Psychiatric Management in Neurological Disease (Clinical Practice)

PSYCHIATRIC MANAGEMENT IN NEUROLOGICAL DISEASE PSYCHIATRIC MANAGEMENT IN NEUROLOGICAL DISEASE Edited by Edward C. L...

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PSYCHIATRIC MANAGEMENT IN NEUROLOGICAL DISEASE

PSYCHIATRIC MANAGEMENT IN NEUROLOGICAL DISEASE

Edited by

Edward C. Lauterbach, M.D.

Washington, DC London, England

Note: The authors have worked to ensure that all information in this book concerning drug dosages, schedules, and routes of administration is accurate as of the time of publication and consistent with standards set by the U.S. Food and Drug Administration and the general medical community. As medical research and practice advance, however, therapeutic standards may change. For this reason and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of a physician who is directly involved in their care or the care of a member of their family. Books published by the American Psychiatric Press, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of the Press or the American Psychiatric Association. Copyright © 2000 American Psychiatric Press, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper First Edition 03 02 01 00 4 3 2 1 American Psychiatric Press, Inc. 1400 K Street, N.W. Washington, DC 20005 www.appi.org Library of Congress Cataloging-in-Publication Data A CIP record is on file with the Library of Congress. British Library Cataloguing in Publication Data A CIP record is available from the British Library.

Dedicated to the Creator, my parents, and clinicians who take care of patients with neuropsychiatric illnesses

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Contents Contributors

ix

Introduction to the Clinical Practice Series Judith H. Gold, M.D., F.R.C.P.C.

xi

Preface

xiii

1

Psychiatric Management Principles in Neurological Disease Edward C. Lauterbach, M.D.

1

2

Parkinson’s Disease Morgan L. Levy, M.D. Jeffrey L. Cummings, M.D.

41

3

Huntington’s Disease Neal G. Ranen, M.D.

71

4

Wilson’s Disease (Progressive Hepatolenticular Degeneration) Edward C. Lauterbach, M.D.

93

5

Fahr’s Syndrome Edward C. Lauterbach, M.D.

137

6

Dystonia Edward C. Lauterbach, M.D.

179

7

Stroke Robert G. Robinson, M.D.

219

8

Multiple Sclerosis Steven R. Schwid, M.D. Amy Weinstein, Ph.D. Heather A. Wishart, Ph.D. Randolph B. Schiffer, M.D.

249

9

Acquired Immunodeficiency Syndrome Jorge Luis Maldonado, M.D. Francisco Fernandez, M.D. Joel K. Levy, Ph.D.

271

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Family Management Issues Edward C. Lauterbach, M.D.

297

Index

305

Contributors Jeffrey L. Cummings, M.D. Augustus S. Rose Professor of Neurology; Professor of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, California Francisco Fernandez, M.D. Professor and Chairman, Department of Psychiatry and Behavioral Neurosciences, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois Edward C. Lauterbach, M.D. Chief, Division of Adult and Geriatric Psychiatry; Professor of Psychiatry and Internal Medicine (Neurology), Department of Psychiatry and Behavioral Sciences and the Department of Internal Medicine (Neurology Section), Mercer University School of Medicine, Macon, Georgia Joel K. Levy, Ph.D. Assistant Professor of Neurology and Physical Medicine/Rehabilitation, Departments of Neurology and Physical Medicine/Rehabilitation, Baylor College of Medicine, Houston, Texas Morgan L. Levy, M.D. Assistant Professor of Psychiatry, Department of Psychiatry, Wake Forest University School of Medicine, Winston-Salem, North Carolina Jorge Luis Maldonado, M.D. Staff Psychiatrist, The Kneibert Clinic, Doctor’s Regional Medical Center, Poplar Bluff, Missouri

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Psychiatric Management in Neurological Disease

Neal G. Ranen, M.D. Medical Director, Health Pathways Geriatric and Neuropsychiatric Assessment Program, Albright Care Services Inc., York, Pennsylvania; and Clinical Associate Professor of Psychiatry, Pennsylvania State University College of Medicine, Hershey, Pennsylvania Robert G. Robinson, M.D. Paul W. Penningroth Professor and Head, Department of Psychiatry, University of Iowa School of Medicine, Iowa City, Iowa Randolph B. Schiffer, M.D. The Vernon and Elizabeth Haggerton Chair in Neurology, and Chair, Department of Neuropsychiatry and Behavioral Sciences, Texas Tech University Health Sciences Center, Lubbock, Texas Steven R. Schwid, M.D. Assistant Professor of Neurology, University of Rochester Medical Center, Rochester, New York Amy Weinstein, Ph.D. Assistant Professor of Neurology and Psychiatry, University of Rochester Medical Center, Rochester, New York Heather A. Wishart, Ph.D. Assistant Professor of Psychiatry, Neuropsychology Program, Dartmouth Medical School, Lebanon, New Hampshire

Introduction

to the Clinical Practice Series

T

he Clinical Practice Series is dedicated to the support of continuing education and enrichment for the practicing clinician. Books in this series address topics of concern and importance to psychiatrists and other mental health clinicians. Each volume provides up-todate literature reviews and emphasizes the most recent treatment approaches to psychiatric illnesses. Theoretical and scientific data are applied to clinical situations, and case illustrations are used extensively to increase the relevance of the material for the practitioner. Each year the series publishes a number of books dealing with all aspects of clinical practice. From time to time some of these publications may be revised and updated. Some books in the series are written by a single clinician widely acknowledged to be an authority on the topic area; other series books are edited volumes in which knowledgeable practitioners contribute chapters in their areas of expertise. Still other series books have their origins in presentations for an American Psychiatric Association Annual Meeting. All contain the newest research and clinical information available on the subjects discussed. The Clinical Practice Series provides enrichment reading in a compact format specially designed to meet the continuing-education needs of the busy mental health clinician. Judith H. Gold, C.M., M.D., F.R.C.P.C., F.R.A.N.Z.C.P. Series Editor

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Preface Edward C. Lauterbach, M.D.

T

he focus of this volume is on managing psychiatric problems in neurological brain disorders. These illnesses are prevalent in clinical psychiatric practices and impose great morbid and economic burdens. Unique treatment complications inherent to these illnesses can challenge clinical skills. Although books on the psychiatry of Alzheimer’s disease and epilepsy exist, there seems to be no single concise work addressing the clinical psychiatric management of other neurological disorders. Therefore, we have synthesized management principles for these other neurological conditions for which suitable clinical information exists. We have selected key representative neurological disorders. These provide clinical principles useful in managing brain diseases of all types. These illnesses, and brain diseases in general, affect limbic connections with the rest of the nervous system. Each illness presents a distinct psychiatric profile requiring a select management approach tailored to the nature of the illness and the level of the nervous system affected. Management principles set forth in Chapter 1 apply to neurological diseases in general. Ensuing chapters detail techniques valuable for treating specific illnesses. These techniques can be further cross-applied to other neurological illnesses not explicitly addressed here. The disorders surveyed in this volume range from basal ganglia diseases (e.g., Parkinson’s, Huntington’s, and Wilson’s diseases) to illnesses affecting white-matter basal ganglia–cortical circuit projections (e.g., acquired immunodeficiency syndrome [AIDS], multiple xiii

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sclerosis). Major movement disorders are covered, including idiopathic dystonia. Diseases with characteristic lesion sites as well as diseases with diffuse or multifocal pathology are discussed. Diseases of the substantia nigra (Parkinson’s), striatum (Huntington’s), putamen (Wilson’s), globus pallidus (Fahr’s), subcortical white matter (AIDS, multiple sclerosis, stroke), and cortex (stroke) are detailed. Physiological disorders (e.g., dystonia), systemic illness (e.g., Wilson’s disease, Fahr’s syndrome, secondary dystonias), and immunological diseases (e.g., AIDS, multiple sclerosis) are considered. Thus, the disorders covered in this volume constitute a representative cross-section of conditions affecting the brain at various levels. We have organized the book for ease of use for the practicing clinician. The first chapter considers important clinical features, psychotherapeutic principles, and pharmacological issues that are critical to successful psychiatric treatment of patients with neurological illnesses. Each subsequent chapter begins with a basic overview of the disorder, followed by a profile of psychiatric disorders occurring in the illness, including drug-induced psychiatric disorders. Each chapter ends with a discussion of specific treatment approaches, including neurological and psychiatric management. In particular, specific pharmacological and psychotherapeutic approaches to treatment of the disease are detailed when available, along with caveats unique to these patients. Explicit information is provided on how to contact and refer patients to support groups. Because these illnesses also dramatically affect family members, the book’s final chapter addresses the family. It is our sincere intent that this book will serve as a time-saving reference that will yield significant clinical dividends in quality of care exceeding many times the initial investment of its purchase. We have summarized and integrated the most recent data in an attempt to formulate a user-friendly approach to comprehensive psychiatric management of patients with neurological illness. The editor’s own private practice experience has convinced him of the need for efficient learning: “so many patients, so little time to read.” Managed care compels outpatient treatment of ever more seriously ill patients with multiple physical illnesses. Knowing these diseases and predicting what may go wrong between outpatient visits is therefore of increasing importance. Recognizing this need, we

Preface

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seek to provide a wealth of practical information on a diversity of disorders to assist the busy clinician. We also endeavor to provide a more explicit detailing of management principles than is available elsewhere.

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C H A P T E R

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Psychiatric Management Principles in Neurological Disease Edward C. Lauterbach, M.D.

T

he focus of this book is on psychiatric conditions in key, representative neurological disorders. These disorders impose great disability and cost on both the patient and the nation (Table 1–1). They also impose substantial complexity of care because of unique treatment considerations. General considerations in neurological disease are offered here and specific aspects of particular conditions are reviewed in the chapters that follow. Neurological disorders disrupt basal ganglia–cortical circuits at various levels. The basal ganglia (Figure 1–1), composed of the striatum and the globus pallidus, are functionally and structurally interposed between the limbic system and the cortex. Basal ganglia–cortical circuits are vital to psychiatry, connecting certain limbic structures to the cerebral cortex and other important brain regions. In addition to limbic inputs, important influences on these circuits include major monoamine projections and other connections. Basal ganglia–cortical circuits constitute essential pathways that integrate and mediate mood, cognition, movement, behavior, and other functions critical to psychiatric disorders (Cummings 1993). The disorders considered in this book have variable causations, presentations, pathologies, and treatments. An equally diverse array of psychopathology in these disorders can variably respond to 1

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Table 1–1.

Annual incidence, prevalence, and annual cost of neurological disorders

Disorder

Prevalence

Annual cost, $

16,000 50,000 1,500 15,000 35,000

80,000 500,000 25,000 100,000 >1,300,000

>1,000,000,000 6,000,000,000 >250,000,000 >250,000,000 >3,000,000,000

500,000 <10,000

3,000,000 <350,000

>30,000,000,000 5,000,000,000

Note. Annual incidence is provided in terms of new U.S. cases per year; prevalence is U.S. cases; annual cost is total cost to the nation. AIDS = acquired immunodeficiency syndrome. Source. 1995 data obtained from the Office of Scientific and Health Reports, National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health.

Psychiatric Management in Neurological Disease

Neurological AIDS Parkinson’s disease Huntington’s disease Dystonias Other motor disorders (including Wilson’s disease and Fahr’s syndrome) Stroke/cerebrovascular Multiple sclerosis

Annual incidence

Psychiatric Management Principles in Neurological Disease

3

Striatum Caudate nucleus Putamen

Lenticular nucleus Putamen Globus pallidus External segment Internal segment

Thalamus

Figure 1–1. Horizontal (axial) image depicting basal ganglia structures and thalamus.

conventional psychiatric treatment and, at times, to treatment of the underlying disorder (e.g., Wilson’s disease). This chapter therefore considers specific diagnostic and treatment principles for managing patients with neurological diseases in general. More detailed considerations of these principles are elaborated elsewhere (see Ovsiew 1992 and Sultzer 1994 for reviews of the neuropsychiatric evaluation).

Approach to Neurological Illnesses: Clinical Recognition, Mental Status, and Neurological Exam Basal ganglia–cortical circuits flow from the cerebral cortex to the striatum (caudate and putamen), to the globus pallidus (internal, ex-

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Psychiatric Management in Neurological Disease

ternal, and ventral segments), and on to the thalamus, which then projects back to the cerebral cortex (Figure 1–2). An alternative route courses through the reticular portion of the substantia nigra instead of the globus pallidus. These circuits are modulated by inputs from the nigra pars compacta and subthalamic nucleus. Five parallel, functionally segregated circuits between the basal ganglia and the cerebral cortex have been identified, each with its own important clinical consequences (Cummings 1993). These circuits project to anterior cingulate, dorsolateral prefrontal, orbitofrontal, sensorimotor, and oculomotor cortical areas.

Frontal Circuit Signs Certain findings can help localize pathology to dorsolateral prefrontal, orbitofrontal, and anterior cingulate frontal lobe circuits (Table 1–2). Findings consistent with dorsolateral prefrontal circuit disease include reduced verbal fluency, psychomotor slowing, dysexecution, perseveration, stimulus-bound behavior, apathy, and impaired abstraction. Dysexecution refers to difficulty in planning, organizing, and sequencing activities that involve complex problem solving. Dysexecution can be detected by excessive perseverative errors and other abnormalities on neuropsychological testing. Stimulus-bound phenomena are manifest in utilization behavior, wherein a patient will pick up an object in the environment and continuously manipulate it until it is taken away. Orbitofrontal circuit involvement can be signaled by emotional lability, behavioral disinhibition (e.g., manic-like behavior), impulsivity, and impaired insight, judgment, and abstraction. Medial frontal circuit involvement can manifest in sparse verbal output, akinesia or paucity of movement, and apathy. Oculomotor circuit involvement is suggested by jerky ocular pursuit (when the patient is asked to follow a moving target) or saccadic intrusions (wherein the patient’s eyes quickly and involuntarily dart away from and then later return to the target). Jerky pursuit occurs in the parkinsonisms and with nigral and cerebellar lesions; saccadic intrusions can be seen in choreic conditions and caudate nucleus lesions, such as in Huntington’s disease. Sensorimotor circuit findings are usually those of a movement disorder or bizarre paresthesia sensations.

Psychiatric Management Principles in Neurological Disease

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Figure 1–2. Basal ganglia pathways and their physiology in the normal (nondiseased) state and in Parkinson’s disease (PD), Huntington’s disease (HD), primary dystonia (DT), and hemiballismus (HB). GPe = globus pallidus externa; GPi = globus pallidus interna; SNc = substantia nigra pars compacta; SNr = substantia nigra pars reticulata; STN = subthalamic nucleus; STR = striatum (caudate nucleus and putamen); VL = ventrolateral nucleus of the thalamus. Connections ending in arrowheads indicate excitatory connections; connections ending in a bar signify inhibitory connections. For simplicity, excitatory glutamatergic projections from the cortex to the striatum are not depicted. With the exception of dopaminergic projections from the SNc (D2 receptors are inhibitory and D1 receptors are excitatory), all other inhibitory connections are GABAergic and all other excitatory connections are glutamatergic. In PD, thalamic stimulation of the cortex is reduced due to excessive GPi activity, presumably leading to hypokinesia. In HD, this physiology is reversed, presumably leading to hyperkinetic chorea. In DT, a hyperkinetic physiological state results, distinguished by excessive directpathway (STR-GPi connection) activity predominating over increases in indirect-pathway (STR-GPe) and STN activity. This may, however, be true only for certain DTs. In HB, the extreme movements are consistent with a hyperkinetic physiological state induced by the loss of GPi stimulation by the STN. Source. Adapted from Vitek et al. 1999.

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Table 1–2.

Psychiatric Management in Neurological Disease

Frontal lobe syndromes

Dorsolateral

Orbitofrontal

Reduced verbal fluency

Medial Sparse verbal output

Psychomotor slowing

Lability

Dysexecution (planning, organizing, sequencing)

Disinhibition

Akinesia

Perseveration Stimulus-bound phenomena (utilization behavior) Apathy

Impulsivity

Impaired abstraction

Impaired judgment, insight, and abstraction

Apathy (occasional)

Signs Localizing to Certain Brain Structures Certain clinical findings sometimes assist in localizing brain pathology. Localization can help in understanding the nature of the illness, predicting disabilities, and planning treatment. Frontal release signs suggest frontal lobe disease and include primitive reflexes (glabellar tap [Meyerson’s sign], grasp, suck, root, palmomental). Decreased verbal fluency and utilization behavior also suggest frontal lobe disease (see “Frontal Circuit Signs” subsection above). Depression is associated with frontal lesions, especially of the left frontal lobe. Mania is often observed in lesions of the right temporal cortex and orbitofrontal regions as well as of the caudate, thalamus, subthalamic nucleus, and cerebellum (see Chapter 7 in this volume). Left cerebellar disturbances can affect caudate and thalamic connections with the right temporal and orbitofrontal cortex (Lauterbach 1996). Obsessions or compulsions may point to frontal lobe disturbance or striatal disease. Right parietal lesions are associated with constructional apraxia (difficulty drawing a complex two- or three-dimensional figure) and neglect (sometimes manifest in a patient’s dressing only the right half of his or her body, or drawing only the right half of a figure). Apraxia can reflect left frontal, left parietal, or callosal lesions. Other neurobehavioral signs that can assist in localizing brain lesions are listed in Table 1–3.

Psychiatric Management Principles in Neurological Disease

Table 1–3.

7

Behavioral findings potentially helpful in localizing neuropathology

Left frontal lobe Broca’s expressive aphasia (can usually comprehend spoken or written language but cannot speak, name, or repeat fluently) Transcortical motor aphasia (like Broca’s, but can repeat fluently) Apraxia (inability to perform complex movements despite intact motor system) Right frontal lobe Reduced social awareness Left temporal lobe Wernicke’s receptive aphasia (comprehension difficulty on reading and listening, repeating, and naming) Verbal amnesia Change in personality Right temporal lobe Amusia (reduced ability to appreciate content of music) Aprosodia (reduced ability to modulate or appreciate the emotional content of speech) Prosopagnosia (reduced ability to recognize familiar faces) Visual amnesia Change in personality Left parietal lobe Angular gyrus syndrome—includes anomia (deficit in naming), alexia with agraphia (deficits in reading and writing), or Gerstmann syndrome—includes apraxia, right–left confusion, finger agnosia (inability to discriminate between fingers), and dyscalculia (difficulty calculating) Right parietal lobe Neglect (inattention to the left hemispace, including left visual field) Constructional apraxia Spatial disorientation and agnosia Left occipital lobe Alexia without agraphia Color agnosia Right occipital lobe Cortical blindness with denial (Anton’s syndrome) (continued)

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Psychiatric Management in Neurological Disease

Table 1–3.

Behavioral findings potentially helpful in localizing neuropathology (continued)

Right occipital lobe (continued) Topographic spatial disorientation Corpus callosum Apraxia of the left hand Anomia for objects in the left hand Alien hand syndrome (unconsciously motivated wandering hand) Source.

Adapted from Mendez 1996.

Cortical and Subcortical Signs It is possible to distinguish between cortical and subcortical disruptions of basal ganglia–cortical circuits (Table 1–4). Certain features can assist in determining whether cortical or subcortical pathology is present. This distinction is best seen in the comparison between cortical and subcortical dementias. Patients with cortical dementias generally exhibit an inability to learn new material, variably accompanied by aphasia, upper motor neuron signs (see below), and normal psychomotor speed and complex attention (e.g., normal execution of a three-stage command). Dysexecution may or may not be present. Patients with subcortical dementias generally manifest an inability to retrieve learned information (retrieval deficits) but may be capable of learning new information that can be retrieved with memory cues, in contrast to cortical dementia. Speech may be dysarthric, but aphasia is usually absent. Other contrasts with cortical dementia include the presence of extrapyramidal movement disorders, psychomotor slowing, abnormal complex attention, and dysexecution. As with cortical disease, the specific findings in subcortical disease depend on the location of the lesion. Movement disorders are recognized by their form and suggest subcortical pathology. They are often best seen by casually observing the patient without the patient’s awareness, such as in the waiting room and on walking from the waiting room to the office. The finding of a movement disorder with minimal other neurological findings can suggest a basal ganglia disease (e.g., Wilson’s disease, Huntington’s disease, Fahr’s syndrome), whereas diverse, distributed

Psychiatric Management Principles in Neurological Disease

Table 1–4.

9

Cortical versus subcortical dementias

Function Psychomotor speed Complex attention (3-stage command) Executive function Memory

Cortical Normal Normal

Frontal–Subcortical Slow Abnormal

Normal or abnormal Amnesic

Speech

Aphasic

Motor disorder

Pyramidal

Abnormal Retrieval errors (can be cued) Dysarthric (aphasia rarely) Extrapyramidal

neurological findings on exam can suggest a multifocal disease (e.g., multiple sclerosis, acquired immunodeficiency syndrome [AIDS], stroke). Upper motor neuron signs and sensory deficits can result from cortical, subcortical, or noncortical lesions. Upper motor neuron signs—including hemiparesis, hemiplegia, hyperreflexia, spasticity, rigidity, clonus, and Babinski sign (upgoing toe when the plantar surface of the foot is stroked)—point to the motor system (Table 1–5). Sensory deficits point to the sensory system.

Movement Disorders as Localizing Signs The form of the movement disorder can sometimes reveal the location of the pathology (see Table 1–5). Hyperkinetic disorders— wherein the patient exhibits excessive, unwanted, involuntary movements—occur with lesions of the caudate (chorea), putamen (dystonia), subthalamic nucleus (ballismus, chorea), thalamus (chorea, dystonia, ballismus, myoclonus), and cerebellum (myoclonus, tremor). Hypokinetic disorders (the parkinsonisms) usually suggest lesions of the substantia nigra or the globus pallidus. This is not to say that other disorders cannot occur with these lesions, or that such disorders always occur with lesions in these areas. Distinguishing features of parkinsonism, chorea, and dystonia are discussed in the chapters on Parkinson’s disease, Huntington’s disease, and idiopathic dystonia (Chapters 2, 3, and 6, respectively). Ballismus is a ballistic movement that is often of extreme amplitude,

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Table 1–5.

Psychiatric Management in Neurological Disease

Localizing neurological signs and symptoms

Sign Upper motor neuron signs Sensory deficit Parkinsonism Chorea Dystonia Ballismus Striatal toe, striatal dishing Cerebellar signs, intention tremor Rubral tremor Alien hand syndrome Pathological affect

Potential localizations Motor cortex, internal capsule, pons, pyramidal tracts, corticospinal tracts Parietal cortex, thalamus, brain stem, spinothalamic tracts, dorsal columns Substantia nigra, globus pallidus Caudate, subthalamic nucleus, thalamus Putamen, thalamus, globus pallidus Subthalamic nucleus, thalamus Striatum Cerebellum, cerebellar outflow tracts Red nucleus Thalamus, corpus callosum Corticobulbar tracts, basal ganglia, thalamus, brain stem

especially when affecting the proximal joints such as the shoulder. It is quite striking in severity, usually involving one or both limbs on one side of the body after a subthalamic vascular lesion. Other signs of basal ganglia dysfunction include striatal dishing (hyperextension of the metacarpophalangeal joints) and striatal toe (the great toe spontaneously extends).

Cerebellar Signs The cerebellum influences basal ganglia–cortical circuit physiology (Figure 1–3) and can also be affected in certain basal ganglia diseases (e.g., Wilson’s disease, Fahr’s syndrome). Cerebellar features evident on the neurological exam include cerebellar rebound, ataxia, dysmetria, dysdiadochokinesia, cerebellar speech, and terminal kinetic tremor. Rebound in an upper extremity can be tested for by asking the patient to flex the biceps muscle while the examiner pulls down on the forearm and then suddenly lets go. Patients with cerebellar disease may be unable to quickly adjust their muscle tone to stop flexing and may strike themselves in the face. Therefore, the examiner must

Psychiatric Management Principles in Neurological Disease

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Figure 1–3. Cerebellar connections. The direction of projection is symbolized from neuronal soma to axonal bouton (e.g., from cerebellum to septum). Amyg = amygdala, CB = cerebellum, DPFC = dorsal prefrontal cortex, Forn = fornix, GP = globus pallidus, HC = hippocampus, LC = locus coeruleus, NA = nucleus accumbens, OBFC = orbitofrontal cortex, PPN = pedunculopontine nucleus, Sept = septum, SN = substantia nigra, Thal = thalamus, TL = temporal lobe, VTA = ventral tegmental area.

interpose his or her other arm between the patient’s forearm and face to protect against this result. Ataxia is seen in side-to-side wandering deviations from the correct path of the limb on finger-to-nose (FTN) testing, heel-to-shin (HTS) exam, or tandem gait (“drunk driving test”). Dysmetria is evident on FTN or HTS tests by stopping before (“undershooting”) or after (“overshooting”) the target. Some patients mask dysmetria by performing the FTN test with excessive slowness, but dysmetria becomes apparent when the patient is required to perform the test more rapidly. Dysdiadochokinesia is elicited by having the patient perform rapid alternating movements, such as repetitive alternating tapping of the dorsal, then ventral hand against the thigh simultaneously with both hands. Dysdiadocho-

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Psychiatric Management in Neurological Disease

kinesia is manifest in a dyscoordinated, dysrhythmic performance, either unilaterally or bilaterally. Cerebellar speech involves inability to properly control the rate and volume of speech. Thus, speech rate, volume, and tone fluctuate during the course of a sentence, conveying the impression that the patient is intoxicated when, in fact, he or she is not.

Tremors Cerebellar terminal kinetic tremor (i.e., tremor at the end of movement) becomes apparent as the patient approaches the target (e.g., on FTN exam). This type of tremor has also been called “intention tremor” and is distinguishable from action-postural tremor (consistently present throughout the range of movement) and resting tremor (evident at rest and attenuating with movement). Rubral tremor combines elements of all of these other tremors and suggests disease involving the red nucleus in the midbrain.

Psychogenic Findings Despite the tendency to misdiagnose movement disorders as psychogenic (see Chapter 6 in this volume), certain clinical findings can signal the presence of psychogenic movement disorders. In one study of 131 patients with such disorders (Williams et al. 1995), clinical tip-offs to a psychogenic origin included abrupt onset after inciting events; multiple coexisting forms of movement disorders; variable and inconsistent motor manifestations fluctuating during the exam; motor signs incongruous with organic origin; increases in movement severity or complexity on examination of the affected body part; diminished movement severity with distraction or when not under direct scrutiny; excessive startle; incongruous or false neurological signs; response to placebo, suggestion, or psychotherapy; and presence of associated psychiatric symptoms. Of course, none of these findings can be considered pathognomonic (see Chapter 6 in this volume for further diagnostic tip-offs and caveats). Moreover, organic movement disorders are also associated with psychiatric disorders. In addition to the clinical tip-offs listed above, the form of the movement disorder can serve to raise the clinician’s index of suspicion. Some movement disorders are more common than others. In

Psychiatric Management Principles in Neurological Disease

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the study of Williams et al. (1995), psychogenic dystonia was the most common psychogenic movement disorder, occurring in 82 (62.6%) of 131 patients with psychogenic movement disorders. The next most common psychogenic movement disorder was tremor (in 21 patients [16%]), followed by gait disorder (14 patients [10.7%]), undifferentiated dyskinesias (14 patients [10.7%]), myoclonus (11 patients [8.4%]), parkinsonism (3 patients [2.3%]), tics (2 patients [1.5%]), and stiff man syndrome (1 patient [0.8%]). Some patients had more than one condition. Obviously, the underlying psychopathology must be addressed in order to successfully treat psychogenic conditions. Certain psychiatric disorders have been observed more frequently than others. Among 24 patients with psychogenic movement disorders undergoing psychiatric treatment in the study of Williams et al. (1995), psychiatric diagnoses included conversion disorder (18 patients [75%]), somatization disorder (3 patients [12.5%]), factitious disorder (2 patients [8.3%]), and malingering (1 patient [4.2%]). Nearly all patients (except 1 with oppositional defiant disorder) had associated mood, anxiety, or adjustment disorders. The most common associated diagnosis was dysthymia. DSM Cluster B and C personality disorders were also common, especially dependent personality disorder. Several patients had learning disabilities. Although 3 patients with psychogenic movement disorders did not experience remission and 1 committed suicide, most were quite improved. The most successful treatment was hypnosis, followed by family therapy and then physical therapy. Most of these patients were also on psychotropics. The use of placebo was helpful in 3 cases.

General Principles of Psychiatric Management in Neurological Illnesses Some of the most germane psychiatric treatment considerations in treating neurological patients are summarized below. For a more comprehensive discussion, the reader may wish to supplement this material with other texts, including comprehensive psychotherapy (Forrest 1992) and psychopharmacology (Stoudemire et al. 1995) treatment reviews.

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Psychiatric Management in Neurological Disease

General Nonpharmacological Treatment Concerns Psychiatrists should be vigilant for disabilities imposed by cognitive deficits, neurobehavioral syndromes, personality changes, affective lability, and more traditional psychiatric diagnoses. DSM-IV (American Psychiatric Association 1994) diagnoses of concern include delirium, dementia, amnestic and other cognitive disorders, and mental disorders due to a general medical condition. Each of these disorders has specific management implications. Special neuropsychiatric treatment concerns. Detection of aphasia, apraxia, agnosia, and other conditions can aid in understanding the nature of the patient’s disability and its psychosocial impact. Elucidating deficits can promote acceptance of limitations and planning of compensatory strategies. Parietal anosognosia, right-hemisphere denial, and organic repression (Weinstein and Friedland 1977) can interfere with treatment. Considerable empathy is needed in dealing with these patients. Patients with orbitofrontal lesions, disinhibition, aggression, hypersexuality, or episodic dyscontrol—including DSM-IV personality change due to a general medical condition (disinhibited, aggressive, and labile types)—may require a quiet environment to prevent overstimulation. Hemineglect can interfere with providing instructions to the patient, and information must be delivered to the correct hemispace in such instances (e.g., stand on the right side of the bed for patients with neglect of the left hemispace). The classical presentation of hemineglect is left-hemispace neglect, which occurs after right parietal lobe lesions; however, neglect can also occur after left-sided lesions. Patients with dementia, cognitive impairment, or amnestic disorders require instructions to be conveyed in a simple, straightforward manner. Patients with dysfunction of subcortical or medial frontal circuits or depression may suffer from amotivation. Communication disorders requiring special effort on the part of both the patient and the psychiatrist include the various aphasias, dysarthria, parkinsonian speech hesitancy, pallilalia, hypophonia, vocal cord dystonia, cerebellar speech, other speech disorders, and thought disorders. Depression is extraordinarily common among people with neu-

Psychiatric Management Principles in Neurological Disease

15

rological disorders. Depression, substance abuse, and suicidality may complicate the treatment course as the patient reacts to disability. Sleep disorders (especially in patients with brain-stem lesions) and sexual disturbances may be caused by the underlying neurological illness (e.g., Huntington’s disease) or its treatment (e.g., Parkinson’s disease). The psychiatrist should monitor the grief process as the patient and family mourn the disease or its functional disabilities. The patient or family may experience guilt, shame, or anger (e.g., parents may engage in self-blame for passing a genetic disease on to their children). Genetic counseling for the patient or family members may be indicated for familial disorders. Neuropsychiatric diagnostic dilemmas. The distinction of apathy from depression chiefly relies on a thorough evaluation of depressive signs and symptoms. The DSM-IV analogue of this behavioral change (apathy) is personality change due to a general medical condition, apathetic type. If depressive cognitions (especially feelings of hopelessness, worthlessness, or pathological guilt), mood, and depressed affect are present, the patient should be treated with antidepressants. If they are absent but reduced affect is apparent, antiapathy agents (bromocriptine, amantadine) may be useful. Limitedsymptom, partially expressed (forme fruste) depression and alexithymia can complicate the diagnosis of apathy. Another problem is the distinction of flat affect from facial akinesia, and of catatonia from parkinsonism. The clinical features of these conditions overlap. Generally, the more symptoms of either disorder are present, the easier the distinction. When the conditions are indiscriminable, the presence of psychosis and response to benzodiazepines may imply flat affect or catatonia, and the absence of psychosis and benzodiazepine nonresponse may imply facial akinesia or parkinsonism. Major depression is associated with both catatonia and parkinsonism; mania is associated with both catatonia and antiparkinsonian medications. Novel neuropsychiatric presentations. Psychiatric disorders may evolve or remit during the course of the illness and must be considered on an ongoing basis. Clinical rating scales are of value to monitor clinical change between visits, reviewed elsewhere (Coffey et al.

16

Psychiatric Management in Neurological Disease

1995). Limited-symptom partial expressions (formes frustes) of psychiatric disorders may sometimes be present, requiring heightened clinical suspicion and necessitating thorough evaluation to determine the diagnosis. Tactile hallucinosis or paresthesias may attend disease of the parietal or temporal lobes, sensory system, thalamus, and basal ganglia and does not necessarily signify primary psychosis or somatization. Certain behaviors should be distinguished from the signs of mania. The childish, impish humor of witzelsucht can be seen in patients with dementia and frontal lobe disease. Disturbed social behavior may attend frontal lobe disease before other symptoms (e.g., cognitive decline) become evident. A wandering, mischievous hand that performs actions that the patient denies intent to perform may signal alien hand syndrome. Pseudobulbar affect with pathological laughter can be distinguished from manic elation or euphoria. The patient with pseudobulbar affect is generally euthymic and may complain of selective loss of control over emotions. Pathological crying or laughter can be triggered by events of mood-incongruent emotional significance. For example, a patient with pathological laughter may laugh uncontrollably after being informed of some terrible tragedy with personal significance. Certain neurological disorders have specific characteristic personality features. For example, patients with epilepsy tend to be moralistic, with intensified religiosity, a sense of urgency and mission, and a tendency toward anger and remorse. (Refer to chapters on specific diseases in this volume for details on the personality traits characteristically seen in these illnesses.) Special neuropsychiatric treatment modalities. Self-help books regarding the disease (e.g., Duvoisin 1984; Mace and Rabins 1991) can be useful to patients and caregivers. Information about the disease often reduces fear of the unknown and fosters acceptance. Both patients and family members can benefit. Support groups exist for some disorders and can provide therapeutic benefits, including socialization, support, education, a sense of control over the illness, and the chance to keep active. Better outcome is associated with attending support groups, although it is not clear whether this improved outcome is cause or effect (Montgom-

Psychiatric Management Principles in Neurological Disease

17

ery et al. 1994). Support group exercise programs can enhance mobility and reduce flexion contractures. Patients can run for office, encouraging preservation of an active, functional lifestyle. Support groups are available for a variety of specific disorders. For guidance on referrals to organizations offering information and resources, contact the Office of Disease Prevention and Health Promotion, U.S. Department of Health and Human Services, P.O. Box 1133, Washington, DC 20013-1133 (phone 1-800-336-4797 or 301-565-4167; fax 301-984-4256). For information about uncommon illnesses, contact the National Organization for Rare Disorders, P.O. Box 8923, New Fairfield, CT 06812-8923 (phone 1-800-999-6673 or 203-746-6518; fax 203-746-6481). Names of support groups and informational resources for spouses of patients can be obtained by contacting the Well Spouse Foundation, 610 Lexington Avenue, Suite 208, New York, NY 10022-6005 (phone 1-800-838-0879 or 212-644-1241; fax 212-644-1338). (See Chapter 10 in this volume for family treatment considerations.) Rehabilitation programs can assist in practical recovery and disability management. Pet therapy may be useful for loneliness and isolation, but the patient’s degree of disability may contraindicate this (e.g., a big dog may knock the patient off his feet; a small animal might lead to problems in a patient who is unable to bend down). Special neuropsychiatric treatment techniques. Management of movement disorders is detailed in the chapters that follow. Gait disturbances in neurological disorders are an important and frustrating source of disability. Impaired sensory, visual, vestibular, and motor systems contribute to gait disturbance, as can frontal apraxia and cerebellar ataxia. Learning to attend more to input from unimpaired systems can improve gait (e.g., attending with greater vigilance to visual input). Patients with visuospatial perceptual problems may require planning and positional mapping to overcome this disability. Running a finger along the wall while walking can provide compensatory sensory information for those with loss of lower-extremity propioception. Apraxia can sometimes be improved with a cane or walker. Parkinsonian freezing can be reduced by avoiding narrow, confined passageways. Gait hesitancy (difficulty initiating gait) can be assisted with the use of mental counting techniques (e.g.,

18

Psychiatric Management in Neurological Disease

“1-2-1-2-1-2 . . . ”). Another technique involves having the spouse rock the patient from foot-to-foot, thereby initiating gait. Any existing foot conditions (e.g., improperly fitting shoes, painful toenails) or other physical impediments should be addressed. Optimizing treatment of the underlying condition may also be helpful (e.g., dopaminergic therapy in Parkinson’s disease, neuroleptics in Huntington’s disease). Orthostatic hypotension caused by underlying diseases (e.g., Shy-Drager parkinsonian syndrome) or treatments (e.g., dopamine agonists) can lead to falls and immobility. Replacement of offending medications, use of support hose, or administration of salt tablets or mineralocorticoids may be useful. Vitamin status should be considered, because treatable gait disorders caused by vitamin deficiency may be present (thiamin, B12 cobalamin, or folate), especially in patients with poor nutritional status. Some patients become phobic of falling and therefore of ambulating (particularly on stairs). Behavior therapy with physical therapists or a personal trainer can often help in these instances. In addition, benzodiazepines, neuroleptics, and sedating agents can sometimes destabilize gait.

General Pharmacological Concerns Double-blind, placebo-controlled studies of psychotropics for psychosis, depression, anxiety, and agitation in neurological diseases have been reviewed recently (Rummans et al. 1999). In general, the choice of psychotropics is initially the same as in traditional treatment, except for the caveats detailed in this book. In particular, clinicians should remain alert for drug interactions with neurological agents. Further, delayed development of compound psychiatric syndromes with differentially responsive components or atypical responsivity can occur with neurological disease (Lauterbach et al. 1994). Strategies to manage noncompliance attributable to attendant neurobehavioral syndromes, amotivation, apathy, cognitive disorders, or depression should be considered. Many patients with neurological illness are elderly, debilitated, or afflicted with disease of other organs. Therefore, the usual rules applying to geriatric psychiatry should be followed. These include considerations of increased drug availability at receptor sites be-

Psychiatric Management Principles in Neurological Disease

19

cause of reduced serum protein, the need for lower initial dosages and slower advances of dosage, functionally prolonged half-lives that result in dose accumulation, reduced metabolism, reduced clearance, and the possibility of therapeutic levels on lower-thancustomary dosages. Patients with neurological disease may also be taking multiple medications, which exponentially increases the possibility of drug interactions. In anticipation of future additions to the regimen by other physicians, drugs with short half-lives are preferred to avoid prolonged clearances in the event of the need for discontinuation (e.g., fluoxetine’s metabolite norfluoxetine can linger for many weeks before eventual clearance). The atypical antipsychotics and the newer antidepressants represent important therapeutic advances. These agents have more favorable side-effect profiles than their predecessors. Theoretically, the lesser proclivity of the atypical antipsychotics (e.g., clozapine, quetiapine, olanzapine, risperidone) to induce extrapyramidal movement disorders is of value in patients with neurological disease who are predisposed to these side effects. However, review of the literature of atypical antipsychotics in these neurological diseases indicates that well-controlled data are scant (Rummans et al. 1999). The few data available suggest mixed results in Parkinson’s disease, with some patients becoming more parkinsonian or delirious on clozapine. As of this writing, a single study (Singh et al. 1997) suggests that risperidone may be the treatment of choice for psychosis in human immunodeficiency virus infection, especially for patients with mania. Although experience is limited and it is too early to declare the superiority of these agents in patients with the neurological diseases considered in this book, it is clear that patients deserve intensive monitoring while on either these agents or conventional neuroleptics, especially those patients with parkinsonian features. The relative absence of anticholinergic effects of the newer antidepressants is a clear theoretical advantage in neurological patients who are predisposed to anticholinergic delirium. Some of the major potential psychotropic–disease and drug– drug interactions are detailed in Tables 1–6 and 1–7, respectively. These and other interactions are elaborated on in greater detail elsewhere (Stoudemire et al. 1995). Furthermore, cytochrome P450 enzyme inhibition by selective serotonin reuptake inhibitors (SSRIs)

Major potential interactions between diseases and psychotropics

Congestive heart failure Cardiac conduction defects

Orthostatic hypotension Dysautonomia

Seizure disorders

Cognitive disorders

Psychiatric Management in Neurological Disease

Hypertension Coronary artery disease

Reduced first-pass effect through liver, increasing plasma drug levels Clozapine can produce hypotension, tachycardia, and dizziness LPNs, TCAs, and carbamazepine prolong conduction times (avoid) Trazodone occasionally produces heart block and ventricular arrhythmias Psychostimulants and venlafaxine can increase blood pressure LPNs, TCAs, MAOIs, and trazodone can produce hypotension, reducing coronary artery perfusion LPNs, clozapine, TCAs, trazodone, MAOIs, carbamazepine, and antihistamines can worsen orthostatic hypotension See orthostatic hypotension LPNs, clozapine, TCAs, paroxetine, MAOIs, carbamazepine, and antihistamines are anticholinergic Bladder outlet obstruction has been reported with trazodone SSRIs are associated with sexual side effects Clozapine, chlorpromazine, lithium, maprotiline, clomipramine, and bupropion are relatively contraindicated Barbiturates, phenytoin, and carbamazepine can lower neuroleptic and TCA levels Valproate can increase neuroleptic and TCA levels Valproate can increase carbamazepine toxicity Anticholinergics, LPNs, clozapine, tertiary-amine TCAs, trazodone, carbamazepine, lithium, antihistamines, and benzodiazepines can lead to delirium, increase cognitive impairment, and impair alertness Neuroleptics may increase sedative effects of barbiturates, and vice versa

20

Table 1–6.

Movement disorders

Hepatic disease

Renal disease

21

(continued)

Psychiatric Management Principles in Neurological Disease

Gait disorders

Lithium can lead to confusion and sedation at low or normal lithium levels Benzodiazepines can lead to behavioral disinhibition USABs (e.g., triazolam) especially likely to produce confusion, dissociation, and anterograde amnesis See orthostatic hypotension, cognitive disorders, and movement disorders (agents that worsen these conditions can lead to impairment of gait) Lithium, valproate, benzodiazepines, beta-blockers, and sedating agents can induce ataxia Antipsychotics can aggravate parkinsonism, dystonia, and akathisia Neuroleptic malignant syndrome is more likely in neurological disease Clozapine can sometimes worsen Parkinson’s disease signs Anticonvulsants, lithium, SSRIs, and antihistamines can worsen action-postural tremors SSRIs can lead to serotonin syndrome SSRIs can produce or worsen akathisia, dystonia, myoclonus, dyskinesias, and, rarely, parkinsonism Buspirone can produce tremor and persistent dystonia Avoid long-half-life drugs Anticonvulsants and many other drugs can further impair liver function Hydrazide MAOIs can be hepatotoxic Avoid benzodiazepines that are oxidized before glucuronidation Avoid LABs (dose accumulation can occur) Quazepam can accumulate Avoid long-half-life drugs Avoid lithium for mood stabilization if possible

Major potential interactions between diseases and psychotropics (continued)

Pulmonary disease

Blood dyscrasias

Note. LAB = long-acting benzodiazepine; LPN = low-potency neuroleptic; MAOI = monoamine oxidase inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; USAB = ultra-short-acting benzodizepine. Source. Charney et al. 1995; DePaulo 1984; Koczerginski et al. 1989; Lauterbach 1993, 1995; Lauterbach and Shillcutt 1997; Ray et al. 1989; Stoudemire and Fogel 1987; Stoudemire et al. 1995.

Psychiatric Management in Neurological Disease

Avoid MAOIs (hypertensive crises with respiratory agents) Benzodiazepines (especially LABs), barbiturates, and beta-blockers can compromise respiration LPNs, clozapine, carbamazepine, and valproate can suppress bone marrow Avoid clozapine

22

Table 1–6.

Potential drug–drug interactions

Aspirin Type 1A antiarrhythmics Propafenone Warfarin, digitoxin, digoxin

Can increase valproate level LPNs and TCAs prolong conduction times (avoid these agents) Can elevate TCA levels SSRIs, TCAs, and MAOIs can increase anticoagulant effect Increased risk for hypertensive hemorrhagic stroke in MAOI hypertensive crisis Lithium may increase digitalis toxicity Carbamazepine increases warfarin metabolism (decreases anticoagulant effect) Psychostimulants can increase prothrombin times Clonidine Neuroleptics can reduce the efficacy on blood pressure control Beta-blockers Increase psychotropic hypotension Increase neuroleptic levels Thiazide diuretics, spironolactone, Increase lithium levels triamterene Calcium channel blockers Variable effects on lithium levels Diltiazem increases carbamazepine to toxic levels Verapamil Bradycardia with lithium Increases carbamazepine to toxic levels ACE inhibitors (e.g., enalapril) Occasional elevated lithium levels Carbamazepine Carbamazepine levels can be lowered by quinidine, phenytoin, warfarin, clozapine, and propranolol Carbamazepine toxicity increased by diltiazem and verapamil

23

(continued)

Psychiatric Management Principles in Neurological Disease

Table 1–7.

Potential drug–drug interactions (continued)

Carbamazepine (continued)

Phenytoin Barbiturates

Benzodiazepines Sympathomimetics

Psychiatric Management in Neurological Disease

Valproate

Carbamazepine induces cytochrome P450 (CYP) 3A3/4/5 Increases the metabolism of anticoagulants Can increase prothrombin times Can lower TCAs, neuroleptic, clozapine, valproate, and benzodiazepine levels SSRIs can increase carbamazepine levels Can increase prothrombin times Can inhibit platelet aggregation Aspirin can increase valproate levels Can increase TCAs, carbamazepine 10-11 epoxide, benzodiazepine (except lorazepam), and phenobarbital levels Can be increased by chlorpromazine Can be decreased by carbamazepine, phenytoin, and phenobarbital Can displace protein-bound phenytoin and carbamazepine Can lower TCAs, neuroleptics, and carbamazepine levels SSRIs, psychostimulants, and carbamazepine can increase phenytoin levels Can lower TCAs, neuroleptics, and carbamazepine levels Can increase carbamazepine 10-11 epoxide levels SSRIs and psychostimulants can increase barbiturate levels Can be potentiated by MAOIs SSRIs can increase benzodiazepine levels Can be potentiated by MAOIs Hypertensive crisis with MAO-A inhibitors

24

Table 1–7.

Fatality, dystonia, and other movement disorders with antipsychotics Hypertensive crisis with MAO-A inhibitors Discontinue before starting antidepressants Serotonin syndrome can result with serotonergic psychotropics Can lower lithium and benzodiazepine levels MAO-A inhibitors contraindicated

Note. ACE = angiotensin-converting enzyme; LPN = low-potency neuroleptic; MAOI = monoamine oxidase inhibitor; MAO-A = monoamine oxidase type A; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant. Source. Charney et al. 1995; DePaulo 1984; Stoudemire and Fogel 1987; Stoudemire et al. 1995.

Psychiatric Management Principles in Neurological Disease

Metoclopramide L-dopa Selegiline Serotonin agonists Theophylline and aminophylline

25

26

Psychiatric Management of Neurological Diseases

may lead to drug–drug interactions with cardiac or other medications the patient may be taking (Table 1–8). These interactions occur with a wide variety of antiarrhythmics, calcium channel blockers, beta-blockers, and warfarin (Nemeroff et al. 1996). The list of interactions of SSRIs with these other drugs seems to be continually growing, and caution is therefore indicated when prescribing these antidepressants. Among the SSRIs, citalopram may be the least likely to produce P450 interactions. Venlafaxine may produce P450 inhibition less frequently than SSRIs. Nevertheless, it is wise to monitor blood levels of cardiac and other drugs during treatment to ensure that such interactions are not occurring, given that new interactions are still being reported. Additional considerations in certain types of patients follow. Heart disease. The treating psychiatrist should consider obtaining an electrocardiogram prior to treating depressed neurological patients, because heart disease may be present (for example, in stroke, Wilson’s disease). Bupropion or one of the SSRIs may be a better choice than tricyclic antidepressants (TCAs) if conduction problems are present. In a study of 36 patients with severe heart disease and DSM-III (American Psychiatric Association 1980) major depression, bupropion was found to be free of effects on myocardial contractility and conduction, although blood pressure was increased (Roose et al. 1991). In an open-label trial, sertraline did not significantly change heart rate, blood pressure, cardiac conduction, or ejection fraction in post–myocardial infarction patients (Shapiro et al. 1999). In contrast to the findings for sertraline, a study of fluoxetine in cardiac patients revealed a 6% decrease in heart rate, a 2% increase in supine blood pressure, and a 7% increase in ejection fraction, although conduction, arrhythmias, and orthostatic blood pressure were unaffected (Roose et al. 1998). Four percent of the patients suffered an adverse cardiovascular event. However, these and newer agents have not been adequately investigated in patients with arrhythmias or heart failure. Moreover, P450 interactions of SSRIs with cardiovascular drugs warrant careful attention to patient selection. Beta-blockers are useful for action-postural tremors and akathisia. Major concerns regarding psychotropic administration in cardiovascular and other diseases are listed in Table 1–6.

Potential cytochrome P450 (CYP) interactions with selective serotonin reuptake inhibitors (SSRIs)

Drug Analgesics Acetaminophen Codeine Dextromethorphan Phenacetin Cardiovascular agents Anticoagulants Warfarin Beta-blockers Metoprolol Propranolol Antiarrhythmics Amiodarone Encainide Flecainide Mexiletine Propafenone

CYP 1A2 (fluvoxamine)

CYP 2D6 CYP 3A4 CYP 2C (fluoxetine, sertraline, (fluoxetine, sertraline, (fluoxetine, sertraline, fluvoxamine, fluvoxamine, fluvoxamine) paroxetine, citalopram) nefazodone)

+

+ + +

+

+

+

+

+

+

+ + + + + + + +

+

27

(continued)

Psychiatric Management Principles in Neurological Disease

Table 1–8.

CYP 1A2 (fluvoxamine)

Antiarrhythmics (continued) Quinidine Lidocaine Calcium channel blockers Verapamil Diltiazem Nifedipine Lipid-lowering agents Lovastatin Gastrointestinal agents Omeprazole Cisapride Phosphodiesterase inhibitors Caffeine Theophylline

CYP 2D6 CYP 3A4 CYP 2C (fluoxetine, sertraline, (fluoxetine, sertraline, (fluoxetine, sertraline, fluvoxamine, fluvoxamine, fluvoxamine) paroxetine, citalopram) nefazodone) +

+ +

+ +

+ + + +

+ +

+ +

+

Psychiatric Management in Neurological Disease

Drug

Potential cytochrome P450 (CYP) interactions with selective serotonin reuptake inhibitors (SSRIs) (continued)

28

Table 1–8.

Psychiatric Management Principles in Neurological Disease

+ + + + + + + + + +

+

+ +

+

+ + + +

29

Hypoglycemics Tolbutamide Oncologic agents Vincristine Vinblastine Immunosuppressants Cyclosporine Steroids Dexamethasone Estrogen Testosterone Antibiotics Erythromycin Clarithromycin Antifungals Ketoconazole Protease inhibitors Indinavir Nelfinavir Ritonavir Saquinavir Cognitive enhancers Tacrine Donepezil

+ (continued)

Potential cytochrome P450 (CYP) interactions with selective serotonin reuptake inhibitors (SSRIs) (continued)

Antipsychotics Haloperidol Perphenazine Thioridazine Risperidone Clozapine Remoxipride Pimozide Olanzapine Quetiapine Anticonvulsants Carbamazepine Ethosuximide Hexobarbital Mephobarbital Phenytoin

CYP 1A2 (fluvoxamine) +

+ + + + + +

+

+ +

+

+ + + + + + +

Psychiatric Management in Neurological Disease

Drug

CYP 2D6 CYP 3A4 CYP 2C (fluoxetine, sertraline, (fluoxetine, sertraline, (fluoxetine, sertraline, fluvoxamine, fluvoxamine, fluvoxamine) paroxetine, citalopram) nefazodone)

30

Table 1–8.

Psychiatric Management Principles in Neurological Disease

Antidepressants Tetracyclics Maprotiline Tricyclics Amitriptyline Nortriptyline Imipramine Desipramine Clomipramine Others Bupropion Mirtazapine Mianserin Trazodone Venlafaxine Nefazodone Monoamine oxidase inhibitors Moclobemide Anxiolytics Alprazolam Diazepam Midazolam

+ +

+

+

+

+

+

+

+ + + + +

+ + + +

+ + + + +

+

+

+

+ + +

31

(continued)

Potential cytochrome P450 (CYP) interactions with selective serotonin reuptake inhibitors (SSRIs) (continued)

Anxiolytics (continued) Triazolam Clonazepam Antihistamines Astemizole Terfenadine Loratadine

CYP 1A2 (fluvoxamine)

+ + + + +

Note. Partial listing of some of the more important potential drug interactions in neurological patients. The strongest inhibitors of cytochrome P450 2D6 are paroxetine, followed by fluoxetine. The weakest 2D6 inhibitors are citalopram and fluvoxamine. Although venlafaxine is considered a weaker inhibitor than the antidepressants listed, it can also inhibit 2D6.

Psychiatric Management in Neurological Disease

Drug

CYP 2D6 CYP 3A4 CYP 2C (fluoxetine, sertraline, (fluoxetine, sertraline, (fluoxetine, sertraline, fluvoxamine, fluvoxamine, fluvoxamine) paroxetine, citalopram) nefazodone)

32

Table 1–8.

Psychiatric Management Principles in Neurological Disease

33

Dysautonomia and orthostatic hypotension. Sympathomimetics used to treat neurological patients with dysautonomia or hypoventilation can lead to anxiety and hypertensive reactions with monoamine oxidase inhibitors (MAOIs). Psychotropics with anticholinergic actions (Table 1–6) and anticholinergics used to treat dystonia and parkinsonism may worsen dysautonomia and produce gastroparesis, tachycardia, dry mouth, blurred vision, and urinary retention. Coadministration of antipsychotics and metoclopramide can lead to severe dystonia that can sometimes prove fatal (Lauterbach 1992). Many drugs can worsen orthostatic hypotension and induce sexual dysfunction, usually through alpha1 receptor blockade. Many of these agents (see Table 1–6) can also be quite anticholinergic. Highpotency neuroleptics, bupropion, and SSRIs might be preferred, although SSRIs have also been associated with sexual side effects, potentially compounding the sexual dysfunctions seen in some dysautonomias. Bupropion may improve erectile failure, and bupropion and desipramine may be useful for anorgasmia (Charney et al. 1995). Bladder outlet obstruction has been reported with trazodone, and paroxetine has sometimes been reported to exhibit clinically significant anticholinergic effects. Seizure disorders. Among antipsychotics, molindone, fluphenazine, thioridazine, and mesoridazine may cause the least reduction in seizure threshold (Edwards et al. 1986; Luchins et al. 1984). Among antidepressants, desipramine, MAOIs, and SSRIs reduce the seizure threshold the least and thus are preferred in treating depressed patients with seizures (Charney et al. 1995). Clozapine, lithium, maprotiline, clomipramine, and bupropion are best avoided in patients at risk for seizures (Charney et al. 1995). The risk of seizures with clozapine is dose related: 1%–2% at doses up to 300 mg/day, 3%–4% at between 300 mg/day and 600 mg/day, and 5% at 600–900 mg/day (Stoudemire et al. 1995). Blood levels for anticonvulsants should be followed, since many psychotropics interact with these agents (Tables 1–7 and 1–8). When valproate is coadministered with carbamazepine, it may displace carbamazepine from protein binding sites and raise the concentration of carbamazepine’s 10-11 epoxide, thereby increasing carbamazepine bioavailability and, potentially, toxicity without increasing clinically detectable blood levels (Stoudemire et al. 1995).

34

Psychiatric Management in Neurological Disease

Cognitive disorders. Many agents (Table 1–7) can further impair cognition in patients with cognitive disorders. High-potency neuroleptics, risperidone, the newer antidepressants, and buspirone carry the least risk for cognitive impairment. Among TCAs, the secondary amines (e.g., nortriptyline, desipramine) have the least potential for causing impairment. SSRI treatment has been associated with several forms of myoclonus, some producing significant distress to the patient (Bharucha and Sethi 1996; Lauterbach 1994). Patients with central nervous system disease may show confusion and sedation on lower levels of lithium than those causing such effects in the general population (DePaulo 1984). Although trazodone and the benzodiazepines can calm agitation in the cognitively impaired, they can sometimes also produce behavioral disinhibition. Ultra-short-acting benzodiazepines (e.g., triazolam) are more likely than long-acting agents to produce acute confusion, dissociation, and anterograde amnesis (Stoudemire et al. 1995), but long-acting benzodiazepines (e.g., clonazepam, flurazepam) can accumulate over several weeks to toxic levels in patients with reduced clearance (e.g., Wilson’s disease with liver complications). Despite having benzodiazepine-1 receptor affinity, quazepam can also accumulate to toxic levels (Stoudemire et al. 1995). Buspirone is less likely than the benzodiazepines to impair cognition and thus is a logical alternative in patients with cognitive impairment attributable to benzodiazepines. Pathological affect. Pathological affect can respond to SSRIs, antidepressants, lithium, L-dopa, amantadine, and methylphenidate (Lauterbach and Schweri 1991; also see Chapter 7 in this volume). Gait disorders. Agents that impair cognition, reduce arousal, or lead to hypotension, parkinsonism, or ataxia can also impair gait. Lithium and valproate can induce or amplify gait ataxia. Carbamazepine can cause dose-related ataxia, diplopia, and sedation, each of which can destabilize gait. Benzodiazepines are associated with hip fractures in the elderly. In a study of 4,501 elderly people taking benzodiazepines compared with 24,041 control subjects, the relative risk for hip fracture was increased 70% by long half-life and 10% by short half-life benzodiazepines (Ray et al. 1989). This increase in risk was observed after controlling for demographic and other clinical factors. Shorter-acting benzodiazepines include alprazolam, triazo-

Psychiatric Management Principles in Neurological Disease

35

lam, lorazepam, and oxazepam. Clonazepam added to therapeutic levels of lithium has led to ataxia and dysarthria (Koczerginski et al. 1989). Movement disorders. Clozapine, quetiapine, olanzapine, risperidone, and low-potency neuroleptics are less apt to aggravate parkinsonism than are high-potency neuroleptics. Nevertheless, these agents can certainly elicit parkinsonism and other movement disorders, and patients should be closely monitored. Neuroleptic malignant syndrome is a possibility in patients taking antipsychotics, given that this condition tends to evolve in patients with neurological impairment and debilitation, especially if dehydration is also present (Stoudemire et al. 1995). In contrast to their ability to precipitate acute neuroleptic-induced dystonia, neuroleptics can either improve or worsen other dystonias (see Chapter 6 in this volume). The heterocyclic antidepressant amoxapine can metabolize to variable concentrations of the neuroleptic loxapine. Clozapine has many side effects, including cognitive impairment, but it can reduce L-dopa dyskinesia, as can the SSRIs and buspirone. Improvement in dystonia and parkinsonism has been reported with clozapine, although double-blind trials in Parkinson’s disease patients have disclosed worsened parkinsonism and precipitation of delirium with clozapine (Rummans et al. 1999). Psychosis may be induced by neurological medications (e.g., dopamine agonists) and can sometimes remit with dosage reduction. In Parkinson’s disease patients, the drug selegiline should be discontinued at least 14 days prior to commencing treatment with antidepressant agents (5 weeks before fluoxetine) because of reported fatalities due to drug interactions. Vigilance for the serotonin syndrome (ataxia, nystagmus, confusion, fever, tremor, and myoclonus) is necessary when combining serotonergic agents with MAOIs or SSRIs. Although probably rare, visual hallucinations and illusions have occurred when SSRIs were administered to Parkinson’s disease patients being treated with L-dopa (Lauterbach 1993). SSRIs can induce a wide variety of movement disorders (Leo 1996). Although SSRIs usually have no effect on parkinsonism and dystonia, they variably improve or worsen different forms of myoclonus and dystonia (Lauterbach 1994, 1995). SSRIs can sometimes improve L-dopa dyskinesia in Parkinson’s disease. Coadministra-

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tion of MAOIs and L-dopa can trigger hypertensive crises, although each of these agents individually can cause hypotension. Electroconvulsive therapy may be useful in some cases of Parkinson’s disease as well as some cases of dystonia (Lauterbach and Moore 1990). Lithium and valproate can amplify ataxia. Benzodiazepines and beta-blockers improve action-postural tremors. Buspirone has led to tremor and persistent dystonia (LeWitt et al. 1993). Hepatic and renal disease. Portal hypertension reduces first-pass effects, and patients with liver disease should be started on one-third to one-half the usual dose of antidepressants until blood levels have been determined or tolerance to side effects occurs. Short-acting agents (e.g., paroxetine instead of fluoxetine) are used because of extended-half-life considerations. Among anxiolytics, oxazepam, temazepam, and lorazepam are directly glucuronidated without first being oxidized and thus are the preferred agents in this class. The tyramine diet required with MAOIs may make these agents an unpalatable option in a patient already on a renal or hepatic diet. Nonhydrazide MAOIs have less hepatotoxic potential than do hydrazide MAOIs. Anticonvulsants should be avoided in liver disease, as should lithium in patients with renal disease. Drug plasma levels should be frequently monitored when possible, especially in patients on dialysis. Pulmonary disease and blood dyscrasias. Hypoventilation can attend neurological diseases, particularly Parkinson’s disease. Concerns regarding sympathomimetics have already been detailed (see “Dysautonomia and orthostatic hypotension,” above). Anticholinergic agents can reduce tracheobronchial secretions in asthma and chronic obstructive pulmonary disease. Steroids carry their own psychiatric risks. Benzodiazepines can impair ventilatory status; buspirone is a logical alternative. Blood dyscrasia can attend Wilson’s disease. Interactions of concern in pulmonary disease and blood dyscrasias are listed in Tables 1–6 and 1–7.

Summary Diseases affecting basal ganglia–cortical circuits are devastating in terms of functional impairment and economic costs. A panoply of

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psychiatric, behavioral, and neurological conditions can occur in these diseases. Certain features can help to localize pathology. Movement disorders are particularly common in basal ganglia–cortical diseases. Psychiatric management involves determining deficits and helping the patient adjust to them, employing specific treatment approaches. Principles of pharmacotherapy involve consideration of drug effects on the underlying illness, associated conditions, other drugs in the regimen, and special proclivities to side effects unique to the condition. A cautious, conservative approach is warranted. Self-help books, support groups, family education and therapy, and, at times, genetic counseling can represent important treatment options in these disorders.

References American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition. Washington, DC, American Psychiatric Association, 1980 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994 Bharucha KJ, Sethi KD: Complex movement disorders induced by fluoxetine. Mov Disord 11:324–326, 1996 Charney DS, Miller HL, Licinio J, et al: Treatment of depression, in The American Psychiatric Press Textbook of Psychopharmacology. Edited by Schatzberg AF, Nemeroff CB. Washington, DC, American Psychiatric Press, 1995, pp 575–601 Coffey CE, Cummings JL, Duffy JD, et al: Assessment of treatment outcomes in neuropsychiatry: a report from the Committee on Research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 7:287–289, 1995 Cummings JL: Frontal-subcortical circuits and human behavior. Arch Neurol 50:873–880, 1993 DePaulo JR Jr: Lithium. Psychiatr Clin North Am 7:587–599, 1984 Duvoisin RC: Parkinson’s Disease: A Guide for Patient and Family, 2nd Edition. New York, Raven, 1984 Edwards JG, Long SK, Sedgwick EM, et al: Antidepressants and convulsive seizures: clinical, electroencephalographic, and pharmacological aspects. Clin Neuropharmacol 9:329–360, 1986

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Forrest DV: Psychotherapy of patients with neuropsychiatric disorders, in The American Psychiatric Press Textbook of Neuropsychiatry, 2nd Edition. Edited by Yudofsky SC, Hales RE. Washington, DC, American Psychiatric Press, 1992, pp 703–739 Koczerginski D, Kennedy SH, Swinson RP: Clonazepam and lithium—a toxic combination in the treatment of mania? Int Clin Psychopharmacol 4:195–199, 1989 Lauterbach EC: Haloperidol-induced dystonia and parkinsonism on discontinuing metoclopramide: implications for differential thalamocortical activity. J Clin Psychopharmacol 12:442–443, 1992 Lauterbach EC: Dopaminergic hallucinosis with fluoxetine in Parkinson’s disease (letter). Am J Psychiatry 150:1750, 1993 Lauterbach EC: Reversible intermittent rhythmic myoclonus with fluoxetine in presumed Pick’s disease. Mov Disord 9:343–346, 1994 Lauterbach EC: Fluoxetine, buspirone, myoclonus, and dystonia (letter). Am J Psychiatry 152:1697, 1995 Lauterbach EC: Bipolar disorders, dystonia, and compulsion after dysfunction of the cerebellum, dentatorubrothalamic tract, and substantia nigra. Biol Psychiatry 40:726–730, 1996 Lauterbach EC, Moore NC: Parkinsonism-dystonia syndrome and ECT (letter). Am J Psychiatry 147:1249–1250, 1990 Lauterbach EC, Schweri MM: Amelioration of pseudobulbar affect by fluoxetine: possible alteration of dopamine-related pathophysiology by a selective serotonin reuptake blocker. J Clin Psychopharmacol 11: 392–393, 1991 Lauterbach EC, Shillcutt SD: Dyskinesia with fluoxetine: tardive or lateonset persistent acute norfluoxetine dyskinesia? (letter). J Clin Psychiatry 58:85–86, 1997 Lauterbach EC, Price ST, Spears TE, et al: Serotonin responsive and nonresponsive diurnal depressive mood disorders and pathological affect in thalamic infarct associated with myoclonus and blepharospasm. Biol Psychiatry 35:488–490, 1994 Leo RJ: Movement disorders associated with the serotonin selective reuptake inhibitors. J Clin Psychiatry 57:449–454, 1996 LeWitt PA, Walters A, Hening W, et al: Persistent movement disorders induced by buspirone. Mov Disord 8:331–334, 1993 Luchins DJ, Oliver AP, Wyatt RJ: Seizures with antidepressants: an in vitro technique to assess relative risk. Epilepsia 25:25–32, 1984

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Mace NL, Rabins PV: The 36-Hour Day: A Family Guide to Caring for Persons With Alzheimer’s Disease, Related Dementing Illnesses, and Memory Loss in Later Life. Baltimore, MD, Johns Hopkins University Press, 1991 Mendez MF: The neuroanatomy of neurobehavioral syndromes. Lecture presented at The American Association for Geriatric Psychiatry 1996 Board Review Course for the Examination for Added Qualifications in Geriatric Psychiatry, Los Angeles, CA, October 1996 Montgomery EB Jr, Lieberman A, Singh G, et al: Patient education and health promotion can be effective in Parkinson’s disease: a randomized controlled trial (PROPATH Advisory Board). Am J Med 97:429–435, 1994 Nemeroff CB, De Vane CL, Pollock BG: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 153:311–320, 1996 Ovsiew F: Bedside neuropsychiatry: eliciting the clinical phenomena of neuropsychiatric illness, in The American Psychiatric Press Textbook of Neuropsychiatry, 2nd Edition. Edited by Yudofsky SC, Hales RE. Washington, DC, American Psychiatric Press, 1992, pp 703–739 Ray WA, Griffin MR, Downey W: Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA 262:3303–3307, 1989 Roose SP, Dalack GW, Glassman AH, et al: Cardiovascular effects of bupropion in depressed patients with heart disease. Am J Psychiatry 148: 512–516, 1991 Roose SP, Glassman AH, Attia E, et al: Cardiovascular effects of fluoxetine in depressed patients with heart disease. Am J Psychiatry 155:660–665, 1998 Rummans TA, Lauterbach EC, Coffey CE, et al: Pharmacologic efficacy in neuropsychiatry: a review of placebo-controlled treatment trials. A report of the ANPA Committee on Research. J Neuropsychiatry Clin Neurosci 11:176–189, 1999 Shapiro PA, Lesperance F, Frasure-Smith N, et al: An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial). Sertraline Anti-Depressant Heart Attack Trial. Am Heart J 137:1100–1106, 1999 Singh AN, Golledge H, Catalan J: Treatment of HIV-related psychotic disorders with risperidone: a series of 21 cases. J Psychosom Res 42:489–493, 1997 Stoudemire A, Fogel BS: Psychopharmacology in the medically ill, in Principles of Medical Psychiatry. Edited by Stoudemire A, Fogel BS. Orlando, FL, Grune & Stratton, 1987, pp 79–112

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Stoudemire A, Moran MG, Fogel BS: Psychopharmacology in the medically ill patient, in The American Psychiatric Press Textbook of Psychopharmacology. Edited by Schatzberg AF, Nemeroff CB. Washington, DC, American Psychiatric Press, 1995, pp 783–801 Sultzer DL: Mental status examination, in The American Psychiatric Press Textbook of Geriatric Neuropsychiatry. Edited by Coffey CE, Cummings JL. Washington, DC, American Psychiatric Press, 1994, pp 99–104 Vitek JL, Chockkan V, Zhang JY, et al: Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 46:22–35, 1999 Weinstein EA, Friedland RP: Behavioral disorders associated with hemiattention. Adv Neurol 18:51–62, 1977 Williams DT, Ford B, Fahn S: Phenomenology and psychopathology related to psychogenic movement disorders. Adv Neurol 65:231–257, 1995

C H A P T E R

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Parkinson’s Disease Morgan L. Levy, M.D. Jeffrey L. Cummings, M.D.

