Textbook of Clinical Neuropsychiatry (Hodder Arnold Publication)

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Textbook of Clinical Neuropsychiatry

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Textbook of Clinical Neuropsychiatry DAVID P. MOORE MD Associate Clinical Professor, Department of Psychiatry, University of Louisville School of Medicine, Louisville, Kentucky, USA

A member of the Hodder Headline Group LONDON Co-published in the United States of America by Oxford University Press Inc., New York

First published in Great Britain in 2001 by Arnold, a member of the Hodder Headline Group, 338 Euston Road, London NW1 3BH http://www.arnoldpublishers.com Co-published in the United States of America by Oxford University Press Inc., 198 Madison Avenue, New York, NY10016 Oxford is a registered trademark of Oxford University Press © 2001 Arnold All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronically or mechanically, including photocopying, recording or any information storage or retrieval system, without either prior permission in writing from the publisher or a licence permitting restricted copying. In the United Kingdom such licences are issued by the Copyright Licensing Agency: 90 Tottenham Court Road, London W1P 0LP. Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the author nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular (but without limiting the generality of the preceding disclaimer) every effort has been made to check drug dosages; however it is still possible that errors have been missed. Furthermore, dosage schedules are constantly being revised and new side-effects recognized. For these reasons the reader is strongly urged to consult the drug companies' printed instructions before administering any of the drugs recommended in this book. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN 0 340 80624 9 (hb) 12345678910 Commissioning Editor: Georgina Bentliff Editorial Assistant: Zoe Elliott Production Editor: Rada Radojicic Production Controller: lain McWilliams Cover Design: Terry Griffiths Typeset in 10 on 12 point Ocean Sans by Phoenix Photosetting, Chatham, Kent Printed and bound in Italy by Giunti What do you think about this book? Or any other Arnold title? Please send your comments to [email protected]

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Contents

Preface Acknowledgements

PART 1

1

PART 2

2

3

DIAGNOSTIC ASSESSMENT

xiii xv

1

Diagnostic assessment

3

Diagnostic interview Mental status examination

3 6

Neurologic examination

10

Neuroimaging Electroencephalography

18 24

SIGNS, SYMPTOMS, AND SYNDROMES

49

'Cortical'al'signs and symptomsms Aphasia Alexia

51

51 55

Agraphia

57

Acalculalia

58

Gerstmann's syndrome Hypergraphia Aprosodia Apraxia

59 59 60 62

Agnosias

63

Neglect

68

Abnormal movements Tremor

80 80

Myoclonus

83

Motor tics Chorea Athetosis Ballismus Dystonia Parkinsonism

87 89 93 95 96 101

Akinesia

108

Akathisia

109

viii Contents Catatonia

4

5

6

7

PART 3

8

112

Asterixis

116

Heightened startle response

117

Other signs and symptoms

137

Mutism

137

Akinetic mutism

138

Stuttering

140

Primitive reflexes

141

Pseudobulbar palsy

143

Mimetic, or involuntary, facial palsy

145

Le fou rire prodromique

146

Abulia

147

Environmental dependency syndrome ('utilization behavior')

148

Kluver-Bucy syndrome

149

Alien hand sign

150

'Phantom' and 'supernumerary' limbs

154

Depersonalization

155

Obsessions and compulsions

157

Amusia

159

Foreign accent syndrome

160

Cataplexy

160

Hallucinations and delusions

162

Schneiderian first rank symptoms

169

Syndromes of cognitive impairment

186

Dementia

186

Delirium

202

Amnesia

216

Mental retardation

222

Syndromes of disturbances of mood and affect

254

Depression

254

Mania

261

Anxiety

270

Other major syndromes

285

Psychosis

285

Personality change

293

Seizures and epilepsy

302

SPECIFIC DISORDERS

365

Neurodegenerative disorders

367

Alzheimer's disease

367

Pick's disease

372

Frontotemporal dementia

373

Amyotrophic lateral sclerosis

374

Parkinson's disease

376

Diffuse Lewy body disease

383

Progressive supranuclear palsy

384

Contents ix

9

10

Corticobasal ganglionic degeneration

386

Multiple system atrophy

387

Huntington's disease

388

Neuroacanthocytosis

391

Senile chorea

391

Benign hereditary chorea

392

Dentatorubropallidoluysian atrophy

392

Wilson's disease

393

Autosomal dominant cerebellar ataxia

395

Hallervorden-Spatz disease

397

Dopa-responsive dystonia

398

Primary torsion dystonia

399

Idiopathic cervical dystonia

400

Writer's cramp

401

Meige's syndrome

401

Spasmodic (spastic) dysphonia

402

Tourette's syndrome

403

Myotonia atrophica

405

Cerebrotendinous xanthomatosis

407

Thalamic degeneration

408

Metachromatic leukodystrophy

408

Adrenoleukodystrophy

410

Essential tremor

412

Hyperekplexia

413

Congenital disorders

439

Sturge-Weber syndrome

439

Tuberous sclerosis

441

von Recklinghausen's disease

442

Down's syndrome

443

Klinefelter's syndrome

445

Fragile X syndrome

446

Lesch-Nyhan syndrome

447

Laurence-Moon-Biedl syndrome

448

Prader-Willi syndrome

449

Congenital rubella syndrome

450

Fetal alcohol syndrome

450

Rett's syndrome

451

Autism

452

Vascular disorders

462

Multi-infarct dementia

462

Lacunar dementia

463

Arteriosclerotic parkinsonism

464

Binswanger's disease

465

Cranial arteritis

466

Cerebral amyloid angiopathy CADASIL

467 468

Granulomatous angiitis

469

Polyarteritis nodosa

470

Wegener's granulomatosis

471

x Contents

11

12

13

14

Behcet's syndrome Hypertensive encephalopathy

472 473

Transient global amnesia

474

Trauma Subdural hematoma

481 481

Diffuse axonal injury Dementia pugilistica Post-concussion syndrome Radiation encephalopathy

483 484 485 486

Hypoxic disorders

490

Postanoxic encephalopathy

490

Delayed postanoxic encephalopathy

491

Carbon monoxide poisoning

492

Nutritional, toxic, and metabolic disorders Vitamin B12 deficiency Folic acid deficiency

495 495 498

Pellagra Wernicke's encephalopathy

499 500

Korsakoff's syndrome

502

Manganism Thallium intoxication

503 504

Arsenic intoxication

504

Bismuth intoxication Tin intoxication Lead intoxication

505 506 506

Mercury intoxication Dialysis dementia

507 509

Dialysis disequilibrium syndrome

510

Hypoglycemia

510

Central pontine myelinolysis Uremic encephalopathy Hepatic encephalopathy

512 514 514

Acquired (non-Wilsonian) hepatocerebral degeneration Hepatic porphyria Basal ganglia calcification (Fahr's syndrome)

516 516 518

Infectious disorders Acquired immune deficiency syndrome (AIDS)

527 527

Cytomegalovirus encephalitis Progressive multifocal leukoencephalopathy

530 531

Arbovirus meningoencephalitis

532

Herpes simplex viral encephalitis

533

Encephalitis lethargica Infectious mononucleosis Mumps Varicella-zoster

535 536 537 538

Rabies Post-infectious and post-vaccinial encephalomyelitis

539 540

Subacute sclerosing panencephalitis

542

Contents xi

15

16

17

18

Subacute measles encephalitis Progressive rubella panencephalitis Neurosyphilis

543 544 544

Lyme disease Tuberculosis

547 548

Whipple's disease

549

Rocky Mountain spotted fever Malaria

550 551

Toxoplasmosis

552

Candidiasis Cryptococcosis

553 554

Coccidioidomycosis Histoplasmosis Aspergilllosis

555 555 556

Prion diseases

566

Creutzfeldt-Jakob disease New-variant Creutzfeldt-Jakob disease Gerstmann-Straussler-Scheinker disease

566 569 569

Fatal familial insomnia Kuru

570 571

Endocrinologic disorders Cushing's syndrome

576 576

Adrenocortical insufficiency

578

Hyperthyroidism

580

Hypothyroidism

582

Immune-related disorders Multiple sclerosis Systemic lupus erythematosus Limbic encephalitis

588 588 592 595

Sarcoidosis

596

Hashimoto's encephalopathy Sydenham's chorea

598 599

Chorea gravidarum

601

Sleep disorders Somnambulism REM sleep behavior disorder

611 611 612

Nightmare disorder Pavor nocturnus

614 614

Jactatio nocturna capitis Enuresis

615 616

Narcolepsy

617

Sleep apnea

620

Pickwickian syndrome Kleine-Levin syndrome Restless legs syndrome Nocturnal myoclonus Painful legs and moving toes

622 622 624 625 626

xii Contents 19

20

21

22

Cerebral tumors and hydrocephalus Cerebral tumors Hydrocephalus

633 633 636

Normal pressure hydrocephalus

639

Idiopathic psychotic, mood, and anxiety disorders Schizophrenia Schizoaffective disorder Delusional disorder Postpartum psychosis Bipolar disorder Major depression Premenstrual syndrome Postpartum depression Postpartum blues Panic disorder Agoraphobia Simple (specific) phobia Social phobia Obsessive-compulsive disorder Post-traumatic stress disorder Generalized anxiety disorder

643 643 648 649 650 651 656 659 660 661 662 664 664 665 667 669 670

Intoxications and withdrawals

688

Amphetamines Cocaine Hallucinogens Phencyclidine Alcohol Sedatives, hypnotics, and anxiolytics

688 689 691 692 693 697

Inhalents (solvents) Cannabis Opioids Nicotine Caffeine Methanol Isopropanol

698 699 700 702 702 703 704

Medication and substance-induced disorders Neuroleptic malignant syndrome Tardive dyskinesia Supersensitivity psychosis Rabbit syndrome Serotonin syndrome

712 712 714 717 718 719

Anticholinergic delirium Cholinergic rebound Alcoholic dementia Alcohol hallucinosis Alcoholic paranoia Marchiafava-Bignami disease

720 721 722 722 723 724

Solvent-induced dementia

725

Index

735

Preface

The Textbook of Clinical Neuropsychiatry is a practical, clinically oriented text designed to equip readers to evaluate, diagnose and treat their neuropsychiatric patients. It is divided into three parts: Part I attends to the methodology and technique of the diagnostic assessment, Part II presents the individual signs, symptoms and syndromes seen in neuropsychiatric practice, and Part III provides an encyclopedic coverage of the specific disorders seen in neuropsychiatric practice, in each case covering pathology and etiology, clinical findings, course, differential diagnosis and treatment. In preparing the text, the English language literature was reviewed from 1879 (the inaugural year of the journal Brain) to the present. Thus, in addition to the latest research, readers will also find references to the works of such physicians as Alzheimer, Binswanger, Bleuler, Hughlings Jackson, Kraepelin and Kinnier Wilson. In all, over 4000 references are included, thus providing readers not only with ready access to further detail on any particular subject, but also with a window on the literature as a whole. Neuropsychiatric practice is a rewarding endeavor. I have learned much in writing the Textbook of Clinical Neuropsychiatry and offer it not only as a comprehensive guide for newcomers, but also as a ready reference for established practitioners. I invite you to try using it in your own practice; I think you may well find it as indispensible as I do.

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Acknowledgements

This book is dedicated to my wife, Nancy G. Moore, PhD, my children, Ethan, Nathaniel and Joshua, and my Editor, Georgina Bentliff, who has graciously welcomed me to Arnold.

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1 Diagnostic assessment Diagnostic assessment

3

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1 Diagnostic assessment Diagnostic interview Mental status examination Neurologic examination

3 6 10

Neuroimaging Electroencephalography

18 24

DIAGNOSTIC INTERVIEW Lord Brain (1964) noted that'in the diagnosis of nervous diseases the history of the patient's illness is often of greater importance than the discovery of his abnormal physical signs', a sentiment echoed by Russell Dejong (1979), who asserted that 'a good clinical history often holds the key to diagnosis'. Obtaining the history, however, as noted by Dejong (1979), 'is no simple task [and] may require greater skill and experience than are necessary to carry out a detailed examination'. The acquisition of this skill is, for most, no easy matter, requiring, above all, practice and supervision. Certain points, however, may be made regarding the setting of the interview, establishing rapport, eliciting the chief complaint, the divison of the interview itself into nondirective and directive portions, concluding the interview and the subsequent acquisition of collateral history from family or acquaintances. Even these general points, however, allow exceptions depending on the clinical situation, and the physician must be flexible and prepared to exercise initiative. THE SETTING The interview should ideally be conducted in a quiet and private setting, set apart from distractions and anything that might inhibit patients as they relate the history. Importantly, that means that family and friends should be excused during the interview, as patients may feel reluctant to reveal certain facts in their presence. If the interview takes place at the bedside, the physician should be seated: standing implies that time is short, and some patients, picking up on this cue, may skip over potentially valuable parts of the history in order not to waste the physician's time. In this regard, it is also important that the physician set aside a sufficient amount of time to take the history, which may range from less than a half hour in uncomplicated cases related by cooperative patients, to well over an hour when the history is long and complex, or the patient is unable to cooperate fully.

4 Diagnostic assessment

ESTABLISHING RAPPORT Dejong (1979) noted that 'interest, understanding, and sympathy' are essential to the successful conduct of the interview: patients who experience a sense of rapport with their physicians are more likely to be truthful and forthcoming; hence establishing rapport is of great importance. First impressions carry great weight here: after introducing themselves, physicians should clearly relate their role in the case and then, as suggested by Dejong (1979), display 'kindness, patience, reserve, and a manner which conveys interest' throughout the interview. Provided with such a forum, most patients will, with only minor help, provide the history required to generate the appropriate differential diagnosis. ELICITING THE CHIEF COMPLAINT 'It is well', noted Lord Brain (1964), 'to begin by asking the patient of what he complains.' The chief complaint is the epitome of the patient's illness: lacking such a focus, digressions are almost inevitable, and the history obtained may be of little diagnostic use. Thus, once introductions are out of the way, the first question put by the physician should focus on what brought the patient to the hospital. Critically, as some patients may be reluctant to reveal the actual reason for their coming to the hospital, it is necessary to weigh the chief complaint offered by the patient and ask oneself whether, in fact, it sounds like a plausible reason to seek medical attention. If not, gentle probing is in order and should generally be continued until the actual chief complaint is revealed. Importantly, the physician should never accept at face value a diagnosis offered by a patient: as Bickerstaff (1980) pointed out, 'it must be made absolutely clear what the patient means by his description of his symptoms. By all means put it down in his words first, but do not be content with that... "Black-outs" may mean loss of consciousness, loss of vision, loss of memory, or just loss of confidence.' It may occasionally not be possible to establish a chief complaint during the interview, as may occur with patients who are delirious, demented, severely psychotic or simply hostile and uncooperative. In such cases, persisting overly long in the pursuit of a chief complaint may become counterproductive as patients may become resentful, and it is generally more appropriate to move on to the 'directive' portion of the interview, described later, always being alert, however, to the possibility that the patient may 'slip in' the chief complaint at an unexpected moment. THE NON-DIRECTIVE PORTION OF THE INTERVIEW Once a chief complaint has been established, the patient, as noted by Brain (1964), 'should be allowed to relate the story of his illness as far as possible without interruption, questions being put to him afterwards to expand his statements and to elicit additional information'. Some patients, once asked to expand on the chief complaint, may, with little or no prompting, provide the 'perfect' history, covering each of the following essential points: • • • • • • •

onset including approximate date, mode of onset (acute, gradual or insidious) the presence or absence of any precipitating factors the temporal evolution of various signs and symptoms the presence or absence of any aggravating or alleviating factors treatment efforts and their results pertinent positives and negatives any history of similar experiences in the past.

Diagnostic assessment 5

Most patients will, however, require, at various times, either encouragement or some gentle shepherding. When patients begin to falter in their history, or seem to be leaving items out, it is appropriate to encourage them to talk by asking 'open-ended' questions such as 'Tell me more about that.' Such a method is much to be preferred over the 'question and answer' approach used by many. The problem with the 'question and answer' approach is that many patients will lose the initiative to speak, and simply await questions from the physician, which is all well and good unless, of course, the physician fails to ask the 'right' questions, in which case potentially critical aspects of the history may remain unrevealed. Gentle shepherding may be required in cases where patients digress or take off at a tangent. One should not, of course, rudely pull the patient back to task, but rather tactfully suggest that refocusing on the illness that prompted admission might be more appropriate. Once the essential points have been covered, it is appropriate to summarize briefly what the patient has said in order to be sure that the history as understood by the physician is correct. Patients should be invited to correct any misapprehensions, and once the history is complete, the physician should move on to the directive portion of the interview. THE DIRECTIVE PORTION OF THE INTERVIEW

The directive portion of the interview should be introduced to the patient as a series of perhaps 'routine' questions relating to the patient's overall health. Here, one obtains information regarding the medications that the patient is taking, allergies, the past medical history, a review of systems, the family medical history and, finally, the mental status examination (discussed in the next section). Here, although a question and answer approach is generally appropriate, the physician must always be ready to adopt a non-directive approach should the patient report a symptom or illenss potentially pertinent to the chief complaint. For example, during the review of systems, if the patient affirms that headaches have been present, it is appropriate to stop and ask the patient to elaborate on this, with an eye towards obtaining information regarding each of the essential points described earlier. Questions regarding alcohol or drug use and suicidal or homicidal ideation, if not already covered in the non-directive portion of the interview, must be directly pursued. These are, of course, delicate areas, but if approached in a straightforward and non-judgmental way, it is remarkable how forthcoming, and indeed relieved, some patients may be at being given an opportunity to speak of them. CONCLUDING THE INTERVIEW

Once the directive portion of the interview has been completed, it is appropriate to give the patient an opportunity to speak freely again. Many patients, if asked whether they have anything else to add, will offer important information that they may have either witheld or simply not recalled earlier. Asking patients whether they have anything they wish to ask the physician is also appropriate, as the patients' questions may reveal much about the concerns that brought them to the hospital in the first place. COLLATERAL HISTORY

According to Brain (1964), 'the history obtained from the patient should always be supplemented, if possible, by an account of his illness given by a relative or by someone who knows him well'. It is remarkable how often a collateral history will change a diagnostic impression, guide further testing or alter proposed treatments.

6 Diagnostic assessment

Some have expressed concern that interviewing the family or acquaintances may violate patient confidentiality, but this is simply not the case provided that the contact knows already that the patient is in the hospital and that the physician reveals nothing about the patient while interviewing the collateral contact. No confidentiality is breached by introducing oneself as the patient's physician or by asking collateral contacts what they know about the patient.

MENTAL STATUS EXAMINATION The mental status examination constitutes an essential part of any neuropsychiatric evaluation and, at a minimum, should cover each of the aspects discussed below. GROOMING AND DRESS

Good habits of grooming and dress may suffer in certain illnesses, sometimes with diagnostically suggestive results. In depression, hopelessness, fatigue and anhedonia may make patients give up all hope of maintaining their appearance, with the result that grooming and dress are left in a greater or lesser degree of disarray. Manic patients, overflowing with exuberance, may truly make a spectacle of themselves with decorations of make-up and garish clothing. Patients with psychosis may be quite unkempt and at times dirty, and their clothing may be bizarre, as for example with multiple layers and a woollen cap, even in the summer. GENERAL DESCRIPTION

An overall and general description of the patient's behavior is essential, also giving room for the exercise of whatever literary talents the physician may possess. Comments on the patient's relationship with the interviewer and any evidence of'psychomotor change' (i.e. hyperactivity and psychomotor agitation or retardation) are generally in order. Relationship with the interviewer

In addition to noting whether or not the patient is cooperative, some comment on the quality of the physician-patient rapport is in order as it may be diagnostically suggestive. For example, as noted by Bleuler (1924), there is often a 'defect in ... emotional rapport' (italics in original) in cases of schizophrenia, such that 'the joy of a schizophrenic does not transport us, and his expressions of pain leave us cold ... [and] just as little do the patients sometimes react to our affects'. By contrast, in mania, as noted by Kraepelin (1921), 'the patient feels the need to get out of himself, to be on more intimate terms with his surroundings', such that the physician, willingly or not, often feels engaged, in one fashion or another, with the patient: in the case of a euphoric manic, it is the rare physician who can keep from smiling, and in the case of an irritable manic, most physicians will find themselves becoming, at the very least, on edge. Psychomotor change

When the overall level of psychomotor activity lies outside the realm of normal, one speaks of a psychomotor change as having occurred, which may in turn tend towards either hyperactivity or retardation. Psychomotor hyperactivity should be futher categorized in terms of whether or not the activity is purposeful. For example, whereas in catatonic excitation the behavior is purposeless and often bizarre, in mania 'the patient feels the need to come out of his shell [and] to have livlier relations with those around him' (Kraepelin 1899). In commenting further on this distinction, Kraepelin (1899) noted that 'the catatonic's urge to move often takes place in the

Diagnostic assessment 7

smallest space, i.e. in part of the bed, whereas the manic looks everywhere for an opportunity to be active, and runs around, occupies himself with other patients, follows the doctor and gets into all kinds of mischief. In between these two extremes lies a large range of behaviors that may perhaps best be subsumed under the general rubric of agitation. Psychomotor retardation is characterized by a general slowing of speech and motor behavior, as if the 'clock' has 'run down'. Although this is commonly associated with depression, it may be seen in other disorders, such as hypothyroidism, wherein, as noted by Kraepelin (1899), it may take patients 'an incredibly long time to do the simplest things, to write a letter [or] to get dressed'. MOOD AND AFFECT

Mood is constituted by an individual's prevailing emotional 'tone'. When this is within the broad limits of normal, one speaks of 'euthymia' or a euthymic mood; significant mood disturbances may tend toward depression, anxiety, euphoria or irritability. Depressed mood may be characterized by 'a profound inward dejection and gloomy hopelessness, sometimes more by indefinite anxiety and restlessness' (Kraepelin 1921); in contrast, euphoria is characterized by an 'overflowing contentment' (Griesinger 1882), such patients being 'penetrated with great merriment' (Kraepelin 1921). Irritable patients are typically 'dissatisfied, intolerant [and] fault-finding' (Kraepelin 1921), often quick to react to any perceived slight or criticism. In the case of euphoria or irritability, one should also note whether or not the mood is 'heightened', that is to say whether or not it is so abundant and at such a level that its display in strong affect is simply inevitable: for example, whereas patients with a heightened sense of irritability may be hostile, argumentative and uncontrollably angry, other patients, whose irritability is not heightened, might present a picture of mere sullenness and withdrawal. Affect has been variously defined as representing either the combination of the immmediately present emotion and its accompanying expression in tone of voice, gesture, facial expression, etc., or less commonly, only the emotional expression itself. Importantly, although most of the time an individual's affect arises seamlessly from the mood, the affect may at times temporarily be at variance with the mood. For example, a patient with a depressed mood may, in the presence of a high-spirited interviewer, both feel and display some happiness; after the interview, however, the affect quickly realigns with the mood. Lability is said to be present when there are violent and swift changes in the patient's affect. Such lability of affect is common in mania: Kraepelin (1921) noted that 'in the midst of unrestrained merriment not only are sudden attacks of rage interpolated, but also uncontrollable weeping and sobbing, which certainly give place again just as quickly to unrestrained cheerfulness'. Inappropriate affect is said to be present when patients' affect is incongruent with their thought, as for example would be the case should a patient laugh while thinking of a sad event. Emotional incontinence (or, as Wilson [1928] called it, 'pathological laughing and crying') is characterized by an uncontrollable affective display that occurs in the absence of any corresponding feeling. Thus 'incontinent' of affective display, patients may burst forth into laughter or tears upon the slightest of stimuli and be unable to control themselves despite the lack of any sense of mirth or sadness. DISTURBANCES IN THE FORM OF SPEECH

Disturbance in the form of speech has traditionally included pressured speech, flight of ideas, circumstantiality, tangentiality, neologisms and looseness of associations. To this list may also be added poverty of speech, poverty of thought, thought blocking and obsessions.

8 Diagnostic assessment

Pressure of speech is experienced by the patient as an 'urge to talk' that is so imperious that 'he cannot keep quiet for long, chatters and shouts out loud, yells, roars, bawls, whistles [and] speaks overhastily' (Kraepelin 1899). To be in the presence of such patient is akin to standing in front of a darn bursting with words and thoughts. Flight of ideas is, according to Kraepelin (1921), characterized by a 'sudden and abrupt jumping from one subject to another': before any given thought is even partially developed, the patient's attention lights on another thought, there to stay for only a short time before moving on yet again. Circumstantiality is said to be present when, perhaps in response to a question, patients take the cognitive 'long way round', traversing superfluous details and dead-ended digressions until finally getting around to the answer. In listening to such patients, the interviewer often has to suppress the urge to tell them to 'get to the point'. Tangentiality differs from circumstantiality in that the patients' thought, although coherent, takes off on a 'tangent' from the initial question, never, in fact, getting 'to the point'. Neologisms represent 'made-up' words that exist in a kind of 'private language' for the patient. Looseness of associations represents a kind of incoherence wherein the steps that are taken in the patient's train of thought 'are unintelligible to the normal person, or appear to be so bizarre, that they would never have entered his mind' (Bleuler 1924). Poverty of thought is characterized by a dearth of thoughts: such patients, lacking anything to say, speak very little. By contrast, patients with poverty of speech may speak much. Their speech is, however, 'empty', being filled with so many stock phrases and repetitions that little is actually 'said'. Thought blocking is characterized by an abrupt termination of speech, sometimes in the midddle of a sentence, as if the train of thought had suddenly been 'blocked'. This is not a matter of simply running out of things to say, but rather an uncanny experience wherein thoughts suddenly stop appearing. Obsessions are distinguished from normal thoughts by the fact that they repeatedly and involuntarily come to mind despite the fact that the patient finds them unwanted and distressing. HALLUCINATIONS

Patients are said to be hallucinated when they experience something in the absence of any corresponding actual object; such hallucinations may occur in the visual, auditory, tactile, olfactory or gustatory sphere. Thus, a patient who 'saw' a group of people, or who 'heard' people murmuring in the next room when the room was in fact empty and silent, would be considered hallucinated. Hallucinated patients may or may not retain 'insight': that is to say, they may or may not recognize that their experience is not 'real'. For example, whereas one patient might say, T hear some people next door, but I know that it's just my imagination and they're not really there', another might be surprised to hear that the physician did not hear them also. As Bleuler (1924) pointed out, 'it is of no avail to try to convince the patient by his own observation that there is no one in the next room talking to him; his ready reply is that the talkers just went out or that they are in the walls or that they speak through invisible apparatus'. Certain auditory hallucinations are included among the Schneiderian first rank symptoms (discussed in Chapter 4, p. 169), and should routinely be sought. They include: audible thoughts (i.e. hearing one's own thoughts 'out loud', as if they were being spoken and as if others could also hear them); hearing voices that comment on what the patients themselves are doing; and hearing voices that argue with one another.

Diagnostic assessment 9

DELUSIONS

A delusion, according to Lord Brain (1964), 'is an erroneous belief which cannot be corrected by an appeal to reason and is not shared by others of the patient's education and station'. Thus, whereas for a Russian in the middle part of the twentieth century to be convinced that the telephones were routinely 'bugged' would not, prima facie, be a delusion, but for a Canadian of the twenty-first century to be so convinced would be suspect. Although at times it may be difficult to decide whether or not a belief is delusional, it is in most cases quite obvious: for example, the belief that a small creature sits inside one's external auditory canal and inserts thoughts is simply not plausible in any culture. Delusions are generally categorized according to their content or theme. Thus, there are delusions of persecution, grandeur, erotic love, jealousy, sin, poverty and reference. Delusions of reference are said to be present when patients believe that otherwise unconnected events in some way or other refer or pertain to them. Thus, patients with a delusion of persecution who believed that they were under surveillance might, upon reading a newspaper article about undercover police, hold that the article, in fact, was a kind of 'warning' or 'message' that they could not escape. Certain delusions are counted among the Schneiderian first rank symptoms, as discussed further in Chapter 4, p. 149. These include beliefs that one is directly controlled or influenced by outside forces, that thoughts can be withdrawn, or alternatively inserted, and that thoughts are being 'broadcast' such that they can be 'picked up' and known by others. LEVEL OF CONSCIOUSNESS

Note should be made of whether or not patients are alert, if not, whether they can be aroused to full alertness, and if so, with what difficulty. Terms such as 'stupor', 'torpor', and the like are best avoided as they are used differently by different authors. PRESENCE OR ABSENCE OF CONFUSION

Confused patients may appear to be in a daze: they have difficulty ordering their own thoughts and a similar difficulty in attending to events around them. An evocative synonym for confusion is 'clouding of the sensorium'. ORIENTATION

Orientation is traditionally assessed for three 'spheres' - person, place and time - and patients who can properly place themselves in each sphere are said to be 'oriented times three'. Orientation to person may be determined by asking patients their full names, to place by asking them the name of the city they are currently in, and to time by asking them to provide the exact date, including month, day and year. Some authors recommend commenting on 'orientation' to situation, which they feel constitutes a 'fourth' sphere. Thus, one determines whether or not patients have an appreciation that they are ill, need to be in a hospital, etc. MEMORY

Memory exists in various types: there is thus memory of 'how to' do things, such as remembering how to ride a bike, and there is memory for facts (such as the name of the US President) and events (such as what one was told recently, just a few minutes earlier, or what happened in the more remote past, as for example in the weeks leading up to admission). From a practical, clinical point of view, it is memory for events that is most

10 Diagnostic assessment

important, and it is this kind of memory which is routinely tested in the mental status examination. Recent memory is tested by giving the patient three unrelated words (e.g. 'rock', 'car' and 'pencil') to remember, and then, after 5 minutes have passed, asking the patient to recall the words. Importantly, during this 5 minute interval, the interviewer should stick to neutral topics (e.g. some innocous 'review of systems' questions) and avoid any emotionally laden subjects that might upset the patient. Remote memory is often assessed during the history taking as one determines how well the patient recalls the events leading up to admission; when there is doubt, it is appropriate to ask specific questions regarding events over a span of time, such as what school was attended, how many children are in the family, where one worked, etc. Synonyms for recent and remote memory are 'short term' and 'long term', respectively. Many clinicians also test for immediate memory by determining the patient's digit span. Here, patients are given a progressively longer string of random digits, which they are asked to repeat back: individuals can normally repeat seven digits forwards and five backwards. In almost all cases, significant difficulty with digit span is accompanied by confusion. ABSTRACTING ABILITY

Abstracting ability is traditionally assessed by asking patients to interpret a traditional proverb, such as 'Don't cry over spilled milk.' Responses to proverb testing may be 'abstract' or 'concrete', as for example if a patient replied, 'Well, it's already spilled.' At times, the abnormality on proverbs interpretation will consist of, instead of a concrete reply, a bizarre response, such as 'Alien milk has no taste.' Such bizarre interpretations are generally seen in psychosis. CALCULATING ABILITY

Calculating ability is traditionally assessed with the 'serial sevens' test, wherein patients are asked to subtract seven from 100, then seven from that number, and are then asked to keep on subtracting seven until they can go no further. Fewer than one-half of normal individuals are able to do this perfectly, most making two or three errors (Smith 1962). In cases in which patients are unable to do serial sevens at all, it is appropriate to ask them to attempt simpler mathematical tasks, such as adding 4 plus 5, or subtracting 8 from 12. JUDGMENT AND INSIGHT

Judgment has traditionally been assessed with test questions such as 'What would you do if you smelled smoke in a theatre?' In many instances, however, it is appropriate to pose situations more relevant to the patients' lives; thus, one might ask a police officer what should be done if a suspect refused to answer questions. Insight, for the purposes of the mental status examination, refers not to some sophisticated appraisal of one's situation, but rather, simply, to whether or not patients recognize that they are ill.

NEUROLOGIC EXAMINATION Bleuler (1924), in his classic Textbook of Psychiatry, insisted that 'a minute physical and especially neurological examination must not be omitted' (italics in original), and the modern physician is urged to take this admonition to heart.

Diagnostic assessment 11

Over the decades, the neurologic examination has 'thinned down' somewhat, and of the dozens of abnormal reflexes that used to be de rigeur, only a few survive today. The scheme presented here constitues a 'middle of the road' approach, and although it may be found skimpy by some, others will consider it overly detailed. I plead guilty on both accounts, but urge the reader to try this approach and then to reshape it in light of future experience and wide reading. Although, in most cases, the examination may be conducted in the order suggested here, flexibility must be maintained, especially with fatigued, agitated or uncooperative patients. Bear in mind that even with a completely uncooperative patient, much may be gathered by a simple observation of eye and facial movements, speech, movement of the extremities, gait, etc. For most findings, further detail on and a consideration of the differential diagnosis of the finding may be found in the appropriate chapter, as noted after each heading. General appearance In some cases, the overall appearance of the patient may immediately suggest a possible diagnosis. Examples include the moon facies of Cushing's syndrome (Haskett 1985; Spillane 1951), the puffy facial myxedema and thinning hair of hypothyroidism (Akelaitis 1936; Nickel and Frame 1958) and the massive obesity of the Laurence-Moon-Biedl and Prader-Willi syndromes (Rathmell and Burns 1938; Robinson et al. 1992) or the Pickwickian syndrome (Meyer et al. 1961). Facial appearance, including facial dysmorphisms, may also be diagnostically suggestive (Wiedemann et al. 1989), as for example the port-wine stain of Sturge-Weber syndrome, the adenoma sebaceum of tuberous sclerosis or the high forehead, large ears and prognathism of the fragile X syndrome. Handedness Inquire as to handedness and observe as patients handle implements such as a pen; if there is doubt, ask which hand the patient uses to throw a ball or which foot is used to kick with. Pupils The pupils are normally round in shape, regular in outline and centered in the iris. Their diameter should be measured, and their reactions to light and to accommodation should be noted. The pupillary reaction to light is tested first by shining a penlight into one eye and observing the reaction, not only of that pupil, but also in terms of the consensual reaction in the opposite pupil. After a short wait, the other eye should be tested in the same fashion. The accommodation, or convergence, reaction is then tested by asking the patient to focus on the examiner's finger as it is slowly moved along the midline toward a spot midway between the patient's eyes: normally, as the eyes converge, both pupils undergo constriction. Fundoscopic examination After examining the optic fundus for any hemorrhages or exudates, attention is turned to the optic disc, which should be flat and demarcated from the surrounding fundus by a sharp margin. The depth of the optic cup should be noted, as should the presence or absence of venous pulsation.

12 Diagnostic assessment

Cranial nerves Cranial nerve I

Cranial nerve I, the olfactory nerve, is tested by first occluding one nostril and then bringing an aromatic substance, such as 'a little powdered coffee' (Brain 1964), to the patent's nostril, inquring as to whether any odor is appreciated, and if so, what it is. In a pinch, one may use a substance readily available at the bedside, such as toothpaste. Cranial nerve II

Cranial nerve II, the optic nerve, is tested not only for acuity, but also for visual fields. Near vision may be tested by asking the patient to read text from a newspaper, and far vision by use of a Snellen chart. If the patient has glasses or contact lenses, vision should be tested both with and without them. The visual fields may be assessed by confrontation testing: while facing each other, the physician and patient are separated by about a metre, each fixing vision on the other's nose; the physician then brings a small object (e.g. the tip of a reflex hammer) in from outside the patient's peripheral field, instructing the patient to say 'yes' as soon as it comes into view, and bringing the target in not only from either side but also from above and below. Cranial nerves III, IV and VI

Cranial nerves III, IV and VI, the oculomotor, trochlear and abducens nerves, are tested by having the patient follow the physician's finger as it moves to either side and both upwards and downwards, the patient's head all the while being kept stationary. Eye movements should be full and conjugate in all directions of gaze, and without nystagmus. The oculomotor nerve also innervates the upper eyelid; thus, note should also be made of the presence or absence of ptosis. Cranial nerve V

Cranial nerve V, the trigeminal nerve, has both motor and sensory components. Masseter muscle strength is checked by lightly placing one's fingers on the patient's cheeks and then instructing the patient to bite down. Sensory testing, to both light touch and pin-prick, is checked in all three divisions, namely the ophthalmic, maxillary and mandibular. The corneal reflex, which tests both the fifth and seventh cranial nerves, may also be performed by lightly touching a wisp of cotton to the patient's cornea, after which there should be a bilateral blink. Cranial nerve VII

Cranial nerve VII, the facial nerve, is first tested for voluntary facial movements by asking the patient to wrinkle the forehead and subsequently to show the teeth. Involuntary or 'mimetic' facial movements may be tested for by telling a joke and observing for a symmetric smile or, if the physician is feeling less than witty, simply observing the patient for any spontaneous smiling. It must be borne in mind that voluntary and involuntary facial movements are quite distinct and that either kind may be paretic while the other is not (Hopf et al. 1992). Cranial nerve VIII

Cranial nerve VIII, the vestibulocochlear nerve, is generally tested by gently rubbing the fingers together about 30 cm from the patient's ear and asking whether anything is heard; alternatively, one may bring a ticking watch in from a distance, asking the patient to indicate when it is first heard. If there are any abnormalities, both Weber and Rinne testing should be performed to determine whether the hearing loss is of the conduction or sensorineural type. In the Weber test, a vibrating tuning fork is placed square on the midline of the patient's forehead, and the patient is asked whether it sounds the same on both sides or is heard louder on one side than the other. In the Rinne test, a vibrating tuning fork is placed against the styloid process and the patient is asked to indicate when the sound vanishes, at which point

Diagnostic assessment 13

the tines of the tuning fork are immediately brought in close approximation to the ear and the patient is asked whether it can now be heard. With conductive hearing loss, the Weber lateralizes to the side with the hearing loss, and on Rinne testing, bone conduction (i.e. with the tuning fork against the styloid process) is louder than air conduction (i.e. with the tines of the fork vibrating in the air just outside the ear). With sensorineuronal loss, the Weber lateralizes to the 'good' side and, on Rinne testing, air conduction is better than bone conduction bilaterally. Cranial nerves IX and X

Cranial nerves IX and X, the glossopharyngeal and vagus nerves, are tested with the gag reflex and by observation for symmetric elevation of the palate during phonation. Cranial nerve XI

Cranial nerve XI, the spinal accessory nerve, is tested by having patients shrug their shoulders against the resistance of the physician's hand and by turning the head to one side or the other while the physician exerts contrary pressure on the jaw. Cranial nerve XII

Cranial nerve XII, the hypoglossal nerve, is tested by asking the patient to protrude the tongue, noting whether it is in the midline and also whether there is evidence of any atrophy or fasciculation. Sensory testing Elementary sensory testing involves light touch, pin-prick and vibration. Light touch may be assessed using a wisp of cotton or it may be tested in conjuction with pin-prick sensation by taking a safety pin and applying both ends alternately, asking the patient beforehand to specify whether it feels sharp or dull (Delong 1979). Vibratory sense is assessed by the applicaton of a vibrating tuning fork to various bony prominences (e.g. the lateral malleolus) and asking whether or not the patient appreciates any vibration. If there is any deficit in elementary sensation, it is critical to test the contralateral body part. Graphesthesia and two-point discrimination also constitute part of the sensory examination, but these should only be tested if elementary sensation is intact. Agraphesthesia is said to be present when patients, with their eyes closed, are unable to identify letters or numerals traced on their palms by a pencil or dull pin. Two-point discrimination may be tested by 'bending a paperclip to different distances between its two points ... [starting] with the points relatively far apart... [then] approximated until the patient begins to make errors' (Dejong 1979). As two-point discriminatory ability varies on different parts of the body (from 2-4 mm at the fingertips to 20-30 mm on the dorsum of the hand), what is most important here is to compare both sides, looking for a difference. Agraphesthesia and diminished two-point discrimination suggest a lesion in the parietal cortex; elementary sensory loss suggests a lesion at the level of the thalamus or below, in the brainstem, cord or peripheral nerves. Cerebellar testing Coordination may be assessed with the finger-to-nose and heel-to-knee-to-shin tests. In the finger-to-nose test, patients are instructed to extend the arm and then to touch the nose with the index finger. In the heel-to-knee-to-shin test patients, while seated or recumbent, are asked to bring the heel into contact with the opposite knee and then to run that heel down the shin

14 Diagnostic assessment

below the knee. In both tests, one observes for any tremor as the target, whether the nose or knee, is approached, as well as for any decomposition of movement. Rapid alternating movements also assess cerebellar function. Here, while seated, patients are asked to pronate the hand and gently slap an underlying surface (e.g. a table top or the patient's own thigh) and then supinate the same hand and again gently slap the underlying surface. Once they have the hang of it, patients are then asked to repeat these movements as quickly and carefully as possible. Decomposition of movement, if present, is generally readily apparent on this test. Dysarthria may also represent cerebellar dysfunction and may be casually assessed by simply listening carefully to the patient's spontaneous speech, noting any evidence of slurring. In doubtful cases, one may ask the patient to repeat a test phrase, such as 'Methodist Episcopal' or 'Third Riding Artillery Brigade' (Dejong 1979). Station and gait Station is assessed by asking patients to stand with their feet normally spaced and then with their feet close together, first with their eyes opened and then with them closed. A loss of balance upon closing the eyes constitutes a positive Romberg test and indicates a loss of proprioceptive sensibility. Gait is assessed by first asking patients to simply walk up and down a hallway, then to walk a straight line and finally to walk heel to toe. In all cases, patients should be instructed to allow their arms to hang freely by their sides. Strength Strength may, according to Brain (1964), be graded as follows: 0, no contraction; 1+, a flicker or trace of movement; 2+, active movement providing that gravity is eliminated; 3+, active movement against gravity; 4+, active movement against some resistance; and 5+, full strength. In the process of assessing muscular strength, one should also observe for any atrophy, fasciculations or myotonia. Myotonia is sometimes apparent in a handshake, as patients may have trouble relaxing their grip, and may also be assessed by lightly tapping a muscle belly, such as at the thenar eminence, with a reflex hammer, watching for the distinctive myotonic dimpling.

Drift A positive pronator drift test may be the first evidence of hemiplegia. This test is, according to Dejong (1979), accomplished by asking patients, with their eyes closed, fully to extend their upper extremities, palms up, and then maintain that position: a positive test consists of 'slow pronation of the wrist, slight flexion of the elbow and fingers, and a downward and lateral drift of the hand'. Rigidity Rigidity should, at a minimum, be assessed at the elbows, wrists and knees by passive flexion and extension at the joint, with close attention to the appearance of spastic, lead pipe or cogwheel rigidity, with this latter type often being best appreciated at the wrist as a sort of ratcheting. After testing for these forms of rigidity, one should then test for gegenhalten at the elbow by repeatedly extending and flexing the arm, feeling carefully for any increasing rigidity.

Diagnostic assessment 15

Abnormal movements Tremor may generally be classified as: • rest, as for example when the hands are resting in the lap of the seated patient • postural, as for example when the hands are outstretched with fingers spread • intention, as in thefinger-to-nosetest described above. It may further be characterized in terms of amplitude (from fine to coarse) and frequency (ranging from slow [3-5 cps] to medium [6-10 cps] to fast [11-20 cpsj). Myodonus consists of 'a shock-like muscular contraction' (Brain 1964) and may be focal, segmental or generalized, occurring either spontaneously, in response to some sudden stimulus (e.g. a loud noise) or as 'intention' or 'action' myoclonus, appearing upon intentional movement. Motor tics are sudden involuntary movements that, importantly, resemble purposeful movements, such as shoulder shrugs, facial grimaces or head jerks. Unlike myoclonus, tics involve 'a number of muscles in their normal synergic relationships' (Brain 1964). Chorea is, according to Brain (1964), characterized by 'quasi-purposive, jerky, irregular, and non-repetitive' movements that are very brief in duration, generally erupting randomly on different parts of the body. Athetosis 'consists of slow, writhing movements' (Brain 1964), generally most evident in the distal portions of a limb, which are persistent and seem to flow into one another in a serpentine fashion. Ballismus, which is generally unilateral, consists of'wild flaillike, writhing, twisting or rolling movements that may be intense and may lead to exhaustion' (Dejong 1979). In severe cases, the flinging movements of the extremity may actually throw the patient off the chair or bed. Dystonia, in contrast to ballismus, consists of slow and sustained movements that variously twist or contort the involved body part. It may be focal (e.g. moving the head to one side or 'cramping' the hand), segmental (e.g. spreading to an adjacent body part, as with the head turning and the shoulder elevating) or generalized (e.g. in severe cases, creating a human 'pretzel'). Parkinsonism, when fully developed, stamps patients with a distinctive clinical picture. A flexion posture is evident, with the patient being stooped over and the arms and legs in flexion, and a rhythmic 'pill-rolling' rest tremor of the hands may be seen, especially with the hands resting on the lap. The face is often 'masked' and expressionless, and bradykinesia is evident in the slowness with which all movements are executed. Upon walking, one may see a festinating gait wherein the patient seems to hurry 'with small steps in a bent attitude, as if trying to catch up [with] his center of gravity' (Brain 1964). Akathisia is typified by an inability to keep still. If standing, patients may rock back and forth, or 'march in place', and if seated, there may be a restless fidgeting with crossing and uncrossing of the arms or legs. In severe cases, the compulsion to move is irresistible, and patients may constantly pace back and forth. Characteristically, the restlessness is worse when lying down or seated, and most patients find some relief upon standing or moving about. Catalonia of the retarded or stuporous type (Barnes et al. 1986) is characterized by varying degrees of immobility, mutism and a remarkable phenomenon known as waxy flexibility (or catalepsy), wherein , as noted by Kraepelin (1899), the limbs, after being passively placed in any position, 'retain this position until they receive another impetus or until they follow the law of gravity as a result of extreme muscular fatigue'. Asterixis (Leavitt and Tyler 1964) is tested for by having patients hold their upper limbs in full extension, with the hands being held in hyperextension: asterixis, if present, appears as a precipitous loss of muscle tone, such that the hands 'flap' down.

16 Diagnostic assessment

Heightened startle response (Saenz-Lope et al. 1984), often precipitated by a sudden loud noise, may go beyond being simply excessively 'jumpy', and some patients may actually be thrown to the ground during the startle.

Deep tendon reflexes At a minimum, the following deep tendon reflexes should be tested: biceps jerk, triceps jerk, supinator jerk, knee jerk and ankle jerk (Brain 1964). The results may, according to Dejong (1979), be graded as 0 for absent, + for present but diminished, ++ for normal, +++ for increased, and ++++ for markedly hyperactive (often with clonus). In those cases in which patients remain so tense that their reflexes cannot be elicited, several manuevers may render the examination possible (Bickerstaff 1980): for the upper limbs, the patient should clench his teeth tightly, or while one arm is being examined he should clench the fist of the other. For the lower limbs these measures can still be used, but the well-tried method of Jendressak is more reliable. The patient interlocks the flexed fingers of the two hands and pulls one against the other at the moment the reflex is stimulated.

Babinski sign The Babinski sign, called 'the most important sign in clinical neurology' (Dejong 1979), may be elicited by lightly dragging a blunt object across the sole of the patient's foot, beginning at the heel and proceeding along the lateral aspect of the sole. The normal plantar response is one of flexion of the toes: an extensor plantar response constitutes the Babinski sign, which, when fully present, consists of dorsiflexion of the great toe and fanning of the rest.

Primitive reflexes The palmomental reflex is tested for by repeatedly and rapidly dragging an object, such as the tip of a reflex hammer, across the thenar eminence: when the reflex is present, one sees 'a wrinkling of the skin of the chin and slight retraction and sometimes elevation of the angle of the mouth' (Dejong 1979). The snout reflex is said to be present when gentle tapping or pressure just above the patient's upper lip, in the midline, is followed by a puckering or protrusion of the lips; in advanced cases, the reflex may be elicited by merely 'sweeping a tongue blade briskly across the upper lip' (Dejong 1979). The grasp reflex may be elicited by laying one's finger across the patient's palm such that it may be readily dragged out between the patient's thumb and index finger. If the reflex is present, the patient's fingers will grasp the physician's finger as it is slowly dragged across the palm (Walshe and Robertson 1933). The grope reflex may be elicited by simply lightly touching the patient's hand with one's finger: when present, the patient's hand will automatically make groping movements until the physician's finger is found and grasped (Seyffarth and Denny-Brown 1948).

Aphasia Aphasia represents a disturbance in either the comprehension and/or production of spoken language. Testing involves listening to the patient's spontaneous speech, giving simple spoken

Diagnostic assessment 17

commands and determining whether the patient understands them, and asking the patient to repeat a test phrase, such as 'No ifs, ands or buts.' With the results of this simple approach in mind, one may then proceed to the complex classification of aphasias, as presented in Chapter 2, p. 51.

Alexia and agraphia Alexia and agraphia represent, respectively, difficulties in reading and writing, and although often seen in combination with aphasia, may also appear in pure form. Testing is accomplished simply by asking the patient to read something, perhaps a headline, and then to write something, such as an address.

Aprosodia Aprosodia represents a disturbance in the production or comprehension of the 'emotional' and melodic aspects of speech (Ross 1981). Thus, the patient's own speech may be flat, lifeless and monotone, lacking all prosodic elements, or the patient may have difficulty in appreciating the emotional tone of another's voice. A lack of prosody in the patient's own speech is generally apparent as the history is related; testing for the patient's ability to 'comprehend' prosody may require that patients close their eyes and then listen as the physician repeats the same neutral phrase repeatedly but with different intonations, asking each time what the tone was.

Apraxia Apraxia may be ideational or ideomotor, constructional or dressing. Ideational and ideomotor apraxia (Dejong 1979; Heilman 1973) are tested by first asking the patient to mime using a common implement, such as a comb or a pair of scissors, and then, if the patient has any difficulty in performing the pantomine, by providing the implement and asking the patient to make use of it. In ideational apraxia, both miming and actual use are defective, whereas with ideomotor apraxia the patient, although unable to mime, has no trouble correctly employing the actual implement. Constructional apraxia is tested for by asking the patient to draw a simple figure, such as a 'stick person', or to copy a geometric design (Dejong 1979) such as a cube. Dressing apraxia is casually assessed by observing the patient put on clothing: when present, patients may put their arms in the wrong sleeve or perhaps attempt to put their shirt on backwards (Hecaen et al. 1956).

Agnosias Visual agnosia, or the inability to recognize an object by sight, is tested by pointing to a common object, such as a comb, and asking patients not only to name it, but also to describe its use. Tactile agnosia represents an inability to recognize an object by touch: with the eyes closed, the patient is given a common object, such as a key, and asked both to identify it and to describe its use. Anosognosia is said to be present when patients fail to recognize a deficit, such as hemiplegia, or grossly minimize it, as for example by characterizing a hemiplegic limb as simply 'stiff'.

18 Diagnostic assessment

Other agnosias described in Chapter 2, p. 63, which are generally not routinely tested for, include color agnosia, prosopagnosia (the inability to recognize faces), auditory agnosia (the inability to recognize common sounds), topographagnosia (a loss of a sense of direction), simultanagnosia (an inability to visually 'grasp' the whole of a scene, to see all of its parts simultaneously) and asomatagnosia (a denial of the 'ownership' or a body part, as may be seen in some cases of hemiplegia).

Neglect Neglect may be of the visual or motor types. Visual neglect is tested by seating the patient squarely in front of a table, with the patient's trunk kept parallel to the edge of the table (Beschin et al 1997). First, draw a line horizontally across a piece of paper, at least 15 cm long (Tegner and Levander 1991), and then place the paper directly in front of, and square to, the patient. The patient is then asked to bisect the line. Next, draw numerous short marks in a random fashion on a piece of paper, placing the paper squarely in front of the patient and asking the patient to mark or cancel out all the lines. Finally, position a blank piece of paper in front of the patient with the instruction to draw a clock face on it, with all the numbers, 1 to 12, on the drawing. These constitute, respectively, the line bisection, line cancellation and clock-drawing tests, and neglect is said to be present if the line is bisected off the midline, a significant percentage of the random lines on one side are not cancelled out or the numerals on the clock face are bunched to one side. Motor neglect is tested by asking the patient to perform a task that requires the use of both upper extremities, such as fastening a button: when motor neglect is present, the patient 'underutilizes' the 'neglected' side and attempts to perform the task primarily with one hand, despite the fact that, with strong urging, normal bilateral manual coordination is possible (Laplane and Degos 1983). Extinction Extinction may be either visual or tactile (Valler et al. 1994). Visual extinction may be tested immediately after performing confrontation testing of the visual fields. While retaining the same position with respect to the patient, the physician holds both hands outstretched laterally, to the edge of the peripheral fields, and then simultaneously wiggles both index fingers, asking the patient to point to the ringer finger or fingers that are moving. When visual extinction is present, the patient notes the motion of only one finger. Tactile extinction may be tested during routine sensory testing. While the patient's eyes are closed, the physician instructs the patient to report which hand or hands are being touched, touching first one hand, then the other and then both simultaneously. When tactile extinction is present, only one hand will be reported to be touched during simultaneous stimulation.

NEUROIMAGING Computed tomography (CT) and magnetic resonance imaging (MRI) have revolutionized neuroimaging. Before the advent of CT in 1972, physicians were limited to skull X-rays, radionuclide scanning and pneumoencephalography, none of which retain any use for imaging the brain today. In the case of both CT and MRI, imaging is accomplished on a voxel-by-voxel basis. A voxel (from volume element) is a specific three-dimensional volume of tissue, each voxel

Diagnostic assessment 19

subsequently being represented on the scan by a pixel (from jncture element). Earlygeneration scanners allowed for only a limited number of voxels; consequently tissue resolution was poor, and the corresponding scan created by the pixels was fuzzy and relatively unedifying. Technical progress has, however, allowed for a much higher number of voxels and pixels with the result, that, especially in the case of MRI, the scans are breathtakingly accurate representations of the intracranial contents. The technology of CT scanning is similar to that utilized in traditional radiography, and is thus conceptually easily grasped by most physicians. MR scanning, however, relies on a fundamentally different technology, which, for most, requires a little getting used to. This chapter will briefly discuss CT and MRI, and then consider their relative merits for clinical neuroimaging. CT scannning CT scanning, developed by Hounsfield (1972), is based upon determining the attenuation of an X-ray beam by any given voxel of tissue. The degree of attenuation is expressed in Hounsfield units (Phelps et al. 1975): by convention, these range from -1000 (for air) to + 1000 (for bone), tissues of biologic interest being assigned intermediate values, for example, 0 for water, 30 for white matter, 38 for gray matter and 81 for freshly clotted blood. A gray scale is then created to represent the various attenuation coefficients, very lowattenuation (or 'hypodense') areas such as air in the sinuses appearing black, and very highattenuation (or 'hyperdense') tissues, such as bone or other areas of heavy calcification, appearing white. CT scanning is most reliable for supratentorial structures: the posterior fossa is particularly likely to be obscured by various artifacts (Mostrum and Ytterbergh 1986). Enhancement is accomplished by the intravenous injection of an iodinated contrast material, which, as it has a high attenuation coefficient, makes the tissue into which it extravasates appear more dense. MR scanning The physics underlying MRI are complex (Edelman and Warach 1993; Pykett 1982; Pykett et al. 1982), so what follows is a very simplified, and very brief, general overview. To begin, consider hydrogen atoms, their nuclei composed of but one proton. Each proton spins at a very fast rate, thus creating a magnetic field and, as it were, becoming a very small magnet itself. These proton 'magnets' are normally arrayed in random directions, but if a very strong external magnetic field is applied, they will all align themselves parallel to the external magnetic field. In such a situation, if a radio pulse of appropriate frequency is fired at the protons, they will absorb this energy, with the result that they begin to spin with an eccentric axis, no longer in parallel alignment to the external magnetic field. Over a variable period of time, however, the protons fall back into line, in so doing releasing the energy absorbed from the earlier radio pulse. The speed with which the protons undergo realignment is determined by various factors, including the availability of nearby tissues that may absorb energy and the presence of any surrounding magnetic inhomogeneities or tissues that, of themselves, have magnetic properties. The released energy may be measured and constitutes the 'signal' of the voxel in question. In conventional MRI scanning, measurement is made at two subsequent times, namely'Tl' and 'T2', the signal intensity at each time being represented in the corresponding pixel via a gray scale, wherein a high signal intensity is light (or 'bright') and a low signal intensity is dark. As might be expected, different tissues will have different signal characteristics, and,

20 Diagnostic assessment

furthermore, for any given voxel, the signal emitted at Tl will be different from that emitted at T2. Thus, whereas cerebrospinal fluid is dark on Tl-weighted scans, it is bright on T2weighted scans, and whereas white matter is relatively light on Tl-weighted scans, it appears darker on T2-weighted images. The enhancement of MRI is accomplished by the injection of a paramagnetic substance such as gadolinium and is best appreciated on Tl-weighted scans (Berry et al. 1986; BrantZawadzki et al. 1986): on such images, as illustrated in Fig. 1.1, the tissues into which the gadolinium has extravasated have a much higher signal intensity and appear much brighter. Progress in MRI is very rapid, and indeed new techniques appear almost every year. Of those which have been developed, the most viable for routine clinical use is diffusion weighted imaging (DWI) which is very sensitive to cytotoxic edema (Warach et al. 1992) and finds special use in the evaluation of recent cortical (Fisher and Albers 1999; Neumann-Haefelin et al. 2000) or lacunar infarction, as noted below.

Figure 1.1 Both of these T1-weighted magnetic resonance imaging scans are of the same patient with a high-grade

Image Not Available

glioma in the right hemisphere; on the left, the tumor appears as an area of decreased signal intensity, but with enhancement, as seen in the scan on the right, the tumor displays increased signal intensity and 'lights up'. (Reproduced from Gillispie and Jackson 2000.)

Clinical indications As with any diagnostic test, the decision to request either CT or MRI should be guided by one's diagnostic suspicions. Furthermore, it is critical to provide the radiologist with a brief summary of the history and findings, along with one's presumptive diagnosis, so that the best imaging parameters may be selected. MRI is preferable to CT in most clinical situations (Armstrong and Keevil 1991; Bradley et al. 1984; Haughton et al. 1986), possible exceptions including the detection of intracranial calcification (Holland et al. 1985) and hemorrhage, wherein CT is very accurate (van der Wee et al. 1995). MRI should, however, not be utilized whenever the patient harbours a metallic object that might undergo any potentially dangerous movement during the application of the external magnetic field. Examples include: aneurysmal clips, depth electrodes, intracranial bullets or shrapnel, some cerebrospinal fluid shunts, some cochlear implants, cardiac pacemakers, some prosthetic valves, some arterial stents, various orthopedic devices, some penile implants, wire sutures, braces and, importantly, any metallic object in the eye. This last contraindication deserves special attention as some patients may not be aware of the presence of a metallic ocular foreign body (e.g. a lathe operator struck in the eye with a minute sliver of metal decades earlier): if any doubt exists, plain films of the orbits should be acquired first. Metallic objects that may be removed include hearing aids, dentures, transcutaneous electrical nerve stimulation units, insulin pumps and some intrauterine devices.

Diagnostic assessment 21

Angiography is now possible with both MR and CT scanning, but CT angiography, albeit impressive, remains, as with routine scanning, inferior to MR angiography (Dillon et al. 1993). Although neither technique is as accurate as conventional angiography, MRA is finding increasing use as a screening instrument for suspected aneurysms and in cases of carotid disease. Some common indications (such as suspected cerebral infarction) for CT or MRI are discussed below. Cerebral infarction

Cerebral infarction demonstrates a definite evolution of pathologic stages, progressing from cytotoxic edema to vasogenic edema and finally to necrosis with varying degrees of cavitation. On CT scanning (Bories et al. 1985; Johnson 1994), cytotoxic edema is reflected in sulcal effacement and a degree of hypodensity within the first 6-24 hours, followed within a day or two by evidence of vasogenic edema with a degree of mass effect, and, in over one-half of patients, contrast enhancement. Eventually, over the following weeks, both mass effect and enhancement resolve, leaving a definite area of hypodensity corresponding to the remaining encephalomalacia. On routine MR scanning (Grain et al. 1991; Elster 1994), cytotoxic edema becomes apparent with sulcal effacement in as little as 2 hours, and vasogenic edema, with increased signal intensity on T2-weighted scans, may be apparent within the first day. Gadolinium enhancement appears later, within the first few days, and is generally universally present within the first 2 weeks. The use of DWI is even more sensitive to cytoxic edema, often revealing an increased signal intensity in less than 2 hours (Fisher and Sotak 1992; Sorensen etal. 1996; Warach et al. 1992,1995), indeed in one case demonstrating edema 39 minutes into the event (Yoneda et al. 1999). Intracerebral hemorrhage

Intracerebral hemorrhage may, at least initially, be more evident on CT than MRI scanning. On CT scanning (Dolinskas et al. 1977), the hemorrhage appears first as an area of hyperdensity. Over time, as the hemoglobin degrades, the lesion gradually becomes isodense with the surrounding tissue, the eventual cavity appearing as an area of radiolucency. With MRI scanning, the evolution of the image is more complex (Gomori et al. 1985; Patel et al. 1996). During the 'hyperacute' phase of the first few hours, when the hemoglobin in the red blood cells is still in its oxyhemoglobin form, there may be no change on MRI scanning. In the following acute phase, spanning the next few days, intracellular oxyhemoglobin is transformed into deoxyhemoglobin, and the lesion may appear as an area of decreased signal intensity on T2-weighted scans. Over the following days and weeks, the intracellular deoxyhemoglobin further degrades into methemoglobin, the lesion at this point appearing as an area of increased signal intensity on Tl-weighted scans, with persisting decreased signal intensity on the T2-weighted scan. Over the following weeks and months, as red blood cell rupture occurs and methemoglobin is released into the extracellular space, increased signal intensity is seen on both T1-, and T2-weighted scans. Finally, with the complete degredation of methemoglobin, a deposition of hemosiderin remains, apparent as an area of greatly decreased signal intensity on the T2-weighted scan. Subarachnoid hemorrhage

Subarachnoid hemorrhage is routinely detected by CT scanning as an area of hyperdensity corresponding to the free blood within the Subarachnoid space (van der Wee et al. 1995; van Gijn and van Dongen 1982). Although routine MR scanning is not as sensitive as CT, use of fluid-attenuated inversion recovery (FLAIR) pulse sequences generates images that are more sensitive than those obtained with CT (Noguchi et al. 1995).

22 Diagnostic assessment

Intracranial calcification

Intracranial calcification is better demonstrated on CT scanning, on which it is evident as an area of hyperdensity, than on MRI scanning, where it may be difficult to detect (Holland et al. 1985; Wasenko et al 1990). Tumors

Tumors are, overall, better demonstrated by MR than CT scanning (Armstrong and Keevil 1991; Bradley et al. 1984; Brant-Zawadzki et al. 1984). With both CT and MR scanning, enhancement increases sensitivity (Sze et al. 1990), and in the case of gliomas, the degree of enhancement may serve as a guide to the malignancy of the tumor, with increased enhancement indicating greater malignancy with both CT (Tchang et al. 1977) and MR (Dean et al. 1990; Graif and Steiner 1986) scanning. In the case of meningiomas, the administration of contrast is especially important (Vassilouthis and Ambrose 1979; Zimmerman et al. 1985): on unenhanced CT scanning, the tumor, albeit generally hyperdense, may be isodense, and on MR scanning there is often no change at all in signal intensity on either Tl- or or T2-weighted scans. With contrast, however, almost all meningiomas will enhance on both CT and MR scanning. Diffuse axonal injury

Diffuse axonal injury, as occurs after closed head injury, is far better detected on MR than CT scanning, which is often normal (Kelly et al. 1988; Mittl et al. 1994; Zimmerman et al. 1986). Multiple sclerosis

Multiple sclerosis is characterized by plaques of demyelinization, which may be either active, with evidence of definite inflammation, or chronic and inactive. CT scanning (Hershey et al. 1979; Mushlin et al. 1993) demonstrates plaques as areas of hypodensity, and active plaques may be identified by contrast enhancement. MR scanning is far more sensitive than CT scanning, even when CT scanning is carried out using double contrast (Mushlin et al. 1993; Young et al. 1981). On MR scanning (Katz et al. 1993; Nesbit et al. 1991; Ormerod et al. 1987), inactive plaques appear as areas of decreased signal intensity on Tl-weighted scans, and increased signal intensity on T2-weighted scans; active plaques demonstrate gadolinium enhancement. Serial MR scanning (Grossman et al. 1988; Guttmann et al. 1995; Thompson et al. 1992) may be used to follow the progress of the disease and may indeed reveal clinically 'silent' lesions. Furthermore, recently activated plaques may be detected by gadolinium enhancement before there is any clinical evidence of their presence (Kermode et al. 1990; Miller et al. 1988). MRI has revolutionized the diagnosis of multiple sclerosis, and no evaluation of a patient suspected of harbouring this dreaded disease is complete without it. Mesial temporal sclerosis

Mesial temporal sclerosis, the most common cause of complex partial seizures, is better detected by MRI than CT (Franceschi et al. 1989). On MR scanning, mesial temporal sclerosis is apparent with atrophy, best seen on Tl-weighted scans, and, on T2-weigh ted scans, increased signal intensity in the same area: importantly, these changes are generally best seen on coronal images (Berkovic et al. 1991). Neuronal migration disorders

Neuronal migration disorders are a common cause of simple or complex partial seizures and of grand mal seizures of focal onset. For the most part, they manifest as subependymal nodular heterotopias, either laminar or band heterotopias in the white matter itself, or areas of cortical dysplasia or microdysgenesis. Although CT scanning may detect subependymal heterotopias (especially if they are calcified), MR scanning is superior, picking up not only these lesions, but also band and laminar heterotopias (Altman et al. 1988; Barkovich and Kjos 1992; Huttenlocher et al. 1994), as illustrated in Fig. 1.2.

Diagnostic assessment 23

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Figure 1.2 A T1-weighted magnetic resonance imaging scan demonstrates a laminar band heterotopia, as indicated by the arrow, in exquisite detail. (Reproduced from Hopkins et al. 1995.)

Lacunar infarctions

Lacunar infarctions, often missed on CT scanning, appear on MR scanning as areas of decreased signal intensity on Tl-weighted scans and increased signal intensity on T2-weighted scans (Brown et al. 1988). As with large cortical infarcts, DWI may reveal acute lacunar infarcts (Singer et al. 1998) and is especially helpful in indicating which lacunae are 'fresh' (OliveiraFilho et al. 2000): indeed, DWI may demonstrate the occurrence of lacunar infarctions despite the absence of any history of a clinical event (Choi et al. 2000). Importantly, lacunae must be distinguished from prominent Virchow-Robin spaces (Heier et al. 1989; Jungreis et al. 1988), which, unlike lacunae, tend to be bilaterally symmetric and quite regular in shape. Binswanger's disease

Binswanger's disease, also known as subcortical arteriosclerotic leukoencephalopathy, is characterized by irregular, patchy and often confluent areas of more or less complete demyelinization in the centrum semiovale. Although these patchy lesions may, in some cases, be seen on CT scans as ill-defined areas of hypodensity, they are much better appreciated on MRI scanning as areas of decreased signal intensity on Tl-weighted scans and, most especially, as areas of increased signal intensity on T2-weighted scans (Kinkel et al. 1985). These patchy lesions must be distinguished from certain normal variants (Fazekas et al. 1991) such as bilaterally symmetric and smoothly contoured periventricular 'caps' and 'rims' or what are known as UBOs (unidentified bright objects): scattered punctate foci with signal characteristics identical to those caused by pathologic patches. AIDS dementia

AIDS dementia has imaging characteristics similar to those just described for Binswanger's disease and is better imaged with MR than CT (Chrysikopoulos et al. 1990). Furthermore, MR

24 Diagnostic assessment

is also more sensitive than CT for AIDS-related illnesses, such as toxoplasmosis (Porter and Sande 1992) and progressive multifocal leukoencephlopathy (Guilleux et al. 1986; Krup et al. 1985). Herpes simplex viral encephalitis

Herpes simplex viral encephalitis, the most common cause of sporadic encephalitis, and a very important diagnosis given its amenability to treatment, is far better imaged by MR than CT (Gasecki and Steg 1991): indeed, CT scanning may be normal during the critical first few days (Greenberg et al. 1981). Herpes simplex encephalitis usually affects first the mesial temporal structures, producing an increased signal intensity on T2-weighted scanning (Tien et al. 1993). Pituitary adenoma

Pituitary macroadenomas may be seen on both CT and MR scanning; microadenomas, however, are generally seen only with MR scanning (Levy and Lightman 1994), which, in the case of prolactinomas, may be used to monitor the results of treatment with bromocriptine (Pojunas et al. 1986)

ELECTROENCEPHALOGRAPHY The existence of cerebral electrical activity was demonstrated in animals in 1875 by an English physician, Caton (1875), the first human electroencephalogram (EEG) being reported by Berger in 1929. By the middle of the twentieth century, the EEG had become highly important in the diagnosis of such intracranial lesions as tumors, but with the advent of CT and MRI, the main indication for electroencephalography today lies in the diagnosis and management of seizures and epilepsy. This section discusses EEG instrumentation, the normal EEG, various EEG abnormalities, activation procedures (e.g. hyperventilation), normal variants and the various artifacts that may mimic pathologic abnormalities. In contrast to CT and MRI scanning, there is nothing 'intuitively' obvious about an EEG tracing: anyone familiar with neuroanatomy can almost immediately grasp an MRI scan. Looking at an EEG tracing is, however, like looking at an electrocardiogram (EGG): without a considerable amount of preparation, the EEG tracing offers no more information about the state of the brain than does the EGG about the heart. Consequently, this section on EEG is relatively longer than that on neuroimaging, as well as more detailed. As with any other diagnostic test, the EEG must be properly performed to yield the most useful data. In particular, the awake EEG should include at least 20 minutes of artifact-free recording, followed by the activating procedures of hyperventilation, photic stimulation and sleep, which should itself last 20 minutes.

Instrumentation Although EEG machines differ in their particulars, all of them have certain things in common. Electrodes are attached to the scalp and are connected via wires to selector switches on the actual EEG machine. Utilizing these switches, the various wires, and the electrodes from which they stem, may be paired in a variety of ways, each pair of wires creating a 'channel'. Within the EEG machine itself, one finds amplifiers and filters, which, respectively, amplify the very weak electrical signals arising from the cortex and filter out, as much as possible, electrical activity that either arises from extracerebral sources or, even though arising from the brain, is of little clinical interest.

Diagnostic assessment 25

The amplified and filtered electrical impulse of each channel is then used to cause a deflection of the appropriate pen over a continuously moving sheet of paper, thus creating the actual EEC tracing. (Although with the advent of 'paperless' digital EEGs, it may seem quaint to still speak of 'pen deflections' and EEC 'tracings', the terminology has remained, and promises to stay with us.) In a standard recording, the sheet moves at a constant rate of 30 mm/sec, and the sensitivity of the pen is set such that an impulse of 50 uV causes a deflection of 7 mm. The specific arrrangement of electrodes on the scalp is known as an array, the international 10-20 system described by Jasper (1958) remaining a world-wide standard. In this system, imaginary lines are drawn on the head between specific landmarks (e.g. the nasion and inion), the electrodes being placed along them at certain fractional intervals, i.e. either 10% or 20% of the total length of the imaginary line. These electrodes are designated with letters, which refer to their location, and with numbers, which indicate whether they are on the left side of the head, the right side or in the sagittal midline. Thus, Fp = frontopolar, F = frontal, T = temporal, O = occipital, C = central, P = parietal, and A = auricular; odd numbers indicate the left side of the head, even numbers the right side and zero (V) the sagittal midline. Fig. 1.3 demonstrates these placements, and Table 1.1 provides the full name for each electrode. Regarding names, a word is in order about electrodes F7 and F8. Although, logically, one might expect these to be called 'frontal', they are, in common usage, referred to instead as 'anterior temporal' leads as, for the most part, they reflect activity arising from the anterior portion of the temporal lobes.

Figure 1.3 Schematic representation of EEC electrode placement according to the international 10-20 system (see text for details).

Table 1.1 Electrode names in the 10-20 system Name

Position

Fp1,Fp2

Pref rental Anterior temporal Mid-temporal Posterior temporal Occipital Frontal Central Parieta Auricular Frontal midline Central vertex Parietal midline

F7, F8 T 3 ,T 4

T 5 ,T 6 0,,02 F3, F4 C3, C4 P3,P4

A1,A2 Fz

Cz Pz

26 Diagnostic assessment This international 10-20 system may be extended and modified by adding more electrodes, and this may be resorted to in order to improve localization or to increase spatial resolution and allow for better computerized EEC analysis. Supplemental leads may also be added in order better to detect and localize foci in the temporal lobe. 'True' anterior temporal leads (to be distinguished from the admittedly misnamed F7 and F8 electrodes) are placed by drawing a line between the external auditory canal and the lateral canthus and placing the electrode anterior to the external auditory canal, one third of the way forward along, and 1 cm above, this line (Roman et al 1988; Silverman 1960). Nasopharyngeal leads, as the name suggests, are inserted into the nostril and so placed as to sample the medial aspect of the temproral lobe (MacLean 1949). Sphenoidal leads are invasive, requiring a trochar to place them through the masseter muscle and up posterior to the zygomatic arch: these also attempt to sample the medial aspect of the temporal lobe (Risinger et al. 1989). There is a debate over which one or combination of supplemental leads is most appropriate for detecting temporal lobe foci. The addition of anterior temporal leads provides more sensitivity than a routine 10-20 array, and it appears that anterior temporal leads are of roughly equivalent sensitivity to nasopharyngeal leads (Sperling and Engel 1985). Sphenoidal leads are probably superior to either anterior temporal leads or nasopharyngeal (Sperling et al. 1986) leads alone (although not all agree on this point [Roman et al. 1988]), but it appears that a combination of anterior temporal and nasopharyngeal leads is equal in sensitivity to sphenoidal leads (Goodin et al. 1990; Sperling and Engel 1985). At the very least, true anterior leads should be used, and an argument could be made for using a combination of anterior temporal and nasopharyngeal leads fairly routinely when a medial temporal focus is suspected, reserving sphenoidal leads only for selected cases. As noted earlier, the EEC machine contains selector switches that allow electrodes to be paired in various ways, and the pattern of such pairings is known as a montage. The two standard montages are known as referential and bipolar (American Electroencephalographic Society 1986). In a referential montage, each scalp electrode is paired with the same 'reference' electrode, usually the ipsilateral ear, producing channels such as F7-A1, T3-At and TS-A!. The scalp electrode is commonly referred to as the 'active' electrode, in contrast to the reference electrode, which is termed 'indifferent'. This terminology is, however, not accurate because the ear electrode in fact picks up electrical activity arising from the temporal lobe and is thus only 'relatively' indifferent. In some instances, other electrodes, or combinations of electrodes, will be used instead of one ear: thus, the reference electrode may be found on the angle of the mandible, or an 'average reference electrode' may be produced by averaging the electrical activity of a large number of scalp electrodes (Goldman 1950). In a bipolar montage, scalp electrodes are paired in two directions - longitudinal and transverse. In a longitudinal bipolar montage, the pairings proceed ipsilaterally, from anterior to posterior, producing 'chains' of channels, such as Fpl-F3, F3-C3, C3-P3 and Ps-Oi. In a transverse bipolar montage, the chain proceeds across the scalp, from left to right, for example F7-F3, F3-FZ, FZ-F4, F4-F8. It is appropriate to note here that, in the chains of a bipolar montage, one individual elecrode may serve as the second electrode in one channel and the first electrode of the next. In the chain noted above containing channels Fpl-F3, F3-C3, C3-P3 and P3-Oi, for example, note that electrode F3 serves as the second electrode for the first channel (Fpl-F3) and the first electrode for the next channel (F3-C3). As will be noted later in the discussion of phase reversal, the commonality of one electrode to two successive channels in a bipolar montage allows for a localization of interictal epileptiform abnormalities.

Diagnostic assessment 27

Normal EEG The electrical activity recorded by the EEG arises from the the apical dendrites of cortical pyramidal neurons (Purpura and Grundfest 1956). Although the electrical activity associated with an action potential is too brief to be recorded on an EEG, lasting less than 1 msec, that derived from both inhibitory and excitatory post-synaptic potentials lasts much longer, from 15 to 200 msec, and it is this activity which is reflected on the EEG. The electrical activity arising from one neuron is obviously simply too weak to affect the surface electrodes, so it is on the summed activity of numerous neurons that the EEG depends. Furthermore, it must be borne in mind that abnormal electrical activity occurring deep below the cortex may not 'reach' the scalp electrodes (Cooper etal. 1965), and thus certain deep lesions, such as lacunar infarcts, while having profound clinical consequences, may not cause any abnormality on the EEG (MacDonnell et al. 1988). EEG activity may or may not be rhythmic, and it appears that rhythmicity occurs secondary to the activity of the thalamus, which acts like a pacemaker or 'conductor', exerting rhythmic control over the cortical 'orchestra', and bringing large groups of neurons into synchrony (Demspey and Morrison 1942; Steriade et al. 1990). This dependence of cortical neurons upon the thalamus for rhythmic firing was demonstrated by experiments in which the destruction of the thalamus abolished rhythmic cortical activity (Jasper 1949). The EEG consists of various waves that may differ in terms of morphology, amplitude and duration. Thus, in terms of morphology, an individual wave may be monophasic, diphasic, triphasic or polyphasic, depending on how many times the 'baseline' is crossed by the wave in question. Amplitude is measured in microvolts from the crest to the trough of the wave: customarily, amplitudes under 20 uV being considered low, those between 20 and 50 uV, medium and those over 50 uV high amplitude. (Some electroencephalographers will, however, rather than using this absolute scale, consider the amplitude of a given wave relative to the overall amplitude of background activity: thus, if the background activity were generally of 60 uV, a 30 uV wave, using this relative scale might be considered low. It is critical thus that the electroencephalographer specify whether an absolute or a relative scale is being used when reporting amplitude.) The duration of the wave is measured in milliseconds: waves lasting less than 70 msec are referred to as 'spikes' and those lasting from 70 to 200 msec as 'sharp waves'; those lasting for over 200 msec are spoken of either as 'slow waves' or simply 'waves'. Waves may be isolated or recurrent. If recurrent, their frequency is reported in cycles per second (Hz): by convention, frequencies less than 4Hz are termed 'delta', those from 4 to under 8 Hz 'theta', those from 8 to 13 Hz 'alpha' and those over 13 Hz as 'beta' waves. Some electroencephalographers also use the terms 'slow' and 'fast', 'slow' referring to both delta and theta activity (i.e. anything uder 8 Hz) and 'fast' referring to any activity in the beta range (i.e. over 13 Hz). Recurrent activity may also be rhythmic and regular in occurrence, or arrythmic and irregular. The EEG will normally have a recognizable background activity, which is more or less persistent and similar throughout the recording. Upon this background, one may at times see isolated events that, for one reason or another, stand out from the background, such events being referred to as 'transients'. Transients may, in turn, consist of an isolated wave or a 'complex' of two or more waves. Complexes themselves are further described in terms of whether they are isolated or recurrent, and if recurrent, whether they recur irregularly or regularly. When complexes are regular, they are generally termed 'periodic', the period referring to the length of time between successive complexes. Among transients, those which are 'paroxysmal' in character are of great importance as they suggest the presence of a seizure disorder. Paroxysmal transients shoot out from the

28 Diagnostic assessment

background, rapidly attain their maximum amplitude and subsequently undergo an abrupt termination. Such paroxysmal events may consist of only one or a few connected waves or may, by contrast, be enduring, persisting for at least several seconds and often much longer. Brief paroxysms, consisting of only one or a few waves, are often referred to as 'epileptiform' as they generally (but not always) reflect interictal activity within the cerebral cortex. Such epileptiform paroxysms generally consist of an isolated spike or sharp wave, or of a complex of various wave combinations, such as spike-and-sharp wave, spike-and-slow wave, sharpand-slow wave or, when more than one connected spike appears, polyspikes; if the connected spikes are followed by a wave, polyspike-and-wave is used. 'Spindles' constitute another specific type of transient, consisting of a group of rhythmic waves that gradually increase, and then just as gradually decrease, in amplitude. The normal adult EEC, as seen during relaxed wakefulness with the eyes closed, contains an alpha rhythm and a beta rhythm. These two terms must not be used loosely: for example, although much EEC activity may occur in the alpha frequency, the activity must, to qualify as an alpha rhythm, fulfill certain other criteria. In a minority of individuals, a mu rhythm may also be seen. The alpha rhythm consists of more or less sinusoidal activity, ranging in amplitude from 20 to 60 \N (averaging about 50), occurring in the alpha range and most prominent posteriorly. The alpha rhythm is generally 'blocked', or attenuated in amplitude, by eye opening, this block lasting at most several minutes. Although the frequency of the alpha rhythm is the same on each side, the actual waves themselves are generally out of phase, and there is also generally an amplitude difference, the left-sided alpha wave being up to 50% lower than the right. The alpha rhythm is best seen in a state of relaxed wakefulness with the eyes closed. The beta rhythm consists of bilateral beta activity of an amplitude of 30 |aV or less, seen best anteriorly, which is blocked unilaterally by contralateral tactile stimulation, movement or merely an intention to move. Although the waves are generally out of phase, the frequency is bilaterally symmetric: an amplitude variance of up to 35% from side to side is considered normal. Beta activity is often increased by sedatives such as benzodiazepines (Frost et al. 1973; Greenblatt et al. 1989). The mu rhythm represents another normal type of EEC activity, one which is not seen as routinely as is the alpha rhythm or the beta rhythm, being present in only about 10% of normal adults. The mu rhythm consists of theta or alpha activity (ranging from 7 to 11 Hz) that appears as long transients ('trains') lasting at least several seconds in the centroparietal region. Although they occur bilaterally, these trains are often not synchronous, one side having a train and then losing it, a train appearing a little later on the opposite side. The mu rhythm is generally 50 \N or less in amplitude. The mu rhythm, like the beta rhythm, may also be unilaterally blocked by contralateral phenomena (Chatrian 1964; Chatrian et al. 1959) including movement (Chatrian et al. 1960), intention to move (Klass and Bickford 1957) and tactile stimuli (Magnus 1954). Each of these three normal rhythms may represent a kind of 'idling' of the underlying cerebral cortex. This hypothesis, poetic as it might be, gains support from the various blocking manuevers. For example, if the alpha rhythm represents an idling occipital cortex, one would expect it to be blocked when the occipital cortex is brought into gear by visual stimuli. Normal sleep may be broadly divided into two types: REM (rapid eye movement) and nonREM (non-rapid eye movement). REM sleep is, as the name suggests, characterized by rapid, saccadic, conjugate eye movements and is typically associated with dreaming. NREM sleep is generally not associated with dreaming, and during such sleep, the eyes are either still or slowly roving about. NREM sleep may further be divided into four stages, I, II, III and IV, each of these stages having a distinctive electroencephalographic signature (Rechtschaffen and

Diagnostic assessment 29

Kales 1968). In order to identify the various stages, one must be familiar with several different transient events: vertex sharp transients, K complexes, sleep spindles and positive occipital sharp transients( POSTs). Vertex sharp transients (also known as 'V waves') are intermittently occurring, bilaterally symmetric sharp waves of high amplitude (rarely more than 250 uV) seen most prominently at the vertex. K complexes are very similar to vertex sharp transients, differing only in that they generally consist of a diphasic slow wave. Sleep spindles are transients lasting from one-half to several seconds, consisting of rhythmic activity in the 11-14 Hz range, which, as with all spindles, demonstrates a gradual increase and decrease in amplitude, with a maximum of generally less than 50 uV. These sleep spindles occur simultaneously on both sides and, although maximal centrally, are widespread. POSTs (Vignaendra et al. 1974), as the acronym suggests, consist of sharp waves of positive polarity seen posteriorly in the occipital regions. They are monophasic and generally of no more than 50 uV in amplitude; although they are seen bilaterally, they are not synchronous. Furthermore, they are not rhythmic, being seen at irregular intervals of anywhere from several to one per second. With these various transients in mind, the four sleep stages may now be defined. Stage I consists of a slowing of the background rhythm into the delta-theta range (2-7 Hz), accompanied by vertex sharp transients. Stage II is characterized by a persistence of the slowing and the vertex sharp transients, but with the appearance of K complexes, sleep spindles and POSTs. Stage III is characterized by further slowing (20-50% of the background activity being in the delta range), an absence of vertex sharp transients, a fading out of K complexes and sleep spindles, but a persistence of POSTs. Stage IV is identified by gross slowing (more than 50% delta activity), an absence of vertex sharp transients and K complexes, and only rare sleep spindles and POSTs. The entire night's sleep typically occurs in cycles, each cycle lasting from 80 to 120 minutes. The first cycle begins as the patient drifts into stage I, progressing down through stages II and III to stage IV and thence back up through stages III and II to stage I, from which REM sleep emerges. The end of REM sleep signals the end of the first cycle and the beginning of the next. During one night's sleep, subjects normally pass through 5-7 of these cycles, and with each successive cycle, the amount of time spent in stage IV sleep decreases. EEC abnormalities The various EEC abnormalities discussed here include decreased amplitude, slowing (either focal or generalized), interictal ('epileptiform') and ictal abnormalities, periodic complexes, triphasic waves and the burst-suppression pattern. DECREASED AMPLITUDE

Low-amplitude EEC activity may result either from an alteration in the media between the cortex and the recording electrode or from decreased electrogenesis by the cortex. For example, both grease and an abnormally thick skull (e.g. in Paget's disease) act as an insulator, and fluid collections, such as subgaleal, epidural or subdural hematomas, act as 'shunts' that divert the electrical field away from the overlying electrode. Cortical electrogenesis may be reduced either because of actual destruction, as in tumors or infarcts, or decreased neuronal activity, as in migraine, the postictal state or various toxic or metabolic encephalopathies. Amplitude changes are best assessed during relaxed wakefulness with the eyes closed. Generalized low-amplitude EEGs of from 20 to 10 uV may be seen in 5-10% of normal adults; an amplitude of less than 10 uV is rarely seen in normal subjects. When the general amplitude is reduced to below 20 uV, it is helpful to be able to compare the current record with

30 Diagnostic assessment

past ones, or to make serial recordings in order to determine whether the low amplitude is stable or worsening. It is also critical to ensure that the recording is made during relaxed wakefulness: tense or anxious patients, or those engaging in some more or less demanding mental activity, will have low-amplitude recordings. A generalized decrease in amplitude may be seen in conditions characterized by widespread cortical neuronal loss (e.g. Huntington's disease, Creutzfeldt-Jakob disease, Alzheimer's disease and postanoxic encephalopathy) or widespread neuronal dysfunction (e.g. hepatic encephalopathy, uremia, hypothyroidism, hypothermia and postictally after a generalized seizure). Unilateral or focal low-amplitude EEGs may be seen in conditions that cause a unilateral increase in the media (e.g. subdural hematoma) and either unilateral neuronal destruction (e.g. infarction or tumor) or dysfunction (e.g. transient ischaemic attacks, migraine and postictally after a simple partial seizure [Kaibara and Blume 1988]). In evaluating amplitude asymmetries of the alpha rhythm, one must not forget that the left side normally has an amplitude of up to 50% less than the right; it is thus only when the alpha rhythm on the left is more than 50% less than that on the right that one can declare that an abnormality is present. The beta rhythm is generally bilaterally symmetric, but even here an amplitude asymmetry is not unusual in normal individuals; thus, for the beta rhythm, any asymmetry must be more than 35% before it can be declared outside the normal range. A unilateral reduction in amplitude of the beta rhythm indicates a frontal lesion. In general, a unilateral reduction of the alpha rhythm suggests a lesion of the underlying occipital cortex, but in the case of the alpha rhythm, an amplitude reduction may also be seen with distant lesions, in the frontal or parietal cortices or the ipsilateral thalamus. Amplitude asymmetry may occasionally be spurious, as for example with 'breach' rhythms. Here, in conditions where the skull has been breached, for example with a burr hole or fracture (regardless of how much scar tissue has formed), an excessive amplitude is seen on the side with the breach, making the normal amplitude activity on the other side appear low by comparison (Cobb et al. 1979). SLOWING

EEC slowing during wakefulness reflects either neuronal dysfunction or destruction and may be either focal or generalized. Focal slowing may contain either theta or delta activity, the center of the focus typically showing the greatest slowing and the periphery evidencing frequencies that gradually merge into those of the normal surrounding activity. The amplitude of the slow waves at the center of the focus may be either decreased or increased, whereas the amplitude of the waves at the periphery of the focus is generally increased relative to that of the normal surrounding background activity (Arfel and Fischgold 1961). Such focal slowing may be seen in a variety of conditions, for example with a tumor (Daly and Thomas 1958) or postictally after a focal onset seizure (Gilmore and Brenner 1981). Generalized slowing of the EEG may be either bilaterally synchronous or asynchronous. Synchronous delta activity, when intermittent, is termed intermittent rhythmic delta activity (IRDA) and generally indicates a deep midline subcortical disturbance that 'orchestrates' both sides such that they undergo slowing in concert. In children, such slowing is generally seen in the occipital region, producing OIRDA, whereas in adults it is generally best seen in the frontal area, as FIRDA (Zurek et al. 1985). Asynchronous generalized slowing may be seen with widespread cortical dysfunction, as typically seen during delirium (Pro and Wells 1977; Romano and Engel 1944). It must be noted, however, that not all delirium is accompanied by slowing and that indeed it may be characterized by fast activity, as for example during delirium tremens (Kennard et al. 1945; Schear 1985). Widespread asynchronous slowing may also be seen in dementing disorders, such as Alzheimer's disease (Deisenhammer and Jellinger

Diagnostic assessment 31

1974). When generalized asynchronous slowing is persistent and in the delta range, the acronym PNDA (for persistent non-rhythmic delta activity) is often used. A mild degree of generalized asynchronous slowing may also be seen as a normal variant in a small minority of subjects; furthermore, occasional scattered theta transients are not at all abnormal in the normal waking record. Generalized slowing also, of course, occurs with sleep, and thus slowing in a drowsy patient who is slipping in and out of sleep is of little significance. INTERICTAL AND ICTAL EEC ABNORMALITIES

Interictal activity Interictal activity consists of epileptiform activity, that is to say paroxysmal transients consisting of isolated spikes, isolated sharp waves, or complexes containing spikes or sharp waves (e.g. spike-and-sharp wave, and sharp-and-slow wave activity). Although epileptiform activity may be seen in a very small percentage of subjects who have never had a seizure (Ajmone-Marsan and Zivin 1970; Gibbs et al. 1943; Zivin and Ajmone-Marsan 1968), they are typically present only in patients with a history of seizures. Importantly, however, although most epileptic patients will have interictal epileptiform abnormalities (Goodin and Aminoff 1984), the absence of such a finding does not rule out a diagnosis of epilepsy as a significant minority of patients with definite and unquestionable seizures have a normal interictal EEC (Ajmone-Marsan and Zivin 1970; Martins da Silva et al. 1984). Epileptiform activity may be either focal or multifocal. Focal epileptiform activity strongly suggests an underlying focal epileptogenic lesion (e.g. a tumor, scar or area of cortical dysplasia), whereas multifocal epileptiform activity, as might be guessed, suggests widespread and multiple lesions (e.g. subsequent to severe head injury). The task of localizing focal epileptiform activity is facilitated by having in mind a spatial image of the electrical activity itself. Most paroxysmal electrical discharges are 'surface negative' (Matsuo and Knott 1977), i.e. their electrical potential is negative with regard to the normal baseline. Furthermore, most of these discharges cover a fairly wide area: although the discharge may at times be 'seen' under but one elctrode, it occurs in most cases over a wider area, subtending two or more adjacent electrodes. The electrical activity itself may be visualized as a landscape, which may in turn contain various topographic features: gently rolling electrical hills and valleys represent the normal EEC background, whereas deep chasms can be likened to epileptiform discharges plunging down from the background. With this image in mind, one can understand the changes produced on either a referential or bipolar montages. To take an example, consider an epileptiform discharge producing an electrical 'chasm' on the left hemisphere that is large enough to subtend electrodes F3, C3 and P3, as illustrated in Fig. 1.4. Keep in mind also that, in this example, the 'walls' of the chasm, rather than going straight up and down, slope down to the greatest electrical depth. Thus, proceeding from Fpl to F3 the depth falls, from F3 to C3 it continues to fall to its nadir, from C3 to P3 it rises, and from P3 to G! it continues to rise back to the surface. Assume, for the purpose of this example, that the gently rolling landscape exists at an electrical potential of-25 uV, and that this is what electrodes F pl , d and AI 'see'. Furthermore, assume also that electrode F3, being over the gently downsloping wall of the chasm, sees a potential of -50 uV, and that electrode C3, being over the nadir of the chasm, sees a potential of-100 uV. Electrode P3, being over the following wall of the chasm, sees -50 uV, and electrode C^ encompasses the normal landscape of -25 uV. Depending on whether a referential or bipolar montage is used, the EEC recording of this same landscape will look quite different. In a referential recording, as noted earlier, each scalp or active electrode is paired with the same reference electrode, in this example the ear; thus, in this example, as illustrated in Fig. 1.5, there are five channels to consider: Fpl-A!, F3-A15 C3-Ai, Ps-Aj and C^-Aj. Channel

32 Diagnostic assessment

A2

Figure 1.4 Highly schematic diagram of a surface-negative epileptiform discharge, of greatest extent at electrode C3 (see text for details).

A2

Fpi - AI

F 3 -Ai

C 3 -Ai

P3-A1

Figure 1.5 Referential recording of the epileptiform discharge shown in Figure 1.4, above (see text for Oi-Ai

details).

Fpl-Aj, with both electrodes 'seeing' the same potential, would register no difference; channel F3-A1 would see a difference of 25 uV (i.e. looking up from a depth of-50 to the surface, which is at -25); channel C3-A1 would see a difference of 75 uV (looking up from a depth of-100 to the surface at -25); channel P3-A1 a difference of 25 uV (looking up from -50 to -25), and the last channel, O1-A1, with both electrodes seeing -25 uV, would register 0. As seen in Fig. 1.5, the greatest pen deflection is seen in the channel containing the electrode, in this example C3, that lies over the deepest part of the electrical chasm. Thus, with referential recordings, it is the

Diagnostic assessment 33

channel showing the greatest amplitude that serves to localize the focus of the electrical paroxysm. It may be noted that the pen deflections in channels F3-A1, C3-A1 and P3-A1 are all positive, and this is according to the convention (Knott 1985) that whenever, in going from the first to second lead of any channel, one is 'looking' up, the pen goes up, but if one is 'looking' down the pen likewise goes down. The situation with bipolar recordings is quite different: here, it is not amplitude that is important but a phenomenon known as phase reversal (Knott 1985; Lesser 1985). Take the same example of an electrical paroxysm as used above, but this time cover it, as illustrated in Fig. 1.6, with a longitudinal chain of electrodes, starting at Fpl and including, sequentially, F3, C3, P3 and O1.Then construct the following channels: Fpl-F3, F3-C3, C3-P3, and, finally, P3-O1. Now consider what each channel will record. For channel Fpl-F3, one looks down from Fpl at -25 to F3 at -50, for a difference of-25 uV. For the next channel, F3-C3, one continues to look down into the electrical chasm, now looking down from -50 to -100, for a difference of -50 uV. At the next channel, C3-P3, however, something very different happens. Here, standing at the nadir of the chasm at -100, one is looking 'up' to -50, for a difference of +50 uV. Similarly, for the next channel, P3-O1, one continues to look up, but here from -50 to -25, for a difference of +25 uV. Fig. 1.6 shows the various pen tracings seen for each channel. As may be noted, both channels Fpl-F3 and F3-C3 show a downward or negative pen deflection. What happens next, however, is most critical: the next two channels, C3-P3 and P3-O1 both show an upward or positive deflection. It is apparent here that there has been a phase reversal as one goes from channel F3-C3 to channel C3-P3. This indicates that, in going from channel F3-C3 to channel C3-P3, one has 'crossed' over the depth of the electrical chasm; furthermore, since the electrode that both these channels have in common is C3, it is now clear that the depth of the chasm lies under that electrode; that is to say, phase reversal is seen at electrode C3.

FP1 - F3

F3-C3

C3-P3

Pa-Oi

Figure 1.6 Bipolar recording of the epileptiform discharge shown in Figure 1.4 (see text for details).

34 Diagnostic assessment

In some cases, focal epileptiform activity will not exhibit phase reversal with a bipolar montage. Specifically, when the focus is either proximal to the start of the chain or distal to its end, phase reversal is not possible. For example, consider a longitudinal chain linking Fpl, F3, C3, P3 and O1, and then imagine that the focus is located anterior to F pl . In this case, all the pen deflections will be positive. Conversely, if the focus were distal to O1, all the pen deflections would be negative. IctaI activity

Ictal activity is distinguished from the interictal activity just described primarily by its duration, lasting at least a few seconds. Electrographically, one sees the paroxysmal onset of sustained rhythmic activity that may either remain more or less focal, begin focally and then generalize, or occur in a generalized fashion from the very outset. Although in some cases in which there was some preceding interictal epileptiform activity, the ictal discharges may resemble the interictal ones, the ictal discharge is in most cases morphologically different (Blume et al. 1984; Geiger and Horner 1978). In general, the ictal activity is rhythmic and may occur at any frequency, from delta to beta; rarely, instead of primarily a change in frequency, one may see a change in amplitude, namely an 'electrodecremental' pattern in which the seizure is accompanied only by a paroxysmal loss of amplitude, or actual flattening of the EEC. In general, ictal activity that remains focal is associated with simple partial seizures; that which begins focally but then generalizes to involve both temporal lobes, with complex partial siezures, and that which begins focally but then generalizes to involve most of the cortex, associated with grand mal seizures. Although in most of these cases of focal onset seizures, the EEC will reveal ictal activity, simple partial seizures represent an exception, and in many of these cases, the scalp EEC during the seizure will be normal (Devinsky et al. 1989); furthermore, in many cases of grand mal seizure, the ictal EEC will be obscured by a muscle artifact. Ictal activity that is generalized from the very outset is typically associated with either grand mal or petit mal seizures. Petit mal epilepsy is characterized electrographically by interictal and ictal acitivity that are essentially morphologically identical, the only difference between them being their duration. The characteristic abnormality seen in petit mal epilepsy is a spike-and-wave complex wherein the spike is very brief, may either precede or follow the wave, and is generally of lower amplitude than the wave, which is itself generally rounded in shape (Dalby 1969). Interictally, these complexes, rather than being focal, are generalized throughout the EEC. Ictally, these generalized complexes recur continuously at a rate of approximately 3 Hz, and a duration of even as little as one-half second may be associated with clinical 'absence' (Browne et al. 1974). There is a variant of petit mal seizures known as 'atypical absences', the EEC of which may show discharges with some focality or lateralization, often of lower frequency (Gastaut et al. 1966). PERIODIC COMPLEXES

Periodic complexes generally consist of one or more sharp waves combined with one or more slow waves that recur on a regular basis, at intervals ranging from 1 to 15 seconds, often on a background of generalized slowing. Although they may begin with a focal predominance, they fairly soon become generalized and synchronous, often with a frontal prominence. Such periodic complexes are often associated with myoclonus and are classically seen in disorders such as subacute sclerosing panencephalitis (Cobb 1966; Cobb and Hill 1950) and Creutzfeldt-Jakob disease (Aguglia et al. 1987; Burger et al. 1972; Chiofalo et al. 1980; Levy et al. 1986; Steinhoff et al. 1996). Importantly, although almost all patients with Creutzfeldt-Jakob disease eventually develop periodic complexes (Browne et . 1986), these

Diagnostic assessment 35

may be absent (Bortone et al. 1994; Zochodne et al. 1988), which appears to be particularly the case with new-variant Creutzfeldt-Jakob disease (Will et al. 1996). Periodic lateralized epileptiform discharges (PLEDs) consist of, as the name suggests, lateralized epileptiform discharges (either spikes or sharp waves) that occur with a fairly regular periodicity, varying from once every one-half to every 5 seconds (Chatrian et al. 1964; Markand and Daly 1971). These are generally associated with acute infarctions or tumors (Walsh and Brenner 1987) but may also occur with herpes simplex encephalitis (Lai and Gragasin 1988) or early in the course of Creutzfeldt-Jakob disease (Au et al. 1980; Upton and Gumpert 1970); clinically, they may be accompanied by partial or generalized seizures. The appearance of PLEDs is an ominous sign as they are associated with a high mortality rate. PLEDs may also occur in situations in which a metabolic disorder, hypoxemia or alcohol withdrawal is superimposed upon a pre-existing scar (Chu 1980; Kuroiwa and Celesia 1980). TRIPHASIC WAVES

Triphaisc waves are slow waves that, as the name indicates, possess a triphasic morphology. They typically occur in a generalized, bilaterally synchronous fashion, often with a frontal predominance, either singly, in an isolated fashion, or in longer bursts. Although they are classically associated with hepatic encephalopathy (Karnatze and Bickford 1984; Summerskill et al. 1956), they may be seen in other types of metabolic delirium (Fisch and Klass 1988) such as that of uremia, hypercalcemia or hyponatremia. BURST-SUPPRESSION

The burst-suppression pattern is characterized by bursts of generalized, bilaterally symmetric and synchronous delta activity, lasting of the order of 1-3 seconds and occurring every 3-10 seconds, in between which the background activity is suppressed to a very low amplitude or, at a normal sensitivity, to a flat line. This pattern is seen in states of severe cortical dysfunction, for example subacute sclerosing panencephalitis (Markand and Panzi 1975), viral encephalitis or postanoxic coma. Although it is typically bilateral, it may occasionally be seen unilaterally, as for example after a very large infarction. Activation procedures Hyperventilation, photic stimulation and sleep are all considered to be activation procedures in that they may activate certain abnormalities that would not otherwise be apparent on the routine EEG. HYPERVENTILATION

Hyperventilation is normally followed by a build-up of generalized bilaterally symmetric and synchronous high-amplitude slow waves, maximal frontally in adults (Goldberg and Strauss 1959). Abnormalities that may occur include asymmetric or focal slowing and epileptiform abnormalities. Asymmetric or focal slowing has the same significance as spontaneous slowing, as discussed above. Epileptiform abnormalities are very common in the case of petit mal seizures, the recordings of most of these patients showing typical 3 Hz spike-and-dome epileptiform changes (Dalby 1969). In the case of complex partial seizures, however, only a small minority of cases will display activation (Adams and Lueders 1981; Gabor and AjmoneMarsan 1969; Miley and Forster 1977; Morgan and Scott 1970). Hyperventilation is generally contraindicated in patients with sickle cell disease or those with significant cerebrovascular or cardiovascular disease.

36 Diagnostic assessment

PHOTIC STIMULATION Photic stimulaton is accomplished by positioning a stroboscopic light about 30 cm from the patient's face, the eyes being either open or closed. The light is then flashed at various frequencies (e.g. 3, 5, 10, 13, 15, 17, 20 and 25 Hz), each frequency being allotted about 10 seconds. In about two-thirds of normal adults, this stroboscopic illumination will produce the photic driving response, wherein bilaterally symmetric and synchronous waves appear at a frequency equal to either the stroboscopic frequency or some harmonic of it (Hughes 1960). Normally, although the photic driving is maximal occipitally, it may extend to the parietal or temporal area. Maximal photic driving is generally seen when the strobe frequency is close to the patient's normal alpha rhythm, and, as with the alpha rhythm, the amplitude of the photic driving response is often lower on the left side. With very high-frequency stroboscopic activity, the resultant wave forms may resemble spikes. Abnormalities seen with photic driving include unexpected amplitude asymmetries, photomyoclonic responses and photoparoxysmal responses. Amplitude asymmetries wherein the left side has an amplitude of less than 50% that of the right, or wherein the right side has an amplitude less than that of the left, indicate a definite abnormality. The photomyoclonic response (Meier-Ewert and Broughton 1976) consists of a myoclonic twitching of the eyelids and, in severe cases, myoclonus of the head and neck; it may be seen in a very small minority of normal individuals (Kooi et al. 1960) and more commonly in those withdrawing from alcohol or sedative-hypnotics (Fisch et al. 1989; Gastaut et al. 1958). The photoparoxysmal response consists of epileptiform changes (Bickford et al. 1952) and is most common in those with primary generalized petit mal or grand mal seizures (Stevens 1962; Wolf and Gooses 1986). A minority of patients with the photoparoxysmal response will experience a seizure during the photic stimulation (Seddigh et al. 1999). SLEEP

Sleep may activate epileptiform activity (Sammaritano et al. 1991); the sleep portion of the recording should last at least 20 minutes and include both stages I and II of sleep. In some cases, patients will simply drift off to sleep on their own at the end of the recording session, whereas in others the administration of chloral hydrate will be required. Some authors recommend sleep deprivation, not only to ensure that the patient falls asleep during the recording, but also in the belief that sleep deprivation per se is activating: this is a controversial notion, supported by some (Ellingson etal. 1984; Mattson et al. 1965) but not all studies (Pratt et al. 1968; Veldhuizen et al. 1983). In interpreting a sleep EEG, it is important to distinguish epileptiform activity from normally occurring POSTs and vertex sharp waves. In addition to revealing epileptiform abnormalities, sleep recordings may, at times, reveal other abnormalities, for example the early onset of REM sleep, as may be seen in narcolepsy or in alcohol or anxiolytic withdrawal (Kales et al. 1974). Finally, in cases of definite or suspected 'reflex' epilepsy, it may be appropriate, as discussed in Chapter 7, p. 302, to expose the patient to the triggering event itself. Thus, in 'musicogenic' epilepsy, the appropriate tune may be played, and in 'reading' epilepsy, the appropriate passage read, etc. Consideration must, of course, be given to the risk of inducing a seizure during the recording.

Normal variants Normal variants may resemble epileptiform changes (e.g. small sharp spikes [SSS]) or pathologic slow waves (e.g. subclinical rhythmic EEG discharges of adults [SREDA]).

Diagnostic assessment 37

SSS, also known as benign epileptiform transients of sleep (BETS), are, as the name suggests, low-amplitude, very sharp spikes (i.e. less than 50 uV in amplitude and less than 50 msec in duration) that are seen intermittently during drowsiness in both temporal areas, either intermittently or in a bilaterally synchronous fashion (Klass and Westmoreland 1985; White et al 1977). Phantom spike-and-wave (also known as 6 cps spike-and-wave) (Klass and Westmoreland 1985; Thomas and Klass 1968) is characterized by brief trains of rhythmic 6 Hz activity that are generalized, bilaterally symmetric and synchronous, generally lasting no longer than a second or two. The name comes from the fact that the rhythmic activity is composed of a peculiar spike-and-wave complex wherein the spike is of such relatively low amplitude and brevity that, next to the much more prominent wave, it, like the 'Phantom', is rarely seen. 'Occipital spikes of blind persons', an aptly named electrographic syndrome, may be seen in patients with congenital or acquired blindness and is characterized by intermittent spikes confined to the occipital area. SREDA (Westmoreland and Klass 1981) is characterized by lengthy trains of rhythmic theta or, less commonly, delta activity, seen best in the centroparietal areas. The trains themselves are often of abrupt onset and may be preceded by some sharp waves. They generally last about a minute and are most commonly seen with hyperventilation in the elderly. Rhythmic mid-temporal discharges (Gibbs et al. 1963; Klass and Westmoreland 1985), also known as rhythmic theta bursts of drowsiness consist of lengthy trains of rhythmic theta activity that occur in both temporal areas, either synchronously or independently. The trains themselves often last about 10 seconds, but they may endure for as long as a minute. This variant was once referred to as the psychomotor variant, but this terminology has been abandoned as there is no connection between rhythmic mid-temporal discharges and complex partial seizures. Ctenoids, also known as '14 and 6 cps positive bursts' (Klass and Westmoreland 1985; Lombroso et al. 1966) consist of brief trains, lasting one-half to one second, of 6 or 14 Hz rhythmic waves, that occur in the temporal regions either independently or in a bilaterally synchronous fashion. They are best seen during stages I and II of sleep, and the waves themselves have a distinctive arciform morphology. Wicket spikes (Klass and Westmoreland 1985; Reiher and Lebel 1977) consist of brief trains of rhythmic activity at a frequency of 6-11 Hz that are most prominent in the temporal regions, where they may appear independently or in a bilaterally synchronous fashion. Like ctenoids, the waves themselves have an arciform morphology. Lambda waves (Barlow et al. 1969; Evans 1953; Green 1957; Scott et al. 1967) are isolated, bilaterally synchronous occipital waves that occur just after saccadic eye movements made by patients as they scan a detailed scene or picture. The waves themselves are of 20-50 uV in amplitude and 200-300 msec in duration, and have a characteristic triangular or sawtoothshaped morphology.

Artifacts Artifacts may be grouped according to the EEG activity that they most closely resemble, such as spikes, slow waves or decreased amplitude, as noted in Table 1.2. There is also a 60 cps artifact, which is usually readily identified as it does not resemble any naturally occurring EEG activity. RESEMBLING SPIKES

Drip artifact reflects the electrical disturbance occurring each time a drip occurs in an intravenous line. It may appear so similar to an epileptiform spike that its correct

38 Diagnostic assessment Table 1.2 EEG artifacts Artefact Resembling spikes

Drip artifact Electrode pop ECG artifact Muscle artifact

Resembling slow waves

Eye movement Movement artifact Pulse artifact Perspiration

Resembling decreased amplitude

Increased electrode resistance Defective calibration

Sixty cycle per second artifact

identification may depend on the EEG technician noting on the record when the drips occur. Electrode pop reflects, as it were, a sudden 'spark' at an individual electrode, often occurring secondary to some impurity. Although it strongly resembles an epileptiform spike, the fact that it is restricted to one electrode betrays its artifactual nature as true epileptiform spikes are almost always seen at more than one electrode. ECG artifact represents cardiac electrical activity picked up by the EEG. In the case of a regular cardiac rhythm, its artifactual nature is immediately obvious as epileptiform spikes simply do not occur with such monotonous regularity. When irregularly occurring premature ventricular contractions are present, however, the distinction may be more difficult and indeed may depend on simultaneously recording the ECG. Muske artifact reflects electrical activity arising from the contraction of the scalp musculature and may appear in any one of three ways: as isolated irregulary appearing 'blips', or as 'blips' superimposed on a 'muddy' black line, the blips occurring either arrythmically or rhythmically. The key to the identification of muscle 'blips' is their extreme brevity. RESEMBLING SLOW WAVES

Eye movement, if vertical, may be reflected in the frontopolar leads and, if horizontal, in the anterior temporal leads. The eye may, heuristically, be considered to be a 'battery', the cornea being positive and the retina negative: thus, whichever electrode the eye 'looks' toward becomes more positive, and whichever one the eyes 'look' away from becomes, conversely, more negative. Consider, for example, the results with a longitudinal bipolar montage when the patient engages in horizontal eye movement looking to the left: F7 becomes more positive relative to T3, and thus, in the channel P7-T3, the pen deflection is downwards; conversely, F8 becomes more negative relative to T4, and thus, in channel F8-T4, the pen deflection is up. Next, consider the situation with vertical eye movements, as occur during a blink (Matsuo et al. 1975), recalling that when a blink occurs, the eyes, in Bell's phenomenon, undergo upward rotation. In this case, both frontopolar electrodes, Fpl and Fp2, become positive relative to their immediate neighbors, F3 and F4, and thus channels Fpl-F3 and Fp2-F4 both show a negative deflection. Eye movement artifacts, whether horizontal or vertical, are suggested by their bilateral synchrony. A further indication, in the case of horizontal movements, is the fact that the resulting pen deflections on either side are in opposite directions. In the case of vertical eye

Diagnostic assessment 39

movements occurring with blinking, the occurrence of eyelid flutter may make identification a little more difficult because the resulting artifact will appear similar to a bifrontal slow wave focus. The restriction of this 'focus', however, to only two electrodes suggests its artifactual nature. Movement artifact occurs when the electrodes are actually moved, as most commonly occurs when the occipital electrodes, pressed between the patient's head and the underlying pillow, are slightly dislodged by the minimal head movements that occur with respiration. The regularity of the resulting artifact, the identity of its frequency with the respiratory rate and its restriction to the occipital leads all highlight its true nature. Pulse artifact occurs in situations when an electrode is accidentally placed over a relatively large scalp artery, which, with every passing pulse, slightly moves the electrode resting on it. The fact that the resulting artifact occurs at a regular rate, identical to the cardiac rate, suggests its true identity: in doubtful cases, a simultaneous ECG will reveal that the pulse artifact follows, after a slight delay, every QRS complex, the delay reflecting the time required for the pulse to travel from the heart to the scalp. Perspiration on the scalp, as may occur if the patient is febrile or anxious, both alters the resistance of the overlying electrodes and allows for some slight slippage between the electrodes and the scalp: the resulting artifact consists of very slow waves (e.g. 0.5 Hz) of very high amplitude, which occur in a generalized, bilateral but asynchronous fashion. RESEMBLING DECREASED AMPLITUDE

Increased electrode resistance may lead to what appears to be decreased amplitude at one electrode. Its restriction, however, to but one electrode betrays its artifactual nature as pathologic conditions capable of causing decreased amplitude are rarely so restricted in location that they will be reflected at only one electrode position. Defective calibration of one channel may result in a decreased deflection of that channel's pen. Its isolation to one pen suggests the correct diagnosis, and the fact that, with changing montages, the same pen continues to show decreased deflection, confirms the diagnosis. SIXTY CYCLE PER SECOND ARTIFACT

A 60 Hz artifact occurs secondary to interference from a nearby alternating current source, typically appearing on the EEG as a thick 'muddy' line. If there is any doubt as to the source of such a 'muddy' line, lowering the paper speed to 15 mm/sec will, by allowing the resolution of the line into orderly 60 Hz deflections, confirm the diagnosis.

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2 Signs, symptoms, and syndromes 'Cortical' signs and symptoms Abnormal movements Other signs and symptoms Syndromes of cognitive impairment Syndromes of disturbances of mood and affect Other major syndromes

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2 'Cortical' signs and symptoms Aphasia Alexia Agraphia Acalculalia Gerstmann's syndrome

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Hypergraphia Aprosodia Apraxia Agnosias Neglect

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APHASIA Aphasia is a controversial subject: the approach offered here, although for the most part representing that favored by most contemporary aphasiologists, nevertheless will not find favor in the eyes of all. Precise correlations between the various aspects of disordered language and lesion sites have been elusive, and in all liklihood the scheme presented here will require change as more data become available. Description of the syndrome Aphasia is characterized by an impairment of one or more aspects of spoken language. Assessment begins by observing the patient's spontaneous speech and determining whether it is non-fluent or fluent. Non-fluent speech is sparse, laconic and often 'telegraphic', that is to say, lacking in prepositions and conjunctions. Fluent aphasic speech, by contrast, may be quite voluble, but it is marked by varying degress of incoherence and by paraphasias, wherein patients utilize words incorrectly. The next step involves determining whether or not patients are able to comprehend complex commands. Finally, one should determine whether or not the patient can correctly name common objects in the room, such as a lamp, and whether or not the patient is able to correctly repeat a phrase, such as 'No ifs, ands or buts.' Once this assessment has been accomplished, it is generally possible to classify the aphasia into one of the following types: motor transcortical motor sensory transcortical sensory global transcortical mixed

52 Signs, symptoms and syndromes

conduction pure word deafness anomic an atypical group. Importantly, however, it must be borne in mind that this classificatory scheme is but an approximation: clinical reality often overflows the nosologic boundaries we erect, and atypical cases are not at all uncommon (Brown and Simonson 1957). Indeed, in bilingual patients, one may see a different aphasia for each language: in one case of a native Spanish speaker who had Hebrew as a second language, there was a motor aphasia for Spanish and a sensory one for Hebrew (Silverberg and Gordon 1979). Each of the various types of aphasia is described further below, with comments on its localizing value. Before proceeding, however, a word is in order regarding aphasia's lateralizing value. As is well known, the dominant hemisphere for language is the left hemisphere, and in the vast majority of cases, an aphasia indicates a left hemisphere lesion. Furthermore, this generally holds true also in left-handers, for even here the dominant hemisphere for language is generally the left (Goodglass and Quadfasel 1954; Humphrey and Zangwill 1952). In those rare cases in which right-handers develop an aphasia secondary to a lesion in the right hemisphere, one speaks of a 'crossed aphasia' (Bakar et al. 1996; Brown and Wilson 1973; Holmes and Sadoff 1966), and this has been noted with motor aphasia (Hindson et al. 1984; Trojanowski et al. 1980), transcortical motor aphasia (Ghika-Schmid and Bogousslavsky 2000) sensory aphasia (Alexander et al. 1989; Henderson 1983; Sweet et al. 1984), global aphasia (Assal et al. 1981) and mixed transcortical aphasia (Cappa et al. 1993). Motor aphasia

Motor aphasia, also known as Broca's aphasia or expressive aphasia, is characterized by nonfluent, effortful speech that is laconic, agrammatic and telegraphic. Although patients can comprehend what is said to them, can follow complex commands and know what they want to say, they yet have great difficulty expressing themselves, and their sparse speech often lacks prepositions and conjunctions; repetition is also impaired. Some patients are reduced to short phrases or single words only, and in severe cases, muteness may be seen. Interestingly, emotionally laden speech, such as cursing, may be relatively unaffected, and some patients may evidence a remarkably preserved ability to sing (Yamadori et al. 1977). The inability to speak may leave patients with motor aphasia frustrated and either irritable or depressed (Benson 1973). In most cases, the responsible lesion is seen to involve the posterior portion of the inferior frontal gyrus (Mohr et al. 1978; Naeser and Hayward 1978; Tonkonogy and Goodglass 1981): the lesion in question may of course be much larger, involving adjacent areas, and in some cases it appears that an involvement of the white matter subjacent to this area may be sufficient (Naeser et al. 1982). Given that most lesions extend beyond the inferior frontal gyrus, it is very common to find associated deficits, such as a right-sided hemiplegia: indeed, although noted (Masdeu and O'Hara 1983), it is very uncommon to find an isolated motor aphasia without any accompanying deficits. Motor aphasia has also been noted with a left thalamic lesion (Megens et al. 1992). Transcortical motor aphasia

Transcortical motor aphasia is essentially identical to motor aphasia, with the exception that repetition is preserved. Transcortical motor aphasia is most often seen with lesions of the medial aspect of the left frontal lobe, as may occur with infarctions in the area of distribution of the anterior cerebral artery (Alexander and Schmitt 1980; Bogousslavsky and Regli 1990; Freedman et al. 1984;

'Cortical' signs and symptoms 53

Racy et al. 1979; Rubens 1975). A syndrome similar to transcortical motor aphasia may also occur with lesions of the putamen or thalamus (Alexander and Lo Verme 1980; Ghika-Schmid and Bogousslavsky 2000). Sensory aphasia

Sensory aphasia, also known as Wernicke's aphasia or receptive aphasia, is characterized by fluent speech that is more or less incoherent and contaminated by paraphasias: such patients are unable to follow complex commands and are also unable to repeat what is told to them. In its most severe form, jargon aphasia is seen with almost incomprehensible speech. In some cases, patients may appear untroubled by their often severe deficit, whereas others may become agitated and suspicious, even to the point of having delusions of persecution (Benson 1973). Sensory aphasia may be seen with lesions involving the temporoparietal area (Naeser and Hayward 1978), especially Wernicke's area on the posterior surface of the superior temporal gyrus (Seines et al. 1985). Lesions of the white matter subjacent to Werncke's area may also occasionally cause a sensory aphasia (Naeser et al. 1982). Transcortical sensory aphasia

Transcortical sensory aphasia resembles sensory aphasia, except that repetition is intact. Transcortical sensory aphasia may be seen with lesions of the parietotemporal area that spare Wernicke's area (Seines et al. 1985), or with lesions of the left thalamus, principally the dorsomedial nucleus (Bogousslavsky et al. 1988a; Tuszynski and Petito 1988). Global aphasia

Global aphasia is characterized by a combination of speech that is effortful and sparse and an inability to follow complex commands; such patients are also unable to repeat phrases. Global aphasia, although most commonly seen with very large lesions involving the frontal, parietal and temporal cortices (Bogousslavsky 1988; Naeser and Hayward 1978), may also be seen secondary to the combined effects of two lesions, one in the frontal and one in the temporoparietal area (as may be seen with embolic infarctions, for example) (Hanlon et al. 1996; Van Horn and Hawes 1982). Transcortical mixed aphasia

Transcortical mixed aphasia resembles global aphasia with the exception that repetition is for the most part spared. Interestingly, such patients, although unable to speak fluently, may be able to sing (Jacome 1984). Transcortical mixed aphasia may be seen with lesions that, in one way or other, 'isolate' the posterior portion of the superior temporal gyrus and adjacent angular gyrus from the rest of the cortex. It has been reported with watershed infarction (Bogousslavsky et al. 1988b) and infarction of the medial aspects of the left frontal and parietal cortices (Ross 1980). Conduction aphasia

Conduction aphasia is characterized by fluent but paraphasic speech, an intact ability to follow complex commands and a striking inability to repeat phrases. Conduction aphasia is classically associated with damage to the arcuate fasciculus (Benson et al. 1973; Damasio and Damasio 1980) but has also been noted with infarction of the basal ganglia (Godefroy et al. 1994) Pure word deafness

Pure word deafness is a remarkable syndrome characterized by an isolated inability to comprehend spoken words and to repeat phrases. Spontaneous speech is preserved. One patient commented, 'Voice comes but no words ... There is no trouble at all with the sound. Sounds come. I can hear, but I cannot understand it.' (Hemphill and Stengel 1940). Another

54 Signs, symptoms and syndromes

patient, although able to recognize non-speech sounds, such as telephone rings or automobile horns, could not understand spoken words: he commented, 'I can hear you talking but I can't translate it' (Kanshepolsky et al. 1973). Pure word deafness has been noted with bilateral damage to the superior temporal gyrus (Coslett et al. 1984; Kanshepolsky et al. 1973) and, in one rare case, with bilateral damage to the inferior colliculi (Meyer et al. 1996). Transcortical pure word deafness, wherein patients, although unable to understand the spoken word are able to repeat it, may or may not occur in pure form: a possible case was noted with a lesion of the left angular gyrus (Heilman et al. 1981). Anomic aphasia

Anomic aphasia is characterized by an inability to find the right word. Such a word-finding difficulty may become apparent when patients are asked to name an object: although they may be able to describe it and say what it does, they nevertheless cannot find the acutal name. Repetition is preserved. Anomic aphasia has poor localizing value and may also be seen as a side-effect of certain medications, such as tricyclic (Schatzberg et al. 1978) and monoamine oxidase inhibitor (Goldstein and Goldberg 1986) antidepressants. Atypical aphasias

Atypical aphasias are not uncommon and simpy do not fit into the categories noted above. They are particularly associated with subcortical lesions (Ciemens 1970; Damasio et al. 1982a).

Differential diagnosis of the syndrome Dysarthria is distinguished from motor aphasia by the fact that although words are slurred and difficult to understand, dysarthric speech is neither laconic nor sparse, and careful listening reveals normal syntax and a normal use of conjunctions and prepositions. Loosened associations, as may be seen in schizophrenia and other psychoses, are distinguished from fluent aphasic speech by their bizarreness (Gerson et al. 1977) and by the presence of other psychotic signs and symptoms not seen in aphasia, such as auditory hallucinations. Delirium is often marked by varying degrees of incoherence but is distinguished from a sensory aphasia by the overall gross confusion. Deafness obviously impairs a patient's ability to follow a spoken command, and may thus present a picture similar to pure word deafness. Cortically deaf patients, however, make no response to any sounds, including automobile horns or ringing telephones (Bahls et al. 1988; Le Gros Clark and Russel 1938), whereas those with pure word deafness, albeit unresponsive to spoken words, do recognize and respond appropriately to other environmental sounds, such as the telephone ringing (Coslett et al. 1984; Kanshepolsky et al. 1973). Focal lesions, such as cerebral infarctions and tumors are the most common causes of aphasia, and in such cases, the clinical characteristics of the aphasia may change over time, worsening as a tumor enlarges or undergoing a partial remission as the edema surrounding a recent infarction subsides (Pedersen et al. 1995). Aphasia has also been noted secondary to a toxoplasma abscess (as may be seen in AIDS [Navia et al. 1986]), focal demyelinization (as in progressive multifocal leukoencephalopathy [Astrom et al. 1958; Krupp et al. 1985] or multiple sclerosis [Achiron et al. 1992; Devere et al. 2000; Olmos-Lau et al. 1977]) and hypoglycemia. Presumably, in the case of hypoglycemia, a subclinical lesion, perhaps a small scar, becomes symptomatic with the added burden of hypoglycemia. In most cases, a hemiplegia accompanies the aphasia, and typically, both the hemiplegia and the aphasia clear with the restoration of normoglycemia (Wallis et al. 1985).

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Aphasia may also occur as but one part of the clinical picture seen in disorders affecting multiple areas of the cerebrum. Thus, aphasia may be seen as a symptom of various neurodegenerative dementias, such as Alzheimer's disease (Faber-Langendoen et al. 1988; Price et al. 1993), Pick's disease, frontotemporal dementia and diffuse Lewy body disease. Aphasia may also be seen in multi-infarct dementia, and a motor aphasia marked by speech hesitancy may be the presenting sign in dialysis encephalopathy (Lederman and Henry 1978; O'Hare et al. 1983). Certain disorders, destined eventually to affect multiple areas of the cerebrum, may present with a slowly progressive aphasia, thus constituting the syndrome of 'primary progressive aphasia'. Although, in most cases, the aphasia is of the motor type, primary progressive aphasia may also be characterized by a sensory or global aphasia (Mendez and Zander 1991). The most common cause of primary progressive aphasia is a neurodegenerative disorder, such as Alzheimer's disease (Galton et al. 2000; Green et al. 1990; Greene et al. 1996), Pick's disease (Graff-Radford et al. 1990; Karbe et al. 1993; Kertesz et al. 1994; Wechsler et al. 1982), frontotemporal dementia (Turner et al. 1996) or, rarely, corticobasal ganglionic degeneration (Ikeda et al. 1996); in some cases, the cause of the degeneration appears unclassifiable (Neary et al. 1993; Schwarz et al. 1998; Snowden et al. 1992). A similar picture may be seen with appropriately placed, slowly growing tumors and, rarely, with Creutzfeldt-Jakob disease (Mandell et al. 1989) or Balo's concentric sclerosis (Balo 1928). Epilepsy may be associated with aphasia, as either an ictal or a postictal phenomenon. Aphasia may be the sole manifestation of simple partial status epilepticus (Labar et al. 1992) (in one case lasting over 24 hours [Hamilton and Mathews 1979]), or it may be associated with twitching of the right side of the face (Williamson et al. 1985). Aphasia may also be seen as part of the symptomatology of a complex partial seizure (Devinsky et al. 1994; Knight and Cooper 1986). Postictal aphasia may also occur and very strongly suggests that the seizure focus is in the left hemisphere (Gabr et al. 1989; Privitera et al. 1991). Developmental aphasia is an idiopathic disorder characterized by a failure to develop speech in the normal course of maturation: motor (Sato and Dreifuss 1973), sensory (Bartak et al. 1975; Cohen et al. 1989; Paul et al. 1983) and pure word deafness (Karlin 1951) types have been described. Developmental aphasia can be distinguished from autism on the basis of the dysphasic child's relatedness: unlike autistic children, who are isolated, dysphasic children generally have good social skills (Bartak et al. 1975; Paul et al. 1983). Developmental aphasia must also be distinguished from cases of acquired aphasia in childhood. The differentiation is straightforward: in developmental aphasia, language is simpy never fully acquired, whereas in acquired cases, language is in fact acquired, only subsequently to be lost. In addition to lesions such as tumors, an important cause of acquired childhood aphasia is the Landau-Kleffner syndrome, characterized by the combination of seizures and aphasia (Mantovani and Landau 1980; Paquier et al. 1992).

ALEXIA (DYSLEXIA) Description of the symptom Alexia may occur on either an acquired or a developmental basis, being in both cases characterized by a predominantly isolated inability to read despite normal visual acuity and otherwise normal cognitive ability.

56 Signs, symptoms and syndromes

ACQUIRED ALEXIA

Acquired alexia, also known as 'pure' alexia, or 'alexia without agraphia' is said to occur when patients, despite being able to understand what is said, and both to speak and to write normally, are unable to read. Not only are such patients unable to read what others have written, but, unless they have memorized what they themselves have written, they are also unable to read their own writing (Leegard et al. 1988). In one case (Cohen et al. 1976), an English teacher commented, 'I can write and I can see, but I can't read.' The authors commented that 'she was able to write sentences on the board and could read them immediately as long as she remembered what she had written, but within several minutes she was unable to comprehend what she had recently written.' The patient herself noted that 'it was as if the writing were in a foreign language.' In some (Stommel et al. 1991; Warrington and Langdon 1994), but not all (McCarthy and Warrington 1986), cases, patients are able to get around their alexia by using a 'letter-by-letter' strategy wherein they say out loud each letter of the word, listening carefully to what they say. As oral comprehension is not impaired, they are able, by listening, to put the spoken letters together and thus make out and understand the word that they still cannot read. DEVELOPMENTAL ALEXIA

Developmental alexia, also known as developmental dyslexia or 'reading disorder' generally comes to light at around the time most children in literate countries are expected to master reading skills, typically between the ages of 6 and 9 years (Goody and Reinhold 1961). Such children seem to stumble over words as they attempt to read out loud and may skip over words or misread them. As pointed out by Orton (1925), these misreadings often result from letter reversals, for example, reading 'gary' when the actual printed word is 'gray'.

Differential diagnosis of the symptom Aphasia, whether acquired or developmental, is distinguished by a concurrent difficulty in either speaking or understanding spoken language: it must be emphasized that patients with alexia have no trouble speaking and can follow complex commands given to them orally. Neglect may at times interfere with reading when patients either fail to read the left half of a word (e.g. reading 'house' for 'birdhouse') or misread the left-hand part of the word (e.g. 'crash' for 'brash') (Kinsbourne and Warrington 1962a). Testing for neglect is therefore appropriate when entertaining a diagnosis of alexia. ACQUIRED ALEXIA

Acquired alexia may occur secondary to appropriately situated lesions such as infarctions or tumors. An understanding of the localizing value of alexia is thus facilitated by reviewing the relevant neuroanatomy. The optic tract terminates in the lateral geniculate body of the thalamus; from the lateral geniculate body, the geniculocalcarine tract arises and proceeds to the calcarine cortex, located on the medial aspect of the ipsilateral occipital cortex. Fibers from the left calcarine cortex proceed directly anteriorly, toward the left angular gyrus, whereas fibers from the right calcarine cortex must first pass forward, and then cross in the splenium of the corpus callosum, after which they proceed laterally to an eventual juncture with the fibers that originated in the left calcarine cortex. These conjoined fibers then proceed anteriorly, finally to terminate in the left angular gyrus. It appears that any lesion or combination of lesions that isolate the left angular gyrus from both the right and the left sides will result in alexia without agraphia. Specifically, the following lesions or combinations of lesions may be responsible:

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1 a combination of lesions of the left lateral geniculate body and the splenium (Stommel et al. 1991) 2 a combination of lesions of the splenium and left calcarine cortex (Ajax et al 1977; Damasio and Damasio 1983) 3 a lesion of the white matter of the left occipitoparietal area (Ajax 1964; Benito-Leon et al. 1997; Iragui and Kritchevsky 1991; Leegard et al. 1988; McCarthy and Warrington 1986; Warrington and Langdon 1994), which may at times be exquisitely placed just subjacent to the angular gyrus itself (Greenblatt 1973, 1976). As might be expected, alexia without agraphia secondary to either the first or the second situation would also be accompanied by a right hemianopia (Geschwind 1965), whereas in the third situation, the patient's visual fields would remain intact. One may rarely see a 'crossed' alexia, as for example in a left-handed patient who developed alexia secondary to a lesion on the right (Pillon et al. 1987): in such cases, the hemianopia would be to the left. From the above, one might expect that it would be safe to say that alexia without agraphia (with or without hemianopia) lateralizes to the dominant hemisphere. Unfortunately, exceptions to this rule do occur. Thus, there are case reports of right-handed patients developing alexia without agraphia secondary to lesions in the right occipital lobe (Fincham et al. 1975) or right occipitotemporal area (Henderson et al. 1985). Finally, a case has been reported of alexia without agraphia occurring during migraine (Bigley and Sharp 1983). DEVELOPMENTAL ALEXIA

Developmental dyslexia is probably an hereditary illness: in some families, there is strong evidence for an autosomal dominant inheritance (Drew 1956; Marshall and Ferguson 1939), and the monozygotic concordance rate is significantly higher than the dizygotic one (Bakwin 1973). Although this is not without controversy (Rumsey et al. 1997), it appears that the normal asymmetry of the planum temporale is absent (Haslam et al. 1981) and that there is neuronal disarray, most prominently in the left perisylvian area (Galaburda et al. 1985).

AGRAPHIA (DYSGRAPHIA) Description of the symptom Agraphia may occur on either an acquired or a developmental basis, being in both cases characterized by a predominantly isolated inability to write, despite normal strength and coordination, and a preserved ability to read. The developmental form of agraphia, also known as developmental dysgraphia or 'disorder of written expression', usually comes to light between the ages of 7 and 10, 'when most children in literate countries master this skill. Such patients may have difficulty spelling (Cole 1964), and overall grammar and syntax are often deficient.

Differential diagnosis of the symptom Aphasia, whether acquired or developmental, is distinguished by a concurrent difficulty in either speaking or understanding spoken language. It must be emphasized that patients with agraphia, in addition to being able to read, also have no difficulty in speaking and can follow complex commands given to them orally.

58 Signs, symptoms and syndromes

Gerstmann's syndrome involves agraphia but is distinguished by the additional presence of finger agnosia and left-right disorientation. Paresis or an abnormal involuntary movement, such as tremor or chorea, may of course interfere with writing, but this is usually fairly obvious. Ideational apraxia may also hamper writing as such patients are unable to manipulate the pen, this diagnosis being suggested by the presence of a similar difficulty with other 'tools', such as a fork or a comb. ACQUIRED AGRAPHIA

Acquired agraphia has been noted with a lesion in the vicinity of Exner's area in the posterior portion of the middle frontal gyrus on the left (Toghi et al. 1995). Unilateral agraphia has also been noted as part of a callosal disconnection syndrome (Yamadori et al. 1980): normally, writing with the left (non-dominant) hand is made possible by fibers that pass from Exner's area on the left, through the corpus callosum and to the homotopic area in the right frontal lobe, which in turn controls the left hand. When the corpus callosum is damaged such that these fibers are disrupted, the right frontal lobe is 'deprived' of direction by the left, and thus, although patients are still able to write with the right hand, they are not able to do so, even clumsily, with the left. A variant of acquired agraphia was reported in one case wherein a lesion of Exner's area produced not only severe agraphia, but also a degree of alexia (Anderson et al. 1990). Another variant has also been reported with a lesion of the left temporal lobe: in this case, although the patient was able to write, what the patient wrote was incoherent (Rosati and De Bastiani 1979). DEVELOPMENTAL AGRAPHIA

Developmental agraphia usually becomes evident between the ages of 7 and 10; although it is probably familial, little else is known.

ACALCULALIA (DYSCALCULALIA) Description of the symptom Acalculalia may occur on either an acquired or a developmental basis. In both cases, patients experience an isolated inability to do calculations, such as addition, subtraction, multiplication and division. A standard test for this is 'serial sevens', wherein patients are asked to subtract seven from 100, then seven from that number, and to continue doing so as far as they can. Patients normally make no more than two or three errors (Smith 1962). Although serial sevens constitutes a reasonable screening test, one may rarely find a patient with acalculalia who, although unable to add, multiply or divide, is yet able to perform subtraction (Lampletal. 1994).

Differential diagnosis of the symptom Dementia, delirium and mental retardation all involve some deficit in calculation, but other cognitive deficits are also present in these disorders. Difficulty with calculation may also occur as part of Gerstmann's syndrome, described below.

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Pure acquired acalculalia has been seen with lesions of the left parietal lobe (Lampl et al. 1994; Takayama et al. 1994) (especially the angular gyrus [Benson and Wier 1972]) and of the left striatum (Corbett et al 1986). Developmental acalculalia, also known as developmental dyscalculia or 'mathematics disorder', generally becomes apparent between the ages of 6 and 10 years. GERSTMANN'S SYNDROME Gerstmann's syndrome has long been a controversial entity, some asserting that, at least in pure form, it does not exist. As the cases noted below demonstrate, however, such a syndrome, albeit rare, can occur. Description of the syndrome Gerstmann's syndrome consists of the tetrad of finger agnosia, left-right disorientation, agraphia and acalculalia (Gerstmann 1940, 1957). Finger agnosia may be tested for by asking patients to close their eyes and then touching their index, middle or ring finger and asking which finger was touched: those with finger agnosia will score no better than chance on identifying the correct finger. Left-right disorientation may be tested by asking patients to touch a contralateral part of the body (Gerstmann 1940) (e.g. 'Touch your right knee with your left hand'): those with left-right disorientation may use the incorrect hand or touch an ipsilateral part of the body. Agraphia is tested by asking the patient to read, and acalculalia by testing for serial sevens. Differential diagnosis of the syndrome Pure Gerstmann's syndrome, according to Gerstmann (1940, 1957), localizes to the left angular gyrus, and subsequent reports of pure cases have been noted with lesions affecting the left angular gyrus and adjacent supramarginal gyrus (Roeltgen et al. 1983; Tucha et al. 1997), as well as the white matter immediately subjacent to the angular gyrus (Mayer et al. 1999). In many instances, the syndrome will not be 'pure', but, because of the size of the lesion and the involvement of adjacent areas, 'contamination' will occur, with accompanying aphasia or apraxia. Gerstmann's syndrome may occasionally occur on a developmental basis (Benson and Geschwind 1970; De Benito et al. 1988). HYPERGRAPHIA Description of the sign Hypergraphia, as defined by Mungas (Hermann et al. 1988), is characterized by a tendency to excessive writing that goes beyond any social, occupational or educational requirements. Differential diagnosis of the sign As the boundaries of this sign are not clear, and there is no precise cut-off between mere wordiness and hypergraphia, clinical judgment is required, with special attention to whether

60 Signs, symptoms and syndromes

or not the writing in question represents a significant change from the patient's characteristic level of written output. Mania may be characterized by hypergraphia, wherein it represents the written equivalent of pressured speech. Kraepelin (1976) noted that manics may produce an 'astonishing' number of documents, all from 'the pleasure in writing'. The presence of other typical symptoms, such as increased energy, pressured speech, a decreased need for sleep, etc. indicate the correct diagnosis. Schizophrenia may also lead to hypergraphia, and Kraepelin (1971) commented on the 'very numerous and monotonous' documents that may appear, all marked by neologisms, delusional thoughts and loosened associations. The interictal personality syndrome, as seen in patients with chronic epilepsy, typically includes hypergraphia (Hermann et al. 1988; Okamura et al. 1993; Waxman and Geschwind 1974, 1975), and is suggested by the history of chronic epilepsy and the appearance of other aspects of the syndrome, such as deep and persistent affect, verbosity, a preoccupation with religious, ethical or philosophical concerns, hyposexuality and irritability. Cerebral infarction of the right hemisphere may be followed by hypergraphia and is suggested by the acute onset of such signs as left hemiparesis, left hemisensory loss or left neglect (Yamadori et al. 1986). Tumor of the right hemisphere caused a mild delirium in an 80-year-old, which was joined by such a vigorous hypergraphia that the patient, in his graphic labor, 'sometimes continued writing on the table without noticing the margins of the paper' (Imamura et al. 1992). The frontal lobe syndrome was, in one case, associated with hypergraphia, which appeared to be part of the syndrome of utilization behavior in that the patient wrote non-stop, often copying whatever he happened to see, such as newspaper headlines or even trade marks on the pencil he was holding (van Pugt et al. 1996).

APROSODIA Prosody refers to the affective or emotional aspects of speech, which are in turn conveyed by the inflection, rhythm and tone with which patients speak (Monrad-Krohn 1947a, b): aprosodia, in turn, represents a defect either in recognizing the prosody with which others speak or in speaking with normal prosody oneself. The subject of aprosodia, as with aphasia and apraxia, is controversial: the scheme advanced here generally follows that proposed by Ross (1981).

Description of the sign Aprosodia is often conceived of as the non-dominant hemisphere 'mirror image' of dominant hemisphere aphasia (Gorelick and Ross 1987; Ross 1981) and, like aphasia, is divided into several types, including pure affective deafness, sensory aprosodia, global aprosodia and motor aprosodia. Pure affective deafness is characterized by an inability on the patient's part to grasp or comprehend the feeling 'behind' what another person has said. For example, if another person said, 'I'm going home' in a lilting, buoyant way, the patient would not have any idea how the speaker felt about going home until and unless the speaker added the words 'and I'm glad about it.'

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Sensory aprosodia is characterized by a prosody that 'makes no sense' relative to the words spoken by the patient: there seems to be a mismatch between what the patient says and the feeling with which it is said. For example, a patient with sensory aprosodia might say 'I'm very sad that I'm going home today', and although meaning it, and in fact feeling sad, would yet speak in a cheerful voice. Motor aprosodia is characterized by a flat, montonous voice wherein all the words spoken by the patient are stripped of emotional tone and valence. Although such patients have definite feelings about what they say, those feelings do not come across unless they are decidedly put into words. One of Ross and Mesulam's (1979) patients found herself having great difficulty in disciplining her children because, although angry, her voice was 'unmodulated, monotonous ... [and] devoid of inflections and coloring.' They noted that she 'was able to circumvent these difficulties by tacking a parenthetical statement, such as "God damnit, I mean it" or "I am angry and mean it," after a sentence, but it should be emphasized that even the parenthetical statement was voiced in a complete monotone without emotion'. Global aprosodia represents a combination of pure affective deafness and motor aprosodia, patients being not only unable to comprehend the prosody of others, but also unable to impart prosody to their own speech. Such patients exist in a monotonous world: not only do they speak in a monotone, but, for them, so also does everyone else.

Differential diagnosis of the sign Aphasia must be clearly distinguished from aprosodia. Aphasia represents a disturbance in what is said, aprosodia a disturbance in how it is said. Consider, for example, two patients, both grief-stricken over a recent loss. The first one, having a motor aphasia (Broca's aphasia), although restricted to simply repeating the word 'sad ... sad ... sad' over and over again, might yet say it so lugubriously that the listener has no doubt about the depth of the patient's grief. By contrast, the second patient, with a motor aprosodia, although able to say the words 'I've never felt so sad in my entire life', would say them in such a monotone that the listener might well doubt whether the patient was, in fact, really feeling any sadness. Motor aprosodia must be distinguished from parkinsonian hypophonia, abulia (as seen with frontal lobe lesions) and flattened affect (as seen in schizophrenia). Parkinsonian hypophonia is suggested by the presence of other parkinsonian signs, such as tremor or rigidity. Both abulia and flattened affect are distinguished by an absence of feeling: patients with motor aprosodia, by contrast, do have feelings but lack the ability to express them. Aprosodia almost always indicates a lesion in the non-dominant hemisphere: examples of 'crossed' aprosodia (Darby 1993; Ross et al. 1989), wherein the sign appears with a lesion of the dominant hemisphere, are rare. Pure affective deafness localizes to the occipitoparietal (Gorelick and Ross 1987) or temporoparietal (Starkstein et al. 1994) areas. Sensory aprosodia, in addition to occurring with lesions of the posterosuperior temporal (Darby 1993) and temporoparietal (Gorelick and Ross 1987; Ross 1981) cortices, has also been noted with a lesion of the right thalamus (Wolfe and Ross 1987). Motor aprosodia generally indicates a lesion in the frontal operculum (Gorelick and Ross 1987; Ross 1981; Ross and Mesulam 1979). It has also, albeit uncommonly, been noted with lesions of the putamen (Speedie et al. 1993) and of the internal capsule, specifically the posterior two-thirds of the anterior limb, the genu and the anterior third of the posterior limb (Rossetal. 1981). Global aprosodia has been noted with large lesions involving the fronto-parietotemporal operculum (Ross et al. 1981).

62 Signs, symptoms and syndromes

APRAXIA In apraxia, patients, although possessed of appropriate strength, sensation and coordination, are yet unable successsfully to perform a learned and more or less complex motor task. Of the various types of apraxia, those considered here include ideational and ideomotor (considered together), dressing and constructional apraxia. Before proceeding, the reader is entitled to a caveat: the field of apraxia is rife with controversy and nosological uncertainty, and the approach adopted here, albeit held by some and commended by this author, will find disfavor in the eyes of others. Description of the sign Ideational and ideomotor apraxia both have to do with the use of tools, considered in the broadest sense, such as hammers, combs and scissors. Bedside testing for these two apraxias is conveniently performed by first asking patients to mime using a pair of scissors to cut an imaginary piece of paper, and then, if patients have trouble doing this, offering an actual pair of scissors and piece of paper and instructing the patient to, in fact, use the scissors to cut the paper. In both ideational apraxia and ideomotor apraxia, patients are unable successfully to mime the use of the tool. When given the tool, however, whereas the patient with ideational apraxia is unable to use it, the patient with ideomotor apraxia can pick up the tool and successfully cut the paper. Ideational apraxia may be obvious on casual inspection, as patients, on morning rounds, are found to be unable to use a comb, toothbrush, etc. Many appear quite perplexed by their dilemma. Although they can name the tool and even say what the tool is for, they nevertheless cannot utilize it: they may pick it up, turn it over, hold it by the wrong end or simply stare at it, sometimes with a bemused expression. By contrast, ideomotor apraxia is generally not evident to casual inspection and must be specifically sought for. Patients with ideomotor apraxia may have no trouble with using, say, a toothbrush, and may be surprised to find that they cannot mime its use. Constructional apraxia is characterized by an inability to draw a simple line figure, such as a house, a star or a daisy, despite an otherwise preserved ability adequately to manipulate the pencil and make marks on the paper. Dressing apraxia becomes apparent when patients attempt to dress themselves. One patient 'put his arms in the wrong sleeve of the shirt [and] put the back of his shirt in the front' (Hecaen et al. 1956). Differential diagnosis of the sign Wernicke's aphasia makes testing for ideational or ideomotor apahsia difficult or impossible as patients simply cannot understand what they are commanded to do. Neglect of the left side, as may be seen with right parietal lesions, may simulate constructional apraxia to a degree. In neglect, however, the deficient drawing is present only on the left side of the figure, whereas the right side of the figure is drawn more or less normally; by contrast, in constructional apraxia, both the left and right halves of the figure are poorly drawn. Left neglect may also simulate dressing apraxia, as patients may leave the left side of their dressing unattended to, with buttons left unfastened, shoes left untied, etc. Here, however, as with the differential with constructional apraxia, the clue to the diagnosis of neglect is the presence of adequate dressing on the right side of the body.

'Cortical' signs and symptoms 63

Delirium may, without specific testing, be difficult to differentiate from ideational apraxia. In both cases, one gets the impression of confusion upon watching the patient attempt to use a tool. With delirium, however, the confusion is real and global, being evident in other tasks; by contrast, in ideomotor apraxia, the 'confusion' is restricted to tool use and patients are otherwise clear, with intact orientation and memory. Ideational apraxia may be seen with left parietal lesions (De Renzi and Lucchelli 1988) and lesions affecting either the left lenticular nucleus (De Renzi et al. 1986) or left thalamus (De Renzi et al. 1986; Warren and Thompson 2000). Ideational apraxia is also seen in various dementing disorders that affect the cortex, such as Alzheimer's disease, multi-infarct dementia, diffuse Lewy body disease and Huntington's disease; indeed, albeit very rarely, Alzheimer's disease may actually present with a slowly progressive ideational apraxia (Ross et al 1996). Special mention must also be made of corticobasal ganglionic degeneration, wherein ideational apraxia plays a very prominent role in the overall clinical picture of parkinsonism, dystonia and myoclonus (Riley et al. 1990; Rinne et al. 1994). Ideomotor apraxia may also be seen with lesions of the left parietal lobe (Heilman 1973) and left thalamus and basal ganglia (Agostoni et al. 1983; Nadeau et al. 1994). In one case, a primarily ideomotor apraxia constituted the presenting feature of Pick's disease (Fukui et al. 1996). Constructional apraxia indicates a lesion in the right hemisphere, principally in the right parietal lobe (Hecaen et al. 1956; Motomura et al. 1986; Piercy et al. 1960). Unilateral constructional apraxia of the right hand has been noted as a 'disconnection syndrome' secondary to a lesion of the corpus callosum in a right-handed patient. Here, although the patient was able to draw with the left hand, performance of the same task with the previously adept right hand was quite poor (Giroud and Dumas 1995). Dressing apraxia indicates a lesion in the right hemisphere, principally the parietal lobe (Brain 1941; McFie et al. 1950).

AGNOSIAS The agnosias are characterized by an inability to recognize certain phenomena, despite intact sensation. The various different types of agnosia are each discussed below. Visual agnosia DESCRIPTION OF THE SYNDROME

Visual agnosia is said to be present when a patient, despite intact visual acuity, is unable to recognize an object by sight alone (Rubens and Benson 1987). When shown a familiar object, such as a pair of scissors, patients are not only unable to name it, but are also unable to say what it might be used for. Importantly, in testing for visual agnosia, it is important not to allow patients to handle the object as recognition by touch may still be retained. DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

Visual agnosia must be distinguished from a mild Broca's aphasia. Like patients with visual agnosia, patients with Broca's aphasia may also be unable to name a familiar object, but, unlike the visually agnostic patient, the patient with Broca's aphasia will often be able to say what the object is used for. For example, although the aphasic patient may not be able to say the word 'scissor', such a patient might still be able to say that the object was for 'cutting pieces of paper'.

64 Signs, symptoms and syndromes

In most cases, visual agnosia occurs with bilateral medial occipitotemporal lesions (Albert et al. 1979; Benson et al. 1974); it has also been noted with unilateral right-sided lesions (McFie et al. 1950). Color agnosia DESCRIPTION OF THE SYNDROME

The patient with color agnosia, although able to distinguish various colors, is yet unable to name them (Kinsbourne and Warrington 1964; Meadows 1974a). DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

Color agnosia must be distinguished from acquired color blindness, or achromatopsia (Damasio et al. 1980), this distinction being readily accomplished with Ishihara plates. Whereas patients with achromatopsia are unable to read the plates, patients with color agnosia are. The patient with achromatopsia exists in a world of grays; by contrast, the patient with color agnosia, although able to discern hues, cannot name them. Color agnosia is often found in association with alexia without agraphia secondary to a lesion affecting the splenium and the medial portion of the left occipital cortex (Geschwind and Fusillo 1966). Prosopagnosia DESCRIPTION OF THE SYNDROME

Prosopagnosia is characterized by an inability to recognize and identify familiar others by their facial features (Sergent and Poncet 1990). Such patients, although able to recognize faces as faces, and indeed able to describe accurately the facial features of others, are yet unable to identify the other person (Tranel et al. 1988). Remarkably, these patients, although unable to identify others by their facial features, may be able to identify them by their voice, dress or characteristic gait (Damasio et al. 1982b). Some examples may help to clarify this remarkable condition. In one case, the patient, a party to a lawsuit, had come to identify his own lawyer by the setting in which the two of them generally met, namely his lawyer's office: when the patient finally appeared in court, and felt the need to discuss a legal question, he went up to the opposing counsel and discussed the case, 'with disastrous consequences' (Pevzner et al. 1962). In another case, the patient had come to rely on his wife's clothing as a means of identifying her: at a party, he found himself unable to recall what she had put on, and though she walked right by him, he failed to recognize her (Hecaen and Angelergues 1962). Another patient (Hecaen and Angelergues 1962) 'failed to recognize a physician who had just examined him after the doctor had substituted his suit jacket for his white coat'. As might be expected, such patients, in addition to being unable to recognize old acquaintances by their facial features, are now also unable to utilize facial features to recognize new acquaintances (Malone et al. 1982). DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

Prosopagnosia generally occurs secondary to bilateral lesions of the occipitotemporal area (Cohn et al. 1986; Damasio et al. 1982b; Meadows 1974b; Pevzner et al. 1962). Unilateral

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lesions, more often on the right than the left (Rosier et al 1997), may also be responsible, and this has been specifically noted with infarction (Cohen et al. 1994; Landis et al. 1986,1988), in idiopathic progressive atrophy of the right temporal lobe (Evans et al. 1995), and subsequent to a right hemispherectomy for intractable seizures in a 13-year-old (Sergent and Villemure 1989). Interestingly, prosopagnosia may also occur as a simple partial seizure: in one case, a patient with left occipitotemporal scarring had seizures characterized by a sense of 'flickering lights' followed by a brief episode of prosopagnosia (Agnetti et al. 1978). Tactile agnosia DESCRIPTION OF THE SYNDROME

Tactile agnosia is characterized by an inability to recognize objects by touch. Importantly, this is not due to any sensory defect or any defect in recognizing the shape of the object in question: patients have normal tactile, vibratory and pin-prick sensation and are able to describe the object placed in the hand (Platz 1996). For example, if a key were placed in the patient's hand, the patient, by feel alone, although able to describe the object as having a rounded shape at one end attached to a longer rectangular shape with a serrated edge, would still be unable to identify that object as a key. Once allowed to see the object, however, it is immediately recognized. Importantly, because tactile agnosia is generally a unilateral phenomenon, it is important to test both hands separately and to prevent the patient from palpating the object with both hands at the same time. DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

Tactile agnosia must be distinguished from astereognosis, which constitutes an inability to recognize the shape of an object by touch alone. For example, whereas the patient with tactile agnosia is able to describe the shape of the object, say a key, the patient with astereognosis is not. Tactile agnosia generally occurs secondary to a lesion in the inferior parietal cortex (Caselli 1993), on either the right (Platz 1996) or the left (Reed et al. 1996). Auditory agnosia DESCRIPTION OF THE SYNDROME

The patient with auditory agnosia is unable to recognize sounds, including both speech and common environmental sounds such as a doorbell or a dog barking (Oppenheimer and Newcombe 1978; Rosati et al. 1982; Vignolo 1982). Although hearing is intact, and the patient indicates that a sound is present, it has no meaning for the patient: all is just 'noise'. DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

Auditory agnosia is clearly distinguished from deafness on the basis that the patient can appreciate noises; it is distinguished from pure word deafness by the fact that the patient with auditory agnosia cannot recognize either speech or environmental sounds, whereas the difficulty in pure word deafness extends only to speech, sounds such as a doorbell being recognized as such. In general, lesions affecting both temporal lobes are found.

66 Signs, symptoms and syndromes

Topographagnosia The definition of topographagnosia is not settled: some use the term to refer to a kind of visual agnosia wherein patients are unable to recognize familiar topographic features, such as buildings or landmarks, whereas others construe it as referring to a loss of a 'sense of direction': it is in this latter sense that the term is used here. DESCRIPTION OF THE SYNDROME

Patients with topographagnosia, although able to recognize landmarks and buildings, are yet unable to find their way (Stracciari et al. 1994): they are unable to imagine the required route to their destination, and have truly lost their 'sense of direction'. In one case, a veteran taxicab driver, suffering an infarction, 'suddenly lost his understanding of the route to his destination ... he could quickly recognize the buildings and landscape around him [but] ... was unable to determine his current location. He stopped taking passengers and tried to return to the main office, but didn't know the appropriate direction to drive' (Takahashi et al. 1997). In another case, the patient: suddenly lost his way home, where he was going on foot. The buildings in front of him were familiar to him, so he could recognize them right away. However, he did not know which direction his home was from there. Relying on cues from buildings, surrounding scenery and signs, but taking several wrong turns along the way, he eventually arrived in front of his own home, and knew immedately that it was in fact his own home (Takahashi et al. 1997).

DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

Topographagnosia must be distinguished from a restricted form of visual agnosia in which patients are unable to identify familiar landmarks. Patients with this form of visual agnosia are unable to find their way because they do not recognize the landmarks: patients with topographagnosia do recognize landmarks but are simply unable to use them to generate an 'internal' map that can be used to chart a course to the destination. Topographagnosia has been noted with lesions involving the left splenium (Alsaadi et al. 2000), the right splenium and right cuneus (Alsaadi et al. 2000), the right retrosplenial area (Takahashi et al. 1997) and bilateral lesions of the medial occipitotemporal cortices (Alsaadi et al. 2000).

Simultanagnosia DESCRIPTION OF THE SYNDROME

Simultanagnosia is characterized by an inability, in a sense, to see the whole for the parts: although patients can readily see individual parts of the whole, they have difficulty seeing them simultaneously as one (Kinsbourne and Warrington 1962b). In one case (Coslett and Saffran 1991), a 67-year-old female complained that: her environment appeared fragmented. Although she saw individual items clearly, they appeared to be isolated, and she could not discern any meaningful realtionship among them ... she reported watching a movie in which, after hearing a heated argument, she noted to her surprise and consternation that the character she had been watching was suddenly sent reeling across the room, apparently as a consequence of a punch thrown by a character she had never seen.

'Cortical' signs and symptoms 67

DIFFERENTIAL DIAGNOSIS OF THE SYNDROME Simultanagnosia has been noted with lesions of the right temporo-occipital area (Cohen et al. 1994; Coslett and Saffran 1991). Anosognosia DESCRIPTION OF THE SYNDROME In anosognosia, patients either fail to appreciate the severity of a deficit (such as hemiplegia) or deny its existence altogether. As Gertsmann (1942) pointed out, 'the patient behaves as though he knew nothing about his hemiplegia, as though it had not existed, as though his paralyzed limbs were normal'. When questioning about the deficit, one hears a range of responses from patients, from a vehement denial of any problem to an admission that perhaps the hemiplegic limb is 'a bit stiff or perhaps suffers from some 'heaviness' (Cutting 1978; Roth 1949). In some cases, the anosognosic patient, although unable to move the limb at all, may report that it is moving (Feinberg et al 2000). Although anosognosia is seen most commonly in relation to hemiplegia (Levine et al. 1991) (and indeed is very common in the first few months after a stroke [Hier 1983a, b]), it may also be seen in relation to hemiballism (Roth 1944), hemianopia (Celesia et al. 1997) and cortical blindness. Anosognosia for cortical blindeness is also known as Anton's syndrome (Bergman 1957; Redlich and Dorsey 1945; Symonds and MacKenzie 1957): here, patients, although completely blind, deny having any significant trouble with sight and will attempt to walk about as if they were sighted, at times injuring themselves in the process. DIFFERENTIAL DIAGNOSIS OF THE SYNDROME Emotionally motivated denial may be distinguished from anosognosia on the basis of the patients' response to counseling: whereas emotionally motivated denial may crumble in the course of an interview with a sympathetic physician, anosognosia does not. Anosognosia is much more common with right than left hemisphere lesions (Cutting 1978; Roth 1949). This may not, however, reflect a true lateralizing tendency but rather the fact that patients with left hemisphere lesions often suffer from a sensory aphasia that prevents the manifestation of ansognosia (Weinstein et al. 1969). In addition to lesions of the right parietal cortex, anosognosia has also been noted with lesions of the posterior limb of the internal capsule and adjacent globus pallidus (House and Hodges 1988), the thalamus (Motomura et al. 1986), the right side of the brainstem (from the caudal midbrain to the pons [Bakchine et al. 1997]), and the pons, on either the right or the left side (Euyapan and Kumral 1999). Asomatagnosia DESCRIPTION OF THE SYNDROME In asomatagnosia, which may be seen in conjunction with left hemiplegia, patients deny that the paretic limb belongs to them, in some cases attributing ownership to someone else, perhaps a family member or the physician (Brock and Merwarth 1957; Feinberg et al. 1990). This syndrome can at times lead to a rather bizarre interview: in one case (Sandifer 1946), a female patient with a left hemiplegia, when her paretic left hand was held up in front of her, indicated that it was not hers but belonged to the physician. When the physician attempted to

68 Signs, symptoms and syndromes

correct her by pointing out that the hand in question had her wedding ring on it, the patient responded, 'That's my ring, you've got my ring, Doctor.' DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

The alien hand sign is distinguished by the fact that the hand in question acts outside the patient's control, as if it had a will of its own. By contrast, the asomatognosic hand does nothing. In most cases, the lesion is found in the right parietal lobe, affecting particularly the supramarginal gyrus (Feinberg et al. 1990). Exceptionally, responsible lesions may be found affecting the right internal capsule and striatum (Healton et al. 1982) or the right thalamus (Motomura et al. 1986).

NEGLECT In this aptly named syndrome, patients, in one fashion or another, neglect or fail to attend to phenomena on one side or the other. In visual neglect, for example, patients, despite having full visual fields, fail to take notice of items in one of the hemifields, usually the left. In motor neglect, patients 'underutilize' the limbs on one side (again, usually the left): although a neglected arm may be possessed of full strength and coordination, it is simply not brought into play during normally bimanual tasks, such as fastening a button. The phenomenon of extinction, considered by some to be a kind of neglect, is also discussed here. It must be stressed that all of the varieties of neglect must be tested for before concluding that neglect, per se, is not present. Visual and motor neglect may occur independently (Laplane and Degos 1983), and each of the various tests for visual neglect (including, as noted below, line bisection, line cancellation and clock-drawing) is independent of the other, some patients failing one test but not the rest (Binder et al. 1992; Ishiai et al. 1993). Extinction and visual neglect may also occur independently (Daffner et al. 1990; Vallar et al. 1994).

Description of the syndrome VISUAL NEGLECT

Visual neglect, also known as spatial neglect, may become evident on any one of a variety of three 'paper and pencil' tests: line bisection, line cancellation and clock-drawing. In order to obtain reliable results for these tests, the patient must be seated squarely in front of a table, the trunk parallel to the edge of the table and the piece of paper placed directly in front of the patient, such that the midline of the paper is continuous with the patient's midline. Although patients may move their head in any direction, and look in any direction, this relative position of the paper and the patient's trunk must be maintained. In the line bisection test, a single line is drawn lengthwise on the piece of paper, with the middle of the line resting at the midline of the piece of paper. The patient is then asked to make a mark right on the middle of the line. When left neglect is present, the mark made by the patient will be to the right of the true midline. Importantly, the line should be of the order of 10 cm or longer because if the line is substantially shorter than this, there may be a 'crossover' effect, whereby the patient with left neglect will place the mark not to the right but to the left of the true midline (Anderson 1997; Tegner and Levander 1991). In the line cancellation test (Albert 1973) the examiner places a large number of short, straight lines randomly on the surface of the piece of paper, the various lines being oriented

'Cortical' signs and symptoms 69

at various and random angles, and then asks the patient to simply mark off each line. In a positive test, the proportion of lines marked off to the left of the midline will be substantially less than the proportion marked off to the right. In the clock-drawing test, the patient is asked to draw a large circle on the paper and then to put in all twelve numbers, as on a clockface. In a positive test, the numbers will be more or less 'bunched up' on the right side. In a similar test, patients are asked to draw a daisy; in a positive test, the petals of the daisy will end up being bunched on the right-hand side. Importantly, patients should be asked to simply 'draw a daisy' and not given instructions to 'arrange' the petals around a circle, because when patients are given such an instruction, the neglect may 'vanish' as the petals are arranged, one by one, evenly around the circle (Ishiai et al. 1997). The reason why the position of the patient's trunk is so important in these three tests is that if the trunk is angled toward the neglected side the portion of the visual field subject to neglect will shrink, to the point at which the tests may become falsely negative (Beschin et al. 1997; Karnath and Hartje 1993). Visual neglect may come to clinical attention in a variety of ways. Patients may fail to comb hair, shave or put on make-up on the neglected side, and food on the neglected side of a dinner plate may go uneaten. In one case (Cherington 1974), left neglect ruined a patient's chess game: although chess pieces on the right side of the board were moved as always, those on the left, neglected, remained in position and were easy prey for his opponent. In another case (Frantz 1950), a patient, while driving, began to run into things (such as pedestrians) on the left. Importantly, as in all cases of visual neglect, these collisions did not occur because of a hemianopia: the patient had full visual fields but simply did not attend to things to his left. Interestingly, visual neglect may also extend to imagined scenes. In one study, for example, patients with neglect were instructed to imagine that they were standing on one side of a famous plaza and then describe what they saw: as might be expected, in their description of the imagined scene, they failed to speak of things on the plaza that were located to their left (Bisiach and Luzzatti 1978). MOTOR NEGLECT

Motor neglect (Triggs et al. 1994) is characterized by'an underutilization of one side, without defects of strength, reflexes or sensibility' (Laplane and Degos 1983). Bedside testing for motor neglect may be accomplished by asking patients to clap their hands or fasten a button: when motor neglect is present, the arm on the neglected side will either not participate in the task or do so only minimally. Importantly, this is not the result of a lack of strength or coordination: with strong urging, patients are generally able to bring the affected arm into play such that there is more or less full bimanual cooperation in the task at hand. Motor neglect may come to clinical attention in a peculiarity of gait: on the affected side, there may be reduced arm swing, and the leg, generally being underutilized and 'left behind', is seen to be 'dragged' along to keep up with the leg on the unaffected side. When patients are in a wheelchair, the arm on the affected side may dangle down from the shoulder and be dragged along passively on the floor as the wheelchair is pushed forward; for patients in bed, the affected leg may be 'left behind', still stretched out on the bed, as the patient swings the leg on the unaffected side over the edge of the bed while attempting to rise. EXTINCTION

Extinction is often considered to represent a subspecies of neglect and may be tested for in both visual and tactile modalities. To test for visual extinction, establish first, with confrontation testing, that the visual fields are full. Stand directly in front of the patient,

70 Signs, symptoms and syndromes

perhaps an arm's length away, and spread your arms to the sides such that your hands end up level with the patient's eyes and perhaps 30 cm in front of the patient. Next, ask the patient to stare at your nose and point to the finger that wiggles, all the while continuing to look straight at your nose. To perform the test, wiggle one index finger at a time: if the patient points to each finger when it wiggles, then, at least on this confrontation testing, the fields are full. At this point, while maintaining the same position, wiggle both fingers simultaneously: with a positive test, the movement on the neglected side is 'extinguished' and the patient points only to the movement on the unaffected side. Testing for tactile extinction is somewhat easier: simply tell the patient that you are going to touch one or both of the patient's hands and that you want the patient to indicate which hand (or hands) you have touched. Then ask the patient to close the eyes, and touch first one, and then the other hand. Presuming that normal sensibility is present, the patient will indicate correctly which hand was touched. Then touch both hands simultaneously: when the test is positive, the tactile sensation on the affected side is 'extinguished' and the patient reports being touched only on the hand of the unaffected side. Both visual and tactile extinction should be tested for because, although they do occur together in some patients, they are more often than not independent, patients having one form of extinction but not the other (Vallar et al. 1994). Differential diagnosis of the syndrome Although neglect may be seen in various dementing disorders that affect a large portion of the cerebrum, such as Alzheimer's disease or multi-infarct dementia, the greatest value of neglect stems from its utility in lateralizing and localizing focal lesions, such as infarctions or tumors. Neglect lateralizes the lesion to the hemisphere contralateral to the neglected side. Most commonly, one finds a left hemineglect with a right hemisphere lesion: although left hemisphere lesions may be followed by a right hemineglect, such right hemineglect is generally neither as severe nor as long-lasting as hemineglect occurring on the left (Stone et al. 1991). Lesions causing neglect may be located in the parietal or frontal lobes or the basal ganglia (Vallar et al. 1994). Although in many cases both the frontal and parietal lobes are involved simultaneously, neglect can occur with lesions restricted to either the frontal lobe (Daffner et al. 1990; Heilman and Valenstein 1972; Maeshima et al. 1994; Stein and Volpe 1983) or the parietal lobe (Bender 1945; Cherington 1974; Critchley 1949; Frantz 1950), and it appears that, between these two lobes, lesions of the frontal lobe are more likely to cause neglect (Laplane and Degos 1983). Within the basal ganglia, neglect has been seen with caudate lesions (Caplan et al. 1990). Thalamic lesions may also cause neglect (Motomura et al. 1986), and, even more discretely, lesions confined to the posterior limb of the internal capsule have also caused this condition (Bogousslavsky et al. 1988c; Ferro and Kertesz 1984).

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1994;57:1423-5. Sweet EWS, Panis W, Levine DN. Crossed Wernicke's aphasia. Neurology 1984; 34:475-9. SymondsC, MacKenzie I. Bilateral loss of vision from cerebral infarction. Brain 1957; 80:415-55. Takahashi N, Kawamura M,ShiotaJefo/. Pure topographic disorientation due to right retrosplenial lesion. Neurology 1997; 49:464-9. TakayamaY, Sugishita M, Akiguchi \etal. Isolated acalculalia due to left parietal \es\on.ArchNeurol 1994; 51:286-91. Tegner R, Levander M. The influence of stimulus properties on visual neglect. J Neurol Neurosurg Psychiatry 1991; 54:882-7. Toghi H, Saitoh K, Takahashi Setal. Agraphia and acalculalia after a left prefrontal (F1, F2) infarction. J Neurol Neurosurg Psychiatry 1995; 58:629-32. Tonkonogy J, Goodglass H. Language function, foot of the third frontal gyrus, and rolandic operculum. Arch Neurol 1981; 38:486-90. Tranel D, Damasio AR, Damasio H. Intact recognition of facial expression, gender, and age in patients with impaired recognition of face identity. Neurology 1988; 38:690-6. Triggs WJ, Gold M, Gerstle G etal. Motor neglect associated with a discrete parietal lesion. Neurology 1994; 44:1164-6. Trojanowski JQ, Green RC, Levine DN. Crossed aphasia in a dextral: a clinicopathological study. Neurology 1980; 30:709-13. Tucha 0, Steup A, Smely C et al. Toe agnosia in Gerstmann syndrome. 7 Neurol Neurosurg Psychiatry 1997; 63:399^103. Turner RS, Kenyon LC, Trojanowski JQ et al. Clinical, neuroimaging, and pathologic features of progressive nonfIuent aphasia. Ann Neurol 1996; 39:166-73. Tuszynski MH, PetitoCK. Ischemicthalamic aphasia with pathologic confirmation. Neurology 1988;

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'Cortical' signs and symptoms 79 VallarG, Rusconi ML, Bignamini ietal. Anatomical correlates of visual and tactile extinction in humans: a clinical CT scan study.y Neural NeurosurgPsychiatry 1994; 57:464-70. Van Horn G, Hawes A. Global aphasia without hemiparesis: a sign of embolic encephalopathy. Neurology 1982; 32:403. van Pugt P, Kees L, Cras P. Increased writing activity in neurological conditions: a review and clincial study. J Neurol Neurosurg Psychiatry 1996; 61:510-14. Vignolo LA. Auditory agnosia. Phil Trans R Soc Lond Biol Sci 1982; 298:49-57. WallisWE, Donaldson I, Scott RSetal. Hypoglycemia masquerading as cerebrovascular disease (hypoglycemichemiplegia)./4flfl A/euro/1985; 18:510-12. Warren JD, Thompson PD. Diencephalic amnesia and apraxia after left thalamic infection.) Neurol Neurosurg Psychiatry 2000; 68:248. Warrington EK, Langdon D. Spelling dyslexia: a deficit in the visual word-form.y Neurol Neurosurg Psychiatry 1994; 57:211 -16. Waxman SG, Geschwind N. Hypergraphia in temporal lobe epilepsy. Neurology 1974; 24:629-36. WaxmanSG, Geschwind N. The interictal behavior syndrome of temporal lobe epilepsy. Arch Gen Psychiatry 1975; 32:1580-6. Wechsler AF, Verity A, Rosenschein S et al. Pick's disease: a clinical, computed tomographic, and histologic study with Golgi impregnation observations. Arch Neurol 1982; 39:287-90. Weinstein EA, Cole M, Mitchell MSet al. Anosognosia and aphasia. Arch Neurol 1969; 10:376-86. Williamson PD, Spencer DD, Spencer SS et al. Episodic aphasia and epileptic focus in the nondominant hemisphere: relieved by section of the corpus callosum./S/euro/ogy 1985; 35:1069-71. Wolfe Gl, Ross ED. Sensory aprosodia with left hemiparesis from subcortical infarction: right hemisphere analogue of sensory-type aphasia with right hemiparesis? Arch Neurol 1987; 44:668-71. Yamadori A, OsumiY, MasuharaSef al. Preservation of singing in Broca's aphasia. J Neurol Neurosurg Psychiatry 1977; 40:221-4. Yamadori A, Osumi Y, Ikeda H etal. Left unilateral agraphia and tactile anomia: disturbances seen after occlusion of the anterior cerebral artery. Arch Neurol 1980; 37:88-91. Yamadori A, Mori E,Tabuchi M et al. Hypergraphia: a right hemisphere syndrome. J Neurol Neurosurg Psychiatry 1986; 49:1160-4.

3 Abnormal movements Tremor Myoclonus Motor tics Chorea Athetosis Ballismus Dystonia

80 83 87 89 93 95 96

Parkinson ism Akinesia Akathisia Catatonia Asterixis Heightened startle response

101 108 109 112 116 117

TREMOR Tremors of various kinds are commonly encountered and may either dominate the overall clinical picture or, conversely, play only a minor role relative to other signs and symptoms.

Description of the sign Tremor is usefully divided into three different types: postural rest intention. Postural tremor is most evident upon the patient maintaining a posture, for example holding the arms outstretched to the front with the fingers spread. Rest tremor, as the name suggests, is most evident at rest, particuarly when the patient's hands are resting in the lap: rest tremor may not be as evident with the hands hanging at the sides. Intention tremor becomes evident when the patient carries out an intentional movement, as for example during the finger-tonose test, when the patient attempts to touch the tip of the nose with the finger. When intention tremor is present, there is an oscillating movement of the hand that typically increases in amplitude as the target is approached but then, when the target is finally touched, disappears. There are other types of tremor in addition to the three just described, as for example dyskinetic and rubral, as described below. Although important, they are less common than the three described earlier.

Abnormal movements 81

Tremors are also described with reference to their amplitude and frequency. Thus, the amplitude may range from 'fine', which may not be visible on casual inspection, to 'coarse', and the frequency may range from slow (3-5 cps) through medium (6-10 cps) to rapid (11-20 cps).

Differential diagnosis of the sign The various tremors, grouped according to the classification noted above, are listed in Table 3.1. Table 3.1 Causes of tremor Postural tremor

Physiologic tremor Essential tremor Primary writing tremor Generalized anxiety disorder Anxiety attacks Hyperthyroidism Hypoglycemia Medication or drug-induced: antidepressants (tricyclics, venlafaxine, nefazodoneand selective serotonin reuptake inhibitors), mood-stabilizers (lithium, divalproex), caffeine, theophylline, sympathomimetics, stimulants (e.g. amphetamines) Alcohol or sedative/hypnotic/anxiolytic drug withdrawal Delirium of various kinds, especially metabolic encephalopathies

Rest tremor

Parkinsonian conditions Rabbit syndrome

Intention tremor

Cerebellar lesions Medication or drug induced

Other types of tremor

Dyskinetic tremor Rubral tremor 'Wing-beating'tremor Orthostatic tremor Simulated tremor, as in malingering

POSTURAL TREMOR

Physiologic tremor is fine, of medium to rapid frequency, and although normally present, may be so fine as to escape casual inspection. Essential tremor, as discussed in Chapter 8, p. 412, is an inherited disorder presenting with a fine, medium-to-rapid frequency tremor (Bain et al. 1994; Martinelli etal. 1987), which may be accompanied by other abnormal movements, such as various dystonias (Jankovic et al. 1991; Lou and Jankovic 1991). Primary writing tremor may be a variant of essential tremor but differs in that the tremor is present only when the patient attempts to write (Klawans et al. 1982a). Generalized anxiety disorder, as discussed in Chapter 20, p. 670, presents with chronic anxiety, which is often accompanied by an enhanced physiologic tremor. Anxiety attacks, as may be seen in panic disorder or various phobias, are acute, episodic

82 Signs, symptoms and syndromes

events characterized by often extreme anxiety with palpitations, diaphoresis and a fine-tocoarse tremor of medium-to-high frequency that, importantly, subsides and clears as the anxiety attack passes. Hyperthyroidism, as discussed in Chapter 16, p. 580, along with increased sensitivity to heat, an increased frequency of bowel movements and diaphoresis, is typically accompanied by an enhanced physiologic tremor. Hypoglycemia, as discussed in Chapter 13, p. 510, may, especially when acute, produce prominent autonomic symptomatology, including an enhanced physiologic tremor. Medication- or drug-induced tremors are very common in clinical practice, and of the agents listed in Table 3.1, prominent offenders in neuropsychiatric practice include tricyclic antidepressants (Kronfol et al. 1983), lithium (Gelenberg and Jefferson 1995; Vestergaard et al. 1988) and divalproex (Hyman et al 1979). Alcohol or sedative/hypnotic/anxioly tic drug withdrawal (e.g. from benzodiazepines or barbiturates) is so commonly accompanied by an enhanced physiologic tremor that it has come to be known as 'the shakes'. Importantly, this tremor may, in chronic alcoholics, eventually become permanent, persisting into long-term sobriety. Delirium may be accompanied by tremor, which is particularly common with the metabolic encephalopathies (lankovic and Fahn 1980), such as hepatic encephalopathy and uremia. Both the serotonin syndrome (Sternbach 1991), occurring in most cases secondary to a combination of serotoninergic drugs (e.g. a selective serotonin reuptake inhibitor [SSRI] plus a monoamine oxidase inhibitor [MAOI]), and the neuroleptic malignant syndrome (Rosebush and Stewart 1989) are also accompanied by tremor, which may be very coarse and prominent in the case of the neuroleptic malignant syndrome. REST TREMOR

Parkinsonian conditions are generally accompanied by a low-frequency rest tremor that is classically of the 'pill-rolling' type, wherein it appears as if the patient is rolling a pill between the thumb and fingers. Of the various parkinsonian conditions discussed below (p. 101), Parkinson's disease (Hughes et al. 1993) is more likely to present with tremor than is either the striatonigral variant of multiple system atrophy (Wenning et al. 1995) or progressive supranuclear palsy (Litvan et al. 1996). Rabbit syndrome, discussed in Chapter 22, p. 718, occurs generally as a side-effect of neuroleptics and presents as a rest tremor of the jaw that resembles the movements made by rabbits when they chew (Deshmukh et al. 1990). INTENTION TREMOR Cerebellar lesions classically cause intention tremor. Medication- or drug-induced intention tremor may occur during intoxication with alcohol or benzodiazepines. OTHER TYPES OF TREMOR

Dyskinetic tremor consists of irregular jerky movements of the outstretched hands, the character of which falls somewhere between an enhanced physiologic tremor and repetitive myoclonus. It is seen with neuroleptics. Rubral tremor occurs with movement of the upper extremity, is very coarse and is almost rhythmically beating in character. The name is somewhat of a misnomer because this tremor occurs not because of lesions of the red nucleus (nucleus ruber), but because of lesions of the brachium conjunctivum, as may be seen with midbrain lesions (Samie et al. 1990).

Abnormal movements 83

'Wing-beating' tremor, although classically associated with Wilson's disase, is in fact the initial sign in this disease in only a small minority of patients (Starosta-Rubinstein et al. 1987). Clinically, the arms are flexed at the elbows, and the upper extremities oscillate rhythmically at the shoulders, beating up and down and giving the appearance of a frightened bird flapping its wings. Orthostatic tremor (Heilman 1984) occurs only when patients stand up and remain still, disappearing if they seat themselves or begin walking. The tremor itself is experienced as a kind of shivering in the lower extremities, is very rapid and gives the patient a very unpleasant sensation of unsteadiness. Although most cases are idiopathic, this tremor may occur secondary to head trauma, aqueductal stenosis or a pontine lesion (Benito-Leon et al. 1997). In idiopathic cases, treatment with clonazepam or gabapentin is effective (Onofrj et al. 1998). Simulated tremor, as in malingering, may be confirmed by one of two maneuvers: either weighting the hand or having the patient engage in rhythmic activity with one hand only. Although hand-weighting dampens most tremors, a simulated tremor may increase in amplitude (Deuschl et al. 1998). When patients with tremor are asked to engage in a rhythmic tapping of the finger against the thumb in one hand, the frequency of the tremor in the contralateral hand does not change: with simulated tremor, however, the frequency of the 'tremor' comes to resemble the frequency with which the finger tapping is occurring (Koller etal. 1989).

MYOCLONUS Although myoclonus, as a sign, does not localize well, being seen with lesions of the cortex, brainstem and spinal cord, it is nevertheless of great differential diagnostic value. For example, if in performing the diagnostic evaluation of a patient with dementia one finds myoclonus, the differential diagnosis is immediately narrowed down to just a few possibilities, as noted below. Given this diagnostic usefulness, myoclonus should always be carefully sought. Description of the sign Myoclonus consits of rapid muscular jerks. These may be focal, segmental or generalized in distribution, and may be irregularly occurring or rhythmic in character. They may occur spontaneously or at times reflexively to certain stimuli, such as a touch or a loud noise. One may occasionally see intention myoclonus in which the myoclonic jerks occur only upon some intentional acitivty, such as extending an arm. Differential diagnosis of the sign Myoclonus must be distingusihed from tremor, tics and chorea. Tremor is distinguished by the fact that it is continuous, with contractions of antagonist muscles following immediately and smoothly upon contractions of the agonist muscles. By contrast, there is in myoclonus a 'silent' interval of muscular inactivity between each jerk. Tics, as seen for example in Tourette's syndrome, are distinguished by their, albeit temporary, suppressibility and by the fact that they often represent fragments of complex activity. By contrast, myoclonic jerks are not suppressible and are always quite simple in character. Chorea may be difficult to distinguish from myoclonus. One clue is the tendency of chorea to appear and disappear on different parts of the body with lightning-like fluidity, myoclonus rarely being so mercurial. Another

84 Signs, symptoms and syndromes

clue resides in the fact that, in many cases of chorea, the choreic movements themselves represent fragments of otherwise normal behaviors, in contrast to the simplicity of myoclonic jerks. Determining the cause of myoclonus in any particular patient is greatly facilitated by attending to the overall clinical picture. Specifically, as outlined in Table 3.2, one should be alert to the presence of the following conditions: delirium, dementia, parkinsonism, ataxia, Table 3.2 Causes of myoclonus Myoclonus occurring with delirium

Metabolic encephalopathies The serotonin syndrome Bismuth intoxication Pellagra of the 'encephalopathic' type Hashimotos's encephalopathy

Myoclonus occurring with dementia

new-variant type) Creutzfeldt-Jakob disease (including the new-variant Fatal familial insomnia Alzheimer's disease AIDS dementia Dialysis dementia Postanoxic dementia Hashimoto's encephalopathy Thalamic degeneration Childhood or adolescent onset dementing disorders oof various types Idiopathic hemochromatosis

Myoclonus occurring with parkinsonism

Diffuse Lewy body disease Corticobasal ganglionic degeneration Multiple system atrophy of the striatonigral type

Myoclonus occurring with ataxia

Multiple system atrophy of the olivopontocerebellar ttype

Myoclonus occurring with psychosis

Hashimoto's disease Adult onset subacute sclerosing panencephalitis

Myoclonus occurring with seizures of various types Myoclonus occurring secondary to medications

Tricyclic antidepressants Trazodone Buspirone Levodopa Clozapine Tacrine Albuterol Tardivedyskinesia

Myoclonus occurring in an isolated fashion

Essential myoclonus Palatal myoclonus Opsoclonus Focal lesions Hypnic jerks

Miscellaneous causes of myoclonus

Intoxication (phencyclidine or leaded gasoline) Whipple's disease Encephalitis lethargica

Abnormal movements 85

psychosis and seizures and various medications. Myoclonus may also occur in an isolated fashion, as for example with lesions of the brainstem or cord. Finally, there is a miscellaneous group of causes. The most common setting for myoclonus seen in general hospital practice is delirium, and this is considered first.

Myoclonus occurring with delirium Metabolic encephalopathies, including hepatic encephalopathy, uremic encephalopathy, hyponatremia, hypomagnesemia and respiratory failure are the most common cause of the combination of delirium and myoclonus seen in general hospital practice. The serotonin syndrome, generally occurring secondary to a combination of serotoninergic drugs (e.g. an SSRI plus an MAOI), is characterized by delirium, and, in many cases, myoclonus (Feighner et al 1990; Sternbach 1991). Bismuth intoxication, as may be seen when bismuth preparations are taken for gastrointestinal problems, may, when severe, be characterized by a delirium that is, in almost all cases, also accompanied by myoclonus (Supino-Viterbo et al. 1977). Pellagra of the 'encephalpathic' type, as may be seen in chronic alcoholics, is characterized by delirium, rigidity and, in perhaps one-half of patients, myoclonus (Serdaru et al. 1988). Hashimotos's disease is an autoimmune disorder that, although usually involving the thyroid gland, may rather present secondary to an autoimmune assault on the central nervous system, which may in turn manifest with delirium and myoclonus (Ghika-Schmid et al. 1996). MYOCLONUS OCCURRING WITH DEMENTIA

Creutzfeldt-Jakob disease is typically accompanied by generalized myoclonus, which is considered to be one of the hallmarks of this disorder (Brown et al. 1986); the 'new variant' of Creutzfeldt-Jakob disease, derived from eating meat from cows with bovine spongiform encephalopathy, is also characterized by myoclonus (Zeidler et al. 1997). Fatal familial insomnia is an inherited prion disease characterized by severe insomnia and dementia, which may also be accompanied by myoclonus (Medori et al. 1992). Alzheimer's disease may also be characterized by myoclonus, but only in its end stages, many years after the dementia is fully established and well progressed (Benesch et al. 1993; Chen et al. 1991). AIDS dementia may also be accompanied by myoclonus (Maher et al. 1997; Navin et al. 1986). Dialysis dementia, although initially presenting with myoclonus in only a very small minority (Garrett et al. 1988), is eventually characterized by this sign in the vast majority (Chokroverty et al. 1976; Garrett et al. 1988; Lederman and Henry 1978). Postanoxic dementia is generally accompanied by myoclonus, which is often intentional in type (Werharhan et al. 1997). Hashimoto's disease may, as noted above, be at times characterized by cerebral involvement, which in some cases may present with a gradually progressive dementia, eventually accompanied by myoclonus (Forchetti et al. 1997). Thalamic degeneration is a rare syndrome that may present in a variety of ways, one of which is dementia and myoclonus (Little et al. 1986). Childhood or adolescent onset dementing disorders of various types may also be accompanied by myoclonus; this is typical of subacute sclerosing panencephalitis (Dawson 1934) and juvenile onset dentatorubropallidoluysian atrophy (Becher et al. 1997). Myoclonus may also accompany the ridigity of juvenile Huntington's disease (Siesling et al. 1997). Idiopathic hemochromatosis is an inherited disease characterized by iron deposition in various organs, generally producing hepatic failure, diabetes mellitus and a cardiomyopathy.

86 Signs, symptoms and syndromes

In a very small minority, the central nervous system may also be involved, with dementia and myoclonus (Jones and Hedley-Whyte 1983). MYOCLONUS OCCURRING WITH PARKINSON ISM

Diffuse Lewy body disease is characterized by parkinsonism, which is often preceded by a dementia or psychosis. In those cases in which the parkinsonism occurs first, differentiating diffuse Lewy body disease from Parkinson's disease may be difficult: one clue is the presence of myoclonus, found in about one-fifth of patients with diffuse Lewy body disease but not in patients with Parkinson's disease (Louis et al. 1997). Corticobasal ganglionic degeneration is typified by an asymmetric onset parkinsonian rigidity of an upper extremity, which may be accompanied by dystonia and apraxia; in almost one-half of patients, myoclonus is also present (Rinne et al. 1994). Multiple system atrophy of the striatonigral type is characterized by parkinsonism accompanied by minimal evidence of autonomic insufficiency or ataxia; furthermore, about one-third of these patients will also have myoclonus (Wenning et al. 1995). MYOCLONUS OCCURRING WITH ATAXIA

Multiple system atrophy of the olivopontocerebellar type is characterized by ataxia, often with minimal evidence of autonomic insufficiency or parkinsonism. More importantly, however, the vast majority of these patients will also have myoclonus, which is often reflex in nature, being evident only upon light touch or a pin-prick (Rodriguez et al. 1994). MYOCLONUS OCCURRING WITH PSYCHOSIS

Psychosis may rarely be caused by conditions capable of causing myoclonus, and this has been noted with both Hashimotos's disease (Cohen et al. 1996) and adult onset subacute sclerosisng panencephalitis (Salib 1988). MYOCLONUS OCCURRING WITH SEIZURES OF VARIOUS TYPES

The combination of myoclonus and seizures may be seen in a number of child or adolescent onset epileptic syndromes. Some of these, such as juvenile myodonic epilepsy (Jain et al. 1998; Pedersen and Petersen 1998), are non-progresive, whereas others display a progressive downhill course, often with dementia. These progressive myoclonic epilepsies (Berkovic et al. 1986) include Unverricht-Lundborg disease (Koskiniemi etal. 1974),Lafora body disease (Yokoi et al 1968), myoclonus epilepsy with ragged red fibers (Berkovic et al. 1989), and Kuf s disease. Isolated myoclonic jerks may be seen in children or adults with idiopathic petit mal or grand mal seizures (Hodskins and Yakovlev 1930) and may also occur as part of epilepsia partialis continua (Thomas et al. 1977) and non-convulsive status epilepticus (Tomson et al. 1992). MYOCLONUS OCCURRING SECONDARY TO MEDICATIONS

Of the various medications capable of causing myoclonus as a side-effect, the most common culprits are the tricydic antidepressants, including imipramine, desipramine, amitriptyline, nortriptyline, doxepin, clomipramine and maprotilene (Casas et al. 1987; DeCastro 1985; Garvey and Tollefson 1987; Lippmann et al. 1977). Other medications implicated include trazodone (Garvey and Tollefson 1987; Patel et al. 1988), buspirone (Ritchie et al. 1988), levodopa (Klawans et al. 1975), the atypical neuroleptic dozapine (Bak et al. 1995; Barak et al. 1996), the anticholinesterase tacrine (Abilleira et al. 1998) and high doses of nebulized albuterol (Micheli et al. 2000).

Abnormal movements 87

Myoclonus may also occur as part of tardive dyskinesia after-long term neuroleptic use, in which case it may occur in an isolated fashion (Little and Jankovic 1987) or in combination with tardive dystonia (Abad and Ovsiew 1993; Wojick et al. 1991). MYOCLONUS OCCURRING IN AN ISOLATED FASHION

Essential myoclonus is an inherited condition with an onset in childhood that is characterized by non-progressive generalized myoclonus, often affecting the face, proximal limb musculature and trunk (Mahloudji and Pikielny 1967). Palatal myoclonus is characterized by a very rapid myoclonic jerking of the palate, which may be appreciated as a clicking by the patient; it may occur secondary to a variety of focal lesions in the central tegmental tract or the dentate nucleus (Lapresle 1986). Opsodonus, or ocular myoclonus, is characterized by continuous, chaotic and rapid conjugate eye movements in all directions of gaze: it may be seen with various lesions of the brainstem, including those occurring on a postencephalitic or paraneoplastic basis (Digre 1986). Focal lesions of the spinal cord (De La Sayette et al. 1996; Hoehn and Cherrington 1977) or brainstem may also cause myoclonus. Hypnic jerks consist of one, or at the most a few, myolconic jerks, often generalized, that occur in normal individuals as they drift off to sleep. MISCELLANEOUS CAUSES OF MYOCLONUS

Intoxication with phencyclidine or by 'sniffing' leaded gasoline (Goldings and Stewart 1982) may be accompanied by myoclonus. Whipples disease, typically characterized by abdominal complaints (e.g. diarrhea and pain) and arthralgia, may, in a small minority, also cause myoclonus (Louis et al. 1996). Encephalitis lethargica may be accompanied by myoclonus (Walsh 1920).

MOTOR TICS Although motor tics are classically associated with Gilles de la Tourette's syndrome, they are not specific for this disorder, being found, as noted below, in a variety of other conditions. Description of the sign Motor tics are sudden, rapid movements that, to a greater or lesser degree, bear some resemblance to purposeful movements. Thus, there may be brow-wrinkling, facial grimacing, head-jerking, shoulder-shrugging, etc. Immediately before the eruption of the tic, patients typically experience what has been called a 'premonitory urge' to make the tic, described by some as almost an 'itch' to tic: S.A.K. Wilson (1928) noted that 'the strain in holding back is as great as the relief in letting go', and commented that one of his patients reported, 'You can't help it any more than you can sneezing.' Tics may range in complexity from such simple movements as facial grimacing to complex behaviors such as gesturing or abruptly rising from a chair. Although any given tic may recur one or more times, patients typically experience a succession of different tics in different locations. Importantly, most patients are also able temporarily, perhaps for 30 seconds to a minute, to suppress the tics voluntarily.

88 Signs, symptoms and syndromes

Differential diagnosis of the sign Tics must be distinguished from three other abnormal movements: chorea, myoclonus and hemifacial spasm. Choreiform movements bear less resemblence to purposeful acts and rarely repeat themselves, instead flowing, lightning-like, from one part of the body to another. Myoclonus, like chorea, rarely resembles purposeful movements but is more a shock-like contraction of a muscle or muscle group, resulting in a sudden movement followed by a brief relaxation. Hemifacial spasm differs from tics in that it is repetitive, involves only musculature innervated by the facial nerve and is confined, as the name suggests, to one side of the face. In addition to these distinguishing characteristics, it is important to note that none of these three abnormal movements is associated with a premonitory urge, nor are any of them suppressible. Once the presence of motor tics has been established, the first diagnosis to consider is Tourette's syndrome, followed by medication- or drug-induced tics, tics occurring as part of a more widespread neurodegenerative disorder and a miscellaneous group, of which Sydenham's chorea is perhaps the most important. TOURETTE'S SYNDROME

Tourette's syndrome (Cardoso et al 1996; Lees et al. 1984), as described further in Chapter 8, p. 403, is the most common cause of chronic motor and vocal tics in childhood and should always be suspected when tics occur in an isolated fashion. Tics appearing for the first time in the adult years are, by contrast, generally not due to Tourette's syndrome (Chouinard and Ford 2000). MEDICATION- OR DRUG-INDUCED TICS

Stimulants (Erenberg et al. 1985), such as methylphenidate (Denckla et al. 1976), pemoline (Bachman 1981; Mitchell and Mathews 1980) and cocaine (Cardoso and Jankovic 1993; Pascual-Leone and Dhuna 1990), may, in a small minority of cases, either cause tics or exacerbate those which are already present. Neuroleptic-induced tardive dyskinesia may be predominantly characterized by tics (Bharucha and Sethi 1995; Stahl 1980), but should of course not be suspected except in patients who have taken neuroleptics chronically. Carbamazepine has been noted to cause tics that eventually spontaneously remit after about 6 months (Robertson et al. 1993). Lamotrigene, in three cases, has been shown to cause a combination of motor and vocal tics (Lombroso et al. 1999). TICS OCCURRING IN NEURODEGENERATIVE DISORDERS

Huntingtons disease may, very rarely, in addition to typical chorea, also cause complex tics (Jankovic and Ashizawa 1995). Neuroacanthocytosis, characterized primarily by chorea, may cause tics in over one-half of all patients (Hardie et al. 1991), in one case (Feinberg et al. 1991) the disorder presenting with clumsiness and tics. MISCELLANEOUS CAUSES OF TICS

Sydenham's chorea may, in additon to chorea, cause tics (Cardoso et al. 1997; Creak and Guttmann 1935) and may rarely present with tics (Kerbeshian et al. 1990). Encephalitis may leave patients with tics as sequelae, as has been noted after herpes simplex encephalitis (Northam and Singer 1991).

Abnormal movements 89

A very rare familial disorder has been described, characterized by tics, parkinsonism and muscular atrophy (Spitz et al. 1985). Finally, there is a report of multiple and complex tics occurring as a sequela to cardiopulmonary bypass surgery (Singer et al. 1997).

CHOREA Many authors prefer the term 'choreoathetosis' to 'chorea', finding, as they do, that there is considerable overlap between the two signs. In this text, however, the traditional distinction between chorea and athetosis is maintained. This is not to deny that there is a large gray area between the two but simply to give due acknowledgement to the fact that 'pure' cases do occur.

Description of the sign Choreic movements are jerky, purposeless, non-rhythmic and non-stereotyped, and very brief in duration. They appear and disappear on various parts of the body with an amazing rapidity and fluidity, flitting about like summer lightning: in severe cases, there is a continual play of abnormal movements over the entire body. The gait may be lurching: when severely affected, it has a 'dancing and prancing' quality, and it is from this characteristic that chorea, which, in Latin, means 'the dance', draws its name. Although choreic movements are purposeless, patients may at times more or less successfully disguise them by tacking a purposeful movement on to the choreic one. Thus, a patient whose arm has been flung up towards the head by a choreic jerk may then voluntarily extend and carry through the motion by pulling the hand across the head, as if the movement had all along been meant to smooth back the hair.

