migraine, 293 Quinine, ototoxicity of, 375
Prednisione
for autoimmune inner ear disease, 308
for herpes zoster oticus, 247 Radial theory, 34
for immune-mediated inner ear disease, 309 Radiating arterioles, 35
plus steroids, 249 Radiation therapy
Presbycusis, 220 for brainstem and cerebellar tumors, 349
Pressure pulse treatment, 282 for middle ear and temporal bone tumors, 341
Prestin, cochlear hair cell electromotility and, 42 Ramsay Hunt syndrome. See Herpes zoster oticus
Presyncope, 132 Reading exercises, 428
Pretectal region Reafference principle, 73
lesions of, effects on eye movements of, 80 Rebound nystagmus, 162, 177f
in visual-vestibular interaction, 93, 95 Recessively inherited hearing loss, 386–87, 386t
Primary afferent neurons, 17f, 52, 53 Recurrent penetrating arteries (RPA), of AICA, 324f
anatomical and physiological properties, 55 Refsum’s syndrome, 396
classification, 53t Relapsing polychondritis, 304f, 307
nerve endings, types of, 52f Renal dialysis, 371
Primary afferent vestibular nerve fibers, 66 Restricted tympanogram, 224
distribution of, 50f, 64f Reticulospinal tract, 99–100
Primary cholesteatomas, 343 Retracted tympanogram, 224
Primary vestibular neurons, 49–56 Retrocochlear hearing loss, 226, 229
anatomy of, 49 Reverse bobbing, 166
innervation of the cristae, 50–52 Reversible saccade slowing, 185
neurotransmitters, 52 Rhabdomyosarcoma, of middle ear, 340
distribution of, 64f Rheumatoid arthritis, cervicomedullary compression, 391,
physiology of, 52 393
afferents from cristae, 53–55 Ribbon synapse, 5f, 40, 54f
afferents to macules, 55–56 Riding in car practice, 429
spontaneous firing rates, 52–53, 53t Rinne test, 220–21
Primidone, dizziness caused by, 137 Rituximab, for paraneoplastic immune disorders, 312
Prochlorperazine (Compazine), 406t, 410, 415–16 Rocking chair exercises, 428–29
antihistaminic effects, 416 Roll, head rotation in, 207
for Meniere’s syndrome, 280, 281t Romberg test, 152
for migraine, 298t Rostral reticularis tegmenti pontes nucleus (RTPN), 94
for nausea and vomiting associated with vertigo, 412t Rotational nystagmus, 156, 191
Promethazine hydrochloride (Phenergan), 406t, 409t, Rotational testing, of horizontal vestibulo-ocular
410, 411 reflex, 156, 190f
for benign positional vertigo, 264 Rotational vertebral artery syndrome, 335
for Meniere’s syndrome, 281t Rotational vestibulo-ocular reflexes, 73–81, 70f
for migraine, 298 compensatory eye
indications for use, 412t movements, 77–78, 77f
for severe vertigo with recurrent nausea and experimental lesions effect, 80
vomiting, 408, 414 eye motion, pattern of, 77f, 80
Propranolol, for migraine, 298t fast component generation, 79–80
Proteus, 235 level of arousal and habituation, 81
Pseudomonas aeruginosa, 235, 239 neuronal mechanisms, 78–79, 79f
Psychological factors, in vestibular rehabilitation, 420 semicircular canal–ocular connections, 75–77, 75t, 76f
Psychophysical studies Round window
of otolith organs, 106–7 anatomy of, 11f, 27f, 28, 33f
of semicircular canals, 105 rupture of, 357
Psychophysiologic dizziness, 134 vein of, 36f
chronic anxiety, 136 Routes of spread, 238–39
diagnosis and management of, 136–37 Rubella, congenital inner ear disorders in, 384
panic disorder, 135
pathophysiology of, 136
phobic dizziness, 135 Saccade system, 89
Pure-bouton afferents, 54f Saccadic eye movements, 183–86, 184f, 186f
Pure-calyx afferents, 54f abnormalities of, lesion location and, 184t
Pure tone audiogram, 221f accuracy of, 184
Pure tone average (PTA), 221, 222t in lateral medullary infarction, 323
Purkinje cells, 160 methods of testing and results in normal
afferents, 75 subjects, 183–85
Pursuit system. See Smooth pursuit results in patients, 185–86
Index 451
Saccadic intrusions, 165–66 Shaft links, 5f

