Cummings Neuropsychiatry PDF
Cummings Neuropsychiatry PDF
Cummings Neuropsychiatry PDF
Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Front of Book > Authors
Authors
Jeffrey L. Cummings, M.D. The Augustus S. Rose Professor of Neurology Professor of Psychiatry and Biobehavioral Sciences Director, UCLA Alzheimer's Disease Center UCLA School of Medicine Jeffrey L. Cummings, M.D., is The Augustus S. Rose Professor of Neurology, Professor of Psychiatry and Biobehavioral Sciences, and Director of the Alzheimer's Disease Center at the University of California, Los Angeles, School of Medicine. He is Past President of the American Neuropsychiatric Association, Past President of the Behavioral Neurology Society, and a Fellow of the American Academy of Neurology. Dr. Cummings is a prolific investigator and writer. He has authored or edited 18 books and has broad interests in neuropsychiatry and the interface of neuroschience and society.
Michael S. Mega, M.D. Laboratory of Neuroimaging UCLA School of Medicine Michael S. Mega, M.D., is a consultant and collaborator in the Laboratory of Neuroimaging at the University of California, Los Angeles. His research interests lie in neuroimaging, with a focus on the cerebral correlates of the symptoms of Alzheimer's disease. He is widely published on this and related themes.
Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Front of Book > Dedication
Dedication
To our wives, Inese and Susan To our daughters, Juliana and Leda To our fellows, colleagues, and international collaborators whose interest, enthusiasm, and dedication have inspired and invigorated us
Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Front of Book > Preface
Preface
Clinical Neuropsychiatry, by Jeffrey L. Cummings, was published in 1985 and represented an integration of behavioral neurology and biological psychiatry into a single volume devoted to explicating brain -behavior relationships. The volume was clinically oriented and intended for practitioners caring for patients with neuropsychiatric disorders. Since Clinical Neuropsychiatry was originally published, there has been a tremendous explosion of information pertinent to neuropsychiatry ranging from molecular biology of neuropsychiatric disorders on one end of the spectrum to neuro -ethology and the neurobiological basis of social interactions and culture at the other. Advances in neurochemistry, neuroanatomy, genetics, neuroimaging, and neuropharmacology have progressed at an unprecedented rate. New treatments have evolved for nearly all neuropsychiatric illnesses and neuropsychopharmacology has become a demanding discipline in its own right. A successor to the book was badly overdue. This volume represents an attempt to integrate the most salient evolving information into a single comprehensive presentation. The clinical emphasis of its predecessor has been maintained and enriched by the integration with evolving neuroscience information. It might be argued that books are obsolete, since information is evolving rapidly and is updated more quickly through electronic resources, thus obviating the need for books such as this that are frozen in time. The dramatic increase in information, however, has made the need for an approach to delivering care to patients and of integrating the expanding information base into a systematic clinical framework even greater. Thus, the emphasis of this volume
is on approaching the patient, understanding brain regions rendered dysfunctional by disease, and optimizing care based on knowledge of brain -behavior relationships. We hope that those who read and study this volume find that their understanding of brain -behavior relationships is enhanced, their clinical assessment and management enriched, and the quality of life of their patients and their families improved. Los Angeles, California J.L.C. M.S.M.
Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Front of Book > Acknowledgments
Acknowledgments
This volume represents a progress report in the evolution of neuropsychiatry and of the authors' understanding of neuropsychiatric disease and treatment. As such it is another step in the long march toward understanding central nervous system function and disease. Many have contributed to our passion for neuropsychiatry; chief among these is the late D. Frank Benson, M.D. Dr. Benson's enthusiasm for behavioral neurology, neuropsychiatry, and for teaching had a profound and lasting influence on the authors and his vision of neuropsychiatry permeates the pages of this book. Others to whom we owe a debt of gratitude for their support or instruction include Martin Albert, Michael Alexander, Simeon Locke, Paul Yakovlev, Robert Collins, Arthur Toga, and John Mazziotta. Our colleagues in the Behavioral Neuroscience program at UCLA also have contributed importantly to our ability to practice neuropsychiatry and develop this volume; among these are Donna Masterman, Tiffany Chow, Mario Mendez, Bruce Miller, David Sultzer, Seth Weingarten, Ron Saul, and Bud Ullman. National and international colleagues too numerous to list have encouraged us through their enthusiasm and by sharing their knowledge. The authors have benefited greatly from the stimulating interaction provided by the many fellows of the UCLA Dementia and Behavioral Neuroscience Research Fellowship as well as the international trainees who have been members of our training program. Financial support from the National Institute on Aging for our Alzheimer's Disease Center, from the State of California for our Alzheimer's Disease Research Center of California, and from the Willard K. and Patricia S. Shaw Memorial Fund has contributed importantly to our endeavors. The tremendous
financial and emotional support provided by the late Katherine Kagan of the Sidell -Kagan Foundation was instrumental in allowing us to advance our research programs. Finally, without the love and support of our families, none of the activities encompassed within this book would have been possible. Inese and Juliana (wife and daughter of J.L.C.) and Susan and Leda (wife and daughter of M.S.M.) have been unfailing in the support and sacrifice required for the time devoted to research, teaching, and writing on which this volume is based.
TABLE OF CONTENTS
[+] Chapter 1 - Introduction [+] Chapter 2 - Neurobiological Basis of Behavior [+] Chapter 3 - Neuropsychiatric Assessment [+] Chapter 4 - Treatment of Neuropsychiatric Disorders [+] Chapter 5 - Principles of Neuropsychiatry [+] Chapter 6 - Disorders of Speech and Language [+] Chapter 7 - Memory Disorders [+] Chapter 8 - Visuospatial, Visuoperceptual, and Right Hemisphere
Disturbances
[+] Chapter 9 - Frontal Lobe Dysfunction [+] Chapter 10 - Dementia [+] Chapter 11 - Delirium [+] Chapter 12 - Psychosis, Delusions, and Schizophrenia [+] Chapter 13 - Hallucinations [+] Chapter 14 - Disturbances of Mood and Affect [+] Chapter 15 - Apathy and Other Personality Disorders [+] Chapter 16 - Obsessive-Compulsive Disorder and Syndromes with
Repetitive Behaviors
[+] Chapter 17 - Anxiety Disorders [+] Chapter 18 - Movement Disorders [+] Chapter 19 - Tics, Startle Syndromes, and Myoclonus [+] Chapter 20 - Catatonia, Motoric Manifestations of Psychiatric Illnesses, and
Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 1 - Introduction
Chapter 1 Introduction
All human experience, emotion, motivation, behavior, and activity are products of brain function. This basic premise underlies contemporary approaches to understanding human behavior and the effects of brain dysfunction in the clinical discipline of neuropsychiatry. This approach does not deny the important influence of interpersonal relationships, social and cultural influences, and the modulating influence of the environment on human emotion and behavior; the brain based approach acknowledges that all of these environmental influences are mediated through central nervous system (CNS) structures and function. For every deviant environmental event there will be a corresponding change in CNS function, and when CNS function is altered there will be corresponding changes in the behavior or experience of the individual. Neuropsychiatry is the clinical discipline devoted to understanding the neurobiological basis, optimal assessment, natural history, and most efficacious treatment of disorders of the nervous system with behavioral manifestations. 1 Neuropsychiatry embraces the rich interplay between the environment and the nervous system both during the development of the individual and throughout adulthood and old age. Neuropsychiatrists seek to understand the disorders of the CNS responsible for abnormal behavior. This volume presents a contemporary view of neuropsychiatry and the advances in neuroscience applicable to understanding and interpreting human behavior. This introductory chapter summarizes themes and perspectives
that provide the philosophical and clinical framework for the book.
Advances In Neuroscience
The last few decades have seen an incredible advance in neuroscience applicable to neuropsychiatry. Studies in genetics and molecular biology have revealed mutations that cause major neuropsychiatric disturbances including familial Alzheimer's disease, familial Parkinson's disease, Huntington's disease, Wilson's disease, and many developmental disorders. Risk genes for some conditions such as Alzheimer's disease have also been identified. These do not by themselves cause disease, but they increase the likelihood that individuals will express the disorder in the course of their lifetime. Genetic testing, available for many conditions, allows P.2 specific diagnoses or risk assessments and raises important ethical issues for neuropsychiatry. Identification of a mutation in an asymptomatic individual, for example, reveals critical aspects of his or her ultimate fate, knowledge not to be taken lightly. Advances in developmental neurobiology have informed our understanding of congenital malformations of the CNS, many with severe associated behavioral disturbances. Progress also has been made in understanding hyperactivity -attention deficit disorder, autism and pervasive developmental disorders, and childhood epilepsies and movement disorders. In addition, there has been an evolving integration of developmental and maturational perspectives to allow a life span approach to human neurological disease and neuropsychiatric conditions. Even late -onset disorders such as Alzheimer's disease interact with educational level and native intellectual abilities to determine the time of onset and duration of the adult disorder. 2 Comprehensive understanding of any neuropsychiatric illness requires a careful developmental history and integration of life span information. Advances in neuroimaging have been important in the growth of neuropsychiatry. Structural imaging techniques such as magnetic resonance imaging (MRI) have revealed,
for instance, that white matter abnormalities are present in many patients with late -onset depressions. 3 The occurrence of white matter disturbances and basal ganglia lesions diminishes these patients' responsiveness to pharmacotherapy and increases the likelihood of confusion following electroconvulsive therapy. 4 , 5, 6 Thus, imaging findings have treatment implications and imaging results are increasingly incorporated in neuropsychiatric assessment and treatment planning. Functional imaging such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) provide critical information about brain function in neuropsychiatric illness. Patients with Alzheimer's disease, for example, have reduced glucose metabolism in the parietal lobes; when psychosis and agitation are present, frontal and anterior temporal hypometabolism is also evident. 7 ,8 Positron emission tomography has shown disturbances in frontal lobe activation in patients with schizophrenia, 9 as well as orbitofrontal hypermetabolism in patients with obsessive -compulsive disorder. 1 0 Functional MRI (fMRI) provides a !stress test!! for the CNS, revealing abnormal patterns of activation in patients with brain disease. This approach may eventually prove sensitive to the earliest changes in incipient neurological conditions. Magnetic resonance spectroscopy provides information about the chemical composition of brain structures, reveals abnormalities in individual diseases, and may provide a window on CNS concentrations of some therapeutic agents. 1 1 Magnetic resonance angiography (MRA) allows noninvasive study of the brain vasculature and MR perfusion studies have shown remarkable sensitivity to the occurrence of recent ischemic brain injury. Together these technologies provide a diverse armamentarium of techniques for diagnosing CNS disease and understanding their pathophysiology. Progress in neuropsychology also informs contemporary neuropsychiatry. There have been substantial advances, for example, in recognizing and characterizing memory subroutines including registration, consolidation, and retrieval. 1 2 Focal brain lesions and degenerative disorders differentially affect these processes, depending on the brain
structures involved. Similarly, the !frontal lobe syndrome!! has been divided into medial frontal, orbitofrontal, and dorsolateral prefrontal types, and neuropsychological mechanisms mediated by the dorsolateral prefrontal cortex including planning, sequencing, implementing, executing, and monitoring of behaviors have been identified. 1 3 Attentional mechanisms, visuospatial processes, and language have been studied and the results integrated into the practice of neuropsychiatry. Many diseases are much better understood as a result of the application of basic science. Idiopathic neuropsychiatric illnesses such as schizophrenia have been the subject of intensive scientific scrutiny. Regional changes in brain structure have been identified and genetic and environmental contributors to the syndrome discovered. The pathophysiology of Alzheimer's disease has been revealed in substantial detail including processing of the amyloid precursor protein to free amyloid " protein leading to neurotoxicity and the formation of neuritic plaques. 1 4 Abnormal accumulation of -synuclein is recognized as characteristic of Parkinson's disease and related conditions. 15 This improved understanding of basic disease processes facilitates identification and interpretation of the clinical syndromes and provides a basis for the development of therapeutic agents. Marked progress has been made in pharmacotherapy. Neurology and neuropsychiatry have changed from clinical disciplines with few available treatments to clinical arenas with major neurotherapeutic options. Epilepsy, migraine, multiple sclerosis, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, psychosis, depression, obsessive -compulsive disorder, anxiety, sleep disorders, substance use disorders, and eating disorders have all been the subjects of development of new pharmacotherapeutic agents capable of P.3 ameliorating disease -related symptoms and restoring more normal function. The advances in all of these areas of neuroscience provide the basis for the update of neuropsychiatry developed in this volume.
Foundations Of Neuropsychiatry
Neuropsychiatry includes both the psychiatric manifestations of neurologic illness and neurobiology of idiopathic psychiatric disorders. Two disciplines have been instrumental in the development of neuropsychiatry!biological psychiatry and behavioral neurology. Biological psychiatry received its primary impetus from the success of biological treatment of psychiatric disorders. Drugs that increase the levels of monoamines and serotonin relieve depressive symptoms and drugs that block dopamine receptors reduce psychosis. These observations imply (but do not prove) that transmitter disturbances are involved in the mediation of these behavioral disorders. In biological psychiatry, the chemistry of behavior is emphasized, with increasingly precise characterization of transmitter receptors and signal transduction mechanisms. 16 Biological psychiatrist, however, have not emphasized a neuroanatomy of behavior or the relationship of focal lesions of the CNS to behavioral disorders. Behavioral neurology is the other cornerstone of neuropsychiatry. This discipline was revived in the 1960s by Norman Geschwind with his description of the disconnection syndromes. 17 Aphasias and amnesias resulting from focal brain injuries were characterized and hemispheric specialization was investigated in patients with injuries to the corpus callosum. Drawing heavily on techniques derived from neuropsychology, behavioral neurology provided detailed descriptions of language disorders, memory disturbances, visuospatial abnormalities, agnosias, and dementias associated with focal brain damage or degenerative CNS disease. In behavioral neurology, a probing mental status examination is used to aid in neuroanatomical interpretation of deficit syndromes. Behavioral neurologists have investigated the deficit disorders of aphasia, amnesia, agnosia, alexia, agraphia, and amusia but do not focus on the positive symptoms of neuropsychiatric disorders such as depression, mania, personality alterations, or obsessive -compulsive disorder associated with brain dysfunction. Thus neither biological psychiatry nor behavioral neurology provides a comprehensive view of brain -behavior
relationships. Neuropsychiatry draws on both disciplines in addition to recent advances in neuroscience to provide a comprehensive understanding of the relationship of brain and behavior.
Terminology
The words organic and functional are eschewed in this volume as they are misleading in their assumptions. Many disorders called !organic,!! such as epilepsy, produce significant functional alterations with few or no structural abnormalities, and many !functional!! illnesses, such as psychosis and depression, are the products of neurologic disorders. Although imperfect, the term idiopathic will be used to describe psychiatric disorders whose etiologies and pathophysiology have yet to be revealed, and neurologic or toxic -metabolic will be used when specific types of brain disorders have been identified that account for behavioral changes. These terms escape some of the objectionable assumptions associated with the traditional terminology.
Clinical Approach
The focus of this volume is on clinical utility and the relationship of clinical observations to the evolving neuroscience. Assessment of signs and symptoms, differential diagnosis, application of technology to explore diagnostic hypotheses, and pharmacotherapy are emphasized. The mental -status examination is borrowed largely from behavioral neurology and is used to help characterize a patient's attention, verbal output, memory, constructional skills, and executive abilities. This approach is augmented by interview techniques taken from psychiatry that emphasize anamnesis and help disclose subjective phenomena such as delusions, hallucinations, and intrusive thoughts. Mental status examination is complemented by elementary neurological and general physical examinations. Occasionally objections are raised to the probing mental status examination as being offensive to patients and insufficiently sensitive to their feelings of failure. A detailed mental status examination can be successfully achieved, however, by an expert clinician without the loss of respect for the patient's sense of vulnerability and exposure. Most errors in neuropsychiatric diagnosis are of omission, not
commission. Dynamically oriented psychiatrists and psychotherapists may object to the absence of dynamic considerations in the neuropsychiatric approach proffered here. Some have charged that neuropsychiatry attempts to turn a brainless psychiatry into a mindless neurology. The past excesses of classical analytic psychiatry are P.4 now apparent, however, and balance is being restored with respect to the relative spheres of psychological, environmental, genetic, and structural factors in behavior. In neuropsychiatry the emphasis is an identification of diseases and on alliance building with patients and families to maximize the success of therapeutic interventions. Dynamic psychological issues emerge during the process of this alliance, and must be considered in both the interpretation of the patient's symptoms and the response to therapy.
Uniqueness Of Neuropsychiatry
The care of patients with neuropsychiatric illness differs from that provided to patients with medical illnesses. Brain disorders, unlike their medical counterparts, are manifest by alterations in the behavior and experience of the victim; in many ways they are disorders of the person rather than disorders that happen to the individual. Patients illness may have pneumonia or congestive heart failure, but those with neuropsychiatric illness are demented, psychotic, or depressed. The difference in the way neuropsychiatric disturbances affect patients necessitates a change in the way the clinician responds. Many neuropsychiatric illnesses, although treatable, may be only partially reversible. After head trauma or stroke or following the onset of a schizophrenic illness, a patient is unlikely to be completely restored to the same !person!! as he or she was in the premorbid state. Thus, the patient has become a !new!! person. The clinician is obligated to respect this change and is responsible for helping the patient and family formulate goals appropriate to the new situation. The patient's goals must be reconciled with the limits imposed by altered brain function while not succumbing to the temptation to allow a disability to unnecessarily circumscribe the patient's life
opportunities. Knowledge of the course and impact of neuropsychiatric illness will aid the clinician in brokering appropriate expectations. Guidance and support provided by the clinician will often be as important as the medications dispensed. In addition to the role of the neuropsychiatrist in treating patients and advising patients and their families, the practice of neuropsychiatry affords an exciting opportunity to learn from the patient. The victim of a neuropsychiatric illness is traversing an uncharted landscape and each pilgrim -patient is a source of information that can be utilized to help guide others with CNS disease. The patient's observations, descriptions, motoric changes, and reported experiences are invaluable information that contributes to the science of neuropsychiatry.
that determine choice prohibit complete modeling of human action and make fulfillment of a strict determinist position as proven by the predictability of behavior impossible. Although many aspects of CNS structure and, consequently, CNS function and behavior are genetically influenced, it is obvious that behavior is modified by development and experience and that there is a constant commerce between the CNS and the environment. Genetics is not fate except in the cases of fatal mutations. Behavior is a summary product of genetic, historical, experiential, and environmental influences, and CNS structure provides a physical basis for integrating and mediating these multiple behavioral determinates. Once this potential for environmental influence and preference-motivated behavior is accommodated within the monist proposition, the free will objection to monism loses force. Likewise, the ability to integrate ongoing experience and environmental interaction with monism deflates the objection that monism inevitably leads to treating human beings like machines. Indeed, monism can provide the basis for increasing respect for human individuality by emphasizing that each individual is the product of a unique blend of genetic, experiential, and environmental influences all mediated through a private P.5 CNS structure. A genetically determined CNS modified and enriched by ongoing environmental interactions unique to each individual provides the basis for human individuality. Reductionism to molecular neuropsychiatry is not the necessary outcome of the monist position; an integrative neuropsychiatry is required to understand the complex interplay of genetic and environmental influences on human behavior.
through speech and writing. The generation of public knowledge is represented as history. The record of private knowledge is biography. Public knowledge, when committed to memory, is semantic, or factual memory, whereas private knowledge comprises episodic memory (Chapter 7 ). Public knowledge includes science, mathematics, history, philosophy, politics, sociology, psychology, law, business, and language. Public knowledge also informs shared social perceptions as part of a culture. The historical continuity of personal knowledge comprises the !self.!! As long as it is personal, it remains subjective and instantaneous; it becomes continuous history only when written or verbalized and made public. Ongoing private knowledge is contained in working memory (Chapter 9 ). Personal knowledge is heavily infused with emotion, including motivation, intention, perception of threat or support, and subjective emotional states such as euphoria, depression, anxiety, and irritability. Public knowledge is without emotion until it is reexperienced privately. Private knowledge and awareness of one's own consciousness is the basis for empathy and the assumption that others are experiencing a similar conscious state and subject to similar emotions. This self -awareness and the related possibility of empathy are heavily dependent on frontal lobe function (Chapter 9 ), are compromised in frontal degenerative disorders (Chapter 10 ) and other frontal disturbances, and reflect the unique expansion of the frontal cortex in humans. Study of brain -behavior relationships and neuropsychiatric syndromes provides insight into abstract concepts such as self and culture, allows understanding of the neurobiological basis of human behavior both individually and in the context of an evolving culture, and allows construction of a neuroepistemology.
Challenges Of Neuropsychiatry
Many influences are propelling neuropsychiatry to the forefront of neurology, psychiatry, and neuroscience. 1 8 The graying of the population and the increase in the number of individuals with age -related brain disease increases the prevalence of neuropsychiatric illness. Alzheimer's disease, Parkinson's disease, and stroke are all major age -related disorders with profound neuropsychiatric consequences.
Developmental disorders are also increasing in society. As more premature infants are sustained, the number of individuals who are developmentally impaired increases. Subnormal intelligence, behavior and conduct disorders, and seizures are among the adverse long-term neuropsychiatric outcomes observed among individuals who survive premature birth. Malnutrition is a worldwide phenomenon associated with lowered I.Q. and deficits in language, personal, and social skills. As the human immunodeficiency virus (HIV) global epidemic continues, the prevalence of HIV is increasing in many countries; HIV encephalopathy is associated with mood disorders, psychosis, hallucinations, executive dysfunction, agitation, and apathy. Substance abuse is second only to anxiety as the most common psychiatric disorder in the United States. Substance abuse causes both acute and chronic changes in brain function and produces a wide variety of neuropsychiatric syndromes including acute intoxication, dependence, delirium, dementia, psychosis, mood disorders, anxiety, and personality changes. Excessive ingestion of alcohol during pregnancy may lead to the fetal alcohol syndrome, characterized by mild to severe mental retardation, irritability, hyperactivity, and distractibility. Head trauma is another major cause of neuropsychiatric disability. Management of the behavioral consequences of head injuries associated with traffic accidents, wars, domestic violence, and urban aggression requires substantial neuropsychiatric expertise. Criminal behavior is a major social concern and is more frequent among neuropsychiatrically ill individuals than among those without CNS disease. The proliferation of neurotoxic compounds worldwide exposes developing and mature individuals to a variety of pollutants and contaminants capable of altering CNS function and producing neuropsychiatric symptoms. Institutional populations, including individuals in nursing homes, prisons, chronic mental hospitals, and residences for the mentally retarded, all contain substantial numbers of individuals with neuropsychiatric disorders and require the attention of those with neuropsychiatric skills. Thus, there are many situations where optimal care and management require neuropsychiatric expertise, and the number of victims of neuropsychiatric illness is growing. P.6
Conclusions
Neuropsychiatry is a clinical discipline applicable to individual patients with specific neuropsychiatric signs and symptoms; it is relevant to the most pressing problems of contemporary human existence. The brain is the organ of all mental life, and the increasing revelation of brain processes underlying behavior provides insight into mental illness, neuropsychiatric disorders, and normal cognition and emotion. A dehumanizing, reductionistic, and mechanical view of humankind is not the obligatory impact of neuroscience on societies; rather, neuroscience can enhance our appreciation of each individual by revealing the neurobiologic underpinnings of the complex interplay of structural, chemical, genetic, environmental, developmental, social, and cultural influences on behavior. Neuropsychiatry enhances intellectual commerce among related disciplines (e.g., psychiatry, neurology, and neuroscience), facilitates the translation of scientific advances into clinical practice, and serves patient care.
References
1. Cummings JL, Hegarty A. Neurology, psychiatry, and neuropsychiatry. Neurology 1994;44:209!213.
2. Cummings JL, Booss J, et al. Dementia Identification and Assessment: Guidelines for Primary Care Practitioners. Washington, DC: U.S. Department of Veterans Affairs and the University Health System Consortium, 1997.
3. Coffey CE, Figiel GS, et al. Subcortical hyperintensity on magnetic resonance imaging: a comparison of normal and depressed elderly subjects. Am J Psychiatry 1990;147:187!189.
4. Figiel GS, Krishnan KRR, et al. Radiologic correlates of antidepressant -induced delirium: the possible significance of basal -ganglia lesions. J Neuropsychiatry Clin Neurosci 1989;1:188!190.
5. Figiel GS, Coffey CE, et al. Brain magnetic resonance imaging findings in ECT -induced delirium. J Neuropsychiatry Clin Neurosci 1990;2:53!58.
6. Hickie I, Scott E, et al. Subcortical hyperintensities on magnetic resonance imaging: clinical correlates and prognostic significance in patients with severe depression. Biol Psychiatry 1995;37:151!160.
7. Hirono N, Mega MS, et al. Left frontotemporal hypoperfusion is associated with aggression in patients with dementia. Arch Neurol 2000;57:861!866.
8. Mega MS, Lee L, et al. Cerebral correlates of psychotic symptoms in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2000;69:167!171.
9. Weinberger DR, Berman KF, Illowsky BP. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. Arch Gen Psychiatry 1988;45:609!615.
10. Baxter LR, Phelps ME, et al. Local cerebral glucose metabolic rates in obsessive -compulsive disorder: A comparison with rates in unipolar depression and normal controls. Arch Gen Psychiatry 1987;44:211!218.
11. Henry ME, Frederick BD, et al. Magnetic resonance spectroscopy in psychiatric illness. In: Dougherty DD, Rauch SL, eds. Psychiatric Neuroimaging Research, Contemporary Strategies. Washington, DC: American Psychiatric Publishing, 2001:291!333.
12. Squire LR, Zola -Morgan S. The medial temporal lobe memory system. Science 1991;253:1380!1386.
13. Boone KB. Neuropsychological assessment of executive functions!impact of age, education, gender,
intellectual level, and vascular status on executive test scores. In: Miller BL, Cummings JL, eds. The Human Frontal Lobes, Functions and Disorders. New York: The Guilford Press, 1999:247!260.
14. Beyreuther K, Masters CL. Alzheimer's disease: physiological and pathogenetic role of the amyloid precursor protein (APP), its AB-amyloid domain and free AB-amyloid peptide. In: Beyreuther K, Christen Y, Masters CL, eds. Neurodegenerative Disorders: Loss of Function Through Gain of Function. New York: SpringerVerlag, 2001:97!117.
15. Lansbury PTJ. The role of a-synuclein in Parkinson's disease: a biophysical analogy to AB and Alzheimer's disease. In: Lee VMY, Trojanowski JQ, Buee L, Christen Y, eds. Fatal Attractions: Protein Aggregates in Neurodegenerative Disorders. New York: SpringerVerlag, 2000:1!9.
16. Trimble MR. Biological Psychiatry. Chichester: John Wiley & Sons, 1996.
Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 2 - Neurobiological Basis of Behavior
FIGURE 2.1 (A) Yakovlev's model of the three phylogenetic zones of brain development, as reflected by myelogentic stages. 151 BLTh, basolateral thalamus; Fx, fornix; Hppc, hippocampus; Hppc Rd, hippocampal radiations; Hth, hypothalamus; Mth, medial thalamus; PMTh, paramedial thalamus. (B) MacLean's rendition of this evolutionary layering produced a triune brain. 152
aversion or attraction to stimuli dominates paleocortical function. A second center of cortical development grew out of the archicortex of the hippocampus and spread posteriorally through the entorhinal, posterior parahippocampal regions, and through the cingulate. The archicortex is largely concerned with the integration of information from different sensory modalities!the first step away from thalamic control, as seen in reptiles, toward cortical dominance. The hippocampal -centered spread emphasizes pyramidal cells and gives rise to the medial supplementary sensory and motor areas. In addition to the hippocampal archicortex this second limbic arm includes the cingulate gyrus, which is composed of four functional centers: 3 the visceral, cognitive, skeletomotor, and sensory processing regions (Fig. 2.3 ). The visceral control region, below the corpus
TABLE 2.1. Yakovlev's Three-layered Model of Brain Organization, Structure, and Function 1
Inner Layer
Intermediate Layer
Outer Layer
Neurons
Short, unmyelinated
Organization
Diffuse
Ganglia, allocortex
Isocortex
Evolution
Invertebrate to reptile
Mammal to primate
Structure
Reticular core
Basal ganglia
Cranial nerves
Limbic thalamus
Periaqueductal gray
Olfactory paleocortex
Corpus callosum
Hypothalamus
Hippocampal archicortex
Association cortex
Function
Consciousness
Motor synergistic
Motor precision
Metabolism
Arousal, motivation
Ppraxis
Respiration
Mood, affect
Language
Circulation
Personality
Gnosis
P.9
FIGURE 2.2 The paralimbic trends of evolutionary cortical development. The orbitofrontal-centered belt (red) extends into the subcallosal cingulate, temporal polar region, and the anterior insula (not shown). The hippocampal -centered trend (blue) extends its wave of cortical development dorsally through the posterior and anterior cingulate. Adapted from Mega et al. (1997). 50
callosum, overlaps with the medial orbitofrontal limbic division. By virtue of the two limbic divisions' connections and the parallel development of other brain regions linked to the two limbic centers, the behavioral evolution of mammals mirrored the progressive trend toward cytoarchitectural complexity emanating from both the orbitofrontal and hippocampal centers. 4 Mesulam has described these two allocortical systems as paralimbic belts. 5 Table 2.2 provides an overview of the orbitofrontal and hippocampal paralimbic divisions.
FIGURE 2.3 The four functional divisions of the cingulate: (1) the visceral effector region; (2) the cognitive effector region; (3) the skeletomotor effector region; and (4) the sensory -processing region. Adapted from Mega and Cummings (1996). 3
P.10
Orbitofrontal Division
Hippocampal Division
Evolutionary trend
Paleocortical
Aichicortical
Cell type
Granule cell
Pyramidal cell
Structures
Amygdala
Hippocampus
Anterior parahippocampal
Posterior parahippocampal
Insula
Retrosplenium
Temporal pole
Posterior cingulate
Infracallosal cingulate
Supracallosal cingulate
Function
Implicit processing
Explicit processing
Visceral integration
Memory encoding
Appetitive drives
Skeletomotor effector
Social awareness
Attention al systems
Mood
Motivation
FIGURE 2.4 The two divisions of the orbitofrontal cortex. The medial division is in red and includes the gyrus rectus and medial orbital gyrus of area 11 in human. The lateral division is in green and includes the lateral orbital gyrus of area 11 and the medial inferior frontal gyrus of areas 10 and 47 in humans.
connections with the amygdala (more dorsal and caudal than the medial orbitofrontal cortex). The dorsal portion of the basal amygdala is the source of projections to the ventral visual processing system in the inferior temporal cortex. Reciprocal connections also occur with the supracallosal cingulate areas 24 and 32, a region that assists in the dorsolateral attentional system and effects cognitive
engagement. The auditory association cortex of dorsolateral temporal pole area 38 is also reciprocally connected to the lateral orbitofrontal cortex. The lateral orbital cortex is a gateway for highly processed sensory information into the orbitofrontal paralimbic center. Reciprocal connections with the inferior temporal cortex area 20, the last processing step for the ventral visual system devoted to object feature analysis, and the supplementary eye fields in the dorsal portion of area 6 highlight the control over sensory processing occurring in the lateral orbitofrontal cortex. The major cortical regions reciprocally connected with the lateral portion of the orbitofrontal paralimbic division are shown in Table 2.3 and Figure 2.5 .
TABLE 2.3. Major Reciprocal Connections for Lateral and Medial Portions of Orbitofrontal Paralimbic Division
P.12
FIGURE 2.5 Major cortical reciprocal areas connected to the medial portion (shown in red), and lateral portion (shown in green) of the orbitofrontal limbic division.
posterior cingulate focus on the dorsolateral cortex. The posterior cingulate has major reciprocal connections with the posterior parahippocampal and perirhinal areas 36 and 35, as well as the presubiculum. These connections modulate the multimodal efferents entering the entorhinal layer III cells that give rise to the perforant pathway into the hippocampus. The dorsal visual system of the inferior parietal lobe 7a, dedicated to spatial processing, 14 and the frontal eye fields in area 8 also have bidirectional connections with the posterior cingulate. Reciprocal connections with lateral prefrontal area 46 allow an interaction between executive and sensory/mnemonic processing that may mediate perceptual working memory tasks. The major reciprocal connections of the posterior cingulate are shown in Table 2.4 and Figure 2.6a . The orbitofrontal and hippocampal paralimbic belts intersect in the infracallosal cingulate region of Brodmann area 24. Cytoarchitectural development progresses from anterior to posterior and from inferomedial to dorsal across area 24. 15 The major pathway for information flow is the cingulum bundle. The cingulum contains the efferents and afferents of the cingulate to the hippocampus, basal forebrain,
amygdala, and all cortical areas, as well as fibers of passage between the hippocampus and prefrontal cortex, and from the median raph to the dorsal hippocampus. 16 Robust connections with the sensory processing region of the posterior cingulate overlap with the reciprocal amygdalar connections present in the anterior cingulate. Thus, area 24 is a nexus in the distributed networks subserving internal motivating drives and externally directed attentional mechanisms. 17 Papez's initial conception of the cingulate as the !seat of dynamic vigilance by which emotional experiences are endowed with an emotional consciousness !! 8 is supported by this anatomic organization. The integration of both divisions of limbic processing in the anterior cingulate influences the dorsolateral executive cortex as Papez predicted: !the sensory excitations which reach the lateral cortex through the internal capsule receive their emotional coloring from the concurrent processes of hypothalamic origin which irradiate them from the gyrus cinguli.!!8
TABLE 2.4. Major Reciprocal Connections for Posterior and Anterior Cingulate Cortex
Posterior Cingulate
Anterior Cingulate
Presubiculum 140 ,
148
144 ,
139 ,
P.13
FIGURE 2.6 Major cortical reciprocal areas connected to the posterior (A; green) and anterior (B; blue) cingulate cortex.
Major reciprocal connections with the cognitive effector region (supracallosal areas 24 and 32) are with the basal amygdala (magno - and parvocellular divisions). The amygdala provides internal affective input to areas 24 and 32. Prefrontal areas 8, 9, 10, and 46 also have reciprocal connections. The anterior cingulate is more developed in its cytoarchitecture and has well -developed connections with phylogenetically more recent neocortex of dorsolateral prefrontal areas 8, 9, 10, and 46 devoted to executive function. Areas reciprocally connected to the anterior cingulate share a general similarity with the orbitofrontal center and include the caudal (dysgranular) orbitofrontal area 12 in monkeys (equivalent to area 47 in humans), which provides processed sensory information concerning object feature analysis; the anterior inferior temporal pole area 38, an auditory association area of the superior temporal gyrus; and the rostral (agranular) insula, a transitional paralimbic region integrating visceral alimentary input with olfactory and gustatory afferents, 18 while reciprocal connections with the anterior parahippocampal areas 35 and 36 allow attentional influence over multimodal sensory afferents entering the hippocampus. The major reciprocal connections of the anterior cingulate are shown in Table 2.4 and Figure 2.6b .
Limbic Chemoarchitecture
Neurotransmitters central to limbic processing arise from the inner core of Yakovlev 1 and are modulatory in action. Serotonin, acetylcholine, dopamine, and norepinephrine are the primordial modulating transmitters, in contrast to the fast signaling transmitters concentrated in the outer layer (e.g., aspartate, glutamate, and " -aminobutyric acid). The limbic distribution of the neuromodulators is currently being mapped and their receptor subtypes are targeted with !designer! ! Pharmaceuticals.
FIGURE 2.7 Subcortical limbic structures involved in both the anterior cingulate and orbitofrontal-subcortical limbic circuits at the level of the caudate and putamen (A), globus pallidus (B), and thalamus (C). Red, anterior cingulate members; green, orbitofrontal members; blue, dorsolateral frontal members.
Serotonergic System
Serotonin (5 -hydroxytryptamine [5 -HT]) is supplied by projections from the raph nuclei. Synapses are well defined in the !basket system!! innervating the limbic belt from M fibers of the median raph (area B 8 ), while diffusely projecting D fibers to frontal cortex have indistinct synapses on the !varicose system!! arising from the rostrolateral portion of area B 7 in the dorsal raph. Of the many serotonin receptor subtypes, the 5 -HT 1A and 5 -HT 3 subtypes predominate in the limbic belt, while the 5!HT 2 subtype predominates in neocortex. The 5 -HT 1A and 5 -HT 2 receptors are G protein coupled to control cyclic adenosine monophosphate (cAMP) and open K + P.15
TABLE 2.5. The Subcortical Limbic Structures and the Related Cortical Limbic Regions
Amygdala
Striatum
Pallidum
Thalamus
Orbitofrontal cortex
Ventromedial caudate
Dorsomedial GP i , Rostromedial SN r
(mc)
Dorsal caudate
Dorsolateral GP i
Anterior cingulate
Ventral striatum
Ventral pallidum
GP i , globus pallidus interna; mc, magnocellular; pc, parvocellular; SN r , substantia nigra reticulata.
channels (5!HT 1A agonist: buspirone), or stimulate phosphoinositide hydrolysis via phospholipase C, a probable antagonistic focus for lithium, 29 and close K + channels (5 !HT 2 agonist: LSD; antagonist: clozapine). The 5!HT 3 receptor (antagonist: ondansetron) is a ligand -gated cation channel that also modulates the release of acetylcholine and dopamine. Serotonergic systems are involved in mood disorders and obsessional syndromes. Patients dying from violent suicide have increased serotonin receptors in the frontal cortex 30 while depressed patients at risk for suicide have decreased serotonergic metabolites in their cerebral spinal fluid. 31 Parkinson's patients with depression and frontal cognitive impairment, when successfully treated with selective serotonin reuptake inhibitors (SRIs) have an increase in metabolism in the basal medial frontal region on [ 18 F] fluorodeoxyglucose positron emission tomography (FDG PET). 32 The anatomy of depression implicates the medial orbitofrontal cortex in general and the serotonin system in particular.
Cholinergic System
Acetylcholine has two sources supplying the forebrain: one arising in the brainstem, the pedunculopontine and laterodorsal tegmental system, and the other from the basal forebrain, which includes the septum (Ch1), the vertical (Ch2) and horizontal (Ch3) diagonal band of Broca, and the basal nucleus of Meynert (Ch4). 33 The brainstem cholinergic system supplies the basal ganglia and most of the thalamus, while cholinergic fibers from the basal forebrain innervate portions of the ventroanterior, mediodorsal, and midline thalamus as well as the limbic structures and neocortex. Muscarinic (M 1!5 ) and nicotinic (N 2!8 , ! 2!4 ) receptors occur throughout the brain with the M 1 receptor predominating in the hippocampus. The muscarinic receptors are G protein coupled while nicotinic receptors are ligand gated ion channels. Acetylcholine facilitates thalamic activation of the cortex and assists in the septal hippocampal pathway supporting mnemonic function. The basal nucleus of Meynert has an organized cortical
projection pattern; by undergoing degeneration early in Alzheimer's disease, its cortical targets, even if spared by plaques or tangles, may become deactivated. Ablation of the posterior basal nucleus of Meynert may result in hypometabolism on FDG -PET in the parietal cortex due to the disconnection of cholinergic activation. 34 Behavioral improvement in patients with Alzheimer's disease, particularly a resolution of apathy 35, 36, 37 associated with anterior cingulate hypoperfusion, 38, 39 occurs with cholinesterase inhibitor therapy. General cognitive improvement may also occur with drugs promoting cholinergic function. 40, 41, 42, 43
Dopaminergic System
Dopamine is manufactured in and projected from the substantia nigra pars compacta. The ventral tegmental area and medial portion of the ventral tier of the substantia nigra pars compacta provide dopaminergic innervation to the cortical and subcortical limbic forebrain. 44, 45, 46 The severity of dementia in Parkinson's disease is related to decreased cortical dopamine 47, 48 and ventral tegmental area cell loss. 49 There are two dopamine receptor families. The D 1 family (D 1 and D 5 antagonist: bromocriptine) are G protein coupled and stimulate adenylyl cyclase; The D 2 family D 2!4 antagonist: butyrophenone neuroleptics) are probably all G protein coupled as well and inhibit adenylyl cyclase. The D 5 subtype is distributed to limbic regions similar to those for the D 4 receptor, which may have a greater concentration in the amygdala and frontal cortex. The D 5 receptor is found in the hippocampus and hypothalamus, while the D 2 subtype is found in sensorimotor striatal regions. This regional difference in dopamine receptor subtypes has instigated P.16 the development of dopamine receptor antagonists specific to limbic regions, such as the D4 antagonist clozapine, with fewer motor side effects for the treatment of psychosis. Dopaminergic innervation of the anterior cingulate may be disrupted with subcortical lesions of the medial forebrain bundle or the ventral pallidum, resulting in profound apathy or even akinetic mutism, which may respond to agents such as bromocriptine. Motivation and attention rely on a distributed network involving the cingulate, dorsolateral prefrontal, and inferior parietal lobule; a balance between dopamine and norepinephrine may subserve the normal functioning of this distributed attentional network.
Norepinephrine System
Norepinephrine is projected from a dorsal pathway that arises from the locus coeruleus to the entire cortex and hippocampus as well as to the spinal cord and cerebellum; a ventral pathway arises below the locus coeruleus to innervate the brainstem and hypothalamus. All the norepinephrine receptors are linked to G proteins. The 1A
!C
receptors inhibit adenylyl cyclase, while the # 1!3 receptors stimulate adenylyl cyclase. In the brain, # 2 receptors predominate in the cerebellum, while the ! 1 receptor is found cortically. A balance between the levels of norepinephrine and dopamine may set the signal -to -noise ratio of the attentional system, enabling the selective filtering of sensory stimuli. Attention deficit disorders, either congenital or acquired by frontal injury, often respond to norepinephrine and dopaminergic pharmacological manipulation with bromocriptine or ritalin.
Clinical Syndromes
A central tenant in the biological basis of behavior is that behavioral disorders should have an anatomy that cuts across disease; a common neuronal network should be affected, regardless of the etiology, when similar signs and symptoms emerge. Neuropsychiatric disorders may be interpreted within a brain -based framework of limbic dysfunction divided into three general groups: decreased, increased, and distorted limbic syndromes. 50 Key imaging findings from patients suffering from these three limbic syndromes aid our understanding of functional brain defects and their resultant neuropsychiatric expressions. Table 2.6 shows the clinical manifestations and regional localization of hypo-, hyper -, and dysfunctional limbic syndromes.
Hypolimbic Syndromes
Hypofunctioning of the medial division of the orbitofrontal cortex is associated with depressive symptoms in patients with Parkinson's disease, Huntington's disease, and primary affective disorders. The medial orbitofrontal cortex and the medial infracallosal region share similar efferent and afferent connections with visceromotor centers and the phylogenetically older magnocellular basolateral amygdala. 3 This amygdalar region may subserve the synthesis of internal mood and visceral functions. Apathy is a common hypolimbic syndrome. Structural or functional lesions of the anterior cingulate above the corpus callosum, or a disconnection of its frontosubcortical circuit, 51 causes a loss of motivation, producing such profound apathy that patients may become akinetic and mute. A loss of motivation may manifest
TABLE 2.6. The Clinical Manifestations and Regional Localization of Hypo-, Hyper-, and Dysfunctional Limbic Syndromes
HYPOLIMBIC SYNDROMES
HYPERLIMBIC SYNDROMES
Syndrome
Region
Syndrome
Region
Syndrome
Region
Depression
Mania
Psychosis
Apathy
Obsessions/compulsions
Orbitofrontal circuit
Social disdecorum
Amnesia
Archicortical structures
Limbic epilepsy
Paleocortical structures
Anxiety/panic
Kl$ver Bucy
Amygdala/temporal pole
Rage
Hypothalamus/amygdala
Utilization behavior
P.17 in the cognitive or motor domains. Anterior cingulate hypofunction produces transcortical motor aphasia 52 or a !loss of the will!! 53 to engage in previously enjoyable pastimes; 54 when functional or structural lesions extend posteriorly into the skeletomotor effector region, a loss of spontaneous motor output will also occur. The hippocampal -cingulate arm of the limbic system unites the dorsolateral spatial attentional network with Papez's circuit, which encodes relevant objects in the environment. Amnesia., the inability to encode new information, occurs when functional or structural lesions affect the hippocampus or other members of Papez's circuit. Encoding defects are present in patients with lesions of the fornix, mammillary bodies, anterior or dorsomedial thalamus, posterior cingulate, and entorhinal cortex!all members of Papez's classical medial circuit. The hypofunctioning of this more phylogenetically recent, archicortical limbic division results in declarative memory abnormalities; episodes of experience can no longer be encoded. This explicit process is contrasted to the implicit stimulus-response associations retained by the amygdala -orbitofrontal limbic arm. When the amygdala, and probably the adjacent temporal cortex, are damaged the Kl$ver -Bucy syndrome 55, 56, 57 may ensue. Patients usually have only a portion of the symptoms associated with the classic lesion seen in nonhuman primates: placidity, hyperorality, hypersexuality, hypermetamorphosis (compulsive environmental exploration), hyperorality, and visual agnosia. Loss of premorbid aggressive tendencies is the common postsurgical sequel of bilateral amygdalectomy in humans. 58 The loss of implicit visceral, or affective, associations with sensory stimuli is the result of human 59 lesions of the amygdala.
Hyperlimbic Syndromes
Mania frequently results from right medial diencephalic lesions 60 that may disrupt hypothalamic circuits or disturb modulating transmitters traversing the adjacent medial forebrain bundle. Mania has also been observed in patients with orbitofrontal lesions, caudate dysfunction in basal ganglia disorders, and lesions of the thalamus. 61, 62, 63 Given the strong hypothalamic -amygdala -orbitofrontal connections and the increase in appetitive drives that often accompany mania, it may reflect hyperfunctioning of this paleocortical limbic arm. Obsessive -compulsive disorder is characterized by involuntary recurrent ego-dystonic thoughts, images, or impulses (obsessions) and the performance of repetitive, stereotyped, involuntary acts or rituals (compulsions). 64 Obsessive -compulsive symptomatology frequently occurs in basal ganglia disorders including parkinsonism, encephalitis lethargica, manganese intoxication, and Gilles de la Tourette syndrome. Surgical resection of the subcallosal cingulate and the medial division of the orbitofrontal cortex provides the best treatment for medically refractory obsessive -compulsive patients. 65 Perhaps the most significant advances in understanding the neuroanatomy of neuropsychiatry have come from functional and structural imaging of both
acquired and idiopathic obsessive -compulsive disorder. As stated above, a central tenant in the biological basis of behavior is that behavioral abnormalities should have an anatomy that cuts across disease; a common neuronal network should be affected, regardless of the etiology, when similar signs and symptoms emerge. Obsessive -compulsive disorder is the best example of this tenant. The search for the structural signature of idiopathic obsessive -compulsive disorder began with computed tomography (CT) evidence of enlarged ventricles 66 and caudate abnormalities. 67 Subsequent studies showed conflicting results, 68, 69, 70, 71 yet an abnormality in frontal and striatal structures, particularly the caudate nucleus, has emerged. 72, 73, 74, 75, 76, 77, 78, 79 Idiopathic obsessive compulsive disorder begins in late adolescence or early adulthood, exhibits a fluctuating course with exacerbations and remissions, and has a tendency to improve gradually over time. 80, 81, 82, 83 There is an increased incidence of neuropsychological abnormalities, enlarged ventricles, and abnormal birth histories in patients with obsessive compulsive disorder, suggesting a role for developmental insult in its pathogenesis. 66, 84, 85 Evidence for developmental abnormalities in idiopathic obsessive -compulsive disorder is also supported by the observation of caudate volume loss in drug-naive children 76 and an enlargement of the thalamus, which normalizes with paroxetine treatment 86 but not behavioral therapy in children. 87 The orbital frontal-striatal circuit is the likely focus of a developmentally aberrant positive feedback loop in idiopathic obsessive -compulsive disorder. 88, 89 Functional imaging data overwhelmingly support abnormal activity in the orbital frontal-subcortical circuit in obsessive compulsive disorder in both resting state 90, 91, 92, 93, 94, 95, 96 and activation studies using provocative stimuli; 97, 98, 99 a reorganization of frontal systems probably occurs that also affects cognitive function and associated activation patterns. 93, 100, 101, 102 The most compelling evidence for determining the neuroanatomic basis of any complex behavior is to demonstrate the functional improvement of an aberrant anatomic network that corresponds to the clinical improvement resulting from successful treatment. This has been accomplished for obsessive -compulsive disorder. P.18 Although initial findings suggested a correlation between an increase in caudate metabolism with successful response to pharmacologic treatment, 90, 103 subsequent studies have confirmed a decrease, or normalization, of the aberrant hyperactivity in the orbital frontal-subcortical circuit with both pharmacologically 104, 105, 106, 107, 108, 109, 110, 111 and behaviorally 106, 110, 111, 112 mediated symptom reduction. Responders to pharmacologic treatment may be different from nonresponders in that increased baseline orbitofrontal activity in some patients may be a compensatory mechanism; in those patients, administration of a serotonin autoreceptor agonist (e.g., sumatriptan) results in decreased frontal activity and exacerbation of symptoms. These patients are then less likely to respond to treatment with a serotonin reuptake inhibitor. 113 Thus, functional neuroimaging can serve as a useful tool in uncovering unique neurobiological mechanisms of disease in neuropsychiatry. The interictal syndrome of Gastaut-Geschwind 114, 115
comprises personality changes that include hypergraphia, hyposexuality, conversationality, obsessionality, and hyperreligiosity or an increased sense of individual destiny. Patients are viscous or !sticky,!! being unaware of social cues for discourse termination. Three subgroups have been described: 116 one with primarily altered physiologic drives, another with philosophical preoccupation, and a third with predominately altered interpersonal skills. These features may represent hyperfunctioning orbitofrontal centers, with such functioning of the medial division resulting in altered physiologic drives; the lateral division, in altered interpersonal skills; and the amygdala, in a sense of awe. Rage attacks result from ventromedial hypothalamic lesions in humans. 117 Episodic explosive behavior may be related to hypothalamic or visceral -amygdalar abnormalities, since the best !calming!! effect may be achieved from lesions involving the lateral part of the corticomedial nuclei. 118 Violent outburst responds to amygdalectomy 119 or posterior hypothalamotomy, 120 capitalizing on the placidity common to the Kl$ver Bucy syndrome.
dysfunction in the limbic system overstimulates the behavioral system responsible for surveillance, vigilance, and stimulus evaluation. The dysfunction results secondarily in the perceptual, cognitive, motoric, and autonomic phenomena comprising the anxious state. The first resting functional imaging study of panic disorder patients 128 suggested a defect of greater left than right parahippocampal cerebral blood flow (CBF) in patients who were lactate inducible, compared to controls or noninducible patients. In normal controls, during anxiety provocation, activations of the insula, 129, 130, 131 anterior cingulate, 129, 130, 132, 133 orbitofrontal, 130, 131, 132, 133, 134 and anterior temporal cortices occur. 129, 130, 131, 132 During lactate induction of anxiety in patients with panic disorder, similar regions show increased CBF, compared to base -line, 135 although the temporal polar increase may be partially due to extracerebral increased flow secondary P.19 to jaw clenching. 129 Following successful treatment in patients with severe anxiety disorder with capsulotomy, which disrupts limbic -frontal connections, marked metabolic reductions in orbitofrontal and subcallosal cingulate cortex occur. 136 Resting metabolism in the left anterior cingulate and right parahippocampal regions are also significantly associated with the degree of anxiety in depressed patients, suggesting that the anatomic behavioral relationship cuts across disease and normal states. 137 This finding supports the central tenant that behavioral disorders should share a common neuroanatomy, regardless of the etiology, when similar signs and symptoms emerge.
Summary
Modern neuropsychiatry is now drawing from diverse disciplines grounded in anatomy, physiology, and clinical neuroscience. In this chapter we provided a model for interpreting neuropsychiatric disorders as fundamentally limbic disorders that combines phylogenetic, anatomic, functional, and clinical data to interpret these diverse diseases of human behavior. An understanding of the development and organization of the limbic system will aid the reader's interpretation of the myriad disorders of human behavior described throughout this volume. With this neurobiological basis, the reunification of psychiatry and neurology will ultimately improve our treatment of the patients who suffer from these disorders.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 3 - Neuropsychiatric Assessment
observations usually made during the initial portion of the interview, such as the appearance and behavior of the patient, the patient's affect, and the form and content of the patient's spontaneous conversation. The mental status examination is then presented with a discussion of each specific area to be explored, including language, memory, visuospatial skills, calculation, abstraction, praxis, and executive functions. Finally, the aspects of the neurological examination of greatest importance to neuropsychiatric and neurobehavioral diagnosis are presented. The role of neuro imaging and neuropsychological testing is briefly prevented. These are expanded in each chapter describing specific disorders. Details of localization and additional information regarding the recognition and characterization of each behavioral disorder observed are provided in chapters addressing specific neurobehavioral and neuropsychiatric syndromes. P.25
TABLE 3.1. Components of the Neuropsychiatric Interview and Mental Status Examination
Interview
Appearance
Motoric behavior
Language
Memory
Verbal output
Constructions
Thought
Calculation skills
Perception
Abstraction
Praxis
Neuropsychiatric Interview
Table 3.1 lists the major components of the neuropsychiatric interview and mental status examination. Each of these elements is described and potential abnormalities are discussed below.
they are dressed, their emotional display and attitude toward the examination, and their motor activity. Dishevelment reflecting a lack of self -care is most striking in frontal lobe syndromes and schizophrenic illnesses. Unilateral dressing disturbances occur in conjunction with hemispatial neglect. Specific dressing disturbances in which patients are unable to correctly orient themselves with regard to their garments and thus fail to dress appropriately occur with right parietal lesions. Dressing with multiple layers of clothing may be seen in the dementias, acute confusional states, and, occasionally, in schizophrenia. Unusual combinations of styles and colors of dress occur in schizophrenic and manic syndromes. 4 The attitude of the patient should also be noted. 3 Patients may be cooperative and engaged, aloof, uncooperative, hostile and belligerent, vacuous, or guarded. These behaviors have important diagnostic implications and also inform the clinician's judgment about the quality of the information obtained. Psychotic patients tend to be guarded; some dementia patients have an empty quality; manic and disinhibited patients tend to be uncooperative, irritable, or hostile. Many patients with dementia are uncertain of their responses and turn to their spouse or other family member to provide answers to questions. Personality features are also often revealed by the patient's attitude toward the examination and the clinician. Disturbances of motor function are among the most revealing of all aspects of the neuropsychiatric examination. No interview is without its behavioral components, and the observed motor characteristics should be part of all diagnostic formulations. Characteristic abnormalities of gait, posture, and spontaneous movement occur in most neuropsychiatric disorders (Table 3.2 ). Retarded depression is characterized by psychomotor slowing, long latency to replies, paucity of verbal output, hypophonia, and bowed posture. Agitated depressions produce abnormal pacing, hand wringing, and an akathisia -like inability to sit calmly. The motor manifestations of mania include psychomotor hyperactivity, pressured speech, and rapid talking (tachyphemia) (Chapter 14 ). Catatonic behavior
Hypokinesias
Paresis
negativism,
Dystonia
Hyperkinesias
Akathisia
Tremor
Tardive dyskinesia
Ballismus
Chorea
Athetosis
Tics
Myoclonus
Agitation
Psychornotor hyperactivity
P.26 (stereotypy, mannerisms, waxy flexibility, passivity, negativism, sustained posturing) may occur in affective disorders, schizophrenic syndromes, and neurological and toxic -metabolic disturbances (Chapter 20 ). Anxiety is reflected by a rigid posture, widened palpebral fissures,
dilated pupils, and action tremor. 4 Obsessions and compulsions are manifested by compulsory stereo-typed acts, checking, cleaning, and rituals. Drugs used in the treatment of psychiatric disorders commonly produce motor system abnormalities such as tremor, dystonia, parkinsonism, dyskinesias, and akathisia (Chapter 20 ). The extrapyramidal diseases manifest rigidity, tremors, ballismus, athetosis, chorea, dystonia, tics, myoclonus, or bradykinesia (Chapter 18 , 19 ).
Verbal Output
The patient's verbal output is one of the principal means of assessing mood, thought, and cognitive abilities. The
clinician must attend to motor aspects (dysarthria, mutism), linguistic features (fluent, non -fluent), and content (delusions, perseveration, obsessions) of the verbalizations. Table 3.3 lists the principal abnormalities of verbal output encountered during the neuropsychiatric interview, and these are presented in more detail in Chapter 6 . Mutism occurs in a wide variety of clinical circumstances, including catatonic states, conversion reactions, pseudobulbar syndromes, early in the course of some aphasic syndromes, and in advanced stages of many neurological diseases. 6 , 7 Speech disturbances include abnormally rapid speech occurring in mania and in many fluent aphasias; slow speech characteristic of depression and nonfluent aphasias; dysarthria secondary to mechanical disruption of articulation; and abnormalities of loudness, particularly hypophonia, in depression and many extrapyramidal syndromes. Aprosodia (also termed dysprosody) refers to the loss of melody, rhythm, and emotional inflection that accompanies nonfluent aphasia, extrapyramidal disturbances, and anterior right hemispheric lesions. 8 , 9
Mutism
Speech disorders
Dysarthria
Hypophonia
Aprosodia
Aphasic syndromes
Nonfluent
Fluent
Reiterative disturbances
Stuttering
Echolalia
Palilalia
Verbigeration
Miscellaneous disorders
Word salad
Coprolalia
Abnormalities of verbal fluency occur in the aphasias. Nonfluent aphasias are characterized by a halting, sparse output with dysarthria, whereas fluent aphasias have a normal or increased verbal output with prominent P.27 paraphasia. Nonfluent aphasias correlate with lesions of the anterior left hemisphere and fluent aphasias, with lesions located posteriorly in the left hemisphere (Chapter 6 ). 1 0 , 1 1 Reiterative speech disturbances occur in a variety of clinical settings. Stuttering, the repetition of single syllables, is seen as a congenital abnormality, in extrapyramidal syndromes and advanced dementia patients, in the recovery phases of aphasia, and with bilateral cerebral insults. Palilalia, the repetition of the patient's own output, and echolalia, the repetition of the examiner's output, occurs in some aphasic syndromes, dementia, and Gilles de la Tourette's syndrome (Chapter 19 ). Verbigeration refers to the constant repetition of a word or phrase sometimes noted in schizophrenic disorders. 1 , 2 Word salad is a rare disorder occurring in schizophrenia
when the derailment of thought and loosening of associations become so profound that the individual words in a sentence bear little relationship to each other. 4 Coprolalia, the involuntary utterance of curse words, occurs primarily in Gilles de la Tourette syndrome, where it is usually accompanied by other involuntary vocalizations such as grunting, snorting, and barking (Chapter 19 ). Coprolalia is occasionally reported in other clinical disorders such as choreic syndromes, Lesch-Nyhan syndrome, and schizophrenia.
Thought Characteristics
No absolute distinctions can be drawn between disorders of verbal output and thought disorders, since the latter must necessarily be inferred from abnormalities of what the patient says. Nevertheless, there are a number of disorders that appear to reflect disturbances in the form or content of thought and are independent of speech or language disorders. Abnormalities in the form of thought are presented first, followed by a discussion of disturbances of thought content.
Autistic thinking
Delusions
Loosening of associations
Obsessions
Phobias
Thought blocking
Hypochondria
Tangentiality
Confabulation
Circumstantiality
Approximate answers
Derailment
Condensation
Illogicality
Neologisms
Word salad
Flight of ideas
Clang association (association by rhyming) Assonance (association by similar sounds) Punning (association by double meaning) Word association (association by semantic meaning)
Racing thoughts
Incoherence
Thought retardation
Perseveration
P.28 (digression without returning to the point of departure), thought blocking, vagueness and poverty of thinking, self reference, derailment, illogicality, condensation of thoughts and sentences, and abnormal word and sentence construction with resulting neologisms or word salad. 4, 1 2 , 13 Circumstantiality (digression from the topic with eventual
return to the intended point) is a frequent finding in some patients with epileptogenic lesions in the limbic system and associated personality alterations. Circumstantiality must be distinguished from circumlocution (talking around a word or defining without naming it because of word -finding difficulties). Flight of ideas is characteristic of mania and is characterized by a rapid flow of ideas in which the direction is determined by specific word characteristics such as rhyming, assonance, punning, or sematic meaning. 4, 13 Manic patients may have tachyphemia (rapid speech). Perseveration is seen in many disorders that disrupt normal thought patterns, including dementia, frontal lobe syndromes, aphasia, and acute confusional states. Likewise, incoherence of thought occurs in schizophrenia and dementia and may be particularly striking in toxic -metabolic confusional states. Retardation of thought (bradyphrenia) occurs in depression and extrapyramidal syndromes.
ruminations, obsessions, phobias, and hypochondriasis. Confabulation refers to fabrication of responses concerning situations that are unrecalled because of an impaired memory. The facts may be benign and trivial or fantastic productions generated without restraint by the patient (Chapter 7 ). 14, 15 , 1 6 Confabulations, unlike delusions, lack stability and vary from day to day. They also lack the affective investment characteristic of many delusional beliefs. The syndrome of approximate answers, or the Ganser syndrome, is an hysterical pseudodementia that usually occurs in patients with head trauma or toxic -metabolic encephalopathies but may also occur in schizophrenia. The pathognomonic sign of the syndrome is the approximate answer given in response to even trivially simple questions (e.g., !How many legs does a dog have ? !!) . 17
Perception
Abnormalities of perception may be classified according to modality (visual, auditory, touch, olfactory, gustatory) or according to positive or negative abnormalities. Table 3.5 presents positive and negative visual perceptual disturbances. Positive visual phenomena include hallucinations and illusions (Chapter 13 ). The former may be either formed or unformed and occur without a corresponding external stimulus; the latter are distortions or misinterpretations of existing stimuli. 1 8 , 1 9 Negative visual phenomena include unilateral neglect in which one-half of the visual universe is ignored; blindness; central color blindness or achromatopsia; and agnosia, or the inability to recognize objects,
Positive phenomena
Hallucinations
Palinopsia
Negative phenomena
Unilateral neglect
Blindness
Agnosia Visual object agnosia Prosopagnosia (agnosia for familiar faces) Environmental agnosia (agnosia for familiar places) Simultanagnosia (inability to perceive two objects at once)
Color agnosia
P.29 faces, or places, despite intact perceptual and naming functions (Chapter 9 ). 20 , 2 1 , 22 , 23 , 2 4 Agnosias may occur in auditory as well as visual modalities. 2 1 Hallucinations may occur in all sensory modalities, including hearing, touch (formication hallucinations), smell, and taste, as well as vision. They may be formed (persons, objects) or unformed. Some specific types of auditory hallucination, such as hearing two voices discussing one or hearing one's own thoughts spoken aloud, occur primarily in schizophrenic conditions.
engagement with the testing. Patients who are uncooperative, inattentive, or anxious may fail tests that they would be able to perform under other circumstances; individuals with limited education will likely have smaller vocabularies, less skill in mathematics, and less familiarity with test-type questions; persons from a minority culture likewise may fail tasks because of unfamiliarity with the majority culture language, differing historical or social exposures, or distrust of the examiner's intentions. In these situations, the clinician should avoid overinterpretation of the test results and failures should be attributed to brain dysfunction only when there is a consistent pattern of behavior and supporting evidence of a neuropsychiatric disorder.
dysfunction of both cerebral hemispheres or of the reticular activating system on a structural or toxic -metabolic basis. The digit span test, in
TABLE 3.6. Major Types of Attentional Deficit and Their Anatomic Correlates
Anatomic Basis
Drowsiness
Distractibility
Frontal lobe
Unilateral neglect
P.30 which the patient is asked to repeat a list of numbers dictated by the examiner (normal, 7 2 digits forward and 5 1 digits in reverse), is a useful test of alertness and
arousal. 1 The ability to consistently sustain vigilance is best assessed by a continuous performance task such as the A test, in which the patient is asked to respond by lifting his or her hand whenever the letter A is heard in a list of letters read aloud by the examiner. 1 Errors of omission usually reflect distractibility or loss of set for the task; errors of commission are usually perseverative or due to impulsiveness or anxiety, with patients raising their hands for letters other than the letter A. Disturbances of sustained concentration and vigilance most often reflect frontal lobe dysfunction or toxic -metabolic encephalopathy. In addition to structural and toxic disorders, other neuropsychiatric syndromes, including dementia with Lewy bodies, depression, mania, anxiety, and schizophrenia, may produce prominent concentration and attentional disturbances (Chapter 11 ). Unilateral disturbances of attention or hemispatial neglect may involve unilateral sensory attention (hemi -inattention) or unilateral motor activity (hemi -inintention) (Chapter 8 ). Behaviorally, patients may ignore all stimuli on the side contralateral to the lesion and will perceive or respond only to those stimuli in the hemispatial universe receiving their attention. They will perceive only one of two simultaneous auditory clicks (finger snaps) and will feel only one of two simultaneous somatosensory stimuli (touching each side of the body at the same time). Visually, they may read only half of written words (northwest as north or west, depending on which side is neglected), will draw only half of constructions they are asked to copy, and will ignore half of vertically written multiple -digit mathematical problems. A useful test of visual neglect is the line -crossing test in which the patient is given a piece of paper on which there are a number of short straight lines scattered across the page in a variety of orientations and is asked to cross each line in the middle. 2 7 All or a portion of the lines in the neglected field will be missed, and the middle of each line may be misjudged, with the line crossings systematically displaced away from the neglected field (Chapter 8 ). The occurrence of a hemianopa is independent of hemispatial neglect: patients with hemianopias may or may not have unilateral
neglect, and neglect may occur with or without a hemianopia. Unilateral sensory neglect occurs primarily with parietal lobe lesions and is more profound and more persistent in patients with right parietal lesions than in those with left -sided insults. 2 3 When motor neglect is present (hemi -inintention), the patient may appear to be hemiparetic because of lack of use of an extremity, but normal motor and sensory function can be demonstrated when the patient's attention is specifically directed to the neglected limb. 23 Motor neglect occurs with frontal lobe and striatal lesions.
Mental Control
Mental control tasks are tests of complex attention that require the interaction of several neuropsychological functions including sustained attention, recent memory, and executive function. Mathematical skills are necessary to perform some mental control tests. Serial subtraction of 7's from 100, serial subtraction of 3's from 20, spelling world backwards, and saying the months of the year in reverse order are tests of mental control. Serial subtraction tasks require mathematical skills and may be impossible for individuals with limited education.
Language
Language disturbances, like attentional deficits, may profoundly influence the patient's ability to perform many aspects of the mental status examination. Memory testing, calculation, abstraction, and comprehension of instructions for all other testing depend on intact language capabilities, and the integrity of linguistic capabilities must be determined early in the course of assessing the patient's mental state. A systematic approach to language evaluation and interpretation is presented in more detail in Chapter 6 ; the principal areas to be tested are presented here and summarized in Table 3.7 . Language disturbances (aphasia) must be distinguished from alterations in the mechanical aspects of sound production (dysarthria) and from thought disturbances (outlined above).
Spontaneous Speech
A major change in the spontaneous speech of language disordered patients is a disturbance in language fluency. Nonfluent aphasias are characterized by decreased verbal output, effortful speech, dysarthria, decreased phrase length, dysprosody (loss of speech rhythm), and agrammatism (omission of the small relational or !functor!! words). Fluent aphasias have a normal or increased verbal output, normal articulation, normal phrase length, preserved prosody, empty speech, circumlocution, and paraphasia. 10 , 1 1 In nearly all right -handed individuals and a majority of left -handed subjects, nonfluent aphasia reflects structural changes in the left frontal lobe, whereas fluent aphasia is indicative of damage to the left posterior temporal, inferior parietal, or temporoparietooccipital P.31
TABLE 3.7. Principal Language Functions Tested or Observed in the Mental Status Examination
Spontaneous speech
Comprehension
Repetition
Naming
Reading
Aloud
Comprehension
Writing
Speech prosody
Miscellaneous
Automatic speech
Completion phenomenon
Singing
junction region. 1 0 , 11 Speech prosody also may be disrupted by right -sided frontal lobe lesions and by subcortical dysfunction in extrapyramidal disturbances. 8 , 9, 2 8
Comprehension
Language comprehension is difficult to assess with precision. It is heavily dependent on attention, concentration, and cooperation as well as linguistic abilities. Comprehension should be tested in a graded fashion beginning with one-, two -, and then three -step pointing to room objects ( !Point to the door, the window, and the chair.!!) Then a series of easy to difficult yes/no questions should be administered (easy: !Is your name !Green! ? !!; difficult:!Do you put your shoes on before your socks? !!) . Finally, comprehension of more sophisticated linguistic structures can be assessed, such as sentences with passive constructions (!If a lion and a tiger are in a fight and the lion is killed by the tiger, which animal is dead? !!) and possessives (!Is my wife's brother a man or a woman ? !!) . 29 Disruption of language comprehension occurs with involvement of the left posterior temporal and temporoparietooccipital junction regions (Chapter 6 ). Left sided anterior lesions generally spare most aspects of language comprehension, although patients may have difficulty following commands that depend on correct interpretation of sequential information (!Touch the pen with the pencil,!! in contrast to !With the pen touch the pencil!!) .
Repetition
Repetition, like comprehension, should be tested with a graded series of phrases and sentences of increasing complexity. The patient is requested to repeat each sentence exactly as spoken by the examiner. From simple phrases such as !he is here,!! the examiner proceeds to longer and more difficult sentences, such as !The quick brown fox jumped over the lazy dog,!! and finally includes more complex and linguistically irregular phrases such as !no ifs, ands, or buts.!! 2 9 Again, concentration and attention deficits may interfere with all but the most simple tests of repetition, and interpretation of repetition failures must take this into account. Repetition span (the number of words that can be repeated) is typically two words longer than the patient's digit span; thus, patients with reduced digit span because of a toxic -metabolic encephalopathy will have a correspondingly limited ability to repeat long phrases.
Hearing abnormalities also limit the patient's ability to cooperate with repetition testing. Patients with disturbances of repetition as a result of aphasia characteristically omit words, alter the word sequence, and have paraphasic intrusions when trying to reproduce the test sentence. Anatomically, failure of repetition occurs in aphasias with lesions situated adjacent to the left Sylvian fissure. Aphasics with preserved repetition have intact peri-sylvian structures. 10 , 1 1
Naming
Naming disturbances are a sensitive indication of language impairment but lack specificity for the type of linguistic compromise. Anomia is most often one aspect of an aphasia syndrome but may occasionally be evident in toxic confusional states, with increased intracranial pressure, and with other nonfocal disturbances. 3 0 , 3 1 Anomia may be manifested in spontaneous speech by word -finding pauses, emptiness, and circumlocution or may be identified by tests of confrontation naming. High - and low -frequency names should be tested (in general, object names, e.g., wristwatch, are high frequency, and object parts, e.g., stem, crystal, band, are lower frequency), as well as names in several linguistic categories (e.g., colors, body parts, room objects, actions). Naming errors may take the form of literal paraphasias (phonemic substitutions such as greel for green), verbal paraphasias (semantic substitutions such as blue for green), neologisms (completely new constructions), failure to make any response, or circumlocutions (descriptions of the object or its use without naming it).
Reading
Reading is a complex neurological function that must be learned and is subject to many cultural and educational influences. Literacy is still uncommon P.32 in much of the world, and the significance of an individual's reading difficulties can be judged only after considering the person's level of educational achievement. The ability to read aloud and reading comprehension must be tested separately, since some lesions may disrupt oral reading, leaving reading comprehension intact, whereas other
disorders may impair reading comprehension but spare the ability to read aloud. Letter, word, and sentence reading should be tested. Failures may include an inability to read letters, an inability to read words, ignoring one-half of the word (hemialexia), or substitution of one word for another. 10, 2 4 Alexias may occur with anterior or posterior left -sided lesions (Chapter 6 ).
Writing
Writing also is an acquired task heavily dependent on one's educational experience and occupational demands. Agraphia, an acquired disturbance of writing, may occur on an aphasic basis secondary to an interruption of linguistic function or on a nonaphasic basis produced by an impairment of the motor system and mechanical aspects of writing. All aphasics will make errors in their written as well as their oral productions, and the characteristics of the written language resemble those of the spoken output. 3 2 Peripheral, corticospinal, extrapyramidal, and cerebellar disturbances all disrupt the motoric aspects of writing and produce distinctive agraphic syndromes. The differential diagnosis of agraphia is presented in Chapter 6 .
Prosody
Prosody refers to the melodic, rhythmic, and inflectional elements of speech, and aprosodic output is typically monotonic, amelodic, and affectless. Two aspects of prosody
should be assessed: spontaneous prosody and prosodic comprehension. Spontaneous prosody is judged simply by listening to verbal utterances occurring during the course of conversation. Prosodic comprehension is tested by having the patient, with eyes closed, listen to a neutral sentence executed by the examiner in four prosodic styles (surprised, happy, angry, sad). The patient is then asked to identify the emotional state of the speaker based on the way the sentence was inflected. Impaired spontaneous prosody is produced by right frontal lesions and extrapyramidal disturbances, whereas prosodic comprehension is most disturbed by right temporoparietal injuries. 8, 9 ,2 8 , 3 3 , 34
Memory
Memory is often divided into three functions!immediate, recent, and remote!with immediate memory representing the ultra -short -term memory tested with digit span, recent memory representing the ability to learn new information and remote memory representing the recall of material learned in the past. Immediate memory is best considered an attentional capacity, since the information is not memorized or committed to memory for later recall. Working memory and mental control tasks utilize this aspect of memory. Attention is a necessary prerequisite for all aspects of memory, and the presence of intact attention must be
demonstrated before conclusions about memory can be drawn. Recent memory refers to the ability to learn and recall new information. Two types of test are commonly used to assess recent memory: orientation and the recall of recently presented verbal or nonverbal information. Orientation in time and space must be learned on a daily basis and inquiring whether one knows the correct year, month, day, date, and time of day as well P.33 as one's current location will reveal important information about learning and recent memory abilities. A more structured assessment of verbal learning can be performed by asking patients to learn three or four unrelated words and then asking them to recall the words after 3 minutes. 1 There are two types of recent memory disturbances: amnesias and retrieval deficit syndromes. In amnestic disorders, there is a failure to store new information, whereas in the retrieval deficit syndrome there is an impairment of timely recall of stored data. The two types of memory failure can be distinguished by the response of the patients to recall clues. Patients with amnesia cannot spontaneously recall recently learned information, are not helped by clues (!One of the words I asked you to remember was the name of a vegetable!! as a clue for remembering the word cabbage), and cannot recognize recently learned words in a list that contains both targets (the recently learned words) and foils (similar words that were not part of the recent memory test). Patients with the retrieval deficit syndrome also have limited spontaneous recall but benefit from clues and are able to distinguish between targets and foils on tests of recognition memory. 36 Amnestic patients have disorders affecting the hippocampus in the medial temporal region, fornix, marnmillary bodies, mammillothalamic tract, or medial thalamus (Chapter 7 ). The retrieval deficit syndrome is associated with disturbances affecting the dorsolateral prefrontal cortex or caudate nucleus. Testing nonverbal memory is more difficult than assessing verbal memory, but an assessment can be made by warning patients when they are copying constructions (discussed in the next section) that they will be asked to reproduce them
later. After a 3 -minute delay, the patient is instructed to redraw the figures from memory. If failures occur, recognition of forgotten figures can be tested by presenting a number of constructions and asking which ones had been shown previously. Unfortunately, many patients spontaneously develop verbal descriptions of the drawings, converting the test into an assessment of verbal memory. A more precise evaluation of nonverbal learning demands use of more specialized neuropsychological techniques and nonsense figures not easily verbally encoded. Nonverbal memory is mediated primarily by right hemisphere structures and verbal memory, by the left hemisphere. Remote memory abilities are revealed during the neuropsychiatric interview by the patient's ability to recapitulate personal history. Such historical information, however, may be unverifiable by the clinician, and a review of public knowledge (past political leaders, dates of historical events, sports facts, etc.) may add another dimension to the testing. Information of this type is dependent on the educational background of the patient and intact language abilities.
Constructions
Assessment of visuoconstructive abilities is performed by asking the patient to copy drawings provided by the examiner (e.g., circle, cross, cube). The drawings should be a graded series of figures of increasing complexity and should include at least one three -dimensional representation. Relatively normal motor skills are an obvious prerequisite for performance of the task. Tests of constructional abilities are an excellent method of screening for acquired brain dysfunction. Most idiopathic psychiatric disorders spare constructional skills, whereas lesions of the frontal or parietooccipital regions of either hemisphere may disrupt visuoconstructive abilities. 21 , 3 7 Neglect of one side of the figures is most consistent with a posterior hemispheric lesion contralateral to the neglected hemispace, whereas a fragmented and disorganized approach to complex constructions occurs most often with frontal lobe lesions or in acute confusional states. 38 , 39 , 4 0 Clock drawing is frequently used as a screening test of
visuospatial abilities and can provide substantial information. The patient is first asked to draw the face of a clock including the numbers; if the patient draws a clock face too small to accommodate the numbers, there is preliminary evidence of a planning and foresight deficit. Once the circle of the clock face is drawn, the patient must place the numbers accurately and disturbances of planning or evidence of unilateral neglect may be apparent (patients may place all the letters on one side of the clock with either condition and additional testing will be required to distinguish the two). Next, the patient is asked to set the clock for 11:10. Patients with executive dysfunction and !stimulus boundedness!! may put one hand on the 10 and one on the 11, thus setting the clock inaccurately (10:50). Clock drawing provides insight into both visuoconstructive and executive abilities and is compromised in patients with parietal or frontal lobe disorders. 4 1, 4 2
Calculation
Calculating abilities are tested by asking the patient to solve arithmetic problems (usually addition and multiplication) presented either orally or in written form. Attention must be intact, and previous competency in calculation must be assured before failures in calculating P.34 abilities can be interpreted. At least three types of acalculia are described: (1) patients with fluent aphasias may make semantic paraphasic errors when reading, writing, or saying numbers, making correct calculation impossible; (2) patients with right -sided parietal lesions may have a visuospatial acalculia, resulting from an inability to correctly align columns of written numbers; and (3) a primary anarithmetria may occur with left -sided posterior hemisphere lesions. This last type of acalculia may occur as an isolated disorder or as part of Gerstmann's syndrome and reflects an inability to perform the actual numerical manipulations. 2 4 , 43
Abstraction
The ability to abstract provides a good index of general intellectual function and, like calculation, is dependent on the patient's level of educational achievement and cultural
experience. Most English -speaking individuals will be able to abstract idioms such as !cold shoulder,!! !heavy heart,!! and !level -headed!! regardless of their educational history, and impairment of this skill usually indicates a disturbance of abstracting abilities. Proverbs can be understood by most individuals with a high school education, and an inability to interpret proverbs by patients with more advanced educational achievement is evidence of compromised intellectual function. Both simple proverbs ( !Don't cry over spilled milk!!) and complex proverbs ( !People who live in glass houses shouldn't throw stones!!) should be tested. 7 In addition to testing the ability to abstract, proverb interpretation often elicits bizarre, paranoid, or idiosyncratic responses from patients with psychoses and macabre, pessimistic, hopeless interpretations from depressed patients. The ability to abstract depends on intact language function as well as higher -order comparative and extrapolation skills mediated by frontalsubcortical circuits.
Praxis
Ideomotor apraxia refers to the inability to perform volitional acts on command despite intact motor and sensory functions and preserved language comprehension. 44 To test praxis, the patient is asked to perform limb, whole -body, and oral-lingual movements. Limb commands include !Show me how you comb your hair!! or !Show me how you brush your teeth!!; whole -body commands include !Take a bow!! and !Show me how you swing a golf club!!; and oral-lingual commands include !Show me
how you blow out a match,!! !Show me how you suck through a straw,!! and !Cough.!! The presence of ideomotor apraxia reflects focal dysfunction in the left hemisphere of right -handed individuals (Chapter 6 ). Ideational praxis refers to the ability to synthesize a series of individual actions into a complex activity. It is tested by asking the patient to pantomime the steps of a complicated task such as putting a letter into an envelope, sealing and addressing the envelope, and adding a stamp. Ideational praxis is disrupted in patients with diffuse or multifocal brain lesions or dementia syndromes.
Executive Function
Executive functions are higher -order cognitive abilities mediated primarily by the dorsolateral prefrontal cortex and subcortical structures linked to this region (Chapter 9 ). 4 5 Dysexecutive syndromes are present in diverse neuropsychiatric conditions including frontotemporal dementias, focal frontal lobe disorders, basal ganglia diseases, schizophrenia, and some patients with depression. Performance of many of the tests described above depends on intact executive function and frontal-subcortical circuit function. Attention and concentration depend on frontalsubcortical circuits, and distractibility is evident in many patients with executive dysfunction. Word list generation requires normal frontal circuits, and reduced generative capacity in a patient without aphasia impugns the integrity of frontal-subcortical circuitry. Retrieval of stored information is mediated by frontal-subcortical circuits, and a retrieval deficit syndrome is present in many patients with executive deficits. Complex constructions are approached in a segmented and fragmented manner by patients with frontal-subcortical dysfunction who lack the ability to develop an effective drawing strategy. As described above, clock drawing and time setting can provide insight into stimulus boundedness, a frequent manifestation P.35 of executive dysfunction. Abstraction, insight, planning, and judgment are also compromised in patients with frontalsubcortical circuit disorders and executive deficits. Motor programming skills also depend on intact frontal-
subcortical circuit function. Tests used to assess this ability include alternating programs, reciprocal programs, multiple loops, serial hand sequences, and rhythm tapping. 3 7 , 3 9 , 4 6, 4 7 All these tests have in common a dependence on the patient's ability to program motor responses in specific repeating or alternating sequences. Failures include an inability to achieve the specific behavioral set required to perform the task, rapid extinction of the appropriate set with consequent deterioration of the expected sequence, or inability to change set with perseveration or intrusion of unwanted activities. The patient is asked to copy the alternating sequences or looped figures provided by the examiner and then to continue the same repeating pattern across the page. Reciprocal programs are performed by having the patient and examiner execute reciprocal maneuvers. For example, the patient is requested to tap once each time the examiner taps twice and twice whenever the examiner taps once. The examiner then proceeds to tap once or twice in random order and observes whether the patient is able to respond reciprocally. Similarly, rhythm tapping abilities are assessed by asking the patient to imitate a rhythmic sequence of taps performed by the clinician. Serial hand sequences are tested by requiring that the patient execute a series of repeating hand postures while announcing aloud the name of each posture (fist-slap side) (Fig. 3.1 ).
Finger Agnosia
Finger agnosia, like right -left disorientation, has localizing significance when it occurs as part of the Gerstmann syndrome. 4 8 In its simplest form, finger agnosia can be detected by asking the patient to point to the little finger, middle finger, ring finger, or index finger. More subtle forms can be detected
FIGURE 3.1 Alternating sequences often reveal perseveration in patients with frontal system defects.
P.36 by touching an individual finger on the patient's hand while it is held out of sight above head level and asking the patient to indicate the corresponding finger on the other hand. Alternatively, the examiner may touch any combination of two fingers on one of the patient's hands and ask the patient how many digits there are between those touched. 5 0
Miscellaneous Observations
During the course of the interview and testing, many additional observations will be made that may require more detailed exploration or may, in themselves, have localizing significance. For example, inability to perceive two objects simultaneously occurs with bilateral parietal lesions. Any deviation from expected behavior may be useful in localization and diagnosis. Unusual responses should be followed up by supplementary observations. Tasks that appear too difficult for the patient should be simplified and repeated, while tests performed rapidly suggest that more taxing assessments are required. The neurobehavioral examination is a process of hypothesis formation and testing as the examiner attempts to understand the patient's difficulty; it resembles a complex choreography with each act of the patient eliciting a corresponding response from the examiner as conceptual and diagnostic clarification is sought.
Neurological Examination
The neurological examination can provide valuable information relevant to the diagnosis of neuropsychiatric and neurobehavioral examination. 51 Each patient presenting for neuropsychiatric assessment requires a comprehensive neurologic evaluation. The examination is guided by diagnostic hypotheses formulated during the course of the neuropsychiatric interview and mental status testing. The usual evaluation includes assessment of cranial nerves, motor system, sensory abilities, muscle stretch reflexes, and primitive reflexes. 5 2
Examination of the second cranial nerve (optic) is critical to the neuropsychiatric evaluation and includes visualization of the nerve head, testing of visual acuity, and assessing the visual fields. Examination of the optic nerve may reveal optic atrophy (a pale disc), papilledema reflecting increased intracranial pressure, or papillitis associated with optic nerve ischemia or inflammatory conditions such as multiple sclerosis. Ophthalmoscopy may also reveal macular degeneration, pigmentary retinopathy, retinal infarction, narrowing of retinal vessels, and retinal hemorrhages or exudates. Visual acuity of each eye is tested with a Snellen chart held 18 inches from the eyes. Patients should wear their glasses to minimize visual disturbances produced by abnormalities of the shape of the optic globe (astigmatism). Acuity should be correctable to 20/20 if optic nerve function is normal, and continued impairment after correction implies the presence of prechiasmatic optic nerve pathology. Visual field defects are identified by systematically bringing a small target in from the periphery toward the center of the patient's visual field and asking them to indicate when the target is first seen. Damage to an optic nerve produces monocular visual field defects of the ipsilateral eye. Postchiasmatic injuries typically produce a homonymous visual field defect. Occipital damage is associated with congruent field defects of similar size and shape in each field, whereas more anterior lesions (damage to the geniculocalcarine radiation in the temporal lobe) produce incongruent field defects of differing size in the two fields. Visual field defects are often associated with release hallucinations and other visual phenomena (Chapter 13 ). Cranial nerves III, IV, and VI (oculomotor, trochlear, and abducens) mediate ocular motility and pupillary responses. The external rectus muscle turns the globe laterally and is innervated by the abducens nerve; the superior oblique moves the globe downward when the eye is adducted and is innervated by the trochlear nerve; all the remaining ocular muscles, the ciliary muscles mediating pupillary constriction, and some of the muscles of the eyelid are innervated by the oculomotor nerve. Pursuit movements and volitional eye movements should be tested. Pursuit is assessed by having the patient follow the examiner's finger through seven positions (adduction, adducted and up, abducted and up,
abducted, abducted and down, adducted and down, convergence). Volitional eye movements are assessed by asking the patient to look right, left, up, and down without following a visual target. P.37 Conjugate gaze is mediated by gaze -coordinating centers in the pons (lateral movements) and the midbrain (vertical movements). Abnormalities resulting from dysfunction of cranial nerves III, IV, and VI include ocular paresis, gaze paretic nystagmus, and pupillary and lid disturbances. Brainstem lesions, extrapyramidal movement disorders, and lesions of the premotor regions of the frontal cortex may produce supranuclear gaze palsies manifested by impaired volitional eye movements. Gaze -paretic nystagmus results from inadequate ocular deviation; the quick or jerk phase of the nystagmus is in the direction of the weakened muscle. Changes in pupillary size occur in response to light stimulation and in conjunction with convergence (constriction of the pupil with near vision). Cranial nerve III is responsible for pupillary constriction through its parasympathetic branches; pupillary dilatation is a function of the sympathetic nervous system. Lid position is determined by input from the third nerve and sympathetic influences responsible for eye opening and from the seventh cranial nerve mediating lid closure. Third nerve palsy results in ptosis, a non -reactive pupil and an inability to adduct, elevate or depress the eye. Pupillary abnormalities occur with brain -stem lesions, syphilis (Argyll -Robertson pupil in which the reaction to light is lost while the convergence mechanism is intact), diabetes, and nerve compression by aneurysms or other mass lesions. The neuro -ophthalmologic examination may contribute essential information to neuropsychiatric diagnosis (see Table 3.8 ). Inspection of the cornea may reveal a Kayser Fleischer ring in Wilson's disease. Retinal assessment may show macular degeneration (associated with blindness and visual hallucinations) or retinal degenerations (produced by phenothiazines, particularly thioridazine, and some hereditary brain disorders). Cataracts are associated with diabetes, hypoparathyroidism, and Wilson's disease and may occur with chlorpromazine and corticosteroid therapy. The fifth cranial nerve (trigeminal) innervates the muscles of
the jaw involved in mastication and is responsible for facial and corneal sensation. Cranial nerve VII (facial) supplies the facial musculature including the platysma muscles of the anterior neck, orbicularis
Conditions
Alzheimer's disease
Inadequate visual exploration; !visual grasp!!; optic ataxia in posterior variant with Balint's syndrome
Frontotemporal dementia
Deficient anti-saccades
Visual hallucinations
Parkinson's disease
Poor upgaze and convergence; diminished blinking; saccadic pursuit; visual hallucinations following dopaminergic therapy
Progressive
supranuclear palsy
deficient vertical gaze (downgaze lost first); microsquare wave jerks; diminished blinking; deficient antisaccades; saccidic pursuit
Huntington's disease
Corticobasal degeneration
Wilson's disease
Ipsilateral gaze deviation in acute phase; contralateral gaze impersistence with chronic lesions
Geniculocalcarine lesions
Midbrain lesion
!Top of the basilar syndrome!! with dream-like state and visual hallucinations
Multiple sclerosis
Delirium
Migraine
Narcolepsy
Mass lesions
P.38 oris and buccinator muscles around the mouth, orbicularis oculi of the eye, and the frontalis of the forehead. Its branches innervate the tear and salivary glands and stapedius muscle of the ear, and it provides taste fibers to the anterior two -thirds of the tongue. The upper facial
muscles receive bilateral cortical input, whereas the lower facial muscles receive contralateral innervation only. Thus, upper motor neuron lesions produce only contralateral lower facial paresis, whereas peripheral nerve lesions cause ipsilateral paralysis of both upper and lower face. The facial nerve nucleus receives descending input from both pyramidal neurons mediating volitional movements and nonpyramidal limbic system connections mediating emotional responses. When one system is affected and the other is spared, the patient will exhibit either retained volitional grimacing but a partially paralyzed smile, or an intact emotional smile with hemifacial paresis of volitional grimacing. 5 3 The eighth cranial nerve consists of an auditory branch and a vestibular branch. Auditory compromise causes deafness and is sometimes associated with auditory hallucinations. Vestibular end -organ or nerve lesions produce horizontal or combined horizontal -rotatory nystagmus and vertigo, whereas lesions disrupting vestibular connections within the central nervous system can produce nystagmus in any direction and usually are not associated with vertigo or nausea. Cranial nerves IX and X (glossopharyngeal and vagus) control pharyngeal and laryngeal motor function, taste, and the gag reflex. The glossopharyngeal nerve conveys sensory information (including taste sensation from the posterior third of the tongue), while the vagus nerve is primarily responsible for the motor aspects of these structures. Dysfunction of the vagus nerve results in a hoarse voice, aphonia, or dysphagia. Supranuclear lesions disinhibit local nerve function and produce an exaggerated gag reflex. This is a common manifestation of pseudobulbar palsy (Chapter 14 ). The eleventh cranial nerve (spinal accessory) innervates the upper half of the trapezius muscle and the sternocleidomastoid muscle; the twelfth cranial nerve (hypoglossal) innervates the tongue.
extrapyramidal, cerebellar, spinal, peripheral, myoneural junction, and muscular function. Assessment of the motor system is particularly important in neuropsychiatry: psychiatric disturbances are often accompanied by motor system manifestations (retardation, agitation, catatonia), movement disorders are often accompanied by neuropsychiatric abnormalities (Parkinson's disease, Huntington's disease), and many of the agents used to treat psychiatric diseases adversely affect the motor system (tremor, tardive dysknesia). Extrapyramidal motor disorders are described in Chapter 18 . Muscle bulk is assessed by visual inspection, palpation and measurement. Muscle atrophy occurs with disuse, muscle diseases, and nerve or spinal diseases, and in generalized weight loss secondary to malnutrition or systemic illness. Strength is evaluated by having the patient exert maximal power of specified muscle groups. Strength is graded as 0, no evidence of muscle contraction; 1, muscle contraction without movement of the limb; 2, limb movement after gravity eliminated; 3, limb movement against gravity; 4, limb movement against partial resistance; and 5, normal strength. Pyramidal tract lesions produce a !predilection !! pattern of weakness affecting the extensor muscles of the upper limbs and the flexor muscles of the lower limbs with resulting flexion of the arm and extension of the leg; this is known as a decorticate posture and imitates the antigravity posture of a bipedal animal. Pyramidal lesions of the pons result in extensor posturing of all limbs, the antigravity posture of the quadrupedal animal. Muscle tone is evaluated by passively manipulating the limbs or neck. Additional information can be garnered by asking the patient to perform motor activities with the contralateral limb while tone in the ipsilateral limb is determined (the patient is asked to draw a square in the air with one arm while the examiner is testing the tone of the other arm). Activation of tone by this maneuver (Froment's sign) is characteristic of parkinsonian -type extrapyramidal rigidity. Muscle tone is decreased in muscle and peripheral nerve disease, cerebellar syndromes, early in the course of many choreiform disorders, and acutely following an upper motor neuron lesion. Increased muscle tone (rigidity) occurs with pyramidal disorders (spasticity and clasp knife rigidity) and
in extrapyramidal syndromes (plastic rigidity or cogwheel rigidity). Gegenhalten (also known as paratonia) refers to resistance to movement encountered in patients with advanced brain diseases. It is characterized by active resistance to all limb movements and may result from release of primitive protective mechanisms. Waxy flexibility is the tone change classically associated with catatonia; there is moderate resistance to passive movement and maintenance of the final position of the movement (like candle wax). Catatonia occurs in a variety of psychiatric, frontal lobe, extrapyramidal, and toxic -metabolic disorders (Chapter 20 ). Coordination may be disrupted by many types of motor and sensory abnormalities but is dependent primarily P.39 on cerebellar function. Coordination is assessed by asking the patient to perform rapid alternating movements (alternating supination and pronation movements of the hand), fine finger movements (repeated apposition of the thumb and first finger), finger-to -nose movements (the patient alternates between touching his or her own nose and the examiner's finger), heel -knee -shin maneuvers (the patient touches the knee of one leg with the heel of the other and then gently slides the heel down the shin), and rebound check tests (the clinician suddenly releases as the patient is pushing his or her extended arms upward against the examiner; the clinician observes whether the patient can arrest the upward movement after the release). Dysdiadokokinesia (abnormal rapid alternating movements), ataxia, loss of rebound check, and intention tremor are characteristic of cerebellar disturbances. Gait and posture are dependent on successful sensory motor integration. Gait analysis should include observation of step initiation, stride length, step height, base width, step symmetry, path deviation, trunk stability, speed, turning, and adventitious movements. Tandem toe-to -heel walking makes cerebellar, sensory, and vestibular disturbances of gait and balance more evident. Posture may be extended, flexed, or unstable. Postural stability is assessed by asking the patient to stand with legs comfortably apart and eyes open; the examiner then stands behind the patient and pulls backward on the patient's shoulders with a short, rapid jerk.
Patients with extrapyramidal disorders fall backward or take a compensatory backward step to maintain balance. Sensory input to posture can be tested by asking the patient to stand with feet together with eyes closed. Patients with sensory abnormalities from peripheral neuropathy or dysfunction of the posterior columns of the spinal cord can stand with eyes open but not with eyes closed (Romberg's sign); patients with cerebellar ataxia cannot stand with feet together, regardless of whether the eyes are open or closed. Soft signs are minor motor abnormalities that are normal early in the course of development but abnormal when they persist beyond childhood. They have been reported with increased frequency in a variety of neurosychiatric disorders. Table 3.9 lists the main soft signs elicited in the course of the neurological examination. 5 1 , 5 4
Sensory Examination
Examination of sensory function includes testing of primary sensory modalities mediated at the thalamic level as well as secondary or cortical sensation. Primary sensory modalities include light touch, pain (tested by examining the patient's ability to distinguish a sharp from a dull point), temperature, and vibration. Cortical sensory modalities include joint position sense, two -point discrimination (ability to discriminate two closely spaced points of stimulation from a single stimulation), graphesthesia (ability to identify numbers !written!! on the tips of the fingers), and stereognosis (ability to recognize objects by touch when placed in the hand). Double simultaneous stimulation is a sensitive means of detecting mild unilateral neglect. Patients with neglect fail to perceive stimuli on one side of the body when they are simultaneously stimulated on both sides.
Test
Soft Sign
Articulation
Mild dysarthria
Finger tapping
Foot tapping
Eye closure
Tongue extrusion
Arms extended
Jerky, clumsy
Heel-to -shin
Jerky, clumsy
Heel walking
limbs
Toe walking
Cannot balance
Unsteady
Tandem walking
Unsteady
Unsteady
Face-hand test
Distal stimulus extinguished when distal and proximal stimuli delivered simultaneously
Perceives two separate points only when more widely separated than normal
Graphesthesia
Errors
Romberg sign
thenar eminence is stimulated; (2) the traction grasp is evident when the examiner withdraws his or her hand from the patient and the patient grips and exerts a counterpull; (3) the groping response or magnetic grasp is elicited by the sight of the examiner's hand or by a light touch of the patient's hand and consists of the patient moving his or her hand to grasp the examiner's hand. Grasp reflexes occur in patients with advanced brain disease and with lesions of the medial frontal lobes. The sucking reflex consists of sucking movements of the lips, tongue, and jaw elicited by gentle stimulation of the patient's lips. Like the grasp reflex, the suck response is a primitive motor program that occurs normally in infants and reappears as an age -inappropriate sign in patients with frontal lobe and diffuse brain dysfunction. In some cases, a suck response can be elicited by the appearance of an object to be placed in the mouth or by approaching the patient's mouth with a reflex hammer handle. The palmomental reflex consists of ipsilateral contraction of the mentalis muscle of the chin in response to stroking of the thenar eminence of the hand. This reflex can be seen in normal aged individuals and may be regarded as pathological only when it is unilateral or when it does not fatigue with repeated elicitation.
FIGURE 3.2 Coronal three -dimensional magnetic resonance images (MRI) and oblique axial slices through the long axis of the hippocampus of [ 1 8 F] fluorodeoxyglucose positron emission tomography (FDG PET) at baseline evaluation and at follow -up 18 months later showing progressive atrophy and metabolic decline in left hippocampus (arrows) for a patient presenting with mild memory impairment who later met clinical criteria for Alzheimer's disease.
use of functional imaging to diagnosis preclinical disease is within the dementia syndrome. The combination of medial temporal atrophy on structural imaging and functional defects in the parietal and temporal regions on PET or SPECT in patients with isolated memory complaints not sufficient to meet clinical criteria for dementia may predate the development of clinically diagnosed Alzheimer's disease by several years (Fig. 3.2 ). 56 Yet even in the evaluation of dementia few functional imaging studies have yet to
prospectively test the diagnostic accuracy of specific regional deficits in individuals with mild complaints followed prospectively. Throughout the following chapters we will provide the current understanding of those regional defects on functional or structural imaging studies that best correlate to behavioral abnormalities but emphasis should always be placed on the clinical examination described above.
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23. Heilman KM, Watson RT, Valenstein E. Neglect and related disorders. In: Heilman KM, Valenstein E, eds. Clinical Neuropsychology, 3rd ed. New York: Oxford University Press, 1993:279!336.
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33. Heilman KM, Bowers D, et al. Comprehension of affective and nonaffective prosody. Neurology 1984;34:917!921.
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39. Carlesimo GA, Fadda L, Caltagirone C. Basic mechanisms of constructional apraxia in unilateral brain damaged patients: role of visuo -perceptual and executive disorders. J Clin Exp Neuropsychol 1993;15:342!358.
40. Luria AR. Higher Cortical Functions in Man. New York: Basic Books, 1980.
41. Freedman M, Leach L, et al. Clock Drawing: A Neuropsychological Analysis. New York: Oxford University Press, 1994.
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44. Geschwind N. The apraxias: neural mechanisms of disorders of learned movement. Am Sci 1975;63:188 !195.
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48. Gerstmann J. Syndrome of finger agnosia, disorientation for right and left, agraphia, and alcalculia. Arch Neurol Psychiatry 1940;44:398!408.
49. Roeltgen DP, Sevush S, Heilman KM. Pure Gerstmann's syndrome from a focal lesion. Arch Neurol 1983;40:46!47.
51. Cummings JL. Neuropsychiatry: clinical assessment and approach to diagnosis. In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry VI. Baltimore: Williams and Wilkins, 1995:167!187.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 4 - Treatment of Neuropsychiatric Disorders
specific psychotropic agents is also addressed. Treatment in neuropsychiatry is not confined to pharmacotherapy; electroconvulsive therapy, psychotherapy, neurosurgery, and rehabilitative therapies also have important roles in the management of some patients; the place of these therapies in a comprehensive management strategy is described briefly. Finally, some general principles of treatment planning and patient management are summarized. Specific sources regarding drug pharmacokinetics, interactions, teratogenicity, side effects, and doses should be consulted prior to prescribing any of the agents discussed in this chapter. P.44
agents, inflammatory processes, neoplastic cells, or neurodegenerative mechanisms. More often, neuropsychiatric symptoms are ameliorated through the use of syndrome specific rather than disease -specific psychotropic medications.