Differential diagnosis of the sign Myodonus, albeit jerky like chorea, has a 'relaxation' phase after each myoclonic jerk; furthermore, myoclonus is more likely to recur in the same area and does not produce a specific gait abnormality. Tics are more similar to chorea but tend to be stereotyped and to resemble fragments of purpseful behavior: furthermore, tics are associated with premonitory urges and are, to a degree at least, voluntarily suppressible. Athetotic movements are more sustained than choreic ones and, rather than being 'jerky' in nature, are, as pointed out by Wilson (1955), 'slow and writhing in character'. Edentulous patients may display some abnormal oromandibular movements simply because of their lack of teeth. In contrast to true chorea, there is no involvment elsewhere on the face or anywhere else on the body, and the tongue is not affected (Koller 1983). Once it has been established that chorea is present, the task is to determine its cause, this being facilitated by considering, step by step, the various groups of chorea as listed in Table 3.3. As chorea may be associated with precipitants of various kinds, it is prudent first to enquire as to whether any of these is present: this is particularly important with respect to certain commonly prescribed medications such as oral contraceptives, anticonvulsants and levodopa. Next, the physician should determine whether or not the patient has a paroxysmal chorea: as these account for a small and distinctive group of cases. Chorea may also occur as part of a more widespread disorder, and attention should thus be directed towards the existence of any associated signs or symptoms that would indicate the presence of such a disorder. For example, in a child, one should seek any evidence of current or recent carditis or polyarthritis, which will

90 Signs, symptoms and syndromes Table 3.3 Causes of chorea Associated with precipitants

Medication or drug induced Oral contraceptives Anticonvulsants Levodopa Stimulants Lithium Baclofen (upon discontinuation) Cimetidine Leaded gasoline intoxication Neuroleptics (as in tardive dyskinesia or the neuroleptic malignant syndrome) Pregnancy (chorea gravidarum) Delayed postanoxicencephalopathy Mercury intoxication

Paroxysmal chorea

Paroxysmal dystonic choreoathetosis Thyrotoxicosis

As part of a more widespread disorder

Cerebral palsy of the extra pyramidal type Sydenham's chorea Wilson's disease Dentatorubropallidoluysian atrophy Acquired hepatocerebral degeneration Lesch-Nyhan syndrome Hallervorden-Spatz disease Ataxia telangiectasia Schizophrenia

Focal lesions

Striatal lesions

Idiopathic or hereditary choreas

Huntington's disease Neuroacanthocytosis Benign hereditary chorea Senile chorea

Miscellaneous causes

Non-ketotic hyperglycemia Hyperthyroidism Systemic lupus erythematosis Polycythemia vera AIDS Paraneoplastic encephalitis

suggest a diagnosis of Sydenham's chorea. Focal lesions of the basal ganglia, specifically the striatum, are an unusual cause of chorea: the most common is a unilateral infarction that occasions the acute onset of a hemichorea that is generally, but not always, contralateral. Once the foregoing have been effectively ruled out, then one is probably confronted with one of the idiopathic or hereditary choreas, of which Huntington's disease is by far the most common. Finally, there are the rare miscellaneous causes, such as non-ketotic hyperglycemia. ASSOCIATED WITH PRECIPITANTS

Oral contraceptives may induce chorea (Gamboa et al. 1971; Green 1980; Nausieda et al 1979), any time from days to months after the initiation of treatment; this appears more likely in women who have a history of Sydenham's chorea.

Abnormal movements 91

Anticonvulsants known to induce chorea include phenytoin (Kooiker and Sumi 1974; Nausieda et al. 1978) and, much less frequently, valproic acid (Lancman et al. 1994) and gabapentin (Buetefisch et al 1996; Chudnow et al.1997). Levodopa, as used in the treatment of parkinsonism, may cause chorea, either at the peak dose or, less commonly, as the levodopa blood level is rising and then as it is falling, with a 'clear' interval in between (Mones et al. 1971). Stimulants are not uncommonly associated with chorea: generalized chorea has been seen with methylphenidate (Extein 1978; Weiner et al. 1978), pemoline (Sallee et al. 1989) and amphetamines (Lundh and Tunving 1981). Intoxication with cocaine may also cause chorea, a phenomenon known as 'crack dancing' (Daras et al. 1994). Although in most cases of stimulant-induced chorea, the chorea subsides after the offending agent has been stopped, exceptions may occur, persistent chorea having been noted after repeated intoxications with either amphetamines (Lundh and Tunving 1981) or cocaine (Daras et al. 1994). Lithium intoxication may be characterized by chorea (Podskalny and Factor 1996), which, in one case, persisted for months after the intoxication cleared (Zorumski and Bakris 1983). Badofen withdrawal was noted in one case to be followed 6 days later by chorea and a psychosis, both of which cleared when the bacolfen was restarted (Kirubakaren et al. 1984). Cimetidine was associated with chorea in one case (Kushner 1982). Leaded gasoline intoxication was noted in one instance to produce a combination of delirium, chorea and myoclonus, and it was felt that the chorea was associated not so much with the gasoline fumes as with the presence of organic lead (Goldings and Stewart 1982). Tardive dyskinesi, as described fully in Chapter 22, p. 714, is a dreaded complication of the long-term use of dopamine blockers. Importantly, although in the vast majority of cases the dopamine blocker in question is a neuroleptic, cases have also occurred secondary to such dopamine blockers as metoclopramide (Sewell et al. 1994). The neuroleptic malignant syndrome, as described in Chapter 22, p. 712, is a rare side-effect of neuroleptic use characterized by delirium, diaphoresis, tachycardia, fever, muscular rigidity and, in a minority, chorea (Rosebush and Stewart 1989). Pregnancy may be associated with chorea, a condition known as chorea gravidarum (Latin for 'chorea of pregnant women'), and, in a minority of these cases, the chorea may be accompanied by delirium or psychosis (Wilson and Preece 1932a, b). As with oral contraceptive-induced chorea, it appears that chorea gravidarum is more likely in women who have had Sydenham's chorea. Delayed postanoxic encephalopathy, as may occur after recovery from a coma resulting from strangulation (Hori et al. 1991) or carbon monoxide intoxication (Davous et al. 1986; Schwartz et al. 1985), may be accompanied by prominent chorea. Mercury intoxication may be followed by ataxia and chorea (Snyder 1972). PAROXYSMAL CHOREA

Paroxysmal dystonic choreoathetosis is described more fully in the section on dystonia, below (p. 96) and this is appropriate as the predominant abnormal movement in these cases is dystonic in character. However, many cases, both of the kinesigenic and non-kinesigenic variety, also show an admixture of chorea (Demirkiran and Jankovic 1995). Thyrotoxicosis, in addition to being associated with sustained chorea, may also, albeit rarely, cause paroxysms of chorea (Fishbeck and Layzer 1979). AS PART OF A MORE WIDESPREAD DISORDER

Cerebral palsy of the extrapyramidal type may be characterized by chorea (Rosenbloom 1994), which is often accompanied by mental retardation and seizures: importantly, the chorea may not become evident for years after the child's birth.

92 Signs, symptoms and syndromes

Sydenham's chorea is one of the major causes of chorea in childhood and adolescence (Bland and Jones 1952; Cardoso et al. 1997; Nausieda et al. 1980a). Although it is often accompanied by other evidence of rheumatic fever, such as carditis or polyarthritis, the onset of the chorea may at times be delayed for so long that the other signs of rheumatic fever have already gone into remission, leaving a case of 'pure' Sydenham's chorea. The chorea is of subacute onset, over weeks, and, although typically generalized, is often most prominent in the face and upper extremities. In a small minority, there may be only hemichorea. Although Sydenham's chorea may in some patients present solely with chorea, there are in the majority other neuropsychiatric features, most notably obsessions and compulsions (Swedo et al. 1993). Wilson's disease may, very rarely, present with chorea (Steinberg and Sternlieb 1984): dystonia, gait abnormalities and tremor are, however, far more common presenting signs (Starosta-Rubinstein et al. 1987). Dentatorubropallidoluysian atrophy, in adults, typically presents with a combination of chorea, ataxia and dementia; seizures are also common (Becher et al. 1997; Warner et al. 1994,1995). This presentation can be similar to that seen in Huntington's disease, and the fact that dentatorubropallidoluysian atrophy is an autosomal dominant disorder further lends to the diagnostic uncertainty. The presence of ataxia or seizures is an important differential clue (Warner et al 1995). Acquired hepatocerebral degeneration typically presents with a complex movement disorder, with a combination of chorea, ataxia, tremor and dysarthria; dementia is also commonly present (Finlayson and Superville 1981; Victor et al. 1965). An obvious clue to the diagnosis is the history of repeated episodes of hepatic encephalopathy. Lesch-Nyhan syndrome presents in very early childhood with chorea that is often accompanied by dysarthria and dystonia. The most characteristic sign, however, generally appearing as soon as the baby-teeth do, is mutilative self-biting (Jankovic et al. 1988; Nyhan 1972; Lesch and Nyhan 1964). Hallervorden-Spatz disease typically has an onset in childhood or adolescence with dystonia, which may be accompanied by chorea (Dooling et al. 1974). Ataxia telangiectasia is characterized by the onset of ataxia in earliest childhood, which may subsequently be joined by dysarthria and chorea (Woods and Taylor 1992). Schizophrenia is not uncommonly accompanied by choreiform movements (Owens et al. 1982) affecting the face and upper extremities. These are, however, typically very mild and are far overshadowed by the more characteristic psychotic symptoms seen in schizophrenia. FOCAL LESIONS

Striatal lesions, such as infarctions, may cause a contralateral chorea (Kase et al. 1981; Pantano et al. 1996; Saris 1983); rarely, an ipsilateral chorea may appear (Dierssen et al. 1961). With multiple lacunar striatal infarctions, bilateral chorea may appear (Tabaton et al. 1985). Multiple metastases to the basal ganglia and thalamus have also been noted to cause chorea (Lewis and Johnson 1968). IDIOPATHIC OR HEREDITARY CHOREAS

Huntingtons disease (Heathfield 1967) is, of all the hereditary causes of chorea in adults, by far the most common. Although the age of onset ranges from childhood to old age, most patients fall ill in their thirties with the insidious onset of a progressive chorea that will, in most cases, eventually be accompanied by other neuropsychiatric features, including personality change, dementia and psychosis. The family history is consistent with autosomal dominant transmission in almost all instances: sporadic cases generally indicate that the father of the patient had a premutation that underwent expansion.

Abnormal movements 93

Neuroacanthocytosis (Critchely et al. 1968; Hardie et al. 1991; Sakai et al. 1981) has an age of onset similar to that of Huntington's disease, and although most patients generally develop chorea, they also tend to have other clinical features not seen in Huntington's disease, such as other abnormal movements (e.g. tics, dystonia and, eventually in some, parkinsonism) or seizures. A classic but uncommon symptom of neuroacanthocytosis is self-mutilative lip-biting. Both sporadic and inherited cases occur, and inherited cases may follow either an autosmal recessive or dominant pattern. The disease gains its name by virtue of the finding of over 10% of acanthocytes on wet preparation peripheral blood smears. Benign hereditary chorea (Behan and Bone 1977) is characterized by a childhood onset of non-progressive generalized chorea, without other clinical features such as personality change or dementia. Senile chorea has an onset in the seventh decade, usually with a buccolingual-facial chorea (Bourgeois et al. 1980; Delwaide and Desseilles 1977; Klawans and Barr 1981; Varga et al. 1982), which may undergo some generalization (Shinotoh et al. 1994). The chorea is very slowly progressive, without the occurrence of dementia or other symptoms, and the family history is negative. MISCELLANEOUS CAUSES Non-ketotic hyperglycemia, as may be seen in some elderly patients, may present with hemichorea or generalized chorea (Chang et al. 1996). Hyperthyroidism may cause more or less generalized chorea and is suggested by other, more typical, signs such as tremor, diaphoresis, increased heat sensitivity, etc. (Fidler et al. 1971; Van Uitert and Russakoff 1979). Other diseases that may, very rarely, present with chorea include systemic lupus erythematosis (Donaldson and Espiner 1971; Fermaglich et al. 1973), polycythemia vera, (Gautier-Smith and Prankard 1967) and AIDS (Gallo et al. 1996; Pardo et al. 1998) and a paraneoplastic encephalitis (Heckmann et al. 1997)

ATHETOSIS 'Pure' athetosis, without any admixed choreic movements, is relatively uncommon.

Description of the sign Athetosis, which may be focal, confined to one limb, unilateral, involving both an upper and a lower extremity on one side, or bilateral and generalized, is characterized by slow, purposeless, writhing, serpentine movements that tend to be persistent and flow into one another. The distal portions of the extremities are more involved than the proximal, and the upper extremity is more often involved than the lower.

Differential diagnosis of the sign Athetosis is distinguished from chorea by its sustained, writhing aspect: choreic movements are very brief jerks that 'flit' rapidly from one part of the body to another. Dystonia differs from athetosis in that dystonic movements are much less mobile and indeed often present with a relatively 'fixed' aspect.

94 Signs, symptoms and syndromes

Athetosis, as indicated in Table 3.4, may be associated with precipitants or, occur as part of a more widespread disorder, as a result of focal lesions, or in association with sensory loss.

Table 3.4 Causes of athetosis Associated with precipitants

Post-cyanide intoxication Post-mercury intoxication

As part of a more widespread disorder

Cerebral palsy of the extrapyramidal type Hallervorden-Spatz disease Acquired hepatocerebral degeneration

Focal lesions

Basal ganglia or thalamus

In association with sensory loss

ASSOCIATED WITH PRECIPITANTS

After cyanide intoxication, patients may be left with a combination of parkinsonism and athetosis (Rosenow et al. 1995). Post-mercury intoxication, patients may be left with a combination of ataxia and athetosis (Snyder 1972). AS PART OF A MORE WIDESPREAD DISORDER

Cerebral palsy of the extrapyramidal type (Rosenbloom 1994), in addition to causing mental retardation and seizures, may also be characterized by 'double athetosis' wherein the athetosis is generalized, involving both sides of the body. Hallervorden-Spatz disease, in one case, presented in the adult years with a combination of dementia, athetosis and coarse tremor (Rozdilsky et al. 1968). Acquired hepatocerebral degeneration, occurring after repeated episodes of hepatic failure, may present with a dementia and a complex movement disorder, including athetosis (Finlayson and Superville 1981). FOCAL LESIONS

Lesions of the basal ganglia or thalamus (Carpeneter 1950), for example infarctions, may cause athetosis, and this has been particularly noted with lesions of the putamen and globus pallidus (Papez et al. 1938; Spiller 1920). In some cases of hemiplegia secondary to infarction, an athetosis may emerge as the hemiplegia partially resolves (Dooling and Adams 1975). IN ASSOCIATION WITH SENSORY LOSS

Athetosis may occasionally occur in the setting of severe sensory loss involving proprioception, as has been noted with lesions of the parietal lobe, thalamus, cervical cord or dorsal root ganglia (Ghika and Bogousslavsky 1997; Sharp et al. 1994). Some authors refer to this as 'pseudoathetosis', but this seems to be making a distinction without a difference, given that the abnormal movements are indistinguishable from those occurring secondary to other lesions.

Abnormal movements 95

BALLISMUS (BALLISM) The recognition of ballismus is critical as symptomatic treatment is available. Haloperidol (Davis 1976) and other neurolpetics, such as chlorpromazine (Klawans et al. 1976a) and perphenazine (Johnson and Fahn 1977), are generally effective; sodium valproate may be an alternative (Chandra et al. 1982; Lenton et al. 1981), but has not been found to be effective by all authors (Lang 1985). Description of the sign Ballismus is characterized by a purposeless flinging of the upper or lower extremity. The proximal musculature is primarily involved, and the movements are either continuous or are interrupted by brief respites. Patients may be thrown off chairs or beds by these forceful movements, and in the past, death from exhaustion could occur. Ballismus may be unilateral or bilateral. Unilateral ballismus involving both the upper and lower extremities, which is by far the most common form (Carpenter and Carpenter 1951; Vidakovic et al. 1994), is called 'hemiballismus', the involvement of but one extremity, either the upper or lower, being known as 'monoballism' and being uncommon (Ohnishi 1993; Vidakovic et al. 1994; Waubant et al. 1997). Bilateral ballismus is also uncommon. It has been reported with a bilateral lesion of the basal ganglia (Lodder and Baard 1981) and with a bilateral lesion of the substantia nigra (Caparros-Lefebvre et al. 1994); it has also, and remarkably, been reported with a unilateral lesion of the frontotemporal cortex (Hoogstraten etal 1986). Differential diagnosis of the sign As will be apparent, ballismus has fairly strong localizing and lateralizing value: the vast majority of cases occur secondary to a lesion of the subthalamic nucleus or its outflow tracts, and in the vast majority of cases of hemiballism, the lesion will be found contralaterally. LOCALIZING VALUE

As noted above, the most common location for a lesion is the subthalamic nucleus or its outflow tracts (Carpenter 1955; Martin 1957; Martin and Alcock 1934; Pfeil 1952; Vidakovic et al. 1994; Whittier 1947). Other locations include the cortex (Hoogstraten et al. 1986; Whittier 1947), striatum (Kase et al. 1981; Schwarz and Barrows 1960; Srinivas et al. 1987), ventral thalamus (Antin et al. 1967; Dewey and Jankovic 1989; Kulisevsky et al. 1993) and substantia nigra (Caparros-Lefebvre et al. 1994). LATERALIZING VALUE

Hemiballism indicates, in the overwhelming majority of cases, a contralateral lesion (Dewey and Jankovic 1989; Whittier 1947); only rarely has it been reported secondary to a lesion in the ipsilateral subthalamic nucleus (Crozier et al. 1996; Moersch and Kernohan 1939). ETIOLOGY

The most common lesion responsible for ballismus is an infarction, either ischemic (Dewey and Jankovic 1989) or hemorrhagic (Melamed et al. 1978; Whittier 1947). Other etiologies include metastatic tumors (Glass et al. 1984; Taylor 1984), toxoplasmosis in AIDS patients

96 Signs, symptoms and syndromes

(Nath et al. 1987), tuberculomas (Bedwell 1960), multiple sclerosis plaques (Waubant et al. 1997) and lupus (Dewey and Jankovic 1989). Ballismus has also been noted with phenytoin toxicity, with which it was bilateral (Oppida et al. 1978), and with non-ketotic hyperglycemia (B-C Lee et al. 1999; Lin and Chang 1994).

DYSTONIA Dystonia occurs in a large number of conditions, as noted below, the most common cause of dystonia seen in neuropsychiatric practice perhaps being acute neuroleptic-induced dystonia.

Description of the sign Dystonia is characterized by slow, sustained, twisting or contorting movements. It may be focal and confined to one body part, segmental, wherein there is spread to an adjacent body part, or generalized. Cervical dystonia is characterized by involvement of the neck musculature, with rotation of the head (torticollis), tilting of the head to one side (lateralcollis) and pulling of the head backwards (retrocollis) or forwards (anterocollis). Dystonia of the facial musculature may result in blepharospasm, with sustained, forceful contraction of the orbicularis oculi, or an oromandibular dystonia with forced opening of the mouth. Dystonic involvement of the extraocular muscles may lead to an oculogyric crisis with sustained, forceful conjugate deviation of the eyes, generally laterally and superiorly. When the hand is involved, there may be a dystonic cramping, and with upper extremity involvement, the arm typically hyperpronates with flexion at the wrist and hyperextension of the fingers. Lower extremity involvement often manifests with plantar flexion and inversion of the foot, and axial involvement may contort the trunk in a variety of ways.

Differential diagnosis of the sign Chorea is distinguished by its mercurial nature, extremely brief movements appearing and disappearing on various body parts with lightning-like rapidity. Athetosis appears to span a gray area between chorea and dystonia, but in athetosis, the movements are more writhing in character and less sustained. The various causes of dystonia are listed in Table 3.5, in which they are divided into several groups with an eye toward facilitating their differentiation. Utilizing the table requires several steps. First, determine whether the dystonia is associated with precipitants, for example drugs such as neuroleptics. Should precipitants be lacking, the next step is to determine whether or not one is dealing with a paroxysmal dystonia, as this is seen in a small and very distinct group. Should the diagnosis still not be clear, careful enquiry and evaluation are directed toward the occurrence of any other signs or symptoms that might suggest that the dystonia is in fact occurring as part of a more widespread disorder, keeping in mind that, in the case of some of these disorders (e.g. dopa-responsive dystonia), a long period of time may have to pass before other signs become apparent. Dystonia may also occur secondary to focal lesions, which may be suggested by the presence of other signs or by a specific onset, as may be seen with sudden onset hemidystonia secondary to infarction. After all the foregoing have been essentially ruled out, one is probably dealing with one of the primary dystonias, which occur for the most part in the absence of any other symptoms and signs.

Abnormal movements 97 Table 3.5 Causes of dystonia Associated with precipitants

Drug-induced Neuroleptics (including both acute neuroleptic-induced dystonia and tardive dystonia) Levodopa Propranolol and gabapentin MDMA (Ecstasy) Cocaine Flunarazine Cimetidine Head trauma Post-anoxia Perinatal asphyxia Peripheral trauma Post-encephalitic Cyanide Rat poison Febrile illness

Paroxysmal dystonias

Secondary (e.g. to infarction) Ictal Nocturnal paroxysmal dystonia Paroxysmal dystonic choreoathetosis Non-kinesigenic Kinesigenic Exercise-induced

As part of a more widespread disorder

Dopa-responsive dystonia (Segawa variant) Wilson's disease Hallervorden-Spatz disease Corticobasal ganglionic degeneration Neuroacanthocytosis Dentatorubropallidoluysian atrophy Lesch-Nyhan syndrome Tourette's syndrome Rapid onset dystonia-parkinsonism

Focal lesions

Basal ganglia Thalamus Frontal lobe Posterior fossa Thoracic outlet syndrome

Primary dystonias

Primary torsion dystonia (dystonia musculorum deformans) Idiopathic cervical dystonia Writer's cramp (occupational dystonia) Meige's syndrome Brueghel's syndrome Axial dystonia

ASSOCIATED WITH PRECIPITANTS

Acute neuroleptic-induced dystonia usually occurs within a matter of days of either starting or increasing the dose of a neuroleptic (Ayd 1961; Keepers et al. 1983), is more common in young males (Boyer et al. 1987) and is more likely to occur with high-potency typical neurolpetics,

98 Signs, symptoms and syndromes

such as haloperidol and fluphenazine (Keepers et al. 1983; Swett 1975). Focal dystonias, including oculogyric crisis, torticollis and involvement of the upper limb, are most common; in some cases, segmental spread may occur, and, rarely, an acute neuroleptic-induced dystonia may become generalized. Lingual dystonia may also occur, and patients may become dysarthric and complain of a 'thick tongue'; very rarely, respiratory embarassment may follow (Flaherty and Lahmeyer 1978). Interestingly, in patients with schizophrenia, such dystonias may be accompanied by a transient increase of psychotic symptoms (Chiu 1989; Thornton and McKenna 1994). Tardive dystonia, a variant of tardive dyskinesia, occurs secondary to chronic treatment with a neuroleptic drug and generally presents with a focal dystonia affecting the neck or face, which may undergo segmental spread and, rarely, become generalized (Burke et al. 1982; Kiriakakis et al. 1998; Wojick et al. 1991; Yassa et al. 1986), in which case it may be disabling (Yadalam et al. 1990). Interestingly, should mania occur, a pre-exisiting tardive dystonia may undergo substantial improvement (Kiriakakis et al. 1998; Yazici et al. 1991). Levodopa, as used in Parkinson's disease, may be associated with a focal dystonia, typically of the foot, which may occur either at peak dose or as a wearing-off, end-of-dose phenomenon (Kidron and Melamed 1987; Melamed 1979; Nausieda et al. 1980b). Propranolol and gabapentin, used in combination, caused bilateral paroxysmal dystonia in one case (Palomeras et al 2000). MDMA (ecstasy) was noted in one case report (Priori et al. 1995) to cause torticollis. Cocaine, upon its withdrawal, was followed in one individual by a generalized dystonia which responded to diphenhydramine (Choy-Kwong and Lipton 1989). Flunarazine, a calcium channel blocker, was noted to cause bilateral blepharospasm in one patient (Koukoulis et al. 1997). Cimetidine (Romisher et al. 1987) has likewise been associated with dystonia in one case report. Head trauma may be followed, after a latent interval lasting from days to many years, by a focal dystonia that will in most cases undergo progression; the presence of such a dystonia has been correlated with lesions in the contralateral basal ganglia or thalamus (Burke et al. 1980; Leeetal. 1994). Postanoxic dystonia, as may be seen after recovery from anoxic coma of various causes (e.g. anesthesia, drowning or cardiac arrest) typically appears only after a latent interval of weeks to months, then undergoing gradual progression for months or years; lesions are found in the basal ganglia (Bhatt et al. 1993). Perinatal asphyxia may be followed by dystonia afer a latent interval averaging about 13 years; the dystonia may range from focal to generalized and may undergo progression over decades (Saint Hilaire et al. 1991). Peripheral trauma, for example to a limb, may be followed by a dystonia localized to the general area of the trauma; furthermore, the severity of the trauma does not appear to be important as dystonia may follow even trivial injury (Schott 1985). Postencephalitic blepharospasm has been seen as a sequela to encephalitis lethargica (Alpers and Patten 1927). Cyanide poisoning, after recovery from coma, may be followed by a generalized dystonia, bilateral putaminal lesions being noted in one case on magnetic resonance imaging (Valenzuela et al. 1992). Rat poison, taken on a 'dare' by one young man, was followed 6 months later by bilateral dystonia of the upper extremities, bilateral blepharospasm and parkinsonism (Keane and Young 1985). Febrile illness, in one case report, was followed by a unilateral dystonia; at autopsy, a lesion was found in the contralateral basal ganglia (Gordin 1939).

Abnormal movements 99 PAROXYSMAL DYSTONIA

Secondary paroxysmal dystonia may occur after infarction (Demirkiran and Jankovic 1995) or with multiple sclerosis (Berger et al. 1984), and was, in one case, the presenting feature of hypoparathyroidism (Soffer et al. 1977). Ictal dystonia may occur as part of an otherwise unremarkable complex partial seizure, and in such cases, the dystonia typically occurs contralateral to the side with the seizure focus (Newton et al. 1992). Nocturnal paroxysmal dystonia is characterized by brief episodes, occurring only during sleep, of dystonia associated with partial awakening. There appear to be two forms: one that does not respond to anticonvulsants (Lee et al. 1985) and another that responds to carbamazepine (Lugaresi et al. 1986; Lugaresi and Cirignotta 1981). The response to carbamazepine suggests of course an epileptic etiology, and in some cases, it appears that the nocturnal paroxysms of dystonia do in fact represent nocturnal complex partial seizures (Tinuper et al. 1990). Paroxysmal dystonic choreoathetosis consists, as the name suggests, of paroxysms, or attacks, of dystonia, and such attacks either occurring spontaneously or being precipitated by activity. Patients with spontaneously occurring attacks are said to have non-kinesigenic paroxysmal dystonic choreoathetosis, whereas those with attacks precipitated by activity may have either kinesigenic paroxysmal dystonic choreoathetosis (if the attacks are precipitated by sudden movement) or exercise-induced paroxysmal dystonic choreoathetosis (if the attacks occur only after relatively prolonged exericise). Non-kinesigenic paroxysmal dystonic choreoathetosis is characterized by spontaneously occurring attacks, lasting from minutes to hours, that do not respond to anticonvulsants. In many cases, the attacks are more likely when patients are fatigued, under stress or indulging in alcohol (Bressman etal. 1988; Demirkiran and Jankovic 1995; Fink etal. 1997; Jarman etal. 1997, 2000; Lance 1977; Matsuo et al. 1999; Mount and Reback 1940; Richards and Barnett 1968; Rosen 1964). Kinesigenic paroxysmal dystonic choreoathetosis (Demirkiran and Jankovic 1995; Kertesz 1967; Lance 1977; Stevens 1966), as noted, occurs with sudden movements, the attacks generally being brief, lasting from seconds to minutes. There is generally an excellent response to anticonvulsants such as carbamazepine, often in low dose (Wein et al. 1996), and it is of interest that an association was recently found between kinesigenic paroxysmal dystonic choreoathetosis and a history of infantile afebrile convulsions (Swodoba et al. 2000). Exercise-induced paroxysmal dystonic choreoathetosis is characterized by attacks that occur only after prolonged exercise, such as walking or cycling, the dystonia generally resolving with rest over a matter of minutes (Bhatia et al. 1997a; Munchau et al. 2000). AS PART OF A MORE WIDESPREAD DISORDER

Dopa-responsive dystonia (Harwood et al. 1994; Nygaard et al. 1990; Nygaard and Duvoisin 1986; Sawle etal. 1991; Tassin etal. 2000) symptomatically resembles primary torsion dystonia (see below) in that it has an onset in childhood or adolescence and typically presents with a focal dystonia involving the foot, which then spreads to involve the other lower extremity, the upper extremities and, in some cases, the trunk. There are three critical differences, however: • patients with dopa-responsive dystonia often note a marked diurnal flucutation of their symptoms, with substantial worsening as the day goes on into the afternoon and evening • in most cases, the dystonia is, with progression, joined by parkinsonism • most importantly, these patients achieve a remarkable and sustained response to low-dose levodopa.

100 Signs, symptoms and syndromes

Wilson's disease may present with dystonia (Walshe and Yealand 1992), but almost all of these patients also have dysarthria (Starosta-Rubinstein et al. 1987). The onset is usually between childhood and the early adult years, and the dystonia may consist of tortcollis, dystonia of the upper or lower extremity, an oculogyric crisis (Lee et al. 1999) or a facial dystonia of the oromandibular type, which may leave the patient with a fixed, vacuous, wide-mouthed smile. Other symptoms and signs, including personality change, gait abnormalities and tremor, eventually accrue. Given that treatment is available, testing for copper and ceruloplasmin levels should be performed if there is any suspicion of Wilson's disease. Hallervorden-Spatz disease generally presents in childhood or adolescence with a slowly progressive dystonic rigidity beginning in the lower extremity (Swaiman 1991). Other abnormal movements, such as tremor or chorea, eventually appear, as does a dementia (Dooling et al. 1974). Corticobasal ganglionic degeneration typically has an onset in the sixties, and although most patients present with an asymmetric rigid parkinsonism affecting one of the extremities (usually the upper), the involved limb may at times be instead more affected by a 'jerky' dystonia. Over time, however, the appearance of other signs, such as apraxia, cortical sensory loss and myoclonus, indicates the correct diagnosis (Litvan et al. 1997b; Riley et al. 1990; Rinneetal. 1994). Neuroacanthocytosis generally has an onset in the late twenties or early thirties, and although it usually presents with chorea, dystonia may in some cases be more prominent (Hardie et al. 1991): other signs, such as parkinsonism, personality change or dementia eventually supervene, and in some cases, one may see the classic self-mutilatory lip-biting. Dentatorubropallidoluysian atrophy, when it has an onset in adult years, may present with dystonia. However, over time, other abnormal movements, such as chorea and ataxia, occur, as does dementia (Warner et al. 1995). Lesch-Nyhan syndrome typically becomes apparent within the first 2 years of life because of either dystonia, chorea or a combination of the two; the characteristic self-biting eventually indicating the correct diagnosis (Jankovic et al. 1988). Tourette's syndrome may, rarely, be associated with dystonia, such as torticollis or blepharospasm, and although in most cases tics precede the dystonia by many years, the syndrome may rarely present with a combination of the two (Stone and Jankovic 1991). Rapid onset dystonia-parkinsonism, discussed further below (p. 107), is a rare familial disorder characterized by the rapid onset, over days, of dystonia and parkinsonism, which then persist. FOCAL LESIONS Infarction, or less commonly tumor (Martinez-Cage and Marsden 1984), involving the basal ganglia or thalamus (Pettigrew and Jankovic 1985; Russo 1983), may cause a contralateral focal or segmental dystonia; there are also case reports of dystonia occurring secondary to a tumor of the frontal lobe (Soland et al. 1996) and to tumors of the posterior fossa (Krauss et al. 1997). Although, in the case of infarction, there may be a latent interval of from weeks to months between the infarction and the onset of the dystonia, the appearance of hemiparesis or hemianesthesia at the time of the infarction will suggest the correct diagnosis (Lehericy et al. 1996). The thoracic outlet syndrome was, in one case, associated with dystonia of the hand, the correct diagnosis being suggested by the accompanying weakness and sensory changes (Quartarone et al. 1998). PRIMARY DYSTONIAS

Before discussing the primary dystonias, a caveat is in order. The classificatory scheme adopted in this text is fairly traditional and divides the primary dystonias into various

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syndromes on the basis of age of onset, location and the extent to which the dystonia progresses. Recent genetic work, however, suggests that at least some of the adult onset focal dystonic syndromes (e.g. idiopathic cervical dystonia) in fact repersent formes frustes of primary torsion dystonia, and, in light of this, some authors have elected to broaden the definition of primary torsion dystonia to include virtually all of the primary dystonias. Thus, a classic 'lumper' versus 'splitter' nosologic argument has begun, and this author, pending more complete genetic data (and hopefully some reliable neuropathologic data), freely admits to a 'splitter' bias. Primary torsion dystonia (dystonia musculorum deformans) (Johnson et al. 1962; Marsden and Harrison 1974), also known as idiopathic torsion dystonia, is an inherited disorder that typically presents in childhood or adolescence with a focal dystonia that very gradually, over many years, becomes generalized. Although the presenting dystonia is usually of the lower extremiety, the upper extremity, or even the face, may at times be involved initially. Idiopathic cervical dystonia (Chan et al. 1991; Jankovic et al. 1991; Sorensen and Hamby 1966) has an onset in the fourth to sixth decades, being characterized by dystonia of the neck musculature, resulting in torticollis, lateralcollis, retrocollis or anterocollis. Although the dystonia is initially intermittent, it becomes chronic over time and may undergo segmental spread to the arm or face. Importantly, patients are, in most cases, able temporarily to relieve the dystonia by a utilizing a geste antagonistique, such as lightly touching the chin. Writer's cramp is one of the 'occupational' or task-specific dystonias; in it, a dystonic cramping affects the hand during the execution of some highly skilled movement such as writing, typing or playing a musical instruement (Cohen and Hallett 1988; Sheehy and Marsden 1982). Meige's syndrome, named after the French neurologist Henri Meige (Tolosa and Klawans 1979), is characterized by an onset in the adult years of bilateral dystonic blepharospasm (Tolosa 1981), which may, over time, undergo spread to the mouth and jaw or even further (Defazio et al. 1999). Patients with Meige's syndrome may be able temporarily to relieve the blepharospasm by a kind of geste antagonistique, such as singing (Weiner and Nora 1984). Brueghel's syndrome, often confused with Meige's syndrome, is characterized not by blepharospasm but solely by an oromandibular dystonia that resembles forced yawning (Gilbert 1996). Axial dystonia is an uncommon idiopathic dystonia of adult onset characterized by, as the name implies, a dystonia of the axial musculature (Bhatia et al. 1997b).

PARKINSONISM There has been some unfortunate confusion between parkinsonism on the one hand, and Parkinson's disease on the other. Parkinsonism is a syndrome and, as such, has multiple different etiologies. Parkinson's disease, however, is a specific entity that in turn constitutes but one of the multiple possible etiologies of parkinsonism.

Description of the syndrome Fully developed classic parkinsonism is, once recognized, almost unforgettable. The patient stands in a flexion posture, the arms feld in flexion and the knees slightly bent. A rhythmic 'pillrolling' tremor is seen in the hands and may also be evident on the lips or the chin: the tremor is a rest tremor and is either abolished or greatly diminished by voluntary movement of the

102 Signs, symptoms and syndromes

limb. The voice is low, soft and monotone, and the facial expression is flattened or mask-like: Wilson (1955) noted that the parkinsonian patient's features are ' "starched", he has a "reptilian state", unblinking eyes set in an unmoving background. Little or no play of expression animates his countenance'. When patients attempt to do anything, bradykinesia becomes evident: all movements are initiated and carried out slowly, as if the patient were encased in molasses. Most patients will also display 'freezing (Giladi et al. 1992), wherein they seem unable to initiate any action, such as starting to walk or turn. Interestingly, such freezing often occurs at a threshold of some sort or other, such as a doorway or at the start of a long runway or hall. When patients do walk, their arm swing is reduced and they display a typical marche a petit pas, taking small, at times mincing steps. One often also sees 'festination', as the patient, almost toppling forwards over him or herself, takes ever faster and smaller steps. Bradykinesia and festination both have cognitive counterparts: in bradyphrenia, thoughts appear and pass through the mind very slowly; 'cognitive' festination may be evident as patients talk, and their speech may become ever more rapid and low as they approach the end of a thought, to the point at which it may degenerate into an unintelligible mumbling. Postural instability also occurs: while the patient is standing at rest, a simple push back on the chest will evoke 'retropulsion', as the patient, unable to make sufficiently rapid compensatory movements, topples over backwards. On further examinaton, rigidity is evident in the limbs; this rigidity is evident both with flexion and extension, and remains of equal severity throughout the full range of motion. It may be either of the 'lead-pipe' variety or 'cogwheeling' in type, appreciated as a sort of ratcheting upon passive extension of the limb. Handwriting often becomes scratchy and micrographic, and a comparison of successive signatures over the years may provde graphic evidence of the progression of the disorder. Although fully developed parkinsonism is not at all uncommon, most patients, especially early in the course of their disease, may evidence only a partial syndrome, and there is thus a need for a set of minimal criteria for the diagnosis of the syndrome. One such set mandates either: • the presence of a combination of tremor and bradykinesia or • either tremor alone or bradykinesia alone plus one or more of rigidity, flexion posture, postural instability and freezing.

Differential diagnosis of the syndrome The differential diagnostic task of determining the cause of any particular case of parkinsonism may be approached in a number of different ways. The method presented here is simple and practical, and although certainly not even close to foolproof, constitutes a reasonable first approach. In Table 3.6, parkinsonism is divided into three large groups: parkinsonism occurring without precipitants, parkinsonism occuring with precipitants and miscellaneous causes of parkinsonism. Cases of parkinsonism occurring without precipitants may or may not possess distinctive features: Parkinson's disease, for example, presents only with unadorned parkinsonism; diffuse Lewy body disease may present similarly or with a combination of dementia and parkinsonism; and progressive supranuclear palsy typically presents with frequent, unexplained falls. Cases of parkinsonism that occur with precipitants are generally easily diagnosed, providing that one keeps in mind the various possible precipitating factors. In the paragraphs that follow, each of the disorders listed in Table 3.6 is discussed in more detail, with special reference to diagnostically important features.

Table 3.6 The causes of parkinsonism Parkinsonism occurring without precipitants

Parkinson's disease Diffuse Lewy body disease Progressive supranuclear palsy Multiple system atrophy Corticobasal ganglionic degeneration Fahr's syndrome Arteriosclerotic parkinsonism Dentatorubropallidoluysian atrophy Huntington's disease of juvenile onset Hallervorden-Spatz disease of late onset Neuroacanthocytosis Wilson's disease Alzheimer's disease

Parkinsonism occurring with precipitants

History of repeated head trauma Dementia pugilistica History of encephalitis Postencephalitic parkinsonism Other encephalitides (e.g. Western equine encephalitis, Japanese encephalitis) Medications Neuroleptics Neuroleptic malignant syndrome Selective serotonin reuptake inhibitors Lithium Phenelzine Calcium channel blockers Disulfiram Valproicacid Toxins MPTP Methanol Diquat Manganese Organophosphates Post-hypoxic Postanoxic encephalopathy Carbon monoxide poisoning Cyanide poisoning

Miscellaneous causes of parkinsonism

Rapid onset dystonia-parkinsonism Hereditary mental depression and parkinsonism Hemiparkinsonism-hemiatrophy syndrome Systemic lupus erythematosus Central pontine myelinolysis Pellagra (encephalopathicform) Focal lesions Hypoparathyroidism (without calcification of the basal ganglia) Guamian amyotrophic lateral sclerosis-parkinsonism complex

104 Signs, symptoms and syndromes

PARKINSONISM OCCURRING WITHOUT PRECIPITANTS

Parkinson's disease is by far the most common cause of parkinsonism occurring without preciptating factors. As exemplified by two large series of patients (Hughes et al., 1993; Martin et al. 1973), the onset is typically with tremor, with or without rigidity, or less commonly with rigidity alone, the symptoms first appearing unilaterally, typically in one of the upper extremities. Over time, symptoms spread, involving the contralateral limb and eventually all four extremities, along with the trunk and head. Of all the causes of parkinsonism, Parkinson's disease is the most likely to cause the fully developed picture of parkinsonism described above. Although dementia occurs in between 11% (Mayeux et al. 1988) and 29% (Marttila and Rinne 1976) of patients with Parkinson's disease, it is a late feature of the disease, appearing years after the motor symptomatology has become well established (Biggins et al. 1992; Marder et al. 1995; Mayeux et al. 1992). Hallucinations, more often visual than auditory, and less commonly delusions, often of persecution, may also occur in patients with Parkinson's disease (Freidman and Sienkiewicz 1991; Graham et al. 1997), but these almost universally appear to be complications of treatment with dopaminergic agents and are generally not seen in untreated patients. A final differential point relates to treatment response: of the many causes of parkinsonism, Parkinson's disease is the one most likely to show a good response to treatment with levodopa: with other etiologies, the response is less robust or even absent. Thus, a failure to obtain a good response to levodopa is a strong point against the diagnosis of Parkinson's disease. Diffuse Lewy body disease (Byrne et al. 1989; Hely et al. 1996) may present in any one of three ways: with parkinsonism alone, with a combination of parkinsonism and dementia, or with dementia alone. Eventually, however, all patients experience both parkinsonism and dementia. The clinical evolution is gradual, and years may pass between an initial onset of parkinsonism and the development of dementia (Byrne et al. 1989). The parkinsonism seen in diffuse Lewy body disease is generally mild (Burkhardt et al. 1988). In addition, in those cases of diffuse Lewy body disease that present with dementia, patients, although lacking any parkinsonism, may display an unusual sensitivity to treatment with neuroleptics (McKeith et al. 1994a), with the development of a severe neuroleptic-induced parkinsonism. The dementia of diffuse Lewy body disease is typically marked by daily symptom fluctuation, many patients having episodes of confusion (Burkhardt et al. 1988; McKeith et al. 1994b). Psychotic symptoms appear early in the course of the dementia (Crystal et al. 1990) and, in contrast to Parkinson's disease, occur whether or not the patient is receiving dopaminergic agents. They generally consist (Klatka et al. 1996; McKeith et al. 1994b) of visual hallucinatons (which may be accompanied by auditory hallucinations) and delusions, generally persecutory in nature. The hallucinations are often quite vivid and complex: one of the author's patients hallucinated cows on the expressway and swerved his truck to avoid them. A minority of patients with diffuse Lewy body disease will also have myoclonus (Louis et al. 1997). Progressive supranudear palsy typically presents (Litvan et al. 1996; Maher and Lees 1986) with postural instability and frequent, unexplained falls. Over time, parkinsonism may develop (Collins et al. 1995), which may be of symmetric or asymmetric onset and is usually characterized by rigidity and bradykinesia, with only a minority having a rest tremor. Importantly, however, patients with progressive supranuclear palsy, rather than having a flexion posture, typically display an erect stance, the neck often in dystonic extension (Litvan et al. 1996; Steele 1972). Classically, patients also develop a supranuclear ophthalmoplegia for downward gaze: this, however, may not appear for years and may, in some cases, never occur (Daniel et al. 1995). Most patients also become demented, many of these developing a pseudobulbar palsy with emotional incontinence (Menza et al. 1995).

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Multiple system atrophy may occur in any one of three different types: the striatonigral variant, the olivopontocerebellar type and the Shy-Drager type. The striatonigral type is characterized by parkinsonism, the olivopontocerebellar type by ataxia and the Shy-Drager type by autonomic failure. The parkinsonism of the striatonigral type is very similar to the classic, fully developed form of parkinsonism described above (Wenning et al. 1995), but, because there is an overlap of the various types of multiple system atrophy, the parkinsonism is typically accompanied (Colosimo et al. 1995; Litvan et al. 1997a; Wenning et al. 1994, 1999) by evidence of autonomic failure (e.g. postural dizziness, repeated syncope, urinary retention or incontinence [Wenning et al. 1999]) or by a degree of ataxia. In a minority, myoclonus or a supranuclear ophthlamoplegia for downward gaze may occur (Wenning et al. 1995). Corticobasal ganglionic degeneration (Litvan et al. 1997b; Rinne et al. 1994) typically presents with parkinsonism (characterized primarily by rigidity and bradykinesia) that, importantly, remains strikingly asymmetric for a long period of time. An upper extremity is generally involved first, and the rigid-bradykinetic parkinsonism seen in this limb may also be accompanied by a jerky dystonia. In addition to this parkinsonism, one or more of the following are typically present: cortical sensory loss, apraxia (which may be quite severe [Riley et al. 1990]), and myoclonus, which is often often stimulus dependant and may occur in up to half of all cases. Dementia eventually supervenes in most patients (Schneider et al. 1997). Fahr's syndrome, or basal ganglia calcification, may occur secondary to hypoparathyroidism (either familial [Mathews 1957] or secondary to thyroidectomy [Berger and Ross 1981; Klawans et al. 1976b]) or on an idiopathic, familial basis (Kobari et al. 1997; Nyland and Skre 1977; Trautner et al. 1988). In the case of thyroidectomy, up to 26 years may pass before the parkinsonism occurs (Tambyah et al. 1993). The symptomatology is quite varied: parkinsonism may occur as an isolated finding (Klawans et al. 1976b; Tambyah et al. 1993), may be preceded by dementia (Kobari et al. 1997; Nyland and Skre 1977; Trautner et al. 1988) or may be accompanied by cerebellar signs such as ataxia (Nyland and Skre 1977) or intention tremor (Mathews 1957). It must be borne in mind, however, that calcification of the basal ganglia is a not uncommon incidental finding: in one study (Koller et al. 1979) of 4219 computed tomography scans, 3.3% had basal gangliar calcification, but only one patient (0.02% of the total) had parkinsonism. Arteriosclerotic parkinsonism, also known as vascular parkinsonism, although at times resembling the classical, fully developed form described earlier (Murrow et al. 1990), generally (Bruetsch and Williams 1954; Keschner and Sloane 1931; Tolosa and Santamaria 1984; Zijlmans et al. 1995) presents only with rigidity and bradykinesia, at times accompanied by postural instability. Tremor is usually absent, and the gait may be of the 'magnetic' type, with the feet seemingly sticking to the floor. Corticobulbar and corticospinal signs are generally evident, including emotional incontinence, hyperreflexia and Babinski signs; some patients may also be demented. Dentatorubropallidoluysian atrophy (Warner et al. 1995), in adults, usually presents with chorea, which may, at times, be accompanied by parkinsonism. Huntingtons disease of juvenile onset (Siesling et al. 1997), also known as the Westphal variant, may present with parkinsonism characterized by rigidity and bradykinesia, which is often accompanied by a dementia (Bird and Paulson 1971; Campbell et al. 1961); in some cases, the dementia may precede the parkinsonism (Hansotia et al. 1968). Chorea or dystonia may appear, and a minority of patients will eventually develop seizures or myoclonus. In almost all cases, the family history is evident, and genetic testing is available. Hallervorden-Spatz disease of the late onset type may cause parkinsonism. In one report (Alberca et al. 1987), two siblings presented with a combination of parkinsonism, dystonia, hyperreflexia and a positive Babinski sign in their mid-twenties. In another report (Jankovic

106 Signs, symptoms and syndromes

et al. 1985), a 55-year-old male developed a slowly progressive, fairly classic, parkinsonism, followed by dementia and dystonia. Neuroacanthocytosis, although generally characterized by chorea, may, in a minority of cases and after many years, cause a parkinsonian syndrome that may eventually replace the chorea (Hardie et al. 1991). Wilson s disease may present with rigidity, but this is generally accompanied by other signs, such as dysarthria or dystonia (Starosta-Rubinstein et al. 1987). Alzheimer's disease may, late in its course, and long after the dementia has been fully established, cause parkinsonism consisting primarily of rigidity (Clark etal. 1997; Goodman 1953). PARKINSONISM OCCURRING WITH PRECIPITATING FACTORS

Dementia pugilistica presents gradually, years after repeated head trauma (as may occur in boxing), with a varying combination of parkinsonism, dysarthria, ataxia and dementia (Harvey and Davis 1974; Martland 1928). The dysarthria and ataxia accompanying the parkinsonism account both for the fact that such patients are often accused of alcohol intoxication, and for the common name for dementia pugilistica, namely 'punch drunk syndrome'. Postencephalitic parkinsonism occurs as a sequel to encephalitis lethargica and may follow the encephalitis after a latent interval ranging from 1 up to 20 years (Duvoisin and Yahr 1965). The onset of the parkinsonism is gradual, the syndrome often being accompanied by other motor abnormalities (Rail et al. 1981), such as dystonia (including, notably, blepharospasm and oculogyric crises). Importantly, although there have been no further epidemics of encephalitis lethargica since 1928, sporadic cases still occur (Howard and Lees 1987). Western equine encephalitis (an arbovirus infection) may also have parkinsonism as a sequel. Here the diagnosis is fairly straightforward as the latent interval between the encephalitis and the onset of the parkinsonism is fairly brief, from a week (Schultz et al. 1977) to several months (Mulder et al. 1951). Japanese encephalitis may, acutely, be accompanied by parkinsonism, which may, in some patients, persist as a sequela (Pradhan et al. 1999). Neuroleptics may cause a parkinsonism very similar to the classic, fully developed form noted above (Hardie and Lees 1988) and indeed are probably the most common cause of parkinsonism overall. Although in the vast majority of cases, the parkinsonism gradually subsides after the discontinuation of neuroleptic treatment, in a small minority, primarily in the elderly, it may persist indefmitedly (Bocola et al. 1996). The neuroleptic malignant syndrome, in its fully developed form, is characterized by delirium, parkinsonism, a coarse tremor, fever, tachycardia, labile hypertension and diaphoresis (Rosebush and Stewart 1989); in general, after delirium, the parkinsonism is the next sign to appear in the evolution of the syndrome (Velamoor et al. 1994). Although the vast majority of cases are caused by treatment with neuroleptics (including clozapine [Miller et al. 1991]), cases have also occurred secondary to the withdrawal of dopaminergic agents such as amantadine (Cunningham et al. 1991; Harsch 1987) and levodopa (Sechi et al. 1984; Tom et al. 1981). SSRIs, such as fluoxetine (Ernst and Steur 1993) and paroxetine (Jimenez-Jimenez et al. 1994), may cause a modest worsening of parkinsonism when used in the treatment of patients with Parkinson's disease; in patients with other disorders, such as depression, this side-effect is not, however, seen. Lithium may cause some mild cogwheel rigidity (Kane et al. 1978) and may aggravate preexisitng parkinsonism (Kelwala et al. 1984). Phenelzine, an MAOI antidepressant, caused a significant parkinsonian syndrome in an elderly female, which cleared when the phenelzine was discontinued (Teusink et al. 1984). This is a very rare occurrence.

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Calcium channel blockers (Sempere et al. 1995), such as amlodipine, flunarazine and cinnarizine (Marti- Masso and Poza 1998) may rarely cause parkinsonism: interestingly, in the case of flunarizine and cinnarizine, the parkinsonism may persist for a long period after the discontinuation of the drug (Negrotti and Calzetti 1997). Disulfiram rarely causes parkinsonism: this has been noted not only when taken in overdose, but also at therapeutic doses, and is associated with the appearance of lenticular lesions on magnetic resonance imaging (de Mari et al. 1993; Laplane et al. 1992). Valproic acid, taken chronically for a year or more, may cause parkinsonism, with one report indicating that this may be common (Armon et al. 1996). MPTP (methylphenyltetrahydropyridine) may occur as a contaminant in illicitly manufactured meperidine (Langston et al. 1983) and may cause a parkinsonism (Tetrud et al. 1989) of fairly rapid onset, within days to weeks (Ballard et al. 1985) after intravenous use. Methanol intoxication may, if severe, be followed by blindness and parkinsonism (Guggenheim et al. 1971; McLean et al. 1980). Diquat is an herbicide that may be absorbed transdermally: in one case (Sechi et al. 1992), dermal exposure to a 10% solution was followed within weeks by a fairly classic case of parkinsonism. Manganese exposure may occur in manganese mines, steel mills and battery factories or via drinking contaminated well-water and may, after a variable latent interval, be followed by a gradually progressive parkinsonism. The parkinsonism (Abd El Naby and Hassanein 1965; Huang et al. 1989) is characterized primarily by rigidity and bradykinesia; tremor may be present but is only rarely of the pill-rolling type. Certain additional features may also be present, including dystonia and what is known as a 'cock-walk'. Dystonic rigidity may be found in the neck or in the face, creating a vacuous, rigid grin (Charles 1927). The cock-walk, which may be seen in up to 38% of patients (Abd El Naby and Hassanein 1965), stems from a dystonic rigidity of the feet, such that patients walk on their metatarsophalangeal joints (as if in high heels [Huang et al. 1997]), at times looking for all the world like they are imitating the walk of a rooster. Interestingly, manganese-induced parkinsonism may progress long after exposure has ceased (Huang et al. 1993). Organophosphates, as found in certain pesticides, may cause parkinsonism (Bhatt et al. 1999), which may, rarely, persist long after the organophosphate-induced cholinergic crisis has passed (Muller-Vahl et al. 1999). Postanoxic encephalopathy, as may occur after drowning, strangulation or cardiac arrest, may be followed within weeks to months by a rigid-bradykinetic parkinsonism (Bhatt et al. 1993; Bucher et al. 1996; Goto et al. 1997), in some cases accompanied by dystonia (Bhatt et al. 1993). Carbon monoxide poisoning may be followed within days to weeks (Choi 1983) by parkinsonism (Grinker 1926; Klawans et al. 1982b), which is generally accompanied by delirium and incontinence (Choi 1983). Cyanide poisoning, generally seen in suicidal overdoses with potassium cyanide, may be followed by parkinsonism (Uitti et al. 1985) after a latent interval of 1-2 weeks (Rosenberg et al. 1989) to a year (Carella et al. 1988); in some cases, dystonia or athetosis may also be present (Rosenow et al. 1995). MISCELLANEOUS CAUSES OF PARKINSONISM

Rapid onset dystonia-parkinsonism is a recently described adult onset familial disorder characterized by the rapid onset of a combination of parkinsonism and dystonia, which progresses for a few days only then to stabilize and become chronic (Brashear et al. 1996, 1997; Kramer et al. 1999).

108 Signs, symptoms and syndromes

Hereditary mental depression and parkinsonism (Terry et al. 1975) is a rare familial disorder presenting in midlife with depression that persists and is joined within years by a gradually progressive parkinsonism. Death finally occurs secondary to respiratory failure. Hemiparkinsonism-hemiatrophy syndrome (Giladi et al. 1990) is a rare disorder, occurring secondary to perinantal or early childhood brain injury, characterized by an onset in the early adult years of a hemiparkinsonism that is sometimes accompanied by ipsilateral hemiatrophy of the body. Imaging reveals brain atrophy contralateral to the hemiparkinsonism. Systemic lupus erythematosus may, very rarely, present with a combination of dementia and parkinsonism (Dennis et al. 1992). Central pontine myelinolysis, occurring secondary to an overly rapid correction of hyponatremia, may, although generally presenting within days with delirium, quadriparesis and pseudobulbar palsy (Karp and Laureno 1993), rarely present primarily with parkinsonism (Dickoff et al. 1988; Tomita et al 1997). Pellagra may occur in either a chronic form or an acute (encephalopathic) form and, in the United States, is generally seen only in malnourished chronic alcoholics. The encephalopathic form is characterized by delirium and rigidity (Serdaru et al. 1988); importantly, a rash, which is typical of the chronic form, is not seen in the encephalopathic form (Ishii and Nishihara 1981). Focal lesions of the basal ganglia or substantia nigra (Boecker et al. 1996) may cause parkinsonism. Infarcts of the left striatum and globus pallidus (Fenelon and Houeto 1997), or of the pontomesencephalic junction (Kulisevsky et al. 1995), have caused a contralateral hemiparkinsonism, and in one case, a unilateral plaque of multiple sclerosis in the left substantia nigra caused a bilateral parkinsonism (Federlein et al. 1997). Hypoparathyroidism may, very rarely, cause parkinsonism in the absence of any calcification of the basal ganglia: in one instance, the patient recovered with treatment with vitamin D (Stuerenburg et al. 1996). Guamian amyotrophic lateral sclerosis-parkinsonism complex is a rare disorder of unknown cause found on Guam, parts of Japan and other Pacific islands (Garruto etal. 1981; Hirano et al. 1967; Malamud et al. 1961).

AMNESIA Akinesia represents a slowing of activity and may manifest itself in either a motor or a cognitive fashion. Motor akinesia is also often called bradykinesia, and cognitive akinesia bradyphrenia.

Description of the symptom Motor akinesia manifests with a slowing of all movements, as if patients were somehow encased in molasses. Cognitive (or psychic) akineisa manifests with a slowing and gelling of thoughts accompanied by a peculiar kind of dysphoria: patients complain of feeling like a Vegetable', or a 'zombie', experiencing a lack of spontaneity and, in some cases, a sense of depression or sadness (Rifkin et al. 1975; Van Putten and May 1978).

Differential diagnosis of the symptom Akinesia must be distinguished from akinetic mutism, the stuporous form of catatonia, abulia and depression. The distinction from akinetic mutism and stuporous catatonia is relatively

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straightforward: akinetic patients, although slowed, continue to engage in their customary behavior, whereas akinetic mutes or stuporous catatonics, even with urging, generally remain immobile. Abulia is distinguished on the basis of the response to supervision: akinetic patients, even with supervision, continue to be slowed, whereas abulic patients, provided that supervision is close, respond with relative alacrity. The distinction from depression may be difficult, especially given the presence of depressed affect or sadness in some patients with akinesia. The presence of other depressive symptoms, such as appetite or sleep change, is helpful, but in their absence, it may be necessary to attempt a 'diagnosis by treatment response' to a trial of an anticholinergic antiparkinsonian agent such as benztropine. Akinesia, in many cases, represents but a fragment of parkinsonism, and the presence of other parkinsonian signs, such as rigidity, flexion posture, tremor, etc., should direct the clinician to the differential diagnosis of parkinsonism discussed above. Most cases of'pure' akinesia occur as a side-effect of a neuroleptic drug (Rifkin et al 1975; Van Putten and May 1978). Rarely, akinesia may be found secondary to lesions of the globus pallidus, as for example after recovery from hypoxic coma (Feve et al. 1993).

Treatment of the symptom Most cases respond to treatment with benztropine or some other anticholinergic antiparkinsonian agent; propranolol is not effective.

AKATHISIA

Description of the symptom Akathisia (Ayd 1961; Braude et al 1983; Gibb and Lees 1986; Halstead et al. 1994; Sachdev and Kruk 1994) is characterized by a sense of restlessnesss and an inability to keep still; there is a dysphoric feeling of having to move, and, in most cases, this 'compulsion' to move is translated into action in various ways. If seated, patients shift restlessly from one position to another and may tap their feet or repeatedly cross and uncross their legs or arms. If standing, patients may rock back and forth, shifting their weight alternatively from one foot to another, or may actually 'march in place'. Restless pacing may occur as patients give way to the irresistible impulsion to move about. In almost all cases, this restless urge to pace or move about is worse when seated, and worst when lying down, most patients obtaining at least some relief by standing up. Coupled with this motoric restlessness, many patients also experience a 'cognitive' or 'psychic' akathisia manifest by restless thoughts: thoughts come too fast, are crowded and may shoot about the mind 'like ping-pong balls'. In some cases, this buzzing jumble of thoughts defies expression in speech, and patients may become mute. Although mild akathisia may be tolerable to some patients, more extreme forms may become unbearable. Agitation may become extreme, propelling patients to suicide attempts (Drake and Ehrlich 1985; Rothschild and Locke 1991) or assaultive behavior (Siris 1985). The appearance of akathisia may also exacerbate symptoms of other illnesses. For example, when neuroleptics are given to patients with Tourette's syndrome to ameliorate tics, the subsequent appearance of an akathisia may lead to an exacerbation of the tics themselves (Weiden and Bruin 1987). Furthermore, patients with schizophrenia who develop a neuroleptic-induced akathisia may experience a dramatic exacerbation of their psychotic symptoms (Van Putten 1975; Van Putten et al. 1974).

110 Signs, symptoms and syndromes

Importantly, patients experiencing an akathisia-mediated exacerbation of their illness may neither appear restless nor complain of restlessness if questioned (Weiden and Bruin 1987): in one of the author's patients with schizophrenia, an akathisia manifested with muteness and withdrawal, and it was only after treatment with propranolol that the patient was able to describe the akathetic 'chaos of thoughts' that had besieged her.

Differential diagnosis of the symptom The diagnosis of akathisia may easily be missed as patients may not complain of their symptoms: indeed, in one study of cancer patients experiencing akathisia secondary to antiemetic treatment, the diagnosis would have been missed in three-quarters had the patients not been specifically questioned (Fleishman et al. 1994). Thus, whenever a patient is treated with one of the medications listed below, which may cause akathisia, it is critical to enquire after this symptom. Furthermore, given that a medication-induced akathisia may appear anywhere from 1 day to 4 weeks after the initiation of treatment or a significant dose increase, these enquiries must be repeated at appropriate intervals. Patients should be asked whether they feel restless or whether they have to pace or move about. One must also enquire after cognitive or psychic akathisia by asking patients whether their thoughts are 'restless', 'coming too fast' or perhaps 'bouncing around, like ping-pong balls'. The diagnosis may also be missed when the akathisia presents as a seeming worsening of the underlying illness for which the medication was prescribed. For example, when patients with schizophrenia who were initially improving with neuroleptic treatment become more psychotic, the differential should, at a minimum, include an exacerbation of the underlying illness itself and an akathisia-mediated exacerbation of symptoms. In some cases, especially when motoric restlessness is absent or minimal, a 'diagnosis by treatment response' is permissible, and a trial with propranolol, or if that is contraindicated, benztropine is indicated. The results are, at times, little short of miraculous. The same holds true for depressed patients treated with fluoxetine or nefazodone, wherein an akathisia may present with agitation, suicidal ideation or suicide attempts, all symptoms easily ascribed to the depression. The restless legs syndrome may be confused with akathisia as there is in both cases motor restlessness and a tendency to pace the floor. Patients with the restless legs syndrome, however, generally experience parasthesiae in the legs and find some relief in rubbing their feet, characteristics not seen in akathisia; conversely, patients with akathisia often 'march in place', a sign not seen in the restless legs syndrome (Walters et al. 1991). Once the diagnosis of akathisia is secure, determining the cause is generally fairly simple as, in the overwhelming majority of cases, the akathisia occurs as a side-effect of a medication that, in the vast majority of instances, is a neuroleptic. As noted in Table 3.7, akathisia may also be seen in other disorders, namely Parkinson's disease, and with lesions of the basal ganglia, but these diagnoses are generally self-evident. MEDICATION INDUCED Acute neuroleptic-induced akathisia is unfortunately a very common complication of treatment with typical neuroleptic drugs, especially the 'high-potency' drugs such as haloperidol (Van Putten et al. 1984). Symptoms typically appear subacutely, some 5-6 days after initiating treatment or after a significant dose increase (Sachdev and Kruk 1994). Uncommonly, akathisia may appear on the first day of treatment or as late as 4 weeks (Van Putten et al. 1984).

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Table 3.7 Causes of akathisia Medication-induced

Neuroleptics Acute neuroleptic-induced akathisia Tardive akathisia Other medications Selective serotonin reuptake inhibitors Nefazodone Antiemetics Metoclopramide Diltiazem Imipramine withdrawal

Other causes

Parkinson's disease Basal ganglia lesions

Tardive akathisia, a variant of tardive dyskinesia, appears in a minority of patients after chronic neuroleptic treatment (Dufresene and Wagner 1988; Hershon etal. 1972; Lang 1994), and is similar, symptomatically, to the 'acute' variety (Burke et al. 1989). SSRIs such as fluoxetine (Lipinski et al. 1989) and paroxetine (Baldassano et al. 1996) may cause an akathisia, perhaps because of a serotonin-mediated inhibition of mesencephalic dopaminergic neurons. Nefazodone was, in one case report (Eberstein et al. 1996), noted to cause akathisia. Antiemetics such as prochlorperazine, as used in patients undergoing cancer chemotherapy, caused akathisia in approximately one-half of these patients (Fleishman et al. 1994). Metoclopramide, used either as an antiemetic or in the treatment of gastroesophageal reflux, may cause acute akathisia (Fleishman et al. 1994; Jungmann and Schofflang 1982). More importantly, chronic treatment with metoclopramide may also cause a tardive akathisia (Shearer et al. 1984). Diltiazem, a calcium channel blocker, may rarely, be responsible for akathisia (Jacobs 1983). Imipramine withdrawal, when abrupt after high-dose (i.e, 300 mg or more) administration, may be followed within 24 hours by severe akathisia (Sathananthan and Geshon 1973). OTHER CAUSES Parkinson s disease may itself cause akathisia, before any antiparkinsonian treatment is instituted (Lang and Johnson 1987): nearly one-half of all patients experience it to some degree, about 20% having severe symptoms (Cornelia and Goetz 1994). Basal ganglia lesions, as for example in bilateral necrosis secondary to carbon monoxide intoxication (Stuppaeck et al. 1995), may also cause akathisia.

Treatment of the symptom Neuroleptic-induced acute akathisia may respond to a simple dose reduction (Braude et al. 1983). When this is unsuccessful or impractical, various medications are helpful, including benztropine (Adler et al. 1993; DiMascio et al. 1976), biperidin (Van Putten et al. 1974), amantadine (DiMascio et al. 1976), diazepam (Donlon 1973), clonazepam (Kutcher et al. 1989) and propranolol. Of all these, propranolol seems most effective; it is usually given in a dose of 20-80 mg/day (Adler et al. 1985, 1986; Lipinski et al 1984); provided that the drug is well tolerated, a higher dose may, if necessary, also be given.

112 Signs, symptoms and syndromes

The treatment of tardive akathisia occurring as part of tardive dyskinesia is discussed in Chapter 22, p. 704. Acute akathisia occurring secondary to other medications may be approached in the same fashion as acute neuroleptic-induced akathisia. The treatment of akathisia occurring in Parkinson's disease has not been thoroughly studied; routine antiparkinsonian treatment may be tried first and, if unsuccessful, may be followed by propranolol or one of the other medications noted earlier.

CATATONIA Catatonia is a syndrome that, although originally described in patients with schizophrenia, is now recognized to occur in a variety of diseases, as described below.

Description of the syndrome Catatonia, as described in the earlier part of the twentieth century by Kraepelin (1899) and Bleuler (1924), occurs in one of two forms: stuporous (or retarded) and excited. The stuporous form is the most common, and will be described first. STUPOROUS CATATONIA

The cardinal signs of stuporous catatonia are immobility, mutism and waxy flexibility (also referred to by its Latin name, cereaflexibilitas). Associated symptoms include posturing, 'echo' phenomena (i.e. echolalia and echopraxia), negativism, automatic obedience and posturing. Immobility in catatonic stupor may persist for hours, days or longer, with little or no change in the patients' position. Some may simply lie in bed, their legs rigidly extended and adducted; others may almost curl up into a ball, resting on the floor, a chair or the bed. The eyes may be open or closed; if the eyes are open, patients often stare fixedly ahead. Patients may not move even to relieve themselves and may become foul with urine or feces. Some may not even swallow, allowing saliva or food to dribble from their mouths; indeed, if food is placed in the mouth, there is a risk of aspiration, which may be fatal (Bort 1976). Importantly, although patients appear to lack conscious activity, they remain alert, and some, upon recovery, may evidence an astonishingly accurate recall of events that occurred during the stupor. Interestingly, a patient's immobility may occasionally undergo a sudden lysis: for example, if a ball is gently thrown to an immobile patient, the patient may suddenly loosen up and catch the ball. Mutism ranges from partial to complete. Those with only partial mutism may mumble or whisper incomprehensible words or phrases. Waxy flexibility derives its name from the fact that, upon passive movement of the limbs, the examiner encounters a rigidity similar to what one would expect upon bending a softened waxen object, such as a taper. This is quite different from the 'clasp-knife' rigidity seen in spasticity or the cogwheel rigidity seen in parkinsonism, sometimes referred to as being 'leadpipe' in character. In most cases, in addition to this waxy flexibility, one also finds that the patient's limbs tend to stay in whatever position the examiner places them, no matter how uncomfortable and regardless of whether or not the examiner instructs the patient to maintain the positionof the limb. Bleuler (1924) recommended a bedside test for waxy flexibility that involved taking 'the patient's pulse and, as if inadvertently, "holding" his arm high and extended. Then, after taking

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the pulse rate, I release the arm.' The test was considered to be positive when the patient's arm remained suspended in essentially the same position. Another bedside test involves checking for the presence of a 'psychological pillow'. Here, when the patient is lying supine in bed with the head resting on an (actual) pillow, the head is lifted slightly and the pillow removed. In a positive test, the patient's head remains in essentially the same position, as if the pillow were still present. Echo phenomena, as noted, consist of either echolalia, wherein the patient automatically, and without prompting, repeats back what the examiner said, or echopraxia, wherein, again without prompting, the patient automatically mimics the examiner's movements, gestures or posture. Negativism does not represent mere contrariness, stubborness or passive-aggressiveness, for in each of these phenomena, patients have not lost control and may be able to cooperate in situations that, to them, appear to be to their advantage. In contrast, negativism presents as a mulish, almost instinctual tendency to resist, which may be either passive, wherein the patient, in response to a command, simply does nothing, or active, wherein the patient does the opposite of what is requested. Negativistic patients may refuse to come to an interview, take a bath, change their clothes, take medicines or even eat food placed in front of them. In extreme cases, negativism may extend to the patient's own urges, leading, for example, to extreme constipation with fecal impaction. Patients with active negativism may get up from a table when food is placed on it, or may back out of a doorway if asked to walk through it. Typically, there is no 'reasoning' with negativistic patients as they generally remain mute and inaccessible. Automatic obedience represents, in a sense, the converse of negativism, in that these patients automatically do what is expected of them, without question or hesitation, regardless of whether the consequences are absurd or harmful. This is far from mere agreeableness as patients often seem to behave in a robotic or automaton-like manner. Posturing is said to occur when patients automatically and spontaneously assume more or less bizarre postures, which are then maintained. The arms may be spread in a cruciform position, or the head thrown back in full extension; some may huddle into balls or stand, stork-like, on one leg. EXCITED CATATONIA

Excited catatonia is characterized by bizarre, frenzied and purposeless hyperactivity. Uninvolved with others, almost sealed off in their own world, patients may gesticulate, march in place or loudly declaim; verbigeration, or rapid, bizarre and senseless speech, may also occur. Excited catatonia may rarely undergo a progression into a condition known as Stauder's lethal catatonia. Here, there is an escalation in the hyperactivity, followed by fever, tachycardia, hypotension, leukocytosis and, in some cases, death (Castillo et al. 1989; Mann et al. 1986). The recognition of this syndrome is critical, for even when the patient is in extremis, with a temperature of 41°C (106°F), treatment with electroconvulsive therapy may result in recovery (Aronson and Thompson 1950).

Differential diagnosis of the syndrome STUPOROUS CATATONIA

Stuporous catatonia must be distinguished from stupor of other causes as well as from akinetic mutism. Stupor of other causes is generally associated with a decreased level of

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consciousness, in contrast to the alertness seen in catatonia. Akinetic mutism is distinguished by the fact that akinetic mutes, in contrast to stuporous catatonics, do withdraw from painful stimuli, do swallow saliva and food, and do not display waxy flexibility. In addition to these clinical features, the response to lorazepam may also be of diagnostic value: with parenteral lorazepam, patients with stuporous catatonia often achieve temporary relief (Rosebush et al. 1990; Salam et al. 1987), whereas those with stupor of other cause or with akinetic mutism do not. Stuporous catatonia has a large number of causes, as listed in Table 3.8, and described further below. Schizophrenia is the prototype cause of stuporous catatonia. Uniquely, here, although some patients may be consistently stuporous, it is not uncommon to find that the same patient may at one point be stuporous and then, later on in the illness, manifest excited catatonia (Johnson 1984; Morrison 1973). Depressive episodes, as occur in major depression or bipolar disorder, may be complicated by stuporous catatonia (Barnes et al. 1986), especially in elderly patients (Starkstein et al. 1996). Manic episodes, as seen in bipolar disorder, may, at their height, evolve into stuporous catatonia (Abrams and Taylor 1976; Taylor and Abrams 1977). Periodic catatonia (Gjessing 1974) is a rare condition, thought probably to be a variant of bipolar disorder, which presents with episodes of catatonia. Medication may cause catatonic stupor, and this has been noted with treatment with neuroleptics (Weinberger and Wyatt 1978) (especially high-potency neuroleptics at fairly high dose [e.g. over 20 mg haloperidol] [Gelenberg and Mandel 1977]) and disulfiram after 1 to 2 months of treatment (Reisberg 1978; Weddington et al. 1980), as well as secondary to a combination of cyclizine and glutethimide (Good 1976). Benzodiazepine withdrawal may, rarely, be associated with catatonic stupor (Rosebush and Mazurek 1996). Epilepsy may be associated with catatonia in a variety of ways. Ictal catatonia represents one kind of complex partial seizure and is suggested by a paroxysmal onset, often accompanied by

Table 3.8 Causes of catatonia Stuporous catatonia

Schizophrenia Depressive episodes of major depression or bipolar disorder Manic episodes of bipolar disorder Periodic catatonia Medication Neuroleptics Disulfiram Cyclizine and glutethimide Benzodiazepine withdrawal Epilepsy Ictal Postictal Psychosis of forced normalization Interictal psychosis Encephalitis Focal lesions Miscellaneous causes

Excited catatonia

Schizophrenia Encephalitis

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confusion: importantly, although most complex partial seizures last only a matter of minutes, ictal catatnoia has persisted for days or longer (Engel et al. 1978; Gomez et al. 1982; Lim et al. 1986; Shah and Kaplan 1980). Postictal psychosis is generally seen only after a flurry of seizures, is separated from the last seizure by a lucid interval lasting days, and lasts itself for days or months; it may, rarely, be characterized by catatonia (Logsdail and Toone 1988). Psychosis of forced normalization may occur when patients with poorly controlled seizures undergoing aggressive treatment experience relief from seizures accompanied by a 'forced normalization' of the electroencephalogram: in one case, this forced normalization was followed by a psychosis characterized by 'flattened affect, persectuory auditory hallucinations and catatonic posturing' (Pakainis et al 1987). Finally, the interictal psychosis, which may be characterized by stuporous catatonia, is a chronic psychosis that appears gradually after many years of frequent seizures (Kristensen and Sindrup 1979; Slater and Beard 1963). Encephalitis may present with stuporous catatonia (Abrams and Taylor 1976; Barnes et al. 1986; Kim and Perlstein 1970; Misra and Hay 1971; Wilson 1976), especially herpes simplex encephalitis (Raskin and Frank 1974) and encephalitis lethargica (Bond 1920; Kirby and Davis 1921). Focal lesions, especially of the inferior or medial frontal lobe (Belfer and d'Autremont 1971; Roberts 1965; Thompson 1970), may cause catatonia. Other examples include a right subdural hematoma (Micheels 1953) and a right hemisphere cerebrovascular accident including the parietal and temporal lobes (Saver et al. 1993). One study of patients with acute hemiplegia secondary to a cerebrovascular accident noted waxy flexibility on the non-hemiparetic side in approximately 2% of cases (Saposnik et al. 1999). Miscellaneous (and rare) causes of catatonic stupor include Wilsons disease (Davis and Borde 1993), cerebral lupus erythematosus (Lanham et al. 1985; Mac and Pardo 1983), paraneoplastic limbic encephalitis (Tandon et al. 1988) and hepatic encephalopathy (Jaffe 1967); as part of an encephalitic presentation of stage II of Lyme disease (Pfister et al. 1993), during stage I of subacute sclerosing panencephalitis (Koehler and Jakumeit 1976), in conjunction with the dementia of late onset Tay-Sachs disease (Rosebush et al. 1995) and as part of thrombotic thrombocytopenic purpura (Read 1983). There is also a fascinating report of an adult who experienced recurrent, minutes-long episodes of unknown cause characterized by stuporous catatonia with prominent tachycardia and hypertension (Wheeler etal. 1985). EXCITED CATATONIA

Excited catatonia must be differentiated from mania, and the extreme form of excited catatonia, namely Stauder's lethal catatonia, must be distinguished from the neuroleptic malignant syndrome. Mania may be distinguished from excited catatonia on the basis of the presence or absence of purposefulness in the patient's overall behavior. As pointed out by Kraepelin (1919), the hyperactivity of excited catatonia 'is often limited to a very small space, perhaps a part of the bed; the manic, on the contrary, seeks everywhere for an opportunity to occupy himself, runs about, busies himself with the other patients, follows the physician, carries on all sorts of mischievious tricks'. The neuroleptic malignant syndrome, as described in Chapter 22, p. 712, occurs as a rare side-effect of neuroleptics, being characterized by delirium, fever, autonomic instability and rigidity. Diagnostic difficulty may arise when a patient with excited catatonic schizophrenia, who happens to be undergoing treatment with a neuroleptic, develops a fever. At this point, the differential question is whether the fever represents the appearance of Stauder's lethal catatonia or the supervening of the neuroleptic malignant syndrome. Although this may be a

116 Signs, symptoms and syndromes

very difficult differential, the course of the evolution of symptoms may be helpful. In the case of Stauder's lethal catatonia, the fever evolves from a setting of ever-worsening frenzied hyperactivity, whereas in the neuroleptic malignant syndrome, the fever often arises after a severe, generalized rigidity has set in (Castillo et al. 1989). Excited catatonia has but a small number of causes, as noted in Table 3.8, being seen in schizophrenia and encephalitis. Schizophrenia is the cause of excited catatonia in almost all cases and is the predominant form in about one-quarter of all patients with catatonic schizophrenia (Morrison 1973). Encephalitis may, exceptionally, present with excited catatonia; indeed, in one case of Eastern equine encephalitis, excited catatonia remained the only symptom of the encephalitis until a fever appeared 3 days later (Penn et al. 1972).

ASTERIXIS Asterixis is a very important diagnostic sign: although, as noted below, it may occasionally be seen in some focal lesions or as a side-effect of some medications, it indicates, in the overwhelming majority of cases, the presence of one of three metabolic encephalopamies: • hepatic encephalopathy • uremic encephalopathy • the encephalopathy of respiratory failure. As such, it should be carefully sought for in any patient with delirium as it immediately and drastically narrows the large differential for delirium down to a very manageable number of conditions.

Description of the sign Asterixis represents a precipitous loss of muscle tone (Adams and Foley 1949; Leavitt and Tyler 1964) and is typically tested for by asking patients to hold their arms straight to the front with the hands hyperextended at the wrist as far back as possible, holding that position for at least 30 seconds. When asterixis is present, there will be irregularly occurring 'flaps' of both hands down, followed after a brief moment by recovery back to the hyperextended position. With patients who are unable to perform this maneuver with the arms, an attempt may be made to elicit asterixis in the lower extremities. First, with the patient supine, the hips and knees are passively placed in flexion, with the soles of the feet resting on the bed; next, the knees are separated and allowed to hang passively apart at 60-90 degrees for at least 30 seconds. When asterixis is present, the 'flapping' may appear as the hip adductors precipitously lose all tone, allowing the knees to fall further toward the bed, followed, again, by a quick recovery.

Differential diagnosis of the sign Asterixis may be unilateral or bilateral. As will be seen, unilateral asterixis may occur with unilateral lesions anywhere from the level of the brainstem to the cerebral cortex; bilateral asterixis, although occasionally occurring secondary to bilateral brainstem lesions, much more often indicates a metabolic encephalopathy or a medication side-effect.

Abnormal movements 117

ASTERIXIS DUE TO FOCAL LESIONS

Unilateral asterixis may be found contralateral to lesions of various types in the cerebral cortex (including the frontal, parietal and occipital lobes), striatum, internal capsule, thalamus, mesencephalon and pons (Degos et al. 1979; Rio et al 1995; Stell et al 1994; Tatu et al. 2000) Bilateral asterixis has been noted with bilateral involvement of the brainstem and also, albeit very rarely, with unilateral mesencphalic or pontine lesions (Rio et al. 1995). ASTERIXIS DUE TO METABOLIC ENCEPHALOPATHIES

Asterixis seen in metabolic encephalopathies is bilateral. Hepatic encephalopathy (Adams and Foley 1949, 1953; Read et al. 1961) is so typically characterized by asterixis that 'liver flap' has become a common synonym for asterixis. Uremic encephalopathy (Raskin and Fishman 1976; Tyler 1965), when productive of a delirium, is almost always accompanied by asterixis. Respiratory failure (Austen et al. 1957; Bacchus 1958), when severe enough to produce a deilirium, may also cause asterixis. ASTERIXIS AS A MEDICATION SIDE-EFFECT

Asterixis has been noted with levodopa (Glantz et al. 1982) and phenytoin.

HEIGHTENED STARTLE RESPONSE The startle response, a normal human reflex to sudden, potentially threatening stimuli, may, in certain conditions, become pathologically heightened. Description of the sign The startle response, as may occur with a loud and unexpected noise such as a nearby gunshot, consists of a sudden generalized withdrawal, accompanied by flexion of the arms. Differential diagnosis of the sign

HEIGHTENED STARTLE RESPONSE IN THE SETTING OF GENERALIZED AUTONOMIC HYPERACTIVITY

Posttraumatic stress disorder, generalized anxiety disorder and withdrawal from alcohol or benzodiazepines may all leave patients quite 'jumpy' and easily startled (Howard and Ford 1992). In between the heightened startles, however, patients remain variously anxious, tremulous or apprehensive. HEIGHTENED STARTLE RESPONSE AS PART OF REFLEX EPILEPSY

'Startle' epilepsy is said to occur when a normally evoked startle response is followed by either a generalized or partial seizure (Aguglia et al 1984; Gimenez-Roldan and Martin 1980; SaenzLope et al. 1984).

118 Signs, symptoms and syndromes

HEIGHTENED STARTLE RESPONSE SECONDARY TO OTHER LESIONS

Roth post-traumatic and postanoxic encephalopathy (Brown et al. 1991) may be characterized by a heightened startle response, as may brainstem lesions such as sarcoidosis, paraneoplastic encephalitis (Brown et al. 1991), infarction (Kimber and Thompson 1997) or, in one case, compression of the pons by an ectatic vertebral artery (Gambardella et al. 1999). HEIGHTENED STARTLE RESPONSE ON AN IDIOPATHIC BASIS

Hyperekplexia, as described in Chapter 8, p. 413, comes in two forms: major and minor (Saenz-Lope et al. 1984). In the major form, the startle response is accompanied by generalized stiffness, which often leads to falling, and it is this stiffening which suggests the correct diagnosis. The minor form, consisting only of a heightened startle without stiffening or falls, may be suggested by a family history of a relative with the major form. HEIGHTENED STARTLE RESPONSE AS A 'CULTURAL' VARIANT

In various cultures, families or small groups of individuals may, in response to a startling stimulus, display a prolonged and at times elaborate reaction. These individuals, otherwise reticient or shy, typically end up saying and doing things, such as swearing or cursing, during the 'startle' that are entirely out of character for them. Such presumably voluntary performances have been noted in Malaysia, where they are known as Latah (Bartholomew 1994) and among French-Canadian lumberjacks of the past century, in whom the condition was known as the 'Jumping Frenchmen of Maine' (Saint-Hilaire et al. 1986).

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4 Other signs and symptoms Mutism Akinetic mutism Stuttering Primitive reflexes Pseudobulbar palsy Mimetic, or involuntary, facial palsy Lefou rire prodromique Abulia Environmental dependency syndrome ('utilization behavior')

137 138 140 141 143 145 146 147 148

Kluver-Bucy syndrome Alien hand sign 'Phantom' and 'supernumerary' limbs Depersonalization Obsessions and compulsions Amusia Foreign accent syndrome Cataplexy Hallucinations and delusions Schneiderian first rank symptoms

149 150 154 155 157 159 160 160 162 169

MUTISM Mutism, from the Latin mutus (inarticulate, incapable of speech), is characterized by an absence of speech despite an intact larnyx. In addition to the causes of mutism noted here, mutism also occurs in the specific syndrome known as akinetic mutism, discussed below. Description of the sign Mutism may or may not be complete: although some patients make no sound, others may be able to utter fragments or entire words. Mute patients may or may not attempt to communicate via other routes, by writing or gesture for example, depending on the underlying cause. Differential diagnosis of the sign Aphonia may result from bilateral recurrent laryngeal nerve paralysis. Although such patients make no sound, they are distinguished from those with mutism by the fact that their lips and tongue move in an otherwise normal speaking fashion: the effect is much like watching a movie with the sound off. Hypophonia, as seen in parkinsonism may, when severe, reduce speech to a soft, unintelligible mumbling. The evolution of the hypophonia hand in hand with other parkinsonian signs, such as rigidity and tremor, makes the diagnosis fairly clear.

138 Signs, symptoms and syndromes

Feigned mutism, as for example in malingering or factitious illness, is suggested by the presence of an advantage secondary to not speaking and by a history, often obtained from others, of normal speech in other circumstances. 'Elective' or 'selective' mutism, as may be seen in young children, is said to occur when the child fails to speak only when around strangers, being capable of speech at home (Dummit et al. 1997; Elson et al 1965; Steinhausen and Juzi 1996; Wergeland 1979): this probably represents a severe form of timidity or shyness. Most cases of mutism occur as part of stroke or as an end stage phenomenon of certain dementing disorders; it has also been reported after neurosurgery on the cerebellum and as a side-effect of cyclosporin. Stroke may be characterized by mutism that, with time, may resolve into one of the aphasias. Thus, mutism occurring with an infarction of the left inferior frontal region or the medial aspect of the left frontal lobe may resolve into a motor (David and Bone 1984; Masdeu and O'Hara 1983) or transcortical motor aphasia (Alexander and Schmitt 1980; Bogousslavksy and Regli 1990), respectively. In both these cases, patients will attempt to communicate in other ways, if only by gesture, and also retain the ability to follow oral instructions. Mutism may also occur with infarction involving both the inferior frontal and the temporoparietal area on the left, and this may resolve into a more or less severe global aphasia, with both motor and sensory aspects: such patients not only have difficulty speaking, but also are impaired in their ability to follow instructions. Mutism occurring secondary to infarction of the inferior aspect of the left frontal lobe may occasionally resolve without an 'intervening' motor aphasia, and in such cases one speaks of'aphemia' (Schiff et al. 1983). Certain dementing disorders, may, in their end stages, and long after a dementia is well established, gradually come to be characterized by mutism, this being particularly characteristic of frontotemporal dementia (Neary et al. 1993; Snowden et al. 1992) and Pick's disease; it may also be seen in Alzheimer's disease. Mention must also be made of multi-infarct dementia, which may, provided that an appropriately placed infarction occurs, also be characterized by muteness. Neurosurgery on the cerebellum may, in children, be followed by a transient mutism (Van Dongen et al. 1994). Cyclosporin, used for immunosuppression in liver transplant patients, has been noted to cause mutism in four patients (Valldeoriola et al. 1996).

AKINETIC MUTISM Description of the syndrome Patients are for the most part mute and globally akinetic, and although at first glance they appear to be in a stupor, closer observation reveals lively conjugate eye movements as patients track objects in the room, such as physicians and nurses. In some cases, the mutism and akinesia may persist through all adversities, but in others, patients may respond to an especially adversive stimulus with a feeble motion of a limb or perhaps by uttering a word. Food may be eaten if placed in the mouth, but patients do not seek it, and urine and feces are passed in the bed. Importantly, there is no generalized rigidity, no waxy flexibility and no negativism. Some examples may serve to flesh out this defintion. The first is taken from Cairns' original description of akinetic mutism (Cairns et al. 1941).

Other signs and symptoms 139 In the fully developed state he makes no sound and lies inert, except that his eyes regard the observer steadily or follow the movement of objects, and they may be diverted by sound. Despite his steady gaze, which seems to give promise of speech, the patient is quite mute, or he answers only in whispered monosyllables. Oft-repeated commands may be carried out in a feeble, slow, and incomplete manner, but usually there are no movements of a voluntary character; no restless movements, struggling or evidence of negativism. Emotional movement is almost in abeyance. A painful stimulus produces reflex withdrawal of the limb, and, if the stimulus is maintained, slow, feeble, voluntary movements of the limbs may occur in an attempt to remove the source of the stimulation, but usually without tears, noise, or other manifestations of pain or displeasure. The patient swallows readily but has to be fed. Food seen may be recognized as such, but there is evidently little appreciation of its taste and other characteristics: objects normally chewed or sucked may be swallowed whole. There is total incontinence of urine and faeces.

Cairns' cases, occurring with third ventricular tumors, were generally of gradual or subacute onset. Another case (Nielsen 1951), secondary to infarction of the cingulate gyri, bears detailed reporting given the remarkable abruptness of its onset. The patient was a 46-year-old woman who: was ironing when she suddenly stopped on the spot, complained of a severe headache, but remained standing. Her son put her to bed, where she lay motionless, without even speaking. She stared at the ceiling, did not ask for anything, not even for a drink. After nine days she was hospitalized and on the ward she continued akinetic and mute. Under strong stimulation she did say, 'It hurts,' and 'Water,' but that was all. She was obviously conscious and took note of her environment but lay day after day motionless, not deigning to call for bed pan or food.

Differential diagnosis of the syndrome Stuporous catatonia (Abrams and Taylor 1976; Morrison 1973) may be distinguished from akinetic mutism by the presence of such signs as waxy flexibility and negativism. Neuroleptic toxicity may be characterized by a syndrome resembling akinetic mutism (Behrman 1972), but the occurrence of the syndrome following the initiation or a dose increase of a neuroleptic will suggest the correct diagnosis. Abulia is distinguished by the fact that abulic patients, if given constant supervision, will arise from their immobility and do as requested, in contrast to akinetic mutes, who will not move. Mutism occurring as the presenting feature of a motor aphasia (or its transcortical variant) is distinguished by the fact that these aphasic patients attempt to communicate in other ways, perhaps by gesture or writing, and do follow commands. Mutism may also constitute the presentation of a global aphasia, and such patients may not attempt to communicate: the fact that such patients are not immobile but do move about, however, readily distinguishes them from patients with akinetic mutism. The 'locked-in syndrome' (Nordgren et al. 1971) may, at first glance, appear to be similar to akinetic mutism. This syndrome, occurring secondary to high brainstem infarction or other lesions, such as central pontine myelinolysis, is characterized by tetraparesis, bilateral facial paresis and a paralysis of lateral gaze, only vertical gaze being left intact. It is the use to which these patients give their preserved vertical gaze that distinguishes them from akinetic mutes: 'locked-in' patients are desperate to communicate and will do so with a kind of morse code of vertical eye movements, whereas akinetic mutes evidence no interest in communication. Stupor is distinguished by somnolence or decreased alertness: stuporous patients are not easily aroused and do not have 'lively' eye movements: if eye movements do occur in stupor, they are generally either roving or dysconjugate.

140 Signs, symptoms and syndromes

The persistent vegetative state, as may be seen upon recovery from coma secondary to closed head injury or global anoxia, is distinguished by the presence of spastic rigidity. Akinetic mutism, thus defined and distinguished from similar syndromes, occurs in only a small number of conditions. Cairns et al. (1941) pointed out that third ventricular masses compressing the surrounding diencephalon may cause the syndrome and noted that this may occur whether or not obstructive hydrocephalus is present; a report of akinetic mutism occurring secondary to surgical damage to the hypothalamus supports this view (Ross and Stewart 1981). Messert et al. (1966), however, presented a case that clearly did occur secondary to obstructive hydrocephalus. Bilateral infarction of the anterior cingulate gyri may be responsible (Barris and Schuman 1953; Nielsen 1951), and the syndrome has also been seen with more widespread infarction involving not only the cingulate gyri, but also other structures in the distribution of the anterior cerebral arteries (Paris 1969; Freemon 1971). Akinetic mutism has also been seen as a side-effect of cyclosporin (Bird et al 1990) and in a patient treated with total body irradiation and amphotericin B (Devinsky et al. 1987). Treatment of the syndrome In a case of akinetic mutism occurring secondary to hypothalamic damage (Ross and Stewart 1981), dopamine agonists were helpful. Whether or not other agents, such as a selective serotonin reuptake inhibitor (SSRI) or a stimulant (e.g. methylphenidate) would also be helpful is unclear.

STUTTERING Description of the symptom The phenomenology of stuttering differs according to whether it occurs on a developmental or an acquired basis (Helm et al. 1978). In developmental stuttering, patients find themselves 'blocked' as they attempt to speak the first letter of a word and have particular difficulty getting past the letters B, D, K, P and T. Unable to surmount the sound, patients repeat it again and again, often with progressively increasing force and volume; with these ever-more vigorous attempts, there may be associated features, such as facial grimacing, blinking, hissing and fist-clenching. The block is eventually overcome, and there is often a cascade of words, all clearly and unhesitatingly pronounced, as if the dam had broken. Interestingly, patients with developmental stuttering may find themselves unblocked if they sing, read aloud or are quite angry. Acquired stuttering differs in several ways. First, the block is as likely to occur on the second or subsequent letter as on the first. Second, although patients may be annoyed at being blocked, and do engage in repeated attempts to make the sound, the effort to do so is rarely as vigorous or as forceful as in developmental stuttering. Finally, when a patient with acquired stuttering does get beyond the block, it is rare to see a subsequent 'cascade' of words. Differential diagnosis of the symptom Developmental stuttering generally appears between the ages of 2 and 10 and in most, but not all, cases remits in later adolescence. A genetic basis is strongly suspected.

Other signs and symptoms 141

Acquired stuttering may occur with lesions of the posterior portion of the inferior frontal gyrus (Freedman et al. 1984), and although most cases occur with lesions on the left side, a 'crossed' stuttering may occasionally be seen, i.e. stuttering secondary to a right-sided cortical lesion in a right-hander (Fleet and Heilman 1985). Stuttering has also been noted with lesions of white matter of the frontal lobe (Ludlow et al. 1987) and of the caudate nucleus, with or without an associated involvement of the internal capsule (Caplan et al. 1990). Acquired stuttering may also occur in Parkinson's disease (Koller 1983), progressive supranuclear palsy (Kluin et al. 1993; Koller 1983) and dialysis dementia (O'Hare et al. 1983). Finally, acquired stuttering has been noted as a side-effect of neuroleptics (Nurnberg and Greenwald 1981) and, in one case, of the SSRI sertraline (Christensen et al. 1996).

PRIMITIVE REFLEXES As infants mature, it is normal for certain reflexes to fade and become unelicitable. Should they reappear in adult years, they may indicate cerebral pathology and are known collectively as 'primitive' reflexes. Four primitive reflexes are presented below: the palmomental reflex, the snout reflex, the grasp reflex and the grope reflex. Of all these primitive reflexes, the grope reflex is the most remarkable.

Description of the signs The palmomental reflex (Blake and Kunkle 1951; Jacobs and Gossman 1980) may be elicited by repeatedly and rapidly dragging an object, such as the tip of the reflex hammer, across the thenar eminence, from the lateral aspect medially toward the center of the palm: the contact should be definite, and slightly disagreeable, but not painful. When the reflex is present, one sees a wrinkling of the patient's mentum, or chin. The snout reflex (Jacobs and Gossman 1980) is elicited by placing one's index finger just above the patient's upper lip, in the midline, centered upon the philtrum, and then gently pressing in: a positive reflex is indicated by a puckering or protruding of the lips. The grasp reflex is tested for by laying one's index finger flat across the palm of the patient's hand (with the tip of the finger pointing toward the hypothenar eminence and the base of the finger resting between the patient's thumb and index finger) and then slowly withdrawing one's finger between the patient's thumb and index finger (Adie and Critchley 1927; Seyffarm and Denny-Brown 1948). When present, the reflex consists of the patient's fingers involuntarily closing upon the examiner's finger, as if grasping it. Once the finger has been grasped, attempts by the examiner to pull it free often result in a stronger grasp, but if the examiner ceases all effort to remove the finger, the patient's hand typically relaxes (Walshe and Robertson 1933). Interestingly, such a grasping reflex may be present in a hemiplegic limb, such that although the patient is unable to flex the fingers voluntarily, grasping occurs with the appropriate stimulation (Stewart-Wallace 1939). The grope reflex (also known as 'instinctive grasping') is a truly remarkable clinical phenomenon. Testing is accomplished by simply touching the patient's hand: when the reflex is present, the patient's hand will involuntarily reach out in a groping fashion to grasp the examiner's finger (Mori and Yamadori 1985). In some cases, one may also demonstrate the 'magnet' reaction, wherein, by successive touches of the patient's hand from successively different positions, one may lead the patient's hand through space, much as if it were being attracted by a magnet (Seyffarth and Denny-Brown 1948). When fully

142 Signs, symptoms and syndromes

developed, actual touch may not be required to elicit the reflex, and the patient's hand may automatically begin groping at the mere sight of another object (Mori and Yamadori 1985). The presence of a grope reflex may significantly interfere with the patient's day-to-day life. One patient, whenever passing through a doorway, found that his 'left hand clung to [the] door handle ... with such tenacity that he had to use his right hand to free himself (Seyffarth and Denny-Brown 1948). In another case (Stewart-Wallace 1939), the patient's right hand 'developed a habit of clutching hold of objects of its own accord, such as the lapel of his coat, the edge of his trouser pocket, or the bed-clothes. This distressed him so much that in order to prevent it, he used to wear a glove most of the time. At other times he would keep his hand in his pocket, holding a coin or a key.' Another patient (Walshe and Hunt 1936), questioned about the experience, noted that T can't leave things alone. If I see anything lying near me, my hand seems to want it.'

Differential diagnosis of the signs The palmomental reflex has been noted in anywhere from 11% (Jensen et al 1983) to 30% (McDonald et al. 1963) or 37% (Jacobs and Gossman 1980) of normal controls and may be more common in the elderly (Jacobs and Gossman 1980); it occurs more frequently bilaterally than unilaterally (Jacobs and Gossman 1980). One study found it to be more common in patients with Parkinson's disease (de Noordhout and Delwaide 1988), although another did not (Gossman and Jacobs 1980). It is not, when appearing by itself, associated with dementia (Tweedy et al. 1981). The snout reflex has been found in up to 17% of normal controls (Jacobs and Gossman 1980) and may be more common with increasing age (Koller et al. 1982). Its presence is associated with various dementing disorders (Tweedy et al. 1981; Waite et al. 1996). The grasp reflex has been associated with various frontal lobe lesions (Stewart-Wallace 1939) and is typically bilateral, regardless of whether the lesion is unilateral or bilateral (De Renzi and Barbieri 1992). It has also been associated in a non-specific way with various dementing disorders (Tweedy et al. 1981; Waite et al. 1996). A transient grasp reflex has also been noted in schizophrenia (Lohr 1985). The grope reflex has also been associated with frontal lesions (Walshe and Hunt 1936; Walshe and Robertson 1933); a subsequent study, however, noted a significant association between groping and right-sided perisylvian or subcortical lesions, noting further that the groping was generally ipsilateral to the lesion (Mori and Yamdori 1985). The groping reflex must be distinguished from the alien hand sign, a distinction made possible by attending to the seeming 'intent' of the moving hand. In groping, the hand reaches for whatever may be nearby, whether a doorknob or the examiner's hand, without regard to the patient's current purposes, whereas the alien hand acts at definite crosspurposes with the normal hand. Consider, for example, a comb that just happened to be lying on the bed. Whereas the alien hand might make no movement towards it, the groping very well might; if the patient tried to pick the comb up with the 'good' hand to comb his or her hair, however, the alien hand might well come into play, grabbing at the comb to prevent its intended use. Although, as noted above, primitive reflexes are not uncommonly found in normal controls, finding more than one strongly suggests intracranial pathology (Brown et al. 1998), such as Alzheimer's disease and multi-infarct dementia (Vreeling et al. 1995) or central nervous system AIDS (Marder et al. 1995).

Other signs and symptoms 143

PSEUDOBULBAR PALSY Pseudobulbar palsy results from bilateral damage to the corticobulbar fibers which descend from the cortex, through the centrum semiovale, to the internal capsule and thence, travelling along with the corticospinal tracts, to the various brainstem nuclei (Besson et al. 1991).

Description of the syndrome When fully developed (Langworthy and Hesser 1940; Tilney 1912), the syndrome of pseudobulbar palsy consists of 'emotional incontinence', dysarthria, dysphagia, a stiff and shuffling gait, an exaggerated jaw jerk and gag reflex, and a variable degree of paresis of the tongue; the corticospinal tracts are often also involved, as evidenced by exaggerated deep tendon reflexes and bilateral Babinski signs. Emotional incontinence, the most striking aspect of the syndrome, is also known as 'pathologic laughing and crying' and is characterized by either laughter or crying, occurring either spontaneously or in response to some otherwise trivial stimulus, such as someone approaching the bed (Lieberman and Benson 1977). One of S.A.K. Wilson's patients (Wilson 1924), after suffering bilateral strokes: was seen to have a distinctly vacant, apathetic facial expression at rest. She was able to move facial muscles voluntarily on both sides, although there was the slightest weakenss of the left corner of the mouth. On the slightest stimulus, even when the observer simply came to her bedside, she at once assumed a most lugubrious expression, her mouth opened widely, and a long, almost noiseless bout of weeping ensued, lasting for many seconds, even minutes, at a time.

Another of Wilson's patients, again after bilateral strokes: exhibited characteristic involuntary laughing. Whatever the emotional stimulus, and however slight, he at once began to laugh and laugh loudly. Thus, on reading the war news he at once began to smile, and the more serious and anxious the news, the more he laughed. On examination, there was some voluntary facial paresis on both sides, especially the left, some dysarthria, and some dysphagia, but during the laughing the facial movements were in no way restricted. A double extensor response was present.

Importantly, these emotional displays are not accompanied by any corresponding feeling of sadness or mirth. In one case (Davison and Kelman 1939), a patient, though feeling no mirth, experienced such 'gales of laughter' that he 'felt foolish and ashamed, and had tears in his eyes, because he could not "control the laughter" '.

Differential diagnosis of the syndrome 'Emotionalism' is not at all uncommon after strokes, but it is readily distinguished from the emotional incontinence of pseudobulbar palsy by the fact that 'emotional' patients experience an affect congruent with their facial expression, whereas the emotionally incontinent patient feels neither sadness nor mirth and is often as surprised at the emotional display as is the observer. Lability of affect, as may be seen in mania, is, like emotionalism, distinguished from emotional incontinence by the presence of an affect congruent with the facial expression. Inappropriate affect, as may be seen in schizophrenia, is similar to emotional incontinence in that there is a lack of congruity between the affect and the emotional expression. However,

144 Signs, symptoms and syndromes

patients with inappropriate affect also invariably display bizarre affect or mannerisms, signs absent in pseudobulbar palsy. Once the syndromal diagnosis of pseudobulbar palsy is secure, a determination of its cause must be made. Table 4.1 lists the various causes, dividing them into vascular disorders, for example bilateral cerebral infarctions, gradually progressive neurodegenerative disorders, such as amyotrophic lateral sclerosis, and a miscellaneous group, including multiple sclerosis. Table 4.1 Causes of pseudobulbar palsy Vascular disorders

Bilateral cerebral infarctions Multi-infarct dementia Lacunar dementia Binswanger's disease Arteriosclerotic parkinsonism CADASIL

Gradually progressive Amyotrophic lateral sclerosis neurodegenerative disorders Progressive supranuclear palsy Alzheimer's disease Miscellaneous

Multiple sclerosis Brainstem tumors Behcet's syndrome

VASCULAR DISORDERS

The most common cause of pseudobulbar palsy is perhaps bilateral damage to the corticobulbar tracts by infarction. Typically, in the evaluation of a patient with pseudobulbar palsy, one finds a distant history of a stroke affecting one side, followed by a subsequent stroke affecting the contralateral side (Wilson 1924). In some cases of vascular pseudobulbar palsy, however, there may be clinical evidence of only one stroke: in such cases, it appears that an earlier infarction had in fact occurred but had remained subclinical (Besson et al. 1991). Bilateral cerebral infarctions, in addition to damaging the corticobulbar tracts, often involve the corticospinal tracts bilaterally, and thus in the history one may find a hemiplegia, from which the patient partially recovered, followed by a contralateral hemiplegia accompanied by the pseudobulbar palsy (Colman 1894; Davison and Kelman 1939; Wilson 1924). Emotional incontinence has also been noted with a vascular lesion of the pons (Asfora et al. 1989). Multi-infarct dementia may also comprise a pseudobulbar palsy and is suggested by the 'stepwise' course of the dementia. Lacunar dementia may demonstrate either a gradual or a 'stepwise' progression, is often accompanied by a frontal lobe syndrome and, in a minority of cases, may also be marked by a pseudobulbar palsy with emotional incontinence (Ishii et al 1986). Binswangers disease typically causes a gradually progressive dementia that may also be accompanied by a pseudobulbar palsy (Caplan and Schoene 1978). Arteriosclerotic parkinsonism is characterized by a rigid akinetic parkinsonism accompanied by a shuffling or 'magnetic' gait and, in some cases, a pseudobulbar palsy (Keschner and Sloane 1931). CADASILy or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, a relatively rare autosomal dominant vasculopathy, is marked by a gradually progressive dementia punctuated by strokes and often accompanied by a pseudobulbar palsy (Bergmann et al. 1996).

Other signs and symptoms 145

GRADUALLY PROGRESSIVE NEURODEGENERATIVE DISORDERS

Amyotrophic lateral sclerosis, when involving the corticobulbar tracts, may cause a pseudobulbar palsy (Ironside 1956; Ziegler 1930); in one study, the syndrome was found in over one-half of all patients (Gallagher 1989). Although most patients will have signs of spinal involvement, such as the combination of brisk reflexes with atrophy and fasciculations, it must be borne in mind that some cases may be primarily 'bulbar', with little or no clinical evidence of cord involvement. Progressive supranudear palsy is suggested by a history of unexplained falls, followed by a slowly progressive rigid parkinsonism with prominent axial dystonia; the subsequent appearance of a supranuclear ophthalmoplegia strongly suggesting the diagnosis (Steele et al. 1964). Dementia typically supervenes, which is, in a minority of cases, accompanied by a pseudobulbar palsy with emotional incontinence (Behrman et al. 1969; Menza et al. 1995). Alzheimer's disease, late in its course, and after the dementia is generally well established, may cause emotional incontinence (Starkstein et al. 1995). MISCELLANEOUS

S

Multiple sclerosis, suggested by a history of neurologic findings 'disseminated in space and time', may, later in its course and generally in those with fairly severe motor disability, cause emotional incontinence (Feinstein et al. 1997). Brainstem tumors, provided that they compress the corticobulbar tracts bilaterally, may cause a pseudobulbar palsy (Achari and Colover 1976; Cantu and Drew 1966); a similar situation obtained with a petroclival menigioma that externally compressed the brainstem (Shafqat et al 1998). Behcet's syndrome may cause a dementia that is almost always accompanied by oral or genital ulcers; interestingly, such demented patients often also have a pseudobulbar palsy (Motomura et al. 1980).

Treatment of the syndrome In addition to treating the underlying cause of the pseudobulbar palsy, it may be possible to relieve the emotional incontinence with either amitriptyline (Schiffer etal. 1985) or levodopa (Udaka et al. 1984; Wolf et al. 1979). Amitriptyline should be started at a low dose and increased gradually to effectiveness; most patients respond to a dose of 50-75 mg daily. If side-effects, especially hypotension, prove unacceptable, it may be appropriate to try a low dose of nortriptyline. Fluoxetine has also been used in non-responders (Seliger and Hornstein 1989).

MIMETIC, OR INVOLUNTARY, FACIAL PALSY

Description of the sign Facial palsies may be either 'peripheral' or 'central'. Peripheral facial palsies occur with destruction of either the facial nucleus or the facial nerve itself, and involve both the upper and the lower divisions of the facial musculature. There is flattening of the forehead, flattening of the nasolabial fold, and an inability to show the teeth or to smile on request; when the patient is smiling involuntarily, as for example at a joke, one sees little or no facial movement on the affected side. Central facial paresis involves only the musculature of the lower half of the face, i.e. those muscles involved in

146 Signs, symptoms and syndromes

showing the teeth or in smiling: normal forehead wrinkles are apparent at rest and when patients are commanded to 'wrinkle your forehead'. Central facial paresis is in turn divided into two types: 'voluntary' and 'involuntary' (also known as 'mimetic' and 'emotional'). Voluntary and involuntary facial pareses display fundamental differences on clinical examination (Monrad-Krohn 1924). Voluntary movements are tested by telling patients to 'smile' or to show their teeth. Involuntary movements are tested either by telling a joke and watching the patients' 'involuntary' smiling or, if the physician lacks such wit, simply observing patients as they relate mirthful stories or experiences. In cases of voluntary central facial paresis, observation of the face at rest generally reveals some flattening of the nasolabial fold, and, when patients are asked to show their teeth or instructed to 'smile', one sees little or no movement of the mouth or surrounding musculature on the affected side. By contrast, if a patient with a voluntary facial paresis is told a joke, one sees symmetric smiling, involving both sides of the face. In cases of involuntary or mimetic facial palsy, observation of the face at rest generally reveals no asymmetry, and when patients are asked to show their teeth or instructed to smile, one sees symmetric activity on both sides. When patients are told a joke, however, one sees only a 'hemismile', with little or no movement on the affected side. Differential diagnosis of the sign

Voluntary central facial paresis occurs with lesions of the contalateral precentral gyrus or its projecting fibers. Invountary or mimetic central facial paresis occurs with lesions of the following contralateral structures: the supplemental motor area of the frontal lobe (Gelmers 1983), the temporal lobe (Remillard et al. 1977), the striatum (Hopf et al. 1992), the thalamus (Bogousslavsky etal. 1988; Graff-Radford etal. 1984; Ross and Mathiesen 1998) and the dorsal upper pons (Hopf et al. 2000). Mimetic facial palsy has also been noted with a large mesencephalic lesion that affected structures both contralateral and ipsilateral to the mimetically paretic side (Wilson 1924).

If FOU RIRE PRODROMIQUE Lefou rire prodromique, first reported by Fere (1903), is an exceedingly rare, and remarkable, phenomenon that not uncommonly heralds a fatal vascular event. Description of the sign N

Le fou rire prodromique manifests as a paroxysmal, uncontrollable fit of laughter, lasting for minutes to a half hour, during which there is full preservation of consciousness and, critically, no corresponding sense of mirth. In one case (Wali 1993), a 35-year-old woman, 'after a warm shower suddenly began to laugh. The laughter was inappropriate to the situation and continued for nearly 15 minutes at the end of which it became a low grade giggle. This lasted for another 15 minutes and ended abrutly when she collapsed'. In another case (Martin 1950), the patient's first attack occurred at his mother's funeral, and, much to his distress, recurred and recurred, without any apparent cause, until he collapsed and died several days later.

Other signs and symptoms 147

Differential diagnosis of the sign Paroxysmal laughter, unaccompanied by a sense of mirth, may occur in schizophrenia, as part of pseudobulbar palsy or as a simple partial ('gelastic') seizure. In schizophrenia, the mirthless, unmotivated laughter is generally quite bizarre and is always accompanied by other, chronic, symptoms such as delusions and hallucinations. In pseudobulbar palsy, mirthless laughter may occur as part of 'emotional incontinence' and is generally accompanied by other evidence of corticobulbar or corticospinal tract damage, such as a brisk jaw jerk, dysphagia, lingual atrophy, exaggerated deep tendon reflexes and extensor plantar responses. Gelastic simple partial seizures (Arroyo et al. 1993; Lehtinen and Kivalo 1965) may be difficult to distinguish from le fou rire prodromique, but in most cases of gelastic epilepsy, the history will reveal other seizures types, such as complex partial, grand mal or more typical simple partial seizures. Lefou rire prodromique has been associated with infarction of the thalamus (Ceccaldi and Milandre 1994), pontine infarction (Wali 1993) and an aneurysm located in the interpeduncular fossa, which eventually burst, with a fatal outcome (Martin 1950).

ABULIA

Description of the sign Abulia is characterized by a more or less complete absence of any impulses to action, or any desires, anger or longings: for such patients, the 'internal horizon', as it were, is simply undisturbed. Importantly, such patients are not bored but rather empty: one patient (Laplane et al 1984) reported that he had 'a blank in my mind'. Abulic patients, thus volitionally impoverished, may be content to sit or lie quietly, doing nothing. Importantly, however, if they are asked to do something or if supervised, one finds that they are able to perform and complete tasks in a timely and successful fashion: once left to themselves, however, they rapidly lapse back into a placid quietude.

Differential diagnosis of the sign Abulia may be seen as part of the frontal lobe syndrome, wherein it may accompany disinhibition and perseveration. Apathy and depression are both distinguished by the presence of dysphoria. Abulic patients experience nothing except an untroubled sense of emptiness; depressed or apathetic patients, by contrast, experience a more or less oppressive mood. Abulia may occur with lesions of the basal frontal cortex (Phillips et al. 1987), the caudate (Bhatia and Marsden 1994; Mendez et al. 1989), the globus pallidus (Bhatia and Marsden 1994; Giroudetal. 1997; Laplane et al. 1984) or the paramedian thalamus (Bogousslavsky et al. 1991). Although bilateral lesions are generally seen, abulia has also been noted with unilateral lesions of the caudate (Bhatia and Marsden 1994; Mendez et al. 1989), globus pallidus (Giroud et al. 1997) and caudal intralaminar nuclei of the thalamus (Van Der Werf et al. 1999). Although the lesion or lesions were, in most cases, ischemic in nature, abulia has also been noted as a sequela to carbon monoxide intoxication, with prominent lesions in the globus pallidus bilaterally (Laplane et al. 1984). Abulia may also play a prominent role in the symptomatology of schizophrenia, especially simple schizophrenia. Kraepelin (1919) noted that such patients 'experience no tediousness,

148 Signs, symptoms and syndromes

have no need to pass the time ... but can lie in bed unoccupied for days and weeks, stand about in corners, "stare into a hole," watch the toes of their boots or wander aimlessly about'.

ENVIRONMENTAL DEPENDENCY SYNDROME ('UTILIZATION BEHAVIOR') This syndrome was initially described in 1983 by Lhermitte, who named it 'utilization behavior'; in a subsequent paper, he changed the name to the 'environmental dependency syndrome' (Lhermitte 1986).

Description of the syndrome In this syndrome, patients appear to lose their autonomy, becoming 'dependent' on their environment such that they feel compelled to pick up and 'utilize' whatever may come to their attention. For example, in describing one of his patients, Lhermitte (1983) noted that both he and the patient: sat down in my office. I put some medical instruments on my desk. She immediately picked up the blood pressure gauge and very meticulously took my blood pressure ... After this she took the tongue depressor and placed it in front of my mouth, which I opened, and she examined my throat ... Last, she picked up the reflex tester and, to make sure she tested the ankle jerks, I knelt down on the chair. When I asked her what she thought, she said she was satisfied with my state of health.

Importantly, patients engage in this behavior without being invited, asked or told to, and are also unable to resist doing so, even if commanded not to. Lhermitte initially proposed a complex testing procedure to elicit the syndrome (Lhermitte 1983); later, however, he adopted a more naturalistic approach, encouraging simple observation in the office, at home or perhaps in a gift shop (Lhermitte 1986).

Differental diagnosis of the syndrome Forced grasping appears similar to the environmental dependency syndrome in that, in both cases, patients will involuntarily reach and grasp objects. The difference lies in what the patient does with the grasped object: the patient with forced grasping simply holds on, whereas the patient with the environmental dependency syndrome will utilize the object. The alien hand sign also appears similar to utilization behavior in that the alien hand involuntarily reaches out and does things with objects: the difference here is that what the alien hand does is at cross-purposes with what the patient is attempting to do with the 'good' hand, whereas in utilization behavior, the two hands act in concert - there is no conflict. Echopraxia or 'imitation behavior' is said to be present when patients involuntarily and automatically imitate what the examiner is doing. This is fundamentally different from environmental dependency, for in the environmental dependency syndrome, the examiner does nothing except perhaps place objects in the patient's view. Delirious patients may take hold of and use nearby objects, but here one also finds confusion, a sign that is absent in the environmental dependency syndrome. The environmental dependency syndrome has been noted with lesions of the frontal lobes (Lhermitte 1983, 1986; Lhermitte et al. 1986; De Renzi et al. 1996; Shallice et al. 1989) and has also been reported in a patient subsequent to recovery from a bilateral paramedian thalamic infarction (Eslinger et al. 1991).

Other signs and symptoms 149

KLUVER-BUCY SYNDROME In 1939, Kluver and Bucy described some striking behavioral changes in monkeys subjected to bilateral anterior temporal lobectomy, the resulting syndrome bearing their names.

Description of the syndrome Kluver and Bucy noted five specific changes in their monkeys: • • • • •

'psychic blindness' 'emotional changes' 'hypermetamorphosis' 'oral tendencies' 'changes in sexual behavior'.

'Psychic blindness' manifested itself in a tendency indiscriminantly to approach and examine objects 'no matter whether they are very large or very small, dead or alive, edible or inedible, moving or stationary ... The monkey seems to be just as eager to examine the tongue of a hissing snake, the mouth of a cat, feces, a wire cage or a wagon as a piece of bread.' 'Emotional changes' consisted, in general, of an 'absence of all emotional reactions ... generally associated with anger and fear'. For example, 'after being attacked and bitten by another animal, it may approach this animal again and again in an attempt to examine it.' 'Hypermetamorphosis' is characterized by: an excessive tendency to take notice of and to attend and react to every visual stimulus ... the monkey seems to be dominated by only one tendency, namely the tendency to contact every object as soon as possible [and]... when turned loose in a room, the monkey often behaves as if it were ceaselessly 'pulled' from one object to another.

'Oral tendencies' consist of a 'strong tendency to examine all objects by mouth', for example 'putting the object into the mouth, biting gently, chewing, licking touching with the lips and smelling ... the object'. 'Changes in sexual behavior' included not only 'an increase in sexual activity' but also an indiscriminant sexual preference, whether for masturbation or heterosexual or homosexual activity. Overall, then, it appears that Kluver and Bucy's monkeys developed a heightened but indiscriminant interest in whatever happened to come into view, an interest which, when coupled with a lack of fear, impelled them to approach anything regardless of whether it was useless or even potentially dangerous. Furthermore, once in contact with the object, there was an 'oral tendency' to examine it with the mouth. Finally, there was also a heightened, but again indiscriminant, sexuality. A similar syndrome may, rarely, appear in humans. In one case (Lilly et al. 1983), a 57-yearold professor suffered head trauma that led to a maceration of the inferior surface of both temporal lobes. After recovering from the trauma, the patient was aphasic and: did not seem to recognize anyone, not even old friends, relatives or colleagues. He failed to recognize objects placed in front of him or into his hand. He ate voraciously and, in fact, had a tendency to place almost everything that came into view in his mouth. For instance, after one meal he drank a cup of tea and then ate the teabag. He wandered aimlessly and did not know the location of his room. He made inappropriate sexual advances, rather indiscriminantly; both

150 Signs, symptoms and syndromes male and female attendants were cautious in his presence. In general, however, his affect was flat and unconcerned. He was readily distracted and there was a constant shifting of his attention. If restrained, he became agitated, but when his attention was diverted, he immediately calmed down.

In another case, a 46-year-old man had a complex partial seizure wherein: he was awake and alert, but almost mute and lacking facial expression. He was observed grabbing for objects on his bedside table, and he masturbated in front of the nursing staff. He also placed objects in his mouth, chewed on tissue paper, and attempted to drink from his own urine container.

Differential diagnosis of the syndrome The human Kluver-Bucy syndrome, when well developed, as in the examples given above, appears to be quite unique, and bears little resemblance to any other syndrome. Full or partial syndromes have been noted as early features in Pick's disease (Cummings and Duchen 1981; Mendez et al. 1993) and frontotemporal dementia (Heutink et al. 1997), and as a late feature in Alzheimer's disease (Mendez et al. 1993; Teri et al. 1988). It has also been noted with damage to the temporal lobes, as for example after bilateral temporal lobectomy (Terzian and Dalle Ore 1955), herpes simplex encephalitis (Greenwood et al. 1983; Marlowe et al. 1975; Shoji et al. 1979), status epilepticus (Mendez and Foti 1997) and bilateral trauma to the temporal lobes (Lilly et al. 1983). The syndrome has also occurred paroxysmally as a complex partial seizure (Nakada et al. 1984), and, in a somewhat similar case, it occurred as a postictal phenomenon after a grand mal seizure (Anson and Kuhlman 1993). Finally, there are isolated reports of the syndrome occurring after heat stroke (Pitt et al. 1995) and as part of the evolving picture of adrenoleukodystrophy in an adult (Powers et al. 1980).

Treatment of the syndrome There are no controlled studies addressing symptomatic treatment of the Kluver-Bucy syndrome. Anecedotally, neuroleptics have been used with some relief.

ALIEN HAND SIGN The alien hand sign represents one of the most remarkable phenomena encountered in neuropsychiatric practice or, for that matter, in the practice of medicine at large.

Description of the sign The alien hand sign is said to be present when one of the patient's hands (almost always the left one) spontaneously and autonomously acts in a way that is at definite cross-purposes to what the patient is intending to do with the right hand (Bogen 1985a). This is not merely a matter of a clumsy or apraxic left hand 'getting in the way' or of reflexive groping or grasping by the left hand, but rather of the appearance of complex and seemingly purposeful activity of the left hand, activity that is at definite cross-purposes with the patient's consciously experienced will and intent. Patients may be astonished to see the left hand acting

Other signs and symptoms 151

independently and outside their control, and may comment that it is as if the left hand had 'a mind of its own'. Some examples of the alien hand sign will serve to flesh out this definition. The complexity of the behavior engaged in by the alien hand ranges from relatively simple activities, such as buttoning or unbuttoning, to very complex behaviors, even to the point of 'murderous' behavior. Examples of relatively simple alien hand behavior include the case of a patient, who, after an infarction of the corpus callosum, found that after he buttoned 'a shirt with the right hand the left hand would proceed to unbutton it and if pulling a cup of coffee toward him with the right hand the left hand would push it away' (Gottlieb et al. 1992). Similarly, subsequent to a corpus callosotomy, 'one patient was seen butoning up his shirt with one hand while the other hand Was following along behind it undoing the buttons' (Bogen 1985b). Akelaitis (1945) noted that one of his patients, also after a corpus callosotomy, 'would be putting on her clothes with her right hand and pulling them off with her left hand, opening a door or drawer with the right hand and simultaneously pushing it shut with the left hand'. More complex behavior is illustrated in the case of a patient who, after suffering an infarction of the corpus callosum, 'told the story of herself frying a steak, turning it over in the frying pan with her right hand and, immediately after, finding herself turning it over once again with her left hand' (Barbizet et al. 1974; Degos et al. 1987). Another patient, after suffering an infarction of the anterior portion of the corpus callosum and adjacent medial aspects of both frontal lobes, found, 'while playing checkers on one occasion, [that] the left hand made a move that he did not wish to make, and he corrected the move with the right hand; however, the left hand, to the patient's frustration, repeated the false move' (Banks et al. 1989). Finally, there are examples of a 'murderous' alien hand. The first reported case of the alien hand sign, described by the German physician Kurt Goldstein (1908), was just such an example: the patient was a 57-year-old female with a callosal infarction whose 'left hand attempted to choke [her] ... and this hand had to be pulled away. Furthermore the left hand did other unpleasant acts, such as tearing the bedclothes off the bed' (Geschwind 1981). The patient herself 'complained, "Es muss wohl ein boser Geist in der Hand sein" [There must be a devil in my hand]' (Hanakita and Nishi 1991). In another case, a patient who had suffered a callosal infarction treated her left arm 'as an alien presence with hostile motivations ... she complained that the arm moved on its own and that it struck her and tried to choke her ... often the hand reached for the neckline of her gown, pinched her right arm or leg, or knocked her glasses off' (Levine and Rinn 1986). Finally, there is the case of a patient who had suffered a callosal infarction (Geschwind et al. 1995) who 'awoke several times with her left hand choking her, and while she was awake her left hand would unbutton her gown, crush cups on her tray, and fight with the right hand while she was using the phone'. Patients' reactions to the presence of the alien hand vary. One patient commented that 'my hands don't agree with each other' (Degos et al. 1987), and another that her hand 'disobeyed her' (Goldenberg et al. 1985), whereas a third felt 'as if someone "from the moon" were controlling her hand' (Geschwind et al. 1995). Patients also adopt different strategies to control the alien hand: one, 'to keep her left hand from doing mischief, ... would subdue it with her right hand' (Geschwind et al. 1995); another found the behavior 'so astonishing and uncontrollable that he occasionally hit his left [hand] ... with the right one' (Leiguarda et al. 1989). Another patient, 'encouraged to "make friends" with the arm by talking to it,... soon came to treat it as a misbehaving child, fondling and talking to it: "There, there, behave yourself now ... Don't be naughty" ' (Levine and Rinn 1986). As noted earlier, the alien hand sign is almost always found on the left: indeed, of all the cases of strictly defined alien hand sign that I could find, in only one was the sign found on the right in a right-handed patient (Delia Sala et al. 1994).

152 Signs, symptoms and syndromes

Differential diagnosis of the sign The alien hand sign must be differentiated from asomatagnosia, the 'levitation' phenomenon, 'mirror' movements, two primitive reflexes, namely the grasp reflex and the grope reflex, and utilization behavior, as seen in the environmental dependency syndrome. Asomatagnosia is said to be present when patients deny that a limb belongs to them. Although patients with asomatagnosia and the alien hand sign both experience the limb as foreign, the phenomena are easily distiguished in that whereas the 'foreign' limb of the patient with asomatagnosia does nothing independently, and generally nothing purposeful, the alien hand acts 'on its own'. The levitation phenomenon, as has been noted in patients with parietal lesions (DennyBrown et al. 1952), as well as in a small minority of patients with progressive supranuclear palsy (Barclay et al. 1999), consists of the upper extremity spontaneously rising up, or 'levitating'. This differs from the alien hand sign in that the levitated arm or hand does not do anything further, engaging in no complex behavior but simply staying 'levitated'. Mirror movements are said to be present when patients, while doing something with one limb, find the contralateral limb involuntarily engaging in a more or less faithful imitation. Such mirror movements are more likely when the intended movement is very forceful or sudden; a common example is when one very tightly clenches one fist and finds that the fingers on the other hand are involuntarily flexing. Mirror movements are normal in early childhood and, in a minority of individuals, may persist into adult life (Haerer and Currier 1966; Regli et al. 1967) They may be associated with agenesis of the corpus callosum (Schott and Wyke 1981) and may also occur in patients with hemiplegia, wherein they are generally found in the paretic limb (Berlin 1951; Walshe 1923). Mirror movements may 'get in the way' and thus seem to be at cross-purposes; a closer inspection, however, will reveal that the abnormal movement does in fact 'mirror' the intended movement in the other limb and that its 'interference' is merely accidental. The grasp reflex is easily distinguished from the alien hand sign if one attends to what the hand does when it comes into contact with an object: the grasping hand merely holds tight and goes no further, whereas the alien hand takes hold and does something with the object. The grope reflexX may be a little harder to distinguish as here the hand appears to be purposefully 'groping' for something. The distinction is again made possible by attending to what the groping hand does once it reaches the object: the groping hand, like the grasping hand, merely holds tight, again in contrast with the alien hand, which does something complex with the object. Utilization behavior appears similar to the alien hand sign, given that patients with utilization behavior involuntarily utilize objects. The difference between utilization behavior and the alien hand sign lies in the fact that in utilization behavior there is no conflict between the hands, which act in concert and with cooperation, whereas in the alien hand sign, the left hand acts at definite cross-purposes with the right. Once one is certain that the clinical phenomenon in question is in fact the alien hand sign, one can be reasonably assured that the patient has a lesion in the corpus callosum. In addition to occurring after section of the corpus callosum for the treatment of epilepsy (Akelaitis 1941, 1945; Akelaitis et al. 1943; Ay et al. 1998; Bogen 1985a, b; Ferguson et al. 1985; Gazzaniga et al. 1962; Rayport et al 1983; Smith and Akelaitis 1942; Sperry 1966; Van Waggenen and Herrin 1940; Wilson et al. 1977), the alien hand sign has also been noted in various pathologic lesions of the corpus callosum, including infarction (Banks et al. 1989; Barbizet et al. 1974; Beukelman et al. 1980; Chan and Ross 1988, 1997; Chan et al. 1996; Degos et al. 1987; Geschwind et al. 1995; Goldberg and Bloom 1990; Goldenberg et al. 1985; Goldstein 1908, 1909; Hanakita and Nishi 1991; Jason and Pajurkova 1992; Tanaka et al. 1990, 1996; Watson

Other signs and symptoms 153

and Heilman 1983; Watson et al. 1985), hemorrhage (Leiguarda et al. 1989; Starkstein et al. 1988) and tumor or angioma (Brion and Jedynak 1972). I could find only three cases of strictly defined alien hand sign that appeared to occur without a callosal lesion. Levine and Rinn (1986) described a case secondary to infarction of the basal aspect of the temporo-occipital area, but the only imaging performed was with computed tomography (CT) scanning and the authors admitted that they could not exclude damage to either the splenium or the adjacent white matter. Gottlieb et al. (1992) described a case occurring with infarction of the medial aspect of the frontoparietal area. Again, only CT scanning was performed, but it appeared that the infarction was in the watershed area between the distributions of the anterior and middle cerebral arteries, and thus may truly have spared the corpus callosum. Perhaps the most convincing case comes from Dolado et al. (1995), who described a patient with an old infarction in the left parietal lobe who went on to develop the alien hand sign after a fresh infarction in the right parietal lobe. It is commonly said that the alien hand sign may also be found in corticobasal ganglionic degeneration, but a close reading of detailed reports reveals, rather than the alien hand sign, a variety of other signs, such as grasping (Green et al. 1995), 'wandering' and grasping (Rinne et al. 1994), and levitation (Gibb et al. 1989; Riley et al. 1990). Creutzfeldt-Jakob disease may, very rarely, present with a combination of myoclonus and the alien hand sign (MacGowan et al. 1997). In one case, the alien left hand 'would grab [the patient's] throat or hit her in the face and she usually limited its activity by holding it in her right hand's grasp'. In another case presented by the same authors, the alien hand, again on the left, unbuttoned the patient's blouse and removed a hair pin. In both cases, the eventual appearance of periodic complexes on the EEG and dementia suggested the correct diagnosis. Before leaving this consideration of the alien hand sign, it is appropriate to remark on some of the controversy in the literature regarding nomenclature. The English name for this sign traces its roots to a French paper by Brion and Jedynak (1972), who termed it 'le signe de la main etrangere: although the authors translated this as 'the "strange hand" sign' (which is indeed a more faithful translation from the French), the phrase 'alien hand' has gained wide currency in English and is retained here. Synonyms include 'anarchic hand' (Delia Sala 1994) and, more commonly, 'diagonistic dyspraxia', a phrase coined by Akelaitls (1941) in the 1940s and still found in use today (e.g. Tanaka et al. 1996). More controversial than the name of the sign, however, is the idea that, rather than just one alien hand sign, there are, supposedly, two. Feinberg et al. (1992), in an influential article entitled 'Two alien hand syndromes', proposed two subtypes, a 'callosal' subtype and a 'frontal' subtype, and other authors (e.g. Chan et al. 1997) have elaborated on this proposal, renaming the 'callosal' subtype 'Bogen's alien hand' and the frontal subtype as 'Goldberg's alien hand'. A close reading of Feinberg et al.'s paper reveals, however, that the supposed 'frontal' subytpe is in fact nothing more than the grasp or grope reflex, as is the case with the patient presented by Goldberg etal. (1981). Although the controversy over whether there are one or two alien hand signs continues, it appears appropriate to retain a clear distinction between the alien hand sign as described in this text and the grasp or grope reflex. Thus, whenever the alien hand sign is referred to in this text, it means the 'callosal' or 'Bogen' type. If the unruly hand in question merely grasps or gropes, one should proceed to the above section on primitive reflexes in Chapter 4, p. 141, and pursue that differential; however, if the unruly hand engages in complex activity that is at cross-purposes with what the patient intends, then one has a true alien hand and should pursue the differential noted above. Clearly, in reading articles ostensibly about the alien hand sign, physicians should subject the case report to close scrutiny in order to be sure that the authors are not in fact describing

154 Signs, symptoms and syndromes

something else, such as a grasp or grope reflex (McNabb et al. 1988; Magnani et al. 1987; Trojano et al. 1993), levitation (Ventura et al. 1995) or aimless, non-purposeful wandering movments (Ball et al. 1993).

'PHANTOM' AND 'SUPERNUMERARY' LIMBS Although phantom limbs and supernumerary limbs both involve the experience of having a limb that is, in fact, not present, they differ not only in terms of the number of limbs experienced, but also in terms of whether or not the responsible lesion is peripheral or central. The phantom limb phenomenon refers to the experience of having a limb that has in fact been lost to amputation. In the supernumerary limb phenomenon, by contrast, the patient, suffering from a lesion of the central nervous system, experiences an additional limb, over and above the normal complement. Description of the symptom Phantom limb (Carlen et al. 1978; Haber 1956; Henderson and Smythe 1948; Jensen et al. 1984; Shukla et al. 1982) appears in the vast majority of amputees within a matter of days after the amputation. The experience itself is a tactile rather than a visual one: although patients do not see the limb, they 'feel' it and have a sense of its presence, most report experiencing some tingling or pins and needles in the phantom itself. About two-thirds of patients with phantom limb will also experience pain in the phantom, variously described as burning, electric, throbbing, cramping, tearing or crushing. Furthermore, well over half are also able to 'move' the phantom at will. Over time, most patients experience what is known as 'telescoping': here, it is as if the phantom were being gradually absorbed back into the remaining limb, the most proximal part of the phantom disappearing first and the remaining portions telescoping after it, with the most distal portion, usually the fingers or toes, disappearing last. In some cases, the phantom may disappear entirely after months or longer, whereas in others it may be permanent. Childhood amputations, before the age of 4 years, are only rarely followed by phantoms (Simmel 1962). The congenital absence of a limb may, interestingly, be followed in a small minority by the development of a phantom 'replacement' (Weinstein and Sersen 1961) after a long latency, most children being around 9 years old at the appearance of the phantom (Mehaketal. 1997). Phantom breast may occur after mastectomy in between one-fifth (Ackerly et al. 1955; Jarvis 1967) and two-thirds of women (Bressler et al. 1956). Supernumerary limb is characterized by the experience of having an extra arm or leg. One patient felt the extra arm lying across his abdomen (Mayeux and Benson 1979), another experienced it growing out of his forearm (Brock and Merworth. 1957), and one patient, after suffering bilateral parietal lobe damage, experienced four legs, two on each side (Vuilleumier et al. 1997). Anosognosia may accompany the supernumerary limb (Halligan et al. 1993; Weinstein et al. 1954), as may left neglect (Weinstein et al. 1954). Differential diagnosis of the syndrome Both phantom and supernumerary limbs must be distinguished from a visual hallucination: the experience of a phantom or supernumerary limb is a tactile one and not a visual one.

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Not all pain in a phantom limb is 'phantom' pain. In two cases of phantom limb after lower extremity amputation, the patients subsequently developed disc disease and then went on to experience typical sciatic pain in the phantom limb (King 1956). Phantom limb occurs not secondary to any central nervous system lesion but rather to a persistence of neuronal activity in those parts of the brain responsible for the maintenance of the body 'schema'. Supernumerary limbs have been noted with lesions of the parietal lobe (Vuilleumier et al. 1997; Weinstein et al. 1954), basal ganglia (Halligan et al. 1993) and pons (Brock and Merwarth 1957). Although most supernumerary limbs appear on the left side, right-sided occurrence has also been noted (Mayeux and Benson 1979). Supernumerary limbs may also occur as a manifestation of a sensory simple partial seizure, a diagnosis immediately suggested by their paroxysmal and brief occurrence. One patient, for a few seconds, would experience a 'phantom arm' next to his actual left arm (Riddoch 1941); another had such a strong sense that an extra right arm was over his head that he asked his wife to help him pull it down (Russell and Whitty 1953).

DEPERSONALIZATION Description of the symptom During depersonalization, patients feel uncannily detached from themselves. Although they may continue to engage in some activity, whether it be talking, running or driving a car, it seems to them as if they are not really doing it but observing it being done, as if it were being carried out by a robot or an automaton. In some cases, visual distortions may occur: arms or legs may appear misshapen or shrunken. Patients may occasionally have the experience of 'floating' above the scene, watching themselves do things from a distance.

Differential diagnosis of the symptom Autoscopy is a kind of visual hallucination wherein patients hallucinate a 'double' and see themselves as vividly as if looking in a mirror. Depersonalization differs from this in that there is always an 'as if quality to the experience of depersonalization, accompanied by the sense of 'floating' over the scene that one is actually in. The various causes of depersonalization, as noted in Table 4.2, are divided into those with precipitants, such as head trauma, and those without precipitants: this second group is further divided into examples of depersonalization with distinctive associated features (such as the headache that follows when depersonalization occurs as a migraine aura), and those occurring in a truly isolated fashion, without associated features, as may be seen in idiopathic depersonalization disorder. WITH PRECIPITANTS Head trauma may have depersonalization as one of its long-term sequelae (Hillbom 1960). Cannabis intoxication, suggested by conjunctival injection, may be accompanied by depersonalization and a sense of the disintegration of time (Melges et al. 1970). Indomethacin was, in one report, associated with depersonalization and intense anxiety (Schwartz and Moura 1983).

156 Signs, symptoms and syndromes Table 4.2 Causes of depersonalization With precipitants

Head trauma Cannabis intoxication Indomethacin Normal response to danger

Without precipitants

With associated features Migraine Depression Panic attacks Ictal Without associated features Depersonalization disorder

Depersonalization may also occur as part of a normal response to danger (Noyes and Kletti 1977; Noyes et al 1977; Sedman 1966). WITHOUT PRECIPITANTS Migraine may, rarely, be preceded by an aura consisting of depersonalization (Lippman 1953). Depression, as may occur in a major depression, may be accompanied by depersonalization (Noyes et al. 1977), the diagnosis being suggested by the accompanying, more typical, depressive symptoms, such as depressed mood, anergia, insomnia, etc. Panic attacks may be accompanied by a sense of depersonalization in approximately one-third of patients (Carsano et al. 1989), this diagnosis being suggested by the paroxysmal occurrence of the preceding associated symptoms of extreme anxiety, tachycarda, diaphoresis, etc. Ictal depersonalization may occur either as an aura to a complex partial or grand mal seizure (lonasescu 1960), or may appear in an isolated fashion, as a simple partial seizure (Williams 1956). One patient who had both complex partial and grand mal seizures preceded by an aura of depersonalization felt 'that the out-of-body aura [was] the most distressing part of her seizures' (Devinsky et al. 1989). Simple partial seizures characterized by depersonalization can be quite remarkable, as the following examples attest. One of Williams (1956) patients would suddenly'feel outside her body, looking at what she was doing'; her surroundings seemed 'unreal' and she reported feeling as if she were not 'there'. Another patient, reported by Russell and Whitty (1955), had very brief attacks wherein 'he would have a sudden feeling of being detached from his body, so that he was observing it as if looking at someone else'. When depersonalization occurs as an aura, the diagnosis is made self-evident by the subsequent seizure; when depersonalization occurs in an isolated fashion, as a simple partial seizure, however, the diagnosis may not be immediately apparent until the history reveals the occurrence of other seizure types. Depersonalization disorder is an idiopathic disorder, with an onset in late adolescence or early adult years, characterized by depersonalization that may either persist, in a chronic, waxing and waning fashion, or be episodic, the duration of the episodes exhibiting an enormous variation, lasting from minutes to years (Davison 1964; Shorvon 1946; Simeon et al. 1997).

Treatment of the symptom For depersonalization occurring secondary to depression (Noyes et al. 1977) or panic disorder (Hollander et al 1990), as a migraine aura or as an ictal phenomenon, the treatment of the

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underlying cause is generally effective. With regard to depersonalization disorder, various treatments have been proposed, including fluoxetine (Fichter et al. 1992) and clonazepam (Stein and Uhde 1989). The treatment of depersonalization secondary to a'fixed' deficit, as for example in head trauma, is not clear: if symptoms were particularly troubling, trials of fluoxetine or clonazepam would not be inappropriate.

OBSESSIONS AND COMPULSIONS Description of the symptom Obsessions are involuntary, unwanted and often distressing thoughts that persistently recur despite attempts on the part of the patient to stop them. Although the subject matter may at times be neutral, it more often than not concerns sexual or violent acts, acts in which the patient would never voluntarily engage. Compulsions represent an overwhelming and anxious need to do something, something that the patient realizes is more or less nonsensical. The compulsion is typically intimately connected with an apprehension on the part of patients that they have done something that they ought not to have done, or that they have left undone something that they ought to have done, the compulsive act serving in some fashion either to undo what was done or to make good something that ought to have been done. An example of an obsession is found in the case of the mother of a newborn infant, who was horrified to find herself recurrently having thoughts of 'stabbing the child, putting the infant in the microwave, or sexually abusing the newborn' (Sichel et al. 1993). In another case, the obsession was, per se, of a neutral character, consisting of 'silly poems that kept running through his consciousness': what 'appalled' the patient was the fact that he could not stop them (Mulder et al 1951). An example of a compulsion is given by Tuke (1894): the patient, a 'young lady', feared 'infecting herself if she touched anything that might have germs on it, with the result that 'the act of washing her hands in the morning is repeated, immediately, again and again' such that the hands 'are quite rough and discoloured afterwards'. In another example (Gordon 1950), a patient felt compelled to repeat his prayers again and again for fear each time that he had left a word out. Finally, Bleuler (1924) notes a common compulsion, arising from the apprehension that one has not locked the door, that 'compels the patient to try it over and over again'. Differential diagnosis of the symptom The character traits of 'obsessiveness' and 'compulsiveness' are fundamentally different from obsessions and compulsions. Obsessive or compulsive people are characteristically and chronically controlled, precise, meticulous, attentive to detail and overly concerned with getting things done in the 'correct' way, and do not in fact experience actual obsessions or compulsions. Perseverations, as may be seen in some patients with frontal lesions, are distinguished from compulsive behaviors by the patients' attitude toward the behavior in question. Perseverative patients can often offer no reason for their repetitive behavior and do not resist engaging in it: by contrast, patients with compulsions engage in their compulsive behavior for a definite purpose and often attempt to resist the urge. The various causes of obsessions and compulsions, as listed in Table 4.3, are divided into those occurring with precipitants, for example those occurring as postencephalitic sequelae,

158 Signs, symptoms and syndromes Table 4.3 Causes of obsessions and compulsions With precipitants

Postencephalitic Postanoxic states Closed head injury Medications Neurosurgery to the right parietal lobe

Without clear precipitants

With associated features Depression Schizophrenia Tourette's syndrome Sydenham's chorea Ictal Infarction of the right parietal lobe or globus pallidus Without associated features Fahr's syndrome Idiopathic obsessive-compulsive disorder

and those occurring without precipitants. This latter group is further divided into two subgroups: those with clear associated features (e.g. obsessions occurring in the midst of the depressive symptoms of a depressive episode) and those without associated features, as for example in Fahr's syndrome and idiopathic obsessive-compulsive disorder. In reviewing these various causes of obsessions and compulsions, it is interesting to note the involvement of the basal ganglia, especially the globus pallidus. Thus, in Fahr's syndrome, one sees calcification of the basal ganglia bilaterally (Lopez-Villegas et al. 1996), and in Sydenham's chorea, the caudate is heavily involved (Husby et al. 1976). Postanoxic lesions preferentially involve the globus pallidus bilaterally (Escalona et al. 1997; Laplane et al. 1989), and unilateral infarction of the globus pallidus has also been implicated (Giroud et al. 1997). Given these findings, it may be appropriate to consider obsessions and compulsions as having localizing value to the basal ganglia. Clearly, however, other structures, for example the right parietal lobe (Paradis et al. 1992; Simpson and Baldwin 1995), may also be involved. WITH PRECIPITANTS Postencephalitic obsessions and compulsions have occurred as sequelae to Western equine encephalitis (Mulder et al. 1951), and, most notably, to encephalitis lethargica: Jelliffe (1929), in a series of articles devoted to this topic, emphasized that these obsessions and compulsions often occurred during oculogyric crises. Postanoxic states, for example after carbon monoxide intoxication, status epilepticus, ventricular fibrillation or general anesthesia, have included obsessions and compulsions; CT and magnetic resonance imaging have strongly implicated damage to the globus pallidus in these cases (Escalona et al. 1997; Laplane et al. 1984, 1989). Closed head injury may also have obsessions and compulsions as one of its sequelae (Hillbom 1960; McKeon et al. 1984) . Medications capable of inducing obsessions and compulsions include clozapine: in one study, approximately 10% of clozapine-treated patients with schizophrenia developed these side-effects within 15 months of the initiation of treatment (Baker et al. 1992). Norplant, a subcutaneous contraceptive, has also been associated with obsessions and compulsions (Wagner 1996).

Other signs and symptoms 159

Neurosurgery to the right parietal lobe, performed to remove a tumor, was followed, in one case, by the appearance of obsessions and compulsions (Paradis et al. 1992). WITHOUT CLEAR PRECIPITANTS

Depression may be accompanied by obsessions (Kraepelin 1921), which occur in the context of the more familiar depressive symptoms such as depressed mood, anergia, insomnia, etc. Schizophrenia may cause recurrent, unwanted ideas, but their appearance in the midst of the chronic psychosis indicates the correct diagnosis. Tourettes syndrome, marked by multiple tics, eventually, after about 5 years, causes obsessions or compulsions in about one-half of all patients (Frankel et al. 1986; Robertson et al. 1988): interestingly, although a variety of different kinds of obsession and compulsion can occur (Miguel et al. 1995), there is a strong tendency for these patients to experience a compulsion to get things 'just right' (Caine et al. 1988; Leckman et al. 1994). Sydenham's chorea may be accompanied by obsessions and compulsions (Swedo et al. 1989), this indeed being seen in the majority of cases (Swedo et al. 1993). Interestingly, although these obsessions and compulsions peak in severity as the chorea does, and clear before the chorea does, they in fact tend to appear before the actual chorea does (Swedo et al. 1993). Ictal obsessions have been reported (Mendez et al. 1996). In one case, a patient had simple partial seizures characterized by obsessions 'that he would harm his mother, women, or babies': the patient also had typical complex partial seizures, treatment with carbamazepine relieving both types of seizure (Kroll and Drummond 1993). Infarction of the right parietal lobe or globus pallidus has been followed by obsessions and compulsions. In the case of the parietal lobe infarction, symptoms appeared after 4 weeks, with the only other clinical manifestation of the infarction being left-sided parasthesiae (Simpson and Baldwin 1995). In the other case, a lacunar infarction occurred in the right globus pallidus and manifested with obsessions, compulsions and anterograde amnesia (Giroud et al. 1997). Fahrs syndrome, indicated by bilateral calcification of the basal ganglia on CT scanning, has been associated with classical obsessions and compulsions (Lopez-Villegas et al. 1996). Idiopathic obsessive-compulsive disorder has an onset in adolescence or early adult years and is, in the overwhelming majority of cases, characterized by both obsessions and compulsions (Rasmussen and Tsuang 1986). Treatment of the symptom Treatment of the underlying cause, if possible, generally ameliorates the obsessions and compulsions. Where such treatment is not possible (e.g. in postanoxic cases), a trial of treatment with a medication effective in idiopamic obsessive-compulsive disorder, such as an SSRI, would not be inappropriate.

AMUSIA Description of the sign Amusia is characterized by a deficiency in the recognition or production of music, either by a musical instrument or vocally, as in humming a tune. On analogy with aphasia, amusia is divided into three forms: sensory, expressive and global. In sensory amusia, patients are unable to recognize music: in one case, although others felt that the patient's singing voice was

160 Signs, symptoms and syndromes

normal, to the patient his voice sounded 'dull' and without melody (Mazzucchi et al. 1982). In expressive amusia, although the ability to recognize tunes is adequate, the ability to produce them suffers: one patient, an organ player, although able to recognize melody and to imagine it in his mind, was yet unable to produce it on the organ (McFarland and Fortin 1982). Global amusia leaves patients bereft of the ability both to appreciate and to produce music: one patient could neither recognize tunes hummed to her nor produce any melody in her own voice (Confavreux et al. 1992).

Differential diagnosis of the sign Aphasia stands to amusia as lyrics stand to melody: aphasics have trouble with the lyrics, amusics only with the melody. Thus although patients with sensory amusia are unable to recognize a tune if it is only hummed, the addition of the lyrics would make the song immediately recognizeable. Aprosodia involves an inability to recognize the melody of voice and spares the ability to recognize the melody produced by musical instruments. Amusia occurs with non-dominant hemisphere lesions. Sensory amusia has been noted with a lesion of the temporal cortex (Mazzucchi et al. 1982), expressive amusia with frontal (Botez and Werheim 1959) and temporoparietal (McFarland and Fortin 1982) lesions and global amusia with atrophy of the frontotemporal cortices (Confavreux et al. 1992).

FOREIGN ACCENT SYNDROME Description of the sign The foreign accent syndrome is a rare condition wherein patients, although neither aphasic nor dysarthric, begin to speak with an accent foreign to their own native tongue. For example, one patient began to speak with an Irish brogue (Seliger et al. 1992), and another, a Japanese woman, began to speak with a Korean accent (Takayama et al. 1993). In one particularly unfortunate case during World War II, a Norwegian woman found herself speaking with a German accent and was assumed by others to be sympathetic to the Germans (Monrad-Krohn 1947).

Differential diagnosis of the sign The foreign accent syndrome is characterized by a change in accent alone, which distinguishes it from aphasia and dysarthria: patients with the foreign accent syndrome have no trouble with syntax or semantics, and their speech is not slurred. The syndrome has been seen secondary to trauma to the left frontal region (Monrad-Krohn 1947) and to a small infarction localized to the mid-fifth of the left precentral gyms (Takayama et al. 1993).

CATAPLEXY Cataplexy, or the occurrence of cataplectic attacks, is most commonly seen in narcolepsy, and it is from the attacks occurring in that syndrome that this description of cataplexy is obtained.

Other signs and symptoms 161

Description of the syndrome Cataplectic attacks (Adie 1926; Dyken et al. 1996; Guilleminault et al. 1974; Kales et al. 1982; Parkes et al. 1975; Wilson 1928) are generally precipitated by some strong emotion, such as laughter or anger, and are characterized by the paroxysmal onset of more or less generalized weakness lasting in the order of a minute or so: subsequent recovery is rapid and complete. During the attack, all voluntary muscle power, with the exception of the diaphragm and, at times, the extraocular muscles, is lost, and patients may fall to the ground or slump in a chair. In some cases, the muscle weakness, although generalized, may be of minor degree, and such patients may merely experience their heads lolling forwards, their jaws slackening and their knees beginning to buckle. Limited attacks, confined perhaps to an arm or leg, have also been reported. Attacks that last much longer than a minute may be joined by visual or auditory hallucinations (Van Den Hoed et al. 1979). Importantly, during the attack, patients remain completely alert and conscious. Differential diagnosis of the syndrome Syncope is distinguished by a partial or complete loss of consciousness. Vertebrobasilar transient ischemic attacks may be characterized by a sudden loss of voluntary control over the limbs, secondary to ischemia affecting the corticospinal fibers as they pass through the brainstem. These attacks are generally fairly long, up to a half hour, and may be accompanied by 'neighborhood' symptoms and signs not seen in cataplexy, such as sensory changes, tinnitus, nausea or vomiting. Seizures may be characterized by paroxysmal falls secondary to a loss of muscle tone, with the preservation of consciousness and complete recovery within a minute or so. Such seizures (variously called 'atonic' or 'astatic' seizures) are clearly very similar to cataplectic attacks: in most cases, however, this kind of seizure occurs only in the context of a longstanding history of other, more typical seizures of either the grand mal or complex partial type (Lipinski 1977; Pazzaglia et al. 1985). In one, very rare, instance, however, an 11-yearold girl presented with seizures almost identical to cataplectic attacks: the clue in this case was the fact that some of the attacks were preceded by unmotivated 'stereotyped giggling' (Jacome and Risko 1984). By far the most common cause of cataplectic attacks is narcolepsy. Although, in such cases, the cataplectic attacks usually either follow or appear concurrently with sleep attacks, the cataplectic attacks may, in a minority of cases of narcolepsy, appear before the narcoleptic sleep attacks (Parkes et al. 1975): consequently, during the follow-up of a pateint with cataplectic attacks, one must always be alert to the subsequent appearance of narcoleptic sleep attacks. A combination of narcoleptic and cataplectic attacks has also been noted with a brainstem glioma (Stahl et al. 1980) and as a postviral encephalitic sequela (Adie 1926; Fournier and Helguera 1934). Independent cataplectic attacks, that is to say those occurring outside of narcoleptic attacks, have been reported with a frontal meningioma (Smith 1983), after the surgical removal of a craniopharyngioma (Schwartz et al. 1984), with a midbrain lesion (Fernandez et al. 1995) and after the excision of a pontine glioma (D'Cruz et al. 1994). Independent cataplexy may also occur on an autosomal dominant inherited basis (Gelardi and Brown 1967) and on an idiopathic basis (Van Dijk et al. 1991); it has also been noted in association with cerebral lupus (Lascelles et al. 1976) and in a female patient with multiple sclerosis while under treatment with levonorgestrol (D'Cruz et al. 1994)

162 Signs, symptoms and syndromes

Treatment of the syndrome Cataplectic attacks occurring as part of narcolepsy may, as discussed further in Chapter 18, p. 617, be treated with imipramine (Akimoto et al. I960), clomipramine (Parkes and Schacter 1979) or protriptyline (Schmidt et al. 1977). Although it is not known whether these medications would also be effective in cataplexy occurring outside narcolepsy, a trial of one of them, perhaps nortriptyline, would not be inappropriate.

HALLUCINATIONS AND DELUSIONS Hallucinations are said to be present when patients have the experience of something that is in fact not actually present. Thus, a patient who hallucinates a dog in the hospital room might report seeing a dog, and even reach down to pat it, whereas others in the room see nothing. Delusions are false beliefs that cannot be explained on the basis of either patients' culture or religion, and that persist despite evidence and reasonable argument to the contrary. Thus, in evaluating patients with false beliefs, it is critical to take into account their culture and religion. Although a belief in zombies would not generally be considered to be a delusion in poor and uneducated Haitians, for example, any well-educated American who maintained such a belief would generally be considered delusional. Although some physicians make much of the 'contextual' nature of beliefs, most delusions are in practice so bizarre and unbelievable that there is no question of their status. There is thus little debate about the status of such beliefs that bodies of family members are inhabited by malevolent aliens or that telepathic listening devices have been implanted inside the spleen. A group of specific hallucinations and delusions, known as Schneiderian first rank symptoms, is discussed separately in the next chapter. As pointed out there, these Schneiderian first rank symptoms are, although found in diverse disorders, highly suggestive of schizophrenia. Description of the symptoms Hallucinations, as noted in Table 4.4, may occur in any sensory modality. Delusions are categorized according to their content: thus, delusions of persecution include beliefs relating to being spied on, conspired against, poisoned, etc. Specific descriptions of hallucinations and delusions follow. Table 4.4 Types of hallucination and delusion Hallucinations

Visual hallucinations (including autoscopy, palinopsia and polyopia) Auditory hallucinations Tactile hallucinations Olfactory hallucinations Gustatory hallucinations

Delusions

Delusions of persecution (including the Capgras and Fregoli syndromes) Delusions of grandeur Delusions of jealousy Erotomanic delusions (De Clerambault's syndrome) Nihilistic delusions (including Cotard's syndrome) Delusions of sin Delusions of reference

Other signs and symptoms 163 HALLUCINATIONS

Visual hallucinations range from simple to complex in form. Simple hallucinations include such phenomena as 'zigzag linear patterns' (Panayiotopoulos 1994) and 'dancing lights, rings and circles' (Parkinson et al. 1952). Complex phenomena may be quite detailed: one patient, a war veteran, saw 'stretcher bearers walking past him and then the figures of nurses whom he would recognize' (Russell and Whitty 1955); another saw 'the Queen, with a bag over her arm [who] walked from the left to the centre of the ward, then vanished' (Lance 1976). In some cases, autoscopy may occur, wherein patients hallucinate an image of themselves (Lukianowicz 1958): one 74-year-old woman 'suddenly noticed a figure seated on [her] left. "It wasn't hard to realize that it was I myself who was sitting there. I looked younger and fresher than I do now. My double smiled at me in a friendly way, as though she wanted to tell me something" ' (Kolmel 1985). 'Lilliputian' hallucinations are said to be present when the hallucinated figures are quite small, much as in the novel Gulliver's Travels (Alexander 1926; Goldin 1955; Leroy 1922). Hallucinations that occur upon falling asleep or upon awakening are known, respectively, as hypnagogic and hypnopompic (Zarcone 1973). Palinopsia represents a peculiar kind of visual hallucination that Critchley (1951) considered to be a type of 'visual perseveration'. Here, objects originally actually seen by the patient are subsequently recurrently hallucinated out of place. For example (Michel and Troost 1980), one patient reported that: each person she saw had the face of someone she had just seen on television. She later peeled a banana and in a few minutes saw multiple vivid images of bananas projected over the wall. She realized they were only images, and not real. Next, after putting a 20-dollar bill in her purse, she saw heaps of 20-dollar bills everywhere.

Another patient (Meadows and Munro 1977), after seeing someone costumed as Santa Glaus at a Christmas party, 'noticed that a replica of the white beard of ... Santa Glaus was superimposed upon the face of everyone she spoke to'. Polyopia refers to a condition in which patients, rather than simply seeing 'double', see multiple reduplications of the same image (Lopez et al. 1993). Whether or not this should be considered to be a variant of palinopsia is unclear. Auditory hallucinations may range from such simple phenomena as 'grinding noises' or a noise 'like a freight train' (Cascino and Adams 1986) to complex experiences such as hearing music (Hammeke et al. 1983) or voices. Voices, the most compelling type of auditory hallucination, may be soft, mere whisperings, or quite clear and distinct. They may come from an internal organ or have their source outside the patient, in 'the air', or perhaps electronic devices or simply the walls. Some patients seem able to ignore them, whereas others will talk back to them. There may occasionally be 'command' hallucinations, which, as noted by Kraepelin (1919), 'in certain circumstances are very precisely obeyed. They forbid the patient to eat and to speak, to work, to go to church ... "Go on, strike him, beat him".' Tactile hallucinations (Berries 1982) are extraordinarily varied. Kraepelin (1919), in describing a tactually hallucinated patient, noted that he 'feels himself laid hold of, touched over his whole body, he feels tickling in his thigh and right up to his neck, pricking in his back and in his calves, a curious feeling in his neck, heat in his face'. When patients hallucinate the feeling of ants or insects crawling on the skin, one speaks of 'formication'. Olfactory hallucinations, although at times consisting of such pleasant aromas as perfume, are generally unpleasant, even repulsive: Kraepelin (1919) noted 'a smell of sulphur; of corpses and chloride of lime, of blood, of fire, of the fumes of hell'. Gustatory hallucinations are perhaps the least common of all types: Kraepelin (1919) reported patients who tasted 'petroleum or arsenic' in the food.

164 Signs, symptoms and syndromes

DELUSIONS

Delusions of persecution take the most varied of forms: patients are spied on and followed; a conspiracy has been set up, and the police, FBI or even the mafia are involved. Neighbors and co-workers, even family members, have turned on them: poison gas surrounds them, and their food, indeed even their medicine, has been adulterated. The Capgras syndrome (Alexander et al. 1979; Christodoulou 1977; Enoch 1963) represents a particular kind of delusion of persecution wherein patients believe that malevolent 'imposters' have somehow entered and taken over the bodies of familiar persons, such as family members or neighbors. In one case (Merrin and Silberfarb 1976), the patient believed that 'the "substitution" first occurred on [her] wedding day, when her husband went to the men's room and an imposter took his place'. Although others could not see anything amiss with her husband, the patient felt able to differentiate the husband from the imposter given that the imposter 'had a rotten green toenail. Once she even went so far as calling the police and demanding that her husband remove his shoe to expose the green toenail to the police'. In some cases of the Capgras syndrome, patients may turn on the 'imposter', in the process assaulting innocent parties (Thompson and Swan 1993). In a related kind of delusion of persecution, known as the Fregoli syndrome, patients believe that the body of a stranger has somehow been invaded and taken over by a familiar person (O'Sullivan and Dean 1991). Delusions of grandeur may involve various themes: The patient 'is "something better," born to a higher place, the "Glory of Israel," an inventor, a great singer, can do what he will' (Kraepelin 1919). Delusions of jealousy (Soyka et al. 1991) fuel patients' jealousies: the infidelities of spouses or lovers are revealed and their 'playing around' is no longer hidden. Protestations of faithfulness have no effect as patients find evidence for their suspicions: the spouse is late coming home; the phone rings at odd times; the sheets are rumpled in a suggestive way. Erotomanic delusions are characterized by a belief in an 'amorous communication with a person of much higher rank who has been the first to fall in love and the first to make advances' (Gillett et al. 1990). Also known as De Clerambault's syndrome (Ellis and Mellsop 1985), these delusions often impel patients to attempt contact with these supposed lovers, even to the point of stalking and kidnapping them. Nihilistic delusions entail the belief that animate objects, such as other people, animals or such living things as trees, are in fact dead. In a variant of this, known as Cotard's syndrome (loseph and O'Leary 1986), patients come to believe that they themselves are in fact dead: in one case (Cohen et al. 1997), a 13-year-old girl had the 'absolute conviction that she was already dead, waiting to be buried, and that she had no teeth and no hair and that her uterus was malformed'. Delusions of sin give form to the patients' sense that they have committed unpardonable acts: they have cursed God, engaged in unspeakable practices, betrayed those close to them and violated all their sacred principles. Such a patient 'is a damned soul, the refuse of humanity' (Kraepelin 1919). Delusions of reference embody a sense that seemingly unrelated and chance events in some fashion pertain to or refer to the patient. 'Indifferent remarks and chance looks, the whispering of other people, appear suspicious to the patient' (Kraepelin 1919). In many cases, such delusions of reference serve, as it were, to bolster or reinforce other delusions. Thus, patients with delusions of persecution, on seeing police officers talking, might immediately believe that the conversation was about them and that it was evidence that the conspiracy had begun in earnest. To take another example, patients with delusions of grandeur might, upon seeing the sun break radiantly through the storm clouds, assume that it was a sign of God's special grace for them.

Other signs and symptoms 165

Differential diagnosis of the symptoms In evaluating a patient with either hallucinations or delusions, the first and most critical task is to determine whether or not the hallucination or delusion is occurring within the context of one of the following major syndromes: delirium, dementia, mania or depression. Thus, in evaluating these patients, one should be alert to the following: • significant confusion, which suggests delirium • cognitive deficits occurring in a clear sensorium, suggestive of dementia • heightened mood, increased energy and pressure of speech and activity, which suggest mania • depressed or irritable mood, anhedonia, anergia and sleep disturbance, all suggestive of depression. If the hallucination or delusion occurs in the context of one of these major syndromes, the differential diagnosis of that syndrome should be pursued. If the hallucination or delusion is occurring outside the context of one of these major syndromes, the next step is to determine whether or not the patient has a psychosis. The syndromal diagnosis of psychosis depends on whether or not the patient has retained insight into the unreality of the symptoms. Here, the term insight refers not to some sophisticated understanding of psychology but rather simply to whether or not patients recognize that the world is not 'really' as they are experiencing it. With this criterion in mind, it is clear that, by definition, all patients with isolated delusions should be considered to have a psychosis and should be evaluated further with that differential diagnosis in mind (see Chapter 7, p. 285). Patients who have isolated hallucinations, however, may or may not have insight, and it is critical to determine whether or not this quality is present. Happily, such a determination is generally not difficult. Begin with observation: patients who pat hallucinated dogs or talk back to hallucinated voices generally lack insight. Where observation does not settle the issue, tactful enquiry is in order. Although some patients may not be put off or put on guard by direct questions such as 'You don't really think that's real, do you?', most patients are more responsive with an indirect approach. Thus, in a more diplomatic vein, one might mention, 'I don't see it. Are you certain it's there, or do you think it might be your imagination?' In cases where patients lack insight and are convinced of the reality of their hallucinations, one should proceed to the differential diagnosis for the syndrome of psychosis. The remaining cases, that is to say those characterized by isolated hallucinations occurring with preserved insight, are relatively uncommon. Their differential diagnosis is summarized in Table 4.5, and described more fully below. VISUAL HALLUCINATIONS

Medications capable of causing hallucinations include, above all, dopaminergic agents. Levodopa, as used in the treatment of Parkinson's disease, may, for example, cause visual hallucinations (Banerjee et al. 1989; Fenelon et al. 2000; Shaw et al. 1980); indeed, after 5 or more years of treatment, this occurs in a little over one-fifth of all patients (Friedman and Sienkiewicz 1991; Graham et al. 1997). The hallucinations themselves may, at times, be quite elaborate: in one case (Graham et al. 1997) a paient had 'hallucinations of miniature people and domestic animals ... the figures were non-threatening, laughed and talked among themselves, and had a male leader who organized them into purposeful activities'. Other drugs noted to cause visual hallucinations include digoxin (Closson 1983), quinidine (Fisher 1981), propranolol (Shopsin et al. 1975), bupropion (Golden et al. 1985), trazodone

166 Signs, symptoms and syndromes Table 4.5 Causes of hallucinations with preserved insight Visual hallucinations

Medications Intoxicants Partial seizures Migraine Significant visual loss (including the Charles Bonnet syndrome) Cortical lesions Mesencephalic lesions (peduncular hallucinations) Pontine tegmental lesions (Pick's visions) Certain dementing diseases Narcolepsy Normal individuals (bereavement, prolonged sleep deprivation or as isolated hypnagogic phenomenon)

Auditory hallucinations

Medication Partial seizures Significant deafness Temporal lobe lesions Brainstem lesions

Tactile hallucinations

Intoxicants

Olfactory hallucinations

Partial seizures Migraine Lesions of the olfactory bulb or nerve

Gustatory hallucinations

Partial seizures

(Hughes and Sessell 1990) and imipramine (Kane and Keeler 1964; Klein 1964). Hypnagogic hallucinations have been noted as a side-efffect of amitriptyline (Hemmingsen and Rafaelsen 1980), and hypopompic hallucinations have been noted with amitriptyline (Hemmingsen and Rafaelsen 1980) and maprotilene (Albala et al. 1983). Intoxicants that may cause visual hallucinations include cocaine (Siegel 1978), LSD (Bercel et al. 1956; Isbell et al. 1956), phencyclidine (Meyer et al. 1959), mescaline (Mitchell 1896) and psilocybin (Hollister et al. 1960). Although the hallucinations are, in most of these cases, fairly simple, for example geometric forms, they may sometimes be complex (e.g. with LSD [Bercel et al. 1956]). Visual hallucinations may also occur as 'flashbacks', wherein, long after hallucinogen intoxication, the patient spontaneously re-experiences some of the visual phenomena that occurred during the intoxication (Abraham 1983; Horowitz 1969). Solvent intoxication may also be complicated by simple visual hallucinations (Channer and Stanley 1983; Evans and Raistrick 1987). Partial seizures may be characterized by visual hallucinations, including palinopsia (Muller et al. 1995), and in some cases, such hallucinations may constitute the entire symptomatology of the seizure, as for example with some simple partial seizures (Penfield and Perot 1963; Sowa and Pituck 1989; Williams 1956). The degree of complexity of these ictal hallucinations is of some localizing value: whereas simple hallucinations may be seen with either a posterior location in the occipital lobe or a more anterior one in the occipitoparietal or occiptotemporal regions, complex hallucinations are generally seen only with the more anteriorly placed lesions (Russell and Whitty 1955). Complex partial seizures, in addition to a defect of consciousness, may also be characterized by visual hallucinations, which may be quite extraordinary: in one case (Mulder and Daly 1952), a patient had an 'exceptionally vivid and complete' hallucination of the very potato patch in which he was standing years earlier when he had his first seizure! In

Other signs and symptoms 167

another case, a patient of Wilson's experienced a visual hallucination as an aura to a complex partial seizure: first, the patient experienced 'a smell of ammonia, followed by the appearance before her of two former school teachers'. As she related it: 'Their faces would come closer and closer to me and they would scream as they came at me' (Gibson 1959). Migraine headaches may be associated with visual hallucinations (Hachinski et al. 1973; Selby and Lance 1960), and when the hallucinations appear as aurae, they are usually, but not always, simple, consisting of flashing lights or zigzagging lines (Panayiotopoulos 1994; Russell and Olesen 1996). An aura may, very rarely, persist long after the headache has cleared, sometimes for years (Liu et al. 1995). Significant visual loss may be associated with either simple or complex visual hallucinations (White 1980), and this has been noted with visual loss caused by cataracts (Bartlett 1951), macular degeneration (Holroyd et al. 1992) and lesions of the optic nerve, chiasm, tract and optic radiations (Lepore 1990). In cases in which the hallucinations are complex, the patient recognizes that they are 'unreal' and the only pathology consists of visual loss, one speaks of the Charles Bonnet syndrome (Schultz and Melzack 1993; Teunisse et al. 1995, 1996). Although the hallucinations of the Charles Bonnet syndrome are traditionally said to be 'Lilliputian' in character, it in fact appears that such miniaturization occurs in only a minority of patients with this syndrome (Teunisse et al. 1994). The onset of the Charles Bonnet syndrome can at times be quite dramatic: in one case (White 1980), a 69 year-old-man, while listening to music, 'suddenly saw a brightly coloured circus troupe burst through the window'. Cortical lesions of the occipital lobe or adjacent areas, such as infarctions, hemorrhages or tumors, may cause either simple (Parkinson et al. 1952) or complex (Kolmel 1985) visual hallucinations. In those cases in which an hemianopia is also present, the hallucination typically occurs within the hemianopic field (Kolmel 1985; Vaphiades et al. 1996). The clinical presentation in such cases may be quite remarkable: one patient (Lance 1976) with a left hemianopia saw animals appearing: from the left one at a time. At various times he saw dogs, goats, a lion and a horse as well as birds and butterflies. The animals would emerge from a door on the left side of the room and walk to the mid-line. If he looked to the left the animals retreated towards the door but would advance again as he looked to the front.

Another patient, a neurologist, after suffering an infarction of the medial left occipital lobe, developed a right hemianopia in which he experienced vivid visual hallucinations: he noted that 'often there was a pony with his head cradled in my right arm' (Cole 1999). Palinopsia has been noted with lesions of the occipital lobe (Michel and Troost 1980), occipitotemporal region (Meadows and Munro 1977), occipitoparietal region (Bender et al. 1968) and the parietal lobe (Critchley 1951). Polyopia has been noted with lesions of the occipital lobe (Kolmel 1985). Mesencephalic lesions may cause visual hallucinations, these often being referred to as 'peduncular' hallucinations, given that the lesion typically involves one of the cerebral peduncles. These peduncular hallucinations are typically complex and vivid (Lhermitte 1922, 1932, McKee et al. 1990): one patient (Geller and Bellor 1987) saw 'cats running about the floor, flowery outdoor scenes in bright purple colors, and the faces of neighbors and friends', whereas another (De La Fuente Fernandez et al. 1994) saw'motorbikes ... dogs, horses ... and people ... entering and driving silently around the room'. Although insight is preserved, and patients recognize the unreality of these peduncular hallucinations, their vivid character can nonetheless have a profound effect: in one case (Dunn et al. 1983), a patient saw 'snakes ... that appeared from any direction' and although 'he knew the snakes were not real [nevertheless] during the examination he frequently jumped because he was pulling away from the perceived snakes'.

168 Signs, symptoms and syndromes

The mesencephalic location of the responsible lesions usually entails 'neighborhood' symptoms of localizing value: thus, a right mesencephalic infarction affecting both the right cerebral peduncle and the midbrain tegmentum also caused left hemiplegia and bilateral ptosis (Geller and Bellor 1987) and a left mesencephalic infarction which primarily involved the substantia nigra also caused a parkinsonian syndrome with prominent tremor on the right (De La Fuente Fernandez et al. 1994). Pontine tegmental lesions may produce 'Pick's visions' wherein 'the patient may see people who are in his room step through the walls into an adjacent room and walk about there. It may seem to him that the walls are bent or otherwise distorted or are actually collapsing' (Bing 1940). Certain dementing diseases may present with complex visual hallucinations, and the diagnosis may remain somewhat obscure pending the onset of cognitive deficits. Diffuse Lewy body disease may present in such a fashion (Ala et al. 1997), the subsequent appearance of parkinsonism or neuroleptic sensitivity suggesting the correct diagnosis. Fatal familial insomnia, an autosomally dominantly inherited prion disease, typically presents with intractable insomnia and complex visual hallucinations to which the patient often responds to, as if acting out a dream (Gallassi et al. 1996; Manetto et al. 1992). Narcolepsy may cause hypnagogic hallucinations (Zarcone 1973), the diagnosis being suggested by the presence of sleep attacks. Normal individuals may experience visual hallucinations in the course of bereavement, during prolonged sleep deprivation or as isolated hypnagogic phenomena. Bereavement in the elderly may be accompanied by visual hallucinations, often of the deceased, which the bereaved usually find comforting. Importantly, these hallucinations gradually clear spontaneously within a matter of months (Grimby 1993); thus, their persistence much beyond this time should prompt a more thorough diagnostic evaluation. Sleep deprivation lasting more than a few days typically causes visual hallucinations (Kollar etal. 1968). Hypnagogic hallucinations may occasionally occur on an isolated basis in normal individuals (McDonald 1971). AUDITORY HALLUCINATIONS

Medications capable of causing auditory hallucinations include pentoxyfylline (Gilbert 1993). Partial seizures, of both the simple and complex type, may be accompanied by auditory hallucinations. Williams (1956) described a patient whose simple partial seizure began with 'a buzz' that was quickly followed by 'music like a loudspeaker in which he heard clearly a recognized section of Veni Creator'. During a complex partial seizure, a patient described by Penfield and Perot (1963) 'heard voices which seemed to come from her right side' as if she were in the middle of a 'crowd of people'. Significant deafnessShas been associated with musical hallucinations (Hammeke et al. 1983; Miller and Crosby 1979; Ross etal. 1975). Temporal lobe lesions may, rarely, cause complex auditory hallucinations (Keschner et al. 1936) Brainstem lesions, including lesions of the mesencephalon or pons, may cause either simple (Cascino and Adams 1986; Murata et al. 1994) or, in the case of an infarction of the dorsal pons, complex auditory hallucinations (Schielke et al. 2000). TACTILE HALLUCINATIONS

Intoxicants such as cocaine (Siegel 1978) and amphetamine (Bell 1973) may cause isolated tactile hallucinations with a full preservation of insight; classically, formication is experienced.

Other signs and symptoms 169

OLFACTORY HALLUCINATIONS

Partial seizures occurring secondary to foci in the temporal lobe classically include olfactory hallucinations, as emphasized by Hughlings Jackson (Jackson and Stewart 1899). Migraine may be preceded by an aura composed of an olfactory hallucination (Fuller and Guiloff 1987; Wolberg and Ziegler 1982). Lesions of the olfactory bulb or nerve have, rarely, been associated with olfactory hallucinations (Paskind 1935). GUSTATORY HALLUCINATIONS

Partial seizures may include gustatory hallucinations, either as an aura to a complex partial seizure (Daly 1958) or as part of a simple partial seizure (Mulder and Daly 1952).

SCHNEIDERIAN FIRST RANK SYMPTOMS Kurt Schneider (1887-1967) was a very influential German psychiatrist whose classic text Clinical Psychopathology went through multiple revisions from its first edition in 1939 up to the fifth, and last, edition, published in 1958. In this text, Schneider described a number of hallucinations and delusions that he believed were of 'first rank' importance in the diagnosis of schizophrenia. Although these Schneiderian first rank symptoms are, indeed, most commonly seen in schizophrenia, they may also, as pointed out by Schneider himself, occur in 'diverse' other conditions, as described below. Description of the symptoms The various Schneiderian first rank symptoms, as noted in Table 4.6, may be divided into those which are auditory hallucinations and those which represent delusions. Audible thoughts are said to occur when patients hear their own thoughts as if they were spoken out loud and indeed as if others might be able to hear them also. One of Schneider's (1959) patients said, 'I hear my own thoughts. I can hear them when everything is quiet.' Voices commenting on what the patient does keep up, as it were, a running commentary on the patient's behavior. One of Schneider's (1959) patients 'heard a voice say, whenever she wanted to eat, "Now she is eating, here she is munching again," ' and one of Kraepelin's (1919) patients heard a voice telling her, 'Mary, you're talking nonsense, the policeman has seen you already.' Voices arguing with each other, or, as Schneider (1959) elaborated, merely 'conversing with one another', may engage patients' attention, as if the voices were carrying on a debate about them. Table 4.6 Schneiderian first rank symptoms Hallucinations

Audible thoughts Voices commenting on what the patient does Voices arguing with each other

Delusions

Delusions of passivity or influence Thought withdrawal Thought insertion Thought broadcasting

170 Signs, symptoms and syndromes

Delusions of passivity or influence are said to be present when 'feelings, impulses (drives) and volitional acts ... are experienced by the patient as the work or influence of others' (Schneider 1959). Such patients believe that their thoughts, feelings or behavior are under the direct and unmediated control of some outside force or agency. Thus, passively played upon by these forces, patients feel as if they were robots or automatons. Patients will typically elaborate on this delusion of influence and express a belief as to the source of the influence, for example an 'electrical device', 'distant computers' or 'powerful magnets'. Thought withdrawal represents a delusion wherein patients experience their thoughts being directly removed and withdrawn from their mind. One of Kraepelin's (1919) patients spoke of his thoughts being 'drawn off. This is quite different from simply losing track of what one was thinking: those who lose track have a sense of having forgotten or lost something, whereas those with thought withdrawal have, as emphasized by Schneider (1959), a definite sense that some other agency or person has directly removed the thought. Thought insertion represents the delusional belief of patients that the thoughts occurring in their minds are not their own but rather originate from, as Schneider (1959) put it, 'other people, who intrude their thoughts upon the patient'. Such inserted thoughts are quite different from obsessions: obsessions are recognized by patients as their own thoughts and as originating within them, whereas inserted thoughts are experienced as a kind of cognitive 'foreign body'. Thought broadcasting represents the delusion that others can know what a patient is thinking without the patient in any way relating those thoughts. This 'thought diffusion' led one of Schneider's (1959) patients to complain that, 'if I think of anything, at once those opposite me know it and it is embarrassing'. As she believed that 'the doctor too knew exactly what she was thinking, ... she suggested that she would stop talking and he could just listen'. In some cases, patients will elaborate on this delusion, developing further beliefs about how such thought transfer is possible: Kraepelin (1919) noted that some patients believe that 'their thoughts are conveyed by a machine, there is a "mechanical arrangement," "a sort of little conveyance," telepathy'.

Differential diagnosis of the symptoms It has, at times, been felt that Schneiderian first rank symptoms are virtually pathognomonic of schizophrenia, occurring in virtually no other condition. The source of this belief is not clear: it certainly does not come from Schneider, who clearly stated that these first rank symptoms could occur secondary to a 'number of diverse morbid cerebral processes' (Schneider 1959). Subsequent research (Carpenter et al. 1973) has borne out Schneider's opinion, and although it is certainly apppropriate to consider strongly a diagnosis of schizophrenia in a patient with a Schneiderian first rank symptom, other 'diverse' entities, as noted in Table 4.7, must also be considered in the differential diagnosis. Schizophrenia is the most common cause of first rank symptoms, such symptoms being seen in anywhere from one-third (Radhakrishnan et al. 1983) to over half (Tandon and Greden 1987) of such patients. Among patients with schizophrenia, it appears that, of all the first rank symptoms, thought broadcasting and thought insertion are probably most common (Mellor 1970). Whenever a first rank symptom occurs in the context of a chronic psychosis that lacks prominent symptoms of mood disturbance, schizophrenia is the most likely diagnosis. Schizoaffective disorder is similar to schizophrenia in that there is a chronic psychosis: the differentiating feature is the intermittent occurrence of prominent and prolonged disturbances of mood, towards either mania or depression. First rank symptoms have been noted in about one-quarter of these patients (Tandon and Greden 1987).

Other signs and symptoms 171 Table 4.7 Causes of Schneiderian first rank symptoms Schizophrenia Schizoaffective disorder Mania Depression Amphetamine intoxication Partial seizures Cushing's syndrome New-variant Creutzfeldt-Jakob disease Subacute sclerosing panencephalitis

Mania is characterized by heightened mood, increased energy and pressure of both speech and activity. In severe cases, these primary symptoms of mania may also be joined by hallucinations and delusions, including first rank symptoms (Jampala et al. 1989). The differentiation from schizoaffective disorder is based on the fact that, in mania, delusions and hallucinations occur only within the context of the mood disturbance, whereas in schizoaffective disorder, delusions and hallucinations are seen not only before the onset of the mood disturbance, but also after it has resolved. Depression may, rarely, be associated with a first rank symptom (Tandon and Greden 1987). Given the rarity of this association, the appearance of a first rank symptom in a patient thought to have depression should give the physician a diagnostic pause and prompt a thorough diagnostic re-evaluation. Amphetamine intoxication, characterized initially by elation, talkativeness and increased activity, may, when severe, cause delusions, including first rank symptoms (Angrist and Gershon 1970; Bell 1973). Partial seizures may be characterized by first rank symptoms. In one case, a patient had simple partial seizures consisting of 'blurry vision, abdominal discomfort, sensation of imminent death, intense fear, and the conviction that his body is controlled by external forces' (Mesulam 1981). Gushing's syndrome was, in one case report (Trethowan and Cobb 1952), associated with first rank symptoms. The patient in question had fairly typical Cushingoid symptoms, such as depression, weight gain, oligomenorrhea, hirsutism, a 'buffalo hump' and prominent abdominal striae; in addition, she had audible thoughts, thought broadcasting and thought insertion, all of which cleared after adrenalectomy. New-variant Creutzfeldt-Jakob disease often presents with psychosis, and, in a minority of such patients, the psychosis may include a first rank symptom (Zeidler et al. 1997). The subsequent appearance of ataxia, dementia or myoclonus suggests the correct diagnosis. Subacute sclerosing panencephalitis, although classically presenting with a dementia that is later joined by myoclonus and ataxia or chorea, may, rarely, present with a psychosis. In one case (Duncalf et al. 1989), a 21-year-old female presented with first rank symptoms and delusions of persecution and reference; there were no other symptoms for 7 weeks, at which time cognitive deficits appeared and prompted further diagnostic evaluation.

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5 Syndromes of cognitive impairment Dementia Delirium

186 202

Amnesia Mental retardation

216 222

DEMENTIA The dementias constitute one of the most common syndromes seen in neuropsychiatric practice. Accurate diagnosis is critical, not only for prognostic purposes, but also because a not insignificant number of the diseases capable of causing dementia are treatable. Description of the syndrome Dementia is a syndrome of multiple different etiologies characterized by a global decrement in cognitive functioning occurring in a clear sensorium, without significant confusion (Cummings 1987). When the condition is fully developed, patients display deficits in memory, abstracting abilities, calculations and judgment. An impairment of memory is manifest with variably severe anterograde amnesia and a relatively less severe retrograde amnesia: patients may not recall being seen by their physician earlier in the day but may be able to recall a singular event that occurred a decade ago. A loss of abstracting ability is evident on proverbs testing and may also appear in daily life, in which patients may not be able to master complex tasks. Calculating ability is measured with serial sevens testing but may also be evident in a patient's inability to keep a checkbook or make change. A loss of good judgment becomes apparent in social situations as patients fail to note subtleties and nuances, and end up committing numerous more or less severe faux pas. Along with these symptoms, one also typically sees a personality change. This may at times take a specific form, as for example in the frontal lobe syndrome, or may be non-specific, with either a magnification of prior traits or the appearance of new ones. For example, a previously strict person may become cruel and punishing, or a previously prudish patient may become lewd and unihibited. Hallucinations and delusions are common as dementia progresses. Hallucinations, although generally visual, may also be auditory. Delusions are often of persecution or misidentification. Other signs that may appear in dementia include aphasia, apraxia, agnosias, and various abnormal movements. As noted below, abnormal movements such as parkinsonism are very useful from a diagnostic point of view.

Syndromes of cognitive impairment 187

Differential diagnosis of the syndrome Dementia must be distinguished from delirium, mental retardation and amnesia. Delirium is distinguished from dementia by the presence of prominent confusion; here, however, one must keep in mind that some diseases may be characterized by both dementia and intermittent delirium. In multi-infarct dementia, for example, each fresh stroke may be heralded by an episode of delirium that, once having cleared spontaneously, leaves the patient not confused but more demented. Furthermore, some diseases, albeit characterized primarily by dementia, may also produce waxing and waning or intermittent confusion. Diffuse Lewy body disease, for example, although primarily a dementing disorder, often causes intermittent confusion of variable severity. Mental retardation is distinguished primarily by its course: in mental retardation, the intellectual development of patients proceeds only to a certain point, at which it 'stalls', leaving patients on an intellectual 'plateau' beyond which they do not progress. Importantly, there is no decrement in intellectual ability but merely a plateauing. In contrast, there is in dementia a definite decrement from a previously acquired level of intellectual ability. Importantly, as pointed out below, some disorders may cause both mental retardation and a dementia: for example, in the setting of mental retardation secondary to Down's syndrome, a dementia eventually devlops in most patients who survive past the age of 40. Amnesia is distinguished from dementia by the restricted nature of the cognitive deficit: in amnestic disorders one finds only a deficit in memory, whereas in dementia, in addition to a defective memory, one also finds other cognitive deficits, such as those with abstraction or calculation. It must be borne in mind, however, that some dementing conditions, such as Alzheimer's disorder, may present with a pure amnesia that persists as such for a prolonged period before being joined by other cognitive deficits. Once the syndromal diagnosis of dementia is secure, it is necessary to determine the particular cause of the dementia. Table 5.1 lists the various causes of dementia, divided in a fashion that assists the physician to organize the clinical findings. The first group contains those dementias which are generally of gradual or subacute onset and often lacking in distinctive features, the prototype of which is Alzheimer's disease. The next group includes those disorders which are associated with stroke, for example multi-infarct dementia. Third are those disorders which may present with the frontal lobe syndrome, such as Pick's disease. Next come several groups with one thing in common, namely that they are associated with one of a number of abnormal movements, such as parkinsonism, chorea, dystonia, ataxia, or myodonus. Following this is a group of disorders each of which is associated with other specific features, as for example tendon enlargement in cerebrotendinous xanthomatosis. Disorders with specific precipitants, such as head trauma, follow. The next two groups are suggested by the occurrence of dementia in certain specific clinical settings, for example dementia occurring in the setting of mental retardation (e.g. the dementia of Down's syndrome) or dementia occurring in the setting of AIDS or other immuncompromised states (e.g. progressive multifocal leukoencephalopathy). Next is a group of disorders which, albeit rarely, may be associated with a presentation with aphasia. Finally there is a miscellaneous group. In the differential diagnosis of any individual case, it must be borne in mind that the patient may have not one but two or more dementing disorders, thus presenting an etiologically 'mixed' dementia. Thus, dementia resulting from a combination of Alzheimer's disease and multi-infarct dementia is not at all uncommon (Molsa et al. 1985). In cases in which the differential diagnosis cannot be reasonably narrowed down, it may be justified to perform a laboratory screen including the following: magnetic resonance imaging (MRI), fluorescent traponemal antibody test (N.B. in screening for neurosyphilis, a VDRL or rapid plasma reagin is not adequate), HIV antigen, thyroid profile with thyroid-stimulating

Table 5.1 Causes of dementia Of gradual or subacute onset and often lacking in distinctive features

Alzheimer's disease Pick's disease Binswanger's disease Lacunar dementia Cerebral amyloid angiopathy Chronic hydrocephalus (including normal-pressure hydrocephalus) Creutzfeldt-Jakob disease Hypothyroidism Hyperthyroidism Vitamin B12 deficiency Folate deficiency Diffuse Lewy body disease AIDS dementia Neurosyphilis (presenting as general paresis of the insane) Depression Lyme disease Multiple sclerosis Huntington's disease Amyotrophic lateral sclerosis Systemic lupus erythematosus Granulomatous angiitis Tumors

Associated with strokes

Multi-infarct dementia Lacunar dementia Binswanger's disease CADASIL Cranial arteritis Cerebral amyloid angiopathy MELAS syndrome

With the frontal lobe syndrome

Tumors Pick's disease Frontotemporal dementia Amyotrophic lateral sclerosis

With parkinsonism

Parkinson's disease Diffuse Lewy body disease Progressive supranuclear palsy Multiple system atrophy (striatonigral degeneration) Corticobasal ganglionic degeneration Fahr's syndrome Arteriosclerotic parkinsonism Hallervorden-Spatz disease (late onset) Huntington's disease of juvenile onset Dementia pugilistica Valproicacid Methanol Carbon monoxide intoxication Systemic lupus erythematosus Hypoparathyroidism Manganese intoxication

With chorea

Huntington's disease Neuroacanthocytosis

Table 5.1 Causes of dementia- continued Dentatorubropallidoluysian atrophy Acquired hepatocerebral degeneration With dystonia

Wilson's disease Hallervorden-Spatz disease

With ataxia

Creutzfeldt-jakob disease Gerstmann-Straussler-Scheinker disease Multiple system atrophy Autosomal dominant cerebellar ataxia Dentatorubropallidoluysian atrophy Dementia pugilistica Solvent abuse Lithium intoxication Mercury Tin intoxication Acquired hepatocerebral degeneration Metachromatic leukodystrophy Progressive rubella panencephalitis

With myoclonus

Creutzfeldt-jakob disease New-variant Creutzfeldt-jakob disease Fatal familial insomnia AIDS dementia Hashimoto's encephalopathy Diffuse Lewy body disease Corticobasal ganglionic degeneration Dentatorubropallidoluysian atrophy Multiple system atrophy (olivopontocerebellar type) Dialysis dementia Alzheimer's disease Whipple's disease Subacute sclerosing panencephalitis Juvenile Huntington's disease Idiopathic hemochromatosis Thalamic degeneration

With other specific features

Cerebrotendinous xanthomatosis (tendon enlargment, cataracts and ataxia) Myotonic dystrophy (myotonia and myopathic facies) Fatal familial insomnia (insomnia) Thallium intoxication (painful polyneuropathyand prominent alopecia) Arsenic intoxication (painful polyneuropathyand less prominent alopecia) Pellagra ('3 D's': diarrhea, dermatitis and dementia) Behcet's syndrome (oral and genital ulcers) Sjorgen's syndrome (sicca syndrome with dry eyes and dry mouth) Polymyalgia rheumatica (severe myalgia of the proximal musculature) Sneddon's syndrome (livedo reticularis)

With specific precipitants

Head trauma Subdural hematoma Diffuseaxonal injury

Table 5.1 Causes of dementia - continued Dementia pugilistica Anoxia Postanoxic encephalopathy Delayed postanoxic leukoencephalopathy Radiation encephalopathy Dialysis dementia Hypoglycemia Post-encephalitic Medication or drug-induced Prednisone Biperidin Valproicacid Disulfiram Lithium intoxication Methanol intoxication Alcoholic dementia Solvent-induced dementia Heroin vapor In the setting of mental retardation

Down's syndrome Sturge-Weber syndrome Congenital rubella syndrome

In the setting of AIDS or other immunocompromised states

AIDS dementia Progressive multifocal leukoencephalopathy

Presentation with aphasia

Alzheimer's disease Pick's disease Frontotemporal dementia Corticobasal ganglionic degeneration Creutzfeldt-Jakob disease Tumors

Miscellaneous

Systemic lupus erythematosus Anti-phospholipid antibody syndrome Polyarteritis nodosa Sarcoidosis Metachromatic leukodystrophy Adrenoleukodystrophy Hallervorden-Spatz disease Fahr's syndrome Hypoparathyroidism Whipple's disease Lead intoxication Thalamic degeneration Sleep apnea Bilateral carotid occlusion Hypereosinophilia Hypertriglyceridemia Hyperviscosity

Syndromes of cognitive impairment 191

hormone, B12 and folate levels, serum calcium level, erythrocyte sedimentation rate and antinuclear antibody. If this initial screen is unrevealing, a secondary screening may be considered, including plasma copper and ceruloplasmin levels, anti-thyroid antibodies, antiborrelia antibodies, a 24-hour urine sample for heavy metals, and a lumbar puncture. OF GRADUAL OR SUBACUTE ONSET AND OFTEN LACKING IN DISTINCTIVE FEATURES

Alzheimer's disease is typically of gradual or insidious onset, often presenting with a gradually worsening amnesia (Goodman 1953; Linn et al. 1995), which is eventually joined by various 'cortical' signs such as aphasia, apraxia, and primitive reflexes (Huff et al. 1987; Price et al. 1993). Pick's disease, although typically presenting with a personality change, often of the frontal lobe type (Munoz et al. 1993), may occasionally present in a fashion quite similar to that of Alzheimer's disease (Wisniewski et al. 1972). Binswanger's disease, as noted by Binswanger (Blass et al. 1991) himself, may present with a slowly progressive dementia, which, although often accompanied by strokes (Caplan and Schoene 1978), may lack them entirely (Kinkel et al. 1985; Yoshitake et al. 1995). Lacunar dementia, like Binswanger's disease, presents with a gradually progressive dementia that may or may not be punctuated by strokes (Ishii et al. 1986; Yoshitake et al. 1995). Cerebral amyloid angiopathy, although classically marked by a gradually progressive dementia punctuated by lobar intracerebral hemorrhages, may cause a progressive dementia alone without any strokes (Bornebroek et al. 1996; Cosgrove et al. 1985; Haan et al. 1990; Nobuyoshi et al. 1984). In some cases, however, there may be transient events, similar to transient ischemic attacks (Greenberg et al. 1993). Chronic hydrocephalus (Gustafson and Hagberg 1978; Harrison et al. 1974; McHugh 1964; Messert and Becker 1966), including normal pressure hydrocephalus (Adams etal. 1965; Hill et al. 1967), typically presents with a combination of dementia, urinary incontinence, and a broad-based, shuffling gait often marked by a 'magnetic' aspect wherein the feet seem to be magnetically 'stuck' to the floor. Creutzfeldt-Jakob disease may present with a dementia with few distinguishing features (Brown et al. 1984; Will and Mathews 1984), although in approximately 80% of cases, myoclonus eventually appears (Brown et al. 1986; Roos et al. 1973), thus suggesting the correct diagnosis. It must be borne in mind, however, that not all cases will develop myoclonus (Zochodne et al. 1988); here, the relative rapidity of the progression, measured in months, may suggest the diagnosis. Hypothyroidism may cause a dementia (Asher 1949) marked by sluggishness (de Fine Olivarious and Roder 1970). In most cases, one will also see other, typical symptoms of hypothyroidism, such as myxedema, cold sensitivity, constipation and hair loss. Hyperthyroidism, rarely, may cause a dementia, in one case accompanied by tremor and tachycardia (Bulens 1981). Vitamin B12 deficiency may cause dementia (Lurie 1919), and although this is usually accompanied by a macrocytic anemia, cases have occurred that lacked both anemia and macrocytosis (Chatterjee et al. 1996; Lindenbaum et al. 1988). Folate deficiency can clearly cause dementia. Cases have been reported of folate deficiency dementia occurring with subacute combined degeneration (Pincus et al. 1972) or spasticity (Reynolds et al. 1973), or in the absence of any other symptoms (Strachan and Henderson 1967). Diffuse Lewy body disease may present with a gradually progressive dementia that is marked by prominent fluctuations in cognitive status and by the early appearance of hallucinations and delusions (Byrne et al. 1989; McKeith et al. 1994). Almost all patients will eventually also

192 Signs, symptoms and syndromes

develop parkinsonism, a helpful clue to this eventuality being a pronounced sensitivity to neuroleptics, with the appearance of prominent neuroleptic-induced parkinsonism early on and with a relatively low dose (McKeith et al. 1992). AIDS dementia, although generally occurring with other symptoms suggestive of AIDS (e.g. Pneumocystis pneumonia, Kaposi's sarcoma and thrush) may, in a small minority, be the presenting symptom of AIDS (Navia et al. 1986). Neuro syphilis, presenting as general paresis of the insane, is, although much less common than early in the twentieth century, when it filled hospital wards, still with us and making something of a comeback, especially in connection with AIDS. The dementia is often marked by mood changes, either manic or depressive, and is accompanied by dysarthria and pupillary changes, including the classic Argyll Robertson pupil (Gomez and Aviles 1984; StormMamisen 1969). Depression, as may be seen in major depression, is a not uncommon cause of dementia (Reding et al. 1985). The dementia of depression used to be called a 'pseudodementia' (Caine 1981; Wells 1979), but this is inappropriate as the dementia of depression is no more 'pseudo' than any other dementia and may indeed be very severe. Clues to the correct diagnosis include the presence of significant depressive symptoms, such as disturbances in sleep and appetite, and above all a history of past depressive episodes (Rabins et al. 1984). Furthermore, the appearance of depression in a patient with a pre-existing dementia may worsen the patient's cognitive deficits (Greenwald et al. 1989). It must be borne in mind that these elderly patients are still liable to other dementing disorders and may indeed develop a dementia of another cause in the future (Alexopoulus et al. 1993). Lyme disease, during its third stage, may cause a mild dementia (Halperin et al. 1989; Logigian et al. 1990). The history may or may not reveal the original tick bite and erythema chronica migrans of stage I or the polyarthralgia of stage II, and patients may or may not have the oligoarthritis that may also occur in stage III. Multiple sclerosis may cause dementia, which is in most cases seen to occur in the context of a history of signs and symptoms indicating lesions 'disseminated in time and space'. In a minority, the dementia may be the primary expression of multiple sclerosis, being accompanied by few other symptoms (Jennekens-Schinkel and Sanders 1986; Mendez and Frey 1992), and, very rarely, it may constitute the presentation of the disease, without any other symptoms or signs (Fontaine et al. 1994; Hotopf et al. 1994). Huntington's disease, although typically presenting with either a personality change or chorea, may rarely present with a dementia, as has been noted in juvenile Huntington's disease (Hansotia et al. 1968) and in a 60-year-old (Case records 1992): in both cases, chorea eventually appeared after a number of years. Amyotrophic lateral sclerosis may present with a combination of dementia and typical upper and lower motor neuron signs (i.e. fasciculations, hyperreflexia, and pseudobulbar palsy) (Horoupian et al. 1984; Robertson 1953; Wechsler and Davison 1932) or may rarely present with dementia alone (Ferrer et al. 1991). Systemic lupus erythematosus may, very rarely, present with a gradually progressive dementia: in one patient, who recovered with steroid treatment, the diagnosis was delayed until the development of a fever and pleural effusion suggested the correct diagnosis (MacNeill et al. 1976). Granulomatous angiitis may present with a dementia (Case records 1989), and although headache is often prominent, it is not invariable. Tumors of the frontal lobe (Sachs 1950), corpus callosum (Alpers and Grant 1931; Ironside and Guttmacher 1929), thalamus (Smyth and Stern 1938), and hypothalamus (Alpers 1937; Liss 1958; Lobosky et al. 1984; Strauss and Globus 1931) may all cause a gradually progressive dementia without striking distinctive features: tumors in other locations may of course cause

Syndromes of cognitive impairment 193

dementia, but these are often accompanied by focal deficits, such as hemiplegia, which are also gradually progressive and strongly suggest a space-occupying lesion. Hypothalamic tumors may cause dementia (Lobosky et al. 1984), often marked by such symptoms and signs as hypersomnolence (Strauss and Globus 1931), massive weight gain (Liss 1958), or diabetes insipidus (Alpers 1937). ASSOCIATED WITH STROKES

Multi-infarct dementia is typically characterized by a dementia that progresses in a 'stepwise' fashion, each step corresponding to a fresh, large cortical or subcortical infarction. Critically, in between the 'steps', the patient experiences a clinical plateau without any between-step deterioration (Erkinjunti et al. 1988; Tomlinson et al 1970; Yoshitake et al. 1995). An examination of such patents typically reveals various focal findings, such as hemiplegia, aphasia, and apraxia, corresponding to the location of the prior infarctions. A dementia will occasionally result from one large or strategically placed infarction: clearly, subsuming these cases under the rubric of 'multi-infarct' constitutes something of a semantic trespass, but a term equivalent to 'single-infarct dementia' has simply not found its way into current usage. Examples of such 'single' infarctions include large cortical infarctions or strategically placed subcortical infarctions (Yoshitake et al. 1995). Lacunar dementia pursues a gradual downhill course that is, in about one-half of all cases, 'punctuated' by strokes (Ishii et al. 1986; Yoshitake et al. 1995). In those cases which are characterized by repeated strokes, the differentiation from multi-infarct dementia rests on demonstrating a peristent downhill course between strokes rather than a plateau. Another helpful distinguishing feature are 'frontal lobe' traits such as abulia, which are relatively common in lacunar dementia (Ishii et al. 1986; Wolfe et al. 1990). Eventually, however, the diagnosis will rest on MRI scanning, which reveals multiple lacunes. Binswanger's disease may also be characterized by a gradual downhill course punctuated by strokes (Caplan and Schoene 1978; Kinkel et al. 1985; Revesz et al. 1989) and is difficult, on a clinical basis, to distinguish from lacunar dementia. MRI scanning will, however, reveal the leukoencephalopathy typical of Binswanger's disease, thus making the diagnosis. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) presents in a fashion similar to that of Binswanger's disease. Distinguishing features include migrainous headaches and a family history consistent with an autosomal dominant inheritance (Dichgans etal. 1998; Jung et al. 1995; Malandrini et al. 1996). Cranial arteritis may rarely cause a dementia, of either the multi-infarct or lacunar type (Caselli 1990, Nightingale et al. 1982). Diagnostic clues include unilateral headache (generally temporal in location), polymyalgia rheumatica and amaurosis fugax. Cerebral amyloid angiopathy classically presents with a gradually progressive dementia punctuated by lobar intracerebral hemorrhages (Cosgrove et al. 1985; Gilles et al. 1984), demonstrable on computed tomography (CT) or MRI and suggested clinically by the prominent headache associated with the lobar hemorrhage. MELAS syndrome (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) is a rare maternally inherited disorder that, although generally presenting in the childhood years, may present in adulthood with stroke-like episodes, progressive dementia, migraine-like headaches, and hearing loss (Clark et al. 1996). WITH THE FRONTAL LOBE SYNDROME

The frontal lobe syndrome, as discussed further in Chapter 7, p. 294, is marked by varying degrees of abulia, affective changes (euphoria or irritability), disinhibition and perseveration, and its appearance may herald various dementing disorders.

