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.


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.


1 Diagnostic assessment Diagnostic assessment

3


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.


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


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.


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.


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


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.


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.


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


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


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.


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.


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


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'.


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


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,


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

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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.


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).


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.


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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


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.


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.


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


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


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


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


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


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


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).


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


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.


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]).


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


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.

REFERENCES Adams DJ, Lueders H. Hyperventilation and 6-hour EEG recording in evaluation of absence seizures. Neurology 1981; 31:1175-81. Aguglia U, FarnarierG.TinuperPefo/. Subacutespongiformencephalopathywith periodic paroxysmal activities: Clinical evaluation and serial EEG findings in 20 cases. Clin Electroencephalogr 1987; 18:147-58. Ajmone-Marsan C, Zivin LS. Factors related to the occurrence of typical paroxysmal abnormalities in the EEG records of epileptic patients. Epilepsia 1970; 11:361-81. Akelaitis AJE. Psychiatric aspects of myxedema.J Nerv Ment Dis 1936; 83:22-36. Altman NR, Purser RK, Rost MJD. Tuberous sclerosis: characteristics at CT and MR imaging. Radiology

1988; 167:523-32.

40 Diagnostic assessment American Electroencephalographic Society. Guidelines on EEG and evoked potentials. Guideline 7: A proposal for standard montages to be used in clinical EEG. J Clin Neurophysiol 1986; 3(suppl 1):26-33. Arfel G, Fischgold H. EEG-signs in tumours of the brain. Electroencephalogr Clin Neurophysiol 1961; 19(suppl):36-50. Armstrong P, Keevil SF. Magnetic resonance imaging. 2. Clinical uses. BMJ 1991; 303:105-9. Au WJ, Gabor AJ, Vijayan N et al. Periodic lateralized epileptiform complexes (PLEDS) in CreutzfeldtJakob disease. Neurology 1980; 30:611-18. Barkovich AJ, Kjos BO. Gray matter heterotopias: MR characteristics and correlation with developmental and neurologic manifestations. Radiology 1992; 182:493-9. Barlow JS, Ciganek L. Lambda responses in relation to visual evoked responses in man. Electroencephalogr Clin Neurophysiol 1969; 26:183-92. Barnes MP, Saunders M, Walls TJ et al. The syndrome of Karl Ludwig Kahlbaum. J Neurol Neurosurg Psychiatry 1986; 49:991-6. Berger H. Uber das elektroencephalogramm des menschen. Archiv fur Psychiatrie und Nervenkrankheiten 1929; 101:452-69. Berkovic SF, Andermann F, Olivier A et al. Hippocampal sclerosis in temporal lobe epilepsy demonstrated by magnetic resonance imaging. Ann Neurol 1991; 29:175-82. Berry I, Brant-Zawadzki M, Osaki L et al. Gd-DTPA in clinical MR of the brain. 2. Extra-axial lesions and normal structures. AJR 1986; 747:1231-5. Beschin N, Cubelli R, DellaSalaSeffl/. Left of what? The role of egocentric coordinates in neglect. J Neurol Neurosurg Psychiatry 1997; 63:483-9. Bickerstaff ER. Neurological examination in clinical practice, 4th edn. Oxford: Blackwell Scientific, 1980. Bickford RG, Sem-Jacobsen CW, White PT et al. Some observations on the mechanism of photic and photo-Metrazol activation. Electroencephalogr Clin Neuropshysiol 1952; 4:275-82. Bleuler E. Textbook of psychiatry, translated by Brill AA. New York: Macmillan, 1924. Rreissued by Arno Press, New York, 1976. Blume WT, Young GB, Lemieux JF. EEG morphology of partial epileptic seizures. Electroencephalogr Clin

Neurophysiol 1984; 57:295-302. BoriesJ, Derhy S, Chiras J. CT in hemispheric ischemic attacks. Neuroradiology 1985; 27:468-83. Bortone E, Bettoni L, Giorgi C et al. Reliability of EEG in the diagnosis of Creutzfeldt-Jakob disease. Electroencephalogr Clin Neurophysiol 1994; 90:323-30. Bradley WG, Waluch W, Yadley RA et al. Comparison of CT and MR in 400 patients with suspected disease of the brain and cervical spinal cord. Radiology 1984; 152:695-702. Brain W. Clinical neurology, 2nd edn. London: Oxford University Press, 1964. Brant-Zawadzki M, Badami JP, Mills CM et al. Primary intracerebral tumor imaging: a comparison of magnetic resonance and CT. Radiology 1984; 150:435-40. Brant-Zawadzki M, Berry I, Osaki L et al. Gd-DTPA in clinical MR of the brain. 1. Intraaxial lesions. AJR

1986; 147:1223-30. Brown JJ, Hessellink JR, Rothrock JF. MR and CT of lacunar infarcts. AJNR 1988; 9:477-82. Browne P, Cathala F, Castaigne P et al. Creutzfeldt-Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann Neurol 1986; 20:597-602. Browne TR, Penry JK, Porter RJ et al. Responsiveness before, during and after spike-wave paroxysms. Neurology 1974; 24:659-65. Burger LJ, Rowan AJ, Goldensohn ES. Creutzfeldt-Jakob disease. An electroencephalographic study. Arch

Neurol 1972; 26:428-33. Caton R. The electrical currents of the brain. BMJ 1875; 2:278. Chatrian GE, Petersen MC, Lazarte JE. The blocking of the rolandic wicket rhythm and some central changes related to movement. Electroencephalogr Clin Neurophysiol 1959; 11:497-510.

Diagnostic assessment 41 Chatrian GE. Characteristics of unusual EEG patterns: incidence, significance. Electroencephalogr Clin Neurophysiol 1964; 17:471-2. Chatrian GE, Shaw CM, Leffman H. The significance of periodic lateralized epileptiform discharges in EEG: an electrographic, clinical and pathological study. Electroencephalogr Clin Neurophysiol 1964; 17:177-93. Chatrian GE, Bergamini L, Dondey M et al. A glossary of terms most commonly used by clinical electroencephalographers. Electroencehalogr Clin Neurophysiol 1989; 73:403-9. Chiofalo N, Fuentes A, Galvez S. Serial EEG findings in 27 cases of Cretuzfeldt-Jakob disease. Arch Neurol 1980; 37:143-5. Choi SH, Na DL, Chung CS et al. Diffusion-weighted MRI in vascular dementia. Neurology 2000; 54:83-9. Chrysikopoulos HS, Press GA, Grafe MR et al. Encephalitis caused by human immunodeficiency virus: CT and MR imaging manifestations with clinical and pathological confirmation. Radiology 1990; 175:185-91. Chu NS. Periodic lateralized epileptiform discharges with preexisting focal brain lesions: role of alcohol withdrawal and anoxic encephalopathy. Arch Neurol 1980; 37:551-4. Cobb WA. The periodic events of subacute sclerosing panencephalitis. Electroencephalogr Clin Neurophysiol 1966; 21:278-94. Cobb WA, Hill D. Electroencephalogram in subacute progressive encephalitis. Brain 1950; 73:392-404. Cobb WA, Guiloff RJ, Cast J. Breach rhythm: the EEG related to skull defects. Electroencephalogr Clin Neurophsyiol 1979; 47:251-71. Cooper R, Winter AL, Crown JJ et al. Comparison of subcortical, cortical and scalp activity using indwelling electrodes in man. Electroencephalogr Clin Neurophysiol 1965; 18:217-28. Crain M, Yuh W, Greene G et al. Cerebral ischemia: evaluation with contrast enhanced MR imaging. AJNR 1991; 12:631-5. Dalby MA. Epilepsy and three per second spike and wave rhythms. A clinical electroencephalographic and prognostic evaluation of 346 patients. Acta NeurolScand 1969; 45(suppl 40):1-180. Daly DD, Thomas JE. Sequential alterations in the electroencephalograms of patients with brain tumors. Electroencephalogr Clin Neurophysiol 1958; 10:395-404. Dean BL, Drayer BP, Bird CR. Gliomas: classification with MR imaging. Radiology 1990; 174:411-15. Deisenhammer E, Jelinger K. EEG in senile dementia. Electroencephalogr Clin Neurophysiol 1974; 36:91-3. Dejong RN. The neurologic examination, 4th edn. New York: Harper & Row, 1979. Dempsey EW, Morrison RS. The production of rhythmically recurrent cortical potentials after localized thalamic stimulation. AmJ Physiol 1942; 135:293-300. Devinsky 0, Sato S, Kufta CV et al. Electroencephalographic studies of simple partial seizures with subdural electrode recordings. Neurology 1989; 39:527-33. Dillon EH, van Leeuwen MS, Fernandez MA et al. Spiral CT angiography: pictorial essay. AJR 1993; 160:1273-8. Dolinskas C, Bilaniuk LT, Zimmerman RA et al. Computed tomography of intracerebral hematomas. I. Transmission CT observations of hematoma resolution. AJR 1977; 129:681-8. Edelman RR, Warach S. Magnetic resonance imaging. N Engl J Med 1993; 328:708-16. Ellingson RJ, Wilken K, Bennet DR. Efficacy of sleep deprivation as an activation procedure in epilepsy patients. J Clin Neurophysiol 1984; 2:83-101. Elster AD. Magnetic resonance contrast enhancement of cerebral infarction. Neurol Clin N.A. 1994; 4:89-100. Evans CC. Spontaneous excitation of the visual cortex and association areas- lambda waves. Electroencephalogr Clin Neurophysiol 1953; 5:69-74. Fazekas F, Schmidt R, Offenbacher H et al. Prevalence of white matter and periventricular magnetic resonance hyperintensities in asymptomatic volunteers. J Neuroimag 1991; 1:27-9. Fisch BJ, Klass DW. The diagnostic specificity of triphaisc wave patterns. Electroencephalogr Clin Neurophysiol 1988; 70:1-8.