Saccadic pursuit, 187 Shrapnell’s membrane, 27f
Saccular macules, 6, 8f, 47, 49, 84t Shunts, for Meniere’s syndrome, 282
anatomy of, 32, 32f Sick headache. See Migraine without aura
mechanism of stimulation of, 49 Signal processing, at the hair cell/afferent nerve
organization of, 84 junction, 43
Saccular nerve, 11f Sinusoidal rotation
Salicylates, ototoxicity of, 375–76 changes in angular velocity, 193–95
Salt restriction, for Meniere’s syndrome, 280, 281 nystagmus responses to, 203f
San Francisco Syncope Rule, 134 test, 193–95
Sarcoma, of temporal bone, 340 Sisomicin, ototoxicity of, 374t
Scarpa’s ganglion, anatomy of, 11f, 37 SLC1A3, 396
Scheibe deformity, 389 SLC26A4, 385, 387
Schwalbe nucleus. See Medial vestibular nucleus Slow-component velocity (SCV), 191, 191f, 194f
Schwannomas, 341–42 Smooth pursuit system, 90–91, 186–87, 187–88f
Antoni type A, 342 methods of testing and results in normal subjects, 186
Antoni type B, 342 results in patients, 187
bilateral vestibular, 343–43 SNA12 (type 2), 385
facial nerve, 342 Sodium fluoride, for otosclerosis, 374
vestibular, 342, 346f Soft-tissue injuries, management of, 364
Schwartze’s sign, 373 Sound pressure level (SPL), 221
Scopolamine (Transderm Scōp), 406t, 409t, 410 SOX10 (type 4), 385
indications for use, 412t Space, caloric testing in, 179
for Meniere’s syndrome, 281t Space phobia, 136
for nausea and vomiting associated with motion Space sickness, 143
sickness, 408, 413 Speech detection threshold (SDT), 223
Sea anemone, mechanoreceptors of, 30f, 31f Speech discrimination test, 223
Second-degree nystagmus, 157 Speech reception threshold (SRT), 223
Sedating drugs Speech recognition tests, 223
dizziness caused by, 137 Spinocerebellar ataxia (SCA) syndrome, 183, 393, 398
Seesaw nystagmus, 165 autosomal dominant, 393–94
Selective serotonin reuptake inhibitors (SSRIs), for autosomal recessive, 394–96
depression, 364 caloric testing, 183
Semicircular canal(s), 4, 6, 105 inherited, 393–98
anatomy of, 43–44 Spinocerebellar atrophy, vertigo in, 132
crista, 43–44 Spiral ganglion, anatomy of, 11f
cupula, 44 Spiral modiolar vein, of patient with autoimmune inner
nerve, cross section of, 51f ear disease, 306f
orientation of, 9f Spondyloepiphyseal dysplasia, 391
physiology of, 44–47 Spontaneous downbeat nystagmus, 159, 176f
historical background, 44–45 Spontaneous nystagmus, 16, 17f, 158–59, 175–76, 176f
pendulum model, 45–47 central, 159–60
Semicircular canal dehiscence syndrome congenital, 160–61
audiogram with, 361f definition of, 156
diagnosis of, 360, 361f dissociated, 165
management of, 360 downbeat, 159, 176f
pathophysiology of, 358–60 latent congenital, 160
symptoms and signs, 358, 359f mechanism, 158–59
of dehiscence, 360t pendular, 160, 313
Semicircular canal–ocular connections, 75–77 periodic alternating nystagmus, 161
with eye muscles, 75t peripheral, 159
excitatory and inhibitory pathways between, 76f torsional, 160
Semicircular canal–otolith interaction, 86, 87f upbeat, 159, 160
Semont maneuver, for posterior canal variant of benign Spontaneous vestibular nystagmus, 80
positional vertigo, 263, 263f, 264 SQSTM1, 373
Sensorineural hearing loss, 219–20, 222 Squamous cell carcinoma, of middle ear, 339
in autoimmune ear disease, 304 Squamous portion of temporal bone, 25, 26f
in labyrinthitis, 248 Square wave jerks, 165
in Meniere’s syndrome, 307 Stapedius muscle, 27f, 28, 29f
in systemic lupus acoustic reflex testing of, 225
erythematosus, 306 Stapes, 27
Serologic tests, in autoimmune ear disease, 405 Staphylococcus aureus, 235
Serotonin antagonists, 406t, 411 Static-force platform
Serotonin reuptake inhibitors, for panic attacks, 137 posturography, 207
Serous labyrinthitis, 236, 237, 246 Static ocular counterrolling, 190t
SETX gene, 396 Static posture test, 152
452 Index
Static tilt experiments, 106 T cell surface protein defect, in autoimmune ear
Statocyst, 4 disease, 304