TABLE 4.1. Effects on Neurotransmitters of Agents Commonly Used in Treatment of Neuropsychiatric Disorders
Transmitter Effect
Transmitter
Synthesis
Dopamine
Levodopa
Serotonin
Tryptophan
Acetylcholine
Choline, lecithin
Release (facilitation)
Dopamine
Amantadine, amphetamine
Release (inhibition)
Norepinephrine
Clonidine
Glutamate
Lamotrigine
Reuptake
Serotonin
Fluoxetine,
inhibition
Norepinephrine
Degradation
Dopamine
Acetylcholine
Norepinephrine, serotonin
Norepinephrine, serotonin
GABA
Depletion
Dopamine, norepinephrine
Reserpine, tetrabenazine
Receptor agonists
Dopamine
Acetylcholine
Milameline, xanomeline
Adrenaline
Dextroamphetamine, clonidine
Receptor antagonists
Dopamine
Neuroleptic agents
Adrenaline
Propranolol, yohimbine
Receptor facilitation
GABA
P.45 Drugs exert their principal effects through interactions with specific receptors. Receptors have differential distributions in
the central nervous system (CNS), thus resulting in regional effects on a chemically defined brain anatomy. The behavioral specificity of drug effects is largely ascribable to the regional distribution of the receptors affected.
time required for the drug to obtain 50% of the steady -state level or to decay 50% from the steady -state concentration after drug discontinuation. 5 Pharmacodynamics concern the relationship between plasma concentration and the agent's physiologic effects. 1 Pharmacodynamic effects are mediated by receptors that exhibit saturability (there are a finite number of receptors), specificity (receptors selectively interact with some compunds and not others), and reversibility (some interactions are irreversible, others are reversible). 2 Receptors have different affinities for compounds; high affinity receptors interact at low doses and low -affinity receptors require higher doses to achieve an effect. A dose response curve describes the relationship of the effect of a drug to its concentration. The potency of an agent is the dose or concentration required to produce an effect. 2
neuropsychiatry because neuropsychiatric disorders are most common in special populations such as children or the elderly. Although polypharmacy is generally avoided to minimize the opportunity for drug-drug interactions, it is P.46 often necessary in neuropsychiatry. Many patients require both treatment for an underlying neurological disorder (i.e., epilepsy) and concomitant neuropsychiatric manifestations of the condition (i.e., interictal psychosis or depression). In Alzheimer's disease, drugs that improve cognitive function, such as anticholinesterase agents, do not slow the progress of the disease and those that slow progression, such as antioxidants (i.e., vitamin E, selegiline), do not improve existing symptoms. To optimize treatment, both types of agents must be used together, sometimes in conjunction with a psychotropic agent. Several neuropsychiatric conditions may coexist and require combined therapy; treatment of depression with psychosis, for example, usually requires using both an antidepressant and an antipsychotic agent. Thus, the dictum to avoid polypharmacy often cannot be adhered to in neuropsychiatry. This imposes an obligation on the clinician to be aware of potential drug-drug interactions when using multiple agents simultaneously. Drug-individual interactions must be monitored in neuropsychiatry. Children, geriatric patients, pregnant women, and women who are nursing may require adjustment of treatment approaches when pharmacotherapy is considered. Dosage levels must be reduced in children and older patients. Children have proportionately less body fat and smaller volumes of drug distribution of fat -soluble drugs. Hepatic activity is higher is children than adults, receding to adult levels during puberty. This results in faster drug metabolism and lower serum levels in prepubertal children. 2 Geriatric patients show more variability in pharmacokinetics and pharmacodynamics than younger individuals and require cautious dosing regimens (dosage should start low and go slow, but not be stopped until the desired effect occurs or side effects limit further dosage increases). With aging, body water and lean body mass are reduced and body fat increases, resulting in higher levels of water-soluble drugs and lower levels of fat -soluble drugs for any specific dose administered. 6 Hepatic and renal blood flow are reduced in the course of aging, often resulting in diminished drug
metabolism and excretion. Some older individuals, however, metabolize and excrete drugs at rates comparable to those in younger patients and dosage regimens must be individualized. Pregnant and lactating women comprise another critically important population in neuropsychiatry. Information on use of pharmacotherapy in this group is lacking for many drugs, but teratogenicity is increased, albeit to only low levels, with first -trimester exposure to low -potency phenothiazines, lithium, anticonvulsants, anticholinergic agents, and benzodiazepines. Antiepilpetic drugs cause neural tube defects such as spina bifida as well as cardiac abnormalities, cleft lip and palate, and microcephaly. 7 Polypharmacy is more freqently associated with congenital malformations than monotherapy. Organ dysgenesis has not been reported to be increased with in utero exposure to tri -cyclic antidepressants. 8 , 9 Neuroleptics and antidepressants appear in breast milk at approximately the same levels as those in maternal serum; benzodiazepines, by contrast, have low milk -to -maternal serum ratios. Scheduling feeding times to coincide with lowest maternal serum levels will help minimize the exposure of the neonate to psychotropic medications. 9 , 10 Valproate therapy, particularly when administered to women under age 20, is associated with an increased frequency of polycystic ovaries, hyperandrogenism, and obesity. 1 1
Side-Effect Monitoring
Adverse events are common in the course of pharmacotherapy and are a major source of morbidity for neuropsychiatric patients. In some cases, drugs produce only minor inconveniences such as constipation or dry mouth whereas in others, orthostatic hypotension in elderly individuals may lead to falls and hip fractures with substantial morbidity or even mortality. Neuroleptic agents have particularly profound effects on brain function, leading to acute dystonic reactions, parkinsonism, and tardive dyskinesia. These are discussed in detail in Chapter 20 . The clinician should be familiar with the range of side effects associated with prescribed medications and should review these with the patient and caregiver when the drug is prescribed and on return visits. In addition, symptoms that emerge in concert with initiating a new drug or increasing the dose must be considered potential drug-induced side effects and dosage adjustments should be made accordingly.
The principal side effects of the major classes of agents used in neuropsychiatry are described below.
Therapeutic Alliance
Drugs can be effective in relieving neuropsychiatric symptoms only if the patient takes them. The rate of compliance with medication regimens is low even among well -intentioned patients. To optimize proper medication use, the patient and the caregiver must enter a therapeutic alliance with the clinician. This alliance is complex and evolves as the patient and physician collaborate over time. It begins with education; P.47 the physician must inform the patient and caregiver about the potential treatability of symptoms, the drugs available for use, the side effects, and the dose and regimen. In some cases, treatment will be declined, and this must be respected except when treatment is compelled by the law (e.g., when patients are dangerous to themselves or others without treatment). If treatment is initiated, the maximal effect of the drug is pursued and side effects must be monitored. If the treatment fails to accomplish its goals or intolerable side effects emerge, then treatment must be reevaluated and a second agent chosen if the patient and caregiver desire to continue with attempts at treatment. The patient and physician will learn to trust each other and the therapeutic alliance should mature in the course of this process. More difficult decisions regarding driving, conservatorship, and other issues that arise in the course of caring for patients with neuropsychiatric conditions can be approached more successfully once a trusting relationship has been established.
agitation. Most of these agents exert their effect on serotonergic systems, but some agents have mixed adrenergic and serotonergic actions. Venlafaxin is a combined reuptake inhibitor affecting serotonin and norepinephrine; roboxetine is a specific noradrenergic reuptake blocker. Tricyclic antidepressants have anticholinergic side effects and may exacerbate confusion and memory loss in neuropsychiatric patients; agents with the least anticholinergic activity (Table 4.2 ) should be used in this population.
Antipsychotic Agents
Antipsychotic agents are used for the treatment of delusional disorders as well as a wide array of other neuropsychiatric conditions. There are several classes of antipsychotic agents available; from a neuropsychiatric perspective they can be divided into those that have prominent D 2 dopamine receptor blocking effects and those that exert less marked D 2 blockade or D 2 blockade in conjunction with other receptor effects that provide antipsychotic efficacy with lower D 2 receptor occupancy. Agents producing marked effects on D 2 receptors (conventional antipsychotics, neuroleptics) at doses producing antipsychotic effects produce parkinsonism, tremor, dystonia, and akathisia in the early phases of treatment and frequently cause tardive dyskinesia with chronic treatment. Agents with relative sparing of the D 2 receptors (atypical or novel antipsychotics) are less likely to cause these effects; in addition, they may have more marked beneficial effects on negative symptoms frequently present in psychotic states, such as apathy, anhedonia, and
asociality. Conventional antipsychotics include phenothiazines (i.e., chlorpromazine, thioridazine, fluphenazine), butyrophenones (i.e, haloperidol), thioxanthenes (thiothixene), dihydroindolones (molindone), and dibenzoxazepines (i.e., loxapine) (Table 4.4 ). 1 2 Lower -potency phenothiazines such as thioridazine produce fewer extrapyramidal side effects and have more anticholinergic side effects, cause greater sedation, and are more likely to produce orthostatic hypotension than highpotency agents such as fluphenazine. Haloperidol has a side effect profile similar to that of the high -potency phenothiazines. Antipsychotic agents that have relatively less D 2 blocking activity or less of a tendency to induce extrapyramidal effects include risperidone, clozapine, olanzapine, quetiapine, and ziprasidone (Table 4.4 ). Risperidone is a benzisoxazole agent whose antipsychotic properties depend on a combination of D 2 and 5 -HT 2 blockade. A lower dose of drug is required for P.48
TABLE 4.2. Classes, Agents, Usual Doses, and Common Side Effects of Antidepressants 2, 69,70,71
Fluoxetine (Prozac)
10 "80
24"330
Sertraline (Zoloft)
50 "200
24"30
Similar to above
Paroxetine (Paxil)
10 "60
3"65
Similar to above
Citalopram (Celexa)
Similar to above
Fluvoxamine (Luvox)
50 "300
17"22
Similar to above
Nefazodone (Serzone)
100 "600
2"5
Venlafaxin (Effexor)
75 "225
Tricyclic antidepressants
50 "200
13"88
Dry mouth, constipation, drowsiness, orthostatic hypotension, tachycardia, weight gain, nausea, headache
Desipramine (Norpramine)
75 "300
12"76
Similar to above
20 "60
54"124
Similar to above
Clomipramine (Anafranil)
75 "300
17"37
Similar to above
Phenelzine (Nardil)
45 "90
1.5"4
Tranylcypromine (Parnate)
20 "50
2.4
Isocarboxazid (Marplan)
30 "60
Moclobemide (Manerix)
300 "600
4"9
Miscellaneous agents
Amoxapine (Asendin)
100 "600
Trazodone (Desyrel)
150 "600
4"9
Maprotiline (Ludiomil)
100 "225
27"58
Bupropion (Wellbutrin)
75 "400
10"14
Mirtazapine (Remeron)
15 "45
20"40
P.49
TABLE 4.3. Agents, Usual Doses, and Common Side Effects of Drugs Used to Treat Mania 2, 69,70,71
Agent (Brand
Elimination Half-life
Common Side
Name)
(mg)
(hr)
Effects
300 "2400
8"35
Carbarnazpine (Tegretol)
300 "1600
12"17
750 "6000
9"20
1"6
20"40
Lamotrigine (Lamictal)
15"24
Gabapentin (Neurontin)
900 "4800
5"7
Topiramate (Topamax)
200 "600
18"30
100"400 when administered with valproic acid; 300"500 when administered without valproic acid.
TABLE 4.4. Agents, Usual Doses, and Common Side Effects of Drugs Used in Management of Psychosis 2, 69,70,71
Atypical antipsychotics
Clozapine (Clozaril)
5"16
Risperidone (Risperdal)
20"24
Olanzapine (Zyprexa)
5"20 (200)
Quetiapine (Seroquel)
25 "400 (800)
Ziprasidone (Geodon)
20 "80 (160)
10
Neuroleptics
1"20 (40)
13"58
Molindone (Moban)
25 "225 (300)
6.5
30 "100 (250)
8"30
Thiothixene (Navane)
4"30 (60)
30"40
Tachycardia, hypotension, sedation, parkinsonism, restlessness, hematologic effects, rash, lactation, amenorrhea, dry mouth, blurred vision, impotence
Haloperidol (Haldol)
12"36
Pimozide (Orap)
2"20 (40)
29"55
Lower doses are commonly effective in patients with neurologic disorders. Dose in parentheses refers to upper limit of range in idiopathic psychoses.
P.50 antipsychotic efficacy and fewer side effects are produced. Extrapyramidal signs and symptoms emerge with higher doses of risperidone. Clozapine, olanzapine, ziprasidone and quetiapine have variable D 2 effects and are antagonists of D 1 , 5 -HT 2 , and 2 receptors. 14 , 1 5, 1 6 Clozapine and olanzapine have marked antimuscarinic receptor effects, although their clinical anticholinergic effects are modest. 1 4 , 1 7 Clozapine may induce agranulocytosis and requires weekly monitoring of the white blood count; it may also produce seizures in previously seizure -free individuals and precipitate them in patients with epilepsy. 1 8 Antipsychotic agents with D 2 blocking effects are useful in suppressing chorea and tics. They are also beneficial in patients with obsessive -compulsive disorder with concomitant tics. Antipsychotic agents that spare the D 2 receptors are particularly beneficial in patients with parkinsonism and psychosis, such as those with levodopainduced psychotic episodes. 1 9, 2 0 Either type of antipsychotic agent may be useful in amelio -rating agitation and psychosis in patients without coexisting extrapyramidal disorders. Antipsychotics are the principal agents used to treat agitation (with or without psychosis) in patients with dementia syndromes.
13
Anxiolytics
Benzodiazepine anxiolytics cause a reduction in anxiety through agonist effects on GABA (subtype A) receptors. 2 1 These agents typically enhance the ability of this inhibitory transmitter to increase the activity of the choloride channel. Metabolism of benzodiazepines is markedly affected by age; lorazepam and oxazepam are well metabolized by elderly individuals. Benzodiazepines are used in neuropsychiatry to reduce anxiety, control seizures, ameliorate tics and chorea, control myoclonus, relieve catatonia, reduce self -injurious behavior in mentally retarded individuals, and induce sedation and sleep. Benzodiazepines may be used to treat agitation but they may increase confusion in elderly individuals and usually should be avoided if continuous administration is required. Benzodiazepines have marked effects on sleep. They
decrease sleep-onset latency and increase total sleep time; they reduce stage 1 sleep and markedly reduce or abolish stage 4 sleep; stage 2 sleep is increased; rapid eye movement (REM) sleep is decreased in the beginning of the night. 2 2 Benzodiazepines are helpful in the treatment of restless legs syndrome and period limb movements during sleep. 2 3 Buspirone, the other major anxiolytic used in neuropsychiatric practice, exerts antianxiety effects by blocking serotonin (5 -HT 1 A ) receptors. 24 Buspirone may have less confusion -inducing actions and may be useful as an antiagitation agent. Table 4.5 summarizes information about the principal anxiolytics. Selective serotonin reuptake inhibitors (SSRIs) have anxiolytic effects and are the agents of choice for chronic anxiety syndromes.
Stimulants
Stimulants are an important part of the armamentarium of the neuropsychiatrist and are useful in a variety of neuropsychiatric conditions. The four principle agents used are dextroamphetamine, methylphenidate, pemoline, and modafinil (Table 4.6 ). 2 5 The drugs are used to treat apathy, attentional disorders in adults, hyperactivity -attention deficit disorder in children, depression, chronic fatigue syndrome, fatigue in multiple sclerosis, and fatigue in human immunodeficiency virus encephalopathy. Adverse effects of these drugs include anxiety, tremor, appetite suppression and weight loss, hypertension, and occasional psychosis. Intravenous amphetamines may cause a cerebral angiitis with intracerebral hemorrhage. Modafonil has been used primarily
TABLE 4.5. Agents, * Usual Dosage, and Common Side Effects of Anxiolytics 2, 69,70,71
Agent (Brand
Elimination Half-life
Common
Name)
(mg)
(hr)
Side Effects
1"6
20"40
Lorazepam (Ativan)
0.5 "10
8"24
Oxazepam (Serax)
30 "120
3"25
Buspirone (BuSpar)
15 "60
1"11
Selective serotonin reuptake inhibitors are the agents of choice for chronic anxiety disorders (Table 5.2 ).
P.51
TABLE 4.6. Psychostimutants and Drugs Used to Treat Apathy in Neuropsychiatric Disorders 2, 69,70,71
Psychostimulants
Methylphenidate (Ritalin)
5"60
1"7
Dextroamphetamine (Addorall)
5"40
6"11
Similar to above
37.5 "112.5
7"12
Similar to above
Modafinil (Provigil)
200 "400
15
Fluoxetine (Prozac)
10
24"330
Insomnia,
"80
anxiety, amphetamine like effects, tremor, orthostatic hypotension, gastrointestinal distress, sexual function disturbances
20 "60
54"124
Dry mouth, constipation, drowsiness, orthostatic hypotension, tachycardia, weight gain, nausea, headache
Bromocriptine (Parlodel)
5 -40
2"8
Pergolide (Permax)
0.25 "5
2"4
Tacrine (Cognex) *
80 "160
2"6
Nausea, diarrhea,
Donepezil (Aricept)
*
5"10
75"90
Rivastlgmine (Exelon)
6"12
Galantamine (Reminyl)
16 "24
in narcolepsy and excessive daytime sleepiness; its use in other circumstances is being explored. Pemoline requires a longer period (often several weeks) to begin its effects, and this agent also has less of a tendency to produce addiction and abuse.
Dopaminergic Agents
Dopaminergic agents include levodopa, levodopa plus carbidopa (a peripheral decarboxylase inhibitor that reduces conversion of levodopa to dopamine outside of the brain), pergolide, bromocriptine, ropinirole, pramipexole, tolcapone, entacapone, and amantadine hydrochloride (Table 4.7 ). Levodopa is a dopamine precursor that is converted to dopamine by cells in the substantia nigra or ventral tegmental area. Dopamine is then transported via axonal transport to receptor sites in the striatum, amygdala, nucleus accumbens, medial frontal cortex, and anterior
cingulate cortex. 2 6 Amantidine facilitates the release and inhibits the reuptake of dopamine from the presynaptic terminal, thus increasing the amount of intrasynaptic dopamine available. Pergolide, bromocriptine, ropinirole, and pramipexole are dopamine receptor agonists that directly stimulate the postsynaptic receptors in these target structures. Ropinirole and pramipexole have relatively selective effects on dopamine D 3 receptors. These agents may have antidepressive as well as antiparkinsonian activity. 2 7 Tolcapone and entacapone are catechol-O methyltransferase inhibitors that reduce the metabolism of levodopa and extend its action. 2 8 Dopaminergic agents improve motor function in Parkinson's disease and a beneficial response to these agents is often considered a criterion for the diagnosis of this disease (Chapter 18 ). Other parkinsonian syndromes such as progressive supranuclear palsy and vascular parkinsonism may have partial responses to dopaminergic therapy. In addition, akinetic mutism may respond to dopamine receptor agonists 29 and apathetic syndromes have also been reported to improve with dopaminergic therapy. 3 0 Restless legs syndrome 3 1 and pseudobulbar palsy 32 are two additional syndromes reported to be responsive to dopaminergic therapy. Amantadine has an important role in treating the P.52
TABLE 4.7. Agents Used in Treatment of Parkinson's Disease and Parkinsonism 2, 69,70,71
1"6
3"24
Trihexyphenidyl (Artane)
1"15
3"4
Similar to above
100 "400
15"24
Orchostatic hypotension, livedo reticularis, ankle edema, vivid dreams, hallucinations, delusions, insomnia urinary retention, dry mouth
2"4
5"10
Bromocriptine (Parlodel)
5"40
2"8
Pergolide (Permax)
0.25 "5
2"4
Ropinerolc (Requip)
0.75 "3
Pramipexole (Mirapex)
0.375 "4.5
8"12
Tolcapone (Tasmar)
300 "600
2"3
Entacapone (Comtan)
200 "1600
1"2
fatigue syndrome of multiple sclerosis. 3 3 Neuropsychiatric side effects of dopaminergic agents include nightmares, hallucinations, delusions, hedonistic homeostatic dysregulation disorder, mania, and sexual behavior changes. Chorea may occur with chronic administration. Anticholinergic agents may ameliorate tremor in parkinsonism. These agents have many adverse side effects and should be avoided in elderly patients.
Cholinomimetic Agents
Cholinesterase inhibitors are available for the treatment of diseases with cholinergic deficiencies, primarily Alzheimer's disease. Four cholinesterase inhibitors"tacrine (Cognex), donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon) (Table 4.8 )"are currently available and others are being developed. These agents have beneficial effects on cognition where they produce modest improvement of memory and other cognitive functions. 34 , 35 , 3 6, 3 7 , 38 They also ameliorate some behavioral disturbances, including psychosis, agitation, apathy, disinhibition, and aberrant motor behavior (pacing, etc.). 39 , 4 0 They delay decline in activities of daily living. Alzheimer's disease is the most common disorder with a cholinergic deficiency, but other conditions also have deficits of choline acetyltransferase and cortical
Tacrine (Cognex)
80 "160
2"6
Donepezil (Aricept)
5"10
75"90
Rivastigmine (Exelon)
6"12
Ga Lincamine (Reminyl)
16 "24
P.53 cholinergic abnormalities including Down's syndrome, Parkinson's disease with dementia, dementia with Lewy bodies, some cases of Creutzfeldt -Jakob disease, and Guamanian dementia-parkinsonism complex. 4 1 Cholinersterase inhibitors may be useful in these disorders and preliminary evidence suggests that some patients with multiple sclerosis, traumatic brain injury, and bipolar mood disorders benefit from treatment with these agents. Cholinergic receptor agonists and nerve growth factors with cholinoprotectic effects are being tested for clinical utility for the treatment of cholinergic deficiency states. Side effects of cholinesterase inhibitors include gastrointestinal cramps, diarrhea, vomiting, nausea, leg cramps, and rare cases of agitation.
Anticonvulsants
Anticonvulsants are used in neuropsychiatry for a wide variety of conditions. Their use in epilepsy is described in Chapter 21. Carbamazepine, valproate, gabapentin, topiramate, and lamotrigine are the agents most used in treating neuropsychiatric syndromes. They are used in patients with mood disorders, particularly rapid -cycling and
atypical bipolar disorders, and conditions with mixed mood states. Patients with mental retardation and mood disorders may respond well to anti-convulsant agents. They have proven to be of benefit in patients with episodic dyscontrol and intermittent explosive disorder. Agitation in patients with dementia often responds to treatment with these agents. Self-injurious behavior occurring in a wide variety of clinical circumstances may also improve following treatment with these compounds. Table 4.9 presents the anticonvulsants most often used in neuropsychiatric syndromes.
Electroconvulsive Therapy
Electroconvulsive therapy (ECT) offers another means of improving the function of patients with neuropsychiatric disorders. This therapy has been shown to be efficacious for depression, mania, schizoaffective disorders, and some types
of schizophrenia. It should be considered when the patient has a potentially responsive condition, has proven to be refractory to other therapies, is intolerant of alternative treatments, or requires a rapid response. 4 7 It should also be considered in treatment of refractory cases of Parkinson's disease, intractable seizures, and catatonia. 4 7 , 48 The use of ECT in patients with epilepsy requires special consideration since the induced seizure may precipitate status epilepticus or, conversely, the presence of anticonvulsants may make it difficult to induce a therapeutic convulsion. Given the low rate of complications, it is currently recommended that patients with epilepsy continue on a stable dose of anticonvulsants through the course of ECT. Unless they have a history of status epilepticus or of recent seizures, they should not receive their antiepileptic drugs during the day on which the ECT is administered until after the treatment is complete. The dose of anticonvulsant should be the minimum necessary to control seizures during this period. The ECT dose should be titrated to the seizure threshold at the time of the first treatment and administered at slightly above threshold for the rest of the course. 4 7 Raised intracranial pressure during ECT makes the presence of a brain tumor a relative contraindication, and because of the increased blood pressure occurring with seizures, caution is required when applying the technique to individuals with cerebrovascular disease. Skull defects may increase the risk of ECT -associated cognitive impairment and placement of electrodes over the area of bone loss should be avoided. P.54
Phenobarbital (Luminal)
60 "240
55"140
hyperactivity, depression
Primidone (Mysoline)
750 "2000
Drowsiness, cognitive dulling, rash, hyperactivity, depression, sexual dysfunction, hematopoetic effects
Phenytoin (Dilantin)
300 "600
6"42
Nystagmus, ataxia, drowsiness, rash, gingtval hyperplasia, hirsuimm, chorea, lupus-like syndrome, lymphadenopathy, peripheral neuropathy
Gabapentin (Neurontin)
900 "4800
5"7
Lamotrigine (Lamictal)
300 "500
Vigahatnn
1500
5"7
Drowsiness,
(Sabril)
"3000
Carbamazepine (Tegretol)
400 "2400
16"24
Oxcarbazepine (Trilepral)
1200 "3000
8"10
Dizziness, fatigue, headache, ataxia, hyponatremia, transient liver enzyme elevations, rash
750 "4000
9"20
Topiramate (Topamax)
200 "600
18"30
Asthenia, dizziness, nausea, weight loss, somnolence, psychomotor slowing, decreased concentration, nervousness
2"20
20"40
Ethosuximidc (Zaronfin)
500 "1500
50"60
Anorexia, nausea, weight loss, gum leukopenia, eosinophilia, drowsiness, irritability, hyperactivity, ataxia, depression, rash
Levetiraceram (Keppra)
1000 "3000
6"8
Tiagabine (Gabitril)
32 "56
7"9
Zonisamide (Zonegran)
200 "600
50"70
Electroconvulsive therapy induces temporary amnesia and patients are often unable to recall part or most of the hospitalization during which the ECT was administered. There may be a slight decrement in cognitive function (up to three points on the Mini -Mental State Examination), which reverses fully when the course is complete. 4 9 Cognitive impairment associated with depression is relieved by ECT, and improvement in neuropsychological test performance commonly follows ECT treatment. 50 Memory impairment in patients with dementia may be temporarily exaggerated following ECT; those with preexisting cognitive compromise and those experiencing prolonged disorientation in the postictal period are most likely to manifest persistent P.55
Addiction
Therapeutic Agent
Therapeutic Action
Alcoholism
Disulfiram
Inhibits dopamine # hydroxylase and causes an adversive syndrome when alcohol is ingested
Naltrexone
Opiotd antagonist
Acromprosate
Smoking
Nicotine therapy
Nicotine substitution
Bupropion
Clonidine
2 "Adrenergic agonist
Opioid dependence
Buprenorphine
Partial $ agonist
Naltrexone
Opioid antagonist
Methadone
$ Agonist
L - acetylmethadyl
$ Agonist
Cocaine
Desipramine
Amamadine
retrograde amnesia following ECT. 5 1 Careful studies with brain imaging reveal no changes in brain structure following ECT. 5 2 , 5 3
Psychotherapy
Every interaction with the patient is important to the patient. The clinician's demeanor, tone of voice, and actions are all of the greatest importance to the patient. 5 4 Every interaction can have therapeutic or counter therapeutic effects, allaying or increasing the concerns of the anxious patient, diminishing or exacerbating the fearfulness of the paranoid individual, enhancing or further decreasing the self -esteem of the depressed. The clinician's behavior can reassure or alarm the caregiver. The clinician must be cognizant of these effects, using them for their therapeutic impact and judging their effectiveness as part of the therapeutic alliance with the patient. Neuropsychiatric patients must be assessed thoroughly before deciding on a psychotherapeutic approach. Patients with neurological disorders may be cognitively impaired, have anosognosia for or denial of deficits, or be unable to remember their therapeutic encounters. The impact of these conditions on the psychotherapeutic process must be anticipated before the patient in therapy. Since each neuropsychiatric patient has a unique combination of altered and retained abilities, each therapeutic plan must also be individualized. While accounting for the patient's deficits in a treatment plan, it is important to retain a commitment to maximizing the patient's autonomy and to avoid falling into the error of making decisions for the "organic"! patient. Most patients have some aspects of cognition retained and personal choice should be honored within these bounds. A challenge to the therapist is to encourage patients to exercise maximum control of their life, while integrating the limitations that may be imposed by neurological illness into the discussions and patient and family expectations. The natural history of the neuropsychiatric disorder must also be considered in the treatment plan: degenerative diseases will require increasingly simple and environmentally oriented approaches, whereas the patient recovering from traumatic brain injury or stroke may be able to entertain progressively more complex interventions demanding personal insight and self -control.
Psychotherapy of the neuropsychiatric patient will likely involve an eclectic mixture of therapeutic approaches modified to fit individual circumstances. Classic insight oriented psychotherapy is appropriate only for a few patients with minimal deficits and retained self -awareness. Among the interventions that may broadly be conceived as psychotherapy are specialized training, structuring of the environment (home or care facility) and supportive, behavioral, cognitive, and psychodynamic approaches. 5 5 Therapy should address three key areas"cognition, emotion, and behavior"in all neuropsychiatric patients. 5 5 Each of these dimensions may P.56 require a somewhat different psychotherapeutic technique, and the resulting treatment program will be an amalgamation of the best approaches to the three areas individualized for each specific patient. Educational approaches can help patients understand what has happened to them, while cognitive, supportive, and at least limited psychodynamic therapies may help the patient respond to the question, "why has this happened to me ? "! 5 6 Psychotherapy may be integrated with traditional rehabilitation approaches including physical therapy, occupational therapy, and speech and language therapy. Most patients will require combinations of psychotherapy, rehabilitation, and the judicious use of medications to optimize treatment outcome. Patients with neuropsychiatric disorders are often inordinately reliant on family members for their care or well being. Many caregivers experience this dependency as a burden and a source of distress, anxiety, and depression. Assessment of the caregiver and referral for appropriate support or therapy is an essential part of the therapeutic process. In some cases, engagement of the patient and caregiver or family members in family therapy may be appropriate. Couples or families with interpersonal problems prior to the onset of the patient's neuropsychiatric disorder are more likely to have significant difficulty responding to the patient's needs than those with good premorbid function and interactions. Many disease -oriented lay groups provide educational information and seminars, family support groups, and services for patients. These groups are active advocates for neuropsychiatric patients.
TABLE 4.11. Conditions Reported to Have Responded to Behavioral Neurosurgical Procedures and Anatomic Target Affected
Neuropsychiatric Condition
Type of Surgery
Surgical Target
Depression
Leucotomy
Subcaudate craccotomy
cortex
Anterior capsulotomy
Cingulumotomy
Cingulate fibers
Anorexia nervosa
Orbitomedial tractotomy
Anxiety
Cingulumotomy
Cingulate fibers or connections between the cingulum and contralateral basal ganglia
Anterior capsulotomy
Pain
Cingulotractotomy
Addiction
Cingulotractotomy
Violence/rage
Cingulumotomy
Cingulate fibers
Obitomedial tractotomy
Amygdalotomy
Amygdalae bilaterally
Sexual aggression/pedophilia
Posterior hypothalamotomy
P.57
FIGURE 4.1 Locations of cingulumotomy for depression (blue, right), amygdalatomy for violent behavior (green, left), and hypothalamotomy for sexual aggression (red, left).
in which psychosurgery is applied. Pain and depression may improve following cingulumotomy. 57 , 5 8 Vagus nerve stimulation also ameliorates depression in some patients with mood disorders. Obsessive -compulsive disorder is treated with anterior capsulotomy, cingulumotomy, or combined surgeries. Uncontrollable violence or rage may decrease following bilateral amygdala surgery, and sexual aggression has been treated with posterior hypothalamotomy. 5 7 , 5 8 While anorexia nervosa, addiction, and anxiety have been reported to benefit from psychosurgery, ablative techniques are rarely used for these conditions unless they become life threatening and all other approaches have been exhausted. Schizophrenic patients may evidence amelioration of any concomitant mood disorder but the psychotic process is typically unaffected by the available surgeries. Figure 4.1 shows the anatomic locations of lesions placed in psychosurgical procedures. There are relatively few complications from contemporary psychosurgical interventions, although postoperative investigations have often been limited in terms of sophistication and duration of follow -up. Postoperative seizure frequency is approximately 2%. When neuropsychological deficits appear, they typically involve executive function and are evident on tests such as the Wisconsin Card Sort Test or the Picture Arrangement Test of the Wechsler Adult Intelligence Test. Lethargy or impulsiveness characteristic of frontal lobe dysfunction (Chapter 9 ) are the most common personality changes following psychosurgical procedures. 5 9 Refinements of the neurosurgical approach to behaviorally relevant targets have decreased the operative morbidity and mortality. Stereotactic approaches allow more exact placement of lesions with limited collateral damage, and use of external radio frequency devices to generate intracranial ablative lesions has eliminated the need for neurosurgery for some type of treatments such as anterior capsulotomy. 5 7 Neurosurgical procedures that are not overtly psychosurgical in intent may have behavioral consequences. Adrenal
medullary transplantation for Parkinson's disease have commonly led to depression, delusions, hallucinations, diurnal rhythm disturbances, and confusion. 6 0 Pallidotomy for Parkinson's disease (Chapter 18 ) has limited cognitive and behavioral effects when limited to the ventral posterior region of the globus pallidus, 6 1 but misplacement may result in cognitive and behavioral abnormalities. 6 2 Unilateral pallidal stimulation is reported to produce mild decrements in verbal fluency and visuoconstructive abilities as well as a decrease in anxiety and depression. 6 3 Temporal lobectomy for treatment -refractory epilepsy may lead to diminished violence and aggression in those exhibiting these behaviors preoperatively. 5 7 P.58
electrodes in subcortical structures. Stimulation of the ventro -intermediate nucleus of the thalamus suppreses rest tremor, and stimulation of the subthalamic nucleus alleviates the akinesia and rigidity of parkinsonism. 6 7 In addition, the technique is being used to treat intention tremor, pain syndromes, intractable dystonia, and some aspects of epilepsy. 6 8 High -frequency stimulation has the same effect as ablation but is reversible and neuropsychiatric consequences have been observed with deep brain stimulation, including acute depression, 6 9 and some patients have executive deficits and behavioral changes consistent with frontal-subcortical circuit dysfunction. 7 0 Vagus nerve stimulation is an approved therapy for treatment -resistant partial -onset seizures. Vagal nerve stimulation results in activation of brainstem nuclei and secondary stimulation of the cerebral cortex. Preliminary observations suggest that vagal nerve stimulation may also improve mood and represents an alternative therapeutic intervention for patients with treatment -resistant depression. 71 , 7 2
Treatment Planning
A plethora of treatment interventions are available to aid the patient with a neuropsychiatric disorder. Pharmacotherapy in conjunction with supportive psychotherapy are the mainstay of neuropsychiatric intervention but many other treatments, including behavioral therapy, cognitive therapy, and psychosurgery, are available if needed. The ideal model of neuropsychiatric care involves multidisciplinary assessment and interdisciplinary treatment planning. Nurses, social workers, physical therapists, occupational therapists, speech therapists, and psychologists/neuropsychologists as well as physicians may all have relevant input to the evaluation and treatment of patients with neuropsychiatric disorders. Treatment plans should be logical algorithms that allow the clinician to work through several steps serially as the patient is treated with specified interventions and the response is assessed. Outcomes should be measurable and feasible and should be jointly accepted by patient, family, and clinician. Reduction of behavioral disturbances, increased independence, return to work, improved quality of life, and deferral or avoidance of placement in a long-term care facility are all goals to be considered in patients with neuropsychiatric disturbances.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 5 - Principles of Neuropsychiatry
Principles Brain-Behavior Relationships Underlying Neuropsychiatric Syndromes Are Rule -Governed and Reproducible across Individuals
This universality assumption implies that an individual's brain is representative of human brains in general and that deviations from normative behavior have corresponding neurobiological correlates. The verity of this observation reflects the shared evolutionary and genetic determinants of brain structure and function. 2
Behavioral Features Unique to Individuals Are More Likely to Be Environmentally Influenced and Representative of Social and Cultural Factors; Aspects of Behavior That Are Invariant across Individuals Are More Likely to Be Neurologically Determined
The individual's psychological environment interacts with brain function to influence the occurrence, nature, persistence and content of behavioral syndromes. Delusional disorders are common products of brain dysfunction and occur with similar frequencies in different world populations. However, the content of delusional disorders varies among cultures and reflects the social and cultural setting of the delusional individual.
Therefore, they exert significant control over normal and abnormal behavior. Brain structure and function are influenced by environmental factors, thus genes are not the only determinant of behavior and genetic influences account for only a portion of the variance of human behavior. While the structure and connectivity of the brain are determined by genetic factors, they may be modified by environmental circumstances. For example, an enriched environment produces increased synaptic connectivity between neurons. 1 2a Thus, memory recall and associations among experiences will be increased by learning and involvement. These environmental influences contribute to individual differences associated with variable social, cultural, familial, and educational backgrounds.
Neuropsychiatric Symptoms Are Related to Regional Brain Dysfunction and Are Not Disease-Specific
Any of a variety of diseases that affect a specific circuit or brain regions will produce similar neuropsychiatric manifestations. Thus, disinhibition may be seen with orbitofrontal dysfunction in the context of vascular dementia, traumatic brain injury, degenerative brain disease, or cerebral infections; the symptom complex reflects the area of the brain involved rather than the specific disease present. 1 3 Likewise, apathy multiple sclerosis, human immunodeficiency infection, vascular disease, or degenerative involving the anterior cingulate and related structures and is not disease -specific. 1 3 may occur with virus (HIV), changes subcortical
anxiety, obsessive -compulsive behavior, personality alterations, and disturbances of sleep, appetite, or sexual behavior. Deficit syndromes traditionally have been the province of behavioral neurology whereas productive syndromes have been the subject of neuropsychiatry. This separation is artificial; deficit and productive syndromes frequently co -occur. The detection of a deficit disorder is an important clue to the presence of a brain disorder in patients with productive syndromes.
Neuropsychiatric Disorders Reflect Abnormalities of Fundamental Functions Whereas Neurobehavioral and Deficit Disorders Reflect Abnormalities of Instrumental Functions
Neuropsychiatric disorders arise from disruption of systems such as the limbic system and frontal-subcortical circuits mediating fundamental functions. Fundamental functions include emotion, motivation, mood, self -protection, and social affiliation. Deficit syndromes reflect lesions of brain modules mediating instrumental functions such as language,
praxis, and gnosis. Neuropsychiatric disorders resulting from abnormalities of fundamental functions include mood disorders, apathy, paranoia, and disinhibition, whereas instrumental dysfunction produces aphasia, apraxia, and agnosia. Fundamental functions are mediated by phylogenetically more primitive brain systems such as the limbic system P.63
Instrumental Disorders
Fundamental Disorders
connected by tracts
Channel function
State function
Heteromodal neocortex
Phylogenetically recent
transmitters
and the basal ganglia, whereas instrumental functions are mediated primarily by the more recently evolved heteromodal cortex (Table 5.1 ). 1 7 Fundamental functions can also be seen as "state"! functions that have important biochemical substrates, whereas instrumental functions may be seen as "channel"! functions more determined by their underlying anatomy (Table 5.1 ). 1 7
Any Psychiatric Condition May Occur as a Product of a Central Nervous System Disorder
Depression, mania, psychosis, anxiety, obsessive -compulsive disorder (OCD), and sexual behavioral changes have occurred in the setting of neurological illness with symptoms indistinguishable from those of idiopathic psychiatric disorders. 18, 19, 20 , 2 1, 2 2 This principle has the practical implication that neurologic disorders must be considered in a differential diagnosis of any patient presenting with a psychiatric syndrome.
There Is a Convergence of Evidence Regarding Regional Brain Dysfunction from Studies of the Psychiatric Aspects of Neurologic Disease and Investigations of the Neurobiology of Psychiatric Disorders
There is dysfunction of similar anatomic regions when disorders share behavioral manifestations. Thus, similar regional abnormalities have been detected in acquired and idiopathic depression, acquired and idiopathic mania, acquired and idiopathic psychosis, and acquired and idiopathic OCD. 18 , 23 , 2 4, 2 5 , 2 6 , 2 7 , 28 , 29 , 3 0
The Occurrence and Type of Neuropsychiatric Disorders Are Contingent on Which Brain Regions Are Affected
Different neuropsychiatric syndromes are associated with distinct patterns of anatomic involvement. Disturbances of the frontal lobes, temporal lobes, caudate nucleus, and globus pallidus are implicated in many neuropsychiatric syndromes but distinctive regions within these structures are affected in different neurological conditions. Table 5.2 provides a summary of the principal relationships between regional brain dysfunction and corresponding neuropsychiatric symptoms.
Neuropsychiatric Symptom
Regional Dysfunction
Mania
Depression
Left anterior frontal cortex, left caudate (in the acute poststroke period)
Right hemisphere
Apathy
Disinhibition
Paraphilia
The Developmental Phase of the Individual Must Be Considered as Part of the Formula That Determines the Frequency and Nature of the Neuropsychiatric Syndromes Occurring in Conjunction with Brain Disease
When Huntington's disease, idiopathic basal ganglia calcification, metachromatic leukodystrophy, or temporal lobe epilepsy begins in adolescence, the patient is more likely to develop psychosis than if these diseases begin later in life. 22, 3 4, 35, 36 In post-encephalitic disorders following epidemic encephalitis, adults manifest parkinsonism and mood disturbances whereas children develop tics and conduct disorders. 37 Thus, the developmental state of the brain is one of the determinants of the type of behavioral disorder emerging with brain dysfunction.
Differences in Symptom Profiles Exist within Neuropsychiatric Disturbances Associated with Differing Neurological Disorders
Suicide is common in depressive syndromes associated with epilepsy and Huntington's disease and rare in depressed patients with Parkinson's disease. 40 , 5 0 , 51 , 5 2 Psychotic depression is common in epilepsy and rare in Parkinson's disease. 40, 52 Self-deprecatory thoughts are common in poststroke depression and rare in the depression of Parkinson's disease. 53, 54 Likewise, each neurologic disorder with depression produces a somewhat different profile of depressive symptoms. Psychosis in Alzheimer's disease is typically associated with delusions of theft, infidelity, and misidentification, whereas
Neurologic Disorder
Alzheimer's disease
Frontotemporal dementia
Disinhibition, apathy
Vascular dementia
Huntington's disease
Parkinson's disease
Apathy, disinhibition
Corticobasal degeneration
Depression
Multiple sclerosis
Depression, psychosis
HIV encephalopathy
Apathy
delusions and mania is associated with grandiose delusions. Investigation of these subtle differences in neuropsychiatric symptomatology may provide insight into the unique contribution of different brain structures to neuropsychiatric symptom complexes.
Specific Regional Brain Changes Are Necessary but Not Sufficient to Produce Neuropsychiatric Symptoms
Neuropsychiatric disorders exhibit anatomic contingency and are more likely to occur after lesions of some regions than with others, but they do not have obligate anatomic relationships with specific lesions consistently dictating the occurrence of unique neuropsychiatric symptoms. For example, depression is common in the acute period following a left anterior or left subcortical stroke, but not all patients with lesions in this area manifest depressive symptoms. 20 , 3 3 The observation that not all patients with specific lesions manifest the commonly associated behavioral syndromes indicates that additional factors contribute to determining which patients with the appropriate lesions will exhibit the neuropsychiatric symptoms. 1 These additional factors may be related to the characteristics of the lesion or of the host. Lesion -related factors include location, size, and laterality of the injury as well as involvement of neurotransmitter systems. Host factors that condition the occurrence of neuropsychiatric symptoms include cerebral atrophy, genetic factors, patient gender, and developmental phase of the brain at the time of the insult. In addition, family support and psychosocial milieu will condition the emergence of neuropsychiatric symptoms following a cerebral insult. Thus, nonlesional influences allow substantial individual variability in the expression of neuropsychiatric symptoms among patients with similar brain lesions or disorders.
simultaneous neuropsychiatric symptoms. 16 This complicates management and distinguishes neuropsychiatric from idiopathic psychiatric disorders in which more monosymptomatic states may prevail.
In Progressive Neurologic Disorders, Neuropsychiatric Symptoms Tend to Emerge as the Disease Progresses
In Alzheimer's disease and other dementias, there are relatively few neuropsychiatric symptoms at disease onset and they become more P.66 common as the disease Prominent behavioral changes are a common precipitant of nursing home admission as the diseases become severe. The emergence of neuropsychiatric symptoms reflects worsening brain disease and greater dysfunction of behaviorally relevant brain regions. progresses. 1 6
Genetic and Environmental Factors Determine a Cerebral Reserve Which Affects the Likelihood That the Individual Will Manifest Neuropsychiatric Symptoms in Conjunction with Brain Dysfunction
Individuals with greater native intellectual endowment and higher educational levels are less likely to exhibit Alzheimer's disease than patients with less robust intellectual function and lower educational levels. 5 6 These factors determine cerebral reserve and make it possible for an individual to sustain higher levels of a pathologic burden without manifesting cognitive dysfunction. Similar effects
have been demonstrated in vascular dementia and HIV encephalopathy. Patients with cerebral atrophy are more likely to develop post-stroke depression than those without underlying atrophic changes. 33 Thus, cerebral reserve is one of the mediating host factors conditioning the development of neuropsychiatric symptoms in association with neurologic disorders.
Neurologic Disorders Produce Both Structural and Chemical Alterations and Neuropsychiatric Disturbances May Be Influenced by Either of These
Post -stroke depression is initiated by the structural brain injury, but the subset of patients with the appropriate lesion most likely to become depressed are those with disturbed serotonergic function. 32 Patients with Alzheimer's disease have neuritic plaques and neurofibrillary tangles in the hippocampus and neocortex as well as a cortical cholinergic deficit. Memory, language, and visuospatial disorders may be determined primarily by the structural cortical pathology,
whereas apathy and hallucinations may be more related to biochemical changes. 56 , 5 7 Cholinergic therapy in Alzheimer's disease has a greater influence on neuropsychiatric manifestations of the disorder than on the associated cognitive abnormalities. An interaction between structural and biochemical changes occurs in brain disorders.
Neuro transmitter
Serotonin
Depression, OCD,
impulsivity/aggression, psychosis
Dopamine
Psychosis, depression
Norepinephrine
Depression, anxiety
Acetylcholine
P.67
and delusions in patients with Parkinson's disease). Symptom-specific pharmacotherapy involves the use of antidepressants, antipsychotics, and anxiolytics to treat depression, psychosis, and anxiety in conjunction with neurologic disorders. The success of similar pharmacotherapies in symptomatic and idiopathic behavioral disturbances supports the presence of shared mechanisms in these conditions.
The Beneficial Effects of Psychotherapy Are Mediated through Changes in Brain Function
The universality assumption that there is deviant brain function in association with all behavioral abnormalities implies that resolution of these disturbances through any means including pharmacotherapy, psychotherapy, and surgical therapy will have an effect on underlying brain function. This has been demonstrated in OCD, where behavioral therapy reduces orbitofrontal and caudate hypermetabolism. 58
Neuropsychiatric Disorders Increase Caregiver Distress and May Precipitate Institutionalization of Patients with Neurologic Conditions
Behavioral abnormalities in patients with neurological disorders have been related to the severity of caregiver distress. 6 2 Patients with behavioral disturbances are also more likely to be institutionalized and behavioral disorders are more common among nursing home residents than among community-dwelling patients with the same neurologic conditions. 63
Summary
These principles regularize considerations of brain -behavior relationships in neuropsychiatric disorders. They relate both to symptomatic and idiopathic neuropsychiatric conditions and standardize expected brain -behavior relationships while allowing for individual variability. They comprise an emerging epistemology of neuropsychiatry.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 6 - Disorders of Speech and Language
Mutism
The term mutism has been used to refer both to loss of propositional speech (but with the retained ability to grunt, cough, sing, etc.) and the complete obliteration of all sound producing abilities in patients who are alert. Table 6.1 presents the differential diagnosis of mutism and lists the wide variety of disorders that may dramatically reduce verbal output. Examination of the function of the jaw, face, and tongue are critical in determining the cause of the mutism, and assessing the patient's attitude toward the loss of speech can also provide important insights.
Myopathies
Neuropathies
Brain disorders
Polioencephalitis
Cerebrovascular disease
Neoplasms
Pseudobulbar palsy
Cerebrovascular disease
Neoplasms
Multiple sclerosis
Parkinson's disease
Wilson's disease
Torsion dystonia
Dementias
Frontotemporal dementias
Broca's aphasia
Global aphasia
Childhood aphasia
Aphemia
Akinetic mutism
Cerebellar disorders
Psychiatric illnesses
Conversion disorder
Malingering
Selective mutism
Autism
Drug-induced mutism
nonverbal vocalization such as laughing and crying is spared or may even be pathologically exaggerated (Chapter 14 ). 1,2,3, 4, 5 Deficits commonly accompanying the mutism of the pseudobulbar syndrome include dysphagia, facial weakness, brisk jaw jerk and facial muscle stretch reflexes, impaired tongue movements, and an exaggerated gag reflex. The bilateral supranuclear lesions responsible for pseudobulbar palsy may be produced by cerebrovascular disease, neoplasms, multiple sclerosis, inflammatory or infectious disorders, or amyotrophic lateral sclerosis. When the lesions involve limbic as well as corticobulbar connections, the mutism may include both verbal and
nonverbal emotional vocalizations. 6 Mutism is combined with limb paralysis in the locked-in syndrome. Advanced neurological disease of practically any type can produce mutism but it is particularly common with the bradykinetic and dystonic extrapyramidal syndromes, in which progressive dysarthria and hypophonia eventually lead to mutism. Extrapyramidal syndromes capable of producing mutism include Parkinson's disease, progressive supranuclear palsy, Wilson's disease, and the dystonias. Occasionally, the facial and laryngeal involvement is out of proportion to limb and truncal involvement, resulting in mutism early in the course of the disease. In some cases the mutism may be overcome when the patient is extremely excited or angry, 6 and singing may be possible even when expository vocalization is not. Cerebellar disorders are also associated with mutism, particularly in children. The syndrome typically occurs after removal of a cerebellar tumor and lasts from a few weeks to a few months. In some cases, the mutism does not begin immediately after surgery but is deferred for 1 or 2 days. The mute period is followed by the development of dysarthric speech and eventual return to normal speech. The syndrome is most common in children who had hydrocephalus at presentation and who have had a tumor adjacent to the fourth ventricle. 7,8,9 Postsurgical meningitis is also a risk factor for the disorder. Cerebellar mutism occurs almost exclusively in children under 10 years of age and has occurred after surgery for medulloblastomas, astrocytomas, and ependymomas. Mutism precludes the recognition of aphasia since mutism is the absence of language production, whereas aphasia refers to the presence of an abnormal language output. Nevertheless, mutism may he present in the initial phases of patients with nonfluent aphasia (Broca's aphasia, global aphasia) and is a standard feature early in the course of aphasia associated with subcortical lesions (thalamus, basal ganglia) and of transcortical motor aphasia. 10 In these cases the mutism is transient, and aphasic agraphia is evident in the patient's writing. P.72 Childhood aphasia, unlike aphasic disturbances in adults, is commonly associated with an initial mute period regardless of the type of aphasia. 11, 12 Mutism may occur in the course of advanced dementia syndromes; it is more common with frontotemporal dementias than Alzheimer's disease (Chapter 10 ). Mutism has also been associated with closed head injury, particularly lesions of the basal ganglia or diffuse axonal injury. 13 Aphemia is an uncommon disorder that presents with an acute right hemiparesis and mutism, but with preserved ability to write. When speech is restored, it has a hoarse, breathy, dysarthric, and often hypophonic quality, but there is no aphasia. 14, 15 The recovered speech of the aphemic patient often has dysprosodic qualities with changes in pitch and syllable stress that make the speech sound like that of a non -native speaker of the language. This disorder has been called the foreign accent syndrome and is uniquely associated with aphemia. 16, 17, 18 Broca's type aphasia may be present in the early phases of the disorder following recovery from the mutism but is not sustained. The lesion producing aphemia is usually an infarction limited to Broca's area in the left precentral frontal cortex or the white matter immediately subtending it. 19, 20 The most common cause of the syndrome is embolic infarction associated with an embolus of cardiac origin.
Lesions of the supplementary motor area on the medial aspect of the left hemisphere commonly produce mutism in the acute stages. During recovery, the patient may manifest a transcortical motor type aphasia (discussed below) or may exhibit a paucity of speech output without aphasia. 21, 22 The lesion associated with transcortical motor aphasia and early mutism has usually been occlusion of the left anterior cerebral artery with infarction of the medial frontal region including the supplementary motor area. Disruption of white matter connections underlying the supplementary motor area and connecting this region with Broca's area may be essential to the occurrence of the disorder (Fig. 6.1 ). 23 The syndrome has also been observed with left medial corticectomies, left medial subdural hematomas and neoplasms, and subcortical infarctions involving the left thalamus and putamen. 22, 24, 25, 26 Akinetic mutism is a state of nearly complete motionlessness combined with total mutism. Two varieties of akinetic mutism have been distinguished: a !vigilant coma!! variety in which the patient is immobile yet seemingly alert, has full extraocular movements, and can occasionally be aroused to move or may even have brief agitated periods; the other is a somnolent variant in which the patient appears asleep most of the time and has oculomotor abnormalities. In the former, the lesion is usually situated at the base of the brain anteriorly in the region of the optic chiasm, medial fore-brain bundle, anterior hypothalamus, or the anterior cingulate bilaterally (Fig. 6.2 ); in the later, the lesion is located more posteriorly in the anterior midbrain or mesodiencephalic junction. 27 The syndrome may be produced by vascular lesions, trauma, multiple sclerosis, or tumors in the region of the third ventricle. 28, 29, 30, 31, 32 Akinetic mutism has been treated successfully with dopamine receptor agonists (bromocriptine), which suggests that interruption of ascending dopamine projections may contribute to the marked reduction in spontaneous activity. 31, 33
FIGURE 6.1 Disconnection of the white matter underlying the supplementary motor area (shown in red) and connecting this region with Broca's area is associated with transcortical motor aphasia.
Mutism may be a manifestation of extreme retardation and fatigue in depression, and it is a common manifestation of catatonia occurring with mood disorders or schizophrenia 28 (Chapters 12 , 14 , and 20 ). Mutism may occur as a conversion symptom and can take the form of either aphonia with whispered speech or complete mutism, sometimes with apparent inability to comprehend as well as to produce spoken language. In most cases the patient is able to read and write normally, and normal vocal cord function can be demonstrated by having the patient cough. 34 Normal P.73
FIGURE 6.2 The lesion responsible for the !vigilant coma!! variety of akinetic mutism is usually situated at the base of the brain anteriorly in the region of the optic chiasm, medial forebrain bundle, anterior hypothalamus, or the anterior cingulate bilaterally (shown by arrows).
coughing is impossible if the vocal cords are paretic, and patients with paretic cords produce a distorted, bovine sound. Hysterical mutism is more common in children than in adults and, like all conversion reactions, may be the harbinger of a major neurological or psychiatric illness (Chapter 22 ). Mutism is an occasional manifestation of malingering. Selective mutism is a syndrome of preadolescent children who evidence language competence in some circumstances, such as among family members and friends, but do not speak in other social situations, particularly school. The syndrome is rare (7 out of 1000 children have transient selective mutism and in 0.7/1000 it persists for more than 6 months) and is more common among children with some other type of communication disorder (articulation defect) and recent immigrants learning a new language. Children with selective mutism often have associated behavioral
disturbances such as negativism, defiance, shyness, poor peer relations, and social isolation. The prognosis for the syndrome is usually excellent. 35, 36 Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine have hastened resolution of the syndrome. 37 Mutism may also occur as part of the childhood autism syndrome. Mutism is occasionally observed in liver transplant patient recipients being treated with cyclosporine or FK506. 38
Dysarthria
Dysarthria refers to impairment in the motor aspects of speech. Dysarthric abnormalities include disturbances in speech rate (too slow, too fast, bursts), volume (hypophonia, megaphonia), tone, pitch, timing, and accuracy of articulation. Six basic types of dysarthria have been described (Table 6.2 ). Each dysarthria corresponds to a predominant motor disorder: flaccid, spastic, ataxic, hypokinetic (parkinsonian), hyperkinetic (choreic), and dystonic (spasmodic dysphonia). 39 In addition, mixed dysarthrias occur in disorders that have more than one type of motor dysfunction such as the mixed spastic-ataxia of multiple sclerosis or the mixed spastic-flaccidity of amyotrophic lateral sclerosis. Speech therapy may be of substantial benefit to many dysarthric patients.
Type of Dysarthria
Principal Features
Typical Diseases
Flaccid
Myasthenia gravis
Spastic
Strained -strangled voice, slow rate, imprecise consonants, reduced stress, harsh voice, low pitch,
monoloudness
Ataxic
Excess stress, irregular rate and rhythm, distorted vowels, imprecise consonants
Multiple sclerosis
Hypokinetic
Monopitch, monoloudness, reduced stress, variable rate, short rushes of speech, inappropriate silences, brcathiness
Parkinson's disease
Hyperkinetic
Imprecise consonants, prolonged intervals, variable rate, monopitch, harsh voice, excess loudness variation, inappropriate silences, distorted vowels
Huntingron's disease
Dystonic
Strained -strangled voice, monopitch, irregular articulation, monoloudness, harsh voice, distorted vowels
Spasmodic dysphonia
Mixed
Multiple sclerosis, ALS with upper and lower motor neuron dysfunction, Wilson's disease
complications, prognosis, treatment, and etiology. The discussion that follows focuses on aphasia syndromes associated with relatively discreet CNS lesions associated with infarctions, neoplasms, or trauma; aphasia associated with dementia syndromes is presented in Chapter 10.
FIGURE 6.3 A systematic approach to aphasia diagnosis based on the cardinal observations of fluency of spontaneous speech, integrity of linguistic comprehension, and ability to repeat phrases and sentences is the best taxonomic aid for assessing language dysfunction.
with little information content. Grammatical words are not omitted, but errors in the use of grammar (paragrammatism) may occur. Paraphasias are prominent, and in the acute phases there is a tendency for the patient to be unaware of or to deny any language deficit. Not all of these distinguishing features are present in every case, and phrase length, agrammatism, and paraphasia are the most useful parameters for differentiation of fluent from nonfluent verbal output. In adults, fluent aphasias correspond to lesions in the posterior left hemisphere, whereas nonfluent aphasias are produced by lesions that include the left frontal lobe. In children, however, nonfluent aphasia may occur regardless of the location of the lesion. 44 Assessment of language comprehension is the second step in evaluation of the aphasic patient. Comprehension deficits may be mild or severe, and a hierarchy of increasingly difficult tests of linguistic understanding must be utilized in aphasia testing (Chapter 3 ). In general, patients with focal lesions limited to the left frontal lobe have preserved comprehension (Broca's and transcortical motor aphasia), whereas patients with left posterior temporal or parietal involvement suffer some degree of comprehension impairment (Wernicke's, global, transcortical sensory, and isolation aphasias). The third step in a systematic examination of the aphasic patient is to determine the patient's ability to correctly repeat words and sentences. For accurate assessment of this ability, the length of the presented material must not exceed the attention span of the subject. Failures in repetition take the form of paraphasic intrusions, alterations in the presented sequence of
Nonfluent Aphasia
Fluent Aphasia
Decreased output
Dysarthria
Normal articulation
Dysprosody
Agrammatism
Paraphasias present
P.76
READING
Aphasia Type
Fluency
Comprehension
Repetition
Naming
Aloud
Comprehension
Writing
Special Features
Broca's
Nonfluent
+a
-b
Transcortical motor
Nonfluent
Global
Nonfluent
Automatic speech (e.g., counting) and singing may be preserved; right hemiparesis innearly all cases
Nonfluent
Echolalia
Wernicke's
Fluent
Transcorrical sensory
Fluent
Conduction
Fluent
Subcortical (nonthalamic)
Fluent
Thalamic
Fluent
words, omission of words, or a tendency to alter the content of the presented sentence. Aphasic syndromes with impaired repetition (Wernicke's, Broca's, and conduction aphasias)
have lesions involving structures immediately adjacent to the sylvian fissure of the left hemisphere, whereas syndromes with intact repetition abilities (transcortical aphasias) are associated with lesions that spare the perisylvian areas. 45, 46 After the initial observations have been made regarding fluency, comprehension, and repetition, further refinements in characterization of the aphasic syndromes and lesion localization are made through use of tests of naming, reading, and writing. Table 6.4 summarizes the principal clinical features of each major type of aphasia.
Broca's Aphasia
Broca's aphasia is a nonfluent aphasic syndrome characterized by effortful, dysarthric, dysprosodic, and agrammatical verbal output. Although comprehension is largely intact in patients with Broca's aphasia, patients often have difficulty in mastering material that involves sequential manipulation based on specific grammatical relationships ( !put the blue square on top of the red circle!!) . This deficit in grammatical comprehension is present for both oral and written material and corresponds to the agrammatism of the individual's spoken language. 47 Repetition, reading aloud, naming, and writing are also impaired. The lesion responsible for Broca's aphasia usually involves the inferior frontal gyrus and adjacent areas of the operculum and insula in the territory of the upper division of the middle cerebral artery. 15, 46, 48, 49 The extent of the lesion determines the features of the aphasic syndrome. Damage to the frontal operculum produces difficulty with speech initiation; injury to the lower motor cortex results in dysarthria and dysprosody; damage that extends more posteriorly to involve the temporoparietal to opercular connections leads to phonemic P.77
FIGURE 6.4 Classic Broca's aphasia is evident when the cortical lesion is accompanied by white matter adjacent to the ventricles and containing limbic -frontal periventricular pathways are included in the lesion (red).
paraphasias similar to those of conduction aphasia (described below). Classic Broca's aphasia combining all these features with agrammatical, shortened utterances is evident when the above regions plus the white matter adjacent to the ventricles and containing limbic -frontal periventricular pathways are included in the lesion (Fig. 6.4 ). 50 When the frontal lesion involves the premotor area and frontal operculum, a right -sided hemiparesis involving
the face and the arm more than the leg usually accompanies the aphasia, and a sympathetic apraxia (discussed below) may affect buccolingual and left -sided limb function. 51, 52, 53
Global Aphasia
Patients with global aphasia have impairments in virtually all aspects of language function, including spontaneous verbal output, comprehension, repitition, naming, reading aloud, reading comprehension, and writing. 15, 45 Often the only spontaneous verbalizations will be stereotyped nonsense productions such as !za, za, za,!! although some patients may have a small repertoire of overlearned stock phrases (!hello,!! !I can't,!! etc.) that can be uttered fluently, and many global aphasics can curse with ease when angered. Automatic speech (counting, reciting the days of the week or months of the year), and humming of learned tunes (!Happy Birthday,!! !Jingle Bells!!) may be possible despite the severe defect in expressive propositional language. Poor comprehension of language distinguishes global aphasia from Broca's aphasia, and poor repetition distinguishes it from mixed transcortical aphasia (isolation aphasia). Even when comprehension is severely impaired, many global aphasics will be able to follow whole body commands (!stand up,!! !sit down!!) , can distinguish foreign language P.78
FIGURE 6.5 Global aphasia occurs when a large, left sided lesion involves the entire territory of the middle cerebral artery (red).
and nonsense speech from their native tongues, can judge inflection sufficiently to differentiate questions and commands, can recognize spoken or written names of personally relevant persons and landmarks, 55 and will reject written language that is presented upside down. 46, 56 Pathologically, the usual lesion producing global aphasia is a large, left -sided infarction involving the entire territory of the middle cerebral artery (Fig. 6.5 ). 46 There is typically an accompanying hemiparesis, hemisensory defect, and homonymous hemianopsia. Rarely, multiple emboli to anterior and posterior language -mediating areas will produce global aphasia without major motor deficits. 57
Wernicke's Aphasia
Wernicke's aphasia entails fluent, paraphasic output with poor comprehension, repetition, and naming. The patient's colorful, often nonsensical, logorrhea, frequently combined with an unawareness or denial of any deficit, creates one of the most striking syndromes in clinical neurology. 15, 45 The patient exhibits press of speech with accelerated output and often has a demanding, intrusive, even quarrelsome conversational style. Spontaneous speech contains primarily semantic paraphasias and neologisms, whereas literal paraphasias may dominate attempts to respond to naming tests. Reading and writing are compromised. The production of logorrheic, paraphasic speech with multiple substitutions and in comprehensible gibberish is called jargon aphasia, a verbal output disorder that may also occur in conduction aphasia and transcortical sensory aphasia. 45, 61 The relative preservation of comprehension in conduction aphasia and repetition in transcortical sensory aphasia distinguish these two disorders from Wernicke's aphasia. P.79
FIGURE 6.6 Mixed transcortical aphasia can occur when a lesion simultaneously affects posterior linguistic regions and the frontal lobes (red) and spares the arcuate fasiculus (green), thereby allowing normal repetition.
Although the cardinal features of Wernicke's aphasia (fluent output, poor comprehension, poor repetition) describe a basic syndrome, there are many variations in the clinical presentation. Comprehension may be mildly impaired with preserved ability to interpret moderately complex sentences, or it may be severely involved, sparing only simple midline and whole -body commands (!close your eyes,!! !open your mouth,!! !stand up,!! !sit down!!) . Comprehension of orally presented material may be relatively spared whereas written information is severely affected, or the reverse may occur. Greater involvement of auditory comprehension corresponds to more extensive involvement of temporal lobe structures, including primary auditory cortex, and greater compromise of reading comprehension may reflect extension of the lesion superiorly into inferior parietal lobe and angular gyrus. 15, 62 Pathologically, the lesion corresponding to Wernicke's aphasia involves the posterior third of the left superior temporal gyrus but rarely is limited to this region and frequently involves adjacent temporal and inferior parietal areas (Fig. 6.7 ). 15, 46 The majority of patients with Wernicke's aphasia have had a cerebral infarction and, in most cases, the vascular occlusion was produced by an embolus arising from the heart. 63 Wernicke's aphasia is occasionally produced by a neoplasm or trauma and is rarely observed in patients with degenerative dementias. A superior quadrantanopsia and cortical sensory loss in the face and the arm are common associated findings in patients with Wernicke's aphasia, and if the lesion extends into the posterior limb of the internal capsule, a hemiparesis will result.
temporal gyrus, and periventricular white matter pathways of the temporal isthmus underlying these cortical areas. 46, 64, 65 When it results from involvement of the angular gyrus, it is frequently accompanied by Gerstmann's syndrome, constructional disturbances, and other evidence of the angular gyrus syndrome (Fig. 6.8 ). 66 Transcortical sensory aphasia may also be seen during one stage of the evolution of Alzheimer's disease. 67 P.80
FIGURE 6.7 The lesion corresponding to Wernicke's asphasia involves the posterior third of the left superior tempral gyrus (red).
Conduction Aphasia
Conduction aphasia is a unique fluent aphasic syndrome in which comprehension is relatively intact and repetition is disproportionately impaired. Spontaneous speech is characterized by word -finding pauses and a predominance of phonemic or literal paraphasias over semantic or neologistic paraphasias. Often the patient is aware of making errors and makes sequentially closer approximations to the intended word (conduit d'approche). Reading aloud is impaired, but reading comprehension is intact. Naming and writing are both abnormal and contain phonemic paraphasic substitutions. 15, 45, 48 Although comprehension
FIGURE 6.8 Transcortical sensory asphasia results from a lesion of the angular gyrus (red) and is similar to Wernicke's aphasia but with intact repetition.
have syntactic comprehension defects similar to those described in Broca's aphasia. 68 The lesion responsible for conduction aphasia typically involves the arcuate fasciculus in the left parietal operculum. Adjacent cortical areas mediating language comprehension are often involved. 46
Anomic Aphasia
Anomia is a ubiquitous finding in disorders affecting the cerebral hemispheres and is present in all types of aphasia as well as in toxic -metabolic encephalopathies and with increased intracranial pressure. In the latter circumstances, anomia is a nonspecific indicator of cerebral dysfunction and has no localizing significance. 15, 69 Three primary types of anomia occur in aphasic syndromes: word production, word selection, and semantic anomia. 69 Word production anomia is characterized by an inability to express the desired word. The primary problem is a disturbance of initiation of the word, and patients respond readily to phonemic cues (the first syllable or first sound of the word). Word production anomias are characteristic of nonfluent aphasias such as Broca's aphasia and transcortical motor aphasia. It is also the principal type of naming deficit in patients with subcortical dementias (Chapter 10 ). Patients with semantic anomia have an impaired ability to name, do not respond to cues, and cannot recognize the word when it is said by the examiner. The sound of the word is bereft of meaning. Semantic anomia occurs in Wernicke's aphasia and transcortical sensory aphasia. Word selection anomia features anomia, a failure to respond to phonemic cues, but an intact ability to recognize the word when provided. Word selection anomia is the principal feature of anomic aphasia. Spontaneous speech has an empty, circumlocutory quality with frequent word -finding pauses, many words of indefinite reference (!it!!, !thing!!, etc.), and little paraphasia. Comprehension is relatively preserved, and repetition, reading aloud, and reading comprehension are spared. Anomia will be present on tests of confrontation naming and in spontaneous writing. The patient can usually, but not invariably, recognize the correct word when it is presented by the examiner. 15, 45, 48, 69 Anomic aphasia usually indicates a lesion in the left angular gyrus or adjacent areas of the posterior second temporal gyrus. Some patients with anomic aphasia have had lesions of the left anterior temporal or temporal polar regions. 46 Anomic aphasia is frequently the residual deficit following recovery from more extensive aphasic syndromes (Wernicke's aphasia, conduction aphasia).
aphasia, but there is often an initial mute period at the time of onset, and articulatory deficits may persist throughout the clinical course. The aphasia is often transient and is usually associated with attentional deficits, right -sided neglect, lack of appropriate concern, perseveration, and right hemiparesis. 10 A similar syndrome has been observed with infarctions of the dominant thalamus although in many cases there is no associated language disorder. Aphasia following circumscribed lesions of the thalamus is usually transient and studies of cerebral blood flow or cortical glucose metabolism indicate that reduced cortical perfusion or metabolism is present when a subcortical lesion is associated with an aphasia syndrome. These observations suggest that the thalamus has an important role in word production and cortical activation but thalamic dysfunction is not sufficient to produce a specific aphasia unless there is associated cortical dysfunction. 70 Infarction of left -sided basal ganglia structures may also produce a syndrome of reduced generative language with prominent dysarthria and hypophonia 45 (Fig. 6.9 ). Syndromes associated with hemorrhage are similar but more severe. Nonhemorrhagic lesions may produce aphasic syndromes by disrupting subcortical white matter tracts and radiations or by extending to involve adjacent cortical regions. 43, 71 The principal characteristics of the language syndrome associated with left basal ganglia dysfunction are word -finding deficits (lexical selection anomia), occasional semantic substitutions, and impaired comprehension of complex syntactically determined material. Generative language is reduced with deficient word list generation, poor sentence generation, increased latency and perseveration, and echolalia. These findings are nonspecific and compatible with loss of facilitating or activating influences exerted by subcortical structures on cortical activities. Metabolic studies reveal a reduction P.82
FIGURE 6.9 Infarction of left -sided basal ganglia structures (red) may produce a syndrome of reduced generative language with prominent dysarthria and hypophonia. The syndrome of subcortical aphasia occurs because of a disconnection of activating influences exerted by subcortical structures on cortical function.
only on the nature of the aphasia syndrome itself but also on the associated neuropsychiatric complications. Table 6.5 lists the neurological and neuropsychiatric disturbances commonly associated with anterior or posterior left hemisphere lesions. Catastrophic reactions may occur with either anterior or posterior lesions, 74, 75 but they tend to be more common in patients with anterior subcortical lesions, particularly those with concomitant depression. 76 Patients with posterior lesions, particularly Wernicke's aphasics, may be unaware of their language deficits, and these patients exhibit the greatest tendency toward becoming suspicious and paranoid during the course of their illness. 77, 78 Anxiety is most often found in patients with anomic aphasia and retrorolandic lesions, 74 although it also occurs with lesions of the left frontal cortex. 79 Depression is more common and more profound among patients with anterior than posterior lesions. Depression is not correlated with severity of physical or cognitive impairment but is related to the proximity of the lesion to the anterior pole of the frontal lobe (Chapter 14 ). 80, 81 Moderate to severe depression in aphasics is associated with neurovegetative disturbances (sleep and appetite alterations) and an abnormal dexamethasone suppression test. 82 Prognosis for language recovery varies with etiology of the aphasia and the type of linguistic deficit. The outcome of aphasias associated with neoplasms depends
TABLE 6.5. Neurological and Neuropsychiatric Disturbances Associated with Anterior and Posterior Left Hemisphere Lesions
Clinical Features
Anterior Lesion
Posterior Lesion
Aphasia
Nonfluent
Fluent
Neurological deficits
Hemiparesis
+/ -
Hemisensory loss
+/ -
Hemianopsia
+/ -
Behavioral alterations
Depression
Anxiety
Paranoia, suspiciousness
Catastrophic reactions
+/ -
P.83 directly on the success of treating the tumor. Traumatic aphasias recover more completely than do aphasias produced by cerebrovascular disease, and among vascular aphasias, the greatest amount of recovery occurs within the first 3 !6 months, although minor degrees of recovery may continue for 5 or more years. 83, 84 Global aphasics have the worst prognosis for recovery of useful language skills; Broca's and Wernicke's aphasics have an overall fair prognosis for recovery with sizable variations from patient to patient; anomic, conduction, and transcortical aphasics have a relatively good prognosis, with some patients recovering completely. 83, 85 Neuroimaging studies provide useful prognostic information. Lesions that directly involve the posterior superior temporal region of the left hemisphere suggest that there will be limited recovery of auditory comprehension, and large lesions affecting the rolandic area correlate with poor recovery of fluency. 86, 87 In many cases, patients with more extensive linguistic deficits evolve into a stage of residual anomic aphasia. Younger patients with aphasia tend to recover more language skills than older patients, and left -handed patients have a better prognosis than dextrals. 83, 88 In general, comprehension of language improves more than fluency of expressive output. 89, 90 Aphasia therapy may facilitate language recovery and should be offered to all interested patients. 91 In addition to traditional re -education techniques, recent efforts have been made to develop individualized techniques for specific types of aphasia, such as utilization of melodic intonation therapy in patients with Broca's aphasia, use of visual communication symbols by patients with global aphasic syndromes, or therapy for specific aspects of aphasic syndromes such as perseveration. 92, 93, 94
Aphasia-Related Syndromes
Alexia
Alexia refers to an acquired inability to read caused by brain damage and must be distinguished from dyslexia, a developmental abnormality in which the individual is unable to learn to read, and from illiteracy, which reflects a poor educational background. 15 Most aphasics are also alexic, but alexia may occur in the absence of aphasia and may
occasionally be virtually the sole disability resulting from specific CNS lesions. The ability to read aloud and reading comprehension may be dissociated by some lesions and must be assessed independently. Table 6.6 presents a classification of alexia, and each alexic syndrome is discussed in the following paragraphs.
Without aphasia
FIGURE 6.10 Infarction of the left occipital cortex and the posterior aspect of the corpus callosum produces alexia without agraphia.
P.84 Alexia without agraphia has rarely been associated with small lesions in the white matter beneath the angular gyrus 95 or with lesions of the left lateral geniculate plus the splenium of the corpus callosum. 96 In both cases, a disconnection similar to that occurring with the classic lesion occurs. In the alexia -without-agraphia syndrome, letter reading is superior to word reading. The patient retains the ability to spell and to recognize words spelled aloud, there is greater difficulty in copying words than in writing spontaneously, and a color anomia is frequently present. 15, 48 In some cases a right hemiparesis, right hemisensory loss, and mild naming disturbance accompany the syndrome. 97
Deep Dyslexia
This syndrome (deep alexia, paralexia) evolves in some aphasics with severe reading impairments in which semantically related paralexias are produced in response to written stimuli. The patient may read automobile as car or infant as baby. Such reading is thought to be mediated by the right hemisphere on the basis of iconic recognition. 98, 99, 100
Hemialexia
Alexia may occur with hemispheric lesions that produce profound unilateral neglect. The syndrome usually occurs in patients with right hemispheric lesions and severe hemispatial inattention. The left half of words is ignored so that northwest is read as west or baseball as ball; or the left half may be misjudged so that navigator is read as indicator, match as hatch, or alligator as narrator. 98, 101
Agraphia
Agraphia indicates an acquired impairment of the ability to write. 15, 102, 103 It may reflect an aphasic disturbance with a writing deficit similar to that of oral language, or it may be a consequence of a motor system abnormality. Like alexia, agraphia must be distinguished from illiteracy, where writing skills were never developed. Table 6.7 presents the classification to be followed here. In the following paragraphs, aphasic agraphias are discussed first, and then nonaphasic agraphias are presented.
Aphasic Agraphia
As shown in Table 6.2 , all aphasias are accompanied by writing disturbances. The type of writing disturbance usually closely parallels the disturbances of oral language, and in some cases the language abnormalities may be more marked in written than spoken language. In the nonfluent aphasias there is sparse graphic output, with clumsy calligraphy, agrammatism, and poor spelling. Fluent agraphias, on the other hand, have a normal quantity of well -formed letters, but with a lack of substantive words and insertion of literal, verbal, or neologistic paragraphias similar to oral paraphasias. 102 Alexia with agraphia was discussed earlier with the alexias. The writing disturbance of alexia with agraphia is severe and has the characteristics of agraphias accompanying fluent aphasias. Similarly, the agraphia of Gerstmann's syndrome (discussed below) is a fluent form of agraphia but in its pure form lacks an accompanying disturbance of reading. Pure agraphia is a controversial entity originally posited to occur with left frontal lobe lesions. No convincing cases with isolated pathologic involvement in this region have been described, but there are cases of relatively pure agraphia with left parietal lobe lesions. 104 Chedru and Geschwind 105, 106 observed that writing disturbances are among the most sensitive measures of confusional states associated with toxic and metabolic encephalopathies, and in some cases a relatively pure agraphia was the most prominent neuropsychological manifestation of the encephalopathy. The characteristics of the writing disturbance occurring in acute confusional P.85
Aphasic Agraphias
Nonapbasic Agraphias
Motor agraphia
Paretic agraphia
Hypokinetic agraphia
Pure agraphia
Hyperkinetic agraphia
Tremor
Deep agraphia
Disconnection agraphia
Apraxic agraphia
Reiterative agraphia
Perserveration
Paligraphia
Echographia
Coprographia
Visuospatial agraphia
Hysterical agraphia
Source: Adapted from Benson DF, Cummings JL. Agraphia. in: Vinken PJ, Bruyn GW, eds. Disorders of Speech, Perception, and Symbolic Behavior, Vol. 4, 2nd ed., Handbook of Clinical Neurology. New York: American Elsevier Publishing Company, 1985, Table 34!1. With permission from Excerpta Medka, Elsevier Science Publishers.a
states include poor coordination and mild tremor, spatial misalignment, agrammatism, omission and substitution of letters (especially consonants), and reduplication of letters and words. Errors are concentrated at the endings of words. Deep agraphia refers to a syndrome similar to deep dyslexia involving writing rather than reading. Concrete imageable words are written much better than abstract or nonsense words, and semantic paragraphias, similar to the semantic paralexias of deep dyslexia, are present. 102, 107 The syndrome usually occurs in patients with severe alexia and left parietal lobe lesions. Disconnection agraphia occurs with other aspects of callosal ideomotor apraxia (discussed below) in patients with lesions resulting in disconnection of the writing hand from the necessary input of the left hemisphere. The agraphia occurs in the left hand of right -handed patients with callosal lesions. The lesion prevents the transfer of linguistic information from the left to the right hemisphere controlling the left hand. Copying is usually superior to spontaneous writing or writing to dictation. 102, 108 Apractic agraphia is one manifestation of ideomotor apraxia affecting the limbs. The patient has difficulty forming letters when writing spontaneously and when copying. Performance may be improved by spelling with anagram letters. The associated lesion is typically located in the left superior parietal lobe. 72, 103
Nonaphasic Agraphia
Writing depends on a complex array of motor and visuospatial skills in addition to language abilities. Disruption of any aspect of the motor system!peripheral, corticospinal, extrapyramidal, cerebellar!will produce agraphia, and in each case the writing disturbance will have distinctive features. Lesions of the muscles, peripheral nerves, or corticospinal tracts produce a clumsy, uncoordinated agraphia secondary to limb paralysis. Micrographia is a common manifestation of parkinsonism and occurs in idiopathic, postencephalitic, and drug-induced parkinsonian disorders. 102 Extrapyramidal micrographia is characterized by a progressive diminution in the size of the letters, often accompanied by increased crowding. The micrographia may be most apparent in writing but eventually includes all written productions including constructions. Tests of micrographia that make the deficit apparent include obtaining the patient's current signature and comparing it with past signatures on licenses or legal documents, asking the patient to execute sequences such as the alphabet or consecutive digits, or having the patient draw repeated connected oval loops. While usually a manifestation of a degenerative P.86 parkinsonian disorder, tumors and other focal lesions of the
basal ganglia can also produce micrographia. 109 Action tremors (Chapter 18 ) of either the cerebellar or postural type produce disturbances in writing and may make written productions unintelligible. Postural tremor is a high frequency (8!12 Hz), low -amplitude tremor that is precipitated by movement and disappears at rest. Postural tremors are very evident in written material, and in some cases writing is the only maneuver that elicits the tremor. 110 Cerebellar tremors are usually large-amplitude, intention tremors that are worsened by attempts to produce fine writing movements. Often the patient can make only a few sweeping marks on the page. Chorea, athetosis, and tics are hyperkinetic movement disorders that influence writing in the same way that they affect all other volitional motor activity. In severe cases writing is impossible, and even in mild cases the output will be visibly distorted. The differential diagnosis and treatment of these disorders is discussed in Chapter 18. !Writer's cramp!! is among the most well -known and most misunderstood of all agraphias. The syndrome of progressive cramping of the hand and forearm among individuals in professions demanding fine finger movements, including writers, telegraphers, pianists, and violinists, was treated as a neurotic disorder by early psychoanalysts and as a learned disturbance by behavioral therapists. The progression of writer's cramp to a segmental dystonia involving the entire limb or even to generalized dystonia musculorum deformans, however, along with the absence of a consistent psychopathology among its victims, indicate that the disorder is a focal dystonia. 111 The cramping begins between ages 20 and 50, and there may be inconspicuous associated neurological deficits, including abnormal posturing or tremor of the affected limb, diminished arm swing, or increased limb tone. Reiterative agraphias refer to the abnormal repetition of letters, words, or phrases in writing. Perseveration is a continuation of activity after the appropriate stimulus has stopped; paligraphia is the rewriting of phrases generated by the patient; and echographia is the rewriting of phrases produced by the examiner. These disorders occur in severely deteriorated patients, including those with advanced degenerative, vascular, or traumatic conditions, and in catatonic disturbances. 102 Coprographia occurs primarily in Gilles de la Tourette syndrome, where the patient occasionally has a compulsion to express coprolalic tendencies in writing. 112 (Chapter 19 ). Visuospatial agraphia is manifested by a tendency to neglect one portion of the writing page; slanting of the lines upward or downward; and abnormal spacing between letters, syllables, or words. It is seen most often with right -sided lesions in the region of the temporoparietooccipital junction and is accompanied by other evidence of left -sided neglect. 103 Agraphia may occasionally occur as a hysterical conversion symptom. The agraphia is usually part of a monoparesis in which the limb is weak throughout with slightly diminished tone and normal muscle stretch reflexes. Sensation may or may not be affected. 113 In some patients, the writing disturbance may be unaccompanied by other functional disturbances. 114 The disorder typically is short -lived, and the psychogenic cause seldom is subtle.
Acalculia
There are three principal types of acalculia: (1) acalculia
associated with language disturbances, including number paraphasia, number agraphia, or number alexia; (2) acalculia secondary to visuospatial dysfunction with malalignment of numbers and columns; and (3) a primary anarithmetria entailing disruption of the computation process (Table 6.8 ). A fourth type of acalculia, symbol agnosia, in which the patient loses the ability to understand the operational symbols that determine the mathematical process to be performed (+, ", , -), has occasionally been observed but has not been well studied and is rare. 115 Aphasia -related disturbances of calculation include paraphasic errors in which the patient makes a verbal paraphasic error, substituting one number for another. Number alexia and number agraphia may also occur and, in some cases, may be disproportionately greater than letter reading and writing disturbances. Acalculia occurs with nearly all aphasias but is more severe in patients with lesions of the posterior aspect of the left hemisphere involving the parietal cortex. 116 Visuospatial acalculia may occur with lesions of either hemisphere but is most common with right parietal
Number paraphasia
Number alexia
Number agraphia
Visuospatial acalculia
Anarithmetria
Symbol agnosia
P.87 dysfunction. Spacing of multidigit numbers, place-holding values, and column alignment are disrupted. 116 Primary anarithmetria occurs mainly in the context of Gerstmann's syndrome with lesions in the region of the dominant angular gyrus, but it may occasionally be seen as an isolated abnormality with disturbances of the same region. In this case there is no significant aphasic or visuospatial disturbance, but errors are made in the computation process. 117
Apraxia
Apraxia refers to disorders of learned movement that cannot be accounted for on the basis of weakness, sensory loss, inattention, or failure to understand the requested action. 121 Two principal types of apraxia have been recognized: (1) ideational apraxia, in which the patient fails to correctly pantomime a multicomponent
FIGURE 6.11 The Gerstmann's syndrome occurs with discrete left angular gyrus lesions and consists of a tetrad of clinical findings including dysgraphia, finger agnosia, inability to distinguish left from right, and acalculia.
P.88
TYPE OF APRAXIA
Characteristic
Parietal
Sympathetic
Callosal
Apraxia distribution
Left limbs
Aphasia
Conduction
Broca's
Hemiparesis
Right hemiparesis
None
Lesion location
Callosal fibers
Associated findings
Commissurotomy ! syndrome *
This involves left tactile anomia, left agraphia, poor intermanual position matching, and right -hand constructional disturbance.
sequence such as folding a letter, inserting it in an envelope, and stamping the envelope, 122 and (2) ideomotor apraxia, in which the patient fails to perform on command actions that can be done spontaneously, such as waving good-bye, hammering, thumbing a ride, sawing, sucking through a straw, or whistling. Ideational apraxias occur in dementias and in acute confusional states. Ideomotor apraxias occur with specific left hemisphere lesions. 121, 123 Table 6.9 presents the three principal types of ideo -motor apraxia and their associated clinical findings. Parietal apraxia refers to the occurrence of apraxic movements in patients with lesions involving the inferior parietal lobule and the adjacent arcuate fasciculus. Thalamic lesions (left) have occasionally produced the syndrome. 124 The patients have fluent aphasia (usually conduction aphasia), may have a mild right hemiparesis and a hemisensory defect, and frequently fail to recognize that the apraxic movements are incorrectly performed. 125, 126 Sympathetic apraxia is the apraxia of the left limbs and
buccolingual structures noted in patients with left frontal lesions. The apraxic limbs are !in sympathy!! with the right hemiparesis produced by the frontal lesion. The patients also manifest a nonfluent Broca-type aphasia, have more prominent involvement of buccolingual than limb movements, and are likely to perceive that the apraxic movements are faulty. 121, 127 Callosal apraxia occurs when verbal directions mediated by the left hemisphere cannot cross the corpus callosum for execution of left -sided limb commands mediated by the right hemisphere (Fig. 6.12 ). The apraxia
FIGURE 6.12 Callosal apraxia occurs when verbal directions mediated by the left hemisphere cannot cross the corpus callosum for execution of left -sided limb commands mediated by the right hemisphere.
P.89 involves only the left arm and leg, and in most cases there is no associated aphasia or hemiparesis. 128, 129, 130, 131 Disruption of interhemispheric communication is manifested in a variety of disturbances in addition to the left limb apraxia, including left -hand tactile anomia, left -hand aphasic agraphia, right -hand constructional disturbances, and a variety of somesthetic disorders such as failure of intermanual tactile matching and intermanual matching of hand positions. 108, 132 Corpus callosum injury may be produced by surgical sectioning for the control of intractable epilepsy, anterior cerebral artery occlusion, trauma, or neoplasm. 108, 132, 133
Aprosodia
Prosody consists of variations in sound pitch, stress, and rhythm that underlie speech melody and inflection. 136 Prosody imbues language with its emotional meaning (affective prosody) and contributes to semantic meaning (the difference between !we were in a hothouse!! and !we were in a hot house!!) (prepositional prosody). Aprosodia or dysprosodia is the syndrome resulting from interruption of the normal prosodic contribution to spoken language. There are both executive (the ability to speak prosodically) and receptive (the ability to comprehend the prosodic elements of speech) aspects of prosody. Prosody is particularly important in neuropsychiatric practice. The patient's emotional state is communicated primarily through prosodic influences on speech! how something is said is often of greater importance than what is said. Any impairment of prosodic executive skills will impair the patient's ability to communicate emotion and will compromise the ability of the clinician and of the patient's family to infer their emotional condition. Receptive prosodic abilities are critical to successful interpersonal function; it is on the basis of affective prosodic comprehension that the individual understands the emotions of others and can respond appropriately. Receptive dysprosody isolates the individual from the emotions of others. Individuals who sustain right brain injuries as children fail to develop interpersonal skills, cannot interpret social cues, have difficulty expressing themselves, and are at increased risk for adult psychopathology including depression, schizoid behavior, and episodic dyscontrol. 34, 137, 138, 139 Several brain regions contribute to the physiologic mechanisms underlying prosody and lesions in several areas will compromise executive or receptive prosody. Executive prosody is abnormal in patients with non -fluent aphasias when the premotor region is affected by the causative lesion. 50, 140 These patients can often impart appropriate emotional inflection to their limited verbal output. Patients with right hemisphere damage involving the equivalent of Broca's area have an executive aprosodia. 31, 140 Basal ganglia dysfunction also produces executive dysprosody with monotonic, uninflected, and often hypophonic output. 141 Cerebellar disorders with ataxic speech produce abnormalities of stress and pitch shift with a resulting characteristic change in prosody. 142 Comprehension of the prosodic features of communication is also affected by lesions in different brain regions. Patients with right temporal -parietal lesions have a receptive aprosodia with impaired comprehension of emotion and affect in spoken language. 143, 144, 145 Comprehension of nonemotional prepositional prosody is compromised by both left and right posterior brain injury. 146, 147 Thus, although not all studies report identical findings, most suggest that right temporoparietal lesions impair comprehension of both emotional and nonemotional prosody, whereas left posterior brain dysfunction affects primarily nonemotional prosodic comprehension. Emotional prosodic comprehension is also abnormal in patients with basal ganglia lesions. 140, 141, 145
Stuttering
Stuttering is a disturbance of speech rhythm with hesitations, prolongations, pauses, and repetitions of sounds within words. Stuttering may be of childhood type beginning insidiously between ages 2 and 10 or of acquired type beginning later in life in concert with a neurologic disorder.
Childhood stuttering is often familial; 20% of sons of stutterers will stutter and 10% of daughters will stutter. 35 Stuttering remits before age 16 in most cases and is life long in 20% of individuals. Conventional structural imaging is normal in stutterers, but studies of cerebral glucose metabolism with positron emission tomography (PET) reveal that stutters have reduced metabolism in the P.90
Clinical Feature
Congenital Stuttering
Acquired Stuttering
Age at onset
Gender
Either gender
Course
Repetitions
Choral speech
Stuttering is rare
Stuttering is common
Emotional response
Anxious, frustrated
None or annoyed
Present
Absent
Cause
Idiopathic; hereditary
anterior cingulate cortex and the superior and middle temporal gyri. The changes are more severe in the left than the right hemisphere. 148 Acquired stuttering is associated with recovery from aphasia, traumatic or vascular injury to subcortical pyramidal and extrapyramidal systems of either hemisphere, or basal ganglia diseases such as Parkinson's disease and progressive supranuclear palsy. 149, 150, 151 Monoamine oxidase inhibitors (MAOIs; tranycypromine, phenelzine) have rarely been observed to induce stuttering. 152 Table 6.10 lists the features that distinguish childhood from acquired stuttering. Speech therapy and use of pacing techniques are of benefit to some patients. Relief of stuttering may also be provided by vocal cord injection with botulinum toxin. 153
Fromotemporal dementias
Huntingron's disease
Postencephalitic parkinsonism
Neuroacanthocytosis
Autism
Schizophrenia
TABLE 6.12. Clinical Features That Distinguish Fluent Aphasia from Verbal Output of Schizophrenia
Clinical Characteristic
Fluent Aphasia
Schizophrenia
Spontaneous speech
Length of response
Shorter
Extended
Awareness of deficit
Often present
Absent
Participation in conversation
Present
Absent
Content
Empty
Common
Prosody
Preserved
Impaired
Language testing
Comprehension
Often impaired
Usually intact
Repetition
Intact
Naming
Impaired
Intact
Diminished
Reading
Impaired
Intact
Writing
Aphasic
Associated characteristics
Negative symptoms
Medical history
Psychiatric history
Age at onset
>50;
<30
Family history
Neurological examination
!Soft singns!!
P.92 speech, schizophrenics tend to have more extended replies to inquiries than do fluent aphasics. They are less aware of their communication deficit, are less engaged in conversational exchange, and care less about the listener's response. The ideational content of their output is more bizarre with a tendency to return to a few main themes and to use a restricted vocabulary. 162, 163, 164 Neologisms and paraphasia are common in fluent aphasia and rare in schizophrenia. When they occur in schiophrema, however, they may be highly distinctive, with the new word often acquiring a stable meaning within the schizophrenic's idiosyncratic vocabulary. For instance, one of the author's patients believed he had a !seisometer!! behind his right eye that could receive and transmit instructions; Forrest reported a patient with a thesaurus of neologisms such as !semitiertology! ! or the study of half hundreds; one of Bleuler's patients used the word !snortse!! to mean !to talk through the walls!!; and a patient studied by Hamilton used a process of condensation to construct words such as !esamaxrider,!! meaning !he's a married man.!! 170, 171, 172, 173 The stability of the paraphasic usage in schizophrenia differs markedly from fluent aphasia, where patients rarely make the same paraphasic substitution consistently. Language abnormalities are more evident in schizophrenic patients with prominent negative symptoms (Chapter 12 ) (affective flattening, avolition, alogia, anhedonia, disturbed attention), and these features are not characteristic of most aphasics. 174 Prosodic abnormalities are more characteristic of the spontaneous speech of schizophrenics than of fluent aphasics. 175 Language testing in the course of the mental status examination can also be helpful in distinguishing aphasia from schizophrenic verbal output if the patient can be engaged in the testing process (Table 6.11 ). 59, 161, 162, 163 Naming ability will invariably be impaired to some extent in aphasia and is usually preserved in schizophrenia. Likewise, comprehension and repetition may be impaired in aphasia, depending on the type of language deficit present, whereas they are preserved in schizophrenia. Generation of word lists such as the maximum number of animals one can name in a minute is diminished in aphasia and may be normal or contain bizarre entries in schizophrenia. For example, one patient examined by the author included !vaginal monster!! and !Phoenician circus woman!! among his
animals. Reading and writing are impaired in aphasia; in schizophrenia reading is preserved, and writing may be normal or may resemble the disordered spoken output. For example, when one patient was asked to describe the weather, he wrote: !Rumors of a fiercer nature were let out about the phloral trumps of our Lord.!! Finally, the clinical circumstances in which the verbal output disorder occurs may also facilitate differentiation of aphasia and schizophrenia (Table 6.11 ). Onset before age 30, history of psychosis, and absence of known medical illness all favor the diagnosis of schizophrenia; whereas onset after age 50 years, presence of a predisposing medical illness, absence of previous psychiatric disturbances, and focal findings on neurological examination all indicate a hemispheric insult and support a diagnosis of aphasia. These features are not infallible, however, and it must be remembered that schizophrenics are at the same risk as the general population for the development of cerebrovascular or neoplastic disease and may develop on aphasia -producing brain disorder.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 7 - Memory Disorders
or where the information was acquired) and episodic memory (e.g., recall of events occurring in one's life and integrally associated with specific times and places). Episodic memory is the autobiographic record of one's personal history and is the basis of autonoetic consciousness!the capacity to mentally represent personal subjective experiences in the past, present and future. 2 Nondeclarative memory is not available to consciousness and includes motor skill learning (procedural memory), habits, and P.98
classical conditioning. Amnesias and retrieval deficit syndromes affect declarative memory; basal ganglia disorders impact nondeclarative memory. Working memory is an attentional system active for only brief periods of time (usually seconds); it allows utilization of acquired knowledge before responding to an environmental event. Working memory is mediated by frontalsubcortical systems and is discussed in Chapter 9 .
indicating intact attention and immediate memory, and has normal linguistic and cognitive functions, including language comprehension, naming, reading, writing, calculating, drawing, and abstracting, but is unable to learn new information, such as the current day, month, or year or the current geographic location. The patient has impaired recall of three test words when asked to recall them after 3 minutes. Patients with amnesia involving nonverbal information cannot reproduce constructions that were drawn a few minutes previously. Amnesia results from the inability to store information and recall is not aided by clues (such as telling the patient that the word to be remembered was a vegetable when the to -be-remembered word was cabbage ), by multiple -choice alternatives (telling the patient that the word to be remembered was either red, blue , or green when the to -be-remembered word was green ), or by embedding the words to be remembered in a list of other words to determine if the patient can recognize previously seen material as evidenced by distinguishing between the target words (those seen earlier) and foils (those not seen previously). Amnesic disorders consist of anterograde amnesia and retrograde amnesia. Anterograde amnesia is difficulty in learning new information. It begins with the onset of the amnesia and continues indefinitely in permanent amnesic disorders or subsides in those amnesic syndromes that are transient. Retrograde amnesia refers to the failure to remember events that preceded the onset of the anterograde amnesia. It may extend for a few minutes (typical of post-traumatic amnesia) or a few years (common in Wernicke -Korsakoff's syndrome). Remote memory (beyond the period included in the retrograde amnesia) is normal. If recent memory recovers, the retrograde amnesia may progressively shrink to some finite period prior to the amnesia -inciting event, and the patient will be left with a period of permanent memory loss that extends from the beginning of the retrograde amnesia to the end of the anterograde amnesia. 3 Procedural memory (memory for motor skills) is typically spared in amnesic syndromes. Patients can learn new motor skills even though they may not be able to remember that they were taught the ability. 4 ,5 Table 7.1 lists the principal causes of amnesia and presents distinguishing findings commonly associated with each amnesic syndrome. Confabulation (discussed below) refers to the production of false answers in response to memory -related questions. Confabulation is common in the early stages of amnesia but rarely persists as a permanent phenomenon. Amnesia is associated with dysfunction of a restricted set of brain structures. Neurologic conditions producing amnesia affect the hippocampus, fornix, mamillary bodies of the hypothalamus, mammillothalamic tract, or medial thalamic
nuclei (Figs. 7.2 and 7.3 ). Hippocampi are affected in temporal lobectomy, head P.99
Syndrome
Clinical Features
Temporal lobectomy
Head trauma
Hippocampal infarction
Anoxia
Neoplasms
Vascular etiology is most common; there may be associated evidence of cerebrovascular disease
Hypoglycemia
Insulin overdose
Psychogenic amnesia
FIGURE 7.2 The medial circuit of Papez, as depicted by MacLean, 48 was proposed to support emotional processing in 1937.
P.100
FIGURE 7.3 Anatomy of the hippocampus in relation to other brain regions (left) showing the anterior pes, body, and tail with extension into the fornix near the splenium of the corpus callosum (CC). Coronal section (right) shows the hippocampal fields transitioning from CA3, into CA2, and then CA1, which in turn extends into the subiculum and eventually into the entorhinal and perirhinal cortex within the banks of the collateral sulcus. amyg, amygdala; thai, thalamus.
trauma, posterior cerebral artery occlusion, hypoglycemia, and Alzheimer's disease; the fornix may be transected in the course of surgery or be affected in trauma and stroke, and can be infiltrated by neoplasms; the mamillary bodies are injured in the Wernicke -Korsakoff syndrome (thiamine deficiency syndrome) and are occasionally affected by neoplasms or during surgery to adjacent structures; the thalamus may be the site of tumors, infarction, hemorrhage, and damage in Wernicke -Korsakoff syndrome. Amnesic disorders affecting primarily verbal information involve left hemisphere structures, whereas amnesias involving nonverbal information are associated with right hemisphere dysfunction. Severe amnesias occur with bilateral lesions and affect both verbal and nonverbal information. Procedural learning is mediated by the basal ganglia and cerebellum and is spared in amnesic disorders. Sparing of remote memory in amnesia suggests that recollection of remote information is independent of the hippocampal -thalamic circuit disrupted in the amnesias.
characteristic memory deficit. A personality change, usually emotional indifference or apathy, frequently accompanies the amnesia. Neuroimaging changes are evident in some cases of Wernicke -Korsakoff's syndrome. Computerized tomography (CT) may reveal bilateral hypodense areas in the medial thalamus in patients with acute Wernicke's encephalopathy, and mamillary body atrophy may be demonstrated by magnetic resonance imaging (MRI) in some patients with the chronic Korsakoff's syndrome. 8 Patients with Korsakoff syndrome have difficulty learning new information and usually have a retrograde amnesia that extends backward 3!20 years prior to the onset of the amnesia. Typically, patients remain amnesic for 1!3 months after onset and then begin to recover over a 1 - to 10 -month period. Of these patients, 25% recover completely, 50% show slight to moderate improvement, and 25% have no demonstrable recovery. 9 Confabulation is common during the early phases of the Korsakoff's syndrome but is unusual in the chronic phase of the condition. In some cases, administration of thiamine during the acute Wernicke phase prevents emergence of the chronic amnesic syndrome. Once the memory defect is established, however, thiamine has little effect except to prevent further deterioration. Chronic nutritional deprivation associated with alcoholism is the most common cause of the thiamine deficiency P.101 producing Korsakoff syndrome, but other causes of thiamine deficiency may also cause the disorder. One of Korsakoff's original patients developed the syndrome from pyloric stenosis associated with intentional sulfuric acid ingestion, and other cases have been attributed to gastric carcinoma, hemodialysis, hyperemesis gravidarum, prolonged intravenous (IV) hyperalimentation, gastric plication, and dietary deprivation in prisoner of war (POW) camps. 9,1 0 An inherited abnormality of transketolase activity may render some patients vulnerable to the development of the Wernicke -Korsakoff syndrome under conditions in which dietary thiamine is marginal or inadequate. Alcoholic Korsakoff syndrome must be distinguished from alcoholic dementia, in which deficits involve attention, word list generation, abstraction, and constructions as well as recent memory.
profound and lasting amnesia. 11 The epileptic patient, H. M., has become one of the most thoroughly studied cases in neuropsychology, and the results of extensive testing carried out on the patient have contributed significantly to understanding the role of temporal lobe structures in memory. Amnesia complicates temporal lobectomy when the hippocampal formations are removed bilaterally or when one hippocampus is removed and the other is dysfunctional. When one hippocampus is removed and the other is normal, the functioning member can compensate to a large extent for the missing structures, and the resulting deficits are relatively mild. In such cases the identifiable memory impairments are specific for the side of the lesion: left temporal lobectomy impairs learning and retention of verbal material, whereas right temporal lobe removal produces deficits in the recognition and recall of visual and auditory patterns that are not verbally coded (places, faces, melodies, nonsense patterns). 1 2 Speculation that lesions outside the hippocampus proper might explain H.M.'s memory impairment and results from animal studies implicate other medial temporal structures subserving memory. The perirhinal cortex became a focus of the medial temporal memory system in monkey 13 because the delayed matching and non -matching -to -sample tasks (primarily recognition tests) were unimpaired if a hippocampal lesion did not also extend into the monkey's rhinal cortex. In H.M., the surgical lesion included the medial temporal pole, most of the amygdaloid complex, and all of the entorhinal cortex bilaterally (Fig. 7.4 ). In addition, the anterior 2 cm of the dentate gyrus, hippocampus, and subicular complex was removed. Given that the collateral sulcus and the cortex lining its banks are visible, then at least some of the posterioventral perirhinal cortex is intact in H.M. The posterior parahippocampal gyrus (areas TF and TH) was only slightly damaged rostrally. The lingual and fusiform gyri, lateral to the collateral sulcus, are also intact. Another surgical case, P.B., had the entire left temporal lobe removed in a two -staged procedure and subsequently suffered a lifelong dense amnesia. 1 4 At autopsy, P.B. also had preservation of the posterior 22 mm of the hippocampus and parahippocampal cortex. Postoperative amnesia can now be avoided by preoperative conduction of a Wada test. In this procedure, the hemisphere ipsilateral to the temporal lobe to be removed is anesthetized with intracarotid injection of amyobarbital. If the contralateral hemisphere also has compromised memory function, memory deficits are evident during the test and surgery is avoided or modified to spare medial temporal lobe structures critical to memory function. 15
In addition to temporal lobectomy, several other surgical procedures have resulted in amnesic syndromes. Bilateral injury to the fornix produced at the time of surgery or by traumatic brain injury has been associated with amnesic syndromes. 1 6 Surgical injury to the mamillary bodies at the time of removal of pituitary tumors has also produced amnesia, and a transient, Korsakoff-like syndrome affecting primarily orientation in time and learning of temporal sequences has been observed following cingulumotomy.