42 Diagnostic assessment Fisch BJ, Hauser WA, Brust JCM et al. The EEG response to diffuse and patterned photic stimulation during acute untreated alcohol withdrawal. Neurology 1989; 39:434-6. Fisher M, Albers GW. Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke. Neurology 1999; 52:1750-6. Fisher M, Sotak CH. Diffusion-weighted MR imaging and ischemic stroke. AJNR 1992; 13:1103-5. Franceschi M,Triulzi F, Ferini-Strambi L et al. Focal cerebral lesions found by magnetic resonance imaging in cryptogenic nonrefractory temporal lobe epilepsy patients. Epilepsia 1989; 30:540-6. Frost JD, Carrie JRG, Borda RP et al. The effects of Dalmane(flurazepam hydrochloride) on human EEG characteristics. Electroencephalogr Clin Neurophysiol 1973; 34:171-5. Gabor AJ, Ajmone-Marsan C. Co-existence of focal and bilateral diffuse epileptiform discharges in epileptics. Epilepsia 1969; 10:453-72. Gasecki AP, Steg RE. Correlation of early MRI with CT scan, EEG and CSF: analyses in a case of biopsyproven herpes simplex encephalitis. Eur Neural 1991; 31:372-5. Gastaut H, Trevisan C, Naquet R. Diagnostic value of electroenephalographic abnormalities provoked by intermittent photic stimulation. Electroencephalogr Clin Neurophsiol 1958; 10:194-5. Gastaut H, Roger J, Soulayrol R et al. Childhood epileptic encephalopathy with diffuse slow spike-waves (otherwise known as 'petit mal variant') or Lennox syndrome. Epilepsia 1966; 7:139-79. Geiger LR, Horner RN. EEG pattern at the time of focal seizure onset. Arch Neurol 1978; 35:276-86. Gibbs FA, Gibbs EL, Lennox WG. Electroencephalographic classification of epileptic patients and control subjects. Arch Neurol Psychiatry 1943; 50:111-28. Gibbs FA, Rich CL, Gibbs EL. Psychomotor variant type of seizure discharge. Neurology 1963;

13:991-8. Gillispie J, Jackson A. MRI and CT of the brain. London: Arnold, 2000. Gilmore PC, Brenner RP. Correlation of EEG, computerized tomography, and clinical findings: a study of 100 patients with focal delta activity. Arch Neurol 1981; 38:371-2. Goldberg HH, Strauss H. Distribution of slow activity induced by hyperventilation. Electroencephalogr Clin Neurophysiol 1959; 11:615. Goldman D. The clinical use of the 'average' reference electrode in monopolar recording. Electroencephalogr Clin Neurophysiol 1950; 2:209-12. Gomori M, Grossman Rl, Goldberg HI et al. High field magnetic resonance imaging of intracranial hematomas. Radiology 1985; 157:87-93. Goodin DS, Aminoff MJ. Does the interictal EEG have a role in the diagnosis of epilepsy? Lancet 1984; 1:837-9. Goodin DS, Aminoff MJ, Laxer KD. Detection of epileptiform activity by different non-invasive EEG methods in complex partial epilepsy. Ann Neurol 1990; 27:330. Graif M, Steiner RE. Contrast-enhanced magnetic resonance imaging of the central nervous system: a clinical review. BrJ Psychiatry 1986; 59:865-73. Green J. Some observations on lambda waves and peripheral stimulation. Electroencephalogr Clin Neurophysiol 1957; 9:691-704. Greenberg SB, Taber L, Septimus E et al. CT in brain biopsy-proven herpes simplex encephalitis. Early normal results. Arch Neurol 1981; 38:58-9. Greenblatt DJ, Ehrenberg BL, Gunderman J et al. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo. Clin Pharmacol Ther 1989; 45:356-65. GriesingerW. Mental pathology and therapeutics. New York: William Wood, 1882. Grossman Rl, Braffman BH, Brorson JR et al. Multiple sclerosis: serial study of gadolinium-enhanced MR imaging. Radiology 1988; 169:117-22. Guilleux M-H, Steiner RE, Young IR. MR imaging in progressive multifocal leukoencephalopathy. AJNR 1986;7:1033-5. Guttmann CRG, Abn SS, Hsu let al. Evolution of multiple sclerosis lesions on serial MRI. AJNR 1995; 16:1481-91.

Diagnostic assessment 43 Haskett RF. Diagnostic categorization of psychiatric disturbance in Cushing's syndrome. AmJ Psychiatry 1985;142:911-16. Haughton VM, Rimm AA, Sobodnski KA et al. A blinded clinical comparison of MR imaging and CT in neuroradiology. Radiology 1986; 160:751-5. Hecaen H, Penfield W, Bertrand C et al. The syndrome of apractagnosia due to lesions of the minor cerebral hemisphere. Arch Neurol Psychiatry 1956; 75:400-34. Heier LA, Bauer CJ, Schwartz J et al. Large Virchow-Robin spaces: MR-clinical correlation. AJNR 1989;

10:929-36. Heilman KM. Ideational apraxia-a re-definition. Brain 1973; 96:861-4. Hershey LA, Gado MH, Trotter JL. Computerized tomography in the diagnostic evaluation of multiple sclerosis. Ann Neurol 1979; 5:32-9. Holland BA, KucharcyzkW, Brant-Zawadzki M et al. MR imaging of calcified intracranial lesions. Radiology 1985; 157:353-6. Homan RW, Jones MC, Rawat S. Anterior temporal electrodes in complex partial seizures. Electroencephalogr Clin Neurophysiol 1988; 70:105-9. Hopf HC, Muller-Forell W, Hopf NJ. Localization of emotional and volitional facial paresis. Neurology

1992; 42:1918-23. Hopkins A, Shorvon S, Cascino G. Epilepsy, 2nd edn. London: Arnold, 1995. Hounsfield GN. Computerized transverse axial scanning (tomography). I. Description of the system. Br J Psychiatry 1972; 46:1016-22. Hughes JR. Usefulness of photic stimulation in routine clinical electroencephalography. Neurology 1960; 10:777-82. Huttenlocher PR, Taravath S, Mojjahedi S. Periventricular heterotopia and epilepsy. Neurology 1994; 44:51-5. Jasper H. Diffuse projection systems: the integrative action of the thalamic reticular system. Elecroencephalogr Clin Neurophysiol 1949; 1:405-20. Jasper HH. The ten-twenty electrode system of the International Federation. Electroencephalogr Clin Neurophysiol 1958; 10:371-3. Johnson MH. CT evaluation of the earliest signs of stroke. Radiologist 1994; 1:189-99. Jungreis CA, Kanal E, Hirsch W et al. Normal perivascular spaces mimicking lacunar infarction: MR imaging. Radiology 1988; 169:101-4. Kaibara M, Blume WT. The postictal electroencephalogram. Electroencephalogr Clin Neurophsyiol 1988; 70:99-104. Kales A, Bixler EO, Tan TL et al. Chronic hypnotic drug use. Ineffectiveness, drug-withdrawal insomnia and dependence. JAMA 1974; 227:513-17. Karnatze DS, Bickford RG. Triphasic waves: a reassessment of their clinical significance. Electroencephalogr Clin Neurophysiol 1984; 57:193-8. Katz D,Taubenberger JK, Cannella B et al. Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol 1993; 5:661-9. Kelly AB, Zimmerman RD, Snow RB et al. Head trauma: comparison of MR and CT-experiencein 100 patients. AJNR 1988; 9:699-708. Kennard MA, Beuding E, Wortis SB. Some biochemical and electroencephalographic changes in delirium tremens. Q J Stud Alcohol 1945; 6:4-14. Kermode AG, Thompson AJ, Tofts P et al. Breakdown of the blood-brain barrier precedes symptoms and other magnetic resonance imaging signs of new lesions in multiple sclerosis. Brain 1990; 113:1477-89. Kinkel W, Jacobs L, Polachini I et al. Subcortical arteriosclerotic encephalopathy (Binswanger's disease): computed tomographic, nuclear magnetic resonance, and clinical correlation. Arch Neurol 1985; 42:951-9. Klass DW, Bickford RG. Observations on the rolandicarceau rhythm. Electroencephalogr Clin Neurophysiol 1957; 9:570.

44 Diagnostic assessment Klass DW, Westmoreland BF. Nonepileptogenic epileptiform electroencephalographicactivity. Ann Neurol 1985; 18:627-35. Knott JR. Further thoughts on polarity, montagesand localization. J Clin Neurophysiol 1985; 2:63-75. Kooi KA, Thomas MH, Mortensen FN. Photoconvulsive and photomyoclonic responses in adults. An appraisal of their clinical significance. Neurology 1960; 10:113-40. Kraepelin E. Psychiatry. A textbook for students and physicians, 1899, translated by Metoui H, Ayed S. Canton, MA: Science History Publications, 1990. Kraepelin E. Manic-depressive insanity and paranoia, translated by Barclay RM. Edinburgh: E&S Livingstone, 1921. Republished by Arno Press, New York, 1976. Krup LB, Lipton RB, Swerlow ML et al. Progressive multifocal leukoencephalopathy: clinical and radiographic features. Ann Neurol 1985; 17:344-9. Kuroiwa Y, Celesia G. Clinical significance of periodic EEG patterns. Arch Neurol 1980; 37:15-20. Lai CW, Gragasin ME. Electroencephalography in herpes simplex encephalitis. J Clin Neurophysiol 1988; 5:87-103. Laplane D, Degos JD. Motor neglect. J Neurol Neurosurg Psychiatry 1983; 46:152-8. Leavitt S, Tyler H. Studies in asterixis. Arch Neurol 1964; 10:360-8. Lesser RP, Luders H, Dinner DS et al. An introduction to the basic concepts of polarity and localization. J Clin Neurophysiol 1985; 2:45-61. Levy A, Lightman SS. Diagnosis and management of pituitary tumors. BMJ 1994; 308:1087-91. Levy SR, Chiappa KH, Burke CJ et al. Early evolution and incidence of electroencephalographic abnormalities in Creutzfeldt-Jakob disease. J Clin Neurophysiol 1986; 3:1-21. Lombroso CT, Schwartz IH, Clark DM et al. Ctenoids in healthy youths: Controlled study of 14- and 6-per second positive spiking. Neurology 1966; 16:1152-8. MacDonnell RAL, Donnan GA, Baldin Pf et al. The electroencephalogram in acute ischemic stroke. Arch Neurol 1988; 45:520-4. MacLean PD. A nasopharyngeal lead. Electroencephalogr Clin Neurophysiol 1949; 1:110-12. Magnus 0. The cerebral alpha-rhythm ('rhythme en arceau'). Electroencephalogr Clin Neurophysiol 1954; 6:349-50. Markand ON, Daly DD. Pseudo-periodic lateralized paroxysmal discharges in electroencephalogram. Neurology 1971; 21:975-81. Markand ON, Panzi JG. The electroencephalogram in subacute sclerosing panencephalitis. Arch Neurol 1975;32:719-26. Martins da Silva A, Aarts JH, Binne CD et al. The circadian distribution of interictal epileptiform EEG activity. ElectroencephalogrClin Neurophsyiol 1984; 58:1-13. Matsuo F, Knott JR. Focal positive spikes in electroencephalography. Electroencephalogr Clin Neurophysiol 1977; 42:15-25. Matsuo F, Peters JF, Reilly EL. Electrical phenomena associated with movements of the eyelid. Electroencephalogr Clin Neurophysiol 1975; 38:507-11. Mattson RH, Pratt KL, Calverley JR. Electroencephalograms of epileptics following sleep deprivation. Arch Neurol 1965; 13:310-15. Meier-Ewart R, Broughton RJ. Photomyoclonic response of epileptic and nonepileptic subjects during wakefulness, sleep, and arousal. Electroencephalogr Clin Neurophysiol 1976; 23:301-4. Meyer JS, Gotham J, Tazaki Y et al. Cardiorespiratory syndrome of extreme obestiy with papilledema. Neurology 1961; 11:950-8. Miley CM, Forster FM. Activation of complex partial seizures by hyperventilation. Arch Neurol 1977; 34:371-3. Miller DH, Rudge P, Johnson G et al. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 1988; 111:927-39. Mittl RL, Grossman Rl, Hieble JF et al. Prevalence of MR evidence of diffuse axonal injury in patients with mild head injury and normal CT findings. AJNR 1994; 15:1583-9.