P

arkinson’s disease (PD) is a common degenerative disease of unknown etiology that primarily affects subcortical brain structures. It produces motor, cognitive and psychiatric abnormalities. Motor symptoms include bradykinesia (slowness of movement), cogwheel rigidity, tremor, and gait dysfunction. Cognitive symptoms include bradyphrenia (slowness of thinking) and executive dysfunction, which involves deficits in problem solving, word list generation, abstracting ability, set shifting, and memory retrieval. More severe dementia syndromes may occur in about 40% of patients. Psychiatric symptoms include depression, anxiety, and reduced motivation. Several psychiatric symptoms may be associated with anti-PD therapy; these include hallucinations, delusions, confusional states, mania, increased libido, and sleep disturbances. In this chapter our focus is primarily on cognitive and psychiatric abnormalities in PD.

Prevalence The prevalence of PD varies widely by geographic location, ranging from 31 per 100,000 in Libya to 328 per 100,000 in India. Most Western countries report prevalence rates of approximately 110 per 100,000. This project was supported by a Department of Veterans Affairs Neuroscience Fellowship, a National Institute on Aging Alzheimer’s Disease Center grant (AG10123), and the Sidell-Kagan Research Fund.

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The mean age at onset is 58–62 years (range: 40–70 years) (Martilla 1987). The average time to death in untreated PD is 8 years (range: 1–30 years). Contemporary therapeutic interventions have extended the life expectancy of patients so that 50% are alive 16 years after disease onset (Di Rocco et al. 1996). Most cases are sporadic, and twins generally lack concordance. However, a family history of either PD or essential tremor is a risk factor for the disease. Increasing age is the only unequivocal risk factor; postulated risks include being exposed to pesticides or heavy metals (Fe, Mn, Al), drinking well water, and living in rural communities. Cigarette smoking and diets rich in vitamin E have been associated with reduced risk of PD (Tanner and Goldman 1996).

Clinical Recognition and Neurological Presentation Motor disturbances in PD include tremor, rigidity, bradykinesia, and loss of righting reflexes. Autonomic abnormalities and oculomotor dysfunction are found in most patients, although these are more subtle than the deficits found in progressive supranuclear palsy or Shy-Drager syndrome (see below). The typical PD tremor is a lowfrequency (4–5 cycles per second), large-amplitude rest tremor. Cogwheel rigidity results from the superposition of the tremor on increased muscle tone when the forearm or another joint is being moved through a full range of motion, whereas plastic rigidity is more common in the lower extremities, where there may be an increase in muscle tone and resistance to movement without apparent jerking or tremor. Bradykinesia is defined as slowness of movement and is one of the most pervasive elements of PD. Patients with bradykinesia have hesitation in initiating movements, impaired repetitive movements, freezing episodes, diminished arm swing, micrographia, facial masking, and sialorrhea. “En bloc” movements can be seen when patients attempt to turn while walking, a maneuver that may require multiple steps. PD patients often have a stooped posture with flexion of the trunk, knees, elbows, and neck, and their gait is characterized by short steps with diminished step height (“marche en petit pas”). Balance is impaired, and patients may lean and step backward (retropulsion) or forward (propulsion) and may fail to

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make the appropriate postural adjustments. Impotence, constipation, postural hypotension, and seborrheic dermatitis that is generally evident on the forehead are among the signs of autonomic dysfunction in PD; impaired convergence, limited up-gaze, and lid retraction are the most common neuro-ophthalmological abnormalities (Barbeau 1986). In addition to idiopathic PD, many disorders manifest parkinsonism (Table 2–1). These “Parkinson-plus” syndromes generally present with features of PD but manifest additional symptoms. Progressive supranuclear palsy is a syndrome that is similar to PD but that may produce impaired vertical gaze (up-gaze as well as downgaze), axial rather than distal rigidity, and hypererect rather than stooped posture. Shy-Drager syndrome is associated with severe autonomic dysfunction early in its course, and cerebellar or pyramidal symptoms suggest the presence of olivopontocerebellar atrophy or some other Parkinson-plus syndrome. A Parkinson-plus syndrome should be suspected when tremor is absent, atypical features are present, or a patient fails to respond to dopaminergic therapy (Koller and Megaffin 1994).

Gender and Pregnancy Gender does not appreciably affect PD expression. Although men predominated in two U.S. studies of PD (Hubble et al. 1993; Marder et al. 1996), the incidence of PD was slightly more common in women than in men in the Netherlands (Hofman et al. 1989). In pregnancy, exacerbations of parkinsonism have been observed in rare cases. PD poses no increased risk to the fetus except when amantadine has been administered to the mother.

Pathological Features Increased muscle tone results from an imbalance between competing inhibitory and disinhibitory neural pathways within the subcortical motor circuit, which projects from the sensorimotor cortex through the putamen, pallidum, thalamus, and back to the cortex (Figure 2–1). Between the striatum and thalamus are dynamically balanced circuits that both decrease and increase thalamic inhibition

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Table 2–1.

Psychiatric Management in Neurological Disease

Differential diagnosis of parkinsonism

Degenerative disorders Idiopathic Parkinson’s disease

Metabolic causes of parkinsonism Hypothyroidism

Progressive supranuclear palsy Huntington’s disease (rigid variant)

Hypoparathyroidism

Striatonigral degeneration Shy-Drager syndrome Idiopathic basal ganglia calcification Guamanian parkinsonism– dementia complex Machado-Joseph disease

Wilson’s disease

Neuroacanthocytosis Lewy body dementia Hallervorden-Spatz disease Olivopontocerebellar atrophy Spinocerebellar degenerations Pallidal degeneration syndromes Ceroid lipofuscinosis Mitochondrial encephalopathy Type III (adult) GM1 gangliosidosis Vascular parkinsonism Lacunar state (a syndrome of punctate lesions in subcortical structures) Binswanger’s disease Infection-related parkinsonism Postencephalitic parkinsonism after epidemic encephalitis Transient parkinsonism after acute viral encephalitis Jakob-Creutzfeldt disease Human immunodeficiency virus encephalopathy Neurosyphilis

Non-Wilsonian hepatocerebral degeneration Drug-induced and toxic parkinsonism Neuroleptics Reserpine Alphamethyldopa Selective serotonin reuptake inhibitors Lithium Diazepam (high doses) Monoamine oxidase inhibitors Calcium channel–blocking agents Cytosine arabinoside Cyanide Organophosphates Manganese Carbon monoxide 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) Miscellaneous disorders Hydrocephalus Brain tumors Subdural hematomas Syringomesencephalia Trauma

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Figure 2–1. Frontal–subcortical circuits. *The indirect path includes the external segment of the globus pallidus and the subthalamic nucleus (DeLong 1990), although recent anatomic evidence suggests that this circuit may be more extensive (Parent and Hazrati 1995). + = excitation; − = inhibition.

(DeLong 1990; Parent and Hazrati 1995). Dopaminergic projections from the substantia nigra to the striatum appear to regulate or stabilize this inhibitory/disinhibitory balance (Saint-Cyr et al. 1995), and loss of dopamine results in unopposed thalamic inhibition and parkinsonism. Bradyphrenia and executive dysfunction are mediated by frontal–subcortical circuits that are parallel to but separate from the motor circuit. These originate in the frontal association cortex and project to the striatum at the caudate, whereas the “motor loop” originates in the supplementary motor cortex and connects to the putamen. Dopamine-mediated stabilization of the inhibitory/disinhibitory balance between direct and indirect pathways probably occurs in this circuit in the same fashion as described for the motor

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circuit (Saint-Cyr et al. 1995), and serotonergic and cholinergic projections also influence these loops. The principal neuropathological changes in PD are depigmentation and loss of dopamine-containing neurons in the substantia nigra, with protein- and sphingomyelin-containing cytoplasmic inclusions known as Lewy bodies developing in many of the remaining neurons. Similar but less severe changes also occur in the locus coeruleus (origin of norepinephrine projections), nucleus basalis (source of acetylcholine connections), and other subcortical nuclei. Deficiency of dopamine is the main neurotransmitter alteration; less-marked deficits of norepinephrine, acetylcholine, serotonin, glutamate, gamma-aminobutyric acid (GABA), and enkephalin also occur.

Neuroimaging Structural imaging has limited diagnostic utility in PD and most parkinsonian syndromes, but functional imaging, such as positron-emission tomography (PET), using [18F]fluorodopa as a tracer, can directly assess neurotransmitter activity in the nigrostriatal dopaminergic system. In contrast with normal aging or other causes of dementia, most causes of parkinsonism, including PD, are associated with reduced striatal [18F]fluorodopa. PD can be further differentiated from other causes of parkinsonism by its particularly low levels of putaminal [18F]fluorodopa. Fluorodopa PET is also useful for detecting preclinical PD and for following disease progression over time (Snow 1996) (Figure 2–2). [18F]fluorodeoxyglucose PET is used to measure cerebral metabolic rate; findings may be normal or may demonstrate global reduction in cerebral metabolism, reduced metabolism in the frontal lobes, or reduced parietal lobe activity.

Psychiatric Manifestations Dementias Cognitive dysfunction exists in a majority of PD patients, and 25%–40% have overt dementia (Aarsland et al. 1996). Bradyphrenia (slow thinking) and executive function impairment are the most

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A

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B

Figure 2–2. [18F]Fluorodopa positron-emission tomography (PET) scans showing (A) dopamine uptake in the striatum (dark areas) in a normal control subject and (B) reduction in dopamine uptake in a patient with Parkinson’s disease. Source. Courtesy of Gary Small, M.D.

common aspects of cognitive dysfunction in nondemented PD patients. Bradyphrenia is usually apparent in the form of slowed response time. Executive dysfunction may be evidenced by impaired insight, judgment, planning, and abstracting ability and may be directly assessed by testing verbal and design fluency, delayed recall, alternating programs, multiple loops, and serial hand sequences (a detailed description of these and other executive function tests can be found in Cummings and Trimble 1995). Memory retrieval, visual constructions, verbal fluency, and naming may be mildly impaired, and the pattern of deficits in these domains also suggests frontal–subcortical system abnormalities or executive dysfunction. Cortical features of dementia, such as aphasia, amnesia, agnosia, and apraxia, can occur and likely signify the presence of cortical Lewy bodies, Alzheimer’s-type pathology, or both (Cummings and Benson 1992; Growdon et al. 1990). Lewy body dementia frequently presents with psychiatric symp-

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toms such as depression, agitation, delusions, and hallucinations early in the course (Beck 1995). Cognitive symptoms can progress rapidly and relentlessly but often fluctuate, and relatively lucid intervals may occur. Patients may have mild extrapyramidal symptoms, vivid visual hallucinations, gait disturbances, orthostatic hypotension, unexplained falls, and transient clouding and/or loss of consciousness. Most PD patients have at least a few cortical Lewy bodies, and most Lewy body dementia patients have brain-stem and diencephalic Lewy bodies in the same distribution as previously described for PD (Olichney et al. 1995).

Apathy and Bradyphrenia Apathy (lack of interest or motivation) and bradyphrenia (cognitive slowing) share many phenomenological and, possibly, physiological features. These symptoms occur frequently in PD and are associated with both cognitive impairment and depression; however, an association with bradykinesia (motor slowing) has not been demonstrated (Mayeux et al. 1987; Rogers et al. 1987). Apathy also occurs in a significant number of nondepressed PD patients and these patients have reduced cognitive speed (Starkstein et al. 1992b). One mechanism suggested to explain these symptoms focuses on forebrain dopaminergic systems, which are involved in motivation and reward and are damaged in PD (Rogers et al. 1987). Mayeux et al. (1987) proposed a role for noradrenergic dysfunction in producing bradyphrenia.

Mood Disorders Thirty percent to 50% of PD patients will develop symptoms of depression at some point during the course of their illness. Bipolar disorder is infrequent unless associated with drug treatment. Crosssectional studies of clinical samples report major depression in approximately 20% and minor depression in another 20% (Starkstein et al. 1990a). In contrast, epidemiological studies report lower rates of depression; in one study of 245 patients, 12 (5.1%) had moderateto-severe depressive symptoms, 19 (7.7%) had major depression, and 106 (45.5%) had mild depressive symptoms (Tandberg et al. 1996). Risk factors for depression in PD include female gender, personal but not family history of depression, early age at onset of PD,

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greater right-sided symptoms (i.e., left-hemisphere dysfunction), and prominence of bradykinesia and gait instability as opposed to tremor- dominant syndromes (Jankovic et al. 1990; Starkstein et al. 1990a). Depression can be reliably diagnosed in PD based on DSM-IV (American Psychiatric Association 1994) criteria, although anergia, motor retardation, and early awakening may be equally severe in PD patients with and without depression (Starkstein et al. 1990b). Depression may appear before the onset of motor symptoms (Mayeux et al. 1981), may be relatively stable over time (Brown et al. 1988; Mayeux et al. 1988), and may be associated with faster progression of the illness and a more rapid decline in ability to perform activities of daily living (Starkstein et al. 1992a). Distinguishing characteristics of the parkinsonian depressive syndrome include sadness without guilt or self-reproach, high levels of anxiety, a relative lack of psychotic features, and frequent suicidal ideation (albeit with a low suicide rate) (Cummings 1992). Cognitive performance is more severe in depressed than in nondepressed PD patients but involves similar deficits, with impairment affecting executive function, memory, and language (Mayeux et al. 1981; Starkstein et al. 1989, 1990a, 1990b; Troster et al. 1995b). However, PD patients with overt dementia have no greater frequency of depression than those without dementia (Huber et al. 1986). Serotonin and norepinephrine are regulatory neurotransmitters that are produced in the brain stem and project diffusely throughout the cerebral cortex. Abnormal mood likely results from a disruption in circuits that depend on these neurotransmitters. Predisposing factors include genetic loading and psychosocial stress. Patients with PD may be predisposed to the development of depression as a result of reduced dopaminergic stimulation of the orbitofrontal cortex, which is the primary source of cortical input to brain-stem serotonergic nuclei (Mayberg and Soloman 1995). The increased frequency of depression in PD may also be related to neuronal cell loss in noradrenergic and serotonergic nuclei (Perry et al. 1991). Psychological factors also appear to play a crucial role in protecting some individuals from depression while making others more susceptible to it. Overall disability, rather than stage of illness, accounts for more of the variance in depression (MacCarthy and

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Brown 1989). Other factors that have been identified include the availability and quality of social support, the types of strategies the individual uses to cope with stress, the explanatory cognitions and perceptions of control, and attitudes and beliefs about the self (Brown and Jahanshahi 1995). Depression may also fluctuate over the course of the illness in response to psychological factors. The initial discovery that one has a chronic disabling disease may result in intense depressive symptoms that abate as acceptance occurs but that may re-ignite in response to acute episodes of increased disability.

Anxiety Disorders In studies of anxiety disorders in PD patients, anxiety symptoms have been reported in 40% of PD patients and anxiety disorders in 29%–38%, with the most frequent diagnoses being simple phobia (34%–41%), panic disorder (8%–28%), social phobia (3%–17%), generalized anxiety disorder (4%–5%), and obsessive-compulsive disorder (0%–17%) (Menza et al. 1993; Stein et al. 1990). Anxiety in PD is more frequent and severe than in elderly patients with other chronic illnesses, and it is highly comorbid with depression (Henderson et al. 1992; Menza et al. 1993; Schiffer et al. 1988). In some patients, the onset of the motor arrests known as “freezing” attenuates the course of preexisting panic disorder, whereas other patients develop limited-symptom panic attacks with the onset of freezing (Lauterbach and Duvoisin 1991, 1993). Deficits in noradrenergic and possibly serotonergic function are theorized to mediate increased susceptibility to anxiety in PD patients (Henderson et al. 1992; Menza et al. 1993). Psychological factors also contribute to a heightened state of anxiety, and problems in social interaction are the most frequently cited as the reason for seeking counseling. The problems reported by more than 80% of PD patients in one study included reduced manual skills, reduced gestures and body language, slowness, reduced motivation and drive, anxiety about helplessness, increase of symptoms under minimal stress, disabling insecurity in social interactions, and fewer activities with partners and family (Ellgring et al. 1993).

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Sexual Disorders In a study by Brown et al. (1990) of PD patients, premature ejaculation and impotence occurred in 13 (65%) and 12 (60%), respectively, of the 20 male patients assessed; among the 11 female patients, 4 (36%) had anorgasmia and 3 (27%) had vaginismus. Nearly all of the patients in this study were taking antiparkinsonian medications. High levels of sexual dysfunction were documented in the spouses of PD patients as well as in the patients themselves, but couples in which the husband was the patient were the most severely affected. A diversity of biopsychosocial factors were important in explaining sexual dysfunction in this study. In another study, however, Lipe et al. (1990) found no difference in sexual desire, arousal, orgasm, and satisfaction between male patients with PD and male patients with arthritis. Sexual dysfunction was associated with increased age, illness severity, and depression in that study. A study of 50 patients with PD found that autonomic dysfunction was common, more common than depression, in those suffering from reduced sexual interest and functioning (Koller et al. 1990).

Medication-Induced Psychiatric Disorders Therapy with dopaminergic agents may be associated with formed visual hallucinations, persecutory delusions, anxiety, depression, mania, hypersexuality, and sleep disturbance; anticholinergic therapy may produce delirium with or without psychotic features (Cummings 1991; Factor et al. 1995; Koller and Megaffin 1994; Saint-Cyr et al. 1993) (Table 2–2). Psychosis is rare in untreated PD and usually indicates an adverse treatment response. Visual hallucinations are the most common neuropsychiatric side effect of PD treatment, occurring in approximately 30% of patients (Cummings 1991; Factor et al. 1995). Dopaminergic agents typically produce silent, nonthreatening visual hallucinations of fully formed human or animal figures in a clear sensorium, although frightening visions, altered sensoria, and hallucinations in other sensory modalities can be experienced. Hallucinations frequently occur at night and are more common in patients with sleep disturbance (Koller and Megaffin 1994). Predicting which patients are at risk for hallucinatory experiences is difficult;

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Table 2–2.

Psychiatric side effects of antiparkinson medications Bromocriptine

Pergolide

Anticholinergics

Amantadine

Selegiline

+++ +++ + + ++ ++ ++

++++ ++ ++ + + + +

+++ ++ ++ + + + +

++ ++ ++++ − − + −

+ ++ + − − + +

+ + + − + + +

++

−

+

+

−

−

Note. + = weak association; ++ = moderate association; +++ = strong association; − = no association. Source. Cummings 1991; Factor 1995; Koller and Megaffin 1994; Saint-Cyr et al. 1993.

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Hallucinations Delusions Confusional state Depression Mania Anxiety Increased libido Sleep disturbance

L-dopa

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the only factors that have been identified are increasing age, premorbid history of psychiatric illness, more marked cognitive impairment, and longer duration of concomitant treatment with anticholinergic agents and amantadine (Glantz et al. 1987). Hallucinatory symptoms caused primarily by anticholinergic toxicity are usually associated with delirium and tend to be threatening, less well formed, and accompanied by hallucinations in other sensory modalities (Goetz et al. 1982). Delusions occur in approximately 10% of patients treated with dopaminergic agents but can be caused by any of the anti-PD medications (Cummings 1992). L-dopa/carbidopa (Sinemet) generally does not produce delusions before 2 years of continuous therapy (Klawans 1978), and delusions are more common among patients treated with higher doses of drugs. Other risk factors include older age and preexisting dementia (Fischer et al. 1990). Delusions often involve well-formed, complex belief systems and are frequently preceded by hallucinations. Although delusions are usually persecutory or paranoid in nature, misidentification syndromes and delusions of grandeur have also been reported (Cummings 1992). Confusional states, or “delirium,” with fluctuating arousal, impaired attention, and incoherent verbal output occur in 5%–25% of patients treated with anti-PD agents. Overt dementia and anticholinergic therapy are major risk factors and, when combined, may cause delirium in 93% of PD patients (de Smet et al. 1982). L-dopa may also produce confusion, but the higher-potency ergot derivatives such as bromocriptine (Parlodel) and pergolide (Permax) appear to cause it more frequently (Cummings 1992). Selegiline (Eldepryl) rarely produces psychiatric symptoms when used alone but can cause confusional states and/or psychosis when added to L-dopa. Depression is no more frequent in treated than in untreated PD patients when measured prospectively (Celesia and Wanamaker 1972), and it should be regarded as a comorbid condition rather than a drug-induced side effect (Factor et al. 1995). Mania, hypomania, and euphoria do not occur in untreated PD but are infrequent side effects of dopaminergic agents and, occasionally, selegiline. Patients with a history of bipolar disorder frequently experience an acute exacerbation when treated with these medications (Goodwin 1971).

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Symptoms may range from mild euphoria to an intense manic episode and typically subside when the offending agent is reduced or removed. Anxiety is frequent in untreated PD patients, and L-dopa does not appear to account for the extent of anxiety symptoms in treated patients. Nevertheless, symptoms ranging from mild jitteriness to panic attacks have been reported to occur in patients without anxiety prior to treatment, and panic attacks may not necessarily correlate with general levels of anxiety during treatment (Vazquez et al. 1993). Dopaminergic agents are the most frequent anxiety-inducing agents and may directly cause or worsen anxiety. Anxiety is common during “off” periods, when blood dopamine levels are rapidly decreasing. Finally, patients with PD may experience akathisia, a symptom that should be differentiated from drug-induced anxiety. Increased libido regularly occurs in patients treated with dopaminergic agents. In a small minority of patients, hypersexuality occurs and can result in increased masturbation, extramarital affairs, and paraphilic behavior such as sadomasochism, pedophilia, voyeurism, exhibitionism, scatological letter writing, and pederastic and rape fantasies. This complication occurs in 0.9%–3.0% of patients receiving L-dopa (Goodwin 1971; Lesser et al. 1979) and is more common in men with early-onset PD. Diminished prolactin levels are associated with dopaminergic therapy and may be involved in increased libido. Sleep disturbance is more common in patients with drug-related hallucinosis, delusions, confusional states, or depression than in those without these conditions. Vivid dreams and nightmares may be associated with dopaminergic agents, as may sleep architecture disturbances, including diminished stage III and stage IV with multiple arousals and awakenings (Emser et al. 1988).

Neurological Management Dopamine Agents The principal therapeutic modalities useful in the treatment of idiopathic PD and other parkinsonian syndromes caused by structural brain changes are dopamine precursor therapy and administration

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of dopamine receptor agonists. Dopamine does not cross the blood– brain barrier, but L-dopa, the biochemical precursor of dopamine, readily enters the brain through active-transport mechanisms. Coadministration of L-dopa/carbidopa results in higher brain levels of dopamine and limits the side effects produced by peripheral L-dopa catabolism. Potential central nervous system side effects of L-dopa therapy include chorea, tics, vivid dreams and nightmares, hallucinations, delusions, and confusional states. Early responses to dopamine therapy are often dramatic, with many PD patients having nearly complete resolution of symptoms. In contrast, people with non-PD causes of parkinsonism may respond poorly or not at all. Response failure and motor fluctuations may become apparent with prolonged therapy. For this reason, L-dopa therapy should be delayed until the disability begins to interfere with daily function. Precursor therapy depends on the integrity of at least a portion of the normal neuronal population of the substantia nigra to metabolize L-dopa to dopamine and transport the product to the synaptic terminals in the striatum. When the functioning cell population is too small, precursor therapy is ineffective, and other means of stimulating striatal receptors must be found. Bromocriptine (Parlodel), an ergot derivative, is a direct dopamine receptor agonist that is used in conjunction with L-dopa and may continue to provide relief of parkinsonism after the beneficial effects of L-dopa have been exhausted. Pergolide (Permax), a semisynthetic ergoline dopamine agonist, is 10 times more potent than bromocriptine. Ergots may also be effective for non-PD causes of parkinsonism. Dopamine agonist therapy may also be used early in the course of PD in order to delay introduction of L-dopa. Two recently approved D2-specific receptor agonists, ropinirole (Requip) and pramipexole (Mirapex), have fewer side effects than the nonspecific dopamine agonists bromocriptine and pergolide. These newer agents are effective in early (Adler et al. 1997; Shannon et al. 1997) and late PD, and they may be more effective than bromocriptine (Guttman 1997; Korczyn et al. 1998). Pramipexole may also have antidepressant properties (Maj et al. 1997).

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Monoamine Oxidase Type B Inhibitors Selegiline (L-deprenyl, Eldepryl) selectively inhibits monoamine oxidase type B (MAO-B) at low doses and may slow deterioration, reduce the amount of L-dopa required for symptomatic relief, and delay the need for L-dopa by 6–9 months (Olanow et al. 1995; Parkinson’s Study Group 1993). Selegiline’s effect may be due to catecholamine-mediated symptomatic relief, or it could confer neuroprotection through its antioxidant effect. It is recommended that all newly diagnosed PD patients be treated with 5 mg of selegiline twice daily (morning and noon) and that L-dopa be added when symptoms become more pronounced. The major side effect of selegiline is insomnia; for this reason, it is often given in the morning (5 mg) and at noon (5 mg). The 10-mg daily dose should not be exceeded, because selegiline loses its selectivity for MAO-B at higher doses.

Catechol-O-Methyltransferase Inhibitor Tolcapone (Tasmar) is a recently approved catechol-O-methyltransferase (COMT)–inhibiting medication for the treatment of PD that works by slowing the peripheral metabolism of L-dopa and reducing the wide fluctuations in blood level. The “wearing-off” phenomenon, which occurs in 50% of patients after 2–5 years of L-dopa therapy, is reduced by this medication. Also, less L-dopa is needed, and there is significant improvement in motor function and performance of activities of daily living (Waters et al. 1997).

Anticholinergic Agents and Amantadine Anticholinergic agents such as trihexyphenidyl (Artane) and benztropine (Cogentin) improve tremor, rigidity, and L-dopa–induced dystonia but have little effect on akinesia. They must be started at low doses and increased slowly to minimize dry mouth, urinary hesitancy, constipation, blurred vision, memory loss, confusion, disorientation, insomnia, and sedation. Amantadine has both dopaminergic and anticholinergic properties and can improve all symptoms of PD, although the effect may decline in 1–3 months.

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Anticholinergics and amantadine may be useful as adjunctive agents in the treatment of PD, but they are rarely sufficiently efficacious to be used alone (Gancher 1992).

Surgical Therapy Four surgical procedures may play increasingly larger roles in the therapy of PD. Pallidotomy (ventroposterolateral globus pallidus lesion) improves most PD symptoms, including bradykinesia, tremor, and L-dopa–induced dyskinesias. Thalamotomy (ventrolateral thalamic nucleus lesion) is effective primarily in reducing tremor. Both pallidotomy and thalamotomy carry a risk of damage to descending motor fibers, which currently restricts their bilateral use (Burchiel 1995). Electrical stimulation of the thalamus is most effective for tremor (Benabid et al. 1996); stimulation of the pallidum (Siegfried and Lippitz 1994) or of the subthalamic nucleus (Pollak et al. 1996) is effective for bradykinesia and rigidity. Neural grafts of fetal mesencephalic dopamine-producing cells into denervated striatum has proven successful in reducing akinesia but currently is still an experimental treatment (Barinaga 1995; Olanow et al. 1994).

Psychiatric Management The American Parkinson’s Disease Association (APDA; 60 Bay Street, Suite 401, Staten Island, NY 10301, 718-981-8001, 1-800-223-2732) has 47 Information and Referral Centers, 80 chapters, and more than 350 support groups located throughout the United States. They can help with referrals to neurologists, therapists, social workers, lawyers, and financial consultants, and many of the local groups offer patient education and peer support.

Treatment of Dementia Cognitive symptoms in PD may be partially improved early in the course of the illness by L-dopa therapy or by treatment of depression. L-dopa produces nonspecific arousal and may improve the performance of cognitive tasks that require effort. Depression in PD is associated with memory, visuospatial (Troster et al. 1995a), and executive function impairment (Cummings 1992). Later in the course of PD,

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Lewy body dementia or Alzheimer’s disease may emerge, and new treatments for the cognitive symptoms in Alzheimer’s disease— including cholinesterase inhibitors (tacrine and donepezil), antiinflammatory agents, estrogen replacement therapy, and vitamin E—may be effective. Patients with Lewy body dementia have been shown to have lower neocortical choline acetyltransferase levels than patients with Alzheimer’s disease, and these patients may respond particularly well to cholinomimetic therapy (Perry et al. 1994). Tacrine (Cognex) requires a liver function test every other week while doses are increasing. The starting dose is 10 mg qid for 6 weeks with an increase of 40 mg/day every 6 weeks up to a maximum dose of 160 mg/day. Donepezil (Aricept) does not require monitoring of liver functions. Patients may be started on 5 mg/day with an increase to 10 mg/day after 4 weeks; no further increase is required. The various cholinesterase inhibitors appear to have approximately equal efficacy, and all produce gastrointestinal side effects.

Treatment of Apathy Apathy is a common neuropsychiatric syndrome in PD. Although a variety of empirical treatment options are available, there have been no controlled trials that target apathy (Marin et al. 1995). The first step is to diagnose and treat depression or systemic illnesses such as hypothyroidism, if present. Next, if neuroleptics are in use, the dosages should be reduced or the patient should be switched to clozapine (Clozaril) or olanzapine (Zyprexa). Apathy is theorized to result from dysfunction in the basal forebrain mesolimbic and mesocortical dopaminergic system; therefore, any medication that improves dopaminergic activity may improve apathy. If severe apathy persists after motor symptoms have resolved, it may be reasonable to cautiously increase dopaminergic agents, taking care to avoid precipitating psychotic symptoms. L-dopa, bromocriptine, pergolide, ropinirole, and pramipexole are the most potent dopaminergic agents; other agents with dopaminergic activity include methylphenidate (Ritalin), amantadine (Symmetrel), and bupropion (Wellbutrin). Methylphenidate may be used specifically for treatment of apathy and can be started at 5 mg qam. It may be increased as tolerated up to 10 mg bid (morning and noon).

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Treatment of Psychosis Psychotic symptoms such as visual hallucinations and persecutory delusions in a patient with PD may be manifestations of delirium caused by anticholinergic agents, overmedication with dopaminergic agents, or underlying systemic disease such as urinary tract or respiratory system infection. Discontinuation of the offending agent or treatment of the underlying disease process usually resolves the psychotic symptoms, although they may persist for days or weeks. Psychotic symptoms are rare in the course of untreated PD; when psychotic symptoms occur prior to initiation of treatment, they may suggest the existence of Lewy body dementia. If a dementia is present, the patient should receive a trial of a cholinesterase inhibitor. Psychotic symptoms are commonly produced in a clear sensorium by dopaminergic agents, and these medications should be minimized as a first step in treating psychosis in PD. Traditional neuroleptics such as haloperidol (Haldol) and newer agents such as risperidone (Risperdal) frequently fail to ameliorate psychosis without producing significant extrapyramidal symptoms, but the atypical antipsychotics clozapine (Clozaril) and olanzapine (Zyprexa) have been shown to be both safe and effective in treating PD. These agents have relatively little impact on the nigrostriatal portion of the dopaminergic system, which may explain their lack of extrapyramidal effects. Hypotension is a concern, and clozapine should be started at 6.25 mg/day and increased as tolerated up to the lowest effective dose, usually under 100 mg/day in PD. Also, the risk of agranulocytosis increases with age, and patients must have weekly hematological monitoring. Olanzapine does not have these side effects.

Treatment of Depressive Mood Disorders Anti-PD medications have variable effects on depressive symptoms. Occasionally, an increase in L-dopa dosage or addition of an agonist may alleviate mild depressive symptoms. Amantadine and anticholinergics may also have a mild stimulatory effect. For moderate or severe depressions, tricyclic antidepressants or bupropion may be used. In the early stages of PD, imipramine (Tofranil) and desipra-

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mine (Norpramin) have been shown to improve rigidity and tremor, possibly as a result of these agents’ anticholinergic effects (Laitinen 1969; Strang 1965); in one study, 10 of 20 patients on bupropion experienced at least 30% improvement in their parkinsonism, possibly due to a dopaminergic effect (Goetz et al. 1984). Selegiline is not approved for treatment of depression in the United States, and the 10-mg dose does not appear to have an antidepressant effect in PD (Factor et al. 1995; Silver and Yudofsky 1992). Antidepressant medications have been used effectively in the treatment of depression in PD and should be tried after adjustments in anti-PD agents have failed or when the depression includes symptoms such as anhedonia, guilt, and suicidal ideation. Nortriptyline (Pamelor) and desipramine are relatively safe and effective, provided they are initiated at low doses (10–20 mg/day) to avoid potentiating the hypotensive effect of L-dopa. These agents can be titrated up to the usual therapeutic dosages over 1–2 weeks, although adequate blood levels (nortriptyline at 50–150 ng/mL, desipramine at >125 ng/mL; drawn 10–14 hours after last dose) can frequently be achieved in the elderly with doses as low as 50 mg/day. Nortriptyline and desipramine can also be effective for comorbid anxiety, especially panic disorder. Bupropion can be started at 75–100 mg/day and increased up to 100 mg tid. Other antidepressants have not been well studied in PD patients. Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and sertraline (Zoloft), are free of hypotensive and anticholinergic effects, and serotonin systems theoretically may play a significant role in the pathophysiology of depression in PD. Paroxetine (Paxil), another SSRI with no hypotensive effect, might also be a good choice because of its antianxiety and mild anticholinergic effects. Although fluoxetine has been reported to cause extrapyramidal side effects in a few patients, a recent series of 13 patients experienced no worsening of their parkinsonism with this agent (Montastruc et al. 1995). In elderly patients, fluoxetine, sertraline, and paroxetine should be started at 10 mg, 25 mg, and 10 mg, respectively, and the dose may be doubled after 1 week. Selegiline must be discontinued at least 14 days prior to initiation of antidepressant therapy, because adverse reactions can occur at the 10-mg dose. Antidepressant medications that are nonselective

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inhibitors of MAO are contraindicated because of the potential for an adverse interaction with L-dopa. Lithium (Eskalith) can be used to augment antidepressant therapy and may potentiate both the effects and the side effects of L-dopa. In the elderly, lithium should be started at 150 mg/day and gradually titrated to a therapeutic dose because it has been reported to occasionally produce extrapyramidal symptoms (Cummings 1992; Koller and Megaffin 1994; Silver and Yudofsky 1992). Electroconvulsive therapy (ECT) remains the safest and most effective treatment for depression in all age groups. About half of PD patients treated with ECT will experience a significant but usually temporary reduction in their motor symptoms independently of the effect on their psychiatric symptoms (Faber and Trimble 1991). Individual and group psychotherapy can be very helpful and should address at least six goals. First, patients should be educated about the course of the illness in order to ameliorate the effect of unexpected deteriorations. Second, strategies must be developed to reduce disability in the face of worsening motor symptoms. Third, social support should be maximized. Fourth, patients should be helped to develop healthy strategies for coping with stress. Fifth, they may need to work through feelings of worthlessness and be helped to appreciate that the illness is not their fault. Finally, caretakers should always be adequately evaluated for psychiatric morbidity, as PD patients usually become emotionally and physically dependent on their caretakers.

Treatment of Anxiety Disorders Anxiety in the elderly may be caused by infections of the urinary or respiratory systems or by emphysema, heart disease, thyroid disorder, arthritic pain, constipation, or other systemic disorders. Medications that frequently produce anxiety include anti-PD agents, thyroid replacement, steroids, and sympathomimetics such as pseudoephedrine and beta-agonists. Withdrawal from alcohol or sedatives and side effects from neuroleptics may also produce anxiety. Underlying systemic conditions should be diagnosed and treated first and the doses of anti-PD agents then adjusted. If anxiety symptoms persist, pharmacological and psychological

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approaches should be employed. Most antidepressants are effective for panic disorder and are a logical choice because of the frequent comorbidity of panic disorder with depression, but benzodiazepines may be required to control the initial stimulatory effects that antidepressants can produce. Benzodiazepines must be administered with caution, because they frequently cause impairments in gait, balance, and cognition that may lead to falls in the elderly. Also, rebound anxiety can occur with short-acting agents such as lorazepam (Ativan) and may require tid or qid dosing. Clonazepam (Klonopin) at 0.5 mg bid is usually adequate to control anxiety in the elderly and has a gradual onset of action with a steady plasma level over 24 hours; however, strict vigilance for drug accumulation and attendant side effects is critical in the elderly. Although buspirone (BuSpar) at 5 mg tid may be helpful for some patients, it requires several weeks to become effective. Buspirone should be given in three divided doses daily; the dose may be increased up to 40 mg/day as tolerated. More data regarding the effectiveness of buspirone is needed, however, because the drug was found to be without effect on anxiety in a small sample of PD patients (Ludwig et al. 1986) The main goal of psychological intervention is to help patients cope with stressful social situations. This goal can be achieved through either individual or group therapy, including relaxation techniques, cognitive restructuring, situational behavioral analysis, and training in social skills, with interventions specifically adapted to the disease (Ellgring et al. 1993).

Treatment of Sexual Disorders Brown et al. (1990) concluded that there is no simple approach to managing sexual disorders in patients with PD. As detailed above, a variety of factors have been implicated in these disorders, including illness severity, autonomic dysfunction, depression, and treatmentrelated side effects. A range of disease, psychological, social, and marital variables were evident in the study of Brown et al. (1990), and the authors advocated a multimodal therapeutic approach. Additional treatment data in PD are lacking. Absent these data, sexual dysfunction may be managed in the same manner as in primary sexual disorders.

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Treatment of Medication-Induced Psychiatric Disorders Confusional states are best managed by treating underlying infections and minimizing all medications, especially anticholinergic agents. Mania or hypomania caused by dopaminergic therapy typically subsides when drug dosage is reduced; some patients may require management on small doses of L-dopa/carbidopa alone without other agents to minimize manic behavior. Lithium administration benefits some patients but not others (Van Woert et al. 1971). Hypersexuality caused by dopaminergic therapy usually decreases with dose reduction (Uitti et al. 1989). If dose reduction is not possible, low-potency neuroleptics or antitestosterone agents may be tried (Factor et al. 1995), although there are no guidelines for these treatments. Sleep disturbances require assessment for a confusional state, reduction of dopaminergic therapy, or treatment for depression. Persistent sleep disturbance may be treated with the triazolopyridine antidepressant trazodone (Desyrel) (50 mg qhs), with a short-acting benzodiazepine such as temazepam (Restoril), or with zolpidem (Ambien).

Treatment of Psychiatric Consequences of Surgical Therapy Subcortical surgical lesions may produce psychiatric symptoms, but there are few reports in the literature of postoperative psychiatric morbidity. Masterman and colleagues at UCLA (personal communication) examined 20 patients at 3-month follow-up postpallidotomy and found essentially no change in depression, anxiety, psychosis, or other psychiatric symptoms. In contrast, Rossitch et al. (1988) observed cognitive and speech changes in patients who had undergone thalamotomy. Similar problems may be encountered with chronic electrical stimulation of subcortical structures but can be reduced with adjustment of frequency intensity (Benabid et al. 1996). Human fetal mesencephalic tissue transplantation appears to have few long-term psychiatric sequelae (Price et al. 1995), although psychotic features are common in the early postoperative period. These procedures are currently receiving intense investigation, and their impact on psychiatric morbidity will be better understood as they are used more widely.

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Summary PD is a progressive and disabling illness of the brain that affects motor, cognitive, and emotional function. Degenerative changes occur in subcortical structures where parallel circuits that modulate these three brain activities are in close proximity. Dopaminergic agents may improve cognitive speed, and cholinergic therapy is effective for both Alzheimer’s disease and Lewy body dementia. Depression, anxiety disorders, and apathy are frequent in PD. These symptoms are independent of anti-PD treatment and appear to respond to pharmacotherapy and psychotherapy; however, very few treatment studies have been done. Psychosis is generally associated with dopaminergic or anticholinergic therapy but may herald the onset of dementia. If psychosis persists after dosage adjustment, it is very difficult to treat but may respond to low doses of clozapine or olanzapine. PD affects its victims over the course of many years and causes considerable psychiatric morbidity; therefore, psychiatric evaluation and treatment are critical elements to the proper care of patients with this relentless illness.

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Troster AI, Paolo AM, Lyons KE, et al: The influence of depression on cognition in Parkinson’s disease: a pattern of impairment distinguishable from Alzheimer’s disease. Neurology 45:672–676, 1995a Troster AI, Stalp MA, Paolo AM, et al: Neuropsychological impairment in Parkinson’s disease with and without depression. Arch Neurol 52: 1164–1169, 1995b Uitti RJ, Tanner CM, Rajput AH, et al: Hypersexuality with antiparkinsonian therapy. Clin Neuropharmacol 12:375–383, 1989 Van Woert MH, Ambani LM, Weintraub MI: Manic behavior and levodopa (letter). N Engl J Med 285:1326, 1971 Vazquez A, Jimenez-Jimenez FJ, Garcia-Ruiz P, et al: “Panic attacks” in Parkinson’s disease: a long-term complication of levodopa therapy. Acta Neurol Scand 87:14–18, 1993 Waters CH, Kurth M, Bailey P, et al: Tolcapone in stable Parkinson’s disease: efficacy and safety of long-term treatment. The Tolcapone Stable Study Group. Neurology 49:665–671, 1997

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Huntington’s Disease Neal G. Ranen, M.D.

H

untington’s disease (HD) is an autosomal dominant inherited degenerative neuropsychiatric disorder caused by an expanded trinucleotide repeat (CAG) in a gene (IT15) on chromosome 4. The clinical features of HD can be thought of as a triad of motor, cognitive, and noncognitive psychiatric disturbances (McHugh and Folstein 1975). Although this triad is always present, there is considerable variability of clinical features among different patients. There is no currently available treatment that can halt or reverse the inexorable progression of HD. Furthermore, much of what is recommended with regard to the symptomatic treatment of HD has been arrived at by consensus of experts in the field rather than by controlled trials (Ranen et al. 1993). This is especially true for treatment of the psychiatric aspects of the disease. Nonetheless, rational treatment of specific psychiatric and motor symptoms can reduce unnecessary morbidity, which in turn can improve the quality of life of patients with HD.

Prevalence The prevalence of HD has been estimated to be in the range of 4.1–7.5 per 100,000 (Folstein et al. 1987). HD is seen throughout the world but is rare in Finland and Japan (Harper 1992). There are a few isolated populations of Western European origin that have a much higher prevalence of the disease, such as the much-studied HD population of Lake Maracaibo, Vene71

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zuela (Gusella et al. 1983; Penney et al. 1990; Wexler et al. 1987), where the prevalence of HD is estimated at 700 per 100,000.

Clinical Recognition and Neurological Presentation Clinical Course Symptoms begin insidiously (Penney et al. 1990), with onset typically between the ages of 35 and 50 years, but onset may occur anytime from childhood to old age (Folstein et al. 1987). The differential diagnosis of chorea is presented in Table 3–1. Adult-onset HD can be roughly divided into three stages. Early in the disease, manifestations include subtle changes in coordination, perhaps some minor involuntary movements, difficulty thinking through problems, and, often, a depressed or irritable mood. In the middle stage, chorea usually becomes prominent, and difficulty with voluntary motor activities will be more evident, with worsening dysarthria and dysphagia. As cognitive deficits increase, the paTable 3–1.

Differential diagnosis of chorea

Huntington’s disease Dentatorubro-pallidoluysian atrophy (DRPLA) Tardive dyskinesia Side effects of medications (e.g., L-dopa–induced dyskinesia) Neuroacanthocytosis Sydenham’s chorea Spinocerebellar ataxias Benign familial chorea Wilson’s disease (hepatolenticular degeneration) Paroxysmal choreoathetosis Senile chorea (diagnosis of exclusion) Stroke Thyrotoxicosis Closed head injury Infectious disease (AIDS/toxoplasmosis) Note.

AIDS = acquired immunodeficiency syndrome.

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tient will be unable to hold a job or carry out most household responsibilities. Patients with late-stage disease may have severe chorea but are more often rigid and bradykinetic. They are largely nonverbal and bedridden, with a more global dementia, although they retain a significant degree of comprehension (Ranen et al. 1993). Psychiatric disorders may appear at any time during the course of the disease, even years before motor symptoms develop (Folstein et al. 1983). Death occurs an average of about 15 years after symptoms start, although some patients die early from falls or suicide, and others survive for 30–40 years, particularly if a feeding tube is placed (Folstein 1989).

The Movement Disorder The movement disorder in HD has two clinical components: a disturbance of involuntary movement and a disturbance of voluntary movement. In addition to chorea (or choreoathetosis), which consists of irregular jerky or writhing movements, other disturbances of involuntary movement consist of myoclonus and seizures. Myoclonus is more common in juvenile-onset HD and in the later stages of adult-onset HD, although it can be seen occasionally in less severely affected adult-onset patients. Epilepsy is also seen most commonly in juvenile-onset HD, but it is occasionally seen in adults with advanced disease. Disturbances of voluntary movement include abnormal eye movements (abnormal saccades and pursuit, among others); uncoordinated, arrhythmic, and slow fine motor movements; and dysphagia, dysarthria, bradykinesia, clumsiness, rigidity, and gait disturbance. In contrast to chorea, which often plateaus and even wanes in the later stages of the disease, disturbances in voluntary movement progress more steadily (Folstein 1989; Penney et al. 1990). The disturbance of voluntary movement is more highly correlated with functional disability than is the chorea (Brandt et al. 1984). The Quantified Neurologic Examination (QNE; Folstein et al. 1983) and the Unified Huntington’s Disease Rating Scale (Huntington Study Group 1996) have been developed as standardized measures of movement disorder in HD.

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Early patient complaints attributable to the motor disorder include clumsiness, difficulty with balance, and jerky movements or tremor. Patients may also note that they are dropping things, have difficulty typing, have noticed a change in their handwriting, have been tripping or stumbling more often, or have become aware that they are applying uneven pressure to the gas pedal in a car. In late-stage HD, patients are akinetic and largely nonverbal, with severe rigidity and joint contractures. At this point, they may have no involuntary movements except for occasional whole-body movements, resembling myoclonic jerks, when they are disturbed. Difficulties with swallowing commonly lead to death in HD, either directly from suffocation or aspiration or indirectly from starvation. HD that begins in childhood (i.e., juvenile-onset HD) often presents with a somewhat different set of signs and symptoms; for example, bradykinesia, rigidity, and dystonia (Van Dijk et al. 1986). Chorea may be completely absent. Involuntary movements may take the form of tremors, and seizures and myoclonus may occur. This rigid, akinetic form is termed the Westphal variant of HD.

Pathological Features Pathology The pathology of HD is restricted to the central nervous system, with selective neuronal vulnerability. Although the brains of patients with HD show some generalized atrophy, there is a particularly marked degeneration within the striatum (caudate and putamen) and in the deep layers of the cerebral cortex. Within the striatum, there is highly selective neuronal loss, with near-complete loss of medium spiny neurons and preservation of several classes of large interneurons. These striatal medium spiny neurons, which are GABAergic, project to the globus pallidus and receive glutamatergic inputs from the cerebral cortex and dopaminergic inputs from the substantia nigra (Albin et al. 1989). Severity of Huntington’s disease is rated with the Vonsattel score, which ranges from 0 to 4, with 4 representing the most severe degree of atrophy as determined by gross and microscopic examination (Vonsattel et al. 1985).

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Much of the clinical presentation of HD can be appreciated in terms of the multiple frontal–subcortical circuits that unite specific regions of the frontal cortex with the basal ganglia and the thalamus and mediate motor activity, eye movements, and behavior (Alexander et al. 1986; Mega and Cummings 1994). Chorea can be appreciated as arising from a disturbance of the motor circuit, which has as its target the supplementary motor area; abnormal eye movements from a disturbance of the oculomotor circuit, which has as its target the frontal eye fields; dementia from a disturbance of the dorsolateral prefrontal cortex circuit, which is important in executive cognitive functions; irritability, disinhibition, and perhaps mania from a disturbance of the lateral orbitofrontal cortex circuit, which is tied to aspects of personality; and apathy from a disturbance of the anterior cingulate circuit, which is important in motivation.

Genetics and Theories of Pathogenesis HD demonstrates autosomal dominant transmission; homozygotes (i.e., individuals who have two copies of the mutated gene—an uncommon occurrence in HD) have no more severe disease than do heterozygotes (i.e., those who have one copy of the mutated gene) (Wexler et al. 1987). In 1983, the gene for HD was localized to the short arm of chromosome 4 (Gusella et al. 1983); 10 years later, the gene was isolated (Huntington’s Disease Collaborative Research Group 1993). The mutation causing HD is an expanded repeating sequence of three nucleotide base pairs, CAG, known as a trinucleotide or triplet repeat. Repeats in the range of 10–29 are normal, repeats of 30–36 are intermediate, and repeats of 37 and above are causative of HD (Duyao et al. 1993; Kremer et al. 1994). An expanded CAG repeat on IT15 is 100% specific and 98.8% sensitive for HD (Kremer et al. 1994). Some cases with signs and symptoms similar to HD but without the IT15 CAG expansion are thought to arise from as-yet-undefined genes (Andrew et al. 1994). Other such cases have been attributed to hysterical symptomatology (e.g., conversion reactions) (Ranen et al. 1997). The length of the trinucleotide repeat is highly correlated with age at onset of the disease (Duyao et al. 1993). Most of the correlation is accounted for by very long repeats. However, for fewer than 55 re-

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peats, which are most common, repeat length is a poor predictor of age at onset. Therefore, the utility of this correlation for individuals seeking presymptomatic genetic testing is limited. As with other triplet-repeat disorders, HD exhibits anticipation. Anticipation is the earlier onset of disease in successive generations within a pedigree. In HD, anticipation is a phenomenon of paternal transmission (Ranen et al. 1995; Ridley et al. 1988) and is associated with further expansion of the trinucleotide repeat when passed from father to child (Ranen et al. 1995). Study results vary as to whether the length of the repeat is associated with rate of progression, with some studies finding more rapid progression with longer repeats (Brandt et al. 1996) and others finding no such relationship (Kieburtz et al. 1994). The process by which the expanded trinucleotide repeat causes HD is unknown. It is known that the expanded CAG repeat is translated into the protein, named huntingtin, as a glutamine repeat (CAG codes for glutamine). The function of huntingtin is not known. Evidence to date suggests that the mutation results in a gain, rather than a loss, of function of the protein. This gain of function may be due to intensified or novel interactions with other proteins (Li et al. 1995). Basal ganglia pathophysiology in HD is depicted in Figure 1–2 in Chapter 1.

Neuroimaging The most striking finding from anatomic neuroimaging (computed tomography [CT] and magnetic resonance imaging [MRI]) of HD patients is striatal degeneration. However, this finding is often not seen early in the disease. With disease progression, ventricular dilatation (“boxcarring”) suggestive of caudate atrophy is seen on MRI. Using volumetric MRI measurements, Aylward et al. (1994) have demonstrated reduced basal ganglia size in presymptomatic, genepositive individuals. Mayberg et al. (1992) found that depression in HD is associated with frontal hypometabolism on positron-emission tomography (PET) scan.

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Laboratory Investigation and Predictive Testing Results of controlled screening programs have been encouraging, with most individuals stating that they were relieved to know the results even if they were adverse (Brandt et al. 1989; Wiggins et al. 1992). A sense of relief regardless of whether the results revealed the presence or absence of the mutation may be due to reduced uncertainty. There have been a few case reports of dramatic adverse consequences of both positive and negative results (Wexler 1992). The International Huntington Association (IHA) and World Federation of Neurology (WFN) Research Group on Huntington’s Chorea have jointly developed guidelines for predictive testing (IHA–WFA Research Group on Huntington’s Chorea 1994). The guidelines include the concepts of full informed consent, presymptomatic counseling, face-to-face disclosure of results, and posttest counseling. A blood sample from the subject is all that is needed to test for the HD gene. The cost is usually about $400, and the test is available at several commercial and university laboratories. Predictive testing should be carried out at an approved center where patient and family anxiety can be best addressed, and where procedures are in place that follow the IHA recommendations. Family members’ questions about their genetic risk should be answered directly—a child of an affected parent has a 50% chance of inheriting the gene, and a grandchild has a 25% chance. It is helpful to express cautious optimism about the possibility that research developments will lead to specific treatments in the future. Despite the presence of guidelines, ethical questions will still arise. For example, should an individual whose grandparent was affected be tested if the parent, who is as yet unaffected, does not want to know his or her gene status? If that individual tests positive for the mutated gene, the parent will probably know that he or she has the mutated gene. A positive gene test does not indicate disease onset, only the likelihood that the disease will occur. Onset of disease remains a clinical diagnosis.

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Psychiatric Manifestations Although the cognitive disorder is well known, in his original manuscript in 1872 George Huntington noted that “the tendency to insanity, and sometimes that form of insanity which leads to suicide, is marked.” The most common noncognitive psychiatric disturbances in HD are mood disorders (depressive and bipolar disorders), irritability, and apathy (Folstein et al. 1987). Psychotic symptoms occur less frequently. Mood disorders have a variety of behavioral manifestations, including aggressive outbursts, impulsiveness, social withdrawal, and suicidal behavior.

Cognitive Impairment and Dementia The cognitive disorder in HD has less-striking aphasia and agnosia than in “cortical dementias” (e.g., Alzheimer’s disease), consistent with the features of “subcortical dementia” (McHugh and Folstein 1975). This is coded in DSM-IV (American Psychiatric Association 1994) as dementia due to HD. Initial cognitive changes involve loss of cognitive speed and flexibility (Mayeux et al. 1986). Patients may have trouble changing from one task to another or keeping track of serial tasks, and thus may need more time to think through a problem. Such cognitive inefficiency may result in patients having difficulty maintaining an accurate checkbook or accounts, trouble in keeping up with assigned work or school load, diminished concentration, and decreased quality of work. Such early HD patients usually perform within the normal range on IQ tests and may be impaired only on neuropsychological testing that requires speed, concentration, mental flexibility, and new verbal learning (Brandt 1994). On the Mini-Mental State Exam (MMSE; Folstein et al. 1975), the Serial Sevens Task (serially subtracting 7, starting from 100) is typically the first task affected (Brandt et al. 1988). Compared with Alzheimer’s disease patients, patients with HD appear to have a disturbance of retrieval rather than of storage of memories, and therefore they are more apt to recognize words from a list they were asked to remember or to respond to cues to help them remember (Brandt et al. 1992; Butters et al. 1986). Cognitive losses accumulate progressively. Deficits in memory,

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visuospatial abilities, and judgment appear. Further along in the course, the dementia becomes more global. Advanced patients become nonverbal, and their cognitive state is more difficult to assess. The patient who presents with an unexpected rapid deterioration of cognition should be evaluated for causes of delirium. In HD, common causes of delirium include alcohol use, illicit substance abuse, dehydration, medications (especially those with anticholinergic effects), subdural hematoma, and infections. Patients taking lithium who become dehydrated may become delirious on dosages that were previously appropriate.

Irritability and Aggressiveness Severe irritability has been found to be present in about one-third of patients with HD (Folstein et al. 1987). In terms of DSM-IV, irritability can be coded as a personality change due to a general medical condition. Alternatively, episodic aggressive behavior can be coded as intermittent explosive disorder. In contrast to the more diffuse catastrophic reactions seen in Alzheimer’s disease, irritability in HD tends to be more specifically directed and to be associated with irritable traits premorbidly (Burns et al. 1990). Violent behavior—including assault, arson, and homicide attempts—in HD patients has been reported in the literature (Dewhurst et al. 1970; Rosenbaum 1941). Baxter et al. (1992) found that “anger/hostility” was higher in subjects at high risk for HD as determined by genetic markers and PET scans. Irritability can take different forms. One form is an overall increase in the patient’s baseline level of irritability punctuated by episodes of explosiveness. Irritable responses become exaggerated in intensity and duration. Patients develop a “short fuse” and are unable to tolerate a high degree of frustration. In another form, patients are not necessarily irritable in general, but they become agitated when they are unable to have their requests met immediately, no matter how inappropriate. These patients often perseverate relentlessly on a single desire or idea and become progressively more irritable when it is not indulged. Patients often will not report irritability in the clinic and when confronted will deny that they are irritable. Furthermore, spouses may be reluctant to report irritability in front of the patient out of fear. For this reason, informants should be interviewed separately.

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Apathy Patients can develop apathy at any time during the course of illness. Once present, it tends to persist or worsen. Performance at work or school becomes sluggish and can result in disciplinary actions. Like irritability, apathy can be thought of as a DSM-IV personality change due to a general medical condition. Apathy may coexist with irritability. Patients can sit around with little motivation to do anything except watch television but then become angry when someone tries to change the channel or asks them to take a bath or eat. Apathy can be a source of conflict when caregivers know that the patient is physically capable of activities but “won’t” do them. Consequently, the patient’s apathy may be inappropriately labeled as willful “laziness” rather than being seen as a symptom of a disease. The most important differential diagnosis for apathy is depression, especially in patients with alexithymia. Even though they appear to be experiencing intense emotional pain, alexithymic patients are unable to identify their emotional state and therefore do not complain that they are depressed. The apathetic patient should be asked not only about mood but also about other features of depression.

Psychosis Schizophrenia occurs in about 4% of patients with HD (Folstein et al. 1987). Patients presenting with hallucinations and delusions usually have coexisting depression, even if the delusions seem bizarre and mood incongruent. Patients who are delirious may also be hallucinating or delusional (see “Cognitive Impairment and Dementia” subsection above).

Mood Disorders Mood disorder is found in about 40% of patients with HD (Folstein et al. 1987). Although most of these patients suffer from major depression, about one-quarter of them (10% of HD patients overall) have bipolar disorder (manic-depressive illness). Depression, when present, frequently begins prior to the onset of the movement disorder (Folstein et al. 1987).

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As with non-HD patients, depressed mood in HD patients can sometimes develop as an understandable reaction to life events such as diagnosis of HD, demoralization due to loss of self-esteem, loss of roles within and outside the family, loss of ability to work or care for one’s family, cessation of driving, or loss of bodily functions. However, these situational mood disturbances are usually short lived, do not meet diagnostic criteria for major affective disorder, and often respond to psychotherapeutic interventions. Patients with HD who have secondary major depression tend to have the same patterns of symptoms as those with idiopathic major depression, such as changes in self-attitude, feelings of worthlessness or guilt, self-blame, and changes in neurovegetative symptoms such as sleep and appetite. Delusions and hallucinations may occur and tend to be mood congruent (Ranen et al. 1993). The diagnosis of major depression may be difficult in patients with advanced disease. It helps to determine whether there has been a change in baseline mood, attitude, or level of functioning. For example, a patient with HD who suffers from moderate apathy and dementia may become completely withdrawn or unable to answer simple questions in the context of a superimposed depression. The suicide rate in patients with HD has been reported to be as high as 12.7% (Schoenfeld et al. 1984).

Anxiety Disorders The presentation of anxiety may range from generalized anxiety to panic disorder. There are many anxiety-provoking issues of concern to both at-risk and affected individuals; for example, engaging in “symptom searching” (i.e., constant concern over whether episodes of clumsiness are normal or actually represent disease onset). From early on in the illness, HD patients are prone to become anxious even about minor issues. Patients may worry for several days about what to wear to an event. Many HD patients are anxious about how their disease will progress, particularly if they remember their parent as having a difficult course. Panic disorder, although uncommon in HD, can be seen. The prevalence of anxiety disorders in HD has not been well studied.

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Obsessive-compulsive disorder. True obsessive-compulsive disorder (OCD) is uncommon in HD but has been reported (Cummings and Cunningham 1992). The exact prevalence is not known. The most common obsessions in HD patients are similar to those in other patients with OCD and relate to cleanliness or whether specific tasks have been carried out, such as having turned off the stove. Although not systematically studied, OCD appears to aggregate in certain HD families. More common than OCD is an obsessive preoccupation with particular ideas or requests (see “Irritability and Aggressiveness” subsection above). This latter behavior is more consistent with DSM-IV personality change due to a general medical condition than with OCD.

Sexual Disorders George Huntington, in his initial manuscript, wrote of two men with advancing disease who were “constantly making love to some young lady” and who, despite marked chorea, “never let an opportunity to flirt with a girl go past unimproved. The effect is ridiculous in the extreme” (Huntington 1872). Although most patients become uninterested in sexual contact (i.e., DSM-IV hypoactive sexual desire disorder due to a general medical condition) and male patients usually become impotent (i.e., male erectile dysfunction disorder due to a general medical condition), hypersexuality and paraphilias have been described by many investigators (Bolt 1970; Dewhurst et al. 1970; Watt and Seller 1993). Men may become aggressive toward their partners if their sexual demands are not met. The prevalence of sexual disorders in HD has not been well studied.

Neurological Management Treatment of Underlying Disease Progression Treatments aimed at retarding the underlying progression of HD have been largely unsuccessful in controlled clinical trials. Medications tested have included baclofen (Shoulson et al. 1989), an agent that attenuates glutamate neurotransmission, in part by inhibiting glutamate release, and idebenone (Ranen et al. 1996a), a benzo-

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quinone antioxidant. d-alpha-Tocopherol (vitamin E) at 3,000 IU/day demonstrated no clear-cut benefit overall, although a post hoc analysis suggested a possible slowing of progression for early-stage HD patients (Peyser et al. 1995). Limitations of these clinical trials included small sample sizes that provided insufficient power to detect modest effects. Investigations into the utility of tissue transplantation are also under way. A protective effect of implanted encapsulated cells producing a neurotrophic factor (CNTF) in a monkey model of HD has been reported (Emerich et al. 1997).

Treatment of the Movement Disorder Neuroleptic medications such as haloperidol and fluphenazine are often used to treat chorea. However, these medications may exacerbate the disturbance of voluntary movement. Neuroleptics may contribute to increased morbidity by making patients more rigid, sedated, and apathetic. Therefore, nonpharmacological interventions should be considered first; for example, having the patient wear wrist weights while eating, thereby decreasing the amplitude of chorea. If pharmacological treatment is attempted, starting doses of neuroleptics, such as haloperidol and fluphenazine, should be low; for example, starting at 0.5–1.0 mg/day. Barr et al. (1988) found that haloperidol doses greater than 10 mg/day yielded little or no increased benefit over lower doses. Neuroleptic medication often has little or no effect on chorea in the later stages of the disease. A variety of medications have been used to manage rigidity, spasticity, and dystonia, but none with much success. An exception is botulinum toxin injections, which have been used with a fair degree of success for cervical dystonia in juvenile-onset HD.

Psychiatric Management Treatment of Cognitive Impairment and Dementia There are no specific treatments for the cognitive disorder in HD. Predictability, reduction of complexity of the environment, reduc-

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tion of the need for decision making, retirement, and providing cues can all be helpful. It is also important to reevaluate the medication regimen and stop all unnecessary medications, particularly those with sedating and/or anticholinergic properties.

Treatment of Irritability and Aggressiveness Underlying causes or triggers of the behavior should be identified if possible. Such factors include hunger, pain, inability to communicate, frustration with failing capabilities, boredom, difficult interpersonal relationships, and, in particular, minor unexpected changes in routine. Improvement in irritability can usually be seen if the patient is relieved of responsibilities, although this may be difficult to accomplish diplomatically and with preservation of the patient’s self-esteem. Often, symptoms of irritability will improve dramatically with retirement. Confrontations and ultimatums should be avoided as much as possible unless the issue is critical. Coping with an irritable patient can be difficult, and often family members will gain support from talking about these issues with other caregivers and family members. Lay organizations, such as the Huntington’s Disease Society of America (1-800-345-HDSA), coordinate local support groups. Other lay organizations include the Huntington Society of Canada (519-622-1002) and the International Huntington Association (315-733-1595). Where no Huntington’sspecific support group exists, caregivers for HD patients can still benefit from support groups for more prevalent dementing illnesses such as Alzheimer’s disease. Nonpharmacological interventions are not always effective in completely eliminating irritability, particularly in severe cases. Several medications have been used successfully. Selective serotonin reuptake inhibitors (SSRIs), particularly sertraline, have been demonstrated to be effective for irritability and severe, physically violent behavior (Ranen et al. 1996b). Prior to the use of the SSRIs, carbamazepine was the first-line agent for irritability. Both carbamazepine and divalproex sodium can be very helpful in the management of these patients. Clomipramine has been used in cases in which irritability seems to be tied to obsessions and perseveration on a particular topic. Clonazepam is occasionally effective at dosages

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ranging from 0.5 mg to 4.0 mg/day (given in divided doses) in late-stage irritable and aggressive patients. Caution must be taken not to oversedate patients, which can predispose to aspiration. Benzodiazepines, including clonazepam, may also cause paradoxical disinhibition, but this seems to be uncommon in patients with HD. Some clinicians have found low-dose neuroleptics useful, although the same precautions regarding worsening of dysphagia and gait in treating patients with neuroleptics for chorea hold true for irritability (see “Treatment of the Movement Disorder” subsection above). Therefore, when antipsychotic agents are used to manage irritability, the newer atypical agents are preferable.

Treatment of Apathy Apathy not associated with depression tends to be unresponsive to medication therapy, even psychostimulant treatment. Although HD patients have difficulty initiating activities, they are often willing to help or participate if someone else suggests a project and works along with them to sustain energy and attention. Neuroleptics can cause or contribute to apathy and should be tapered if possible.

Treatment of Psychosis Psychoses presenting early in the course of disease tend to be more difficult to treat than late-onset psychotic features. Also, anecdotally, delusions tend to respond better than hallucinations to neuroleptic therapy (Ranen et al. 1993). Clozapine, because of its reduced extrapyramidal side effects, may be especially useful in HD (Bonucelli et al. 1994; Sajatovic et al. 1990). Risperidone and olanzapine may also be useful for this purpose. In cases of delirium presenting with psychotic features, lowdose, high-potency neuroleptics may be helpful in managing behavior while the underlying cause is being treated more definitively.

Treatment of Mood Disorders Treatment of bipolar disorder. HD patients may not need pharmacological treatment for their spells of elevated mood if these are brief and not associated with dangerous behavior. For those who re-

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quire treatment, lithium has been effective only rarely (Ranen et al. 1993). Furthermore, because patients with HD are vulnerable to dehydration, there is a greater risk for lithium toxicity. Carbamazepine has been the initial treatment of choice, but valproate has also been used for bipolar disorder. Again, neuroleptic medication or a benzodiazepine may be added to control disorganization or agitation in mania. Although there is less experience with electroconvulsive therapy (ECT) for mania than for depression in HD, it should nonetheless remain an option in refractory cases. Treatment of depression. Despite its high prevalence, depression in HD historically has been undertreated (Korenyi and Whittier 1967; Ringel et al. 1973). Major depression in HD responds to the same treatments used in idiopathic depression. Tricyclic antidepressants, particularly nortriptyline, and the SSRIs have traditionally represented the standard first-line agents for treatment of depression in patients with HD (Caine and Shoulson 1983; Ranen et al. 1993; Whittier et al. 1961). Sertraline has the added benefit of having been reported to successfully treat the irritability that often accompanies depression in HD patients (Ranen et al. 1996b). Although the greatest amount of clinical experience in HD patients has been with nortriptyline and the SSRIs, all of the marketed antidepressants are used, although, again, there are no systematic studies supporting their use. Some patients will respond to a monoamine oxidase inhibitor who have not responded to other agents (Ford 1986). Antipsychotic medication added to antidepressant medication is indicated for depression accompanied by delusions, hallucinations, or a high degree of agitation. If the goal is to also diminish chorea, a low-dose traditional antipsychotic agent could be used; otherwise, one of the newer atypical agents is preferable. Benzodiazepines such as clonazepam, or lorazepam if an intramuscular route is necessary, can be used in addition to or instead of neuroleptics, thus avoiding the risks of extrapyramidal reactions in patients who are very agitated. Neuroleptics and benzodiazepines should be tapered as soon as the clinical picture allows (Ranen et al. 1993). ECT is indicated for depressed patients who are refractory to treatment with medication, particularly patients who have delu-

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sions, who are not eating or drinking because of their depression, or who are such a danger to themselves that immediate treatment is necessary. ECT is administered in the same way for depression in HD as it is for idiopathic affective disorder. As with idiopathic affective disorder, the presence of delusions seems to predict a favorable response (Ranen et al. 1994).