Post-traumatic Amnesia
Traumatic brain injuries are undoubtedly the most common cause of amnesic syndromes seen in clinical practice. The position of the temporal lobe in the middle cranial fossa, suspended between the petrous pyramid inferiorly and the greater wing of the sphenoid anteriorly and medially, renders it vulnerable to contusions with both coup and contrecoup injuries. Contusions following head injury are most commonly located in the anterior temporal lobes and the orbitofrontal cortex, and diffuse axonal injury and ischemic necrosis may contribute to the post-traumatic memory impairment. The amnesia induced by closed head injury includes a period of retrograde memory loss extending for a few minutes to a few years prior to the injury, a variable period of unconsciousness caused by the injury, and a period of anterograde amnesia that lasts for a few hours to a few months or longer following recovery from coma. In cases with resolution of the anterograde amnesia, P.102
FIGURE 7.4 Coronal magnetic resonance images of H.M. from rostral (A) to caudal (C) showing the extent of bilateral hippocampal ablation (left) compared to a normal 66!year -old subject (right). Note the destruction of the amygdala (A), hippocampus (H), and entorhinal cortex (EC) anterior to the level of the mamillary bodies (MMN) with relative sparing of the posterior perirhinal cortex (PR) in the banks of the collateral sulcus (CS). V, temporal horn of lateral ventricle. Adapted from Corkin et al. (1997). 4 9
there is often a concomitant shrinking of the period of retrograde amnesia to within a few minutes or hours of the trauma. Duration of the coma after head trauma is the best predictor of the severity of post-traumatic memory and
cognitive deficits and duration of post-traumatic amnesia is correlated with post-trauma intellectual disorders. 1 7
Hippocampal Infarction
The hippocampus receives its blood supply from penetrating branches of the posterior cerebral artery, and occlusion of the basilar artery or proximal portions of both posterior cerebral arteries with bilateral hippocampal infarction will produce an amnesic syndrome. 18 The infarction is rarely limited to the hippocampal formation, and extension of the injury to include other occipital structures results in the frequent occurrence of visual field defects, prosopagnosia, environmental agnosia, central achromatopsia, alexia without agraphia, hemiparesis, or hemisensory loss with the amnesia. Occlusion of the posterior cerebral artery may be produced by embolism, thrombosis, or compression against the tentorium P.103 by an expanding hemispheric lesion or hemispheric edema. Most cases of amnesia secondary to hippocampal infarction have had bilateral lesions, but a few cases appear to have damage limited to the hippocampal formation of the left hemisphere, which suggests that a unilateral infarction of the hippocampus of the language -dominant hemisphere can produce at least transient amnesia.
realms of intellectual activity. The amnesia is often permanent, but a few cases have shown gradual resolution over a period of months to nearly normal levels of function. In addition to its occurrence following cardiopulmonary arrest, post-anoxic amnesia has occurred following anesthetic accidents, carbon monoxide intoxication, and strangulation due to hanging. When the period of oxygen deprivation is more prolonged, widespread damage is incurred, and a postanoxic dementia ensues if the patient survives. Acute hypoglycemia, like acute anoxia, has its greatest impact on hippocampal function, and subacute or chronic recurrent hypoglycemia often produces a memory disturbance. In many cases, however, other intellectual functions are also impaired and a dementia syndrome results. 21
Neoplasms
Neoplasms producing amnesic syndromes fall into two general categories: extracerebral tumors such as craniopharyngiomas that produce pressure on the base of the brain, and intracerebral tumors, particularly gliomas,
that involve structures in the wall and floor of the third ventricle. 2 1 The extracerebral compressive lesions exert upward pressure on the mamillary bodies and adjacent tracts, and the gliomas invade the nuclei of the thalamus and hypothalamic structures to produce the disruption of memory function.
Alzheimer's Disease
Patients cannot meet diagnostic criteria for Alzheimer's disease (AD) if their cognitive deficits are limited to changes in memory (Chapter 10 ). Memory abnormalities, however, can be the initial manifestation of AD and in some cases may be the sole deficit for several years until other intellectual disturbances appear. 25 The syndrome of minimum cognitive impairment (MCI) consists of an isolated
memory disorder, and patients with this syndrome progress to AD at the rate of 15% per year. The memory disorder of AD closely resembles amnesia, although at least subtle deficits in remote recall are typically present in addition to the severe alterations in recent memory. The most marked changes of AD involve the medial temporal regions, particularly entorhinal cortex, which serves as a major gateway for input to the hippocampus.
Electroconvulsive Therapy
Electroconvulsive therapy (ECT) produces both a retrograde amnesia for items learned a few minutes prior to the treatment and an anterograde amnesia for information introduced immediately after the treatment. The anterograde amnesia usually subsides within 4!6 hours of the most recent treatment, but mild memory deficits may persist for several weeks following termination of a full course of therapy (6!12 treatments). 2 6 Long -term follow -up studies show no objective evidence of memory impairment 6!9 months following a standard course of ECT. Use of bilateral electrodes induces impairment of both verbal and nonverbal learning; right unilateral ECT produces less memory disruption and preferentially affects memory for nonverbal material. The pathophysiology of the amnesia induced by ECT is unknown. The discharge is most likely mediated by nonspecific reticulothalamocortical circuits and may have a preferential effect on limbic mechanisms rendered vulnerable by their low seizure threshold. Electroconvulsive therapy also induces a variety of neurotransmitter, neuropeptide, and neuroendocrine changes that resemble those produced by antidepressant medications and may participate in the depression -resolving effects.
episode although a few patients have evidence of minor brainstem dysfunction. The amnesia is disproportionately severe compared to other intellectual abnormalities, but passivity and difficulty copying complex constructions have been observed among patients carefully assessed while in the midst of an episode. Most patients with TGA have a single attack and suffer no further amnesic episodes, but a few have repeated attacks and eventually have infarctions in the vertebrobasilar or posterior cerebral arterial territories. In some cases, specific circumstances such as intense emotional excitement, pain, sexual intercourse, or abrupt variations in temperature may acutely alter circulation and precipitate TGA in vulnerable individuals. In addition to cerebrovascular disease, a variety of other causes of TGA have been reported, including migraine, mild head trauma, valium overdose, seizures, and tumors (Table 7.2 ). Cerebral blood flow studies of patients with TGA reveal diminished blood flow in the posterior hemispheric or inferior temporal regions or the thalamus. 2 8
Psychogenic Amnesia
There are several types of psychogenic memory disturbances including dissociative P.105
TABLE 7.2. Characteristics That Distinguish Psychogenic Amnesia from Transient Global Amnesia
Psychogenic Amnesia
personal information
Indifference to amnesia
amnesia (psychogenic amnesia), dissociative fugues (fugue states), and dissociative identity disorder (multiple personality disorder). 2 9 The latter two disorders entail the partial or total assumption of different identities for a finite period (usually days to weeks) that the patient has difficulty recalling later. These patients are not amnesic during the dissociated period and can learn and recall new information; later, however, they have no recall of the period during which they were in the dissociative state. Dissociation, fugues, and multiple personality are discussed in Chapter 22 . Psychogenic amnesia or psychogenic loss of personal identity can, however, be confused with amnesias associated with dysfunction of medial limbic structures. Psychogenic amnesia is a hysterical conversion symptom in which patients suddenly forget their personal identities and life situations. They may not recall their names, addresses, families, or any other personal information. In some cases there is a selective loss of specific emotionally charged information such as whether one is married or the identity and whereabouts of one's parents. In other cases there is a failure to recall all autobiographical information. General information (how many inches in a foot) and skills (how to drive, etc.) are retained despite the loss of all personal memory. The amnesia is usually of short duration (24!48 hours) and either stops spontaneously or may be terminated by hypnosis, suggestion, or an amyobarbital (Amytal)
interview. Unlike other types of conversion reaction, which are more common in women, there is an equal preponderance of men and women among patients exhibiting psychogenic amnesia. Psychogenic amnesia is often linked to anxiety and depression. Malingering is also common as a cause of psychogenic amnesia, particularly among !absconding treasurers, reluctant bridegrooms, and other criminals and wrongdoers seeking to evade the consequences of their actions.!!30 Psychogenic amnesia is most likely to be confused with TGA, but there are several characteristics that aid in the differentiation of psychogenic amnesia from TGA and from other types of amnesia associated with hippocampal, hypothalamic, or thalamic dysfunction (Table 7.2 ). Transient global amnesia almost never entails a loss of personal identity, whereas it is one of the hallmarks of psychogenic amnesia. By definition, patients with TGA have difficulty learning and retaining new information, whereas patients with psychogenic amnesia may be able to learn many details about their current situation at a time that they cannot recall information concerning their remote histories. The pattern of memory loss in TGA patients includes a temporal gradient with relative preservation of remote memory beyond the period of retrograde amnesia; patients with psychogenic amnesia do not exhibit a temporal gradient, and memory loss may be highly specific for selected personal information. Depression is common among patients with psychogenic amnesia, and they are usually indifferent to their memory losses, whereas TGA patients show no preponderance of any associated psychopathology and are distressed by their memory deficits. Psychogenic amnesia patients are usually in their teens, twenties, or thirties, whereas TGA is most common in patients in their fifth to seventh decade. Psychogenic amnesia must also be distinguished from episodic disturbances of consciousness that may accompany seizures (Chapter 21 ). Partial complex seizures may occasionally produce twilight states lasting several hours, during which the patient is behaviorally active but later has no recall of the period. If they are observed P.106
FIGURE 7.5 [ 18 F] -fluorodeoxy glucose positron emission tomography (FDG -PET) studies, registered to a probabilistic anatomic atlas of the average Alzheimer's disease (AD) brain, 5 0 were normalized across the groups' mean intensity levels, and subjected to a voxel by-voxel subtraction of the post-minus pre -treatment studies using the cholinesterase inhibitor donepezil in 19 AD patients. Subvolume thresholding (SVT) corrected random lobar noise to produce a three -dimensional functional significance map. Note the bilateral perirhinal activation associated with cognitive improvement in the group after treatment.
during such states, most patients are confused and exhibit difficulty learning and remembering. They may have a history of seizures or past head injury. Headaches can signal the presence of a brain tumor as the cause of the seizures. In some cases, evaluation with neuroimaging and electroencephalography may be necessary to aid in differentiating the two conditions.
Treatment of Amnesia
Amnesic disorders are treatment -resistant and no therapeutic intervention has produced marked improvement. Modest benefit in post-traumatic and post-encephalitic amnesias from treatment with physostigmine has been reported. Memory impairment in the Wernicke -Korsakoff syndrome has shown mild response to treatment with clonidine, methlysergide, or methylphenidate. 31 Memory impairment in AD may respond to treatment with cholinesterase (ChE) inhibitors. 3 2 (Chapter 10 ). The cholinergic hypothesis of AD is supported by pharmacological studies that implicate the cholinergic system in cognitive and
functional abilities. Scopolamine, for example, an antagonist of cholinergic transmission at muscarinic receptors, impairs neuropsycho -logical function (attention and memory performance) in normal individuals, and exacerbates behavioral and cognitive symptoms in AD patients. Conversely, physostigmine, a ChE inhibitor, reverses the effects of scopolamine and improves cognitive performance in animals, normal subjects, and some AD patients. If ChE inhibitors influence memory function in AD, then augmentation of medial temporal activity should occur with treatment. Preliminary evidence using [ 18 F] fluorodeoxyglucose positron emission tomography (FDGPET) before and after 8 weeks of ChE inhibitor (donepezil) treatment in 19 AD patients showed an increase in parahippocampal and prefrontal activity with increased cholinergic tone (see Fig. 7.5 ). 33 These increases were associated with significant post-treatment improvement in Mini -Mental State exam (MMSE) scores. Cholinergic therapy may exert effects on memory, through increasing attentional function.
from type -type memory abnormalities that commonly presage the emergence of diagnosable AD. The pathologic basis for AAMI has not been determined. Cell loss, biochemical changes, and atrophy of medial temporal lobe structures have all been suggested as responsible for the memory alterations of AAMI. Disorders that affect the frontal-sub cortical circuits also produce a retrieval deficit syndrome. Diseases affecting the frontal lobes and the basal ganglia produce a deficit in executive function that includes poor organization of material to be remembered, diminished recall of stored information, and preserved recognition of learned data. 3 5 The retrieval disorder is evident in attempts to recall remote as well as recently learned information; there is no temporal gradient of the type seen in amnesias. In all these situations, the patient is better able to recognize than recall the information. The member structures of the frontalsubcortical circuit mediating executive function and attention include the dorsolateral prefrontal cortex and anterior cingulate as well as their subcortical connections in the caudate nucleus, globus pallidus, and medial thalamus (Fig. 7.6 ). As noted above, thalamic dysfunction produces a true amnesia, but disorders affecting the other structures of the dorsolateral prefrontal -subcortical circuits manifest executive dysfunction and a retrieval deficit syndrome. Retrieval abnormalities are present in patients with frontotemporal dementias, Huntington's disease, progressive supranuclear palsy, and subcortical vascular dementia (Chapter 10 ). Table 7.3 summarizes the principal differences between amnesia and the retrieval deficit syndrome.
FIGURE 7.6 The dorsolateral frontal cortex is linked by reciprocal connections with the anterior cingulate and the posterior association cortex of the parietal lobe (outlined in yellow on right). The cingulate, in turn, has strong reciprocal connections with the anterior perirhinal and parahippocampal cortex (outlined in yellow on left). This anatomic circuit supports the coordinated interaction of attentional -executive functions with encoding and retrieval.
TABLE 7.3. Principal Differences between Amnesia and Retrieval Deficit Syndrome
Feature
Amnesia
Registration
Intact
Recall
Impaired
Impaired
Recognition
Impaired
Intact
Impaired
Intact
Anatomy
P.108 structures in the encoding process (see Fig. 7.7 ). Application of either distracter tasks or varying the level of cognitive processing during the presentation of items to be learned can affect encoding success. 3 7 By judging the abstract quality, or deeper associations, of words, as opposed to their surface orthographic features, subsequent recall is significantly enhanced. Such strategies of leveraging the associations of items to be remembered has been used since the ancient Greek orators. Modern imaging has revealed that this deeper processing, compared to the shallow inspection of individual letters, recruits dorsolateral prefrontal regions during encoding that are also engaged during retrieval (see Fig. 7.8 ). Most functional imaging studies are focused on the assessment of activity occurring on the same day of testing. Long -term dynamic changes occur with the eventual consolidation of learned information. Functional imaging studies have just begun to probe this dynamic consolidation process. After hippocampal and medial temporal regions are engaged with initial encoding, anterior cingulate and temporal cortices appear to mediate the retrieval of learned information. The anterior cingulate has been consistently activated in paradigms
FIGURE 7.7 Regional mapping of the medial temporal activations found in encoding and retrieval tasks of episodic memory for both fMRI and PET studies of normals. Adapted from Schacter et al. (1999). 5 1
P.109
FIGURE 7.8 Functional magnetic resonance imaging (fMRI) activation maps for !shallow!! and !deep!! encoding tasks, both contrasted with fixation. Both activate posterior visual areas whereas only the deep encoding task shows increased activation of left inferior and dorsolateral frontal areas (arrows). These activations are at peak Talairach 5 2 coordinates (x, y, z) of 40, 9, 34 and -46, 6, 28 for the more dorsal activations and -40, 19, 3 and -43, 19, 12 for the more ventral prefrontal activations. Adapted from Buckner and Koutstaal (1998). 5 3
that require sustained attention to novel tasks. In a subtraction -based paradigm of memory encoding combined with a motor task demanding sustained divided attention, 38 the anterior cingulate was singularly activated by the sustained vigilance demanded with dividing effort between the two tasks. PET activation studies using varied designs 39 , 4 0 consistently activate the anterior cingulate when subjects are motivated to succeed in whatever task is given them. When motivation to master a task is no longer required, and accurate performance of a task becomes routine, the anterior cingulate returns to a baseline activity level. In addition to its role in the consolidation of
declarative memory, the posterior cingulate is also active during associative learning in classical conditioning paradigms.
FIGURE 7.9 Summary of the peak regions of significance in functional imaging studies mapping the success and effort in the retrieval of verbal and nonverbal material. Adapted from Carbeza and Nyberg (2000). 54
can be divided into those that are short -lived (usually less than 24!48 hours), those that are either more prolonged or are stable (lasting for more than 48 hours), and those that are progressive. Transient, short -duration episodes of memory loss include psychogenic amnesia, some cases of post-traumatic amnesia, and TGA. These must be distinguished from other brief interruptions of consciousness with memory lapses, including complex partial seizures, alcoholic blackout spells, migraine, and toxic -metabolic confusional states. Seizures as a cause of memory lapses should be considered in individuals with a history of head trauma or other predisposing circumstances, a known history of epilepsy, or other symptoms suggestive of an epileptic ictus such as an aura, incontinence, or postictal confusion. Most seizure -related episodes are short lived, lasting for only minutes, but automatic behavior may occasionally persist for hours or even several days. Integrated, purposeful behavior is rare during seizures. Alcoholic blackouts are periods of unrecalled behavior during which the intoxicated individual's behavior seems normal but the episode cannot be recalled later. Amnesia may occur
with relatively low blood alcohol levels and becomes more common as the concentration rises. The amnesia of alcoholic blackouts is a product of impaired information storage. Memory lapses also occur with benzodiazepine ingestion. Migraine as a cause of confusional states with memory lapses is usually accompanied by other migrainous symptoms such as photophobia, visual hallucinations, nausea, and head-ache, although the latter need not be prominent. Toxic and metabolic encephalopathies, particularly those associated with drug ingestion and transient hypoglycemia, must also be considered in the differential diagnosis of transient memory alterations. Memory disturbances lasting for more prolonged periods include the amnesia syndromes discussed earlier (Table 7.1 ) and the more long-lasting dissociative states, including fugues and multiple personality. The latter are not amnesias as defined here, in that there is no disturbance of recent memory during the episode. Rather, on recovering from the dissociative state, the patient is unable to recall all or most of the events transpiring during the dissociated period. Progressive memory loss is characteristic of dementia syndromes (Chapter 10 ).
Psychogenic amnesia
Seizures
Alcoholic blackouts
Migraine
Amnestic syndromes
Dissociative states
Fugues
Multiple personality
Cortical dementias
P.111 Two principal types of memory disorders occur in dementing illnesses: a type -type storage disorder characterized by impaired recall and recognition and a retrieval deficit syndrome featuring diminished recall with preserved recognition. The amnesic type disorder occurs in AD and other conditions in which the medial temporal structures are affected. The retrieval deficit syndrome occurs in diseases that involve the frontal lobes and the basal ganglia. It is essential when attempting to differentiate these two disorders that the patient have sufficient attention to ensure information registration. Distractible, inattentive individuals will have reduced storage and an amnesic pattern of performance regardless of the cause or the site of any underlying pathology. Information registration is a pre requisite for demonstrating a distinction between storage and retrieval deficits. Dementia syndromes have impairments in other cognitive domains as well as memory. Patients with AD evidence language and visuospatial deficits, and patients with frontal-subcortical dementias typically manifest executive function deficits and prominent mood and behavior changes. 18 Progressive memory abnormalities must be distinguished from AAMI. The latter is confined to memory performance and does not involve other major cognitive domains. It is not incapacitating. Individuals with AAMI do not meet criteria for the definition of dementia (Chapter 10 ).
Reduplicative Paramnesia
Reduplicative paramnesia or double orientation refers to a peculiar disorientation syndrome in which the patient claims to be present simultaneously in two or more locations. The reduplicative paramnesia may take the form of believing that the location has two names, that the two locations are contiguous, or that the patient has recently made a journey from one to the other. For example, one of the author's patients insisted that he was in the Rose Garden Hotel,
which was a branch of UCLA Medical Center (his actual location). He explained that the hospital had been built around the hotel. Reduplicative paramnesia most commonly occurs during the recovery phase of post-traumatic encephalopathy, but it has been observed in patients with tumors, infarctions, and arteriovenous malformations as well as in metabolic and toxic encephalopathies. 4 3 In most cases with focal lesions, there has been damage to the right hemisphere and to both frontal lobes. A right frontal lesion may be sufficient to produce the syndrome. A possible explanation for the unique phenomenon is that the right hemispheric lesion makes it difficult for patients to integrate spatially significant information, whereas concomitant frontal lobe dysfunction or the confusional state impairs patients' abilities to appreciate and correct the discrepancy in their beliefs. Alexander et al. 4 4 have suggested that the Capgras syndrome , the delusional belief that people have been replaced by identical -appearing imposters, shares many features with reduplicative paramnesia, including the combination of right hemispheric and frontal dysfunction, and might be regarded as a similar paramnesia syndrome. The Capgras syndrome is presented more thoroughly in Chapter 12 .
Confabulation
Confabulation refers to the production of erroneous answers by patients with memory defects and represents a failure of error recognition rather than a desire to deliberately mislead. Two basic forms of confabulation have been distinguished: (1) confabulation of embarrassment, in which the amnesic patient provides in-correct answers based on personal past experience, and (2) fantastic confabulation, in which patients with impaired P.112 judgment and current or recent amnesia spontaneously describe impossible, adventurous, and often gruesome experiences. 4 5 Confabulation of embarrassment typically occurs in the acute stages of Wernicke -Korsakoff syndrome. Patients respond to questions regarding the date, location, and their employment with answers derived from their past. The answers are usually coherent or possible, but incorrect. If the syndrome enters its more chronic phases, confabulation diminishes and may ultimately disappear altogether. Studies of confabulation demonstrate that it represents a failure of error recognition and self -monitoring and most likely reflects impairment of executive function. 4 6
Confabulation frequently coexists with other evidence of executive dysfunction such as perseveration and apathy. Functional imaging demonstrates abnormalities of orbital and medial frontal regions that resolve in concert with resolution of the confabulatory state. 4 7 Confabulation of embarrassment may occur in other amnesic states and in degenerative dementias as well as in Korsakoff's syndrome, but appears to be most common in patients with lesions in the mamillary bodies or thalamus. Fantastic confabulation is a more rare and more colorful syndrome. One of the present authors' patients described how he had been taken into a spaceship by extraterrestrial visitors and taught how to drive their ship; on another occasion he told how he had singlehandedly decapitated 39 enemy soldiers as they were lined up shooting from behind a log. Most patients with fantastic confabulation have obvious frontal lobe syndromes, but their amnesia may be mild. The syndrome has been observed in post-traumatic encephalopathy, the Wernicke -Korsakoff syndrome, and degenerative dementias. If the patient consistently tells the same story and appears to endorse the story as true, the syndrome may be better viewed as a delusional disorder. Confabulation must be distinguished from prevarication , where the patient attempts to deliberately mislead the examiner. Pseudologia fantastica is a distinctive form of lying often associated with Munchausen's syndrome.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 8 - Visuospatial, Visuoperceptual, and Right Hemisphere Disturbances
TABLE 8.1. Classification of Visuospatial Functions and Corresponding Deficits Observed Clinically
Visuospatial Function
Clinical Deficit
Visual acuity
Impaired acuity
Homonymous hemianopia
Color vision
Achromatopsia
Depth perception
Astereopsis
Motion perception
Cerebral akinetopsia
Visual perception
Cortical blindness
Facial matching
Visual recognition
Familiar faces
Prosopagnosia
Familiar places
Color
Color agnosia
Object features
Object identity
Visuospatial attention
Spatial attention
Unilateral neglect
Simultanagnosia
Awareness of deficit
Anosognosia
Visuomotor ability
Constructional disturbances
Visuospatial cognition
Revisualization
Visuospatial imagination
Visual organization
Design generation
Visuospatial memory
Visuospatial amnesia
Finger recognition
Finger agnosia
Dressing
Dressing disturbance
Map reading
Planotopokinesia
P.116 characteristics of agnosia reflect the stage of recognition disrupted and the class of stimulus object most involved.
reading (alexia) usually accompanies the associative visual agnosias, although there have been rare cases of agnosia for nonverbal material with preserved reading abilities. 7 ,8 Associative visual agnosia can be distinguished from anomia by the intact ability of anomic patients to select the correct name from a list of choices or to describe the correct use of the object. Patients with associative agnosia cannot name a visual stimulus but demonstrate intact naming abilities when auditory or tactile information is available. Pathologically, nearly all autopsied cases of associative visual agnosia have had bilateral medial occipitotemporal lesions involving the inferior longitudinal fasciculi connecting occipital and temporal lobes (Fig. 8.1 ). 9 , 10 , 11
Prosopagnosia
Prosopagnosia is a unique syndrome in which the patient's major difficulty is an inability to recognize familiar
FIGURE 8.1 Transaxial magnetic resonance imaging shows the location of the inferior longitudinal fasciculi involved in associative visual agnosia.
P.117 faces. Although able to see normally and demonstrating no visual agnosia for most other classes of objects, patients
with prosopagnosia are unable to recognize spouses, friends, or relatives. They may be able to correctly describe who they see, but no sense of recognition ensues, and they must develop alternate strategies to compensate for the visual recognition deficit (e.g., the sound of the unrecognized person's voice or specific identifying features such as mustache, hair color, etc., are used to aid identification). 1 2 , 13 , 1 4 Although the defect in prosopagnosia involves primarily recognition of familiar faces, some patients have deficits in recognizing individual members of other classes of objects, such as specific animals (e.g., individual cows) or specific automobiles, with which the patient was previously familiar. 12 , 1 5 Patients with prosopagnosia may be able to discriminate and match unfamiliar faces normally, but they cannot learn new faces and recognize them at a later time. 1 6 Difficulty with discriminating and matching unfamiliar faces is a ubiquitous abnormality among patients with posterior right hemisphere lesions, and such patients seldom have concomitant prosopagnosia. 17 , 1 8, 1 9 Patients with prosopagnosia have electrodermal responses to familiar faces, which suggests that they have preserved psychophysiological recognition even though they have no conscious or declarative recognition. 2 0, 21 The anatomic basis of prosopagnosia is controversial. Most cases have had bilateral medial occipital lesions, 1 2 , 2 2 but several cases studied have had unilateral right -sided posteromedial lesions, suggesting that uni -lateral right -sided lesions may be sufficient to interrupt recognition of familiar faces. 23 , 2 4
Environmental Agnosia
Environmental agnosia (also called topographagnosia, topagnosia , and topographic memory loss), like prosopagnosia, involves loss of recognition of a specific class of familiar visual stimuli!in this case, one's own environment. The patient can see adequately, can usually describe the environment correctly, can often correctly utilize maps to find directions, and may even be able to draw an accurate map. When faced with the actual
environment, however, the patient has no sense of familiarity or recognition. 2 5 , 26 Most patients capitalize on their intact linguistic capacities and adopt verbal strategies to help compensate for their deficits. For example, they use street names and house numbers to find their way around, and they may not be able to find their own houses, except in this way! Environmental agnosia frequently occurs as part of a clinical triad with prosopagnosia and central achromatopsia (described below), but a variety of concomitant abnormalities have been described, including palinopsia, absent mental revisualization (Charcot -Wilbrand syndrome), dressing disturbances, visual allesthesia, and disturbances of brightness modulation. 2 6 The underlying defect in environmental agnosia appears to be an inability to relate current perceptions to stored memories that would allow environmental recognition to occur.
Color Agnosia
Color agnosia refers to the specific inability to recognize colors. 2 7 Color agnosia is difficult to assess, since color is exclusively a visual phenomenon and it is not possible to demonstrate that patients who are unable to name colors or point to named colors could recognize them when presented in another modality (e.g., colors have no auditory or tactile dimension). Disturbances of color -related cognition from which color agnosia should be distinguished include achromatopsia (discussed below), color -specific naming defects that occur in patients with alexia without agraphia, and color aphasia (aphasic syndrome with disproportionate severity for color naming and understanding color words). 1,2 8 Patients with color agnosia can sort by color category or arrange colors by shade, whereas patients with achromatopsia cannot perform these tasks.
Finger Agnosia
Finger agnosia occurs as one element of Gerstmann's syndrome along with dysgraphia, right -left disorientation, and acalculia. When all four elements of the syndrome are simultaneously present in the absence of dementia or delirium, it reliably indicates the presence of a lesion of the left angular gyrus. 29 Finger agnosia is a form of
autotopagnosia reflecting a deficit in the ability to localize stimuli applied to one's body (described below). When the syndrome is present in its most severe form, the patient cannot point to named fingers. In its more mild forms, the syndrome can be demonstrated by asking the patient to show the finger on his or her hand that corresponds to a finger on the other hand touched by the examiner when the patient's eyes are closed, or by asking the patient to state how many fingers are between two touched by the examiner while the patient's eyes are closed.
Simultanagnosia
Simultanagnosia refers to a curious neuropsychological deficit in which the patient is unable to simultaneously perceive more than one stimulus item or more than one P.118 part of a complex pattern. For example, if shown a piece of paper with a circle and a cross on it, the patient will see only one of the items; or, if shown a complex picture, only one portion of it is visible to the patient. 30 , 3 1 The disorder cannot be attributed to elementary visual abnormalities or to hemispatial neglect. Simultanagnosia does not meet the usual criteria for an agnosia since the patient has a narrowing of effective visual field excluding more than one element and allowing recognition of only one element at a time. The patient cannot see the other elements, thus simultanagnosia is a specific type of visual attentional failure rather than an agnosia. Simultanagnosia is thought to be due to an impaired ability to integrate more than one item at a time or an inability to use visual cues that allow rapid analysis of complex figures. 31 Most patients with Simultanagnosia have had bilateral parietooccipital lesions, although simultanagnosia due to a lesion of the left occipital lobe has been described. 1 Simultanagnosia often occurs as one element of Balint's syndrome (described below).
which the patient fails to notice, report, or respond to stimuli in one-half of space. All sensory modalities can be included in a neglect syndrome, and the severity of the attentional deficit varies considerably among patients. In severe cases, the patient notices nothing in the neglected half -field; will draw only one-half of constructions; may dress, shave, or apply makeup to only one-half of the body; ignores visual, auditory, and tactile stimuli on the neglected side; and will frankly deny the presence of any motor or sensory deficit on the side of the body in the affected hemispace. In milder cases, there will be a less pronounced tendency to ignore stimuli on the involved side, the patient's attention can be directed to the affected hemispace, and the patient will not overtly deny the deficits. In its least severe form, the neglect will be revealed only by extinguishing one of a pair of stimuli during double simultaneous sensory stimulation. 32, 33 The severity of neglect tends to be greater in patients with larger lesions and in those with coexisting cerebral atrophy. 34 Right parietal lesions produce the most marked neglect syndrome, but hemispatial neglect is not uniquely related to damage to this brain region. Neglect has also been observed in patients with left parietal lesions, damage to the left and right dorsolateral frontal areas, left and right medial frontal regions, left and right striatum, right thalamus, and the white matter of the internal capsule and hemispheric white matter. 3 2, 35, 36 , 3 7, 38 , 3 9, 4 0, 4 1, 4 2, 4 3 These structures receive projections from the ascending reticular activating system and comprise a reticulolimbic -neocortical network responsible for directed attention. 44 Thalamoparietal dysfunction produces primarily sensory neglect; dorsolateral frontal and striatal lesions produce motor neglect; and anterior cingulate injury results in diminished motivation 45, 46, 4 7 (Table 8.2 ) The right hemisphere is dominant for spatial attention and mediates aspects of attention directed to both right and left hemispace, whereas the left hemisphere
TABLE 8.2. Anatomic Location of Lesions Producing Hemispatial Neglect and Clinical Features of the Corresponding Syndrome
Location
Clinical Features
Parietal lobe
Failure to detect contralateral stimuli and extinguishing contralateral stimuli during bilateral simultaneous stimulation
Anosognosia
Medial thalamus
Contralateral hypokinesia, hypometric limb movements, and reduced action directed toward contralateral space
Striaton
Motor neglect similar to that observed in patients with dorsolateral prefrontal lesions
Reduced motivation to perform sensory and motor tasks in the contralateral hemispace
P.119
FIGURE 8.2 On this line -crossing test, a patient with hemispatial neglect was instructed to cross each line in the middle. He crossed only the lines on the right side of the page, neglecting the left hemispace.
mediates only contralateral attention. Thus, right brain dysfunction produces contralateral as well as ipsilateral attentional deficits, while left brain lesions produce only contralateral neglect. 44 , 4 8 Compensation for left hemisphere dysfunction by the right brain leads to early resolution of right -sided neglect following left brain injury, but the left hemisphere is less able to compensate for right brain dysfunction and there is more sustained left -sided neglect after right brain injury. Cortical dysfunction may be the
essential element in all forms of neglect. Subcortical lesions with neglect have associated functional disruption of cortical activity when studied with single photon emission computed tomography (SPECT), and recovery of neglect corresponds to the recovery of cortical function. 3 5 Subcortical lesions may cause cortical dysfunction through disconnection of cortical afferent connections, concomitant hypoperfusion, or diaschesis. Tests for unilateral neglect should include both sensory and motor function. The line -crossing test (Fig. 8.2 ) is one simple and effective way of demonstrating visual neglect. 49 The patient is presented with a sheet of paper with random lines on it and asked to mark the center of each line. If neglect is present, all or a portion of the lines in the neglected field will not be marked. Drawing and copying tasks may also reveal hemispatial neglect. The patient will reproduce only the portion of the model figure in the non neglected field or will omit details of the figure that appear in the neglected hemifield (Fig. 8.3 ). Likewise, when drawing new figures (rather than copying model figures), the patient will make errors of omission or placement on the side of the figure in the neglected hemispace (Fig. 8.4 ). There is a tendency for patients with lesions of the parietal cortex to make more errors when copying than when drawing and for patients with frontal lobe lesions to make more errors when drawing than when copying. Neglect can also be demonstrated by cancellation tasks (requiring the patient to search a visual space and mark or !cancel!! specific target letters or objects. 5 0 Hemialexia is best demonstrated by asking the patient to read compound words such as baseball and northwest; the patient will read only the word in the non -neglected hemifield. 51 Hemiacalculia is observed when patients are asked to add figures arranged in columns; they will add only the numbers in the non -neglected field. Patients with motor neglect often appear to have a hemiplegia, since they fail to use the neglected limbs. When each limb is tested individually, the strength on the neglected side is found to be normal or only partially diminished. Motor neglect is also evidenced by motor impersistence and hypokinetic movements of the neglected side (for example, when asked to draw large circles in the air with arms extended, the patient will draw smaller circles
FIGURE 8.3 When asked to copy the Rey -Osterrieth Complex Figure (top), the patient neglected the left half of the figure and copied only the portion appearing in the right hemifield (bottom) .
Neglect is not a product of any coexisting visual field defect; many patients with homonymous hemianopia do not have neglect syndromes, and many with neglect syndromes do not have hemianopias. Extinction of one stimulus during double simultaneous sensory stimulations is a mild form of neglect and can be demonstrated in the visual sphere by stimulating homonymous portions of the visual fields during confrontation testing (a visual field defect will, if present, also obliterate perception of one stimulus and in-validate this test), in the auditory sphere by snapping one's fingers behind the ears on each side, and in the somatosensory sphere by simultaneously stimulating both sides of the
body. 3 2 Neglect is most pronounced during the acute phases of an acquired cerebral insult and, in the case of static lesions, gradually improves. Subtle evidence of neglect may persist for months or even longer, however, and may be one of the factors most limiting to the rehabilitation of the brain injured patients. 5 3 Improvement in neglect of hemispace can be encouraged by tasks that require the patient to direct their attention toward the neglected side, such as extending a line in that direction or producing a series of numbers that extend into the neglected space. 5 4, 5 5
Anosognosia
The term anosognosia was originally used by Babinski to describe patients with denial of hemiparesis. A variety of types of behavioral disturbances have been observed in patients with unilateral weakness, ranging from indifference to the deficit (anosodiaphoria), to denial of weakness (anosognosia), hatred of the paralyzed limbs (misoplegia) or denial of ownership of the weak extremities (somatoparaphrenia) (Table 8.3 ). 36 , 56 , 5 7 , 5 8, 5 9 , 6 0 , 6 1 Most patients with anosognosia have right brain lesions with left hemisensory loss of left -sided neglect. In
FIGURE 8.4 The patient was asked to draw a man. The left side of the figure is less developed (note the small ear of the left side of the drawing) and has several errors (discontinuity of the arm and leg on the left side of the drawing).
P.121
Syndrome
Clinical Abnormality
Asomatognosia
Distorted awareness of a
Extinguishing
Nonperception of stimulus on affected side during double simultaneous stimulation to analogous areas on two sides of the body
Anosognosia
Unawareness of hemiparesis
Denial of illness
Anosodiaphoria
Indifference to hemiparesis
Misoplegia
Personification
Somatoparaphrenia
Denial of ownership of paralyzed limbs and belief that they belong to someone else
Conscious hemiasomatognosia
Nosagnosic overestimation
Hyperscheraatia
Autotopagnosia
Allochiria
Mislocation of sensory stimuli to the corresponding point on the opposite side of the body
Allesthesia
Kinesthetic hallucinations
Macrosornatognosia
Microsomatognosia
addition, most patients with the more marked forms of the syndrome are apathetic and have mild to moderate cognitive impairment. 62 , 6 3 Anosognosia is most common in patients with acute stroke involving the supramarginal gyrus of the inferior parietal lobule of the right hemisphere or the underlying white matter of the thalamoparietal peduncle. 6 2 , 6 4 Cerebral atrophy is commonly present in anosognosic patients. Up to 80% of patients with acute left hemiparesis will have anosognosia or anosognosic phenomena, while approximately 20% of patients with left brain lesions and right -sided weakness will exhibit such behaviors. 5 7 Patients with Wernicke's aphasia or jargon aphasia (Chapter 6 ) often have a language -related form of anosognosia, denying the presence of language disturbances in the acute period immediately following the onset of the disorder. 6 5 , 6 6
Anton's Syndrome
Anton's syndrome features blindness and denial of blindness. 67 The patient is blind but denies sightlessness and readily confabulates answers to questions concerning visual information. If pressed, the patient may admit to having vision that is !slightly blurred!! or that !the light is dim!! but gives no other hint concerning the presence or severity of the deficit. The syndrome occurs
most commonly with cortical blindness produced by bilateral lesions of the occipital cortex or retrogeniculate P.122 visual radiations, but it also has been described in patients with blindness from ocular or optic tract disease and who have an associated dementia or confusional state. 6 8 , 69 , 7 0
Constructional Disturbances
Constructional disturbances have traditionally been called apraxias in the neurological and neuropsycho -logical literature, but they do not fit the definition of apraxia adopted in Chapter 6 and are referred to simply as constructional disturbances in this discussion. The evaluation of constructional abilities is a rapid and discriminating technique for assessment of the integrity of visuospatial skills and should be included in all neuropsychiatric assessments. Constructional abilities are disturbed by a variety of brain disorders and by lesions in several different brain regions. Most idiopathic psychiatric disorders spare constructional abilities and the occurrence of constructional abnormalities usually indicates the presence of a neurologic disease. 71 Many tasks can be used to evaluate constructional abilities, including copying model figures such as a circle, cross and cube; copying complex scorable figures such as the Rey Osterrieth Figure (Fig. 8.2 ); drawing figures without a model such as a flower, house, clock, or person (Fig. 8.3 ); or reproducing model figures using matchsticks. Deficits are more evident with tests requiring reproduction of three dimensional perspective or complex figures than with less demanding tasks. 7 2 Constructional disturbances are one manifestation of the disruption of visuospatial skills produced by a brain disorder, and other types of visuospatial abnormalities!dressing disorders, environmental disorientation!are present in most patients with constructional deficits. Successful completion of a constructional task depends on integrating a variety of contributing neuropsychological abilities including spatially distributed attention, accurate perception, development of a drawing or copying strategy, execution of a sequence of motor acts, and use of feedback
to modify the process as the construction evolves. Many brain regions contribute to this process, and the presence of a constructional deficit has little localizing value. Isolated lesions of the temporal lobes have few effects on drawing, but dysfunction of the frontal lobes, parietal lobes, occipital lobes, and basal ganglia of either hemisphere can adversely affect constructional abilities. Constructional deficits are most marked with right posterior lesions. 73 The features of the patient's drawing or copying may provide some insight into the location of brain lesions, although additional information from the clinical history, neurologic examination, and neuroimaging is usually necessary to confirm the localization suggested by the characteristics of the constructions. Lesions of the right and left hemispheres tend to have different effects on construction (Table 8.4 ). Right brain lesions are associated
TABLE 8.4. Contrasting Features of Constructions Produced by Right or Left Brain Dysfunction *
Segmented approach
Tendency to add
extraneous detail
what is requested
Faulty orientation
Elaboration of details
Overscoring of lines
Single lines
Faster execution
Slower execution
Better recovery
laterality of the lesion; taken together, they provide tentative evidence of the side of the disorder.
P.123 with left -sided neglect, a right -to -left drawing strategy, loss of perspective, abnormalities of the external configuration, and inappropriate relationships of the constituent parts. Left brain lesions produce less marked abnormalities, with a tendency toward right -sided neglect and omission or simplification of the internal detail of the design. 73 , 7 4 Copies made by patients with right brain damage tend to be larger than the model, while copies from patients with left brain lesions are more likely to be smaller than, or the same size as, the model. 7 5 Patients with right brain damage have more difficulty with judgment of line orientation and figure matching, which suggests that their constructional deficits are a product of an inability to accurately perceive the figures. 76 Frontal lobe lesions, particularly those on the right, disrupt planning and result in segmented drawings developed with a piecemeal approach. Observing exactly how the patient performs the task is critical to detecting this type of disturbance. 7 7 Frontal lobe lesions tend to disrupt drawing more than copying, while parietal lobe lesions have a greater effect on copying than drawing. Patients with frontal lobe disturbances are also likely to evidence perseveration and to overemphasize high -stimulus areas of a drawing at the expense of other details. They may convert emotionally neutral stimulus items of a construction into !happy faces.!! 7 8 Constructional deficits are etiologically nonspecific. They may be observed in patients with stroke, tumors, multiple sclerosis, or trauma, as well as in patients with delirium and dementia (Chapters 10 , 11 , and 26 ). 7 9, 80
bilaterally. The most frequent cause of cortical blindness is vertebrobasilar artery disease and bilateral occlusion of the posterior cerebral arteries. It also has been reported following surgery, particularly cardiac surgery, following cerebral angiography, and in patients with trauma and carbon monoxide intoxication. 8 1 There may be an accompanying amnesia secondary to anoxic injury or infarction of the hippocampi. Recovery is most limited in older patients who have sustained a stroke and who have visible lesions on cerebral. 81 Patients with cortical blindness may exhibit the phenomenon of blindsight , an apparently paradoxical syndrome that reflects the capacity for visual processing in the extrageniculocortical system. Twenty to 30 percent of fibers of the optic tract are directed to nongeniculate destinations, particularly the superior colliculi and pretectal region of the brainstem. The nongeniculate system allows cortically !blind! ! patients to orient toward visual stimuli and to detect object movement while experiencing no conscious visual perception. 8 2 These phenomena are not demonstrable if the blindness is the result of preginuculate lesions. 8 3 Blindsight must be distinguished from residual rudimentary vision mediated by small islands of preserved cortex. 8 4 Blindness from cortical lesions or ocular pathology must occasionally be differentiated from hysterical blindness. Patients with cortical blindness have retained pupillary responses but lose optokinetic nystagmus (produced by moving a striped target in front of the patient's eyes); patients with anterior blindness typically lose both pupillary responses and optokinetic responses; and patients with blindness as a conversion reaction retain both pupillary responses and optokinetic nystagmus. 8 5
Balint's Syndrome
Balint's syndrome is a complex disturbance including (1) !psychic paralysis of visual fixation!! (or !sticky fixation!!) in which the patient cannot volitionally shift gaze from one object to another; (2) !optic ataxia,!! evidenced by an inability to execute visually guided manual movements; and (3) simultanagnosia, characterized by an
inability to see any but the most prominent visual stimuli 2 9 (described below). Pathologically, Balint's syndrome is produced by bi -lateral parietooccipital lesions involving the lateral aspects of the hemisphere. 8 6 , 87 , 8 8
Charcot-Wilbrand Syndrome
The Charcot -Wilbrand syndrome, or !irreminiscence,!! is characterized by the inability to generate an internal mental image or !revisualize!! an object. 3 6 When asked to imagine an elephant, flag, bicycle, or any other object, the person is unable to generate an internal mental image. One of the authors' patients said of the experience, !Doc, it's like having your picture tube go out.!! Patients with the syndrome typically have much more difficulty generating objects through drawing than copying model figures. Some patients have reported a loss of dream imagery. 3 6 , 8 9, 9 0 Most patients with Charcot -Wilbrand syndrome have bilateral parietal lobe lesions and in some cases the patients have both Charcot -Wilbrand and Balint's syndrome. 3 6 , 90 , 9 1 P.124
Central Achromatopsia
Central achromatopsia refers to loss of color vision produced by occipital lobe lesions. It must be distinguished from inherited abnormalities of color vision, acquired disorders of the optic nerves that impair color vision, color agnosia, and color anomia. Central processing of color perception in the occipital lobes occurs inferior to the calcarine sulcus and anterior to the region mediating visual field information. Bilateral injury to this area produces complete color blindness, whereas unilateral damage produces contralateral hemiachromatopsia. 9 2
Dressing Disturbances
Dressing disturbances may be produced by a variety of CNS lesions and occur in the context of several different clinical syndromes: (1) in disorders with profound unilateral neglect, only the non -neglected side of the body may be bathed,
toileted, and dressed; (2) in acute confusional states, dementing disorders, and schizophrenia, patients may don multiple layers of clothing when such bundling is inappropriate for the weather; and (3) a disturbance of true body-garment orientation may occur. In the third case, the patient may be unable to correctly orient the arm to the sleeve, may try to wear a shirt on the legs, or may put pants on back -wards. The syndrome appears to be uniquely associated with right parietal lesions. 9 3
Dazzle
Central dazzle is a syndrome of painless photophobia. 9 4 It is associated with lateral geniculate lesions and may be analogous to a thalamic pain syndrome in the visual domain.
Planotopokinesia
Planotopokinesia refers to the inability to use a map. Patients cannot draw a map or use a map to orient themselves in the environment. 9 5 This syndrome is commonly accompanied by left neglect and constructional disturbances.
environments, likewise, is a personally relevant ability and may be impaired in patients with right occipital -temporal lesions in the syndrome of environmental agnosia (discussed above). Display of mood -congruent facial expression, important for telegraphing one's emotional state, is more abnormal in patients with right brain lesions than in those with left brain lesions. 98 Recognition of familiar voices and deduction of the speaker's emotional state are also primarily dependent on right hemisphere function and may be abnormal in patients with right parietal damage. 9 9, 10 0 Execution of prosodic speech qualities that allow listeners to perceive the speaker's emotion is disturbed by right brain lesions. 10 1 Table 8.5 lists the clinical disorders observed in patients with right brain lesions that are highly relevant to personal emotional -social function. When these disorders
TABLE 8.5. Disorders of Personal Relevance and Social-Emotional Function That Are Associated with Damage to the Right Hemisphere
Acceptance of the identity of a familiar -looking individual (Capgras syndrome and related misidentification disorders)
P.125 occur in adults, they produce emotional isolation along with an inability to communicate one's emotions or to comprehend the emotions of others; when they occur in children, they may permanently disrupt the ability to develop interpersonal relationships and result in isolating,
shy, aggressive, and schizoid behaviors. 8 5 , 1 0 2 Of the three major axes of emotion!perception of emotionally relevant stimuli, execution of emotionally relevant behaviors, and subjective emotion experience!the right hemisphere is vitally concerned with mediation of perception of emotions and execution of emotional behaviors. Emotional experience is mediated primarily by limbic system structures. In addition to the disorders of personal relevance and abnormalities of emotional perception and expression, a variety of other neuropsychiatric disorders have been linked to right hemisphere dysfunction. Secondary mania occurs nearly exclusively with lesions of the right hemisphere (Chapter 14 ), visual hallucinations are common with posterior right brain dysfunction (Chapter 13 ), and psychosis may also occur with right hemisphere disorders. Misidentification disorders!Capgras syndrome, Frigoli syndrome, intermetamorphosis syndrome, and related conditions!are more common with right than with left hemisphere lesions (Chapter 12 ). Anxiety has been linked to lesions of the right medial temporal lobe (Chapter 17 ). Reduced sexual activity has been observed more commonly after right than left brain lesions (Chapter 23 ). Frontotemporal dementia with disproportionate right frontal involvement produces more marked disruption of social behavior than does frontal degenerative syndrome affecting primarily the left hemisphere.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 9 - Frontal Lobe Dysfunction
The frontal lobes are not homogenous entities but are divided into functionally specialized subregions, and injury to different areas produces clinically distinct psychosyndromes and behavioral alterations. This chapter presents the recognized syndromes resulting from restricted frontal damage and describes additional behavioral symptoms to which frontal dysfunction contributes. The anatomic correlates of the principal syndromes and the common etiologies of frontal damage are discussed. The anatomic relationships between the frontal lobes and subcortical structures as well as the similarity of behavioral changes associated with frontal lobe, basal ganglionic, and thalamic dysfunction are described. Finally, the treatment of behavioral disorders associated with frontal lobe dysfunction is presented. P.129
lesions have particular difficulty with antisaccadic tasks requiring them to look away from a visual stimulus.
Primitive Reflexes
Primitive reflexes are characteristic of frontal lobe disorders (Chapter 2 ). These represent the re -emergence of motor acts that were appropriate at developmentally earlier stages, were suppressed by the maturation of the frontal lobes, and reappear with frontal lobe dysfunction. The grasp and suck reflexes are the two most prominent primitive reflexes encountered in patients with frontal lobe disorders (Chapter 2 ). 3 , 4
Memory Disturbances
Memory deficits may also occur in patients with frontal lobe disorders (Chapter 7 ). Retrieval deficit syndromes are
common in patients with dorsolateral prefrontal dysfunction and true amnesias may occur in patients with inferomedial lesions affecting the nucleus basalis of Meynert or the fibers of the fornix. 8
Prefrontal Syndromes
Three principal behavioral syndromes are associated with frontal lobe dysfunction (Table 9.2 ): an orbitofrontal syndrome, characterized by disinhibition and impulsiveness; a dorsolateral prefrontal syndrome, manifested primarily by executive dysfunction; and a medial frontal syndrome featuring apathy and akinesia (Fig. 9.1 ). Each of these syndromes is associated with abnormalities of a distinct region within the frontal lobe. Similar behaviors may be seen with disorders of the caudate nucleus, globus pallidus, and thalamus, to which the frontal lobes are connected in frontal-subcortical circuits (described below). 9 Thus, these behaviors are markers of frontal-subcortical circuit dysfunction and are not uniquely !frontal lobe!! syndromes. Frontal lobe syndromes are rarely seen in isolation. Few diseases affect only one region of the frontal lobe, and mixed syndromes with elements of dorsolateral, orbitofrontal, and medial frontal dysfunction are common. Moreover, because the two frontal lobes are juxtaposed, bilateral frontal lobe involvement is common.
Orbitofrontal Syndrome
Behaviorally, the outstanding feature of the orbitofrontal syndrome is disinhibition. These patients P.130
TABLE 9.1. Principal Behavioral Symptoms and Syndromes Associated with Frontal Lobe Dysfunction
Behavioral
Alteration
Executive deficits
Dorsolateral prefrontal
Memory disorders
Dorsolateral prefrontal
Amnesia
Confabulation
Dorsolateral prefrontal
Reduplicative paramnesia
Right frontal
Broca's aphasia
Aphemia
Dysprosody
Ideomotor apraxia
Sympathetic apraxia
Callosal apraxia
Corpus callosum
Neuropsychiatric disorders
Disinhibition
Orbitofrontal
Apathy
Medial frontal
Mania
Depression
Schizophrenia
Dorsolateral prefrontal
Catatonia
Miscellaneous
Perseveration
Motor neglect
Hemiparesis
Motor cortex
Gaze abnormalities
Primitive reflexes
lack social judgment, make tactless and socially inappropriate comments, may commit antisocial acts, and exhibit a general coarsening of interpersonal style. They may manifest an inane euphoria and inappropriate jocularity (Witzelsucht) . Sexual preoccupations, inappropriate sexual jesting, and improper sexual comments are frequent, but overt sexual aggression is rare. 10, 11, 12 Orbitofrontal dysfunction has also been associated with imitation and utilization behavior. 1 3 , 1 4 , 15 Utilization behavior is manifested by the drive to pick up available objects (pencils, stethoscope, tongue blades) and use them or pantomime their use; imitation behavior refers P.131
FIGURE 9.1 Anatomy of three prefrontal regions corresponding to orbitofrontal (green), dorsolateral (blue), and medial frontal (pink) syndromes.
to the drive to imitate the behavior of the clinician or others in the environment. The patients' insight into their own behavior is limited. Empathy, the ability to appreciate another's feelings, is also compromised in patients with orbitofrontal lesions, often dramatically so. 16 A variety of mood changes have been associated with orbitofrontal dysfunction. Emotional lability with rapid shifts among affective states!happiness, anger, frustration, sadness!is common. Mania or hypomania may occur in a minority of patients with lesions in this area. 17 Depression has also been associated with
Prefrontal Region
Clinical Disorder
Orbitofrontal cortex
Impulsiveness
Limited insight
Irritability
Dorsolateral convexity
Poor abstraction
Depression
Reduced interest
Poor motivation
Impaired initiation
Reduced activity
P.132 dysfunction of orbitofrontal cortex: depressed patients with Parkinson's disease and Huntington's disease have decreased metabolism of the orbitofrontal area, compared to nondepressed patients with these diseases. 18, 19 Neuropsychological deficits are minimal in patients with orbitofrontal lesions. Impulsiveness, distractibility, and lack of concern for correct performance may interfere with intellectual assessment; however, when these can be contained, basic language, memory, and cognitive skills are usually found to be intact. 11, 20 When the lesion affects the descending columns of the fornix or the medial forebrain nuclei, an amnesic -type memory disorder is present. 21 , 22 Elementary neurological deficits are not prominent in patients with lesions limited to the orbitofrontal cortex.
Primary motor, somatosensory, and visual functions are normal if the lesion is limited to the orbitofrontal region. Anosmia may be present in patients with orbitofrontal trauma or compressive neoplasms.
Difficulty altering set in response to changing contingencies is typical of patients with prefrontal convexity lesions. 1 6 , 2 4 , 2 8 On the Wisconsin Card Sort Test (WCST), for example, they may exhibit loss of set or they may be unable to change set when necessary, exhibiting perseveration. 2 5, 29 Delayed -alternation tasks, requiring patients to respond to the last unrewarded stimulus and ignoring the last rewarded stimulus, are another means of testing the patient's ability to change sets in response to changing circumstances. 26 Impaired planning with development of poor strategies for solving complex problems is typical of patients with dorsolateral prefrontal dysfunction and is evident in memory tests, construction tasks, and cognitive assessment. 1, 24 The California Verbal Learning Test (CVLT), for example, assesses learning strategies by determining if the patient exhibits the clustering of semantically related words observed in normal individuals. The CVLT requires patients to learn a list of 16 words consisting of four groups of four related words (e.g., tools, fruit). Patients with intact frontal function cluster related words together to facilitate learning, whereas patients with frontal dysfunction fail to generate this learning strategy. Likewise, when confronted with a complex construction such as the Rey -Osterrieth Figure or Taylor Figure, patients with frontal lobe syndromes do not generate a coherent integrated structure but exhibit a piecemeal segmented approach (Fig. 9.2 ). 30 They may also exhibit stimulus boundedness, emphasizing elements that attract their attention, and they may assign affective value to emotionally neutral stimuli such as putting a !smiley!! face on the figures. 3 1 Another visuospatial task requiring generative capacity, which is frequently compromised in frontal lobe disorders, is the test of design fluency. 27, 32 Several versions of this test exist. The form shown in Figure 9.3 requires the patients to draw as many different figures as possible in 1 minute. Each figure is to consist of four lines, and every line should touch at least one other line. The lines are to be approximately the same length, and no figure should be repeated. Patients with frontal lobe syndrome have difficulty generating novel figures
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TABLE 9.3. Assessment of Neuropsychological Deficits Associated with Dorsolateral Prefrontal Dysfunction
Neuropsychological function
Clinical Test
Remote memory
Historical facts
Effort-demanding memory
CVLT
Set maintenance
WCST (categories)
Alternating programs *
Reciprocal programs
Go-no go test
Complex constructions
Figure (copy)
Design fluency
Advanced planning
Tower tests
Alternating programs
Reciprocal programs
Go-no go test
Abstraction
Proverbs
Mental control
Consonant trigrams
Trails B
CVLT, California Verbal Learning Test; WCST, Wisconsin Card Sort Test.
*
Some tests appear on this list more than once because more than one type of deficit associated with frontal lobe dysfunction contributes ro failures on the test.
(8 to 10/minute is normal) and tend to reproduce the same figure or closely related variants several times. Planning and strategy generation are assessed with tower tests (e.g., the Tower of London, Tower of Toronto, Tower of Hanoi) that require the patient to rearrange blocks with the fewest possible moves to achieve a specified end configuration. 2 9 , 3 0 Patients with frontal disorders have impoverished strategies and use more than the minimum number of moves to solve the problem. Patients with frontal dysfunction tend to make more bizarre responses on tests of cognitive estimation (e.g., P.134
FIGURE 9.2 Rey -Osterrieth Figure drawn by a patient with a frontal lobe syndrome (model above , copy below). The figure was drawn in a segmented fashion and exaggerates areas with high stimulus value.
!How long is an average man's spine ? !!) , a deficit interpreted in terms of poor use of available information and absence of response monitoring. 33 Sequential motor acts also depend on intact dorso -lateral prefrontal function. Alternating programs, multiple loops, reciprocal programs, go-no go tests, and serial hand sequences provide insight into the ability of the frontal lobe to guide sequential behaviors. 20 , 34 Alternating programs require the patients to alternate between two shapes such as squares and points or m's and n's (Fig. 9.4 ). Patients with dorsolateral prefrontal dysfunction frequently perseverate, failing to alternate regularly between figures. A test copying multiple loops (Fig. 9.5 ) can reveal a variety of types of frontal lobe -related abnormalities. The figures may be misinterpreted concretely and copied as 3's, or the patient may perseverate, adding additional loops beyond
those of the model. It is important when administering both the alternating programs and multiple loops that the patient be encouraged to make more figures than provided in the clinician's model. Patients with frontal lobe dysfunction are frequently stimulus-bound, can slavishly copy models, and may reveal their perseverative tendencies only when they are required to personally generate the features of the figure beyond the model provided by the examiner. Reciprocal program tasks require the patient to perform different movements with each hand or to respond reciprocally to a movement made by the clinician. For example, the patient may be asked to make a fist with one hand and to extend the other and to rapidly alternate between the two positions. When executing reciprocal programs, if the examiner taps once, the patient must tap twice, if the examiner taps twice, the patient taps once. Patients with frontal lobe lesions are likely to lose set and echo the taps of the clinician. The go-no go test requires the patient to withhold a response. The patient is asked to tap twice if the examiner taps once and to do nothing if the examiner taps twice. Response inhibition is difficult for many patients with frontal lobe disorders and they may echo the examiner's movements. Serial hand sequence tasks require the patient to move through a series of hand positions from fist, to slap, and to cut (Fig. 3.1 ). The examiner begins by demonstrating the sequence and asking patients to produce it on their own. If the patients fail, they are asked to say aloud !fist, slap, side!! to determine if they can use verbalization to guide their motor behavior. Patients with frontal lobe disorders frequently cannot take advantage of verbal input and have a verbal -manual dissociation, saying one sequence while executing another. Verbal -manual dissociation is an indication of executive dysfunction consistent with a frontal lobe disorder. Other types of failures observed on the serial hand sequences (e.g., difficulty learning the sequences) have less localizing value. Abstraction abilities also depend on frontal lobe integrity. 3 0 Interpretation of proverbs requires the patient to make generalizations based on an example. For instance, they must derive a generalizable meaning from a saying such as
!People who live in glass houses should not throw stones. !! Abstract interpretation of similarities requires that the patient derive a common theme from two examples!for instance, !How are a tulip and a rose alike ? !! or !How are a watch and ruler alike ? !! Interpretation of differences requires the patient to infer the essential difference between two items that are superficially similar !for example, !What is the difference between a child and a midget ? !! or !What is the difference between a lie and a mistake ? !! Patients P.135
FIGURE 9.3 In a test of design fluency, the patient is asked to make as many figures as possible consisting of four lines, each of which touch at least one other line. The figures should not be repeated. The test is terminated after 1 minute. The first two figures are examples provided by the examiner. The patient produced few figures and they are all similar.
with frontal lobe dysfunction are stimulus-bound, concrete, and environmentally dependent. These qualities interfere with their ability to abstract meaning beyond the surface content of these tests. Thus, they find little that is similar between a watch and a ruler (they don't look alike) and little that is different between a lie and a mistake (they seem similar). They cannot derive a second meaning or
moral from the superficial features of a proverb (e.g., !They will break their windows!! for the proverb given above). Proverb interpretation is conditioned by education and cultural background and cannot be used to test poorly educated persons or individuals unfamiliar with the proverb. Mental control tests are tasks assessing complex attentional mechanisms mediated in part by the frontal lobes. Patients with frontal lobe dysfunction may do well on elementary attentional tests such as digit span. They may perform normally on continuous performance tasks (for example, requiring patients to raise their hand each time the examiner reads an A among
FIGURE 9.4 In the alternating program test; the patient is provided with a sample (above) and asked to copy the sample and extend the pattern (below). Perseveration is evident.
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FIGURE 9.5 In the multiple loops test, the patient is provided with a sample (three figures on the left) and asked to make multiple copies. Perseveration is demonstrated here.
a long list of letters) or may be distractible and exhibit errors of omission. 2 9 More challenging for patients with frontal lobe disorders are mental control tasks, such as repeating the months of the year in reverse order. If patients fail this task, less demanding tests may be tried !e.g., serial subtraction or reverse spelling!to explore the severity of the deficit. Consonant trigrams are another type of mental control task that is difficult for patients with frontal lobe disorders to perform. 2 5 The patient is given three letters to remember and then immediately asked to count backward by 3's for 15 or 30 seconds. This requires the patient to perform two tasks at the same time (rehearse the letters and count backwards), and this may exceed the attentional resources of the patient. Suppression of routine responses in favor of novel responses is another type of mental control task that is difficult for patients with dorsolateral prefrontal dysfunction. On the Trails B test, the patient is required to alternate sequentially between numbers and letters (1!A!2!B!3!C . . .), and the patients tend to fall out of set, executing the conventional sequences (1, 2, 3 or A, B, C). Similarly, in the Stroop Test (Part C), the patient must suppress the usual response (read the color name) in favor of a novel response (state the color in which the word is written). Patients cannot suppress the habitual response in favor of the novel response and fail the tests. 25 The emotional concomitants of dorsolateral pre -frontal
dysfunction have not been fully explored. Depression is the most commonly described neuropsychiatric disorder observed in patients with lesions in the region, and anxiety frequently accompanies the depressive syndrome occurring with dorsolateral pre -frontal injury. 35 A few generalizations about dorsolateral prefrontal dysfunction are warranted. First, inferences about pre frontal functions are justified only when other more basic instrumental abilities are intact. The function of the frontal lobes is to synthesize information, create a strategy for problem resolution, and implement the action plan. Deficits in the elementary component of these functions make it impossible to assess the integrity of the frontal lobe. For example, aphasia will adversely affect word list generation and make if difficult to draw conclusions about frontal lobe function on the basis of verbal fluency tests. Likewise, amnesia or aphasia will affect the patient's performance on the WCST, and right parietal lobe disorders will disrupt visuospatial skills and affect deductions concerning frontal dysfunction that are based on copying or drawing performances. 3 6 Similarly, attentional disorders will disrupt mental control abilities, and motor system disorders will adversely affect sequential motor tasks. Inferences about frontal lobe function can be drawn only when other relevant cognitive and motor abilities are known to be intact. Second, patients rarely fail all tests of functions ascribed to the dorsolateral prefrontal cortex. Most patients fail some tasks and pass others. It is the overall performance that permits the conclusion that dorsolateral prefrontal dysfunction is present, rather than performance on any single test. Moreover, patients with prefrontal lesions exhibit more than usual day -to -day variability in cognitive performance. Third, a few basic types of dysfunction appear to underlie most of the clinical phenomena observed in patients with prefrontal disorders. Loss of generative and strategic capacities with a consequent stimulus-boundedness and environmental dependence is the principal determinant of the retrieval deficit syndrome, reduced verbal fluency, impaired nonverbal fluency, abnormalities in set shifting, poor planning and problem solving, poor abstraction, and abnormalities of mental control. Another major deficit is the
failure to adjust behavior on the basis of ongoing information collection. This contributes to loss of set and perseveration and the observed lack of flexibility in the behavior of patients with frontal lobe disorders. This suggests that the critical contributions of the dorsolateral frontal region P.137 to human behavior are the uncoupling of the perception of the immediate environmental stimulus from a considered action plan based on rule -guided behavior, reflection and judgment, synthesis of historical information, and abstraction of common themes from one setting to another.
initial stage of the disorder with gradual improvement to a state of reduced motivation as the patient recovers. Treatment with psychostimulants or dopaminergic agents (discussed below) may improve motivation and reduce apathy. The most marked apathetic syndrome accompanies bilateral anterior cingulate lesions and is characterized by akinetic mutism. In this remarkable syndrome, the patients are typically awake and may follow environmental activities with their eyes. They are not paralyzed and will eat if fed, urinate or defecate if taken to toilet, and may occasionally make voluntary postural adjustments or utter brief statements. They show no response to pain and no concern about their dramatic impairment. The state often has a fatal outcome. Akinetic mutism must be distinguished from lock-in syndrome, where the patient is paralyzed and from persistent vegetative state in which widespread brain injury prohibits meaningful behavior. The syndrome may be mistaken for catatonic unresponsiveness. Akinetic mutism is produced by lesions that involve both anterior cingulate gyri or interrupt cingulate connections. 39 , 40, 41 Neuropsychological deficits in patients with the me -dial frontal syndrome are relatively modest. In testable patients, general intellectual functions are not affected. As noted, patients with left medial lesions may have transcortical motor aphasia, and those with damage to the adjacent corpus callosum will manifest a callosal apraxia with apraxic movements of the left limbs (Chapter 6 ). In addition, patients with anterior cingulate lesions produce excessive failures on the WCST and on go-no go tests. 16, 42, 43 Elementary neurological deficits will be present if the lesion extends sufficiently far posteriorly to affect the medial aspect of the motor and sensory cortex. The leg and sphincters are represented medially and lesions of this region will produce leg weakness, sensory deficits in the leg, and incontinence. 4 4 Grasp and suck reflexes are frequently present in patients with medial frontal lesions.
dysfunction have distinct behavioral profiles, they share at least one common feature. A major theme of each syndrome is the loss of internally generated behavioral schemata and an ensuing enslavement to external influences. The impulsiveness of the orbitofrontal syndrome occurs in response to external contingencies without reflection on the consequences. The transcortical motor aphasia of the medial frontal syndrome is characterized by markedly reduced spontaneous (internally generated) speech but preservation of repetition and echolalia (repetition of external stimuli). Patients with dorsolateral prefrontal dysfunction exhibit poor recall of information (self -generated) but preserved recognition memory (externally structured) and poor word list generation (internally generated) but preserved confrontation naming (externally structured). Thus, all three of the prefrontal syndromes share a basic principle of loss of volitional control of behavior and generative function with ensuing dependency on the environment for response options. P.138
suggest that confabulation occurs when memory disturbances are present in patients with concomitant frontal lobe dysfunction (Chapter 7 ), 4 6 , 47 Reduplicative paramnesia is a disorder of spatial orientation in which patients insist that their current environments are relocated elsewhere, usually nearer to their homes (Chapter 7 ). In most cases the patients are recovering from posttraumatic encephalopathy or other acute cerebral insults and have combined frontal and right parietal lesions. 48, 4 9 Mood disorders are commonly associated with frontal lobe dysfunction. As noted above, patients with orbitofrontal lesions may exhibit euphoria, irritability, mood and affect lability, and inappropriate jocularity. Mania and hypomania have also been associated with frontal lobe dysfunction. Lesions producing mania usually affect the inferior medial frontal regions of the right hemisphere and are produced by stroke or trauma. 5 0 , 5 1 , 5 2 Both idiopathic and symptomatic depression are associated with frontal lobe dysfunction. Fluorodeoxyglucose positron emission tomography (FDGPET) in patients with idiopathic depression reveals diminished metabolism in the dorsolateral prefrontal regions. The reductions are more marked on the left than on the right. 5 3 , 54 Depression is common in the acute post-stroke period in patients with lesions affecting the left dorsolateral prefrontal cortex, 35 and patients with depression accompanying Parkinson's disease and Huntington's disease have reduced metabolism in the orbitofrontal area. 1 8 , 1 9 Frontal lobe function has been studied in obsessive compulsive disorder (OCD) using PET. Patients with OCD have increased metabolism in the orbitofrontal cortex 55 and increased blood flow in medial prefrontal regions. Agitation is a frontal lobe syndrome that results from a loss of behavioral modulation interacting with other types of psychopathology. Psychosis, depression, and mania are all associated with agitation; the features of the syndrome reflect the comorbid syndrome. Agitation results from frontal lobe dysfunction and reduction of the threshold for behavioral disturbances relating to the associated psychopathological process.
Schizophrenia is consistently associated with both neuropsychological and neuroimaging evidence of pre -frontal dysfunction. Despite normal intelligence, patients with schizophrenia perform poorly on tests of frontal lobe function, including the WCST, verbal fluency, design fluency, and tower tests. 5 6 , 5 7 Many schizophrenic patients have reduced blood flow or metabolism in the frontal lobes while in the resting state and they fail to activate the frontal lobe normally during tests that increase frontal function in nonschizophrenic individuals. 58 Catatonia is a clinical syndrome characterized by immobility, mutism, and withdrawal. Associated symptoms include staring, rigidity, posturing, negativism, waxy flexibility, echophenomena, mannerisms, stereotypy, and verbigeration (Chapter 20 ). 5 9 Catatonia is etiologically nonspecific and frontal lobe disorders are among the conditions that may induce catatonic states. Frontal lobe disorders that have produced catatonia include anterior communicating artery aneurysms, frontal lobe trauma and neoplasms, arteriovenous malformations, and frontal infections. 60 Perseveration refers to the continuation or recurrence of an experience or activity without appropriate stimulus. 61 Three types of perseveration are recognized: (1) recurrence of a previous response to a subsequent stimulus (recurrent perseveration), (2) inappropriate maintenance of a category or framework of activity (stuck -in-set perseveration), and (3) abnormal prolongation or continuation without cessation of a current behavior (continuous perseveration). 62 Recurrent perseveration is observed in tasks such as naming, word list generation, drawing, and design fluency in which a previous response recurs at a later time in the testing. Stuck -in-set perseveration occurs on tasks such as the WCST, in which the patient is required to change sets. Continuous perseveration is evident on graphic tests P.139
FIGURE 9.6 Anatomy of the frontal cortex Motor strip is depicted in red; premotor cortex, green; frontal eye fields, purple; prefrontal cortex, blue.
such as alternating programs (Fig. 9.5 ) and multiple loops (Fig. 9.6 ), the patient continues an ongoing behavior inappropriately. Perseveration is common in frontal lobe disorders but is not unique to frontal dysfunction and is seen in patients with lesions in other brain regions. 6 1, 62
these areas has different afferent and efferent relationships with other cortical and subcortical structures that reflect the different role each plays in human behavior. Likewise, the behavioral syndromes associated with each area are determined by their contrasting structures and functions. The dorsolateral prefrontal cortex receives remarkably diverse input. It has afferent connections from posterior sensory association cortex via the long hemispheric white matter tracts. It also receives input from the limbic cortical regions via short association fibers from the adjacent cingulate and orbital cortices. From subcortical structures, it receives a robust projection from the dorsomedial nucleus of the thalamus and more limited input from the hypothalamus. 6 4 , 6 5 Thus, the dorsolateral prefrontal cortex is poised to integrate information regarding the external environment through sensory regions, the internal milieu from the hypothalamus, and the emotional state of the organism from limbic regions. Historical information is available through thalamic and hippocampal -limbic projections. The frontal lobes initiate activity, monitor the effect of the action (through its widespread afferent connections), and modify actions accordingly. They P.140 modulate their own input to allow focusing of attention on relevant information and exclude irrelevant information. Deficits corresponding to disruption of these activities include distractibility, impersistence, perseveration, and failure to adjust behavior on the basis of feedback. The frontal lobes are the only anatomical areas with information sufficient to form a global view of the person, the environment, and the individual's history. They are positioned to defer immediate environmentally determined responses and construct a response informed by the past history and future goals of the individual. Lesions of the frontal lobes return the individual to a state of environmental dependency and stimulus-boundedness. The dorsolateral prefrontal cortex also has extensive efferent connections. It has reciprocal connections with most of the areas from which it receives input. In addition, it has a large projection to the head of the caudate nucleus, the first link of the dorsolateral prefrontal -subcortical circuit that includes the frontal convexity, caudate nucleus, globus pallidus and substantia nigra, and the dorsomedial nucleus of the
thalamus (Fig. 9.7 ). 9 , 6 6 The orbitofrontal cortex receives projections from the temporal lobe via the uncinate fasciculus, dorsomedial nucleus of the thalamus, hypothalamus, and amygdala. 63, 6 4 There is also input from the sensory association areas and the frontal association cortex. In addition to reciprocal connections with these areas, the orbitofrontal cortex serves as the origin of the orbitofrontal-subcortical circuit projecting to ventral caudate nucleus, globus pallidus and substantia nigra, and dorsomedial thalamus. This circuit is parallel to, but discrete from, the dorsolateral prefrontal subcortical circuit. 6 6 Lesions of this area interrupt the monitoring function of the orbitofrontal cortex, release limbically mediated behaviors, and produce impulsive, disinhibited behaviors. Social rules of conduct, consideration of consequences of one's behavior, and concern for the feelings of others are abandoned in favor of un -governed behavior responsive to immediate environmental stimuli and bodily urges. The anterior cingulate cortex receives major input from the hippocampus, dorsomedial nucleus of the thalamus, hypothalamus, amygdala, sensory association cortex, and dorsolateral prefrontal cortex. 6 3, 64 The anterior cingulate subcortical circuit projects to the nucleus accumbens, ventral globus pallidus and substantia nigra, and the dorsomedial nucleus of the thalamus. 66 Several member structures of this circuit!anterior cingulate, nucleus accumbens, ventral pallidum!receive dopaminergic projections from the
FIGURE 9.7 Frontal -subcortical circuits. There are five circuits, each consisting of projections from the frontal cortex to striatum (1); striatum to globus pallidus/substantia nigra (2, 3); pallidum to and from subthalamic nucleus (4, 5); pallidum to thalamus (6); and thalamus to frontoparietal cortex (7).
P.141 ventral tegmental area. 6 7 The anterior cingulate cortex mediates motivation, and dysfunction of this region results in apathy. 9
irregular bony surface (Fig. 9.8 ). 68, 6 9 A second common etiology is compression by a subfrontal neoplasm arising from the pituitary fossa, olfactory groove, or sphenoid ridge. Meningiomas and chromophobe adenomas are particularly frequent in these locations. 1 1 Aneurysms arising from the anterior communicating artery can act as mass lesions or rupture into the orbitofrontal and medial frontal areas. 12, 7 0 Frontotemporal dementias may present with an orbitofrontal syndrome and the gradual occurrence of such changes for the first time late in life nearly always signals the presence of a degenerative or neoplastic brain disease (Chapter 21 ). 71 Intrinsic brain tumors, vascular infarction, infections, psychosurgery, and demyelinating diseases are less frequent causes of the orbitofrontal syndrome. 10 Frontal convexity lesions result from disorders similar to those producing the orbitofrontal syndrome, accounting for the frequent simultaneous occurrence of orbitofrontal and convexity symptoms. The differential diagnosis of etiologies of the frontal convexity syndrome includes trauma, stroke, hydrocephalus, external compressive neoplasms (meningiomas) and intrinsic tumors (gliomas), infectious disorders, demyelinating disorders, and degenerative diseases. 1 0 , 7 1 , 7 2 The akinetic frontal lobe syndrome and its variants are associated with bilateral medial lesions, usually of a vascular nature. 3 9 The syndrome has also been produced by midline tumors, hydrocephalus, and trauma. 4 0, 73, 7 4 Apathetic states less marked than akinetic mutism may occur with unilateral lesions affecting the anterior cingulate region. Occlusion of an anterior
FIGURE 9.8 Computerized tomogram showing orbitofrontal injury associated with closed head trauma.
cerebral artery is the most common cause of this disorder (Fig. 9.9 ), but it may also be seen with falcine meningiomas, lateralized gliomas, and other focal pathology. Apathy may be prominent early in the course of frontotemporal dementias and is the rule late in their course. 7 2 Behavioral neurosurgery may produce any of the frontal syndromes, depending on the site and extent of the surgical lesions. Orbitofrontal lesions occasionally produce marked personality changes manifested by euphoria, increased motor activity, and impulsiveness. Neuropsychological testing of patients who have undergone traditional psychosurgery reveals deficits on the WCST reflecting abnormalities in abstracting and maintaining and shifting mental sets appropriately. 7 5 , 7 6 , 7 7 , 7 8 , 7 9 More laterally placed lesions (Fig. 9.10 ) produce different personality alterations and more extensive neuropsychological deficits. The personality changes include loss of drive, stimulus-boundedness, and impaired ability to elaborate experiences. 80 Neuropsychological assessment reveals difficulty with abstraction as well as deteriorated performance on tests of intelligence. 8 1
P.142
FIGURE 9.9 Magnetic resonance imaging (coronal section) reveals a left anterior cerebral artery territory infarction (arrow) in a patient who presented with mutism, apathy, and leg weakness.
FIGURE 9.10 Computerized tomography (horizontal section) demonstrates large bilateral lucencies in the frontal lobes of a patient who had undergone a conventional frontal leukotomy.
Frontal lobe syndromes are usually the result of overt structural changes, but some chronic toxic encephalopathies appear to involve primarily frontal lobe functions. Chronic alcoholic dementia has a predilection for affecting neuropsychological abilities mediated by the frontal lobes or related subcortical structures. Typical personality changes include an irritable apathy, and cognitive deficits include impaired word list generation, poor attention, visuospatial abnormalities, impaired memory, and poor abstraction. 8 2 , 8 3 , 8 4 The deficits may partially or completely remit if the patient remains abstinent.
be treated first with dopaminergic agents, since these drugs have fewer adverse long-term side effects. In those who fail to respond, a trial of psychostimulants is warranted. Pharmacotherapy should be combined with education, family therapy, and individual therapy as appropriate for the underlying condition (Chapter 4 ). 87
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 10 - Dementia
Chapter 10 Dementia
Dementia is a syndrome of acquired intellectual impairment characterized by persistent deficits in at least three of the following areas of mental activity: memory, language, visuospatial skills, personality or emotional state, and cognition (abstraction, mathematics, judgment). 1 Its acquired nature distinguishes dementia from mental retardation, whereas its persistence differentiates it from the delirium of acute confusional states (ACSs). The requirement, in the above criteria, that the intellectual alterations include multiple areas of mental function distinguishes dementia from aphasic, amnesic, and other monosymptomatic cognitive deficits. A second, more constrained definition of dementia is found in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria, 2 which require acquired impairment in memory with additional decline in at least one other domain (e.g., language, praxis, gnosis, executive skills) that interfere with either occupational or social functioning or interpersonal relationships. Abnormalities cannot be secondary to a delirium and should not be based on depression, schizophrenia, or other psychiatric illness). The application of the DSM-IV criteria is often hampered in the nursing home setting where no social or occupational challenges exist but where patients frequently manifest an acquired, persistent decline in multiple domains. For either set of criteria, dementia is a clinical syndrome with many etiologies that may be reversible or irreversible. Although dementia prevalence estimates are affected by the dementia criteria applied, 3 75% of patients with moderate to severe dementia and over 95% with mild impairment escape diagnosis in the primary care setting. 4 Dementia is a rapidly growing public health concern. It is largely a problem of elderly individuals, and the size of the aged population is expanding more rapidly than any other segment of the population. Approximately 5% of individuals over age 65 are severely demented, and an additional 10%!15% are mildly
to moderately intellectually impaired. 5 In 1950, 8% of the population was over age 65 (12.3 million individuals), and by 1978 the proportion had increased to 11% (22 million); it is estimated that by the year 2030 it will represent 20% of the U.S. population (51 million persons). As the number of aged persons increases, dementia will demand an increasing share of the health -care budget, health-care work-hours, and hospital and nursing home beds. Responding to this challenge demands an integrated, comprehensive, and systematic approach to identification of dementing illnesses, differentiation of the many etiologies of dementia, and development of management programs. P.147
Alzheimer's disease
Frontotemporal dementia
Vascular dementia
Parkinson's disease
Corticobasal degeneration
Huntington's disease
Prion diseases
HIV dementia
Syphilis
Chronic meningitis
Hydrocephalic dementias
Traumatic dementias
Neoplastic dementias
Depression
Schizophrenia
Etiologies Of Dementia
Table 10.1 presents the differential diagnosis of the dementia syndrome. Each major etiology of dementia is discussed and the distinguishing clinical features are described. The relationship between the topography of central nervous system (CNS) involvement and the pattern of intellectual alteration and profile of neuropsychiatric symptoms is emphasized.
Alzheimer's Disease
Alzheimer's disease (AD) almost invariably begins after the age of 50 and becomes increasingly common with advancing age. In 3% of cases the disease is inherited as an autosomal dominant condition, and in the remaining 97% there is an increased incidence of AD among family members. 5 Clinical diagnostic criteria for probable AD 6 (see Table 10.2 ) have helped standardize its assessment and diagnosis. The accuracy of the clinical diagnosis of AD, compared with pathological assessment, has increased from above 80% in the 1980s to above 90% in the 1990s, mainly because of the application of standardized diagnostic criteria. 7 ,8 Alzheimer's disease progresses through three stages in a relatively orderly and consistent manner (Table 10.3 ). 5 In the first stage the patient has empty speech with few substantive words and a paucity of ideas. There may be an anomia on tests of naming, and the patient will have difficulty generating word lists (e.g., number of animals names produced in 1 minute). Memory, cognition, and visuospatial skills are also compromised in the early phases of the disease, but speech articulation and other motor
functions remain normal. Patients usually are indifferent to their deficits, and an electroencephalogram (EEG) may be normal while computerized tomographic (CT) or magnetic resonance imaging (MRI) scans are remarkable only for medial temporal atrophy. 9 Functional imaging using single photon emission computed tomography (SPECT) or positron emission tomography (PET) may be the best diagnostic tools for distinguishing early AD from early frontotemporal dementia (Fig. 10.1 ). In the second stage of the disease all intellectual functions continue to deteriorate. Language is characterized by a fluent paraphasic output, impaired comprehension, and relatively preserved repetition. 1 0 Memory, for both recent and remote information, is severely impaired; visuospatial abilities are further compromised, and patients cannot find their way about or copy constructions; cognitive skills, including calculation and abstraction, are severely impaired. Apraxia and agnosia are present but difficult to demonstrate because of the patients' limited language and memory. Motor strength and coordination are normal, but the patients become
1 . Dementia present 2 . Onset between 40 and 90 years of age 3 . Deficits in two or more cognitive areas 4 . Progression of deficits >6 months 5 . Consciousness undisturbed 6 . Absence of other potential etiology
The best that can be achieved in the premorbid diagnosis for these and most other degenerative disorders is a !probable!! diagnosis. The diagnosis shifts to !possible Alzheimer's disease!! if it is very early in its course, or another brain -based disorder is present but does not significantly contribute to the clinical picture, or if there is an atypical presentation. !Definite!! diagnosis requires a clinically probable diagnosis
P.148
TABLE 10.3. Characteristics of the Three Stages of Alzheimer's Disease and Frontotemporal Dementia
Stage
Alzheimer's Disease
Frontotemporal Dementia
Stage I
Language
Anomia
Memory
Defective
Relatively spared
Visuospatial skills
Impaired
Relatively spared
Calculation
Impaired
Relatively spared
Personality
Indifferent
Disinhibited
Absent
Present
Motor system
Normal
Normal
EEG
Normal
Normal
Structural scan
Normal
Stage II
Language
Fluent aphasia
Memory
Severely impaired
Impaired
Visuospatial skills
Severely impaired
Impaired
Personality
Indifferent
Disinhibited
Motor system
Restlessness
EEG
Background slowing
Structural scan
Stage III
Intellectual function
Severely impaired
Severeley impaired
Language
Echolalia, mutism
Sphincter control
Incontinence
Incontinence
EEG
Diffuse slowing
Structural scan
Diffuse atrophy
EEG, etectroencehalogram.
markedly restless, wandering and pacing incessantly. There is usually theta -range slowing of the EEG, and structural imaging shows greater medial temporal atrophy with moderate parietal cortical atrophy as well. In the final stage all intellectual functions are severely impaired, and the patients' cognitive abilities are largely untestable. Verbal output is reduced to echolalia, palilalia, or mutism. Sphincter control is lost, and the patient's limbs assume a rigid, flexed position. The EEG reveals delta -range slowing, and structural imaging demonstrates diffuse cerebral atrophy with ventricular dilatation and general sulcal enlargement. Death results from aspiration pneumonia or urinary tract infection with sepsis. The diagnosis of AD is conventionally approached as a matter of exclusion based on the elimination of other more easily diagnosed causes of dementia. Negative laboratory evaluations and nonspecific physical findings, however, also characterize other types of dementia, such as the dementia syndrome of depression, dementia with Lewy bodies (DLB), some insidiously progressive toxic and metabolic processes, and some types of vascular dementia. Diagnosis by exclusion results in the inclusion of all such unrecognized dementias as AD and thus renders AD a nonspecific diagnosis. To ensure that the diagnosis of AD is applied to a homogeneous group of patients suffering from the same illness, all patients identified as suffering from AD P.149
FIGURE 10.1 [ 1 5 'Fluorodeoxyglucose positron emission tomography (FDG PET) scans of a normal elderly control (left), a patient with early Alzheimer's disease (AD) (middle), and a patient with frontotemporal dementia (FTD) (right). Note the presence of a metabolic defect in the posterior parietal cortex in the AD patient, but realtively preserved frontal metabolism as noted by absence of !cooler!! colors.
should have clinical features and course similar to that described here and thus be called AD through a diagnostic process of inclusion. They should have an insidiously progressive clinical syndrome, including aphasia, amnesia, and visuospatial abnormalities, and motor, reflex, and sensory function should be normal throughout most of the clinical course. The diagnosis of AD should be viewed skeptically if the patient's clinical features or course deviates substantially from this pattern. The neuropsychiatric features of AD include prominent apathy, agitation, anxiety, irritability, and depression. 1 0a Delusions are present in approximately 25% of patients in cross-sectional studies and the cumulative prevalence approaches 50%. Hallucinations are present in approximately 10%. Most neuropsychiatric symptoms are increasingly common with disease progression. Agitation and psychosis have been linked to neurofibrillary tangles in the frontal lobes, 1 0b and the cholinergic abnormalities also contribute to the psychopathology. 1 0 c Pathologically, the brains of AD patients are atrophic with ventricular and sulcal enlargement. Histological investigation reveals progressive neuronal loss, amyloid deposition within senile and neuritic plaques, and neurofibrillary tangles. 11, 12 Early changes are most abundant in the hippocampus, then parietal, and frontal association areas, and finally in primary sensory -motor cortex at the end stage of the disease. Neurons in the hippocampus also exhibit numerous intracellular granulovacuolar changes. Neurochemical analyses demonstrate a preferential loss of presynaptic cholinergic neurons in late -stage patients. 1 3 Loss of cholinergic neurons from the nucleus basalis in the inferior medial forebrain area correlates with the loss of cholinergic innervation of the cerebral cortex. 1 4 Cortical cholinergic markers may be normal in early and mid -stage patients. 15 The overproduction of beta-amyloid protein (in hereditary cases of AD) or the abnormal accumulation of beta-amyloid protein (in sporadic cases) is increasingly viewed as the central pathophysiologic event in AD. Beta -amyloid is released from amyloid precursor protein by beta- and gamma -secretases. The amyloid protein oligomerizes to protofibrils which are neurotoxic and initiate a cascade of events including oxidation, inflammation, apoptosis -like neurodegenerative changes, and formation of neurofibrillary tangles. 1 6 The protein accumulates in plaques, one of the key histopathologic hallmarks of the disease.
Treatment
Although the etiology of AD is unknown, treatment is directed toward symptomatic improvement with cholinergic agents, use of psychotropic agents to reduce behavioral disturbances, and disease modification. 1 7 , 1 8 Antiinflammatory agents, and estrogen replacement in postmenopausal woman, 1 9 , 2 0 may reduce the rate of development of AD. Treatment with a cholinesterase inhibitor such as donepezil, 2 1 rivastigmine, 2 2 or galantamine 2 3 is standard therapy for AD (Table 10!4a ). Patients may exhibit cognition improvement or slowing of cognitive decline, greater preservation of daily function, or behavioral benefit. Behavioral improvement with cholinergic treatment may be more robust than cognitive response. 2 4 Behavioral response to therapy may be predicted by a baseline orbital frontal paralimbic functional defect in the brains of AD patients as assessed with functional imaging. 2 5 After treatment with a cholinesterase inhibitor, metabolic increases in the anterior P.150
Agent
Initial Dose
Final Dose
Comment
Donepezil (Aricept)
5 mg/d
10 mg/d
Galantamine (Reminyl)
4 mg b.i.d.
8 !12 b.i.d.
Twice per day dosing; allosteric nicotine modulation plus acetylcholinesterase inhibition
Rivastigmine (Exelon)
1.5 mg
3 !6
b.i.d.
mg b.i.d.
cingulate and dorsolateral association cortex have been found in patients who evidenced a cognitive response (Fig. 10.2 ). 2 6
Frontotemporal Dementia
Frontotemporal dementia (FTD), like AD, affects primarily cortical structures. The two diseases are clinically similar, beginning in late middle life or later and progressing through a series of stages (Table 10.3 ). 5 It may be difficult to distinguish the two disorders in the early stages, but several clinical, imaging, and EEG features have differentiating value, particularly when the patient is observed in the early phases of the illness. Progressive nonfluent aphasia, semantic dementia, and a disinhibition syndrome are the three recognized forms of FTD. 27 Table 10.4b provides one approach to the diagnosis of FTD. 28 Compared with AD patients, FTD victims have less memory, calculation, and visuospatial impairment and more extravagant personality alterations. Both diseases produce aphasia, but FTD patients have a greater tendency to produce a stereotyped verbal output, repeating the same story or joke again and again. Those with progressive nonfluent aphasia or semantic dementia have aphasia syndromes distinct from the transcortical sensory aphasia of AD. Features of the Kl"ver -Bucy syndrome (hyperorality, dietary changes, hypermetamorphosis, placidity, hypersexuality, sensory agnosia) may appear early in the course of FTD, whereas they are confined to the late stages of AD. 29 The EEG and structural imaging scans are normal in the initial stages of FTD, but as the disease progresses, frontotemporal slowing may appear on the EEG, and focal frontal and/or temporal abnormalities may be evident on structural and functional imaging (Fig. 10.1 ); an exclusionary criterion for FTD is prominent post-central imaging defects. 2 7 The most prominent neuropsychiatric features of FTD are apathy and disinhibition. 2 9 a Mood changes including irritability, depression, and a fatuous euphoria may be present. Some patients develop a distant or bizarre affect with unusual laughter. Tactlessness, loss of concern for the feelings of others, lack of empathy, and reduced emotional engagement are common.
Pathologically, the brains of FTD patients have focal atrophy involving the frontal or anterior temporal lobes. 5 Histologically there is gliosis and neuronal loss in the frontal lobe and temporal lobe. Subcortical white matter may be affected. Occasionally the presence of inflated neurons and neurons containing highly argyrophilic
FIGURE 10.2 (A) Behavioral response to cholinesterase inhibitor therapy may be predicted by a baseline orbital frontal paralimbic functional defect in the brains of Alzheimer's disease (AD) patients as assessed with technetium !99m D, L hexamethylpropeleneamine oxime ( 9 9m Tc-HMPAO) single photon emission computed tomography (SPECT). 5 0 (B) After treatment with metrifonate (a cholinesterase inhibitor), metabolic increases in the anterior cingulate and dorsolateral association cortex were found in a separate group of AD patients who achieved criteria for a cognitive response. 5 1
P.151
1 . Development of a behavioral or cognitive decline manifested by: a. Progressive personality or behavioral change, or b . Progressive expressive language or naming impairment 2 . Deficits significantly impair social or
occupational function 3 . Course is manifested by gradual and significant decline 4 . No other CNS or systemic cause is responsible 5 . Deficits do not occur exclusively during a delirium 6 . Deficits are not due to a psychiatric diagnosis
Pick bodies are found in the Pick's disease subtype of FTD. Familial FTD resulting from mutations within chromosome 17, some of which are located within the tau gene, may manifest a clinical-pathological spectrum within affected families that includes frontal lobe dementia, progressive aphasia, lobar atrophy without distinctive histopathology, and Pick-like inclusions. 3 0 , 3 1 , 3 2 Immunolabeling with antibodies to individual tau epitopes has revealed neuronal and glial tauopathy in these families and several related sporadic degenerative brain diseases with tau inclusions (e.g., progressive supranuclear palsy, and corticobasal degeneration) are regarded as tauopathies. 3 3, Treatment of FTD is directed at the control of aberrant behavior and prevention of secondary complications.
Vascular Dementia
Vascular occlusions lead to tissue infarction with progressive disruption of brain function and may produce dementia. The characteristics of the dementia are highly variable and may include predominantly cortical features (aphasia, amnesia, agnosia, apraxia) or mainly subcortical symptoms (slowness, depression, forgetfulness, cognitive dilapidation). 5 Combinations of cortical and subcortical characteristics are common, but some neurobehavioral features, including psychomotor retardation and emotional lability are present in most cases. Table 10.5 lists the clinical criteria for vascular dementia (VaD). 3 4
1. Dementia is present
The criterion for the diagnosis of possible vascular dementia is met if the 3!month time requirement is not achieved.
Sustained hypertension leading to fibrinoid necrosis and occlusion of cerebral arterioles is the most common cause of VaD. Infarctions (lacunes) are concentrated in the thalamus, basal ganglia, and internal capsule near the base of the brain. In Binswanger's disease, the ischemic injury preferentially involves the hemispheric white matter (Fig. 10.3 ) and functional imaging shows multifocal defects (Fig. 10.4 ). 3 4 The most common form of VaD includes multiple lacunaes and white matter ischemia.
FIGURE 10.3 Differing manifestations of periventricular subcortical white matter disease on structural imaging studies, computed assisted tomography, T 1 -weighted magnetic resonance imaging (MRI), T 2 weighted MRI, and FLAIR MRI, from left to right.
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FIGURE 10.4 [15 ] Fluorodeoxyglucose positron emission tomography (FDG -PET) scans of a normal elderly control (left), and a patient with multiple cerebral vascular lesions (right).
In addition to hypertension-related arteriosclerosis, a variety of other vascular disorders can produce multiple cerebral infarctions, including arteriosclerosis of larger vessels, emboli from the heart or vessels of the neck, inflammatory conditions, and hematologic disorders. 5
Infarctions are frequently visible on brain imaging, but in some cases they may be too small to be visualized on CT or MRI scans with thick slices (10 mm). A scan similar to that seen in obstructive hydrocephalus may be produced in VaD when concentration of the infarctions in the deep periventricular structures leads to ventricular dilation with little enlargement of the cortical sulci. Electroencephalography may reveal multifocal slowing in cases of VaD. Treatment of VaD is directed at resolving the underlying condition and prevention of future ischemic disease. Dysarthria and aphasia may improve with speech and language therapy, while cholinesterase inhibitor therapy may also be of benefit. 35
Prion Diseases
Creutzfeldt -Jakob disease (CJD) is one of the many transmissible spongiform encephalopathies that are caused by prions affecting humans and animals. Prion diseases are fatal neurodegenerative disorders caused by proteaseresistant isoforms of the prion protein (PrPres). An epidemic of bovine spongiform encephalopathy (!mad cow!! disease) and cross-species transmission to humans in the form of variant Creutzfeldt -Jakob disease (vCJD) has heightened public awareness of prion diseases. 36 , 3 7 Scrapie is a naturally occurring form of prion diseases first recognized 200 years ago in sheep and goats. In humans, the phenotypic spectrum of prion disease now encompasses CJD, vCJD, the familial Gerstmann -Straussler-Scheinker syndrome, fatal familial insomnia, kuru, and other less distinct neuropsychiatric disorders. In contrast to kuru, now almost eradicated since the outlawing of ritualistic endocannibalism, sporadic CJD occurs in 85%!90% of patients suffering from prion diseases while the genetically determined forms occur in 8%!13% of patients; 38 , 3 9 the remaining transmitted cases are usually caused by invasive medical procedures such as corneal transplantations and surgical or dental procedures from an infected to an uninfected host and in cases where contaminated depth electrodes were used for recording in uninfected patients. 40 Infectivity of prions is due to an abnormal structural conformation of the cell surface protein known as the prion protein (PrP). 4 0 The wild-type isoform (PrPC) in humans is encoded by a single copy gene (PRNP) on chromosome 20, and detailed analysis in sporadic cases has failed to show any primary sequence or post-translational differences between PrPC and the abnormal, protease-resistant, disease associated isoform, PrPres. Prion replication and infectivity have an absolute dependence on the simultaneous presence
of PrPres and ongoing de novo synthesis of PrPC. PrPres is unusually resistant P.153
FIGURE 10.5 Differing manifestations of sporadic Creutzfeldt -Jakob disease (CJD) on structural imaging studies demonstrating striatal pathology (top row ) on T 1 -weighted magnetic resonance imaging (MRI), T 2 weighted MRI, and proton-dense MRI, from left to right. Adapted from Finkenstaedt et al. (1996). 8 7 Thalamic involvement can also be seen in the variant form of CJD (vCJD) on MRI; prion disease is shown (bottom row) on computed assisted tomography and T 2 MRI. Adapted from Zeidler et al.(1997). 8 8
to traditional physical and chemical disinfectant techniques, thus continued surgical or dental transmissions are of great concern when a suspected case is identified. Creutzfeldt -Jakob disease can be caused by six clinicopathological subtypes that comprise the entire phenotypic range. Seventy percent of cases present with the classic rapidly progressive dementia, periodic sharp wave complexes (PSWC) on EEG, and myoclonus, while the remaining 30% of cases are due to five less common subtypes presenting either with a slower dementia greater than a year without the typical EEG findings, initial ataxia, prominent thalamic degeneration, or kuru plaques. 4 1, 42 Detection of the 14!3!3 protein in cerebrospinal fluid (CSF) and the finding of hyperintensity of the basal ganglia
(sporadic CJD) 4 3 or thalamus (vCJD) 44 on MRI (Fig. 10.5 ) are additional useful diagnostic signs of CJD, since the EEG findings of PSWC are only reliable in a subset of patients. The CSF identification for 14!3!3 protein shows high sensitivity in most subgroups. 4 5 The sensitivity of MRI can be 70% across subgroup and is highest for Kuru patients. 45 The diagnostic criteria for definite, probable, and possible CJD are shown in Table 10.6. Pathologically all prion diseases show widespread vacuolation of gray matter (spongiform change), hypertrophy of large fibrous astrocytes, neuronal loss, and deposition of PrPres that stain similar to amyloid deposits. 46 2 No effective treatment is available.
Definite CJD
Probable CJD
Myoclonus
Akinetic mutism
Possible CJD
Clinical features as for probable CJD, but no PSWCs, and CSF negative for 14!3!3 proteins
CJR, Creutzfeldt -Jakob disease; CSF, cerebrospinal fluid; EEG, electroencephal electroencephalogram; PrPres, protein -resistant isoforms of the prion protein; PSWC, periodic sharp wave complex.