Diagnostic assessment 45 Morgan MH, Scott DF. EEG activation in epilepsies other than petit mal. Epilepsia 1970; 11:255-61. Mostrum V, Ytterbergh C. Artifacts in computed tomography of the posterior fossa: a comparative phantom study. J Comput Assist Tomogr 1986; 10:560-6. Mushlin Al, Detsky AS, Phelps CE et al. The accuracy of magnetic resonance imaging in patients with suspected multiple sclerosis. JAMA 1993; 269:3146-51. Nesbit GM, Forbes GS, Scheithauer BW et al. Multiple sclerosis: histopathologic and MR and/or CT correlation in 37 cases at biopsy and three cases at autopsy. Radiology 1991; 180:467-74. Neumann-Haefelin T, Moseley ME, Albers GW. New magnetic resonance imaginig methods for cerebrovascualr disease: emerging clinical applications. Ann Neurol 2000; 47:559-70. Nickel SN, Frame B. Neurologic manifestations of myxedema. Neurology 1958; 8:511-17. Noguchi K, Ogawa T, Inugami A et al. Acute subarchnoid hemorrhage: MR imaging with fluid-attenuated inversion recovery pulse sequences. Radiology 1995; 196:773-7. Oliveira-Filho J, Ay H, Schaeffer PW et al. Diffusion-weighted magnetic resonance imaging identifies the 'clinically relevant' small-penetratorinfarcts. Arch Neurol 2000; 57:1009-14. Ormerod IEC, Miller DH, McDonald Wl et al. The role of NMR imaging in the assessment of multiple sclerosisand isolated neurological lesions. Brain 1987; 110:1579-616. Patel MR, Edelman RR, Warach S. Detection of hyperacute primary intraparenchymal hemorrhage by magnetic resonance imaging. Stroke 1996; 27:2321-4. Phelps ME, Hoffman EJ, Ter-Pogossian MM. Attenuation coefficients of various body tissues, fluids and lesions at photon energies of 18 keV to 136 keV. Radiology 1975; 117:537-83. PojunasKW, Daniels DL, Williams AL et al. MR imaging of prolactin-secretingmicroadenomas. AJNR

1986; 7:209-13. Porter SB, Sande MA. Toxoplasmosis of the central nervous system. N EnglJ Med 1992; 327:1643-1648. Pratt KL, Mattson RH, Weikers NJ et al. EEG activation of epileptics following sleep deprivation: a prospective study of 114 cases. Electroencephalogr Clin Neurophysiol 1968; 24:11-15. Pro JD, Wells CE. The use of the electroencephalogram in the diagnosis of delirium. Dis Nerv Syst 1977; 38:804-8. Purpura DP, Grundfest H. Nature of dendritic potentials and synaptic mechanism in cerebral cortex of cat. J Neurophysiol 1956; 19:573-95. Pykett IL NMR imaging in medicine. Sci Am 1982; 246:78-88. Pykett SL, Newhouse JH, Buonanno BS et al. Principles of nuclear magnetic imaging. Radiology 1982; 143:157-68. Rathmell TK, Burns MA. The Laurence-Moon-Biedl syndrome occurring in a brother and a sister. Arch Neurol Psychiatry 1938; 39:1033-42. Rechtschaffen A, Kales A. A manual of standardized terminology, technique and scoring system for sleep stages of human subjects. Washington DC: US Government Printing Office, 1968. Reiher J, Lebel M. Wicket spikes: clinical correlates of a previously undescribed EEG pattern. Can J Neurol Sci 1977; 4:39-47. Risinger MW, Engel J, Van Ness PC et al. Ictal localization of temporal lobe seizures with scalp sphenoidal recordings. Neurology 1989; 39:1288-93. Robinson WP, Bottani A, Yagang X. Molecular, cytogenetic, and clinical investigations of Prader-Willi syndrome patients. Am J Hum Genet 1992; 49:1219-34. Romano J, Engel GL. Delirium, I: electroencephalographic data. Arch Neurol Psychiatry 1944; 51:356377. Ross ED. The aprosdias: functional-anatomic organization of the affective components of language in the right hemisphere. Arch Neurol 1981; 38:561-9. Saenz-Lope E, Herranz-Tanarro FJ, Masdeu JC et al. Hyperekplexia: a syndrome of pathological startle responses. Ann Neurol 1984; 15:36-41. Sammaritano J, Gigli GL, Gotman J. Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology 1991; 41:290-7.

46 Diagnostic assessment Schear HE. The EEG pattern in delirium tremens. Clin Electroencephalog 1985; 16:30-2. Scott DF, Groetheysen UC, Bickford RG. Lambda responses in the human electroencephalogram. Neurology 1967; 17:770-8. Seddigh S, Thomke F, Vogt Th. Complex partial seizures provoked by photic stimulation. J Neurol Neurosurg Psychiatry 1999; 66:801-2. Seyffarth H, Denny-Brown D. The grasp reflex and the instinctive grasp reaction. Brain 1948; 71:109-83. Silverman D. The anterior temporal electrode and the ten-twenty system. Electroencephalogr Clin Neurophysiol 1960; 12:735-7. Singer MB, Chong J, Lu D et al. Diffusion-weighted MRI in acute subcortical infarction. Stroke 1998;

29:133-6. Smith A. The serial sevens subtraction test. Arch Neurol 1962; 17:78-80. Sorensen AG, Buonanno FS, Gonzalez RG et al. Hyperacute stroke: evaluation with combined multidirection diffusion-weighted and hemodynamically weighted echo-planar MR imaging. Radiology 1996; 199:391-401. Sperling MR, Engel J. Electroencephalographic recordings from the temporal lobe: a comparison of ear, anterior temporal and nasopharyngeal electrodes. Ann Neurol 1985; 17:510-13. Sperling MR, Mednius JR, Engel J. Mesial temporal spikes: a simultaneous comparison of sphenoidal, nasopharyngeal and ear electrodes. Epilepsia 1986; 27:81-6. Spillane JD. Nervous and mental disorders in Cushing's syndrome. Brain 1951; 74:72-94. Steinhoff BJ, Racker S, Herrendorf G et al. Accuracy and reliability of periodic sharp wave complexes in Creutzfeldt-Jakob disease. Arch Neurol 1996; 53:162-6. Steriade M, Gloor P, Llinas RD et al. Basic mechanisms of cerebral rhythmical activities. Electroencephalogr Clin Neurophysiol 1990; 76:481-508. Stevens JR. Central and peripheral factors in epileptic discharge: clinical studies. Arch Neurol 1962; 7:330-8. Summerskill WHJ, Davidson EA, Sherlock S et al. The neuropsychiatric syndrome associated with hepatic cirrhosis and extensive portal circulaton. QJ Med 1956; 25:245. Sze G, Milano E, Johnson C et al. Detection of brain metastases: comparison of contrast-enhanced MR with unenhanced MR and enhanced CT.AJNR1990; 11:785-91. Tchang S, Scotti G, Terbrugge K et al. Computed tomography as a possible aid to histological grading of supratentorial tumors. J Neurosurg 1977; 46:735-9. Tegner R, Levander M. The influence of stimulus properties on visual neglect. J Neurol Neurosurg Psychiatry 1991; 54:882-7. Thomas JE, Klass DW. Six-per-second spike-and-wave pattern in the electroencephalogram: a reappraisal of its clinical significance. Neurology 1968; 18:587-93. Thompson AJ, Miller D, Youl B et al. Serial gadolinium-enhanced MRI in relasping/remitting multiple sclerosis of varying disease duration. Neurology 1992; 42:60-3. Tien RD, Felsberg GJ, Osumi AK. Herpes virus infection of the CNS: MR findings. AJR 1993; 161:283-9. Upton A, Gumpert J. Electroencephalography in diagnosis of herpes simplex encephalitis. Lancet 1970; 1:650-2. Valler G, Rusconi ML, Bignamimi L et al. Anatomical correlates of visual and tactile extinction in humans: a clinical CT scan study. J Neurol Neurosurg Psychiatry 1994; 57:464-70. van der Wee N, Rinkel GJ, Hasan D et al. Detection of subarachnoid hemorrhage on early CT: is lumbar puncture still needed after a negative scan? J Neurol Neurosurg Psychiatry 1995; 58:357-9. van Gijn J, van Dongen KJ. The time course of aneurysmal hemorrhage on computed tomograms. Neuroradiology 1982; 23:153-6. Vassilouthis J, Ambrose J. Computerized tomography scanning appearances of intracranial meningiomas: an attempt to predict the histological features. J Neurosurg 1979; 50:320-7. Veldhuizen R, Binnie CD, Beintema DJ. The effect of sleep deprivation on the EEG in epilepsy. Electroencephalogr Clin Neurophysiol 1983; 55:505-12.