Treatment of Anxiety In addressing anxiety, as in addressing irritability, attempts should be made to decrease the complexity of the patient’s environment. Stopping a job that has become too difficult will usually result in a decline in symptoms. Assisting the caregiver in establishing a predictable routine for the patient is also helpful. Some caregivers find it useful to refrain from discussing any special events until the day before they occur. Patients should be assured that their symptoms will be followed carefully and that if any new ones arise, such as depression, they will be treated aggressively. Treatment of obsessive-compulsive disorder. Both clomipramine and the SSRIs have been effective in managing OCD in HD at doses similar to those used in idiopathic OCD.

Treatment of Sexual Disorders Successful treatments for sexual disorders have included oral medroxyprogesterone (Provera), parenteral medroxyprogesterone (Depo-Provera), and depot leuprolide (Lupron) (Rich and Ovsiew 1994).

Summary Patients with HD present with a triad of cognitive, noncognitive psychiatric, and movement disturbances. Although there are currently no treatments for the underlying course of HD, good symptomatic treatments are available, particularly for the psychiatric aspects of the disease.

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References Albin RL, Young AB, Penney JB: The functional anatomy of basal ganglia disorders. Trends Neurosci 12:366–375, 1989 Alexander GE, DeLong MR, Strick PL: Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–381, 1986 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994 Andrew SE, Goldberg YP, Kremer B, et al: Huntington disease without CAG expansion: phenocopies or errors in assignment? Am J Hum Genet 54:852–863, 1994 Aylward EH, Brandt J, Codori AM, et al: Reduced basal ganglia volume associated with the gene for Huntington’s disease in asymptomatic at-risk persons. Neurology 44:823–828, 1994 Barr AN, Fischer JH, Koller WC, et al: Serum haloperidol concentration and choreiform movements in Huntington’s disease. Neurology 38:84–88, 1988 Baxter LR, Mazziotta JC, Pahl JJ, et al: Psychiatric, genetic, and positron emission tomographic evaluation of persons at risk for Huntington’s disease. Arch Gen Psychiatry 49:148–154, 1992 Bolt JMW: Huntington’s chorea in the west of Scotland. Br J Psychiatry 116:259–270, 1970 Bonucelli U, Ceravolo R, Maremmani C, et al: Clozapine in Huntington’s chorea. Neurology 44:821–823, 1994 Brandt J: Cognitive investigations in Huntington’s disease, in Neuropsychological Explorations of Memory and Cognition: Essays in Honor of Nelson Butters. Edited by Cermak LS. New York, Plenum, 1994, pp 4135–4146 Brandt J, Strauss ME, Larus J, et al: Clinical correlates of dementia and disability in Huntington’s disease. J Clin Neuropsychol 6:401–412, 1984 Brandt J, Folstein SE, Folstein MF: Differential cognitive impairment in Alzheimer’s disease and Huntington’s disease. Ann Neurol 23:555–561, 1988 Brandt J, Quaid KA, Folstein SE, et al: Presymptomatic diagnosis of delayed onset disease with linked DNA markers: the experience in Huntington’s disease. JAMA 261:3108–3114, 1989 Brandt J, Corwin J, Krafft L: Is verbal recognition memory really different in Huntington’s and Alzheimer’s disease? J Clin Exp Neuropsychol 14: 773–784, 1992

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Brandt J, Bylsma FW, Gross R, et al: Trinucleotide repeat length and clinical progression in Huntington’s disease. Neurology 46:527–531, 1996 Burns A, Folstein SE, Brandt J, et al: Clinical assessment of irritability, aggression, and apathy in Huntington and Alzheimer disease. J Nerv Ment Dis 178:20–26, 1990 Butters N, Wolfe J, Granholm E, et al: An assessment of verbal recall, recognition and fluency abilities in patients with Huntington’s disease. Cortex 22:11–32, 1986 Caine ED, Shoulson I: Psychiatric syndromes in Huntington’s disease. Am J Psychiatry 140:728–733, 1983 Cummings JL, Cunningham K: Obsessive-compulsive disorder in Huntington’s disease. Biol Psychiatry 31:263–270, 1992 Dewhurst K, Oliver JE, McKnight AL: Socio-psychiatric consequences of Huntington’s disease. Br J Psychiatry 116:255–258, 1970 Duyao M, Ambrose C, Myers R, et al: Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4:387–392, 1993 Emerich DF, Winn SR, Hantraye PM, et al: Protective effect of encapsulated cells producing neurotrophic factor CNTF in a monkey model of Huntington’s disease. Nature 386:395–399, 1997 Folstein MF, Folstein SE, McHugh PR: “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198, 1975 Folstein SE: Huntington’s Disease: A Disorder of Families. Baltimore, MD, Johns Hopkins University Press, 1989 Folstein SE, Jensen B, Leigh RJ, et al: The measurement of abnormal movement: methods developed for Huntington’s disease. Neurobehav Toxicol Teratol 5:605–609, 1983 Folstein SE, Chase GA, Wahl WE, et al: Huntington disease in Maryland: clinical aspects of racial variation. Am J Hum Genet 41:168–179, 1987 Ford MF: Treatment of depression in Huntington’s disease with monoamine oxidase inhibitors. Br J Psychiatry 149:654–656, 1986 Gusella JF, Wexler NS, Conneally PM, et al: A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 306:234–238, 1983 Harper PS: The epidemiology of Huntington’s disease. Hum Genet 89: 365–376, 1992 Huntington G: On chorea. Med Surg Rep 26:317–321, 1872 Huntington’s Disease Collaborative Research Group: A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72:917–983, 1993

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Huntington Study Group: The Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 4:136–142, 1996 International Huntington Association and World Federation of Neurology Research Group on Huntington’s Chorea: Guidelines for the molecular genetics predictive test in Huntington’s disease. Neurology 44:1533– 1536, 1994 Kieburtz K, MacDonald M, Shih C, et al: Trinucleotide repeat length and progression of illness in Huntington’s disease. J Med Genet 31:872–874, 1994 Korenyi C, Whittier JR: Drug treatment in 117 cases of Huntington’s disease with special reference to fluphenazine (Prolixin). Psychiatr Q 41:203– 210, 1967 Kremer B, Goldberg P, Andrew SE, et al: A worldwide study of the Huntington’s disease mutation: the sensitivity and specificity of measuring CAG repeats. N Engl J Med 330:1401–1406, 1994 Li X-J, Li S-H, Sharp AH, et al: A Huntington-associated protein enriched in brain with implications for pathology. Nature 378:398–402, 1995 Mayberg HS, Starkstein SE, Peyser CE, et al: Paralimbic frontal lobe hypometabolism in depression associated with Huntington’s disease. Neurology 42:1791–1797, 1992 Mayeux R, Stern Y, Herman A, et al: Correlates of early disability in Huntington’s disease. Ann Neurol 20:727–731, 1986 McHugh PR, Folstein MF: Psychiatric syndromes of Huntington’s chorea: a clinical and phenomenological study, in Psychiatric Aspects of Neurologic Disease. Edited by Benson DF, Blumer D. New York, Grune & Stratton, 1975, pp 267–286 Mega MS, Cummings JL: Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci 6:358–370, 1994 Penney JB Jr, Young AB, Shoulson I, et al: Huntington’s disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals. Mov Disord 5:93–99, 1990 Peyser CE, Folstein M, Chase GA, et al: Trial of d-alpha-tocopherol in Huntington’s disease. Am J Psychiatry 152:1771–1775, 1995 Ranen NG, Peyser CE, Folstein SE: A Physician’s Guide to the Management of Huntington’s Disease: Pharmacologic and Non-Pharmacologic Interventions. New York, Huntington’s Disease Society of America, 1993 Ranen NG, Peyser CE, Folstein SE: ECT as a treatment for depression in Huntington’s disease. J Neuropsychiatry Clin Neurosci 6:154–159, 1994

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Ranen NG, Stine OC, Abbott MH, et al: Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet 57:593–602, 1995 Ranen NG, Peyser CE, Coyle JT, et al: A controlled trial of idebenone in Huntington’s disease. Mov Disord 11:549–554, 1996a Ranen NG, Lipsey JR, Treisman G, et al: Sertraline in the treatment of severe aggressiveness in Huntington’s disease. J Neuropsychiatry Clin Neurosci 8:338–340, 1996b Ranen NG, Rosenblatt A, Ross CA: Differential diagnosis of Huntington’s disease. Poster abstract presented at the American Association of Geriatric Psychiatry 10th Annual Meeting, Orlando, FL, March 1997 Rich SS, Ovsiew F: Leuprolide acetate for exhibitionism in Huntington’s disease. Mov Disord 9:353–357, 1994 Ridley RM, Frith CD, Crow TJ, et al: Anticipation in Huntington’s disease is inherited through the male line but may originate in the female. J Med Genet 25:589–595, 1988 Ringel SP, Guthrie M, Klawans HL: Current treatment of Huntington’s chorea. Adv Neurol 1:797–801, 1973 Rosenbaum D: Psychosis with Huntington’s chorea. Psychiatr Q 15:93–99, 1941 Sajatovic M, Verbanac P, Ramirez LF, et al: Clozapine treatment of psychiatric symptoms resistant to neuroleptic treatment in patients with Huntington’s chorea. Neurology 41:156, 1990 Schoenfeld M, Myers RH, Cupples LA, et al: Increased rate of suicide among patients with Huntington’s disease. J Neurol Neurosurg Psychiatry 47:1283–1287, 1984 Shoulson I, Odoroff C, Oakes D, et al: A controlled trial of baclofen as protective therapy in early Huntington’s disease. Ann Neurol 25:252–259, 1989 Van Dijk JG, Van der Velde EA, Roos RA, et al: Juvenile Huntington disease. Hum Genet 73:235–293, 1986 Vonsattel JP, Myers RH, Stevens TJ, et al: Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577, 1985 Watt DC, Seller A: A clinico-genetic study of psychiatric disorder in Huntington’s chorea. Psychol Med Suppl 23:1–46, 1993 Wexler NS: The Tiresias complex: Huntington’s disease as a paradigm for testing for late-onset disorders. FASEB J 6:2820–2825, 1992 Wexler NS, Young AB, Tranzi RE, et al: Homozygotes for Huntington’s disease. Nature 326:194–197, 1987

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Whittier J, Haydu G, Crawford J: Effect of imipramine (Tofranil) on depression and hyperkinesia in Huntington’s disease. Am J Psychiatry 118:79, 1961 Wiggins S, Whyte P, Huggins M, et al: The psychological consequences of predictive testing for Huntington’s disease. N Engl J Med 327:1401– 1405, 1992

C H A P T E R

4

Wilson’s Disease (Progressive Hepatolenticular Degeneration) Edward C. Lauterbach, M.D.

W

ilson’s disease (WD), an autosomal recessive disorder, is caused by copper deposition in the brain, liver, cornea, skeletal system, and, occasionally, other organs, such as the heart. The tendency toward cuprification of the liver and brain lenticular nucleus (putamen and globus pallidus) leads to the disorder’s alternative name, hepatolenticular degeneration. Specific treatments for WD exist in the form of decoppering agents. Although various aspects of the disease were described earlier, Wilson (1912) first linked liver cirrhosis with basal ganglia movement disorders, forming the modern conceptualization of this disease. Today, WD responds well to decoppering agents if detected early enough.

Prevalence WD occurs at a rate of approximately 1 per 40,000 births. The incidence is 12–30 cases per million population (mean of 20 per million) across the world. The somewhat higher prevalence of WD in Japan has been linked to greater consanguinity. The carrier frequency of the gene is about 1%. 93

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Clinical Recognition and Neurological Presentation While the potential manifestations of WD are legion, a rule of thirds applies, with approximately one-third of WD patients initially presenting with hepatic (hepatic WD), neurological (neurological WD), or psychiatric (psychiatric WD) symptomatology. The mean age at onset is 17 years (range: 5–35 years), and phenotypic presentations such as age at onset and initial manifestations sometimes vary between families. Disease progression varies but generally involves the liver initially (i.e., in childhood and adolescence) and the brain later (in the second to third decade of life). WD is divided into three stages: asymptomatic, early symptomatic (hepatic), and late symptomatic (extrahepatic). Prognosis depends on clinical manifestations once effective treatment is undertaken. Without treatment, patients can die within 5 years, but with treatment, they can live 20 years or longer. If left untreated, patients can die within 6 months after the onset of neurological signs. Liver manifestations are quite variable (Table 4–1). If hepatic WD is not treated, cirrhosis develops. Neurological manifestations (Tables 4–1 and 4–2) develop as the liver loses its ability to store copper. The frequency of neurological signs in 48 WD patients studied by Oder et al. (1991) is shown in Table 4–2. Symptoms begin with subtle abnormalities, including mild tremor, speech problems, and micrographia (small handwriting), that are usually accompanied by Kayser-Fleischer rings (see next paragraph), hypoceruloplasminemia, or thrombocytopenia (Brewer and Yuzbasiyan-Gurkan 1992). In one study that assessed 19 WD patients more than 10 years after the illness was first diagnosed, 17 (89%) of the patients had basal ganglia signs and 2 (11%) had oculomotor or cerebellar signs (Arendt et al. 1994). Dystonia and chorea are especially common in childhood-onset and end-stage WD (Walshe 1995). Seizures occur in 6% of WD patients, but remit with WD treatment in over 60% (Dening et al. 1988). Visual and sensory systems are curiously spared, despite observations of high copper concentrations in the sensory cortex. Without WD treatment, patients become dysarthric, bedridden, and unable to perform activities of daily living; develop flexion contractures; and die. Greater detail on liver manifestations

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Table 4–1.

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Hepatic and neurological manifestations in Wilson’s disease

Hepatic manifestations Primary Abnormal liver tests Hepatomegaly Acute hepatitis Chronic active hepatitis Chronic cirrhosis Secondary Portal hypertension Esophageal varices Hypersplenism Hepatorenal syndrome Jaundice Spider angiomata Palmar erythema Asterixis Hypoalbuminemia Ascites Hyperammonemia Hemolysis of cirrhosis Hepatic encephalopathy Reduced clotting factor synthesis Bleeding diatheses Gallstones Delayed puberty Amenorrhea Gonadal insufficiency Hyperpigmented skin

Neurological manifestations Oculomotor signs Cerebellar signs Ataxia Dysdiadochokinesia Other Dysarthria (dystonic, cerebellar, parkinsonian, or spastic types) Drooling Movement disorders Bradykinesia Parkinsonism Dystonia Dystonic arm posturing Risus sardonicus Chorea Tics Tremors Postural tremor Wing beating tremor Other Pyramidal tract signs Dysautonomia Seizures Pathological emotionality

Source. Brewer and Yuzbasiyan-Gurkan 1992a (hepatic manifestations); Arendt et al. 1994 and Oder et al. 1991 (neurological manifestations).

has been provided elsewhere (Hoogenraad 1996). Greenish-brown, muddy brown (Figure 4–1), or golden KayserFleischer (KF) rings resulting from copper deposition are best seen on slit-lamp ophthalmological exam but, when prominent, can also

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Table 4–2.

Frequency of neurological signs in Wilson’s disease patients (n = 45) No. Frequency, %

Neurological signs Dysdiadochokinesia Dysarthria Bradykinesia (in isolation) Postural tremor Parkinsonism Chorea/dystonia Ataxia Source.

27 25 23 17 14 8 3 1

60 56 51 38 31 18 7 2

Oder et al. 1991.

Figure 4–1. Kayser-Fleischer ring, most apparent at corneal junction with sclera. Source. Reproduced from Yanoff M, Fine BS: Ocular Pathology: A Color Atlas. Philadelphia, PA, JB Lippincott, 1988, p. 105. Copyright © 1988, Mosby International. Used with permission.

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be seen with an ophthalmoscope near the junction of the cornea and the sclera. The rings initially appear superiorly and may be less apparent medially and laterally. In one study, 85% of patients with neurological WD manifested KF rings, in contrast to fewer than 15% of patients with hepatic WD (Oder et al. 1991). Sunflower cataracts can occur, and progressive lens and retinal changes vary with treatment. Some of the other less-prominent features of WD are listed in Table 4–3. Aside from the characteristics detailed in this table and the considerations mentioned below, no other clinically important interactions between WD and patient gender have been reported.

Pathological Features Pathology The physiological importance of copper is immense. Studies in rats indicate that copper is a potent releaser of catecholamines (Wang 1999) and a potent inhibitor of GABA-A receptors (Sharonova et al. 1998), possibly contributing to neuropathological or pathophysiological processes in WD. Copper is integral to cytochrome-c oxidase in the mitochondrial electron transport chain, catecholamine metabolism (tyrosine metabolism, dopamine beta-hydroxylase, and monoamine oxidase), melanin formation, collagen and elastin cross-linkage, and free radical deactivation (superoxide dismutase). Excessive copper accumulation can lead to cellular demise through a number of potential mechanisms. These include free radical–induced cellular oxidation, inhibited protein synthesis, inactivation of enzymes (in mitochondria, cytosol, and cell membrane), intracellular failure (of mitochondria, peroxisomes, microtubules, plasma membranes, enzymes, and DNA cross-linking), and induction of cellular injury, inflammation, and cell death due to unbound ionic copper (Hoogenraad and Van den Hamer 1996; Walshe 1995). Mitochondrial copper accumulation can produce premature oxidative aging and mitochondrial DNA mutations, further impairing cell function (Mansouri et al. 1997). A thorough review of normal copper metabolism can be found elsewhere (Hoogenraad and Van den Hamer 1996). Early hepatic intracellular fatty accumulations proceed to stea-

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Table 4–3.

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Other nonpsychiatric features of Wilson’s disease

Renal Urolithiasis Hematuria Renal tubular dysfunction Hypokalemia Aminoaciduria Proteinuria Uricosuria Hypercalciuria Abnormal glucose tolerance Defective urinary acidification Fanconi syndrome Nephrolithiasis Hepatorenal syndrome Immunoglobulin A (IgA) glomerulonephritis Penicillamine immunoglobulin G (IgG) glomerulonephritis Musculoskeletal Osteoarthritis Osteomalacia Hypertrophic osteoarthropathy Chondrocalcinosis Arthralgias Stiffness of back, knee, hip, and wrist Rhabdomyolysis Muscle weakness of hypokalemia

Cardiac Cardiac interstitial fibrosis Myocarditis Cardiac arrhythmia Electrocardiogram (ECG) abnormalities Endocrinological Oligomenorrhea Amenorrhea Hyperglycemia Hypertestosteronemia Hyperestradiolemia Hypogonadism of cirrhosis Pancreatic disease Hypoparathyroidism Miscellaneous Orthostatic hypotension Skin abnormalities Cholelithiasis Dermatopathies Ruptured spleen Hemolysis

tosis in hepatic WD. Subsequently, inflammatory cellular infiltration (lymphocytes and histiocytes), collagen deposition, fibrosis, and necrosis ensue. Fibrosis progresses to nodular cirrhosis with cholestasis. Nodules can measure as large as 2 cm, and individual liver lobules vary in color (yellow, red, green, brown). Brain pathology in WD can include widespread copper deposi-

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tion, gliosis, and astrocytic proliferation, especially in gray matter. Spongy necrosis, demyelination, and denervation may be evident in frontal, parietal, and occipital cortical areas. Macroscopically, ventricular dilatation, lenticular atrophy, yellowish or reddish-brown discoloration, softening, and spongy degeneration are seen. Cavitation is especially apparent in rapidly progressive juvenile dystonic forms of WD, whereas atrophy is more common in more slowly progressive adult forms. The pathology of hepatic encephalopathy is similar to WD pathology and is occasionally superimposed (Hoogenraad 1996). Liver failure can increase pallidal manganese concentrations.

Etiology and Genetics The ATP7B gene responsible for WD is located on band 14.1–21.1 of chromosome 13q14 (Nanji et al. 1997). The gene product is a copper-containing P-type adenosine triphosphatase (ATPase), important to the process of binding copper to apoceruloplasmin to form holoceruloplasmin. Holoceruloplasmin is integral to hepatobiliary copper excretion. In WD, however, apoceruloplasmin fails to bind copper (Kojimahara et al. 1995). Mutant forms of the ATPase in WD have difficulty migrating from the trans-Golgi network to cytoplasmic vesicles, where they would normally assist in binding excess copper to form holoceruloplasmin (Schaefer et al. 1999). Although WD patients have holoceruloplasmin in the liver, holoceruloplasmin is lacking in the biliary system (Chowrimootoo et al. 1997), reflecting impaired copper transport from hepatocytes to the biliary system. Biliary excretion normally accounts for 10% of daily copper loss (Hoogenraad and Van den Hamer 1996), and impaired biliary excretion soon leads to copper accumulation. WD differs from the other major abnormal P-type ATPase copper disease, X-linked Menkes’ disease. Menkes’ disease is caused by copper deficiency secondary to intestinal copper malabsorption resulting from mutations in the ATP7A gene. It leads to death in childhood (Walshe 1995). More than 100 mutations of the WD gene have been documented, some of which are associated with ethnicity, severity, age at onset, or presentation (Forbes and Cox 1998; Nanji et al. 1997; Walshe 1995). Highly dysfunctional mutations lead to early-onset,

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severe hepatic WD, whereas milder mutations lead to late-onset neurological WD (Houwen et al. 1995). A cytosine-to-adenine transversion may be responsible for 30% of North American WD cases (Hoogenraad and Houwen 1996). Animal models include the Bedlington terrier and the Long Evans Cinnamon rat. Recently, a strain of mice has been developed with a mutation of the ATP7B gene, resulting in the development of WD features in these mice (Buiakova et al. 1999).

Neuroimaging Increased putaminal signal (hyperintensity) due to copper deposition is usually present on magnetic resonance imaging (MRI) scan T2-weighted images (Figure 4–2). Increased T2 signal can also sometimes be seen in the thalamus, globus pallidus, caudate, cerebellum, subcortical white matter, midbrain, and pons. Although reduced T1 signal is common, increased pallidal T1 signal sometimes occurs and may correlate with hepatic demise (Saatci et al. 1997). MRI abnormalities occurred most frequently in the putamen and pons (present in 80%–90% of subjects) in two studies (King et al. 1996; Saatci et al. 1997), whereas pallidal abnormalities occurred in WD patients with portosystemic shunting in another study (van Wassenaer– van Hall et al. 1996). On computed tomography (CT), the most common findings are ventricular dilatation, basal ganglia hyperdensities, and atrophy of the cerebral cortex, brain stem, or cerebellum. Similar findings in other brain regions are sometimes seen. Basal ganglia MRI hypointensity and CT hypodensity are consistent with cavitation in more aggressive WD. On positron emission tomography (PET), glucose metabolism may be reduced in the cerebellum and striatum as well as in cortical and thalamic regions (Kuwert et al. 1992); reduced striatal glucose metabolism has been correlated with neurological severity (Schlaug et al. 1996). Dopamine D2 receptor binding on single-photon emission computed tomography (SPECT) imaging has correlated negatively with neurological severity (Oder et al. 1996; Schlaug et al. 1996).

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Figure 4–2. Appearance of Wilson’s disease at two adjacent levels on T2-weighted magnetic resonance imaging (MRI). Note variegated increased signal in putamen and caudate heads due to copper deposition and reduced signal in globus pallidus. Source. Reproduced from Martin WRW, Snow B, Ashforth R: “Abnormalities of Movement and Posture Due to Disease of the Extrapyramidal Motor Systems,” in Neuroimaging: A Companion to Adams and Victor’s Principles of Neurology. Edited by Greenberg JO. New York, McGraw-Hill, 1995, pp. 5–24. Copyright © 1988, The McGraw-Hill Companies. Used with permission.

Clinical and Laboratory Investigation: Diagnosis Clinical suspicion is critical to diagnosing WD. The disease must be actively considered in the neuropsychiatric differential diagnosis in order to avoid missing the diagnosis. In a retrospective review of 136 cases of neurological WD, the diagnosis was missed in two-thirds of WD initial presentations, resulting in a 13-month delay in diagnosis (Walshe and Yealland 1992). In another series, two-thirds of patients with neurological WD exhibited psychiatric symptoms, but psychiatrists missed the diagnosis despite the uniform presence of KF rings (Brewer and Yuzbasiyan-Gurkan 1992). Clinicians must

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therefore remain vigilant for signs of WD, particularly because prompt detection is critical for successful treatment. Initial presentation with hepatic, neurological, or psychiatric symptoms, especially when accompanied by KF rings or a family history of WD, cirrhosis, or neurological disorder, warrants a diagnostic workup to exclude WD. Psychiatric features precede other symptoms in at least 20% of WD patients. In the remaining 80%, liver disease usually precedes other WD manifestations (Walshe 1995). Manifestations such as renal, endocrinological, hematological, cardiac, or joint disease may also elicit clinical suspicion. The diagnosis of WD is made by measuring blood ceruloplasmin and 24-hour urine copper levels. WD is confirmed by liver biopsy. Ceruloplasmin is reduced in 95% of cases, but it can also be normal or elevated, especially in early WD. Although urinary copper is usually elevated, 40% of presymptomatic homozygotes (i.e., future WD patients) have values lower than the 100 µg/day observed in typical WD patients (Lindahl and Sharp 1982). Hepatic needle biopsy disclosing copper is diagnostically definitive (although liver biopsy copper concentrations can vary in children) in early and end-stage WD (Hoogenraad 1996), and in different liver nodules (Faa et al. 1995). Although the finding of KF rings on slit-lamp exam supports the diagnosis, rings are usually absent when WD is confined to the liver (Akil and Brewer 1995). Serum copper levels are not of diagnostic utility. Once the diagnosis is established in a patient, definitive diagnoses in siblings can be made by DNA analysis (Roberts and Cox 1998) (see “Family Considerations and Genetic Testing” under “Neurological and Psychiatric Management” section later in chapter). Laboratory test values are summarized in Table 4–4 and are reviewed in detail elsewhere (Brewer and Yuzbasiyan-Gurkan 1992). Values vary somewhat among laboratories. Presymptomatic WD homozygotes generally exhibit low concentrations of ceruloplasmin, normal to high concentrations of urinary copper, and high concentrations of liver copper. The differential diagnosis of WD as it relates to disease signs and laboratory manifestations is summarized in Table 4–5. Although other diseases are associated with excessive copper accumulation, only WD results in copper deposition in the brain (Walshe 1995). False negatives and false positives can occur, as with all tests.

Laboratory investigation of Wilson’s disease

Test

Normal

Wilson’s disease

Heterozygous carriers

Ceruloplasmin 24-hour urinary copper Hepatic copper

20–35 mg/d 20–50 µg/d 20–50 µg/g

0–10 mg/d 100 µg/d 200 µg/g

0–35 mg/d 20–75 µg/d 20–150 µg/g

Wilson’s Disease

Table 4–4.

Note. Values for normal control subjects, homozygous Wilson’s disease patients, and asymptomatic carriers. mg/d = milligrams per day; µg/d = micrograms per day; µg/g = micrograms per gram of dry liver tissue.

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Table 4–5.

Differential diagnosis of Wilson’s disease

Heritable liver disorders Wilson’s disease Hemochromatosis Alpha-1 antiprotease (antitrypsin) deficiency Cystic fibrosis Excessive copper accumulation Wilson’s disease Primary biliary cirrhosis Indian childhood cirrhosis Non-Indian childhood cirrhosis Severe familial intrahepatic cholestasis Prolonged biliary obstruction Hypoceruloplasminemia Wilson’s disease homozygotes (patients) 10% of heterozygous Wilson’s disease carriers Normal infants up to age 6 years 1% of normal adults Menkes’ syndrome Hereditary hypoceruloplasminemias Copper deficiency High urinary copper levels Wilson’s disease Copper storage diseases other than Wilson’s Severe proteinuria Obstructive liver disease Primary biliary cirrhosis Cholestasis Indian childhood cirrhosis Non-Indian childhood cirrhosis High hepatic copper levels and high urinary copper levels Wilson’s disease Obstructive liver disease (see “High urinary copper levels” above for details) Kayser-Fleischer rings Wilson’s disease Obstructive liver disease (see “High urinary copper levels” above for details) Source.

Hoogenraad 1996; Kumar and Riely 1995; Walshe 1995.

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Moreover, in hepatic WD, one-third of patients lack KF rings, abnormal ceruloplasmin, and urinary copper (Steindl et al. 1997). In ambiguous cases, DNA marker analysis can be helpful (see “Family Considerations and Genetic Testing” under “Neurological and Psychiatric Management” section later in chapter). DNA analysis can distinguish between homozygous WD patients and heterozygous WD carriers (Gaffney et al. 1992). Western blot analysis of ceruloplasmin has successfully distinguished WD homozygotes, WD heterozygotes, and non-WD hypoceruloplasminemic patients (Chowrimootoo et al. 1997). Although prenatal diagnosis is now possible, there is no reason to undertake this, given the excellent prognosis of well-treated presymptomatic homozygotes (Hoogenraad 1996). Although the biliary isoform of ceruloplasmin is reduced in neonates, reductions in the plasma isoform of ceruloplasmin in cord blood can assist in the neonatal diagnosis of WD (Chowrimootoo et al. 1998). Other tests are supportive but not diagnostic of WD. Putaminal abnormalities on MRI T2 images can suggest WD (see “Neuroimaging” section above). Although the neurological exam is more diagnostically sensitive than CT imaging (Roach et al. 1985), basal ganglia hypodensities on CT can also suggest the diagnosis of WD. Additional tests of suggestive or supportive diagnostic value include elevated serum transaminases, reduced serum alkaline phosphatase, slowing or epileptiform activity on electroencephalogram (EEG), abnormal auditory evoked responses (peaks I–IV), reduced striatal D2 receptor binding or basal ganglia hypometabolism on SPECT, and reductions in striatal, cerebellar, cortical, or thalamic glucose metabolism on PET (Kuwert et al. 1992). An abnormal 65Cu test (see Lyon et al. 1995 for a description of this test) at 72 hours is also supportive of a diagnosis of WD (Merli et al. 1998).

Psychiatric Manifestations Psychiatric symptoms are evident at initial presentation in between one-third and two-thirds of patients (including those with neurological WD), and psychiatric symptoms occur in isolation in about 20% (Akil and Brewer 1995; Dening and Berrios 1989a; Schwartz et al. 1993). Half of patients undergo psychiatric hospitalization before

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WD is recognized (Akil et al. 1991; Rathbun 1996). Because improvement in WD depends on treatment within the first 5 years of disease onset, clinical vigilance and early diagnosis is critical. Cognitive, mood, and personality disturbances dominate psychiatric presentations (Table 4–6). Wilson observed prominent psychiatric symptoms in his patients, including silliness, euphoria, sexual preoccupation, hebephrenia, catatonia, occasional hallucinations, “hysterical” behavior, and “narrowing of mental horizons.” He concluded that “facility, docility, childishness, and emotional overaction form the chief features of the more chronic cases” (Wilson 1912). Among 129 WD patients examined in one study, the most common psychiatric symptoms were incongruous behavior, irritability, depression, and cognitive impairment (Dening and Berrios 1990). Akil and Brewer (1995) observed that personality disturbances, depression, and academic or employment failure were the most common psychiatric presentations. Thus, WD can profoundly affect intellectual, emotional, and behavioral aspects of the patient’s life. Table 4–6.

Frequency of psychiatric manifestations in Wilson’s disease Frequency, %

Psychiatric presentation frequencies across studies Pure psychiatric initial presentation Predominantly psychiatric initial presentation Psychiatric features present on initial presentation Psychiatric features present during illness course

20 33 33–67 50–100

Psychiatric feature frequencies across studies Any psychiatric features Depression Suicidality Irritability/aggression Elation Cognitive impairment Delusions Hepatocerebral syndrome and catatonia

65 27 4 46 13 <24 1–7 Rare

Source. Data approximated from Akil and Brewer 1995; Akil et al. 1991; Brewer and Yuzbasiyan-Gurkan 1992a; Dening and Berrios 1989a, 1989b; Oder et al. 1991; Scheinberg and Sternlieb 1984; Schwartz et al. 1993; Walshe 1995.

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Two-thirds of Wilson’s original 12 patients had “psychical” abnormalities (Wilson 1912). Point prevalences of psychiatric disorders in WD range as high as 100%, but 50% may represent a better estimate (Dening and Berrios 1989a). Lifetime prevalences of cognitive impairment, psychosis, mood and anxiety disorders, impulsivity, and personality disturbances may, together, approach 100% (Scheinberg and Sternlieb 1984). In a retrospective review of 42 WD patients undergoing zinc treatment, irritable and aggressive personality disturbances occurred in 17 (45.9%) of the 37 symptomatic patients, whereas cognitive changes, anxiety, psychosis, and catatonia were less common (Akil et al. 1991). Of 24 neurological WD patients assessed in one study, 17 (71%) had various personality changes, 10 (42%) depression, 4 (17%) cognitive changes, 3 (13%) anxiety, 2 (8%) psychosis, 2 (8%) catatonia, and 5 (21%) other psychiatric presentations (Brewer and Yuzbasiyan-Gurkan 1992). Specific psychiatric disturbances are discussed in the following subsections. Psychiatric manifestations (Akil and Brewer 1995; Dening and Berrios 1989a) and neuropsychological impairment (Lang et al. 1990) usually occur with neurological rather than hepatic disease.

Cognitive Impairment Patients should be scrutinized for DSM-IV (American Psychiatric Association 1994) amnestic disorder due to Wilson’s disease and for cognitive disorder not otherwise specified. The rate of cognitive impairment varies, but overall, such impairment occurs in less than 25% of WD patients (Lauterbach et al. 1998). Impairment increases with disease duration (Knehr and Bearn 1956). In a study of 19 patients with neurological WD (Medalia et al. 1988), patients scored lower on the Full Scale IQ, Dementia Rating Scale, and Wechsler Memory Scale than did either 15 normal control subjects or 12 WD patients without neurological WD. Slowing on time-dependent psychometric tests increases with neurological WD severity (Arendt et al. 1994), but this may result from slowed motor speed rather than from reduced information-processing speed (Littman et al. 1995). Cognitive impairment also attends occasional hepatic encephalopathies (Tarter et al. 1987). Cognitive function, memory, and IQ can improve with treatment (references cited in Lauterbach et al. 1998).

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Pathological Affect Emotional lability with forced laughter and crying may occur in WD (see Chapter 1 for treatment approaches).

Behavioral and Personality Changes Among WD patients with significant psychiatric disturbances, the majority have antisocial or impulse-control features. Nearly half of WD patients manifest personality changes, including impulsivity, aggression, disinhibition, recklessness, emotionality, irritability, anger, bizarre and odd behavior, and other less easily definable presentations (references cited in Lauterbach et al. 1998). These presentations correspond to DSM-IV personality change due to Wilson’s disease, including disinhibited, labile, and aggressive types. In 42 patients treated with zinc, Akil et al. (1991) found that 37 were symptomatic; of these, 17 (45.9%) had irritable or aggressive personality disturbances. These personality features can lead to marital troubles and occasional criminality. Irritability, incongruous behavior, and personality disturbances are associated with brain-stem signs and dystonia but not with tremor (Dening and Berrios 1989a). Personality syndromes also correlate with dyskinesia, dysarthria, and putaminal and pallidal lesions (Oder et al. 1993). Psychopathic personality features, in particular, correlate with dysarthria (Dening and Berrios 1989b). Incongruous, disinhibited, aggressive, hyperactive, and hypersexual behaviors have improved with treatment of WD, but irritability has not (Akil and Brewer 1995; Dening and Berrios 1990).

Functional Decline A common problem in WD is deterioration in work or academic performance (Akil and Brewer 1995). Such deterioration can lead patients to drop out of school or to quit or be fired from their jobs, more as a result of attentional deficits than of intellectual impairments or personality disturbances (Akil and Brewer 1995). Diminished functional capacity correlates with ataxia, tremor, and focal thalamic lesions (Oder et al. 1993). Occasionally, WD is mistaken for a psychiatric diagnosis.

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Walshe and Munro (1995) reported the case of a 17-year-old with intractable vomiting who was misdiagnosed with anorexia nervosa for 9 years. In reality, the patient was suffering from gastrointestinal manifestations of WD.

Psychosis Psychosis can be the presenting sign of WD—hence the clinical admonition to exclude WD in first-onset psychosis. Although early studies suggested an association of psychosis and WD related to basal ganglia pathology (Slater and Cowie 1971), later studies indicated that schizophreniform disorders, catatonia, and hallucinations are not increased in WD (Dening and Berrios 1989a; Oder et al. 1991). Delusions occurred in 3 (7%) of 45 WD patients in a prospective study by Oder et al. (1991). In a study of 24 patients with neurological WD, psychosis and catatonia each occurred in 2 (8%) (Brewer and Yuzbasiyan-Gurkan 1992). Psychotic features occasionally reverse with WD treatment, and incongruous behavior can improve over the disease course (Dening and Berrios 1990). Great care is necessary when using antipsychotics in patients with neurological WD (see “Psychotropic Treatment” under “Neurological and Psychiatric Management” section later in chapter). Occasionally, reversible psychosis is precipitated after commencing WD treatment (McDonald and Lake 1995). Although this treatment complication would likely be diagnosed in DSM-IV as a psychotic disorder due to a general medical condition, the exact diagnoses corresponding to psychotic features observed in WD have not yet been determined.

Mood Disorders Mania WD affects brain structures associated with mania, including the striatum, thalamus, and cerebellum (see Chapter 7 in this volume). Elation occurs in about 13% of WD patients across studies (Akil et al. 1991; Dening and Berrios 1989a; Oder et al. 1991). Although manic presentations have been observed ever since Wilson’s original report (1912), the prevalences of such presentations have yet to be determined. In conducting future epidemiological studies, it will be im-

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portant to distinguish the various DSM-IV bipolar disorders and mood disorder due to Wilson’s disease with manic features, because WD personality changes can also resemble mania (see “Behavioral and Personality Changes” subsection above). Whereas irritability tends not to respond to WD treatment (Dening and Berrios 1990), hypersexuality, hyperactivity, and aggression occasionally improve with such intervention (Akil and Brewer 1995). Depression Depressive illness occurs in about 30% (Akil et al. 1991; Dening and Berrios 1989a, 1989b; Oder et al. 1991) or more of WD patients (Akil and Brewer 1995). In a prospective study of 45 patients with WD, 12 (27%) had mood disorders consistent with major depression; in all of these subjects, the major depression was attended by the features of neurological WD (Oder et al. 1991). Some depressive symptoms correlate with hepatic dysfunction (Dening and Berrios 1989b). Depression may evolve over the disease course, eventually occurring in perhaps all WD patients (Arendt et al. 1994) and coexisting with (Oder et al. 1993) or without (Arendt et al. 1994) cognitive impairment. In a follow-up study of 129 WD patients, neither depression nor irritability improved with WD treatment, especially in patients with neurological and hepatic WD (Dening and Berrios 1990). Nevertheless, some case reports indicate that depression can improve with treatment. Major depression in WD can be associated with delusions, suicide attempts, and personality disturbances. Across studies, suicidal behavior is observed in 4%–16% of patients (references cited in Lauterbach et al. 1998). Disinhibited, impulsive, and aggressive WD personality changes may compound the risk of suicide. Consequently, depressed WD patients should be thoroughly evaluated for suicide potential. Mild depression correlates with cognitive impairment, parkinsonian rigidity, bradykinesia, and third-ventricle dilatation (Oder et al. 1993) as well as with gait disorders (Dening and Berrios 1989b). Mood disturbances have not been found to correlate with evoked potential abnormalities (Arendt et al. 1994). Whether depression is a psychological reaction to illness or a biological event is unresolved

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(Akil and Brewer 1995), but both mechanisms probably apply to varying degrees in individual patients. Consequently, as for psychoses and mania, it is unclear what percentage of depressive disorders in WD represent DSM-IV mood disorders due to WD. Future studies using diagnostic criteria will be useful in separating out adjustment disorders from major depression and dysthymia.

Anxiety Disorders Although several reports have identified anxiety in WD subjects (Akil and Brewer 1995; Akil et al. 1991; Loiseau and Demangeat 1956), the prevalence, clinical and pathological correlates, psychosocial determinants, and treatment of specific anxiety disorders in WD remain to be determined.

Impulse Control Disorders In one study of 124 WD patients, 6 (4.8%) displayed increased sexual preoccupation and reduced sexual inhibition (Akil and Brewer 1995). Sexual behaviors included exhibitionism and promiscuity. Hypersexual, disinhibited, aggressive, and hyperactive behavior can improve with treatment of WD (Akil and Brewer 1995; Dening and Berrios 1990). Impulsive behavior was discussed earlier in this chapter (see “Behavioral and Personality Changes” subsection above). The types, prevalences, clinical and pathological correlates, psychosocial determinants, and treatment of impulse control disorders in WD need elucidation.

Substance Abuse Disorders Reports of substance abuse in WD patients have been published (Akil et al. 1991; Hawkins et al. 1987; Lhermitte and Muncie 1980). Personality disturbances and mood disorders may pose special risk, but prevalences, correlates, determinants, and special treatment issues associated with substance abuse in WD are unknown. Further work is needed to delineate substance abuse disorders in WD patients.

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Neurological and Psychiatric Management Three aspects of treatment merit discussion: 1) psychotherapeutic considerations, 2) treatment of the underlying neurological disease, and 3) treatment of psychiatric manifestations.

Psychotherapeutic Considerations Clinicians should attempt to provide psychological support to patients, and help them to grieve and adapt to the illness. Patients should be assisted in the process of working through the issues of disease acceptance. They should be encouraged to maintain their daily routines to the extent possible. Denial of illness and noncompliance with treatment may be particular problems in younger patients or those with behavioral disinhibition. Poor insight into both the illness and its consequences is another issue that complicates treatment. Practical aspects of coping with the disease and with the limitations of lifestyle imposed by its attendant disabilities and its treatment should be addressed. Hope can be offered with treatment, but it is important to guard against unrealistic expectations. Enlisting the patient’s support system may be helpful for adaptation and adjustment to the illness, as well as for monitoring compliance to the treatment regimen. Vigilance for suicide is important in those who are depressed. Evaluation of depression is particularly indicated for those with parkinsonism or gait disturbance. Conventional psychotherapeutic strategies should be employed as indicated for the specific psychiatric disorders identified in the individual patient. Support groups can also be very helpful, providing camaraderie and education for the patient and family. Such groups reduce fear of the unknown about the disease, provide practical tactics useful for coping with WD, and can also help patients gain a sense of mastery over the illness by allowing them to actively do something about the disease rather than feel like its passive victim. Support groups provide a forum wherein the patient can confront the illness, grieve it, and come to terms with it. Some patients derive added benefit from organizing these groups or serving in leadership positions. Although WD is an uncommon illness, referral can be made to support groups for Parkinson’s disease, dystonia, or stroke, depending on the patient’s neurological features. Further information on support

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groups and informational resources for patients and their families can be obtained by contacting the Wilson’s Disease Association (P.O. Box 75324, Washington, DC 20012-5324) or the National Center for the Study of Wilson’s Disease (432 West 58th Street, Suite 614, New York, NY 10019, phone 212-523-8717, fax 212-523-8708).

Treatment of the Underlying Neurological Disease First-Line Treatments The introduction of functional ATP7B protein by recombinant adenovirus-mediated gene delivery holds promise as a future treatment of Wilson’s disease (Terada et al. 1998). However, at present, treatment options are limited to agents that reduce the level of toxic copper in the body. First-line agents for treating WD include Dpenicillamine, zinc, trientine, and tetrathiomolybdate. Early recognition and treatment of WD is paramount, because improvement with treatment is usually limited to the first 5 years of symptomatic illness and the first 2 years of treatment (Akil and Brewer 1995; Dening and Berrios 1990). Improvement generally occurs only after the first 6 months of treatment. Both psychiatric and other manifestations can improve with WD treatment. Gastroenterological, neurological, or other consultation is advisable, depending on disease manifestations. WD treatments include copper chelating agents that increase urinary copper excretion (e.g., penicillamine and trientine) and copper depleting agents (zinc and thiomolybdate). Specific indications for the various drugs are controversial (e.g., LeWitt 1999). Some experts recommend using penicillamine and switching to trientine followed by dimercaprol in the event of side effects or lack of efficacy. Brewer (1995a) has outlined indications for the use of these agents. A combination of trientine and zinc is advised for patients with mild liver failure. Zinc is recommended for maintenance therapy, presymptomatic treatment, and treatment during pregnancy. Tetrathiomolybdate may be the treatment of choice for neurological disease because it infrequently causes neurological exacerbations (Brewer and Yuzbasiyan-Gurkan 1992). Zinc monotherapy is suboptimal for the initial treatment of neurological WD, because improvement occurs too slowly.

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Recent reports suggest the utility of plasma exchange and peritoneal dialysis in fulminant WD and hemolytic anemia, but these are rarely necessary and may foster neurological exacerbations. Penicillamine. Walshe introduced D-penicillamine (Cuprimine, Depen) in 1956, and for many years it remained the drug of first choice for the treatment of WD. Because of its many side effects, the drug is gradually titrated upward to 8.3 mg/kg tid (250 mg qid to 500 mg tid in adults) over several weeks. It is given at least 30 minutes before meals and no sooner than 2 hours after meals. Pyridoxine 25 mg/day is coadministered to prevent penicillamine-induced deficiency. Copper–penicillamine complexes are excreted in the urine, resulting in an initially large cupruresis of several milligrams per day that declines to 0.5 mg/day after several months (Brewer and Yuzbasiyan-Gurkan 1992). Baseline complete blood counts and renal function tests should be obtained before commencing treatment, because both WD and penicillamine can produce leukopenia and thrombocytopenia. If either of these conditions is present, the initial dose should be smaller and more gradually titrated. The majority of WD patients treated with penicillamine make an excellent recovery in hepatic, neurological, and psychiatric function and can return to gainful employment (Walshe 1986a). Of 137 WD patients undergoing chelation in one study, 57 (42%) became asymptomatic, another 36 (26%) experienced significant neurological improvement, and only 24 (18%) failed to recover function (Walshe and Yealland 1993). Penicillamine treatment leads to regression of copper depositions in the brain seen on T2-weighted MRI imaging and improvement in D2 dopamine receptor binding (Schwarz et al. 1994). Improved motor function after penicillamine therapy correlates with increased cerebral glucose metabolism and dopamine receptor binding (Schlaug et al. 1994). Adverse side effects occur in 10%–30% of patients, and 10% of patients are unable to tolerate long-term penicillamine therapy (Saito et al. 1991). Major side effects are summarized in Table 4–7. Gastrointestinal upset is common. Switching to zinc (Barbosa et al. 1992), dimercaprol, or trientine (Castellano et al. 1992) has been useful in the event of D-penicillamine–induced renal exacerbations. The two most important side effects of penicillamine therapy are

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Side effects of penicillamine

Gastrointestinal conditions Anorexia Nausea Vomiting Pyridoxine deficiency Lysyl oxidase inhibition Dermatological conditions Collagen-elastin damage Cutis laxa Dermal atrophy, wrinkling, and bleeding Elastosis performans serpiginosa Aphthous stomatitis Gingival hyperplasia Conjunctival inflammation Follicular conjunctivitis Penicillamine dermatopathy Pemphigus Lichen planus Pseudoxanthoma elasticum Abnormal collagen development Abnormal wound healing Pleural effusion Fever Lymphadenopathy Rash

Immunologically induced conditions Goodpasture’s syndrome Systemic lupus erythematosus Rash Immune complex nephritis Fatality Polyarthritis Myasthenia gravis Optic neuritis Nephrotic syndrome Proteinuria Hypersensitivity Urticaria Urticaria with hematuria Immunoglobulin A (IgA) deficiency Endocrinological conditions Hirsutism Mastodynia Hematological conditions Pancytopenia Bone marrow depression Aplastic anemia Retinal hemorrhages Acute polyarthritis

Source. Brewer and Yuzbasiyan-Gurkan 1992; Hoogenraad 1996; Karkos 1996; Katz 1967; Walshe 1986a.

hypersensitivities (in 30% of patients) and neurological exacerbations (Brewer and Yuzbasiyan-Gurkan 1992). Both can lead to death. Among immune reactions, urticaria is the most common, and only immune nephritis responds to drug withdrawal. Therefore, brief courses of an antihistamine or prednisolone are sometimes necessary before resuming a lower dose of penicillamine, with more gradual dose titration (Walshe 1986a).

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Even with gradual titration, a serious concern with this drug is initial exacerbation of neurological symptoms in up to 21% of WD patients (Walshe and Yealland 1993) and in about 50% of patients with neurological WD (Brewer and Yuzbasiyan-Gurkan 1992). Neurological exacerbations have included seizures, movement disorders, neuropsychiatric disturbances, and, sometimes, irreversible neurological disability (Brewer et al. 1994c). Neurological exacerbations can occur in patients free of neurological manifestations. Possible psychiatric exacerbations (new onset of psychosis) may also occur (McDonald and Lake 1995). Switching to zinc (Huang and Chu 1996) or continuing treatment with penicillamine (McDonald and Lake 1995) has sometimes led to resolution. In the latter case, the established procedure is to discontinue penicillamine for 1 week and then resume treatment at a lower dose. To monitor penicillamine treatment, some authorities recommend following serial plasma free copper (see “Zinc,” below), maintaining levels below 10 µg/dL and measuring ceruloplasmin levels every 6 weeks for the first year and annually thereafter. Zinc. Indications for zinc include maintenance therapy, initial treatment in presymptomatic patients, and treatment of pregnant patients (Brewer 1995b). Zinc is administered as zinc acetate (50 mg po tid) or zinc sulfate (300 mg po tid) as far between meals as possible (at least 1 hour before or after meals) (Brewer et al. 1990; Hoogenraad 1996). Lower doses are insufficient for effective treatment of WD (Brewer 1995b), and higher doses may be required in some patients. Zinc induces the production of intestinal and hepatic metallothionein (Sturniolo et al. 1999), thereby reducing intestinal absorption of copper and binding circulating copper to a nontoxic pool in the liver (Brewer 1995b; Brewer et al. 1994b). Side effects of zinc include nausea, epigastric pain, occasional vomiting, and the potential for sideroblastic anemia (Walshe 1995). Zinc acetate (Galzin) is better tolerated by the stomach than is zinc sulfate (Brewer et al. 1990). Tolerance to gastrointestinal irritation develops within a few weeks of commencing treatment, and morning nausea can be avoided by giving the first dose of the day between breakfast and lunch. If food must be taken with zinc to reduce irritation, meat is associated with the least reduction in zinc absorp-

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tion (Brewer et al. 1990). Hemolysis, dermatitis, mild serum amylase elevation, and reductions in high-density lipoprotein cholesterol have been reported with zinc therapy (Hoogenraad 1996). Although some authorities recommend zinc as the initial treatment in neurological WD (Bona et al. 1993), fatal neurological deterioration can occur (Lang et al. 1993). Improvement in the neurological exam as well as on MRI has been documented with zinc treatment (Heckmann et al. 1994). Neurological exacerbations occurring during zinc therapy have been effectively treated by combining penicillamine with dimercaprol and a zero-copper diet (Walshe and Munro 1995). Zinc’s effect on copper balance takes at least 3 weeks to become evident on laboratory testing. Treatment compliance is critical, because patients who discontinue therapy develop serious medical conditions or can even die within several months (Brewer 1995b). Compliance and copper balance can be monitored by means of the oral 64Cu uptake test, urinary copper and zinc levels, and plasma free copper concentrations. In patients who are compliant with their zinc regimens, the peak blood concentration 1–2 hours after 64Cu ingestion is reduced to an average of 1.2% of the administered dose; in patients who are noncompliant, however, the peak blood concentration increases back up toward 6% of the administered dose (as in untreated WD) and reduces when they again become compliant. The desired values are ≤125 µg/24 hours for urinary copper and ≥2 mg/24 hours for urinary zinc in WD patients taking zinc (Brewer et al. 1990). Plasma free copper should be kept at ≤25 µg/dL. Plasma free copper (i.e., copper not bound to ceruloplasmin) can be determined by measuring plasma copper and ceruloplasmin levels and subtracting 3 µg of copper for each milligram of ceruloplasmin from the total plasma copper value. An increase suggests noncompliance. Percutaneous liver biopsies may reveal increased copper over the first 3 years of zinc treatment, but liver copper levels eventually return to normal with continued treatment (Brewer et al. 1990). Trientine. Trientine (triethylene tetramine dihydrochloride; Syprine) is usually given as 600 mg tid between meals (not sooner than 30 minutes before meals and 2 hours after meals), with reduction in dose to 600 mg/day once evidence of treatment response is seen

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(Brewer and Yuzbasiyan-Gurkan 1992; Walshe 1986a). Trientine reduces gastrointestinal copper absorption and increases urinary copper excretion (Siegemund et al. 1991). Both transient (Saito et al. 1991) and irreversible (Dahlman et al. 1995) neurological exacerbations have occurred with trientine therapy, suggesting that dosages should be titrated upward very gradually. Although side effects are minimal, iron deficiency, sideroblastic anemia, hepatic adenocarcinoma, colitis, and duodenitis have been associated with trientine (Dahlman et al. 1995), and it is expensive (Walshe 1995). Tetrathiomolybdate. Tetrathiomolybdate combines with copper to form a tripartite complex with protein, reducing intestinal copper absorption and inactivating circulating copper (Brewer 1995b). Ammonium tetrathiomolybdate is used as an initial treatment in neurological presentations because it infrequently causes neurological exacerbations and produces more rapid improvement than does zinc (Brewer 1995b). Most patients make good to excellent neurological recovery (Brewer et al. 1996). Tetrathiomolybdate is given both with meals (to prevent absorption) and between meals (to complex plasma copper). The drug is begun at 20 mg tid with meals, with the between-meal dose escalated over 1 week (usually to 20–60 mg tid between meals) until all non– ceruloplasmin-bound plasma free copper is complexed (see “Zinc,” above, for explanation of plasma free copper). After 8 weeks of treatment, maintenance zinc therapy is begun, and tetrathiomolybdate is discontinued 2 weeks later (Brewer 1995b). Alternatively, the drug can be chronically administered at 40 mg bid, although it is no more effective than zinc when given this way and is not considered useful in hepatic WD (Hoogenraad 1996). However, long-term maintenance therapy is useful in patients refractory to other treatments (Walshe 1995). Because tetrathiomolybdate can cause epiphyseal plate destruction, its use is generally contraindicated in children (Walshe 1995); if absolutely necessary, however, the total daily dose is usually ≥2.9 mg/kg (Brewer and Yuzbasiyan- Gurkan 1992). In addition to requiring special synthesis for clinical use in individual patients, tetrathiomolybdate is unstable, requiring storage under argon gas to prevent deterioration (Brewer et al. 1994a). Other

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drawbacks include bone marrow suppression and intestinal lesions, which have been reported in a few patients (Harper and Walshe 1986; Hoogenraad 1996). The drug is not yet available in the United States and is currently under U.S. Food and Drug Administration (FDA) review. Other Treatments Dimercaprol. In 1951, Cumings proposed dimercaprol (British anti-Lewisite, or BAL) as the first WD treatment. When used alone, dimercaprol is administered in painful daily intramuscular injections (300 mg in oil) for 20 consecutive days every 4 weeks for up to 4 courses (Hoogenraad 1996). As supplemental therapy, the dosage is 200 mg bid with D-penicillamine 500 mg tid (Walshe and Munro 1995). Although dimercaprol is initially effective, tachyphylaxis usually soon leads to inefficacy, and penicillamine provides a more sustained response (Brewer and Yuzbasiyan-Gurkan 1992; Saito et al. 1991). Other side effects include headache, fever, nausea, vomiting, salivation, and lacrimation; hallucinosis, delirium, coma, and death have also been reported (Walshe 1995). Other drugs. Drugs of yet-unproven value include potassium disulfide, ascorbic acid (vitamin C), and d-alpha-tocopherol (vitamin E). The chelating agent sodium 2,3-dimercaptopropane sulfonate is used in Russia and China (Hoogenraad 1996). Combination strategies. Some investigators recommend commencing treatment with D-penicillamine or trientine and switching to zinc after the first several months (Brewer and YuzbasiyanGurkan 1992). Regardless of the agent used, once therapy is initiated, it should be continued without interruption throughout life (Brewer and Yuzbasiyan-Gurkan 1992; McIntyre 1991). If neurological exacerbation or side effects require a switch from penicillamine, that agent can be stopped and zinc (acetate 40 mg tid or sulfate 200 mg tid) can be started the same day (Hoogenraad 1996). Simultaneous administration of chelators with zinc does not increase effectiveness and is theoretically counterproductive (Brewer et al. 1993), although this combination has sometimes been used in severely ill patients.

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Drinking water and diet. Deionized or distilled water may be helpful in communities with high levels of copper in the drinking water (Brewer and Yuzbasiyan-Gurkan 1992). A “low copper diet” is ineffective in preventing WD and is not usually necessary in patients undergoing decoppering therapy (Scheinberg and Sternlieb 1996). Most patients absorb no more than 1 mg/day of copper, an amount that poses no problem for decoppering therapy. However, some authorities recommend that WD patients limit their consumption of shellfish to no more often than once a week and of liver to no more than half an ounce each month (Brewer and Yuzbasiyan-Gurkan 1992). There is some evidence that a vegetarian diet may be sufficient for adequate maintenance therapy (Hoogenraad 1996). Liver transplantation. When liver disease is irreversible, transplantation should be considered. Acute hepatic failure, complications of cirrhosis, and a factor V reduction of greater than 25% are considered indications for transplantation (Cuthbert 1995; Hoogenraad 1996; Khanna et al. 1999; Walshe 1995). Graft survival rate in WD exceeds 73%, and patient survival rate exceeds 80%. Survival is better with chronic advanced liver disease (90%) than with fulminant hepatic failure (73% survival rate) (Bellary et al. 1995). Liver transplantation provides a phenotypic cure, sometimes reversing brain abnormalities (Bax et al. 1998; Bellary et al. 1995). Neurological improvement may be evident as early as 4–6 weeks after transplantation (Schumacher et al. 1997). Psychiatric improvement following liver transplantation has not been systematically studied. Specific Patient Populations Patients with liver disease. Penicillamine or trientine is recommended in hepatic WD, sometimes in combination with each other or with zinc (Brewer 1995b; Schilsky 1996). Patients with portal hypertension should not be switched from penicillamine to zinc (Hoogenraad 1996). Of course, management of ascites, edema, coagulopathy, and other complications of liver disease is necessary. Secondary manifestations of hepatic disease can reverse with WD treatment (Schilsky et al. 1991; Santos Silva et al. 1996). Plasmapheresis (Milovanovic et al. 1998) and peritoneal dialysis (Kuno et al. 1998) have been employed to treat acute hepatic complications in WD.

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Neurological patients. Tetrathiomolybdate produces good to excellent recovery, usually without any functional deterioration in neurological or psychiatric WD, and it is preferred by some authorities (Brewer 1995b; Brewer et al. 1994a). Although zinc may act too slowly to be given as the sole treatment to the neurological patient (Brewer and Yuzbasiyan-Gurkan 1992), it may be useful during exacerbations (Barbosa et al. 1992). Among 137 neurological WD patients treated with chelators, 57 (42%) became symptom free, 36 (26%) improved substantially, 24 (17%) were disabled, and 20 (15%) died; across groups, 30 (22%) suffered initial neurological exacerbations (Walshe and Yealland 1993). Psychiatric patients. Although research is needed, psychiatric WD should probably be treated in the same manner as neurological WD. In a study of WD patients with psychiatric initial presentations treated with thiomolybdate, exacerbations did not occur and most made a good recovery over a 1-year treatment course (Brewer 1995b). Incongruous behavior and cognitive impairment improve more than do irritability and depression with WD treatment (Dening and Berrios 1990). Psychiatric symptoms may resolve more often in patients lacking dysarthria, incongruous behavior, and hepatic symptoms. Other features resolving with WD treatment have included amnestic disorder, dementia, hypersexuality, aggression, hyperactivity, and disinhibition. In evaluating treatment responses, clinicians should remember that patients experience “good” days and “bad” days (as a function of stress, fatigue, etc.) in terms of neuropsychiatric symptom severity. Pregnant patients. A review of contraceptive options and their effects on hepatic function is provided elsewhere (Haimov-Kochman et al. 1997). Lack of WD treatment can lead to amenorrhea and infertility in female patients and can result in miscarriage in pregnant patients (Schagen van Leeuwen et al. 1991). WD is one disease in which the pregnant patient should be treated. Successful pregnancies have been documented in patients receiving D-penicillamine (Berghella et al. 1997), zinc acetate, and trientine (Walshe 1986b). Zinc is preferred, because penicillamine is associated with teratogenic birth defects, including cutis laxa, micrognathia, low-set ears, inguinal hernias, hy-

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drocephalus, and cerebral palsy. Assuming that the mother received adequate decoppering prior to conception, the dose can be reduced to 25 mg tid during pregnancy and re-increased to 50 mg tid after lactation (Brewer 1995b; Brewer and Yuzbasiyan-Gurkan 1992). Zinc may actually protect against some forms of birth defects (Nunns et al. 1995). Trientine is also considered useful in pregnancy. Obviously, consultation with an obstetrician is indicated, especially in the presence of severe liver disease. Presymptomatic patients. Zinc is recommended for initial treatment in presymptomatic patients, starting with half the usual dose (in children, one-quarter of the usual adult dose) and adjusting the dose according to plasma copper levels (Hoogenraad 1996). Penicillamine can induce neurological symptoms and other side effects and is not recommended (Hoogenraad 1996). Monitoring Disease Progression and Treatment Efficacy Clinical methods of following WD include videotaped quantitative neurological exam, audiotaped speech examination, T2 MRI (Schwarz et al. 1994; Thuomas et al. 1993), photographed KF rings, and liver function tests (Brewer et al. 1990). Auditory and somatosensory evoked potentials detect treatment-related neurological improvement but may not correlate with psychiatric improvement (references cited in Lauterbach et al. 1998). Glucose metabolism and dopamine receptor binding have correlated with improved motor function (Schlaug et al. 1994), but metabolic improvements may precede clinical improvements (Cordato et al. 1998). A reduction in KF rings may occur within several years after commencing treatment. Monitoring a reduction in positive copper balance can be useful, and a negative copper balance can signify deterioration (Hoogenraad 1996). Plasma free copper concentration can be monitored, maintaining the level at 10 µg/dL (for other measures, see “Zinc” under “Treatment of Underlying Disease” subsection earlier in chapter). Measurement of urinary copper is not useful in patients treated with chelating agents, because urinary copper is complexed with the chelator. Serial liver biopsies have been used to follow WD, but their results can be quite variable (Faa et al. 1995).

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Family Considerations and Genetic Testing When WD is detected, siblings should also be screened, because one in four will have presymptomatic WD (Brewer 1995b). The risk of WD is approximately 1 in 200 in the patient’s children, 1 in 800 in cousins, and 1 in 600 in nieces and nephews (Bachmann et al. 1991). Presymptomatic molecular genetic diagnosis is useful in studying siblings (Maier-Dobersberger et al. 1995). For example, the 5-year-old sister of a WD patient was asymptomatic and had normal ceruloplasmin, serum copper, and 24-hour urinary copper excretion. Nevertheless, restriction fragment length polymorphisms and polymerase chain reaction–based analysis with microsatellite markers disclosed her to be homozygous for disease-associated markers. A liver biopsy revealed a 20-fold increased liver copper content, confirming WD and allowing diagnosis before irreparable liver damage occurred. Genetic polymorphic satellite markers identified a heterozygous asymptomatic patient who had previously been assumed to be homozygous, allowing discontinuation of lifetime treatment with penicillamine (Vidaud et al. 1996). Unfortunately, the applicability of DNA analysis is limited to siblings of patients with established diagnoses of WD. Genetic diagnosis in the absence of a relative affected with WD is unlikely, because there are so many different mutations that can cause the illness.

Treatment of Psychiatric Manifestations Psychotropic Treatment Controlled studies of psychotropic treatment in psychiatric WD have not been reported (Rummans et al. 1999). Thus, the usual pharmacological armamentarium would seem to apply in WD, with the added consideration of potential copper deposition in the brain, liver, kidney, heart, and bone marrow (see Chapter 1 in this volume for a discussion of management principles in the context of specific organ system disease). Basal ganglia cuprification may lead to a heightened susceptibility to dystonia brought on by neuroleptics or selective serotonin reuptake inhibitors (SSRIs). Neuroleptic malignant syndrome and parkinsonism are more likely in WD patients, and atypical antipsychotics may be safer in this regard. Psycho-

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tropics that lower the seizure threshold may increase the likelihood of seizures in WD, especially in patients receiving WD treatment (Dening et al. 1988). Patients on anticonvulsants are at risk for the many drug interactions that can occur between these agents and psychotropics (Stoudemire and Fogel 1987; Stoudemire et al. 1995). Liver disease may affect the metabolism of psychotropics and prolong the functional half-life of the drug, leading to dose accumulation and toxic blood levels. Use of shorter-half-life drugs, lower doses, and drugs that are minimally metabolized before elimination may circumvent this problem. There is some evidence that the benzodiazepine antagonist flumazenil may have utility in treating the delirium of hepatic encephalopathy (Bostwick and Masterson 1998). Renal dysfunction in WD may lead to elevated lithium concentrations. Cardiac copper deposition can affect conduction pathways, leading to dysrhythmias, including tachycardia or bradycardia, with reduced cardiac efficiency (Hilz et al. 1990). Electrocardiogram abnormalities occur in about 30% of patients with WD, and orthostatic hypotension and sudden death have been reported. Therefore, use of psychotropics with low dysrhythmogenic and hypotensive potentials will be critical in some cases (Stoudemire and Fogel 1987; Stoudemire et al. 1995) (see “Heart disease” under “General Pharmacological Concerns” subsection in Chapter 1). Bone marrow suppression can occur with certain psychotropics as well as in WD. Attention must also be given to the effects of psychotropics on nonpsychotropic drugs that the medically ill patient is taking. For example, SSRIs can inhibit the metabolism of many drugs, leading to toxic elevations of plasma levels, which then can act upon already-diseased organs such as the heart or brain. Identifying targets of treatment. Absent specific empirical data regarding psychotropic use in psychiatric WD, several considerations germane to subcortical disease are of potential importance. These include the potential for delayed evolution, forme fruste presentations, compound syndromes, differential responsivity, and atypical responsivity of psychiatric disorders. Both neurological and psychiatric manifestations of a subcortical lesion can develop after a delay of months or years (Lauterbach et al. 1994, 1997a), and greater scrutiny of patients is therefore needed over a longer follow-up period than

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usual. Psychiatric forme fruste syndromes (limited-symptom presentations) can develop after subcortical lesions (Lauterbach et al. 1997b), requiring thorough evaluation for detection. Compound forms of illness may also exist, such as several different types of depression simultaneously coexisting after thalamic lesions. Moreover, different simultaneously coexisting depressions may selectively respond to different serotonergic and noradrenergic antidepressants (Lauterbach et al. 1994). Thus, the clinician should be alert to compound syndromes with differential or atypical responses. In addition, certain psychotropics may be ineffective in certain lesions, necessitating alternative treatment approaches. For example, lithium may be useful in cases of neuroleptic-refractory psychosis in basal ganglia disease (Munir 1986). A novel and creative pharmacological approach may therefore be necessary. Treatment should commence with lower doses, and doses should be titrated upward more gradually than in disease-free patients. It should be borne in mind that no controlled trials regarding psychotropic treatment of psychiatric manifestations of WD have been carried out. Antipsychotics. Because of the danger of severe extrapyramidal syndromes with neuroleptic use in WD (Hoogenraad 1996), quetiapine, clozapine, olanzapine, or risperidone might be preferable. Furthermore, these 5-HT2A receptor antagonists, which may act in part at the cortex, may be useful when subcortical dopaminergic systems are unresponsive. Moreover, clozapine can attenuate parkinsonian and dystonic features, although bone marrow suppression, seizure risk, and exacerbation of impaired liver function should be considered. In light of the paucity of data for these agents and mixed findings in Parkinson’s disease, however, patients treated with these agents deserve intensive monitoring (see Chapter 1 in this volume). Vigilance for cognitive impairment, cardiac dysrhythmia, and hypotension is necessary with the more anticholinergic agents (e.g., lowpotency neuroleptics, clozapine). Chlorpromazine has multiple metabolites, some with very long half-lives. These may accumulate in the context of hepatic failure. High-potency neuroleptics can either exacerbate or improve the various types of dystonia (see Chapter 6 in this volume), but there are no good predictors of effect. In one case report, neuroleptic malignant syndrome in WD responded to dan-

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trolene and bromocriptine (Kontaxakis et al. 1988). Given the potentially lethal impact of antipsychotic treatment in WD, a thorough discussion of benefits, risks, and side effects should be undertaken as part of informed consent, as with any drug treatment in WD. Mood stabilizers. For mania, disinhibited behavior, aggression, neuroleptic-refractory psychosis, and irritability, lithium may be of value if there is no renal impairment, seizure proclivity, or exacerbation of a tremor or a gait disorder. Anticonvulsants and benzodiazepines may be useful if gait, cognitive, liver, and bone marrow status do not contraindicate. Patients with the psychiatric manifestations of mania, disinhibited behavior, or irritability coupled with dystonia may benefit from lithium or anticonvulsants (see Chapter 6 in this volume). Similarly, WD patients with tremor and aggression may benefit from propranolol if cardiovascular status does not contraindicate. Of course, patients should be screened for the usual contraindications to beta-blockers before enlisting these agents in the treatment regimen. Antidepressants. SSRIs (see below) and antidepressants may be of value for mood disorders, obsessive-compulsive disorder, and panic disorder. Because of the possibility of unmasking subclinical cognitive impairment, sedating and strongly anticholinergic tricyclic antidepressants should be reserved for later trials. The same caveats listed for low-potency neuroleptics should be regarded for tricyclics, particularly those with tertiary amine structures. Amoxapine should be used cautiously, because it metabolizes to loxapine and can provoke extrapyramidal reactions (dystonia, parkinsonism, neuroleptic malignant syndrome). Bupropion may prove useful in dysautonomia or sexual dysfunction, but the risk of seizures should be considered. Buspirone and selective serotonin reuptake inhibitors. Patients with impulse control disorders, aggression, irritability, anxiety, or substance abuse may also benefit from serotonergic agents such as SSRIs or buspirone. However, these agents occasionally worsen akathisia, parkinsonism, dystonia, and other movement disorders such as myoclonus (see Chapters 1 and 6 in this volume). Cyto-

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chrome P450 drug interactions are another consideration in SSRI administration (see Chapter 1). Benzodiazepines. Benzodiazepines that have short half-lives (e.g., oxazepam, triazolam) or that are glucuronidated but not oxidized (e.g., lorazepam) may be of value in patients with liver disease. The possibility of precipitating or worsening cognitive impairment, disinhibition, reaction-time delays, ataxia, or substance abuse should be considered when using benzodiazepines. Nevertheless, benzodiazepines may have utility in treating catatonia (Davis and Borde 1993), anxiety, aggression, mania, postural tremor, and dystonia in selected patients. The long half-life of clonazepam, which can result in toxic dose accumulation, calls for frequent blood-level monitoring, especially in the presence of hepatic disease. Electroconvulsive Therapy Although experience is limited, electroconvulsive therapy (ECT) can be risky in WD. Negro Junior and Lousa Neto (1995) described a case in which a 46-year-old man with WD and major depression with mood-incongruent psychotic symptoms was treated with ECT after 2 years of treatment with penicillamine. He also exhibited disorganized behavior, disorientation, negativism, loose associations, persecutory and control delusions, and evidence of dementia. CT showed cortical atrophy but no enlargement of the lateral ventricles, and the EEG was normal. The patient was given one bilateral briefpulse ECT (12.4 J of charge), leading to a 3-minute motor seizure. He switched to mania the next day. When the depression recurred several days later, the patient was successfully treated with imipramine 150 mg/day and haloperidol 10 mg/day. The authors of the case report caution that ECT should be used with care, especially in untreated WD patients, who may have higher brain copper levels. They suggest that such patients may be more sensitive to ECT. The protracted 3-minute seizure in this case is consistent with the increased risk of seizures in this disease.