Condition
Specific Disorder(s)
Viral diseases
Bacterial
encephalitis
Whipple's disease
Chronic meningitis
Bacterial
Tuberculosis
Fungal
Parasitic
Neuropathological changes include pallor of the myelin sheaths, astrocytic proliferation, and multinucleated giant cells (syncytia). Microglia and brain macrophages are the main cellular targets for HIV infection in the brain, and syncytium formation is a signature finding for infection. The syncytium results from viral glycoproteins gp120 and gp41 interaction with the principal cellular HIV!1 receptors in microglia: CD4 and CCR5. The presence of multinucleated giant cells in the CNS is the most specific finding in HIV infection and is a better correlate of the dementia than the extent of brain viral load. 4 8 Similar findings in the simian immunodeficiency virus (SIV) animal model suggest that in late -stage HIV infection, an increase in trafficking of monocytes (the precursors of macrophages) to the brain may be associated with the development of HIV -related neurological disease. 4 9 HIV replication in bone marrow, along with chronic systemic inflammation, could further increase activated monocytes. Thus, the best proposed treatment for HIV dementia would be effective control of systemic HIV replication and decreasing chronic macrophage activation.
Chronic Meningitis
Syphilis, tuberculosis, fungi, or parasites may produce a chronic meningitis that causes a dementia. In addition to intellectual deterioration, affected patients manifest cranial nerve palsies, stiff neck, and headache. Focal neurological deficits may occur, and hydrocephalus may be an acute or late complication. Early recognition and treatment reverses the deficits in most cases. 5
cerebral metabolism and affects intellectual function. The anoxia may be a product of cardiac failure, pulmonary disease, or severe anemia. 5 Severe pulmonary disease with continuous oxygen deprivation and carbon dioxide retention produces a syndrome of confusion, headache, papilledema, tremor and twitching of the extremities, and evidence of cardiopulmonary decompensation. 5 Acute profound anoxia, as occurs with cardiopulmonary arrest, may produce a prominent post-anoxic dementia syndrome. 5 Patients with chronic renal failure may develop a uremic encephalopathy, and patients on dialysis are vulnerable to dialysis dementia. Uremia-related dementias are characterized by mental status changes, tremor, asterixis, and slowing of the EEG. 5 Dialysis dementia is a progressive fatal encephalopathy with intellectual deterioration, prominent dysarthria, and myoclonus. 5 The EEG in dialysis dementia reveals generalized slowing with intermittent bursts of polyspike complexes. The occurrence of dialysis dementia appears to be related to the amount of aluminum in the dialysis solution, and the incidence has diminished with attention to the amount of parenteral aluminum received by dialysis patients. Hepatic (portosystemic) encephalopathy is produced by advanced hepatic disease and shunting of portal venous blood into the general circulation. Clinically, the syndrome includes a chronic confusional state, tremor, asterixis, and evidence of hepatic dysfunction. The EEG is generally slow, with bursts of delta frequency triphasic waves. Strict limitation of dietary protein and prevention of ammonia production by gastrointestinal P.156
Metabolic Disorders
Toxic Disorders
Hypoxia
Drugs
Psychotropic agents
Anemia
Anticholinergic drugs
Antihypertensive agents
Hepatic encephalopathy
Anticonvulsants
Vitamin deficiencies
Antineoplastic drugs
B12
Antibiotics
Folate
Niacin
Endocrine diseases
Metals
Lead
Adrenal abnormalities
Mercury
Electrolyte disturbances
Manganese
Porphyria
Arsenic
Thallium
Industrial agents
Organic solvents
Organophosphate insecticides
Carbon monoxide
flora through the use of neomycin and lactulose frequently result in an improved mental state. A few patients with persistent hepatic encephalopathy develop an irreversible dementia syndrome and a choreiform movement disorder. Vitamin deficiencies, including lack of B 12 , folate, or niacin, produce dementia syndromes. Thiamine deficiency leads to the Wernicke -Korsakoff syndrome, an amnesic state with little impairment of other intellectual functions (Chapter 7 ). Vitamin B 12 deficiency leads to dementia, myelopathy, peripheral neuropathy, optic neuropathy, and anemia. The dementia may be the predominant neurological abnormality and may precede blood and marrow changes. 5 Folate deficiency may exist without concomitant neurological deficits but in some cases leads to a clinical syndrome, including a dementia closely resembling that of B 1 2
deficiency. Lack of niacin produces a syndrome manifested by gastrointestinal tract lesions (gingivitis, glossitis, enteritis), diarrhea, dermatitis, and dementia. Endocrine disturbances are well -known causes of dementia. 5 Hypothyroidism produces dementia, psychosis, neuropathy, and myopathy. Hyperthyroidism classically produces anxiety, restlessness, tachycardia, palpitations, and heat intolerance, but in the elderly it may present as a !simple!! dementia syndrome with little systemic evidence of excessive thyroid activity. Hyperparathyroidism causes elevated serum calcium levels, dementia, weight loss, renal colic, abdominal pain, and bone and joint pain. In some cases, dementia may be the presenting manifestation. Hypoparathyroidism leads to basal ganglia calcification, dementia, and parkinsonism or choreoathetosis. In both Cushing's and Addison's disease, reflecting excessive and inadequate adrenal function respectively, dementia is one manifestation of the clinical symptomatology.
attention and abstraction, visuospatial alterations, and memory deficits. 5 4 The dementia syndrome includes many deficits beyond the restricted memory disturbance occurring in alcoholics with the Wernicke -Korsakoff syndrome, and alcoholic dementia is far more common than the Korsakoff state. The dementia is at least partially reversible with abstinence, and the atrophy visible on structural imaging of some alcoholics also reverses in many who remain abstinent. Metals (lead, mercury, manganese, arsenic, thallium) are highly toxic to the nervous system, and excessive exposure produces dementia and peripheral neuropathy. 5,5 3, 54 Industrial and agricultural agents, including organic solvents (trichloroethylene, toluene, carbon tetrachloride, carbon disulfide), organophosphate insecticides, and carbon monoxide, produce dementia in circumstances involving chronic excessive exposure. As in other toxic and metabolic conditions, elimination of the exposure leads to symptomatic improvement in a majority of cases.
Hydrocephalic Dementias
Hydrocephalus refers to the presence of excessive CSF in the head and in essentially all cases entails ventricular enlargement with increased fluid within the ventricular cavities. Hydrocephalus can be the end result of several processes as shown in Table 10.9. In hydrocephalus ex vacuo, the ventricular dilatation is a product of tissue loss with no change in the dynamics of CSF flow (nonobstructive hydrocephalus). Obstructive
Nonobstructive hydrocephalus
Obstructive hydrocephalus
Noncommunicating
Intraventricular blockade
Aqueductal stenosis
Ventricular masses
Basilar meningitis
Congenital malformations
Post -traumatic
Post -hemorrhagic
Post -infectious
Idiopathic
hydrocephalus, by contrast, occurs when there is a blockage of CSF pathways. The obstruction may be within the ventricular system or at the level of the outlet foramina, preventing the fluid from moving from within the ventricular system to the subarachnoid space (noncommunicating hydrocephalus), or it may be within the subarachnoid space, preventing absorption of the fluid by the pacchionian villi of the arachnoid granulations (communicating hydrocephalus). In the former, ventricular pressure is usually increased, whereas in communicating hydrocephalus the intracranial pressure often remains normal (normal -pressure hydrocephalus). 5 The clinical characteristics of obstructive hydrocephalus include dementia, gait disturbance, and incontinence. Apathy, inattention, poor memory, and impaired judgment and abstraction are typical of hydrocephalic dementia. The gait disturbance is varied and may present as ataxic, apraxic, or spastic; the incontinence is usually a late feature. Intraventricular blockade in noncommunicating obstructive hydrocephalus may be produced by aqueductal stenosis or ventricular masses (neoplasms, hematomas, colloid cysts). Foraminal obstruction can occur with posterior fossa neoplasms, basilar meningitis, or P.158 congenital malformations. Absorption blockade in communicating hydrocephalus usually follows trauma with subarachnoid bleeding, subarachnoid hemorrhage from aneurysms or vascular malformations, or CNS infections. Determination of the type of hydrocephalus is made by a combination of structural imaging and cisterno -graphic findings, although cisternography does not aid in prediction of treatment response. Structural imaging reveals large ventricles in all cases of hydrocephalus. Patients with hydrocephalus ex vacuo usually have symmetrically dilated ventricles and enlarged cerebral sulci, whereas patients with obstructive hydrocephalus have ventricular enlargement out
of proportion to the sulcal enlargement, the anterior portions of the ventricles are more enlarged than the posterior portions, and there may be periventricular edema. Radioisotope flow studies in hydrocephalus ex vacuo show ventricular reflux of the tracer substance and normal flow over the cerebral convexities; in normal -pressure hydrocephalus (obstructive communicating hydrocephalus) there is ventricular reflux and blockage of flow over the convexities, and in noncommunicating hydrocephalus there is no ventricular reflux and normal flow over the convexities. 5 Differentiating AD with ventricular enlargement from the dementia associated with normal pressure hydrocephalus may be aided by functional imaging abnormalities in the high parietal region and preferential medial temporal atrophy on structural imaging characteristic of AD. 55, 56 , 5 7, 58 Patients with normal pressure hydrocephalus who benefit from shunting may have a greater CSF resistance to outflow 5 9 and those who receive a low pressure shunt appear to do better than those who receive a medium pressure shunt. 6 0
Traumatic Dementias
Cerebral trauma is the most common cause of dementia in young individuals and in Western countries is usually a product of motor vehicle accidents. The lesions may be primarily contusions of the cerebral gray matter or shearing lesions of the subcortical white matter. 5 ,53 Amnesia and personality changes are common and reflect medial temporal and orbitofrontal damage, respectively. Aphasia, impaired concentration, poor abstracting abilities, and apraxia occur in some cases. The long-term prognosis for recovery is good in most cases, but intellectual restitution may take several years and may never be complete. Subdural hematomas should be considered in any patient with mental status changes following trauma, and in the elderly the inciting traumatic event may be minimal. 5 4 Mental status alterations include fluctuating arousal, irritability, poor attention, and impaired memory. Focal neurological signs may be present. In most cases, subdural blood collections are visible on CT or MRI scans, but they may become isodense on CT with brain tissue and thus be difficult to detect. Dementia pugilistica is an uncommon dementia syndrome occurring in boxers who have sustained multiple episodes of cerebral trauma. The dementia begins late in the boxer's career or after retirement and gradually progresses. The intellectual impairment is combined with ataxia and extrapyramidal disturbances, and autopsy studies reveal
Neoplastic Dementias
Brain tumors produce dementia syndromes by causing local tissue destruction or compression, by compromising cerebral blood flow, by increasing intracranial pressure, and, in some cases, by obstructing CSF flow and producing hydrocephalus. Dementia is most common with tumors of the frontal lobe. Such tumors may impair judgment and abstraction and increase intracranial pressure without producing focal neurological disturbances. 5 0 Temporal lobe tumors, tumors of subcortical structures, and neoplastic meningitis may also produce dementia syndromes.
Affective disorders
Depression
Mania
Schizophrenia
Hysteria
Conversion symptoms
Ganser syndrome
Miscellaneous
Anxiety
Malingering
prefix pseudo- is inappropriate when dementia is defined as a clinical syndrome produced by a variety of diverse disorders. Patients with intellectual impairment associated with psychiatric disturbances meet the syndromic definition of dementia used here. Their potential treatability makes recognition of the dementia syndromes occurring with psychiatric disorders particularly important. Table 10.10 lists the psychiatric conditions that may compromise intellectual performance.
Depression
Depression is the most common psychiatric disorder that produces a syndrome of intellectual impairment. Follow -up studies of patients diagnosed as suffering from degenerative dementia have revealed that 30%!50% do not undergo the expected neuropsychological deterioration and are eventually rediagnosed. The disorder most frequently misidentified as degenerative dementia is depression and can be difficult to distinguish from a degenerative process without a comprehensive evaluation. 6 1 New onset late life depression increases the risk for developing AD and thus suggests that personality and mood changes may predate the cognitive dysfunction in AD. 62 , 6 3 The dementia syndrome of depression occurs primarily in elderly individuals with manic -depressive illness, recurrent unipolar depression, or late -onset endogenous depression. Attention and memory deficits are ubiquitous in depressed patients of all ages, but intellectual impairment sufficient to produce a dementia syndrome is rare in young patients and occurs in at least 10% of aged depressed patients. 5 The dementia usually occurs in patients with retarded depressions manifesting both neurovegetative and motor disturbances. They have a parkinsonian -like appearance with psychomotor retardation, bowed posture, and hypophonic speech. In addition, they suffer from insomnia, loss of appetite, constipation, and diminished libido. Mental status alterations characteristic of the dementia syndrome of depression include slowness of responses, lack of attention, poor memory, disorientation, impaired motivation, and disturbed ability to abstract and grasp the meaning of situations. Poor word list generation and simplification of constructions are also common, and incomplete performances and !I don't know!! and !I can't!! responses are frequent. These patients may have mood congruent hallucinations and delusions and ideas of
reference. Laboratory studies of patients with the dementia syndrome of depression usually reveal cerebral atrophy on structural imaging, a positive dexamethasone suppression test (failure of suppression of endogenous cortisol secretion by administration of dexamethasone), and a normal EEG. Unfortunately, enlarged ventricles and sulci are common in normal elderly individuals as well as those with dementia, and abnormal dexamethasone suppression tests occur in many types of dementia without depression. These tests do not effectively distinguish depressed patients from those with other causes of dementia; focal left hippocampal atrophy may suggest underlying AD. 6 4 In some cases, the diagnosis of depression -related dementia may depend on treatment responsiveness, and antidepressant therapy should be considered in any patient in whom depression may be producing or exacerbating a dementia syndrome. Serotonin reuptake inhibitors (SSRIs) heterocyclic antidepressants, monoamine oxidase (MAO) inhibitors, lithium, and electroconvulsive therapy (ECT) have all been used successfully to treat the depression of patients with an associated dementia syndrome and can stabilize cognition for many years. 6 5 Even if the cognitive dysfunction normalizes with successful treatment of the mood disorder these individuals remain at a higher risk for ensuing AD than depressed patients without associated cognitive difficulty. 66
Mania
Mania is a rare cause of dementia, but a few cases have been reported in which the disorganized, disinhibited behavior led to a dementia syndrome. 5 Memory disturbances and disorientation are common in advanced stages of mania, but in most cases the associated hyperactivity, flight of ideas, pressured speech, and expansive grandiosity make the diagnosis obvious. Improvement usually follows treatment with lithium, carbamazapine or valproate, and many patients require P.160 an antipsychotic to control the acute episode. Elderly manic patients may develop confusional states in the course of manic episodes and respond more slowly to treatment.
Schizophrenia
Intellectual impairment may occur in schizophrenia as part of an acute psychotic episode in the buffoonery syndrome when the patient manifests clowning, jocularity, and facetious responses or as an integral part of the schizophrenic disorder in a specific subpopulation of
schizophrenic patients. 5 The latter group is distinguished from schizophrenia without neuropsychological deterioration by ventricular enlargement on structural imaging, a preponderance of negative schizophrenic symptoms (apathy, withdrawal, flat affect, anhedonia), poor premorbid adjustment, and poor response to treatment (Chapter 12 ).
Hysteria
Dementia as a manifestation of an hysterical conversion reaction is rare. The hallmark of the syndrome is the marked contrast between the patient's relatively normal performance in unstructured circumstances and markedly impoverished performance in the testing situation. Whenever an hysterical conversion syndrome is identified, it must be borne in mind that the symptom complex is usually the harbinger of a neurological or major psychiatric disorder (Chapter 15 ).
Ganser Syndrome
The Ganser syndrome is considered by many to be a variant of hysterical dementia but has separate and unique clinical features. 5 The most unusual and characteristic feature is the patient's penchant for replying to simple questions (e.g., !How many legs does a dog have ? !! !Where was the battle of Waterloo fought ? !!) with ridiculous or approximate answers. In addition, the typical Ganser syndrome includes disturbances of consciousness, amnesia for the episode, hallucinations, and motor or sensory deficits similar to those found in conversion reactions. The disorder usually improves spontaneously, but in many cases an underlying metabolic or neurological disorder contributes to the symptomatology.
Miscellaneous Psychosyndromes
with Dementia In rare cases, severe anxiety, disabling obsessive -compulsive symptoms, or malingering may interrupt the patient's performance and create an appearance of dementia. Observation and response to treatment usually clarify the diagnosis.
Dementia Evaluation
It is impossible to construct a laboratory battery that would adequately screen for all the causes of dementia. In addition, many syndromes (degenerative dementias, depression) lack pathognomonic laboratory features that would allow such identification. Instead, recognition of the different causes of dementia depends on integration of information from the clinical history, neurological and general physical examinations, and mental status assessment as well as from selected laboratory tests (Table 10.11). A thorough history will reveal any evidence of
Syphilis serology
Sedimentation rate
HIV testing
Chest X-ray
Serum vitamin B 1 2
toxicology screen
Neuropsychological testing
Lumbar puncture
Electroencephalograpby
P.161 past physical illnesses or psychiatric disturbances, and any family history suggestive of an inherited systemic, neurologic, or psychiatric disability. A general physical examination may uncover evidence of a systemic or toxic disturbance that may be compromising intellectual function, and a neurological examination will provide evidence for focal, multifocal, or diffuse involvement of the CNS. The mental status assessment may be of great value in determining whether the pattern of intellectual deficits is most consistent with pre -dominantly cortical dysfunction (AD, FTD), subcortical dysfunction (extrapyramidal syndromes, lacunar state), or mixed cortical and subcortical involvement (VaD, DLB, CNS infections, etc.). Mental status examination will also provide evidence for any psychiatric disturbance (depression, mania, schizophrenia) that may be etiologically relevant to the dementia syndrome. Laboratory assessment of patients with a question of dementia is targeted at identifying reversible causes. With the improvement in primary care screening the percentage of patients with a reversible dementia presenting to specialty memory disorder clinics has declined from 11% in 1972 to 1% in 1994. 67 A core group of laboratory studies should be obtained on all demented patients to evaluate the most common systemic disorders responsible for dementia syndromes (Table 10.11). This required laboratory assessment includes a complete blood count, serum electrolytes, blood glucose, blood urea nitrogen, serum calcium and phosphorous levels, liver function and thyroid function tests, and analyses of serum vitamin B 12 ; 68 ancillary determination of erythrocyte sedimentation rate
(ESR) and a serologic test for syphilis is recommended if suspicion is high. A lumbar puncture should be performed whenever there is question of an infectious, inflammatory, or demyelinating disorder involving the CNS. Structural imaging is also required in the initial assessment to identify reversible causes as well as focal lesions, significant white matter disease implicating VaD and preventative treatment, or significant medial temporal atrophy consistent with AD. 68 Enlarged ventricles and cortical sulci are evident on the scans of many demented patients, but this atrophy correlates best with the patient's age, is a poor index of intellectual function, and cannot be used as evidence for the existence of a cortical degenerative process such as AD. Repeated imaging studies after a diagnosis is made are unnecessary unless an acute process is suspected. In AD, functional studies such as PET or SPECT typically show abnormalities most marked in the parietal and temporal lobes bilaterally; 9 they are most useful in differentiating early AD from normal aging or FTD. Apolipoprotein E genotyping is not useful in isolation from applying the clinical criteria of AD but may increase specificity of the diagnosis (correctly identifying those without the disease), when patients do not have the !4 allele, if the diagnosis is in question. 6 9 Another potential biomarker is the combined assessment of CSF amyloid # (1 !42) protein (A# 42 ) and tau concentrations (low A# 42 protein with high tau), which have a positive predictive value of 90% and negative predictive value of 95% based on the clinical diagnosis of probable AD. 7 0 The best current biomarker based on the pathologic diagnosis of definite AD, which is superior to the clinical diagnosis of probable AD, is the combination of medial temporal atrophy on structural imaging with parietal impairment on functional imaging. 71 The EEG may aid in the evaluation of the dementia patient. Focal abnormalities are most consistent with localized disorders such as tumors, abscesses, subdural hematomas, or cerebral infarctions; diffuse slowing occurs in toxic and metabolic disorders and in advanced degenerative diseases; and normal records suggest a dementia syndrome of depression or an early degenerative disorder.
impairment. Dementia cannot be appropriately managed when considered as a unitary syndrome of brain failure. Rather, dementia must be recognized as a complex clinical syndrome produced by a multitude of different disease processes. Proper management depends on identifying the etiologic disorder and instituting disease -specific treatment. Thus control of hypertension or elimination of a source of emboli can halt the progression of VaD, shunting may reverse the deficits in hydrocephalic dementia, some infectious dementias can be treated with antibiotics, metabolic dementias respond to treatment of the underlying condition, toxic dementias usually resolve when harmful exposure is eliminated, and the dementia syndrome of depression responds to pharmacotherapy or ECT. The dementia of Parkinson's disease may show limited improvement with levodopa therapy, and the dementia of Wilson's disease may be prevented or P.162 reversed by the timely administration of penicillamine (Chapter 18 ). Cholinesterase inhibitors are useful in AD, VaD, dementia with Lewy bodies and Parkinson's disease with dementia. For many demented patients, however, no specific treatment is available (e.g., FTD and other degenerative dementias), and it is not uncommon for patients with treatable illnesses to remain partially impaired even after appropriate therapy has been initiated. Treatment of these patients is directed at minimizing the disabling effects of the dementia and controlling unacceptable behaviors. A safe, contained environment is necessary for AD and FTD patients whose restless wandering and hyperoral behavior may lead to their getting lost or ingesting inappropriate items. Adequate hydration and nutrition must be maintained and social and sensory deprivation eliminated. Nocturnal confusion can he minimized by a nightlight, and a soft restraint may be necessary to keep the patient in bed; however, restraints should be used as sparingly as possible. Urinary infections and aspiration pneumonia must be guarded against, and, in the final stages when the patient is bed-bound, decubiti must be avoided by frequent turning and protective cushioning. When drugs are necessary to gain control of unacceptable behavior atypical antipsychotic, given in small doses, should be utilized. Minor tranquilizers and soporific agents should be avoided, since they tend to increase confusion in the intellectually compromised patient. Depression may accompany many dementia syndromes, particularly extrapyramidal disorders and VaD, and can exacerbate any preexisting neuropsychological impairment. Treatment of the depression may reverse at least a portion of the mental
status deficits. Anticoagulants, cerebral stimulants, and vasodilators have all been used in the treatment of dementia patients, but with limited success, and their role in the management of dementia is not established. Attention must also be directed toward the family of the demented patient. Education is a primary goal: family members should be informed about the cause of the patient's changed behavior, any available treatments, and the patient's prognosis. In addition, provision of social supports such as home health aids and visiting nurses may allow the patient to be maintained in the home for an extended period of time. Legal advice is necessary to aid the family regarding estate disposition and conservatorship. Finally, psychotherapy, either with an individual therapist or through disease -oriented support groups, may provide insight into feelings of loss, grief, and guilt that are common among family members.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 11 - Delirium
Chapter 11 Delirium
Delirium, synonymous with the acute confusional state, is a condition of relatively abrupt onset and short duration whose major behavioral characteristic is altered attention. 1 ,2 , 3, 4 The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for delirium 5 are outlined in Table 11.1 . Other behavioral abnormalities frequently coexist with the clouded, reduced, or shifting attention, including other cognitive disturbances, hallucinations and delusions, sleep cycle abnormalities, and autonomic dysfunction. In most cases the EEG reveals diffuse slowing. 6 ,7 Standardized assessments for delirium may also be useful in the clinical and research settings and are of benefit in diagnosis as well as following treatment response. 8, 9 Confusion is among the most misused of all behavioral terms. It is often applied vaguely and indiscriminately to patients whose behavior is erratic, incoherent, or psychotic. Confusion is often linked to disorientation, dementia, delirium, or psychosis without specifying the behavior to which it refers, When used in this vague and undefined way, confusion loses all meaning as a behavioral descriptor and fails to communicate any relevant information about the state of the patient. In this chapter, confusion is used to refer only to states characterized predominantly by attentional alterations. The terms acute confusional state and delirium are used synonymously; chronic confusional state is one of the etiologies of the dementia syndrome and is considered in Chapter 10 .
Clinical Characteristics
Table 11.2 lists the principal behavioral manifestations of delirium. The behavioral change that defines the syndrome and determines many of the other clinical alterations is an alteration of attention. 2 The level of consciousness may be reduced or may fluctuate between drowsiness and hypervigilance, but the patient is unable to maintain attention for any substantial period of time. Even when arousal and level of consciousness per se are not abnormal, subtle attentional deficits can usually be elicited on examination. Digit span (number of digits the patient can repeat forward after presentation by the examiner; normal performance is 7 2) and continuous-performance tests (asking patients to raise their hand each time they hear an A within a sequence of spoken letters) are among the best mental status tests for detecting attentional deficits and should be performed on all patients in whom delirium is a consideration. P.166
Disturbance of consciousness
There is evidence that the disturbance is caused by the direct physiological consequences of a general medical condition
The attentional impairment is associated with and contributes to alterations in language, memory, constructions, perceptions, and mood. 1 0 Language abnormalities noted during delirium include abnormal spontaneous speech, anomia, the syndrome of nonaphasic misnaming, and agraphia. Spontaneous speech is often incoherent, rambling, and shifts from topic to topic. Intelligibility is further limited by the hypophonia and slurring of speech that frequently coexist with the language changes. Anomia may be noted in the course of spontaneous speech or on tests of confrontation naming. Paraphasia is rare, and the anomia is usually manifested as a simple failure to recall the correct name. 2 ,1 1 In the syndrome of nonaphasic misnaming, naming errors are most pronounced for illness -related items, the anomia propagates (i.e., all misnamed items are named according to a specific theme), the speech style is pedantic
Factor
Characteristics
Alertness
Clouded or fluctuating
Attention
Language
Anomia
Agraphia
Agraphia
Nonaphasic misnaming
Memory
Constructions
Visuospatial deficits
Cognition
Incoherent thought
Concrete thinking
Dyscalculia
Occupational pantomime
Neuropsychiatric disorders
Hallucinations
Delusions
Mood alterations
Action tremor
Asterixis
Myoclonus
Dysarthria
Miscellaneous
Sleep disturbances
Autonomic dysfunction
Electroencephalogram
Diffuse slowing
P.167 or bombastic, and there is a tendency to make facetious and bizarre responses. 12 , 1 3, 14 In almost all reported cases, patients manifesting aphasic misnaming have experienced delirium and have an anomia in association with their !nonaphasic! ! abnormalities. Agraphia may be marked in delirium, and writing errors may be out of proportion to other behavioral and linguistic alterations. Writing abnormalities include illegibility and abnormal spatial alignment, abbreviated agrammatical sentences, and spelling errors. The latter tend to involve small grammatical words and ends of words, and omissions, substitutions, and duplication errors are particularly
common. 11 , 1 5 Memory and learning abnormalities are virtually always present in delirium, although their severity may vary. The leaning deficits are attributed to abnormalities of registration produced by the attentional limitations. Memory abnormalities are evident in the patient's inability to recall three words after 3 minutes, and the patient may even be unable to repeat the three words immediately after hearing them. The patients are usually disoriented with regard to time and place and may exhibit reduplicative paramnesia (the belief that the hospital has been relocated closer to one's home) (Chapter 12 ). 8 Disorientation, however, is a nonspecific finding occurring in amnesia, dementia, and a variety of other disorders, and its occurrence does not necessarily imply the presence of delirium. Constructional tasks, like writing, are also abnormal in delirium. The drawings may be distorted or unrecognizable. Three -dimensional aspects are lost, and lines and angles are omitted. 8 Executive function abnormalities are also pervasive in delirium. Errors in calculation occur, particularly when the problem requires the patient to !carry!! one sum to the next column. There is a lack of coherent thought with loss of normal associations and intrusion of abnormal associative connections. Discrepancies do not trouble the patient, who is unlikely to recognize incongruities when they are pointed out. 2,3 ,8 Thinking is concrete, and abstraction and categorization skills are limited. Perseveration is common in all aspects of behavior of patients in delirium. It contributes to the duplication errors in writing and speaking, is apparent in recurrent but irrelevant themes of conversation, and contaminates the motor system examination. 2 , 3, 8 Paradoxically, impersistence may occur in the same patient, with some tasks completed and perseverated while others go unfinished. Occupational delirium refers to elaborate pantomimes performed by the patient in delirium. 1 6 Patients act as if they are continuing their usual occupations of sweeping, driving, or working, despite being in a hospital bed. Patients
in delirium may remove nonexistent glasses, take nonexistent pills, and pantomime other activities of everyday life. Neuropsychiatric abnormalities, including hallucinations, delusions, and mood alterations, are common in delirium. In some cases, these disturbances dominate the clinical picture to such an extent that the patient is thought to be suffering from an idiopathic psychiatric disorder and is referred for psychiatric care. The hallucinations of delirium tend to be silent visual images that may be fully formed, such as dogs walking through the room or people standing at the bedside or peering in through the window. 3 ,7 Tactile (formication) hallucinations are not unusual in delirium, particularly in alcohol and cocaine withdrawal syndromes. Auditory hallucinations (voices, sounds) may occur but are less common than visual hallucinations. The delusions occurring in delirium may be simple, transient, and loosely held or may be complex, intricately structured, and rigidly endorsed (Chapter 12 ). 1 7 , 1 8 Occasionally, specific delusional beliefs such as the Capgras syndrome (the belief that significant others have been replaced by identical appearing impostors) may be the principal manifestation of delirium. 17 , 19 , 2 0 Delusions can motivate combative, self destructive, or paranoid behavior and can be among the most difficult aspects of delirium to manage. Improvement in the underlying condition usually leads to resolution of the false beliefs, but in some cases small doses of a tranquilizer may have to be used to treat the delusions, limit abnormal behavior related to the delusions, and facilitate management of the etiologic disorder. A diverse array of mood alterations has also been observed in patients in delirium. The most common is a labile, perplexed, excitable state. Affective alterations ranging from euphoria to depression and fearful paranoia to indifference and apathy also occur. 2 ,3 ,8 Mood changes are often congruent with the belief content of delusions in delusional patients. Patients in delirium may be entirely devoid of motor system abnormalities, but more commonly they manifest alterations in general activity level, tremor, asterixis, myoclonus, or
tone and reflex alterations. Changes in activity level may be in the direction of hypo- or hyperactivity. 8 Myxedema is most likely to lead to diminished psychomotor activity, whereas hyperthyroidism and delirium tremens are characterized by increased activity and motor restlessness. Patients in delirium may not have such predictable alterations and many factors such as rate of change in metabolic status, age of the patient, and severity of the encephalopathy influence the behavioral manifestations. P.168 In some cases, patients may have alternating periods of hypo- and hyperactivity. Tremor is one of the most frequent concomitants of toxic metabolic disturbances. The typical tremor is a slightly irregular, oscillating, distal movement that is absent at rest and precipitated by action (Chapter 18 ). It is visible in the outstretched hands and may also be apparent in the neck, lids, tongue, or jaw. Asterixis is the sudden jerk produced by brief interruptions of the muscular activity involved in sustaining a fixed posture. Although it is common in hepatic encephalopathy and has been called !liver flap,!! it occurs in many toxic and metabolic derangements and is an etiologically nonspecific sign of encephalopathy. 21 Focal lesions involving the midbrain, thalamus, and parietal cortex may produce unilateral asterixis affecting the contralateral limb and must be excluded before asterixis can be attributed to a metabolic disorder. 21 Myoclonus is common in uremic and postanoxic encephalopathy but, like asterixis, is a nonspecific finding and occurs in a large number of toxic and metabolic disturbances. 22 Alterations in muscle tone and reflexes are also frequent in metabolic encephalopathies. The tone is symmetrically increased, imparting a plastic resistance to passive movement, and reflex changes include generalized hyperreflexia and extensor plantar responses. Sleep disturbances comprise an important part of delirium. There may be a disruption of the normal circadian cycle with excessive drowsiness during the day and restless wakefulness at night. 3 ,7 ,8 When delirium results from
withdrawal from alcohol or other agents that suppress rapid eye movement (REM) sleep, REM rebound may occur and the nocturnal sleep pattern will be dominated by REM sleep. Autonomic disturbances, including tachycardia, diaphoresis, and pupillary dilatation, are common in delirium, particularly those associated with alcohol and drug withdrawal. 3 ,8 The electroencephalogram (EEG) is the most useful laboratory tool for the identification of metabolic encephalopathies. The tracing reveals a generalized symmetrical slowing in the theta or delta range. 7 ,8
Etiologies
Delirium reflects an acute interruption of cerebral function and as such can be produced by a large number of metabolic, toxic, and intracranial conditions (Table 11.3 ). It is particularly likely to occur in patients with preexisting intellectual impairment and in the elderly. 7 , 23 , 2 4 The prevalence of delirium in the hospitalized elderly is 10% to 40%, while 51% of postoperative patients develop delirium and up to 80% of terminally ill patients will become delirious. 8 ,25
Systemic conditions
Cardiac failure
Pulmonary disease
Uremia
Hepatic encephalopathy
Electrolyte disturbances
Hypogtycemia
Inflammatory disorders
Anemia
Porphyria
Carcmoid syndrome
Endocrinopathies
Thyroid dysfunction
Parathyroid dysfunction
Adrenal dysfunction
Pituitary dysfunction
Nutritional deficiencies
Niacin
B 12
Folic acid
Intoxications
Drugs
latrogenic
Self-administered
Alcohol
Metals
Industrial agents
Biocides
Withdrawal syndromes
Drugs
Alcohol
Infections
Meningitis
Encephalitis
Intracranial disorders
Head trauma
Cerebral edema
Hypertensive encephalopathy
Migraine
Subdural hematoma
Miscellaneous conditions
Heatstroke
Radiation
Electrocution
Hypetsensitivity reaction
Sleep deprivation
Postoperative confusion
Schizophrenia
Depression
Intracranial disorders presenting as delirium include head trauma, cerebral edema, hypertensive encephalopathy P.169 intracranial inflammatory diseases, acute cerebrovascular accidents, meningitis, encephalitis, epilepsy, and migraine. Confusional behavior in epilepsy occurs in the ictal and postictal stages and may last for hours or (rarely) days in complex partial status epilepticus or petit mal status epilepticus. 3, 26 Acute confusional migraine occurs almost exclusively in children and adolescents and is characterized by confused behavior occurring as a prodrome to the migraine headache. 2 7 The metabolic and toxic disorders producing delirium include systemic disturbances, endocrinopathies, nutritional deficiencies, drug intoxications, withdrawal syndromes, and infections. Among the most common metabolic conditions producing delirium are infections, dehydration and electrolyte abnormalities, cardiopulmonary failure, uremia, and hepatic encephalopathy. 3 , 7 Drug-induced delirium is also common. Encephalopathies are particularly likely to be produced by anticholinergic agents but may occur with virtually any drug reaching high serum concentrations. Altered drug metabolism and disposition in the elderly render them vulnerable to developing an
iatrogenic delirium even when conventional dosages of medications are prescribed. 2 8 Postoperative confusion deserves special consideration because of its frequency and because its etiology is often perplexing. Acute confusional states presenting immediately after surgery are usually due to anoxia or persistent medication effects, particularly the effects of anticholinergic medication. 3 When delirium appears later in the postoperative course, it is likely to be a product of multiple factors, including metabolic abnormalities, sleep deprivation, pain, and sensory isolation. 3 In addition to the acute disruption of cellular function produced by metabolic and toxic encephalopathies and the disturbances of arousal resulting from epilepsy, migraine, and sleep deprivation, delirium can also be produced by specific focal central nervous system (CNS) lesions and, rarely, by idiopathic psychiatric disorders. The common manifestation of all these conditions is a disturbance of attention, the hallmark of delirium. Two focal lesions that have been associated with acute confusional behavior are right parietal lesions and bilateral medial occipitotemporal lesions. 2 9 , 3 0, 3 1 Idiopathic psychiatric disorders usually present with distinctive behavioral alterations indicative of schizophrenia, mania, or depression. Rarely, however, such patients appear to have delirium as a major feature of their psychiatric disorder. The most frequent circumstance in which this is noted is in the course of a manic or depressive episode in an elderly individual. 3 The patients manifest a significant attentional impairment in addition to the typical symptoms of mania or depression, and the attentional deficits resolve with successful treatment of the psychiatric disorder. Other medical and drug-induced causes of delirium must be carefully excluded in these patients, but the evaluation will frequently be unrevealing, and delirium will be determined to be a product of the psychiatric illness.
Differential Diagnosis
The differential diagnosis of delirium includes dementia, amnesia, catatonic stupor, and hysterical
unresponsiveness. 3, 7,2 8 The only definitive criterion distinguishing delirium from dementia is duration: delirium persists for hours, days, or rarely weeks, whereas dementia usually implies persistence of intellectual deficits for months or years. Other features that may facilitate differentiation between the two syndromes include greater attentional impairment in delirium, along with more frequent delusions and hallucinations. The EEG is also more abnormal in delirium than in most dementias (Chapter 10 ). Amnesia enters the differential diagnosis of delirium because disorientation is a prominent feature of both. 8 Amnesia, however, refers to an impairment of new leaning with intact attention and intellect (Chapter 7 ). Delirium, by contrast, has prominent attentional deficits along with impairment of language, memory, cognition, visuospatial skills, and personality. Disorientation in delirium is a product of inattention and is one among a host of deficits. The amnesic patient is not !confused!! when !confusion!! implies an attentional disturbance, and the disorientation accompanying amnesia is a product of the failure to retain spatial and temporal information. Catatonia, including catatonic stupor, can occur in affective disorders and schizophrenia as well as in a variety of neurological and metabolic disturbances (Chapter 18 ). 3 2 When stupor is a manifestation of an idiopathic psychiatric disturbance, it usually persists for less than 1 week and is distinguished from other causes of stupor by normal reflex function and a normal EEG. Similarly, hysterical unresponsiveness is characterized by normal reflex responses and a normal EEG.
Management
The principal effort in the management of the patient in delirium is directed at identifying and treating the underlying disease process. Once the presence of delirium is recognized by careful mental status testing and P.170
Agent
Dose
Antipsychotics
Droperidol
5 mg (intramuscular)
Haloperidol
0.25!2 mg every 4 hr
Benzodiazepines
Lorazepam
0.5!1 mg
Cholinergics
Physostigmine
Donepezil
5 mg p.o qd
identification of the attentional deficits, the clinician must immediately search for the etiology of the encephalopathy. In most cases a reversible metabolic or toxic condition will be discovered. A careful history may suggest the presence of drug intoxication, a medical illness resulting from exposure to industrial toxins, or alcoholism. Hypoxia, uremia, hepatic encephalopathy, electrolyte disorders, and endocrine disturbances can be identified by the appropriate laboratory studies. In addition to these measures, there are general management strategies that apply to most patients in delirium, including maintaining proper nutrition, hydration, and electrolyte balance; ensuring adequate sleep; providing an appropriate amount of sensory and social stimulation; and sedating patients whose agitation prevents evaluation and management of the underlying condition. 33 Drugs should be used sparingly since they may exaggerate delirium and are avoided unless agitation becomes severe. Table 11.4 lists those agents commonly used for the treatment of delirium with agitation. When drug management is necessary to control agitation, small doses of a major tranquilizer should be utilized. 3 3, 3 4 Droperidol has been shown to be superior over haloperidol in delirium 3 5 and is preferred over benzodiazepines (except in alcohol or benzodiazepine withdrawal). Cholinergic agents may also be useful; the most refractory agitation is best treated with intubation, morphine, and paralysis. Restoration of the metabolic milieu of the CNS lags behind normalization of the peripheral blood and serum values, and delirium may persist for several days or more after appropriate treatment of the etiologic condition. In the elderly, delirium may endure for several weeks after improvement of the underlying disorder. Death is not an uncommon outcome of delirium because of the seriousness of many of the etiologic conditions.
References
1. Berrios GE. Delirium and confusion in the 19th century: a conceptual history. Br J Psychiatry 1981;139:439!449.
2. Chedru F, Geschwind N. Disorders of higher cortical functions in acute confusional states. Cortex 1972;10:395!411.
3. Lipowski ZJ. Delirium: Acute Confusoinal States. New York: Oxford University Press, 1990.
4. Liptzin B, Levkoff SE, Cleary PD, et al. An empirical study of diagnostic criteria for delirium. Am J Psychiatry 1991;148:454!457.
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press, 1994.
6. Liptzin B, Levkoff SE, Gottlieb GL, et al. Delirium. J Neuropsychiatry Clin Neurosci 1993; 5:154!160.
7. Rummans T, Evans JM, Krahn LE, et al. Delirium in elderly patients: evaluation and management. Mayo Clin Proc 1995; 70:989!998.
9. Bettin KM, Gabe JM, et al. Measuring delirium severity in older general hospital inpatients without dementia. Am J Geriatr Psychiatry 1998; 6:296!307.
10. Trzepacz PT, Mittal D, et al. Validation of the Delirium Rating Scale-Revised!98:Comparison with the Delirium Rating Scale and the Cognitive Test for Delirium. J Neuropsychiatry Clin Neurosci 2001; 13:229 !242.
11. Benson DF. Aphasia, Alexia, and Agraphia. New York: Churchill Livingston, 1979.
12. Cummings JL, Hebben NA, et al. Nonaphasic misnaming and other neurobehavioral features of an unusual toxic encephalopathy: case study. Cortex 1980; 16:315!323.
14. Weinstein EA, Kahn RL. Nonaphasic misnaming (paraphasia) in organic brain disease. Arch Neurol Psychiatry 1952; 67:72!79.
15. Chedru F, Geschwind N. Writing disturbances in acute confusional states. Neuropsychologia 1972; 10:343!353.
16. Wolff HG, Curran D. Nature of delirium and allied states. Arch Neurol Psychiatry 1935; 33:1175!1215.
17. Cummings JL. Organic delusions: phenomenology, anatomic correlations, and review. Br J Psychiatry 1985; 46:184!197.
19. Hay GG, Jolley DJ, Jones RG. A case of the Capgras syndrome in association with pseudohypoparathyroidism. Psychiatr Scand 1974; 50:73!77.
20. Madakasira S, Hall TB. Capgras syndrome in a patient with myxedema. Am J Psychiatry 1981; 138:1506!1508.
21. Weiner WJ, Lang AE. Mov Disord: A comprehensive survey. Mount Kisco, New York: Future Publishing Company, 1989.
P.171 22. Lang AE. Movement disorders: approach, definitions, and differential diagnosis. In: Drug-induced Movement Disorders. Lang AE, Weiner WJ (eds). Mount Kisco, New York: Future Publishing Co., 1992; pp. 1!20.
23. O'Keeffe S, Lavan J. The prognostic significance of delirium in older hospital patients. J Am Geriatr Soc 1997; 45:174!178.
24. Pompeii P, Foreman M, Rudberg MA, et al. Delirium in hospitalized older persons: outcomes and predictors. J Am Geriatr Soc 1994; 42:809!815.
26. Ellis JM, Lee SI. Acute prolonged confusion in later life as an ictal state. Epilepsia 1978; 19:119!128.
27. Ehyai A, Fenichel GM. The natural history of acute confusional migraine. Arch Neurol 1978; 35:368!369.
28. Lindesay J, Macdonald A, Starke I. Delirium in the elderly. Oxford: Oxford University Press, 1990.
29. Horenstein S, Chamberlain W, Conomy J. Infarction of the fusiform and calcarine regions: agitated delirium and hemianopsia. Trans Am Neurol Assoc 1967; 92:85 !87.
30. Medina JL, Chokroverty S, Rubino FA. Syndrome of agitated delirium and visual impairment: a manifestation of medial temporal -occipital infarction. J Neurol Neurosurg Psychiatry 1977; 40:861!864.
31. Mesulam MM, Waxman SG, et al. Acute confusional states with right middle cerebral artery infarctions. J Neurol Neurosurg Psychiatry 1976; 39:84!89.
32. Carroll BT, Anfinson Tj, Kennedy JC, et al. Catatonic disorder due to general medical conditions. J Neuropsychiatry Clin Neurosci 1994; 6:122!133.
33. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Delirium. Am J Psychiatry 1999; 156:(Supplement): 1!20.
34. Breitbart W, Marotta R, Platt MM, et al. A double blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996; 153:231!237.
35. Thomas H, Schwartz E, Petrilli R. Droperidol versus haloperidol for chemical restraint of agitated and combative patients. Ann Emerg Med 1992; 21:407 !413.
36. Francis J, Martin D, Kapoor WN. A prospective study of delirium in hospitalized elderly. JAMA 1990; 263:1097!1101.
Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 12 - Psychosis, Delusions, and Schizophrenia
Secondary Psychoses
A wide variety of neurological, toxic, and metabolic disorders can have secondary psychosis as their presenting manifestation or as one aspect that emerges during the course of the disorder. The principal etiologies of secondary psychoses are presented in Tables 12.1 , 12.2 , and 12.3 .
Extrapyramidal Disorders
Psychoses are not uncommon in von Economo's encephalitis and postencephalitic Parkinson's disease. Delusions were the principal neuropsychiatric manifestation of the disease in up to 25% of Fairweather's large sample, 5 and similar frequencies of schizophrenia -like disorders and paranoia have been noted by others. 6 ,7, 8 Among patients with idiopathic Parkinson's disease (paralysis agitans), psychosis is much less common. Individuals with paralysis agitans and schizophrenia -like disorders have rarely been reported and most psychoses unrelated to depression are induced by the drugs required to treat the Parkinson's disease. 9 ,1 0 , 1 1 , 12 , 1 3 Choreiform disorders may also be associated with psychosis, and psychosis is more frequent among hyperkinetic diseases (choreic conditions) than among most parkinsonian disorders. Psychosis may occur in P.173
Disorder Type
Specific Disorder
Extrapyramidal disturbances
Postencephalitic Parkinson's disease Huntington's disease Sydenham's chorea Wilson's disease Idiopathic basal ganglia
Herps Rabies Mumps Asian influenza HIV encephalopathy Subacute sclerosing panencephalitis Creutzfeldt -Jakob disease Malaria Syphilis Cysticercosis Trypanosomiasis Schistosomiasis
Multiple sclerosis Metachromatic leukodystrophy Adrenoleukodystrophy Marchiafava -Bignami disease Cerebrotendinous xanthornatosis Ischemic demyelination
Alzheimer's disease Parkinson's disease with dementia Dementia with Lewy bodies
Epilepsy Primary generalized seizures Complex-partial seizures Stroke Vascular dementia Post -traumatic encephalopathy Postanoxic encephalopathy Neoplasms Hydrocephalus
Miscellaneous disorders
Leber's hereditary aptic atrophy Cerebral lipidoses Niemann-Pick disease Narcolepsy Agenesis of corpus callosum Intracranial cysts GM2 gangliosidosis Neuronal ceroid lipofuscinosis Leigh's syndrome Mitochondrial encephalopathy
Disorder Type
Specific Disorders
Systemic illnesses
Uremia and dialysis dementia Hepatic encephalopathy Pancreatic encephalopathy Anoxia (cardiopulmonary insufficiency) Hypoxia Subacute bacterial endocarditis Hyponatremia Hypercalcemia Hypoglycemia Poryphria Postoperative and intensive care unit psychoses
Endocrine disturbances
Addison's disease (adrenal insufficiency Cushing's disease (hyperadrenalism.) Hypothyroidism Hyperthyroidism Hypoparathyroidism Hyperparathyroidism Panhypopituitarism Recurrent menstrual psychosis Postpartum psychosis
Deficiency states
Inflammatory disorders
syndrome
Huntington's diseases. 14 Among 186 patients assessed by Folstein, 1 5 a schizophrenia -like disorder was present in 6%; most studies report psychosis in 4% to 12% of patients. 1 6 Among patients with Sydenham's chorea, which is chorea associated with rheumatic fever in childhood, psychosis may occur concomitantly with the movement disorder. Psychoses also occur in patients with Wilson's disease, idiopathic basal ganglia calcification, and the spinocerebellar degenerations. Patients with Wilson's disease may manifest schizophrenia -like illnesses with paranoid delusions and auditory hallucinations indistinguishable from those occurring in idiopathic schizophrenia. 1 7 , 18 Idiopathic basal ganglia calcification P.174
Anticholinergic agents
Dopaminergic drugs
Endocrine agents
Anticonvulsants
Antidepressants
Sedative -hypnotics/anxiolytics
Hallucinogens
Psychostimulants
Appetite suppressants
Antihypertensive agents
Cardiac agents
Antibiotics
Antineoplastic agents
Analgesics
Toxins
commonly presents in the third or fourth decade of life with a schizophrenia -like illness. 1 9, 2 0 Psychosis is less common in patients with spinocerebellar degenerations but has been observed in association with Friedreich's ataxia and olivopontocerebellar degenerations. 2 1, 2 2 , 2 3
schistosomiasis. 35 , 3 6, 3 7, 38 , 39 Creutzfeldt -Jakob disease, a prion disorder, may also produce a delusional disorder. 40
Dementia with Lewy bodies (Chapters 10 ,18 ) is frequently accompanied by delusions. Patients have prominent visual hallucinations and endorse the hallucinatory experiences as veridical. 5 2, 53
A number of other neurological conditions with secondary psychoses have been described, including Leber's hereditary optic atrophy, Niemann-Pick disease, agenesis of the corpus callosum, lipoid proteinosis, intracranial cysts, and inherited metabolic disorder. 4 ,7 3, 7 4 , 7 5 , 7 6 , 77 A small number of cases of narcolepsy with psychosis have been reported. Most often, psychosis in a narcoleptic patient will be a product of treatment with psychostimulants, but in a few instances psychosis not attributable to medications have been described. 78, 7 9
neuropathy. 89 , 9 0 Magnetic resonance imaging demonstrates areas of increased signal intensity during acute attacks; the lesions resolve following the episode. 9 1 Endocrine disturbances are commonly associated with secondary psychoses. Adrenal insufficiency and excess, hypo- and hyperthyroidism, hypo- and hyperparathyroidism, and panhypopituitarism have all produced secondary psychoses. 92 , 9 3 , 94 , 9 5, 9 6 Recurrent psychoses have been associated with menstrual disorders, and endocrinologic factors are suspected to contribute to postpartum psychoses. 97 , 9 8 , 99 Deficiency states associated with psychosis include thiamine deficiency, producing Korsakoff's psychosis, vitamin B 1 2 deficiency, folate deficiency, and niacin deficiency. 1 0 0, 1 0 1, 1 0 2 Inflammatory diseases causing secondary psychoses include systemic lupus erythematosus, antiphospholipid antibody syndrome, temporal arteritis, and sarcoidosis. 1 03 ,
1 04, 105, 10 6, 107
Antiribosomal P-protein antibodies are increased in the cerebrospinal fluid (CSF) of patients with systemic lupus erythematosus and psychosis. 108
Toxic Encephalopathies
Toxic encephalopathies induced by drugs and metals are associated with secondary psychoses in some cases (Table 12.3 ). Essentially every drug can produce psychosis when administered in sufficiently large doses; in most cases the delusions are part of a delirious syndrome. The does required to cause psychosis differs P.176 substantially among individuals. Some agents, however, are reported to produce delusions without delirium or are associated with psychosis with an unusually high frequency. Drugs with a propensity to cause psychosis include anticholinergic agents, dopaminergic drugs, antituberculosis agents, anticonvulsants, endocrine agents, antimalarials, appetite suppressants, antidepressants, antihypertensive agents, hallucinogens, and psychostimulants. 11 , 1 3, 1 09 , 1 1 0, 11 1 , 1 12 , 1 13 , 1 14 , 1 1 5, 1 1 6 Abrupt withdrawal of drugs can precipitate a toxic psychosis
with delusions. The principal agents capable of producing withdrawal syndromes when abruptly discontinued include alcohol, sedative -hypnotics, and psychostimulants such as amphetamines, cocaine, and even sympathomimetics. 1 1 7 Psychosis has also been associated with withdrawal of propranolol or baclofen in occasional patients. Metal intoxications associated with secondary psychosis include the encephalopathies induced by excess mercury, arsenic, manganese, thallium, and bismuth. 11 3 , 1 14
Content-Specific Delusions
Most of the secondary psychoses are manifested by paranoid delusions, ideas of reference, and persecutory thoughts. In some cases, however, delusions have a specific theme or are confined to a single topic. Table 12.4 presents the principal content -specific delusions. These specific types of delusion have been associated with both idiopathic psychoses (mania, depression, schizophrenia, delusional disorder) and neurological and toxic -metabolic conditions. None of these delusions is disease -specific; any of them may be the sole manifestation of psychosis or may occur in conjunction with other delusional beliefs. Schneiderian first -rank symptoms are specific psychotic symptoms that occur primarily in schizophrenia but have also been noted in a small number of patients with manic, depressive, and neurological psychoses. 1 1 8, 1 1 9 First -rank symptoms include aberrations of thought such as thought insertion, thought withdrawal, and thought broadcasting, as well as certain types of auditory hallucination, delusional perception, and passivity experiences involving the feeling that bodily sensations or one's emotions, impulses, or actions are imposed from the outside (Table 12.4 ). Neurological and toxic -metabolic disorders producing first rank symptoms include idiopathic basal ganglia calcification, post-traumatic encephalopathy, temporal lobe neoplasms, postencephalitic parkinsonism, temporal lobe epilepsy, viral encephalitis, cerebrovascular disease, hydrocephalus, hypothyroidism, Addison's disease, isosafrol, LSD, amphetamines, diethylproprion, clonazepam, podophyllin, Actifed, Inderal, and metrizamide encephalopathy. 1 9, 27 , 55 , 5 6 , 6 4 , 71 , 10 5
The Capgras syndrome is a specific delusional belief in which the patient is convinced that some important person (usually the spouse) has been replaced by an identical -appearing impostor. This syndrome occurs most commonly in schizophrenia but has also been described in manic depressive psychosis, paraphrenia, and postpartum psychosis. 120, 12 1 , 1 22 Neurological disorders producing the Capgras syndrome include intracerebral hemorrhage, HIV encephalopathy, post-traumatic encephalopathy, temporal lobe epilepsy, postencephalitic parkinsonism, varicella encephalitis, migraine, neurocysticercosis, and tuberous sclerosis. 123, 1 24, 1 25 , 12 6 Among reported cases with structural lesions, there is a preponderance of right hemispheric lesions, suggesting that right -sided dysfunction may predispose to this particular delusional misinterpretation. 12 3, 12 7 , 1 2 8 Metabolic disorders reported to produce the Capgras syndrome include vitamin B 1 2 deficiency, hepatic encephalopathy, pneumonia, malnutrition, metrizamide myelography, diabetic encephalopathy, hypothyroidism, and pseudohypoparathyroidism. 12 9 , 1 30 , 13 1, 1 32 , 1 3 3 Capgras syndrome is sometimes associated with violence directed at the presumed impostor and the clinician should evaluate the threat of aggression in patients with this disorder. 13 4 Two syndromes that resemble the Capgras syndrome are the Fregoli syndrome and the intermetamorphosis syndrome. The Fregoli syndrome refers to a delusion in which the patient believes that a persecutor is able to take on the appearance of others in the patient's environment, changing faces like an actor. 1 35, 13 6 In the intermetamorphosis syndrome one believes that those in one's environment begin to look like a persecutor or other object of the delusion. Both of these syndromes have been noted in schizophrenia and in behavioral syndromes associated with epilepsy. 1 37 Heutoscopy (the syndrome of doubles, the doppelgnger) is the delusion that one has an exact double. The double may or may not be visible. It occurs primarily in schizophrenia but is also observed in migraine, toxic psychoses, encephalitis, post-traumatic encephalopathy, epilepsy, and intracranial hemorrhage. 1 38 The syndrome of doubles must
be distinguished from autoscopy, where one has an hallucination of oneself but recognizes that the experience is hallucinatory. De Clerambault syndrome, or erotomania, is a delusional belief, most common in women, that an older, more influential male is in love with her despite outward evidence to the contrary. The patient may pursue P.177
Delusion Name
Delusion Content
Thought insertion
Thought withdrawal
Thought broadcasting
Imposition of sensations
Imposition of emotions
Imposition of impulses
Imposition of actions
Capgras syndrome
Someone (usually a family member) has been replaced by an identical -appearing impostor (in dementias this often takes a more elementary form of denying that someone is who they claim to be without necessarily claiming replacement by an impostor)
Fregoli syndrome
Intermetamorphosis syndrome
Individuals in the environment take on the appearance of others significant to the patient (i.e., one's nurse begins to look like one's mother or sister)
Othello syndrome
Lycanthropy
de Clerambault's syndrome
Incubus syndrome
Phantom boarder
Picture sign
Koro
Cotard's syndrome
One is dead
her victim relentlessly, trying to establish contact and allow him to demonstrate his love. The syndrome has occurred in schizophrenia and in toxic psychoses, epilepsy, Alzheimer's disease, post-traumatic encephalopathy, and CNS tumors. 13 9, 1 40, 1 41 Incubus syndrome is one of the most common monosymptomatic delusions. Also known as the Othello syndrome, delusional jealousy is manifested by an unjustified conviction of the spouse's infidelity. Delusional jealousy occurs in idiopathic psychoses as well as in Huntington's disease, encephalitis, CNS neoplasms, Alzheimer's disease, multiple sclerosis, epilepsy, Parkinson's
disease, general paresis, and drug intoxication. 2 6 , 1 4 2 Delusions of infestation, Ekbom syndrome (acrophobia, parasitophobia), or the delusional belief that one's body is inhabited by worms or insects, habr been observed in patients with vitamin B 12 deficiency, iron deficiency, and toxic psychoses. 1 43 , 14 4 In lycanthropy, or werewolfism, one believes that one have been turned into a wolf. The syndrome has been produced by LSD use and an undiagnosed primary dementing illness. 1 45 Phantom boarder, picture sign, and the Dorian Gray delusion are all delusional syndromes that have been observed in patients with Alzheimer's disease and occasionally occur with other neurological disorders. 1 46 , 1 47 Koro is the unusual delusion that one's penis is shrinking P.178 and retracting into the abdomen. While usually occurring as a culture -bound manifestation of anxiety and depersonalization among Asian individuals. 1 4 8 it has been observed among non -Asians with corpus callosum tumors, frontotemporal tumors, or right brain strokes. 1 4 9, 1 5 0 Cotard's syndrome is the delusional belief that one is dead. It has been observed in patients with multifocal post-traumatic contusions and with frontal lobe atrophy. 1 51 , 1 52 A few delusions that have more closely determined associations with specific CNS lesions have been mentioned in previous chapters. Denial of illness must be regarded as a delusional belief in one's well -being; thus anosognosia syndromes, such as the denial of hemiparesis and denial of blindness (Anton's syndrome), are delusional disorders (Chapter 8 ). 153 When the patient claims that the neglected limb belongs to someone else, the term somatoparaphrenia may be used. Occasional patients with anosognosia develop a delusional conviction that a third limb exists on the paretic side. 15 4 Anosognosic syndromes are commonly associated with unilateral neglect and occur with posterior hemispheric lesions (Chapter 8 ). Reduplicative paramnesia, another delusion closely correlated with specific CNS lesions, is the belief that one has been relocated, usually to a position closer to one's home. It occurs in patients with right hemispheric lesions in conjunction with frontal lesions or
disease), which suggests that dopamine plays a critical role in the pathopsychology of psychosis. There may also be critical balances between dopamine and other transmitters such as acetylcholine or serotonin that, when affected, result in psychosis. Delusions are common in Alzheimer's disease when dopamine levels are preserved and cholinergic activity is reduced, 1 5 7 and delusions with hallucinations are characteristic features of dementia with Lewy bodies; in this disorder, the ratio of acetylcholine to serotonin and to dopamine found at autopsy has the highest correlation with psychotic features. 1 58 Dopaminergic hyperactivity has been posited to play a central role in schizophrenia (discussed below). Dopamine is a major neurotransmitter within the limbic system and thus both anatomic and neurochemical observations suggest that limbic system dysfunction is a key pathogenetic feature in psychosis. Psychotic disorders produced by neurologic conditions are typically manifested by paranoia with persecutory delusions. 159, 1 60 Mood changes are common in neurologic disorders and grandiose or nihilistic delusions may occur when there is an associated major mood change. 1 61 , 1 62 Content -specific delusions may also be the principal manifestation of a brain disorder with psychosis. Auditory hallucinations are common, and visual hallucinations are more frequent than in idiopathic psychiatric disorders. 1 6 3 Lack of insight, neuropsychological deficits, sleep disorders, self -neglect, social withdrawal, and appetite disorders are common among patients with neurologic disorders and psychosis. 159, 16 1 Aggressive behavior occurs in approximately one-third of patients with neurologic disease and psychosis. 1 47 , 1 61 Thought disorganization and fragmentation may occur but formal thought disorders P.179 of the type seen in schizophrenia are not common. In patients with dementia, there is a limited relationship between the psychosis and the specific neuropsychological deficits, although psychosis tends to be more common in the middle and later phases of dementing diseases. 1 4 7 The intellect is in the service of the psychotic process; patients with cognitive impairment associated with their neurologic disorder (such as patients with dementing disorders) tend to
16 1 , 16 4
manifest loosely structured delusions, whereas those with greater cognitive integrity (such as epilepsy patients) have more complex delusional content. Schneiderian first -rank symptoms are more indicative of left hemisphere dysfunction, 16 5 while misidentification syndromes and prominent visual hallucinations are more typical of right hemisphere disorders. 16 6
detection of most types of cerebral pathology. Magnetic resonance imaging is contraindicated in patients who have pacemakers or who have metal clips in their head. Patients with symptoms suggestive of epilepsy and those with possible toxic encephalopathies should have an electroencephalogram (EEG), and patients with suspected or documented cognitive deficits should have neuropsychological assessment. More advanced imaging studies such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) may be useful in selected circumstances. Specific additional laboratory tests are chosen on the basis of a careful history and examination and might include HIV antibodies, antiphospholipid antibodies, blood and urine drug screens, and other specialized measures. Cerebrospinal fluid examination is indicated in patients with evidence of demyelinating, inflammatory, or infectious brain disorders and should usually follow imaging procedures. Clinical features that should trigger consideration of a neurodiagnostic assessment of psychotic patients include atypical age of onset, especially after age 45; absence of a family history of psychiatric illness; absence of any past psychiatric disturbances or premorbid behaviors characteristic of idiopathic psychiatric disorders; presence of family history of a neurologic disorder such as Huntington's disease; presence of focal neurological signs; presence of mental status deficits suggestive of focal or degenerative brain disorder; presence of unusual psychiatric syndromes or atypical mixed states (such as prominent mood changes with mood -incongruent delusion); history of a medical disorder or neurologic condition, even if remote; presence of unusual temporal features such as abrupt onset, quick resolution, or rapid fluctuation; and treatment resistance or unusual treatment responses.
disease develops in adolescence or early adulthood, and the active phase is often preceded by a prodrome of deteriorating abilities and social withdrawal. The course of the disease is lifelong, although periods of active illness are followed by remissions or a residual phase similar to the prodromal P.180
Clinical features
Hallucinations
Blunted affect
Delusions
Anhedonia
Bizarre behavior
Avolition
Neurological abnormalities
Neuropsychological deficits
Educational attainment
Higher
Lower
Higher
Lower
Genetic influence
Less evident
More evident
Prognosis
Better
Worse
Vulnerability to EPS
Lower
Higher
Worsened or no effect
Improved or no effect
Worsened or no effect
Improved or no effect
Improved or no effect
Worsened or no effect
Improved
Improved
Abnormal CT or MRI
CT, computerized tomography; EPS, extrapyramidal syndrome, including both parkinsonism and tardive dyskinesia; MR], magnetic resonance imaging.
period. 1 The abnormalities of verbal output characterizing the speech of some schizophrenics are described in Chapter 6. Attempts to subdivide schizophrenia into clinical types that have clinical or prognostic significance have generally met
with limited success. Subtypes that are currently recognized include the paranoid, disorganized, catatonic, undifferentiated, and residual types. Subtypes are based on the symptom complex observed during the treatment episode and may change over time. Identification of positive and negative features of schizophrenia offers another avenue of insight into the disorder (Table 12.5 ). These characteristics do not distinguish two types of schizophrenia; mixtures of positive and negative symptoms are present in most schizophrenic patients; and patients may vary in the proportion of positive and negative symptoms they display during different periods of their illness. The two sets of clinical characteristics, however, have differing clinical and prognostic correlates, and they may provide useful information when one set of symptoms predominates. Generally, negative symptoms are found in patients who have a poor premorbid adjustment, exhibit more neuropsychological deficits and more neurological abnormalities, are more likely to have a positive family history of psychosis, and tend to have more evidence of atrophy on brain imaging studies. Negative symptoms tend to worsen with neuroleptic therapy and improve with levodopa treatment, whereas positive symptoms exhibit the reverse treatment response. 1 67 , 16 8 , 1 69 Neurological abnormalities are commonly present when schizophrenic patients are examined. These abnormalities are more common in those with negative symptoms but are not limited to any schizophrenic subtype. 16 9 , 1 70 Abnormalities are most evident on examination of cranial nerves, motor system, and sensory function. Neuro ophthalmologic abnormalities commonly observed include increased blinking, difficulty moving the eyes without moving the head, and eyetracking P.181 dysfunction (volitional eye movements) during smooth pursuit tasks. 170 , 17 1 !Soft!! (or subtle) signs of neurologic dysfunction are present in 30% to 80% of patients, including poor coordination, clumsiness, and impaired graphesthesia (Chapter 3 ). 1 7 2, 1 7 3, 1 7 4 Neuropsychological abnormalities are common in schizophrenia. While some of the deficits may be
attributable to poor motivation, intrusion of psychotic thoughts, formal though disorder, or medication effects, cognitive abnormalities are identified even when these factors are absent or controlled. Abnormalities involve most cognitive domains but affect frontally mediated tasks such as the Wisconsin Card Sort Test, verbal fluency, and spontaneous recall disproportionately. 1 7 5 , 17 6 , 1 77 Computerized tomography of the brain commonly reveals abnormalities in schizophrenia. Enlarged lateral ventricles with an abnormal ventriculo -brain ratio (VBR) is the most frequently reported abnormality. The abnormal VBR has been found to correlate with poor premorbid adjustment, poor prognosis, negative symptoms, less benefit from antipsychotic medication, and higher prevalence of extrapyramidal drug-induced side effects. 1 7 8 An enlarged third ventricle and increased cortical sulcal size, particularly in the frontal lobe, have also been found in schizophrenics, compared to normal controls. 17 8 , 1 79 Studies using MRI have confirmed and extended observations made with CT. 18 0 , 1 81 In a study of identical twins discordant for schizophrenia, it was demonstrated that the affected twin had larger ventricles in all but one of the twin pairs. 182 The ventricles in the affected twin were not necessarily abnormal in size compared to age -matched controls but were enlarged when compared to the ventricles of their genetically identical sibling. This suggests that ventricular enlargement is present in most schizophrenic patients and the frequency of ventriculomegaly is underestimated in group studies. The temporal lobe and thalamus have been shown to be smaller in schizophrenia than in normal controls, 18 3 , 1 84 and some studies have reported that the frontal lobes are smaller. 1 8 5 Verbal memory, abstraction, and categorization deficits correlate with the reduced temporal lobe volume. 1 8 6 Moreover, the severity of the schizophrenic thought disorder is also related to the size of the temporal lobe. 18 7 Functional brain imaging also demonstrates abnormalities in schizophrenia, although there is less consistency among these studies. Reduced blood flow in anterior brain regions, particularly in patients with chronic schizophrenia, has been
observed commonly, 1 88 and patients fail to exhibit an increase in cerebral blood flow in response to neuropsychological tests that normally activate brain function. 18 9 Cerebral glucose metabolism measured by PET shows a reduced ratio of anterior -to -posterior metabolic activity, consistent with underactivation of frontal lobe structures. 19 0 Postmortem studies have failed to identify a consistent pathognomonic abnormality in the brains of schizophrenic patients. Several changes, however, have been observed. Grossly, the brains of schizophrenic patients tend to have reduced weight, cortical atrophy, and ventricular enlargement. 191 Neuronal density is reduced in the prefrontal cortex and cingulate gyrus. 1 9 2 Temporal lobe volume is reduced, hippocampal neuronal density is decreased, and hippocampal pyramidal cells exhibit excessive architectural disarray. 1 9 3, 1 9 4 Thus, limbic and frontal cortical abnormalities, although subtle, are present in the brains of many schizophrenic patients studied at autopsy. The evidence robustly supports the proposition that schizophrenia is a neurologic disorder manifested by behavioral, neuropsychological, neuroimaging, and neuroanatomic alterations. Dopamine hyperactivity is implicated in the pathogenesis of schizophrenia because of the fidelity with which amphetamines and levodopa can reproduce the positive features of the syndrome and the readiness with which these symptoms respond to dopamine blockade with neuroleptics. The discovery of elevated levels of dopamine D 4 receptors in schizophrenics supports the dopamine theory of schizophrenic psychosis. 1 9 5 Weinberger 196 has proposed a neurodevelopmental theory of schizophrenia placing dopamine dysfunction in a developmental context. It is proposed that there is a congenital brain insult that becomes symptomatic when developmental demands exceed the capacity of the system, usually in early adulthood. Dorsolateral prefrontal dysfunction produces the negative symptom complex, whereas dopamine hyperactivity in limbic system structures causes positive symptoms. Individuals vary in the amount of
prefrontal and limbic system dysfunction, accounting for the clinical heterogeneity of the disorder. The congenital damage could be produced by a variety of conditions (traumatic, infectious, vascular, etc.), allowing etiologic heterogeneity for schizophrenia.
References
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> Table of Contents > Chapter 13 - Hallucinations
Chapter 13 Hallucinations
Hallucinations are sensory experiences that occur without external stimulation of the relevant sensory organ. 1 They may occur in any sensory modality!visual, auditory, tactile, olfactory, or gustatory. Hallucinations may be appreciated objectively as false events not corresponding to external reality (sometimes called pseudohalludnations) or they may be thought to represent actual external events. The latter are hallucinations with delusional endorsement and comprise part of a psychotic experience. Hallucinations occur in the course of a large number of pathological processes and may occasionally occur in normal individuals in the absence of any disease. The neuropsychiatric differential diagnosis and pathophysiology of hallucinations in each sensory modality are presented in this chapter.
Visual Hallucinations
A visual hallucination has been defined operationally as a symptom in which the patient claims to see something or behaves as though having seen something that the observer cannot see. 2 Visual hallucinations occur in a wide variety of ophthalmologic, neurological, toxic -metabolic, and idiopathic psychiatric disorders. 3
Differential Diagnosis
Table 13.1 presents the differential diagnosis of visual hallucinations. Ophthalmologic disorders that reduce or eliminate the patient's vision frequently produce hallucinations. They have been described by patients
suffering acute blindness from traumatic enucleation and in patients with poor vision secondary to cataract formation or diseases of the macula, choroid, or retina. 4, 5 ,6 , 7 ,8 Brief, unformed flashes of light may also occur with ocular pathology and are noted with vitreous detachment (Moore's lightning streaks), with sudden ocular motion in individuals with no ocular pathology (flick phosphenes), or may be induced by sound in patients with a variety of ocular disorders (auditory-visual synesthesia). 9 Hallucinations must be distinguished from entoptic phenomena such as particles floating in the vitreous humor, Haidingers brushes (nerve bundles made visible by macular edema), and Scheerer's phenomenon (red blood cells circulating in the paramacular region. 8 Hallucinations commonly occur following ocular surgery, particularly if both eyes are patched in the postoperative period. Such postsurgical hallucinations are more likely to occur if a toxic psychosis is also present. 1 0 The hallucinations associated with reduced vision P.188
Opthalmologic disorders
Enucleation
Cataract formation
Macular degeneration
Choroidal/retinal disease
Vitreous traction
Thalamtc lesions
Degenerative diseases
Alzheimer's disease
Encephalitis
Epilepsy
Narcolepsy
Migraine
Medical illnesses
Delirium
Toxic disturbances
Delirium
Hallucinogens
Psychiatric disorders
Schizophrenia
Mania
Psychotic depression
!Normal! ! individuals
Dreams
Hypnagogic hallucinations
Hypnosis
Imaginary companions
Sensory deprivation
Sleep deprivation
Bereavement
are usually fully formed, brightly colored images of people, animals, flowers, or scenery. Although formerly considered a condition with spontaneous visual hallucinations in the elderly, the Charles Bonnet syndrome, now appears to be associated with ocular pathology in most cases, and the onset of hallucinations in aged individuals should lead to a search for eye disease. 11, 12 , 1 3 , 14 Suggested criteria for the identification of the Charles Bonnet syndrome include the occurrence of visual hallucinations that are formed, complex, persistent or repetitive, and stereotyped; fully or partially retained insight; absent delusions; and no hallucinations in other modalities. 1 3 Both ocular and brain disorders can produce the syndrome, although most patients will be found to suffer from ocular abnormalities. Charles Bonnet syndrome can occur in the absence of cognitive changes or emotional disturbances. 14 Retinal ischemia in the course of amaurosis fugax associated with carotid artery disease may be manifested as blindness (typically a !descending curtain!!) or as visual hallucinations. The hallucinations are typically unformed and
appear as scintillations, colored streaks or blobs, or flashing lights. 15, 16 These visual changes closely resemble those of migraine (described below) and may lead to misdiagnosis. Optic nerve disease, particularly optic neuritis, is also associated with brief unformed visual hallucinations. The phosphenes occur with movement of the eyes or may be induced by sounds. 1 7, 18 Focal lesions in a number of locations in the brain are associated with visual hallucinations. Lesions in the midbrain region produce the syndrome of peduncular hallucinosis. In this condition there are complex visual hallucinations that typically occur in the evenings, are associated with disturbances of the sleep-wake cycle, and are usually viewed as benign, entertaining phenomena. Other evidence of brainstem dysfunction is usually present. The syndrome of peduncular hallucinosis has been associated with bilateral lesions of the substantia nigra (pars reticulata), infarction of the right paramedian or posterior thalamus, and focal insults of the right midbrain tegmentum and cerebral peduncle. 19, 2 0 , 21 , 2 2, 2 3 Auditory -visual synesthesia has also occasionally been described by patients with lesions involving the upper brainstem. The upper region of the brainstem is perfused by the basilar artery and occlusion of the upper basilar produces the !top of the basilar syndrome.!! 2 4 This distinctive syndrome includes abnormalities of ocular movement, eyelid retraction, and skew deviation. Peduncular hallucinosis is frequently present and patients are often somnolent, report excessive dreaming, and have difficulty distinguishing dreams from reality (oneroid states). When the temporal P.189
FIGURE 13.1 Computed tomogram showing a right occipital infarction associated with release hallucinations.
or occipital lobes are infarcted, an agitated delirium may occur. Thalamic disorders have occasionally been associated with visual hallucinations. Focal lesions and degenerative conditions such as fatal familial insomnia have produced visual hallucinations. 1 9, 25 , 26 Hemispheric lesions can produce visual hallucinations in two clinical circumstances: as part of focal seizure activity or as release phenomena associated with visual field defects. Release hallucinations are generally formed images, lasting from minutes to hours. They are variable in content, may be modified by altering the visual input such as opening or closing the eyes, and tend to occur within the field defect. 27, 28 , 29 , 3 0, 3 1, 32 , 3 3 The underlying pathological lesion is usually an infarction, but any focal lesion within the visual pathways in the temporal, parietal, or occipital lobes may produce release hallucinations (Fig. 13.1 ). Hallucinations have occasionally been reported with frontal lobe lesions, but this is rare and, when described, they have usually been associated with mass lesions capable of exerting distant effects on the temporal lobes or brainstem.
Ictal hallucinations occurring as expressions of seizure activity can usually be distinguished from release hallucinations on the basis of their clinical features (Table 13.2 ). 3 ,34 Ictal hallucinations are brief, stereotyped visual experiences. 35 There may or may not be an associated visual field defect; they rarely are lateralized to one portion of the visual field; and when they are formed, they may consist of visual recollections of past experiences. Epileptic lesions in primary and associative cortex give rise to unformed or semiformed hallucinations (flashes, lights, colors, etc.), whereas more anterior foci situated in the temporal lobe produce formed hallucinations and remembered scenes. 3 6 Consciousness may be altered during or after an ictal hallucination, and there may be ictal motor phenomena
TABLE 13.2. Distinction between Ictat and Release Hallucinations Associated with Hemispheric Lesions
Ictal Hallucinations
Release Hallucinations
Stereotyped
Variable content
Seldom lateralized
May be modified by environmental alterations (e.g., opening or closing the eyes or deviating the gaze)
P.190 such as head or eye deviation. A variety of visual distortions, including macropsia, micropsia, and metamorphopsia, also occur as ictal visual phenomena, either without hallucinations or concomitantly with them. 37 Ictal hallucinations are more often associated with right -than left -sided lesions. These observations regarding ictal hallucinations have largely been confirmed by stimulation of
the occipitotemporal cortex during surgical procedures. 38 Diseases affecting the cerebral hemispheres can also produce visual hallucinations. Formed hallucinations are particularly common in dementia with Lewy bodies, 3 9 , 4 0 and they also occur, though less frequently, in Alzheimer's disease, 41, 42 and Creutzfeldt -Jakob disease. 4 3 Two syndromes causing visual hallucinations and unassociated with focal central nervous system (CNS) lesions are migraine and narcolepsy. Visual hallucinations occur in about half of all patients with migraine. The most common hallucination is a fortification -type zig -zag spectrum often associated with a scotoma, but fully formed complex hallucinations may also occur. 4 4 , 45 , 46 , 4 7 The migrainous aura may also include macropsia and micropsia, a clinical complex called the !Alice in Wonderland syndrome!! after Lewis Carroll, whose personal experiences with migraine were utilized in that famous tale. 48, 49 , 5 0 A few patients with migraine experience persistent positive visual phenomena, including perceptual experiences such as television static, snow, lines of ants, dots, or rain lasting months to years after migrainous attacks. 5 1 The visions of Hildegard of Bingen, a mystic nun who lived from 1098 to 1180, provide an unusually rich account of migrainous hallucinations. 5 2 Narcolepsy, is in its fully expressed form, consists of a tetrad of sleep attacks, cataplexy, sleep paralysis, and hallucinations (Chapter 23 ). 5 3, 5 4 Hallucinations occur in 20%!50% of narcoleptics and are noted most often in the drowsy period as the patient is falling asleep (hypnagogic hallucinations). Hypnopompic hallucinations experienced just as the patient is awakening occur in a smaller number of cases. Hypnagogic visions occur most commonly in association with nocturnal sleep and rarely occur with daytime narcoleptic attacks. The hallucinations are primarily visual, but auditory and somesthetic hallucinations have been reported, as well as macropsia and micropsia. 5 5 The hallucinations are accompanied by electroencephalographic (EEG) changes characteristic of rapid eye movement (REM) or dreaming sleep and represent the intrusion of dreams into
the drowsy state. 56 , 57 , 5 8 Hypnagogic hallucinations unaccompanied by other evidence of narcolepsy can occur in normal individuals and have been described in a variety of psychiatric disorders, including schizophrenia, depression, paranoid state, and puerperal psychosis. 59 Hallucinations frequently occur in the course of acute confusional states induced by medical illnesses. They have been noted in 40%!75% of delirious patients. In delirium, the hallucinations are relatively brief, are often nocturnal, and may be regarded as real. Hallucinations in delirium are usually clear, brightly colored visions, that are experienced as three -dimensional images in nearby space. 6 0 The patients are often fearful and respond to the hallucinations with self protective measures. The visions are typically formed, moving, silent images but in some cases may be accompanied by auditory or tactile hallucinations. Among toxin -related disturbances, hallucinations occur in four major circumstances: nonspecific acute confusional states, alcohol and sedative withdrawal, hallucinogeninduced conditions, and states induced by dopaminergic agents (Table 13.3 ). Any drug when taken in excess may produce an acute confusional state with concomitant hallucinations. In some cases hallucinations may occur as the primary manifestation of toxicity with little evidence of delirium or confusion. Among agents that have been reported to produce hallucinations and may be particularly prone to cause this symptom are cimetidine, antidepressants, inhalants, lithium, cyclosporin, digoxin, sympathomimetics, quinidine, anticholinergics, antibiotics, hormonal agents, narcotics, antimalarials, phenacetin, disulfiram, propranolol, heavy metals, metrizamide, and bromide. 3 Patients with Parkinson's disease may experience visual hallucinations following treatment with dopaminergic agents. This is particularly common in patients with a dementia syndrome. 6 1, 62 , 6 3 Hallucinations also are common during withdrawal states, occurring in up to 75% of those manifesting an acute abstinence syndrome. 64 Withdrawal syndromes develop following abrupt cessation of intake of a variety of agents, including alcohol, barbiturates, benzodiazepines, chloral hydrate, paraldehyde, meprobamate, methaqualone, opioid
compounds, and cocaine. The type of hallucination is very similar to that occurring in medical illnesses. Zoopsia, or hallucinations of animals, is particularly common in, although not limited to, withdrawal syndromes. Alcohol and sedativehypnotics produce chronic suppression of REM sleep, and withdrawal is associated with REM rebound. When visual hallucinations emerge during alcohol withdrawal, REM sleep accounts for most of sleep time and begins almost immediately when the patient falls asleep. This suggests that visual hallucinations associated with alcohol withdrawal, like those occurring in narcolepsy, P.191
Hallucinogens
Dimethylrrypptamine(DMT)
Psilocin Antibiotics
Harmine
Mescaline
MDMA (ectasy)
Tetrahydrocannabinol
Phencyclidine (PCP)
Ketamine
Abused inhalants
Ether
Gasoline
Glue
Nitrites
Nitrous oxide
Anriparkinsonian agents
Anticholinergic drugs
Amantadine hydrochbride
Levodopa
Bromocriptme
Pergolide
Ropinerole
Pramipexole
Entacapone
Tolcapone
Selegiline
syndromes
Glutethimide
Ethyl alcohols
Barbiturates
Benzodiazepines
Chloral hydrate
Paraldehyde
Meprobamate
Methaqualone
Opiates
Cocaine
Hormonal agents
Steroids
Thyroxin
Antibiotics
Sulfonamides
Penicillin
Tetracycline
Miscellaneous agents
Antidepressants
Imipramine
Maprotiline
Nitrous oxide
Cocaine
Amphetamines
Lithium
Cyclosporin
Aminophylline
Bismuth
Corticosteroids
Disulfram
Indomethacin
Ranitidine
Bromide
Digoxin
Sympathomimetics
Cimetidine
Propranolo!
Phencaetin
Disultiram
Narcotics
Antimalarials
Heavy metals
Metrizamide
may be a product of dream phenomena intruding into the waking state. 6 5 Hallucinogens (psychotomimetics, utopiates) are pharmacological agents that produce perceptual distortions and hallucinations. The latter may be associated with concomitant alterations in affect and cognition resembling those occurring in the psychoses, as well as with physiological alterations such as mydriasis, elevated heart rate and blood pressure, increased muscle tone, tachypnea, and nausea. 6 6 In general, hallucinogens do not produce an acute confusional state, and hallucinations are disproportionately prominent, compared to other druginduced mental changes. Several classes of agent are included among the hallucinogens: compounds with an indole structure such as lysergic acid diethylamide (LSD), dimethyltryptamine, psilocybin, pscilocin, and harmine; cannabinols such as tetrahydrocannabinol; and a variety of other agents such as phencyclidine and ketamine (Table 13.3 ). 3 3, 66 Self-reports and studies of subjects who have ingested LSD and mescaline reveal that in the preliminary stages one sees nonpatterned or geometric shapes; this progresses to more structured geometric images such as lattices, chessboards, cobwebs, funnels, and spirals; finally, fully formed images of landscapes, people, and animals may appear. Visual distortions, movement of patterns, and alterations in color intensity are common. Brief recurrences of the visual experiences (!flashbacks!! or persisting perception disorder) may occur for several years following exposure to LSD. 67 , 6 8, 69
Auditory hallucinations are far more characteristic of the idiopathic psychiatric illnesses than visual hallucinations, but the latter are not uncommon. Between 24% and 46% of acute schizophrenics and up to 72% of chronic schizophrenics report having had visual hallucinations at some time during the course of their illnesses. 7 0 , 7 1 , 7 2 The visual hallucinations of schizophrenia may occur with auditory hallucinations, or they may be visual memories, bizarre, fragmented images, or even unformed flashes of light. Substance abuse in schizophrenic patients with dual diagnoses is associated with higher rates of visual hallucinations. 72 Visual hallucinations have been reported in 10%!70% of patients with affective disorders. 7 3 Hallucinations occurring in the context of major affective disorders usually are mood -congruent. Finally, visual hallucinations occur in normal individuals in specific circumstances (Table 13.1 ). The best examples of unbidden spontaneous visual images are dreams. These unique visual hallucinations are common to the experience of all intact individuals, meet most definitions of visual hallucinations, and are pathological P.192 only when not confined to the sleep state. Children may have imaginary companions and play objects that they !see! ! with realitylike clarity, 7 3 and they also appear to be more likely to respond to emotional stress with hallucinatory syndromes. 7 4, 7 5 In adults, visual hallucinations occur during periods of sleep deprivation, as a product of suggestion during hypnosis, and as hypnagogic phenomena. 59 , 7 6 In addition, hallucinations occur during sensory deprivation, a state that may share essential features with hallucinations reported with blindness of all types. 7 7, 78 Hallucinations occur during intense emotional experiences such as in the course of grief reactions and appear to be influenced by the cultural experiences of the involved individuals. 5 9, 79 , 8 0 Hallucinations have been described by many !visionaries!! who found them to be sources of guidance and inspiration; thus, hallucinations played a role in the lives of Socrates, St. Paul, Joan of Arc, Mohammed, Luther, Moses, Pascal, Swedenborg, George Fox, Shelley, William Blake, Bunyan, Napoleon, Raphael,
Phenomenology
There are no etiologically specific or pathognomonic types of hallucinations, but features of visual hallucinations may facilitate identification of the clinical disorders from which they originate. The characteristics that distinguish ictal from release hallucinations are described in Table 13.2. The form of epileptic hallucinations has localizing significance: posterior occipital lesions produce unformed, simple flashes; the patterns become more complex if the focus is located in visual association cortex; and more anteriorly placed lesions in the medial temporal lobe produce complex, formed images and visual memories. 35 , 3 6 Release hallucinations, by contrast, have little localizing value. They occur with lesions of the eye, optic nerve and chiasm, and cerebral hemispheres. Lilliputian hallucinations, visions of tiny human and animal figures named for the diminutive inhabitants of the Isle of Lilliput described by Jonathan Swift in Gulliver's Travels, 8 2 are distinctive but appear to have little etiologic significance. They have been described in toxic and metabolic disorders, hypnagogic states, structural CNS disturbances, epilepsy, ocular diseases, affective disturbances, and schizophrenia. 8 3, 8 4, 8 5 Hallucinations of giants, or Brobdingnagian hallucinations, have been recorded in a small number of confusional states. 86 Lilliputian and Brobdingnagian hallucinations involve seeing small and large individuals, respectively, and must be distinguished from micropsia and macropsia, where the entire scene, along with an included figure, appears altered in size. Autoscopy (heutoscopy) is another striking hallucinatory experience in which one sees one's own image. Such hallucinations occur in epilepsy, brain tumors, cerebral trauma, subarachnoid hemorrhage, cerebral syphilis, migraine, postencephalitic parkinsonism, typhus and other infectious diseases, drug intoxications, schizophrenia, and depression. 87 , 8 8, 89 If the patient endorses the vision as a true double or believes that a double exists, even though invisible, the syndrome merges into the delusion of the
double, or the doppelganger. 9 0 The syndrome is put to literary use in Dostoyevsky's The Double, Edgar Allen Poe's William Wilson, Steinbeck's Great Valley, and Oscar Wilde's The Portrait of Dorian Gray. 1 2 , 87 , 89 !Psychedelic! ! hallucinations consisting of geometric forms, spirals, funnels, and chessboards are most characteristic of the hallucinogenic drugs 9 1 , 92 but also occur with sensory deprivation 77 , 78 , and have been described in CNS disorders, such as during recovery from acute viral encephalitis and with acute occipital lobe insults. 93 Illusions are misperceptions or perceptual distortions of an existing external stimulus. 1 They differ from hallucinations in that the perceptual activity has its original stimulus in the external environment. Many simple and complex distortions of visual perceptions have been described among the metamorphoses. Changes in size, shape, position, motion, number, or personal relationship to the object have been described (Table 13.4 ). 9 4 , 9 5, 9 6, 9 7, 9 8 Although illusions and hallucinations can be differentiated clinically, the distinction has little etiologic significance, since both phenomena are found in the same disorders. Illusions occur in epilepsy, migraine, narcolepsy, and infections disorders, and with hallucinogens. Synesthesias are cross-modal experiences reported by patients who have one sensory -type experience (e.g., color) when another is stimulated (e.g., sound). 9 9 , 1 0 0 Palinopsia is a unique form of visual hallucination that involves the persistence or recurrence of visual images after the exciting stimulus has been removed. 1 0 1, 1 0 2 , 1 0 3 The image remains when the patient changes direction of gaze and may spontaneously recur for up to several hours. The phenomenon usually begins abruptly with a cerebral infarction, neoplasm, or trauma and persists only a few days, but in some cases it has endured for years. 1 01 , 1 02, 10 4, 1 05 Palinopsia can occur with lesions of either hemisphere but is most common with acute damage to the posterior aspect of the right hemisphere. 1 0 6 Originally considered an ictal manifestation, palinopsia shares many features with hallucinations originating
P.193
Type
Ma nifestations
Simple
Micropsia (objects appear small) Macropsia (objects appear large) Squeezed, tilted objects Wavy edges or other changes in contour Color enhanced, changed, or dimmed Apparent motion of nontnoving object Objects pulsating Objects appear far away Objects appear unusually close
Complex
Polyopia/emomopia (multiple simultaneous objects) Palinopsia (preservation of visual stimulus) Allesthesia (lateral transpositions) Upside-down reversal of vision Prosopo-metamorphopsia (face- specific metamorphopsia) Auditory -visual synesthesia
Dejav (unusual familiarity) Jamais v (unusual strangeness) Unreality (derealization) Undue personal significance
from hemispheric lesions involving the visual radiations, which suggests that it is a unique type of release hallucination. 1 0 7 Palinopsia has been reported as a side effect of trazodone and can occur during the course of mescaline and LSD intoxication. 1 0 8
Pathophysiology
The remarkable similarity of many aspects of visual hallucinations suggests that a few basic CNS mechanisms are responsible for generation of most of the images. The most common situation in which hallucinations merge involves the reduction of visual input. This occurs in sensory isolation, enucleation, cataract formation, retinal disorder, choroidal change, macular disease, and optic nerve and tract disease, and with hemispheric lesions involving the geniculocalcarine pathways. The blindness may be partial or total, monocular or hemianoptic, and in all cases may be associated with hallucinations of similar character. West 8 1 proposed a !perceptual release theory,!! which suggests that decreased sensory input results in release of spontaneous activity of CNS structures normally mediating perceptual experience. This basic mechanism might also account for hallucinations associated with diminished arousal in narcolepsy, hypnotic and trance states, confusional states, and some idiopathic psychiatric disorders. Studies with functional magnetic resonance imaging (fMRI) demonstrate that patients with blindness due to ocular disease who experience spontaneous visual hallucinations have increased activity in the ventral occipital region. 10 9 Another basic mechanism associated with several types of
visual hallucination involves the appearance of dreams in the waking state. Dreams themselves are a unique variety of visual hallucinations occurring in normal individuals. The emancipation of dreams from the sleep state appears to account for hypnagogic hallucinations occurring in normal individuals and in narcoleptics and for hallucinations occurring during alcohol withdrawal, and it may play a role in the hallucinations of peduncular hallucinosis where a consistent diurnal pattern has been observed. The typical occurrence of vivid dreams before the emergence of visual hallucination in parkinsonian patients treated with dopaminergic agents suggests a relationship to sleep mechanisms. The ability of the hallucinogens to induce vivid hallucinatory experiences is not understood. An effect on retinal function has been demonstrated but is insufficient to account for the diversity of their actions or the similarity between hallucinogen-induced visions and those of certain CNS lesions. 93 , 110 Lysergic acid diethylamide is also capable of inducing hallucinations in patients who have been enucleated, demonstrating the independence of the LSD effects of ocular function. The hallucinogenic effects of these agents appear to be mediated by interactions between the drugs and 5 -HT 2 serotonin receptors. 66 Removal of the temporal lobes diminishes the hallucinogenic effects of LSD, suggesting that temporal lobe structures play a major role in mediating the effects of hallucinogenic agents. 11 1 Cholinergic mechanisms may also have an important role in mechanisms associated with hallucinosis. Anticholinergic toxicity is accompanied by prominent hallucinations, and diseases with cholinergic deficits, including dementia with Lewy bodies, Alzheimer's disease, and Parkinson's disease with dementia, may produce visual hallucinations. 4 0 Treatment with cholinergic agents may reduce visual hallucinations. 11 2 Antipsychotic agents reduce both hallucinations and delusions in patients with psychotic disorders. Dopaminergic and serotonergic mechanisms have been implicated. Hallucinations can thus be correlated with a few basic mechanisms!perceptual release, ictal discharges, dream
intrusions, and neurochemical effects. These few P.194 mechanisms provide the foundations for understanding many aspects of these unique experiential phenomena.
Treatment
Visual hallucinations respond poorly to treatment except in specific circumstances. Those associated with epilepsy, migraine, and narcolepsy may respond to anticonvulsants, antimigrainous, and stimulant medications, respectively. Visual hallucinations occurring with degenerative disorders, such as Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease with dementia, may improve with therapy with cholinesterase inhibitors. 1 12 There are anecdotal reports of improvement in post-LSD persisting perceptual disorder following treatment with naltrexone. 11 3 Antipsychotic agents relieve hallucinations in patients with schizophrenia and other psychoses.
Auditory Hallucinations
Auditory hallucinations, unlike visual hallucinations, are more characteristic of idiopathic psychiatric disorders than of neuromedical or toxic disorders. An important exception to this observation is the common occurrence of auditory hallucinations in schizophrenia -like psychoses that may be associated with a variety of neurological and toxic -metabolic disorders (Chapter 12 ). Table 13.5 presents the disorders to be considered in the differential diagnosis of auditory hallucinations. Deafness produced by disease of the middle ear (e.g., otosclerosis) or of the inner ear and auditory nerve can produce both unformed and formed hallucinations. The unformed hallucinations are referred to as tinnitus and consist of buzzing or tones of varying pitch and timbre. The formed hallucinations consist of melodies, organ music, hymns, songs, and, occasionally, voices. In some cases the content can be influenced by imagining or vocalizing a song or melody. 11 4 , 115 Deafness and auditory hallucinations appear to predispose to the development of a paranoid syndrome, particularly in the elderly. 11 6 The association between auditory hallucinations and deafness resembles the
similar correlation of visual hallucinations with blindness and of phantom limbs with amputation. Musical hallucinations are a unique type of auditory hallucination that often surprise the individual who begins to experience them for the first time; the patient may try to find the radio or television that they think is the origin of the sound. Musical hallucinations have a wide differential diagnosis and can been seen in any disorder producing other types of auditory hallucinations, but they are most common with deafness. Typically the individual is an elderly woman, has longstanding sensorineural deafness, and begins to experience vocal or instrumental music known from childhood. 117, 11 8 Musical hallucinations also occur with hemispheric and brainstem lesions, 1 1 7, 1 1 9, 1 2 0 , as well as with epilepsy and alcoholic hallucinosis. 1 1 7, 1 2 1 Depression and schizophrenia have also been accompanied by musical hallucinations. 11 7, 1 18 , 12 1, 1 22 Musical hallucinations are treatment resistant; they may improve with treatment of any associated psychopathology or, in the case of hallucinations with deafness, an improvement in hearing. 118, 1 22
Peripheral lesions
Pontine lesions
Stroke
Arteriovenous malformation
Syncope
Toxic-metabolic disturbances
Delirium
Hallucinogens
Psychiatric borders
Schizophrenia
Mania
Psychotic depression
Multiple personality
Among CNS disorders, partial seizures may give rise to auditory hallucinations. Currie and colleagues 12 3 studied 514 patients with temporal lobe epilepsy and found that 17% had auditory hallucinations as one component of their seizures. Crude sensations were five times more common than elaborate, formed sounds or voices. The hallucinations are brief, stereotyped sensory impressions and, if formed, may be trivial sentences, previously heard phrases, or commands. 1 23 P.195 Central nervous system neoplasms also give rise to auditory hallucinations in 3%!10% of cases. 1 2 4 The hallucinations may be either formed or unformed and are associated predominantly with frontal and temporal lobe tumors.
Vascular lesions have rarely been associated with auditory hallucinations. Hemorrhages and arteriovenous malformations in the region of the pontine tegmentum and lower midbrain have been associated with the acute onset of auditory hallucinations. The sounds have typically been unformed mechanical or !seashell -like!! noises or music. 12 5, 126 Syncope may be associated with hallucinations. Sixty percent of individuals who experience transient cerebral hypoxia report visual changes such as gray haze, colored patches, or bright lights. Thirty -six had auditory hallucinations consisting or rushing or roaring noises, screaming, or voices. 12 7 Auditory hallucinations may occur as part of delirious psychoses in the course of toxic and metabolic encephalopathies or during withdrawal states. Alcoholic hallucinosis is a unique auditory hallucinatory syndrome related to chronic alcoholism and alcohol withdrawal. The hallucinations are usually vocal in nature and typically consist of accusatory, threatening, and critical voices directed at the patient. The voices begin in the withdrawal period in most cases and usually cease within a few days. In a few cases, however, the auditory hallucinations become chronic, persisting for years. The patient may have no insight into the unreality of the experiences and may act on directions received from the voices or may seek protection from them with relatives or police. 12 8 , 1 29 , 1 30 Auditory hallucinations are most characteristic of the idiopathic psychoses. They occur in 60%!90% of schizophrenic patients and up to 80% of patients with affective psychoses. 1 31 The hallucinations vary from !inner voices!! sensed by the patient to vivid hallucinations heard as if coming from the outside. 1 32 Some patients may hear their own thoughts spoken aloud (Gedankenlautwerden}. Schizophrenic patients experience the voices as objective, involuntarily present and having unique and immediate relevance to them, but a minority expect that other members of the public should be able to hear them. There is a tendency for some patients with affective disorders to lateralize their hallucinations to the
right side of space. 1 3 3 Auditory hallucinations, like visual hallucinations, reflect the predominant mood state of the individual when they occur in the affective disorders. 1 Studies of glucose metabolism in schizophrenic patients with hallucinations have demonstrated diminished metabolism in the posterior superior temporal region of the left hemisphere (auditory cortex and Wernicke's area). 1 3 4 Hallucinations were positively correlated with metabolism of anterior cinguiate and striatal regions. Dichotic listening studies have also suggested left hemisphere dysfunction in hallucinating schizophrenics. 13 5 Evoked -response studies during auditory hallucinations in schizophrenia have shown response delays similar to those observed with externally originating sounds. 13 6 Thus, emerging physiologic investigations suggest that auditory hallucinations in schizophrenic patients are associated with left temporal dysfunction. Wearing headphones has decreased auditory halluci-nations in some patients and others report temporary amelioration of the hallucinations with humming or mouth opening (maneuvers that disrupt subvocalization). 7 0 , 1 37 , 1 38 Antipsychotic agents relieve auditory hallucinations in most psychoses. In addition to their occurrence in the psychoses, auditory hallucinations also occur as manifestations of hysterical conversion reactions, multiple personality disorder, and post-traumatic stress disorder. 13 9 , 1 40 , 14 1 The presence of auditory hallucinations in these syndromes contributes to their frequent misdiagnosis as schizophrenia. Auditory hallucinations must be distinguished from palinacousis, in which there is a persistence or late recurrence of existing auditory stimuli. Palinacousis has been associated with a variety of cerebral lesions (particularly neoplasms and infarctions), and the lesions usually involve the temporal lobe. 9 6, 1 42
common hallucinations recorded in clinical investigations. Olfactory hallucinations are well known in epilepsy; they are associated with medial temporal lobe lesions and complex partial seizures (uncinate seizures). 7 1, 14 3 Such hallucinations may also occur in migraine and in both situations are usually described as unpleasant. 14 4 Olfactory hallucinations have also been described in multi -infarct dementia, Alzheimer's disease, and alcoholic psychosyndromes. 14 5 Among psychiatric disorders, olfactory hallucinations occur in schizophrenia, post-traumatic stress disorder, depression, and in at least 20%!25% of patients with Briquet's syndrome. In depression, the hallucinations are commonly mood -congruent smells of death, decay, and personal filth. Similar delusional beliefs that one is emitting a foul odor characterize the olfactory reference syndrome 1 4 6 , 1 4 7 , 14 8 In this disorder, the patient develops the monosymptomatic belief that they are the source of an offensive odor. The syndrome may be a P.196
Phantom Organs
Phantom Sensations
stable monosymptomatic delusion or a form of hypochondriasis or may progress to an affective disorder. 1 4 6 Gustatory hallucinations occur in manic -depressive illness, schizophrenia, Briquet's syndrome, and partial seizures. Tactile hallucinations (formication hallucinations; haptic hallucinations) are most common in withdrawal states but also can occur in association with other brain disorders. 149, 1 5 0 Somewhat related to tactile hallucinations are abnormal perceptions regarding body size and shape. These experiences are described in patients with peripheral nerve lesions, brain disorders, and psychiatric illnesses such as body dysmorphic disorder and anorexia nervosa. 1 51 , 15 2 , 1 53 , 1 54 , 15 5 , 15 6 Patients who have lost limbs or other body parts may have !phantom! ! sensations based on hallucinations that the body part remains. 15 7, 1 58 , 1 59 , 1 6 0, 16 1 , 1 6 2 Table 13.6 lists types of phantoms reported in patients with lost appendages.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 14 - Disturbances of Mood and Affect
found in the chapter on Alzheimer's disease and other dementias (Chapter 10 ), movement disorders (Chapter 18 ), epilepsy and temporal lobe syndromes (Chapter 21 ) and focal and infectious central nervous system disorders (Chapter 26 ).
latency. Occasionally, patients sleep excessively. Patients often evidence diurnal variability in mood manifested by more severe sadness in the morning that remits partially by the afternoon and evening. Loss of libido is characteristic of depression. Neuroendocrine disturbances notable in depression include failure to suppress endogenous cortisol secretion with administration of exogenous dexamethasone in the dexamethasone suppression test (DST) and abnormalities on the thyrotropin-releasing hormone (TRH) test. Neuroimaging changes associated with depression include increased periventricular white matter abnormalities on computerized tomography (CT) or magnetic resonance imaging (MRI) and decreased cerebral blood flow or cerebral metabolism involving primarily the frontal regions (discussed in greater detail below) observed on single photon emission computerized tomography (SPECT) or positron emission tomography (PET). 1 ,2,3 The presence of CNS disease may make the recognition of a depression syndrome more difficult and frequently modifies the manifestations of the disorder. Aphasic patients, for example, cannot voice the usual propositional expression of their internal emotional state; patients with right hemisphere injury or basal ganglia disease have dysprosodia and frequently lack the ability to inflect their voice. They lack the emotional vocal changes that allow the clinician to gauge the severity of the patient's mood changes. Patients with parkinsonism may have slowed movements, vocal changes, and facial hypomimia similar to depression without any corresponding mood abnormality. Likewise, patients with Alzheimer's disease and other dementias may experience apathy, cognitive disturbances, retardation or agitation, changes in appetite, and changes in sleep pattern in the absence of a depressed mood. Patients with pseudobulbar palsy may sob or tear, expressing a sad affect that is dissociated from any underlying mood changes. Apathy is common in many neurological diseases in the absence of depression 4 (Chapter 15 ). Assessment of the core psychological features of depression, including sadness, feelings of guilt, worthlessness, hopelessness, and helplessness, is critical to recognizing the depression syndrome in patients with neuropsychiatric disorders. Rating scales that include clinical features confounding the manifestation of depression and neurological disease must be used with caution in this population.
usually associated with periods of major depressive episodes), bipolar II disorder (characterized by one or more depressive episodes accompanied by at least one hypomanic episode), cyclothymic disorder (featuring periods with hypomanic symptoms and periods with depressive symptoms that do not meet criteria for a major depressive episode or bipolar disorder), mood disorders due to a general medical condition P.202
TABLE 14.1. Characteristics of a Depression Syndrome (Not All Manifestations Are Present in All Patients)
General Characteristic
Manifestations
Mood alterations
Sadness
Anhedonia
Feelings of guilt
Feelings of helplessness
Feelings of hopelessness
Feelings of worthlessness
Changes in verbal
expression
Disturbances of affect
Sad expression
Crying
Furrowed brow
Motor alterations
Slumped shoulders
Catatonia
Cognitive impairments
Reduced associations
Motivational changes
Reduced interest
Neurovegetative disturbances
Sleep disturbances
Multiple awakenings
Loss of libido
Neuroendocrinologic changes
P.203 including neurological disorders, and substance -induced mood disorders. 1 The features required for a diagnosis of mood disorder due to a general medical condition are not specified in the Diagnostic and Statistical Manual of Mental Disorders (DSM), 1 but most researchers have used the criteria of major depressive episodes or minor depression, with the latter defined according to the same criteria as dysthymic disorder but beginning coincidentally or after the onset of the CNS disorder.