Diagnostic assessment 47 Vignaendra V, Mathews RL, Chatrian GE. Positive occipital sharp transients of sleep: relationships to nocturnal sleep cycle in man. Electroencephalogr Clin Neurophysiol 1974; 37:239-46. Walsh JM, Brenner RP. Periodic lateralized epileptiform discharges- long-term outcome in adults. Epilepsia 1987; 28:533-6. Walshe FMR, Robertson EG. Observations upon the form and nature of the 'grasping' movements and 'tonic innervation' seen in certain cases of lesions of the frontal lobe. Brain 1933; 56:40-70. Warach S, Chien D, Li W et al. Fast magnetic resonance diffusion weighted imaging of acute brain stroke. Neurology 1992; 42:1717-21. Warach S, Gaa J, Stewart B et al. Acute human stroke studied by whole echo-planar diffusion weighted imaging. Ann Neurol 1995; 37:231-41. Wasenko JJ, Rosenbloom SA, Duchesneau PM et al. The Sturge-Weber syndrome: comparison of MR and CT characteristics. AJNR 1990; 11:131-4. Westmoreland BF, Klass DW. A distinctive rhythmic EEG discharge of adults. Electroencephalogr Clin Neurophysiol 1981; 51:186-91. White JC, Langston JW, Pedley TA. Benign epileptiform transients of sleep: clarification of the small sharp spike controversy. Neurology 1977; 17:1061-8. Wiedemann H-R, KunzeJ, Grosse f-R et al. An atlas of clinical syndromes, 3rd edn. St Louis: Mosby-Wolfe, 1989. Will RG, lonsideJW, Zeidler M et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996;

347:921-5. Wilson SA. Modern problems in neurology. London, Edward Arnold, 1928. Wolf P, Gooses R. Relation of photosensitivity to epileptic syndromes. J Neurol Neurosurg Psychiatry 1986; 49:1386-91. Yoneda Y, Tokui K, HaniharaTet al. Diffusion-weighted magnetic resonance imaging: detection of ischemic injury 39 minutes after onset in a stroke patient. Ann Neurol 1999; 45:794-7. Young IR, Hall AS, Pallis CA et al. Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet 1981; 2:1063-6. Zimmerman RD, Floeming CA, Saint-Louis LA et al. Magnetic resonance imaging of meningiomas. AJNR 1985; 6:149-157. Zimmerman RD, Bilaniuk LT, Hackney DB et al. Head injury: early results of comparing CT and high-field MR.AJNR 1986; 7:757-764. Zivin L, Ajmone-Marsan C. Incidence and prognostic significance of 'epileptiform' activity in the EEG of non-epileptic subjects. Brain 1968; 91:751-79. Zochodne DW, Young GB, McLachlan RS et al. Creutzfeldt-Jakob disease without periodic sharp wave complexes: a clinical, electroencephalographicand pathologic study. Neurology 1988; 38:1056-60. Zurek R, Schiemann-Delgado J, Froescher W et al. Frontal intermittent rhythmical delta activity and anterior bradyarrythmia. Clin Electroencephalogr 1985; 16:1-10.


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

51 80 137 186 254 285


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

51 55 57 58 59

Hypergraphia Aprosodia Apraxia Agnosias Neglect

59 60 62 63 68

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


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).


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.


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:


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.


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.


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


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.'


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).


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.


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'.


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


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.


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.


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


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


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,


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).

REFERENCES Achiron A, Ziv l, Djaldetti R et al. Aphasia in multiple sclerosis: clinical and radiologic correlation. Neurology 1992; 42:2195-7. Agnetti V, Carreras M, Pinna L et al. Ictal prosopagnosia and epileptogenic damage of the dominant hemisphere. Cortex 1978; 14:50-7. Agostoni E, Coletti A, Orlando G et al. Apraxia in deep cerebral lesions. J Neurol Neurosurg Psychiatry

1983; 46:804-8.

'Cortical' signs and symptoms 71 Ajax ET. Acquired dyslexia. Arch Neurol 1964; 11:66-72. Ajax ET, Schenkenberg T, Kosteljanetz M. Alexia without agraphia and the inferior splenium. Neurology

1977;27:685-8. Albert ML A simple test of visual neglect. Neurology 1973; 23:658-64. Albert ML, Soffer D, Silverberg R et al. The anatomic basis of visual agnosia. Neurology 1979; 29:876-9. Alexander MP, LoVerme SR. Aphasia after left hemispheric intracerebral hemorrhage. Neurology 1980; 30:1193-202. Alexander MP, Schmitt MA. The aphasia syndrome of stroke in the left anterior cerebral artery territory. Arch Neurol 1980; 37:97-100. Alexander MP, Fischette MR, Fischer RS. Crossed aphasias can be mirror image anomalous: case reports, review and hypothesis. Brain 1989; 112:953-73. Alsaadi T, Binder JR, Lazar RM et al. Pure topographic disorientation: a distinctive syndrome with varied localization. Neurology 2000; 54:1864-6. Anderson B. Pieces of the true crossover effect in neglect. Neurology 1997; 49:809-12. Anderson SW, Damasio AR, Damasio H. Troubled letters but not numbers. Domain specific cognitive impairments following focal damage in the frontal cortex. Brain 1990; 113:749-66. Assal G, Perentes E, Deruaz J-P. Crossed aphasia in a right-handed patient. Arch Neurol 1981; 38:455-8. Astrom K-E, Mancall EL, Richardson EP. Progressive multifocal leukoencephalopathy: a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain 1958; 81:93-111. Bahls FH, Chatrian GE, Mesher RA et al. A case of persistent cortical deafness: clinical, neurophysiologic, and neuropathologic observations. Neurology 1988; 38:1490-3. Bakar M, Kirshner HS, Wertz RT. Crossed aphasia: functional brain imaging with PET or SPECT. Arch Neurol 1996; 53:1026-32. Bakchine S, Ctassaro I, Seilhan D. Anosognosia for hemiplegia after a brainstem haematoma: a pathological case. J Neurol Neurosurg Psychiatry 1997; 63:686-7. Bakwin H. Reading disability in twins. Dev Med Child Neurol 1973; 15:184-7. Balo J. Encephalitis periaxialis concentrica. Arch Neurol Psychiatry 1928; 19:242-64. Bartak L, Rutter M, Cox A. A comparative study of infantile autism and specific developmental receptive language disorders. I. The children. BrJ Psychiatry 1975; 126:127-45. Bender MB. Extinction and precipitation of cutaneous sensations. Arch Neurol Psychiatry 1945; 54:1-9. Benito-Leon J, Sanchez-Suarez C, Dias-Guzman J et al. Pure alexia could not be a disconnection

syndrome. Neurology 1997; 49:395-6. Benson DF. Psychiatric effects of dysphasia. BrJ Psychiatry 1973; 123:555-66. Benson DF, Geschwind N. Developmental Gerstmann syndrome. Neurology 1970; 20:293-8. Benson DF, Wier WF. Acalculalia: acquired anarithmetia. Cortex 1972; 8:465-72. Benson DF, Sheremata WA, Bouchard Ret al. Conduction aphasia: a clinicopathological study. Arch Neurol 1973; 28:339-46. Benson DF, Segarra J, Albert ML. Visual agnosia-prosopagnosia. A dinicopathologic correlation. Arch

Neurol 1974; 30:307-10. Bergman PS. Cerebral blindness. Arch Neurol Psychiatry 1957; 78:568-84. Beschin N, Cubelli R, Delia Sala S et al. Left of what? The role of egocentric coordinates in neglect. J Neurol Neurosurg Psychiatry 1997; 63:483-9. Bigley GK, Sharp FR. Reversible alexia without agraphia due to migraine. Arch Neurol 1983; 40:114-15. Binder J, Marshall R, Lazar R et al. Distinct syndromes of hemineglect. Arch Neurol 1992; 49:1187-94. Bisiach E, Luzzatti C. Unilateral neglect of representational space. Cortex 1978; 14:129-33. Bogousslavsky J. Global aphasia without other lateralizing signs. Arch Neurol 1988; 45:143. Bogousslavsky J, Regli F. Anterior cerebral artery territory infarction in the Lausanne stroke registry: clinical and etiologic considerations. Arch Neurol 1990; 47:144-50.

72 Signs, symptoms and syndromes Bogousslavsky J, Regli F, Uske A. Thalamic infarcts: clinical syndromes, etiology, and prognosis. Neurology 1988a; 38:837-48. Bogousslavsky J, Regli F, Assal G. Acute transcortical mixed aphasia: a carotid occlusion syndrome with pia and watershed infarcts. Brain 1988b; 111:631-41. Bogousslavsky J, Miklossy J, Regli F et al. Subcortical neglect: neuropsychological, SPECT, and neuropathological correlations with anterior choroidal artery territory infarction. Ann Neurol 1988c; 23:448-52. Brain WR. Visual disorientation with special reference to lesions of the right cerebral hemisphere. Brain 1941;64:244-72. Brock S, Merwarth HR. The illusory awareness of body parts in cerebral disease. Arch Neurol Psychiatry 1957;77:366-75. Brown JR, Simonson J. A clinical study of 100 aphasic patients: observations on lateralization and localization of lesions. Neurology 1957; 7:777-83. Brown JW, Wilson FR. Crossed aphasia in a dextral: a case report. Neurology 1973; 23:907-11. Caplan LR, Schmahmann JD, Kase CS et al. Caudate infarcts.ArchNeurol 1990; 47:133-43. Cappa SF, Perani D, Bressi S et al. Crossed aphasia: PET follow up study of two cases. J Neurol Neurosurg Psychiatry 1993; 56:665-71. Caselli RJ. Ventrolateral and dorsomedial somatosensory association cortex damage produces distinct somesthetic syndromes in humans. Neurology 1993; 43:762-71. Celesia G, Brigell MG, Vaphiades MS. Hernianopic anosognosia. Neurology 1997; 49:88-97. Cherington MS. Single case study: visual neglect in a chess player.J Nerv Ment Dis 1974; 159:145-7. Ciemens VA. Localized thalamic hemorrhage: a case of aphasia. Neurology 1970; 20:776-82. Cohen DN, Salanga VD, Hully W et al. Alexia without agraphia. Neurology 1976; 26:455-9. Cohen L, Gray F, Meyrignal C et al. Selective deficity of visual size perception: two cases of hemimicropsia. J Neurol Neurosurg Psychiatry 1994; 57:73-8. Cohen M, Campbell R, Yaghmai F. Neuropathological abnormalities in developmental dysphasia. Ann Neurol 1989; 25:567-70. Cohn R, Neumann MA, Wood DH. Prosopagnosia: a clinicopathological study. Ann Neurol 1986; 20:177-82. Cole M. Specific educational disability involving spelling. Neurology 1964; 14:968-70. Corbett AJ, McCosker EA, Davidson OR. Acalculalia following a dominant-hemisphere subcortical infarct. Arch Neurol 1986; 43:964-6. Coslett HB, Saffran E. Simultanagnosia: to see but not to see. Brain 1991; 114:1523-45. Coslett HB, Brashear HR, Heilman KM. Pure word deafness after bilateral primary auditory cortex infarcts. Neurology 1984; 34:347-52. Critchley M. Phenomenon of tactile inattention with special reference to parietal lesions. Brain 1949; 72:538-61. Cutting J. Study of anosognosia.J Neurol Neurosrug Psychiatry 1978; 41:548-55. Daffner KR, Ahern GL, Weintraub S et al. Dissociated neglect behavior following sequential stroke in the right hemisphere. Ann Neurol 1990; 28:97-101. Damasio H, Damasio AR. The anatomical basis of conduction aphasia. Brain 1980; 30:337-50. Damasio AR, Damasio H. The anatomic basis of pure alexia. Neurology 1983; 33:73-83. Damasio AR, Yamada T, Damasio H et al. Central achromatopsia: behavioral, anatomic and physiologic aspects. Neurology 1980; 30:1064-71. Damasio AR, Damasio H, Rizzo M et al. Aphasia with nonhemorrhagic lesion in the basal ganglia and internal capsule. Ann Neurol 1982a; 39:15-20. Damasio AR, Damasio H, Van Hoesen GW. Prosopagnosia: anatomic basis and behavioral mechanisms. Neurology 1982b; 32:331-41. Darby DG. Sensory aprosodia: a clinical clue to lesions of the inferior division of the right middle cerebral artery? Neurology 1993; 43:567-72.