Summary Clinicians must remain vigilant for signs of hepatic and neurological disease. If WD is suspected, appropriate laboratory investigation and

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consultation should be obtained. If WD is diagnosed, siblings and family members of patients should be evaluated for WD. Early recognition and treatment is crucial for optimal outcome. WD is an illness presenting a panoply of psychiatric conditions that can be treated with a variety of modalities, including interventions targeting both the underlying neurological disease and the psychiatric manifestations of the disease. In the patient with WD, the clinician is confronted with an intriguing array of psychiatric manifestations with the potential for novel presentations, illness courses, and treatments. The co-occurrence of neurological and other WD manifestations can challenge the clinician’s pharmacological and therapeutic skills. Certain psychiatric conditions in WD may improve with decoppering treatments. WD can be a devastating disease, and improvement after psychiatric intervention is rewarding to both the clinician and the patient.

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C H A P T E R

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Fahr’s Syndrome Edward C. Lauterbach, M.D.

C

alcification of the basal ganglia has been variably referred to as Fahr’s disease, Fahr’s syndrome (FS), striopallidodentate calcification, striatopallidodentate calcification, and calcinosis nucleorum cerebri, among other terms. The course of FS is progressive. In adult FS, calcium deposition generally begins in the third decade of life, with neurological deterioration developing two decades later. FS has also been reported to occur in pediatric populations. The condition has been known since the middle 1800s, and Fahr (1931) actually was not the first to describe the illness. Ostertag (1922), Spatz (1922), and Weimann (1922) had previously published extensive reviews (Lowenthal 1986).

Prevalence A number of studies have determined the frequency of basal ganglia calcification (BGC) on computed tomography (CT) in patients undergoing radiological neuroimaging. Averaging these frequencies yields a BGC rate of 0.93% (274 BGC cases from a combined sample of 29,484 scans) (references cited in Lauterbach et al. 1998). The radiological prevalence of calcification is higher in children (15%) than in adults (Kendall and Cavanagh 1986). As discussed in the following section, the prevalence of FS depends on how the syndrome is defined. To avoid confusion with incidental BGC, it is advisable to require the presence of clinical findings ascribable to the calcification. Viewed from this perspec137

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tive, the prevalence of FS is probably somewhat less than 50 patients per 10,000 population, or 0.5%. In a review of 6,348 subjects’ CT scans, 62 (0.98%) had BGCs, but only 31 (0.49%) actually had FS (Konig 1989). There is some variance in this estimate of FS prevalence, because clinical findings vary widely among CT studies of FS. For example, in a study of 33 patients with calcification, none had clinical signs (Vles et al. 1981). In another study of 72 patients with calcification, extrapyramidal manifestations occurred in 15 (20.8%) and seizures in 13 (18.1%) (Kazis 1985). Psychiatric and neurological findings are inconsistently reported in prevalence studies of BGC ascertained by CT. The prevalences of specific etiological types of FS, including idiopathic Fahr’s disease, remain to be clarified.

Clinical Recognition and Neurological Presentation FS can be distinguished from other brain calcifications (e.g., calcified angiomas, infections, encephalitides, Addison’s disease lesions) by its greater severity and characteristic distribution (see “Neuroimaging” section later in chapter). FS should not be confused with normal calcification of cerebral structures such as the petroclinoid ligaments, falx cerebri, tentorium, choroid plexus, and pineal body. Non-FS calcification can also accompany phacomatosis, Hallervorden-Spatz disease, and paramyloidosis and can occur as a sequel to intoxication with lead or carbon monoxide. The term Fahr’s syndrome has been applied to BGC regardless of etiology, whereas Fahr’s disease has been used to refer to primary, heretofore idiopathic FS (Delplace et al. 1989). Lowenthal (1986) has set forth criteria defining FS (including Fahr’s disease): 1) the calcification must have a characteristic distribution, involving at least the globus pallidus, with or without cerebellar calcification, 2) the calcification must be evident on CT, and 3) the calcification must be of sufficient size to be detected on macroscopic pathological exam. Supportive nondiagnostic findings include 1) a definable clinical presentation and 2) an underlying metabolic abnormality, especially hypoparathyroidism (Lowenthal 1986). Subsequent definitions (Beall et al. 1989; Trautner et al. 1988) have required the presence of certain neurological features to allow FS to be distinguished from

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incidental BGC. Some specify that bilateral calcifications be present for the diagnosis of FS (Trautner et al. 1988); however, clinical manifestations vary widely, and calcifications occasionally present unilaterally (Kashihara and Yabuki 1992). Moreover, presymptomatic patients and patients with pure psychiatric presentations would be missed by these definitions. Perhaps a better clinical approach to diagnosing FS would be to require the presence of neurological or neuropsychiatric sequelae known to occur in FS in patients with radiological evidence of bilateral calcifications of the basal ganglia or cerebellum. In contrast to the clinician’s viewpoint, radiologists view BGCs as a common, generally asymptomatic finding on CT (Flint and Goldstein 1992). However, the presence of psychiatric or neurological manifestations associated with basal ganglia disease should dissuade the clinician from accepting the radiological finding as merely “incidental” and without clinical significance. Moreover, the patient may develop symptoms at some later date, even if he or she is asymptomatic at the time of the scan. Consequently, incidental discovery of BGC before age 50 years merits diagnostic investigation (Rasmussen et al. 1991). Despite variable calcification distributions and severities, certain clinical FS findings demonstrate remarkable constancy (Lowenthal 1986); these include seizures of all types, electroencephalogram (EEG) abnormalities, movement disorders (see “Neurological Features” subsection below), and cognitive and other psychiatric disorders (see “Psychiatric Manifestations” section later in chapter). Clinical features vary among FS cases, and other presentations are known. Endocrinological findings consistent with calcium metabolism disorders are present when these disorders constitute the disease etiology. Other than sex-linked inherited and intrauterine causes of FS, no important effects between FS and either gender or pregnancy have been reported.

Neurological Features A variety of neurological features are associated with FS. (Infantile and childhood manifestations are discussed later in this chapter in

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the subsection titled “Infantile and Juvenile Basal Ganglia Calcification.”) In adults, loss of consciousness, seizures, and cardiomyopathy have been reported in the context of FS associated with hypoparathyroid hypocalcemia (Arias Mayorga et al. 1991; Arranz Perez et al. 1992). The tetany of hypocalcemia is sometimes difficult to distinguish from the occasional fused tetanic myoclonus of some epileptic disorders. Paresthesias are not infrequent. Other associated features include spasticity, gait disorder, speech impairment, dementia, parkinsonism, chorea, tremor, dystonia, myoclonus, and coma (Lauterbach et al. 1998). Papilledema of intracranial hypertension and cerebrospinal fluid (CSF) pleocytosis may be present. Paroxysmal choreoathetosis (Klein et al. 1997) and paroxysmal dystonic choreoathetosis (Yamamoto and Kawazawa 1987) have also been reported. The reported prevalences of neurological sequelae in FS vary among studies. Kazis (1985) studied 72 patients in whom symmetrical intracranial calcifications had been identified by CT and found extrapyramidal syndromes in 15 (20.8%). In a literature review of 213 FS cases undertaken by Konig (1989), seizures were present in 46 (22%) and extrapyramidal movement disorders in 119 (56%). Konig found similar frequencies in his follow-up study (Table 5–1). Patients with complex partial seizures may manifest bizarre behavior, such as screaming or crying. Seizures may be due to underlying etiologies (e.g., hypoparathyroidism, hypocalcemia) or the brain pathology of FS itself. Dysarthria ranges from slow, slurred speech to Table 5–1.

Neurological presentations in Fahr’s syndrome

Headache/vertigo Extrapyramidal movement disorder Paresis/apoplexy Transient ischemic attacks Seizures Syncope

Initial (n = 62), no. (%)

Follow-up (n = 35), no. (%)

8 (13.0) 6 (10.0)

21 (60.0)

6 (10.0) 4 (6.0) 4 (6.0) 3 (5.0)

6 (17.1)

Note. Data from Konig (1989) indicating prevalence of neurological disorders on initial presentation and on long-term follow-up.

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marked impairment attributable to cerebellar and putaminal calcification. In a door-to-door study of parkinsonism in 982 rural Bavarians, 1 (5.9%) of 17 parkinsonian subjects had FS (Trenkwalder et al. 1995). Neurological features may be confined to one side of the body despite the presence of bilateral calcifications (el Maghraoui et al. 1995). In the study of Konig (1989), about half of FS patients had neurological symptoms (see Table 5–1), as opposed to about one-third of patients in the study of Kazis (1985). These studies suggest that the prevalence of neurological symptoms may vary in FS. Most studies conclude that there is little relation between the extent or localization of calcifications and the extent or type of neurological manifestations (Kazis 1985; Taxer et al. 1986), apart from suggestions of greater severity of extrapyramidal features and dementia in patients with more extensive calcifications (Taxer et al. 1986). Although clinical findings may sometimes correlate with calcification location (e.g., parkinsonism with midbrain, globus pallidus, or thalamus calcification), the presence of calcification in structures that are traditionally associated with particular clinical findings does not predict the manifestation of those findings in FS. In a study of 18 ambulatory FS patients identified by CT and then evaluated clinically (LópezVillegas et al. 1996), 2 (11.1%) had parkinsonism (both with pallidal calcification, 1 with additional thalamic and cerebellar dentate calcification), 7 (38.9%) had seizures (7 with pallidal calcification, 1 with putaminal calcification), 4 (22.2%) had transient ischemic attacks (3 with pallidal calcification, 1 with putaminal calcification), and 1 (5.6%) had dysarthria and orthostatic hypotension (caudate and putaminal calcification). The lesion locations in this study included the globus pallidus in 16 (88.9%), the putamen in 3 (16.7%), the caudate in 2 (11.1%), the thalamus in 1 (5.6%), and the cerebellar dentate nucleus in 1 (5.6%) (López-Villegas et al. 1996). In another study (Taxer et al. 1986), neurological features led to faster diagnosis of FS than did psychiatric manifestations.

Pathological Features Pathology is similar in infantile and adult-onset FS (Matsui et al. 1992). Microscopic examination reveals perivascular granules above

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the midbrain but not in the pituitary or pia mater. In a review of 30 patients with globus pallidus calcifications demonstrated on CT, Adachi et al. (1994) found that the lateral pallidum was more often calcified than the medial pallidum. However, in another study of 72 patients with symmetrical intracranial calcifications, Kazis (1985) found a subgroup with isolated medial pallidal calcification. It is not clear why calcifications develop in certain brain structures and not others. Defective iron transport and free radical production may damage tissue, initiating calcification (Beall et al. 1989). Calcium is then increased several hundredfold. Calcific deposits are composed of calcium phosphate and carbonate; glycoproteins; mucopolysaccharides; and metals, including iron, copper, magnesium, zinc, aluminum, silver, and cobalt (Kobayashi et al. 1987; Lowenthal 1986). Calcification mineral composition varies by anatomic site and by proximity to vasculature (Bouras et al. 1996). Deposits occur mainly in blood vessel adventitial cells and, occasionally, glial cells. Deposits are connected by filamentous cytoplasmic processes between cells. Attempts to find a unifying pathophysiological explanation for calcifications resulting from diverse etiologies have failed.

Idiopathic and Primary Fahr’s Disease Until recently, primary Fahr’s disease has been considered to be idiopathic in origin. However, study of a multigenerational family using polymorphic microsatellite markers has led to linkage of primary Fahr’s disease to chromosome 14q between D14S75 and D14S306 (Geschwind et al. 1999). The age at onset decreased by more than 20 years with each transmission, consistent with genetic anticipation. This is a new finding and it will be interesting to follow this important development. It is possible that multiple mutations of this gene will be found. Other genes may be linked to Fahr’s disease in the future. It will be of value to study the neuropsychiatric sequelae of specific types of Fahr’s disease as these gene linkages emerge.

Etiologies of Secondary FS In addition to the 14q gene for primary Fahr’s disease, several patterns of inheritance have been observed in FS (see “Genetic Asso-

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ciations” subsection below). FS is associated with a diversity of conditions (Table 5–2). Several problems arise when one attempts to catalogue FS etiologies from the literature. First, few reports actually examine causal relationships between the associated condition and FS. Second, variable nosologies are applied, with FS diagnosed in the absence of clinical features in some reports. Third, attribution difficulties arise when clinical features are present, because it is difficult to discern whether the clinical findings are manifestations of FS itself or, instead, of the underlying associated condition (e.g., seizures in FS due to hypoparathyroidism). Finally, case ascertainment is problematic, because calcifications reported to be asymptomatic may subsequently progress to become symptomatic. In view of these problems and the need to diagnostically investigate BGC in patients younger than age 50 years regardless of whether clinical signs or symptoms are in attendance (Rasmussen et al. 1991), conditions associated with BGC (rather than conditions associated with documented FS) are detailed in the following subsections. These include endocrine, vitamin D, genetic, mitochondrial, neurological, infectious, neoplastic, dermatological, and pharmacological conditions (see Table 5–2). Similarly, an array of clinical conditions are associated with juvenile presentations of BGC, including many of the ones just listed, as well as inborn errors of metabolism and several other unique associations. Each of these conditions is discussed in turn in the subsections that follow. The term FS is used when the condition clearly represents FS. Otherwise, BGC is used when it is unclear whether the clinical presentation of FS was actually apparent in the report. Until the case ascertainment problems enumerated in the preceding paragraph can be resolved, the precise etiological differential diagnosis of FS per se will remain obscure. From a clinical viewpoint, it is therefore safer and more conservative to consider the broader differential diagnosis of BGC in patients with clinical manifestations of FS.

Endocrine Disorders Parathyroid and endocrine disturbances are the conditions most commonly associated with FS (Table 5–3). In particular, the clinician should be alert for idiopathic hypoparathyroidism, secondary hypoparathyroidism (e.g., postthyroidectomy), pseudohypoparathyroidism, pseudo-

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Table 5–2.

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Causes of Fahr’s syndrome (FS)

Adult FS Primary Fahr’s disease 14q (between D14S75 and D14S306) Idiopathic Endocrine disorders Hypoparathyroidism Primary hypoparathyroidism Postthyroidectomy hypoparathyroidism Pseudohypoparathyroidism Defective parathormone binding Defective guanine nucleotide binding protein Pseudo-pseudohypoparathyroidism Vitamin D disorders Genetic causes Associated with parathyroid disturbances Associated with ataxia and pigmentary macular degeneration Associated with hypertension Trisomy 21 (Down syndrome) Trisomy 5 Autosomal recessive FS With spondyloenchondrodysplasia With reduced homocarnosine and histidine With encephalopathy, microcephaly, dwarfism, retinal degeneration, or demyelination Aicardi-Goutieres syndrome Autosomal dominant FS With elevated homocarnosine With 25-hydroxyvitamin D3 deficiency With normal calcium metabolism With psychiatric disturbances Mitochondrial myopathies and encephalopathies MELAS MERRF Kearns-Sayre syndrome Mitochondrial ophthalmoplegia Alport syndrome (continued)

Fahr’s Syndrome

Table 5–2.

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Causes of Fahr’s syndrome (FS) (continued)

Degenerative diseases Motoneurone disease Early-onset Alzheimer’s disease Infectious diseases Neurobrucellosis AIDS Toxoplasmosis Encephalitis Inflammatory diseases CNS lupus Tuberous sclerosis Anoxia Trauma Neoplastic diseases Multiple myeloma Metastatic astrocytoma Dermatopathies Lipoid proteinosis (Urbach-Wiethe disease) Hidrotic ectodermal dysplasia Lipomembranous polycystic osteodysplasia Drugs Anticonvulsants Pediatric FS Genetic causes With neurological signs Without neurological signs Metabolic causes Abnormal calcium metabolism Biotinidase deficiency Dihydropteridine reductase deficiency with hyperphenylalaninemia Folate deficiency with dihydropteridine reductase Hyperammonemia with reduced ornithine transcarbamylase activity Propionic acidemia (continued)

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Causes of Fahr’s syndrome (FS) (continued)

Metabolic causes (continued) Type I GM1 gangliosidosis Mitochondrial myopathies MERFF Diffuse cerebral microangiopathy with leukodystrophy Infantile neuraxonal dystrophy Infectious diseases AIDS Epstein-Barr virus Pertussis encephalitis Cocksackie encephalitis Meningitis Acute hemorrhagic leukoencephalitis Congenital encephalopathy Anoxic Prenatal viral Intrauterine transfusion Juvenile rheumatoid arthritis Coats’ disease Juvenile nephronolithiasis and pancreatic lipomatosis Neurofibromatosis Neoplasia Tuberous sclerosis Myotonic muscular dystrophy Note. AIDS = acquired immunodeficiency syndrome; CNS = central nervous system; MELAS = mitochondrial myopathy, encephalopathy, lactacidosis, and stroke-like syndromes; MERRF = myoclonic epilepsy and myopathy with ragged red fibers.

pseudohypoparathyroidism, and hyperparathyroidism. Bruyn et al. (1964) reviewed the literature of 150 FS cases and found that 35 (23.3%) had idiopathic hypoparathyroidism, whereas 23 (15.3%) had postthyroidectomy hypoparathyroidism. In 62 FS subjects identified clinically and subsequently diagnosed following CT imaging, Taxer et al.

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(1986) found that 9 (14.5%) had undergone thyroidectomy an average of 25 years prior to FS presentation. Among studies of CTidentified FS-type calcifications regardless of FS clinical signs (Brannan et al. 1980; Harrington et al. 1981; Kazis 1985; Murphy 1979; Vles et al. 1981), meta-analysis reveals a lower prevalence (18 [8.4%] of 215 cases) of parathyroid disturbances than in the earlier literature review of Bruyn et al. (1969). Consequently, parathyroid disorders constitute a more important cause of FS than of BGC without neurological signs. In a review of the reported endocrinological literature, Danowski et al. (1960) found that BGC occurred in 20 (21.5%) of 93 patients with idiopathic hypoparathyroidism, 26 (42.6%) of 61 patients with pseudohypoparathyroidism, and 2 (6.1%) of 33 patients with pseudo-pseudohypoparathyroidism. Review of a series of 41 cases of postsurgical hypoparathyroidism revealed 2 (4.9%) with BGC (Basser et al. 1969). Reduced parathormone (in hypoparathyroidism) or reduced renal response to parathormone (in pseudohypoparathyroidism) decreases renal tubular phosphorus excretion, with consequent hyperphosphatemia and hypocalcemia, which, in turn, promote calcification (Lowenthal 1986). More rarely, hyperparathyroidism is associated with FS (Lowenthal 1986). Each of these parathyroid disorders (see Table 5–3) can be recognized by clinical features and laboratory evidence. The laboratory values most instructive in differentiating these disorders are serum calcium, phosphorus, and parathyroid hormone levels. Hypoparathyroidism is of either primary or secondary (postthyroidectomy) origin. Primary hypoparathyroidism usually presents within the first six decades of life and is genetically transmitted through several modes, including autosomal dominant, recessive, and X-linked inheritance. Multiple forms of mutation can occur for each mode of inheritance, with different mutation forms in different families. Hypoparathyroidism can be clinically recognized by cataracts, tetany, seizures (or EEG abnormalities), dysarthria, increased intracranial pressure, papilledema, soft tissue calcification, congestive heart failure, pernicious anemia, and a variety of autoimmune, extrapyramidal, and psychiatric features. Not all of these features would be expected to be present in a given patient, because different

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Table 5–3.

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Endocrine disorders

Hypoparathyroidism Clinical features Cataracts Tetany Seizures EEG abnormalities Dysarthria Increased intracranial pressure Papilledema Extrapyramidal signs (parkinsonism, chorea) Psychiatric features Dementia Delirium Psychosis Bipolar disorders Depression Anxiety (panic, hyperventilation) Soft tissue calcifications Congestive heart failure Variable autoimmune disorders (especially against endocrine organs) Pernicious anemia Onset First to sixth decades of life Laboratory evidence Hypocalcemia Hyperphosphatemia Low parathyroid hormone (parathormone [PTH]) Reduced 1,25-dihydroxyvitamin D3 Variable thyroid, ovary, or thymus dysfunction (in primary hypoparathyroidism) Genetics Autosomal dominant, recessive, and X-linked involving multiple mutations Treatment Vitamin D and oral calcium; thiazide diuretics (continued)

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Table 5–3.

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Endocrine disorders (continued)

Pseudohypoparathyroidism Clinical features Resemble hypoparathyroidism Moon facies Short stature Thickset body type Shortened metacarpals and metatarsals Soft tissue calcification Dental abnormalities Laboratory evidence Parathormone levels normal or quite high Hypocalcemia Hyperphosphatemia Genetics Linked to chromosome 20 Several subtypes exhibiting variable clinical and laboratory features Treatment Similar to hypoparathyroidism Pseudo-pseudohypoparathyroidism Clinical features Resembles pseudohypoparathyroidism Blue sclerae Laboratory evidence Normocalcemia Normophosphatemia Normal parathormone response Genetics Usually first-degree relatives of patients with pseudohypoparathyroidism Possible pseudohypoparathyroidism variant Hyperparathyroidism Clinical features Nephrolithiasis Proximal muscle weakness, atrophy (continued)

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Table 5–3.

Endocrine disorders (continued)

Hyperparathyroidism (continued) Clinical features (continued) Abdominal complaints Chondrocalcinosis Pseudogout Osteopenia (rare) Laboratory evidence Hypercalcemia Fasting morning hypophosphatemia Elevated parathormone Osteitis fibrosa cystica on bone biopsy Treatment Medical referral Surgical treatment may be necessary Note.

EEG = electroencephalogram.

signs occur in different patients. When present, autoimmune disorders can involve a variety of tissues, but immunity is most often directed against endocrine organs. Extrapyramidal disorders usually involve parkinsonism or chorea. Psychiatric manifestations include dementia, delirium, psychosis, bipolar disorders, depression, and anxiety disorders. Anxiety symptoms have included panic and hyperventilation. Because extrapyramidal and psychiatric disturbances occur as manifestations of hypoparathyroidism, psychiatric findings in patients with hypoparathyroid FS may be caused by hypoparathyroidism, FS, or both. Laboratory findings indicative of hypoparathyroidism include hypocalcemia, hyperphosphatemia, low parathyroid hormone levels, and reduced 1,25-dihydroxyvitamin D levels. In primary hypoparathyroidism, variably present additional hormonal disturbances of the thyroid, ovary, or thymus may also be evident. Treatment involves oral vitamin D supplementation, calcium supplementation, and thiazide diuretic administration. Pseudohypoparathyroidism has been linked to chromosome 20. Several subtypes exist, with variable clinical and laboratory features. Clinical signs include those of hypoparathyroidism, as well as short stature, thick-set body type, moon facies, shortened metacarpals

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and metatarsals, and dental abnormalities. Although laboratory evidence of pseudohypoparathyroidism involves hypocalcemia and hyperphosphatemia, just as in hypoparathyroidism, parathyroid hormone levels are either normal or elevated in pseudohypoparathyroidism. Other laboratory findings differ among the various subtypes. One subtype involves defective parathyroid hormone binding to endorgans; another type involves defective guanine nucleotide binding protein. Despite these differences, treatment is essentially the same as for hypoparathyroidism. Pseudo-pseudohypoparathyroidism may represent a variant of pseudohypoparathyroidism, because that condition is usually present in first-degree relatives. Moreover, the clinical features of the two conditions are identical, except for the finding of blue sclerae on ophthalmological exam in patients with pseudo-pseudohypoparathyroidism. In light of the normal laboratory values for calcium, phosphorus, and parathyroid hormone in individuals with pseudopseudohypoparathyroidism, no treatment is indicated. Hyperparathyroidism can be recognized by the clinical features of proximal muscle weakness and atrophy, chondrocalcinosis, pseudogout, abdominal complaints, and nephrolithiasis. Osteopenia may occasionally be present. Laboratory evidence includes hypercalcemia, fasting morning hypophosphatemia, elevated parathyroid hormone level, and the finding of osteitis fibrosa cystica on bone biopsy. Medical referral can assist with determining whether surgical treatment is indicated.

Vitamin Disorders Vitamin D is involved in calcium metabolism. In view of the role of disturbed calcium metabolism in FS (discussed above under “Endocrine Disorders”), it is not surprising that derangements of vitamin D metabolism—for example, 25-hydroxyvitamin D3 deficiency—have also been associated with FS (Martinelli et al. 1993).

Genetic Associations Genetic causes of FS are diverse, and manifestations vary. Many investigators have reported familial cases, reviewed elsewhere (Lowenthal 1986). No specific gene has yet been identified. Modes of inheritance include autosomal dominant (Kobari et al. 1997) and re-

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cessive forms, X-linked dominant (one form of pseudohypoparathyroidism), and possibly others. Fried syndrome is linked to Xp22 and involves severe mental retardation, spastic diplegia, ventricular dilatation, and BGC (Strain et al. 1997). BGC is associated with trisomy 5 (5q35,1→qter) (Nakayama et al. 1993), Down syndrome (trisomy 21) (Okano et al. 1992), and consanguinity. Trisomy 5 is associated with obesity, short stature, extremity and facial malformations, mental retardation, and eczema. Familial BGCs have been associated with hypoparathyroidism (Garcia Urra et al. 1990), ataxia and pigmentary macular degeneration (Strobos et al. 1957), and elevated serum alpha-fetoprotein (Tokoro et al. 1993). Autosomal dominant FS (Ellie et al. 1989; Rossi et al. 1993) is sometimes associated with elevated homocarnosine, a central nervous system (CNS)–specific peptide (Manyam et al. 1992), or with 25-hydroxyvitamin D3 deficiency (Martinelli et al. 1993). FS has been observed in patients with Alport syndrome (Schafer and Ferbert 1998), an autosomal dominant nephritis associated with nerve deafness and occasional ocular defects, including cataracts and defects of the lens, cornea, and retina. Males are more affected than females, and patients usually die of renal failure before the age of 40 years. Autosomal recessive BGC (Rysz et al. 1988) in children is often attended by encephalopathy, microcephaly, dwarfism or short stature, retinal degeneration or optic atrophy, or symmetrical patchy demyelination (Billard et al. 1989). Another form of autosomal recessive BGC is associated with short stature and spondylometaphyseal skeletal dysplasia and can be seen in consanguineous families (Frydman et al. 1990). Other specific types of autosomal recessive BGC involve associations with reduced homocarnosine and histidine levels and the Aicardi-Goutieres syndrome (see “Infantile and Juvenile Basal Ganglia Calcification” subsection below). X-linked dominant BGC is associated with various psychiatric disorders (Francis 1979; Francis and Freeman 1984). Many cases of genetically related BGC have their onset in childhood.

Mitochondrial Myopathies BGC can occur in mitochondrial myopathies. In some mitochondrial myopathies, serum lactic acid is increased and CSF proteins and

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calcium metabolism may be abnormal. One of these, Kearns-Sayre syndrome, is associated with BGC, progressive external ophthalmoplegia, pigmentary retinal degeneration, and increased CSF protein. BGC has also been associated with an infantile variant of mitochondrial ophthalmoplegia (Bastiaensen et al. 1984). In a review by Pavlakis et al. (1984) of 11 patients with MELAS (mitochondrial myopathy, encephalopathy, lactacidosis, and stroke-like syndromes) and MERRF (myoclonic epilepsy and myopathy with ragged red fibers on histological muscle examination), 5 (45.4%) had BGCs and 3 (27.3%) had symptoms consistent with FS. A recent study of 24 subjects from six kindreds with MELAS revealed BGC to be the most common radiological finding in this mitochondrial disease (Sue et al. 1998).

Neurological and Degenerative Diseases BGC has been described in association with CNS infections (see below) and CNS lupus (Matsumoto et al. 1998), as well as following head injury and anoxia. Although FS is associated with seizure disorders, it may also be associated with anticonvulsant treatment (see “Drugs” subsection below). Several diseases of a progressive or neurodegenerative nature have been associated with BGC. These include earlyonset Alzheimer’s disease, motor neuron disease, and tuberous sclerosis.

Infectious and Immunological Diseases Neurobrucellosis is linked to BGC. Of 65 patients presenting with neuropsychiatric manifestations of brucellosis in one study, 9 (13.8%) had BGC (Mousa et al. 1987). BGC has also been associated with encephalitis and with toxoplasmosis (Lishman 1987). BGC in acquired immunodeficiency syndrome (AIDS) may occur in patients with abnormal calcium metabolism, possibly augmenting the vascular pathology of AIDS and hastening calcification (Fenelon et al. 1993).

Neoplastic Diseases BGC has been associated with malignancies, particularly with multiple myeloma (probable FS), metastatic astrocytoma, and radiation

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therapy (see “Infantile and Juvenile Basal Ganglia Calcification” subsection below).

Dermatological Disorders BGC is associated with dermatological diseases, a sometimes important clinical tip-off (Lowenthal 1986). One of these conditions is lipoid proteinosis (Urbach-Wiethe disease), with manifestations including seizures, dementia, hyalinosis of the skin and mucosa, alopecia, photosensitivity, and dwarfism (Newton et al. 1971). BGC has also been associated with hidrotic-ectodermal dysplasia and mental retardation (Copeland et al. 1977) and with lipomembranous polycystic osteodysplasia and dementia (Matsuo et al. 1982).

Medications Given the utility of anticonvulsants in managing psychiatric disorders, it is worth emphasizing that anticonvulsant treatment has been associated with BGC. Of 72 subjects with BGC identified on CT, 13 (18%) were taking anticonvulsants, of whom 11 were on phenytoin with or without barbiturates and 2 were on carbamazepine (Kazis 1985). It was suggested that anticonvulsant effects on calcium or phosphorus, or the activity of alkaline phosphatase, may relate to this finding.

Infantile and Juvenile Basal Ganglia Calcification Microencephaly, pigmentary macular degeneration, progeria, and abnormal calcium metabolism are variably associated with infantile and juvenile BGC. Infantile FS is rare and heterogeneous in etiology, but it can be associated with infantile spasms, microcephaly, blindness, a burstsuppression pattern on EEG, early death, hyperammonemia, reduced hepatic ornithine transcarbamylase activity, and consanguinity (Matsui et al. 1992). Aicardi-Goutieres syndrome (familial early-onset encephalopathy with BGC and chronic CSF lymphocytosis) is an autosomal recessive disorder characterized by increased CSF interferon-alpha and en-

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cephalopathy evident shortly after birth and associated with developmental arrest (Tolmie et al. 1995). In a retrospective study of 27 patients with Aicardi-Goutieres syndrome, 19 experienced onset within the first 4 months of life, with microcephaly and severe, progressive brain atrophy developing between 3 and 12 months of age (Goutieres et al. 1998). CSF lymphocytosis persisted beyond 12 months of age in 7 of the children. The 19 patients still alive (6 older than 10 years) at the time of the study were profoundly disabled. There were individual variations in disease severity, rapidity of evolution, and imaging features. Neuropathological examination revealed only focal necrosis and widespread demyelination. High levels of interferon-alpha were found in the serum and CSF in 14 patients, suggesting intrathecal synthesis and the possibility that interferon-alpha may play a role in the pathogenesis of the disorder. Consistent with this hypothesis, transgenic mice have been developed that produce interferon-alpha(l) from astrocytes (Campbell et al. 1999). These mice develop depletion of cholinergic neurons, gliosis, and progressive calcification of the basal ganglia and cerebellum, along with hippocampal hyperexcitability and seizures. Thus, interferon-alpha may foster the development of FS occurring in the context of the Aicardi-Goutieres syndrome. Bode and Rudin (1995) reported a case of human immunodeficiency virus (HIV) infection in a 4-month-old with BGC that they thought might relate to lenticulostriate arteriopathy. Seizures occurred 3 years later in association with then-evident BGC. Infantile BGC has also been reported after intrauterine herpes simplex virus infection. The major associations of juvenile-onset BGC include metabolic, endocrine, genetic, mitochondrial, neurological, systemic, infectious, and neoplastic diseases. A variety of metabolic diseases have been implicated, including abnormal calcium metabolism, dihydropteridine reductase deficiency (with hyperphenylalaninemia or with folate deficiency), biotinidase deficiency, proprionic acidemia, and hyperammonemia with reduced ornithine transcarbamylase activity. Recently, FS was found to be associated with Type I GM1 gangliosidosis presenting in a 10-month-old boy with diffuse cerebral atrophy, craniofacial and skeletal malformations, hepatosplenomegaly, poor oculomotor control, profound hypo-

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tonia, weakness, and brisk reflexes (Chen et al. 1999). Childhood BGC linked to abnormal calcium metabolism can occur with seizures and encephalopathy (Guerreiro and Scotoni 1992). Cases associated with Down syndrome and trisomy 5 may have pediatric presentations. In some cases, presentation may be delayed until puberty (Francis 1979). BGC has been associated with congenital anomalies. Some mitochondrial diseases (see “Mitochondrial Myopathies” subsection earlier in this chapter) may present with BGC in pediatric patients, particularly MERRF. In a study by Legido et al. (1988) involving 4,283 children undergoing CT scans, tuberous sclerosis was present in 14 (29%) of 48 children with radiologically identified BGC. Other neurological disease associations include infantile neuraxonal dystrophy, diffuse cerebral microangiopathy with leukodystrophy, acute hemorrhagic leukoencephalitis, pertussis encephalitis, Cocksackie encephalitis, meningitis, congenital encephalopathies of anoxic and prenatal viral origins, myotonic muscular dystrophy, and neurofibromatosis. Systemic diseases associated with juvenile BGC involve juvenile rheumatoid arthritis, juvenile nephronolithiasis and pancreatic lipomatosis, and intrauterine transfusion. The chief infectious association documented is AIDS. Chronic Epstein-Barr viral infection is also associated with BGC. In the study of Legido et al. (1988) mentioned above, neoplasms of various types were found in 16 (33%) of 48 children with radiologically identified BGC. All of these patients had received radiation therapy to the diencephalon. Coats’ disease, a retinopathy of obscure etiology occurring mainly during the first decade of life, has recently been reported in association with BGC (Goutieres et al. 1999). Occasionally, intraocular bone formation can also occur in Coats’ disease (Senft et al. 1994). Given the substantial number of conditions associated with BGC, it is likely that many more conditions will be identified in the future. It will be important to distinguish between chance associations and causal relationships with BGC. Hopefully, future work will determine which of these conditions cause FS. In the meantime, it is wise to consider the numerous associations of BGC when evaluating patients with FS.

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Neuroimaging Radiological findings on CT vary from barely noticeable dustlike opacification to more significant radiodensities (Lowenthal 1986). The distribution of calcification is generally limited to the pallidum (i.e., globus pallidus) and striatum (putamen and caudate), cerebellar dentate nucleus, thalamus, centrum semiovale, cerebral cortex, and cerebellar cortex. The pallidum is most commonly involved (Taxer et al. 1986), although the cerebellum is sometimes calcified in isolation (Koller and Klawans 1980). Cortical calcification occurs at the base of the sulci, especially in the frontal, frontoparietal, and posterior temporal areas (Lowenthal 1986). BGC is usually bilaterally symmetrical (Lowenthal 1986) but can present unilaterally (Kashihara and Yabuki 1992). CT has greater diagnostic specificity for FS than does magnetic resonance imaging (MRI), but MRI correlates better with functional impairment (Avrahami et al. 1994; Manyam et al. 1992). CT lesions appear as hyperdensities (Figure 5–1), but deposits can be exaggerated (Kulczycki et al. 1994) and do not correlate well with neurological features (Avrahami et al. 1994). Blood flow to calcified regions is markedly decreased and correlates with clinical condition (Uygur et al. 1995). T2 hyperintensity of white matter and, sometimes, gray matter on MRI is consistent with FS (Avrahami et al. 1994); however, MRI appearance of calcification varies by site, disease stage, and metabolic state. BGCs (Figure 5–2) exhibit reduced signal (Scotti et al. 1985). In children, MRI findings resemble those seen in Hallervorden-Spatz disease (Okano et al. 1992). After birth hypoxia, calcification can be evident by 5 months of age (Akimov 1991). Postanoxic calcification can actually develop within 17 days (Midroni and Willinsky 1992). Calcification in primary hypoparathyroidism is more diffuse than that in BGC of other etiologies (Kazis 1985; Ogata et al. 1987), but postthyroidectomy hypoparathyroidism calcifications are more focal (Konig 1989). Among subjects with postthyroidectomy BGC in the study of Konig (1989), 70% had pallidal calcifications; 12% both pallidal and putaminal calcifications; 6% pallidal and cerebellar calcifications; 3% pallidal, putaminal, caudate, and thalamic calcifications; 5% calcifications of the caudate

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Figure 5–1. Appearance of globus pallidus calcification at several levels, as viewed on computed tomography (CT). Source. Reproduced from Lauterbach EC, Spears TE, Prewett MJ, et al.: “Neuropsychiatric Disorders, Myoclonus, and Dystonia in Calcification of Basal Ganglia Pathways.” Biological Psychiatry 35:345–351, 1994a. Copyright © 1994, Elsevier Science, Inc., 655 Avenue of the Americas, New York, NY 10010-5107. Used with permission.

alone; and 4% pontine calcifications (Konig 1989). Among the patients with BGC who had not undergone thyroidectomy, 53% had pallidal calcifications; 23% pallidal, putaminal, caudate, thalamic, cerebellar, and white matter calcifications; 14% pallidal and cerebel-

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Figure 5–2. Reduced signal in the globus pallidus due to calcification, as viewed on T2-weighted magnetic resonance imaging (MRI). Source. Reproduced from Lauterbach EC, Spears TE, Prewett MJ, et al.: “Neuropsychiatric Disorders, Myoclonus, and Dystonia in Calcification of Basal Ganglia Pathways.” Biological Psychiatry 35:345–351, 1994a. Copyright © 1994, Elsevier Science, Inc., 655 Avenue of the Americas, New York, NY 10010-5107. Used with permission.

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lar calcifications; and 10% pallidal and caudate calcifications. In Kazis’ study of 72 patients with BGC, selective calcification of the globus pallidus was not associated with parathyroid disturbances, in contrast to the findings in Konig’s study.

Clinical and Laboratory Investigation FS must be actively considered by the clinician in order to avoid missing the diagnosis. For example, a 60-year-old patient diagnosed with delusional disorder and tardive dyskinesia was later found to have Fahr’s disease with secondary delusions and choreoathetosis (Chiu et al. 1993). Gradually progressive symptoms with atypical onset, neurological signs, or family history of neuropsychiatric diagnoses, especially in patients with conditions known to be associated with BGC, warrant workup. One guideline is that every first-onset case of dementia, psychosis, or mood disorder deserves an MRI scan. Mineralization on MRI should be evaluated by CT scan. The presence of calcification on imaging in patients under 50 years of age merits an etiological workup (Rasmussen et al. 1991). Following clinical and radiological ascertainment of FS, serum calcium, ionized calcium, magnesium, parathormone (i.e., PTH or parathyroid hormone), and fasting morning phosphorus levels should be obtained to exclude the disorders of calcium metabolism detailed above (Avrahami et al. 1994). The clinician should determine whether the patient has undergone thyroidectomy (parathyroid glands are sometimes removed with thyroid tissue); look for the clinical features of these disorders (see “Endocrine Disorders” under “Etiologies” section earlier in chapter); and obtain endocrinological consultation if endocrinological signs are present or laboratory findings are abnormal. Following this initial evaluation, the clinician should consider clinical features consistent with other causes. The EEG displays many different abnormalities in FS; there is no characteristic pattern. Triphasic EEG waves with normal brainstem auditory evoked responses and somatosensory evoked potentials have been observed in Fahr’s disease (Aguglia et al. 1990). Other tests of potential diagnostic value include alkaline phosphatase, 24-hour urinary calcium and phosphorus excretion, calcitonin, serum cyclic adenosine monophosphate (cAMP), urinary cAMP,

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serum creatine, osteocalcin, serum lactic acid at rest and after exercise, and 1,25-dihydroxyvitamin D3 (Martinelli et al. 1993).

Psychiatric Manifestations A wide variety of psychopathology has been associated with FS. Cognitive disturbances, dementia, delirium, hallucinations, delusions, ideas of reference and influence, paranoia, catatonia, and mood disorders are not infrequent (Lowenthal 1986). Symptomatic features and age at onset can vary from patient to patient, regardless of FS etiology. Clinical features may change over time, progressing from psychosis to frank dementia (Rosenberg et al. 1991) as basal ganglia–thalamofrontal and other circuits become calcified (Lauterbach et al. 1994a). Psychiatric symptoms are common in FS. Among 62 subjects with FS studied by Konig (1989), about half had psychiatric symptoms. Mental disorders are more common with more extensive calcification (Kazis 1985; Konig 1989) and subarachnoid space dilatation (Kazis 1985), although psychiatric symptoms have not been found to correlate with calcific distribution (Konig 1989). Prevalences of specific DSM-III (American Psychiatric Association 1980) psychiatric diagnoses from the study of Konig (1989) are listed in Table 5–4. Prevalences of psychiatric disorders grow over the disease course, especially those of cognitive, mood, and compulsive disorders. Possible pathophysiologies underlying psychiatric phenomena in FS have been discussed elsewhere (Lauterbach et al. 1994a). More evidence is needed to determine whether the underlying etiologies of FS influence the frequency of psychiatric presentation. Konig (1989) compared the rates of psychiatric disorders in cases of parathyroid disorder (n = 418) and BGC of other etiologies (n = 213) reported in the literature and found that the rates were similar. Kazis (1985), however, found mental disorders in 7 (50%) of 14 patients with hypoparathyroid BGC, in contrast to 20 (34.5%) of 58 patients with BGC of other etiologies.

Cognitive Impairment and Dementia Follow-up of 18 subjects within 2 years after CT identification of BGC revealed impaired motor speed, executive function, visuospatial

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Table 5–4.

Psychiatric presentations and their frequencies in Fahr’s syndrome Follow-up (n = 35), no. (%)

FS lit, %

PT lit, %

5 (7.6) 1 (1.6) 13 (21.0) 1 (1.6) 5 (8.0)

12 (34.3) 1 (2.9) 23 (65.7) 4 (11.4)

24 5 12 1

22 7 11 1

3 (8.6)

2

1

Note. Data from Konig (1989) indicating prevalences of DSM-III (American Psychiatric Association 1980) and ICD-9 (World Health Organization 1978) disorders on initial presentation (n = 62) and on long-term follow-up (n = 35), as well as rates from a literature review of 213 Fahr’s syndrome (FS lit) and 418 parathyroid (PT lit) patients.

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Dementia/mental retardation Organic paranoia/hallucinations Organic affective disorder Compulsions Alcoholism Addictions/personality alterations

Initial (n = 62), no. (%)

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skills, and selected memory functions in patients with BGC compared with matched controls. These findings were consistent with neuropsychological impairment attributable to basal ganglia, frontal, and limbic dysfunction (López-Villegas et al. 1996). Cognitive impairment may occur in association with depression, dysarthria, postural tremor, and parkinsonism, all of which have been observed in autosomal dominant FS with striopallidodentate calcifications and 25-hydroxyvitamin D3 deficiency (Martinelli et al. 1993). Apathy (Seidler 1985) and amnesia (Lauterbach et al. 1994a) can also occur. FS may present as a dementia with subcortical features (poor memory retrieval, movement disorder, and amotivation) occurring in the sixth decade of life (Cummings 1985). Patients may develop dementia as lesions progress. Dementia and associated emotional lability and anxiety are progressive (Lowenthal 1986). For example, in a case reported by Rosenberg et al. (1991), a patient with FS experienced psychosis at age 19 years, with subsequent development of intellectual impairment and speech dyscoordination by age 50 years and dementia with impaired calculations, abstraction, construction, and praxis by age 63 years. The dementia was attended by agitation and dehydration. The neuropathology of the dementia of FS involves frontotemporal atrophy, neocortical neurofibrillary tangles, and neuronal loss in the nucleus basalis of Meynert, but senile plaques are absent (Shibayama et al. 1992). Other neuropathological features of the dementia include calcareous deposition, white matter demyelination, and fibrous gliosis. In a follow-up study of 35 patients with FS, nearly all of the patients showed intellectual impairment, and almost one-third had dementia or mental retardation (Konig 1989). This represented nearly a fivefold increase in dementia relative to the initial evaluation. More severe mental deterioration has been correlated with more extensive calcification (Konig 1989; Taxer et al. 1986). Dementia has also been associated with centrum semiovale calcification (Avrahami et al. 1994).

Psychosis Paranoid and psychotic features often present between the ages of 20 and 40 years (Cummings 1985). Symptoms include auditory halluci-

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nations (sometimes musical), complex visual hallucinations, perceptual distortions, paranoid delusions or trends, and fugue states (Lauterbach et al. 1994a; Rosenberg et al. 1991; Wodarz et al. 1995). In a study of a kindred with FS, seven family members with autosomal dominant probable FS exhibited schizophreniform psychoses over four generations, with variable constellations of hallucinations, delusions, thought disorders, and abnormal sensitivity to neuroleptic extrapyramidal side effects; one child had developmental delays (Francis 1979; Francis and Freeman 1984). A statistical association between psychosis and BGC has been disputed (Flint and Goldstein 1992). The frequency of psychotic features in BGC patients is not significantly higher than that in subjects lacking such lesions (Forstl et al. 1991, 1992; Konig 1989). However, nonspecific paranoia occurs more commonly in BGC patients than in control subjects who have neuropsychiatric disorders but lack BGC (Forstl et al. 1991). Even if schizophrenia is not increased in BGC, BGC may be increased in schizophrenia (Fernandez-Bouzas et al. 1990). Cummings (1985) has suggested that psychosis is associated with FS initially presenting during the third decade of life. It is possible that the lack of a formal association (Forstl et al. 1991) may relate to the low frequency of psychosis and its limitation to the early stages of BGC.

Mood Disorders Mood disorders are the most common feature of FS. Among subjects with BGC, mood disorders are initially present in one-fifth, eventually develop in two-thirds, and occur more commonly than in control subjects who have neuropsychiatric disorders but lack BGC (Forstl et al. 1991; Konig 1989). Mania eventually develops in up to 20%, with unipolar mania occurring in an additional 11% (Konig 1989; LópezVillegas et al. 1996; Trautner et al. 1988). Reduced excitation of temporo-orbitofrontal areas in the context of subcortical or cerebellar calcifications may lead to bipolar syndromes (Lauterbach 1996; Lauterbach et al. 1992). Perhaps half of patients with BGC will develop depression at some point over the illness course. One study found DSM-III depressive disorders in 13 (37%) of 35 BGC patients (Konig 1989), and another found DSM-III-R (American Psychiatric

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Association 1987) minor depressive symptomatology in 3 (16.7%) of 18 patients (López-Villegas et al. 1996). Pathophysiological mechanisms leading to depression in FS are discussed in Figure 5–3.

Anxiety Disorders Up to one-third of patients with BGC have DSM-III-R obsessivecompulsive disorder (Konig 1989; López-Villegas et al. 1996). The exact rates of other anxiety disorders in BGC patients remain to be determined. In our own studies of patients with focal basal ganglia vascular lesions, left external pallidal lesions occurred significantly more often in patients with secondary generalized anxiety than in patients with focal basal ganglia lesions but no anxiety (Lauterbach et al. 1994c); however, the lesions were not attributable to BGC. The correlates of anxiety in FS remain to be defined.

Other Psychiatric Disorders Substance abuse and personality alterations occurred in 3 (8.6%) of 35 patients with BGC in the study of Konig (1989), similar to rates in the general population. Rates of other disorders in FS patients have not been reported.

Neurological and Psychiatric Management Early detection of FS and treatment of the underlying cause may be critical in some cases and may abate the calcification process. For example, Chow and Lu (1989) described a case in which the discovery of hypoparathyroidism with subsequent prompt treatment led to reversal of mental retardation in a 3-year-old. In other cases, treating the underlying etiology can result in symptomatic improvement. Seizures and movement disorders (e.g., hemichorea) in FS attributable to parathyroid disorders may improve with correction of phosphate and calcium levels (el Maghraoui et al. 1995). For example, treatment with alpha-hydroxyvitamin D3 markedly improved neurological manifestations in one patient with BGC associated with hypoparathyroidism (Abe et al. 1996). In another patient with BGC associated with MELAS, corticosteroid treatment reversed neurological deficits (Gubbay et al. 1989). Genetic etiologies of FS should be

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Figure 5–3. Depression in Fahr’s syndrome may occur through any of several neural circuitry mechanisms: 1. Calcification (signified by diagonal shading) of the internal globus pallidus (GPi) disinhibits magnocellular mediodorsal (MDmc) thalamic stimulation to the orbitofrontal cortex (OBFC), leading to inhibition of the dorsal prefrontal cortex (DPFC) and the medial frontal cortex (MFC). Reduced DPFC function has been correlated with both depression and dementia (explained in Lauterbach et al. 1994a). 2. Calcification of the external globus pallidus (GPe) disinhibits noncalcified GPi neurons, thereby inhibiting parvocellular mediodorsal (MDpc) thalamic stimulation to the DPFC, reducing DPFC function, consistent with physiological findings in depression and cognitive dysfunction (discussed in Lauterbach et al. 1997a, 1997b). This physiological state results because GPi circuitry directly regulated by the caudate nucleus projects to the MDmc thalamic neurons that regulate the OBFC, whereas GPi circuitry directly regulated by GPe projects to the MDpc thalamic neurons that regulate the DPFC (reviewed in Lauterbach et al. 1997a). Consistent with this second mechanism, recent data suggest that in Fahr’s syndrome, the external pallidum is more often calcified than the internal pallidum (see “Pathological Features” section); furthermore, depression correlated best with left external pallidal lesions among patients with focal basal ganglia infarcts (Lauterbach et al. 1997a). 3. Calcification of thalamic projections to the DPFC, the MFC, and the lateral frontal regions would result in the frontal dysfunction that attends depressive and cognitive disorders. In addition, destruction of pulvinar or central thalamic nuclei can lead to depression, possibly through connections with limbic structures (Lauterbach et al. 1994b). Thus, it is possible that several mechanisms could lead to the development of different types of depressive disorders. Legend: Lines ending in arrowheads signify excitatory connections; lines ending in bars indicate inhibitory connections. Dashed lines indicate reduced transmission; other lines indicate increased transmission. Source. Reproduced from Lauterbach EC, Jackson JG, Wilson AN, et al.: “Major Depression After Left Posterior Globus Pallidus Lesions.” Neuropsychiatry, Neuropsychology, and Behavioral Neurology 10:9–16, 1997a. Copyright © 1997, Lippincott-Raven Publishers. Used with permission.

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considered as a possible cause, especially in the absence of nongenetic causes, and family members of patients with FS should be screened for FS and genetic causes (e.g., familial hypoparathyroidism). Beyond treating the underlying conditions, there are no treatments capable of limiting calcification progression, although a theoretically appealing but unconfirmed report has described beneficial effects with chelators (xydifon, penicillamine, deferoxamine) used with antioxidants and calcium antagonists (Skvortsov et al. 1987). Loeb (1998) described a patient with Fahr’s disease who was treated with disodium etidronate. Despite improvement in gait and speech, there was no improvement in calcifications, spasticity, dystonia, or ataxia. No systematically conducted controlled studies have examined psychotropic treatment in FS (Rummans et al. 1999). Given this lack of data, treatment depends on the manifestations present as well as on the presence of features that may limit treatment options (e.g., dementia is worsened by anticholinergic side effects, parkinsonism is worsened by neuroleptics). Thus, patients should be thoroughly evaluated medically and neurologically. Knowing the neurological and psychiatric problems for which FS patients are at risk (Tables 5–1 and 5–4) can assist the clinician in planning treatment. Patients with FS may also have heart, renal, or other organ system diseases that influence the use of psychotropics (see Chapter 1 in this volume). No specific gender-related treatment concerns exist; however, the usual caveats regarding pharmacotherapy during pregnancy apply. Assignment to support groups depends on the type of symptomatology present (see Chapter 1 for information on support group resources). Patients may or may not respond to conventional treatments. Most FS parkinsonisms have been reported to respond to L-dopa, but some fail to respond to either L-dopa or treatment of underlying hypoparathyroidism (Lauterbach et al. 1998). Patients with psychosis may be unresponsive to neuroleptics and may be predisposed to neuroleptic malignant syndrome (NMS). NMS may at times be refractory to bromocriptine but responsive to dantrolene (Rosenberg et al. 1991). In treating psychosis (especially in parkinsonian FS patients), 5-HT2A receptor antagonists (olanzapine, risperidone, quetiapine,

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clozapine) may be useful, because they are less likely to cause extrapyramidal syndromes. Atypical antipsychotics may offer a distinct advantage in treating patients with FS and psychosis; however, the caveats discussed in Chapter 1 of this volume should be borne in mind. Although clozapine can improve some parkinsonian features, it can also produce cognitive impairment and seizures, conditions for which FS patients are at special risk. Some cases of FS may respond in an unconventional manner to treatment. Munir (1986) described the case of a 20-year-old man with Fahr’s disease and psychosis. The psychosis was refractory to haloperidol pharmacotherapy but responded to lithium carbonate. In contrast, Trautner et al. (1988) reported the case of a patient with Fahr’s disease and chronic mania who failed to respond to lithium, haloperidol, and carbamazepine. Despite a possible theoretical association of anticonvulsants with FS as suggested by Kazis (1985) (see “Drugs” under “Etiologies” section earlier in chapter), there is no evidence at present to suggest that anticonvulsant therapy hastens the progression of calcifications. Caution is indicated when using lithium, because it can further increase the risk of seizures in patients with FS. Treatment of seizure, bipolar, behavioral, and anxiety disorders requires special vigilance in FS. Sedating drugs such as carbamazepine, benzodiazepines, and barbiturates may exacerbate underlying cognitive impairment and gait disorders. Because of its lower propensity to impair cognition, valproate may be particularly useful in treating epilepsy with psychosis, and it may also be effective in treating the psychotic element of bipolar psychoses (McElroy et al. 1996). Patients with subcortical lesions may exhibit forme fruste (limited-symptom) presentations, complex hybrid disorders, and unusual responses. For example, we encountered a patient with a thalamic lesion who developed pathological laughter, two different diurnally varying major depressions occurring simultaneously, and superimposed bouts of atypical depression. These syndromes (excepting the evening major depression) responded well to fluoxetine. The evening major depression responded selectively to bupropion (Lauterbach et al. 1994b). Given the multiple lesion sites in FS, including the thalamus, a flexible pharmacological approach may be needed in some patients.

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Absent controlled data, conventional antidepressant and anxiolytic agents may be used for the variety of psychiatric disorders that can beset the FS patient, but the psychiatrist must remain vigilant for side effects, especially neurological side effects, which may be precipitated at a lower threshold in FS patients than in individuals without the syndrome. Of four patients with Fahr’s disease and depression whose cases were reported by Trautner et al. (1988), three responded in a conventional manner to antidepressant treatments, including imipramine and electroconvulsive therapy (ECT). Because selective serotonin reuptake inhibitors and buspirone can elicit dystonia (see Chapter 6 in this volume), caution is indicated. Bupropion and tricyclic antidepressants can increase seizure risk. Tricyclics and benzodiazepines can impair cognition. Whether tacrine or donepezil has utility is unknown. Although ECT has been successfully used in depressed FS patients (Trautner et al. 1988), it is probably best avoided, given the risk of seizures associated with the syndrome, the presence of an intracranial mass in the form of calcification, and the variably increased intracranial pressure seen in some FS patients. In any event, vigilance and careful attention are indicated in treating patients with FS and psychiatric manifestations.

Summary FS is a disorder involving basal ganglia calcification, especially the globus pallidus. Calcifications are best seen on CT. Various neuropsychiatric manifestations occur, ranging from seizures and extrapyramidal reactions to dementia and other psychiatric syndromes. Mood disorders are especially common. Psychiatric manifestations vary from individual to individual and may relate to variable degrees of calcification. There are many potential causes of FS, some genetic and others related to clinical conditions. The age of presentation can range from infancy to late adulthood, depending on the cause. It is essential to exclude disorders of calcium metabolism (e.g., hypoparathyroidism) as well as other etiologies. Treatment consists of addressing the underlying cause and treating the neuropsychiatric sequelae. Treatment of these sequelae poses special considerations, necessitating considerable vigilance in anticipating and monitoring side effects. Much more data are needed regarding psychiatric

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sequelae, their treatment, and interventions aimed at preventing progression of the lesions when treatable underlying etiologies are absent.

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Lauterbach EC, Jackson JG, Price ST, et al: Clinical, motor, and biological correlates of depressive disorders after focal subcortical lesions. J Neuropsychiatry Clin Neurosci 9:259–266, 1997b Lauterbach EC, Cummings JL, Duffy J, et al: Neuropsychiatric correlates and treatment of lenticulostriatal diseases: a review of the literature and overview of research opportunities in Huntington’s, Wilson’s, and Fahr’s diseases. J Neuropsychiatry Clin Neurosci 10:249–266, 1998 Legido A, Zimmerman RA, Packer RJ, et al: Significance of basal ganglia calcification on computed tomography in children. Pediatr Neurosci 14:64–70, 1988 Lishman WA: Organic Psychiatry, 2nd Edition. Oxford, UK, Blackwell Scientific Publications, 1987 Loeb JA: Functional improvement in a patient with cerebral calcinosis using a bisphosphonate. Mov Disord 13:345–349, 1998 López-Villegas D, Kulisevsky J, Deus J, et al: Neuropsychological alterations in patients with computed tomography-detected basal ganglia calcification. Arch Neurol 53:251–256, 1996 Lowenthal A: Striopallidodentate calcifications, in Handbook of Clinical Neurology, Vol 5 (49): Extrapyramidal Disorders. Edited by Vinken PJ, Bruyn GW, Klawans HL. Amsterdam, Elsevier Science BV, 1986, pp 417–436 Manyam BV, Bhatt MH, Moore WD, et al: Bilateral striopallidodentate calcinosis: cerebrospinal fluid, imaging, and electrophysiological studies. Ann Neurol 31:379–384, 1992 Martinelli P, Giuliani S, Ippoliti M, et al: Familial idiopathic strio-pallidodentate calcifications with late onset extrapyramidal syndrome. Mov Disord 8:220–222, 1993 Matsui K, Yamada M, Kobayashi T, et al: An autopsy case of Fahr disease (infantile form) [in Japanese]. No To Hattatsu 24:358–363, 1992 Matsumoto R, Shintaku M, Suzuki S, et al: Cerebral perivenous calcification in neuropsychiatric lupus erythematosus: a case report. Neuroradiology 40:583–586, 1998 Matsuo T, Suetsugu M, Eguchi M, et al: Membranous lipodystrophy: a case report. Arch Psychiatr Nervenkr 231:123–130, 1982 McElroy SL, Keck PE, Stanton SP, et al: A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania. J Clin Psychiatry 57:142–146, 1996 Midroni G, Willinsky R: Rapid postanoxic calcification of the basal ganglia. Neurology 42:2144–2146, 1992

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Mousa AM, Muhtaseb SA, Reddy RR, et al: The high rate of prevalence of CT-detected basal ganglia calcification in neuropsychiatric (CNS) brucellosis. Acta Neurol Scand 76:448–456, 1987 Munir KM: The treatment of psychotic symptoms in Fahr’s disease with lithium carbonate. J Clin Psychopharmacol 6:36–38, 1986 Murphy MJ: Clinical correlations of CT scan–detected calcifications of the basal ganglia. Ann Neurol 6:507–511, 1979 Nakayama T, Sakakihara Y, Hanaoka S, et al: Calcification of basal ganglia in a patient with partial trisomy 5q and partial monosomy 18q. Acta Paediatr Jpn 35:340–344, 1993 Newton FH, Rosenberg RN, Lampert PW, et al: Neurologic involvement in Urbach-Wiethe’s disease (lipoid proteinosis): a clinical, ultrastructural, and chemical study. Neurology 21:1205–1213, 1971 Ogata A, Ishida S, Wada T: A survey of 37 cases with basal ganglia calcification (BGC): CT-scan findings of BGC and its relationship to underlying diseases and epilepsy. Acta Neurol Scand 75:117–124, 1987 Okano S, Takeuchi Y, Kohmura E, et al: Globus pallidus calcification in Down syndrome with progressive neurologic deficits. Pediatr Neurol 8:72–74, 1992 Ostertag B: Über die besondere Lokalisation gebundenen Konkremente des ZNS und ihre Beziehungen zur Verkalkung intrazerebraler Gefässe Erkrankungen. Virchows Arch Path Anat 275:829–859, 1922 Pavlakis SG, Phillips PC, Di Mauro S, et al: Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive syndrome. Ann Neurol 16:481–488, 1984 Rasmussen MJ, Pilo L, Nielsen HR: Basal ganglia calcifications demonstrated by CT: is further investigation necessary when this is found incidentally? [in Danish]. Ugeskr Laeger 153:2051–2053, 1991 Rosenberg DR, Neylan TC, El-Alwar M, et al: Neuropsychiatric symptoms associated with idiopathic calcification of the basal ganglia. J Nerv Ment Dis 179:48–49, 1991 Rossi M, Morena M, Zanardi M: Calcification of the basal ganglia and Fahr disease: report of two clinical cases and review of the literature [in Italian]. Recenti Prog Med 84:192–198, 1993 Rummans TA, Lauterbach EC, Coffey CE, et al: Pharmacologic efficacy in neuropsychiatry: a review of placebo-controlled treatment trials. A report of the ANPA Committee on Research. J Neuropsychiatry Clin Neurosci 11:176–189, 1999 Rysz A, Gajkowski K, Empel A: Familial occurrence of calcinosis of the basal ganglia [in Polish]. Neurol Neurochir Pol 22:459–462, 1988

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Schafer M, Ferbert A: Calcinosis of the basal ganglia and hypoparathyroidism [in German]. Nervenarzt 69:873–878, 1998 Scotti G, Scialfa G, Tampieri D, et al: MR imaging in Fahr disease. J Comput Assist Tomogr 9:790–792, 1985 Seidler GH: Psychiatric and psychological aspects of Fahr syndrome [in German]. Psychiatr Prax 12:203–205, 1985 Senft SH, Hidayat AA, Cavender JC: Atypical presentation of Coats disease. Retina 14:36–38, 1994 Shibayama H, Kobayashi H, Nakagawa M, et al: Non-Alzheimer non-Pick dementia with Fahr’s syndrome. Clin Neuropathol 11:237–250, 1992 Skvortsov IA, Rudenskaia GE, Karaseva AN, et al: Effectiveness of the therapeutic use of complexones in various diseases of the extrapyramidal system in children [in Russian]. Zh Nevropatol Psikhiatr 87:1457–1462, 1987 Spatz H: Über den Eisennachweis im Gehirn, besonders in Zentren des extrapyramidal-motorischen Systems. Zentralbl Gesamte Neurol Psychiatry 77:261, 1922 Strain L, Wright AF, Bonthron DT: Fried syndrome is a distinct X-linked mental retardation syndrome mapping to Xp22. J Med Genet 34:535– 540, 1997 Strobos RRJ, De La Torre E, Martin JF: Symmetrical calcification of the basal ganglia with familial ataxia and pigmentary macular degeneration. Brain 80:313–318, 1957 Sue CM, Crimmins DS, Soo YS, et al: Neuroradiological features of six kindreds with MELAS tRNA(Leu) A2343G point mutation: implications for pathogenesis. J Neurol Neurosurg Psychiatry 65:233–240, 1998 Taxer F, Haller R, Konig P: Clinical early symptoms and CT findings in Fahr syndrome [in German]. Nervenarzt 57:583–588, 1986 Tokoro K, Chiba Y, Ohtani T, et al: Pineal ganglioglioma in a patient with familial basal ganglia calcification and elevated serum alpha-fetoprotein: case report. Neurosurgery 33:506–511, 1993 Tolmie JL, Shillito P, Hughes-Benzie R, et al: The Aicardi-Goutieres syndrome (familial, early onset encephalopathy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis). J Med Genet 32:881–884, 1995 Trautner RJ, Cummings JL, Read SL, et al: Idiopathic basal ganglia calcification and organic mood disorder. Am J Psychiatry 145:350–353, 1988

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C H A P T E R

6

Dystonia Edward C. Lauterbach, M.D.

D

ystonia is generally best understood as a clinical manifestation of disturbed basal ganglia physiology. The history of a relation between psychiatry and dystonia is as old as the concept of dystonia itself. The condition was first alluded to by Destarac (1901) as dystonia with functional spasms. Schwalbe (1908), who first described dystonia, considered it a hereditary psychiatric manifestation. Today, dystonia continues to be misdiagnosed as a psychiatric disorder in more than 25% of patients because of its bizarre nature (Marsden 1995).