Observations that have emerged consistently across neurological populations include the following: depression is underecognized in neurological conditions, even when recognized; depression tends to be under-treated in patients with neurological disorders; depression
Depression is underrecognized and undertreated in neurological disorders (e.g., those with a personal or family history of depression).
Neurologic disorders may produce depression as a sentinel event preceding other manifestations of brain disease.
Depression may accompany the onset of a neurologic disorder as a neurobiological component of the condition.
Depression can reduce motivation and decrease willingness to answer questions, imitating a
Neurological disorders can produce signs !slowness, hypomima, apathy!that imitate depression (pseudodepression).
Depression commonly co -occurs with other types of psychopathology (psychosis, agitation) in patients with neurologic disorders.
Neurological disorders can produce affective changes of depression without a corresponding mood change (sham emotions; pseudobulbar palsy).
Depression is most common in patients with conditions affecting the basal ganglia, frontal cortex, or temporal cortex.
Depression symptom profiles may vary among neurologic disorders (depression is associated with paranoia in epilepsy and psychomotor retardation in post-stroke syndromes; depression has less guilt and self -blame in Parkinson's disease compared to that in idiopathic depressive disorders).
Drugs used to treat neurological disorders can cause depression (phenobarbital, interferon).
Drugs used to treat neurological disorders can improve or prevent the emergence of depression (prarnipexole).
Depression in neurologic disease often responds poorly to pharmacotherapy and ECT; treatment related delirium is common.
P.204 hinders rehabilitation of patients with acute neurological conditions such as stroke or traumatic brain injury; depression exacerbates functional abnormalities and disturbances of activities of daily living; depression increases cognitive disturbances; depression and apathy are frequently inadequately distinguished. Patients with diseases affecting the basal ganglia and frontal and temporal lobes appear to be at particularly high risk for the development of depression, but depressive symptoms are common in nearly all types of brain disorders that have been assessed. There have been very few randomized double -blind, placebocontrolled trials of antidepressants in patients with neurological disease and depression, and antidepressant treatment is based primarily on extrapolation from treatment approaches developed for idiopathic depressive disorders. These extrapolations must be accepted with caution since the presence of a brain disorder may modify the response to antidepressant therapies.
and minor depression in 25%!50% of cases. In all, approximately 50% of patients with Parkinson's disease will manifest depressive symptoms of varying severity. 5, 6 Female gender and a past history of depression increase the likelihood of developing depression during the course of the illness. 5 Depression in Parkinson's disease is associated with more impaired cognitive functioning, the presence of psychotic features, and greater physical disability. 7, 8 ,9 , 10, 11 Several studies have found that depression is more common in patients with left hemisphere involvement and right hemi Parkinsonism. 12 , 1 3 The profile of depressive symptoms in Parkinson's disease includes dysphoria, pessimism, and prominent somatic symptoms with less evidence of guilt and self -blame. 5,7 Patients with major depression show more rapid cognitive decline, deterioration of activities of daily living, and more severe disability than patients with no mood changes or minor depression. 14 In patients with the !on -off!! phenomenon, depressive symptoms are more common when the patient is !off!! and mood normalizes or may even become elevated during !on!! periods. 15 , 1 6
Neurological Disorders
Systemic Disorders
Cortical degenerations
Infections
Alzheimer's disease
Viral
Frontotemporal dementias
Bacterial
Endocrine disorders
Extrapyramidal diseases
Hyperthyroidism
Parkinson's disease
Hypothyroidism
Huntingdon's disease
Hyperparathyroidism
Hypoparathyroidism
Corticobasal degeneration
Cushing's syndrome
Wilson's disease
Addison's disease
Hyperaldosteronism
Premenstrual depression
Diabetes mellitus
Cerebrovascular disease
Acromegaly
Stroke
Prolactinonia
Hypopituatarism
Arteriovenous malformations
Cerebral neoplasms
Inflammatory disorders
Cerebral trauma
Temporal arteritis
CMS infections
Sjogren's syndrome
Lyme encephalitis
Vitamin deficiencies
Viral encephalitis
Folate
Vitamin B 12
Multiple sclerosis
Niacin
Vitamin C
Epilepsy
Narcolepsy
Cardiopulmonary disease
Hydrocephalus
Systemic neoplasms
Porphyria
Klinefelter's syndrome
Neurobiological studies provide insight into the pathophysiological basis of depression in Parkinson's disease. Levels of 5 -hydroxyindoleacetic acid (5 -HIAA) are significantly lower in depressed than in nondepressed P.205 patients. At autopsy, patients with Parkinson's disease and depression have been found to have significantly greater involvement of the locus coeruleus, the nuclear origin of norepinephrine, than nonde -pressed patients. 18 Studies of regional cerebral glucose metabolism using [ 18 F] fluorodeoxyglucose (FDG) PET reveal diminished metabolism in the caudate nucleus and the inferior frontal regions 1 9 or the medial frontal and anterior cingulate regions. 20 Depression is reported with variable frequency among other parkinsonian syndromes. Depressive symptoms were detected in approximately 20% of patients with progressive supranuclear palsy in a study using a prospective interview
17
evaluation technique. 2 1 Through a similar approach, depression was found in approximately 75% of patients with corticobasal degeneration. 22 Depression has been reported in approximately 50% of patients with dementia with Lewy bodies. 23, 24 , 2 5 In Wilson's disease, 10%!25% of patients manifest psychiatric disturbances before the onset of neurological abnormalities, and in 10%!15% depression is the initial symptom. 26 , 2 7 Up to 40 or 50% of patients eventually manifest a psychiatric illness; 20%!40% show depressive symptoms. 2 8 , 2 9 Psychiatric symptoms are more common in patients with the neurological form of the disease than in those with the hepatic form. There is little relationship between motor, psychiatric, and cognitive symptoms, suggesting that the psychiatric manifestations are independent manifestations of the underlying neuropathological changes. 28 , 3 0
Huntington's Disease
Approximately 40% of patients with Huntington's disease have mood disorders: 20%!30% meet criteria for major depressive episodes, 10% have depression with hypomanic episodes, and 5% have dysthymic disorder. 31 , 3 2, 33 The association between mood disorder and Huntington's disease appears to be more common in specific families in whom the 'two disorders occur together on a recurrent basis. 33 Huntington's disease is associated with a marked increase in suicide rate; suicide was eight times more common among Huntington's disease patients aged 50!69 years than in a control group of un -affected individuals. Suicide is most common early in the course of the illness. 3 4 No correlation has been identified between the dementia syndrome, severity of motor abnormalities, or CAG repeat length in the causative mutation of Huntington's disease on chromosome 4. 35 The independence of psychiatric symptoms from cognitive and motor symptoms in Huntington's disease suggests that the mood changes are not a reaction to the illness but are a neuropsychiatric manifestation of the underlying pathophysiological alterations. Studies with FDG PET show reduced metabolism in the orbitofrontal-inferior prefrontal cortex in depressed patients with Huntington's disease compared to that in nondepressed Huntington's disease patients. 3 6 Studies of cerebrospinal fluid (CSF) have indicated no differences in concentrations of 5 -HIAA between patients with Huntington's disease and normal volunteers. However, corticotropin -releasing factor (CRF) is elevated in Huntington's disease, and there is a positive correlation between CRF levels and the severity of major depression. 3 7
Cerebrovascular Disease
Depression following stroke has been investigated and relationships between time of assessment, lesion location, lesion size, and a variety of clinical features have emerged. In the immediate post-stroke period (7!10 days) there is a higher frequency of depression with left hemispheric lesions than with right hemispheric lesions. This relationship is observed for both major depression (approximately 15% of
patients) and minor depression (approximately 25% of patients). 62 , 6 3 After 3 to 6 months, this hemispheric asymmetry is no longer evident: patients with both right and left hemispheric lesions evidence depressive disorders and there is an inverse correlation between the distance of the lesion from the frontal pole of either hemisphere and the severity of depression (Fig. 14.1 ). 6 2 After 1 year, patients with right hemisphere lesions are more likely to be depressed than patients with left hemisphere strokes. 62 When anxiety complicates depression, the lesion is more likely to involve cortical than subcortical structures. 9 Among patients with subcortical lesions, depression is more common following injury to the left caudate nucleus than injury to the right basal ganglia or thalamic nuclei. 63, 64 Several investigators have documented a relationship between lesion size and severity of depressive disorders. 65, 66 Patients with depression and left hemisphere stroke have greater cognitive impairment than patients with depression and right hemisphere stroke or patients with stroke without depressive disorders. 6 7, 68 , 69 Post -stroke depression is more common in patients who have enlarged ventricles, which suggests that atrophy may predispose to the occurrence of post-stroke mood changes. 6 4 Women are more likely to exhibit post-stroke depression than men. 70 The profile of depressive symptoms is essentially identical in post-stroke depression and idiopathic late -onset depression, although psychomotor retardation is more prominent in post-stroke disorders. 71 Depression is correlated with impaired activities of daily living, both acutely and at long-term follow -up. 72, 73 Patients with post-stroke depression have significantly lower concentrations of CSF 5 -HIAA than non -depressed poststroke patients and have higher serotonin receptor (S 2 ) binding in uninjured regions of right parietal and temporal cortex than do nondepressed subjects. 74 Post -stroke depression may be mediated in part through serotonergic mechanisms, with reduced serotonin availability and failure to up -regulate serotonin receptors in the injured hemisphere. Vascular depression refers to the accruing evidence that many cases of late -onset depression are related to overt stroke, silent cerebral infarction, or subcortical
FIGURE 14.1 Lesion location and time course in poststroke depression. 62 Regions in red were more commonly associated with depression for each time period.
P.207
Cardinal features
Clinical and/or neuroimaging evidence of cerebrovascular disease Clinical evidence includes a history of transient ischemia attack or focal signs, gait disturbance, or incontinence Neuroimaging evidence includes structural or functional evidence of focal ischemia, hemorrhagic brain injury, or subcortical ishcemia injury. Onset of depression after age 65 or change in course of early -onset depressive disorder
Secondary features
Vascular risk factors (hypertension, history of myocardial infarction, atrial fibrillation, carotid stenosis. hyperlipidemia, hypercholesterolemia, obesity, smoking habit) Cognitive impairment with executive dysfunction Psychomotor retardation Mood abnormalities with less guilt Poor insight Impaired activities of daily living Absence of a family history of mood disorder
Prognosis
Mood changes respond to antidepressant phannacotherapy but the response is less predicatble than when these agents are used in idiopathic depression. Confusion following initiation of treatment is not uncommon. Mood changes may respond to ECT; prolonged post-ECT confusion is more common than when applying ECT to idiopathic depression.
white matter ischemic injury. 7 5, 76 Table 14.4 presents a summary of the characteristics of vascular depression. Onset is typically after the age of 65 or there is a change in the course of an early -onset depressive disorder. There is clinical or imaging evidence of cerebrovascular disease, and vascular risk factors (especially hyper -tension) are commonly present. Neuropsychological dysfunction, particularly executive abnormalities, is evident. The profile of mood symptoms includes less prominent guilt than is typical in most cases of idiopathic depression, poor insight, psychomotor retardation, and an absence of family history of a mood disorder. 7 7 , 7 8 From a treatment perspective, vascular depression may respond to either pharmacotherapy or treatment with electroconvulsive therapy (ECT); the response is less robust than in patients with idiopathic depression and complications such as confusion are more common. 79, 8 0 , 8 1, 82 Increased white matter hyperintensities consistent with ischemic injury and vascular damage to the basal ganglia are particularly common substrates for vascular depression. 83 , 8 4, 85
Epilepsy
The neuropsychiatry of epilepsy is discussed more comprehensively in Chapter 21 . Depression is common in this disorder; it may occur as a prodromal emotional change prior to a seizure, comprise part of an aura at the beginning of an ictal event, be present as an ictal manifestation during the course of the seizure, follow a seizure as part of a postictal state or may be an interictal manifestation. The interictal depression associated with epilepsy is common in those with complex partial seizures, particularly those with left -sided foci. 8 6, 87 Interictal depression is the most common type of psychopathology observed among epilepsy patients. It is characterized by mood changes, psychotic traits, paranoia, chronic dysthymia, anxiety, and hostility. 8 6, 88 Although suicide and suicide attempts are common among epileptic patients, they are more often associated with personality disorders and psychosis than with depression. 8 9 Studies with FDGPET reveal reduced metabolism in the inferior frontal cortex bilaterally 90 or unilaterally in the left temporal lobe. 87 In treating depression and epilepsy, clinicians must take into account the interactions of the seizures and the therapeutic interventions. Amoxapine and maprotiline lower seizure threshold and may exacerbate seizures. Monoamine oxidase inhibitors (MAO-I) are the agents least likely to increase seizure frequency. 91 Interactions between anticonvulsants and antidepressants also must be considered. Tricyclic antidepressants may increase carbamazepine and phenytoin
levels, while phenobarbital and phenytoin may decrease tri cyclic antidepressant levels. Selective serotonin reuptake inhibitors (SSRIs) may increase levels of carbamazepine, phenobarbital, phenytoin, and valproate; and carbamazepine, phenobarbital, and phenytoin may all decrease paroxetine levels. 91 Patients with epilepsy requiring ECT to relieve their depression should remain on their anticonvulsant regimen during the course of ECT treatment. Their anticonvulsant drug should not be administered on the morning prior to the treatment. The seizure threshold should be determined at the time of the first treatment and a stimulant dosage at least moderately above seizure threshold should be administered during the subsequent treatments. 9 1
Multiple Sclerosis
The neuropsychiatry of multiple sclerosis is described in Chapter 26 . Mood abnormalities P.208 are common manifestations of multiple sclerosis and a management challenge for the clinician providing care to these patients. Up to 80% of patients with multiple sclerosis have depressive symptoms, and approximately 20% have symptom severity sufficient to warrant treatment with antidepressants. 9 2 The profile of mood abnormalities in multiple sclerosis includes sadness, self -reproach, and somatic features. Neurovegetative and somatic abnormalities are common in multiple sclerosis without mood abnormalities and may mislead clinicians into overestimating the prevalence of depression. 93 , 9 4 Depression is unrelated to physical disability, but mood changes are more likely to occur during exacerbation or progression. 9 3, 9 5 Rates of mood disorders are not elevated among first -degree relatives of patients with multiple sclerosis, suggesting that the high rate of mood changes in these patients is not genetically determined. 96 Depression is one of the principal determinants of quality of life of patients with multiple sclerosis. 9 7 Patients with cerebral lesions are much more likely to suffer depressive episodes than patients with spinal lesions who are equally disabled. 98 Patients with mood abnormalities have higher plaque counts in frontal and temporal regions than patients with multiple sclerosis and no associated mood changes. 99 , 1 00 , 10 1 A variety of treatment issues arise with regard to multiple sclerosis and depression. Treatment with inter -feron "ndash;lb (IFN -/!"!lb) has been reported to induce new -onset depression or worsen depressive symptoms. 1 02 Treatment with antidepressants or psychotherapy improves adherence to IFN -/3 -lb therapy. 1 03 Depression in multiple sclerosis has been reported to respond to both tricyclic
antidepressants and SSRIs. 10 4 , 1 05 Psychotherapy has an important role in aiding patients with this complex relapsing and remitting disorder to adjust to the challenges presented by the disease. 10 6
therapeutic option but should be avoided in those with increased intercranial pressure, headache, or focal neurological deficits. 12 3
deep white matter and periventricular hyperintensities are typically present. These lesions are significantly less common among patients with early -onset depression. 130 , 131 Studies of CBF using SPECT or PET reveal diminished blood flow in the inferior frontal, dorsolateral prefrontal, and anterior cingulate regions. 13 2 , 1 33 , 134 Studies with FDG -PET show diminished activity of the left dorsal anterior lateral prefrontal cortex and the caudate nuclei. 135 Positron emission tomography studies using ligands to identify serotonin receptors (5 -HT 2 ) indicate reduced receptor density in the posterolateral orbital frontal cortex and the anterior insular cortex of the right hemisphere. While not completely consistent, these studies demonstrate abnormalities of the frontal lobes and basal ganglia across different metabolic, perfusion, and structural studies. Neuropsychological testing also suggests frontal and frontalsubcortical dysfunction in patients with major depression. Executive abnormalities are consistently found and skills mediated predominantly by the right hemisphere tend to be more impaired than those mediated by the left. Nonverbal memory abnormalities and a discrepancy in the verbal/performance I.Q., with more pronounced deficit in the performance I.Q., have been described. 13 6, 137 Verbal memory abnormalities have been identified in some studies. 138 , 139 Executive abnormalities become more apparent in more severe depressions. 1 3 6 These neuropsychological deficits correlate with reduced blood flow in the medial prefrontal cortex. 1 40, 141 In addition, depressed patients fail to activate cingulate cortex and striatum in the course of a test demanding executive function. 142 There have been relatively few postmortem studies of patients with major depression. Histopathologic studies have revealed diminished cortical thickness and decreased neural and glial densities in the rostral orbitofrontal cortex, reductions in glial densities in the caudal orbitofrontal cortex, and reductions in the density and size of neurons and glial cells in the dorsolateral prefrontal cortex. 143 Findings from postmortem studies of receptor binding are not completely consistent but have usually shown increased serotonergic binding involving the 5 -HT 2A and 5 -HT 1A receptors. 14 4 Several studies have identified a reduced number of neurons in the locus coeruleus of suicide victims. 14 4 Studies in idiopathic and acquired depressive disorders suggest dysfunction of complex neurological circuits mediating mood and responsible for depression (Fig. 14.2 ). Orbitofrontal and anterior temporal paralimbic cortex are commonly involved in idiopathic and secondary depressions. Similarly, the caudate nucleus has often been observed to be abnormal in depression syndromes. Frontal -subcortical
circuits linking the orbital frontal cortex and caudate are involved in many conditions with depression. Orbitofrontal cortex is joined via white matter tracts to adjacent anterior temporal paralimbic cortex. These cortical regions are also connected to subcortical and brainstem structures involved in Parkinson's disease and parkinsonian syndromes. Mayberg et al. 145 proposed that together these structures comprise a network that produces symptoms of depression when it is functionally compromised. This network includes paralimbic structures responsible for the emotional/experiential aspect of depression, limbic -hypothalamic influence mediating neurovegetative manifestations, limbic -basal ganglia connections responsible for affective and motor features, and limbic -dorsolateral prefrontal interactions P.210
Category
Agents
Category
Agents
Antihypertensive drugs
Clonidine
Withdrawal syndromes
Barbiturates
Oxprenolol
Alcohol
Propranolol
Beiuodiazepines
Reserpine
Amphetamines
Methyldopa
Corficosteroids
Guanethidine
Hallucinogens
Indole hallucinogens
Hydralazine
Antineoplastk
Azathioprine
drugs
Bethanidine
C -Asparaginase
Nifedipine
Plicamycin (raithramycin)
Ptazosin
Vincristine
Antiarrhythmics
Cardiac glycosides
6 -Azauridine
Procainamide
Bleomycin
Lidocaine
Triniethoprim
Antiparkinsonian drugs
Amaniadifie
Interferon
Bromocriptine
Endocrine agents
Corticosteroids
Levodopa
Oral contraceptives
Analgesics
Androgens
Triamcinolone
Narcotics
Norethisterone
Phenacetin
Danazol
Incdomethacin
Amphetamines
Anticonvulsants
Phenytoin
Fenfluramine
Barbiturates
Diethylpropion
Ethosuximide
Phenmetrazine
Lamorrigine
Miscellaneous drugs
Acetazolarnide
Felbamate
Anticholinesterase
Sedative hypnotics
Bcnzodiazepines
Baclofen
Chloral hydrate
Choline
Ethanol
Cyproheptadine
Clomethiazole
Diltiazem
Clotazepate
Diphenoxylate
Neuroleptics
Butyrophenones
Disulfiram
Phenothiazines
Goseretin
Antibiotics
Penicillins
Halothane
Sulfamethoxazole
Interfeton -2a
Clotrimazole
Interferon " -2
Cycloserine
Mebeverine
Dapsone
Meclizine
Ethionamide
Methoserpidine
Tetracycline
Methysergide
Griseofulvin
Metoclopramide
Metromdazoic
Metrizamide
Streptomycin
Tacrolimus
Nitrofurantoin
Naltrexone
Nalidixic acid
Phenindione
Sulfonamides
Pizotifen
Procaine penicillin
Procaine
Thiocarbanilide
Salbutamol
Acyclovir
Tetrabenazine
Isoniazid
Veratrum
P.211
for common paralimbic cortex hypometabolism in primary and secondary depressions include 1. Connections of mesencephalic monamine neurons (vta, dr, Ic) and their cortical projections; 2. projections to basotemporal limbic regions and amygdala; 3 and 4, cortical -basal ganglia circuits; and 5. serotonergic neuron projections from orbital cortex. BG, basal ganglia; Cd, caudate; Cg, anterior cingulate; dr, dorsal raphe; iPF, inferior prefrontal cortex; Ic, locus cerulerus; OF, orbital frontal cortex; T, temporal cortex; Th, thalamus; vta, ventral tegmental area. Modified from Mayberg et al. 1 45
Treatment of Depression
Table 14.6 outlines the typical starting dose and dosage range of a variety of classes of antidepressant agents. IThe choice of antidepressant is dictated largely by side effects. Clinicians should familiarize themselves with the use of a few agents from each class and become expert in the anticipation of adverse events and in administration regimens. There have been few studies of antidepressants in secondary depression associated with neurological disorders, and the efficacy of these agents may vary from that observed in clinical trials of patients with idiopathic mood disorders. Electroconvulsive therapy represents an alternative treatment intervention for patients requiring rapid resolution of their mood disorder, those who are intolerant of pharmacotherapy, or those who are treatment resistant. 14 6
Mania
Mania is a mood disorder featuring an elevated or expansive mood, increased physical activity, accelerated thought and speech, and neurovegetative changes. Idiopathic mania appears to be a genetically determined disorder and secondary mania is produced by a wide variety of neurological and endocrine disorders. Many types of drugs have also been associated with induction of secondary mania. Currently recognized types of mania and cyclical mood disorders include bipolar I disorder, characterized by recurrent manic episodes or mixed manic and depressive episodes; bipolar II disorder, characterized by the occurrence of one or more major depressive episodes accompanied by at least one hypomanic episode; cyclothymic disorder, evidenced by numerous periods with hypomanic symptoms and numerous periods with depressive symptoms;
mood disorder due to a neurological or medical condition and featuring an elevated expansive or irritable mood; and a substanceinduced P.212
Initial Dose
25!75 mg qhs
100 !300
Amoxapine (Asendin)
50 mg bid
100 !400
Desipramine (Norpramin)
25!75 mg qhs
100 !300
25!75 mg qhs
100 !300
25!75 mg qhs
100 !300
Maproriline (Ludiomil)
25!75 mg qhs
100 !225
25!50 mg qhs
50 !150
Protriptyline (Vivactil)
15 mg qAM
15!60
Trimipramine (Surmontil)
25!75 mg qhs
100 !300
Citalopram (Celexa)
20 mg qAM
20!60
Fluoxetine (Prozac)
10!20 mg qAM
20!80
Fluvoxamine (Luvox)
50 mg qhs
100 !300
Paroxetine (Paxil)
10!20 qAM
20!50
Sertraline (Zoloft)
25!50 mg qAM
50 !150
Bupropion (Wellbutrin,
100 mg rid IR
300 !450
*
25 mg bid-tid IR
75 !375
37.5 mg qd XR
Nefazodone (Serzone)
100 mg bid
300 !600
Trazodone (Desyrel)
50 mg rid
150 !600
Mirtazapine (Remeron)
15 mg qhs
15!45
Phenelzine (Nardil)
15 mg rid
15!90
Tranylcypromine (Parnate)
10 mg bid
10!60
Not to exceed ISO mg/dosc to minimize seizure risk for IR and 200 rngfttose for SR.
mood disorder characterized by elevated, expansive, or irritable mood. 1 Manic episodes may have psychotic features or catatonic features and may sometimes begin in the postpartum period. Rapid -cycling bipolar disorders feature the occurrence of four or more mood episodes during the previous 12 -month period. 1
of ideas, (d) grandiosity, (e) decreased sleep, (f) distractibility, (g) lack of judgement. Exclusionary criteria included (1) a clear previous history of manic -depressive or other mood disorder or (2) the coexistence of the manic syndrome with symptomatology of an acute confusional state or delirium. Table 14.8 lists neurological disorders reported to produce secondary mania. Several generalizations emerge from review of the focal and degenerative disorders that have been associated with secondary mania. First, right -sided lesions are far more common than left -sided lesions. Second, within the right hemisphere, involvement of the frontal lobe, basal ganglia (particularly the inferior caudate nucleus), thalamus, and inferior temporal regions are the most common locations for lesions associated with secondary mania. Parietal and occipital lesions have rarely produced this condition. 15 1 Third, many patients exhibiting secondary mania in association with a focal neurological disorders have a family history of psychiatric disturbance or mood disorder. This suggests that the combination of a strategically placed lesion with a genetic vulnerability may be necessary to produce the syndrome of secondary mania. Fourth, the presence of cerebral atrophy as evidenced by enlargement of the anterior lateral
Aspect
Features
Mood
Elation
Euphoria
Irritability
Impatience
Self-perception
Denial of illness
Certainty of success
Social interactions
Unable to empathize
Intrusive
Provocative
Judgement
Impaired
Rash confidence
Reckless
Thought processes
Racing thoughts
Flight of ideas
Increased associations
Clang associations
Rhyming puns
Speech
Short latencies
Pressured
Loud
Motor behaviors
Smiling, laughing
Expansive gestures
Assertive posture
Neurovegetative features
High energy
Increased libido
Increased appetite
Mood-congruent hallucinations
P.214
Neurologic Disorders
Systemic Disorders
Extrapyramidal diseases
Infections
Neurosyphilis
Dialysis dementia
calcification
Hyperthyroidism
Parkinson's disease
Pellagra
After dopaminergic
Q fever
Carcinoid
treatment
syndrome
After thalamotomy
Influenza
Vitamin B 1 2 deficiency
After pallidotomy
Cryptococcosis
Postparsurn mania
Mononucleosis
Cerebral anoxia
Huntington's disease
HIV encephalopathy
Wilson's disease
Idiopathic dysconia
Congenital disorders
Cerebrovascular disorders
Fragile X syndrome
Pontine infarction
(mutation of 22q11)
Miscellaneous conditions
Cerebral trauma
Multiple sclerosis
Cerebral neoplasms
Frontotemporal dementia
Craniopharyngioma
Hemispherectomy (right)
Cerebellar degenerations
Kleine-Levin syndrome
Cerebral sarcoidosis
Multiple metastases
ventricles or third ventricle also appears to be a pre disposing factor to secondary mania, indicating that reduced cerebral reserve may have a role in the syndrome. Finally, patients with seizures in association with their neurological disease appear to be at particularly high risk for the development of secondary mania. Extrapyramidal disorders are among the most common syndromes associated with secondary mania, although only a minority of patients develop the disorder. Hypomania, occasionally progressing to mania, occurs in approximately 10% of patients with Huntington's disease. 32 In patients with Parkinson's disease, mania may occur following treatment with dopaminergic therapy, after pallidotomy or thalamotomy, or with deep brain stimulation. Mania also has been observed in patients with idiopathic basal ganglia calcification, postencephalitic Parkinson's disease, Wilson's disease, and idiopathic dystonia. 15 2, 153 Cerebrovascular disease is another common cause of secondary mania. The most common location for a lesion producing secondary mania is in the right perithalamic area. 154 , 155, 15 6 , 1 57 Hemiballismus, hemidystonia, postural tremor, or left -sided chorea frequently accompany the thalamic and subthalamic lesions. 15 6, 157, 15 8 In some cases a combination of a strategically placed lesion and a precipitating medication such as a SSRI was simultaneously present. 158 Pontine infarctions and temporal arteriovenous malformations have been associated with secondary mania. 15 9, 16 0, 16 1 Vascular dementia is a rare cause of
secondary mania. 1 6 2 P.215 A variety of cerebral neoplasms have produced secondary mania, including diencephalic tremors, medial frontal meningiomas, subtemporal bone tumors, multiple metastases, hypothalamic teratomas, craniopharyngiomas, acoustic neurinomas, and brainstem tumors. 1 55, 16 3, 164 , 1 65 Traumatic brain injury is another potential cause of secondary mania. Most lesions have involved the midline orbitofrontal regions or thalamic or parathalamic structures including the temporal lobe, thalamus, or paralimbic striatum. 9 ,166 , 1 67, 1 6 8, 1 69 The mania may appear immediately following the brain injury or may be delayed for up to 3 years. Most cases appear within the first few months following the brain injury. 16 9 Irritable mood is more common than euphoria in post-traumatic bipolar disorder and psychosis occurs in approximately 15% of patients. 170 Post traumatic mania is not associated with overall severity of brain injury, degree of physical impairment, degree of cognitive impairment, or level of social function. 17 1 Euphoria or eutonia (an unwarranted sense of well -being) are second only to depression as mood manifestations in patients with multiple sclerosis. Frank mania is more unusual, and has been recorded in approximately 10% of patients with multiple sclerosis. Determination of the prevalence of mania in multiple sclerosis is complicated by the common use of steroids to treat this disorder and these agents are known to precipitate mania in some patients. 1 04, 1 7 2 A variety of infections have also been associated with secondary mania, including neurosyphilis (the general paretic form), herpes simplex encephalitis, St. Louis encephalitis, Q fever, influenza, cryptococcosis, mononucleosis, HIV encephalopathy, and following streptococcal infection with Sydenham's chorea. 17 3 , 1 74 , 17 5 , 1 7 6, 177 , 1 7 8 Other disorders that have been associated with secondary mania include cerebellar degenerations, cerebral sarcoidosis, cardiac arrest, temporal lobe epilepsy, hemispherectomy, Kleine-Levin syndrome and Kline -felter's syndrome, and frontotemporal dementia. 17 9, 1 80 , 18 1, 1 82, 183, 1 84 , 185 Certain chromosomal abnormalities, including fragile X syndrome and velo-cardio -facial syndrome resulting from a microdeletion on chromosome 22qll, are associated with bipolar mood disorders. 1 86, 1 87 These mutation associations may provide insight into the genetic basis of mood disorders.
produce secondary mania (Table 14.8 ). Uremia and hemodialysis, dialysis-related dementia, hyperthyroidism, pellagra, carcinoid syndrome, vitamin Bi2 deficiency, and postpartum conditions have all been associated with secondary mania. 1 7 9, 1 82
Drug-Induced Mania
A large number of drugs have been reported to produce secondary mania (Table 14.9 ). Some classes of agents are particularly likely to produce manic syndromes, including antihypertensive and cardiovascular compounds, antiparkinsonian compounds (especially dopaminergic agents), anticonvulsants, antidepressants, atypical antipsychotics, CNS stimulants, some types of antimicrobial agents, and hallucinogens. Withdrawal syndromes may also include secondary mania 1 8 8, 1 89 , 19 0, 191, 19 2, 1 93 P.216
Category
Agents
Antihypertensive drugs
Antiparkinsonian drugs
Analgesics
Anticonvulsants
Sedatlve -hypnotics
Antidepressants
Bupropion Fluoxetine Fluvoxamine Monoamine oxidase inhibitors (MAOls} Mirtazapine Nefazodone Paroxetine Sertraline Tricyclic agents Trazodone
Antipsychotics
Olanzapine Risperidone
Antimicrobial agents
Cycloserine Dapsone Penicillins Podophyllin Zidovudine (AZT) Antimalarials Isoniazid Iproniazid Cephalosporins
H 2 blockers
Cimetidine
Withdrawal syndromes
Alcohol Amphetamines Baclofen Diethylpropion Monoamine oxydase inhibitors (MAOIs) Nicotine Opiates Propranolol Tricyclie agents
Hallucinogens
Anrineoplastic drugs
Procarbazine
Endocrine agents
Amphetamine Cocaine Diethylpropion Ephedrine Fenfluramine Isoetharine Methylphenidate Pemoline Phenylephrine Phenylpropanolamine Pseudoephedrine Sympathornimetics
Miscellaneous drugs
Albuterol Aspartame
Baclofen Bromide Calcium Cyclobenzaprine Cyclosporin A Cyproheptadine Dithyl -m -toluamide Diltiazem Flutamide Interferon L -Glutamine Mepacrine Metrizamide Oxandrolone Oxymetholone Procarbazine Procyclidine Propafenone Theophylline Tryptophan Yohimbine Zidovudine(AZT)
P.217 In patients with an underlying bipolar illness, treatment with antidepressants may precipitate a manic episode and change the pattern of cycling to more accelerated cyclic variations or change the severity of the manic behavior. L -dopa has been noted to have a similar property in some patients. 194 In a review of 128 case reports of drug-induced mania, Sultzer and Cummings 1 94 a noted that steroids, levodopa and other dopaminergic agents, proniazid, sympathomimetic amines, triazolobenzodiazepines, and hallucinogens were the agents most likely to cause secondary mania. Common characteristics of drug-induced manic episodes included hyperactivity, rapid speech, elevated mood, and insomnia. A majority of the patients had a personal history of mood disorder, a family history of a psychiatric disturbance, or symptoms of a mood abnormality at the time the inciting agent precipitated the manic episode.
Monozygotic twins have a concordance rate of 65% while dizygotic twins exhibit a 20% concordance rate. No specific mutation has been identified but linkage has been demonstrated and replicated to chromosomes 18 and 21. 196 While onset of bipolar illness in adolescence and mid -life is typically an inherited condition, late -onset mania (over 65) is typically associated with an underlying neurological condition. 4 4, 19 7 , 1 98 , 1 99 Neuroimaging has revealed abnormalities in patients with bipolar illness. Those with bipolar I disorder more commonly have periventricular hyperintensities, unlike bipolar II patients or normal controls. 2 00 Magnetic resonance imaging studies also reveal enlarged amygdalae in bipolar patients. 2 01 Studies with SPECT show marked right -left asymmetries of temporal perfusion during mania. 202, 2 03
Treatment of Mania
Mania usually impairs social and occupational function and requires treatment. Antimanic agents are outlined in Table 14.10. In the acute phase of management of a manic patient, an antipsychotic or sedating agent may be necessary. For control of mania and reduction of recurrence of manic episodes, lithium, carbamazapine, or valproate are typically used. Gabapentin and lamotrigine are newer anticonvulsants that may have mood -stabilizing properties. 2 0 4, 20 5 Clonazepam may be useful as an adjunct to mood stabilizer therapy. 20 4 , 2 0 6 Electroconvulsive therapy produces remission of mania in 80% of patients who have responded poorly to pharmacotherapy. 17 0
Usual Dosage
600 !1800
0.5!105 mEq/L
Lithonate; Lithotabs)
mg/day
N/A
1!3 g/day
50!125 #g/mL
Gabapentin (Neurontin)
N/A
Lamotrigine (Lamictal)
N/A
P.218 and mood disorders associated with violence and aggression are presented in Chapter 24 .
Ictal Fear
In his classic paper on emotions occurring in the course of epileptic seizures, Dennis Williams 2 07 called attention to the common occurrence of fear as an ictal experience. Of patients who experienced an ictal emotional disorder, 61% experienced fear as their primary emotion. Fear was most common when the epileptic lesion was in the anterior temporal region. Fear has been observed in patients with foci in either temporal lobe, but it appears to be more common in patients whose seizures originate in the right temporal cortex. 2 08 Fear is occasionally the only manifestation of temporal lobe seizures or status epilepticus and must be distinguished from panic attacks (Chapter 17 ). 209
Catastrophic Reactions
The frequency of catastrophic reactions in patients with
brain disorders is controversial. Agitation and aggression outbursts are common in dementia syndromes (Chapter 10 ) but they are less common in patients with focal brain injuries. Gainotti 210 described anxiety reactions as complex emotional syndromes including anxiety, tears, aggressive behavior, swearing, displacement activities, and refusal. He found such reactions to be more common in patients with left hemisphere lesions. More recent studies fail to confirm a lateral predominance of lesions but note that catastrophic reactions are more common in patients with depression, individuals with a personal or family history of psychiatric disorder, and patients with lesions in the basal ganglia. 21 1
loss of both aggressive and fear responses. 220, 2 21 The syndrome typically follows damage to the amygdalae and their cortical connections. 22 2 Emotionally, patients show a diminution in the amplitude of emotional responses. They fail to exhibit anger in provocative circumstances, are indifferent toward family and friends, and lack emotion related interests. Facial amimia and monotony of vocal expression are common accompaniments of the absence of emotion. 223 The characteristics of the syndrome overlap with apathy (Chapter 16 ) and the lack of engagement observed in patients with Alzheimer's disease (Chapter 10 ) and some frontal lobe disorders (Chapter 9 ).
Disturbances Of Affect
Disturbances of mood!the emotion experienced by the patient!must be distinguished from abnormalities of affect!the emotion expressed by the patient but not necessarily corresponding to an underlying mood state. In normal circumstances, mood and affect are congruent, but in many neuropsychiatric conditions the two may be dissociated. Three principal situations in which brain lesions result in alterations of affect are (1 ) pseudobulbar palsy; (2 ) ictal effective changes; and (3 ) motor disturbances such as
dysprosody, effecting vocal inflection, and parkinsonism, effecting facial emotional display.
Pseudobulbar Palsy
Exaggerated emotional expression and unintended laughing or unmotivated weeping occur in pseudobulbar palsy. The emotion expressed may be completely unrelated to the mood of the patient or may reflect the appropriate emotion but is out of proportion to the intensity of the feeling experienced. 2 28, 2 2 9 Patients may have episodes of either laughing or crying or both, and in some cases one affect may gradually change into the other, making it difficult to judge from the facial contortion which emotion is being displayed. Once initiated, the emotional expression is difficult or impossible to arrest, although with redirection of the conversation the patient's affect may be changed from weeping to laughter or vice versa. In general, older patients with pseudobulbar palsy tend to exhibit weeping as the primary affected manifestation, whereas younger patients tend to have exaggerated mirthless laughter. Pseudobulbar palsy is typically produced by bilateral lesions located in the corticonuclear tracks between the cerebral cortex and the brainstem. Table 14.11 presents the phenomenology of pseudobulbar palsy, demonstrating that the syndrome results from a combination of impaired supranuclear control and preserved or exaggerated function of subcortical and brainstem mechanisms. Volitional facial paresis occurs with lesions of the descending pyramidal tract, and pseudobulbar palsy results when lesions release motor programs of the limbic system and subcortical structures. The converse, the preservation of volitional facial movements with paresis of emotionally related facial expression, occurs with lesions of the limbic system including the frontal white matter, anterior thalamus, and insula. 230 In addition to the pseudobulbar affect, patients with pseudobulbar palsies have several other clinical features (Table 14.12). The three cardinal features of pseudobulbar palsy are disturbed emotional expression, dysarthria, and dysphagia. 229 Dysarthria is often severe and is characterized by imprecise articulation, slow speech rate, low pitch, and a strained-strangled sound of effortful phonation. Occasionally the dysarthria is so profound that the patient is completely unintelligible or mute. Lieberman and Benson 231 reported a patient with amyotrophic lateral sclerosis and severe pseudobulbar palsy who could not speak and eventually communicated only through eye movement Morse code. Examination of the face of pseudobulbar patients reveals a variety of signs of upper motor neuron dysfunction. The face is masked, showing little spontaneous emotional expression in the resting state and partial paralysis of the facial
muscles is common. Weakness of forced lip and eye closure is present and the patient has difficulty grimacing and voluntarily contracting the platysma. Tongue protrusion is weak. The jaw-jerk is exaggerated and the muscle stretch reflexes of the face, including the orbicularis oris and orbicularis oculi, are increased. Palatal movement is diminished when the patient is asked to phonate (say !aah! !) but the gag reflex response to posterior pharyngeal stimulation is hyperactive. Many patients also have supranuclear ophthalmoplegia, limb weakness and spasticity, exaggerated muscle stretch reflex of the limb, and extensor plantar responses. Martin 232 reported a 25 -year-old man who had an attack of uncontrollable laughter while attending his mother's funeral and a 23 -year-old woman who began laughing uncontrollably when a boxer was knocked P.220
Level/Function
CN III, IV, VI
CN V
CN VII
CN IX, X
CN XII
Tongue weakness
Swallowing
Dysphagia
Speech articulation
Dysarthria
Hypomimia
The clinical features reflect loss of supranuclear control and preservation or exaggeration of subcortical and brainstem mechanisms. CN, cranial nerve.
from the ring and fell almost at her feet. In both cases, pseudobulbar palsy was associated with a brainstem aneurysm and acute subarachnoid hemorrhage. A few such patients have literally died laughing when acute pseudobulbar palsy with sustained laughter was initiated by a fatal event. Martin 23 2 commented that !this is the greatest mockery of all when the patient should be forced to
Dysarthria
Dysphagia
Drooling
Facial amimia/hypomimia
Supranuclear ophthalmoplegia
Limb weakness
Pseudobulbar palsy has been produced by multiple sclerosis, traumatic brain injury, amyotropic lateral sclerosis, progressive supranuclear palsy, meningiomas of the clivus, vascular dementia, anoxic brain injury, encephalitis, basal artery aneurysms, chordomas of the clivus, brainstem tumors, Creutzfeldt -Jakob disease, and neurosyphilis. 2 33, 23 4 Bilateral lacunar infarctions in the internal capsule disconnecting the descending supranuclear pathways from brainstem mechanisms are a particularly common cause of pseudobulbar palsy. 23 5 , 2 36 Rarely, apparently unilateral lesions of the limbic system may result in the acute onset of sustained laughter, which gradually subsides over a period of days or weeks. 237 A variety of types of medications may be successful in reducing the affective dyscontrol associated with pseudobulbar palsy. Levodopa, tricyclic antidepressants including amitriptyline and nortriptyline, and SSRIs have all been successful in ameliorating pseudobulbar palsy. 238 , 23 9, 24 0 , 2 41
Ictal Affect
Alterations of emotional expression in epilepsy may be secondary to mood changes caused by the focal seizure or may be sham emotional responses induced by the focal epileptic activity. Patients are frequently amnestic P.221 for the period of the seizure and distinction between these two causes of altered emotional expression may be impossible in some cases. The two principal affective alterations described in epilepsy involve either laughing or crying. Ictal seizures with pronounced changes in affect during the ictus include complex partial seizures, infantile spasms, and seizures associated with hypothalamic lesions. In adults, ictal affect is typically a manifestation of limbic epilepsy and complex partial seizures. Seizures manifesting
laughter as an ictal automatism have been called !gelastic! ! seizures, and those with ictal crying have been called quiritirian (meaning to scream or cry) or !dacrystic! ! (meaning to tear). 242, 24 3, 24 4 Ictal laughter is more common in epileptic patients than ictal crying. The laughter is inappropriate, stereotyped, and occurs without a precipitating stimulus. There is frequently an associated alteration of consciousness, and other seizure manifestations may be evident. Postictal confusion is typically present and the patient is usually amnestic for the event. Psychiatric and psychomotor phenomena accompanying the laughter may include running (cursive epilepsy), macropsia and metamorphopsia, deja -vu feelings, olfactory hallucinations, feelings of sexual orgasm, or limb or verbal automatisms. When consciousness persists during the attacks, the laughter is usually recalled as being disagreeable and incongruent, not the pleasurable experience the affect would suggest. 24 3 Lesions producing gelastic seizures have most commonly been in the right hemisphere and involve the mesiofrontal anterior cingulate or the anteromesial temporal regions. 2 45, 2 4 6 Treatment of gelastic and dacrystic seizures is with the same medications indicated for the treatment of complex partial seizures (Chapter 21 ). Infantile spasms (Chapter 21 ) is a form of primary generalized seizure disorder occurring in infants and young children. It results from a wide variety of CNS disturbances and laughter may be one manifestation of the seizures. The laughing varies from prolonged violent attacks lasting for as long as several minutes or short periods of giggling or grinning. The epileptic nature of the laughter is indicated by the lack of external precipitants, the odd nature of the laughter (mothers recognize it as uncharacteristic of their children), the accompanying manifestations of epilepsy, motoric evidence of seizure activity, and the response to anticonvulsants. The third clinical syndrome in which ictal laughter occurs is in association with hamartomas involving the hypothalamus. The characteristic syndrome in which hypothalamic hamartomas and ictal laughter are associated is characterized by onset of laughing seizures in infancy, normal early childhood psychomotor development, increasing length of seizures and appearance of other seizure types between ages 4 and 10, and progressive cognitive deterioration and severe behavioral problems in late childhood and early adolescence. Seizure control with anticonvulsants or cortical resection is poor. 24 7 The hamartomas can typically be visualized by MRI and SPECT performed during the epileptic attack, and such studies show hyperperfusion in the hypothalamic region and adjacent thalamus without cortical or cerebellar changes. 2 48 The
laughter associated with the epileptic syndrome of hypothalamic hamartomas is described as pleasant laughter or giggling lasting a few seconds and occurring two to six times per day. The seizures continue daily throughout early childhood and may persist into later childhood and adolescence. 2 47 Treatment with anticonvulsants is usually partially effective at best; corticectomies have produced little improvement, and anterior corpus callosotomy may reduce some types of associated seizures. 2 49
Angelman Syndrome
Angelman syndrome, disparagingly referred to as the !happy puppet syndrome,!! 2 50 is an unusual disorder characterized by mental deficiency, abnormal puppet -like gait, a characteristic facies (described below), and frequent paroxysms of laughter. Also characteristic are microcephaly, maxillary hypoplasia, a large mouth with tongue protrusion, and widely spaced teeth. Prognathia is present and there is decreased pigmentation of the choroid and iris, the latter resulting in pale blue eyes. Seizures are common.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 15 - Apathy and Other Personality Disorders
Apathy
Apathy or decreased motivation can affect performance on nearly all aspects of cognitive, instrumental, or interpersonal functions. The loss of motivation to engage in previously enjoyable behaviors is sometimes associated with depression; however, apathy can be present in the absence of sadness. 2,3 Apathy is perhaps most severe in akinetic mutism resulting from anterior cingulate lesions or from damage to this region's frontal-subcortical circuit. 4 In patients suffering from cerebrovascular disease, apathy is greatest in those with subcortical and right frontal lesions involving the anterior cingulate and related structures. 4
Apathy is the most prominent neuropsychiatric symptom in degenerative dementias including Alzheimer's disease (AD), 5 frontotemporal degeneration (FTD), 6 progressive supranuclear palsy (PSP) 7 and the dementia of Parkinson's disease (PD). 8 In AD and in individuals with mild cognitive impairment (MCI), functional defects in the anterior cingulate appear to subserve the manifestation of apathy, thus supporting a major role for the anterior cingulate in general motivation across disease etiologies (see Fig. 15.1 ). 9 , 10 Placidity is a personality alteration that has frequently been observed in association with bilateral limbic system lesions; it has been reported in patients with the Kl"ver -Bucy syndrome, the Wernicke -Korsakoff syndrome, and following frontal lobotomy. Apathy may respond to psychostimulants 11 and apathy in AD often improves following treatment with cholinesterase inhibitors (Chapter 10 ). P.229
FIGURE 15.1 Statistical parametric map derived from technetium!99m D, L hexamethylpro -peleneamine oxime ( 9 9 m Tc-HMPAO) single photon emission computed tomography (SPECT) of patients with mild cognitive impairment (top row) and patients with Alzheimer's disease (bottom row}. The map shows the location of anterior cingulate hypoperfusion in those with high apathy scores compared to those with low apathy scores as measured by the Neuropsychiatric Inventory. Adapted from Migneco et al. (2001). 10
Personality Disorder
Dependent personality
Histrionic personality
Narcissistic personality
Compulsive personality
Schizoid personality
Avoidant personality
Schizotypal personality
Antisocial personality
Borderline personality
Paranoid personality
Brain damage
Organic personality
EEG, electroencephalogram.
temporal volume conducted in female patients with borderline personality disorder showed significant hippocampal and amygdalar atrophy in patients compared to controls. 1 5 These findings may represent the effect of stress on the medial temporal lobe and not the relationship of these brain regions to the borderline personality, since hippocampal atrophy was significantly related to the extent and duration of early traumatic experiences. Functional defects implicate medial frontal, orbitofrontal, superior temporal, insular, thalamic, and striatal metabolic dysfunction 1 6 , 1 7 in patients with borderline personality disorder on positron emission tomography (PET). Patients using fenfluramine have a more blunted metabolic response to serotonergic challenge than controls in bilateral anterior cingulate/orbitofrontal, left superior and middle temporal, and left parietal cortex as well as the left body of the caudate, this response implicates a serotonergic defect in patients. 17 Support for a serotonergic defect in borderline personality disorder has been found with -[ 1 1 C]methyl-L tryptophan ( 1 1 C -MTrp) PET, reflecting serotonergic synthetic capability. In one study, patients demonstrated significantly decreased 1 1 C -MTrp -PET in medial frontal, superior temporal, and striatal regions (Fig. 15.2 ). 18 The
overlap of these functional imaging studies supports a medial and orbitofrontal abnormality that may subserve the impulsive aggression demonstrated by patients with the borderline personality disorder. The personality change syndrome described in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (1994) 1 is characterized by emotional lability and impaired impulse control. It most closely resembles the personality alteration that follows damage to the orbitofrontal aspects of the brain, as discussed in the following paragraphs and in Chapter 9 . The principal clue that an acquired neurological disorder is responsible for a particular personality pattern is the occurrence of a sudden change in the patient's behavioral style. Regardless of the type of change manifested, the patient who suddenly exhibits an altered personality is often harboring a neurological illness. The types of personality change induced by neurological disease may be variable, and most current personality nosologies are inadequate to account for the diversity of personality changes that have been noted in patients with neurological disturbances. Table 15.2 lists some of the personality changes reported in patients with specific neurological conditions. Damage to the frontal lobe may produce different behavioral alterations, depending on the site of the lesion (Chapter 26 ). Patients with orbitofrontal injuries lack tact and restraint. They are often irritable, facetious, and euphoric and tend to be uncritical, disinhibited, and impulsive. Patients with lesions of the medial frontal lobes, by contrast, are apathetic and indifferent, and they lack initiative. Combinations of frontal lobe symptoms are common. 1 9 Frontal lobe syndromes occur with frontal neoplasms, demyelinating P.231
FIGURE 15.2 Statistical maps of alpha -[ 11 C]methyl-L tryptophan ( 11 C -MTrp) positron emission tomography (PET) reflecting significantly decreased serotonergic synthetic capability in patients with borderline personality disorder compared to controls. The top maps reveal significantly decreased regions of 1 1 C MTrp -PET signal in eight female patients, while the bottom maps show regions of significant decrease in five males. Adapted from Leyton et al. (2001). 1 8
disorders, degenerative diseases, and infectious and inflammatory illnesses and are particularly common following closed head injury. Correlation of personality alterations with the lateralization of brain injuries has received little study, but a few observations are available. Patients with left hemisphere lesions may become depressed or paranoid. 20 Patients who sustain right hemisphere damage as adults manifest denial of illness and tend to be abnormally euthymic. 2 1 Injury to the right hemisphere occurring early in life may lead to a personality pattern characterized by shyness, depression, isolation, and schizoid behavior. 1 9 The schizotypal personality disorder has been associated with atrophy of the prefrontal region, 22 increased sulcal space 2 3 and lateral ventricles 2 4 , 2 5 with predominant enlargement of the left temporal and frontal ventricles; 2 6 decreased temporal lobe volume 2 7 with possible focal gray matter loss in the left superior temporal gyrus, 28 and decreased
mediodorsal thalamic and pulvinar volumes 29 compared to controls. The existence of a personality pattern specifically associated with epilepsy is controversial, but considerable evidence suggests that patients with seizure disorders, particularly those with complex partial seizures, are subject to several types of personality alteration. 30 One characteristic personality change consists of interpersonal viscosity, circumstantial speech, religiosity and increased attention to nascent philosophical concerns, hyposexuality, and hypergraphia (Chapter 21 ). 3 1 The personality syndrome is not pathognomonic of epilepsy and occurs in other psychiatric disorders, but its emergence after the onset of a limbic system injury implies the existence of a relationship between the lesion site and the development of the behavioral characteristics. Pond and Bidwell 32 found this type of personality alteration in approximately 5% of all epileptics followed P.232
Neurological Condition
Personality Alteration
Orbitofrontal
Mediofrontal
Left
Paranoia, depression
Right
Adult onset: denial, neglect, paranoia Childhood onset: shyness, depression, social isolation
Epilepsy
Epileptic personality: viscosity, circumstantiality, religiosity, hyposexuality, hypergraphia Borderline personality: paranoia
in general medical practices in Great Britain. Another personality pattern found in epileptics is the borderline personality disorder described above. Personality alterations occur with many neurological disorders in addition to those described here, but this aspect of neuropsychiatry has received little systematic study. Alterations in personality also overlap with the chronic changes in mood, described in Chapter 14 .
References
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 16 - Obsessive -Compulsive Disorder and Syndromes with Repetitive Behaviors
or compulsions that are excessive or unrealistic, cause marked distress, and are not limited to the specific content of a co -occurring disorder (e.g., preoccupation with food in an eating disorder or hair pulling in trichotillomania). 1 The incidence of OCD is approximately 7.5 new cases per 1000 persons; 1 -year prevalence rates of approximately 1.65% have been identified and lifetime prevalence rates in North American populations have been found to be between 2.6% and 3.2%. 2 The mean age of onset of OCD symptoms is 21 to 25 years, although 20% of cases begin in childhood and 30% begin in adolescents. Long -term follow -up studies indicate that the course is chronic and fluctuating, with most patients experiencing some degree of improvement after several decades of symptoms. Twenty percent of patients exhibit complete recovery and an additional 30% have only residual subclinical symptoms. 3 Table 16.1 provides a list of obsessions and compulsions observed in OCD patients that is derived from the Yale Brown Obsessive Compulsive Scale. 4 , 5 Among the most common obsessions occurring in patients with OCD are concerns regarding contamination, pathologic doubt (e.g., concerning having hurt or contaminated P.235
Obsessions
Compulsions
Aggressive obsessions
Checking compulsions
Contamination obsessions
Repeating rituals
Rereading or rewriting
Need to repeat routine activities (e.g., going in and out of a door, or getting up and down from a chair)
Sexual obsessions
Counting compulsions
Miscellaneous compulsions
Mental rituals
Religious obsessions
Superstitious behaviors
Somatic obsessions
Trichotillomania
Miscellaneous obsessions
Intrusive
Superstitious fears
P.236 someone or something), excessive somatic concerns (e.g., regarding illness, disease, or bodily appearance), need for symmetry, aggressive obsessions, and sexual obsessions. Among the most common compulsions are checking, washing, counting, experiencing the need to ask or confess, excessive need for symmetry and precision, and hoarding. 6 Factor analysis of the symptoms collected using symptom rating scales suggests that four general areas of concern and behavior account for most symptoms of OCD: checking, symmetry and ordering, cleanliness and washing, and hoarding. 7 The obsessional and compulsive symptoms of OCD vary in severity from mild to extremely disabling. Patients with severe OCD may take many hours to perform toileting rituals, cleaning, washing, and arranging. The symptoms of childhood and adolescent onset of OCD are essentially identical to those of adult OCD. 8 ,9 , 1 0 Patients with Gilles de la Tourette's syndrome frequently suffer from OCD (Chapter 19 and discussed below). Patients
with OCD and Gilles de la Tourette syndrome have significantly more violent, sexual, and symmetry obsessions, and more touching, blinking, counting, and self -damaging compulsions. Patients with OCD without a concurrent tic disorder have more obsessions concerning dirt or germs and more cleaning compulsions. 1 1 Neuropsychological deficits have been observed consistently in patients with OCD. Executive abilities, verbal memory, attention, and intelligence are normal when compared to unaffected controlled populations. However, spatial working memory, spatial recall, and speed of motor initiation and execution (on executive tasks, such as the Tower of London planning task) are impaired. 12 , 1 3, 1 4, 1 5 These neuropsychological abnormalities distinguish patients with OCD from those with social phobia, unipolar depression, and panic disorder. 13 , 1 4 The deficits suggest an abnormality of frontal-striatal processing of nonverbal information. Patients with OCD frequently have coexisting major mental illnesses. Among OCD patients the lifetime risk of major depressive disorder is approximately 70%; simple phobia, 20%; social phobia, 20%; eating disorder, 20%; alcohol dependence, 14%; panic disorder, 12%; separation anxiety disorder, 2%; and Gilles de la Tourette syndrome, 10%. 6 Comorbid psychiatric disorder must be distinguished from OCD -spectrum disorders and from illnesses that have repetitive behaviors as major manifestations (discussed below). The heredity of OCD has been difficult to define with precision and no single mutation has been found to be responsible for the disorder. Twin studies and family studies support a model of polygenic inheritance with at least one major gene effect. 16 , 17 Familial studies of patients with Gilles de la Tourette syndrome and chronic multiple tics show an increased prevalence of OCD among first -degree relatives, suggesting that some forms of OCD may be alternate expressions of a pathophysiology shared with tic syndromes. 18
Caudate nuclear volume is subtly but significantly smaller in patients with OCD than in healthy controls when measured with either X-ray computed tomography (CT) or magnetic resonance imaging (MRI). 19 , 20 Functional imaging using fluorodeoxyglucose (FDG) positron emission tomography (PET) consistently reveals hypermetabolic activity of the brain in OCD compared to the activity in normal controls. Brain regions most consistently observed to be hypermetabolic include the orbitofrontal cortex, anterior cingulate cortex, and heads of the caudate nuclei. 8, 9,1 0, 2 1, 2 2, 23 Similarly, studies with technetium hexamethyl -propyleneamineoxime (Tc -HMPAO) single-photon emission computed tomography (SPECT) indicate increased cerebral blood flow in the orbitofrontal cortex and medial frontal cortex as well as in dorsal parietal regions. 2 4 , 2 5 Regional activation of cortical structures has been investigated in patients with OCD using PET or functional MRI to measure changes in regional cerebral blood flow (rCBF). 26, 27 Exposure to provocative stimuli (pictures of a person about whom the patient had sexual and violent obsessions or objects considered to be contaminated and offensive to patients with contamination obsessions) resulted in increased blood flow in anterior cingulate orbitofrontal, anterior temporal, insular, and caudate nuclear regions. Significant reductions in regional brain metabolism and blood flow have been documented following pharmacotherapy or behavioral therapy in patients who exhibited a clinical response to the treatment intervention. 2 8 , 2 9 , 3 0, 3 1
Pathophysiology
There is no established pathology of OCD and the putative pathophysiology of OCD is inferred from abnormalities observed on structural and functional imaging studies, as well as from the anatomical distribution of lesions associated with OCD in patients with acquired OCD syndromes (described below). Substantial evidence impugns frontalstriatal circuitry in the mediation P.237 of OCD. Five frontal-striatal thalamic circuits have been described 32 connecting supplementary motor cortex, frontal
eye fields, dorsolateral prefrontal cortex, anterior cingulate cortex, and orbital frontal cortex to striatal and thalamic structures. In each circuit a direct excitatory link is in dynamic balance with an indirect inhibitory link. 3 2 Orbitofrontal cortex is involved in modulating socially appropriate behaviors and when impaired, results in tactless, impulsive, disinhibited behavior (Chapter 9 ). Medial frontal cortex mediates motivation, persistence, and environmental engagement. 3 3, 34 Hyperactivity of these regions may result in abnormal capture of cognitive themes relating to violence, hygiene, order, and sex, the subjects of obsessions and compulsions in OCD. 35 This abnormality may result from an imbalance between inhibitory and excitatory pathways within frontal-striatal circuits and could reflect abnormalities at frontal, striatal, pallidal, or thalamic nuclear levels. 3 5 , 3 6 , 3 7 The response of these symptoms to serotonergic therapy (described below) suggests that serotonergic input in these circuits is critical to normal function and is disturbed in patients with OCD. 3 8 Figure 16.1 demonstrates the frontalstriatal pathways implicated in mediation of OCD.
FIGURE 16.1 Frontal -subcortical circuits implicated in the mediation of obsessive -compulsive disorder (orbitofrontal cortex, globus pallidus, medial thalamus).
P.238
Disorder
Obsessional Symptoms
Anorexia nervosa
Hypochondriasis
Obsessions about being ill and compulsions to check with others for either diagnosis and treaiment or reassurance that one is not ill
Trichorillomania
Compulsive hair -pulling in which the patient is unable to resist impulses to pluck hair from scalp, eyebrows, eyelashes, or other body regions
Ego -dystonic intrusive thoughts about sexual matters or compulsive sexual hyperactiviry such as promiscuity or compulsive masturbation
Pathologic gambling
Preoccupation with gambling and urges to gamble resulting in irresistible gambling impulses
Compulsions to remove small irregularities on the skin (e.g. blemishes, dry skin), usually associated with extensive cleaning rituals
Pseudologia fantastica
Pyromania
Kleptomania
Impulsive theft
anorexia nervosa, hypochondriasis, trichotillomania, sexual obsessions and compulsions, pathological gambling, self mutilation, alcohol and substance abuse, compulsive skin picking, compulsive drinking, and pathological
lying. 3 9, 40, 41 , 4 2 , 43 , 4 4, 4 5, 46 , 47 , 4 8 The relationship of these disorders to OCD is a subject of current research; recognizing these disorders to be within the OCD spectrum may facilitate treatment choices for some patients. Impulse control disorders may also bear a relationship to OCD and OCD -spectrum disorders. They share with OCD the inability to resist specific behaviors although their phenomenology differs in many other respects. Impulse control disorders include intermittent explosive disorder (episodic loss of control of aggressive impulses), pyromania (impulsive, repetitive, deliberate fire -setting), and kleptomania (impulsive stealing). 4 9 A variety of neurological and psychiatric disorders have been associated with obsessive -compulsive behaviors (Table 16.3 ). The most common clinical circumstances in which OCD is encountered include mental retardation syndromes, particularly those with autistic features; post-encephalitic Parkinson's disease; Sydenham's chorea; Gilles de La Tourette syndrome; and frontotemporal degenerations. 8 ,9, 10 , 1 1, 5 0, 5 1, 5 2, 5 3 , 54 , 55 , 5 6 , 5 7, 5 8 , 5 9 , 6 0, 6 1 , 6 2 In addition, OCD has been induced by cocaine, psychostimulants, and manganese intoxication. 6 3 , 64 Obsessions and compulsions may occasionally be seen in patients with schizophrenia or major depression. 6 5 , 6 6
of haloperidol or an other neuroleptic agent may further improve the response in treatment -refractory P.239
TABLE 16.3. Neurological Conditions in Which ObsessiveCompulsive Disorder Has Been Reported
Condition/Disorder
Subtype(s)
Degenerative disorders
Frontotemporal dementia
Huntington's disease
Parkinson's disease
Neuroacanthocytosis
Brain tumors
Frontal
Striatal
Cerebral infarction
Striatal
Fragile X syndrome
Epilepsy
Temporal lobe
Cingulate
Sydenham's chorea
Meige's syndrome
(idiopachic blepharospasm)
Head injury
Multiple sclerosis
Hypoglycemia
Intoxications
Amphetamine
Cocaine
Manganese
Lesch-Nyhan syndrome
Mental retardation
Autism
Asperger's syndrome
OCD -spectrum disorders may respond to the same treatments used for OCD. In some cases, self -injurious behavior (discussed below) has responded to treatment with opioid antagonists such as naloxone. In patients refractory to pharmacotherapy, ECT may provide an effective alternative. 72 Patients with treatment -refractory and very disabling OCD may be considered for psychosurgery. Stereotactic anterior capsulotomy, cingulotomy, and ventromedial leukotomy may produce beneficial effects. 7 3 P.240
dementia. 51, 52, 76 , 7 7, 7 8, 79 Head banging (jactatio capatis) is a specific type of stereotypic movements observed most commonly in mental retardation but may occur in any of the SIB disorders. 7 7 Self-injury syndromes have been treated with neuroleptic agents, opioid antagonists, selective serotonin reuptake inhibitors, proponalol, carbamazepine, and lithium. 80 Obsessive -compulsive behavior must occasionally be distinguished from other types of repetitive motor acts (Table 16.5 ). These include echolalia, palolalia, coprolalia, echopraxia, copropraxia, perseveration, stereo-typies, mannerisms, chorea, dyskinesia, stereotypic hand waving, stereotypic catatonia, and tics. Diogenes' syndrome (also known as senile squalor) refers to a disorder observed in the elderly of hoarding or abnormal accumulation of trash and useless objects. 8 1 Kluver-Bucy syndrome and the temporal lobe epilepsy personality are two other neurological conditions in which obsessive and compulsive-like behaviors are observed. Kluver-Bucy patients exhibit hypermetamorphosis, a syndrome characterized by compulsive exploration of high -stimulus items in the environment. 82 Patients with temporal lobe epilepsy personality exhibit circumstantiality, hypergraphia, and overinclusive involvement with religious and philosophical topics (Chapter 21 ).
TABLE 16.4. Neurologic and Psychiatric Syndromes Associated with Self-Injurious Behavior
Acute intoxications
Transexualism
Mental retardation
Mental retardation
Autism
Lesch-Nyhan syndrome
Rett syndrome
Aicardi syndrome
Goubert syndrome
Fragile X syndrome
Asperger's syndrome
Neuroacanthocytosis
Frontotemporal dementia
Personality disorders
Sadomasochistic disorder
Flagellation
Piercing
Combat disorder
P.241
Movement
Manifestation
Echolalia
Palolalia
Coprolalia
Involuntary cursing
Myoclonus
Tics
Chorea
Dyskinesia
induced
Mannerisms
Perseverarion
Catatonia
Hoarding
Hoarding and accumulation of trash or useless material; also known as Diogenes syndrome
Hypermetamorphosis
Component of the KluverBucy syndrome with compulsive exploration of high -stimulus items in the environment
Personality alteration associated with focal temporal dysfunction, characterized by over detailed explanations, writing, and concern with philosophical and religious topics
In some cases, these phenomena may respond to treatment used to manage OCD.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 17 - Anxiety Disorders
discussed with other repetitive behaviors in Chapter 16 . P.245 Panic attacks are discrete periods of intense fear or discomfort accompanied by a variety of somatic or cognitive symptoms that begin suddenly and build to a peak rapidly (usually 10 minutes or less). The subject has a sense of imminent danger or impending doom and has a desire to escape the situation. Panic attacks occur in several different anxiety disorders including panic disorder, social phobia, specific phobia, post-traumatic stress disorder, and acute stress disorder. Panic disorder is characterized by recurrent unexpected panic attacks. Agoraphobia is anxiety about being in places or situations from which escape might be difficult or embarrassing and in which help may not be available in the event of a panic attack or panic symptoms. Agoraphobia leads to avoidance of these situations, such as being outside the home alone, being in a crowd of people, traveling in an automobile, bus, or airplane, or being on a bridge or in an elevator. Social phobia features marked and persistent fear of social or performance situations in which embarrassment may occur. Social phobia often occurs when anxious anticipation is normal but the individual's response in this situation is excessive and disabling. Specific phobia (also called simple phobia) is characterized by marked and persistent fear of clearly discernable circumscribed objects or situations. Individuals may fear travel in airplanes because of concern about crashing, may fear dogs because of concerns about being bitten, or may fear driving because of concerns about being hit by other vehicles on the road. They may be afraid of blood and injury, or fear being in closed-in situations. Post -traumatic stress disorder includes persistent reexperiencing of a traumatic event, persistent avoidance of stimuli associated with the trauma, numbing of general responsiveness, and persistent symptoms of increased arousal. The syndrome follows exposure to an extreme traumatic stressor that entails direct personal experience of an event in which actual or threatened death or serious injury occurred or the witnessing of an event that involves death, injury, or threat to the physical integrity of another person. Acute stress disorder comprises anxiety, dissociative, and other symptoms that occur within 1 month after exposure to an extreme traumatic stressor. In generalized anxiety disorder, patients experience excessive anxiety and worry, on most days for a period of at least 6 months, about numerous events or activities. Substance -induced anxiety disorder is characterized by prominent anxiety symptoms judged to be due to the direct physiological effects of a substance (discussed below). Anxiety disorder due to a general medical condition is clinically significant anxiety judged to be due to the direct physiological effects of a general medical condition (described below). 1 Neurological, medical, and drug-induced anxiety are emphasized in this chapter and would usually be classified as anxiety disorder due to a general medical condition or substance -induced
anxiety disorder. These conditions provide insight into the neurobiology of anxiety by implicating structural and biochemical changes in brain regions involved in mediating anxiety symptoms.
Cognitive Symptoms
Behavioral Signs
Nervousness
Hyperkinesis
Tachycardia
Apprehension
Palpitations
Racing thoughts
Chest tightness
Worry
Dry mouth
Fearfulness
Pressured speech
Hyperventilation
Irritability
Startle response
Pareschesias
Distractibiliry
Light headedness
Dread
Urge to urinate
Desire to escape
Sweating
Tremor
Depersonalization/derealization
Anxiety tremors are typically high -frequency, low -amplitude tremors involving the hands and occasionally the lower extremities (Chapter 18 ).
hospitalized for stroke, 27% experienced early -onset generalized anxiety disorder and an additional 23% experienced the onset of anxiety symptoms 3 or more months after the stroke. Depressive symptoms were present in 75% of the patients. Anxiety symptoms commonly lasted 1 and " to 3 months and were not related to social, cognitive, or physical disability. 1 1 Anxiety was recorded in 20% of a population -based study of Parkinson's disease 6 and has been observed in 30%!40% of clinically based samples. 1 2 , 1 3 In Parkinson's disease, anxiety commonly co -occurs with depression and when the on -off phenomenon develops, it is more severe during the off period. 14, 1 5 Among patients with focal lesions, a relationship has emerged between anxiety or panic and temporal lobe lesions, predominantly those affecting right sided structures. 1 6 , 1 7 , 1 8 , 1 9 , 2 0 These focal brain lesions have included post-traumatic encephalomalacia, compressive meningiomas, metastatic brain tumors, and primary intraparenchymal brain tumors. Anxiety has been observed in patients with Wilson' disease, central nervous system syphilis, and
Stroke
Parkinson's disease
Multiple sclerosis
Huntington's disease
Wilson's disease
Encephalitis
Syphilis
Meningiomas
Epilepsy
P.247 encephalitis. 2 1 Anxiety has been recorded in 10%!50% of patients with Huntington's disease. 2 2 Typical anxiety symptoms can occur in the course of partial complex seizures originating in the temporal lobes. 2 3 , 2 4 Ictal attacks with panic symptoms are usually more brief and more stereotyped than classical panic attacks, and in some cases they progress to partial complex or generalized seizures. Patients are amnestic for the attacks, in contrast to panic disorders occurring in the absence of epilepsy, which can be recalled. Patients with atypical panic attacks should be investigated for possible partial complex seizures. 2 5 Electroencephalographic (EEG) abnormalities are uncommon in classical anxiety disorders. 2 6 In some cases, panic symptoms in patients with EEG abnormalities in the temporal regions may respond to anticonvulsant therapy even in the absence of a diagnosis of epilepsy. 2 7 , 2 8 Anxiety has been reported in a large number of medical illnesses (Table 17.3 ). Cardiopulmonary disease and hypoxia are commonly associated with anxiety, and anxiety has been associated with angina, cardiac arrhythmias, congestive heart failure, asthma, acute pulmonary emboli, mitral valve prolapse, and pneumothorax. Endocrine disorders associated with anxiety include hyperthyroidism, hypothyroidism, parathyroid dysfunction, Cushing's disease (hyperadrenalism) and other adrenal abnormalities, pheochromocytoma, and virilization disorders of females. Gastrointestinal disorders associated with anxiety include peptic ulcer, gastrointestinal reflux, ulcerative colitis, and irritable bowel syndrome. Inflammatory conditions that have induced anxiety include lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, and temporal arteritis. Deficiency states, including deficiencies of vitamin B 1 2 , vitamin B 1 vitamin B 6 , niacin, and folk acid, have also been related to anxiety states. Other conditions that have been related to anxiety include hypoglycemia, carcinoid syndrome, systemic malignancies, premenstrual syndrome, febrile illnesses, porphyria, infectious mononucleosis, post-hepatic syndrome, uremia,
hepatic failure, tuberculosis, brucellosis, cerebral malaria, and mastocytosis. 2 1 , 2 9 , 3 0 , 3 1 , 3 2 , 3 3 , 3 4 , 3 5 , 3 6 Many types of drugs have been associated with the emergence of anxiety disorders (Table 17.4 ). In some cases it has been difficult to distinguish anxiety from the threats to life and survival that are associated with being ill, anxiety induced by the medical illness itself, and anxiety induced by treatment. In the conditions described here, anxiety was reported to emerge with introduction of therapy and to subside with its withdrawal. Classes of drugs associated with monoaminergic
TABLE 17.3. Medical and Systemic Disorders Associated with Anxiety Syndromes
Disorder Type
Specific Disorders
Cardiopulmonary diseases
Angina
Cardiac arrythmias
Pulmonary embolis
Pneumothorax
Endocrinopathies
Hyperthyroidism
Hypoglycemia
Pheochromocytoma
Hypoparathyroidism
Carcinoid syndrome
Gastrointestinal disorders
Peptic ulcer
Gastrointestinal reflux
Ulcerative colitis
Deficiency states
Vitamin B 1 2
Vitamin B 6
Vitamin B 1
Niacin
Folic acid
Rheumatoid arthritis
Polyarteritis nodosa
Temporal arteritis
Mononucleosis
Tuberculosis
Brucellosis
Cerebral malaria
Febrile illnesses
Miscellaneous conditions
Premenstrual syndrome
Prophyria
Nephritis
Uremia
Hepatic failure
P.248
TABLE 17.4. Medications, Illicit Substances, Withdrawal Syndromes, and Toxic Compounds Associated with Anxiety Syndromes
Medications
Illicit Substances
Withdrawal Syndromes
Toxic Substances
Oxprenolol
Canuabmois
Barbiturates
Benzene
Captopril
Alcohol
Alcohol
Carbon disulfide
Amantadine
Ecstasy
Benzodiazepines
Heavy metals
Bromocriprine
Amphetamines
Mercury
Levodopa
Corticosteroids
Organophosphates
Salicylates
Propanolol
Organic solvents
Narcotics
Reserpine
Barbiturates
Ethosuximide
Tricyclic antidepressants
Tricyclic antidepressants
Caffeine
Buproprion
Meprobamate
Fluoxetine
Nicotine
Penicillin
Opiates
Cycloserine
Anticholinergics
Dapsone
Aspartame
Sulfonamides
Procaine penicillin
Isoniazid
Interferon
Lidocaine
Digitalis
Corticosteroids
Thyroid hormones
Cocaine
Sympathomimetics
Amphetamine
Fenfluramine
Diethylpropion
Caffeine
Methylphenidate
Pemoline
Pheny Ipropanolamine
Isoproterenol
Theophylline
Yohimbine
Nicotinic acid
P.249 metabolism induce anxiety more frequently than other types of compounds, which suggests an important role for monoaminergic substances in the mediation of anxiety symptoms and signs. Agents associated with anxiety include oxprenolol, captopril, amantadine, bromocriptine, levodopa, salicylates, narcotics, barbiturates, ethosuximide, tricyclic antidepressants, buproprion, fluoxetine, penicillin, cycloserine, dapsone, sulfonamides, procaine penicillin, isoniazid, interferon, lidocaine, monoamine oxidase inhibitors, digitalis, corticosteroids, thyroid hormones, all classes of central nervous system (CNS) stimulants, theophylline, yohimbine, and nicotinic acid. 2 1 , 3 3 , 3 4 , 3 7 Intramuscular injection of procaine G penicillin has been associated with Hoigne's syndrome, which is characterized by doom, anxiety, psychosis, and seizures. 3 8 Illicit substances associated with anxiety include cannabinols, cocaine, amphetamines, alcohol, and ecstasy. 3 7 , 3 9 , 4 0 Withdrawal syndromes are frequently associated with autonomic hyperactivity and anxiety. Withdrawal from the following substances has been observed to produce signs and symptoms of anxiety: barbiturates, alcohol, benzodiazepines, amphetamines, chlorohydrate, corticosteroids, propanolol, reserpine, monoamine oxidase inhibitors, tricyclic antidepressants, caffeine, meprobamate, nicotine, opiates, and anticholinergics. 3 4 , 3 7 Central nervous system stimulants associated with anxiety include cocaine, sympathomimetics, amphetamine, fenfluramine, diethylpropion, caffeine, methylphenidate, pemoline, phenylpropanolamine, and isoproterenol. 3 7 Exposure to toxic substances in the course of a variety of occupations has been related to the occurrence of anxiety. Compounds thought to induce anxiety signs and symptoms include aspartame, benzene, carbon disulfide, heavy metals, mercury, organophosphates, phosphorus, and organic solvents. 3 7, 4 1
perihippocampal area. 4 4 Patients with social phobia were found to have markedly decreased striatal dopamine reuptake site density compared to that in normals. 4 5 Patients vulnerable to lactate-induced panic have abnormal cerebral blood flow compared to control subjects, and they have abnormally high perfusion in the inferior frontal cortex and left occipital cortex and significantly lower perfusion in the hippocampal regions bilaterally. 4 6 Lactate infusion results in greater increases of brain lactate in patients with lactate-induced panic than in control subjects. Elevations are also more prolonged in the brain and are decoupled from falling blood lactate levels. 4 7 Hyperventilation also causes a disproportionate increase in brain lactate levels in subjects with panic disorder. 4 8
Benzodiazapines
Alprazolant (Xanax)
1!4
Chlordiazepoxide (Librium)
15!40
Clonazepam (Klonopin)
1!6
Clorazepate (Tranxene)
15!60
Diazepam (Valium)
5!40
Hakizepam (Paxipam)
60!160
Lorazepam (Ativan)
1!6
Oxazepam (Serax)
45!120
Fluoxetine (Prozac)
20!60
Fluvoxamine (Luvox)
100!200
Paroxetitie (Paxil)
20!50
Sertraline (Zoloft)
50!200
Citalopram (Celexa)
10!30
Tricyclic antidepressanrs
Desipramine (Norpramin)
150!300
Amitripeyline (Elavil)
150!300
Clomipramine (Anafranil)
100!250
Imipramine (Tofranil)
150!300
Normptyline (Pamelor)
50!150
Azapirones
Buspirone (BuSpar)
15!60
Phenelzine (Nardil)
45!90
Tranylcypromine (Parnate)
30!50
Other
Trazodone (Desyrel)
150!300
Nefazodone (Serzone)
300!500
Venlafaxine (Effexor)
75!375
Propanolol (Inderal)
60!160
Clonidine (Catapres)
0.2!0.6
300!400
Amobarbital (Amytal)
60!150
The high frequency of abnormalities in the temporal regions discovered by neuroimaging and the relationship of focal temporal lobe disorders to anxiety suggest that the temporal brain regions may mediate aspects of anxiety symptoms. Cumulative observations suggest that anxiety is a complex behavioral response programmed into the nervous system to facilitate the individual's survival. The fear response involves complex neural networks involving perception, assessment of threat potential, and planning a response. The anatomical network includes limbic, neocortical, and subcortical structures. In addition, neural activation must coordinate a complex peripheral response consisting of a sympathetic activation of cardiopulmonary mechanisms and neuroendocrine responses involving the pituitary-adrenal axis. An abnormally low threshold for activating this response or failure to extinguish the response following exposure to a traumatic event may underlie clinical anxiety disorders. 52
weeks) than benzodiazepines, and requires dosing three times per day. 5 4 Selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors have an anxiolytic potential. 5 5 Serotonin reuptake inhibitors are the agents of choice for long-term management of anxiety disorders. # -Adrenergic receptor blockers may also benefit some patients, particularly those who have primarily somatic manifestations. 2 Adrenergic receptor agonists such as clonidine may also be helpful in anxiety, particularly anxiety symptoms associated with withdrawal syndromes. Valproic acid, trazodone, venlafaxine, and nefazodone have also been observed in preliminary studies to have anxiolytic effects. 5 5 , 56 P.251 Psychosurgery has been used to ameliorate chronic, severe, medically intractable anxiety. Limbic leukotomy and subcaudate tractotomy alleviate anxiety in 50%!60% of patients who have failed pharmacotherapy. 5 3
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 18 - Movement Disorders
level of the neuraxis, from the cortex through basal ganglia, cerebellum, spinal cord, peripheral nerves, myoneural junction, and muscles (Fig. 18.1 ). Weakness and spasticity are hallmarks of the interaction of the pyramidal motor system while weakness and diminished muscle tone are characteristic of nerve and muscle disorders. Extrapyramidal or basal ganglia diseases do not produce weakness but cause abnormalities in the initiation of movement (hypokinetic parkinsonian P.254
disorders) or exhibit abnormal activation of muscle programs and plans leading to hyperkinetic disorders. Figure 18.2 provides an approach to the classification of extrapyramidal movement disorders. Akinetic rigid syndromes are parkinsonian disorders characterized by reduced initiation of movement (akinesia), a slowed execution of movement (bradykinesia), and plastic or lead pipe rigidity. Cog wheel or a ratchet type of rigidity is
present if the disorder also has a tremor component. The typical tremor of Parkinson's disease has a rest tremor as well as akinesia and rigidity. Other parkinsonian syndromes may or may not be accompanied by tremor. Dystonia refers to a movement disorder caused by sustained muscle contractions causing twisting and repetitive movement or abnormal postures. 1 Dystonia may be focal (e.g., blepharospasm or torticollis); segmental, affecting two or more contiguous body parts; or multifocal; it may affect one-half of the body (hemidystonia) or be generalized. Tremor results from involuntary oscillations of a body part produced by alternating or synchronous contractions of reciprocally enervated muscles. 1 , 2 Several types of tremor are recognized, including essential tremor, intentional or cerebellar tremor, rest tremor, often associated with parkinsonism, physiologic tremor, and tremors associated with specific conditions (rubral with midbrain disease, dystonic in association with dystonia syndromes, wing beating with Wilson's disease, and orthostatic). Myoclonus refers to sudden shock -like muscle contractions that may be focal, multifocal, or generalized. It is typically random and irregular. 1 Chorea consists of arrhythmic, rapid, and often jerky movements that may be simple or complex and involve one body part or another in a continuous random sequence. 1 ,2 Choreic movements are purposeless but may be incorporated into deliberate movements to make them less obvious. Fidgety movements, facial grimacing, and abnormal respiration may all be manifestations of chorea. Tardive dyskinesia is a special case of a choreaform disorder following exposure to dopamine blocking agents. Athetosis refers to slow, sinuous, writhing movements of the distal parts of limbs. Ballism or ballismus describes wild flinging or throwing P.255
P.256 movements usually involving the proximal musculature of one side of the body. 2 Tics are repetitive, irregular, stereotyped movements or vocalizations that are subject to
partial voluntary control. 2 Akathisia is a subjective sensation of restlessness associated with an inability to remain still. Patients move to relieve involuntary sensations and the syndrome is expressed as changes in body positions, standing, or pacing. 1 ,2 Other movement disorders include hyperaplexias or startle syndromes (Chapter 19 ), periodic leg movements of sleep, the painful legs and moving pose syndrome, restless leg syndrome, stiff persons syndrome, stereotypies and mannerisms, hemifacial spasm, and psychogenic movement disorders. 1
Group A: features characteristic of Parkinson's disease Resting tremor Bradykinesia Rigidity Asymmetric signs
Features unusual early in the clinical course Prominent postural instability in the first 3 years after symptom onset Freezing phenomena in the first 3 years Hallucinations unrelated to medications in the first 3 years
Supranuclear gaze palsy (other than restriction of upward gaze or slowing of vertical saccades)
Documentation of a condition known to produce parkinsonism and plausible connected to the patient's symptoms (such as suitably located focal brain lesions or neuroieptic use within the past 6 months)
All criteria for possible Parkinson's disease (below) are met and
None of the features in group B is present (note: symptom duration of at least 3 years is necessary to meet this requirement) and
Substantial and sustained response to levodopa or a dopamine agonist has been documented
At least two of the four features in group A are present: at least one of these is tremor or bradykinesia, and
None of the featutes in group B is present (or symptoms have been present for less than 3 years, and none of the features in group B is present to date) and
Substantial and sustained response to levodopa or a dopamine agonist has been documented (or patient has not had an adequate trial of levodopa or dopamine agonist)
P.257 and related therapies the survival increased to approximately 15 years following diagnosis. 3
Clinical Features
The classical clinical features of Parkinson's disease include rest tremor, rigidity, and bradykinesia. Abnormalities of postural righting reflexes and symmetry of onset are also characteristic features. Diagnosis is supported by a substantial and sustained response to levodopa therapy. 4 , 5 Table 18.1 provides an approach for the identification of definite, probable, and possible Parkinson's disease. 6 In addition to the core clinical features, patients with Parkinson's disease also manifest a hypophonic and monotonic verbal output, micrographia with progressive diminution in the size of written figures, reduced armswing, flexed posture and enblock turns, shuffling gait (reduced stride length and reduced step height) festination (a tendency to accelerate; the phenomenon may occur in speech or gait), a failure to suppress blinking with repeated tapping of the forehead between the eyes (Glabellar tap reflex or Myerson's sign), and a marked increase in tone in the ipsilateral limb when the contralateral limb is active
(Froment's sign). Pursuit eye movements are broken into multiple saccadic steps and up -gaze and convergence may be moderately limited. There is no impairment of vertical gaze, an observation that helps distinguish Parkinson's disease from progressive supranuclear palsy (discussed below). 7
Neuropathology
Pathologically, Parkinson's disease is characterized by nerve cell loss and the formation of Lewy bodies in remaining neurons in a variety of brainstem nuclei and, to a lesser extent, cortical structures. 8 The structures with the greatest involvement include the substantia nigra, ventral tegmental area, locus coeruleus, and nucleus basalis. In the cerebral cortex, Lewy bodies tend to be distributed in the temporal and frontal cortex, entorhinal areas, anterior cingulate cortex, and insular cortex. Cell loss in the substantia nigra correlates well with akinesia and rigidity, whereas cognitive deficits and neuropsychiatric features of Parkinson's disease are more likely related to the cholinergic deficit associated with nucleus basalis lesions, cortical dopaminergic deficits related to cell loss in the ventral tegmental area, serotonergic deficits secondary to involvement of the raphe nuclei, and Lewy body formation in the cerebral cortex. From a neurochemical perspective, the principal abnormality is the deficiency of dopamine. This central deficit is accompanied by abnormalities in serotonin, norepinephrine, and acetylcholine. The differential diagnosis of Parkinson's disease includes a large number of parkinsonian syndromes (Table 18.2 ). The most common disorders considered in the differential diagnosis include dementia with Lewy bodies (DLB), vascular parkinsonism, progressive supranuclear palsy (PSP), cortical basal degeneration, and drug-induced Parkinsonism. Dementia with Lewy bodies typically has a less pronounced parkinsonian
Encephalitis lethargica
Olivopontocerebellar degeneration
Shy-Drager syndrome
Striaionigral degenerations
Pallidal degenerations
Wilson's disease
Alzheimer's disease
Cortical!basal degeneration
Frontotemporal dementia
Neuroacanthocytosis
GM1 gangliosidosis
Gaucher's disease
Mitochondrial encephalopathies
Secondary parkinsonism
Postanoxic, carbon monoxide intoxication, cyanide poisoning, carbon disulfide, methanol, ethanol
Multiple cerebral infarcts (atherosclerotic parkinsonism, including Bin swa tiger's disease, amyloid angiopathy, lacunar state)
P.258 syndrome, often without tremor. Onset of the dementia is within 1 year of the recognition of the parkinsonian syndrome. Patients with DLB tend to have a limited or no response to levodopa therapy. Vascular parkinsonism can be distinguished from Parkinson's disease by a history of stroke, transient ischemic attacks, vascular risk factors such as hypertension, and combined pyramidal and extrapyramidal signs on physical examination. Patients with PSP have abnormalities of vertical gaze, more pronounced axial rigidity, and more marked bradykinesia, apathy, and dysarthria. Corticobasal degeneration is distinguished by the
Treatment
A variety of agents are available to relieve the symptoms of Parkinson's disease (Table 18.3 ). Selegiline, a monoamine oxidase B inhibitor, may have a neuroprotective effect in Parkinson's disease, but its efficacy in this regard is controversial. The goal of the use of all other agents is to relieve the symptoms of Parkinson's disease. Anticholinergic agents decrease the tremor and have less marked effects on bradykinesia and rigidity. The common occurrence of adverse side effects, particularly in elderly and cognitively compromised patients, makes these agents less useful. Dopaminergic agents available for the treatment of Parkinson's disease include amantadine, an agent that facilitates dopamine release and inhibits its reuptake into the synaptic terminal, levodopa and combined levodopa/carbidopa, dopamine receptor agonists (bromocriptine, pergolide, ropinerole, pramipexole), and Catechol -O -methyltransferase inhibitors (tolcapone, entacapone). Treatment is typically initiated with a dopamine receptor agonist and levodopa/carbidopa is added when increased efficacy is required. Addition of a catechol-O methyltransferase inhibitor may further enhance the effect of levodopa/carbidopa. 9 Patients who develop severe !onoff!! symptoms with prolonged dopaminergic therapy may benefit from surgical therapy with pallidotomy or deep brain stimulation. Patients with tremor may have their motor disorder ameliorated by thalmotomy.
Class
Initial Dose
HalfLife
Amantadine (Symmetrel)
2!4 hr
Dopamine precursor
Varies Late in
25/100 mg tid
1.5 hr
peripheral do pa decarboxylase inhibitor (carbidopa [in 4:1 and 10:1 ratios]) (Sinemet)
Con (rolled release (CR) formulations (with carbidopa [4:l]) (Sinemet CR}
8 !12hr
Bromocriptine (Parlodel)
30!40 mg/day
1.25 mg bid
3!8 hr
Pergolide (Permax)
3!5 mg/day
27 hr
Ropinerote (Requip)
0.25 mg tid
6 hr
Pramipexole (Mirapcx)
0.125 mg tid
8 !12 hr
5 mg bid
8 !10 hrs
Catechol
Tolcapone
100 or 200
100 mg tid
2!3
O -methyltransferase inhibitor
(Tasmar)
hr
Emacapone (Comtan)
2.4 hr
P.259 Cholinergic disturbances are present in most patients with Parkinson's disease and dementia. This suggests a role for cholinesterase inhibitors in ameliorating the cognitive symptoms. Preliminary reports suggest that some cholinesterase inhibitors may be useful. 1 0
Neuropsychiatric Aspects
Patients with Parkinson's disease exhibit a complex repertoire of neuropsychiatric symptoms occurring as a product of the disease state or following treatment with dopaminergic agents (Table 18.4 ). Cognitive deficits are ubiquitous in Parkinson's disease and are less common among patients who have tremor at onset or who have tremorpredominant syndrome. 1 1 The most common form of neuropsychological deficit observed in patients with Parkinson's disease is an executive function disorder or mild subcortical dementia characterized by difficulty with word list generation, a retrieval deficit disorder type of memory impairment, abnormalities of organizational skills when copying complex figures, and difficulty with set switching on tests such as the Wisconsin Card Sort Test or Trails B. 12, 13 , 1 4 , 1 5 Some studies have suggested a specific deficit in visuospatial dysfunction in patients with Parkinson's disease, but further study suggests that these visuospatial abnormalities may be attributable to executive dysfunction. 1 6 Overt dementia meeting criteria of the Diagnostic and Statistical Manual of Mental Disorders 1 7 is present in 30% !40% of patients with Parkinson's disease. 1 8 , 1 9 , 2 0 The features of this dementia include more marked memory impairment, subtle to marked language abnormalities, variable visuospatial deficits, and variable degrees of executive dysfunction. The heterogeneity of the clinical syndrome associated with dementia in Parkinson's disease reflects the heterogeneous neuropathological underpinnings of this disorder (Table 18.4 ). Executive deficits are
associated with dopaminergic abnormalities. 2 1 Many patients with Parkinson's disease have atrophy of the nucleus basalis and a cortical cholinergic deficiency complicating the dopaminergic deficit. In addition, patients with Parkinson's disease may have cortical Lewy bodies, Alzheimer-type pathology in the cerebral cortex, or a combination of Alzheimer-type pathology and cortical Lewy
Cognitive impairment
Executive dysfunction
Dementia
Subcortical type
Depression
Anxiety
Apathy
Sleep attacks
Hallucinations
Hypersexualiry, paraphilia
Delirium
P.260 bodies. Clinical findings that reliably distinguish these syndromes have not been identified. 1 5 , 2 2 Depression is the most common psychiatric disturbance identified in patients with Parkinson's disease, occurring in approximately 40% of patients. 2 3 , 2 4 Major depression, observed in 7%!10% of patients with Parkinson's disease, is more uncommon, and occurs more frequently in patients who are cognitively impaired and those who exhibit the akinetic, rigid variant of Parkinson's disease. 2 4 , 2 5 Correlates of depression in Parkinson's disease include the presence of psychosis, greater impairment in activities of daily living, the presence of motor fluctuations, and early onset of Parkinson's disease. 2 6 , 2 7 Depression correlates poorly with disability in patients with Parkinson's disease and appears to be an independent neurobiological manifestation of the disorder rather than a reaction to physical impairment. Depressed patients with Parkinson's disease exhibit diminished metabolism and cerebral blood flow in the medial frontal, orbital frontal, and anterior cingulate cortices as well as in the head of the caudate nuclei. 2 8 , 2 9 Depressed patients also exhibit reductions in cerebrospinal fluid (CSF), 5!hydroxyindoleacetic acid (5!HIAA), the principal metabolite of serotonin, in the CSF compared to patients without depression. 3 0 At autopsy, depressed patients exhibit more marked cell loss in the locus coeruleus. 3 1 Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used agents for the treatment of depression in Parkinson's disease. 3 2 , 3 3 , 3 4 Tricyclic antidepressant agents and buproprion have also been utilized. 2 3 Levodopa and anticholinergic agents appear to have little effect on depression; bromocriptine, a dopamine receptor agonist, has been reported to have antidepressant activity. 3 5 The 03 selective dopamine agonists such as pramipexole and ropinirole may reduce the emergence of depression in patients with Parkinson's disease and reduce existing symptoms. 3 6 , 3 7 Patients who experience intolerable side effects from antidepressant medications or who are treatment unresponsive may have their depression ameliorated with electroconvulsive therapy (ECT), 3 8 , 3 9 which produces transient benefit in motor function as well as more sustained improvement in mood. Anxiety is a common symptom in Parkinson's disease, occurring in 20%!40% of patients, 1 8 , 4 0 , 4 1 , 4 2 and is more common among patients with
depression than in those without mood changes. Apathy has also been described in patients with Parkinson's disease both with and without accompanying mood abnormalities. 4 3 Depression and irritability occur in approximately 10% of patients with Parkinson's disease. 1 8 From a personality perspective, Parkinson's disease patients are often described as rigid, stoic, slow tempered, frugal, and orderly, characteristics that may relate to damage to the mesal limbic dopaminergic system. 4 1 , 4 4 Rapid eye movement (REM) sleep behavior disorder (RED) may herald Parkinson's disease and is eventually present in up to 15% of patients. 4 5 A variety of neuropsychiatric symptoms have been associated with dopaminergic therapy of Parkinson's disease. The earliest manifestations of levodopa excess include nightmares, nocturnal vocalization, and myoclonus. 4 6 Patients with more severe responses experience visual hallucinations and those with the most severe adverse events manifest delusions. Hallucinations occur in approximately 30% of patients treated with dopaminergic agents and delusions emerge in approximately 10%. 4 7 Cognitive impairment, age, duration of disease, apolipoprotein E, e!4 allele, history of depression, and history of a sleep disorder are associated with the emergence of visual hallucinations. 4 8 , 4 9 , 5 0 Hallucinations tend to be well formed and relatively stereotyped, are images of animals or humans, are typically silent, and are more likely to be experienced in the night or twilight hours than during the day. 5 1 Psychotic symptoms are also associated with age, stage of Parkinson's disease, severity of depression, and presence of cognitive impairment. 5 2 It is notable that in several studies the dose of dopaminergic drugs was similar in patients with and without hallucinations and delusions, suggesting that while dopaminergic therapy is critical for the emergence of these phenomena, the group that experienced these symptoms is determined by host factors (presence of dementia, age, etc.). 5 2 Clozapine is the most efficacious treatment for dopamine -associated psychosis in Parkinson's disease; 5 3 olanzapine, quetiapine, and risperidone are other atypical antipsychotics potentially useful in the treatment of Parkinson's disease. 5 4 , 5 5 , 5 6 Patients must be closely monitored for the worsening of parkinsonism. 5 7 Cholinesterase inhibitors have been reported to reduce delusions and hallucinations in some patients with Parkinson's disease, dementia, and psychosis. 1 0 Mood swings are common, in concert with the !on-off!! phenomenon in Parkinson's disease. Many patients experience more sadness and depression while off and up to 10% experience euphoria during on periods. 4 7, 5 8 Rarely,
mania occurs during the on period. 5 9 Hypersexuality and paraphillic sexual behavior (particularly sadomasochism) have been reported to occur with the introduction or elevation of levodopa dosage. 6 0 , 6 1 , 6 2 Obsessive and compulsive behaviors have also been described in conjunction with levodopa therapy. Some patients exhibit an addiction syndrome labeled !hedonistic homeostatic dysregulation!! in association with dopamine therapy. This syndrome is most likely P.261 to occur in men with early -onset Parkinson's disease who take increasing quantities of dopaminergic agents despite increasingly severe drug-related dyskinesias, social impairment, and disturbed occupational functioning. They may exhibit cyclical mood changes with hypomania or mania. 6 3
The cell loss is less severe in the substantia nigra and other brainstem nuclei in DLB than in classical Parkinson's disease. It tends to be more severe than is typical of Alzheimer's disease without Lewy body pathology. 6 9 At the level of the cortex, Lewy bodies are preferentially distributed in the limbic and paralimbic regions including the anterior cingulate cortex, amygdaloid complex, insula, and entorhinal and transentorhinal cortex. The hippocampal formation is spared. Neocortical involvement is usually most severe in the temporal lobe and least severe in the occipital lobe, with parietal and frontal cortex showing intermediate levels of involvement. 6 9 , 7 0 Many patients with DLB have prominent Alzheimer-type neuritic plaques in the cortex and modest presence of neurofibrillary tangles. This observation has given rise to some
TABLE 18.5. Consensus Criteria for Clinical Diagnosis of Probable and Possible Dementia with Lewy Bodies 64
1 . Progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention and of frontal!subcortical skills and visuospatial ability may be especially prominent. 2 . Two of the following core features are essential for a diagnosis of probable DLB, and one is essential for possible DLB: a. Fluctuating cognition with pronounced variations in attention and alertness b . Recurrent visual hallucinations that are typically well formed and detailed c. Spontaneous motor features of parkinsonism 3 . The following features are supportive of the diagnosis: a. Repeated falls
b . Syncope c. Transient loss of consciousness d . Neuroleptic sensitivity e. Systematized delusions f . Hallucinations in other modalities g . REM behavior disorder 2 5 9 h . Depression 2 5 9
P.262
Disorder
Parkinson's disease
disease
Ataxia telangiectsia
Corticobasal degeneration
Down's syndrome
Neuroaxonal dystrophy
uncertainty as to whether DLB is best regarded as a variant of Alzheimer's disease 7 1 or a distinct clinical pathological entity. 7 2 At autopsy patients with DLB have marked deficits in cholinergic markers as well as reductions in basal ganglia dopamine comparable to those in patients with Parkinson's disease. 7 3 , 7 4 Lewy bodies have been observed in a variety of disorders in addition to Parkinson's disease and DLB (Table 18.6 ). 6 9 , 7 5 The dementia of DLB is characterized by memory impairment with disproportionately severe visuospatial abnormalities and disturbances of executive function. 7 6 , 7 7 Visual hallucinations occur in 60%!70% of patients with DLB, auditory hallucinations in approximately 50%, depression in 50% !70%, and delusions in 50%!70%. 7 8 , 7 9 Delusional misidentification such as Capgras symptoms is particularly common in DLB. 7 8 , 8 0 The REM behavior disorder is a common feature of DLB, particularly among men with this disorder. 8 1 , 8 2 Parkinsonism of DLB is characterized by rigidity, bradykinesia, and dystonia. Myoclonus is more common than in typical Parkinson's disease and rest tremor is less frequent. 8 3 Patients with DLB are less likely to respond to levodopa therapy than patients with classical Parkinson's disease, but a substantial number exhibit at least moderate responses to therapy. 8 3 Imaging studies aid in distinguishing DLB from Alzheimer's disease. Hippocampal atrophy is less severe in DLB than in patients with Alzheimer's disease. 8 4 , 8 5 Studies of cerebral blood flow and
brain glucose metabolism reveal greater involvement of the occipital lobes in DLB than in Alzheimer's disease. Other cortical regions have similar levels of involvement. 8 6 Studies of the dopaminergic system assessing either uptake of labeled fluoradopa or measurement of postsynaptic dopamine receptors have the greatest specificity for distinguishing DLB from Alzheimer's disease. Patients with DLB have abnormalities of subcortical dopaminergic systems whereas patients with Alzheimer's disease do not. 8 7 , 8 8 Patients with DLB experiencing visual hallucinations have greater preservation of cortical serotonin and more severe depletion of cortical cholinergic markers than patients without hallucinations. 8 9 , 9 0 Treatment of DLB involves use of cholinesterase inhibitors and judicious administration of atypical antipsychotics. Cholinesterase inhibitors have been reported to improve cognition and reduce psychotic symptoms in DLB. 9 1 , 9 2 Conventional neuroleptics must be avoided in DLB, given the risk of exaggerated toxicity; atypical antipsychotics may reduce delusions and hallucinations without exacerbating parkinsonism. 9 3 , 9 4 All patients treated with antipsychotic agents must be carefully monitored for the emergence or exacerbation of parkinsonism. Patients with disabling degrees of P.263 spontaneous parkinsonism should be treated with dopaminergic agents. The response is typically less robust than that observed in Parkinson's disease but may be sufficient to warrant continuation of therapy.
presents criteria for the diagnosis of definite, probable, and possible PSP. 1 0 0
TABLE 18.7. National Institute of Neurological Diseases and StrokeSociety for Progressive Supranuctear Palsy (NINDS-SPSP) Criteria for Diagnosis of Progressive Supranuclear Palsy 100
Diagnostic Class
Criteria
Diagnostic, definite
Diagnostic, probable
Vertical (upward or downward gaze) supranuclear palsy and prominent postural instability with falls in the first year of disease onset
No evidence of other diseases that could explain the foregoing features, as indicated by mandatory exclusion criteria
Diagnostic, possible
Either vertical (upward or downward gaze) supranuclear palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of disease onset
Supportive criteria
Early onset of cognitive impairment, including at least two of the following: apathy, impairment in abstract thought, decreased verbal fluency, utilization or imitation behavior, or frontal release signs
Exclusionary criteria
Alien limb syndrome, cortical sensory deficits, focal frontal or temporoparietal atrophy
Cortical dementia of Alzheimer's type (severe amnesia and aphasia or agnosia, according to NINCDSADRDA criteria)
Prominent, early cerebellar symptoms or prominent, early unexplained dysautonomia (marked hypotension and urinary disturbances)
Neuroradiologic evidence of relevant structural abnormality (i.e., basal ganglia or brainstem infarcts, lobar atrophy)
NINCDS-ADRDA, National Institute of Neurologic as Communication; Disorder as Stroke-Alzheimer's Disease and Rotated Disorders Association; PSP, progressive supranuclear palsy.