194 Signs, symptoms and syndromes

Tumors of the frontal lobe may present with a dementia marked by a frontal lobe syndrome (Avery 1971; Frazier 1936; Williamson 1896), this being true not only of tumors confined to the frontal lobe, but also of those tumors of the corpus callosum which extend into the adjacent frontal lobes (Moersch 1925). Pick's disease classically presents with the frontal lobe syndrome (Bouton 1940; Ferraro and Jervis 1936), and it is indeed this presentation which helps to distinguish Pick's disease from other neurodegenerative dementias, such as Alzheimer's disease (Litvan et al. 1997d; Mendez et al. 1993). Frontotemporal dementia, like Pick's disease, typically presents with a frontal lobe syndrome. A distinguishing feature in some cases is the early appearance of an expressive aphasia (Heutink et al. 1997; Mann et al 1993; Neary et al 1993). Amyotrophic lateral sclerosis, once thought to spare the cortex outside the precentral gyrus, is now known to involve the frontal lobes. In a minority, the disease may present with a frontal lobe syndrome followed by a dementia and typical upper and lower motor neuron signs (Cavalleri and De Renzi 1994; Neary et al 1990; Peavy et al 1992). WITH PARKINSONISM

Parkinsons disease may cause dementia, but not until the prototypical motor symptoms of tremor, rigidity, and bradykinesia have become fully established. The prevalence of dementia in patients with Parkinson's disease increases with age (Biggins et al 1992; Marder et al 1995), and overall, in population-based studies, the prevalence of dementia ranges from 18% (Tison et al. 1995) to 41% (Mayeux et al 1992). Importantly, depression may also be caused by Parkinson's disease, and in some cases, the depression may be of such severity as to cause a dementia in its own right (Aarsland et al 1996). Diffuse Lewy body disease, although eventually causing a combination of parkinsonism and dementia in all cases, may present in a variety of ways (Byrne et al. 1989): with parkinsonism alone (Hely et al 1996), with a combination of parkinsonism and dementia, or with dementia alone. Importantly, the parkinsonism may be mild and indeed may be 'subclinical', manifesting only as a particular sensitivity to neuroleptics, prominent drug-induced parkinsonism occurring secondary to low doses (McKeith et al 1992). The dementia is often marked by the early appearance of confusion, visual hallucinations, and delusions, features that help distinguish it from the dementia seen in Parkinson's disease (Burkhardt et al 1988; Klatka et al 1996; McKeith et al 1994). Progressive supranuclear palsy typically presents with postural instability and unexplained falls; over time, parkinsonism develops, marked by rigidity, bradykinesia, and, notably, a dystonic axial extension, which may also be evident in the neck (Collins et al 1995; Daniel et al 1995; Litvan et al 1996a, b, c, 1997b). Most, but not all, patients eventually demonstrate the hallmark of this disease, namely supranuclear ophthalmoplegia for vertical gaze. Most patients eventually become demented, and many will also develop a pseudobulbar palsy with emotional incontinence (Menza et al 1995). Multiple system atrophy of the striatonigral degeneration type presents with parkinsonism that is typically accompanied by evidence of either autonomic failure or cerebellar involvement (Colosimo et al 1995; Litvan et al 1997a; Wenning et al 1994, 1995). The autonomic failure may include postural hypotension and dizziness, urinary incontinence or retention, fecal incontinence, and impotence; cerebellar signs include ataxia and intention tremor. A minority of these patient will eventually develop a dementia (Robbins et al 1992). Corticobasal ganglionic degeneration typically presents with a strikingly asymmetric rigidakinetic parkinsonism, generally in an arm, which may be accompanied by a dystonic rigidity.

Syndromes of cognitive impairment 195

Apraxia is a common accompaniment, and some patients may also develop myoclonus (Litvan et al. 1997c; Riley et al. 1990; Rinne et al. 1994). A minority may eventually become demented. Uncommonly, the disease may present with dementia (Grimes et al. 1999), and in such cases, parkinsonism may appear later (Schneider et al. 1997). Fahr's syndrome (Margolin et al 1980; Mathews 1957; Nyland and Skre 1977) may present with parkinsonism and dementia. Cerebellar signs such as dysarthria, intention tremor, and ataxia may also be present, but the distinctive finding is basal ganglia calcification, evident on CT or MRI scanning. Arteriosderotic parkinsonism is characterized by a gradually progressive rigidity, bradykinesia, and gait abnormality. In some cases, a dementia may appear (Bruetsch and Williams 1954; Keschner and Sloane 1931). Hallervorden-Spatz disease of the late-onset type may present with a slowly progressive parkinsonism that is eventually joined by dementia and dystonia (Jankovic et al. 1985). Huntingtons disease of juvenile onset, seen in late childhood or adolescence, may present with parkinsonism and dementia (Bird and Paulson 1971; Campbell et al. 1961; Siesling et al. 1997). Dementia pugilistica has a gradual onset anywhere from 5 to 40 years after repeated head trauma (e.g. as in boxing), with a combination of parkinsonism, ataxia, and dementia (Harvey and Davis 1974; Martland 1928). Valproic acid, with chronic use, as for epilepsy or bipolar disorder, may cause a combination of dementia and parkinsonism, which, importantly, is potentially reversible on discontinuation of the drug (Armon et al. 1996). Methanol intoxication may, as a sequela, leave patients with dementia, parkinsonism, and blindness (McLean et al. 1980). Carbon monoxide intoxication may, after a lucid interval of from days to weeks, be followed in a minority of cases by a fairly abrupt onset of dementia and parkinsonism (Choi 1983; Min 1986). Systemic lupus erythematosus very rarely presents with a combination of dementia and parkinsonism (Dennis et al. 1992). Hypoparathyroidism may cause parkinsonism and dementia, but this is usually in the context of Fahr's syndrome, which, as noted above, includes calcification of the basal ganglia. In one rare case, however, dementia and parkinsonism occurred with hypoparathyroidism in the absence of calcification and with a normal serum calcium level. The only clue to the diagnosis was cataracts; the parathyroid hormone level was low, and the patient recovered with dihydroxy-cholecalciferol (Stuerenburg et al. 1996). Manganese intoxication may cause a gradually progressive parkinsonism that may be joined by a dementia (Cook et al. 1974). WITH CHOREA

Huntingtons disease is the prototypical cause of a combination of chorea and dementia (Pflanz et al. 1991), a combination noted by George Huntington himself (Brody and Wilkins 1967). Neuroacanthocytosis may also present with chorea and dementia. A diagnostic clue, not, however, seen in all, is involuntary lip-biting or other self-injurious behavior (Critchley et al. 1968; Hardieetfl/. 1991). Dentatorubropallidoluysian atrophy may likewise present with chorea and dementia, diagnostic clues including elements of ataxia and dystonia (Becher et al. 1997; Warner et al. 1994, 1995). Acquired hepatocerebral degeneration, occurring after repeated bouts of hepatic encephalopathy, is seen most often in chronic alcoholics and may present with a dementia in

196 Signs, symptoms and syndromes

company with a complex movement disorder, often with choreiform elements (Finlayson and Superville 1981; Victor et al 1965). WITH DYSTONIA

Wilsons disease may present with dystonia, later to be joined by a dementia (Walshe and Yealland 1992). The fact that this disease is treatable mandates testing in any young person who presents with a compatible clinical picture. Hallervorden-Spatz disease of childhood onset typically presents with a progressive dystonia and dementia (Dooling et al. 1974, 1980). WITH ATAXIA

Creutzfeldt-Jakob disease may present with ataxia, followed within weeks or months by a dementia (Brown et al. 1986, 1994; de Villemeur et al. 1996). Gerstmann-Straussler-Scheinker disease, an inherited prion disease, typically presents with ataxia and dementia (Barbanti et al. 1996; Brown et al. 1991). Multiple system atrophy of the olivopontocerebellar type may present with ataxia (Wenning et al. 1994) and may also cause dementia (Robbins et al. 1992). The presence of evidence of autonomic failure (e.g. postural hypotension and dizziness, urinary incontinence or retention, fecal incontinence, or impotence) or mild parkinsonism is an important diagnostic clue. Autosonal dominant cerebellar ataxia presents with a progressive ataxia, which, in a minority, is eventually joined by dementia (Carter and Sukavajuna 1956; Chandler and Bebin 1956; Goldfarb et al. 1989; Modi et al. 2000; Sasaki et al. 1996; Zhou et al 1998). Dentatorubropallidoluysian atrophy may rarely present with a combination of ataxia and dementia (Potter et al 1995). Dementia pugilistica, as may be seen in boxers, follows repeated head trauma after a latent interval of from 5-40 years and may present with dementia and prominent ataxia, a sign that accounts for the colloquial name for this disorder: 'punch-drunk' (Harvey and Davis 1974; Martland 1928). Solvent abuse may, if chronic, cause a dementia accompanied by ataxia and other cerebellar signs such as intention tremor, nystagmus, and titubation (Escobar and Aruffo 1980; Fornazzari et al 1983; Holmes et al. 1986; Lazar et al 1983; Rosenberg et al 1988). Lithium intoxication, if severe, may leave patients permanently ataxic and demented (Schou 1984). Mercury, in large amounts, may cause dementia and ataxia: this has been noted with mercury salts (as found in a laxative [Davis et al 1974]), methyl mercury (as used in a fungicide for wheat [Rustam and Hamri 1974]) and ethyl mercury (as occurred with industrial exposure [Hay et al. 1963]). Tin intoxication, in one case, caused a coma from which the patient emerged with dementia and ataxia (Wu et al. 1990). Acquired hepatocerebral degeneration, generally occurring in chronic alcoholics after repeated bouts of hepatic encephalopathy, may present with a dementia and a complex movement disorder, with, in some cases, prominent ataxia (Raskin et al 1984; Victor et al. 1965). Metachromatic leukodystrophy typically causes a dementia that may be accompanied by ataxia in both juvenile (Haltia et al 1980) and adult onset cases (Hirose and Bass 1972; ReiderGrosswasser and Bornstein 1987). Progressive rubella panencephalitis, although usually occurring in the setting of the congenital rubella syndrome with mental retardation, may occasionally present in the late teenage years in patients of normal premorbid intelligence. One patient had cataracts and

Syndromes of cognitive impairment 197

microphthalmos due to congenital rubella (Townsend et al. 1976), whereas another had contracted rubella in childhood but had no sequelae at the time (Wolinsky et al. 1976); in both cases, the dementia was accompanied by ataxia. WITH MYOCLONUS

Creutzfeldt-Jakob disease is the classic example of a disease causing dementia with myoclonus: approximately 80% of patients eventually display this sign (Brown et al. 1986; 1994; Roos et al. 1973). New-variant Creutzfeldt-Jakob disease, contracted by eating beef from cows with 'mad cow' disease (bovine spongiform encephalopathy), like Creutzfeldt-Jakob disease also eventually causes myoclonus in most patients (Zeidler et al. 1997). Fatal familial insomnia is, as noted earlier, distinguished primarily by severe insomnia; over time, however, myoclonus may develop (Medori et al. 1992). AIDS dementia, once well established, may, in a minority, be accompanied by myoclonus (Naviaeta/. 1986b). Hashimoto's encephalopathy rarely presents with a dementia, which is, over time, joined by myoclonus (Forchetti et al. 1997). Diffuse Lewy body disease is, as noted earlier, distinguished by parkinsonism; in a minority of these patients, myoclonus may supervene (Louis et al. 1997). Corticobasal ganglionic degeneration is generally distinguished by an asymmetric onset parkinsonism accompanied by dystonia and apraxia. Myoclonus may also be present (Litvan etal. 1997e). Dentatorubropallidoluysian atrophy of childhood onset is typified by dementia and myoclonus. This is in contrast to adult onset cases, which are, as noted earlier, distinguished by either chorea or ataxia (Becher et al. 1997). Multiple system atrophy of the olivopontocerebellar type is, as noted earlier, typified by ataxia. A majority of these patients will, however, also have reflex myoclonus (Rodriguez et al. 1994). Dialysis dementia, as noted earlier, is immediately suggested by the appearance of dementia after several years of hemodialysis. Myoclonus is common and helps to solidify the diagnosis (Burks etal. 1976; Lederman and Henry 1978). Alzheimer's disease, during its end stages, may cause myoclonus (Benesch et al. 1993; Chen et al. 1991): importantly, this sign is not seen early in the disease. Whipple's disease may cause a dementia, and although a history of abdominal complaints (especially diarrhea) and arthopathy is generally most helpful diagnostically, about onequarter of these patients will also have myoclonus (Louis et al. 1996). Subacute sclerosing panencephalitis, typically with an onset in childhood or adolescence, presents with dementia that is eventually joined by myoclonus (Dawson 1934). Juvenile Huntingtons disease is, as noted previously, distinguished by parkinsonism and dementia. In a minority of cases, myoclonus may also appear (Siesling et al. 1997). Idiopathic hemochromatosis may, very rarely, present with dementia and myoclonus (Jones and Hedley-Whyte 1983). Other, suggestive clinical features include hepatic failure, diabetes mellitus, and cardiomyopathy. Thalamic degeneration is a rare syndrome that may present with dementia and myoclonus (Little etal. 1986). WITH OTHER SPECIFIC FEATURES

Cerebrotendinous xanthomatosis, when fully developed, manifests with dementia, tendon enlargement, cataracts, and ataxia. Tendon enlargement is the most distinctive feature, and although it may appear in a variety of areas, it is most commonly, and classically, found in the

198 Signs, symptoms and syndromes

Achilles tendon. The disease evolves very slowly and may present with any one of these features anywhere from childhood or adolescence to the adult years (Berginer et al. 1988; Farpour and Mahloudji 1975; Watts et al. 1996). Myotonic dystrophy typically presents with myotonia in late adolescence or early adult years. Over time, a 'myopathic fades', with frontal baldness, ptosis, and temporal wasting appears, as does weakness and atrophy, most prominent distally. In a small minority, a dementia may also occur (Huber et al. 1989; Perini et al. 1989). Fatal familial insomnia, is as the name suggests, marked by a progressive and intractable insomnia: patients also typically develop both 'oneiroid' states, wherein they appear to act out dreams, and various autonomic disturbances (Gallassi et al. 1996; Manetto et al. 1992). Thallium intoxication may be followed by dementia with a painful polyneuropathy and prominent alopecia (Thompson et al. 1988; Reed et al. 1963). Arsenic intoxication with organic arsenicals may cause a picture similar to that of thallium intoxication but with less prominent hair loss. Pellagra of the chronic, gradual onset type classically presents with the '3 D's': diarrhea, dermatitis, and dementia (Langworthy 1931; Pierce 1924). Behcet's syndrome causes dementia in only a small minority of patients, virtually all of whom have both oral aphthous ulcers and genital ulcers (Serdaroglu et al. 1989). The dementia may follow upon numerous prior attacks (Rubinstein and Urich 1963) or may be slowly progressive (Borson 1982). Sjorgens syndrome is an autoimmune disorder that typically involves the exocrine glands, producing the 'sicca syndrome' with dry eyes and a dry mouth. Rarely, a dementia (Kawashima et al. 1993) may occur, probably secondary to a cerebral vasculitis (Caselli et al. 1991). Polymyalgia rheumatica, distinguished by severe pain and stiffness of the proximal muscle groups, is rarely associated with a dementia, both the dementia and the polymyalgia responding to treatment with steroids (Nightingale et al. 1982). Sneddons syndrome is a rare disorder characterized in adults by livedo reticularis, strokes, transient ischemic attacks, and, in some, dementia (Tourbah et al. 1997). WITH SPECIFIC PRECIPITANTS

Subdural hematoma of the chronic type may cause a dementia (Arieff and Wetzel 1964; Black 1984), but there may be an interval lasting anywhere from months to years between the initial trauma and the onset of the dementia. In some cases, the trauma itself may have been forgotten. Diffuse axonal injury, occurring secondary to violent acceleration-deceleration or a 'closed head' injury, may, depending on its severity, leave patients in a coma, a persistent vegetative state, or a dementia of varying severity (Strich 1956). Dementia pugilistica (Harvey and Davis 1974; Martland 1928) is one of the sequelae of repeated head trauma, as may occur in boxers, which appears after a latent interval of anywhere from 5 to 40 years. As noted above, it is often accompanied by a combination of parkinsonism and ataxia. Postanoxic encephalopathy (Richardson et al. 1959) becomes evident shortly after patients awaken from an anoxic coma, as may occur after strangulation or drowning. Delayed postanoxic leukoencephalopathy presents with a delirium generally within weeks of recovery from an anoxic insult. Although most patients eventually recover, some, after the confusion clears, are left with a dementia (Plum et al. 1962). Radiation encephalopathy of the late-delayed type may present with a gradually progressive dementia anytime from months to decades after brain irradiation. Interestingly, this sequela

Syndromes of cognitive impairment 199

may occur after either whole-brain (DeAngelis et al. 1989; Duffy et al. 1996) or focal irradiation, provided, in the case of focal irradiation, that critical structures such as the temporal lobes have been exposed (Crompton and Layton 1961; Shewmon and Masdeu 1980). Dialysis dementia may appear gradually after approximately 3 years of hemodialysis, often presenting with a stuttering type of aphasia (Garrett et al. 1988; O'Hare et al. 1983). Hypoglycemia, if severe (e.g. a glucose level of less than 1.11-1.37 mmol/L [20-25 mg/dL]) and prolonged, may cause neuronal death, leaving the patient demented (Kalimo and Olsson 1980). Post-encephalitic dementia has been noted after both herpes simplex encephalitis (McGrath et al. 1997) and arbovirus encephalitis (Przelomski et al. 1988; Richter and Shimojyo 1961). Prednisone, in doses of 60 mg or more, has been reported to cause a dementia that cleared on discontinuation of the drug (Varney et al. 1984). Biperidin, an anticholinergic anti-parkinsonian agent, was reported to cause a dementia in an elderly patient being treated for Parkinson's disease, with recovery after the biperidin was discontinued (Kurlan and Como 1988). Valproic acid may, with chronic use, cause a dementia, which, as noted earlier, may be accompanied by parkinsonism (Armon et al. 1996) or may occur without any distinguishing features (Guerrini et al. 1998; Papazian et al. 1995). Disulfiram, taken over decades at a therapeutic dosage, in one case caused a dementia and polyneuropathy (Borrett et al. 1985). Lithium intoxication, if severe, may leave patients with a dementia, which, as noted above, may be accompanied by ataxia (Schou 1984). Methanol intoxication, when severe, may leave patients demented with, as previously noted, parkinsonism (McLean et al. 1980). Alcoholic dementia appears in the setting of chronic, severe and ongoing alcoholism, and is distinguished by apathy and an overall coarsening of the personality (Lee et al. 1979; Lishman 1981). Solvent-induced dementia makes a gradual appearance in the setting of chronic, ongoing solvent use, and, as noted earlier, is often accompanied by ataxia and other cerebellar signs (Escobar and Aruffo 1980; Fornazzari et al. 1983; Holmes et al. 1986; Lazar et al. 1983; Rosenberg et al. 1988). Heroin vapor, produced by heating heroin on aluminum foil, may cause dementia accompanied by a varying degree of bradykinesia and ataxia (Kriegstein et al. 1999) IN THE SETTING OF MENTAL RETARDATION

Downs syndrome, in those who survive past the age of 40, is eventually complicated by the development of Alzheimer's disease in over one-half of all patients (Lai and Williams 1989). In those with pre-existing mild mental retardation, the dementia presents with a typical loss of cognitive function; in those with a moderate or more severe degree of retardation, a loss of cognitive ability may be difficult to appreciate, and the dementia may instead come to attention because of apathy and decreased social interaction. Sturge-Weber syndrome is characterized by a unilateral facial port-wine stain, seizures, hemiplegia, and mental retardation. In those with frequent seizures, a dementia may supervene, with a drop in cognitive ability below the baseline that characterized the preexisting mental retardation (Lichtenstein 1954; Petermann et al. 1958). Congenital rubella syndrome is characterized by cataracts, deafness, and mental retardation; in a minority, a dementia may appear in childhood or adolescence secondary to progressive rubella panencephalitis (Townsend et al. 1975; Weil et al. 1975).

200 Signs, symptoms and syndromes

IN THE SETTING OF AIDS OR OTHER IMMUNOCOMPROMISED STATES

AIDS dementia, initially characterized by forgetfulness, poor concentration, and slowness of thought, may, although typically occurring in the setting of other features of AIDS (e.g. Pneumocystis carinii pneumonia, thrush, and Kaposi's sarcoma), in a small minority constitute the presenting symptom of the disease (Navia and Price 1987; Navia et al. 1986b). Progressive multifocal leukoencephalopathy typically presents with a focal sign such as hemiplegia or aphasia, which is eventually joined by a gradually progressive dementia (Krupp et al. 1985; Richardson 1961); rarely, the presentation may be with dementia alone (Sellal et al. 1996; Zunt et al 1997). PRESENTATION WITH APHASIA

A number of different dementing diseases may present with an isolated aphasia in a syndrome known as 'primary progressive aphasia'. In such cases, the aphasia progressively worsens and is eventually joined by a dementia. Motor aphasia may constitute the presentation of Alzheimer's disease (Green et al 1990; Greene et al 1996; Karbe et al 1993), Pick's disease (Kertesz et al 1994), and frontotemporal dementia (Neary et al. 1993; Snowden et al 1992; Turner et al 1996). Other, much less common, causes of primary progressive aphasia include corticobasal ganglionic degeneration (Ikeda et al 1996) and Creutzfeldt-Jakob disease (Mandell et al. 1989). It must be borne in mind that a similar picture may occur with slowly growing, appropriately situated tumors. MISCELLANEOUS

Systemic lupus erythematosus may cause a dementia (Johnson and Richardson 1968; Kirk et al 1991) via a number of different mechanisms (Devinsky et al 1988b). In most cases, the dementia is accompanied by such systemic symptoms as arthralgia, rash, pleural effusion, and constitutional symptoms such as fever, fatigue, and weight loss. Anti-phospholipid antibody syndrome is characterized by recurrent arterial and venous thrombosis and, in women, by a history of recurrent miscarriage. Strokes may occur, producing a multi-infarct dementia (Coull et al 1987). In some cases, however, the dementia may occur without specific MRI findings, suggesting a direct antineuronal effect (Van Horn etal 1996). Polyarteritis nodosa may cause a dementia (MacKay et al 1950), but, as with lupus, this is usually in the setting of systemic symptoms such as renal or gastrointestinal disease or constitutional symptoms. Sarcoidosis may cause dementia (Camp and Frierson 1962; Sanson et al. 1996) but only in a very small minority - fewer than 1% - of patients (Oksanen 1986); in such cases, granulomata have been found in the cerebrum (Cordingly et al 1981; Miller et al 1988). A clue to the diagnosis is a chest X-ray finding of either bilateral hilar lymphadenopathy or bilateral reticulonodular infiltrates. Metachromatic leukodystrophy may, in addition to ataxia (as noted above), also cause dementia associated with seizures, spasticity, or chorea (Alves et al 1986; Haltia et al 1980; Wulff and Trojaborg 1985); polyneuropathy may also be obvious (Bosch and Hart 1978). Personality change is also prominent, especially in adults, with aggressiveness and irritability (Hageman et al. 1995) and 'frontal lobe' symptoms such as disinhibition, poor judgment, and socially inappropriate behavior (Shapiro et al 1994). Adrenoleukodystrophy may present in childhood, adolescence or adulthood. Childhood or adolescent onset often occurs with a personality change and dementia accompanied by hemianopia or cortical blindness and spasticity of the lower extremities (Moser et al 1984;

Syndromes of cognitive impairment 201

Schaumburg et al. 1975). Adult onset adrenoleukodystrophy may likewise be accompanied by visual symptoms such as blindness (Powers et al. 1980) or Balint's syndrome (Uyama et al. 1993), but in some cases visual symptoms are lacking: in one patient, the clue to the correct diagnosis was generalized hyperreflexia (Coria et al. 1993), whereas in another it was bronzing of the skin (Weller et al. 1992). Hallervorden-Spatz disease., although, as noted above, typically presenting with dystonia, may occasionally present in the adult years with a dementia accompanied by various different abnormal movements, such as parkinsonism (Murphy et al. 1989), fine tremor (Dooling et al. 1974), or dysarthria and clumsiness (Rozdilsky et al. 1968). Fahr s syndrome, although typically presenting with dementia and parkinsonism may rarely, as noted above, present with a combination of dementia and basal ganglia calcification on imaging (Slyter 1979). Hypoparathyroidism, without basal ganglia calcification, may present with a dementia accompanied by seizures and cataracts (Mateo and Gimenez-Roldan 1982). Whipple's disease is, very rarely, confined to the central nervous system; in such cases, there may be no gastrointestinal symptomatology or arthropathy. One case was marked by hypothalamic involvement with hypersomnia (Adams et al. 1987), and another by seizures (Romanul et al. 1977). Lead intoxication may initially cause a delirium, and upon recovery, patients may be left demented (Jenkins and Mellins 1957). Thalamic degeneration, a rare syndrome, may present with dementia alone (Moosy et al. 1987) or dementia accompanied by somnolence (Stern 1939). Sleep apnea, in one extraordinary case, presented with a dementia: the only clue to the diagnosis was the presence of daytime sleepiness and a history of prominent snoring (Scheltens et al. 1991). Bilateral carotid occlusion, the brain being perfused primarily by only one vertebral artery, has been shown to cause a dementia that was reversed by intracranial-extracranial bypass surgery (Tatemichi et al. 1995). Very rare causes include hypereosinophilia (92% eosinophils) (Kaplan et al. 1990), extreme hypertriglyceridemia (with values of at least 10 times normal) (Heilman and Fisher 1974; Mas et al. 1985), and hyperviscosity, as occurred in one case secondary to multiple myeloma (Mueller et al. 1983).

Treatment of the syndrome Patients' liberty should be circumscribed proportionate to their reduced abilities; thus, financial affairs should usually be managed by others, and guardianship may be required. Driving privileges are often retained by patients with great tenacity, but these too must eventually be withdrawn. If patients move, for example to a retirement community or a nursing home, every effort should be made to preserve old routines and make the new surroundings feel as familiar as possible. The need for prosthetic devices (e.g. glasses, hearing aids, dentures, and 'quad canes') should be assessed, and medical regimens should be kept as simple as possible. Although many patients eventually require a wheelchair, ambulation should be encouraged and maintained for as long as possible. Delusions, hallucinations, or agitation may be treated with neuroleptics, but these agents must be used cautiously and, at least initially, in a low dose. They are not useful for apathy, withdrawal, or cognitive deficits (Hamilton and Bennett 1962; Rada and Kellner 1976). Chlorpromazine is helpful but carries the risk of sedation and falls (Seager 1955). Haloperidol is also helpful but exposes patients to the risk of extrapyramidal side-effects

202 Signs, symptoms and syndromes

(Devanand et al. 1998; Sugerman et al. 1964) and may, in some cases, although helpful with regard to overall behavior, cause some further decrement in intellectual ability (Devanand et al. 1989). The atypical neuroleptic risperidone, in very low doses (e.g. approximately 1 mg) is effective and generally has no more side-effects than does a placebo (De Deyn et al. 1999; Katzef al 1999). Carbamazepine, in a low dose of 300 mg or less, is also helpful for aggressiveness and agitation (Tariot et al. 1998).

DELIRIUM Delirium is one of the most common neuropsychiatric disorders seen in general hospital practice and is especially common among the hospitalized elderly (Francis 1992). Prompt diagnosis is critical as, in many cases, the underlying cause of the syndrome, untreated, carries a grave prognosis (Cameron et al. 1987; Pompeii et al. 1994; Rabins and Folstein 1982). Description of the syndrome

Delirium, as reviewed by Lipowski (1983, 1987, 1989), is characterized by confusion, disorientation, memory loss, and often other symptoms such as hallucinations and delusions. The syndrome is typically of acute or subacute onset, most patients developing the full syndrome within a day or two (Levkoff et al. 1992). Confusion, or, as it is also known, 'clouding of the sensorium', is present in all cases. Patients may appear dazed, their attention wanders, and they often seem to drift off. In most cases, a varying degree of incoherence will also be seen (Johnson et al. 1992; Sirois 1988). Disorientation, found in almost all cases (Morse and Litin 1971) is generally for time but may also be for place. Memory loss is typically of the short-term or anterograde type: patients are unable to remember all of three words after 5 minutes and consequently have grave difficulty in keeping track of what happens around them. Retrograde amnesia may also be present but is generally less prominent: patients may have trouble recalling clearly what happened in the days or weeks prior to the onset of the delirium. Hallucinations are seen in about one-half of all cases (Morse and Litin 1971) and may be either visual or, less commonly, auditory (Cutting 1987; Sirois 1988). Patients may see family members in the hospital room, and bugs or small animals may hide in the sheets. Auditory hallucinations range from such simple phenomena as bells or sirens to hearing voices. Delusions are generally fragmentary and unsystematized. One typically finds evidence of delusions of persecution (Morse and Litin 1971; Sirois 1988), and patients may report that family members are trying to get rid of them or that the medicine given by the nurse is actually poison. The overall behavior of patients with delirium may be characterized by either agitation or quietude. Although, in a minority of cases, patients are either consistently hyperactive or hypoactive, one sees in most a mix, patients now agitated, now quiet (Johnson et al. 1992; Liptzin and Levkoff 1992). In some cases, one may see an 'occupational delirium' wherein patients act as if they were at work (Wolff and Curran 1935): one patient, a former truck driver, was found with his hands held out in front of him as if gripping a steering wheel, busily 'driving' his bed around the ward. Sleep reversal is common (Johnson et al. 1992), and many patients display what is known as 'sundowning', wherein their confusion markedly worsens with the coming of darkness.

Syndromes of cognitive impairment 203

Differential diagnosis of the syndrome Dementia is distinguished from delirium by an absence of confusion. In some cases, however, the same disease process may be capable of causing both delirium and dementia. In Alzheimer's disease, for example, after many years of a slowly progressive dementia, a delirium with confusion and incoherence may eventually supervene. Furthermore, the presence of preexisting brain damage renders patients more susceptible to delirium (Layne and Yudofsky 1971; Koponen and Riekkinen 1993; Koponen et al. 1989; O'Keefe and Lavan 1997). Thus, whereas a normal individual might be able to tolerate a modest hyponatremia without becoming confused, a patient with reduced cerebral 'reserves', for example secondary to multiple cerebral infarctions, might promptly become delirious. Amnestic disorders are also distinguished from delirium by an absence of confusion. Here also, however, one may find disease processes capable of causing both syndromes. With severe thiamine deficiency, for example, one may first see a Wernicke's encephalopathy with confusion, and, in a minority of cases, ataxia and nystagmus: over time, if the patient survives, the confusion clears and the patient is left with a Korsakoff's syndrome, with both anterograde and retrograde amnesia. Once the syndromal diagnosis of delirium is secure, it is imperative to determine its cause. All of the etiologies listed in Table 5.2 share one thing in common: either directly or indirectly, they cause a global disturbance of cerebral function. An example of a directly acting cause of such global dysfunction is hypoglycemia, wherein the function of each and every neuron is compromised by a lack of the nutrient. An example of an 'indirectly' acting cause is a thalamic infarction: here, by virtue of the extensive and widespread thalamocortical connections, localized thalamic damage leads to widespread and global cerebral dysfunction. Although well over one-hundred causes are listed in Table 5.2, the differential diagnosis of delirium is not as daunting as it may at first glance appear, provided that one adopts a systematic approach. First, determine whether medications might be at fault, looking closely to see whether a medicine was either started shortly before the onset of the delirium or underwent a substantial dose increase. Next, enquire as to whether intoxicants might be involved, keeping in mind that many drug users will deny their use. Alcohol and drug withdrawal, especially alcohol withdrawal delirium (delerium tremens, or the DTs), must also be high on the list. Metabolic causes are, as a group, the most comon cause of delirium seen in general hospital practice: indeed, these are so common that when the cause of a delirium is not immediately apparent, it is justifiable to screen for these, as described below. Specific precipitants should always be sought, but it must be borne in mind that one will, in most cases, have to question collateral sources for the history as patients may not be able to recall the precipitant: head trauma in the elderly, with a resultant subdural hematoma, is a good example of this. Infarction is suggested by a very acute onset, often with associated lateralizing signs, such as hemiplegia or hemianopia. Encephalitis is suggested by the presence of headache, lethargy, and fever: herpes simplex encephalitis should be high on the list in such cases, given that it is treatable. Delirium may also occur with specific associated features, such as malignant hypertension or a temperature elevation over 41°C (106°F) for any reason. Delirium occurring with malnourisment, as may be seen in chronic alcoholism, should always suggest a vitamin deficiency disease such as Wernicke's encephalopathy. Delirium occurring during immunosuppression, as for example in patients with AIDS or cancer, or those undergoing therapeutic immunosuppression, is often caused by an opportunistic infection, as in the case of the JC virus causing progressive multifocal leukoencephalopathy. A paroxysmal onset, over seconds, should always suggest a complex partial or petit mal seizure. Finally, there is a large group of miscellaneous, but very important causes, such as diffuse Lewy body disease and cerebral tumors.

Table 5.2 Causes of delirium Medications

Neuroleptic malignant syndrome Typical neuroleptics Risperidone Clozapine Discontinuation of levodopa Discontinuation of amantadine Serotonin syndrome Combination of serotoninergic agents (e.g. a selective serotonin reuptake inhibitor with a monoamine oxidase inhibitor) Anticholinergic delirium Anti-parkinsonian anticholinergics (e.g. benztropine and trihexyphenidyl) Cyclobenzaprine Amitriptyline Imipramine Scopolamine Antidepressantsand mood stabilizers Bupropion Lithium intoxication Valproicacid Dopaminergic agents Levodopa Bromocriptine Lergotrile Cardiovascular agents Digoxin Quinidine Lidocaine Antimicrobials Ciprofloxacin Oflaxacin Clarithromycin Ganciclovir Vidarabine Acyclovir Metronidazole Ketoconazole Amphotericin-B Podophyllin Opioid analgesics Meperidine Fentanyl Miscellaneous agents Propranalol Verapamil Interleukin Paclitaxel Aspirin (in overdose) Gold Metrizamide Disulfiram Bismuth Bromide

Table 5.2 Causes of delirium - continued Intoxicants

Cannabis Phencyclidine Methyl alcohol Solvents Stimulants (amphetamines and cocaine) Nutmeg

Withdrawals

Alcohol Benzodiazepines Barbiturates

Metabolic causes

Hypoglycemia Hyperglycemia Hyponatremia Hypernatremia Hypocalcemia Hypercalcemia Hypomagnesemia Hypermagnesemia Hypokalemia Hepatic encephalopathy Uremic encephalopathy

With specific precipitants

Subdural hematoma 'Postoperative' delirium Severe burns Central pontine myelinolysis (subsequent to a rapid correction of hyponatremia) Delayed postanoxic leukoencephalopathy

Infarction

Cortical Thalamic

Encephalitis

Herpes simplex encephalitis Arbovirus encephalitis HIV Mononucleosis Mumps Varicella-zoster Encephalitis lethargica Rabies Post-infectious or post-vaccinia I encephalitis Rocky Mountain spotted fever Malaria

With specific associated features

Hypertensive encephalopathy (diastolic pressure over 130 mmHg) Febrile delirium (a temperature of 41°C [106°F] or more) Hashimoto's encephalopathy (myoclonus) Sydenham's chorea (chorea) Chorea gravidarum (chorea) Pulmonary insufficiency (dyspnea) Porphyria (abdominal pain) Pancreatitis (abdominal pain) Heavy metal intoxication (abdominal pain and convulsions) Adrenocortical insufficiency (abdominal pain and lethargy) Thyroid 'storm' (tremor and exophthalmos)

Table 5.2 Causes of delirium - continued Cushing's syndrome (Cushingoid habitus) Behcet's syndrome (oral and genital aphthous ulcers) Wegener's granulomatosis (upper and lower respiratory involvement) Rheumatoid arthritis (chronic arthritis) Migraine (headache) Occurring with malnourishment (e.g. in alcoholism)

Wernicke's encephalopathy Pellagra Marchiafava-Bignami disease

Occurring during immunosuppression (e.g. AIDS, cancer)

Progressive multifocal leukoencephalopathy Toxoplasmosis Mycoses Cytomegalovirus encephalitis Subacute measles encephalitis

Paroxysmal onset

Complex partial seizures Petit mal seizures

Miscellaneous

Diffuse Lewy body disease Tumors and abscesses Limbic encephalitis Granulomatous angiitis Thrombotic thrombocytopenic purpura Sepsis Systemic lupus erythematosus Polyarteritisnodosa Sarcoidosis Tuberculosis Lyme disease

This appoach, albeit useful, may not always yield a diagnosis. In such cases, other diagnostic approaches must be called into play. One might, for example, look carefully for such highly diagnostic signs as myoclonus or asterixis, described in Chapter 3. If, after a thorough history and physical examination, the differential cannot be substantially narrowed down, then it is appropriate to consider a laboratory screen, consisting of the following: complete blood count, glucose, sodium, calcium, magnesium, potassium, ammonia, liver enzymes, blood urea nitrogen, and creatinine levels, a drug screen, and imaging with either CT or, preferably, MRI. Lumbar puncture is reserved for cases of suspected encephalitis. In the diagnostic evaluation, one must keep in mind that, in a significant minority of cases, the delirium is multfactorial (Francis et al. 1990). In an alcoholic with delirium, for example, one must consider not only delirium tremens, but also hypoglycemia, hypomagnesemia, hepatic encephalopathy, head trauma, Wernicke's encephalopathy, and 'encephalopathic' pellagra. MEDICATIONS Medications are a common cause of delirium (Inouye 1994) and should always be suspected in the evaluation of any patient with delirum, looking carefully for any temporal relationship between the onset of the delirium and the initiation of or a significant dose increase in any medication. Table 5.2 lists medications that have been clearly implicated in delirium; special

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attention should be paid to the neuroleptic malignant syndrome, the serotonin syndrome, and anticholinergic delirium as these are important and potentially fatal medication-induced syndromes. The neuroleptic malignant syndrome occurs secondary to any pharmacologic manipulation that leads to an abrupt diminution in dopaminergic tone. Most commonly, such a diminution occurs secondary to the use of a dopamine blocker, such as one of the typical neuroleptics (Keck et al. 1987; Pope et al. 1986; Rosebush and Stewart 1989). Atypical neuroleptics, such as risperidone (Meterissian 1996) and dozapine (Miller et al. 1991; Sachdev et al. 1995), may also be at fault. The neuroleptic malignant syndrome will occasionally be seen secondary not to dopamine blockade, but to an abrupt discontinuation of a dopaminergic agent. Thus, the neuroleptic malignant syndrome has been seen after an abrupt discontinuation of long-term treatment with levodopa (Sechi et al. 1984; Toru et al. 1981) or with amantadine (Cunningham et al. 1991; Harsch 1987). Clinically, within a day or two of the abrupt diminution of dopaminergic tone, patients develop varying combinations of delirium, fever, rigidity, and autonomic instability (Pope et al. 1986; Rosebush and Stewart 1989; Velamoor et al. 1994) The serotonin syndrome occurs secondary to pharmacologically enhanced serotoninergic tone, which in turn generally requires the administration of a combination of serotoninergic agents. Of the various combinations of medications reported to cause this syndrome (as described by Bodner et al. [1995] and listed in Table 5.3), the most common is the combination of a selective serotonin reuptake inhibitor and a monoamine oxidase inhibitor. Clinically, the serotonin syndrome presents with a combination of delirium, myoclonus, dysarthria or ataxia, and hyperreflexia (Feighner et al. 1990; Sternbach 1991). Anticholinergic delirium may occur secondary to any medication with substantial anticholinergic properties, including anti-parkinsonian anticholinergics (De Smet et al. 1982) such as benztropine or trihexyphenidyl, antispasmodics such as cyclobenzaprine (Engel and Chapron 1993), tricyclic antidepressants such as amitriptyline (Preskorn and Simpson 1982) and imipramine (Goodwin 1983), and transdermal scopolamine (Minagar et al. 1999; Ziskind 1988), as used for vertigo. Clinically, one sees a delirium with such classic 'anticholinergic' signs as dry flushed skin, a dry mouth, tachycardia, and pupillary dilatation. Antidepressants and mood stabilizers of various kinds can cause delirium, and in addition to the anticholinergic delirium occurring with tricyclic antidepressants, as noted above, this Table 5.3 Causes of the serotonin syndrome

Tryptophan Selective serotonin reuptake inhibitor Clomipramine Tricyclic antidepressant Venlafaxine Carbamazepine Pentazocine Meperidine Dextromethorphan Trazodone

X X X X X

X X X X X

X X X

X

208 Signs, symptoms and syndromes

has been seen with bupropion (Ames et al. 1992), during lithium intoxication (DePaulo et al. 1982; Simard et al. 1989), and after long-term treatment with valproic acid; in this case, the delirium occurred concurrent with a rise in the serum ammonia level and was effectively treated with carnitine (Beversdorf et al. 1996). Dopaminergic agents, as used in the treatment of Parkinson's disease, may cause delirium, as seen with both levodopa (Friedman and Sienkiewicz 1991) and with the direct-acting dopaminergic agents bromocriptine and lergotrile (Serby et al. 1978). Cardiovascular agents capable of causing delirium include digoxin (Shear and Sacks 1978) and the anti-arhythmics quinidine (Qunitanilla 1957) and lidocaine (Saravay et al. 1987). In the case of digoxin, delirium has been noted with not only an excessive (Wamboldt et al. 1986), but also a therapeutic (Eisendrath and Sweeney 1987) serum level. Antimicrobials capable of causing delirium include antibiotics such as ciprofloxacin (Altes et al. 1989), oflaxacin (Fennig and Mauas 1992), and clarithromycin (Mermelstein 1997), antivirals such as ganciclovir (Davis et al. 1990), vidarabine (Cullis and Gushing 1984), and, in those with renal failure, acyclovir (Tomson et al. 1985), and antifungal agents such as metronidazole (Kusumi et al. 1980), ketoconazole (Fisch and Lahad 1989), and amphotericin-B, when given intrathecally (Haber and Joseph 1962). Podophyllin, applied topically for the treatment of genital warts, may also, if not throughly washed off, cause delirium (Filley et al. 1981; Stoudemire et al. 1981). Opioid analgesics noted to cause delirium include meperidine (Eisendrath et al. 1987; Morisy and Platt 1986) andfentanyl, given either parenterally (Crawford and Baskoff 1980) or via a transdermal patch (Steinberg et al. 1992). Miscellaneous agents capable of causing delirium include propranalol (Topliss and Bond 1977), verapamil (Jacobsen et al. 1987), interleukin-2 (Illowsky et al. 1996), paclitaxel (Perry and Warner 1996), aspirin (in overdose [Steele and Morton 1986]), gold injections, as for rheumatoid arthritis (McCauley et al. 1977), metrizamide contrast, as used in myelography (Elliot et al. 1984) and three others, disulfiram, bismuth, and bromide, each discussed below. Disulfiram may cause delirium not only if taken in overdose (Kirubakaran et al. 1983; Laplane et al. 1992), but also if taken at a therapeutic dose. Importantly, with therapeutic doses, delirium may not appear for from weeks until a year or so later, and it may be accompanied by cerebellar signs (Hotson and Langston 1976; Knee and Razani 1974). Bismuth subsalicylate, taken for gastrointestinal symptomatology, has been noted in case reports (Gordon etal. 1995; Jungreis and Shaumberg 1993; Molina etal. 1989) and a large case series (Supino-Viterbo et al. 1977) to cause a delirium marked by myoclonus and tremor. Bromide preparations, now rarely if ever used, may cause delirium (Palatucci 1978), which is characteristically accompanied by pupillary dilatation, dysarthria, and tremulousness (Curran 1938). INTOXICANTS

Each of the following intoxications, with the exception of nutmeg, is a not uncommon cause of delirium seen in the emergency setting. Nutmeg intoxication, in the United States at least, is rare except in prison settings. Cannabis intoxication may, when high doses are used, be marked by the development of a delirium with confusion, disorientation, delusions of persecution, and both auditory and visual hallucinations (Chopra and Smith 1974; Palsson et al. 1982). The presence of conjunctival injection and mild ataxia is a clue to the diagnosis. Phencyclidine intoxication, suggested by nystagmus, dysarthria, and ataxia, may, when severe, also cause a delirium (Pearlson 1981), which is typically accompanied by delusions (Allen and Young 1978).

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Methyl alcohol intoxication, usually seen only in desperate alcoholics who take to denatured spirits such as 'wood alcohol' or 'canned heat', may, when severe, cause a delirium that is typically accompanied by vomiting, abdominal pain, and, in some, visual dimming (Bennett et al. 1953; Erlanson et al. 1965; Wood and Buller 1904). Solvent intoxication, when severe, may be accompanied by a degree of confusion and is suggested by dysarthria, diplopia, nystagmus, and ataxia (Evans and Raistrick 1987). Stimulant intoxication with either amphetamines or cocaine may, when severe, be accompanied by delirium; the presence of agitation, hypertension, and mydriasis suggesting the diagnosis (Fischman et al. 1976; Hollister and Gillespie 1970). Nutmeg may occasionally be taken for intoxication. The active agent is myristicine, and some patients may become delirious with a dry mouth, dizziness, and nausea (Faguet and Rowland 1978). WITHDRAWALS

Alcohol withdrawal delirium, or delirium tremens (Isbell et al. 1955; Lundquist 1961; Nielsen 1965; Rosenbaum et al. 1941), is characterized by a combination of delirium and autonomic signs. The delirium is often accompanied by visual hallucinations, which may be quite vivid. Among the autonomic signs, a rapid tremor, which may at times be quite coarse, is most prominent. Seizures may occur, either before or during the delirium (Rosenbaum et al. 1941) Benzodiazepine withdrawal may present a picture almost identical to that of delirium tremens, as has been noted with alprazolam (Levy 1984; Zipursky et al. 1985) and triazolam (Heritch et al. 1987). Barbiturate withdrawal, likewise, may be characterized by a picture similar to that of delirium tremens (Fraser et al. 1958; Isbell et al. 1950). METABOLIC CAUSES

Hypoglycemia, as may occur with insulinomas or in patients on oral antidiabetic agents or insulin who skip meals (Hart and Frier 1998), may present with delirium that may or may not be accompanied by autonomic symptoms such as tremor or diaphoresis (Case records 1988a; Malouf and Brust 1985; Moersch and Kernohan 1938). In one case, the delirium was accompanied by hemiplegia, both the delirium and the hemiplegia responding to glucose (Shintani et al 1993). Hyperglycemia, as may occur in diabetic ketoacidosis or in the hyperglycemic, hyperosmolar, non-ketotic syndrome, is accompanied by hyperosmolality and may cause delirium and coma. Hyponatremia may cause a delirium that is typically accompanied by nausea or vomiting; seizures may also occur (Karp and Laureno 1993; Swanson and Iseri 1958; Welti 1956). Hypernatremia, as may occur during dehydration, may also cause delirium (Jana and Romano-Jana 1973). Hypocalcemia may cause a delirium (Denko and Kaelbling 1962), that may, in turn be accompanied by other typical signs, such as tetany (Hossain 1970). Hypercalcemia may cause delirium, which has been noted in primary hyperparathyroidism (Karpati and Frame 1964) and as a paraneoplastic phenomenon (Weizman et al. 1979). Hypomagnesemia may present with delirium and myoclonus (Fishman 1965; Hall and Joffe 1973). Hypermagnesemia may present with fatigue and delirium followed by generalized muscle weakness. Hypokalemia typically presents with fatigue and weakness, and, as the potassium level continues to fall, lethargy and delirium may supervene. Hepatic encephalopathy typically presents with delirium, which is often, but not always, accompanied by asterixis (Fraser and Arieff 1985; Read et al. 1961; Summerskill et al. 1956).

210 Signs, symptoms and syndromes

Although the serum ammonia level is generaly elevated, delirium has occurred with a normal ammonia level, and hence such a value does not rule out the diagnosis. Uremic encephalopathy may present with a delirium (Raskin and Fishman 1976; Stenback and Haapanen 1967; Tyler 1968), and although the blood urea nitrogen level is inevitably elevated, the presence of delirium correlates not so much with the absolute rise in blood urea nitrogen as it does with the rapidity of that rise. WITH SPECIFIC PRECIPITANTS

Subdural hematoma, whether occurring acutely or subacutely after head trauma, may present with delirium (Black 1984). Importantly, especially in the elderly, the trauma itself need not be severe; indeed, the patient may have dismissed it as trivial. 'Postoperative' delirium is a common occurrence, especially with cardiotomy (Dubin et al. 1979; Smith and Dimsdale 1989), and is probably multifactorial in etiology, with contributions from the anesthetic, cerebral anoxia or ischemia during the operation, and from the use of medications, especially those with anticholinergic properties (Mach et al. 1995; Tune etal. 1981). Severe burns (Andreasen et al. 1977) may, through a variety of mechanisms, cause delirium. Central pontine myelinolysis (Adams et al. 1959) occurs secondary to an overly rapid correction of hyponatremia (Brunner et al. 1990) and presents after a latency of 1-7 days from this correction. There may be delirium or lethargy, and in the fully developed condition there is quadriparesis and pseudobulbar palsy (Karp and Laureno 1993). Delayed postanoxic leukoencephalopathy generally appears a matter of weeks after an anoxic insult (Plum etal. 1962), for example carbon monoxide poisoning (Choi 1983; Gottfried et al. 1997; Norris et al. 1982), and is characterized by delirium that is often accompanied by a gait abnormality, parkinsonism, or other abnormal movements. INFARCTION

Either cortical or thalamic infarction may present acutely with delirium. This has been noted with infarction in the area of distribution of the right middle cerebral artery (Mesulam et al. 1976; Mori and Yamadori 1987; Price and Mesulam 1985) (especially when the temporoparietal area is involved [Caplan et al. 1986]), the posterior cerebral artery (Devinsky et al. 1988a; Medina et al. 1974, 1977), and, rarely, the right anterior cerebral artery (Bogousslavsky and Regli 1990). In such cases of cortical infarction, the delirium is generally accompanied by other clinical evidence indicative of the location of the infarction, such as apraxia, agnosia, hemianopia, or hemiplegia. Infarction of the thalamus may present with delirium (Fromm et al. 1985), whether on the right (Bogousslavsky et al. 1988) or the left (Graff-Radford et al. 1984) side. Specific areas implicated include the paramedian and anteromedial areas (Bogousslavsky et al. 1988; Friedman 1985). ENCEPHALITIS

Encephalitis typically has an acute onset, over perhaps days, and is characterized clinically by delirium, a degree of drowsiness or lethargy, headache, fever, and, in most cases, either seizures or focal signs, such as hemiplegia. Meningeal signs, such as neck stiffness or photophobia, may or may not be present. Although most cases occur secondary to viral infection, other organisms may also be involved, and in some instances an autoimmune reaction to a preceding infection or vaccination may produce a post-infectious encephalitis. Of the various

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viral encephalitides described below, herpes simplex encephalitis is perhaps the most important as it is treatable. Whenever encephalitis is suspected, both imaging and, provided that there is no significant degree of cerebral edema, lumbar puncture are indicated as emergency procedures. Herpes simplex encephalitis, although most common in the middle aged, may be seen at any age. It typically presents with fever and headache, followed by delirium, seizures, and focal signs (Kennedy 1988; Koskiniemi etal. 1996; McGrath etal 1997; Marton etal. 1996; Williams and Lerner 1978). Arbovirus encephalitis may have an explosive onset with headache, fever, meningeal signs, delirium, and seizures; focal signs are somewhat less common (Baker and Noran 1942; Lewis etal 1947). HIV infection may, during seroconversion, present with an aseptic meningitis in the setting of an influenza-like illness, and in a minority of these patients, in addition to the headache and fever, there may also be a delirium (McArthur 1987; Malouf et al. 1990). Mononudeosis is characterized by fever, sore throat, and cervical lymphadenopathy. In a small minority, these symptoms may be joined by evidence of an encephalitis, such as a delirium or seizures (Bergin 1960; Schlesinger and Crelinsten 1977; Schnell et al. 1966; Tselis etal 1997). Mumps typically presents with fever, malaise, myalgia, and, within a week, parotitis. In a minority, meningeal signs may occur, and in a minority of these cases, an encephalitis may also be seen, presenting with drowsiness, delirium, and, in some, seizures or focal signs. Importantly, the encephalitis may in some cases precede the parotitis (Bistrian et al. 1972; Finklestein 1938; Levitt etal 1970). Varicella, or chicken-pox, occurs secondary to an initial infection with the varicella-zoster virus and presents with an exanthem, which may rarely be accompanied by an encephalitis (Applebaum et al. 1953). Zoster occurs as a sequela to varicella and represents a reactivation of the varicella-zoster virus from its latent status within the sensory ganglia. Clinically, patients present with a segmental rash; in a minority of these patients, an encephalitis may occur, which may or may not be accompanied by meningeal signs (Applebaum et al. 1962; Jemsek et al 1983; Krumholz and Luhan 1945). Such an outcome is more likely in immunocompromised patients, such as those with Hodgkin's disease (McCormick et al. 1969) or AIDS (Gilden et al. 1988). Subsequent to the resolution of the zoster, a varicella-zoster arteritis may develop, which, in a minority, may present with a delirium (Geny et al. 1991; MacKenzie et al. 1981; Ryder et al. 1986) Encephalitis lethargica, or von Economo's disease (Hohman 1921; Kirby and Davis 1921; Wilkins and Brody 1968), may present with delirium accompanied by sleep reversal, oculomotor pareses, and oculogyric crises. Although there have been no recent epidemics, sporadic cases still occur (Howard and Lees 1987), so this dread disorder must not be forgotten. Rabies follows the bite of an infected animal after a latency of weeks to a year, being heralded by paresthesiae at the site of the bite and followed by headache, fever, and, in most cases, delirium, which may be accompanied by the classic hydrophobia (Adle-Biassette et al. 1996; Blatt et al. 1938; Dupont and Earle 1965). Importantly, if the latency is long enough, patients may have forgotten the fateful bite. Furthermore, rabies has in some cases been contracted via aerosol, as for example in spelunkers, and, in one case, in a laboratory worker in the process of homogenizing an infected brain (Conomy et al. 1977). Post-infectious or post-vaccinial encephalitis has an onset of anywhere from days to several weeks after the inciting viral illness or vaccination. Clinically, patients present with typical encephalitic symptoms such as delirium, headache, fever, lethargy, and, in some, focal signs such as hemiplegia (Dolgopol et al. 1955; Giffm et al. 1948; Miller et al. 1956).

212 Signs, symptoms and syndromes

Rocky Mountain spotted fever occurs between 2 days and 2 weeks after inoculation with Rickettsia rickettsii via a tick bite and presents with malaise, fever, headache, and a characteristic rash that begins on the ankles and wrists and spreads to involve the extremities and, in over one-half of patients, the soles and palms. In a small minority, a delirium may ensue (Bell and Lascarni 1970; Homey and Walker 1988; Miller and Price 1972). Importantly, the tick bite itself may have gone unnoticed, and thus an absence of this history does not rule out the diagnosis. Malaria, although rare in the United States and Europe, remains a scourge in Africa. A small minority of patients with falciparum malaria may develop delirium (Blocker et al. 1968), a fact noted by Kraepelin (1907). WITH SPECIFIC ASSOCIATED FEATURES

Hypertensive encephalopathy is generally seen only when the diastolic pressure is sustained at over 130 mmHg, being characterized by prominent headache with delirium. Seizures and focal signs may occur, as may a bilateral blurring of vision (Chester et al. 1978; Healton et al. 1982; Oppenheimer and Fishberg 1928). Febrile delirium typically accompanies temperatures of 41°C (106°F) or over (Ebaugh et al. 1936, 1938). Such a temperature elevation may occur secondary to systemic infection or in other conditions such as heat stroke and the neuroleptic malignant syndrome. Critically, it must be recalled that encephalitis can also cause high fever, and in such cases the delirium is due more to the encephalitic process than to the fever per se. Hashimoto's encephalopathy often presents with the subacute onset of delirium, which is typically accompanied by myoclonus; seizures and focal findings may be present in some cases. Importantly, although antithyroid antibodies are present in all cases, the thyroidstimulating and thyroid hormone levels may be normal (Bohnen et al. 1997; Ghika-Schmid et al. 1996; Henchey et al. 1995; Shaw et al. 1991; Thrush and Boddie 1974). Sydenhams chorea may be accompanied by delirium (Diefendorf 1912) in a very small minority of cases (Nausieda et al. 1980); importantly, the chorea in such cases may be quite mild (Winkelman and Eckel 1932). Chorea gravidarum, Latin for 'chorea of pregnant women', may likewise, in a very small minority, be accompanied by delirium (Wilson and Preece 1932). Pulmonary insufficiency, as may be seen during pneumonia or an exacerbation of chronic obstructive pulmonary disease, may be characterized by 'carbon dioxide narcosis', with delirium, drowsiness, and, importantly, asterixis (Austen et al. 1957; Bacchus 1958; Dulfano and Ishikawa 1965; Westlake et al. 1955). Porphyria typically causes abdominal pain and may also cause a delirium that may in turn be accompanied by seizures (Cross 1956; Goldberg 1959; Hierons 1957). Pancreatitis presents with acute abdominal pain that is not uncommonly accompanied by delirium (Estrada et al. 1979; Menza and Murray 1989). Heavy metal intoxication, when acute, with lead (Akelaitis 1941; Morris et al. 1964; Whitfield et al. 1972), thallium (Bank et al. 1972; Reed et al. 1963), arsenic (Freeman and Couch 1978; lenkins 1966), or tin (Feldman et al. 1993; Wu et al. 1990) may cause a delirium in the setting of abdominal pain, often accompanied by convulsions. A hint for the diagnosis of arsenic intoxication is the classic sign of an odor of garlic on the breath. Adrenocortical insufficiency of the chronic type typically causes fatigue, lethargy, abdominal pain, and other abdominal complaints, such as nausea, vomiting, diarrhea, or constipation. In a minority, a delirium may appear (Engel and Margolin 1941; Fang and Jaspan 1989). Thyroid 'storm' is typified by severe agitation with prominent tremor and exophthalmos, all of which may be accompanied by delirium (Friedman and Kanzer 1937).

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Gushings syndrome, suggested by a Cushingoid habitus of moon facies, truncal obesity, and violaceous abdominal striae, may, in a very small minority of patients, also be characterized by a delirium (Kelly 1996). Behcet's syndrome may, in a small minority of cases, involve the central nervous system, producing episodes of 'neuro-Behcet's' characterized by delirium often associated with focal findings (Akman-Demir et al. 1993; Serdaroglu etal. 1989). In all cases, patients will have oral aphthous ulcers, genital ulcers, or, most commonly, both. Wegener's granulomatosis typically presents with upper and lower airway disease along with renal disease; the central nervous system may rarely be involved, with delirium and focal findings (Nishino etal. 1993; Weinberger etal. 1993). Rheumatoid arthritis may, very rarely, be complicated by a delirium occurring secondary to a cerebral rheumatoid vasculitis (Siomopoulos and Shah 1979). Migraine, rarely, may be characterized by a delirium along with the severe headache (Gardner et al. 1997). OCCURRING WITH MALNOURISHMENT Wernicke's encephalopathy, although most commonly seen in alcoholics (Harper 1983), may occur secondary to thiamine deficiency of any cause, including fasting (Frantzen 1966), prolonged vomiting (as in post-gastric restriction surgery [Abarbanel et al. 1987; Paulson et al. 1985]), or prolonged intravenous feeding without adequate thiamine supplementation (Vortmeyer et al. 1992). Although most of us were taught to look for the classic 'triad' of delirium, ataxia, and nystagmus, this combination is, in fact, the exception (Cravioto et al. 1961), most patients with Wernicke's encephalopathy presenting with delirium alone (Harper et al. 1986). The recognition of this syndrome is critical: treated promptly, patients may survive without sequelae; untreated, or with delayed treatment, patients may recover but be left with a permanent Korsakoff's syndrome (Malamud and Skillicorn 1956). Pellagra occurs secondary to niacin deficiency, occurring in both chronic and acute forms. In the past, the chronic form, characterized by the '3 Ds' of dementia, diarrhea, and dermatitis, was most common, but with the enrichment of flour with niacin, it is the acute 'encephalopathic' form of pellagra that is most commonly seen today, generally in malnourished alcoholics. This encephalopathic form presents with delirium and generalized rigidity, and is generally not accompanied by diarrhea or dermatitis (Ishii and Nishihara 1981; Serdaru et al. 1988). Marchiafava-Bignami disease, seen generally only in chronic alcoholics, typically presents with a complex syndrome including delirium, ataxia, seizures, and long-tract signs (e.g. hyperreflexia and extensor plantar responses) (Bohrod 1942; Ironside et al. 1961; Karnaki et al. 1993; Koeppen and Barron 1978; Rosa et al. 1991). OCCURRING DURING IMMUNOSUPPRESSION Progressive multifocal leukoencephalopathy typically presents with focal signs (e.g. aphasia and apraxia), reflecting the focal onset of the demyelinization. Over time, however, and with spread of the demyelinization, a delirium may occur (Astrom et al. 1958; Davies et al. 1973; Richardson 1961; Sponzilli etal. 1975). Toxoplasmosis may present with delirium, often accompanied by focal signs and seizures (Navia et al. 1986a; Porter and Sande 1992). Mycoses, including candidiasis (Parker et al. 1981), cryptococosis (Chuck and Sande 1989), coccidioidomycosis (Caudill et al. 1970), and aspergillosis (Woods and Goldsmith 1990), may, in some cases, present with delirium, which may or may not be accompanied by meningeal or focal signs.

214 Signs, symptoms and syndromes

Cytomegalovirus encephalitis, generally seen in AIDS only when the CD4+ cell count is below 50 cells mm3, typically presents with confusion and lethargy, without focal signs (Berman and Kim 1994; Holland et al. 1994). Subacute measles encephalitis is a rare sequela to measles, typically seen only in the immunocompromised host, which may present with a delirium (Agamanolis et al. 1979). WITH PAROXYSMAL ONSET

Both complex partial and petit mal seizures may be characterized by delirium; in both cases, it is the exquisitely paroxysmal onset of the confusion that suggests the correct diagnosis. Complex partial seizures are typically accompanied by confusion, but the typical brevity of their duration, on the order of minutes, leaves little doubt as to their ictal nature. There are, however, cases of complex partial status epilepticus (Tomson et al. 1992) lasting up to days that are characterized by delirium alone, without other symptoms such as automatisms (Mayeux and Lueders 1978; Rennick et al. 1969). Petit mal seizures, like complex partial seizures, may, although generally brief, also occur in status, and in two such cases, one lasting 6 hours (Zappoli 1955) and the other 36 hours (Tucker and Forster 1958), the only evidence of the petit mal seizure was delirium, without any myoclonic twitching or automatism. MISCELLANEOUS

Diffuse Lewy body disease may present with a delirium that is either episodic or flucuating; patients typically also have mild parkinsonism or an undue sensitivity to neuroleptics (McKeith et al. 1994a, b). Dementia eventually supervenes, but the history of early delirium is very important from a diagnostic point of view. Tumors may cause delirium, as has been noted with tumors of the brainstem (Wallack et al. 1977), hypothalamus (Alpers 1940), and temporal lobe (Keschner et al. 1936). Cerebral abscesses may likewise cause delirium (Jefferson and Keogh 1977). Limbic encephalitis is a paraneoplastic syndrome that typically has a subacute presentation with delirium (Antoine etal. 1995; Bakheit etal. 1990; Case records 1988b; Glaser and Pincus 1969), which may be accompanied by siezures (Alamowitch et al. 1997; Brennan and Craddock 1983). Importantly, this limbic encephalitis may be the first sign of the underlying cancer (Alamowitch et al. 1997). Granulomatous angiitis very commonly presents with a delirium of subacute onset, which is typically accompanied by headache (Hughes and Brownell 1966; Koo and Massey 1988; Vollmer et al. 1993). This rare disease generally has an onset in those over 40 years of age and, as noted in Chapter 10, p. 469, may require a brain biopsy for diagnosis. Thrombotic thrombocytopenic purpura, generally occuring in young adults, may present either acutely or subacutely with evidence of central nervous system dysfunction (i.e. delirium with either seizures or focal signs [Bakshi et al. 1999; Silverstein 1968]) in the setting of varying combinations of fever, skin purpura, microangiopathic hemolytic anemia, thrombocytopenia, and evidence of renal involvement such as proteinuria, microscopic hematuria,or azotemia. Sepsis, with fever, chills, tachycardia, tachypnea, and hypotension eventually produces delirium in over 50% of patients (Eidelman et al. 1996). Systemic lupus erythematosus may affect the central nervous system, causing, among other signs, a delirium (O'Connor and Musher 1966). Importantly, there is in most cases evidence of systemic involvement, such as constitutional symptoms (fever, malaise and weight loss), arthralgia, arthritis, myalgia, or rashes, especially a malar rash (Johnson and Richardson 1968).

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Polyarteritis nodosa may cause delirium, but, as in the case of lupus, evidence of systemic disease, such as constitutional symptoms, is generally also present (Ford and Siekert 1965). Sarcoidosis may, very rarely, cause a delirium (Douglas and Maloney 1973; Silverstein and Siltzbach 1965; Wiederholdt and Siekert 1965). Other evidence of the disease is always present: the chest X-ray will reveal either hilar lymphadenopathy or a diffuse retiuclonodular pattern in over 90% of patients. Tuberculosis of the central nervous system is generally characterized by a basilar meningitis and may present with a gradually developing delirium (Traub et al. 1984; Williams and Smith 1954), often accompanied by either a stiff neck or a cranial neuropathy (Kennedy and Fallen 1979; McKendrick and Grose 1957). Lyme disease may, during stage II, cause a delirium. This can be an elusive diagnosis because the majority of patients do not remember the fateful tick bite, and a history of the preceding erythema chronica migrans may also be lacking. Furthermore, although most stage II patients with central nervous system involvement will have symptoms such as stiff neck or seizures, in some cases the only clinical evidence of central nervous system involvement will be a delirium (Pachner et al. 1989).

Treatment of the syndrome In addition to treating the underlying cause of the delirium, certain symptomatic measures may be very helpful. Efforts should be undertaken to enable patients to stay 'in touch' with the environment and the current situation. Large calendars and digital clocks should be kept in full view, and the importance of having a window in the room cannot be overstated (Wilson 1972). At night, the room should be as quiet as possible, and nursing procedures that can be delayed to the daylight hours should be. A night-light should be left on, and a nurse's call button should be within easy reach. For patients with a quiet or hypoactive delirium, the above measures may suffice while efforts are underway to treat the underlying cause of the delirium. For agitated patients, however, who may pull lines out or refuse 'poisoned' medicines, pharmacologic treatment may be required. Both haloperidol and chlorpromazine are useful, both being superior to lorazepam (Breitbart et al. 1996). The choice between haloperidol and chlorpromazine is based primarily on the outcome of expected side-effects in the patient in question, particular attention being paid to extrapyramidal side-effects for haloperidol and hypotension, sedation, and anticholinergic effects for chlorpromazine. Both these drugs may be given on a prn basis, beginning with a low dose (e.g. 1 mg haloperidol or 25 mg chlorpromazine given orally, or, if required, intramuscularly in one-half the oral dose), with repeat dosing every 2 hours if the oral route is used (and every hour if the drug is given intramuscularly), until the patient is calm, unacceptable side-effects have occurred, or a maximum dose (e.g. 50 mg haloperidol or 500 mg chlorpromazine over 24 hours) has been reached. With repeat doses, the dosage itself may be raised or lowered depending on the clinical response: in general, no more than 5-10 mg haloperidol or 100-200 mg chlorpromazine should be given orally at any time. Haloperidol has also been given intravenously (Fernandez et al. 1988; Tesar et al. 1985) and may indeed be less likely to produce extrapyramidal side-effects when given by this route (Menza et al. 1987). Intravenous use, however, carries a small (Wilt et al. 1993) but definite (Metzger and Friedman 1993) risk of torsades de pointes and should therefore, in this author's opinion, be reserved for situations in which other measures are not appropriate. Once the patient is calm and cooperative with care, a regular dose of the neuroleptic may be given, the total daily dose being approximately equal to that required in prn doses. If

216 Signs, symptoms and syndromes

further prn doses are needed, the regular dose may have to be proportionately increased. Once the underlying cause of the delirium has been treated, the neuroleptic may be discontinued. Droperidol, a medication very similar to haloperidol, has recently become very popular (Hooper and Minter 1983; Resnick and Burton 1984; Thomas et al. 1992; van Leeuwen et al. 1977) and indeed may be more rapidly effective than haloperidol (Resnick and Burton 1984). In some cases, restraints and round-the-clock sitters may be required.

AMNESIA Amnesia, as conceived of here, is a syndrome characterized by an isolated defect in the patient's ability either to store new events in memory or to retrieve memories of prior events. Memory is technically divided into two broad types: declarative and procedural. Declarative memory involves a recall of facts and events, and is usually what is meant by most people when they speak of memory and its impairment. Procedural memory refers to the ability to perform tasks previously learned. Thus, declarative memory is a matter of remembering the 'what' and 'when', whereas procedural memory refers to remembering 'how to'. Declarative and procedural memory are often selectively impaired: one may well be able to remember 'how' to ride a bicycle yet not be able to recall when or where that task was learned. This dissociation of declarative and procedural memory can, in cases of amnesia, often be striking: one patient, a professional pianist, albeit able flawlessly to perform Beethoven's Fifth Symphony, was yet unable to remember either the name of the symphony or that of the composer (Crystal et al. 1989). Declarative memory may further be subdivided into two forms: semantic and episodic. Semantic memory involves the recall of facts, such as the name of the President of the United States, whereas episodic memory involves the recall of specific episodes or events, such as what one did just a few minutes ago or what happened in the distant past, for example at one's wedding or on graduation from high school. Episodic memory is further divided into anterograde and retrograde components. Anterograde amnesia refers to an inability to lay down new memories, whereas retrograde amnesia refers to an inability to recall memories already formed. From a practical, clinical point of view, it is disorders of episodic declarative memory that are most important, and the remainder of this chapter is confined to these. As disorders of episodic declarative memory localize reasonably well to the circuit of Papez, a review of the relevant neuroanaotmy may be helpful. The circuit of Papez involves the mamillary body, thalamus, hippocampus, and fornix. Fibers from the mamillary body project to the anterior thalamic nuclei via the mamillo-thalamic tract. The anterior thalamic nuclei, in turn, project to the cingulate cortex and its cingulum, which in turn projects to the entorhinal and subicular cortices on the medial aspect of the temporal lobe. Fibers from the entorhinal cortex extend, via the perforant pathway, to terminate in the dentate gyrus, from whence fibers arise that project to the pyramidal cells of the hippocampus proper. In their turn, these hippocampal fibers become incorporated into the fornix, which also receives fibers directly from the subicular cortex. The fornix then proceeds posteriorly and superiorly, arching up under the splenium to course anteriorly under the corpus callosum, eventually turning inferiorly, as the columns of the fornix, to dive down into and through the hypothalamus, finally coming to rest in the mamillary body and thus completing the circuit. Amnesia has occurred secondary to lesions of the mamillary body (Kahn and Crosby 1971; Tanakas et al. 1997). Amnesia has also occurred with thalamic lesions, but it has been difficult to pinpoint exactly which nuclei or tracts in the thalamus are involved. Lesion studies strongly implicate the mamillo-thalamic tract (Graff-Radford et al. 1990; Malamut et al. 1992; von

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Cramon et al. 1985), the anterior thalamic nuclei (Pepin and Auray-Pepin 1993), and perhaps the mediodorsal nucleus (Clarke et al. 1994; Gorelick et al. 1988). Temporal lobectomy may cause amnesia (Penfield and Mathieson 1974), and lesions confined to the hippocampus (Duyckaerts et al. 1985), specifically fields CA1 and CA2 of the hippocampus (Kartsounis et al. 1995) or CA1 alone (Zola-Morgan et al. 1986), have also been responsible. Lesions of the fornix have been implicated (D'Esposito et al. 1995; Gaffan et al. 1991; Sweet et al. 1958), including those located beneath the splenium (Heilman and Sypert 1977) and those involving the columns (Calabrese et al. 1995; Hodges and Carpenter 1991). Although the lesions have in most cases been bilateral, it appears that a properly situated unilateral lesion may also be to blame. Thus, amnesia has occurred with unilateral lesions of the thalamus, either on the left (Choi et al 1983; Clarke et al. 1994; Gorelick et al. 1988; Landi et al. 1982) or on the right (Pepin and Auray-Pepin 1993), and with unilateral lesions of the temporal lobes, with either temporal lobectomy (Scoville and Milner 1957; Walker 1957) or infarction (Gaffan et al. 1991). Some doubt has been cast on the ability of unilateral lobectomy to cause amnesia: for example, in one instance where unilateral lobectomy was felt to have been responsible (Penfield and Milner 1958), it turned out, at autopsy, that the contralateral temporal lobe had in fact sustained some damage before the surgery (Penfield and Mathieson 1974). There is also a case report of amnesia following an infarction limited to the right basal forebrain (Hashimoto et al. 2000). Pure retrograde amnesia (without any anterograde component), a rare entity, has been noted with bilateral damage involving the polar areas of the temporal lobes and prefrontal areas (Kapur et al 1992; Kroll et al 1997; Markowitsch et al 1993).

Description of the syndrome Amnesia of the declarative episodic type occurs, as noted above, in two forms: anterograde and retrograde. Anterograde amnesia refers to an inability to form new memories, so a patient in the midst of an ongoing anterograde amnesia, although able to recall events that occurred before the amnesia began, is unable, after a few minutes, to recall anything that has happened since the amnesia began. Furthermore, after the anterograde amnesia ceases, patients, although once again able to form new memories, will generally have little or no memory of any of the events that occurred while the anterograde amnesia was in place. In a sense, as patients look back in time, they find an 'island' of amnesia, or a gap, that extends from when the amnesia began until when it cleared. Retrograde amnesia, by contrast, refers to a situation in which patients are unable to recall events that, before the start of the retrograde amnesia, they were able to remember. Such retrograde amnesias, as it were, throw a blanket of amnesia over past events, which may extend back in time for as little as an hour or so, to up to a decade or more. In many cases, retrograde amnesia displays a temporal gradient such that patients have the greatest difficulty recalling events of the recent past, whereas the amnesia for events progressively more distant in time becomes progressively more patchy, patients being able to summon up partial memories (Albert et al. 1979; Seltzer and Benson 1974). The vast majority of amnesias are composed of a combination of anterograde and retrograde amnesia, the anterograde component being the most prominent. Such amnesias may be either transient or persistent. Although persistent amnesias of this sort are often referrred to as 'Korsakoff's syndrome', the use of this eponym may in some cases cause confusion: whereas some authors use 'Korsakoff's syndrome' in a generic sense, referring to any persistent amnesia with both anterograde and retrograde components, others confine its use to cases in which the amnesia occurs as a sequela of Wernicke's encephalopathy, as is often seen in alcoholics. Korsakoff's syndrome may, in addition to the amnesia itself, also be

218 Signs, symptoms and syndromes

characterized by what is known as confabulation. When this is present, patients, when asked about events for which they have no memory, make up or 'confabulate' answers. For example, one alcoholic with a Korsakoff's syndrome, when asked how he had come to to be in the hospital, replied that he had dropped by to make a delivery and had decided to stop and talk with some of his friends. The mental status examination of a patient in the midst of an amnesia with both anterograde and retrograde components reveals an intact digit span, an inability to recall three words after 5 minutes, and an inability to recall autobiographical events (e.g. the place of occupation or the school he or she graduated from) that occurred for a variable period of time before the amnesia began. In cases of transient amnesia, these findings on the mental status examination change dramatically once the amensia clears. With the resolution of the amnestic episode, digit span remains intact, and patients become able to recall three out of three words after 5 minutes as well as once again to keep track of current events. The retrograde amnesia 'shrinks' and may entirely disappear (Benson and Geschwind 1967), patients once again being able to summon up memories of events that occurred before the amnesia began. When looking back, however, patients experience an island of amnesia: although able to recall events that occurred up to the start of the amnesia, and now able to recall events that occurred since the termination of the amnesia, they are still unable to recall any of the events that transpired during the amnestic episode itself, a gap thus remaining in their recollection. One may rarely encounter an amnesia composed primarily or purely of a retrograde component alone. Such patients, although able to 'keep track' of ongoing events, now find themselves unable to remember events that occurred prior to onset of the amnesia, as if the memories of those events have been destroyed. The extent of this retrograde amnesia varies from a matter of years (Kroll et al. 1997) to almost an entire lifetime, back to childhood (Kapuretal. 1992).

Differential diagnosis of the syndrome Amnesia must be distinguished from delirium and dementia. Although both of these syndromes include difficulty with memory, they are distinguished by the presence of additional features, not seen in amnesia, such as confusion in delirium, and in dementia deficits in abstracting and calculating ability. 'Benign senescent forgetfulness' (Krai 1962) refers to the tendency, seen in otherwise normal elderly individuals, to experience the insidious onset of a very mild memory defect. This diagnosis, however, should probably always be tentative, given the fact that, as noted below, Alzheimer's disease may present in a similar fashion. Depression may mimic an amnestic condition, especially when the task of recall is effortful (Cohen et al. 1982; Roy-Byrne et al. 1986): such depressed patients essentially 'give up' on the task. The presence of other depressive symptoms, such as depressed mood, fatigue, and insomnia, suggests the correct diagnosis. Once the syndromal diagnosis of amnesia is secure, the cause of the amnesia in question must be determined. The various causes of amnesia are listed in Table 5.4, the task of differentiating between them being facilitated by first determining whether the amnesia is of the combined type, primarily anterograde with a variable retrograde component, or is a relatively pure retrograde amnesia. In the case of a combination of anterograde and retrograde amnesia, the task is further simplified by determing which of the following three categories the amensia belongs in: those which are transient and of acute onset, those which are persistent and of acute or gradual onset, and those which are persistent and occur with clear precipitants.

Syndromes of cognitive impairment 219 Table 5.4 Causes of amnesia Anterograde with a variable retrograde component

Pure retrograde amnesia

Transient and of acute onset Transient global amnesia Pure epileptic amnesia Blackouts Concussion Transient ischemic attacks 'Transient tumor attacks' 'Dissociative' amnesia Persistent and of acute or gradual onset Korsakoff's syndrome secondary to Wernicke's encephalopathy Stroke Tumors Limbic encephalitis Prodrome to Alzheimer's or Pick's disease Persistent and occur with clear precipitants Closed head injury Global anoxia Encephalitis Status epilepticus Certain neurosurgical procedures Head trauma Herpes simplex encephalitis Seizures

ANTEROGRADE WITH A VARIABLE RETROGRADE COMPONENT

Transient and of acute onset Transient global amnesia usually has an onset in the seventh decade of life and is characterized by the appearance of one or more episodes, lasting anywhere from 4 to 18 hours, and sometimes longer, during which there is a dense anterograde amnesia coupled with a retrograde amnesia of variable duration, from hours to decades. Characteristically during the episode, patients, although not confused, may repeatedly ask what is happening (Hodges and Ward 1989; Kritchevsky and Squire 1989; Kushner and Hauser 1985; Miller et al. 1987; Shuttleworth and Morris 1966). Recovery is typically complete except for an 'island' of amnesia extending backwards in time from when the episode resolved to perhaps an hour or two before the episode began. In some cases, it appears that the episode is precipitated by some emotionally laden event, such as sexual intercourse or an argument (Fisher 1982; Kushner and Hauser 1985). Pure epileptic amnesia represents a partial seizure characterized solely by a combination of anterograde and variable retrograde amnesia (Lee et al. 1992; Palmini et al. 1992; Stracciari et al. 1990). These amnestic episodes differ from those of transient global amnesia in that they are of hyperacute, or paroxysmal, onset, relatively brief, and generally not accompanied by anxious questioning on the patient's part. Furthermore one typically finds evidence of either complex partial or grand mal seizures in the history. Blackouts (Goodwin 1971; Goodwin et al. 1969a, b) may complicate moderate or severe alcohol intoxication, and although characteristic of chronic alcoholism, they may at times be seen in normal subjects. The patients themselves are generally not aware anything is amiss, and apart from other evidence of intoxication (e.g. dysarthria), others may not be able to

220 Signs, symptoms and syndromes

discern any problem either. The next day, however, patients may find that they have no memory of the night before, and may anxiously (and often circumspectly) ask others what happened. Importantly, although alcohol is the usual culprit, blackouts may also occur with benzodiazepines, especially those of high potency, such as triazolam (Greenblatt et al. 1991). Concussion, as may occur after minor head injury (Fisher 1966) or whiplash (Miller 1982), may be accompanied by a dense anterograde and variable retrograde amnesia, and upon recovery, the patient is left with the typical 'island' of amnesia, extending back from the time of recovery to, generally, either the injury itself or a short time before that. In one famous example (as reported in the New York Daily News of 3 August 1928), Gene Tunney, a heavyweight contender, recalled nothing of a boxing match even though he won the fight. He later decided to quit boxing before a blow would, as he put it, 'permanently hurt my brain' (Markand 1928). Transient ischemic attacks may be characterized in whole or in part by an episode of amnesia. This has been noted with ischemia of the left thalamus (Gorelick et al. 1988) and in the area of distribution of the posterior cerebral arteries; in the latter case, the presence of visual problems, such as hemianopia or cortical blindness, served to indicate the cortical areas involved (Benson et al. 1974). In another case, an episode occurred during cardiac angiography, presumably on an embolic basis (Shuttleworth and Wise 1973). Distinguishing between amnesia resulting from a transient ischemic attack and that caused by transient global amnesia may be difficult unless there are associated symptoms such as hemianopia. 'Transient tumor attacks' occur in association with cerebral tumors and may happen either because of transient compression of a nearby artery or because of a tumor-related seizure. In one case of a left-sided temporoparietal mass, the attack was characterized by an episode of amnesia (Lisak and Zimmerman 1977). Dissociative amnesia, or, as it is also known, 'psychogenic' amnesia, is similar, phenomenologically, to transient global amnesia, with the important exception that, after recovering from the episode, patients may, with either psychotherapy or hypnosis, be able to remember events that had previously been hidden in the 'island' of amnesia (Abeles and Schilder 1935; Kanzer 1939). It must be borne in mind that this is a rare disorder: indeed, some doubt whether it even exists. Persistent and of acute or gradual onset

Korsakoff's syndrome secondary to Wernicke's encephalopathy is the prototype of a persistent amnesia. Wernicke's encephalopathy, characterized by delirium alone or by a delirium with nystagmus or ataxia, occurs secondary to thiamine deficiency and is most commonly found in chronic alcoholics; as it clears, patients may be left with a Korsakoff's syndrome (Malamud and Skillicorn 1956). Classically, these patients appear normal on casual inspection, the anterograde and retrograde amnesia only becoming evident upon detailed mental status examination or when the patient engages in confabulation (Victor and Yakovlev 1955). Stroke may be characterized by amnesia, this having been noted with infarction of the medial aspect of the temporal lobe or the medial portion of the thalamus. Infarction of the medial aspect of the temporal lobe, in the area of distribution of the posterior cerebral artery, involves, among other structures, the hippocampus, and it is from this lesion that the amnesia arises (Dejong et al. 1969; Victor et al. 1961). The involvement of other 'downstream' structures may lead to symptoms that suggest the correct diagnosis, including hemianopia, cortical blindness, tunnel vision, or alexia without agraphia (Benson et al. 1974). In the case of thalamic infartion, the stroke may be initially characterized by coma (Hodges and McCarthy 1993; Malamut et al. 1992) or delirium (Clarke et al. 1994), the amnesia appearing only upon the recovery of full consciousness. In one case, however, amnesia was the dominant and initial manifestation of the infarction, with other symptoms, such as

Syndromes of cognitive impairment 221

hypophonia or a mild anomia, being relatively insignificant (Pepin and Auray-Pepin 1993). Thalamic hemorrhage may also be at fault with, in one such case, an amnesia emerging after the clearing of a delirium (Choi et al. 1983). Amnesia has also been noted as a sequela of infarction of the fornices (Fukatsu et al. 1998; Park et al. 2000). Tumors, if properly situated, may cause a progressive amnesia, which has been noted with the following: craniopharyngiomas (which compress the overlying mamillary bodies) (Kahn and Crosby 1971; Palmai et al. 1967; Tanaka et al. 1997; Williams and Pennybacker 1954), thalamic tumors (Ziegler et al. 1977), large tumors affecting structures such as the corpus callosum, fornices, and thalami (Sprofkin and Sciarra 1952), and a subsplenial tumor, which damaged both fornices (Heilman and Sypert 1977). Limbic encephalitis is a paraneoplastic syndrome resulting from an autoimmune assault on the limbic system. Although most patients present with delirium, the delirium will, in a small minority, be preceded by the subacute onset of an amnestic syndrome (Alamowitch et al. 1997; Nokura et al. 1997). Alzheimer's disease (Crystal et al. 1989; Didic et al. 1998; Linn et al. 1995; Sim et al 1966) or, less commonly, Pick's disease (Wisniewski et al. 1972) may present with an amnesia that evolves very slowly into a dementia; in a sense, the amnesia represents a 'prodrome' to the dementia. Persistent and occur with clear precipitants

Closed head injury characteristically causes coma, and upon recovery from the coma, the patient may be left with various cognitive deficits, prominent among which may be an amnesia. The amnesia has both anterograde and retrograde components, the duration of the anterograde amnesia generally (but not always) correlating well with the severity of the injury itself (Russell and Smith 1961; Wilson et al. 1994). The retrograde amnesia exhibits a temporal gradient (Levin et al. 1988), and as the patient experiences some recovery, the period of time covered by the retrograde amnesia gradually shrinks (Russell and Nathan 1946). Importantly, neither missile nor crush injuries are associated with much in the way of amnesia, and indeed, in some cases, there may be none at all (Russell 1951; Russell and Schiller 1949). Global anoxia, as may occur with attempted hanging (Berlyne and Strachan 1968; Medalia et al. 1991), carbon monoxide intoxication (Allison 1961), cardiorespiratory arrest (Broman etal. 1997; Cummings et al. 1984), or after inhalation anesthesia (Muramoto et al. 1979), may, upon the recovery of consciousness, be followed by an amnesia. Encephalitis may have an amnesia as one of its sequelae (Rose and Symonds 1960); this is particularly true of herpes simplex encephalitis, which often affects medial temporal structures (Hokkanen et al. 1996; Kapur et al. 1994; McGrath et al. 1997; Young et al. 1992). Status epilepticus may leave an amnesia in its wake, as occurred in one case after grand mal status (Meierkord etal. 1997). Certain neurosurgical procedures may have amnesia as a complication. Unilateral temporal lobectomy may be at fault (Walker 1957), but in some cases at least, this appears to be because the remaining temporal lobe had already been damaged in some fashion (Penfield and Mathieson 1974). Surgery for an anterior communicating artery aneurysm may be followed by an amnesia (Abe et al. 1998; Phillips et al. 1987; Talland et al. 1967), and this appears to be not uncommon when preceded by actual rupture of the aneurysm (Lindquist and Norlen 1966). Neurosurgical intervention directed toward the third ventricle, as in an attempt to remove a colloid cyst, may cause injury to the fornices, with a resulting amnesia (Hodges and Carpenter 1991). Pure retrograde amnesia

Head trauma., when affecting the temporal poles, may be followed by a retrograde amnesia (Kroll et al. 1997; Markowitsch et al. 1993). In one case, a young woman, despite being

222 Signs, symptoms and syndromes

eventually able to recall most of the events that had occurred after the head trauma, was unable to remember anything that happened before the trauma, all the way back to early childhood (Kapur et al 1992). Herpes simplex encephalitis, with residual damage to the anterior portions of the temporal lobes, may leave patients with a pure retrograde amnesia (Calabrese et al. 1996). In one case, the patient, although able to recall events that occurred subsequent to her recovery from the encephalitis, could not recall autobiographical events that occurred before the encephalitis, such as her own wedding (Tanaka et al. 1999) Seizures may, very rarely, be characterized solely by a pure retrograde amnesia. In one case, which probably represented a seizure, the patient experienced the paroxysmal onset of an inability to recall any facts of his life but was able to store in mind and recall what was happening during the episode itself (Venneri and Caffarra 1998). Treatment of the syndrome In cases in which the underlying cause has a specific treatment (e.g. anticonvulsants for amnestic seizures), this should be utilized. Supervision of a variable degree is often required during the amnesia, and this may suffice for the transient forms. In the case of persistent amnesias, various techniques, such as the use of mnemonics and lists, may enable the patient to better navigate the temporal landscape.

MENTAL RETARDATION Description of the syndrome Mental retardation is characterized by a failure to progress, despite adequate opportunity, beyond a certain developmental point, in both an intellectual and a social sense. Thus, those with mild mental retardation generally progress no further than an elementary school level, those with moderate mental retardation a second-grade level, those with severe mental retardation a preschool level, and those with profound mental retardation the level seen in infants or very small children. By convention, these various grades of mental retardation are also demarcated by IQ level, these being presented in Table 5.5, along with the 'developmental' age at which the patients' intellectual and social progress generally stalls. Importantly, although mental retardation is a congenital condition, the diagnosis is often not made until the patients, for no apparent reason, fail academically and socially to 'keep up' with their peers. Mild mental retardation, as noted, generally becomes apparent sometime in elementary school. Although these patients may master some reading, writing, and arithmetic, their thinking remains more or less concrete, and social nuances are generally not grasped. Affects tend to be broad, with little shading, and judgment is often poor. As adults, these patients may

Table 5.5 Grades of mental retardation

Grade

Developmental age (years)

IQ

Mild Moderate Severe Profound

7-11 3-7 1-3 <1

50-55 to 65-75 35-40 to 50-55 20-25 to 35-40 < 20-25

Syndromes of cognitive impairment 223

be able to live independently, but outside guidance is typically required at times of major change or stress. Moderate mental retardation generally becomes apparent in the preschool years, with such patients eventually mastering, at best, only a rudimentary degree of reading, writing, and arithmetic. Thinking is very concrete, and there is generally little appreciation of social customs. Although independent living is generally not possible, some may be able to live in a community setting such as a group home. Severe mental retardation generally becomes apparent in the first few years of life, such patients being limited to developing only rudimentary language. At best, they may be able to count on their fingers or read a few very simple words. Close supervision is required, and many are unable to be cared for in the community. Profound mental retardation is generally apparent in the first year of life. Speech is generally not acquired, and some patients may never be able to walk or even sit. Institutional care is often required. Malformations and seizures are associated with the higher grades of mental retardation and are particularly common in profound and severe types. Those with mild mental retardation may, by contrast, escape both malformations and seizures. Although a history of early school failure or being placed in 'special' classes is suggestive of mental retardation, it is not diagnostic. As pointed out below, there are multiple other reasons for such academic failure, including a lack of educational opportunity or a developmental disability such as dyslexia. The mental status examination is as important as the history, and one should pay close attention to the patients' vocabulary and syntax, ability to grasp complex ideas, and performance on testing for proverbs, similarities, and calculations. Aggressiveness, impulsivity, and a low frustration tolerance are common in all grades of mental retardation; in those with moderate-to-profound retardation, stereotypic and selfinjurious behaviors may be seen, and in those with severe or profound grades, rectal digging and coprophagia may occur. Other neuropsychiatric disorders are seen in one-half or more of patients with mental retardation (Gillberg et al. 1986; Gostason 1985) and may include attention deficit disorder with hyperactivity, depression, bipolar disorder, or schizophrenia.

Differential diagnosis of the syndrome Academic subjects, such as reading, writing, and arithmetic, are all acquired skills, and if educational resources are lacking, children will not, no matter how intelligent, develop them. Various other conditions may, even in the presence of adequate educational resources, prevent the acquisition of these skills, these including significant deafness or reduced visual acuity, developmental disabilities (such as developmental dyslexia or developmental dysphasia), attention deficit disorder with hyperactivity, schizophrenia, and significant depression. Profound deprivation may also leave a child so withdrawn and apathetic that schoolroom progress simply does not occur. Autism, with its disturbed social interaction, may resemble mental retardation, but autistic children are, on close inspection, in many cases found to be of normal intelligence. Autism is also of course often associated with mental retardation; thus, the diagnosis of autism does not rule out mental retardation. Dementia is clearly distinguished from mental retardation by its course. In mental retardation, there is no falling off or decrement in intellectual ability from a previously acquired level: rather, there is, as noted above, a 'stalling' of development wherein patients reach a plateau, significantly below that expected for their age, beyond which there is no

224 Signs, symptoms and syndromes

further progress. By contrast, there is in dementia a definite falling off from a previously acquired level, this decrement being more or less profound. Once the diagnosis of mental retardation is secure, it is important to delve further and determine the cause of the retardation. This is a formidable task: there are hundreds of known causes, new ones being discovered every year. From an adult neuropsychiatric point of view, however, only a handful of these are of great interest, and these are listed in Table 5.6. Should the patient in question not merit one of these diagnoses, then consultation may be in order. Table 5.6 Some causes of mental retardation Genetic and chromosomal abnormalities

Polygenic and autosomal recessive inheritance Down's syndrome Fragile X syndrome Klinefelter's syndrome Tuberous sclerosis Sturge-Weber syndrome von Recklinghausen's syndrome Prader-Willi syndrome Laurence-Moon-Biedl syndrome Lesch-Nyhan syndrome Rett's syndrome Phenylketonuria

Intrauterine insults

Fetal alcohol syndrome Anticonvulsants Rubella Toxoplasmosis

Peri natal factors

Cerebral palsy Prematurity Malnutrition

GENETIC AND CHROMOSOMAL ABNORMALITIES

Polygenic inheritance is of particular importance, especially in cases of mild mental retardation (Thapar et al. 1994). A gene for autosomal recessive mild mental retardation, with no significant dysmorphism, was recently located on chromsome 3 (Higgins et al. 2000). Down's syndrome is suggested by a characteristic appearance with narrowed palpebral fissures, epicanthal folds, a broad nasal root, and an often-protruding tongue. Importantly, any substantial decrement in intellectual capacity in adults with Down's syndrome suggests either Alzheimer's disease (Evenhuius 1990) or hypothyroidism (Lai and Williams 1989). The fragile X syndrome may cause mental retardation in affected males, being suggested by facial dysmorphism with a long, narrow face, prognathism, and, in those who have passed puberty, macoorchidism (Finelli et al. 1985; Wisniewski et al. 1985b). Klinefelter's syndrome may also cause mental retardation and is suggested by a tall stature, small testicular size, and, in some, gynecomastia (Ratcliffe et al. 1982). Tuberous sclerosis commonly causes mental retardation and is suggested by the presence of adenoma sebaceum and seizures (Lagos and Gomez 1967; Pampiglione and Moynahan 1976; Ross and Dickerson 1943). The Sturge-Weber syndrome is suggested by a facial port-wine stain, a contralateral hemiplegia, and, in those with seizures, mental retardation (Lichtenstein 1954; PascualCastroviejo et al. 1993; Petermann et al. 1958).

Syndromes of cognitive impairment 225

Von Recklinghausens disease, suggested by cafe au lait spots and neurofibromas (Huson et al. 1988), may, in a minority, also cause mental retardation (Rosman and Pearce 1967). Both the Prader-Willi syndrome and the Laurence-Moon-Biedl syndrome may cause mental retardation, both being characterized by massive obesity and hypogondadism. Distinguishing characteristics for the Prader-Willi syndrome (Bray etal. 1983; Hall and Smith 1972; Robinson et al. 1992) include a characteristic dysmorphism, with almond-shaped eyes, and for the Laurence-Moon-Biedl syndrome (Rathmell and Burns 1938; Roth 1947), retinitis pigmentosa and either polydactyly or syndactyly. The Lesch-Nyhan syndrome often causes mental retardation and is suggested by choreoathetosis and self- mutilating lip- or finger-biting (Jankovic et al. 1988; Lesch and Nyhan 1964; Nyhan 1972). Rett's syndrome is seen virtually only in females and is suggested by a characteristic history (Hagberg 1993; Hagberg et al. 1983): at around the age of one and one-half years, mental retardation becomes apparent, along with a characteristic stereotyped hand movment, much like hand-washing. Microcephaly also gradually becomes apparent. At around the age of 3, there may be some partial recovery of communicative ability, and seizures often appear. Patients may then remain stable until the adult years, when scoliosis and dystonia gradually ensue. Phenylketonuria as a cause of mental retardation is uncommon today, thanks to newborn screening. Importantly, however, adherence to the low-phenylalanine diet should be lifelong in order to prevent deterioration. It is especially critical that mothers with phenylketonuria adhere strictly to the diet during pregnancy in order to prevent neurologic damage to the fetus. Mothers who are heterozygous for the gene should also adopt the diet during pregnancy in order to prevent fetal damage (Lenke and Levy 1980). INTRAUTERINE INSULTS The fetal alcohol syndrome, a very common cause of mental retardation (Abel and Sokol 1986; Spohr et al. 1993), is characterized by mental retardation, short stature, microcephaly, and a characteristic facies, with shortened palpebral fissures, epicanthal folds, a thin upper lip with a smooth philtrum, maxillary hypoplasia, and a degree of micrognathia. Anticonvulsants, notably phenytoin (Hanson and Smith 1975), taken during pregnancy may cause retardation. Maternal infection with either rubella (Miller et al. 1982) or toxoplasmosis (Desmonts and Couvrer 1974) may cause severe mental retardation. PERINATAL FACTORS

Of all the disorders of perinatal origin that may cause mental retardation, cerebral palsy (Nicholson and Alberman 1992) is the most important. Both prematurity (Collin et al. 1991; Volpe 1991) and malnutrition (Chase and Martin 1970) may also cause the syndrome.

Treatment of the syndrome In addition to any treatment specific for the condition responsible, several measures are generally applicable for mental retardation, regardless of the cause. Educational and training measures are especially important for those with mild and moderate mental retardation, and family members generally will benefit from counseling. Aggressivenenss and impulsivity may be reduced by lithium (Craft et al. 1987; Spreat et al. 1989) or risperidone (Vanden Borre et al. 1993): older neurolpetics, such as haloperidol

226 Signs, symptoms and syndromes

(Aman et al. 1989; Burk and Menolascino 1968) and thioridazine (Heistad et al. 1982; Singh and Aman 1981), may also be effective, not only with aggressiveness, but also with stereotypic and self-injurious behavior. Attention deficit disorder with hyperactivity may be treated with stimulants in the usual fashion (Aman et al. 1991; Gadow 1985; Handen et al 1990; Payton et al. 1989). Mood disorders and schizophrneia may also be treated in the usual way.

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Neurol 1990; 47:129-32. WolinskyJS, Berg BO, Maitland CJ. Progressive rubella panencephalitis./Ard? Atewro/1976; 33:722-3. Wood CA, Buller F. Poisoning by wood alcohol. Cases of death and blindness from Columbian spirits and other methylated preparations. J Am Med Assoc 1904; 43:972-7,1058-62,1117-23,1213-21. Woods GL, Goldsmith JC. Aspergillus infection of the central nervous system in patients with acquired immunodeficiency syndrome. Arch Neurol 1990; 47:181-4. Wu R-M, Chang Y-L, Chiu H-C. Acute triphenyltin intoxication: a case report. J Neurol Neurosurg Psychiatry 1990; 53:356-7. Wulff CH, TrojaborgW. Adult metachromatic leukodystrophy: neuropsychologicfindings. Neurology 1985; 35:1776-8. YoshitakeT, Kiyohara Y, Kato I et al. Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama study. Neurology 1995; 45:1161-8. Young CA, Humphrey DM, Ghadiali EJ et al. Short-term memory impairment in an alert patient as a presentation of herpes simplex encephalitis. Neurology 1992; 42:260-1. Zappoli R. Two cases of prolonged twilight state with almost continuous 'wave-spikes'. Electroencephalogr Clin Neurophysiol 1955; 7:421-3. Zeidler M, Stewart GE, Barraclough CR et al. New variant Creutzfeldt-Jakob disease: neurological features and diagnostic tests. Lancet 1997; 350:903-7. Ziegler DK, Kaufman A, Marshall HE. Abrupt memory loss associated with thalamic tumor. Arch Neurol

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6 Syndromes of disturbances of mood and affect Depression

254

Mania

261

Anxiety

270

DEPRESSION Depression, as conceived of here, is a syndrome that may result from any one of a large number of underlying causes. Although the most common cause of depression is an idiopathic disorder, major depression, it is critical to subject each depressed patient to a thorough diagnostic evaluation before concluding that major depression, or perhaps one of the other idiopathic disorders, is the cause.

Description of the syndrome Depression as a syndrome includes not only a depressed mood, but also other symptoms, as listed in Table 6.1. There is debate over how many symptoms should be required to make this syndromal diagnosis. An example of a fairly strict diagnostic approach is that presented in the fourth edition of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV), which requires five or more of the symptoms listed in Table 6.1 (at least one of which must be depressed mood or anhedonia). Although such a strict approach helps to avoid overdiagnosis, it runs the risk of missing partial syndromes, as may occur in many of the secondary cases. Provisionally, this author recommends a 'broad' definition, which requires a depressed mood plus one or more of the Vegetative' symptoms of depression, namely anhedonia, anergia, sleep disturbance, appetite disturbance, or psychomotor change. In addition to deciding how many symptoms are required to make the syndromal diagnosis of depression, one must also specify a duration for these symptoms. The DSM-IV specifies 2 weeks, and as most of the secondary cases meet this criterion, it is reasonable to utilize it. There are, however, important exceptions, which must be kept in mind. The depression of the premenstrual syndrome, for example, may last only days, and partial seizures presenting with depression, although at times profound, may last only minutes or hours.

Syndromes of disturbances of mood and affect 255 Table 6.1 Symptoms of depression Depressed mood Low self-esteem, guilt, or pessimism Suicidal ideation Difficulty with concentration, or forgetful ness Anhedonia, or lack of interest in formerly pleasurable activities Anergia, or lack of energy Sleep disturbance (either insomnia or hypersomnia) Appetite disturbance (either anorexia or increased appetite) Psychomotor change (either agitation or retardation)

Differential diagnosis of the syndrome The syndrome of depression must be distinguished not only from normal reactions to life's misfortunes, for example bereavement after the death of a loved one, but from an underappreciated, extrapyramidal side-effect of neurolpetic drugs, known as akinesia. Bereavement is a normal reaction to loss, but, in contrast to pathologic depression, it is not autonomous: in the natural course of events, most individuals emerge from their bereavement after 6 months, and almost all have recovered by 1 year (Harlow et al. 1991). A persistence of symptoms beyond 1 year strongly suggests that the patient in fact has a major depression and that the current depressive symptoms actually represent a depressive episode precipitated by the loss. In such cases, a careful history will generally reveal that a depressive episode had occurred earlier in the patient's life (Zisook and Schucter 1993). Akinesia occurs as a side-effect of neuroleptics, typically developing slowly, after days or weeks of treatment. Patients may complain of sadness or of feeling 'like a zombie', and typically lack spontaneity (Rifkin et al. 1975; Van Putten and May 1978). The diagnosis is suggested by the preceding neuroleptic treatment and is confirmed when symptoms resolve with discontinuation of the drug or with treatment with benztropine. Once the syndromal diagnosis of depression has been established, the next step is to determine its cause. The various causes of depression listed in Table 6.1 are divided into two large groups: primary or idiopathic and secondary. Although the overwhelming majority of patients with depression will have one of the primary causes, secondary causes are not uncommon and must be kept in mind. Assessing patients for secondary causes is facilitated by dividing them, as in the table, into the following groups: • those occurring secondary to precipitants, for example medications such as propranalol • those occurring secondary to diseases with distinctive features, such as the 'moon' fades of Cushing's syndrome • those occurring as part of certain heredodegenerative or dementing disorders, such as Alzheimer's disease • a large group of miscellaneous or rare causes. Although this list may appear formidably long, keeping the various precipitants and associated distinctive features in mind is readily achieved, and the presence of the various neurodeodegenerative or dementing disorders is fairly obvious. PRIMARY OR IDIOPATHIC CAUSES

Major depression and bipolar disorder are both characterized by recurrent episodes of depression, the two disorders being distinguished by the fact that in bipolar disorder one also

Table 6.2 Causes of depression Primary or idiopathic causes

Major depression and bipolar disorder Dysthymia Premenstrual syndrome Schizoaffective disorder Post-psychotic depression in schizophrenia

Secondary to precipitants

Medications Anticholinergic withdrawal ('cholinergic rebound') Alcoholism Stimulant withdrawal Anabolic steroid withdrawal Post-stroke depression Head trauma Whiplash Postpartum blues Postpartum depression Interictal depression of epilepsy

Secondary to diseases with distinctive features

Cushing's syndrome (moon fades, hirsutism, acne, buffalo hump, abdominal striae, hypertension, and diabetes) Hypothyroidism (hair loss, dry skin, and voice change) Hyperthyroidism (includingapathetic hyperthyrodisim) (weight loss with increased appetite, tachycardia, atrial fibrillation, and congestive heart failure) Chronic adrenocortical insufficiency (nausea, vomiting, abdominal pain, and postural dizziness) Obstructive sleep apnea (prominent snoring) Multiple sclerosis (various focal findings) Fahr's syndrome (dementia, and parkinsonism) Partial seizures (paroxysmal onset)

As part of certain neurodegenerative or dementing disorders

Alzheimer's disease Multi-infarct dementia Diffuse Lewy body disease Parkinson's disease General paresis of the insane (tertiary neurosyphlis) Limbic encephalitis Down's syndrome

Miscellaneous or rare causes

Cerebral tumors Hydrocephalus Pancreatic cancer Systemic lupus erythematosus New-variant Creutzfeldt-Jakob disease Hyperparathyrodisim Hypercalcemia Pernicious anemia Pellagra Lead encephalopathy Hyperaldosteronism Hallervorden-Spatz disease Behcet's syndrome Hereditary mental depression with parkinsonism

Syndromes of disturbances of mood and affect 257

sees, at some point in the patient's history, a manic episode, whereas in major depression, manic episodes never occur. Given that bipolar disorder may commence with one, or several, episodes of depression before the first episode of mania occurs, one must, in evaluating a patient who has only had depressive episodes, allow a lengthy period of observation to pass before making a firm diagnosis of major depression. Statistically speaking, in patients with bipolar disorder, the first episode of mania will, in over 90% of cases, occur within 10 years of the first depressive episode or by the time five or more episodes of depression have occurred, whichever comes first (Dunner et al. 1976). Although not as reliable, certain clinical characteristics of the depressive episode may also suggest whether that depressive episode is occurring on a basis of bipolar disorder or major depression. Specifically, depressive episodes of bipolar disorder are, in contrast to those of major depression, more likely to have an acute onset (over weeks rather than months) (Winokur et al. 1993) and also more likely to be accompanied by psychotic features (Guze et al. 1975). Dysthymia is characterized by chronic, low-level and generally fluctuating depressive symptoms. This condition is of uncertain nosologic status. In many cases, there will be an exacerbation of symptoms to the degree found in a depressive episode (Devanand et al. 1994), and, from this author's point of view, it may be appropriate to think of dysthymia simply as a chronic, low-level depressive episode that could be part of either major depression or bipolar disorder. Premenstrual syndrome is characterized by relatively brief depressions that occur with each menstrual cycle, beginning anywhere from hours to one and one-half weeks before the onset of menses and remitting spontaneously 2-3 days after menstrual flow begins. The depression is typically characterized by prominent lability of mood (Bloch et al. 1997a). Schizoaffective disorder is characterized by chronic, persistent psychotic symptoms with the 'superimposition' of episodes of either depression or of mania, during either of which the preexisting psychotic symptoms undergo a significant exacerbation. Differentiating schizoaffective disorder from bipolar disorder may be difficult (Pope et al. 1980), and the reader is directed to Chapter 20, p. 648, for a discussion of this. Post-psychotic depression in schizophrenia is seen in about one-third of patients with schizophrenia. In these patients, after a more or less - complete remission of psychotic symptoms (whether occurring spontaneously or by virtue of neuroleptic treatment), a depressive episode occurs, typically within a matter of months (Mandel et al. 1982). In contrast to schizoaffective disorder, however, there is during this post-psychotic depression no exacerbation of psychotic symptoms. SECONDARY TO PRECIPITANTS

Medications definitely associated with depression include propranalol (Petrie et al. 1982; Pollack et al. 1985), nifedipine (Hullett et al. 1988), ranitidine (Billings and Stein 1986), pimozide (Bloch et al. 1997b), long-term treatment with subdermal estrogen/progestin preparations (Wagner 1996; Wagner and Berenson 1994), interferon beta-lb (Neilley et al. 1996) and the seldom-used antihypertensives reserpine (Jensen 1959; Quetsch et al. 1959) and alpha-methyldopa (DeMuth and Ackerman 1983). Depression may also occur secondary to treatement with adrenocorticotrophic hormone (ACTH) (Falk et al. 1979) or high-dose prednisone (Wolkowitz et al. 1990); it should, however, be kept in mind that, of the mood changes seen with steroids, depression is much less common than mania. Depression has also been associated with chronic bismuth use, and in such cases, with continued use, one generally eventually sees myoclonus, ataxia and delirium (SupinoViterbo et al. 1977)

258 Signs, symptoms and syndromes

Anticholinergic withdrawal, also known as 'cholinergic rebound', may occur with an abrupt discontinuation of long-term treatment with anticholinergic agents, such as tricyclic antidepressants; clues to this diagnosis include associated nausea and prominent insomnia (Dilsaver et al 1983). Alcoholism is commonly associated with depression, such depression being found in the majority of newly admitted alcoholics (Davidson 1995). Importantly, the symptoms typically resolve spontaneously during the first 4 weeks of abstinence (Brown et al. 1995). Stimulant withdrawal is typically characterized by depressive symptoms, this having been noted with amphetamines (Watson et al. 1972) and cocaine (Weddington et al. 1990). Anabolic steroid withdrawal, as may be seen in athletes who have abused steroids, may be accompanied by significant depressive symptoms (Pope and Katz 1988) Post-stroke depression, which can be quite severe (Lipsey et al. 1986) is a not-uncommon sequela to cerebral infarction, most (Hermann et al. 1993; Robinson et al. 1983, 1984, 1985), but not all (House et al. 1990; MacHale et al. 1998; Stern and Bachman 1991), studies noting that such depression is more likely with infarctions in the left frontal lobe than elsewhere. Such patients typically recover within a year (Astrom et al. 1993; Robinson et al. 1987). Post-stroke depression has also been associated with infarction of the left basal ganglia (Morris et al. 1996; Starkstein et al. 1987, 1988a). Head trauma, when severe, maybe followed by depression in almost one-half of the patients who survive (Federoff et al. 1992). Whiplash injuries may also be followed by depression, with symptoms such as depressed mood, loss of energy, and poor motivation (Ettlin et al. 1992). Postpartum blues is immediately suggested by its onset within the first few days postpartum and by its characteristic lability of affect (Pitt 1973; Rohde et al. 1997; Yalom et al. 1968). Postpartum depression is distinguished from the postpartum blues by its later onset, with a latency of at least several weeks between delivery and the onset of the depression. Interictal depression of epilepsy occurs in a large proportion of patients with recurrent seizures (Mendez et al. 1986), especially those with recurrent complex partial seizures (Indaco et al. 1992; Perini et al. 1996). SECONDARY TO DISEASES WITH DISTINCTIVE FEATURES

Cushing's syndrome, seen with pituitary or adrenal tumors (Haskett 1985), may, as noted by Gushing himself (Gushing 1932), be characterized by depression, this in fact being seen in over one-half of all cases (Cohen 1980; Haskett 1985; Kelly 1996; Starkman 1981). Suggestive features include weight gain, moon facies, hirsutism, acne, a buffalo hump, violaceous abdominal striae, hypertension, and diabetes mellitus (Haskett 1985; Spillane 1951). Cushing's syndrome may also occur on a paraneoplastic basis, and, in one case secondary to Hodgkin's disease, the patient presented with depression and slight facial puffiness (Anderson and McHugh 1971). Hypothyroidism may cause severe depression (Tonks 1964; Whybrow et al. 1969). In addition to such features as weight gain, hair loss, dry skin, and voice change, the condition is also suggested by prominent fatigue, sluggishness, and drowsiness (Nickel and Frame 1958). Hyper thy roidism, although generally associated with anxiety and agitation, appears just as likely to cause depression (Kathol and Delahunt 1986; Trzepacz et al. 1988), and the correct diagnosis may be suggested by the presence of weight loss in the face of increased appetite (Trzepacz et al. 1988) or autonomic signs such as tremor and tachycardia (Taylor 1975). Apathetic hyperthyroidism is a condition seen in elderly patients with hyperthyrodism; this, in addition to prominent apathy (Lahey 1931; Thomas et al. 1970), may also be characterized by depression (Thomas et al. 1970). Important clues to the correct diagnosis include sinus

Syndromes of disturbances of mood and affect 259

tachcardia, atrial fibrillation, or congestive heart failure (Arnold et al. 1974; Thomas et al. 1970). Chronic adrenocortical insufficiency may cause depression (Engel and Margolin 1941; Varadaraj and Cooper 1986) and is suggested by associated features such as nausea, vomiting, abdominal pain, and postural dizziness. Obstructive sleep apnea may cause a chronic depressed, mood, tiredness, indecisiveness, irritability, and complaints of insomnia (Millman et al. 1989). The diagnosis is suggested by a history of prominent snoring, the symptoms being relieved upon successful treatment of the sleep apnea, for example with continuous positive airway pressure. Multiple sclerosis is more likely to cause depression than are other comparably debilitating disorders such as amyotrophic lateral sclerosis (Schiffer and Babigian 1984; Whitlock and Siskind 1980). Although this depression is correlated with overall disability early in the course of the disease (Millefiorini et al. 1992), this correlation vanishes as the disease progresses (Fassbender et al. 1998; Moller et al. 1994), one finding rather that the presence of depression is correlated with the extent of cerebral (rather than cord) involvement (Rabins et al. 1986; Schiffer et al. 1983), specifically with involvement of the left arcuate fasciculus (Pujol et al. 1997). As with other signs of multiple sclerosis, the depression may also have a relapsing and remitting course (Dalos et al. 1983). Fahr's syndrome may, rarely, present with depression, which is eventually joined by more typical signs such as dementia (Slyter 1979) and parkinsonism (Trautner et al. 1988); calcification of the basal ganglia eventually becomes apparent on computed tomography or magnetic resonance imaging scanning. Partial seizures (Weil 1956, 1959; Williams 1956) may manifest with the paroxysmal onset of depression, which may be severe, with psychomotor retardation or agitation, and which may last from minutes to weeks. In addition to the paroxysmal onset, important clues to the diagnosis are the presence of olfactory hallucinations and a history of more typical seizures at other times. AS PART OF CERTAIN NEURODEGENERATIVE OR DEMENTING DISORDERS

Alzheimer's disease, suggested by the gradual onset of a dementia with prominent amnestic features, is accompanied by prominent depressive symptoms in about one-fifth of all cases (Burns et al. 1990; Starkstein et al. 1997). Multi-infarct dementia, suggested by its stepwise course and prominent focal findings, produces depression in over one-half of all sufferers (Cummings et al. 1987). Diffuse Lewy body disease, suggested by an onset with intermittent confusion, visual hallucinations and mild parkinsonism (or an undue susceptibility to parkinsonism secondary to neuroleptic drugs) is characterized by depression in about one-half of patients (Klatka et al. 1996). Parkinsons disease in most (but not all [Hantz et al. 1994]) studies is associated with depression of varying degrees of severity in up to 40% of cases (Mayeux et al. 1986; Starkstein et al. 1990a). General paresis of the insane, a form of tertiary neurosyphilis, may be characterized by a dementia with prominent depressive features (Dewhust 1969; Gomez and Aviles 1984) in almost one-fifth of all cases (Storm-Mathisen 1969). Limbic encephalitis, a paraneoplastic syndrome, may present with a depression, which is later joined by other, more typical evidence of the encephalitis such as delirium (Glaser and Pincus 1969) or dementia (Corsellis et al. 1968). Downs syndrome, immediately suggested by mental retardation and a characteristic facies, may cause depression in adult sufferers (Collacott et al. 1992) and maybe of such severity that a dementia is produced (Warren et al. 1989).

260 Signs, symptoms and syndromes

MISCELLANEOUS OR RARE CAUSES

Cerebral tumors may cause depression, especially with tumors of the anterior portion of the corpus callosum (Ironside and Guttmacher 1929). Hydrocephalus may present with depression (Jones 1993), and in a minority of cases of normal-pressure hydrocephalus, it may play a prominent part in the overall clinical picture (Pujol et al. 1989). The presence of an ataxic/apraxic gait may suggest the correct diagnosis. Pancreatic cancer is associated with depression (Holland et al. 1986; McDaniel et al. 1995) and may indeed present with depression (Fras et al. 1967; Rickles 1945). The eventual appearance of abdominal pain suggests the correct diagnosis. Systemic lupus erythematosus can definitely cause depression (Dennis et al. 1992). What is disputed, however, is how frequently it does so: some have found depression to be common in lupus (Ganz et al. 1972; Lim et al. 1988; Miguel et al. 1994), whereas others have not (Guze 1967; Hugo et al 1996). New-variant Creutzfeldt-Jakob disease may present with depression (Zeidler et al. 1997a) but eventually, over months, also produces other signs, such as ataxia and dementia (Zeidler 1997b). Importantly, in this new-variant type of Creutzfeldt-Jakob disease, the EEG does not show periodic complexes. Hyperparathyroidism may be accompanied by depression (Linder et al. 1988; Petersen 1968; Reinfrank 1961) and may in some cases present with depression (Gatewood et al. 1975; Karpati and Frame 1964). Hypercalcemia is constant and may be the only clue to the diagnosis. Hypercalcemia occurring on another basis, for example, in one case, as a paraneoplastic expression of Hodgkin's disease (Weizman et al. 1979), may also cause depression. Pernicious anemia has been reported to present with a chronic depression; here the clue to the correct diagnosis was a concurrent anemia (Fraser 1960). Pellagra, in one case (Hardwick 1943), presented with a combination of depression and the familiar rash and diarrhea. Lead encephalopathy may be characterized by depression (Schottenfeld and Cullen 1984), the diagnosis being suggested by the presence of a motor peripheral neuropathy with wrist or, less commonly, foot drop. Hyperaldosteronism, as may occur with adrenal tumors, presented in one case with depression, the diagnosis being suggested by leg weakness and cramping, and an accompanying hypokalemia (Malinow and Lion 1979). Hallervorden-Spatz disease may rarely present in the adult years; in one of these cases, the disease was heralded by a depression that was eventually joined by dementia and limb rigidity (Murphy et al. 1989). Behcet's syndrome in one instance presented with depression and headache: the presence of oral and genital ulcers indicated the correct diagnosis (Wadia and Williams 1957). Hereditary mental depression with parkinsonism is a very rare familial disorder that presents with depression, followed, years later, by parkinsonism (Perry et al. 1975).

Treatment of the syndrome The treatment of the primary or idiopathic syndromes is discussed in their respective chapters. In the case of depressions secondary to other conditions, it is appropriate, wherever possible, to treat that condition in the hope of also relieving the depresssion. When this is not possible, symptomatic treatment with an antidepressant drug is appropriate. With some notable exceptions, there are few double-blind, placebo-controlled studies of the antidepressant treatment of secondary depression. With regard to post-stroke depression,

Syndromes of disturbances of mood and affect 261

citalopram was found to be superior to placebo in one study (Anderson et al. 1994), and in another (Robinson et al. 2000) nortriptyline was superior to fluoxetine, which was in turn not significantly better than placebo: if nortriptyline is used, however, it must be borne in mind that it may cause a delirium in a minority of these post-stroke patients (Lipsey et al. 1984). For depression associated with Parkinson's disease, nortriptyline is effective (Anderson et al. 1980). Selective serotonin reuptake inhibitors (SSRIs) are also probably effective, but, as seen with both fluoxetine (Ernst and Steur 1993) and paroxetine (Jimenez-Jimenez et al. 1994), they may also increase the parkinsonism. Overall, it appears prudent to use either an SSRI, such as citalopram, or nortriptyline. Nortriptyline, however, should be used with extra caution in conditions that could predispose to seizures, for example head trauma (Wroblewski et al. 1990).

MANIA Mania is most often associated with bipolar disorder, or, as it is also known, manic-depressive illness; indeed, the mania seen in bipolar disorder provides the prototype of the syndrome. It must be borne in mind, however, that mania is a syndrome of multiple different etiologies, of which bipolar disorder is only one. Description of the syndrome

In general, one finds heightened mood, increased energy, and pressure, both of speech and activity. Pressured speech is rapid and voluble, often being characterized by a flight of ideas. Pressure of activity, also known as hyperactivity, manifests in all manner of injudicious involvement with others, with projects, plans, and manifold endeavors. In severe forms, delusions, either of grandeur or of persecution, make an appearance, and in the most severe forms, incoherence and a fragmented disintegration of behavior occur. The best descriptions of mania are found in Emil Kraepelin's (1921) Manic-depressive insanity and paranoia, a sampling of these being offered below. Heightened mood may be either predominantly euphoric or irritable. The euphoric patient: is in imperturbable good temper, sure of success, 'courageous,' feels happy and merry, not rarely overflowingly so, wakes up every morning 'in excellent humor'. He sees himself surrounded by pleasant and aristocratic people, finds complete satisfaction in the enjoyment of friendship, of art, of humanity; he will make everyone happy, abolish social wretchedness, convert all in his surroundings. For the most part an exuberant unrestrained mood inclined to practical jokes of all kinds is developed. Occasionally there is developed a markedly humorous trait, the tendency to look at everything and every occurrence from the jocular side, to invent nicknames, to make fun of himself and others. A patient called himself a 'thoroughbred professional fool'; another declared that the hospital was a 'nerve-ruining institution'; a third stated that he was a 'poet, cattle-driver, author, tinker, teacher, popular reformer, chief anarchist and detective'. On the other hand there often enough exists a great emotional irritability. The patient is dissatisfied, intolerant, fault-finding, especially in intercourse with his immediate surroundings, where he lets himself go; he becomes pretentious, positive, regardless, impertinent and even rough, when he comes up against opposition to his wishes and inclinations; trifling external occasions may bring about extremely violent outbursts of rage. In his fury he thrashes his wife and children, threatens to smash everything to smithereens, to run amuck, to set the house on fire, abuses the 'tribe' of his relatives in the most violent language, especially when under the influence of alcohol.

262 Signs, symptoms and syndromes

Increased energy leaves the patient a stranger to fatigue, his activity goes on day and night; work becomes very easy to him; ideas flow to him. He cannot stay long in bed; early in the morning, even at four o'clock he gets up, he clears out lumber rooms, discharges business that was in arrears, undertakes morning walks, excursions.

Pressure of speech is evident as patients 'talk a great deal, hastily, in loud tones, with great verbosity and prolixity, jumping from one subject to another'. Further, those with flight of ideas: are not able to follow systematically a definite train of thought, but they continually jump from one series of ideas to a wholly different one and then let this one drop again immediately ... They complain that they cannot concentrate or gather their thoughts together. The thoughts come of themselves, obtrude themselves, impose upon the patients. 'I can't grasp all the thoughts which obtrude themselves,' said a patient. 'It is so stormy in my head,' declared another, 'everything goes pell-mell.' 'My thoughts are all tattered,' 'I am not master over my thoughts.'

Pressure of activity fills the patient with a 'need to get out of himself, to be on more intimate terms with his surroundings, to play a part.' It causes him: to change about his furniture, to visit distant acquaintances, to take himself up with all possible things and circumstances, which formerly he never thought about. Politics, the universal language, aeronautics, the women's question, public affairs of all kinds and their need of improvement, give him employment. A physician advertised about 'original sin, Genesis, natural selection and breeding.' Another patient drove about in a cab and distributed pictures of the saints. The patient enters into numerous engagements, suddenly pays all his business debts without it being necessary, makes magnificent presents, builds all kinds of castles in the air, and with swift enthusiasm precipitates himself in daring undertakings much beyond his powers. He has 16,000 picture post-cards of his little village printed ...'.

In the more severe forms of mania, delusions, often of grandeur, make an appearance: 'The patient asserts that he is descended from a noble family, that he is a gentleman; he calls himself a genius, the Emperor William, the Emperor of Russia, Christ; he can drive out the devil. A patient suddenly cried out on the street that he was the Lord God; the devil had left him.' Other symptoms, such as increased energy and pressure of speech and activity, also become more severe, with the result that the patient's overall behavior begins to undergo an outlandish disintegration. For example: They run out of the house in a shirt, go to church in a petticoat, spend the night in a field of corn, give away their property, disturb the service in church by screaming and singing, kneel and pray on the street, fire a pistol in the waiting-room, put soap and soda in the food, try to force their way into the palace, throw objects out at the window. A female patient jumped into the carriage of a prince for a joke ... A male patient appropriated the property of others in taverns. Another appeared in the court of justice in order to catch a murderer.

In the most severe forms of mania, patients become incoherent: 'Their linguistic utterances alternate between inarticulate sounds, praying, abusing, entreating, stammering, disconnected talk, in which clang-associations, senseless rhyming, diversion by external impressions, persistence of individual phrases, are recognized.' Hallucinations in various modalities make their appearance: 'The patient sees heaven open, full of camels and elephants, the King, his guardian-angel, the Holy Ghost; the devil has assumed the form of the Virgin Mary. The ringing of bells is heard, shooting, the rushing of water, a confused noise; Lucifer is speaking;

Syndromes of disturbances of mood and affect 263

the voice of God announces to him the day of judgment, redemption from all sins.' Overall behavior becomes very fragmented, and patients may 'become stupefied, confused, bewildered', they may: dance about, perform peculiar movements, shake their head, throw the bedclothes pell-mell, are destructive, pass their movements under them, smear everything, make impulsive attempts at suicide, take off their clothes. A patient was found completely naked in a public park. Another ran half-clothed into the corridor and then into the street, in one hand a revolver in the other a crucifix.

Subsequent studies have largely borne out Kraepelin's initial description of mania. Thus, grandiosity, pressured speech, and hyperactivity are noted in the vast majority of patients with mania (Abrams and Taylor 1976; Carlson and Goodwin 1973; Carlson and Strober 1978; Clayton et al. 1965; Winokur et al. 1969), irritability is seen in most (Winokur and Tsuang 1975), and about one-half will become assaultive (Taylor and Abrams 1973, 1977). Delusions are generally of grandeur or persecution (Loudon et al. 1977; Rosenthal et al. 1979, 1980; Taylor and Abrams 1973, 1977), incoherence may appear (Brockington et al. 1980; Carlson and Strober 1978; Taylor and Abrams 1977), and hallucinations may be auditory, visual, or olfactory (Black and Nasrallah 1989; Bowman and Raymond 1931; Rosenthal et al. 1979,1980; Taylor and Abrams 1973; Winokur 1984). Differential diagnosis of the syndrome The differential diagnostic task of determining the cause of any particular case of mania is greatly simplified by considering, as set forth in Table 6.3, whether the mania has occurred without any obvious precipitating factors or whether it is preceded by a more or less obvious precipitant, such as a closed head injury. Cases of mania occurring without precipitants may or may not have distinctive features: the mania of bipolar disorder, for example, is generally unaccompanied by other features, whereas the mania of neurosyphilis is typically accompanied by a dementia. Cases of mania occurring secondary to precipitants are generally obvious, providing of course that one has kept in mind the various possible precipitating factors. MANIA OCCURRING WITHOUT PRECIPITATING FACTORS

Bipolar disorder is by far the most common cause of mania and is characterized, in most cases, by recurrent episodes of mania and recurrent episodes of depression throughout the lifetime of the patient. Critically, in the intervals between these episodes, patients are either asymptomatic or experience very mild residual symptoms, tending towards either euphoria or depression. The first episode of illness is usually a depressive one, typically occurring in the late teenage or early adult years; in those cases in which the first episode of illness is a depressive one, the first manic event typically appears within 10 years (Dunner et al. 1976). In the natural course of events, depressive episodes generally last about 6 months and manic episodes several months. As noted in more detail in Chapter 20, p. 651, the mania seen in this disorder is often accompanied by dysphoria and may also be divided into three stages, depending on the severity of the mania: in the more severe stages, psychotic symptoms, such as delusions, hallucinations, and incoherence, are common (Carlson and Goodwin 1973; Jampala et al. 1989). Importantly, however, although in the intervals between episodes, there may be mild disturbances of mood, as noted above, there are never any psychotic symptoms. Some variations on the typical course of bipolar disorder described earlier are worthy of note. First,

264 Signs, symptoms and syndromes Table 6.3 Causes of mania Mania occurring without precipitating factors

Bipolar disorder Cyclothymia Schizoaffective disorder Alzheimer's disease Neurosyphilis Stroke Huntington's disease Sydenham's chorea Chorea gravidarum Cushing's syndrome Thyrotoxicosis Cerebral tumors Multiple sclerosis Systemic lupus erythematosus Vitamin B12 deficiency Hepatic encephalopathy Uremia Creutzfeldt-Jakob disease Ictal Post-ictal psychoses

Mania occurring with precipitants

Closed head injury Hemodialysis Post-infectious encephalomyelitis Postpartum psychosis Encephalitis lethargica Corticosteroids or adrenocorticotrophk hormone Anabolic steroid abuse Levodopa Zidovudine Antidepressants Oral contraceptives Other medications Baclofen discontinuation Reserpine discontinuation Methyldopa discontinuation Aspartame Metrizamide

Miscellaneous causes of mania

Metachromatic leukodystrophy Adrenoleukodystrophy Tuberous sclerosis

it rarely appears that some patients (often referred to as 'unipolar manic') have only manic episodes during their lifetime (Pfohl et al. 1982; Shulman and Tohen 1994) and never experience a depressive one. Second, a minority of cases may also be characterized by 'rapid cycling', wherein four or more episodes of illness occur during a year (Dunner et al. 1977). Cyclothymia is best thought of as a very mild form of bipolar disorder (Akiskal et al. 1977). Like bipolar disorder, it is characterized by episodes of mood disturbance, but these are much milder in intensity and indeed may not bring the patient to clinical attention. Schizoaffective disorder, bipolar type (Grossman et al. 1984; Pope et al. 1980; Rosenthal et al. 1980), possesses a distinctive overall course: patients with this illness are not only chronically

Syndromes of disturbances of mood and affect 265

psychotic, but also, in the context of this ongoing psychosis, experience episodes of mania and episodes of depression. The chronic psychosis, which leaves them with psychotic symptoms (such as delusions and hallucinations) in the intervals between mood disturbances, clearly distinguishes this illness from bipolar disorder, which is free of psychotic symptoms in the intervening periods. Alzheimer's disease may, in a small minority, be characterized by mild manic symptoms such as an elevated mood (Burns et al. 1990), but this is seen only well after the dementia has become well established. Neurosyphilis, when manifesting as parenchymatous general paresis of the insane, presents with a dementia that may be marked by mania (Merritt and Springlova 1932): indeed, in one large study of 203 patients, approximately one-half were euphoric and excited (StormMa thisen 1969). Rarely, neurosyphilis may present with mania (Binder and Dickman 1980). Whenever a diagnosis of neurosyphilis is entertained, it is critical to carry out a serum fluorescent treponemal antibody absorption test and, if that is positive, to proceed to lumbar puncture regardless of whether the serum VDRL is positive or not. Stroke may be characterized by mania, this having been noted with infarction of the midbrain, thalamus, anterior limb of the internal capsule and adjacent head of the caudate nucleus, and frontal lobe. Although the other signs and symptoms accompanying the mania varied, the clinical presentation in each case was, as expected for stroke, acute, and it is the acuteness of the presentation that suggests the underlying cause of the mania. Midbrain infarctions have been followed by a cycling of mania and depression; this has been noted after an infarction secondary to a subarachnoid hemorrhage (Blackwell 1991) and after an ischemic lesion of the right mesencephalo-pontine area (Kulisevsky et al. 1995). This latter case is of particular interest as it apparently triggered an illness similar to classic bipolar disorder. The patient was a 59-year-old female who suddenly lost consciousness and fell to the ground. After coming to, she experienced transient dizziness and right ptosis, and then did well for about 2 weeks. She subsequently developed a psychotic depression accompanied by left hemiparkinsonism, both of which persisted, only to spontaneously remit after 19 months. She progressed well for the next 5 months and then developed mania characterized by elation, heightened activity and sexual interest, logorrhea, intrusiveness, and decreased sleep. Eventually she was successfully treated with lithium 4 weeks later. Thalamic infarctions capable of causing mania may be either unilateral on the right side, or bilateral. Regarding unilateral lesions, Cummings and Mendez (1984) reported a case of mania accompanied by left-sided hemianesthesia and slight hemiparesis, and Bogousslavsky et al. (1988) described a sudden onset of delirium that cleared in a few days, leaving behind mania as the sole indication of a right paramedian thalamic infarction. Kulisevsky et al. (1993) reported a case of mania accompanied by chorea and ballismus occurring secondary to an infarction of the ventral tier nuclei on the right. Bilateral thalamic infarction caused mania in two cases. In the first case (McGilchrist et al. 1993), there was an acute onset of drowsiness, followed by a cycling of mania and depression. The depression lasted for weeks and was characterized by apathy and increased eating and sleeping. The manias were brief, lasting only 1-2 days and being characterized by elation, pressured speech, and flight of ideas. The second case (Gentilini et al. 1987) presented, like the first, with somnolence, which was accompanied by amnesia and a vertical gaze paresis. As the patient, a 66-year-old male, became more alert, he displayed hypersexuality and grandiosity, asserting that he had a Swiss bank account and was a General in the Air Force. After 7 months, the amnesia had cleared but not the mania: he was 'cheerful ... garrulous ... [and] looking for a young girl who, enticed by his wealth, would be willing to marry him'.

266 Signs, symptoms and syndromes

Capsular infarction involving the anterior limb of the internal capsule and the adjacent head of the caudate nucleus has been noted to cause either depression followed within a month by mania, or mania alone (Starkstein et al. 1990c). Cortical or subcortical white matter infarction of the right frontoparietalregion (Jampala and Abrams 1983; Starkstein et al. 1988) or the right basotemporal or bilateral orbitofrontal areas (Starkstein et al. 1990c) has been associated with mania. Huntington's disease, in addition to chronic chorea and dementia, may also, in a small minority of patients, cause manic symptoms, which range from simple 'excitement' (Oliver 1970) or 'euphoria' (Tamir et al. 1969) to a fuller syndrome with delusions of grandeur (Bolt 1970; Heathfield 1967). Sydenham's chorea may, in addition to the acute onset of chorea, be characterized by mania (often with prominent lability [Adams 1975; Gatti and Rosenheim 1969]), which may in turn be characterized by prominent hallucinations and delusions, typically of persecution (Powell 1889; Reaser 1940; Shaskan 1938; Van Der Horst 1947). Chorea gravidarum, which essentially represents a recurrence of Sydenham's chorea during pregnancy, may also, in addition to chorea, be characterized by mania (Wilson and Preece 1932). Cushing's syndrome may produce manic symptoms, which have been noted in 11% (Starkman et al. 1981) to 30% (Haskett 1985) of cases. Other symptoms of Cushing's syndrome, such as weight gain, hypertension, diabetes mellitus, acne, hirsutism, and easy bruising, accompany these manic changes (Haskett 1985) and serve to suggest the correct diagnosis. Thyrotoxicosis may be accompanied by mania (Lee et al. 1991; Trzepacz et al. 1988), the correct diagnosis usually being suggested by such signs as proptosis, tremor, and tachycardia. In one case (Ingham and Nielsen 1931), however, the only clue as to the correct diagnosis was a tachycardia of 130 beats per minute. The patient,, a 53-year-old male, had: [prominent] 'psychomotor hyperkinesis. His thought processes were so rapid that he could not wait for a question to be asked but would complete the question himself and answer it. He could not stand still but turned and swayed while carrying on a conversation ... he had definite hallucinations of sight. Somatic delusions were numerous, especially the delusion that he had syphilis with paralysis.

Cerebral tumors may be characterized by mania, and this has been noted with a tumor of the mesencephalon (Greenberg and Brown 1985), a craniopharyngioma (Malamud 1967) or pituitary adenoma (Alpers 1940) compressing the overlying hypothalamus, a glioma of the right thalamus (Stern and Dancey 1942), and bifrontal meningiomas (Starkstein et al. 1988). As an aside, it is worth noting the remarkable ability of hypothalamic disturbances to cause mania. In one case (Alpers 1940), the patient was undergoing surgery for the removal of a craniopharyngioma; when the surgeon produced traction on the hypothalamus, 'the patient burst forth in a push of speech, quoting passages in Latin, Greek and Hebrew ... and with every word of the [surgeon] broke into a flight of ideas.' Intercurrent seizures accompanying an ongoing mania suggest an underlying mass lesion. For example, mania secondary to a tumor in the right cingulate gyrus was accompanied by complex partial seizures (Angelini et al. 1980) and that secondary to a parasaggital meningioma by convulsions (Oppler 1950). In another case (Gross and Herridge 1988), mania secondary to an arteriovenous malformation of the inferior right frontal lobe was accompanied by complex partial seizures and a Babinski sign on the left. Multiple sclerosis has long been associated with manic symptomatology; indeed, Cottrell and Wilson (1926), noted euphoria in 63% of their 100 patients. Subsequent case series have reported a lower rate, varying from 42% (Rabins et al. 1986) to 26% (Surridge 1969), and a nationwide survey in Israel found euphoria in only 5% of cases (Kahana et al. 1971). Of all

Syndromes of disturbances of mood and affect 267

reasons underlying the admission of patients with multiple sclerosis to a psychiatric hospital, mania is, however, one of the most common: in one study, of over 2000 psychiatric admissions, 10 had multiple sclerosis, and of these 10,7 were admitted because of mania (Pine et al. 1995). Importantly, in patients with multiple sclerosis, the presence of mania correlates with brain, rather than spinal cord, involvement (Rabins et al. 1986). Systemic lupus erythematosus may be marked by manic symptoms, but other typical symptoms, such as rash, arthralgia, pleurisy, pericarditis, nephritis or cytopenia, suggest the diagnosis (Johnson and Richardson 1968). Vitamin B12 deficiency may, very rarely, present with mania, as was reported in one 81-yearold male (Goggans 1984). Hepatic encephalopathy is often characterized by manic symptomatology, with euphoria and gregariousness (Murphy et al. 1948). Uremia may rarely present with mania: in one case (El-Mallakh et al. 1987) the only sign of uremia, despite a blood urea nitrogen level of 100 mg/dL and a creatinine concentration of 5.0 mg/dL, was mania. Creutzfeldt-Jakob disease is rarely characterized by mania, and in one very rare case, the disease presented with mania (Lendvai et al. 1999). Ictal mania may occur as an aura or as part of a complex partial seizure. Dostoyevsky described his ecstatic aura as follows: 'the air was filled with a big noise ... I felt that Heaven was going down upon the Earth and that it had engulfed me. I have really touched God ... healthy people ... can't imagine the happiness which we epileptics feel during the second before our fit ... for all the joys that life may bring, I would not exchange this one' (Alajouanine 1963). Complex partial seizures may themselves occasionallly be characterized by manic symptoms: one patient (Mulder and Daly 1952), during her attack, 'was euphoric, talkative and pleasant. When asked how she felt, she replied "wonderful"'. Post-ictal psychoses may be characterized by mania (Barczak et al. 1988; Kanemoto et al. 1996). In the case of one patient (Logsdail and Toone 1988), a 'run' of complex partial seizures, with or without secondary generalization, would be followed within a day by euphoria, overtalkativeness, and grandiose and persecutory delusions. MANIA OCCURRING WITH PRECIPITANTS Closed head injury may result in diffuse axonal injury, subdural hematoma, contusions (especially in the orbitofrontal and inferior temporal areas), and lacerations. Mania was found in 9% of 66 patients recovering from a closed head injury over a 1 year follow-up, a correlation being found between this sequela and damage to the inferior and polar regions of the temporal lobes, either on the left or on the right (Jorge et al. 1993b). In some cases, the mania may appear almost immediately after the patient recovers from the post-coma delirium (Bakchine et al. 1989; Bracken 1987), or after an interval of months (Clark and Davison 1987; Nizamie et al. 1988). Although, in most cases, the mania is either persistent or eventually remits without recurrence, there may rarely be an episodic course, closely resembling that seen in bipolar disorder, with alternating episodes of mania and episodes of depression (Parker 1957). The manic syndrome following closed head injury may be quite classic in character (Bakchine et al. 1989); one patient (Bracken 1987) with euphoria, pressured speech, and flight of ideas had the grandiose delusion that he was writing a 'best seller'. Hemodialysis may cause mania (Cooper 1967); in one patient, mania was the presenting sign of a dialysis dementia (Jack et al. 1983). Post-infectious encephalomyelitis results from an autoimmune assault on the brain triggered by a preceding, usually viral, infection and generally has an acute onset within 2-21 days of

268 Signs, symptoms and syndromes

the initial infection. Although the typical presentation is with delirium, a mania may occasionally appear. In one case (Moscovich et al. 1995), 2 weeks after an influenza infection, a 32-year-old female developed mania, which remained the only indication of the underlying encephalitis for almost 2 weeks, after which she became delirious and incontinent. In another case (Paskavitz et al. 1995), a post-mononucleosis encephalitis presented with a combination of mania and a grand mal seizure. Postpartum psychosis has an abrupt onset between 3 days and several weeks after delivery (Munoz 1985) and is, in many cases, characterized by manic symptoms (Brockington et al. 1981). Importantly, these patients are well at other times, and although they may have recurrent postpartum psychoses after subsequent deliveries (Hadley 1941; Kumar et al. 1983), they do not have manic symptoms outside the puerperium. This is the critical difference between postpartum psychosis and bipolar disorder, for although female patients with bipolar disorder may indeed have manic episodes in the puerperium, they also have them at other times in their lives (Bratfos and Haug 1966). Encephalitis lethargica typically presents with headache, fever, sleep reversal, delirium, and oculomotor paralyses. In some cases, patients display euphoria, sometimes accompanied by lability and pressured speech (Hohman 1921). Corticosteroids orACTH (Minden et al. 1988) may induce mania. In a double-blind study of 80 mg prednisone in normal subjects, 75% experienced manic symptomatology such as euphoria, irritability, increased energy, and increased talkativeness within 5 days (Wolkowitz et al. 1990). Acute exacerbations of multiple sclerosis are often treated with methylprednisolone and or prednisone, and in one study of 240 such patients, four became euphoric (Lyons et al. 1988). Some patients may be exquisitely sensitive to corticosteroids, as for example one patient with bipolar disorder in remission who developed mania after using a steroid nasal spray (Goldstein 1989). Anabolic steroid abuse, as seen in weight-lifters (Pope and Katz 1994) and American football players (Pope and Katz 1988), may cause mania, which may be marked by extreme irritability and violence (Pope and Katz 1990). Manic symptoms occurring in a 'bulked-up' athlete should always suggest anabolic steroid use and prompt a search for corroborating clinical evidence, such as gynecomastia and testicular atrophy (Pope and Katz 1994). Levodopa, as used in Parkinson's disease, may cause mania (Ryback and Schwab 1971; Van Woert et al. 1971), which has been noted in 10% of 20 patients (O'Brien et al. 1971) and 9% of 45 patients (Celesia and Barr 1970). Celesia and Barr's (1970) patients became euphoric with 'excessive self-confidence, over optimism, buoyancy, lack of inhibition, exaggerated motor activity and drive. They made inappropriate jokes, were garrulous, and were often impudent.' In some cases, levodopa-induced mania may be accompanied by hallucinations (Lin and Ziegler 1976). It sometimes appears that patients have abused levodopa in order to remain manic (Giovannoni et al. 2000). Zidovudine, as used in the treatment of AIDS, may cause mania (Maxwell et al. 1988; O'Dowd and McKegney 1988; Wright et al. 1989). Antidepressants (including bupropion [Fogelson et al. 1992]) may precipitate mania in patients with bipolar disorder (Stoll et al. 1994). Furthermore, there is some evidence, albeit controversial, that antidepressants may induce rapid cycling in these patients (Altshuler et al. 1995). Oral contraceptives may cause a combination of mania and chorea (Sale and Kalucy 1981). Other medications capable of inducing mania include isoniazid (Chaturvedi and Upadhyaya 1988; Jackson 1957), buspirone (Liegghid and Yeragani 1988; Price and Bielfeld 1989), bromide (Sayed 1976), procyclidine (in high dose [Coid and Strang 1982]), procarbazine (Mann and Hutchinson 1967), and propafenone (Jack 1985).

Syndromes of disturbances of mood and affect 269

Baclofen discontinuation may cause mania: in one case (Kirubakaren et al. 1984), 6 days after discontinuing treatment with 80 mg/day baclofen, the patient developed mania accompanied by chorea, tremor, and torticollis, all the symptoms resolving with the reinstitution of treatment. Reserpine discontinuation may also cause mania. In this case (Kent and Wilber 1982), the patient was an 85-year-old female who had taken 0.1 mg reserpine daily for 20 years; 3 days after discontinuing it, she became euphoric and hyperactive, had loud, rapid speech and was awake all night. She also had visual hallucinations such as 'animals dancing before my eyes'. One week after restarting the reserpine, she recovered. Methyldopa discontinuation (Labbatte and Holzgang 1989) has also been noted to cause mania. Aspartame, taken in a high dose, caused mania and a seizure in one patient (Walton 1986). Metrizamide myelography was followed within 7 hours by mania, which resolved spontaneously after 9 days (Kwentus et al. 1984). MISCELLANEOUS CAUSES OF MANIA

Metachromatic leukodystrophy may, very rarely, present with mania. One patient, a 22-year-old female (Besson 1980), was grandiose, 'spent money irresponsibly ... and called out the fire brigade'; she eventually became demented after several years. Adrenoleukodystrophy, when occurring in the adult years, often presents with a dementia, the dementia in one case (Weller et al. 1992) being accompanied by mania. Tuberous sclerosis, in a very rare case, presented with classic mania in a 5-year-old child (Khanna and Borde 1989).

Some remarks regarding the localizing and lateralizing value of mania A review of the cases of mania secondary to strokes and mass lesions allows for some speculation regarding both the localizing and the lateralizing value of this syndrome. The localizing value of mania does not appear to be high as it has been noted with lesions of the mesencephalon (Blackwell 1991; Greenberg and Brown 1985; Kulisevsky et al. 1995), thalamus (Bogousslavsky et al. 1988; Cummings and Mendez 1984; Gentilini et al. 1987; Kulisevsky et al. 1993; Liebson 2000; McGilchrist et al. 1993; Starkstein et al. 1988a; Stern and Dancey 1942), hypothalamus (Alpers 1940; Malamud 1967), anterior limb of the internal capsule and adjacent head of the caudate (Starkstein et al. 1990c), cingulate gyrus (Angelini et al 1980), and frontal (Benjamin et al 2000; Gross and Herridge 1988; Starkstein et al 1988b, 1990c) and temporal lobes (Starkstein et al 1990c). The lateralizing value of mania may, however, be higher. In all but one of the instances cited above, the lesion responsible for mania was either on the right side or bilateral: in only one case, namely after the excision of an arteriovenous malformation from the left frontal lobe (Benjamin et al. 2000), did mania occur secondary to a left-sided lesion. This impression is bolstered by some controlled studies: although not all agree (House et al 1990), it appears that when the frontal, temporal, or limbic areas of the cerebrum are involved, mania is more likely with right-sided lesions (Robinson et al. 1988; Starkstein et al 1987b). This impression is further reinforced by a study of 19 patients who underwent hemispherectomy: of the 14 who had a right hemispherectomy, 12 became euphoric and none depressed; of the 5 who had a left hemispherectomy, 1 was euphoric, 1 was depressed, and the other 3 showed no mood change (Sackeim et al 1982).

270 Signs, symptoms and syndromes

Treatment of the syndrome Treatment efforts are directed at the underlying cause of the mania. Should that not be possible, or should the mania be so severe as to require immediate symptomatic measures pending effective treatment of the underlying condition, pharmacologic measures should be considered. In general, proceeding by analogy with the acute treatment of mania in bipolar disorder, as discussed in Chapter 20, p. 651, most clinicians have utilized one of the three principal moodstabilizing agents: lithium, divalproex, or carbamazepine. In very severe cases, again proceeding by analogy with bipolar disorder, either lorazepam or a neurolpetic such as haloperidol or chlorpromazine may be used emergently pending the effectiveness of the mood stabilizer. Corticosteroid-induced mania has been best studied, and both lithium (Falk et al. 1979; Siegal 1978) and valproic acid (Abbas and Styra 1994) have been used preventively in patients who have experienced mania during prior courses of steroid treatment. With regard to mania following closed head injury, there are reports of the successful use of valproic acid (Pope et al. 1988), electroconvulsive therapy (Clark and Davison 1987), and, interestingly, clonidine (Bakchine et al. 1989). In one case of zidovudine-induced mania, lithium was effective (O'Dowd and McKegney 1988). Overall, and all other things being equal, divalproex is probably a reasonable first choice and should certainly be considered in cases in which seizures are a possibility. Lithium is often poorly tolerated in patients with cerebral lesions, and carbamazepine is, by and large, more difficult to use than divalproex.

ANXIETY Description of the syndrome Anxiety is, in addition to an anxious mood, typically also accompanied by various autonomic symptoms, such as a rapid, fine tremor, tachycardia, and diaphoresis, and may occur in either a paroxysmal or a non-paroxysmal fashion. Differential diagnosis of the syndrome Anxiety is an ubiquitous normal human experience and is not considered pathologic unless it occurs de novo without any precipitants or, if there are precipitants, the severity or duration of the anxiety is significantly out of proportion to the precipitant itself. Anxiety is commonly found in depression, and whenever evaluating a patient for anxiety, one must look for a depressed mood and vegetative signs and symptoms: missing the diagnosis of depression is probably the most common error in the diagnostic work-up of a patient complaining of anxiety. Evaluating a patient with pathologic anxiety is facilitated by dividing the various causes of anxiety into several groups, as in Table 6.4. First determine whether the anxiety is associated with various medications or drugs, or their withdrawal, for example caffeine use or alcohol withdrawal. Next, determine whether or not the anxiety has a paroxysmal onset, that is to say, whether it exists in more or less well-circumscribed attacks or, conversely, exhibits a gradual onset with a more or less chronic course. Paroxysmal anxiety is typified by the 'panic attacks' seen in panic disorder and by simple partial seizures, which may present with anxiety alone. Non-paroxysmal anxiety has as its prototype generalized anxiety disorder, but it may also be seen after a stroke or, classically, in hyperthyroidism.

Syndromes of disturbances of mood and affect 271 Table 6.4 Causes of anxiety Associated with various medications or drugs, or their withdrawal

Caffeine Cannabis Lysergic diethylamide (LSD) Levodopa Alcohol withdrawal Benzodiazepine withdrawal Nicotine withdrawal Anticholinergic withdrawal

Paroxysmal anxiety

Panic disorder Partial seizures Parkinson's disease Pheochromocytoma Hypoglycemia Paroxysmal atria I tachycardia Angina or myocardial infarction Pulmonary embolus Asthmatic attack Phobias Post-traumatic stress disorder Obsessive-compulsive disorder

Non-paroxysmal anxiety

Generalized anxiety disorder Post-stroke Post severe head trauma Hyperthyroidism Cushing's syndrome Hypocalcemia Chronic obstructive pulmonary disease Congestive heart failure

ASSOCIATED WITH VARIOUS MEDICATIONS OR DRUGS, OR THEIR WITHDRAWAL

Caffeine, taken in excessive amounts, may cause chronic anxiety, tremulousness, and tachycardia (Greden 1974; Hughes et al. 1991a). Cannabis intoxication may, in a minority, turn 'bad', leading to severe anxiety (Bromberg 1934). Lysergic diethylamide (LSD) intoxication may, likewise, become a 'bad trip', with severe anxiety and Tearfulness (Isbell et al. 1956; Kuramochi and Takahashi 1964). Levodopa, as used in Parkinson's disease, may, in a minority of cases, cause anxiety (Celesia and Barr 1970). Alcohol withdrawal is classically characterized by anxiety, tremulousness, and easy startability (Isbell et al. 1955). Benzodiazepine withdrawal, like alcohol withdrawal, is characterized by anxiety; such withdrawal may also occur after an abrupt discontinuation of therapeutic doses (Rickels et al. 1990). Nicotine withdrawal is characterized by anxiety, irritability, and a craving for a smoke (Hughes and Hatsukami 1986; Hughes et al. 1991b). Anticholinergic withdrawal, occurring after an abrupt discontinuation of drugs with strong anticholinergic properties, such as tricyclic antidepressants, may cause anxiety, jitteriness, insomnia, and nausea (Dilsaver et al. 1983).

272 Signs, symptoms and syndromes

PAROXYSMAL ANXIETY

Panic disorder is characterized by prototypical anxiety attacks, or 'panic attacks', consisting of the abrupt onset of severe anxiety and autonomic symptoms (e.g. tremor and tachycardia) that rapidly crescendo and then gradually defervesce, the entire attack usually lasting less than one-half hour. Such attacks may also awaken patients from sleep (Mellman and Uhde 1989) and may, in a minority, be accompanied by such 'temporal lobe phenomena' as micropsia and macropsia (Coyle and Sterman 1986). Partial seizures may present with paroxysmal anxiety of an intense degree. In the case of complex partial seizures, the aura to the seizure may consist of fear (Daly 1958; Weil 1959); in the case of simple partial seizures, anxiety may constitute the sole expression of the seizure. Although such ictal anxiety often lasts only seconds or minutes (Williams 1956), the seizure may in rare cases be very prolonged: one patient for 12 hours endured ictal fear of such a degree that she 'continually looked back over her shoulder' (McLachlan and Blume 1980); another suffered from an 'almost continuous' state of anxiety for 3 months (Henriksen 1973). There are two clues to the correct diagnosis of these simple partial seizures: first, the exquisitely paroxysmal nature of the onset, and second, the occurrence, at other times in the patient's life, of more obvious ictal phenomena such as complex partial or grand mal seizures. Parkinson's disease will, in a significant minority of levodopa-treated patients, be characterized by anxiety attacks during the 'off' interval as the effectiveness of the previous dose of levodopa wanes (Vazquez et al. 1993). Pheochromocytoma may present with paroxysms of anxiety, headache, and hypertension (Doust 1958; Modlin et al. 1979; Starkman et al 1985; Thomas et al. 1966). Hypoglycemia, as may be seen in diabetics treated with insulin or oral hypoglycemics who omit meals, is characterized by anxiety, tremulousness, tachycardia, diaphoresis, and hunger. Paroxysmal atrial tachycardia is suggested by the almost instantaneous onset of severe tachycardia, followed immediately by severe anxiety as the patient becomes aware of the fluttering in his or her chest. The onset with tachycardia is suggestive, and the ability of the patient to terminate the attack with a Valsalva maneuver is also suggestive of the diagnosis. Angina or myocardial infarction may, in a minority, present primarily with anxiety, chest discomfort and dyspnea being relatively minor symptoms. A history of risk factors (e.g., smoking, hypertension, and hypercholesterolemia) suggests the diagnosis, which is confirmed, in the case of angina, by relief with nitroglycerine. Pulmonary embolus, at the moment of its lodging in a large artery, can produce severe anxiety and dyspnea. The diagnosis is suggested by the dyspena and by such clinical settings as prolonged immobilization or deep venous thrombophlebitis. Asthmatic attacks may be characterized by severe anxiety and wheezing. Phobias, including simple phobia, social phobia, and agoraphobia, may all be characterized by anxiety attacks when patients are brought into close proximity to the phobic object, such as a snake for a simple phobic, speaking to an audience for the social phobic with a fear of public speaking, and venturing away from home for the agoraphobic. Post-traumatic stress disorder may also be characterized by anxiety attacks when patients are exposed to events or objects that remind them of the original trauma, thus, a combat veteran might be seized with anxiety if a combat scene appeared on a television program. Obsessive-compulsive disorder may likewise be characterized by anxiety attacks when patients attempt to resist their compulsions. Thus, patients with a hand-washing compulsion may experience unbearable anxiety if they attempt to resist the urge to wash.

Syndromes of disturbances of mood and affect 273

NON-PAROXYSMAL ANXIETY

Generalized anxiety disorder is characterized by the gradual onset of chronic anxiety that flucuates in severity and is accompaneid by such symptoms as tremulousness, tension, headache, and insomnia (Anderson et al. 1984; Nisita et al. 1990). Post-stroke anxiety occurs chronically in a minority of patients and appears to be more likely with a right hemisphere infarction (Castillo et al. 1993, 1995; Starkstein et al. 1990b). Post severe head trauma may cause chronic anxiety in a small minority of those who survive (Fann et al. 1995; Jorge et al. 1993a). Hyperthyroidism classically causes chronic anxiety and may be suggested by such signs and symptoms as heat intolerance, diaphoresis, and lid retraction (Dietch 1981; Greer et al. 1973; Kathol and Delahunt 1986; MacCrimmon et al. 1979; Trzepacz et al. 1988). Cushing's syndrome, although classically associated with depression, may at times be characterized by severe anxiety (Kelly 1996). The diagnosis is suggested by such features as a 'moon' facies, buffalo hump, acne, hirsutism, violaceous abdominal striae, hypertension, and diabetes mellitus. Hypocalcemia, as seen with hypoparathyroidism (Carlson 1986; Denko and Kaelbling 1962; Lawlor 1988), may cause anxiety, which in turn may or may not be accompanied by other signs such as tetany or Chvostek's or Trousseau's sign. Chronic obstructive pulmonary disease and congestive heart failure may both leave patients not only chronically dyspneic, but also chronically anxious. The physical examination immediately suggests the correct diagnosis. Treatment of the syndrome Treatment of the underlying condition generally relieves the anxiety. Should this not be possible, cautious use of an anxiolytic may be appropriate. Benzodiazepines are popular, and of the benzodiazepines, either lorazepam or clonazepam is a reasonable choice.

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7 Other major syndromes Psychosis

285

Personality change

293

Seizures and epilepsy

302

PSYCHOSIS In the past, the word 'psychosis' has been used loosely, the definition at times being so broad as to render the word almost meaningless. In this chapter, the definition is tightened such that if the clinician abides by it, the work of differential diagnosis will be significantly lightened.

Description of the syndrome Psychosis is a syndrome of multiple different etiologies characterized by the occurrence of delusions or hallucinations in the absence of significant confusion or other cognitive deficits (e.g. deficient calculating ability). Importantly, in cases in which only hallucinations appear, it is necessary that the patient believe that the hallucinatory experience is real.

Differential diagnosis of the syndrome Delirium and dementia are clearly distinguished by the presence of confusion or other cognitive deficits. Although patients with delirium or dementia not uncommonly suffer delusions or hallucinations, these symptoms occur in the context of confusion or other cognitive deficits rather than appearing by themselves, as in a psychosis. This is a critical distinction to make as the differential diagnoses for delirium or dementia are quite different from those for psychosis. Hallucinations with preserved 'insight' do not merit the diagnosis of a psychosis. 'Insight', a much-belabored term, means here simply that the patient is aware that the hallucinatory experience is just that, an hallucination and not 'real'. Consider for example, two patients, both of whom reported seeing a 'dog' in the hospital room. In the first case, the patient commented, 'It looks real, but I know it's not; it's just my imagination', whereas in the second case, the patient got out of bed to pat the dog. The first patient, with preserved insight, would be said to have an isolated hallucination only, as discussed in Chapter 4, whereas the second patient would merit the diagnosis of a psychosis.

286 Signs, symptoms and syndromes

Depression and mania, especially when severe, may be accompanied by delusions or hallucinations, but as these symptoms appear only in the context of the depression or mania, they do not call for an additional diagnosis of psychosis. Although some authors may use terms such as 'psychotic depression' or 'depression with psychotic features', it is important, in such cases, to look to the differential diagnosis for the appropriate mood disturbance rather than to that for psychosis. Both obsessive-compulsive disorder (Eisen and Rasmussen 1993; Gordon 1950; Insel and Akiskal 1986) and body dysmorphic disorder (McElroy et al. 1993) may have psychotic subtypes wherein patients 'lose insight' and come to accept their troubling ideas as true. Thus, a patient with obsessive-compulsive disorder might come to believe that his troubling need to pray recurrently was, in fact, ordained by God (Gordon 1950), or a patient with body dysmorphic disorder may come to believe that his or her face, in fact, is deformed. Patients with a borderline personality disorder may, when under great stress, develop transient auditory hallucinations or delusions of persecution (Chopra and Beatson 1986): such patients are distinguished by the chronic characteristic traits of intolerance of being alone, anger, impulsivity, and disturbed relationships (Gunderson and Kolb 1978). Finally, simulated psychoses, as seen in malingering, factitious illness andfolie a deux, must be distinguished from 'true' psychoses. Malingerers may simulate a psychosis in order to avoid unpleasant consequences, as may occur in prisoners facing trial (Tsoi 1973). Factitious psychosis is said to occur when the simulation has the purpose of simply being a patient in the hospital (Pope et al. 1982). Folie a deux, is said to occur when a person with a true psychosis, usually paranoid schizophrenia, exerts such a profound influence on close relatives or acquaintances that they come to adopt the patient's own delusional beliefs as true. Importantly, in such cases, if the psychotic person is successfully treated or if a prolonged separation is enforced, the others gradually come to see the falseness of the patient's beliefs (Dewhurst and Todd 1956; Kashiwase and Kato 1997; Partridge 1950; Waltzer 1963). Once the syndromal diagnosis of psychosis is secure, the next step is to determine the cause of the psychosis in question. Table 7.1 lists the various causes of psychosis, organized into groups designed to facilitate the task of differential diagnosis. The first group includes three idiopathic disorders, namely schizophrenia, schizoaffective disorder and delusional disorder. Although these three disorders account for the overwhelming majority of cases of chronic psychosis, other causes must not be ignored. There is a saying in medicine that 'when one hears hoofbeats, think horses instead of zebras'. In the case of the hoofbeat of psychosis, these three idiopathic disorders represent the horses, and although in most cases one of them will in fact account for the chronic psychosis in question, that fact must not lull one into diagnostic complacency: the other groups must also be considered. The first of these groups to consider includes those psychoses associated with precipitants, such as those induced by drugs of abuse or by medications. Following this are those psychoses which present acutely secondary to stroke. Psychoses with an encephalitic onset, considered next, are suggested by an acute onset with fever, headache, or lethargy. Psychoses associated with epilepsy are not uncommon, and a history of seizures should be sought in any patient with psychosis. Psychoses with specific associated features, such as the chorea of Huntington's disease, are considered next: the specific associated features are listed in the table for easy review. Finally, there is a miscellaneous group, which must not be neglected, including, as it does, psychoses secondary to such disorders as cerebral tumors and Wilson's disease. IDIOPATHIC DISORDERS

Schizophrenia is by far the most common cause of chronic psychosis. The onset typically occurs in the late teens or early twenties with the subacute or gradual elaboration of a

Table 7.1. Causes of psychosis Idiopathic disorders

Schizophrenia Schizoaffective disorder Delusional disorder

Associated with precipitants

Drugs of abuse and medications Amphetamines Cocaine Hallucinogens Phencyclidine Cannabis Anabolic steroids Chronic alcoholism (alcoholic paranoia and alcohol hallucinosis) Neuroleptic-induced supersensitivity psychosis Dopaminergic drugs (levodopa, bromocriptine, and lergotrile) Disulfiram Phenylpropanolamine Phenylephrine Bupropion Fluoxetine Vigabatrin Baclofen withdrawal Other precipitants Postpartum psychosis Postencephalitic psychosis Traumatic brain injury

Secondary to stroke

Temporoparietal area Frontal lobe Thalamus

Encephalitic onset

Herpes simplex encephalitis Infectious mononucleosis Encephalitis lethargica

Associated with epilepsy

Ictal psychosis Post-ictal psychosis Psychosis of forced normalization Chronic interictal psychosis

With specific associated features

Huntington's disease (chorea) Sydenham's chorea (chorea) Chorea gravidarum (chorea) Manganism (parkinsonism) Creutzfeldt-Jakob disease, especially the new-variant type (myoclonus) Hashimoto's encephalopathy (myoclonus) AIDS (AIDS-related illnesses, e.g. thrush and Pneumocystis pneumonia) Systemic lupus erythematosus (arthralgia, rash and pericarditis or pleurisy) Hyperthyroidism (tremor and tachycardia) Hypothyroidism (cold intolerance, voice change, constipation, hair loss, and myxedema) Cushing's syndrome ('Cushingoid' habitus, e.g. moon facies) Adrenocortical insufficiency (abdominal complaints and dizziness) Hepatic porphyria (abdominal pain) Autosomal dominant cerebellarataxia (ataxia) Prader-Willi syndrome (massive obesity)

288 Signs, symptoms and syndromes Table 7.1. Causes of psychosis - continued

Miscellaneous

Cerebral tumors Wilson's disease Multiple sclerosis Neurosyphilis Vitamin B12 deficiency Metachromatic leukodystrophy Subacute sclerosing panencephalitis Fahr's syndrome Thalamic degeneration Aqueductal stenosis

psychosis characterized by varying combinations of hallucinations, delusions, incoherence, and bizarre behavior. In many cases, the symptomatology will crystallize into an enduring and recognizable subtype: paranoid, hebephrenic, catatonic, or simple (Fenton and McGlashon 1991; Kendler et al. 1994). Although the symptoms gradually wax and wane over time, the illness is generally chronic and lifelong, almost never going into a spontaneous and full remission. Schizoaffective disorder is, like schizophrenia, characterized by a chronic psychosis: the difference is that in schizoaffective disorder, one also finds recurrent episodes of either depression or mania, during either of which the chronically present psychotic symptoms undergo a significant exacerbation. Delusional disorder, also like schizophrenia, is characterized by a chronic psychosis: here, however, hallucinations, incoherence, and bizarre behavior are negligible or absent, the primary or sole symptom of the illness being one or more delusions. Importantly, these delusions are not bizarre but indeed have a certain plausibility to them (Kendler 1980; Opjordsmoen and Rettersol 1991; Winokur 1977). Certain variants of this disorder deserve special mention: parasittosis is characterized by a persistent belief that one is infested by some parasitic bug or other (Andrews et al. 1986; Mitchell 1989) and the olfactory reference syndrome by a delusion that one is emitting a foul odor (e.g. as in halitosis or flatus) that others detect and comment on (Videbech 1966). ASSOCIATED WITH PRECIPITANTS

Amphetamines, if taken in a sufficiently high dose, may cause a psychosis (Bell 1973; Griffith et al. 1972) that is typically characterized by delusions of persecution and often of reference. Hallucinations may also occur, being much more commonly auditory than visual. The psychosis typically clears within a week, but in some cases longer durations, of up to 3 months, have been seen (Iwanami et al. 1994). Cocaine may cause a psychosis characterized by hallucinations, more often auditory than visual, and delusions of persecution and reference (Brady et al. 1991; Satel et al. 1991; Sherer et al. 1988). Although such a psychosis may occur in 'recreational' users (Siegel 1978), it is more characteristic of addicts, who often note that a progressively lower 'dose' becomes capable of inducing the psychosis (Brady et al. 1991). Although, in most cases, the psychosis clears either with the intoxication itself or shortly thereafter, it may persist in some until after the withdrawal 'crash' resolves (Satel et al. 1991). Hallucinogens, such as LSD, typically cause visual hallucinations, but most patients remain aware of their unreality. In a minority, however, the intoxication will be complicated by delusions of persecution (Bercel et al. 1956; Kuramochi and Takahashi 1964).

Other major syndromes 289

Phencyclidine intoxication may render patients agitated and psychotic (Allen and Young 1978), with delusions of grandeur or persecution and auditory hallucinations. The finding of nystagmus is a very important diagnostic clue. Cannabis intoxication, if a sufficiently high dose is taken, may be characterized by fearfulness and delusions of persecution and reference (Kroll 1975; Thacore and Shukla 1976) that may outlast the intoxication itself by a matter of days. Anabolic steroids, as may be abused by athletes, may, in a small minority, cause a psychosis variously characterized by delusions of persecution or grandeur, delusions of reference, and auditory hallucinations (Pope and Katz 1988). The appearance of a psychosis in a 'bulked-up' young person should suggest this diagnosis. Chronic alcoholism may be complicated by two different psychoses: alcoholic paranoia and alcohol hallucinosis. Alcoholic paranoia (Albert et al. 1996; Soyka et al. 1991) is characterized by the gradual development of delusions, often of either jealousy or persecution. By contrast, alcohol hallucinosis typically appears as a sequela to an alcohol withdrawal delirium: whereas the other symptoms of the DTs, such as tremor, clear, the auditory hallucinations, often accompanied by delusions of persecution, persist (Soyka 1990; Victor and Hope 1958). Neuroleptic-induced supersensitivity psychosis appears in a very small minority of patients treated with neuroleptics for a year or more and is characterized by delusions and hallucinations, which may appear either while the patient is still taking the neuroleptic or shortly after discontinuation or a significant dose reduction (Chouinard and Jones 1980; Steiner et al. 1990). This psychosis probably has an etiology similar to that of tardive dyskinesia and, like tardive dyskinesa, exists as a strong reminder not to use neuroleptics chronically unless they are absolutely necessary. Dopaminergic drugs, such as levodopa or directly acting agents, for example bromocriptine or lergotrile, as used in the treatment of parkinsonism, may cause a psychosis. In the case of levodopa (Celesia and Barr 1970;Fenelonetfl/. 2000; Moskovitz ef a/. 1978), the psychosis may occur either upon the initiation of treatment (Lin and Ziegler 1976) or only after many years (Friedman and Sienkiewicz 1991), and may be characterized by hallucinations, often visual but also auditory (Fenelon et al. 2000; Inzelberg et al. 1998), and delusions of persecution (Graham et al. 1997). Both bromocriptine and lergotrile are reported to cause hallucinations and delusions of persecution (Serby et al. 1978). Disulfiram, as used in the treatment of alcoholism, may cause delusions and hallucinations accompanied by ataxia (Bicknell and Moore 1960). Phenylpropanolamine and phenylephrine, as used in the symptomatic treatment of colds, may rarely cause a psychosis with delusions and hallucinations (Lambert 1987). Bupropion (Golden et al. 1985), as used in the treatment of depression, has been noted to cause a psychosis. Fluoxetine, also an antidepressant, was in one case (Mandalos and Szarek 1990) noted to cause a dose-dependent syndrome of agitation and delusions of persecution and reference. Vigabatrin, an anticonvulsant not yet approved in the United States, may cause psychosis (Sander et al. 1991). Baclofen withdrawal may rarely be followed within about a week by a psychosis with agitation, delusions of persecution, and hallucinations (Swigar and Bowers 1986), accompanied, in one case, by a complex movement disorder, with chorea, tremor, and dystonia (Kirubakaren et al. 1984). Postpartum psychosis may appear between several days and several months postpartum and is often characterized by prominent agitation (Bagedahl-Strindlund 1986). Importantly, it is not uncommon for certain disorders, such as schizophrenia, to undergo an exacerbation postpartum, and such patients should not receive an additional diagnosis of postpartum psychosis.

290 Signs, symptoms and syndromes

Postencephalitic psychosis may occur as a sequela to an encephalitis such as herpes simplex encephalitis (Rennick et al. 1973) or encephalitis lethargica (Fairweather 1947). Traumatic brain injury may also be followed by psychosis (Buckley et al. 1993; Hillbom 195 l;Nasrallaheffl/. 1981). SECONDARY TO STROKE

Lesions of the temporoparietal area or frontal lobe may present with psychosis. Cerebral infarction in the temporoparietal area may present with a psychosis (Peroutka et al. 1982); in one case (Thompson and Nielsen 1949), the patient, a 58-year-old man, suddenly began to hear 'unusual noises which he believed were caused by wires placed in his house', and soon after, 'while in a restaurant, he suddenly declared that someone had put ground glass into his food. He then ran out of the restaurant into the street, shouting that his son-in-law had been killed after having been held captive by a gang of criminals.' In another case, a ruptured frontal lobe aneurysm presented acutely in a 23-year-old woman with auditory hallucinations, delusions of persecution, and loosening of associations (Hall and Young 1992). Thalamic infarction involving the right dorsomedial area was, in one case (Feinberg and Rapcsak 1989), associated with vivid visual hallucinations; indeed, the patient 'reached down to pat the dog' that he had hallucinated at his side. ENCEPHALITIC ONSET

Viral encephalitis is suggested by fever, headache, and lethargy, and may in some cases present with psychosis, as has been noted with herpes simplex encephalitis (Drachman and Adams 1962; Johnson et al. 1972; Williams and Lerner 1978; Wilson 1976) and infectious mononucleosis (Raymond and Williams 1948). Encephalitis lethargica may present similarly (Kirby and Davis 1921; Meninger 1926; Sands 1928) and is suggested by sleep reversal and oculomotor pareses. ASSOCIATED WITH EPILEPSY

The various psychoses seen in epileptics may be distinguished by their relationship to the seizures experienced by the patient. Ictal psychoses are in fact seizures and are immediately suggested by their paroxysmal onset. Post-ictal psychoses, as the name suggests, follow seizures and, critically, are separated from the last seizure by a 'lucid' interval. The psychosis of forced normalization represents a paradoxical event in that it appears when the patient's seizures are finally brought under control with anticonvulsant treatment. Finally, chronic interictal psychosis occurs in the setting of a chronically uncontrolled seizure disorder. Ictal psychosis consists of a complex partial seizure wherein there are, rather than confusion or other gross defect of consciousness, delusions and hallucinations (Ellis and Lee 1978; Wells 1975): the diagnosis is suggested by the paroxysmal onset of the psychosis and confirmed by finding ictal activity on the EEC. Post-ictal psychosis (Kanner et al. 1996; Lancman et al. 1994; Logsdail and Toone 1988; Savard et al. 1991; Umbricht et al. 1995) may follow a bout of seizures and, critically, is separated from the last seizure by a 'lucid' interval, lasting from hours to days, during which the patient's mental status is 'clear'. The psychosis itself is characterized by delusions of persecution and hallucinations, most commonly auditory, and may last for hours or months, although most patients clear spontaneously within a matter of days. Most patients have a long history of recurrent complex partial seizures. Psychosis of forced normalization is a relatively rare condition, first described by Landolt (1953, 1958) and characterized by the appearance of a psychosis after anticonvulsants

Other major syndromes 291

(Pakainis et al. 1987), or, in one case, vagus nerve stimulation (Gatzonis et al. 2000), have controlled the seizure disorder and 'normalized' the electroencephalogram (EEC). Chronic interictal psychosis may occur in the setting of chronic epilepsy, generally of over a decade in duration. Either insidiously or subacutely, patients develop a psychosis with delusions, often of persecution and reference, auditory hallucinations and various other symptoms, all of which occur in the setting of a clear sensorium (Kristensen and Sindrup 1979; Perez and Trimble 1980; Slater and Beard 1963a,b). WITH SPECIFIC ASSOCIATED FEATURES

Huntingtons disease is not uncommonly characterized by a combination of chorea and psychosis (Bolt 1970; Garron 1973; Heathfield 1967), and, albeit rarely, the disease may present with a psychosis (Caine and Shoulson 1983; Garron 1973; James et al. 1969): in such cases, the correct diagnosis may be suggested by a positive family history and confirmed by genetic testing. Sydenhams chorea may rarely be complicated by a psychosis with hallucinations and delusions (Hammes 1922; Putzel 1879), the diagnosis being immediately suggested by the context of subacutely developing chorea in a child or adolescent. Chorea gravidarum, Latin for 'chorea of pregnant women', may, rarely, be accompanied by psychosis (Beresford and Graham 1950; Wilson and Preece 1932). Manganism may present with a combination of parkinsonism and 'manganese madness', with excitation, delusions, and hallucinations (Abd El Naby and Hassanein 1965). Creutzfeldt-Jakob disease (Brown et al. 1984), especially the new-variant type (Zeidler et al. 1997b), may present with psychosis, the diagnosis finally being suggested by the appearance of myoclonus or a dementia. Hashimoto's encephalopathy very rarely presents with a combination of psychosis and myoclonus (Cohen et al. 1996). AIDS may cause a psychosis (Bulrich et al. 1988; Harris et al. 1991), and the presence of other AIDS-related illnesses, such as thrush or Pneumocystis pneumonia may serve to suggest the correct diagnosis. Rarely, AIDS may present with psychosis (Thomas and Szabadi 1987), and in such cases the diagnsois may prove elusive until other, more typical, features of AIDS make their appearance. Systemic lupus erythematosus may cause psychosis (Devinsky et al. 1988a; Johnson and Richardson 1968; Lim et al. 1988; Miguel et al. 1994), and although this usually occurs in the context of other symptoms, such as arthralgia, rash, pericarditis, or pleurisy, psychosis may rarely constitute the presenting feature of lupus (Agius et al. 1997). Hyperthyroidism may be accompanied by a psychosis, with prominent delusions of persecution: in one case, the hyperthyroid patient slashed his throat rather than let his 'persecutors' capture him (Ingham and Nielsen 1931). When the psychosis occurs in the setting of'thyroid storm' (Bursten 1961; Greer and Parsons 1968), the prominent autonomic signs (increased temperature, tachycardia, and tremor) immediately suggest the diagnosis; however, when the responsible hyperthyroidism is milder, the diagosis may be elusive (Hodgson et al. 1992). Hypothyroidism may present with psychosis in a condition known as 'myxedema madness', typically characterized by delusions of persecution and reference and by hallucinations, generally auditory (Asher 1949). The delusions of persecution may at times be so compelling that patients become assaultive (Reed and Bland 1977); in other cases, patients may be reduced to a seclusive 'mumbling' (Karnosh and Stout 1935). Pertinent clues to the correct diagnosis include slowness and a certain 'fogginess' of thought, cold intolerance, deepening of the voice, constipation, hair loss, and myxedema of the face, supraclavicular fossae, and dorsa of the hands and feet.

292 Signs, symptoms and syndromes

Cushing's syndrome may be characterized by a psychosis, the diagnosis being suggested by the typical cushingoid habitus of moon facies, truncal obesity, buffalo hump, violaceous abdominal striae, and so on. One patient had classic Schneiderian first rank symptoms, including audible thoughts, thought broadcasting and thought insertion (Trethowan and Cobb 1952), whereas another presented with auditory hallucinations and delusions of a grandiose and religious nature (Hertz et al. 1955). Adrenocortical insufficiency is suggested by abdominal complaints (nausea, vomiting, diarrhea or constipation, and abdominal pain) and orthostatic hypotension with postural dizziness. A psychosis may rarely also be seen (Cleghorn 1951; McFarland 1963). Hepatic porphyria typically presents in attacks accompanied by abdominal pain, often with vomiting and constipation or, less commonly, diarrhea. Rarely, such patients may also have a psychosis (Mandoki and Sumner 1994), which, in one case, was accompanied by bizarre behavior (Hirsch and Dunsworth 1955). Autosomal dominant cerebellar ataxia, typically presenting with ataxia and other cerebellar signs, may also cause a psychosis with delusions of persecution (Chandler and Bebin 1956). In one family (Benton et al 1998), the disorder presented with auditory hallucination and delusions, eventually being joined by various abnormal movements. Prader-Willi syndrome, a rare disorder characterized by massive obesity and dysmorphic facies, may rarely cause a psychosis with delusions and hallucinations (Clarke 1993). MISCELLANEOUS

Cerebral tumors may present with psychosis, as has been noted with tumors of the frontal lobe (Strauss and Keschner 1935), corpus callosum (Murthy et al. 1997), and especially the temporal lobe (Gal 1958; Keschner et al. 1936; Malamud 1967; Strobos 1953; Tucker et al. 1986). Headache, seizures, or focal signs (e.g. paresis, aphasia, and apraxia) may suggest the correct diagnosis. Wilson's disease may cause psychosis (Beard 1959; Jackson and Zimmerman 1919), and although most such cases also have other, more typical symptoms (such as a movement disorder [Gysin and Cooke 1950]), the disease may present with a psychosis alone: indeed, one of Wilson's first patients presented in such a way (Wilson 1912). Multiple sclerosis may cause psychosis (Geocaris 1957; Langworthy et al. 1941; Mathews 1979), generally in the company of signs suggestive of disseminated lesions (e.g. concurrent with nystagmus [Parker 1956]). Rarely, multiple sclerosis may present with a psychosis, as in one patient who developed 'mystic' hallucinations and religious delusions, who eventually was found to have compatible lesions on magnetic resonance imaging (MRI) scanning (Fontaine etal 1994). Neurosyphilis rarely presents with a psychosis (Rothschild 1940; Schube 1934), and the diagnosis may remain elusive until other, more typical symptoms appear, such as a dementia, pupillary changes (e.g. Argyll Robertson pupil), tremor, or seizures. Vitamin B12 deficiency may present with psychosis. In one case, the diagnosis became clear only when symptoms of subacute combined degeneration appeared (Smith 1929), and in another, the only evidence of B12 deficiency was the psychosis itself: there was no anemia and no evidence of spinal cord involvement (Evans et al. 1983). Metachromatic leukodystrophy, although rare, is of particular interest in that it can cause a psychosis that very closely resembles that caused by schizophrenia (Hyde et al. 1992; Muller et al. 1969). Indeed, in some cases, it was not initially possible to distinguish between the two disorders until other symptoms suggestive of metachromatic leukodystrophy, as for example a peripheral neuropathy (Manowitz et al. 1978) or a dementia (Belts et al. 1968; Waltz et al. 1987) developed years later.

Other major syndromes 293

Subacute sderosing panencephalitis, a vanishingly rare disease in developed countries thanks to measles vaccination, may cause psychosis and myoclonus (Cape et al. 1973; Salib 1988) or may present with a psychosis, the diagnosis only becoming clear with the later appearance of a delirium (Duncalf et al. 1989; Koehler and Jakumeit 1976). Fahr's syndrome, or basal ganglia calcification, may rarely present with psychosis, as in one familial case wherein the illness was manifest symptomatically with basal ganglia calcification on imaging and a psychosis similar to that produced by schizophrenia (Francis and Freeman 1984). Thalamic degneration, a rare and poorly characterized disorder, in one case initially presented with bizarre behavior and delusions of persecution, which were over time joined by a dementia (Deymeer et al. 1989). Aqueductal stenosis, one of the causes of non-communicating hydrocephalus, has also been associated with a psychosis (Roberts et al. 1983).

Treatment of the syndrome Neuroleptics are required for each of the three idiopathic disorders, as described in Chapter 20. For the other causes, treatment of the underlying disease itself may be sufficient; where it is not, treatment with a neuroleptic may be instituted, much as described for schizophrenia (see Chapter 20). As noted there, the atypical neuroleptic olanzepine is a good first choice. In choosing among the other neuroleptics, due consideration must be given to the age and general medical condition of the patient; in many cases, 'starting low and going slow' is appropriate.

PERSONALITY CHANGE Every individual has a definite personality structure, which, once formed in childhood and adolesence, persists in a lifelong fashion, being very resistant to any modification. Thus, the appearance of a fundamental change in personality, that is to say a far-reaching transformation of the patient's characteristic personality traits, is an ominous clinical sign and demands prompt diagnostic evaluation. Although the change is in most cases non-specific in type, there do exist two fairly welldelineated types, namely the frontal lobe syndrome and the interictal personality syndrome, which are treated first. The frontal lobe syndrome is by far the more common of the two and is characterized by disinhibition and various other signs. The interictal personality syndrome is seen only in patients with long-standing epilepsy, and is characterized by a difficult to describe sign known as 'viscosity'. It must be borne in mind that the boundaries between these specific types and the non-specific type are not clear and that there is a large gray area. Thus, in cases in which the patient has an indisputable personality change that appears to fall within the frontal lobe type, but does not seem to be accounted for by any of the disorders listed in the differential diagnosis of the frontal lobe syndrome, it is entirely appropriate to look to the differential for the non-specific type. Many dementias are characterized not only by cognitive deficits, but also by a personality change, and in some cases the dementia may present with a personality change. Those dementing disorders, such as Alzheimer's disease, which not uncommonly present with a personality change are noted below; in those clinical situations in which a dementia is already well established, the reader should proceed to the section in Chapter 5 on dementia and pursue the differential diagnosis discussed there.

294 Signs, symptoms and syndromes

Many psychoses also are accompanied by an alteration in the sufferer's personality, this being particularly true of schizophrenia. The psychoses, however, are marked by delusions or hallucinations, symptoms not seen in personality change, and their presence should prompt the clinician to refer to the differential diagnosis for psychosis, as set forth above. Personality change of any type must be distinguished from what is known as a personality disorder. Personality disorders, for example borderline personality disorder or antisocial personality disorder, do not represent a change in the patient's personality makeup but rather have been present, at least in a nascent form, since childhood or adolescence. Rather than replacing a pre-existing personality structure, the personality disorder just does, in fact, constitute the patient's lifelong personality. Thus, in the history of an adult patient with a personality disorder, one finds that the various personality traits may be traced back into the patient's adolescence or childhood in a seamless and continuous fashion: by contrast, in a patient with a personality change, one finds a more or less distinct boundary in the history that separates the patient's original personality from that which currently exists. Relatives and friends may indicate such a change by saying that the patient is 'not himself any more. There are two syndromes, namely the environmental dependency syndrome (also known as 'utilization behavior') and the Kluwer-Bucy syndrome, that are considered by some to be personality changes: to this author, however, they are so dissimilar from any conceivable personality trait or type that they are discussed elsewhere, in Chapter 4. Frontal lobe syndrome DESCRIPTION OF THE SYNDROME

The frontal lobe syndrome is characterized by varying combinations of disinhibition, affective change (euphoria, irritability, or depression), perseveration, and abulia or apathy. Although it has become customary to delineate at least two subtypes, namely 'orbitofrontal' and 'dorsolateral', most patients do not fit neatly into one or the other subtype but rather display a mixture of symptoms. The orbitofrontal subtype is marked by disinhibition and mood changes, and the dorsolateral subtype is marked by perseveration and apathy. Disinhibited patients seem to lose regard for customs or morals: they may eat with gluttony, curse with no regard for company, and tell coarse and crude jokes. Inappropriate sexual advances are not uncommon, and patients may, with no hint of shame, proposition much younger individuals, even at times children. Some may engage in reckless masturbation, at the dinner table or in the front yard. Affective changes may have some lateralizing value: euphoria is seen more often with rightsided, and depression with left-sided, lesions. The euphoria may occasionally be accompanied by witzelsucht, or a tendency to make simple, silly puns. Perseveration is characterized by a tendency to repeat the same behavior over and over, as for example opening and closing a book, or buttoning and unbuttoning a shirt. Abulia represents an impoverishment of volition: without desires or impulses, patients may be content to sit for hours or days doing nothing. Importantly, such patients are not depressed and, if given close ongoing supervision, may be able to complete tasks with relative alacrity. Left to their own devices, however, and thus undisturbed by any urges to do things, patients rapidly lapse into placidity. Some examples may help to fix the picture of the frontal lobe syndrome. One case (Mulder et al. 1951) was marked by prominent disinhibition. The patient's wife complained that the patient:

Other major syndromes 295 no longer cared about his appearance, that he drove through red lights, threw bills in the wastebasket remarking they were 'only bills,' and frequently threatened to harm his family. He spilled his food on his clothing and on the floor, and to his family's dismay, he then picked it up and ate it. He did not wait for food to be served, but would snatch it off platters with his fingers as his wife neared the table. His sexual activity became uninhibited, and he sought intercourse with neighborhood children and prostitutes with no concern for possible consequences.

Another case (Moersch 1925) was marked by abulia and perseveration. The patient, a 54-yearold man was: brought to the clinic ... Because of loss of bladder and rectal control, and lack of interest. The patient himself made no complaint. About three months before, a gradually increasing mental change had been observed. The patient lost his ambition and interest in work, although he had continued at this trade of carpentry until two weeks before. He had become careless in his work, would forget what he was doing, and seemed little concerned about his short-comings. For two weeks before his examination he had been content to sit aimlessly at home, or to play with his children. He voided at any time and even defecated in his clothes ... During general examination, the patient was indifferent and aimless, would sit and look at a newspaper, which might be upside down. He was oriented in all spheres, and his attention might be held for a few moments when aroused. He would follow his son about in a fairly good-natured manner, but always object to being examined, saying that he was not sick. He showed considerable perseveration, repeating movements at times for long periods. For example, one evening he sat before a wash bowl for over a half hour, turning the faucets on and off.