Prevalence Dystonia is a syndrome of forceful, sustained muscle contractions, resulting in twisting and repetitive movements or abnormal postures. Occasionally, fast dystonic movements are present that can resemble chorea. Dystonic movements can be activated by voluntary movements. The prevalence of primary dystonia is about 250 per 1 million population (Nutt et al. 1988). 179

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Clinical Recognition and Neurological Presentation Forms and Distribution of Dystonia Primary dystonia is dystonia due to a genetic cause, whereas nonprimary dystonia is secondary to or symptomatic of some other underlying cause (see “Etiologies” section later in this chapter and Table 6–1). The distribution of dystonia varies with its etiology and age at onset. Primary dystonia is more often bilateral than is nonprimary dystonia. Primary dystonia presenting in childhood usually begins in the lower extremities and, over several years, progresses bilaterally up the body to involve at least several contiguous body parts (i.e., generalized dystonia). Often, the entire body becomes involved. Synonyms for generalized dystonia have included dystonia musculorum deformans, dysbasia lordotica progressiva, torsion dystonia, torsion spasms, torsion neurosis, hereditary torsion dystonia, and progressive torsion spasm of childhood. The average age at onset is 8 years (Bruyn and Roos 1986). The earlier the onset, the more severe the disorder. Dysarthria, dysphagia, and total disability may complicate the course. Adult presentations of primary dystonia generally are either focal (involving a single body region) or segmental (involving two contiguous body parts). Average onset is between the ages of 30 and 50 years. Of the various primary dystonias, 90% initially present in midlife with minimally progressive focal or segmental dystonia (Nutt et al. 1988) involving the upper extremities, neck, or face. Blepharospasm involves involuntary closure of the eyelids. Oromandibular dystonia (Brueghel’s or Meige’s syndrome) involves jaw and mouth muscles and is usually accompanied by blepharospasm. Neck dystonia (torticollis) usually occurs after age 30 years in women (Bruyn and Roos 1986). Focal wrist/hand dystonia (writer’s cramp) often interferes with handwriting. Spasmodic dysphonia is vocal cord dystonia; abductor spasm produces a whispering or intermittent breathy voice, whereas adductor spasm results in a hoarse, forced vocal quality. The presence of multifocal dystonia (affecting several noncontiguous body parts) suggests nonprimary dystonia symptomatic of some

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Causes of dystonia

Primary dystonia Oppenheim’s dystonia (DYT1 gene on 9q34 between D9S2161 and D9S63) Italian non-DYT1 autosomal dominant dystonia with nearly complete penetrance Adult-onset cervical dystonia (DYT7 gene on 18p near D18S1098) Familial cranial dystonia Adult-onset cervical-cranial dystonia Familial cranial-limb dystonia Whispering dysphonia (DYT4 gene) Mennonite mixed dystonia (DYT6 gene on 8p21–q22) Autosomal recessive dystonia (DYT2 gene) Other familial dystonia Sporadic torsion dystonia Dystonia-plus syndromes Dopa-responsive dystonia GTP–cyclohydrolase I mutation (DYT5 gene on 14q22.1) 6-Pyruvoyltetrahydropterin synthase deficiency (I114V mutation) Tyrosine hydroxylase mutations (gene on 11p) Rapid-onset dystonia–parkinsonism (19q13) Myoclonic dystonia (11q23) Neurodegenerative and heredodegenerative disorders Lubag dystonia–parkinsonism (DYT3 gene on Xq13.1) Huntington’s disease (IT15 huntingtin gene on 4p16.3) Wilson’s disease (copper–ATPase gene on 13q14.3) GM1 and GM2 gangliosidosis Metachromatic leukodystrophy Glutaric aciduria type I Homocystinuria Guanidinoacetate methyltransferase deficiency 3-Methylcrotonyl–CoA carboxylase deficiency 3-Methylglutaconic aciduria Hexosaminidase A and B deficiency Triosephosphate isomerase deficiency Lesch-Nyhan syndrome Methylmalonic aciduria (continued)

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Causes of dystonia (continued)

Neurodegenerative and heredodegenerative disorders (continued) Hartnup’s disease Juvenile neuronal ceroid lipofuscinosis Adult neuronal ceroid lipofuscinosis (Kufs’ disease) Dystonic lipidosis (Niemann-Pick disease, sea-blue histiocytosis) Neuroacanthocytosis Ataxia–telangiectasia Neuronal intranuclear inclusion disease Mitochondrial encephalopathies Leigh’s syndrome Other Familial basal ganglia calcifications (Fahr’s syndrome) Hallervorden-Spatz disease Pelizaeus-Merzbacher disease Dystonia with striatal lucencies Infantile bilateral striatal necrosis Progressive pallidal degeneration (pure pallidal atrophy, pallidoluysian atrophy, other) Progressive supranuclear palsy Olivopontocerebellar degeneration Machado-Joseph disease Spinocerebellar degeneration Parkinson’s disease Multiple system atrophy Cortical–basal ganglionic degeneration Rett syndrome Hereditary spastic paraplegia Dystonia secondary to environmental and other etiologies Perinatal injury Athetoid cerebral palsy Delayed-onset dystonia Hypoxia Encephalitis and postinfectious diseases Reye’s syndrome AIDS Subacute sclerosing leukoencephalopathy (continued)

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Causes of dystonia (continued)

Brain abscess Head trauma Arteriovenous malformation Lesions (especially putamen, pallidum, thalamus, and brain stem) Focal cerebral vascular injury Brain tumor Multiple sclerosis Epilepsy Ictal dystonia Postictal dystonia Cervical cord injury Peripheral injury (including dental extraction) Hemolytic uremic syndrome Influenza Wasp sting Toxins Manganese Carbon monoxide Carbon disulfide Methanol Cyanide 3-Nitroproprionic acid Substance abuse Cocaine Alcoholic hepatocerebral degeneration Psychogenic dystonia Drugs D2 receptor antagonists (neuroleptics, metoclopramide) Risperidone Clozapine SSRIs Levodopa Ergot alkaloids Sumatriptan Anticonvulsants Disulfiram (continued)

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Causes of dystonia (continued)

Dystonia secondary to environmental and other etiologies (continued) Ranitidine Rh(D) immune globulin Note. Further elaboration can be found in Fahn 1997; Fahn et al. 1997, 1998; and Calne and Lang 1988. AIDS = acquired immunodeficiency syndrome; ATPase = adenosine triphosphatase; GTP = guanosine 5′-triphosphate; SSRIs = selective serotonin reuptake inhibitors.

identifiable cause. In contrast to primary dystonias, nonprimary dystonias are often unilateral and are attended by additional focal neurological signs. Peripheral dystonia can occur after peripheral trauma relating to nerve, plexus, or root injury in the absence of central nervous system (CNS) pathology.

Initial Signs and Associated Features Dystonia onset is usually gradual and subtle, sometimes beginning with clumsiness, tension or pulling sensations, vague pains, intermittent foot inversion, finger hyperextension, or intermittent shoulder hunching. Initially, dystonia occurs only with particular muscle actions. Later, additional actions may evoke dystonia. Still later, the activity of distant, uninvolved muscle groups may trigger dystonia. In the final stages, dystonia may be present even at rest. Features sometimes associated with dystonia include gait disorders (e.g., hyperlordotic gait), tortipelvis, kyphoscoliosis, increased or decreased extrapyramidal tone, striatal toe (spontaneous extension of the big toe), and action-postural tremor (Bruyn and Roos 1986). Hypertrophy of the involved muscle groups develops over time. Parkinsonism–dystonia syndromes usually occur in childhood but may appear later in life. In nonprimary dystonias, other neurological features may add to the clinical findings.

Gender Considerations and Pregnancy In clinical samples, adult-onset dystonia is more common in women than in men. Writer’s cramp is more common in men. Generalized dystonia with childhood onset occurs with equal frequency in both genders. In primary dystonia, maternal transmission is more com-

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mon than paternal transmission (LaBuda et al. 1993). The penetrance of guanosine 5′-triphosphate (GTP)–cyclohydrolase I mutations associated with dopa-responsive dystonia (see “Etiologies” section and Table 6–1) is 2.3 times greater in females than in males (Furukawa et al. 1998). Tardive dystonia was more common in men in a large Italian study (Raja and Azzoni 1996). The presence of dystonia does not appear to compromise pregnancy, although the effects of botulinum toxin and some of the other dystonia treatments are not yet definitively known. Lurie et al. (1996) described a woman with dopa-responsive dystonia who successfully gave birth to two children despite taking L-dopa throughout both pregnancies. Kumar et al. (1997) published an interesting case report of cervical dystonia that occurred after Rh(D) immune globulin administration but improved with steroids.

Conversion Disorder or Dystonia? The bizarre features of dystonia can lead to an erroneous diagnosis of conversion disorder. Action specificity refers to the fact that only certain actions of affected muscles evoke dystonia (e.g., dystonia may occur while walking forward but not while walking sideways or backward or while dancing or running). Although this phenomenon might be interpreted as signaling inconsistencies indicative of a conversion disorder, it is actually quite consistent with dystonia. Unusual dystonia distributions and disabilities can also lead to misdiagnosis. An inability to eat, speak, walk, write, or open the eyes or mouth, and turning away of the head or other functional disabilities, each can errantly suggest conversional symptomatology. Exercise, environmental stimuli, and stress can trigger dystonic spasms. Sensory stimulation (sensory tricks) and countering movements (geste antagonistique) can be employed by some patients to attenuate dystonic spasms. For example, a woman in her late 40s with severe cervicotruncal dystonia found that the spasms attenuated with a light touch to the skin of the back of her neck (sensory trick) or with elevation of her left shoulder (geste antagonistique). She discovered that if she assumed a model’s posture, with her left hand positioned behind her neck, her dystonic spasms were markedly relieved. Occasionally, in some patients, dystonia spontaneously remits, but it

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usually recurs subsequently. These features can lead to a false impression that the disorder is of psychogenic origin. In contrast, conversional psychogenic dystonia is often more abrupt in onset. Although there is no pathognomonic presentation of psychogenic dystonia, two broad guiding diagnostic principles are 1) a presentation less than consistent with organic dystonia and 2) a “guilt by association” with other suspicious findings suggestive of conversional origin (e.g., recent psychosocial stressor, previous conversion disorder, extant psychiatric disorder). However, organic dystonia should first be suspected to avoid misdiagnosis. Complicating matters further, psychogenic movement disorders can also develop in patients with organic dystonias (Ranawaya et al. 1990). Moreover, psychiatric disorders are prevalent in primary dystonia, and their presence cannot be relied on to establish the diagnosis of psychogenic dystonia. The prevalence of psychogenic dystonia at dystonia referral centers is approximately 1%–3% (Marsden 1995). Psychogenic dystonia is discussed in more detail below (see “Somatoform Disorders and Psychogenic Dystonia” under “Psychiatric Manifestations” section later in chapter).

Pathological Features Reductions in plasma dopamine beta-hydroxylase (autosomal dominant dystonia), cerebrospinal fluid (CSF) homovanillic acid (adult dystonia), and CSF methoxyhydroxyphenylglycol (childhood dystonia) suggest reduced dopamine and norepinephrine turnover (Bruyn and Roos 1986). Reduced CSF tetrahydrobiopterin (especially in dopa-responsive dystonia) has been found, and some cases of dystonia respond markedly, albeit transiently, to tetrahydrobiopterin (LeWitt et al. 1986). Despite numerous investigations, no histopathological abnormalities have been observed in primary dystonia (Zeman 1976). Consequently, primary dystonia is presumed to represent a functional disturbance of basal ganglia circuits. Pathological findings in nonprimary dystonias are the pathological features of their individual causes. Although the pathophysiology of dystonia is still emerging and may not be unitary, dystonia is thought to arise from reduced internal pallidal inhibition of the thalamus (see Figure 1–2 in Chapter 1)

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resulting from a simultaneous increase of putaminopallidal GABAergic inhibition and either a decrease (Crossman and Brotchie 1997) or an increase (Vitek et al. 1999) in subthalamic glutamatergic stimulation of the internal pallidum. Electromyography (EMG) studies indicate that reciprocal inhibition of antagonist musculature is lost in dystonia. Normally, contraction of agonist musculature leads to reciprocal inhibition of opposing muscle groups (e.g., contraction of the biceps leads to relaxation of the triceps muscle). However, in dystonia, both sets of opposing muscle groups (e.g., biceps and triceps) contract simultaneously because of this loss of reciprocal inhibition. There is some evidence from evoked potential studies of an excessive response by the precentral cortex to somatosensory inputs because of basal ganglia dysfunction (Tinazzi et al. 1999). This excessive response may be related to deficient intracortical inhibition (Siebner et al. 1999) resulting from abnormal basal ganglia input or other influences. Thus, basal ganglia dysfunction may result in deficient neuronal inhibition, leading to dystonic spasms and loss of reciprocal inhibition (Berardelli et al. 1998).

Etiologies Dystonia can be of primary origin (genetic or idiopathic etiology), associated with dystonia-plus syndromes, or secondary to a wide variety of causes, including neurodegenerative and heredodegenerative disorders (see Table 6–1). Primary dystonia runs in families. A recent case–control study of primary dystonia revealed risk factors including concussive head injury, local injury, and family histories of dystonia and postural tremor, whereas hypertension and cigarette smoking constituted protective factors (Defazio et al. 1998). Several distinct genetic associations have been found (see Table 6–1). The dystonia gene DYT1 is autosomal dominant with approximately 30% penetrance in Ashkenazi Jews (Pauls and Korczyn 1990) and 40% in non-Jews (Fahn et al. 1998). DYT1 codes for torsin A, an adenosine triphosphate (ATP)–binding protein, but the pathological relation of this protein to dystonia remains unknown. In Ashkenazi Jews, DYT1 mutations arise from GAG deletions in this gene on chromosome 9q34.1. The carrier frequency is between 1 in 1,000 and

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1 in 5,000 in Jews and one-third this rate in non-Jews. European Jews have a higher prevalence of the gene than do Afro-Asian Jews (Korczyn et al. 1980). Multiple DYT1 mutations appear to be involved in non-Jewish populations (Bressman 1997). Genetic anticipation implicates trinucleotide repeats in DYT1 dystonia (Cheng et al. 1996). Presymptomatic testing can be performed, but low penetrance reduces the odds of developing dystonia even if the gene is present. Genetic testing for DYT1 (i.e., for the associated haplotype of alleles D9S62, D9S63, and ASS) costs about $350 per sample. There is no need to involve other family members in testing Ashkenazi Jews with childhood-onset dystonia because of the consistency of the mutation form. However, because of the variety of mutations in non-Jewish patients, simultaneous testing of 8–10 other family members with dystonia is necessary to accurately determine the presence of a DYT1 mutation (Bressman 1997; Harding 1994). A variety of genetic dystonias are listed in Table 6–1. These include several primary dystonias, particularly DYT1 dystonia (Oppenheim’s dystonia). Sporadic primary torsion dystonia is usually focal with cranial or cervical distribution and is only rarely familial. Among dopa-responsive dystonias, Segawa’s syndrome usually begins before age 16 years in girls (female:male ratio = 19:6), may show diurnal variation with worsening of leg dystonia or gait disorder later in the day, is associated with parkinsonian features, and responds to L-dopa. The two most common forms include autosomal (14q) dominant GTP–cyclohydrolase I (GCI) and autosomal (11p) recessive tyrosine hydroxylase mutations. Segawa’s syndrome is linked to multiple mutations of the gene for GCI. GCI synthesizes a precursor of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase. Tyrosine hydroxylase is critical to the synthesis of dopamine. GCI dysfunction can therefore reduce tyrosine hydroxylase activity, resulting in dopamine deficiency. Similarly, mutations in the genes for 6pyruvoyl-tetrahydrobiopterin synthase and tyrosine hydroxylase have also been linked to dopa-responsive dystonia. Recently, the gene for autosomal dominant rapid-onset dystonia–parkinsonism has been linked to 19q13 at D19S198, between D19S587 and D19S900 (P. L. Kramer et al. 1999). Myoclonic dystonia is rare, is associated with myoclonic jerking (arms, shoulders, neck, or trunk), is improved by

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alcohol consumption, and exhibits autosomal dominant transmission (Kyllerman et al. 1990). Myoclonic dystonia has recently been linked to chromosome 11q23 at D11S897, a region containing the gene for the D2 dopamine receptor (Klein et al. 1999). X-linked dystonia–parkinsonism (Lubag) is a hereditary basal ganglia degeneration affecting adult Filipino males. Dystonia is also a component of other genetic syndromes not listed in Table 6–1. Dystonia occurs in the Xq22-linked recessive syndrome, a disorder associated with sensorineural deafness, cortical blindness, fractures, and mental deficiency (Jin et al. 1996). The gene is linked to Xq22 locus DXS101 (Tranebjaerg et al. 1995). The gene product is a mitochondrial protein, DDP, that mediates the import of metabolite transporters from the cytoplasm to the mitochondrial inner membrane (Koehler et al. 1999). Dystonia more rarely has been associated with the 18q22.2 deletion syndrome, which is linked to mental retardation, seizures, nystagmus, incoordination, and chorea. Gordon et al. (1995) have described a case report of a 36-year-old woman with an 18q deletion who presented with adolescent onset of mandibular dystonia, retrocollis, and writer’s cramp, associated with postural tremor, hypothyroidism, diabetes mellitus, borderline intelligence, short stature, short neck, sensorineural hearing loss, and sensorimotor ataxia (Gordon et al. 1995). Deletion of 18p11.1 has been associated with progressive dystonia, mental retardation, seizures, tremor, chorea, and androgen insensitivity (Awaad et al. 1999). Dystonia can occur in a wide variety of hereditary, neurological, metabolic, and other diseases (Janavs and Aminoff 1998; Hartmann et al. 1998). CNS pathology may predispose to dystonia. Persistent dystonia has occurred in a patient with acquired immunodeficiency syndrome (AIDS) dementia complex after brief exposure to lowdose neuroleptic therapy (Factor et al. 1994). Generalized encephalitis and substantial neural loss in both the medial and the lateral globus pallidus was evident in the patient at autopsy. Substance abuse, notably cocaine, can precipitate dystonia or aggravate primary dystonia (Cardoso and Jankovic 1993). Alcoholic hepatocerebral degeneration can lead to dystonia, and acute alcohol intoxication can precipitate neuroleptic-induced acute dystonic reactions (Neiman et al. 1990).

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A variety of medications can also cause dystonia (Table 6–1), an important fact to consider when evaluating patients. Neuroleptics can produce acute dystonia, tardive dystonia, and neuroleptic malignant syndrome. Delirium with dystonia may represent a variant of neuroleptic malignant syndrome (Dowling and Patrick 1989). Dystonia has also been reported with risperidone and clozapine treatment and on clozapine withdrawal (Radford et al. 1995). Leaning truncal dystonia, the Pisa syndrome (Yassa 1985), can occur during chronic neuroleptic maintenance therapy (Guy et al. 1986) and in documented tardive dystonia (Saxena 1986). Acute administration of selective serotonin reuptake inhibitors (SSRIs) may trigger dystonia (Leo 1996), as may SSRI withdrawal (Stoukides and Stoukides 1991). Buspirone may lead to intractable movement disorders, including dystonia (LeWitt et al. 1993).

Neuroimaging Nonprimary dystonia most commonly occurs after putaminal and pallidal lesions. Putaminal increased signal on magnetic resonance imaging (MRI) (in 35%) is the most common finding in dystonias, but putaminal decreased signal and, more rarely, mixed signal in the globus pallidus can also be seen (Rutledge et al. 1988). Positron-emission tomography (PET) studies indicate pallidothalamic and cortical abnormalities. Evidence suggests that medial pallidal inhibition of the thalamus is reduced in dystonia, leading to overactivation of premotor areas such as the supplementary motor cortex (Playford et al. 1998). A reduction in putaminal dopamine D2 receptor binding on PET was found in a study of focal dystonia (Perlmutter et al. 1997), in contrast to a finding of elevated D2 binding in a study of doparesponsive dystonia (Kishore et al. 1998). These findings suggest that not all types of dystonia have the same pathophysiology.

Clinical and Laboratory Investigation Dystonia should be distinguished from muscle spasms, which generally develop abruptly. Unilateral hemidystonia suggests a nonprimary etiology. Pyramidal tract signs (spasticity, Babinski sign, clonus, hyperreflexia), sensory deficits, and other neurological fea-

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tures (cranial nerve signs) also usually suggest an etiology other than primary dystonia. MRI or computed tomography (CT) of the brain may then be revealing. Structural pathology is lacking in primary dystonia, however. The workup of dystonia in children is more aggressive than that in adults and has been explicitly detailed elsewhere (Marsden 1988). It involves Wilson’s disease studies (see Chapter 4 in this volume), serology, complete blood count with differential, erythrocyte sedimentation rate, antinuclear antibody test, routine chemistry profiles, and MRI or CT scan. Uric acid elevation can indicate LeschNyhan syndrome as an etiology. Striatal lesions on MRI or CT can reflect Wilson’s disease, Leigh’s syndrome, mitochondrial cytopathy, postanoxic state, infection, allergic reactions, toxin ingestion (e.g., methanol), hemolytic uremic syndrome, sickle-cell disease, acidosis (e.g., methylmalonic acidemia), and striatal necrosis. Striatal atrophy can occur in neuroacanthocytosis and Huntington’s disease (see Chapter 3 in this volume). Pallidal mineralization occurs in Fahr’s syndrome and hypoparathyroidism (see Chapter 5 in this volume). Thus, the workup reflects the possible causes of nonprimary dystonia. The workup in adults is similar, including CT or MRI, complete blood count with differential, erythrocyte sedimentation rate, routine chemistry profile, serology, and exclusion of Wilson’s disease; however, if the dystonia conforms to the typical course and features of primary dystonia, many clinicians defer the workup in adults because of low yield, unless the condition progresses unexpectedly. The presence of additional features suggesting nonprimary dystonia (e.g., hemidystonia, pyramidal signs), however, merits investigation. If the etiology remains cryptic after these preliminary considerations, further evaluation is undertaken (Marsden 1988). Somatosensory evoked potential abnormalities can be consistent with ceroid lipofuscinosis. An electroretinogram may reveal pigmentary retinopathy, as has been observed in Hallervorden-Spatz disease and ceroid lipofuscinosis. Electromyography can reveal a peripheral neuropathy. Lysosomal enzymes may elucidate GM1 or GM2 gangliosidoses or metachromatic leukodystrophy. Alpha-fetoprotein and immunoglobulin A (IgA) levels can disclose ataxia telangiectasia. Ar-

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terial blood gases with pH, lactate, and pyruvate levels can suggest Leigh’s syndrome. A fresh blood smear showing acanthocytes suggests neuroacanthocytosis, especially in consanguineous families. Twenty-four-hour urine collection for amino acids, organic acids, and oligosaccharides can disclose other metabolic disorders, including homocystinuria. Although most of these disorders occur in childhood, some may insidiously become symptomatic in adult life and lead to dystonia. When these tests do not lead to etiological discovery, biopsies of liver (for Wilson’s disease), bone marrow (for dystonic lipidosis), muscle (for mitochondrial cytopathies), or skin or conjunctiva (for ceroid lipofuscinosis) may be revealing (Marsden 1988). Karyotype analysis should be undertaken in nonprimary dystonia associated with features suggestive of chromosomal aberrancies, such as short stature or endocrinopathies (Gordon et al. 1995).

Psychiatric Manifestations Primary psychiatric features are associated with primary dystonia. Many nonprimary dystonia etiologies are associated with their own psychiatric morbidities (unrelated to the dystonia), such as mental retardation, dementia, other cognitive disturbances, psychoses, mood disorders, personality disturbances, and possibly anxiety and other disorders. The neuropsychiatry of primary dystonia is reviewed in the following subsections.

Cognitive Impairment Although early studies suggested greater intelligence in primary dystonia, later work has not supported this impression (Imperio et al. 1979). Neither is intelligence diminished by primary dystonia. Intellectual deterioration can occur secondary to underlying pathology in nonprimary dystonia, as seen in striatopallidal degeneration (Stehbens 1972) and progressive supranuclear palsy (Barclay and Lang 1997).

Psychosis Thought disorders have been described in two patients with dystonia (Kraft 1966), and elevated scores on the Minnesota Multi-

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phasic Personality Inventory (MMPI; Hathaway and McKinley 1970) Schizophrenia scale were reported in a study of 30 patients with primary dystonia (Imperio et al. 1979). However, systematic studies in untreated primary dystonia, like those in untreated Parkinson’s disease, have not revealed diagnosable psychoses. In primary psychoses, however, acute neuroleptic-induced ocular dystonia is associated with exacerbated auditory hallucinosis (Chiu 1989; Thornton and McKenna 1994). Similar attenuating mechanisms for dystonia and psychotic symptoms may involve dopamine (Chiu 1989) and the basal ganglia (Lauterbach 1990).

Mood Disorders Elevated prevalences of mood disorders have been observed in dystonia. Determination of lifetime prevalences of DSM-III-R (American Psychiatric Association 1987) mood disorders in 28 subjects with primary dystonia from a movement disorder referral center identified 5 (18%) subjects with bipolar disorders, 8 (29%) with major depression, 4 (14%) with dysthymia (1 also had major depression), and 1 (4%) with atypical depression (Lauterbach et al. 1992a). Mood disorders tended to occur after the onset of dystonia and were significantly more common in dystonia patients than in normal populations. Subjects with dystonia were compared with demographically matched controls from the Epidemiologic Catchment Area (ECA) study (Robins and Regier 1991). The prevalences of bipolar disorders and unipolar major depression in patients with dystonia were increased to the levels seen in Huntington’s disease, suggesting a relationship between these mood disorders and underlying basal ganglia pathophysiology. Dystonic severity, disability, and pain did not predict these disorders. Consequently, vigilance for a variety of DSM-IV (American Psychiatric Association 1994) mood disorders due to a general medical condition as well as primary mood disorders seems indicated in dystonia patients. Although illness-related psychosocial variables were not associated with the clear elevation of mood disorder rates, the possibility that other psychosocial variables contribute to mood disorders in dystonia patients cannot be excluded at present. In another study, DSM-III-R mood disorders were assessed in

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23 subjects with dystonia secondary to focal lesions of the basal ganglia, thalamus, or cerebellum. Two (8.7%) dystonia subjects had bipolar disorder not otherwise specified, and 4 (17.4%) had major depression (Lauterbach et al. 1994a). Thus, bipolar disorders and major depression were also more common in poststroke dystonia than in the population at large (i.e., matched ECA controls). Bipolar disorders. Rapid-cycling bipolar disorders have been associated with cervicocranial primary dystonia. In one study of patients presenting to a movement disorder referral center, subjects were found to have developed bipolar disorders soon after the initial manifestations of dystonia (Lauterbach et al. 1992b). Dystonia with rapid-cycling bipolar disorder has been reported in patients after lesions associated with abnormal cerebellar function (Lauterbach 1996). Tardive dystonia has been reported to alternate with mania (Lal et al. 1988). Although retrospective data have suggested that acute neuroleptic-induced dystonia occurs more commonly in bipolar disorder than in schizophrenia (Nasrallah et al. 1988), prospective studies have not confirmed this (Khanna et al. 1992; Remington et al. 1990). Depression. Depression may vary with the anatomic distribution of the dystonia. Depression of any type occurs in 20%–80% of patients with blepharospasm (Diamond et al. 1984; Trobe et al. 1985; Volow 1985). In Meige’s syndrome, depression affects 25%–41% (Jankovic and Ford 1983; Tolosa 1981). In contrast, in two studies of patients with writer’s cramp dystonia, depression prevalences were not increased despite occupational and functional disabilities (Grafman et al. 1991; Sheehy and Marsden 1982). As detailed above, multifold increases in DSM-III (American Psychiatric Association 1980) and DSM-III-R depressive disorders have been documented in patients with predominantly craniocervical primary dystonia (Lauterbach et al. 1991). In a study of 22 patients with primary torticollis, Beck Depression Inventory (BDI) scores were higher than in age- and sexmatched healthy controls (Bihari et al. 1992), although another study found no difference (Matthews et al. 1978). In yet another study, 33 (39%) of 85 patients with torticollis had moderate or severe

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BDI depression scores, and the depression was more severe than that in patients with cervical spondylosis (Jahanshahi and Marsden 1988b). Depression in torticollis is characterized by cognitions involving self-blame, self-accusation, self-punishment, and negative body image. Perceived disfigurement was found to predict depression in one study (Jahanshahi and Marsden 1990); improvement in torticollis with botulinum toxin treatment reduced depression and disability in another study, although body concept and self-esteem did not improve (Jahanshahi and Marsden 1992).

Anxiety Disorders Anxiety is common in dystonia patients, and certain anxiety disorders are especially prevalent. Analysis of DSM-III anxiety disorders in 28 patients with primary cervicocranial dystonia disclosed anxiety diagnoses in 20 (71.4%), including panic disorder in 1 (3.6%), agoraphobia in 3 (10.7%), social phobia in 5 (17.9%), simple phobia in 7 (25%), obsessive-compulsive disorder (OCD) in 0 (0%), generalized anxiety disorder (GAD) in 7 (25%), and atypical anxiety (GAD-like) in 4 (14.3%) (Lauterbach et al. 1993a). Thus, these patients exhibited more than a fourfold increase in GAD and GAD-like anxiety and a greater tendency to manifest phobias than that in normal (ECA) populations. These findings contrast with results from a study of Parkinson’s disease that used the same methodology, in which the prevalence of DSM-III panic disorder was found to be five times higher than that in normal (ECA) populations (Lauterbach and Duvoisin 1987). In the study of DSM-III anxiety disorders (Lauterbach et al. 1993a), primary dystonia patients with social phobia, agoraphobia without panic, and simple phobia often showed bilateral dystonic muscle involvement. Findings similar to those of the DSM-III dystonia study obtained for all of the DSM-III-R anxiety disorders (Lauterbach et al. 1993c) except panic disorder and agoraphobia (diagnoses of panic disorder without agoraphobia in 2 patients [7.1%] and of agoraphobia in 2 [7.1%]). Although the rates of certain anxiety disorders in dystonia patients are well above the rates observed in the ECA study (Robins and Regier 1991) and in patients with Parkinson’s disease, psychosocial factors may contribute to

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these findings. Clinicians who treat patients with dystonia should be on the alert for DSM-IV anxiety disorders, especially GAD, specific phobias, and anxiety disorder due to a general medical condition (“with generalized anxiety” specifier). In contrast to the case for primary dystonia, GAD was no more common in poststroke dystonia than in the general population (Lauterbach et al. 1994a). Of 45 subjects with focal subcortical infarcts, 4 (8%) had DSM-III-R generalized anxiety disorders (2 subjects with GAD and 2 with forme fruste GAD) (Lauterbach et al. 1994b). All 4 had pallidal lesions. Posterior pallidal lesions tended to be associated with more severe GAD and parkinsonism, whereas more anterior pallidal lesions tended to be associated with less severe, forme fruste GAD and dystonia. All 4 subjects had major depression and lower mental status scores than control subjects with subcortical lesions (Lauterbach et al. 1994c). Anxiety may be especially common in patients with cervicocranial and generalized dystonias. Rorschach findings suggesting anxiety are seen in as many as one-third of blepharospasm patients (Diamond et al. 1984; Trobe et al. 1985), although not all studies have reported this result (Tarbox and Morse 1985). One study found that 50% of dystonia patients had twice as many nonspecific neurotic symptoms as controls, although it was concluded that, overall, there was no increase in psychopathology (Sheehy and Marsden 1982). Among childhood generalized dystonia patients, other investigators have noted Rorschach anxiety findings (Riklan et al. 1976) and elevations on the MMPI Psychasthenia scale (Imperio et al. 1979), which they attributed to difficulties in adjusting to disability (Riklan et al. 1976). Clinical anxiety has been reported in a study of Meige’s syndrome; however, specific diagnoses and their prevalences were not reported (Jankovic and Ford 1983). Focal hand/wrist dystonia has not been found to be associated with increased anxiety (Harrington et al. 1988). Obsessions and compulsions. OCD and obsessive-compulsive symptomatology have been observed in dystonia, especially in patients in whom putaminal abnormalities are observed on MRI (Rothfeld 1995). Although none of the 28 patients in one study of primary dystonia met the disability criteria for OCD, 2 (7.1%) had obses-

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sions and 4 (14.3%) had compulsions (Lauterbach et al. 1993a). This contrasts with findings from a study in Parkinson’s disease patients, in whom the prevalence of DSM-III OCD was found to be five times greater than that in demographically matched controls from the ECA study (Lauterbach and Duvoisin 1987). In the foregoing dystonia study, dystonia patients with obsessive-compulsive symptomatology showed more cerebellar signs and fewer basal ganglia signs than did dystonia patients without obsessive-compulsive symptomatology (Lauterbach et al. 1993b). In a study of torticollis patients, Symptom Checklist—90—Revised obsessionality scores were higher in patients with primary spasmodic torticollis than in age- and sexmatched controls (Bihari et al. 1992). Obsessive-compulsive symptomatology may, therefore, be linked to dystonia and may possibly relate pathophysiologically to striatal dysfunction in dystonia or to cerebellar–frontal dysfunction.

Eating Disorders Eating disorders have also been identified in dystonia. In a study of primary cervicocranial dystonia, DSM-III atypical eating disorder, bulimic type (DSM-III-R eating disorder not otherwise specified) was diagnosed in 2 (7.1%) of 28 subjects (Lauterbach et al. 1993b, 1993d). No patient had diagnosable classical anorexia nervosa or bulimia.

Somatoform Disorders and Psychogenic Dystonia About two-thirds of patients with psychogenic dystonia present with continuous dystonia; the remaining one-third have paroxysmal dystonia. In one study of 21 psychogenic dystonia patients, females predominated (10:1), and many of them worked in the health care field (Fahn and Williams 1988). All but 4 of these patients experienced improvement or resolution of their symptoms. The most common features of psychogenic dystonia are listed in Table 6–2. (Additional signs pointing to a psychogenic etiology are presented in Chapter 1 of this volume.) In a retrospective chart review of psychogenic dystonia patients (n = 18), all subjects were found to have features inconsistent or in-

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Table 6–2.

Clinical tip-offs to psychogenic dystonia: atypical features of dystonia

Findings in psychogenic dystonia Movements inconsistent with dystonia Onset with dystonia at rest False weakness Pain spontaneously or on passive movement Multiple somatizations Bizarre tremors or other movements Sudden weakness False sensory changes (e.g., blindness) Excessively slow voluntary movement Tenderness on light touch Startle-induced elaborate movements Source.

Frequency in psychogenic dystonia patients, % 86 79 67 43 38 33 29 24 24 19 10

Fahn and Williams 1988.

congruous with organic dystonia (Lang 1995). Although 14 patients had clear precipitants, many of the precipitating events (particularly injuries) were ones that can also precede organic dystonia. Most patients had abrupt onset and rapid progression, often to the point of fixed dystonic postures. Rapid progression to fixed postures can occur with organic rapid-onset dystonia; however, this is a rare condition in which other psychogenic signs would usually be absent. Other common psychogenic features included pain, leg dystonia despite adult onset, paroxysmal worsening of the dystonia, other coexisting psychogenic movement disorders, multiple somatizations, and psychogenic neurological signs. The outcomes were quite variable, with some dystonias completely resolving and others persisting. Other clinical tip-offs to psychogenic dystonia include variable movement patterns that occur when performing the same provocative action and severe, spreading causalgic pain with dystonia after trivial injury (Marsden 1995). The presence of reciprocal inhibition on EMG (see “Pathological Features” section earlier in chapter) suggests psychogenic dystonia, whereas dystonia occurring during the early stages of sleep suggests an organic etiology (Marsden 1995). The psychopathological origins and psychiatric diagnoses un-

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derlying psychogenic dystonias are diverse and can include a history of abuse and diagnoses of conversion disorder, somatization disorder, factitious disorder, and malingering, usually attended by dysthymic or adjustment disorders (Williams et al. 1995). Secondary conversion and other psychogenic disorders can also occur in primary organic movement disorders (Ranawaya et al. 1990).

Substance Abuse Disorders Dystonia can lead to alcohol abuse and dependence (Neiman et al. 1990). In one study, 7 of 26 subjects with myoclonic dystonia (a condition often improved by alcohol) developed alcohol abuse (Kyllerman et al. 1990). The frequencies of anxiety, depression, and alcohol-related symptom improvement in dystonia may contribute to findings of increased alcoholism in primary dystonia. In our study of DSM-III substance abuse disorders in 28 dystonia patients, 5 (17.9%) of the patients had alcohol diagnoses (3 [10.7%] with abuse and 2 [7.1%] with dependence) (Lauterbach et al. 1993b). Patients with alcohol abuse had less dystonia at rest than did subjects without alcoholism. Dependence was associated with longer dystonia duration and greater dystonia severity and disability. All of the patients with alcohol dependence began drinking after the onset of their dystonia. Similar results were obtained when we applied DSM-III-R criteria (Lauterbach et al. 1993d). As a result of the greater sensitivity of the newer criteria, alcohol abuse was diagnosed in 3 (10.7%) of the patients and alcohol dependence in 5 (17.9%). Drinking began after dystonia onset in 4 (80%) of the dystonia patients with dependence and in 1 (33%) of those with abuse. These findings in dystonia patients contrast with those in Parkinson’s disease patients, in whom DSM-III alcoholism was found to be one-fifth as common as in demographically matched control subjects from the ECA study (Lauterbach and Duvoisin 1987.).

Personality Disorders Dystonia patients may have obsessional, schizoid, and sociopathic personality traits. In blepharospasm patients evaluated in one study,

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elevated MMPI Hysteria scale and F − K Defensiveness Index scores were found in 9 (69%) of 13, suggesting an effort to appear normal (Diamond et al. 1984; Trobe et al. 1985). In addition, histrionic personality features were found in about two-thirds of female patients. Obsessive-compulsive and schizoid personality characteristics have been noted in Meige’s syndrome (Jankovic and Ford 1983). Writer’s cramp patients have been characterized as tense, strong, sensitive, conscientious, precise, and emotionally overcontrolled with obsessive- compulsive personality features (Crisp and Moldofsky 1965). Rates of diagnosable personality disorders in dystonia patients, however, have not yet been determined. Study results of personality profiles in torticollis vary, with researchers reporting more, less, or no difference in obsessivecompulsive personality features relative to control subjects (Cockburn 1971; Crisp and Moldofsky 1965; Jahanshahi and Marsden 1988a; Matthews et al. 1978; Meares 1971b). “Neuroticism” is a common finding in torticollis patients (Choppy-Jacolin et al. 1977; Jahanshahi and Marsden 1988a; Meares 1971a). In one study, the only MMPI difference between patients with spasmodic torticollis and control subjects with Parkinson’s disease was that the torticollis patients endorsed items on the MMPI Psychopathic Deviate scale significantly more often (Naber et al. 1986). In a patient with dystonia due to striatopallidal degeneration, MMPI Schizophrenia, Psychasthenia, Hypomania, and Depression scales were elevated (Stehbens 1972).

Behavioral Disorders Dystonia can be painful and can produce agitation. In one report, agitated behavior in a demented patient remitted after treatment of cervical dystonia (Auchus et al. 1995). Dystonia treatments can also lead to delirium and disordered behavior.

Medication-Induced Psychiatric Disorders When evaluating dystonia patients, psychiatrists should be alert for delirium and psychotic disorders precipitated by oral dystonia medications, particularly the anticholinergics, benzodiazepines, and dopamine agonists (see “Neurological Management” section below).

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Illusions, hallucinations, paranoia, inattention, cognitive impairment, and agitation may be particularly common in patients treated with these agents. Medication-induced mood and anxiety disorders may also be present. Mood disorders can result from dystonia medications such as anticholinergics and benzodiazepines (often administered at very high doses), as well as from L-dopa, dopamine agonists, and other agents (see “Neurological Management” section below). Neuroleptics in particular have been associated with mood disturbances (Young et al. 1994).

Neurological Management Focal dystonia is now commonly treated by administration of local injections of botulinum A toxin (Botox, Dysport) approximately every 3 months. This agent reduces local cholinergic neuromuscular transmission at dosages low enough to only occasionally induce mild signs of systemic botulism (dose depends on muscle size). Antibody resistance, which occurs in about 10% of dystonia patients, is managed by switching to a different serotype (e.g., F or B). In a study of 303 patients who had been undergoing treatment with botulinum A toxin for at least 5 years, no long-term adverse events occurred (Kessler et al. 1994). Transient dysphagia after injections was the most common side effect, and loss of response occurred in only 5% of patients, with antibodies to the toxin in only 2%. Many patients require concomitant treatment with oral systemic agents, especially when the dystonia is generalized. These agents include anticholinergics, benzodiazepines, dopamine agonists, baclofen, and, on occasion, neuroleptics, lithium, carbamazepine, valproic acid, and clozapine. Some knowledge of the medications used to treat dystonia is necessary because of these agents’ critical impact on psychiatric conditions. Anticholinergics are usually the most effective oral agents for the treatment of dystonia, except in Meige’s syndrome, where baclofen is superior (Greene et al. 1988). Dopamine agonists (e.g., lisuride, bromocriptine) are effective in cranial dystonias but less so in torticollis (Lang 1988). In one study, Lang (1988) found that haloperidol

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was effective in 37 (46%) of 81 torticollis patients and 16 (34%) of 47 cranial dystonia patients, while phenothiazines produced improvement in 9 (53%) of 17 patients with generalized or segmental dystonia. Benzodiazepines are especially useful in paroxysmal dystonic choreoathetosis, whereas anticonvulsants are indicated in paroxysmal kinesogenic dystonia, a dystonic movement triggered by exercise or activity (Marsden 1988). Dosages needed for successful treatment can be quite high for anticholinergics (e.g., up to 120 mg/day for trihexyphenidyl) and benzodiazepines (up to 30 mg/day for clonazepam). Drugs are started at conventional doses and then, if there is no response, are gradually titrated upward, allowing time for the patient to develop a therapeutic response and tolerance to side effects. Anticholinergics and benzodiazepines are the most effective agents overall for dystonia, but because dystonia patients occasionally respond to L-dopa, an initial brief trial of L-dopa/carbidopa (e.g., Sinemet) is recommended, beginning at half of a 25-mg/250-mg tablet tid for 1 week and then advancing the dose to a whole 25-mg/250-mg tablet qid for 2 weeks. A small percentage of dystonia patients respond to L-dopa, especially patients with early-onset childhood dystonia, dystonia associated with juvenile parkinsonism, or Segawa’s syndrome. If no response is seen, L-dopa should be discontinued and anticholinergic treatment initiated (e.g., trihexyphenidyl 2 mg tid for 1–2 weeks, advancing the dose as indicated). Monotherapy trials with other agents may be sequentially attempted when inadequate responses occur. Neuroleptics can improve or worsen dystonia. Beta-blockers are useful for dystonic tremor. More recently, four patients with severe generalized dystonia and one with Meige’s syndrome underwent an open trial of clozapine (Karp et al. 1999). All subjects evidenced significant improvement with clozapine on a dystonia rating scale as well as by subjective report. Although sedation and orthostatic hypotension occurred in all five patients, these side effects interfered with treatment in only one subject. In patients benefiting from the employment of sensory tricks, mechanical devices can be fashioned to provide the same therapeutic effect (Krack et al. 1998). Although intrathecal infusions of baclofen have helped some patients with severe dystonia, it is not yet

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apparent which patients benefit. When dystonia is very severe and other treatments have failed, surgical procedures are considered. Surgical treatments are not definitively curative but often have an additive therapeutic effect when combined with pharmacotherapy. Surgical procedures include myectomy, anterior spinal rhizotomy, selective peripheral denervation, posterior ramisectomy, limb tendon section or transfer, and thalamotomy. More recently, posteroventral pallidotomy and ansotomy have proven effective (Iacono et al. 1997; Ondo et al. 1998; Vitek et al. 1997). Myectomy (Anderson procedure) is used for blepharospasm but carries the side effects of disfigurement, infections, and corneal erosions. Rhizotomy in torticollis can produce an unstable neck and requires multiple laminectomies. Posterior ramisectomy usually requires several operations, because dystonia may recur in other muscles. Denervation of a vocal cord is called the Dedo procedure. Tendon transfers or sections usually are not very helpful, because dystonia involves co-contraction of agonist and antagonist musculature, resulting in either flexion or extension, depending on which muscle group is disconnected. Thalamotomy leads to mild or moderate improvement but has a high complication rate, including dysarthria, dysphagia, cerebral infarction, and death.

Psychiatric Management When confronted with a dystonia patient, clinicians must consider the etiology of the dystonia (including tardive or psychogenic origin), the need for workup, the patient’s psychiatric vulnerabilities, the treatment regimen for the dystonia, the psychiatric and other effects of this regimen, the effects of psychiatric treatment on the dystonia, the potential benefit of psychotherapy, and the possibility of referral to support groups. Because of the complex nature of these management issues, psychiatrists may wish to seek neurological consultation for management of the dystonia itself, leaving them free to focus on psychiatric concerns. Information on support groups and informational resources for patients and their families can be obtained by contacting the National Spasmodic Torticollis Association (P.O. Box 424, Mukwonago, WI 53149-0424, phone 1-800-487-8385, fax 414-662-9887) or the Dystonia Medical Research Foundation

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(One East Wacker Drive #2430, Chicago, IL 60601-2001, phone 1-800-377-DYST or 312-755-0198, fax 312-803-0138).

General Supportive Treatment Complications of dystonia can be stressful. Activities of daily living may be impeded by the movements. Embarrassment can occur, especially when the face or speech is involved. In one study, nearly all torticollis patients experienced social embarrassment, with reluctance to go out in public (Matthews et al. 1978). Social ostracization may occur (e.g., harmful teasing) in childhood, although siblings can be important allies. Educating the patient and family members about the nature, course, and prognosis of dystonia can be helpful. Some experienced clinicians find value in informing the patient and family that the condition is not usually painful and that cognition is typically preserved, alleviating the fear of the unknown (Marsden 1995). In adult-onset dystonia, the clinician can help the patient maintain hope by explaining that progression is uncommon. Similarly, educating primary care physicians, pediatricians, teachers, and school authorities about dystonia may be useful. Encouragement to develop abilities not dependent on motor function can help individuals with dystonia to develop successful careers in computers, publishing, languages, or library science (Marsden 1995). Vigilance for psychiatric disorders is indicated, especially adjustment disorders in adolescence or early adulthood. Genetic counseling for families may be helpful.

Pharmacological Treatment There are no controlled studies of psychotropic treatment in dystonia (Rummans et al. 1999). Some psychotropics improve dystonia; others worsen it. Both neuroleptics and SSRIs can either improve or worsen dystonia. Buspirone may lead to persistent dystonia (LeWitt et al. 1993). Thus, psychotropic treatment involves choosing an effective medication for the psychiatric condition and selecting the agent least likely to worsen dystonia or associated conditions. Coadministration of antipsychotics and metoclopramide has been associated with severe, sometimes fatal dystonia (Lauterbach 1992). Patients with nonprimary dystonia may have underlying conditions (e.g.,

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heart disease, dysautonomia) that can be worsened by psychotropics (see Chapter 1 of this volume). Psychotropics may also interact with dystonia treatments. Attention must therefore be given to the management principles outlined in Chapter 1. Blood levels should be monitored, because high-dose dystonia therapies may have unpredictable pharmacokinetic effects on psychotropic levels. Unpredictable pharmacodynamic effects may also occur, necessitating a switch to a different class of psychotropic medication (e.g., atypical antipsychotics rather than neuroleptics). Atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine) may be of particular value in patients with psychotic or bipolar disorders who experience dystonic exacerbations with conventional neuroleptics. However, data are currently insufficient to make any clear recommendations about these agents in patients with dystonia and psychiatric disturbances (see “Treatment of psychosis,” below). Treatment of psychosis. Clozapine may be of value for patients who experience uncontrollable dystonia when taking high-potency antipsychotic agents. Clozapine is useful in primary psychoses with tardive dystonia, including those unresponsive to thioridazine (Wolf and Mosnaim 1994). Moreover, preliminary clinical evidence (Karp et al. 1999) indicates that clozapine is a promising agent for the treatment of primary dystonia (see “Neurological Management” section above). Dystonia has been observed following clozapine withdrawal (Dickson et al. 1994; Wolf and Mosnaim 1994). Clozapine withdrawal dystonia has responded to reinstituting clozapine or treating the patient with risperidone or olanzapine (Ahmed et al. 1998). Clozapine can also trigger dystonia, but the condition is usually responsive to anticholinergics and benzodiazepines (Kastrup et al. 1994). In the event of clozapine-induced dystonia, it is possible that conventional neuroleptics may then be useful. Although neuroleptics improve dystonia in about one-third of patients (Greene et al. 1988; Lang 1988), they can also worsen the disorder. Persistent dystonia can develop in psychiatric AIDS patients after only brief neuroleptic exposure (Factor et al. 1994). Because patients with CNS disease may be at increased risk for neuroleptic-induced dystonia and neuroleptic malignant syndrome (Stoudemire et al. 1995), cau-

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tion is indicated when using these agents in such populations. When high-potency neuroleptics worsen dystonia, low-potency agents may be useful if not otherwise contraindicated (e.g., the risk of cardiovascular compromise). One further caveat is that tardive dyskinesia or tardive dystonia can develop in dystonia patients just as it can in any other patients taking antipsychotics. It is too early to determine the role of other atypical antipsychotics in managing patients with dystonia. Although tardive dystonia and other movement disorders are perhaps less likely than with traditional neuroleptics, atypical antipsychotics nevertheless can still cause these disorders. Tardive torticollis has been reported with risperidone (Fdhil et al. 1998). Moreover, in a prospective study of 350 consecutive neuroleptic-naive patients admitted to an acutecare psychiatry service (34 treated with risperidone at a mean dose of 3.2 mg/day and 212 treated with haloperidol at 3.7 mg/day), Rosebush and Mazurek (1999) found that the incidences of dystonic reactions and of other acute movement disorders were similar between the two drugs. Notwithstanding these data, however, some patients may benefit from switching drugs. Yoshida et al. (1998) reported the case of a patient with schizophrenia who experienced marked improvement in tardive dystonia after haloperidol was replaced with risperidone. Much more data are needed before inferences can be drawn about the role of atypical antipsychotics in managing psychiatric disorders in dystonia patients. Treatment of bipolar disorders. In bipolar disorder, conventional treatments may have a salutary effect on dystonia, may have no effect, or may even worsen it (Lauterbach et al. 1992b). In addition to the effects of neuroleptics and clozapine discussed above, lithium, carbamazepine, and valproate may, in a minority of patients, produce improvement in dystonia (Greene et al. 1988). More rarely, these agents have also triggered acute dystonia, but a beneficial effect on dystonia is more likely. In one patient with myoclonic tardive dystonia, calcium channel blockers dramatically improved the dystonia (Abad and Ovsiew 1993). This is of interest in dystonia patients with bipolar disorders, given the occasional utility of these agents in this psychiatric condition. Benzodiazepines may also benefit dystonia, especially clonazepam, although conventional anti-

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manic doses may not be high enough to render improvement. Propranolol is useful for both dystonic tremor and lithium tremor (Lauterbach et al. 1992b). Electroconvulsive therapy (ECT) improved dystonia in a patient with parkinsonism–dystonia syndrome (Lauterbach and Moore 1990) and in another patient with tardive dystonia (Adityanjee et al. 1990). Treatment of depression. All commercially available SSRIs have been associated with acute dystonic reactions (Al-Adwani 1995; Dave 1994; George and Trimble 1993; Shihabuddin and Rapport 1994). Serotonin reuptake–inhibiting tricyclic antidepressants have also been associated with dystonia (Lee 1988). In one case report, trazodone precipitated acute lingual dystonia, disorientation, tachycardia, diaphoresis, and incontinence at 400 mg/day, progressing to akathisia, facial dyskinesia, catatonia, and parkinsonism (M. S. Kramer et al. 1986). The effect of noradrenergic antidepressants on dystonia is less clear. In secondary dystonia, however, fluoxetine is sometimes beneficial (Lauterbach 1995). In a case report, Kato et al. (1994) found that trazodone improved frontal blood flow and ameliorated nuchal dystonia in progressive supranuclear palsy. Dystonia and autonomic disturbance following fluoxetine withdrawal has also been reported (Stoukides and Stoukides 1991). Treatment of anxiety disorders. For coexisting obsessive-compulsive symptoms, panic attacks, and GAD, serotonin reuptake–inhibiting agents, other antidepressants, and benzodiazepines may be helpful, as discussed previously. Circumspection is indicated when prescribing benzodiazepines, given the proclivity of dystonia patients toward substance abuse. Buspirone, however, has triggered dystonia refractory to anticholinergics and responsive only to clonazepam (Ritchie et al. 1988). There are other reports of dystonia and intractable movement disorders with buspirone (LeWitt et al. 1993). Treatment of substance abuse disorders. In treating substance abuse, disulfiram intoxication has produced dystonia in association with lenticular nucleus lesions, which were possibly attributable to the metabolite carbon disulfide (Krauss et al. 1991). The effects of

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naltrexone on dystonia are not clear. Alcohol withdrawal is associated with movement disorders, and alcohol alleviates some forms of dystonia (Neiman et al. 1990), an effect that may potentially reinforce certain forms of substance abuse in dystonia patients.

Psychogenic Dystonia When confronted with apparent psychogenic dystonia, clinicians must be careful to establish the correct underlying diagnosis (see “Somatoform Disorders and Psychogenic Dystonia” under “Psychiatric Manifestations” section earlier in chapter). About 25% of patients with psychogenic dystonia experience full remission; conversion disorders and depressive illnesses respond best, whereas somatization, factitious disorders, and malingering rarely improve with treatment (Marsden 1995). Antidepressants may help, given the high rates of mood disorders in this population (Williams et al. 1995). Among 21 patients undergoing treatment for psychogenic dystonia, 15 patients (71%) benefited from suggestion, 12 (57%) from formal psychotherapy, 10 (48%) from physiotherapy, 10 (48%) from placebo, 5 (24%) from antidepressants, and 3 (14%) from behavior modification (Fahn and Williams 1988). In psychotherapy, clinicians should look for and attend to abuse issues, which are common in patients with psychogenic dystonia. Hypnosis is sometimes useful (Williams et al. 1995). In 4 patients with psychogenic dystonia, a combined hypnobehavioral approach involving postural hypnotic differential muscle retraining, hierarchical desensitization, sensory imaging conditioning, and ego-boosting suggestions was reported to be successful (De Benedittis 1996). Good to excellent outcomes were reported, with reductions in torticollis, muscle hypertrophy, and functional disability.

Summary Dystonia is an intriguing disorder with many unusual features and strange phenomena that can lead to misdiagnosis. It has many forms, with more generalized dystonias occurring earlier in life. Dystonia can have many etiologies, and causes of nonprimary dystonias can be determined by history, physical, and laboratory workup. A num-

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ber of genetic types exist. Patients with primary dystonia are at high risk for mania, depression, generalized anxiety disorder, and alcohol dependence; in addition, they possess distinguishing personality profiles. Principles of psychotherapy and psychopharmacology are complex and require careful planning and monitoring. Psychiatric treatment can improve the course and outcome of dystonia.

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C H A P T E R

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Stroke Robert G. Robinson, M.D.

C

erebral infarction, or stroke, represents a major health problem facing the geriatric population in the United States. It is the third leading cause of death in the United States and most European countries. Approximately 77% of strokes are thromboembolic, with 30% thrombotic, 22% embolic, and 25% uncertain. The remaining 23% of strokes are hemorrhagic, with 11% intracranial hemorrhage and 12% subarachnoid hemorrhage (Caplan and Stein 1986). Hypertension is the greatest risk factor for stroke.

Prevalence The annual incidence of stroke in the United States is approximately 400,000. The prevalence rises steadily with each decade of life, increasing from 810 per 100,000 at ages 55–65 years to 5,970 per 100,000 after age 75 years (Wolf et al. 1984). Due primarily to the greatly improved control of hypertension, the incidence of stroke declined steadily from the 1940s through the 1970s (Garraway et al. 1979). This work was supported in part by National Institute of Mental Health Research Scientist Award MH00163 and by NIMH grants MH52879 and MH53592. The author thanks Thomas R. Price, John R. Lipsey, Rajesh Parikh, Carlos Castillo, Krishna Rao, Godfrey D. Pearlson, Lynn Book Starr, and Paula Andrezewski, who participated in many of the studies described. 219

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Clinical Recognition, Neurological Presentation, Pathological Features, Neuroimaging, and Laboratory Investigation A discussion of these topics is quite involved and is beyond the scope of this chapter but is available elsewhere (Adams 1993; Bogousslavsky and Caplan 1995).

Psychiatric Manifestations Cognitive Impairment Cognitive impairment is probably the most frequent mental consequence of stroke. A discussion of the cognitive impairments resulting from stroke is the topic of textbooks of neuropsychology and is well beyond the scope of this chapter. Multi-infarct disease, found in 15%–20% of dementia cases, is second only to Alzheimer’s disease as the leading cause of dementia in the United States (Herskovits and Figueroa 1988). There is, however, one form of poststroke cognitive impairment that appears to be amenable to treatment, and that is cognitive impairment associated with poststroke depression. Several studies have demonstrated that patients with poststroke major depression display a greater degree of cognitive impairment than nondepressed patients with comparable lesions (Bolla-Wilson et al. 1989; House et al. 1990a; Robinson 1998; Starkstein et al. 1988c) (Figure 7–1). Among patients with left-hemisphere lesions, a neuropsychological test battery revealed that patients with major depression had greater overall cognitive impairment in the domains of orientation, language, visuoconstruction, executive function, and frontal lobe functioning compared with nondepressed patients with comparable lesions. In contrast, among patients with right-hemisphere lesions, overall severity of cognitive impairment did not differ significantly between depressed and nondepressed patients. These findings suggest that left-hemisphere stroke may produce a neurophysiological response that leads to both major depression and cognitive dysfunction and right-hemisphere stroke may lead to depression by a very different mechanism.

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Figure 7–1. Mean (±SD) Mini-Mental State Exam (MMSE; Folstein et al. 1975) scores of patients with major depression, minor depression, or no mood disorder following acute stroke. Patients with major depression were significantly more impaired than those in the other two groups. *F2, 272 = 6.99, P = .001.

Apathy Apathy—the absence or lack of feeling, emotion, interest, or concern—has been reported frequently among patients with brain injury. Using an apathy scale, we examined a consecutive series of 80 patients with single-stroke lesions and no significant impairment in comprehension (Starkstein et al. 1993). Of these patients, 9 (11%) manifested only apathy (without depression), and another 9 (11%) had both apathy and depression. The only demographic correlate of apathy was age; apathetic patients (with or without depression) were significantly older than nonapathetic patients. Also, apathetic patients showed significantly more severe deficits in activities of daily living (ADL), and there was a significant interaction between depression and apathy on ADL scores, with the greatest impairment

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found in patients who were both apathetic and depressed. Nondepressed patients with apathy also had a significantly higher frequency of lesions involving the posterior limb of the internal capsule compared with patients with no apathy (Starkstein et al. 1993). A clinical example will illustrate some of these characteristics. The patient, a 58-year-old man, had bilateral infarctions of the caudate nuclei. He had been a very active and hard-working florist; however, after the strokes, which occurred within a few weeks of each other, he became uninterested in his business and his home. He stopped working, and his wife couldn’t even get him to mow their small yard. He would stop in the middle of jobs and would have no explanation. Although he denied depression, he stated that he got no pleasure from doing tasks and was content just sitting. His condition did not improve with antidepressants but showed some improvement after treatment with stimulant medication.

Pathological Emotions Pathological laughing and crying represent a severe form of emotional lability characterized by episodes of laughing and/or crying that are not appropriate or that are markedly excessive to the situation. They may appear spontaneously or may be elicited by nonemotional events, and they do not correspond or are excessive to underlying emotions. Pseudobulbar affect is another name that has been applied to pathological laughing and crying. This disorder has classically been explained as secondary to the bilateral interruption of neocortical upper motor neuron innervation of bulbar motor nuclei (Poeck 1969). Several investigators have examined the prevalence of this disorder in patients with stroke. Morris and colleagues (1993b) found that pathological emotions occurred in 12 (18%) of 66 patients examined 2–3 months poststroke in a rehabilitation hospital.

Psychosis The phenomena of hallucinations and delusions in stroke patients have been described in patients with agitated delirium, acute atypical psychosis, peduncular hallucinosis, release hallucinations, or acute organic psychosis. In a study of psychosis after stroke lesions,

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Rabins et al. (1991) found a very low prevalence of psychosis among stroke patients (only five cases in 5 years of geriatric psychiatric admissions). All five patients, however, had right-hemisphere lesions, primarily involving frontoparietal regions. When compared with five age-matched patients with cerebrovascular lesions in identical locations but no psychosis, patients with secondary psychosis had significantly greater subcortical atrophy, as manifested by significantly larger areas of the frontal horn and body of the lateral ventricle (measured on the side contralateral to the brain lesion). Several other investigators have reported a high frequency of seizures among patients with secondary psychosis (Levine and Finklestein 1982). These seizures usually started after the brain lesion but before the onset of psychosis. The Rabins et al. study (1991) found seizures in three of five patients with poststroke psychosis compared with none of five poststroke nonpsychiatric control subjects. We have hypothesized that three factors may be important in the mechanism of organic hallucinations: a right-hemisphere lesion involving the temporoparietal cortex, seizures, and/or subcortical brain atrophy (Starkstein et al. 1992). Another clinical example will illustrate the presentation and correlates of psychosis following stroke. The patient, a 72-year-old right-handed woman with no prior psychiatric history, had experienced the sudden onset of a right occipital headache, followed by numbness of her left arm and left facial droop. She had focal seizures of her left arm. Two days after this event, the patient heard a buzzing noise she thought was made by a bee. She later heard the voice of a relative saying that he was going to kill her, and she hid in the closet. She also saw people sitting at her kitchen table discussing her. The patient was oriented and had no sign of delirium. She improved following treatment with haloperidol and after 1 month had no further hallucinations.

Mood Disorders Mania. Manic symptoms following stroke occur much less frequently than depressive symptoms. In our studies of patients over the first 2 years after a stroke, we found only 3 cases among more than 400 patients seen at various times following stroke (Robinson et al.

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1988). We and others have had to use patients with cerebral injury resulting from one of several etiologies in order to archive an adequate sample size. When we compared 11 patients with secondary mania and 25 patients with functional (i.e., no known neuropathology) mania, both groups of patients showed similar frequencies of elation, pressured speech, flight of ideas, grandiose thoughts, insomnia, hallucinations, and paranoid delusions (Starkstein et al. 1987a). Thus, secondary mania had the same phenomenological appearance as primary mania. Cummings and Mendez (1984) described two patients who developed mania following right thalamic lesions. We subsequently examined 17 patients with secondary mania, 31 stroke patients with major depression, and 28 stroke controls with no mood disturbance (Robinson et al. 1988). Compared with patients with poststroke major depression or no mood disorder following stroke, a significantly greater number of manic patients had right-hemisphere lesions involving either cortical limbic areas (i.e., orbitofrontal cortex or basotemporal cortex) or subcortical nuclei (i.e., head of the caudate or thalamus) (Figure 7–2). In another study involving 45 highly selected poststroke patients, all 3 with mania had left cerebellar or cerebellothalamic tract lesions, presumably affecting cerebellar connections with the right caudate or thalamus (Lauterbach 1996). Occasionally, secondary mania has been followed by recurrent manic episodes, whereas in other instances the mania has been followed or preceded by episodes of depression. In an effort to determine which factors affect this bipolar course, we examined 19 patients with the diagnosis of secondary mania (Starkstein et al. 1991). Subjects were divided into two groups, one with bipolar disorder (i.e., mania preceded by depression) and the other with single or recurrent episodes of mania. The bipolar group (n = 7) was found to have greater cognitive impairment than the mania-only group (n = 12), and 5 of the bipolar patients had lesions restricted to the subcortical area of the right hemisphere. In contrast, 11 of the mania-only patients had cortical lesions of the right hemisphere (only 1 patient had a subcortical lesion) (P < .05). These interesting findings suggest that disruption of subcortical mechanisms in the right hemisphere may be important in bipolar disorder, whereas disruption of right cortical mechanisms may mediate a unipolar mania.

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Figure 7–2. Frequency of lesions restricted to the right hemisphere in patients with mania, major depression, or no mood disorder following acute stroke. Patients with mania were significantly more likely to have a right-hemisphere lesion than were patients with depression or no mood disturbance. *P < .01.

Depressive disorders. Depression is probably the most common poststroke emotional disorder, occurring in 20%–50% of patients following acute stroke (Burvill et al. 1995; Morris et al. 1990). DSM-IV (American Psychiatric Association 1994) now categorizes poststroke depression as a mood disorder due to a general medical condition (i.e., stroke), with the following specifiers: 1) with depressive features, 2) with major depressive–like episode, 3) with manic features, or 4) with mixed features (American Psychiatric Association 1994). Prior to the publication of DSM-IV, two types of depressive disorders associated with cerebral ischemia had been identified under DSM-III (American Psychiatric Association 1980) criteria: 1) major depression, which occurs in about 20% of patients, and 2) minor depression, which also occurs in about 20% of patients (Robinson et al. 1983). In prior studies, we defined minor depression as meeting DSM-III-R

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(American Psychiatric Association 1987) symptom criteria for dysthymic depression (excluding duration) criteria. There are now DSM-IV research criteria for minor depression—i.e., depressed mood or loss of interest and 2–4 symptoms of major depression of at least 2 weeks’ duration (American Psychiatric Association 1994, pp. 720–721). Diagnosis. A study of depressive symptoms among stroke patients found that, except for early morning awakening, all of the psychological as well as vegetative symptoms of depression occurred more frequently among depressed stroke patients than among comparable stroke patients without a depressed mood (Fedoroff et al. 1991). Therefore, the use of DSM-IV criteria in an acutely medically ill population does not appear to produce significant numbers of falsepositive or false-negative cases. The difficulty of assessing symptomatology in the presence of language impairment is another aspect of the poststroke patient that may influence phenomenology. Virtually all studies of patients with depression following stroke have excluded patients with impaired language comprehension. The obvious question raised by the exclusion of patients with comprehension deficits from systematic studies of poststroke depression is whether the exclusion of these patients has significantly influenced the clinical or lesion correlates of poststroke depression. Although this question cannot be definitively answered, our assessments of patients with mild comprehension deficits did not reveal a high frequency of depression (Starkstein and Robinson 1988). Numerous investigators have assessed the prevalence of poststroke depression. Representative publications from institutional and community survey studies are shown in Table 7–1. Overall, about 20%–40% of patients may develop depression within the first few months after an acute stroke. The rates depend on whether the general population or specific institutionalized patients are studied. Approximately half of patients who develop poststroke depression will meet criteria for major depression; the remaining half will have the less severe form of minor depression. A number of studies have assessed the duration of poststroke depression (Astrom et al. 1993; House et al. 1991; Morris et al. 1990; Rob-

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Table 7–1.

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Prevalence of poststroke depression

Setting/investigator Community studies Burvill et al. 1995 House et al. 1991 Rehabilitation hospital Eastwood et al. 1989 Morris et al. 1990 Acute care hospital Astrom et al. 1993 Castillo et al. 1993 Note.

No.

Major Minor Overall depression, depression, depression, % % %

294 89

15 11

8 12

23 23

87 99

10 14

40 21

50 35

80 291

25 20

NR 18

25+ 38

NR = not reported.

inson et al. 1987). In all of these studies, the majority of patients with major depression experienced remission within the first year, with a minority of cases becoming chronic major depression persisting up to 3 years following stroke. For example, Morris et al. (1990) found a mean duration of major depression of 42 weeks, whereas Astrom et al. 1993) reported that 5 of 14 patients (36%) with in-hospital major depression were still depressed at 3-year follow-up. Three factors have been identified that can influence the natural course of poststroke depression: 1) active treatment of the depression with antidepressant medication (Lipsey et al. 1984), 2) the location of the stroke lesion (Starkstein et al. 1988b), and 3) the presence or absence of adequate social support (Morris et al. 1991). A recent study examined the effect of gender on the frequency of poststroke depression (Paradiso et al. 1998). In a consecutive series of 301 patients with acute stroke, women were significantly more likely to develop major depression than were men (24% versus 12%). Among men, major depression was associated with impairments in ADL and social functioning. Among women, however, major depression was associated with left anterior brain lesions, prior history of psychiatric disorder, and cognitive impairment. These findings suggest that the etiology of major depression may be different in men and women. The first study to report a significant clinical–pathological corre-

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lation in poststroke depression found a significant inverse correlation between the severity of depression and the distance of the anterior border of the lesion from the left frontal pole (r = − 0.76) as measured on computed tomography (CT) imaging (Robinson and Szetela 1981) (Figure 7–3). This surprising finding led to a number of subsequent investigations both of this phenomenon and of the laterality of lesion location. Many studies have confirmed the association of poststroke major depression with left anterior brain injury (Astrom et al. 1993; Eastwood et al. 1989; Herrmann et al. 1993; Morris et al. 1996; Robinson et al. 1984), but several have not (Dam et al. 1989; House et al. 1990b; Sinyor et al. 1986); however, some of the latter studies have supported the correlation of severity of depression with frontal proximity of the lesion without the association with left-hemisphere lesions (House et al. 1990b; Sinyor et al. 1986). Longitudinal assessment has suggested that the association of major depression with left anterior lesions is a phenomenon of the acute poststroke period, whereas the correlation of depression with proximity of the lesion to the frontal pole lasts for about 6–9 months following stroke (Shimoda and Robinson 1999). Subsequent work has examined the effect of cortical and subcortical lesion location on the severity and presence of depressive symptoms following stroke (Starkstein et al. 1987b). Patients with acute ischemic lesions in the left hemisphere were found to have significantly higher rates of both major and minor depression than patients with right-hemisphere lesions, regardless of the cortical or subcortical location of the lesion (Figure 7–4). Additionally, correlations between depression scores and the distance of the lesion from the frontal pole were significant for patients with either left cortical or left subcortical lesions. These clinical–pathological correlations, however, were not significant for patients with acute right-hemisphere lesions. Among patients with left subcortical lesions, the frequency of major depression was found to be significantly greater in patients with left basal ganglia lesions than in patients with left thalamic lesions (Starkstein et al. 1988a). Lauterbach et al. (1997a) examined 45 patients with focal subcortical lesions and found a 20% frequency of major depression and a 4% frequency of minor depression. Left posterior globus pallidus lesions were significantly associated with major depression (Lauterbach et al. 1997b).