P.264
TABLE 18.8. Principal Features Distinguishing Progressive Supranuclear Palsy from Other Basal Ganglia Disorders
Disorder
Dementia
Severe limb apraxia (inability to use correctly mimed objects, or perform symbolic gestures on command)
Parkinson's disease
Fluctuating cognition/consciousness
Prominent cerebellar symptomatology or unexplained early and prominent incontinence, impotence, or marked postural hypotension
Vascular parkinsonism
Multiple strokes, one of which involves the brainstem and basal ganglia
Whipple's disease
Ocular -masticatory myorhythmia, laboratory confirmation (e.g., polymerase chain reaction), if indicated
Neuropsychiatric assessment of patients with PSP reveals marked apathy in a majority of patients; depression, anxiety, and disinhibition are relatively common and rare patients exhibit psychosis. 4 1 , 1 0 0 , 1 0 1 Computerized tomography (CT) and magnetic resonance imaging (MRI) in PSP patients indicate atrophy of the midbrain and quadrigeminal plate with prominent CSF spaces around the brainstem and dilatation of the aqueduct and posterior third ventricle. 1 0 2 Assessment of fructose metabolism with positron emission tomography (PET) reveals reduced metabolic activity in the caudate nucleus, putamen, thalamus, pons, and cerebral cortex, particularly the cortical, motor, and premotor regions. 1 0 3 Frontal association cortex and paralimbic regions are only moderately affected. Studies of the dopaminergic system reveal reduced fluoradopa uptake in the caudate nucleus and anterior and posterior putamen in PSP; this contrasts with Parkinson's disease, in which the posterior putamen is disproportionately severely affected. 1 0 4 A similar pattern of involvement of the dopaminergic system is found with studies assessing the distribution of the dopamine transporter. 1 0 5 Neuropathologically, PSP is characterized by the presence of neurofibrillary tangles or neurophil threads and brainstem, diencephalic, and basal ganglia structures P.265
including the pallidum, subthalamic nucleus, substantia nigra, pons, striatum, oculomotor complex, medulla, and ventate nucleus of the cerebellum. 1 0 6 , 1 0 7 The tangles of PSP are composed of straight filaments, contrasting with the paired helical filaments characteristic of Alzheimer's disease. Neuronal loss also occurs in the areas of tangle -bearing neurons. Cholinergic marker activity is reduced throughout the brain. 1 0 8 Progressive supranuclear palsy must be distinguished from cortical basal degeneration (discussed below), Parkinson's disease, DLB, Alzheimer's disease, multiple system atrophy, parkinsonism associated with multi -infarct states, Whipple's disease, post-encephalitic parkinsonism, Creutzfeldt -Jakob disease, frontotemporal degenerations, pallidal systems degenerations, progressive subcortical glyosis, and hydrocephalus. 2 3 , 1 0 6 , 1 0 9 , 1 1 0 Table 18.8 presents a summary of features that assist in distinguishing PSP from Parkinsonian syndromes with overlapping features. There is no consistently efficacious treatment for PSP. Some patients have limited responses to dopaminergic therapy for variable periods of time and a few patients have responded to treatment with methysergide or tricyclic antidepressants. 1 1 1 , 1 1 2 , 1 1 3 Cholinesterase inhibitors have not proven to be beneficial. 1 1 4 Intramuscular botulinum toxin may relieve painful neck and limb spasms. 1 1 5
Corticobasal Degeneration
Corticobasal degeneration is a parkinsonian syndrome characterized by asymmetric rigidity, dystonia, and myoclonus associated with apraxia of the affected limb and cortical sensory loss (Table 18.9 ). 1 1 6 Tremor, hyperreflexia, Babinski signs, oculomotor paralysis, dysarthria, and dysphagia may also occur. Myoclonus of corticobasal degeneration is primarily distal, occurring in the limb affected by apraxia and parkinsonism. Action and reflex myoclonus are typical; attempts to move the limb voluntarily are interrupted by repetitive myoclonic jerks. 1 1 7 Apraxia of corticobasal degeneration is an ideiomotor type (Chapter 6 ) characterized by spatial, temporal, and sequencing errors that result in unrecognizable action products when the patient is asked to perform specific transitive and intransitive actions. 1 1 8 Patients may exhibit a frank alien hand phenomenon in which they can exert little control over the actions of a limb and experience the limb activity as involuntary. This type of alien limb phenomenon must be distinguished from a marked grasp reflex, which also lacks voluntary control and may result in unusual groping and grasping movements of the affected limb. This type of alien hand may also occur in corticobasal degeneration.
Inclusion criteria
Rigidity plus one cortical sign (apraxia, cortical sensory loss, or alien limb phenomenon); or
Apraxia: more than simple use of limb as object; clear absence of cognitive or motor deficit sufficient to explain disturbance
Exclusion criteria
Early dementia (this will exclude some patients who have corticobasal degeneration, but whose illness cannot clinically be distinguished from other primary dementing diseases
Rest tremor
Neuropsychologically, patients with corticobasal degeneration exhibit modest decline in most cortical functions, a disproportionately severe dysexecutive syndrome, a retrieval deficit disorder, and marked visuospatial disturbances (particularly if the left limb and right hemisphere are predominantly involved). 1 1 9 , 1 2 0 Patients with corticobasal degeneration are subject to depression and may exhibit apathy, irritability, and agitation. 1 2 1 Anxiety, disinhibition, delusions, and hallucinations are uncommon. The specificity of the clinical syndrome described here is high for the diagnosis of corticobasal degeneration but the sensitivity is low, with many patients with this diagnosis going undetected. 1 2 2 Studies of cerebral metabolism and cerebral blood flow with PET and single photon emission computerized tomography (SPECT) reveal a marked asymmetry of cerebral activity, reduced opposite the most affected limb; dorsolateral frontal, medial frontal, inferior parietal, sensory motor, and lateral temporal cortices exhibit
P.266 reduced metabolism. At the subcortical level, the striatum and thalamus are also affected. 1 2 3 , 1 2 4 , 1 2 5 Neuropathological examination reveals swollen achromatic neurons and cellular loss in the affected regions. At the cortical level, the pre - and postcentral gyri are most affected. Balloon cells may also be found in the anterior cingulate gyrus and insular cortex. The hippocampus and perihippocampal regions are typically unaffected. Cell loss and tau -immunoreactive lesions are evident in the caudate nucleus, putamen, substantia nigra, locus coeruleus, raphe nuclei, and tegmental gray areas. The red nucleus, subthalamic nucleus, and thalamic nuclei are more mildly affected. 1 2 6 , 1 2 7 No treatment has been found to be efficacious in ameliorating the symptoms of corticobasal degeneration.
FIGURE 18.3 Basal ganglia calcifications with idiopathic basal ganglia calcification syndrome (Fahr's disease).
P.267
Type of Condition
Disorders
Idiopathic
Paroxysmal dystonic
choreoathetosis
Adrenoleukodystrophy
Endocrine
Pseudohypoparathyroidism
Pseudo -pseudohypoparathyroidism
Hyperparathyroidism
Hypothyroidism
Infections
AIDS
Toxoplasmosis
Cysticercosis
Trichinosis
Nocardia
Tuberculosis
Echinococcosis
Coccidiodomycosis
Malaria
Cerebral syphilis
Anoxia
Lead poisoning
Radiation
Methotrexate exposure
Congenital disorders
Biotinidase deficiency
Down's syndrome
Cockeyne's syndrome
Tuberous sclerosis
Lissencephaly
Neurofibromatosis
Leigh's disease
Vascular disorders
Infarctions
Aneurysms
Arteriovenous malformations
Brain tumors
Meningiomas
Astrocytomas
Craniopharyngiomas
Metastases
Medulloblastoma
Teratomas
Ependymomas
Oligodendroglioma
Miscellaneous
Subdural hematomas
Hamartomas/lipomas
Lipoid proteinosis
Physiological
Choroid plexus
Pineal
P.268 study. Hallervorden -Spatz disease (also known as neurodegeneration with brain iron accumulation type I) is an autosomal recessive disease characterized by the accumulation of iron -containing pigments in the globus pallidus and substantia nigra. In adults, onset form of the disease with parkinsonism and a subcortical dementia pattern has been described. 1 3 2 , 1 3 3 -Synuclein containing Lewy bodies have been observed in this syndrome. 1 3 4 The basal ganglia deposits are readily seen on CT or MRI. 1 3 5 , 1 3 6 Vascular parkinsonism is a common cause of the parkinsonian syndrome in the elderly. 1 3 7 , 1 3 8 Gait
abnormalities in vascular parkinsonism are often identical to those of Parkinson's disease, with short stride length and reduced step height producing a shuffling gait. Patients with vascular parkinsonism are less likely to manifest tremor, do not have levodopa-responsive syndromes, and often have a combination of pyramidal and extrapyramidal findings on neurological examination. Neuropsychologically, patients with subcortical lacunar infarctions and Vingschwanger's disease exhibit executive dysfunction with deficits in shifting mental set, response inhibition and generative cognition. 1 3 9 Depression and apathy are common neuropsychiatric manifestations observed in patients with subcortical vascular disease. 1 4 0 , 1 4 1 , 1 4 2 Magnetic resonance imaging readily reveals subcortical ischemic injury (Fig. 18.4 ). 1 4 3 Multiple system atrophy (MSA) includes three syndromes: olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome. Clinical and pathological features of these three disorders overlap. When parkinsonian features predominate the term striatonigral degeneration is generally used; if cerebellar features predominate, sporadic olivopontocerebellar atrophy is commonly used. When autonomic failure predominates, the term Shy-Drager syndrome is invoked. Table 18.11 presents the diagnostic features of MSA. 1 4 4 Parkinsonism occurs in 87% of patients, autonomic dysfunction in 74%, and cerebellar signs in 54%. Pyramidal signs are almost common, occurring in 49% of patients, and dysarthria and dystonia occur in a minority. Patients appear to be vulnerable to levodopa-induced kinesias. The diagnostic criteria have moderate sensitivity (approximately 70%) and good specificity (97%). 1 4 5 Approximately 25% of patients exhibit overt dementia and a larger number have abnormal performance on test of executive function. 1 2 0 , 1 4 5 , 1 4 6 Depression occurs at about the same rate in MSA as in idiopathic Parkinson's disease, where it is a common feature. 1 4 7 Magnetic resonance imaging reveals putamenal abnormalities with dorsolateral hypointensity P.269
FIGURE 18.4 Magnetic resonance image of patient with Binswanger's disease showing extensive ischemic injury of the cerebral white matter.
and a lateral hyperintense rim. 1 4 8 Bilateral hypometabolism is evident in the putamen and caudate when MSA patients are studied with [ 1 8 F] -fluorodeoxyglucose (FDG) PET. 1 4 9 Pathologically, cell loss and glyosis are evident in the putamen, caudate, nucleus, external pallidum, substantia nigra, locus coeruleus, inferior olives, pontine nuclei, cerebellar purkinje cells, and intermediolateral cell columns of the spinal cord. 1 5 0 Glial and neuronal cells contain ctyoplasmic inclusions that stain positively for synuclein. 1 5 1 -Adrenergic agonists such as midodrine may be useful in ameliorating the postural hypotension observed in MSA. 1 5 2 The Chamorro population of Guam suffers from an endemic parkinsonism dementia complex (known locally as !bodig !! and a disorder resembling amyotrophic lateral sclerosis (ALS) (lytico). Similar pathology is found in the two syndromes consisting of neurofibrillary tangles in the neocortex, basal ganglia, and thalamus. 1 5 3 A similar syndrome is occasionally seen on a sporadic basis outside of Guam. Parkinsonism and motor neuron disease can also be seen in frontotemporal dementia (Chapter 10 ). Post -encephalitic parkinsonism was a common seguelae of the epidemic of von Economo's encephalitis occurring between 1917 and 1927. These patients exhibited parkinsonism, frequently complicated by catatonia, tic disorders, and chorea. A plethora of neuropsychiatric symptoms accompanied the syndrome, including mood disorders, obsessions and compulsions, and a subcortical dementia syndrome in adults; children manifested hyperactivity, conduct disorders, and paraphillic sexual
behavior. 1 5 4
Wilson's Disease
Wilson's disease is an autosomal recessive disorder produced by a mutation on chromosome 13q14.3. The gene encodes a transport protein and the mutations associated with Wilson's disease result in abnormal copper deposition in the liver, the basal ganglia, and the cornea of the eyes. 1 5 5 Wilson's disease typically begins in childhood or adolescence, with a modal age of 19 years for those with neurological symptoms. In some cases, the disease may have its onset delayed until as late as the fifth or sixth decade. 1 5 6 Roughly one-third
Multiple system atrophy is a sporadic, progressive, adult-onset disorder characterized by autonomic dysfunction, parkinsonism, and ataxia in any combination. The features of this disorder include the following:
A. Parkinsonism (bradykinesia with rigidity or tremor or both), usually with a poor or unsustained motor response to chronic levodopa therapy B. Cerebellar or corticospinal signs C . Orthostatic hypotension, impotence, urinary incontinence, or retention, usually preceding or within 2 years after the onset of the motor symptoms
When parkinsonian features predominate, the term striatonigral degeneration is often used; when cerebellar features predominate, sporadic olivopontocerebellar atrophy is often used; when autonomic failure predominates, the term Sky Drager syndrome is used. 1 4 4
P.270 of patients with Wilson's disease present first with psychiatric symptoms, one-third present with neurological symptoms, and one-third with evidence of hepatic disease. Dysarthria, dystonia, abnormalities of rapid, alternating movements, parkinsonian -type rigidity, disturbances of gait and posture, and a fixed facial expression are common manifestations of the disease. About one-third of patients have a rhythmic proximal tremor (wing -beating tremor), abnormal eye movements, and hypereflexia. Drooling, bradykinesia, frontal release signs, and athetosis are less common manifestations. 1 5 7 Examination of the eye reveals a golden brown or greenish ring of pigmentation at the margin of the cornea near the limbus. It can often be detected with the naked eye, but certain identification requires a slit -lamp examination. While highly characteristic of Wilson's disease, the Kayser -Fleischer ring is not completely specific for the disease and is also found in non -Wilsonian liver disorders. A sunflower cataract is present in approximately 20% of patients with Wilson's disease, and rarely there is progressive loss of vision associated with retinal dysfunction. 1 5 6 From a neuropsychiatric perspective, four symptom clusters have been identified in patients with Wilson's disease: mood and affect, behavior/personality, schizophrenia -like symptom, and cognitive impairment. 1 5 8 Personality and mood changes are the most common behavioral manifestations. Patients may manifest depression, suicidal behavior, incongruous behavior suggestive of a frontal lobe syndrome, aggression, and irritability. 1 5 9 , 1 6 0 At least half of the patients have neuropsychiatric symptoms early in the disease course. Personality alterations, frontal lobe symptoms, irritability, and aggression are highly correlated with specific neurological symptoms including dysarthria, dysphasia, drooling, and rigidity. Neuropsychologically, patients with Wilson's disease exhibit retrieval deficit -type memory abnormalities, impairment on trail -making tests, and poor word list generation, consistent with disturbance of the frontal-subcortical systems. 1 6 1 , 1 6 2 Computerized tomography reveals characteristic hypodense areas in the basal ganglia in approximately half of Wilson's disease patients. 1 6 3 In nearly all patients with Wilson's disease MRI shows abnormalities. High -signal intensity lesions on key 2 -weighted images are seen in the thalamic nuclei, brainstem, and lenticular nuclei. 1 6 4 Investigations with glucose PET indicate a diffusely reduced brain metabolism that is most marked in the lenticular nuclei. 1 6 5
Investigation of the dopaminergic system using fluorodopa PET demonstrates that most patients have abnormally low dopamine uptake into basal ganglionic regions. 1 6 6 Pathologically, there is cell loss and marked glial proliferation, particularly in the putamen, with less marked changes in the globus pallidus and caudate nucleus. The deeper layers of the cerebral cortex and adjacent white matter are also affected. Opalski cells are large, round cells characteristic of Wilson's disease that are most prominent in the thalamus, pallidum, and substantia nigra. 1 6 7 Treatment of Wilson's disease is aimed at reducing copper availability by decreasing copper intake, limiting copper absorption, increasing copper elimination, or liver transplantation. 1 6 8 Ammonium tetrathiomolybdate or zinc is commoly used to reduce gastrointestinal absorption of copper and penicillamine or trientine is used as copper chelators to enhance copper elimination. A penicillamine may precipitate neurological worsening. 1 6 9 Psychiatric symptoms may improve following chelation therapy, but many patients require management with psychotropic agents.
Huntington's Disease
Huntington's disease is an autosomal dominant disorder resulting from a mutation on chromosome 4 at a novel 4p16.3 and consisting of an increased number of CAG trinucleotide repeats. 1 7 0 Normal chromosomes possess 6 !34 CAG repeats at this location, whereas patients with Huntington's disease exhibit from 39 to 86 repeating units. The average age of onset is between 35 and 40; the earliest cases manifest symptoms at 2 or 3 years of age and patients with onset as late as the seventh or eighth decade have been recorded. Patients with longer trinucleotide repeat lengths have an earlier age of onset and more rapid progression than those with fewer repeats. 1 7 1 Clinically, Huntington's disease is manifested by the triad of choreaform movements, dementia, and neuropsychiatric disturbances. A more uncommon rigid (Westfall) variant of Huntington's disease also occurs and is more likely to occur in children. Choreiform movements of Huntington's disease tend to be more proximal than distal and first appear in the form of fidgety or restless movements. Patients often incorporate the movements into semi-intentional gestures creating unusual mannerisms. Both the upper and lower face are involved with intermittent wrinkling of the forehead as well as perioral and tongue movements. Truncal and proximal leg chorea may impose a lurching and high stepping (peacock) quality to the gait. Hyperkinetic movements of the abdominal, chest, and diaphragmatic musculature may produce irregularities of speech. 1 7 2 Movement abnormalities include slow and hypometric
saccades, increased saccadic latencies, difficulty maintaining fixation, or performing antisaccades. 1 7 3 , 1 7 4 Huntington's disease must be distinguished from a variety of other causes of chorea (Table 18.12). P.271
Neurodegenerative disorders
Huntington's disease
Sydenham's chorea
Dentatorubropallidoluysian atrophy
Lupus erythematosus
Neuroacanthocytosis
Chorea gravidarum
Polycythemia vera
Pallidal degenerations
Periarteritis nodosa
Behcet's disease
Vascular (stroke)
Neoplastic
Renal failure
Infectious (encephalitis)
Paraneoplastic syndrome
Inflammatory
Drugs
Senile chorea
Antiparkinsonian agents
Stimulants
Paroxysmal chorea
Opiates
Antiepileptic agents
Paroxysmal dystonic
choreoathetosis
Lithium
Wilson's disease
Metabolic conditions
Hyperthyroidism
Lesch-Nyhan syndrome
Hyperglycemia
Galactosemia
Hypoglycemia
Hypernatremia
Glutaric acidemia
Hyponatremia
Hypoparathyroidism
Intoxications
Hypocalcemia
Carbon monoxide
Hypomagnesemia
Alcohol
Thiamine deficiency
Manganese
Niacin deficiency
Toluene
Organophosphates
Miscellaneous
Subdural hematoma
Multiple sclerosis
Postvaccinial
Cerebral palsy
Kernicterus
P.272 Mood disorders and personality alterations are the most common behavioral changes exhibited by patients with
Huntington's disease. 1 7 5 , 1 7 6 Approximately 40% of patients exhibit major depressive disorders or meet criteria for dysthymia. The relationship of mood disorder to Huntington's disease is consistent across families, with some kindreds manifesting this combination of symptoms and others evidencing chorea and dementia without concomitant mood changes. 1 7 7 Irritability, anger, and intermittent explosive disorder are the most common types of personality alterations exhibited. 1 7 5 , 1 7 8 , 1 7 9 Antisocial behavior and conduct disturbances are also common. 1 7 5 , 1 7 6 Approximately 10% of patients exhibit hypomania and a few may have manic episodes. 1 7 5 Apathy, irritability, and disinhibition are other behaviors reported in patients with Huntington's disease. 1 8 0 Psychosis is relatively unusual in Huntington's disease, but a schizophrenia -like disorder with delusions, auditory hallucinations, and thought disorder has been described. 1 75 , 1 7 6 Obsessive -compulsive behavior is a reported but uncommon manifestation of Huntington's disease. 1 8 1 Sexual misconduct is more common, occurring in up to 20% of Huntington's disease patients. 1 8 2 , 1 8 3 The rate of suicide is increased in Huntington's disease. It is at least twice that in the general population and is increased at least fourfold in those after the diagnosis is suspected or established. 1 8 4 Psychiatric symptoms do not correlate with the CAG repeat length 1 8 5 but the occurrence of anger and hostility are among the earliest clinical features to predict the emergence of Huntington's disease in mutation carriers. 1 8 6 Huntington's disease patients with depression exhibit relative hypometabolism of the orbital and inferior prefrontal cortex compared to nondepressed patients. 1 8 7 Psychotic patients with Huntington's disease exhibit diminished frontal lobe metabolism compared to those without psychosis, and patients with minor behavioral changes have reduced metabolic activity in the ventrobasal regions of the striatum. 1 8 8 Dementia eventually supervenes in all patients with Huntington's disease. The pattern of cognitive impairment is consistent with a subcortical dementia and involvement of frontal-subcortical circuits. 1 8 9 Memory is affected early in the disease course but changes are less profound than those observed in dementias such as Alzheimer's disease. Patients generally exhibit a retrieval deficit -type disorder with relatively intact memory storage. 1 9 0 , 1 9 1 Learning abnormalities may occur in Huntington's disease and reflect deficiencies in perceptual analysis rather than an aphasic type of anomia. 1 9 2 Executive functioning is compromised early in the disease course. 1 9 3 , 1 9 4 Psychomotor speed and attentional abilities are highly correlated with deficits and activities of daily living in Huntington's disease. 1 9 5 There is
a relationship between severity of cognitive decline and number of CAG repeats. 1 9 6 Structural imaging in patients with Huntington's disease reveal reduced size of the caudate nuclei in a majority of patients, with low signal intensity in the caudate and lentiform nuclei (Fig. 18.5 ). 1 9 7 Thalamus and medial temporal structures are also reduced in size and there is evidence of white matter degeneration. 1 9 7 Glucose PET demonstrates diminished metabolic activity in the caudate nuclei prior to the occurrence of structural atrophy. 1 9 8 , 1 9 9 Subcortical as well as cortical hypometabolism and hypoperfusions are detectable as the disease progresses. 2 0 0 , 2 0 1 At autopsy, Huntington's disease is characterized by striking atrophy of the caudate nucleus and less dramatic changes in the putamen and globus pallidus. 2 0 2 Changes begin in the medial paraventricular portions of the caudate nucleus, the tail of the caudate, and the dorsal part of the putamen. 2 0 3 Medium -sized spiny neurons of the striatum are most vulnerable. Striatal levels of g -aminobutyric acid (GABA) and its synthetic enzyme glutamate decarboxylase are decreased. Choline acetyltransferase and several striatal neuropeptides are also decreased. Dopamine and glutamate levels are largely preserved. 2 0 2 Striatal projections to the globus pallidus are more affected in the akinetic rigid form of Huntington's disease than in the more common choreic form. 2 0 4 The CAG repeat comprising the mutation of Huntington's disease appears to lead to an alteration in the huntingtin protein and its accumulation in neuronal intranuclear inclusions in the cortex and the striaturn. 2 0 5 No therapy that halts or reduces the progression of Huntington's disease has been discovered. D 2 blocking agents and benzodiazepines may reduce the severity of chorea. Clozapine has been reported to be useful in reducing the psychosis of Huntington's disease, 2 0 6 and SSRIs and buspirone have been reported to reduce aggressive behavior. 2 0 7 , 2 0 8 Conventional antidepressants are used to address the depression of Huntington's disease and ECT may be useful in treatment -resistant patients. 2 0 9 , 2 1 0 Luprolide may be useful in reducing sexual aggression in male patients with Huntington's disease. Mania and hypomania can be treated with mood -stabilizing agents such as carbamazapine and valproic acid.
Neuroacanthocytosis
Neuroacanthocytosis is an autosomal recessive disorder characterized by involuntary movements, cognitive and behavioral changes, peripheral neuropathy, and the presence
FIGURE 18.5 Computerized tomogram (A) showing reduced caudate volume and enlargement of the anterior horns of the lateral ventricles. Magnetic resonance imaging (B) reveals caudate and cortical atrophy in a patient with more advanced Huntington's disease.
projections). 2 1 1 , 2 1 2 , 2 1 3 The movement disorder is typically choreiform in nature, but dystonia, tics, involuntary vocalization, and parkinsonian features also occur. In some cases, lip biting has been prominent. Dementia is a prominent feature of most cases as the disease progresses. Personality changes consistent with a frontal lobe syndrome and depression have been described in patients with neuroacanthocytosis. 2 1 2 , 2 1 4 , 2 1 5 A retrieval deficit -type memory abnormality is present and executive dysfunction may be prominent. 2 1 2 , 2 1 6 , 2 1 7 At autopsy, patients have extensive neuronal loss and glyosis involving the stiratum, pallidum, and substantia nigra. Dopamine and substance P are depleted in the affected areas. Neuroacanthocytosis can be distinguished from Huntington's disease by its autosomal recessive inheritance, presence of acanthocytes on peripheral blood smears, and peripheral neuropathy. 2 1 1 , 2 1 8
Sydenham's Chorea
Sydenham's chorea has its onset between the ages of 5 and 15 years of age and follows infection with group A b hemolytic streptococcus. It is more common in girls than boys and evidence of the preceding infection can be elicited in approximately one-third of cases. The streptococcal infection, usually a pharyngitis, precedes movement disorder
by 1 to 6 months. The chorea is primarily distal, affecting the hands and feet, and produces a characteristic milking movement of the examiner's hands when the patient grips the examiner (milkmaid's grip). Infection -related carditis and arthritis may accompany the chorea. Hypometric saccades, an occasional oculogyric crises, have also been reported. 2 1 9 , 2 2 0 Cognitive impairment and personality alterations, particularly irritability and obsessive -compulsive behavior, frequently accompany the choreiform syndrome. It is now recognized that obsessive -compulsive disorder and Gilles de la Tourette's syndrome may represent late complications of streptococcal infections. This complex set of disorders have been labeled pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). 2 2 1 The basal ganglia, including putamen, caudate, and globus pallidus, are enlarged in subjects manifesting Sydenham's chorea. 2 2 2 Glucose PET may show increased metabolism in the basal ganglia at the time of the chorea. 2 2 3 There is also an increased occurrence of psychosis among patients with Sydenham's chorea. 2 2 4 , 2 2 5
Dystonia
There is a wide variety of primary and secondary dystonias (Table 18.13). Substantial progress has been made in defining the genetic basis of the early -onset dystonias (onset under age 26); a mutation in the DYT1 gene on 9q34is responsible for most cases. 2 2 6 , 2 2 7 The genes responsible for a few late -onset dystonic syndromes have been defined, but most familial cases are currently produced by unknown mutations. In addition, sporadic cases of primary dystonia are not infrequent. Late-onset dystonias, including blepharospasm, oral mandibular dystonia, spasmodic dystonia (laryngial P.274
Primary dystonia
Sporadic
Inherited
Secondary dystonia
Sporadic
Inherited
Dopa-responsive dystonia GTP cyclohydrolase 1 deficiency (DYT5); Tyrosine hydroxylase deficiency; Other bioptcrin deficient diseases
Sporadic
Parkinson's disease
Corticobasal degeneration
Inherited
Wilson's disease
Huntington's disease
Juvenile parkinsonism-dystonia
Hypoprebeta lipoproteinemia, acanthyocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome)
Ataxia relangiectasia
Neuroacanthocytosis
Rett's syndrome
Spinocerebellar degeneration
Olivopontocerebellar atrophy
Deletion of 18q
Glutaric acidemia
Methylmalonic acidemia
Homocystinuria
Hartnup's disease
Tyrosinosis
Lipid disorders
Metachromatic ieukodvstronhv
Ceroid lipofuscinosis
Mitochondrial encephalopathies
Leigh's disease
Lesch-Nyhan syndrome
Leber's disease
Vitamin E deficiency
Biopterin deficiency
Perinatal cerebral injury and kemicterus: athetoid cerebral palsy, delayed-onset dystonia
Infection: viral encephalitis, encephalitis lethargica, Reye's syndrome, subacute sclerosing panencephalitis, Creutzfeldt -Jakob disease, HIV
Brain tumor
Arteriovenous malformation
Cervical injury
Peripheral trauma
Brainstem lesion
Hypoxia
Multiple sclerosis
Toxicants: manganese, carbon monoxide, carbon disulfide, cyanide, methanol, disulfiram, 3 nitroproprionic acid
Metabolic: hypoparathyroidism
Drugs: levodopa, bromocriptine, antipsychotics (acute and tardive dystonia), metoclopramide, fenfluramine, Flecainide, anticonvulsants, certain
Paroxysmal dyskinesias
Psychogenic
Pseudodystonia
Syringomyelia
Congenital nystagmus
Vestibular torticollis
Isaac's syndrome
Sandifer's syndrome
Satoyoshi syndrome
Stiff-person syndrome
Spinal deformities
Spasticity
P.275 dystonia), pharyngeal dystonia, spasmodic torticollis, truncal dystonia, and writer's cramp, are more likely to be focal in nature. 2 Many secondary dystonias occur, including dystonias associated with movement disorders such as Parkinson's disease and corticobasal dystonia and dystonic syndromes induced by long-term use of dopamine -blocking agents (tardive dystonia). The pathophysiology of dystonia is not certain. No pathological or biochemical abnormalities have been consistently identified in the brains of patients suffering from primary dystonic disorders. Positron emission tomographic studies suggest abnormal brain networks involving the frontal lobe and basal ganglia. There is a dissociation between activity of the lentiform nucleus and the thalamic nuclei as well as hyperactivity of supplementary motor and prefrontal areas. 2 2 8 , 2 2 9 The pathways involved in the production of dystonia appear to spare circuitry involved in cognition and emotion. There are few consistent emotional, mood, behavioral, personality, or psychiatric syndromes observed in patients with dystonia. 2 3 0, 2 3 1 , 2 3 2 Formal personality assessments have shown elevated subscale scores on mesaures of somatization, interpersonal sensitivity, and depression. The changes were modest in severity and likely reflected the presence of the disabling movement disorder and the secondary psychosocial consequences. 2 3 3 A few cases of bipolar disorder have been associated with idiopathic dystonia. 2 3 4 Dystonia is often misdiagnosed as a conversion disorder. Its unusual nature misleads many clinicians into believing that the disorder has a psychogenic basis. Psychogenic causes of movement disorders are rare, and criteria for identifying them are presented in Chapter 22 .
Ataxias
Ataxia is a manifestation of cerebellar or sensory dysfunction leading to disequilibrium. Cerebellar ataxias are accompanied by additional signs such as ataxia on the finger-to -nose and heel -to -shin test, dysdiadokokinesia on tests of rapid alternating movements, past pointing when asked to touch a point in space, abnormalities of rebound check when the pressure against which a patient is pushing is suddenly released, and hypotonia and a variety of eye signs, reflecting loss of coordination of ocular movements. A wide range of disorders can cause ataxic syndromes (Table 18.14). These include autosomal recessive disorders; autosomal dominant ataxias; mitochondrial diseases with ataxia; prion diseases leading to spongiform encephalopathies; congenital malformations of the cerebellum; early -onset cerebellar diseases; inborn errors of metabolism; acquired disorders including paraneoplastic cerebellar syndromes; vitamin deficiencies; hypothyroidism; infectious illnesses; vascular disorders; multiple sclerosis; traumatic brain injury; heatstroke; and a variety of toxins. Substantial progress has been made in defining the genetic basis of the autosomal dominant cerebellar ataxias. At least nine syndromes have been identified with specific mutations (Table 18.15). There is phenotypic variety within each family carrying one of the mutations, but there are also shared neurologic and neuropsychiatric features. Five to ten percent of patients with spinocerebellar ataxia (SCA) -1 have a dementia syndrome and other members of the kindreds have had frontal lobe syndromes with euphoria and emotional lability. 2 3 5 , 2 3 6 , 2 3 7 Five to thirty percent of patients with P.276
Hereditary ataxias
Autosomal recessive
Freidreich's ataxia
Ataxia relangiectasia
A-b lipoproteinemia
Retsum's disease
Cerebrotendinous xanthomatosis
Adrenoleukodystrophy
Metachromatic leukodystrophy
Ceroid lipofuscinosis
GM2 gangliosidosis
ADCAI
SCA-1
SCA-2
SCA-4
ADCA II
SCA-7
ADCA III
SCA-5
SCA-6
Dentatorubral-pallidoluysian atrophy
Periodic ataxia
Type I
Type 2
Leigh's disease
Keams-Sayre syndrome
Kuru
Non-hereditary ataxias
Metabolic conditions
Vitamin E deficiency
Vitamin B 1 2 deficiency
Hypothyroidism
Hypoparathyroidism
Gluten ataxia
Ataxia
Miller Fisher syndrome (form of Guillain -Barre syndrome with ophthalmoplegia, ataxia, and areflexia)
Vascular (ischemia, hemorrhage, arceriovenous malformation, including von Hippd -Lindau syndrome)
Neoplasms
Multiple sclerosis
Traumatic injury
Alcohol
Heat stroke
Phenytoin
Phenobarbital
Thallium
Lead
Mercury
Joubert's syndrome (neonatal hyperpnea, abnormal ocular movements, mental retardation, ataxia)
COACH syndrome (cerebellar vermis agenesis, oligophrenia, acaxia, coloboma, hepatic fibrosis)
Vermian hypoplasia with coloboma and hepatic fibrosis (oligophrenia, cerebellar ataxia}
Cerebellar ataxia, Holmes type (hypogonadism, mental retardation, deafness, retinopathy, corticospinal signs, neuropathy)
Louis Bar syndrome (telangiec Eases, tremor, choreoafhetosis, oculomotor apraxia, immune deficiency, increased a-feroproteion level).
Xeroderma pigmentosum (skin photosensitivity, mental retardation, dwarfism, spasticity, choreoathetosis, deafness, hypogonadism)
Cockayne's syndrome (skin photosensitivity, mental retardation, retinopachy, extra pyramidal features, deafness, neuropathy)
Marinesco -Sjgren syndrome (mental retardation, cataracts, short stature, skeletal abnormalities)
Ataxia and pigmentary retinopathy (pigmentary retinopachy, hearing loss, mental retardation)
P.277 SCA-2 manifest dementia and in some cases a frontal dysexecutive syndrome has been prominent. 2 3 8 , 2 3 9 Most patients with SCA-3, also known as Machado -Joseph disease, have normal intellectual function but a few cases with
cognitive impairment have been recorded. 2 4 0 Dementia has been reported in approximately 15% of patients with SCA-6 and a few patients with SCA-7 have exhibited dementia and psychosis. 2 41 , 2 4 2 Dementia is common in dentatorubropallidoluysian atrophy. 2 4 3 , 2 4 4 There is pathologic as well as clinical heterogeneity within the families with the various autosomal dominant cerebellar atrophy mutations. In general, those mutations associated with more widespread pathology, such as a mutation producing dentatotrubropallidoluysian atrophy, have more widespread pathology involving the dentate nucleus invariably; the globus pallidus, thalamic nucleus and red nucleus typically; and other areas, including the thalamus and striatum, variably. 2 4 3 All of the autosomal dominant cerebellar atrophy syndromes described in this section are due to CAG repeat expansions on specific chromosomes (Table 18.15) and the extent of pathology varies with the length of the CAG repeat. 2 4 1 Friedreich's ataxia is the most common hereditary ataxia, occurring with a prevalence of 1 per 50,000. The disease typically has its onset between 5 and 15 years of age and features progressive ataxia of all limbs, loss of deep tendon reflexes and a vibration sense in the lower extremities, cerebellar -type dysarthria and pyramidal signs, muscle weakness, and Babinski signs. A majority of patients with Friedreich's ataxia are homozygous
Gene
Chromosome
Usual Neuropathology
Neuropsychiatric Features
SCA1
Olivopontocerebellar atrophy
Dementia late; mental status changes early in 10%; mood disorders and personality changes
SCA2
12
Olivopontocerebellar atrophy
14
Spinopontine atrophy
SCA4
16
Unknown
None described
SCA5
11
None described
SCA6
19
Dementia in 25%
SCA7
Olivopontocerebellar atrophy
SCA10
22
Unknown
None described
12
Multisystem degeneration
P.278
Tremor
Action Characteristic
Amplitude
Frequency
Etiology
Physiological
Action
Small
Essential
Action
Small
Parkinsonian
Resting
Large
Low (4 !6 Hz)
Parkinsonian syndromes
Cerebellar
Action
Crescendo
Low
for a GAA repeat expansion of the x25 gene. 2 4 5 Pathologically, there is degeneration of the posterior columns of the spinal cord resulting from loss of the primary sensory neurons of the dorsal ganglia. The spinocerebellar tracks are atrophic and the descending corticospinal tracks are also atrophied, although the motor neurons in the ventral horns are well preserved. The deep cerebellar nuclei are severely affected and there may be mild loss of Purkinje cells in the cerebellar cortex. Other cerebral structures are typically unaffected. 1 3 0 Given the limited involvement of neuronal structures outside of the spinal cord and cerebellum, few neurobehavioral changes would be expected among patients with Friedreich's ataxia. Slowing of information -processing speed and deficits on some tests of visuospatial cognition have been suggested in some studies. 2 4 6 , 2 4 7
Tremor
Tremor is a common product of many disturbances affecting the central nervous system. Like dystonia, tremor appears to be generated by pathways that lie outside of circuits critical to cognition and emotion and tremor has few links to specific neuropsychiatric disorders. However, it is common for tension, anxiety, and distress to exaggerate any existing tremor. Moreover, many drugs used to treat psychiatric illnesses induce tremor syndromes. Thus, knowledge of tremor is critical to appropriate patient assessment and treatment in neuropsychiatry. There are four major varieties of tremors (Table 18.16). Parkinsonian tremors are large-amplitude, low -frequency resting tremors that accompany Parkinson's disease and other parkinsonian syndromes. Physiological tremors are small -amplitude, high -frequency action tremors that occur during activity and disappear at rest. Physiological tremors may be exaggerated by anxiety, fatigue, and a variety of drugs, toxins, and metabolic disorders. Essential tremors share the same amplitude and frequency characteristics of physiological tremors but occur in sporadic, familial, or !senile! ! situations. Cerebellar tremors are also action (intention) tremors. They are of low frequency and increase in amplitude as the target is approached (crescendo pattern). Cerebellar tremors are produced by degenerative, demyelinating, toxic, and traumatic disorders of the cerebellum and midbrain. 2 4 8 , 2 4 9 Two other circumstances in which tremors occur include task -specific tremors, particularly orthostatic tremors, and primary writing tremors that appear only when the patient is in specific provocative circumstances (standing or writing). In addition, tremor has been associated with peripheral neuropathies, and disruption of peripheral feedback mechanisms may be responsible for some tremor disorders. Table 18.17 lists the principle etiologies of tremors. Beta -blockers such as propranolol and metoprolol, primidone, or benzodiazepines are the principle treatments for central tremor. Dopaminergic or anticholinergic agents may provide relief to parkinsonian type rest tremors. 2 4 8
patients with basal ganglia disorders reflects the disruption of function of a complex set of frontal subcortical circuits that link P.279
Nonpsychotropic drugs: epinephrine, isoproterenol, ineiaproterenol, terbutaline, xanthine (coffee, tea} theophylline, levodopa, ampheramines, thyroid hormone, hypoglycemic agents, adrenocorttcosteriods, valproate sodium
Miscellaneous agents and conditions: alcohol or sedative withdrawal, mercury, lead, arsenic, bismuth, carbon monoxide, methyl bromide, raonosodium glutamate
Essential tremor
With other movement disorders: parkinsonism, torsion dystonia, torticollis, writer's cramp, hereditary nonprogressive chorea
Cerebellar tremor
Cerebellar degenerations
Multiple sclerosis
Wilson's disease
Parkinsonian tremor
Parkinson's disease
Parkinsonian syndrome
Dopamine-blocking agents
Orfhostatic tremor
the cortex (predominantly frontal areas) to regions of the striatum, globus pallidus/substantia nigra, and thalamus. Dysfunction in basal ganglia disorders at the level either of the striatum or the globus pallidus can produce a complex array of cognitive, behavioral, motoric, and oculomotor symptoms, depending on which of the frontal subcortical circuits are disrupted. The similarity between frontal cortical dysfunction and disorders of the basal ganglia can also be linked plausibly to this frontal-subcortical architecture. There are five basic frontal-subcortical circuits that link regions of the frontal cortex to areas within the striatum, subregions within the globus pallidus and substantia nigra, and nuclei within the thalamus. 2 5 0 , 2 5 1 , 2 5 2 Each of the circuits includes a direct pathway that connects the striatum to the globus pallidus/substantia nigra and thalamus before projecting via thalamal -cortical projections back to the frontal cortex and an indirect pathway that connects the striatum to the globus pallidus externa, which projects to the subthalamic nucleus and then to the thalamus. A dynamic balance between the direct circuit and the indirect circuit on the thalamus produces the final common thalamal cortical output processed at the level of the basal ganglia. Each of these five major circuits contains multiple subchannels that connect more restricted regions of anatomy
within each of the member structures of the frontalsubcortical circuits. 2 5 3 Four subchannels (medial, lateral, dorsal, and ventral) have been identified within the dorsolateral prefrontal projection; five subchannels have been identified within the orbitofrontal projection; and two subchannels have been identified within the anterior cingulate -subcortical circuit. Each of the major circuits has a similar anatomy (Figs. 18.6 and 18.7 ). The motor circuit begins in the primary motor areas as well as the supplementary motor regions and projects to the putamen, which in turn projects to globus pallidus interna and lateral portions of the substantia nigra. These structures project to the ventral anterior and centromedian nuclei of the thalamus, which in turn projects to premotor cortex and supplementary motor area, closing the frontal-subcortical loop. The indirect pathway within the motor circuit projects to globus pallidus externa and then to the subthalamic nucleus, which in turn projects to the ventral anterior regions of the thalamus. 2 5 0 , 2 54 The oculomotor circuit originates in the frontal eye fields, which project to the body of the caudate nucleus then to the dorsal medial sector of globus pallidus interna and ventral lateral substantia nigra. These project to the ventral anterior and medial dorsal nuclei of the thalamus, which project in turn to the frontal eye fields. An indirect pathway connects the body of the caudate with globus pallidus externa and subthalamic nucleus. Dysfunction of the motor circuit results in hypokinetic or hyperkinetic disorders, whereas dysfunction of the ocular motor circuit produces supranuclear ocular motor disorders. P.280
FIGURE 18.6 Principal structures included in the five principal subcortical circuits.
FIGURE 18.7 Anatomical structures involved in the frontal-subcortical circuits. 1) cortico -striato, 2) striatoglobus pallidum interna, 3) striato-globus pallidus esterna, 4) globus pallidus externa-subthalamic nucleus, 5) subthalamic nuclear-globus plallidus interna, 6) globus pallidus interna -thalamus, 7) the femur-cortical projections.
P.281 The dorsolateral prefrontal circuit, orbitofrontal-subcortical circuit, and anterior cingulate -subcortical circuit mediate important aspects of cognition and emotion (Fig. 18.8 ). The dorsolateral prefrontal circuit mediates executive function, and executive control disorders result from interruption of the circuit or dysfunction of any member structure of the dorsolateral prefrontal -subcortical circuitry. The orbitofrontal circuit mediates aspects of civil behaviors and impulse control; dysfunction of this region results in disinhibition, tactlessness, impulsiveness, and disrupted social interaction. The anterior cingulate -subcortical circuit mediates motivation, and dysfunction of this circuitry results in apathy, disinterest, affective flattening, loss of affection, and reduced emotional valence in environmental interactions. 2 5 5 , 2 5 6 The dorsolateral prefrontal circuit begins in dorsolateral prefrontal cortical regions projecting to the dorsolateral head of the caudate nucleus and throughout the body and tail of the caudate. The caudate then projects to dorsomedial globus pallidus and rostral substantia nigra. The internal globus pallidus sends projections to ventral anterior thalamic nuclei and the substantia nigra projects to the medial dorsal thalamus. The thalamic nuclei project to the dorsolateral prefrontal cortex. An indirect circuit connects the dorsolateral caudate to globus pallidus interna, subthalamic nucleus, and medial dorsal thalamus. A lateral orbitofrontal-subcortical circuit projects to the ventral medial segment of the caudate nucleus and from there to the globus pallidus interna and substantia nigra before projecting to the ventral anterior and medial dorsal nuclei of the thalamus, which in turn project back to the lateral orbitofrontal cortex. This prefrontal -subcortical circuit may mediate the ability to alternate between behavioral sets. 2 5 1 !Limbic! ! circuits include projections from both the anterior cingulate region and the medial orbitofrontal region. The anterior cingulate projects to the nucleus
FIGURE 18.8 Illustration of the three principal behaviorally relevant frontalsubcortical circuits. (A) anterior cingulate -medial orbitofrontal cortex; (B) dorsolateral prefrontal and lateral orbitofrontal cortex, (C) interior temporal center. The anterior cingulate -medial orbito -frontal circuit (A) may not have direct and indirect pathways present in other frontal-subcortical circuits. Short association fibers connect the circuits at the level of the prefrontal cortex. GPE, globus pallidus external; GPI, globus pallidus interna; MD, medial dorsal nucleus of the thalamus; SN, substantia nigra; STN, subthalamic nucleus; VA, ventral interior nucleus of the thalamus.
P.282 accumbens and the ventral or limbic striatum. This ventral striatal region in turn projects to the ventral pallidum, which connects to the medial dorsal thalamus projecting back to frontal regions. The ventral pallidum is not clearly differentiated into internal and external segments and the existence of a direct and indirect pathway in this circuit is less certain. 2 5 1 The limbic circuitry receives input from the amygdala at several points including the ventral striatum, medial dorsal nucleus of the thalamus, and anterior cingulate and medial orbital frontal cortex. The limbic circuit also has extensive efferent connections from the ventral pallidum to limbic subcortical structures, including the hypothalamus and ventral tegmental area. 2 5 1
The frontal-subcortical circuits represent parallel processing loops and remain largely discrete at subcortical levels. The frontal portions of the frontal-subcortical circuits are connected via short association fibers, a feature that emphasizes the integrative activity of the frontal cortex, where executive and limbic function can be integrated with motivational activation to produce volitional motor and oculomotor activity. The frontal-subcortical circuits receive noncircuit information from related cortical regions. For example, posterior association cortex projects to the anterior dorsolateral prefrontal association cortex, where it can be integrated into the activity of the dorsolateral prefrontal -subcortical circuit. Similarly, limbic structures of the anterior and medial temporal cortex project widely into the limbic -frontalsubcortical circuit. Thus, the frontal-subcortical circuits serve not only to link frontal and subcortical structures in integrated loops but also to integrate information from posterior hemispheric structures, projecting to frontal regions via long, intrahemispheric tracks. Frontal -subcortical circuits may intersect with other complex cortical, subcortical circuits relevant to behavior. For example, connections from visual association regions of the temporal cortex project to visual striatunl, substantia nigra, ventral anterior thalamus, and back to visual association cortex. 2 5 7 This circuit may provide the neurobiological basis for complex visual phenomena, including hallucinations observed with basal ganglia disorders and their treatment. The principal transmitters employed in the frontal-subcortical circuits have been defined (Fig. 18.9 ). 2 5 8 The excitatory transmitter glutamate projects to the striatum from the cortex and to the thalamus from the cortex and to the cortex from the thalamus. Projections from the striatum to the globus pallidus (both internal and external segments) utilize the inhibitory transmitter GABA. Similarly, projections from globus pallidus externa to subthalamic nucleus and from globus pallidus interna to thalamus utilize GABA for inhibitory transmission. The subthalamic nucleus employs the excitatory transmitter glutamate and its connection to thalamus. Thus, the direct pathway has two consecutive inhibitory neurons, whereas the indirect pathway has two consecutive inhibitor neurons and one excitatory neuron. The influence on the thalamus via the direct pathway will be excitatory (inhibition of inhibition) whereas the thalamic influence via the indirect pathway will be inhibitory (via inhibition of the subthalamic excitatory connection). This arrangement emphasizes the dynamic balance between inhibitory and excitatory pathways in the frontal-subcortical circuit and the critical role of the thalamus as the subcortical structure that integrates the inhibitory and excitatory influences prior to its cortical projection,
representing the final integrated balance. Dopaminergic projections from substantia nigra inhibit the indirect pathway and facilitate the direct subcortical pathway (Fig. 18.7 ). Serotonergic fibers from the raphe nuclei also project widely to regions within the frontal-subcortical circuits. Enkephalin is a peptide transmitter coexisting in the striatal globus pallidus externa projection. Substance P is a peptide transmitter coexisting in the GABAergic projection from striatum to globus pallidus interna. 2 5 4 This chemoarchitecture of the frontal-subcortical circuits provides a basis for understanding the complex, motoric, cognitive, and emotional effects of dopamine depletion in Parkinson's disease and therapeutic intervention with dopaminergic and serotonergic compounds in basal ganglia disorders. Disturbances of the balance between direct (excitatory) and indirect (inhibitory) pathways in the frontal-subcortical circuits may provide a means of understanding some behavioral disturbances commonly observed in patients with basal ganglia disorders. Overactivity of thalamal -cortical projections may lead to agitation, irritability, euphoria, and anxiety common in hyperkinetic disorders and similar to the excitatory thalamal -cortical stimulation producing chorea. In contrast, apathy may be a product of reduced thalamal cortical activation and parallel the reduced thalamocortical stimulation occurring with parkinsonism. 1 2 1 The imbalance occurring between direct and indirect pathways in the motor circuit led to the introduction of pallidotomy to reduce the hyperkinetic disorders occurring with the !on-off!! phenomenon in patients chronically treated with levodopa. It also led to the development of deep brain stimulation to equalize excitatory and inhibitory input within these frontalsubcortical structures. Similar interventions may eventually allow treatment of neuropsychiatric and cognitive disturbances associated with frontal-subcortical circuit dysfunction. P.283
FIGURE 18.9 Multiple transmitters including glutamate (Glu), " -aminobutyric acid (GABA), and dopamine (DA) play major roles in the frontal-subcortical circuits. Excitatory connections are shown with solid arrows and inhibitory connections are shown with striped arrows. SN, substantia nigra.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 19 - Tics, Startle Syndromes, and Myoclonus
Tic disorders can be primary or secondary to a variety of other conditions (Table 19.1 ). The primary tic disorders to be considered include transient tic disorder, chronic motor or vocal tic disorder, adult-onset tic disorder, and GTS. Transient tic disorder consists of single or multiple motor or vocal tics that occur many times per day, nearly every day, for at least 4 weeks, but persist for no longer than 12 consecutive months. The disorder begins before the age of 18 and typically occurs in early childhood. It affects approximately 12% of children. 2,3 Chronic motor or vocal tic disorder is characterized by single or multiple motor or vocal tics but not both, occurring several times a day, nearly every day or intermittently throughout a period of more than 1 year. This disorder has its onset before the age of 18. Adult tic disorder is similar to chronic motor or vocal tic disorder but begins later in life, usually after age 30. 2 , 3 Gilles de la Tourette syndrome is characterized by multiple motor plus one or more vocal tics that occur many times per day, nearly every day for more than a year. The onset of the disorder is before the age of 18 and P.291
Chromosomal abnormalities
Down's syndrome
Fragile X syndrome
18q22 translocations
XYY male
XXX + 9p mosaicism
Lesch-Nyhan disease
Developmental
Autistic syndrome
Rett syndrome
Static encephalopathies
Degenerative
Neuroacanthocytosis
Huntington's disease
Wilson's disease
Infectious/post -infectious
PANDAS
Sydenham's chorea
Encephalitis
Rubella syndrome
Drug-induced or drug-precipitated
Anticonvulsants
Other
Stroke
the mean age of onset is approximately age 7 years (Table 19.2 ). 2 Secondary tics occur in a variety of neurological disorders (Table 19.1 ). Hereditary and chromosomal abnormalities can produce tic syndromes, and developmental disorders such as the autistic disorders (autism, Asperger's syndrome), Rett's syndrome, pervasive developmental delay, and static encephalopathies have all been associated with tic disorders. Neuroacanthocytosis is a neurodegenerative disease affecting primarily the caudate nuclei and producing tics, chorea, and a dementia syndrome. The disorder typically begins in early adulthood and is associated with a peripheral neuropathy. Huntington's disease and Wilson's disease have also been associated with tics. Among infectious and post-infectious syndromes associated with tics are Sydenham's chorea, encephalitis lethargica, viral encephalitis, and rubella syndromes. A variety of medications have been noted to induce tics including chronic treatment with neuroleptics (tardive Tourette's syndrome), levodopa and related dopaminergic agents, and anticonvulsants. Stimulants such as pemoline, dextroamphetamine, methylphenidate, and cocaine may either induce tics or precipitate them in predisposed individuals. Given the high rate of attentiondeficit hyperactivity disorder in GTS (discussed below), it is not unusual that the tics are first observed in children treated with stimulants for their attention deficit disorder. Other conditions that have been associated with tic syndromes include carbon monoxide poisoning, traumatic brain injury, and stroke. 4
Tics occur many times per day nearly every day for more than 1 year
Tics are not due to direct effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington's disease)
Source: Adapted from the Diagnostic and Statistical Manual of Mental Disorders, 4th ed 2
a two -part article describing nine French men and women with the disorder. 5 The tics of GTS usually begin around the age of 7 and vocalizations are most likely to begin at approximately 11 years of age. 1 Eye blinking is the most common symptom heralding the onset of the disorder, but rolling of the eyes, opening eyes widely, facial grimacing, nose twitching, or licking or biting of the lips are not uncommon. Presenting vocalizations include sniffing, throat clearing, coughing, panting, or spitting. 6 The tics tend to become more frequent and more complex through adolescence and then may partially abate. 7 Although temporary remissions may occur, permanent disappearance of the tics is unusual. Simple motor tics consist of eye blinking, shoulder shrugs, nose flare, or arm jerking while complex motor tics include tossing of the head, touching, rubbing, jumping, hopping, hitting oneself, squatting, sniffing one's hands, sniffing objects, licking, and echoing the movements of others and copxopraxia (Table 19.3 ). Simple local tics include throat clearing, sniffing, grunting, clicking, squeaking, coughing, and snorting while complex local tics include whistling, belching, humming, sucking, coprolalia, echolalia, and pallilalia (Table 19.3 ). Dystonic tics (repetitive, slow, head turning, or repeated dystonic moving of limbs) are common in GTS, and a few patients have coexistent persistent dystonia. 8 Gilles de la Tourette syndrome is not a purely motor disorder. Sensory tics and premonitory urges frequently precede the movements. The regions where premonitory urges are most common include the palms, shoulders, midline, abdomen, and throat. Performance of motor acts following the premonitory urge is accompanied by a sense of relief. 9, 10 There is no associated dementia syndrome and most patients complete high school and find employment despite substantial challenges posed by the tics and related disorders.
Neuropsychiatric Features
Gilles de la Tourette syndrome is characterized by a plethora of neuropsychiatric disorders (Table 19.4 ). Approximately
50% of children with GTS have co -morbid attention deficit or attention deficit -hyperactivity disorder. 11 Fifty to sixty percent of patients with GTS manifest OCD. 1 2 Obsessions and compulsions in GTS overlap phenomenologically with complex tics and include blurting obscenities, imitating the movements of others, counting compulsions, and compulsions to hurt oneself. When compared with OCD patients without tics, GTS patients with OCD have more violent, sexual
Types of Tics
Common Examples
Eyeblink
Shoulder shrug
Nose flare
Arm jerking
Touching
Rubbing
Spitting
Copropraxia
Jumping
Hopping
Hitting self
Squatting
Sniffing hands
Sniffing objects
Licking
Echokinesis
Throat clearing
Sniffing
Grunting
Clicking
Squeaking
Coughing
Snorting
Whistling
Belching
Humming
Sucking
Coprolalia
Echolalia
Palilalia
Sensory tics
Pulling sensation
Popping sensation
Urge to tic
Itch
Tightness
P.293
Conduct disorder
Uttering insults
Self-injurious behavior
Head banging
Scratching body
and symmetrical obsessions and more touching, blinking, counting, and self -damaging compulsions. They also have more sensory symptoms and more autonomic symptoms. Patients with OCD have more obsessions concerning dirt or germs and more cleaning compulsions. 1 3, 14 , 1 5 !Just right!! perceptions are also common in GTS, characterized
by the need to perform acts until they are felt to be exactly right. 1 6 Behavioral disorders including conduct disorder and oppositional defiant disorder also can complicate the course of childhood GTS. These conditions are present in approximately one-third of children first presenting for assessment of GTS. 16 Coprolalia and copropraxia are particularly problematic and dramatic symptoms in GTS. Coprolalia has been reported in 21% to 37% of series of patients with GTS. 1 The coprolalia tends to involve common visceral -type swear words; religious and deity -derived swearing is uncommon (Table 19.5 ). Copropraxia occurs in approximately 10% -15% patients and includes touching one's own genitals, obscene finger gestures, masturbatory movements, attempting to touch other's genitals, and staring or looking at the crotch. Mental coprolalia has been reported in a variable number of patients (5% -35%) and involves obsessions with repetitive, intrusive consideration of the same words involved in coprolalia. Repetitive and compulsive exhibitionism has also been reported as a manifestation of GTS. 1 7 In addition to obscene words and gestures, nonobscene complex, socially inappropriate behavior can be a manifestation of GTS. 1 8 Insulting others, adversely commenting on the characteristics of others, or the need to suppress the urge to insult others occurs in up to 40% of patients in clinical samples. Self-injurious behavior can complicate the course of GTS. Thirty -three percent of patients in one clinical investigation manifested such behaviors. Typical behaviors included head banging, body or head punching and slapping, striking the body or head with hard objects, piercing the body or poking sharp objects into it, scratching body parts, and putting hands through windows or other hard or dangerous surfaces.
structure and function. Smaller volumes of basal ganglia (putamen or caudate) have been identified in children with GTS than in normal controls. 19 Metabolic imaging using [ 1 8 F] -fluorodeoxyglucose positron emission tomography (FDGPET) has shown increased metabolism in the lateral premotor and supplementary motor regions and decreased metabolism in the caudate and thalamic nuclei. 2 0
TABLE 19.5. Coprolalia, Copropraxia, and Related Disorders Occurring in Gilles de la Tourette's Syndrome
Disorder
Manifestations
Fuck
Shit
Mother -fucker
Cunt
Prick
Cocksucker
Cockey
Copropraxia
Masturbating movements
Mental coprolalia
Other
Exhibitionism
P.294 Cerebral perfusion studies using single photon emission computerized tomography (SPECT) similarly revealed
diminished blood flow in the caudate and anterior cingulate of patients with GTS. 2 1 Studies of dopamine metabolism also showed abnormalities in GTS: binding to D 2 dopamine receptors in the caudate nucleus was greater in children with GTS than in their discordant twin, 2 2 and dopamine transporter activity (as studied with ligand -based SPECT) was increased in patients with GTS. 2 3 Electroencephalographic studies show that voluntary jerks that mimic the tics of GTS are prefaced by premovement, negative potentials, whereas no such premovement potential is evident prior to spontaneous tics. 2 4 These observations are consistent with the involuntary nature of tics. Consistent with the elevated dopamine receptor activity observed in the basal ganglia, cerebrospinal fluid levels of homovanillic acid (HVA) are reduced. This suggests that the increased receptor and transporter activity results in reduced dopamine turnover. 25 , 26
Inheritance
Genetic investigations suggest that OCD, chronic motor tics, and GTS are alternate expressions of an autosomal dominant trait. The trait is highly penetrant when all three syndromes are considered. Penetrance is gender influenced, with males more likely to manifest the syndrome than females. 2 7 , 2 8 Maternal transmission of GTS seems to be associated with greater motor tic complexity and more frequent rituals, whereas paternal transmission is associated with increased vocal tic frequency, earlier onset of vocal tics relative to motor tics, and more permanent attention deficit hyperactivity disorder.
Pathology
There have been relatively few postmortem examinations of patients with GTS. Haber and colleagues 2 9 examined one patient at autopsy and found a striking absence of dynorphin -like fibers in the dorsal part of the external segment of the globus pallidus. The ventral pallidum also showed only faint staining for this compound. Singer and colleagues 3 0 examined three patients with GTS pathologically
and found that dopamine up -take carrier sites were significantly increased in the caudate and putamen.
Pathophysiology
The available clinical neuroimaging and neuropathological data allow construction of a possible model for the pathophysiology of GTS. Autopsy and neuroimaging studies suggest a hyperactivity of dopaminergic systems in the basal ganglia, including the caudate and putamen. Genetic studies indicate that this hyperactivity is inherited as an autosomal dominant condition that may become manifest as a chronic motor tic syndrome, OCD, GTS, or GTS plus OCD. Hyperactivity within the putamen would mediate tic symptoms, as this structure is involved primarily in the motor circuitry of the frontal-subcortical circuits. 31 , 3 2 Obsession, whose content is highly emotional in nature, would be mediated through limbic portions of the frontalsubcortical circuitry, particularly the ventral striatum. 3 1, 3 2 Coprolalia and copropraxia are aspects of GTS that have been particularly difficult to explain. These emotional vocalizations may be related phylogenetically to limbic vocalizations in animals and designed to communicate fear or anger. 33, 34 Emotional communications differ from propositional language that has as its primary intention the provision of information in spoken or written form. Hyperactivity within limbic areas of the striatum may result in abnormal, involuntary activation of mechanisms mediating limbic vocalization with ejaculation of the usual human means of expressing fear and anger (cursing).
Differential Diagnosis
Secondary etiologies of GTS and tic syndromes were discussed above and they are listed in Table 19.1 . The relationship between Syndenham's chorea or group A hemolytic streptococcal infection without chorea has emerged as being particularly important. Children experiencing this infection may develop pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). 35, 36 Diagnostic criteria for PANDAS include (1 ) presence of OCD or a tic disorder; (2 ) onset between age 3 years and the beginning of puberty; (3 ) abrupt onset of
symptoms or a course characterized by dramatic exacerbations of symptoms; (4 ) onset or exacerbation of symptoms temporally related to infection with group A " hemolytic streptococcus; and (5 ) abnormal neurological examination during exacerbation (hyperactivity, choreiform movements, tics). 3 7 Evidence of a group A hemolytic streptoccocal infection may be garnered through throat culture, ASO titer, or antistreptococcal deoxyribonuclease -B titer. 3 8 Many children with this syndrome also have a trait marker for rheumatic fever susceptibility (D8/17). 3 9 A substantial number of cases currently diagnosed as idiopathic OCD, GTS, or tic syndrome likely can be explained by the PANDAS syndrome. P.295
Disorder(s) Treated
Agent
Daily Dosage
Tics
Pimozide
2!18 mg/day
Haloperidol
2!1 mg/day
Clonidine
Risperidone
6!10 mg/day
Fluoxetine
10 !40 mg/day
Fluvoxamine
Methylphenidate
5!30 mg/day
Dextroamphetamine
5!20 mg/day
Examples are provided; similar agents in each class may also be effective.
Treatment
Pharmacotherapy of GTS is summarized in Table 19.6 and examples of medications frequently used are provided (alternative agents in the same classes may have equal efficacy). Dopamine-blocking agents are the mainstay of the treatment of the tic disorder of GTS. Pimozide is the most commonly used compound, although haloperidal is a frequent alternative. 40 Side effects of pimozide include sedation,
weight gain, depression, parkinsonism, and akathisia. 4 1 Clonidine has been used to treat GTS and may be most useful in those patients with associated behavioral disturbances. 42 Some patients, however, do not respond to this agent, 43 and one double -blind, placebo-controlled study failed to demonstrate any effect of this agent in GTS. 4 4 Obsessional and compulsive symptoms in GTS have responded to treatment with selective serotonin reuptake inhibitors (SSRIs), including fluoxetine and fluvoxamine. 4 5 , 4 6 Treatment of the attention-deficit hyperactivity disorder that may accompany GTS depends on use of psychostimulants, including methylphenidate or dextroamphetamine. Twenty to twenty -five percent of patients will have an increase of tics with treatment; the majority of patients, however, will tolerate these agents well with improvement in their attention-deficit disorder. Tricyclic antidepressants, clonidine, and fluoxetine have benefitted attention deficit or hyperactivity in GTS in selected patients.
Type of Disorder
Disorders
Physiologic
Hypnic jerks
Surprise
Pathologic
Hyperekplexia
Startle syndromes
Latah
Miryachit
Startle epilepsy
Anxiety disorders
Generalized anxiety
Related disorders
P.296
Hyperekplexias
Primary hyperekplexias are autosomal dominant disorders with two phenotypic expressions. The major form includes (1 ) hyperekplexia and hypertonia in infants manifested by hesitant, wide -based gait when they begin walking; (2 ) prominent hypnagogic and sometimes generalized myoclonic jerks; (3 ) an enhanced startle response to any stimulus; (4 ) a typical autosomal dominant familial occurrence; and (5 ) amelioration with clonazepam in most cases. 4 7 The startle responses in this major form of the disease are characterized by a generalized stiffening, sometimes accompanied by a glottic sound and frequently leading to a fall without loss of consciousness. In some cases, the disorder does not become apparent until early adulthood. 4 8 In the minor form of the disease, excessive startle is
triggered by acute febrile illness in childhood or stress in adult life; this is the only feature of the condition. 4 9 The disorder has been linked to chromosome 5Q. 5 0
Startle Syndrome
Of substantial neuropsychiatric interest are the three classical startle syndromes: the Jumping Frenchman of Maine, latah, and miryachit. These three syndromes all share the four common features of echopraxia, echolalia, automatic obedience, and increased startle, and in many cases coprolalia is present. 49 Whether these disorders are neurological diseases or represent culture -bound syndromes has been the subject of debate. These conditions first came to scientific attention when George Beard observed !jumpers! ! in the Moose -head Lake region of Maine in 1880. He emphasized two features. First, he remarked on the temporariness and momentariness of the phenomenon, which was over in a second after the startle response had occurred. Second, he commented on the persistence of the syndrome, which was lifelong and usually occurred in several members of a family. Latah is a similar disorder, first described in the Malay Archipelago and miryachit was first observed in Siberia. Startle epilepsy occurs in patients with severe brain damage such as prenatal anoxic injury or Tay -Sach's disease. 4 7 Loud sounds precipitate a violent jerk with limb and trunk flexion. There is coincident desynchronization of the electroencephalographic pattern. Startle myoclonus occurs in Creutzfeldt -Jakob disease. It may occur early in the illness; patients have a startle response when the telephone rings or some other unexpected sound occurs. The response may persist until late in the disease when touching the patient, tapping their reflexes, or bumping the bed may result in an excessive startle response. Startle reactions have been seen in GTS when sudden surprise precipitates an excessive response, with or without associated exacerbation of tics. Delirious patients, particularly those experiencing withdrawal from sedative -hypnotics or depressants such as alcohol,
Related Disorders
Two related conditions that must be distinguished from startle reactions are catalepsy, which occurs when patients with narcolepsy are suddenly surprised, resulting in a loss of limb tone and a subsequent fall, and paroxysmal kinesiogenic choreoathetosis, in which patients have a brief choreoatheototic episode in response to movement. Surprise may precipitate the choreoathetotic events. 4
Myoclonus
Myoclonus consists of brief, asymmetric, and usually asynchronous jerks of sufficient intensity to move a limb or body part. Table 19.8 provides an etiologic classification of myoclonus. 4 ,5 2 Most of the causes of myoclonus are discussed in other sections of this book and will not be re addressed here. The neuropsychiatric syndromes associated with myoclonus depend on the underlying etiology of the myoclonic disorder. The epilepsies, dementias, basal ganglia degenerations, and central nervous system infections associated with myoclonus are described in the Chapters 21 , 10 , 18 , and 26 ; respectively. Palatal myoclonus differs from other forms of myoclonus in that it is very regular, beating rhythmically at rates of 60 to 200 per minute. The myoclonic movement involves the palate and in some cases also affects the larynx, pharynx, eyeballs, corner and floor of the mouth, and diaphragm. 53 , 5 4 The lesions associated with palatal myoclonus are located in
the brainstem and frequently involve the central segmental tract. At autopsy there is enlargement of the inferior olivary nucleus ipsilateral P.297
Physiologic myoclonus
Cortical dementias
Hiccup (singultus)
Alzheimer's disease
Essential myoclonus
Viral encephalopathies
Hereditary
Sporadic
Encephalitis lethargica
Arbovirus encephalitis
Epileptic myoclonus
Herpes encephalitis
Metabolic disorders
Photosensitive myoclonus
Hepatic failure
Renal failure
Infantile spasms
Hyponatremia
Hypoglycemia
Non-kerotic hyperglycemia
Biotin deficiency
Toxic encephalopathies
Symptomatic myoclonus
Drug-induced
Lithium
Tricyclic antidepressants
Gaucher's disease
Clozapine
Tatdive myoclonus
Sialidosis
Other intoxications
Ataxic syndromes
Bismuth
Aluminum
Friedreich's ataxia
Mercury
Ataxia-telangiectasia
Lead
Bromide
Strychnine
Corticobasal degeneration
Palatal myoclonus
Torsion dystonia
Wilson's disease
Huntington's disease
Parkinson's disease
Psychogenic myoclonus
P.298
Factor
Tics
Myoclonic jerks, *
Duration
Brief
Brief
Repetitive
Yes
No
Stereotyped in location
Yes
No
Premonitory urge
Yes
No
Sometimes
No
Distraction
Decreases
No effect
Voluntarily suppressible
Yes
No
Movement -related
No
Often
Treatment
to the damage of the tract and contralateral to the most affected side of the palate. Herrmann and Brown 5 6 and Yakovlev 57 noted that the muscles involved in palatal myoclonus are those derived from the branchial arches and suggested that the movements represent a release of primitive gill motions programmed into the central nervous system and released from phylogenetic suppression by lesions of the central segmental tract. Occasionally, it will be necessary to distinguish tics from myoclonus, particularly in the adult who has the new onset of a tic disorder. Table 19.9 presents the distinguishing features of these two disorders, both of which are characterized by brief, hyperkinetic movements. Tics tend to be repetitive and stereotyped compared to myoclonic jerks; they are preceded by a premonitory urge or other sensation that is lacking in myoclonus. Distraction tends to decrease tic frequency and has no effect on myoclonic jerks; tics are often voluntarily suppressible, at least for brief periods of time, whereas myoclonic jerks are not subject to voluntary control. Myoclonic jerks are often precipitated by movement, whereas tics are independent of other motor activities. Tics may be accompanied by other complex motor activities, whereas myoclonic jerks are always simple motor acts. Dopamine-blocking agents are the treatment of choice for tic disorders, whereas benzodiazapines such as clonazepam provide relief in some myoclonic disorders. Rarely, myoclonic movement disorders have a psychogenic basis; clinical features and a thorough evaluation may help identify these conditions. The character of the movement is often inconsistent in contrast to the brief, repetitive jerks characteristic of neurologically based myoclonus. There may be associated myoclonic symptoms such as nonanatomic sensory loss, nonepileptic seizures, or transient blindness or paralysis. Psychogenic myoclonus is often decreased by distraction, may be reduced by placebo treatment, and can be enhanced by suggestion. Psychogenic myoclonus often has an acute onset, sudden resolution, or spontaneous remission. Finally, there must be evidence of underlying psychopathology and no evidence of an identifiable cause for the myoclonus (Table 19.10). 5 5 Patients with psychogenic
Spontaneous remission
Acute onset
Sudden resolution
P.299
References
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 20 - Catatonia, Motoric Manifestations of Psychiatric Illnesses, and Drug-Induced Motor System Disturbances
Chapter 20 Catatonia, Motoric Manifestations of Psychiatric Illnesses, and Drug-Induced Motor System Disturbances
Movement of body, limbs, mouth, and tongue provide the only evidence for human mental life. Without speech and movement the completely paralyzed but alert individual cannot be distinguished from one in a coma. Movement provides the means by which human cognition is made manifest in the world through engineering, art, and science. Movement allows persons to meet their basic needs for food, drink, and pleasure. The complex interaction between the limbic system and the motoric system provides the basis for relating one's emotional state to speech and movement (hence the term e-motion ) and is of particular relevance in neuropsychiatry. Structures critical to normal movement include the dorsolateral prefrontal cortex (mediating willed movement), anterior cingulate (mediating motivational aspects of motoric activities), pyramidal motor system (responsible for cortically mediated movements), and extrapyramidal motor system, including the basal ganglia (responsible for mediating nonpyramidal influences on motor activity). Frontal -subcortical circuits mediating motor function are arranged in parallel with circuits involved in volitional eye movements, executive function, civil and socially integrated behavior, and motivation. 1, 2 The representations of motor, executive, and emotional function at the level of the basal ganglia account for the common occurrence of motor disturbances in patients with psychiatric illnesses and the frequent emergence of neuropsychiatric abnormalities in patients with basal ganglia diseases (Chapter 18 ). Psychotropic medications useful in controlling psychiatric symptoms commonly exert their effects on basal ganglionic structures of frontal-subcortical circuits and hence motor abnormalities (such as parkinsonism and tardive dyskinesia)
are common side effects of these agents. This chapter addresses the principal motor abnormalities occurring in psychiatrically ill patients, including catatonia, syndrome -specific motor disturbances, and movement abnormalities induced by psychotropic substances.
obtundation or coma. Negativism, including gegenhalten (active resistance to movement), may accompany the stuporous state. Stupor appears to be the extreme form of the retarded type of catatonia, characterized in its more mild form by negativism, mutism, rigidity, catalepsy, and staring. Catatonic excitement (furor) is characterized by the abrupt or rapid onset of impulsive, combative behavior. 8 Catatonia is sometimes described as a rare phenomenon that is not often seen in contemporary neuropsychiatric practice. However, adequate examination for catatonic signs is rarely performed, and when specific observations for spontaneous and solicited catatonic phenomena are made, the syndrome is not uncommon in psychiatric, neurologic, and toxic metabolic disorders. In the course of the examination it may also be observed that catatonic patients perform externally
Abnormalities of posture
Psychological pillow (patients retain their head in an elevated position as if lying on a pillow)
Limb stereotypies (movement that is not goal directed and is carried out in a uniform way)
Grimacing and facial movements (including Schnauzkrampf, consisting of marked wrinkling of the nose with pouting of the lips)
Gegenhalten (opposition movement in which patient resists passive movements of the body to precisely the same degree as the pressure exerted by examiner)
Automatic obedience (patient carries out every command given in an automatic manner)
Mitmachen (patient allows passive movement of the body made by examiner but returns limb to resting position when the examiner releases the patient)
Abnormalities of speech
Speech -prompt catatonia (patient answers with intelligible words that are the first thing that comes to mind)
Abnormalities of arousal
P.303 guided tasks (catching a ball) better than internally guided movements (throwing, kicking). 9
Etiologies of Catatonia
The catatonic syndrome may be a manifestation of idiopathic psychiatric disorders, neurological diseases, metabolic encephalopathies, or toxic conditions (Table 20.2 ). Catatonia is more common in mania than any other psychiatric illness and has been reported in approximately 30% of manic patients systematically examined for catatonic signs. 1 0 , 1 1 Subtle types of catatonia (clumsiness, awkwardness, or postural disturbance) are common among schizophrenics, whereas more severe catatonic signs such as stereotypies, mannerisms, ambitendency, catalepsy, automatic obedience, excitement, and stupor are rarely observed in contemporary psychiatric practice. 1 2 When present in schizophrenia, catatonic symptoms commonly co -occur with features of formal thought disorder, affective blunting, and neurological
Schizophrenia
Diabetic ketoacidosis
Mania
Hypercalcemia (hyperparathyroidism)
Depression
Pellagra
Neurological disorders
Porphyria
Homocystinuria
Glomerulonephritis
Hepatic encephalopathy
Hypernatremia
Herpes encephalitis
Typhoid fever
Mononucleosis
Neoplasms
Mescaline
Diencephalic lesions
Ethyl alcohol
Amphetamine
Hemorrhage
Phencyclidine
Wernicke's encephalopathy
Glutethimide withdrawal
Neoplasm
Morphine
Disulfiram
Aspirin intoxication
Traumatic contusion
Arteriovenous malformation
Cortisone
Neoplasms
Neuroleptics
Hallucinogens
Mental retardation
Pinealoma
Benzodiazepine withdrawal
Brainstem lesions
Paraneoplastic encephalopathy
individuals who are older, more cognitively impaired, more disabled in activities of daily living, and more severely depressed. 13 Patients with psychiatric illnesses and catatonia are more likely to have had a history of previous brain injury or to have a physical illness at the onset of the catatonic period than patients not exhibiting catatonic phenomena. 1 4 Neurological disorders exhibiting catatonia include basal ganglia disorders such as post-encephalitic parkinsonism, bilateral lesions of the globus pallidi, primary pallido -nigro subthalamic atrophy, right hemisphere stroke, akinetic mutism, hydrocephalus, bacterial meningitis, acquired immunodeficiency syndrome (AIDS), and idiopathic basal ganglia calcification. Disorders of the limbic system producing catatonia include herpes encephalitis, temporal lobe infarction, temporal lobe neoplasms, subacute sclerosis panencephalitis, and lyme disease with encephalitis. Diencephalic lesions can also produce catatonic behaviors including thalamotomy for Parkinson's disease, thalamic hemorrhage, Wernicke's encephalopathy, and thalamic brain tumors. Frontal lobe disorders also present with or produce catatonic syndromes, including anterior cerebral artery aneurysms, traumatic contusions, arteriovenous malformations, general paresis of the insane, frontal lobe neoplasms, and cortical venous thrombosis with frontal infarction. 1 5, 1 6, 1 7, 1 8, 1 9, 2 0 , 2 1 , 2 2 , 2 3 , 2 4 , 2 5 Miscellaneous neurological conditions reported to produce catatonia include epilepsy and postictal states, brainstem lesions, multiple sclerosis, paraneoplastic encephalopathy, pinealomas, tuberous sclerosis, and brain disorders associated with mental retardation. Systemic and metabolic disturbances described as producing catatonic symptoms include diabetic ketoacidosis, hypercalcemia (hyperparathyroidism), pellagra, porphyria, homocystinuria, postpartum psychosis, Addison's disease, Cushing's disease, hyperthyroidism, glomerulonephritis with renal failure, hepatic encephalopathy, hyponatremia, typhoid fever, mononucleosis, thrombotic, thrombocytopenic purpura, and systemic lupus erythematosus. Toxic agents and drug reactions capable of inducing catatonia include mescaline, ethyl alcohol, amphetamines, phencyclidine, diazepam, aspirin, steroids, neuroleptics, hallucinogens, dopamine depleting agents (e.g., tetrabenazine), dopamine withdrawal (e.g., levodopa), morphine, glutethimide withdrawal, and benzodiazepine withdrawal. 1 5 , 1 6 , 1 7 , 1 8 , 19 , 2 0 , 21 , 2 2 , 2 3 , 2 4 , 2 5 Table 20.2 presents a comprehensive differential diagnosis of disorders reported to produce catatonic phenomena. Two syndromes require special discussion in the context of catatonia: neuroleptic malignant syndrome and lethal or malignant catatonia. Neuroleptic malignant syndrome
(described in detail below) is a disorder characterized by severe muscle rigidity and fever in association with the use of neuroleptic medication and including at least two of the following signs: diaphoresis, dysphasia, tremor, incontinence, changes in level of consciousness ranging from confusion to coma, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, or laboratory evidence of muscle injury (e.g., elevated creatine phosphokinase). 2 6 Neuroleptic malignant syndrome can have catatonic features and it occurs primarily in patients with psychiatric illnesses receiving treatment with neuroleptic medications. The presence of a psychiatric disorder may lead to misdiagnosis as a catatonic syndrome secondary to psychotic episode. Onset of the disorder with extrapyramidaltype muscle rigidity progressing to obtundation and coma in the presence of substantial autonomic instability usually comprises an accurate diagnosis. Lethal catatonia associated with an idiopathic psychiatric disorder typically begins with extreme psychotic excitement leading to fever, exhaustion, and death mediated by dehydration and cardiac arrest. 2 1 , 27 , 2 8 Neurologic, metabolic, and toxic causes of catatonia can also be lethal and herpes encephalitis, intracranial neoplasms, systemic organ failure, and drug intoxication or withdrawal must be considered in all cases presenting with catatonia and serious medical comorbidity.
Management of Catatonia
There are three aspects to the management of patients exhibiting catatonic syndromes. First, patients must undergo comprehensive evaluation for neurologic, metabolic, and toxic causes of catatonic phenomenon. This may include neuroimaging, lumbar puncture, electroencephalography (EEG), serum tests, and drug screens, depending on the clinical circumstances. A high index of suspicion of comorbid disease must be maintained in patients presenting with a catatonic syndrome. The second aspect of management of a patient manifesting catatonic phenomena addresses the potential medical consequences of catatonia. These include aspiration, dehydration, pulmonary emboli, thrombophlebitis, urinary tract infection, and, in extreme cases, acute renal failure and cardiopulmonary arrest. 2 1 Third, in patients whose catatonia does not resolve in response to treatment of an identified underlying disorder or in whom no specific neuromedical etiologic process is identified, therapy of the catatonia itself may be warranted. Benzodiazepines (diazepam and lorazepam) and sodium amobarbital produce rapid and dramatic relief of catatonia in 50%!75% of patients
P.305 receiving the agents intravenously. There may be immediate restoration of the ability to talk and move normally. The effect tends to resolve as the action of the agent resides; some patients benefit from long-term benzodiazepine therapy. 29, 30, 31 , 32 , 33 Catatonic patients who are refractory to treatment with benzodiazepines or lorazepam usually respond well to treatment with electroconvulsive therapy (ECT). 34, 35, 36 , 37 Occasional catatonic patients have responded to treatment with lithium, anticholinergic agents, atypical antipsychotics, or carbamazepine.
Mania
Manic patients also exhibit observable motoric behaviors that are diagnostically useful (Chapter 14 ). Their speech is often rapid and circumstantial, revealing flight of ideas characterized by clang associations, rhyming, punning, joking, and grandiosity. 6 These patients are hyperactive, restless, and agitated. They may be aggressive, threatening, or menacing when upset. In some cases, they are sexually provocative or seductive and may engage in nudity or sexual
exposure. Their dress may be bizarre, outlandish, or peculiar and they may exhibit catatonic features. 6 , 4 3 Neurological soft signs may be elicited on examination more commonly in patients with mania than in normal controls. 4 4 , 4 5
Depression
Depressed patients also display a rich repertoire of motor system abnormalities relevant to clinical diagnosis
Area Affected
Movements
Eyes
Opening wide, squeezing shut, abnormal blinking, rapid lateral glances, staring, gaze deviation away from examiner
Nose
Tongue
Face
Wrinkling forehead
Extremities
kneading, grasping, tapping, rubbing, intertwining fingers, wringing hands, folding hands, spreading fingers, flinging arms
Shoulder shrugging, contortionist movements, back -arching, rocking, shuffling, hopping, turning, skipping, running, excessive leg lifting, marionette -like movements
P.306 and an understanding of their psychopathology (Chapter 14 ). Diagnostic schemes such as those of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders 2 6 include only superficial reference to agitation or retardation and do not draw attention to the importance and utility of careful observation and examination of motor behaviors in depressed patients. Depressed patients may exhibit abnormalities of gait, with slowing or diminished stride length. In conversation they frequently do not initiate interaction or react normally to the examiner. Postural slumping, body immobility, slowed body movements, delay in initiation of motor activity, and slowness of movements are evident in patients with retarded depression. Facial immobility, staring, and loss of emotional expression are also characteristic. The verbal output of depressed patients features delay of responses, shortened responses, and a reduction in the variety of themes developed in conversation or produced in response to queries by the examiner. 4 6 , 4 7 Patients with agitated depression evidence motor and facial agitation and often exhibit speech perseveration. Retarded depressions must be distinguished from apathetic syndromes (Chapter 14 ).
Anxiety
Anxious patients also exhibit motility disturbances. The eyebrows are raised and there is deepening of the furrows of the forehead and widening of the palpebral fissures. The mouth is often held slightly open, the body is rigidly upright, and when the patient is seated the knees are typically pressed together. Respiratory movements are fast and shallow, perspiration is increased, and the pupils may be dilated 48 (Chapter 17 ).
Obsessive-Compulsive Disorder
Patients with obsessive -compulsive disorder may exhibit
their compulsions and rituals during the course of the examination (Chapter 16 ). Patients may be unable to resist cleaning, touching, or avoiding certain objects, repeating specific acts, checking, counting, or pursuing other involuntary activities. They may act with obsessional slowness, devoting long periods of time to repetitive acts or trying to achieve the !just right!! sensation. Gilles de la Tourette syndrome and frontotemporal dementia are often accompanied by obsessive -compulsive disorders (Chapter 16 ).
Akathisia
Parkinsonism
Rest tremor
Rabbit syndrome
Tremor
Myoclonus
Choreoathetosis
Tardive dyskinesia
Tardive dystonia
Toricollis
Blepharospasm
Spasmodic dysphonia
Segmental/generalized dystonia
Tardive akathisia
Tardive tics
Invariant tics
Tardive myoclonus
Tardive complex
Akathisia
Akathisia is a syndrome consisting of a subjective sense of restlessness and a need to move and objective restless movements, including repeated leg crossing, swinging of the legs, lateral knee movements, pacing, and rocking from foot to foot while standing. 53 , 54 , 5 5, 5 6 Akathisia is one of the most distressing drug-induced conditions experienced by patients and promotes both noncompliance and agitation. Akathisia typically develops within the first 6 weeks of initiating therapy with a neuroleptic agent and occurs in approximately 20% of exposed individuals. 53 Akathisia is more common with higher doses of medication. Subacute drug-induced akathisia must be distinguished from pseudoakathisia, which features motor restlessness without the usual corresponding sense of a subjective need to move, and tardive akathisia, which begins after long-term exposure to neuroleptics or upon withdrawal from neuroleptic therapy. 57 Akathisia has been observed following treatment with a variety of non -neuroleptic psychotropic agents, including buspirone, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), trazodone, benzodiazepines, carbamazepine, levodopa, lithium, nefazodone, flunarizine, metoclopramide, prochlorperazine, and clozapine. 49 , 5 8 , 5 9 , 6 0 , 6 1 In addition, akathisia may occur in idiopathic Parkinson's disease 6 2 and with focal brain lesions involving the basal ganglia and frontal lobes. 6 3 Beta -blockers are the agents most likely to ameliorate akathisia. In addition, treatment with clonidine, anticholinergic agents, amantadine, and benzodiazepines may be successful. 53 , 6 4
Parkinsonism
Drug-induced parkinsonism is one of the most common side effects of neuroleptic therapy. Akinesia and rigidity are the two most common manifestations, but rest tremor of the extremities or rest tremor of the mouth and perioral structures (rabbit syndrome) may also occur. The principal differential diagnostic challenge concerns idiopathic Parkinson's disease (Chapter 18 ). Rigidity may either be of the cog-wheel or plastic type and is best elicited by performing flexion -extension movements of the wrist and elbow with the patient at rest. Incipient rigidity may be elicited by asking the patient to perform movements with
the contralateral limb while the ipsalateral limb is being tested for rigidity. Rigidity and tremor may be asym-metrical in patients with drug-induced parkinsonism. 6 5 Akinesia is manifested by a paucity of spontaneous movements and a loss of automatic movements such as blinking and swallowing. Bradykinesia, a slowness of movement, commonly accompanies this syndrome. 6 6 Loss of associated movements such as swinging the arms while walking and !en block!! turns are common subtle manifestations of drug-induced parkinsonism. Tremor is less frequent in drug-induced than idiopathic parkinsonism, but a classical type of resting tremor may be observed in some cases. Parkinsonism begins within 2 weeks of therapy with neuroleptic agents and is detectable in 50% to 80% of patients, at least in mild form. The elderly are at particularly high risk for the development of drug-induced parkinsonism. 6 6 Higher-potency neuroleptics such as perphenazine and haloperidol are more likely to induce parkinsonism than lower -potency agents and those with concomitant anticholinergic effects. Atypical antipsychotics are also less likely to induce drug-induced parkinsonism. Rabbit syndrome refers to a peculiar -appearing disorder in which the perioral tremor results in rapid movements of the lips resembling those observed around a rabbit's mouth. The tongue is typically not involved, a characteristic that helps distinguish rabbit syndrome from tardive dyskinesia. Drug-induced parkinsonism is managed by reducing the dose of the inciting agent or treatment with amantadine or an anticholinergic drug. Levodopa and related dopaminergic agents may be required in severe cases. Parkinsonism typically resolves within 2!4 weeks of intervention but may persist for 12!18 months.
Action Tremor
Many psychotropic agents are capable of inducing an action tremor. These tremors are high frequency (12 cycles per second) P.308
Tremor
Action Characteristic
Amplitude
Frequency
Etiology
Exaggerated physiological
Action
Small
Essential
Action
Small
Parkinsonian
Resting
Large
Low (4 !6 Hz)
Parkinsonian syndromes
Cerebellar
Action
Crescendo
Low
and low amplitude and represent exaggerated physiologic tremors. Tricyclic antidepressants, lithium, anticonvulsants, and neuroleptic agents have all been implicated in producing action tremors. Management typically involves stopping the offending drug. Beta -blocking drugs, primidone, or benzodiazepines such as clonazepam may be useful if the tremor -inducing agent is critical to treatment of the underlying psychiatric disorder. 49 , 6 7 , 6 8 , 6 9 , 7 0 Drug-induced action tremors must be distinguished from rest tremors associated with parkinsonism, essential tremors, and cerebellar intention tremors (Table 20.5 ). The causes of exaggerated physiological tremors are listed in Table 20.6 .
Myoclonus
Myoclonus refers to brief, irregular, and usually asymmetric jerks involving a sufficient number of motor units to produce movement of a limb or body part (Chapter 19 ). Myoclonus has been induced by a variety of drugs, including the anticonvulsants (carbamazepine and phenytoin),
Nonpsychotropic agents: epinephrine, isoproterenol, metaproterenol, ter but aline, xanthines (coffee, tea), theophylline, levodopa, amphetamines, thyroid hormone, hypoglycemic agents, adrenocorticosteroids, valproare sodium, lamotrigine, fenfluramine, flunatizine, cimetidine
Miscellaneous agents and conditions: alcohol or sedative withdrawal, mercury, lead, arsenic, carbon monoxide, methyl bromide, monosodium glutamate
Essential tremor
With other movement disorders: parkinsonism, torsion dystonia, toricollis, writer's cramp, hereditary nonprogressive chorea
Cerebellar tremor
Cerebellar degenerations
Multiple sclerosis
Wilson's disease
Parkinsonian tremor
Parkinson's disease
Idiopathic
Post -encephalitic
P.309 tricyclic antidepressants, SSRIs, metoclopramide, neuroleptics, levodopa, opiates, MAOIs, and cocaine.
Choreoathetosis
Choreoathetotic movements are relatively fast (slower than tics or myoclonus and faster than athetosis or dystonia), asymmetric, writhing movements that are irregular but relatively stereotyped. Tardive dyskinesia (discussed below) is a particular type of chorea but in some cases choreoathetosis begins relatively soon after initiation of therapy, unlike the deferred onset characteristic of the tardive syndromes. Agents reported to induce chorea include neuroleptic agents, amino -phylline, amphetamines, amoxapine, anabolic steroids, anticholinergic drugs, carbamazepine, ethosuximide, phenobarbital, phenytoin, valproic acid, baclofen, cimetidine, cocaine, cyclosporin, levodopa, lithium, methadone, oral contraceptives, theophylline, and tricyclic antidepressants. 49
Tardive Dyskinesia
Classic tardive dyskinesia is a relatively rapid choreic movement disorder that follows chronic exposure to neuroleptic medications. Patients over age 55 are particularly vulnerable to the development of tardive dyskinesia; 25% exhibit the syndrome after 1 year of neuroleptic therapy and 50% to 60% have dyskinetic
movements after 3 years of cumulative antipsychotic treatment. 69 , 7 0 Once present, tardive dyskinesia may be permanent despite cessation of antipsychotic therapy. After onset, the movements tend to be relatively stable, although they may fluctuate from examination to examination. 7 1 , 7 2 Female gender, mood disorder as the underlying psychiatric illness, history of neuroleptic -induced parkinsonism, and the presence of a brain disorder all increase the likelihood of developing tardive dyskinesia. 73 Likewise, higher doses of neuroleptics and increasing duration of neuroleptic exposure increase the prevalence of tardive dyskinesia. Tardive dyskinesia produces a distinctive syndrome with stereotyped, smacking -type movements of the lips, tongue, and cheeks. In addition, piano -playing movements of the fingers are often evident, and toes may !dance!! or show irregular flexion -extension and fanning movements. Truncal and respiratory musculature is involved in some cases. 73 In many cases, the diagnosis of tardive dyskinesia is obvious whereas in others it must be distinguished from catatonia (discussed above), neurological disorders with chorea such as Huntington's disease drug-induced disorders, or idiopathic rest tremor. Table 20.7 presents features that distinguish tardive dyskinesia from other movement disorders in patients with psychiatric illnesses. The tendency of tardive dyskinesia to involve the lower face and distal limbs and to be decreased when the limb is called into action and increased when attention is distracted from the movements helps differentiate tardive dyskinesia from other movement disorders. The ability to volitionally suppress the dyskinetic movements and the minimal subjective awareness of the movements are also helpful distinguishing features. Tardive dyskinesia must be distinguished from other types of choreiform movement disorders (Chapter 18 ). As noted above, a variety of non -neuroleptic medications are also capable of inducing choreiform
TABLE 20.7. Differential Diagnosis of Tardive Dyskinesia, Catatonia, and Huntington's Disease
Features
Tardive Dyskinesia
Catatonia
Huntington's Disease
Rest Tremor
Facial distribution
Lower
Upper and
Lower
lower
Limb distribution
Distal
Distal
Proximal>distal
Distal
Frequently
Rarely
Frequently
No
Decreases
Variable effects
No effect
Decreases
Decreases
No effect
No effect
Increases
Volitionally suppressible
Yes
Yes
No
No
Increases
No effect
No effect
Increases
Minimal
Minimal
Variable
Yes
Usually not
Yes
Usually not
No
Stable or worsen
Steadily progressive
Stable
P.310
Category
Disorders
Dystonia
Blepharospasm
Oromandibular dystonia
Cervical dystonia
Spasmodic dysphonia
Oculogyric crises
Tardive dystonia
Chorea
Tardive dyskinesia
Other choreatic disorders: Huntington's disease, Sydenham's chorea, chorea gravidarum, LeschNyhan syndrome, hyperthyroidism, hypernatremia, and drug reactions (dopaminergic, anticonvulsants, oral contraceptives, and antihistamines)
Tremor
Parkinson's disease
Drug-induced parkinsonism
Dystonic tremor
Head flopping
Tics
Neuroacanthocytosis
Miscellaneous
psychosis
Mannerisms
Habits
Facial myoclonus
Hemifacial spasm
Oculogyric crises
Drug-induced
Palatal myoclonus
P.311 movements, and these must be considered in the differential diagnosis. In addition to the classic dyskinetic movements, a variety of alternate manifestations of tardive dyskinesia have been identified, including tardive dystonia, tardive akathisia, tardive tic syndrome, tardive myoclonus, and a tardive complex consisting of three or more types of tardive movement disorders occurring simultaneously. 7 4 , 7 5 The most common manifestation of tardive dystonia is dystonic posturing of the neck such as toricollis or anterocollis. Blepharospasm with tonic or clonic eye blinking may occur and oral mandibular dystonia is not uncommon. The combination of oral mandibular dystonia and blepharospasm is known as tardive Meige's syndrome. Spasmodic dysphonia with dystonic type of speech can also be a manifestation of a tardive movement disorder. Segmental dystonia (involving two adjacent body segments such as the neck and shoulder) or generalized dystonia are rare manifestations of tardive dystonic disorder. Tardive akathisia is a pseudoakathisia syndrome with marked restlessness and forced movement with a limited subjective sense of restlessness. Tardive tics may consist of either invariant tics or a full-blown tic and vocalization disorder similar to Gilles de la Tourette's syndrome (Chapter 19 ). Finally, tardive myoclonus with intermittent, asymmetric myoclonic jerking may also occur on a tardive basis (Table 20.4 ). Tardive dyskinesia must be distinguished from a variety of hyperactive facial movements (Table 20.8 ). The pathophysiology of tardive dyskinesia is unclear. Fluorodeoxyglucose positron emission tomography reveals marked hyperactivity in the globus pallidus and primary motor cortex of patients with the syndrome, 7 6 which suggests that chronic dopamine blockade has resulted in a hyperactivity of basal ganglia motor circuits. Tardive dyskinesia is a treatment -resistant syndrome. It can be temporarily suppressed through the introduction or increased dosing of neuroleptic medications; however, this may eventually lead to exacerbation of the dyskinesia. Atypical neuroleptics such as clozapine, risperidone, olanzapine, ziprasidone, and quetiapine tend not to produce tardive dyskinesia and may allow the resolution of dyskinetic movements when administered chronically to dyskinetic patients. Dopamine-depleting agents such as reserpine may
reduce the movements. b -Adrenergic -blocking drugs such as propranolol are useful in some patients. Tardive dystonia syndromes may respond to administration of high doses of anticholinergic drugs, but these agents may worsen classical dyskinesia. Baclofen, clonazapam, or diazepam have been useful in individual patients. 7 3 Prevention of the emergence of tardive dyskinesia through minimizing use of conventional neuroleptics and employing atypical antipsychotics when chronic therapy is necessary is a more successful strategy than suppressing or eliminating tardive dyskinesia once it has appeared.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 21 - Epilepsy and Temporal -Limbic Syndromes
manifestations of limbic dysfunction (Chapter 23 ). Orbitorontal abnormalities involving the limbic system produce utilization and imitation behaviors. Addiction and related disorders appear to be mediated by the nucleus accumbens and a related system of limbic structures. Limbic hypothalamic disorders include abnormalities P.315
Syndrome Category
Syndromes
Epilepsy
Memory disorders
Amnesia
Confabulation
Paramnesia
Personality changes
Apathy
Disinhibition
Irritability
Gastaut-Geschwind syndrome
Psychoses
Schizophrenia
Mood disorders
Depression
Mania/hypomania
Euphoria
Anger/rage
Ecstacy/religious feelings
Hyperorality
Hypersexuality
Hyposexuality
Paraphilia
Utilization behavior
Imitation behavior
Limbichypothalamic syndromes
Precocious puberty
Kleine-Levin syndrome
Miscellaneous
Autonomic dysfunction
Anxiety
Aggression
Agitation
Dissociative disorder
Gourmand syndrome
of eating and appetite, disorders of sexual function, precocious puberty, disorders of thirst and drinking, and the Kleine-Levin syndrome (Chapter 23 ). In addition, autonomic dysfunction, anxiety, agitation, aggression, dissociative disorders, and the Gourmand syndrome (preoccupation with food) also reflect limbic dysfunction. Seizures and epileptic disorders will be presented first in this chapter, with an emphasis on temporal lobe epilepsy and related conditions, and then non -epileptic P.316 temporal -limbic and related disorders not discussed in other chapters, particularly the Kl!ver -Bucy syndrome, will be described.