Should the frontal lobe syndrome appear in childhood, there may be profound consequences on the individual's eventual personality make-up. For example, in two cases (Price et al. 1990), the young children engaged in 'impulsive behavior ... with childish abandon and shallow foresight. Neither was able to learn from negative experience' and neither had much 'sense of remorse, empathy or fairness'. Neither developed any'self-governance over their behavior', and both, when in their twenties, evidenced full sociopathy, as defined in the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-III; American Psychiatric Association 1980). DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

Differential considerations for the frontal lobe syndrome include mania when euphoria is dominant and depression when abulia is foremost. Mania is distinguished by the quality of the euphoria: in contrast to the deep and broadly felt euphoria of mania, the euphoria of the frontal lobe syndrome is shallow and at times silly. Depression is distinguished, appropriately, by the depressed mood: abulic patients do not experience a sense of depression or sadness; rather, they feel a not-unpleasant sense of calm emptiness. The frontal lobe syndrome itself has some localizing value. As might be expected, the frontal lobe syndrome may occur with lesions of the frontal lobe, but it may also occur when other structures are involved. The frontal lobe exists in a cortical-subcortical circuit that involves projections from the frontal cortex to the caudate, then from the caudate to the lenticular nucleus, thence to the thalamus and finally back to the frontal lobe, and it appears that lesions anywhere in this circuit may lead to the syndrome. Thus, lesions of the frontal lobe (Frazier 1936; Williamson 1896), caudate (Mendez et al. 1989; Petty et al. 1996; Richfield et al. 1987), globus pallidus (Strub 1989), and thalamus (Sandson et al. 1991; Smyth and Stern 1938) have all been implicated. There is also a report of the frontal lobe syndrome occurring secondary to a midline lesion in the ventral tegmental area of the mesencephalon (Adair et al. 1996). Lesions of the anterior portion of the corpus callosum may also be at fault (Moersch 1925),

296 Signs, symptoms and syndromes

but this is perhaps because of a lateral extension of the lesion into the adjacent frontal lobes (Alpers and Grant 1931; Beling and Martland 1919). The syndrome may not have much lateralizing value: although in most cases, the lesions are bilateral, unilateral lesions may also cause the syndrome, this having been noted with lesions of either the right or left frontal lobe (Frazier 1936; Strauss and Keschner 1935; Williamson 1896), the right caudate nucleus (Degos et al. 1993), and the left thalamus (Sandson et al. 1991; Smyth and Stern 1938). Once the syndromal diagnosis is secure, the next step is to determine which of the causes listed in Table 7.2 is to blame. The various etiologies are divided into three groups: those which cause a syndrome of gradual or sub acute onset, such as a tumor or a neurodegenerative disease (e.g. Pick's disease); those which occur secondary to clear precipitants, such as closed head injury; and those which occur as strokes secondary to appropriately placed infarctions, for example of the frontal lobe itself. Table 7.2 Causes of the frontal lobe syndrome Of gradual or subacute onset

Tumors or abscesses of the frontal lobe Tumors of the corpus callosum Pick's disease Frontotemporal dementia Amyotrophic lateral sclerosis Alzheimer's disease Lacunar dementia Corticobasal ganglionic degeneration Multiple system atrophy (olivopontocerebellar atrophy type) Progressive supranuclear palsy

Secondary to clear precipitants

Closed head injury Subarachnoid hemorrhage Gunshot wounds Viral encephalitis

Strokes

Frontal lobe Caudate Thalamus

Of gradual or subacute onset

Tumors or abscesses of the frontal lobe not uncommonly cause a frontal lobe syndrome (Avery 1971; Frazier 1936; Hunter etal. 1968; Williamson 1896), and in a smaller minority, the tumor may present with this syndrome (Strauss and Keschner 1935). Tumors of the anterior portion of the corpus callosum may also cause a frontal lobe syndrome, but, as noted earlier, this is probably due to lateral extension and involvment of the adjacent frontal lobes (Alpers and Grant 1931; Beling and Martland 1919; Moersch 1925). Pick's disease is, of all the late-onset neurodegenerative dementing diseases, most likely to present with a frontal lobe syndrome (Bouton 1940; Litvan et al. 1997), this being particularly helpful in distinguishing it from Alzheimer's disease (Mendez et al. 1993). Frontotemporal dementia, like Pick's disease, commonly presents with a frontal lobe syndrome, which is often accompanied by a gradually progressive motor aphasia (Brun et al. 1994; Heutink et al. 1997; Neary et al. 1993). Amyotrophic lateral sclerosis may, in perhaps one-tenth of cases, cause a dementia, which, in a minority, is accompanied by a frontal lobe syndrome (Massman et al. 1996); rarely, the

Other major syndromes 297

frontal lobe syndrome may precede both the dementia and the typical upper and lower motor neuron signs (Cavalleri an De Renzi 1994; Neary et al. 1990; Peavy et al. 1992). Alzheimer's disease often presents with a personality change, which may be of the frontal lobe type (Mega et al. 1996; Petry et al. 1988). Such a 'frontal' presentation is, however, more characteristic of Pick's than Alzheimer's disease (Mendez et al. 1993). Lacunar dementia may or may not be seen in relation to definite strokes and is often accompanied by elements of the frontal lobe syndrome (Ishii et al. 1986). Corticobasal ganglionic degeneration may very rarely present with a frontal lobe syndrome, which, in one case, was eventually followed by a dementia and parkinsonism (Bergeron et al. 1996). Multiple system atrophy (olivopontocerebellar atrophy type) rarely presents with a combination of frontal lobe syndrome, dementia and ataxia (Critchley and Greenfield 1948). Progressive supranudear palsy is typified by an onset with postural instability and falls, joined by akinetic-rigid parkinsonism; a dementia may occur that may be accompanied by elements of the frontal lobe syndrome (Verny et al. 1996). Secondary to clear precipitants

Closed head injury may leave those who recover from coma with a frontal lobe syndrome marked by irritability (Oder et al. 1992; Roberts 1976). Subarachnoid hemorrhage secondary to the rupture of an anterior or anterior communicating artery aneurysm may leave a frontal lobe syndrome in its wake (Alexander and Freedman 1984; Greene et al. 1995; Logue et al. 1968), presumably on the basis of infarction secondary to vasospasm of the nearby penetrating arteries. Paraparesis and an amnesia of the Korsakoff's type may also be seen. Gunshot wounds to the frontal area may leave patients with a frontal lobe syndrome (Lishman 1973). In one case, the substitution of the euphoria of the frontal lobe syndrome for the depression that prompted the suicidal gunshot actually constituted an improvement (Lebensohn 1941). Viral encephalitis may rarely have the frontal lobe syndrome as a sequela (Friedman and Allen 1969; Mulder et al 1951). Strokes Frontal lobe infarction, in the area of distribution of the anterior cerebral artery, may cause the frontal lobe syndrome. Caudate infarction may present with a frontal lobe syndrome, with little in the way of accompanying symptomatology (Mendez et al. 1989; Petty et al. 1996) Thalamic infarction, in one case, presented with lethargy, which rapidly cleared, leaving the patient with a frontal lobe syndrome and a dementia (Sandson et al. 1991).

Treatment of the syndrome With the exception of tumors or abscesses, there are generally no specific treatments for the various causes of the syndrome, and thus treatment is generally symptomatic. Supervision is generally appropriate and, in severe cases, institutionalization may be required. When depression is prominent, an antidepressant (e.g. citalopram or nortriptyline) may help, and where disinhibition is prominent, a neuroleptic may be indicated. Of the various neuroleptics, one may consider one of the atypical agents (e.g. olanzepine, risperidone, or quetiapine), and of the typical agents, haloperidol or chlorpromazine may be helpful. Due consideration must be given to the general medical condition of the patient in selecting a neuroleptic, and in most cases, it is prudent to start with a low dose and titrate

298 Signs, symptoms and syndromes

slowly. Prominent irritability may respond to propranolol, but high doses (e.g. 360 mg or more) may be required, and this may limit its use. Interictal personality syndrome The interictal personality syndrome is said to appear insidiously in epileptics after years of uncontrolled complex partial seizures. It should be emphasized that this is a controversial entity and that it has not as yet been possible to prove conclusively that such a specific syndrome exists. Nevertheless, the clinical impression of many is that it does occur and that it may have a profound effect on patients' lives. Description of the syndrome The outstanding characteristic of this syndrome is a trait known variously as Viscosity', 'adhesiveness' or 'stickiness' (Waxman and Geschwind 1975). In this, patients seem unable to break away from a train of thought or a certain emotion, thoughts and feelings plodding on and adhering to one another in a sort of viscous mass. Bleuler, writing of epileptics in the early part of the twentieth century (Bleuler 1924), asserted that: the most conspicuous anomaly concerns the affectivity, which reacts to a morbid degree, and at the same time shows the peculiarity, that an existing affect lasts a long time and is difficult to divert by new impressions; it is not merely irritability that shows itself in this manner but the other affects, as attachments, or joy, all take the same course ... In speaking and writing we have the same peculiarities: the patient does not get anywhere with his talking, not only because of its slowness, but especially because of its circumstantiality, which must depict all trivialities in repitition and in manifold expression of the same idea in different forms. Besides this the manner of speaking is verbose and clumsy, and always vague, (italics in original).

Bear et al. (1982), in addition to this viscosity of thought and emotion, also emphasized an 'interpersonal adhesiveness' manifest in 'interpersonal clinging' and a 'tendency to draw out interpersonal encounters'. In some cases, patients, on shaking hands while saying good-bye to the physician, will simply continue to 'hang on', requiring the physician to extricate him or herself. The viscosity of thought may have a written expression in hypergraphia, wherein patients may write voluminous amounts, far and above what is required for any social or professional purposes (Hermann et al. 1988), often writing about philosophic or religious concerns (Waxman and Geschwind 1974). In addition to viscosity, patients also tend to be preoccupied with religious, ethical, or philosophical concerns and to experience hyposexuality. Religiosity is, according to Mudsley (1874) 'often very notable in epileptics' and Kraepelin (1902), writing in the early part of the twentieth century, noted that 'the religious content of [epileptic's] thought is another striking symptom, many patients spending a large part of their time in reading the Bible or praying aloud'. Bear et al. (1982) noted the 'nascent metaphysical or cosmological preoccupations' of patients. Hyposexuality manifests primarily as a loss of libido (Blumer 1970; Blumer and Walker 1967). DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

Slowly growing tumors of the temporal lobe may cause not only epilepsy, but also, by virtue of a direct effect on the temporal lobe itself, a personality change. Thus, the appearance of a personality change in an epileptic demands MRI scanning.

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Interictal psychosis is clearly distinguished by delusions or hallucinations, symptoms not seen in the interictal personality syndrome. As noted earlier, the interictal personality syndrome is a controversial entity. Early attempts to validate it (Bear 1979; Bear and Fedio 1977) made use of a complex rating instrument, and subsequent attempts to replicate these earlier findings met with no (Mungas 1982, 1983; Nielsen and Kristensen 1981; Rodin and Schmaltz 1984) or only partial (Bear et al. 1982; Hermann and Reil 1981) success. I have provisionally recommended (Moore 1997) that the diagnosis be reserved for cases wherein: • the patient's behavior represents an enduring change in personality • the disorder occurs after 3 or more years of repeated complex partial or generalized tonic clonic seizures • the patient displays viscosity, as manifested by one or more of deep and persistent affects, verbose, overly detailed and circumstantial speech, or hypergraphia • the patient displays either a preoccupation with religious, ethical, or philosophical concerns or hyposexuality • this change in personality cannot be accounted for on the basis of some other disorder, for example the effect of a tumor • there are no delusions or hallucinations and no prominent depressive symptoms. If the interictal personality syndrome does exist, it may represent a 'functional hyperconnection' (Bear 1979; Bear and Fedio 1977) in the limbic system, which may in turn occur secondary to the 'kindling' effect of frequently repeated seizures (Adamec and StarkAdamec 1983). TREATMENT OF THE SYNDROME

As there is no established treatment for the syndrome, the emphasis must be on prevention by the vigorous treatment of the underlying epilepsy.

Non-specific personality change DESCRIPTION OF THE SYNDROME

Personality change of a non-specific nature may be constituted by either an accentuation of previously existing personality traits or the de novo appearance of traits foreign to the patient's character. For example, a person previously careful with money may become a penny-pinching miser, or a previously somewhat prudish individual may become promiscuous. DIFFERENTIAL DIAGNOSIS OF THE SYNDROME

The various causes of non-specific personality change are listed in Table 7.3, which divides them into two groups, those of gradual or subacute onset, such as tumors of the temporal lobe, and those secondary to clear precipitants, such as closed head injury. Of gradual or subacute onset

Of the following etiologies, tumors and the heredodegenerative disease (Pick's, Alzheimer's, and Huntington's disease) are by far the most common causes of a non-specific personality change.

300 Signs, symptoms and syndromes Table 7.3 Causes of non-specific personality change Of gradual or subacute onset

Secondary to clear precipitants

Tumors of the temporal lobe Pick's disease Alzheimer's disease Huntington's disease Normal-pressure hydrocephalus Neurosyphilis (general paresis of the insane) Wilson's disease Creutzfeldt-Jakob disease, including the new-variant type Granulomatous angiitis Limbic encephalitis Metachromatic leukodystrophy Adrenoleukodystrophy Vitamin B12 deficiency Mercury intoxication Manganism Whipple's disease Closed head injury Chronic subdural hematoma Viral encephalitis Thallium intoxication

Tumors of the temporal lobe may cause a personality change (Strobos 1953), a personality change indeed being the presenting feature in almost one-quarter of all cases (Keschner et al. 1936). Pick's disease typically presents with a personality change, which may, as noted above, be of the frontal lobe type or rather be merely non-specific (Mendez et al. 1993). Alzheimer's disease may also present with a personality change, but this type of presentation is less common than is the case with Pick's disease (Mendez et al. 1993), the majority of cases of Alzheimer's disease presenting with an amnesia. Huntington's disease may present with a personality change (Pflanz et al. 1991), and a positive family history of the disease will suggest the diagnosis; lacking such a history, the diagnosis may prove elusive until chorea appears. Normal-pressure hydrocephalus is generally characterized by dementia, gait disturbance, and urinary incontinence or urgency. In a minority, however, a personality change may dominate the clinical picture (Rice and Gendelman 1973). Neurosyphilis (general paresis of the insane) may be characterized by a change in personality towards slovenliness and disinhibition. The presence of dysarthria or pupillary changes suggests the correct diagnosis (Storm-Mathisen 1969) Wilson's disease may present with a personality change (Bridgman and Smyth 1944), but this is seen in only a small minority of cases (Starosta-Rubinstein et al. 1987): 'disinhibited, bizarre and reckless behavior' was noted in one study (Dening and Berrios 1989) and 'facile laughter, inappropriate and occasionally aggressive behavior, labile mood, lack of insight and disinhibition' in another (Walshe and Yealland 1992). It is of interest that Wilson's first case (Wilson 1912), a 25-year-old woman, presented with a personality change wherein she became 'restless, unable to settle to anything, easily provoked to laughter, constantly smiling and unnaturally cheerful'. Other signs included a slight tremor of the hand and a 'little' dysarthria. Creutzfeldt-Jakob disease may present with a personality change but eventually leaves almost all patients with a dementia and myoclonus (Brown et al. 1994; Roos et al. 1973). The

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'new-variant type' of Creutzfeldt-Jakob disease, acquired by eating beef from cows with bovine spongiform encephalopathy ('mad cow' disease), appears more likely to present with psychiatric features, including personality change (Zeidler et al. 1997a., b). Gmnulomatous angiitis may present with a subacute personality change, eventually joined by the typical prominent headache (Koo and Massey 1988). Limbic encephalitis typically presents subacutely with a delirium, but in some cases, the confusion of the delirium may be overshadowed by a personality change (Alamowitch et al. 1997). Metachromatic leukodystrophy may undergo an insidious presentation in the third decade with a personality change marked variously by inappropriate behavior, heightened sexual interest, and irritability (Finelli 1985; Hageman et al. 1995). The diagnosis may be delayed for years pending the development of more suggestive symptoms such as dementia, ataxia, parapareis, polyneuropathy, or seizures. Adrenoleukodystrophy of childhood or adolescent onset may present with a personality change, either concurrent with or followed by gait or visual abnormalities (Schaumburg et al 1975). Vitamin B12 deficiency may present with a personality change, and although most cases will also show evidence of macrocytosis with or without an anemia, the personality change may rarely occur without any hematologic changes at all In some cases, the only 'tip-off' has been the presence of a peripheral polyneuropathy, manifested by either reduced vibratory sense or a positive Romberg test (Lindenbaum et al. 1988). Mercury intoxication with elemental mercury (as may occur in factories making thermometers [Vroom and Greer 1972]) or organic mercury (O'Carroll et al. 1995), may cause a personality change known as erithism, with prominent timidity and irritability, often accompanied by tremulousness. Manganism, as may be seen in manganese miners, may present with a personality change marked by asthenia, fatigue, irritability, emotional lability, and a peculiar unmotivated laughter (Abd El Naby and Hassanein 1965). One author (Charles 1927), in commenting on the laughter, noted that 'excessive smiling without any adequate cause is very common, and the patient, if asked any simple question, will not infrequently burst out into hilarious laughter'. Parkinsonism, if not already present, generally supervenes. Whipple's disease may present with a personality change, typically accompanied by other, suggestive, evidence such as abdominal symptoms or polyarthralgia (Louis et al. 1996). Secondary to clear precipitants

Closed head injury is not uncommonly followed by a personality change with prominent childishness and irritability (Brooks et al. 1986; Thomsen 1984). Chronic subdural hematoma, showing up any time from months to years after head trauma, may present with a personality change (Cameron 1978). Importantly, some patients may not recall the trauma. Viral encephalitis, for example herpes simplex encephalitis, may leave a non-specific personality change in its wake (McGrath et al. 1997). Thallium intoxication, marked by delirium, alopecia, and a peripheral neuropathy, once cleared, left a personality change in its wake, with irritability and aggressiveness (McMillan et al. 1997) Treatment of the syndrome

In addition to any possible treatment of the underlying cause, some degree of supervision is generally required. Pharmacologic treatment is not well worked out; use of neuroleptics or carbamazepine for agitation may not be unreasonable.

302 Signs, symptoms and syndromes

SEIZURES AND EPILEPSY A seizure, or ictus, is paroxysmal in onset, is generally brief in duration, and occurs secondary to an equally paroxysmal electrical discharge within the cerebrum. Although, as detailed below, the actual symptomatology seen during a seizure, as well as the cause of the responsible electrical discharge, are both extraordinarily varied, the essential formal characteristic of the seizure, namely its 'paroxysmal-ness,' remains. The term 'epilepsy' is generally reserved for cases in which there has been more than one seizure and the cause of the seizures is such that one may reasonably expect that the patient, in the absence of definitive treatment, will continue to have seizures. Thus, whereas it might not be proper to consider a patient who has only had but one seizure, and that while taking a medication such as clozapine, to have epilepsy, it would be appropriate in the case of a patient with recurrent seizures and mesial temporal sclerosis. This chapter first describes the various kinds of seizure and then discusses their differential diagnosis and causes. A section concerned with the diagnostic work-up of the adult with seizures follows, the chapter ending with a brief section on treatment. Description of the syndrome The classification of the various seizure types has changed over time, as evidenced by the evolution of criteria set forth by the International League Against Epilepsy (ILAE) in 1964 (Gastaut et al. 1964), 1970 (Gastaut 1970), 1981 (Commission of Classification and Terminology 1981), and 1989 (Commission of Classification and Terminology 1989). The 1981 ILAE criteria have proved the most clinically enduring, and, with some modification, are adhered to in this text. In differentiating among the various seizure types indicated in Table 7.4, the first step is to determine the patient's state of consciousness during the seizure. If consciousness remains clear, that is to say the patient remains alert, with intact memory, and without any clouding or confusion a simple partial seizure is present. If, however, consciousness is in some fashion impaired, but not entirely lost, either a complex partial or a petit mal seizure is present. The distinction between complex partial and petit mal seizures, as elaborated further in the text, is based on the overall nature of the seizure: complex partial seizures are often preceded by an aura, lasting in the order of minutes, and are typically followed by some post-ictal confusion, whereas petit mal seizures occur without an aura, are very brief, lasting of the order of seconds, and terminate abruptly, without any post-ictal confusion. If consciousness is entirely Table 7.4 Seizure types*

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lost, one is typically dealing with a grand mal seizure, with its accompanying tonic-clonic activity. Atonic seizures may or may not be accompanied by an impairment or loss of consciousness, but they are always characterized by an abrupt loss of muscle tone with, in most cases, a resulting fall. Amnestic seizures are unusual in that they are characterized solely by a paroxysmal amnesia in a clear consciousness. Reflex seizures are said to be present when any of the foregoing types occurs on a 'reflexive' basis, being provoked by some specific stimulus, such as hearing music or reading. Finally, each of the foregoing seizure types may also occur over a prolonged time, in which case status epilepticus is said to be present. The reader may note the absence of coverage of myoclonic seizures here, but a discussion of these may be found in Chapter 3. Although any given patient with epilepsy may experience but one type of seizure during the entire course of the illness, the history more often than not reveals different seizure types at disparate times. Thus, the course of epilepsy may be marked by varying combinations of simple partial, complex partial, and grand mal seizures (Devinsky et al. 1988; Golub et al. 1951; Mauguire and Courjon 1978; Sperling et al. 1989); furthermore, patients with petit mal epilepsy often also experience grand mal seizures (Livingston et al. 1965; Sato et al. 1976). Importantly, in many cases, a given ictal event or seizure may in fact represent an amalgamation of two different seizure types, the first merging seamlessly into the following one. Thus, a simple partial seizure may immediately precede a complex partial seizure (Bare et al. 1994; Sperling et al. 1989) or, in other cases, a simple partial seizure may precede a grand mal seizure (Maughuire and Courjon 1978; Theodore et al. 1994). In such cases, it is customary no longer to refer to the ictal event that occurred in clear consciousness as a simple partial seizure but rather to speak of it as an 'aura' to the following seizure type. Furthermore, complex partial seizures may also transform without interruption into grand mal seizures (Theodore et al. 1994; Tinuper et al. 1996a), and in such cases one speaks of the complex partial seizure undergoing 'secondary generalization' into a grand mal seizure. Each of the various seizure types noted in Table 7.4 is now considered in detail. SIMPLE PARTIAL SEIZURES

Simple partial seizures usually last of the order of a minute or two, uncommonly extending for up to 5 minutes, and exceptionally perservering for as long as 15 (Devinsky et al. 1988b; Mauguire and Courjon 1978). Following the 1981 ILAE criteria, they may be subdivided according to their predominant symptomatology into simple partial seizures with motor signs, with somatosensory or special sensory symptoms, with autonomic symptoms or signs, or with psychic symptoms. Furthermore, there is a group, not specified in the ILAE criteria, of miscellaneous simple partial seizures. Simple partial seizures with motor signs are most commonly characterized by unilateral clonic or tonic activity, or a combination of the two, such motor activity being seen most frequently in the hand, arm, or face and somewhat less so in the lower extremity (Russell and Whitty 1953). Jacksonian seizures represent a variety of simple partial seizure in which there is a 'march' of the ictal symptomatology from one part of the body to another. Such marches may begin variously in the hands or the fingers, proceed proximally to the face, and then march inferiorly; less commonly, they begin in the lower extremity. In most cases, the march is completed within a matter of minutes (Penfield and Jasper 1954; Russell and Whitty 1953). In some cases, such motor simple partial seizures will be followed by a temporary weakness of the part involved, a phenomenon known as Todd's paralysis (Todd 1855). 'Versive' seizures represent a variety of motor simple partial seizure wherein there is a 'forced' tonic version of the head, and sometimes the trunk, to one side or the other (Mauguire and Courjon 1978; Russell and Whitty 1953). Motor aphasia may be seen in what the ILAE calls a 'phonatory'

304 Signs, symptoms and syndromes

seizure. Such a motor aphasia may constitute the sole manifestation of the seizure (Labar et al. 1992) or may be accompanied by motor activity on the face. In one case (Williamson et al. 1985c), the seizure began with right-sided facial twitching followed by muteness: although the patient could follow commands and was still able to communicate by writing, she was unable, much to her distress, to speak. In another case (Walshe 1943), the seizure began with muteness and was 'followed by the advance of the tongue to the line of the teeth and the utterance of a rapid series of "D" sounds (D-D-D-D-D-D). The throat then "constricts", the mouth is drawn to the right and finally the head and eyes turn in a series of jerks to the right'. Rarely, simple partial seizures with motor signs may be characterized by bilateral motor activity (Kanner et al. 1990; Tachibana et al. 1996). Such seizures often lead to diagnostic uncertainty as they 'break the rule' that bilateral epileptic motor activity is always accompanied by some impairment of consciousness (Morris et al. 1988). In one case (Tukel and Jasper 1952): seizures began with a stiffness in the right arm and leg. The patient then stared and the right arm raised to the level of the chest. This was followed by the extension of both arms. There was then adversive movement of the head and eyes to the right and vocalization. The patient remained conscious throughout... she heard herself vocalize but could not speak.

Although the motor behavior in these supplementary motor area seizures may be simple, as in the foregoing example, or perhaps involve non-directed thrashing (Salanova et al. 1995), it may at times be fairly complex. In one case (Weinberger 1973), the patient's 'head and neck turned to the right. Both arms moved to the right and turned rythmically on their axis at the wrist in a fashion best described as turning two door knobs, but in opposite directions': although the patient 'was aware of what was happening to her, and could understand what people were saying ... she could only utter a phrase such as "uh-uh-uh".' Although, in almost all cases, such simple partial seizures with bilateral motor signs arise from seizure foci in the supplemental motor area on the medial aspect of the frontal lobe, exceptions do occur, as in a case where the focus was in the parietal lobe (Bell et al. 1997). Inhibitory motor simple partial seizures represent a kind of 'inverse' motor seizure, wherein, rather than seeing tonic or clonic muscle contraction, there is a paroxysmal paresis or paralysis. The hand, arm, or leg may be involved (Noachtar and Luders 1999; Russell and Whitty 1953), and in some cases hemiparesis may result (Globus et al. 1982; Hanson and Chodos 1978). The spread of epileptic electrical activity from the precentral gyrus to nearby areas may sometimes produce a more complex picture: in one case, a patient experienced not only ictal paresis of the right upper extremity, but also an associated motor aphasia (Lee and Lerner 1990). Simple partial seizures with somatosensory or special sensory symptoms are characterized by relatively crude and unelaborated hallucinations. Thus, somatosensory simple partial seizures may consist of such tactile hallucinations as unilateral paresthesiae, numbness, pain, or a sensation of warmth or coldness. The hands and fingers are most frequently affected, followed by the face, foot, or entire upper or lower extremity (Mauguire and Courjon 1978). Ictal pain may be either diffuse (Wilkinson 1973) or localized (Young and Blume 1983, 1986) (as for example with muscle cramping in one extremity [Balkan 1995]) and may be quite severe (Russell and Whitty 1953). Although the vast majority of somatosensory seizures are unilateral, involving only one side of the body, there may rarely be bilateral involvment, for example simultaneous paresthesiae of both hands (Blume et al. 1992). Somatosensory simple partial seizures may also undergo a Jacksonian 'march' (Lende and Popp 1976; Sittig 1925). These somatosensory Jacksonian marches tend to follow the same distribution as motor marches, most often beginning in the hand or fingers (Mauguire and Courjon 1978), but they are, unlike motor marches, generally quite rapid, completing their

Other major syndromes 305

trek in a matter of seconds (Russell and Whitty 1953). One may at times encounter a kind of 'mixed' march with both somatosensory and motor components; interestingly, in such cases, one almost always finds the sensory component appearing first, followed by the motor one (Penfield and Jasper 1954; Russell and Whitty 1953). Special sensory symptoms include visual, auditory, olfactory and gustatory hallucinations, and vertigo. Ictal visual hallucinations may consist of such crude phenomena as 'weaving patterns, zigzag lights, showers of sparks or coloured clouds' (Russell and Whitty 1955). One of William Gower's patients (Holmes 1927) had simple partial seizures that 'commenced with the appearance of several small spheres, white in the center with an intermediate zone of blue and outisde this a ring of red ... [which] moved either at a uniform rate or in jerks to the left and downwards.' Hemianopia or blindness may occur on an inctal basis (Barry et al. 1985; Russell and Whitty 1955). Ictal auditory hallucinations may consist of such phenomena as buzzing or ringing noises (Mauguire and Courjon 1978). Ictal olfactory hallucinations (Mauguire and Courjon 1978) tend to be unpleasant, such as the smell of something rotton or burning: one of Jackson's patients (Jackson and Beevor 1890) had 'a very nasty smell - "burning dirty stuff". Ictal gustatory hallucinations tend likewise to be unpleasant, the taste being described as foul or metallic. Ictal vertigo may be characterized either by mere gidiness or by a classic sense of rotation (Russell and Whitty 1953). Simple partial seizures with autonomic symptoms or signs may be characterized by such phenomena as a 'rising' epigastric sensation, vomiting (Mitchell et al. 1983; Shukla and Mishra 1985), or diarrhea with abdominal cramping (Zarling 1984). Simple partial seizures with psychic symptoms may consist of 'dysmnesic' phenomena (e.g. deja vu), 'cognitive' disturbances such as depersonalization, affective experiences such as fear, illusions such as macropsia, and complex, 'structured' hallucinations in either the auditory or the visual realms. Dysmnesic experiences represent a disturbance in the sense of familiarity, and include deja vu, jamais vu, deja entendu and jamais entendu. In deja vu, patients have the uncanny sense that they have already seen or experienced something that they are in fact encountering for the first time; in jamais vu, the opposite phenomenon occurs in that patients, although in the presence of something they 'intellectually' know they have experienced before, yet have the sense that it is entirely new. Deja entendu and jamais entendu represent analagous experiences concerning not sight but hearing. Cognitive experiences most commonly involve depersonalization. One of Wilson's patients (Wilson 1930) noted that it was 'as if my mind were looking at myself from afar'. In another case (Daly 1958), the patient, while 'dissociated from his body' had the classic sense that he 'was looking down on the scene'. In other cases, the cognitive distortion may be difficult to categorize: one of Wilson's (1930) patients described her seizure as an experience wherein 'her "thoughts just stopped".' Affective experiences may include anxiety, depression, or, rarely, euphoria. Anxiety and fear have been frequently noted (Kennedy 1911; Macrae 1954a,b; Weil 1959; Williams 1956) and may be quite severe, progressing to a full anxiety attack (Alemayehu et al. 1995). In one case, the seizures were characterized by anxiety, palpitations, dizziness, and pallor (Rush et al. 1977), and in another the patient was 'afraid, perspired and did not want to be left alone' (McLachlan and Blume 1980). As might be expected, some patients may become agoraphobic on the basis of such ictal anxiety attacks: one patient, whose ictal anxiety attacks lasted of the order of 1 minute, 'went to the emergency room', and, fearful 'she could have spells while driving, at work, or in social situations ... confined herself to home' (Weilburg et al. 1987). Ictal depressions 'are characterized by rather sudden let-down of mood and psychomotor retardation ... from simple listlessness and apathy to agitated depresion with suicidal

306 Signs, symptoms and syndromes

attempts' (Weil 1959). One patient's ictal depressions were ushered in by olfactory hallucinations, like 'stuffed cabbage in a dirty outhouse', and could last for hours, during which the patient 'felt paralyzed inside and couldn't follow through an act' (Weil 1955). Euphoria may occur (Williams 1956) but was in one case followed, after 10-20 seconds, by an intense depression (Mulder and Daly 1952). In one case (Dewhurst and Beard 1970), the patient had, rather than simple euphoria, a complex and ectsatic religious experience: 'he had a vision in which he was in the cockpit of an aeroplane ... the aircraft gained altitude and brought him to a different land, a land of peace. He had no cares and no burdens. He felt that the power of God was upon him and changing him for the better.' The experience was so powerful that the patient converted from Judaism to Pentecostalism. Illusions may include macropsia, wherein objects appear larger than they are, micropsia, wherein they appear smaller, and various illusory movements of objects (Heilman and Howell 1980; Russell and Whitty 1955). Also possible are hyperacusis or hypoacusis, wherein sounds appear louder or fainter, respectively, than they in fact are. The phantom limb experience may also be included here: one patient had such a strong ictal sense that his arm was raised above his head that he asked his wife to pull it down even though he acknowledged that he could in fact see his actual arm at his side (Russell and Whitty 1953). Structured hallucinations are characterized by complex visual or auditory experiences. One of Russell and Whitty's (1955) patients, wounded in the right occipital area, saw 'stretcher bearers walking past and then the figures of nurses whom he could recognize', all in the left hemifield; another, wounded in the right occipitoparietal area, 'felt that as if he was in a dream he was back in Khartoum during the war. He saw and recognized friends around him.' In another case (Sowa and Pituck 1989) the patient saw the 'right side of people's faces missing' and 'water coming out of a clock'. Diurnal ictal visual hallucinations may rarely reappear in dreams (Reami et al. 1991). Although, in most cases, these complex visual hallucinations occur in only one hemifield, they may at times spread to appear in the entire visual field (Russell and Whitty 1955). Palinopsia may also occur, one patient's seizures being characterized by seeing 'non-existent pedestrians in an empty street, having seen these people minutes before in different surroundings' (Muller et al. 1995). Autoscopy may occur, and patients may hallucinate themselves (Brugger et al. 1994; Devinsky et al. 1989a). Auditory structured hallucinations may consist of voices or music: one patient heard the same song, repeated over and over again (Wieser 1980). Miscellaneous kinds of simple partial seizure include such phenomena as prosopagnosia (Agnetti etal. 1978) and asomatognosia (Russell and Whitty 1955). Other miscellaneous types of simple partial seizures, of perhaps more interest from a neuropsychiatric point of view, include unexplained urges, sexual experiences, involuntary laughing or crying, forced thoughts, and, rarely, delusions. Inexplicable urges have included impulses to laugh (Sturm et al. 2000) or to run (Strauss 1960). Sexual experiences include strong sexual arousal (Erickson 1945) or orgasm (Reading and Will 1997; Ruff 1980). Seizures characterized by involuntary laughing ('gelastic' seizures) or crying ('dacrystic' seizures) differ from those characterized by ictal emotion (e.g. anxiety or depression, as noted earlier) in that these patients, although laughing or crying, do not experience any associated mirth or sadness. One patient happened to see herself in the mirror in the midst of a gelastic seizure and 'was puzzled by the discrepancy between her facial expression and her feelings' (Arroyo etal. 1993); in another case, the smile accompanying the laughter reminded observers of a '"toothpaste advertisement" smile' (Lehtinen and Kivalo 1965). Dacrystic seizures manifest with a sad facial expression and tears (Luciano et al. 1993; Marchini et al. 1994), in one case capping off a sensory march that began in the left leg, ascended to the left shoulder, and was then succeeded by weeping (Efron 1961).

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Forced thoughts may occur and are quite similar to obsessions (Mendez et al. 1996). Delusions noted during simple partial seizures include the Capgras phenomenon (delusion of doubles) (Kanemoto 1997) and a Schneiderian first rank symptom, namely a conviction on the patient's part 'that his body is being controlled by external forces' (Mesulam 1981). COMPLEX PARTIAL SEIZURES

Typical complex partial seizures (Delgado-Escueta et al. 1982; Escueta et al. 1977; Golub et al. 1951; Holmes 1984; Theodore etal. 1983) generally last of the order of one to several minutes and may or may not be preceded by an aura. The seizure proper is characterized, in all cases, by some 'impairment' of consciousness, ranging in severity from the slightest degree of confusion to a more or less profound stupor. Although, in some cases, the seizure manifests with this impairment of consciousness alone, one will in most cases also see either a 'motionless stare' or automatisms. The 'motionless stare' is characterized by the abrupt appearance of a vacant stare and a complete arrest of all behavior, leaving the patient quite still and unmoving. Automatisms range in complexity from such simple, stereotyped behavior as lip-smacking or chewing to highly complex activity, which is, to a greater or lesser degree, 'reactive' to the environment. Such reactive automatisms may consist of a more or less faithful continuation of pre-ictal behavior or may represent behavior which, though still reactive to the environment, represents a break with the patient's pre-ictal behavior. After the seizure ends, most patients will display a degree of post-ictal confusion, lasting from one to several minutes, after which they generally recover. Patients are subsequently totally, or sometimes only partially, amnestic for the events that occurred during the seizure. Some descriptions of more or less typical cases will help to 'flesh out' this definition. The first to be considered is Hughlings Jackson's famous patient, considered by many to be the 'paradigm of temporal lobe epilepsy' (Taylor and Marsh 1980), whom Jackson referred to as 'Dr Z' (Jackson 1889; Jackson and Colman 1898). Dr Z's first complex partial seizure was preceded by an aura of deja vu. In his own words: I was waiting at the foot of a college staircase, in the open air, for a friend who was coming down to join me. I was carelessly looking round me, watching people passing, etc., when my attention was suddenly absorbed in my own mental state, of which I know no more than that it seemed to me to be a vivid and unexpected 'recollection'; - of what, I do not know. My friend found me a minute or two later, leaning my back against the wall, looking rather pale, and feeling puzzled and stupid for the moment. In another minute or two I felt quite normal again, and was as much amused as my friend at finding that I could give no distinct account of what had happened, or what I had 'recollected.'

In another case (Golub et al. 1951), the patient had a seizure while in the physician's office. He: suddenly stopped talking, looked off into space, staring. He slumped down in his chair for a brief moment, then sat up and began to rub his abdomen with both hands. A flashlight was shined into his eyes and he turned away. He began to rummage about the desk as if looking for something. When questioned as to what he wanted, he said, 'I wanna, I wanna.' At this point he took a cigarette from his pocket, lit it and started to smoke. He then got up from his chair, walked out of the office, wandered down the hall opening all the doors saying 'I want a toilet.' Next he walked down the hall, but could not be distracted by any outside contact. He then lay down on the bed and appeared to regain contact gradually.

In the following, each of the the various elements of a complex partial seizure (aura, impairment of consciousness, the motionless stare, and automatisms) are considered in turn, followed by a discussion of the contentious issue of ictal violence.

308 Signs, symptoms and syndromes

Aurae, as noted earlier, are simply simple partial seizures that happen to generalize into complex partial seizures: they thus include all of the forms of simple partial seizure noted above. Several studies (Boon et al. 1991; Gupta et al. 1983; Kanemoto and Janz 1989; Sperling et al 1989) provide a rough estimate of the frequency with which various aurae are found: the most common is a rising epigastric sensation; next come dysmnesic symptoms (deja vu or jamais vu), affective symptoms (fear, anxiety, and depression), sensory symptoms (visual, tactile, gustatory, olfactory, or auditory hallucinations), vertigo, and nausea. Least common are illusions (macropsia, micropsia, hyperacusis, and hypoacusis) and various unclassified symptoms such as thirst or simply an 'indescribable' sensation. In some cases, the aura may be a combination of two or more symptoms: in an early report, Anderson (1886) noted an aura compounded of auditory and visual hallucinations and deja vu, and Hughlings Jackson (Jackson and Stewart 1899) noted a combination of an olfactory hallucination with deja vu. Although aurae are typically remembered, amnesia for the aura may be found in approximately one-quarter of all patients upon recovering from a complex partial seizure (Schulz et al. 1995). Impairment of consciousness., of one sort or another, is present in all cases. As noted by Hughlings Jackson (Taylor 1931), this impairment may involve 'all degrees of obscuration of consciousness', from a profound clouding of the sensorium to the slightest trace of confusion or inattention. Indeed, determining the presence of an impairment of consciousness may in some cases be difficult: Murray Falconer (1954), in commenting on this, noted that a patient, during a seizure 'may carry on with what he is doing, such as playing the piano or driving a car. His performance may seem without fault, or he may betray himself [only] by ignoring the traffic light.' The motionless stare, although appearing in most complex partial seizures, is certainly not seen in all (Delgado-Escueta et al. 1982; Holmes 1984). Some authors have categorized complex partial seizures into two types - 'type I' referring to those seizures which are characterized by the motionless stare, and 'type II' being those without one - and have gone on to assert that, in type I seizures, the stare always precedes automatisms (Delgado-Escueta et al. 1982; Escueta et al. 1977). It appears, however, that this sequencing may not be always present, as subsequent work (Theodore et al. 1983) has shown that, in type I seizures, the motionless stare may be preceded by automatisms. Automatisms represent behavior that is performed in a more or less automatic way, such that the patient is, to a greater or lesser degree, left in a less adaptive 'fit' with the environment. Spratling (1902) felt that a patient in the midst of an automatism acted 'like a machine', Kraepelin (1902) describing patients as acting in 'a mechanical or automatic manner'. Penfield (Penfield and Jasper 1954) echoed these impressions, noting a range in the severity of the automatism such that 'when the condition is severe, the patient acts like an automaton or a robot', but when mild, the patient 'may be cooperative and only slightly confused, but still unable to deal with new problems normally'. Automatisms are currently roughly divided into those which are stereotyped and those which are still, to some or other degree, 'reactive' to the environment. Stereotyped automatisms generally consist of simple, purposeless behavior. Table 7.5 lists various commmon stereotyped automatisms, as noted in studies by Delgado-Escueta et al. (1982), Golub (1951), Holmes (1984), and Gibbs and Gibbs (1952), roughly arranged from most (top) to least (bottom) frequent. Although most of these stereotyped automatisms (e.g. lip-smacking) require little elaboration, comments on some are in order. Speaking or mumbling may consist of simple, but coherent, phrases, such as 'Oh my God', or may be characterized by varying degrees of incoherence (Bell et al. 1990; Serafetinides and Falconer 1963; van der Horst 1953), which may at times be extreme (Gillig et al. 1988; Knight and Cooper 1986). In one case, the patient simply repeated neologisms such as 'exeverdedeen' over and over again (Bell et al. 1990).

Other major syndromes 309 Table 7.4. Common stereotyped automatisms Chewing or lip-smacking Looking around Fumbling with sheets or clothing; groping, and searching Speaking or mumbling Laughing or crying Sitting or standing up Walking or running Thrashing or kicking; 'bicycling' movements Dystonia of the arm or leg

Laughing or crying may, if prominent, justify referring to the seizure as 'gelastic' or 'dacrystic', respectively. The automatic laughter seen during a seizure may or may not be accompanied by a sense of mirth (Yamada and Yoshida 1977) and may or may not sound natural: in one case it was 'identical' to the patient's 'natural laughter', and in another, it was 'most contagious'. More commonly, however, the laughter is unnatural (Ames and Enderstein 1975; Gascon and Lombroso 1971), not 'infectious' (Sethi and Surya 1976), and has been described as cackling (Gumpert et al. 1970; Lehtinen and Kivalo 1965). Dacrystic seizures may or may not be accompanied by a sense of sadness (Luciano et al. 1993). Running, if prominent, may allow one to speak of'cursive' epilepsy (Chen and Forster 1973; Sethi and Surya 1976; Sisler etal. 1953). The running is generally uncontrollable: one patient's seizure consisted of'howling and running' (Marsh 1978). Bicycling movements of the lower extremities exhibit varying degrees of coordination and may or may not be accompanied by rhythmic movements of the upper extremities (Sussman etal. 1989;Swartz 1994). Dystonic posturing may occur and, when unilateral, has definite lateralizing significance (Kotagal et al. 1989), as discussed further under 'differential diagnosis', below. Rarely, stereotyped automatisms consist of sexual activity. There may be pelvic thrusting (Geyer et al. 2000), genital manipulation (Leutmezer et al. 1999), and sexual arousal and orgasm (Remillard etal. 1983): in one case (Spencer etal. 1983), the patient's seizure consisted of lip-smacking, snorting, grimacing, thrashing about, uttering obscenities, and masturbation. Coital movements have been noted (Freemon and Nevis 1969), and in one remarkable case (Currier etal. 1971), a 50-year-old woman: began having what her daughter and husband described as 'sexual' seizures. One was as follows. The patient was sitting at the kitchen table with her daughter making out a shopping list. She stopped making the list, appeared dazed, and gradually slumped to the floor helped by her daughter. She lay on the floor on her back, lifted up her skirt, spread her knees, and elevated her pelvis rhythmically. She made appropriate vocalizations for intercourse, such as 'it feels good' and 'further, further.'... Following these episodes the patient would appear confused and have no memory of them.

Other, rare, stereotyped automatisms include the Kluver-Bucy syndrome (Nakada etal. 1984) and stuporous catatonia with waxy flexibiltiy (Shah and Kaplan 1980), Reactive automatisms may, as noted earlier, consist either of behavior that represents a more or less faithful continuation of the patient's pre-ictal behavior or of behavior that, although still 'reactive' to the environment, represents a definite break, with what the patient was doing before the seizure began. Examples of 'continuation' reactive automatisms include delivering newspapers (Steegmann and Winer 1961) or continuing to drive a car (Falconer 1954). One of

310 Signs, symptoms and syndromes

Hughlings Jackson's patients (Jackson 1889), if she suffered a seizure while serving tea, 'would go on pouring out but would pour out wrongly'. In another example, Forster and Liske (1963) describe 'a patient, who worked in his father's shirt and pyjama factory as a sorter, [who] would, in the course of a seizure, continue to place the shirts, as they came off the line, into the same stack regardless of the size of the shirt. When the seizure ended, he would correctly place the shirts coming off the line.' In a similar example, Liddell (1953) described a 38-year-old clerk who was 'adding up a column of figures when the attack would occur. To other people he would appear to carry on as if nothing had happened. When he came to he would discover that he had written in something irrelevant or the wrong figures.' Reactive automatisms that represent a break with pre-ictal behavior may be quite startling to observers. One patient, while walking down the street, began to 'throw away' his money (McCarthy 1900); another, a church organist, suddenly stopped playing the service music and broke out into 'hot jazz' (Forster and Liske 1963). One of Hughling Jackson's patients (Taylor 1931), in the middle of an interview, suddenly stopped responding. Jackson: waited a little time, and then, looking at him, I saw that he was grinning as if amused at something. Next, whilst sitting quietly in his chair, he tore a piece off a packet of prescriptions, and put it in his mouth. I took it away, but he picked up another piece from the floor and began to chew it. In about a minute more he came to himself, and then spat out into the fire a pellet of chewed paper.

In a further example, one of Penfield's patients (Penfield and Jasper 1954), a 16-year-old girl, had a complex partial seizure at a formal ball. During the seizure, she: proceeded to take her clothing down as though she were about to sit on the toilet. Her friends gathered round and tried to hide the performance but she seemed to come to herself and finding certain articles of apparel around her ankles, she said, 'well if they are off we had better take them off completely.' She did this and hid them in her handbag. Finally, as complete awareness returned, she was overwhelmed by shame and chagrin.

As a final example, consider a patient of Gloor's (1975), who, during a depth electrodemonitored seizure: got up from his chair and began to hum and sing ... He suddenly looked very cheerful, which was in marked contrast to the solemn expression which he had had prior to the attack. The radio in the room was on and some dance music was being broadcast. The patient now approached the female technician and started to dance with her to the tune coming over the radio. He continued to hum at the same time.

Other manifestations that may occur during a complex partial seizure include abdominal pain (Peppercorn et al. 1978), vomiting (Kramer etal 1988; Panayiotopoulus 1988), testicular pain (York et al. 1979), fever (Semel 1987), and bradycardia followed by sinus arrest and syncope (Smaje et al. 1987) Violence during a complex partial seizure is a rare event, usually occurring when an attempt is made to restrain patients to protect them from harm (Delgado-Escueta et al. 1982). In one case (Rodin 1973), for example, a patient, during a seizure, 'suddenly lunged forward, having a bewildered and angry facial expression. An unsuccessful attempt to keep him in the chair by the attending physician resulted in making the patient angrier'; the patient then 'clenched [his] right fist... assumed a boxer-type stance, and violence [seemed] imminent. As soon as the patient was released, however, he merely got out of the chair, then sat down again and began typical fussing type behavior with the pillow.'

Other major syndromes 311

Spontaenous violence is rare, and in most of the reported cases, the patient had been accused of a crime, thus raising the question of malingering. Nevertheless, there have been reports of violence occurring during monitored seizures (Delgado-Escueta et al 1981): two patients 'shouted and spat at nurses' and another 'suddenly knelt on the bed and tried to scratch the psychologist's face.' Such violence may at times be extreme: in another report of monitored violence (Ashford et al. 1980), the patient: when unrestrained in his hospital room ... would jump up and run around the room. On one occasion he grabbed the drapes next to his bed and kicked out from the wall on them. On another occasion he pulled the nurse's call button out of the wall, ran into the bathroom and swung it around his head so that it was crashing against the walls. In all observations, he was locked by himself in a closed room, having no opportunity to direct aggression against people.

PETIT MAL SEIZURES

Petit mal seizures (Delgado-Escueta 1979; Penry et al. 1975) are abrupt in onset and occur without aura or prodrome; they are very brief, lasting of the order of 10 seconds, and generally consist of an arrest of all activity accompanied by a blank stare: the seizure ends as abruptly as it began, and there is no post-ictal confusion or drowsiness. To the observer, it may appear that the patient had a 'blank' spell or was merely momentarily 'out of it' then 'snapped to'. In some cases, there may be some myoclonic fluttering of the eyelids and occasionally some myoclonic jerks of the hands. Some patients will also experience a partial loss of muscle tone: the head may drop forwards, or the patient may slump somewhat, but falls are unusual. Many patients will also have some simple automatisms, such as lip-smacking, chewing or fumbling, during the absence (Fuster et al. 1954; Penry and Dreifuss 1969; So et al. 1984). There may very rarely be other features, such as auditory or visual hallucinations (Guinena and Taher 1955). Of all the seizure types considered in this chapter, petit mal seizures are the only ones which have a distinctive EEC, consisting of generalized 3 Hz spike and dome activity. A variant of petit mal, known as 'atypical absence' may be seen, most commonly in patients with mental retardation. These atypical absences are of more gradual onset and offset, tend to last longer overall, and may be associated with prominent increased muscle tone (Holmes et al. 1987). GRAND MAL SEIZURES

Grand mal seizures, also known as tonic-clonic seizures, may be preceded by an aura composed of any of the symptoms or signs seen during simple partial seizures or may rapidly evolve out of a complex partial partial seizure, a process known as secondary generalization. Aurae may or may not be recalled by the patient: in one study (Schulz et al. 1995), approximately one-half of patients with definite aurae failed to recall them. Typical grand mal seizures (Theodore et al. 1994) begin with an abrupt loss of consciousness coupled with tonic activity in all four extremities. After perhaps 15-20 seconds, the tonic activity slowly fades, to be gradually replaced by regular clonic activity, which in turn may last anywhere from one-half to one and one-half minutes. In some cases, there may be variations, the tonic phase being preceded by a few clonic jerks, or the tonic phase constituting the majority of the seizure, with only a few clonic jerks trailing behind. During the tonic activity, respirations cease and cyanosis may appear. There is often incontinence of urine, and, during the clonic phase, the tongue may be bitten. Upon cessation of the seizure proper, most patients remain in a coma or stupor for a matter of minutes. A delirium then supervenes, with prominent confusion, and lasts perhaps 15-30 minutes, after which most patients fall into a deep sleep.

312 Signs, symptoms and syndromes

ATONIC SEIZURES

Atonic seizures (Gambardella et al. 1994; Lipinski 1977; Pazzaglia et al. 1985), also known as 'astatic' seizures or 'drop attacks', occur without prodrome or aura and are characterized by a sudden loss of motor tone. In most cases, this atonus is generalized, and patients fall or slump to the ground; occasionally, however, the lack of tone may be focal, with, for example, only an abrupt drooping of the head. The atonus itself generally lasts of the order of a few seconds and may or may not be associated with a loss of consciousness. After the restoration of normal tone, most patients arise immediately, without any post-ictal confusion; however, others may, for a minute or two, experience a more or less profound degree of post-ictal confusion. Atonic seizures generally occur only in patients who have already suffered from complex partial or grand mal seizures for many years (Gambardella et al. 1994; Lipinski 1977; Tinuper etal 1998). AMNESTIC SEIZURES

Amnestic seizures are characterized solely by the appearance of amnesia. As such, they differ from complex partial seizures in that there is no impairment of consciousness, no motionless stare, and no automatic behavior. Typically, the amnesia itself is primarily of the anterograde type, but in some cases, the amnesia represents a combination of anterograde and retrograde types. Rarely, the seizure will be characterized by retrograde amnesia alone. Examples of each type follow. Amnestic seizures of the anterograde type are characterized by the abrupt onset of a loss of short-term memory: patients are able to recall events that occurred up to the onset of the seizure, and behave normally during the seizure itself, but subsequent to the termination of the seizure, they have no recall of the events that transpired concurrent with the seizure itself. Palmini et al. (1992) provide some interesting examples. In one case, a waitress, during her seizure, 'was able to compute a customer's bill accurately and to bring him a correct amount of change'; later, upon recovery, 'she then realized she had a blank in her memory and could not recall her interaction with that customer'. In another case, the patient: was in the cafeteria at his work place, where he had to present a card and sign a register to pick up his meal. After having eaten he presented himself a second time and ate lunch twice. That same afternoon, the cook telephoned and upbraided him for having eaten two meals. He had no recollection of having done so.

Finally, there is the case of a young woman, who, during a monitored seizure, answered a telephone, spoke with her cousin, and then went to sleep. 'The next morning she did not recall having received a phone call. When confronted with the video replay of her seizure, she was incredulous.' The investigators later contacted the cousin, who told them that 'their conversation had been entirely normal. He had not noticed anything amiss with the patient.' Of some historical interest is the possibility that Hughlings Jackson's illustrious 'Dr Z' (Jackson 1889) may also have suffered from amnestic seizures of the anterograde type. In the midst of examining a patient, Dr Z remembered: taking out my stethescope and turning away a little to avoid conversation. The next thing I recollect is that I was sitting at a writing-table in the same room, speaking to another person, and as my consciousness became more complete, recollected my patient, but saw that he was not in the room. I was interested to ascertain what had happened, and had an opportunity an hour later of seeing him in bed, with the note of a diagnosis I had made of 'pneumonia of the left base'. I gathered indirectly from conversation that I had made a physical examination, written these words, and advised him to take to bed at once. I re-examined him with some

Other major syndromes 313 curosity, and found that my conscious diagnosis was the same as my unconscious - or perhaps I should say, unremembered diagnosis had been. I was a good deal surprised, but not so unpleasantly as I should have thought probable.

Amnestic seizures of the anterograde and retrograde types are characterized not only by a defect of short-term memory, but also by an inability, during the seizure itself, to recall events that occurred for a variable period of time before the onset of the seizure proper (Stracciari et al. 1990). Such patients may be quite alarmed at their retrograde amnesia and may ask others to fill them in (Zeman et al. 1998): one patient (Cole et al. 1987) suddenly became unable to recall whether he had gone to work that morning, long before the seizure began, and repeatedly asked others whether or not he had shown up for work. Upon termination of the seizure, the retrograde amnesia resolves, and patients are once again able to recall what events transpired up to the onset of the seizure and are also able to recall events that occurred after the termination of the seizure; those events, however, which transpired concurrent with the seizure are in almost all cases lost to memory (Deisenhammer 1981). Amnestic seizures characterized by retrograde amnesia alone are very rare. In such cases, although patients are able to keep track of events during the seizure itself, they are nevertheless unable to recall events that occurred before the seizure. In one case (Venneri and Caffarra 1998), the retrograde amnesia itself was limited to only autobiographical events. Thus, during the seizure, the patient, although able to recall public events, was unable to recall personal events from her own past. Once the seizure ended, her recall of personal events was restored, and she also was able to recall being in the seizure itself and having trouble recalling those personal events. REFLEX SEIZURES Reflex seizures are of interest, from not only a therapeutic point of view, but also a general neuropsychiatric one. Therapeutically, they offer an obvious means of seizure reduction, namely avoiding the precipitating stimulus. In general, however, their interest lies in the fact that an experience, sometimes a very complex one (as in Penfield's example below), can 'spark' off an equally complex epileptic event. Reflex simple partial seizures, albeit reported, appear to be uncommon. In one series, a startling stimulus, generally a loud noise, was noted to cause tonic activity (Manford et al. 1996), and in another, reading could induce motor phenomena such as myoclonic jerking of the jaw or, less frequently, alexia (Koutroumaniois et al. 1998). In one patient, voluntary movement was noted to induce ictal dystonia (Falconer and Driver 1963). In another case, listening to certain kinds of music induced ictal structured visual hallucinations (Daly and Barry 1957), and ictal blindness has been induced by intermittent photic stimulation (Barry et al. 1985). Marchini et al. (1994) report the case of dacrystic seizures induced by speaking, and, in a most unusual case (Falconer 1954; Mitchell et al. 1954), gazing at a safety pin was capable of precipitating a simple partial seizure characterized by a sense of profound, almost sexual, satisfaction. Reflex complex partial seizures have, in some cases, earned specific names according to the provoking stimulus, for example 'musicogenic', 'reading' and 'eating' epilepsy. One rarely encounters cases of other stimuli, such as hearing the voices of specific people, assuming a certain posture, experiencing a specific emotion, and, in a most remarkable case of Penfield's, having a certain complex experience. Musicogenic complex partial seizures, although extensively reported, are rare events (Critchley 1942; Forster 1977). Critchley (1937) provided an illustrative case: the patient, after hearing 'a rather loud fox-trot with a well defined tempo ... suddenly became pale ... [and] leaned forward in her chair with frightened look in her eyes ... and ... began smacking her

314 Signs, symptoms and syndromes

lips'. In some cases, it appears that only specific kinds of music are capable of inducing seizures (Newman and Saunders 1980), for example the pealing of church bells (Poskanzer etal. 1962), organ music (Joynt et al. 1962), 'a large dance band playing "swing" music' (Daly and Barry 1957), emotionally laden music (Gastaut and Tassinari 1966), and 'Italian' songs (Wieser et al. 1997). This last case is of interest in that, upon hearing the Italian song, the patient's complex partial seizure was preceded by an aura composed of an auditory hallucination of 'pleasing female murmuring voices, which took increasing possession of her mind', following which she had a complex partial seizure with a motionless stare. Reading-induced complex partial seizures may occur with 'silent' reading (Gastaut and Tassinari 1966) or only upon reading aloud (Forster et al. 1969a). In one case (Crtichley et al. 1959), not just any reading material would do, but rather it was reading a newspaper, especially the patient's hometown newspaper, that constituted the effective stimulus. Eating-induced complex partial seizures may occur regardless of what is eaten (Ahuja et al. 1980; Fiol et al. 1986; Forster 1971) or may occur only with eating certain foods, in one case, for example, apples (Abenson 1969). Other stimuli capable of inducing complex partial seizures appear to be highly idiosyncratic: thus one patient's seizures were induced only by the voices of certain radio announcers (Forster et al. 1969b), another's by experiencing a feeling of sadness (Fenwick and Brown 1989), and another's by arching his back (Jacome et al. 1980). Finally, there is a fascinating case reported by Penfield (Penfield and lasper 1954) wherein it appears that it was the evocation of a memory of a specific event that served as the trigger. The history is a bit lengthy and complex but worth retelling. The patient, when 13 'was playing with a dog which belonged to a neighbor. He remembered grabbing a stick out of the mouth of the dog and throwing it to a distance. The dog chased the stick and brought it back to him.' At the age of 17, the patient had his first seizure: 'he was in a crowd of people at the military school which he was attending [and] watched a demonstration of military tactics in which one of his classmates grabbed a rifle out of the hands of another man.' At that instant, 'there immediately came to the patient's mind' a memory of playing with the dog when he was 13, and 'in his mind he associated these two incidents and tried to put himself into the past memory. Following this, he became confused and was unable to speak for several seconds. Then he evidently lost consciousness and had a convulsive seizure.' The patient remained well until a half year later, when: while in a night club, he heard a man saying, 'Give me my hat.' He saw him grab his hat from the hat-check girl. Immediately the memory of the dog chasing the stick, and the memory of grabbing the stick from the dog's mouth, came back to him. Following that he was confused and behaved in an automatic manner.

Reflex grand mal seizures are not uncommon and may be induced by such intermittent photic stimulation as playing electronic video games (Quirk et al. 1995). Reflex atonic seizures were noted in the case of one girl, wherein seizures could be 'triggered by laughing if she was told jokes or watched a comedy on television' (Jacome and Risko 1984). STATUS EPILEPTICUS

Status epilepticus is said to be present when, for at least a half-hour, the patient is either undergoing a continuous seizure or has so many closely spaced seizures that there is no time for full recovery between them. Status epilepticus may be seen with simple partial, complex partial, petit mal, grand mal, and amnestic seizures, and, as the examples below demonstrate, may be very prolonged. Although the serious morbidity and mortality attending grand mal status epilepticus (Meierkord et al. 1997) is generally appreciated, it must be borne in mind

Other major syndromes 315

that partial status epilepticus may also, albeit rarely, have severe sequelae: simple partial status epilepticus with motor signs has been followed by hemiparesis (Desbiens et al. 1993), which may be permanent (Borchert and Labar 1995), and complex partial status epilepticus by amnesia or dementia (Krumholz et al. 1995). Simple partial status epilepticus, although most commonly presenting with motor signs, has also been reported with psychic symptoms such as fear or structured hallucinations. Motor simple partial status epilepticus is traditionally referred to as epilepsia partialis continua. These seizures typically consist of persistent clonic jerking involving the face, arm, or leg, and can last any time from hours to years (Cockerell et al. 1996; Scholtes et al. 1996); indeed in one series, the mean duration was 25 months, the longest seizure lasting 18 years (Thomas et al. 1977). Clonic activity may or may not persist into sleep (Cockerell et al. 1996; Thomas et al. 1977) and may be accompanied by other symptoms such as aphasia (Cockerell et al. 1996). Although the motor activity is, in the vast majority of cases, unilateral, there may in a small minority be bilateral involvement (Ashkenazi et al. 2000; Thomas et al. 1977). Rarely, inhibitory simple partial status epilepticus may occur, with prolonged ictal paresis (Smith etal 1997). Fear or anxiety may be the sole manifestation of simple partial status epilepticus and has been noted to last for between 10 days (Scott and Masland 1953) and 3 months (Henriksen 1973). Isolated ictal depression has also been noted; in one case (Weil 1956), the patient for 2 weeks 'felt "blue" and cried, and the smell of fat on a hot stove kept coming back'. Structured hallucinations occurring in status have consisted of the auditory hallucination of a 'song' persisting for 3 hours (Wieser 1980) and a 5 day episode during which the patient experienced 'aphasia, acoustic hallucinations (strange sounds, music, voices), left sided headache, and visual hallucinations (red balls in the front of the right eye)'. Complex partial status epilepticus is always characterized by a more or less profound impairment of consciousness, may or may not be accompanied by automatisms, and generally lasts from an hour or less up to days (Cockerell et al. 1994; Goldensohn and Gold 1960; Mayeux and Lueders 1978; Rennick et al. 1969; Tomson et al. 1986, 1992; Van Rossum et al. 1985; Williamson et al. 1985b). The seizure may rarely be very prolonged, durations of seven and one-half months (Roberts and Humphrey 1988) and 18 months (Cockerell et al. 1994) having been reported. Reactive automatisms seen in complex partial status epilepticus include such simple behavior as feeding oneself Qaffe 1962) or wandering off. In one case (Coats 1876), immediately after the seizure began, the patient, a craftsman, 'laid aside his tools, took off and hung up his leather apron, and after muttering some unintelligible words to the foreman, left the shop. He himself remembers nothing of this, but woke to consciousness to find himself sitting on one of the benches in George Square.' When the wandering is quite prolonged, one speaks of 'poriomania': in one case the patient, after a seizure lasting 24 hours, came to find that he had travelled 'several hundred miles' (Mayeux et al. 1979). In some cases of complex partial status epilepticus, hallucinations, delusions, and bizarre behavior may be prominent (Ballenger et al. 1983; Ellis and Lee 1978; Mitaki et al. 1985). In one case (Drury et al. 1985), the patient, an elderly clergyman, 'became agitated and paranoid and had delusional thinking with religious overtones'; 2 days later he was still in status, and when seen 'was tremulous, had bizarre posturing and was masturbating'. In another case (Wells 1975): the patient became withdrawn ... refused to e a t . . . grew restless, fitful and irritable; episodes of violent anger requiring restraints followed. She appeared to be hallucinating, crying out on several occasions, 'I am God.' When placed on a stretcher for transfer... she became hostile and resistant, screaming 'I'm dying' and 'They're taking me to the morgue.'

316 Signs, symptoms and syndromes

After 2 days, she was eventually treated with anticonvulsants, 'with prompt clearing. On recovery, she described her experience as though recovering from a bad dream.' In some cases, stuporous catatonia occurs (Engel et al. 1978): one patient (Lim et al. 1986) 'held his arms and legs rigidly in the air and would maintain his extremities in any bizarre posture indefinitely'. Petit mal status epilepticus, which may occur in both childhood and the adult years (Belafsky et al. 1978; Michelucci et al. 1996; Nightingale and Welch 1982; Novak et al. 1971; Schwab 1953; Thompson and Greenhouse 1968; Tucker and Forster 1958; Zappoli 1955), is characterized by varying degrees of confusion, often accompanied by 'rhythmic blinking or small amplitude myoclonic jerking of the face and arms', and generally lasts anywhere from a half-hour to 2 days (Andermann and Robb 1972). In some cases, the confusion may be very slight: in the case of one 30-year-old woman seen during petit mal status (Friedlander and Feinstein 1956), 'during the first minute or so of the examination nothing unusual in her manner was noted, but as she was questioned further it became apparent that there was slowness in comprehending certain questions', the presence of myoclonus of the eyelids and eyebrows suggested the correct diagnosis. Rarely, there may be prominent automatisms. One patient went for a walk and took a bus while in petit mal status (Vizioli and Magliocco 1953), and, in another case (Bornstein et al. 1956), a 16-year-old girl, while playing cards in her dormitory room, 'suddenly got up, walked out without a coat, went to the airport, and boarded a plane to New York without a ticket. Upon arrival in New York she was charged as a stowaway. She was found to be confused and incoherent.' Grand mal status epilepticus (Aminoff and Simon 1980), the most dramatic and lifethreatening of all kinds of status epilepticus, is characterized by closely spaced grand mal seizures and may, if persistent, result in status epilepticus characterized solely by coma, with no motor activity (Lowenstein and Aminoff 1992; Towne et al. 2000). Amnestic status epilepticus has been noted, in some cases persisting for days (Zeman et al. 1998).

Differential Diagnosis The first step in differential diagnosis is to determine whether the paroxysmal event in question is occurring on an epileptic or non-epileptic basis. NON-EPILEPTIC PAROXYSMAL EVENTS

Table 7.6 lists various non-epileptic paroxysmal events organized according to the type of seizure they most closely mimic. In each case, any one of several findings may suggest the correct diagnosis, including a history of other seizure types, epileptiform abnormalities on the EEC, and the disclosure of potentially epileptogenic lesions on neuroimaging. Transient ischemic attacks may be closley mimicked by simple partial seziures with 'inhibitory' motor signs (Lee and Lerner 1990). The exquisitely paroxysmal onset of the seizure, in contrast to the slightly more leisurely evolution of the transient ischemic attack, may suggest the correct diagnosis. Anxiety attacks may be closely mimicked by simple partial seizures with psychic symptoms, which, as noted earlier, may indeed manifest with classic attacks of anxiety, even to the point of inducing agoraphobic avoidance. The correct diagnosis may be suggested when patients with presumed panic disorder fail to respond to standard treatment. Parasomnias may be mimicked by nocturnal complex partial seizures, which may resemble night terrors (Boiler et al. 1975; Plazzi et al. 1995), REM sleep behavior disorder (Pedley and

Other major syndromes 317 Table 7.6 Non-epileptic paroxysmal events Simple partial seizures

Transient ischemic attacks Anxiety attacks

Complex partial seizures

Parasomnias Intermittent explosive disorder

Atonic seizures

Cataplexy Syncope

Amnestic seizures

Transient global amnesia Blackouts

All seizure types

Pseudoseizures

Guilleminault 1977), or somnambulism. As it is rare for complex partial seizures to occur only nocturnally, a special search should be made for similar events occurring during wakefulness, the existence of which is not compatible with a diagnosis of parasomnia. In doubtful cases, a 'diagnosis by treatment response' to anticonvulsants may be justified (Boiler et al. 1975). Intermittent explosive disorder is a controversial entity putatively characterized by episodes wherein patients, either without any precipitants or with only trivial ones, experience a growing sense of tension and irritability, culminating in an explosion of violence, after which they have only a spotty memory of the event; importantly, at other times in the patients' lives, there are no significant psychopathologic abnormalities (e.g. no chronic irritability). As demonstrated by the examples provided earlier regarding violence during complex partial seizures, it is clear that the similarities between the putative intermittent explosive disorder and a complex partial seizure with reactive automatisms may be compelling. In fact, some believe that intermittent explosive disorder is in fact a species of complex partial epilepsy. Resolving this nosologic question will require further research; in the meantime, one should, when evaluating patients with sporadic, seemingly unmotivated episodes of violence, enquire closely regarding the all-important history of other seizure types. Cataplexy may be suggested by atonic seizures with preserved consciousness, as was especially the case in a patient whose atonic seizures occurred on a reflexive basis when she heard jokes (lacome and Risko 1984). As noted earlier, atonic seizures generally occur in the setting of a chronic history of complex partial or grand mal seizures, which will immediately indicate the correct diagnosis. Syncope may be difficult to distinguish from an atonic seizure (Lempert et al. 1994). A 'swoon', in contrast to the 'stricken' fall of an atonic seizure, suggests a vasovagal syncopal episode, and syncope upon standing suggests hypotension. Cardiac syncope may be very similar to an atonic seizure, and, in some cases, monitoring may be required to demonstrate that the syncope is preceded by an appropriate arrhythmia. Even here, questions may remain as some complex partial seizures may be accompanied by complete atrioventricular block (Wilder-Smith 1992), sinus arrest (Kiok et al. 1986), or asystole (Rugg-Gunn et al. 2000). In such cases of suspected ictal arrhythmia, the differential may rest on the presence or absence of ictal EGG activity before the onset of the arrhythmia and loss of consciousness. Transient global amnesia may be very closely mimicked by amnestic seizures of the anterograde and retrograde type. Transient global amnesia is generally a condition of the middle-aged or elderly, and patients often have but one, or at the most, several amnestic episodes. By contrast, amnestic seizures generally first appear in younger patients and have a tendency to recur with some frequency.

318 Signs, symptoms and syndromes

Blackouts, as may be seen during intoxication with alcohol or with anxiolytics such as benzodiazepines, may be almost indistinguishable from amnestic seizures of the anterograde type. In such cases one would clearly want to look for any other signs of intoxication, such as dysarthria. Pseudoseizures are paroxysmal events that, rather than occurring on the basis of an electrical paroxysm in the brain, represent a simulation of a seizure, as may be seen in malingering, conversion disorder, and factitious disorder (including 'epileptic Munchausen's syndrome' [Savard et al. 1988]). Simple partial, complex partial, grand mal, and atonic seizures may all be simulated, and the diagnosis of a pseudoseizure is often suspected when the paroxysmal event in question has features that are significantly atypical for 'true' seizures. Clinical atypicality, however, cannot be taken, ipso facto, as definitive evidence of a pseudoseizure, because, as the many examples earlier in this section have demonstrated, the manifestations of cerebral electrical paroxysms can be very unusual indeed. Consequently, the diagnosis of a pseudoseizure generally rests on a failure to find evidence of paroxysmal electrical activity: as the negative results of various investigations and tests accumulate, the case for a diagnosis of a pseudoseizure becomes proportionately stronger. Clinically, one should always test for a Babinski sign after complex partial seizures. Investigations may include post-ictal prolactin or neuron-specific enolase levels, ictal surface electroencephalography, neuroimaging, attempts at placebo induction, and, in selected cases, single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging, or, in limiting cases, intracranial recording. A positive Babinski sign may be seen for about one-half hour post-ictally in about one-fifth of complex partial seizures (Walczak and Rubinsky 1994). As this phenomenon will generally lie outside the knowledge of most pseudoseizure patients, even medically sophisticated ones, its presence is a reliable sign of epileptic activity. Its absence, of course, is of little diagnostic import. The prolactin serum level rises with depth-electrode stimulation of either the hippocampus or the amygdala (Gallagher et al. 1987; Parra et al. 1980; Sperling and Wilson 1986), thus serving as a marker for paroxysmal activity in these or related structures and as an indicator that the clinical event in question is a 'true' rather than a 'pseudo' seizure (Laxer et al. 1985; Pritchard et al. 1985a). Prolactin elevation is, however, not entirely specific to epileptic events as such elevations may also be seen after hypotensive syncope (Oribe et al. 1996). A two-fold or greater rise in serum prolactin level is found about 15 minutes postictally in most cases of complex partial seizures with temporal lobe onset (Bauer et al. 1994; Sperling et al. 1986) and in grand mal seizures (Wyllie et al. 1984). However, with seizures arising from foci outside the temporal lobe, whether complex partial (Meierkord et al. 1992) or simple partial (Dana-Haeri et al. 1983; Laxer et al. 1985; Sperling et al. 1986), prolactin elevation is less likely to occur. Furthermore, after frequent seizures (Jackel et al. 1987; Malkowitz et al. 1995) or after status epilepticus (Tomson et al. 1989), one may find a normal prolactin level, presumably reflecting an exhaustion of the pituitary prolactin stores secondary to prolonged stimulation. Neuron-specific enolase is a marker of neuronal injury, and, in contrast to the prolactin level, which tends to be normal after status epilepticus, the level of enolase is elevated in such situations (DeGiorgio et al. 1999), peaking at 1 (DeGiorgio et al. 1995) or 2 days (Rabinowicz et al. 1995). Neuron-specific enolase may also be elevated after single, brief complex partial or grand mal seizures (Rabinowicz et al. 1996). Ictal scalp EEGs should be a routine part of a pseudoseizure work-up as the finding of ictal electrical activity is obviously very important. The absence of any electrical change, however, does not necessarily argue against an epileptic etiology: in the case of simple partial seizures, the ictal EEC is more often than not normal, and even in complex partial seizures, ictal surface

Other major syndromes 319

EEGs may be normal despite clear paroxysmal activity on depth recordings (Lieb et al. 1976; Morris et al. 1988; Williamson et al 1986). Neuroimaging, preferably by MRI scanning, is indicated to determine whether or not a lesion is present that could, with some probability, be supposed to cause seizures. Interpretation here must proceed with some caution, however: in some cases, epileptogenic lesions (e.g. small areas of focal cortical dysplasia) may be very difficult to detect on MRI, and, conversely, not all lesions, even though they are easily detected (e.g. a small convexity meningioma), are likely to cause seizures. Placebo induction, for example with saline infusion (Cohen and Suter 1982; Devinsky et al. 1996; Walczak et al. 1994), has been used as a diagnostic test for psuedoseizures on the notimplausible assumption that placebos are unlikely to induce paroxysmal electrical activity. It must be borne in mind, however, that placebo may, albeit rarely, induce seizures (Lesser et al. 1983). Cumulatively, the absence of a Babinski sign, normal prolactin and neuron-specific enolase levels, and a normal ictal EEC and MRI scan, coupled with a reproduction of the event in question by placebo induction, would, when present in combination, argue very strongly for the diagnosis of pseudoseizure. It must, however, be borne in mind that some 'true' seizures will, albeit rarely, 'slip by' all these tests. Consequently, in doubtful cases, consideration may be given to ictal SPECT or PET recordings, or, if the clinical situation warrents, intracranial recording. Essentially, in the work-up of a suspected pseudoseizure, one is attempting to 'prove a negative', that is, to 'prove' that the event in question is not accompanied by a paroxsmal electrical discharge. Given that one can never definitively prove a negative, however, the diagnosis of pseudoseizure should always remain somewhat tentative A further complication in the diagnostic work-up of pseudoseizures is the fact that it is not uncommon for patients to have both pseudoseizures and 'true' seizures (Krumholz and Niedermeyer 1983). Thus, simply demonstrating that a patient has had a pseudoseizure does not mean that the patient does not also have epilepsy. EPILEPTIC PAROXYSMAL EVENTS

Once it has been determined that the paroxysmal event in question is epileptic, the etiology of the seizure must be determined. Table 7.7, although not exhaustive, lists the common (and most of the uncommon) causes of seizures. In order to facilitate the differential diagnostic task, these causes are divided into several more or less homogenous groups, including mass lesions and vascular malformations, such as tumors; precipitating factors, such as scarring secondary to an earlier infarction; neuronal migration disorders; mesial temporal sclerosis; metabolic causes, such as hypoglycemia; acute encephalitis or meningitis; dementing or neurodegenerative disorders, such as Alzheimer's disease; congenital disorders, such as the Sturge-Weber syndrome; primary generalized epilepsy, such as classic petit mal epilepsy; and a large collection of miscellaneous causes, such as hyperthryoidism. Determining which seizure type the patient has helps in narrowing down the differential diagnosis. Patients with simple partial seizures, complex partial seizures, grand mal seizures of focal onset, atonic seizures, and amnestic seizures almost always harbor some kind of lesion. Conversely, patients with classic petit mal seizures and those with grand mal seizures of the primary generalized type generally lack any detectable lesion, and in such cases, the epilepsy is considered to be hereditary or idiopathic. Clearly, in the case of grand mal seizures, it is critical to determine whether the seizure has any focal features such as an aura or a post-ictal Todd's paralysis or Babinski sign. Of these various groups of possible causes, the following stand out as being particuarly common among adults: mass lesions and vascular malformations (especially tumors),

Table 7.7 Causes of seizures

Mass lesions and vascular malformations

Tumors Vascular malformations Cerebral abscesses

Precipitating factors

Infarction Head trauma Alcohol withdrawal Benzodiazepine or barbiturate withdrawal Medications Drugs of abuse Contrast agents Migraine Hypoxic coma Radiation encephalopathy Meningitis and encephalitis Hypertensive encephalopathy Eclampsia Dialysis dementia Electroconvulsive therapy Aspartame

Neuronal migration disorders Mesial temporal sclerosis Metabolic causes

Hypoglycemia Hyperglycemia Hyponatremia Hypocalcemia Hypomagnesemia Uremia

Acute encephalitis or meningitis

Viral encephalitis Bacterial meningitis Post-infectious encephalitis

Dementing or neurodegenerative disorders

Alzheimer's disease Multi-infarct dementia and Binswanger's disease Neurosyphilis AIDS dementia Granulomatous angiitis Creutzfeld-Jakob disease Cerebral amyloid angiopathy Juvenile Huntington's disease Neuroacanthocytosis Dentatorubropallidoluysian atrophy Wilson's disease Hallervorden-Spatz disease Cerebrotendinous xanthomatosis Metachromatic leukodystrophy Adrenoleukodystrophy Subacute sclerosing panencephalitis Progressive rubella panencephalitis

Congenital disorders

Sturge-Weber syndrome Tuberous sclerosis

Other major syndromes 321 Table 7.7 Causes of seizures - continued Von Recklinghausen's disease Down's syndrome Klinefelter's syndrome Fragile X syndrome Prader-Willi syndrome Rett's syndrome Autism Cerebral palsy Mental retardation Primary generalized epilepsy

Petit mal epilepsy Grand mal epilepsy of the primary type

Miscellaneous causes

Hyperthyroidism Hashimoto's disease Limbic encephalitis Systemic lupus erythematosus Sarcoidosis Wegener's granulomatosis Whipple's disease Celiac disease Hepatic porphyria Central pontine myelinolysis Multiple sclerosis Sydenham's chorea Autosomal dominant partial epilepsy Rasmussen's syndrome Landau-Kleffner syndrome Lead intoxication Tin intoxication Cysticercosis Marchiafava-Bignami disease Domoicacid intoxication

precipitating factors (especially infarction, head trauma, and alcohol withdrawal) and neuronal migration disorders (Currie et al. 1971; Jensen and Klinken 1976; King and Marsan 1977; Mauguire and Courjon 1978; Rasmussen 1963, 1983; Sander et al. 1990; Zentner et al. 1995). Furthermore, and again among adults (Dam et al. 1985) (especially older adults [Loiseau et al. 1990a]), tumors and infarctions are the most common cause of new onset seizures, alcohol withdrawal seizures also being a very common cause in adults in their fourth decade (Sander et al. 1990). In evaluating a patient with seizures, the possibility that more than one cause may be operative must also be borne in mind. For example, any patient with epilepsy may develop a metabolic derangement, such as hypoglycemia, with a subsequent increase in seizure frequency. Furthermore, some patients may have 'double' or 'dual' pathology, for example a combination of mesial temporal sclerosis and some other lesion, such as a tumor (Bruton 1988). Among alcoholics, the temptation immediately to attribute a seizure to alcohol withdrawal must be resisted, as such patients are prone to head injuries, such as subdural hematomas, which may cause seizures in their own right (Earnest et al. 1988).

322 Signs, symptoms and syndromes

Mass lesions and vascular malformations

Tumors may cause seizures, this being more likely to occur with tumors of the cortical gray matter than with those in the white matter or subcortical gray structures (Scott and Gibberb 1980). Given their frequency in adults (Dam et al. 1985), the clinical 'rule' that a new onset seizure disorder in an adult, is until proven otherwise, secondary to a tumor, is a sound clinical guide. Vascular malformations, such as arteriovenous malformations and various angiomas, are a common cause of seizures which may indeed constitute their sole clinical expression (Kramer andAwad 1994). Cerebral abscesses, which may or may not be accompanied by fever and leukocytosis, are frequently associated with seizures, not only when acute, but also amongst those patients who survive (Legg et al. 1973). Precipitating factors

Infarction may be associated with seizures, either during the stroke itself (Richardson and Dodge 1954) or subsequently, occurring either early, within the first week or two, or later (Daniele et al 1989; Kilpatrick et al. 1992; So et al 1996). Both partial and grand mal types may occur (Bogousslavsky et al 1992; Kilpatrick et al 1990). Head trauma may be followed by either early or late onset (after 1 year) seizures (Jennett 1973; Jennett et al 1973). After a closed head injury characterized by diffuse axonal injury alone, the incidence is about 5% (Phillips 1954), but after an injury accompanied by dural penetration, cortical laceration, retained foreign bodies, or intracerebral hemorrhage, the incidence is much higher, rising to approximately 50% (Annegers et al. 1980; Annegers et al 1998; Ashcroft 1941; Caveness 1976; Jennett 1975; Lishman 1968; Russell and Whitty 1952; Salazaretfl/. 1985). Alcohol withdrawal may be followed by seizures, especially in patients with a long history of heavy drinking (Lechtenberg and Worner 1992; Leone et al. 1997; Schuckitt et al. 1993). Seizures may occur either in an isolated fashion as 'rum fits' or in association with delirium tremens (Isbell et al 1955). 'Rum fits' are generally restricted to the first 48 hours of abstinence, and although repeated seizures, even status, may occur, most patients have only one or two seizures (Earnest et al 1988; Espir and Rose 1987; Victor and Brausch 1967). Delirium tremens, marked by delirium and prominent tremor, generally appears within the first few days of abstinence, and seizures, which may either 'usher in' the delirium or occur in the midst of it, are seen in between 10% (Rosenbaum et al 1941) and 20% (Lundquist 1961) of patients. Importantly, although most seizures occurring in an abstinent alcoholic are related to the alcohol withdrawal per se, other epileptogenic factors, such as head trauma, hypoglycemia, hypomagnesemia, Wernicke's encephalopathy, or meningitis, may also be present (Earnest et al. 1988; Lechtenberg and Worner 1992). Benzodiazepine or barbiturate withdrawal may both cause seizures (Kalinowsky 1942; Levy 1984), and in the case of barbiturates, status epilepticus is not uncommon. Medications are a not-uncommon cause of seizures. Tricyclic and tetracyclic antidepressants may cause seizures, as has been noted with amitriptyline (Betts et al 1968b) and imipramine (Petti and Campbell 1975). Maprotilene (Jabbari et al 1985) and clomipramine (Clomipramine Collaborative Study Group 1991) are particularly likely to at therapeutic doses, and in the case of amoxapine, seizures are very common in overdose (Litovitz and Troutman 1983). As might be expected, the risk of seizures with cyclic antidepressants is higher in those with a history of head trauma (Wroblewski et al. 1990). Bupropion, a non-cyclic antidepressant, may cause seizures in over 2% of patients treated with doses of 600 mg or more daily and is particularly likely to cause seizures in patients with a history of bulimia nervosa (Davidson 1989; Johnston et al. 1991). Phenothiazine

Other major syndromes 323

neuroleptics may cause seizures (Olivier et al. 1982), especially with higher doses (Logothetis 1967). Clozapine, an atypical neuroleptic, causes seizures overall in 1.3% of patients (Pacia and Devinsky 1994), a higher incidence being found in patients with a history of seizures (Wilson and Claussen 1994): the risk is higher with rapid dose titration (Baker and Conley 1991; Devinsky et al. 1991) and with high doses, rising to approximately 10% in those taking over 600 mg daily (Haller and Binder 1990). Lithium may cause grand mal seizures (Wharton 1969) and may increase the frequency of seizures in those with petit mal epilepsy (Moore 1981). Bismuth, as may be used in the treatment of peptic ulcer, is known to cause delirium with myoclonus and either partial or grand mal seizures (Supino-Viterbo et al. 1977); uncommonly, bismuth intoxication may present with a seizure (Molina et al. 1989). Other medications noted to cause seizures include penicillin (Snavely and Hodges 1984), cefipine (Dixit et al. 2000), chemotherapeutic agents such as busulfan (Murphy et al. 1992) and cyclosporin A (Appleton et al. 1989), and either isoniazid or theophylline (Messing et al. 1984). Drugs of abuse noted to cause seizures include phencyclidine (Alldredge et al. 1989) and cocaine: in the case of cocaine, complex partial status epilepticus has been noted (Merriam et al. 1988; Ogunyemi et al. 1989). Contrast agents may cause seizures, as has been noted with iodinated contrast material given intravenously for computed tomography scanning (Aurahami et al. 1987), intra-arterially during angiography (Vickrey and Bahls 1989), and intrathecally during myelography (Greenberg and Vance 1980) or cisternography (Shiozawa et al. 1981). Migraine appears to be capable of precipitating seizures in patients with epilepsy. In particular, it appears that a migraine aura may trigger either a partial or a grand mal seizure, the seizure being intercalated between the migraine aura and the migraine headache (Marks and Ehrenberg 1993). Hypoxic coma, as may be seen after cardiopulmonary resuscitation, may be associated with seizures (Krumholz et al. 1988). Radiation encephalopathy, occurring after a course of cerebral radiation, may be characterized by seizures, in both the early and the delayed form (Shewmon and Masdeu 1980). Meningitis and encephalitis may each have seizures as sequelae (Marks et al. 1992), and this appears to be more likely in cases in which the acute phase was characterized by seizures (Annegers et al. 1988) and where there are other sequelae indicative of cerebral damage (Pomeroy et al. 1990). Hypertensive encephalopathy may, in addition to headache and delirium, also cause seizures (Chester et al. 1978; Healton et al. 1982). Eclampsia, seen during the last trimester of pregnancy, is characterized by hypertension, proteinuria, and seizures (Manfredi et al. 1997). Dialysis dementia, currently rare, is characterized by dementia, hesitant, stuttering speech, seizures, and myoclonus (Burks et al. 1976; Garrett et al. 1988; Lederman and Henry 1978; O'Hare et al. 1983). Electroconvulsive therapy may, as is well known, induce prolonged seizures; it may, however, also be followed by spontaneous seizures, both grand mal and complex partial (Devinsky and Duchowny 1983), including complex partial status epilepticus (Varma and Lee 1992). Aspartame, taken in very high dose, may cause seizures (Walton 1986). Neuronal migration disorders

Neuronal migration disorders comprise a large group of conditions, all of which result from defective neuronal migration during embryogenesis. In the normal course of embryogenesis, neurons migrate along radially oriented glial fibers from the periventricular area to the

324 Signs, symptoms and syndromes

overlying cortical plate, where they come to rest in an orderly fashion, eventually resulting in a properly laminated and appropriately convoluted cortex. Disordered migration, depending on its timing and degree, may result in a variety of morphologic changes (Raymond et al. 1995), including gyral malformations (Brodtkorb et al. 1992) such as polymicrogyria, pachygyria, and lissencephaly, cortical microdysgenesis (Armstrong 1993; Meencke and Janz 1984) or focal cortical dysplasia (Palmini et al. 1991; Sisodiya et al. 1995; Taylor et al. 1971), and various heterotopias (e.g. nodular [Dubeau et al. 1995; Kothare et al. 1998; Raymond et al. 1994] and band or laminar [Barkovich and Kjos 1992; Ono et al. 1997]). With the advent of MRI, these disorders are being found more and more frequently (Barkovich et al. 1995; Sisodiya et al. 1996), and it appears that they may constitute one of the most comon causes of partial seizures or grand mal seizures of focal onset (Raymond et al. 1995). Hamartoma is another name for an area of cortical dysgenesis wherein the only abnormality is the organization and architecture of neurons, which are otherwise normal. One syndrome that has attracted special interest is that seen with hypothalamic hamartomas: such patients often have an onset of gelastic simple or complex partial seizures in infancy, combined with precocious puberty (Berkovic et al. 1988; Cascino et al. 1993c; Kuzniecky et al. 1997). Importantly, however, the syndrome of gelastic seizures and precocious puberty is not always caused by a hamartoma of the hypothalamus (Ames and Enderstein 1980; Breningstall 1985): in some cases, other lesions, such as a ganglioglioma, may be present (List et al. 1958). Mesial temporal sclerosis

Mesial temporal sclerosis is characterized by sclerosis of one or more of the structures on the medial aspect of the temporal lobe, including the hippocampus, amygdala, and parahippocampal gyrus (Cavenaugh et al. 1956; Cendes et al. 1993b; Falconer 1971; Hudson et al. 1993), as illustrated in Figure 7.1. Ammon's horn (cornu Ammonis) is an older term for the hippocampus, and some authors, rather than using 'hippocampal sclerosis', will speak of

Image Not Available

Figure 7.1 Coronal magnetic resonance Imaging scan demonstrating mesial temporal sclerosis on the right. On the Tl-weighted scan, atrophy of the hippocampus, indicated by the arrow, is fairly apparent, increased signal intensity being seen in the same area on the T2-weighted scan. (Reproduced from Hopkins etal. 7995J

Other major syndromes 325

'Ammon's horn sclerosis'. The pathogenesis of mesial temporal sclerosis is not known with certainty. Childhood febrile seizures are probably etiologic in a proportion of cases, but in some cases of mesial temporal sclerosis, there is simply no history of such an event (Adam et al. 1994; Cendes etal. 1993a; French et al 1993; Saygi etal. 1994). Among patients with a seizure focus in the temporal lobe, mesial temporal sclerosis is the most common cause (Bruton 1988; Engel et al. 1975; Falconer 1971; Falconer et al. 1974b; Margerison and Corsellis 1966; Sano and Malamud 1953). Given that most (but certainly not all) cases of complex partial epilepsy result from a focus in the temporal lobe, mesial temporal sclerosis turns out to be the most common cause of this type of epilepsy. Metabolic causes

Hypoglycemia may cause seizures, and although such seizures may be acompanied by autonomic signs (e.g. tremor) or delirium, it must be borne in mind that a seizure can be the presenting manifestation of hypoglycemia (Hoefer etal. 1946; Malouf and Brust 1985). Hyperglycemia, occurring without ketosis, has been strongly associated with simple partial seizures with either sensory (Maccario et al. 1965) or, more commonly, motor sympotms (Grant and Warlow 1985; Hennis et al. 1992b): in some cases, these simple partial seizures with motor symptoms display a reflex character, being induced by motion (Brick et al. 1989). Occasionally, simple partial status epilepticus with motor symptoms (epilepsia partialis continua) may occur (Singh etal. 1973; Singh and Strobos 1980). Hyponatremia may cause seizures, often accompanied by delirium (Swanson and Iseri 1958). Hypocalcemia may provoke seizures that may or may not be accompanied by other signs, such as tetany (Glaser and Levy 1960). In cases of chronic hypocalcemia secondary to hypoparathyroidism, seizures may be the presenting sign (Berger and Ross 1981) or may be preceded by other signs, for example cataracts or parkinsonism (Eraut 1974). Hypomagnesemia, in addition to causing delirium and myoclonus, may also lead to seizures (Hall and Joffe 1973). Uremia may be accompanied by seizures (Tyler 1968), one study finding this to be the case in approximately one-third of uremic patients (Locke et al. 1961). Rarely, seizures in uremia may be caused not so much by the uremia per se, but by aluminum intoxication, as occurred in some patients with renal failure who had chronically taken antacids (Russo et al. 1992). Acute encephalitis or meningitis

Viral encephalitis, typified by headache, fever, and varying degrees of delirum, often causes seizures (Annegers et al. 1988), seizures being the rule in herpes simplex encephalitis (Haymaker 1949; Kennedy 1988; Williams and Lerner 1978). The encephalitis of infectious mononucleosis may present in this typical fashion (Gautier-Smith 1965) or may rarely be evidenced by a seizure alone (Silverstein et al. 1972). Bacterial meningitis, suggested by headache, fever, and a stiff neck, may cause seizures (Annegers et al. 1988): in the case of viral, or aseptic, meningitis, the appearance of a seizure suggests a concurrent encephalitis. Post-infectious encephalitis presents between days and weeks after a viral infection, with headache, fever, delirium, and, occasionally, seizures (Paskavitz et al. 1995). Dementing and neurodegenerative disorders

Alzheimer's disease, late in its course and long after the dementia is well established, may also be characterized by seizures (Goodman 1953; Hauser et al. 1986; Romanelli et al. 1990). Multi-infarct dementia and Binswanger's disease (Rosenberg et al. 1979) may both be characterized by seizures.

326 Signs, symptoms and syndromes

Neurosyphilis, in particular general paresis of the insane may cause either grand mal or simple partial seizures, most especially simple partial seizures with a Jacksonian march (Merritt et al. 1932; Storm-Mathisen 1969). Importantly, the Jarisdi-Herxheimer reaction to penicillin treatment may also be characterized by seizures (Hahn et al. 1959; Zifko et al. 1994). AIDS dementia may, late in its course, be accompanied by seizures (Navia et al. 1986a). Seizures occurring in the setting of an AIDS dementia may, however, arise from other causes, for example toxoplasmosis (Navia et al. 1986b; Porter and Sande 1992). Granulomatous angiitis, or isolated angiitis of the central nervous system, presents subacutely with headache and altered mental status (delirium, dementia, personality change, or psychosis), and may, in a minority, be accompanied by seizures (Vollmer et al. 1993). Creutzfeldt-Jakob disease, classically characterized by a dementia or delirium and myoclonus, may, in a minority of patients in the later stages of the disease, also cause grand mal or partial seizures (Brown et al. 1986). Cerebral amyloid angiopathy, classically causing lobar hematomas and, in some cases, a dementia, may also manifest with simple partial seizures, which may occur before any lobar hemorrhages and either before or concurrent with a dementia (Greenberg et al. 1993). Juvenile Huntington's disease is classically characterized not by chorea but by a combination of parkinsonism and dementia, and may be accompanied by seizures (Campbell et al. 1961; Siesling et al. 1997). Neuroacanthocytosis, typified by a movement disorder (generally choreiform but in some dystonic or parkinsonian) and personality change or dementia, may cause seizures in a minority (Hardie et al. 1991), and may rarely present with seizures (Feinberg et al. 1991). Dentatorubropallidoluysian atrophy exhibits considerable inter- and intrafamilial phenotypic variability: among those patients with adult onset disease, a combination of dementia, a movement disorder (often choreiform but occasionally with dystonia or parkinsonism), and ataxia is common, and may be accompanied by seizures (Porter et al. 1995; Warner et al. 1995). Wilson's disease, eventually marked by a combination of a movement disorder (tremor, chorea, dystonia, or parkinsonism) and mental status changes (dementia, personality change, or psychosis) may, in a small minority, also cause seizures (Dening et al. 1988). Hallervorden-Spatz disease, typically presenting with a movement disorder (classically dystonia but at times chorea or parkinsonism) followed by dementia, may, rarely, also cause seizures (Rozdilsky et al. 1968). Cerebrotendinous xanthomatosis, typified by a combination of either mental retardation or dementia with achilles tendon enlargement or cataracts, may also cause seizures (Fiorelli et al. 1990). Metachromatic leukodystrophy of juvenile (Haltia et al. 1980) or adult onset type (Alves et al. 1986; Betts et al. 1968a; Hageman et al. 1995) eventually causes a dementia, often accompanied by ataxia and, in a minority of cases, seizures. Adrenoleukodystrophy, often presenting with behavioral change, dementia, and visual changes, may, in a minority, also cause seizures (Moser et al. 1984). Subacute sderosing panencephalitis, caused by a reactivation of a defective measles virus years after a natural infection (or rarely vaccination), may present with either a dementia or, in adults, a psychosis and may, in a minority, be accompanied by seizures (Kornberg et al. 1991; Koehler and Jakumeit 1976). Progressive rubella panencephalitis, a late sequela of congenital or, less commonly, acquired rubella, generally presents with a slowly progressive dementia with ataxia, spasticity, and, in some cases, seizures (Townsend et al. 1975, 1976).

Other major syndromes 327

Congenital disorders

Sturge-Weber syndrome is classically characterized by a unilateral facial port-wine stain, hemiplegia contralateral to the port-wine stain, mental retardation, and seizures (Bebin and Gomez 1988; Pascual-Castroviejo et al. 1993). Importantly, there is an association between frequent seizures and dementia in this disorder (Lichenstein 1954; Petermann et al 1958), an association that underlines the importance of seizure control. Tuberous sclerosis classically presents in childhood with the triad of seizures, adenoma sebaceum, and mental retardation (Critchley and Earl 1932). Seizures generally, but not always, precede the appearance of adenoma sebaceum (Alsen et al. 1994; Ross and Dickerson 1943), and although generally of the 'salaam' type in infancy, manifest with typical grand mal or partial seizures by early or mid-childhood (Pampiglione and Moynahan 1976). Tuberous sclerosis may rarely present in the adult years: in one case, a 26-year-old developed adenoma sebaceum, followed, at age 31, by partial seizures (Kofman and Hyland 1959). Von Recklinghausen's disease (neurofibromatosis type I) is characterized by neurofibromas and cafe au lait spots: seizures may occur in 4-5% of sufferers (Korf et al. 1993; Kulkantrakorn and Geller 1998). Downs syndrome, typified by a variable degree of mental retardation and a characteristic dysmorphism with narrowed palpebral fissures, epicanthal folds, and a small mouth, often with a large protruding tongue, may be accompanied by partial or grand mal seizures in adults (Pueschel et al. 1991), the proportion affected rising from about one-tenth of young adults, to about one-half of those over 50 (McVicker etal. 1994) and to over three-quarters of those who go on to develop a dementia (Lai and Williams 1989). Klinefelter's syndrome, characterized by tall stature and eunuchoidism in post-pubertal males, may, albeit rarely, be accompanied by complex partial or grand mal seizures (Tatum et al. 1998). Fragile X syndrome, seen generally, but not always, in males, is typified by a variable degree of mental retardation, macroorchidism, and a characteristic dysmorphism, with a long, narrow face, prominent forehead, and large ears. A minority of these patients will also have either partial or grand mal seizures (Finelli et al. 1985; Wisniewski et al. 1985). Prader-Willi syndrome is characterized by extreme obesity secondary to a ravenous hunger. Dysmorphic features are common, with a narrow head, almond-shaped eyes, a thin upper lip, thin arms, and, in males, micropenis and cryptorchidism. Perhaps one-half will also have mental retardation, generally of a mild degree. Seizures may occur in about one-fifth of these patients (Bray etal. 1983). Rett's syndrome (Hagberg et al. 1983), seen virtually only in females, is suggested by a typical evolution of symptoms in childhood, resulting in microcephaly and mental retardation. In a minority of adults, either partial or grand mal seizures may be seen. Autism, marked by a peculiar machine-like relatedness to others, may in adults be accompanied by partial or grand mal seizures (Gillberg 1991; Olsson et al. 1988), regardless of whether or not the patient also has mental retardation. Cerebral palsy may cause seizures to occur in the adult years, this almost always being the case in those who had seizures in the neonatal period (Cohen and Duffner 1981). Mental retardation of any cause may be accompanied by partial or grand mal seizures (Steffenburg et al. 1996), and this appears more likely in those with more severe cases. Primary generalized epilepsy

Petit mal epilepsy typically first appears in childhood, between the ages of 4 and 12; at the height of the disorder, patients may have literally hundreds of attacks a day. Eventually, however, the frequency of attacks decreases, and by the adult years remission may occur.

328 Signs, symptoms and syndromes

Grand mal epilepsy of the primary type occurs on an hereditary basis. As noted earlier one must very carefully exclude evidence of a focal onset in a grand mal seizure before assuming that it is of the primary type. Miscellaneous causes Hyperthyroidism, suggested by anxiety, restlessness, tremor, tachycardia, diaphoresis, and heat intolerance, may, in a minority, cause seizures (Korczyn and Bechar 1976; Jabbari and Huott 1980). Hashimoto's disease may affect either the thyroid or the cerebrum. With thyroid involvement, a thyroiditis may occur, with transient hyperthyrodism, and with cerebral involvement, there is often a delirium, typically accompanied by myoclonus and, in some cases, partial or grand mal seizures (Henchey et al. 1995; Shaw et al. 1991). It is important to recall that Hashimoto's encephalopathy can, and often does, occur independently of any clincial evidence of thyroiditis. Limbic encephalitis typically presents subacutely, over days or weeks, with delirium that is generally accompanied by seizures (Alamowitch et al. 1997). Uncommonly, the presenting feature will be a seizure, followed by delirium (Brennan and Craddock 1983; Corsellis et al. 1968), and rarely a seizure may consitute the primary manifestation of limbic encephalitis (Shavit et al. 1999; Tsukamoto et al 1993). Systemic lupus erythematosus may affect the cerebrum but usually does so only in the setting of systemic symptomatology, such as constitutional symptoms, arthralgia, myalgia, rash, etc. Seizures may occur but generally only in the company of other symptoms suggesting cerebral involvement, such as dementia or various focal deficits (Devinsky et al. 1988a). Sarcoidosis, suggested by systemic signs and symptoms, most prominently bilateral hilar lymphadenopathy or a diffuse reticulonodular pattern on chest X-ray, affects the cerebrum in only a very small minority of patients, some of whom may have seizures that may be grand mal or, less frequently, partial (Krumholz et al. 1991; Oksanen 1986). Wegener's granulomatosis, suggested by a combination of upper respiratory symptoms and renal involvement, affects the cerebrum in a minority and may, in an even smaller minority, cause seizures (Nishino et al. 1993). Whipple's disease generally manifests with abdominal symptomatology (e.g. abdominal pain and diarrhea) and arthralgia: in a small minority, cerebral involvement may occur, which may include seizures (Louis et al. 1996). Whipple's disease may rarely present with a seizure in the absence of any systemic symptoms (Romanul et al. 1977). Celiac disease, also known as gluten enteropathy, is generally characterized by abdominal bloating and diarrhea and may be associated with both grand mal and partial seizures (Chapman et al. 1978). In some cases, the seizures are associated with a distinctive occipital calcification (Gobbi et al. 1992; Tinuper et al. 1996b). Hepatic porphyria presents in attacks characterized by abdominal pain with diarrhea or constipation and often delirium. Seizures are seen in a minority of cases (Byelsjo et al. 1996) and may occur either with or without delirium (Goldberg 1959). Central pontine myelinolysis, occurring within 1-7 days of an overly rapid correction of hyponatremia, typically presents with lethargy or delirium, generally accompanied by a variable degree of quadriparesis. Seizures maybe seen in a small minority (Karp and Laureno 1993). Multiple sclerosis, rarely, may cause seizures (Thompson et al. 1993; Trouillas and Courjon 1972), and in one very rare case, multiple sclerosis presented with simple partial status epilepticus with motor signs secondary to a plaque in the precentral gyrus (Spatt 1995). Sydenham's chorea is rarely accompanied by seizures (Nausieda et al. 1980) or, and again rarely, may have partial seizures as one of its sequelae (Aron et al. 1965).

Other major syndromes 329

Autosomal dominant partial epilepsy, with either simple or complex partial seizures, is being increasingly recognized, and several syndromes have been isolated, including autosomal dominant nocturnal frontal lobe epilepsy (Hayman et al. 1997; Hirose et al. 1999; Oldani et al. 1998; Phillips et al. 2000; Saenz et al 1999; Scheffer et al. 1994, 1995), familial temporal lobe epilepsy (Berkovic et al. 1996), autosomal dominant partial epilepsy with auditory features (Ottman et al. 1995; Winawer et al. 2000), and the closely related autosomal dominant lateral temporal epilepsy (Poza et al. 1999). These probably represent but the tip of the iceberg, however, as many, if not most, families with autosomal dominantly inherited partial epilepsy do not fall into one of these recognized groups (Picard et al. 2000; Provini et al. 1999).What is unclear in these cases is not that the partial seizures occur on an hereditary basis but rather what is inherited. It may well be that these syndromes represent hereditary neuronal migration disorders of a very subtle type that, to date, still elude MRI detection. Rasmussen s syndrome (Aguilar and Rasmussen 1960; Rasmussen et al. 1958) occurs secondary to a chronic focal encephalitic process in one cerebral hemisphere, which, classically, causes a slowly progressive neurologic deficit, such as hemiparesis, and seizures, either grand mal or partial in type. Partial seizures in Rasmussen's syndrome are often of the simple partial type with either motor or somatosensory symptoms, and simple partial status is not uncommon (Rasmussen and Andermann 1989; Rasmussen et al. 1958). Although the onset is generally in childhood under the age of 10, adult onsets may also be seen (McLachlan etal 1993). Landau-Kleffner syndrome is characterized by a childhood onset of aphasia and seizures (Landau and Kleffner 1957; Mantovani and Landau 1980; Paquier et al. 1992). Lead intoxication in adults, when acute, often presents with delirium, abdominal pain, and seizures, as may be seen in adults who drink illicit 'moonshine' whiskey made in old radiators (Morris et al. 1964; Whitfield et al. 1972) or, in one case, where adults burned discarded lead storage battery boxes for fuel (Akelaitis 1941). Acute lead intoxication in children, as can be seen in those who ingest leaded paint chips, may, when severe, cause seizures and delirium or coma (Jenkins and Mellins 1957). Tin intoxication may cause a delirium with seizures, as has been noted with trimethyl (Fortemps et al. 1978) and with triethyl tin (Alajouanine et al. 1958); in one case, upon recovery from trimethyl tin intoxication, a patient subsequently developed complex partial seizures (Feldman et al. 1993). Cysticercosis represents an infestation by larval forms of Taenia solium, the pork tapeworm. The larvae tend to encyst in skeletal muscle and brain, but as the living larvae provoke little inflammation, the symptoms are generally delayed for many years until the larvae die, whereupon an intense inflammatory response is seen, often followed by calcification of the cyst. The most common manifestation of neurocysticercosis is seizures, either partial or grand mal, and indeed, in some undeveloped countries, cysticercosis is the leading cause of epilepsy; accordingly, the disease should be suspected in immigrants from such countries who develop seizures. It must be borne in mind, however, that the disease has also been reported to be common in such developed nations as Portugal (Monteiro et al. 1995). Marchiafava-Bignami disease, generally seen only in chronic alcoholics, is marked by delirium, various focal signs, and seizures, which may be partial or grand mal (Ironside et al. 1961; Koeppen and Barren 1978). Domoic acid intoxication, as may occur with the ingestion of mussels, is a very rare event but is noted here because the resulting neuropathology is similar to that of mesial temporal sclerosis. Domoic acid is an excitotoxin, similar to kainic acid, and in the reported case, ingestion was followed by the development of hippocampal atrophy and complex partial seizures (Cendes et al. 1995).

330 Signs, symptoms and syndromes

Diagnostic work-up of the syndrome In the case of seizures with a focal onset, the aim of the diagnostic work-up is to localize the lesion and determine its nature. As noted earlier, one should assume, in the case of simple partial, complex partial, atonic, and amnestic seizures, that a lesion of some sort is present and search diligently for it. This holds true even when the etiology, for example hypoglycemia, seems obvious, for even in this case, if the seizure shows 'focality', one may assume that the metabolic derangement 'took advantage' of the presence of some hitherto unexpressed lesion such as a small tumor, a scar, or a bit of focal cortical dysplasia. In the case of grand mal seizures, the importance of a full diagnostic evaluation varies with the evidence of 'focality': the fact that up to one-half of all patients who have an aura before a grand mal seizure do not recall it should make one pause before making the diagnosis of a primary generalized grand mal seizure. By contrast, in cases of classic petit mal seizures, the pressure to perform a full diagnostic work-up is substantially less as almost all of these seizures are either idiopathic or hereditary. When, after a full work-up, the cause of a focal seizure cannot be determined, the diagnosis should be of'cryptogenic' epilepsy. Such a diagnosis does not close the door to future investigation but stands simply as a confession of our current ignorance. The diagnostic work-up should include, at a minimum, attention to clinical lateralizing and localizing signs, electroencephalography, and appropriate neuroimaging (King et al. 1999). Further testing is dictated by one's clinical suspicions, and may include testing for metabolic causes (e.g. blood glucose level), encephalitis (lumbar puncture), etc. More specialized testing, for example with SPECT or PET scanning, is generally reserved for presurgical work-ups. CLINICAL LATERALIZING AND LOCALIZING SIGNS

Although seizures may display lateralizing and localizing signs, these may escape detection by the patient or by lay observers. Although the physician may at times be fortunate enough to observe the seizure, videotape recordings are often required. In some cases, these may be obtained by family members using video cameras (Newmark 1981; Samuel and Duncan 1994), and in others, when the diagnostic need justifies it, hospital admission for video-EEC recording may be indicated. In either case, with a patient who has reflex seizures, it may be appropriate, if having the seizure itself involves minimal risk to the patient, to re-enact the triggering situation under video observation (Fariello et al. 1983). Simple partial seizures often display both lateralizing and localizing signs. In the case of simple partial seizures with either motor or somatosensory signs, the focus is typically, but not always (Herskowitz and Swerdlow 1972), lateralized to the hemisphere contralateral to the side on which the patient is experiencing the symptoms (Mauguire and Courjon 1978). With regard to localization to a particular lobe, in most cases motor signs suggest the frontal lobe, somatosensory symptoms the parietal lobe, simple visual hallucinations or hemianopia the occiptal lobe, structured visual hallucinations the occiptoparietal or occiptotemporal region, and most 'pychic' symptoms the temporal lobe (Acharya et al. 1998; Bien et al. 2000; Mauguire and Courjon 1978; Morris et al. 1988; Nystrom 1966; Russell and Whitty 1955; Salanova et al. 1995). In cases in which more than one sort of symptom is seen, careful attention must be paid to which occurred first as this is the one with most localizing value: for example, a simple partial seizure that began with a crude visual hallucination and was immediately followed by a motor sign would indicate a focus in the occipital rather than the frontal lobe (Salanova et al. 1992; Williamson et al. 1992a). Complex partial seizures, like simple partial seizures, may also display both lateralizing and localizing signs. Of the lateralizing signs, the presence of speech is of strong value. Speech may occur either during an aura, during the seizure itself, or post-ictally, and may be either

Other major syndromes 331

coherent or aphasic. Ictal speech that is coherent suggests a focus in the non-dominant hemisphere (Fakhoury et al. 1994; Gabr et al. 1989; Koerner and Laxer 1988; Marks and Laxer 1998; Yen et al. 1996), whereas aphasic speech occurring either during the aura (Kanemoto and Janz 1989) or post-ictally (Ajmone-Marsan and Ralston 1957; Devinsky et al. 1994a; Fakhoury et al 1994; Gabr et al. 1989; Koerner and Laxer 1988; Marks and Laxer 1998; Privitera et al. 1991; Serafetinides and Falconer 1963) suggests a focus in the dominant hemipshere. Unilateral ictal clonic, tonic or dystonic movement (Kotagal et al. 1989; Marks and Laxer 1998), and unilateral paresis (Oestreich et al. 1995) all suggest a focus on the contralateral side. Unilateral automatisms (Marks and Laxer 1998) or unilateral ictal eye-blinking (Benbadis et al. 1996) both generally indicate an ipsilateral focus. Interictal mimetic palsy suggests that the focus is contralateral to the side with the palsy (Cascino et al. 1993b; Remillard et al. 1977). Head version at the start of a seizure is of controversial lateralizing significance: some studies (e.g. Quesney et al. 1990; Salanova et al. 1995) report that the head turns away from the side with the focus, whereas others (e.g. Geier et al. 1977; Ochs et al. 1984) have not found such a relationship. Localization of the focus of a complex partial seizure may not be as straightforward as was once thought. In the not-too-distant past, the assumption that complex partial seizures (or, as they were once called, 'psychomotor' seizures) all originated from foci in the temporal lobe was so unquestioned that some authors used the terms 'complex partial epilepsy' and 'temporal lobe epilepsy' synonymously. It has become clear, however, that even though most complex partial seizures do arise from foci in the temporal lobe (Nystrom 1966), they may also occur secondary to foci in the frontal (Geier et al. 1977; Rasmussen 1983; Salanova et al. 1995; Sutherling et al. 1990; Williamson et al. 1985a), occipital (Ludwig and Marsan 1975; Salanova et al. 1992; Williamson etal. 1992a), or parietal (Cascino etal 1993a; Ho etal 1994; Williamson etal. 1992b) lobes. In cases where the focus is in a site other than the temporal lobe, electrical activity spreads rapidly from the originating lobe to the temporal lobes, thus producing the symptomatology of the complex partial seizure itself. As suggested by Jackson (1894), it stands to reason that, in such cases, the aura to the complex partial seizure may indicate the lobe of origin, and this does in fact appear to be the case (Boon etal. 1991; Palmini and Gloor 1992), the various aurae having the same localizing value as discussed for simple partial seizures, above. Before leaving the subject of localization in complex partial seizures, note should be made of the significance of ictal bilateral 'bicycling' movements. Some have held that these indicate a frontal lobe onset (Williamson et al. 1985a), but such movements have also been noted in complex partial seizures of temporal lobe origin (Sussman et al. 1989; Swartz 1994). Grand mal seizures rarely, of themselves, display any lateralizing or localizing signs. Should an aura or a complex partial seizure immediately precede the grand mal seizure, however, an abundance of data may be available, as noted above. Furthermore, in the post-ictal state, a unlateral paresis or Babinski sign may be used to sugggest a contralateral focus. ELECTROENCEPHALOGRAPHY

Interictal and, whenever possible, ictal surface EEGs should be obtained in all cases. In the case of simple partial, complex partial, and focal grand mal seizures, interictal epileptiform activity may be both lateralizing and localizing, and ictal recordings may reveal a focal onset. In the case of classic petit mal seizures, one typically finds generalized 3 Hz spike and dome activity, both interictally and ictally. As important as the finding of interictal or ictal activity is, its absence does not rule out the diagnosis of epilepsy. In the case of simple partial seizures, both interictal (Devinsky et al. 1989b, Mauguire and Courjon 1978) and ictal (Bare et al. 1994; Devinsky et al. 1988b, 1989b)

332 Signs, symptoms and syndromes

EEGs are often normal. In the case of complex partial seizures, interictal EEGs may likewise be normal (Goodin et al. 1990); furthermore, although ictal EEGs are more likely to be abnormal, even here the EEG may be normal during a seizure, especially when the seizure focus is on the medial surface of the frontal (Williamson and Spencer 1986; Williamson et al. 1985a) or temporal (Lieb et al. 1976) lobe. Employing supplemental leads may increase the chances of finding EEG abnormalities in the case of complex partial seizures. Sphenoidal, nasopharyngeal, and anterior temporal leads have all been advocated: sphenoidal leads are invasive, and nasopharyngeal leads are uncomfortable: many patients simply cannot tolerate their insertion. Anterior temporal leads, by contrast, are readily placed and furthermore appear to be as effective as nasopharyngeal (Sperling and Engel 1985) leads. Although anterior temporal leads are not as effective as sphenoidal leads, it appears that a combintion of anterior temporal and nasopharyngeal leads is (Goodin et al. 1990; Sperling and Engel 1985). NEUROIMAGING Neuroimaging should, whenever possible, be with MRI rather than CT scanning as MRI scanning is far more sensitive (Franceschi et al. 1989; Swartz et al. 1992). When MRI scanning is utilized, it is important to obtain coronal images, which are superior to axial or sagittal images for the detection of mesial temporal sclerosis (Berkovic et al. 1991). Furthermore, it must be borne in mind that in some cases of mesial temporal sclerosis, the temporal lobes and their contents may appear quite symmetric, and the only abnormality may be increased signal intensity on the T2-weighted scan (Jackson et al. 1994). Although MRI is more sensitive, a normal MRI examination certainly does not rule out a focal lesion (Devinsky et al. 1988; Williamson et al. 1993). CT or MRI findings, rather than representing an independent lesion, may rarely represent cerebral edema secondary to the seizure activity itself. After complex partial status epilepticus, for example, transient radiolucency on CT scanning (Kramer et al. 1987; Sammaritano et al. 1985) and decreased signal intensity on Tl-weighted and increased signal intensity on T2weighted scans have been noted (Henry et al. 1994; Kramer et al. 1987). Treatment of the syndrome In cases in which the underlying cause of the seizure is not readily treatable and recurrent seizures are anticipated, it is reasonable to consider treatment with an anticonvulsant. The number of different anticonvulsants available is growing rapidly, so rapidly in fact that the overall place of some of the newer anticonvulsants in the treatment of epilepsy is not as yet clear. What follows is an admittedly conservative approach, which, with time and accumulated evidence from controlled trials, will certainly have to be changed. All other things being equal, the inital choice of an anticonvulsant should be based on the seizure type. For simple partial seizures, complex partial seizures, grand mal seizures of focal onset, atonic seizures, and amnestic seizures, treatment may be initiated with either carbamazepine or phenytoin (Heller et al. 1995; Mattson et al. 1985; Ramsey et al. 1983; Simonsen et al. 1976; Troupin et al. 1977). Valproic acid is a reasonable alternative to either of these two (Beydoun et al. 1997; Callaghan et al. 1985; Heller et al. 1995) but may be a little less effective than carbamazpeine in the case of complex partial seizures (Mattson et al. 1992). With regard to newer anticonvulsansts, one study found lamotrigene to be equally efficacious as carbamazepine and somewhat better tolerated (Brodie et al. 1995), and oxcarbazepine has been found effective as monotherapy in patients with refractory partial seizures (Beydoun et al. 2000; Schacter et al. 1999).

Other major syndromes 333

In cases in which partial seizures or grand mal seizures of focal onset are refractory to single-agent treatment, then one may consider combining two different anticonvulsants. Thus, in the case of either carbamazepine or phenytoin, there is good evidence for increased control with the addition of valproic acid (Willmore et al. 1996), lamotrigene (Binnie et al. 1989; Boas et al. 1996; Jawad et al 1989; Loiseau et al. 1990b; Matsuo et al 1993; Messenheimer et al 1994), gabapentin (Fuerstein et al 1994; Sivenius et al 1991; US Gabapentin Study Group 1993), topriamate (Faught et al 1996; Privitera et al 1996), tiagabine (Sachdeo etal. 1997; Uthman etal 1997), and levetiracetam (Cereghino etal 2000). When seizures persist at an unacceptable frequency despite combination treatment with two anticonvulsants, several alternatives are open. First, one may consider a different combination. Second, consideration may be given to 'triple' treatment with three anticonvulsants; although this may help some patients, the probability of various pharmacokinetic and pharmacodynamic drug interactions becomes alarmingly high when three anticonvulsants are combined, making this a very problematic option. Third, one may consider either vagal nerve stimulation (Handforth et al 1998; Salinsky et al 1996) or, in the case of focal onset seizures, resective surgery (Engel 1996). Finally, there is the option of simply 'living with' less than perfect control, an option that, in some cases, when all things are considered, may be best. For classic petit mal seizures, both ethosuximide and valproate are effective, but as ethosuximide is not effective for grand mal seizures, and many patients with classic petit mal seizures also have grand mal seizures, valproate is preferred. For grand mal seizures of the primary generalized type, that is to say, grand mal seizures that occur without an aura or any other evidence of a focal lesion, valproate is, likewise, a good first choice, phenytoin and carbamazpine being reasonable alternatives. In patients refractory to monotherapy with one of these agents, topriamate may be used as an 'add-one' (Biton et al 1999). Although anticonvulsants constitute the mainstay of epilepsy treatment for most patients, other measures may also be brought to bear. In the case of reflex seizures, reflexive stimuli may be avoided, and in the case of simple partial and complex partial seizures, some patients may be able to discover certain abortive manouvers. Certain non-specific stresses, such as poor sleep, should be attended to, finally, there are certain concurrent conditions that may exacerbate a seizure disorder, and these should be treated. Reflex seizures constitute an invitation to the exercize of commonsense behavioral treatment by simply avoiding the reflex stimulus. In cases in which this is not feasible, it may be possible, in certain cases, to blunt the provocative effect of the stimulus by repeatedly exposing the patient to that stimulus, as has been demonstrated in cases of musicogenic (Forster et al 1967) and reading (Forster et al. 1969a) epilepsies. Simple partial seizures that undergo a Jacksonian march may, in some cases, be aborted by vigorously rubbing that part of the body which lies just proximal to the advancing march; this holds true not only for motor (Russell and Whitty 1953; Symonds 1959), but also for sensory (Efron 1961; Sutherling et al 1990) marches. In the case of complex partial seizures, Penfield (Penfield and Jasper 1954) noted that, when the aura consisted of some 'change in the stream of thought', the patient might be able to prevent the development of the seizure by 'forcing his thoughts with "might and main" into some other channel'. Other techniques have been reported: one patient, whose aura consisted of an olfactory hallucination, was able to prevent a complex partial seizure by the application of a 'strong odor' (Efron 1956,1957), and another patient, whose aura consisted of an auditory hallucination of music, was able to abort the seizure by'imagining himself fishing, his favorite leisure pursuit' (Pritchard et al 1985b). Non-specific stresses capable of aggravating epilepsy include poor sleep, irregular dietary habits, dehydration, febrile illnesses, hyperventilation, and excessive alcohol use, and all these should be avoided or treated.

334 Signs, symptoms and syndromes

Concurrent conditions that may exacerbate epilepsy include migraine, sleep apnea, and, in some females, the menstrual cycle. In the case of migraine, seizures may, as noted earlier, be precipitated by a migraine aura, and in such cases effective migraine prophybds is essential: valproate is a logical choice in such cases, as it is effective not only as an anticonvulsant, but also as a prophylaxis against migraine. Obstructive sleep apnea may aggravate seizures, and treatment of the apnea with continuous positive airway pressure may be very effective (Devinsky et al. 1994b). Finally, some women will experience an increase in seizure frequency either towards the end of the follicular phase or during menstrual flow (Backstrom 1976), and although oral contraceptives have been advocated in such situations (Mattson etal. 1986), this is controversial (Dana-Haeri and Richens 1983). Status epilepticus may or may not require emergency treatment: whereas grand mal status is acutely life-threatening, other types of status (e.g. simple partial or complex partial status) are not and may thus be approached in a somewhat more leisurely fashion. Intravenous lorazepam is a good initial first choice for status, followed, in most cases, by intravenous fosphenytoin (Browne et al. 1996; Lowenstein et al. 1998; Ramsey and DeToledo 1996) with the subsequent substitution of oral phenytoin. In selected cases, patient's caregivers may be given the option of administering rectal diazepam on an outpatient basis (Dreifuss et al. 1998). Eminently correctable metabolic causes should be checked for immediately with determinations of glucose, sodium, calcium, and magnesium level, and if there is any suspicion of hypoglycemia, intravenous glucose is immediately given, provided, of course, that the patient is not alcoholic. If there is any suspicion of alcoholism, it is necessary to give intravenous thiamine before glucose in order to avoid precipitating a Wernicke-Korsakoff syndrome. Furthermore, if the patient in status had been prescribed anticonvulsants, blood levels are required to ascertain compliance. Further investigations are dictated by one's diagnostic suspicion, and may include neuroimaging, lumbar puncture, etc.

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Other major syndromes 361 Thacore VR, Shukla SRP. Cannabis psychosis and paranoid schizophrenia. Arch Gen Psychiatry 1976; 33:383-6. Theodore WH, Porter RJ, PenryJK. Complex partial seizures: clinical characteristics and differential diagnosis. Neurology 1983; 33:1115-21. Theodore WH, Porter Rj, Albert P et al. The secondarily generalized tonic-clonic seizure: a videotape analysis. Neurology 1994; 44:1403-7. Thomas CS, Szabadi E. Paranoid psychosis as the first presentation of a fulminating lethal case of AIDS. BrJ Psychiatry 1987; 151:693-5. Thomas JE, Reagen TJ, Klass DW. Epilepsia partialis continua. A review of 32 cases. Arch Neurol 1977; 34:266-75. Thompson AJ, Kermode AG, Moseley JF et al. Seizures due to multiple sclerosis: seven patients with MRI correlations.;NeurolNeurosurgPsychiatry 1993; 56:1317-20. Thompson GN, Nielsen JM. The organic paranoid syndrome. J Nerv Ment Dis 1949; 110:478-96. Thompson SW, Greenhouse HH. Petit mal status in adults. Ann Intern Med 1968; 68:1271-9. Thomsen IV. Late outcome of very severe blunt head trauma: a 10-15 year second follow-up. J Neurol Neurosurg Psychiatry 1984; 47:260-8. TinuperP, Provini F, Marini C et al. Partial epilepsy of long duration: changing semiology with age. Epilepsia 1996a; 37:162-4. Tinuper P, Plazzi G, Provini fet al. Celiac disease, epilepsy, and occipital calcification: histopathological study and clinical outcome. J Epilepsy 1996b; 9:206-9. Tinuper P, Cerullo A, Marini C et al. Epileptic drop attacks in partial epilepsy: clinical features, evolution, and prognosis.) Neurol Neurosurg Psychiatry 1998; 64:231-7. Todd R. Clinical lectures on paralysis, diseases of the brain, and other affections of the nervous system. Philadelphia: Lindsay & Blakiston, 1855. Tomson T, Svanborg E, Wedlund J-E. Nonconvulsive status epilepticus: high incidence of complex partial status. Epilepsia 1986; 27:276-85. Tomson T, Lindbom U, Nilsson BYetal.Serum prolactin during status ep\\epticus.J Neurol Neurosurg Psychiatry 1989; 52:1435-7. Tomson T, Lindbom U, Nilsson BY. Nonconvulsive status epilepticus in adults. Thirty-two consecutive patients from a general hospital population. Epilepsia 1992; 33:829-35. Towne AR, Waterhouse EJ, Boggs JG et al. Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 2000; 54:340-5. TownsendJJ, BaringerJR, WolinskyJSefo/. Progressive rubella panencephalitis: late onset after congenital rubella. N EnglJ Med 1975; 292:990-3. Townsend JJ, Wolinsky JS, BaringerJR. The neuropathology of progressive rubella panencephalitis of late onset. Brain 1976; 99:81-90. Trethowan WH, Cobb S. Neuropsychiatric aspects of Cushing's syndrome. Arch Neurol Psychiatry 1952;

67:283-309. Trouillas P, Courjon J. Epilepsy with multiple sclerosis. Epilepsia 1972; 13:325-33. Troupin A, Ojemann LM, Halpern let al. Carbamazepine-a double-blind comparison with phenytoin. Neurology 1977; 27:511-19. Tsoi WF. The Ganser syndrome in Singapore: a report on ten cases. BrJ Psychiatry 1973; 123:567-72. TsukamotoT, Mochizuki R, Mochizuki H et al. Paraneoplasticcerebellar degeneration and limbic encephalitis in a patient with adenocarcinoma of the colon. J Neurol Neurosurg Psychiatry 1993; 56:713-16. Tucker GJ, Price TRP, Johnson VB et al. Phenomenology of temporal lobe dysfunction: a link to atypical psychosis: a series of cases. J Nerv Ment Dis 1986; 174:348-56. Tucker WM, Forster FM. Petit mal epilepsy occurring in status. Arch Neurol Psychiatry 1958; 64:823-7. Tukel K, Jasper H. The electroencephalogram in parasaggital lesions. ElectroencephalogrClin NeurophysiolWSI; 4:481-94.

362 Signs, symptoms and syndromes Tyler RH. Neurologic disorders in renal failure. Am] Med 1968; 44:734-48. Umbricht D, Degreef G, BarrWBefo/. Postictaland chronic psychoses in patients with temporal lobe epilepsy. 4m7 Psychiatry 1995; 152:224-31. US Gabapentin Study Group. Gabapentin as add-on therapy in refractory partial epilepsy: a doubleblind, placebo-controlled, parallel-group study. Neurology 1993; 43:2292-8. Uthman BM, Rowan AJ, Ahmann PA et al. Tiagabine for complex partial seizures. A randomized, add-on, dose response trial. Arch Neurol 1997; 55:56-62. van der Horst L Affective epilepsy../ NeurolNeurosurgPsychiatry 1953; 16:25-9. Van Rossum J, Groeneveld-Ockhuysen AAW, Arts RJHM. Psychomotor status. Arch Neurol 1985; 42:989-93. Varma NK, Lee SI. Nonconvulsive status epilepticus following electroconvulsive therapy. Neurology 1992; 42:263-4. Venneri A, Caffarra P. Transient autobiographic amnesia: EEG and single-photon emission G" evidence of an organic etiology. Neurology 1998; 50:186-91. Verny M, Jellinger KA, Hauw J-J et al. Progressive supranuclear palsy: a clinicopathological study of 21 cases. Acta Neuropathologica 1996; 61:427-31. Vickrey BG, Bahls FH. Nonconvulsive status epilepticus following cerebral angiography. Ann Neurol

1989; 25:199-201. Victor M, Brausch J. The role of abstinence in the genesis of alcohol epilepsy. Epilepsia 1967; 8:1-20. Victor M, Hope JM. The phenomenon of auditory hallucinations in chronic alcoholism. J Nerv Merit Dis

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Other major syndromes 363 Weinberger]. Simultaneous bilateral focal seizures without loss of consciousness. MtSinaiJ Med1973;

40:693-6. Wells CE. Transient ictal psychosis. Arch Gen Psychiatry 1975; 32:1201-3. Wharton RM. Grand mal seizures with lithium treatment./Amy Psychiatry 1969; 125:1446. Whitfield CL, Ch'ien LT, Whitehead JD. Lead encephalopathy in adults. AmJ Med 1972; 52:289-98. Wieser HG. Temporal lobe or psychomotor status epilepticus. A case report. Electroencephalogr Clin NeurophysionWQ; 48:558-72. Wieser HG, Hungerbuhler H, Siegel AM et al. Musicogenic epilepsy: review of the literature and case report with ictal single photon emission computed tomography. Epilepsia 1997; 38:200-7. Wilder-Smith E. Complete atrio-ventricular block during complex partial seizure. J Neural Neurosurg Psychiatry 1992; 55:734-6. Wilkinson HA. Epileptic pain. An uncommon manifestation with localizing value. Neurology 1973; 23:518-20. Williams BB, Lerner AM. Some previously unrecognized features of herpes simplex encephalitis. Neurology 1978; 28:1193-6. Williams D. The structure of emotions reflected in epileptic experiences. Brain 1956; 79:29-67. Williamson PD, Spencer SS. Clinical and EEG features of complex partial seizures of extratemporal origin. Epilepsia 1986; 27(suppl 2):46-63. Williamson PD, Spencer DD, Spencer SSetal.Complex partial seizures of frontal lobe origin. Ann Neurol 1985a; 18:497-504. Williamson PD, Spencer DD, Spencer SS et al. Complex partial status epilepticus: a depth-electrode study. Ann Neurol 1985b; 18:647-54. Williamson PD, Spencer DD, Spencer SS et al. Episodic aphemia and epileptic focus in the nondominant hemisphere: relieved by section of the corpus callosum. Neurology 1985c; 35:1069-71. Williamson PD, Thadani VM, Darcey TM et al. Occipital lobe epilepsy: clinical characteristics, seizure spread patterns, and results of surgery. Ann Neurol 1992a; 31:3-13. Williamson PD, Boon PA, Thadani VM et al. Parietallobe epilepsy: diagnostic considerations and results of surgery. Ann Neurol 1992b; 31:193-201. Williamson PD, French JA, Thadani VM et al. Characteristics of medial temporal lobe epilepsy. II. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging, surgical results, and pathology. Ann Neurol 1993; 34:781-7. Williamson RT. On the symptomatology of gross lesions (tumours and abscesses) involving the prefrontal regions of the brain. Brain 1896; 19:346-65. Willmore LJ, Shu V, Wallin B. Efficacy and safety of add-on divalproex sodium in the treatment of complex partial seizures. Neurology 1996; 46:49-53. Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain 1912; 34:295-509. Wilson SAK. Nervous semiology, with special reference to epilepsy. BMJ1930; 2:50-4. Wilson LG. Viral encephalopathy mimicking functional psychosis. Am J Psychiatry 1976; 133:165-70. Wilson P, Preece AA. Chorea gravidarum. Arch Intern Med 1932; 49:671-97. Wilson WH, Claussen AM. Seizures associated with clozapine treatment in a state hospital.J Clin Psychiatry 1994; 55:184-8. Winawer MR, Ottman R, Hauser A et al. Autosomal dominant partial epilepsy with auditory features: defining the phenotype. Neurology 2000; 54:2173-6. WinokurG. Delusional disorder (paranoia). Compr Psychiatry 1977; 18:511-21. Wisniewski KE, FrencyJH, Fernando Set al. Fragile X syndrome: associated neurological abnormalities and developmental disabilities. Ann Neurol 1985; 18:665-9. Wroblewski BA, McColgan K, Smith Ket al. The incidence of seizures duringtricyclic treatment in a brain-injured population. J Clin Psychopharmacol 1990; 10:124-8.

364 Signs, symptoms and syndromes Wyllie E, Luders H, MacMillanJPefo/. Serum prolactin levels after epileptic seizures. Neurology 1984; 34:1601-3. Yamada H,Yoshida H. Laughing attack: a review and report of nine cases. Folia Psychiatr Neurol Japonica 1977; 31:129-37. Yen D-J, Su M-S, Shih Y-H et al. Ictal speech manifestations in temporal lobe epilepsy: a video-EEG study. Epilepsia 1996; 37:45-9. YorkGK, Gabor AJ, Dreyfuss PM. Paroxysmal genital pain: an unusual manifestation of epilepsy.

Neurology 1979; 29:516-19. Young GB, Blume WT. Painful epileptic seizures. Brain 1983; 106:537-44. Young GB, Blume WT. Painful epileptic seizures involving the secondary sensory area. Ann Neurol 1986; 19:412. Zappoli R. Two cases of prolonged twilight state with almost continuous 'wave-spikes'. ElectroencephalogrClin Neurophysiol 1955; 7:421-3. ZarlingEJ. Abdominal epilepsy: an unusual cause of recurrent abdominal pain. Am J Gastroenterol 1984; 79:687-8. ZeidlerM, Stewart GE, BarracloughCRefo/. New variant Creutzfeldt-Jakob disease: neurological features and diagnostic tests. Lancet 1997a; 350:903-7. ZeidlerMJohnstoneEC, Bamber RWKetal.New variant Creutzfeldt-Jakob disease: psychiatric features. Lancet 1997b; 350:908-10. Zeman AZJ, Boniface SJ, Hodges JR. Transient epileptic amnesia: a description of the clinical and neuropsychological features in 10 cases and a review of the literature. J Neurol Neurosurg Psychiatry 1998;64:435-43. ZentnerJ, Hufnagel A, Wolf HKefo/. Surgical treatment of temporal lobe epilepsy: clinical, radiological, and histopathological findings in 178 patients. J Neurol Neurosurg Psychiatry 1995; 58:666-73. Zifko U, Lindner K, Wimberger D et al. Jarisch-Herxheimer reaction in a patient with neurosyphilis. J Neurol Neurosurg Psychiatry 1994; 57:865-7.

3 Specific disorders Neurodegenerative disorders Congenital disorders Vascular disorders Trauma Hypoxic disorders Nutritional, toxic, and metabolic disorders Infectious disorders Prion diseases Endocrinologic disorders Immune-related disorders Sleep disorders Cerebral tumors and hydrocephalus Idiopathic psychotic, mood, and anxiety disorders Intoxications and withdrawals Medication and substance-induced disorders

367 439 462 481 490 495 527 566 576 588 611 633 643 688 712

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8 Neurodegenerative disorders Alzheimer's disease Pick's disease Frontotemporal dementia Amyotrophic lateral sclerosis Parkinson's disease Diffuse Lewy body disease Progressive supranuclear palsy Corticobasal ganglionic degeneration Multiple system atrophy Huntington's disease Neuroacanthocytosis Senile chorea Benign hereditary chorea Dentatorubropallidoluysian atrophy Wilson's disease Autosomal dominant cerebellar ataxia

367 372 373 374 376 383 384 386 387 388 391 391 392 392 393 395

Hallervorden-Spatz disease Dopa-responsive dystonia Primary torsion dystonia Idiopathic cervical dystonia Writer's cramp Meige's syndrome Spasmodic (spastic) dysphonia Tourette's syndrome Myotonia atrophica Cerebrotendinous xanthomatosis Thalamic degeneration Metachromatic leukodystrophy Adrenoleukodystrophy Essential tremor Hyperekplexia

397 398 399 400 401 401 402 403 405 407 408 408 410 412 413

ALZHEIMER'S DISEASE PATHOLOGY AND ETIOLOGY

Macro scop ically, as illustrated in Figure 8.1, there is widespread cortical atrophy affecting primarily the temporal, parietal,and frontal lobes, with, however, prominent sparing of the pre- and post-central gyri; the occipital lobe is, relative to the other lobes, less affected. Within the temporal lobe, the hippocampus and amygdala are also prominently involved. Subcortical and brainstem nuclei, including the nucleus basalis of Meynert (especially its cholinergic neurons) (Whitehouse et al. 1981), the locus ceruleus (Mann et al. 1984) and the dorsal raphe nucleus (Yamamoto and Hirano 1985), also undergo significant damage. Microscopically (Kidd 1964), there are widespread neurofibrillary tangles and senile plaques, accompanied by neuronal loss (Terry et al. 1981). Neurofibrillary tangles are fibrillar structures found in the neuronal cytoplasm that, by electron microscopy, are seen to be composed of paired helical filaments. These paired helical filaments are composed of hyperphosphorylated tau proteins, which are one of the microtubule-associated proteins (MAP) that ensure the integrity and stability of the cellular microtubules. Senile plaques, or, as they are also known, neuritic plaques, are spherical extracellular structures composed of an

368 Specific disorders

Image Not Available Figure 8.1 Note the relative sparing of the pre- and post-central gyri compared with the rest of the cortex in this case of Alzheimer's disease. (Reproducedfrom Rees et al. 1996.)

amyloid core surrounded by 'neurites' or swollen axonal fragments. The amyloid core of the senile plaque is composed primarily of beta-A4 amyloid. Interestingly, although the clinical severity of Alzheimer's disease correlates with the number of neurofibrillary tangles, there is little correlation with the number of senile plaques (Arriagada et al. 1992; Bierer et al. 1995). In addition, there appears to be a correlation between the depth of the memory loss in Alzheimer's disease and the extent of damage in the cholinergic nucleus basalis of Meynert (Neary et al. 1986; Rasool et al. 1986; Whitehouse et al. 1982). There is also a correlation between depression and cell loss in the superior central nucleus (Zweig et al. 1988) and probably the locus ceruleus (Zubenko and Moosy 1988; Zweig et al. 1988), although not all have replicated this finding (Hoogendijk et al. 1999). Much progress has been made in the search for the etiology of Alzheimer's disease, genetic factors appearing to be quite important. In a small minority of cases, especially those of early onset before the age of 65, Alzheimer's disease is clearly inherited in an autosomal dominant fashion. Mutations have been identified in three genes: the APP (amyloid precursor protein) gene on chromosome 21 (Chartier-Harlin et al. 1991), the presenilin-1 gene on chromosome 14 (Bird et al. 1996; Wasco et al. 1995), and the presenilin-2 gene on chromsome 1 (LevyLahad et al. 1995). Although the mechanism whereby mutations in the presenilin-1 and -2 genes cause Alzheimer's disease is not clear, progress has been made regarding the APP gene. The amyloid precursor protein, when cleaved at the appropriate sites, releases beta-A4 amyloid, which, as noted above, is the main constituent of the core of senile plaques, and the mutations in the gene for APP affect those cleavage sites. The role of genetic factors in the vast majority of cases of apparently sporadic Alzheimer's disease is not clear. Some studies support a higher concordance among monozygotic than dizygotic twins (Breitner et al. 1995), whereas others do not (Cook et al. 1981), and, whereas some studies indicate a higher prevalence of Alzheimer's disease among the first-degree relatives of probands than among the equivalent relatives of controls, others do not. One of the reasons for these discordant results might be that although Alzheimer's disease may be inherited, there is such great intrafamily variability in the age of its expression that most cases among relatives are missed in cross-sectional studies. Life-table studies support this notion: indeed, studies using the life-table approach have found that the projected risk among firstdegree relatives is approximately 50% (Mohs et al. 1987), just what would be expected if sporadic Alzheimer's disease were, in fact, an autosmal dominant trait. Another gene associated with Alzheimer's disease is that for apolipoprotein E, on chromosome 19. Apoliporotein E comes in several types, depending on which alleles are present - epsilon-2, epsilon-3, or epsilon-4 - and there is a correlation beween which alleles

Neurodegenerative disorders 369

are present and the risk of Alzheimer's disease. Thus, the risk for patients with one or two of the epsilon-4 alleles is substantially higher (Corder et al. 1993; Saunders et al. 1993) than that for patients who lack this allele.The mechanism whereby the various epsilon alleles influence the risk of developing Alzheimer's disease is not clear, but it may be related to an effect of apoliprotein E on amyloid metabolism. Finally, Alzheimer's disease is very common in Down's syndrome (Evenhuius HM 1990; Jervis 1948; Lai and Williams 1989; Olson and Shaw 1969), and is indeed seen in almost all those patients who survive past the age of 40. Presumably, the extra twenty-first chromosome leads to an overabundant production of the amyloid precursor protein, with a resultant excess of amyloid beta-4 protein and senile plaque formation. In contrast with the foregoing positive results in genetic studies, efforts to identify environmental causes have generally been unsuccessful, with one exception: it does appear that a history of significant head trauma may increase the risk (Schofield et al. 1997). On an historical note, it is of interest that Alzheimer was reluctant to lend his name to the disease he described and that it was only at the urging of his colleague, Emil Kraepelin, that he did so (Amaducci et al. 1986; Maurer et al. 1997), thus giving us one of the best known eponyms in medicine. Clinical features

Although onsets in early adulthood may occur, the vast majority of cases present gradually and insidiously past the age of 50. In most instances, the presentation is with an amnesia or a personality change. With amnesia as the presenting feature, patients may gradually become more and more forgetful (Bowler et al 1997; Didic et al. 1998; Linn et al 1995): the location of keys, wallets, or purses is forgotten, and patients may have difficulty recollecting what had happened earlier in the day. Over time, the anterograde component of the amnesia grows more profound and is typically joined by a progressvely worsening retrograde component: patients may forget where they have worked, the names of their children, the fact that they have been married, where they went to high school, etc. The fact that the amnesia is of the declarative or 'episodic' form, rather than the 'procedural' type, can make for some startling contrasts in the clinical picture. Thus, profoundly amnestic patients may still 'remember' how to play card games, such as bridge, or musical instruments (Beatty et al. 1994). For example, one patient (Crystal et al. 1989), a professional musician, although unable to remember the names of various musical pieces or their composers, was nevertheless still able to play Beethoven's fifth symphony flawlessly on the piano. Although the presenting personality change may take various forms, apathy, indifference, and withdrawal are most common. Patients may also become coarse, impulsive, and disinhibited (Litvan et al. 1996; Mega et al 1996; Petry et al 1988). Rarely, Alzheimer's disease may present with an aphasia that may be expressive or, much less commonly, receptive, which gradually worsens as dementia supervenes (Galton et al. 2000; Green et al 1990; Greene et al 1996; Karbe et al. 1993). Even more rarely, the presentation may be with a gradually worsening apraxia (Ross et al 1996). The dementia of Alzheimer's disease also often comprises agitation, apathy, affective, and psychotic symptoms (Mega et al 1996). Depressive symptoms are fairly common, found in between 14% (Klatka et al 1996) and 24% (Burns et al 1990c) of patients, and these symptoms tend to persist over a long follow-up period (Starkstein et al 1997). The severity of the depression varies from mild to that encountered in the depressive episodes of a major depression (Migliorelli et al 1995). Euphoria is less common, found in from 4% (Burns et al. 1990c) to 8% (Mega et al 1996) of cases. Anxiety and irritability are more common than depression, being found in a little less than one-half of patients (Mega et al. 1996; Litvan et al 1996c).

370 Specific disorders

Psychotic symptoms include hallucinations, either visual or auditory, and delusions. Hallucinations are noted in from 10% (Mega et al. 1996) to 35% (Klatka et al. 1996) of patients and are more commonly visual than auditory (Burns et al. 1990b; Forstl et al. 1993). Delusions are found in between 16% (Burns et al. 1990a) and 53% (Klatka et al. 1996). Common delusional themes (Binetti et al. 1993; Burns et al. 1990a; Devanand et al. 1997; Forstl et al. 1993; Hirono et al. 1998) include misidentification, theft, the Capgras phenomenon, and the phantom boarder. Patients may misidentify other people and sometimes their own homes. They may insist that things have been stolen or taken from them, and may be terrified that family members are actually imposters come to annoy or torment them; some may insist that someone, perhaps someone malevolent, is in fact hiding in the house, perhaps in the attic or the cellar. In some cases, misidentification may be quite remarkable, and patients may insist that their own reflection in the mirror is in fact not them (Forstl et al. 1993). Interestingly, although it is rare for Alzheimer's disease to present with psychosis, this was in fact the presentation in Alzheimer's first patient, Auguste D., who presented, at the age of 51, with a delusion of jealousy regarding her husband (Maurer et al. 1997; Wilkins and Brody 1969a). As the dementia progresses, patients typically develop various 'cortical' signs, such as aphasia (Faber-Langendoen et al. 1988; Price et al. 1993), 'frontal release' signs (such as snout and grasp reflexes), and astereognosis and agraphesthesia (Huff et al. 1987). Parkinsonism may be seen late in the course in a minority of causes, being typically characterized by rigidity and bradykinesia, with tremor being relatively rare (Clark et al. 1997). Seizures may also occur (Goodman 1953), and these tend to be grand mal and occur late in the course of the disease (Romanelli et al. 1990). Very late in the course, a minority may also have myoclonus (Benesch et al. 1993; Chen et al. 1991; Faden and Townsend 1976). Other possible symptoms include emotional incontinence (Starkstein et al. 1995), the Kluver-Bucy syndrome (Lilly et al. 1983) and, very rarely, hemiparesis (Jagust et al. 1990). Magnetic resonance imaging (MRI) and computed tomography (CT) scanning reveal cortical atrophy and ventricular dilatation. Early on in the course, the degree of this change may still be within the broadly defined limits of normal for the elderly population, but with progression, the changes become quite pronounced, as illustrated in Figure 8.2. The electroencephalogram typically shows diffuse slowing. The cerebrospinal fluid is generally normal.

Image Not Available

Figure 8.2 This Tl-weighted magnetic resonance imaging scan demonstrates the cortical atrophy and ventricular dilatation found in advanced Alzheimer's disease. Note in particular that the hippocampus, indicated by the arrows, has shrunk down to but a thin remnant. (Reproduced from Gillespie and Jackson 2000.)

Neurodegenerative disorders 371 Course

Although a small minority of patients may experience temporary plateaus, Alzheimer's disease, for the most part, is relentlessly and steadily progressive, death occurring for most within 5-7 years. At the end, patients are vegetative, bedfast, and incontinent. Although it is generally held that cases with an early onset, before the age of 65, tend to run a more rapid course (Koss et al. 1996), not all studies agree on this (Bracco et al. 1994). Differential diagnosis

Dementia of gradual onset and slow, steady progression, in addition to being seen with Alzheimer's disease, may occur in a number of other disorders, noted below. Binswanger's disease may be very difficult to differentiate on a clinical basis, and the differential diagnosis may rest on MRI imaging, which reveals diffuse leukoencephalopathy in Binswanger's disease, in contrast to atrophy alone in Alzheimer's disease. Cerebral amyloid angiopathy, in its pre-hemorrhagic phase, may likewise be difficult to distinguish from Alzheimer's disease, and indeed an accurate clinical diagnosis may not be possible until the patient experiences the first lobar intracerebral hemorrhage. Normal-pressure hydrocephalus is suggested by an ataxic or 'magnetic' gait and by the early appearance of urinary incontinence. Diffuse Lewy body disease is suggested by the early appearance of hallucinations, episodes of confusion, or extreme sensitivity to neuroleptics. Pick's disease is suggested by the early presence of a personality change, and by its prominence relative to the cognitive changes, which may initially be minor indeed. Alcoholic dementia is immediately suggested by the presence of other evidence of the ravages of alcoholism. The dementia syndrome of depression is intimated by a history of depression, by other evidence of depression (e.g. sleep and appetite change) and by the 'given-up' or apathetic reaction to mental status questions. Treatment

Available treatments may be grouped in terms of whether they reduce the risk of the disease, retard its progression, or alleviate symptoms. Agents that may reduce the risk of the disease include non-steroidal anti-inflammatory drugs (Aisen and Davis 1994; McGeer et al. 1996; MacKenzie and Munoz 1998; Stewart et al. 1997) and, in postmenopausal women, estrogens (Scooter et al. 1999; Tang et al. 1996). Epidemiologic studies indicate that patients who have taken NSAIDs are at lower risk for Alzheimer's disease, similar findings being reported for postmenopausal women who take estrogen replacement therapy. It is not at all clear whether, and to whom, these treatments should be recommended. Pending prospective studies, it might be reasonable to discuss them with patients who are at high risk, such as those with a family history of Alzheimer's disease, or those with two epsilon-4 alleles of apolipoprotein E. Agents that may retard the progression of the disease include (Sano et al. 1997) vitamin E, at a dose of 1000IU bid, and selegeline (Schneider et al. 1993), at a dose of 10 mg qd. Agents capable of causing a modest improvement in cognition in patients with mild-tomoderate disease include the acetylcholinesterase inhibitors donepezil (Greenberg et al. 2000; Rogers and Friedhoff 1996; Rogers et al. 1998) rivastigmine (Rosier et al. 1999), metrifonate (Cummingsef al. 1998;Raskindef al. 1999), and tacrine (Raskind et al. 1997). As noted above, there is a correlation between the loss of cholinergic neurons in the nucleus basalis of Meynert and memory loss, and it is by partly restoring cholinergic tone that the acetylcholinesterase inhibitors exert their therapeutic effect. Of these inhibitors, tacrine is, given its hepatotoxicity, probably the least desirable; among the others, donepezil has been most extensively used, but whether it has advantages over the other two is not known.

372 Specific disorders

Other agents capable of effecting a mild-to-modest cognitive improvement include Gingko biloba (Le et al. 1997; Oken et al 1998) and cycloserine (Tsai et al 1999). In addition to the above measures, various other symptomatic treatments are available. Psychotic symptoms, agitation, and aggression may respond to a neuroleptic, generally at a low dosage, such as risperidone in doses of 1 or 2 mg. Although 'low-potency' neuroleptics such as chlorpromazine may further impair memory because of their anticholinergic activity, they may at times, especially with agitated patients, be so much more effective than other neuroleptics that the benefits far outweigh the induced memory decrement; low doses, such as 25 mg, are also appropriate here. When neuroleptics are used, it is appropriate to administer them in the late afternoon or early evening in order to mitigate the 'sundowning' phenomenon. Depressive symptoms may respond to an antidepressant. A selective serotonin reuptake inhibitor (SSRI), such as citalopram, is a reasonable choice, given the general lack of sideeffects. If a tricyclic is indicated, nortriptyline is preferred. Hypnotics may at times be required. If the patient also requires a neurolepetic or an antidepressant, every effort should certainly be made to utilize one of these agents in such a way as also to control insomnia. If this is not practical, a benzodiazepine, such as lorazepam, may be used, beginning with a low dose, such as 0.5 mg at bedtime. Should patients be admitted, it is imperative to employ the standard measures described in Chapter 5, concerning dementia, in order to mitigate the deleterious effects of removing patients from their familiar surroundings.

PICK'S DISEASE Pathology and etiology

Pick's disease is an example of 'lobar' atrophy, the frontal and temporal lobes bearing the brunt of the disease process. Interestingly, even when the temporal lobes are very hard hit, the posterior two-thirds of the superior temporal gyrus is generally spared, often to a remarkable degree, as illustrated in Figure 8.3. Although in most cases, both the frontal and the temporal lobes are clearly affected, in a minority only one lobe will be macroscopically abnormal (Sjorgen et al. 1952). Microscopically, one sees widespread neuronal loss and gliosis. Pick cells (large, ballooned neurons) and Pick bodies (rounded or oval argentophilic intracytoplasmic inclusions) may be seen in affected areas: the Pick bodies are composed of neurofilaments that are straight (Murayama et al. 1990; Rewcastle and Ball 1968), in contrast to the helical filaments of Alzheimer's disease.

Image Not Available Figure 8.3 Sparing of the posterior twothirds of the superior temporal gyrus relative to the frontal lobe and the rest of the temporal lobe in a case of Pick's disease. (Reproduced from Graham and Lantos 1996.)

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Although most cases of Pick's disease are sporadic (Malamud and Waggoner 1943), hereditary cases do occur (Groen and Endtz 1982) and are usually consistent with dominant inheritance (Sjorgen et al 1952). Clinical features

The onset is gradual and insidious, typically occurring in the fourth through the seventh decades; onsets as young as 21 years of age have, however, been noted (Lowenberg et al 1939). In most cases, the presentation is with a personality change, typically of the frontal lobe type (Bouton 1940; Ferraro and Jervis 1936; Litvan et al. 1997a; Mendez et al. 1993; Munoz et al. 1993; Munoz-Garcia and Ludwin 1984; Nichols and Weigner 1938). In a minority, rather than a personality change, the presentation may be characterized by a slowly progressive aphasia (Graff-Radford et al. 1990; Kertesz et al. 1994; Wechsler et al. 1982) or amnesia (Wisniewski et al. 1972), or apraxia (Fukui et al. 1996). As the dementia progresses, elements of the Kluver-Bucy syndrome may appear, with indiscriminate eating and a tendency to manipulate things (Cummings and Duchen 1981; Mendez et al. 1993; Munoz et al. 1993; Munoz-Garcia and Ludwin 1984). Some patients may also be prone to restless wandering; in contrast to patients with Alzheimer's disease, who tend to wander off and get lost, however, patients with Pick's disease tend to get back to their starting point (Mendez et al. 1993; Munoz et al. 1993). CT or MRI scanning reveals lobar atrophy (Knopman et al. 1989; Wechsler et al. 1982), typically affecting the frontal and anterior temporal lobes; in some cases, the atrophy is so severe as to present a 'knife-blade' appearance. Course Pick's disease is relentlessly progressive, leading to a profound dementia, with death within 5-10 years (Robertson et al. 1958), generally from an intercurrent pneumonia. Differential diagnosis

Alzheimer's disease is suggested by an onset with amnesia rather than a personality change, and by the lack of lobar atrophy on MRI scanning. Frontotemporal degeneration is discussed below. Treatment

The general treatment of dementia is discussed in Chapter 5. In contrast to Alzheimer's disease, acetylcholinesterase inhibitors are not useful in Pick's disease.

FRONTOTEMPORAL DEMENTIA Pathology and etiology Before discussing frontotemporal dementia (dementia of the frontal lobe type; dementia lacking distinctive histologic features), it is necessary to make some comments regarding the nosology of this disorder. Some authors (e.g. Brun et al. 1994) consider this disorder to be a syndrome rather than a specific disease, defined clinically by symptomatology commonly seen with lesions in the frontal or temporal lobe, and include within this broadly defined syndrome several disorders, including Pick's disease, amyotrophic lateral sclerosis with dementia, and a disease entity characterized by spongiform change most prominent in the frontal cortex. This seems to this author to be an inappropriate 'lumping' together of conditions, and in this text, frontotemporal dementia refers specifically and solely to the disease characterized by cortical spongiform change, as described below. Pathologically (Heutink et al. 1997; Mann et al. 1993a), there is cortical atrophy in the frontal and temporal lobes; microscopically, neuronal loss, gliosis, and spongiform change are

374 Specific disorders

seen primarily in the superficial layers of the frontal and temporal cortices. Similar, although less severe, changes may be seen in the insula, cingulate cortex, hippocampus, and caudate nucleus. There are no neurofibrillary tangles, senile plaques, or Pick cells, and there is no loss of lower motor neurons in the anterior horns of the spinal cord. Both familial, autosomal dominant (Basun et al 1997; Heutink et al. 1997), and sporadic cases occur. Clinical features

The onset is insidious and generally in the sixth decade. Clinically (Heutink et al. 1997; Mann et al. 1993a; Neary et al. 1998), a personality change is usually the first sign of the disease, this often having the features of a frontal lobe syndrome: patients may be either apathetic or restless, grooming and personal hygiene falter, and disinhibition is frequent. Some patients exhibit elements of utilization behavior or the environmental dependency syndrome, and compulsively examine and make use of whatever objects fall into view. Gluttony may occur, and there may be elements of a Kluver-Bucy syndrome, with a tendency to place inedible objects in the mouth, such as, in one case, coffee grounds or banana peel (Edwards-Lee et al. 1997). Aphasia of the expressive type is common early in the disorder (Neary et al. 1993; Snowden et al. 1992); over time, the aphasia worsens, gathers receptive elements, and finally leads to mutism. Judgment and abstract thinking fail early, but memory is relatively preserved, as are visuospatial and constructional abilities. Frontotemporal dementia may rarely present with an expressive aphasia (Turner et al. 1996). CT or MRI scanning reveals atrophy of the frontal or temporal lobes, or both. Although this is prominent, it is rarely of the 'knife-blade' variety seen in Pick's disease. Course Frontotemporal dementia is gradually progressive, with death in an average of 8 years. Differential diagnosis

A reliable differentiation from Pick's disease on clinical grounds may not be possible; the finding of knife-blade lobar atrophy on MRI scanning would, however, strongly suggest Pick's disease. Amyotrophic lateral sclerosis is indicated by the presence of upper and lower motor neuron dysfunction. Alzheimer's disease is suggested by prominent, early memory defect and by a more diffuse pattern of cortical atrophy on MRI scanning. Treatment

The general treatment of dementia is discussed in Chapter 5; there is no known specific treatment for frontotemporal dementia.

AMYOTROPHIC LATERAL SCLEROSIS Pathology and etiology Amyotrophic lateral sclerosis is primarily a disease of both the upper and lower motor neurons (Brownell et al. 1970): the upper motor neurons include those sending fibers into both the corticobulbar tracts and the corticospinal tracts, whereas the lower motor neurons include those found in certain cranial nerve nuclei (especially the hypoglossal nucleus and the dorsal motor nucleus of the vagus) and in the anterior horn of the spinal cord. Concurrent with the degeneration of the upper motor neurons, Wallerian degeneration leads to a thinning of both the corticobulbar and corticospinal tracts. In a small minority, widespread cell loss is

Neurodegenerative disorders 375

also found in the cerebral cortex of the frontal lobe (Kiernan and Hudson 1994; Neary et al. 1990) and, to a lesser degree, the temporal lobe. Over 90% of all cases of amyotrophic lateral sclerosis are sporadic, and although the etiology of these sporadic cases is not known, a disturbance in excitotoxin function is strongly suspected. Familial cases of amyotrophic lateral sclerosis occur in an autosomal dominant fashion, about one-fifth of these occurring secondary to a mutation in the gene for superoxide dismutase on chromosome 21 (Rosen et al. 1993; Siddique et al. 1991). Clinical features

Onset is gradual, most patients falling ill betwen the ages of 40 and 70. Typically, weakness is noted first in one of the upper extremities, often in the hand, and patients may have difficulty buttoning their clothes or using small tools; over time, atrophy and fasciculations appear, and other limbs are involved. Eventually, with the involvement of both upper and lower neurons, one finds the distinctive combination of brisk deep tendon reflexes and atrophic muscular weakness. With an involvement of the upper motor neurons destined for the cranial nerve nuclei, a 'pseudobulbar palsy' may appear, with dysarthria, dysphagia and 'emotional incontinence' with forced laughter and crying (Gallagher 1989; Ironside 1956); the jawjerk reflex tends also to be quite brisk. With involvement of the lower motor neurons in the cranial nerve nuclei, the tongue may become atrophic and demonstrate fasciculation. Importantly, there are no sensory changes and no evidence of peripheral nerve involvement. A small minority, perhaps 10%, of patients with amyotrophic lateral sclerosis will develop a dementia, which often has elements of a frontal lobe syndrome. Dementia may either occur concurrent with typical upper and lower motor neuron signs (Robertson 1953; Wecshler and Davison 1932) or may precede the onset of motor symptomatology (Ferrer et al. 1991), sometimes by as much as a year (Wilkstrom et al. 1982). In some cases, the dementia may be accompanied by delusions or visual hallucinations (Horoupian et al. 1984). Frontal lobe symptomatology may occur concurrent with the dementia (Cavalleri and De Renzi 1994) or precede the dementia (Neary et al. 1990), sometimes by up to 2 years (Peavy et al. 1992). In this last case, a 66-year-old patient experienced a gradual onset of irritability, social inappropriateness, uncharacteristic laughter and poor judgment, followed about 2 years later by a gradually progressive dementia and then, eventually, by evidence of psuedobulbar palsy and cranial nerve nuclear involvement. Electromyogram studies reveal evidence of denervation, whereas nerve condition velocity studies, except in advanced disease, are normal. MRI scanning may reveal increased signal intensity bilaterally in the centrum semiovale, corresponding to the corticospinal tracts; rarely, atrophy will be noted in the prefrontal gyrus. Course Amyotrophic lateral sclerosis is almost invariably progressive, with death, often from respiratory failure or an intercurrent pneumonia, within a matter of years. Differential diagnosis

A syndrome clincially very similar to amyotrophic lateral sclerosis may occur secondary to lymphoma (Younger et al. 1991). Amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam is a rare disorder of unknown cause, found in Guam, parts of Japan, and other Pacific islands (Garruto et al. 1981; Hirano et al. 1967; Malamud et al.196l). Syringomyelia and compression of the cervical spinal cord (as may be seen in cervical spondylosis or with foramen magnum tumors) may both cause a clinical picture similar to that of amyotrophic lateral sclerosis, but these are also typically accompanied by sensory changes.

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There are two syndromes, both sporadic and of gradual onset in the middle years, namely primary lateral sclerosis (Younger et al. 1988) and progressive muscular atrophy, which involve, respectively, solely the upper motor neurons and lateral corticospinal tracts, and solely the lower motor neurons of the anterior horn of the spinal cord. Clinically speaking, primary lateral sclerosis presents with a progressive spastic ridgidity, most evident in the lower extremities, whereas progressive muscular atrophy presents with widespread weakness, fasciculations, and atrophy. In many cases, these syndromes represent merely an atypical onset of amyotrophic lateral sclerosis, with the eventual development of the typical syndrome described above; in others, although the combination of upper and lower motor neuron involvement is not seen clinically, evidence for such a combination is found at autopsy (Brownell and Trevor-Hughes 1970; Lawyer and Netsky 1953). In some cases, however, both clinical and autopsy evidence suggests the sole involvement of either the upper or the lower motor neurons, but not both, and it is not clear whether these cases represent diseases sui generis or very atypical forms of amyotrophic lateral sclerosis. Familial spastic paraplegia is an autosomal dominant condition characterized by progressive spasticity of the lower extremities. Adrenoleukodystophy may present with progressive spasticicty of the lower extremities, but here one finds evidence of a peripheral neuropathy. There are two rare, recessively inherited disorders that present with isolated involvement of the lower motor neuron. Spinal muscular atrophy type III (or the Kugelberg-Welander syndrome [Kugelberg and Welander 1956]) presents in adolescence or early adulthood with proximal muscle weakness, whereas X-linked spinal muscular atrophy (or Kennedy's disease [Harding et al. 1982; Kennedy et al. 1968]) presents in the middle years with progressive weakness and fasciculations, often accompanied by a degree of gynecomastia. Motor neuropathies may simulate progressive muscular atrophy but are betrayed by prolonged nerve conduction velocity or the presence of conduction blocks. Multiple sclerosis may mimic primary lateral sclerosis but is identified by evidence of white matter involvement elsewhere in the central nervous system, for example the optic nerves. Treatment

Riluzole, although capable of slowing the progress of the disease to a mild degree, does not prevent the eventual fatal outcome. Various supportive measures are indicated, but eventually a decision must be made as to whether to provide mechanical ventilation: although mechanical ventilation may greatly prolong life, most patients are eventually left in a 'locked in' state that, for some, becomes a living death.

PARKINSON'S DISEASE Pathology and etiology

Macroscopically, as illustrated in Figure 8.4, there is depigmentation of the substantia nigra and the locus ceruleus. Microscopically (Hughes et al. 1993), neuronal loss is present not only in these structures, but also in the nucleus basalis of Meynert, the dorsal raphe nucleus, the dorsal motor nucleus of the vagus, and the thalamic nuclei, particularly the centre median and parafascicular nuclei (Henderson et al. 2000): importantly, in some of the remaining neurons of these structures, one also finds Lewy bodies, which are rounded or oval eosinophilic intracytoplasmic inclusion bodies, as illustrated in Figure 8.5. Lewy bodies may also be found in cerebral cortical neurons. Diffuse amyloid plaques may be found in the cortex. Motor symptoms do not appear until at least 60% of the neurons in the substantia nigra

Neurodegenerative disorders 377

Image Not Available

Figure 8.4 Note the depigmentation, especially evident in the substantia nigra, of the case of Parkinson's disease on the left compared with a normal control on the right. (Reproduced from Stern 1990.)

have been lost. The loss of these dopaminergic neurons to the striatum correlates with decreased dopamine level in the striatum, and it is here that the dopaminergic treatments for Parkinson's disease, described below, have their effect. Dementia appears to correlate with pathology in the cortex (Hurtig et al 2000) and the nucleus basalis of Meynert, and there is suggestive evidence that depressive symptomatology correlates with pathology in the midbrain raphe nuclei (Becker et al. 1997). Although the etiology of Parkinson's disease is not known, much progress has been made in this area. Current research supports the notion that genetic factors paly a role (Piccini et al. 1999), perhaps in conjunction with some as yet unidentified environmental toxin, resulting in enhanced oxidative stress and subsequent neuronal damage and death. Clinical features

Clinical features have been described in two large series (Hughes et al. 1993; Martin et al. 1973): the onset generally occurs in the sixth or seventh decades and is typically gradual and insidious. Patients typically present with asymmetric tremor or rigidity affecting an upper or,

378 Specific disorders

Image Not Available

Figure 8.5 Lewy bodies in surviving neurons of thesubstantia nigra. (Reproduced from Stern 1990.)

less commonly, lower extremity. Over time, the opposite side becomes involved, all four limbs eventually being affected. Once fully established, Parkinson's disease leaves a stamp on patients that is, once recognized, almost unforgettable. Patients stand in a stooped, 'flexion' posture, with their

Neurodegenerative disorders 379

arms and knees in flexion. A rhythmic, 3-7 cps rest tremor is present, most noticeably in the hands but also evident, when seated, in the feet; the jaw is also often tremulous. The face is often 'masked' and expressionless, and there may be copious drooling. Speech is hypophonic, soft, monotonous, and lacking in emotional inflection. Handwriting undergoes a 'micrographic' change, producing scratchy, small letters. Passive extension of the limbs reveals the rigidity, which, although often of the 'cogwheel' type, may at times be 'lead pipe' in character. While walking, there is reduced arm swing, and patients often display 'marche a petit pas', wherein they take small, shuffling steps; furthermore, they often display 'festination' in which as they walk, their steps become ever more rapid and closely spaced, to the point at which a catastrophic fall forward seems almost inevitable. Upon evaluating the station of these patients, one typically finds retropulsion, wherein a gentle push on the patient's chest will induce a gradual toppling backward that the patient cannot keep up with by backward steps. Another important symptom is bradykinesia, which manifests as a slowness in virtually any activity. For example, even in the absence of tremor or significant rigidity, it may take many minutes to, say, fasten a button. A related phenomenon is bradyphrenia, wherein thoughts, although coherent and logical, move very slowly, as if stuck in molasses. Another, curious phenomenon is 'freezing': in this, patients on the brink of an intentional act suddenly become 'frozen' and unable to move at all (Giladi et al 1992). For example, a patient standing in a doorway and desirous of walking down the hall may be unable to lift a foot, take a step, or move at all. Amazingly, however, such 'freezing' may be prevented by providing apppropriate visual 'cues': for example, if the hallway in question were marked off by pieces of tape set apart down the hall at about one foot pace, the patient might well be able to begin and finish the walk down the hall without any difficulty; furthermore, in some cases, patients may be able to lyse their own frozen state by simply imagining such cues (Morris et al. 1996). Dementia is more common in patients with Parkinson's disease than in age-matched controls (Biggins et al. 1992), prevalence figures of 11% (Mayeux et al. 1988), 17% (Aarsland et al 1996) 18% (Tison et al. 1995), 19% (Marder et al. 1995), and 29% (Marttila and Rinne 1976) being noted. The prevalence of dementia in Parkinson's disease rises with age: Mayeux et al. (1992) noted an overall prevalence of 41%, rising from 0% for those under 50 years to 69% for those over 80. It also appears that dementia is more likely in those with more severe motor symptoms (Kuzis et al. 1997; Marder et al. 1995). Importantly, the dementia does not appear until after the motor symptoms have become well established. It is of interest that James Parkinson, who described this disease in 1817 (Ostheimer 1922; Wilkins and Brody 1969b), maintained that dementia did not occur, an opinion that was echoed in textbooks for over one and one-half centuries. This mistake of his may be forgiven, based, as it was, on observation of a mere six patients, two of whom were encountered only 'casually' and one of whom was 'seen only at a distance.' The dementia itself is fairly non-specific: patients may experience difficulty with memory and concentration, and, less commonly, such focal deficits as aphasia or apraxia may appear. Depressive symptoms, of sufficient severity to meet the criteria for a depressive episode as set out in DSM-III (American Psychiatric Association 1980), have been noted in 3% (Hantz et al. 1994), 5% (Tandberg et al. 1996), and, in two separate studies (Mayeux et al. 1984; Starkstein et al. 1990), 21% of patients; minor depressive symptomatology may be found in others (Tandberg et al. 1996), indeed up to 20% (Mayeux et al. 1986; Starkstein et al. 1990). As might be expected, the presence of depression worsens the cognitive deficits in those also demented (Kuzis et al. 1997). Of interest, it appears that in patients with primarily unilateral motor symptomatology, depressive symptoms are more likely when the right side of the body is affected than the left, indicating an involvement of the left hemisphere (Starkstein et al.

380 Specific disorders

1990). Furthermore, there is suggestive evidence correlating the presence of depression in Parkinson's disease with a low cerebrospinal level of 5-hydroxy indoleacetic acid, a metabolite of serotonin (Mayeux et al 1984, 1986). Panic attacks have been noted in between 18% (Hillen and Sage 1996) and 24% (Vazquez et al. 1993) of patients, typically during the 'off period in patients on levodopa (Vazquez et al. 1993). Although parkinsonian tremor usually subsides with sleep, it may, in some cases, persist (Stern et al. 1968) or reappear during shifts from one sleep stage to another (April 1966). Akathisia may occur in Parkinson's disease (Cornelia and Goetz 1994) and may appear early in the course of the disease, before any pharmacologic treatment (Lang and Johnson 1987). Mention here may also be made of what is known as 'juvenile Parkinson's disease'. This is an autosomal recessively inherited disorder, with an onset anywhere from childhood to the early adult years of parkinsonism, which is generally, but not always, accompanied by lower extremity dystonia (Lucking et al. 2000). The fact that, at autopsy, Lewy bodies are not seen (Mori et al. 1998; Takahashi et al. 1994) raises the question of whether this disorder should be considered to be a variant of Parkinson's disease or perhaps a disease sui generis. Course Parkinson's disease is gradually progressive, most patients becoming disabled within 15 years. Differential diagnosis

The diagnosis of Parkinson's disease should be doubted when any of the following features are present: a lack of response to levodopa; an early onset of dementia; early postural instability with frequent falls; an extension, rather than flexion, posture; ataxia; myoclonus; prominent autonomic insufficiency; and supranuclear ophthalmoplegia. Diffuse Lewy body disease is distinguished by the early appearance of dementia, often with confusion and psychotic symptoms, such as hallucinations and delusions. Multiple system atrophy of the striatonigral variant is distinguished by the presence of cerebellar signs (e.g. ataxia), autonomic insufficiency (e.g. incontinence and dizziness), or myoclonus. Progressive supranuclear palsy is distinguished by the presence of early falls, an extension rather than flexion posture, and supranuclear ophthalmoplegia. Arteriosclerotic parkinsonism is distinguished by an extension posture, a magnetic gait, and signs of corticospinal and corticbulbar tract damage, in particuar pseudobulbar palsy. Calcification of the basal ganglia may produce a dementia before the onset of parkinsonism, which would be quite distinctive; in cases in which the parkinsonism occurs first, the presence of ataxia would be suggestive. Most important, however, is the finding of calcification of the basal ganglia upon imaging. Dementia pugilistica is distinguished by the presence of ataxia and a history of repeated head trauma. Corticobasal ganglionic degneration is distinguished by the presence of apraxia and myoclonus. Dopa-responsive dystonia may be difficult to distinguish from juvenile Parkinson's disease, as discussed further below. Treatment

Motor symptoms may be treated with a variety of agents, including selegeline, anticholinergics (e.g. benztropine and trihexyphenidyl), amantadine, levodopa/carbidopa, and direct-acting dopamine agonists (bromocriptine, cabergoline, pergolide, pramipexole and ropinirole). Each

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of these agents will be discussed in turn, followed by a discussion of an overall treatment strategy. Selegeline (Myllyla et al. 1997; Palhagen et al. 1998), at a dose of 10 mg or less per day is a selective monoamine oxidase-B inhibitor and as such inhibits the intracellular breakdown of dopamine, thus increasing the amount available for release in the striatum and thereby having a modest therapeutic effect. Although highly controversial, there are also some data suggesting that selegeline may have a neuroprotective effect and may slow down the progression of the disease. Anticholinergics, although useful for tremor, have a limited effect on bradykinesia and rigidity, and in some patients may cause confusion or a memory deficit. Amantadine, in a dose of 200-300 mg/day, may have a mild effect on motor symptoms, but the effect may be short lived. Levodopa is the most effective treatment for the motor symptomatology of Parkinson's disease, generally being given in combination with a peripheral aromatic amino acid decarboxylase inhibitor (carbidopa or benzaride) in order to prolong its effect: both regular and sustained-release preparations are available. The initial response to levodopa/carbidopa is, as noted below, generally quite gratifying, but as levodopa does not retard the progression of the disease, a dosage increase is necessary over time, and most patients eventually begin to show motor fluctuations: such fluctuations can be 'peak dose' with dyskinesias, 'end of dose' with an early wearing off of effectiveness, or unpredictable. When fluctuations appear, using lower and more closely spaced doses of levodopa may help, or one may add tolcapone. Tolcapone is a peripheral catechol-O-methyltransferase inhibitor that extends the duration of levodopa's effect and also allows for a lowering of the levodopa dose (Adler et al. 1998; Kurth et al 1997; Rajput et al. 1997; Waters et al. 1997); although hepatotoxicity is a concern (Baas et al. 1997), the medication may be used safely with appropriate monitoring (Olanow et al. 2000). Dopamine agonists include, as noted above, a number of different agents: although bromocriptine is the oldest member of this group, problematic side-effects, combined with the fact that newer agents (e.g. ropinirole [Korczyn et al. 1999]) may be more effective, have limited its use. Dopamine agonists have been used as 'add-on' drugs to levodopa both to smooth out the levodopa fluctuations and to allow for a levodopa dose reduction, this effect having been shown for cabergoline (Hutton et al. 1996; Inzelberg et al. 1996), pergolide (Olanow et al. 1994), pramipexole (Guttman et al. 1997; Lieberman et al. 1997; Pinter et al. 1999), and ropinirole (Lieberman et al. 1998). In addition, dopamine agonists have also been used as monotherapy in early, mild Parkinson's disease, as with cabergoline (Rinne et al. 1997), pergolide (Barone et al. 1999), pramipexole (Parkinson Study Group 1997; Shannon et al 1997), and ropinirole (Adler et al 1997; Korczyn et al. 1999; Rascol et al. 2000). Should bromocriptine, pergolide, pramipexole, or ropinirole be used, patients must be cautioned that these agents have been associated with sleep attacks and, possibly, motor vehicle accidents (Ferreira et al 2000; Frucht et al 1999; Hauser et al 2000). The optimum overall treatment strategy is still a matter of some debate, and although the strategy recommended here is intended as a middle of the road approach, not all authors will be in agreement. In general, pharmacologic treatment should not be initiated until the motor symptomatology significantly interferes with the patient's ability to function. In mild cases, one may begin with selegeline, and, when tremor is prominent, some clinicians advocate the use of an anticholinergic. With disease progression, however, one must at some point add either levodopa or a dopamine agonist, the question of which to use first not being settled. Given the at times stunning effectiveness of levodopa, some advocate using this first, especially when a prompt response is required, for example when a patient is threatened with job loss.

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Others, however, with an eye towards delaying the emergence of levodopa-induced dsykinesias, advocate starting with dopamine agonist monotherapy and adding levodopa only as the disease progresses. All other things being equal, it may be prudent to begin with a dopamine agonist (cabergoline, with a half-life that allows once-daily dosing, being quite attractive), increasing the dose as required until limiting side-effects occur or further dose increases are not effective, and then adding levodopa. Between the regular and sustained-release preparations of levodopa, the sustained-release preparation may be preferable as it may allow for a longer duration of effect: given its slower onset of action, however, some patients may have to take a 'regular' release preparation first thing in the morning in order to 'jump start' themselves. When fluctuations in levodopa responsiveness begin to appear, the addition of tolcapone may be considered. If, rather than dopamine agonist monotherapy, one begins with levodopa, one will at some point have to add a dopamine agonist in order to smooth out the effect of levodopa and to allow a dose reduction and a reduction in levodopa-induced dyskinesias. In addition to the problem of motor fluctuations, most patients treated with levodopa and/or dopamine agonists will also eventually experience neuropsychiatric side-effects, which at times may be disabling. These include isolated visual or auditory hallucinations with preserved insight (Fenelon et al. 2000; Friedman and Sienkiewicz 1991; Graham et al. 1997; Inzelberg et al. 1998), psychosis (Fenelon et al. 2000; Inzelberg et al. 1998; Lin and Ziegler 1976; Serby et al. 1978), mania (Celesia and Barr 1970; O'Brien et al. 1971), or delirium (Celesia and Barr 1970; Friedman and Sienkiewicz 1991; Serby et al. 1978). Of these neuropsychiatric side-effects, hallucinations and psychosis are the most common. A dose reduction of the offending agent is effective, but this sometimes allows for a disabling resurgence of the motor symptoms. In such cases, it may be appropriate to add a neuroleptic for symptomatic control of the hallucinations or delusions. Clozapine, in very low doses, is effective (Parkinson Study Group 1999), but the risk of agranulocytosis may raise a question mark over its use. Olanzepine may be an alternative (Wolters et al. 1996) but may aggravate motor symptoms (Jimenez-Jimenez et al. 1998; Molho and Factor 1999), in which case quetiapine may be considered (Fernandez et al 1999; Weiner et al. 2000): regardless of whether olanzepine or quetiapine is used, a low dose, in the range of 2.5 and 50 mg, resepctively, is in order. In treating patients with levodopa or dopaminergic agents, it is important to not suddenly stop them as this may precipitate a neuroleptic malignant syndrome, as has been reported for levodopa (Sechi et al. 1984; Toru et al. 1981); the combination of levodopa and bromocriptine (Figa-Talamanca et al. 1985), and amantadine (Cunningham et al. 1991; Harsch 1987). Treatment-resistent patients are candidates for electroconvulsive therapy (ECT) or neurosurgery. ECT has been shown, in a double-blinded study, to ameliorate the motor symptoms of Parkinson's disease, regardless of whether or not patients were depressed (Andersen et al. 1987). Surgical interventions include pallidotomy, thalamotomy, and deep brain thalamic stimulation (Hallett et al. 1999). The treatment of parkinsonian dementia is similar to that of dementia in general, as described in Chapter 5. If neuroleptics are required, those with the least propensity to cause parkinsonism (i.e. olanzepine or quetiapine) should be used, beginning with a very low dose. Depression may be treated with antidepressants. SSRIs, although effective, may worsen motor symptoms and, if selegeline is also being used (especially if the dose is over 10 mg), may also cause a serotonin syndrome. Tricyclic agents are overall best tolerated, and of them, nortriptyline is probably the best choice. Panic attacks may be treated with nortriptyline or with clonazepam.

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DIFFUSE LEWY BODY DISEASE Pathology and etiology

Macroscopically, there is, in diffuse Lewy body disease (cortical Lewy body disease; Lewy body dementia; senile dementia of the Lewy body type) widespread, generally mild, cortical atrophy. Microscopically, one finds throughout the cortex, but especially in the temporal lobe, neuronal loss and, within many remaining cells, rounded, intracytoplasmic eosinophilic inclusion bodies known as Lewy bodies (Gibb et al. 1987; Lennox et al. 1989). Lewy bodies are also found within the nucleus basalis of Meynert and the substantia nigra. Clinical features

Diffuse Lewy body disease generally presents in an insidious fashion in the seventh or eighth decade with parkinsonism, dementia, or a combination of the two (Byrne et al. 1989); virtually all patients eventually exhibit both features. The parkinsonism is similar to that seen in Parkinson's disease (Hely et al. 1996), with rigidity, akinesia, and a stooped posture, with the exceptions that tremor is less frequent and that, in a minority, there may be myoclonus (Louis et al. 1997). The dementia is, in addition to memory loss and certain focal signs, such as aphasia or apraxia, characteristically accompanied by episodes of confusion (McKeith et al. 1994a). Furthermore, hallucinations (visual more often than auditory) and delusions (often of persecution) very commonly accompany the dementia; depressive symptoms may also be seen (Burkhardt et al. 1988; Klatka et al. 1996). In cases in which the presentation is with dementia, one often finds an unusual sensitivity to typical neuroleptics (McKeith et al. 1992, 1994b), with the prompt appearance of relatively severe neuroleptic-aggravated parkinsonism. Course Diffuse Lewy body disease is progressive. Differential diagnosis

Alzheimer's disease may be considered when diffuse Lewy body disease presents with dementia; the early appearance of psychotic symptoms, such as hallucinations and delusions, is, however, strongly suggestive of diffuse Lewy body disease (Ala et al. 1997; Ballard et al. 1999; Crystal et al. 1990; Weiner et al. 1996), as is the unusual sensitivity to typical neuroleptics (McKeith et al. 1992, 1994b) and the presence of episodes of confusion early in the course of the disease. Parkinson's disease may be considered when diffuse Lewy body disease presents with parkinsonism; the presence of myoclonus (Louis et al. 1997) and the early appearance of delusions (Klatka et al. 1996) are clues to the presence of diffuse Lewy body disease. It must however, be kept in mind that, early on in the course, diffuse Lewy body disease may be indistinguishable from Parkinson's disease (Hely et al. 1996). Treatment

Parkinsonism may respond to levodopa (Byrne et al. 1989). Psychotic symptoms respond to neuroleptics, but, in order to avoid a significant aggravation of parkinsonism, one should use either an atypical neuroleptic (e.g. olanzepine) or a low-potency typical neuroleptic (e.g. thioridazine), starting with a low dose (e.g. 2.5mg olanzepine; 25 mg thioridazine) and titrating up slowly in small increments.

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PROGRESSIVE SUPRANUCLEAR PALSY Pathology and etiologyT

In progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) there is macroscopically atrophy of the midbrain and pontine tegmentum, globus pallidus, and, less commonly, the frontotemporal cortex; microscopically, neuronal loss, astrocytosis, and neurofibrillary tangles are seen in these areas, along with the malamus (particularly the centromedian and parasfascicular nuclei), subthalamic nucleus, red nucleus, substantia nigra, locus ceruleus, tectum and periaqueductal grey, dorsal, and medial raphe nuclei and the dentate nucleus of the cerebellum (Collins et al. 1995; Henderson et al. 2000; Litvan et al. 1996a; Steele et al. 1964). Importantly, the neurofibrillary tangles are dissimilar to those found in Alzheimer's disease (Takahashi et al. 1989). Although some cases of autosomal dominant inheritance have been reported (Brown et al. 1993; de Yebenes et al. 1995; Rojo et al. 1999; Stanford et al. 2000), it appears that the vast majority of cases are sporadic and of unknown etiology. Clinical features

The general clinical features have been descirbed in several reports (Collins et al. 1995; Litvan et al 1996a; Maher and Lees 1986; Messert and Van Nuis 1966; Steele 1972; Steele et al. 1964). The onset is insidious, generally in the sixth or seventh decade, the first symptom typically consisting of frequent unexplained falls caused by postural instability. An atypical parkinsonism then gradually appears, characterized by a more or less symmetric onset of rigidity, generally without tremor, and an abnormal gait characterized by a wide-based stance with short, shuffling steps. Importantly, rather than the typical flexion posture seen in most cases of parkinsonism, patients with progressive supranuclear palsy typically display a dystonic axial rigidity, which may also affect the neck. Dystonic rigidity also affects the facial musculature, at times creating an 'astonished' appearance, as seen in Figure 8.6. Classically, from 1 to 3 years after the parkinsonism is established, one also sees a supranuclear ophthalmoplegia for vertical gaze, wherein patients have difficulty voluntarily looking down, a difficulty that may make walking down stairs particularly treacherous. Dementia occurs in about one-half of all patients, generally well after the parkinsonism has become established: patients have difficulty with concentration and memory, and there may be elements of a frontal lobe syndrome (Verny et al. 1996) with prominent apathy (Litvan et al. 1996c). Rarely, dementia may constitute the presenting symptom of progressive supranuclear palsy (Davis et al. 1985). Over time, pseudobulbar palsy with emotional incontinence (Menza et al 1995) may occur, as may seizures. Aphasia, agnosia and apraxia are rare. MRI scanning may reveal atrophy of the midbrain and, in some cases, of the frontal and temporal cortices. Course Progressive supranuclear palsy is progressive, with death in 5-7 years (Golbe et al 1988; Maher and Lees 1986). Differential diagnosis

Various other causes of parkinsonism must be considered, including Parkinson's disease, arteriosclerotic parkinsonism, corticobasal ganglionic degeneration, dementia pugilistica, and the striatonigral variant of multiple system atrophy. Although the combination of supranuclear ophthalmoplegia (for downward gaze) and severe postural instability is quite specific (Litvan et al 1996b, 1997b) and rules out these other disorders, supranuclear

Neurodegenerative disorders 385

Image Not Available

Figure 8.6 'Astonished'facial appearance in progressive supranuclear palsy. (Reproduced from Stern 1990.)

ophthalmoplegia may in some cases never develop (Daniel et al. 1995). Consequently, other differential points should be kept in mind. Parkinson's disease is distinguished by a flexion posture and prominent tremor, in contrast to the axial rigidity and general absence of tremor seen in progressive supranuclear palsy. Arteriosclerotic parkinsonism may be very difficult to distinguish from progressive supranuclear palsy, especially early in the course of the patient's illness. Finding multiple lacunes on MRI scanning points to arteriosclerotic parkinsonism; should supranuclear ophthalmoplegia appear, however, the diagnosis of progressive supranuclear palsy becomes almost certain. Corticobasal ganglionic degeneration is suggested by the often strikingly asymmetric onset of parkinsonism and by the prominence of apraxia. Dementia pugilistica is suggested by the history of repeated head trauma and by the prominent ataxia. Multiple system atrophy of the striatonigral variant may also be characterized by ataxia, and

386 Specific disorders

there may also be evidence of autonomic failure, such as urinary incontinence, postural dizziness, and impotence. Treatment t

An overall improvement, including in gait, has been reported with amitriptyline (Kvale 1982; Newman 1985), and agitation has been successfully treated with trazodone (Schneider et al. 1989). A small minority may benefit from levodopa (Litvan et al. 1996a)

CORTICOBASAL GANGLIONIC DEGENERATION Pathology and etiology The pathology of corticobasal ganglionic degeneration has been described in a number of papers (Gibb et al. 1994; Rebeiz et al. 1968; Riley et al. 1990; Rinne et al 1994b). Macroscopically, there is asymmetric cortical atrophy, affecting primarily the parietal lobe and the posterior portion of the frontal lobe; over time, the atrophy may spread to the contralateral side, and the temporal lobes and anterior portions of the frontal lobes may become involved. Microscopically, neuronal loss and astrocytosis are found in affected areas; surviving neurons may be swollen and achromatic. Although the basal ganglia and substantia nigra do not show atrophy, these areas show similar histologic changes. Most cases are sporadic; ultrastructural studies have demonstrated abnormal filaments in the cytoplasm of the ballooned cells. Clinical features

The onset is gradual, usually in the sixties. Clinically (Litvan et al. 1997c; Riley et al. 1990; Rinne et al. 1994b; Wenning et al. 1998), most patients present with a strikingly asymmetric rigid akinetic parkinsonism affecting an upper limb; at times, a 'jerky' dystonia may be more prominent than parkinsonism. Cortical sensory loss and apraxia are common, as is myoclonus. Dementia occurs in about one-half of patients, and although this usually follows the motor disturbance by years, it may at times be the presenting feature (Bergeron et al. 1996; Schneider et al. 1997); indeed, in one series (Grimes et al. 1999), the majority of patients presented with dementia. Corticobasal ganglionic degeneration may rarely present with a slowly progressive aphasia (Ikeda et al. 1996). Many authors also comment on the presence of an alien hand sign in corticobasal ganglionic degeneration, but, as pointed out in Chapter 4, this sign is in fact not well described in this disorder: rather, patients display such purposeless movements as grasping, 'wandering' (Rinne et al. 1994b; Sawle et al. 1991), and levitation (Gibb etal 1994; Riley et al. 1990) . MRI scannng may reveal the asymmetric cortical atrophy. Course Over years, the rigidity spreads and generally eventually becomes bilateral. In some cases, a supranuclear gaze palsy and mild cerebellar signs may develop. Death usually occurs after 6-10 years (Rinne et al 1994b). Differential diagnosis

Parkinson's disease is distinguished by the absence of apraxia and myoclonus (Litvan et al. 1997c). Pick's disease may be suggested when corticobasal ganglionic degeneration presents with aphasia, but the subsequent appearance of a movement disorder indicates the correct diagnosis. Progressive supranuclear palsy may be suggested by the supranuclear gaze palsy but is

Neurodegenerative disorders 387

distinguished by the presence of parkinsonism of more symmetric onset and by the absence of apraxia. Treatment

No specific treatment is known; levodopa is not effective (Rinne et al. 1994b).

MULTIPLE SYSTEM ATROPHY Pathology and etiology Macroscopically, there is variable atrophy of the cerebral cortex (particularly the frontal area), striatum (more so the putamen than the caudate), and pontine nuclei, inferior olives, and cerebellum (Wenning et al. 1996). Microscopically, cell loss and astrocytosis are seen not only in these areas, but also in the subtantia nigra, locus ceruleus, ventrolateral medulla (Benarroch et al l 1998), and intermediolateral gray of the spinal cord. Cytoplasmic inclusions are seen in oligodendroglia (Papp et al. 1989), and it is the presence of these glial cytoplasmic inclusions which constitutes the microscopic hallmark of multiple system atrophy. Multiple system atrophy is a sporadic disorder of unknown etiology. Clinical featuress

The onset is gradual in the fifth or sixth decades (Quinn 1989). The clinical presentation is quite variable, being related, as might be expected, to which parts of the nervous system bear the brunt of the disease process (Papp and Lantos 1994). In general, three different clinical presentations are recognized, but it must be kept in mind that overlap is the rule and that no one of these types is often encountered in a pure form. The three different types are striatonigral, olivopontocerebellar, and Shy-Drager. The striatonigral variant of multiple system atrophy (Colosimo et al. 1995; Wenning et al. 1995), seen when the striatum and substantia nigra are most involved, is characterized by the gradual onset of parkinsonism in the middle years. The parkinsonism is similar to that seen in Parkinson's disease, the exception being that tremor is seen in only a minority and is typically not of the classic pill-rolling type. Furthermore, patients with the striatonigral variant may have other signs, not typical for Parkinson's disease, such as hyperreflexia and extensor plantar responses, myoclonus, and, in a small minority, supranuclear ophthalmoplegia for downward gaze (Wenning et al. 1995). The olivopontocerebellar variant of multiple system atrophy is characterized by the gradual onset, in middle age, of ataxia, dysarthria, and scanning speech; reflex myoclonus is also commonly seen (Rodriguez et al. 1994). The Shy-Drager (Shy and Drager 1960) variant of multiple system atrophy, seen when the intermediolateral gray of the spinal cord is heavily involved, is characterized by evidence of autonomic failure, such as urinary retention or incontinence, postural dizziness or syncope, impotence, and, rarely, fecal incontinence (Wenning et al. 1994). Dementia may occur in a minority of patients with multiple system atrophy and may be distinguished by elements of a frontal lobe syndrome (Robbins et al. 1992). Rarely, multiple system atrophy may present with a personality change and dementia, this having been noted for the olivopontocerebellar type (Critchley and Greenfield 1948). As noted above, it is rare for any of these variants to occur in a pure form, and it is the presence of overlap signs and symptoms that greatly facilitates the differential diagnosis, as noted below. Interestingly, there is a strong association between multiple system atrophy and rapid eye movement (REM) sleep behavior disorder: one report (Plazzi et al. 1997) noted that the vast

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majority of patients with multiple system atrophy had this disorder, which could precede the development of typical symptomatology by years. T2-weighted MRI scanning may reveal decreased signal intensity in the putamen as well as atrophy of the pons and cerebellum. Course

Multiple system atrophy is gradually progressive, death generally occurring within 7 years (Quinn 1989). Differential diagnosis The striatonigral variant (Colosimo et al. 1995; Litvan et al. 1997d; Wenning et al. 1995,1999) is distinguished from Parkinson's disease, diffuse Lewy body disease, and corticobasal ganglionic degeneration by the presence of ataxia and autonomic insufficiency. The olivopontocerebellar variant is distinguished from autosomal dominant cerebellar ataxia by the absence of a family history and by the presence of mild parkinsonism and autonomic insufficiency. The Shy-Drager type may be distinguished from pure autonomic failure not only by the presence of mild parkinsonian or cerebellar signs, but also by a history of REM sleep behavior disorder (Plazzi et al. 1998). Treatment The parkinsonism of the stratonigral variant generally does not respond to levodopa, and, in those cases which do, the response is generally soon lost (Wenning et al. 1995). Importantly, if levodopa is used, one must watch closely for postural dizziness as these patients are particularly prone to developing this side-effect.

HUNTINGTON'S DISEASE Pathology and etiology Macroscopically, as illustrated in Figure 8.7, there is atrophy of the striatum (especially the caudate nucleus), and mild-to-marked cortical atrophy (particularly in the frontal lobes). Microscopically, neuronal loss is found in these areas, and, specifically, in the caudate, spiny neurons are lost first, eventually followed by aspiny neurons (Mann et al. 1993b; Myers et al. 1988).

Image Not Available

Figure 8.7 Marked atropy of the caudate, with compensatory ventricular dilatation, in a case of Huntington's disease compared with a control brain on the right. (Reproduced from Graham and Lantos 1996.)