'Cortical' signs and symptoms 73 De Benito R, Fisch CB, Fisch ML Developmental Gerstmann's syndrome. Arch Neurol 1988; 45:977-82. De Renzi E, Lucchelli F. Ideational apraxia. Brain 1988; 111:1173-85. DeRenzi E, Faglioni P, Scarpa M et al. Limb apraxia in patients with damage confined to the left basal ganglia or thalamus.J Neurol Neurosurg Psychiatry 1986; 49:1030-8. Devere TD, Trotter JL, Cross AH. Acute aphasia in multiple sclerosis. Arch Neurol 2000; 57:1207-9. Devinsky O, Kelley K,Yacubia EMT et al. Postictal behavior. Arch Neurol 1994; 51:254-9. Drew AL A neurological appraisal of familial congenital word-blindness. Brain 1956; 79:440-60. Euyapan D, Kumral D. Pontine anosognosia for hemiplegia. Neurology 1999; 53:647-9. Evans JJ, Heggs AJ, Antoun N et al. Progressive prosopagnosia associated with selective right temporal lobe atrophy: a new syndrome? Brain 1995; 118:1-13. Faber-Langendoen K, Morris JC, Knesevich JW et al. Aphasia in senile dementia of the Alzheimer type. Ann Neurol 1988; 23:365-70. Feinberg TE, Haber LD, Leeds NE. Verbal asomatognosia. Neurology 1990; 40:1391-4. Feinberg TE, Roane DM, Ali J. Illusory limb movements in anosognosia for hemiplegia. J Neurol Neurosurg Psychiatry 2000; 68:511-13. Ferro JM, Kertesz A. Posterior internal capsule infarction associated with neglect. ArchNeurol1984; 41:422-4. Fincham RW, Nibelink DW, Aschenbrenner CA. Alexia with left homonymous hemianopia without agraphia. Neurology 1975; 25:1164-8. Frantz KE. Amnesia for left limbs and loss of interest and alteration in left fields of vision.J Nerv Ment Dis 1950; 112:240-4. Freedman M, Alexander MP, Naeser MA. Anatomic basis of transcortical motor aphasia. Neurology 1984; 34:409-17. Fukui T, Sugita K, Kawamura M et al. Primary progressive apraxia in Pick's disease: a clinicopathologic report. Neurology 1996; 47:467-73. Gabr M, LudersH, Dinner D et al. Speech manifestations in lateralizaton of temporal lobe seizures. Ann Neurol 1989; 25:82-7. Galaburda AM, Sherman GF, Rosen GD et al. Developmental dyslexia: four consecutive patients with cortical anomalies. Ann Neurol 1985; 18:222-33. Galton CJ, Patterson K, Xuereb JH et al. Atypical and typical presentations of Alzheimer's disease: a clinical, neuropsychological, neuroimaging and pathological study. Brain 2000; 123:484-98. Gerson SN, Benson DF, FrazierSH. Diagnosis: schizophrenia versus posterior aphasia. Am J Psychiatry 1977;134:966-9. Gerstmann J. Syndrome of finger agnosia, disorientation for right and left, agraphia and acalculalia. Arch Neurol Psychiatry 1940; 44:398-408. Gerstmann J. Problem of misperception of disease and of impaired body territories with organic lesions: relation to body scheme and its disorders. Arch Neurol Psychiatry 1942; 48:890-913. Gerstmann J. Some notes on the Gerstmann syndrome. Neurology 1957; 7:866-9. Geschwind N. Disconnexion syndromes in animals and man. 6ra/A?1965; 88:585-644. Geschwind N, Fusillo M. Color-naming defects in association with alexia./Ard? Neurol 1966; 15:137-46. Ghika-Schmid F, Bogousslavsky j. The acute behavioral syndrome of anterior thalamic infarction: a propsective study. Ann Neurol 2000; 48:220-7. Giroud M, Dumas R. Clinical and topographical range of callosal infarction: a clinical and radiological correlation study.) Neurol Neurosurg Psychiatry 1995; 59:238-42. Godefroy 0, Rousseaux M, PruvoJPef a/. Neuropsychological changes related to unilateral lenticulostriate infarcts.y Neurol Neurosurg Psychiatry 1994; 57:480-5. Goldstein DM, Goldberg RL. Monoamine oxidase inhibition-induced speech blockage.) Clin Psychiatry 1986; 47:604. Goodglass H, Quadfasel FA. Language laterally in left-handed aphasics. Brain 1954; 77:521-48. Goody W, Reinhold M. Congenital dyslexia and asymmetry of cerebral function. Brain 1961; 84:231—42.

74 Signs, symptoms and syndromes Gorelick PB, Ross ED. The aprosodias: further functional-anatomical evidence for the organization of affective language in the right hemisphere.) Neurol Neurosurg Psychiatry 1987; 50:553-60. Graff-Radford NR, Damasio AR, Hyman Bletal. Progressive aphasia in a patient with Pick's disease: a neuropsychological, radiologic and anatomic study. Neurology 1990; 40:620-6. Green J, Morris JC, Sandson J etal. Progressive aphasia: a precursor of global dementia? Neurology 1990;

40:423-9. Greenblatt SH. Alexia without agraphia or hemianopsia. Brain 1973; 96:307-16. Greenblatt SH. Subangular alexia without agraphia or hemianopia. Brain Lang 1976; 3:229-^45. Greene JDW, Patterson K, Xuereb J et al. Alzheimer disease and nonfluent progressive aphasia. Arch Neurol 1996; 53:1072-8. Hamilton NG, Mathews T. Aphasia: the sole manifestation of focal status epilepticus. Neurology 1979; 29:745-8. Hanlon RE, Lux WE, Dromerick AW. Global aphasia without hemiparesis: language profiles and lesion distribution. 7 Neurol Neurosurg Psychiatry 1996; 66:365-9. Hecaen H, Angelergues R. Agnosia for faces (prosopagnosia)./4rd) Neurol 1962; 7:92-100. Hecaen H, Penfield W, Bertrand Cetal. The syndrome of apractagnosia due to lesions of the minor cerebral hemisphere. Arch Neurol Psychiatry 1956; 75:400-34. Healton EB, Navarro C, Bressman Set al. Subcortical neglect. Neurology 1982; 32:776-8. Heilman KM. Ideationalapraxia-a re-definition. Brain 1973; 96:861^. Heilman KM, Valenstein E. Frontal lobe neglect in man. Neurology 1972; 22:660^. Heilman KM, Rothi L, McFarlingDefo/. Transcortical sensory aphasia with relatively spared spontaneous speech and naming. Arch Neurol 1981; 38:236-9. Hemphill RE, Stengel E. A study on pure word deafness.) Neurol Neurosurg Psychiatry 1940; 3:251-62. Henderson VW. Speech fluency in crossed aphasia. Brain 1983; 106:837-57. Henderson VW, Friedman RB, Teng EL et al. Left hemisphere pathways in reading: inferences from pure alexia without hemianopia. Neurology 1985; 35:962-8. Hermann BP, Whitman S, Wyler AR et al. The neurological, psychosocial and demographic correlates of hypergraphia in patients with ep\\epsy.J Neurol Neurosurg Psychiatry 198; 51:203-8. Hier DB, Mondlock J, Caplan LR. Behavioral abnormalities after right hemisphere stroke. Neurology 1983a; 33:337-44. Hier DB, Mondlock J, Caplan LR. Recovery of behavioral abnormalities after right hemisphere stroke. Neurology 1983b; 33:345-50. Hindson DA, Westmoreland DE, Carroll WA et al. Persistent Broca's aphasia after right cerebral infarction in a right-hander. Neurology 1984; 34:387-9. Holmes JE, Sadoff RL. Aphasia due to a right hemisphere tumor in a right-handed man. Neurology 1966; 16:392-7. House A, Hodges J. Persistent denial of hardship after infarction of the right basal ganglia: a case study. J Neurol Neurosurg Psychiatry 1988; 51:112-15. Humphrey ME, ZangwillOL. Dysphasia in left-handed patients with unilateral brain lesions. J Neurol Neurosurg Psychiatry 1952; 15:184-93. Ikeda K, Akiyama H, Iritani Setal. Corticobasal degeneration with primary progressive aphasia and accentuated cortical lesion in superior temporal gyrus: case report and review. Acta Neuropathol 1996; 92: 534-9. Imamura T, Yamadori A, Tsuburaya K. Hypergraphia associated with a brain tumor of the right cerebral hemisphere. J Neurol Neurosurg Psychiatry 1992; 54:25-7. Iragui VJ, Kritchevsky M. Alexia without agraphia or hemianopia in parietal infarction. J Neurol Neurosurg Psychiatry 1991; 54:841. Ishiai S, Sugishita M, Ichikawa Jet al. Clock-drawing test and unilateral spatial neglect. Neurology 1993; 43:106-10.