of ctenophore comb, 30, 30f Temporal bone, 25–29
octopus, 31f facial nerve, 28–29, 29f
Stenger test, 223 middle ear, 27–28
Step stimulus medial view of, 26f
advantage of, 193 metabolic disorders of, 371–74
Stereotaxic radiosurgery, for vestibular schwannomas, 347 diagnosis of, 373
Steroids management of, 373–74
for multiple sclerosis, 313 otosclerosis, 371–73
plus penicillin, 249 Paget’s disease, 373
for syphilitic inections, 249 trauma to
Streptococcus pneumoniae, 234, 239 diagnosis of, 354–55
Streptomycin, ototoxicity of, 374t fracture, 353
for Meniere’s syndrome, 283 intracranial complications associated with, 362
Striola, 6, 8f labyrinthine concussion, 353–54
Stroke syndromes, 321–25 management of, 355–56
cerebellar infarction, 324–25 posttraumatic positional vertigo, 354
diagnosis, 325 tumors of, 339–41
labyrinthine infarction, 321–22 tympanic membrane, 26–27
lateral medullary infarction, 322–23 Temporal lobe
lateral pontomedullary infarction, 323–24 abscess of, 239
treatment for, 331–32 lesions of, vertigo in, 130t, 131
Subarachnoid hemorrhage, 362 Tensor tympani muscle, 27
Subclavian steal syndrome, 319 Terminal cerebellar branches, of AICA, 324f
Subjective vestibular sensation TGFB1, 372
functional brain imaging in normal human Thalamic astasia, 105
subjects, 104–5 Thalamic relay neurons, response properties of, 104
psychophysical studies, 105–7 Thiamine deficiency, in alcoholism, 368–70
response properties of thalamic relay neurons, 104 Third-degree nystagmus, 157–58
response properties of vestibular cortex neurons, 104 35delG mutation, 387, 390
vestibulocortical pathways in patients, lesions of, 105 Three-dimensional (3D) FLAIR, 332
vestibulothalamocortical connections, 102–4, 103f Thrombolysis, for basilar artery occlusion, 331
Suboccipital surgery, for cerebellopontine angle Thrombolytics, for acute ischemic stroke, 331
tumors, 347 Thrombophlebitis, 238
Sudden deafness lateral sinus, 239
atherosclerosis and, 321 Ticlopidine, for transient ischemic attacks, 330
in head trauma, 354 Tilt-translation ambiguity, solving, 73, 74f
vascular occlusion and, 321 Tip-links, 5, 5f, 40, 40f
viral infections associated with, 245–46 Tobramycin, 374t
Sudden sensorineural hearing loss (SSNHL), 242, 245 Tone decay test, 229
diagnosis of, 245 Topiramate, for migraine, 298t, 299
and labyrinthine concussion, 353–54 Top shelf vertigo,” 258
Sumatriptan, for migraine, 298t Toxic disorders, 367–78
Superior cerebellar artery (SCA), 329f Toxic labyrinthitis, 236
Superior vestibular nucleus (Bechterew’s nucleus), 66 Tranquilizers
Suppurative labyrinthitis, 236, 246 dizziness caused by, 137t
Surgical resection, for brainstem and cerebellar saccadic abnormalities and, 185
tumors, 349 smooth pursuit abnormalities and, 187
Symmetric gaze-evoked nystagmus, 161 Transcranial Doppler (TCD) imaging, for vertebrobasilar
Symptomatic treatment of acute spells, 280 ischemia, 328
Syncope Transesophageal echocardiography (TEE), for
cardiac-related, 134 vertebrobasilar ischemia, 328
vasodepressor light headedness and, 134 Transient ischemic attacks (TIAs), 320–21
Synostosis, congenital cervical, 391 treatment for, 329–31
Syphilis otologic manifestations of, 248–49, 249t Transient migrainous accompaniments,” 292
diagnosis of, 248–49 Translabyrinthine surgery, for Cerebellopontine angle
management of, 249 tumors, 347
Syphilitic labyrinthitis, 246, 248–49 Translational vestibulo-ocular reflex, 17, 81–85
Syringobulbia, 392 eye movements, characteristics of, 82f, 84–85, 85f
Systemic lupus erythematosus (SLE), 306 otolith–ocular connections, 83–84, 83f
Systemic metabolic disorders, and dizziness, 367–71 Transmastoid approach, for semicircular canal dehiscence
syndrome, 360
Transverse fracture of temporal bone, 353, 355f
Tandem gait tests, 152 management of, 356
Tardive dyskinesia, 411 Trauma353–64
Index 453
benign positional vertigo after, 258 Valproate, for migraine, 298t