Neurodegenerative disorders 389

Huntington's disease is a fully penetrant autosomal dominant disorder; the affected gene codes for a protein known as huntingtin and is located on chromosome 4. The gene normally contains anywhere from 10 to 29 CAG trinucleotide repeats, whereas in Huntington's disease, anywhere from 36 to 121 repeats may be found (Kremer et al. 1994). Very rarely, sporadic cases may occur: in such cases, it appears that the patient's father, himself unaffected, harboured a number of CAG repeats that, although still within the bounds of normal, were unstable and underwent expansion (Myers et al. 1993). Clinical features

The onset is generally highly insidious and may occur anywhere from childhood to the seventh decade, most patients falling ill in the fourth decade. In most cases, the presentation is with either chorea or a personality change; over time, as noted below, almost all patients develop a combination of chorea and dementia (Pflanz et al. 1991). Onsets in childhood or adolescence are often (but not always) with the akinetic-rigid Westphal variant, described below. Cases with an onset in the sixth decade or beyond are generally characterized only by chorea, with little or no dementia (Britton et al. 1995). Chorea may initially present as fidgetiness, clumsiness, or a tendency to drop things; obvious choreiform movements are generally first visible on the face (including the forehead), from where they spread to involve the trunk and extremities. There may be facial grimacing, brow-wrinkling, and blinking; upper extremity involvement may lead to shoulder-shrugging, abrupt flinging of the arms, or purposeless 'piano-playing' movements of the hands. Lower extremity involvement may lead to a lurching, staggering, or 'dancing and prancing' gait: in some cases, patients have been accused of alcohol intoxication (Lesse 1946). Importantly, these choreiform movements are quite brief, appearing and disappearing on a random basis from one location to another with lightning-like rapidity. Early on in the course of the disease, patients may attempt, with varying degrees of success, to disguise the choreic movements by merging them with purposeful movements: for example, a choreic fling of the arm up to the head may be purposefully extended to draw the fingers through the hair, as if the purpose had all along been to straighten the hair. Dysarthria often occurs, as does dysphagia, which may lead to aspiration (Leopold and Kagel 1985). The chorea eventually makes almost all purposeful activity, whether eating, dressing, or walking, almost impossible, and patients eventually become chair-bound or bed-ridden. At the end, the chorea may gradually disappear, to be replaced by a rigid, akinetic state (Feigin et al. 1995). The personality change presents with poor judgment, impulsivity, irritability, and an overall coarsening of behavior. Over time, a dementia develops, characterized by deficits in memory, concentration, calculation, and abstraction; such focal signs as aphasia and apraxia are generally not seen. Mood changes may occur, and although they are usually depressive, manic symptomatology may also be seen; in some cases, Huntington's may present with a mood disturbance (Folstein etal 1983). Psychosis may occur; indeed, as noted by George Huntington (Brody and Wilkins 1967) in 1872, 'the tendency to ... insanity ... is marked'. Rarely, psychosis may be the presenting feature of Huntington's disease. Delusions, generally of persecution, are common, and hallucinations, more often visual than auditory, also commonly occur. Importantly, there is no correlation between the severity of mood changes or psychosis and the severity of chorea or the number of CAG repeats (Zappacosta et al. 1996). Suicide is not uncommon (Schoenfeld et al. 1984) In childhood or adolescent onset cases, one may see the Westphal variant of Huntington's disease, wherein there is often, rather than chorea, a rigid, akinetic state that is generally

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accompanied by severe dementia, often with seizures, myoclonus and ataxia (Bird and Paulson 1971; Campbell et al. 1965; Hansotia et al 1968; Jervis 1979; Siesling et al. 1997). As noted above, Huntington's disease is fully penetrant, and the disease can generally be easily traced back into preceding generations, in some cases for centuries (e.g. in one American family, back to the Puritans [Vessie 1932]). CT or axial MRI scanning reveals a characteristic change in the configuration of the frontal horns of the lateral ventricles, wherein, due to atrophy of the caudate nuclei, they assume a 'butterfly' shape. Cortical atrophy may also be seen. Importantly, early in the course of the disease, CT and MRI scanning may be normal. Genetic testing for the CAG repeat is highly specific and sensitive (International Huntington Association 1994; Kremer et al. 1994). Course Huntington's disease is relentlessly progressive, with death in 10-30, averaging about 15 years. The Westphal variant pursues a more rapid course, death occurring in an average of 8 years. Differential diagnosis

In the past, diagnosis, especially early in the course, was at times very difficult. Although the availability of genetic testing has dramatically simplified the diagnostic task, an attention to clinical differences from similar disorders remains important. Neuroacanthocytosis is distinguished by the presence of self-mutilating lip-biting and acanthocytosis. Senile chorea is distinguished by the absence of a family history and the late onset in the seventh decade. Benign hereditary chorea is distinguished from childhood or adolescent onset Huntington's disease by the absence of dementia, seizures, chorea, or ataxia. Dentatorubropallidoluysian atrophy is distinguished from adult-onset Huntington's disease by the presence of seizures, ataxia, or parkinsonism. Distinguishing childhood onset dentatorubropallidoluysian atrophy from childhood onset Huntington's disease may be very difficult, making genetic testing mandatory. Wilson's disease is distinguished by the presence of Kayser-Fleischer rings and abnormalities in copper and ceruloplasmin levels. Schizophrenia, especially when complicated by tardive dyskinesia, may closely resemble Huntington's disease. Schizophrenia is distinguished by the prominence of auditory hallucinations and the presence of loosening of associations. Tardive dyskinesia is distinguished by the presence of stereotyped, repetitive movements, in marked contrast to the fluid, ever-changing chorea of Huntington's disease, and by the fact that the chorea of tardive dyskinesia does not affect the forehead and rarely affects the gait, in contrast to Huntington's disease, in which forehead chorea and a lurching, choreic gait are common. Treatment Tr

Treatment is only symptomatic; there is no cure. The general treatment of dementia is described in Chapter 5. Depression maybe treated with antidepressants, such as nortriptyline, and mania with mood stabilizers, such as divalproex. Psychosis may respond to neuroleptics, which are also useful in the suppression of chorea. Although haloperidol (starting at 5 mg/day) is traditional, newer atypical agents such as olanzepine may be preferable (Dipple 1999); in some cases, clozapine has been used with success. Clinically unaffected siblings and children should be offered genetic testing, and provision should be made for extensive counseling for those carrying the mutation.

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NEUROACANTHOCYTOSIS Pathology and etiology

Macroscopically, there is in neuroacanthocytosis (choreoacanthocytosis) atrophy of the caudate and putamen. Microscopically, neuronal loss and gliosis are seen in the caudate and putamen, to a lesser degree in the globus pallidus, and to only a mild degree in the substantia nigra (Rinne et al. 1994a). Axonal loss may occur in the peripheral nerves (Hardie et al. 1991; Ohnishieffl/. 1981). Both sporadic and familial cases occur; familial cases may be consistent with either autosomal dominant or recessive inheritance: the nature of the inherited defect is unclear. Clinical features

Onset is generally in the late twenties or early thirties but may occur anywhere from late childhood to the seventh decade. Clinically (Critchley etal. 1968; Feinberg etal. 1991; Hardie et al. 1991; Kartsounis and Hardie 1996; Sakai etal. 1981), although chorea is the most prominent movement disorder, one may also see tics or dystonia. Furthermore, after many years, parkinsonism may supervene: Both dementia and personality change may be seen, and seizures may occur. A classic symptom, seen, however, in only a minority, is self-mutilation by lip- or tongue-biting. Importantly, the self-mutilation is outside the patient's control: one patient (Medaliaeta/. 1989), despite attempting to 'restrain herself... by placing her fingers or a folded towel in her mouth... nevertheless had bleeding and scarred lesions of her oral mucosa and lips'. Acanthocytosis, to a degree of 10% or more, is seen on peripheral smears; importantly, the smears must be fresh wet preparations, and given the chance of false negatives, at least three smears should be examined (Hardie et al. 1991). The creatinine kinase is elevated in most cases. MRI scanning reveals atrophy of the caudate. Course Neuroacanthocytosis is gradually progressive. Differential Diagnosis

Huntington's disease is distinguished by the absence of acanthocytosis and self-mutilation. Abetalipoproteinemia and hypobetalipoproteinemia may be difficult to distinguish clinically, so the plasma betalipoprotein level should be obtained. Treatment

Neuroleptics, such as olanzepine, may be useful in reducing chorea; the general treatment of dementia is discussed in Chapter 5.

SENILE CHOREA Pathology and etiology A mild degree of neuronal loss is seen in the striatum. The etiology of this cell loss is not clear, and there may indeed be multiple etiologies; the disorder is not familial. Clinical features

Onset is insidious, generally in the seventh decade. Mild chorea may be seen in the buccofacial area (Delwaide and Desseilles 1977; Klawans and Barr 1981; Varga et al. 1982), or in the limbs (Shinotoh et al. 1994). There is no dementia.

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Course

In general, there is a very slow progression; the chorea, however, never becomes severe. Differential diagnosis

Edentulousness may cause similar buccofacial movements (Roller 1983). Huntington's disease is typified by an earlier onset, a positive family history, more severe chorea, and the presence of dementia; atypical onsets in later years with chorea alone do, however, occur (Garcia Ruiz etal. 1997), genetic testing for Huntington's disease consequently probably being warranted in such cases. Tardive dyskinesia is distinguihshed by the history of neuroleptic use and by the involvement of the tongue. Benign hereditary chorea is distinguished by the positive family history and the early age of onset. Treatment

In general, no treatment other than reassurance is required.

BENIGN HEREDITARY CHOREA Pathology and etiology

Benign hereditary chorea is probably an autosomal dominant condition with variable penetrance. Clinical features

Onset is in childhood with chorea, which may be generalized and is often associated with tremor. There is no dementia (Behan and Bone 1977). Course

Once established, the chorea, although chronic, is not progressive. Differential diagnosis

Benign hereditary chorea is probably a very rare condition: the follow-up of most cases has revealed the existence of other disorders (Schrag et al. 2000). Of all the childhood onset choreas, particular attention should be paid to Sydenham's chorea and the Westphal variant of Huntington's disease. Sydenham's chorea is distinguished by its acute onset and episodic course, and by the presence of other evidence of rheumatic fever. The Westphal variant of Huntington's disease is often characterized more by rigidity than by chorea, is often accompanied by dementia, and may also be accompanied by seizures, ataxia, and chorea; in doubtful cases, genetic testing will settle the issue. Treatment

Generally none is required.

DENTATORUBROPALLIDOLUYSIAN ATROPHY Pathology and etiology

Neuronal loss and gliosis, while most prominent in the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus (corpus Luysii), may also be found in the cerebral cortex, striatum, thalamus, substantia nigra, and inferior olives (Becher et al. 1997; Goto et al. 1982; lizuka et al. 1984; Warner et al. 1994).

Neurodegenerative disorders 393

Dentatorubropallidoluysian atrophy is inherited in an autosomal dominant fashion, with an expanded trinucleotide repeat on chromosome 12 (Nagafuchi et al. 1994). Importantly, there is considerable phenotypic variation, not only between families, but also among affected members of an individual family (Potter et al. 1995). Clinical features

The onset is gradual and may be in childhood or the adult years. Adults (Becher et al. 1997; lizuka et al. 1984; Nielsen et al 1996; Villani et al. 1998; Warner et al. 1994, 1995; Yoshii et al. 1998) typically present with a combination of dementia, ataxia, and chorea; in a minority there may be a psychosis, seizures, dystonia or parkinsonism. Although myoclonus may occur in adults, it is more likely in children, who tend to present with a combination of dementia and myoclonus (Becher et al. 1997). Course Dentatorubropallidoluysian atrophy is progressive. Differential diagnosis

Adult onset Huntington's disease is distinguished from dentatorubropallidoluysian atrophy by an absence of ataxia and myoclonus; in doubtful cases, genetic testing for both disorders is available. Autosomal dominant cerebellar ataxia (ADCA) may be clinically indistinguishable from cases of dentatorubropallidoluysian atrophy with prominent ataxia, and genetic testing is advised. Treatment

The general treatment of dementia is discussed in Chapter 5; it would not be unreasonable to use a neuroleptic, such as olanzepine, for the chorea.

WILSON'S DISEASE Pathology and etiology

Macroscopically (Howard and Royce 1919), there is atrophy and a brownish discoloration of the striatum, with, in advanced cases, cavitation (Wilson 1912) and a mild degree of cortical atrophy. Microscopically, there is neuronal loss and astrocytosis in the striatum (more so the putamen than the caudate) and to a lesser degree in the glob us pallidus; other affected structures are the cerebral cortex (especially the frontal lobes [Barnes and Hurst 1926]), thalamus, red nucleus, substantia nigra, dentate nucleus, and cerebellar cortex. Pericapillary copper deposition is evident in all these areas. Copper deposition is also seen in the liver, and a degree of cirrhosis is uniformly present in those who survive for any considerable period of time. Copper deposition in Descemet's membrane gives rise to the classic Kayser-Fleischer ring, described below. Wilson's disease is an autosomal recessive disease, the responsible gene being found on chromosome 13 (Bull et al. 1993; Chelly and Monaco 1993); the disease can result from multiple different mutations (Thomas et al. 1995). The basic disturbance lies in the metabolism of copper. Normally, copper is absorbed from the gut, bound to ceruloplasmin, and eliminated for the most part through the biliary system. In Wilson's disease, both the incorporation of copper into ceruloplasmin and the biliary excretion of copper are abnormal, with the result that the serum free copper level is elevated, leading to a deposition of copper in the brain, the liver, and Descemet's membrane.

394 Specific disorders

Clinical features

The clinical features of Wilson's disease have been described in three large series (Dening and Berrios 1989; Starosta-Rubinstein et al. 1987; Walshe and Yealland 1992). The onset is typically between childhood and early adult years, and the presentation may be with a movement disorder, psychosis, personality change, or dementia, most patients eventually developing a combination of these features. The movement disorder may consist of dystonia, chorea, tremor, or parkinsonism; dysarthria may also appear. Dystonia may present with torticollis, dystonia of the upper or lower extremity, oculogyric crisis (Lee et al. 1999), or facial dystonia: classically, there is a fixed, vacuous, wide-mouthed dystonic smile. Chorea may involve either the upper or the lower extremities. The tremor may be rhythmic or irregular; at times, one may see the classic 'wingbeating' tremor wherein a rhythmic elevation and lowering of the upper extremities, combined with flexion at the elbows, gives an overall appearance of a frightened bird flapping its wings. Parkinsonism presents with rigidity of one or more extremities and may be accompanied by bradykinesia. Personality change is generally characterized by lability, disinhibition, and, at times, bizarre behavior (Bridgman and Smyth 1944; Dening and Berrios 1989; Walshe and Yealland 1992). Psychosis is characterized by hallucinations and delusions (Dening and Berrios 1989; Gysin and Cooke 1950) and may be quite bizarre, with Schneiderian first rank symptoms. Indeed, one of Wilson's (1912) patients heard 'God and the devil talking to him simultaneously' and said that he was 'influenced, willed or hypnotized to do certain things'. In one case (Davis and Borde 1993), stuporous catatonia dominated the presentation. The Kayser-Fleischer ring is a golden-brown discoloration of the corneal limbus, visible either on slit-lamp examination or to the naked eye. Although this Kayser-Fleischer ring is present in the overwhelming majority of cases, exceptions do occur of unequivocal Wilson's disease (with a movement disorder) without a Kayser-Fleischer ring (Demirkiran et al 1996). Hepatic damage may lead to clinical hepatitis, with fever, malaise abdominal pain, and an elevated transaminase level. With significant hepatic dysfunction, hepatic encephalopathy may occur (Starosta-Rubinstein et al. 1987). A Coombs-negative hemolytic anemia may occur. The ceruloplasmin and total serum copper levels are both low, but the serum free copper is elevated, as is the 24 hour urinary copper; in a small minority, the ceruloplasmin level may be normal. Liver biopsy reveals an elevated copper level. T2-weighted MRI scanning reveals increased signal intensity in the basal ganglia (particularly the putamen) and, to lesser degree, in the thalamus and dentate nucleus. Course Although there may be partial, temporary remissions, the overall course is one of progression, with death in 5-10 years. Differential diagnosis

Given the pleomorphic symptomatology of Wilson's disease, the differential diagnosis is large. In practice, given the availability of treatment, and the consequent importance of not missing the diagnosis, it is appropriate to test for Wilson's disease in any young person with a clinical presentation consistent with Wilson's disease that cannot be readily and fully accounted for by another disease process. One disorder in particular deserves mention as it may mimic Wilson's disease not only clinically, but also with respect to laboratory values: hereditary ceruloplasmin deficiency, like Wilson's disease, is characterized by low ceruloplasmin and total serum copper levels, but, unlike Wilson's disease, hereditary ceruloplasmin deficiency is characterized by a low 24 hour urinary copper level (Kawanami et al 1996).

Neurodegenerative disorders 395 Treatment

Treatment is aimed at decreasing the total copper burden, either by decreasing absorption or by removing copper by chelation treatment. Copper is found in shellfish, legumes, nuts, grains, coffee, chocolate, and organ meats, and these food should be avoided. Potassium iodide binds copper in the gut and may be given in a dose of 20-40 mg before meals. Zinc may also be given (Hoogenraad et al. 1987), in a dose of 50 mg between meals, and may be preferable to potassium iodide. Chelation may be accomplished with penicillamine, but, in a minority of patients, this agent exacerbates the symptoms (Starosta-Rubinstein et al. 1987) or, in those who are asymptomatic, may precipitate de novo symptoms (Brewer et al. 1994; Glass et al. 1990). Tetrathiomolybdate (Brewer et al. 1996) is preferable, as it does not exacerbate symptoms; it is, however, currently only available in experimental programs. Asymptomatic patients may be treated with dietary restriction and zinc (although zinc should not be given with penicillamine as it may complex with it, rendering it ineffective); should these measures fail to reduce the coppper burden, chelation therapy is considered. Patients requiring chelation treatment should probably be considered for tetrathiomolybdate. Improvement with chelation is slow, and a year or more may be required to see maximal improvement. In fulminant or treatment-resistant cases, liver transplantation (Bax etal. 1998; Stracciari et al. 2000) is a reasonable option. Siblings should be encouraged to undergo, at a minimum, serum and urine copper studies.

AUTOSOMAL DOMINANT CEREBELLAR ATAXIA (ADCA) Pathology and etiology

ADCA is an autosomal dominantly inherited syndrome that may occur secondary to mutations in any of a large number of different genes. Twelve different gene loci have been identified, including SCA1 on chromosome 6 (Goldfarb et al. 1989, 1996; Sasaki et al. 1996; Schols et al. 1997b; Tang et al. 2000), SCA2 on chromosome 12 (Adams et al. 1997; Burk et al. 1999; Giunti et al. 1998; Hsieh et al 1999; Schols et al. 1997a, b; Tang et al. 2000; Ueyama et al. 1998; Zhou et al. 1998), SCA3 (this ADCA also being known as Machado-Joseph disease) on chromosome 14 (Durr et al. 1996; Lopes-Cendes et al. 1996; Schols et al. 1996, 1997b; Takiyama et al. 1994; Tang et al. 2000; Zhou et al. 1997), SCA4 on chromosome 16 (Nagaoka et al. 2000), SCA5 on chromosome 11 (Stevanin et al. 1999), SCA6 on chromosome 19 (Arpa et al. 1999; Ikeuchi et al. 1997; Ishikawa et al. 1999; Kaseda et al. 1999; Matsumara et al. 1997; Schols et al. 1998; Stevanin et al. 1997), SCA7 on chromosome 3 (Benton et al. 1998; Jobsis et al. 1997; Modi et al. 2000), SCA8 on chromosome 13 (Ikeda et al. 2000), SCA10 on chromosome 22 (Matsuura etal. 1999), SCA11 on chromosome 15 (Worth etal. 1999), SCA12 on chromosome 5 (Seltzer etal. 1999), and SCAM on chromosome 19 (Yamashita etal. 2000). Some authors also include dentatorubropallidoluysian atrophy among the SCAs (specifying it as 'SCA9'}, but given that patients with dentatorubropallidoluysian atrophy may have little or no ataxia, this inclusion may not be warranted. Parenthetically, it may be added that the initials 'SCA stand for 'spinocerebellar ataxia' and that one may at times see this syndrome referred to as 'spinocerebellar ataxia' rather than ADCA. The pathologic hallmark of this syndrome is atrophy of the cerebellum, pons, and inferior olives; in addition to these findings, associated atrophy may also be found in one or more of the following structures: the spinocerebellar tracts, Clarke's column, the globus pallidus, the subthalamic nucleus, the substantia nigra, arid the cerebral cortex (Durr et al. 1996; Ikeuchi et al. 1997; Ishikawa et al. 1999; Jobsis et al. 1997; Takiyama et al. 1994).

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Clinical features

The clinical hallmark of ADCA, as described in the reports cited above, is the appearance of a gradually progressive cerebellar ataxia, which is generally accompanied by dysarthria and nystagmus. The onset, although generally in the early to mid-adult years, may occur anywhere from childhood to senescence. With disease progression, almost all patients will also develop one or more of the following associated features: hyperreflexia, extensor plantar responses; decreased vibratory sense, atrophy, fasciculations; supranuclear ophthalmoplegia; tremor (including titubation), dystonia, chorea, myoclonus or parkinsonism; dementia or psychosis; and, finally, pigmentary retinopathy. The plenitude of these associated features should not, however, distract attention from the central feature of this syndrome, namely a progressive cerebellar ataxia: the associated features, usually few in number in any given case, generally play only a minor part in the overall clinical picture. The occurrence of dementia or psychosis deserves emphasis as these associated features are often not described in texts. Dementia has been found in ADCA secondary to mutations at SCA1 (Sasaki etal 1996), SCA2 (Zhou et al 1998), SCA3 (Schols et al 1997b), SCA6 (Ikeuchi et al. 1997), and SCA7 (Modi et al. 2000). Psychosis, although apparently much rarer, may figure quite prominently, as in one family (Benton et al. 1998) in which 'progressive psychosis, auditory hallucinatons, delusions, and behavioral disturbances' were noted. Before leaving this discussion of clinical features, note should be taken of the scheme proposed by Harding (1982, 1984) that subclassified the ADCA syndrome into three different types, namely types III, II and I. Type III was described as being characterized solely by cerebellar signs, without any associated features. Types II and I, by contrast, did encompass associated features, the difference between type II and type I being that type II could be accompanied by pigmentary retinopathy, whereas type I cases were specifically free of this sign. The nosologic status of this proposed subdivision is, however, in doubt, on both clinical and etiologic grounds. From a clinical point of view, it appears that type III cases are exceeedingly rare, perhaps (with a sufficiently long follow-up) non-existent, and that, as between types II and I, 'type I' cases (that is to say, those with associated features but without pigmentary retinopathy) comprise the overwhelming majority of cases. From an etiologic point of view, it appears that the subdivision does not 'cleave' nature at the genetic 'joints', in that mutations at the same gene locus may cause two different clinical types (e.g. SCA6 being associated with both type III [Ishikawa et al. 1999] and type I [Schols et al 1998]). Given this nosologic uncertainty, it may be prudent, for the time being, to refrain from subtyping cases as III, II, or I, but rather to concentrate on being sure that one has a case of ADCA and then proceeding to identify which gene locus is responsible. Genetic testing is available. Interestingly, given wide phenotypic heterogeneity, it does not appear possible reliably to predict which SCA type is present based on the clinical picture (Giunti et al. 1998; Schols et al. 1998; Tang et al. 2000). MRI scanning may reveal atrophy of the cerebellum, pons, and inferior olives (Arpa et al. 1999; Ueyama et al. 1998). Course The disease is relentlessly progressive, death occurring within 15-30 years. Differential diagnosis

The olivopontocerebellar form of multiple system atrophy is distinguished by the presence of parkinsonism and evidence of autonomic failure, such as urinary incontinence, postural dizziness, or impotence, and by the absence of a family history. Dentatorubropallidoluysian atrophy may be clinically indistinguishable from some cases of ADCA, genetic testing being indicated.

Neurodegenerative disorders 397

Gerstmann-Straussler-Scheinker disease may also be difficult to distinguish from ADCA, and genetic testing is advised. Friedrich's ataxia is suggested by its early age of onset and recessive mode of inheritance; when there is any doubt, genetic testing is in order. Treatment

In one double-blind study (Botez et al. 1996), amantadine reduced ataxia in patients with SCA1 and SCA2 ADCA. The general treatment of dementia is discussed in Chapter 5 and of psychosis in Chapter 7. Genetic testing should be offered to at-risk relatives.

HALLERVORDEN-SPATZ DISEASE Pathology and etiology

Macroscopically, the globus pallidus is atrophic and exhibits a rust-brown discoloration. Microscopically, iron deposition and axonal spheroids are seen not only in the globus pallidus, but also in the pars reticulata of the substantia nigra and in the cerebral cortex (Dooling et al. 1974). Hallervorden-Spatz disease is inherited in an autosomal recessive fashion. Clinical features

The onset is gradual and may occur early, in childhood or adolescence, or late, anywhere from the third to the sixth decade. Early onset cases (Dooling et al. 1974, 1980) generally present with a slowly progressive dystonic rigidity (which usually begins in the lower extremities [Swaiman 1991]), which may be joined by tremor or choreoathetosis; eventually a dementia supervenes. Late onset cases may present with athetosis and tremor (Rozdilsky et al. 1968) or, more commonly, parkinsonism (Alberca et al. 1987; Jankovic et al. 1985), accompanied by dementia and dystonia. Rarely, late onset Hallervorden-Spatz disease may present with a dementia (Dooling et al. 1974; Rozdilsky et al. 1968), followed within years by a movement disorder, or with dementia accompanied by depression (Murphy et al. 1989). T2-weighted MRI scanning may demonstrate decreased signal intensity in the external segment of the globus pallidus and increased signal intensity in the internal segment, creating what has been termed the 'eye of the tiger' sign (Angelini et al. 1992). Course The disease is progressive, with death in from 10 to 15 years (Angelini et al. 1992; Dooling et al. 1974). Differential diagnosis

Early onset Hallervorden-Spatz disease must be distinguished from the Westphal variant of Huntington's disease, Wilson's disease, primary torsion dystonia, and dopa-responsive dystonia. The Westphal variant of Huntington's disease, which presents with rigidity, may be distinguished by the family history consistent with autosomal dominant inheritance and by genetic testing. Wilson's disease is suggested by Kayser-Fleischer rings and confirmed by abnormalities in copper metabolism. Primary torsion dystonia and dopa-responsive dystonia may be difficult to distinguish early on in the course of the disorder: the appearance of choreoathetosis or dementia points towards Hallervorden-Spatz disease, as would finding the 'eye of the tiger' sign on MRI scanning. Late onset Hallervorden-Spatz disease must be distinguished from other conditions presenting with parkinsonism in the adult years, such as Parkinson's disease, multiple system

398 Specific disorders

atrophy (striatonigral variant), and corticobasal ganglionic degeneration. Finding the 'eye of the tiger' sign is most helpful. Failing that, the differential diagnosis might rest on ascertaining such distinctive findings as ataxia and autonomic failure, which point toward multiple system atrophy, or apraxia, which points toward corticobasal ganglionic degeneration. Treatment

There is no known treatment; iron chelation therapy does not appear to be effective.

DOPA-RESPONSIVE DYSTONIA Pathology and etiology Depigmentation may be seen in the substantia nigra (Rajput et al. 1994). Dopa-responsive dystonia is an autosomal dominant condition with variable penetrance occurring secondary to a mutation of the gene responsible for the enzyme GTP cyclohydrolase I on chromosome 14 (Bandmann et al. 1998; Illarioshkin et al. 1998; Ohye et al. 1994). This enzyme is rate-limiting in the synthesis of tetrahydrobiopterin, which is in turn a co-factor for tyrosine hydroxylase, which, in turn, is the rate-limiting enzyme in the synthesis of dopamine. The net result is a fall in dopamine level. Clinical features

As described by Deonna (1986), Harwood et al. (1994), Nygaard and Duvoisin (1986), Nygaard et al. (1990, 1991), and Harwood et al. (1991), the onset is generally in childhood, with intermittent dystonia of the foot or lower extremity. Over time, other limbs are involved, including the other lower extremity and the upper extremities; the truncal and cervical musculature may also be affected. Importantly, in some cases, parkinsonism may also occur, with rigidity and bradykinesia, and although this usually happens only long after the dystonia has become established, the two may in some cases appear concurrently. A notable feature of the dystonia is diurnal variation: symptoms are usually least severe, and may be absent, in the morning after a night's sleep, only to worsen as the day progresses. Other presentations, in addition to this classic one, include dystonia of the upper extremity, hemidystonia, writer's cramp, and tremor (Bandmann et al. 1998; Tassin et al. 2000). Course

The dystonia gradually generalizes over a matter of 3 or 4 years. Differential diagnosis

Primary torsion dystonia is distinguished by an absence of parkinsonism. This point, however, may not be very helpful as some cases of dopa-responsive dystonia also lack parkinsonism, and in those which are charactererized by it, years may be required before it appears. More important, in diagnostic terms, is the fact that primary torsion dystonia does not respond to levodopa, whereas dopa-responsive dystonia does. Juvenile Parkinson's disease may present with dystonia and may thus be difficult to distinguish from levodopa-responsive dystonia; the concurrence of a progressive parkinsonism is suggestive (Tassin et al. 2000), but genetic testing may be required to settle the issue. Treatment

Both the dystonia and, if present, the parkinsonism are exquisitely sensitive to low-dose levodopa. Importantly, unlike the case with Parkinson's disease, the levodopa effect is not lost over time, nor is there generally a need to increase the dose (Nygaard et al. 1991).

Neurodegenerative disorders 399

PRIMARY TORSION DYSTONIA Pathology and etiology

Primary torsion dystonia (idiopathic torsion dystonia, dystonia musculorum deformans) is inherited in an autsomal dominant fashion (Bressman et al. 1989; Fletcher et al. 1990) with incomplete penetrance and is genetically heterogenous. Although DYT1 on chromosome 9 accounts for many cases (Kramer et al. 1990; Ozelius et al. 1992), it is clear that some otherwise clinically typical patients do not carry a mutation here (Bentivoglio et al. 1997; Lebre et al. 1999; Valente et al. 1998). Another locus, named DYT6, has recently been located on chromsome 8 (Almasy et al. 1997). Although autopsy studies have generally been unrevealing, two cases have shown a reduced concentration of norepinephrine in the hypothalamus, subthalamic nucleus and locus ceruleus (Hornykiewicz et al. 1986). Clinical features

Clinically (Johnson et al. 1962; Marsden and Harrison 1974), the onset is gradual and often insidious, typically occurring between the ages of 5 and 15 years. Although the initial dystonia may first be seen in the upper extremities, or rarely even in the face, the initial manifestation in most cases is in the lower extremities. Typically, and only intermittently, the young patient may, while walking, experience some dystonic inversion and plantar flexion of the foot. Curiously, this dystonia is not present at rest, and it may also be absent with walking backwards or with dancing. Over time, however, the dystonia becomes more frequent and begins to involve more proximal portions of the lower extremities, often with flexion at the knees and hips. With progression of the disease, the dystonia becomes more and more constant and spreads not only to the upper extremities, but also to the trunk, producing lordosis and tortipelvis. In a small minority, the face may be involved, with dystonic grimacing. Formes frustes of dystonia musculorum deformans may exist in family members and may present with focal or segmental dystonias (Bressman et al. 1989; Fletcher et al. 1990; Gasser et al. 1998; Johnson et al. 1962). Genetic testing is available for the DYT1 type and should be considered in any patient with an early onset dystonia that has generalized (Brassat et al. 2000; Bressman et al. 2000). Course In most cases, there is progressive worsening for some 5 or 10 years, followed by a more or less static course; in a very small minority, remissions may occur, which, except in rare instances, are only temporary. Differential diagnosis

Dopa-responsive dystonia may, early in the course, be indistinguishable from primary torsion dystonia, and some authors recommend a 'diagnosis by treatment response' by observing the effects of levodopa. Perinatal asphyxia may cause generalized dystonia. When the dystonia first appears in infancy, there is little diagnostic confusion with primary torsion dystonia, which has an onset after the age of 5; in a minority of these cases, however, the onset of dystonia secondary to asphyxia may be delayed until childhood or adolescence (Burke et al. 1980), and, in such cases, the diagnosis may rely on genetic testing. Wilson's disease may, rarely, present in a fashion very similar to that of primary torsion dystonia, and copper testing is probably appropriate. Likewise, Hallervorden-Spatz disease may also be difficult to distinguish, and MRI testing is probably advisable here.

400 Specific disorders

Treatment

Trihexyphenidyl is often beneficial and may be started at 5 mg/day, increasing in 5 mg increments weekly until the symptoms are relieved or unacceptable side-effects occur: children are often able to tolerate very high doses (Burke et al. 1986). Thalamotomy may be considered in severe cases.

IDIOPATHIC CERVICAL DYSTONIA Pathology and etiology

Idiopathic cervical dystonia, often in the past referred to as 'spasmodic torticollis', is a familial disorder (Bressman et al. 1996; Chan et al. 1991; Jankovic et al. 1991) that has, in some cases, been shown to occur secondary to a mutation at the DYT7 locus on chromsome 18 (Leube et al 1997). Clinical features

Clinically (Chan et al. 1991; Jankovic et al. 1991; Rondot et al. 1991; Sorensen and Hamby 1966), the onset is generally between the ages of 30 and 50 with some intermittent dystonia of the neck musculature, pulling the head into a dystonic posture. The most common position is torticollis, the head being rotated to one side or the other; other positions, in order of decreasing frequency, include lateralcollis, with the head tilted to one side, retrocollis, with the head bent back, or anterocollis, with the head pulled down toward the chest. Isolated positions are the exception: most patients exhibit a combination, such as torticollis and lateralcollis. Pain is a common accompaniment. In most cases, patients are able to use a geste antagonistique to temporarily relieve the dystonia (Jahanshahi 2000). These 'tricks' consist of lightly touching a specific body part, such as the chin, face or occiput, with a prompt relief of the dystonic stiffness. Over time, the dystonia becomes more constant and sustained, and will, in a minority, undergo segmental spread to an adjacent part such as the arm. Tremor, similar to that seen in essential tremor, is present in a substantial minority of patients. Course In most cases, the course is chronic: although remissions do occur in a small minority (Chan et al. 1991; Friedman and Fahn 1986; Jayne et al. 1984), they are often only temporary. In a minority of cases, the sustained dystonia leads to hypertrophy of the involved muscle or to cervical spondylosis. Differential diagnosis

Formes frustes of idiopathic torsion dystonia may be characterized by cervical dystonia, the diagnosis being suggested by the positive family history of childhood onset generalized dystonia. Cervical dystonia may occur secondary to a multitude of causes, including tardive dykinesia, posterior fossa tumors (Krauss et al. 1997), spinal tumors, cervical spondylosis, cervical subluxation, and local muscle trauma; in one exceptional case, it was also associated with a frontal meningioma (Soland et al. 1996). Treatment

The local injection of botulinum toxin (Greene et al. 1990) is effective, and although some patients may benefit from treatment with trihexyphenidyl, botulinum toxin is more effective (Brans et al. 1996).

Neurodegenerative disorders 401

WRITER'S CRAMP Pathology and etiology

Writer's cramp (occupational dystonia, task-specific dystonia) generally appears on a sporadic basis and is of unknown cause; a few cases, however, are caused by mutations at the DYT7 locus on chromosome 18. Clinical features

Although the term 'writer's cramp' has wide currency, it may be more accurate to speak of this disorder as 'occupational dystonia' or 'task-specific dystonia', as the task in which the dystonia makes its appearance, although most often writing, may be any of a number of highly skilled movements, such as playing the violin or typing. Clinically (Cohen and Hallett 1988; Sheehy and Marsden 1982), the onset is generally in the early to mid-adult years as the patient begins to experience cramping in the hand during the execution of a highly skilled and wellrehearsed movement. The cramping may initially occur only with fatigue or only intermittently and well after the task has been begun; with time, however, the hand may be affected immediately upon beginning the task, for example when picking up the pen, regardless of whether or not the patient is fatigued. Importantly, as soon as the patient abandons the task, the cramping ceases. The cramping is itself in fact a dystonia, and, in some cases, the dystonia may spread up to the forearm or even higher. Furthermore, and again over time, other, simpler tasks, for example buttoning a shirt or using a knife or fork, may trigger the dystonia. The dystonic cramping may also be accompanied by a tremor (Rosenbaum and Jankovic 1988). Course In general, the condition worsens over a few years and then remains static; only in a small minority does spontaneous remission occur. Differential diagnosis

Writer's cramp may occur as a forme fruste of dystonia musculorum deformans, a diagnosis suggested by a family history of childhood onset generalized dystonia or by an onset of the writer's cramp in childhood or adolescence (Gasser et al. 1998). Treatment

Some patients will learn to write with the non-dominant hand; unfortunately for these patients, the dystonia may eventually appear in that hand too. Botulinum toxin injections may help (Rivest et al. 1991) but are not as effective as they are in other dystonias.

MEIGE'S SYNDROME Pathology and etiology

Meige's syndrome, as described by the French neurologist Henri Meige (Tolosa and Klawans 1979), is an inherited disorder probably related to dysfunction within the basal ganglia. Clinical features

Clinically (Grandas et al. 1988; Paulson 1972; Tolosa 1981) speaking, the onset is usually in the middle years, the primary symptom being one of bilateral blepharospasm. The blepharospasm initially is neither prolonged nor frequent, but over time it becomes persistent, forceful, and

402 Specific disorders

at times almost constant. Over a year or two, the adjacent musculature, especially the jaw and mouth, may also become involved, and in a small minority, the neck musculature may likewise be affected (Defazio et al. 1999). The blepharospasm may be worsened by bright light, or sometimes by walking, and may be lessened by yawning, talking, or singing (Weiner and Nora 1984). Gestes antagonistiques, such as touching the eyebrow or the temple, may also relieve the blepharospasm. Course In general, the symptoms worsen over the first few years and remain generally static thereafter. In some 15% of cases, the symptoms may be so severe as to render patients functionally blind. Differential diagnosis

Blepharospasm may occur as a forme fruste of dystonia musculorum deformans (Bressman et al. 1994; Ozelius et al. 1989), a diagnosis suggested by the family history of childhood onset generalized dystonia. Brueghel's syndrome, a focal dystonia, is distinguished by an involvement of the oromandibular musculature alone, without any associated blepharospasm (Gilbert 1996). Blepharospasm may also occur secondary to lesions in the basal ganglia (Jankovic 1986) or brainstem (Jankovic and Pat el 1983). Tardive dyskinesia, as described in Chapter 22, may also cause blepharospasm. Hemifacial spasm is distinguished by its unilateral occurrence, and facial tics by their fleeting, unsustained nature. Ocular pathology, such as inflammation of the lids, conjunctiva or iris, may cause blepharospasm. Treatment

Botulinum toxin injection is generally the most successful treatment; medications that may help in some patients include anticholinergics, baclofen or clonazepam.

SPASMODIC (SPASTIC) DYSPHONIA Pathology and etiology

Spasmodic dysphonia is one of the focal dystonias and is characterized by dystonic contraction of either the abductor or adductor muscles of the larynx, with, respectively, either forced closure or forced opening of the vocal cords. Clinical features

The onset is usually in middle age or later. Clinically (Aminoff et al. 1978; Bicknell et al. 1968; Pool et al. 1991) the symptoms depend on the kind of dystonia present: with adductor spasm, the voice is strained, coarse, and strangled, often being broken by pauses, whereas with abductor spasm, the voice is quiet and breathless. The adductor type is most common, followed by a mixture of the two, the abductor type being least common. In many cases, a voice tremor will also be present. Course After a short period of progression, the course is generally static. Differential diagnosis

Lesions of the vagus or recurrent laryngeal nerve may cause hoarseness, as may laryngitis. Patients with chronic obstructive pulmonary disease, especially the emphysematous type, often have a 'breathy' voice, and patients with parkinsonism will often have hypophonia.

Neurodegenerative disorders 403 Treatment

Botulinum injections may be very helpful, but may be difficult to perform (Ludlow 1990).

TOURETTE'S SYNDROME Pathology and etiology Most cases of Tourette's syndrome are inherited on an autosomal dominant basis with incomplete penetrance (Eapen et al. 1993; Pauls and Leckman 1986; Pauls et al. 1990); a recent study found evidence for serum antibodies directed against the putamen in such cases (Singer et al. 1998). Of the minority that occur on a sporadic basis (Pauls and Leckman 1986), an uncertain number may occur as a sequel to an autoimmune assault on the basal ganglia occurring during the course of rheumatic fever (Swedo et al. 1998). MRI studies strongly suggest a reduced size of the basal ganglia (Hyde et al. 1995; Peterson et al. 1993; Singer et al. 1993), and one autopsy report found reduced dynorphin staining in the basal ganglia (Haber et al. 1986). Of interest, another study found increased levels of dynorphin in the cerebrospinal fluid (Leckman et al. 1988). Another indication of pathology in the basal ganglia is an autopsy study by Singer et al. (1991), which demonstrated a decreased number of dopamine reuptake sites in the striatum. Clinical features

The first tic usually appears in childhood, around the age of 7; the range is, however, wide, from infancy to the adult years (Marneros 1983). In clinical terms (Cardoso et al 1996; Lang et al. 1993; Lees et al. 1984; Nee et al. 1980; Regeur et al. 1986), Tourette's syndrome is, in its fully developed form, characterized by motor tics, vocal tics, and, in a significant minority, sensory tics. Motor tics are usually the first to appear and may be either simple or complex. Simple motor tics include blinking, brow-wrinkling, grimacing and shoulder-shrugging; complex motor tics may include touching, smelling, hopping, throwing, clapping, bending over, squatting, or even such very complex acts as echopraxia or copropraxia, wherein patients make obscene gestures. Motor tics usually appear first in the face or head and then spread in a caudal direction. In most cases, patients, before having a tic, experience first an urge to tic (Lang 1991), an urge that may, albeit with difficulty, be at times resisted. Furthermore, some patients are able to abort a motor tic with ageste antagonistique, such as placing a hand under the chin to prevent the emergence of a tic of the head (Wojcieszek et al. 1995). Vocal tics, like motor tics, may also be simple or complex. Simple vocal tics include snorting, hissing, coughing, throat-clearing, grunting, and, classically, barking. Complex vocal tics include the utterance of words, simple phrases, or entire sentences. Echolalia or pallilalia may occur, and, in about 10%, classic coprolalia, or involuntary swearing, may be seen. Sensory tics appear in a significant minority of patients and appear to exist in two forms. In one, there is simply the experience of an itch or a tingle (Chee and Sachdev 1997); in the other, the sensory tic appears more as a premonitory urge to a motor tic (Cohen and Leckman 1992; Leckman et al. 1993). Remarkably, in one case, a premonitory urge to itch was experienced by a patient as residing in another person, whom the patient then proceeded to scratch (Karp and Hallett 1996). Attention deficit disorder with hyperactivity very commonly accompanies Tourette's syndrome, and in those cases of Tourette's syndrome in which it does occur, the hyperactivity usually precedes the tics by a little over a year (Cardoso et al. 1996). Obsessions and compulsions begin to appear 5 or more years after the onset of tics, eventually being seen in close to one-half of all patients (Frankel et al. 1986; Robertson et al.

404 Specific disorders

1988). Interestingly, compulsions experienced by patients with Tourette's syndrome often center on getting things 'just right' (Leckman et al. 1994). Rarely, dystonic movements, especially cervical or facial dystonias, may appear in the course of Tourette's syndrome, but not until 10-38 years have passed (Stone and Jankovic 1991). Course

Although Tourette's syndrome is, in general, a lifelong illness, most patients experience a partial remission in the early adult years. Occasionally, full remissions may occur, which may, in some, be followed by relapses years or decades later (Klawans and Barr 1985). Differential diagnosis A diagnosis of Tourette's syndrome should technically not be made until the patient has both motor tics and vocal tics: those with only motor or only vocal tics are said to have 'transient tic disorder' if the tics last no longer than a year or 'chronic motor or vocal tic disorder' if they last longer than a year. This distinction may be unwarranted, however, as it appears that these 'disorders' merely represent formes frustes of the full Tourette's syndrome (Golden 1978; Kurlan et al/. 1988). Autism may present with tics but is distinguished by the peculiar 'machine-like' quality of the patients' relations with others. Sydenham's chorea may include tics but is differentiated by the concurrent chorea and, in most cases, by other evidence of rheumatic fever. Stimulants, such as methylphenidate, may cause tics, and lamotrigene has been noted to cause a combination of motor and vocal tics (Lombroso 1999). Tardive dyskinesia may present primarily with tics, producing a 'tardive Tourette's'. However, as noted in Chapter 22, these cases are accompanied by chorea, which is not found in Tourette's syndrome. Overall, the de novo appearance of tics in an adult argues against a diagnosis of Tourette's syndrome; one must recall, however, that patients with Tourette's may experience a remission in adolescence, only to have a recurrence in the adult years (Chouinard and Ford 2000), a fact that emphasizes the importance of taking a careful history in evaluating adults with tics. Treatment Both neuroleptics and clonidine may be employed to reduce the severity and frequency of tics. Of the neuroleptics, both haloperidol and pimozide are effective (Shapiro et al. 1989), pimozide being somewhat superior to haloperidol (Sallee et al. 1997); risperidone has shown promise in an open study (Bruun and Budman 1996). Haloperidol may be started at 0.25-0.5 mg/day and increased in 0.5 mg increments every week until satisfactory control, unacceptable side-effects or a maximum dose of approximately 10 mg is reached. Pimozide, given the risk of cardioxicity, is generally held in reserve, but may be initiated at 1 mg/day, with an incremental increase of 1 mg per week until one of the same endpoints employed for haloperidol is reached. When a neuroleptic is used, one must watch closely for an akathisia as it may increase tic severity (Weiden and Bruin 1987). Clonidine, although superior to placebo in some (Cohen et al. 1980; Leckman et al. 1991), but not all (Goetz et al. 1987), double-blind studies, is probably not as effective as a neuroleptic. If used, it should be started at 0.1 mg/day and increased in 0.1 mg increments every few days until satisfactory control, unacceptable side-effects, or a maximum dose of about 1.0 mg has been reached; divided doses are generally required. There is debate over whether to start with a neuroleptic or clondine: given the risk of tardive dyskinesia, it may be prudent to try clonidine first. As noted earlier, attention defiict disorder with hyperactivity is commonly seen in patients with Tourette's syndrome, and this creates a dilemma. Stimulants, such as methylphenidate,

Neurodegenerative disorders 405

may cause tics (Denckla et al. 1976), and should thus, on the face of it, not be used. However, it appears that, in practice, the increase in tics is minimal (Gadow et al. 1992,1999) and offset by the overall improvement in the patient's behavior.

MYOTONIAATROPHICA Before discussing myotonia atrophica, a word on nomenclature is in order. Myotonia atrophica is the classically described hereditary disease characterized by myotonia and muscle weakness (Batten and Gibb 1909), and for many years this disease has also been referred to as 'mytonic dystrophy'. Recently, however, other disorders, also characterized by myotonia and weakness, have also been recognized, and, prompted by this, the International Myotonic Dystrophy Consortium (2000) recently decided to expand the definition of the term 'myotonic dystrophy' to include not only myotonia atrophica, but also these other, newly recognized disorders, and to rename them 'DM type 1' (equivalent to the classic myotonia atrophica), 'DM type 2', etc. The Consortium, however, did not forbid the use of the traditional nomenclature, and it is retained in this text. Pathology and etiology

Myotonia atrophica is inherited as an autosomal dominant disorder with variable expression but almost 100% penetrance. The gene responsible codes for an enzyme known as myotonin protein kinase and is located on chromsome 19; the mutation consists of an increase in a CTG trinucleotide repeat (Brook et al. 1992). Within the central nervous system, a variable number of neuronal heterotopias may be found in the cerebral cortex (Rosman and Kakulas 1966). As noted below, some patients will experience hypersomnia, and in these patients, there is a loss of serotonin-containing neurons in the dorsal raphe and superior central nuclei of the midbrain (Ono et al. 1998); furthermore, and also as noted below, some patients also are at risk for alveolar hypoventilation, and in these cases, cell loss is found in the reticular formation of the medulla (Ono et al. 1996). Clinical features

The onset is gradual and insidious; most fall ill in their late teens or early twenties, but the range of onset is wide, from childhood up to the sixth decade. The first symptom is often myotonia, and patients may report difficulty in letting go of doorknobs or disengaging from a handshake. 'Percussion' myotonia may be elicited with a brisk tap of a reflex hammer on the thenar eminence or on the anterior surface of the forearm. As noted earlier, the degree of expression of myotonia atrophica is quite variable, even within the same family, some members evidencing only partial, and often quite mild, symptomatology (Pryse-Phillips et al. 1982). Fully expressed cases are characterized by a distinctive 'myopathic fades' composed of frontal baldness, ptosis, and wasting of the facial and neck musculature. Pharyngeal weakness may cause the patient to speak in a nasal, monotone voice. Atrophy and weakness are most pronounced distally and are evident first in the upper, followed by the lower, extremities. Cataracts are seen at some point in over 90% of patients, and indeed, in some cases, may be the only evidence of the disease. A varying degree of deafness (Wright et al. 1988) is also common, and there may be gonadal failure, with impotence in the male and menstrual irregularity in the female. Cardiac conduction defects are common, including atrioventricular block, fascicular block, and intraventricular delays; ventricular arrythmias may occur, as may sudden cardiac death. Occasionally, there may be a cardiomyopathy, with congestive failure.

406 Specific disorders

Hypersomnia is not uncommon (Manni et al. 1991) and may be the presenting symptom of the disease (Hansotia and Frens 1981): some patients may literally sleep for days (Phemister and Small 1961). Although some of these hypersomnic patients demonstrate sleep apnea (of either the central or obstructive type), the number of apneic episodes is not high enough to account for the degree of hypersomonolence (van der Meche et al. 1994). A majority of patients with myotonia atrophica will evidence some decrement in intellectual functioning (Perini et al. 1989), and in a minority, dementia will occur (Huber 1989). Personality change may also occur, and appears to be of a mixed, non-specific type (Delaporte et al. 1998). Apathy appears to be more common in myotonia atrophica than among comparable controls (Rubinsztein et al. 1998). Although depression may occur, it appears, in contrast to apathy, to be no more common among these patients than comparable controls: in considering the diagnosis of depression, one must guard against misinterpreting the expressionless 'myopathic fades' as a depressed affect (Adie and Greenfield 1924; Billings and Ravin 1941; Bungener et al. 1998). Myotonia atrophica may demonstrate the phenomenon of anticipation (Harper et al. 1992; Howeler et al. 1989), wherein subsequent generations have an earlier onset or more severe disease. In the case of children born of mothers with myotonia atrophica, a substantial minority will be afflicted with severe congential myotonia atrophica (Koch et al. 1991). Rarely, congenital myotonia atrophica will also occur with paternal inheritance (Nakagawa et al. 1994) CT scanning may reveal some cortical atrophy (Avrahami et al. 1987). Genetic testing is also available. Course Although myotonia atrophica is progressive, the rate of progression is quite variable: in severe cases, death, often from respiratory failure, may occur within 15-20 years, whereas in mild cases, the life span is normal, and there is little if any disability. Differential diagnosis

Although myotonia atrophica is the most common of the inherited myotonic dystrophies, others also exist, the best described of which is known as 'PROMM'. PROMM (Proximal Myotonic Myopathy) (Ricker et al. 1994) is characterized by proximal muscle weakness, myotonia and cataracts, without any associated baldness or facial wasting, and is inherited in an autosomal dominant fashion with a genetic locus on chromsome 3 (Ricker et al. 1999). From a differential diagnosis point of view, the location of the weakness and wasting is most important: proximal in PROMM (Ricker et al. 1995) and distal in myotonia atrophica. Myotonia congenita is an inherited, non-progressive condition characterized by myotonia and a degree of muscular hypertrophy; autosomal dominant cases are referred to as Thomsen's disease and recessive cases as the Becker variant. Since the phenomenon of myotonia may be the only symptom of myotonia atrophica for many years, the clinical differential between myotonia congenita and mytonia atropica may depend on long-term follow-up, watching closely for other symptoms to appear (Maass and Paterson 1950). Treatment

Although phenytoin, quinidine, or procainamide will reduce myotonia, these are generally not used, for two reasons: first, the myotonia per se is generally not troublesome enough to warrant treatment, and second, the side-effects of these agents often outweigh their benefit, especially in the case of quinidine-like drugs, which may increase the risk of arrythmia. Although there is no specific treatment for the muscular atrophy and weakness, various support devices or orthotics are very useful. The hypersomnia may respond to

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methylphenidate. There is no specific treatment for the dementia; general measures being discussed in Chapter 5. Should third-degree atrioventricular block occur, a pacemaker may be considered. Patients with myotonia atrophica are liable to alveolar hypoventilation, placing them at risk during any operative procedures that require general anesthesia.

CEREBROTENDINOUS XANTHOMATOSIS Pathology and etiology

Cerebrotendinous xanthomatosis is an autosomal recessive disorder occurring secondary to any of a large number of different mutations (Verrips et al. 2000a) in the gene, located on chromosome 2, for the mitochondrial enzyme sterol 27-hydroxylase. It is characterized (Menkes et al. 1968) by a progressive deposition of cholestanol in the brain, peripheral nerves, lens, and tendons. Cholestanol accumulation within myelin is followed by demyelinization in the cerebrum, cerebellum, and brainstem, with, in some cases, the formation of xanthomas (Schimschock et al. 1968). The accumulation of cholestanol and cholesterol in the lens causes cataracts, deposition in the tendons leading to tendon enlargement, which is particularly common in the Achilles tendon. Clinical features

The onset is gradual, anywhere from infancy to the middle adult years, and although most fall ill in late childhood or early adolescence, late onsets, as late as the age of 49 (Swanson and Cromwell 1986), have been reported. The disease may present with dementia (or, in cases of infantile onset, mental retardation [Fierello et al. 1990]), tendon enlargement, or cataracts (Farpour and Mahloudji 1975). The dementia is often accompanied by ataxia and long tract signs such as hyperreflexia and extensor plantar responses; a mixed sensorimotor peripheral polyneuropathy is common, and seizures may occur in a minority (Bencze et al. 1990; Farpour and Mahloudji 1975; Soffer et al. 1995; Verrips et al. 2000a; Watts et al. 1996). It has recently become apparent that intractable, chronic diarrhea is also very common (Verrips et al. 2000b). Tendon enlargement, although most common in the Achilles tendon, may also occur in the toes, fingers, and lumbosacal region (Canelas et al. 1983). Critically, the interval between the appearance of the various symptoms may be quite long: in one case, for example, cataracts appeared at age 9 and Achilles tendon enlargement at 18, dementia, ataxia, and a peripheral neuropathy eventually following at the age of 33 (Bencze et al 1990). CT or MRI scanning may reveal evidence of demyelinization (Swanson and Cromwell 1986), and xanthomas may in some cases be seen in the cerebellum or cerebrum. The cholesterol level is generally normal, whereas the serum cholestanol level is elevated (Salen 1971). Genetic testing may be accomplished with a polymerase chain reaction assay (Meiner et al. 1994). Course

Although cerebrotendinous xanthomatosis is progressive, the rate of progression varies fairly widely: those with severe, childhood onset disease may survive for only 10 or 20 years, whereas those with mild, adult onset disease may experience little disability and live out a normal life span.

408 Specific disorders

Differential diagnosis The combination of dementia and Achilles tendon enlargement is almost pathognomonic, the onset of dementia in the setting of early onset cataracts or intractable chronic diarrhea also being very suggestive. When dementia appears independently of other symptoms, finding widespread demyelinization in the cerebellum and cerebrum is highly suggestive. Treatment

Chenodeoxycholic acid (Berginer et al. 1984) may either retard the progression of the disease or, in some cases, lead to a partial remission. Genetic counseling should be made available. THALAMIC DEGENERATON Pathology and etiology

Thalamic degeneration is probably best conceived of as a syndrome of multiple different etiologies, all of which have in common degenerative changes that, although by far most prominent in the thalamus, may also be seen in other areas of the brain. Thus, degenerative changes have been noted, in addition to the thalamus, in the cerebral cortex, cerebral white matter, and inferior olives (Stern 1939) as well as in the basal ganglia and nucleus basalis of Meynert (Moosey et al. 1987). Within the thalamus, although all the nuclei may be involved, the dorsomedial (Moosey et al. 1987) and anterior (Martin et al. 1983) nuclei seem hardest hit. Both familial (Little et al. 1986) and sporadic cases have been reported. Clinical features

As might be expected, the clinical presentation of this syndrome exhibits considerable variability (Martin et al. 1983), the age of onset ranging from late adolescence to the seventh decade, and the mode of onset ranging from subacute to insidious. Dementia is a common denominator in all cases, and this may be accompanied by apathy and somnolence (Stern 1939), emaciation (Martin et al. 1983), or myoclonus (Little et al. 1986). In one case (Deymeer et al. 1989), a 46-year-old female presented with 'bizarre behavior and paranoid ideas', eventually followed by a dementia accompanied by fasciculations. Course Survival ranges from a matter of several months (Stern 1939) to up to 20 years (Martin et al. 1983). Differential diagnosis

Given the variable, and at times non-specific, clinical features of this syndrome, ante mortem diagnosis is difficult: finding selective involvement of the thalamus on MRI scanning would be suggestive, but other disorders, such as Creutzfeldt-Jacob disease or fatal familial insomnia, would also have to be considered. Treatment

The general treatment of dementia is discussed in Chapter 5; there is no available specific treatment. METACHROMATIC LEUKODYSTROPHY Pathology and etiology Metachromatic leukodystrophy is an autosomal recessively inherited disorder occurring, in almost all cases, secondary to a mutation of a gene on chromosome 22 that encodes the

Neurodegenerative disorders 409

enzyme arylsulfatase A (Earth et al. 1993): with reduced activity of arylsulfatase A, sulfatides accumulate in various organs, especially the nervous system, kidney, and gallbladder. Within the central nervous system, sulfatide accumulation is prominent in oligodendroglia, and within the peripheral nervous system, Schwann cells are affected, with consequent central and peripheral demyelinization. Rarely, metachromatic leukodystrophy will occur secondary to a mutation of a gene on chromsome 10 that codes for a sulfatide activator protein (Schlote et al. 1991), which acts as a cofactor for arylsulfatase A. Within the brain, there is widespread demyelinization in the centrum semiovale, with relative sparing of the U fibers: in advanced cases, the centrum semiovale may be shrunken down to a thin gliotic remnant, with very little distance between the depths of the sulci and the underlying ventricles. The cerebellar white matter is also heavily affected. Sulfatide accumulation in tissues causes the phenomenon of metachromasia upon staining: both toluidine and cresyl violet undergo a chromatic metamorphosis, turning from blue or violet to a brown or golden color, respectively. Clinical features

Metachromatic leukodystrophy is of insidious onset and may occur in any one of three forms: late infantile, juvenile or adult. Late infantile onset metachromatic leukodstrophy (Brain and Greenfield 1950) presents within the first 2 years of life with weakness, hypotonia, and seizures. Juvenile onset metachromatic leukodystrophy (Haltia et al. 1980) presents between the age of 5 and early adolescence, often with a dementia: school performance falls, and there may be a personality change. Other symptoms include ataxia and seizures. Adult onset metachromatic leukodystrophy may present any time from adolescence to the seventh decade (Bosch and Hart 1978). The presenting symptomatology (Hageman et al. 1995) may include personality change, dementia, ataxia, spasticity or a peripheral polyneuropathy: as noted below, adult onset metachromatic leukodystrophy may also present with psychosis. Personality changes seen at the presentation of metachromatic leukodystrophy include (Austin et al. 1968; Finelli 1985; Trojaborg 1985; Wulff and Hageman et al. 1995) irritability, socially inappropriate behavior, and a general neglect of personal affairs. Dementia seen at the onset of metachromatic leukodystrophy may be accompanied by ataxia (Alves et al. 1986; Hirose and Bass 1972; Reider-Grosswasser and Bornstein 1987) or a peripheral polyneuropathy (Bosch and Hart 1978), and may be marked by frontal lobe symptoms such as 'disinhibition, impulsivity, poor judgment, [and] emotional lability' (Shapiro et al. 1994). When metachromatic leukodystrophy presents with a psychosis, the clinical picture may be very reminiscent of schizophrenia. One patient developed bizarre delusions, auditory hallucinations, loosening of associations, and flat affect at the age of 19, and the diagnosis became apparent only 12 years later when a peripheral polyneuropathy was noted (Manowitz et al. 1978). Another, at the age of 28, developed 'bizarre elation, true auditory hallucinations, and poorly formulated paranoid ideas', followed by a gradually progressive dementia over the next 4 years (Betts et al. 1968). In a third example (Waltz etal. 1987), a 31-year-old male began to talk to himself and pace the floor; he was eventually fired from his job, and his wife left him; by the age of 38, he had 'poor concentration, inappropriate smiling and laughing, ... irrelevant remarks ... with nonsequiturs, restlessness and occasional auditory hallucinations'. The diagnosis was eventually suggested when nerve conduction velocity studies showed mild slowing. In some cases, the psychosis may have a distinct manic flair: one patient (Besson 1980) was 'grandiose ... and called out the fire brigade', and another (Van Bogaert and Dewulf 1939)

410 Specific disorders

'had ideas of grandeur, thought he was going to become an ambassador and gave himself honorary titles'. In both these cases, the patient eventually became demented. Regardless of how adult onset metachromatic leukodystrophy presents, most patients end up with a dementia accompanied by ataxia, paraparesis, polyneuropathy, or seizures (Hageman et al. 1995). The dementia itself is accompanied by hallucinations or delusions in about one-third of cases (Hyde et al. 1992). T2-weighted MRI scanning (Reider-Grosswasser and Bornstein 1987) reveals diffuse increased signal intensity in the centrum semiovale, which is often quite shrunken, with little separation between the depths of the sulci and the underlying ventricles. Aryl sulfatase A activity may be measured in the leukocytes and is depressed in all cases. However, as noted below, depressed arylsulfatase A activity may be found in a small percentage of the general population so this finding must be followed up with testing for metachromasia, in either the urinary sediment or a sural nerve biopsy. Course

Metachromatic leukodystrophy is slowly progressive, with a fatal outcome in from 2-10 years for infantile and juvenile onset forms, and up to 15 years or more for adult onset cases. Differential diagnosis 'Pseudodeficiency' of arylsulfatase A is seen in several per cent of the general population (Nelson et al. 1991). In such individuals, even though there is a reduction in arylsulfatase A activity, there are no symptoms, no sulfatide accumulation, and thus no metachromasia (Hageman et al. 1995). Juvenile onset metachromatic leukodystrophy must be distinguished from adrenoleukodystrophy: visual symptoms suggest adrenoleukodystrophy. Adult onset metachromatic leukodystrophy may occasion different differential diagnostic problems depending on its presentation. The dementia, when marked by frontal lobe symptoms, may suggest Pick's disease, whereas if marked by ataxia, consideration might be given to multiple system atrophy or a sporadic case of autosomal dominant cerebellar ataxia. The psychosis, when unaccompanied by other symptoms, such as ataxia or a peripheral polyneuropathy, may be difficult to distinguish from schizophrenia. Treatment Bone marrow transplantation may retard or halt the progression of the disease (Kidd et al. 1998; Krivit et al. 1987; Navarro et al. 1996). Neuroloeptics may be required for psychotic symptoms.

ADRENOLEUKODYSTROPHY Pathology and etiology Adrenoleukodystrophy is one of the peroxisomal disorders and is characterized by a mutation in the gene coding for a peroxisomal membrane-associated protein (Mosser et al. 1994), resulting in the accumulation of very long-chain fatty acids in various tissues, most notably the central nervous system and the adrenal cortex. Adrenoleukodystrophy is inherited in an Xlinked recessive pattern, the full syndrome thus being seen only in males; a minority of female carriers, will however, develop very mild symptoms. Within the brain (Schaumburg et al. 1975), one typically finds an advancing wave of demyelinization that begins in the occipital lobe and then moves forwards into the parietal and temporal lobes; the frontal lobes are broached in only a minority. An inflammatory response is seen at the border between the demyelinization and the normal tissue, behind

Neurodegenerative disorders 411

which much of the white matter is replaced by gliotic tissue. Importantly, the subcortical U fibers are generally spared, as is the gray matter. Demyelinization also occurs in the spinal cord, especially in the corticospinal tracts, and the peripheral nerves may also be involved, albeit generally to a much lesser extent. Clinical features

Clinically (Moser et al. 1984), adrenoleukodystrophy may be characterized according to either age of onset or primary site of pathology. Thus, onset may be in childhood (at an average age of 8 years), adolescence, or the adult years, and the primary site may be cerebral, spinal, or adrenal. Childhood onset adrenoleukodystrophy usually presents with cerebral symptomatology, often with a personality change and visual symptoms. These patients may become withdrawn and irritable, their school performance beginning to decline. Varying degrees of hemianopia or cortical blindness may occur, followed by a dementia accompanied by spasticity (Moser et al. 1984; Schaumburg et al. 1975). Adolescent onset adrenoleukodystrophy tends to present in a fashion similar to that of the childhood onset form. Adult onset adrenoleukodystrophy tends to present with spinal symptoms in a syndrome known as adrenomyeloneuropathy (Griffin et al. 1977). The gait becomes clumsy and stiff, a spastic paraplegia eventually appearing. Some adults, however, may present with cerebral symptoms, such as dementia (Coria et al. 1993): the dementia was in one case accompanied by hypomania (Weller et al. 1992), and in another by a Kluver-Bucy syndrome (Powers et al. 1980). Peripheral nerve involvement tends to be mild and may in some cases only be apparent with nerve conduction velocity studies. Seizures occur in about one-fifth of all patients, usually late in the course of the disease. Adrenal involvement may occur at any age and may indeed be the sole presentation of adrenoleukodystrophy (O'Neill et al. 1982). In some cases, the only evidence of adrenal cortical involvement may be a decreased cortisol level or an increased adrenocorticotrophic hormone level, whereas in others, there may be melanoderma, nausea, vomiting, abdominal pain, diarrhea, and hyperkalemia. Phenotypic variability is the rule in adrenoleukodystrophy, and even members of the same family may have different presentations (Erlington et al. 1989). Indeed, even monozygotic twins may exhibit phenotypic heterogeneity (Sobue etal. 1994), to the point of one twin being affected while the other is not (Korenke et al. 1996). T2-weighted MRI scanning often reveals enhancement at the border of the advancing wave of demyelinization. Cerebrospinal fluid findings include an elevated total protein and, in some cases, a mild lymphocytic pleocytosis. Very long-chain fatty acid levels are elevated in plasma and in cultured fibroblasts. Course Childhood onset cases generally progress fairly rapidly, death supervening within a few years; adolescent and adult onset cases, especially those with the adrenomyeloneuropathy syndrome, may progress very slowly. There may rarely be periods of partial remission, only to be followed eventually by relapse (Walsh 1980). Differential diagnosis

In the case of children, metachromatic leukodystrophy is suggested by ataxia, and subacute sclerosing panencephalitis by myoclonus. In adults, the distinction between adrenoleukodystrophy and progressive multiple sclerosis may rest on finding cerebrospinal fluid changes characteristic of multiple sclerosis, such as oligoclonal bands.

412 Specific disorders

Treatment

Adrenal failure is treated in the usual way with exogenous steroids. There is no specific treatment for the cerebral or spinal symptoms; despite much hope, it appears that the use of 'Lorenzo's oil', although capable of reducing the plasma very long-chain fatty acid level, does not affect the clinical course of the disease (van Geel et al. 1999). Bone marrow transplantation may help some patients. Genetic counseling should be offered; female carriers may be detected with a plasma or cultured fibroblast very long-chain fatty acid level.

ESSENTIAL TREMOR Pathology and etiology

Essential tremor is an autosomal dominant disorder with essentially complete penetrance by the mid-seventh decade (Bain et al. 1994). Although the pathophysiology is unknown, it is suspected that the tremor results from a dysfunction of the brainstem rubro-olivary-cerebello-rubral circuit (Findlay and Koller 1987), and positron emission tomography scanning, which reveals increased blood flow in the cerebellum (Jenkins et al. 1993), is consistent with this hypothesis. Clinical features

Although the range is wide, from the first to the ninth decades of life, most patients experience the onset of tremor on the average in the fifth decade. Clinically speaking (Bain et al. 1994; Critchley 1949; Koller et al. 1994; Lou and Jankovic 1991; Martinelli et al. 1987) in almost all cases, the tremor first becomes evident in the hand, and generally bilaterally; only in a small minority is the onset unilateral. The tremor, at least initially, is fine, ranging in frequency from 4 to 8 cps, and postural, being most evident when the hands are held outstretched with the fingers spread. In most cases, over time, the tremor also becomes apparent elsewhere, including, in decreasing order of frequency, the head, the voice, the chin and, in a small minority, the feet. Head tremor is generally of the 'no-no' type (Bain et al. 1994) with a trembling oscillation of the head from side to side. Involvement of the voice may impart a quavering quality to the patients' speech (Ardran et al. 1966). A significant minority of patients will also experience a focal dystonia, such as cervical dystonia or writer's cramp (Lou and Jankovic 1991). Course In most cases, the course is characterized by progressive worsening to a certain static plateau, which may persist for years or decades, after which there may again be a progressive decline. As the tremor worsens, it characteristically becomes of greater amplitude and slower frequency. Differential diagnosis

Rest (e.g. parkinsonian) and intention (e.g. cerebellar) tremors are immediately distinguished by their occurrence, respectively, at rest or with intentional movement. Of the chronic postural tremors, consideration should also be given to hyperthyroidism, generalized anxiety disorder, alcoholism, and the chronic use of certain medications or drugs such as lithium, valproic acid, tricyclic antidepressants, caffeine, theophylline, sympathomimetics, and various stimulants. 'Orthostatic tremor' (Martinelli et al. 1987) is characterized by tremulousness in the legs upon standing. Such tremor may be quite severe but is relieved by walking and is absent at rest.

Neurodegenerative disorders 413

Treatment Although alcohol may dramatically relieve the tremor (Growdon et al. 1975), its chronic use is, for obvious reasons, not recommended. Both propranolol (Findlay et al. 1987; Winkler and Young 1974) and primidone (Koller and Royse 1986) are effective, initiating treatment at a low dose and gradually increasing to effectiveness or a maximum of 320 mg propranolol or 350 mg primidone (Koller et al. 2000). Gabapentin, in doses of 1200 mg or more, has been found to be effective by some (Gironell et al. 1999; Ondo et al. 2000), but not all (Pahwa et al. 1998), double-blind studies.

HYPEREKPLEXIA Pathology and etiology Although sporadic cases do occur (Saenz-Lope et al. 1984), most cases are inherited in an autosomal dominant fashion, only a few recessive cases being noted (Rees et al. 1994). As noted below, hyperekplexia may occur in either a major or a minor form, and such forms may occur in the same family (Andermann et al. 1980; Suhren et al. 1966). Given this familial pattern, it seems reasonable to assume that the minor form represents a forme fruste of the major form, but the genetics are probably complicated. For example, although the major form has been associated with mutations of the glycine receptor on chromosome 5 (Shiang et al. 1993; Andrew and Owen 1997), there are families in which only those with the major form have carried the mutation, this being absent in those with the minor form (Tijssen et al 1995). Clinical features The major and minor forms of hyperekplexia differ both in age of onset and in the nature of the exaggerated startle response (Andermann et al. 1980; Kirsten and Silfverskiold 1958; Ryan etal 1992; Suhren et al. 1966; Tijssen et al. 1995). The major form of hyperekplexia becomes apparent in earliest infancy, with episodes of hypertonus. By the time the child is able to walk, or shortly thereafter, the response typical of hyperekplexia becomes apparent: to an appropriate stimulus, often a loud, unexpected noise, patients experience an exaggerated startle response (Brown et al. 1991) characterized by grimacing, flexion of the neck, arms and trunk, abduction of the arms, and generalized stiffness; many fall 'like a log', and injuries are common. Consciousness is maintained throughout, and the stiffness resolves immediately, allowing the patient to stand again. The minor form of hyperexplexia typically does not become apparent until childhood or later and consists simply of the exaggerated startle response without any associated stiffness.

Course Although some partial reduction in severity of the startle response may occur in the adult years, the course is overall chronic and unremitting. Symptoms are typically worse during fatigue or stress. Differential diagnosis The differential diagnosis of hyperekplexia is discusssed in Chapter 3; of all the disorders with which it could be confused, probably the most important is a kind of reflex epilepsy, 'startle epilepsy', wherein a startle can reflexively trigger a seizure. Naturally, when the seizure is generalized or prolonged, the distinction from hyperekplexia is obvious; however, when the precipitated seizure is a partial motor seizure characterized by a brief tonic component alone, the distinction may be more difficult. Observing the patient may help: in hyperekplexia one sees a generalized and symmetric flexion, whereas in the partial

414 Specific disorders

seizure, the motor manifestation may be asymmetric and generally consists of extension rather than flexion. Treatment

Clonazepam is generally effective in reducing the severity of the startle response (Ryan et al. 1992); divalproex has also been successfully used (Dooley and Andermann 1989).

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9 Congenital disorders Sturge-Weber syndrome Tuberous sclerosis von Recklinghausen's disease Down's syndrome Klinefelter's syndrome Fragile X syndrome Lesch-Nyhan syndrome

439 441 442 443 445 446 447

Laurence-Moon-Biedl syndrome Prader-Willi syndrome Congenital rubella syndrome Fetal alcohol syndrome Rett's syndrome Autism

448 449 450 450 451 452

STURGE-WEBER SYNDROME Pathology and etiology

Pathologically (Roizen etal. 1972; Weber 1929; Wohlwill and Yakovlev 1957), in Sturge-Weber syndrome (encephalotrigeminal angiomatosis) the leptomeninges show increased vascularity, composed primarily of small veins. Subjacent to the affected meninges, the cortical arteries show calcification, and free calcium may be seen in the nearby parenchyma; there is also a degree of cortical atrophy with associated neuronal loss and gliosis. These changes are generally unilateral and, although seen most commonly in the occipitoparietal area, may affect an entire hemisphere; those with bilateral involvement tend to have worse seizures and mental retardation (Bebin and Gomez 1988). Sturge-Weber syndrome is one of the neurocutaneous syndromes, the cutaneous involvement manifesting as a facial nevus flammeus ipsilateral to the cerebral calcification. The etiology of this syndrome is not clear: although familial cases have been reported, the overwhelming majority are sporadic. Clinical features

Clinically speaking (Chao 1959; Lichtenstein 1954; Pascual-Castroviejo et al. 1993; Petermann et al. 1958), the Sturge-Weber syndrome is characterized by a unilateral facial port-wine stain ipsilateral to the cerebral calcification, and by seizures, hemiplegia, and mental retardation. The port-wine stain is present at birth. At a minimum, the ophthalmic division of the trigeminal nerve is involved, especially the upper eyelid; in more severe cases, the stain appears in the maxillary or even mandibular divisions, and, in some cases, it is bilateral. Very rarely, the port-wine stain may not be present (Aydin et al. 2000). Seizures appear in the first year of life in over three-quarters of all patients and may be partial motor, complex partial, or grand mal. When partial motor seizures are present, they

440 Specific disorders

involve the side of the body contralateral to the cerebral calcification and facial port-wine stain. Hemiplegia is seen in about one-third of patients and may be accompanied by a hemiatrophy. As might be expected, the hemiplegia is contralateral to the cerebral calcification and the facial port-wine stain. A hemianopia often accompanies the hemiplegia. Mental retardation of variable degree is present in about two-thirds of patients and appears to be restricted to those with seizures. Congenital buphthalmos ('ox eye') may be present, and glaucoma may occur in about onequarter of patients. Cortical calcification is not evident on imaging until after the age of 2 but becomes progressively more common with the passage of time, eventually appearing in approximately 90% of patients over the age of 20. On skull films, the calcification appears in a classic curvilinear 'trolly-track' pattern, computed tomography (CT) scanning generally demonstrating a serpiginous pattern, as illustrated in Figure 9.1. Magnetic resonance imaging (MRI) scanning must be carried out with enhancement as the unenhanced scan may be normal.

Image Not Available

Figure 9.1 This unenhanced computed tomography scan demonstrates the serpiginous calcification seen in the Sturge-Webersyndrome. (Reproduced from Gillespie and Jackson 2000.)

Course Frequent seizures are associated with progressively worsening hemiplegia and cognitive deficit (Lichtenstein 1954; Petermann et al. 1958). When the cognitive deficit worsens past the baseline mental retardation, it may be more proper to speak of a progressive dementia. Differential diagnosis

The combination of a facial port-wine stain, seizures, contralateral hemiplegia, and cognitive deficit is distinctive. Treatment

Given the association between ongoing seizures and a progressive course, seizure control is imperative, and, in some cases, neurosurgery may be indicated. Port-wine stains may be treated with laser surgery. Intraocular pressure should be monitored periodically.

Congenital disorders 441

TUBEROUS SCLEROSIS Pathology and etiology Tuberous sclerosis gains its name from the presence of multiple sclerotic tubers found in the cerebral cortex and subependymal area (Richardson 1991). Tubers are nodules of varying size, from millimeters to 2 or more centimeters, composed of glial and abnormal neuronal-like cells. Those located subjacent to the ependyma of the lateral or third ventricles often undergo calcification, becoming 'brain stones' (Yakovlev and Corwin 1939), and may be so numerous as to impart the appearance of 'candle-guttering' to the surface of the ventricle. Tubers near the foramen of Monro may grow large enough to cause obstruction and hydrocephalus. An association between tubers in the temporal lobe and autism has recently been noted (Bolton and Griffiths 1997). In some cases, tubers may undergo malignant transformation into astrocytomas (Morimoto and Mogami 1986). Tuberous sclerosis may either occur sporadically (Webb and Osborne 1992) or be inherited as an autosomal dominant trait, the genes responsible being located on chromosomes 9 or 16 (European Chromosome 16 Tuberous Sclerosis Consortium 1993; Fryer et al. 1987; Hyman and Whittemore 2000). Importantly, there is considerable intrafamilial phenotypic variability. Clinical features

Fully developed tuberous sclerosis is characterized by the classic triad of seizures, adenoma sebaceum, and mental retardation (Alsen et al. 1994; Critchely and Earl 1932; Lagos and Gomez 1967; Monaghan et al. 1981; Pampiglione and Moynahan 1976; Ross and Dickerson 1943; Webb and Osborne 1995). The first sign of tuberous sclerosis is, in most cases, the presence of hypomelanotic macules, evident in 90% or more of affected infants. These macules, which are best seen with Wood's light, range in size from a few millimeters to 2 or 3 cm, and are sometimes oval shaped, giving rise to the name 'ash leaf spots. Seizures typically appear in the first 2 years of life and are initially of the 'salaam' or infantile spasm type (Roth and Epstein 1971); over the years, these salaam seizures are replaced by partial and grand mal seizures. Adenoma sebaceum consists of multiple minute facial nodules, generally arranged in a symmetrical butterfly shape over the nose, cheeks, and chin, and typically sparing the upper lip. Most patients have some evidence of adenoma sebaceum by middle childhood, and the lesion gradually progresses over the years. Mental retardation of variable severity is present in most cases, and autism (Alsen et al. 1994; Lawlor and Maurer 1987) is common. In addition to autism, Alsen et al. (1994) noted 'severe aggressive outbursts, self-destruction, and pica'. Although the great majority of cases present in childhood, adult onsets have been noted (Bundey and Evans 1969): in one case (Kofman and Hyland 1959), adenoma sebaceum appeared at 26 years of age, followed by partial seizures at the age of 31. Other lesions include subungual fibromas, 'shagreen' patches (leathery areas, generally in the lumbar region), cardiac rhabdomyomata (Gibbs 1985), renal angiomyolipomata, renal cysts, and, in a small minority, pulmonary cysts. In one very rare case, a 5-year-old girl presented with classic mania (Khanna and Borde 1989). 'Brain stones' are best visualized with skull films or CT scanning; uncalcified tubers, on the other hand, are best imaged with MRI. Course

Tuberous sclerosis is a gradually progressive disease. Those with an early childhood onset, especially those with severe epilepsy, rarely survive more than 15 years, eventually succumbing to status epilepticus or cardiac or renal complications. In adult onset cases, the progression tends to be much slower, and the disease may be compatible with a normal life span.

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Differential diagnosis

The classic triad of seizures, adenoma sebaceum, and mental retardation is distinctive. Treatment

Partial and grand mal seizures may be treated with routine anticonvulsants; 'salaam' seizures may require treatment with adrenocorticotrophic hormone. Mental retardation is discussed in Chapter 5 and autism later in this chapter. Genetic counseling should be offered.

VON RECKLINGHAUSEN'S DISEASE Pathology and etiology

von Recklinghausen's disease (neurofibromatosis type 1) occurs as an autosomal dominant disorder in about one-half of all cases, the remaining sporadic cases representing new mutations (Creange et al. 1999). The gene for neurofibromatosis is found on chromsome 17 (Wallace et al. 1990) and encodes a protein known as neurofibromin (von Deimling et al 1995); although over 90 different mutations have been recorded, there does not appear to be any correlation between a specific mutation and the actual phenotype. Neurofibromas are the hallmark of the disease, and these may be found on both cranial and peripheral nerves, in both their central and peripheral portions. Neurofibromas of the peripheral nerves may be pedunculated, sessile, or plexiform, and, in a small minority, neurofibromas may undergo sarcomatous change. Within the brain, there may be multiple areas of cortical dysplasia, small hamartomas and neuronal heterotopias (Rosman and Pearce 1967). Tumors may also occur (Creange et al. 1999; Listernick et al. 1989; Rodriguez and Barthrong 1966), for example meningiomas, astrocytomas, and, most commonly, optic gliomas. Clinical features

The cardinal features of von Recklinghausen's disease are neurofibromas and cafe au lait spots (Huson et al. 1988). Cafe au lait spots are generally present in infancy and grow in number and size throughout adolescence. Neurofibromas appear around puberty, are generally either pedunculated or sessile, and may be as large as a walnut or no bigger than a grain of sand; they typically appear on the trunk or the extremities, generally sparing the face, and range in number from a few up to literally thousands. Large plexiform neurofibromas may occasionally occur, and these may be extremely disfiguring. Other features found in adults include Lisch nodules and axillary freckling. Lisch nodules (Lubs et al. 1991) are small, yellow-brown spots on the iris that are at times visible only by slit-lamp examination. Axillary freckling, although found only in a minority, is virtually pathognomonic of von Recklinghausen's disease. A significant minority of patients with von Recklinghausen's disease will have a developmental disability, such as dyslexia, and a small minority will be mentally retarded; these clinical findings are probably related to the presence of neuronal dysplasia and heterotopias (Rosman and Pearce 1967). Optic gliomas may be asymptomatic or cause visual loss; meningiomas and astrocytomas present as they would in any other patient. Seizures may occur in a small minority (Kulkantrakorn and Geller 1998) and may be either secondary to a tumor or related to a hamartoma, neuronal heterotopia, or cortical dysplasia. Infertility may occur and is probably related to the presence of a hypothalamic hamartoma. A small minority of patients will also have pheochromocytoma or Wilms' tumor, or experience the sarcomatous degeneration of a neurofibroma.

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MRI scanning will reveal tumors and may show multiple areas of increased signal intensity (DiMario and Ramsby 1998), consistent with hamartomas and similar lesions. Course Childhood and adolescence are characterized by slow progression. Although the disease tends to be relatively quiescent in the adult years, exacerbations may occur during pregnancy or at unpredictable times. Differential diagnosis

The combination of cafe au lait spots and neurofibromas is distinctive; to qualify, however, there must be at least six cafe au lait spots (measuring at least 0.5 cm in diameter in children and 1.5 cm in adults) and two or more neurofibromas. As noted earlier, axillary freckling is virtually specific for von Recklinghausen's disease, and although Lisch nodules may appear in other disorders, they are very suggestive of this condition. von Recklinghausen's disease, or neurofibromatosis type 1, must be differentiated from neurofibromatosis type 2. Neurofibromatosis type 2 is a clinically and genetically distinct entity: clinically, it presents with intracranial tumors, classically with bilateral acoustic neuromas, and genetically, it results from mutations in a gene on chromosome 22 (Rouleau et al 1987). Treatment

Neurofibromas should not be removed unless they are disfiguring, painful, or causing significant compressive injury to nearby structures. Central nervous system tumors may require surgical removal. Genetic counseling should be offered, and prospective parents should be reminded that, because of the wide intrafamilial variation in phenotype, a mildly affected parent may yet have a severely affected child. Furthermore, those patients with spontaneous mutations must be reminded that they too can pass the disease on to their children.

DOWN'S SYNDROME Pathology and etiology

In Down's syndrome (trisomy 21), the cerebrum and cerebellum are small, and, as illustrated in Figure 9.2, the occiput is flattened and the superior temporal gyrus narrow and poorly developed. Overall, the sulcal pattern is primitive and underdeveloped. With advancing age, neurofibrillary tangles and senile plaques, almost identical to those seen in Alzheimer's disease (Schochet et al. 1973), begin to accumulate, being almost universal in those who survive into the fourth decade (Wisniewski et al. 1985a). Over 90% of cases of Down's syndrome occur secondary to trisomy 21 (Petersen and Luzzatti 1965), and in 95% of these cases, the non-disjunction occurs in the maternal line. Furthermore, the risk of non-disjunction rises with increasing maternal age, especially after the age of 40. Those 5-10% of cases not caused by trisomy 21 result from translocations. Clinical features

Down's syndrome, first described by John Langdon Down in 1866, imparts a characteristic facial appearance: the palpebral fissures are narrow, epicanthal folds are present, the root of the nose is broad, and the tongue, generally large, typically protrudes from a small mouth. In addition, patients are usually of short stature, and their hands are generally stubby, with a transverse simian crease on the palm and a fifth finger that is usually short and curved inward.

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Image Not Available Figure 9.2 Note the marked hypoplasia of the superior temporalgyrus in this case of Down's syndrome. (Reproduced from Graham and Lantos 1996.)

Mental retardation ranges from mild to severe, but, in many cases, social skills are more advanced than cognitive ones, and patients with Down's syndrome tend to be affable, outgoing and pleasant; a small minority, however, will suffer from autism (Lund and MunkJorgensen 1988). Depression occurs more often in Down's syndrome than in the general population (Collacott et al. 1992) and may at times be quite severe, being accompanied by hallucinations (Warren et al. 1989). Hypothyroidism is common and is often of the autoimmune type (Chinta 1988), that is, Hashimoto's thyroiditis. Dementia occurs in adults with Down's syndrome (Collacott et al. 1992; Jervis 1948; Lund and Munk-Jorgensen 1988): over 50% of patients over 35 are affected, with an average age at onset of 54 years (Lai and Williams 1989). In contrast to the stable level of reduced cognitive performance characteristic of the mental retardation, there is a gradual deterioration in functioning (Wisniewski et al. 1985b): those with severe retardation may become more apathetic and less sociable, while in those with only a moderate degree of retardation, the dementia may present with decreased memory, disorientation to time, and reduced verbal output (Lai and Williams 1989) Seizures occur in a bimodal pattern in Down's syndrome: among infants and children, infantile spasms and grand mal seizures may be seen, whereas in adults, simple or complex partial seizures are more common, with a somewhat smaller percentage also having grand mal siezures (Pueschel et al. 1991). During the adult years, the prevalence of seizures increases dramatically with increasing age, almost one-half of all patients over 50 experiencing them (McVicker et al. 1994): indeed, among those with dementia, the figure approaches 80% (Lai and Williams 1989). Other features that may be seen in Down's syndrome include: gastrointestinal defects such as duodenal stenosis, megacolon and imperforate anus; congenital heart disease, such as atrial or ventricular septal defects (Rowe and Uchida 1961); hypogonadism; and atlantoaxial instability, which may lead to cord compression, with such symptoms as urinary retention and spasticity (Davidson 1988). There is also an increased risk of leukemia (Krivit and Good 1957). MRI scanning may reveal the characteristic changes noted under pathology, above. In addition, among adults, calcification of the basal ganglia may be seen.

Course A significant number of patients die of congenital heart disease in infancy or childhood (Baird and Sadovnik 1987); of those who survive into the adult years, almost half will live into the

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seventh decade (Baird and Sadovnik 1988). Those who become demented, however, survive on average for only another 5 years (Evenhuius 1990). Differential diagnosis

The appearance of patients with Down's syndrome is distinctive. Should a dementia supervene in adulthood, consideration should be given not only to that caused by Alzheimer's-like pathology, but also to that resulting from hypothyroidism. The same concern applies when depression occurs in patients with Down's syndrome as this too may be caused by hypothyroidism. Treatment

There is no specific treatment for Down's syndrome: treatment of mental retardation, autism, depression, dementia, and seizures may proceed as outlined in the respective chapters. Because of the risk of atlantoaxial dislocation, all patients should have cervical spine films taken before participating in sporting activities. In some cases, surgical repair is appropriate.

KLINEFELTER'S SYNDROME Pathology and etiology Klinefelter's syndrome, seen only in males, occurs secondary to non-disjunction during either spermatogenesis or oogenesis, resulting in the presence of two or more X chromosomes. The most common karyotype is 47,XXY, and, in about 10% of cases, mosaicism is present, with a 46,XY/47,XXY karyotype. Rarely, more severe abnormalities may occur, yielding karyotypes such as 48,XXXY or 49,XXXXY. Although much of the symptomatology of Klinefelter's syndrome can be explained on the basis of primary hypogonadism secondary to a progressive fibrosis of the testes, it is clear that hypogonadism alone is not sufficient to explain all the neuropsychiatric features of the disorder, such as mental retardation (Pasqualini et al. 1957; Wakeling 1972). The additional neuropatholgic basis of the syndrome is, however, as yet unknown. Clinical features The classic clinical picture (Ratcliffe et al. 1982) of Klinefelter's syndrome becomes apparent in post-pubertal males and is characterized by tall stature, eunuchoidism, and infertility. Excessive height is primarily caused by a late closure of the epiphyseal plates and results from increased leg length. Eunuchoidism is apparent with gynecomastia, a female escutcheon, and a small penis and testes; although most patients have a heterosexual orientation, libido is often low, and impotence may occur (Pasqualini et al. 1957). Moderate-to-severe azoospermia is present, which accounts for the infertility. Importantly, in an unclear but probably significant proportion of patients, this classic picture is not present, and some patients may come to clinical attention only during a work-up for infertility or impotence. Mental retardation may be seen in a minority, and language deficits, such as dyslexia, have been noted; rarely, seizures may occur (Graham et al. 1988; Pasqualini et al. 1957; Ratcliffe et al. 1982; Swanson and Stipes 1969; Tatum et al. 1998; Wakeling 1972). The presence of more than two X chromosomes is associated with more severe retardation (Forsman 1970). In those who are retarded, the personality may be characterized by a sullen sort of withdrawal, with a liability to hostile outbursts (Hunter 1969). There is an association between Klinefelter's syndrome and various other disorders, such as alcoholism (Nielsen 1969) and schizophrenia (Nielsen 1969; Pomeroy 1980; Roy 1981). Other associated disorders include Hashimoto's thyroiditis, acute myeloid leukemia, diabetes mellitus, chronic obstructive pulmonary disease, and breast cancer.

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Pre-pubertally, hormone levels are generally within normal limits, but after puberty, the testosterone level is low or low-normal. The follicle-stimulating hormone level is uniformly elevated, and the luteinizing hormone level may be high or high-normal. The estradiol level is generally elevated. Except in mosaic cases, buccal smears are sufficient to make the diagnosis; if a buccal smear is negative for an extra X chromosome, but the clinical suspicion is high, karyotyping is indicated. Course The clinical picture tends to coalesce during adolescence, with a stable subsequent course. Differential diagnosis

The classic clinical picture is distinctive. Treatment Testosterone, given either as testosterone enanthate or via a testosterone patch, may improve libido and relieve impotence (Beumont et al. 1972) but will not reverse the azoospermia and may actually worsen the gynecomastia, which may require surgical correction. Mental retardation is treated as described in Chapter 5.

FRAGILE X SYNDROME Pathology and etiology gy The fragile X syndrome occurs secondary to an expansion of the trinucleotide repeat CGG on the long arm of the X chromosome: whereas normally anywhere from six to 45 repeats are present, in the fragile X syndrome, over 230 are found. Adults harbouring fewer than 230 repeats, but more than 45, are said to have a 'premutation', and although they themselves are asymptomatic, they may act as 'carriers' in that the number of repeats may undergo expansion, resulting in affected offspring. Interestingly, this expansion of a parental 'premutation' is far more likely during oogenesis than spermatogenesis, with the result that, in the vast majority of cases, the disease is inherited through the maternal line. The gene in question is known as FMR-1 (Verkerk 1991) and the protein as FMRP: although the FMRP protein is widely expressed, especially in brain and testis, its function is not yet clear. The fragile X syndrome derives its name from the fact that when the cells of patients are cultivated in a medium deficient in thymidine and folic acid, a fragile site will be found on the long arm of the X chromosome (Sutherland 1977), which, as might be expected, corresponds to the location of the expanded CGG repeat. Pathologically, neuronal heterotopias are found (Dunn et al. 1963), and many neurons appear to have abnormal dendritic spines (Rudelli et al. 1985).

Clinical features

Among males harbouring the full trinucleotide expansion, penetrance is almost complete, but among females, only about one-half show clinical evidence of the disease. The classic syndrome (Baumgardner et al. 1995; Finelli et al. 1985; Wisniewski et al. 1985c) is most evident in males and is characterized by mental retardation, a characteristic dysmorphic facies, and macroorchidism. Mental retardation ranges from mild to severe, and a significant minority of these patients will have autism. Dysmorphic features include a long, narrow face, prognathism, a high forehead and large ears (De Arce and Kearns 1984). Macroorchidism is a constant feature in post-pubertal patients and may also be seen in a minority during childhood (Chudley and Hagerman 1987; De Arce and Kearns 1984).

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Seizures, either complex partial or grand mal, occur in a significant minority (Finelli et al. 1985; Wisniewski et al. 1985c). Other features include hyper extensible joints and mitral valve prolapse (Chudley and Hagerman 1987), and in a minority there may also be hyperreflexia and Babinski signs (Finelli et al. 1985). Affected females tend to have much milder clinical symptomatology: a minority may have mild mental retardation, and in those with a normal IQ, there may be specific learning disabilities (Wisniewski et al. 1985c). Interestingly, among female carriers, that is to say females with a premutation, there may be traits reminiscent of autism or schizotypal personality disorder, such as emotional withdrawal, odd thoughts, ideas of reference, and mannerisms (Freund et al. 1992; Reiss et al. 1988). DNA testing by polymerase chain reaction assay is the preferred diagnostic approach (Rousseau et al. 1991). Although diagnosis has also been made by culturing cells in a medium deficient in folic acid and thymidine, false negatives have been noted (Tarleton and Saul 1993). Course

Although there is some evidence that, in males, intellectual functioning may undergo a decline in late childhood or early adolescence (Dykens et al. 1989), it appears that, for the most part, the clinical picture becomes set in adolescence and generally remains stable thereafter. Differential diagnosis

The finding of either the characteristic facial dysmorphism or macroorchidism in any male with mental retardation or autism is highly suggestive of the condition and should prompt genetic testing. It is unclear whether females with mental retardation or schizotypal traits should be routinely tested. Treatment

The general treatment of mental retardation is discussed in Chapter 5 and that of autism below. There is some evidence that, in pre-pubertal patients, folic acid may improve some aspects of behavior (Aman and Kern 1991), but it does not appear to be useful in adults.

LESCH-NYHAN SYNDROME Pathology and etiology The Lesch-Nyhan syndrome is inherited as an X-linked recessive trait (Lesch and Nyhan 1964) and is caused by an almost complete deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. The structure of the HPRT gene is known, over 100 different mutations having been identified (Davidson et al. 1989; Edwards et al. 1990; Gibbs and Caskey 1987; Yang et al. 1984). Very rarely, females have been affected, apparently secondary to de novo mutations (Ogasawara et al. 1989; van Bogaert et al. 1992). Although one of the clear consequences of this deficient HPRT activity is an elevation of uric acid level, this elevation does not by itself seem to account for the central nervous system symptoms. Although macroscopic changes have not been found in the brain, the dopamine concentration is reduced in the basal ganglia, and this could account for at least some of the symptomatology seen in the disease (Jankovic et al. 1988). Clinical features

The onset is in the first or second year of life, with choreoathetosis and dystonia, followed by a slow progression of spasticity, which may eventually become so severe as to disguise the choreoathetosis (Jankovic et al. 1988; Lesch and Nyhan 1964; Nyhan 1972). Although mental

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retardation of a mild-to-moderate degree is present in most patients, it must be borne in mind that some are of normal intelligence. The distinctive and striking characteristic of the Lesch-Nyhan syndrome is mutilative selfbiting, which although usually becoming apparent as soon as the baby teeth appear, may be delayed, in one case as late as the age of 8 (Hatanaka et al. 1990). Patients may bite their lips and fingers, and often require restraints to prevent injury (Jankovic et al. 1988). Importantly, there is no anesthesia here, and the biting is involuntary: Lesch and Nyhan (1964) commented that one of their patients 'appeared terrified and screamed as if in pain during the process and appeared happy only when restrained securely'. In some cases, patients may chew off their lips and into their cheeks, or amputate their own fingers. Seizures and a megaloblastic anemia may occur. Hyperuricemia leads to tophaceous gout and a gouty nephropathy. The serum uric acid level is elevated, and urinalysis may reveal hematuria. HPRT activity may be measured in erythrocytes, cultured fibroblasts, hair roots, and amniotic fluid cells. Course

Untreated, most patients die of renal failure before reaching the age of 30. Differential diagnosis

Although self-biting is common in mental retardation of almost any cause, it rarely reaches the mutilating level seen in the Lesch-Nyhan syndrome. Neuroacanthocytosis may present with chorea and self-mutilating biting, but here the onset is much later, in the late twenties or early thirties. Treatment

Although allopurinol is successful in treating tophi and gouty nephropathy, it has no effect on the central nervous system symptomatology. Neuroleptics such as fluphenazine and haloperidol have partially ameliorated the choreoathetosis and self-biting. If neuroleptics are used, a case could be made for starting with olan/epine, given its overall superiority in other neuroleptic-responsive conditions. A recent case report described a dramatic reduction in self-biting with gabapentin (McManaman and Tarn 1999). Restraints and mittens are often required to prevent injury, and in some cases teeth must be extracted (Jankovic et al. 1988). Gene replacement therapy is a very attractive possibility, but has not as yet been successful.

LAURENCE-MOON-BIEDL SYNDROME Pathology and etiology

The Laurence-Moon-Biedl (Bardet-Biedl) syndrome is inherited in an autosomal recessive fashion and appears to be genetically heterogenous, loci being noted on more than one chromosome. The pathologic basis of the syndrome is not known; suspicions that it represents a primary pituitary disorder have not been borne out. Clinical features

The onset is in early childhood with retinitis pigmentosa and obesity. In a majority of cases, one also finds polydactyly or syndactyly, hypogonadism, and a degree of mental retardation (Klein and Ammann 1969; Rathmell and Burns 1938; Roth 1947). Retinitis pigmentosa presents first with difficulties in night vision and is progressive,

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leading eventually, in the majority of cases, to blindness by the early adult years. Obesity is generalized, with a truncal prominence. Polydactyly may manifest with an extra finger or toe, which ranges in morphology from rudimentary to fully formed. Hypogonadism may be accompanied by testicular hypoplasia and micropenis, and by amenorrhea in females. Other features, found in a minority, include diabetes insipidus (Koepp 1975), cardiac and hepatic disease, and renal failure. Course Except in cases of renal failure, the life span is usually normal. Differential diagnosis

The Alstrom-Hallgren syndrome, another autosomal recessive disorder characterized by obesity, retinitis pigmentosa, and hypogonadism, is distinguished by the presence of sensorineuronal hearing loss (Goldstein and Fialkow 1973). The Prader-Willi syndrome, characterized by obesity, hypogonadism, and mild mental retardation, is distinguished by the absence of both retinitis pigmentosa and polydactyly. Treatment

There is no specific treatment; testosterone does not appear to be helpful with the hypogonadism.

PRADER-WILLI PRADER-WILLI SYNDROME Pathology and etiology In about three-quarters of cases, the Prader-Willi syndrome results from a deletion on chromsome 15 and represents an example of genetic imprinting: when the deletion occurs on the paternal chromosome 15, the Prader-Willi syndrome is seen, but if it occurs on the maternal chromosome, the Angelman syndrome results (Knoll et al. 1989). In the remaining cases, the syndrome results not from a deletion on chromosome 15 but rather from maternal uniparental disomy, wherein both chromsome 15s are derived from the mother (Nicholls et al. 1989). Clinical features

The syndrome has received consistent description in a large number of reports (Bray et al. 1983; Burke et al. 1987; Butler et al. 1986; Dunn 1968; Hall and Smith 1972; Robinson et al. 1992). The onset of the disorder is in infancy with hypotonia and feeding difficulties, which may, at times, necessitate tube-feeding. Typically, between the ages of 1 and 2, these phenomena clear and are replaced by a ravenous hunger that eventually leads to extreme obesity: one patient literally 'took off running' and, 'as soon as she could walk, she was constantly near the refrigerator, begging for food' (Zellweger and Schneider 1968). Patients often go to any lengths to satisfy this hunger and, if refrigerators and food cabinets are locked, may turn to other sources: one patient 'ate catfood, begged food from neighbors, and ate rotting chicken carcasses and other items removed from dustbins' (Clarke 1993). Mental retardation occurs in about one-half of patients but tends to be of mild degree. Some patients display considerable stubborness, and temper tantrums may occur. Rarely, a psychosis may appear (Clarke 1993). Typically, the head is narrow, the eyes are almond shaped, and the upper lip is narrow and at times tented. Micromelia, with relatively slender arms and legs, and small hands and feet, is common. Hypogonadism in males manifests with micropenis and cryptorchidism, and in females with a lack of breast development, hypoplastic labia, and variable amenorrhea. Seizures are seen in a minority.

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With extreme obestiy, patients may develop sleep apnea, the Pickwickian syndrome, or diabetes mellitus. Course The disorder is chronic, premature death often being caused by one of the complications of obesity. Differential diagnosis

The Laurence-Moon-Biedl syndrome is distinguished by the presence of retinitis pigmentosa and polydactyly. Treatment

Prompt attention to the obesity is critical; in some cases, fenfluramine may be useful. The treatment of mental retardation is discussed in Chapter 5.

CONGENITAL RUBELLA SYNDROME Pathology and etiology Maternal rubella infection, especially during the first trimester, may, via transplacental spread, be accompanied by fetal infection. In those who survive into childhood or beyond, the brain displays various areas of focal necrosis, primarily in the basal ganglia, mesencephalon and cord (Desmond et al 1967; Plotkin et al. 1965; Rorke 1973; Rorke and Spiro 1967); microcephaly and spina bifida may also be present (Tartakow 1965). Clinical features

The full syndrome of congenital rubella is composed of mental retardation, cataracts, deafness and various cardiac abnormalities, such as patent ductus arteriosus and ventricular septal defect (Forrest and Menser 1970; Hardy 1973; Miller et al. 1982; Tartakow 1965). Chorioretinitis is common, and one may also see evidence of spasticity. Rarely, autism may occur (Fombonne et al. 1997). Course In those who survive into late childhood or beyond, the course is static, except in the small minority who go on to develop the dementia of progressive rubella panencephalitis, as discussed in Chapter 14. Differential diagnosis

Fetal infection with cytomegalovirus and toxoplasmosis may cause a similar syndrome. Treatment

The treatment of mental retardation is discussed in Chapter 5. Hearing aids are generally required. Prevention is critical, and females of child-bearing age, if they have not already had rubella, should be vaccinated. Contraception for the 3 months post-vaccination is critical, as, albeit rarely, congenital rubella has occurred in fetuses conceived during this time period.

FETAL ALCOHOL SYNDROME Pathology and etiology gy

The brain is smaller than normal, and neuronal heterotopias are found in the periventricular white matter and the leptomeninges. In more severe cases, there may be cerebellar dysgenesis,

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agenesis of the corpus callosum, porencephaly, and other malformations (Clarren et al. 1978; Pfeiffer et al 1979; Wisniewski et al. 1983). The syndrome results from maternal alcohol use, especially early in pregnancy. Clinical features Classic fetal alcohol syndrome (Clarren and Smith 1978; Jones and Smith 1973) is characterized by mental retardation, short stature, microcephaly, and a characteristic facies, with shortened palpebral fissures, epicanthal folds, a thin upper lip with a smooth philtrum, maxillary hypoplasia and a degree of micrognathia. Patients with only partial syndromes are said to have 'fetal alcohol effects': thus, some patients may present only with various learning disorders (Larsson et al. 1985; Shaywitz et al. 1981), hyperactivity, distractability, or irritability. Associated cardiac abnormalities include atrial and ventricular septal defects. Course

Some of the features of the fetal alcohol syndrome (especially the facial features) may become less prominent during adolescence, and, in mild cases, the diagnosis may indeed become difficult unless one has access to childhood pictures or accurate pediatric records (Spohr et al. 1993; Streissguth et al 1991). Differential diagnosis The facial anomalies, when fully present, are quite distinctive and, when coupled with the history of maternal alcohol use, make the diagnosis almost certain. Partial syndromes, presenting, for example, with hyperactivity, may be difficult to distinguish from developmental disorders such as attention deficit disorder with hyperactivity. Treatment The treatment of mental retardation is discussed in Chapter 5. Prevention is critical, and females of child-bearing age should be informed that bingedrinking is as dangerous as daily drinking, and that there may indeed be no minimal 'threshold' of alcohol consumption below which a pregnant woman can drink without endangering the fetus.

RETT'S SYNDROME Pathology and etiology Among the numerous pathologic changes reported for Rett's syndrome, the most robust are that the brain is small and that the pars compacta of the substantia nigra is hypopigmented (Jellinger and Seitelberger 1986; Jellinger et al 1988). Rett's syndrome, occurring secondary to a mutation on the X chromsome (Amir et al. 1999), is seen almost exclusively in females. This female preponderance has prompted the suggestion that the mutation is lethal in males, but the presence of a normal proportion of males in the sibships of girls with Rett's syndrome makes this unlikely (Akesson et al. 1992). Clinical features Rett's syndrome is best described in terms of four more or less distinct stages (Coleman et al. 1988; Hagberg 1989; Hagberg and Witt-Engerstrom 1986; Hagberg et al. 1983; WittEngerstrom 1990). Stage I, or the stagnation stage, generally occurs around the age of 10 months and is characterized by a general slowing of normal development. Weight gain may be less than expected, and, rather than progressively better crawling, one may see persistent 'bottomshuffling'.

452 Specific disorders

Stage II, or the stage of regression, generally occurs around the age of one and one-half years, being characterized by hand stereotypies, mental retardation, autistic features, and microcephaly. The onset of stage II disease generally occurs over weeks or a few months, but, in rare cases, it may occur subacutely, over a matter of days. The hand stereotypies are fairly distinctive: patients may initially suck their hands, or perhaps grasp their tongues, but in time they begin to display the hand-wringing and washing movements characteristic of the syndrome. Mental retardation becomes evident and is usually severe. Autistic features include withdrawal and a lack of communication: patients may also engage in more or less bizarre behavior, with teeth-gnashing, screaming, and peculiar laughter, typically heard in the middle of the night. Microcephaly becomes apparent as head growth decelerates relative to the rest of the body. Stage HI, or the 'pseudostationary' stage, is characterized by a gradual 'come-back' of patients, with a partial remission of some of the signs seen during stage II, and generally begins around the age of 3 years. Specifically, there may be some reduction in withdrawal and some restoration of communicative ability. Other signs, such as mental retardation, however, remain stable. During this stage (or occasionally, in stage II), seizures, including both complex partial and grand mal types, may appear. Stage IV, or the stage of late motor deterioration, may not appear until the adult or middle years and is characterized by scoliosis, dystonia, especially of the lower extremities, and neurogenic muscle atrophy, also most evident in the lower extremities. Most patients in this stage eventually become wheelchair-bound. MRI or CT studies reveal cortical atrophy and ventricular dilatation. Course Death may result from respiratory infection or during postoperative periods, but, in most cases, patients live until their middle years or even into the seventh decade. Differential diagnosis

Two features are important for differential diagnostic purposes: the hand-washing stereotypies that appear in stage II, and the overall course of the illness in childhood, especially the rapid onset of stage II and the partial 'come-back' during stage III. Although handwashing stereotypies may be seen in other causes of mental retardation, the 'come-back' is virtually unique. Treatment

There is no specific treatment for Rett's syndrome: trials of bromocriptine and naltrexone have not supported their use. Seizures may be treated with either carbamazepine or divalproex. The overall treatment of mental retardation is discussed in Chapter 5.

AUTISM Pathology and etiology

Autism (Kanner's syndrome) may occur on an idiopathic basis or secondary to other diseases. Secondary cases comprise only a minority of all cases of autism: one large study gave a figure of 11% (Ritvo et al. 1990). Established causes of secondary autism include the fragile X syndrome (Wisniewski et al. 1985c), Down's syndrome (Lund and Munk-Jorgensen 1988), tuberous sclerosis (Alsen et al 1994; Lawlor and Maurer 1987), Rett's syndrome (during Stage II) (Percy et al. 1990), and others (Fombonne et al. 1997; Ritvo et al. 1990), including von Recklinghausen's disease, congenital rubella syndrome, phenylketonuria and mucopolysaccharidosis.

Congenital disorders 453

The pathology and etiology of the primary, idiopathic cases is as yet unclear. Genetic factors appear to play a role, given that the concordance rate for monozygotic twins is higher than that for dizygotic twins (Folstein and Rutter 1977). Although neuropathologic and imaging studies have often yielded conflicting results, one finding, although not without some detractors, appears to be fairly robust, namely that the cerebellar vermis is hypoplastic. Biochemical studies indicate a disturbance in serotonin metabolism: serum levels of serotonin are increased in about one-third of cases, and the cerebrospinal level of 5-hydroxyindoleacetic acid has also been found to be elevated. Furthermore, a depletion of tryptophan, a precursor of serotonin, will cause an exacerbation of symptoms (McDougle et al. 1996a). In the not-too-distant past, it was taught that autism occurs secondary to faulty childrearing, but this theory has now been soundly discredited. Clinical features

Autism has an insidious onset in infancy. Parents may recall that the child cried infrequently and seemed indifferent to being held or cuddled; some parents, as noted by Kanner (1943), were 'astonished at the children's failure to assume at any time an anticipatory posture to being picked up' (italics in original). The full picture of autism is generally present by middle childhood. Autistic children prefer solitary play and, rather than playing with other children, occupy themselves with objects such as toys or machines of some sort. They seem, as noted by Kanner (1943), to be unable 'to relate themselves in the ordinary way to people and situations' (italics in original): indeed, other people, whether adults or children, are often treated as if they were machines or perhaps mere props to be used during play. Attempts to make contact with such children generally fail. If one tries to catch their eyes, they will often exhibit 'gaze avoidance' (Richer and Coss 1976), staring fixedly at something else, perhaps something just to the side of the examiner's head. One gets the impression that a mannequin would be more satisfactory to the autistic child than an actual playmate. The behavior of autistic children may, at times, seem bizarre. There are often what are known as 'fascinations', in which the child becomes intently interested in and fascinated with certain objects, such as a piece of cloth, jewelry, or, classically, spinning things, such as tops. One of Kanner's patients (Kanner 1944) spun 'toys and lids of bottles and jars by the hour ... He would watch them and get severely excited and jump up and down in ecstasy'. Stereotypies such as repetitive hand-flapping or finger-flicking, may occur, and some patients may engage in posturing or, classically, toe-walking. The persistence of Stereotypies can be astonishing: one child (Ornitz and Ritvo 1968) sustained 'oscillatory hand-flapping throughout the entire day'. Some patients seem insensitive to pain, whereas others display an inordinate, often terrifying, sensitivity to innocuous stimuli: one of Kanner's (1943) patients 'was so afraid of the vacuum cleaner that she would not even go near the closet where it was kept, and when it was used, ran out into the garage, covering her ears with her hands'. Another, classic, symptom of autism is an 'anxiously obsessive desire for the maintenance of sameness' (Kanner 1943; italics in original). As noted further by Kanner (1951): the autistic child desires to live in a static world, a world in which no change is tolerated. The status quo must be maintained at all cost. Only the child himself may sometimes take it upon himself to modify exisiting combinations. But no one else may do so without arousing unhappines and anger... The slightest change of arrangement, sometimes so minute that it is hardly perceived by others, may evoke a violent outburst of rage.

Not only arrangements, but also routines and sequences must be maintained inviolate: the aisles in the grocery store must be traversed in exactly the same order and direction every time, and the exact same route must be taken to school every day.

454 Specific disorders

Speech and language are also disturbed. Some patients are mute, those who do speak often displaying a curious aprosody, wherein they not only seem insensitive to the emotional inflections of those speaking to them, but also display a monotonous or 'sing-song' quality in their own speech. There may also be echolalia and, classically, pronomial reversals, wherein the patients refer to themselves in the third person. Some patients (Kanner 1944) may display'an astounding vocabulary ... excellent memory for events of several years before ... [and] phenomenal rote memory for poems and names'. Kanner (1944) was impressed with their 'strikingly intelligent physiognomies', believing that most, if not all, of his patients were of normal intelligence. It is now clear, however, that Kanner's original sample of 20 patients was not representative and that, in fact, about threequarters of autistic patients have mental retardation, ranging in severity from mild to severe. The mental retardation seen in autism is, however, peculiar, in that, unlike most examples of mental retardation, the decrement in abilities is not even: on the contrary, one often finds 'islets' of normal, or even superior, functioning in an otherwise retarded patient. For example, one autistic man with an IQ of 71, although unable to abstract on proverbs testing or do simple arithmetic, was nevertheless able to 'correctly give the day of the week of any day this century' (Hurst and Mulhall 1988). In the past, such patients have been referred to as 'idiots savants' (Treffert 1988), and although this terminology is perhaps unfortunate, it does forcefully convey the sometimes astounding contrast between the 'islets' of superior functioning and the overall intellectual decrement. Seizures occur in a significant minority of patients, and although these are most common in those with mental retardation, they may also occur in those of normal intelligence. Infantile spasms and complex partial or grand mal seizures may be seen (Olsson et al. 1988). Course Middle childhood, from a prognostic point of view, is a critical time: those who attain some language and some social skills around this time have a much more favorable outcome than those who do not. By adulthood, however, most patients experience some partial remission of their symptoms: no matter how great the spontaneous recovery however, residual symptoms, such as aprosodia, social awkwardness, and a reduced awareness of social conventions, persist (Rumseyetfl/. 1985). Differential diagnosis

Other causes of mental retardation, developmental dysphasia (mixed expressive-receptive language disorder) (Bartak et al. 1975), and congenital deafness or blindness are all distinguished from autism by the preservation of a desire for social contact: in contrast to those with autism, children with these disorders will 'warm up' in response to a friendly adult. Childhood onset schizophrenia is distinguished from autism on the basis of age of onset and the presence of certain distinctive clinical features. Schizophrenia rarely, if ever, has an onset before the age of 6; furthermore, patients with schizophrenia experience delusions and hallucinations, symptoms not seen in autism. Treatment

The treatment of autism generally involves family counseling, special education, and, in many cases, medication. Parents must be clearly informed that they are not at fault and that autism is not the result of inadequate child-rearing. Intensive psychosocial treatment is clearly very helpful, and produces a substantial improvement in academic and intellectual functioning (McEachin et al. 1993). Special education classes should be highly structured, and children should be considered for special schools if any are nearby. Haloperidol reduces withdrawal and stereotypies (Campbell et al. 1996), and risperidone, in both open (McDougle et al. 1997) and double-blind (McDougle et al. 1998) studies, has

Congenital disorders 455

shown similar effectiveness. Although neuroleptics such as these are often very helpful, their continued use must be weighed against the risk of tardive dyskinesia. Clomipramine may reduce stereotypies, withdrawal and self-injurious behavior (Gordon et al. 1993), and fluvoxamine, in adults (but not adolescents or children), has a similar action (McDougle et al. 1996b). Clonidine may reduce stereotypies and self-stimulation (Frankhauser et al. 1992). Naltrexone may reduce restlessness and hyperactivity (Campbell et al. 1993) but does not appear to reduce the incidence of self-injurious behavior.

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98:249-51. Rorke LB, Spiro AJ. Cerebral lesions in congenital rubella syndrome.J Pediatrics 1967; 70:243-55. Rosman NP, Pearce J.The brain in multiple neurofibromatosis (von Recklinghausen's disease): a suggested basis for the associated mental defect. Brain 1967; 90:829-37. Ross AT, Dickerson WW. Tuberous sclerosis. Arch Neurol Psychiatry 1943; 50:233-57. Roth AA. Familial eunuchoidism: the Laurence-Moon-Biedl syndrome. 7 Urology 1947; 57:427-42.J Roth JC, Epstein CJ. Infantile spasms and hypopigmented macules: early manifestations of tuberous sclerosis. Arch Neurol 1971; 25:547-51. Rouleau GA, Wertelecki BR, Martuza Rl et al. Genetic linkage of bilateral acoustic neurofibromatosis to a DMA marker on chromosome22. NaturenSJ; 329:246-8. Rousseau F, Heitz D, Biancalana V et al. Direct diagnosis by DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med 1991; 325:1673-81.

460 Specific disorders Rowe DR, Uchida IA. Cardiac malformation in mongolism. A prospective study of 184 mongoloid children. Am J Med 1961; 31:726-35. Roy A. Schizophrenia and Klinefelter's syndrome. Can J Psychiatry 1981; 26:262-4. Rudelli RD, Brown WT, Wisniewski K et al. Adult fragile X syndrome: clinico-neuropathologic findings. Acta Neuropathol 1985; 67:289-95. RumseyJM, RapoportJL, Sceery WR. Autistic children as adults: psychiatric, social, and behavioral outcomes. J Am Acad Child Psychiatry 1985; 24:465-73. SchochetSS, Lampert PW, McCormick WF. Neurofibrillary tangles in patients with Down's syndrome: a light and electron-microscopic study. Acta Neuropathol 1973; 23:342-6. Shaywitz SE, Caparulo B, Hodgson ES. Developmental language disability as a result of prenatal exposure to ethanol. Pediatrics 1981; 68:850-5. Spohr H-L, Wilms J, Steinhausen H-C. Prenatal alcohol exposure and long-term developmental consequences. Lancet 1993; 341:907-10. Streissguth AP, Aase JM, Clarren SK et al. Fetal alcohol syndrome in adolescents and adults. J Am Med Assoc1991;265:1961-7. Sutherland GR. Heritable fragile sites on human chromosomes. Demonstration of their dependence on the type of tissue culture medium. Science 1977; 197:265. Swanson DW, Stipes AH. Psychiatric aspects of Klinefelter's syndrome. Am J Psychiatry 1969; 126:814-22. TarletonJC.Saul RA. Molecular genetic advances in fragile X syndrome.J Pediatrics 1993; 122:169-85. Tartakow IJ. The teratogenicity of maternal rubella.J Pediatrics 1965; 66:380-91. Tatum WO, Passaro EA, Elia M et al. Seizure in Klinefelter's syndrome. Pediatr Neurology 1998;

19:275-82. Treffert D. The idiot savant: a review of the syndrome. Am J Psychiatry 1988; 145:563-72. van Bogaert P, Ceballos I, Desguerre I et al. Lesch-Nyhan in a girl.J Inhert Metabol Dis 1992; 15:790-1. Verkerk AJ, Pieretti M, SutcliffeJSef al. Identification of a gene (FMR1) containing a CGG repeat coincident with a breakage point cluster region exhibiting length variation in fragile X syndrome. Cell 1991; 65:905-14. von Deimling A, Krone W, Menon AG. Neurofibromatosis type 1: pathology, clinical features and molecular genetics. Brain Pathol 1995; 5:153-62. Wakeling A. Comparative study of psychiatric patients with Klinefelter's syndrome and hypogonadism. Psychol Med 1972; 2:139-54. Wallace MR, Marchuk DA, Andersen LB et al. Type 1 neurof ibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990; 249:181-6. Warren AC, Holroyd S, Folstein MF. Major depression in Down's syndrome. Br J Psychiatry 1989; 155:202-5. Webb DW, OsborneJP. New research in tuberous sclerosis. Br Med J 1992; 304:1647-8. Webb DW, Osborne JP. Tuberous sclerosis. Arch Dis Child 1995; 72:47-4. Weber FP. A note on the association of extensive haemangiomatous naevus of the skin with cerebral (meningeal) haemangioma especially cases of facial vascular naevus with contralateral hemiplegia. Proc R Soc Med 1929; 22:431-42. Wisniewski K, Dambska M, Sher JH et al. A clinical neuropathological study of the fetal alcohol syndrome. Neuropediatrics 1983; 14:197-201. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol 1985a; 17:278-82. Wisniewski KE, Dalton AJ, McLachlan DRC et al. Alzheimer's disease in Down's syndrome: clinicopathologic studies. Neurology 1985b; 35:957-61. Wisniewski KE, Frency JH, Fernando S et al. Fragile X syndrome: associated neurological abnormalities and developmental disabilities. Ann Neurol 1985c; 18:665-9. Witt-Engerstrom I. Rett syndrome in Sweden. Neurodevelopment- disability - pathophysiology. A ct a Pediatr Scand 1990; (suppl 369).

Congenital disorders 461 Wohlwill FS, Yakovlev PI. Histopathology of meningo-facial angiomatosis (Sturge-Weber's disease). J Neuropathol Exp Neural 1957; 16:341-64. Yakovlev PI, Corwn W. Roentgenographic sign in cases of tuberous sclerosis of the brain (multiple 'brain stones'). Arch Neurol Psychiatry 1939; 40:1030-7. Yang TP, Patel PI, Stout JT et al. Molecular evidence for new mutations in the HPRT locus in Lesch-Nyhan patients. Nature 1984; 310:412-14. Zellweger H, Schneider HJ. Syndrome of hypotonia-hypomentia-hypogonadism-obesity (HHHO) or Prader-Willi syndrome. Am J Dis Child 1968; 115:588-98.

10 Vascular disorders Multi-infarct dementia Lacunar dementia Arteriosclerotic parkinsonism Binswanger's disease Cranial arteritis Cerebral amyloid angiopathy

CADASIL

462 463 464 465 466 467 468

Granulomatous angiitis Polyarteritis nodosa Wegener's granulomatosis Behcet's syndrome Hypertensive encephalopathy Transient global amnesia

469 470 471 472 473 474

MULTI-INFARCT DEMENTIA Pathology and etiology

In most cases of multi-infarct dementia, there are multiple, bilateral, large cortical or subcortical infarctions (Erkinjunti et al. 1988; Jayakumar et al 1989; Ladurna et al. 1982; Liu et al. 1992; Tomlinson et al. 1970); rarely, dementia may be found secondary to one or only a small number of infarcts (Yoshitake et al. 1995) that are, however, 'strategically' placed, for example in the temporal lobe. Most cases result from arteriosclerosis, with either thrombotic or embolic infarction; a substantial minority, however, probably derive from 'watershed' infarctions (Meyer et al. 1988). Other causes include polyarteritis nodosa, cranial arteritis (Caselli 1990), systemic lupus erythematosus, meningovascular syphilis, tuberculous meningitis, sickle cell disease, hypertensive encephalopathy, and the rare Sneddon's syndrome, a diagnosis suggested by the presence of livedo reticularis (Jura et al. 1994; Rebollo et al. 1983). Multiple intracerebral hemorrhages, as may occur in cerebral amyloid angiopathy, should probably also be included here: although, strictly speaking, hemorrhages do not fall under the rubric of infarct, the clinical end result is the same. Clinical features

As most large cortical or subcortical infarctions caused by arteriosclerosis typically make their first appearance in the fifties or sixties, the onset of multi-infarct dementia is generally found in this age range. Exceptions, of course, occur with etiologies such as sickle cell disease that have an earlier age of onset: in most cases, one finds a history of sequential strokes preceding the onset of the dementia. In its fully developed form, the dementia is often accompanied by delusions (typically of persecution or infidelity), depressive symptoms, and hallucinations (Cummings et al. 1987). In severe cases, one may see a pseudobulbar palsy with emotional

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incontinence. Typically, one also finds focal signs, reflecting the location of the underlying infarcts, such as hemiplegia, aphasia, apraxia, and aprosodia; seizures may also occur. Magnetic resonance imaging (MRI) or computed tomography scanning reveals evidence of the infarctions. Course One typically finds a 'stepwise' or 'stuttering' downhill course, each fresh infarction bringing the patient down yet one further 'step' into the dementia. Exceptions include dementia secondary to a single, strategically placed infarction, in which the patient takes one 'large' step down all at once, and conditions, such as hypertensive encephalopathy, wherein the patient suffers multiple infarctions closely spaced in time, after which, presuming that the hypertension is controlled, there are no further incidents. In many cases, the 'step' down may be characterized by a delirium, which gradaully clears as the peri-infarction edema resolves, leaving the patient once again with a clear sensorium but a more severe degree of cognitive deficit. Differential diagnosis

Lacunar dementia is distinguished by the presence of elements of a frontal lobe syndrome and by the appearance of small lacunes on MRI scanning. Although Alzheimer's disease is easily distinguished by its course, which is one of gradual rather than 'step-wise' progression, it must be borne in mind that a minority of patients may have a 'mixed' dementia, suffering from both Alzheimer's disease and a multi-infarct process (Tomlinson et al 1970). In evaluating a patient with dementia who also happens to have evidence of one or more infarctions, it is important to consider the location of those infarctions before making the diagnosis of multi-infarct dementia. For example, whereas a single large infarction in the temporal lobe might cause a dementia, it is highly improbable that a comparably sized infarction in the occipital lobe would. Treatment

The general treatment of dementia is discussed in Chapter 5. Treatment is also directed at the underlying etiology of the infarctions. In the case of arteriosclerosis, attention to risk factors such as hypertension and diabetes is essential; importantly, however, in the case of hypertension, one must avoid creating hypotension, with its attendant risk of watershed infarctions. Preventive treatment with a combination of aspirin and dipyridamole (Wilterdink and Easton 1999) or with clopidogrel is appropriate in most cases.

LACUNAR DEMENTIA Pathology and etiology

Lacunes are small, fluid-filled cysts, ranging in size from 5 to 15mm, that result from infarction in the territories of small penetrating arterioles; they may be found in the brainstem, thalamus, internal capsule, basal ganglia, and centrum semiovale. Although single lacunes, if strategically placed (e.g. in the thalamus [Katz et al. 1987; Mori et al. 1986; Sandson et al. 1991]) may cause a dementia, in most cases dementia does not appear until a dozen or more lacunes appear (Ishii et al. 1986). Occlusion of the penetrating arterioles generally occurs secondary to lipohyalinosis (Fisher 1969); embolic occlusion may also occur (Laloux and Brucher 1991; Cacciatore and Russo 1991). Although most patients are hypertensive (Fisher 1965; Sacco et al. 1991), a substantial minority are not (Millikan and Futrell 1990). Rarely, lacunar dementia may result from cranial arteritis (Nightingale et al. 1982).

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Clinical features

The onset is in the fifties or sixties, and the dementia may either undergo a smooth and gradual progression, or pursue a 'stepwise' course (Ishii et al. 1986; Yoshitake et al. 1995). In its fully developed form (Ishii et al. 1986; Wolfe et al. 1990), the dementia is often accompanied by a frontal lobe syndrome, with prominent abulia, and often also by a pseudobulbar palsy with emotional incontinence. Specific 'lacunar syndromes' may be found, such as pure motor hemiplegia, pure sensory stroke, and ataxic hemiparesis. Routine MRI scanning reveals the lacunes, diffusion-weighted imaging indicating those which are 'fresh' (Choi et al. 2000; Oliveira-Filho et al 2000).

Course As noted above, the progression of this dementia may be either gradual or 'stepwise'. Differential diagnosis

Multi-infarct dementia is distinguished by the presence of prominent cortical infarcts on MRI scanning. Binswanger's disease is distinguished by MRI findings of a diffuse leukoencephalopathy. CADASIL is distinguished by migrainous headaches, a positive family history, and MRI evidence of a leukoencephalopathy. Treatment

t

This is similar to that described for multi-infarct dementia, above.

ARTERIOSCLEROTIC PARKINSONISM Pathology and etiology In arteriosclerotic parkinsonism (vascular parkinsonism), multiple lacunes are found in the basal ganglia (Bruetsch and Williams 1954; Keschner and Sloane 1931; Murrow et al. 1990); lacunes may also be found in the internal capsule, centrum semiovale, and brainstem. The etiology of these lacunes is presumably as that described for lacunar dementia, above. Clinical features

The clinical features of arteriosclerotic parkinsonism have been described in a number of reports (Bruetsch and Williams 1954; Keschner and Sloane 1931; Murrow et al. 1990; Tolosa and Santamaria 1984). The onset is in the seventh or eighth decade and is characterized by a gradually progressive parkinsonism. The parkinsonism is generally initially asymmetric, being typically characterized by rigidity, bradykinesia, and a gait abnormality; tremor is generally not present. Although the patient's posture is generally erect, there may, at times, be a flexion posture. The gait is unsteady, and patients may walk with small shuffling steps or display a 'magnetic' gait, wherein they have trouble lifting their feet from the floor, as if the feet were magnetically held in place. Corticospinal tract findings, such as hyperreflexia and Babinski signs, are often present, and some patients may display a pseudobulbar palsy with emotional incontinence. Some patients develop a dementia (Bruetsch and Williams 1954; Keschner and Sloane 1931), characterized by slowness and sluggishness of thought, poor concentration and poor memory. MRI scanning reveals the subcortical iscehemic lesions (Zijlmans et al. 1995). Course Although not well characterized, the course of arteriosclerotic parkinsonism appears to be one of gradual progression to a bedfast state.

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Differential diagnosis

Parkinson's disease generally produces tremor and a flexion posture; furthermore, patients typically display a marche a petite pas rather than a shuffling or magnetic gait. Finally, corticospinal tract findings and pseudobulbar palsy are lacking. Dementia pugilistica is suggested by the history of repeated head trauma and the presence of ataxia. The striatonigral variant of multiple system atrophy is distinguished by the presence of ataxia and signs of autonomic failure such as urinary incontinence, postural dizziness, and impotence. Corticobasal ganglionic degeneration is distinguished by the presence of dystonia and apraxia. Progressive supranuclear palsy closely mimics arteriosclerotic parkinsonism, and the two diseases may be difficult to distinguish, especially early on in the course of the patient's illness. The appearance of multiple lacunes on MRI scanning favors arteriosclerotic parkinsonism, while the appearance of supranuclear ophthalmoplegia points definitively towards progressive supranuclear palsy. Treatment

This is similar to that for multi-infarct dementia (see above); although levodopa may be effective in some cases (Murrow et al. 1990), it is generally not of benefit. The general treatment of dementia is discussed in Chapter 5.

BINSWANGER'S DISEASE Pathology and etiology

Binswanger's disease (progressive subcortical arteriosclerotic encephalopathy) (Bennett et al. 1990) is characterized by lipohyalinosis of the penetrating arterioles subserving both the white matter of the centrum semiovale, and the diencephalon and basal ganglia. In the centrum semiovale there is widespread demyelinization, at times with cystic changes; at the base of the brain, one may find lacunar infarcts (Revesz et al. 1989). Although hypertension is suspected to be the cause (van Swieten et al. 1991), some patients with Binswanger's disease have been normotensive. Clinical features

As described by Binswanger in 1894 (Blass et al. 1991), the onset is generally in the fifties or sixties with a 'slow development of the deterioration of the intellectual capacities'. Patients experience gradually worsening forgetfulness, slowness of thought, and concreteness. As noted above, lacunar infarcts may also occur (Kinkel et al. 1985; Revesz et al. 1989), with various focal findings: in some cases, a pseudobulbar palsy may appear (Caplan and Schoene 1978). In addition, some patients may suffer typical cortical infarcts (Loizou et al. 1981). T2-weighted MRI scanning reveals generally symmetric, confluent patches of increased signal intensity in the centrum semiovale (Bennett et al. 1990), as illustrated in Figure 10.1. Course Binswanger's disease is gradually progressive. Differential diagnosis

Lacunar dementia is distinguished by the absence of prominent leukoencephalopathy on MRI scanning.

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Image Not Available

Figure 10.1 A T2-weighted magnetic resonance imaging scan in a case of Binswanger's disease, with large confluent areas of increased signal intensity in the centrum semiovale. (Reproduced from Gillispie and Jackson 2000.)

CADASIL is distinguished by the history of migrainous headaches and by the positive family history. Alzheimer's disease is distinguished by a presentation with progressive amnesia, which would be very unusual for Binswanger's disease; furthermore, Alzheimer's disease does not produce the leukoencephalopathy seen on MRI scanning in Binswanger's disease. Normal-pressure hydrocephalus generally presents with a combination of dementia, gait abnormality ('magnetic' gait) and urinary incontinence: such a combination, although possible in Binswanger's disease (Rosenberg et al. 1979), is very rare. In such cases, MRI scanning is helpful, demonstrating prominent ventriculomegaly in normal-pressure hydrocephalus and prominent leukoencephalopathy in Binwanger's disease. Treatment

Hypertension should be judiciously controlled, guarding against overtreatment with hypotension and possible 'watershed' infarcts. The general treatment of dementia is as outlined in Chapter 5.

CRANIAL ARTERITIS Pathology and etiology

Cranial arteritis (giant cell arteritis, temporal arteritis) is a systemic vasculitis primarily affecting the branches of the external carotid artery (including the superficial temporal, occipital, and facial arteries), branches of the internal carotid artery (especially the ophthalmic artery), the vertebral arteries, and, rarely, the coronary arteries. The arteries involved show a granulomatous panarteritis, with giant-cell involvement; importantly, these arteries are

Vascular disorders 467

affected not through their entire length but rather in a patchy, segmental fashion. Thrombosis may occur, with infarction of the subserved tissue; in some cases, emboli may be generated, leading to downstream occlusion and infarction (Wilkinson and Russell 1972). Although the etiology of the vasculitis is not clear, an autoimmune mechanism is suspected. The disease is rare in blacks, is most common in those of Scandinavian descent, and has been associated with HLA-DR4. Clinical features

The onset typically occurs in those over 50 years of age. Common features include constitutional symptoms (fever, malaise, and weight loss), polymyalgia rheumatica, headache, and visual disturbances. Polymyagia rheumatica presents with aching pain and stiffness, primarily in the neck and shoulders, but also affecting the hips and thighs and the lower back. The headache, caused by an involvement of the superficial temporal or occipital artery, is generally severe and, although typically unilateral, may at times be bilateral. Although usually temporal in location, it may also occur in the occipital region. Visual involvement may include amaurosis fugax or, in a small minority with occlusion of the ophthalmic artery, permanent blindness (Caselli et al. 1988). Involvement of the facial artery may cause jaw claudication, and myocardial infarction may follow inflammation of a coronary artery. Involvement of the internal carotid artery or its branches generally occurs only in the setting of other symptoms, such as headache or visual disturbance: involvement of multiple large branches may lead to a multi-infarct dementia (Caselli 1990), whereas an involvement of the small penetrating arteries at the base of the brain may cause a lacunar dementia (Nightingale et al 1982). With but rare exceptions (Kansu et al. 1977), the erythrocyte sedimentation rate (ESR) is elevated, often markedly so, and there may also be a mild anemia. Diagnosis is confirmed by the biopsy of an involved artery; given the segmental nature of the inflammation, false-negative biopsies may occur. Course Spontaneous remissions typically occur between a few months and 3 years after the onset of the disease. Differential diagnosis

Other vasculitides must be considered: polyarteritis nodosa is suggested by renal or gastrointestinal involvement, and systemic lupus erythematosus by a positive antinuclear antibody test. Treatment t

Prednisone, in doses of 60 mg or more per day, is urgently required whenever there is evidence of ophthalmic, intracranial or coronary artery involvement. Once the symptoms have been controlled, the dose may be reduced to the minimum required to suppress inflammation.

CEREBRAL AMYLOID ANGIOPATHY Pathology and etiology Cerebral amyloid angiopathy (congophilic amyloid angiopathy) may occur on either a sporadic or an hereditary basis, sporadic cases being by far the most common. In both the sporadic and the hereditary type, there is amyloid fibril deposition in small cortical and meningeal arteries, eventually resulting in fibrinoid necrosis, with, in some cases, microaneurysm formation (Okazaki et al. 1979). The amyloid fibrils characteristically stain

468 Specific disorders

well with Congo red, which accounts for the synonym 'congophilic amyloid angiopathy.' Over time, widespread fibrinoid necrosis leads to a progressive leukoencephalopathy (Gray et al. 1985), and aneurysms may enlarge and burst, causing lobar intracerebral hemorrhages. The etiology of the sporadic type is not known. There are two hereditary types, both demonstrating autosomal dominant inheritance: 1. hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) (Haan et al. 1990a, b; Wattendorff et al. 1995), which occurs secondary to a mutation in the gene for the beta-amyloid precursor protein on chromosome 21 (Levy et al. 1990), producing a variant of the beta-amyloid peptide 2. hereditary cerebral hemorrhage with amyloidosis, Icelandic type (HCHWA-I) (Gudmundsson et al. 1972), which occurs secondary to a mutation in the gene for cysplatin C on chromosome 20 (Palsdottir et al. 1988), with the production of a variant of cystatin C. Clinical features

The onset is in the middle or older years and may be with either a gradually progressive dementia or a lobar intracerebral hemorrhage. Several different clinical pictures are possible (Cosgrove et al. 1985; Gilles et al. 1984; Haan et al. 1990b; Nobuyoshi et al. 1984). In some, the disease manifests only with a gradually progressive dementia; in others, the only manifestation is a recurrence of lobar intracerebral hemorrhage; and, finally, in some, there is the distinctive (Nobuyoshi et al. 1984) clinical picture of a combination of a gradually progessive dementia and recurrent lobar intracerebral hemorrhages. In some cases of dementia (Greenberg et al. 1993), one may also see minor transient focal signs, or perhaps partial seizures, and it is believed that these occur secondary to petechial hemorrhages arising from microaneurysms. MRI scanning, in addition to revealing evidence of lobar hemorrhage, may also show up old petechial hemorrhages. Course

Cerebral amyloid angiopathy is progressive. Differential diagnosis

The combination of a progressive dementia with lobar intracerebral hemorrhage is distinctive. It must be emphasized, however, that cerebral amyloid angiopathy is associated with lobar hemorrhages rather than deep-seated hypertensive hemorrhage, as may occur in the basal ganglia. In cases in which cerebral amyloid angiopathy manifests only with a progressive dementia, the clinical picture may be indistinguishable from that of Binswanger's disease. Treatment

There is no specific treatment. Lobar hemorrhages may require removal, but the fragility of the nearby vessels carries an increased risk of postoperative bleeding (Greene et al. 1990). The general treatment of dementia is discussed in Chapter 5. Heparin, warfarin, and tissue plasminogen activator (Pendlebury et al. 1991) all increase the risk of lobar hemorrhage in these patients.

CADASIL Pathology and Etiology gy

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Jnfarcts and Leukoencephalopathy) is characterized pathologically by concentric fibrous thickening of small penetrating arteries (Sourander and Walinder 1977), leading to both subcortical infarcts

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and a widespread leukoencephalopathy (Baudrimont et al. 1993). Although peripheral nerves (Schroder et al 1995) and skin (Ruchoux et al. 1994) may also be involved, symptoms referable to them are generally absent. CADASIL is an autosomal dominant condition occurring secondary to mutations in the Notch3 gene on chromosome 19 (Joutel et al 1997; Tournier-Lasserve et al 1993). Although the mechanism underlying the fibrous thickening is unknown, an autoimmune process is suspected. Clinical features

The onset is generally in middle age, patients generally presenting with migrainous headaches or stroke. Over time, about one-quarter will manifest a progressive dementia. Focal signs and ataxia may occur, as may a pseudobulbar palsy; seizures occur in a small minority (Bergmann et al 1996; Dichgans et al 1998; Jung et al 1995; Malandrini et al 1996; Sourander and Walinder 1977). CADASIL may rarely present with a progressive dementia without any stroke-like episodes (Mellies et al 1998). MRI scanning reveals subcortical infarctions and a diffuse leukoencephalopathy. Sural nerve biopsy may be diagnostic (Lechner-Scott et al 1996). Course CADASIL is progressive, a mean survival of 14 years being noted in one study (Dichgans et al 1998). Differential diagnosis

Binswanger's disease is similar to CADASIL in that it manifests with a progressive dementia associated with leukoencephalopathy, but it lacks the migrainous headaches and family history, and is only uncommonly associated with subcortical infarctions. Lacunar dementia resembles CADASIL in that it manifests with a progressive dementia, often associated with subcortical infarctions; lacunar dementia, however, lacks the headaches and family history, and MRI scanning fails to reveal a leukoencephalopathy. Multi-infarct dementia resembles CADASIL in that it manifests with a dementia associated with strokes, although it differs in several respects: unlike CADASIL, wherein the dementia is gradually progressive, the dementia of multi-infarct dementia shows a 'stepwise' progression; furthermore, the infarctions in multi-infarct dementia are cortical, in contrast to the subcortical location of the infarctions of CADASIL. Treatment

There is no specific treatment for CADASIL; the general treatment of dementia is discussed in Chapter 5.

GRANULOMATOUS ANGIITIS (PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM) Pathology and etiology There is a widespread granulomatous angiitis (Cravioto and Feigin 1959), affecting both the small leptomeningeal and small and medium-sized parenchymal vessels. Although the cerebrum is most heavily affected, the cerebellum, brainstem, and even the spinal cord may also be involved. Multiple small thrombotic infarcts are found, and in severe cases, portions of the subarachnoid space may be filled with exudate. The angiitis is confined to the central nervous system.

470 Specific disorders

Although the etiology is unknown, an autoimmune response, perhaps triggered by a viral infection, is suspected. Clinical features The onset is generally fairly acute, over days to weeks, and most patients are aged over 40. Clinically (Calabrese and Mallek 1987; Case Records 1989; Hughes and Brownell 1966; Kolodnyetal. 1968; Koo and Massey 1988; Moore 1989;Vollmer et al. 1993), headache is often prominent, and patients may also present with personality change, delirium, or dementia. Seizures may occur, as may focal findings. The ESR is normal or only mildly elevated (Lie 1992; Moore 1989). Analysis of the cerebrospinal fluid (Vollmer et al. 1993) may reveal a mononuclear pleocytosis and an elevated protein level; the glucose concentration is normal. MRI scanning may be normal (Alhalabi and Moore 1994; Ehsan et al. 1995) or, on T2weighted scans, may reveal multifocal areas of high signal intensity. Angiography may reveal multifocal 'beading' but, in one study, was normal in over one-half of patients (Alrawi et al. 1999) Biopsy of the leptomeninges and underlying cortex typically reveals the granulomatous angiitis; occasionally, however, the biopsy may miss the 'target', yielding a false-negative result (Alhalabi and Moore 1994; Lie 1992). Course

The disease is generally progressive, death occurring from days up to 2 or more years later, most patients surviving only a few months. Differential diagnosis Subacute meningitis is suggested by a decreased cerebrospinal glucose level, and polyarteritis nodosa by manifestations outside the central nervous system. Treatment Prednisone and cyclophosphamide are recommended. The general treatment of dementia and delirium are discussed in Chapter 5.

POLYARTERITIS NODOSA Pathology and etiology Polyarteritis nodosa (periarteritis nodosa, panarteritis nodosa) is a systemic vasculitis affecting virtually every organ system except the lungs. Both medium and small arteries are affected, typically in a patchy, multifocal fashion; the entire vascular coat undergoes inflammation, which may at times be necrotizing. Thrombosis may occur, with infarction in the tissues served, and the vessel walls may become so thinned that aneurysmal dilatations occur. Occasionally, these aneurysms burst, but generally they become fibrosed into nodular masses along the arteries involved. The organ systems most affected are the kidneys and those of the musculoskeletal system, and gastrointestinal tract; the central and peripheral nervous systems are involved in only a minority. Although the etiology is unknown, an autoimmune mechanism is suspected. In cases associated with hepatitis B or C, a deposition of antigens on the vessel walls may be the inciting factor for the immune response. Clinical features The onset is typically in the middle years. Central nervous system manifestations generally do not occur in isolation but rather appear in the setting of other manifestations (Sigal 1987),

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71

such as constitutional symptoms (malaise, fever, and weight loss) or evidence of renal or gastrointestinal disease. Delirium may occur (Ford and Siekert 1965), as may dementia (MacKay et al. 1950). Other symptoms include headache, seizures, and focal signs, such as hemiplegia. Peripheral nervous system involvement may result in a mononeuritis multiplex, which may become so extensive as to mimic a diffuse peripheral polyneuropathy. Anemia, leukocytosis, and an elevated ESR are common, and the VDRL test for syphilis may be falsely positive. MRI scanning may show evidence of multiple infarcts. Definitive diagnosis rests on biopsy of affected tissue, often taken from muscle, peripheral nerve, or testis. Course

The 5 year survival rate is less than 15%, most dying within the first year. Differential diagnosis

Other systemic disorders capable of causing central nervous system disease in the context of constitutional symptoms or other organ disease include systemic lupus erythematosus and Wegener's granulomatosis. Systemic lupus erythematosus is indicated by a positive antinuclear antibody test, and Wegener's granulomatosis by upper airway involvement. Not all deliria occurring in patients with polyarteritis nodosa is secondary to direct central nervous system involvement. Renal or hepatic failure may cause, respectively, uremic or hepatic encephalopathy, furthermore, renal hypertension may lead to a hypertensive encephalopathy. Treatment

Prednisone suppresses inflammation and, when combined with cyclophosphamide, may induce a remission.

WEGENER'S GRANULOMATOSIS Pathology and etiology Wegener's granulomatosis is a systemic vasculitis involving both small arteries and veins, affecting primarily the vessels in the upper respiratory tract and kidneys; central or peripheral nervous system involvement occurs in a minority, generally in the setting of respiratory or renal damage (Hoffman et al. 1992). In the respiratory tract, the paranasal sinuses and nasopharnyx are most involved. Lower respiratory tract involvement may manifest with granulomatous pulmonary infiltrates, and granuloma formation may also occur in the orbit. Renal involvement typically involves a glomerulonephritis. Central nervous system involvement (Drachman 1963, Nishino et al. 1993a) may include isolated infarctions secondary to vasculitis, a widespread cerebral vasculitis, or granuloma formation, which may at times be extensive. Peripheral nervous system involvement may include a mononeuritis multiplex or cranial neuropathies. Although the etiology is unknown, an immune response, perhaps triggered by some inhaled substance, is strongly suspected. Clinical features

Disease onset is typically in the thirties or forties. Respiratory tract involvment may cause rhinorrhea, epistaxis, or otitis media; lower respiratory tract involvement may be asymptomatic or cause cough or hemoptysis. The nasal septum, if severely involved, may collapse, leading to a saddle-nose deformity. Orbital granulomas may lead to proptosis. Glomerulonephritis may

472 Specific disorders

present with microscopic hematuria and proteinuria. Cerebral involvement may manifest with strokes, seizures, and delirium (Nishino et al. 1993a,b; Weinberger et al. 1993). Hypothalamic involvement may be indicated by diabetes insipidus (Rosete et al, 1991). The ESR is elevated, and antineutrophil cytoplasmic antibody (c-ANCA) is generally present. MRI scanning may reveal vasculitis, infarctions, or granulomatous masses. Cerebrospinal fluid analysis may reveal a lymphocytic pleocytosis and an elevated protein concentration. Diagnosis is confirmed by biopsy of affected tissue, usually from the respiratory tract. Course The disease typically pursues a progressive course. Once renal involvement appears, death generally occurs within a few months. Differential diagnosis

Wegener's granulomatosis is distinguished from polyarteritis nodosa by respiratory involvement and by the presence of c-ANCA. Treatment t

A combination of prednisone and cyclophosphamide induces a remission in the majority of patients.

BEHCET'S SYNDROME Pathology and etiology gy

Behc,et's syndrome is a systemic, primarily venular, vasculitis with a predilection for the pharynx, eyes, and genitalia; the central nervous system is involved in a minority of cases, and the skin and gastrointestinal tract may also be affected. Beliefs syndrome is probably an autoimmune disease. In some cases, it appears to be familial. Clinical features

Bel^et's syndrome usually occurs in attacks, the first attack generally occurring in the twenties. Almost all patients have both aphthous and genital ulcers during attacks. Neurologic involvement, although occasionally seen early on, is generally delayed until later attacks, and, in any case, is seen in only a minority of patients (Serdaroglu et al. 1989; Wolf et al. 1965). Symptoms referrable to the central nervous system include headache, meningitis, stroke, ataxia, seizures, abnormal movements (e.g. chorea), and dementia (Akman-Demir etal. 1999; Altinors et al. 1987; Chajek and Fainaru 1975; Farah et al. 1998; Iragui and Miravi 1986; Kidd et al. 1999; Motomura et al. 1980). Interestingly, the dementia is not uncommonly accompanied by a pseudobulbar palsy with emotional incontinence (Pallis and Fudge 1956; Motomura et al. 1980; Rubinstein and Urich 1963; Wechsler et al. 1990). In some cases, attacks may be accompanied by delirium (Akman-Demir et al. 1993; Serdaroglu et al. 1989). Rarely, central nervous system involvement may present with depression (Wadia and Williams 1957) or psychosis (Akman-Demir et al. 1993). Other clinical features include dural sinus thrombosis, uveitis, erythema nodosum, arthritis, migratory thrombophlebitis, and, classically, pathergy, wherein pustules form at the site of minor trauma, such as venipuncture. The ESR may be elevated, and there may be a mild leukocytosis. MRI scannning may, with T2-weighting, reveal multiple areas of increased signal intensity, more so in the white than the gray matter, some of which may have a mass effect.

Vascular disorders 473

The cerebrospinal fluid contains a lymphocytic pleocytosis in the majority of cases, which may or may not be accompanied by an elevated protein level (Akman-Demir et al. 1999; Farah etal 1998). Course

Recurrent attacks, with only a partial remission of symptoms in the intervals, are the rule; in some cases, this relapsing and partially remitting pattern may merge into one of steady progression, whereas in others there may be a progressive course from the outset (AkmanDemir et al. 1999); in some cases, one may see a progressively worsening dementia (Borson 1982). Differential diagnosis

The combination of central nervous system symptomatology with aphthous and genital ulcers is fairly distinctive and distinguishes Behcet's syndrome from multiple sclerosis. Systemic lupus erythematosus is indicated by a positive antinuclear antibody. Treatment t

Prednisone and immunosuppressive therapy with azothiaprine or cyclosporin are indicated during attacks with central nervous system findings.

HYPERTENSIVE ENCEPHALOPATHY Pathology and etiology With sustained rises in diastolic pressure to 130mmHg or above, cerebral arterial autoregulation fails, leading to extravasation from the arteries and fibrinoid necrosis. There is widespread cerebral edema, petechial hemorrhages, and infarctions, most of which are small (Chester et al. 1978). Such sustained rises in diastolic pressure may occur in essential hypertension, renal disease, pheochromocytoma, eclampsia (Manfredi et al. 1997), and intoxication with stimulants (e.g. cocaine), and in patients on monoamine oxidase inhibitors who take restricted foods or medications. Clinical features

The onset is gradual, over a day or so, with headache, nausea and vomiting, and delirium. Nuchal rigidity and seizures may occur, as may focal signs such as hemiplegia, aphasia, and cortical blindness (Chester etal 1978; Healton et al. 1982; Oppenheimer and Fishberg 1928). On examination, there may be papilledema. T2-weighted MRI scanning may demonstrate symmetric, diffuse increased signal intensity in the cerebral white matter, most prominently in the posterior regions (Hauser et al. 1988). Course

Untreated, the encephalopathy may progress to coma and death. Those who survive may be left with permanent sequelae, including a multi-infarct dementia. Differential diagnosis

Not all deliria occurring in hypertensive patients are secondary to hypertensive encephalopathy: a hypertensive intracerebral hemorrhage may present with delirium, and patients with hypertensive renal disease may develop a uremic encephalopathy. Treatment t

Hypertensive encephalopathy is a medical emergency, and the pressure must be lowered within the hour. Critically, the goal here is not to achieve a normotensive level but merely to

474 Specific disorders

lower the pressure to the point at which the symptoms begin to resolve, usually at a diastolic pressure of a little below 120mmHg; rapid lowering of the diastolic pressure to a normotensive level may be followed by cerebral ischemia and 'watershed' infarctions. Once the patient is out of danger, the pressure may gradually be lowered over several days, which will allow enough time for the cerebral autoregulation to reset. Intravenous nitroprusside is preferrred; in less urgent situations, sublingual nifedipine may suffice. Seizures may be treated with intravenous lorazepam.

TRANSIENT GLOBAL AMNESIA Pathology and etiology gy

Although the etiology of transient global amnesia is not clear, it probably represents transient dysfunction of one or more of those structures crucial to memory, such as the hippocampus, the fornix, or the thalamus. The cause of this dysfunction is presumed to be ischemic, migrainous, or perhaps epileptic (Hodges and Warlow 1990). Transient ischemia in the distribution of the posterior cerebral artery or the penetrating central arteries, affecting, respectively, the medial temporal lobes and the thalamus, could certainly cause an amnestic disturbance. Such an event has been noted during medical procedures, for example vertebral (Jackson et al. 1995) and cardiac (Shuttleworth and Wise 1973) angiography. Migraine has been associated with transient global amnesia (Crowell et al. 1984). Presumably the underlying pathophysiologic process of migraine, perhaps the 'spreading depression of Laeo', involves the temporal lobes, thereby producing the amnesia. Epileptic factors have long been suspected, but it may be more appropriate here to speak of amnestic seizures, as discussed in Chapter 7. There is also a report of a familial clustering of transient global amnesia (Corston and Godwin-Austen 1982). Clinical features

The first episode of transient global amnesia generally occurs in the early sixties (Kushner and Hauser 1985; Miller et al. 1987). In clinical terms (Bolwig 1968; Fisher and Adams 1958, 1964; Gordon and Marin 1979; Heathfield et al. 1973; Hodges and Ward 1989; Kushner and Hauser 1985; Miller et al. 1987; Regard and Landis 1984; Shuttleworth and Morris 1966), the episode begins abruptly as patients are suddenly beset with an amnesia comprising both anterograde and retrograde components. The anterograde component is manifest in patients' inability to track what goes on around them: to formal testing, although the digit span is intact, patients are unable to recall any of three words after 5 minutes. The retrograde component covers a variable period of time before the episode began, ranging from only hours to up to years or longer; the retrograde amnesia often displays a 'gradient', being denser for those events relatively close in time to the episode and only patchy for those which occurred long before (Kritchevsky and Squire 1989). During the episode, patients are, although not confused, nevertheless bewildered as they find themselves unable to recall what they were doing or how they came to be where they are: typically, patients ask again and again where they are or what is happening. Remarkably, other abilities are left quite intact, and some patients may be able to carry out quite complex activities, such as playing a musical instrument, during the episode (Byer and Crowley 1980). The episodes themselves tend to last of the order of 4-18 hours, remission generally being gradual. After the episode has ended, although patients are once again able to recall events

Vascular disorders 475

leading up to the onset of the episode and are also able to recall events that occurred subsequent to its remission, there is yet a permanent 'island' of amnesia covering the episode itself, and patients remain unable to recall what transpired during it. Interestingly, the onset of the episode may be associated with such emotional or stressful experiences as sexual intercourse, pain, or arguments (Fisher 1982; Kushner and Hauser 1985). Course Most patients have but one episode: of the small minority who have more than one, the interval between episodes is generally a little over 2 years (Miller et al. 1987). Although most patients find themselves fully recovered, detailed examination may reveal some subtle, subclinical deficits (Steinmetz and Vroom 1972). Differential diagnosis

Blackouts, as may be seen with alcohol or sedative-hypnotics, are suggested by other signs of intoxication. There are cases on record of unquestionable transient ischemic attacks causing a syndrome identical to transient global amnesia, and it may be a matter of definition here whether one wishes to include these attacks under the rubric of transient global amnesia or keep them separate as definite, unquestionably ischemic events. Thus, episodes have been recorded with ischemia of the thalamus (Gorelick et al. 1988) and ischemia in the area of distribution of the posterior cerebral artery (Benson et al. 1974): in the latter case, the amnesia was accompanied by visual defects, such as hemianopia, cortical blindness, or tunnel vision. Amnestic seizures, as discussed in Chapter 7, are distinguishable from transient global amnesia by their onset in early adulthood, their relative brevity, a tendency to frequent recurrence, and the presence, at other times, of other seizure types, such as complex partial seizures (Palmini et al. 1992). Treatment

Reassurance and observation are generally sufficient. The best preventive treatment is not clear: some clinicians, suspecting a vascular etiology, recommend low-dose enteric-coated aspirin, whereas others, leaning toward a migrainous or epileptic cause, prescribe divalproex.

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11 Trauma Subdural hematoma Diffuse axonal injury Dementia pugilistica

481 483 484

Post-concussion syndrome Radiation encephalopathy

485 486

SUBDURALHEMATOMA SUBDURAL HEMATOMA Pathology and etiology

Subdural hematomas may occur in any one of three forms: acute, subacute, and chronic. Acute subdural hematomas result from arterial bleeding, with, as might be expected, a rapid expansion of the hematoma. Subacute and chronic hematomas, by contrast, result from venous bleeding, often because of rupture of the bridging veins between the parenchyma and the dura mater, and are of much slower onset. Typically, subdural hematomas are found over the convexity and are, not uncommonly, bilateral. In a small minority, the hematoma tracks along the interhemispheric fissure or between the occipital lobe and the tentorium cerebelli. Coagulation occurs, and, over a week or two, hemolysis converts much of the hematoma into a clear, colorless fluid. Although, in most cases, 'the hematoma undergoes complete resorption (Dolinskas et al. 1979), in a minority it becomes encapsulated and remains chronic, as seen in Figure 11.1. Such chronic subdural hematomas may expand over time, presumably because of repeated bleeding from small fragile vessels arising from the underlying parenchyma (Markwalder 1981). Some chronic subdural hematomas eventually undergo calcification. Subdural hematomas may result from falls, blows to the head, or 'whiplash' type injuries: in

Image Not Available

Figure 11.1 Bilateral encapsulated subdural hematomas seen over the convexities. (Reproduced from Graham and Lantos 1996.)

482 Specific disorders

each case, there is a violent injury of the acceleration-deceleration type, with rupture of the subdural vessels. Hematomas are more likely in those taking anticoagulants and in the elderly: indeed, the subdural vessels in the elderly may be so fragile that even trivial injuries, long forgotten by the patient, may be responsible (Cameron 1978; Fogelholm and Waltimo 1975). Clinical features

In the case of acute subdural hematoma, there may or may not be a 'lucid interval', lasting perhaps hours, between the trauma and the onset of symptoms. Patients may present with the rapid evolution of delirium or stupor. With progression, coma occurs, and there may be uncal herniation, with ipsilateral mydriasis and contralateral hemiparesis (although uncommonly, the hemiparesis may be ipsilateral, and, rarely, the mydriasis may be contralateral). Subacute subdural hematoma may present anywhere from days up to 2 weeks post-trauma: patients may present with delirium (Black 1984), the symptoms fluctuating in severity over a matter of days. Focal signs, such as hemiparesis, may gradually appear, and stupor or coma may supervene. Chronic subdural hematomas may not become symptomatic for from months to years post-trauma. Typically, patients present with a dementia (Arieff and Wetzel 1964, Black 1984), which is often accompanied by headache. Focal signs, such as hemiparesis, may or may not be present; occasionally, seizures may occur. Less commonly, the presentation may be with a personality change (Cameron 1978) or with depression (Black 1984). Computed tomography (CT) or magnetic resonance imaging (MRI) is diagnostic, and, in the case of acute subdural hematomas, this is one of the rare situations in which CT scanning is diagnostically superior to MRI. With both imaging techniques, the hematoma is seen as a more or less thin mass between the dura and the parenchyma; in the case of convexity hematomas, the mass presents a concave border over the brain. With CT scanning, the mass is initially hyperdense, but as hemolysis occurs, it gradually become less dense and, at a certain point, may be isointense with the underlying parenchyma and be missed on non-contrast scans. When hemolysis is complete, the mass is radiolucent. With Tl-weighted MRI scanning, the appearance also changes over time: initially, the hematoma has an intensity midway between that of cerebrospinal fluid and cortex; with hemolysis, the signal intensity increases; eventually, with complete hemolysis, the hematoma may become relatively 'isointense' compared with the underlying cortex. Electroencephalograms may show slowing and a reduced amplitude over the hematoma. Lumbar pucture is not necesssary and may indeed be dangerous. Course Acute subdural hematoma is generally rapidly fatal. Subacute subdural hematoma progresses gradually, over weeks, and may terminate in uncal herniation and death, undergo resorption, or evolve into a chronic subdural hematoma. Chronic subdural hematoma may take one of two courses: in some cases, after a variable amount of progression, further expansion ceases and the lesion remains static for the remainder of the patient's life; in others, the symptoms very slowly worsen and may eventually terminate in uncal herniation. Differential diagnosis

In the case of acute and subacute subdural hematomas, other traumatic injuries, such as contusions, lacerations, intracerebral hematomas and subarachnoid hemorrhage, may also be present. An epidural hematoma may be difficult to distinguish from an acute subdural hematoma. Traditionally, it was taught that the presence of a 'lucid' interval could distinguish the two, being absent with epidural hematomas, but in a minority of cases of acute subdural hematoma, a 'lucid' interval does not appear, and the diagnosis may rest on surgical findings or CT scanning: whereas subdural hematomas are often thin and concave, epidural

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hematomas are typically thick and lenticular in shape. In the case of chronic subdural hematomas, especially when the trauma has been forgotten, the clinical presentation may be very similar to that of a slowly growing tumor, for example a meningioma. Treatment

Acute subdural hematomas present as a neurosurgical emergency, demanding immediate evacuation. Subacute and chronic subdural hematomas may or may not require evacuation, depending on their size and the prospect of resorption.

DIFFUSE AXONAL INJURY Pathology and etiology gy

Diffuse axonal injury (Adams et al. 1982; Strich 1956) occurs secondary to a sudden, violent acceleration or deceleration of the head. At that moment, the various long and delicate structures inside the brain, such as arterioles and axons, undergo tremendous shearing and rotational stress, leading to damage or outright rupture; in some cases, petechial hemorrhages may occur. The corpus callosum and the dorsolateral quadrants of the mesencephalon are generally hardest hit; the cortex is also typically involved, especially at the gray-white junction. In those who survive, one finds diffuse, widespread glial scarring and evidence of extensive demyelinization. Importantly, the actual impact of the head with a stationary object is not necessary for the development of diffuse axonal injury; in some cases, severe whiplash alone has been sufficient. Clinical features

In severe cases, death occurs; those who survive may be left in a coma or may, after a period of time, 'awaken' into a persistent vegetative state (Levin et al. 1991). In cases with less severe damage, patients may 'awaken' into a delirium, which, upon resolving, leaves the patient with a dementia (Strich 1956). Patients typically have trouble concentrating, are inattentive and easily distracted, and have considerable trouble memorizing things. A personality change is common, often being characterized by childishness, disinhibition, irritability, or aggressiveness (Oder et al. 1992; Thomsen 1984); depressive symptoms may also be seen. In a little under 10% of patients, manic symptoms may appear (Jorge et al. 1993), either immediately upon recovery from coma (Bakchine et al. 1989; Bracken 1987; Nizamie et al. 1988) or after an interval that may last up to a year (Jorge et al. 1993). MRI scanning may reveal cerebral atrophy, widespread glial scarring, and evidence of old petechial hemorrhages. Course In most cases, a gradual improvement is seen over the first half year and may continue for up to a year and a half; after that, a stable chronicity is seen. Differential diagnosis

Although diffuse axonal injury can occur independently, in most cases other injuries also occur, for example contusions, lacerations, subarachnoid hemorrhage, subdural hematoma, and intracerebral hematoma. Given the course of this condition, any deterioration in the patient's condition should suggest another condition, such as hydrocephalus (as may occur secondary to subarachnoid hemorrhage), pneumocephalus (as can occur after a basilar fracture), or chronic subdural hematoma.

484 Specific disorders

Treatment

The general treatment of dementia is described in Chapter 5. Irritability, when prominent, may be treated with propranolol, in doses of 240-600 mg per day. Depression may be treated with an antidepressant such as a selective serotonin reuptake inhibitor (SSRI) (e.g. citalopram) or a tricyclic antidepressant (e.g. nortriptyline). Manic symptoms may respond to divalproex or carbamazepine.

DEMENTIA PUGILISTICA Pathology and etiology

In dementia pugilistica ('punch-drunk' syndrome), there is, as described by Corsellis et al. (1973), cortical atrophy, ventricular dilatation, an enlarged cavum septi pellucidi (as seen in Figure 11.2), and cerebellar atrophy; microscopically, there are widespread neurofibrillary tangles. Senile plaques are also present, but, unlike the discrete plaques seen in Alzheimer's disease, these are diffuse in character (Roberts et al. 1990). Both the substantia nigra and the locus ceruleus show cell loss, but Lewy bodies are not seen. Although the mechanism is unknown, it is clear that dementia pugilistica occurs secondary to repeated head trauma; notably, however, there may be a long symptom-free interval between the last head trauma and the onset of the dementia. Most cases occur in boxers, although jockeys may also be afflicted.

Image Not Available

Figure 11.2 Note the wide cavum septi pellucidi in the brain of professional boxer. (Reproduced from Graham and Lantos 1996.)

Clinical features

The symptom-free interval may last anywhere from 5 up to 40 years. Clinically (Corsellis 1989; Critchley 1957; Harvey and Davis 1974; Jordan 1987; McLatchie et al. 1987; Martland 1928; Mawdsley and Ferguson 1963), one sees the gradual onset of varying combinations of parkinsonism, ataxia, dysarthria, and dementia; the presence of ataxia and dysarthria often give the impression of alcohol intoxication, thus accounting for the term 'punch-drunk'. The dementia is generally non-specific, except perhaps for an undue amount of irritability. MRI scanning reveals cortical atrophy and a prominent cavum septi pellucidi. Course In some cases, the course is unremittingly progressive; in others, symptom severity gradually 'plateaus off after a number of years, with no further progression.

Trauma 485

Differential diagnosis

Other parkinsonian conditions (e.g. Parkinson's disease and diffuse Lewy body disease) are distinguished by the absence of a history of repeated head trauma. Head trauma may be followed by chronic subdural hematoma or hydrocephalus (e.g. secondary to the late effects of a traumatic subarachnoid hemorrhage), both of which may cause dementia: in neither case, however, is parkinsonism seen. Treatment

The general treatment of dementia is outlined in Chapter 5. If psychotic symptoms complicate the dementia and a neuroleptic is required, preference should be given to those least likely to exacerbate parkinsonism, such as olanzepine or quetiapine. Irritability may respond to propranolol in doses of 240 mg or more per day, and parkinsonism may be treated with levodopa. If boxing itself is not banned, consideration should be given to mandating the use of head gear and larger gloves.

POST-CONCUSSION SYNDROME Pathology and etiology

After a concussion, it is suspected that some patients may suffer a subtle degree of diffuse axonal injury (Jane et al. 1985; Oppenheimer 1968; Povlishock et al. 1983). Clinical features

Concussion occurs after a blow to the head or an acceleration-deceleration injury (e.g. whiplash [Miller 1982]). Patients may either lose consciousness for a minute or so or merely be dazed ('seeing stars'); upon recovery, there is a generally mild amnesia with both retrograde (for the immediate period of time before the concussion) (Fisher 1966) and anterograde (for a variable, but generally brief, period of time after the concussion) (Martland 1928) components. Although most patients suffer no sequelae, the post-concussion syndrome appears in a small minority (Alves et al. 1993), generally within a day. The symptoms of the post-concussion syndrome (Lishman 1968; Mapothar 1937; Symonds 1962) consist of headache, dizziness, and various cognitive and affective changes. Headache may be severe, chronic or paroxysmal, either steady or throbbing in character, and exacerbated by loud noises, coughing, sneezing, or stress. Dizziness may be either a kind of giddy lightheadedness or a true vertigo, which may in turn be aggravated or precipitated by a sudden change in position and may, at times, be accompanied by nystagmus. Cognitive changes consist of difficulty with concentration and memory; affective changes may consist of irritability (which may be extreme), depression, or anxiety; insomnia may be severe. Other symptoms include fatigue, photophobia, hyperacusis, and hyperhidrosis (which may, at times, be quite impressive). Alcohol typically exacerbates the affective symptoms. MRI scanning is generally normal. Course Gradual improvement is the rule, and, for most, recovery occurs from weeks up to 3 years later, with an average of 3 months: symptoms present beyond 3 years may persist indefinitely. Differential diagnosis

Subacute subdural hematoma is distinguished by the progression of symptoms to delirium and beyond.

486 Specific disorders

Post-traumatic stress disorder may follow head injury but is distinguished by the recurrent re-experiencing of the event in dreams, unwanted thoughts, and unbidden memories. Malingering is suggested by the presence of litigation or other potential 'rewards' (e.g. sympathy and time off work). The presence of certain signs, such as nystagmus and hyperhidrosis, argues against malingering; in many cases, however, the resolution of this differential diagnosis may not be possible until litigation has been completed. Treatment

Reassurance is critical, and patients should be encouraged to gradually resume their former activities. Headache is treated with non-narcotic analgesics, dizziness with antihistamines, and affective changes with antidepressants such as nortriptyline. Abstinence from alcohol is prudent until the syndrome resolves.

RADIATION ENCEPHALOPATHY Pathology and etiology Radiation damage of the brain occurs in three forms: • acute, occuring during or shortly after irradiation • early-delayed, occurring within 4 months of irradiation • late-delayed, occurring after 8-24 months have passed since exposure. Radiation damage may also be categorized as either focal, for example after the focal irradiation of a tumor, or whole-brain, as may occur after prophylatic irradiation. Acute radiation encephalopathy is characterized by edema, probably due to a temporary dysfunction of the vascular endothelium. Early-delayed radiation encephalopathy is characterized by both demyelinization and focal vascular hyalinization (Lampert and Davies 1964). Late-delayed radiation encephalopathy is characterized by a progressive proliferation of the vascular endothelium with an occlusion of capillaries and an intraluminal thrombosis of small and medium-sized arteries (Pennybaker and Russell 1948). In severe cases, large areas of coagulative necrosis may form. Clinical features

Acute radiation encephalopathy may occur towards the end of a series of radiation treatments or within a week or so after treatment has stopped. Those who have undergone focal irradiation may experience an exacerbation of their pre-existing symptoms, and those who have undergone whole-brain irradiation may experience drowsiness, headaches, clumsiness, and, in some cases, seizures. Early delayed radiation encephalopathy appears in from one and one-half to four months after treatment has stopped, with a clinical picture similar to that seen in acute radiation encephalopathy. Late-delayed radiation encephalopathy typically occurs 8-24 months after treatment has stopped: in some cases, however, the latent interval may be much longer, in one case 33 years (Duffy et al. 1996). Focal irradiation may be followed by localizing signs such as aphasia (Kaufman et al. 1990; Shewmon and Masdeu 1980). In some cases, focal irradiation may, however, be followed by global symptoms such as dementia, and this may occur when critical areas with widespread cortical connections are damaged, as occurred in one case after the hypothalamus and both medial temporal lobes were irradiated during the treatment of a pituitary tumor (Crompton and Layton 1961). Whole-brain irradiation may be followed by a

Trauma 487

dementia characterized initially by forgetfulness, headache, fatigue, and dizziness, which gradually progresses in severity and is joined by a significant gait disturbance (DeAngelis et al. 1989). In cases wherein large arteries are exposed to significant radiation, as for example branches of the internal carotid artery during pituitary irradiation, late-delayed sequelae may consist of large-vessel occlusion and stroke (Grattan-Smith et al. 1992). Irradiation of the hypothalamus or pituitary may also, as one might suspect, be followed by significant vegetative and endocrinologic symptoms: in one case, hypothalamic irradiation was followed by hyperphagia of such severe degree that despite the fact that the refrigerator was padlocked, the patient still gained 62 pounds (Christiansen et al. 1994). T2-weighted MRI scanning reveals an increased signal intensity of focal or generalized distribution, depending on the extent of the original irradiation. In late-delayed radiation encephalopathy resulting from whole-brain irradiation, one sees, in addition to changes in the centrum semiovale, a degree of cortical atrophy and ventriculomegaly (DeAngelis et al. 1989). Course

Both the acute and early-delayed forms of radiation encephalopathy resolve spontaneously, within days to weeks in acute cases, and in 6-8 weeks for early-delayed cases. In late-delayed encephalopathy, however, symptoms gradually progress, resulting in severe dementia or death. Differential diagnosis

In cases in which irradiation was used for a brain tumor, a recurrence of symptoms a year or more later could arise from either a recurrence of the original tumor or a focal area of coagulative necrosis. In such cases, MRI scanning may not be able to distinguish between the two possibilities and one may have to resort to positron emission tomography: tumors will show metabolic activity, whereas necrotic areas will, of course, not. Radiation itself may cause brain tumors (Robinson 1978), such as an astrocytoma (Zampieri et al. 1989), or a meningioma (Brada et al. 1992; Soffer et al. 1983), and this may occur after either focal or whole-brain irradiation. Treatment

Acute and early-delayed cases are generally treated with steroids such as dexamethasone. In the case of late-delayed radiation encephalopathy, however, the response to steroids is generally not good although there are exceptions (Kaufman et al. 1990). In some cases, it appears that anticoagulation has been of benefit.

REFERENCES

Adams JH, Graham Dl, Murray LS et al. Diffuse axonal injury due to non-missile injury in humans: an analysis of 45 cases. Ann Neural 1982; 12:557-63. Alves W, Macciocchi SN, Barth JT. Postconcussive symptoms after uncomplicated minor head inury. J Head Trauma Rehabil 1993; 8:48-59. Arieff AJ, Wetzel N. Subdural hematoma following epileptic convulsion. Neurology 1964; 14:731-2. Bakchine S, Lacomblez L, Venoit N et al. Manic-like state after bilateral orbitofrontal and right temporoparietal injury: efficacy of clonidine. Neurology 1989; 39:777-81. Black DW. Mental changes resulting from subdural hematoma. Br J Psychiatr 1984; 145:200-3. Bracken P. Mania following head injury. Br J Psychiatry 1987; 150:690-2. Brada M, Ford D, Ashley S et al. Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma. BMJ 1992; 304:1343-6.

488 Specific disorders Cameron MM. Chronic subdural hematoma: a review of 114 cases. J Neurol Neurosurg Psychiatry 1978; 41:834-9. Christianson SA, Neppe V, Hofman H. Amnesia and vegetative abnormalities after irradiation treatment: a case study. Acta Neurol Scand 1994; 90:360-6. Corsellis JAN. Boxing and the brain.BMJ 1989; 298:105-9. Corsellis JAN, Bruton CJ, Freeman-Browne D. The aftermath of boxing. Psychol Med 1973; 3:270-303. Critchley M. Medical aspects of boxing particularly from a neurological standpoint. BMJ 1957; 1:357-66. Crompton MR, Layton DD. Delayed radionecrosisof the brain following therapeutic X-irradiation of the pituitary. Brain 1961; 84:85-101. DeAngelisLM, DelattreJ-Y, PosnerJB. Radiation-induced dementia in patients cured of brain metastases. Neurology 1989; 39:172-7. DolinskasCS, Zimmerman RA, Bilaniuk LT et al. Computed tomography of post-traumatic extracerebral hematomas.y Trauma 1979; 19:163-9. Duffy P, Chari G, Cartlidge NEF et al. Progressive deterioration of intellect and motor function occurring several decades after cranial irradiation. Arch Neurol 1996; 53:814-18. Fogelholm R, Waltimo O. Epidemiology of chronic subdural haematoma. Acta Neurochirug 1975;

32:247-50. Graham DL, Lantos PL. Greenfield's neuropathology, 6th edn. London: Arnold, 1996. Grattan-Smith PJ, Morris JG, LanglandsAO. Delayed radiation necrosis of the central nervous system in patients irradiated for pituitary tumor. J Neurol Neurosurg Psychiatry 1992; 55:949-55. Harvey PKP, Davis JN. Traumatic encephalopathy in a young boxer. Lancet 1974; 2:928-9. Jane A, Steward 0, Gennarelli T. Axonal degeneration induced by experimental noninvasive minor injury. J Neurosurg 1985; 62:96-100. Jordan BD. Neurologic aspects of boxing. Arch Neurol 1987; 44:453-9. Jorge RE, Robinson RG, Starkstein SE et al. Secondary mania following traumatic brain injury. Am] Psychiatry 1993; 150:916-21. Kaufman M, Swartz BE, Mandelkern M et al. Diagnosis of delayed cerebral radiation necrosis following proton beam therapy. Arch Neurol 1990; 47:474-6. Lampert PW, Davies RL. Delayed effects of radiation on the human central nervous system. Neurology 1964; 14:912-17. Levin HS, Saydjari C, EisenbergHMefo/. Vegetative state after closed-head injury. A traumatic coma data bank report. Arch Neurol 1991; 48:580-5. Lishman WA. Brain damage in relation to psychiatric disability after head injury. Br J Psychiatry 1968; 114:373-410. McLatchie G, Brooks N, Galbraith S et al. Clinical neurologic examination and computed tomographic head scanning in active amateur boxers. J Neurol Neurosurg Psychiatry 1987; 50:96-9. Mapothar E. Mental symptoms associated with head injury: the psychiatric aspects. BMJ 1937; 2:1055-61. MarkwalderT-M. Chronic subdural hematomas: a review. J Neurosurg 1981; 54:637-45. Martland HS. Punch drunk. JAMA 1928; 91:1103-7. Mawdsley C, Ferguson FR. Neurological disease in boxers. Lancet 1963; 2:795-801. Miller CM. Whiplash amnesia. Neurology 1982; 32:667-8. NizamieSH, NizamieA, Borde M et al. Mania following head injury: case reports and neuropsychological findings. Acta Psychiatr Scand 1988; 77:637-9. OderW, GoldenbergG, Spatt J et al. Behavioral and psychosocial sequelae of severe closed head injury and regional cerebral blood flow: a SPECT study. J Neurol Neurosurg Psychiatry 1992; 55:475-80. Oppenheimer DR. Microscopic lesions in the brain following head injury. J Neurol Neurosurg Psychiatry 1968;31:299-306. Pennybaker J, Russell DS. Necrosis of the brain due to radiation therapy: clinical and pathological observations.J Neurol Neurosurg Psychiatry 1948; 11:183-98.

Trauma 489 Povlishock JT, Becker DP, Cheng CLY et al. Axonal change in minor head injury. J Neuropath Exp Neurol 1983;42:225-42. Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 1990; 53:373-8. Robinson RG. A second brain tumor and irradiation. J Neurol Neurosurg Psychiatry 1978; 41:1005-12. Shewmon DA, Masdeu JC. Delayed radiation necrosis of the brain contralateral to original tumor. Arch Neurol 1980; 37:592-4. Soffer D, Pittaluga S, Feiner M et al. Intracranial menigiomas following low-dose irradiation to the head. J Neurosurg 1983; 59:1048-53. Strich SJ. Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J Neurol Neurosurg Psychiatry 1956; 19:163-85. Symonds CP. Concussion and its sequelae. Lancet 1961; 1:1-5. Thomsen IV. Late outcome of very severe blunt head trauma: a 10-15 year second follow-up. J Neurol Neurosurg Psychiatry 1984; 47:260-8. Zampieri P, Zorat PL, Mingrino S et al. Radiation-associated cerebral gliomas: a report of two cases and review of the literature.7A/euraswrgSc/1989; 33:271-9.

12 Hypoxic disorders Postanoxic enchephalopathy Delayed postanoxic leukoencephalopathy

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Carbon monoxide poisoning

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POSTANOXIC ENCEPHALOPATHY

Pathology and etiology

Global cerebral anoxia, as pointed out by Barcroft (1920), may occur via several mechanisms: a decrease in oxygenation of the blood (as in strangling, drowning, or hanging); a decrease in the oxygen-carrying capacity of the blood (as in carbon monoxide poisoning or severe anemia); or a decreased blood flow to the brain (as in cardiac arrest). Although the brain can withstand brief periods of anoxia, global anoxia lasting more than 5 minutes is generally associated with structural damage. Pathologically (Richardson et al. 1959; Weinberger et al. 1940), there is cortical atrophy, ventricular dilatation, and, within the cerebral cortex, either a laminar or a multifocal pattern of necrosis. Importantly, the hippocampus, although occasionally relatively spared (Brierley and Cooper 1962), is generally heavily involved. Clinical features

Upon awakening from the coma, patients are generally left with a dementia of variable severity: accompanying features may include aphasia, visual agnosia, cortical blindness, seizures, intention myoclonus (Werhahan et al. 1997), and abnormal movements such as athetosis or parkinsonism. Occasionally, one may see rather than a dementia, a Korsakoff's syndrome with prominent anterograde and variable retrograde amnesia (Berlyne and Strachan 1968; Bowman et al. 1997; Broman et al. 1997; Medalia et al. 1991). As might be expected, such a development reflects prominent hippocampal damage (Cumings et al. 1984; Muramoto et al. 1979). Course Some improvement may be expected during the first few months, after which the course is static. Differential diagnosis

The critical differential point between postanoxic encephalopathy and delayed postanoxic leukoencephalopathy is whether or not there is a latent interval of more or less normal

Hypoxic disorders 491

functioning between recovering from the coma and the onset of the syndrome. In postanoxic encephalopathy, there is no latent interval, and patients awaken from the coma directly into the encephalopathy; by contrast, in delayed postanoxic leukoencephalopathy, patients awaken from the coma into a period of normal functioning, which, after a latent interval of variable extent, is terminated by the onset of the encephalopathy. Treatment The general treatment of dementia is covered in Chapter 5. Intention myoclonus, if troublesome, may be treated with clonazepam.

DELAYED POSTANOXIC LEUKOENCEPHALOPATHY

Pathology and etiology Global anoxia, if relatively brief, may cause but a short period of coma, or merely delirium, after which the patient generally fully recovers. Although, in the vast majority of cases, this recovery is permanent, in a small minority it may constitute only a temporary lucid interval, following which there is a profound neuropsychiatric deterioration. The anoxic insult itself may stem from varied causes, such as drowning, hanging, strangulation, cardiac arrest, or carbon monoxide poisoning. Pathologically, there is a generalized leukoencephalopathy affecting the cerebral hemispheres (Plum et al. 1962), with variable involvement of the striatum and globus pallidus (Bhattefa/. 1993). Although the mechanism underlying these pathological changes is not known, it may well be secondary to an autoimmune assault triggered by a mild degree of neuronal or axonal damage incurred during the preceding anoxic insult. Clinical features Clinically (Bhatt et al. 1993; Choi 1983; Courville 1957; Gottfried et al. 1997; Min 1986; Murata et al. 1995; Norris et al. 1982; Plum et al. 1962), the lucid interval averages about 2-3 weeks, ranging from as little as 2 days to up to 2 months. The onset of the encephalopathy itself is fairly sudden, occurring over a matter of a day or two, and patients generally present with a combination of delirium and a movement disorder. Confusion, amnesia, apathy, irritability, and incontinence are prominent, and some patients may become mute. Parkinsonism is the most common movement disorder seen here, but some patients may develop dystonia, and some may experience a combination of the two syndromes. Spasticity is common, with hyperreflexia and extensor plantar responses. Delirium may occasionally be absent, and patients may present only with a movement disorder, such as parkinsonism (Goto et al. 1997; Grinker 1926; Klawans et al. 1982; Rosenberg et al. 1989), dystonia (Valenzuela et al. 1992), or chorea (Davous et al. 1986; Schwartz et al. 1985). T2-weighted MRI scanning generally reveals widespread increased signal intensity within the centrum semiovale (Chang et al. 1992; Gottfried et al. 1997). Course

The course is variable (Choi 1983; Min 1986; Plum et al. 1962; Shillito et al. 1936). Most experience a very gradual improvement over months or a year or more, with eventual complete, or near-complete recovery, but in a minority, recovery is not substantial, and patients are left with a permanent dementia and movement disorder. Finally, in a small minority, stupor and coma gradually supervene, with an eventually fatal outcome. In some cases, parkinsonism or dystonia may, rather than undergoing a variable degree

492 Specific disorders

of recovery, undergo a gradual, progressive worsening, over months to years (Bhatt et al. 1993). Differential diagnosis

Provided the history of global anoxia is available, the diagnosis is fairly straightforward. Postanoxic encephalopathy is immediately distinguished by an absence of a lucid interval. Treatment

The general treatment of delirium and dementia are discussed in Chapter 5. It is tempting to consider the use of steroids, such as dexamethazone, during the acute delirium. The optimal treatment of any persistent parkinsonism, dystonia, or chorea is not clear.

CARBON MONOXIDE POISONING Pathology and etiology

The affinity of carbon monoxide for hemoglobin is over 200 times greater than that of oxygen, and when a high fraction of hemoglobin exists as carboxyhemoglobin, tissue anoxia supervenes. Anoxia may not, however, be the only mechanism of toxicity here as carbon monoxide also binds to mitochondrial cytochrome oxidase, thus impairing cellular respiration. Exposure to a toxic concentration of carbon monoxide may occur accidentally, for example when gas or wood undergoes incomplete combustion in an underventilated area, or intentionally, as when patients attempt suicide by running their car inside a closed garage or funneling the carbon monoxide from the exhaust into the closed car via a hose. In fatal cases, widespread petechial hemorrhages are found throughout the cerebrum (Finck 1966). Clinical features

The onset of intoxication may be gradual or sudden, and, given that carbon monoxide is colorless and odorless, victims may be unaware of their plight. In general (Sayers and Davenport 1930), although the correlation between carboxyhemoglobin level and clinical symptomatology is only a rough one, headache and delirium appear with a level between 10% and 30%, worsening and being joined by nausea and vomiting as the level rises to 40%. At level of 40-50%, stupor and ataxia appear, and cyanosis may be seen. When the level rises to 60%, coma and convulsions occur; levels over 60% are often fatal. Although it is traditional to associate carbon monoxide poisoning with a cherry-red color, this discoloration is in fact rare: if anything, most patients will display a degree of cyanosis. Course If the intoxication ceases before stupor or coma occurs, recovery is usually complete, within, in the natural course of events, hours or weeks (Smith and Brandon 1970). Should coma occur, and even in some cases in which only delirium has occurred, a minority of patients may experience significant sequelae, such as a postanoxic dementia or a delayed postanoxic leukoencephalapathy, as described above. Differential diagnosis

The circumstances wherein the patient is found usually leave little doubt as to the diagnosis: in cases of attempted suicide, however, one must keep in mind that the patient may also have overdosed.

Hypoxic disorders 493 Treatment

The goal of treatment is to eliminate the carbon monoxide as rapidly as possible. The half-life of carboxyhemoglobin ranges from 4 to 6 hours; with inhalation of 100% oxygen, however, this is cut to about an hour, and with hyperbaric oxygen it falls to one-half hour or less. Thus, all patients should receive 100% oxygen, and those with a carboxyhemoglobin level of 40%, as well as those with delirium or stupor, should undergo hyberbaric treatment. Bed rest is appropriate, and treatment should continue until the patient is asymptomatic and the carboxyhemoglobin level has fallen below 10%.

REFERENCES BarcroftJ. Anoxemia. Lancet 1920; 2:485-9. Berlyne N, Strachan M. Neuropsychiatric sequelae of attempted hanging. Br J Psychiatry 1968; 114:411-22. Bhatt MH, Obeso JA, Marsden CD. Time course of postanoxic akinetic-rigid and dystonic syndromes. Neurology 1993; 43:314-17. Bowman M, Rose AL, Hotson G et al. Severe anterograde amnesia with onset in childhood as a result of anoxicencephalopathy. Brain 1997; 120:417-33. Brierley JB, Cooper JE. Cerebral complications of hypotensive anaesthesia in a healthy adult. J Neurol Neurosurg Psychiatry 1962; 25:24-30. Broman M, Rose AL, Hotson G et al. Severe anterograde amnesia with onset in childhood as a result of anoxicencephalopathy. Brain 1997; 120:417-33. Chang KH, Han MH, Kim HS et al. Delayed encephalopathy after acute carbon monoxide intoxication: MR imaging features and distribution of cerebral white matter lesions. Radiology 1992; 184:117-22. Choi IS. Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neurol 1983; 40:433-5. Courville CB. The process of demyelination in the central nervous system. IV. Demyelination as a delayed residual of carbon monoxide asphyxiation. J NervMentDis 1957; 125:534-46. Cummings JL, Tomiyasu U, Read S et al. Amnesia with hippocampal lesions after cardiopulmonary arrest. Neurology 1984; 24:679-81. Davous P, Rondot P, Marion MH et al. Severe chorea after acute carbon monoxide poisoning. J Neurol Neurosurg Psychiatry 1986; 49:206-8. FinckPA. Exposure to carbon monoxide: review of the literature and 567 autopsies. Milit Med 1966; 131:1513-39. GotoS, Kunitoku N, Suyama N et al. Posteroventral pallidotomyina patient with parkinsonism caused by hypoxic encephalopathy. Neurology 1997; 49:707-10. Gottfried JA, Mayer SA, Shungu DC et al. Delayed posthypoxic demyelination: association with arylsulfatase A deficiency and lactic acidosis on proton MRspectroscopy. Neurology 1997; 49:1400-04. GrinkerRR. Parkinsonism following carbon monoxide poisoning. J Nerv Ment Dis 1926; 64:18-28. Klawans HL, Stein RW, Tanner CM et al. A pure parkinsonian syndrome following acute carbon monoxide intoxication. Arch Neurol 1982; 39:302-4. Medalia AA, Merriam AE, Ehrenreich JH. The neuropsychological sequelae of attempted hanging. J Neurol Neurosurg Psychiatry 1991; 54:546-8. Min SK. A brain syndrome associated with delayed neuropsychiatric sequelae following acute carbon monoxide intoxication. Acta PsychatrScand 1986; 73:80-6. MuramotoO, Kuru Y, Sugishita Metal. Pure memory loss with hippocampal lesions: a pneumoencephalographic study. Arch Neurol 1979; 36:54-6.

494 Specific disorders MurataT, ItohS, Koshino Y et al. Serial proton magnetic resonance spectroscopy in a patient with the interval form of carbon monoxide poisoning. J Neural Neurosurg Psychiatry 1995; 58:100-3. Morris CR, Trench JM, Hook R. Delayed carbon monoxide encephalopathy: clinical and research implications. J Clin Psychiatry 1982; 43:294-5. Plum F, PosnerJB, Main RF. Delayed neurological deterioration after anoxia. Arch Intern Med 1962; 110:56-63. Richardson JC, Chambers RA, Heywood PM. Encephalopathies of anoxia and hypoglycemia. Arch Neurol 1959;1:178-90. Rosenberg NL, Myers JA, Martin WRW. Cyanide-induced parkinsonism: clinical MRI and 6-fluorodopa PET studies. Neruology 1989; 39:142-4. Sayers PR, Davenport SJ. Review of carbon monoxide poisoning. Public Health Bulletin No. 195. Washington DC. US Government Printing Office, 1930. Schwartz A, Hennerici M, Wegener OH. Delayed choreoathetosis following acute carbon monoxide poisoning. Neurology 1985; 35:98-9. Shillito FH, Drinker CK, Shaughnessy TJ.The problem of nervous and mental sequelae in carbon monoxide poisonmg.JAMA 1936; 106:669-74. Smith JS, Brandon S. Acute carbon monoxide poisoning-3 years experience in a defined population. Postgrad Med J 1970; 46:65-70. Valenzuela R, Court J, Godoy J. Delayed cyanide induced dystonia.J Neurol Neurosurg Psychiatry 1992; 55:198-9. Weinberger LM, Gibbon MH, Gibbon JH. Temporary arrest of the circulation to the central nervous system. II. Pathologic effects. Arch Neurol Psychiatry 1940; 43:961-86. Werhahan KJ, Brown P, Thompson PD et al. The clinical features and prognosis of chronic posthypoxic myoclonus. Mov Disord 1997; 12:216-20.

13 Nutritional, toxic, and metabolic disorders Vitamin B12 deficiency Folic acid deficiency Pellagra Wernicke's encephalopathy Korsakoff's syndrome Manganism Thallium intoxication Arsenic intoxication Bismuth intoxication Tin intoxication Lead intoxication

495 498 499 500 502 503 504 504 505 506 506

Mercury intoxication Dialysis dementia Dialysis disequilibrium syndrome Hypoglycemia Central pontine myelinolysis Uremic encephalopathy Hepatic encephalopathy Acquired (non-Wilsonian) hepatocerebral degeneration Hepatic porphyria

507 509 510 510 512 514 514 516

516 Basal ganglia calcification (Fahr's syndrome) 518

VITAMIN B12 DEFICIENCY Pathology and etiology

Vitamin B12, or cobalamin, is formed only by certain plant-associated bacteria; animals eating these plants thus become the source of this vitamin for humans, B12 being found in liver, beef, pork, milk, and eggs. The path from the ingestion to the cellular utilization of cobalamin is somewhat tortuous. Within the stomach, cobalamin is first bound to the gastric R binder; then, in the duodenum, this cobalamin-R binder complex is digested by pancreatic enzymes, the free cobalamin becoming bound to intrinsic factor, a molecule produced by gastric partietal cells. The cobalmin-intrinsic factor complex then travels down to the ileum, where it binds to a specific receptor on the luminal surface of the ileal epithelial cell. The complex is absorbed into the ileal cell, where it is lysed, the liberated cobalamin then being bound by transcobalamin II. The transcobalamin II-cobalamin complex is released from the ileal cell into the circulation, from which it is taken up by liver, bone marrow, and central and peripheral nervous systems. Causes of vitamin B12 deficiency include: • dietary deficiency (e.g. as in strict vegetarians) • inherited abnormalities of the R binder • autoimmune destruction of the parietal cells, with a deficiency of intrinsic factor (as in pernicious anemia)

496 Specific disorders

• total (or partial [Roos 1974]) gastrectomy • chronic pancreatitis • intestinal infection by parasites or bacteria that consume cobalamin (e.g. tapeworms or bacterial overgrowth in surgically created blind alleys, as may be seen in a Billroth II operation) • ileal damage (as in sprue or Crohn's disease) • ileal resection • abnormalities of transcobalamin (Reynolds et al. 1993). B12 deficiency is also seen in AIDS and may be a factor in the cognitive decline seen in these patients (Shor-Posner et al. 1995). Of all the possible causes of intracellular B12 deficiency, pernicious anemia is by far the most common (Healton et al. 1991). Cobalamin is stored in the liver and is present in such abundant amount that years may pass before clinical evidence of B12 deficiency appears. Hematologic evidence of vitamin B12 deficiency consists primarily of a macrocytic anemia. Demyelinization occurs in both the central (Ferraro et al. 1945; Lurie 1919) and the peripheral nervous system. Within the brain, patchy, at times confluent, areas of demyelinization are seen in the white matter of the centrum semiovale, especially in the frontal lobes. Within the spinal cord (Russell et al. 1900), the posterior columns are hardest hit, followed by the lateral corticospinal tracts. Peripheral neuropathy primarily affects sensory nerves. Clinical features

Symptoms referable to the nervous system tend to appear subacutely over weeks or months. Cerebral involvement may manifest with a personality change, dementia, depression, mania, or psychosis ('megaloblastic madness'). Dementia may be complicated by delusions and hallucinations (Lurie 1919), and, as noted below, may occur in the absence of anemia or macrocytosis (Lindenbaum et al. 1988); indeed, it may occur without any other symptoms suggestive of B12 deficiency (Chatterjee et al. 1996). Depression secondary to vitamin B12 deficiency can be chronic, the correct diagnosis in one case being suggested by the presence of macrocytosis (Fraser 1960). Mania was observed in an 81-year-old male with B12 deficiency secondary to anti-partietal cell antibodies; he recovered with B12 injections (Goggans 1984). Psychosis, independent of any cognitive changes suggestive of dementia, may also occur secondary to B12 deficiency. In one case (Smith 1929), a 46-year-old female developed delusions of persecution and jealousy, only being correctly diagnosed when symptoms of subacute combined degeneration of the cord became evident. In another (Evans et al. 1983), a 47-year-old female became withdrawn, guarded, and suspicious, heard the voice of God commanding her to board a spaceship, and prayed fervently; she recovered with B12 injections. Spinal cord involvement is typically accompanied by a peripheral sensory polyneuropathy and presents with what is classically known as 'subacute combined degeneration' (Russell et al. 1900). Patients initially complain of distal numbness and dysesthesiae, first affecting the lower extremities; a sensory ataxia follows and the Romberg test is positive. With involvement of the lateral corticospinal tracts, Babinski signs may appear, but, because of the peripheral polyneuropathy, the deep tendon reflexes, rather than being increased, may actually be depressed. It has recently become apparent that patients with borderline low intracellular B12 levels may, in response to nitrous oxide anesthesia, rapidly develop cerebral or cord symptomatology (Beltramello et al. 1998; Marie et al. 2000). Two facts deserve repeated emphasis here. First, although most patients with nervous system involvement also have a macrocytic anemia, a substantial minority, almost one-third,

Nutritional, toxic, metabolic disorders 497

of those with nervous system involvement will not only not be anemic, but also not have any macrocytosis (Lindenbaum et al. 1988). Second, involvement of the cerebrum may occur in isolation, without any clinical evidence of spinal cord or peripheral nerve damage. Magnetic resonance imaging (MRI) may reveal confluent areas of demyelinization in the cerebrum (Chatterjee et al. 1996; Stojsavljevic et al. 1997). Although the serum B12 level is generally low, a minority of patients will have intracellular B12 deficiency in the face of a normal or low-normal serum B12 result. A much more reliable test involves measuring the serum homocysteine and methylmalonic acid levels (Lindenbaum et al. 1988). In the face of intracellular B12 deficiency, these levels are reliably increased: furthermore, not only are they a more sensitive test, but they are almost 100% specific for B12 deficiency. Once intracellular B12 deficiency has been confirmed, the next step is to determine the cause of this deficiency. In this regard, the Schilling test is helpful. This is carried out in two phases. In phase I, the patient is given an intramuscular injection of 1000 ug cyanocobalamin, after which radiolabelled B12 is ingested. A 24 hour urine is then obtained, and the amount of radiolabelled cobalamin is determined. If this is normal, one may be assured that the defect lies beyond the ileal epithelial cell, perhaps in an overly strong binding of cobalamin to transcobalamin II; if the urinary level of radiolabelled cobalamin is, however, low, the defect lies at the level of the ileal cell or above. If the phase I Schilling test is abnormal, one then proceeds to phase II. In phase II, the patient ingests a combination of radiolabelled cobalamin and hog-derived intrinisc factor. A 24 hour urine is again collected, and the amount of radiolabelled cobalamin is determined in this collection. If this is normal, the defect probably lies in a deficiency of intrinsic factor, as may be seen in pernicious anemia; if it is low, other causes must be sought, for example chronic pancreatitis, bacterial overgrowth, and ileal disease. It must be emphasized that a normal phase I Schilling test does not 'rule out' vitamin B12 deficiency but rather focuses the physician's attention on defects beyond the ileal epithelial cell. Course Most patients experience a progressive course, with death within years. Differential diagnosis

Progressive multiple sclerosis may mimic vitamin B12 deficiency, with white matter lesions in the cord and the centrum semiovale, and the differentiation may rest on laboratory findings, such as elevated serum homocysteine and methylmalonic acid levels in B12 deficiency, and pleocytosis, oligoclonal bands, and increased myelin basic protein in multiple sclerosis. Folic acid deficiency is essentially clinically indistinguishable from B12 deficiency, the differential diagnosis resting on laboratory findings: in B12 deficiency both the serum homocysteine and methylmalonic acid levels are increased, whereas in folic acid deficiency, only the homocysteine level is increased, the methylmalonic acid level remaining normal. It is critical not to miss the diagnosis of B12 deficiency here, because the treatment of patients with B12 deficiency with folic acid, while improving any macrocytic anemia, will be followed by an actual deterioration in neuropsychiatric status. Given that some cases of B12-induced dementia, affective syndromes, or psychosis may occur without macrocytosis or evidence of subacute combined degeneration, it is appropriate to, at the very least, obtain a B12 level in those situations in which the etiology of these syndromes cannot be positively identified. Patients with pernicious anemia should be assessed for thyroid and adrenal abnormalities: in addition to anti-parietal cell antibodies, pernicious anemia may also be characterized by anti-thyroid and anti-adrenal antibodies, leading to hypothyroidism or adrenal insufficiency, either of which may cause neuropsychiatric symptomatology.