'Cortical' signs and symptoms 75 Ishiai S, Seki K, Koyama Y etal. Disappearance of unilateral spatial neglect following a simple instruction.) Neurol Neurosurg Psychiatry 1997; 63:23-7. Jacome DE. Aphasia with elation, hypermusia, musicophilia and compulsive whistling, y Neurol Neurosurg Psychiatry 1984; 47:308-10. Kanshepolsky J, Kelley JJ, Waggener JD. A cortical auditory disorder: clinical, audiologic and pathologic aspects. Neurology 1973; 23:699-705. Karbe H, Kertesz A, Polk M. Profiles of language impairment in primary progressive aphasia. Arch Neurol

1993;50:192-201. Karlin IW. Congential verbal-auditory agnosia. Pediatrics 1951; 7:60-8. Karnath HO, Hartje W. Decrease of contralateral neglect by neck muscle vibration and spatial orientation of trunk midline. Brain 1993; 116:383-96. Kertesz A, Hudson L, Mackenzie IRAef al. The pathology and nosology of primary progressive aphasia. Neurology 1994; 44:2065-72. Kinsbourne M, Warrington EK. A disorder of simultaneous form perception. Brain 1962b; 85:461-86. Kinsbourne M, Warrington EK. A variety of reading disability associated with right hemisphere lesions. J Neurol Neurosurg Psychiatry 1962a; 25:339-44. Kinsbourne M, Warrington EK. Observations on color agnosia. J Neurol Neurosurg Psychiatry 1964; 27:296-9. Knight RT, Cooper J. Status epilepticus manifesting as reversible Wernicke's aphasia. Epilepsia 1986;

27:301^. Kraepelin E. Dementia praecoxandparaphrenia. Huntington, NY: Robert E. Krieger, 1971. Kraepelin E. Manic-depressive insanity and paranoia. NY: Arno Press, 1976. Krupp LB, Lipton RB, Swerdlwo Mletal. Progressive multifocal leukoencephalopathy: clinical and radiologic features. Ann Neurol 1985; 17:344-9. Labar DR, Solomon GE, Wells CR. Aphasia as the sole manifestation of simple partial status epilepticus. Epilepsia 1992; 33:84-7. Lampl Y, Eshel Y, Gilad R et al. Selective acalculalia with sparing of the subtraction process in a patient with left parietotemporal hemorrhage. Neurology 1994; 44:1759-61. LandisT, CummingsJL, Benson Dfetal. Loss of topographic familiarity: an environmental agnosia. Arch Neurol 1986; 43:132-6. LandisT, Regard M, Bliestle A et al. Prosopagnosia and agnosia for noncanonical views. Brain 1988;

111:1287-97. Laplane D, Degos JD. Motor neglect. J Neurol Neurosurg Psychiatry 1983; 46:152-8. Lederman RJ, Henry CE. Progressive dialysis encephalopathy. Ann Neurol 1978; 4:199-204. Leegard OF, Riis JO, Andersen G. Pure alexia without hemianopia of colour anomia. Acta NeurolScand 1988; 78:501-5. Le Gros Clark WE, Russell WR. Cortical deafness without aphasia. Brain 1938; 61:375-83. Levine DN, Calvanio R, Rinn WE. The pathogenesis of anosognosia for hemiplegia. Neurology 1991; 41:1770-81. McCarthy R, Warrington EK. Visual associative agnosia: a clinico-anatomical study of a single case. J Neurol Neurosurg Psychiatry 1986; 49:1233-40. McFie J, Piercy MF, Zangwill OL. Visual spatial agnosia associated with lesions of the right cerebral hemisphere. Brain 1950; 73:167-90. MaeshimaS, Funahashi K, Ogura M et al. Unilateral spatial neglect due to right frontal lobe hematoma. J Neurol Neurosurg Psychiatry 1994; 57:89-93. Malone DR. Morris HH, Kay MC et al. Prosopagnosia: a double dissociation between the recognition of familiar and unfamiliar faces. J Neurol Neurosurg Psychiatry 1982; 45:820-2. Mandell AM, Alexander MP, Carpenter S. Creutzfeldt-Jakob disease presenting as isolated aphasia.

Neurology 1989; 39:55-8.

76 Signs, symptoms and syndromes Mantovani JF, Landau WM. Acquired aphasia with convulsive disorder: course and prognosis. Neurology 1980;30:524-9. Marshall W, Ferguson JH. Hereditary word-blindness as a defect of selective association.J Nerv Ment Dis 1939;89:164-73. Masdeu JC, O'Hara RJ. Motor aphasia unaccompanied by faciobrachial weakness. Neurology 1983; 33:519-21. Mayer E, Martory M-D, Pegna AJ et al. A pure case of Gerstmann's syndrome with a subangular lesion. Brain 1999; 122:1107-20. Meadows JC. Disturbed perception of colours associated with localized cerebral lesions. Brain 1974a;

97:615-32. Meadows JC. The anatomical basis of prosopagnosia.J Neurol Neurosurg Psychiatry' 1974b; 37:489-501. MegensJ, van Loon J, GoffinJ et al. Subcortical aphasia from a thalamic abscess. J Neurol Neurosurg Psychiatry 1992; 55:319-22. Mendez MF, Zander BA. Dementia presenting with aphasia: clinical characteristics. J Neurol Neurosurg Psychiatry 1991; 54:542-5. Meyer B, Krai T, Zentner J. Pure word deafness after resection of a tectal plate glioma with preservation of wave V of brain stem auditory evoked potentials.7 Neurol Neurosurg Psychiatry 1996; 61:423-^. Mohr JP, Pessin MP, Finkelstein Set al. Broca aphasia: pathologic and clinical. Neurology 1978; 28:311-24. Monrad-Krohn GH. Dysprosody or altered 'melody of language'. Brain 1947a; 70:405-15. Monrad-Krohn GH. The prosodic quality of speech and its disorders. Acta Psychiatr NeurolScam/ 1947b; 22:255-69. Motomura N, Yamadori A, Mori E et al. Unilateral spatial neglect due to hemorrhage in the thalamic region. Acta Neurol Scand 1986; 74:190-4. Nadeau SE, Reltgen DP, Sevush S etal. Apraxia due to a pathologically documented thalamic infarction. Neurology 1994; 44:2133-7. Naeser MA, Hayward RW. Lesion localization in aphasia with cranial computed tomography and the Boston diagnostic aphasia exam. Neurology 1978; 28:545-51. Naeser MA, Alexander MP, Helm-Estabrooks N et al. Aphasia with predominantly subcortical lesion sites: description of three capsular/putaminal aphasia syndromes. Arch Neurol 1982; 39:2-14. Navia BA, Petito CK, Gold JWM etal. Cerebral toxoplasmosis complicating the acquired immunodeficiency syndrome: clinical and neuropathological findings in 27 patients. Ann Neurol 1986;19:224-38. Neary D, Snowden JS, Mann DMA. Familial progressive atrophy: its relationship to other forms of lobar atrophy. J Neurol Neurosurg Psychiatry 1993; 56:1122-5. O'Hare JA, Callaghan NM, Murnaghan DJ. Dialysis encephalopathy. Clinical, electroencephalographic, and interventional aspects. MedidneWSl; 62:129-41. OkamuraT, Fukai M, Yamadori A etal. A clinical study of hypergraphia \nep\\epsy.J Neurol Neurosurg Psychiatry 1993; 56:556-9. Olmos-Lau N, Ginsberg MD, Geller JB. Aphasia in multiple sclerosis. Neurology 1977; 27:623-6. Oppenheimer DR, Newcombe F. Clinical and anatomic findings in a case of auditory agnosia. Arch Neurol 1978; 35:712-19. Orton ST. 'Word blindness' in school children./4/t/? Neurol Psychiatry 1B25; 14:581-615. Paquier PF, Van Dongen HR, Loonen CB. The Landau-Kleffner syndrome or 'acquired aphasia with convulsive disorder': long-term follow-up of six children and a review of the recent literature. Arch Neurol 1992; 49:354-9. Paul R, Cohen DJ, Caparulo BK. A longitudinal study of patients with severe developmental disorders of language \earn\r\g.JAmAcadChildPsychiatry 1983; 22:525-34. Pedersen PM, Jorgensen HS, Nakayama H etal. Aphasia in acute stroke: incidence, determinants, and recovery. Ann Neurol 1995; 38:659-66.

'Cortical' signs and symptoms 77 PevznerS, Bornstein B, Loewenthal M. Prosopagnosia. J Neurol Neurosurg Psychiatry 1962; 25:336-8. Piercy M, Hecaen H, de Ajuriaguerra J. Constructional apraxia with unilateral cerebral lesions - left and right sided cases compared. Brain 1960; 83:225-42. Pillon B, Bakchine S, Lhermitte F. Alexia without agraphia in a left-handed patient with a right occipital lesion. Arch Neurol 1987; 44:1257-62. Platz T. Tactile agnosia: casuistic evidence and theoretical remarks on modality-specific meaning representations and sensorimotor integration. Brain 1996; 119:1565-74. Price BH, Gurvit H, Weintraub Set at. Neuropsychological patterns and language deficits in 20 consecutive cases of autopsy-confirmed Alzheimer's disease. Arch Neurol 1993; 50:931-7. Privitera MD, Morris GL, Gilliam F. Postictal language assessment and lateralization of complex partial seizures. Ann Neurol 1991; 30:391-3. Racy A, Jannotta FS, Lehner LH. Aphasia resulting from occlusion of the left anterior cerebral artery: report of a case with an old infarct in the left rolandic region. Arch Neurol 1979; 36:221^4. Redlich FC, DorseyJF. Denial of blindness by patients with cerebral disease. Arch Neurol Psychiatry 1945;53:407-17. Reed CL, Caselli RJ, Farah MJ. Tactile agnosia: underlying impairment and implications for normal tactile object recognition. Brain 1996; 119:875-88. Riley DE, Lang AE, Lewis A etal. Cortical-basal ganglionic degneration. Neurology 1990; 40:1203-12. RinneJO, Lee MS, Thompson PDetal. Corticobasal degeneration: a clinical study of 36 cases. Brain 1994; 117:1183-96. Roeltgen DP, SevushS, Heilman KM. Pure Gerstmann's syndrome form a focal lesion. Arch Neurol 1983; 40:46-67. Rosati G, De Bastiani P. Pure agraphia: a discrete form of aphasia.) Neurol Neurosurg Psychiatry 1979; 42:266-9. Rosati G, De Bastiani P, Paolino E etal. Clinical and audiological findings in a case of auditory agnosia.7 Neurol 1982; 227:21-7. Rosier A, Lanquillon S, Dippel Oetal. Impairment of facial recognition in patients with right cerebral infarcts quantified by computer aided 'morphing'.y Neurol Neurosurg Psychiatry 1997; 62:261—4. Ross ED. Left medial parietal lobe and receptive language functions: mixed transcortical aphasia after left anterior cerebral artery infarction. Neurology 1980; 30:144-51. Ross ED. The aprosodias: functional-anatomic organization of the affective components of language in the right hemisphere. Arch Neurol IW]; 38:561-9. Ross ED, Mesulam M-M. Dominant language functions of the right hemisphere: prosody and emotional gesturing./Ard? Neurol 1979; 36:144-8. Ross ED, HarneyJH, deLacoste-UtamsingCefo/. How the brain interprets affective and propositional language into a unified behavioral function: hypothesis based on clinicoanatomic evidence. Arch Neurol 1981; 38:745-8. Ross ED, Anderson B, Morgan-Fisher A. Crossed aprosodia in strongly dextral patients. Arch Neurol 1989; 46:206-9. RossSJM, Graham N, Stuart-Green letal. Progressive biparietal atrophy: an atypical presentation of Alzheimer's disease. 7 Neurol Neurosurg Psychiatry 1996; 61:388-95. Roth N. Unusual types of anosognosia and their relation to the body image.) Nerv Ment Dis 1944;