Epilepsy
The term epilepsy derives from the Greek epilepsia, meaning "to take hold or to seize."! 1 Epilepsy is a common disorder affecting approximately 1% of the population and may involve individuals of any age. It is associated with a plethora of behavioral changes ranging from minor alterations of consciousness during a brief seizure to chronic schizophrenia -like psychoses and affective disorders persisting throughout the interictal period. Some of the behaviors observed in epileptic patients are a direct manifestation of the epileptic cerebral discharge, whereas others may be related to the existence of a lesion giving rise to both the epilepsy and the behavioral changes. The effects of chronic anticonvulsant therapy and the psychological consequences of suffering from an unpredictable, socially disabling disease also contribute to the behavioral alterations of epileptic patients.
syndromes (Fig. 21.1 ). Epilepsies are characterized by recurrent seizures and their classification is based on a variety of types of information in addition to seizure type such as age of onset, intellectual development, findings on neurological examination, and results of neuroimaging studies. 2 No seizure type is pathognomonic of any epileptic syndromes and most epileptic syndrome involve more than one type of seizure. When evaluating a patient presenting with a seizure, the first consideration is whether the seizure is one manifestation of an epileptic syndrome or secondary to some other condition. Seizures also must be distinguished from a variety of nonseizure causes of loss of consciousness or transient behavioral disturbances (Table 21.2 ). These include pseudoepileptic seizures, syncope, hypoglycemia, delirium, transient ischemic attacks, sleep disorders including narcolepsy and rapid eye movement (REM) behavior
FIGURE 21.1 Differential diagnostic approach to seizures. (Table 22.3 provides additional information on seizures and Table 22.4 provides information on epilepsies.)
P.317
TABLE 21.2. Causes of Loss of Consciousness or Transient Behavioral Changes to Be Distinguished from Epileptic
Systematic disorders
Syncope
Paroxysmal ataxia
Respiratory syncope
Tics
Hypotensive syncope
Cardiac syncope
Heart block
Myoclonus
Asterixis
Circulatory syncope
Hypovolemia
Pulmonary embolism
Sleep disorders
Narcolepsy
Drug-related syncope
Idiopathic hypersomnolence
Nitrates
Isolated cataplexy
Sleep apnea
Vasodilators
Antihypertensive
Night terrors
Reflex syncope
Enuresis
Bruxism
Other reflex triggers (glossopharyngeal, postmicturition, post-tussive, ocular, splanchnic, cerebral, esophageal)
Endocrine disorders
Psychiatric disorders
Hypoglycemia
Psychogenic seizures
Hyperglycemia
Episodic dyscontrol
Pheochromocytoma
Malingering
Cardnoid syndrome
Dissociative states
Psychogenic fugue
Depersonalization
Self-mutilatory behavior
Neurologic disorders
Anxiety
Panic attacks
Cerebrovascular events
Hyperventilation
Childhood disorders
Drop attacks
Temper tantrums
Migraine
P.318
I . Partial seizures A. Simple partial seizures (consciousness not impaired) 1 . With motor signs a. Focal motor without march b . Focal motor with march (jacksonian) c. Versive d . Postural e. Phonatory (vocalization or arrest of speech) 2 . With somatosensory or special sensory symptoms (simple
hallucinations, e.g., tingling, light flashes, buzzing) a. Somatosensory b . Visual c. Auditory d . Olfactory e. Gustatory f . Vertiginous 3 . With autonomic symptoms or signs (including epigastric sensation, pallor, sweating, flushing, piloerection, and pupillary dilation) 4 . With psychic symptoms (disturbance of higher cerebral function); these symptoms rarely occur without impairment of consciousness and are much more commonly experienced as complex partial seizures a. Dysphasic b . Dynamic (e.g., dj -vu) c. Cognitive (e.g., dreamy states, distortions of time sense) d . Affective (fear, anger, etc.) e. Illusions (e.g., macropsia) f . Structured hallucinations (e.g., music, scenes) B. Complex partial seizures (with impairment of consciousness; may sometimes begin with simple symptomatology) 1 . Simple partial onset followed by impairment of consciousness a. With simple -partial features (I.A.1"I.A.4) followed by impaired consciousness b . With automatisms 2 . With impairment of consciousness at onset a. With impairment of consciousness only b . With automatisms
C . Partial seizures evolving to secondarily generalized seizures (may be generalized tonic -clomc, tonic, or clonk) 1 . Simpie -partial seizures (I.A) evolving to generalized seizures 2 . Complex-partial seizures (I.B) evolving to generalized seizures 3 . Simple -partial seizures evolving to complex -partial seizures evolving to generalized seizures II. Generalized Seizures A. Absence seizures (typical) 1 . Impairment of consciousness only 2 . With mild clonic components 3 . With atonic components 4 . With tonic components 5 . With automatism 6 . With autonomic components (2 through 6 may be used alone or in combination). B. Atypical absence 1 . Changes in tone that are more pronounced than in II.A.1 2 . Onset and/or cessation that is not abrupt C . Myoclonic seizures; myoclonic jerks (single or multiple) D . Clonic seizures E . Tonic seizures F . Tonic -clonic seizures G . Atonic seizures (astatic) H. Combinations of the above may occur, e.g., C and G, C and E
disorder, intermittent movement disorders, psychogenic seizures, rage attacks, dissociative states, and anxietyrelated syndromes. 3,4 In children, seizures must be distinguished from migraine, night terrors, hyperventilation attacks, temper tantrums, Sandifer's syndrome (episodic tonic axial extension caused by hiatus hernia), breath holding spells, pallid infantile syncope, cardiac disorders,
cataplexy, and movement disorders. 5 Seizures associated with epileptic syndromes may be either partial or generalized (Table 21.3 ). Simple -partial seizures have a focal onset and produce no impairment of consciousness. There may focal be motor manifestations (limb movement, head turning, postural changes, vocalization), somatosensory symptoms (visual hallucinations, auditory hallucinations, etc.), autonomic signs, or "psychic"! symptoms such as aphasia. P.319
I . Localization -related (focal, local, partial) epilepsies and syndromes 1 . Idiopathic (with age -related onset) Benign childhood epilepsy with centre Temporal spikes Childhood epilepsy with occipital paroxysms Primary reading epilepsy 2 . Symptomatic Chronic progressive epilepsia partialis continua of childhood (Kojewnikow's syndrome) Syndromes characterized by seizures with specific modes of precipitation (for example, reflex epilepsy) Temporal lobe epilepsies (amygdalohippocampal, lateral) Frontal lobe epilepsies (supplementary motor, cingulate, anterior frontopolar, orbitofrontal, dorsolateral, opercular, motor cortex) Parietal lobe epilepsies Occipital lobe epilepsies 3 . Cryprogenic II. Generalized epilepsies and syndromes 1 . Idiopathic (with age -related onset) Benign neonatal familial convulsions
Benign neonatal convulsions Childhood absence epilepsy (pyknolepsy) Juvenile absence epilepsy Juvenile myoclonic epilepsy Epilepsy with grand mal seizures (generalized tonic -clonic seizures) on awakening Other generalized idiopathic epilepsies not defined above Epilepsies with seizures precipitated by specific modes of activation 2 . Cryptogenic or symptomatic West syndrome (infantile spasms, BlitzNick-Salaam Krmpfe) Lennox -Gastaut syndrome Epilepsy with myoctonic -astatic seizures Epilepsy with myoclonic absences 3 . Symptomatic a. Nonspecific cause Early myoclonic encephalopathy Early infantile epileptic encephalopathy with suppressionburst Other symptomatic generalized epilepsies not defined above b . Specific syndromes Epileptic seizures complicating disease states III . Epilepsies and syndromes undetermined, whether focal or generalized 1 . With both generalized and focal seizures Neonatal seizures Severe myoclonic epilepsy in infancy Epilepsy with continuous spike-wave activity during slow-wave sleep Acquired epileptic aphasia (Landau Kleffner syndrome) Other undetermined epilepsies not defined above
2 . Without unequivocal generalized or focal seizures IV . Special syndromes 1 . Situation -related seizures Febrile convulsions 2 . Isolated seizures or isolated status epilepticus
Complex-partial seizures involve impairment of consciousness. Impaired consciousness may be the only manifestation of the seizure or there may be associated automatisms. Seizures with psychic symptoms commonly evolve to complex -partial seizures with impaired consciousness. Partial seizures may spread to adjacent structures, producing secondary generalized seizures of tonic -clonic, tonic, or clonic type. Generalized seizures include absence seizures, atypical absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonicclonic seizures, and atonic (astatic) seizures or combinations of any of these. Epilepsies consist of recurrent seizures. Table 21.4 provides the international classification of epilepsies and epileptic syndromes. 6 The primary distinction among the epileptic syndromes are those that are localization related and those that are generalized. Localization -related epilepsies include idiopathic syndromes such as benign childhood epilepsy with centrotemporal spikes, childhood epilepsy with occipital paroxysms, and primary reading epilepsy. Symptomatic localization -related epilepsies are those most important in neuropsychiatry and include the temporal lobe epilepsies and frontal lobe epilepsies. Cryptogenic localization -related epilepsies are those of undetermined etiology. Among the generalized epilepsies are a series of idiopathic syndromes, disorders that may be either cryptogenic or symptomatic, and conditions that are symptomatic and of known cause. Idiopathic generalized epilepsies include benign neonatal convulsions, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and other generalized idiopathic P.320 epilepsies. Disorders that may be either cryptogenic or symptomatic include infantile spasms, West syndrome, Lennox -Gastaut syndrome, and epilepsy with myoclonic seizures or absences. Symptomatic generalized epilepsies include myoclonic encephalopathies and epileptic seizures complicating disease states such as the phakomatoses (e.g., tuberous sclerosis). Syndromes whose focal or generalized origin is unknown include acquired epileptic aphasia (Landau -Kieffner syndrome) and severe myoclonic epilepsy in infancy. Special syndromes whose origins are uncertain include febrile convulsions and isolated seizures (Table
21.4 ). Among the most challenging differential diagnoses confronting the clinician caring for patients with epilepsy is identification of pseudoseizures or pseudoepileptic seizures. These events may closely imitate partial -complex or generalized seizures although they typically have a more gradual onset, less stereotyped body movements, less tongue biting, less micturition and defecation, less self injury, limited impairment of consciousness, brief or no postictal confusion and a longer duration of seizures activity (Table 21.5 ) 4 ,7 (see also Chapter 22 ). Interictal electroencephalograms (EEGs) may be of little value in distinguishing the two conditions. The EEGs obtained during the event may capture the epileptic activity in those with epilepsy -related seizures, and telemetry with video monitoring may help to distinguish the two disorders. Prolactin is elevated in approximately 80% of patients with partial -complex and generalized seizures and is not elevated in those with nonepileptic seizures. The elevation is maximal approximately 20 minutes after the episode and is elevated from 3 to 10 times above baseline levels. 8 Reduction or elimination of anticonvulsants will exacerbate epileptic seizures and typically has little effect on pseudo-epileptic seizures. Pseudoepileptic seizures occur in up to 20% of epileptics and are a manifestation of significant concomitant psychopathology. Among the types of psychopathology occurring in patients with pseudoepileptic seizures, personality disorders such as borderline personality and antisocial personality are most common. Depression is a frequent
Characteristic
Pseudoepileptic
Epileptic
Clinical features
Onset
Often gradual
Abrupt
Body movements
Struggling, asynchronous
Biting
Tongue
Micturition
Rare
Common
Defecation
Rare
Occasional
Self-injury
Rare
Common
Postictal confusion
Absent
Present
Consciousness
Lost
Duration
Yes
No
EEG
Interictal
Abnormal
Abnormal
Ictal
No change on
Abnormal
artifact
Neuroendocrinology
Prolactin
No change
Increase
No increase in seizures
Increase in seizures
P.321 finding. Bipolar illness may also be observed and some patients satisfy criteria for Briquet's syndrome (somatization disorder). 9
Parietal Disorder
The least intensively studied of the epilepsy -associated behavioral disorders are the parietal disturbances. These anticipate the occurrence of seizures by days or weeks, are most typical of the severe epilepsies, and are characterized by vague changes in mood, irritability, or, occasionally, psychosis. 10
Personality changes
Mood disturbances
Dissociative disturbances
Depersonalization
Multiple personality
Aggression
Partial -complex seizures may give rise to psychomotor automatisms that are usually simple, perseverative, poorly executed, purposeless motor behaviors (Table 21.7 ). Typical examples are pushing, groping, chewing, swallowing, spitting, lip smacking, rubbing, and plucking. Automatisms preceded by an initial motionless stare typically originate in the temporal lobe whereas automatisms without an initial stare usually originate from nontemporal lobe areas. 11 Speech automatisms may include shouting, screaming, or verbal reiteration such as repeating a brief statement over and over. Ictal changes of affect include epileptic laughter (gelastic seizures) or crying (dacrystic or quiritarian seizures). More complex automatisms include running (cursive seizures), drinking, removal of clothing, and masturbation. Directed aggression in the course of seizures is extremely rare, although injury may occur from poorly directed scratching, pushing, or agitated behavior occurring during the ictal or postictal confusional period. In some cases, status epilepticus with prolonged psychomotor
automatisms may occur. Such patients have confusional behavior with automatisms persisting for hours to days. Any combination of these phenomena may occur in TLE and in some cases a temporal lobe "march"! can be discerned, with one symptom followed by another as the seizure activity spreads within temporal -limbic structures. Partial -complex seizures comprised of a P.322
Intellectual symptomatology
Psychomotor symptomatology
Aphasia
Memory distortion
Incoordination
Dj
vu, jamais vu
Negativism
Staring
Dj
pen se
Pushing
Cognitive alterations
Groping
Dreamy state
Searching
Depersonalization
Chewing
Forced thinking
Swallowing
Thought blocking
Spitting
Lip smacking
Rubbing
Fear
Plucking
Depression
Speech automatisms
Miscellaneous
Shouting
Screaming
Unpleasant experience
Verbal reiteration
Anxiety
Embarrassment
Affective automatisms
Anger, irritability
Psycho sensory
symptomatology
Illusions
Complex automatisms
Hallucinations
Auditory
Drinking
Visual
Undressing
Gustatory
Masturbation
Olfactory
Formication (tactile)
Experential symptomatology
Compound forms
Feeling a presence
Feeling possessed
Ictal psychosis
Feeling dead
combination of hallucinations, thought and memory disturbances, and psychomotor automatisms may produce an ictal psychosis. Automatisms may occur during petit mal seizures as well as during complex -partial seizures and the two must be distinguished to allow appropriate therapeutic decisions. Table 21.8 contrasts the typical motor characteristics of these two types of seizures.
Postictal Phenomena
Complex automatisms can also occur during the postictal confusional state immediately following a seizure. The postictal confusional period may last from minutes to hours and in some cases the initiating seizure may have been so brief as to go unnoticed. During the postictal period, the patient may talk or walk around, but is usually disoriented and amnestic for both the ictal and postictal P.323
TABLE 21.8. Characteristics that Distinguish Complex Partial Seizures Manifested Solely by Impaired Consciousness and Petit Mal Seizures
Characteristic
ComplexPartial Seizures
Age of onset
Childhood
Aura
Yes
No
Duration
Minutes
Seconds
Frequency
Precipitants
No
Hyperventilation
Postictal confusion
Yes
No
EEG
Etiology
Genetic
Treatment
Phenytoin
Ethosuximide
Carbamazepine
Valproate
Valproate
episode. It may be impossible to distinguish ictal and postictal behavioral activity unless the patient has on -going EEG monitoring.
compared to patients with other types of epilepsy. The presence of cognitive impairment and mental retardation is significantly associated with increased psychopathology among patients with epilepsy. Likewise, intractable seizures are more likely to be associated with psychopathology than are well -controlled seizure disorders. 12, 13, 14 Among patients with partial seizures and auras preceding their epileptic events, those with cognitive auras (derealization, depersonalization, dreamy states, forced thought, altered time perception) are more likely to evidence psychopathology than those with other types of auras. 15
Psychopathology in Epilepsy
Personality Alterations
The existence of an "epileptic personality"! is controversial. Several of the personality alterations formally ascribed to epileptics can now be recognized to be the consequences of re -current uncontrolled seizures with repeated anoxic insults or head injuries, the result of treatment with potentially toxic agents, or the effects of chronic institutionalization and social ostracism. Many of these factors have now been modified through use of improved anticonvulsant medications. Some types of personality traits have repeatedly been observed among patients with epilepsy, particularly those with complex -partial seizures and temporal lobe foci. Aggression, altered sexual interest, circumstantiality, decreased emotionality, dependence, passivity, lability, guilt, humorlessness, sobriety, hypergraphia, hypermoralism, irritability, obsessionalism, paranoia, philosophical interests, religiosity, sadness, sense of personal destiny, and viscosity are among the features commonly described. 1 6 The GastautGeschwind syndrome includes many of these features and is characterized by hypergraphia, hyposexuality, hyperreligiosity, exaggerated philosophical concern, interpersonal "stickiness,"! and circumstantiality. 17 , 18 , 19 In some cases, the obsessionalism manifested in interpersonal stickiness, P.324 circumstantiality, and hypergraphia may be evidenced in other ways such as excessive painting or collecting. These characteristics differentiate patients with TLE from normal controls and are among the most distinctive personality alterations that occur in patients with epileptic disorders. The symptom complex, however, can also be seen in patients suffering from other types of psychiatric illness and is not pathognomonic of epilepsy. The major instrument used for personality assessment in the clinical setting is the Minnesota Multiphasic Personality Inventory (MMPI). Application of this tool to patients with TLE has yielded varying results and the tool was not designed to identify psychopathology in patients with neurological disorders. In most cases, epileptic patients have
been found to have elevated paranoia and schizophrenia scale scores. An increased incidence of dissociative experiences, fugue states, poriomania (wondering epilepsy), border-line personality disorder, and multiple personality have been associated with epilepsy 20 , 2 1 (Chapter 22 ).
Psychoses
Among the most well -documented neuropsychiatric complications of epilepsy is a schizophrenia -like psychosis that occurs in patients with TLE. Psychosis occurs with increased frequency in all types of epilepsy, whereas the schizophrenia -like disorder is associated primarily with TLE. 22 Hill 23 was among the first to observe that some epileptic patients developed a chronic paranoid hallucinatory psychosis that resembles idiopathic schizophrenia. Slater and Beard 24 studied the occurrence of psychoses among epileptics and confirmed Hill's observation that the two disorders occur together too frequently to be ascribed to chance. In their series, the mean age of onset of psychosis was 30 years and followed the onset of epilepsy by approximately 14 years. Of the patients who had paranoid delusions and auditory hallucinations, approximately half had a formal thought disorder. There was no consistent relationship between the severity and course of the psychoses and the frequency of seizures. In several cases, the seizures had greatly diminished in frequency or ceased at the time the psychosis emerged. Slater and Beard 24 noted that the psychosis occurred specifically in patients with TLE. They observed that the patients tended to have less flattening of affect than patients with idiopathic schizophrenia, and there was an increase in obsessional traits in their personalities (pedantry, circumstantiality). The disorder was further distinguished from idiopathic schizophrenia by an absence of psychosis among family members. Most recent studies have refined, extended, and largely confirmed these original observations and have established the frequency of psychosis to be between 5% and 10% among patients with epilepsy, with higher rates found among those with complex -partial seizures and TLE. 10 Interictal psychoses may resemble nuclear schizophrenia, paranoid psychosis, or psychosis with mood symptoms. 10, 22 Risk factors for psychosis with epilepsy include complex partial -type seizures, onset of seizures in early adolescence, female gender, left -sided seizure foci within the temporal lobe (particularly in the mediobasal region), left handedness, cognitive impairment or mental retardation, and the presence of psychic auras. 10, 2 2, 25, 26, 27 Compared to patients with epilepsy and no psychosis, psychotic epileptic patients at autopsy have larger cerebral ventricles, more periventricular glyosis, and more focal cerebral damage. 26 Several types of psychoses have been associated with epilepsy and must be distinguished from the interictal
psychosis syndrome (Table 21.9 ). Parietal psychoses are those that occur in the parietal period in both localization related and generalized epilepsies. They develop gradually over days to weeks, occur primarily in severe epilepsies, and are more likely to occur during periods of increased seizure activity. 10 As noted above, ictal psychoses can occur as manifestations of psychomotor epilepsy, psychomotor status epilepticus, absence status, or spike-wave stupor. There is impairment of consciousness with delusions, hallucinations, and paranoid ideation. Typically, these
Parietal psychoses
Ictal psychoses
Postictal psychosis
Interictal psychosis
Paranoid psychosis
Anriconvulsam toxicity
Anciconvulsani withdrawal
P.325 ictal psychoses last hours to days, are most common with severe epilepsies, and occur with withdrawal of antiepileptic medication. 10 Postictal psychoses occur with complex -partial seizures or primary or secondary generalized tonic -clonic seizures. There is typically a lucid interval between the seizures and the onset of the psychosis. The psychotic period commonly lasts several days. Postictal psychoses are commonly associated with withdrawal of antiepileptic drugs, a series of recurrent seizures, or status epilepticus. 10 Postictal psychosis is also associated with later age of onset, better intellectual function, and more evidence of bilateral epilepti -form activity than chronic interictal psychosis. 29 Postictal psychoses may be precipitated by withdrawal of antiepileptic medication, which should be monitored as a possible hazard of discontinuing medication for video EEG monitoring. 3 0 Unilateral hippocampal sclerosis is frequently evident on magnetic resonance images (MRIs) of patients with postictal psychoses. 3 1 Forced normalization refers to the emergence of psychopathology when the EEG becomes normal or nearly normal compared to previous and subsequent EEG findings. 22 Psychosis is one of the forms of psychopathology that may occur under these circumstances. The syndrome is also called "alternate psychosis."! The phenomenon has been observed more often with primary generalized than localization -related epilepsies. Typically, there is a prodromal phase with insomnia, anxiety and social withdrawal, followed by either a delusional hallucinatory psychosis or a nonpsychotic syndrome with depressive features. Treatment of this syndrome depends on the resumption of at least occasional seizure activity. 10 Psychosis may be associated with anticonvulsant toxicity or anticonvulsant withdrawal or with an underlying brain
disorder that may produce psychotic disturbances (traumatic brain injury, degenerative brain disorders, etc.). Treatment of epilepsy -associated psychosis depends on the relationship of the psychosis to the seizures. Parietal, ictal, and postictal psychoses are all ameliorated by effective treatment of seizures. Psychosis associated with forced normalization may be treated by allowing occasional ictal events. Interictal psychoses usually require treatment with antipsychotic agents. Of the conventional neuroleptics, chlorpromazine and loxapine should be avoided because they lower the seizure threshold and may precipitate or exacerbate seizures in patients with epilepsy. Of the atypical antipsychotic agents, clozapine is most likely to precipitate seizures. 32 Table 21.9 summarizes the etiologies of psychosis that occur in patients with epilepsy.
Mood Disorders
Mood disorders are the most common type of psychopathology encountered in patients with epilepsy. Among patients receiving care in specialized settings, approximately 30% exhibit depressive symptoms. Depression is the most common reason for psychiatric hospitalization of epileptic patients. 33, 34 Among patients with intractable disorders, 60% have lifetime histories of depressive syndromes. 14 Similar to psychoses, mood disorders have complex relationships to ictal events. Parietal, ictal, postictal, and interictal depressive disorders have been described. Depressive twilight states associated with status epilepticus have also been noted. Forced normalization with alternate behavior disorders is frequently manifested by mood abnormalities. 2 2 Finally, depression may be related to the use of anticonvulsants or to an underlying brain disorder (Table 21.10). Depression is more common in patients with TLE than in those with other forms of epileptic syndromes. Most, but not all, studies of patients with complex -partial seizures and depression have found that depression is more common with left -sided than with right -sided lesions. 3 3, 35 , 36 Studies that did not identify more depression among patients with left temporal foci found evidence of bilateral frontal dysfunction. 37 , 38 The phenomenology of the interictal depression associated with epilepsy features anxiety, hostility, and paranoia. 3 3 , 39 The characteristics are those of an endogenous depression with chronic mood changes and occasional severe depressive episodes. Suicide and suicidal attempts are common among hospitalized epileptics. Compared to non -epileptic patients attempting suicide, those with
Ictal depression
Postical depression
P.326 epilepsy and suicidality are more likely to exhibit borderline personality disorders and impulsivity. 40 Anticonvulsants often have beneficial effects on mood. Carbamazapine, lamotrigine, and valproate have all been shown to ameliorate mood disorders in patients with epilepsy. 34 Conversely, phenobarbital and vigabatrin have been associated with depressive episodes. 3 4
Antidepressants may lower the seizure threshold and increase seizures, particularly in epileptic patients with marginal seizure control. Amoxapine, maprotiline, mianserin, and clomipramme have relatively high epileptogenic potentials. 32 Interictal elation, mania, and hypomania are much less common than depression. When they occur, they are associated with right -sided brain lesions. 34
Anxiety
Anxiety may occur as a psychological reaction to the diagnosis of epilepsy and the associated psychosocial challenges; as a parietal psychological change in the hours to days preceding a seizure; as an aura at the onset of an ictal event, as part of a partial seizure in association with epileptic psychosis or epileptic mood disorders; in association with underlying brain injury; or in association with anticonvulsant -induced mood alterations. 41 Anxiety and panic attacks can be particularly difficult to distinguish from seizures with fear as an important subjective manifestation. In general, patients with epilepsy -related fear have more brief, stereotyped attacks with associated epileptic phenomena. Electroencephalographic tracings may be useful in distinguishing the two disorders and a response to anticonvulsant agents may also be helpful.
Ictal
Sensory seizures
Genital sensations
Orgasmic sensations
Cognitive seizures
Sexual thoughts
Arousal
Motor seizures
Coital movements
Masturbation
Erection
Postal
Erection
Undressing
Interictal
Hyposexuality
Hypersexuality
Fetishism
Transvestism
Transsexualism
Voyeurism
Exhibitionism
Sadism
Masochism
Pedophilia
Frotteurism
Genital mutilation
TABLE 21.12. Neuropathologicat Diagnosis in Patients with Temporal Lobe Epilepsy Treated with Lobectomy 47
Diagnostic Group
Cases n (%)
Operation (year)
107
(43)
5.19
22.64
Inflammatory
(3)
8.62
24.75
Double pathology
18
(7)
9.53
22.33
Indefinite
25
(10)
14.72
31.24
No apparent lesion
41
(16)
15.37
28.56
38
(15)
16.93
26.77
Trauma
(3)
17.31
33.14
Developmental lesion
(2)
22.80
38.20
memory defects and those with left temporal lobe abnormalities may exhibit anomia or difficulties with verbal fluency. Executive abnormalities are often present in patients with complex -partial seizures of frontal origin. Memory performance has been correlated with both MRI, measurements of hippocampus, and post-surgical volumetric cell densities in regions CA1 and CA2 of hippocampus. 4 4, 4 5 Anticonvulsants may further impair cognition, particularly when high blood levels must be obtained for seizure control or when multiple drug regimens are required. Phenobarbital has disproportionate adverse neuropsychological effects compared to other anticonvulsants. 46
Etiologies of Seizures
Identification of seizures in an epilepsy syndrome should be followed by a careful search for the cause of the recurrent epileptic attacks. Table 21.12 presents the causes of complex -partial seizures in patients subjected to temporal lobe resection. 47 Mesial temporal sclerosis was the most common cause followed by "alien tissue"! lesions (neoplasms, hemartomas, cortical dysplasia), indefinite pathology and no apparent lesions, double pathology, inflammatory lesions, trauma, and developmental lesions. Ammon's horn sclerosis consists of loss of nerve cells in the hippocampus with accompanying fibrous glyosis and a variable degree of shrinkage and atrophy. In most cases, the nerve cell loss is most severe in the Sommer sector (HI) of the hippocampus. Ammon's horn sclerosis has been associated with febrile convulsions, birth injury, and episodes of status epilepticus. 47 Vascular malformations,
congenital cerebral malformations, and a variety of miscellaneous conditions including encephalitis, cerebral infarctions, abscesses, meningitis, and aneurysms account for the remaining cases of TLE. Neoplasms, (meningiomas, astrocytomas, glioblastomas or metastases), trauma, vascular malformations, infections, and infarctions can also produce simple -partial seizures. Most primary generalized epilepsies are genetically determined disorders.
Treatment of Epilepsy
Many agents are currently available for the treatment of epilepsy. The mechanism of action through which they exert
their anticonvulsant effects is not completely understood, but most of these agents affect ion channels and appear to decrease neuronal excitation or increase neuronal inhibition. First -line agents for partial seizures and generalized tonic clonic seizures include carbamazapine, phenytoin, and valproate (Table 21.13).
Agent
Indication
Starting Dose
Maintenance Dose
Phenytoin (Dilantin)
200"400 mg/day
Carbamazepine (Tegretol)
100 mg/day
400"1600 mg/day
Valproate (Depakote)
First -line or add -on for partial seizures, GTCS, and Lennox Gastaut syndrome
500"2500 mg/day
Phenobarbital (Bellatal)
Alternate therapy for partial seizures, GTCS, Lennox Gastaut syndrome, childhood epilepsy syndrome
30 mg/day
30"180 mg/day
Clonazepam (Klonopin)
0.25 mg/day
0.5"4 mg/day
Ethosuximide (Zarontin)
250 mg/day
750"2000 mg/day
Felbamate (Felbatol)
1200 mg/day
Gabapentin (Neurontin)
300 mg/day
900"3600 mg/day
Lamotrigine (Lamictal)
100"200 mg/day
Levetiracetam (Keppra)
1000 mg/day
Oxcarbazepine
Adjunctive
600
900"2400
(Trileptal)
mg/day
mg/day
Tiagabine (Gabatril)
15 mg/day
30"45 mg/day
Topiramate (Topomax)
Adjunctive therapy for partial, secondarily, generalized seizures, Lennox Gastaut syndrome, and primary generalized GTCS
25 "50 mg/day
200"600 mg/day
Vigabatrin (Sabril)
Adjunctive therapy for partial and secondarily generalized seizures, Lennox Gastaut syndrome, and infantile spasms
1000 mg/day
Zonisamide (Exegran)
400"600 mg/day
P.329 First -line therapy for generalized absence seizures is ethosuximide. Adjunctive therapies that have become available include felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, and zonisamide (Table 21.13). 5 0, 51 Surgical treatments for patients with epilepsy are used when seizures prove to be medically refractory. Limbic resections include anterior temporal lobectomies and amygdalohippocampectomies. Neocortical resections include extratemporal resections of lesions occurring in other cortical regions and lesionectomies aimed at specific neocortical targets (such as neoplasms or arteriovenous malformations). Other less commonly used interventions include hemispherectomy and multilobar resections, corpus callosotomy, subpial transections (used for treatment of epileptic foci in eloquent cortex), and vagus nerve stimulation. 32 There is typically substantial improvement in seizure control following surgery, even in these medically intractable cases, and there may be concomitant improvement in depression, psychosis, and aggression. Not all patients evidence behavioral improvement and in some cases depression and psychosis emerge following surgery. 22, 5 2 Vagus nerve stimulation has an increasing role in seizure treatment and appears to ameliorate depression as well as epileptic activity.
Kl!ver-Bucy Syndrome
Kl!ver and Bucy 5 3 first reported the syndrome that bears their names in 1939. They described the behavioral effects of removal of both temporal lobes in Macaque monkeys. The monkeys exhibited (1 ) "psychic blindness"! or visual agnosia; (2 ) strong oral tendencies in examining available objects (licking, gently biting, chewing, touching with lips, smelling); (3 ) a marked tendency to attend and react to visual stimuli (hypermetamorphosis); (4 ) a marked change in emotional behavior or absence of emotional reactions in the sense that motor and vocal reactions generally associated with anger and fear were not exhibited; and (5 ) an increase in sexual activities. Later reports of animals observed for longer periods of time after the surgery included descriptions of dietary changes and ingestion of food items of a type not eaten prior to the lobectomy. Further investigations revealed that the syndrome is more obvious in
animals kept in captivity than in animals subjected to the same surgery and observed in more natural social circumstances. Anatomical studies of the syndrome indicate that production of the disorder depends critically on bilateral dysfunction of the amygdaloid nuclei. Surgery targeted on the amygdala has reproduced the syndrome, and surgeries of surrounding cortical regions but leaving the amygdala and its limbic connections intact failed to cause the syndrome. Fragments of the condition, or partial Kl!ver -Bucy syndromes, have been observed with thalamic and hypothalamic lesions. Any condition with bilateral medial temporal -amygdaloid nuclear injury can produce the Kl!ver -Bucy syndrome. The most common causes include herpes encephalitis, frontotemporal dementias, traumatic brain injury, late -stage Alzheimer's disease, paraneoplastic limbic encephalitis, bilateral temporal lobe infarction, and seizure -related disorders (as a manifestation of psychomotor status or occurring in the postictal state). 54, 55 , 56, 57, 58, 59, 6 0 The Kl!ver -Bucy syndrome is difficult to modify but the behavior of some patients has improved following treatment with carbamazepine. 6 1 , 6 2 The sexual aggression sometimes observed in patients with the Kl!ver -Bucy syndrome may respond to treatment with leuprolide, a gonadotropin releasing hormone agonist that decreases testosterone levels. 6 3
Hyperoral Behaviors
Hyperoral behaviors are not confined to Kl!ver -Bucy syndrome and occur in a variety of central nervous system conditions (Table 21.14). Alterations in diet and eating are seen in frontotemporal dementia, the Gourmand syndrome, and eating disorders such as anorexia and bulimia. Hyperphagia occurs in acquired and congenital syndromes including ventromedial hypothalamic injury, the Kleine-Levin syndrome, Prader -Willi syndrome, and the Laurence -MoonBiedle syndrome. Lip biting and self -mutilation occur in Gilles de la Tourette syndrome, Lesch-Nyhan syndrome, neuroacanthocytosis, and obsessive -compulsive disorder. Oral movements are present in a variety of epileptic conditions and basal ganglia syndromes. Rett's syndrome includes hand and nail biting as manifestations. Pica, or the ingestion of non -food items, occurs in autism, mental retardation, and certain dietary deficiency states. Polydipsia occurs in major psychiatric illnesses, and belching, spitting, and rumination also occur in varied neuropsychiatric circumstances. 64 , 6 5 , 6 6, 6 7 P.330
Oral movements
Hyperorality
Tardive dyskinesia
Frontotemporal dementia
Dietary/eating compulsions
Carbohydrate craving
Hemifacial spasm
Meige's syndrome
Facial tics
Gourmand syndrome
Aberrant innervation of
Eating disorders
Miscellaneous conditions
Anorexia
Bulimia
Autism
Hyperphagia
Mental retardation
Kleine-Levin syndrome
Polydipsia"excessive drinking
Belching/eructations
Spitting
Agitation syndrome
Mental retardation
Lesch-Nyhan syndrome
Neuroacanthocytosis
Infants
Mental retardation
Gastroesophajeal disorders
Suck reflex
Infants
Dementia
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26. Mendez MF, Grau R, et al. Schizophrenia in epilepsy: seizure and psychosis variables. Neurology 1993; 43:1073"1077.
27. Umbricht D, Degreef G, et al. Postictal and chronic psychoses in patients with temporal lobe epilepsy. Am J Psychiatry 1995; 152:224"231.
28. Bruton CJ, Stevens JR, Frith CD. Epilepsy, psychosis and schizophrenia: clinical and neruopathologic correlations. Neurology 1994; 44:34"42.
29. Szabo CA, Lancman M, Stagno S. Postictal psychosis: a review. Neuropsychiatry Neuropsychol Behav Neurol 1996; 9:258"264.
30. Kanner AM, Stagno S, et al. Postictal psychiatric events during prolonged video-electroencephalographic monitoring studies. Arch Neurol 1996; 53:258"263.
31. Kanemoto K, Takeuchi J, et al. Charactristics of temporal lobe epilepsy with mesial temporal sclerosis, with special reference to psychotic episodes. Neurology 1996; 47:1199"1203.
32. McConnell H, Duncan D. Treatment of psychiatric comorbidity in epilepsy. In: McConnell HW, Snyder PJ, eds. Psychiatric Comorbidity in Epilepsy: Basic Mechanisms, Diagnosis and Treatment. Washington, DC: American Psychiatric Press, Inc., 1998:245"361.
33. Mendez MF, Cummings JL, Benson DF. Depression in epilepsy: significance and phenomenology. Arch Neurol
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34. Robertson M. Mood disorders associated with epilepsy. In: McConnell HW, Snyder PJ, eds. Psychaitric Comorbidity in Epilepsy. Washington, DC: American Psychiatric Press, 1998:133"167.
35. Altshuler LL, Devinsky O, et al. Depression, anxiety, and temporal lobe epilepsy: laterality of focus and symptoms. Arch Neurol 1990; 47:284"288.
36. Victoroff JI, Benson DF, et al. Depression in complex partial seizures. Arch Neurol 1994; 51:155"163.
37. Bromfield EB, Altshuler L, et al. Cerebral metabolism and depression in patients with complex partial seizures. Arch Neurol 1992; 49:617"623.
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43. Hermann BP, Seidenberg M, et al. Neuropsychological characteristics of the syndrome of mesial temporal lobe epilepsy. Arch Neurol 1997; 54:369"376.
44. Lencz T, McCarthy G, et al. Quantitative magnetic resonance imaging in temporal lobe epilepsy: relationship to neuropathology and neuropsychological function. Ann Neurol 1992; 31:629"637.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 22 - Dissociative States, Multiple Personality, and Hysteria
Dissociative disorders currently recognized include dissociative amnesia, dissociative fugue, dissociative identity disorder (multiple personality disorder), depersonalization disorder, and a variety of more limited dissociative phenomena such as derealization, dissociation occurring in individuals undergoing torture or coercion, trance states, and possession syndromes (Table 22.1 ). 1 Dissociative experiences are common in the general population and many normal individuals report minor dissociative or inattentive episodes such as being unable to recall part of a conversation or feeling abnormally absorbed by television programs or movies. Other experiences, however, are more unique and usually indicative of a dissociative disorder. These include being approached by people one doesn't know who call P.334
Dissociative amnesia Dissociative fugue Dissociative identity disorder multiple personality) Depersonalization disorder Other dissociative conditions Derealization Depersonalization during torture and coercion Trance states Hypnosis Possession states Ganser syndrome
one by a different name; feeling as though one is two different people; driving a car and realizing one doesn't remember part of the trip; not remembering important
events in one's life; being in a familiar place but finding it unfamiliar; finding drawings that one must have done but doesn't remember doing; seeing oneself as if looking at another person; feeling as though other people and objects are not real; finding unfamiliar things among one's belongings; feeling as though one's body is not one's own; finding oneself in a place without being aware of how one got there; or finding oneself dressed in clothes one doesn't remember buying or putting on. 2 In one large Canadian study the overall prevalence of dissociative disorder was 12.2%: 6% had dissociative amnesia, 2.8% had depersonalization disorder, and 3% had multiple personality disorder. 2
Dissociative Amnesia
Dissociative (psychogenic) amnesia refers to the inability, too extensive to be explained by normal forgetfulness, to recall important personal information. 1 Several patterns of memory impairment have been observed. In localized amnesia the individual fails to recall events that occurred during a circumscribed period of time. In selective amnesia the person can recall some but not all events during a circumscribed period of time, and the amnesia usually involves information of a highly personal nature. Generalized amnesia is characterized by a failure to recall all of a person's past life. These are the classical !amnesiacs!! brought to police stations unable to state their personal identity. Continuous amnesia is a condition featuring an inability to recall events subsequent to a specific time up to and including the present. Systematized amnesia is characterized by a loss of memory for a certain category of information such as material relating to one's family or a particular person. 1 Careful testing of individuals with localized, selective, or systematized amnesia often reveals dissociations between explicit and implicit recall involving the same periods of time. For example, a patient may be unable to recall information regarding their own past life whereas they can remember details of a family member or friend's life occurring during the same period. 2 a The amnesia usually begins and ends abruptly and its onset is typically related to emotionally stressful events. Psychogenic amnesia differs from amnestic disorders associated with identifiable neurological disorders by the absence of typical anterograde and retrograde aspects of memory loss (Chapter 7 ). Psychogenic amnesia is a conversion syndrome occurring at times of stress in patients predisposed by an underlying
psychiatric or neurologic condition. Depression is the most common predisposing illness but psychogenic amnesia also occurs in patients with mania, schizophrenia, and personality disorders. 1 Malingering accounts for a portion of cases.
Dissociative Fugue
Dissociative (psychogenic) fugue is characterized by sudden unexpected travel away from home or customary place of daily activities with an inability to recall some or all of one's past. There may be confusion about personal identity or the assumption of a new identity but patients do not regularly alternate between distinct identities as in dissociative identity (multiple personality) disorder. 1 The behavior is more purposeful and integrated than that occurring in patients in psychogenic amnesia, but the new identity is less complete than in multiple personality disorder. As in the case of dissociative amnesia, depression is the most common condition predisposing to dissociative fugue. Fugues are also more likely to occur in certain personality disorders, including histrionic, compulsive, schizoid, avoidant, and borderline personalities. 3
In addition to behavioral changes exhibited by alternate personalities, there may also be changes in pain sensitivity, galvanic skin responses, electroencephalographic (EEG) patterns, evoked response patterns, and handedness. 8,9, 10
Depersonalization Disorder
Depersonalization disorder is characterized by persistent or recurrent episodes of feeling detachment or estrangement from oneself. The individual may feel like an automaton or as if he or she is living in a dream or movie. There may be a sensation of being an outside observer of one's own body. 1 Some studies using functional neuroimaging have shown dysfunction of the left frontotemporal structures. 11
Possession States
Possession states are culturally syntonic dissociative phenomena. They include ritualized trance states such as religious possession, mediumship and channeling, and phenomena such as voodoo, witchcraft, and faith healing. 12 Some cultures have given specific names to these phenomena: Amok (Indonesia), Bebainin (Indonesia), Latah (Malaysia), Pibloktoq (Arctic), Ataquedenerbious (Latin America), and possession (India). 1 Demonic possession may be a special example of a ritualized trance state.
Idiopathic psychiatric disorders and unusual psychosocial circumstances Childhood abuse or neglect Acute stress disorder Post -traumatic stress disorder
Substance abuse Borderline personality disorder Histrionic personality disorder Compulsive personality disorder Schizoid personality disorder Avoidant personality disorder Briquet's syndrome (somatization disorder) Eating disorders Depression Schizophrenia Neurologic disorders Epilepsy Dj v, Jaimais v
Poriomania Petit mal Status Partial -complex status Seizure -related identity shifts in dissociative identity disorder Migraine Transient global amnesia Post -concussion syndrome Anosognosia with hemidepersonalization Toxic-metabolic disorders Alcoholic blackouts Drug-induced amnestic episodes Delirium Sleep disorders REM behavior disorder Narcolepsy
Somnambulism Malingering
P.336
Neurological Disorders
Neurological disorders are among the most common causes of episodic alterations in behavior that cannot be recalled, and the evaluation of any patient with periodic memory lapses must include a careful search for central nervous system disease. Epilepsy, migraine, transient global amnesia, and post-concussion syndrome all produce temporary impairment of memory. Epilepsy and migraine may be associated with dissociative phenomena and right parietal lesions with anosognosia may produce a hemidepersonalization.
Epilepsy
The diagnosis of epilepsy is not difficult if the patient manifests a typical convulsion (Chapter 21 ). In some cases, however, the patient may be amnestic for any aura preceding the ictus and may manifest psychomotor automatisms during the ictal or postictal period without a generalized convulsion. In such cases, diagnostic confusion may arise. There are several clues to the ictal nature of these events. Seizures begin abruptly in a stereotyped manner and end suddenly, although there is usually a variable period of postictal confusion. Seizures are typically short -lived, although more prolonged confusional periods
may occur in epileptic twilight states and status epilepticus. The patient is often fatigued and postictal headache is common. Behavior during the seizure or postictal state is typically simple and repetitive, lacking complexity and purpose. The patient is either partially responsive or unresponsive to external stimuli. Most patients have a history of previously diagnosed seizures or a predisposing brain injury. Patients in status epilepticus may have petit mal seizures or partial complex seizures as the underlying epileptic disorder. 13, 14, 15, 1 6 Patients may have prolonged confusional states following seizures, which must be distinguished from dissociative episodes. 17 Nonconvulsive status epilepticus from seizures originating in the frontal lobe may be particularly difficult to identify, since the motor automatisms are often bizarre. Features that may help identify frontal lobe complex -partial seizures include occurrence in clusters of many per day, brief episodes lasting less than 1 minute, sudden onset and termination with little postictal confusion, prominent complex motor automatisms, complex vocalizations, nonspecific warnings preceding the attacks, bizarre behavior during the attack that is stereotyped for individual patients, a history of similar episodes, and onset following a brain injury. 18 , 19 Epilepsy also can be a cause of depersonalization and dissociative identity disorders. Dissociative phenomena are not unusual among patients with epilepsy, particularly those with temporal lobe epilepsy. 1 0 , 2 0 In addition, patients with multiple personality and possession states have an unusual frequency of abnormal EEGs, 1 3 and switching from one personality to another has been associated with spontaneous seizures 21 or with lateralized hemispheric inactivation occurring in the course of the intracarotid amobarbital test. 22 Drake and colleagues 2 3 studied 15 patients with clinical histories of epilepsy and multiple personality and suggested the following general principles relating the two conditions: (1) temporary personality disintegration may occur as part of postictal confusion or psychosis; (2) elaboration of multiple independent personalities is more often a manifestation of personality disorder than epilepsy; (3) epilepsy and multiple personality disorder may in some cases be related to right hemispheric dysfunction; and (4) multiple or disordered personalities may be precipitated or exacerbated by anticonvulsant medications. A rare dissociated state associated with epilepsy is poriomania, 24 in which the patient experiences prolonged
episodes of aimless wandering followed by retrograde amnesia for the experience. Temporal lobe epilepsy can produce depersonalization. Experiences common in complex -partial seizures include dreamy states, micropsia, macropsia, dj V, jamais v, metamorphopsia, and anxiety. These phenomena may also occur in idiopathic depersonalization syndromes, complicating diagnostic efforts. The two syndromes can usually be distinguished by the occurrence in epileptic patients of brief and stereotyped depersonalization experiences, a history of generalized seizures, epileptiform EEG abnormalities, and a predisposing brain disease. Compared with partial -complex seizures, anxietydepersonalization syndromes are more likely to have emotional precipitants, occur more frequently (at least daily), resolve more slowly, lack postictal confusion, have an earlier age at onset, P.337 and are more likely to involve patients from families with psychiatric illness. 2,25 Patients with anxietydepersonalization also experience more depression, anxiety, irrational fears, phobias, and hypochondriacal symptoms.
Migraine
Migraine may produce recurrent episodes of automatic behavior, depersonalization, or even loss of consciousness. These patients may be amnestic for the episode. The attacks are usually preceded by visual distortions, hallucinations, vertigo, numbness, or other migrainous phenomena and typically are followed by a prominent, unilateral throbbing headache.
in body temperature, highly emotional circumstances, and pain. Transient global amnesia can usually be distinguished from psychogenic amnesia by the retention of personal identity, the character of the retrograde amnesia, and the patient's emotional upset regarding the amnesia. 26
Post-Concussion Amnesia
Amnesia is a frequent consequence of trauma and is associated with medial temporal lobe injury (Chapters 7 and 26 ). These periods of amnesia typically last a few minutes to a few hours and follow cerebral concussion. During the amnestic period, the patient may accomplish complex activities and appear to behave normally. The onset of the amnesia is associated with a blow to the head, but loss of consciousness may not necessarily occur. The most dramatic cases of post-concussion amnesia have been reported in boxers. 27, 28 Winterstein 29 described several such cases including one boxer who was amnestic for a period of several hours between the fourth round of a match and his return home that evening. During the unrecalled period he completed and won the fight, washed and dressed, collected his money, bought train tickets for himself and three friends, and traveled home. Gene Tunney, a former heavyweight champion of the world, had a similar episode in association with a training bout while preparing for his second fight with Jack Dempsey, and the experience significantly influenced his desire to retire from the ring. 30 The amnesia includes both a retrograde period preceding the concussion and a longer anterograde period following the concussion -producing blow. The victim does not recall being struck and, therefore, unless external trauma is apparent, the etiology of the amnestic episode may not be obvious.
as belonging to someone else. The depersonalization syndrome is one manifestation of anosognosia and occurs primarily in patients with right -sided parietal lobe lesions. 33, 34 Left -sided brain injuries are more likely to be associated with a general sense of depersonalization and derealization. 3 5 Depersonalization must be distinguished from delusions in which one believes that either oneself or the world has changed and from hallucinations in which one has an actual visual perception of one's own body (autoscopy) (Chapter 13 ). These experiences may simulate the delusional syndrome of subjective doubles and autoscopic hallucinations, but the depersonalized patient is usually aware that it is the experience of the self or external reality that is altered and not the self or external reality per se.
Sleep Disorders
Unrecallable behavior may occur with sleep-wakefulness disorders. Automatic unrecalled behavior may occur during the period of sleep in the case of rapid eye P.338 movement (REM) sleep disorder or somnambulism or during apparently wakeful periods in the case of narcolepsy. The REM behavior disorder is a parasomnia characterized by the occurrence of complex motor behaviors during REM sleep. Punching, kicking, and leaping from the bed have been described. The syndrome occurs predominantly in men (90%) in their 60's and 70's. An association between REM behavior disorder and Parkinsons's disease and dementia with Lewy bodies (Chapter 10 ) has been described; the disorder also has been observed following stroke and as an idiopathic condition. 36 Somnambulism (sleepwalking) occurs in 1% to 6% of the population, is more common in children than adults, and affects males more than females. In 25% of cases there is a family history of sleepwalking. Somnambulism may last for only a few seconds, with the patient simply sitting up in bed, or it may last up to an hour and include modestly complex behavior such as walking around objects, dressing, and opening doors. The patient's eyes are open and efforts to communicate may elicit slurred or mumbled responses. There is complete amnesia for the episode. Kleitman 3 7 described a man who walked along a window ledge 12 stories above the ground and returned to bed without awakening. Somnambulism usually occurs within the first 3
hours after going to bed when the patient is in stage III or stage IV sleep. In some cases, called !night terrors,!! the patient sits up in bed crying or screaming uncontrollably with a fast heart rate and rapid breathing. 3 6 Unrecalled automatic behavior may also occur in narcolepsy and other hypersomnias. Patients may perform complex behavior such as walking or driving without mishap. These patients are completely amnestic for the episodes and are surprised by their behavior when normal consciousness resumes. The episodes have been attributed to multiple micro -episodes of disturbed consciousness. 38 , 39 , 40
Ganser Syndrome
Ganser syndrome has been labeled an hysterical pseudodementia with features of depersonalization and dissociation. 41, 4 2 The syndrome includes hallucinations, prominent sensory changes of an hysterical type, alterations of consciousness with amnesia for the episodes, and verbal responses that are either illogical or !near misses.!! 42 Whittlock 42 noted that !a Ganser reaction is a hysterical pseudo-stupidity which occurs almost exclusively in jails and in old -fashioned German textbooks. It is now known to be almost always due more to conscious malingering than to unconscious stupefaction.!! However, the Ganser syndrome has occurred in association with toxic confusional states, head injuries, alcohol-related dementias, general paresis, postpartum psychoses, and a variety of psychiatric conditions, including schizophrenia and depression. 42 Also known as the syndrome of approximate answers, Ganser patients tend to reply to simple questions with answers that are incorrect but whose nature and consistency suggest that there is knowledge of the correct answer. For example, when asked how many legs a dog has, the patient may respond !3!!. When asked how many inches in a foot, they may respond !13!!; or asked how many days in the week, they may reply !8!!. 4 3 Recovery from the syndrome is usually abrupt. The patient is amnestic for the period encompassing the Ganser behavior.
Conversions Disorders
Of the somatiform disorders, it is conversion disorder that is most likely to come to neuropsychiatric attention. The older term hysteria has been used to describe a plethora of clinical phenomena. It is applied to a particular personality disorder (histrionic personality) characterized by self dramatization, excessive attention seeking, overreaction to minor events, irrational emotional outbursts, and a tendency toward manipulative suicide threats, gestures, or attempts. Epidemic or mass hysteria refers to the occurrence of similar physical symptoms or unusual behaviors that affect a group of individuals and have no identifiable neurological or medical cause. In the lay literature, hysterical has been applied to excessive emotional displays that may occur in individuals who receive unexpected favorable or unfavorable news. Briquet's syndrome is characterized by many physical complaints beginning before age 50, persisting for a period of several years, and including at least four pain symptoms, gastrointestinal symptoms, one sexual symptom, and one pseudoneurological symptom. 1 Conversion disorders (or hysterical conversion disorders) feature the occurrence of neurological symptoms in the absence of confirmatory signs of neurological disease or in excess of any disability attributable to an existing neurological condition. Conversion symptoms reported in the literature include mutism, paralysis, amnesia, blindness, ataxia, and seizures. 4 7 Neuro -ophthalmic signs consistent with hysteria include spurious blindness, nonphysiologic visual field defects such as cylindrical tunnel -shaped fields, and convergence spasm. 48 A conversion disorder is suspected when the motor or sensory disturbance fails to conform to anatomic and physiologic patterns, results change on multiple examination, or responses change with suggestion. 48 Fahn 49 has provided criteria for documented, clinically established, probable, and possible psychogenic movement disorders (Table 22.3 ). Features that suggest a psychogenic movement disorder include a sudden onset; inconsistent movements (changing characteristics over time); incongruous movements and postures (not fitting within recognized patterns or normal physiological profiles); bizarre features of the movement disorder; control of the movement disorder with suggestion; exhaustion and fatigue of the movements; spontaneous remissions; disappearance of the movements with distraction; response to placebo, psychotherapy, or physiotherapy; and history of a psychiatric disorder. The
presence of psychogenic weakness, sensory complaints, multiple somatization, self -inflicted injuries, obvious psychiatric illness, the presence of secondary gain, or involvement in litigation or compensation are also suggestive of circumstances facilitating the emergence of psychogenic movement disorders. Tremors and gait disorders are the most common psychogenic movement disorders observed in neuropsychiatric practice. Studies of psychogenic tremors reveal unusual clinical and temporal profiles, absence of other neurological signs, inconsistent and incongruous phenomenology, selective disability with preserved performance of some functions despite severe tremors, lessening or abolition of the tremor with distraction, unusual handwriting and drawing, presence of multiple somatizations, unresponsiveness to treatment, absence of evidence of neurological disease, presence of a psychiatric condition, spontaneous remission, or recovery with psychotherapy. Pseudoepileptic seizures are another relatively common manifestation of conversion disorders and can be difficult to distinguish from epileptic seizures (Chapter 21 ). Table 22.4 summarizes features that help distinguish pseudoepileptic from epileptic convulsions. 5 0 , 51 , 52 , 53 Pseudoepileptic seizures tend to last longer and exhibit more variability, occur in response to emotional precipitants, are rarely associated with incontinence or self -injury, and often terminate without evidence of postictal confusion. Out -of -phase clonic movements, forward pelvic thrusting, and side -to -side head movements P.340
Documented psychogenic movement disorder Movements are completely relieved by psychotherapy, psychological suggestion (including physiotherapy), or placebos, Remission is often dramatic, with sudden improvement occurring within a few hours or days of intervention. Clinically established psychogenic movement disorder
The disorder is inconsistent over are different when the patient is or is incongruent with a classical disorder, and at least one of the present:
Other neurological signs are present that are definitely psychogenic in nature (false weakness, false sensory findings). Multiple somatizations are present. An obvious psychiatric disturbance is present. The movement disorder disappears with distraction. Excessive (appearing deliberate) slowing of movement is present. Probable psychogenic movement disorder The movements are inconsistent or incongruent but there are no other associated features. The movements are consistent and congruent with a known neurological disorder but the movements can be made to disappear with distraction. The movements are consistent and congruent with a known neurological disorder but other signs are present that are definitely psychogenic in origin. The movements are consistent and congruent with a known neurological disorder but multiple somatizations are also present. Possible psychogenic disorder Movements are consistent and congruent with a neurological disorder and an obvious emotional disturbance is present.
are substantially more common in pseudoepileptic seizures than in epileptic seizures. 5 4 The clinician must be wary of the diagnosis of hysteria despite the apparent nonphysiologic nature of symptoms presented by the patient. Classical features of conversion disorders, including !la belle indifference,!! nonanatomical sensory loss, splitting of the midline to pain
or vibratory stimulation, changing sensory loss, and !give way!! weakness, have all been documented in patients with stroke or brain tumors. 55 , 56 , 57 Follow -up studies confirm the need for caution in the diagnosis of conversion disorder and attributing neurological symptoms to somatiform conditions. In his original study, Slater 58 found that 60% of patients diagnosed with conversion hysteria developed diagnosable neurological illness in the ensuing decade. More recently, Mace and Trimble 59 found that 15% of patients with a diagnosis of hysteria and investigated for neurological symptoms had an established neurological diagnosis 10 years later. Only 3% of the patients had relief from their original symptoms, indicating that the prognosis for recovery is poor. The significance of conversion symptoms is controversial. Psychoanalytic schools of thought conceived of the symptoms as symbolically significant, and believed that physical symptoms substituted for repressed, instinctual, and unacceptable impulses. An alternative psychodynamic explanation suggests that the symptoms represent a form of nonverbal communication between patient and physician by which the patient can covertly transmit personal needs or distress. Some believe that the patient simply exaggerates existing symptoms to focus the physician's attention, whereas others suggest that the symptoms arise directly from existing physical disturbances too subtle to be detected by the clinician. In view of the difficulties of defining, understanding, and diagnosing conversion symptoms, as well as the high rate of chronicity and emergence of medical, neurological, and psychiatric disturbances among patients P.341
Clinical Features
Pseudoepileptic Seizures
Epileptic Seizures
Age
Adolescence,
Common in
Age
Gender
1 M:4 F
1 M:1 F
Psychiatric history
Common
Variable
Place
Anywhere
Presence of others
During sleep
Rare
Frequently
Frequency
Pattern of seizure
Stereotyped
Stereotyped
Onset
Often gradual
Usually sudden
Duration
Incontinence
Rare
Micturition common
Biting
Lips
Usually tongue
Scream
During seizure
At onset mainly
Motor activity
Consciousness
Often retained
Injury
Infrequent
Frequent
Pupillary reflexes
Sluggish or nonreactive
Babinski's sign
Not seen
May be seen
Present at times
Oriented
Effect of suggestion
No effect
Rare
Frequent
Postictal headache/pain
Rare
Common
presenting with these symptoms, the most defensible clinical approach is to regard conversion phenomena as important harbingers of an underlying condition that must be identified and treated. Perhaps the best understanding of the neural mechanisms of hysteria come from functional imaging's confirmation of a classical theory. Charcot (1889) 60 theorized that hysterical paralysis reflected !dynamic or functional lesions ... of which no trace is found after death.!!61 General support of Charcot's position has been provided from regional cerebral
blood flow (rCBF) mapping using PET in a patient with hysterical left hemiparesis of 2 years duration. 62 Functional maps revealed similar activations of the appropriate premotor and cerebellar regions when the patient attempted to move either her paretic or good leg, suggesting good effort, but showed a localized failure to increase rCBF in right motor cortex with attempted movements of the left paretic limb. When she tried to move the left paretic limb, significant activations, compared to those during the contralateral condition, were found in the right anterior cingulate and right orbitofrontal cortex; these limbic regions appear to have actively inhibited movement of the left leg despite premotor and downstream cerebellar activation (see Fig. 22.1 ). These findings suggest that the orbitofrontal cortex may be the source of unconscious inhibition while the anterior cingulate functions to decouple premotor from primary motor cortex in hysterical paralysis. These same structures are activated in hypnotic paralysis, 63 lending further support to the subconscious limbic suppression of consciously directed motor systems. P.342
FIGURE 22.1 Statistical maps demonstrating relative regional blood flow increases (p < 0.001) as measured by H 2 15 O positron emission tomography (PET) resulting from movement of the right (good) leg in a patient with hysterical paralysis of the left leg. When the patient prepared to move the bad left leg, normal activation was seen in the left lateral premotor cortex and the
cerebellar hemispheres bilaterally (relative to baseline), indicating the patient's !readiness!! to move the paralyzed leg and that the hemiparalysis was not feigned. The top maps show activated regions when the normal (right) leg is moved that do not occur when attempts to move the bad (left) leg are made. The bottom maps show activated regions during attempts to move the bad (left) leg that did not occur when the good (right) leg was moved. Adapted from Marshall et al. (1997). 62
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 23 - Disturbances of Sleep, Appetite, and Sexual Behavior
Sleep Disorders
Sleep disturbances can be divided into disorders of excessive sleepiness (hypersomnias), disorders in which the patient is unable to sleep adequately (insomnias), and a variety of sleep-related conditions that do not alter the total amount of sleep but are nocturnal in occurrence (parasomnias) (Table 23.1 ).
Hypersomnias
Narcolepsy
Narcolepsy is a disorder of excessive somnolence characterized by sudden irresistible attacks of sleep. The sleep attacks often occur in combination with other features of a clinical tetrad including cataplexy, sleep paralysis, and
hypnagogic hallucinations. 4 Narcoleptic sleep attacks most commonly begin between the ages of 15 and 25 and persist throughout life. Onset of this disorder rarely occurs before the age of 10 or after the age of 50. Most patients have between one and six attacks per day. The disorder has a prevalence in the population of 0.3% to 1% and is more common in men than women. Most narcolepsy cases are sporadic, associated with a loss of the hypothalamic neuropeptide orexin; rarely, focal lesions in the pons 5 or diencephalon 6 ,7 can cause narcolepsy. Familial occurrence of narcolepsy is also common, as 10%!30% of patients demonstrate autosomal dominant inheritance of the disorder, with genetic defects localized to the HLA-DR2, DRW15, and DW6 genes. Cerebrospinal fluid level of hypocroten are decreased. 8 P.345
FIGURE 23.1 Statistical parametric maps of regional cerebral blood flow increases as measured by H 2 1 5 O positron emission tomography (PET) resulting from (A) rapid eye movement (REM) sleep compared to wakefulness in six subjects who were trained on a serial reaction time task; (B) REM sleep compared to wakefulness in five different subjects who were not trained on the serial reaction time task; (C) regions activated more during REM sleep versus wakefulness in trained subjects compared to untrained subjects. Color scale reflects t values; subject's left is on the left. Note that during REM sleep in trained subjects greater blood
flow occurs in the left premotor cortex, left thalamus, and bilateral cuneus compared to untrained subjects. These regions are also activated by learning the task that requires visual attention and right hand output, supporting the theory that REM sleep strengthens neural circuits entrained by learning during wakefulness. Adapted from Maquet et al. (2000). 3
Sleep attacks are the first manifestation of the disorder in 90% of cases, but most patients eventually develop other elements of the syndrome, with the narcolepsy -cataplexy combination being most common. 4 Cataplexy refers to the sudden loss of muscular tone and occurs in 60% of narcoleptic patients; sleep paralysis is the inability to move during the transition period from sleep and wakefulness and occurs in 20%!40% of patients; and hypnagogic and hypnopopic hallucinations are visual or auditory hallucinations occurring upon falling asleep or awakening, respectively, and are experienced by 15%!50% of narcolepsy patients. Pathophysiologically, narcolepsy results from an aberrant intrusion of rapid eye movement (REM) sleep into the waking state. The sleep attack itself represents the sudden onset of REM sleep, the sleep paralysis and cataplexy result from the loss of muscle tone that accompanies REM sleep, and the hallucinations reflect the dreams that occur during REM periods. 4 Electroencephalographic (EEG) studies also reveal the abrupt onset of REM sleep is coincident with the occurrence of the narcoleptic sleep attack. In addition to the classic clinical and EEG characteristics, narcoleptic patients also have disturbed nocturnal sleep and episodes of unrecalled automatic behavior. Narcoleptic patients are at increased risk for personality disorders, depression, and, occasionally, psychoses. 9 In addition to idiopathic and hereditary narcolepsy, symptomatic forms of hypersomnia secondary to structural neurological insults have also been reported. The majority of central nervous system (CNS) disorders associated with hypersomnia involve the brainstem or thalamus, where they can influence neurological mechanisms mediating sleep processes. Narcolepsy has been P.346
Hypersomnias
Insomnias
Parasomnias
Narcolepsy
Disorders of arousal
Primary
insomnia
Somnambulism
Secondary
Mood disturbances
Somniloquy
Night terrors
Sleep apnea
Occlusive type
Central type
Mixed forms
Toxicmetabolic hypersomnias
Medical illness
Sleep apnea
Miscellaneous conditons
Toxic conditions
Nocturnal seizures
Cluster headache
Miscellaneous insomnias
With nocturnal
Asthma
hypersomnia
myoclonus
Cardiovascular symptoms
Depression
Gastrointestinal disturbances
Painful erections
Chronic primary
Head banging
Periodic hypersomnia
insomnia
Kleine-Levin syndrome
Bruxism
Miscellaneous hypersomnias
Sleep drunkenness
Idiopathic hypersomnias
noted to occur with von Economo encephalitis lethargica, with malarial brainstem infections, and with a variety of other forms of viral encephalitis. Brainstem trauma, cerebrovascular disease, neoplasms, shunt failure without hydrocephalus, developmental disorders, and multiple sclerosis have been associated with hypersomnolence in rare cases. 10 , 12 Idiopathic hypersomnolence has also been described that is resistant to treatment. Narcolepsy usually requires treatment with amphetamines or modafinil methylphenidate, whereas cataplexy, sleep paralysis, and hypnagogic hallucinations respond best to imipramine hydrochloride.
Sleep Apnea
Sleep apnea is a potentially life -threatening illness characterized by multiple episodes of nocturnal apnea excessive snoring and daytime sleepiness. The apnea is a product of insufficient air exchange and may be of central origin, reflecting inadequate stimulation of the respiratory muscles, a product of peripheral or occlusive conditions with obstruction of the oropharynx, or the result of mixed central and peripheral components. The patients may have frequent nocturnal awakenings and complain of nocturnal insomnia with daytime fatigue and somnolence. Systemic hypertension, cardiac arrhythmias, and morning head-aches are common consequences of sleep apnea. Although P.347 extreme obesity may produce occlusive sleep apnea (Pickwickian syndrome), few sleep apnea patients are obese, and the diagnosis should be considered in any individual complaining of excessive daytime sleepiness. The diagnosis of sleep apnea is based on observation of a minimum of 30 episodes of apnea lasting for at least 10 seconds during a 7!hour period of sleep. The number of abnormal respiratory events per hour of sleep is recorded by polysomnography and reported as the apnea -hypopnea index. 13 Obstructive episodes are more common during REM than non -REM sleep stages, probably because of muscle atonia that occurs during REM stage sleep, allowing the upper airway collapse. For relief of sleep apnea, a variety of treatment modalities are used. Aggravating agents such as hypnotics and propranolol should be discontinued, sleeping upright may reduce symptoms, and loss of excessive weight should be encouraged. Protriptyline enhances ventilatory drive and may help patients with moderately severe apnea syndromes. Advanced sleep apnea may require tracheostomy to ensure adequate nocturnal ventilation. Like narcolepsy, the central form of sleep apnea may be idiopathic or may result from a
variety of CNS disorders, including syringomyelia, posterior fossa neoplasms, bulbar poliomyelitis, brainstem infarction, Shy-Drager syndrome (a parkinsonian syndrome with prominent autonomic dysfunction), and olivopontocerebellar degeneration. 1 4 , 15
Toxic-Metabolic Hypersomnias
Tolerance of CNS stimulants (amphetamines, methylphenidate, and caffeine) or their withdrawal may result in a paradoxical increase in daytime somnolence. Likewise, sustained use of depressants such as opiates, barbiturates, alcohol, antihistamines, and anxiolytics may result in excessive daytime sleep. A wide variety of medical illnesses, including systemic infections, hormonal disorders, and environmental toxins, can also produce hypersomnia either directly or by disturbing nocturnal sleep.
Periodic Hypersomnias
Periodic hypersomnias are disorders of excessive sleep that recur at prolonged intervals. Kleine-Levin syndrome is a periodic hypersomnia that involves primarily adolescent males. These patients have irregular episodes lasting for a few days or weeks and characterized by increased somnolence, increased hunger, exaggerated sexual activity, and a confusional state with hallucinations, delusions, and poor attention and memory. The episodes recur at approximately 5 -month intervals and eventually spontaneously disappear 1 7 , 1 8 or may be due to focal lesions of the pituitary-hypothalamic axis. 1 9 A syndrome sharing many of the features of the Kleine-Levin syndrome has been described in women, in which the periodic sleep disturbance is temporally linked to the menstrual cycle. 2 0
Miscellaneous Hypersomnias
In addition to the hypersomnias previously discussed, a variety of other disorders with excessive somnolence have also been described. Sleep drunkenness refers to a syndrome characterized by extended sleep with otherwise normal sleep architecture. Patients have difficulty awakening completely and are confused, uncoordinated, and slow for the first few hours after arising. 2 1 Nocturnal myoclonus and the restless legs syndrome usually cause insomnia but in some cases may present as a compensatory daytime somnolence. Excessive sleep may also occur with CNS lesions, particularly those involving the brainstem and diencephalon. Increased daytime sleepiness may follow trauma or may occur with tumors or infarctions affecting the brainstem, hypothalamus, or thalamus. 1 0 , 11 , 1 2 , A few patients demonstrate an idiopathic hypersomnia unlike any of the primary or symptomatic hypersomnias described. Also called slow-wave narcolepsy or hypersomnia with normal sleep, the syndrome is characterized solely by increased daytime sleepiness. The sleep is of the slow-wave type and, unlike the sleep of narcolepsy, does not refresh the patient. 2 2
Insomnias
Psychiatric Disorders Depression is the most prevalent cause of insomnia, accounting for approximately 20% of patients referred to sleep disorder clinics with a chief complaint of inability to sleep. Sleep during a major depressive episode is characterized by a decreased latency period between sleep onset and the beginning of the first REM period and by an increased density of REMs during REM periods. 2 3 Patients also P.348 have less total REM sleep and less deep sleep and complain of difficulty in falling and staying asleep as well as early morning awakening. Insomnia is also common in mania but rarely is the dominant clinical feature. Insomnia is a frequent complaint of patients with personality disorders and may occur in individuals with somatoform disorders, obsessive -compulsive disorders, or schizophrenia. Situational disturbances with anxiety also produce insomnia, and their greatest effect is on the time interval between retiring and sleep onset.
Toxic-Metabolic Disorders
The most common toxic conditions with insomnia involve the use of CNS stimulants and the withdrawal of CNS depressants. Amphetamines, methylphenidate, and caffeine all produce increased arousal and diminished sleep. Withdrawal of alcohol or of sedative -hypnotic agents
produces a withdrawal insomnia that may persist for up to 6 weeks following cessation of drug use. Even mildly sedating agents such as benzodiazepines, anticonvulsants, steroids, antipsychotic agents, antidepressant drugs, opiates, marijuana, and propranolol can be associated with insomnia when they are withdrawn. 2 3 A wide variety of medical conditions can produce disturbances of nocturnal sleep. Pain syndromes can be particularly disruptive and produce insomnia in patients with arthritis, headache disorders, and other chronic pain problems. Hyperthyroidism, pregnancy, gastrointestinal diseases, eating disorders, and cardiovascular disorders may also cause repeated awakening.
Sleep Apnea
Sleep apnea, as noted earlier, usually presents with excessive daytime sleepiness, but some patients, particularly those with central-type apneas, have multiple nocturnal arousals and may have insomnia as their chief complaint.
Miscellaneous Disorders
Sleep -related periodic myoclonus is a syndrome characterized by difficulty in falling asleep and sustained nocturnal awakenings associated with repetitive myoclonic jerking of the legs. The jerking occurs every 20!40 seconds for periods of a few minutes to as long as 2 hours. The disorder occurs between ages 30 and 60 and is a chronic, persistent problem. 24 Periodic nocturnal myoclonus must be distinguished from the common myoclonic jerks that occur just as one is falling asleep, myoclonic jerks occurring in the toxic -metabolic disturbances, epileptic myoclonic jerks, and flexor spasms associated with cervical spondylosis and other spinal cord diseases. 24 The restless legs syndrome is an idiopathic disturbance characterized by creeping-crawling sensations in the distal lower extremities that are most disagreeable when the patient is at rest and are relieved by walking. The sensations are most marked in the evening and night and may prevent the patient from sleeping. 2 4 The restless legs syndrome and periodic nocturnal myoclonus may present with excessive daytime sleepiness if nocturnal insomnia is severe. Brainstem lesions such as neoplasms and basilar artery strokes can produce almost complete loss of REM sleep, slow-wave sleep, or all phases of sleep. 2 5 , 2 6 , 27 Similarly, degenerative brainstem disorders such as Parkinson's disease and progressive supranuclear palsy produce diminished REM sleep and decreased total sleep time. Epileptic patients may have decreased sleep even in the absence of overt nocturnal seizures.
Chronic primary insomnia is an idiopathic sleep disturbance characterized by prolonged sleep latencies, diminished total sleep time, and decreased slow-wave sleep. The syndrome occurs in patients without identifiable psychiatric, neurological, or toxic -metabolic disturbances.
Treatment Of Insomnia
The treatment of insomnia is fraught with difficulty. Many sedativehypnotics, although effective in the first few weeks of administration, soon lose efficacy and may even exaggerate sleep problems through tolerance and withdrawal effects. Benzodiazepine sedative agents have fewer side effects than barbiturate or antihistaminic drugs but are not without adverse consequences and may lead to dependency and intellectual impairment and exaggerate the effects of alcohol or other CNS depressants. To the fullest extent possible, the clinician should direct efforts at eliminating the underlying cause of the insomnia (depression, sleep apnea, medical illness, stimulant use), encouraging the patient to regularize sleeping habits and avoiding the chronic use of sedating medications.
Parasomnias
Parasomnias are a diverse group of disorders that occur during sleep or are exacerbated by sleep but do not necessarily result in either hypersomnia or insomnia (Table 23.1 ).
Disorders Of Arousal
Sleepwalking (somnambulism), sleep-talking (somniloquy), enuresis (bedwetting), and night terrors (pavor nocturnus, incubus) are all disorders of nocturnal arousal. 2 8 Each of these nighttime events is initiated during stage IV slow-wave sleep and represents automatic behavior with incomplete arousal. The patient is in a confusional state while P.349 the behavioral automatons are executed. Although sleepwalking and sleep-talking were originally suspected to be dream related, they do not occur during REM sleep when dreams are most prevalent, and patients rarely report dream memories when awakened from a somnambulistic episode. Night terrors differ from nightmares in that the patient suddenly cries out and exhibits signs of acute anxiety, such as tachypnea, tachycardia, diaphoresis, and dilated pupils. Frequently, the patient does not awaken and has no memory of the episode the following morning. If awakened at the time of the attack, the patient may give a vague description of an apprehensive feeling but lacks the de-tailed dream recall of patients awakened from REM sleep. Stage IV sleep
Miscellaneous Conditions
Finally, there are a group of disorders whose occurrence is exaggerated during periods of nocturnal sleep. These include nocturnal seizures, cluster headache, asthma attacks, some cardiovascular and gastrointestinal symptoms, head banging (jactatio capitis nocturnus), and bruxism (tooth grinding). Penile erections occur during nocturnal REM periods and may occasionally be sustained and painful.
Appetite Disturbances
Profound loss of appetite (anorexia) or increased appetite (hyperphagia) may be produced by a number of neurological, medical, and psychiatric disorders (Table 23.2 ). Although hyperphagia frequently leads to obesity, the latter also has complex genetic, dietary, psychosocial, and activity -level determinants and is not considered separately here.
Anorexia
Loss of appetite is more commonly a product of idiopathic psychiatric conditions than of neurological or medical illness, but a few neurological diseases can produce anorexia and must be considered in the differential diagnosis. Hypothalamic lesions are more likely to cause hyperphagia than anorexia, but when the lateral hypothalamic region is involved, there may be a marked loss of appetite. Tumors
are the usual cause of hypothalamic injury, but appropriately placed vascular infarctions
Neurological disorders
Neurological disorders
Hypothalamic lesions
Hypothalamic lesions
Kleine-Levin syndrome
Psychiatric disorders
Psychiatric disorders
Depression
Mania
Anorexia nervosa
Depression
Bulimia
P.350
FIGURE 23.2 Statistical parametric maps of resting regional cerebral blood flow increases (top row) and decreases (bottom row) as measured by ( 1 23 I) -iodoamphetamine (I 1 23 IMP) single photon emission computed tomography (SPECT) in 14 females with anorexia nervosa compared to 8 normal control females. Color maps reflect uncorrected significance values with a threshold of p < 0.05. Note that anterior cingulate hypoperfusion occurs with hyperperfusion of medial temporal and thalamic regions, suggesting general limbic dysfunction in anorexia nervosa compared to controls. Adapted from Takano et al. (2001). 3 4
and infectious lesions may also produce anorexia. When such conditions occur in adolescents, they may be misdiagnosed as anorexia nervosa. 3 1 A related disorder is the diencephalic inanition syndrome that occurs in infants as a consequence of anterior hypothalamic neoplasms. 3 2 Patients typically have a clinical triad consisting of marasmus (severe weight loss), euphoria, and nystagmus. The illness ends in death by the age of 2 years. Anorexia is also seen in many degenerative brain diseases and may be particularly severe in the advanced stages of Alzheimer's disease and Huntington's disease.
Medical illnesses, including cardiopulmonary diseases, liver and kidney failure, endocrine disturbances, and infections, may produce anorexia leading to severe loss of weight. Systemic cancer may have particularly profound effects on appetite, and neoplasms of prostate, pancreas, lung, or gastrointestinal tract may present with weight loss as the first indication of their presence. Depression is the most common cause of anorexia. The loss of appetite may accompany acute grief reactions and is a principal feature of major depressive episodes. The anorexia is accompanied by sleep disturbances, loss of libido, and neuroendocrinologic alterations consistent with limbic -hypothalamic -pituitary dysfunction. Anorexia nervosa is the most dramatic of the disorders of eating and weight control. Although actual loss of appetite is uncommon until the late phases of the disorders, the patients take extreme measures to lose weight, including avoidance of high -calorie foods, self -induced vomiting, use of diuretics and laxatives, and excessive exercising. Despite these efforts, the patients manifest an intense fear of obesity and continue to feel as though overweight even when emaciated. The disorder commonly begins in adolescence, although onset may occur in the third decade and rarely even later. It rarely involves males. In most cases there is a single episode that resolves with full recovery; a few patients have a relapsing and remitting course with recurrent P.351 episodes; and a few have an unremitting course ending in death by starvation. There is a familial predisposition to the disorder, and patients with urogenital abnormalities and Turner's syndrome appear to be particularly vulnerable to the development of anorexia nervosa. Functional imaging in patients has implicated limbic dysfunction with hypoperfusion in the caudate and anterior cingulate, and hyperperfusion in the medial temporal and thalamic regions, compared to controls (see Fig. 23.2 ). 33 , 34 There is also a relationship between anorexia nervosa and affective disorder, and follow up studies show an increased incidence of mood disturbances among patients with previous episodes of anorexia nervosa. A wide variety of clinical and metabolic alterations accompany anorexia nervosa (Table 23.3 ). Most of the changes appear to be secondary to the severe weight loss and occur with starvation of any etiology. The clinically evident abnormalities include hypothermia, dependent edema, bradycardia, hypotension, constipation, and the development of lanugo. 3 5 Many endocrinologic alterations have also been described in patients with anorexia nervosa. There are diminished levels of thyroid -stimulating hormone
(thyrotropin) (TSH), thyroxin (T4), luteinizing hormone (luteotropin) (LH), follicle -stimulating hormone (FSH), and gonadal steroids. There is a prepubertal LH secretory pattern, diminished responses to luteinizing hormone releasing hormone (LHRH), impaired dexamethasone -induced suppression of cortisol secretion, and decreased response to insulin -induced hypoglycemia. Plasma cortisol and growth hormone levels are elevated. Amenorrhea occurs in all females and is the feature least likely to normalize after weight has been restored. Cerebrospinal fluid (CSF) abnormalities include decreased homovanillic acid (HVA) and 5 -hydroxyindoleacetic acid (5!HIAA) levels during the anorectic episode. Studies of sleep architecture reveal decreased REM latency similar to but less marked than the shortened REM latency found in depression. Treatment of anorexia nervosa depends on a combination of behavioral therapy, psychotherapy, and psychopharmacological treatment. In some cases, crisis -oriented intervention and forced feedings may be required to prevent death from starvation.
Hyperphagia
Hyperphagia, the pathological increase in appetite, is a relatively rare symptom that may complicate neurological or psychiatric disorders. Lesions of the ventromedial hypothalamus commonly produce hyperphagia that may be associated with diabetes insipidus, rage,
Clinical features Onset between adolescence and age 30 years Female predominance (95%) Mortality rate of 15%!20% Familial predisposition Sleep alterations (decreased REM latency) Increased occurrence of urogenital abnormalities and Turner syndrome Intense fear of becoming overweight Disturbed body images, !feel fat!! even when emaciated
Eating behavior Anorexia uncommon until late in clinical course Decreased intake of high -calorie food, self induced vomiting, use of laxatives and diuretics, excessive exercising, use of stimulants and appetite suppressants Physical signs Hypothermia Dependent edema Cardiovascular changes Bradycardia Hypotension Lanugo (neonatal -like hair) Constipation Endocrinologic alterations Amenorrhea Decreased TSH and T4 Diminished levels of LH, FSH, gonadal steroids Prepubertal LH secretory pattern Diminished response to LHRH Increased plasma cortisol levels Impaired responsiveness to insulin -induced hypoglycenmia Impaired dexamethasone -induced suppression of cortisol secretion Elevated growth hormone levels Cerebrospinal fluid abnormalities Decreased homovanillic acid Decreased 5 -hydroxyindoleaceric acid
FSH, follicle -stimulating hormone; LH, lureinizing hormone; LHRH, luteinizing hormone -releasing hormone; REM, rapid eye movement; TSH, thyroid stimulating hormone.
P.352 somnolence, hypogonadism, and/or memory loss. The Kleine-Levin syndrome (discussed earlier) is a product of presumed hypothalamic dysfunction characterized by periodic episodes of hyperphagia, somnolence, and altered sexual behavior in adolescent males. 1 7 , 1 8 Hyperphagia is also seen in association with noncommunicating hydrocephalus and may be relieved by ventriculoperitoneal shunting. 3 7 The Kl"ver -Bucy syndrome is a unique behavioral syndrome that was first described in monkeys subjected to bilateral anterior temporal lobectomy. The syndrome complex includes changes in dietary habits with bulimia, emotional placidity, psychic blindness, hypermetamorphosis (compulsive exploration of objects in the environment), hypersexuality, and hyperorality (Table 23.4 ). 3 8 In humans, the core symptoms are frequently complicated by the co occurrence of amnesia, aphasia, dementia, or seizures. 3 9 The Kl"ver -Bucy syndrome may occur with any etiologic process producing bilateral temporal dysfunction and has been reported in herpes encephalitis, trauma, bitemporal surgery, paraneoplastic disorders, adrenoleukodystrophy, bilateral temporal infarction, Pick's disease, Alzheimer's disease, hypoglycemia, temporal lobe seizures, and toxoplasmosis (Table 23.5 ). Hyperphagia may also occur in the course of affective disorders. Anorexia is the most common appetite alteration in depression, but a few patients have a paradoxical increase in appetite. Exaggerated hunger is frequent in mania. Bulimia is an idiopathic disorder manifest by episodic binge eating. 3 5 Patients are aware that the eating pattern is abnormal and attempt to eat inconspicuously. They are fearful of not being able to stop eating voluntarily, and depressed mood and self -deprecatory thoughts are common following the binges. The binging is interspersed with programs for weight loss, including restrictive diets, self induced vomiting, and use of cathartics, stimulants, and diuretics. The bulimia may coexist with anorexia nervosa (bulimorexia) or may occur as an independent disease entity. The disorder begins in adolescence or early adult life, occurs primarily in females, and has a chronic intermittent course. Most bulimics are of normal weight, but a few are obese and a few are slightly underweight. A few patients have improved with treatment with anticonvulsants, and monoamine oxidase inhibitors (MAOIs) have been successful in those with prominent depression and anxiety.
36
Additional Features
Core Features
Common in Humans
Emotional placidity
Aphasia
Hyperorality
Amnesia
Hypermetamorphosis
Dementia
Dietary changes
Seizures
Temporal lobectomy (bilateral) Post -traumatic encephalopathy Paraneoplastic limbic encephalitis Adrenoleukodystrophy Bilateral temporal lobe infarction Pick's disease Alzheimer's disease Hypoglycemia Toxoplasmosis Bilateral epileptic foci
FIGURE 23.3 Regional cerebral blood flow increases measured by blood oxygen level -dependent (BOLD) signal using functional magnetic resonance imaging (MRI). Scent from a peri-ovulatory female marmoset increased blood flow in the hypothalamus (top row) and posterior orbitofrontal paleocortex (bottom row) of male marmosets more than scent from an ovariectomized female implicating these limbic regions as supporting the sexual appetitive dive. Adapted from Ferris et al. (2001). 4 0 PVN, paraventricular nucleus; DMN, dorsomedial hypothalamus; VMH, ventromedial hypothalamus; 3V, third ventricle; PIT, pituitary gland; SEP, septum; BST, bed nucleus of the stria terminalis; POA, preoptic area; OC, optic chaism; AC, anterior commissure.
Hyposexuality, defined by a frequency of less than one episode of sexual behavior (masturbation or intercourse) per month, is present in 40%!65% of patients with partial complex seizures (temporal lobe epilepsy) and 10% of patients with primary generalized seizures. 41 In some cases a patient with occult seizure disorder may present with diminished libido and impotence as a chief complaint. Such patients are likely to be misidentified as suffering from a psychogenic disorder if the neurological causes of reduced sexual drive are not considered.
Hyposexual epileptic patients have no interest in sexual activity, lack sexual fantasies, and, if the onset is prior to puberty, fail to develop any interest in sexual functions. At least four influences may contribute to this profound lack of sexual interest: the limbic lesion itself, the influence of drug therapy, endocrinologic alterations, and depression. Patients with temporal lobe epilepsy have a focal lesion of the limbic system, the anatomic substrate of emotional experience, including sexually oriented emotions, and the limbic dysfunction may interfere with sexual interest. Blumer 4 2 has proposed that irritative temporal lobe foci produce hyposexuality analogous to the hypersexuality produced by destructive limbic lesions in the Kl"ver -Bucy syndrome. Anticonvulsant therapy may also contribute to the diminished sexual drive. As shown in Table 23.8, barbiturate anticonvulsants may impair libido and diminish sexual arousal. A correlation has also been found between anticonvulsant therapy and reduced free serum testosterone activity, suggesting that anticonvulsants exert subtle hormonal effects that may alter sexual drive. 4 3 The onset of hyposexuality in some patients prior to initiation of anticonvulsant therapy and the P.354
Decreased sexual drive Epilepsy Hypothalamic lesions Drug-induced changes Medical illnesses Depression Schizophrenia (chronic) Increased sexual drive Neurological disorders Epilepsy Diencephalic lesions Kleine-Levin syndrome
Bilateral temporal lobe injury (Kl"ver -Bucy syndrome) Frontal lobe syndromes Medical conditions and pharmacological agents Hyperthyroidism Cushing's disease and steroid administration Androgen administration Levodopa administration Psychiatric disorders Mania Schizophrenia (early stages)
significant reduction in sexual drive of patients with temporal lobe epilepsy, compared with patients with primary generalized seizures requiring comparable drug therapy, however, suggest that other functions must also contribute to the hyposexuality of patients with temporal lobe foci. An endocrinologic influence that may contribute to the reduced sexual drive is the periodic elevation of serum prolactin that follows epileptic discharge. 44 Sustained hyperprolactinemia leads to decreased libido and impotence, and intermittent prolactin levels may have a similar effect. Finally, depression is common in epileptics, and diminished libido may be a product of the affective disturbance. Hypothalamic lesions also produce hyposexuality. Naturally occurring lesions impair sexual interest, and stereotactic lesions in the region of the ventromedial nuclei of the hypothalamus have been successfully utilized to reduce sexual drive in patients with a variety of types of sexually motivated criminal behavior. Among other causes of hyposexuality, a large number of drugs impair sexual function. 4 5 The impact may be on libido, erection, or ejaculation, as shown in Table 23.8. Psychotropic agents such as stimulants, antidepressants, neuroleptics, lithium, sedative -hypnotics, anxiolytics, and narcotics may all impair sexual function in some patients. Likewise, many classes of antihypertensive agents, estrogens, adrenal steroids, and disulfiram may compromise sexual interest or performance. Trazodone and neuroleptic agents have been associated with priapism. Amoxapine and thioridazine have produced ejaculatory disturbances, and tricyclic agents may produce spontaneous seminal emission.
A number of medical conditions can also impair sexual behavior or diminish sexual drive. Testosterone or thyroid deficiency, prolactin or estrogen excess, chronic hepatic or renal disease, Addison's disease, debilitating cardiopulmonary failure, and systemic cancer will also reduce libido and decrease sexual arousal. Neuropathies causing autonomic dysfunction (e.g., diabetes) and local pelvic surgery frequently impair erection and ejaculation. Among idiopathic psychiatric disorders, hyposexuality is a major feature of depressive episodes and is common in chronic schizophrenia.
Ictal
Interictal
Sensory seizures
Hyposexuality
Genital sensations
Limbic dysfunction
Orgasmic sensations
Depression
Motor seizures
Coital movements
Drug-related
Hypersexuality
Postictal
Masturbation
Post -lobectomy
Fetishism
Transvestism
Voyeurism
Exhibitionism
Sadism
Masochism
Pedophilia
Frotteurism
Genital mutilation
P.355
Drug
Libido
Arousal/Erection
Orgasm/Ejaculation
Psychotropic agents
Tricyclic antidepressants
May be
May be
Serotonin reuptake
inhibitors
Trazodone
Lithium carbonate
Neuroleptic agents
May be
(rare priapism)
Narcotics
in high doses
in high doses
in high doses
Reserpine, methyldopa
(common)
May be
Diuretics
May be
Clonidine
Propranolol
May be
May be
Anticholinergte agents
May be
Harmonal agents
Androgens
(men)
(men)
Estrogens
(men)
May cause
Delay
/ (women)
impotence in men
Delay
Thyroxin
Adrenal steroids
in high doses
Miscellaneous
Levodopa
May be
Disulfiram
Occasional impotence
Delayed
specific female victims, whereas ictal disrobing occurs in individuals of either gender at any age and occurs in diverse interpersonal circumstances. Medial basal or diencephalic injuries have also produced hypersexual behavior. The lesions have usually been inflammatory or neoplastic in origin and involve the medial thalamic, infrastriatal, and mesencephalicdiencephalic junction regions. 5 1 The Kleine-Levin syndrome is assumed to be a product of hypothalamic dysfunction and is manifest by periodic somnolence, hypersexuality, and hyperphagia. 5 2 The Kl"ver -Bucy syndrome was discussed previously with regard to the associated bulimia (Tables 16.4 and 16.5 ). Animals with the Kl"ver -Bucy syndrome exhibit hypersexuality and altered sexual behavior, including interspecies copulation. 5 3 Humans exhibit alterations in sexual interest but may have no increase in the quantity of sexual activity. Patients may be sexually disinhibited and publicly demonstrative, and a number have changed from heterosexual to homosexual preferences. Some patients with other elements of the Kl"ver -Bucy syndrome, particularly those with dementing disorders, may have no change in sexuality or may be hyposexual. Frontal lobe syndromes resulting from damage to the orbitofrontal portion of the brain produce disinhibition, jocularity, poor judgment, and impulsivity (Chapter 9 ). Patients with orbitofrontal lesions (neoplasms, trauma, infarctions, and infection) may make sexual jokes or openly solicit sexual activity. Despite the verbal hypersexuality, there is rarely an increase in actual copulation, although patients may masturbate openly, go about in the nude, or attempt to fondle members of the opposite sex. Medical conditions and pharmacological agents can also produce increased sexual behavior (Table 23.8 ).
Disorder
Fetishism
Nonliving objects
Transvestism
Zoophilia (bestiality)
Animals
Pedophilia
Prepubertal children
Exhibitionism
Voyeurism
Observes unsuspecting people who are naked, disrobing, or engaging in sexual activity
Masochism
Sadism
Atypical paraphilias
Vampirism
Blood
Coprophilia
Feces
Urophagia
Urine
Klismaphilia
Enema
Frotteurism
Necrophilia
Corpse
Telephone scatologia
P.357 Hyperthyroidism, Cushing's disease or exogenous steroid administration, and androgen excess may all cause heightened libido and increased sexual activity. 4 5 Levodopa has induced hypersexual behavior in parkinsonian patients either as one component of secondary mania or as an independent behavioral alteration. 5 4 Hypersexuality occurs in most, but not all, manic patients and consists of increased sexual thoughts and statements, flirtation, and increased sexual contacts. Schizophrenic patients may rarely have hypersexual behavior, particularly in the prodromal phase of their illness.
Sexual Deviations
Sexual deviations (paraphilias) are a group of disorders in which unusual or bizarre imagery or acts are necessary for sexual excitement. 3 5 Table 23.9 lists the paraphilias that have been identified. Sexual deviations include fetishism, transvestitism, zoophilia, pedophilia, exhibitionism, voyeurism, masochism, and sadism, as well as a variety of atypical paraphilias. 55 Homosexuality is considered a psychosexual disorder only if the behavior is ego-dystonic for the individual. Endocrinologic assessments of homosexuals reveal markers of sexual orientation that may reflect altered CNS function. 5 6 Post -encephalitic parkinsonism followed the epidemic of von Economo's encephalitis that persisted from 1919 to 1926. Pathologically, there were inflammatory changes in the rostral brainstem and diencephalon. The parkinsonian state was accompanied by a variety of behavioral changes, including psychosexual disorders. The latter occurred in a majority of patients requiring psychiatric hospitalization and included homosexuality, pedophilia, exhibitionism, sadism, and zoophilia. 5 7
Frontal lobe syndromes can lead to public masturbation, exhibitionism, pedophilia, and frotteurism as part of the impulsive, disinhibited change in behavior. Frontal system alterations may also underlie the open masturbation and exhibitionism described in some patients with Huntington's disease and with multiple sclerosis. 5 8 , 5 9 , 6 0 Investigations of individuals arrested for sexually related crimes, particularly pedophilia, have revealed an increased prevalence of EEG abnormalities, neuropsychological deficits, dyslexia, cerebral blood flow abnormalities, and computerized tomographic (CT) scan changes. 61 A small number of pedophilics have been found to have elevated serum levels of testosterone. These findings suggest that subtle neurological and endocrinologic abnormalities may contribute to some cases of idiopathic paraphilic behavior. Sexual deviations may occur in schizophrenia, where they are frequently motivated by delusional ideas or precepts. Paraphilias also occur in patients with personality disorders or may occur in the absence of any other identifiable psychopathology. Psychosexual disorders have been reported with a number of neurological illnesses (Table 23.10). Patients with temporal lobe epilepsy are particularly vulnerable to such deviations, although the percentage of affected individuals is small. Fetishism and transvestitism are the two disorders most commonly reported. 6 1 Rare instances of voyeurism, exhibitionism, sadism, masochism, pedophilia, frotteurism, genital self -mutilation, and homosexuality have also been described. The Gilles de la Tourette syndrome is a disorder manifest by involuntary tics and vocalizations beginning before the age of 15 years (Chapter 19 ). The motor behaviors frequently include copropraxia (lewd) gestures), and 50% have coprolalia. 6 1 , 6 2
Sexual Deviation
Exhibitionism
Huntington's disease
Multiple sclerosis
Epilepsy
Sadism
Epilepsy
Frotteurism
Epilepsy
Fetishism
Epilepsy
Pedophilia
Epilepsy
Dyslexia
Kliniefelter's syndrome
Masochism
Epilepsy
Voyeurism
Epilepsy
Zoophilia
P.358
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 24 - Violence and Aggression
most important in this caldron of contributing ingredients? In most cases it will be impossible to do more than identify the final precipitating circumstances. The importance of seeking neurological components in violent behavior is twofold: 1) neurological factors can easily be overlooked in a psychologically minded milieu in which clinicians are most attuned to the influence of early childhood experiences on adult behavior; and 2) detection of neurological factors may offer treatment alternatives that will go unexplored if the brain disorder is undiscovered. Animal models have been widely used to investigate the neurobiologic basis of aggressive behavior. These studies have been particularly useful in delineating anatomic regions of the brain most likely to be involved in mediating violent behavior and have identified the limbic system as the most important anatomic substrate of violence and aggression. 1 The greater extent of intraspecies violence and interindividual cruelty among P.361 humans, however, clearly separates human behavior from that of other animals and limits the applicability of animal research to the understanding of human violence. Two general approaches have been used to study the neurology of human violence. In the first, violent offenders have been investigated to determine whether they have evidence of neurological dysfunction that might have contributed to their violent behavior. In the second, violent behavior ensuing in the course of known neurological disorders is observed and studied. The results of each of these approaches are reviewed, and the latter is further divided into violent behavior directed at others and violent self -destructive behavior. Recent studies using functional imaging to explore the neural systems subserving reactions to, and evocations of, fear and violence in normal controls have implicated regions similar to those found dysfunctional in impulsive violent criminals. These preliminary findings, along with studies evaluating aggression in dementia patients, will be reviewed to highlight a common neuronal system underlying violence and aggression across health and disease. Finally, an approach to the evaluation and treatment of the violent individual is outlined.
Electroencephalographic Abnormalities
The most thoroughly studied parameter of neurological dysfunction in violent individuals is the electroencephalogram (EEG). Studies that assessed EEG abnormalities in prison inmates and patients with antisocial behavior have found an increased frequency of EEG changes in violent populations. Antisocial and criminal populations studied had EEG abnormalities in 24% -78% of individuals. Electroencephalographic changes were found to be more common in subjects who had committed violent acts than in those associated with nonviolent crimes and were more frequent in those with repeated violence than in those who had committed isolated violent acts. 3 When the violence had no apparent motive, there was also an increased chance of finding an EEG abnormality, compared to when violence had been provoked. No specific relationship has been found between the type of EEG abnormality and characteristics of the crime, nor between EEG changes and degree of violence committed. 4 , 5 However, when continued violence is monitored within an institution, a left frontal abnormality on EEG appears to correlate with the frequency of ongoing violent incidents. 6 Several types of EEG abnormalities have been found in violent offenders: generalized slowing, focal slowing, and epileptiform abnormalities. Williams 3 noted that when focal abnormalities were present they were most likely to be located in the temporal and frontal lobes. Wong et al 4 also found a higher incidence of focal abnormalities in a subgroup with the highest violence scores (30.7% focal abnormalities and 20% temporal abnormalities in the high -violent group versus 7.2% and 2.4% in the low -violence group). Pillmann et al. 5 found a lower prevalence (9%) of focal abnormalities in a more general population of 222 defendants referred for psychiatric evaluation regardless of the degree of violent acts. Interpretation of these findings is fraught with difficulty. A small percentage of the patients (0 -15%) have epilepsy. As discussed later in this chapter, violence as an ictal event is rare, and it is unlikely that many of the violent acts are ictal in nature. The EEG alterations may reflect non -epileptic central nervous system (CNS) changes relevant to the violent behavior. The presence of lesions within the limbic system can lead to personality alterations that may in turn lead to antisocial behavior. Head trauma also produces frontal and temporal lesions, reduces the threshold of
impulsive behavior and violence, and may be reflected in EEG abnormalities. Despite the difficulty in drawing direct inferences from these data, the EEG findings indicate that brain dysfunction is common among violent offenders and that, in many cases, the limbic system is the site of neurological abnormality.