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Figure 7–3. Scatter plot of the relationship between severity of depression in patients with stroke or traumatic brain injury, as measured by three depression rating scales, and distance of the anterior border of the lesion from the frontal pole, as measured on computed tomography (CT) scan. For both stroke and trauma lesions, depression increased with proximity of the lesion to the frontal pole (r = .76, P < .01). Source. Reproduced from Robinson RG, Szetela B: “Mood Change Following Left Hemispheric Brain Injury.” Annals of Neurology 9:447–453, 1981. Copyright © 1981, Lippincott-Raven Publishers. Used with permission.

Another study that examined the lesion correlates of poststroke depression compared patients with brain-stem cerebellar lesions (posterior circulation) and patients with cerebral hemisphere lesions (middle cerebral artery circulation) (Starkstein et al. 1988b). This study found that patients with brain-stem cerebellar lesions had a significantly lower frequency of major depression than patients with middle cerebral artery infarcts and that the duration of major depression was also significantly shorter (Starkstein et al. 1988b) (Figure 7–5). Noradrenergic and serotonergic cell bodies located within the brain stem send ascending projections through the median fore-

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Figure 7–4. Frequency of depression in patients with acute first-ever stroke lesions restricted to cortical or subcortical brain regions. Lefthemisphere cortical (LC) and subcortical (LS) lesions were associated with a greater frequency of depression than were right-hemisphere cortical (RC) and subcortical (RS) lesions. *χ2 = 4, P < .05.

brain bundle to the frontal cortex. These axons then run longitudinally through the deep layers of the cortex (Morrison et al. 1979). Based on these neuroanatomic facts and the clinical finding that the severity of depression correlates with the proximity of the lesion to the frontal pole, we have suggested that poststroke depression may be the consequence of severe depletion of norepinephrine and/or serotonin resulting from interruption of these ascending biogenic amine pathways by left frontal or left basal ganglia lesions (Robinson et al. 1984). We also found a lateralized biochemical response to ischemia in human subjects (Mayberg et al. 1988). Right-hemisphere lesions resulted in significantly higher amounts of ipsilateral spiperone binding (presumably 5-HT2 [serotonin] receptor binding) in the noninjured temporal and parietal cortex compared with left-hemisphere lesions. Patients with left-hemisphere lesions, on the other hand, showed a decrement in serotonin binding in the left temporal cortex that inversely correlated with depression scores. These find-

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Figure 7–5. Percentage of patients who remained depressed 6 months and 12–24 months following a brain-stem cerebellar (BST/CB) lesion or a hemispheric middle cerebral artery (MCA) infarct. Patients with MCA infarcts were significantly more likely to remain depressed at 6 and 12–24 months follow-up than were patients with BST/CB lesions.

ings are intriguing and suggest that, from a biochemical standpoint, the left hemisphere recovers from injury less robustly than the right hemisphere. Consequently, the left hemisphere may be in some way more vulnerable to lesion-induced biogenic amine depletion than the right hemisphere.

Anxiety Disorders Anxiety disorder is an important but rarely studied consequence of stroke. Depending upon the population being studied, the prevalence of generalized anxiety disorder (GAD) varies from 1% in community studies (House et al. 1991) to 28% of patients hospitalized with acute stroke (Astrom 1996). We examined a consecutive series of 98 patients with acute stroke lesions for the presence of both anxiety and depressive disorders (Starkstein et al. 1990). Modified DSM-III criteria for GAD (M-GAD; i.e., excluding 6-month-duration criteria)

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were used for the diagnosis of anxiety disorder. Of 98 patients with first-episode stroke, only 6 met the M-GAD criteria in the absence of any other mood disorder. The only finding that distinguished these patients from the others was a significantly higher frequency of prior history of alcohol abuse. Although alcohol withdrawal may be associated with anxiety, only 9 of 29 patients with M-GAD had a history of alcoholism. On the other hand, 23 of 29 patients (79%) with M-GAD also met criteria for major depression. Examination of CT scans obtained during the initial hospitalization revealed that patients with both major depression and M-GAD had a significantly higher frequency of cortical lesions than did either depressed patients without anxiety or nondepressed, nonanxious patients (Figure 7–6). On the other hand, depressed patients without anxiety were noted to have a significantly higher frequency of subcortical lesions compared with the anxious–depressed group (Figure 7–6).

Sexual Disorders Several studies have found marked impairment in sexual functioning after stroke. Fewer than one-third of men and women enjoyed their sex lives after a stroke, in contrast to 85% and 60%, respectively, before the stroke (Monga et al. 1986). This study identified reductions in desire, excitement, and orgasm. The most commonly identified factor explaining these reductions was fear of elevating blood pressure during sex, thereby causing another stroke. Women with righthemisphere lesions had the least impairment in sexual function. In men, in contrast, sexual dysfunction was significantly more common after right-hemisphere strokes than after left-hemisphere strokes (Coslett and Heilman 1986). Another study found that the degree of need for assistance with ADL and impaired cutaneous sensibility were major factors leading to reduced sexual intercourse (Sjogren and Fugl-Meyer 1982). Consequently, both physical and psychological factors may contribute to reduced sexuality after a stroke.

Neurological Management Neurological management of stroke is a rapidly evolving field. Acute management involves the maintenance of adequate respiration and

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Figure 7–6. Frequency of basal ganglia or cortical lesions among acute poststroke patients with major depression, major depression plus generalized anxiety disorder, or no mood or anxiety disorder. Major depression without anxiety was associated with basal ganglia infarcts, whereas anxious depression was associated with cortical infarcts. * P < .05 compared with other groups.

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blood circulation. Over the first day or two, blood pressure must be monitored and cerebral edema and increased intracranial pressure must be controlled. Longer-term concerns include cardiac function and skin care; development of pulmonary embolism, pneumonia, and other infectious processes; and prevention of recurrence through control of hypertension, smoking, and other risk factors (Brott 1993). Perhaps the most exciting developments, however, involve the antithrombotic and thrombolytic treatment of acute ischemic stroke. Antithrombotic agents have been demonstrated to significantly reduce the frequency of completed infarction in patients who had previously suffered a transient ischemic attack (TIA) (Marler 1993). Thrombolytic therapy, which has been demonstrated to be so effective in the acute treatment of myocardial infarction, has been more problematic in the treatment of acute cerebral infarction. Although some patients treated within the first 2 hours following stroke have made remarkable recovery from the effects of stroke, many patients have suffered intracerebral hemorrhages leading to further complication or death (Hacke et al. 1995). Thus, the neurological management of acute stroke is still evolving, and safer, more specific agents need to be developed. Other treatments for stroke are being developed that aim at reducing the amount of neuronal damage produced by the ischemia. Some of these treatments include the use of gangliosides, opiate receptor antagonists, N-methyl-D-aspartate receptor antagonists, and free radical scavengers (Candelise 1993). All of these treatments have shown promise in preliminary human studies or animal studies, but none have become standard treatment for acute stroke. There are numerous texts available for those seeking a more detailed discussion of neurological management in stroke (Adams 1993; Bogousslavsky and Caplan 1995).

Psychiatric Management Treatment of Cognitive Impairment The finding that cognitive impairment is associated with the presence of poststroke major depression (Bolla-Wilson et al. 1989) sug-

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gests that treatment of depression may result in improvement in cognitive functioning. Our study of nortriptyline treatment of poststroke depression did not show a significant difference in MiniMental State Exam (MMSE; Folstein et al. 1975) scores between the nortriptyline-treated and the placebo-treated patients over 6 weeks of treatment. Patients were, on average, 6 months poststroke, however, and the relatively long period since stroke may have contributed to the lack of improvement following antidepressant treatment (Lipsey et al. 1984). Another study, however, did assess cognitive function during the first 3 months following stroke in patients with major or minor depression (Gonzalez-Torrecillas et al. 1995). This study involved 6 weeks of open-label treatment with either nortriptyline or fluoxetine. Both antidepressants produced significantly greater improvement in MMSE scores than placebo. In this study, patients were given nortriptyline (increasing weekly doses from 20 mg to 100 mg) (n = 11) or fluoxetine (20 mg) (n = 26). Thus, although there are no controlled trials specifically addressing the effect of antidepressant treatment on cognitive function, preliminary evidence suggests that during the first few months following stroke, cognitive impairment may improve with treatment of depression.

Treatment of Apathy Although apathy is a relatively common consequence of stroke, no controlled trials of the treatment of poststroke apathy have been conducted, and there are few anecdotal reports in the literature. We have treated patients with nortriptyline, apomorphine, and amphetamine with only marginal success (R. G. Robinson and S. E. Starkstein, unpublished data, 1988). Treatment trials are urgently needed to address this condition, which can be devastating to the recovery of physical and social activities following stroke.

Treatment of Pathological Emotions We developed a Pathological Laughter and Crying Scale (PLACS; Robinson et al. 1993) to assess the existence and severity of poststroke emotional lability. Using the PLACS, a double-blind drug trial of nortriptyline (n = 14) versus placebo (n = 14) was conducted to deter-

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mine the responsiveness of this condition to tricyclic antidepressants (TCAs) (Robinson et al. 1993). The dose of nortriptyline was titrated from 20 mg/day (week 1) to 50 mg/day (weeks 2 and 3), 70 mg/day (week 4), and 100 mg/day (weeks 5 and 6). Of the 28 patients who completed the 6-week protocol (4 dropped out), those on nortriptyline showed significantly greater improvement in PLACS scores than did placebo-treated controls (Figure 7–7). These group differences were statistically significant at weeks 4 and 6. Citalopram, a selective serotonin reuptake inhibitor (SSRI), has also been evaluated in the treatment of pathological emotions (Andersen et al. 1993). Sixteen patients were evaluated in a double-blind, placebo-controlled crossover study. Three patients were dropped from the study. Citalopram (20 mg) was given for 3 weeks after a week of washout. All of the citalopram-treated patients reported a greater than 50% reduction in the number of crying episodes. Of the 13 patients who completed treatment, 8 responded within 24 hours of taking citalopram, and 3 responded within 3 days. Thus, citalopram as well as nortriptyline appears to be an effective method of treatment for pathological crying following stroke.

Treatment of Psychosis There are no controlled treatment trials among patients with delusions or hallucinations following stroke. Anecdotal reports have suggested two basic approaches to treatment, one using anticonvulsant therapy and the other using neuroleptic therapy. The rationale for the use of anticonvulsants is the frequent coexistence of seizures with psychotic disorders following stroke. In Levine and Finklestein’s series (1982), however, secondary psychotic features did not usually respond to anticonvulsant treatment. Price and Mesulam (1985), on the other hand, described a patient whose repeated psychotic episodes (lasting from 1 day to 1 week) were controlled with phenobarbital. The second approach to the treatment of hallucinations and delusions is the use of neuroleptic medications. Although some patients have been noted to be resistant to neuroleptic medications (e.g., trifluoperazine up to 80 mg/day [Levine and Finklestein 1982]),

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Figure 7–7. Pathological Laughter and Crying Scale (PLACS; Robinson et al. 1993) scores during 6 weeks of double-blind treatment (nortriptyline or placebo) of poststroke pathological emotions. * Repeated-measures analysis showed significant treatment effects, with nortriptyline being superior to placebo at 4 and 6 weeks of treatment. Source. Reprinted from Robinson RG, Parikh RM, Lipsey JR, et al.: “Pathological Laughing and Crying Following Stroke: Validation of a Measurement Scale and a Double-Blind Treatment Study.” American Journal of Psychiatry 150:286–293, 1993. Copyright © 1993, American Psychiatric Association. Used with permission.

many patients with secondary psychotic disorders have improved with neuroleptics. The atypical antipsychotics await study in stroke patients.

Treatment of Poststroke Mania There are no systematic studies on the treatment of mania following brain injury, and the existing case reports reflect anecdotal treatments and responses. Overall, the consensus is that secondary mania is inherently more difficult to treat than primary mania (Evans et al.

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1995). Some reports have also suggested that although patients who develop secondary mania (particularly manias associated with seizure disorders) may not be as responsive to lithium as patients with primary mania, they may respond to treatment with anticonvulsant drugs such as carbamazepine and valproate (Shukla et al. 1987). Thus, if lithium is not effective, carbamazepine, clonidine, valproate, verapamil, and neuroleptic augmentation may be useful alternatives. The anticonvulsants, such as carbamazepine and valproate, may also be particularly beneficial for stroke patients because of the risk of seizures in this population.

Treatment of Poststroke Depression Despite early anecdotal reports suggesting the clinical utility of TCAs or stimulant medications in the treatment of poststroke depression, only a few randomized double-blind treatment studies of the efficacy of antidepressant treatment have been published. The first published study involved 14 poststroke depressed patients treated with nortriptyline and 20 poststroke depressed patients given placebo (Lipsey et al. 1984). In the group treated with nortriptyline (20 mg/ day for week 1, 50 mg/day for weeks 2 and 3, 75 mg/day for week 4, and 100 mg/day for weeks 5 and 6), the 11 patients who completed the 6-week study showed significantly greater improvement in their scores on the Hamilton Rating Scale for Depression (HAMD; Hamilton 1960) compared with the 15 placebo-study completers (Figure 7–8). Nortriptyline levels in the treated group were between 50 and 150 ng/mL following 2 weeks of treatment with 100 mg of nortriptyline per day. Of the 6 noncompleters taking nortriptyline, 5 dropped out because of side effects, including delirium (2 patients), dizziness (1 patient), and sedation (2 patients), and 1 experienced a second stroke. Thus, although side effects were a significant problem, this study demonstrated by double-blind methodology that depression can be effectively treated with nortriptyline in patients with stroke. Reding et al. (1986) reported that patients with either a clinical diagnosis of depression or an elevated Zung Self-Rating Depression Scale (Zung 1965) score treated with trazodone (target dosage of 200 mg/day) showed greater improvement in ADL scores, as measured by the Barthel Index (Barthel and Mahoney 1965), over

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Figure 7–8. Hamilton Rating Scale for Depression (HAMD; Hamilton 1960) scores during 6 weeks of double-blind treatment (nortriptyline or placebo) of poststroke depression. *Repeated-measures analysis showed significant treatment effects, with nortriptyline being superior to placebo at 4 and 6 weeks of treatment (P = .006). Source. Reprinted from Lipsey JR, Robinson RG, Pearlson GD, et al.: “Nortriptyline Treatment of Post-Stroke Depression: A Double-Blind Study.” Lancet 1(8372):297–300, 1984. Copyright © 1984, The Lancet Ltd. Used with permission.

6 weeks of treatment than did patients receiving placebo. The most recent study that has investigated the treatment of poststroke depression used citalopram, one of the SSRIs (Andersen et al. 1994). HAMD scores were found to be significantly more improved over 6 weeks of treatment in patients receiving citalopram (20 mg) (n = 27) than in those receiving placebo (n = 32). At both 3 weeks and 6 weeks, the active-treatment group had significantly lower HAMD scores than the placebo group. Interestingly, this antidepressant effect was primarily accounted for by subjects who became depressed 7 or more weeks after a stroke, as those who became depressed early after an acute stroke had a substantial rate of spon-

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taneous recovery. The most important contribution of this study, however, was that it established the efficacy of SSRIs in the treatment of poststroke depression. Newer agents such as nefazodone and venlafaxine also hold promise but await investigation in controlled trials to establish efficacy in this population. A few studies have evaluated the use of stimulants such as methylphenidate in the treatment of poststroke depression, although placebo-controlled, double-blind trials have not been completed to date (Johnson et al. 1992; Lingam et al. 1988). One open trial of methylphenidate involved 25 poststroke patients diagnosed with DSM-III major depression (Lingam et al. 1988). Electroconvulsive therapy (ECT) has also been demonstrated to be a potentially effective treatment for poststroke depression. Currier et al. (1992) evaluated 20 medically ill patients with poststroke depression treated with ECT. Nineteen subjects improved, and no patient displayed an exacerbation of preexisting neurological deficits. However, 37% relapsed (typically 4 months after completing ECT) despite maintenance treatment with antidepressant medication. The role of continuation or maintenance ECT in the treatment of poststroke depression has not yet been investigated. In summary, a variety of antidepressant therapies have been shown to be potentially efficacious in the treatment of poststroke depression, including TCAs, SSRIs, stimulants, and ECT. Further research is needed to distinguish the relative advantages of each of these treatments and to delineate their role in the poststroke population. At present, except in the case of hemorrhagic strokes, SSRIs appear to be a wise clinical choice for fewer side effects. In hemorrhagic stroke, SSRIs have been associated with bleeding and could exacerbate the infarction. The possibility of drug interactions with underlying medical conditions and with other agents taken by stroke patients must also be considered (see Chapter 1).

Treatment of Poststroke Anxiety Disorders There have been no systematic studies of the treatment of anxiety disorders following stroke. Benzodiazepines are the most commonly used medications in generalized anxiety disorders, although, as previously mentioned, controlled trials have been problematic, and

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there are no studies addressing the poststroke population. Shortacting benzodiazepines are a prudent choice, as longer-acting agents may place the patient at a greater risk for adverse effects, such as sedation, ataxia, disinhibition, and confusion. As with TCAs, very conservative dosages and careful monitoring must be employed. In light of the comorbidity of anxiety and depression, antidepressants (TCAs or SSRIs) may also be of benefit for the poststroke GAD patient. It has been demonstrated that TCAs may be efficacious in the treatment of GAD even in the absence of depression (although, again, the specific needs of the poststroke patient have not been investigated). Optimal treatment of poststroke anxiety disorders, however, awaits definition in controlled trials.

Treatment of Sexual Disorders As indicated earlier in this chapter, sexual dysfunction after stroke can be affected by reductions in desire, excitement, and orgasm. Lesion location can affect outcome, as can sensory impairment, fear that engaging in sexual activity will trigger another stroke, and dependence on a spouse for ADL. Optimization of physical status, adequate blood pressure control, discussion of fears, reassurance, and physical and occupational therapy may therefore lead to improvement in sexuality, but outcome data are lacking. It has also been suggested that development of disease-related, interpersonal, and intrapersonal coping skills may be beneficial (Sjogren and FuglMeyer 1982). Adopting new coital positions may compensate for physical deficits. Brief sexual counseling has been recommended for couples as a part of rehabilitation, especially for those who were particularly sexually active before the stroke (Hawton 1984). Other than these possible approaches, treatment would be similar to the treatment for primary sexual disorders.

Summary Numerous emotional and behavioral disorders occur following cerebrovascular lesions. Depression is probably the most common of these, affecting up to 40% of individuals poststroke. The most compelling reason to accurately identify and treat poststroke depression

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is the substantial impact the disorder may have on quality of life, physical and intellectual recovery, and even survival following stroke (Morris et al. 1993a; Parikh et al. 1990). The relative benefits of SSRIs versus TCAs versus benzodiazepines for this patient population have not been clearly elucidated and await further research. Other syndromes, such as poststroke mania, bipolar disorder, psychosis, apathy, and pathological emotions, also pose problems for the clinician, and—with the exception of pathological emotions—all of these disorders await the demonstration of effective treatment regimens using randomized, blinded control methodology.

References Adams HP Jr: Handbook of Cerebrovascular Diseases. New York, Marcel Dekker, 1993 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition. Washington, DC, American Psychiatric Association, 1980 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised. Washington, DC, American Psychiatric Association, 1987 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994 Andersen G, Vestergaard K, Riis JO: Citalopram for post-stroke pathological crying. Lancet 342:837–839, 1993 Andersen G, Vestergaard K, Lauritzen L: Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke 25:1099–1104, 1994 Astrom M: Generalized anxiety disorder in stroke patients: a 3-year longitudinal study. Stroke 27:270–275, 1996 Astrom M, Adolfsson R, Asplund K: Major depression in stroke patients: a 3-year longitudinal study. Stroke 24:976–982, 1993 Barthel D, Mahoney F: Functional evaluation: the Barthel index. Maryland State Medical Journal 2:61–65, 1965 Bogousslavsky J, Caplan L: Stroke Syndromes. New York, Cambridge University Press, 1995 Bolla-Wilson K, Robinson RG, Starkstein SE, et al: Lateralization of dementia of depression in stroke patients. Am J Psychiatry 146:627–634, 1989

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Brott T: Urgent evaluation and management of stroke, in Handbook of Cerebrovascular Diseases. Edited by Adams HP Jr. New York, Marcel Dekker, 1993, pp 385–399 Burvill PW, Johnson GA, Jamrozik KD, et al: Prevalence of depression after stroke: the Perth Community Stroke Study. Br J Psychiatry 166:320– 327, 1995 Candelise L: New treatments in acute ischemic stroke, in Handbook of Cerebrovascular Diseases. Edited by Adams HJ Jr. New York, Marcel Dekker, 1993, pp 415–432 Caplan LR, Stein RW: Stroke: A Clinical Approach. Boston, MA, Butterworths, 1986 Coslett HB, Heilman KM: Male sexual function: impairment after right hemisphere stroke. Arch Neurol 43:1036–1039, 1986 Cummings JL, Mendez MF: Secondary mania with focal cerebrovascular lesions. Am J Psychiatry 141:1084–1087, 1984 Currier MB, Murray GB, Welch CC: Electroconvulsive therapy for poststroke depressed geriatric patients. J Neuropsychiatry Clin Neurosci 4:140–144, 1992 Dam H, Pedersen HE, Ahlgren P: Depression among patients with stroke. Acta Psychiatr Scand 80:118–124, 1989 Eastwood MR, Rifat SL, Nobbs H, et al: Mood disorder following cerebrovascular accident. Br J Psychiatry 154:195–200, 1989 Evans DL, Byerly MJ, Greer RA: Secondary mania: diagnosis and treatment. J Clin Psychiatry 56 (suppl 3):31–37, 1995 Fedoroff JP, Starkstein SE, Parikh RM, et al: Are depressive symptoms nonspecific in patients with acute stroke? Am J Psychiatry 148:1172–1176, 1991 Folstein MF, Folstein SE, McHugh PR: “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198, 1975 Garraway WM, Whisnant JP, Furlan AJ, et al: The declining incidence of stroke. N Engl J Med 300:449–452, 1979 Gonzalez-Torrecillas JL, Mendlewicz J, Lobo A: Repercussion of early treatment of post-stroke depression on neuropsychological rehabilitation. Int Psychogeriatr 7:547–560, 1995 Hacke W, Kaste M, Fieschi C, et al: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 274:1017– 1025, 1995

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Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62, 1960 Hawton K: Sexual adjustment of men who have had strokes. J Psychosom Res 28:243–249, 1984 Herrmann M, Bartles C, Wallesch C-W: Depression in acute and chronic aphasia: symptoms, pathoanatomical-clinical correlations and functional implications. J Neurol Neurosurg Psychiatry 56:672–678, 1993 Herskovits E, Figueroa E: Planning Clinical Trials of Treatment for Vascular and Multi-Infarct Dementia. Mount Kisco, NY, Futura, 1988 House A, Dennis M, Warlow C, et al: The relationship between intellectual impairment and mood disorder in the first year after stroke. Psychol Med 20:805–814, 1990a House A, Dennis M, Warlow C, et al: Mood disorders after stroke and their relation to lesion location: a CT scan study. Brain 113:1113–1129, 1990b House A, Dennis M, Mogridge L, et al: Mood disorders in the year after first stroke. Br J Psychiatry 158:83–92, 1991 Johnson ML, Roberts MD, Ross AR, et al: Methylphenidate in stroke patients with depression. Am J Phys Med Rehabil 71:239–241, 1992 Lauterbach EC: Bipolar disorders, dystonia, and compulsion after dysfunction of the cerebellum, dentatorubrothalamic tract, and substantia nigra. Biol Psychiatry 40:726–730, 1996 Lauterbach EC, Jackson JG, Price ST, et al: Clinical, motor, and biological correlates of depressive disorders after focal subcortical lesions. J Neuropsychiatry Clin Neurosci 9:259–266, 1997a Lauterbach EC, Jackson JG, Wilson AN, et al: Major depression after left posterior globus pallidus lesions. Neuropsychiatry Neuropsychol Behav Neurol 10:9–16, 1997b Levine DN, Finklestein S: Delayed psychosis after right temporoparietal stroke or trauma: relation to epilepsy. Neurology 32:267–273, 1982 Lingam VR, Lazarus LW, Groves L, et al: Methylphenidate in treating post-stroke depression. J Clin Psychiatry 49:151–153, 1988 Lipsey JR, Robinson RG, Pearlson GD, et al: Nortriptyline treatment of post-stroke depression: a double-blind study. Lancet 1(8372):297–300, 1984 Marler JR: Antithrombotic and thrombolytic therapy for acute ischemic stroke, in Handbook of Cerebrovascular Diseases. Edited by Adams HP Jr. New York, Marcel Dekker, 1993, pp 401–414 Mayberg HS, Robinson RG, Wong DF, et al: PET imaging of cortical S2-serotonin receptors after stroke: lateralized changes and relationship to depression. Am J Psychiatry 145:937–943, 1988

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Monga TN, Lawson JS, Inglis J: Sexual dysfunction in stroke patients. Arch Phys Med Rehabil 67:19–22, 1986 Morris PL, Robinson RG, Raphael B: Prevalence and course of depressive disorders in hospitalized stroke patients. Int J Psychiatry Med 20:349– 364, 1990 Morris PL, Robinson RG, Raphael B, et al: The relationship between the perception of social support and post-stroke depression in hospitalized patients. Psychiatry 54:306–316, 1991 Morris PL, Robinson RG, Andrzejewski P, et al: Association of depression with 10-year post-stroke mortality. Am J Psychiatry 150:124–129, 1993a Morris PL, Robinson RG, Raphael B: Emotional lability after stroke. Aust N Z J Psychiatry 27:601–605, 1993b Morris PL, Robinson RG, Raphael B, et al: Lesion and location and poststroke depression. J Neuropsychiatry Clin Neurosci 8:399–403, 1996 Morrison JH, Molliver ME, Grzanna R: Noradrenergic innervation of cerebral cortex: widespread effects of local cortical lesions. Science 205:313– 316, 1979 Paradiso S, Robinson RG: Gender differences in poststroke depression. J Neuropsychiatry Clin Neurosci 10:41–47, 1998 Parikh RM, Robinson RG, Lipsey JR, et al: The impact of poststroke depression on recovery in activities of daily living over a 2-year follow-up. Arch Neurol 47:785–789, 1990 Poeck K: Pathophysiology of emotional disorders associated with brain damage, in Handbook of Clinical Neurology. Edited by Vinken PJ, Bruyn GW. Amsterdam, North Holland, 1969, pp 219–225 Price BH, Mesulam M: Psychiatric manifestations of right hemisphere infarctions. J Nerv Ment Dis 173:610–614, 1985 Rabins PV, Starkstein SE, Robinson RG: Risk factors for developing atypical (schizophreniform) psychosis following stroke. J Neuropsychiatry Clin Neurosci 3:6–9, 1991 Reding MJ, Orto LA, Winter SW, et al: Antidepressant therapy after stroke: a double-blind trial. Arch Neurol 43:763–765, 1986 Robinson RG: The Neuropsychiatry of Stroke. Cambridge, UK, Cambridge University Press, 1998 Robinson RG, Szetela B: Mood change following left hemispheric brain injury. Ann Neurol 9:447–453, 1981 Robinson RG, Starr LB, Kubos KL, et al: A two-year longitudinal study of post-stroke mood disorders: findings during the initial evaluation. Stroke 14:736–741, 1983

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Robinson RG, Kubos KL, Starr LB, et al: Mood disorders in stroke patients: importance of location of lesion. Brain 107:81–93, 1984 Robinson RG, Bolduc PL, Price TR: Two-year longitudinal study of poststroke mood disorders: diagnosis and outcome at one and two years. Stroke 18:837–843, 1987 Robinson RG, Boston JD, Starkstein SE, et al: Comparison of mania and depression after brain injury: causal factors. Am J Psychiatry 145:172–178, 1988 Robinson RG, Parikh RM, Lipsey JR, et al: Pathological laughing and crying following stroke: validation of a measurement scale and a double-blind treatment study. Am J Psychiatry 150:286–293, 1993 Shimoda K, Robinson RG: The relationship between poststroke depression and lesion location in long-term follow-up. Biol Psychiatry 45:187–192, 1999 Shukla S, Cook BL, Mukherjee S, et al: Mania following head trauma. Am J Psychiatry 144:93–96, 1987 Sinyor D, Jacques P, Kaloupek DG, et al: Poststroke depression and lesion location. An attempted replication. Brain 109:537–546, 1986 Sjogren K, Fugl-Meyer AR: Adjustment to life after stroke with special reference to sexual intercourse and leisure. J Psychos Res 26:409–417, 1982 Starkstein SE, Robinson RG: Aphasia and depression. Aphasiology 2:1–20, 1988 Starkstein SE, Pearlson GD, Boston J, et al: Mania after brain injury: a controlled study of causative factors. Arch Neurol 44:1069–1073, 1987a Starkstein SE, Robinson RG, Price TR: Comparison of cortical and subcortical lesions in the production of poststroke mood disorders. Brain 110:1045–1059, 1987b Starkstein SE, Robinson RG, Berthier ML, et al: Differential mood changes following basal ganglia versus thalamic lesions. Arch Neurol 45:725– 730, 1988a Starkstein SE, Robinson RG, Berthier ML, et al: Depressive disorder following posterior circulation as compared with middle cerebral artery infarcts. Brain 111:375–387, 1988b Starkstein SE, Robinson RG, Price TR: Comparison of patients with and without post-stroke major depression matched for size and location of lesion. Arch Gen Psychiatry 45:247–252, 1988c Starkstein SE, Cohen BS, Fedoroff P, et al: Relationship between anxiety disorders and depressive disorders in patients with cerebrovascular injury. Arch Gen Psychiatry 47:785–789, 1990

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Starkstein SE, Fedoroff JP, Berthier MD, et al: Manic depressive and pure manic states after brain lesions. Biol Psychiatry 29:149–158, 1991 Starkstein SE, Robinson RG, Berthier ML: Post-stroke hallucinatory delusional syndromes. Neuropsychiatry Neuropsychol Behav Neurol 5: 114–118, 1992 Starkstein SE, Fedoroff JP, Price TR, et al: Apathy following cerebrovascular lesions. Stroke 24:1625–1630, 1993 Wolf PA, Kannel WB, Verter J: Cerebrovascular disease in the elderly: epidemiology, in Clinical Neurology of Aging. Edited by Albert ML. New York, Oxford University Press, 1984, pp 458–477 Zung WWK: A self-rating depression scale. Arch Gen Psychiatry 12:371– 379, 1965

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C H A P T E R

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Multiple Sclerosis Steven R. Schwid, M.D. Amy Weinstein, Ph.D. Heather A. Wishart, Ph.D. Randolph B. Schiffer, M.D.

M

ultiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease affecting the central nervous system (CNS). It is characterized pathologically by plaques of inflammation, demyelination, and gliosis that are disseminated in space (location within the CNS) and time (separate symptomatic attacks).

Prevalence The prevalence of MS in the United States is approximately 80–100 per 100,000 population, making it the most frequent cause of disability in early to middle adulthood other than trauma. Disease onset occurs during young adulthood, with symptoms rarely starting before age 15 or after age 50 years. Whites have a much higher incidence than blacks or Asians, and females are affected twice as often as males. Prevalence is somewhat higher in temperate climates; migration studies suggest that a critical environmental exposure occurs before age 15 years. The nature of this environmental exposure has yet to be defined. 249

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Clinical Recognition and Neurological Presentation Symptoms and signs in MS depend on the location of the demyelinating lesions within the CNS, which may occur almost anywhere. Common features include optic neuritis from optic nerve lesions; diplopia, internuclear ophthalmoplegia, facial weakness and numbness, and vertigo from brain-stem lesions; ataxia from cerebellar lesions; spasticity and weakness from upper motor neuron lesions; bowel and bladder urgency and retention from autonomic lesions; and paresthesias and hypesthesia from sensory tract lesions. Later in the course of MS, paraparesis is common, resulting from the accumulation of white matter damage in the spinal cord and cerebral hemispheres. Seizures may occur in up to 5% of MS patients, usually coinciding with an active lesion near the cerebral cortex. Fatigue is common throughout the disease course but is not clearly related to nervous system lesions. The course of the disease is quite variable but can be conceptually divided into two patterns: a relapsing–remitting pattern of distinct attacks and relatively symptom-free or stable periods, and a chronic, progressive pattern of steadily worsening symptoms without clear attacks. Approximately half of patients that start with a relapsing–remitting pattern will subsequently develop a progressive course. This pattern is termed secondary progressive MS to distinguish it from a course that is progressive from the onset (primary progressive MS). Primary progressive MS occurs more commonly in older males, with predominantly spinal cord lesions leading to paraparesis. Regardless of the clinical disease course, serial magnetic resonance imaging (MRI) scanning indicates that the disease process is dynamic, with new lesions occurring and old lesions enlarging in relapsing, progressing, and even stable patients. For reasons that remain unknown, exacerbations are relatively uncommon during pregnancy and are more common during the postpartum period. Pregnancy does not appear to have an overall effect on the development of sustained disability. By 15 years after diagnosis, approximately half of patients require an assistive device for ambulation and only 20% of patients remain employed. Favorable prognostic signs for ambulatory status

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include earlier onset (after childhood), a relapsing course, and minimal or mild disability 5 years after the onset of symptoms. Employment depends on these factors as well as on physical status (visual and cognitive impairment, incontinence, fatigue), education level, and available social supports (Rao et al. 1991b). Life expectancy is not significantly affected except in the severely debilitated, who are more susceptible to overwhelming infections.

Pathological Features Pathophysiology Although the ultimate etiology of MS remains poorly understood, pathological and experimental evidence suggests that damage is mediated by the immune system. Current theories suggest that an undefined activating process triggers the immune response against one or more myelin antigens. A variety of inflammatory mediators, including tumor necrosis factor and other cytokines, oxygen radicals, and nitric oxide, are likely the proximate causes of the demyelination and blood–brain barrier disruption that ensue. Systemic immune dysregulation has also been demonstrated on several in vitro and in vivo tests, but the significance of these findings is unclear. Demyelination causes symptoms through slowed axonal conduction, variable conduction block, and ectopic signal transmission.

Genetics Although the prevalence of MS is roughly 1 per 1,000 in the general population, siblings of MS patients have a 2%–5% lifetime risk, and parents and children of MS patients have a 1% risk. Linkage studies implicate the major histocompatibility complex and other genes involved in the immune system as some of the determinants of this hereditary risk (Hillert 1994).

Neuroimaging and Laboratory Investigation The diagnosis of MS depends on the identification by neurological examination of signs disseminated in space and time. MRI and

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evoked potential testing may provide evidence for dissemination of lesions in areas of the CNS that were not evident on clinical examination. MRI most often shows ovoid subcortical white matter lesions oriented perpendicular to the lateral ventricles, but other lesions with nonspecific appearances can be seen anywhere within the CNS. Even large hemispheric lesions with mass effect mimicking a tumor can be seen. Cerebrospinal fluid typically has increased immunoglobulins and oligoclonal banding of proteins on electrophoresis. Other tests may be helpful in ruling out vascular and neoplastic disorders, CNS infections, collagen–vascular diseases, sarcoidosis, pernicious anemia, adrenoleukodystrophy, and mitochondrial diseases in specific cases.

Psychiatric Manifestations Cognitive Impairment Impairment of one or more cognitive abilities is present in 54%–65% of patients in clinic-based studies and in 43%–46% in communitybased studies (McIntosh-Michaelis et al. 1991; Rao et al. 1991a). The full spectrum of deficits that can occur includes impairment of attention, information-processing speed, learning, memory, executive ability, visual information processing, and interhemispheric transfer. Basic language skills and verbal intelligence are relatively spared (Rao 1995). Standard cognitive screening tests, such as the Mini-Mental State Exam (Folstein et al. 1975), appear quite insensitive to cognitive deficits in MS, even in patients who show cognitive impairment on formal neuropsychological evaluation and in everyday functioning (Beatty and Goodkin 1990; Rao 1995). Furthermore, accepted measures of overall impairment in MS, such as the Expanded Disability Status Scale (Kurtzke 1983), do not reflect the presence or extent of cognitive impairment. A number of measures have been devised to assist in screening MS patients for cognitive impairment and in deciding whether to refer for comprehensive neuropsychological evaluation. For example, Beatty et al. (1995) devised a screening examination that could be administered in the doctor’s office, requiring 5–10 minutes of profes-

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sional contact and an additional 20 minutes of self-administered testing by the patient. The screening examination showed 86% sensitivity and 90% specificity in determining which patients have significant deficits on complete neuropsychological evaluation testing. Nevertheless, such screening tests are still fairly cumbersome and are not in widespread use. Furthermore, results from screening tests cannot fully describe the extent and pattern of deficits present, making full neuropsychological evaluation testing the established standard for patients with suspected impairment. Cross-sectional studies of MS patients have found little correlation between the severity of cognitive deficits and either disease duration or the degree of physical disability (Rao et al. 1991a). Cognitive impairment may present as an early isolated symptom of MS, or it may be minimal in an otherwise severely affected patient (Fontaine et al. 1994; Klonoff et al. 1991). Furthermore, high relapse rates and worsening physical disability are not strongly associated with cognitive impairment (Filippi et al. 1994). Several studies have found that measures of lesion severity are related to the severity of cognitive dysfunction in MS (e.g., Comi et al. 1995). Various indices of damage, including lesion scores, third-ventricle size, corpus callosum size, and ventricle–brain ratios, are modest predictors of impairment. More complex techniques allow the determination of lesion areas and volumes that show stronger associations with cognitive deficits, but even these measures are limited because they do not account for differences in lesion distribution (Swirsky-Sacchetti et al. 1992). Studies suggest, for example, that temporal lobe lesions near the hippocampi are associated with anterograde memory deficits (Brainin et al. 1988) and that frontal lobe lesions are associated with conceptual reasoning deficits as measured by the Wisconsin Card Sorting Test (Arnett et al. 1994). Similarly, corpus callosum size is a strong predictor of impaired information-processing speed and poor performance on tasks requiring interhemispheric transfer, whereas anterior corpus callosum atrophy is specifically associated with decreased verbal fluency (Damian et al. 1994; Pozzilli et al. 1992). Lesion activity, measured with serial MRI scans to determine ongoing pathological changes, is modestly associated with cognitive deterioration over 6 months (Feinstein et al. 1993). Although this result makes intuitive sense, it

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has not been replicated (Mattioli et al. 1993), so longer prospective studies will be needed to clarify this association. The P300, a long-latency component of cortical event-related potentials, is prolonged in MS, as it is in other neurological disorders that cause cognitive deficits (van Dijk et al. 1992). The latency is related to the degree of cognitive impairment, with longer latencies associated with poorer performance, especially on tests sensitive to impairment of learning and memory retrieval (Giesser et al. 1992).

Attention and Information-Processing Speed Simple attention span, measured by rote repetition of brief randomnumber sequences, is generally intact in MS patients (Beatty 1993a; Rao et al. 1991a). However, on more complex tests of attention, deficits are consistently observed (Grigsby et al. 1994). For example, on the Symbol Digit Modalities Test (Smith 1982), MS patients show deficits in sustained attention and rapid information processing (Litvan et al. 1988). Meta-analysis of neuropsychological test performance in MS patients suggests poorer performance on tasks requiring rapid information processing, regardless of the specific cognitive domain tested (Wishart 1996).

Learning and Memory Immediate memory is generally intact in MS patients, as noted on tests of simple attention span (Beatty 1993a; Rao et al. 1991a). In contrast, patients show consistent deficits in recall of verbal and nonverbal information presented minutes to hours previously (Beatty 1993a, 1993b; Rao 1986, 1995). Although spontaneous recall appears to be impaired, recognition (e.g., on multiple-choice or forced-choice testing) is relatively spared. This discrepancy has been interpreted as evidence of impaired memory retrieval with relative preservation of memory encoding and storage (Rao 1986). On learning tasks in which target information is presented repeatedly over a series of trials, MS patients recall less on the initial presentation and show poorer overall learning than do control subjects. However, their learning curve is similar to that of healthy controls, indicating that they benefit from repeated presentations of new material (Rao 1986).

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Conceptual and Executive Ability Abstract reasoning and mental flexibility are frequently impaired in MS (Beatty 1993a, 1993b; Rao 1995). Rao et al. (1991a) found significant impairment in 8%–19% of patients on tests such as the Wisconsin Card Sorting Test, a measure of conceptual and executive function (Heaton 1981). On this test, MS patients require extra trials to discover the correct sorting principle, and they perseverate, using the same sorting principle when it is no longer effective. Although these behaviors are consistent with dysfunction of the frontal– subcortical axis, conceptual and executive deficits can also result from diffuse brain dysfunction (Beatty 1993a).

Visual Information Processing On standardized measures of visual information processing, MS patients show impairment compared with healthy controls (Caine et al. 1986; Rao et al. 1991a). Some of these tests address more than one cognitive, perceptual, or motor domain, however, so the nature of the deficits reported remains uncertain.

Language Classic aphasias have rarely been reported in MS (Achiron et al. 1992; Olmos-Lau et al. 1977), but deficits have been noted on confrontation-naming tests and word-list-generation tasks (Beatty et al. 1989; Caine et al. 1986; Klonoff et al. 1991). Related abilities, such as reading and writing, have received little empirical attention.

Intrahemispheric and Interhemispheric Transfer Given the white matter lesions characteristic of MS, it is not surprising that disconnection syndromes have been reported. Interhemispheric transfer deficits are seen in auditory, tactile, visual, and motor modalities (Lindeboom and Horst 1988; Rao et al. 1989; Schnider et al. 1993; Wishart et al. 1995). For example, on verbal dichotic listening tests, in which verbal stimuli are presented to each ear simultaneously, left-ear suppression is consistently observed in MS patients, suggesting impaired transfer of information from the right auditory cortex through the corpus callosum to language-

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processing areas in the left hemisphere (Lindeboom and Horst 1988). Pelletier et al. (1993) demonstrated that specific regions of demyelination in the corpus callosum may lead to specific interhemispheric transfer deficits. Intrahemispheric syndromes, such as conduction aphasia and alexia without agraphia, have not yet been thoroughly studied (Rao 1995).

Dementia The pattern of cognitive deficits seen in MS patients appears similar to that described in other neurological disorders that cause predominantly subcortical lesions, such as Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, and acquired immunodeficiency syndrome (AIDS) (Mahler and Benson 1990; Rao 1986). As noted above, however, recent research casts some doubt on the efficiency of memory encoding in MS (Rao 1986), and certain cortical functions thought to be spared in subcortical dementia (e.g., language and praxis) have yet to be fully examined in MS. Based on differences in the pattern of deficits observed, Filley et al. (1989) proposed a more detailed classification of subcortical dementias, with MS described as a white matter dementia to distinguish it from the pattern of deficits seen in gray matter disorders, such as Parkinson’s disease. The usefulness of these classification schemes remains controversial (Filley et al. 1989; Rao 1993).

Cognitive Emotional Processing Disorders Recent studies of the interpretation and analysis of emotional behavior have shown that MS patients have difficulty with facial and prosodic emotional identification but not with emotional discrimination. These results may signify disruption of callosal pathways that connect facial and prosodic emotional perception from semantic networks that serve to verbally identify emotions (Weinstein et al. 1996). Because the development of an appropriate mood state depends in part on comprehending others’ emotional facial expressions, prosody, and gestures and expressing propositional and prosodic emotional communication, disturbed cognitive emotional processing in MS can have an impact on both the internal affective state and its external expression.

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Euphoria Euphoria in MS is a persistent frame of mind, not a fluctuating affective state. This apparently permanent change in personality is considered pathological because it is incongruous with the patient’s medical condition. Although Cottrell and Wilson (1926) reported that euphoria was common in MS, its true prevalence remains uncertain (Minden and Schiffer 1990). Although euphoria may have a neurological basis, related to lesions in the frontal lobes, basal ganglia, and limbic system, resulting in diminished modulation of limbic/ diencephalic centers by the frontal lobes (Minden and Schiffer 1990), some investigators have suggested that the state may instead be an indirect consequence of dementia (Surridge 1969).

Pathological Laughing and Crying Affective expressions are termed pathological when they are exaggerated relative to or completely discordant with the patient’s emotional state. The prevalence of these symptoms in MS may be as high as 22% for pathological laughing and 29% for pathological crying (Pratt 1951). When the type and intensity of facial expression in response to an emotional stimulus were formally rated in MS patients, outward expressions were inconsistent with the patients’ reports of their internal emotional state (Patterson et al. 1996), suggesting a discrepancy between subjective mood state and overt affective expression. These symptoms appear to be related to lesions that interrupt the corticobulbar motor pathways bilaterally, releasing reflex mechanisms for facial expression from cortical control. To avoid inappropriate diagnoses and treatment, it is important to recognize that patients with these symptoms may have affective expressions that do not accurately reflect their emotional state.

Psychosis The prevalence of psychosis in MS patients is not known, although it occurs much less frequently than do affective disorders. A temporal link, with neurological symptoms of MS either preceding or occurring around the time of psychotic manifestation, suggests an etiolog-

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ical association (Ron and Logsdail 1989). Psychosis also occurs at a later age in MS patients (mean age of 36 years compared with 28 years in patients without MS), a finding that further supports the possibility of a causal relationship between MS and psychotic symptoms. MRI studies show that psychotic MS patients tend to have more lesions around the temporal horns of the lateral ventricles compared with other MS patients (Feinstein et al. 1992).

Mood Disorders Bipolar disorder. As many as 10% of MS patients may fulfill criteria for bipolar disorder, compared with fewer than 1% of the general population (Joffe et al. 1987; Schiffer et al. 1986). Hypomania is also more common in MS. The reason for this excess incidence has not been thoroughly explored but may relate to demyelination in critical pathways. Depression. The lifetime incidence of major depression in MS patients is as high as 60% (Minden et al. 1987). Cross-sectional prevalence rates for depression in MS range from 14% to 57%, depending on the diagnostic criteria and selection process used (Joffe et al. 1987; Minden et al. 1987). MS patients have a greater prevalence of depression than do patients with comparable disability from other neurological conditions (Dalos et al. 1983; Minden et al. 1987; Schiffer and Babigian 1984; Schubert and Foliart 1993). The suicide rate among MS patients is 7.5 times the rate among the age-matched general population (Sadovnick et al. 1991). Affective symptoms do not correlate well with physical disability (Joffe et al. 1987; Moller et al. 1994) or with cognitive deficits (Moller et al. 1994; Schiffer and Caine 1991). This lack of association suggests that affective symptoms are not simply responses to physical and cognitive deficits but rather may be relatively independent expressions of neurological damage. Depressive symptoms occur more commonly in patients with extensive cerebral lesions than in those with similar physical disability from predominantly spinal cord involvement (Rabins et al. 1986; Schiffer et al. 1983). Honer et al. (1987) found that patients with temporal lobe lesions were more likely to have depressive symptoms than patients with similar lesion

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burdens that spared the temporal lobes. On the basis of these observations, depression may be caused directly by cerebral lesions, particularly in the temporal lobes, but a contribution from other indirect “reactive” causes cannot be ruled out. The relationship between affective state and lesion activity, burden, and distribution on MRI has not been studied thoroughly. Moller et al. (1994) found that ventricle–brain ratios, corpus callosal area, temporal lobe lesion and total lesion burden, and lesion activity were unrelated to depression. In contrast, Honer et al. (1987) found that temporal lobe lesions, but not overall lesion burden, were associated with both depression and other psychiatric disorders in MS patients. Further studies using MRI have the potential to determine whether lesions in specific areas are responsible for the increased incidence of depression, bipolar disorder, and other affective symptoms in MS, thus providing a better understanding of the neurological substrates for these psychiatric disorders. The growing field of psychoneuroimmunology has begun to show convincing evidence that depression can have a marked effect on immune functioning. Given that MS is an immune-mediated disease, it is possible that affective symptoms could indirectly alter disease activity. For example, Foley et al. (1992) found that lymphocyte subpopulations changed in association with depressive symptoms, leading to higher CD4/CD8 ratios during times of distress. Others have found changes in lymphocyte β-adrenergic receptor expression associated with disease activity in MS patients, providing another possible link between psychological, endocrine, and immune processes in MS (Zoukos et al. 1992). Whether these changes may lead to fluctuations in disease activity remains uncertain. Other types of stressors influence immune function as well, raising questions about the effect of psychological stress on MS in general. Although there is no evidence that stress can actually cause MS, significant stressors are often reported to have occurred before the onset of MS exacerbations in retrospective studies (Grant et al. 1989). Prospective studies have failed to find similar associations, however, casting doubt on this relationship (Nisipeanu and Korczyn 1993). In fact, stress can actually prevent relapses in animal models of MS (Levine and Saltzman 1987), which suggests that a more complex connection may be present.

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Other Psychiatric Disorders Anxiety and personality disorders occur in MS patients, but it is not clear whether MS somehow causes these disorders. Peyser et al. (1980) described six psychological profiles in MS patients with a range of personality characteristics, but further research is needed to confirm these personality abnormalities and to explore clinicopathological associations.

Sexual Dysfunction Sexual dysfunction occurs in approximately 78% of men and 45% of women with MS. Men most often report erectile dysfunction, and women have decreased vaginal lubrication. Both sexes experience anorgasmia, decreased genital sensation, and reduced libido. These symptoms are more common in patients with bowel and bladder dysfunction. Sexual dysfunction is a common contributor to reduced quality of life and marital problems in patients with MS (Mattson et al. 1995). Very few studies address therapeutic approaches to these problems.

Medication-Induced Psychiatric Symptoms Corticosteroids, which are often used in high doses to treat MS exacerbations, are associated with increased energy, decreased sleep, and variable euphoria (Kershner and Wang-Cheng 1989). Depressive symptoms may also occur with long-term use or on discontinuation, and mania or psychosis is precipitated less commonly. It is not clear whether patients with prior or current affective symptoms are more prone to these symptoms or whether symptoms are likely to recur during future use of corticosteroids in patients who have experienced corticosteroid-induced symptoms previously. Case reports suggest that psychosis may be avoided in patients thought to be prone to corticosteroid effects by administration of antipsychotic agents or lithium concomitantly (Bloch et al. 1994; Falk et al. 1979). Interferon-beta-1b, an immunomodulatory cytokine used to reduce disease activity in patients with relapsing–remitting MS, may cause depression and an increased risk of suicide attempts (IFNB Multiple Sclerosis Study Group 1993). Experts recommend that pa-

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tients who develop severe depression during treatment should discontinue the agent, particularly if antidepressant therapy has been ineffective in managing depressive symptoms (Lublin et al. 1996). Interferon-beta-1a, which is structurally similar to interferon-beta1b, was not associated with depression or suicide attempts in a placebo-controlled study (Jacobs et al. 1996), but caution may still be warranted in clinical situations. The mechanism of the depressive effect of interferon-beta-1b remains uncertain, but it provides further evidence for functional connections between neurological and immunological systems.

Neurological Management Acute attacks of symptoms can be treated with high-dose corticosteroid pulses (e.g., intravenous methylprednisolone 1,000 mg daily for 3 days) to reduce symptoms more rapidly than they would improve spontaneously, but long-term steroid use has no clear benefit and has significant side effects (Troiano et al. 1987). Patients with a regular pattern of attacks may have fewer and milder exacerbations when they undergo long-term treatment with interferon-beta (e.g., interferon-beta-1b 0.25 mg subcutaneously every other day; IFNB Multiple Sclerosis Study Group 1993; Jacobs et al. 1996) or glatiramer acetate (20 mg subcutaneously daily; Johnson et al. 1995), a myelin basic protein analogue. The utility of these medications for milder relapsing disease and progressive disease remains uncertain. Methotrexate (7.5–20 mg weekly), azathioprine (50–200 mg daily), cyclophosphamide, and other immunosuppressants may help slow disease progression, but concerns about long-term side effects limit their use (Carter and Rodriguez 1989). Plasmapheresis, total lymphoid irradiation, and a host of immunomodulating medications are in various phases of study. Symptomatic treatment for spasticity, fatigue, dysesthesias, and urinary and sexual symptoms are also important in maintaining quality of life.

Psychiatric Management The psychiatric approach to MS patients is similar to that in patients with other neuropsychiatric illnesses. Consequently, this discussion

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is limited to psychiatric conditions in which controlled data are available for MS patients.

Treatment of Cognitive Disorders In general, the same neuropsychological rehabilitation principles established in the care of patients with stroke, brain injury, and other neurological insults apply to MS. Following thorough evaluation of the deficits present, an individualized plan for restoration of function, compensation with relatively spared cognitive functions, and adaptation using external aids may significantly improve functional ability (Prosiegel and Michael 1993). Physiatrists or neuropsychologists with experience in cognitive therapy are generally best equipped to develop appropriately comprehensive plans. Although preliminary studies suggest that these strategies may be helpful, their overall success and the relative utility of specific interventions in MS patients have not been thoroughly assessed in controlled studies (Jonsson et al. 1993). The effect of interventions aimed more directly at the underlying disease process was explored with glatiramer acetate in the same study that demonstrated this agent’s positive effect on the frequency of MS relapses (Johnson et al. 1995). However, neither the placebo nor the glatiramer group showed a cognitive decline during the study period, making it difficult to assess whether this disease-modifying treatment had a protective effect for cognition (Weinstein et al. 1999). A more thorough understanding of the natural history of cognitive deficits in MS would be invaluable in designing studies that are better able to assess the effects of diseasemodifying treatments on cognitive function. Agents that improve conduction through demyelinated regions, such as 4-aminopyridine, may have the potential to improve cognitive function. However, Smits et al. (1994) were unable to show an effect of 4-aminopyridine on cognitive function in a brief crossover study of 20 patients. Whether this result related to the design of the study or to the specific tests used deserves further consideration, however, because this is one of the few possible approaches to restoring cognitive function. Although the presence of an acetylcholine deficit has not been established in MS patients, demyelination and disruption of sub-

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cortical pathways that distribute acetylcholine to the cortex are likely in this population. Donepezil, an acetylcholinesterase inhibitor that improves cognition in Alzheimer’s disease, had a dramatic effect on cognitive impairment in a 12-week open-label study of MS patients with relatively severe cognitive impairment (Greene et al., in press). Further studies confirming this effect in a placebo-controlled, blinded setting are planned.

Treatment of Affective Disorders Affective symptoms in MS patients are treated with the same psychotherapeutic methods and medications that would be used in other patients. Cognitive-behavioral, group, and family therapy can be effective in treating depressed MS patients (Crawford and McIvor 1985; Larcombe and Wilson 1984). Support groups for MS patients and their families are available in most areas and can be located by contacting the National Multiple Sclerosis Society (1-800- FIGHTMS). There is little evidence that any specific pharmacological approach to treatment of emotional changes in MS is better than another. Desipramine (25–150 mg qhs) has been shown to be effective in the treatment of depression in MS (Schiffer and Wineman 1990), but other antidepressant medications can also be effective. Pharmacotherapy with low-dose amitriptyline (10–20 mg qhs) can be beneficial in controlling affective dysregulation (Schiffer et al. 1993). Typically, low doses of these medications are well tolerated, but higher doses may precipitate fatigue, dizziness, constipation, bladder dysfunction, and, rarely, confusion. Selective serotonin reuptake inhibitors (SSRIs; e.g., sertraline 50–200 mg daily) may be useful alternatives. The possibility that affective symptoms should be treated as a type of MS exacerbation, using corticosteroids or other immunomodulatory medications, has not been explored, despite evidence that depressive symptoms tend to increase during exacerbation and to abate upon remission (Dalos et al. 1983).

Summary Multiple sclerosis is associated with a variety of cognitive deficits, including impairments in sustained attention, information-processing

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speed, memory retrieval, learning, and executive functions. Depression, bipolar disorder, and other affective disorders are also common. These manifestations appear to be directly related to lesions detectable on MRI, suggesting that MS may serve as a model for understanding brain–behavior relationships. Little attention has been paid to specific strategies for symptom management and rehabilitation in MS patients, but as new treatments for MS emerge, studies aimed at these issues should be forthcoming.

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Grant I, Brown GW, Harris T, et al: Severely threatening events and marked life difficulties preceding onset or exacerbation of multiple sclerosis. J Neurol Neurosurg Psychiatry 52:8–13, 1989 Greene YM, Tariot PN, Wishart H, et al: A 12-week open trial of donepezil hydrochloride in multiple sclerosis patients with associated cognitive impairment. J Clin Psychopharmacol (in press) Grigsby J, Ayarbe SD, Kravcisin N, et al: Working memory impairment among persons with chronic progressive multiple sclerosis. J Neurol 241:125–131, 1994 Heaton RK: Wisconsin Card Sorting Test Manual. Odessa, FL, Psychological Assessment, 1981 Hillert J: Human leukocyte antigen studies in multiple sclerosis. Ann Neurol 36 (suppl):S15–S17, 1994 Honer WG, Hurwitz T, Li DK, et al: Temporal lobe involvement in multiple sclerosis patients with psychiatric disorders. Arch Neurol 44:187–190, 1987 IFNB Multiple Sclerosis Study Group: Interferon beta-1b is effective in relapsing-remitting multiple sclerosis, I: clinical results of a multicenter, randomized, double-blind, placebo controlled trial. Neurology 43:655– 661, 1993 Jacobs LD, Cookfair DL, Rudick RA, et al: Intramuscular interferon beta 1-a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRF). Ann Neurol 39:285– 294, 1996 Joffe RT, Lippert GP, Gray TA, et al: Mood disorder and multiple sclerosis. Arch Neurol 44:376–378, 1987 Johnson KP, Brooks BR, Cohen JA, et al: Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Neurology 45:1268–1276, 1995 Jonsson A, Korfitzen EM, Heltberg A, et al: Effects of neuropsychological treatment in patients with multiple sclerosis. Acta Neurol Scand 88: 394–400, 1993 Kershner P, Wang-Cheng R: Psychiatric side effects of steroid therapy. Psychosomatics 30:135–139, 1989 Klonoff H, Clark C, Oger J, et al: Neuropsychological performance in patients with mild multiple sclerosis. J Nerv Ment Dis 179:127–131, 1991 Kurtzke JF: Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452, 1983

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Larcombe NA, Wilson PH: An evaluation of cognitive-behavior therapy for depression in patients with multiple sclerosis. Br J Psychiatry 145:366– 371, 1984 Levine S, Saltzman A: Nonspecific stress prevents relapses of experimental allergic encephalomyelitis in rats. Brain Behav Immun 1:336–341, 1987 Lindeboom J, Horst R: Interhemispheric disconnection effects in multiple sclerosis. J Neurol Neurosurg Psychiatry 51:1445–1447, 1988 Litvan I, Grafman J, Vendrell P, et al: Slowed information processing in multiple sclerosis. Arch Neurol 45:281–285, 1988 Lublin FD, Whitaker JN, Eidelman BH, et al: Management of patients receiving interferon-beta-1b for multiple sclerosis. Neurology 46:12–18, 1996 Mahler ME, Benson DF: Cognitive dysfunction in multiple sclerosis: a subcortical dementia? in Neurobehavioral Aspects of Multiple Sclerosis. Edited by Rao SM. New York, Oxford University Press, 1990, pp 88–101 Mattioli F, Cappa SF, Cominelli C, et al: Serial study of neuropsychological performance and gadolinium-enhanced MRI in MS. Acta Neurol Scand 87:465–468, 1993 Mattson D, Petrie M, Srivastava DK, et al: Multiple sclerosis: sexual dysfunction and its response to medications. Arch Neurol 52:862–868, 1995 McIntosh-Michaelis SA, Roberts MH, Wilkinson SM, et al: The prevalence of cognitive impairment in a community survey of multiple sclerosis. Br J Clin Psychol 30:333–348, 1991 Minden SL, Schiffer RB: Affective disorders in multiple sclerosis: review and recommendations for clinical research. Arch Neurol 47:98–104, 1990 Minden SL, Orav J, Reich P: Depression in multiple sclerosis. Gen Hosp Psychiatry 9:426–434, 1987 Moller A, Wiedemann G, Rohde U, et al: Correlates of cognitive impairment and depressive mood disorder in multiple sclerosis. Acta Psychiatr Scand 89:117–121, 1994 Nisipeanu P, Korczyn AD: Psychological stress as risk factor for exacerbations in multiple sclerosis. Neurology 43:1311–1312, 1993 Olmos-Lau N, Ginsberg MD, Geller JB: Aphasia in multiple sclerosis. Neurology 27:623–626, 1977 Patterson KM, Weinstein A, Rao SM: Spontaneous emotional expression and subjective emotional experience in MS. Arch Clin Neuropsychol 11:434, 1996

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Pelletier J, Habib M, Lyon-Caen O, et al: Functional and magnetic resonance imaging correlates of callosal involvement in multiple sclerosis. Arch Neurol 50:1077–1082, 1993 Peyser JM, Edwards KR, Poser CM: Psychological profiles in patients with multiple sclerosis: a preliminary investigation. Arch Neurol 37:437– 440, 1980 Pozzilli C, Fieschi C, Perani D, et al: Relationship between corpus callosum atrophy and cerebral metabolic asymmetries in multiple sclerosis. J Neurol Sci 112:51–57, 1992 Pratt RTC: An investigation of psychiatric aspects of disseminated sclerosis. J Neurol Neurosurg Psychiatry 14:326–336, 1951 Prosiegel M, Michael C: Neuropsychology and multiple sclerosis: diagnostic and rehabilitative approaches. J Neurol Sci 115 (suppl):S51–S54, 1993 Rabins PV, Brooks BR, O’Donnell P, et al: Structural brain correlates of emotional disorder in multiple sclerosis. Brain 109:585–597, 1986 Rao SM: Neuropsychology of multiple sclerosis: a critical review. J Clin Exp Neuropsychol 8:503–542, 1986 Rao SM: White matter dementias, in Neuropsychology of Alzheimer’s Disease and Other Dementias. Edited by Parks RW, Zec RF, Wilson RS. New York, Oxford University Press, 1993, pp 438–456 Rao SM: Neuropsychology of multiple sclerosis. Curr Opin Neurol 8:216– 220, 1995 Rao SM, Bernardin L, Leo GJ, et al: Cerebral disconnection in multiple sclerosis: relationship to atrophy of the corpus callosum. Arch Neurol 46: 918–920, 1989 Rao SM, Leo GJ, Bernardin L, et al: Cognitive dysfunction in multiple sclerosis, I: frequency, patterns, and prediction. Neurology 41:685–691, 1991a Rao SM, Leo GJ, Ellington L, et al: Cognitive dysfunction in multiple sclerosis, II: impact on employment and social functioning. Neurology 41:692–696, 1991b Ron MA, Logsdail SJ: Psychiatric morbidity in multiple sclerosis: a clinical and MRI study. Psychol Med 19:887–895, 1989 Sadovnick AD, Eisen K, Ebers GC, et al: Cause of death in patients attending multiple sclerosis clinics. Neurology 41:1193–1196, 1991 Schiffer RB, Babigian HM: Behavioral disorders in multiple sclerosis, temporal lobe epilepsy, and amyotrophic lateral sclerosis: an epidemiologic study. Arch Neurol 41:1067–1069, 1984

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Schiffer RB, Caine ED: The interaction between depressive affective disorder and neuropsychological test performance in multiple sclerosis patients. J Neuropsychiatry Clin Neurosci 3:28–32, 1991 Schiffer RB, Wineman NM: Antidepressant pharmacotherapy of depression associated with multiple sclerosis. Am J Psychiatry 147:1493–1497, 1990 Schiffer RB, Caine ED, Bamford KA, et al: Depressive episodes in patients with multiple sclerosis. Am J Psychiatry 140:1498–1500, 1983 Schiffer RB, Wineman NM, Weitkamp LR, et al: Association between bipolar affective disorder and multiple sclerosis. Am J Psychiatry 143:94–95, 1986 Schiffer RB, Cash J, Herndon RM: Treatment of emotional lability with low-dosage tricyclic antidepressants. Psychosomatics 24:1094–1096, 1993 Schnider A, Benson F, Rosner LJ: Callosal disconnection in multiple sclerosis. Neurology 43:1243–1245, 1993 Schubert DS, Foliart RH: Increased depression in multiple sclerosis patients: a meta-analysis. Psychosomatics 34:124–130, 1993 Smith A: Symbol Digit Modalities Test. Los Angeles, CA, Western Psychological Services, 1982 Smits RC, Emmen HH, Bertelsmann FW, et al: The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study. Neurology 44:1701–1705, 1994 Surridge D: An investigation into some psychiatric aspects of multiple sclerosis. Br J Psychiatry 115:749–764, 1969 Swirsky-Sacchetti T, Mitchell DR, Seward J, et al: Neuropsychological and structural brain lesions in multiple sclerosis: a regional analysis. Neurology 42:1291–1295, 1992 Troiano R, Cook SD, Dowling PC: Steroid therapy in multiple sclerosis: point of view. Arch Neurol 44:803–807, 1987 van Dijk JG, Jennekens-Schinkel A, Caekebeke JF, et al: Are event-related potentials in multiple sclerosis indicative of cognitive impairment? Evoked and event-related potentials, psychometric testing and response speed: a controlled study. J Neurol Sci 109:18–24, 1992 Weinstein A, Patterson KM, Rao SM: Hemispheric asymmetries and processing of affective stimuli: contribution of callosal communication. Brain Cogn 36:223–225, 1996 Weinstein A, Schwid SI, Schiffer RB, et al: Neuropsychologic status in multiple sclerosis after treatment with glatiramer. Arch Neurol 56:319–324, 1999

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Wishart HA: Neuropsychological aspects of multiple sclerosis: a metaanalysis. Paper presented at the International Neuropsychology Society Annual Meeting, Chicago, IL, February 1996 Wishart HA, Strauss E, Hunter M, et al: Interhemispheric transfer in multiple sclerosis. J Clin Exp Neuropsychol 17:937–940, 1995 Zoukos Y, Leonard JP, Thomaides T, et al: β-adrenergic receptor density and function of peripheral blood mononuclear cells are increased in multiple sclerosis: a regulatory role for cortisol and interleukin-1. Ann Neurol 31:657–662, 1992

C H A P T E R

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Acquired Immunodeficiency Syndrome Jorge Luis Maldonado, M.D. Francisco Fernandez, M.D. Joel K. Levy, Ph.D.

T

he human immunodeficiency virus (HIV) epidemic has affected an increasing number of persons over the last two decades and has become a major health and social issue of this era. In 1995, HIV infection was the leading cause of death among adults ages 25–44 years, surpassing homicide, suicide, and other medical diseases such as cancer and cardiovascular illness. Recently, new and more effective antiretroviral medications have emerged that allow for more effective patient management, and patients are living longer, even when severely immunosuppressed. Over time, HIV infection results in a wide spectrum of central nervous system (CNS) pathological abnormalities in a substantial proportion of individuals. It is anticipated that the CNS dysfunction secondary to HIV infection may increase as the new anti-HIV systemic therapies reduce mortality and overall physical disability. To assist clinicians in the recognition and treatment of HIV–CNS involvement, we review in this chapter the neuropathology of HIV infection, clinical neuropsychiatric presentations, and multimodal therapies for the neuropsychiatric disorders associated with HIV infection.