100:35^3. Roth N. Disorders of body image caused by lesions of the right parietal lobe. Brain 1949; 72:89-111. Rubens AB. Aphasia with infarction in the territory of the anterior cerebral artery. Cortex 1975; 11:239-50. Rubens A, Benson DF. Associative visual agnosia. Arch Neurol 1987; 24:305-16. RumseyJM, Donohue BC, Brady DR etal. A magnetic resonance imaging study of planum temporale asymmetry in men with developmental dyslexia. Arch Neurol 1997; 54:1481—4. Sandifer PH. Anosognosia and disorders of body scheme. Brain 1946; 68:122-37.

78 Signs, symptoms and syndromes Sato S, Dreifuss FE. Electroencephalographic findings in a patient with developmental expressive aphasia. Neurology 1973; 23:181-5. Schatzberg AF, Cole JO, Blumer DP. Speech blockage: a tricyclic side effect. Am J Psychiatry 1978; 135:600-1. Schwarz M, De Bleser R, Poeck K et al. A case of primary progressive aphasia: a 14-year follow-up study with neuropathological findings. Brain 1998; 121:115-26. Seines OA, Knopman DS, Miccum Netal. The central role of Wernicke's area in sentence repetition. Ann Neurol 1985; 17:549-57. SergentJ, Poncet M. From covert to overt recognition of faces in prosopagnosia. Brain 1990; 113:989. SergentJ, VillemureJG. Prosopagnosia in a right hemispherectomized patient. Brain 1989; 112:975-95. Silverberg R, Gordon HW. Differential aphasia in two bilingual individuals. Neurology 1979; 29:51-5. Smith A. The serial seven subtraction test. Arch Neurol 1962; 17:78-80. SnowdenJS, Neary D, Mann DMhetal. Progressive language disorder due to lobar atrophy. Ann Neurol 1992; 31:174-83. Speedie LJ, Wertman E, Ja'\r \etal. Disruption of automatic speech following a right basal ganglia lesion. Neurology 1993; 43:1768-74. Starkstein SE, Federoff JP, Price JRetal. Neuropsychological and neuroradiologic correlates of emotional prosody comprehension. Neurology 1994; 44:515-22. Stein S, Volpe BT. Classical 'parietal' neglect syndrome after subcortical right frontal lobe infarction. Neurology 1983; 33:797-9. Stommel EW, Friedman RJ, Reeves AG. Alexia without agraphia associated with spleniogeniculate infarction. Neurology 1991; 41:587-8. Stone SP, Wilson B, Wroot A etal. The assessment of visuo-spatial neglect after acute stroke. J Neurol Neurosurg Psychiatry 1991; 54:345-50. Stracciari A, Lorusso S, Pazzaglia P. Transient topographical amnesia. J Neurol Neurosurg Psychiatry

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;

38:800-2.

'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


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).


'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


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


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.


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).


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.


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).


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.


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.


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.


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.


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


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.


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


(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


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,


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.


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


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


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


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).


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


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.


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).


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


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).


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).


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.


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


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


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


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


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.


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).


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).

REFERENCES Abad V, Ovsiew F. Treatment of persistent myoclonic tardive dystonia with verapamil. Br J Psychiatry 1993; 162:554-6. Abd El Naby S, Hassanein M. Neuropsychiatric manifestations of chronic manganism. J Neurol Neurosurg Psychiatry 1965; 28:282-5. Abilleira S, Viguera ML, Miquel F. Myoclonus induced by tacrine. J Neurol Neurosurg Psychiatry 1998;

64:280. Abrams R, Taylor MA. Catatonia. A prospective clinical study. Arch Gen Psychiatry 1976; 33:579-81. Adams RD, Foley J. The neurological changes in the more common types of liver disease. Trans Am Neurol Assoc 1949; 74:217-19. Adams RD, Foley JM. The neurological disorder associated with \\verd\sease.Assoc Res Nerv Ment Dis Proc 1953; 32:198-237. Adler LA, Angrist B, Peselow E et al. Efficacy of propranolol in neuroleptic-induced akathisia. j Clin Psychopharmacol 1985; 5:164-6. Adler LA, Angrist B, Peselow E et al. Controlled assessment of propranolol in the treatment of neuroleptic-induced akathisia. Br J Psyhiatry 1986; 149:42-5. Adler LA, Peselow E, Rosenthal M et al. A controlled comparison of the effects of propranolol, benztropine and placebo on akathisia: an interim analysis. Psychopharmacol Bull 1993; 29:283-6. Aguglia U, Tinuper P, Gastaut H. Startle-induced epileptic seizures. Epilepsia 1984; 25:712-20. Alberca RA, Chinchon I, Vadillo j et al. Late onset parkinsonian syndrome in Hallervorden-Spatz Disease. J Neurol Neurosurg Psychiatry 1987; 50:1665-8. Alpers BJ, Patten CA. Paroxysmal spasm of the eyelids as a postencephalitic manifestation. Arch Neurol Psychiatry 1927; 18:427-32. Antin SP, Prockop LD, Cohen SM. Transient hemiballism. Neurology 1967; 17:1068-72.

Abnormal movements 119 Armon C, Shin C, Miller P et al. Reversible parkinsonism and cognitive impariment with chronic valproate use. Neurology 1996; 47:626-35. Aronson MJ, Thompson SV. Complications of acute catatonic excitement. Am J Psychiatry 1950; 107:216-20. Austen FK, Carmichael MW, Adams RD. Neurologic manifestations of chronic pulmonary insufficiency. N EnglJ /Wed 1957; 257:579-90. Ayd FJ. A survey of drug-induced extrapyramidal reactions. J Am Med Assoc 1961; 175:1054-60. Bacchus M. Encephalopathy and pulmonary disease. Arch Int Med 1958; 102:194-8. Bachman DS. Pemoline-induced Tourette's disorder: a case report Am J Psychiatry 1981; 138:1116-17. Bain PG, Findley LJ, Thompson PD et al. A study of hereditary essential tremor. Brain 1994; 117:805-24. Bak TH, Bauer M, Schaub RT et al. Myoclonus in patients treated with clozapine: a case series. J Clin Psychiatry 1995; 56:418-22. Baldassano CF, Truman CJ, Nierenberg A et al. Akathisia: a review and case report following paroxetine treatment. Compr Psychiatry 1996; 37:122-4. Ballard PA Tetrud JW, Langston JW. Permanent human parkinsonism due to 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 1985; 35:949-56. Barak Y, Levine J, Weisz R. Clozapine-induced myoclonus: two case reports. J Clin Psychopharmacol 1996; 16:339-0. Barnes MP, Saunders M, Walls TJ et al. The syndrome of Karl Ludwig Kahlbaum.y Neurol Neurosurg Psychiatry 1986; 49:991-6. Bartholomew RE. Disease, disorder or deception? Latah as habit in a Malay extended family. J Nerv Ment Dis 1994; 182:331-8. Becher MW, Rubinsztein DC, Leggo J et al. Dentatorubral and pallidoluysian atrophy (DRPLA): clinical and neuropathological findings in genetically confirmed North American and European pedigrees. Mov Disord 1997; 12:519-30. Bedwell SF. Some observations on hemiballismus. Neurology I960; 10:619-22. Behan PO, Bone I. Hereditary chorea without dementia. J Neurol Neurosurg Psychiatry 1977; 40:687-91. Belfer ML, d'Autremont CC. Catatonia-like symptomatology. Arch Gen Psychiatry 1971; 24:119-20. Benesch CG, McDaniel KD, Cocdetal. End-stage Alzheimer's disease: Glasgow coma scale and neurologic examination. Arch Neurol 1993; 50:1309-15. Benito-LeonJ, Rodriguez J, Orti-Pareja M et al. Symptomatic orthostatic tremor in pontine lesions. Neurol 1997; 49:1439-41. Berger JR, Ross DB. Reversible Parkinson syndrome complicating postoperative hypoparathyroidism. Neurology 1981; 31:881-2. Berger JR, Sheremata WA, Melamed E. Paroxysmal dystonia as the inital manifestation of multiple sclerosis. Arch Neurol 1984; 41:747-50. Berkovic SF, Andermann F, Carpenter S et al. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med 1986; 315:296-305. Berkovic SF, Carpeneter S, Evans A et al. Myoclonus epilepsy and ragged-red fibers (MERRF). Brain 1989; 112:1231-60. Bharucha KJ, Sethi KD. Tardive Tourettism after exposure to neuroleptic therapy. Mov Disord 1995; 10:791-3. Bhatia KP, Soland VL, Bhatt MH. Paroxysmal exercize-induced dystonia: eight new sporadic cases and a review of the literature. Mov Disord 1997a; 12:1007-12. Bhatia KP, Quinn NP, Marsden CD. Clinical features and natural hsitory of axial predominant adult onset primary dystonia. J Neurol Neurosurg Psychiatry 1997b; 63:788-91. Bhatt MH, Obeso JA, Marsden CD. Time course of postanoxic akinetic-rigid and dystonic syndromes. Neurology 1993; 43:314-17. Bhatt MH, Elias MA, Mankodi AK. Acute and reversible parkinsonism due to organophosphate pesticide intoxication. Five cases. Neurology 1999; 52:1467-71.