to brain, 360–64. See also Brain trauma Valproic acid, for migraine, 299
to temporal bone, 353–56 Vascular compression syndromes, 334–35
Tricyclic amines rotational vertebral artery syndrome, 335
for depression, 364 vertebrobasilar dolichoectasia, 334
dizziness caused by, 137 vestibular paroxysmia, 334–35
for ion channel disorder, 293 Vascular disorders, 319–35
for migraine, 299 Vascular occlusion, and sudden deafness, 321
Trigeminal nerve, compression of, 341 Vasospasm, and migraine, 294–95
Trigeminal vascular system, in pathogenesis of nerve, 294 Vasovagal attacks, 133–34
Trimethobenzamide hydrochloride (Tigan), 406t, 415 Velocity storage effect, 73–75, 74f, 78
indications for use, 412t Venereal disease research laboratory (VDRL) test, 248
for mild to moderate nausea and vomiting, 415 Ventricle, fourth
Trinucleide repeat syndromes, 395 lesions of, perverted caloric nystagmus in, 183
Triptans, for migraine, 297, 298 tumor of, 348
Truncal ataxia, in cerebellar infarction, 325 Verapamil, for migraine, 299
Tuberculous mastoiditis, 249–50 Vermian cortex, 101, 101f
Tumors339–349 Vertebrobasilar dolichoectasia, 334, 334f
of middle ear and temporal bone Vertebrobasilar ischemia (VBI), 319–32
malignant tumors, 339–40 causes of, 319
glomus body tumors (paragangliomas), 340 diagnosis of, 325–29
diagnosis of, 340 angiography, 328–29
management of, 341 brain imaging, 326–28
of internal auditory canal and cerebellopontine angle clinical examination, 325–26
schwannomas, 341–42 ultrasound, 328
meningiomas, 343 pathophysiology of, 319–20
epidermoid cysts, 343 stroke syndromes, 321–25
cholesterol granulomas, 344 cerebellar infarction, 324–25
metastatic tumors, 344 labyrinthine infarction, 321–22
diagnosis of, 344–46, 345f lateral medullary infarction, 322–23
management of, 346–47 lateral pontomedullary infarction, 323–24
brain transient ischemic attacks, 320–21
brain stem, 347–48 treatment, 329–32
fourth ventricle, 348 infarction, 331–32
cerebellum, 348 transient ischemic attacks, 329–31
diagnosis and management of, 348–49 vertigo in, 319
12S Ribosomal ribonucleic acid (rRNA), 375, 388 Vertigo, 3
Tympanic cavity. See Middle ear and brain stem hemorrhage, 332
Tympanic membrane central versus peripheral causes, 128–29, 129t
anatomy of, 26–27, 26f compensation, 131
appearance of, 150f diagnosis and management, 132
Tympanic portion of temporal bone, 25, 26f common causes, duration of, 129, 129t
Tympanometry, 224, 225f family history, 131–32
acoustic reflex, 224–25 lifetime prevalence of, 123f
Tympanosclerosis, 150 precipitating factors, 129–30
predisposing factors, 131
recurrent attacks, 329–30f
Ultrasound, for vertebrobasilar ischemia, 328 symptoms of, 130–31, 130t
Unilateral peripheral lesions, 196–200 time course, 129
Unilateral vestibular lesions, 423–24, 423t and vertebrobasilar ischemia, 319–20
balance, 423–24 symptoms associated with, 321t
gaze stability, 423 viruses associated with, 242t
Upright pitch rotation, 190t Vestibular afferent neurons, classification of, 54f
Uremia, 368 Vestibular aqueduct
Usher 1B syndrome, 384–85, 385t enlarged, 385, 387, 390
Utricle vein at, 35, 36f
connection with eye muscles, 84t Vestibular compensation, failure of, 422
and semicircular canals, 37 Vestibular cortex neurons, response properties of, 104
Utricular macule, 6, 8f Vestibular disorders, 131
anatomy of, 48f, 49 Vestibular-evoked myogenic potentials (VEMPs), 210–13,
Utricular nerve, 11f 212f, 389–90
stimulation of, ocular tilt reaction and, 167 mechanism of stimulation, 210–11
for multiple sclerosis, 313
normative data, 211
Vagus nerve, glomus tumors in, 340 results in patients, 211–13
Valacycolvir, for herpes zoster oticus, 247 test methodology, 211
454 Index
Vestibular-evoked potentials, 209 Vestibular system, anatomy and physiology of, 3