Prevalence Reported cases of HIV infection and acquired immunodeficiency syndrome (AIDS) have risen in number since first described in the lit271

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erature in 1981 (Masur et al. 1981). A cumulative total of 688,200 adult and pediatric cases of AIDS and 106,575 cases of HIV (not AIDS) have been reported to the Centers for Disease Control and Prevention (CDC 1998) through December of 1998. Worldwide, the World Health Organization (WHO) estimates 33.4 million persons living with the HIV infection and AIDS (UNAIDS/WHO 1998). Although in 1995 HIV infection and related complications were the leading cause of death in U.S. adults 25–44 years of age, by 1997 they had dropped to the fifth leading cause of death (Hoyert et al. 1998). As of December 1998, according to the semiannual CDC surveillance report, 270,839 persons were living with AIDS and 97,962 were living with HIV (not AIDS).

Clinical Recognition and Neurological Features CNS involvement in HIV infection can result either from the direct effect of the virus on the nervous system or from secondary opportunistic infections and malignancies, as shown in Table 9–1 (Bredesen et al. 1988; American Academy of Neurology AIDS Task Force 1991). The clinical neurological findings will vary, depending on the underlying CNS pathology, from minor cognitive changes identifiable only by neuropsychological testing to acute neurological events Table 9–1.

Central nervous system (CNS) involvement in human immunodeficiency virus (HIV) infection

Primary HIV–CNS infection Secondary opportunistic infections • Aspergillus • Candida albicans • Coccidioides immitis • Cryptococcus neoformans • Cytomegalovirus • Herpes simplex virus • Mycobacterium (atypical) • Mycobacterium tuberculosis

• Papovavirus • Toxoplasma gondii • Treponema pallidum • Varicella zoster virus Malignancies • Kaposi’s sarcoma • Primary or secondary CNS lymphoma Cerebrovascular accidents

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such as stroke (Becker et al. 1995). Patients may initially present with complaints of minor changes in their cognition or with signs and symptoms of advanced neurological disease. This population of patients has a higher prevalence of substance abuse and related disorders. A careful assessment is always required, as these disorders could affect the course of the primary illness, interfere with the patient’s compliance with the medical treatment, and even be responsible for the initial presentation or exacerbation of the neuropsychiatric symptoms. No information is available on gender and neuropsychiatric disorders in the HIV/AIDS population. Whether (and how) pregnancy affects the course of HIV disease is still controversial, and conflicting findings are reported in the literature. There is no information on the effect of pregnancy on the course of the neuropsychiatric disorders in HIV-infected women.

Laboratory Investigation Among the laboratory assays used to test for the presence of HIV, antibody detection tests are the ones most commonly used. Of these, the enzyme-linked immunosorbent assay (ELISA) and the Western blot are the two most preferred (Saag 1995). These tests are relatively inexpensive, can provide results more quickly, and are easier to perform than other tests (e.g., viral culture, antigen detection tests, or viral genome amplification tests). However, the test results become positive only after the production of a detectable amount of antibodies has taken place in the body, which usually requires 6–8 weeks but can take as long as 3 months (and infrequently up to 18 months). Viral culture, antigen detection, and viral genome amplification are useful in cases in which antibody detection methods are inconclusive. Assessment of immunological status is also a key factor in the management of patients with HIV infection because of HIV’s devastating effects on T-cell lymphocytes. Cell markers help to differentiate the subsets of lymphocytes based on their primary functions. The lymphocytes with the CD4 (T4) surface marker are responsible for activating and augmenting the immunological response to antigens (and hence are called “helper/inducer” cells), and their receptor is a primary binding site for HIV. Because the number of CD4 cells

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becomes depleted as the HIV infection progresses, CD4 cell numbers have been used as one of the most important indicators in the clinical staging of disease status of the HIV-infected patient. The CD8 (T8) surface marker is present in the subset of lymphocytes responsible for controlling or suppressing the ongoing immunological response (and hence are known as “suppressor/cytotoxic” cells). The total number of CD4 cells (normal = 500–1,600 per cubic millimeter [mm3]), their percentage in relation to the total lymphocyte count (normal = 40%–70%), and the CD4/CD8 ratio (normal = 0.5–2.0) are useful in the assessment and follow-up of immunological status in HIV-infected individuals. More recently, the methodology to determine “viral load” (copies of HIV mRNA per mm3 of blood) has added a new dimension to the medical workup of patients with HIV infection, predicting disease progression and risk of death (Volberding 1996). Greater than 100,000 copies per mm3 is associated with a poorer prognosis, whereas fewer than 10,000 is associated with a more favorable prognosis. It is clear that viral load is surpassing CD4 count as the preferred indicator for monitoring treatment responsiveness and treatment resistance. The relationship of peripheral viral load to the development of HIV-related neurological disease is not yet known. Likewise, it is not known whether cerebrospinal fluid (CSF) viral load will be an important predictor of CNS involvement or progression of neurological disease.

Pathological Features and Neuroimaging HIV has affinity both for the CD4 receptor on lymphocytes and for a similar receptor found in some CNS cells (Hill et al. 1987). However, HIV is unable to cross the blood–brain barrier by itself; in order to do so, it must first infect monocytes that can enter the CNS and convert to multinucleated macrophages. CNS penetrance by HIV may occur early in the course of the infection (Koenig et al. 1986). When the infected monocytes transform into macrophages, HIV can actively replicate (Wiley 1994). The virus invades and destroys subcortical areas, especially basal ganglia and temporolimbic structures, but also sup-

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port cells such as astrocytes. HIV can also affect cortical regions, as demonstrated by the clinically observed decline of the cortical cognitive functions, by quantitative measurements of neuronal populations (Wiley et al. 1991), and by magnetic resonance imaging (MRI) measurements in patients with HIV dementia (Aylward et al. 1995). HIV infects the macrophages/microglia in the CNS. Studies using immunohistochemical and in situ hybridization studies have not found other cells to be significantly infected (Tyor et al. 1995). Cellular damage may take place through a sequence of chemical reactions that result in neurotoxicity from the endogenous excitatory amino acid neurotransmitters glutamate and aspartate and from the viral surface glycoprotein gp120 (Ushijima et al. 1995). The N-methyl-D-aspartate (NMDA) receptor is sensitized by various mechanisms, including direct effects of gp120, release of arachidonic acid via activation of phospholipase A2, and secretion of neurotoxins—such as quinolinic acid, tumor necrosis factor-receptor (TNF-R), tumor necrosis factor α (TNF-α), platelet-activating factor, cysteine, interleukin-1B (IL-1B), nitric oxide, superoxide anion—by the infected macrophages (Heyes et al. 1989; Nakamura et al. 1993; Puccioni-Sohler et al. 1995). Through the activation of the NMDA receptor, an influx of calcium into the cell triggers a series of events that lead to cellular necrosis or apoptosis (Adle-Biassette et al. 1995; Codazzi et al. 1995; Lipton 1994), a mechanism known to be active in other neurological diseases (Cohen 1993). Multinucleated giant cells in the brain are found in 25%–50% of patients with HIV-associated dementia, and the presence of these cells is the pathognomonic histopathological finding for that diagnosis (Sharer 1992). Measurements of the viral load in the CNS via in situ hybridization or polymerase chain reaction (PCR) for viral nucleic acids have shown a higher amount of HIV in demented patients compared with nondemented HIV-positive patients (Wiley and Achim 1994). Microglial and glial changes, as well as the multinucleated giant cells, can be found anywhere in the CNS but are more commonly found in the deep white matter of the cerebral hemispheres, basal ganglia, and brain stem (Sharer 1992). Less frequently, white matter pallor with astrogliosis, diffuse or focal vacuolation associated with axonal or myelin loss, and cortical atrophy are found (Wiley et al. 1991).

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Psychiatric Manifestations Delirium Delirium is very common in HIV-infected patients (Lipowski 1987). It is estimated that nearly 30% of hospitalized medical and surgical patients may have an undetected delirious process, and delirium has been found to be the most frequent neuropsychiatric disorder in patients with AIDS. Prevalences of delirium in medically ill AIDS inpatients have been reported to be as high as 30%–40% (Breitbart et al. 1996). As more aggressive outpatient treatments become available, patients with delirium may also go undiagnosed in ambulatory settings (Fernandez et al. 1989a). The etiology of delirium in the HIV-infected patient is usually multifactorial (Fernandez et al. 1989a, 1989b); however, a rapid and aggressive diagnostic workup is mandatory to detect causes that can lead to permanent brain damage, such as Wernicke’s encephalopathy, hypoglycemia, hypoxemia, opportunistic infections (e.g., toxoplasmosis, cryptococcosis, and others), metabolic disturbances, and electrolyte imbalances (Fernandez et al. 1989b). In some cases, complete resolution of the delirium can be achieved by treating the primary cause, such as infectious processes or intracranial malignancies.

Dementia Because the cognitive dysfunction in HIV-infected individuals is usually progressive, diagnostic criteria have been established by the American Academy of Neurology AIDS Task Force (1991) to characterize the early cognitive changes and to differentiate them from the more advanced cognitive disorder, dementia (Tables 9–2 and 9–3). It is estimated that approximately 70% of HIV-infected patients will develop HIV- associated minor cognitive/motor disorder at some point during the course of their disease, and that 20%–30% will fulfill diagnostic criteria for HIV-associated dementia complex. Clinically, neuropsychological tests can reflect the earlier involvement of subcortical areas, with cognitive functions showing impairment in memory registration, storage, and retrieval; psychomotor speed; information-processing rate; and fine motor function (Becker et al. 1995). As HIV neurotoxicity advances, these impair-

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Table 9–2.

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American Academy of Neurology criteria for clinical diagnosis of human immunodeficiency virus type 1 (HIV-1)–associated minor cognitive/motor disorder

1. Cognitive/motor/behavioral abnormalities (each of the following) a. At least two of the following present for at least 1 month (1) Impaired attention or concentration (2) Mental slowing (3) Impaired memory (4) Slowed movements (5) Incoordination (6) Personality change, irritability, or emotional lability b. Acquired cognitive/motor abnormality verified by clinical neurological examination or neuropsychological testing (e.g., fine motor speed, manual dexterity, perceptual motor skills, attention/concentration, speed of processing information, abstraction/reasoning, visuospatial skills, memory/learning, or speech/language). 2. Disturbance from criterion 1 causes mild impairment of work or activities of daily living. 3. Does not meet criteria for HIV-1–associated dementia complex or HIV-1–associated myelopathy (see Table 9–3). 4. No evidence of another etiology, including active CNS opportunistic infection or malignancy, severe systemic illness, active alcohol or substance use, acute or chronic substance withdrawal, adjustment disorder, or other psychiatric disorders. 5. HIV seropositivity (ELISA test confirmed by Western blot, polymerase chain reaction, or culture). Note. CNS = central nervous system; ELISA = enzyme-linked immunosorbent assay. Source. Adapted from American Academy of Neurology AIDS Task Force: “Nomenclature and Research Case Definitions for Neurologic Manifestations of Human Immunodeficiency Virus–Type 1 (HIV-1) Infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force.” Neurology 41:778–785, 1991. Copyright © 1991, American Academy of Neurology. Used with permission.

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Table 9–3.

American Academy of Neurology criteria for clinical diagnosis of HIV-1–associated cognitive/motor complex

Criterion A or B required for the diagnosis: A. HIV-1–associated dementia complex Each of the following: 1. Acquired abnormality in at least two of the following cognitive abilities for at least 1 month: attention/concentration, speed of processing information, abstraction/reasoning, visuospatial skills, memory/learning, and speech/language. Cognitive dysfunction causing impairment of work or activities of daily living should not be attributable solely to severe systemic illness. 2. At least one of the following: (a) Acquired abnormality in motor function or performance verified by clinical examination, neuropsychological testing, or both. (b) Decline in motivation or emotional control or change in social behavior. 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, other psychiatric disorders (e.g., depression), active alcohol or substance use, or acute or chronic substance withdrawal. 5. HIV seropositivity (ELISA test confirmed by Western blot, polymerase chain reaction, or culture). B. HIV-1–associated myelopathy Each of the following: 1. Acquired abnormality in lower-extremity neurologic function disproportionate to upper-extremity abnormality verified by reliable history and neurologic examination. 2. Myelopathic disturbance is severe enough to require constant unilateral support for walking. 3. Criteria for HIV-1–associated dementia complex are not fulfilled. (continued)

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4. No evidence of another etiology, including neoplasm, compressive lesion, or multiple sclerosis. 5. HIV seropositivity (ELISA test confirmed by Western blot, polymerase chain reaction, or culture). Note. CNS = central nervous system; ELISA = enzyme-linked immunosorbent assay. Source. Adapted from American Academy of Neurology AIDS Task Force: “Nomenclature and Research Case Definitions for Neurologic Manifestations of Human Immunodeficiency Virus–Type 1 (HIV-1) Infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force.” Neurology 41:778–785, 1991. Copyright © 1991, American Academy of Neurology. Used with permission.

ments become more pronounced, and changes consistent with cortical damage also appear. Aphasia, agnosia, and apraxia may occur, and other sensory and perceptual functions also become progressively more impaired. During later stages, opportunistic infections and neoplasms also must be considered when patients develop severe cognitive impairment and focal findings in the presence of advanced disease. Cognitive changes such as forgetfulness, inattention, difficulty with concentration, mental slowing, loss of interest, and anhedonia should always be investigated, even early in HIV infection. If present, such symptoms should be clearly distinguished from a depressive disorder and must not be considered as simply part of the psychosocial difficulties of adapting to the disease. In late stages of the disease, moderate to severe cognitive deficits, confusion, psychomotor slowing, and seizures may appear. Patients may become mute or catatonic and/or may exhibit socially inappropriate behavior. Other neuropsychiatric disorders, including depression, mania, psychosis, and delirium, and marked neurological abnormalities, such as ataxia, spasticity, hyperreflexia, hypertonia, seizures, and bladder and bowel incontinence, can also be present, and these require specific treatment when possible.

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Psychosis Psychoses in HIV disease have been found in almost 8% of patients. Psychoses and HIV infections are related by two different means. The chronically mentally ill have a higher risk of HIV exposure (Cournos et al. 1994) and thus may become infected at some point during the course of their primary mental illness. Psychoses can also be secondary to HIV infection and the neurotoxicity it causes in the brain. The latter form of psychosis usually presents late in the course of the infection. The majority of patients with HIV-associated psychosis also have signs and symptoms of significant cognitive decline (HIV-associated minor cognitive/motor disorder or HIV-associated dementia complex), and these patients report higher rates of stimulant and sedative-hypnotic abuse or dependence. In many cases, the course of the disease is rapidly progressive, with death often occurring within a short period of time (Sewell et al. 1994). Secondary psychosis can thus be a sign of terminal AIDS and, more specifically, of advanced CNS involvement. In the assessment of the psychotic HIV-positive patient, the clinician must also consider the possibility of substance-induced psychosis, as both medication and illicit drug use is highly prevalent in this group of patients. Delirium secondary to metabolic abnormalities, CNS opportunistic infections, and neoplasms should also be considered. The medical workup should include imaging studies, CSF examination, and electroencephalogram (EEG) in addition to a general medical evaluation to assess the metabolic (Pneumocystis carinii pneumonia), endocrinological (e.g., euthyroid sick syndrome, hypothyroidism, thyroiditis), and immunological status of the patient.

Mood Disorders Although mania and hypomania have been described in HIV disease (Lyketsos et al. 1993), depressive disorders are more frequently found, with nearly 85% of HIV-infected individuals showing some evidence of depression during the course of the disease (Perry and Tross 1984). Specific epidemiological data of different mood disorders are lacking. Depressive symptoms in HIV-infected patients can range from

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appropriate sadness to a diagnosable major depressive disorder. Depression can occur secondary to substance abuse, HIV neurotoxicity, HIV-related therapies, opportunistic infections, malignancies, or other CNS organic factors. The diagnostic process can become quite complicated, because the usual indicators of depression are frequently present in HIV systemic disease and HIV-related neurological impairment regardless of the presence of depression (Ostrow et al. 1988). It is important to adopt an inclusive perspective, with all criterion signs and symptoms—regardless of their etiology—being considered in the diagnosis of depression. Clinically, symptoms of questionable physical or psychological origin are considered valid diagnostic indicators of depression, because, depressive disorders tend to be underdiagnosed and undertreated, a common problem in all medically ill populations. Suicidal ideation is almost always a sign of depression, and its presence needs to be taken into consideration to provide proper management of patients. The concept of suicide as a rational decision has been described (Siegel 1986), but should be should be viewed as inappropriate, as suicide should be considered neither a normal nor an understandable reaction to having a fatal and stigmatized disease. Rundell et al. (1992) studied risk factors for suicide attempts in HIV patients. They found that possible risk factors for a suicide attempt included current major depression, previous suicide attempt, and history of alcohol abuse; definite risk factors included social isolation, perceived lack of social support, adjustment disorder, personality disorder, alcohol abuse, HIV-related interpersonal or occupational problems, and a past history of depression. A thorough assessment of the patient is required, and it must include a realistic appraisal of the psychosocial situation and the motivation for completing a suicide. Again, a complete medical workup is mandatory to search for reversible organic causes, and pain, if present, should be properly treated.

Anxiety Disorders Anxiety is a common symptom among HIV-infected individuals, with 17%–36% of patients having anxiety disorders sometime during the course of their systemic disease (Atkinson et al. 1988). The se-

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verity of the anxiety varies, and the presentation can range from an appropriate fearful or apprehensive reaction to a severe, incapacitating anxious mood. In about 20% of patients, the anxiety is persistent and may interfere with the medical management of the disease. Denial or avoidant behaviors may prevent proper follow-up, treatment, compliance, or adherence to more positive health-related behaviors (Blaney et al. 1991). Groups at higher risk for anxiety disorders include alcohol and drug abusers, who may have not only chronic anxiety but also severe withdrawal symptoms mimicking anxiety features, especially when admitted to a hospital for inpatient treatment; homosexual men, who have a higher prevalence of premorbid anxiety in comparison with heterosexual men matched on other demographic characteristics; patients with preexisting anxiety disorders; and those with limited psychosocial support. Specific epidemiological data on the frequency of specific anxiety disorders in HIV-infected individuals are lacking. However, among these conditions, adjustment disorder with anxious mood seems to be the most prevalent. This disorder may present shortly after the detection of HIV seropositivity or the diagnosis of HIV infection by symptoms, or at any time subsequently when the disease progresses, new complications arise, or patients become aware of their deterioration even if they remain asymptomatic (e.g., a significant drop in CD4 count). Panic disorder and generalized anxiety disorder may also be frequently encountered. A syndrome resembling posttraumatic stress syndrome (PTSD), with distressing, intrusive recollections and/or dreams about the moment the notification of seropositivity was received, can also occur. Clinicians may also need to consider anxiety associated with medical conditions, especially in patients with respiratory compromise due to pneumonia, pain, neurological compromise due to opportunistic infections or malignancies, and substance-induced anxiety (i.e., from agents such as zidovudine [ZDV], steroids, or other prescribed or over-the-counter medications). In the evaluation process, the usual psychiatric and medical history, along with a medical workup including thyroid function tests, arterial blood gases, and a urine drug screen, is required. According to the patients’ needs, specific tests—such as X rays, neuroimaging

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studies, EEG, electrocardiogram (ECG), and others—must be obtained to identify or rule out medical problems that could be the source of the anxiety. Also, a neuropsychiatric evaluation should be considered, because a depressed, delirious, or demented patient would require different treatments than an anxious patient without those disorders.

Sexual and Other Disorders Few data are available regarding other psychiatric disorders in HIV/AIDS. In regard to sexual and libido symptoms, there is no specific information. Reduced libido can result from some of the neuropsychiatric disorders that attend HIV disease and may be no different from that seen in other populations with neuropsychiatric disorders. For instance, decreased libido may occur in patients suffering from depression, and sexual dysfunction may result from antidepressant medications. Management would be no different from that in other populations.

Neurological and Psychiatric Management Treatment of Delirium Delirium in HIV-infected individuals can be effectively treated with orally or intramuscularly administered high-potency neuroleptics without serious adverse effects. Breitbart and co-workers (1996) reported the results of a controlled study that showed that low doses of either oral or intramuscular haloperidol (2.8 ± 2.4 mg/day) and chlorpromazine (50 ± 23 mg/day) were beneficial in treating delirious patients without inducing significant extrapyramidal reactions. In that study, lorazepam as a single agent was not as effective and was not well tolerated, and some patients were even observed to decline further with this treatment. In HIV patients who are known to be unable to tolerate haloperidol or chlorpromazine, molindone in doses up to 225 mg/day can be very useful in the control of both delirium and psychosis and can be given without incurring major adverse effects (Fernandez and Levy 1993). Atypical neuroleptics have also

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been used effectively, especially in hypoactive delirium, but there are no reports of their use in delirious HIV-infected individuals as yet. Intravenous pharmacotherapy with haloperidol has been demonstrated to be effective when oral or intramuscular haloperidol or other neuroleptics have not achieved the necessary control of delirious symptomatology (Fernandez et al. 1989b). Although the intravenous administration of haloperidol remains investigational at this time and has not been approved by the U.S. Food and Drug Administration (FDA), a large volume of anecdotal reports testify to the infrequency of adverse effects. Considering the dangers of untreated delirium, the risk–benefit ratio has always been favorable. In extremely medically compromised patients, intravenous haloperidol can be of great benefit, since it does not further alter the patient’s hemodynamics. Guidelines for intravenous use of haloperidol have been formulated by the Massachusetts General Hospital Psychiatric Consultation Service (Table 9–4; Murray 1991).

Treatment of Dementia The class of antiretrovirals that has been demonstrated to combat HIV infection most effectively in the brain is the reverse transcriptase Table 9–4.

Intravenous use of haloperidol for control of agitation

1. Assess the severity of the agitation and determine the initial intravenous dose of haloperidol: Severity of agitation Mild Moderate Severe

Initial dose of intravenous haloperidol (mg) 0.5–2.0 5.0–10.0 10.0 or more

2. Evaluate response 20 minutes after intravenous infusion. If agitation persists, double the initial dose. 3. Repeat step 2 until effective control of the agitation is achieved. Source. Adapted from Murray GB: “Confusion, Delirium and Dementia,” in Handbook of General Psychiatry, 3rd Edition. Edited by Cassem NH. St. Louis, MO, Mosby–Year Book, 1991, pp. 89–120. Copyright © 1991, Mosby–Year Book Inc. Used with permission.

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inhibitors. Of these, the most commonly used is ZDV. ZDV’s CSF levels are half of those recovered from plasma (Wong et al. 1992). It can help reduce morbidity and mortality both in AIDS patients and in asymptomatic patients with fewer than 500 CD4 cells/mm3 (Fischl et al. 1987), but it has not been as helpful in asymptomatic patients with more than 500 CD4 cells/mm3 (Volberding et al. 1995). ZDV has been shown to ameliorate cognitive impairment, and it may delay progression to HIV-associated dementia complex (Baldeweg et al. 1995). The optimal dose of ZDV for this effect has not been determined; however, Sidtis and co-workers (1993) found significant improvements in cognition with doses of 2,000 mg/day. Didanosine (ddI) has been used to treat HIV-associated cognitive impairment (Yarchoan et al. 1990), but controlled studies confirming ddI’s efficacy in improving cognitive function or preventing further decline have not been reported. Other nucleosides—zalcitabine (ddC), stavudine (D4T), and lamivudine (3TC)—and the nonnucleoside reverse transcriptase inhibitors are being investigated for use alone or in multiagent therapy (Fischl 1995), but these have not been demonstrated to be especially effective in the treatment of neurocognitive dysfunction in HIV infection. A new class of anti-HIV agents that prevents maturation of HIV virions is the protease inhibitors (Deeks and Smith 1997). There are as yet no studies demonstrating the effect of these agents on cognitive functions or dementia, but they are an encouraging addition to the armamentarium of medications that may be used in combination therapy with the reverse transcriptase agents to fight HIV infection. Four protease inhibitors are currently on the market for clinical use: indinavir, nelfinavir, ritonavir, and saquinavir. Some nucleoside agents are themselves psychoactive and can engender such side effects as mania (Brouillette et al. 1994; Maxwell et al. 1988), delirium (Fernandez et al. 1989b), myopathy (Brew 1993; Miller 1991), and peripheral neuropathies (Fischl 1995). Confusion, insomnia or somnolence, and anxiety or nervousness may also occur with use of these agents (Richman et al. 1987). Treatment with vitamin B12 may be helpful in reducing the risk of ZDV’s hematological toxicity (Richman et al. 1987). Beyond the standard antiviral treatments based on systemic viral infection, the beneficial effect of agents that target the CNS have

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been reported. Attempts to prevent the neurotoxic chain of events secondary to HIV CNS involvement have focused on reducing NMDA receptor stimulation by removing or antagonizing excitatory amino acids with receptor antagonists (e.g., memantine or dizocilpine [MK-801]) or by preventing calcium influx with calcium channel blockers (e.g., nimodipine), dantrolene, or BAPTA (bis-oaminophenoxyethane-N,N,N,’N’-tetra-acetic acid) (Harbison et al. 1991; Lipton 1994; Ushijima et al. 1995). Although nimodipine has been effective in vitro in preventing the neurotoxic effect, other agents, such as verapamil, have potentiated the replication of the virus in lymphoid cells (Harbison et al. 1991), and currently there is no clinical indication for any of these drugs. Psychostimulants have improved cognitive functioning in HIVassociated minor cognitive/motor disorder (Brown 1995). Methylphenidate is a representative agent that most patients can tolerate; useful dosages range from 10 to 90 mg/day in a divided schedule. Treatment may be started at 5–15 mg/day and then raised progressively to meet the patient’s therapeutic needs. The usual dosage schedule would be 5–10 mg of methylphenidate administered at 7 A.M., 10 A.M., and 1 P.M.. Stimulant-related side effects are mild and include anxiety, insomnia, and tachycardia. Rarely, anorexia is seen, but it is never significant enough to cause weight loss. The use of stimulants must be carefully assessed in patients with a history of substance abuse disorders, and the benefit should clearly outweigh the risk involved.

Treatment of Psychosis The psychosis induced by HIV CNS infection requires the same timely intervention accorded to psychoses and delirium from other causes. This is often accomplished with rapid tranquilization with neuroleptics. However, HIV-infected patients are more likely to experience side effects such as extrapyramidal reactions, neuroleptic malignant syndrome (with high-potency neuroleptics), and confusion and seizures (with low-potency neuroleptics) (Breitbart et al. 1996). The newer neuroleptics risperidone and olanzapine have demonstrated control of HIV-related psychosis without sedation or notable cognitive impairment (Levy and Fernandez 1997).

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Treatment of Mood Disorders Tricyclic antidepressants (TCAs) with sedating effects, such as amitriptyline, imipramine, and doxepin, can additionally be used to treat agitation or insomnia. Patients with psychomotor retardation may find the least-sedating TCAs, such as the secondary amines desipramine or protriptyline, more useful. TCAs may also be of benefit in the treatment of the pain of neuropathies. Therapy with TCAs can begin with a low dose of 10–25 mg at bedtime, with progressive increments to full therapeutic doses (Fernandez and Levy 1994). TCAs with significant affinity for central muscarinic receptors (e.g., amitriptyline, imipramine, and doxepin) may induce anticholinergic effects that can exacerbate HIV-related cognitive impairment or trigger delirium or seizures. Drying of the oral mucosa from the anticholinergic effects can lead to a risk of thrush. Trazodone has minimal anticholinergic effects and is often well tolerated by HIV patients (Fernandez and Levy 1994). Trazodone dosages can be initiated at 25–50 mg at bedtime and increased by 25–50 mg every 3–5 days until clinical response is evident. Although trazodone is sedating, this effect can be used to benefit the insomniac patient. Orthostatic hypotension has also been reported and can be of significance in patients with HIV-related dysautonomia. All selective serotonin reuptake inhibitors (SSRIs) are known to have little if any anticholinergic effects. Fluoxetine at 10–40 mg daily is useful for treating HIV-related depression (Fernandez and Levy 1991). Sertraline and paroxetine have also been confirmed as effective in open clinical trials (Rabkin et al. 1994; Singh and Catalan 1993). Fluvoxamine was shown to be poorly tolerated in one trial with HIV-infected depressed patients (Grassi et al. 1995). Bupropion has a stimulatory effect and thus may be useful in withdrawn or anhedonic patients (Fernandez and Levy 1991, 1994). However, it should be used with care in patients with CNS lesions, because seizures have been induced by dosages greater than 200 mg/day. Nefazodone and venlafaxine have been reported to be well tolerated and effective (Fernandez and Levy 1996). No reports on the use of mirtazapine are yet available; however, in our clinical experience, it has been well tolerated and effective, even in patients receiving marrow-toxic therapy. No added hematopoietic toxicity has been observed.

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Psychostimulants can be effective in treating patients who have coexisting depression and cognitive impairments, and in those in whom other antidepressants have proven to be ineffective as a single agent or intolerable because of severe or untoward side effects (Fernandez and Levy 1991, 1994; Fernandez et al. 1995). Methylphenidate has been found especially useful in this regard. Benefit may be observed rapidly, often within hours after the first dose, producing psychomotor activation, appetite stimulation, and overall improvement of cognition. Dosages similar to that used adjunctively for dementia (see “Treatment of Dementia” subsection above) have been reported to have antidepressant effects equivalent to those of desipramine at 150–200 mg/day (Fernandez et al. 1995). The role of psychostimulants in the treatment of depression in patients with a current or previous history of drug abuse is problematic, however, and use of these agents should be avoided in this subgroup of patients. Patients who have used lithium carbonate or monoamine oxidase inhibitors (MAOIs) for their depression before HIV was diagnosed can continue with these regimens (Fernandez and Levy 1994). From a biochemical standpoint, however, MAOIs are theoretically incompatible with concurrent administration of ZDV, which is reported to have a catechol-O-methyltransferase (COMT)–inhibiting effect. Careful monitoring is mandatory, as HIV patients are at increased risk of developing toxicity. Patients with diarrhea or significant fluid loss from any source may readily develop neurotoxicity or nephrotoxicity with lithium carbonate. For this reason, alternative agents, such as anticonvulsants, may be substituted. Anticonvulsant medications can also help control psychosis and mania in HIV patients with these disorders (Fernandez and Levy 1994). Halman et al. (1993) found that valproic acid (750–1,250 mg/ day) controlled mania associated with brain lesions (as indicated by abnormal MRI scans) in HIV disease. In this study, an abnormal MRI also was associated with a poor response to lithium and neuroleptics. Carbamazepine theoretically is contraindicated in HIV patients who are receiving antivirals because of its propensity to intensify potential hematopoietic toxicity; however, anecdotal accounts support its use in the treatment of mania. An important consideration in the use of antidepressants and

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anticonvulsants in HIV-infected individuals is the potential interaction between these agents and the protease inhibitors, because they all are metabolized through the cytochrome P450 system, and an increase in plasma levels is possible as a result of competition for the enzymatic system. There are as yet no pharmacokinetic studies that offer more specific guidelines; therefore, clinicians should exercise care when adding a psychotropic to a medication regimen that includes one of the protease inhibitors. Clinical and, when possible, laboratory monitoring is recommended.

Treatment of Anxiety Disorders When anxiolytic therapy is deemed necessary for severe anxiety, short- to intermediate-acting benzodiazepines may be of benefit (Fernandez and Levy 1991, 1994). Long-acting benzodiazepines are not recommended in patients with cognitive compromise, including disinhibition, frontal lobe dysfunction, delirium, or confusion. Oxazepam, lorazepam, and alprazolam are considered good choices in this population because they are simpler to use and less neurotoxic. A regimen combining benzodiazepines with buspirone 5–10 mg tid can be helpful. Buspirone can be increased by 5–10 mg every 3 days until a therapeutic dose (30–60 mg/day) is reached over a 2-week course of concomitant benzodiazepine therapy. It is then advisable to institute a taper of the benzodiazepine. Buspirone can be continued as long as clinically indicated, because it does not have the varied side-effect profile associated with the benzodiazepines. It has been observed that patients with advanced HIV systemic disease exhibit some confusion while on buspirone; however, lesssymptomatic patients are less likely to show this effect (Levy and Fernandez 1997). In patients treated with ZDV, buspirone is better tolerated with ZDV dosages lower than 600 mg/day. Buspirone has also been reported to diminish drug-seeking behavior in anxious patients with addictions (Batki 1990).

Summary The AIDS epidemic continues, and with it the risk that a considerable proportion of patients will develop clinically significant neuro-

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behavioral disorders. These complications are serious not only because of the excess morbidity they cause but also because they can potentially compromise the ability of patients to follow the complex medical regimens required in AIDS treatment. Because several neuropsychiatric disorders may present concurrently, it is unlikely that any single therapeutic strategy will work over the long term. It thus becomes vital to rapidly assess the patient’s condition and to formulate specific pharmacotherapies that can effect significant quantitative improvements. In many of the neuropsychiatric disorders, long-term administration of psychotropic agents, either alone or in combination, is likely to be beneficial. HIV-infected patients are still subject to prejudices and misconceptions that are often complicated and further aggravated by these neuropsychiatric disturbances. Effective and innovative psychopharmacotherapies can do much to optimize patients’ overall medical care—and ultimately their quality of life.

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Rundell JR, Kyle KM, Brown GR, et al: Risk factors for suicide attempts in a human immunodeficiency virus screening program. Psychosomatics 33:24–27, 1992 Saag MS: AIDS testing now and in the future, in The Medical Management of AIDS, 4th Edition. Edited by Sande MA, Volberding PA. Philadelphia, PA, WB Saunders, 1995, pp 65–88 Sewell DD, Jeste DV, Atkinson JH, et al: HIV-associated psychosis: a study of 20 cases. San Diego HIV Neurobehavioral Research Center Group. Am J Psychiatry 151:237–242, 1994 Sharer LR: Pathology of HIV-1 infection of the central nervous system: a review. J Neuropathol Exp Neurol 51:3–11, 1992 Sidtis JJ, Gatsonis C, Price RW, et al: Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. AIDS Clinical Trials Group. Ann Neurol 33:343–349, 1993 Siegel K: Psychosocial aspects of rational suicide. Am J Psychother 3:405– 418, 1986 Singh AN, Catalan J: The use of selective serotonin re-uptake inhibitors (SSRI) for the treatment of depression in patients with AIDS. Paper presented at the International Conference on AIDS, Westminster, London, June 1993 Tyor WR, Wesselingh SL, Griffin JW, et al: Unifying hypothesis for the pathogenesis of HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy. J Acquir Immune Defic Syndr Hum Retrovirol 9:379–388, 1995 UNAIDS/WHO: AIDS epidemic update: December 1998. Joint United Nations Programme on HIV/ATDS, London, England, 1998, pp 1–18 Ushijima H, Nishio O, Klocking R, et al: Exposure to gp120 of HIV-1 induces an increased release of arachidonic acid in rat primary neuronal cell culture followed by NMDA receptor-mediated neurotoxicity. Eur J Neurosci 7:1353–1359, 1995 Volberding PA: HIV quantification: clinical applications. Lancet 347:71–73, 1996 Volberding PA, Lagakos SW, Grimes JM, et al: A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. AIDS Clinical Trials Group. N Engl J Med 333:401–407, 1995 Wiley CA: Pathology of neurologic disease in AIDS. Psychiatr Clin North Am 17:1–15, 1994

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Wiley CA, Achim C: Human immunodeficiency virus encephalitis is the pathological correlate of dementia in acquired immunodeficiency syndrome. Ann Neurol 36:673–676, 1994 Wiley CA, Masliah E, Morey M, et al: Neocortical damage during HIV infection. Ann Neurol 29:651–657, 1991 Wong SL, Wang Y, Sawchuk RJ: Analysis of zidovudine distribution to specific regions in rabbit brain using microdialysis. Pharm Res 9:332–338, 1992 Yarchoan R, Pluda JM, Thomas RV, et al: Long-term toxicity/activity profile of 2′-3′-dideoxyinosine in AIDS or AIDS-related complex. Lancet 336: 526–529, 1990

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C H A P T E R

1 0

Family Management Issues Edward C. Lauterbach, M.D.

T

he impact of neurological illnesses extends beyond the patient to involve family members and caregivers. Despite this obvious consequence, there is very little empirical outcome research regarding treatment for neurologically well family members. Clinical trials are uncommon, and most of the literature is anecdotal or theoretical. In this final chapter, some current clinical concepts regarding the family in neurological disorders are summarized, as well as the scant clinically relevant family therapy research findings in the specific disorders discussed in this volume.

Neurological Disorders and the Family Avenues of Approach The Lazarus–Folkman model (Lazarus and Folkman 1984) provides one way of understanding the effects of neurological disorders on family caregivers. According to this formulation, caregiver physical, psychological, and social outcomes are influenced by caregiver perceptions, appraisals, and coping strategies. Negative perceptions and appraisals (e.g., the condition is hopelessly untreatable, hostile behavior by the patient is intentional) are influenced by factors relating to the caregiver, the patient, the family, social relations, and the environment. Consequently, interventions targeted toward these influences may be of value to caregivers and family members. Miller and Borden (1992) have suggested that effective family interventions 297

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help to reduce maladaptive appraisals (by reframing and managing reactions to illness phenomena), improve coping skills (by providing disease education, enhancing problem-solving skills, and teaching stress management), and increase social supports (including selfhelp groups, social casework, family therapy, and group therapy). A range of approaches may be necessary, because different family members react to the patient’s illness in different ways at different points in the illness course (Miller and Borden 1992). In an experimental and practical review of family therapy in the context of chronic illnesses, fundamental interventions included disease education, support of the family, and formal family therapy (Strozier 1996). Specific therapeutic recommendations included listening to the family, facilitating family communication, empowering patients and families, normalizing their experience, facilitating equalization of caregiving tasks, reinforcing age-appropriate behaviors and roles of family members, finding practical ways to optimize activities of daily living, and addressing disease-imposed financial, spiritual, and sexual concerns. Listening to the family members to achieve catharsis involves hearing the saga of the disease, the different family members’ perspectives of that saga, and a willingness to listen to the details. Empowering of the patient and the family relates to minimizing overly critical or overly solicitous treatment of the patient. Normalization involves addressing family fears and the facilitation of grief and adjustment to the illness through the realization that these are normal, common experiences and a part of life. Equalizing caregiving tasks involves reducing disproportionate caretaking burdens upon individual family members. Reinforcement of appropriate roles refers to minimizing patient infantilization and caregiver parentification. Certain issues affected by chronic diseases are often unspoken by family members and deserve attention. Discussion of financial, spiritual, and sexual concerns may remedy misunderstanding and lead to improved coping.

Support Groups Support groups can be useful in some of these areas, including education, problem solving, and social support. A number of studies have found a relationship between caregiver distress and social iso-

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lation, a problem these groups can effectively address (Miller and Borden 1992). Studies have documented that participation in support programs is associated with reductions in psychiatric and other hospitalizations (Eisdorfer and Cohen 1981), increased participation in rehabilitation programs that foster functional improvement (Chiverton and Caine 1989), and enhanced perceptions of competence, mastery, and independent functioning (Chiverton and Caine 1989). Contacts for support group referral for specific diseases (where available) are provided in the individual foregoing chapters; more general neurological support group contacts are provided in Chapter 1. Family caregivers are often reluctant to request or obtain help for themselves (Montgomery and Borgatta 1985). Intervention can be facilitated if the clinician consistently demonstrates an understanding of and empathy for caregiver hardships, especially during initial contacts with the family, and seizes opportunities to recommend support groups or other interventions at points of crisis, when caregivers may be more amenable to such referrals (Miller and Borden 1992).

Other Programs Although there are few data substantiating the effectiveness of family or other therapies in neuropsychiatric illness, caregivers receiving training in communication, memory, and problem-solving skills have shown diminished perceptions of burden and higher levels of psychological well-being (Quayhagen and Quayhagen 1989). Clinical findings in specific neurological diseases are discussed below.

Huntington’s Disease The difficulties for family members of Huntington’s disease patients have been well detailed and include several types of denial and their consequences, more subtle financial difficulties, and socioeconomic, psychological, and psychiatric impacts, according to Hans and Gilmore (1968). Education, family planning, case management, and resource referral were found to be the most helpful interventions in their study. Another study of family members of Huntington’s disease patients found significant changes in psychosocial patterns in

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spouses of patients and an inability to cope in some spouses, indicating a need for external social support (Leimkuhler 1987). A description of conjoint family therapy in Huntington’s disease has been published that emphasizes that therapists should develop an understanding of genetic and social aspects of Huntington’s disease and a long-term commitment to the family because of increasing family needs as the disease progresses (Martindale and Bottomley 1980). Conjoint therapy facilitating expression of emotions is considered particularly beneficial in families with psychotic members and young children, but impaired engagement can impede the therapy and there is a need for a flexible approach involving liaison work with social agencies.

Stroke Several studies document the utility of the Lazarus–Folkman and Miller–Borden theories in helping stroke patients and their families. Systemic family therapy has been suggested as a useful method of support in stroke rehabilitation, allowing both the patient and the family to accept the condition and to develop a new and meaningful outlook by reorganizing relationships according to changed psychic needs in the context of stroke (Scholze 1995). In a study by Borenstein et al. (1987), a program of aphasia education, psychological counseling, and language training for stroke patients and their family members led to self-reports of improved psychological function and increased social support, which were associated with positive effects on coping with chronic disability. In another study (Evans et al. 1987), prestroke family interaction measures of behavior control and effective responsiveness predicted the number of days of rehospitalization better than traditional stroke outcome variables. Interdiction of family members’ self-defeating efforts to be supportive and encouraging toward the patient has also been suggested to constitute an important aspect of family therapy (Watzlawick and Coyne 1980).

Multiple Sclerosis In addition to concern for their loved one with multiple sclerosis, family members of these patients have feelings of guilt and inade-

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quacy, worries about the heritability of the illness, and concerns regarding finances and changes from the role of spouse or parent to that of nurse’s aide (Block and Kester 1970). At a clinical level, individual or group therapy for family members has been viewed as helpful in coping with these issues.

Acquired Immunodeficiency Syndrome (AIDS) It has been suggested that an important task in counseling family members of human immunodeficiency virus (HIV)–infected patients is to maintain the integrity and supportiveness of the patient’s social unit through open communication and education about AIDS (Lippmann et al. 1993). Significant others might be encouraged to retain outside interests and seek help for the patient from supportive social agencies. A retrospective impressionistic study of 50 relatives of AIDS patients over several years identified a range of psychosocial stressors affecting family members (Frierson et al. 1987). These included substantial fears of contagion, spousal guilt about “driving” the patient to homosexuality, anger about the patient’s “deviant” lifestyle, grief, spousal denial of emotions, and communication difficulties between homosexual patients and their fathers. Paroxysmal exacerbations of familial grief paralleled disease exacerbations. Bargaining in grief sometimes took the form of willingness to accept the patient’s lifestyle in exchange for his survival. Familial rejection of the patient sometimes occurred, and the quality of premorbid relationships seemed to predict acceptance versus rejection. Anticipatory grief was common. At times, panic, psychosis, and suicidal depressive disorders developed in family members. Some family members experienced stigmatization at work or school because of AIDS in their relatives. A change in role to that of caregiver was sometimes attended by domineering behavior and restriction of patient autonomy by the caregiver. These observations led the authors of this study to conclude that providing reliable AIDS educational information, addressing grief, and assuming a nonjudgmental attitude are useful for helping family members of AIDS patients. A brief standardized intervention program for children of par-

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ents with terminal diseases required special adaptations to overcome implementation problems, which included estimation of the parent’s life expectancy, engagement of the family in crisis, adherence of the therapist and those undergoing therapy to parental guidance, and therapy termination issues (Christ et al. 1991). In a review of the largely anecdotal literature regarding the related issue of working with family members of homosexuals, it was concluded that effective therapeutic interventions involve use of commonsense tactics while listening for underlying issues apart from the offspring’s sexual preference (Mattison and McWhirter 1995). A key issue that emerged in this study was the importance of maintaining a professional demeanor while simultaneously conveying a sense of caring and concern for individuals. The authors concluded that family therapy is of great value in helping families navigate their own “coming-out” process, but that there is a need for more research in this area.

Summary Neurological illnesses devastate patients and family members alike. Relatively little is known about effective interventions to minimize the psychosocial and physical effects of neurological disorders on family members. Primary strategies include improving coping strategies and perceptions by employing elements of supportive, interpersonal, cognitive, and educational psychotherapy as well as by referring family members to support groups and community resources. Formal group therapy or family therapy may be indicated. Interventions vary over the illness course and also depend on the specific circumstances. Support groups are especially valuable, often combining several elements of intervention, especially education. Reduced hospitalization and improved family function have been documented in some support group settings. Clinicians may need to apply special persuasion to encourage family members to avail themselves of these resources. Various intervention strategies have been described for specific illnesses, and special approaches may be necessary in certain illnesses or demographic groups. Family intervention outcome data are urgently needed to identify effective tactics for helping family members cope with neurological disorders.

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Effective strategies will directly benefit family members, thereby also benefiting neurological patients.

References Block JM, Kester NC: Role of rehabilitation in the management of multiple sclerosis. Mod Treat 7:930–940, 1970 Borenstein P, Linell S, Wahrborg P: An innovative therapeutic program for aphasia patients and their relatives. Scand J Rehabil Med 19:51–56, 1987 Chiverton P, Caine ED: Education to assist spouses in coping with Alzheimer’s disease. J Am Geriatr Soc 37:593–598, 1989 Christ GH, Siegel K, Mesagno FP, et al: A preventive intervention program for bereaved children: problems of implementation. Am J Orthopsychiatry 61:168–178, 1991 Eisdorfer C, Cohen D: Management of the patient and family coping with dementing illness. J Fam Pract 12:831–837, 1981 Evans RL, Bishop DS, Matlock AL, et al: Prestroke family interaction as a predictor of stroke outcome. Arch Phys Med Rehabil 68:508–512, 1987 Frierson RL, Lippmann SB, Johnson J: AIDS: psychological stresses on the family. Recommendations for counseling relatives of the AIDS patient. Psychosomatics 28:65–68, 1987 Hans MB, Gilmore TH: Social aspects of Huntington’s chorea. Br J Psychiatry 114:93–98, 1968 Lazarus R, Folkman S: Stress, Appraisal, and Coping. New York, Springer, 1984 Leimkuhler AM: “Self-help potential of the family” can overtax the abilities of the marital partner. Report on a family group of Huntington chorea patients. Psychiatr Prax 14:78–83, 1987 Lippmann SB, James WA, Frierson RL: AIDS and the family: implications for counselling. AIDS Care 5:71–78, 1993 Martindale B, Bottomley V: The management of families with Huntington’s chorea: a case study. J Child Psychol Psychiatry 21:343–351, 1980 Mattison AM, McWhirter DP: Lesbians, gay men, and their families. Some therapeutic issues. Psychiatr Clin North Am 18:123–137, 1995 Miller FE, Borden W: Family caregivers of persons with neuropsychiatric illness: a stress and coping perspective, in The American Psychiatric Press Textbook of Neuropsychiatry, 2nd Edition. Edited by Yudofsky SC, Hales RE. Washington, DC, American Psychiatric Press, 1992, pp 755–772

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Montgomery RJV, Borgatta EF: Family support project: final report, Administration on Aging. Seattle, WA, University of Washington Press, 1985 Quayhagen MP, Quayhagen M: Differential effects of family-based strategies in Alzheimer’s disease. Gerontologist 29:150–155, 1989 Scholze M: Systemic family therapy with stroke patients. Wien Med Wochenschr 145:544–546, 1995 Strozier AM: Families with chronic illness and disability, in Treating The Changing Family—Handling Normative and Unusual Events. Edited by Harway M. New York, Wiley, 1996, pp 246–270 Watzlawick P, Coyne JC: Depression following stroke: brief, problemfocused family treatment. Fam Process 19:13–18, 1980

Index Page numbers printed in boldface type refer to tables or figures.

ACE (angiotensin-converting enzyme) inhibitors, 23 Acetaminophen, 27 Acetylcholine in multiple sclerosis, 262–263 in Parkinson’s disease, 46 Acquired immunodeficiency syndrome (AIDS). See Human immunodeficiency virus infection Addison’s disease, 138 Adenosine triphosphatase (ATPase), P-type, 99 Adjustment disorders, 13, 204, 282 Affect depressed, 15 flat, distinction from facial akinesia, 15 pathological (pseudobulbar), 16, 222 (See also Pathological emotions) Affective disorders. See Mood disorders Aggressiveness, 14 in Huntington’s disease, 78, 79 treatment of, 84–85 in Wilson’s disease, 106, 108, 110, 121 treatment of, 126

Agitation drug-induced, 201 in dystonia, 200 intravenous haloperidol for, 284, 284 Agnosia, 7, 14, 279 Agoraphobia, 195 Agranulocytosis, 59 Agraphia, 7 Aicardi-Goutieres syndrome, 152, 154–155 AIDS (acquired immunodeficiency syndrome). See Human immunodeficiency virus infection Akathisia, 207 Akinesia, 4, 6 drug-induced, 126 facial, distinction from flat affect, 15 in Huntington’s disease, 74 Alcohol, for dystonia, 208 Alcoholism. See Substance abuse disorders Alexia, 7, 256 Alexithymia, 15, 80 Alien hand syndrome, 8, 10, 16 Alpha-hydroxyvitamin D3, 165 Alport syndrome, 152

305

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Alprazolam, 34 selective serotonin reuptake inhibitor interactions with, 31 use in HIV infection, 289 Alzheimer’s disease, 78, 79, 220 basal ganglia calcification and, 153 treatment of, 58, 64, 263 Amantadine, 15 for Parkinson’s disease, 56–59 for pathological affect, 34 psychiatric side effects of, 52 Ambien. See Zolpidem American Parkinson’s Disease Association, 57 Aminophylline, 25 4-Aminopyridine, 262 Amiodarone, 27 Amitriptyline selective serotonin reuptake inhibitor interactions with, 31 use in HIV infection, 287 use in multiple sclerosis, 263 Amnestic disorders. See also Memory impairment anterograde amnesis, and ultra-short-acting benzodiazepines, 20–21, 34 visual, verbal amnesia, 7 Amoxapine, 126 Amphetamine, 235 Amusia, 7 Amygdala, 11 Analgesics, 27 Anderson procedure, 203 Anemia pernicious, 147 sideroblastic, 116, 118 Anger, 15, 16, 108

Angiotensin-converting enzyme (ACE) inhibitors, 23 Angular gyrus syndrome, 7 Anhedonia, 60, 279 Anomia, 7, 8 Anorexia, 186 Anorgasmia. See also Sexual disorders drug therapy for, 33 in multiple sclerosis, 260 in Parkinson’s disease, 51 Anosognosia, parietal, 14 Ansotomy, for dystonia, 203 Antiapathy agents, 15 Antiarrhythmic agents, 23, 27–28 Anticholinergic drugs disease interactions with, 20 dysautonomia and orthostatic hypotension, 33 pulmonary disease, 36 for dystonia, 201, 202, 205 for Parkinson’s disease, 56–57, 59 psychiatric side effects of, 51, 52, 200–201 Anticholinergic effects, 19, 33, 287 Anticipation, genetic in dystonia, 188 in Fahr’s syndrome, 142 in Huntington’s disease, 76 Anticoagulants, 23, 24, 26, 27 Anticonvulsants. See also specific drugs disease interactions with, 20–22 hepatic disease, 36 drug interactions with, 23, 24, 33, 124 selective serotonin reuptake inhibitors, 30 Fahr’s syndrome and, 153, 154, 169

Index

for poststroke patients, 236, 238 use in dystonia, 201, 202, 206 use in HIV infection, 288–289 use in Huntington’s disease, 84, 86 use in Wilson’s disease, 126 Antidepressants, 15, 19. See also specific drugs and classes disease interactions with, 20–21 cognitive disorders, 34 heart disease, 26 hepatic disease, 36 seizure disorders, 33 drug interactions with, 23–25 selective serotonin reuptake inhibitors, 31 selegiline, 35, 60 for panic disorder, 62 for pathological affect, 34 for poststroke patients, 235, 238–241, 239 side effect profile of newer agents, 19 use in dystonia, 207, 208 use in Fahr’s syndrome, 169–170 use in HIV infection, 287–289 use in Huntington’s disease, 86 use in multiple sclerosis, 263 use in Parkinson’s disease, 59–62 use in Wilson’s disease, 126 Antihistamines, 20, 32, 115 Antimicrobial agents, 29 Antipsychotics, 18 atypical, 19 disease interactions with, 20–22 cognitive disorders, 34 dysautonomia and orthostatic hypotension, 33 movement disorders, 35 seizure disorders, 33

307

drug interactions with, 23–25 selective serotonin reuptake inhibitors, 30 for poststroke patients, 236–238 use in dystonia, 190, 201–202, 204–206 use in Fahr’s syndrome, 168–169 use in HIV infection, 283–284, 284, 286 use in Huntington’s disease, 18, 83, 85, 86 use in Parkinson’s disease, 58, 59, 63 use in Wilson’s disease, 109, 123, 125–126 Antiretroviral therapy, 271, 284–285 protease inhibitors, 285, 289 psychiatric side effects of, 285 reverse transcriptase inhibitors, 284–285 selective serotonin reuptake inhibitor interactions with, 29 Antitestosterone agents, 63 Antithrombotic therapy, 234 Anton’s syndrome, 7 Anxiety disorders, 13 drug-induced, 61, 201, 282, 285, 286 antiparkinsonian agents, 51, 52, 54 in dystonia, 195–197 treatment of, 207 in Fahr’s syndrome, 163, 165 in HIV infection, 281–283 treatment of, 289 in Huntington’s disease, 81–82 treatment of, 87 in hypoparathyroidism, 150 in multiple sclerosis, 260

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Anxiety disorders (continued) in Parkinson’s disease, 41, 50, 54 drug-induced, 51, 52, 54 treatment of, 61–62 pathophysiology of, 232, 233 poststroke, 231–232, 233 treatment of, 240–241 related to medical conditions, 61 in Wilson’s disease, 107, 111 treatment of, 126 Anxiolytics. See also Benzodiazepines; specific drugs hepatic disease and, 36 selective serotonin reuptake inhibitor interactions with, 31–32 Apathy, 4, 6 definition of, 221 distinction from depression, 15 in Fahr’s syndrome, 163 in Huntington’s disease, 78, 80 treatment of, 85 medications for, 15 in Parkinson’s disease, 41, 48 treatment of, 58 pathophysiology of, 58, 221–222 poststroke, 221–222 treatment of, 235 Aphasia, 7, 8, 14, 255, 256, 279 Apomorphine, 235 Apoplexy, 140 Apoptosis, 275 Apraxia, 6, 7, 8, 14, 17, 279 Aprosodia, 7 Arachidonic acid, 275 Aricept. See Donepezil Artane. See Trihexyphenidyl Arthritis, 61 Ascites, 95

Ascorbic acid, 119 Ashkenazi Jews, DYT1 gene in, 187–188 Aspartate, in HIV infection, 275 Aspergillosis, 272 Aspirin, 23, 24 Astemizole, 32 Asterixis, 95 Asthma, 36 Astrocytes, 275 Astrocytoma, 153 Astrogliosis, 275 Ataxia, 10, 11 drug-induced, 34–36 in HIV infection, 279 in multiple sclerosis, 250 in serotonin syndrome, 35 in Wilson’s disease, 96 Ataxia telangiectasia, 191 Ativan. See Lorazepam ATPase (adenosine triphosphatase), P-type, 99 ATP7B gene, 99–100, 113 Attention deficits, 8, 201, 254, 279 Auditory evoked potentials, in Wilson’s disease, 105, 122 Autoimmune disorders, in hypoparathyroidism, 147, 150 Azathioprine, 261 Babinski sign, 9, 190 Baclofen use in dystonia, 201, 202 use in Huntington’s disease, 82 BAL (British anti-Lewisite) for Wilson’s disease, 113, 119 Balance impairment, 17, 42–43 Ballismus, 9–10, 10 BAPTA (bis-o-aminophenoxyethane-N,N,N ,N -tetra-acetic acid), 286

Index

Barbiturates disease interactions with, 20, 22 drug interactions with, 24 Barthel Index, 238 Basal ganglia, 1, 2 in HIV infection, 274, 275 lesions among poststroke patients with depression and/or anxiety disorders, 232, 233 in Wilson’s disease, 100, 105, 109, 123 Basal ganglia calcification (BGC), 137–142. See also Fahr’s syndrome autosomal dominant, 152 autosomal recessive, 152 conditions associated with, 143–156, 144–146, 148–150 familial, 152 frequency of, 137–139 infantile and juvenile, 154–156 X-linked, 152 Basal ganglia–cortical circuits, 1–4 disruption of, 1, 36–37 in dystonia, 5, 186–187 in hemiballismus, 5 in Huntington’s disease, 5, 75 localization of (See Localizing neurological signs and symptoms) in Parkinson’s disease, 5 function of, 1 influences on, 1, 4 projections of, 4, 5 routes of, 2–4, 5 Beck Depression Inventory (BDI), 194–195

309

Behavioral disorders, 7, 16 in dystonia, 200 in HIV infection, 279 in Wilson’s disease, 108 Behavioral therapy, for psychogenic dystonia, 208 Benzodiazepines, 15, 18 disease interactions with, 20–22 cognitive disorders, 34 hip fracture, 34 pulmonary disease, 36 drug interactions with, 24, 25 selective serotonin reuptake inhibitors, 32 for poststroke patients, 240–241 psychiatric side effects of, 200–201 paradoxical disinhibition, 85 risk of falling with, 34, 62 short-acting, 34–35, 127 for tremor, 36 use in dystonia, 201, 202, 205–207 use in Fahr’s syndrome, 170 use in HIV infection, 289 use in Huntington’s disease, 84–86 use in Parkinson’s disease, 62 use in Wilson’s disease, 34, 126, 127 Benztropine, for Parkinson’s disease, 56 Beta-blockers, 26 disease interactions with, 21, 22 drug interactions with, 23 selective serotonin reuptake inhibitors, 26, 27 for tremor, 36, 202 BGC. See Basal ganglia calcification Biogenic amines, 231 Biotinidase deficiency, 155

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Bipolar disorder in dystonia, 193–194 treatment of, 206–207 in Fahr’s syndrome, 164 in Huntington’s disease, 78, 80 treatment of, 85–86 in hypoparathyroidism, 150 in multiple sclerosis, 258 in Parkinson’s disease, 48, 53 Bis-o-aminophenoxyethaneN,N,N ,N -tetra-acetic acid (BAPTA), 286 Bladder dysfunction, 250, 251, 260, 279 Bladder outlet obstruction, 33 Blepharospasm, 180, 199, 203 Blindness, cortical, 7 Blood-brain barrier, 251, 274 Blood dyscrasias, 22, 36 Bone marrow suppression, 119, 124, 125 Botox. See Botulinum A toxin Botulinum A toxin, 83, 201 Bowel dysfunction, 250, 251, 260, 279 “Boxcarring,” 76 Bradycardia, 124 Bradykinesia in Huntington’s disease, 73, 74 in Parkinson’s disease, 41, 42, 48 in Wilson’s disease, 96, 110 Bradyphrenia, 41, 45–48 Brain calcifications, 137–142. See also Fahr’s syndrome Brain stem in HIV infection, 275 in multiple sclerosis, 250 in Wilson’s disease, 100 British anti-Lewisite (BAL) for Wilson’s disease, 113, 119

Broca’s aphasia, 7 Bromocriptine, 15 for dystonia, 201 for neuroleptic malignant syndrome, 126, 168 for Parkinson’s disease, 55, 58 psychiatric side effects of, 52, 53 Brucellosis, 153 Bupropion disease interactions with, 20 dysautonomia and orthostatic hypotension, 33 heart disease, 26 seizure disorders, 33, 126, 287 selective serotonin reuptake inhibitor interactions with, 31 for sexual dysfunction, 33 use in Fahr’s syndrome, 169, 170 use in HIV infection, 287 use in Parkinson’s disease, 58–60 use in Wilson’s disease, 126 BuSpar. See Buspirone Buspirone disease interactions with, 21 cognitive disorders, 34 movement disorders, 35, 36 pulmonary disease, 36 dystonia induced by, 190, 204, 207 use in Fahr’s syndrome, 170 use in HIV infection, 289 use in Parkinson’s disease, 62 use in Wilson’s disease, 126 Caffeine, 28 Calcinosis nucleorum cerebri. See Fahr’s syndrome

Index

Calcium channel blockers drug interactions with, 23 selective serotonin reuptake inhibitors, 26, 28 for dystonia, 206 use in HIV infection, 286 Calcium metabolism disorders, 140, 143–151, 155–156. See also Fahr’s syndrome Candidiasis, 272 Carbamazepine disease interactions with, 20, 22 gait disorders, 34 drug interactions with, 23–24 selective serotonin reuptake inhibitors, 30 valproate, 33 Fahr’s syndrome and, 154 for poststroke mania, 238 use in dystonia, 201, 206 use in HIV infection, 288 use in Huntington’s disease, 84, 86 Carbon monoxide poisoning, 138 Cardiac conduction defects, 20, 26 Cardiomyopathy, 140 Cataracts in hypoparathyroidism, 147 in Wilson’s disease, 97 Catatonia depression and, 15 distinction from parkinsonism, 15 HIV infection and, 279 mania and, 15 trazodone-induced, 207 in Wilson’s disease, 106, 107, 109 Catechol-O-methyltransferase (COMT), 56, 288

311

Caudate nucleus, 2, 2, 5, 6, 9 calcification in Fahr’s syndrome, 141, 157–160 in Huntington’s disease, 74 in Wilson’s disease, 100 Cavitation, in Wilson’s disease, 99, 100 CD4/CD8 ratio, 259, 274 CD4 cells in HIV infection, 273–274, 282, 285 CD8 cells in HIV infection, 274 Centers for Disease Control and Prevention (CDC), 272 Centrum semiovale calcification, 157 Cerebellar rebound, 10–11 Cerebellar signs, 6, 9, 10, 10–12 Cerebellum, 11 calcification in Fahr’s syndrome, 141, 157–158 in Wilson’s disease, 100, 109 Cerebral cortex, 1, 74 calcification in Fahr’s syndrome, 157 cortical and subcortical signs, 8–9, 9 disruption of basal ganglia– cortical circuits, 1, 36–37 in HIV infection, 275 lesions among poststroke patients with depression and/or anxiety disorders, 232, 233 in Wilson’s disease, 99 Cerebral glucose metabolism, in Wilson’s disease, 100, 105, 122 Cerebral infarction. See Stroke Cerebral metabolic rate, in Parkinson’s disease, 46

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Cerebrospinal fluid (CSF) findings in Aicardi-Goutieres syndrome, 154–155 in dystonia, 186 in Fahr’s syndrome, 140 in multiple sclerosis, 252 Cerebrovascular accident. See Stroke Ceruloplasmin differential diagnosis of abnormal levels of, 104 in Wilson’s disease, 94, 99, 102, 103, 105 Chemotherapy agents, 29 Chlorpromazine, 125 disease interactions with, 20 drug interactions with, 24 use in HIV infection, 283 Choline acetyltransferase, 58 Cholinesterase inhibitors, 58 Chondrocalcinosis, 151 Chorea differential diagnosis of, 72 L-dopa–induced, 55 in Fahr’s syndrome, 140 in Huntington’s disease, 72–73 in hypoparathyroidism, 150 as localizing sign, 9, 10, 75 in Wilson’s disease, 94, 96 Choreoathetosis in Fahr’s syndrome, 140, 160 in Huntington’s disease, 73 Chromosomes. See Genetics; specific disorders Chronic obstructive pulmonary disease, 36 Cirrhosis, in Wilson’s disease, 94, 95 Cisapride, 28 Citalopram, 26 drug interactions with, 27–32 for poststroke patients, 236, 239–240

Clarithromycin, 29 Clinical presentation of neuropsychiatric disorders, 15–16 Clomipramine disease interactions with, 20–21 seizure disorders, 33 for obsessive-compulsive disorder, 87 selective serotonin reuptake inhibitor interactions with, 31 use in Huntington’s disease, 84, 87 Clonazepam, 35 cognitive disorders and, 34 selective serotonin reuptake inhibitor interactions with, 32 use in dystonia, 202, 206–207 use in Huntington’s disease, 84–86 use in Parkinson’s disease, 62 use in Wilson’s disease, 127 Clonidine drug interactions with, 23 for poststroke mania, 238 Clozapine, 19 disease interactions with, 20–22 movement disorders, 35 seizure disorders, 33 drug interactions with, 23 selective serotonin reuptake inhibitors, 30 side effects of, 125 agranulocytosis, 59 dystonia, 190 use in dystonia, 201, 205 use in Fahr’s syndrome, 169

Index

use in Huntington’s disease, 85 use in Parkinson’s disease, 19, 21, 35, 58, 59 use in Wilson’s disease, 125 Clozaril. See Clozapine Clumsiness, 72–74 Coats’ disease, 156 Coccidioidomycosis, 272 Codeine, 27 Cogentin. See Benztropine Cognex. See Tacrine Cognitive disorders, 14 drug-induced, 201 in dystonia, 192 in Fahr’s syndrome, 139, 161–163, 162 in HIV infection, 276–279 HIV-1–associated cognitive/ motor complex, 278–279 HIV-1–associated minor cognitive/motor disorder, 277 treatment of, 283–286 in Huntington’s disease, 72–73, 78–79 treatment of, 83–84 in multiple sclerosis, 252–256 attention and informationprocessing speed, 254 cognitive emotional processing disorders, 256 conceptual and executive ability, 255 dementia, 256 disease severity and, 253 intrahemispheric and interhemispheric transfer, 255–256 language, 255 learning and memory, 254

313

screening for, 252–253 treatment of, 262–263 visual information processing, 255 in Parkinson’s disease, 41, 46–49 Lewy body dementia, 47–48 treatment of, 57–58 pathophysiology of, 220, 253–254 poststroke, 220 depression and, 220, 221, 235 treatment of, 234–235 psychotropic drug therapy and, 20–21, 34 in Wilson’s disease, 106, 107, 121 Cognitive enhancers for Fahr’s syndrome, 170 for multiple sclerosis, 263 for Parkinson’s disease, 58 selective serotonin reuptake inhibitor interactions with, 29 Collagen, 97 Coma, 140 Communication disorders, 4, 6, 14. See also Aphasia; Speech Compliance with drug therapy, 18, 117 Compulsions, 6. See also Obsessive-compulsive disorder Computed tomography (CT) in dystonia, 191 in Fahr’s syndrome, 157, 158 frequency of basal ganglia calcification on, 137–139 in Huntington’s disease, 76 in Wilson’s disease, 100, 105, 127 COMT (catechol-Omethyltransferase), 56, 288 Confrontation-naming tests, 255

314

Psychiatric Management in Neurological Disease

Confusion drug-induced, 34 antiparkinsonian agents, 41, 52, 53, 55, 63 reverse transcriptase inhibitors, 285 in HIV infection, 279 in serotonin syndrome, 35 Congestive heart failure, 20, 147 Constipation, 61 Constructional apraxia, 6, 7 Contractures, 17 in Huntington’s disease, 74 in Wilson’s disease, 94 Conversion disorder, 13 dystonia and, 185–186, 208 Coordination problems, 72–74 Copper differential diagnosis of abnormal levels of, 104 in drinking water and diet, 120 drugs to reduce toxic levels of, 113–119 effects of excessive accumulation of, 97–98 hepatic, 102, 103, 104 physiological importance of, 97 urinary, 102, 103, 104, 122 in Wilson’s disease, 93, 94, 98–99, 102, 122 Coronary artery disease, 20 Corpus callosum, in multiple sclerosis, 253, 255–256, 259 Cortical blindness, 7 Cortical dementia, 8, 9 Corticosteroids for basal ganglia calcification and MELAS, 165 for multiple sclerosis, 261, 263 psychiatric symptoms induced by, 260

Cost of neurological disorders. See Economic cost of neurological disorders Criminality, 108 Crying, pathological, 16 in multiple sclerosis, 257 poststroke, 222 Pathological Laughter and Crying Scale for assessment of, 235–236, 237 treatment of, 235–236 in Wilson’s disease, 108 Cryptococcosis, 272, 276 CSF. See Cerebrospinal fluid findings CT. See Computed tomography Cuprimine. See Penicillamine Cyclophosphamide, 261 Cyclosporine, 29 Cysteine, 275 Cytochrome P450-related drug interactions with selective serotonin reuptake inhibitors, 19, 26, 27–32, 126–127 Cytokines, 251 Cytomegalovirus, 272 Dantrolene, 125–126, 168, 286 ddC, 285 ddI, 285 Dedo procedure, 203 Delirium, 14 drug-induced anticholinergic agents, 19 antiparkinsonian drugs, 52, 53 clozapine, 35 reverse transcriptase inhibitors, 285 dystonia and, 190, 200