498 Specific disorders

Treatment

Emergency treatment with vitamin B12 is required, and cyanocobalamin, rather than hydroxycobalamin, must be used. Patients with nervous system involvement should receive 1000 jig intramuscularly daily for a week, once weekly for 4 weeks, and then monthly thereafter. In cases in which the cause of the deficiency defies treatment, lifelong B12 injections are required. Oral vitamin B12, even when combined with hog-derived intrinsic factor, is not reliable. After 2 weeks of treatment, patients should also be given folate, 2 mg orally on a daily basis: it is critical, however, that patients with B12 deficiency do not receive folate earlier than this, given the possibility of a deterioration in their neuropsychiatric status, as noted above. Some patients may also require iron supplementation. The potassium level should occasionally be checked as hypokalemia may develop with successful B12 treatment.

FOLK ACID DEFICIENCY Pathology and etiology Despite considerable controversy, it does appear that, albeit rarely, folic acid deficiency causes neuropsychiatric disease. Folic acid is abundantly available in fresh green vegetables, some fruits, yeast, kidney, and liver, and is a necessary factor in the synthesis of DNA. Because only a relatively small amount, of the order of 5-20 mg, is stored in the liver, clinical evidence of deficiency may develop within as little as 3 months. Dietary deficiency is rare except in alcoholics or patients with malabsorption, as for example in non-tropical sprue and regional enteritis. Certain medications may also be associated with symptoms of folate deficiency, including oral contraceptives, phenytoin, primidone, phenobarbital, pyrimethamine, trimethoprim, pentamidine, and methotrexate. Marginal folic acid reserves may be rapidly depleted in conditions of increased metabolic demand, for example pregnancy and hemolytic anemia. Clinical features

Reynolds et al. (1973) found an association between dementia with spasticity and folate deficiency, and Pincus et al. (1972) reported a convincing case of a folate-induced combination of dementia and subacute combined degeneration. Strachan and Henderson (1967) described two very convincing cases of dementia secondary to folate deficiency, one occurring in combination with a peripheral neuropathy and the other without any other symptoms. Claims have also been made for an association with 'affective' symptoms (Shorvon et al. 1980), but these are not as convincing. A macrocytic anemia may or may not be present. The red blood cell folate level is a more reliable indication of tissue stores than is the serum level, which tends to be very responsive to immediate dietary changes, such as may occur in a malnourished patient after being in hospital. The homocysteine level is increased and the methylmalonic acid level normal. Course This is uncertain. Differential diagnosis

As the overall clinical symptomatologies of folic acid deficiency and vitamin B12 deficiency are essentially identical, and as these two conditions not uncommonly coexist, the differential diagnosis may depend on laboratory testing, with attention not only to folate and vitamin B12 levels, but also to serum homocysteine and methylmalonic acid levels. In folic acid deficiency,

Nutritional, toxic, metabolic disorders 499

only the homocysteine level is increased, whereas in B12 deficiency, both the homocysteine and methylmalonic levels rise. It is critical not to miss the diagnosis of vitamin B12 deficiency because the treatment of such patients with folic acid, while improving the macrocytosis, may prompt a deterioration in their neuropsychiatric status. Treatment

Parenteral treatment is rarely required; 2 mg orally daily is generally sufficient.

PELLAGRA Pathology and etiology

Pellagra occurs secondary to a chronic deficiency of niacin. Niacin is found in liver, yeast, poultry, fish, and meat; although it is also found in corn, it exists there in a bound, biologically unavailable form. In the body, niacin may also be produced from tryptophan, a conversion that is dependent on pyridoxine, or vitamin B6. In the past, pellagra was endemic in the southern United States, where a large proportion of the population subsisted on cornmeal; however, since flour was 'enriched' with niacin in 1939, endemic pellagra, at least in the United States, has become very rare. Pellagra is currently seen primarily in malnourished alcoholics. Rarely, syndromes similar to pellagra may also occur because of a deficient endogenous production of niacin. For example, in Hartnup's disease, an autosomal recessive condition, there is a decreased absorption and increased excretion of tryptophan. Isoniazid-induced pellagra constitutes another example: isoniazid prevents the conversion of vitamin B6 into an active coenzyme, thus leaving available tryptophan unconverted into niacin (Ishii and Nishihara 1985). Pathologically (Hauw et al. 1988; Ishii and Nishihara 1981; Langworthy 1931), there is widespread neuronal chromatolysis, most prominent in cerebral cortical pyramidal cells, basal ganglia, dentate nuclei of the cerebellum, and various cranial nerve nuclei in the brainstem. Clinical features

The onset of pellagra may be either insidious or acute, with correspondingly different clinical presentations. Pellagra of insidious onset was typified by the endemic cases seen in the southern United States and is classically characterized by the 'three D's': dementia, dermatitis and diarrhea. The dementia often presented with depression, apathy, anxiety, or insomnia; over time, memory and concentration failed, and hallucinations or delusions (Pierce 1924) could appear. There are also reports of pellagra presenting with prominent depression (Hardwick 1943). The dermatitis is first seen on sun-exposed areas, presenting initially as erythema; in time, the skin becomes rough and hyperpigmented, and areas typically hidden from the sun become involved. The diarrhea may be severe and is at times blood-tinged; stomatitis and glossitis may also occur. Pellagra of acute onset (also known as 'encephalopathic' pellagra) is probably the most common form of pellagra encountered today and is, for the most part, seen only in chronically malnourished alcoholics. Patients present acutely with delirium and generalized cogwheel rigidity; dysarthria and myoclonus may also appear (Ishii and Nishihara 1981; lolliffe et al. 1940; Serdaru et al. 1988). Dermatitis and diarrhea may be entirely lacking. Although the blood niacin level may be low, this is not reliable, a 24 hour urine collection for one of niacin's metabolites, N-methylnicotinamide, being a better guide.

500 Specific disorders

Course Pellagra of insidious onset, assuming an ongoing deficiency of dietary niacin, is gradually progressive, with death in a matter of years. Pellagra of acute onset is often rapidly fatal, coma and death ensuing in as little as a few days. Differential diagnosis

In the case of pellagra of insidious onset, the 'three D's' are quite distinctive. Pellagra of acute onset may be mimicked by Wernicke's encephalopathy and Marchiafava-Bignami disease, and indeed may coexist with them (Serdaru et al. 1988). Treatment

Niacin, in a dose of 300-1000 mg daily, or, for those intolerant of niacin, niacinamide 400-600 mg/day, may be given orally; in acute cases, niacinamide may also be given intravenously. The response may be dramatic. Once recovered, patients may be maintained on 50-100 mg niacin daily. In those cases of pellagra occurring secondary to isoniazid, pyridoxine, in a dose of 50 mg orally daily, is generally curative. Alcoholics suspected of having encephalopathic pellagra should, in addition to niacin, also receive thiamine.

WERNICKE'S ENCEPHALOPATHY Pathology and etiology

Wernicke's encephalopathy occurs secondary to thiamine, or vitamin Bl, deficiency. Once absorbed, thiamine is converted to its active form, thiamine pyrophosphate, which functions as a coenzyme for transketolase, which in turn plays a critical role in the hexose monophosphate shunt pathway. Some patients have an inherited form of transketolase that displays a decreased affinity for thiamine pyrophsophate (Blass and Gibson 1977); these individuals are at higher risk for developing Wernicke's encephalopathy and may do so even if their thiamine reserves are only marginally depleted. Pathologically (Cravioto et al. 1961; Harper 1983; Malamud and Skillicorn 1956; Victor et al. 1971), petechial hemorrhage is found primarily in the gray matter adjacent to the third ventricle, aqueduct and fourth ventricle. Thus, the structures involved include the mammillary body, mediodorsal nucleus of the thalamus, periaqueductal gray matter, pontine tegmentum (especially the nuclei of cranial nerve VI), and superior cerebellar vermis. If the patient survives, these structures eventually demonstrate atrophy, with neuronal loss and gliosis. Although most cases of Wernicke's encephalopathy are seen in malnourished alcoholics, cases have also been noted in a number of other conditions, including hunger strikes (Frantzen 1966), anorexia nervosa (Handler and Perkin 1982), prolonged parenteral nutrition (Vortmeyer et al. 1992) with inadequate thiamine supplementation, gastric restriction surgery (Abarbanel et al. 1987; Paulson et al. 1985) with subsequent prolonged vomiting, peritoneal dialysis or hemodialysis (Jagadha et al. 1987), hyperemesis gravidarum (Gardian et al. 1999), and prolonged vomiting occurring after liver transplantation (DiMartini 1996) or as a sideeffect of digitalis (Richmond 1959). Importantly, two or more of these factors may at times be required to produce the encephalopathy. There are, for example, case reports of patients developing Wernicke's encephalopathy anywhere from 2 to 20 years post-gastrectomy, the precipitant being a modestly decreased intake, for example secondary to a loss of appetite during an upper respiratory infection (Shimomura et al. 1998).

Nutritional, toxic, metabolic disorders 501 Clinical features

Classically, Wernicke's encephalopathy presents subacutely with the triad of delirium, nystagmus, and ataxia. Autopsy studies have, however, revealed that this classic triad is in fact unusual, being found in between only 14% (Cravioto etal. 1961) and 16% (Harper etal. 1986) of cases; by far the most common presentation is with delirium alone, or with a combination of delirium plus either nystagmus or ataxia (Harper etal. 1986). Nystagmus is initially evident on lateral gaze: in some cases, vertical nystagmus may occur, and over time bilateral sixth cranial nerve palsies appear. Ataxia primarily affects the lower extremities and the trunk, and patients may be unable to walk or even to sit up in bed. Convulsions may occur in some patients. Vital signs may reveal a decreased temperature, an increased pulse rate and postural hypotension. The pupillary reaction to light, although preserved, is often sluggish. T2-weighted MRI scanning may reveal increased signal intensity in the mammillary bodies. The cerebrospinal fluid may be normal or show an increased total protein level. Erythrocyte transketolase activity is decreased (Dreyfus 1962). Course Untreated, stupor and coma often supervene, and death may occur, often suddenly (Harper 1979). Among the survivors, a substantial proportion will be left with a Korsakoff's syndrome (Malamud and Skillicorn 1956). Differential diagnosis

Wernicke's encephalopathy is underdiagnosed (Harper 1979): one large autopsy study of alcoholics found that only 20% had been correctly diagnosed ante mortem (Harper 1983). Thus, a high index of suspicion is required: in this regard, one must not be fooled by the age of the patient, as Wernicke's encephalopathy has occurred in alcoholics as young as 18 years old (Turner etal. 1989). Delirium tremens is suggested by the prominent tremor, and pellagra of the acute 'encephalopathic' form by prominent rigidity. In the past, the term 'Wernicke-Korsakoff syndrome' was used to refer to two clinically disparate syndromes, namely Wernicke's encephalopathy and Korsakoff's syndrome. This has led to all manner of confusion, and the term should be avoided: Wernicke's encephalopathy refers to a subacute condition characterized by delirium and often nystagmus or ataxia, whereas Korsakoff's syndrome, which often occurs as a sequela to Wernicke's encephalopathy, is quite different, being characterized by a combination of anterograde and retrograde amnesia, and lacking any accompanying evidence of delirium, such as confusion. Treatment

All alcoholics should receive lOOmg of parenteral thiamine on admission; in cases of suspected Wernicke's encephalopathy, this should be given slowly intravenously. Because glucose can precipitate a Wernicke's encephalopathy in patients with marginal thiamine reserves, patients should not be allowed to eat or drink (other than water), nor should they be given intravenous solutions containing glucose or dextrose for several hours after receiving parenteral thiamine. In cases of suspected or confirmed Wernicke's encephalopathy, parenteral thiamine should be continued at 100mg bid until clinical improvement is seen and patients are able to take oral medication. At that point, thiamine may be given orally and continued until maximum improvement is seen, usually within a month. The response to thiamine is often prompt and gratifying: the nystagmus may begin to clear within hours or a day, and the delirium and ataxia show an improvement within a few days; a

502 Specific disorders

lack of such prompt improvement may indicate hypomagnesemia. Should improvement fail to occur with magnesium sulfate, the diagnosis of Wernicke's encephalopathy is very doubtful.

KORSAKOFF'S SYNDROME Pathology and etiology

Korsakoff's syndrome (secondary to Wernicke's encephalopathy) is one of the amnestic disorders and, as noted in Chapter 5, may occur secondary to multiple different etiologies. By far the most common cause, however, is thiamine deficiency, and in such cases Korsakoff's syndrome occurs as a sequela to a Wernicke's encephalopathy (Malamud and Skillicorn 1956). Neuropathologically, one sees atrophy and fibrosis in those structures damaged during the Wernicke's encephalopathy. Clearly, not all patients who survive a Wernicke's encephalopathy go on to develop a Korsakoff's syndrome, and it appears that this outcome is most likely when the mediodorsal and anterior nuclei of the thalamus are heavily involved (Halliday et al. 1994; Malamud and Skillicorn 1956; Victor et al. 1971). Clinical features

As the confusion of Wernicke's encephalopathy clears, patients are left with an amnesia characterized by a generally dense anterograde component and a retrograde component of variable duration. Such patients, as pointed out by Korsakoff himself (Victor and Yakovlev 1955), may not, at least to casual inspection, appear ill at all. They are typically able to carry on a conversation and may be reasonably sociable. Formal testing, however, reveals that although immediate recall, as with a digit span, is intact, short-term memory, tested by asking the patient to recall three objects after 5 minutes, is severely deficient. Indeed, patients may not be able to recall a conversation they had with the physicain just minutes before. The retrograde component of the amnesia becomes apparent on asking patients about their lives before the Wernicke's encephaloapthy: answers often display a 'temporal gradient' (Albert et al. 1979; Seltzer and Benson 1974), such that patients, although having no recall of the events occurring for perhaps months before the Wernicke's encephalopathy, may have a hazy or partial recall of events occurring years earlier and a fairly clear memory of childhood events. In questioning patients about recent events, one often encounters the phenomenon of confabulation: here, the patient blithely makes up responses, as if to 'fill in' the amnestic gap. Thus, if a patient were asked whether he or she had ever met the physicain before, the patient might respond in the affirmative and go on to talk about meeting the physician at a local tavern the week before, where they had a 'few' beers, played some pool, etc. In most cases, confabulation wanes over time. Course

Some recovery may be seen over the first year or so, after which the course is chronic. Differential diagnosis

Wernicke's encephalopathy, like all deliria, is distinguished by the presence of confusion, in stark contrast to the clear-headedness of patients with Korsakoff's syndrome. Treatment

Prevention is crucial, and all alcoholics, or any other patients liable to thiamine deficiency, should have their thiamine stores repleted. One early study (Martin et al. 1989) suggested that fluvoxamine may be helpful, but this was not confirmed (O'Carroll et al. 1994). Lifelong supervision may be required.

Nutritional, toxic, metabolic disorders 503

MANGANISM Pathology and etiology

Neuronal loss and gliosis are most prominent in the globus pallidus, and the pars reticulata of the substantia nigra (Yamada et al. 1986); the striatum, thalamus, and cerebral cortex are involved to a lesser extent. The mechanism whereby managanese leads to cell death is not clear. In most cases, exposure occurs in the course of working in manganese mines, steel mills, and battery factories; rarely, exposure may occur via contaminated well-water. Clinical features

The onset of symptoms is typically gradual, occurring after months or years of exposure, and patients may present with parkinsonism, a personality change, or both (Abd El Naby and Hassanein 1965). The parkinsonism (Abd El Naby and Hassanein 1965; Cook et al. 1974; Huang et al. 1989) is characterized by rigidity, bradykinesia, postural instability, and a tendency to 'freeze' and fall upon turning. Cogwheeling is often seen, and although tremor may also be present, it is generally not of the 'pill-rolling' type. The parkinsonism may also be accompanied by dystonia, often affecting the cervical musculature or the face. The most characteristic feature of manganese-induced parkinsonism is, however, a distinctive dystonic gait abnormality, known as a 'cock-walk'. Here, patients walk on their metatarsophalangeal joints as if walking in high heels; at times, the elbows may be flexed, creating the overall appearance of the walk of a rooster. Such a 'cock-walk' has been reported in anywhere from a small minority (Cook et al. 1974; Huang et al. 1993) to a large majority (Abd El Naby and Hassanein 1965) of patients. The personality change (Abd El Naby and Hassanein 1965; Cook et al. 1974) typically consists of asthenia, fatigue, irritability, emotional lability, and a peculiar kind of 'incongruous' laughter, reminiscent of the emotional incontinence seen in pseudobulbar palsy: patients may smile without cause, or burst out in laughter, again for no apparent reason (Charles 1927). Sleep changes (Abd El Naby and Hassanein 1965; Cook et al. 1974), either insomnia or somnolence, may accompany these changes. Psychosis ('manganese madness') may occur, characterized by excitation, hallucinations and delusions (Abd El Naby and Hassanein 1965). Dementia may occur concurrent with the parkinsonism, being associated with prominent memory loss (Cook et al. 1974). Manganese may be found in urine or blood samples. Course With the termination of the exposure, symptoms may undergo a partial remission, eventually stabilizing at a 'plateau' that then remain chronic. Interestingly, however, both the parkinsonism (Huang et al. 1993) and the 'cock-walk' (Huang et al. 1997) may in some cases continue to progress, long after the exposure has ended, sometimes for up to 10 years (Huang etal. 1998). Differential diagnosis

In evaluating a patient with parkinsonism, personality change, psychosis, or dementia? the presence of a history of exposure to manganese should suggest the diagnosis. When manganism presents with parkinsonism, Parkinson's disease may be considered, but the appearance of cervical or facial dystonia, and particularly a 'cock-walk', would suggest the correct diagnosis. Should manganism present with a personality change, the diagnosis may remain in doubt until parkinsonism appears; one clue is incongruous laughter.

504 Specific disorders

Treatment

Although some patients may benefit from levodopa, the improvement is not sustained (Huang et al. 1993) and may indeed represent a placebo response (Lu et al. 1994). If psychotic symptoms require treatment, either a low-potency typical neuroleptic (e.g. chlorpromazine) or an atypical neuroleptic (e.g. olanzepine) should be chosen to reduce the risk of aggravating the parkinsonism.

THALLIUM INTOXICATON Pathology and etiology Although thallium can gain access through the lungs or skin, by far the most common route of thallium intoxication is the ingestion of rat or insect poison, either accidentally or with suicidal or homicidal intent. With acute ingestion, there is widespread cerebral edema, often with petechial hemorrhages. In chronic cases, there is widespread axonal damage in the white matter of the cerebrum and cerebellum, and neuronal loss, primarily in the basal ganglia and thalamus (Cavanagh et al. 1974). The peripheral nervous system typically displays axonal damage. Clinical features

With acute intoxication (Bank et al. 1972; Reed et al. 1963; Thompson et al. 1988), gastrointestinal symptoms, including vomiting, abdominal pain, and diarrhea (which may be bloody), occur within a day. Soon thereafter, there is a delirium, which may be accompanied by convulsions, and an often painful sensorimotor polyneuropathy. The cranial nerves may be affected, with visual loss, diplopia, or facial palsies. Alopecia follows within 2-3 weeks of ingestion. Chronic, gradual ingestion may be followed by dementia, a painful sensorimotor polyneuropathy, and alopecia. Thallium may be detected in serum, a 24 hour urine sample, and hair. Course Acute intoxication is fatal in about 10% of cases; those who survive acute intoxication may be left with a dementia (Reed et al. 1963) or a personality change (McMillan et al. 1997). In cases of chronic ingestion, there is a variable degree of recovery over the ensuing months. Differential diagnosis

Arsenic intoxication is distinguished by the absence of alopecia and, in acute cases, by the presence of an odor of garlic on the breath. Treatment

If patients are seen within 6 hours of acute ingestion, emesis and gastric lavage are accomplished; activated charcoal may be given to reduce enterohepatic recirculation. Prussian blue, given orally, traps thallium in the gut and should be given to all patients. Chelation therapy is contraindicated as it may be followed by a deterioration in the patient's condition (Wainwright et al. 1988). In severe cases, dialysis is indicated.

ARSENIC INTOXICATION Pathology and etiology Elemental arsenic does not readily cross the blood-brain barrier and hence is not toxic to the central nervous system; it is, however, toxic to the peripheral nerves. By contrast, both trivalent

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and pentavalent arsenic compounds do cross the blood-brain barrier and thus exert toxicity not only on the peripheral nerves, but also on the central nervous system. Arsenical compounds may be found in weed and rat-killers, and may be ingested accidentally or with suicidal or homicidal intent. In acute intoxication (Hurst 1959; Russell 1937), there are widespread petechial hemorrhages throughout the central nervous system, accompanied by an extensive peripheral axonopathy. Clinical features

The rapid ingestion of a large amount of arsenic is followed within the day by gastrointestinal symptoms (vomiting, abdominal pain, and diarrhea, which may be bloody) and, in many cases, delirium (Freeman and Couch 1978), which may be accompanied by convulsions. Uniquely, there may be an odor of garlic on the breath. Within 1-3 weeks, a painful, predominantly sensory polyneuropathy develops. The chronic ingestion of a small amount may be followed by a dementia, a painful polyneuropathy, and increased skin pigmentation. Arsenic may be detected in a 24 hour urine collection, as well as in hair and nails. Course Acute intoxication may be fatal; survivors may be left with a dementia. After chronic intoxication, there is a variable amount of recovery over many months. Differential diagnosis

Thallium intoxication is suggested by alopecia. Treatment

Following acute intoxication, emesis should be induced, followed by activated charcoal and osmotic catharsis. Chelation may be accomplished with DMSA (dimercaptosuccinic acid) or DMPS (dimercaptopropane sulfuric acid); dimercaprol (British anti-Lewisite, BAL) should not be used, as it may produce a higher central nervous system level of arsenic.

BISMUTH INTOXICATION Pathology and etiology Bismuth is found in a number of preparations and is used for the control of diarrhea as well as in the treatment of infection with Helicobacter pylori. Within the central nervous system, bismuth is found in the cerebral and cerebellar cortices, and in the basal ganglia and thalamus; neuronal loss has been noted among the Purkinje cells of the cerebellum and in the hippocampus (Liessens et al. 1978). Clinical features

The onset is determined by the pace at which bismuth is accumulated: in many cases, this is gradual, over weeks or months, and here one finds affective changes (tending towards depression or irritability, but at times with euphoria) and insomnia: rarely, there may be delusions or visual hallucinations (Supino-Viterbo et al. 1977). Eventually, with a sufficient accumulation, there is a subacute onset of delirium, accompanied by tremulousness, myoclonus, and ataxia (Burns et al. 1974 ; Supino-Viterbo et al. 1977); generalized or partial seizures may be seen in a minority (Supino-Viterbo et al. 1977). Course In most cases, there is a gradual recovery.

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Differential diagnosis

The differential diagnosis of delirium accompanied by myoclonus is discussed in Chapter 3; of the causes noted there, the metabolic encephalopathies deserve particular attention. Treatment

There is no specific treatment.

TIN INTOXICATION Pathology and etiology Alkyltin compounds are potentially neurotoxic, but the pathology appears to differ with different compounds. With trimethyltin, for example, neuronal loss has been observed in the temporal cortex, amygdala, basal ganglia, and cerebellum (Besser et al. 1987). In contrast, with triethyltin intoxication, the myelin becomes edematous, and vacuolization may be seen in the white matter (Cossa et al. 1958). An exposure to tin may occur in certain industries, and, in one exceptional case (Alajouanine et al. 1958), an antibiotic was contaminated with triethyltin. Clinical features

Trimethyltin intoxication may cause a delirium (Feldman et al. 1993), which may be accompanied by seizures (Fortemps et al. 1978). Triethyltin intoxication has been followed by delirium, seizures, and symptoms of raised intracranial pressure (Alajouanine et al. 1958). There is a case report of attempted suicide by the ingestion of triphenyltin, with yet a different clinical picture, one characterized by vomiting, abdominal pain, and diarrhea, progressing to delirium and ataxia. After passing into a coma the patient eventually recovered but was left demented, ataxic, and suffering from a peripheral polyneuropathy (Wu et al. 1990). Course Although most patients survive trimethyltin intoxication, recovery may not be complete (Besser et al. 1987; Feldman et al. 1993). With triethyltin, the prognosis has been much worse, with a mortality of over 50% (Alajouanine et al. 1958). Differential diagnosis

The deliria of trimethlytin and triethyltin do not appear to have distinctive characteristics, and the diagnosis would probably be prompted by a history of exposure. Triphenyltin intoxication bears a clinical resemblance to acute arsenic intoxication. Treatment

There is no known specific treatment.

LEAD INTOXICATION Pathology and etiology Among children, the most common source of lead is lead-based paints, found on the walls and window sills of older homes. In adults, lead intoxication may occur acutely in alcoholics who drink 'moonshine' whiskey made in old radiators (Akelaitis 1941; Morris et al. 1964; Whitfield et al. 1972); chronic intoxication may be seen in workers in smelters or battery factories, and

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in solderers. Intoxication may also occur secondary to drinking from improperly glazed pottery (Matte et al. 1994). Leaded gas, now banned, used to be a significant source of intoxication. Acute lead intoxication (Pentschew 1965; Smith et al. 1960) is followed by cerebral edema with widespread petechial hemorrhages and minute areas of necrosis. The pathology associated with chronic exposure is not clearly described. Clinical features

The symptomatology differs between children and adults, and also varies according to whether the intoxication is acute or chronic. In children, acute cases are characterized by a several week prodrome of irritability, abdominal pain, and lethargy, followed by a relatively sudden onset of delirium, stupor and convulsions (Jenkins and Mellins 1957; Mellins and Jenkins 1955). Chronic, low-level lead exposure in children is associated with a fall in IQ, poor school performance, and the development of attention deficit hyperactivity disorder (Baghurst et al. 1992; Bellinger et al. 1987; Needleman et al. 1990). In adults, acute cases are characterized by delirium, seizures, and abdominal pain (Akelaitis 1941; Morris et al. 1964; Whitfield et al. 1972). Chronic cases, however, are characterized primarily by a motor peripheral neuropathy that mostly affects the extensor muscles of the wrist and, less frequently, the foot, with wrist drop or foot drop. There may also be fatigue, abdominal pain, and irritability; in some cases, depressive symptoms may be seen (Schottenfeld and Cullen 1984). The whole-blood lead level is increased above 80 |ig/dL in acute intoxication and generally above 10|lg/dL in chronic cases. The zinc protoporphyrin level is also reliably increased.

Course Acute lead encephalopathy in children is fatal in up to 20% of cases; in those who survive, dementia is not uncommon (Jenkins and Mellins 1957). Differential diagnosis

The diagnosis is often suggested by a history of exposure (e.g. young children living in older houses, 'moonshine' alcoholics, or employment in smelting or battery factories). The combination of delirium and abdominal pain may suggest hepatic porphyria. Treatment

Acute lead intoxication demands chelation treatment with edetate calcium disodium and/or dimercaprol; chronic cases may be treated with penicillamine. It is imperative to prevent further exposure.

MERCURY INTOXICATION Pathology and etiology

Mercury may occur in three forms: elemental mercury; salts of mercury (including monovalent [mercurous] and divalent [mercuric] mercury); and organic mercury (e.g. the alkylmercury compunds methylmercury and ethylmercury). The neurotoxic effect of mercury appears to hinge on its ability to bind to sulfhydryl groups, thereby fatally disturbing cellular metabolism. Elemental mercury is found in some dental amalgam and in certain medical instruments (e.g. mercury thermometers and sphygmomanometers); exposure may also occur in certain

508 Specific disorders

industries. The ingestion of elemental mercury is generally not toxic as it is poorly absorbed from the gastrointestinal tract. Elemental mercury, however, readily vaporizes, and in this gaseous state, it is well absorbed via the lungs. Elemental mercury easily crosses cell membranes and, after being absorbed, either makes its way across the blood-brain barrier to be taken up by neurons, or is taken up inside red blood cells, wherein it undergoes enzymatic conversion to divalent mercuric mercury. The neuropathology of elemental mercury intoxication is not clear. Salts of mercury were once widely used in medicinal preparations (e.g. mercurous chloride or Calomel) and are still widely used in certain industries. Salts of mercury are extremely corrosive to the gastrointestinal tract and are very poorly absorbed. The chronic ingestion of small amounts may, however, eventually cause widespread neuronal loss, especially affecting the granule cells of the cerebellum (Davis et al. 1974). Organic mercury is most toxic as methylmercury, which, by accidental introduction into human food, has caused disastrous epidemics. In the Minamata Bay incident (Kurland et al. 1960), elemental mercury, discharged into the bay with other industrial effluents, was converted by micro-organisms to methylmercury, which in turn found its way into the fish that ate the micro-organisms: eventually, the humans who ate the fish assumed an intolerable burden of methylmercury. In another incident, methylmercury was used as a fungicide on seed grain sent to Iraq (Amin-Zaki et al. 1978): although civilians had been warned not to eat, but only to plant, the grain, the contaminated grain was nevertheless made into flour and bread, leading to hundreds of deaths. Methylmercury is well absorbed from the gastrointestinal tract and easily crosses the blood-brain barrier. Pathologically, there is widespread neuronal loss in both the cerebrum and cerebellum, affecting especially the calcarine cortex in the cerebrum and the granule cell layer of the cerebellum (Hunter and Russell 1954). Although methylmercury is the most toxic of the organic mercury compounds, cases have been recorded secondary to ethyl (Hay et al. 1963) and phenyl (O'Carroll et al. 1995) compounds. Clinical features

Chronic exposure to elemental mercury, or the chronic ingestion of small amounts of the mercury salts, may lead to a condition known as 'erithism': patients experience a personality change towards timidity, seclusiveness and irritability; tremulousness with an intention component may also be seen, and, in some cases, forgetfulness may occur (Vroom and Greer 1972). The chronic ingestion of mercury salts (e.g. Calomel) may be followed by the gradual onset of a dementia with accompyaning tremulousness and cerebellar signs (intention tremor and ataxia) (Davis et al. 1974). Exposure to large amounts of methylmercury (Rustam and Hamri 1974) is followed within weeks by the subacute onset of a dementia often accompanied by prominent tremulousness, cerebellar signs (dysarthia, intention tremor, and ataxia), choreoathetosis (Snyder 1972), visual disturbance (often tunnel visison), and parasthesiae of the mouth, tongue, and extremities. Methylmercury also crosses the placenta and may lead to mental retardation (Snyder 1971). Exposure to a very small amount of dimethylmercury was, in one case, followed in 5 months by the subacute onset of ataxia, followed by dementia and eventual death (Nierenberg et al. 1998). Course With separation from the mercury, there may or may not be some improvement. Differential diagnosis

Diagnosis leans heavily on a history of exposure. Lacking such a history, erithism may be distinguished from other personality changes by the tremulousness, and the dementia of

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mercury salt or organic mercury poisoning may be distinguished from most other dementias by the prominent cerebellar signs. Treatment

Intoxication with elemental, salt, or organic forms of mercury may be treated with penicillamine. Elemental and salt forms of mercury intoxication may also be treated with dimercaprol, but dimercaprol should not be used in methylmercury poisoning as there is evidence from animal studies that it may actually cause an increase in the brain levels of mercury. Organic mercury compounds may also be removed from the gut with polythiol resins. Organic mercury poisoning may in addition be treated with hemodialysis, provided that cysteine is added to the arterial blood: methylmercury itself is not dialysable, but the complex of cysteine and methylmercury is.

DIALYSIS DEMENTIA Pathology and etiology Dialysis dementia, in all likelihood, occurs as a result of aluminium intoxication secondary to a high aluminum concentration in the dialysate. Pathologically, the aluminum level is increased in the brain (Alfrey et al. 1976), and there is neuronal loss in the cerebral cortex with, at times, laminar spongiform change. Aluminium intoxication with dementia may also occur in patients not on dialysis, for example those with uremia receiving aluminum-containing phosphate binders (Andreoli et al. 1984) or aluminum hydroxide. Clinical features

The onset is subacute, on average after 37 (Lederman and Henry 1978) to 40 (Garrett et al. 1988) months of dialysis. Typically (Burks et al. 1976; Chokroverty et al. 1976; Garrett et al. 1988; Lederman and Henry 1978; O'Hare et al. 1983), patients present with a peculiar, stuttering type of aphasia, followed by myoclonus, seizures, and dementia. In a minority (Garrett et al. 1988), psychotic symptoms may occur, with delusions, hallucinations, and bizarre behavior (Chokroverty et al. 1976; Scheiber and Ziesat 1976); in one case (Jack et al. 1983), mania occurred. The electroencephalogram (EEC) typically shows bursts of high-amplitude slow waves with interspersed spikes and spike-waves. Course With continued exposure to aluminum, the dementia is progressive and fatal. Differential diagnosis

Dementia in patients with renal failure may also occur secondary to multiple infarcts. Treatment

Diazepam may transiently relieve myoclonus and other aspects of the dementia (Nadel and Wilson 1976), but the effect is generally not sustained. Elimination of the aluminum may be followed by improvement (Poisson et al. 1979). Chelation may be accomplished with desferoxamine. Critically, patients with renal failure, whether on dialysis or not, should abstain from any aluminum-containing medicines, and the aluminum level of the dialysate should be as low as possible.

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DIALYSIS DISEQUILIBRIUM SYNDROME Pathology and etiology Although the dialysis disequilibrium syndrome is characterized by cerebral edema, the precise cause of the edema is not clear. Theories include osmotic shifts due to rapid changes in extracellular osmolality and the presence of intracellular acidosis. Clinical features

The dialysis disequilibrium syndrome (Mawdsley 1972; Peterson and Swanson 1964; Raskin and Fishman 1976; Tyler 1965) typically occurs within 3-4 hours after the start of a dialysis run and is particularly likely with rapid dialysis; rarely, it may appear after a run has ended, sometimes being delayed for up to 24 hours. The onset is fairly rapid; patients become delirious, and a small minority may have convulsions. In severe cases, stupor or coma may supervene. Papilledema may also occur. The EEC usually shows generalized slowing. Course Spontaneous recovery generally occurs within hours; rarely, the symptoms may last for days. Differential diagnosis

Subdural hematoma or intracerebral hemorrhage, both related to anticoagulation, may produce a similar picture. Treatment

In general, no specific treatment is required, supportive care for delirium, as outlined in Chapter 5, generally being sufficient. Future episodes may be avoided by scrupulous attention to fluid and electrolyte balance and by slowing the dialysis run.

HYPOGLYCEMIA Pathology and etiology The neuronal energy requirement is met almost entirely by circulating glucose: glycogen storage in the brain is extremely limited, sufficient to meet metabolic requirements for only about 30 minutes, after which neuronal failure begins. From a diagnostic point of view, it is useful to distinguish between postprandial hypoglycemia and fasting (or 'post-absorbtive') hypoglycemia. Postprandial hypoglycemia occurs several hours after a meal and may be seen in the following conditions: early type II diabetes; after vagotomy, gastrectomy, pyloroplasty, or gastrojejeunostomy; and in a rare (Palardy et al. 1989) and somewhat controversial condition known as 'functional' or 'essential' postprandial hypoglycemia. Fasting hypoglycemia generally occurs after a fast of 6 or more hours (for example, overnight) and may be seen in the following conditions: diabetics on insulin or oral antidiabetic agents who take too large a dose or skip a meal; malingerers who surreptitiously take insulin or an oral antidiabetic agent; insulinoma; large sarcomas (which secrete insulin-like growth factor); cirrhosis or significant liver disease that precludes glucose production by hepatic glycogenolysis or gluconeogenesis; and alcoholism. The deficit in alcoholism has two sources: first, many alcoholics are malnourished, and thus have little in the way of hepatic glycogen stores; second, alcohol interferes with hepatic gluconeogenesis. A blood glucose level below 2.5mmol/L (45mg/dL) usually causes symptoms, which, provided glucose is made available, remit entirely without any residual effect. With a sustained blood glucose level of below 1.11 or 1.39mmol/L (20 or 25mg/dL), however, neuronal

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damage occurs (Kalimo and Olsson 1980; Lawrence et al. 1942; MacKeith and Meyer 1939): this is most prominent in the superficial layers of the cerebral cortex, the dentate gyurus and hippocampus, and, to a lesser degree, the basal ganglia; Purkinje cell loss in the cerebellum may also occur, but is not as prominent. In severe cases, laminar cortical necrosis may occur, and, in very severe cases, almost the entire cortical mantle is destroyed. Clinical features

Hypoglycemia may produce two different kinds of symptomatology: autonomic and neuroglycopenic. Autonomic symptoms tend to occur acutely and include anxiety, diaphoresis, tremor, tachycardia, and pallor. Neuroglycopenic symptoms are of more gradual onset and include (Hart and Frier 1998; Malouf and Brust 1985) stupor or coma, delirium, bizarre, automatic behavior, seizures, and, in a small minority, focal signs such as hemiplegia or aphasia. Delirium, seen in perhaps one-third of cases of hypoglycemia (Malouf and Brust 1985), may or may not be accompanied by any autonomic symptoms (Case Records 1988; Malouf and Brust 1985; Moersch and Kernohan 1938). Bizarre, automatic behavior may occur in episodes that may recur for years before the correct diagnosis is made. Two cases, both secondary to insulinoma, are instructive. In the first (Bosboom et al. 1996), the patient had recurrent attacks for over two years; during one observed attack, the patient 'was restless, opening and closing his eyes, and thrashing about with his arms and legs, occasionally hitting onlookers and spitting in their faces'. In the second (Zivin 1970), the patient, during the first episode: automatically walked into the mess hall ... [dressed] in his underwear ... more incidents occurred. On one occasion, his mother noted him to have a detached appearance with automatic acting out. Recognizing he had not eaten breakfast, he was given a sweetened carbonated beverage. Almost immediately, he became aware of his surroundings ... [and] was surprised to learn of his behavior.

In both cases, the patients were amnestic for their behavior during the episode, and both recovered with excision of the insulinoma. Focal signs are uncommon, occurring in fewer than 2% of patients (Malouf and Brust 1985), and may include hemiplegia or, less commonly, aphasia (Shintani et al. 1993; Wallis et al. 1985). Postprandial hypoglycemia, in general, initially causes autonomic symptoms, which, if the hypoglycemia persists, may eventually be followed by neuroglycopenic symptoms. In fasting hypoglycemia, however, there may be few or no autonomic symptoms, patients presenting only with neuroglycopenic symptomatology. An exception to these patterns may be seen in some diabetics who develop the 'syndrome of hypoglycemic unawareness': here, after one or more episodes of autonomic symptoms, a kind of tolerance develops, such that in these patients, postprandial hypoglycemia may be followed by neuroglycopenic symptoms alone. Another exception involves patients on beta-blockers, which may mask most of the autonomic symptoms. Blood should, if possible, be drawn while the patient is symptomatic and tested for glucose and insulin levels; furthermore, if there is any suspicion of the surreptitious ingestion of insulin or oral antidiabetic agents, a 'C-peptide' level should also be ascertained, and both urine and serum should be tested for the presence of oral antidiabetic drugs. C-peptide is secreted by the pancreas, its levels paralleling those of endogenously derived insulin. Thus, in cases in which the insulin level is inappropriately high relative to the glucose level, a high Cpeptide level indicates that the insulin is of endogenous origin (as may, for example, be found in an insulinoma), whereas a low C-peptide level indicates an exogenous source of insulin, as seen, for example, in malingering (Scarlett et al. 1977).

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Course

As noted earlier, a sustained blood glucose level of below 1.11 or 1.39 mmol/L (20 or 25 mg/dL) may be associated with neuronal damage or death, and if sufficient damage has occurred, a dementia may appear. Differential diagnosis

Delirium or bizarre behavior in a diabetic treated with insulin or an oral antidiabetic agent should always suggest hypoglycemia. Delirium tremens is, clinically speaking, similar to hypoglycemic delirium, and, in practice, as soon as an alcoholic has been given thiamine, it is standard practice to ensure an adequate glucose level. Complex partial seizures may, in clinical terms, be quite similar to the episodes of bizarre behavior that may occur with hypoglycemia. Complex partial seizures, however, are generally of paroxysmal onset, short (several minutes) in duration, and unaffected by glucose: by contrast, neuroglycopenic symptoms are generally of gradual onset and long duration (until glucose is given), and are promptly responsive to glucose. Anxiety attacks, as may occur in panic disorder, bear a resemblance to hypoglycemia characterized by prominent autonomic symptoms: the difference here is that whereas glucose aborts the hypoglycemic attack, it has no effect on a panic attack. Many patients attribute various symptoms to postprandial 'low blood sugar'; however, before accepting this self-diagnosis, it is imperative that the criteria of'Whipple's triad' be met, namely: 1. the presence of the patient's typical symptoms 2. the concurrent presence of significant hypoglycemia. 3. the prompt relief of the symptoms with glucose. The mere presence of hypoglycemia on a 5-hour glucose tolerance test is not sufficient as many individuals have hypoglycemia on such a test yet develop no symptoms at all. Treatment

The glucose level may be increased either by supplying exogenous glucose or by stimulating hepatic gluconeogeneis. Patients able to take oral fluids may be given a glass of orange juice mixed with two or three tablespoonfuls of sugar; those unable to take fluids orally may be given 50 cc3 of a 50% solution of dextrose and water intravenously. When intravenous administration is not possible, hepatic gluconeogenesis may be stimulated by glucagon, 1 mg intramuscularly. Such therapy depends, of course, on a generally intact liver and will have little or no effect in patients with cirrhosis. Providing the diagnosis is correct, most patients respond to glucose replenishment within minutes. Therapy must be continued until the underlying cause of the hypoglycemia has been corrected. Importantly, in alcoholics, parenteral thiamine should be given first, glucose replenishment being delayed as long as is clinically feasible in order to reduce the risk of precipitating a Wernicke's encephalopathy.

CENTRAL PONTINE MY ELINOLYSIS Pathology and etiology

Although the myelinolysis of central pontine myelinolysis is most commonly seen in the central portion of the pons, extrapontine sites, including the cerebral white matter, striatum,

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thalamus, and cerebellum, may also be involved (Wright et al. 1979). Within the pons (Adams et al. 1959), there is a variable degree of symmetric demyelinization located primarily in the rostral two-thirds of the basis pontis. Importantly, the demyelinization generally does not reach the surface of the pons, a rim of preserved white matter, of variable width, typically separating the area of demyelinization from the surface of the pons. In severe cases, cavitation may occur. In all likelihood, the demyelinization occurs secondary to an overly rapid correction of chronic hyponatremia (Brunner et al. 1990; Karp and Laureno 1993; Messert et al. 1979; Norenberg et al. 1982; Sterns et al. 1986), with a consequent osmotic shift of water from the interior of the cells (such as oligodendroglia) to the extracellular space. Although such a scenario is most likely in chronic alcoholics given intravenous fluids, other groups at risk include the recipients of liver transplants (Estol et al. 1989), patients with severe burns (McKee et al. 1988), those suffering from severe malnutrition, and patients hyponatremic because of protracted vomiting (Dickoff et al. 1988) or diarrhea (Price and Mesulam 1987). Clinical features

The onset is subacute, occurring within 1-7 days after the rapid correction of hyponatremia. Patients may become delirious or lethargic (Karp and Laureno 1993), and both visual and auditory hallucinations have been reported (Sterns et al. 1986). Typically, a quadriparesis of variable severity is seen, and patients may also develop pseudobulbar palsy, with, in some cases, cranial nerve palsies. In severe cases, a 'locked-in' state may occur. The dominant feature of central pontine myelinolysis may rarely be parkinsonism (Dickoff et al. 1988; Tomita et al. 1997), which in one case was intermittently accompaneid by intention myoclonus (Seiser et al. 1998). Tl-weighted MRI scanning generally reveals a centrally placed area of decreased signal intensity in the basis pontis. Importantly, however, this finding may not appear until up to a day after the onset of the symptoms. In those cases characterized solely by parkinsonism, the pons may appear normal, lesions appearing in the striatum alone (Tomita et al. 1997). Course In severe cases, coma may occur, with death days to weeks later. Milder cases are characterized by a variable degree of recovery; rarely, full recovery may occur. Differential diagnosis

The appearance of delirium or quadriplegia shortly after the correction of hyponatremia is highly suggestive. Basilar artery stroke is distinguished by its acute onset and also by MRI findings: in stroke, the lesion is generally asymmetric and typically reaches to the surface of the pons, in contrast to the centrally placed, symmetric lesion of central pontine myelinolysis, which does not reach the surface. Treatment

As there is no treatment per se for central pontine myelinolysis, prevention is the goal. As noted earlier, the cause of central pontine myelinolysis is in all likelihood an overly rapid correction of chronic hyponatremia. It must be emphasized that asymptomatic patients with hyponatremia may be treated successfully with fluid restriction alone (i.e. 800-1200 mL daily) rather than intravenous fluids. When hyponatremia is symptomatic (i.e. with nausea, vomiting, delirium, or seizures [Karp and Laureno 1993]), normal saline may be given, but the rate should be adjusted such that the serum sodium concentration does not rise at a rate any faster than 0.33 (Norenberg et al. 1982) to 0.42 (Sterns et al. 1986)mEq/L per hour.

514 Specific disorders

UREMIC ENCEPHALOPATHY Pathology and etiology The mechanism whereby delirium occurs in the context of renal failure is not clear. One theory suggests that it is due to the toxic effects of metabolites of protein and amino acid metabolism normally excreted by the kidneys; another suggests that it is related to the effects of secondary hyperparathyroidism, or perhaps to a direct toxic effect of parathormone itself. It is clear that there is not a good correlation between the severity of delirium and the blood urea nitrogen (BUN) level. In some cases, an excess of Alzheimer-type II astrocytes is found in the cortex. Clinical features

The onset parallels the onset of the renal failure: acute renal failure may be followed by a delirium of acute onset, over hours or days, whereas chronic renal failure may occasion a delirium of insidious onset. In those cases characterized by an insidious onset, one initially finds lassitude and a mild degree of somnolence: over time confusion and disorientation appear, in some cases joined by visual hallucinations. In most cases (Raskin and Fishman 1976; Tyler 1968), asterixis is also present, and, with progression, multifocal myoclonus and seizures may appear. In one rare case, uremia presented with mania alone, without any other symptoms (El-Mallakh et al. 1987). Chronic renal failure may also be accompanied by a peripehral polyneuropathy (Thomas et al. 1971). This is initially primarily sensory, and patients may experience a syndrome very similar to the restless legs syndrome; over time, a motor component may appear, which, in severe cases, may progress to quadriplegia. The BUN and creatinine levels are elevated, but, as noted above, there is not a good correlation between BUN and the delirium; indeed, if the renal failure is of very slow onset, some patients may develop a BUN of over 200 mg/dL without any neuropsychiatric symptoms. MRI or computed tomography may show some cerebral atrophy. The EEG typically shows generalized slowing. Course With progression of the renal failure, stupor and coma develop. Differential diagnosis

Subdural hemorrhage (Fraser and Arieff 1988), intracerebral hemorrhage, hyponatremia and hypocalcemia may all complicate renal failure, and each one may independently cause a delirium. In some cases of delirium accompanying renal failure, the delirium, rather than being related to the renal failure per se, may rather be caused directly by the underlying etiology of the renal failure itself. Thus, for example, both polyarteritis nodosa and systemic lupus erythematosus may, in addition to causing renal failure, also directly lead to delirium. Another important cause is drug toxicity secondary to drugs normally excreted by the kidneys. Treatment

In most cases, uremic encephalopathy clears fairly promptly with hemodialysis or renal transplantation.

HEPATIC ENCEPHALOPATHY Pathology and etiology Toxins found in portal blood are normally removed by the liver before the blood reaches the systemic circulation: with significant hepatic failure, or with the surgical creation of a

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portosystemic shunt (Read et al. 1961), these toxins appear in the systemic circulation, and it is their effect on the brain that causes hepatic encephalopathy. Hepatic failure may occur secondary to a large number of causes, such as viral hepatitis, hepatotoxic drugs, halothane anesthesia, or alcoholic cirrhosis. In some cases of subclinical failure, patients may remain asymptomatic until some precipitant either impairs hepatic function slightly further or creates a nitrogenous load in the gut that overwhelms the detoxifying capacity of the damaged liver. Examples of precipitants that might further worsen hepatic function include hypokalemia, azotemia, anesthesia, and alcohol. Examples of precipitants that increase the nitrogenous contents of the gut include high-protein meals, bleeding from esophageal varices or peptic ulcers, and constipation. It is not clear which one, or combination, of portal toxins is responsible; candidates include ammonia, mercaptans, short-chain fatty acids, and various aromatic amino acids. Gammaaminobutyric acid and various endogenous benzodiazepines (Basile etal. 1991) may also play a role. Within the central nervous system, an excessive number of Alzheimer-type II astrocytes (Adams and Foley 1953) is found in the cerebral cortex, basal ganglia, brainstem, and cerebellum. Clinical features

The onset of the delirium of hepatic encephalopathy parallels the rapidity of onset of the underlying hepatic failure. In cases of fulminant failure caused by acute viral hepatitis, delirium may appear acutely, over hours; at the other extreme, a very slowly progressive failure, as may be seen in patients with alcoholic cirrhosis who continue to drink, may lead to a delirium of insidious onset. The delirium of hepatic encephalopathy (Eraser and Arieff 1985; Read et al. 1961; Summerskill et al. 1956) may be marked by euphoria and is typically accompanied by asterixis (Adams and Foley 1953); constructional apraxia and myoclonus may also occur, but convulsive seizures are uncommon. Rarely, catatonic symptoms, such as waxy flexibility, may occur (Jaffe 1967). Fetor hepaticus, a sickly-sweet musty odor to the breath, is seen in about half the cases. With progression, coma may occur. The ammonia level is typically elevated, but there is not a good correlation between the extent of elevation and the severity of the delirium; indeed, in a small minority of cases, the ammonia level may be within normal limits (Sherlock 1993). The EEC classically shows triphasic delta waves, maximal frontally. Course The severity of the delirium typically fluctuates during the day. Depending on the severity of the hepatic failure, death, often secondary to cerebral edema, may occur, and this is very likely in cases in which coma supervenes. Severe or recurrent episodes of hepatic encephalopathy may be followed by acquired hepatocerebral degeneration, described below. Differential diagnosis

Among alcoholics with cirrhosis, delirium, in addition to being seen with hepatic encephalopathy, may also result from other alcohol-related disorders, such as delirium tremens, Wernicke's encephalopathy, hypoglycemia, or subdural hematoma. Hepatic failure may be accompanied by a bleeding diathesis, and intracerebral hemorrhage may occur. Treatment

In addition to treating the underlying cause of the hepatic failure, an effort is undertaken to reduce the nitrogenous load in the gut. Patients are placed on a 20g/day low-protein diet, and

516 Specific disorders

lactulose is given, initially in a dose of 30-45 mL hourly until bowel movements begin, followed by a regular dose sufficient to ensure three or four soft stools daily (usually 30-45 mL lactulose three or four times daily). Neomycin, in a dose of 4-8 g daily in divided doses, may be given to kill nitrogenous bacteria in the gut, but this carries the risk of oto- or nephrotoxicity. In cases of chronic hepatic failure, it may be possible to maintain the patient on a modest protein reduction (e.g. 40-60 g daily) and a low dose of lactulose. In some cases, intravenous flumazenil, a benzodiazepine antagonist, may partially relieve the symptoms. Liver transplantation is very effective. Should the delirium require symptomatic treatment, benzodiazepines are generally contraindicated as they may worsen the delirium. Neuroleptics may be used, but only with caution as all of them depend on hepatic metabolism.

ACQUIRED (NON-WILSONIAN) HEPATOCEREBRAL DEGENERATION Pathology and etiology

Acquired hepatocerebral degeneration (Victor et al. 1965) is characterized by cortical laminar necrosis; microcavitation may be seen in the cerebral cortex as well as in the striatum and cerebellar cortex. Microscopically, there is a widespread protoplasmic astrocytosis. Degeneration occurs secondary to repeated or severe episodes of hepatic encephalopathy, as may be seen in alcoholic cirrhosis, in biliary cirrhosis, or with portocaval shunts. Clinical features

Dementia may occur in the context of cerebellar signs, such as ataxia, intention tremor, or dysarthria, or a movement disorder, such as chorea, athetosis, or grimacing (Finlayson and Superville 1981; Graham et al. 1970; Raskin et al 1984; Victor et al. 1965). Course With repeated or sustained episodes of hepatic insufficiency, the symptoms progress, this progression occurring in either a gradual or a stepwise fashion. Differential diagnosis

Wilson's disease is distinguished by the presence of Kayser-Fleischer rings and disturbances of copper metabolism. Huntington's disease is distinguished by the absence of cerebellar signs, by the presence of a positive family history, and by genetic testing. Treatment

Hepatic insufficiency must, if possible, be corrected or prevented. The general treatment of dementia is discussed in Chapter 5.

HEPATIC PORPHYRIA Pathology and etiology

There are four hepatic porphyrias capable of causing neuropsychiatric symptomatology. The first three, namely acute intermittent porphyria, variegate porphyria and coproporphyria, are all inherited in an autosomal dominant fashion. The fourth, ALA dehydratase deficiency porphyria, is an autosomal recessive disorder that is so vanishingly rare that it is not considered further here.

Nutritional, toxic, metabolic disorders 517

All the hepatic porphyrias result from specific enzymatic defects in the heme synthetic pathway, leading to an accumulation of heme precursors in the serum, urine, and feces. Although the mechanism whereby central and peripheral nervous system damage occurs is not clear, a toxic effect of one or more of these precursors is suspected. Autopsy studies of the cerebrum have generally been unrevealing, the minor changes that have been noted probably resulting from incidental ischemic changes (Hierons 1957). Within the peripheral nervous system, axonal damage (Cavanagh and Mellick 1965; Sweeney et al. 1970) with associated chromatolysis of the spinal motor neurons (Hierons 1957) has been noted. Clinical features

All of the dominantly inherited porphyrias may cause attacks, described below. In addition, both variegate porphyria and coproporphyria may cause a photosensitive rash, which, importantly, may or may not accompany the attacks. The first attack usually appears after puberty, often in the third decade. Attacks, rather than appearing spontaneously, usually occur in response to one of the precipitants noted below. The overall symptomatology of attacks has been reviewed in a number of papers (Becker and Kramer 1975; Goldberg 1959; Rowland 1961; Stein and Tschudy 1970), Typically, the attack is of acute onset and is characterized by abdominal pain accompanied by vomiting and constipation or, less commonly, diarrhea. Delirium typically occurs and may be accompanied by visual hallucinations (Cross 1956), which may be extremely vivid and compelling (Paredes and Jones 1959). Rarely, rather than a delirium, a psychosis may appear: in one case (Mandoki and Sumner 1994) a girl with 'stomachaches' became labile and aggressive, and saw and heard 'ghosts'; in another case (Hirsch and Dunsworth 1955), a young woman with abdominal pain and a motor polyneuropathy experienced auditory hallucinations and delusions of persecution, and engaged in bizarre behavior such as urinating on the floor. A peripheral sensorimotor polyneuropathy also appears: although pain and other sensory complaints may be reported, the dominant manifestation is a motor polyneuropathy, which may, in severe cases, progress to quadriplegia and respiratory failure. Tachycardia and increased blood pressure are also common, as is hyponatremia, which may occur secondary to a syndrome of inappropriate antidiuretic hormone secretion or to fluid loss. Seizures are seen in a minority and may result from hyponatremia or direct cerebral involvement. On an historical note, it appears that the periodic 'madness' of King George III was a manifestation of hepatic porphyria (Macalpine and Hunter 1966; Macalpine et al. 1968). Precipitating factors for attacks include fasting (or merely a low-carbohydrate diet), infection, surgery, menstruation, pregnancy, and a host of drugs including barbiturates, phenytoin, valproic acid, carbamazepine, sulfonamides, griseofulvin, meprobamate, glutethimide, methyprylon, ethchlovynol, ergot derivatives, synthetic estrogens and progestins, danazol, alpha-methyldopa, chlorpropamide and alcohol. Importantly, the following drugs have been shown to be safe: phenothiazines (e.g. chlorpromazine), opioid analgesics, chloral hydrate, diazepam, diphenhydramine, aspirin, and acetaminophen. MRI scanning during an acute attack may reveal scattered lesions, which clear after the attack resolves (King and Bragdon 1991). The diagnosis is made by finding elevated levels of specific heme precursors. In all three forms of dominantly inherited hepatic porphyria, both the plasma and 24 hour urine levels of aminolevulenic acid and porphobilinogen are elevated; in variegate porphyria and coproporphyria the 24 hour urine level of coproporphyrin is also elevated. Distinguishing variegate porphyria from coproporphyria requires a stool sample: in variegate porphyria, the level of protoporphyrin is greater than that of coproporphyrin, whereas in coproporphyria,

518 Specific disorders

coproporphyrin is greater than protoporphyrin. Importantly, all these tests may be normal in between attacks. Course Most patients gradually recover from the acute attack, generally within weeks; in some cases, recovery from the motor polyneuropathy may take up to a year and may never be complete. Severe attacks may result in death from respiratory failure or cardiac arrhythmia. In females, attacks may cease after menopause. Differential diagnosis

The appearance of delirium or psychosis in the context of abdominal pain or a peripheral polyneuropathy is highly suggestive. A positive family history is also very helpful, but a negative family history does not argue against the diagnosis: although the hepatic porphyrias are autosomal dominant conditions, penetrance is low, and, in fact, most individuals are only carriers and never have symptoms. Treatment

Chlorpromazine, 25-50 mg every 4 hours, may control the delirium and reduce the abdominal pain; if pain persists, opioid analgesics, such as meperidine, may be required. Chloral hydrate may be used for sleep. Propranolol may be used for tachycardia or hypertension. If anticonvulsants are required, consideration may be given to gabapentin, which, unlike the other agents available, does not appear to be porphyrogenic (Hahn et al. 1997). In some cases, attacks may be aborted or limited by a high-carbohydrate diet or intravenous dextrose. Should this fail, or should the attack be fulminant, hematin (also known as hemin) may be given intravenously. Hematin effectively reduces the activity in the heme biosynthetic pathway, thus leading to a reduction in the level of heme precursors. Preventive measures include avoiding preciptating factors wherever possible. In some cases of menstrually related attacks, the administration of luteinizing hormone releasing hormone may be protective.

BASAL GANGLIA CALCIFICATION (FAHITS SYNDROME) Pathology and etiology

Calcification is heaviest in the basal ganglia (more so in the globus pallidus and putamen than the caudate) but may also be seen in the thalamus, in the dentate nuclei of the cerebellum, and at the gray-white junction in the cerebral and cerebellar cortices. Calcification may occur secondary to hypoparathyroidism (surgical [Berger and Ross 1981; Klawans et al. 1976; Tambyah et al. 1993), idiopathic hypoparathyroidism [Kazis 1985; Slyter 1979], pseudohypoparathyroidism [Mathews 1957], and pseudo-pseudohypoparathyroidism [Nyland and Skre 1977]), rarely due to hyperparathyroidism (Margolin et al. 1980), on a familial basis (Boiler et al. 1977; Kobari et al. 1997), often with autosomal dominant inheritance, and on an idiopathic (Trautner et al. 1988) basis. The term 'Fahr's disease' has been defined differently by different authors; some include all cases of basal ganglia calcification, others only familial or idiopathic cases. Given that each definition acknowledges etiologic heterogeneity, it appears more appropriate to speak of Fahr's syndrome rather than Fahr's disease. Clinical features

The onset of the symptoms is generally insidious, occurring in the early or mid-adult years, the presentation typically being with either a movement disorder (Klawans et al. 1976;

Nutritional, toxic, metabolic disorders 519

Margolin et al 1980; Tambyah et al. 1993) or a dementia (Kobari et al. 1997; Slyter 1979). The movement disorder is generally characterized by parkinsonism, but choreathetosis and, less commonly, dystonia, may also be seen; in some cases, there may also be cerebellar symptoms such as ataxia or dysarthria. The dementia is characterized by poor memory and concentration, and overall slowness of thought. Rare presentations of Fahr's syndrome include depression (Trautner etal. 1988), eventually followed by parkinsonism, and, in one family (Francis and Freeman 1984), a psychosis similar to schizophrenia, without any movement disorder. An association has also been noted between bilateral basal ganglia calcification and classic obsessions and compulsions (LopezVillegas et al. 1996). Skull films, computed tomography or MRI scans reveal symmetric calcification in the structures noted above. Course

This syndrome is very slowly progressive: for example, many years may elapse between a presentation with dementia and the onset of a movement disorder. Differential diagnosis Without imaging, the differential diagnosis for such cases is very wide, but imaging greatly facilitates the diagnostic task. It must be borne in mind, however, that bilateral calcification of the basal ganglia is a very common incidental finding, noted in between 0.3% (Koller et al. 1979) and 0.6% (Harrington et al. 1981) of the population. Thus, an individual patient's illness ought not be considered to be an example of Fahr's syndrome unless the clinical picture is consistent with that noted above. Treatment Hypoparathyroidism, if present, should be treated as this may prompt a partial remission of symptoms (Berger and Ross 1981; Slyter 1979). Parkinsonism may or may not respond to levodopa.

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524 Specific disorders Norenberg MD, Leslie KO, Robertson AS. Association between rise in serum sodium and central pontine myelinolysisMw? Neurol 1982; 11:128-35. Nyland H, Skre H. Cerebral calcinosis with late onset encephalopathy. >4cta Neurol Scorn/1977; 56:309-25. O'Carroll RE, Moffoot APR, Ebmeier KPet al. Effects of fluvoxamine on cognitive functioning in the alcoholic Korsakoff syndrome. PsychopharmacologyWW; 116:85-8. O'Carroll RE, Masterton G, Dougall N et al. The neuropsychiatric sequelae of mercury poisoning: the Mad Hatter's disease revisited. Br J Psychiatry 1995; 167:95-8. O'HareJA, Callaghan NM, Murnaghan DJ. Dialysis encephalopathy. Clinical, electroencephalographic, and interventional aspects. Medicine 1983; 62:129-41. PalardyJ, Havrankova J, Lepage R et al. Blood glucose measurements during symptomatic episodes in patients with suspected postprandial hypoglycemia. NEnglJ Med 1989; 321:1421-5. Paredes A, Jones H. Psychopathology of acute intermittent porphyria: case report. J NervMent Dis 1959; 129:291-301. Paulson GW, Martin EW, Mojzisik C et al. Neurologic complications of gastric partitioning. Arch Neurol

1985; 42:675-7. PentschewA. Morphology and morphogenesis of lead encephalopathy. Acta Neuropathol 1965; 5:133-60. Peterson H, Swanson AG. Acute encephalopathy occurring during hemodialysis. Arch Int Med 1964; 113:877-80. Pierce LB. Pellagra: report of a case. AmJ Psychiatry 1924; 81:237-43. Pincus JH, Reynolds EH, Glaser GH. Subacute combined system degeneration with folate deficiency. J Am Med Assoc 1972; 221:496-7. Poisson M, Marshaly R, Lafforgue B. Progressive dialysis encephalopathy. Ann Neurol 1979; 6:88-92. Price BH, Mesulam M-M. Behavioral manifestation of central pontine myelinolysis. Arch Neurol 1987;

44:671-3. Raskin NH, Fishman RA. Neurologic disorders in renal failure. NEnglJl j M Med 1976; 294:143-8,204-10. Raskin NH, Bredesen D, Ehrenfeld WK et al. Periodic confusion caused by congenital extrahepatic portocaval shunt. Neurology 1984; 34:666-9. Read AE, Laidlaw J, Sherlock S. Neuropsychiatric complications of portocaval anastamosis. Lancet 1961; 1:961^. Reed D, Crawley J, Faro SN et al. Thallotoxicosis. J Med Assoc 1963; 183:516-22. Reynolds EH, Rothfeld P, PincusJH. Neurological disease associated with folate deficiency. BMJ1973; 2:398-400. Reynolds EH, Bottiglieri T, Laundy M et al. Subacute combined degeneration with high serum vitamin B12 level and abnormal vitamin B12 binding protein: new cause of an old syndrome. Arch Neurol

1993; 50:739-42. Richmond]. Wernicke's encephalopathy associated with digitalis poisoning. Lancet 1959; 1:344-5. Roos D. Neurological symptoms and signs in a selected group of partially gastrectomized patients with particular reference to B12 deficiency. Acta NeurolScand 1974; 50:719-52. Rowland LP. Acute intermittent porphyria: search for an enzymatic defect with implications for neurologyand psychiatry. DisNervSyst 1961; 22 (suppl):1-12. Russell DS. Changes in the central nervous system following arsphenamine medication.J Pathol 1937; 45:357-66. Russell JSR, Batten FE, Collier J. Subacute combined degeneration of the spinal cord. Brain 1900;

23:39-110. Rustam H, Hamri T. Methyl mercury poisoning in Iraq. Brain 1974; 97:499-510. Scarlett JA, Mako ME, Rubenstein Mi et al. Factitious hypoglycemia: diagnosis by measurement of serum C-peptideimmunoreactivityand insulin-binding antibodies. NEnglJ g l j Med 1977; 297:1029-32. Scheiber SC, Ziesat H. Brief communication: clinical and psychological test findings in cerebral dyspraxia associated with hemodialysis. J Nerv Ment Dis 1976; 162:212-14.

Nutritional, toxic, metabolic disorders 525 Schottenfeld RS, Cullen MR. Organic affective illness associated with lead intoxication. Am J Psychiatry 1984; 141:1425-6. Seiser A, Schwarz S, Aichinger-Steiner MM et al, Parkinsonism and dystonia in central pontine and extrapontine myelinolysis.j Neurol NeurosurgPsychiatry 1998; 65:119-21. Seltzer B, Benson DF. The temporal pattern of retrograde amnesia in Korsakoff's disease. Neurology 1974; 24:527-30. Serdarlu M, Hausser-Hauw C, Laplane D et al. The clinical specturm of alcoholic pellagra encephalopathy. Brain 1988; 111:829^*2. Sherlock S. Fulminant hepatic failure. Adv Intern Med 1993; 38:245-67. Shimomura T, Mori E, Hirono N et al. Development of Wernicke-Korsakoff syndrome after long intervals following gastrectomy. Arch Neurol 1998; 55:1242-5. Shintani S, Tsuruoka S, Shiigai T. Hypoglycemic hemiplegia: a repeat SPECT study.J Neurol Neurosurg Psychiatry 1993; 56:700-1. Shor-PosnerG, Morgan R, WilkieFefo/. Plasma cobalamin levels affect information processing speed in a longitudinal study of HIV-1 disease. Arch Neurol 1995; 52:195-8. Shorvon SD, Carney MWP, Chanarin I et al. The neuropsychiatryof megaloblastic anemia. BM/1980; 281:1036-8. Slyter H. Idiopathic hypoparathyroidism presenting as dementia. Neurology 1979; 29:393-4. Smith JF, McLaurin RL, Nichols\Petal. Studies in cerebral oedema and cerebral swelling. 1. The changes in lead encephalopathy in children compared with those in alkyl tin poisoning in animals. Brain 1960; 83:411-24. Smith LH. Mental and neurologic changes in pernicious anemia. Arch Neurol Psychiatry 1929; 22:551-7. Snyder RD. Congenital mercury poisoning. NewEnglJ Med 1971; 284:1014-6. Snyder RD. The involuntary movements of chronic mercury poisoning. Arch Neurol 1972; 26:379-81. Stein JA, Tschudy DP. Acute intermittent porphyria. A clinical and biochemical study of 46 patients. Medicine 1970; 49:1-16. Sterns RH, RiggsJE, SchochetSS. Osmotic demyelination syndrome following correction of hyponatremia. NEnglJMedW86; 314:1535-42. Stojsavljevic N, Levic Z, Drulovic J et al. A 44-month clinical-brain MRI follow-up in a patient with B12 deficiency. Neurology 1997; 49:878-81. Strachan RW, Henderson JG. Dementia and folate deficiency. QJ Ato/1967; 36:189-204. Summerskill WHJ, Davidson EA, Sherlock Setal. The neuropsychiatric syndrome associated with hepatic cirrhosis and extensive portal collateral circulation. QJ Med 1956; 25:245-66. Supino-Viterbo V, Sicard C, Risvegliato M et al. Toxic encephalopathy due to ingestion of bismuth salts: clinical and EEG studies of 45 patients. J Neurol Neurosrug Psychiatry 1977; 40:748-52. Sweeney VP, Pathak MA, Asbury AKef al. Acute intermittent porphyria. Increased ALA-synthetase activity during an acute attack. Brain 1970; 93:369-80. Tambyah PA, Ong BKC, Lee KO. Reversible parkinsonism and asymptomatic hypocalcemia with basal ganglia calcification from hypoparathyroidism 26 years after thyroid surgery. AmJ Med 1993; 94:444-5. Thomas PK, Hollinrake K, Lascelles RG et al. The polyneuropathy of chronic renal failure. Brain 1971; 94:761-80. Thompson C, Dent J, Saxby P. Effect of thallium poisoning on intellectual functioning. Br J Psychiatry 1988;153:396-9. Tomita I, Satoh H, Satoh bet al. Extrapontine myelinolysis presenting with parkinsonism as a sequel of rapid correction of hyponatremia. J Neurol Neurosurg Psychiatry 1997; 62:422-3. Trautner RJ, CummingsJL, Read SL et al. Idiopathic basal ganglia calcification and organic mood disorders. AmJ Psychiatry 1988; 145:350-3. Turners, DanielsL, GreerS. Wernicke's encephalopathy in an 18-year-old woman. BrJ Psychiatry 1989; 154:261-2.

526 Specific disorders Tyler RH. Neurological complications of dialysis, transplantation and other forms of treatment in chronic uremia. Neurology 1965; 15:1081-8. Tyler RH. Neurologic disorders in renal failure. Am J Med 1968; 44:734-48. Victor M, Yakovlev PI. Korsakoff's psychic disorder in conjunction with peripheral neuritis: a translation of Korsakoff's original article with brief comments on the author and his contribution to clinical medicine. Neurology 1955; 5:394^06. Victor M, Adams RD, Cole M. The acquired 'non-Wilsonian' type of chronic hepatocerebral degeneration. Medicine 1965; 44:345-96. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome. Oxford: Blackwell, 1971. Vortmeyer AO, Hagel C, Laas R. Haemorrhagic thiamine deficient encephalopathy following prolonged parenteral nutrition. J Neurol Neurosurg Psychiatry 1992; 55:826-9. Vroom FQ, Greer M. Mercury vapor intoxication. Brain 1972; 95:305-18. Wainwright AP, Kox WJ, House IM et al. Clinical features and therapy of acute thallium poisoning. QJ Med 1988; 69:939-44. WallisWE, Donaldson I, Scott RS et al. Hypoglycemia masquerading as cerebrovascular disease (hypoglycemic hemiplegia). Ann Neurol 1985; 18:510-12. Whitfield CL, Ch'ied LT, Whitehead JD. Lead encephalopathy in adults. AmJ Med 1972; 52:289-98. Wright DG, Laureno R, Victor M. Pontine and extrapontine myelinolysis. Brain 1979; 102:361-85. Wu R-M, Chang Y-C, Chiu H-C. Acute triphenyltin intoxication: a case report J Neurol Neurosurg Psychiatry 1990; 53:356-7. Yamada M, Ohno S, Okayasu I et al. Chronic manganese poisoning: a neuropathological study with determination of managanese distribution in the brain. Acta Neuropathol 1986; 70:273-8. Zivin I. The neurological and psychiatric aspects of hypoglycemia. Dis Nerv Syst 1970; 31:604-7.

14 Infectious disorders Acquired immunodeficiency syndrome (AIDS)

Cytomegalovirus encephalitis Progressive multifocal leukoencephalopathy Arbovirus meningoencephalitis Herpes simplex viral encephalitis Encephalitis lethargica Infectious mononucleosis Mumps Varicella-zoster Rabies Post-infectious and post-vaccinal encephalomyelitis Subacute sclerosing panencephalitis

527

530 531 532 533 535 536 537 538 539 540 542

Subacute measles encephalitis Progressive rubella panencephalitis Neurosyphilis Lyme disease Tuberculosis Whipple's disease Rocky Mountain spotted fever Malaria Toxoplasmosis Candidiasis Cryptococcosis Coccidioidomycosis Histoplasmosis Aspergillosis

543 544 544 547 548 549 550 551 552 553 554 555 555 556

ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) Pathology and etiology

AIDS is caused by infection with the human immunodeficiency virus (HIV). This RNA virus is found in blood, semen, vaginal fluid, breast milk, and colostrum, and may be spread via all these fluids. In the United States, spread occurs most commonly with homosexual contact, in particular anal intercourse; however, as the virus spreads among females, it is likely that the most common mode of transmission in the United States will eventually become heterosexual contact, as is the case in Africa. Transfusion-related transmission, with an improved screening of blood products, is now becoming quite rare, but blood-borne transmission remains a significant problem among intravenous drug users who fail to sterilize their needles. Although the virus is also found in saliva, urine, and tears, there is as yet no convincing evidence that it can be spread by these. HIV gains attachment to cells such as lymphocytes, monocytes, and macrophages by virtue of the CD4 molecule found on their cell membrane (Pantaleo et al. 1993). Once inside the cell, the enzyme reverse transcriptase catalyzes the reverse transcription of genomic viral RNA into DNA, which eventually becomes inserted into the chromosomes of the host cell. With cell activation, this inserted DNA is copied, and is eventually followed by the production of mature HIV virus particles; importantly, one of the enzymes required for this production is protease.

528 Specific disorders

Subsequent to infection, there is an intense viremia, followed by a vigorous cellular and humoral immune response, such that the viremia is, in most cases, substantially contained within about 3 months. The virus, however, is not eradicated but rather continues to reproduce within lymphoid tissue. Tragically, the cell most likely to be infected is the CD4+ Tlymphocyte, with the result that eventually, over many years, with the gradual loss of these 'helper' lymphocytes, the body's defenses are subverted to the point at which a significant viremia again occurs. In addition, with the loss of these CD4+ helper lymphocytes, opportunistic infections begin to appear. It is not entirely clear how HIV gains entry into the central nervous system: one plausible theory posits that infected peripheral monocytes act as 'trojan horses', carrying the virus with them as they cross the blood-brain barrier. Within the central nervous system, HIV is found for the most part within monocytes, macrophages, and microglia: although HIV has also been noted in astrocytes and oligodendroglia, this does not appear to be significant with regard to the overall pathology of central nervous system infection. Although HIV infection of the central nervous sytem is found at autopsy in 90% or more of patients with AIDS, the percentage of patients with AIDS dementia is not that high, ranging from 15% (McArthur et al 1993) to 65% (Navia et al. 1986a). In these cases (Gray et al. 1988; Navia et al. 1986b), there are widespread multinucleated giant cells and microglial nodules; the white matter, in both the cerebrum and cerebellum, shows pallor and, in some cases, vacuolization. Clinical features

Early on in the infection, often concurrently with seroconversion, patients may develop a mononucleosis-like syndrome, which may be accompanied by an aseptic meningitis. Cranial nerve palsies, particularly affecting the fifth, seventh, and eighth nerves, may accompany the meningitis, and there may rarely also be an encephalitis, with delirium (McArthur 1987; Maloufefa/. 1990). AIDS dementia typically appears about 10 years after the initial infection, generally only when the CD4+ count has fallen below 200 cells/mm3. Clinically speaking (Navia et al. 1986a; Price et al. 1988), the dementia is of subacute or gradual onset and is characterized by apathy, poor concentration and forgetfulness: in some cases, there may be agitation, delusions, and visual hallucinations. Accompanying the dementia, one often sees dysarthria, ataxia, and longtract signs, such as hyperreflexia and Babinski signs; in one case, the dementia was accompanied by chorea (Pardo et al. 1998). With progression, there may be muteness, confusion, seizures, and myoclonus (Maher et al 1997). Along with AIDS dementia, patients may also develop a vacuolar myelopathy (Sharer et al. 1986), with paraparesis and sensory ataxia; mononeuritis multiplex and an often painful polyneuropathy (de la Monte et al. 1988) may also occur. Opportunistic infections include toxoplasmosis, progressive multifocal leukoencephalopathy, cytomegalovirus encephalopathy and mycoses (cryptococcosis, histoplasmosis, coccidioidomycosis, candidiasis, and aspergillosis); patients with AIDS are also prone to develop tuberculosis, neurosyphilis, herpes simplex encephalitis, and varicella-zoster encephalitis. Primary central nervous system lymphoma (Hochberg and Miller 1988) is not uncommon in AIDS, and, rarely, Kaposi's sarcoma may develop in the brain. Magnetic resonance imaging (MRI) in AIDS dementia generally reveals a degree of cortical atrophy and ventricular dilatation, and there may also be multiple areas, some confluent, of increased signal intensity in the centrum semiovale on T2-weighted scans (Dooneief et al. 1992; Navia et al 1986a), as illustrated in Fig. 14.1. The cerebrospinal fluid in AIDS dementia generally displays a mild mononuclear pleocytosis and an elevated total protein level.

Infectious disorders 529

Image Not Available

Figure 14.1 This T2-weighted magnetic resonance imaging scan shows both patchy and confluent areas of increased signal intensity in the centrum semiovale of a patient with AIDS dementia. (Reproduced from Gillispie and Jackson 2000.)

Although AIDS dementia may rarely be the presenting symptom of AIDS (Navia and Price 1987), in most cases, patients already have other evidence of the illness, such as generalized lymphadenopathy, constitutional symptoms, thrush, diarrhea, shingles, cytopenia, including thrombocytopenia, Kaposi's sarcoma, and Pneumocystis pneumonia. Serologic testing generally becomes positive within 2-12 weeks of the initial infection and is inevitably positive by 6 months; thus, in patients with AIDS dementia, the enzyme-linked immunosorbent assay (ELISA) test will be positive, as will the confirmatory Western blot test. Course AIDS dementia is relentlessly progressive, death usually following within months (McArthur et al. 1993); rarely patients may survive for up to a year. Differential diagnosis

The delirium seen with HIV seroconversion may be distinguished from infectious mononucleosis by a positive monospot test. AIDS dementia must be distinguished from other conditions, including opportunistic infections, which are commonly found in patients with AIDS. Cytomegalovirus (CMV) encephalitis may be very difficult to distinguish, clinically, from AIDS dementia but may be diagnosed by polymeras chain reaction (PCR) assay of the cerebrospinal fluid. Tuberculosis and most mycoses present with a basilar meningitis, which is suggested by cranial nerve palsies and confirmed by MRI. Toxoplasmosis, primary central nervous system lymphoma, and aspergillosis all tend to present with mass lesions and focal signs, MRI scanning again being confirmatory. Progressive multifocal leukoencephalopathy likewise presents with focal findings and a distinctive MRI appearance. Neurosyphilis should always be considered, a serum fluorescent treponemal antibody absorption (FTA-ABS) test and, if positive, a

530 Specific disorders

cerebrospinal fluid Venereal Disease Research Laboratory (VDRL) test being carried out on all patients suspected of having AIDS dementia Vitamin B12 deficiency is, for unclear reasons, not uncommon in patients with AIDS, and as it may produce a dementia or a spinal cord syndrome similar to that of vacuolar myelopathy, it should always be checked for (Beach et al. 1992). Treatment

Although improvement has been seen with zidovudine alone (Sidtis et al. 1993), it is prudent to use a combination of agents, i.e. two reverse transcriptase inhibitors (e.g. zidovudine plus lamivudine) and a protease inhibitor (e.g. indinavir). It must be borne in mind that, given the enormous amount of research into this illness, treatment recommendations for AIDS change rapidly; consequently, it is appropriate to refer all patients with AIDS dementia to an expert in the treatment of AIDS. Selegeline, in a low dose, may produce mild cognitive improvement (Dana Consortium 1998). Patients with AIDS dementia are particularly liable to develop extrapyramidal side-effects to neuroleptics (Hriso et al. 1991); consequently, should one of these be indicated for the treatment of AIDS dementia, consideration should be given to olanzepine or to a low-potency typical neuroleptic (e.g. chlorpromazine) in order to reduce this risk. Whatever agent is chosen, treatment should begin with a low dose (e.g. 2.5 mg/day of olanzepine or 25 mg/day chlorpromazine) with cautious titration up to the lowest effective dose. All patients should be reminded to practice 'safe sex', with an emphasis on latex condoms and the use of nonoxynol-9 spermicide. Patients should also be reminded that AIDS may be spread via fellatio and cunnilingus. All intravenous drug users, if unable to stop, should be instructed to sterilize their needles with household bleach. Blood and organ donation are prohibited, as is breast-feeding.

CYTOMEGALOVIRUS ENCEPHALITIS Pathology and etiology

CMV is found in saliva, feces, urine, semen, and vaginal secretions. Infection is very common between childhood and early adult years and may either cause an infectious mononucleosis-like syndrome or be asymptomatic. Subsequent to the initial infection, CMV becomes latent and may undergo reactivation during periods of immunoincompetence, such as after transplantation or during AIDS. When reactivated, CMV may again cause an infectious mononucleosis-like syndrome, in addition possibly leading to encephalitis, retinitis, esophagitis, gastritis, colitis, pneumonitis, hepatitis, or adrenalitis. Encephalitis may occur in immunocompetent adults (Studahl et al. 1994), but this is very rare: CMV encephalitis is far more common during the reactivation of the virus in an immunocompromised host. With encephalitis, microglial nodules are found in the gray matter and, especially in patients with AIDS, in the periventricular white matter. Clinical features

CMV mononucleosis is characterized by malaise, myalgia, fatigue, headache, and fever: although pharyngitis and cervical lymphadenopathy may be present, they are usually mild. There is a relative lymphocytosis with atypical lymphocytes, but the monospot test is negative. CMV encephalitis usually does not occur in AIDS until the CD4+ cell count is below

Infectious disorders 531

50 cells/mm3; at autopsy, evidence of CMV encephalitis is found in up to one-third of patients dying of AIDS (Vintners et al. 1989). Clinically, patients present with a generally mild delirium, characterized by lethargy, withdrawal, and periods of confusion (Berman and Kim 1994; Holland et al. 1994). In addition to encephalitis, CMV may also cause a myelitis or a polyradiculopathy. PCR assay may detect CMV DNA in the cerebrospinal fluid. MRI scanning may reveal irregular periventricular increased signal intensity. Course Most patients with CMV encephalitis die within months. Differential diagnosis

In patients with AIDS who are demented, it is very difficult to ascertain the role played by CMV relative to that played by HIV itself or by other opportunistic infections. Treatment

Treatment with antiviral agents, such as ganciclovir, may not be helpful (Berman and Kim 1994).

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Pathology and etiology

Progressive multifocal leukoencephalopathy occurs secondary to infection by a papovavirus, which is in almost all cases the JC virus (Padgett et al. 1971). Over 80% of the adult population harbors the JC virus in a latent state, where it remains in immunocompetent patients. With an impairment of cellular immune function, however, the virus reactivates and undergoes hematogenous spread (Tornatore et al. 1992) to the brain, where it infects primarily the oligodendrocytes. Astrocytes are enlarged with bizzare nuclei, and oligodendrocytes contain intranuclear inclusions. There are multiple, often confluent, foci of demyelinization, some of which may undergo cystic change, and very little, if any, inflammatory response. Although any part of the central nervous system may be involved, the cerebral white matter is favored, particularly in its posterior portions. In most cases, foci appear first in only one hemisphere; over time, however, both hemispheres are affected. The most common underlying cause of the immunoincompetence is AIDS, and progressive multifocal leukoencephalopathy may indeed constitute the presentation of AIDS. Other causes include Hodgkin's disease and leukemia (Astrom et al. 1958), therapeutic immunosuppression (as for example for transplantation or in the treatment of rheumatoid arthritis [Sponzilli et al. 1975]), and systemic lupus erythematosus (Krupp et al. 1985). Progressive multifocal leukoencephalopathy has also been seen in association with tuberculosis and sarcoidosis. Very rarely, it has occurred in apparently otherwise normal adults (Fermaglich et al. 1970). Clinical features

The onset is subacute or gradual, over days to weeks, and tends to be most rapid in those with AIDS. In keeping with the initial unilateral location of the foci of demyelinization, most patients present with unilateral focal deficits (Astrom et al. 1958; Krupp et al. 1985; Richardson 1961) such as hemiplegia, aphasia, or hemianopia; rarely, patients present with Balint's syndrome (Ayuso-Peralta et al. 1994). With time, either a delirium or a dementia ensues; very

532 Specific disorders

occasionally, progressive multifocal leukoencephalopathy may present with personality change (Astrom et al. 1958), delirium (Davies et al. 1973), or dementia (Sellal et al 1996; Zunt et al 1997). MRI scanning reveals multifocal areas of decreased signal intensity on Tl-weighted scans, which, importantly, do not enhance. The cerebrospinal fluid is usually normal; in some cases, there may be a mild lymphocytic pleocytosis and a slight elevation of total protein. PCR assay typically demonstrates JC virus DNA (Hensen et al. 1991; Koralnik et al. 1999). Course

With but rare exceptions, progressive multifocal leukoencephalopathy is a relentlessly progressive disease, with a mortality rate of approximately 80% in 9 months. Patients may rarely survive for years, and, exceptionally, the disease may undergo a spontaneous remission (Price et al 1983). Differential diagnosis

Other opportunistic infections that may be confused with progressive multifocal leukoencephalopathy include toxoplasmosis and various mycoses: MRI scanning may be helpful here as lesions secondary to these other opportunistic infections enhance, whereas the lesions seen in progressive multifocal leukoencephalopathy do not. Treatment

There is no specific treatment for progressive multifocal leukoencephalopathy; the successful treatment of the underlying cause of the immunoincompetence may, however, be followed by improvement.

ARBOVIRUS MENINGOENCEPHALITIS Pathology and etiology

There are over 500 arthropod-borne, or arbovirus, species. Only 18, however, are capable of causing meningoencephalitis, and of these 18, only 7 are indiginous to the contiguous 48 states of the United States. Of these 7, 6 (Eastern equine, Western equine, Venezualan equine, St Louis, La Crosse, and California) utilize mosquitoes as vectors, and 1 (Powasen) utilizes a tick. Although the severity of the pathologic changes varies widely among these different types, one in general finds widespread perivascular inflammation in the leptomeninges, cortical gray matter, cerebral white matter, subcortical gray structures, and, in some cases, brainstem. At times, thrombus formation may occur in the vessels involved, with the infarction of downstream tissues (Leech and Harris 1977; Reyes et al. 1981). Mention should also probably be made of Japanese encephalitis: although this virus is not indiginous to the United States and Europe, it is very common in Japan, Korea, and China, where it causes severe disease (Lewis et al. 1947; Solomon et al. 2000) and may be contracted by visitors to those countries. Clinical features The onset is typically acute, over hours to days, patients developing headache, fever, meningeal signs (e.g. photophobia and neck stiffness), delirium (Baker and Noran 1942), lethargy, seizures, and, in some cases, focal signs such as hemiplegia or aphasia. In particular, tremor is prominent in St Louis encephalitis (Wasay et al. 2000), and some cases of Japanese encephalitis may be marked by parkinsonism (Pradhan et al. 1999). Rarely, the encephalitis may present with psychosis with prominent catatonic features (Penn et al. 1972).

Infectious disorders 533

MRI scanning may reveal focal areas of increased signal intensity on T2-weighted scanning (Deresiewicz et al. 1997). Cerebrospinal fluid analysis reveals a pleocytosis (initially polymorphonuclear, eventually lymphocytic) and increased protein; the glucose level is generally normal. IgM antibodies may be detected in cerebrospinal fluid or serum, generally within a week.

Course The mortality rate varies, from as little as 2% to, in the case of Eastern equine encephalitis, up to 50%. Survivors usually recover within days or a few weeks, but, in some cases, further recovery may be seen over the following several months. Permanent sequelae may occur, these being more likely with the more severe infections: these include seizures, dementia, personality change, and the persistence of any focal signs that may have occurred during the encephalitis itself (Herzon et al. 1957; Przelomski et al. 1988; Smardel et al. 1958); in the case of Western equine encephalitis, parkinsonism has been noted as a sequel (Mulder et al. 1951; Schultz et al. 1977). Japanese encephalitis has been noted to cause dementia with prominent psychotic symptoms as a sequela (Richter and Shimojyo 1961). Differential diagnosis

Herpes simplex encephalitis is suggested by the absence of meningeal signs and by the presence of medial temporal lobe involvement on MRI scanning; it is confirmed by PCR assay of the cerebrospinal fluid, which reveals herpes DNA. Bacterial meningitis is indicated by a reduced glucose level in the cerebrospinal fluid. Treatment

There is no specific treatment for arbovirus meningoencephalitis; intensive supportive care is required. Travelers to areas where Japanese B encephalitis is endemic may wish to consider vaccination.

HERPES SIMPLEX VIRAL ENCEPHALITIS Pathology and etiology

Although, compared with the epidemic encephalitides, herpes simplex virus encephalitis is not common, it remains the most common cause of sporadic encephalitis in North America. Herpes simplex conies in two types, type 1 and type 2: type 1 usually causes orolabial infections, and type 2 generally causes genital infections. Although the vast majority of cases of herpes simplex encephalitis are caused by type 1 virus, type 2 may be at fault in a small minority (Koskiniemi et al. 1996). The majority of the adult population has been at some time infected with herpes simplex type 1, and the virus may remain in a latent state in various sites, including the trigeminal ganglion (Baringer and Swoveland 1973). Although it is known that the virus can undergo retrograde axonal transport, it is not clear precisely how the virus gains entry into the central nervous system. One theory suggests that, after the reactivation of a latent infection in the trigeminal ganglion, the virus undergoes anterograde transport through the ophthalmic division of the trigeminal nerve to the olfactory mucosa, whereupon it gains access to the olfactory filia and undergoes retrograde transport through the olfactory nerve and thence to the temporal lobes. Macroscopically (Adams and Miller 1973), there is hemorrhagic necrosis affecting, initially, the medial portions of the temporal lobe along with, in most cases, other areas, including the lateral aspects of the temporal lobe, the insula, and inferior portions of the frontal lobes. Although involvement is always bilateral, it is often highly asymmetric. In those who survive, scarring, cavitation, and cystic change is seen in the involved areas.

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Microscopically, herpes viruses are found in neurons and glial cells, and there is an intense inflammatory response. Clinical features

Although most patients are middle-aged (Koskiniemi et al. 1996), the disease can occur at any age from childhood to the eighth decade. In some cases, there may be a prodrome, lasting several days, of malaise, headache, irritability, and mild fever. The onset itself ranges from gradual, over weeks or even very rarely months (Sage et al. 1985), to explosive, over hours; in most cases, it spans several days. Typically (Kennedy 1988; McGrath et al. 1997; Marton et al. 1996; Williams and Lerner 1978), patients present with fever, headache, and delirium. Behavioral changes, which may be bizarre, are also common, as are seizures, which may be either partial or generalized, and nausea and vomiting. Focal signs, such as aphasia or hemiparesis, although uncommon at the onset, are typically seen with progression. In one case (Wilson 1976), the encephalitis presented with a psychosis characterized by bizarre behavior and delusions. Untreated, coma may ensue, as may death, often from uncal or subfalcal herniation. Computed tomographic (CT) scanning may show radiolucent areas in the medial aspects of one or both temporal lobes, but it may be normal for up to a week. MRI scanning is much more sensitive, showing increased signal intensity on T2-weighted scans in the medial temporal lobe, as seen in Fig. 14.2. The electroencephalogram (EEG) may show temporal slowing with periodic sharp waves. PCR assay of the cerebrospinal fluid (Aurelius et al. 1991) is almost 100% sensitive for

Image Not Available

Figure 14.2 Increased signal intensity is seen on this T2-weighted magnetic resonance imaging scan in the left temporal lobe (especially its medial aspect) of a patient with Herpes simplex encephalitis. (Reproduced from Gillispie and Jackson 2000.)

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herpes simplex DNA and is the diagnostic procedure of choice. The cerebrospinal fluid itself may be normal during the first few days but will in most cases show an elevated protein level with a lymphocytic and polymorphonuclear pleocytosis; red cells may also be present, reflecting the hemorrhagic nature of the inflammatory process. Although the glucose level is typically normal, it may occasionally be low. If lumbar puncture is not possible, brain biopsy may be necessary to make a definitive diagnosis; however, as noted below, treatment rarely waits upon such a procedure. Course

Untreated, over one-half of patients will die in days or a few weeks. Of those who survive, the majority will be left with significant sequelae, such as Korsakoff's syndrome (Hokkanen et al. 1996;Kapuretfl/. 1994; Young etal. 1992), the Kluver-Bucy syndrome (Greenwood et al 1983; Lilly et al. 1983; Marlowe et al. 1975), dementia (Hokkanen et al. 1996; McGrath et al. 1997), or focal signs such as hemiparesis or aphasia (McGrath etal. 1997). In one case (Northam and Singer 1991), complex motor and vocal tics occurred as a sequela. Differential diagnosis

The clinical differentiation of herpes simplex encephalitis from other viral encephalitides is difficult. Meningeal signs, generally lacking in herpes simplex, point to another cause, as does the concurrence of an epidemic of, for example, arbovirus encephalitis. MRI scan evidence of medial temporal involvement is very suggestive of herpes simplex, but the most important test is assaying the cerebrospinal fluid for herpes simplex DNA with PCR. In doubtful cases, many physicians will treat the patient as if herpes simplex were present: such treatment runs little risk of doing harm and may indeed be life-saving. Treatment

Intravenous acyclovir should be started as soon as possible. Cerebral edema may be treated with dexamethasone, and seizures with standard anticonvulsants such as phenytoin.

ENCEPHALITIS LETHARGICA Pathology and etiology Encephalitis lethargica (Von Economo's disease, European sleeping sickness), first described by Baron Constance von Economo in 1917 (Wilkins and Brody 1968), existed in pandemic form from 1917 to 1928 and had a mortality rate in the region of 25%. Autopsies of those dying in the acute stage revealed inflammation with a perivascular accumulation of lymphocytes and plasma cells in the midbrain, basal ganglia, and cortex (Buzzard and Greenfield 1919). Of those who survived, over half developed one of the sequelae of encephalitis lethargica, such as postencephalitc parkinsonism. In those with sequelae, autopsy studies (Geddes et al. 1993; Ishii and Nakamura 1981; Rail et al. 1981) have revealed neuronal loss, gliosis, and, in the remaining neurons, neurofibrillary tangles similar to those seen in Alzheimer's disease, in the substantia nigra, locus ceruleus, hippocampus, basal ganglia, thalamus, and cerebral cortex. Macroscopically, there was cortical atrophy and depigmentation of the substantia nigra and locus ceruleus. Although influenza A is suspected to be the etiologic agent of acute encephalitis lethargica, proof is as yet lacking. Clinical features

Acute encephalitis lethargica (Hohman 1921; Kirby and Davis 1921) is characterized by headache, fever, sleep reversal (nocturnal wakefulnes and diurnal somnolence), delirium, and

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various oculomotor pareses; some patients have displayed euphoria, some a psychosis (Kirby and Davis 1921; Meninger 1926; Sands 1928), and some stuporous catatonia (Bond 1920). Oculogyric crises can also occur. Course Acute encephalitis lethargica was fatal in about one-fourth of cases and ran its course in about a month; in those who survived, sequelae, as noted below, were common. Postencephalitic parkinsonism occurred in over one-half of survivors after a latent interval of 1 to over 20 years (Duvoisin and Yahr 1965). Patients gradually developed a syndrome similar to that seen in idiopathic Parkinson's disease (Rail et al. 1981). In addition, other motor abnormalities, including dystonia, blepharospasm (Alpers and Patten 1927) and, most importantly, oculogyric crises (Taylor and McDonald 1928), were often present. Interestingly, these transient oculogyric crises could also be accompanied by classic obsessions or compulsions (Jelliffee 1929); in some cases, pallilalia (Van Bogaert 1934) or agitation and excitation (McCowan et al. 1928) were noted to accompany the oculogyric crises. Oculogyric crises, although most commonly seen in conjunction with postencephalitic parkinsonism, at times occurred independently (McCowan et al. 1928). Dementia was noted in a minority of survivors. Narcoleptic and cataplectic attacks also appeared, in a small minority, as sequelae (Adie 1926; Fournier and Helguera 1934). Children might be left with a disorder similar to attention deficit/hyperactivity disorder, with restlessness and inattentiveness (Hohman 1922). Differential diagnosis

Acute encephalitis lethargica is distinguished from other viral encephalitides by sleep reversal, oculomotor abnormalities, and oculogyric crises. Although epidemics have not occurred since 1928, sporadic cases are still seen (Howard and Lees 1987), thus making familiarity with encephalitis lethargica of more than academic interest. Treatment

There is no known treatment for the acute encephalitis. Postencephalitic parkinsonism may be treated with levodopa, but these patients are very sensitive to this agent and are prone to develop dyskinesias; anticholinergics, although somewhat less effective, are better tolerated.

INFECTIOUS MONONUCLEOSIS Pathology and etiology Infectious mononucleosis is caused by the Epstein-Barr virus (Epstein and Achong 1977) and is transmitted primarily via oral secretions passed during intimate contact such as kissing. The virus gains access to the bloodstream and infects lymphocytes, spreading later to various other organs. Although it is presumed that central nervous system effects occur secondary to direct infection and subsequent inflammation, there have been too few autopsies to confirm this hypothesis. Clinical features

Infectious mononucleosis is primarily a disease of childhood and adolescence. Typically, there is a prodrome, lasting 1-2 weeks, of fatigue, malaise, and headache, followed by the typical fever, sore throat, and cervical lymphadenopathy. Central nervous system effects occur in a minority of patients (7% in one series [Gautier-Smith 1965]), and although they generally follow the onset of these typical symptoms, they may occasionally precede them. Patients may experience delirium (Bergin 1960; Schlesinger and Crelinsten 1977; Schnell et

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al. 1966; Tselis et al. 1997), meningitis, convulsions (Freedman et al. 1953; Silverstein et al. 1972), ataxia (Gautier-Smith 1965; Leavell et al. 1986), or cranial nerve palsies, such as a Bell's palsy. Very rarely, there may be a transverse myelitis or a Guillian-Barre syndrome. Peripheral leukocytosis is generally present, the monospot test being positive in most cases. Ebstein-Barr virus DNA may be detected by PCR assay of the cerebrospinal fluid (Tselis et al. 1997). False-positive antinuclear antibody and VDRL tests may occur. Course Infectious mononucleosis usually runs its course in about a month; in some cases, however, there may be persistent fatigue and malaise for several months. Rarely, the encephalitis is fatal (Bergin 1960), but in most cases, there are no sequelae. Differential diagnosis

HIV seroconversion may produce a similar illness. Treatment

Treatment is generally supportive; corticosteroids have been used for encephalitis, with uncertain results.

MUMPS Pathology and etiology

The mumps virus is trophic for the salivary glands, gonads, pancreas, and nervous system. Spread is via the respiratory route, most cases occurring in the spring or late winter. When the central nervous system is involved, meningeal and perivascular inflamation is seen. Clinical features

The onset is usually in the childhood years, but epidemics have occurred in Army camps and other examples where adults are housed in crowded living conditions. Typically, patients fall ill with fever, malaise, and myalgia, followed, within 1-7 days, by a parotitis, which is usually bilateral. Although over one-half of patients have central nervous system involvement, as indicated by a cerebrospinal fluid pleocytosis (Russell and Donald 1958), only a minority become symptomatic with either a meningitis or a meningoencephalitis. Importantly, the meningitis or meningoencephalitis may occur either before or after the parotitis (Levitt etal. 1970). Meningitis, with headache, drowsiness, stiff neck, and fever occurs in perhaps 15% of cases, and is usually mild. Meningoencephalitis occurs in a small minority and may present with significant drowsiness, delirium, seizures, ataxia, focal signs, and high fever (Azimi etal. 1969; Bistrian etal. 1972; Finklestein 1938; Levitt etal 1970). The cerebrospinal fluid shows a lymphocytic pleocytosis, with an elevated protein level, and, in perhaps 5-10% of cases, a reduced glucose concentration. Mumps virus may be isolated from the cerebrospinal fluid and grown in a variety of host cultures. Course In most cases, the symptoms resolve in a matter of 3 or 4 weeks. The meningitis does not usually have sequelae; the encephalitis is rarely fatal (Bistrian et al. 1972) and may have sequelae such as seizures, or aqueductal stenosis (Thompson 1979) with hydrocephalus. Differential diagnosis

Parotitis is fairly distinctive; in its absence, it is difficult clinically to distinguish mumps meningitis from any other acute viral meningitis or meningoencephalitis; the diagnosis may

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wait upon the isolation of the virus from the cerebrospinal fluid or the demonstration of a four fold rise in serum antibody titer. A post-mumps encephalomyelitis may be difficult to distinguish from an acute mumps meningoencephalitis; here, finding white matter lesions on MRI scanning may be very important as this points toward a post-infectious etiology. Inquiry should always be made regarding a history of either mumps or mumps vaccination as lifelong immunity, with but rare exceptions, is conferred by each. Treatment

There is no specific treatment for mumps.

VARICELLA-ZOSTER Pathology and etiology

The varicella-zoster virus is the etiologic agent of two separate diseases: varicella, or chickenpox, and herpes zoster, or shingles (Strauss et al. 1984). Chickenpox is a disease of childhood or adolescence spread via respiratory droplets. The pharynx is the initial seat of the infection; subsequently, a viremia occurs, resulting in a characteristic rash. Rarely the central nervous system may also be involved during acute chickenpox. With the resolution of the chickenpox, the varicella-zoster virus becomes latent, residing primarily in the trigeminal or spinal sensory ganglia (Mahalingam et al. 1990). A reactivation of the virus may occur in those over 50, presumably because of waning immunologic competence with age (Miller 1980), or at any age in a patient immunocompromised by such conditions as Hodgkin's disease, AIDS, or treatment with corticosteroids or immunosuppressants. When reactivated, the varicella-zoster virus travels down the axon to the subserved skin, leading to herpes zoster. Herpes zoster is pathologically characterized by inflammation in the sensory ganglion: viral spread down the axon eventuates in the skin rash, whereas viral spread centrally may lead to inflammation of the spinal cord itself. In cases of zoster-associated encephalitis, although the virus may be found in the brain parenchyma, it is unclear whether it gets there by virtue of a viremia or because of centripetal spread along a cranial nerve. In cases of zoster-associated cerebral arteritis, wherein a viral invasion of the arterial walls occurs (Melanson et al. 1996), it appears that the virus reaches the cerebral vasculature via centripetal spread along the trigeminal nerve. Clinical features

Chickenpox is a viral exanthem characterized by crops of vesicular lesions; rarely, the exanthem may be accompanied by transverse myelitis, acute cerebellar ataxia (Johnson and Milbourn 1970), meningitis, or encephalitis (Applebaum et al. 1953). Herpes zoster is typically ushered in by a prodrome, lasting several days, of malaise, after which a unilateral, painful rash appears in a dermatomal pattern: favored sites are the face, typically in the distribution of the ophthalmic division of the trigeminal nerve, and the thorax. In some cases, the geniculate ganglion is involved, resulting in the Ramsey-Hunt syndrome, with a rash in the external auditory canal and a Bell's palsy. Rarely, one sees zoster sine herpete (Gilden et al. 1994): here, rather than a zosteriform rash, the patient experiences only dermatomal pain. In a small minority of patients, herpes zoster is accompanied by myelitis (Devinsky et al. 1991; Hogan and Krigman 1973), encephalitis, or cerebral arteritis (Doyle et al. 1982; Linnemann and Alvira 1980).

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Zoster encephalitis is more likely to occur in the immunocompromised, for example in patients with Hodgkin's disease (McCormick etal. 1969) or AIDS (Gilden etal. 1988). Patients may present with delirium with or without meningeal signs (Applebaum et al. 1962; Jemsek et al. 1983; Krumholz and Luhan 1945); exceptionally, the presentation may be delayed for months after resolution of the zoster (Weaver et al. 1999). Arteritis may present weeks or months after the zoster, with focal signs such as hemiplegia (Hilt et al. 1983) or aphasia, or with a delirium (MacKenzie et al 1981). Course Fatalities, especially in the immunocompromised, may occur with herpes zoster or zoster encephalitis. Among the survivors, a substantial minority will develop a post-herpetic neuralgia. Differential diagnosis

Zoster encephalitis or arteritis is immediately suggested by the presence of shingles; in cases in which the encephalitis precedes the shingles, other viral encephalitides must be considered. Post-infectious encephalomyelitis may be difficult to distinguish from an acute zoster encephalitis: in cases wherein the post-infectious encephalomyelitis is delayed for weeks after the shingles, the diagnosis is fairly straightforward, but in cases where the post-infectious encephalomyelitis follows the rash by only days, a reliable clinical diagnosis may not be possible. Treatment

Although routine cases of shingles may be treated with oral acyclovir, famcyclovir, or valacyclovir, involvement of the spinal cord, cerebellum or brain demands immediate treatment with intravenous acyclovir.

RABIES Pathology and etiology

Although infection with the rabies virus is usually via the bite of a rabid animal (such as a dog, skunk, raccoon, fox, cat, or vampire bat), respiratory transmission has occurred inside batinfested caves and in a veterinarian who had homogenized the brain of a rabid animal (Conomy et al. 1977). In the case of the more typical bite route, the virus travels up the peripheral nerve to gain access to the brain and spinal cord, where inflammation is largely confined to the gray matter with a predilection for the limbic system; in most cases, microscopy reveals classic intracytoplasmic Negri bodies (Chopra et al. 1980; Dupont and Earle 1965). Clinical features

After the bite of an infected animal, there is a latent period (lasting anywhere from weeks to a year) the duration of which appears to depend on both the severity of the bite and the distance between the bite and the nervous system, bites on the face having the shortest latencies. The onset is typically characterized by parasthesiae at the bite site and malaise, headache, and fever; the illness then evolves in one of two forms: 'furious' rabies or 'dumb' ('paralytic') rabies. Furious rabies (Adle-Biassette et al. 1996; Blatt et al. 1938; Dupont and Earle 1965) is seen in perhaps 80% of cases and is characterized by restlessness, agitation, excitability, excessive startability, and convulsions; delirium is typical, and patients may engage in bizarre behavior. The combination of excessive salivation and dysphagia caused by pharyngeal spasm may literally cause the patient to 'foam at the mouth'. Pharyngeal spasm may also be provoked by

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swallowing water, or even by the sight of water, giving rise to the classic symptom of hydrophobia. Dumb rabies (Chopra et al 1980) is characterized by a flaccid paralysis that typically begins in one limb and rapidly becomes generalized and symmetric. Anti-rabies antibodies are found in the serum in a higher titer than that seen secondary to vaccination. The cerebrospinal fluid shows a lymphocytic pleocytosis, elevated protein level, and antirabies anti-bodies. Rabies virus RNA may be detected by PCR assay. Course

Death usually occurs several days to a week and a half later; only rarely have patients survived (Porrasetfl/. 1976). Differential diagnosis

Furious rabies is suggested by the history of a bite and, when present, parasthesiae at the bite site: excessive salivation and hydrophobia are also highly suggestive. Lacking these clues, consideration may be given to other viral encephalitides and to delirium tremens. Treatment

There is no specific treatment for clinically established rabies: the only effective approach is prevention. Suspicious bites should be vigorously cleaned; human rabies immune globulin is given intramuscularly and is also infiltrated into the wound site; the patient is then actively immunized with human diploid cell vaccine. Those caring for patients with rabies must avoid any contact with the patients' saliva.

POST-INFECTIOUS AND POST-VACCINAL ENCEPHALOMYELITIS Pathology and etiology

Post-infectious and post-vaccinial encephalomyelitis (acute disseminated encephalomyelitis; hereafter referred to as PIE) is the end result of an autoimmune assault on myelin triggered by a preceding infection (usually viral) or vaccination. The infections responsible include childhood infections (Hart and Earle 1975) such as measles, rubella, varicella, and mumps; infectious mononucleosis (Paskavitz et al. 1995), influenza (Moscovich et al. 1995), nonspecific viral illnesses, mycoplasma (Fisher et al. 1983), and typhoid. Vaccinations include those for measles, varicella, mumps, influenza, rabies (including the human diploid cell vaccine), and typhoid (Giffin et al. 1948). Both smallpox and vaccination (Dolgopol et al. 1955) for smallpox were once very common causes, but with this disease now apparently eradicated, they are no longer of immediate concern. Perivenous inflammation and concurrent demyelinzation, with relative sparing of the axon, are hallmarks of the illness (Greenfield 1929; Hart and Earle 1975). In severe cases, known as acute hemorrhagic leukoencephalitis (Hart and Earle 1975; Russell 1955), widespread petechial hemorrhages are also seen. Although any part of the central nervous system (including the cerebrum, brainstem, cerebellum, cord, and optic nerves) may be involved, in most cases there is a concentration of lesions in one area or another. Clinical features

In general, anywhere from 2 to 21 days passes from the onset of the viral illness or vaccination to the onset of PIE, the onset of PIE itself being acute, over hours or days. Clinically (Miller et al. 1956), patients experience headache, fever, lethargy, and meningeal signs; other symptoms depend on which part of the central nervous system bears the brunt of the

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autoimmune assault. When the cerebral white matter is involved, there may be delirium, seizures, mania (Moscovich et al. 1995; Paskavitz etal. 1995), and multiple focal findings, such as hemiplegia. Cerebellar involvement is announced by ataxia, and cord involvement by a myelitis, the symptoms varying depending on the level of the lesion. T2-weighted MRI scanning (Kesserling et al. 1990) may, as illustrated in Fig. 14.3, reveal multifocal areas of increased signal intensity in the white matter. Cerebrospinal fluid assay reveals a predominantly lymphocytic pleocytosis with increased protein and normal glucose levels; myelin basic protein may also be elevated. Rarely, the cerebrospinal fluid may be normal. Course Mortality is highest, up to 20%, after measles infection. Survivors may be left with permanent sequelae such as seizures, dementia, or a persistence of any focal signs present during the acute illness. Differential diagnosis

When an encephalitis occurs shortly after the onset of a childhood exanthem (e.g. measles or varicella), mumps, or infectious mononucleosis, it may not be possible clinically to differentiate an encephalitis directly caused by the virus from a post-infectious autoimmune process; however, with a long latency between the viral illness itself and the onset of an encephalitis, one can be more confident in diagnosing a post-infectious process.

Image Not Available

Figure 14.3 Multiple bilateral areas of increased signal intensity on a T2-weighted magnetic resonance imaging scan of a patient with post-infectious encephalomyelitis. (Reproduced from Marsden and Fowler 1998.)

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Multiple sclerosis of acute onset may be difficult to distinguish from a post-encephalitic encephalitis, especially when the preceding infection was a non-specific viral upper respiratory illness, which may have been forgotten. Since PIE is almost always a monophasic illness, any recurrence will point towards multiple sclerosis. In a similar vein, if T2-weighted MRI scanning discloses multiple areas of increased signal intensity in the white matter, but only a portion of them enhanced (indicating the occurrence of prior lesions, no longer active and thus no longer enhancing), this too points toward multiple sclerosis (Kesserling et al. 1990). Treatment

In addition to intensive supportive care, high-dose methylprednisolone is indicated to blunt the autoimmune assault.

SUBACUTE SCLEROSING PAN ENCEPHALITIS Pathology and etiology

Subacute sclerosing panencephalitis is caused by a reactivation of a latent measles virus infection. For as yet unclear reasons, the measles virus assumes a latent status within the host neurons, wherein it undergoes multiple mutations. Eventually, the infection reactivates, and viral spread occurs by extension from one cell to an adjacent one; intranuclear and intracytoplasmic inclusion bodies are found in both neurons and glial cells. Macroscopically, provided the patient has survived long enough, there is cerebral cortical atrophy and ventricular dilatation. Microscopically (Ohya et al. 1974), perivascular inflammation of varying degree and glial scars are found throughout the cortex and basal ganglia, and there are widespread foci of demyelinization. Clinical features

Although subacute sclerosing panencephalitis can follow measles vaccination, it is more likely to occur after natural measles infection. More than one-half of patients had measles before the age of 2, followed by a latent period averaging 7 years (Bellman and Dick 1980). Although most cases occur in the age range of 5-15, later onsets, in the twenties (Singer et al. 1997) or even the early thirties (Cape et al. 1973), have been recorded; males outnumber females by a factor of four. Classically (Dawson 1934), subacute sclerosing panencephalitis has been described as occurring in three stages. In the first stage, there is an insidious onset of dementia, with restlessness and poor school performance. In the second stage, the dementia progresses, being joined by myoclonus, ataxia, choreoathetosis, visual disturbances, and seizures, which may be focal. In the third and final stage, stupor supervenes, with quadriparesis. Variations from this classic evolution of the disease are, however, common (Risk and Haddad 1979). In some cases, particularly in those with adult onset, the first stage may be characterized by a psychosis (Cape et al. 1973; Salib 1988), which may faithfully mimic schizophrenia, with delusions (including Schneiderian first rank symptoms [Duncalf et al. 1989]) and stuporous catatonia (Koehler and lakumeit 1976). MRI scanning reveals variable cortical atrophy and ventricular dilatation, with widespread focal areas of increased signal intensity on T2-weigh ted scans, representing areas of active inflammation (Anlar et al. 1996). A classic 'burst-suppression' pattern may be seen in the EEC of about 80% of patients (Wulf 1982).

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The cerebrospinal fluid is typically acellular, with only a mildly elevated total protein level. Importantly, however, the IgG fraction of the total protein is markedly increased, oligoclonal bands are typcially present, and measles antibody may be detected. Course In most cases, the disease is progressive, death occurring in an average of 1 year (Freeman 1969), ranging from as little as months to, exceptionally, up to 10 years. In about 5% of cases (Risk et al. 1978), however, spontaneous arrest may occur, with partial remissions lasting, in some cases, for many years (Cobb et al. 1984; Donner et al. 1972; Landau and Luse 1958). Differential diagnosis

The combination of dementia, myoclonus, and a burst-suppression pattern on the EEC is fairly distinctive. Progressive rubella panencephalitis may be considered but usually has more prominent ataxia and minimal or no myoclonus. Treatment

Although a combination of intraventricular interferon and oral inosiplex may produce some improvement (Yalaz et al. 1992), relapse is the rule after the discontinuation of treatment (Anlareffl/. 1997).

SUBACUTE MEASLES ENCEPHALITIS Pathology and etiology Subacute measles encephalitis (measles inclusion body encephalitis; Agamanolis et al. 1979; Aicardi et al. 1977) results from a reactivation of measles virus in an immunocompromised patient. Within the central nervous system, intranuclear inclusion bodies are found in neurons throughout the gray and white matter, with very little, if any, inflammatory response. Although most patients have been children with leukemia, cases have occurred in adults with Hodgkin's disease (Wolinsky et al. 1977), adults undergoing therapeutic immunosuppression (Gazzola et al. 1999), patients with AIDS (Budka et al. 1996), and, rarely, apparently normal adult patients (Chadwick et al. 1982). Clinical features

The onset is generally subacute, several months after recovery from measles or contact with a patient with measles. Patients present with lethargy and delirium; over time, myoclonus, focal signs, and seizures generally appear (Agamanolis et al. 1979). The cerebrospinal fluid is usually normal although, there may occasionally be a mild lymphocytic pleocytosis or a mildy elevated total protein. Course The disease is progressive, death generally occurring within weeks in the majority; those who survive may be left with various sequelae, including dementia. Differential diagnosis

Acute measles encephalitis is distinguished by the concurrent rash. Post-infectious encephalomyelitis generally occurs within weeks after the onset of the rash, well before the anticipated onset of subacute measles encephalitis. Treatment

No treatment is known.

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PROGRESSIVE RUBELLA PAN ENCEPHALITIS Pathology and etiology Progressive rubella panencephalitis occurs as a sequela to congenital rubella (Townsend et al. 1975a; Weil et al. 1975) or, less commonly, to a case of German measles in an otherwise healthy child (Lebon and Lyon 1974). Although the rubella virus has been detected in the brain (Wolinsky et al. 1976), inclusion bodies are absent, and the precise etiology of the disease is not clear. Pathologically (Townsend et al. 1982), there is widespread perivascular inflammation, with neuronal loss and demyelinization. The cerebellum is often hardest hit, followed by the cerebrum and then the brainstem. Clinical features The onset is anywhere from 4 to 19 years after rubella infection, the presentation often being with an insidiously progressive dementia with prominent ataxia. Spasticity often eventually appears, and, in some cases, there may be seizures (Townsend et al. 1975a, 1976). The EEC generally reveals only diffuse slowing; occasionally there may be a periodic burstsuppression pattern. MRI scanning reveals cortical and cerebellar atrophy. The cerebrospinal fluid shows a lymphocytic pleocytosis, an elevated total protein level, and oligoclonal bands. Anti-rubella antibodies may be found in both cerebrospinal fluid and serum. Course

The disease is progressive, death generally occurring within 10 years. Differential diagnosis In cases where progressive rubella panencephalitis occurs in the context of the congenital rubella syndrome (characterized by mental retardation, deafness, and cataracts), the diagnosis is immediately suggested. In those instances in which progressive rubella panencephalitis occurs in an otherwise healthy child, the differential diagnosis includes subacute sclerosing panencephalitis: in progressive rubella panencephalitis, ataxia is prominent and myoclonus absent or minor, whereas the converse is true for subacute sclerosing panencephalitis. Treatment There is no specific treatment.

NEUROSYPHILIS Pathology and etiology Syphilis is caused by the spirochete Treponema pallidum (Mclntosh and Fildes 1914) and is divided into three stages: primary, secondary, and tertiary. Primary syphilis represents the initial infection and is characterized by a chancre. Weeks or months later, hematogenous spread is indicated by the occurrence of secondary syphilis, characterized by a more or less widespread rash. During this secondary stage, invasion of the central nervous system occurs in about one-third of patients (Lukehart et al. 1988), as evidenced by pleocytosis and other findings in the cerebrospinal fluid. With the resolution of the rash, the syphilis then enters a latent period, generally lasting years, after which a minority of patients will develop tertiary syphilis. Tertiary syphilitic infection may be evident in a number of organ systems, most importantly the cardiovascular system and the brain: involvement of the brain is known as neurosyphilis and is eventually seen in a little fewer than 10% of all patients with syphilis.

Infectious disorders 545

Neurosyphilis occurs in several forms (Merritt et al. 1946): meningovascular syphilis, gumma, and general paresis (also known as general paresis of the insane, dementia paralytica, and paretic neurosyphilis). Tabes dorsalis, representing an involvement of the spinal cord, may also occur but is not covered here. Meningovascular syphilis is characterized by an indolent granulomatous meningitis, which is generally most prominent in the basilar regions. The cranial nerves, especially the seventh, third, and sixth, may be involved, as may arteries traversing the subarachnoid space, with subsequent infarction of the parenchyma. Obstruction of the cerebrospinal fluid outflow may occur, with hydrocephalus. Gummas are granulomatous masses that develop in relation with the meninges but which may extend deep into the underlying parenchyma. They may be small and miliary, or occasionally quite large, up to 5 cm in diameter. General paresis occurs secondary to a direct invasion of the brain parenchyma by spriochetes, with widespread gliosis and neuronal loss: although the frontal and temporal cortices are preferentially involved, any part of the cerebrum or cerebellum may be affected. Clinical features

Meningovascular syphilis and gummas may present any time from 2 to 15 years after the initial infection, whereas the onset of general paresis tends to be delayed, sometimes for 30 years. As noted below, neurosyphilis may present much sooner in patients with AIDS. The presentation of meningovascular syphilis is quite varied, as might be expected given its neuropathology. Arteritis affecting the large vessels may lead to obvious strokes: the middle and posterior cerebral arteries are preferentially involved, with symptoms such as hemiplegia and hemianopia. Interestingly, these strokes tend to evolve very slowly, over perhaps days. Arteritis affecting the small penetrating vessels may present gradually with a dementia. Basilar meningitis may present with a gradually worsening dementia or delirium, which may be accompanied by evidence of cranial nerve palsies (e.g. diplopia and facial diplegia): the occurrence of hydrocephalus will bring a substantial worsening of any dementia. Gummas, when large, may present as any other mass lesion, and truly large gummas may cause a dementia (Bianchi and Frera 1957). General paresis presents with a gradually progressive dementia that may be marked by euphoria, depression, or psychotic symptoms (Gomez and Aviles 1984; Storm-Mathisen 1969). In addition (Storm-Mathisen 1969), one typically finds dysarthria, pupillary changes (including the Argyll Robertson pupil, as described below), tremor and seizures. Rarely, general paresis may present with a psychosis (Rothschild 1940; Schube 1934). Importantly, although patients may in some cases have only one type of neurosyphilis, there is in many instances a mixture of these pathological types. The Argyll Robertson pupil, although not present in all cases of neurosyphilis, is fairly specific for the disease and hence should be sought. The pupils are often small and irregular: more importantly, however, although they constrict to accommodation testing, they either do not react to direct illumination or show only a sluggish and incomplete reaction. Congenital syphilis, although rare, may produce neuropsychiatric symptomatology in children or adolescents and may present, for example, with a dementia secondary to paretic neurosyphilis. Although many patients with congenital syphilis display 'Hutchinson's triad', with visual loss caused by interstitial keratitis, sensorineuronal deafness and 'Hutchinson's teeth', this triad may be absent in young people with congenital neurosyphilis. MRI scanning will reveal basilar meningitis, infarcts, obstructive hydrocephalus, and any large gummas. In long-standing general paresis, cortical atrophy and ventricular dilatation will be evident, but in cases of short duration, these findings may be minimal or absent. Both the serum and the cerebrospinal fluid may be tested for the presence of antibodies

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directed against the spirochete: there are two kinds of tests, 'non-treponemaF (including the VDRL and the RPR [rapid plasma reagin]) and 'treponemal' (including the FTA-ABS and the MHA-TP [microhemagglutination-Treponemfl pallidum]}. In testing patients with neurosyphilis, both false negatives and false positives may occur with all these tests, and thus great care is required in their interpretation. Serum is routinely tested with either the VDRL or the RPR: in neurosyphilis, these are falsely negative in up to 30% of cases (Simon 1985), and false positives may occur with systemic lupus erythematosus and rheumatoid arthritis, and in intravenous heroin addicts. The serum FTA-ABS is only very rarely falsely negative, as may occur in patients with AIDS, and is likewise only very rarely falsely positive, for example in patients with Lyme disease. The MHA-TP test is not as sensitive as the FTA-ABS and is not recommended. Cerebrospinal fluid is routinely tested with the VDRL, but false negative VDRLs are more frequent here than with serum (Davis and Schmitt 1989). The cerebrospinal fluid FTA-ABS may also be falsely negative, and this occurs in perhaps one-quarter of all cases. There is currently a debate over whether, because of the possibility of false positives, the cerebrospinal fluid should be tested with the FTA-ABS. Since the serum FTA-ABS remains positive indefinitely, patients who have never had any form of neurosyphilis will nevertheless have a positive serum FTA-ABS, and, unfortunately, even microscopic contamination of the cerebrospinal fluid with blood may produce a false-positive cerebrospinal fluid FTA-ABS in such a patient (Davis and Sperry 1979). In practice, a positive serum VDRL or RPR is followed up by a serum FTA-ABS; if the FTAABS is negative, syphilis is very unlikely, and if the FTA-ABS is positive, one may assume a prior or current infection with Treponema pallidum. In patients with a clinical picture consistent with neurosyphilis, given the high number of false-negative results with the VDRL, one proceeds directly to a serum FTA-ABS. Cerebrospinal fluid is routinely tested with the VDRL, its titer being noted. In cases in which the cerebrospinal fluid VDRL is negative but there is a strong clinical suspicion of neurosyphilis, performing a cerebrospinal fluid FTA-ABS is not inappropriate. It must be emphasized that neurosyphilis has been confirmed in patients with both a negative serum VDRL and a negative cerebrospinal fluid VDRL (Ch'ien et al. 1970). Clinical judgment must not defer to laboratory testing: if the clinical picture is consistent and there are any abnormalities in the cerebrospinal fluid (e.g. a few cells or a slightly elevated protein level), treatment for presumptive neurosyphilis is probably warranted. The cerebrospinal fluid typically displays other abnormalities. There is usually a mild lymphocytic pleocytosis, at least 5 cells/mm3 usually being present, and a mild elevation of the total protein level; the IgG fraction may be elevated, and oligoclonal bands may also be present. In patients with AIDS, the clinical and laboratory presentation of neurosyphilis may differ from that outlined above. Clinically, neurosyphilis may present much sooner; furthermore, general paresis is relatively less common in patients with AIDS, whereas meningovascular syphilis is more common (Katz etal. 1993). Furthermore, as noted above, the serum FTA-ABS may be falsely negative in AIDS, and thus a very high index of suspicion is required. Course General paresis is progressive and fatal within 3-5 years. Differential diagnosis

Meningovascular syphilis may be mimicked by tuberculosis, sarcoidosis, meningeal carcinomatosis, and fungal meningitis. Gummas may be mimicked by other tumors, for example tuberculomas and fungal granulomas. General paresis may be mimicked by a host of other dementing illnesses: here, it is

Infectious disorders 547

important to remember that syphilis is still the 'Great Imitator', so it is appropriate to consider a serum FTA-ABS test for any patient with dementia of uncertain cause. Since the treatment of primary or secondary syphilis with benzathine penicillin may not prevent the development of neurosyphilis (Holmes et al. 1984), a history of such treatment should not argue against this diagnosis. Treatment

A 2-week course of penicillin G is required: intravenous aqueous penicillin G is strongly preferred, however intramuscular procaine penicillin may also be used. It is prudent to supplement this course of treatment with probenecid. Critically, benzathine pencillin does not produce treponemocidal levels in the cerebrospinal fluid and is not effective in neurosyphilis. Patients allergic to penicillin should be given a course of desensitization. In a minority of patients with neurosyphilis, a Jarisch-Herxheimer reaction will occur within the first few hours or days of penicillin treatment. Although in most cases this consists only of fever and malaise, in a minority there may be an exacerbation of the patient's symptoms (Hahn et al. 1959), which, in the case of a large gumma, may prove fatal (Zifko et al. 1994). Since a course of penicillin G is not universally effective, it is necessary to follow patients with serial examinations of the cerebrospinal fluid every 3-6 months until there has been a satisfactory response. In general, the first evidence of improvement is a fall in the cell count, the total protein level falling later. The VDRL titer is the last to fall, a fourfold fall being seen as significant. Since treatment failure is most common in patients with AIDS, serial cerebrospinal fluid examinations are particularly important in this group.

LYME DISEASE

Pathology and etiology

Borrelia burgdorferi (Burgdorfer et al. 1982), the causative spirochete of Lyme disease, is transmitted by the bite of an ixodid tick. As noted below, the disease can be roughly divided into three stages. In stage I, the local spread of the spriochete causes the characteristic rash of erythema chronica migrans. Stage II is characterized by a hematogenous spread with seeding to various organs, including joints, heart, nervous system, and other areas of the skin. Stage III follows a more or less lengthy period of latency and is characterized by involvement of the joints and the nervous system. In Stage II (Pachner and Steere 1985), both the central and the peripheral nervous system may be involved. Centrally, there may be meningitis, cranial neuritis, and an encephalitis; peripherally, there may be a polyradiculopathy, mononeuritis multiplex, or polyneuropathy. In Stage III (Pachner et al. 1989), although the peripheral nerves may also be involved, the central nervous system bears trie brunt of the disease. Vasculitis may occur (Meurers et al. 1990), and periventricular demyelinization has been noted (Halperin et al. 1989). Clinical features

Stage I occurs anywhere from several days to a month after the tick bite and is characterized by an annular erythematous rash, centered about the site of the bite which gradually migrates outwards, often becoming quite large. This erythema chronica migrans occurs in only about 75% of cases, and, interestingly, the majority of patients do not remember the bite. Stage II follows stage I weeks or months later; in most cases, the original rash has cleared before the onset of stage II. With the hematogenous spread that occurs during stage II, there may be polyarthralgia, atriaventricular block, and, in about 15% of patients, involvement of

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the nervous system. In the United States, nervous system involvement is characterized primarily by meningitis and cranial and peripheral neuritis. There may be malaise, fatigue, headache, nausea and vomiting, and a stiff neck. Encephalitic changes may also occur, with somnolence, a mild delirium, seizures, or chorea. Of the cranial nerves, the facial nerve is most often involved, with a unilateral or bilateral Bell's palsy. A painful polyradiculopathy may occur, as may mononeuritis multiplex; rarely, a widespread peripheral polyneuropathy may be seen. The cerebrospinal fluid shows a lymphocytic pleocytosis, an elevated total protein level, and, in a minority, reduced glucose (Pachner and Steele 1985); anti-Borrelia antibodies may be detected. Stage II generally resolves within a matter of months, usually with no residual effects. Stage III appears months or many years after the fateful bite and may be characterized by an oligoarthritis or a dementia. The dementia is usually mild, with symptoms such as poor concentration, impaired memory, insomnia, and fatigue (Halperin et al. 1989; Shadick et al. 1994); in some cases, depression or somnolence may also be seen (Logigian et al. 1990). T2weighted MRI scanning may reveal both periventricular increased signal intensity and scattered focal areas of increased signal intensity in the centrum semiovale. The cerebrospinal fluid may display a lymphocytic pleocytosis, an elevated protein level and anti-Borrelia antibodies. It is not clear whether, in the natural course of events, the long-term course of stage III dementia is one of steady progression or eventual spontaneous remission. Rarely, rather than a dementia, there may be a stuporous catatonia, with 'negativism, stereotyped movements, [delusions] ... of persecution, and [auditory] hallucinations' (Pfister etal. 1993). Serum anti-Borrelia antibodies are generally present. IgM antibodies characterize stages I and II, whereas IgG antibodies are seen in stage III. Testing is via ELISA, with Western blot confirmation. It must be borne in mind that many Borrelia infections are asymptomatic, and a large percentage of the population in endemic areas is seropositive. Course This is as described above. Differential diagnosis

A history of erythema chronica migrans is very suggestive, but as this may not have been noticed, or may have been forgotten, the absence of such a history is probably not significant for diagnostic purposes. Stage II, when characterized by meningitis and cranial nerve palsies, is quite distinctive and rarely mimicked by other diseases. The dementia of stage III, when considered in isolation, is easily confused with that of other diseases, such as Alzheimer's disease, Binswanger's disease, etc. A history of stage I or stage II is very helpful, as is the concurrent presence of oligoarthritis. Distinguishing Lyme dementia from chronic progressive multiple sclerosis may be difficult, as the MRI findings are quite similar: differentiation may rest on cerebrospinal fluid findings. Treatment Although cardiac and joint involvement may respond to oral medication, nervous system involvement demands treatment with intravenous ceftriaxone, 2 g/day for a total of 28 days.

TUBERCULOSIS Pathology and etiology Tuberculosis is caused by infection with Mycobacterium tuberculosis. Primary infection occurs in the lung; in severe cases, hematogenous spread may carry the organism to the brain (Rich

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and McCordock 1933), and in the immuncompromised, reactivation may occur, again with hematogenous spread to the brain. There is in most cases, a thick, basilar meningitis; cranial nerves, particularly the third, fourth, sixth, and seventh, may be entrapped, and an obstruction of the cerebrospinal fluid outflow may lead to obstructive hydrocephalus. Arteries traversing the subarachnoid space may become inflamed, with thrombosis and subsequent infarction: penetrating arteries serving the basal ganglia are often involved. Small tuberculous granulomas are not uncommon in the parenchyma of either the cerebrum or the cerebellum. Large tuberculomas may also occur, and although these tend to be multiple, solitary tuberculomas may also be seen. Tuberculomas may also be found in the hypothalamus and pituitary gland. With the advent of AIDS, tuberculosis, which had become something of a rarity in the United States, has now once again become common, and tuberculosis may indeed be the presenting symptom of AIDS (Barnes etal. 1979). Furthermore, AIDS patients are particularly prone to developing tuberculous meningitis (Berenguer etal. 1992). Clinical features

Basilar meningitis (Kennedy and Fallen 1979), although occasionally of acute onset, generally presents gradually, over several weeks, with headache, malaise, mild fever, and delirium (Sanchez-Portocarrero et al. 1996; Traub et al. 1984; Williams and Smith 1954); neck stiffness may or may not be present. Cranial nerve palsies are fairly common, generally involving cranial nerves VII, III, VI, and IV (McKendrick and Grose 1957), and hydrocephalus may dramatically worsen the clinical picture. Hypothalamic involvement may produce diabetes insipidus and hypernatremia. Tuberculomas present as any other mass lesion; seizures are common. MRI scanning reveals the basilar meningitis and any tuberculous masses. The cerebrospinal fluid demonstrates a lymphocytic pleocytosis, as well as elevated protein and reduced glucose levels. Acid-fast staining reveals the bacillus in only a minority of cases, and although culture is more often positive, a delay is required pending the results. PCR assay may reveal tubercular DNA (Lin etal. 1995). The PPD, although generally positive, may be falsely negative in patients with AIDS (Sanchez-Portocarrero et al. 1996). Course Untreated, tuberculous meningitis is almost invariably fatal within a week to 2 months later. Tuberculomas may occasionally stabilize and undergo calcification. Differential diagnosis

Syphilis and opportunistic fungal infections must be considered. Treatment

A triple regimen of isoniazid (with vitamin B6), rifampin, and pyrazinamide is employed; given the long duration of treatment, extra efforts are made to ensure compliance. Drug resistance is becoming increasingly common (Frieden et al. 1993) and is difficult to manage.

WHIPPLE'S DISEASE Pathology and etiology Whipple's disease results from a systemic infection by the bacterium Tropheryma whippelii (Raoult et al. 2000; Relman et al. 1992); although the intestines and joints are most often affected, the central nervous system is not uncommonly involved. Within the central nervous

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system (Smith et al. 1965), focal areas of inflammation and necrosis, along with glial scars, are found in the cerebral cortex, basal ganglia, hypothalamus, brainstem (especially the periaqueductal gray matter) and cerebellar cortex. PAS-positive macrophages are found in all the affected areas, and electron microscopy may reveal the rod-shaped bacterium within the macrophage (Powers and Rawe 1979). Clinical features

The onset is typically in the middle years, males being preferentially affected. Although, in the vast majority of cases with central nervous system involvement, patients also have systemic symptoms, such as diarrhea, abdominal pain, polyarthralgia, weight loss, and mild fever, it must be kept in mind that, albeit rarely, Whipple's disease may manifest with central nervous system invovlement alone (Adams et al. 1987; Lampert et al. 1962; Romanul et al. 1977). Central nervous system involvement (Louis et al. 1996; Manzel et al. 2000) may present with dementia, delirium, personality change, lethargy, supranuclear ophthalmoplegia, myoclonus, seizures, ataxia, and hypothalamic involvement, including diabetes insipidus, hyperphagia, changes in libido, and somnolence. In some cases, a peculiar movement disorder, named oculomasticatory myoarrythmia (Schwartz et al. 1986) may be seen, wherein pendular convergence or vertical eye movement may occur synchronously with jaw movements. MRI scanning may reveal focal changes consistent with those areas of the central nervous system involved. The cerebrospinal fluid generally demonstrates a mild lymphocytic pleocytosis, with or without an elevated total protein level; a PAS-positive macrophage may occasionally be found. Jejeunal biopsy typically reveals abundant PAS-positive macrophages; rarely, however, there may be central nervous system involvement with a negative small bowel biopsy (Pollock et al. 1981). In cases complicated by substantial diarrhea with steatorrhea, vitamin B12 deficiency may occur. Course The disease is gradually progressive, and, in the natural course of events, fatal. Differential diagnosis

The occurrence of central nervous symptoms in a middle-aged male with abdominal and articular symptoms is highly suggestive. In cases without these systemic symptoms, a high index of suspicion will be required to make the diagnosis; the finding of oculomasticatory myoarrythmia is very suggestive. Treatment

Trimethoprim-sulfamethoxazole, in most cases, halts the progression of the disease and should be given for at least 2 years; in some cases, lifelong treatment may be required to prevent relapses.

ROCKY MOUNTAIN SPOTTED FEVER Pathology and etiology After inoculation by a tick bite, Rickettsia rickettsii, the etiologic agent of Rocky Mountain spotted fever, undergoes hematogenous spread and invades the endothelial cells, primarily of the capillaries and arterioles; the skin, lungs, liver, and brain being the preferred targets. Vascular damage is followed by perivascular edema, hemorrrhage, and, in some cases,

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thrombosis, with downstream 'mini-infarcts.' Within the central nervous system, there is perivascular inflammation, petechial hemorrhages and small, scattered areas of infarction (Miller and Price 1972). Although Rocky Mountain spotted fever is most common in the western Rockies and the Appalachians, it has occurred throughout the continental United States. Clinical features

The tick bite, which may be forgotten, is followed by an incubation period of between 2 days and 2 weeks; patients then fall ill with fever, headache, malaise, and myalgia. After a few days, a characteristic maculopapular rash appears; initially present at the ankles and wrists but then spreading to involve the extremities and, in over half the cases, the soles and palms. Central nervous system manifestations (Bell and Lascari 1970; Homey and Walker 1988) include lethargy or delirium, which may be accompanied by delusions and hallucinations (Miller and Price 1972); various focal signs are common. The cerebrospinal fluid may display a mixed polymorphonuclear and lymphocytic pleocytosis and elevated total protein level, with a normal or slightly reduced glucose. Serologic testing with an indirect immunofluorescence assay is a sensitive test but generally does not become positive until the patient has been ill for a week. Rapid diagnosis may be accomplished with a punch biopsy specimen. Course If the condition is untreated, the fatality rate is about 20%. Differential diagnosis

Meningococcal meningitis, rubella, and rubeola must all be considered. The classic triad of fever, rash, and a history of a tick bite is extremely important, but, as noted above, the tick bite may not be recalled. Treatment

Intensive care is often required, especially with pulmonary involvement. Doxycycline is recommended, an alternative being chloramphenicol.

MALARIA Pathology and etiology

Malaria occurs secondary to infection with any one of four species of the protozoon Plasmodium, including P. malariae, P. vivax, P. ovale, and P. falciparum. Of these four species, only one, P. falciparum, invades the central nervous system. Malaria is endemic in tropical and subtropical areas, including Africa, South America, Haiti, and much of Asia and Oceana: although it has been eradicated from most of North America and Europe, cases may still be seen in those returning from travel in endemic areas who did not take adequate prophylactic medication. Malaria is transmitted by the bite of an Anopheles mosquito; once in the bloodstream, P. falciparum invades the erythrocytes, where it reproduces, with the eventual lysis of the erythrocytes and the release of new organisms into the blood. Involvement of the central nervous system occurs at the level of the capillary, and, most importantly, the post-capillary venule. Inside these vessels, there may be actual sludging of non-deformable erythrocytes, more importantly, however, infected erythrocytes develop what are known as 'knobs' on their cell membranes, which promote the adhesion of the erythrocyte to the vascular endothelium (Oo et al. 1987). Petechial hemorrhages are found throughout the central nervous system,

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often accompanied by perivascular inflammation. In long-term survivors, there may be scattered glial scars (Toro and Roman 1978). Clinical features

After a 1-4 week incubation period, patients fall ill with fever, headache, malaise, and myalgia. In about 2% of patients with falciparum malaria, this non-specific illness is joined, within days to 3 weeks, by delirium (Blocker et al. 1968), severe headache, and often generalized convulsions. Occasionally, the first evidence of central nervous system involvement is a convulsion. Focal signs, such as hemiplegia, are generally not present. Coma often rapidly ensues. An examination of thin and thick films of peripheral blood generally reveals the parasite within the erythrocytes. The cerebrospinal fluid is generally normal however there may occasionally be a few cells and a mild elevation of the total protein level. Course Cerebral malaria is fatal in at least 20% of cases. Sequelae, including hemiplegia and seizures, are seen in only about 10% of survivors. Differential diagnosis

Cerebral malaria may be mimicked by viral encephalitis and bacterial meningitis. Treatment

Cerebral malaria is a medical emergency, requiring treatment in an intensive care unit. Quinine or, alternatively, quinidine is recommended. Corticorsteroids are contraindicated (Warrell et al. 1982).

TOXOPLASMOSIS Pathology and etiology Infection by Toxoplasma gondii is very common in mammals: the cat is the definitive host, the parasite being abundant in cat feces and surviving for up to a year in contaminated soil. Humans acquire the parasite through the ingestion of contaminated material or by eating the improperly cooked meat of infected animals, such as pork, mutton, or beef. In immunocompetent patients, the infection is usually subclinical, the parasite undergoing cyst formation and remaining latent, generally for the life of the patient. With the advent of immunoincompetence, as for example with AIDS, the parasite undergoes reactivation and hematogenous spread to various organs, particularly the central nervous system. Toxoplasmosis is the most common opportunistic infection in patients with AIDS and generally does not appear until the CD4+ count falls below 100 cells/mm3. Rarely, central nervous system involvement may occur in otherwise healthy adults (Townsend et al. 1975b). Lesions within the central nervous system (Navia et al. 1980) may be found throughout the cerebrum, often at the corticomedullary junction or in the basal ganglia, and range in size from minute areas of cerebritis to large abscesses. Although most patients have several abscesses, the range is wide, from a diffuse, miliary presentation to a solitary large abscess. Clinical features

The onset ranges from subacute, over weeks, to acute, over a matter of days. The presentation may be either with focal signs, such as hemiparesis, aphasia, abnormal movements (e.g. choreoathetosis), and ataxia, or with delirium and headache; in most cases, the delirium will also be accompanied by focal findings (Navia et al. 1986c; Porter and Sande 1992). Seizures

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may also occur (Pascual-Sedano et al. 1999). In a small minority, the presentation is with a psychosis or agitation (Navia et al. 1986c). CT scanning with double-dose contrast generally reveals ring-enhancing lesions; false negatives, however, may occur, and MRI scanning is more sensitive. The cerebrospinal fluid may display a pleocytosis, which may range from lymphocytic to polymorphonuclear depending on the acuity of the case; the total protein concentration is usually elevated. Serum antibody titers may not be helpful in immunoincompetent patients: almost all patients with AIDS have evidence of prior infection, and, given their immunoincompetence, there is usually not a rise of antibody titer during the reactivation. Course In immunoincompetent patients, cerebral toxoplasmosis is usually rapidly fatal. Differential diagnosis

The presence of multiple, ring-enhancing lesions on MRI scanning in a Toxoplasmaseropositive adult with AIDS allows for a presumptive diagnosis of toxoplasmosis and justifies a 'diagnosis by treatment response' trial with antibiotics: clinical improvement within a week or two confirms the diagnosis, and a lack of improvement is an indication for the needle biopsy of a lesion. A solitary lesion in a patient with AIDS is consistent not only with toxoplasmosis, but also with primary lymphoma. Treatment

Most patients respond to a combination of pyrimethamine (with leukovorin) and sulfadiazine: in patients with AIDS, chronic treatment may be necessary to prevent relapses.

CANDIDIASIS Pathology and etiology

Candida is part of the normal human flora and generally causes disease only in the immunocompromised or those taking broad-specturm antibiotics; it is the most common cause of fungal infection in patients with AIDS. Hematogenous spread to the brain results in widely scattered lesions (Parker et al. 1981): these may take the form of microabscesses (Roessman and Friede 1967) or granulomas and abscesses of varying size. Meningitis may also occur but is less common than parenchymal abscesses. In some cases, vasculitis with thrombus formation and infarction may occur (Roessman and Friede 1967). Clinical features

Delirium and focal signs have been noted. MRI scanning reveals granulomas, abscesses, and, if present, meningitis. Cerebrospinal fluid generally displays a mononuclear pleocytosis and increased protein and decreased glucose levels; in some cases, Candida may be evident on staining, but the definitive diagnosis requires culturing. Course Untreated, central nervous system candidiasis is almost invariably fatal.

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Differential diagnosis

In the immunocompromised host, other fungal infections, such as cryptococcosis, must be considered. Treatment

Amphotericin B is given, followed by fluconazole.

CRYPTOCOCCOSIS Pathology and etiology

Cryptococcus is a round, yeast-like fungus that gains entry via the lungs, from whence it undergoes hematogenous spread to the brain. Although central nervous system infection can occur in immnocompetent patients, it is much more likely in the immunocompromised and is one of the most common fungal infection in patients with AIDS, generally seen only when the CD4+ count falls below 100 cells/mm3. In most cases, there is a basilar granulomatous meningitis. Cryptoccoci are also widespread throughout the cerebral cortex and basal ganglia, and multiple abscesses or granulomas may be found: although, in most cases, these are small, occasionally only one or several large abscesses will be found. Clinical features

The onset is generally subacute, patients typically (Chuck and Sande 1989; Edwards et al. 1970) presenting with headache, nausea and vomiting, and delirium; meningeal signs, such as neck stiffness, are present in no more than one-half of patients at presentation and tend to be relatively mild, especially in patients with AIDS. In those rare cases in which large abscesses dominate the pathologic picture, meningeal signs are generally lacking (Selby and Lopes 1973) and the presentation will be similar to that for any mass lesion. In one rare case (Thienhaus and Khosla 1984), a patient with cryptococcal meningitis presented with mania, followed, within several weeks, by delirium. Hydrocephalus is not uncommon with progression of the basilar meningitis. MRI scanning reveals the basilar meningitis and any appreciably large abscesses or granulomas. The cerebrospinal fluid (Chuck and Sande 1989) may be under increased pressure, and in almost all cases, one or more of the following is found: increased total protein; decreased glucose; and pleocytosis, which is usually lymphocytic. Because Cryptococcus is surrounded by a polysaccharide capsule, India ink preparations reveal a clear 'halo' around the yeast, this test being positive in well over one-half of cases. Capsular antigen is usually demonstrable, and it is almost always possible to culture the organsim on Sabouraud's medium. In those rare instances in which meningitis is absent, the cerebrospinal fluid may be normal (Selby and Lopes 1973). Course Central nervous system cryptococcosis is, in the natural course of events, almost invariably fatal within weeks to years. Differential diagnosis

Tuberculosis, toxoplasmosis, and other fungal infections must be considered. Treatment

Amphotericin B, generally with flucytosine, is required.

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COCCIDIOIDOMYCOSIS Pathology and etiology

Coccidioides immitis is a fungus endemic in the American southwest and infects the host via the lungs; hematogenous spread may occur to various organs, including the brain. Coccidioidomycosis may occur in both immunocompetent and immunocompromised patients, and may be seen in AIDS when the CD4+ count falls below 250 cells/mm3. Although abscesses and granulomas may be seen in the brain parenchyma, a basilar granulomatous meningitis is far more common, with the potential involvement of the cranial nerves and an obstruction of cerebrospinal fluid outflow. Clinical features Patients may present with delirium and lethargy (Caudill et al. 1970); cranial nerve palsies may ensue, as may hydrocephalus (McCullough and Harbert 1969). MRI scanning reveals the meningitis. The cerebrospinal fluid may display a lymphocytic pleocytosis with elevated protein and decreased glucose levels. Cultures and smears are often negative, but coccidioidal antibody can usually be detected. Course Untreated, central nervous system coccidioidomycosis is invariably fatal. Differential diagnosis

Tuberculosis and other fungal infections must be considered. Treatment

Fluconazole may be preferable to intrathecal amphotericin B, and must be given for the life of the patient to prevent relapse.

HISTOPLASMOSIS Pathology and etiology

Infection with Histoplasma capsulatum occurs world wide and is endemic in the Ohio river valley. The initial infection is usually in childhood via the lungs, and it is usually asymptomatic. In patients with depressed cell-mediated immunity, reactivation may occur, with hematogenous spread to various organs, including the brain. Histoplasmosis is found in a little over 1% of patients with AIDS, and in about a fifth of these, central nervous system involvement occurs. In most patients, there is a thick, indolent basilar meningitis (Cooper and Goldstein 1963); cerebral abscesses and granulomas, some of which may be large, can also occur (Wheat et al. 1990). Clinical features

Delirium and cranial nerve palsies may occur with meningitis; large granulomas may present as any other mass lesion. MRI scanning will reveal the meningitis. The cerebrospinal fluid reveals a mononuclear pleocytosis and increased protein and decreased glucose concentrations. Histoplasma antigen may be detecteed in the cerebrospinal fluid, and the organism may be grown in culture. Course Untreated, disseminated histoplasmosis is usually rapidly fatal.

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Differential diagnosis In patients with AIDS, consideration is given to tuberculosis and other fungal infections, such as cryptococcosis. Treatment

Amphotericin B is followed by suppressive therapy with itraconazole.

ASPERGILLOSIS Pathology and etiology Aspergillus species exist in a mold form, with septate, branching hyphae. Infection in immunocompetent hosts is very rare; most patients with aspergillosis are either undergoing chronic treatment with corticosteroids or are neutropenic (Walsh et al. 1985). Although aspergillosis does occur in patients with AIDS (Woods and Goldsmith 1990), it is surprisingly uncommon in this group (Lang et al. 1989). Aspergillus is ubiquitous in the environment, infection usually occurring via the inhalation of spores, resulting in lower, or less frequently upper, airway involvement; the central nervous system may be affected by hematogenous spread (Young et al. 1970) from a pulmonary focus or via local extension from a paranasal sinus. Within the central nervous system arteries often become plugged, resulting in, variously, thrombosis and infarction, mycotic aneurysms, granulomas, or abscesses; the cerebral hemispheres are preferentially involved, and meningeal involvement is unusual. Clinical features

Given the variety of pathologic lesions possible, it is difficult to describe anything like a typical clinical presentation. Granulomas or abscesses, when large and solitary, may present as any other expanding mass lesion; when their number is large, however, a delirium may occur. Infarctions may present with a variety of focal signs, and mycotic aneurysms may rupture, with subarachnoid hemorrhage. Biopsy is often required for a definitive diagnosis. Course

Untreated, central nervous system aspergillosis is usually fatal. Differential diagnosis

Other opportunistic infections, such as other fungal infections or toxoplasmosis, must also be considered. Treatment

Amphotericin B and 5-fluorocytosine are often required, and every attempt should be made to restore the patient's immune competence.

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Neurol 1972; 26:353-8. Simon RP. Neurosyphilis. Arch Neurol 1985; 42:606-13. Singer C, Lang AE, Suchowersky 0. Adult-onset subacute sclerosing panencephalitis: Case reports and review of the literature. Mov Disord 1997; 12:342-53. Smardel JE, Bailey P, Baker AB. Sequelae of the arthropod-borne encephalitides. Neurology 1958; 8:873-96. Smith WT, Frency JM, Guttsmann M et al. Cerebral complications of Whipple's disease. Brain 1965; 88:137-50. Solomon T, Dung NM, Kneen Ret al. Japanese encephalitis.) Neurol Neurosurg Psychiatry 2000; 68:405-15. Sponzilli EE, Smith JK, Malamud N etal. Progressive multifocal leukoencephalopathy: a complication of immunosuppressive treatment. Neurology 1975; 25:664-8. Storm-Mathisen A. General paresis: a follow-up study of 203 patients. Ada PsychiatrScand 1969; 45:118-32. Strauss SE, Reinhold W, Smith HA et al. Endonuclease analysis of viral DNA from varicella and subsequent zoster infections in the same patients. N EnglJ Med 1984; 311:1362-4. Studahl M, Rickstein A, Sandberg T et al. Cytomegalovirus infection of the CNS in non-compromised patients. Acta Neurol Scand 1994; 89:451-7. Taylor EW, McDonald CA. Forced conjugate upward movement of the eyes following epidemic encephalitis. Arch Neurol Psychiatry 1928; 19:95-103. ThienhausOJ, Khosla N. Meningeal cryptococcosis misdiagnosed as a manic episode. Am J Psychiatry

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15 Prion diseases Creutzfeldt-Jakob disease New-variant Creutzfeldt-Jakob disease Gerstmann-Straussler-Scheinker disease

566 569 569

Fatal familial insomnia Kuru

570 571

CREUTZFELDT-JAKOB DISEASE Pathology and etiology Creutzfeldt-Jakob disease is the prototype of prion diseases in humans, and to understand it, one must first understand the biology of prion proteins. Prion proteins are normally found on the cell surface of neurons, and although their function is not yet clear, it appears that they undergo a kind of cycling from the exterior of the cell membrane back into the cell itself, whereupon they undergo digestion within lysosomes. Abnormal, or pathogenic, prion proteins also undergo this cycling, but once inside the cell, they resist digestion and undergo aggregation into a large proteinaceous particle, known as a prion; it is the accumulation of these prions that apparently leads to the pathologic changes noted below. Pathogenic prion proteins may appear on any one of three bases: inherited, sporadic, and iatrogenic. Inherited cases occur secondary to any one of a large number of mutations in the gene for normal cellular prion proteins (designated PRNP), located on chromsome 20 (Goldfarb et al. 1990; Hsiao et al. 1991a; Owen et al. 1989). Sporadic cases currently do not have a good explanation: some believe that they represent spontaneous, age-related transformations of normal cellular prion proteins into pathogenic prion proteins, whereas others suspect that sporadic cases may represent infections with a long incubation period (Galvezefa/. 1980). Iatrogenic cases have occurred upon inadvertent exposure to tissue from patients with Creutzfeldt-Jakob disease via the following procedures: corneal transplants (Duffy et al. 1974; Heckmann et al. 1997); dura mater grafts (Miyashita et al. 1991); the use of contaminated electrodes during neurosurgical procedures (Bernouilli et al. 1977); injections of human growth hormone (Billette de Villemeur et al. 1991, 1996); and the injection of human pituitary gonadotrophins (Cochius et al. 1992; Healy and Evans 1993); it is of especial interest that a case also occurred secondary to the use of lyophilized dura mater in the treatment of a nasopharyngeal angiofibroma, a procedure wherein the dura mater remained extracranial (Antoine et al. 1997). The persistence of prions cannot be overemphasized: in one case (Gibbs et al. 1994), electrodes that had been used during neurosurgery on a patient

Prion diseases 567

with Creutzfeldt-Jakob disease 2 years earlier were cleaned three times and repeatedly sterilized in ethanol and formaldehyde vapor, yet were still able to transmit the disease to a chimpanzee. The basic difference between the normal cellular prion protein and the pathogenic prion protein appears to be one of molecular conformation: the normal cellular prion protein exists primarily in an alpha-helical conformation, whereas the pathogenic prion protein exists for the most part in a beta-sheet conformation (Pan et al. 1993). Apart from these conformational differences, which apparently account for their digestibility (or non-digestibility) in the lysosomes, there does not appear to be any fundamental difference between the normal cellular and the pathogenic prion proteins. As noted earlier, pathogenic prion proteins may occur on any one of three bases, the mechanism whereby the conformational change occurs differing according to the basis. In inherited cases, various specific amino acid changes are at fault. In iatrogenic cases, the foreign pathogenic prion protein acts as a template such that the host's normal cellular prion proteins, upon contacting the template, undergo the fatal conformational change from alphahelix to beta-sheet, then acting as templates themselves in a cascading chain reaction. In sporadic cases, the mechanism whereby that first pathogenic prion protein appears is not clear: it could result from an age-related spontaneous mutation in just one single neuron or it might have been contracted decades earlier during some, as yet unknown, environmental event. The abbreviations used for prion proteins are sometimes confusing and are changing with time. Currently, normal cellular prion proteins are known as PrPc, those which are found in inherited cases are known as APrP, and those which are found in sporadic cases as PrPcjd: there does not appear to be a specific abbreviation for prion proteins found in iatrogenic cases. To make things a little more confusing, the abbreviation 'PrPsc' has been used in the past to refer to all forms of pathogenic prion protein, and is still currently used by some authors today: the superscript 'sc' refers back to the prion disease of sheep known as scrapie. The pathologic hallmark of Creutzfeldt-Jakob disease is widespread spongiform change seen in the gray matter of the cerebral cortex, basal ganglia, thalamus, and cerebellar cortex (Masters and Richardson 1978). Electron microscopy reveals that this spongy appearance is caused by the presence of large vacuoles in the neuropil, which in turn appear to represent hugely swollen dendrites and axons (Beck et al. 1982; Chou et al. 1980). Although neuronal drop-out occurs, this is not particularly pronounced. In a small minority, perhaps 5-10% of cases, plaques resembling the amyloid plaques seen in Alzheimer's disease may be found. In contrast to the plaques of Alzheimer's disease, however, these plaques are not composed of amyloid beta-protein but appear to be, at least in part, composed of prions (Kitamoto et al. 1986). Importantly, although there is a widespread reactive astrogliosis, there is no evidence of an inflammatory response. Clinical features

Of all cases of Creutzfeldt-Jakob disease, about 85% are sporadic, 10-15% inherited (Masters et al. 1979), and the rest iatrogenic. Sporadic cases, on average, appear in the early sixties, but the range is wide, from late teenage years to the tenth decade. Inherited cases tend to appear a bit earlier, mostly in the early fifties. Iatrogenic cases appear anywhere from 6 months to 25 years after the infectious event. Although most cases appear subacutely, over weeks to months, fulminant onsets, spanning only a few days, have in some cases occurred. The overall symptomatology of Creutzfeldt-Jakob disease has been described in several studies (Brown et al. 1986, 1994; Roos et al. 1973). The presentation may be with dementia, personality change, psychosis, cerebellar signs (such as ataxia), or visual symptomatology, such as hemianopia or cortical blindness. With progression, almost all patients become

568 Specific disorders

profoundly demented, the dementia being accompanied by myoclonus in almost 90% of cases. Parkinsonism, of the rigid-akinetic variety, may occur, as may upper motor neuron signs, and in a small minority, evidence of lower motor neuron dysfunction, such as fasciculations, may be seen. Seizures occur in a small minority. Rare presentations of Creutzfeldt-Jakob disease include aphasia (Mandell et al. 1989), the alien hand sign (MacGowan et al. 1997), and mania (Lendvai et al. 1999). Although computed tomography or magnetic resonance imaging (MRI) may be normal early in the course of the disease, cortical atrophy eventually appears. Although exceptions occur (Zochodne et al. 1988), the electroencephalogram (EEC) eventually becomes abnormal in most cases, being characterized by periodic spike and slow wave complexes (May 1986). The cerebrospinal fluid usually displays a normal glucose and cell count; the total protein level may be normal or modestly elevated. The 14-3-3 protein is found in most cases and displays good sensitivity and specificity for the disease (Hsich et al. 1996; Rosenmann et al. 1997; Zerr et al. 1998a), false positives being found in acute stroke, herpes simplex encephalitis, and paraneoplastic cerebellar degeneration and limbic encephalitis (Hsich et al. 1996; Saiz et al. 1999). Course

Although most die after a progressive illness lasting from 4 to 12 months (Masters and Richardson 1978; Will and Mathews 1984), exceptions occur, and some patients may survive more than 2 years. Such long courses have been characterized by a relative stability of symptoms followed, at the end, by a precipitous decline over only weeks or months (Brown et al. 1984). Differential diagnosis Dementia of subacute or acute onset should always suggest Creutzfeldt-Jakob disease, and the diagnosis should be strongly considered in cases in which the dementia is accompanied by the characteristic EEC pattern and by other signs, especially myoclonus, ataxia, blindness, or hemianopia (Brandel et al. 2000). Myoclonus, although highly suggestive that the dementia is secondary to Creutzfeldt-Jakob disease, may also be seen in dementia secondary to newvariant Creutzfeldt-Jakob disease, fatal familial insomnia, and Hashimoto's encephalopathy. The new-variant type is suggested by early behavioral changes, such as depression, and fatal familial insomnia by prominent insomnia. Hashimoto's encephalopathy may be difficult to distinguish clinically, and accurate diagnosis may depend on testing for anti-thyroid antibodies (Seipelt et al. 1999). Treatment The general treatment of dementia is outlined in Chapter 5. There does not at present appear to be any specific treatment for the disease. Earlier reports of benefit from amantadine (Braham 1971; Sanders 1979; Sanders and Dunn 1973; Terzano et al. 1983) have not been replicated. The question inevitably arises as to what sorts of precaution should be in place to guard against transmission of the disease. Although isolation does not appear to be necessary, routine universal precautions are appropriate. It is, however, critical to avoid contamination via cerebrospinal fluid, blood, or biopsy specimens, and it must be borne in mind that routine sterilization procedures, including autoclaving and alcohol immersion, are not effective. In cases of accidental contact, consideration may be given to washing with a 1:10 solution of common 5% hypochlorite bleach, which is effective. Pins used for sensory testing in any patient should never be used twice.

Prion diseases 569

NEW-VARIANT CREUTZFELDT-JAKOB DISEASE Pathology and etiology

New-variant Creutzfeldt-Jakob disease represents a human prion infection acquired by eating beef products obtained from cows suffering from bovine spongiform encephalopathy. Bovine spongiform encephalopathy, or 'mad cow' disease is, in turn, a prion disease that cows acquire by eating cattle feed made from the offal of sheep who had themselves been suffering from the sheep prion disease scrapie. Interestingly, it appears that host factors are very important in determing which humans will develop the disease: all patients who have developed the newvariant form of Creutzfeldt-Jakob disease possess the same normal allellic variant, MM, at codon 129 of the gene for the normal cellular prion protein (Collinge et al. 1996; Will et al. 2000). Pathologically, new-variant Creutzfeldt-Jakob disease is quite different from 'traditional' Creutzfeldt-Jakob disease described in the preceding section. In the new-variant form, one finds widespread prion plaques surrounded by spongiform change throughout the cerebral and cerebellar cortices (Will et al. 1996). Clinical features

The age of onset has ranged from the late teens to the end of the fifth decade. Clinically, patients present with behavioral changes followed by ataxia and, eventually, a dementia that is often accompanied by myoclonus (Allroggen et al. 2000; Collinge and Rossor 1996; Will et al. 1996; Zeidler et al. 1997a). The 'behavioral' presentation may include personality change, withdrawal, agitation, insomnia, apathy, depression, emotional lability, or psychosis, which in turn could comprise visual and auditory hallucinations and Schneiderian first rank symptoms (Will etal 2000; Zeidler 1997a,b). The EEC fails to reveal periodic spike and slow wave complexes. MRI scanning may reveal increased signal intensity on T2-weighted scans in the pulvinar (Zeidler et al. 2000), and the 14-3-3 protein may be present in the cerebrospinal fluid (Will et al. 2000). Recent work suggests that tonsilar biopsy may be both sensitive and specific for newvariant Creutzfeldt-Jakob disease, even to the point of distinguishing it from other prion diseases (Hill etal 1999). Course Death occurs generally within one-half to three years (Will et al. 2000). Differential diagnosis

This is similar to that for Creutzfeldt-Jakob disease, noted above. Treatment

Treatment may proceed along the lines suggested for Creutzfeldt-Jakob disease. Prevention is clearly essential, and any infected sheep or cows must be destroyed.

GERSTMANN-STRAUSSLER-SCHEINKER DISEASE Pathology and etiology

Gerstmann-Straussler-Scheinker disease is a prion disease inherited in an autosomal dominant fashion, occurring secondary to any one of several mutations in the PRNP gene. Mutations have been noted at codons 102 (Brown et al. 1991; Goldhammer et al. 1993; Hsiao et al. 1989; Kretzchmar et al. 1992; Young et al. 1995), 105 (Kitamoto et al. 1993; Yamada et al.

570 Specific disorders

1993), 117 (Hsiao etal 1991b; Nochlin etal. 1989), 198 (Farloweta/. 1989; Ghetti etal. 1989) and 217 (Hsiao et al. 1992). Pathologically, all cases of Gerstmann-Straussler-Scheinker disease, regardless of which mutation is at fault, share a common feature, namely the presence of multicentric amyloid plaques that stain positively for prion proteins (Kitamoto et al. 1986; Roberts et al. 1986). In some cases, unicentric spiky plaques, similar to those seen in kuru, may also occur, and in others neurofibrillary tangles may be seen. Spongiform change is either minimal or absent. Although the distribution of these microscopic changes varies, the cerebellar cortex, basal ganglia, and cerebral cortex are generally involved. Clinical features

The onset is gradual, occurring any time from the fourth to the sixth decade. Classically, the disease presents with a combination of ataxia and dementia, but parkinsonism may at times be seen, and there may also be wide intrafamilial variation (Barbanti et al. 1996; Farlow et al. 1989). Both the EEC and MRI may be normal (Young et al. 1995) Course The disease is progressive, with death within 1-10 years. Differential diagnosis

Autosomal dominant cerebellar ataxia and dentatorubropallidoluysian atrophy may both be difficult to distinguish from Gerstmann-Straussler-Scheinker disease, and genetic testing may be requited. Treatment

Treatment may be conducted as for Creutzfeldt-Jakob disease; genetic counselling should be offered.

FATAL FAMILIAL INSOMNIA Pathology and etiology Fatal familial insomnia is an autosomal dominantly inherited prion disease, occurring secondary to a mutation at codon 178 of the PRNP gene (Medorietal. 1992a,b). Interestingly, this mutation causes fatal familial insomnia only if there is a methionine polymorphism at codon 129: if the polymorphism at codon 129 is valine, then, rather than fatal familial insomnia, one sees familial Creutzfeldt-Jakob disease (Goldfarb et al. 1992). Pathologically (Lugaresi et al. 1986; Manetto et al. 1992), there is extensive neuronal loss and astrocytosis in the anterior and mediodorsal nuclei of the thalamus and in the inferior olives; in some cases, mild cell loss and spongiform change may also be seen in the cerebral and cerebellar cortices and in the dorsal raphe and superior central nuclei (Aimer et al. 1999). Clinical features

The onset is subacute, generally in the middle years. In general (Gallassi et al. 1996; Manetto et al. 1992; Medori et al. 1992a,b; Nagayama et al. 1996; Reder et al. 1995; Silburn et al. 1996; Tabernero et al. 2000), patients develop intractable insomnia, followed, in many cases, by 'oneiroid' states wherein patients appear confused, experience visual hallucinations, and behave as if they were acting out dreams: in one case (Aimer et al. 1999), 'the patient performed movements of sawing with a virtual saw and stopped bewildered when told there was no saw.' Paroxysms of autonomic disturbance often occur, with hyperhidrosis, tachycardia, hypertension, and irregular respiration. Over time, cerebellar symptomatology, such as ataxia

Prion diseases 571

and dysarthria, appears, and dementia, myoclonus, and spasticity may also be seen. Stupor and coma eventually supervene. The EEC generally shows diffuse slowing. Course Death occurs in between one-half and three years. Differential diagnosis

The presence of dementia with intractable insomnia, oneiroid states, or autonomic crises is distinctive; it must be borne in mind, however, that, despite the name of this disease, not all patients suffering from it have insomnia, and thus the lack of insomnia does not rule out the diagnosis (Zerr et al. 1998b). Treatment

Treatment should probably be conducted as for Creutzfeldt-Jakob disease. Although the insomnia is often intractable, pessimism is not justified, and multiple trials with different hypnotics are appropriate.

KURU Pathology and etiology

Kuru is a unique human prion disease, spread by cannibalism and present only in the Fore people of New Guinea (Gajdusek 1977). Pathologically (Gajdusek and Zigas 1959; Kakulas et al. 1967), there is atrophy of the cerebellar vermis and flocculonodular lobe; microscopically, there is widespread spongiform change, neuronal loss, and astrocytosis, together with 'kuru plaques'. These plaques are distinguished from the amyloid plaques found, for example, in Alzheimer's disease by the presence of'spikes' that radiate out around the circumference of the plaque. Clinical features

After an incubation period of between 4 and 20 years, patients develop ataxia and tremor, followed, in a minority, by dementia (Gajdusek and Zigas 1957; Zigas et al. 1957). Course The disease is invariably fatal, generally within a year of onset. Differential diagnosis

The disease is found only in the Fore people. Treatment

Since cannibalism was abolished, the disease has gradually died out.

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572 Specific disorders Barbanti P, Fabbrini G, Salvatore M etal. Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity in a previously unreported family with Gerstmann-Straussler-Scheinker disease (Prp-P102L mutation). Neurology 1996; 47:734-41. Beck E, Danile PM, Davey AJ etal. The pathogenesis of transmissible spongiform encephalopathy - an ultrastructural study. Brain 1982; 105:755-86. Bernouilli C, Siegfried J, Baumgartner G etal. Danger of accidental person to person transmission of Creutzfeldt-Jakob disease by surgery. Lancet 1977; 1:478-9. Billette de VillemeurT, Beuavais P, Gourmelon M etal. Creutzfeldt-Jakob disease in children treated with growth hormone. Lancet 1991; 337:864-5. Billette de Villemeur T, BeslysJ-P, Pradel Aef al. Creutzfeldt-Jakob disease from contaminated growth hormone extracts in France. Neurology 1996; 47:690-5. Braham J. Jakob-Creutzfeldt disease: treatment by amantadine. BMJ1971; 4:212-13. Brandel J-P, Delasnerie-Laupretre N, Laplanche \-letal. Diagnosis of Creutzfeldt-Jakob disease: effect of clinical criteria on incidence estimates. Neurology 2000; 54:1095-9. Brown P, Rodgers-Johnson P, Cathala fet al. Creutzfeldt-Jakob disease of long duration: clinicopathological characteristics, transmissibility, and differential diagnosis. Ann Neurol 1984; 16:295-304. Brown P, Cathala F, Castaigne P etal. Creutzfeldt-Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann Neurol 1986; 20:597-602. Brown P, Goldfarb LG, Brown WTefo/. Clinical and molecular genetic study of a large German kindred with Gerstmann-Straussler-Scheinker syndrome. Neurology 1991; 41:375-9. Brown P, GibbsCJ, Rodgers-Johnson Petal. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994; 35:513-29. Chou SM, Payne WN, Gibbs CG et al. Transmission and scanning electron microscopy of spongiform change in Creutzfeldt-Jakob disease. Brain 1980; 103:885-904. CochiusJI, Hyman N, Esiri MM. Creutzfeldt-Jakob disease in a recipient of human pituitary-derived gonadotrophin: a second case.7 Neurol Neurosurg Psychiatry 1992; 55:1094-5. Collinge J, Rossor M. A new-variant of prion disease. Lancet 1996; 347:916-17. CollingeJ, Brown J, Hardy \etal. Inherited prion disease with 144 base pair insertion. Brain 1992; 115:687-710. CollingeJ, Sidle KCL, Meads J etal. Molecular analysis of prion strain variation and the aetiology of 'new-variant' CJD. Nature 1996; 383:685-90. Duffy P, Wolf J, Collins G etal. Possible person to person transmission of Creutzfeldt-Jakob disease. N EnglJ Mo/1974; 290:692-3. Farlow MR, Yee RD, DIouhySRef al. Gerstmann-Straussler-Scheinker disease. I. Extending the clinical spectrum. Neurology 1989; 39:1446-52. Gajdusek DC. Unconventional viruses and the origin and disappearance of Kuru. Science 1977; 197:943-60. Gajdusek DC, Zigas V. Degenerative disease of the central nervous system in New Guinea: the endemic occurrence of 'Kuru' in the native population. N EnglJ Med 1957; 257:974-8. Gajdusek DC, Zigas V. Clinical, pathological and epidemiological study of the central nervous system among natives of the eastern highlands of New Guinea. AmJ Med 1959; 26:442-69. Gallassi R, Morreale A, Montagna Petal. Fatal familial insomnia: behavioral and cognitive features. Neurology 1996; 46:935-9. Galvez S, Masters C, Gajdusek C. Descriptive epidemiology of Creutzfeldt-Jakob disease in Chile. Arch Neurol 1980; 37:11-14. Ghetti B, Tagliavini F, Masters CLetal. Gerstmann-Straussler-Scheinker disease. II. Neurofibrillary tanglesand plaques with PrP-amyloid coexist in an affected family. Neurology 1989; 39:1453-61. Gibbs CJ, Asher DM, Kobrine A et al. Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery.y Neurol Neurosurg Psychiatry 1994; 57:757-8.

Prion diseases 573 GoldfarbLG, Mitrova E, Brown Petal. Mutation in codon 200 of scrapieamyloid protein gene in two clusters of Creutzfeldt-Jakob disease in Slovakia. Lancet 1990; 336:514-15. Goldfarb LG, Petersen RB, Tabaton M etal. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DMA polymorphism. Science 1992; 258:806-8. GoldhammerY, Gabison R, MeinerZe? al. An Israeli family with Gerstmann-Straussler-Scheinker disease manifesting the codon 102 mutation in the prion protein gene. Neurology 1993; 43:2718-19. Healy D, Evans J. Creutzfeld-Jakob disease after pituitary gonadotrophins. BMJ1993; 307:517-18. HeckmannJG, LangCJG, Petruch fetal. Transmission of Creutzfeldt-Jakob disease via a corneal transplant.7 Neurol Neurosurg Psychiatry 1997; 63:388-90. Hill AF, Butterworth RJ, Joiner S etal. Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy specimens. Lancet 1999; 353:183-9. Hsiao K, Doh-ura K, Kitamoto T et al. A prion protein amino acid substitution in ataxic Gerstmann-Straussler-Scheinker syndrome. Ann A/euro/1989; 26:137. Hsiao K, MeinerZ, Kahana Eetal. Mutation of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease. N EnglJ Med 1991a; 324:1091-7. Hsiao K, Cass C, Schellenberg GD etal. A prion protein variant in a family with the telencephalic form of Gerstmann-Straussler-Scheinker syndrome. Neurology 1991b; 41:681-4. Hsiao K, Dlouhy S, Farlow MRetal. Mutant prion proteins in Gerstmann-Straussler-Scheinkerdisease with neurofibrillary tangles. Nat Genet! 992; 1:68-71. Hsich G, Kenney K, Gibbs CJ etal. The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephalopathies. N EnglJ Med 1996; 335:924-30. Kakulas BA, Lecours AR. Gajdusek DC. Further observations on the pathology of Kuru (a study of two cerebra in serial section).) NeuropatholExp Neurol 1967; 26:85-97. Kitamoto T, Tateishi J, Tashima I etal. Amyloid plaques in Creutzfeldt-Jakob disease stain with prion protein antibodies. Ann Neurol 1986; 20:204-8. Kitamoto T, Amano N, Terao Y etal. A new inherited prion disease (PrP-P105L mutation) showing spastic paraparesis. Ann Neurol 1993; 34:808-13. Kretzchmar HA, Kufer P, ReithmullerGefo/. Prion protein mutation at codon 102 in an Italian family with Gerstmann-Straussler-Scheinker syndrome. Neurology 1992; 42:809-10. Lendvai I, Saravay SM, Steinberg MD. Creutzfeldt-Jakob disease presenting as secondary mania. Psychosomatic* 1999; 40:524-5. Lugaresi E, Medori R, Montagna P etal. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N EnglJ Med 1986; 315:997-1003. MacGowan DJL, Delanty N, PetitoFefo/. Isolated myoclonic alien hand as the sole presentation of pathologically established Creutzfeldt-Jakob disease: a report of two patients.) Neurol Neurosurg Psychiatry 1997; 63:404-7. Mandell AM, Alexander MP, Carpenter S. Creutzfeldt-Jakob disease presenting as isolated aphasia. Neurology 1989; 39:55-8. ManettoV, Medori R, Cortelli Petal. Fatal familial insomnia: clinical and pathological study of five new cases. Neurology 1992; 42:312-19. MastersCL, Richardson EP. Subacutespongiform encephalopathy (Creutzfeldt-Jakob disease)-the nature and progression of spongiform change. Brain 1978; 101:333-44. Masters CL, Harris JO, Gajdusek DC et al. Creutzfeldt-Jakob disease: patterns of worldwide occurrence and significance of familial and sporadic clustering. Ann Neurol 1979; 5:177-88. May WW. Creutzfeldt-Jakob disease. Acta NeurolScand 1986; 44:1-32. Medori R, Tritschler HJ, LeBlancAefo/. Fatal familial insomnia with a mutation at codon 178 of the prion protein gene. N EnglJ Mea"\992a; 326:444-9. Medori R, Montagna P, Tritschler HJ etal. Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178. Neurology 1992b; 42:669-70.

574 Specific disorders Miyashita K, InuzukaT, Kondo Hefo/. Creutzfeld-Jakob disease in a patient with a cadaveric dural graft. Neurology 1991; 41:940-1. Nagayama M.Shinohara Y, Furukawa Metal. Fatal familial insomnia with a mutation at codon 178 of the prion protein gene: First report from Japan. A/ewro/ogy1996; 47:1313-16. Nochlin D, Sum! SM, Bird TD etal. Familial dementia with PrP-positive amyloid plaques: a variant of the Gerstmann-Straussler syndrome. Neurology 1989; 39:910-18. Owen F, PoulterM, LofthouseRefo/. Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet 1989; 1:51-2. Pan K-M, Baldwin M, Nguyen J et al. Conversion of alpha-helices into beta-sheets features in the formation of thescrapie prion proteins. ProcNatlAcadSci USA 1993; 90:962-6. RederAT, Mednick AS, Brown Petal. Clinical and genetic studies of fatal familial insomnia. Neurology 1995; 45:1068-75. RobertsGW, LofthouseR, Brown Retal. Prion-protein immunoreactivity in human transmissible dementias. N EnglJMed 1986; 315:1231-3. Roos R, Cajdusek DC, Gibbs CJ. The clinical characteristics of transmissible Creutzfeldt-Jakob disease. Brain 1973; 96:1-20. Rosenmann H, Meiner Z, Kahana E et al. Detection of 14-3-3 protein in the CSF of genetic Creutzfeldt-Jakob disease. Neurology 1997; 49:593-5. SaizA, GrausF, Dalmaujefo/. Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurological disorders. Ann Neurol 1999; 46:774-7. Sanders WL Creutzfeldt-Jakob disease treated with amantadinej Neurol Neurosurg Psychiatry 1979; 42:960-1. Sanders WL, Dunn TL Creutzfeldt-Jakob disease treated with amantadinej Neurol Neurosurg Psychiatry 1973; 36:581^. Seipelt M, Zerr I, Nau R et al. Hashimoto's encephalitis as a differential diagnosis of Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 1999; 66:172-6. Silburn P, Cervenakova L, Varghese Petal. Fatal familial insomnia: a seventh family./Vo/ra/ogy 1996; 47:1326-8. Tabernero C, Polo JM, Sevillano MD etal. Fatal familial insomnia: clinical, neuropathological, and genetic description of a Spanish family../ Neurol Neurosurg Psychiatry 2000; 68:774-7. Terzano MG, Montanari E, Calzetti Setal. The effect of amantadine on arousal and EEC patterns in Creutzfeldt-Jakob diseaseM/r/? Neurol 1983; 40:555-9. Will RG, Mathews WB. A retrospective study of Creutzfeldt-Jakob disease in England and Wales 1970-1979 I. Clinical features../ Neurol Neurosurg Psychiatry 1984; 47:134-140. Will RG, Ironside JW, Zeidler M et al. A new-variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347:921-5. Will RG, Zeidler M, Stewart GE etal. Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 2000;47:575-82. Yamada M, ItohY, Fujigasaki \\etal. A missense mutation at codon 105 with codon 129 polymorphism of the prion protein gene in a new-variant of Gerstmann-Straussler-Scheinker disease. Neurology 1993;43:2723-4. Young K, Jones CK, Piccardo P etal. Gerstmann-Straussler-Scheinker disease with mutation at codon 102 and methionine at codon 129 of PRNPin previously unreported patients. Neurology 1995; 45:1127-34. Zeidler M, Stewart GE, Barraclough CRetal. New-variant Creutzfeldt-Jakob disease: neurological features and diagnostic tests. Lancet 1997a; 350:903-7. Zeidler M, Johnstone EC, Bamber RWK etal. New-variant Creutzfeldt-Jakob disease: psychiatric features. Lancet 1997b; 350:908-10. Zeidler M, Sellar RJ, Collie DA. The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease. Lancet 2000; 355:1412-18.

Prion diseases 575 Zerr I, BodemerM.GefellerOefo/. Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease. Neurology 1998a; 43:32-40. Zerr I, Giese A, Windl 0 etal. Phenotypic variability in fatal familial insomnia (D178N-129M) genotype. Mwo/ogy1998b; 51:1398-405. Zigas V, Gajdusek DC. Kuru: clinical study of a new syndrome resembling paralysis agitans in natives of the Eastern Highlands of Australian New Guinea. MedJAust ^57; 2:7 45-54. Zochodne DW, Young GB, McLachlan RS etal. Creutzfeldt-Jakob disease without periodic sharp wave complexes: a clinical, electroencephalographic, and pathologic study. Neurology 1988; 38:1056-60.

16 Endocrinologic disorders Cushing's syndrome

576

Hyperthyroidism

580

Adrenocortical insufficiency

578

Hypothyroidism

582

CUSHING'S SYNDROME Pathology and etiology Cushing's syndrome is caused by the sustained presence of excessive corticosteroids, which may be of either exogenous or endogenous origin. Exogenous corticosteroid administration, as for example with the use of prednisone, is the most common cause and is readily diagnosed; endogenous hypercortisolemia may result from a number of causes, its diagnosis being facilitated by an understanding of the normal regulatory mechanisms for cortisol. The cortisol level is normally maintained within normal limits by the hypothalamopituitary-adrenal axis: the hypothalamus secretes corticotrophin-releasing hormone (CRH), which in turn stimulates the pituitary to produce aderenocorticotrophic hormone (ACTH); the ACTH then stimulates the adrenal cortex to produce cortisol, which in turn exerts a negative feedback effect on the hypothalamus and pituitary. A sustained, excessive production of cortisol by the adrenal gland may result from the following causes: an enhanced release of CRH from the hypothalamus; an ACTH-secreting pituitary adenoma; ectopic ACTH production (e.g. by an oat cell carcinoma of the lung); and, finally, adrenal tumors. In most instances, the excessive adrenal production of cortisol is caused by a pituitary adenoma; the ectopic production of ACTH and adrenal tumors are less common causes, and the excessive production of CRH is quite rare (Orth 1995). The term 'Cushing's syndrome' includes all the foregoing etiologies, both exogenous and endogenous, whereas the more restricted term 'Cushing's disease' applies only to those cases resulting from a pituitary adenoma. The mechanism whereby excessive corticosteroids affect the central nervous system is not yet clear. Clinical features

The onset is determined by the underlying cause: the use of high-dose prednisone may produce symptoms within days; ectopic ACTH production may be followed by a subacute onset, within months; and Cushing's disease, occurring secondary to a pituitary tumor, may be of very gradual onset, over years.

Endocrinologic disorders 577

The clinical picture of fully developed Gushing' syndrome (Orth 1995) is distinctive and includes the following: a plethoric 'moon' facies, truncal obesity, a 'buffalo hump', violaceous abdominal striae, acne, easy bruising, a proximal myopathy, and, in females, hirsutism and oligomenorrhea. In addition, hypertension, diabetes mellitus, osteopenia, and pathologic fractures may be seen. Neuropsychiatric features include mood changes, either depressive or manic, anxiety, psychosis, delirium, and, rarely, dementia. Many of these features, especially the physical signs (e.g. moon facies and obesity), take a long time to develop and may not be seen in cases of acute onset, as for example with exogenous corticosteroid adminstration. Of course, if high-dose steroids are used for long enough, the full clinical picture will eventually emerge. Depression is the most prominent neuropsychiatric feature of Cushing's syndrome (Spillane 1951); it has been noted in between one-half (Haskett 1985; Jeffcoate et al. 1979; Kelly 1996) and three-quarters (Cohen 1980; Starkman et al. 1981) of patients with Cushing's syndrome and indeed may be the presenting feature (Kelly 1996). The depression at times may be severe, with psychotic features (Cohen 1980), which may be either mood-congruent (Anderson and McHugh 1971; Maclay and Stokes 1939) or mood-incongruent (Trethowan and Cobb 1952), with Schneiderian first rank symptoms of thought-broadcasting and thought insertion. Both suicide attempts and completed suicides may occur (Jeffcoate et al. 1979). Mania is less common than depression in Cushing's syndrome of endogenous origin (Haskett 1985; Jeffcoate et al. 1979; Kelly 1996), but the converse holds true in exogenous cases, in which mania is common (Wolkowitz et al. 1990). Anxiety of pathologic degree has been noted in about one-tenth of patients (Kelly 1996). Psychosis, although rare, can occur secondary to Gushing' syndrome. One patient evidenced delusions of persecution, auditory and visual hallucinations, and bizarre behavior, all of which cleared with adrenalectomy (Hickman etal. 1961); another experienced agitation, auditory hallucinations, and religious and grandiose delusions, which, again, cleared with adrenalectomy (Hertz et al. 1955). Delirium and confusion are rare, noted in about 1% of cases (Kelly 1996). Dementia is likewise rare, being characterized by prominent memory loss (Varney et al. 1984). In cases of exogenous origin, the frequency of neuropsychiatric symptoms varies directly with the dose of corticosteroid administered (Boston Collaborative Drug Surveillance Program 1972). The diagnosis of Cushing's syndrome of endogenous origin requires the demonstration of an elevated cortisol level in a 24 hour urine sample: given that cortisol is released from the adrenal gland in a pulsatile fashion, the plasma cortisol level is not reliable for this purpose. Once hypercortisolemia has been established, the next task is to determine its cause. The first step here is to obtain a simultaneous morning cortisol and ACTH level. If the ACTH level is low, one may assume that the source of the endogenous cortisol is within the adrenal gland itself, for example a tumor. If the ACTH level is high, one looks either to the pituitary or to an ectopic source of ACTH. The way to distinguish these two sources of ACTH is with a high-dose dexamethasone suppression test: dexamethasone is given in a dose of 8 mg orally at bedtime, and the next morning an ACTH level is drawn and a 24 hour urine collection for free cortisol is begun (Tyrell et al. 1986). If the ACTH and cortisol levels are low, one may assume that the source of the ACTH is suppressible, for example the pituitary gland; if, however, the ACTH and cortisol levels remain high, one looks to an autonomous, non-suppressible source such as an oat cell carcinoma of the lung. When an adrenal tumor is suspected, computed tomography of the abdomen is appropriate, and when a pituitary tumor is suggested, an enhanced magnetic resonance imaging (MRI) scan, focusing on the sella turcica, is required. Importantly, however, ACTH-secreting pituitary adenomas may be so small that they are missed on MRI scanning. If an ectopic ACTH source is suspected, one utilizes diagnostic measures

578 Specific disorders

appropriate to the various tumors responsible: cancer of the lung, thymus, pancreas, or thyroid, and pheochromocytoma. Course This is determined by the underlying cause. Differential diagnosis

The appearance of neuropsychiatric symptomatology in a patient receiving relatively high doses of exogenous corticosteroids immediately implicates the drug. Diagnostic uncertainty may arise, however, in cases in which the condition that prompted the treatment with corticosteroids may itself affect the central nervous system, as is the case with multiple sclerosis or systemic lupus erythematosus. In such cases, a careful history, with due attention to the existence of neuropsychiatric symptoms before steroid treatment, may resolve the issue. In other cases, it may be necessary to change the corticosteroid dose significantly: if the dose is increased and symptoms worsen (or, conversely, if the dose is decreased and symptoms lessen), the steroid is implicated. In endogenous cases of Cushing's syndrome, the appearance of a typical 'Cushingoid habitus' is highly suggestive: thus one should be alert to moon facies, buffalo hump, etc. Treatment

In exogenous cases of Cushing's syndrome, every effort should be made either to discontinue or to reduce the dose of the offending corticosteroid. In cases in which the repeat administration of corticosteroids is necessary (e.g. in relapsing-remitting multiple sclerosis), the prophylactic administration of lithium may prevent steroid-induced mania (Falk et al. 1979). In endogenous cases, treatment is determined by the underlying cause: pituitary adenomas and ectopic ACTH-producing tumors should, if possible, be removed, but when this is not possible, bilateral adrenalectomy may be performed. Postoperatively, patients must be given adequate doses of steroids, and one must watch for the development of Nelson's syndrome with hyperpigmentation. Adrenal tumors should be removed. Effective treatment is followed by a gradual resolution of the neuropsychiatric symptomatology (Kelly et al. 1983). In cases in which symptomatic treatment is required, depression may be treated with an antidepressant, mania with lithium, anxiety with an anxiolytic, and psychosis with a neurolpetic.

ADRENOCORTICAL INSUFFICIENCY Pathology and etiology gy

Adrenocortical insufficiency may be either primary or secondary: primary cases result from the destruction of the gland itself, whereas secondary cases occur in the setting of pituitary failure and a deficient stimulation of the adrenal cortex by the pituitary hormone ACTH. Primary cases are, currently, generally caused by autoimmune destruction of the adrenal cortex; importantly, this autoimmune onslaught may target not only the adrenal gland, but also other glandular structures, resulting variously in thyroiditis, diabetes mellitus, hypoparathyroidism, and pernicious anemia. Other causes of primary adrenocortical insufficiency include tuberculosis, cytomegalovirus infection (which may occur in AIDS), sarcoidosis, adrenoleukodystrophy, amyloidosis, metastatic cancer, and hemorrhagic necrosis (as may occur during septicemia or in the setting of excessive anticoagulation). Secondary cases may arise from pituitary failure of any cause, such as apoplexy, tumor, or, rarely, hypothalamic failure with a deficient secretion of CRH. Currently, however, the most

Endocrinologic disorders 579

common cause of secondary adrenocortical insufficiency is the abrupt discontinuation of chronic treatment with supraphysiologic doses of corticosteroids. Chronic steroid treatment inhibits ACTH release from the pituitary, eventually leading to atrophy of the adrenal cortex; consequently, the dose of the steroid must be tapered slowly to allow the adrenal cortex sufficient time to resume normal activity. The mechanism whereby cerebral activity is disturbed in adrenocortical insufficiency is not entirely clear. In passing, it is appropriate to say a few words about the name 'Addison's disease.' As this eponym has been used to refer not only to those cases secondary to autoimmune destruction of the gland, but also to all cases of primary adrenocortical insufficiency, it lacks definitional clarity and is thus not used further in this text. Clinical features

The onset of symptoms is determined by the underlying cause and may be either gradual, for example with the gradual destruction of the gland in primary autoimmune adrenocortical insufficiency, or acute, as occurs after hemorrhagic necrosis or the abrupt discontinuation of chronic steroid treatment. Adrenocortical insufficiency of gradual onset is marked by fatigue, apathy, listlessness, irritability, and poor concentration. The appetite is poor, and weight loss is common. Gastrointestinal complaints include nausea, vomiting, diarrhea or constipation, and abdominal pain, which may be severe. The blood pressure is low, and postural dizziness is common. Furthermore, in chronic primary adrenocortical insufficiency, hyperpigmentation often occurs secondary to the chronic stimulation of melanocytes by ACTH: this increased pigmentation is generally most prominent in sun-exposed areas, in the skin creases, and on the buccal and gingival mucosa. Depressive symptomatology (Engel and Margolin 1941; Varadaraj and Cooper 1986) has been noted, but distinguishing depression per se from the typical symptoms noted above may be merely a matter of perspective. Delirium (Engel and Margolin 1941; Fang and Jaspan 1989) may occur, and, in a small minority, psychosis with hallucinations and delusions is seen (Cleghorn 1951; McFarland 1963). Adrenocortical insufficiency of acute onset presents as a medical emergency, with delirium or stupor, vomiting, abdominal pain, and pronounced hypotension with eventual hypovolemic shock. The laboratory differentiation between primary and secondary adrenocortical insufficiency begins with a cortisol and ACTH level. In both primary and secondary cases, the cortisol level is low, or perhaps only low-normal; in primary cases, the ACTH concentration is high, and in secondary cases, it is low. In doubtful cases, a cosyntropin test may be helpful: here, 0.25 mg cosyntropin, a synthetic ACTH analogue, is injected, cortisol levels being obtained 30 minutes pre-injection, and 30 and 60 minutes post-injection. In primary cases, there is, as the gland has been destroyed, little response to the cosyntropin, whereas in secondary cases, presuming that the gland has not atrophied because of lack of stimulation, a significant rise in plasma cortisol level is seen. Other laboratory changes may be seen in cases of primary adrenocortical insufficiency in which, because of the destruction of the adrenal cortex, not only steroid production but also mineralocorticoid production is decreased or absent. In such cases, the aldosterone level is low; consequently, the sodium level is low and the potassium level high. Course This is determined by the underlying cause: importantly, chronic cases, in the face of some intercurrent stress such as surgery or infection, may undergo an exacerbation into a potentially fatal case of acute adrenocortical failure.

580 Specific disorders

Differential diagnosis

Chronic adrenocortical insufficiency may be misdiagnosed as depression from some other cause, for example dysthymia or major depression: nausea, vomiting, abdominal pain, and postural dizziness are important clues to adrenocortical insufficiency, either primary or secondary, and hyperpigmentation immediately suggests primary destruction of the gland itself. Anorexia nervosa, in its terminal stages, may produce a picture similar to that of chronic adrenocortical insufficiency, but in anorexia nervosa, one finds a history of a 'pursuit of thinness', with dieting and vigorous exercise, findings that are absent in adrenocortical insufficiency. Treatment

Glucocorticoids, such as prednisone, are the mainstay of treatment for both primary and secondary cases, and a mineralocorticoid, such as fludrocortisone, is given in primary cases. Dosages should be inceased during times of stress. Acute adrenocortical insufficiency is a medical emergency, demanding treatment in an intensive care setting.