brain stem and cortical, 209–10 central vestibular pathways, 11–12
vestibular evoked myogenic potentials lesions, central compensation for, 21–22
(VEMPs), 210–13 motion perception and orientation, 19–20
Vestibular exercises, 420, 425–26 peripheral vestibular receptors, 4–10
controlled trials of, 422–23 cristae, 6–10
strategy for designing, 423–25, 423t, 424t, 425t hair cells, 4–6
Vestibular lesions inner ear receptor organs, 10
bilateral, 424–25 macules, 6
central, 425 symptoms, pathophysiology of, 20–21
unilateral, 423–24, 423t vestibular reflexes, 12–19
Vestibular loss horizontal canal-ocular reflex, 13–15
bilateral, 377 nystagmus, 15–17
in children, 421–22 ocular tilt reflex, 17–18
in elderly, 422 translational vestibulo-ocular reflexes, 17
mechanisms for compensation after, 420–21, 421t vestibulo-autonomic reflexes, 19
Vestibular Meniere’s syndrome, 290 vestibulospinal reflexes, 18–19
Vestibular neurectomy Vestibular system
for Meniere’s syndrome, 283 bedside examination of, 149–67
Vestibular neuritis, 244–45, 423 central, 63–107
diagnosis of, 245–46 orientation role of, 3
pathologic findings, 243f peripheral, 25–57
Vestibular neurons Vestibular testing
compensation after labyrinthectomy, 71–72, 71f for Meniere’s syndrome, 280
intrinsic membrane properties of, 70–71 and suborgans, 190t
in rodent medial vestibular nucleus, 70, 71t Vestibular vertigo, 121
types of, 68–70, 70f Vestibule-ocular reflexes and vestibulo-ocular reflexes,
Vestibular nuclei, 11–12, 64f comparison of, 92, 92f
afferent and efferent connections of, 12f Vestibulo-autonomic reflexes, 19
anatomy, 66–68 Vestibulocerebellum, 11, 12f
descending (inferior), 67 Vestibulocochlear vein, 35, 36f
field potential in, 69f Vestibulocochlear vein, 35, 36f
immunohistochemical staining of, 65f Vestibulo-collic reflexes, 101–2
interstitial, 67–68 Vestibulocortical pathways in patients, lesions of, 105
lateral, 66–67 Vestibulo-ocular reflex (VOR), 72–86, 74f, 179, 368, 420,
medial, 67 421, 423
neurotransmitters, 68 and cervico-ocular, synergistic interaction of, 88, 89f
phylogeny, 65–66 gain and phase of, 199f
physiology, 68–72 ocular counterrolling, 85–86
superior, 66 response to step rotation in cerebellar atrophy
Vestibular-only (VO) neurons, 102 patients, 206f
Vestibular paresis rotational, 73–81, 75t, 76f, 77f, 79f
with caloric stimulation, 182t semicircular canal–otolith interaction, 86, 87f
definition of, 181 tests of, 153
Vestibular paroxysmia, 334–35 cold caloric test, 155–56
Vestibular physical therapy, 247 doll’s eye test, 153
Vestibular reflexes, 12–19 dynamic visual acuity, 155
adaptive control of, 420 head-thrust test, 153–55
basic elements, 13f rotational testing, 156
horizontal canal-ocular reflex, 13–15 translational, 81–85, 82f, 83f, 84t, 85f
nystagmus, 15–17 and vestibule-ocular reflexes, comparison of, 92, 92f
ocular tilt reflex, 17–18 with vision, adaptive modification of, 96, 96f
translational vestibulo-ocular reflexes, 17 Vestibulo-ocular reflexes, rotational testing of, 189, 190f
vestibulo-autonomic reflexes, 19 stimulus and response, relationship between, 191–93
vestibulospinal reflexes, 18–19 active head rotation, 192–93
Vestibular rehabilitation, 419–26 high-acceleration small-amplitude rotation, 192
Vestibular schwannoma (acoustic neuroma), 342, 343t, passive whole-body yaw rotation, 191–92
346f results in normal subjects, 193–96
Vestibular sensation, subjective. See Subjective vestibular active head rotation, 196
sensation high-acceleration, low-amplitude rotation, 195–96,
Vestibular suppressants, 407–10 196f
instructions to patients, 410 passive whole-body yaw rotation, 193–95
precautions, 408, 410 results in patients, 196–203
reactions of, 407–8 bilateral peripheral lesions, 200–202
usage of, 408 central vestibular lesions, 202–3
indications for, 408, 409t unilateral peripheral lesions, 196–200
Index 455
Vestibulopathy Visual ocular control abnormalities, summary of, 184t