Index

in HIV infection, 276 treatment of, 283–284, 284 in Huntington’s disease, 79, 80, 85 in hypoparathyroidism, 150 Delusions antiparkinsonian agent–induced, 41, 51–53, 52, 55 in Fahr’s syndrome, 160, 164 in Huntington’s disease, 80, 81, 85–87 poststroke, 222 in Wilson’s disease, 106, 109, 110 Dementia, 14 Alzheimer’s, 78, 79, 220 basal ganglia calcification and, 153 treatment of, 58, 64, 263 cortical versus subcortical, 8, 9 in Fahr’s syndrome, 140, 162, 163 in HIV infection, 276–279 treatment of, 284–286 in Huntington’s disease, 73, 75, 78–79 in hypoparathyroidism, 150 multi-infarct, 220 in multiple sclerosis, 256 in Parkinson’s disease, 41, 46–48 Lewy body dementia, 47–48 treatment of, 57–58 in Wilson’s disease, 107, 121 Dementia Rating Scale, 107 Demyelination in HIV infection, 275 in multiple sclerosis, 249–251, 255–256 Denervation procedures, for dystonia, 203 Denial, right-hemisphere, 14

315

Depen. See Penicillamine Depo-Provera. See Medroxyprogesterone L-Deprenyl. See Selegiline Depression, 6, 14–15 catatonia and, 15 distinction from apathy, 15 drug-induced, 260–261 in dystonia, 193–195 treatment of, 207 in Fahr’s syndrome, 163–165, 166–167 treatment of, 169–170 forme fruste presentation of, 15 in HIV infection, 280–281 treatment of, 287–289 in Huntington’s disease, 72, 78, 80–81 diagnosis of, 81 treatment of, 86–87 in hypoparathyroidism, 150 in multiple sclerosis, 258–259 etiology of, 258–259 immune mechanisms and, 259 prevalence of, 258 psychological stress and, 259 treatment of, 263 in Parkinson’s disease, 15, 41, 48–50, 53 drug-induced, 51, 52 treatment of, 59–61 pathophysiology of, 166–167, 227–231, 229–231, 233 poststroke, 225–231 basal ganglia or cortical lesions and, 232, 233 cognitive impairment and, 220, 221, 235 diagnosis of, 226 DSM criteria for, 225–226

316

Psychiatric Management in Neurological Disease

Depression (continued) poststroke (continued) duration of, 226–227, 229, 231 gender and, 227 lesion location and severity of, 227–230, 229–231 prevalence of, 226, 227 right-hemisphere lesions and, 224, 225, 230–231 treatment of, 238–240, 239 in Wilson’s disease, 110–112 frequency of, 106, 107, 110 treatment of, 126, 127 Dermatological disorders, Fahr’s syndrome and, 154 Desipramine for anorgasmia, 33 cognitive disorders and, 34 seizure threshold and, 33 selective serotonin reuptake inhibitor interactions with, 31 use in HIV infection, 287 use in multiple sclerosis, 263 use in Parkinson’s disease, 60 Desyrel. See Trazodone Dexamethasone, 29 Dextromethorphan, 27 Diagnosis. See clinical recognition and/or laboratory investigation under specific neurological disorders Diagnostic dilemmas, 15 Diazepam, 31 Didanosine, 285 Diet, Wilson’s disease and, 120 Diffuse cerebral microangiopathy, 156 Digitoxin, 23 Digoxin, 23

Dihydropteridine reductase deficiency, 155 1,25-Dihydroxyvitamin D, 150, 151 Diltiazem, 23, 28 Dimercaprol for Wilson’s disease, 113, 119 Diplopia, 34, 250 Disconnection syndromes in multiple sclerosis, 255–256 Disinhibition, 4, 6, 14, 75 drug-induced, 21, 34, 85 in Wilson’s disease, 108, 110, 111, 121, 126 Dissociation, 34 Disulfiram, 207 Divalproex sodium. See Valproate Dizocilpine, 286 Donepezil, 170 for multiple sclerosis, 263 for Parkinson’s disease, 58 selective serotonin reuptake inhibitor interactions with, 29 L-Dopa, 55, 58 central nervous system effects of, 55 for dementia, 57 drug interactions with, 25, 35–36 monoamine oxidase inhibitors, 36, 60–61 for dystonia, 188, 202 other drugs used with, 56–57 for pathological affect, 34 psychiatric side effects of, 52, 53, 201 use in Fahr’s syndrome, 168 “wearing-off” phenomenon with, 55, 56

Index

L-Dopa/carbidopa

for dystonia, 202 for Parkinson’s disease, 53, 55, 63 Dopamine dystonia and, 193 Parkinson’s disease and, 45–46, 48 Dopamine beta-hydroxylase, 97, 186 Dopamine D2 receptor binding in dystonia, 190 in Wilson’s disease, 100, 105, 114, 122 Dopaminergic therapy for dystonia, 201 for Parkinson’s disease, 18, 54–55, 58, 64 psychiatric side effects of, 15, 35, 51–54, 52, 59, 201 Dorsolateral prefrontal circuit involvement, 4, 6, 75 Down syndrome, 152, 156 Doxepin, 287 Drinking water, Wilson’s disease and, 120 Drug-disease interactions, 20–22 blood dyscrasias, 36 cognitive disorders, 34 dysautonomia and orthostatic hypotension, 33 gait disorders, 34–35 heart disease, 26 hepatic disease, 36 movement disorders, 35–36 pathological affect, 34 pulmonary disease, 36 renal disease, 36 seizure disorders, 33

317

Drug-drug interactions, 18, 19, 23–25, 124 cytochrome P450-related interactions with selective serotonin reuptake inhibitors, 19, 26, 27–32, 126–127 “Drunk driving test,” 11 D4T, 285 Dysarthria, 8, 9, 14 drug-induced, 35 in Fahr’s syndrome, 140–141, 163 in Huntington’s disease, 72 in hypoparathyroidism, 147 in Wilson’s disease, 94, 96, 108 Dysautonomia in multiple sclerosis, 250 in Parkinson’s disease, 42, 43 psychotropic drug therapy and, 20, 33, 205 in Shy-Drager syndrome, 43 Dyscalculia, 7 Dysdiadochokinesia, 10–12, 96 Dysexecution, 4, 6, 8. See also Executive function deficits Dyskinesia drug-induced L-dopa, 35 trazodone, 207 psychogenic, 13 tardive, 160, 206 in Wilson’s disease, 108 Dysmetria, 10, 11 Dysphagia botulinum A toxin–induced, 201 in Huntington’s disease, 72–74 Dysphonia, spasmodic, 180 Dysport. See Botulinum A toxin

318

Psychiatric Management in Neurological Disease

Dysrhythmias psychotropic drug therapy and, 20, 26 in Wilson’s disease, 124 Dysthymia, 13, 193 Dystonia, 9, 179–209 action specificity of, 185 age at onset of, 180 clinical and laboratory investigation of, 190–192 clinical recognition and neurological presentation of, 180–186 distinction from conversion disorder, 185–186 forms and distribution, 180, 184 gender considerations and pregnancy, 184–185 initial signs and associated features, 184 dopa-responsive, 188, 202 drug-induced, 126, 190 amoxapine, 126 L-dopa, 56 neuroleptics, 35, 123, 125, 190, 194 economic cost of, 3 etiologies of, 181–184, 187–190 in Fahr’s syndrome, 140 focal versus generalized, 180 genetics of, 181, 187–189 in Huntington’s disease, 74 incidence of, 3 leaning truncal, 190 as localizing sign, 9, 10 multifocal, 180 myoclonic, 188–189 neuroimaging in, 190 neurological management of, 201–203

nonprimary, 180, 184 Oppenheim’s (DYT1), 181, 188 oromandibular, 180 pathophysiology of, 5, 186–188 peripheral, 184 prevalence of, 3, 179 primary, 180, 187 psychiatric features of, 192–201 anxiety disorders, 195–197 behavioral disorders, 200 cognitive impairment, 192 drug-induced, 200–201 eating disorders, 197 mood disorders, 193–195 personality disorders, 199–200 psychosis, 192–193 somatoform disorders and psychogenic dystonia, 13, 186, 197–199, 198 substance abuse disorders, 199 psychiatric management of, 203–208 electroconvulsive therapy, 36 general supportive treatment, 204 pharmacotherapy, 204–208 anxiety disorders, 207 bipolar disorders, 206–207 depression, 207 psychosis, 205–206 substance abuse disorders, 207–208 psychogenic dystonia, 208 segmental, 180 selective serotonin reuptake inhibitors and, 35, 123 sporadic primary torsion, 188 support groups for, 203–204 tardive, 185, 190, 194, 203, 205, 206

Index

unilateral hemidystonia, 190 vocal cord, 14, 190 in Wilson’s disease, 94, 96, 108 Dystonia Medical Research Foundation, 203–204 DYT1 gene, 181, 187–188 Eating disorders, in dystonia, 197 ECA (Epidemiologic Catchment Area) study, 193, 197 ECG (electrocardiography), 26, 124, 283 Economic cost of neurological disorders, 1, 3, 36 ECT. See Electroconvulsive therapy EEG. See Electroencephalography 18q22.2 deletion syndrome, 189 Elastin, 97 Eldepryl. See Selegiline Elderly persons and psychotropic drug therapy, 18–19, 34 Electrical stimulation of brain, for parkinsonism, 57, 63 Electrocardiography (ECG), 26, 124, 283 Electroconvulsive therapy (ECT), 36 in Fahr’s syndrome, 170 in Huntington’s disease, 86–87 in Parkinson’s disease, 36, 61 for poststroke patients, 240 in Wilson’s disease, 127 Electroencephalography (EEG) in Fahr’s syndrome, 139, 160 in HIV infection, 280, 283 in Wilson’s disease, 105 Electrolyte imbalances, 276 Electromyography (EMG), 187, 191 Electroretinography, 191

319

ELISA (enzyme-linked immunosorbent assay), 273 EMG (electromyography), 187, 191 Emotional lability, 4, 6, 14. See also Pathological emotions in Fahr’s syndrome, 163 poststroke, 222 in Wilson’s disease, 108 Emotional processing disorders, 256 Empathy, 14 Emphysema, 61 Empowering patient and family, 298 “En bloc” movements, 42 Enalapril, 23 Encainide, 27 Encephalitis, 153, 156 Endocrine disorders, Fahr’s syndrome and, 143–151, 148–150 Enkephalin, 46 Enzyme-linked immunosorbent assay (ELISA), 273 Epidemiologic Catchment Area (ECA) study, 193, 197 Epilepsy. See Seizures Episodic dyscontrol, 14, 79 Epstein-Barr virus, 156 Erythromycin, 29 Eskalith. See Lithium Estrogen, 29 Estrogen replacement therapy, for Parkinson’s disease, 58 Ethics of predictive testing for Huntington’s disease, 77 Ethosuximide, 30 Euphoria, in multiple sclerosis, 257 Evoked potential studies in dystonia, 187, 191 in multiple sclerosis, 254 in Wilson’s disease, 105, 110, 122

320

Psychiatric Management in Neurological Disease

Executive function deficits, 4, 6, 8 in Fahr’s syndrome, 161 in multiple sclerosis, 255 in Parkinson’s disease, 41, 45–47 poststroke, 220 Exercise, 17 Expanded Disability Status Scale, 252 Eye movements. See Oculomotor dysfunction Facial masking, 42 Facial weakness and numbness, 250 Factitious disorder, 13 Fahr’s syndrome (FS), 137–171 age at onset of, 142 clinical and laboratory investigation in, 160–161 clinical course of, 137 clinical recognition and neurological presentation of, 8, 138–141 correlation with sites of brain calcification, 141 diagnostic criteria, 138–139 distinction from other brain calcifications, 138 neurological features, 10, 139–141, 140 economic cost of, 3 idiopathic and primary, 138, 142 incidence of, 3 modes of inheritance of, 142, 151–152 neuroimaging in, 157–160, 158, 159 neurological management of, 165–168 pathophysiology of, 141–142, 163

prevalence of, 3, 137–138 psychiatric features of, 161–165 anxiety disorders, 165 cognitive impairment and dementia, 161–163 correlation with etiology, 161 frequency of, 161, 162 mood disorders, 164–165 personality changes, 165 psychosis, 163–164 substance abuse disorders, 165 psychiatric management of, 168–170 secondary, etiologies of, 142–156, 144–146 anticonvulsant drugs, 154 dermatological disorders, 154 endocrine disorders, 143–151, 148–150 genetic associations, 142, 151–152 infantile and juvenile basal ganglia calcification, 145–146, 154–156 infectious and immunological diseases, 153 mitochondrial myopathies, 152–153 neoplastic diseases, 153–154 neurological and degenerative diseases, 153 vitamin D metabolism disorders, 151 Falls, 18, 34, 62, 73 Family management issues, 297–303 avenues of approach, 297–298 empowering patient and family, 298 family therapy, 13, 37, 298

Index

Lazarus–Folkman model, 297 listening, 298 normalizing family experience, 298 reinforcing appropriate family roles, 298 family effects of neurological disease, 15, 297 genetic counseling, 15, 37, 204 (See also Genetic testing) other programs, 299 related to HIV infection, 301–302 related to Huntington’s disease, 299–300 related to multiple sclerosis, 300–301 related to stroke, 300 support groups, 16–17, 298–299 (See also Support groups) Fatigue, 250, 251 Fetal mesencephalic tissue transplantation, for parkinsonism, 57, 63 Fever, in serotonin syndrome, 35 Finger-to-nose (FTN) test, 11 Flecainide, 27 Flumazenil, 124 Fluoxetine, 19 disease interactions with heart disease, 26 hepatic disease, 36 drug interactions with, 27–32 selegiline, 35 for poststroke depression, 235 use in dystonia, 207 use in HIV infection, 287 use in Parkinson’s disease, 60 Fluphenazine, 33, 83 Flurazepam, 34

321

Fluvoxamine drug interactions with, 27–32 use in HIV infection, 287 Foot conditions, 18 Fornix, 11 Free radicals, 97, 142, 251 Freezing, parkinsonian, 17, 42, 50 Fried syndrome, 152 Frontal circuit signs, 4–6, 6, 7 Frontal release signs, 6 Frontal-subcortical circuits, 43–45, 45 FS. See Fahr’s syndrome FTN (finger-to-nose) test, 11 Full Scale IQ, 107 GABA. See Gamma-aminobutyric acid GAD. See Generalized anxiety disorder Gait disturbance, 17 drug-induced, 18 dystonia and, 184 in Fahr’s syndrome, 140 gait hesitancy, 17–18 in Huntington’s disease, 73 “marche en petit pas,” 42 in Parkinson’s disease, 41, 42 psychogenic, 13 psychotropic drug therapy and, 21, 34–35 tandem gait, 11 vitamin deficiency and, 18 Gamma-aminobutyric acid (GABA) copper inhibition of GABA-A receptors, 97 Parkinson’s disease and, 46 Gangliosidoses, 155, 191 Gastrointestinal drugs, 28

322

Psychiatric Management in Neurological Disease

Gastrointestinal side effects of dimercaprol, 119 of penicillamine, 114 of trientine, 118 of zinc, 116 Gender dystonia and, 185 multiple sclerosis and, 249 Parkinson’s disease and, 43 poststroke depression and, 227 Generalized anxiety disorder (GAD) in dystonia, 195–196, 207 in HIV infection, 282 in Huntington’s disease, 81 in Parkinson’s disease, 50 poststroke, 231–232, 233, 241 Genetic counseling, 15, 37, 204 Genetic testing for DYT1 gene, 188 for Huntington’s disease, 77 for Wilson’s disease, 123 Genetics of dystonia, 181, 187–189 of Fahr’s syndrome, 142, 151–152 of Huntington’s disease, 71, 75–76 of multiple sclerosis, 251 of Wilson’s disease, 99–100 Gerstmann syndrome, 7 Geste antagonistique, 185 Glabellar tap reflex, 6 Glatiramer acetate, 261, 262 Globus pallidus, 1, 2, 2–4, 5, 9, 11 calcification in Fahr’s syndrome, 141, 142, 157–160, 158, 159 in dystonia, 186–187, 190 electrical stimulation of, for parkinsonism, 57 in Huntington’s disease, 74

in Parkinson’s disease, 43 in Wilson’s disease, 100, 101 Glucose metabolism, in Wilson’s disease, 100, 105, 122 Glutamate in HIV infection, 275 in Parkinson’s disease, 46 gp120, 275 Grasp reflex, 6 Grief, 15, 301 Guilt, 15, 60 Haldol. See Haloperidol Hallervorden-Spatz disease, 138, 191 Hallucinations drug-induced, 201 antiparkinsonian agents, 41, 51–53, 52, 55 in Fahr’s syndrome, 162, 163–164 in Huntington’s disease, 80, 81, 85 poststroke, 222–223 Hallucinosis auditory, 193 peduncular, 222 tactile, 16 Haloperidol intravenous, 284, 284 for poststroke psychosis, 223 selective serotonin reuptake inhibitor interactions with, 30 use in dystonia, 201–202, 206 use in Fahr’s syndrome, 169 use in HIV infection, 283–284 use in Huntington’s disease, 83 use in Parkinson’s disease, 59 Hamilton Rating Scale for Depression (HAMD), 238–239, 239

Index

HD. See Huntington’s disease Head injury, 153 Headache, in Fahr’s syndrome, 140 Heart disease, 20, 26, 61, 205 Heel-to-shin (HTS) test, 11 Hemiballismus, 5 Hemidystonia, unilateral, 190 Hemineglect, 6, 7, 14 Hemiparesis, 9 Hemiplegia, 9 Hepatic adenocarcinoma, 118 Hepatic disease psychotropic drug therapy and, 21, 36, 124 in Wilson’s disease, 94, 95, 97–99, 102 treatment strategies and, 120 Hepatic encephalopathy, 95, 99, 107, 124 Hepatocerebral syndrome, in Wilson’s disease, 106 Hepatolenticular degeneration. See Wilson’s disease Herpes simplex virus, 272 Hexobarbital, 30 Hidrotic-ectodermal dysplasia, 154 Hip fracture, 34 Hippocampus, 11 HIV. See Human immunodeficiency virus infection Holoceruloplasmin, 99 Homocarnosine, 152 Homovanillic acid, 186 Hopelessness, 15 HTS (heel-to-shin) test, 11 Human immunodeficiency virus (HIV) infection, 271–290 clinical recognition and neurological features of, 9, 272, 272–273

323

dystonia and, 189, 205 economic cost of, 3 family management issues in, 301–302 incidence of, 3 laboratory investigation in, 273–274 mortality from, 271, 272 neuroimaging in, 275 neurological and psychiatric management of, 283–289 anxiety disorders, 289 delirium, 283–284, 284 dementia, 284–286 mood disorders, 287–289 psychosis, 286 pathophysiology of, 274–275 basal ganglia calcification, 153, 155, 156 pregnancy and, 273 prevalence of, 3, 271–272 psychiatric manifestations of, 276–283 anxiety disorders, 281–283 delirium, 276 dementia, 256, 276–279, 277–279 mood disorders and suicidality, 280–281 psychosis, 280 sexual disorders, 283 substance abuse disorders, 273, 280 viral load determination in, 274, 275 Huntingtin protein, 76 Huntington Society of Canada, 84 Huntington’s disease (HD), 9, 71–87 age at onset of, 72, 75–76 genetic anticipation and, 76

324

Psychiatric Management in Neurological Disease

Huntington’s disease (HD) (continued) basal ganglia–cortical circuits in, 5 clinical recognition and neurological presentation of, 8, 72–74 clinical course, 72–73 movement disorder, 4, 72–74 economic cost of, 3 family management issues in, 299–300 genetics and theories of pathogenesis of, 71, 75–76 geographic distribution of, 71–72 incidence of, 3 laboratory investigation and predictive testing for, 77 life expectancy in, 73 mode of inheritance of, 71, 75 neuroimaging in, 76 neurological management of, 71, 82–83 treatment of movement disorder, 83 treatment of underlying disease progression, 82–83 pathophysiology of, 5, 74–76 prevalence of, 3, 71–72 psychiatric management of, 83–87 anxiety, 87 apathy, 85 bipolar disorder, 85–86 cognitive impairment and dementia, 83–84 depression, 86–87 irritability and aggressiveness, 84–85

obsessive-compulsive disorder, 87 psychosis, 85 sexual disorders, 87 psychiatric symptoms of, 78–82 anxiety disorders, 81–82 apathy, 80 cognitive impairment and dementia, 72–73, 78–79 irritability and aggressiveness, 79 mood disorders, 80–81 psychosis, 80 sexual disorders, 82 suicidal behavior, 73, 78, 81 support groups for, 84 Vonsattel score of severity of, 74 Huntington’s Disease Society of America, 84 Hyperactivity, 5, 9 in Wilson’s disease, 108, 110, 111, 121 Hyperammonemia, 155 Hypercalcemia, 151 Hyperparathyroidism, 146, 149–150, 151 Hyperphosphatemia, 150 Hyperreflexia, 9, 279 Hypersexuality, 14. See also Sexual disorders antiparkinsonian druginduced, 51, 52, 54, 63 in Huntington’s disease, 82 in Wilson’s disease, 108, 110, 111, 121 Hypertension, 20 Hypertensive crisis, drug-induced, 22, 36 Hypertonia, 279 Hyperventilation, 150 Hypesthesia, 250

Index

Hypnosis, 13, 208 Hypoactive sexual desire disorder, 82. See also Sexual disorders Hypocalcemia, 140, 150 Hypoglycemia, 276 Hypoglycemic agents, 29 Hypokinetic disorders, 9. See also Bradykinesia Hypomania, 258, 280 Hypoparathyroidism, 140, 143–150, 148 clinical features of, 147–150 laboratory findings in, 150 modes of inheritance of, 147 postthyroidectomy, 147 primary, 147, 150 treatment of, 150, 165 Hypophonia, 14 Hypotension, orthostatic, 18 in Fahr’s syndrome, 141 in Parkinson’s disease, 43 psychotropic drug therapy and, 20, 33, 287 Hypothyroidism, 58 Hypoventilation, 36 Hypoxemia, 276 Idebenone, for Huntington’s disease, 82 IL-1B (interleukin-1B), 275 Illusions, 201 Imipramine selective serotonin reuptake inhibitor interactions with, 31 use in Fahr’s syndrome, 170 use in HIV infection, 287 use in Parkinson’s disease, 59 Immobility, 18 Immunological disorders Fahr’s syndrome and, 153

325

multiple sclerosis and, 251, 259 Immunosuppressants, 261 Impotence. See also Sexual disorders in Huntington’s disease, 82 in multiple sclerosis, 260 in Parkinson’s disease, 43, 51 Impulsivity, 4, 6 in Huntington’s disease, 78 in Wilson’s disease, 107, 108, 110, 111, 126 Incidence of dystonia, 3 of Fahr’s syndrome, 3 of HIV infection, 3 of Huntington’s disease, 3 of multiple sclerosis, 3, 249 major depression in, 258 of neurological disorders, 3 of Parkinson’s disease, 3, 43 of stroke, 3, 219 of Wilson’s disease, 3, 93 Incontinence, 250, 251 Indinavir, 29 Infantile neuraxonal dystrophy, 156 Infections Fahr’s syndrome and, 153, 156 HIV infection, 271–290 opportunistic, in HIV infection, 272, 276, 279 parkinsonism and, 44 respiratory tract, 61 urinary tract, 61 Information-processing speed, in multiple sclerosis, 254 Interferon-beta-1a, 261 Interferon-beta-1b, 260–261 Interhemispheric transfer deficits, in multiple sclerosis, 255–256 Interleukin-1B (IL-1B), 275

326

Psychiatric Management in Neurological Disease

Intermittent explosive disorder, 79 International Huntington Association, 84 Internuclear ophthalmoplegia, 250 Intracranial hypertension, in Fahr’s syndrome, 140 Intrahemispheric transfer deficits, in multiple sclerosis, 255–256 Iron deficiency, 118 Iron transport defect, 142 Irritability in Huntington’s disease, 72, 75, 78, 79 treatment of, 84–85 in Wilson’s disease, 106, 108, 110 treatment of, 126 IT15 gene, 71, 75–76 Jews, DYT1 gene in, 187–188 Judgment, impaired, 4, 79 Kaposi’s sarcoma, 272 Kayser-Fleischer (KF) rings, 94–97, 96, 101, 102, 104, 122 Kearns-Sayre syndrome, 153 Ketoconazole, 29 KF (Kayser-Fleischer) rings, 94–97, 96, 101, 102, 104, 122 Kidney disease, 21, 36 Klonopin. See Clonazepam Kyphoscoliosis, 184 Laboratory investigation in dystonia, 190–192 in Fahr’s syndrome, 160–161 in HIV infection, 273–274 in Huntington’s disease, 77 in multiple sclerosis, 251–252 in Wilson’s disease, 101–105, 103 Lamivudine, 285

Laughter, pathological, 16 in multiple sclerosis, 257 poststroke, 222 Pathological Laughter and Crying Scale for assessment of, 235–236, 237 treatment of, 235–236 in Wilson’s disease, 108 Lead poisoning, 138 Learning, 8, 13 in multiple sclerosis, 254 Leigh’s syndrome, 192 Lenticular nucleus, 2 Lesch-Nyhan syndrome, 191 Leukodystrophy, 156, 191 Leukoencephalitis, 156 Leuprolide, 87 Lewy bodies, 46–48 Lewy body dementia, 47–48 treatment of, 58, 64 Libido, increased. See Hypersexuality Lidocaine, 28 Limbic system, 1 Lipid-lowering agents, 28 Lipoid proteinosis, 154 Lipomembranous polycystic osteodysplasia, 154 Listening, 298 Lisuride, for dystonia, 201 Lithium disease interactions with, 20–21 cognitive disorders, 34 gait disorders, 34 movement disorders, 36 renal disease, 36 seizure disorders, 33 drug interactions with, 23, 25 for pathological affect, 34 for poststroke mania, 238

Index

use in dystonia, 201, 206 use in Fahr’s syndrome, 169 use in HIV infection, 288 use in Huntington’s disease, 86 use in Parkinson’s disease, 61, 63 use in Wilson’s disease, 124, 126 Liver disease psychotropic drug therapy and, 21, 36, 124 in Wilson’s disease, 94, 95, 97–99, 102 treatment strategies and, 120 Liver transplantation, for Wilson’s disease, 120 Localizing neurological signs and symptoms, 6, 7–8, 75 cerebellar signs, 6, 9, 10, 10–12 cortical and subcortical signs, 8–9, 9 frontal circuit signs, 4, 6 movement disorders, 9–10 tremors, 12 Locus coeruleus, 11, 46 Loneliness, 17 Loratadine, 32 Lorazepam, 35 hepatic disease and, 36 use in HIV infection, 283, 289 use in Huntington’s disease, 86 use in Parkinson’s disease, 62 use in Wilson’s disease, 127 Loss of consciousness, in Fahr’s syndrome, 140 Lovastatin, 28 Lung disease, 22, 36 Lupron. See Leuprolide Lupus, 153 Lymphocyte subpopulations in HIV infection, 273 in multiple sclerosis, 259

327

Lymphoma, central nervous system, 272 Macrophages, 274–275 Macular degeneration, 154 Magnetic resonance imaging (MRI) in dystonia, 190, 191 in Fahr’s syndrome, 157, 159, 160 in HIV infection, 275 in Huntington’s disease, 76 in multiple sclerosis, 250–252, 258, 259 in Wilson’s disease, 100, 101, 105, 114, 117, 122 Major histocompatibility complex, 251 Malingering, 13 Mania, 4, 6, 75. See also Bipolar disorder catatonia and, 15 distinction from other behaviors, 16 drug-induced, 260, 285 antiparkinsonian agents, 15, 41, 51, 52, 53–54, 63 in dystonia, 194 in Fahr’s syndrome, 164 in HIV infection, 280 treatment of, 288 poststroke, 223–224 right-hemisphere lesions and, 224, 225 treatment of, 237–238 in Wilson’s disease, 106, 109–110 treatment of, 126 MAOIs. See Monoamine oxidase inhibitors

328

Psychiatric Management in Neurological Disease

Maprotiline disease interactions with, 20, 33 selective serotonin reuptake inhibitor interactions with, 31 “Marche en petit pas,” 42 Medial frontal circuit involvement, 4, 6 Medroxyprogesterone, 87 Meige’s syndrome, 200–202 Melanin, 97 MELAS (mitochondrial myopathy, encephalopathy, lactacidosis, and stroke-like syndromes), 153, 165 Memantine, 286 Memory impairment, 7, 8, 14 drug-induced, 34 in Fahr’s syndrome, 163 in Huntington’s disease, 78 in multiple sclerosis, 253, 254 in Parkinson’s disease, 41 in Wilson’s disease, 107, 121 Meningitis, 156 Menkes’ disease, 99 Mental disorders due to general medical condition, 14 Mental retardation, Fahr’s syndrome and, 152, 156, 162, 163 Mephobarbital, 30 MERRF (myoclonic epilepsy and myopathy with ragged red fibers), 153, 156 Mesoridazine, 33 Metabolic diseases, Fahr’s syndrome and, 145–146, 155–156 Metacarpophalangeal joint hyperextension, 10, 10

Metachromatic leukodystrophy, 191 Methotrexate, 261 Methoxyhydroxyphenylglycol, 186 N-Methyl-D-aspartate (NMDA) receptor, 275, 286 Methylphenidate for pathological affect, 34 for poststroke patients, 240 use in HIV infection, 286, 288 use in Parkinson’s disease, 58 Methylprednisolone, 261 Metoclopramide, 25, 33, 204 Metoprolol, 27 Mexiletine, 27 Meyerson’s sign, 6 Mianserin, 31 Microcephaly, 154 Microglia, 275 Micrographia, 42, 94 Midazolam, 31 Midbrain, in Wilson’s disease, 100 Mini-Mental State Exam (MMSE), 78, 221, 235, 252 Minnesota Multiphasic Personality Inventory (MMPI), 192–193, 196, 200 Mirapex. See Pramipexole Mirtazapine selective serotonin reuptake inhibitor interactions with, 31 use in HIV infection, 287 Mitochondrial copper accumulation, 97 Mitochondrial myopathies, Fahr’s syndrome and, 152–153, 156 Mitochondrial myopathy, encephalopathy, lactacidosis, and stroke-like syndromes (MELAS), 153, 165

Index

Mitochondrial ophthalmoplegia, 153 MK-801, 286 MMPI (Minnesota Multiphasic Personality Inventory), 192–193, 196, 200 MMSE (Mini-Mental State Exam), 78, 221, 235, 252 Mobility, 17 Moclobemide, 31 Molindone, 33 use in HIV infection, 283 Monoamine oxidase, 97 Monoamine oxidase inhibitors (MAOIs) disease interactions with, 20–22 hepatic disease, 36 seizure disorders, 33 drug interactions with, 23–25 L-dopa, 36, 60–61 selective serotonin reuptake inhibitors, 31 serotonergic agents, 35 sympathomimetics, 33 use in HIV infection, 288 use in Huntington’s disease, 86 use in Parkinson’s disease, 56 Monocytes, 274 Mood disorders, 13, 15. See also specific mood disorders drug-induced, 201 in dystonia, 193–195 treatment of, 206–207 in Fahr’s syndrome, 162, 164–165, 166–167 treatment of, 169–170 in HIV infection, 280–281 treatment of, 287–289 in Huntington’s disease, 78, 80–81 treatment of, 85–87

329

in multiple sclerosis, 258–259 treatment of, 263 in Parkinson’s disease, 41, 48–50, 53–54 treatment of, 59–61 poststroke, 223–231 treatment of, 237–240, 239 in Wilson’s disease, 107, 109–111 treatment of, 126 Moralism, 16 “Motor loop,” 45 Motor neuron disease, 8, 9, 10, 153, 250 Movement disorders, 17, 37 with diverse, distributed neurological findings, 8–9 in dystonia, 180 economic cost of, 3 in Fahr’s syndrome, 139, 140, 140 in Huntington’s disease, 72–74, 83 in hypoparathyroidism, 150 as localizing signs, 9–10 with minimal other neurological findings, 8 in Parkinson’s disease, 41, 42 prevalence of, 3 psychogenic, 12–13, 13, 186, 197–199, 198, 208 psychotropic drug therapy and, 21, 35–36 in Wilson’s disease, 94, 95, 96 MRI. See Magnetic resonance imaging MS. See Multiple sclerosis Multinucleated giant cells, 275 Multiple myeloma, 153

330

Psychiatric Management in Neurological Disease

Multiple sclerosis (MS), 249–264 age at onset of, 249 ambulatory status in, 250–251 clinical course of, 250 clinical recognition and neurological presentation of, 9, 250–251 definition of, 249 economic cost of, 3 employment and, 250–251 family management issues in, 300–301 genetics of, 251 incidence of, 3, 249 laboratory investigation in, 251–252 life expectancy in, 251 neuroimaging in, 250–252 neurological management of, 261 pathophysiology of, 251 pregnancy and, 250 prevalence of, 3, 249, 251 primary progressive, 250 psychiatric features of, 252–261 anxiety disorders, 260 bipolar disorder, 258 cognitive disorders, 252–256 attention and informationprocessing speed, 254 cognitive emotional processing disorders, 256 conceptual and executive ability, 255 dementia, 256 disease severity and, 253 intrahemispheric and interhemispheric transfer, 255–256

language, 255 learning and memory, 254 screening for, 252–253 visual information processing, 255 depression and suicidality, 258–259 drug-induced, 260–261 euphoria, 257 pathological emotions, 257 personality changes, 260 psychosis, 257–258 sexual disorders, 260 psychiatric management of, 261–263 affective disorders, 263 cognitive disorders, 262–263 racial and gender distribution of, 249 secondary progressive, 250 support groups for, 263 Muscular dystrophy, 156 Mutations. See Genetics; specific disorders Mutism, 279 Mycobacterial infection, 272 Myectomy, for dystonia, 203 Myoclonic dystonia, 188–189 Myoclonic epilepsy and myopathy with ragged red fibers (MERRF), 153, 156 Myoclonus in Fahr’s syndrome, 140 in Huntington’s disease, 73, 74 as localizing sign, 9, 10 psychogenic, 13 selective serotonin reuptake inhibitors and, 34, 35, 126 in serotonin syndrome, 35 Myopathy, 285

Index

Naltrexone, 208 National Center for the Study of Wilson’s Disease, 113 National Multiple Sclerosis Society, 263 National Organization for Rare Disorders, 17 National Spasmodic Torticollis Association, 203 Nefazodone drug interactions with, 27–32 for poststroke patients, 240 use in HIV infection, 287 Nelfinavir, 29 Neoplasia basal ganglia calcification and, 153–154, 156 in HIV infection, 272 selective serotonin reuptake inhibitor interactions with chemotherapy agents for, 29 Nephrolithiasis, 151, 156 Neurobrucellosis, 153 Neurofibromatosis, 156 Neuroimaging in dystonia, 190 in Fahr’s syndrome, 157–160, 158, 159 in HIV infection, 275 in Huntington’s disease, 76 in multiple sclerosis, 250–252 in Parkinson’s disease, 46, 47 in Wilson’s disease, 100, 101, 105 Neuroleptic malignant syndrome (NMS), 21, 35, 123, 125–126, 168, 190, 205, 286 Neuroleptics. See Antipsychotics Neurological disorders distinction from psychiatric disorders, 15

331

dystonia, 179–209 economic cost of, 1, 3, 36 Fahr’s syndrome, 137–171 family management issues for, 15, 297–303 in HIV infection, 271–290 Huntington’s disease, 71–87 incidence of, 3 localizing signs and symptoms of, 6, 7–8 cerebellar signs, 6, 9, 10, 10–12 cortical and subcortical signs, 8–9, 9 frontal circuit signs, 4, 6 movement disorders, 9–10 tremors, 12 multiple sclerosis, 249–264 Parkinson’s disease, 41–64 pathophysiology of, 5 personality characteristics of, 16 prevalence of, 3 psychiatric management of, 13–36 nonpharmacological treatment, 14–18 pharmacological treatment, 18–36 psychogenic movement disorders, 12–13 resources for information about, 17 self-help books on, 16 stroke, 219–242 support groups for, 16–17 Wilson’s disease, 93–128 Neurological management of dystonia, 201–203 of Fahr’s syndrome, 165–168 of HIV infection, 284–285 of Huntington’s disease, 82–83 of multiple sclerosis, 261

332

Psychiatric Management in Neurological Disease

Neurological management (continued) of Parkinson’s disease, 54–57 of stroke, 232–234 of Wilson’s disease, 113–123 Neurotoxins, 275 Nifedipine, 28 Nightmares, L-dopa–induced, 55 Nimodipine, 286 Nitric oxide, 251, 275 NMDA (N-methyl-D-aspartate) receptor, 275, 286 NMS (neuroleptic malignant syndrome), 21, 35, 123, 125–126, 168, 190, 205, 286 Nonpharmacological neuropsychiatric treatment, 14–18 concerns related to, 14–15 diagnostic dilemmas and, 15 modalities for, 16–17 novel clinical presentations, 15–16 techniques for, 17–18 Norepinephrine Parkinson’s disease and, 46, 49 poststroke depression and, 230 Norfluoxetine, 19 Normalization of family experience, 298 Norpramin. See Desipramine Nortriptyline cognitive disorders and, 34 for poststroke patients, 235–236, 238, 239 selective serotonin reuptake inhibitor interactions with, 31 use in Huntington’s disease, 86 use in Parkinson’s disease, 60 Nucleus accumbens, 11

Nucleus basalis, 46 Nutritional status, 18 Nystagmus, 35 Obsessions, 6 Obsessive-compulsive disorder (OCD) in dystonia, 195–197, 207 in Fahr’s syndrome, 162, 165 in Huntington’s disease, 82, 87 in Parkinson’s disease, 50, 197 selective serotonin reuptake inhibitors for, 87, 126 Oculomotor circuit involvement, 4, 75 Oculomotor dysfunction, 4 in Huntington’s disease, 73, 75 in Parkinson’s disease, 42, 43 in progressive supranuclear palsy, 43 in Wilson’s disease, 94 Office of Disease Prevention and Health Promotion, 17 Olanzapine, 19, 35 selective serotonin reuptake inhibitor interactions with, 30 use in dystonia, 205 use in Fahr’s syndrome, 168 use in HIV infection, 286 use in Parkinson’s disease, 58, 59 use in Wilson’s disease, 125 Olivopontocerebellar atrophy, 43 Omeprazole, 28 Ophthalmoplegia internuclear, 250 mitochondrial, 153 Oppenheim’s dystonia, 181, 188 Oppositional defiant disorder, 13 Optic neuritis, 250

Index

Orbitofrontal cortex, 11 Orbitofrontal lesions, 4, 6, 6, 14 Ornithine transcarbamylase deficiency, 155 Oromandibular dystonia, 180 Orthostatic hypotension, 18 in Fahr’s syndrome, 141 in Parkinson’s disease, 43 psychotropic drug therapy and, 20, 33, 287 Oxazepam, 35 hepatic disease and, 36 use in HIV infection, 289 use in Wilson’s disease, 127 P300, in multiple sclerosis, 254 Pallidotomy for dystonia, 203 for Parkinson’s disease, 57, 63 Pallilalia, 14 Palmomental reflex, 6 Pamelor. See Nortriptyline Pancreatic lipomatosis, 156 Panic disorder antidepressants for, 126 in dystonia, 195, 207 in HIV infection, 282 in Huntington’s disease, 81 in hypoparathyroidism, 150 in Parkinson’s disease, 50, 62 Papilledema, 140, 147 Papovavirus, 272 Paramyloidosis, 138 Paranoia, 201 Paraparesis, 250 Paraphilias, 82 Parathyroid disorders, Fahr’s syndrome and, 143–151, 148–150 Paresis, 140 Paresthesias, 4, 16, 140, 250

333

Parietal lesions, neurobehavioral signs of, 6, 7 “Parkinson-plus” syndromes, 43 Parkinsonism, 43 in degenerative disorders, 44 depression and, 15 differential diagnosis of, 43, 44 distinction from catatonia, 15 drug-induced, 44, 126 amoxapine, 126 trazodone, 207 dystonia and, 184 in Fahr’s syndrome, 140, 141, 163, 168 freezing, 17, 42, 50 in hypoparathyroidism, 150 infection-related, 44 as localizing sign, 9, 10 metabolic, 44 “Parkinson-plus” syndromes, 43 psychogenic, 13 psychotropic drug therapy and, 35 vascular, 44 in Wilson’s disease, 96, 123 Parkinson’s disease (PD), 9, 41–64 age at onset of, 42 clinical recognition and neurological presentation of, 42–43 economic cost of, 3 gender distribution of, 43 incidence of, 3, 43 life expectancy in, 42 motor symptoms of, 4, 41, 42 neuroimaging in, 46, 47 neurological management of, 54–57 amantadine, 56–57 anticholinergic agents, 56–57 catechol-O-methyltransferase inhibitor, 56

334

Psychiatric Management in Neurological Disease

Parkinson’s disease (PD) (continued) neurological management of (continued) dopamine agonists, 18, 54–55 monoamine oxidase type B inhibitors, 56 surgical procedures, 57 pathophysiology of, 5, 43–46, 45 pregnancy and, 43 prevalence of, 3, 41–42 psychiatric management of, 57–63 anxiety disorders, 61–62 apathy, 58 dementia, 57–58 depression, 59–61 drug-induced disorders, 63 electroconvulsive therapy, 36, 61 psychiatric sequelae of surgery, 63 psychosis, 59 sexual disorders, 62 psychiatric symptoms of, 41, 46–54, 64 anxiety disorders, 50, 54 apathy and bradyphrenia, 48 cognitive disorders/ dementias, 41, 46–48 drug-induced, 51–54, 52 mood disorders, 48–50, 53–54 sexual dysfunction, 43, 51 suicidal behavior, 49, 60 risk factors for, 42 support groups for, 57 Parlodel. See Bromocriptine Paroxetine anticholinergic effects of, 33 disease interactions with, 20 hepatic disease, 36

drug interactions with, 27–32 use in HIV infection, 287 use in Parkinson’s disease, 60 Pars compacta, 4, 5 Pars reticulata, 5 Pathological emotions, 16 as localizing symptoms, 10 in multiple sclerosis, 257 pathophysiology of, 222, 257 poststroke, 222 treatment of, 34, 235–236 in Wilson’s disease, 108 Pathological Laughter and Crying Scale (PLACS), 235–236, 237 Pathology, 1–4, 5 of central nervous system HIV infection, 274–275 of dystonia, 186–187 of Fahr’s syndrome, 141–142, 163 of Huntington’s disease, 74–75 of multiple sclerosis, 251 of Parkinson’s disease, 43–46, 45 of Wilson’s disease, 97–99 Pathophysiology. See also Pathology of anxiety in stroke, 232, 233 of apathy in Parkinson’s disease, 58 in stroke, 221–222 of cognitive impairment in multiple sclerosis, 253–254 in stroke, 220 of depression in Fahr’s syndrome, 166–167 in multiple sclerosis, 258–259 in stroke, 227–231, 229, 230, 231, 233 of dystonia, 5, 186–187 dopa-responsive dystonias, 188

Index

of euphoria in multiple sclerosis, 257 of Fahr’s syndrome, 142 of hemiballismus, 5 of HIV infection, 274–275 of Huntington’s disease, 5, 75–76 of mania, 5 in multiple sclerosis, 258 in stroke, 224 of multiple sclerosis, 251 of neurological disorders, 5 of Parkinson’s disease, 5, 45 45–46 of pathological emotions in multiple sclerosis, 257 in stroke, 222 of psychosis in multiple sclerosis, 257–258 of sexual disorders in stroke, 232 of stroke, 219 of Wilson’s disease, 97–98, 99–100 Paxil. See Paroxetine PCR (polymerase chain reaction), 275 PD. See Parkinson’s disease Pedunculopontine nucleus, 11 Penicillamine for Wilson’s disease, 114–116 dose and administration of, 114 efficacy of, 114 indications for, 113 monitoring therapy with, 116 other drugs used with, 119 for patients with liver disease, 120 for pregnant patients, 121–122 pyridoxine and, 114 side effects of, 114–116, 115

335

Pergolide for Parkinson’s disease, 55, 58 psychiatric side effects of, 52, 53 Peripheral neuropathy, 285 Peritoneal dialysis, for Wilson’s disease, 120 Permax. See Pergolide Perphenazine, 30 Perseveration, 4, 6, 79, 255 Personality changes, 7, 14 due to general medical condition, 14 apathetic type, 15 in Fahr’s syndrome, 162, 165 in multiple sclerosis, 260 in Wilson’s disease, 107, 108, 110 Personality characteristics of neurological disorders, 16 Personality disorders, 13 in dystonia, 199–200 PET. See Positron-emission tomography Pet therapy, 17 Phacomatosis, 138 Phenacetin, 27 Phenobarbital drug interactions with, 24 for poststroke psychosis, 236 Phenytoin disease interactions with, 20 drug interactions with, 23, 24 selective serotonin reuptake inhibitors, 30 Fahr’s syndrome and, 154 Phobias in dystonia, 195–196 Parkinson’s disease and, 50 Phosphodiesterase inhibitors, 28 Phospholipase A2, 275 Physical therapy for psychogenic movement disorders, 13

336

Psychiatric Management in Neurological Disease

Pimozide, 30 Pisa syndrome, 190 Placebo therapy, 13 PLACS (Pathological Laughter and Crying Scale), 235–236, 237 Plasmapheresis, 120, 261 Platelet-activating factor, 275 Polymerase chain reaction (PCR), 275 Pons calcification in Fahr’s syndrome, 158 in Wilson’s disease, 100 Portal hypertension, 36, 120 Positron-emission tomography (PET) in dystonia, 190 in Huntington’s disease, 76 in Parkinson’s disease, 46, 47 in Wilson’s disease, 100, 105 Posterior ramisectomy, for dystonia, 203 Posttraumatic stress disorder (PTSD), 282 Potassium disulfide, 119 Pramipexole, for Parkinson’s disease, 55, 58 Prednisolone, 115 Pregnancy dystonia and, 185 HIV infection and, 273 multiple sclerosis and, 250 Parkinson’s disease and, 43 Wilson’s disease and, 121–122 Premature ejaculation, 51 Presymptomatic testing. See Genetic testing Prevalence of neurological disorders, 3 Primitive reflexes, 6 Progeria, 154

Progressive hepatolenticular degeneration. See Wilson’s disease Progressive supranuclear palsy, 42, 43, 192, 207, 256 Propafenone, 23, 27 Propionic acidemia, 155 Propranolol drug interactions with, 23 selective serotonin reuptake inhibitors, 27 for tremor, 207 use in Wilson’s disease, 126 Proprioception, 17 Prosopagnosia, 7 Protease inhibitors, 285 drug interactions with, 289 selective serotonin reuptake inhibitors, 29 Protriptyline, use in HIV infection, 287 Provera. See Medroxyprogesterone Prozac. See Fluoxetine Pseudo-pseudohypoparathyroidism, 143–147, 149, 151 Pseudohypoparathyroidism, 143, 147, 149, 150–151 Psychiatric disorders delayed development of compound syndromes, 18 diagnostic dilemmas, 15 in dystonia, 192–201 in Fahr’s syndrome, 161–165, 162 forme fruste presentations of, 15, 16, 124, 125, 169, 196 in HIV infection, 276–283 in Huntington’s disease, 73, 78–82 in multiple sclerosis, 252–261

Index

neuropsychiatric treatment and, 14–15 novel clinical presentations of, 15–16 in Parkinson’s disease, 41, 46–54 poststroke, 220–232 in Wilson’s disease, 102, 105–111 Psychiatric management, 13–36 of dystonia, 203–208 of Fahr’s syndrome, 168–170 of HIV infection, 283–289 of Huntington’s disease, 83–87 of multiple sclerosis, 261–263 nonpharmacological, 14–18 of Parkinson’s disease, 57–63 pharmacological, 18–36 poststroke, 234–241 of Wilson’s disease, 123–127 Psychogenic movement disorders, 12–13 dystonia, 13, 186, 197–199, 198, 208 Psychomotor slowing, 4, 6, 8, 9, 279 Psychoneuroimmunology, 259 Psychosis, 15, 16 drug-induced, 35 in dystonia, 192–193 treatment of, 205–206 in Fahr’s syndrome, 162, 163–164 treatment of, 168–169 in HIV infection, 280 treatment of, 19, 286 in Huntington’s disease, 78, 80 treatment of, 85 in hypoparathyroidism, 150 in multiple sclerosis, 257–258 in Parkinson’s disease, 51, 64 treatment of, 59 pathophysiology of, 257–258

337

poststroke, 222–223 treatment of, 236–237 in Wilson’s disease, 107, 109 treatment of, 125–126 Psychotherapy for family, 13, 37, 298 for multiple sclerosis, 263 for Parkinson’s disease, 61 for psychogenic dystonia, 208 for Wilson’s disease, 112–113 Psychotropic drug therapy, 13, 18–36 antidepressants, 19 atypical antipsychotics, 19 choice of drugs for, 18 double-blind, placebo-controlled studies of, 18 drug-disease interactions, 20–22 blood dyscrasias, 36 cognitive disorders, 34 dysautonomia and orthostatic hypotension, 33 gait disorders, 34–35 heart disease, 26 hepatic disease, 36 movement disorders, 35–36 pathological affect, 34 pulmonary disease, 36 renal disease, 36 seizure disorders, 33 drug-drug interactions, 18, 19, 23–25 cytochrome P450-related, with selective serotonin reuptake inhibitors, 19, 26, 27–32 for dystonia, 204–208 for elderly persons, 18–19 for Fahr’s syndrome, 168–170 for HIV infection, 283–289

338

Psychiatric Management in Neurological Disease

Psychotropic drug therapy (continued) for Huntington’s disease, 83–87 for multiple sclerosis, 262–263 noncompliance with, 18 for Parkinson’s disease, 57–63 for poststroke patients, 234–241 for Wilson’s disease, 123–127 PTSD (posttraumatic stress disorder), 282 Pulmonary disease, 22, 36 Putamen, 2, 2, 5, 9, 101 calcification in Fahr’s syndrome, 141, 157–158 in dystonia, 190 in Huntington’s disease, 74 in Parkinson’s disease, 43 in Wilson’s disease, 100, 105 Pyramidal tract signs, 190 Pyridoxine, 114 Quantified Neurologic Examination (QNE), 73 Quazepam, 21 Quetiapine, 19, 35 selective serotonin reuptake inhibitor interactions with, 30 use in dystonia, 205 use in Fahr’s syndrome, 168 use in Wilson’s disease, 125 Quinidine, 23, 28 Quinolinic acid, 275 Radiation therapy, 153–154, 156 total lymphoid irradiation, 261 Rapid tranquilization, 286 Recklessness, in Wilson’s disease, 108 Reflexes, primitive, 6 Rehabilitation programs, 17

Reinforcement of appropriate family roles, 298 Religiosity, 16 Remorse, 16 Remoxipride, 30 Renal disease, 21, 36 Repression, organic, 14 Requip. See Ropinirole Restoril. See Temazepam Retrieval deficits, 8, 9. See also Memory impairment in Huntington’s disease, 78 in multiple sclerosis, 254 in Parkinson’s disease, 41 Reverse transcriptase inhibitors, 284–285 Rheumatoid arthritis, juvenile, 156 Rhizotomy, for dystonia, 203 Rigidity, 9 cogwheel, 41, 42 in Huntington’s disease, 73, 74 in Parkinson’s disease, 41, 42, 56 plastic, 42 in progressive supranuclear palsy, 43 in Wilson’s disease, 110 Risperdal. See Risperidone Risperidone, 19, 35 cognitive disorders and, 34 dystonia induced by, 190, 206 selective serotonin reuptake inhibitor interactions with, 30 use in dystonia, 205 use in Fahr’s syndrome, 168 use in HIV infection, 19, 286 use in Parkinson’s disease, 59 use in Wilson’s disease, 125 Ritalin. See Methylphenidate Ritonavir, 29 Root reflex, 6

Index

Ropinirole, for Parkinson’s disease, 55, 58 Rorschach test, 196 Saccadic intrusions, 4 Saquinavir, 29 Schizophrenia. See also Psychosis dystonia and, 193 Huntington’s disease and, 80 Seborrheic dermatitis, 43 Sedating agents, 18, 21 Sedation, drug-induced, 34 Segawa’s syndrome, 188 Seizures in Fahr’s syndrome, 138–141, 140, 153, 170 in HIV infection, 279 in Huntington’s disease, 73, 74 in hypoparathyroidism, 147 in multiple sclerosis, 250 poststroke, 223, 236, 238 psychotropic drug therapy and, 20, 33, 126, 287 in Wilson’s disease, 94, 95, 124 Selective serotonin reuptake inhibitors (SSRIs). See also specific drugs disease interactions with, 20–21 cognitive disorders, 34 dysautonomia and orthostatic hypotension, 33 heart disease, 26 movement disorders, 35 seizure disorders, 33 drug interactions with, 23, 24, 124 cytochrome P450-related, 19, 26, 27–32, 126–127 L-dopa, 35 serotonergic agents, 35

339

dystonia induced by, 190, 204, 207 for obsessive-compulsive disorder, 87, 126 for pathological emotions, 34, 236 for poststroke patients, 236, 239–241 use in Fahr’s syndrome, 170 use in HIV infection, 287 use in Huntington’s disease, 84, 86 use in multiple sclerosis, 263 use in Parkinson’s disease, 60 use in Wilson’s disease, 126 Selegiline dosage of, 56 drug interactions with, 25, 35 antidepressants, 35, 60 insomnia induced by, 56 for Parkinson’s disease, 56, 60 psychiatric side effects of, 52, 53 Self-help books, 16, 37 Sensorimotor circuit involvement, 4 Sensory deficits, 9, 10, 17 Sensory tricks, 185, 202 Septum, 11 Serial Sevens Task, 78 Serotonin Parkinson’s disease and, 46, 49, 60 poststroke depression and, 230 Serotonin agonists, 25 Serotonin syndrome, 21, 25, 35 Sertraline drug interactions with, 27–32 heart disease and, 26 use in HIV infection, 287 use in Huntington’s disease, 84, 86 use in multiple sclerosis, 263 use in Parkinson’s disease, 60

340

Psychiatric Management in Neurological Disease

Set shifting, 41 Sexual disorders, 14, 15 bupropion for, 33 drug-induced, 33 antiparkinsonian agents, 41, 52, 54 in HIV infection, 283 in Huntington’s disease, 82 treatment of, 87 in multiple sclerosis, 260 in Parkinson’s disease, 41, 43, 51, 52, 54 treatment of, 62 pathophysiology of, 232 poststroke, 232 treatment of, 241 in Wilson’s disease, 108, 110, 111 Shame, 15 Shy-Drager syndrome, 18, 42, 43 Sialorrhea, 42 Sinemet. See L-Dopa/carbidopa Single-photon emission computed tomography (SPECT), in Wilson’s disease, 100, 105 Sleep disturbances, 15 drug-induced antiparkinsonian agents, 41, 51, 52, 54, 56, 63 reverse transcriptase inhibitors, 285 stimulants, 286 Smoking, Parkinson’s disease and, 42 Social embarrassment, 204 Social phobia dystonia and, 195 Parkinson’s disease and, 50 Social withdrawal, 17, 78 Sodium 2,3-dimercaptopropane sulfonate, 119 Soft tissue calcification, 147

Somatization disorder, 13, 16 Somatosensory evoked potentials in dystonia, 191 in Wilson’s disease, 122 Spasticity, 9, 140, 250, 279 Spatial disorientation, 7, 8 SPECT (single-photon emission computed tomography), in Wilson’s disease, 100, 105 Speech. See also Aphasia cerebellar, 10, 12, 14 disorders of, 14 in Fahr’s syndrome, 140–141 in Huntington’s disease, 73 parkinsonian hesitancy of, 14 reduced verbal fluency, 4, 6, 6 sparse verbal output, 4, 6 in Wilson’s disease, 94 Spiperone, 230 Spironolactone, 23 SSRIs. See Selective serotonin reuptake inhibitors Stavudine, 285 Steatosis, 97–98 Steroids, 36, 61 selective serotonin reuptake inhibitor interactions with, 29 Stiff man syndrome, 13 Stimulants disease interactions with, 20 drug interactions with, 23, 24 for poststroke patients, 222, 240 side effects of, 286 use in HIV infection, 286, 288 Stimulus-bound phenomena, 4, 6 Striatal dishing, 10, 10 Striatal toe, 10, 10, 184 Striatum, 1, 2, 5 calcification in Fahr’s syndrome, 157

Index

clinical findings related to disease of, 6 in Huntington’s disease, 74 in Parkinson’s disease, 45 in Wilson’s disease, 100, 109 Striopallidodentate calcification. See Fahr’s syndrome Stroke, 9, 219–242 economic cost of, 3 family management issues in, 300 heart disease and, 26 HIV infection and, 272, 273 hypertension and, 219 incidence of, 3, 219 neurological management of, 232–234 acute support, 232–234 antithrombotic and thrombolytic therapy, 234 pathophysiology of, 219 prevalence of, 3, 219 psychiatric management of, 234–241 anxiety disorders, 240–241 apathy, 235 cognitive impairment, 234–235 depression, 238–240, 239 mania, 237–238 pathological emotions, 235–236, 237 psychosis, 236–237 sexual disorders, 241 psychiatric manifestations of, 220–232 anxiety disorders, 231–232, 233 apathy, 221–222 cognitive impairment, 220

341

depression, 221, 225, 225–231, 227, 229–231 mania, 223–234, 225 pathological emotions, 222 psychosis, 222–223 sexual disorders, 232 seizures and, 223, 236, 238 types of, 219 Subcortical dementia, 8, 9 Subcortical nuclei, 46 Substance abuse disorders, 15 in dystonia, 189, 199 treatment of, 207–208 in Fahr’s syndrome, 162, 165 in HIV infection, 273, 280 in Wilson’s disease, 111 treatment of, 126 Substantia nigra, 4, 5, 9, 11, 45, 46 Subthalamic nucleus, 4, 5, 6, 9 electrical stimulation of, for parkinsonism, 57 Suck reflex, 6 Suicidality, 13, 15 in HIV infection, 281 in Huntington’s disease, 73, 78, 81 in multiple sclerosis, 258, 260–261 in Parkinson’s disease, 49, 60 in Wilson’s disease, 106, 110, 112 Superoxide anion, 275 Superoxide dismutase, 97 Support groups, 16–17, 37, 298–299 for dystonia, 203–204 for Huntington’s disease, 84 for multiple sclerosis, 263 for Parkinson’s disease, 57 for Wilson’s disease, 112–113 Surgical therapy for dystonia, 203 for Huntington’s disease, 83 for Parkinson’s disease, 57, 63 for Wilson’s disease, 120

342

Psychiatric Management in Neurological Disease

Symbol Digit Modalities Test, 254 Symmetrel. See Amantadine Sympathomimetics, 61 drug interactions with, 24, 33 “Symptom searching,” 81 Syncope, in Fahr’s syndrome, 140 Tachycardia, 124, 207, 286 Tacrine, 170 liver function and, 58 selective serotonin reuptake inhibitor interactions with, 29 use in Parkinson’s disease, 58 Tardive dyskinesia, 160, 206 Tardive dystonia, 185, 190, 194, 203, 205, 206 Tardive torticollis, 206 Tasmar. See Tolcapone TCAs. See Tricyclic antidepressants Temazepam, 36, 63 Temporal lobe, 11 Teratogenicity of penicillamine, 121–122 Terfenadine, 32 Testosterone, 29 Tetany, 140, 147 Tetrahydrobiopterin, 186, 188 Tetrathiomolybdate for Wilson’s disease, 118–119 dose and administration of, 118 indications for, 113 for neurological patients, 121 for psychiatric patients, 121 side effects of, 119 storage of, 118 use in children, 118 Thalamotomy for dystonia, 203 for Parkinson’s disease, 57, 63

Thalamus, 2, 4, 5, 6, 9, 11 calcification in Fahr’s syndrome, 141, 157–158 in dystonia, 190 electrical stimulation of, for parkinsonism, 57 in Parkinson’s disease, 43 in Wilson’s disease, 100, 109 Theophylline, 25, 28 Thiazide diuretics, 23 Thioridazine, 30, 33 Thought disorders, 14, 192 3TC, 285 Thrombocytopenia, 94 Thrombolytic therapy, 234 Thyroid disorders, 61 Thyroid replacement therapy, 61 TIAs. See Transient ischemic attacks Tics L-dopa–induced, 55 psychogenic, 13 TNF-α (tumor necrosis factor α), 251, 275 d-alpha-Tocopherol. See Vitamin E Tofranil. See Imipramine Tolbutamide, 29 Tolcapone, for Parkinson’s disease, 56 Torsin A, 187 Torticollis, 180, 194–195, 200–204. See also Dystonia tardive, 206 Toxoplasmosis, 153, 272, 276 Transient ischemic attacks (TIAs), 234 in Fahr’s syndrome, 140, 141 Trazodone bladder outlet obstruction induced by, 33 disease interactions with, 20 cognitive disorders, 34

Index

dystonia induced by, 207 selective serotonin reuptake inhibitor interactions with, 31 for sleep disturbance, 63 use in HIV infection, 287 Treatment options, 37 Tremor action-postural, 12, 21 benzodiazepines for, 36 beta-blockers for, 36, 202 cerebellar terminal kinetic (intention), 10, 10, 12 drug-exacerbated, 21, 36 dystonia and, 184, 207 in Fahr’s syndrome, 140, 163 in Huntington’s disease, 74 as localizing sign, 9, 10, 12 in Parkinson’s disease, 41, 42, 56 propranolol for, 207 psychogenic, 13 resting, 12 rubral, 10, 12 in serotonin syndrome, 35 in Wilson’s disease, 94, 96 Treponemiasis, 272 Triamterene, 23 Triazolam, 34–35 disease interactions with, 21 cognitive disorders, 34 selective serotonin reuptake inhibitor interactions with, 32 use in Wilson’s disease, 127 Tricyclic antidepressants (TCAs). See also specific drugs disease interactions with, 20 cognitive disorders, 34 heart disease, 26 drug interactions with, 23, 24 selective serotonin reuptake inhibitors, 31

343

for poststroke patients, 235–236, 238, 239, 241 use in dystonia, 207 use in Fahr’s syndrome, 170 use in HIV infection, 287 use in Huntington’s disease, 86 use in Parkinson’s disease, 59–60 use in Wilson’s disease, 126 Trientine for Wilson’s disease, 117–118 dose and administration of, 117 indications for, 113 for patients with liver disease, 120 for pregnant patients, 121–122 side effects of, 118 Trifluoperazine, 236 Trihexyphenidyl for dystonia, 202 for Parkinson’s disease, 56 Trinucleotide repeats in DYT1 gene, 188 in IT15 gene, 71, 75–76 Trisomy 5, 152, 156 Trisomy 21, 152, 156 Tuberculosis, 272 Tuberous sclerosis, 153, 156 Tumor necrosis factor α (TNF-α), 251, 275 Tyrosine, 97 Tyrosine hydroxylase, 188 Unified Huntington’s Disease Rating Scale, 73 Upper motor neuron lesions, 8, 9, 10, 250 Urbach-Wiethe disease, 154 Urticaria, 115 Utilization behavior, 4, 6, 6

344

Psychiatric Management in Neurological Disease

Vacuolation, 275 Vaginismus, 51 Valproate disease interactions with, 20–22 gait disorders, 34 movement disorders, 36 drug interactions with, 23, 24 carbamazepine, 33 for poststroke mania, 238 use in dystonia, 201, 206 use in Fahr’s syndrome, 169 use in HIV infection, 288 use in Huntington’s disease, 84, 86 Varicella zoster, 272 Venlafaxine cytochrome P450 inhibition by, 26 disease interactions with, 20 for poststroke patients, 240 selective serotonin reuptake inhibitor interactions with, 31 use in HIV infection, 287 Ventral tegmental area, 11 Ventricular dilatation “boxcarring,” 76 in Wilson’s disease, 99, 100, 110 Verapamil drug interactions with, 23 selective serotonin reuptake inhibitors, 28 for poststroke mania, 238 use in HIV infection, 286 Verbal fluency, reduced, 4, 6, 6 Verbal output, sparse, 4, 6 Vertigo, 140, 250 Vinblastine, 29 Vincristine, 29 Violent behavior. See also Aggressiveness in Huntington’s disease, 79

Viral load in HIV infection, 274, 275 Visual impairment, 7, 251 Visual information processing, in multiple sclerosis, 255 Visuospatial perceptual problems, 17 in Fahr’s syndrome, 161–163 in Huntington’s disease, 79 Vitamin B12, 285 Vitamin C, 119 Vitamin D deficiency, Fahr’s syndrome and, 150, 151, 163 Vitamin deficiency, 18 Vitamin E for Huntington’s disease, 82 for Parkinson’s disease, 42, 58 for Wilson’s disease, 119 Vocal cord dystonia, 14, 190 Vonsattel score, 74 Warfarin, 23, 26, 27 WD. See Wilson’s disease Wechsler Memory Scale, 107 Well Spouse Foundation, 17 Wellbutrin. See Bupropion Wernicke’s aphasia, 7 Wernicke’s encephalopathy, 276 Western blot, 273 White matter in HIV infection, 275 in multiple sclerosis, 252, 255 WHO (World Health Organization), 272 Wilson’s Disease Association, 113 Wilson’s disease (WD), 2, 93–128 age at onset of, 94 animal models of, 100 blood dyscrasia and, 36 clinical course of, 94

Index

clinical recognition and neurological presentation of, 8, 94–97 Kayser-Fleischer rings, 94–97, 96, 101, 102 liver disease, 94, 95, 97–99, 102 neurological features, 10, 94, 95, 96 other nonpsychiatric features, 98 differential diagnosis of, 102, 104 economic cost of, 3 etiology and genetics of, 99–100 carrier frequency of gene, 93 genetic testing, 123 gastrointestinal manifestations of, 109 heart disease and, 26 incidence of, 3, 93 laboratory investigation and diagnosis of, 101–105, 103 life expectancy in, 94 mode of inheritance of, 93 neuroimaging in, 100, 101, 105 neurological management of, 113–123 family considerations and genetic testing, 123 first-line treatments, 113–119 indications for, 113 penicillamine, 114–116, 115 tetrathiomolybdate, 118–119 trientine, 117–118 zinc, 116–117

345

monitoring disease progression and treatment efficacy, 122 other treatments, 119–120 combination strategies, 119 dimercaprol, 119 drinking water and diet, 120 liver transplantation, 120 other drugs, 119 for specific patient populations, 120–122 neurological patients, 121 patients with liver disease, 120 pregnant patients, 121–122 presymptomatic patients, 122 psychiatric patients, 121 pathophysiology of, 97–100 prevalence of, 3, 93 psychiatric features of, 102, 105–111 anxiety disorders, 111 behavioral and personality changes, 108 cognitive impairment, 107 depression and suicidality, 110–112 frequency of, 105–107, 106 functional decline, 108–109 impulse control disorders, 111 mania, 109–110 pathological affect, 108 psychosis, 109 substance abuse disorders, 111

346

Psychiatric Management in Neurological Disease

Wilson’s disease (WD) (continued) psychiatric management of, 123–127 electroconvulsive therapy, 127 psychotropic treatment, 123–127 antidepressants, 126 antipsychotics, 109, 123, 125–126 benzodiazepines, 34, 126, 127 buspirone and selective serotonin reuptake inhibitors, 126–127 identifying targets of, 124–125 mood stabilizers, 126 psychotherapeutic considerations in, 112–113 sites of copper deposition in, 93, 94 support groups for, 112–113 Wisconsin Card Sorting Test, 253, 255 Witzelsucht, 16 Word-list-generation deficits, 41, 255

World Health Organization (WHO), 272 Worthlessness, 15 Writer’s cramp, 180, 184, 189, 194 Zalcitabine, 285 Zidovudine (ZDV), 282, 285 buspirone and, 289 monoamine oxidase inhibitors and, 288 Zinc for Wilson’s disease, 116–117 compliance with, 117 dose and administration of, 116 indications for, 113, 116 monitoring therapy with, 117 for neurological patients, 121 other drugs used with, 119 for pregnant patients, 121–122 for presymptomatic patients, 122 side effects of, 116–117 Zoloft. See Sertraline Zolpidem, 63 Zung Self-Rating Depression Scale, 238 Zyprexa. See Olanzapine