HYPERTHYROIDISM Pathology and etiology

The clinical condition known as hyperthyroidism results from an excessive amount of circulating thyroxine (or, rarely, triiodothyronine), which may in turn arise from overactivity of the thyroid gland itself or from some other source, such as the excessive ingestion of medicinal thyroid. Overactivity of the thyroid gland is the most frequent cause of hyperthyrodisim, common causes of this including Grave's disease, toxic multinodular goiter, solitary toxic adenoma, and thyroiditis. The thyroiditides, which include Hashimoto's thyroiditis and subacute (De Quervain's) thyroiditis, are characterized by a 'leakage' of thyroxine from the inflamed thyroid and, typically, cause a hyperthyroidism that is time limited and that may, depending on the amount of inflammatory damage and scarring, be followed by hypothyroidism. Rarely, the thyroid gland may be stimulated into overproduction by an excessive release of thyroidstimulating hormone (TSH) from the pituitary gland, as may occur with a TSH-secreting adenoma (Carlson et al. 1983; Wynne et al. 1992), or by the rare condition of inherited pituitary resistance to thyroid hormone. Other rare causes of the overproduction of thyroid hormone by the thyroid gland include hydatidiform mole, choriocarcinoma of the uterus, and choriocarcinoma of the testis, all of which secrete a TSH-like substance. Of the other sources of excessive thyroid hormone, the most common is the purposeful ingestion of medicinal thyroid, as in thyrotoxicosis factitia. Rarely, the extrathyroidal production of thyroxine may occur in struma ovarii or with metastatic follicular carcinoma of the thyroid. Although it is quite clear that the central nervous system is affected in hyperthyroidism, it is not clear what the mechanism is. Clinical features

The age of onset depends on the underlying cause: in the case of Grave's disease, patients are generally in their twenties or thirties; with toxic multinodular goiter, most are elderly; and Hashimoto's thyroiditis is typically seen in the early adult or middle years. Although the onset itself is usually gradual, subacute onsets may be seen, which, in some cases, appear to be related to some antecedent stress.

Endocrinologic disorders 581

Patients are typically anxious, tense, and often irritable; some may experience emotional lability. Restlessness is common, and although most patients experience fatigue, they are often unable to keep still. There is intolerance to heat, increased sweating, tachycardia, and a rapid, fine tremor; the skin is warm and smooth. Bowel movements occur with increased frequency, and diarrhea may ensure. Although the appetite is often increased, weight loss is common and may be severe. Females may develop amenorrhea and males impotence. Lid retraction and widened palpebral fissures may give patients a wide-eyed appearance. The deep tendon reflexes are in general diffusely brisk; rarely, choreoathetosis may occur (Fidler et al. 1971; Van Uitert and Russakoff 1979), which may be paroxysmal (Fishbeck and Layzer 1979), and seizures may also be seen (Jabbari and Huott 1980). A proximal myopathy is not uncommon, and patients may have difficulty in climbing stairs or arising from a seated position. The gland itself is generally abnormal to inspection or palpation, either being diffusely enlarged or containing one or more nodules. Exceptions to this rule, however, do occur, as in some cases of thyroiditis or with a retrosternal placement of the gland. Thyroid storm represents a severe degree of hyper thy roidism and is often preceded by some significant stress, such as surgery. During thyroid storm, all of the patient's preceding symptoms undergo an exacerbation, often being joined by fever and delirium; seizures may also occur. Untreated, stupor, coma, and death may follow. Apathetic hyperthyroidism (Lahey 1931; Thomas et al. 1970) represents a peculiar presentation of hyperthyroidism and is generally only seen in the elderly. In these patients, apathy and psychomotor retardation are the rule, the only evidence of autonomic hyperactivity generally being a tachycardia. Lahey (1931) commented that such patients appear 'considerably older than they actually are ... almost apathetically senile'. Congestive heart failure and atrial fibrillation are common. Other neuropsychiatric symptoms of interest include depression, anxiety, psychosis, mania, and dementia. Depression occurs in a substantial minority of patients (Kathol and Delahunt 1986; Trzepacz et al. 1988) and may be accompanied by mood-congruent delusions (Taylor 1975) or considerable agitation (Van Uitert and Russakoff 1979). Such depression may be particularly common in apathetic hyperthyroidism (Thomas et al. 1970), and the only clue to the correct diagnosis in this variety of hyperthyroidism may be tachycardia or congestive heart failure (Arnold et al. 1974; Brenner 1978). Chronic anxiety is common (Greer et al. 1973; MacCrimmon et al. 1979) and may constitute the presenting symptomatology of hyperthyroidism (Dietch 1981); it is often accompanied by depressive symptoms (Kathol and Delahunt 1986; Trzepacz et al. 1988). Psychosis, unaccompanied by confusion, may occur during thyroid storm: one patient, in the midst of 'considerable excitement and agitation', developed delusions of persecution (Bursten 1961), while another experienced delusions of reference and persecution with auditory hallucinations (Greer and Parsons 1968). Rarely, psychosis may appear without storm. One patient developed a delusion of jealousy, and, convinced that his wife was having an affair, had her followed: when his hyperthyroidism was treated, his psychosis resolved (Hodgson et al. 1992). Mania is less common than depression in hyperthyroidism (Trzepecz et al. 1988). In one case of mixed mania, the only clues to the correct diagnosis were a tachycardia and a proximal myopathy (Ingham and Nielsen 1931). Dementia is a rare complication of hyperthyroidism. In one case, a 72-year-old patient experienced a gradually progressive dementia over 6 months, the diagnosis being suggested only by a tachycardia, a fine tremor, and a proximal myopathy (Bulens 1981). The free thyroxine index is increased in almost all cases: when the clinical diagnosis is

582 Specific disorders

hyperthyroidism but the free thyroxine index is normal, 'T3 thyrotoxicosis' should be suspected and a 'free T3' level should be obtained. Except in those very rare cases of TSHsecreting pituitary tumors, the serum TSH level is low. Course

The overall course of any particular case of hyperthyroidism is determined by the underlying cause; in some cases, for example, Hashimoto's thyroiditis, the hyperthyroidism may undergo a spontaneous remission, which may then, in some, be followed by hypothyroidism. Differential diagnosis

The depression of hyperthyroidism is suggested by the presence of weight loss in the face of an increased, rather than, as in most depressions, decreased appetite (Trzepacz et al. 1988). Especially in the elderly with depression, apathetic hyperthyroidism must be borne in mind, being suggested by the concurrent presence of congestive heart failure or atrial fibrillation. Chronic anxiety of other causes (e.g. generalized anxiety disorder) may be very difficult to distinguish from the chronic anxiety seen in hyperthyroidism, and, for that reason, a thyroid profile is probably always justified in the work-up of any patient with chronic anxiety. One clinical clue, however, is the appreciation of a warm, sweaty palm upon shaking the patient's hand, rather than the cold palm possessed by patients with generalized anxiety disorder. Mania, psychosis, and dementia may be suggested by prominent autonomic symptomatology or other signs, such as goiter, thyroid nodules, lid retraction, or proximal myopathy. Treatment

If autonomic symptoms are pronounced, propranalol, in a dose of 20-40 mg every 4-6 hours, may be given. It is critical, however, to reduce the production of thyroxine, and, to this end, an anti-thyroid medication, such as propylthiouracil is given. In severe cases, iodide, which inhibits the release of thyroxine from the gland, may be started after the propylthiouracil is in place. In some cases, radioactive iodine treatment or subtotal thyroidectomy may be required. Thyroid storm is a medical emergency, generally requiring treatment in an intensive care unit. The symptomatic treatment of depression or anxiety is generally not required, presuming that the hyperthyroidism itself may be brought fairly promptly under control. Psychosis or mania may, if necessary, be treated with neuroleptics or lorazepam.

HYPOTHYROIDISM Pathology and etiology Structures involved in thyroid hormone regulation include the hypothalamus, the anterior pituitary, and the thyroid gland itself. The hypothalamus secretes thyrotrophin-releasing hormone (TRH), which in turn stimulates the anterior pituitary to secrete thyroidstimulating hormone (TSH). TSH then acts to stimulate the thyroid gland to produce thyroxine (T4) and small amounts of triiodothyronine (T3), which are released into the systemic circulation. Hypothyroidism occurs when there is a deficiency of circulating thyroxine. Hypothyroidism is logically divided into three types - tertiary, secondary, and primary depending on which structure is at fault: the hypothalamus in tertiary hypothyrodism, the pituitary in secondary hypothyrodisim, and the thyroid gland itself in primary hypothyroidism.

Endocrinologic disorders 583

Tertiary hypothyroidism may occur when the hypothalamus is damaged by infarction, granulomatous infiltration, or tumor. In such cases, the TSH level is low, as is the circulating thyroxine level; furthermore, because of a compensatory upregulation of TRH receptors in the pituitary, the TSH response to exogenous TRH is augmented. Secondary hypothyroidism may occur with pituitary damage secondary to infarction or tumor. In these cases, the TSH level is low, as is the circulating thyroxine level, but, as might be expected, the TSH response to exogenous TRH is decreased. Primary hypothyroidism, which is by far the most common cause of hypothyroidism, may occur secondary to an abrupt discontinuation of long-term treatment with thyroid hormone or to damage of the thyroid gland itself. With long-term treatment with thyroid hormone, the thyroid gland, lacking stimulation, undergoes a variable degree of involution, and if the exogenous thyroid hormone is abruptly stopped, there is insufficient time for the gland to respond to the circulating TSH. Common causes of damage to the gland include Hashimoto's thyroiditis, radioactive iodine treatment or thyroidectomy, iodione deficiency, and various medications, of which lithium is perhaps the most important. Lithium induces primary hypothyroidism in a significant minority of patients (Lindstedt et al. 1977), this being especially likely to happen in cases in which anti-thyroid antibodies are present before treatment is begun (Calabrese et al. 1985). As noted below, both the peripheral and the central nervous system may be damaged during hypothyroidism. In the case of the peripheral nervous system, it appears that a myxedematous infiltration of the peripheral nerves, or their entrapment by surrounding structures (which themselves may have undergone myxedematous enlargement), is the mechanism responsible. In the case of the central nervous system, however, the mechanism is not clear. Clinical features

In general, the onset of hypothyroidism is gradual, the age of onset being determined by the underlying cause. In the case of Hashimoto's thyroiditis, females are much more commonly affected than males, the onset usually being in the late thirties or the forties. In the case of thyroidectomy, symptoms may begin to appear in as little as a few weeks. In general, patients become slowed down and apathetic. Minutes may pass before patients respond to questions, and even simple activities, such as fastening a button, may take up to a minute. Patients often experience fatigue, sluggishness, drowsiness, and a certain fogging of memory (Nickel and Frame 1958). Other neuropsychiatric symptoms include depression, psychosis, and dementia. Depression may be severe and may be accompanied by hallucinations and delusions (Whybrow et al. 1969). Psychosis occurring secondary to hypothyroidism has traditionally been referred to as 'myxedema madness' (Asher 1949) and is often characterized by delusions of persecution and reference, as well as auditory hallucinations (Crowley 1940; de Fine Olivarius and Roder 1970; Karnosh and Stout 1935; Logothetis 1963; Reed and Bland 1977). One case of myxedema madness (Ziegler 1930) deserves to be quoted at length, as it illustrates the sometimes exquisite nature of the dependence of the psychosis on the level of circulating thyroid hormone. The patient had undergone radiation treatment for hyperthyroidism 3 years earlier and had subsequently done well with an appropriate dosage of supplemental thyroid hormone. At the age of 48, however, she became non-compliant and soon thereafter: she began to feel that her husband was paying attention to another woman and that he was trying to do away with her by means of gas or the electric chair. During a game at a party in her own home during the holidays in 1928, she refused to sit in a chair designated for her, thinking it might be a plot to kill her. She also felt that her husband was trying to poison her and refused to take desiccated thyroid gland at home on account of such a belief. On several occasions

584 Specific disorders subsequently, when desiccated thyroid was administered in sufficient quantity, at the repeated and urgent request of her physician, the delusions entirely disappeared and she felt so much better that she concluded that it was foolish to be taking medicine and discontinued taking it. On such occasions, the psychosis would slowly return in the same form as before.

Dementia (Akelaitis 1936; de Fine Olivarius and Roder 1970; Uyematsu 1920) may present with failing memory, followed by deficits in calculation and orientation: in some cases, the dementia may be accompanied by delusions of persecution and auditory hallucinations. In addition to the neuropsychiatric symptomatology noted above, most patients develop a characteristic appearance: myxedematous infiltration of the skin creates a doughy, non-pitting edema most evident on the face, on the dorsa of the hands and feet, and in the supraclavicular fossae. The tongue may undergo myxedematous infiltration, with macroglossia and possibly obstructive sleep apnea. In addition, patients typically experience thinning and loss of their hair, increased sensitivity to cold, and constipation. Bradycardia and hypotension may occur, and some patients may become hypothermic. There may be a pericardial effusion with cardiomegaly on chest X-ray. Men may become impotent, and women may experience menorrhagia. Peripheral nervous system involvement may manifest with a polyneuropathy or with a carpal or, less commonly, tarsal tunnel syndrome. Ataxia may occur (Jellinek and Kelly 1960). Another common sign is the 'hung-up' ankle jerk, wherein the relaxation phase of this deep tendon reflex is markedly prolonged. In primary, secondary, and tertiary hypothyroidism, the free thyroxine index is decreased. Primary hypothyroidism is distinguished from secondary and tertiary cases by an elevated TSH level, in contrast to the decreased TSH level seen in the secondary and tertiary cases. Secondary and tertiary cases may, in turn, be distinguished from each other by the response to the TRH stimulation test: in secondary cases, the response is blunted, whereas in tertiary cases, it is augmented. Whenever primary hypothyroidism is diagnosed, and the cause (such as thyroidectomy) is not clear, it is important to check for Hashimoto's thyroiditis by obtaining anti-microsomal and anti-thyroglobulin antibody titers. Furthermore, as the same autoimmune process that attacks the thyroid may also involve the parathyroids, adrenals, pancreas, and gastric mucosa, it is imperative, in patients with Hashimoto's thyroiditis, to check for hypoparathyroidism, adrenal insufficiency, diabetes mellitus, and vitamin B12 deficiency. The EEC typically shows diffuse slowing and low amplitude waves. Course The course depends on the cause of the hypothyroidism. In the case of primary hypothyroidism secondary to Hashimotos's thyroiditis, for example, the autoimmune attack on the gland may, in some cases, be temporary and relatively mild, leaving behind a variable amount of functioning thyroid tissue that may, in some cases, be sufficient to keep patients euthyroid. In more severe cases, however, patients will be left with a greater or lesser degree of hypothyroidism. Differential diagnosis

The distinctive, puffy myxedematous appearance is a valuable diagnostic clue and helps to distinguish the depression, psychosis, and dementia of hypothyroidism from that of other causes of these syndromes. Treatment

Treatment with thyroxine is aimed at bringing the free thyroxine index up into its normal range and, in cases of primary hypothyroidism, bringing the TSH level back down to within its normal limits. Prior to initiating treatment, it is critical to correct any accompanying adrenal insufficiency in order to avoid an Addisonian crisis of acute adrenal failure.

Endocrinologic disorders 585

Both the initiating dose of the thyroxine and the rapidity with which it is titrated upwards depend on the age and general condition of the patient, in particular the patient's cardiac status. Otherwise healthy young adults may be started on 0.05 mg daily, the dose being increased in weekly increments of 0.025 mg. In the elderly, or those with cardiac disease, however, the initial dose should be lower, perhaps 0.0125 or 0.025 mg, increases being made only once every 4-8 weeks in increments of only 0.0125-0.025 mg. There is clearly a wide range here, and clinical judgment is required: in some cases, for example with stuporous patients, the urgency of the clinical situation may demand very rapid replacement. In general, the eventual full replacement dose ranges from 0.075 to 0.1 mg for females and from 0.1 to O.lSmg for males. Treatment should be continued unless the underlying cause has been corrected, which means, in most cases, lifelong treatment. If the decision is made to discontinue treatment, this should be done incrementally in order to allow time for the endogenous production of thyroxine to 'gear up'. A recent study suggested that the use of a combination of thyroxine and triiodothyronine may provide for a greater improvement in mood and cognition than the use of thyroxine alone (Bunevicius et al. 1999), and this option may be pursued by reducing the dose of thyroxine by 0.050 mg and adding triiodothyronine in a dose of 0.0125 mg. Sedative drugs should be avoided as they may worsen the overall clinical status; indeed, phenothiazines have been noted to cause coma in patients with myxedema (Mitchell et al. 1959).

REFERENCES AkelaitisAJE. Psychiatric aspects of myxedema. J NervMentDis 1936; 83:22-36. Anderson AE, McHugh PR. Oat cell carcinoma with hypercortisolemia presenting to a psychiatric hospital as a suicide attempt. J Nerv Merit Dis 1971; 152:427-31. Arnold BM, Casal G, Higgins HP. Apathetic thyrotoxicosis. CMAJ1974; 111:957-8. Asher R. Myxoedematous madness. BMJ1949; 2:555-62. Boston Collaborative Drug Surveillance Program. Acute adverse reactions to prednisone in relation to dosage. Clin Pharmacol TherW72; 13:694-8. Brenner I. Apathetic hyperthyroidism.y Clin Psychiatry 1978; 39:479-80. Bulens C. Neurologic complications of hyperthyroidism: remission of spastic paralysis, dementia, and optic neuropathy. Arch NeurolWSl; 38:669-70. Bunevicius R, KazanaviciusG, Zalinkevicius R et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999; 340:424-9. Bursten B. Psychosis associated with thyrotoxicosis. Arch Gen Psychiatry 1961; 4:267-73. CalabreseJR, GulledgeAD, Hahn Ketal. Autoimmune thyroiditis in manic-depressive patients treated with lithium. Am J Psychiatry 1985; 142:1318-21. Carlson HE, LinfootJA, Burnstein GD et al. Hyperthyroidism and acromegaly due to a TSH and GHsecreting tumor: lack of hormonal response to bromocriptine. AmJ Med 1983; 74:915-23. Cleghorn RA. Adrenal cortical insufficiency: psychological and neurological observations. CMAJ 1951;

65:449-54. Cohen SI. Cushing's syndrome: a psychiatric study of 29 patients. BrJ Psychiatry 1980; 136:120—4. Crowley RM. Psychoses with myxedema. Am J Psychiatry 1940; 96:1105-16. de Fine Olivarius B, Roder E. Reversible psychosis and dementia in myxedema. Acta PsychiatrScand 1970; 46:1-13. Dietch JT. Diagnosis of organic anxiety disorders. Psychosomatic* 1981; 22:661-9.

586 Specific disorders Engel GL, Margolin SG. Neuropsychiatric disturbances in Addison's disease and the role of impaired carbohydrate metabolism in the production of abnormal cerebral function. Arch Neural Psychiatry 1941; 45:881^. Falk WE, Mahnke MD, Poskanzer MD. Lithium prophylaxis of corticotropin-induced psychosis. JAMA 1979; 241:1011-12. Fang VBS, Jaspan JB. Delirium and neuromuscular symptoms in an elderly man with isolated corticotroph deficiency syndrome completely reversed with glucocorticoid replacement. 7 Clin Endocrinol Metab 1989; 69:1073-7. Fidler SM, O'Rourke RA, Buschbaum HW. Choreoathetosis as a manifestation of thyrotoxicosis. Neurology 1971; 21:55-7. Fishbeck KH, Layzer RB. Paroxysmal choreoathetosis associated with thyrotoxicosis. Ann Neural 1979;

6:453^. GreerS, Parsons V. Schizophrenia-like psychosis in thyroid crisis. BrJ Psychiatry 1968; 114:1357-62. GreerS, Ramsay I, Bagley C. Neurotoxicand thyrotoxic anxiety: clinical, psychological and physiological measurements. BrJ Psychiatry 1973; 122:549-54. Haskett RF. Diagnostic categorization of psychiatric disturbance in Cushing's syndrome. Am J Psychiatry 1985;142:911-16. Hertz PE, Nadas E, Wojtkowiki H. Case report: Cushing's syndrome and its management. AmJ Psychiatry 1955; 112:144-5. HickmanJW, Atkinson RP, Flint LDetal. Transient schizophrenic reaction as a major symptom of Cushing's syndrome. N EnglJ Med 1961; 264:797-800. Hodgson RE, Murray D, Woods MR. Othello's syndrome and hyperthyroidism. J Nerv Ment Dis 1992;

180:663-4. Ingham SD, Nielsen JM. Thyroid psychosis: difficulties in diagnosis.) Nerv Ment Dis 1931; 74:271-7. Jabbari B, Huott AD. Seizures in thyrotoxicosis. Epilepsia 1980; 21:91-6. JeffcoateWJ.SilverstoneJT, EdwardsCRWefo/. Psychiatric manifestations of Cushing's syndrome: response to lowering of plasma cortisol. QJ Med 1979; 191:465-72. Jellinek EH, Kelly RE. Cerebellar syndrome in myxoedema. Lancet 1960; 2:225-7. Karnosh LJ, Stout RE. Psychoses of myxedema./Amy Psychiatry 1935; 91:1263-74. Kathol RG, Delahunt JW. The relationship of anxiety and depression to symptoms of hyperthyroidism using operational criteria. Gen Hasp Psychiatry 1986; 8:23-8. Kelly WF. Psychiatric aspects of Cushing's syndrome. QJ Med 1996; 89:543-51. Kelly WF, Checkley SA, Bender DA et al. Cushing's syndrome and depression - a prospective study of 26 patients. BrJ Psychiatry 1983; 142:16-19. Lahey FH. Non-activated (apathetic) type of hyperthyroidism. N EnglJ Med 1931; 204:747-8. Lindstedt G, Nilsson L, Walinder J et al. On the prevalence, diagnosis and management of lithiuminduced hypothyroidism in psychiatric patients. BrJ Psychiatry 1977; 130:452-8. Logothetis J. Psychotic behavior as the initial indicator of adult myxedema. y Nerv Ment Dis 1963; 136:561-8. Maclay WS, Stokes AB. Mental disorder in Cushing's syndrome. J Neurol Neurosurg Psychiatry 1939; 1:110-18. MacCrimmon DJ, Wallace JE, Goldberg WM et al. Emotional disturbances and cognitive deficits in hyperthyroidism. Psychosom Med 1979; 41:331-40. McFarland HR. Addison's disease and related psychoses. Compr Psychiatry 1963; 4:90-5. Mitchell JRA, Surridge DHC, Willison RG. Hypothermia after chlorpromazine in myxoedematous psychosis. BMJ1959; 2:932-3. Nickel SN, Frame B. Neurologic manifestations of myxedema. Neurology 1958; 8:511-17. Orth DN. Cushing's syndrome. N EnglJ M«/1995; 332:791-803. Reed K, Bland RC. Masked 'myxedema madness'. Acta PsychiatrSeand 1977; 56:421-6. SpillaneJD. Nervous and mental disorders in Cushing's syndrome. Brain 1951; 74:72-94.

Endocrinologic disorders 587 Starkman MN, Schteingart DE, Schork MA. Depressed mood and other psychiatric manifestations of Cushing's syndrome: relationship to hormone levels. Psychosom Med 1981; 43:3-18. Taylor JW. Depression in thyrotoxicosis. Am J Psychiatry 1975; 132:552-3. Thomas FB, Mazzaferri EL, Skillman TG. Apathetic thyrotoxicosis: a distinctive clinical and laboratory entity. Ann Intern Med 1970; 72:679-85. Trethowan WH, Cobb S. Neuropsychiatric aspects of Cushing's syndrome. Arch Neurol Psychiatry 1952; 67:283-309. TrzepaczP, McCue M, Klein I etal. A psychiatric and neuropsychological study of patients with untreated Grave's disease. Gen Hasp Psychiatry 1988; 10:49-55. Tyrell JB, FindlingJW, Aron EDC etal. An overnight high-dose dexamethazone suppression test for rapid differential diagnosis of Cushing's syndrome. Ann Intern Med 1986; 104:180-6. Uyematsu S. A case of myxedematous psychosis. Arch Neurol Psychiatry 1920; 3:252-76. Van Uitert RL, Russakoff LM. Hyperthyroid chorea mimicking psychiatric disease. AmJ Psychiatry 1979; 136:1208-10. Varadaraj R, Cooper AJ. Addison's disease presenting with psychiatric features. Am J Psychiatry 1986; 143:553-4. Varney NR, Alexander B, MaclndoeJH. Reversible steroid dementia in patients without steroid psychosis. AmJ Psychiatry 1984; 141:369-72. Whybrow PC, Prange AJ, Treadway CR. Mental changes affecting thyroid gland dysfunction: a reappraisal using objective psychological measurement. Arch Gen Psychiatry 1969; 20:48-63. WolkowitzOM, Rubinow D, Doran \Retal. Prednisone effects on neurochemistryand behavior. Arch Gen Psychiatry 1990; 47:963-8. Wynne AG, Gharib H, Scheithauer BW et al. Hyperthyroidism due to inappropriate secretion of thyrotropin in 10 patients. AmJ Med 1992; 92:15-24. Ziegler LH. Psychosis associated with myxedema.y Neurol Psychopathol1930; 11:20-7.

17 Immune-related disorders

Multiple sclerosis

588

Hashimoto's encephalopathy

598

Systemic lupus erythematosus Limbic encephalitis Sarcoidosis

592 595 596

Sydenham's chorea Chorea gravidarum

599 601

MULTIPLE SCLEROSIS Pathology and etiology The characteristic lesion of multiple sclerosis is a plaque, which ranges in size from a millimeter or less to several centimeters in diameter. Such plaques, although characteristically limited to the white matter, may also be found in the gray matter and are preferentially found in a periventricular location or at the corticomedullary junction (Brownell and Hughes 1962). Active plaques are characterized by perivenular inflammation and demyelinization, with a relative sparing of axons: this axonal sparing is, however, certainly not complete, and in severe cases, axons may be totally lost (Greenfield and King 1936). With subsidence of the inflammatory response and resolution of the edema, a chronic plaque, composed of a glial scar and residual axons, is left behind; in severe cases, however, after profound inflammation, all that may be left behind is a cyst. Multiple sclerosis is, as noted below, generally a relapsing and more or less remitting disease, these relapses and remissions correlate with plaque activity. During active inflammation, clinical relapses or exacerbations are generally seen, whereas with subsidence of the inflammation, there is a more or less substantial remission of symptoms, any persisting symptomatology being accounted for by the presence of chronic plaques. Although the etiology of multiple sclerosis has not as yet been fully clarified, it appears that it represents an autoimmune response, in genetically susceptible individuals, which has in turn been initiated by some environmental event in childhood or adolescence, such as a viral infection. Multiple sclerosis, although found at all latitudes, is more common in temperate areas. Furthermore, if individuals remain in a high-risk area past the age of 15 and then move to a low-risk area, they 'carry' the increased risk with them (Dean 1967), a fact that supports the importance of environmental exposure at a critical age. Genetic influences are suggested by an elevated concordance rate among monozygotic twins compared with dizygotic twins or siblings (Ebers et al. 1986; Mumford et al. 1994), and by the association of multiple sclerosis with certain HLA haplotypes.

Immune-related disorders 589

As noted below, some of the neuropsychiatric features seen in multiple sclerosis include euphoria, depression, and dementia, and it has been possible to correlate the occurrence of these features with the location or number of plaques. Euphoria is correlated with substantial cerebral involvement and is more severe in those with cerebral rather than spinal cord involvement (Rabins et al. 1986). Depression may occur on a reactive basis in any debilitating disease, and multiple sclerosis is no exception. Certain facts, however, suggest strongly that depression in multiple sclerosis may also be a direct result of plaque formation. Patients with multiple sclerosis are more likely to experience depression than are normal controls (Fassbender et al. 1998) or those with comparably disabling neurologic diseases that generally spare the cerebrum, such as amyotrophic lateral sclerosis (Schiffer and Babigian 1984; Whitlock and Siskind 1980). Furthermore, in contrast to what one might expect if the depression were reactive, there is little or no correlation between the occurrence of depression and the extent of the patient's disability (Moller et al. 1994), and, regardless of the degree of overall disability, patients are more likely to experience depression when the plaques are in the cerebrum rather than the cerebellum or spinal cord (Rabins et al. 1986; Schiffer et al. 1983). Finally, a correlation has been noted between depression and the presence of plaques in the region of the left arcuate fasciculus (Pujol et al. 1997). The dementia is correlated not only with the burden of plaques in the periventricular area (Franklin et al. 1988; Ron et al. 1991), but also with atrophy of the corpus callosum (Huber et al. 1987). Such callosal atrophy occurs primarily because of axonal loss (Barnard and Triggs 1974) and may reflect overall disease activity in the hemispheric white matter. Clinical features

Although cases may occur in childhood or the middle or later years, this is unusual, most patients fall ill in their twenties or thirties. The onset itself ranges from acute to gradual, and the severity of the first symptoms likewise exhibits a wide range, from evanescent and mild to disabling. The nature of the symptomatology of multiple sclerosis depends on the location of the offending plaques. Common signs and symptoms include retrobulbar neuritis, spastic weakness, numbness or parasthesiae, and cerebellar symptoms such as ataxia, nystagmus, dysarthria, or scanning speech. Other symptoms include diplopia, Lhermitte's sign, painful, tic-like dysesthesiae, trigeminal neuralgia, and incontinence. Uncommon symptoms encompass seizures, vertigo, hemifacial spasm, and facial myokymia; aphasia, although rare, may also occur (Achiron et al. 1992; Devere et al. 2000; Olmos-Lau et al. 1977). Another uncommon, but relatively specific, sign is internuclear ophthalmoplegia: although this may occur with other disease processes that affect the medial longitudinal fasciculus, such other diseases are very unusual in the early adult years when most patients with multiple sclerosis fall ill. Other symptoms include sexual dysfunction, such as a loss of libido, impotence, decreased vaginal lubrication, etc. (Hulter and Lundberg 1995). Finally, a very common symptom is fatigue, which can be severe. Important neuropsychiatric symptoms include euphoria, depression, dementia, emotional incontinence, and psychosis. A 'bland' euphoria may be found in anywhere from a quarter (Surridge 1969) to the vast majority of patients (Cottrell and Wilson 1926): one of S.A.K. Wilson's (1955) patients, 'bedridden and unable to stand, remarked, "you will not believe me when I say I feel thundering well".' This bland euphoria is typically not accompanied by hyperactivity or pressure of speech and is often seen in concert with some degree of intellectual impairment (Surridge 1969). In addition to this bland euphoria, definite manic episodes, although unusual, may also occur (Joffe et al. 1987; Schiffer et al. 1986); indeed, of all the reasons for psychiatric admission for patients with multiple sclerosis, mania is the most common (Pine et al. 1995).

590 Specific disorders

Depression is seen in perhaps one-quarter of patients (Surridge 1969) and, as noted earlier, may be either reactive or exist as a direct result of plaques in the cerebrum. Dementia, of variable severity, ranging from mild, almost subclinical impairment to debilitating, is eventually seen in the majority of patients (Franklin et al. 1989; Surridge 1969). In rare cases, dementia may constitute the sole, or predominant, presenting feature of multiple sclerosis (Bergin 1957; Hotopf et al. 1994; Koenig 1968; Young et al. 1976). In one case, for example, the only symptom in addition to the dementia was optic neuritis (JennekensSchinkel and Sanders 1986), and in two others, it was unsteady gait (Mendez and Frey 1992). In one, very rare, case, a gradually progresssive dementia was the only clinical evidence of multiple sclerosis (Fontaine et al. 1994). Emotional incontinence, with uncontrollable laughter or crying in the absence of a corresponding affect, is seen in about one-tenth of patients (Feinstein et al. 1997; Surridge 1969). Psychosis may rarely dominate the clinical picture (Mathews 1979; Parker 1956), and in one very rare case, multiple sclerosis presented with a psychosis characterized by social withdrawal, 'mystic' visual hallucinations and various delusions. The patient eventually became demented, but the examination was otherwise unremarkable, as were evoked potentials and cerebrospinal fluid studies: the finding of periventricular areas of high signal intensity on magnetic resonance imaging (MRI) eventually led to a biopsy that disclosed active plaque formation (Fontaine et al. 1994). MRI reveals lesions in almost all patients with clinically definite multiple sclerosis (Ormerod et al. 1987), serial MRI scanning often disclosing lesions that, although 'active', are clinically 'silent' (Thompson et al. 1992; Willoughby et al. 1989). MRI scanning should always be carried out with gadolinium enhancement: whereas both chronic and active plaques are seen on unenhanced scans, only the active plaques 'light up' with enhancement, as illustrated in Fig. 17.1. As noted below, the diagnosis of multiple sclerosis is generally based on the demonstration of lesions disseminated in both time and space. Before the advent of MRI, evoked potentials were often used, in addition to clinical evidence, to detect evidence of lesions in various sensory pathways (i.e. visual evoked potentials, brainstem auditory evoked potentials and

Image Not Available

Figure 17.1 In the T2-weighted magnetic resonance imaging scan on the left, there are multiple areas of increased signal intensity corresponding to both chronic and active plaques; in the T1-weighted scan with gadolinium enhancement on the right, however, only the active lesions enhance. (Reproduced from Graham and Lantos 1996.)

Immune-related disorders 591

somatosensory evoked potentials). MRI has revolutionized the diagnosis of multiple sclerosis and has basically rendered evoked potential testing obsolete for this purpose. The cerebrospinal fluid is abnormal in most cases of active plaque formation. Although a mild mononuclear pleocytosis, an elevated total protein level or myelin basic protein may be found, evidence of autoimmune activity is both more specific and more common. The IgG level is elevated in perhaps 90% (Hershey and Trotter 1979), oligoclonal bands being found in a similar percentage (Miller et al. 1983). The IgG index, which specifically indicates intrathecal IgG production, may also be determined but requires a simultaneous serum protein electrophoresis. Course

In the majority of cases, multiple sclerosis pursues a relapsing and remitting course characterized by recurrent episodes. Both the duration of the individual episodes and the intervals between them show considerable variation: the duration of episodes may range from days to months, or longer, and the interval may range from months to decades. At the end of any episode, there may or may not be a complete clearing of symptoms. Residual symptoms, related to the presence of chronic, inactive plaques, are not uncommon, and, with repeated episodes, the residuals tend to accumulate, in both severity and number. In contrast to this relapsing-remitting course, a small minority of cases, perhaps 10%, will be characterized by a 'primary progressive' course wherein the symptoms gradually worsen and accumulate without any remission. Such a progressive, unrelenting worsening may also supervene upon an initially relapsing-remitting course, and in such cases one speaks of a 'secondary progressive' type of course. Finally, in a small minority, there may be only one episode of illness during the patient's life. Symptoms of multiple sclerosis may undergo transient exacerbation with stress, infection, or temperature elevation, as may occur with a hot bath, fever, or exercise. These exacerbations do not reflect inflammatory plaque activity, but rather impaired conduction through partially damaged axons, and thus should not be interpreted as relapses. Interestingly, this kind of transient exacerbation was, in the past, used as a diagnostic test for multiple sclerosis: in such a 'hot bath' test, the patient was immersed in hot water and observed for the emergence of signs or symptoms. Predicting the patient's overall course at the onset of the illness is not possible: in general, years must pass before the physician can get an idea of the pattern of the patient's condition. Multiple sclerosis, with optimal management, is compatible with a long-term survival of 35 or more years. Those who do succumb usually die of complications such as pneumonia, decubitus ulcers or urinary tract infection. Importantly, the relapsing and remitting course of multiple sclerosis applies not only to such straightforward symptoms as paresis, but also to such neuropsychiatric findings as depression (Dalos et al. 1983) and dementia (Franklin et al. 1989). Differential diagnosis

Relapsing-remitting multiple sclerosis may be confused with systemic lupus erythematosus (SLE), polyarteritis nodosa, Behcet's syndrome, neurosyphilis, and sarcoidosis. Primary progressive multiple sclerosis may resemble vitamin B12 deficiency, adrenoleukodystrophy and progressive multifocal leukoencephalopathy; acute primary cases may also call to mind post-infectious encephalomyelitis. An important differential point is that multiple sclerosis is confined to the central nervous system, whereas most of these other disorders also involve other organ systems, such as the muscles and joints in SLE. The diagnosis of multiple sclerosis is, in general, reserved until one can demonstrate a dissemination of lesions in space and time. Thus, one looks not only for evidence of plaques

592 Specific disorders

in different parts of the neuraxis, but also for a temporal pattern consistent with the sequential appearance of new active plaques or a sequential reactivation of one or more established plaques. In the past, such evidence of dissemination in space and time had to be based on the history of a sequential appearance and more or less complete remission of signs and symptoms referable to different parts of the nervous system. The advent of MRI has simplified the diagnostic task as it may reveal evidence consistent with inactive plaques in a patient undergoing an exacerbation consistent with the location of an active plaque on gadoliniumenhanced scanning. Although, as noted above, mood changes are not uncommon in multiple sclerosis, their appearance in a patient under-going treatment with steroids should always suggest a steroidinduced disorder, as discussed in Chapter 16 with regard to Cushing's syndrome. Furthermore, patients treated with interferon-beta Ib may also develop severe depression as a side-effect (Neilley et al. 1996). Treatment

Exacerbations of moderate or greater severity may be treated with steroids: such treatment, although not improving the overall course of the illness, may nevertheless shorten the duration of the individual episode. Methylprednisolone, 250 mg intravenously every 6 hours may be given for 3 days, followed by oral prednisone at a dose of 1 mg/kg/day for 2 weeks and then a rapid tapering off over 3 or 4 days. Recent work (Sellebjerg et al. 1998) has suggested that oral methylprednisolone may also be effective. Should steroid-induced mania occur, treatment with lithium may be considered, both acutely and preventively, as noted in Chapter 16. Several treatments are now available for relapsing-remitting multiple sclerosis, any one of which may reduce the frequency of episodes. These include interferon-beta Ib (European Study Group 1998), interferon-beta la (Li et al. 1999; PRISMS 1998; Rudick et al. 1997), and copolymer 1 (Johnson et al. 1998). The benefits of these treatments are modest at best, and, in the case of the interferons, neutralizing antibodies occur in a significant minority within the first year. In cases characterized by a malignant course, consideration may be given to immunosuppression, for example with azathioprine, cyclophosphamide, or methotrexate. Spasticity may respond to baclofen. Bladder dysfunction is often treatable, but special studies are appropriate first in order to tailor the treatment to the kind of dysfunction present. Depression may be treated symptomatically with antidepressants such as citalopram. Euphoria of the 'bland' variety often does not require treatment, but should mania occur, treatment with a mood stabilizer such as lithium, carbamazepine, or divalproex may be considered. The general treatment of dementia is discussed in Chapter 5 and that of psychosis in Chapter 7. Fatigue may be relieved by amantadine in a dosage of lOOmg bid (Rosenberg and Appenzeller 1988): although pemoline may also be effective, its potential hepatotoxicity makes it a second choice.

SYSTEMIC LUPUS ERYTHEMATOSUS Pathology and etiology

SLE is an autoimmune disease characterized by the presence of multiple different antibodies directed at multiple different targets, including, importantly, vascular endothelium, neurons, and phospholipids. The anti-phospholipid antibodies, which include the 'lupus anticoagulant', may be particularly important as they predispose to infarction.

Immune-related disorders 593

Autopsy studies have revealed multiple small infarctions located in the cerebral cortex and subcortical white matter; large infarctions, corresponding to the distribution of large cerebral vessels, are relatively uncommon (Devinsky et al. 1988; Hanley et al. 1992; Johnson and Richardson 1968; Mitsias and Levine 1994; Weiner and Allen 1991). The pathogenesis of the infarctions is not clear. Although, in a minority, true vasculitic changes may be found, it appears in most cases that a non-inflammatory vasculopathy, characterized by fibrinoid necrosis, is at fault (Ellis and Verity 1979; Hanley et al. 1992; Johnson and Richardson 1968; Malamud and Saver 1954). Additional mechanisms (Devinsky et al. 1988; Mitsias and Levine 1994; Tsokos et al. 1986) include cardiogenic emboli and a thrombotic microangiopathy characteristic of thrombotic thrombocytopenic purpura (Devinsky et al 1988). Although multiple infarctions undoubtedly play a major role in the production of central nervous system symptomatology in SLE, the fact that, in some autopsies of patients with indisputable central nervous system involvement, no infarctions are seen (O'Connor and Musher 1966; Tsokos et al. 1986) indicates that other factors are also at work. Immune complexes have been found in the choroid plexus (Atkins et al. 1972), and it is possible that direct neuronal damge by anti-neuronal antibodies may contribute to the overall symptomatology (Kelly and Denburg 1987) . Clinical features

Although symptoms referable to the central nervous system may constitute the presentation of SLE, this is uncommon, neuropsychiatric symptomatology in most cases occurring in the setting of either constitutional symptoms or symptoms referable to other organ systems, such as the musculoskeletal system, skin, heart, lungs, or kidneys (Johnson and Richardson 1968). Musculoskeletal symptomatology is very common and includes arthalgia, myalagia, and a non-deforming polyarthritis. Cutaneous manifestations include photosensitivity, rashes (especially a malar rash), and alopecia. Cardiac symptomatology incorporates pericarditis and Libman-Sacks endocarditis. Pulmonary involvement may cause pleurisy, which may or may not be accompanied by pleural effusion. Renal involvement may manifest with proteinuria and cellular casts. Constitutional symptoms are almost universal, encompassing fatigue, malaise, weight loss, and fever. Neuropsychiatric symptomatology includes (Feinglass et al. 1976; Johnson and Richardson 1968) depression, mania, psychosis, delirium or dementia, headache, seizures, focal signs, chorea, parkinsonism, and a peripheral neuropathy. Although these findings may occur independently, patients will usually have a mixture (Devinsky et al. 1988). Depression, in some cases accompanied by hallucinations or delusions, has been found commonly by some (Ganz et al. 1972; Miguel et al. 1994), but not all (Guze 1967; Hugo et al. 1996), authors. Mania, although reported (Johnson and Richardson 1968), is far less common than depression. Psychosis is relatively uncommon (Guze 1967; Lim et al. 1988; Miguel et al. 1994), and although it is often accompanied by changes suggestive of delirium, such as confusion or disorientation (Lief and Silverman 1960; O'Connor and Musher 1966), it can appear in 'pure' form: indeed, in one case, psychosis constituted the sole presenting symptomatology of SLE, with the abrupt onset of delusions and auditory hallucinations (Agius et al. 1997). The psychosis may rarely be characterized by catatonic symptomatology (Lanham et al. 1985; Mac and Pardo 1983). Delirium may occur (Devinsky et al. 1988; Hugo et al. 1996; Miguel et al. 1994) and is often accompanied by hallucinations, either visual or auditory (O'Connor and Musher 1966). Dementia may also be seen (Kirk et al. 1991; Johnson and Richardson 1968; MacNeil et al. 1976; Robin et al. 1995) but is relatively uncommon (Devinsky et al. 1988).

594 Specific disorders

Headache is common and may resemble that seen in migraine (Lim et al. 1988). Seizures are relatively common (Devinsky et al. 1988) and may be either partial or grand mal. Focal deficits may also occur (Devisky et al. 1988), hemiplegia, in one case, constituting the presentation of SLE (Bennett et al. 1972). Chorea may occur and has constituted the presentation of SLE (Donaldson and Espiner 1971; Fermaglich et al. 1973). Parkinsonism is a rare symptom of SLE and was, in one case, accompanied by a dementia (Dennis et al. 1992). A peripheral neuropathy may occur and may be either of the polyneuropathy (McCombe et al. 1987) or mononeuritis multiplex (Hughes et al. 1982) variety. The erythrocyte sedimentation rate (ESR) is generally elevated. Although the presence of antinuclear antibody (ANA) is not specific, it is highly sensitive, being positive in up to 95% of cases (Venables 1993). Other antibodies, albeit less sensitive, are more specific: these include anti-native (double-stranded) DNA, anti-ribonucleoprotein (anti-RNP), and anti-Sm (anti-Smith), the last of which is virturally specific for SLE. Another antibody that may be sought is anti-ribosomal P: although some reports have suggested a close relationship between psychosis and the presence of anti-ribosomal P protein antibodies (Agius et al. 1997; Bonfa et al. 1987; Nojima et al. 1992), others have not agreed, its status thus being unclear. EEC abnormalities are seen in only a minority of patients (Sibley et al. 1992) and may consist of generalized or focal slowing. MRI scanning may disclose gadolinium-enhancing focal areas of increased signal intensity (Miller et al. 1992), but there may not be a good correlation between the presence of such abnormalities and clinical neuropsychiatric symptomatology (Hugo et al. 1996). The cerebrospinal fluid (Johnson and Richardson 1968; McClean et al. 1995; West et al. 1995) may be normal or may show an elevated protein level, a mild lymphocytic pleocytosis, oligoclonal bands, an elevated IgG index, and, uncommonly, antineuronal antibodies. Course Overall, the course is characterized by waxing and waning symptoms; full remissions are unusual and generally not permanent. Although SLE is in general compatible with long-term survival, the appearance of central nervous system (Rubin et al. 1985) or renal involvement is an ominous sign. Differential diagnosis

Certain drugs, notably procainamide and hydralazine, may induce a lupus-like syndrome. Importantly, however, drug-induced lupus rarely causes central nervous system damage. Antihistone antibodies, although common in drug-induced lupus, are relatively rare in naturally occurring SLE and may help to confirm the diagnosis. Cushing's syndrome secondary to steroid treatment, as discussed in Chapter 16, may cause considerable neuropsychiatric symptomatology, including mania, depression, or psychosis. Immunosuppressed patients may fall prey to opportunistic central nervous system infections (Futrell et al. 1992). Renal failure, not uncommon in SLE, may be followed by a uremic encephalopathy or, with severe hypertension, an hypertensive encephalopathy (Wong et al. 1991). In general, the occurrence of neuropsychiatric symptomatology in the setting of constitutional symptoms, arthralgia, myalgia, or rashes should raise the suspicion of SLE. Treatment

The occurrence of central nervous system involvement in SLE is generally an indication for treatment with steroids, such as prednisone; in severe cases, concurrent immunosuppression,

Immune-related disorders 595

for example with cyclophosphamide, may be required (Neuwelt et al. 1995). The steroid dose must be kept as low as possible, and frequent monitoring is required. In cases in which depression, mania, psychosis, delirium, or dementia persists despite treatment, symptomatic treatment is justified. Of the antidepressants, a selective serotonin reuptake inhibitor is probably best, and if a mood stabilizer is required, consideration may be given to divalproex. Neuroleptics, such as risperidone or olanzepine, may be required for psychosis; the symptomatic treatment of dementia and delerium is discussed in Chapter 5.

LIMBIC ENCEPHALITIS Pathology and etiology

Limbic encephalitis is one of the paraneoplastic syndromes, being distinguished pathologically by a predilection for the limbic system, and clinically by prominent neuropsychiatric symptomatology, especially amnesia and delirium. Within the limbic system, especially the hippocampus and amygdala, there is neuronal drop-out, perivascular lymphocytic infiltration, and microglial nodules. In all likelihood, the pathological changes occur secondary to an autoimmune assault triggered by an antigen found on a distant tumor. In most cases, the responsible tumor is oat cell carcinoma of the lung (Alamowitch et al. 1997); other tumors include cancer of the thymus (Antoine et al. 1995; Ingenito et al. 1990), testicle (Ahern et al. 1994; Burton et al. 1988; Voltz et al. 1999), ovary (Nokura et al. 1997), and colon (Tsukamoto et al. 1993). Clinical features

The onset of symptoms is subacute, spanning days or weeks (Alamowitch et al. 1997), and, in most cases, the limbic encephalitis will be apparent before the underlying tumor is detected (Alamowitch et al. 1997; Dalmau et al. 1992), in some cases preceding detection of the tumor by years (Ahern et al. 1994). The most common presentation is with delirium marked by prominent anterograde and retrograde amnesia, often accompanied by seizures and personality change or hallucinations (Alamowitch et al. 1997; Antoine et al. 1995; Bakheit et al. 1990; Gultekin et al. 2000). Other, less common, presentations include depression (Brierly et al. 1960; Corsellis et al. 1968; Glaser and Pincus 1969), isolated amnesia (Nokura et al. 1997; Sutton etal. 2000), seizures (Corsellis et al. 1968), somnolence (Byrne et al. 1997), and catatonia (with 'confusion, stereotypy, echolalia, stiffness, verbigeration, formal thought disorder, and negativism' [Tandon et al. 1988]). In addition to clinical features arising from inflammation of the limbic system, perhaps a half of patients will have paraneoplastic symptoms referable to other parts of the nervous system, such as ataxia or a neuropathy (Alamowitch et al. 1997). The serum may or may not contain antineuronal antibodies; specifically, small cell carcinoma of the lung is associated with anti-Hu antibody (Anderson et al. 1988; Alamowitch et al. 1997) and testicular cancer (Voltz et al. 1999) and breast cancer (Sutton et al. 2000) with anti-Ma2. T2-weighted MRI scanning may reveal increased signal intensity in the medial portion of the temporal lobe or may be within normal limits (Alamowitch et al. 1997; Bakheit et al. 1990; Gultekin et al. 2000; Tsukamoto et al. 1993). The cerebrospinal fluid may be normal or may show a mild lymphocytic pleocytosis, increased protein level, oligoclonal bands, and, at times, antineuronal antibodies (Alamowitch et al. 1997; Gultekin et al. 2000).

596 Specific disorders

Course In most cases, there is a progressive deterioration with the development of dementia; death generally occurs within a few months (Alamowitch et al. 1997). Differential diagnosis

Other disorders that may accompany cancer must be considered; these include metastases, endocrinologically mediated disorders (e.g. Cushing's syndrome, hypercalcemia, hypoglycemia, and hyponatremia), and opportunistic infections, such as cytomegalovirus encephalitis or progressive multifocal leukoencephalopathy. Those who are undergoing chemotherapy are subject to a large range of neuropsychiatric side-effects. Treatment

Although the detection and treatment of the underlying tumor are imperative, improvement following successful treatment of the tumor, although reported (Burton et al. 1988), is not the rule. Rarely, spontaneous improvement may occur despite the persistence of the tumor (Byrne et al. 1997). The overall treatment of dementia and delirium are discussed in Chapter 5.

SARCOIDOSIS Pathology and etiology The characteristic lesion of sarcoidosis is a non-caseating granuloma, and such granulomas may be found in almost any organ system, including the central nervous system. Within the central nervous system (Delaney 1977; Herring and Urich 1969; Jefferson 1957), the basal leptomeninges and the walls and floor of the third ventricle are often involved, and there may be granulomatous infiltration into the hypothalamus and down the pituitary stalk to invade the posterior pituitary, and, less commonly, the anterior pituitary. An adhesive arachnoiditis often occurs, with an entrapment of various cranial nerves and obstructive hydrocephalus. Rarely, relatively large granulomas may appear, which may mimic gliomas (Powers and Miller 1981). Although granulomatous involvement of the posterior and, less commonly, anterior pituitary may occur, most of the endocrinologic derangement seen in sarcoidosis in fact arises from hypothalamic damage, with a disruption of the normal production of releasing and inhibiting factors (Winnacker et al. 1968). Although it seems clear that the granulomas arise secondary to an enhanced helper T-cell response directed at the host tissue, it is not as yet clear what prompts this immunologic onslaught. Clinical features

Although onsets in adolescence or the middle or later years may occur, most patients fall ill in their twenties or thirties. The onset itself is often gradual, many cases indeed being discovered serendipitously when a chest X-Ray reveals pulmonary findings characteristic of the disease. Sarcoidosis is a systemic disease, affecting multiple organs, most prominently the lung. Nervous system involvement in sarcoidosis occurs in only a small minority, perhaps 5%, of patients (Delaney 1977; Sharma and Sharma 1991; Stern et al. 1985). Lung involvement occurs in over 90% of patients and may cause dyspnea or cough or be asymptomatic; characteristic X-ray findings include either bilateral hilar lymphadenopathy or a diffuse bilateral reticulonodular infiltrate. Other common manifestations include arthropathy, peripheral lymphadenopathy, uveitis, and various skin lesions, including erythema nodosum and lupus pernio. Hepatic involvement is also common but generally manifests only as hepatomegaly or

Immune-related disorders 597

an elevated alkaline phosphatase level. Uncommon manifestations include parotid gland enlargement and cardiac involvement. Central nervous system involvement may manifest with cranial nerve palsies, personality change, delirium, dementia, endocrinologic derangements, various focal findings appropriate to the location of granulomas, and seizures (Oksanen 1986). Cranial nerve palsies are common and may affect multiple cranial nerves (Symonds 1958). Of all the cranial nerves, however, the seventh is most commonly involved (Scott 1993; Sharma and Sharma 1991), with unilateral or bilateral facial palsy: when the palsy is bilateral, the respective sides are often involved sequentially rather than simultaneously. Personality change may manifest with a frontal lobe syndrome (Hook 1954). Other, more diffuse changes may reflect hypothalamic involvement and include somnolence and hyperphagia. Delirium may appear (Douglas and Maloney 1973), accompanied, in one case by meningism (Silverstein and Siltzbach 1965) and in another by dysarthria and hyperreflexia (Wiederholdt and Siekers 1965). Dementia may occur (Camp and Frierson 1962; Cordingly et al. 1981; Miller et al. 1988; Sanson etal. 1996) and generally reflects widespread parenchymal involvement; in some cases, the dementia may be accompanied by delusions and auditory hallucinations (Thompson and Checkley 1981). Endocrinologic derangements include diabetes insipidus, hyperprolactinemia, hypogonadism, hypothyroidism and adrenocortical insufficiency. Peripheral nervous system involvement may occur with a mononeuritis multiplex or, less commonly, a polyneuropathy. The serum angiotensin-converting enzyme level is elevated in the majority during active disease; hypercalcemia is seen in a small minority, and in a still smaller minority, hypercalcuria may occur, possibly resulting in nephrocalcinosis. The MRI scan may reveal areas of increased signal intensity on T2-weighted scans, corresponding to granulomas; furthermore, active granulomas may show enhancement with gadolinium. A cerebrospinal fluid assay may reveal a lymphocytic pleocytosis, elevated protein level, decreased glucose concentration, and, in a minority, an elevated IgG level and oligoclonal bands (Kinnman and Link 1984; McLean et al. 1995). Definitive diagnosis generally requires the biopsy demonstration of typical granulomatous tissue, the lung being the favored site. Course The course is variable: those with an acute onset may eventually experience a spontaneous remission and stay in remission indefinitely; by contrast, those with a gradual or insidious onset are more likely to experience a relapsing and remitting or chronic course. Although central nervous system involvement is considered to be a grave sign, the overall course is not necessarily poor, up to half of patients experiencing recovery (Pentland et al. 1985). Differential diagnosis

In the evaluation of dementia or a personality change, the suspicion of sarcoidosis is often raised by evidence of other organ involvement, especially the lung and the skin. Additional granulomatous disorders that might be confused with sarcoidosis include tuberculosis and the mycoses. Meningovascular neurosyphilis may also produce a similar picture. Treatment

Although it may, in some asymptomatic cases, be prudent simply to observe for a spontaneous remission and thus spare the patient steroid-induced side-effects, central nervous system

598 Specific disorders

involvement is generally an indication for treatment with prednisone. Prednisone is given in a dose of approximately 1 mg/kg/day for 4-6 weeks; assuming that there has been a substantial improvement, the dose may then be gradually tapered over the following 8-12 weeks. Should the symptoms recur, repeat courses of treatment may be required. In those with neurologic involvement who are intolerant or non-responsive to steroids, there is some evidence for the effectiveness of chloroquine and hydroxycholoroquine (Sharma 1998). The general treatment of dementia is discussed in Chapter 5.

HASHIMOTO'S ENCEPHALOPATHY Pathology and etiology Hashimoto's disease is an autoimmune disorder wherein the thyroid and, less frequently, the cerebrum are subject to an immunologic onslaught: when the thyroid is principally involved, one speaks of Hashimoto's thyroiditis, and when the cerebrum bears the brunt of the attack, the phrase 'Hashimoto's encephalopathy' is used. In Hashimoto's thyroiditis, there is a lymphocytic infiltration of the thyroid gland, with a varying degree of fibrosis. The pathology of Hashimoto's encephalopathy is not as clear, both vasculitic (Shein et al. 1986) and encephalitic (Henderson et al. 1987) processes are suspected. Importantly, in patients with Hashimotos's encephalopathy, involvement of the thyroid gland may be quite minimal. Clinical features

Hashimoto's encephalopathy may manifest with delirium or, rarely, dementia or psychosis. The delirium of Hashimoto's encephalopathy presents subacutely, typically being accompanied by myoclonus. Seizures, either partial or grand mal, may occur, and some patients may experience stroke-like episodes with focal findings such as aphasia (Bohnen et al. 1997; Ghika-Schmid et al 1996; Henchey et al. 1995; Shaw et al. 1991; Thrush and Boddie 1974). Anti-thyroid antibodies (either antimicrosomal or anti-thyroglobulin antibodies) are present, and the thyroid profile may range from completely normal to an elevated thyroidstimulating hormone (TSH) alone or an elevated TSH plus a decreased free thyroxine index (Henchey et al. 1995; Shaw et al. 1991). The electroencephalogram is generally abnormal and may show generalized slowing, focal slowing, or triphasic waves; an MRI scan may be normal or show mild cortical atrophy, subcortical infarcts (Henchey et al. 1995), or a diffuse leukoencephalopathy (Bohnen et al. 1997). The dementia of Hashimoto's encephalopathy is generally accompanied by myoclonus, but the appearance of this sign may be delayed for months (Forchetti et al. 1997; Hernandez Echebarria et a/. 2000). There is also a case report (Cohen et al. 1996) of a relapsing and remitting psychosis accompanied by myoclonus. Course The delirium of Hashimotos's encephalopathy is typically remitting and relapsing (Henchey et al. 1995; Shaw et al. 1991), as is the psychosis (Cohen et al. 1996). Differential diagnosis

Various metabolic deliria may be accompanied by myoclonus, as discussed in Chapter 5; these include hyponatremia, hypomagnesemia, uremic encephalopathy, hepatic encephalopathy, and respiratory failure with hypercarbia. Of the dementias that may be accompanied by myoclonus, as outlined in Chapter 5, the most important to distinguish is Creutzfeldt-Jakob

Immune-related disorders 599

disease. As noted in Chapter 15, the finding of a 14-3-3 protein in the cerebrospinal fluid is a sensitive and generally specific test for Creutzfeldt-Jakob disease, but such a finding may also appear in Hashimoto's encephalopathy (Hernandez Echebarria etal. 2000), and as the clinical presentations of the two disorders may be very similar, testing for anti-thyroid antibodies is essential. Treatment

Steroids, such as prednisone, typically relieve the delirium (Barker et al. 1996; Bohnen et al. 1997; Henchey et al. 1995) and have also been shown to be effective in psychosis (Cohen et al. 1996).

SYDENHAM'S CHOREA Pathology and etiology

Sydenham's chorea is one of the major manifestations of rheumatic fever (Anonymous 1992; Bland and Jones 1951,1952) and occurs secondary to an autoimmune attack directed towards the central nervous system, which is in turn triggered by a preceding group A beta-hemolytic streptococcal pharyngitis. Antineuronal antibodies may be detected in the serum (Husby et al. 1976, 1979; Kiessling et al. 1993; Swede et al. 1991) and are directed at a variety of structures, including pial arteries and parenchymal capillaries (Kingston and Glynn 1971), fibrous astrocytes found in the white matter (Kingston and Glynn 1976), and the caudate and subthalamic nuclei, as well as, to a lesser extent, the cerebrtal cortex, certain brainstem nuclei (Husby et al. 1976), and the ependyma (Kingston and Glynn 1976). Autopsy studies of patients dying during acute Sydenham's chorea have revealed two kinds of damage: vasculitic and encephalitic. Vasculitic changes (Buchanen 1941; Buchanen et al. 1942; Poynton and Holmes 1906; Van Bogaert and Bertrand 1932; Winkelman and Eckel 1932) affecting small vessels have been noted in the cerebral cortex and basal ganglia; encephalitic changes (Bradley 1904; Buchanen et al. 1942; Colony and Malamud 1956; Coombs 1912; Gordon and Norman 1934; Greenfield and Wolfsohn 1922; Ziegler 1927), with neuronophagia, have been found throughout the cerebral cortex and the basal ganglia, without any corresponding vasculitis. Autopsies of patients who died from unrelated causes long after recovering from the chorea have revealed evidence of old endarteritis (Benda 1949) and, in other cases, patchy gliosis and neuronal loss (Lange et al. 1976). Clinical features

The diagnosis of rheumatic fever is made according to the 'Jones criteria' (Anonymous 1992), which demand the presence of: 1, laboratory evidence of recent pharyngeal infection with group A beta-hemolytic streptococci; and, 2, either two 'major' criteria or, alternatively, one 'major criterion' plus two 'minor' criteria. Major criteria include carditis, migratory polyarthritis, Sydenham's chorea, subcutaneous nodules, and erythema marginatum. Minor criteria include fever, arthralgia, a prolonged PR interval on electrocardiography, and either an elevated ESR or an elevated C-reactive protein level. Acceptable laboratory evidence of recent infection includes a positive throat culture or an elevated anti-streptolysin O, anti-DNAase B, or anti-hyaluronidase titer. Although most of the clinical manifestations of rheumatic fever appear about 10 days after the pharyngitis (Taranta 1959), Sydenham's chorea is an exception in that the latency between the pharyngitis and the onset of the chorea is, on average, of the order of 2 or 3 months (Taranta 1959; Taranta and Stollerman 1956). Consequently, it is not unusual to see a case of 'pure' chorea (Feinstein and Spagnuola 1962; Taranta and Stollerman 1956) wherein the other

600 Specific disorders

manifestations of rheumatic fever have already undergone a full remission, leaving the chorea as the sole remaining manifestation of the disease. Sydenham's chorea generally presents subacutely, over several weeks (McCullogh 1938; Nausieda et al. 1980), in children aged 10-15 years (Thayer 1906); later onsets, however, are certainly possible, as late, indeed, as the ninth decade (Goyal and Williams 1967). The onset itself is typically characterized by restlessness, fidgetiness, irritability, and emotional lability; choreiform movements, if present, are mild and evanescent (Diefendorf 1912; Gerstley et al. 1935). When the chorea does settle in, it is usually generalized but most prominent in the limbs and face; one may occasionally see hemichorea (Abt and Levinson 1916; Nausieda et al. 1980), the chorea being confined to one side only; alternatively there may be, rather than chorea, a profound weakness, known as 'chorea mollis'. Neuropsychiatric features are very common during Sydenham's chorea and include obsessions and compulsions, tics, delirium, mania or, less commonly, depression, and psychosis. In addition to these features, seizures (Ch'ien et al. 1978; Nausieda et al. 1980), either complex partial or grand mal, may be seen in a small minority, along with various signs, such as a positive Babinski reflex (Ganji et al. 1988). Obsessions and compulsions have been noted in Sydenham's chorea (Swedo et al. 1989), one prospective study reporting them in 82% of patients (Swedo et al. 1993). The course of these obsessions and compulsions is of interest: although they tend to peak in severity along with the worsening of the chorea and to remit before the chorea does, they in fact generally make their appearance before the chorea sets in (Swedo et al. 1993); importantly, it appears that, in cases of rheumatic fever, it is only those patients who develop Sydenham's chorea who develop obsessions and compulsions; those without chorea remain free of them (Asbahr et al. 1998). Tics, similar to those seen in Tourette's syndrome, may also occur during Sydenham's chorea (Creak and Guttmann 1935). Delirium is seen in fewer than 10% of patients (Nausieda et al. 1980) but may be profound (Diefendorf 1912). Mania is a rare manifestation of Sydenham's chorea (Abt and Levinson 1916; MacKenzie 1887) and may present as either pure mania or mixed mania (Bradley 1904; Ebaugh 1926; Gay 1889; Lewis and Minski 1935; Powell 1889; Reaser 1940; Shaskan 1938) or, rarely, be coupled with a depression (Abt and Levinson 1916; Haskell 1914). Depression is even rarer than mania in Sydenham's chorea (Abt and Levinson 1916). Psychosis, with hallucinations and delusions, may occur in a small minority (Hammes 1922) and may symptomatically resemble the psychosis seen in schizophrenia (Leys 1946; Putzel 1879). On average, an episode of Sydenham's chorea gradually remits after 4-6 months, the range being a week up to 2 years (Aron et al. 1965; Lessof 1958; Swedo et al. 1993). Although there may be some very mild residual chorea, especially evident when the patient is under stress (Lessof 1958; Swedo et al. 1993) recovery is, in most cases, essentially complete; the mortality rate is less than 1% (Abt and Levinson 1916; Bussiere and Rhea 1926; Lessof and Bywaters 1956).

Course The overall course of Sydenham's chorea parallels that of the underlying rheumatic fever, and if there are recurrences of rheumatic fever, the patient is at risk for another episode of Sydenham's chorea. Indeed, it appears that, with repeated bouts of rheumatic fever the likelihood that future episodes of rheumatic fever will be characterized by Sydenham's chorea increases (Aron et al. 1965; Bland and Jones 1951; Jones and Bland 1935). Although most recurrences of Sydenham's chorea occur after about 2 years (Nausieda et al. 1980;

Immune-related disorders 601

Schwartzman et al. 1948), in some cases a very long interval may separate individual episodes, in one case up to 52 years (Gibb and Lees 1989). In addition to relapses of chorea consequent upon recurrrent group A beta-hemolytic pharyngitis, patients who have recovered from Sydenham's chorea are also at risk for other sequelae. Females with a history of Sydenham's chorea may develop chorea gravidarum during pregnancy (Beresford and Graham 1950; Wilson and Preece 1932a) and are also at increased risk for developing chorea during treatment with oral contraceptives (Nausieda et al. 1983). There is also suggestive evidence that some cases of obsessive-compulsive disorder (Swedo 1994; Swedo et al. 1994), Tourette's syndrome (Kerbeshian et al. 1990; Swedo et al. 1994), and even schizophrenia (Wilcox and Nasrallah 1986, 1988) occur as sequelae. Differential diagnosis

The differential diagnosis of chorea is discussed at length in Chapter 3; in a young person, consideration should always be given to Wilson's disease. Treatment

Patients should, if possible, be treated in a calm, quiet environment. Treatment for streptococcal pharyngitis, consisting of penicillin VK, 500 mg bid for 10 days, should be provided regardless of whether there is any evidence of current infection; erythromycin may be given to those allergic to penicillin. The chorea itself may be treated with divalproex, in doses of 15-20mg/kg/day (Daoud et al. 1990; Dhanaraj et al. 1985); in resistant cases, haloperidol, in a low dose of 1-4 mg/day (Axley 1981; Shenker et al. 1973), may be added to the divalproex or used as single-agent treatment. Corticosteroids have been used, but it is not clear whether they are superior to divalproex or haloperidol. Theoretically, given the autoimmune basis of Sydenham's chorea, corticosteroids would be preferable as they would constitute etiologic rather than mere symptomatic treatment, but, again, their superiority has not been demonstrated. Prednisolone, in a dose of 2 mg/kg/day has been used (Kalra and Ghai 1980). The general treatment of delirium is described in Chapter 5. It is not clear whether moodstabilizing agents (such as divalproex) or antidepressants are useful should mania or depression occur. If antidepressants are used, those which might provoke arrythmias are best avoided. Psychosis may be treated with a neuroleptic, such as haloperidol, or perhaps risperidone or olanzepine. Upon recovery, it is prudent to institute prophylactic treatment with benzathine penicillin, 1.2 million units every 3 weeks, to prevent future bouts of rheumatic fever. In cases in which benzathine penicillin is not acceptable, penicillin VK 250 mg bid may be substituted.

CHOREA GRAVIDARUM Pathology and etiology

Chorea gravidarum (Latin for 'chorea of pregnant women') probably represents a reapperance of the chorea of Sydenham's chorea under the influence of the hormonal changes of pregnancy. Although chorea gravidarum is a rare event, occurring in between 0.001% (Wilson and Preece 1932a) and 0.003% (Beresford and Graham 1950) of pregnancies, the risk rises over a thousand-fold in women with a history of Sydenham's chorea, from 4% (Beresford and Graham 1950) to an astounding 26% (Wilson and Preece 1932a) of patients. Given the essentially benign nature of this illness, autopsy studies are rare: one case revealed neuronal loss and astrocytosis in the striatum (Ichikawa et al. 1980).

602 Specific disorders

Clinical features

The onset of the chorea is usually during the first half of pregnancy, with a resolution of symptoms either towards the end of the third trimester or during the puerperium. In addition to the chorea, anwhere from 7% (Wilson and Preece 1932b) to 26% (Thiele 1935) of females with chorea gravidarum may also experience hallucinations or delusions. Mania or delirium may also occur (Wilson and Preece 1932b). The chorea itself is generally fairly well tolerated and does not usually present a risk to the fetus. Course

Recurrence with subsequent pregnancies is common (Wilson and Preece 1932a). Differential diagnosis

Although chorea occurring during pregnancy is generally caused by chorea gravidarum, other causes must be considered, as discussed in Chapter 3. Treatment

Although termination of the pregnancy is followed by a resolution of the symptoms, chorea gravidarum, given its essentially benign nature, is generally not considered to be an indication for abortion. Medications such as neuroleptics or divalproex should be used only if the symptoms are severe, and should then be reserved for as late as possible during the pregnancy in order to reduce the teratogenic potential with respect to the fetus. Furthermore, when deciding between neuroleptics and divalproex, neuroleptics (e.g. haloperidol) are probably safer for the fetus.

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Immune-related disorders 609 Surridge D. An investigation into some psychiatric aspects of multiple sclerosis. BrJ Psychiatry 1969; 115:749-64. Sutton I, Winer J, Rowlands Detal. Limbic encephalitis and antibodies to Ma2: a paraneoplastic presentation of breast cancer. 7 Neurol Neurosurg Psychiatry 2000; 69:266-8. Swedo SE. Sydenham's chorea: a model for childhood autoimmune neuropsychiatric disorders. JAMA 1994;272:1788-91. Swedo SE, RapoportJL, CheslowDLefo/. High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea. Am J Psychiatry 1989; 146:246-9. Swedo SE, Kilpatrick K, Schapiro M etal. Antineuronal antibodies (AnA) in Sydenham's chorea (SC) and obsessive-compulsive disorder (QCD). Pediatr Res 1991; 29:364A Swedo SE, Leonard HL, Schapiro MB etal. Sydenham's chorea: physical and psychological symptoms of St Vitus dance. Pediatrics 1993; 91:706-13. Swedo SE, Leonard HL, Kiessling LS. Speculations on antineuronal antibody-mediated neuropsychiatric disorders of childhood. Pediatrics 1994; 93:323-6. Symonds C. Recurrent multiple cranial nerve palsies.) Neurol Neurosurg Psychiatry 1958; 21:95-100. Tandon R, Walden M, Falcon S. Catatonia as a manifestation of paraneoplastic encephalopathy.y Clin Psychiatry 1988; 49:121-2. Taranta A. Relation of isolated recurrences of Sydenham's chorea to preceding streptococcal infection. N EnglJ M«H959; 260:1204-10. Taranta A, Stollerman GH. Relationship of Sydenham's chorea to infection with Group A streptococcus. AmJMed 1956; 20:170-5. Thayer WS. An analysis of 808 cases of chorea with special reference to cardiovascular manifestations. JAMA 1906; 47:1352^. Thiele R. Clinical observations on chorea of pregnancy. Arch Neurol Psychiatry 1935; 39:1077. Thompson AJ, Miller D, Youl Betal. Serial gadolinium-enhanced MRI in relapsing/remitting multiple sclerosis of varying disease duration. Neurology 1992; 42:60-3. Thompson C, Checkley S. Short term memory deficit in a patient with cerebral sarcoidosis. BrJ Psychiatry 1981; 139:160-1. Thrush DC, Boddie HG. Episodic encephalopathy associated with thyroid disorders.) Neurol Neurosurg Psychiatry 1974; 37:697-700. Tsokos GC, Tsokos M, LeRiche NGH etal. A clinical and pathological study of cerebrovascular disease in patients with systemic lupus erythematosus.Semin Arthritis Rheum 1986; 16:70-8. Tsukamoto T, Mochizuki R, Mochizuki H et al. Paraneoplastic cerebellar degeneration and limbic encephalitis in a patient with adenocarcinoma of the colon. J Neurol Neurosurg Psychiatry 1993; 56:713-16. Van Bogaert L, Bertrand I. Hemorrhagic affection of cortico-neostriatal site revealed clinically by acute and fatal chorea.7 Neurol Psychopathology 1932; 13:1-13. Venables PJW. Diagnosis and treatment of systemic lupus erythematosus. BMJ1993; 307:663-6. Voltz R, Gultekin H, Rosenfeld MR et al. A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N EnglJ Med 1999; 340:1788-95. Weiner DK, Allen NB. Large vessel vasculitis of the central nervous system in systemic lupus erythematosus: report and review of the literature../ Rheumatoid!; 18:748-51. West SG, Emlen W, Wener MH et al. Neuropsychiatric lupus erythematosus: a 10-year prospective study on the value of diagnostic tests. AmJ Med 1995; 99:153-63. WhitlockFA, Siskind MM. Depression as a major symptom of multiple sc\eros\s.J Neurol Neurosurg Psychiatry 1980; 43:861-5. Wiederholdt WC, Siekert RG. Neurological manifestations of sarcoidosis. Neurology 1965; 15:1147-54. WilcoxJA, Nasrallah HA. Sydenham's chorea and psychosis. Neuropsychobiology 1986; 15:13-14. WilcoxJA, Nasrallah HA. Sydenham's chorea and psychopathology. Neuropsychobiology 1988; 19:6-8.

610 Specific disorders Willoughby EW, Growchowski E, Li DKBetal. Serial magnetic resonance scanning in multiple sclerosis. A second retrospective study in relapsing patients. Ann Neural 1989; 25:43-9. Wilson P, Preece M. Chorea gravidarum. Arch Intern Afe/1932a; 49:471-533. Wilson P, Preece M. Chorea gravidarum./4/t/j Intern /lto/1932b; 49:671-97. Winnacker JL, Becker KL, Katz S. Endocrine aspects of sarcoidosis. N EnglJ Med 1968; 278:483-92. Winkelman NW, Eckel JL. The brain in acute rheumatic fever. Arch Neurol Psychiatry 1932; 28:844-70. Wong KL, Woo EKW, Yu YL etal. Neurologic manifestations of systemic lupus erythematosus. QJ Med 1991;81:857-70. Young AC, Saunders J, Ponsford JR. Mental change as an early feature of multiple sclerosis. J Neurol Neurosurg Psychiatry 1976; 39:1008-13. Ziegler LH. The neuropathological findings in a case of acute Sydenham's chorea.; Nerv Ment Dis 1927; 65:273-81.

18 Sleep disorders Somnambulism

611

REM sleep behavior disorder Nightmare disorder

612 614

Sleep apnea Pickwickian syndrome Kleine-Levin syndrome

Pavor nocturnus

614

Restless legs syndrome

Jactatio nocturna capitis Enuresis Narcolepsy

615

Nocturnal myoclonus

616 617

Painful legs and moving toes

620 622 622 624 625 626

SOMNAMBULISM Pathology and etiology Somnambulism (sleepwalking disorder) appears to be hereditary: the disorder is clearly familial (Kales et al. 1980a), and the concordance rate among twins is higher for monozygotic than dizygotic twins (Bakwin 1970; Hublin et al. 1997). Clinical features The onset of somnambulism is generally in childhood, betweeen the ages of 4 and 12, an onset in the adult years being very uncommon (Hublin et al. 1997). Sleepwalking arises from non-rapid eye movement (NREM) sleep, generally in the first third of the night (Kales and Kales 1974; Kavey et al. 1990). Typically (Kales et al. 1966), the patient sits up in bed: the eyes may be closed or open, and if open, the patient may look about the room with a blank stare. Some patients engage merely in some simple, stereotyped behavior such as fumbling with pyjamas or sheets, but most will get out of bed and begin to walk. Although some patients may bump into furniture or walls, many are able to navigate in such a way as to avoid obstacles. Some patients may simply wander, whereas others may attempt to climb out windows or go down stairs. Rarely, patients may engage in complex activities, such as eating, writing, or even driving a car. Patients may be mute or mumble incoherently; some may respond to requests with a few simple words. Attempts to redirect patients or lead them back to bed may or may not be met with success; some patients actively resist any attempts to interfere with them. If a patient is awakened, there is no dream recall. Most episodes end spontaneously within 15-30 minutes; some patients may make it back to bed, whereas others will lie down on a couch, or even the floor, and resume sleep. Upon awakening the next day, patients are either amnestic for the episode or, at most, have only a patchy recall of the events that transpired.

612 Specific disorders

Childhood onset cases are generally not associated with other forms of psychopathology; by contrast, some (Kales et al. 1980b; Sours et al. 1963), but not all (Parkes 1986), authors have found an association between adult onset cases and various forms of psychopathology, such as personality disorders or schizophrenia. Polysomnography reveals the onset of sleepwalking in stage III or IV sleep; there are no associated epileptiform events. Course

Childhood onset cases tend to remit by the age of 15 (Kales et al. 1980b), the persistence of somnambulism into the adult years being seen in only a small minority (Hublin et al. 1997). The frequency of episodes may increase with febrile illnesses, alcohol use, or sleep disruption, as may be seen with shift work (Driver and Shapiro 1993). Differential diagnosis

Isolated episodes of sleepwalking may be seen in up to 15% of normal children (Kales et al. 1987) and are not considered pathologic. Sleepwalking may occur as a side-effect of various medications, most notably combinations of lithium with neuroleptics, such as haloperidol, chlorpromazine, or thioridazine (Charney etal. 1979). REM sleep behavior disorder differs from somnambulism in that it arises from REM sleep and is associated with dreaming. Complex partial seizures may mimic episodes of sleepwalking (Pedley and Guilleminault 1977). In most cases, however, complex partial seizures may also be seen during wakefulness, and patients may have a history of other seizure types, such as grand mal seizures. In doubtful cases, polysomnography may reveal ictal activity during the episode. Treatment

Patients and parents should be reassured regarding the essentially benign nature of somnambulism, and common sense precautions, such as locking windows or doors and removing potentially dangerous objects, should be taken to reduce the risk of any injury. In severe cases, diazepam may prevent episodes (Kales et al. 1987); it can be given in a bedtime dose of 5-20 mg.

REM SLEEP BEHAVIOR DISORDER Pathology and etiology

REM sleep behavior disorder is a syndrome that may occur either on an idiopathic basis or in association with various other disorders. The fact that all cases are associated with a loss of atonia during REM sleep strongly suggests that lesions responsible are to be found in the brainstem. Of the disorders associated with REM sleep behavior disorder, the most common are parkinsonian conditions such as multiple system atrophy (Plazzi et al. 1997), diffuse Lewy body disease, and Parkinson's disease (Olson et al. 2000). Interestingly, REM sleep behavior disorder may be the presenting feature of certain parkinsonian conditions, preceding the movement disorder by many years (Schenck et al. 1996b), from 3-5 years in the case of Parkinson's disease (Tan et al. 1996) to up to 17 years in one case of diffuse Lewy body disease (Turner et al. 1997). Indeed, in one autopsied case, REM sleep behavior disorder was the only sign of diffuse Lewy body disease (Uchiyama et al. 1995). Other disorders associated with REM sleep behavior disorder include Alzheimer's disease (Schenck et al. 1996a), subarachnoid hemorrhage, and the Guillian-Barre syndrome (Schenck et al. 1986).

Sleep disorders 613 Clinical features

The illness most commonly presents in middle-aged or older males, episodes occurring with a frequency of between several per night and one every 3 months (Olson et al. 2000). Schenck and colleagues have comprehensively described this condition (Schenck and Mahowald 1990; Schenck et al 1986, 1987, 1989). Episodes typically arise out of REM sleep, in the middle or latter third of the night. Patients, only dimly aware of their actual surroundings, begin literally to 'act out' their part in a dream, the bedroom serving as the 'stage'. Violent or potentially dangerous behavior is not at all uncommon, and patients may suffer bruises, lacerations, or even fractures; in one case (Dyken et al. 1995), a subdural hematoma was sustained. Patients are generally difficult to awaken, and if they do come to full consciousness, they may relate a vivid dream that, in retrospect, clearly provides the context for their behavior. Some examples wil help to convey a sense of the remarkable phenomenology of this disorder. In one case (Schenck et al. 1986), a 67-year-old man described his dream and what he found when he woke up: I was a halfback playing football, and after the quarterback received the ball from the center he lateraled it sideways to me and I'm supposed to go around end and cut back over tackle and this is very vivid - as I cut back over tackle there is this big 280-pound tackle waiting, so I, according to football rules, was to give him my shoulder and bounce him out of the way, supposedly, and when I came to I was standing in front of our dresser and I had knocked lamps, mirrors, and everything off the dresser, hit my head against the wall and my knee against the dresser.

Damage to property is not the only danger here: during one incident (Schenck et al. 1989), the patient 'was awakened one night by his wife's yelling as he was choking her. He was dreaming of breaking the neck of a deer he had just knocked down'; during another (Culebras and Moore 1989), a 70-year-old man 'dreamed that an alligator was trying to get into his car, and in order to prevent it, he held the animal's snout with great force ...' After finally being awakened by his wife's calling him, he found himself 'strongly grabbing her arm'. There may be an association between REM sleep behavior disorder and narcolepsy, one study finding REM sleep behavior disorder in 12% of patients with narcolepsy (Schenck and Mahowald 1992). Polysomnography may reveal a typical event arising from REM sleep. Course This condition probably has a chronic course. Differential diagnosis

Somnambulism differs from REM sleep behavior disorder in that it arises from NREM sleep and is not associated with dreaming. Complex partial seizures are suggested by the occurrence of more obvious seizure activity, such as partial seizures during the day or grand mal seizures at any time. Furthermore, patients in a complex partial seizure cannot be 'awakened', and, after the seizure ends and the patient has been awakened, there is no dream recall. In doubtful cases, polysomnography may reveal ictal activity during the event. Treatment

Clonazepam is very effective (Schenck and Mahowald 1990) and may be given in a dose of 0.5-2mg at bedtime; carbamazepine (Bamford 1993) may constitute an alternative. Pending the suppression of the episodes, it is prudent to make the bedroom as safe as possible.

614 Specific disorders

NIGHTMARE DISORDER Pathology and etiology The etiology of nightmare disorder (incubus) is unknown. Clinical features

The onset of the disorder is generally in childhood. Nightmares (Kales et al. 1980c) arise from REM sleep, generally in the latter two-thirds of the night. During the nightmare, most patients lie quite still; as the fear crescendoes, however, many will awake with a cry of fear and remain apprehensive, tremulous, diaphoretic, and tachycardic for a few minutes. Dream recall is usually quite vivid, and many patients will have trouble falling back to sleep. Various factors may increase the intensity or frequency of nightmares, including febrile illnesses, fatigue, emotional stress, and watching or reading frightening material before bedtime. Course

Nightmares recur one or more times weekly. In most cases, remission occurs by adolescence, but in a small minority, frequent nightmares may perist into adulthood. Differential diagnosis Occasional nightmares are normal. Pavor nocturnus is distinguished by the appearance of the attack during NREM sleep, the greater evidence of terror, the inability to awaken the patient, and the lack of dream recall. Various other disorders, such as delirium, depression, and, especially, post-traumatic stress disorder, maybe associated with nightmares (Ross et al. 1989). Various medications may cause an increase in the frequency of normally occurring nightmares, including tricyclic antidepressants and neuroleptics (Solomon 1983; Strayhorn and Nash 1978), beta-blockers, clonidine, and dopaminergic agents such as levodopa. An increased frequency of nightmares may also be seen as part of the phenomenon of 'REM rebound' after the abrupt discontinuation of chronic treatment with monoamine oxidase inhibitors (MAOI), tricyclic antidepressants, or benzodiazepines. Treatment Behavioral treatments, including systematic desensitization and rehearsal techniques, appear to be effective (Kellner et al. 1992; Neidhardt et al. 1992). Benzodiazepines may be effective, but if they are used for more than a few weeks, the dose must not be rapidly decreased as an REM rebound may occur. Anecdotally, cyproheptadine (Harsch 1986) maybe effective.

PAVOR NOCTURNUS Pathology and etiology Apart from the fact that pavor nocturnus (night terror) is familial, little is known about its etiology. Clinical features The onset is generally in childhood, between the ages of 3 and 12; rarely, the first attack may occur in the early adult years. Attacks (Fisher et al. 1973a; Kales and Kales 1974) arise from NREM sleep in the first third

Sleep disorders 615

of the night. Patients typically scream or cry out in terror, sit bolt upright, and appear dazed; the heart rate is increased, and respiration is rapid and panting. The sheets may be grasped, and patients may cry out for help. Attempts to awaken the child are generally unsuccessful, and the episode generally runs its course in a matter of minutes. Afterwards, patients may simply fall back into sleep, or may awaken; those who do awaken, although recalling the sense of terror, nevertheless find either no memory of a dream or merely fragments of one. Remarkably, in contrast to their parents, who are generally quite shaken at witnessing the episode, the children themselves are generally able to fall back to sleep without any difficulty. Otherwise typical attacks may rarely occur during daytime naps, thus constituting a 'pavor diurnus'. Course

The attacks occur with varying frequency and, in most cases, cease entirely by early adolescence. Attacks that persist into the adult years are generally chronic. Differential diagnosis

Nightmares are distinguished by their development from REM sleep, generally in the middle or latter third of the night, and by the often vivid recall of the dream itself, coupled with difficulty in going back to sleep. Nocturnal complex partial seizures may closely resemble attacks of pavor nocturnus: in one case (Tinuper et al. 1990), a teenager had nocturnal 'episodes of sudden arousal, screaming, grimacing, and violent, repetitive movments of the trunk and all four limbs' lasting 5-10 minutes. A family history of epilepsy prompted nocturnal monitoring, which disclosed ictal activity on the EEC. Nocturnal panic attacks may also closely resemble night terrors. Although, in patients with panic disorder, the panic attacks generally occur during wakefulness, almost half of patients will also have nocturnal attacks (Mellman and Uhde 1989a), and, in a very small minority of patients with panic disorder, the panic attacks occur solely during sleep (Mellman and Uhde 1990). Nocturnal panic attacks arise from NREM sleep, and although there is no dream recall, patients typically have trouble falling back asleep (Hauri et al. 1989; Mellman and Uhde 1989b). The occurrence of waking panic attacks suggests the diagnosis, as does the trouble falling back to sleep. Treatment

Parents should be reassured regarding the benign nature of pavor nocturnus, and in most cases, as the episodes do not appear to bother patients much, this is all that is required. Should suppression of the episodes be necesssary, diazepam (Fisher et al. 1973b) may be given, in a dose of from 2.5 to 10 mg at bedtime. Imipramine (Burstein et al. 1983; Cooper 1987) constitutes an alternative and is often effective in low doses of 25-50 mg at bedtime. Paroxetine, in an open study, was also reported to be effective (Wilson et al. 1997).

JACTATIO NOCTURNA CAPITIS Pathology and etiology

The etiology of persistent and frequent jactatio nocturna capitis (nocturnal head-banging) is not known. Clinical features

Head-banging usually begins around the age of 8 or 9 months and appears at the transition from wakefulness to sleep (Kravitz et al. 1960).

616 Specific disorders

Course In the vast majority of cases, head-banging ceases in early childhood, only very rarely, persisting into the adult years (Chisolm and Morehouse 1996; Whyte et al 1991). Differential diagnosis

Occasional head-banging is not abnormal in infants. In one case, head-banging was precipitated by significant head trauma to the frontotemporal region in a teenager (Drake 1986). Head-banging may occur as a stereotypy in mental retardation, autism, or schizophrenia. Treatment

If treatment is required, clonazepam, in doses of approximately 1 mg at bedtime, may be effective (Chisholm and Morehouse 1996).

ENURESIS Pathology and etiology There is some variability in the definition of enuresis. Some use it to refer to wetting regardless of whether it occurs at night or during wakefulness, whereas others restict it to nocturnal events. Furthermore, some apply it to all cases of wetting, regardless of whether the cause is idiopathic or some other disorder, such as cystitis. In this text, enuresis refers to nocturnal, rather than diurnal, wetting and to nocturnal wetting of any cause: the various etiologies of nocturnal wetting are, however, divided into idiopathic and secondary types. Idiopathic enuresis is by far the most common type and appears to be familial. Numerous mechanisms have been proposed, ranging from deficient vasopressin release to the presence of a small bladder. Secondary enuresis may result from a number of different causes, including the following: nocturnal seizures, cerebral palsy, cord lesions (such as spina bifida), diabetes mellitus or insipidus, cystic medullary disease, sickle cell disease, bladder outlet obstruction, urethral valves, meatal stenosis, external pressure on the bladder as may occur with pelvic masses or impacted stool, and sedating drugs. Clinical Features

In the normal course of events, nocturnal continence is established by the age of 5 or 6, and persistent bedwetting much past that age is considered abnormal (Forsythe and Redmond 1974). Although, in most cases of primary enuresis, continence has simply never been attained, in a minority bedwetting may appear after a substantial period of continence. Although the bedwetting of primary enuresis usually occurs in the first third of the night, wetting during the latter two-thirds may also be seen. Although wetting tends to be more common in NREM sleep, it may occur during any sleep stage (Mikkelsen et al. 1980); furthermore, it is generally not associated with dreaming (Pierce et al. 1961). Secondary enuresis is suggested by symptoms such as polyuria, dribbling, or dysuria. Course In primary enuresis, spontaneous remission occurs at a rate of about 15% per year (Forsythe and Butler 1989), and only a very small minority continue to experience bedwetting in adult years (Forsythe and Redmond 1974). Differential diagnosis

Those with mental retardation of moderate or higher grade generally do not attain a developmental age of 7, and thus bedwetting in these patients is not considered abnormal.

Sleep disorders 617

Treatment

For secondary enuresis, treatment is directed at the underlying cause. For primary enuresis, it is appropriate to reassure young children and their parents regarding the benign nature and good prognosis of the condition. In some cases, simple measures may be effective. Caffeinated beverages are prohibited, and fluids, except for ice chips for thirst and a small amount of water for tooth-brushing, are restricted for 3 hours before bedtime. A 'star calendar' is put up, and the child receives a 'star' for every dry night, along with a small toy or sum of money. If the bed is wet, the young patient is required to strip the bed before breakfast. Shaming or scolding the child is not helpful, and it is probably also not helpful to insist that the child clean a wet sheet, given the chances for creating an even greater mess. Such a behavioral approach may bear fruit within a month. When a simple behavioral program fails, consideration may be given to an enuresis alarm (Forsythe and Butler 1989). Here, a bell or alarm is set off by even a minute quantity of urine, thus waking the child up before the bed can be fully wetted. Such alarms are very successful, generally within weeks to a month or more. Desmopressin, given in a dose of 20 ug at bedtime, has an advantage of immediate effectiveness but is helpful in a slightly smaller percentage of patients than is the alarm (Wille 1986). Imipramine, although effective, is generally reserved for treatment failures, given the possibility of side-effects. Treatment is begun at a dose of approximately 1 mg/kg at bedtime and increased in 0.5 mg/kg increments every 2 weeks until substantial improvement, limiting side-effects or a maximum dose of 2.5 mg/kg is reached. When continence is established, it is appropriate to continue the effective treatment for at least 1 month of continuous dryness, after which treatment may be discontinued (in the case of imipramine, the dose should be tapered gradually). Relapses may occur but generally respond to a reinstitution of the previously effective treatment.

NARCOLEPSY Pathology and etiology Narcolepsy may occur on either a familial (Baraitser and Parkes 1978) or a sporadic basis. Although the mechanism whereby symptoms are produced is unknown, the fact that symptoms appear to represent the 'intrusion' of REM sleep into waking activity strongly suggests disturbances in the brainstem mechanisms responsible for REM sleep. There is a strong association between narcolepsy and certain HLA haplotypes. Of whites and Japanese with narcolepsy, almost 100% will have the HLA-DR2 (also known as HLADRwl5) haplotype (Billiard and Seignalet 1985; Guilleminault et al. 1989). Among blacks, there is a strong association with the HLA-DQwl haplotype: although an association also exists with the HLA-DR2 haplotype, it is not as strong as in whites and Japanese, making it less useful diagnostically (Kramer et al. 1987; Neely et al. 1987). The basis for this association of narcolepsy with certain HLA haplotypes is not clear: there is no evidence that narcolepsy is an inflammatory disease. Clinical features

In its fully developed form (Adie 1926; Kales et al. 1982; Parkes et al. 1975; Wilson 1928), narcolepsy presents the classic 'tetrad' of: 1. narcoleptic attacks 2. cataplexy

618 Specific disorders

3. sleep paralyis 4. hypnogogic or hypnopompic hallucinations. However, although all patients have narcoleptic attacks, cataplexy is seen in only about threequarters of patients, sleep paralysis in one-third, and hypnogogic hallucinations likewise in about one-third: only about 1 in 10 patients experience the full tetrad. In over 90% of cases, the first manifestation of the illness is a narcoleptic attack, and although this may appear anywhere from childhood to the middle years, most patients fall ill in their late teens or early adult years. Narcoleptic attacks are ushered in by an overwhelming and irresistible desire to sleep: although such attacks are most likely to occur in situations conducive to drowsiness, such as long-distance driving or sitting through a boring lecture or meeting, they can occur at any time, even during otherwise lively and engaging conversations at the dinner table. Undisturbed, patients may sleep for minutes or even up to one-half hour, after which they awaken, feeling more or less refreshed. Importantly, awakening patients from a narcoleptic attack is not at all difficult and may be accomplished by a light touch or simply by calling the patient's name. Distinctively, the narcoleptic attack itself consists of REM sleep (Dement et al. 1964,1966; Hishikawa and Kaneko 1965; Hishikawa etal. 1968), and most patients will be able to recall dreams upon awakening. Narcoleptic attacks are most frequent in the afternoon or evening and may recur anywhere from once to dozens of times per day. Nocturnal sleep is often broken, and some patients may complain of insomnia: indeed, for most patients, the total 24 hour sleep time is actually not increased. Cataplectic attacks tend to begin several years after the narcoleptic attacks make their appearance and may be either generalized or focal. Typically, the cataplectic attack is precipitated by some strong emotion, such as laughter, fear, anger, or a sudden surprise. In the generalized form, all voluntary muscle power, except for that of the diaphragm and, at times, the extraocular muscles, is lost, and patients collapse to the floor. In the focal type, the sudden muscle weakness is confined to one part, for example the neck musculature, with consequent head droop, the forearm and hand musculature, with items being dropped, or the extraocular muscles, with diplopia. Most attacks last for about a minute. During the attack, patients, even if fully paralyzed, remain conscious and alert, and are able, upon recovery, to give a full description of the event. In some cases, cataplectic attacks may be prolonged, lasting 5 minutes or more, and during such lengthy attacks, patients may experience vivid visual hallucinations. Sleep paralysis may occur upon either falling asleep or awakening. Patients, although fully conscious, yet find themselves unable to move. Most attacks last only a minute or so, and some may be accompanied by visual hallucinations. Importantly, although patients appear to the observer to be sound asleep, they may nevertheless be easily awakened by simply calling their name or lightly touching them. Hypnogogic hallucinations appear upon falling asleep, being generally visual and quite vivid and complex, as if the patient were dreaming while still awake. Hypnopompic hallucinations are quite similar and appear upon awakening. In addition to the classic tetrad just described, perhaps one-third or so of patients will also experience episodes of'automatic behavior'. During these episodes, patients appear to be halfasleep, and although they may continue to engage in complex behavior, such as driving a car, there is generally a decrement in the quality of behavior: if writing, patients may write a gibberish scrawl, and if speaking, they may engage in incoherent muttering. Importantly, upon comng to full alertness, these patients generally have no recall of what they did during the event; thus a patient who drove automatically may, upon 'coming to', have no idea of how many exits were passed.

Sleep disorders 619

Furthermore, a small minority of patients with narcolepsy will also have REM sleep behavior disorder (Schenck and Mahowald 1992). Narcolepsy is characterized by sleep onset REM (Rechtschaffen et al. 1963) activity, this forming the basis for the MSLT (multiple sleep latency test), which ascertains the presence or absence of REM activity as the patient begins to nap. Although helpful, this test may yield both false-negative and false-positive results. In addition to the MSLT, it is appropriate to test whites and Japanese for the HLA-DR2 antigen, and blacks for HLA-DQwl: although these antigens may be found in normal controls, they are rarely absent in patients with narcolpesy, and thus a negative test result, while not absolutely ruling out the diagnosis, definitely calls it into question. Course Although there may be some diminution in the frequency of attacks with age, and even some termporary remissions, narcolepsy is, for the most part, chronic. A combination of narcoleptic and cataplectic attacks has also been noted with a brainstem glioma (Stahl et al. 1980) and as a postviral encephalitic sequela (Adie 1926; Fournier and Helguera 1934). Differential diagnosis

Finding a combination of narcoleptic and cataplectic attacks is very helpful: although other conditions (e.g. as sequela to an encephalitis [Adie 1926; Fournier and Helguera 1934], lesions in the upper brainstem or floor of the third ventricle [Clavelou et al. 1995], and brainstem gliomas [Stahl et al. 1980]), can cause such a combination this is very rare. As noted earlier, however, the illness begins in most patients with narcoleptic attacks alone, and in a small percentage of cases, narcoleptic attacks may remain the sole manifestation of the disease; in these cases, other causes of 'excesive daytime sleepiness' enter the differential diagnosis. Excessive sleepiness may also be seen in psychomotorically retarded depressions, alcoholism, sleep apnea, and the Pickwickian syndrome, but in these conditions, the sleepiness rarely assumes the 'attack' pattern seen in narcolepsy. Attacks of sleepiness may also be seen in patients taking direct dopamine agonists, such as bromocriptine, pergolide, pramipexole, and ropinirole (Ferreira et al. 2000; Frucht et al. 1999; Hauser et al. 2000). Treatment

Treatment is aimed at eliminating, or at least reducing, the frequency of both narcoleptic and cataplectic attacks as these are the items of the tetrad that are potentially dangerous. Narcoleptic attacks may be treated with scheduled naps and various medications. Brief naps (Roehrs et al. 1986) may 'protect' the patient from a narcoleptic attack for an hour or more and, if judiciously spaced during the day, may be very helpful. In most cases, medications are required, these including either stimulants or antidepressants. Stimulants (Mitler et al. 1993) include methylphenidate, pemoline, dextroamphetamine, and, as a recent addition, modafmil (Laffont et al. 1994). Modafinil should be started at 200 mg daily: although the 400 mg dose may be more effective in some, it is much more likley to cause significant side-effects (Broughton et al. 1997; US Modafinil in Narcolepsy Multicenter Study Group 1998, 2000). Methylphenidate is often tried first, the eventual dose ranging from 20 to 60 mg daily in most patients. Pemoline, in a dosage of 37.5-150 mg/day has been much used in the past, but recent reports of hepatotoxicity warrant some caution in its use. It is not as yet clear how modafmil compares with a stimulant such as methylphenidate. Antidepressants include protriptyline, imipramine, desipramine, and clomipramine (Parkes and Schacter 1979); MAOIs, such as phenelzine, tranylcypromine, and selegeline, are also effective but, given their potentially fatal drug-drug and drug-food interactions, are

620 Specific disorders

rarely used. Protriptyline may be given in doses of 20mg/day (Schmidt et al. 1977), imipramine in doses of 50mg/day (Akimoto et al. 1960), and either desipramine or clomipramine in a dosage of 25-75 mg/day. Given the sedative effect of clomipramine, beginning with protriptyline or desipramine may be appropriate. Although most clinicians begin treatment with a stimulant, the antidepressants offer a distinct advantage in that, unlike the stimulants, they are effective against not only narcoleptic attacks, but also the other elements of the tetrad, including cataplexy, sleep paralysis, and hypnogogic hallucinations. Pending effective control of the narcoleptic and cataplectic attacks, patients should not drive, operate hazardous machinery, or engage in any activity that puts them or others at risk in the event of an attack.

SLEEP APNEA Pathology and etiology Sleep apnea may exist in any one of three forms: obstructive, central, and mixed. Each of these forms shares one characteristic, namely nocturnal episodes wherein inspiratory airflow through the nose and mouth ceases. The mechanism underlying this cessation of airflow differs, however, among the three forms. In the obstructive type, a collapse or occlusion of the airway occurs and prevents inspiration despite ongoing and vigorous inspiratory movements of the diaphragm and intercostal musculature; in the central type, airflow fails to occur simply because inspiratory muscular activity fails to occur; and in the mixed type, one sees a biphasic course, wherein there is initially an absence of inspiratory effort, leading to a central type of apnea, followed by a resumption of inspiratory effort, which, however, then meets with occlusion or collapse of the airway, prompting an evolution into an obstructive type of event. Obstruction may occur because of micrognathia (Coccagna et al. 1976), wherein the tongue falls back to occlude the airway, lingual hypertrophy, as may occur in hypothyroidism or acromegaly, and, most commonly, obesity, wherein the presence of excessive adipose tissue leads to a narrowing of the airway; cases have also been reported following recovery from traumatic coma (Guilleminault et al. 1983). In the remainder of cases, it appears that occlusion or collapse occurs because of a generalized 'pharyngeal crowding* or a failure of the neuromuscular apparatus that serves to keep the airway musculature 'stiff', and the airway open, during inspiration. Central sleep apnea may be idiopathic or caused by lesions affecting the brainstem, such as, in one case, arterial compression of the medulla (Miyasaki et al. 1991). Clinical features

Although the range of age of onset is quite wide, most cases of obstructive sleep apnea come to light in the middle years; central types tend to be of later onset. Apneic episodes (Strollo and Rogers 1996; Whyte et al. 1989) may last anywhere from 10 seconds up to 2 minutes, and may occur several dozen or several hundreds of time a night. Obstructive types are by far the most common and pure central types relatively rare, with mixed types falling somewhere in between. Obstructive episodes may at times be quite dramatic. Despite an ever more vigorous activity of the diaphragmatic and intercostal musculature, inspiration does not occur until, at long last, with a gasping snort, a breath is taken in. Patients typically awaken for a few seconds at this point but rapidly fall back asleep. In between apneic episodes, these patients tend to snore loudly, and it may indeed be the bed-partner's inability to tolerate the snoring that actually brings the patient to medical attention. Most patients complain of excessive daytime

Sleep disorders 621

sleepiness; the multiple brief awakenings are generally not recalled, and insomnia is not complained of. Central episodes, in contrast with obstructive ones, are typically quiet and peaceful events: inspiratory effort simply ceases, and patients remain asleep and unmoving, seemingly untroubled by the absence of any breathing. Respiratory effort eventually resumes, a breath occurs, and the episode is over. A transient awakening accompanies this resumption of breathing, and patients often complain of restless sleep or insomnia; they may or may not experience excessive daytime sleepiness. Mixed episodes, although beginning with a central component, clinically resemble the obstructive type, with frequent snoring and complaints of daytime sleepiness. During the day, most patients experience a varying degree of drowsiness and a certain 'fuzziness' of thought, with difficulty in concentrating and poor memory. Mechanical ability is impaired, and traffic accidents are more frequent in patients with obstructive sleep apnea than in the general public (George et al. 1987). Irritability and headaches are common, and men may experience impotence. Depressive symptoms are also common (Millman et al. 1989), with indecisiveness, low self-esteem, helplessness, tearfulness, and, in some cases, suicidal ideation. Patients may rarely present with a dementia, which is fully reversible with adequate treatment (Scheltens et al. 1991; Steiner et al. 1999). During apneic episodes, the Po2 falls, the Pco2 rises, and there is bradycardia, with, in some cases, sinus arrest. Upon resumption of inspiration, a tachycardia often ensues. Ventricular ectopy may also occur. Over time, the innumerably repeated episodes of hypercarbia lead to pulmonary hypertension and cor pulmonale; systemic hypertension may also be seen. Although a presumptive diagnosis can be made on the basis of descriptions provided by a reliable bed-partner, definitive diagnosis requires polysomnography. Course Lacking effective treatment, sleep apnea is chronic. Differential diagnosis

Occasional apneic episodes are normal in adults, and up to 10 a night may be seen. Obstructive and mixed sleep apnea must be distinguished from respiratory failure, myotonic muscular dystrophy, and various focal lesions, all of which may produce excessive daytime sleepiness. Polysomnography will, however, fail to reveal obstructive episodes in these other disorders. The Pickwickian syndrome is distinguished by hypercarbia during the waking hours, in contrast to obstructive sleep apnea, wherein, outside the apneic episodes, blood gases are normal Central sleep apnea must be distinguished from other causes of restless sleep and insomnia, such as nocturnal myoclonus, and here again polysomnography is definitive. Treatment

Any underlying cause should, if possible, be treated. Thus, obese patients should lose weight (Smith et al. 1985), and hypothyroidism should be corrected. Patients should avoid sleeping in the supine position and be instructed to sleep on their side, a position that favors airway patency (Cartwright et al. 1985, 1991). Medications such as protriptyline (Brownell et al. 1982), in doses of 20 mg at bedtime, or paroxetine, also in a dose of 20 mg on retiring (Kraiczi et al. 1999) are helpful in some but may not provide sufficient relief. Oral appliances may help, but, in many cases, continuous positive airway pressure (CPAP) is eventually required. CPAP is very effective, but, given the cumberous nature of the device, compliance may be poor. Surgical alternatives include uvulopalatopharyngoplasty and tracheostomy. Central sleep apnea is occasionally relieved by protriptyline or by acetazolamide 250 mg

622 Specific disorders

qid. In severe cases, diaphragmatic pacing may be required. Mixed apnea often requires a combination of the approaches used for the obstructive and central types. Importantly, any substance that decreases respiratory drive, such as alcohol (Scrima et al. 1982), sedatives, or hypnotics (Mendelson et al. 1981), should be avoided.

PICKWICKIAN SYNDROME Pathology and etiology

In states of extreme obesity, the burden of adipose tissue both encircling the rib cage and pushing up from the abdomen below severely compromises inspiration, leading to alveolar hypoventilation with chronic hypercapnia and hypoxia. Clinical features

The Pickwickian syndrome, as described by several authors (Burwell et al. 1956; Drachman and Gumnit 1962; Sicker et al. 1955; Ward and Kelsey 1962), is named after the fat boy in Dicken's The Pickwick Papers, who apparently had the syndrome. The age of onset is determined by the age of onset of the obesity; the mode of onset is gradual, mirroring the gradual accumulation of adipose tissue. These extremely obese patients present with somnolence, lethargy, inattentiveness, and headache. Chronic hypoxia leads to eyrthrocytosis, which may create a 'ruddy' complexion. Chronic hypercarbia leads to pulmonary hypertension and cor pulmonale. In severe cases, the hypercarbia may lead to increased intracranial pressure with papilledema (Meyer et al. 1961). Obstructive sleep apnea is common in these patients and leads to increased somnolence during the day. Course Barring the patient achieving a significant weight loss, the Pickwickian syndrome is chronic. Differential diagnosis

As indicated above, obstructive sleep apnea is commonly found in patients with the Pickwickian syndrome, and it is probably appropriate to evaluate all extremely obese somnolent patients with polysomnography, an erythrocyte count and waking arterial blood gases. Patients with obstructive sleep apnea alone will lack erythrocytosis and will have normal Po2 and Pco2 levels while awake, whereas patients with pure Pickwickian syndrome will not have apneic episodes at night but will show erythrocytosis and waking blood gas abnormalities. Patients with both syndromes will, of course, show all these abnormalities. Obese patients are prone to thrombophlebitis and thus pulmonary emboli: the rapid worsening of somnolence in any obese patient should suggest this. Treatment

Weight loss is critical. If obstructive sleep apnea is present, it may be treated as described in the foregoing section. Supplemental oxygen, although initially beneficial, may soon be followed by respiratory failure.

KLEINE-LEVIN SYNDROME Pathology and etiology

Although the etiology of the Kleine-Levin syndrome remains obscure, numerous reports of the syndrome following an influenza-like illness (Fernandez et al. 1990; Garland et al. 1965;

Sleep disorders 623

Levin 1936; Sagar et al. 1990), and one autopsy report noting encephalitic changes in the thalamus (Carpenter et al. 1982) all suggest that the syndrome represents a postencephalitic entity. Certainly, however, not all cases support this notion as there are some recorded that appear after concussion (Will et al. 1988), and in many cases, there does not appear to be any precipitating factor at all. The prominence of vegetative changes, such as somnolence, hyperphagia, and altered sexuality, all suggest a disturbance of hypothalamic functioning, disturbances in hypothalamic-pituitary axis functioning supporting this notion (Chesson et al. 1991; Fernandez et al. 1990; Malhotra et al. 1997). Clinical features

The Kleine-Levin syndrome is an episodic illness, and although the range of age of onset of the first episode is wide, most patients fall ill in late childhood or early adolescence. Importantly, the overwhelming majority of patients are male; cases in females, although reported (Kesler et al. 2000; Malhotra et al. 1997), are unusual. The episode proper may be preceded by a prodrome, lasting from one to several days, consisting of malaise, lethargy, and headache (Critchley 1962). Levin (Levin 1936), in describing behavior during the episode, notes that 'the patient sleeps excessively day and night, in extreme instances waking only to eat and go to the toilet. He can always be roused. When roused he is usually irritable and wants to be left alone so that he can go back to sleep. He is abnormally hungry and eats excessively.' Critchley (1962) expanded on this description, noting that, when awake, patients may be 'uninhibited, insolent, and quarrelsome'. The hyperphagia seen during the episode is often indiscriminant, patients eating whatever is at hand (Critchley 1962), sometimes begging food from other patients (Garland et al. 1965) or exhibiting unusual food preferences (Will et al. 1988). An indiscriminant hyper sexuality may also occur: one patient masturbated in public (Fernandez et al. 1990) and another continued his 'vigorous attempts at masturbation' during the interview, refusing laboratory testing unless 'the house physician was prepared to "come into bed and give me a feel over" '(Garland et al. 1965). Other symptoms include confusion, disorientation, visual and auditory hallucinations, and delusions (Critchley 1962; Critchley and Hoffman 1942; Fernandez et al. 1990). Interestingly, some authors have commented that patients would 'sing inappropriately' (Chiles and Wilkus 1976); in one case, the patient 'frequently burst into song' but sang the same song over and over again (Garland et al. 1965). The episodes themselves may last anywhere from days to a month, and, upon recovery, most patients are more or less amnestic for the events that occurred during the episode (Critchley 1962; Levin 1936): some may experience a residual mood disturbance (Critchley 1962), tending towards either depression (Gallinek 1954) or elation (Gilbert 1964), which passes within a week or so. In some cases, focal findings, such as anisocoria, dysarthria, and a Babinski sign may be seen during the episode (Critchley 1962), The electroencephalogram may show slowing and polysomnography may reveal reduced REM latency, frequent awakenings and decreased delta sleep (Pike and Stores 1994; Reynolds et al. 1980), and the MSLT may reveal sleep onset REM while the patient is suffering an episode of the syndrome (Reynolds et al. 1984). Course

In the natural course of events, episodes tend to recur, perhaps once every half-year. Over the years, however, the episodes tend to become shorter and further apart until finally, by the adult years, they generally stop altogether (Critchley 1962). In between episodes, although it appears that most patients return to normal, there is some suggestive evidence that there may be some residual quarrelsomeness and slightly reduced academic ability (Sagar et al. 1990).

624 Specific disorders

Differential diagnosis A history of episodes characterized by hypersomnolence, hyperphagia and hypersexuality is fairly distinctive. A mixed-manic episode, as may be seen in bipolar disorder, may come to mind, but one would expect to see at least some evidence of pressured speech and activity. Treatment

Both stimulants (such as amphetamines [Gallinek 1962]) and lithium (Ogura etal. 1976; Will et al. 1988) have been used, but there are no controlled studies of these. Carbamazepine has not been found to be helpful (Will et al. 1988).

RESTLESS LEGS SYNDROME Pathology and etiology The restless legs syndrome (Ekbom's syndrome) may occur on either an idiopathic basis or secondary to certain other conditions. In the case of idiopathic restless legs syndrome, hereditary factors are important, and instances of autosomal dominant transmission have been reported (Trenkwalder et al. 1996). Secondary causes include uremia (Winkelman et al. 1996, 2000), chronic hemodialysis, iron deficiency anemia, pregnancy, spinal cord lesions (Hartmann et al. 1999), and various peripheral neuropathies. Electromyographic and nerve conduction velocity studies are probably indicated given that underlying peripheral neuropathies may, in perhaps one-half of cases, have no clinical manifestations other than the restless legs syndrome itself (Ondo and Jankovic 1996). Clinical features

Idiopathic cases generally have an onset in the late twenties or early thirties, the onset of secondary cases being, of course, determined by the age of onset of the underlying cause. Clinically (Ekbom 1960; Montplaisir et al. 1997; Ondo and Jankovic 1996), patients describe an uncomfortable sensation in their legs, which becomes markedly worse upon lying down, and which can only be relieved by getting up and walking. Falling asleep is almost impossible, and if patients are lucky enough to fall asleep but awaken later in the night, the restlessness returns and makes falling back to sleep very difficult. Many patients spend long, tortured sleepless nights, often getting but a few hours of sleep in the early morning hours when the restlessness begins spontaneously to abate. Patients describe the uncomfortable sensation variously as a restless urge to move or a crawling or creeping feeling; actual pain is unusual, although some may describe an aching or cramping feeling. The sensation itself is often felt deep within the calf, and some patients, over time, begin to experience the restlessness in the upper extremities too. Although symptoms typically begin unilaterally, bilateral involvement fairly rapidly ensues. In a majority of cases, nocturnal myoclonus is also present (Montplaisir et al. 1997; Ondo and Jankovic 1996). Course Although temporary remission occurs in a minority (Walters et al. 1996), idiopathic restless legs syndrome is generally chronic; in one case, paroxetine appeared to aggravate the symptomatology (Sanz-Fuentenebro et al. 1996). Differential diagnosis

Although neuroleptic-induced akathisia is clinically very similar to restless legs syndrome, certain features help to distinguish them: patients with neuroleptic-induced akathisia are likely to 'march in place', a behavior rarely seen in the restless legs syndrome, whereas in the

Sleep disorders 625

restless legs syndrome, patients are likley to rub their feet for relief, a maneuver which akathetic patients do not engage in (Walters et al. 1991). Treatment

A variety of medications are helpful in restless legs syndrome, including dopaminergic agents such as pergolide (Earley et al. 1998), pramipexole (Montplaisir et al. 1999), and levodopa/carbidopa (Brodeur et al. 1988): should levodopa be used, consideration may be given to using the sustained-release preparation in order to provide coverage for middle of the night awakenings (Collado-Seidel et al. 1999). Other agents include clonazepam, clonidine (Wagner et al. 1996), opioids (e.g. propoxyphene, codeine, and oxycodone), and propranalol. In secondary cases, the underlying cause should, if possible, be treated.

NOCTURNAL MYOCLONUS Pathology and etiology

Little is known regarding the etiology of nocturnal myoclonus (periodic leg movements of sleep); the similarity of the abnormal movement to a Babinski sign (Smith 1985) has suggested that it may result from a lack of supraspinal inhibition. Clinical features

The onset is typically anywhere from the middle years to old age. Nocturnal myoclonus is something of a misnomer as the abnormal movements do not, in fact, partake of the lightning or shock-like character of true myoclonus; rather, they evolve in a relatively more leisurely way. Although 'periodic leg movements of sleep' (among others) has been proposed as an alternative name, the term 'nocturnal myoclonus' has maintained its currency in standard texts and is retained here. The abnormal movements (Coleman et al. 1980) consist, at the least, of dorsiflexion of the foot, which is, in most cases, accompanied by flexion at the knee and, in some cases, by flexion at the thigh to create a classic 'triple flexion' response. The movements themselves last anywhere from one-half to 10 seconds and tend to recur, with remarkable periodicity, every 20-40 seconds. These recurrent movements, in turn, tend to come in episodes, lasting minutes or hours, in between which the patient is generally still. Typically, although patients generally complain of poor sleep, they are often unaware of the movements, and it may be a bed-partner who, tired of being repeatedly kicked, eventually brings the patient to medical attention. Polysomnography reveals the movements and demonstrates their occurrence during nonREM sleep. A minority of patients with nocturnal myoclonus will also have the restless legs syndrome.

Course Nocturnal myoclonus tends to be chronic and may be exacerbated by tricyclic antidepressants (Wareetal 1984). Differential diagnosis

Nocturnal myoclonus may at times be an incidental finding on polysomnography, not associated with any complaints of insomnia (Mendelson 1996). Hypnic jerks (Oswald 1959) or, as they are also called, 'sleep starts', are distinguished by their appearance during the transition from wakefulness to sleep and by their brevity and generalized nature, involving, as they typically do, all four extremities rather than just the lower extremities.

626 Specific disorders

Treatment

Levodopa (Becker et al. 1993; Brodeur et al. 1988), clonazepam (Mitler et al. 1986; Ohanna et al. 1985), and opioids, such as propoxyphene (Hening et al. 1986), have all been shown to be effective. If levodopa is used, begin with a time-release preparation (e.g. Sinemet 25/100 at bedtime), and increase the dose gradually as needed; clonazepam may be given in a dose of 0.5-2 mg at bedtime.

PAINFUL LEGS AND MOVING TOES Pathology and etiology This syndrome has been reported with lesions of various structures (Dressier et al. 1994), including the spinal cord, lumbar roots (Nathan 1978), cauda equina, and peripheral nerves (Montagna et al. 1983; Pla et al. 1996). Minor trauma (Schott 1981) can also be the cause. Clinical features

The syndrome (Dressier et al. 1994; Spillane et al. 1971), which generally has an onset in the sixth or seventh decades, is characterized by a combination of pain in the legs and involuntary movements of the toes; in most cases, pain appears first, and although the symptoms may begin unilaterally, bilateral involvement eventually follows. The pain, as noted by Spillane et al. (1971), varies 'in intensity from discomfort to a pain of great severity... an ache, an intense pressure, a tightness, a feeling that the toes were pulling or being pulled, a throbbing, bursting, crushing . . . [or] a deep burning', the movements consisting of a 'sinuous clawing and restraightening, fanning and circular movements of the toes'. The effect of the toe movements can be remarkable: one of Spillane et al.'s patients 'was surprised to see that the toes were actually moving "as though they were playing a piano on their own" '. The symptoms are not relieved by walking about, and insomnia can be severe (Montagna et al. 1983). When sleep does come, the abnormal movements cease. Course This syndrome is apparently chronic. Differential diagnosis

The restless legs syndrome is distinguished by the absence of abnormal movements, the absence of severe pain, and relief with ambulation. Causalgia is distinguished by an absence of abnormal movements. Treatment

Treatment is uncertain.

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628 Specific disorders Dressier D.Thompson PD, MarsdenCD. The syndrome of painful legs and moving toes. MovDisord 1994; 9:13-21. Driver HS, Shapiro CM. Parasomnias. BMJ1993; 306:921-4. Dyken ME, Lin-Dyken DC, Seaba Petal. Violent sleep-related behavior leading to subdural hematoma. Arch Neurol 1995; 52:318-21. Earley CJ, Yaffee JB, Allen RP. Randomized double-blind, placebo-controlled trial of pergolide in restless legs syndrome. Neurology 1998; 51:1599-602. Ekbom KA. Restless legs syndrome. Neurology 1960; 10:868-73. Fernandez J-M, Lara I, Gila let at. Disturbed hypothalamic-pituitary axis in idiopathic recurring hypersomnia syndrome. Acta Neurol Scand 1990; 82:361-3. Ferreira JJ, Galitzky M, MontrastrucJLef al. Sleep attacks and Parkinson's disease treatment. Lancet 2000; 355:1333-4. Fisher C, Kahn E, Edwards A etal. A psychophysiological study of nightmares and night terrors. I. Physiological aspects of the stage 4 night terror. J Nerv Ment D/s1973a; 157:75-98. Fisher C, Kahn E, Edwards A et al. A psychophysiological study of nightmares and night terrors: the suppression of stage 4 night terrors with diazepam. Arch Gen Psychiatry 1973b; 28:252-9. Forsythe Wl, Butler RJ. Fifty years of enuretic alarms. Arch Dis Child 1989; 64:879-85. Forsythe Wl, Redmond A. Enuresis and spontaneous cure rate of 1129 enuretics. Arch Dis Child 1974; 49:259-63. FournierJCM, Helguera RAL Postencephalitic narcolepsy and cataplexy: muscle and motor nerves electrical inexcitability during the attack of cataplexy. y Nerv Ment Dis 1934; 80:159-62. FruchtS, RogersJD, Greene PEetal. Falling asleep at the wheel: motorvehicle mishaps in persons taking pramipexole and ropinirole. Neurology 1999; 52:1908-10. GallinekA. Syndrome of episodes of hypersomnia, bulimia and abnormal mental states. JAMA 1954; 154:1081-3. GallinekA. The Kleine-Levin syndrome: hypersomnia, bulimia, and abnormal mental states. World Neurology 1962; 3:235-43. Garland H, Sumner D, Fourman P. The Kleine-Levin syndrome: some further observations. Neurology 1965; 15:1161-7. George CF, Nickerson PW, Janley PJ et al. Sleep apnoea patients have more automobile accidents. Lancet

1987; 2:447. Gilbert GJ. Periodic hypersomnia and bulimia: the Kleine-Levin syndrome. Neurology 1964; 14:844-50. GuilleminaultC, Faull KF, Miles et al. Posttraumatic excessive daytime sleepiness: a review of 20 patients. Neurology 1983; 33:1584-9. Guilleminault C, Mignot E, Grumet FC. Familial patterns of narcolepsy. Lancet 1989; 2:1376-1379. Harsch HH. Cyproheptadine for recurrent nightmares. Am J Psychiatry 1986; 143:1491-2. Hartmann M, Pfister R, Pfadenhauer K. Restless legs syndrome associated with spinal cord lesions. J Neurol Neurosurg Psychiatry 1999; 66:688-9. Hauri PJ, Friedman M, Ravaris CL. Sleep in patients with spontaneous panic attacks. Sleep 1989; 12:323-37. Hauser RA, Gauger L, McDowell Anderson W et al. Pramipexole-induced somnolence and episodes of daytime sleep. Mov Disord 2000; 15:658-63. Hening WA, Walters A, Kavey KV et al. Dyskinesia while awake and periodic movements in sleep in restless leg syndrome: treatment with opioids. Neurology 1986; 36:1363-6. Hishikawa Y, Kaneko Z. Electroencephalographic study on narcolepsy. Electroencephalogram Neurophysiol 1965; 18:249-59. Hishikawa Y, Nanno H, Tachibana M et al. The nature of sleep attack and other symptoms of narcolepsy. Electroencephalogr Clin Neurophysiol 1968; 24:1-10. HublinC, KaprioJ, Partinen Metal. Prevalence and genetics of sleepwalking: a population-based twin study. Neurology 1997; 48:177-81.

Sleep disorders 629 Kales A, Kales JD. Sleep disorders: recent findings in the diagnosis and treatment of disturbed sleep. N EnglJ Med 1974; 290:487-99. Kales A, Jacobson A, Paulson M]etal. Somnambulism: psychophysiological correlates. Arch Gen Psychiatry 1966; 14:586-94. Kales A, SoldatosCR, Bixler EQetal. Hereditary factors in sleepwalking and nightmares. BrJ Psychiatry 1980a; 137:111-18. Kales A, SoldatosCR, Caldwell ABetal. Somnambulism: clinical characteristics and personality patterns. Arch Gen Psychiatry 1980b; 37:1406-10. Kales A, Soldatos CR, Caldwell AB et al. Nightmares: clinical characteristics and personality patterns. Am J Psychiatry 1980c; 137:1197-201. Kales A, Cadieux RJ, Soldatos CRetal. Narcolepsy-cataplexy. I. Clinical and electroencephalographic characteristics. Arch Neurol 1982; 39:164-8. Kales A, Soldatos CR, Kales JD. Sleep disorders: insomnia, sleepwalking, night terrors, nightmares and enuresis. Ann Int Med 1987; 106:582-92. Kavey NB, WhyteJ, ResorSRetal. Somnambulism in adults. Neurology 1990; 40:749-52. Kellner R, Neidhardt J, Krakow B et al. Changes in chronic nightmares after one session of desensitization or rehearsal instructions. Am) Psychiatry 1992; 149:659-63. Kesler A, Gadoth N, Vainstein G etal. Klein Levin syndrome (KLS) in young females. Sleep 2000; 23:563-7. Kraiczi H, HednerJ, Dahlof Petal. Effect of serotonin reuptake inhibition on breathing during sleep and daytime symptoms in obstructive sleep apnea. Sleep 1999; 22:61-7. Kramer R, Dinner D, Braun Wetal. HLA-DR2and narcolepsy. Arch Neurol 1987; 44:853-5. Kravitz H, Rosenthall V, Teplitz Z et al. A study of head-banging in infants and children. Dis NervSyst 1960;21:203-8. Laffont F, Mayer G, MinzM. Modafinil in diurnal sleepiness: a study of 123 patients. Sleep 1994; 17(suppl 8):S113-15. Levin M. Periodic somnolence and morbid hunger: a new syndrome. Brain 1936; 59:494-504. Malhotra S, Das MK, Gupta N etal. A clinical study of Kleine-Levin syndrome with evidence for hypothalamic-pituitary axis dysfunction. Biol Psychiatry 1997; 42:299-301. Mellman TA, Uhde TW. Sleep panic attacks: new clinical findings and theoretical implications. AmJ Psychiatry 1989a; 146:1204-7. Mellman TA, Uhde TW. Electroencephalographic sleep in panic disorder: a focus on sleep-related panic attacks. Arch Gen Psychiatry 1989b; 46:178-89. Mellman TA, Uhde TW. Patients with frequent sleep panic: clinical findings and response to medication treatment.; Clin Psychiatry 1990; 51:513-16. Mendelson WB. Are periodic leg movements associated with clinical sleep disturbance? Sleep 1996; 19:219-23. Mendelson WB, Garnett D, Gillin JC. Single case study: flurazepam-induced sleep apnea syndrome in a patient with insomnia and mild sleep-related respiratory changes.) NervMentDis 1981; 169:261-4. Meyer JS, Gotham J, Tazaki Y etal. Cardiorespiratory syndrome of extreme obesity with papilledema. Neurology 1961; 11:950-8. Mikkelsen EJ, Rapoport JL, Nee Let al. Childhood enuresis. I. Sleep patternsand psychopathology./Ard? Gen Psychiatry 1980; 37:1139-44. Millman RP, Fogel BS, McNamara MEetal. Depression as a manifestation of obstructive sleep apnea: reversal with nasal continuous positive airway pressure../ Clin Psychiatry 1989; 50:348-51. Miller MM, Browman CP, Menn SJ etal. Nocturnal myoclonus: treatment efficacy of clonazepam and temazepam. Sleep 1986; 9:385-92. Mitler MM, Hajdukovic R, Erman MK. The treatment of excessive somnolence with stimulant drugs. Sleep 1993; 16:203-6.

630 Specific disorders Miyasaki M, Hashimoto T, Sakurama N et al. Central sleep apnea and arterial compression of the medulla. Arch Neurol 1991; 29:564-5. Montagna P, Cirignotta F, Sacquegna T et al. 'Painful legs and moving toes' associated with polyneuropathy.y Neurol Neurosurg Psychiatry 1983; 46:399^103. MontplaisirJ, Boucher S, PoirierGef a/. Clinical, polysomnographic and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord 1997; 12:61-5. MontplaisirJ, Nicolas A, Denesle Ret al. Restless legs syndrome improved by pramipexole. A doubleblind randomized trial. Neurology 1999; 52:938-43. Nathan PW. Painful legs and moving toes: evidence on the site of the lesion. J Neurol Neurosurg Psychiatry 1978; 41:934-9. Neely S, Rosenberg R, Spire \Petal. HLA antigens in narcolepsy. Neurology 1987; 37:1858-70. Neidhardt EJ, Krakow B, Kellner R. The beneficial effects of one treatment session and recording of nightmares on chronic nightmare sufferers. Sleep 1992; 15:470-3. Ogura C, Okuma T, Nakazawa A. Treatment of periodic somnolence with lithium carbonate. Arch Neurol 1976; 33:143. Ohanna N, Peled R, Rubin AH et al. Periodic leg movements in sleep: effect of clonazepam treatment. Neurology 1985; 35:408-11. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behavior disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000; 123:331-9. Ondo W, Jankovic J. Restless legs syndrome: clinicopathologic correlates. Neurology 1996; 47:1435-41. Oswald I. Sudden bodily jerks on falling asleep. Brain 1959; 82:92-103. Parkes JD. The parasomnias./.omren986; 2:1021-5. ParkesJD, Schacter M. Clomipramine and clonazepam in cataplexy. Lancet 1979; 2:1085-6. Parkes JD, Baraitser M, Marsden CD etal. Natural history of symptoms and treatment of the narcoleptic syndrome. Acta NeurolScand 1975; 52:337-53. Pedley TA, Guilleminault C. Episodic nocturnal wanderings responsive to anticonvulsant drug therapy. Ann Neurol 1977; 2:30-5. Pierce CM, Whitman RM, Gay ML. Enuresis and dreaming: experimental studies. Arch Gen Psychiatry 1961;4:166-70. Pike M, Stores G. Kleine-Levin syndrome: a cause of diagnostic confusion. Arch Dis Child 1994; 71:355-7. Pla MER, DillinghamTR, Spellman LT etal. Painful legs and moving toes associated with tarsal tunnel syndrome and accessory soleus muscle. Mov D/so/tf1996; 11:82-6. Plazzi G, Corsini R, Provini fetal. REM sleep behavior disorders in multiple system atrophy. Neurology 1997; 48:1094-7. Rechtschaffen A, Wolpert EA, Dement WCetal. Nocturnal sleep of narcoleptics. ElectroencephalogrClin Neurophysiol 1963; 15:599-609. Reynolds CF, Black RS, Coble P etal. Similarities in EEG sleep findings for Kleine-Levin syndrome and unipolar depression. Am] Psychiatry 1980; 137:116-18. Reynolds CF, Kupfer DJ, Christiansen CL et al. Multiple sleep latency test findings in Kleine-Levin syndrome. J Nerv Ment Dis 1984; 172:41-4. Roehrs TA, Zorick FJ, Wittig RM et al. Alerting effects of naps in patients with narcolepsy. Sleep 1986; 9:194-9. Ross RJ, Ball WA, Sullivan KA etal. Sleep disturbance as the hallmark of posttraumatic stress disorder. AmJ Psychiatry 1989; 146:697-706. Sagar RS, Khandelwal SK, Gupta S. Interepisodic morbidity in Kleine-Levin syndrome. BrJ Psychiatry 1990;157:139-41. Sanz-Fuentenebro FJ, Huidobro A, Tejadas-RivasAeto/. Restless legs syndrome and paroxetine. Acta Psych iatr Scand 1996; 94:482-4.

Sleep disorders 631 Scheltens P, Visscher F, Van Keimpema ARJ el al. Sleep apnea syndrome presenting with cognitive impairment. Neurology 1991; 41:155. Schenck CH, Mahowald MW. Polysomnographic, neurologic, psychiatric, and clinical outcome report on 70 consecutive cases with REM sleep behavior disorder (RBD): sustained clonazepam efficacy in 89.5% of 57 treated patients. Cleve ClinJ Med 1990; 57(suppl):S9-23. Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Ann Neurol 1992; 32:3-10. Schenck CH, Bundlie SR, Ettinger MG et al. Chronic behavioral disorders of human REM sleep: a new category of parasomnia. Sleep 1986; 9:293-308. Schenck CH, Bundlie SR, Patterson Metal. Rapid eye movement sleep behavior disorder. A treatable parasomnia affecting older adults. JAMA 1987; 257:1786-9. Schenck CH, Milner DM, Hurwitz TD etal. A polysomnographic and clinical report on sleep-related injury in 100 adult patients. Am J Psychiatry 1989; 146:1166-73. Schenck CH, Garcia-Rill E, Skinner RD etal. A case of REM sleep behavior disorder wth autopsyconfirmed Alzheimer's disease: postmorten brain stem histochemical analyses. Biol Psychiatry 1996a; 40:422-5. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology 1996b; 46:388-93. Schmidt HS, Clark RW, Human PR. Protriptyline: an effective agent in the treatment of the narcolepsycataplexy syndrome and hypersomnia. AmJ Psychiatry 1977; 134:183-5. Schott GD. 'Painful legs and moving toes': the role of trauma../ Neural Neurosurg Psychiatry 1981; 44:344-6. Scrima L, Broudy M, Nay KN etal. Increased severity of obstructive sleep apnea after bedtime alcohol ingestion: diagnostic potential and proposed mechanism of action. Sleep 1982; 5:318-28. Sicker HO, EstesEH, KelserGArto/. Cardiopulmonary syndrome with extreme obesity.yC//A7 Invest 1955; 34:916. Smith PL, Gold AR, Meyers DA efo/. Weight loss in mildly to moderately obese patients with obstructive sleep apnea. Ann Intern Med 1985; 103:850-5. Smith RC. Relationship of periodic movements in sleep (nocturnal myoclonus) and the Babinski sign. Sleep 1985; 8:239-43. Solomon K. Thiothixene and bizarre nightmares: an association?./ Clin Psychiatry 1983; 44:77-8. Sours JA, Frumkin P, Indermill RR. Somnambulism: its clinical significance and dynamic meaning in late adolescence and adulthood. Arch Gen Psychiatry 1963; 9:400-13. SpillaneJD, Nathan PW, Kelly REetal. Painful legsand moving toes. Brain 1971; 94:541-56. Stahl SM, Layzer RB, Aminoff MJ etal. Continuous cataplexy in a patient with a midbrain tumor: the limp man syndrome. Neurology 1980; 30:1115-18. Steiner MC, Ward MJ, AN NJ. Dementia and snoring. Lancet 1999; 353:204. Strayhorn JM, Nash JL. Frightening dreams and dosage schedule of tricyclic and neuroleptic drugs. J Nerv Merit Dis 1978; 166:878-80. Strollo PJ, Rogers RM. Obstructive sleep apnea. N Englj Med 1996; 334:99-104. Tan A, Selgado M, Fahn S. Rapid eye movement sleep behavior disorder preceding Parkinson's disease with therapeutic response to levodopa. Mov Disord 1996; 11:214-16. TinuperP.CerulloA, Cirignotta fetal. Nocturnal paroxysmal dystonia: three cases with evidence for an epileptic frontal lobe origin of seizures. Epilepsia 1990; 31:549-56. Trenkwalder C, Seidel VC, Gasser fetal. Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 1996; 11:389-94. Turner RS, Chervin RD, Fray KAetal. Probable diffuse Lewy body disease presenting as REM sleep behavior disorder. Neurology 1997; 49:523-7. Uchiyama M, Isse K, Tanaka K etal. Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology 1995; 45:709-12.

632 Specific disorders US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann A/o/ro/1998; 43:88-97. US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime sleepiness of narcolepsy. Neurology 2000; 54:1166-75. Wagner ML, Walters AS, Coleman RG et at. Randomized, double-blind, placebo-controlled study of clonidinein restless legs syndrome. Sleep 1996; 19:52-8. Walters AS, HeningW, Rubinstein Metal. A clinical and polysomnographic comparison of neurolepticinduced akathisia and the idiopathic restless legs syndrome. Sleep 1991; 14:339-45. Walters AS, Hickey K, Maltzman J et al. A questionnaire study of 138 patients with restless legs syndrome: the 'Night-Walker's' survey. Neurology 1996; 46:92-5. Ward WA, Kelsey WM. The Pickwickian syndrome: A review of the literature and report of a case. JPediatr 1962; 61:745-50. WareJC, Brown FU, Moorad ?}etal. Nocturnal myoclonusand tricyclicantidepressants.5/eep/to 1984; 13:72. Whyte KF, Allen MB, Jeffrey AA et al. Clinical features of the sleep apnoea/hypopnoea syndrome. QJ Med 1989;72:659-66. Whyte J, Kavey NB, Gidro-Frank S. A self-destructive variant of jactatio capitis nocturnaj Nerv Ment Dis 1991;179:49-50. Will RG, Young JPR, Thomas DJ. Kleine-Levin syndrome: report of two cases with onset of symptoms precipitated by head trauma. BrJ Psychiatry 1988; 152:410-12. Wille S. Comparison of desmopressin and enuresis alarm for nocturnal enuresis. Arch Dis Child 1986; 61:30-3. Wilson SAK. The narcolepsies. Brain 1928; 51:63-109. Wilson SJ, Lillywhite AR, PotokarJPef o/. Adult night terrors and paroxetine. Lancet 1997; 350:185. WinkelmanJW, ChertowGM, Lazarus JM. Restless legs syndrome in end-stage renal disease. Am J Kidney Dis 1996; 28:372-8. Winkelmann J, Wetter TC, Collado-Seidel V et al. Clinical characteristics of the hereditary restless legs syndrome in a population of 300 patients. Sleep 2000; 23:597-602.

19 Cerebral tumors and hydrocephalus Cerebral tumors Hydrocephalus

633 636

Normal-pressure hydrocephalus

639

CEREBRAL TUMORS Pathology and etiology Cerebral tumors can be divided into two main groups: metastatic and primary. Metastatic tumors most commonly have their source in the lung, breasts, skin (i.e. melanoma), gastrointestinal tract (especially the colon and rectum), and kidneys. Testicular and thyroid cancers, although not common in themselves, are, however, particularly likely to metastasize to the brain. Metastases generally occur by hematogenous spread, may be solitary or multiple, and are often found at the gray-white junction (Delattre et al. 1988). Rarely, widespread leptomeningeal metastases may occur, giving rise to a condition known as carcinomatous meningitis. Of all the primary cerebral tumors, gliomas are the most common, followed by menigiomas. Other types include neuronal and neuronal-glial tumors, primary central nervous system lymphomas, and colloid cysts of the third ventricle. Gliomas arise from various glial cells, such as astrocytes, oligodendroglia, ependymal cells, and are named accordingly: thus, there are astrocytomas, oligodendrogliomas, and ependymomas. Each type has various distinctive features. Astrocytomas tend to involve the subcortical white matter and may be found in the corpus callosum and frontal, temporal, or parietal lobes. These tumors tend to be infiltrative and are not sharply demarcated from the surrounding tissue. They are subdivided according to their malignant potential into four grades: grades I and II are often referred to as 'low-grade', and grades III and IV 'high-grade', astrocytomas, grade IV being the highly malignant tumor known as glioblastoma multiforme. A rare form of high-grade astrocytoma appears in a multifocal, miliary fashion, creating a condition known as 'gliomatosis cerebri'. Oligodendrogliomas are generally subcortical and tend to involve the frontal or temporal lobes. These tumors are generally slower growing than astrocytomas (Wilkinson et al. 1987), and about one-third of them exhibit calcification. Ependymomas arise from the ventricular ependyma and may grow into the ventricle itself or expand into the adjacent tissues. Meningiomas arise from the meninges, with which they maintain a connection. Common meningeal sites of origin include the falx cerebri, olfactory groove, lateral convexity, tentorium

634 Specific disorders

cerebelli, and tuberculum sellae. These tumors are generally very slow growing and are sharply demarcated from the surrounding tissue, as illustrated in Fig. 19.1. Neuronal and neuronal-glial tumors include gangliocytomas and gangliogliomas (the terminology here derives from the older designation for pyramidal neurons, namely ganglion cells). Gangliocytomas (Kernohan etal. 1932) and gangliogliomas (Morris etal. 1993) maybe either infratentorial or supratentorial; when supratentorial, they are generally found in the temporal, frontal, or parietal cortices, often presenting with seizures. Primary central nervous system lymphoma may occur in both immunocompetent and immunocompromised patients, for example transplant patients (Schneck and Penn 1970) and in AIDS, where it is seen in a significant minority (Feiden et al. 1993; Lang et al. 1989). Colloid cysts of the third ventricle may compress the surrounding diencephalic tissue or, by obstructing the foramen of Monro, cause hydrocephalus, as illustrated in Fig. 19.2. Certain inherited disorders are characterized by cerebral tumors, including tuberous sclerosis and von Recklinghausen's disease, discussed in Chapter 9. Clinical features

The onset of brain tumors ranges from acute to insidious, depending, in large part, on the aggressiveness of the tumor involved. Certain astrocytomas, such as glioblastoma multiforme, may evolve rapidly over several weeks or months, whereas some meningiomas may attain a large size without causing symptoms (Olivero et al. 1995) and may indeed be found incidentally on imaging for other reasons or at autopsy. Acute, stroke-like onsets may also occur, as for example with hemorrhage inside a high-grade astrocytoma or if a tumor compresses and occludes a nearby cerebral vessel and causes infarction. Although the presenting symptomatology of the tumor necessarily varies according to its location and to the amount of surrounding edema, there are nevertheless three common presentations. First, there may be a slowly progressive focal deficit, for example, hemiparesis

Image Not Available

Figure 19.1 A sagittal Tl-weighted magnetic resonance imaging scan demonstrates the clear demarcation between a meningioma and the surrounding tissue. (Reproduced from Gillispie and Jackson 2000.)

Cerebral tumors and hydrocephalus 635

Image Not Available

Figure 19.2 This unenhanced computed tomography scan demonstrates a colloid cyst, which has, by obstructing the foramen of Monro, caused obstructive hydrocephalus with dilatation of the lateral ventricles. (Reproduced from Gillispie and Jackson 2000.)

or aphasia. Second, when the cortex is involved, there may be seizures, which may be either partial or partial with secondary generalization. Finally, the onset may be of the 'global' or 'non-focal' type. Patients in this latter group may present with personality change, dementia, somnolence (Davison and Demuth 1945, 1946; McKendree and Feinier 1927), or headache. The headache is often caused by pressure exerted by the tumor on pain-sensitive structures and tends to be worse in the morning and when lying down. Increased intracranial pressure may occur, because of an expansion of the tumor itself, peri-tumoral edema, or the appearance of hydrocephalus. Should intracranial pressure increase, headache, if already present, worsens and is typically joined by vomiting, somnolence, gait disturbance, and incontinence. Frontal lobe tumors may present with either a personality change (Direkze et al. 1971; Strauss and Keschner 1935), often of the frontal lobe type (Avery 1971) (see Chapter 7), or a dementia (Sachs 1950), many patients eventually exhibiting both syndromes (Frazier 1936). The dementia is often characterized by apathy, dullness, and somnolence (Williamson 1896). Uncommonly, a psychosis may also appear (Strauss and Keschner 1935). Corpus callosum tumors involving the genu or anterior portion of the body may present with depression (Ironside and Guttmacher 1929) or with symptomatology similar to that seen in tumors of the frontal lobes (Alpers and Grant 1931; Beling and Martland 1919; Moersch 1925), including a dull, forgetful dementia, a personality change of the frontal lobe type, or a psychosis (Murthy et al 1997). Temporal lobe tumors may present with a personality change, a delirium (Keschner et al. 1936), or a psychosis (Gal 1958; Keschner et al. 1936; Malamud 1967; Strobos 1953; Tucker et al 1986); complex partial seizures are also characterisitic (Mulder and Daly 1952). Hypothalamic tumors may be suspected when endocrinologic changes, such as diabetes insipidus or amenorrhea occur; other cases may be marked by anorexia with profound weight loss (Heron and lohnston 1976; White et al 1977) or hyperphagia with extreme weight gain

636 Specific disorders

(Real et al. 1981; Fulton and Bailey 1929; Liss 1958), which is, in some cases, accompanied by episodic rage (Haugh and Markesbery 1983; Reeves and Plum 1969). In addition to these endocrinologic and vegetative changes, patients may also undergo a personality change or develop a dementia (Alpers 1937; Liss 1958; Strauss and Globus 1931) or a delirium (Alpers 1940). Colloid cysts of the third ventricle may cause dementia (Kelly 1951), this resulting from either obstruction of the foramen of Monro with hydrocephalus or compression of the surrounding diencephalic tissue (Paris and Terrence 1989; Lobosky et al. 1984). Magnetic resonance imaging (MRI) is indicated in all cases of suspected cerebral tumor. The electroencephalogram may show focal slowing but is far less sensitive than MRI. Lumbar puncture carries the risk of herniation and is generally not required. Except in the case of tumors with distinctive MRI characteristics (e.g. a meningioma of the falx), brain biopsy is often required to make a definitive diagnosis. Course The course is, for the most part, determined by the malignancy of the tumor, survival ranging from months in the case of, for example, glioblastoma multiforme, to decades in the case of certain meningiomas. Acute exacerbations may occur secondary to intra-tumoral hemorrhage or obstructive hydrocephalus. Differential diagnosis

In patients wilh systemic cancer, the appearance of neuropsychiatric symptomatology should, in addition to suggesting metastatic disease, also prompt the consideration of a paraneoplastic syndrome, such as limbic encephalitis. The treatment of brain tumors may itself cause significant neuropsychiatric symptomatology, for example mania with steroid treatment and delirium or dementia with chemotherapy. When radiation is used, an early- or late-delayed radiation encephalopathy must also be considered. Immunoincompetent patients with cerebral mass lesions must also be evaluated for opportunistic infections. Treatment

Corticosteroid treatment with dexamethasone is indicated whenever there is any significant edema and may at times offer dramatic, albeit temporary, relief. Accessible tumors may be approached surgically for either debulking or, in the case of well-demarcated lesions, excision. Except in cases in which the lesion is totally excised, radiation treatment is also generally indicated. The indications for chemotherapy for primary brain tumors are, although expanding, still limited. Seizures constitute an indication for anticonvulsant treatment, with for example phenytoin, divalproex, or carbamazepine. Anticonvulsants are also used prophylatically in the case of tumors that are very likely to produce seizures, as for example high-grade astrocytomas. The general treatment of dementia and delirium is discussed in Chapter 5.

HYDROCEPHALUS Pathology and etiology

The overall volume of the cerebrospinal fluid is about 140 cc3, of which about 20 cc3 is contained within the lateral ventricles and only about 5 cc3 is found within the third and fourth ventricles. Cerebrospinal fluid is produced at a rate of about 20 crrrYhour, and about three-quarters of the total cerebrospinal fluid production occurs in the choroid plexus, the rest

Cerebral tumors and hydrocephalus 637

Image Not Available

Figure 19.3 Massive enlargement of the lateral ventricles in a case of communicating hydrocephalus, as demonstrated on a T2-weighted magnetic resonance imaging scan. (Reproduced from Gillispie and Jackson 2000.)

originating via transependymal flow. Cerebrospinal fluid produced within the lateral ventricles normally flows through the foramen of Monro into the third ventricle and thence via the aqueduct of Sylvius into the fourth ventricle, from which it exits via the foramina of Magendie and Luschka into the subarachnoid space sourrounding the brainstem. From here, the cerebrospinal fluid circulates around the cord and brain, and finally arrives at the cerebral convexity; here, it leaves the subarachnoid space via the villi of the arachnoid granulations into the dural sinuses, where it is mixed with venous blood. Hydrocephalus is characterized by an enlargement of one or more of the ventricles owing to an increase in cerebrospinal fluid pressure, and is usefully divided into two types: noncommunicating and communicating. In non-communicating hydrocephalus, the 'communication' between the ventricular system and the subarachnoid space is partially or totally blocked, thus hindering or totally preventing the egress of cerebrospinal fluid from the ventricles into the subarachnoid space. Thus, non-communicating hydrocephalus may occur secondary to tumors that occlude the foramen of Monro, tumors of the third ventricle (Riddoch 1936), compression of the third ventricle by an ectatic basilar artery (Brieg et al. 1967; Ekbom et al. 1969), aqueductal stenosis (Nag and Falconer 1966; Wilkinson et al. 1966), tumors of the fourth ventricle, or an obstruction of the exit foramina, as may occur secondary to meningeal scarring after a bout of meningitis. In communicating hydrocephalus, although the egress of cerebrospinal fluid into the subarachnoid space is not blocked, there may be a block further 'downstream', usually at the level of the arachnoid granulations, as may occur after subarachnoid hemorrhage when blood

638 Specific disorders

in the arachnoid granulations prompts a degree of inflammatory scarring (Ellington and Margolis 1969; Theander and Granholm 1967). Rarely, communicating hydrocephalus may occur secondary to an actual overproduction of cerebrospinal fluid, as may occur with a choroid plexus papilloma (Eisenberg et al. 1974). Communicating hydrocephalus is, as might be expected, generally associated with an increase in cerebrospinal fluid pressure as measured at lumbar puncture. An important exception to this rule is the condition known as normal-pressure hydrocephalus, which is treated separately below. Clinical features

From a clinical point of view, it is useful to divide hydrocephalus into acute and chronic forms. Acute hydrocephalus generally results from a total or near-total blockade of cerebrospinal fluid flow and presents over days, or even hours, as a medical emergency with stupor or coma. By contrast, chronic hydrocephalus, occurring secondary to only a partial block to cerebrospinal fluid flow, presents gradually, even insidiously. The full syndrome of chronic hydrocephalus (Gustafson and Hagberg 1978; Harrison et al. 1974) comprises a gait disturbance, dementia, and urinary incontinence, and typically presents with either a disturbance in gait or a dementia. The gait is usually broad based and shuffling, and may, at times, exhibit a 'magnetic' quality wherein patients have difficulty initiating each step, as if the feet were somehow magnetically'stuck' to the floor. The dementia is often characterized by loss of initiative, fbrgetfulness, and a slowing of emotional and cognitive activity; rarely, akinetic mutism may occur (Messert et al. 1966). In addition to the foregoing, headache is also common, and there may be hyperreflexia in the lower extremities and extensor plantar responses. Papilledema may be seen but is not a constant feature. Of interest, there is also an association between aqueductal stenosis and psychosis (Revely and Revely 1983; Roberts et al 1983). Although ventriculomegaly may be demonstrated by both computed tomography (CT) and MRI scanning (see Fig. 19.3 above), MRI scanning is far more capable of demonstrating the various lesions responsible. Course Acute hydrocephalus may be rapidly fatal. The course of chronic hydrocephalus is dependent on the underlying etiology: in some cases, a new equilibrium is reached between the effects of the increased cerebrospinal fluid pressure and the resistance of the surrounding cerebral tissue such that further ventriculomegaly no longer occurs, resulting in 'arrested' hydrocephalus. Differential diagnosis

Hydrocephalus must be distinguished from a condition known as 'hydrocephalus ex vacuo': in this, widespread cortical atrophy leads not only to sulcal enlargement, but also to a proportionate degree of ventricular enlargement. The clue here is the fact that the sulcal enlargement is proportionate, indicating that the ventricular enlargement reflects not increased pressure of the cerebrospinal fluid within the ventricles but simply a compensatory enlargement in the face of the shrinkage of the surrounding cerebral tissue. Another differential point is the presence or absence of an increased signal intensity on T2-weighted MRI scanning around the entire ventricular border: this pattern of increased signal intensity reflects widespread transependymal fluid extravasation secondary to the increased pressure of the fluid within the ventricle and is thus not generally present in cases of hydrocephalus ex vacuo. Chronic hydrocephalus may present a clinical picture similar to that seen in Alzheimer's disease or Binswanger's disease, but this differential question is rapidly answered upon imaging.

Cerebral tumors and hydrocephalus 639

Normal-pressure hydrocephalus, discussed in the following section, is distinguished from other causes of communicating hydrocephalus by the fact that the cerebrospinal fluid pressure upon lumbar puncture is within normal limits. Treatment

Treatment is directed at the underlying cause; in many causes, shunting is required, and this should be considered even in cases of arrested hydrocephalus as these patients may also benefit (Larsson et al. 1999). The overall treatment of dementia is discussed in Chapter 5.

NORMAL-PRESSURE HYDROCEPHALUS Pathology and etiology

Normal-pressure hydrocephalus is a kind of chronic, communicating hydrocephalus, as described above. As noted there, the distinguishing characteristic of this hydrocephalus is the fact that the cerebrospinal fluid is, on lumbar puncture, generally of normal pressure or, if elevated in pressure, only slightly so. This absence of an increased pressure initially posed a significant puzzle as there then seemed to be no clear explanation for the ventriculomegaly. Eventually, however, it was found that, although the pressure was not consistently elevated, intermittent waves of increased pressure did in fact occur, especially at night (Packard 1982). Although, in some cases, a cause such as head injury (Hakim and Adams 1965), meningitis (Packard 1982), or subarachnoid hemorrhage (Symon and Dorsch 1975), can be determined, in many the mechanism underlying the block to cerebrospinal fluid passage through the arachnoid villi is unknown. Clinical features

Normal-pressure hydrocephalus generally presents gradually in the seventh or eighth decade. The clinical picture is similar to that described for chronic hydrocephalus in the preceding section, with the exception that headache is uncommon. Thus, when the condition is fully evolved, one generally sees dementia, gait disturbance, and urinary incontinence or, at times, merely urinary urgency (Adams et al. 1965; Gallassi et al. 1991; Hill et al. 1967). As with other forms of chronic hydrocephalus, the dementia is typcially characterized by indifference, forgetfulness, and slowness of thought and action. In a minority of cases, however, other features may dominate the clinical picture, for example depression (Pujol et al. 1989), personality change (Rice and Gendelman 1973), or, rarely, either aggressiveness (Crowell et al. 1973; Sandyk 1984) or mania (Kwentus and Hart 1987). MRI scanning reveals the ventriculomegaly. Course Although spontaneous arrest may occur, the symptoms, in most cases, gradually progress to the point at which the patient becomes bedfast and mute. Differential diagnosis

Other forms of communicating hydrocephalus are distinguished by an elevated cerebrospinal fluid pressure at lumbar puncture. Treatment

In some cases, shunting may be followed by a significant, even dramatic, degree of recovery (Graff-Radford et al. 1989; Raftapoulos et al. 1994). The best method for determining which patients are most likely to benefit from shunting has not as yet been determined. It appears

640 Specific disorders

that shunting is more likely to be of benefit when it is carried out early in the course, especially when the onset has been relatively acute. It also appears that a good response is likely if, after the withdrawal of a large amount of fluid at lumbar puncture, there is significant, albeit temporary, improvement (Sand et al. 1994).

REFERENCES Adams RD, Fisher CM, Hakim S, et al. Symptomatic occult hydrocephalus with 'normal' cerebrospional fluid pressure. N EnglJ Med 1965; 273:117-26. Alpers BJ. Relation of the hypothalamus to disorders of personality: report of a case. Arch Neurol Psychiatry 1937; 38:291-303. Alpers BJ. Personality and emotional disorders associated with hypothalamic lesions. In: Fulton JF, Ranson SW, Frantz AM (eds). Research publications. Association for Research in Nervous and Mental Disease. Vol XX. The hypothalamus and central levels of autonomic function. Baltimore: William & Wilkins, 1940. Alpers BJ, Grant FC. The clinical syndrome of the corpus callosum. Arch Neurol Psychiatry 1931;

25:67-86. AveryTL. Seven cases of frontal tumor with psychiatric presentation. BrJ Psychiatry 1971; 119:19-23. Beal MF, Kleinman GM, Ojemann RG, et al. Gangliocytoma of third ventricle: hyperphagia, somnolence, and dementia. Neurology 1981; 31:1224-8. Beling CC, Martland HS. A case of tumor of the corpus callosum and frontal lobes, y Nerv Ment Dis 1919; 50:425-32. BriegA, Ekbom K, Greitz T, et al. Hydrocephalus due to elongated basilar artery: a new clinicoradiological syndrome. Lancet 1967; 1:874-5. Crowell RM, Tew JM, Mark VH. Aggressive dementia associated with normal pressure hydrocephalus. Neurology 1973; 23:461^. Davison C, Demuth EL. Disturbances in sleep mechanism: a clinicopathologic study. I. Lesions at the cortical level. Arch Neurol Psychiatry 1945; 53:399-406. Davison C, Demuth EL. Disturbances in sleep mechanism: a clinicopathologic study. III. Lesions at the diencephalic level (hypothalamus). Arch Neurol Psychiatry1946; 55:111-25. DelattreJY, KrolG, Thaler H~[,etal. Distribution of brain metastases./4rc/j Mwo/1988; 45:741^. Direkze M, BaylissSG, Cutting JC. Primary tumors of the frontal lobe. BrJClin Practl971; 25:207-13. Eisenberg HM, McComb JG, Lorenzo AV. Cerebrospinal fluid overproduction and hydrocephalus associated with choroid plexus papilloma.y Neurosurg 1974; 40:381-5. Ekbom K, Greitz T, KugelbergE. Hydrocephalus due to ectasia of thebasilarartery.y/Vew/'o/Sc/1969; 8:465-77. Ellington E, Margolis G. Block of arachnoid villus by subarachnoid hemorrhage, y Neurosurg 1969; 30:651-7. FarisAA, TerrenceCF. Limbic system symptomatology associated with colloid cyst of the third ventricle.) Neurol 1989; 236:60-1. Feiden W, Bise K, Steude U, et al. The stereotactic biopsy diagnosis of focal intracerebral lesions in AIDS patients. Acta Neurol Scand 1993; 87:228-33. Frazier CH. Tumor involving the frontal lobe alone: a symptomatic survey of one hundred and five verified cases. Arch Neurol Psychiatry 1936; 35:525-71. Fulton JF, Bailey P. Tumors in the region of the third ventricle: their diagnosis and relation to pathological sleep.) Nerv Ment Dis 1929; 69:1-25. Gal P. Mental symptoms in cases of tumor of the temporal \obe.AmJ Psychiatry 1958; 115:157-60.

Cerebral tumors and hydrocephalus 641 Gallassi R, MorrealeA, Montagna P,etal. Binswanger's disease and normal-pressure hydrocephalus: clinical and neuroradiological comparison. Arch Neurol 1991; 48:1156-9. GillispieJ, Jackson A. MRI and CTof the brain. London: Arnold, 2000. Graff-Radford NR, GoderskyJC, Jones MP. Variable predicting surgical outcome in symptomatic hydrocephalus in the elderly. Neurology 1989; 39:1601-4. Gustafson L, Hagberg B. Recovery in hydrocephalic dementia after shunt operation. J Neurol Neurosurg Psychiatry 1978; 41:940-7. Hakim S, Adams RD. The special clinical problems of hydrocephalus with normal cerebrospinal pressure. 7 Neurol Sci 1965; 2:307-27. Harrison MJG, Robert CM, Uttley D. Benign aqueductal stenosis in adults. J Neurol Neurosurg Psychiatry 1974; 37:1322-8. Haugh RM, Markesbery WR. Hypothalamic astrocytoma: syndrome of hyperphagia, obesity and disturbances of behavior and endocrine and autonomic function. Arch Neurol 1983; 40:560-3. Heron GB, Johnson DA. Hypothalamic tumor presenting as anorexia nervosa. Am) Psychiatry 1976; 133:580-2. Hill ME, Lougheed WM, Barnett HJM. A treatable form of dementia due to normal pressure, communicating hydrocephalus. CMAJ1967; 97:1309-11. Ironside R, Guttmacher M. The corpus callosum and its tumors. Brain 1929; 52:442-83. Kelly R. Colloid cysts of the third ventricle: analysis of twenty-nine cases. Brain 1951; 74:23-65. Kernohan JW, Learmonth JR, Doyle JB. Neuroblastomas and gangliocytoma of the central nervous system. Brain 1932; 55:287-310. Keschner M, Bender MB, Strauss I. Mental symptoms in cases of tumor of the temporal lobe. Arch Neurol Psychiatry 1936; 35:572-96. KwentusJA, Hart RP, Normal pressure hydrocephalus presenting as manla.J Nerv Ment Dis 1987; 175:500-2. LangW, MiklossyJ, DeruazJP, rto/. Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland. Ada Neuropathon989; 77:379-90. Larsson A, Stephenson H, Wikkelso C. Adult patients with 'asymptomatic' and 'compensated' hydrocephalus benefit from surgery. Acta Neurol Scand 1999; 99:81-90. Liss L Pituicytoma, a tumor of the hypothalamus./4/rto Neurol Psychiatry 1958; 80:567-76. LoboskyJM, VangilderJC, DamasioAR. Behavioral manifestations of third ventricular colloid cysts.7 Neurol Neurosurg Psychiatry 1984; 47:1075-80. McKendree CA, Feinier L. Somnolence: its occurrence and significance in cerebral neoplasms. Arch Neurol Psychiatry 1927; 17:44-56. Malamud N. Psychiatric disorder with intracranial tumors of limbic system. Arch Neurol 1967; 17:113-23. Messert B, Henke TK, Langheim W. Syndrome of akinetic mutism associated with obstructive hydrocephalus. Neurology 1966; 16:635^9. Moersch FP. Psychic manifestations in cases of brain tumors. AmJ Psychiatry 1925; 81:707-24. Morris HH, Estes ML, Gilmore R, etal. Chronic intractable epilepsy as the only symptom of primary brain tumor. Epilepsia 1993; 34:1038-43. Mulder DW, Daly D. Psychiatric symptoms associated with lesions of temporal \obe.JAMA 1952; 150:173-6. Murthy P, Jayakumar PN, Sampat S. Of insects and eggs: a case report. J Neurol Neurosurg Psychiatry

1997;63:522-3. Nag TK, Falconer MA. Non-tumoral stenosis of the aqueduct in adults. BMJ1966; 2:1168-70. Olivero WC, Lister JR, Elwood PW. The natural history and growth rate of asymptomatic menigiomas.y Neurosurg 1995; 83:222-4. Packard JD. Adult communicating hydrocephalus. BrJ Hosp Med 1982; 27:35-44.

642 Specific disorders Pujol J, Leal S, Fluvia X, etal. Psychiatric aspects of normal pressure hydrocephalus. BrJ Psychiatry 1989; 154(suppl4):77-80. Raftapoulos C, Deleval J, Chaskis C, etal. Cognitive recovery in idiopathic normal pressure hydrocephalus: a prospective study. Neurosurgery 1994; 35:397-405. Reeves AG, Plum F. Hyperphagia, rage and dementia accompanying a ventromedial hypothalamic neoplasm. Arch Neural 1969; 20:616-24. Reveley AM, Revely MA. Aqueduct stenosis and schizophrenia.) Neural Neurosurg Psychiatry 1983;

46:18-22. Rice E, Gendelman S. Psychiatric aspects of normal pressure hydrocephalus. JAMA 1973; 223:409-12. Riddoch G. Progressive dementia, without headache or changes in the optic discs, due to tumors of the third ventricle. Brain 1936; 59:225-33. Roberts JKA, Trimble MR, Robertson M. Schizophrenic psychosis associated with aqueduct stenosis in adults. 7 Neurol Neurosurg Psychiatry 1983; 46:892-8. Sachs E. Meningiomas with dementia as the first and presenting feature.) MentSci 1950; 96:998-1007. Sand T, Bovin G, Grimse R, et al. Idiopathic normal pressure hydrocephalus: the CSF tap-test may predict the clinical response to shunting. Acta Neurol Scand 1994; 89:311-16. SandykR. Aggressive dementia in normal-pressure hydrocephalus. SAfrMedJ 1984; 65:114. SchneckSA, Penn I. Cerebral neoplasms associated with renal transplantation. Arch Neurol 1970; 22:226-33. Strauss I, Globus JH. Tumor of the brain with disturbance in temperature regulation. Arch Neurol Psychiatry 1931; 25:506-22. Strauss I, Keschner M. Mental symptoms in cases of tumor of the frontal lobe. Arch Neurol Psychiatry 1935; 33:986-1007. Strobos RRJ. Tumors of the temporal lobe. Neurology 1953; 3:752-60. Symon L, Dorsch NWG. Use of long-term intracranial pressure measurements to assess hydrocephalic patients prior to shunt surgery../ Neurosurg 1975; 42:258-73. Theander S, Granholm L Sequelae after spontaneous subarachnoid hemorrhage, with special reference to hydrocephalus and Korsakoffs syndrome. Acta Neurol Scand 1967; 43:479-88. Tucker GJ, Price TRP, Johnson VB,et al. Phenomenology of temporal lobe dysfunction: a link to atypical psychosis: a series of cases. J Nerv Merit Dis 1986; 174:348-56. White JH, Kelly P, Dorman K. Clinical picture of atypical anorexia nervosa associated with a hypothalamic tumor. AmJ Psychiatry 1977; 134:323-5. Wilkinson HA, Lemay M, Drew JH. Adult aqueductal stenosis. Arch Neurol 1966; 15:643-8. Wilkinson I M, Anderson JR, Holmes AE. Oligodendroglioma: an analysis of 42 cases.] Neurol Neurosurg Psychiatry 1987; 50:304-12. Williamson RT. On the symptomatology of gross lesions (tumors and abscesses) involving the pre-frontal regions of the brain. Brain 1896; 19:346-65.

20 Idiopathic psychotic, mood, and anxiety disorders Schizophrenia

643

Postpartum blues

Schizoaffective disorder Delusional disorder Postpartum psychosis

648 649 650

Panic disorder Agoraphobia Simple (specific) phobia

Bipolar disorder

651

Social phobia

Major depression

656

Obsessive-compulsive disorder

Premenstrual syndrome

659

Post-traumatic stress disorder

Postpartum depression

660

Generalized anxiety disorder

661 662 664 664 665 667 669 670

SCHIZOPHRENIA Pathology and etiology

Schizophrenia, first identified as dementia praecox by Morel in 1860 (Anonymous 1954), was definitively described first by Emil Kraepelin, followed by Eugen Bleuler. Although the neuropathology of schizophrenia has attracted investigative effort for over a century, it is only recently that such efforts have begun to bear fruit. Both computed tomography (CT) and magnetic resonance imaging (MRI) studies have amply demonstrated the presence of ventricular dilatation and cortical atrophy, most prominently in the mesial temporal cortex (Andreasen et al. 1990a; Chua and McKenna 1995; Suddah et al. 1989). Furthermore, several studies have also demonstrated a correlation between the degree of atrophy seen in the left temporal cortex and the severity of such psychotic symptoms as loosening of associations and auditory hallucinations (Barta et al. 1990; Hirayasu et al. 2000; Menon et al. 1995; Shenton et al. 1992). Autopsy studies support the results of neuroimaging, demonstrating a reduced volume in the medial temporal lobe structures (Bogerts et al. 1985, 1990) and a prominence of ventricular enlargement in the temporal horn (Crow et al. 1989). It is of interest that modern research has brought us full circle to Kraepelin's (1919) observation, made almost a century ago, that the clinical features of schizophrenia 'probably point to the temporal lobe being involved.' Microscopic studies have demonstrated the presence of an excessive number of ectopic neurons within the white matter (Akbarian et al. 1993 a, b, 1996) and neuronal disarray within the temporal lobe, specifically the hippocampus (Conrad et al. 1991). Strikingly,

644 Specific disorders

and importantly, gliosis is absent (Bogerts et al. 1985; Bruton et al. 1990; Roberts et al. 1987). The etiology of these neuropathologic changes, although not entirely clear, probably involves, at the very least, a disorder of neuronal migration. The fact that ventricular enlargement is present at the onset of the illness (Nopoulos et al. 1995; Turner et al. 1986), and that it does not undergo progression (Jaskiw et al. 1994), argues for an early lesion, such as might be seen in a disorder of neuronal migration. During normal fetal development neurons migrate out along radial fibers from the ventricular surface through the white matter, eventually to settle, in an orderly fashion, in the overlying cortex, and, again normally, one does not find neurons in the white matter. The presence of ectopic neurons in the white matter, as noted in the studies by Akbarian et al. (1993 a, b), is consistent with a failure of neuronal migration, as is the presence of neuronal disarray in the hippocampus (Conrad et al. 1991). The cause of such a disorder of neuronal migration in all likelihood has both genetic and environmental elements. Schizophrenia is clearly familial: whereas the overall risk of schizophrenia among unrelated members of the general populaton is about 1%, it rises to about 5% among siblings, 20% among dizygotic twins and approximately 50% for monozygotic twins. Although adoption studies have clearly indicated a genetic basis for this familial clustering (Kendler and Gruenberg 1984; Kety 1987), the fact that the monozygotic concordance rate is not even close to 100% strongly suggests that one or more environmental factors are at work, perhaps during a critical phase of embryogenesis (Davis and Bracha 1996). Several such environmental factors have been suggested, including maternal infection by a neurotropic virus (Murray 1994), maternal malnutrition (Susser and Lin 1992) and obstetrical complications (Kendell et al. 1996); it may indeed be that one or more factors may be operative in any given case. If indeed the neuropathology of schizophrenia represents a non-progressive disorder of neuronal migration, one must also explain why the onset of the disease is delayed until the late teenage or early adult years. One hypothesis is that the phenotypic expression of the disease is dependent upon an interaction beween the fixed neuronal migration defect and the normally evolving neuroanatomic changes seen during adolescence. During normal childhood and adolescence, there is a progressive and selective 'pruning' of dendrites, and, according to this hypothesis, the ability of the fixed neuronal migration defect to express itself clinically may have to wait until a specific degree and type of 'pruning' has cleared the way. Clinical features

The age of onset of schizophrenia, although generally falling in the late teens or early twenties, may range anywhere from late childhood to the seventh decade (Brodaty et al. 1999; Grahame 1984). A prodrome may or may not be present: in some cases; the premorbid personality may have been completely normal, whereas in others, peculiarities may have been present for years or even decades (Walker and Lewine 1990). The mode of onset ranges from gradual or insidious, spaning months or a year or more, to acute, the illness developing over a matter of weeks. The range of symptoms seen in schizophrenia is extraordinarily wide and includes hallucinations, delusions, formal thought disorder, 'negative' symptoms such as flattening of affect, avolition, poverty of thought or speech and catatonia. Hallucinations may occur in the auditory, visual, tactile, gustatory, and olfactory realms (Mueser et al. 1990). As noted by Kraepelin (1919), however, it is 'the hearing of voices' (italics in original) that is by far most 'peculiarly characteristic' of schizophrenia. Voices may come from inside the body or perhaps the air; sometimes they are sent by electronic devices or emerge from the walls or furniture. They often speak in short phrases and may, at times,

Idiopathic psychotic, mood, and anxiety disorders 645

manifest as commands, which patients may or may not be able to resist. Certain auditory hallucinations, included among the Schneiderian first rank symptoms although not specific for schizophrenia, are highly suggestive: these include voices that repeat the patient's thoughts, voices that comment on what the patient is doing, and voices that argue with each other. Visual hallucinations range from indistinct shadows to vivid, compellingly realistic scenes: patients may see other humans, the devil, or various creatures. Tactile hallucinations range from torturing pricks and stabbings to ineffably sweet caresses. Gustatory or olfactory hallucinations often come to light when patients complain that they can taste the poison in the food or perhaps smell the poisonous gas in the air. Delusions may be of persecution, grandeur, or reference. Patients may feel themselves persecuted by neighbors, co-workers, or perhaps various organizations, such as the FBI or the mafia. Grandiose delusions are exemplified by such beliefs that one is divine or perhaps possessed of great wealth and power. Referential delusions often accompany delusions of persecution or grandeur and, in a way, reinforce them. Patients experience otherwise random or unconnected events as being pregnant with meaning and pertaining, directly or indirectly, to themselves. The tolling of a church bell is a sign for the persecutors to close in; rays of sun emerging beyond parting clouds are a sign of God's special favor to them. Certain bizarre delusions, also included among the Schneiderian first rank symptoms, may occur, including the beliefs that one's thoughts are broadcast to others, that alien thoughts may somehow be directly inserted into the patient's mind, that thoughts may be directly withdrawn from the patient's mind, and, finally, that one's thoughts, feelings, or actions are controlled or influenced by outside forces. Formal thought disorder refers to specific disurbances not in the content of thought, but in its form, and includes loosening of associations, neologisms, tangentiality, and circumstantiality. In loosening of associations, thought becomes more or less incoherent, disconnected, and lacking in any discernible goal. At its most extreme, loosening of associations produces a 'word salad' wherein successive spoken words have no more inherent connection with each other than do the tossed leaves of a salad. Neologisms constitute fragments of a private language: one patient spoke often of 'murkies' but could offer no definition of the word. In tangentiality, the patient's train of associations literally takes off on a tangent, carrying the patient ever further away from the subject at hand. Circumstantiality is characterized by a lengthy and circuitous route to the subject at hand and may be distinguishable from tangentiality only after a long period of observation finally reveals that the patient does, eventually, get 'to the point'. 'Negative', or 'defect', symptoms (Andreasen 1982; Andreasen and Olson 1982; Andreasen et al. 1990b) include flattening of affect, avolition, and poverty of thought or speech. Patients with flattened affect seem affectively impoverished and dead: they neither evidence any emotional expression nor, importantly, feel any emotions. Avolition may leave patients in a peculiar state of quietude: although not depressed, and being able to do as they are instructed, these patients experience no strivings, inclinations, or intentions; if left alone, they may, thus unmotivated, pass hours doing literally nothing. Poverty of thought is allied to avolition: here patients simply have few, if any, thoughts and thus, having nothing to say, remain silent. Poverty of speech is said to occur when, despite a normal amount of speech, there is little content to what patients say: such impoverished speech may be vague, superficial, or composed largely of'stock' phrases. Catalonia, as described more fully in Chapter 3, exists in either of two forms: excited or stuporous. Both forms may be seen in schizophrenia, and, indeed, it is not uncommon to see individual patients with catatonic schizophrenia exhibit both forms at different times (Morrison 1973). Excited catatonics often engage in frenzied, bizarre, and purposeless behavior but, importantly, in the midst of this hyperactivity, remain isolated and to

646 Specific disorders

themselves: there is little or no drive to be involved with others. Stuporous catatonics display various combinations of immobility, negativism, mutism, bizarre posturing, and waxy flexibility. Other, more or less bizarre, symptoms include mannerisms and stereotypies. Mannerisms constitute gestures or facial expressions that have undergone bizarre transformations: a wave good-bye may be performed with the fingers of the hand bizarrely arched upward, and facial expressions may be distorted by grimaces and contortions. Speech may also undergo manneristic transformation, becoming dysmodulated, sing-song, telegraphic, or bizarrely accented. Stereotypies are mannerisms that repeatedly recur, to no apparent purpose. Affective symptoms, whether depressive or manic, are not uncommon in schizophrenia, but, importantly, they are not sustained but rather transient, lasting perhaps only hours or a few days. Schizophrenia is usefully divided into several subtypes, including paranoid, catatonic, hebephrenic (or 'disorganized'), simple, and a final residual category known as undifferentiated schizophrenia. Paranoid schizophrenia is characterized primarily by hallucinations and delusions, catatonic schizophrenia by catatonic symptoms, hebephrenic schizophrenia by loosening of associations, mannerisms and grossly disorganized and bizarre behavior, and simple schizophrenia (Black and Boffeli 1989; Kendler et al. 1994a) by the negative or 'defect' symptoms. The boundary line between these subtypes is not sharp, and although clear-cut cases commonly occur, many patients fall into gray areas and are best characterized as undifferentiated. Schizophrenia is a devastating disease; suicide attempts are seen in about one-third of patients (Allebeck et al. 1987), about one-tenth of sufferers eventually taking their lives (Tsuang 1978). Course Schizophrenia generally pursues one of two courses: in one, after an initial period of relatively severe symptomatology, there is a partial remission followed by a course that is either static or characterized by a very slow worsening; in the other, the symptoms gradually wax and wane over long periods of time. In some cases, exacerbations simply happen, with little or no recognizable environmental cause; in others, various environmental stresses, especially contact with harsh and critical family members, may precede exacerbations. Importantly, in about one-quarter of patients, partial remissions of psychotic symptoms may be followed, within months, by the appearance of a depression, the 'post-psychotic depression' (Mandel et al. 1982). Overall, patients with paranoid schizophrenia tend to have the best prognosis and those with hebephrenic schizophrenia the worst (Fenton and McGlashan 1991; Kendler et al. 1994b). Although it is clear that most patients with schizophrenia remain chronically disabled (McGlashan 1984; Tsuang et al. 1979), there is considerable controversy regarding whether or not schizophrenia ever, in the natural course of events and even in a small minority of patients, undergoes a full and complete remission. In this regard, Bleuler's opinion (Bleuler 1950) remains definitive. Bleuler doubted that a full cure, a restitutio ad integrum, ever occurred. Although he had seen 'far reaching improvements' to the point of'social restitution', he was always able, upon careful examination, always to 'see distinct signs of the disease'. Differential diagnosis

The differential diagnosis of psychosis is wide, as indicated in Chapter 7. Of the various differential possibilities, however, several deserve special comment here. In bipolar disorder and major depression, affective episodes, whether manic or depressive, may be accompanied by psychotic symptoms. Critically, however, in these mood disorders,

Idiopathic psychotic, mood, and anxiety disorders 647

psychotic symptoms always and only occur within the context of the affective symptoms and are not seen in the intervals between affective episodes. In schizoaffective disorder, patients experience not only sustained affective episodes, lasting 2 or more weeks, but also a worsening of their psychotic symptoms during the affective episodes. This sustained aspect of the affective episodes distinguishes schizoaffective disorder from schizophrenia, wherein the affective symptoms are typically transitory. In addition, regarding that minority of patients with schizophrenia who experience a post-psychotic depression, the fact that the post-psychotic depression of schizophrenia is not accompanied by an exacerbation of psychotic symptoms clearly distinguishes this kind of affective episode from that seen in schizoaffective disorder, wherein the affective episodes are routinely marked by a worsening of the pre-existing psychotic symptoms. Delusional disorder is distinguished from paranoid schizophrenia by the fact that, in delusional disorder, hallucinations are either not seen or at most occupy only a very minor part of the overall clinical picture. Alcohol hallucinosis and alcoholic paranoia may be suspected when a psychosis occurs in the setting of a chronic history of severe alcoholism. These disorders are, however, ruled out should one find evidence of loosened associations, mannerisms, or bizarre behavior, symptoms that are not seen in these alcohol-induced disorders. Neuroleptics used in the treatment of schizophrenia may, at times, cause side-effects that resemble the symptoms seen in schizophrehia itself. Neuroleptic-induced akathisia may, for example, be characterized by a gross exacerbation of psychotic symptoms (Van Putten 1975; Van Putten et al. 1974), and, importantly, this exacerbation may or may not be accompanied by restlessness. Certainly, in cases in which patients initially improve with neuroleptic treatment only then to deteriorate, a 'diagnosis by treatment response' approach should be considered, consideration being given to propranolol or, alternatively, benztropine. Neuroleptic-induced akinesia may also cause diagnostic problems as it may strongly resemble a depressive episode (King et al. 1995; Van Putten and May 1978). Thus, whenever depression appears to develop shortly after the institution of neuroleptic treatment, one might consider administering benztropine, again as a 'diagnosis by treatment response' intervention. Treatment

Neuroleptics constitute the mainstay of treatment in schizophrenia. The neuroleptics are currently divided into two broad groups: typical and atypical. The typical neuroleptics, also referred to as 'traditional' or 'classical', include such drugs as chlorpromazine, fluphenazine and haloperidol. Although generally effective, they often produce significant side-effects. The atypical neuroleptics include risperidone (Chouinard etal. 1993; Glaus et al. 1992), olanzepine (Tollefson et al. 1997; Tran et al. 1998), and clozapine (Rosenheck et al. 1997; Wahlbeck et al. 1999), these agents being, by and large, more effective than the typical neuroleptics. Of the atypical neuroleptics, although clozapine is the most effective (Kane et al. 1988), its numerous side-effects, including agranulocytosis, militate against its use except in treatmentresistant cases. Of the other two atypical neuroleptics, olanzepine probably has an edge over risperidone (Tran et al. 1997), especially with regard to side-effects. All other things being equal, olanzepine should probably be the first choice, risperidone following a close second. When non-compliance is a significant problem, as is often the case, consideration should be given to fluphenazine or haloperidol, both of which also come in long-acting injectable decanaote forms. A final neuroleptic to consider is quetiapine: although this drug is claimed to be 'atypical', and does indeed have fewer side-effects than the typical neuroleptics, it is unclear whether it is therapeutically superior to them (Copolov et al. 2000; Peuskens and Link 1997). In cases in which negative symptoms prove resistant to treatment, consideration may be

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given to adding an antidepressant such as fluvoxamine (Silver and Shmugliakov 1998), bearing in mind that fluvoxamine has the potential to increase the level of clozapine five-fold or more (Olesen and Linnet 2000). In general, given the chronic nature of schizophrenia, chronic treatment with a neuroleptic is indicated, dosage adjustments being made with respect to the level of symptoms and the presence of side-effects. One side-effect to be diligently watched for is tardive dyskineisa, as discussed in Chapter 22. Post-psychotic depression may be treated by adding an antidepressant to the neuroleptic (Siris et al. 1987), with plans to taper off and discontinue the antidepressant after the patient has been free of depressive symptoms for a month or more. In addition to ongoing treatment with a neuroleptic, most patients with schizophrenia will benefit from half-way houses, case management services, and ongoing counselling to help them weather the vicissitudes of life.

SCHIZOAFFECTIVE DISORDER Pathology and etiology Little is known regarding the etiology of this disorder. Among family members, there is an increased risk not only for schizoaffective disorder, but also for schizophrenia and for either major depression or bipolar disorder (Angst et al. 1979; Cohen et al. 1972; Pope et al. 1980), suggesting that the disorder could either 'breed true' or perhaps represent the concurrence of two disorders (i.e. schizophrenia plus a mood disorder) in the same unfortunate individual. Clinical features

The onset of schizoaffective disorder is in the late teens or early twenties, and, viewed over time, this disorder appears to represent an amalgamation of two disorders: a chronic one, namely schizophrenia, and an episodic one, either major depression or bipolar disorder. Thus, these patients, in addition to being chronically psychotic, also experience 'superimposed' episodes of either depression or of mania. Notably, during each episode of mood disturbance, the pre-existing psychotic symptoms worsen, and, critically, after the episode of either depression or mania clears, the psychotic symptoms, although lessening, do not clear entirely but persist. Course As noted above, this is a chronic disorder. Those cases which are characterized by both episodes of depression and episodes of mania are, appropriately enough, categorized as schizoaffective disorder, bipolar type, and those with only episodes of depression as schizoaffective disorder, depressed type. Differential diagnosis Schizophrenia may, at times, be characterized by transient mood shifts, towards either depression or excitation, but these are very brief, lasting hours or a few days at the most, rather than weeks, as seen in episodes of depresion or mania. Post-psychotic depression (McGlashan and Carpenter 1976), as seen in some cases of schizophrenia, is distinguished by the fact that, during the depression, there is no exacerbation of psychotic symptoms. Neuroleptic-induced akinesia (Van Putten and May 1978) may resemble depression and may, when occurring in the midst of an exacerbation of schizophrenia when neuroleptics are either started or increased, raise the suspicion of schizoaffective disorder. The occurrence of

Idiopathic psychotic, mood, and anxiety disorders 649

symptoms after the initiation of treatment with a neuroleptic or a substantial increase in dosage suggests the correct diagnosis, which may be confirmed by the response to treatment with an anticholinergic, such as benztropine. Both major depression and bipolar disorder may cause episodes of mood disturbance that are accompanied by psychotic symptoms. The critical differential feature here is the fact that, in the euthymic interval between the episodes, there are no psychotic symptoms. Treatment

In many cases, treatment with a neuroleptic alone will be effective for not only psychotic, but also mood symptoms; in this regard, it appears that olazepine is superior to haloperidol (Tran et al. 1999) and, by analogy, to other typical neuroleptics. Treatment with a mood stabilizer alone is generally not as effective (Prien et al. 1972). In those cases in which treatment with a neuroleptic alone is not able to control the mood symptoms, the addition of either a mood stabilizer (in patients with schizoaffective disorder, bipolar type) or an antidepressant (in schizoaffective disorder, depressed type) may be undertaken, using the guidelines suggested in the sections on bipolar disorder and major depression, below. In resistant cases electroconvulsive therapy (ECT) may be used (Abrams and Taylor 1976a).

DELUSIONAL DISORDER Pathology and etiology Little is known about the etiology of delusional disorder (paranoia), except that it is familial and that it is not associated with schizophrenia (Kendler et al. 1982,1985; Watt 1985; Winokur 1985). Clinical features

The onset of delusional disorder is gradual, even insidious, any time between the ages of 20 and 50 (Winokur 1977). Clinically (Kendler 1980, 1988), as pointed out by Kraepelin (1921), delusional disorder is characterized by 'the insidious development of a permanent and unshakable delusional system ... accompanied by perfect preservation of dear and orderly thinking, willing, and acting' (italics in original). Starting from one, or at the most, several, delusional 'premises', patients gradually elaborate an internally coherent and systematized corpus of belief. Common themes (Winokur 1977) include persecution, grandeur, jealousy, erotic longing, litigation, and various bodily or somatic concerns. Delusions of reference typically also occur and serve, as it were, to buttress the patients' primary delusions. Importantly, in addition to being systematized, the patients' delusions are also, at least to casual scrutiny, plausible: there is nothing bizarre about them. Furthermore, in those areas of life that lie 'outside' the patients' delusional system, patients often behave in a normal and totally unremarkable fashion. 'Inside' their delusional system, however, their behavior is consistent with their beliefs, and this may at times lead to violence (Kennedy et al. 1992): for example, patients with the persecutory subtype of delusional disorder who feel that their persecutors are 'closing in' might well feel justified in striking a blow for their own safety. Hallucinations may be seen in some cases, but they play at most only a very minor part in the overall symptomatology: the persecuted patient may 'hear' footsteps in the hallway, or the grandiose patient may occasionally hear angels whisper encouragement. Some peculiar variants of delusional disorder may be mentioned. These include parasittosis (Mitchell 1989), wherein patients believe that they are infested (Andrews et al. 1986), and the

650 Specific disorders

olfactory reference syndrome, wherein patients believe that they are emitting a foul odor that others can, and do, detect (Videbech 1966). Course

Delusional disorder generally pursues a chronic, waxing and waning course (Opjordsmoen and Rettersol 1991). Differential diagnosis

Of the various disorders capable of causing psychosis that are discussed in Chapter 7, two deserve special emphasis. Schizophrenia can cause delusions similar to those seen in delusional disorder, but in schizophrenia, in contrast to delusional disorder, the delusions are non-systematized, implausible, and often bizarre, often including Schneiderian first rank symptoms, which are not seen in delusional disorder. Furthermore, schizophrenia is also often characterized by symptoms and signs never seen in delusional disorder, such as loosening of associations, mannerisms, and 'negative' symptoms such as apathy, poverty of speech, or poverty of thought. Dysmorphophobia, or body dysmorphic disorder, may, at times, present with a delusional subtype wherein patients believe, rather than simply worry, that they may be disfigured. Here, although the clinical picture resembles that seen in the somatic subtype of delusional disorder, certain features allow a distinction bertween the two. First, patients with dysmorphophobia are concerned with appearance, whereas patients with delusional disorder are often concerned with other bodily matters, such as having an internal tumor or some disease. Second, in dysmorphophobia, there is a long symptomatic period before the development of delusions, during which patients display the typical picture of dysmorphophobia, a picture that is not present in the prodrome to delusional disorder. Treatment

Clinical management rests on a diplomatic and respectful approach to the patient: argument must be avoided, and coercion should be reserved as a last resort. Neuroleptics may partially reduce the strength of the delusions, and one should pick an agent that carries the least risk of side-effects, as patients with delusional disorder tend to be unaccepting of any adverse effects: in this regard, olanzepine is a reasonable choice. In offering a neuroleptic, it is important to present its indication in a fashion that patients might accept: whereas a prescription for 'nerves' might find acceptance, one for 'paranoia' would probably not. In some cases, for example when violence threatens, hospitalization, on an involuntary basis if necessary, is appropriate.

POST-PARTUM PSYCHOSIS Pathology and etiology

Although the etiology of postpartum psychosis is unknown, it appears reasonable to assume that it is, in some fashion, related to the dramatic endocrinologic changes occuring in the puerperium. Clinical features

The onset is acute, within several days or several months postpartum (Brockington etal. 1981; Munoz 1985). Clinically (Bagedahl-Strindlund 1986; Brockington et al. 1981; Hadley 1941; Kumar et al 1983), patients may present with agitation, lability, delusions, and hallucinations. Psychotic

Idiopathic psychotic, mood, and anxiety disorders 651

symptoms often center on the baby: the child is in fact the Christ, or perhaps the devil incarnate; voices may instruct the mother to kill the child or herself. Mood is often heightened, and insomnia may be severe. Some patients become delirious, with confusion and disorientation. Rarely, infanticide may occur (Rohde and Marneros 1993). Course

In the natural course of events, the psychosis spontaneously remits within a matter of weeks or months. The risk of another psychosis after subsequent pregnancies is high, up to one-third (Davidson and Robertson 1985; Kendell et al. 1987). Differential diagnosis Bipolar disorder may become partially entrained to the puerperium (Bratfos and Haug 1966), and a manic episode of bipolar disorder may, symptomatically, be quite similar to a postpartum psychosis. The essential differential point is the occurrence of affective episodes, either depressive or manic, outside the puerperium: these are not found in postpartum psychosis, whereas they are the rule in bipolar disorder. Schizophrenia or schizoaffective disorder may undergo a severe exacerbation in the puerperium, but the presence of symptoms during and before pregnancy will indicate the correct diagnosis. Eclampsia will rarely present during the puerperium. Here, the presence of hypertension, proteinuria, and seizures point away from postpartum psychosis. Treatment Neuroleptics have traditionally been used, but there are also case reports of effective treatment with mood stabilizers, used in a fashion similar to that for a manic episode of bipolar disorder: divalproex would seem a logical choice. Hospitalization is generally indicated, and the patient should be separated from the baby until sufficient recovery has occurred to allow for safe interaction: in general, it is best to have the first few mother-infant visits monitored by an experienced nurse. Breast-feeding is generally contraindicated. Treatment with a neuroleptic or mood stabilizer should generally be continued until the psychosis has had a chance to run its course. Should the patient elect to become pregnant again, close monitoring, at a minimum, is indicated after the next delivery, and, in some instances, a case might be made for instituting prophylactic treatment.

BIPOLAR DISORDER Pathology and etiology Bipolar disorder (manic-depressive illness, circular type) has a definite genetic component. The incidence of bipolar disorder is higher among the first-degree relatives of probands than among the general population (Gershon et al. 1982; Tsuang et al. 1985), and the monozygotic concordance rate is higher than the diszygotic one (Bertelsen et al. 1977). Although genetic studies have offered tantalizing clues, nothing definite can as yet be said about the mechanism of inheritance of this disorder. Although no definite neuropathologic findings have so far been identified, endocrinologic changes strongly suggest hypothalamic disturbances: the dexamethasone suppression test (DST) is generally positive (Rush et al. 1997), and the thyroid-stimulating hormone (TSH) response to thyrotrephin-releasing hormone (TRH) stimulation is blunted (Extein et al. 1980). It also appears that there may be a disturbance of cholinergic transmission in bipolar disorder: the infusion of physostigmine reliably precipitates depression in patients currently

652 Specific disorders

manic (Janowsky et al. 1973), and the latency to rapid eye movement (REM) sleep upon the infusion of arecoline is shortened in bipolar patients as compared with controls. Clinical features

Bipolar disorder is, above all, an episodic, or cyclic, illness and is characterized in almost all cases by more or less lengthy episodes of illness that are separated by intervals of more or less normal functioning. All patients with bipolar disorder have at least one episode of mania or mixed mania, and most patients will, in addition, also have at least one episode of depression. The onset of bipolar disorder is heralded by the appearance of a first episode of illness, which may be depressive, manic or mixed-manic. In general, most patients have their first episode in their late teens or early twenties, and by the age of 50, over 90% of patients will have had their first episode. The range of age of onset is, however, wide, from as young as 11 (McHarg 1954) up to the eighth decade (Charron et al. 1991), even as late as the age of 79 (Summers 1983). Manic episodes, as originally proposed by Kraepelin (Kraepelin 1921; Stevens 1904), and as elegantly outlined by Carlson and Goodwin (1973), may be usefully divided into three stages: stage I, or hypomania; stage II, or acute mania; and stage III, or delirious mania. All patients who enter a manic episode partake of hypomania, or stage I, most also progressing into stage II, or acute mania; only a minority, however, ascend to the very height of mania, stage III, or delirious mania. As described below, mania is often characterized by psychotic symptoms (Abrams and Taylor 1981; Black and Nasrallah 1989; Bowman and Raymond 1931; Brockington et al 1980; Lipkin et al. 1970; Rosenthal et al. 1979, 1980; Winokur 1984), and it is indeed the appearance of psychotic symptoms that marks the boundary between stages I and II. The onset of a manic episode may be gradual, with indistinct and fleeting symptoms appearing for days or weeks, or be abrupt, patients being propelled from normalcy to hypomania in less than a day. Hypomania, or stage I, is characterized by the cardinal manic symptoms of heightened mood, increased energy, and pressure of activity and of speech (Abrams and Taylor 1976a; Beigel and Murphy 1971a; Clayton et al. 1965; Loudon et al. 1977; Taylor and Abrams 1973; Winokur and Tsuang 1975; Winokur et al. 1969). The heightened mood may be one of either euphoria or irritability, or be a mixture of the two, and is often quite labile. Euphoric patients are in great good cheer and wish to share their immense enjoyment with others: they are often full of jokes, puns, and wisecracks, and their humor is often irresistibly infectious to those around them. Indeed, it is the rare physician who can resist at least inwardly smiling when in the presence of a euphoric manic. Irritable manics are, by contrast, irascible, fault-finding, and accusatory, and when their intemperate demands are not immediately met, they may erupt into a tirade of curses and threats, and indeed may become violently assaultive. Increased energy leaves these patients strangers to fatigue and in little need of sleep. Pressure of activity impels them to be ever on the go and perpetually involved in schemes, plans, projects, and activities, activities in which they also often seek to involve others. Pressured speech is rapid and voluble. Patients have much to say, their thoughts come rapidly and race pell-mell, and in extreme cases they cannot speak fast enough to express them. Although patients may, with great urging, be able momentarily to dam up their words, such respites, wherein an interviewer may be able to get a few words in, are but transient events before the dam bursts and the interviewer is again inundated with a torrent of words. Such pressured speech is also typically characterized by flight of ideas, wherein patients' interests change abruptly from one subject to another, successive subjects having little in common with each other. As might be expected, hypomanic patients often become involved in impetuous and illconsidered ventures: there may be spending sprees, intense, injudicious, and often sexual,

Idiopathic psychotic, mood, and anxiety disorders 653

relationships, and ruinous business ventures. Attempts to reason with such patients, and to bring them back to some good judgment, are typically in vain: hypomanic patients rarely see anything wrong with themselves; indeed, they often opine that if only others saw as they did, and partook of their confidence, all would be well. Acute, or stage II, mania is characterized by an intensification of all the symptoms seen in hypomania and by the appearance of delusions. The mood becomes extraordinarily heightened and labile, and irritability may be quite pronounced, with unpredictable assaults and tirades. Energy seems boundless, and the pressure of activity and speech may begin to fragment the patients' overall behavior: patients may shout, then cry, hop on the floor or race to the nurse's station, making one demand, then an opposite one, and be completely incapable of channelling themselves towards any one purpose. Delusions are typically either of grandeur or of persecution, according to the patients' mood. Euphoric patients may announce their divinity or lavish listeners with promises to share their great wealth; irritable patients may accuse others of irrationally thwarting and persecuting them. Such patients may occasionally also hear voices. Delirious, or stage III, mania represents the height of mania and is characterized by a sometimes startling metamorphosis. Speech and behavior become profoundly fragmented (Bond 1980). Loosening of associations may occur, and patients are often confused; some may become mute. Hallucinations and delusions abound, and in addition to delusions of grandeur or persecution, one may also see bizarre delusions, including Schneiderian first rank symptoms (Jampala et al. 1989). Catatonic stupor may appear, with immobility, waxy flexibility, and bizarre posturing (Abrams and Taylor 1976b; Taylor and Abrams 1977). The overall duration of a manic episode is generally of the order of weeks or months: the range, however, varies from as little as a few days, or even less, to up to a decade (Wertham 1929). As noted earlier, although all patients in a manic episode will experience hypomania, and most acute mania, only a minority progress to delirious mania. Regardless of the stage a given patient ascend to, the manic episode eventually resolves and defervesces, such that patients who do reach stage III gradually descend back through stage II into stage I and finally back into normalcy, a normalcy that is, however, often temporarily tinged with mild depressive symptoms and regret over what transpired during the mania. Mixed mania (Himmelhoch et al. 1976; Kotin and Goodwin 1972; McElroy et al. 1992) is a variant of mania wherein there is a strong admixture of depressive symptoms. In some cases, manic and depressive symptoms may rapidly alternate, and in others, they may exist simultaneously. Euphoric patients, singing and proclaiming their glory and beneficence, may suddenly be thrust into the profoundest of despair, weeping, bereft of all hope and energy, and intensely suicidal. Mixtures of manic and depressive symptoms may present a startling clinical picture: one patient strode through the ward, shouting unstoppably that he was the greatest of sinners and would die of unspeakable tortures. Such mixed episodes are less common than straight manic episodes but tend to last longer. Depressive episodes of bipolar disorder (Casper et al. 1985) tend to come on subacutely, over several weeks (Winokur et al. 1993), and tend to be characterized by depressed or irritable mood, anergia, anhedonia, poor concentration and memory, and changes in psychomotor activity, appetite, and sleep. In contrast to the depressive episodes of major depression, bipolar depressions tend to be characterized by psychomotor retardation (which may progress to the point of stupor [Johnson 1984]), an increased need for sleep, and an increased appetite (Beigel and Murphy 1971b; Hartmann 1968). Delusions and hallucinations are far more common in bipolar depressions than unipolar ones (Guze et al. 1975) and are 'mood congruent' in that they seem fitting when viewed in the context of the patients' overall mood. Patients may believe themselves to be the worst of sinners and that they are to be taken

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into imprisonment or to execution. Voices may accuse and condemn them, urging them on to suicide. These depressive episodes tend to last a half-year or so, but the range is wide, from as little as weeks up to years. Course As noted earlier, the first episode of illness may be either depressive, manic, or mixed-manic. The interval between episodes is generally measured in years but varies widely among patients, from the extremes of decades on the one hand, to days, or even hours, on the other (Bunney et al. 1972; Sitaram et al. 1978). Thus, in those with very long intervals, there may be only one or several episodes in their lifetime, whereas in those with very short intervals and correspondingly short episode durations, there may literally be well over a hundred episodes per year (Bunney and Hartmann 1965; Jenner et al. 1967). The relative proportion of episodes that are depressive, manic, or mixed-manic also varies widely, from depressive prominent to manic prominent to, rarely, cases wherein there are only manic episodes and no depressive ones during the patient's lifetime (Pfohl et al. 1982; Shulman and Tohen 1994). In cases in which the first episode of illness is a depressive one, it appears that in over 90% of cases, a manic episode will ensue within either 10 years or a total of five episodes of depression, whichever comes first (Dunner et al. 1976). Patients who experience four or more episodes of illness per year are customarily referred to as 'rapid cyclers' (Bauer et al. 1994; Dunner et al. 1977). Interestingly, it appears that, rapid cycling is, in some instances, associated with subclinical hypothyroidism (Bauer et al. 1990; Cowdry et al. 1983) (as may be induced by treatment with lithium [Terao 1993]), and, although controversial, it also appears that treatment of patients with bipolar disorder with antidepressants may induce rapid cycling (Altschuler et al. 1995). Manic episodes in patients with bipolar disorder may also become 'entrained' to certain biologic events, such as the puerperium (Bratfos and Haug 1966; Viguera et al. 2000) or the premenstruum (D'Mello et al. 1993). Certain medications and conditions may also precipitate manic episodes in patients with bipolar disorder, these including antidepressants, dopaminergic agents, corticosteroids, stimulants (e.g. cocaine and amphetamines), sympathomimetic drugs, the abrupt discontinuation of long-term treatment with clonidine, and withdrawal from alcohol or sedatives. Herbal preparations, such as St John's wort (Moses and Mallinger 2000), may also be at fault. Differential diagnosis

Of the many causes of mania discussed in Chapter 6, several deserve special emphasis. Cyclothymia is distinguished from bipolar disorder by the mildness of its symptoms: during manic periods in cyclothymia, the symptoms never become severe enough to qualify even for a diagnosis of hypomania. Cyclothymia is probably a forme fruste of bipolar disorder; indeed, in a substantial minority of cases of cyclothymia, a full bipolar disorder will emerge over time (Akiskal et al. 1977). Schizoffective disorder, bipolar type, is distinguished from biploar disorder by the presence of psychotic symptoms in the intervals between episodes of mood disturbance. Although psychotic symptoms certainly do occur in mania, they are confined to the manic episode itself and do not occur in the intervals, whereas in schizoaffective disorder, the psychotic symptoms persist beyond the resolution of the manic episode. Postpartum psychosis often has a distinct manic aspect but may be distinguished from a bipolar disorder that has become entrained to the puerperium by the fact that, in postpartum psychosis, symptoms occur only in the puerperium, whereas in bipolar disorder, episodes will be seen at other times in the patient's life.