familial bilateral, 388 Visual tracking eye movements, 89–91
inherited bilateral, 388 Visual–vestibular conflict, in motion sickness, 143
Vestibulospinal connections, 98–100, 99f Visual–vestibular interaction, 95, 95f, 204
lateral vestibulospinal tract, 98–99, 100f cellular basis for, 96–97, 97f
medial vestibulospinal tract, 99, 100f methodology, 204
reticulospinal tract, 99–100 results in normal subjects, 204–5, 204f
Vestibulospinal reflexes, 18–19, 18f, 421, 424 results in patients, 205–7
cellular mechanisms, 102 vestibular -and visual-induced eye movements,
cerebellar–vestibular interaction, 100–101, 101f comparison of, 92
ocular and spinal vestibular reflexes, comparison vestibulo-ocular reflext with vision, adaptive
of, 97–98 modification of, 96, 96f
vestibulo-collic reflexes, 101–2 visually guided tracking eye movements, organization
vestibulospinal connections, 98–100, 99f, 100f of, 91–92
tests of, 151 visual tracking eye movements, 89–91
pastpointing, 151–52 visual–vestibular interaction, 95
static posture, 152 cellular basis for, 96–97, 97f
walking tests, 152–53 visuo-vestibulo-ocular connections, 92–95, 93f, 94f
Vestibulospinal testing, 208 Visualvestibulo-ocular reflex (VisVOR), 204
bedside test, 151f Visuo-vestibulo-ocular connections, 92–95, 93f, 94f
moving-platform posturography, 208–9 Vitamin E deficiency, in spinocerebellar ataxia, 395
static-force platform posturography, 208 Voluntary ocular oscillations (voluntary nystagmus), 165
Vestibulospinal tract Vomiting. See Nausea and vomiting
ipsilateral, 67 von Hippel-Lindau disease, 132, 332
lateral, 98–99, 100f
Vestibulothalamocortical projections, 102–4, 103f
Vibration-induced nystagmus, 164 Waardenburg type 1 syndrome, 385, 385t, 389
Videonystagmography (VNG), 172, 173f Wackenheim’s clivus–canal line, 392
Video recordings, of eye movements, 173–74 Walking, delayed, in congenital vestibular loss, 383
Visual acuity test, dynamic, 155 Walking exercises, 425
Visually guided tracking eye movements, organization Walking tests, 152–53
of, 91–92 Wallenberg’s syndrome. See Lateral medullary infarction
Visual-ocular control, laboratory tests of, 183, 184t Warfarin, for transient ischemic attacks, 330
Visual–ocular control, tests of, 183–89 Weber test, 221
optokinetic nystagmus, 187–89 Wegener’s granulomatosis, 306
methods of testing and results in normal Wernicke’s encephalopathy, 370
subjects, 187–88 Western blot assay, in autoimmune inner ear disease, 305
results in patients, 188–89 Whiplash injuries
saccadic eye movements, 183–86 definition of, 363
methods of testing and results in normal management of, 364
subjects, 183–85
results in patients, 185–86
smooth pursuit, 186–87 X-linked disorder, 386t
methods of testing and results in normal
subjects, 186
results in patients, 187 Zolmitriptan, for migraine, 298, 299