Functional Imaging
Functional imaging studies of murderers may underscore variable brain abnormalities, depending on the type of violent acts committed by the murderer. If the murder was an impulsive act, a greater orbitofrontal metabolic defect has been found in perpetrators' scans than in normal controls, while a greater dorsolateral frontal defect has been found in predatory murderers' scans. 7 This differential pattern of functional defects between the two classes of violent acts, impulsive versus predatory, may underscore differential system dysfunction subserving violent behavior. Because head trauma in prisoners is common, it is problematic to extrapolate regional brain abnormalities identified from cross-sectional studies of inmates to models of the neuropsychiatry of violence in humans. Evidence of a common brain system being involved across health and various diseases will strengthen any proposed model of the anatomy of a complex behavior. This is the case with violence and aggression. P.362
FIGURE 24.1 Statistical maps demonstrating (A) increased right orbitofrontal perfusion in 13 normal subjects shown angry faces
compared to sad faces (adapted from Blair et al., 1999); 1 0 (B) decreased left orbitofrontal perfusion in 15 normal subjects induced with fear generating aggressive stimuli compared to neutral stimuli (adapted from Pietrini et al., 2000); 9 (C) increased right amygdalar perfusion in 8 normal subjects shown fearful faces compared to happy faces (note that more anterior left amygdalar activation was also found in this study; adapted from Whalen PJ, et al., 1998); 1 2 (D) increased bilateral amygdalar perfusion in 6 normal subjects shown threatening words compared to neutral words (adapted from Isenberg et al., 1999); 1 1 (E) increased left orbitofrontal perfusion in 18 normal subjects induced with anger generating stimuli compared to neutral stimuli (adapted from Kimbrell et al., 1999); 8 (F) decreased left temporal polar resting perfusion in 10 demented subjects with high agitation/aggression compared to 10 demented subjects with low agitation/aggression (adapted from Hirono et al., 2000). 1 3
In normal individuals who were asked to recall prior life events to evoke anger and anxiety while viewing affect appropriate faces, the left lateral orbitofrontal cortex and bilateral temporal poles were found to be significantly more perfused in a H 2 1 5 O positron emission tomography (PET) activation study than under neutral conditions. 8 When anger was compared to anxiety, significantly greater perfusion in the left orbitofrontal cortex was found. In other studies that exposed normal subjects to threatening images or words, orbitofrontal 9 ,1 0 or amygdalar functional correlates have been found. 1 1 , 1 2 In aggressive patients with dementia, left temporal polar and dorsolateral frontal perfusion defects were found, compared to nonaggressive P.363 patients (see Fig. also, an increase in the pathological burden of neurofibrillary tangles in the orbitofrontal cortex and anterior cingulate distinguished aggressive Alzheimer's disease patients from nonaggressive patients. 1 4 24.1 ); 1 3
Neuropsychological Assessment
Neuropsychological testing of criminal subjects has produced variable results, but there is a tendency for such patients to perform more poorly than matched control subjects. Performance on tests assessing frontal lobe function is often preferentially compromised. 1 5
Neurological Abnormalities
Examination of violent delinquents and patients with impulsive character disorders reveals an increased incidence of neurological soft signs indicative of nonlocalizing neurological dysfunction. 1 5
Epilepsy
Behavioral disturbances occurring in epileptic patients may occur during the ictal, postictal, and interictal period (Chapter 21 ). Likewise, violence may occur during any of these periods, and any violent act committed by epileptic patients must be considered in relation to this behavioral framework. Many unresolved areas of controversy exist regarding the relationship of epilepsy to criminal behavior and violence. The principal questions include the following: Is violence more common among epileptics than nonepileptics ? Can violence occur as an ictal manifestation ? Does violence occur with abnormal frequency during the interictal period in epileptics ? If so, what are the determinants of interictal violence ? Is violence more common with one type of epilepsy (e.g., temporal lobe epilepsy) than another (e.g., idiopathic epilepsy) ? Unambiguous answers to these questions are not yet available, but tentative conclusions can be drawn from existing information.
Epilepsy
Ictal
Postictal
Interictal
XYY genotype (? )
Nonpsychotic disturbances
Personality disorders
Antisocial personality
Traumatic injuries
Borderline personality
Neoplasms
Paranoid personality
Degenerative dementias
Explosive disorders
Mental retardation
Intermittent
Isolated
Paraphilia
Sexual sadism
Childhood disorders
Metabolic disorders
Conduct disorder
Psychotic disturbances
Endocrine dysfunction
Mania
Schizophrenia
Paranoid disorders
Testosterone excess
Depression
Toxic disorders
Ethanol
The question regarding the prevalence of violent behavior among epileptics has been approached by investigating the frequency of violent acts in populations of epileptics (such as those attending seizure clinics) or determining the frequency of epilepsy among violent individuals. Although studies of the first type demonstrate that violence is uncommon in epilepsy, the latter technique has generally yielded results suggesting that epilepsy is two to four times more common among prison inmates than in the general population. 1 6 , 1 7 If violence and antisocial behavior are more common among epileptics, do they occur during the ictal, postictal, or interictal period? This question has been the P.364 subject of heated debate. Rare cases of serious offenses, including murder, have been reported to have occurred during epileptic seizures or at least during a seizure -related amnesic period that could have been in either the ictal or immediate postictal period. 1 8 , 1 9 Despite occasional reports of ictal violence, recordings of epileptic patients during ictal periods have shown that behavioral activity occurring as part of a seizure is usually brief, stereotyped, undirected, poorly organized, and unlikely to account for goal -directed
violence. 2 0 , 2 1 The current consensus suggests that although interpersonal injury could occur during an epileptic attack manifested by psychomotor automatisms, such activity is unpremeditated, usually poorly structured, and easily redirected. The greatest danger is during the postictal confusional period, when the actions of others may be misinterpreted and a more organized attack may occur. If aggression is increased in epilepsy and is rare during ictal episodes, when does the violence occur ? As noted above, violence may occur during the postictal confusional period, but most episodes of violence appear to occur during the interictal period and are related to behavioral and psychiatric alterations occurring interictally (Chapter 21 ). Although a few investigators have found equal rates of violence among patients with generalized and temporal lobe epilepsy, most have found violence to be more common among patients with the latter. 2 2, 23 The observation that violence is more common among patients with left than right temporal lesions emphasizes the potential importance of anatomic factors in determining the occurrence of violence in the interictal period. Several interpretations have been offered for the observations concerning interictal violence in epileptics. Stevens and Hermann 2 2 suggest that basal forebrain damage gives rise to both seizures and behavioral alterations and that the two consequences are behaviorally independent. Similarly, Trieman and Delgado -Escueta 23 point out that interictal violence is most common in young, intellectually impaired men with histories of psychiatric abnormalities and long-standing, severe epilepsy. In such cases, the associated neurological and psychiatric abnormalities may be responsible for the violent behavior. Violence may be a learned behavior occurring in response to the adverse educational and social circumstances of the epileptic. Lewis et al. 2 4 suggest that the violence is associated with paranoid and hallucinatory symptoms occurring in the epileptic and is a product of the psychosis occasionally associated with epilepsy. It seems likely that all these factors as well as others (anticonvulsant intoxication, economic, and cultural influences) play varying roles in each epileptic patient manifesting aggressive behavior.
behaviors: (1) a history of physical assault, especially wife and child beating; (2) pathologic intoxication (violent behavior following ingestion of small amounts of alcohol); (3) impulsive sexual behavior, often including sexual assault; and (4) a history of many traffic violations and automobile accidents stemming from impulsive and reckless driving. They cited a number of patients with temporal lobe epilepsy with the symptom complex and argued that the dyscontrol syndrome was a product of limbic system dysfunction and that many of the patients manifesting the syndrome improved markedly when treated with anticonvulsants. Similarly, Monroe 2 6 suggested that episodic disinhibition of action with violent behavior could be a product of epilepsy or of !epileptoid!! loss of control of instinctual drives or impulses. He proposed that there was a continuum of increasing dynamic and diminishing neurological determinants of violence as one moved from epilepsy through instinct and impulse dyscontrol to acting out. The principal feature that distinguishes patients with episodic dyscontrol from patients with sociopathic personality disorders is that the violent activity is isolated and infrequent, not in conjunction with an overall pattern of malevolence. Despite these contributions, the nosologic validity of the episodic dyscontrol syndrome as a distinct diagnostic entity is controversial. As discussed previously, violent activity is uncommon as an ictal manifestation in epileptics, and the violence of those with episodic dyscontrol syndrome is likely to be an ictal manifestation in only a very small percentage of cases. In addition, in many patients with episodic dyscontrol, social and environmental factors play an important part in determining or triggering the violence. The episodic dyscontrol syndrome thus might be viewed as a nonspecific syndrome of violence with many possible contributing etiologic factors. The more primitive and disorganized and the more distinctly episodic the behavior is, the more likely it is that acquired neurological factors are playing a significant role. Occasionally, recognition of the syndrome will lead to the discovery of previously undiagnosed epilepsy, and in some cases where epilepsy is equivocally present, an empirical trial with anticonvulsants may be warranted.
(Chapter 9 ). Violent behavior may either accompany orbitofrontal injury, as a manifestation of disinhibition and lack of the usual restraints on antisocial impulses, or may occur with dorsolateral injuries, after which the patient manifests brief outbursts of violence in response to trivial irritations. Attacks of explosive rage that follow head trauma are more likely to be a product of the frontal lobe damage that commonly accompanies traumatic head injury. Frontal lobe involvement is also common in dementia and mental retardation and may account for the occasional acts of violence or aggressive behavior reported in these syndromes. 2 7 Neuropsychologic investigations of criminals have revealed a subgroup with deficits consistent with frontal lobe dysfunction. 1 5 This finding suggests that in some cases of idiopathic violent behavior, occult frontal lobe dysfunction secondary to head trauma or delayed maturation may be a contributing factor.
Metabolic Disorders
Metabolic factors contribute to violent behavior in two general circumstances: acute confusional states and disorders of endocrine function. Acute confusional states are reviewed in Chapter 11 , and violence can be a manifestation of any of the metabolic disturbances discussed there. The violence is usually poorly organized and undirected when it is a manifestation of confusion and impaired judgment but may result in serious injury. Hill and colleagues 3 1 recorded a case of matricide occurring during a hypoglycemic episode.
Two types of endocrine alteration have been shown to contribute to violent behavior: 1) perimenstrual states, and 2) elevated testosterone levels. D'Orban and Dalton 3 2 found that 44% of 50 women charged with violent crimes committed their offenses during the perimenstrual period and that there was a significant lack of offenses during the ovulation and post-ovulation phases of the menstrual cycle. Although results have not always been consistent, several studies have indicated correlations between measures of aggression and serum testosterone levels. Significantly elevated levels have been found in violent rapists and prisoners with histories of violent and aggressive crimes. 3 3 , 3 4 The levels of testosterone were rarely beyond the range of normal; as a group, violent offenders had significantly higher levels than did nonviolent offenders. Similarly, testosterone levels in violent females were also elevated when compared with control populations. 3 5 The principal role of endocrine factors appears to be to lower the threshold for, and thus increase the likelihood of, violence in predisposed individuals, although prolonged exposure to elevated testosterone levels may have effects on personality development as well.
Toxic Disorders
Alcohol is the intoxicant most commonly used by individuals involved in violent crime. Violence may occur during a period of intoxication with impaired judgment, during an alcoholic blackout (Chapter 22 ) for which the patient is amnesic, or as part of the syndrome of pathological intoxication. In the latter, chaotic disturbed behavior, often with violent outbursts, occurs following ingestion of small amounts of alcohol. The patient is completely or partially amnesic for the period of the aberrant behavior, and delusions, hallucinations, anxiety, or fear may occur during the episode. 3 6 In some cases, alcohol withdrawal may be an activating agent for preexisting epileptic abnormalities, and the ensuing violence may be ictal or postictal in origin. Among the many other intoxicants used, violence is particularly likely with phencyclidine (PCP) ingestion but may also occur after use of LSD, psilocybin, stimulants, anticholinergics, and sedative -hypnotics. Violence has also been reported as a manifestation of neuroleptic -induced akathisia.
Delusions are a frequent manifestation of neurological disease. In dementing illnesses they are simple, loosely held, and transient, whereas in diseases affecting subcortical structures they tend to be more elaborate, rigid, and chronic (Chapter 12 ). 3 7 Paranoid ideation and persecutory P.366 fears are the most common manifestations of delusional thought, and action on delusional beliefs leading to violent activity is an unfortunate but frequent product of persecutory delusions.
XYY Genotype
Surveys of criminal populations have revealed an increased incidence of inmates with an XYY genotype and led to the suggestion that XYY individuals were more likely to be violent and aggressive than individuals with normal karyotypes. Further studies, however, have failed to confirm the possibility that XYY patients are at increased risk for violent behavior or suggest that the risk is minimal. 3 9 Genotype XYY individuals do not have elevated testosterone levels, but they tend to be of lower intelligence and to be more mentally immature and impulsive!factors that may contribute to aggressive activity. Until more information is obtained, the possible role of the XYY genotype in determining violent behavior remains unresolved.
violent behavior. They can usefully be divided into psychotic disorders in which the aggression is in response to a delusional belief and those that are nonpsychotic. Among the latter, personality disorders account for the majority of violent actions, but violence may be a manifestation of intermittent or isolated explosive disorders, sexual sadism, or childhood conduct disorders. The personality disturbance most likely to produce repeated violence as a habitual behavioral style is the antisocial personality. 1 5 Such personalities are characterized by the onset before age 15 of a disorder that, when fully evident, includes the inability to sustain a job, failure to adhere to the law and social norms of behavior, inability to provide consistent parenting or maintain enduring close personal relationships, irritability and aggressiveness, failure to honor financial obligations, and lack of forethought, poor judgment, and recklessness (Chapter 15 ). The antisocial personality pattern is most marked in late adolescence and early adulthood and tends to be ameliorated with age. In addition to the antisocial personality, violence is common among individuals with borderline and paranoid personality disorders. Explosive disorders are disturbances of impulse control in which an individual has a discrete episode of aggressiveness with property destruction or assault. There is an absence of generalized impulsivity, aggressiveness, or sociopathic behavior between episodes. The violence is usually out of proportion to the precipitating stimulus and may occur more than once (intermittent explosive disorder) or be confined to a single episode. This behavior is similar to the episodic dyscontrol syndrome, and explosive patients must be carefully evaluated for neurological determinants of their behavior. Violence may also be a product of certain disturbances of sexual behavior, particularly sexual sadism. Sadism is a paraphilic disturbance in which sexual excitement is achieved by humiliating or injuring either a nonconsenting or a consenting partner (Chapter 23 ). 38 Violence is not a common consequence of psychosis, and few psychotic individuals commit acts of violence. Under specific circumstances, however, psychotic ideation, particularly paranoid thinking, can lead to organized acts of aggression directed at presumed persecutors. Such actions may occur in any of the psychoses but have been found most commonly among patients with schizophrenia, women felons with affective disorders, and geriatric patients with late -onset paranoid delusional disorders. The importance of recognizing
the psychotic origin of violent behavior stems from the readiness with which some of these disorders respond to neuroleptic medication.
Neurological Disorders
Mental retardation
Autism
Schizophrenia
Lesch-Nyhan syndrome
Depression
Choreoacanthocytosis
children with mental retardation or autism, self -injury may occur in the course of head banging or other bizarre activities. In the Lesch-Nyhan syndrome (an X-linked disease characterized by overproduction of uric acid, deficiency of hypoxanthine -guanine phosphoribosyl -transferase, mental retardation, spasticity, and choreoathetosis), the afflicted children engage in selfmutilative behavior and are generally aggressive. The aggression often appears to be one manifestation of a compulsive disorder. Likewise, self -harm may occur as a result of some of the irresistible compulsive urges that occur in some patients with Gilles de la Tourette syndrome. 4 0 Some Gilles de la Tourette patients sustain significant ocular trauma as a result of compulsive striking of the eyes. 4 1 Another neurological syndrome in which self injury may be prominent is choreoacanthocytosis, which is manifested by a choreiform disorder resembling Huntington's disease, and studies of peripheral blood show a significant number of acanthocytes among red blood cells. Tongue and lip biting is often an early and prominent expression of the choreic syndrome. Idiopathic psychiatric disorders that may produce conspicuous self -injury behaviors include borderline personality, obsessive -compulsive disorders with selfmutilation rituals, schizophrenia, and depression.
examinations will help in identifying systemic diseases or focal neurological deficits. In cases where violence has occurred as an isolated, ego-alien act or cannot be completely recalled by the patient, an EEG should be obtained to search for epileptiform abnormalities. Nasopharyngeal or sphenoidal electrodes and sleep deprivation prior to obtaining the recording may increase the likelihood of discovering an existing EEG abnormality. Structural and functional brain imaging are an integral part of the evaluation of any patient with findings suggestive of brain disease. Laboratory assays of urine and blood may help in identifying metabolic disorders or the presence of toxic substances. In some cases, even after completion of a thorough evaluation, there is insufficient evidence to establish a definitive diagnosis or to determine the relative importance of factors contributing to the violent behavior. In these patients, empirical trials of the treatments discussed in the next section may aid not only in controlling the aggression but also in determining its etiology.
Agents
Violent Disorders
Anticonvulsants
Propranolol
Neurological disorders (posttraumatic encephalopathy, mental retardation, etc.) with unprovoked violence
Personality disorders with violence; recurrent unprovoked violence; mania with violence
Methylphenidate
Antiandrogens
Progesterone
Premenstrual violence
Anxiolytics
Antipsychotics
Antidepressants
cause of the violence will not be straightforward and treatment may involve any of a number of pharmacologic agents as well as behavioral therapy and/or psychotherapy.
Pharmacotherapy
Table 24.3 summarizes the pharmacological agents commonly used in the treatment of violent individuals and lists the principal disorders in which they have been used with some success.
Anticonvulsants
The rare cases in which violence is an ictal manifestation are obviously best managed by reducing the number of seizures. Since ictal violence occurs almost exclusively in complex partial seizures, the anticonvulsants most likely to be successful are carbamazepine or phenytoin (Chapter 21 ). Phenobarbital sometimes produces irritability and disinhibition and may increase the likelihood of violence in the epileptic. Violence occurring in the postictal confusional state will also be decreased if the number of seizures can be limited. Anticonvulsants have also been used successfully in the management of the episodic dyscontrol syndrome. Carbamazepine and phenytoin have both been reported to decrease the number of violent outbursts. 4 2 Anticonvulsants may also ameliorate the chronic aggressiveness and outbursts of violence occurring in some chronically psychotic patients.
Propranolol
Propranolol, a " -adrenergic receptor blocking agent, has been noted to decrease belligerent behavior as well as rage attacks in post-traumatic states, Alzheimer's disease, mental retardation, and schizophrenia. 4 3, 44 Dosages necessary for the control of violence have been in the range of 100!500 mg/day. The drug should be used with caution in those with a history of congestive heart failure, asthma, diabetes, or depression.
independently of their antimanic effects. Dosages have been the same as those used in the treatment of manic depressive illness (Chapter 14 ).
Methylphenidate
Attention-deficit disorder, as noted earlier, may persist into adulthood and predispose to antisocial personality disorders with violent behavior. Prescribing stimulants to this population entails a significant risk of abuse of the drugs, but in some cases improvement in behavior and reduction of violence have followed administration of methylphenidate or amphetamines. 4 5 In closely controlled circumstances, stimulant administration may be a viable therapeutic alternative for adults with persistent or acquired attentiondeficit disorders.
Hormonal Agents
Antiandrogens such as medroxyprogesterone acetate, leuprolide, and cyproterone P.369 acetate diminish sexual preoccupations in the paraphilias and improve self -control of aggressive sexual impulses. 4 6 These agents have also been reported to diminish interictal violence in temporal lobe epileptics and in patients exhibiting idiopathic chronic assaultiveness. In the latter conditions, aberrant sexual impulses are not necessarily present, and the antiviolence potential of antiandrogens does not appear to be specific for sexually related aggressiveness. Progesterone has been used to limit premenstrual aggression.
Anxiolytics
The use of anxiolytics in the management of aggression is controversial. Like alcohol, anxiolytics have the potential for disinhibiting antisocial impulses, and, indeed, paradoxical rage reactions and increased hostility have occasionally been reported following administration of anxiolytics. Most investigators, however, have noted an improvement in aggressive impulses with anxiolytics.
Behavioral Therapy
The potential excesses of behavioral conditioning in the treatment of violent individuals have been dramatically portrayed by Anthony Burgess in his novel, A Clockwork Orange. 4 7 When properly used, however, behavioral therapies can increase the patient's repertoire of adaptive skills, allow increased control of maladaptive responses, and decrease the number of violent outbursts. In selected cases behavior therapy can offer an important therapeutic dimension to the treatment and management of violent patients.
Psychosurgery
Psychosurgery is now rarely used in treatment of aggressive behavior but may be considered in some extreme cases where aggression is unmanageable and all other treatment modalities have failed. The two procedures that have relatively high success rates in the amelioration of violent behavior are bilateral amygdalotomy and posterior hypothalamotomy. 4 8 , 4 9
References
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4. Wong MT, Lumsden J, et al. Electroencephalography, computed tomography and violence ratings of male patients in a maximum -security mental hospital. Acta Psychiatr Scand 1994; 90:97!101.
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7. Raine A, Meloy JR, et al. Reduced prefrontal and increased sub -cortical brain functioning assessed using positron emission tomography in predatory and affective murderers. Behav Sci Law 1998; 16:319!332.
8. Kimbrell TA, George MS, et al. Regional brain activity during transient self -induced anxiety and anger in healthy adults. Biol Psychiatry 1999; 46:454!465.
9. Pietrini P, Guazzelli M, et al. Neural correlates of imaginal aggressive behavior assessed by positron emission tomography in healthy subjects. Am J Psychiatry 2000;157:1772!1781.
10. Blair RJ, Morris JS, et al. Dissociable neural responses to facial expressions of sadness and anger. Brain 1999; 122:883!893.
11. Isenberg N, Silbersweig D, et al. Linguistic threat activates the human amygdala. Proc Natl Acad Sci USA 1999; 96:10456!10459.
12. Whalen PJ, Rauch SL, et al. Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. J Neurosci 1998; 18:411 !418.
13. Hirono N, Mega MS, et al. Left frontotemporal hypoperfusion is associated with aggression in patients with dementia. Arch Neurol 2000; 57:861!866.
14. Tekin S, Mega MS, et al. Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol 2001; 49:355!361.
15. Raine A, Lencz T, Scerbo A. Antisocial behavior: neuroimaging, neuropsychology, neurochemistry, and
psychophysiology. In: Neuropsychiatry of Personality Disorders. Ratey JJ (eds). Cambridge, Massachusetts: Blackwell Science, 1995;50!78.
17. Whitman S, Coleman TE, et al. Epilepsy in prison: elevated prevalence and no relationship to violence. Neurology 1984; 34:775!782.
18. Pincus JH. Can violence be a manifestation of epilepsy. Neurology 1980; 30:304!307.
19. Saint -Hilaire JM, Gilbert M, et al. Epilepsy and aggression: two cases with depth electrode studies. In: Robb P, ed. Epilepsy Undated: Causes and Treatment. Chicago: Year Book Medical Publishers, 1980:145!176.
20. Ashford JW, Schulz SC, Walsh GO. Violent automatism in a partial complex seizure. Arch Neurol 1980; 39:120!122.
21. Delgado -Escueta A, Mattson RH, et al. The nature of aggression during epileptic seizures. N Engl J Med 1981; 305:711!716.
22. Stevens JR, Hermann BP. Temporal lobe epilepsy, psychopathology, and violence, the state of the evidence. Neurology 1981; 31:1127!1132.
23. Trieman DM, Delgado -Escueta AV. Violence and Epilepsy: A Critical Review. New York: Churchill Livingston, 1983.
24. Lewis DO, Pincus TH, et al. Psychomotor epilepsy and violence in a group of incarcerated adolescent boys. Am J Psychiatry 1982; 139:882!887.
25. Mark VH, Ervin FR. Violence and the Brain. New York: Harper and Row, 1970.
P.370 26. Monroe R. Episodic Behavioral Disorders. Cambridge, MA: Harvard University Press, 1970.
27. Kaufer DI, Cummings J. Personality alterations in degenerative brain diseases. In: Neuropsychiatry of Personality Disorders. Ratey JJ (eds). Cambridge, Massachusetts: Blackwell Science, 1995; pp. 172!209.
28. Haugh RM, Markesberry WR. Hypothalamic astrocytoma. Syndrome of hyperphagia, obesity, and disturbances of behavior and endocrine and autonomic function. Arch Neurol 1983; 40:560!563.
29. Reeves AG, Plum F. Hyperphagia, rage, and dementia accompanying a ventromedial hypothalamic neoplasm. Arch Neurol 1969; 20:616!624.
30. Schvarcz JR, Driollet R, et al. Stereotactic hypothalamotomy for behavior disorders. J Neurol Neurosurg Psychiatry 1972; 35:356!359.
31. Hill D, Sargent W, Heppenstall ME. A case of matricide. Lancet 1943; 1:526!527.
32. D'Orban PT, Dalton J. Violent crime and the menstrual cycle. Psychol Med 1980; 10:353!359.
33. Kreuz LE, Rose RM. Assessment of aggressive behavior and plasma testosterone in a young criminal population. Psychosom Med 1972; 34:321!332.
34. Rada RT, Laws DR, Kellner R. Plasma testosterone levels in the rapist. Psychosom Med 1976:257!268.
35. Ehlers CL, Rickler KC, Hovey JE. A possible relationship between plasma testosterone and aggressive behavior in a female outpatient population. In: Girgis M, Kiloh LG, eds. Limbic Epilepsy and the Dyscontrol Syndrome. New York: Elsevier-North Holland Biomedical Press, 1980:183!194.
36. Bach-y-Rita G, Lion JR, Ervin FR. Pathological intoxication: clinical and electroencephalographic studies. Am J Psychiatry 1970; 127:698!703.
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38. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Press, 1994.
39. Schiavi RC, Theilgaard A, et al. Sex chromosomes anomalies, hormones, and aggressivity. Arch Gen Psychiatry 1984; 4:93!99.
40. Shapiro AK, Shapiro ES, et al. Gilles de la Tourette Syndrome. New York: Raven Press, 1978.
41. Frankel M, Cummings JL. Neuro -ophthalmic abnormalities in Tourette syndrome: anatomic and functional implications. Neurology 1984; 34:359!361.
42. Tunks ER, Dernier SW. Carbamazepine in the dyscontrol syndrome associated with limbic system dysfunction. J Nerv Ment Dis 1977; 164:56!63.
43. Ratey JJ, Morrill R, Oxenkrug G. Use of propranolol for provoked and unprovoked episodes of rage. Am J Psychiatry 1983; 140:1356!1357.
44. Yudofsky S, Williams D, Gorman J. Propranolol in the treatment of rage and violent behavior in patients with chronic brain syndromes. Am J Psychiatry 1981; 138:218!220.
45. Stringer AY, Josef NC. Methylphenidate in the treatment of aggression in two patients with antisocial personality disorder. Am J Psychiatry 1983; 140:1365 !1366.
46. Berlin FS, Meinecke CF. Treatment of sex offenders with antiandrogenic medication: conceptualization, review of treatment modalities, and preliminary findings. Am J Psychiatry 1981; 138:601!607.
48. Sano K, Mayanagi Y, et al. Results of stimulation and destruction of the posterior hypothalamus in man. J Neurosurg 1970; 33:689!707.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 25 - Developmental Neuropsychiatric Syndromes
discussion is provided to complement other chapters in this volume in which the cognitive disturbances of brain dysfunction (language disturbances, memory impairment, visuospatial abnormalities, and executive dysfunction) are discussed. This chapter provides an overall approach to syndromes that are unique to developmental neuropsychiatry (e.g., autism, developmental learning disorders, mental retardation, etc.) and to inherited conditions and focal lesions occurring in childhood and accompanied by neuropsychiatric symptoms. A brief discussion of the approach to the pediatric neuropsychiatric patient is provided first, followed by a discussion of mental retardation and developmental delay. Next, autism and other pervasive developmental disorders are described. Learning disorders P.372 are summarized, followed by a description of childhood -onset movement disorders, conditions causing progressive cognitive decline, and childhood -onset acquired diseases such as stroke and multiple sclerosis. Tic disorders commonly beginning in childhood, such as Gilles de la Tourrette syndrome, are discussed in Chapter 19 , and the classification of epilepsy and childhood epileptic disorders are described in Chapter 21.
be reviewed. Review of communication skills, including language and prosody, are an important aspect of the inquiry. The use of toys, engagement in play, and social interactions with other children require discussion. Any special behavioral syndromes such as fears, anxieties, repetitious movements, obsessions, compulsions, aggressive behavior, and evidence of psychosis or mood abnormalities should be investigated. 1 During the interview with the child, the clinician should observe and examine affect and temperament, mood and emotional lability, attention, language processing, fund of age -appropriate general information, memory, and visuospatial skills. 2 The general physical examination can be extremely important in pediatric neuropsychiatry. Neurocutaneous disorders have revealing skin stigmata. Neurofibromatosis patients often have caf -au -lait spots; patients with tuberous sclerosis evidence hypopigmented oval or leaf-shaped spots; and Sturge -Weber syndrome is characterized by afacial angioma. Von Hippel-Lindau disease produces retinal hemangioblastomas and ataxia-telangictasia features oculocutaneous telangiectasia affecting the exposed areas of the skin and the sclerae of the eyes. 3 General physical examination may also reveal minor physical abnormalities and morphological disorders indicative of developmental disturbances. These include cleft lip and palate, absent or extranumerary digits, hypertelorism or hypotelorism (increased or decreased distance between the eyes), low -set ears, and hair whorls. 2 As in adults, neurological examination should include routine testing of cranial nerves, motor function, sensory abilities, coordination, assessment of reflexes, and review of gait and station (Chapter 3 ). In addition, children should be assessed for the presence of neurological !soft signs!! such as delays in relation to chronological and mental age in speech, motor coordination, right -left discrimination, and perception. Clumsiness on tests of coordination, minor choreiform movements of the outstretched limbs, the inability to balance on one foot, and difficulty with precise articulation are all counted among neurological soft signs. They may be associated with mental retardation, genetically determined maturation disorders, brain damage, or childhood -onset psychiatric disorders. 4 Neuropsychological examination follows the principles of that applied in adults (Chapter 3 ) but must be modified by a developmental perspective. Formal developmental assessments such as the Denver Developmental Screening Test II 5 are helpful for gauging the child's developmental sophistication in relation to ageexpected norms. Several
intelligence tests have been developed for children of various ages, including the Catell Infant Intelligence Scale (applicable to children ages 3 months to 30 months), Columbia Mental Maturity Scale (applicable to children 3 " years through 9 years of age), and Detroit Test of Learning Aptitude!3 (for children 6 through 17 years of age). 2 The Stanford -Binet Intelligence Scale is applicable from ages 2 through 23 years. Achievement tests help to determine the child's performance in specific cognitive areas in relation to their age and expected grade level (the Wide Range Achievement Test is an example of such an examination). Specific tests are also available for assessment of reading, spelling, mathematics, writing, motor skills, and perceptual abilities. 2 These tests may be particularly useful in the identification of specific learning disabilities in school -age children. Relevant P.373
Syndrome
Prevalence/1000
Dyslexia
50
46
5.9
Childhood/adolescent psychosis
5.4
Asperget's syndrome
3.6!7.1
Mental retardation
3.7
2.0
Autism
0.4!1.6
neuroimaging, electroencephalographic (EEG), and specific laboratory tests should be conducted to assess individual disorders. Table 25.1 provides an overview of the neuropsychiatric disorders most commonly encountered in childhood.
Mental Retardation
Mental retardation is defined as subaverage general intellectual functioning accompanied by significant limitations in adaptive functioning in at least two of the following skill areas: communication, self -care, home living, social and interpersonal skills, use of community resources, self direction, functional academic skills, work, leisure, health, and safety. 6 By convention, the onset must occur before the age of 18. This age of onset criterion is somewhat confusing in that it allows the syndrome of mental retardation to overlap with that of dementia (Chapter 10 ). It would be more consistent to define mental retardation as delays in the acquisition of the usual social and cognitive milestones, and dementia as the decline from a previous higher level of cognitive function regardless of age. In practice, however, the distinction between these syndromes is not difficult, since early -onset dementia syndromes are rare. Four degrees of severity of mental retardation are recognized. Patients with mild mental retardation generally have IQs between 50!55 and 70; those with moderate retardation have IQs between 35!40 and 50!55; persons with severe mental retardation have IQs of 20!25 to 35!40; and those with profound mental retardation have IQ levels below 20 or 25. 6 Epidemiologically, mild mental retardation occurs in 3 to 6 per 1000 of the general population, moderate retardation in 2 per 1000, severe retardation in 1.3 per 1000, and profound retardation in 0.4
per 1000. 7 Rates may vary depending on the occurrence of specific circumstances that may jeopardize early life brain development. Males are more likely to evidence mental retardation than females by a ratio of 1.6:1. Specific etiologic diagnoses are most difficult to identify in those with mild to moderate mental retardation. In this group, 45% to 60% of syndromes are of unknown etiology. Perinatal insults account for 10%!25% of cases and chromosomal abnormalities for 5%!10%. 7 Among those with severe mental retardation, chromosomal abnormalities account for 30%, gestational and peri- and postnatal injuries for 15%!20%, central nervous system (CNS) malformations for 10%!15%, congenital anomaly syndromes for 5%, and endocrine and metabolic disorders for 5%. The cause of 25%!30% of cases of severe mental retardation remains undetermined. 7,8 Among the chromosomal abnormalities contributing to the occurrence of severe mental retardation, Down syndrome accounts for 20% of cases, fragile X syndrome for 60%, and all other chromosomal abnormalities for 20%. 8 The most common cause (94%) of Down syndrome is a de novo trisomy of chromosome 21. 9 The brain is small, with a simplified convolutional pattern. The frontal cortex and limbic structures are disproportionately reduced in volume. Histological studies reveal that granule cells are small in all cortical regions. Children with Down syndrome acquire language slowly and manifest impoverished vocabulary and grammar as well as difficulty with word meanings and appropriate contextual use of language and syntax. Mathematical skills and executive function are poorly developed. Visuospatial function is relatively well preserved. Approximately 25% of individuals with Down syndrome manifest neuropsychiatric disorders, including attentiondeficit hyperactivity disorder (ADHD) (6.1%), oppositional defiant and conduct disorders (5.4%), aggression (6.5%), and self -injurious behavior (1%). Anxiety disorders, mood disturbances, and autistic symptoms may be associated with Down syndrome. 9 Fragile X syndrome is the most common form of inherited mental retardation. 10 The fragile X gene (located at Xq21.3 !q22) contains a cytosine-guanine trinucleotide repeat that is dramatically expanded in affected individuals. A variety of neuropsychiatric manifestations have been associated with fragile X syndrome, including mood and anxiety disorders, ADHD, schizotypal behaviors, obsessive -compulsive disorder, Gilles de la Tourette syndrome, Asperger's syndromespectrum disorders, and autistic-spectrum disorders. 9
P.374 Neuropsychological abnormalities are disproportionately severe for nonverbal memory, visuospatial abilities, visuomotor coordination, sequential processing, and attention. Language is acquired slowly and linguistic expression is typically characterized as rapid, perseverative, jocular, tangential, cluttered, and echolalic. 9 Female carriers of the fragile X mutation manifest more mild neuropsychological deficits including conceptual disorganization and relative deficits on performance measures of IQ tests. They often exhibit schizotypal features and are vulnerable to depression. 9 ,1 0 Magnetic resonance imaging (MRI) indicates a relative increase in the volume of the hippocampus and a decrease in the volume of the superior temporal gyrus in individuals with fragile X syndrome. 11 Two genetic syndromes are particularly informative from a neuropsychiatric perspective: Williams syndrome and Prader Willi syndrome. Williams syndrome occurs at a rate of 1 per 25,000!50,000 live births. Patients have a characteristic elfin facial appearance with medial eyebrow flair, small and low -set ears, thick lips, and epicanthal folds. The voice has a peculiar, lowpitched quality. The syndrome is produced by a mutation at 7q11.23. 9 The most characteristic feature of Williams syndrome is a relative preservation of expressive language skills, leading to a verbose and pseudomature linguistic output. Both spatial and motor skills are significantly impaired. Major psychopathology is not common in these children, but they are described as fussy, fearful, distractible, and anxious. 9 The brain has a reduced volume of gray matter and posterior structures are disproportionately effected. 9 ,1 2 Prader -Willi syndrome occurs at a rate of 1 per 10,000 !25,000 live births and about 70% of individuals have a deletion of 15q11!13, with the affected chromosome being of paternal origin. 9,1 3 In the neonatal period, patients with Prader -Willi syndrome exhibit hypertonia, diminished movements, and poor cry. They have characteristic facial features with a narrow face, almond -shaped eyes, thin upper lip, and down-turned corners of the mouth. There is hypogonadism and cryptorchidism. Neuropsychiatrically, patients typically are friendly and outgoing but exhibit unusual features such as hyperphagia, food seeking, and an obsession with food. Temper tantrums with violent outbursts, obsessive -compulsive behavior, and repetitive skin picking are not uncommon. Patients may exhibit depression and, rarely, psychosis. 9 ,14
Tables 25.2 and 25.3 provide a summary of the principal identifiable etiologies of mental retardation. The causes of mental retardation are increasingly intertwined. For example, developmental malformations of the brain are increasingly linked to specific genetic mutations, inborn errors of metabolism and developmental malformations can both produce epilepsy with consequences for cognitive development, and the presence of severe retardation can in some cases lead to child abuse and neglect, further exacerbating the cognitive and behavioral disorder.
studies have not yielded consistent abnormalities. There is evidence of increased brain volume in autism and diminished corpus callosum size. 16 17 18 19 Only a few brains of autistic patients have been P.375
Prenatal causes
Infection
Stroke
Trauma
Chromosomal disorders
Fragile X syndrome
XO syndrome (Turner)
XYY syndrome
Angelman's syndrome
Williams syndrome
Syndromic disorders
Neurocutaneous disorders
Neurofibromatosis
Tuberous sclerosis
Ocular disorders
Lowe syndrome
Craniofacial disorders
Phenylkeronuria
Histidinemia
Hyperleucine-isoleucinemia
Propionic acidemia
Methylmalonic acidemia
Homocystinuria
Hartnup disease
Carbohydrate disorders
Galactosemia
Mucopolysaccharide disorders
Mucolipid disorders
Lesch-Nyhan disease
Orotic aciduria
Wilson's disease
Menkes' disease
Mitochondrial disorders
Wolfram syndrome
Peroxisomal disorders
Zellweger syndrome
Pipecolic acidemia
Developmental malformations
P.376
Non-neoplastic
Hemitnegaloencephaly (HMEG)
Ganglioglioma
Gangliocytoma
Cobblestone complex
Heterotopia
Subependymal (periventricular)
Marginal glioneuronal
Microdysgenesis
Peroxisomal disorders
Sublobar dysplasia
Others
P.377
Autistic disorders
Rett's disorder
Asperger's syndrome
Atypical autism
examined neuropathologically. These studies reveal abnormalities of the limbic system (hippocampus, subiculum, entorhinal cortex) and a decrease in the number of Purkinje and granular cells in the cortex of the cerebellum. 20 Childhood disintegrative disorder is characterized by apparently normal development during the first 2 years of life, including social skills and adaptive behavior, bowel and bladder control, play, and motor skills. After the period of normal development, progressive deterioration in functions begins and affects at least two areas of function, including social interaction and communication, or there may be the appearance of restrictive, repetitive, and stereotyped patterns of behavior. 6 In approximately 75% of cases, the child's behavior and development deteriorate to a low level of function and they remain at that level with only limited recovery. In the few cases associated with an identified progressive neurological disorder, there may be continuing deterioration and eventual death. Although most cases have had no recognized underlying neurological condition, the syndrome has been associated with neurolipidoses, metachromatic leukodystrophy, adrenoleukodystrophy, and subacute sclerosing panencephalitis. 2 1 Asperger's syndrome consists of an impairment in social interaction and restricted, repetitive, and stereotyped patterns of behavior, interest, and activities. 6 The disturbance of social interaction is manifested by marked impairment of multiple nonverbal behaviors. Disturbance is sufficiently severe to cause clinically significant impairment in social, occupational, or other important areas of functioning. There is no clinically significant delay in language acquisition or cognitive development, or in the development of age -appropriate self -help skills, adaptive
behavior, and curiosity about the environment. Asperger's syndrome shares two core features of autism (impaired social interaction, repetitive and stereotyped behavior) but is distinguished from autism by the absence of delay in language or clinically significant delay in cognitive development or self -help skills. 2 2 Children with Asperger's syndrome are at risk for depression and schizophrenia in adulthood but a reasonable level of functioning is possible in some circumstances. No compelling neuroimaging or neuropathological observations have been related to Asperger's syndrome. In some cases, an Asperger's-like syndrome has been a manifestation of an underlying inherited inborn error of metabolism, a leukodystrophy, or a CNS infection. 23 Asperger's syndrome has been described in patients with neuronal migration disturbances such as macrogyria and polymicrogyria. 2 4 Rett's disorder (also known as Rett's syndrome) is characterized by deceleration of head growth between the ages of 5 months and 48 months after an apparently normal period of prenatal and perinatal development; loss of previously acquired purposeful hand skills, with subsequent development of stereotyped hand movements (hand ringing or hand washing); loss of social engagement, appearance of poorly coordinated gait or trunk movements, and severely impaired language development; and marked psychomotor retardation. 6 Most cases of Rett's disorder are produced by a mutation located on Xq28. The disorder occurs primarily in females and it is likely that the mutation is lethal to males. 25 Clinically, patients evidence a variety of stereotyped movement and gait disorders including bruxism, oculogyric crises, parkinsonism, and dystonia. Myoclonus and choreoathetosis may occur but are infrequent. In general, younger patients tend to exhibit more hyperkinetic disorders, while bradykinesia is more evident in older Rett's disorder patients. 2 6 Neuroimaging studies reveal global reduction in gray and white matter volumes. Prefrontal, posterior frontal, and anterior temporal regions show the largest reductions in gray matter volume, whereas white matter is reduced uniformly throughout the brain. There is a disproportionate reduction in caudate nucleus volume. 1 1, 2 7 At autopsy, two consistent observations have emerged: there is hypopigmentation of the substantia nigra and diffuse reduction in brain size, 2 8 and in the cortex there is a reduction in neuronal size and increased cellpacking density. 2 9 Abnormalities of dopaminergic and cholinergic systems have been described. 2 9, 30
Learning Disorders
Learning disorders are diagnosed from the child's school performance and achievement on standardized tests. Abilities are substantially below what is expected for age, schooling, and level of intelligence. A discrepancy of more than two standard deviations between achievement on tests assessing the specific disability and IQ is a common means of defining a specific learning P.378 disability. Currently, three learning disabilities are recognized: reading disorder (developmental dyslexia), mathematics disorder (developmental dyscalculia), and a disorder of written expression (developmental dysgraphia). 6 Of patients with ADHD (discussed below), 10%!25% exhibit learning disorders. Developmental dyslexia is the most thoroughly studied of the learning disabilities. It is the most common neurobehavioral deficit affecting children, with prevalence rates ranging from 5% to 10% of the population. Longitudinal studies indicate that dyslexia is persistent over time and remains detectable in adults. The condition is highly heritable, with between 25% and 65% of affected children having a dyslexic parent. Studies of brain structure using morphological imaging techniques have provided inconsistent findings. Studies of brain activation using positron emission tomography (PET) reveal diminished activation of left posterior structures with reading -related tasks. Autopsies of patients with severe persistent dyslexia who died of accidental deaths show neuronal ectopias and architectonic dysplasias in the peri-sylvian regions of the left hemisphere. 31 Individuals with childhood learning disabilities are at increased risk for adult psychopathology, particularly depression and anxiety. 32
activities. In addition, the child will have exhibited six or more of the following symptoms of hyperactivityimpulsivity for at least 6 months: fidgeting with hands or feet or squirming in seat; leaving his or her seat in the classroom or other situations in which remaining seated is expected; running about or climbing excessively in situations where it is inappropriate; failing to play or engage in leisure activities quietly. The child is often !on the go!! or acts as if !driven by a motor!!; excessive talking; blurting out answers before questions have been completed; failing to await his or her turn; and frequent interrupting or intruding on others. At least some of the symptoms must be evident before the age of 7 years and must be present in two or more settings. Three subtypes of ADHD are recognized: a combined attention-deficit and hyperactivity type, a predominantly inattentive type with a predominance of cognitive over motor disturbances, and a predominantly hyperactive -impulsive type with a predominance of motoric and impulsive features. 6 Attention-deficit hyperactivity disorder is common in the population, with reported prevalence ranging from 2% to 15%. Boys are more likely to manifest the syndrome than girls, with ration of at least 2!3:1. 33 The disorder has a marked genetic influence; 75% of children of parents with ADHD evidence the disorder. 34 The prevalence of the disorder is highest in school -age children and it persists into early adolescence, decreasing through mid and late adolescence to lower levels in adulthood. 33 When ADHD persists into adolescence it is often associated with substance abuse and antisocial personality. 33 Neuroimaging studies using both morphological and functional techniques have often identified abnormalities of prefrontal cortex and striatum, though there is substantial variability across studies. 3 5 Nongenetic risk factors for the development of ADHD include head injury and prenatal exposure to alcohol. Patients with ADHD commonly respond with improved attention and reduced motor activity to treatment with psychostimulants. Currently available stimulants include methylphenidate, dextroamphetamine, and pemoline. 3 3, 35 Two disruptive behavior disorders somewhat related to ADHD are conduct disorder and oppositional defiant disorder. Conduct disorder is characterized by aggression toward people and animals, destruction of property, deceitfulness or theft, and serious rule violations. Oppositional defiant disorder features the following behaviors: loss of temper, argument with adults, active defiance or refusal to comply with adults' requests or rules, deliberate annoyance of
people, blame of others for one's mistakes or misbehavior, easy annoyance by others, expression of anger and resentment and of spite or vindication. 6
TABLE 25.5. Inherited Metabolic Disorders with Cognitive and Neuropsychiatric Symptoms 38
Disease
Clinical Symptoms
Tests
Fabry's disease
-galactosidase
Horizontal supranuclear gaze defect, developmental delay, hydroccphalus, skeletal abnormalities, psychosis
# -glucosidase
GM1 gangliosidosis
Extrapyramidal signs, flattening of vertebral bodies, normal cognitive function, sometimes with psychosis
(i) Lower motor neuron disease with onse t at 20!40 years, pyramidal signs, and cerebellar degeneration
Krabbe's leukodystrophy
leukocyte # galactocerebrosidase
Metachromatic leukodystrophy
Loss of cognitive function or behavioral abnormalities, neuromuscular weakness with impaired nerve conduction, leukodystrophy
Sialidosis (mucolipidosistype 1)
Dementia cherry red spot (type II), myoclonus, blindness, cherry red spot, dysmorphic features, angiokeratoma
Arginase deficiency
Disoricntation, coma
Citrullinacmia
Hartnup's disease
disturbances
Parasthesia, hallucinations, tremor, withdrawal, mental retardation, limb weakness, memory loss
Plasma ammonia (1 hr postprandial) plasma amino acids, urine amino acids and orotic acid
Propionic acidemia
Peroxisomal disorders
X linked adrenoleukodystrophy
Onset at 20 !30 years in males, gait disturbance, spastic paraparesis, intellectual function usually
intact, impotence Addison's disease, occasionally cerebral symptoms may occur, e.g., dementia and psychosis
Lactic acidaemias
Other disorders
Aceruloplasminemia
Upper and lower motor neuron signs, sensory loss, neurogenic bladder, dementia
Leukocyte glycogen brancher enzyme (some forms may show normal muscle activity)
Cerebrotendinous xanthomatosis
Skin or rectal biopsy for histological analysis, DNA analysis for the common mutation
Kuf's disease
Lesch-Nyhan syndrome
Some forms may present late with choreiform movements, dysarthria renal problems
Porphyrias
Limb, neck, and chest pain, muscle weakness, senosry loss, seizures, behavioral abnormalities abdominal symptoms photosensirivity
Urine delra amino levutinic acid and porphobilimogen, urine and fecal porphyrins
Pyridoxine-responsive seizures
Refsum's disease
Segawa disease
Cyclical dystonia
Sjogren-Larrson syndrome
Wilson's disease
pseudobulbar palsy, parkinsonian features, renal failure, liver disease, Kayser Fleischer rings, dementia
ceruloplasmin
MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episode; MERRF, mitochondrial encephalomyopaihy with tagged red fibers; NARP, neuropathy, aiaxia, and rerinitis pigmentosa.
P.381 cognitive deterioration in children, while meeting criteria for dementia and representing a decline from a previous level of function, will be identified as causes of mental retardation. Progressive neurological disorders producing cognitive deterioration in children include inborn errors of metabolism, infections, leukoencephalopathies, polioencephalopathies, toxic metabolic disorders, and seizure disorders (Table 25.2 ). Progressive polioencephalopathies of childhood include the lipidoses, neuronal steroid lipofuscinoses, mucopolysaccharidoses, mucolipidoses, glycogen storage disease, the mitochondrial disorders, Rett's disorder, and epileptic encephalopathies. 3 6 Leukodystrophies producing progressive deterioration in children include metachromatic leukodystrophy, adrenoleukodystrophy, Krabbe's disease (galactosylceramidase deficiency), Alexander's disease, Canavan's disease, and Pelizaeus -Merzbacher disease 36 , 3 7 (see Chapter 26 on multiple sclerosis and leukoencephalopathies). Chronic viral infections that may produce a slowly progressive decline in cognitive function in children include acquired immunodeficiency syndrome (AIDS), progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis (SSPE), progressive rubella panencephalitis, and Creutzfeldt -Jakob disease. 3 6 Table 25.5 presents the inborn metabolic disorders with cognitive and neuropsychiatric symptoms and lists the principal tests used for diagnosis. 3 8
rare in adults and must be weighted differently in the differential diagnosis. Among the causes of childhood chorea (Table 25.6 ) is the athetoic form of cerebral palsy, which follows perinatal asphyxia with or without kernicterus. 3 9 The juvenile form of Huntington's disease, benign familial chorea, hereditary paroxysmal disorder, and a variety of inborn errors of metabolism including gangliosidoses, lipofuscinoses, Lesch-Nyhan syndrome, and Hallervorden Spatz disease can also produce chorea in childhood. Infectious and inflammatory causes of chorea among children include Sydenham's chorea, systemic lupus erythematosus, and viral encephalopathies. A variety of drugs can induce chorea, including neuroleptics, psychostimulants, and anticonvulsants. The relative frequency of disorders producing parkinsonism in children also differs from the usual differential diagnosis in adults (Chapter 18 ). The juvenile form of Huntington's disease (Westphal variant) typically presents as a parkinsonian disorder. Perinatal brain insults may produce parkinsonism, and drugs, toxins, and inborn metabolic disorders also feature in the differential diagnosis (Table 25.7 ).
Gangliosidoses
Lipofuscinoses
Lesch-Nyhan syndrome
Sydenham's chorea
Viral encephalitis
Drug-induced chorea
Neuroleptic agents
Psychostimulants
Anticonvulsants
Metabolic disorders
Hepatic encephalopathy
Hyperthyroidism
Stroke
Stroke In Children
Focal cortical strokes in children can produce neurobehavioral deficits and neuropsychiatric syndromes as described in adults (Chapter 26 ). The etiologies of stroke in childhood vary from those in adulthood; hypertension and atherosclerotic disease are much more rare in children than in adults. Cardiac abnormalities and hematologic disorders account for a majority of strokes occurring in the perinatal, infant, and childhood period. 40 Table 25.8 presents a differential diagnosis of the etiologies of stroke in children. P.382
Ceroid lipofuscinosis
Gaucher's disease
GM1 gangliosidosis
Metachromatic leukodystrophy
Neuroacanthocytosis
Wilson's disease
Juvenile parkinsonism
Infectious/post -infectious
Mycoplasma
Viruses
Measles
Varicella
Japanese B
Western equine
Human immunodeficiency
Perinatal anoxia
Perinatal kernicterus
Mass lesion
Artcriovenous malformation
Neoplasm
Carbon monoxide
Neuroteptics
Antiemetics
Stroke
Hydrocephalus
Cardiac disease
Infective endocarditis
Valvular disease
Marantic endocarditis
Infective endocarditis
Arrhythmia
Myocarditis
Cardiomyopathy
Hematologic
Inherited coagulopathy
Protein C deficiency
Protein S deficiency
Acquired coagulopathy
Lupus anticoagulant
Myeloproliferative disorders
Moyamoya disease
Fibromuscular dysplasia
Takayasu arteritis
Infectious vasculitis
Trauma
Metabolic
Homocystinuria
Volume depletion
Drugs
Cocaine
Amphetamine
Sympathomimetics
Oral contraceptives
Surgical intervention
Cardiac surgery
Cardiac catheterization
Cerebral angiography
Neurocutaneous syndromes
Neurofibromatosis
Tuberous sclerosis
Fabry's disease
Lipoprotein abnormalities
Migraine
Arteriovenous malformation
Cavernous angioma
Intracranial aneurysm
P.383 predominantly over the temporal and parietal regions. Associated behavioral disturbances, including hyperactivity, rage outbursts, aggressiveness, stereotypy and poor social communication skills, are present in most children with the syndrome. 41 PANDAS refers to pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. 4 2 The syndrome is identified in a group of children manifesting tics and obsessive -compulsive disorder whose symptoms occur following infection with bhemolytic streptococcus. Sydenham's chorea is known to be a post-infectious autoimmune syndrome, and obsessions and compulsions have been observed to be more common among children who experienced the condition. In some cases, however, children with PANDAS have no known history of either streptococcal infection or Sydenham's chorea, and the diagnosis must be sought on the basis of laboratory evidence of a past streptococcal infection. PANDAS should be considered in children manifesting tic syndromes or obsessions and compulsions who have no family history of a similar disorder.
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Authors: Cummings,, Jeffrey L.; Mega,, Michael S. Title: Neuropsychiatry and Behavioral Neuroscience, 1st Edition Copyright 2003 Oxford University Press
> Table of Contents > Chapter 26 - Focal Brain Disorders and Related Conditions
in neurological function persisting less than 24 hours. Stroke refers to rapidly developing clinical symptoms or signs of focal (or sometimes global) impairment of cerebral function with symptoms lasting more than 24 hours and having no other cause than cerebrovascular disease. The distinction between TIA and stroke is arbitrary and they represent a continuum of increasingly severe and irreversible brain infarction. 2 Vascular dementia (Chapter 10 ) refers to a syndrome characterized by memory impairment plus compromise in at least one additional cognitive domain (language, praxis, visuospatial ability, P.386 executive function) produced by cerebrovascular disease. Cerebrovascular disease ranks second behind heart disease as the leading cause of death worldwide and third behind heart disease and cancer as a cause of death in the United States. 3 The incidence of stroke doubles every 10 years after the age of 55: approximately 2 per 1000 individuals experience stroke between the ages of 55 and 64; approximately 4 individuals per 1000 experience a new onset of cerebrovascular disease between the ages of 65 and 74; and approximately 8!10 individuals per 1000 have the onset of stroke after the age of 75. 4 Cerebral infarction accounts for approximately 80% of cerebrovascular events; primary intracerebral hemorrhage accounts for 10%; subarachnoid hemorrhage causes 5%; and 5% of strokes are of uncertain cause. 1 Approximately 40% of cerebral infarctions undergo hemorrhagic transformation within 2 weeks after infarction. This is most likely to occur when infarcts are large or anticoagulants or thrombolytic agents are used for treatment. 2 Table 26.1 lists the principal neurobehavioral and neuropsychiatric syndromes associated with focal lesions of the brain. Neuropsychiatric symptoms are common as poststroke manifestations. Major depression occurs in approximately 10%!25% of patients and minor depression in 10%!40%. Anxiety accompanies depression in 20% of depressed post-stroke patients and occurs without depression in 7%!10%. Apathy occurs in 20% of patients (10% with depression; 10% without depression). Anosognosia with denial of illness is present in 25%!45% of patients, particularly those with right posterior lesions. Catastrophic reactions appear in approximately 20% and
TABLE 26.1. Neurobehavior and Neuropsychiatric Syndromes Associated with Focal Brain Infarctions of the Hemisphere
Blood Vessel
Structures Affected
Syndrome
Broca's aphasia
Global aphasia
division
Arcuate fasciculus
Conduction aphasia
Angular gyrus
Transcortical sensory aphasia; alexia with agraphia; angular gyrus syndrome; anomia
Wernicke's aphasia
Hippocampus
Verbal amnesia
Occipital cortex
Calcarine cortex
Hemianopsia; achromatopsia
Callosal apraxia
Executive aprosodia
Receptive aprosodia
Posterior parietal
Hippocampus
Nonverbal amnesia
Posterior
Inferior
Prosopagnosia;
cerebral (R)
longitudinal fasciculus
environmental agnosia
Occipital cortex
Akinetic mutism
Auditory agnosia
Occipital cortex
Hippocampi
Amnesia
Cerebral peduncle
Peduncular hallucinosis
Basilar artery
Midbrain
Dorsomedial nuclei
Lateral geniculate
Thalamic dazzle
Executive dysfunction
Disinhibition
Nucleus accumbens
Apathy
Globus pallidus
Subthalamic nucleus
Mania
P.387 described in post-stroke conditions but are relatively unusual. 5 There are many potential causes of cerebral thrombosis and cerebral embolism. Table 26.2 provides a differential diagnosis of thrombotic and embolic conditions that may result in cerebrovascular events. The principal stroke syndromes include hemorrhages in the area of the basal ganglia and thalamus (usually hypertensive in origin); lobar hemorrhages (often associated with amyloid angiopathy); focal cortical infarctions (embolic or thrombotic); borderzone infarctions (between territories of major arteries); lacunar infarctions involving the basal ganglia, thalamus, brainstem, and cerebellum; and white matter ischemic injury. When there is extensive white matter damage and the individual has dementia, the diagnosis of Binswanger's disease is considered. Typical abnormalities on neurological examination include hemiparesis, hemisensory deficits, homonymous visual field defects, gait disturbance, parkinsonism, incontinence, spasticity, brisk muscle stretch reflexes, pseudobulbar palsy, and Babinski signs. Treatment of stroke includes acute interventions to open the artery and reverse the deficit and preventive strategies to reduce stroke risk. Where acute stroke teams are available, thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) is used for treatment of strokes when the patient is seen within 3 hours of onset. Emboli originating from high -risk cardiac conditions, particularly atrial fibrillation, are prevented most effectively with long-term oral anticoagulants. Antiplatelet agents are recommended as a primary prevention strategy for patients with atherothrombotic stroke; aspirin (in doses of 50!325 mg daily) is the most P.388
Thrombotic
Embolic
Atherosclerosis
Cardiac disease
Arteriosclerosis
Diabetes
thrombus
Fibromuscular dysplasia
Atrial fibrillation
Amyloidosis
Rheumatic endocarditis
Fabry's disease
Homocystinemia
Marantic endocarditis
Neoplastic angioendotheliosis
Prosthetic valves
Cardiomyopathy
Atrial myxoma
Sarcoidosis
Polyarteritis nodosa
Endocardial fibroelastosis
Granulomatous arteritis
Wegener's granulomatosis
emboli
Hypersensitivity angiitis
Scleroderma
Metastatic deposits
Takayasu's aortitis
Cogan's syndrome
Septic emboli
Bchet's syndrome
Air emboli
Sjogren's syndrome
Fat emboli
Vascular trauma
Dermatomyositis
Kohlmeier-Degos disease
Angiography
Chemical -arteritis
Attempted strangulation
Amphetamines
Crack cocaine
Hematologic disorders
Neck fracture
Leukemia
Waldenstrom's macrogloblinemia
Polycythemia vera
Dysproteinemias
Idiopathic thrombocytosis
Hyperlipidemia
Cryoglobulinemia
Lupus anticoagulant
Bacterial arteritis
Syphilis
Tuberculosis
Miscellaneous
Rickettsia arteritis
Viral arteritis
Cysticercosis
Miscellaneous
Vascular trauma
Vascular dissection
Pregnancy/puerperium
Oral contraceptives
Migraine
Ergot compounds
Mitochondrial disorders
Marfan's syndrome
Pseudoxanthoma elasticum
P.389 commonly used agent. Other antiplatelet drugs that have been shown to be at least as effective as aspirin include ticlopidine, clopidogrel, and a combination of low -dose aspirin and dipyrimidol. 6
prevalence varies with geographic distribution; it is least common in the tropics and becomes more common in the northern latitudes. In the United States, Canada, and northern Europe the prevalence is approximately 100 per 100,000 whereas in the tropics the average prevalence is 5 per 100,000. 8 The disease is twice as common among women as men and typically begins in mid -life between the ages of 15 and 50. The diagnosis of definite MS depends on the occurrence of at least two attacks and clinical evidence of at least two separate lesions in the CNS or two attacks with clinical evidence of one lesion and paraclinical (neuroimaging) evidence of another (Table 26.3 ). A combination of clinical and laboratory evidence can also be employed to make a diagnosis of definite MS (Table 26.3 ). 9 Several different courses of MS are recognized (Table 26.4 ). Seventy percent of patients have relapsingremitting MS with discrete episodes and complete or nearly complete recovery between attacks. Approximately 50% of patients with MS change gradually from relapsing -remitting to secondary progressive (relapsing progressive MS). These patients begin with discrete attacks but gradually accumulate increasing neurological disability and slowly worsen. Approximately 15% of patients have chronic progressive MS, characterized by a slow and steady progression of increasing neurological P.390
TABLE 26.3. Criteria for Diagnosis of Definite and Probable Multiple Sclerosis
A. Clinically definite MS 1 . Two attacks and clinical evidence of two separate lesions 2 . Two attacks with clinical evidence of one lesion and paraclinical evidence of another (separate) lesion B. Laboratory -supported definite MS 1 . Two attacks with either clinical or paraclinical evidence of one lesion and
demonstration in CSF, of IgG OB or increased CNS synthesis of IgG 2 . One attack, clinical evidence of two separate lesions, and demonstration of CSF OB/lgG 3 . One attack, clinical evidence of one lesion, paraclinical evidence of another (separate) lesion, and demonstration of CSF OB/lgG C . Clinically probable MS 1 . Two attacks and clinical evidence of one lesion 2 . One attack and clinical evidence of two separate lesions 3 . One attack, clinical evidence of one lesion, and paraclinical evidence of another (separate) lesion D . Laboratory -supported probable MS 1 . Two attacks and presence of CSF OB/lgG
CSF, cerebrospinal fluid; IgG, immunoglobulin G; MS, multiple scoerosis; OB, oligoclonal hands.
deficit without discrete episodes. Acute (malignant) MS features polysymptomatic progression to severe disability or death in a few months. Benign MS is manifested by a relapsing course with discrete episodes without significant neurological deficit after 10 to 15 years of disease. 9 Motor neuron signs, sensory abnormalities, visual changes, and evidence of cerebellar dysfunction are the most common findings on neurological examination of the MS patient. There are hyperactive muscle stretch reflexes (76%), ataxia of the lower extremities (57%), bilateral Babinski signs (54%), diminished vibratory sensation (47%), incoordination of one or more limb (40%), evidence of optic neuritis (38%), nystagmus (35%), decreased joint position sense
(33%), spasticity of one or more limb (31%), diminished two -point discrimination (24%), decreased pain or temperature sense (22%), dysarthria (19%), paraparesis (17%), internuclear opthalmoplegia (11%), and signs of neurogenic bladder (10%). 1 0
Category
Features
Relapsingremitting
Discrete attacks with subsequent recovery and little or no residual neurological deficit between attacks. Some patients have a step-wise increase in neurological deficit.
Onset with attacks but patients develop significant neurological deficits that increase during follow up. Most patients slowly worsen.
Slow and steady progression of a chronic neurological deficit from onset without discrete episodes
Acute (malignant)
Polysymptomatic disease that progresses to severe disability and/or death in a few months.
Benign
P.391
FIGURE 26.1 Magnetic resonance image of patient with multiple sclerosis showing multiple high -signal lesions on the T 2 -weighted image.
Neuroimaging and laboratory studies are useful in supporting the clinical diagnosis of MS. Magnetic resonance imaging (MRI) reveals focal discrete or confluent high -signal lesions on T 2 -weighted images in the periventricular deep white matter or superficial gray -white matter junction. 1 1 Patients also show hypointense lesions on T 1 -weighted spin -echo images and increased hypointense lesion load correlates significantly with increasingly disability (Fig. 26.1 ). 1 2 , 1 3 Cerebrospinal fluid (CSF) abnormalities are present in 90% of patients with clinically definite MS. The CSF cell counts are typically normal, although a mild pleocytosis may be evident. Similarly, the total protein level is normal in approximately 80% of patients, although 60%!75% have an increased " -globulin content. A " -globulin fraction of >12% reflects increased IgG synthesis in the CNS. The elevated IgG levels give rise to oligoclonal banding on
protein electrophoresis, a feature present in 90% of patients with clinically definite MS and between 30% and 40% of those with possible MS. 1 0 , 1 4 Increased CSF IgG is not specific and can be seen in other inflammatory neurological disorders, including subacute sclerosis panencephalitis, progressive rubella encephalitis, inflammatory neuropathies, cryptococcal meningitis, and other encephalitides. Abnormal visual evoked potentials, auditory evoked potential, or somatosensory evoked potentials may aid in identifying asymptomatic or minimally symptomatic lesions useful in corroborating the presence of multiple lesions necessary for the diagnosis. 1 0 Cognitive abnormalities are common in patients with MS. Memory and executive function abnormalities occur in patients with chronic progressive MS and during acute exacerbations in patients with relapsing remitting disease. 1 5 Semantic (fact) memory is more impaired than episodic (autobiographical) memory. 1 6 Working memory and other executive function deficits are frequent. 1 7 , 1 8 Specific types of neuropsychological impairments are correlated with anatomically relevant lesions on MRI. 1 9, 2 0 , 2 1 Patients with cognitive impairment commonly have atrophy of the corpus callosum. 2 0 , 2 2 Patients with MS commonlly manifest neuropsychiatric symptoms, particularly depression. Major depression is present in approximately 35% of patients with MS and depressive symptoms are present in 65%!80% 2 3 , 2 4 , 2 5 (Chapter 14 ). The depression is unrelated to the degree of disability 26 , 2 7 or to genetic factors, 2 8 suggesting that the mood abnormality is the product of the CNS disease itself. This is further confirmed by the observation that depression is more prominent in patients with MS affecting brain regions than in those with predominantly spinal cord disease with similar levels of disability. 2 7 Mood disturbances correlate with CSF cell counts during periods of acute exacerbation in patients with relapsing -remitting MS, 2 9 and mood disturbances also correlate with frontal or temporal abnormalities on MRI. 3 0 , 3 1 , 3 2 Several studies have suggested that treatment with interferon # -1B (described below) is associated with increased depression. 3 3 , 3 4 Quality of life in MS is influenced by the presence of depressive symptoms. 3 5 Bipolar illness is also increased in prevalence in MS. 3 6 , 3 7 , 3 8 Euphoria is more common than mania and is most likely to
appear in patients with chronic progressive MS who have enlarged ventricles and cognitive impairment. 2 7 Psychosis may be a manifestation of MS and is most common with the acute encephalitic form of the illness. 3 9 , 4 0 , 4 1 Psychotic patients have a greater lesion load in the temporal or temporal -parietal regions than those without psychosis. 4 0 , 41 Other psychiatric symptoms recorded in patients with MS include panic attacks, obsessive -compulsive disorder, paraphillic and hypersexual behavior, anxiety, irritability, apathy, and disinhibition. 2 3 , 4 2 , 4 3 , 4 4 Fatigue is a common symptom in patients with MS, occurring in up to 90% of patients. 4 5 Fatigue correlates with the presence of pyramidal track signs and reaction P.392 time on memory tasks but is independent of depression. 4 6 , 4 7 , 4 8 Patients with MS and fatigue have greater reductions in glucose metabolism in lateral and medial prefrontal regions, premotor cortex, putamen, and supplementary motor areas. 4 9 At autopsy, plaques of various sizes are distributed throughout the CNS white matter. They are particularly prominent in periventricular regions and those located between the body of the caudate nucleus and the corpus callosum have been referred to as the Wetterwinkle or !storm center.!!5 0 However, plaques may be seen virtually anywhere within the white matter of the hemispheres or corpus callosum as well as in the midbrain pons, medulla, cerebellum, and spinal cord. The optic nerves are commonly affected. The MS plaque consists of inflammatory activity, demyelination, and gliosis. The inflammatory infiltrate consists of lymphocytes and monocytes in the periventricular spaces and the leptomeninges; in the parenchyma of the lesion, lymphocytes, monocytes, and macrophages are present. Axonal transection is common in active lesions. 7 Management of MS includes rehabilitation aimed at maintaining or improving activities of daily living and ambulation; anti-inflammatory therapy with steroids and immunomodulators; and management of neuropsychiatric symptoms with psychotropic agents. Adrenocorticotrophic hormone and steroids do not affect the long-term course of MS but appear to shorten individual episodes in patients
with relapsing -remitting disease. Neuropsychiatric complications of steroid use include psychosis and mood disorders. 51 Immunomodulation has been shown to reduce the number of relapses and the degree of neurological disability in patients with relapsing -remitting MS. Available immunomodulators include glatiramer acetate (administered subcutaneous daily), interferon # -lb (administered subcutaneously every other day), interferon # -la (administered intramuscularly weekly), and mitoxantrone (administered every 3 months intravenously) (Table 26.5 ). 5 2 , 5 3, 5 4 , 5 5 , 5 6 Depression has been reported as a complication of interferon # -lb treatment (Chapter 14 ). Fatigue in MS may respond to treatment with amantadine or pemoline. 57, 5 8 Treatment of depression in patients with MS with selective serotonin reuptake inhibitors, tricyclic antidepressants, or monoamine oxidation inhibitors has generally been successful in reducing depressive symptoms. 5 9 , 6 0 , 6 1 Psychotherapy can be of substantial value in allowing patients to respond to the unpredictable vicissitudes of their illness. 6 2 Multiple sclerosis must be distinguished from a wide variety of other white matter disorders (Table 26.6 ). Demyelinating, infectious, toxic, vascular, genetic, inflammatory, metabolic, neoplastic, and hydrocephalic processes may all result in an increased signal on T 2 -weighted MRI and evidence of demyelination at autopsy. There are no pathognomonic neurobehavioral or neuropsychiatric symptoms of white matter disorders, but bradykinesia (slowing of cognition), attentional abnormalities, retrieval deficit -type memory impairment with intact procedural memory, visuospatial dysfunction, and executive cognitive impairment with relative preservation of language are typical of the cognitive syndromes associated with white matter disease. 6 3 Personality alterations, depression, and psychosis may also occur. Psychosis is common in metachromatic leukodystrophy, occurring in 53% of patients presenting
Dose
Indication
Side Effect
30 $gIM* daily
Relapsing MS
Relapsing MS
Flu -like symptoms, injection site reactions, menstrual irregularities, CBC and liver enzyme abnormalities; depression
20 $g SC every day
Relapsing MS
Mitoxantrone (Novantrone)
Chronic progressive MS
Nausea, hair loss, urinary tract infection, menstrual irregularities, upper respiratory tract infection
CBC, complete blood count; IM, intramuscular; IV, intravenous; SC, subcutaneous.
P.393
Demyelinaring
Multiple sclerosis
Infectious
HIV encephalopathy
Cytomegalovirus encephalitis
Lyme encephalopathy
Toxic
Anti-neoplastic therapy (cranial irradiation, methotrexate, BCNU, cytosine arabinoside, 5 -FU, levamisole, fludaribine, cisplatin, thiotepa, interleukin -2, interferon -)
Drugs of abuse (inhalation of toluene, ethanol, glue, heroin pyrolysate, cocaine, gasoline; ingestion/intravenous administration of heroin, MDMA [ecstasy], psilocybin)
Miscellaneous (valproate)
Vascular
Binswanger's disease
Sneddon's syndrome
Fabry's disease
Traumatic
Genetic
Metachromatic leukodystrophy
Adrenoleukodystrophy
Alexander's disease
Canavan disease
Membranous leukodystrophy
Cerebrotendinous xanthomatosis
Leigh's disease
Cockayne syndrome
Sjogren-Larrson syndrome
Polyglucosan disease
Phenylketonuria
Neurofibromatosis
Myotonic dystrophy
Zellweger syndrome
Neonatal adrenoleukodystrophy
Inflammatory
Behet's disease
Sjogren's syndromes
Wegener's granulomatosis
Temporal arteritis
Polyarteritis nodosa
Scleroderma
Sarcoidosis
Metabolic
Cobalamin deficiency
Folate deficiency
Hypoxia
Hypertensive encephalopathy
Eclampsia
Neoplastic
Gliomatosis cerebri
Hydrocephalus
Miscellaneous
BCNU, 1, 3 bis (2 -chloroerhyl) -J-nirrosourea; FK 506, tacrolimus; 5 -FU, 5 -fluorouracil; MDMA, methylenedioxymethamphetamine.
P.394 with disease between the ages of 12 and 30. Adrenoleukodystrophy may manifest learning difficulties, cognitive impairment, personality alterations, schizophrenia like symptoms, apathy and withdrawal, particularly in patients who become symptomatic before the age of 21. 6 5 Bipolar illness and psychotic depression have been observed as prominent symptoms in patients with
64
adrenoleukodystrophy. 6 6 In rare cases, adrenoleukodystrophy may present in adulthood as a progressive dementia syndrome. 6 7 , 6 8 Similarly, rare cases of Krabbe disease (globoid cell leukodystrophy) may present as an adult-onset dementing disorder. 6 9 Cerebrotendinous xanthomatosis typically presents in the second or third decade of life with juvenile cataracts, tendon xanthomas, and diverse neurological abnormalities including dementia-peripheral neuropathy, cerebellar ataxia, pyramidal signs, extrapyramidal disturbances, and psychiatric disorders. 70 Rare cases of Pelizaeus -Merzbacher disease with onset in adulthood with intellectual deterioration and psychotic episodes have been described. 7 1 Membranous lipodystrophy (Nasu -Hakola's disease) may present in adulthood with multiple pathologic fractures, progressive dementia, and seizures. Apathy, euphoria, and disinhibition are common. 7 2
consciousness or short Post -traumatic amnesia), severe TBI (with loss of consciousness or Post -traumatic amnesia lasting more than
Whiplash
Moderate TBI
Severe TBI
Fractures
Skull
Facial bones
Cerebral injury
Contusion
Laceration
Hemorrhage
Intracerebral
Subarachnoid
Subdural
Epidural
Herniation
Stroke
Neck injury/fracture
Neuropsychiatric consequences
Depression
Psychosis
Anxiety
Mania/euphoria
LOC, loss of consciousness; PTA, post-traumatic amnesia; TBI, traumatic brain injury.
P.395 24 hours), TBI with complications, secondary neurologic consequences of TBI, and neuropsychiatric consequences of TBI. Whiplash refers to the sprain or strain of the cervical region caused by sudden flexion -extension movements, most typically as a result of rear -end collisions. 7 5 Complaints of neck pain are common following this injury and are typically managed with nonsteroidal antiinflammatory drugs. Most patients recover by 6 months, but 15%!25% complain chronically of forgetfulness, distractibility, poor concentration, and mental fatigue. It is currently uncertain if whiplash without loss of consciousness can produce sufficient
disruption of brain structures to produce TBI. Patients may show deficits on complex attentional and executive tasks but they also score higher on depression and anxiety scales, have more pain, and receive more medication, and it is unclear if the neuropsychological abnormalities are attributable to the secondary consequences or are a product of brain dysfunction. 7 6 Magnetic resonance imaging is normal in the postwhiplash syndrome. Studies of brain metabolism or cerebral blood flow may show abnormalities, but the tests have sufficiently low sensitivity and specificity in this setting as to be unhelpful. 7 7 Management efforts of this syndrome should be directed at treatment of pain, depression, anxiety, and sleep disorder. There should be optimistic education of patients, families, and employers about a likely good ultimate outcome and vigorous efforts to increase physical and mental activity. 7 5 Mild TBI accounts for a majority of cases of brain injury. At the time of head injury, there is either brief loss of consciousness or no loss of consciousness and simply a brief period of dazed consciousness or clouding of memory for events. Any associated Post -traumatic amnesia is less than 24 hours in duration and on examination there are no focal neurological signs. 7 8 , 7 9 The underlying neuropathology of mild TBI is diffuse axonal injury disrupting axons and small vessels, particularly in the perisagittal deep white matter. The severity of this injury is on a continuum from mild to severe in patients with correspondingly mild to severe TBI. 7 8 There may be associated focal cortical contusions. Magnetic resonance imaging frequently shows increased signal intensity on T 2 -weighted images that resolve over time. Immediately after the injury, patients complain of poor concentration, forgetfulness, disturbances of the sleep-wake cycle, headache, dizziness, anxiety, irritability, and depression. These symptoms gradually resolve in most patients and after 1 year 85%!90% of patients have largely recovered. Those over the age of 55 or with more severe TBI recover more slowly and may have more residual complaints. Psychological assessment reveals deficits in attentional and executive function attributable either to disruption of frontalsubcortical circuitry or the effects of depression and anxiety. 8 0 Approximately 10%!15% of patients develop a chronic post-concussional disorder (Table 26.8 ). The etiology of this likely represents a combination of
the effects of diffuse axonal injury and neuropsychiatric symptoms (which themselves may be a product of brain injury). Treatment of pain, depression, and anxiety should be the focus of psychopharmacologic management. Rehabilitation efforts aimed at counseling, vocational support, and adaptive strategies may aid reemployment. 7 8 Head injury and mild to moderate TBI are common in a variety of sports including boxing, football, and soccer. 8 1 , 82
A. A history of head trauma that has caused significant cerebral concussion. B. Evidence from neuropsychological testing or quantified cognitive assessment of difficulty in attention (concentrating, shifting focus of attention, performing simultaneous cognitive tasks) or memory (learning or recalling information). C . Three (or more) of the following occur shortly after the trauma and last at least 3 months: 1 . Becoming fatigued easily 2 . Disordered sleep 3 . Headache 4 . Vertigo or dizziness 5 . Irritability or aggression on little or no provocation 6 . Anxiety, depression, or affective lability 7 . Changes in personality (e.g., social or sexual inappropriateness) 8 . Aparhy or lack of spontaneity D . The symptoms begin following head trauma or represent a substantial worsening of
preexisting symptoms. E . The disturbance causes significant impairment in social or occupational functioning and represents a significant decline from a previous level of functioning. In school -age children, the impairment may be manifested by a significant worsening in school or academic performance dating from the trauma. F . The symptoms do not meet criteria for dementia due to head trauma and are not better accounted for by another mental disorder (e.g., amnestic disorder due to head trauma, personality change due to head trauma).
Patients may have retrograde amnesia plus anterograde amnesia beginning at the time of the head injury (Chapter 7 ). Patients with more severe head injury or who are older at the time of their TBI recover Post -traumatic P.396 memory function more slowly than those with more mild head injuries or who are younger. 8 3 After the recovery of post-traumatic amnesia, cognitive slowing is a major feature of the neuropsychological performance of patients with TBI. This includes both simple and complex reaction times as well as other timed neuropsychological assessments. 8 4 Performance of difficulties on executive function tasks requiring establishment and maintenance of a set such as the Wisconsin Card Sort Test is also sensitive to the chronic effects of TBI. 8 5 Patients with severe TBI tend to underestimate the degree of their neuropsychological impairment. 8 6 Penetrating head injuries (particularly gunshot wounds) have the worst prognosis for functional outcome. Factors contributing to poor outcome include post-traumatic epilepsy, paresis, visual field loss, verbal memory loss, visual memory loss, behavioral difficulties, and violent behavior. 8 7 Neuropsychiatric symptoms are a major feature of both the post-concussion syndrome (discussed above) and the consequences of moderate and severe TBI. Depression occurs in approximately 25% of patients in the immediate
post-traumatic period and is most common with injury to the left or right frontal lobes. 7 4 , 8 8 , 8 9 , 9 0 Anxiety also occurs in approximately 20% of patients following trauma. 7 4 , 9 0 Substance abuse is a common predisposing factor to head injury, is present in approximately 10% of patients with TBI, 7 4 and may continue after the injury. Late-onset depression within the first year following TBI is common and may be more related to the situational effects of the injury than to the neurobiological effects. 9 1 A variety of less common behavioral disturbances have been reported following TBI, including post-traumatic stress disorder and psychosis. Personality changes reflecting frontal lobe dysfunction with impulsiveness, disinhibition, and irritability are common. 9 2 Psychiatric features contribute substantially to long-term compromise of quality of life. 9 3 Neuroimaging with MRI of patients with TBI reveals enlarged ventricle-to -brain ratios and atrophy of the corpus callosum particularly anteriorly. Abnormalities on timed tests such as the Digit -Symbol Subtest of the Weschler Adult Intelligence Scale correlate with the ventricular enlargement. 9 4 , 9 5 Functional imaging with measures of cerebral blood flow and cerebral metabolism reveal cortical functional abnormalities in patients with TBI. Reduced activity in frontal, temporal, and parietal areas as well as the thalamus has been visualized. There is often a poor correlation among MRI changes, functional measures, and neuropsychological deficits. 96 Figure 26.2 shows the MRI of a patient with a frontal contusion and a posterior cerebral artery territory infarction. The latter is a common consequence of trauma related cerebral edema and compression of the posterior cerebral artery against the tentorium.
FIGURE 26.2 Magnetic resonance image of a patient with a post-traumatic inferior frontal contusion and an infarction in the territory of the posterior cerebral artery. Compression of the posterior cerebral artery against the tentorial edge is a common consequence of Post -traumatic cerebral edema.
The most severely impaired survivors of TBI have persistent vegetative state, which is characterized by wakefulness without alertness patients. The patient apparently goes through periods of wakefulness with eyes open and periods of sleep with eyes closed. Eye movements may be nonpurposeful or may briefly track an object or orient toward a sudden light, sound, or movement. Limbs are usually spastic and there are responses to pain with facial grimacing or groaning. Grasp reflexes may be present. No meaningful emotional or cognitive responses are observed. 9 7 Cerebral ventricles are enlarged on structural imaging and functional imaging reveals a 40%!60% reduction in cortical glucose metabolism. At autopsy there is cortical shrinking, the greatest damage being to layers III and V of the cortex. There is generalized demyelination of the deep P.397 white matter throughout the cerebral hemispheres. The prognosis for recovery from persistent vegetative state is poor. Of patients discharged from the hospital in a vegetative state, one-half recover consciousness over the ensuing 3 years, although the probability of recovery
diminishes markedly after the first year. 9 8 Treatment of patients with TBI includes cognitive and physical rehabilitation, psychopharmacologic management of depression, anxiety, and other behavioral syndromes, and family and personal support.!! Psychostimulants such as dexedrine may improve performance on attentional and timed tests and some patients evidence improved attention and concentration following treatment with amantadine. 1 0 0 , 1 0 1 , 1 0 2
internalized. A double -stranded DNA copy of the viral RNA migrates to the nucleus and enters into the host chromosomes. Transcribed viral MRA is translated into viral proteins and complete viruses are assembled. The integrated viral protein is permanently incorporated into the host cell genome, where it may remain latent or engage in vigorous production of the viruses. 1 0 6 Definitions for the neurologic manifestations of HIV infection are shown in Table 26.9 including criteria for the HIV -1 associated dementia complex and the HIV -1 associated minor cognitive -motor disorder. 1 0 7 The HIV -1 -associated dementia complex is sufficient for a diagnosis of AIDS in an individual with laboratory evidence for systemic HIV -1 infection. The presence of an HIV -1 -associated minor cognitive -motor disorder is not sufficient for a diagnosis of AIDS, although it may be present in persons with AIDS. The critical difference between the two syndromes is the degree of impairment in activities of daily living. Patients with HIV 1 -associated dementia complex have obvious impairments, while those with HIV -1 -associated minor cognitive -motor disorder can accomplish all but the most demanding daily functions. The HIV -1 -associated dementia complex is characterized by mental slowness, impaired complex attention, poor executive function, and memory deficits. Language abnormalities are uncommon. 1 0 7 , 1 0 8 , 1 0 9 , 1 1 0 Behavioral disturbances are frequent in patients with HIV encephalopathy. Apathy is the most commonly reported behavior and mania and psychosis also have been described as complications of HIV encephalopathy. 1 0 9 , 1 1 1 Depression is highly prevalent among patients with HIV encephalopathy but is also common among individuals at risk for this condition. Neuroimaging studies reveal diminished basal ganglia size and diminished white matter volume in patients with HIV encephalopathy. 1 1 2 , 1 1 3 The decreased size of the caudate nuclei is associated with poor performance on neuropsychological tests requiring complex motor and sequencing skills. 1 1 4 At autopsy, patients with the HIV associated dementia complex have evidence of HIV encephalitis. Multinucleated giant cells are the most characteristic feature of the process. Abundant macrophages and microglial nodules are often seen. Leukoencephalopathy is also a frequent accompaniment of the AIDS dementia
complex. There is diffuse myelin pallor, astrocytosis, activated macrophages, and some multinucleated giant cells in the cerebral white matter. Activated microglial cells are evident and there is mild neuronal loss in the cerebral cortex. 11 5 , 1 16 The AIDS dementia complex must be distinguished from a variety of other opportunistic infections that may occur in AIDS patients. Table 26.10 lists the opportunistic infections and secondary neoplasms that occur with increased prevalence among patients with AIDS. 1 1 6 , 1 1 7 P.398
TABLE 26.9. Criteria for Clinical Diagnosis of Severe and Mild HIVassociated Cognitive-Motor Complex
All of the following diagnoses require laboratory evidence for systemic HIV -1 infection (ELISA test confirmed by Western blot, polymerase chain reaction, or culture)
Prubable (must have each of the following): 1 . Acquired abnormality in at least two of the following cognitive abilities (present for at least 1 month): attention/concentration, speed of processing of information, abstraction/reasoning, visuospatialskills, memory/learning, and speech/language. The decline should he verified by reliable
history and mental status examination. In all cases, when possible, history should be obtained from an informant, and examination should be supplemented by neuropsychological testing. 2 . At least one of the following: a. Acquired abnormality in motor function or performance verified by clinical examination (e.g., slowed rapid movements, abnormal gait, limb incoordination, hyperreflexia, hyperronia, or weakness), neuropsychological tests (e.g., fine motor speed, manual dexterity, perceptual motor skills, or both). b . Decline in motivation or emotional control or change in social behavior. This may be characterized by any of the following: change in personality with apathy, inertia, irritability, emotional lability, or new onset of impaired judgement characterizedby socially inappropriate behavior or disinhibition. 3 . Absence of clouding of consciousness during a period long enough to establish the presence of criterion 1. 4 . No evidence of another etiology, including active CNS opportunistic infection or malignancy, psychiatric disorders (e.g., depressive disorder), active alcohol or substance use, or acute or chronic substance withdrawal; must be sought from history, physical and psychiatric examination, and appropriatelaboratory and radiologic investigation (e.g., lumbar puncture, neuroimaging). If another potential etiology (e.g., major depression) is present, it is not the cause of the above cognitive, motor, or behavioral symptoms and signs.
Passible (must have one of the following): 1 . Other potential etiology present (must have each of the following): a. As above (see Probable) criteria 1, 2 and 3 b . Other potential etiology is present but the cause of criterion 1 above is uncertain. 2 . Incomplete clinical evaluation (must have each of the following): a. As above (see Probable) criteria 1, 2, and 3 b . Eriology cannot be determined (appropriate laboratory or radiologic investigations not performed). II. HIV -1 -associated minor cognitive/motor disorder Probable (must have each of the following); 1 . Cognitive/motor/hehavioral abnormalities (must have each of the following): a. At least two of the following acquired cognitive, motor, or behavioral symptoms (present for at least I month) verified by reliable history (when possible, from an informant): 1 . Impaired attention or concentration 2 . Mental slowing 3 . Impaired memory 4 . Slowedmovements 5 . Incoordination 6 . Personality change, or irritability or emotional lability
b . Acquired cognitive/motor abnormality verified by clinical neurologic examination or neuropsychological testing (e.g., fine motor speed, manual dextetity, perceptual motor skills, attention/concentration, speed of processingof information, abstraction/reasoning, visuospatial skills, memory/learning, or speech/language). 2 . Disturbancefrom cognitive/motor/behavioral abnormalities (see criterion 1) causes mild impairment of work or activities of daily living (objectively verifiable or by report of a key informant). 3 . Does not meet criteria for HIV -1 associated dementia complex. 4 . No evidence of another etiology, including active CNS opportunistic infection or malignancy, or severe systemic illness determined by appropriate history, physicalexamination, and laboratory and radiologic investigation (e.g., lumbar puncture, neuroimaging). The above features should not be attributable solely to the effects of active alcohol or substance use, acute or chronic substance withdrawal, adjustment disorder, or other psychiatric disorders. Possible (must have one of the following): 1 . Other potential etiology present (must have each of the following): a. As above (see Probable) criteria 1, 2, and 3 b . Other potential etiology is present and the cause of the cognitive/motor/behavioral
abnormalities is uncertain. 2 . Incomplete clinical evaluation (must have each of the following): a. As above (see Probable) criteria 1, 2, and 3 b . Etiology cannot be determined (appropriate laboratory or radiologic investigations not performed).
* For restarch purposes, HIV -1 -associated dementia complex can be coded to describe the major features: HIV -1 -associated dementia complex requires criteria 1, 2a, 3 and 4; HIV -1 -associated dementia complex (motor) requires criteria 1, 2a, 3, and 4; HIV -1 -associated dementia complex (behavior) requires criteria 1, 2h, 3, and 4.
P.399 Treatment of HIV has the goal of controlling or reducing viral replication. Nucleoside reverse transcriptase inhibitors, non -nucleoside reverse transcriptase inhibitors, and protease inhibitors are used in a variety of combinations. 1 1 8 Neuropsychiatric manifestations are treated with the usual psychotropic agents (Chapter 4 ). Ziduvoine (AZT) used in the treatment of AIDS appears to have a beneficial effect on neuropsychological performance in patients with the HIV dementia complex. 1 1 9 Some patients improve with selegiline 1 2 0 or psychostimulants. 1 2 1
Creutzfeldt -Jakob disease is unique among neurological disorders as it is both an inherited neurodegenerative disorder and a transmissible disease. Worldwide incidence of Creutzfeldt -Jakob disease is approximately 1 per 10 6 population annually, 85%!90% of cases are sporadic and 10%!15% are inherited. The disease affects men and women equally and the frequent age of onset is 60 years with a range of 40!90 years for all but the iatrogenic cases, in which onset has been between the ages of 20 and 40. In most cases the disease is rapidly progressive, leading to death in 4!12 months; however, chronic cases lasting 2!5 years are well described. 1 2 3
TABLE 26.10. Opportunistic Infections and Secondary Central Nervous System Complications of AIDS
Meningitis
Encephalitis
Cryptococcal meningitis
HIV encephalitis
Cerebral toxoptasmosis
Neurosyphilis
Cytomegalovirus encephalitis
Herpes encephalitis
Progressive muttifocal
leukoencephalopathy
Syphilitic meningitis
Listeria
Coccidioidomycosis
Cryptococcoma
Histoplasmosis
Vascular disorders
Blastomycosis
Nocardia
Mycobacterium
P.400
Familial
Sporadic
latrogenic
New variant
Kuru
Thalamic dementia
The principal event leading to the lethality of prions is a conformational exchange that occurs during the conversion of a native protein (PRP C ) to prion protein SC (PRP Sc ). 1 2 2 Susceptibility to sporadic Creutzfeldt -Jakob disease is influenced by individual genotype; homozygoticity at codon 129 of the prion protein gene is overrepresented among those with sporadic disease, new variant disease (described
below), and disease transmitted by infected dura mater. 1 2 4 Mutations in families with inherited Creutzfeldt -Jakob disease occur on chromosome 20. latrogenic Creutzfeldt -Jakob disease has been transmitted by improperly sterilized depth electrodes, transplanted corneas, human growth hormone and gonadotrophin derived from cadaveric pituitaries, and dura mater graphs. 1 2 5 Kuru, a cerebellar form of prion disease, was transmitted among individuals in the Fore tribe in New Guinea by ritualistic cannibalism. latrogenic Creutzfeldt -Jakob disease offers a modern analogy with the disease transmitted in the course of medical technocannabilism through use of human products to treat other humans. 1 2 5 New variant Creutzfeldt -Jakob disease appears to result from the transmission of spongiform bovine encephalopathy (!mad cow disease!!) to humans. 1 2 6 The clinical features of Creutzfeldt -Jakob disease include dementia, myoclonus, pyramidal track signs, aphasia, cerebellar signs, primitive reflexes, and extrapyramidal dysfunction. Seizures occur in a minority of cases. Cortical blindness characterizes a posterior variant of the disease and many patients enter a state of akinetic mutism or persistent vegetative state prior to death. 1 2 7 The rapid and relentless progression of the illness is the most characteristic feature of the disease. A prodromal phase preceding the onset of overt neurological symptoms and signs may include depression, sleep disturbance, and headache. New variant Creutzfeldt -Jakob disease tends to have an earlier age of onset (mean 29 years) and to progress somewhat more slowly (average 14 months from onset to death). In addition, most patients with the new variant form of the disease manifest early and persistent psychiatric symptoms. Depression, anxiety, and withdrawal are most common, but some patients evidence frank psychosis. 1 2 8 Table 26.12 presents diagnostic criteria for new variant Creutzfeldt -Jakob disease. 1 2 8 Neuroimaging, electroencephalography (EEG) and CSF analysis may be useful in the diagnosis of Creutzfeldt -Jakob disease. Magnetic resonance imaging frequently reveals bilateral symmetric high -signal intensity on T 2 -weighted images 12 9 and diffusion -weighted MRI may demonstrate increased signal intensity in the basal ganglia as well as in widespread regions of the cerebral cortex. 1 3 0 Studies with PET reveal diminished glucose metabolism distributed
heterogeneously and
TABLE 26.12. Diagnostic Criteria for New Variant Creutzfeldt-jakob Disease 128
I . Key features A. Progressive neucopsychiatric disorder B. Duration of illness >6 months C . Routine investigations do not suggest an alternative diagnosis D . No history of potential iatrogenic exposure II. Supportive features A. Early psychiatric symptoms * B. Persistent painful sensory symptomst C . Ataxia D . Myoclonus or chorea or dystonia E . Dementia III . Laboratory features A. EEG does not show the typical appearance of sporadic CJD ! (or no EEG performed) B. Bilateral pulvinar high signal on MRI scan
* These include depression, anxiety, apathy, withdrawal, delusions. ! These include frank pain and unpleasant dysesthesia. ! Generalized tnphasic periodic complexes are at approximately I/second. ** Spongiform change andextensive prion protein deposition with florid plaques throughout the cerebrum and ceiebellum. CJD, Creudtzfeldt-Jakob disease; EEG, electroencephalogram; MRI, magnetic resonance imaging; nvCJD, new variant Creutifeldr-Jakoh disease.
P.401 asymmetrically throughout the brain. Periodic sharp and slow-wave complexes on EEG are characteristic of Creutzfeldt -Jakob disease, occurring in 65%!85% of cases. 1 3 3 , 134 The classical periodic sharp - and slow-wave complexes are not a feature of new variant disease. 1 2 8 Testing of CSF for evidence of prion protein may be diagnostically useful. The 14!3!3 protein is strongly suggestive of the presence of prion protein and occurs in over 90% of cases. 1 3 4 , 1 3 5 , 1 3 6 The 14!3!3 protein occurs rarely in other dementias and is not completely specific for Creutzfeldt -Jakob disease. Current diagnostic criteria for sporadic Creutzfeldt -Jakob disease incorporate these laboratory features (Table 26.13). Brain examination in Creutzfeldt -Jakob disease reveals spongiform degeneration of neurons and their processes, loss of neurons, intense reactive astrocytic gliosis, and amyloid plaque formation. The vacuolization characteristic of
1 3 1, 1 3 2
spongiform degeneration consists of vacuoles located in the neurophil between nerve cell bodies. In some cases vacuolization is also evident within neurons. The spongiform degeneration can be found throughout cortical and subcortical structures and the cerebellum, although the globus pallidus portions of the hippocampus, brainstem, and spinal cord are typically spared or minimally affected. 1 2 3 No treatment is currently available for this rapidly progressive, tragic, and inevitably fatal illness. Gerstmann -Straussler-Scheinker disease is an autosomal dominant disorder presenting with ataxia and progressing to a mixture of cognitive and motor disturbances and exhibiting multicentric amyloid plaques at autopsy. 1 2 3 The families carry a mutation in the prion protein gene. Fatal familial insomnia consists of the subacute onset of a clinical syndrome characterized by progressive insomnia, complex hallucinations, stupor, and eventually coma. Autonomic disturbances and motor abnormalities including myoclonus and pyramidal signs are common. The onset is between the ages of 35 and 60. This order is a dominantly inherited prion protein mutation and the pathological changes are typically limited to the thalamus. 1 2 3 Insomnia has been absent in some cases with related prion -induced thalamic degeneration although prominent sleep disturbances, enacted dreams, and hallucinations were common. 1 3 7
frontal, medial temporal, and anterior cingulate limbic regions (Figure 26.3 ). 1 4 1 , 1 4 2 An EEG may be helpful in revealing focal spike- and slow-wave activity over the temporal regions. Cerebrospinal fluid analysis shows a lymphocytic pleocytosis with red cells in over half of the cases. Analysis of CSF for evidence of herpes virus DNA confirms the diagnosis and may be particularly useful in patients with atypical presentations. 1 4 3 Treatment with acyclovir has reduced the mortality from 70% to 30%, but long-term neuropsychological sequelae are common. 1 4 4 , 1 4 5
Definite CJD
Probable CJD
clinical features:
14 -3 -3 proteins in CSF
Possible CJD
No 14 -3 -3 detection in CSF
P.402
FIGURE 26.3 Magnetic resonance imaging shows high signal regions bilaterally in the medial temporal regions in a patient with herpes simplex encephalitis.
Postmortem studies of patients succumbing to herpes simplex encephalitis reveal extensive necrosis of the gray and white matter in the frontal and temporal regions. Histologically, there is abundant white blood cell infiltration, microglial activation, and intranuclear inclusions in neurons in the area of necrosis. The virus is readily demonstrated by immunostaining in autopsy tissues. 1 1 5
although the pathological hallmarks of a viral infection were evident. The acute encephalitis was protean in its manifestations but frequently included severe lethargy and disturbances of the sleep-wake cycle (hence the name encephalitis lethargica ). Acute mortality was high (30%); 80% of survivors developed post-encephalitic parkinsonism within 10 years of their recovery from the acute episode. Both the acute disorder and the post-encephalitic syndrome included prominent neuropsychiatric manifestations of depression, euphoria, catatonia, abnormalities of sexual behavior, and conduct disorders in children. 1 3 8 , 1 4 6 Syphilis has produced a variety of CNS syndromes including tabes dorsalis, meningovascular syphilis and general paresis of the insane (GPI). General paresis results from a spirochetal invasion of the cerebral cortex predominantly affecting the frontal lobes and manifested by a mania -like syndrome. Syphilis was a common cause of mental illness and a common reason for psychiatric hospitalization until successful treatment with penicillin was discovered. General paresis is one of the few major mental illnesses with an established cure or prevention.
and medulloblastomas. Meningiomas account for approximately 15% of all primary intracerebral tumors, pituitary adenomas for 5%, and craniopharyngiomas for 3%. 1 48 Of patients with intracerebral metastases, 40% originate in the lung, 20% are from breast tumors, 10% are melanomas, 7% arise from the genitourinary tract, 7% from the gastrointestinal tract, and 5% are of gynecologic origin. 1 49 In addition to the direct effects of cancer on the nervous system, there are many mechanisms of indirect effects including vascular disorders, hydrocephalus, side effects of therapy (chemotherapy, radiation therapy, surgery), and paraneoplastic syndromes (Table 26.14). P.403
Indirect Effects
Vascular disorders
Lung
Hydrocephalus
Breast
Melanoma
Chemotherapy
Gastrointestinal
Radiation therapy
Renal
Surgery
Ovarian
Paraneoplastic syndromes
Glioma
Glioblastoma/malignant astrocytoma
Astrocytoma (benign/lowgrade)
Oligodendroglioma
Ependymoma
Medulloblastoma
Meningioma
Pituitary adenomas
Craniopharyngioma
Lymphoma
Others
Neuropsychiatric assessment indicates that patients with tumors of the ventral frontal cortex or temporal parietal cortex report a significant increase in anxiety/depression, irritability/anger, and fatigue. Those with right posterior lesions report higher levels of fatigue and irritability/anger and those with left anterior lesions have higher levels of anxiety/depression. 1 5 0 Paraneoplastic limbic encephalitis, typically associated with small cell tumors of the lung, is a paraneoplastic syndrome manifested by disturbances of memory and neuropsychiatric symptoms including delusions, hallucinations, and agitation. 1 51, 1 5 2 Seizures may occur. Examination of the CSF reveals an inflammatory pleocytosis. Structural imaging is usually normal, although abnormalities in one or both medial temporal lobes may be evident. At autopsy there is extensive loss of neurons with reactive glyosis, perivascular cuffing, and microglial proliferation. 1 4 9 The detection of antiHu antibodies in the serum supports the diagnosis. 1 5 3 No treatment effective for paraneoplastic limbic encephalitis has been identified.
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