Idiopathic psychotic, mood, and anxiety disorders 655

Treatment

The treatment of bipolar disorder is best considered by discussing manic and mixed manic episodes first and then depressive ones, in each instance touching on acute treatment, maintenance treatment and then preventive treatment. Manic or mixed-manic episodes are best treated acutely with a mood-stabilizing agent, such as lithium (Schou 1997), divalproex (Bowden et al. 1996; Keck et al 1993a), or carbamazepine (Ballenger and Post 1980; Okuma et al. 1990). Verapamil may also be effective (Garza-Trevino et al. 1992; Hoschl and Kozemy 1989), but not all studies have found this to be the case (Janicak et al. 1998). Trials are currently underway for gabapentin and lamotrigene, preliminary reports indicating that each of these may also be effective. Some authors advocate instituting acute treatment with a neuroleptic, such as olanzepine (Tohen et al. 1999) or haloperidol, but as haloperidol is no more efffective than divalproex alone (McElroy et al. 1996), and one is going to use a mood stabilizer at some point, it makes sense to start with a mood stabilizer first and then add a neuroleptic if the mood stabilizer, by itself, is not rapidly effective enough. Such use of a neuroleptic (or, alternatively, a benzodiazepine such as lorazepam) should be temporary and on a prn basis only, with plans to discontinue such adjunctive treatment when the clinical situation stabilizes. Among lithium, divalproex, and carbamazepine, although lithium has the longest track record, divalproex, by virtue of its ease of use and relative lack of side-effects, is currently more popular; carbamazepine, although effective, is difficult to use and is generally held in reserve. Once the mania is in remission, it is prudent to continue the treatment effective during the acute phase on a maintenance basis until the underlying episode has had time to run its course. Once the maintenance phase of treatment is accomplished, a decision has to be made as to whether or not to continue the mood stabilizer on a preventive basis. In general, a history of frequent or very severe episodes argues for preventive treatment. Although, of the mood stabilizers, only lithium has been shown to be an effective preventive agent, both divalproex and carbamazepine probably are too, and are, in fact, used as such. If lithium is chosen, it is appropriate to continue it at a dose sufficient to keep the blood level within the therapeutic range: a lower blood level is not as effective in prevention (Gellenberg et al. 1989). Treatment-resistant manic or mixed-manic episodes are more commonly seen among rapid-cyclers. There is, as yet, no well-established approach: choices include ECT (Mukherjee et al. 1994; Small et al. 1988) or a combination of mood stabilizers. Depressive episodes may respond to lithium or carbamazepine alone (Ballenger and Post 1980; Compton and Nemeroff 2000; Post et al. 1986), and a recent study showed a response to lamotrigene (Calabrese et al. 1999). Should the depressive episode not respond to a mood stabilizer alone, one may consider using a combination of lithium and carbamazepine, adding an antidepressant to the single mood stabilizer or utilizing ECT (Compton and Nemeroff 2000). If a decision is made to employ an antidepressant, it is critical not to start the antidepressant until the patient is receiving a mood stabilizer as all antidepressants are liable to precipitate a manic episode (Zornberg and Pope 1993). Once the depressive symptoms have been controlled, continuation treatment may consist of either a mood stabilizer alone, if that had been effective acutely, or the combination of a mood stabilizer and an antidepressant. Once the depressive episode has had a chance to run its course, any antidepressant that has been used should be discontinued. Maintenance treatment is accomplished with a mood stabilizer alone. Whenever lithium has been used chronically, it is important to discontinue it slowly, over 2-4 weeks, as it appears that more rapid discontinuation predisposes patients to an earlier relapse (Baldessarini et al. 1996, 1997).

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MAJOR DEPRESSION Pathology and etiology

Major depression (unipolar depression) is in all likelihood an inherited disorder: the prevalence of major depression is higher in the relatives of patients than of controls, and the monozygotic concordance rate is significantly higher than the dizygotic one (McGuffin et al. 1996). Although stressful life events, such as divorce, death in the family, etc., are often found as triggering factors early on, subsequent episodes are more and more likely to occur spontaneously, with little need for a precipitating event (Brown et al. 1994; Frank et al. 1994). There is abundant evidence for endocrinologic disturbances in depression, all of which point to disturbances in the hypothalamus. Within the hypothalamus, for example, the level of messenger RNA in the paraventricular nucleus for corticotrophin-releasing hormone (CRH) is elevated (Raadsheer etal. 1995), as is the cerebrospinal fluid level of CRH (Nemeroff et al. 1984); consistent with this, the low-dose DST test is generally positive (Carroll et al. 1968, 1976). The thyroid axis also shows disturbances: the cerebrospinal fluid level of TRH is elevated (Banki et al. 1988), and, consistent with this, the response of TSH to exogenous TRH is blunted (Prange et al. 1972). Disturbances in sleep suggest changes in the brainstem. REM sleep latency is reduced in depression (Hauri etal. 1974; Rush et al. 1986), and, when given the cholinergic agent arecoline, the latency to REM is shorter in depressed patients than in controls (Gillin et al. 1991). These endocrinologic and sleep changes also suggest perturbations in biogenic amine functioning, a suggestion buttressed by several findings, especially regarding the serotoninergic system. Platelets serve as models for neurons, and the number of serotonin receptors on platelets is reduced in depression. Another finding suggesting the importance of serotonin is the response to tryptophan depletion. Tryptophan is the dietary precursor of serotonin, and, in patients with an antidepressant-induced remission of depression, tryptophan depletion is promptly followed by a relapse of depressive symptoms (AbergWistedt etal. 1998; Delgado etal. 1990; Smith etal. 1997). Although neuropathologic studies are lacking, it is not unreasonable to propose that the hypothalamus is intimately involved in the genesis of major depression. The hypothalamus serves as the central biologic 'clock', which could time the depressive episodes; furthermore, the hypothalamus normally controls the kinds of 'vegetative' functions that are disturbed in depression, such as appetite and sleep. Furthermore, hypothalamic involvement can also explain the endocrinologic changes noted earlier. Clinical features

Major depression is characterized by the occurrence of episodes of depression, in between which patients return to more or less normal functioning. The first episode of depression generally appears in the mid-twenties, the range in age of onset being, however, wide, from childhood to old age. Depressive episodes tend to come on gradually, over weeks, months, or longer. Once fully established, the episode is characterized by a depressed or irritable mood, decreased selfesteem, pessimism, crying spells, suicidal ideation, anergia, anhedonia, difficulty with concentration and memory, and changes in sleep, appetite, and overall psychomotor functioning. Patients may also describe an overall diurnal variation in the intensity of their symptoms, their suffering being more intense in the morning. During some episodes (usually the more severe ones) delusions, hallucinations, or catatonia may appear. Anergia may be profound: patients lack energy and find even simple tasks overwhelmingly fatiguing. Many complain of a sense of opppression, of being weighted down.

Idiopathic psychotic, mood, and anxiety disorders 657

Anhedonia becomes apparent as patients take less and less pleasure in activities they used to enjoy: vacations, outings, sports, and sex excite little or no interest and become chores. Concentration becomes more and more of an effort (Roy-Byrne et al. 1986), and patients may have to read the same paragraph again and again: some complain of feeling as if in a 'fog' or of being 'wooden-headed'. Memory likewise becomes effortful and inexact. Short-term memory is most affected (Sternberg and Jarvik 1976), and patients may forget where they put their keys or what was said to them just minutes earlier. Sleep change tends toward insomnia: hypersomnia is seen in only a minority. Patients describe initial insomnia, or trouble falling asleep, middle insomnia, or awakening in the middle of the night and being unable to get back to sleep, and 'terminal' insomnia, wherein patients awaken early, well before the alarm, and are unable to return to sleep at all. Appetite change tends to be fairly consistent across episodes, and most patients will experience a loss of appetite with varying degrees of weight loss (Stunkard et al. 1990). Psychomotor change generally tends toward agitation, psychomotor retardation being less common in the depressive episodes of major depression than those of bipolar disorder. Agitated patients complain of inner tension and anxiety, and may pace about or wring their hands. Other features seen in a minority of depressive episodes include panic attacks (VanValkenburg et al. 1984) and what have been called 'anger attacks' wherein generally hostile and irritable patients occasionally experience episodes of violence and autonomic arousal (Fava et al. 1993). Hallucinations and delusions are, as noted, generally seen only during severe episodes (Lykouras et al. 1986; Maj et al. 1990): importantly, these hallucinations and delusions are mood-congruent, in that they, in some fantastic way, 'make sense' in light of the prevailing mood. Thus, guilt-ridden patients may believe that they have committed unpardonable sins, that others know about it and are talking about them, and that the authorities are in pursuit, perhaps to take their lives. Voices may condemn patients, or announce their imminent execution. In some cases, patients may develop stuporous catatonia (Starkstein et al. 1996). In some cases of severe depression in the elderly, a dementia may appear (Rabins et al. 1984), which may be particularly severe. One 76-year-old became disoriented to time, was unable to recall any items after 3 minutes, and presented cachectic and curled up in a fetal position (McAllister and Price 1982); another, a 66-year-old, was disoriented to time and place, confused, and incontinent (Kramer 1982): both recovered with adequate antidepressant treatment. The duration of a depressive episode ranges, on average, from 6 to 12 months; but the range is wide, from as little as several weeks up to chronic depression lasting many years (Scott 1988). Course

Major depression is essentially an episodic illness, recurrences being the rule (Thase 1990). In between episodes, although most patients return to euthymia, about one-quarter will continue to experience some lingering, low-level depressive symptoms. The interval between episodes varies widely among patients, from as little as a year to up to decades: in some cases, the interval may be so long that the patient dies before the next episode can occur, and in such cases, major depression may be characterized by only one lifetime episode. Differential diagnosis

Of the many causes of depression discussed in Chapter 6, several deserve special emphasis. Bipolar disorder generally causes depressive episodes, and a history of mania in a patient currently in a depression rules out a diagnosis of major depression. As noted above, however, some patients with bipolar disorder may have one or more episodes of depression before the

658 Specific disorders

first manic episode occurs, and thus, in a patient in a first episode of depression, or a patient with a history of only depressive episodes, some guidelines are needed to help to decide when a diagnosis of major depression is justified. The fact that, in patients with bipolar disorder whose first affective episode is one of depression, a manic episode will be seen in over 90% of cases within either 10 years or five episodes of depression, whichever comes first (Dunner et al. 1976), supplies this guideline. Thus, in interviewing a patient with depression, one should always enquire about prior episodes, noting carefully when the first episode occurred and how many prior episodes have occurred overall. If the first episode was 10 years or more earlier, or if there have already been five or more episodes, and the patient in question has never been manic, a diagnosis of major depression is quite likely. Other, perhaps less reliable, diagnostic clues to the presence of bipolar disorder are found in the symptomatology of the depressive episode itself. Bipolar depressions tend to be characterized by increased sleep and appetite, and psychomotor retardation (Beigel and Murphy 1971b; Hartmann 1968), unipolar ones by insomnia, anorexia, and psychomotor agitation. Furthermore, hallucinations and delusions are more common in bipolar than unipolar depression (Guze et al. 1975). Schizoaffective disorder, depressed type, is clearly distinguished by the presence of psychotic symptoms in between the episodes of depression. Both postpartum depression and the premenstrual syndrome are distinguished by the fact that the depressions occur only in relation with certain biologic events (i.e. the puerperium or the luteal phase) and not at any other time. By contrast, depressive episodes will be seen at other times in major depression. Dysthymia is characterized by the early onset of chronic low-level depressive symptoms, which may, indeed, be lifelong. The dementia of depression must be distinguished from other forms of depression, especially Alzheimer's disease and Binswanger's disease. Important clues to the diagnosis of major depression include a history of prior episodes of depression, a subacute onset of the dementia rather than a prolonged insidious onset, and the presence of more typical depressive symptoms such as depressed mood, guilt, and loss of appetite (Rabins et al. 1984). Of these diagnostic clues, the most reliable is the history of prior episodes. Importantly, recovery with antidepressant treatment does not mean that a future onset of dementia is of the same etiology; indeed, patients who have recovered from a dementia of depression are more likely than controls to subsequently develop another form of dementia (Alexopoulos et al. 1993). Treatment

The treatment of major depression is conveniently discussed in three parts: the acute treatment of a current depressive episode; continuation treatment designed to prevent a relapse into the current episode of depression; and maintenance treatment to prevent another episode from occurring in the future. Acute treatment may be accomplished with an antidepressant or, in the case of depression of mild-to-moderate degree, either interpersonal therapy or cognitive-behavioral therapy (Elkin et al. 1989). There are a large number of antidepressants to choose from, and it is appropriate to become familiar with certain representatives of each class: of the monoamine oxidase inhibitors (MAOIs), phenelzine; of the tricyclic antidepressants, nortriptyline; of the selective serotonin reuptake inhibitors (SSRIs), fiuoxetine, paroxetine, or citalopram; and of the remaining, large miscellaneous group (including bupropion, trazodone, nefazodone, mirtazepine, and venlafaxine), mirtazepine and venlafaxine. Phenelzine, like all non-selective MAOIs, is difficult to use and is generally not a first choice. Nortriptyline appears to be of equal efficacy to the SSRI paroxetine (Mulsant et al. 1999), but, in patients with ischemic cardiac disease, conveys a greater risk of arrythmias and angina

Idiopathic psychotic, mood, and anxiety disorders 659

(Nelson et al. 1999; Roose et al. 1998). Recent studies have demonstrated a therapeutic superiority of mirtazepine over fluoxetine (Wheatley et al. 1998), and venlafaxine over fluoxetine (Silverstone and Ravindran 1999) and paroxetine (Poirier and Boyer 1999). All other things being equal, these studies support the use of either venlafaxine or mirtazepine as the antidepressant of first choice: it must be borne in mind, however, that head-to-head comparisons between different antidepressants are relatively scarce and that replication studies are needed to confirm these results. As between the SSRIs and the tricyclic nortriptyline, the SSRIs are safer; one of them, citalopram, has few if any significant drug-drug interactions with other agents, a fact that recommends its use over that of the other SSRIs. Nortriptyline remains, however, a viable choice, provided that the patient does not have significant cardiac disease. Regardless of which of these antidepressants is chosen, it must be borne in mind that all antidepressants require a considerable length of time before symptom relief occurs, and, assuming that the patient is receiving an adequate dose and has no, or readily tolerable, side-effects, at least 4 weeks should be allowed to pass before deciding that the depression is resistant to this particular antidepressant (Quitkin et al. 1996). In cases of treatment resistance, several options are available. First, with the exception of nortriptyline, which has a 'therapeutic window', one could substantially increase the dose. Another option is to switch to an antidepressant from a different group. A third is to add either lithium (with a blood level in the therapeutic range) (Bauer and Dopfmer 1999; Baumann etal. 1996) or, in the case of a tricyclic, triiodothyronine (in doses of 25-50 mu/day) (Aronson et al. 1996;Ioffe 1988; Joffeef al. 1993). A fourth option is to consider a combination of different antidepressants. The only combination shown to be effective is that of the addition of an MAOI to a tricyclic agent (White and Simpson 1981); other combinations, such as a tricyclic plus an SSRI, although popular, have not as yet been demonstrated, in double-blind trials, to be effective. Finally, one may consider ECT (Janicak et al. 1985), which is by far the most effective treatment for depression. Once acute treatment has relieved the symptoms, continuation treatment is in order and should persist until the underlying depressive episode has had a chance to run its course. In many cases, it is difficult to estimate how long the underlying episode will endure, and, in such cases, it is appropriate to continue treatment until the patient has been continuously symptom free for 6 months (Altamura and Percudani 1993; Kupfer et al. 1992; Prien and Kupfer 1986; Reimherr et al. 1998). In general, continuation treatment requires the same regimen as was used during acute treatment, at substantially the same dose (Frank et al. 1990). If ECT was used for acute treatment, it is appropriate to add an antidepressant (e.g. paroxetine [Lauritten et al. 1996]) in order to prevent an early relapse during the continuation phase. Maintenance treatment should be considered for patients with frequent episodes and patients whose episodes are so severe that one would not wish ever to risk a relapse. As in the case of continuation treatment, the same treatment as was effective acutely is in general appropriate for maintenance purposes (Kupfer et al. 1992); another option for maintenance treatment is lithium (Coppen 2000). It is not as yet clear whether or not interpersonal therapy or cognitive-behavioral therapy is effective as maintenance treatment.

PREMENSTRUAL SYNDROME Pathology and etiology

Although the etiology is not known, it is suspected that the premenstrual syndrome (premenstrual dysphoric disorder) represents an entrainment, mediated through the

660 Specific disorders

hypothalamus or related structures, of a major depression to the episodic neuroendocrine events of the menstrual cycle. Importantly, the premenstrual syndrome is clearly not an emotional reaction to the approach of menstruation as the syndrome persists after hysterectomy (Backstrom et al. 1981). Clinical features

The first episode of premenstrual dysphoria may occur anywhere from shortly after menarche until the late twenties. The episode of dysphoria may begin anywhere from several hours to one and one-half weeks prior to the onset of menses. The mood (Bloch et al. 1997) may be depressed, anxious, or irritable and is often labile: patients may experience uncontrollable crying or, at times, inexplicable anger. Fatigue or lethargy is common, and patients often experience difficulty with concentration, loss of interest, and sleep change, demonstrating either insomnia or hypersomnia. The appetite may change, often being increased, with a particular interest in sweets, such as chocolates. In addition to these dysphoric symptoms, patients may also experience bloating, mastalgia, edema of the hands and feet, clumsiness, nausea, and constipation. The episode ends fairly abruptly within 2 to 3 days after the beginning of menstrual flow. Importantly, patients then remain well throughout the rest of menstruation and the follicular phase of the cycle and into the luteal phase until the next episode begins. Course Episodes continue to occur with each menstrual cycle until menopause: many patients report that the episodes become not only more severe, but also longer lasting as the years go by. Differential diagnosis

A depressive episode of a major depression or bipolar disorder may undergo an exacerbation premenstrually, but here symptoms are also present during the follicular phase. Dysmennorhea, characterized by cramps, headaches, and bloating, is easily distinguished by its course, beginning not before but after the menstrual flow commences. Treatment

Fluoxetine (Pearlstein and Stone 1994; Pearlstein et al. 1997; Steiner et al. 1995) and sertraline (Yonkers et al. 1997; Young et al. 1998) are both effective; alprazolam (Freeman et al. 1995), in a dosage of 2 mg/day, beginning at the end of the follicular phase and continuing into the early part of menstruation, is also therapeutic. Leuprolide (Schmidt etal. 1998) is also effective, but other treatments, such as progesterone, diuretics, pyridoxine, and bromocriptine are generally without effect.

POSTPARTUM DEPRESSION Pathology and etiology Although the etiology of postpartum depression is not known, a recent study demonstrated that such patients, although clinically remitted, are more likely than controls to experience depression during pharmacologically induced precipitious falls in gonadal steroid levels (Bloch etal. 2000). Clinical features

The onset is subacute, within several weeks or months postpartum. Clinically, patients develop a depressive episode with depressed mood, crying spells, difficulty with concentration, anhedonia, anorexia, and insomnia. Self-esteem is routinely decreased, and patients typically doubt their ability to care for their baby. Some patients

Idiopathic psychotic, mood, and anxiety disorders 661

may experience obsessions, known as 'horrific temptations', consisting of an urge to kill the child.

Course Although most patients experience a spontaneous remission within months or years, the depression may be chronic in a minority. Those who do recover are at increased risk for another episode after a subsequent pregnancy. Differential diagnosis

The postpartum blues is distinguished by its course: the postpartum blues begin within days, rather than weeks, of delivery and clear within a week or two, rather than lasting months or longer. Major depression may, at times, present with a depressive episode during the puerperium, but in major depression, one sees depressive episodes at other times in the patient's life, in contrast to postpartum depression, which occurs only in the puerperium. Sheehan's syndrome is suggested by a failure of lactation, persistent amenorrhea, and, often, by loss of pubic and axillary hair. Treatment

Pharmacologic treatment is the same as that described for the acute and continuation phases of the treatment of a depressive episode, as for major depression, above. Should the patient desire to have another child, consideration may be given to instituting preventive treatment after the next delivery.

POSTPARTUM BLUES Pathology and etiology The etiology of the postpartum blues is unknown. The fact that it is seen in over half (Pitt 1973) of postpartum women has led some to suggest that, rather than being pathologic, it is in fact 'normal'. The dramatic and striking difference between the 'blues' and the patient's functioning at other times, however, argues against this notion. Clinical features

Clinically (Pitt 1973; Rohde et al 1997; Yalom et al. 1968), the onset is acute, usually within the first few days postpartum. The mood may be depressed, anxious, or irritable, and there is often a striking lability. Crying spells may erupt and then evaporate within moments, yet patients may, at times, all the while unable to stop the tears coursing down their cheeks, insist that they have never been happier. In addition to these striking mood changes, there may be a relatively minor degree of fatigue, poor concentration, and insomnia. The blues remits spontaneously, generally within 2 weeks.

Course The blues may or may not recur after subsequent pregnancies. Differential diagnosis

Postpartum depression has a later onset, usually of the order of several weeks postpartum. Treatment

Given the brevity of the syndrome, treatment with antidepressants is not indicated, as a spontaenous remission may be anticipated before an antidepressant could be expected to take effect. Support, reassurance, and assistance are generally sufficient; in some cases, a short

662 Specific disorders

course of treatment with a benzodiazepine, such as lorazepam, may be considered, but it must be kept in mind that these drugs do appear in the breast milk.

PANIC DISORDER Pathology and etiology Panic disorder is clearly familial: the risk for panic disorder is higher in the first-degree relatives of patients than in those of controls (Crowe et al. 1983; Noyes et al. 1986), and the monozygotic concordance rate is higher than the dizygotic one (Torgerson 1990). Whether this familial aspect represents the effects of a shared environment or a genetic effect is, however, not yet clear and will have to await adoption studies. The existence of 'panicogens' clearly indicates an underlying biochemical abnormality and has prompted intense research. Panicogens are substances that, although generally innocuous in normals and psychiatric controls, fairly reliably induce typical panic attacks in patients with panic disorder. Panicogens include the following: 1. noradrenergic agents such as isoproterenol (Pohl et al. 1988) and yohimbine (Charney et al. 1992) 2. the mixed agonist/antagonist serotoninergic agent m-chlorophenylpiperazine (Kahn and Wetzler 1991) 3. agents capable of disturbing the acid-base balance, such as an inhalation of 5% carbon dioxide (Gorman et al. 1988) or an infusion of bicarbonate (Gorman et al. 1989) or lactate (Cowley and Arana 1990; Liebowitz et al. 1984) 4. miscellaneous agents such as cholecystokinin (Bradwejn et al. 1991) and caffeine (Charney et al. 1985), and possibly the benzodiazepine receptor antagonist flumazenil (Nutt et al. 1990), although not all studies concur with this (Strohle et al. 1998). Although the wide range of mechanisms represented by these various panicogens argues against any unitary biochemical hypothesis, it does support the involvement of a wider system involving multiple biochemical agents. Speculatively, this could involve two mesencephalic nuclei, the noradrenergic locus ceruleus and the serotoninergic dorsal raphe nucleus, both of which project widely to the cortex, and temporal lobe structures such as the parahippocampal gyrus and the hippocampus, both of which are rich in benzodiazepine receptors and both of which are involved in the generation of anxiety. Possible involvement of the parahippocampal gyrus is further supported by positron emission tomography (PET), which has revealed a reduced blood flow (Reiman et al. 1986) and glucose metabolism (Nordahl et al. 1990) in the left parahippocampal gyrus in panic disorder patients. The efficacy of agents that disturb the acid-base balance further suggests that a trigger for the activation of this mesencephalictemporal lobe circuit could be an unusually sensitive 'suffocation alarm' in the brainstem, which, when activated, precipitates the sort of reaction that anyone might have during actual suffocation (Klein 1993). There is also an association between panic disorder and mitral valve prolapse (Katerndahl 1993). The nature of this association is not clear: in all likelihood, neither mitral valve prolapse causes panic disorder nor does panic disorder cause mitral valve prolapse. It may well be that both are related to some, as yet unknown, common cause. Clinical features

Clinically, panic disorder is characterized by recurrent panic attacks, the first of which generally occurs in late adolescence or the early adult years. Panic attacks are paroxysmal events that erupt over a minute or so, crescendo rapidly and

Idiopathic psychotic, mood, and anxiety disorders 663

terminate soon thereafter, generally lasting from 5 to 15 minutes, and rarely up to an hour. Although there may, in some cases, appear to be a 'cue' or precipitant for the attack, in most patients they occur spontaneously. Symptoms and signs include: severe anxiety or panic, often accompanied by a sense of impending doom or the fear of a heart attack; tachycardia, palpitations; tremulousness; diaphoresis; dyspnea, chest discomfort or pain; dizziness or faintness; and acral parasthesiae. Rare symptoms seen during panic attacks include blindness, hemianesthesia, and macropsia or microspia (Coyle and Sterman 1986). Most patients are devastated by the attack: some fear that they are 'going crazy', whereas others, convinced that they are having a heart attack, rush to the emergency room. Rarely, patients may have 'panic attacks without panic': here, the panic attacks are identical to regular attacks in all respects except that patients report little or no anxiety at all (Russell et al. 1991). Although most panic attacks occur during waking hours, a majority of patients will also have nocturnal attacks (Mellman and Uhde 1989a), and, in a small minority, attacks may occur only nocturnally (Mellman and Uhde 1990). Nocturnal attacks arise from nonNREM sleep (Mellman and Uhde 1989b) and often awaken the patient, who typically has trouble falling back asleep and is able to recall the panic the next morning (Hauri et al. 1989). Course Panic disorder appears to be a chronic disorder, with the frequency of attacks gradually waxing and waning over the years, ranging from several times weekly to once yearly or even less frequently. In a subset of patients, agoraphobia may develop, as described below. Differential diagnosis

Panic disorder is but one of many possible causes of anxiety attacks, the differential diagnosis for such attacks being discussed in Chapter 6. Treatment

Given the brevity of panic attacks, acute treatment is not indicated, therapeutic efforts instead being directed toward the prevention of future attacks. Two methods are available: cognitive-behavioral therapy (Beck et al. 1992) and treatment with one of a variety of antidepressants, benzodiazepines, or divalproex (Keck et al. 1993b). Gabapentin may also have some effect, but this appears to be minimal (Pande et al. 2000). Appropriate antidepressants include certain tricyclic agents (imipramine [Mavissakalian and Perel 1989], clomipramine [Modigh et al. 1992]) and SSRIs (paroxetine [Ballenger et al. 1998; Oehrberg etal 1995], sertraline [Dohl et al. 1998; Londborg et al 1998], citalopram [Wade et al. 1997], and fluvoxamine [Hoehn-Saric et al. 1993]); effective benzodiazepines include diazepam (Noyes et al. 1996), alprazolam (Ballenger et al. 1988), and clonazepam (Rosenbaum et al. 1997; Tesar et al 1991). Although, in most cases, a 'full' antidepressant dose is required to prevent the attacks, it is critical to start at a very low dose (e.g. approximately 10% the 'full' dose) and increase the dose gradually in order to avoid causing agitation or an increased frequency of attacks. Furthermore, patients must be reminded that, once the 'full' dose has been reached, a preventive effect may not become apparent for weeks. Diazepam may be used in doses of 30-50 mg, alprazolam in a dose of 2-6 mg/day, and clonazepam in a dose of 2-4 mg/day. These benzodiazepines have the advantage of an almost immediate prophylactic effect, but they carry a significant risk of withdrawal, with an increased frequency of attacks, should the dose be tapered off too rapidly (Pecknold et al. 1988;Rickelsefa/. 1993a). Given the chronic nature of panic disorder, chronic treatment may be required.

664 Specific disorders

AGORAPHOBIA Pathology and etiology Although somewhat controversial (Lelliott et al. 1989), it appears, in most cases, that agoraphobia represents a complication of panic disorder (Horwarth et al. 1993). Patients with panic disorder generally develop a more or less severe degree of anticipatory anxiety over whether or not another attack may occur; when this anticipatory anxiety becomes severe, patients may become very reluctant to leave the safety of their home or be in any situation in which help might not be immediately available or from which immediate escape is difficult or impossible. The genesis of those cases which develop in the absence of panic disorder is not as yet clear. Clinical features Common situations that, in one way or another, forbid immediate escape include (Page 1994) travelling in airplanes, travelling across bridges or through tunnels, and, in exteme cases, simply waiting in long lines, and the prospect of being caught in such a situation may fill patients with a catastrophic, yet difficult to describe, sense of dread (Goisman et al. 1995). Such dread may also accompany the prospect of simply leaving home, and some patients may in fact become truly house-bound, unable to even step foot outside the front door. Interestingly, patients may, in some cases, be able to temporarily overcome their agoraphobia when they can bring their 'safety' with them in the guise of a good friend who will accompany them throughout the trip.

Course Agoraphobia appears, in the natural course of events, in most cases to be chronic. Differential diagnosis

A similar picture may develop in any condition that creates an uncomfortable selfconsciousness about being seen outside the home. Examples include patients with paranoid schizophrenia, who fear the persecution that awaits them outside, or patients with dysmorphophobia, who cannot bear the thought of others seeing their 'disfigurement'. Treatment

The key to the successful treatment of agoraphobia is a graded, hierarchical exposure to the feared situations. Importantly, however, it is, in those cases with panic disorder, critical to treat the panic disorder first, because no matter how successful exposure therapy might be, the occurrence of one panic attack may destroy all gains and send the patient back to square one. Although it appears that some patients may be able to 'treat' themselves once the panic disorder has been controlled (Mavissakalian and Perel 1995), in most cases a combination of panic disorder treatment and exposure treatment is most effective (de Beurs et al. 1995; Mavissakalian and Michelson 1986; Zitrin et al. 1983).

SIMPLE (SPECIFIC) PHOBIA Pathology and etiology Although simple phobias appear to be familial (Fyer et al. 1990), it is unclear whether this reflects a genetic predisposition to fear certain objects or 'modelling' on the part of the parents whereby children 'learn' to fear certain objects.

Idiopathic psychotic, mood, and anxiety disorders 665

Clinical features

In general, animal phobias and blood-injury phobia tend to have an onset in childhood, whereas others make their appearance in the late teens or early adult years (Marks and Gelder 1966). Common phobic objects or situtations include snakes, spiders, air travel, train travel, being in enclosed spaces, heights, darkness, storms, and either the sight of blood or the prospect of an injury, such as a venipuncture (Chapman et al. 1993). Patients, although admitting the irrationality of their fear, typically go out of their way to avoid the phobic object or situation and, if forced to be in proximity to it, experience varying degrees of anxiety with autonomic symptoms such as tremor, tachycardia, piloerection, etc. Blood-injury phobia is unique and differs from the other simple phobias in that proximity to the phobic object elicits a biphasic reaction: first, patients experience anxiety and autonomic symptoms similar to those experienced by other patients; second, patients experience a vasovagal response, with bradycardia, hypotension, faintness, and, in many cases, actual syncope (Curtis and Thyer 1983). Course Childhood onset animal phobias tend to remit spontaneously in a matter of months or a year, those which persist much beyond this tending to become chronic. Later onset phobias tend to be chronic. Differential diagnosis

Agoraphobia and 'school phobia' (or, as it is also called, 'separation anxiety disorder') are distinguished by the nature of the fear: in these two disorders, it is the fear of being away from home and safety that is paralyzing, in contrast to simple phobias, in which it is fear of a specific thing or situation, regardless of whether or not the phobic object is at home. Social phobia differs from simple phobia in that social phobics fear not so much the situation but rather being humiliated in that situation: a patient with a social phobia, for example a fear of public speaking, does not fear speaking per se and may in fact be able to deliver a speech without fear provided that the auditorium is empty. By contrast, a patient with a simple phobia, say of reptiles, is unable to enter the herpetarium at the zoo regardless of whether others are present or not. Treatment

All successful treatments of simple phobia have one thing in common: the patient eventually comes, and remains in contact, in vivo, with the phobic object or situation. In some cases, this contact may be effected with supportive psychotherapy and encouragement alone; in others, specific techniques, such as systematic desensitization or 'flooding' may be employed (Marks etal.1971).

SOCIAL PHOBIA Pathology and etiology Social phobia appears to be familial. Clinical features

The onset of social phobia is usually in the teenage years (Marks and Gelder 1966). Social phobia occurs in two forms, circumscribed and generalized (Heimberg et al 1990; Mannuzza

666 Specific disorders

et al. 1995): in each form patients experience an overwhelming fear of embarrassment or humiliation upon doing something in public. Circumscribed phobias may involve a fear of speaking, or of writing, or of eating in public, or urinating in public restrooms. Approaching the phobic public performance often incites blushing, sweating, and a dry mouth, and there may also be tremor and shortness of breath (Amies et al. 1983; Reich et al. 1988). Importantly, it is not the performance itself that incites the anxiety but rather the act of performing in public that frightens the patient. Thus, a patient with a fear of public speaking, although terrorized at the prospect of giving a presentation, might, if the lecture theatre were empty, be able to mount the podium and give the presentation without any apprehension at all. Generalized social phobia entails the fear of a wide variety of everyday social situations, such as dating or speaking up in classrooms or groups, patients viewing these social situations as settings for embarrassment or humiliation, and avoiding them. In extreme cases, almost all social contact is avoided. Course Social phobia appears to be chronic. Differential diagnosis

Simple phobia differs from circumscribed social phobia in that simple phobics fear the phobic object regardless of whether the encounter is public or private, whereas social phobics have no trouble in private: it is only performance in public that terrifies them. Agoraphobia differs from generalized social phobia in that agoraphobics stay home out of a fear of leaving the safety of the home, whereas those with generalized social phobia stay home out of a fear of embarrassment or humiliation outside the home (Page 1994). Some patients with schizophrenia, or other psychoses, who experience delusions of reference and persecution may fear being in public, but here the fear is based on their delusional misinterpretation of the situation rather than a concern over embarrassment. Treatment

The pharmacologic treatments of the circumscribed and generalized types of social phobia are different. Circumscribed social phobia, especially fears of speaking, writing, or giving a musical performance, may be treated with a beta-blocker, such as propranolol, given on a prn basis in anticipation of the public performance (Brantigan et al. 1982; Hartley et al 1983; James et al. 1977; Liden and Gottfries 1974). The dose of propranolol ranges from 20 to 60 mg, and the drug appears to work not so much by reducing anxiety per se as by reducing autonomic symptoms such that patients no longer 'shake like a leaf. Generalized social phobia may be treated with any one of a variety of antidepressants, including sertraline 50-200 mg/day (Katzelnick et al. 1995), paroxetine (Allgulander 1999; Baldwin et al. 1999; Stein et al. 1998), fluvoxamine 150 mg/day (Stein et al. 1999; van Vliet et al. 1994), phenelzine 60-90 mg/day (Heimberg et al. 1998; Liebowitz et al. 1992; Versiani et al. 1992), and moclobemide (Versiani et al. 1992) (not yet available in the United States). Both clonazepam 0.5-3.0 mg/day (Davidson et al. 1993) and gabapentin (Pande etal. 1999) are also effective. Beginning with an antidepressant, such as sertraline, is probably best; clonazepam, given the risk of neuroadaptation, should probably be held in reserve, and the experience with gabapentin in this disorder is still limited. Cognitive-behavioral group therapy, although helpful, does not appear to be as effective as phenelzine (Heimberg et al. 1998).

Idiopathic psychotic, mood, and anxiety disorders 667

OBSESSIVE-COMPULSIVE DISORDER Pathology and etiology Although reliable neuropathologic studies are lacking, PET scanning strongly implicates an involvement of the orbitofrontal gyri, the cingulate gyrus and the caudate nucleus (Baxter et al 1987, 1992; Benkelfat et al 1990; Perani et al 1995). Obsessive-compulsive disorder is familial (Pauls et al. 1995), and there is very suggestive evidence that, at least in some cases, it may represent a differing phenotypic expression of the same genotype responsible for Tourette's syndrome (Apter et al. 1993; Frankel et al. 1986). There is also evidence that, in other cases, obsessive-compulsive disorder may represent a sequela to Sydenham's chorea (Swedo et al. 1993) and, like Sydenham's chorea, may occur secondary to an autoimmune attack on the brain. Serotoninergic transmission is clearly disturbed in obsessive-compulsive disorder: the only medications (noted below) found to be successful in this disorder are all primarily serotoninergic; furthermore, oral administration of the mixed serontonin agonist/antagonist meta-chlorophenylpiperazine (m-CPP) reliably exacerbates the symptoms (Hollander et al. 1992). Clinical features

The onset is usually in the late teens or early twenties, with a range from childhood to the middle years; in some cases, the onset will be in the puerperium (Sichel et al. 1993). As the name of this disorder indicates, it is characterized by the occurrence of obsessions and compulsions (Rasmussen and Tsuang 1986): although most patients have both symptoms (Foa et al. 1995), a small minority will experience only obsessions or only compulsions. Obsessions are unwanted, intrusive, and troubling ideas, impulses or images, often related to sexual or violent themes. A minister recurrently found himself thinking of bestiality; a physician found himself repeatedly experiencing an urge to question his patients about their bowel movements; and a young mother, to her distress, continually had thoughts of her toddler being run over by a truck. Most patients are, at the very least, distressed by these obsessions, many being horrified. All, will at least initially, try their best somehow to stop the obsessions from occurring. Compulsions arise in reponse to irrational fears or concerns and in some way or other serve to allay these fears. These strong urges give patients no peace, typically waxing ever stronger as patients try to resist carrying them out. Compulsions are often categorized according to what patients feel compelled to do: thus, for example, there are checkers, washers, touchers, counters, and arrangers. A 'checker', after going upstairs to bed, had doubts that he had turned off the electric light downstairs and felt compelled to go back downstairs to check on it: despite finding the light off, however, the fear again arose once he had returned upstairs, forcing him to go back once again, the process being repeated many times before the patient could finally get to bed (Tuke 1894). 'Washers' are convinced that they have been contaminated in some way, perhaps by dirt, 'germs', or fecal material, and feel compelled to wash their hands no matter how clean they may be or how many times they have already been washed: some may wash to the point of rawness yet still feel unclean. 'Counters' feel compelled to count to a certain number and do it repeatedly, whereas 'arrangers', under the compulsion to arrange things 'just so', may spend much time arranging and then rearranging things on the desk or in the closet, always, however, finding afterwards on inspection that some critical point of symmetry has been missed. These counters and arrangers are sometimes at a loss to explain what they fear might happen should they fail to act; it is as if a there were a nameless dread motivating them.

668 Specific disorders

Although most compulsive behaviors are visible and evident to others, some patients may at times engage in 'silent' or private compulsions, for example repeating the Lord's Prayer to themselves a certain number of times. Almost all patients, at least initially, recognize the 'senselessness' or irrationality of their compulsions and will attempt to resist them (Stern and Cobb 1978); over the years, however, many will give in, carrying out the compulsion without even a token show of resistance. Although, as noted above, most patients have insight, in that they recognize the irrationality of their compulsive behavior, insight may in a minority be lost, patients becoming convinced, to a delusional degree, that their behavior is, in fact, reasonable and appropriate (Eisen and Rasmussen 1993; Insel and Akiskal 1986). Such patients with psychotic obsessive-compulsive disorder, now finding their compulsions reasonable, pursue them with purpose rather than resisting them: one patient (Gordon 1950), after 25 years of resisting the urge to repeat his prayers for fear that he had left a word out, eventually came to believe that he was a sinner and that God had given him the compulsion in order specifically to ensure that he said the prayers with the perfection that salvation and eternal life demanded: subsequently, he gave himself to the repeating of his prayers whenever he had the slightest doubt he had left anything out. Course Obsessive-compulsive disorder generally pursues a chronic, waxing and waning course: in only a minority is spontaneous remission seen, and, in most of these, relapse eventually follows. Differential diagnosis

Of all the disorders capable of causing obsessions and compulsions that are discussed in Chapter 4, several deserve special emphasis. Both major depression and schizophrenia may, at times, cause obsessions or compulsions; here, however, the obsessions and compulsions occur only in the context of the overall symptomatologies of these disorders and, importantly, clear when these disorders are successfully treated, regardless of whether or not, in the case of major depression, a serotoninergic antidepressant is used. Furthermore, in the case of patients being treated for schizophrenia with clozapine, the medication itself may cause obsessions and compulsions. Obsessive-compulsive disorder must also be differentiated from obsessive-compulsive personality disorder. The unfortunate similarity of the names of these two separate disorders reflects an earlier belief that one arose from the other. Specifically, it was believed that the obsessive-compulsive personality disorder provided the proper 'soil' from which obsessivecompulsive disorder would arise. Subsequent studies have, however, clearly shown that patients with obsessive-compulsive disorder are no more likely to have a pre-exisitng obsessive-compulsive personality disorder than any other personality disorder (Baer et al. 1990; Black et al. 1993; Joffe et al. 1988). Treatment

Obsessive-compulsive disorder may respond either to behavioral treatment involving exposure and response prevention (Foa et al. 1984; Steketee et al. 1982) or to a variety of serotoninergic medications, and it appears that a combination of behavior therapy and medication may work best, at least for some patients. Importantly, however, behavior therapy is relatively ineffective for obsessions, whereas the serotoninergic drugs noted below are effective. Serotoninergic drugs effective in obsessive-compulsive disorder include clomipramine and the SSRIs. Clomipramine is effective in the dose range 200-250 mg/day (Clomipramine Collaborative Study Group 1991), fluoxetine (Pigott et al. 1990) in doses of 20-60 mg/day (Tollefson et al. 1994), fluvoxamine (Freeman et al. 1994; Koran et al. 1996) in doses of 100 to

Idiopathic psychotic, mood, and anxiety disorders 669

300 mg/day, sertraline in doses of 50-200 mg/day (Greist et al 1995; Krong et al. 1999), and paroxetine (Zohar and Judge 1996) in doses of 20-40 mg/day. Most clinicians will start with an SSRI, given their favorable side-effect profile relative to clomipramine (Zohar and Judge 1996). Importantly, regardless of which medication is used, 6 weeks must be allowed to see an initial response, and a full response may not be seen for 3 months. When one medication fails, despite an adequate dose and duration of treatment, it may be reasonable to switch to the other group. If, for example, an SSRI failed, one might consider clomiprimine, or vice versa. Importantly, if one switches from an SSRI to clomipramine, one must allow five half-lives to pass before starting the clomipramine in order to avoid the risk of a serotonin syndrome. Other strategies in treatment-resistant cases include the addition of clonazepam (Hewlett et al. 1992), or risperidone in a dose of 2-3 mg (McDougle et al. 2000) or, in patients with a history of tics, haloperidol (McDougle et al. 1994) (importantly, halperidol is not effective in cases that lack tics). In severe cases, cingulotomy (Baer et al. 1995; Hay et al. 1993) may be considered.

POST-TRAUMATIC STRESS DISORDER Pathology and etiology

Although the chances of developing post-traumatic stress disorder (PTSD) rise with increasing severity of the trauma itself, it is clear both that not all persons exposed to severe trauma develop the disorder and that, conversely, some persons exposed to relatively minor trauma do (Feinstein and Dolan 1991; McFarlane 1989). Clearly, individual vulnerability of as yet unknown type plays a role here. The autonomic nervous system, or its central control mechanisms, appear to be involved. Patients with PTSD not only have a heightened startle response (Butler et al. 1990; Shalev et al. 1992) to sudden events, such as loud noises, but also show heightened sensitivity to stimuli reminiscent of the original trauma (Pitman et al. 1987). Furthermore, it appears that the administration of yohimbine, an alpha-2-autoreceptor antagonist, causes an increase in symptoms (Southwick et al. 1993). Endocrinologic changes are also noted: the 24 hour urine free cortisol level is decreased (Mason et al. 1986), and the DST is 'hyper-negative', with an enhanced suppression of the cortisol level (Goenjian et al. 1996; Yehuda et al. 1993). This is in contrast to the response to the DST in major depression, which is positive, with a failure of suppression of the cortisol level. Although neuropathologic studies are lacking, an MRI study demonstrated that the right hippocampus is smaller in these patients than in controls (Bremmer et al. 1995). Clinical features

PTSD may appear either within days or weeks of the inciting trauma, or in a delayed fashion, after a latent interval lasting months or even years (Watson et al. 1988): in one case of PTSD secondary to combat in World War II, the syndrome was delayed for 30 years (Van Dyke et al. 1985). Various inciting traumas have been reported, each of which lies outside the realm of normal human experience. These include combat (Lee et al. 1995), torture (Basoglu et al. 1994; Ramsey et al. 1993), concentration camps (Kinzie et al. 1984), mass shootings (North et al. 1994), earthquakes (Goenjian et al. 1994), and fire, as in the famous Coconut Grove disaster in Boston in 1943 (Adler 1943). One predictor of which survivors of the trauma will go on to develop PTSD is a history of dissociation during the trauma itself, these patients being more likely to develop the syndrome (Koopman et al. 1994; Shalev et al. 1996).

670 Specific disorders

Clinically (Gersons and Carlier 1992), patients become numb to, and detached from, the world around them, find themselves repeatedly remembering or re-experiencing the trauma in some fashion or other, and experience chronic anxiety and apprehensiveness. Detachment or numbing manifests as a loss of interest and withdrawal from life's normal pursuits: some patients complain of feeling 'dead' inside and may appear listless and apathetic. The recollection of the trauma is involuntary and recurrent, and may take the form of vivid memories, nightmares, and, at times, illusory, almost hallucinatory remembrances of the inciting trauma. Plagued by these memories, patients typically go out of their way to avoid anything that might be reminiscent of the trauma: thus, a combat veteran with PTSD might avoid war movies. Anxiety is often accompanied by apprehensiveness and 'jumpiness', patients often being very easily startled. Insomnia may occur and may be severe, and patients often fight against fatigue and have trouble with concentration. Irritability may occur and may be quite labile. Patients with PTSD are liable to other disorders, in particular major depression, alcohol dependence, and various drug addictions.

Course In perhaps one-half of all cases, the symptoms remit spontaneously within a matter of months. In the remainder, the symptoms are chronic, this unfavorable outcome being more likely in those with a delayed onset or in any patient whose symptoms have persisted beyond a half-year. Differential diagnosis

Major depression, as noted above, may coexist with PTSD, but, in some cases after a significant trauma, patients may develop not PTSD but solely a major depression. In such a case, although the depressed patient may be withdrawn, anxious and complain of insomnia and poor concentration, complaints of intrusive recollections will either be absent or occupy only a very minor part of the overall clinical picture. Post-concussion syndrome is distinguished by the absence of numbing and intrusive recollections. Malingering by claiming PTSD is not uncommon and, whenever suspected, should prompt a review of whatever records are available concerning the original trauma: some soldiers claiming to have PTSD have never even been in combat. Treatment

Various forms of psychotherapy have been advocated for PTSD. Of the pharmacologic treatments, the following antidepressants, each used in a full antidepressant dose, have been found, in double-blind studies, to be useful: fluoxetine (Connor et al. 1999; van der Kolk et al. 1994), sertraline (Brady et al. 2000), imipramine (Davidson et al. 1990), and phenelzine (Frank et al. 1988). Of all of these, one of the SSRIs, either fluoxetine or sertraline, is probably the best choice. The side-effects of imipramine are often troubling, and the dietary restrictions required for the MAOI phenelzine are difficult to follow. Importantly, if alcoholism or drug addiction is present, that must be treated first.

GENERALIZED ANXIETY DISORDER Pathology and etiology

Generalized anxiety disorder appears to be familial (Noyes et al. 1987), twin studies supporting a role for genetic factors (Kendler et al. 1992).

Idiopathic psychotic, mood, and anxiety disorders 671 Clinical features

The onset is gradual and may occur in either teenage or early adult years. Clinically (Anderson et al. 1984; Hoehn-Saric et al. 1989a; Marten et al. 1993; Nisita et al. 1990; Starcevic et al. 1994), patients experience a chronic, pervasive sense of anxious apprehension and tension. They frequently worry about the future and are easily startled. Some complain of a sense of shakiness, and there may be a mild degree of a fine tremor of the hands. There is occasionally tachycardia, and the skin is often cold and clammy. Insomnia may occur, and many complain of nausea and headache. Some patients can offer no explanation for their symptoms, whereas others will offer 'reasons' and blame their state on some life event or other. Observation over time, however, typically reveals that the anxiety is in fact autonomous and 'free-floating'. Course The overall course of generalized anxiety disorder is not as yet clear: it appears that, in some patients, the disorder is chronic and unremitting, whereas in others, there may be a remission after a matter of years. It is not clear, however, whether these remissions are permanent or whether a relapse is to be expected. Differential diagnosis

Panic disorder and simple and social phobias are immediately distinguished by the occurrence of anxiety in discrete attacks, in contrast to the chronic nature of the symptomatology of generalized anxiety disorder. Dysthymia may, at times, be difficult to distinguish. Whereas a depressive episode of a major depression or bipolar disorder is distinguished by the severity of symptoms, dysthymia characteristically has only low-grade symptoms, similar in the degree of severity to those seen in generalized anxiety disorder. Clues to the correct diagnosis include guilt, pervasive despair, and crying spells, symptoms common in dysthymia but unusual in generalized anxiety disorder. Treatment

Both cognitive-behavior therapy (Durham et al. 1994) and various medications appear to be effective. Of the antidepressants, imipramine (Hoehn-Saric et al. 1988; Kahn et al. 1986; Rickels et al. 1993b), trazodone (Rickels et al. 1993b), and venlafaxine (Davidson et al. 1999; Gelenberg et al. 2000; Rickels et al. 2000) are all effective, and effectiveness has also been found for buspirone (Rickels et al. 1988; Sramek et al. 1996). All of these agents, however, take weeks to become effective, in contrast to either alprazolam (Enkelmann 1991; Hoehn-Saric et al. 1988) or diazepam (Rickels et al. 1993b), which are immediately effective. The immediate action of the benzodiazepines is a definite advantage, but, after 2 or more weeks of treatment, it appears that the antidepressants are actually more effective for the tense worrisomeness experienced by these patients. Eventual doses for these agents are 150 mg for imipramine, 250 mg for trazodone, 75-225 mg for venlafaxine, 60 mg for buspirone, 15-25 mg for diazepam and 2-6 mg for alprazolam. If a benzodiazepine is used, great care must be exercized in tapering it as an over-hasty taper invites withdrawal and rebound anxiety.

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Idiopathic psychotic, mood, and anxiety disorders 685 Stern RS, CobbJP. Phenomenology of obsessive-cornpulsive neurosis. BrJ Psychiatry 1978; 132:233-9. Sternberg DE, Jarvik ME. Memory functions in depression: improvement with antidepressant medication. Arch Gen Psychiatry 1976; 33:219-24. Stevens JW. Manic-depressive insanity, with the report of a typical case.7 Nerv Ment Dis 1904; 31:513-25. StrohleA, KellnerM,YassouridisA, etal. Effect of flumazenil in lactate-sensitive patients with panic disorder. AmJ Psychiatry 1998; 155:610-12. Stunkard AJ, Fernstrom MH, Price A, etal. Direction of weight gain in recurrent depression: consistency across episodes. Arch Gen Psychiatry 1990; 47:857-60. Suddah RL, Casanova MF, GoldbergTE, et al. Temporal lobe pathology in schizophrenia: a quantitative magnetic resonance imaging study. AmJ Psychiatry 1989; 146:464-72. Summers WK. Mania with onset in the eighth decade: two cases and a review.) Clin Psychiatry 1983; 44:141-3. Susser ES, Lin SP. Schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944-1945. Arch Gen Psychiatry 1992; 49:983-8. Swedo SE, Leonard HL, Shapiro MB, et al. Sydenham's chorea: physical and psychological symptoms of St. Vitus dance. Pediatrics 1993; 91:706-13. Taylor MA, Abrams R. The phenomenology of mania: a new look at some old patients. Arch Gen Psychiatry 1973; 29:520-2. Taylor MA, Abrams R. Catatonia: prevalence and importance in the manic phase of manic-depressive illness. Arch Gen Psychiatry 1977; 34:1223-5. TeraoT. Subclinical hypothyroidism in recurrent mania. Biol Psychiatry 1993; 38:853-4. Tesar GE, Rosenbaum JF, Pollack MH, etal. Double-blind, placebo-controlled comparison of clonazepam and alprazolam for panic disorder.) Clin Psychiatry 1991; 52:69-76. Thase ME. Relapse and recurrence in unipolar major depression: short-term and long-term approaches. Compr Psychiatry 1990; 51 (suppl 26):51 -7. Tohen M, Sanger TM, McElroy SL, et al. Olanzepine versus placebo in the treatment of acute mania. AmJ Psychiatry 1999; 156:702-9. Tollefson GD, Rampey AH, Potvin JH, etal. A multicenter investigation of fixed-dose fluoxetine in the treatment of obsessive-compulsive disorder. Arch Gen Psychiatry 1994; 51:559-67. Tollefson GD, BeasleyCM,Tran PV, et al. Olanzepine versus haloperidol in the treatment of schizophrenia and schizoaffective disorders: results of an international collaborative trial. AmJ Psychiatry 1997; 1545:457-65. Torgerson S. Comorbidity of major depression and anxiety disorders in twin pairs. AmJ Psychiatry 1990; 147:1199-202. Tran PV, Hamilton SH, KuntzAJ.efo/. Double-blind comparison of olanzepine versus risperidone in the treatment of schizophrenia and other psychotic disorders. 7 Clin Psychopharmacoliyyj; 17:407-18. Tran PV, Dellva MA, Tollefson GD,etal. Oral olanzepine versus oral haloperidol in the maintenance treatment of schizophrenia and related psychoses. BrJ Psychiatry 1998; 172:499-505. Tran PV, Tollefson GD, Sanger TM, etal. Olanzepine versus haloperidol in the treatment of schizoaffective disorder: Acute and long-term therapy. BrJ Psychiatry 1999; 174:15-22. Tsuang MT. Suicide in schizophrenics, manics, depressives, and surgical controls: a comparison with general population suicide mortality. Arch Gen Psychiatry 1978; 35:153-5. Tsuang MT, Woolson RF, Fleming JA. Long-term outcome of major psychoses. I. Schizophrenia and affective disorders compared with psychiatrically symptom-free surgical controls. Arch Gen Psychiatry 1979; 36:1295-304. Tsuang MT, FaraoneSV, Fleming JA. Familial transmisson of major affective disorders: is there evidence supporting the distinction between unipolar and bipolar disorders? BrJ Psychiatry 1985; 146:268-71. Tuke DH. Imperative ideas. Brain 1894; 17:179-97.

686 Specific disorders Turner SW, Toone BK, Brett-Jones JR. Computerized tomographic scan changes in early schizophrenia preliminary findings. Psychol Med 1986; 16:219-25. van der Kolk BA, Dreyfuss D, Michaels M, etal. Fluoxetine in posttraumatic stress disorder. 7 Clin Psychiatry 1994; 55:517-22. Van Dyke C, Zilberg NJ, McKinnon JA. Posttraumatic stess disorder: a thirty-year delay in a World War II veteran. Am J Psychiatry 1985; 142:1070-3. Van Putten T. The many faces of akathisia. Compr Psychiatry 1975; 16:43-7. Van Putten T, May PRA. 'Akinetic depression' in schizophrenia. Arch Gen Psychiatry 1978; 35:1101-7. Van Putten T, Multalipassi LR, Malkin MD. Phenothiazine-induced decompensation. Arch Gen Psychiatry 1974; 30:102-5. VanValkenbergC, WinokurG, BeharD,efo/. Depressed women with panic attacks. J Clin Psychiatry 1984; 45:367-9. van Vliet IM, den Boer JA, Westenberg HG. Psychopharmacological treatment of social phobia: a double blind placebo controlled study with fluvoxamine. Psychopharmacology 1994; 115:128-34. Versiani M, Nardi AE, Mundim FD,etal. Pharmacotherapy of social phobia: a controlled study with moclobemideand phenelzine. BrJ Psychiatry 1992; 161:353-60. Videbech T. Chronic olfactory paranoid syndromes. Acta PsychiatrScana"\966; 42:183-213. Viguera AC, Nonacs R, Cohen LS, etal. Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry 2000; 157:179-84. Wade AG, Lepola U, Koponen HJ, etal. The effect of citalopram in panic dsorders. BrJ Psychiatry 1997; 170:549-53. Wahlbeck K, Cheine M, Essali A, etal. Evidence of dozapine's effectiveness in schizophrenia: a systematic review and meta-analysisof randomized trials. AmJ Psychiatry 1999; 156:990-9. Walker E, Lewine RJ. Prediction of adult-onset schizophrenia from childhood home movies of the patients. Am J Psychiatry 1990; 147:1052-6. Watson CG, KucalaT, Manifold V,etal. Differences between post traumatic stress disorder patients with delayed and undelayed onset. JNervMentDis 1988; 176:568-72. Watt JAG. The relationship of paranoid states to schizophrenia. AmJ Psychiatry 1985; 142:1456-8. Wertham Fl. A group of benign psychoses: prolonged manic excitements./Amy Psychiatry 1929; 86:17-78. Wheatley DP, van Moffaert M,Timmerman I, etal. Mirtazepine: efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder.) Clin Psychiatry 1998; 59:306-12. White K, Simpson G. Combined MAOI-tricyclic antidepressant treatment: a revaluation../ Clin Psychopharmacol 1981; 1:264-82. WinokurG. Delusional disorder (paranoia). Compr Psychiatry 1977; 18:511-21. Winokur G. Psychosis in bipolar and unipolar affective illness with special reference to schizo-affective disorder. BrJ Psychiatry 1984; 145:236-42. WinokurG. Familial psychopathology in delusional disorder. Compr Psychiatry 1985; 26:241-8. Winokur G, Tsuang MT. Elation versus irritability in mania. Compr Psychiatry 1975; 16:435-6. Winokur G, Clayton PJ, Reich T. Manic depressive illness. St. Louis, Mosby, 1969. WinokurG, Coryell W, Endicott J, et al. Further distinction between manic-depressive illness (bipolar disorder) and primary depressive disorder (unipolar depression). Am J Psychiatry 1993; 150:1176-181. Yalom ID, Lunde DT, Moos RH, et al. 'Postpartum blues' syndrome: a description and related variables. Arch Gen Psychiatry 1968; 18:16-27. Yehuda R, SouthwickSM, Krystal JH, etal. Enhanced suppression of cortisol followingdexamethasone administration in posttraumatic stress disorder. Am J Psychiatry 1993; 150:83-6. Yonkers KA, Halbreich U, Freeman E, etal. Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment: a randomized controlled trial. JAMA 1997; 278:983-8.

Idiopathic psychotic, mood, and anxiety disorders 687 Young SA, Hurt PH, Benedek DM, etal. Treatment of premenstrual dysphoric disorder with sertraline during the luteal phase: a randomized, double-blind, placebo-controlled crossover trial. J Clin Psychiatry 1998; 59:76-80. Zitrin CM, Klein DF, Woerner MG, el al. Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo. Arch Gen Psychiatry 1983; 40:125-38. Zohar J, Judge R. Paroxetine versus clomipramine in the treatment of obsessive-compulsive disorder. Br J Psychiatry 1996; 169:468-74. ZornbergGL, Pope HG. Treatment of depression in bipolar disorder: new directions for research. J Clin Psychopharmacon993; 13:397^108.

21 Intoxications and withdrawals

Amphetamines Cocaine Hallucinogens Phencyclidine Alcohol

688 689 691 692

Sedatives, hypnotics, and anxiolytics

693 697

Inhalants (solvents)

698

Cannabis Opioids Nicotine Caffeine Methanol Isopropanol

699 700 702 702 703 704

AMPHETAMINES Pathology and etiology

Amphetamines, such as methamphetamine, dextroamphetamine, and amphetamine itself, both block reuptake and increase the release of dopamine and norepinephrine. It appears, for the most part, that the 'central' effects are due to heightened dopaminergic tone whereas the peripheral cardiovascular effects ensue upon heightened noradrenergic tone (Nurnberger et al 1984). Clinical features

Amphetamines may be taken orally, intravenously, or, after smoking, by inhalation, the onset of intoxication ranging from almost immediate, with intravenous administration or inhalation, to a delay of an hour or so with ingestion. Mild intoxication (Hollister and Gillespie 1970) is characterized by increased energy, varying degrees of elation, increased self-confidence, and talkativeness. Mydriasis is present, blood pressure is increased, and the pulse may either be increased or reflexively decreased. With more severe intoxication, agitation may ensue, with fleeting hallucinations and delusions of persecution and reference. The blood pressure is greatly elevated, the body temperature is elevated, and there may be profuse diaphoresis; in some cases, chorea (Lundh and Tunving 1981), delirium, seizures, and various arrythmias may occur. With severe hypertension, a hypertensive encephalopathy may ensue. Most intoxications last between several hours and a day. Urine or serum toxicology screens generally detect the drug. Some intoxications may also be complicated by a psychosis (Angrist and Gershon 1970; Bell 1973; Ellinwood 1967; Griffith et al. 1972; Iwanami et al. 1994) that may or may not be accompanied by agitation. Commonly, patients experience delusions of persecution and reference, with or without hallucinations, which may in turn be either auditory or visual. In

Intoxications and withdrawals 689

some cases, there may be bizarre delusions, including Schneiderian first rank symptoms, such as thought-broadcasting or delusions of control. The delusions of persectuion are rarely sufficiently compelling to lead the patient to murder the 'persecutor' (Ellinwood 1971). This amphetamine-induced psychosis generally clears within a matter of days or weeks, but it may occasionally last many months (Iwanami et al. 1994). Withdrawal symptoms (Kramer et al. 1967; Watson et al. 1972) include dysphoria, either insomnia or, more commonly, hypersomnia, and drug-craving: in most cases, these symptoms undergo significant remission after a matter of days or weeks and then linger at a much reduced severity for weeks or months before clearing entirely. Course Although intoxication after one episode of use may last, as noted above, from hours to a day, many addicts will go on 'binges', taking repeated doses and thus greatly prolonging the intoxication (Kramer et al. 1967). Differential diagnosis

Cocaine intoxication may be clinically indistinguishable from amphetamine intoxication. Mania may be considered, and, in some cases, only observation during a period of enforced abstinence will resolve the question. The combination of mydriasis and bradycardia, if present, is generally not found in mania and thus strongly suggests an intoxication. Schizophrenia may be closely mimicked by an amphetamine-induced psychosis. Two factors enable the correct diagnosis: first, amphetamine-induced psychosis has an acute onset, in the midst of intoxication, in contrast to the relatively gradual onset of schizophrenia; and second, amphetamine-induced psychosis clears spontaneously, whereas schizophrenia is chronic and unremitting. Treatment

Mild intoxication may require only observation. More severe cases may be treated with a dopamine blocker, such as a neuroleptic. Chlorpromazine maybe given in doses of 50-100 mg, or haloperidol in a dosage of 5-10 mg, every hour if given intramuscularly or every 2 hours if given orally, until the patient is calm, limiting side-effects occur or a maximum dose of approximately 1000 mg chlorpromazine or 60 mg haloperidol has been given. Severe hypertension may be treated with nifedipine or nitroprusside, seizures with intravenous lorazepam, and arrythmias with propranolol. Acidification of the urine may hasten excretion. Amphetamine-induced psychosis may be treated in a fashion similar to that of schizophrenia, with the exception that one should attempt a tapering and discontinuation of the neurolepetic fairly soon, within weeks or, at the latest, months. Withdrawal symptomatology may at times be severe enough to require hospitalization in order to prevent suicide and the craving-induced resumption of drug use.

COCAINE Pathology and etiology Cocaine blocks reuptake and facilitates the release of dopamine, norepinephrine, and serotonin: of these three, it appears that dopamine is primarily responsible for cocaine's euphoriant effect. Clinical features

Cocaine may, as a powder, be insufflated ('snorted'), or it may be dissolved and injected intravenously. Cocaine may also be extracted with sodium bicarbonate and then either

690 Specific disorders

allowed to dry into 'crack' cocaine or extracted with ether to form 'free base' cocaine, both of these forms then being smoked. Intoxication begins within 15 minutes or so after snorting and almost immediately upon smoking or intravenous injection. Mild intoxication (Kleber and Gawin 1984) is characterized by euphoria, alertness, talkativeness, and grandiosity; libido increases, and delayed ejaculation occurs. Severe intoxication entails agitation, tachycardia and hypertension (Fischman et al. 1976), mydriasis, and, in some cases, hallucinations (Siegel 1978), chorea ('crack dancing') (Daras et al. 1994) or tics (Pascual-Leone and Dhuna 1990). Although, overall, intoxication persists for 20-60 minutes, the 'rush' seen after smoking or intravenous use may fade substantially after only 5 minutes. Uncommonly, severe intoxication may be complicated by a delirium, which may persist for several hours. Other complications of cocaine intoxication include myocardial infarction (Virmani et al. 1988), rhabdomyolysis (Roth etal. 1988), subarachnoid hemorrhage (Lichtenfeld et al. 1986), intracerebral hemorrhage (Nolte et al. 1996), and, with chronic, repeated use, a cerebral vasculitis (Fredericks etal 1991; Krendel etal. 1990). With the chronic use of cocaine, after perhaps 2 years or so, intoxication may also become complicated by prominent psychotic symptoms, including auditory and visual hallucinations, and delusions, often of reference and persecution (Brady et al. 1991; Satel et al. 1991; Sherer et al. 1988). Patients may hear police talking outside the door, and flashes of red light may be seen, betraying the laser sights of police sharpshooters. Classically, patients both see and feel insects, 'cocaine bugs', on them and may excoriate themselves in an attempt to get at them. Although this cocaine-induced psychosis generally clears within a day (Brady et al. 1991), it may, in a minority of cases, persist for days or weeks (Manschreck et al. 1987). Urine and serum toxicology may be negative for cocaine as it has a very short half-life: metabolites, however, especially benzoylecgonine, may be detected for up to a week and a half. Withdrawal symptomatology (Weddington etal. 1990) includes dysphoria, a craving for the drug, anhedonia, fatigue, irritability, insomnia, and, in some cases, hyperphagia. The symptoms peak in a matter of days and then deverfesce over days to weeks. Rarely, dystonia may appear during withdrawal (Choy-Kwong and Lipton 1989). Course The pattern of cocaine intoxication varies: snorters often use on a daily basis, snorting once or twice a day, whereas those who smoke cocaine or use it intravenously often do so in binges or 'runs' of continuous use, which may last for days. Differential diagnosis

Amphetamine intoxication may be clinically indistinguishable from cocaine intoxication. Mania may be suggested, and, in some cases, only observation during enforced abstinence will resolve the diagnostic issue. Schizophrenia may be considered when psychosis complicates the intoxication, but the brevity of the psychosis, relative to the chronic, enduring nature of schizophrenia, makes the diagnosis. Depression, as may be seen in major depression or bipolar disorder, may mimic cocaine withdrawal. As with amphetamines, observation during an enforced abstinence may be critical: as significant withdrawal symptoms rarely persist beyond 2 weeks, the presence of depressive symptomatology much beyond that time suggests a depression. Treatment

The treatment is similar to that outlined for amphetamines in the preceding section.

Intoxications and withdrawals 691

HALLUCINOGENS Pathology and etiology Hallucinogens appear to act on serotonin receptors, where they function primarily as agonists (Glennon 1990; Titelier et al. 1988). The existence of chronic sequelae (e.g. flashbacks) suggests that these agents cause permanent damage, both animal and clinical data supporting this: in primates, methylenedioxymethamphetamine (MDMA; also known as ecstasy) damages serotoninergic fibers arising from the dorsal raphe nuclei (Ricaurte et al. 1988), and in subjects abstinent from MDMA, positron emission tomography scanning has demonstrated a reduction in the number of serotonin transporter sites (McCann et al. 1998). Clinical features

Hallucinogens include lysergic acid diethylamide (LSD) and similar compounds, such as psilocybin and dimethyltryptamine (DMT), and mescaline and compounds similar to mescaline, such as dimethoxymethylamphetamine (STP), dimethoxyamphetamine (DMA), methylenedioxyamphetamine (MDA), and MDMA. With the exception of DMT (Strassman et al. 1994a, b), which must be smoked, insufflated, or injected, all of the hallucinogens are active orally. Although the intoxications produced by these do show some differences, these are of such minor degree that the hallucinogens may be considered together as a group. Intoxication begins within 20-60 minutes after oral ingestion and is characterized (Bercel et al. 1956; Freedman 1968; Hollister et al. 1960; Isbell et al. 1956; Ungerleider et al. 1966) by a profound, 'cosmic' sense, without any drowsiness or sedation. Patients may experience vivid memories, and commonplace events may appear exceedingly meaningful. Visual illusions and hallucinations are common, and a minority may experience synesthesiae or simple auditory hallucinations. Mild degrees of tachycardia, elevated blood pressure, mydriasis, fine tremor, hyperreflexia, and poor coordination may be seen, and the temperature may be elevated. In a minority of cases, the intoxication may turn into a 'bad trip', with the developement of severe anxiety, which may be accompanied by delusions of persecution and reference (Kuramochi and Takahashi 1964). MDMA (ecstasy) (Kosten and Price 1992; Liester et al. 1992) deserves special emphasis as it has recently become very popular, especially among young people who may use it during allnight parties known as raves. As with other hallucinogens, the intoxication may be complicated by panic (Whitaker-Azmita and Aronson 1989) and delusions of persecution (Winstock 1991), but MDMA further carries a risk of seizures, fever, rhabdomyolysis, and renal failure (Fahal et al. 1992; Henry 1992; Shearman et al. 1992). Most intoxications last of the order of 6-24 hours; exceptions include psilocybin and DMT, which produce intoxications lasting 2-6 hours. Hallucinogens are generally not sought for in routine urine or serum toxicology, but may be detected by more sophisticated methods. Withdrawal phenomena do not appear to occur. This is interesting in light of the fact that tolerance does occur: after a few days use, the hallucinogenic effects are lost, and patients must wait a few days before they can once again achieve the desired intoxication (Isbell et al. 1956). Flashbacks (Abraham 1983; Frosch et al. 1965; Horowitz 1969) constitute a sequela to hallucinogen intoxication that may occur in up to one-quarter of patients. They consist of a re-experiencing of part of the intoxication and are quite brief, often lasting only seconds. Visual phenomena are most common, with visual hallucinations and 'trailing', a persistent after-image being left behind a moving object. Other sequelae include depression and, less commonly, mania, these mood changes lasting days or weeks. Another sequela is a psychosis (McGuire et al. 1994), which, although in most cases clearing after a few days or weeks, may, in a small minority, remain chronic and closely

692 Specific disorders

resemble schizophrenia. It also appears that the use of ecstasy may leave patients with subtle cognitive deficits (Bolla et al. 1998; Gouzoulis-Mayfrank et al. 2000). Course Occasional intoxication is generally the rule, and for those who pursue the intoxication more avidly, the rapid development of tolerance, as noted above, generally limits prolonged use to only a few days, after which a 'rest' period is required. Differential diagnosis

Phencyclidine intoxicaton is distinguished by the presence of nystagmus and other signs, such as miosis, ataxia, dysarthria, myoclonus, and decreased sensation in the lower extremities. Treatment

Patients experiencing a bad trip may generally be 'talked down'; occasionally a benzodiazepine, such as lorazepam, may also be helpful, but neuroleptics are generally contraindicated as they may actually worsen the intoxication.

PHENCYCLIDINE Pathology and etiology Phencyclidine and related arylcyclohexylamines appear to exert their hallucinogenic effect via a blockade of the NMDA glutamate receptor. Clinical features

Although phencyclidine may be taken by nasal insufflation or intravenously, the most popular route is by ingestion, intoxication occurring within an hour, or smoking, the intoxication appearing within minutes. Clinically (Javitt and Zukin 1991; Luby et al. 1959; Meyer et al. 1959; Pearlson 1981), mild intoxication is characterized by euphoria, a sense of detachment from the surroundings, and visual illusions; agitation may be seen, as may lability and bizzare, and at times violent, behavior. Vertigo, nausea, and vomiting may occur, and, upon physical examination, there is nystagmus, dysarthria, ataxia, decreased sensation in the lower extremities, and, in some cases, myoclonus. The temperature, pulse, and blood pressure may all be mildly increased, and there may be generalized hyperreflexia. With more severe intoxication, a delirium may ensue, which is typically characterized by agitation and psychotic symtomatology (Allen and Young 1978). Delusions, often of persecution, hallucinations, typically visual, and stuporous catatonia may appear. Other possible findings include seizures (Alldredge et al. 1989a) and dystonia, which may be generalized. With higher doses, stupor and coma may supervene: myoclonus is frequent, respirations are decreased, and the blood pressure may rise high enough to cause a hypertensive encephalopathy; stroke has occurred (Sloan et al. 1991). Intoxication, for the most part, generally clears in 4-8 hours, but lingering effects may persist for 1 or 2 days (Pearlson 1981). Whether or not withdrawal occurs in humans is not as yet clear. Course Phencyclidine abusers may take the drug in relatively small amounts on a daily basis, or in binges, using high doses for several days in a row. Differential diagnosis

The differentiation from hallucinogen intoxication is as described in the preceding section.

Intoxications and withdrawals 693 Treatment

The appearance of delirium demands admission or emergency room care. In contrast to patients undergoing hallucinogen intoxication, attempting to 'talk down' a patient with phencyclidine intoxication is not helpful and may indeed make the patient more agitated. Patients should be kept in a quiet, dimly lit area. Agitation and psychotic symptoms may be treated with a neuroleptic, such as haloperidol in doses of 5-10mg, or chlorpromazine in dosage of 50-100 mg, given every hour intramuscularly. Restraints should be used only if absolutely necessary as they may increase the risk of rhabdomyolysis and renal failure (Lahmeyer and Stock 1983). Hyperthermia may be treated with a cooling blanket, hypertension with nitroprusside, and dystonia with intravenous lorazepam. Isolated seizures do not require treatment; recurrent seizures may be treated with intravenous lorazepam and fosphenytoin. Intubation may be required for respiratory depression. Efforts to hasten the removal of phencyclidine from the body include the use of activated charcoal and acidification of the urine (Done et al. 1980; Lyddane et al. 1988). Phencyclidine is a weak base (Busto et al. 1989), being 'trapped' within the acidic gastric juices and then reabsorbed from the intestines; furthermore, as a weak base, it may, provided it is acidic enough, also be trapped in the urine. Activated charcoal interdicts the gastroenteric recirculation, and acidification of the urine may increase the urinary excretion of phencyclidine more than 100-fold. Acidification may be accomplished with either ascorbic acid or ammonium chloride, both given in a dose of 1 gm every 6 hours, either orally or intravenously, with the urine pH maintained at or below 5.0. Furosemide may be given concurrently to hasten excretion.

ALCOHOL

This section deals with the following: alcohol intoxication, blackouts, pathologic intoxication, the alcohol withdrawal syndrome, 'rum fits' (alcohol withdrawal seizures), and delirium tremens (alcohol withdrawal delirium). Pathology and etiology

The cellular mechanisms of alcohol intoxication are as yet unclear. In the past, disturbances in membrane fluidity were held responsible; subsequent attention turned to the GABA receptor, and current research focuses on the role of the NMDA glutamate receptor (Tsai et al. 1995). The mechanism whereby alcohol causes blackouts is not clear, and apart from an association with prior head trauma, the cause of pathologic intoxication is likewise elusive. The alcohol withdrawal syndrome may be related to long-term changes in the GABA and glutamate receptors, and this may also be the case with 'rum fits'; it appears, however, that rum fits are more likely to occur in patients with pre-existing cortical lesions. The cause of delirium tremens is probably similar to that of alcohol withdrawal. Clinical features

Alcohol intoxication of mild degree is characterized by euphoria, talkativeness, and a degree of disinhibition; in some patients, there may be, rather than euphoria, some irritability or depression. In moderate intoxication, the behavior becomes coarse, and the thinking is slow and unclear. There is facial flushing, conjunctival injection, dysarthria, nystagmus, and ataxia. With severe intoxication, there is drowsiness, stupor, and disabling ataxia; coma may ensue, with respiratory depression and death. The blood alcohol level (BAL) is customarily reported in mg/dl or, as it is often worded,

694 Specific disorders

mg%. In an alcohol-naive subject, mild intoxication is seen at 100 mg%, moderate intoxication at 200 mg%, and severe intoxication at 300 mg%, coma and respiratory arrest becoming likely at a level of over 400 mg%. With the development of tolerance, however, as seen in alcoholics, a level of 300 mg% may produce only mild intoxication, and a level of 500 mg% may be tolerated without loss of consciousness (Minion et al. 1989). In general, in a 70 kg subject, the rapid consumption of 15 cc of pure, 100% ethanol will elevate the BAL by about 20 mg%, this amount of pure ethanol generally being found in one mixed drink, one 360 ml (12 fl oz) can of beer, or one glass of wine. In those with normal hepatic function, ethanol is metabolized at a rate of 5-10 cc/hour. Of interest, females tend to become intoxicated on a smaller amount of ingested alcohol than do males, which may be because of a reduction in gastric alcohol dehydrogenase activity, thus allowing a greater percentage of the ingested alcohol to escape the gastric first pass (Frezza et al. 1990). Blackouts may occur during moderate or severe alcohol intoxication and consist of transient episodes of anterograde amnesia, lasting anywhere from minutes to days, depending on how long the BAL remains high (Goodwin 1971; Goodwin et al. 1969a). During a blackout, patients' behavior may, to casual inspection, not seem to be changed: patients may recall what they were doing at the start of the blackout and may also be able to keep track of ongoing events sufficiently well such that they are able to keep up a conversation, play cards, etc. If, however, short-term memory is tested during the blackout, one finds that patients are unable to recall anything that happened much more than 3 minutes earlier. Furthermore, once the blackout ends, the time period covered by the blackout remains an 'island of amnesia' to patients, who can recall little or nothing of the events that transpired during the blackout. Should blacked-out patients fall asleep during the blackout, they may, upon awakening the next day, anxiously ask acquaintances what they did the night before. Those who are still awake when the blackout abruptly ends may be quite startled at their situation: one patient (Goodwin et al. 1969b) 'found himself dancing with no recollection of what he had been doing during the previous six hours'. A variant of blackouts, known as 'brownouts', may occur wherein the amnesia is not complete, and patients can recall some of what happened (Tamerin etal 1971). Pathological intoxication (Perr 1986), although long written of (Banay 1944; May and Ebaugh 1953), is a controversial diagnosis (Coid 1979). Putatively, patients, after only a small amount of alcohol, undergo a dramatic change, becoming uncharacteristically irritable and often violent. One study was able to reproduce these symptoms in patients thought to have suffered pathologic intoxication (Maletzky 1976), whereas another was not (Bach-y-Rita et al. 1970). Alcohol withdrawal (Isbell et al. 1955), although generally seen only in alcoholics, may however also be seen in anyone who engages in heavy, prolonged drinking. The symptoms appear gradually, anywhere from 4 to 12 hours after the BAL has fallen below the patient's 'theshold' for intoxication. Importantly, this implies that, for some patients, such as alcoholics who have developed tolerance, that withdrawal symptoms may appear while the patient is still drinking, provided that the alcohol consumption has 'slowed down' sufficiently. The symptoms include tremulousness, anxiety, easy startability, poor memory and concentration, fleeting and poorly formed visual or auditory hallucinations, insomnia (Johnson et al. 1970), elevated temperature, pulse and systolic blood pressure, mydriasis, and generalized hyperreflexia. The most prominent symptom of alcohol withdrawal is often tremor, which is postural, rapid, ranging in severity from fine to coarse, and either confined to the outstretched hands or more widespread, in some cases becoming generalized, involving even the eyelids and tongue. Given this prominence, the common name for alcohol withdrawal, the 'shakes', seems to be quite justified. Alcohol withdrawal generally peaks in a couple of days, then undergoing a significant reduction in severity over the next 2 or 3 days. Among 'social' drinkers, the symptoms may

Intoxications and withdrawals 695

gradually resolve fully within a week, but among alcoholics, residual symptoms may persist for up to 6 month. 'Rum fits', or alcohol withdrawal seizures, may be seen during the first 2 days of alcohol withdrawal in up to 5% of alcoholics (Shuckit et al. 1993). Typically, they are grand mal in type and may or may not have a focal onset. Most patients have only one seizure; a minority may have two or three, and, rarely, status epilepticus may appear. Delirium tremens (Lundquist 1961; Nielsen 1965; Rosenbaum et al. 1941), or the 'DTs', is generally seen only in alcoholics, usually only in those alcoholics who have experienced the alcohol withdrawal syndrome on multiple prior occasions. The patient destined to develop the DTs typically first experiences the alcohol withdrawal syndrome for hours or up to 3 days, after which all of the signs and symptoms of the alcohol withdrawal syndrome undergo an exacerbation and are joined by a delirium. This delirium, in addition to confusion, disorientation to time and place, and deficient memory, is also typically characterized by vivid hallucinations, which may be either visual or auditory. Visual hallucinations are often of animals or insects and may be very complex and well formed. Auditory hallucinations are often of voices, which tend to be critical and persecutory. Seizures may occur in 10-20% of patients suffering the DTs. The mortality rate for delirium tremens, if untreated, ranges from 5% to 15%; among those who survive, the delirium clears within days to weeks. Course The occurrence of the alcohol withdrawal syndrome or blackouts is generally sufficient to make drinkers either stop altogether or severely limit their intake. Repeated occurrences, and certainly the appearance of rum fits or delirium tremens, should be a 'red flag' for the diagnosis of alcoholism (Shuckit et al. 1993). Differential diagnosis

Alcohol intoxication may be mimicked by sedative-hypnotic intoxication, methanol intoxication, isopropyl alcohol intoxicaton, and intoxication with ethylene glycol. Sedativehypnotic intoxication, for example with benzodiazepines, is very similar to ethanol intoxication, with the exception that there is no odor of alcohol and no conjunctival injection. Both methanol (Sharpe et al. 1982; Wood and Buller 1904) and isopropyl alcohol (Rich et al. 1990) intoxications are suggested by a relatively mild euphoria and prominent nausea, vomiting, and abdominal pain; in addition, there may be a dimming of vision with methanol intoxication. Ethylene glycol intoxication, unlike intoxication with ethanol, methanol, or isopropyl alcohol, is not accompanied by an odor of alcohol on the breath. The anion gap is increased in ethylene glycol ingestion, and emergency treatment is required. Blackouts may be mimicked by other causes of episodic anterograde amnesia, such as transient global amnesia and complex partial seizures. The distinguishing feature is, of course, the absence of intoxication in these other entities. Pathologic intoxication is, as noted above, a controversial diagnosis and should be made sparingly, if at all. 'Mean' drunks are not uncommon, but here one finds either that the patient is characteristically mean whether drunk or sober, or that the 'meanness', if it is confined to periods of intoxication, occurs only with moderate or severe intoxication rather than after only one or two drinks, as is said to be characteristic of pathologic intoxication. Malingering may also be considered, especially when the 'pathologic' behavior in question attracted legal attention. Alcohol withdrawal may be duplicated by withdrawal from sedative-hypnotics, such as benzodiazepines. Hypoglycemia may occur during and after intoxication (Fredericks and Lazor 1963; de Moura et al. 1967), with tremulousness and autonomic signs. In addition to obtaining a blood glucose level, the administration of a sweetened beverage or candy is a

696 Specific disorders

diagnostic tool; however, as noted below, this must not be carried out until the patient has been given thiamine. Rum fits are, by definition, seen only during alcohol withdrawal. It is critical to keep in mind, however, that not all seizures occurring during withdrawal are examples of rum fits: alcoholics are prone to other conditions that may themselves cause seizures, such as subdural hematoma, Wernicke's encephalopathy, hypoglycemia, hypomagnesemia, and meningitis. Delirium tremens may be duplicated by sedative-hypnotic withdrawal delirium. Other causes of delirium, not uncommon in the alcoholic, include the Wernicke-Korsakoff syndrome, pellagra of the encephalopathic type, hypoglycemia, hypomagnesemia, hepatic encephalopathy, central pontine myelinolysis, meningitis, and the rare Marchiafava-Bignami syndrome. Treatment

Alcohol intoxication generally requires no treatment other than observation. Should the patient fall asleep or into a stupor, placement in the postoperative position is appropriate, given the possibility of vomiting and aspiration. Should coma and respiratory depression approach, or the BAL suggest that they are imminent, consideration may be given to hemodialysis. Blackouts require no treatment except observation; the end of the blackout is signalled by the patient's ability consistently to recall three out of three words after 5 minutes. Pathologic intoxication may necessitate the use of seclusion or restraints until after the intoxication has passed. The alcohol withdrawal syndrome may or may not require treatment beyond supportive care. Patients should routinely be given 100 mg thiamine intramuscularly, followed by daily oral thiamine and multivitamins. Adequate hydration and nutrition should be assured, but food or glucose (including intravenous feeding) should not be given until after thiamine has been administered as this may otherwise precipitate a Wernicke's encephalopathy. If necessary, the 'shakes', along with anxiety and autonomic symptoms, may be treated with a benzodiazepine, such as lorazepam, and/or carbamazepine. For some patients, having the shakes may serve a useful instructive purpose, but when they are severe or could aggravate another condition (e.g. coronary artery disease or epilepsy), treatment is indicated. Lorazepam may be given in 2 mg doses, either intramuscularly every hour or orally every 2 hours until any one of the following endpoints has been reached: satisfactory control, limiting side-effects, or a maximum dose of 12mg. Assuming that satisfactory control has been established, the total required to achieve this control is given on a scheduled basis, in divided doses, with provision for prn doses should there be significant 'escape' symptoms. An alternative to a benzodiazepine is carbamazepine (Malcolm et al. 1989; Stuppacek et al. 1992), which may be given in a dose of approximately 800 mg daily, lower doses being used in cases of hepatic insufficiency. Given that carbamazepine may take a day or more to quell the withdrawal symptoms, some physicians, when the symptoms are severe, will begin lorazepam, which works almost immediately, concurrently with carbamazepine, with plans rapidly to taper and discontinue the lorazepam and maintain the patient on carbamazepine alone. Regardless of whether ongoing treatment will be with lorazepam alone or with carbamazepine, it is prudent to continue treatment until the withdrawal itself has had a chance to run a substantial part of its natural course. At that point, the medication may be tapered off and discontinued over 2 or 3 days time. Rum fits generally do not require specific treatment. Should a seizure be prolonged, lorazepam may be given intravenously. If there are frequent seizures, fosphenytoin may be added. In patients currently in withdrawal who have a history of rum fits, it may be appropriate to use carbamazepine, not only to treat the withdrawal, but also, hopefully, to

Intoxications and withdrawals 697

prevent seizures. It appears that phenytoin is not effective here on a preventive basis (Alldredge et al. 1989b). Delirium tremens is treated with either lorazepam or carbamazepine, as for alcohol withdrawal, and a case can be made for using both. Should hallucinations or delusions be troublesome, patients may be given haloperidol, 5-10 mg intramuscularly or, slowly, intravenously, every hour until the symptoms are acceptably controlled, limiting side-effects occur, or a maximum dose of around 30 mg has been given. Aggressive supportive care is indicated, with special attention to fluid and electrolyte balance: thiamine should be given parenterally for at least 3 days, and the magnesium level checked and, if necessary, replenished.

SEDATIVES, HYPNOTICS, AND ANXIOLYTICS Pathology and etiology

This section deals with the intoxication and withdrawal phenomena seen with sedatives, hypnotics, and anxiolytics (collectively referred to as the sedative-hypnotics). Of all the sedative-hypnotics, the most important are currently the benzodiazepines, barbiturates being much less commonly used. Other agents, such as meprobamate, paraldehyde, chloral hydrate, and ethchlorvynol, although commonly used in the past, are now rare birds. Benzodiazepines exert their effect by interacting with GABA-A receptors (Pritchett et al. 1989). Clinical features

With the exceptions noted below, intoxication and withdrawal phenomena are symptomatically quite similar to those described for alcohol in the preceding section. Sedative-hypnotic intoxication with barbiturates (Curran 1938, 1944; Isbell et al. 1950), meprobamate (Roache and Griffiths 1987), or benzodiazepines closely resembles alcohol intoxication, with the exception that there is no conjunctival injection and, or course, no odor of alcohol on the breath. Sedative-hypnotic-induced blackouts, likewise quite similar to those seen with alcohol, are, although possible with long-acting benzodiazepins, such as diazepam (Wolkowitz et al. 1987), particularly noted with short-acting, high-potency benzodiazepines (Scharf et al. 1987) such as triazolam (Ewing et al. 1988; Greenblatt et al. 1991; Morris and Estes 1987). Sedative-hypnotic withdrawal, as seen with benzodiazepines (Busto et al. 1986; Covi et al. 1973; Hollister et al. 1961; luergens and Morse 1988; Murphy et al. 1984, 1989; Shader et al. 1993; Tyrer et al. 1983) and barbiturates (Fraser et al. 1958; Isbell et al. 1950), although symptomatically quite similar to alcohol withdrawal, differs in its course (Rickels et al. 1990). Whereas with short-acting agents, for example, lorazepam, the onset may occur within a day, peak in 2 days, and defervesce over a week, with longer-acting agents such as diazepam, the onset may be delayed for 2 days and peak in 4, clearing after 2-3 weeks. Notably, benzodiazepine withdrawal may occur after therapeutic use, providing that the drug has been taken on a generally regular basis for more than 1 or 2 months. As with alcohol withdrawal, some patients may experience lingering, low-level withdrawal symptoms for weeks or months after withdrawing from benzodiazepines (Ashton 1984; Shader et al. 1993). In addition to this typical picture of withdrawal, a recent report described the occurrence of stuporous catatonia as a withdrawal phenomenon (Rosebush and Mazurek 1996). Sedative-hypnotic withdrawal seizures may occur with benzodiazepines (e.g. aprazolam [Breier et al. 1984; Noyes et al. 1986]) and barbiturates, and, in the case of barbiturates, there is a significant risk of multiple seizures and status epilepticus. Sedative-hypnotic withdrawal delirium, noted with benzodiazepines (such as alprazolam

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[Levy 1984; Zipursky et al. 1985] and triazolam [Heritch et al. 1987]) and barbiturates (Fraser et al. 1958; Isbell et al 1950), is clinically quite similar to alcoholic DTs. Course

The abusive use of sedative-hypnotics is generally coupled with use of other substances, in particular alcohol. Differential diagnosis The differential diagnosis for sedative-hypnotic intoxication, withdrawal, withdrawal seizures, and withdrawal delirium is essentially identical to that for the same phenomena seen with alcohol, as discussed in the preceding section. Treatment Sedative-hypnotic intoxication with benzodiazepines may, if severe, be treated with the benzodiazepine antagonist flumazenil (Brogden and Goa 1991). Flumazenil is given intravenously, initially in a bolus of 0.2 mg. If, after 60 seconds, the patient is still unresponsive, a second bolus of 0.3 mg is given. After another 60 seconds, if the patient remains unresponsive, 0.5 mg may be given, that dose being repeated every 60 seconds until either the patient improves or a total dose of 3.0 mg has been given. A failure to respond to 3.0 mg is strong evidence against intoxication with a benzodiazepine alone, and indicates that the intoxication has been caused by either another agent alone, such as a barbiturate, or a combination of a benzodiazepine and another agent. As flumazenil can precipitate seizures and withdrawal in patients physiologically dependent on benzodiazepines, its use should probably be reserved for those facing respiratory depression. Sedative-hypnotic-induced blackouts, as with alcoholic blackouts, require observation until the episode has cleared. Sedative-hypnotic withdrawal may, and probably should, be treated with the selfsame 'offending' agent. This is particularly important in the case of withdrawal from barbiturates, for which benzodiazepines may not be effective, and also for the benzodiazepine alprazolam, withdrawal from which may not be alleviated by another benzodiazepine, such as diazepam (Zipursky et al. 1985). In addition, it appears that carbamazepine may be effective for benzodiazepine withdrawal (Schweizer et al. 1991). Sedative-hypnotic withdrawal seizures, which usually occur in the setting of sedativehypnotic withdrawal, may be approached by aggressively treating the withdrawal syndrome; fosphenytoin may also be used for status or frequent seizures. Sedative-hypnotic withdrawal delirium is, likewise, approached by aggressively treating the withdrawal syndrome, and by using, if necessary, haloperidol, as described in the preceding section for treatment of DTs.

INHALANTS (SOLVENTS) Pathology and etiology The mechanism whereby inhaled aliphatic or aromatic hydrocarbons, such as toluene, cause intoxication is not known. Clinical features Various readily available commercial products may be utilized, including airplane glue, paint thinner, kerosene, gasoline, fingernail polish remover, and typewriter correction fluid. The volatile substance may be placed in a bag, which the user then places over the nose and mouth, or soaked onto a rag, which is held to the face.

Intoxications and withdrawals 699

Intoxication (Evans and Raistrick 1987) occurs within minutes and is characterized by a dreamy euphoria, drowsiness, dizziness, dysarthria, diplopia, nystagmus, and ataxia. Some may also experience confusion and hallucinations, which may be either visual or, less commonly, auditory, and others may become irritable and impulsive. Cardiac arrythmias may occur and may be fatal (King et al. 1985). Convulsions, coma, and respiratory depression may also be seen (King et al. 1981). If leaded gasoline is sniffed, intoxication may be accompanied by chorea and myoclonus (Goldings and Stewart 1982). Withdrawal (Evans and Raistrick 1987; Watson 1979) may appear within 1-2 days, is characterized by irritability, sweating, tremulousness, and insomnia, and generally clears within 2-5 days. Course

Among those who have passed the 'experimentation' phase, daily use is common, and some may use around the clock, titrating their dose to sustain a permanent intoxication. Differential diagnosis

Alcohol or sedative-hypnotic intoxication may resemble inhalant intoxication. In some cases, a tell-tale facial rash may indicate where a bag was held to the face, and, if toluene were used, it may be detected in the blood for days (King et al. 1981). Treatment

Observation is generally sufficient for intoxication; there is no known treatment for the withdrawal.

CANNABIS Pathology and etiology

Cannabis, its name derived from the Greek word for hemp, refers to the flowering top of the plant Cannabis sativa: marijuana is simply a dried collection of the flowers and nearby stems, whereby hashish, a more potent preparation, consists of resin scraped from the leaves and flowers of the plant. Of the many cannabinoids found in cannabis, it appears that the most important, with regard to intoxication, is delta-9-tetrahydrocannabinol (Isbell et al. 1967). Of note, a specific cannabinoid receptor has been found in the brain (Compton et al. 1993). Clinical features

Although cannabis is usually smoked, it may at times be taken orally, often mixed with foods such as brownies. After smoking, intoxication begins in minutes and peaks in about one-half hour. Clinically (Allentuck and Bowman 1942; Bromberg 1934; Clark and Nakashima 1968; Clark etal. 1970; Klonoff etal. 1973; Melges 1976), patients experience a dreamy sense of wellbeing, and the senses may seem unusally heightened: time may seem to slow down or disintegrate (Melges et al. 1970). Thinking becomes slowed, and patients often develop a heightened sense of the ridiculous, laughing and giggling at otherwise prosaic things. Typically, intoxication is accompanied by conjunctival injection, dry mouth, mild ataxia, mild tachycardia, and a combination of increased supine blood pressure and orthostatic hypotension. The intoxication undergoes substantial resolution after 3 or 4 hours and generally clears entirely after about 12 hours. In a minority of cases, intoxication may be accompanied by anxiety, which may be very severe, to the point of panic (Bromberg 1934). Happily, this anxiety clears with the intoxication itself. In a still smaller minority, and generally only after using a high dose of cannabis, a psychosis

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(Kroll 1975; Mathers and Ghodse 1992; Talbott and Teague 1969; Weil 1970) may occur that is characterized primarily by delusions of persecution and reference, and severe anxiety. Notably, such patients with this 'cannabis delusional disorder' are not confused. This psychosis usually persists beyond the intoxication, generally clearing after 1-3 days. In a similarly small minority, and again usually only with high-dose cannabis, a delirium may occur, with confusion, poor short-term memory, disorientation, affective lability, and various delusions and hallucinations (Chopra and Smith 1974; Palsson et al. 1982). This delirium persists beond the intoxication, generally clearing within 1-3 days. Withdrawal may appear within 3-12 hours after intoxication and is characterized by dysphoria, anorexia, insomnia, tremulousness, diaphoresis, and lateral gaze nystagmus (Duffy et al. 1996; Mendelson et al. 1984). Overall, the withdrawal syndrome is generally mild, clearing within 4-5 days. Flashbacks (Keeler et al. 1968) may occur for variable periods of time and consist of transient, brief recurrences of phenomena experienced during prior intoxication. Urine toxicology may be positive for cannabinoids for up to 5 days in casual users (Schwartz and Hawks 1986), and in chronic, high-dose users, the urine may remain positive for over a month. Course Occasional intoxication with marijuana, at least among adolescents and younger adults, is probably as common as intoxication with alcohol. Differential diagnosis

Cannabisnntoxication may resemble the intoxication seen with alcohol and with sedativehypnotics, but the absence of an odor of alcohol argues against alcohol intoxication, and the presence of conjunctival injection argues against sedative-hypnotic intoxication. Treatment

Intoxication requires only observation: patients who become panicked may often be 'talked down'; when such reassurance fails, treatment with diazepam, 5-10 mg orally, may be helpful. Psychosis may be treated with a neuroleptic, such as haloperidol or chlorpromazine, given in doses of 5 and 50 mg, respectively, either orally every 2 hours or intramuscularly every hour until the patient is comfortable, unacceptable side-effects occur, or a maximum dose of 30 mg haloperidol or 600 mg chlorpromazine has been reached. Once the patient is comfortable, extra doses may be required until the psychosis remits, but treatment beyond a few days is rarely necessary. Delirium may be treated as outlined in Chapter 5.

OPIOIDS Pathology and etiology Opioids include the naturally occurring opiates morphine and codeine, and their synthetic and semi-synthetic derivatives, such as heroin (diacetylmorphine), hydromorphone, meperidine, and pentazocine. Intoxication is mediated by endogenous opiate receptors (Pert and Snyder 1973), of which the mu receptor is most important. Withdrawal symptomatology is probably mediated, in large part, by the noradrenergic locus ceruleus (Aghajanian 1978; Maldonado and Koob 1993). Clinical features

When used for intoxication, most opioids are injected, either subcutaneously or, more

Intoxications and withdrawals 701

commonly, intravenously; in some cases, heroin may be vaporized and then inhaled, a practice known as 'chasing the dragon'. The intoxication itself is heralded by an intense euphoric 'rush', which gives way, after a minute or so, to a drowsy, less intense euphoria. Other signs and symptoms include miosis, constipation, and dysarthria. Severe intoxication may produce coma, pinpoint pupils, pulmonary edema, respiratory depression, and death. Intoxication with meperidine (Kaiko et al. 1983) may be accompanied by agitation and, possibly, seizures, both of which are caused by one of meperidine's metabolites, normeperidine. Pentazocine intoxication, with high doses, may be accompanied by dysphoria, bizzare thoughts, and hallucinations. Withdrawal begins with dysphoria, yawning, lacrimation, rhinorrhea, and diaphoresis. After a few hours, patients may fall into a restless 'yen' sleep, only to awaken to an intensification of the earlier withdrawal symptoms, which are now joined by 'gooseflesh', intense bone and muscle pain, nausea, vomiting, abdominal cramping and diarrhea, mydriasis, and elevation of the temperature, pulse, and blood pressure. The course of the withdrawal syndrome is determined by the drug that has been used: for meperidine, symptoms begin in a few hours, peak in 8-12 hours and clear in 4-5 days; for heroin, withdrawal begins in 6-12 hours, peaks in 2 or 3 days, and subsides over a week or so. Importantly, after the acute withdrawal clears, there may be a protracted syndrome of mild, lingering symptoms lasting from weeks to a half-year (Martin and Jasinski 1969). Course There are but few 'casual' users of intravenous opioids, and such use should be taken as prima facie evidence of addiction. The inhalation of vaporized heroin may be followed by a leukoencephalopathy with dementia and ataxia (Kriegstein et al. 1999). Differential diagnosis

The presence of miosis may serve to distinguish opioid intoxication from that caused by sedative-hypnotics or alcohol. One exception to this rule is meperidine intoxication, which may be characterized by mydriasis. Treatment

Provided that neither coma nor respiratory depression threatens, intoxication may be treated by simple observation. Should severe intoxication be present, consideration may be given to reversing it with intravenous naloxone. In general, one may begin with anywhere from 0.4 to 1.0 mg, repeat doses being given every 3-5 minutes until the patient is out of danger or a maximum dose of 10 mg has been given: a lack of response to 10 mg argues strongly against the diagnosis of opioid overdose. With patients dependent on opioids, one must start with a lower dose in order to guard against precipitating an acute withdrawal syndrome. Presuming that the patient responds, repeat doses will generally be required every 30-60 minutes until the offending drug has been 'washed out'. Withdrawal may be treated in one of three ways: simple supportive measures, clonidine, and methadone. Supportive measures include prochlorperazine for vomiting, loperamide for diarrhea, amitriptyline (in doses of approximately 50 mg at bedtime) for insomnia (Srisurapanont and Jarusuraisin 1998), and intravenous fluids should vomiting and diarrhea lead to dehydration. For mild cases of withdrawal, such supportive measures may be satisfactory, but most addicts find withdrawal so intensely adversive that other measures may be required. Clonidine (Charney et al. 1981; Gold et al. 1978; Jasinski et al. 1985), while not reducing opioid craving or having much effect on bone and muscle pain, will help to reduce other symptoms, and may be given in a dose of 0.1-0.3 mg orally every 2 hours until the patient is

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comfortable or unacceptable side-effcts (e.g. sedation and hypotension) occur. The total dose may then be given on a divided basis to cover the duration of the withdrawal, with provision for prn doses during the first few days in the event the symptoms should worsen. Once the withdrawal has passed, the clonidine may be tapered over a few days and then discontinued. Methadone, a synthetic opioid, reliably substitutes for other opioids. It is given intially in a dose of 20 mg orally, repeat doses being given as required until the patient is comfortable. The dose is then gradually tapered off, a process that may be accompanied by significant depressive symptoms (Kanof et al. 1993). The use of methadone is controversial, and, in the United States, currently restricted to specially licensed facilities.

NICOTINE Pathology and etiology

Nicotinic acetylcholine receptors are found in the central nervous system and mediate the effect of nicotine itself. Clinical features

The most common vehicle by far for the delivery of nicotine is the cigarette, which provides between 1 and 3 mg (Benowitz and Henningfield 1994). With inhalation, a relatively mild intoxication occurs, with a mild sense of satisfaction, a reduction of stress (Schacter 1978), mild tachycardia, increased blood pressure, and increased peristaltic activity. Withdrawal occurs within hours to a day after the last cigarette and is characterized by craving, irritability, anxiety, restlessness, increased appetite, and insomnia (Hughes and Hatsukami 1986; Hughes et al. 199la). Symptoms generally peak in a day or two and, for the most part, clear within a matter of weeks: intermittent craving may, however, persist for many months or even years. Course There are very few 'social' smokers, and most, despite their best intentions, are unable to stop and stay stopped on their own. Differential diagnosis

There is generally no problem in diagnosis. Treatment

Intoxication requires no treatment. Withdrawal may be treated with nicotine, delivered as a nicotine gum, a transdermal patch (Fiore et al. 1994), a nasal spray (Sutherland et al. 1992) or an inhaler (Tonnesen et al. 1993). Clonidine (Classman et al. 1988) may also be effective but is a second choice. In those who wish to stop smoking but cannot, certain pharmacologic measures are available, including the use of the nicotine patch and of bupropion (Hurt et al. 1997; Jorenby etal. 1999).

CAFFEINE Pathology and etiology

Caffeine exerts its effect via an antagonism of adenosine receptors in the central nervous system.

Intoxications and withdrawals 703 Clinical features

A cup of coffee contains about 100 mg caffeine, which, in a caffeine-naive subject, may produce a mild degree of stimulation; at a dose of 200-500 mg, evidence of intoxication may appear, with anxiety, jitteriness, tremulousness, diaphoresis, tachycardia, and, in some, premature cardiac beats and muscular twitches (Hughes et al. 1991b; Rapoport et al. 1981). With ongoing use, tolerance develops but is not complete, and death may occur with very high doses (e.g. 5-10 g) (Curatolo and Robertson 1983). Some individuals are exquisitely sensitive to the effects of caffeine, and, in those with panic disorder, caffeine acts as a panicogen and fairly reliably precipitates attacks (Boulenger et al. 1984;Charneyeta/. 1985). Withdrawal may appear within 12-24 hours after the last caffeine use, generally peaks in 1-2 days, and then gradually clears in 1-2 weeks. Symptoms include headache, fatigue, poor concentration, anxiety, irritability, and depressed mood (Griffiths et al. 1990; Hughes et al. 1991b; Silverman et al. 1992; Strain et al. 1994). Course Intoxication or withdrawal may prompt abstinence or, more commonly, merely moderation, with continued caffeine consumption. Differential diagnosis

Chronic intoxication may mimic generalized anxiety disorder, and, in such cases, abstinence from caffeine may be required to make the correct diagnosis (Greden 1974). Treatment

Specific treatment for intoxication or withdrawal is generally not required.

METHANOL Pathology and etiology

Methanol (methyl alcohol) is metabolized by alcohol dehydrogenase to formaldehyde; this is in turn further metabolized by aldehyde dehydrogenase to formic acid, which is the ultimate cause of the devastating sequelae of methanol intoxication. Formic acid is not only directly toxic to neuronal mitochondria, but also produces a severe systemic acidosis. In severe cases, there is a widespread hemorrhagic encephalopathy: the putamina are hardest hit and may undergo cystic necrosis (Erlanson et al. 1965; McLean et al. 1980). Both the retina and the adjacent optic nerve are damaged (Benton and Calhoun 1953; Sharpe et al. 1982). Clinical features

Methanol, also known as 'wood alcohol', is added as a denaturant to ethanol in order to make 'denatured' alcohol and may also be obtained from 'canned heat' preparations. Intoxication may be seen in desperate alcoholics or, at times, through accidental contamination. Clinically (Bennet et al. 1953; Erlanson et al. 1965; Wood and Buller 1904), intoxication is characterized by mild euphoria, an odor of alcohol on the breath, headache, and nausea. In more severe intoxication, visual dimming or blindness may occur along with vomiting, abdominal pain, dizziness, vertigo, and delirium. Pancreatitis has been noted (Kaplan 1962). Respiratory failure and death may occur with doses of 60 cc or more. The serum methanol level is increased, and the anion gap, reflecting the presence of formic acid, is increased.

704 Specific disorders

Whether or not withdrawal could occur is unclear as the consumption of the requisite amount of methanol would itself be disabling or fatal. Course

Those who survive generally stabilize in a matter of 2 or 3 days. Blindness is permanent (Wood and Duller 1904), and parkinsonism (Guggenheim et al. 1971) or dementia (McLean et al. 1980) may ensue. Differential diagnosis

Methanol intoxication is distinguished from ethanol or isopropyl alcohol intoxication by visual loss. Treatment

Gastric lavage is indicated if the ingestion occurred less than 2 hours earlier. Given that formic acid is responsible for the damage seen in methanol intoxication, efforts are undertaken to retard the metabolism of methanol to this toxic metabolite. As ethanol has a much stronger affinity for alcohol dehydrogenase than does methanol, patients are given sufficient ethanol to maintain a BAL of 100-150 mg%. This may be accomplished with intravenous ethanol in a loading dose of 0.6-l.Omg/kg, followed by a maintenance dose of 0.125mg/kg/hour, all diluted to make a 10% ethanol solution. When intravenous adminstration is not possible, oral ethanol may be given in a loading dose of 1-3 mg/kg , followed by a maintenance dose of 0.5-1.0 mg/kg/hour. The oral alcohol should be diluted to make a 20% solution (i.e. a '40 proof alcoholic beverage). The BAL is maintained at 100-150 mg% until the methanol level has fallen below 20 mg% and all symptoms of intoxication have cleared. Folic acid hastens the metabolism of formic acid, and may be given intravenously in a dose of 50 mg every 6 hours. Bicarbonate is given to combat acidosis. When the above measures fail to ensure the safety of the patient, or if the methanol concentration is over 50 mg%, hemodialysis is indicated.

ISOPROPANOL Pathology and etiology The mechanism whereby isopropanol (isopropyl alcohol) causes intoxication is probably similar to that for ethanol. Clinical features

Isopropanol is commonly known as 'rubbing' alcohol and may also be found in aftershave lotions, hair tonics, etc. Course

Intoxication (Lacouture et al. 1983; Rich et al. 1990) is characterized by euphoria, an odor of alcohol on the breath, dizziness, and ataxia, and may also be accompanied by headache, nausea, vomiting, and, in some cases, hematemesis. With high doses, coma and respiratory depression may occur. Isopropanol is converted to acetone, leading to both acetonemia and acetonuria. The intoxication generally passes within 12 hours. Although withdrawal is probably similar to that with ethanol, this has not been documented. Differential diagnosis

Ethanol intoxication is less likely to produce gastric distress, and methanol intoxication is suggested by visual loss.

Intoxications and withdrawals 705

Treatment Simple observation and supportive care are generally sufficient. If coma or respiratory depression threaten, and ingestion occurred less than 2 hours previously, gastric lavage is indicated. Hemodialysis is effective (Freireich et al. 1967).

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22 Medication and substance-induced disorders Neuroleptic malignant syndrome

712

Cholinergic rebound

Tardive dyskinesia

714

Alcoholic dementia

Supersensitivity psychosis

717

Alcohol hallucinosis

Rabbit syndrome

718

Serotonin syndrome

719

Alcoholic paranoia Marchiafava-Bignami disease

Anticholinergic delirium

720

Solvent induced dementia

721 722 722 723 724 725

NEUROLEPTIC MALIGNANT SYNDROME Pathology and etiology The neuroleptic malignant syndrome may occur in any setting wherein there is an abrupt diminution of dopaminergic tone within the central nervous system, as may occur with the use of dopamine-blocking agents (e.g. neuroleptics) or the discontinuation of chronically used dopaminergic agents (e.g. levodopa). Thus, in addition to the 'classical' neuroleptics, the neuroleptic malignant syndrome has also been seen with risperidone (Levin et al. 1996; Meterissian 1996), olanzepine (Levenson 1999), and clozapine (Anderson and Powers 1991; Das Gupta and Young 1991; Miller et al. 1991; Sachdev et al. 1995): in general, the syndrome is seen with high-dose neuroleptics, soon after either initiating treatment or after a rapid dose increase (Kellam 1990). The neuroleptic malignant syndrome has also been seen upon the cessation of treatment with not only levodopa (Friedman et al. 1984, 1985; Gibb and Griffith 1986; Keyser and Rodnitzky 1991; Sechi et al. 1984; Toru et al. 1981), but also amantadine (Cunningham et al. 1991; Harsch 1987) and a combination of levodopa and bromocriptine (Figa-Talamanca etal. 1985). In addition, the neuroleptic malignant syndrome has been reported secondary to tetrabenazine (Ossemann et al. 1996) and to amoxapine (Taylor and Schwartz 1988), an antidepressant whose metabolite, loxapine, is a neuroleptic. There is also a report of a patient chronically treated with trifluoperazine who, immediately upon the addition of venlafaxine, and without any increase of the trifluoperazine dose, developed the syndrome (Nimmagadda etal 2000). Although this is speculative, it is thought that it is specifically a diminution of dopaminergic tone in the hypothalamus and the basal ganglia that mediates the symptoms seen. In this light,

Medication and substance-induced disorders 713

it is of interest that focal necrosis has been noted in the anterior and lateral hypothalamic nuclei (Horn et al. 1988). Clinical features

The onset is usually within a day or two subsequent to a diminution in dopaminergic tone; exceptionally, the syndrome may appear within an hour or, at the other extreme, be delayed for weeks (Keck et al. 1987). The full syndrome is characterized by delirium, fever, rigidity, and autonomic instability, and although it typically presents with delirium, any one of these elements may be the presenting feature (Addonizio et al. 1987; Caroff 1980; Kellam 1987; Pope et al. 1986; Rosebush and Stewart 1989; Velamoor et al. 1994). Delirium may be profound, and patients may become mute or catatonic. Fever is generally over 38.9°C (102°F), but, rarely, an otherwise typical syndrome has occurred without fever (Peiris et al. 2000). Rigidity may be of either the lead pipe or cogwheel type, is typically generalized, and may be profound, to the point of compromising chest wall movement. Rigidity may be accompanied by a generalized, coarse tremor, and, in some cases, dystonia or chorea may occur. Autonomic instability manifests with pallor, diaphoresis, tachycardia, and elevated blood pressure, which may be quite labile. Rhabdomyolysis may occur (Jones and Dawson 1989), with myoglobinuria, and, in some cases, acute renal failure. The white count is typically elevated to around 15 000 cells/mm3, and the creatine phosphokinase level is likewise increased, also to around 15 000 units/L. Lactate dehydrogenase, serum glutamic oxaloacetic transaminase and alkaline phosphatase levels are also often elevated. Aspiration or pulmonary emboli may occur, and, in some cases, respiratory failure may occur secondary to extreme rigidity of the chest wall. A minority of patients develop disseminated intravascular coagulation. Course

The mortality rate is between 10% and 20%. Those who survive generally recover, without sequelae, within a week or two, although an exception to this rule occurs in the case of the neuroleptic malignant syndrome occurring secondary to treatment with long-acting depot neurolpetics such as fluphenazine or haloperidol decanoate, wherein the syndrome may extend for a month or more. Differential diagnosis

Malignant hyperthermia, phencyclidine intoxication and encephalitis (e.g. St Louis encephalitis) are all ruled out by their occurrence in the absence of a preceding diminution of dopaminergic tone. Heat stroke occurring in patients with Parkinson's disease who may have skipped some doses of dopaminergic agent, or in patients with schizophrenia who may recently have increased their dose of neuroleptic, may be difficult to distinguish from the neuroleptic malignant syndrome. Certainly, in the history, one would want to see both an exposure to an elevated ambient temperature and the occurrence of an elevated temperature as the first symptom before considering a diagnosis of heat stroke. Stauder's lethal catatonia, as discussed in Chapter 3, often arises out of catatonic schizophrenia, and, as schizophrenia is often treated with a neuroleptic, the clinical picture may be quite similar to that seen in the neuroleptic malignant syndrome. One important differential point is that the onset of Stauder's lethal catatonia is marked by agitation and excitation, in contrast to the onset of the neuroleptic malignant syndrome, which is generally characterized by delirium and rigidity (Castillo et al. 1989). Treatment

In addition to supportive care and the treatment of any complications, it is critical to restore dopaminergic tone as quickly as possible. Thus, if a neuroleptic was at fault, it should be

714 Specific disorders

discontinued, and if a dopaminergic agent has been stopped, it should be restarted. Another strategy includes the use of bromocriptine and/or dantrolene (Granato et al. 1983; Guze and Baxter 1985; May et al. 1983; Mueller et al. 1983). Although these agents have not been assessed in controlled trials, anecdotal reports support their use. Bromocriptine is given orally, by nasogastric tube if necessary, in doses ranging from 2.5 to 20 mg tid, and dantrolene is given intravenously in a dose of 1-2 mg/kg and repeated as necessary to a maximum of 10 mg/kg/24 hours. Another, very important, treatment option is electroconvulsive therapy (ECT) (Davis et al. 1991; Hermesh et al. 1987), which appears to be as safe and as effective as using bromocriptine and dantrolene. Fever may be treated with cooling blankets, and patients must be kept adequately hydrated to reduce the risk of renal failure. Ventilatory support may be required. In many cases of the neuroleptic malignant syndrome occurring secondary to a neuroleptic, patients require ongoing treatment. In such cases, it has been found possible to reinstitute treatment with a neuroleptic (Rosebush et al. 1989) provided that one waits for at least 2 weeks after the neuroleptic malignant syndrome has entirely cleared and then reintroduces a neuroleptic cautiously: low doses and slow increases are appropriate, and, although there are cases in which the same neuroleptic has been re-used safely, prudence might dictate using a different neuroleptic, preferably a 'low-potency' one.

TARDIVE DYSKINESIA Pathology and etiology Tardive dyskinesia is a movement disorder that occurs secondary to long-term treatment with dopamine-blocking drugs such as neuroleptics. Of those treated with 'typical' neuroleptics, on average one-fifth (Woerner et al. 1991) will eventually develop tardive dyskinesia: although the atypical neuroleptics are less likely to cause tardive dyskinesia (Beasley et al. 1999), it has been noted with both olanzepine (Tollefson et al. 1997) and clozapine (Dave 1994). In addition to neuroleptics, other drugs capable of causing tardive dyskinesia include metoclopramide (Sewell and Jeste 1992; Sewell et al. 1994) and the antidepressant amoxapine (Huang 1986; Thornton and Stahl 1984) (probably, in the case of amoxapine, because one of its metabolites, loxapine, is a neuroleptic). There is also a case report of tardive dyskinesia occurring secondary to fluoxetine (Sandier 1996). Given that all of the drugs capable of causing tardive dyskinesia have one thing in common, namely a blockade of the post-synaptic dopamine receptors, and given that the risk of tardive dyskinesia increases with higher doses (Morganstern and Glazer 1993) and a longer duration of treatment (Glazer et al. 1993; Kane et al. 1988), it seems reasonable to suppose that it is some effect of the chronic dopamine blockade that is etiologic in this disorder, and, indeed, this is the basis for the dopamine upregulation hypothesis. According to this hypothesis, there is, with chronic dopamine blockade, a gradually worsening compensatory upregulation of the post-synaptic receptors to the point at which, if the dose of the dopamine blocker is reduced, the 'unmasking' of these upregulated receptors leads to a hyperdopaminergic state and the production of the abnormal movements. Further support for a disturbance in dopamine transmission is provided by the response to anticholinergics in tardive dyskinesia. Dopaminergic and cholinergic systems exist in a balance in the basal ganglia, such that an increase in dopaminergic tone may be mimicked by a reduction in cholinergic tone and vice versa. Given this, one would predict that, in patients with tardive dyskinesia, a reduction in cholinergic tone, as might occur with the administration of an anticholinergic medication,

Medication and substance-induced disorders 715

would increase the abnormal movements, and this is generally what happens (Klawans and Rubovits 1974). As attractive as this dopamine theory is, it does not account for several important findings. First, the fact that neuroleptic-induced parkinsonism can coexist with tardive dyskinesia (Richardson and Craig 1982) argues against any generalized hyperdopaminergic state, as this should, theoretically, bring a relief of the parkinsonism. Second, some cases of the dystonic subtype of tardive dyskinesia may, as noted below, be relieved by, rather than worsened by, anticholinergic agents. Finally, if it were simply a matter of the compensatory upregulation of the post-synaptic dopamine receptors, then, providing that the dose of a neuroleptic were held constant, with no dose decrease, one should not see any abnormal movements as there would be no 'unmasking' and thus no hyperdopaminergic state. Unfortunately for the theory, however, tardive dyskinesia does in fact emerge while patients continue at the same dose, a fact strongly suggesting that some other process, in addition perhaps to a progressive upregulation, is at work. The nature of this other process is not clear. Theories include disturbances in GABAergic transmission and progressive neuronal destruction by free radicals produced in the course of neuroleptic treatment. This last theory is of some interest, given the evidence, noted below, for the treatment efficacy of vitamin E, an anti-oxidant. Clinical features

Although some cases of tardive dyskinesia have been reported after only a month of treatment with a neuroleptic, this is quite rare, and, in general, the risk does not become significant until at least 6 or more months have passed, most cases not becoming apparent for a year or more. It appears, however, that, in the elderly, the interval between the initiation of treatment and the occurrence of tardive dyskinesia is shorter (Kane and Smith 1982; Saltz et al. 1991). The mode of onset may be either acute or gradual. An acute onset may occur when the neuroleptic is discontinued or the dose rapidly decreased, in which case an abrupt 'unmasking' occurs with an equally abrupt appearance of abnormal movements. Conversely, if the dose is maintained, or decreased only slightly, the abnormal movements may make their appearance gradually, even insidiously. Tardive dyskinesia may present in a variety of different ways. The most common presentation is with abnormal involuntary movements, such as chorea or, less frequenlty, dystonia; tics may be seen in a small minority. Tardive akathisia may also occur, and then there are some very rare presentations, for example with pain. Cases characterized by abnormal movements may not be 'pure': for example, most patients with tardive dystonia will also have choreiform movements (Sachdev 1993a; Wojcik et al. 1991). Choreiform movements in tardive dyskinesia are most commonly found in the face (Burke et al. 1982; Kang et al. 1986), less so in the extremities, and only rarely in the trunk, and range in severity from mild to disabling (Kennedy 1969). Classically, in the face, one sees buccolinguo-masticatory movements, with pursing or puckering of the lips, chewing motions, and repetitive tongue protrusions. Facial grimacing may also be seen; this, importantly, spares the forehead. Extremity involvement may present with shoulder-shrugging or a restless pianoplaying movement of the fingers and hands; in the lower extremities, there may be foottapping. Truncal involvement may manifest with axial to-and-fro rocking or with pelvic thrusting. Uncommonly, respiratory dyskinesias may occur, with irregular, grunting respirations (Chiang et al. 1985; Ivanovitch et al. 1993; Rich and Radwany 1994; Yassa and Lal 1986a). Critically, the choreiform movements of tardive dyskinesia tend to be repetitive and stereotyped (Stacey et al. 1993). Dystonic movements (Burke et al. 1982; Kang et al. 1986; Kiriakakis et al. 1998; Sachdev 1993a; Wojcik et al. 1991; Yassa et al. 1986) typically appear focally, most commonly involving

716 Specific disorders

the face or neck, followed by the upper extremity, the trunk, and the lower extremity. Over a long period of time, segmental spread to adjacent body parts may occur, and, rarely, the dystonia may become generalized (Burke et al. 1982; Wojcik et al. 1991). Facial involvement may manifest with blepharospasm (Ananth et al. 1988; Glazer et al. 1983; Weiner et al. 1981), oromandibular dystonia (Tan and Jankovic 2000), or oculogyric crises (FitzGerald and Jankovic 1989; Sachdev 1993b). The severity of tardive dystonia ranges, as with chorea, from mild to disabling (Yadalam et al. 1990). Tics may occur as part of tardive dyskinesia and may be so extensive as to mimic the clinical picture of Tourette's syndrome (Bharucha and Sethi 1995; Stahl 1980). Akathisia occurring on a tardive basis is symptomatically very similar to that occurring as an acute extrapyramidal side-effect of a neuroleptic, with restlessness, marching in place, and 'restless' thoughts (Burke et al. 1989; Dufresne and Wagner 1988; Lang 1994; Sachdev and Loneragan 1991). Rare presentations of tardive dyskinesia include pain and dysphagia. Tardive pain may present with burning in the mouth or genital area and occurs in the setting of chorea or akathisia (Ford et al. 1994). Dysphagia for both solids and liquids was noted in one case concurrent with facial tics (Gregory et al. 1992). Course With continued treatment with a neuroleptic, the symptoms initially worsen but eventually stabilize, after which the course may be marked by either a gradual waxing and waning of severity or a gradual, but only partial, remission (Gardos et al. 1988, 1994; Glazer et al. 1984; Yagi and Itoh 1995). If the neuroleptic is discontinued, there will initially be an exacerbation of symptoms, followed by a very gradual diminution, with, in some cases, complete clearing over about a year's time (Glazer et al. 1990). Anticholinergics, as noted earlier, typically makes the symptoms worse, this being especially the case with choreiform movements (Reunanen et al. 1982). Interestingly, the symptoms worsen with depression (Sachdev 1989) and may improve with mania (de Potter et al. 1983; Yazici et al. 1991); symptom improvement has also been noted during catatonic stupor (Assmann and van Woerkom 1987). Differential diagnosis

Huntington's disease may occasionally be confused with tardive dyskinesia of the choreiform type, but genetic testing will resolve the issue. Clinical clues to the differential diagnosis include a positive family history, the presence of forehead chorea, and the presence of a 'dancing and prancing' gait, all of which may be seen in Huntington's disease but not in tardive dyskinesia. The nature of the chorea itself provides another differential point: in Huntington's disease, it is extremely transient, flickering from one part of the body to another in an almost random pattern, whereas in tardive dyskinesia, the chorea tends to be stereotyped, repetitive, and persistently recurring in the same area. Other conditions to consider, such as side-effects of phenytoin, levodopa, and so on are discussed in Chapter 3. Schizophrenia may at times be characterized by choreiform movements, as pointed out by Kraepelin in the early part of the twentieth century and confirmed by subsequent investigators (Farran-Ridge 1926; Mettler and Crandall 1959; Owens etal. 1982; Yarden and Discipio 1971). These choreiform movements are mild, generally involve the face, and are present before any treatment with neuroleptics. It is their pre-treatment presence that allows for the correct diagnosis. Both dystonia and akathisia may occur as acute extrapyramidal side-effects of neuroleptics but are readily distinguished from tardive dystonia or tardive akathisia by their course: acute side-effects occur shortly after the initiation or dose increase of a neuroleptic and subside

Medication and substance-induced disorders 717

with a dose decrease or discontinuation; by contrast, tardive dystonia and akathisia come on only after a long period of treatment and worsen when the dose is decreased or the neuroleptic discontinued. Other dystonic conditions to consider and a differential diagnosis for akathisia are discussed in Chapter 3. Tourette's syndrome may occasionally enter into the differential, as for example in cases where children have been treated with neuroleptics. The presence of choreiform movements points toward tardive dyskinesia. Treatment

The best 'treatment' is prevention, and chronic neuroleptic treatment should not be undertaken for those disorders where other medications, with better side-effect profiles, would be as effective. When tardive dyskinesia does first appear, a decision must be made regarding whether ongoing treatment with a neuroleptic is required, carefully weighing the risk of worsening dyskinesia against the risk of relapse. In the case of schizophrenia, the balance often tips towards continuing neuroleptic treatment. If treatment is continued, efforts, if not already in place, should be made to keep the dose as low as possible consistent with adequate symptomatic control. In the past, it was felt that intermittent 'drug holidays' for patients with schizophrenia might reduce the risk of tardive dyskinesia, but subsequent studies have suggested that drug holidays may actually increase the risk (Goldman and Luchins 1984; leste et al. 1979; van Harten et al. 1998). If treatment is discontinued, the course is as described above. Should the symptoms persist, whether or not treatment is discontinued, it is appropriate to consider several symptomatic treatments, including vitamin E, clonidine, or reserpine. Vitamine E, in doses of 1200-1600 lU/day, has been shown to be effective in most (Adler et al. 1993; Dabiri et al 1994; Egan et al. 1992; Elkashef et al. 1990; Lohr and Caligiuri 1996) but not all (Adler et al. 1999; Shriqui et al. 1992) double-blind studies; however, weeks or months may be required to see a response. Clonidine, in a dose of 0.4 mg/day (Browne et al. 1986) or from 0.2-0.9 mg (Freedman et al. 1980) is effective in double-blind studies. Both reserpine and tetrabenazine (not available in the United States) are effective for tardive dyskinesia (Kang et al. 1986), including the akathetic subtype (Burke et al. 1989). The choice among vitamin E, clonidine, and reserpine may be guided by their side-effect profiles: vitamin E, in the doses proposed, is essentially without side-effects, in marked contrast to clonidine and especially reserpine, and should thus generally be used first. The dystonic subtype of tardive dyskinesia may, at times, also be successsfully treated with high-dose anticholinergic agents (Burke et al. 1982), such as 20 mg trihexyphenidyl (Fahn 1983). This is in marked contrast to the other subtypes of tardive dyskinesia, which are made worse by anticholinergics and partially relieved upon their discontinuation (Greil et al. 1984). ECT has, anecdotally, been found to be effective (Adityanjee 1990), especially when the patient also suffers from depression (Hay et al. 1990).

SUPERSENSITIVITY PSYCHOSIS Pathology and etiology

Supersensitivity, or 'tardive', psychosis occurs as a side-effect of chronic treatment with dopamine-blocking drugs, such as neuroleptics. Although little research has been accomplished regarding this disorder, it is hypothesized that its etiology is similar to that of tardive dyskinesia. Specifically, it is believed that, with chronic dopamine blockade in the

718 Specific disorders

limbic system, an upregulation of the dopamine receptors occurs, with a consequent limbic hyperdopaminrgic state and a resultant psychosis. Clinical features Clinically (Kirkpatrick et al. 1992; Steiner et al. 1990), after a year or more of neuroleptic treatment, a small minority of patients develop psychotic symptoms, such as delusions or hallucinations, which then persist.

Course Although it is assumed that the course is similar to that described for tardive dyskinesia, this is not as yet known. Differential diagnosis

In patients with schizophrenia who have been treated with neuroleptics, it is difficult to decide whether an increase in the psychotic symptoms upon neuroleptic dose reduction represents an exacerbation of the schizophrenia or a supersensitivity psychosis. One differential point exists in the course of the exacerbation. In patients with schizophrenia who have enjoyed a stable, low level of symptoms for months or more, relapses after a dose reduction are not immediate but are delayed for weeks. By contrast, with a supersensitivity psychosis, the appearance of symptoms should be fairly abrupt. In patients who have been treated with neuroleptics for a non-psychotic condition (e.g. some patients with mood disorders), the appearance of psychotic symptoms upon a dose reduction of the neuroleptic, especially if unaccompanied by any mood symptoms, strongly suggests the presence of a supersensitivity psychosis. Treatment

As with tardive dyskinesia, the best treatment is prevention, and neuroleptics should not be prescribed for conditions treatable by other, more benign, means. It is not clear whether treatments effective in tardive dyskinesa, such as vitamin E, are effective for supersensitivity psychosis.

RABBIT SYNDROME Pathology and etiology The rabbit syndrome is a rare movement disorder (Chiu et al. 1993), generally seen as an uncommon side-effect of neuroleptic treatment (Yassa and Lal 1986b). Clinical features

Clinically (Decina et al. 1990; Deshmukh et al. 1990), this syndrome presents as a rest tremor of the jaw, at a frequency and amplitude such that the appearance is for all the world that of a rabbit chewing. Course The syndrome may resolve shortly after discontinuation of the neuroleptic (Todd et al. 1983). Differential diagnosis

The appearance of the tremor in relation to neuroleptic treatment suggests the correct diagnosis. Essential tremor might be considered, but, although the jaw can be involved in essential tremor, this is almost never the case until long after the tremor has become evident elsewhere, such as the hands. Parkinsonism may be considered, but in parkinsonism, jaw tremor rarely occurs without other signs and symptoms, such as tremor of the hands, rigidity, bradykinesia, etc.

Medication and substance-induced disorders 719

Treatment

Anticholinergics, such as benztropine, are effective (Todd et al. 1983).

SEROTONIN SYNDROME Pathology and etiology This syndrome occurs secondary to any one of a variety of pharmacologic manuevers, all of which have one thing in common, namely an enhancement of serotoninergic tone within the central nervous system. In general, a combination of two different serotoninergic agents is required, those noted in the literature being recorded in Table 22.1 (reviewed in Bodner et al. 1995). As may be seen in the table, a monoamine oxidase inhibitor (MAOI) is involved in most cases; tryptophan, a serotonin precursor, was banned by the Food and Drug Administration, but is now appearing in certain unregulated herbal preparations, which, in some instances, may not be so labelled. In addition to those combinations noted in Table 22.1, the serotonin syndrome has also been reported secondary to a combination of nefazodone and fluoxetine (Smith and Wenegrat 2000) and paroxetine and risperidone (Hamilton and Malone 2000). The serotonin syndrome may rarely occur as a side-effect of a single serotoninergic agent, which has been described with fluvoxamine (Lenzi et al. 1993) and clomipramine (Insel et al. 1982; Lejoyeux et al. 1992). Table 22.1 Medication combinations capable of causing the serotonin syndrome

Monoamine Tryptptophan Selective oxidase serotonin reuptake inhibitor inhibitor Tryptophan Selective serotonin reuptake inhibitor Clomipramine Tricyclic antidepressant Venlafaxine Carbamazepine Pentazocine Meperidine Dextromethorphan Trazodone

Buspirone

Bupropion

X

X

X X

X

X X X

X X X X

X X

Clinical features

The onset occurs within hours or days of one of the pharmacologic manuevers noted above. Clinically (Feighner et al. 1990; Sternbach 1991), patients present with varying admixtures of delirium, myoclonus, dysarthria or ataxia, and hyperreflexia (especially in the lower extremities). Other signs and symptoms may include extensor plantar reflexes, coarse tremor, shivering, and diaphoresis. In severe cases, seizures, rhabdomyolysis, renal failure, cardiac arrythmias, and disseminated intravascular coagulation may occur. Course Fatalities may occur; in those who survive, recovery is gradual, over days or a week or more.

720 Specific disorders

Differential diagnosis

Other causes of a combination of delirium and myoclonus are discussed in Chapter 3: in most cases, the appearance of the myoclonic delirium subsequent to treatment with a serotoninergic combination strongly suggests the diagnosis. Treatment

In addition to supportive measures, the serotonin antagonist cyproheptadine, in a dosage of 8-32 mg/day, may hasten the resolution of the syndrome. The best treatment is prevention: of the various combinations noted in Table 22.1, those involving an MAOI should in general be avoided: one exception is the use of a combination of an MAOI and a tricyclic antidepressant in the treatment of resistant depression. If an MAOI and one of these medications must be used sequentially, it is critical to allow enough time for the preceding medicine to wash out before starting the second one. If an MAOI is the medicine being washed out, one must wait at least 2 weeks for a new 'crop' of monoamine oxidase to appear; and, in some cases, even 2 weeks may not be sufficient (Diamond et al 1998). The other combinations noted in the table (e.g. a selective serotonin reuptake inhibitor [SSRI] plus a tricyclic, or an SSRI plus carbamazepine) are generally safe, the serotonin syndrome occurring only rarely as a side-effect: if one of these combinations is used, it is, however, prudent to keep a watch out for any signs suggestive of the syndrome.

ANTICHOLINERGIC DELIRIUM Pathology and etiology

Any of a number of anticholinergic drugs may, if given in sufficient dose, cause a delirium (Tune et al. 1981): although, in most cases, relatively high doses are required, individual sensitivity varies widely, and in some patients, especially the elderly, seemingly innocuous doses can have devastating results. Drugs commonly implicated include: various anticholinergics used in the treatment of Parkinson's disease (De Smet et al. 1982) (e.g. trihexyphenidyl [Porteous and Ross 1956]); tricyclic antidepressants (e.g. imipramine [Goodwin 1983] and amitriptyline [Preskorn and Simpson 1982]); transdermal scopolamine (Ziskind 1988), as used for motion sickness; cyclobenzaprine (Engel and Chapron 1993), used for muscle spasm; hyoscine (Vonderahe 1929); and certain plants containing anticholinergics (e.g. Angel's trumpet [Hall et al. 1977]). Of some literary interest is the possibility that the Reverend Dimmesdale, of Nathaniel Hawthorne's The Scarlet Letter, may himself have succumbed to an herbal preparation with anticholinergic properties, administered by the good Doctor Chillingworth (Khan 1984). Clinical features

Clinically (Itil and Fink 1966), there is delirium and restlessness, often accompanied by visual hallucinations. On examination, the temperature and pulse are elevated, the skin dry and flushed (at times to a scarlet hue), the pupils dilated, and the deep tendon reflexes brisk. Urinary retention may occur, and, in severe cases, there may be seizures, coma, respiratory depression, and death. Course Those who survive generally recover slowly over a time course consistent with the half-life of the anticholinergic involved. Differential diagnosis

Heat stroke may present in a similar fashion, but this diagnosis should be considered only when the ambient temperature is appropriately high. In cases in which the temperature is high

Medication and substance-induced disorders 721

and the patient in question also happens to be taking an anticholinergic preparation, it may well be that there is a combination of both heat stroke and anticholinergic delirium. Certainly, however, should the tempeature rise above 41°C (106°F), one must conclude that heat stroke is present. Treatment

If ingestion was recent, gastric lavage and activated charcoal may be considered. In addition to general supportive measures (including adequate hydration), cooling blankets and fanning may be indicated if the temperature is significantly elevated. In severe intoxication, physostigmine may be effective (Duvoisin and Katz 1968; Stern 1983), which may be given intravenously in a dose of 1-2 mg, at a rate no faster than 1 mg/minute, every 5-10 minutes until the patient is out of danger. A failure to respond to physostigmine essentially rules out an anticholinergic delirium. Physostigmine is held in reserve as it can cause seizures and bradycardia; furthermore, in the case of tricyclic-induced anticholinergic delirium, even though physostigmine may reverse the delirium, it does not reduce the risk of arrythmia, which is the most dangerous aspect of tricyclic toxicity.

CHOLINERGIC REBOUND Pathology and etiology After chronic treatment with any drug possessing anticholinergic properties, there is a compensatory upregulation of the post-synaptic acetylcholine receptors, such that, if the drug is abruptly discontinued and there is insufficient time for a gradual 'downregulation', the increased number of post-synaptic acetylcholine receptors is 'unmasked', with a resultant increase in cholinergic transmission. Such cholinergic rebound or overdrive (Dilsaver et al. 1983a; Luchins et al. 1980) may result in a clinical syndrome characterized, in part, by a depressed mood. Such a syndrome is not uncommonly seen after the abrupt discontinuation of tricyclic antidepressants or of'low-potency' typical neuroleptics (e.g. chlorpromazine and thioridazine). Clinical features

The onset of cholinergic rebound is in large part determined by the half-life of the drug that has just undergone abrupt discontinuation. For most tricyclic agents, the onset may be anticipated within 36-48 hours. Clinically (Dilsaver 1989; Dilsaver et al. 1983b; Petti and Law 1981), patients present with depressed mood, anxiety, malaise, and insomnia; typically, there is also nausea and abdominal cramping, with, at times, vomiting and diarrhea. Course

In the natural course of events, the symptoms subside over 1-3 days. Differential diagnosis

The appearance of depressed mood and insomnia shortly after stopping a tricyclic antidepressant may suggest a relapse of depression, but the abruptness of the onset of symptoms is inconsistent with a relapse of depression, which would not be expected for at least a matter of weeks after stopping an antidepressant. Treatment

The syndrome may be avoided by gradually tapering drugs with strong anticholinergic properties over 3 or 4 days. Should the syndrome occur, it may be treated by simply restarting the previously used drug or by using a drug such as benztropine, which itself has strong anticholinergic properties.

722 Specific disorders

ALCOHOLIC DEMENTIA Pathology and etiology

Autopsy studies of chronic alcoholics have demonstrated both reduced brain weight (Harper and Blumbergs 1982; Torvik et al. 1982) and cerebral atrophy (Harper and Kril 1985; Lynch 1960; Neuberger 1957), findings that have been reinforced by computed tomography (CT) (Carlen et al. 1981; Gurling et al. 1984; Harper et al. 1985) and magnetic resonance imaging (MRI) (Jernigan et al. 1991; Schroth et al. 1988) studies. Although it is not certain what part nutritional and vitamin deficiencies play in the genesis of this atrophy, there is some evidence that alcohol itself acts as a direct toxin (Lynch 1960). Clinical features

Alcoholic dementia appears insidiously after many years or decades of chronic, severe alcoholism. Clinically (Lee et al. 1979; Lishman 1981), the dementia is characterized by apathy, a coarsening of personality, poor judgment, concreteness and poor memory, and minor degrees of such 'cortical' signs as aphasia, apraxia, and agnosia. CT or MRI scanning reveals atrophy, there being a rough correlation between the degree of atrophy and the depth of the dementia (Carlen et al. 1981; Carlsson et al. 1979). Course

With continued drinking, the dementia progesses; conversely, with abstinence, some improvement may be seen over the first half year (Grant et al. 1984; Hambidge 1990). Differential diagnosis

Alcoholic dementia, which is persistent and chronic, must not be confused with the 'fog' of poor concentration and memory seen after alcohol withdrawal, which clears entirely with abstinence. Other causes of dementia in alcoholics must be sought, and it is indeed not uncommon to find that dementia in alcoholism is multifactorial. These other causes include subdural hematoma, acquired non-Wilsonian hepatocerebral degeneration, pellagra, and the rare Marchiafava-Bignami disease. Korsakoff's syndrome is distinguished by the fact that it is characterized by memory deficit alone, without other evidence of cerebral damage, such as concreteness or personality change. Treatment

Although adequate nutrition and vitamin supplementation, especially with thiamine, are in order, they pale in importance next to abstinence, without which there is no hope of any recovery.

ALCOHOL HALLUCINOSIS Pathology and etiology Alcohol hallucinosis (alcohol-induced psychotic disorder with hallucinations) occurs only in chronic alcoholics and then only after years or a decade or more of heavy drinking, with multiple episodes of alcohol withdrawal. Although the mechanism underlying the appearance of alcohol hallucinosis is not known, it is suspected that, with multiple episodes of withdrawal, 'kindling' occurs within the temporal lobes, with the eventual production of a focus of persistent neuronal dysfunction.

Medication and substance-induced disorders 723

It was, in the past, thought that alcohol hallucinosis represented the activation of a latent schizophrenia, but this does not appear to be the case (Schuckit and Winokur 1971). Clinical features

The onset is usually, although not always, within an episode of alcohol withdrawal: after the typical autonomic signs and symptoms clear, the patient is left with persistent auditory hallucinations in a clear sensorium. Clinically (Victor and Hope 1958; Soyka 1990), patients hear voices, which may speak either about them or directly to them. The voices are often derogatory or persecutory, and are often quite vivid and realistic, to the point at which patients may hunt about the house to find their source, or invite the physician to participate in a search for their source on the ward. Delusions are commonly seen, often being of persecution or reference; in a minority, there may also be Schneiderian first rank delusions, such as thought-broadcasting or delusions of influence (Soyka 1990). Patients are typically apprehensive and irritable. Course With abstinence, the voices will, in most cases, fade and clear in a matter of weeks; with a resumption of drinking, however, the voices, should they recur, persist for longer periods of time and may, in some cases, become chronic. In chronic cases, the irritability and anxiety often fade, patients becoming resigned, even indifferent, to the persistent hallucinations. Differential diagnosis

Alcohol withdrawal may be accompanied by auditory hallucinations, but these are fleeting and clear with the resolution of the autonomic symptoms. Likewise, in delirium tremens, hallucinations (which are, in any case, more often visual than auditory), also clear with resolution of the delerium tremens. Paranoid schizophrenia is distinguished by the presence of symptoms not seen in alcohol hallucinosis, such as loosening of associations, mannerisms, and overall disorganization of behavior. Furthermore, most cases of schizophrenia have an onset in the late teens or early twenties, long before most alcoholics could have imbibed for the necessary years or decades required to produce alcoholic hallucinosis. Alcoholic paranoia, discussed in the next chapter, is distinguished by the prominence of delusions over hallucinations and also by its onset, which occurs simply with ongoing drinking and not during alcohol withdrawal. Treatment

Abstinence is essential. Neuroleptics, used as described for schizophrenia, may reduce symptoms and allow patients to participate in rehabilitative efforts for alcoholism, such as Alcoholics Anonymous.

ALCOHOLIC PARANOIA Pathology and etiology

Apart from the fact that alcoholic paranoia (alcohol-induced psychotic disorder with delusions) develops only after many years of chronic severe alcoholism, the etiology of this disorder is not known. Clinical features

The onset is gradual, typically occurring while the patient is still drinking heavily. Delusions, either of persecution or jealousy (Albert et al. 1995), appear, and begin to exert a compelling influence over the patients' behavior. Those with delusions of persecution may believe that the

724 Specific disorders

police are looking for them or that neighbors are spying on them. They may lock the doors, arm themselves, and peek outside the blinds in an attempt to spot their persecutors. Those with delusions of jealousy may accuse their lovers or spouses of infidelity and either follow them or keep them in the house. Hallucinations, generally auditory, may occur, but these play a only a minor part in the overall clinical picture. Course Should patients become abstinent early on in the course of the paranoia, the delusions may gradually fade over weeks or many months. With a resumption of drinking, however, the symptoms eventually recur and may eventually become chronic, regardless of how long patients remain abstinent. Differential diagnosis

Delusional disorder is distinguished by the elaborate systematization of delusions, in contrast with the relatively simple and 'unworked-up' delusions seen in alcoholic paranoia. Schizophrenia is distinguished by the presence of symptoms not seen in alcoholic paranoia, such as loosening of associations and mannerisms. Alcohol hallucinosis is distinguished by its typical onset within a period of alcohol withdrawal and by the prominence of auditory hallucinations over delusions. Treatment

Abstinence is essential. Symptomatic control may be achieved with neuroleptics, used as described for schizophrenia.

MARCHIAFAVA-BIGNAMI DISEASE Pathology and etiology

Marchiafava-Bignami disease, described by Doctors Marchiafava and Bignami in 1903, is pathologically characterized by demyelinating lesions within the corpus callosum and, to a lesser degree, the anterior and posterior commissures and the middle cerebellar peduncles (Bohrod 1942; Ironside et al 1961; Poser 1973). Within the corpus callosum, the demyelinization is typically localized within its central portion, leaving a superior and inferior rim of myelin more or less intact. Chronically, the corpus callosum is shrunken and may display more or less confluent areas of cystic necrosis. Although the vast majority of cases have been described in alcoholics (Ironside et al. 1961), cases in poorly nourished non-alcoholics have also been reported (Leong 1979). Although the mechanism underlying the demyelinization is not known, the association of Marchiafava-Bignami disease with central pontine myelinolysis (Ghatak et al. 1978) and Wernicke's encephalopathy (Koeppen and Barron 1978) suggests that Marchiafava-Bignami disease might share some etiologic commonalities with these two disorders. Clinical features

The onset of Marchiafava-Bignami disease may be either acute or gradual and is typically seen only in chronic alcoholics after many years or decades of heavy drinking. Acute onsets are marked by delirium, stupor, or coma, and are often accompanied by seizures, either focal or generalized, long-tract signs (e.g. hemiparesis and bilateral Babinski signs), aphasia, or ataxia (Bohrod 1942; Ironside et al. 1961; Kamaki et al 1993; Koeppen and Barron 1978; Rosa et al. 1991). Gradual onsets are marked by a dementia that is accompanied by signs of callosal disconnection (Lechevalier et al. 1977; Lhermitte et al. 1977; Mayer et al. 1987).

Medication and substance-induced disorders 725

CT scanning reveals atrophy of the corpus callosum, and MRI scanning will, in addition, reveal decreased signal intensity in the same area (Kamaki et al. 1993; Kawamura etal. 1985). One MRI study captured the entire evolution of the pathologic process, displaying first edema of the corpus callosum, followed by atrophy (Chang et al. 1992). Course Those with an acute onset may die within days or weeks; those who do recover may be left with a dementia. With gradual onsets, the dementia progresses as long as the drinking does. Differential diagnosis

Marchiafava-Bignami disease of acute onset may be confused with Wernicke's encephalopathy, and the differential diagnosis may rest on imaging. Marchiafava-Bignami disease of gradual onset may be confused with alcoholic dementia and may also be mimicked by tumors of the corpus callosum. Here again, the diagnosis may rest on imaging. Treatment

In addition to general supportive measures, patients should receive adequate doses of vitamins, including thiamine, niacin, and folic acid. For those who survive, abstinence is essential.

SOLVENT-INDUCED DEMENTIA Pathology and etiology Solvent intoxication, as described in Chapter 21, may, if chronic over many years, produce a dementia, and autopsy studies have revealed both cerebral and cerebellar atrophy, with widespread demyelinization (Escobar and Aruffo 1980; Kornfeld et al. 1994; Rosenberg et al. 1988). The mechanism whereby solvents induce these changes is not clear but may involve their effects on cell membranes. Clinical features

The onset of the dementia is gradual, in the setting of ongoing, chronic solvent use. Clinically (Fornazzari et al. 1983; Grabski 1961; Hormes et al. 1986; Knox and Nelson 1966; Lazar et al. 1983; Lewis et al. 1981; Rosenberg et al. 1988), patients become apathetic and concrete, and have difficulty with memory; 'cortical' signs, such as aphasia, are lacking. In concert with the dementia, cerebellar signs are very common, including ataxia, dysarthria, titubation, intention tremor, and ocular abnormalities such as nystagmus or ospoclonus; a minority of patient may also have spasticity. In some cases, there may also be a peripheral neuropathy (Korobkin et al. 1975). CT scanning reveals cerebral and cerebellar cortical atrophy (Fornazzari et al. 1983; Hormes et al. 1986; Lazar et al. 1983); MRI scanning will also reveal diffuse increased signal intensity on T2-weighted scans in the cerebral and cerebellar white matter (Rosenberg et al. 1988), the severity of which correlates with the severity of the dementia (Filley et al. 1990). Course With continued solvent use, the dementia progresses; with abstinence, there may be partial improvement. Differential diagnosis

Diagnostic consideration might also be given to a combination of alcoholic dementia with alcoholic cerebellar degeneration, or to autosmal dominant cerebellar ataxia, but the history of chronic solvent use, which is difficult to miss, makes the diagnosis.

726 Specific disorders

Treatment Abstinence is essential and may require institutionalization.

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732 Specific disorders Sewell DD, Jeste DV. Metoclopramide-associated tardive dyskinesia: an analysis of 67 cases. Arch Fam Med 1992; 1:271-8. Sewell DD, Kodsi AB, Caligiuri MP, et al. Metoclopramideand tardive dyskinesia. Biol Psychiatry 1994; 36:630-2. Shriqui CL, Bradwejn J, Annable L, et al. Vitamin E in the treatment of tardive dyskinesia: a double-blind placebo-controlled study. AmJ Psychiatry 1992; 149:391-3. Smith DL, Wenegrat BG. A case report of serotonin syndrome associated with combined nefazodone and fluoxetine.y Clin Psychiatry 2000; 61:146. Soyka M. Psychopathological characteristics in alcohol hallucinosis and paranoid schizophrenia. Acta PsychiatrScandWW; 81:255-9. Stacy M, Cardoso F, Jankovic J. Tardive stereotypy and other movement disorders in tardive dyskinesias. Neurology 1993; 43:937^1. Stahl SM. Tardive Tourette syndrome in an autistic patient after long-term neuroleptic administration. AmJ Psychiatry 1980; 137:1267-9. Steiner W, Laporta M, Chouinard G. Neuroleptic-induced supersensitivity psychosis in patients with bipolar affective disorder. Acta Psychiatr Scand 1990; 81:437-40. Stern TA. Continuous infusion of physostigmine in anticholinergic delirium: case report. J Clin Psychiatry 1983; 44:463-4. Sternbach H. The serotonin syndrome. >4/rjy Psychiatry 1991; 148:705-13. Tan E-K, Jankovic J. Tardive and idiopathicoromandibulardystonia: a clinical comparison. J Neurol Neurosurg Psychiatry 2000; 68:186-90. Taylor NE, Schwartz HI. Neuroleptic malignant syndrome following amoxapine overdose. J Nerv Ment Dis 1988; 176:249-51. Thornton NE, Stahl SM. Case report of tardive dyskinesia and parkinsonism associated with amoxapine therapy. AmJ Psychiatry 1984; 141:704-5. Todd R, LippmannS, Manshadi M,etal. Recognition and treatment of rabbit syndrome, an uncommon complication of neuroleptic therapies. Am J Psychiatry 1983; 140:1519-20. Tollefson GD, Beasley CM, Tamura RN. Blind, controlled, long-term study of the incidence of treatmentemergent tardive dyskinesia with olanzepine or haloperidol. AmJ Psychiatry 1997; 154:1248-54. Toru M, MatsudaO, Makiguchi K,etal. Single case study: neuroleptic malignant syndrome-like state following withdrawal of antiparkinsonian drugs../ Nerv Ment Dis 1981; 169:324-7. Torvik A, Lindboe CF, Rogde S. Brain lesions in alcoholics. A neuropathological study with clinical correlations.) NeurolSci 1982; 56:233^8. Tune LE, Dainloth NF, Holland A, et al. Association of postoperative delirium with raised serum levels of anticholinergic drugs./.om:ef 1981; 2:651-3. van Harten PN, Hoek HW, MatroosGE, etal. Intermittent neuroleptic treatment and risk of tardive dyskinesia: Curacao extrapyramidal syndromes study \\\. AmJ Psychiatry 1998; 155:565-7. VelamoorVR, Norman RMG,Caroff SN,ef al. Progression of symptoms in neuroleptic malignant syndrome.; Nerv Ment Dis 1994; 182:168-73. Victor M, Hope JM. The phenomenon of auditory hallucinations in chronic alcoholism.) Nerv Ment Dis 1958; 126:451-8. Vonderahe AR. Lilliputian hallucinations: report of a case of hyoscine poison ing. Arch Neurol Psychiatry 1929; 22:585-8. Weiner WJ, Nausieda PA, Glantz RH. Meige syndrome (blepharospasm-oromandibular dystonia) after long-term neuroleptic therapy. Neurology 1981; 31:1555-6. Woerner M, Kane JM, Lieberman JA, et al. The prevalence of tardive dyskinesia. 7 Clin Psychopharmacol 1991;11:34-42. WojcikJD, Falk WE, Fink JS, etal. A review of 32 cases of tardive dystonia. AmJ Psychiatry 1991; 148:1055-9.

Medication and substance-induced disorders 733 Yadalam KG, Korn ML, Simpson GM. Tardive dystonia: four case histories. J Clin Psychiatry 1990; 51:17-20. Yagi G, Itoh H. Follow-up study of 11 patients with potentially reversible tardivedyskinesia. AmJ Psychiatry 1993; 150:966-8. Yarden PE, DiscipioWJ. Abnormal movements and prognosis in schizophrenia. Am J Psychiatry 1971; 128:317-23. Yassa R, Lai S. Respiratory irregularity and tardive dyskinesia: a prevalence study. Acta Psychiatr Scand 1986a;73:506-10. Yassa R, Lai S. Prevalence of the rabbit syndrome. AmJ Psychiatry 1986b; 143:656-7. Yassa R, NairV, DimitryA. Prevalence of tardive dystonia. Acta Psychiatr Scand 1986; 73:629-33. Yazici 0, Kantemir E, Tastaban Y, etal. Spontaneous improvement of tardive dystonia during mania. BrJ Psychiatry 1991; 158:847-50. Ziskind AA. Transdermal scopolamine-induced psychosis. Postgrad Med 1988; 84:73-6.

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Index

abnormal movements 15, 58,80-136 abstracting ability 10 abulia61,109,147 description 147 differential diagnosis 139,147-8 acalculalia (dyscalculalia) 58-9 description 58 differential diagnosis 58-9 acquired alexia 56 acquired agraphia 58 acquired hepatocerebral degeneration 92, 94,195,196 acquired immunodeficiency syndrome (AIDS) 93,291, 527-30, 549 clinical features 528-9 course 529 dementia 23-4,85,192,197,200,326 differential diagnosis 529 etiology 527-8 pathology 527-8 treatment 530 acquired (non-Wilsonian) hepatocerebral degeneration 516 activation procedures 35-6 Addison's disease 579 adenoma sebaceum 441 adrenocortical insufficiency 292, 578-80 clinical features 579 course 579 differential diagnosis 580 etiology 578-9 pathology 578-9 adrenoleu kodystrophy 200,269,301,326 clinical features 411 course 411 differential diagnosis 411 etiology 410-11 pathology 410-11 treatment 412 agnosias 17-18,63-8 see also specific types agoraphobia 664 agraphesthesia 13 agraphia (dysgraphia) 17, 57-8 description 57 differential diagnosis 57-8

AIDS see acquired immunodeficiency syndrome (AIDS) akathisia 15,109-12,110,380 causes 111 differential diagnosis 110 description 109 medication-induced 110-11 treatment of symptom 111 akinesia108 description 108 differential diagnosis 108-9 treatment of symptom 109 akinetic mutism 138 description 138-9 differential diagnosis 139^0 alcohol hallucinosis 722-3 ' alcohol intoxication 693-7 clinical features 693-5 differential diagnosis 695-6 etiology 693 pathology 693 treatment 696 alcohol withdrawal 82,694-6 alcoholic dementia 722 alcoholic paranoia 723-4 alexia (dyslexia) 55-7 description 55 without agraphia 57 alien hand sign 68,150 description 150-1 differential diagnosis 152^4 alpha rhythm 28 Alzheimer's disease 55,85,106,187,191,197,221, 259, 265,297,300, 325, 367-72, 373,466, 638,658 clinical features 369-70 course 371 differential diagnosis 371 etiology 367-9 pathology 367-9 treatment 371-2 amantadine381, 382 amnesia 187,216-22 causes 219 description 217-18 differential diagnosis218

736 Index amnesia -continued persistent and occurring with clear precipitants 221 persistent and of acute or gradual onset 220-1 treatment 222 see also specific types amnestic seizures 312-13 amphetamines, intoxication 688-9 amusia description 159-60 differential diagnosis 160 amyotrophic lateral sclerosis 145,192,194,296,374-6 clinical features 375 course 375 differential diagnosis 375-6 etiology 374 pathology 374 treatment 376 anomic aphasia 54 anosognosia 17 description 67 differential diagnosis 67 anterograde amnesia 216,217 with variable retrograde component 219 anticholinergic delirium 720-1 anti-phospholipid antibody syndrome 200 anxiety 270-3 associated with various medications or drugs, or their withdrawal 271 attacks 81-2,316 causes 271 description 270 differential diagnosis 270 non-paroxysmal 273 paroxysmal 272 treatment 273 anxiety disorders, see also generalized anxiety disorder; specific disorders apathetic hyperthyroidism 581 aphasia 16-17, 51-6,61 dementia presentation with 200 description 51-4 differential diagnosis 54-5 see also specific types apraxia 17,62-3 description 62 differential diagnosis 62-3 see also specific types aprosodia 17,60-1 description 60-1 diffrential diagnosis 61 arbovirus encephalitis 211 arbovirus meningoencephalitis 532-3 Argyll Robertson pupil 545 arsenic intoxication 504-5 arteriosclerotic parkinsonism 105,144,195,464-5 asomatagnosia 152 description 67-8 differential diagnosis 68 aspergillosis556 asterixis15,116

as medication side-effect 117 description 116 differential diagnosis 116 due to focal lesions 117 due to metabolic encephalopathies 117 ataxia 86 dementia with 196-7 ataxia telangiectasia 92 athetosis 15, 89, 93-4 as part of a more widespread disorder 94 associated with precipitants 94 causes 94 description 93 differential diagnosis 93-4 in association with sensory loss 94 atonic seizures 312 atypical aphasias 54 auditory agnosia description 65 differential diagnosis 65 auditory hallucinations 168 aurae 308 autism 223, 327, 452-5 clinical features 453-4 course 4 54 differential diagnosis454 etiology 452-3 pathology 452-3 treatment 454-5 automatic obedience 113 automatisms 308-10 autoscopy155,163,306 autosomal dominant cerebellar ataxia (ADCA) 196, 292, 395 clinical features 396 course 396 differential diagnosis 396-7 etiology 395 pathology 395 treatment 397 autosomal dominant partial epilepsy 329 Babinski sign 16 ballismus (ballism) 15, 95-6 description 95 differential diagnosis 95 etiology 95-6 lateralizing value 95 localizing value 95 Bale's concentric sclerosis 55 basal ganglia calcification 518-19 Behcet's syndrome 145,198,213,260,472-3 benign hereditary chorea 93, 392 benign senescent forgetful ness 218 beta rhythm 28 Binswanger's disease 23,144,191,193, 325,371, 465-6, 638, 658 bipolar disorder 255,263, 651-5,658 clinical features 652^1 course 654

Index 737

differential diagnosis 654 etiology 651 pathology 651 treatment 655 bipolar montage 26 bismuth intoxication 85, 505-6 blackouts 219, 318, 694-7 blepharospasm96,401,536,716 bovine spongiform encephalopathy 569 brain tumors see cerebral tumors brainstem lesions 168 brainstem tumors 145 Broca's aphasia 52,63 Brueghel's syndrome 101 burst-suppression 35 CADASIL 144, 193, 466, 468-9 cafe au lait spots 442 caffeine 702-3 calculating ability 10 candidiasis 553^1 cannabis intoxication 699-700 Capgras syndrome 164 carbon monoxide poisoning492-3 cataplexy160-2,317 description 161 differential diagnosis 161 treatment 162 catatonia15,112-16, 645 causes of 114 description 112 see also specific types celiac disease 328 central pontine myelinolysis 328, 512-13 clinical features 513 course 513 differential diagnosis 513 etiology 512-13 pathology 512-13 treatment 513 cerea flexibilitas see waxy flexibility cerebellar testing 13-14 cerebral amyloid angiopathy 191,193,326, 371,467-8 cerebral infarction 21, 54, 60 cerebral palsy 225,327 of the extrapyramidal type 91-2,94 cerebral tumors 260,266,292,633-6 clinical features 634-6 course 636 differential diagnosis 636 etiology 633^1 pathology 633-4 treatment 636 cerebrotendinousxanthomatosis 197,326,407-8 Charles Bonnet syndrome 167 chickenpox538 cholinergic rebound 721 chorea 15,83, 89-93 as part of more widespread disorder 91-2 associated with precipitants 90-1

causes 90,93 dementia with 195-6 description 89 differential diagnosis 89-90 chorea gravidarum 212,266,291,601-2 choreoacanthocytosisseeneuroacanthocytosis circumstantiality 8 clock-drawing test 69 cobalamin see vitamin B12 deficiency cocaine, intoxication 689-90 coccidioidomycosis 555 cock-walk 107, 503 cogwheel rigidity 14,102,106,379,499, 503,713 color agnosia 64 description 64 differential diagnosis 64 complex partial seizures 307-11,330-1 compulsions causes 158 description 157 differential diagnosis 157-8 with precipitants 158-9 without clear precipitants 159 computed tomography (CT) scanning 18-24 concussion 220,485 conduction aphasia 53 confabulation 218, 502 confusion 9 congenital disorders 439-61 see also specific congenital disorders congenital rubella syndrome 199,450 congophilic amyloid angiopathy see cerebral amyloid angiopathy constructional apraxia 17,62,63 cortical or subcortical white matter infarction 266 'cortical' signs and symptoms 51-79 corticobasal ganglionic degeneration 55,63,86,105, 194,197,297,386,388 clinical features 386 course 386 differential diagnosis 386-7 etiology 386 pathology 386 Cotard's syndrome 164 cranial arteritis 193, 466-7 cranial nerves I to XII 12-13 Creutzfeldt-Jakob disease 55, 85, 191, 196, 197, 267, 291,300-1,326,566-8 clinical features 567 course 568 differential diagnosis 568 etiology 566 pathology 566 treatment 568 see also new-variant Creutzfeldt-Jakob disease cryptococcosis 554 Cushing's syndrome 11, 171, 213, 258, 266, 273, 292, 576-8 clinical features 576-8 course 578

738 Index Cushing's syndrome -continued differential diagnosis 578 etiology 576 pathology 576 treatment 578 cyanide intoxication 94 cyclothymia 264,654 cystiercosis 329 cytomegalovirus (CMV) encephalitis 214, 530-1 DeClerambault's syndrome 164 deafness 54, 65 deep tendon reflexes 16 delayed postanoxic leukoencephalopathy 91, 198, 491-2 delirium 54, 63, 82, 202-16 causes 204-6 description 202 differential diagnosis 203-8 during immunosuppression 213-14 inencephalitis210-12 infarction in 210 intoxicants in 208-9 medications in 206-8 metabolic causes 209-10 occurring with malnourishment213 treatment 215-16 with paroxysmal onset 214 with specific associated features 212-13 with specific precipitants210 withdrawals in 209 delirium tremens 322, 501,695-7 delusional disorder 288, 649-50 delusions 9,162,382, 645,657 description 162, 164 differential diagnosis 165 dementia 186-202, 223, 325-6, 657 causes 188-90 description 186 differential diagnosis 187-91 in mental retardation 199 in Parkinson's disease 379 of gradual or subacute onset 191-3 treatment 201-2 with aphasia 200 with ataxia 196-7 with chorea 195-6 with dystonia 196 with frontal lobe syndrome 193-4 with myoclonus 197 with parkinsonism 194-5 with specific features 197-8 with specific precipitants 198-9 with strokes 193 see also specific types dementia paralytica 545 dementia pugilistica 106, 195, 196, 198, 484-5 denatured alcohol see methanol dentatorubropallidoluysian atrophy 85,92,105,195, 196,326,392-3,396

of childhood onset 197 depersonalization 155-7 causes 156 description 155 differential diagnosis 155 treatment 156-7 with precipitants 155-6 without precipitants 156 depression 109, 156, 159, 171, 192, 254-61 causes 255-7 description 254 differential diagnosis 255 in neurodegenerative or dementing disorders 259 in Parkinson's disease 379 medication-associated 257-8 miscellaneous or rare causes 260 secondary to diseases with distinctive features 258-9 secondary to precipitants 257-8 symptoms 255 treatment 260-1 developmental agraphia 58 developmental alexia 56, 57 developmental aphasia 55 diagnostic assessment 3-47 diagnostic interview 3-6 collateral history 5-6 concluding the interview 5 directive portion 5 eliciting the chief complaint 4 establishing rapport 4 non-directive portion 4-5 setting 3 dialysis dementia 85, 197, 199, 509 dialysis disequilibrium syndrome 510 diffuse axonal injury 22, 198, 483-4 diffuse Lewy body disease 55, 86, 104, 191-2, 194, 197, 214,259,371,380,383-6,388 clinical features 383 course 383 differential diagnosis 383 treatment 383 dissociative amnesia 220 domoicacid intoxication 329 dopa-responsive dystonia 398 dopamine agonists 381-2 Down's syndrome 199,224,259, 327,443-5 clinical features 443-4 course 444-5 differential diagnosis 445 etiology 443 pathology 443 treatment 445 draw a daisy test 69 dress 6 dressing apraxia 17, 62,63 drift 14 dysarthria 14, 54 dyscalculalia see acalculalia (dyscalculalia) dysgraphia see agraphia (dysgraphia)

Index 739 dyskinetic tremor 82 dyslexia see alexia (dyslexia) dysmennorhea 660 dysthymia257 dystonia15,96-101,715-16 as part of widespread disorder 99-100 associated with precipitants 97-8 causus97 dementia with 196 description 96 differential diagnosis 96 see also specific types dystonia musculorum deformans see primary torsion dystonia echo phenomena 113,148,403 Ecstasy 691 EEG 24-35 abnormalities 29-39 artifacts 37 resembling decreased amplitude 39 resembling slow waves 38-9 resembling spikes 37-8 decreased amplitude 29-30 epilepsy 331-2 epileptiform 31^1 epileptiform activity 31^ ictal activity 34 instrumentation 24-6 intericta I activity 31-4 normal 27-9 normal variants 36-7 seizures 331-2 sixty cycle per second artifact 39 slowing 30-1 Ekbom's syndrome see restless legs syndrome elective mutism 138 electrode names 25 electroencephalography see EEG emotional incontinence 7, 143 encephalitis 88, 115, 116, 221, 290, 297, 325, 527-39 delirium in 210-12 encephalitis lethargica 87, 211, 268, 535-6 endocrinologic disorders 576-87 enuresis 616-17 environmental dependency syndrome ('utilization behavior') 148, 152 description 148 differential diagnosis 148 epilepsy 55, 114, 117, 302-34 description 302-16 diagnostic work-up 330-2 differential diagnosis 316-29 EEG 331-2 in dementing and neurodegenerative disorders 325-6 lateralizing and localizing signs 330-1 metabolic causes 325 miscellaneous causes 328-9 neuroimaging332

precipitating factors 322-3 psychosis associated with 290-1 treatment 332^ see also seizures; specific types epileptic paroxysmal events 319-29 epileptiform activity 31-4 Erithism 508 essential myoclonus 87 essential tremor 81,412-13 excited catatonia 113,115-16 expressive aphasia 52 extinction 69-70 eye movement 38 facial palsies, description 145-6 Fahr's syndrome 105,159,195,201,259,293 see also basal ganglia calcification fatal familial insomnia 85,197,198, 570-1 febrile delirium 212 festination102, 379 fetal alcohol syndrome 225,450-1 first rank symptoms see Schneiderian first rank symptoms flashbacks 166,691 flattened affect 61, 645 flight of ideas 8 folicacid deficiency 191,498-9 foliea deux 286 foreign accent syndrome description 160 differential diagnosis 160 formal thought disorder 645 fragile X syndrome 11,224,327,446-7 freezing 102, 379 Fregoli syndrome 164 frontal lobe syndrome 60,147,187,294-8 causes 296 dementia with 193-4 description 294-5 differential diagnosis 295-7 gradual or subacute onset 296-7 secondary to clear precipitants 297 treatment 297-8 frontotemporal dementia 55,194,296,373-4 clinical features 374 course 374 differential diagnosis 374 treatment 374 gait 14 general paresis of the insane 192,259, 545 generalized anxiety disorder 81,273, 670-1 German measles 544 Gerstmann-Straussler-Scheinker disease 196,397, 569-70 Gerstmann's syndrome 58, 59 description 59 differential diagnosis 59 geste antagonistique 400,402,403 giant cell arteritis see cranial arteritis

740 Index Gilles de la Tourette's syndrome seeTourette's syndrome global aphasia 53 global aprosodia 61 grand mal seizures 311,330,331,333 granulomatous angiitis 192,214,301,326,469-70 graphesthesia13 grasp reflex 16,141,142,152 grope reflex 16,141-2,152 gumma 545 gustatory hallucinations 169 Hallervorden-Spatz disease 92,94,105,195,196,201, 260, 326, 397-8 hallucinations 8,162,382,644, 657 causes 166 description 162,163 differential diagnosis 165 see also specific types hallucinogens, intoxication 691-2 handedness11 Hashimoto's encephalopathy 85,86,197,212,291, 328,598-9 Hashimoto's thyroiditis 584 head-banging see jactatio nocturna capitis head trauma 481-6 heavy metal intoxication 212, 503-9 see also specific heavy metals heightened startle response 16 as part of reflex epilepsy 117 'cultural' variant 118 idiopathic basis 118 secondry to other lesions 118 with generalized autonomic hyperactivity 117 hepatic encephalopathy 267, 514-16 clinical features 515 course 515 differential diagnosis 515 etiology 514-15 pathology 514-15 treatment 515-16 hepatic porphyria 292, 328, 516-18 hepatocerebral degeneration see acquired (nonWilsonian) hepatocerebral degeneration hereditary mental depression with parkinsonism 260 herpes simplex viral encephalitis 24,211,222, 533-5 clinical features 534-5 course 535 differential diagnosis 535 etiology 533-4 pathology 533^1 treatment 535 herpes zoster see varicella zoster hightened startle response 117-18 description 117-18 differential diagnosis 117-18 histoplasmosis 555-6 human immunodeficiency virus (HIV) 211, 527-8 Huntington's disease 85,88,90,92,105,192,195,266, 291,300,388,391,716

clinical features 389-90 course 390 differential diagnosis 390 etiology 388-9 of juvenile onset 195 pathology 388-9 treatment 390 hydrocephalus260,636-9 clinical features 638 course 638 differential diagnosis 638-9 etiology 636-8 pathology 636-8 treatment 639 see also normal-pressure hydrocephalus hyperaldosteronism 260 hypercalcemia 209,260 hyperekplexia 413-14 hypereosinophilia201 hyperglycemia 93,209,325 hypergraphia description 59 differential diagnosis 59-60 hypermagnesemia 209 hypernatremia 209 hyperparathyroidism 260 hypertensive encephalopathy 212,473-4 hyperthyroidism 82,93,191,258,273,291,328, 580-2 clinical features 580-1 course 582 differential diagnosis 582 etiology 580 pathology 580 treatment 582 hypertriglyceridemia 201 hypnic jerks 87 hypnogogic hallucinations 163,168,618 hypocalcemia 209,273,325 hypoglycemia 54,82,199,209,272,325, 510-12 clinical features 511 course 512 differential diagnosis 512 etiology 510-11 pathology 510-11 treatment 512 hypokalemia209 hypomagnesemia 85,209,325, 502,697 hyponatremia 85,209,325, 513 hypoparathyroidism 105,108,273,195,201, 519 hypothyroidism 11,191,258,291, 582-5 clinical features 583-4 course 584 differential diagnosis 584 treatment 584-5 hypoxic disorders 490-4 see also specific hypoxic disorders ictal psychosis 290 ideational apraxia 17, 58, 62,63 ideomotorapraxia 17,62, 63

Index 741 idiopathic cervical dystonia 400 idiopathic hemochromatosis85,197 immune-related disorders 588-610 see also specific immune-related disorders incubus see nightmare disorder infectious disorders 527-65 see also specific infectious disorders infectious mononucleosis 536-7 inhalants (solvents) 698-9 intention tremor 80-2 interictal personality syndrome 60,298 description 298 differential diagnosis 298-9 treatment 299 interictal psychosis 291 intermittent explosive disorder 317 intoxications 688-711 isopropanol, intoxication 704-5 Jacksonian seizures 303 jactatio nocturna capitis 615-16 Japanese encephalitis 106 jargon aphasia 53 Jarisch-Herxheimer reaction 547 Jumping Frenchman of Maine 118 juvenile Huntington's disease 197, 326 juvenile myoclonic epilepsy 86 K complexes 29 Kayser-Fleischer ring 394 Kleine-Levin syndrome 622-4 clinical features 623 course 623 differential diagnosis 624 etiology 622 pathology 622 treatment 624 Klinefelter's syndrome 224,327,445-6 etiology 445 Kluver-Bucy syndrome 149, 373,374 description 149-50 differential diagnosis 150 Korsakoff's syndrome 217,220, 502 Kuru 571 lability 7 lacunar dementia 144,191,193,297,463-4 Lafora body disease 86 Landau-Kleffner syndrome 55,329 Latah118 Laurence-Moon-Biedl syndrome 11,225,448-9 lefou rire prodromique 146 description 146 differential diagnosis 147 lead intoxication 260,329, 506-7 leaded gasoline intoxication 91 Lesch-Nyhan syndrome 92,225,447-8 level of consciousness 9 levitation phenomenon 152,386 Ievodopa91,381,382

Lewy body disease see diffuse Lewy body disease limbic encephalitis 214,221,259,301, 328, 595-6 line bisection test 68 line cancellation test 68 liver flap 117 locked-in syndrome 139, 513 looseness of associations 8, 54 lupus see systemic lupus erythematosus Lyme disease 192,215, 547-8 Magnetic gait 105, 464, 638 magnetic resonance imaging (MRI) 18-24 major depression 656-9 clinical features 656-7 course 657 differential diagnosis 657-8 treatment 658-9 malaria 212, 551-2 manganism 291, 301, 503-4 mania 60, 171, 261-70, 651-5 causes 264 description 261-3 differential diagnosis 263-9 localizing and Iateralizing 269 miscellaneous causes 269 treatment 270 with precipitants 267-9 without precipitating factors 263-7 manic-depressive illness see bipola disorder Marchiafava-Bignami disease 213, 329, 724-5 Marijuana see cannabis intoxication measles 543 medication-induced disorders 712-33 megalobalstic madness 496 Meige's syndrome 101, 401-2 MELAS syndrome 193 memory 9-10 see also amnesia meningiomas 633—4 meningitis 325 meningovascular neurosyphilis 597 mental retardation 187, 222-6, 327 causes 224 dementia in 199 description 222-3 differnetial diagnosis 223-4 grades 222 treatment 225-6 mental status examination 6-10 mercury intoxication 91,301, 507-9 mesial temporal sclerosis 22,324-5 metachromatic leukodystrophy 196,200,269,292, 301,326 clinical features 409-10 course 410 differential diagnosis 410 etiology 408-9 juvenile onset 410 pathology 408-9 treatment 410

742 Index methanol 703-4 mimetic facial palsy 145, 331 mirror movements 152 mononucleosis see infectious mononucelosis 211 mood 7 mood disturbances 254-84 see also specific disorders motor aphasia 52 motor aprosodia 61 motor neglect 18, 69 motor tics 15, 87-8 description 87 MRI scanning see magnetic resonance imaging mu rhythm 28 multi-infarct dementia 55, 193, 259, 325 clinical features 462-3 course 463 differential diagnosis 463 etiology 462 pathology 462 treatment 463 multiple sclerosis 22, 54, 145, 192, 259, 266, 292, 328, 542, 588-92 clinical features 589-90 course 591 differential diagnosis 591-2 etiology 588-9 pathology 588-9 treatment 592 multiple system atrophy 105, 196, 387 clinical features 387-8 course 388 differential diagnosis 388 etiology 387 of the olivopontocerebellar type 86, 197, 297 of thestriatonigral type 86,194 pathology 387 treatment 388 mumps 211,537-8 mutism 137-40 description 137 differential diagnosis 137 mycoses 213, 553-6 myocardial infarction 272 myoclonus15,83-7,89 causes 84,87 dementia with 197 description 83 differential diagnosis 83-5 isolated 87 secondary to medication 86-7 with ataxia 86 with delirium 85 with dimentia 85-6 with parkinsonism 86 with psychosis 86 with seizures of various types 86 myotonia atrophica 198,405-7 clinical features405-6 course 406

differential diagnosis 406 etiology 405 pathology 405 treatment 406 myotonia congenita 406 myotonic dystrophy see myotonia atrophica myxedema mad ness 291, 583 narcolepsy 617-20 clinical features 617-19 course 619 differential diagnosis 619 etiology 617 pathology 617 treatment 619-20 negative symptoms 645 negativism 113 neglect 18, 56,62, 68-70 differential diagnosis 70 see also specific types neologisms 8,645 neuroacanthocytosis 88,93,106,195,326 clinical features 391 course 391 differential diagnosis 391 etiology 391 pathology 391 treatment 391 neurodegenerative disorders 325-6,367^38 see also specific neurodegenerative disorders neurofibromatosisseevon Recklinghausen's disease neuroimaging 18-24 neuroleptic-induced tardive dyskinesia 88, 714-17 neuroleptic malignant syndrome 91,106,115,207, 382, 712-14 clinical features 713 course 713 differential diagnosis 713 etiology 712-13 pathology 712-13 treatment 713-14 neurologic examination 10-17 neuronal migration disorders 22,323-4 neurosyphilis 192,265,292,300, 326, 529, 544-7 clinical features 545-6 course 546 differential diagnosis 546-7 etiology 544-5 pathology 544-5 treatment 547 new-variant Creutzfeldt-Jakob disease 171,197,260, 569 niacin499 nicotine intoxication and withdrawal 702 nightmare disorder 614 night terror see pavor nocturnus nitrous oxide anesthesia 496 nocturnal myoclonus 625-6 non-epileptic paroxysmal events 316-19 non-ketotic hyperglycemia 93,209

Index 743 non-specific personality change causes 300 description 299 differential diagnosis 299-301 gradual or subacute onset 299-301 secondary to clear precipitants 301 treatment 301 normal-pressure hydrocephalus 639^0 nutmeg intoxication 209 nutritional, toxic and metabolic disorders 495-526 obesity 11,448,449, 577,620 see also Pickwickian syndrome obsessions 8 causes 158 description 157 differential diagnosis 157-8 with precipitants 158-9 without clear precipitants 159 obsessive-compulsive disorder 272, 667-9 clinical features 667-8 course 668 differential diagnosis 668 etiology 667 pathology 667 treatment 668-9 obstructive sleep apnea 259, 620 occupational dystonia see writer's cramp oculogyric crisis 96,98,158,211, 536,716 olfactory hallucinations 169 olfactory reference syndrome 288 opioids intoxication 700-2 opsoclonus87 orientation 9 orthostatic tremor 83,412 painful legs and moving toes 626 palatal myoclonus87 palinopsia 163,167,306 palmomental reflex 16,141,142 panarteritis nodosa see polyarteritis nodosa pancreatic cancer 260 pancreatitis 212 panic disorder 156,272,380, 382, 657 clinical features 662-3 course 663 etiology 662-3 pathology 662-3 treatment 663 paraneoplastic encephalitis 93, 595 see also limbic encephalitis parasittosis288 parasomnias316-17,611-16 parkinsonism 15,86,101-8 causes 103 dementia with 194-5 description 101-2 differential diagnosis 102 miscellaneous causes 107 with precipitating factors 106-7

without precipitants 104-6 Parkinson's disease 82,86,101,104,111,194,208,259, 272, 376-82, 384-5,386, 388 clinical features 377-80 course 380 dementia in 379 depression in 379 diagnosis 380 etiology 376-7 juvenile 380 pathology 376-7 treatment 380-2 paroxysmal anxiety 272 paroxysmal atrial tachycardia 272 paroxysmal chorea 91 paroxysmal dystonia 99 paroxysmal dystonic choreoathetosis 91 partial seizures 166,168,169,171,214,259,272 pathologic intoxication 694, 695 pathological laughing and cryingsee emotional incontinence pavor nocturnus 614-15 peduncular hallucinations 167 pellagra 85,198,213,260,499-500 periarteritis nodosa see polyarteritis nodosa periodic complexes 34-5 periodic leg movements of sleep see nocturnal myoclonus pernicious anemia 260,496,497, 578 perseveration 157,294 personality change 293-301 personality disorder 294 petit mal seizures 214,311,333 phantom limbs 154 phase reversal 33 phencyclidine intoxication 692-3 phenylketonuria225 pheochromocytoma 272 phobias 272,664-6 photic stimulation 36 Pick's disease 55,150,191,194,296,300,372-3,386 clinical features 373 course 373 differential diagnosis 373 etiology 372-3 pathology 372-3 treatment 373 Pick's visions 168 Pickwickian syndrome 11,619,622 polyarteritis nodosa 200,215,470-1 polycythemia vera 93 polymyalgia rheumatica 198,467 polyopia 163, 167 poriomania 315 porphyria 212 see heptaicporphyria port wine stain 439 post-anoxic dementia 85 see postanoxic encephalopathy

744 Index post-anoxic encephalopathy 198, 490-1 post-concussion syndrome 485-6 post-encephalitic compulsions 158 post-encephalitic dementia 199 post-encephalitic obsessions 158 post-encephalitic parkinsonism 106 post-ictal psychosis 290 post-infectious encephalitis see post-infectious and post-vaccinal encephalomyelitis post-infectious and post-vaccinial encephalomyelitis (PIE) 267-8, 540-2 clinical features 540-1 course 541 differential diagnosis 541-2 etiology 540-2 pathology 540-2 treatment 542 post-infectious encephalitis 211 post-partum blues 661-2 post-partum depression 660-1 post-partum psychosis 268,650-1, 654 post-psychotic depression 257,646 post-traumatic stress disorder (PTSD) 272, 669-70 post-vaccinial encephalitis 211 see post-infectious and post-vaccinal encephaloymelitis POSTs 29 Postural instability 102,104,105,384 postural tremor 80-2 see also specific types posturing 113,315,316,646,653 poverty of thought 8, 645 Prader-Willi syndrome 11,225,292,327,449-50 premenstrual syndrome 257, 659-60 pressure of speech 8,262,652 primary angiitis of the central nervous system see granulomatous angiitis primary dystonias 100-1 primary generalized epilepsy 327-8 primary progressive aphasia 55 primary torsion dystonia 399^00 primary writing tremor 81 primitive reflexes 16,141-2 description 141 differential diagnosis 142 prion diseases 566-75 see also specific diseases progressive multifocal leukoencephalopathy 54,200, 213,531-2 progressive rubella panencephalitis 196,326, 544 progressive supranuclear palsy 104,145,194,297, 384-6 clinical features 384 course 384 differential diagnosis 384 etiology 384 pathology 384 treatment 386 PROM M 406 prosopagnosia 64

description 64 differential diagnosis 64-5 pseudobulbar palsy 143 causes 144 description 143 differential diagnosis 143^t pseudodementia 192 pseudoseizures318 psychogenic amnesia 220 psychomotor change 6-7 psychomotor hyperactivity 6-7 psychomotor retardation 6-7,7 psychosis 86,165,285-364 associated with epilepsy 290 associated with precipitants 288-90 description 285 differential diagnosis 285-93 encephalitic onset 290 idiopathic disorders 286-8 of forced normalization 115,290 secondary to stroke 290 specific associated features 291-2 psychotic disorders see specific disorders punchdrunk484 pure affective deafness 60,61 pure epileptic amnesia 219,312 pure retrograde amnesia 217,221-2 pure word deafness 53-4, 65 rabbit syndrome 82,718-19 rabies 211,539-40 radiation encephalopathy 486-7 Rasmussen's syndrome 329 receptive aphasia 53 referential montage 26 reflex seizures 313-14,333 reflexes, primitive 141 REM sleep behvior disorder 612-13 rest tremor 80,81,82 restless legs syndrome 624-5 retrograde amnesia 217 Rett's syndrome 225,327,451 rheumatoid arthritis 213 rigidity 14,102 Rocky Mountain spotted fever 212, 550-1 rubella 225 see also congenital rubella syndrome; progressive rubella panencephalitis rubral tremor 82 rum fits 322,695 sarcoidosis 200,215,328, 596-8 clinical features 596-7 course 597 differential diagnosis 597 etiology 596 pathology 596 treatment 597-8 schizoaffective disorder 170,257,264,288,648-9, 654, 658

Index 745 schizophrenia 60,92,114,116,159,170,257,286, 643-8,716 causes 287-8 clinical features 644-6 course 646 differential diagnosis 646-7 etiology 643^ pathology 643-4 subtypes 646 treatment 647-8 Schneiderian first rank symptoms 169-71 causes 171 description 169 differential diagnosis 170 school phobia 665 sedative-hypnotic-induced blackouts 697 sedative-hypnotic intoxication 697 differential diagnosis 698 treatment 698 sedative-hypnotic withdrawal delirium 697-8 sedative-hypnotic withdrawal seizures 697 seizures 161,302-34, 636 causes 320-1 description 302-16 diagnostic work-up 330-2 differential diagnosis 316-29 EEG331-2 lateralizing and localizing signs 330-1 metabolic causes 325 miscellaneous causes 328-9 neuroimaging332 precipitating factors 322-3 treatment 332-4 types 302 see also epilepsy; specific types of seizure selective mutism 138 senile chorea 93, 391-2 sensory aphasia 53 sensory aprosodia 61 sensory testing 13 serial sevens test 10, 58 serotonin syndrome 85,207,719-20 simple partial seizures 303-7,330,333 simple phobia 664-5 differential diagnosis 666 treatment 666 simultanagnosia 66 description 66 differential diagnosis 67 Sjorgen's syndrome 198 sleep apnea 201,620-2 clinical features 620-1 course 621 differential diagnosis 621 etiology 620 pathology 620 treatment 621-2 sleep disorders 611-32 see also specific sleep disorders sleep spindles 29

sleepwalking disorder see somnambulism Sneddon's syndrome 198 snout reflex 16,141,142 social phobia 665-6 solvent-induced dementia 196,725-6 solvents see inhalants (solvents) intoxication somnambulism 611-12 spasmodic (spastic) dysphonia 402-3 spasmodic torticollis see idiopathic cervical dystonia specific phobia see simple phobia spinocerebellar ataxia see autosomal dominant cerebellarataxia startle response see heightened startle response station 14 status epilepticus 221,314-16, 334 Stauder's lethal catatonia 113,115,713 stimulants 88,91,688-90 stuporous catatonia 112-15,139 Sturge-Weber syndrome 11,199,224,319,327,439 clinical features 439^40 course 440 differential diagnosis 440 etiology 439 pathology 439 treatment 440 stuttering 140 description 140 differential diagnosis 140-1 subacute combined degeneration 496 subacute measles encephalitis 214, 543 subacute sclerosingpanencephalitis 85,86,171,197, 293,326, 542-3 subdural hematoma 481-3 clinical features482 course 482 differential diagnosis 482-3 etiology 481-2 of the chronic type 198 pathology 481-2 substance-induced disorders 712-33 supernumeracy limbs 154 description 154 differential diagnosis 154-5 supersensitivity psychosis 717-18 Sydenham's chorea 88,90,92,159,212,266,291,328, 404, 599-601 clinical features 599-600 course 600-1 differential diagnosis 601 etiology 599 pathology 599 treatment 601 syphilis see neurosyphilis systemic lupus erythematosus (SLE) 93,192,195,200, 214,260,267,291,328,591, 592-5 clinical features 593-4 course 594 differential diagnosis 594 etiology 592-3 pathology 592-3

746 Index systemic lupus erythematosus (SLE) - continued treatment 594-5 tactile agnosia 17 description 65 differential diagnosis 65 tactile extinction 18, 70 tactile hallucinations 168 tangentiality 8 tardiveakathisia 111 tardive dyskinesia 87, 91, 404, 714-17 clinicaI features 715-16 course 716 differential diagnosis 716 etiology 714-15 pathology 714-15 treatment 717 tardive psychosis see supersensitivity psychosis temporal arteritis see cranial arteritis thalamic degeneration 85,197,293,408 thallium intoxication 198, 504 thiamineSOO thromboticthrombocytopenic purpura 214 thyrotoxicosis 91,266 tics 87-8 see also Tourette's syndrome tin intoxication 329, 506 Todd's paralysis 303 topographagnosia 66 description 66 differential diagnosis 66 Tourette's syndrome 87,88,109,159,716,717 clinical features 403-4 course 404 differential diagnosis 404 etiology 403 pathology 403 treatment 404-5 toxic disorders see nutritional, toxic and metabolic disorders toxoplasmosis 213, 225, 552-3 transcortical mixed aphasia 53 transcortical motor aphasia 52-3 transcortical sensory aphasia 53 transient global amnesia 219, 317, 474-5 trauma 481-9 tremor 15, 80-3 causes 81 description 80-1 differential diagnosis 81 see also specific types triphasic waves 35 trisomy 21 see Down's syndrome tuberculosis 548-9 tuberous sclerosis 224, 269, 327 clinical features 441 course 441-2 etiology 441 pathology 441 treatment 442

tumors 22, 54, 60, 192, 194, 214, 221, 296, 635 see also cerebral tumors two-point discrimination 13 unipolar depression see major depression Unverricht-Lundborg disease 86 uremia 267,325 uremic encephalopathy 514 'utilization behavior'see environmental dependency syndrome ('utilization behavior') varicella 211 see also varicella zoster varicella-zoster 538-9 vascular dementia 193 vascular disorders 462-80 see also specific types of vascular disorder vascular parkinsonism see arteriosclerotic parkinsonism vertex sharp transients 29 viral encephalitis 527-39 viscosity 298 visual agnosia 17, 63 description 63 differential diagnosis 63-4 visual extinction 18 visual hallucinations 165-8 visual neglect 18,69 description 68-9 vitamin B12 deficiency 191,267,292,301,495-526, 530 causes 495-6 clinical features496-7 course 497 differential diagnosis497 etiology 495-6 pathology 495-6 treatment 498 von Economo's disease see encephalitis lethargica von Recklinghausen's disease 225,327 clinical features 442-3 course 443 differential diagnosis 443 etiology 442 pathology 442 treatment 443 waxy flexibility 112-13, 309, 515, 646, 653 Wegener's granulomatosis 213, 328,471-2 Wernicke'saphasia 53,62 Wernicke's encephalopathy 213,220, 500-2 clinical features 501 course 501 differential diagnosis 501 etiology 500 pathology 500 treatment 501 western equine encephalitis 106 whiplash 482,483,485 Whipple's disease 87,197,201,301,328, 549-50

Index 747 Wilson's disease 92,106,196,292,300,326,393,601 clinical features 394 course 394 differential diagnosis 394 etiology 393 pathology 393 treatment 395

wing beating tremor 83,394 withdrawals 688-711 Witzelsucht 294 Wood alcohol see writer's cramp (occupational dystonia) 401 Zoster see varicella zoster