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CLINICAL NEUROPHYSIOLOGY

OF THE VESTIBULAR SYSTEM

Contemporary Neurology Series

53 SLEEP MEDICINE 69 PALLIATIVE CARE IN NEUROLOGY

Robert W. Baloh, MD, FAAN

Oxford New York

Copyright © 2011 by Oxford University Press, Inc.

Published by Oxford University Press, Inc.

Oxford is a registered trademark of Oxford University Press

All rights reserved. No part of this publication may be reproduced,

Library of Congress Cataloging-in-Publication Data

Baloh, Robert W. (Robert William), 1942-

PART 1 ANATOMY AND PHYSIOLOGY OF THE

1. OVERVIEW OF VESTIBULAR ANATOMY AND PHYSIOLOGY 3

PERIPHERAL VESTIBULAR RECEPTORS 4

CENTRAL VESTIBULAR PATHWAYS 11

MOTION PERCEPTION AND ORIENTATION 19

2. THE PERIPHERAL VESTIBULAR SYSTEM 25

INNER EAR (LABYRINTH) 29

THE HAIR CELL 39

THE INNER EAR VESTIBULAR RECEPTORS 43

PRIMARY VESTIBULAR NEURONS 49

EFFERENT VESTIBULAR NEURONS 56

3. THE CENTRAL VESTIBULAR SYSTEM 63

SUBJECTIVE VESTIBULAR SENSATION 102

PART 2 EVALUATION OF THE DIZZY PATIENT

4. EPIDEMIOLOGY OF DIZZINESS 121

SPECIFIC DISORDERS 123

5. THE HISTORY OF THE DIZZY PATIENT 127

NEAR-FAINT DIZZINESS 132

PSYCHOPHYSIOLOGIC DIZZINESS (CHRONIC SUBJECTIVE DIZZINESS) 134

DRUG-INDUCED DIZZINESS 137

OCULAR DIZZINESS 140

MULTISENSORY DIZZINESS 142

PHYSIOLOGIC DIZZINESS 142

SUMMARY: DISTINGUISHING BETWEEN VESTIBULAR AND

6. BEDSIDE EXAMINATION OF THE VESTIBULAR SYSTEM 149

EXAMINATION OF THE EAR 149

TESTS OF VESTIBULOSPINAL REFLEXES 151

TESTS OF VESTIBULO-OCULAR REFLEXES 153

TESTS FOR PATHOLOGIC NYSTAGMUS 156

TYPES OF PATHOLOGIC NYSTAGMUS 158

OTHER OCULAR OSCILLATIONS 165

OCULAR TILT REACTION 166

7. LABORATORY EXAMINATION OF THE VESTIBULAR SYSTEM 171

ROTATIONAL TESTING OF VESTIBULO-OCULAR REFLEXES 189

VISUAL-VESTIBULAR INTERACTION 204

TESTS OF OTOLITH-OCULAR REFLEXES 207

VESTIBULOSPINAL TESTING 208

VESTIBULAR-EVOKED POTENTIALS 209

8. CLINICAL EVALUATION OF HEARING 219

TYPES OF HEARING DISORDERS 219

BEDSIDE TESTS OF HEARING 220

IMPEDANCE AUDIOMETRY 223

AUDITORY-EVOKED RESPONSES 225

GENERATING POTENTIALS 226

RESULTS IN PATIENTS 227

PART 3 DIAGNOSIS AND MANAGEMENT OF COMMON

9. INFECTIOUS DISEASES 233