120 Signs, symptoms and syndromes Biggins CA, Boyd JL, Harrop FM et al. A controlled, longitudinal study of dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry 1992; 55:566-71. Bird MT, Paulson JW. The rigid form of Huntington's chorea. Neurology 1971; 21:271-6. Bland EF, Jones TD. The natural history of rheumatic fever: a 20 year perspective. Ann Int MedV352; 37:1006-26. Bleuler E. Textbook of psychiatry, 1924, translated by Brill AA. New York: Arno Press, 1976. Bocola V, FabbriniG, SolledtoAefo/. Neuroleptic induced parkinsonism: MRI find ings in relation to clinical course after withdrawal of neuroleptic drugs. J Neurol Neurosurg Psychiatry 1996; 60:213-16. Boecker H, Weindl A, Leenders K et al. Secondary parkinsonism due to focal substantia nigra lesions: a PET study with [18F]FDG and [18F]flourodopa. Acta Neurol Scand 1996; 93:387-92. Bond ED. Epidemic encephalitis and katatonic symptoms. Am J Insanity 1920; 76:261-4. Bort RF. Catatonia, gastric hyperacidity, and fatal aspiration: a preventable syndrome. Amy Psychiatry 1976;133:446-7. Bourgeois M, Bouilh P, Tignul J et al. Brief communication: spontaneous dyskinesias vs. neurolepticinduced dyskinesias in 270 elderly patients. J Nerv Ment Dis 1980; 168:177-6. Boyer WF, Bakalar NH, Lake CR. Anticholinergic prophylaxis of acute haloperidol-induced dystonic reactions. J Clin Psychopharmacon987; 7:164-6. Brashear A, Farlow MR, Butler I et al. Variable phenotype of rapid-onset dystonia-parkinsonism. Mov Disord 1996; 11:151-6. Brashear A, DeLeon D, Bressman SBetal. Rapid-onset dystonia-parkinsonism in a second family. Neurology 1997; 48:1066-9. Braude WM, Barnes TRE, Gore SM. Clinical characteristics of akathisia: a systematic investigation of acute psychiatric in-patient admissions. BrJ Psychiatry 1983; 143:139-50. Bressman SB, Fahn S, Burke RE. Paroxysmal non-kinesigenic dystonia./U/v/vewro/1988; 50:403-13. Bruetsch WL, Williams CL Arteriosclerotic muscular rigidity with special reference to gait disturbances. Am J Psychiatry 1954; 111:332-6. Brown P, Cathala F, Castaigne P et al. Creutzfeldt-Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann Neurol 1986; 20:597-602. Brown P, Rothwell JC, Thompson PD et al. The hyperekplexias and their relationship to the normal startle reflex. Brain 1991; 114:1903-28. BucherSF, Seelos KC, Dodel RCetal. Pallidal lesions: structural and functional magnetic resonance imaging. Arch Neurol 1996; 53:682-6. Buetefisch CM, Gutierrez A, Gutmann L Choreoathetotic movements: a possible side-effect of gabapentin. Neurology 1996; 46:851-2. Burke RE, Fahn S, Gold AP. Delayed-onset dystonia in patients with 'static' encephalopathy.y Neurol Neurosurg Psychiatry 1980; 43:789. Burke RE, Fahn S, Jankovic J efo/.Tardive dystonia: late-onset and persistent dystonia caused by antipsychotic drugs. Neurology 1982; 32:1335-46. Burke RE, Kang UJ, Jankovic J et al. Tardive akathisia: an analysis of clinical features and response to open therapeutic trials. Mov Disord 1989; 4:147-75. BurkhardtCR, FilleyCM, Kleineschmidt-DemastersBKef al. Diffuse Lewy body disease and progressive dementia. Neurology 1988; 38:1520-8. Byrne EJ, Lennox G, LoweJ et al. Diffuse Lewy body disease: clinical features in 15 cases../ Neurol Neurosurg Psychiatry 1989; 52:709-17. Campbell AMG, Corner B, Norman RM et al. The rigid form of Huntington's disease.) Neurol Neurosurg Psychiatry 1961; 24:71-7. Caparros-Lefebvre D, DeleumeJF, Bradai Netal. Ballism caused by bilateral infarction in the substantia nigra. Mov Disord 1994; 9:108. Cardoso F, Jankovic J. Cocaine-related movement disorders. Mov Disord 1993; 8:175-8.

Abnormal movements 121 Cardoso F, Veado CCM, de Oliveira JT. A Brazilian cohort of patients with Tourette's syndrome. 7 Neural Neurosurg Psychiatry W96; 60:209-12. Cardoso F, Eduardo C, Silva AP etal. Chorea in fifty consecutive patients with rheumatic fever. Mov Disord 1997; 12:701-3. Carella F, Grass! MP, Savoiardo M etal. Dystonic-parkinsonian syndrome after cyanide poisoning: clinical and MRI findings.] NeurolNeurosurgPsychiatry 1988; 51:1345-8. Carpenter MB. Ballism associated with partial destruction of the subthalamic nucleus of Luys. Neurology 1955;5:479-89. Carpenter MB, Carpenter CS. Analysis of somatotopic relations of the corpus Luysi in man and monkey. J Comp Neurol 1951; 95:349-70. Carpenter MR. Athetosis and the basal ganglia. Arch Neurol 1950; 63:895-901. Casas M, Garcia-Ribera C, Alvarez E etal. Myoclonic movements as a side-effect of treatment with therapeutic doses of clomipramine. IntJ PsychopharmacolWSJ; 2:333-6. Castillo E, Rubin RT, Holsboer-Trachsler E. Clinical differentiation between lethal catatonia and neuroleptic malignant syndrome. Am J Psychiatry 1989; 146:324-8. Chan DB, Lang MF, Fahn S. Idiopathic cervical dystonia. Mov Disord 1991; 6:119-26. Chandra V, Wharton S, Spunt AL. Amelioration of hemiballismus with sodium valproate. Ann Neurol 1982; 12:407. Chang M-H, LiJ-Y, Lee S-R etal. Non-ketotichyperglycaemic chorea: a SPECT study. J Neurol Neruosurg Psychiatry 1996; 60:428-30. Charles JR. Manganese toxaemia, with special reference to the effects of liver feeding. Brain 1927; 50:30-43. Chen J-Y, Stern Y, Sano M etal. Cumulative risks of developing extrapyramidal signs, psychosis, or myoclonus in the course of Alzheimer's disease. Arch Neurol 1991; 48:1141-3. Chiu LPW. Transient recurrence of auditory hallucinations during acute dystonia. BrJ Psychiatry 1989; 155:110-13. Choi IS. Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neurol 1983; 40:433-5. Chokroverty S, Bruetman ME, BergerVetal. Progressive dialytic encephalopathy.J Neurol Neurosurg Psychiatry 1976; 39:411-19. Chouinard S, Ford B. Adult onset tic disorders. J Neurol Neurosurg Psychiatry 2000; 68:738^3. Choy-Kwong M, Lipton RB. Dystonia related to cocaine withdrawal: a case report and pathogenic hypothesis. Neurology 1989; 39:996-7. Chudnow RS, Dewey RB, Lawson CR. Choreoathetosis as a side-effect of gabapentin therapy in severely neurologically impaired patients. Arch Neurol 1997; 54:910-12. Clark CM, Ewbank D, Lerner A et al. The relationship between extrapyramidal signs and cognitive performance in patients with Alzheimer's disease enrolled in the CERAD study. Neurology 1997; 49:70-5. Cohen LG, Hallett M. Hand cramps: clinical features and electromyographic patterns in a focal dystonia. Neurology 1988; 38:1005-12. Cohen L, Mouly S, Tassan P et al. A woman with a relapsing psychosis who got better with prednisone. Lancet 1996; 347:1228. Collins SJ, Ahlskog JE, Parisi JE et al. Progressivesupranuclear palsy: neuropathologically based diagnostic clinical criteria. J Neurol Neurosurg Psychiatry 1995; 58:167-73. Colosimo C, Albanese A, Hughes AJ el al. Some specific clinical features differentiate multiple system atrophy (striatonigral variety) from Parkinson's disease. Arch Neurol 1995; 52:294-8. Cornelia CL, GoetzCG. Akathisia in Parkinson's disease. Mov Disord 1994; 9:545-9. Creak M, Guttmann E. Chorea, tic, compulsive utterances. J MentSci 1935; 81:834-9. Critchley EMR, Clark DB, Wikler A. Acanthocytosis and neurological disorder without abetalipoproteinemia./4rd?A/ewra/1968; 18:134-40. Crozier S, Lehericy S, Verstichel P etal. Transient hemiballism/hemichorea due to ipsilateral subthalamic nucleus infarction. Neurology 1996; 46:267-8.

122 Signs, symptoms and syndromes Crystal HA, Dixon DW, Lizard! JE et al. Antemortem diagnosis of diffuse Lewy body disease. Neurology 1990; 40:1523-8. Cunningham MA, Darby DG, Donnan GA. Controlled-release delivery of L-dopa associated with nonfatal hyperthermia, rigidity and autonomic dysfunction. Neurology 1991; 41:942-3. Daniel SE, de Bruin VMS, Lees AJ. The clinical and pathological specturm of Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy): a reappraisal. Brain 1995; 118:759-70. Daras M, Koppel BS, Atos-Radzion E. Cocaine-induced choreoathetoid movements ('crack dancing'). Neurology 1994; 44:751-2. Davis EJB, Borde M. Wilson's disease and catatonia. BrJ Psychiatry 1993; 162:256-9. DavisJM. Response of hemiballismustohaloperidol.y>4/VM 1976; 235:281-2. Davous P, Rondot P, Marion MH et al. Severe chorea after acute carbon monoxide poisoning. J Neurol Neurosurg Psychiatry 1986; 49:206-8. Dawson JR. Cellular inclusions in cerebral lesions of epidemic encephalitis. Arch Neurol Psychiatry 1934;

31:685-700. DeCastro RM. Antidepressants and myoclonus: case report../ Clin Psychiatry\98S; 46:284-7. Defazio G, Berardelli A, AbruzzeseGef al. Risk factors for spread of blepharospasm: a multicentre investigation of the Italian movement disorders study group.) Neurol Neurosurg Psychiatry 1999;

67:613-9. DegosJ-D, VerroustJ, BouchareineAefa/. Asterixis in focal brain lesion. Arch Neurol 1979; 36:705-7. De La Sayettte V, Schaeffer S, Querel C et al. Lyme neuroborreliosis presenting with propriospinal myoclonus.y Neurol Neurosurg Psychiatry 1996; 64:420. Delwaide PJ, Desseilles M. Spontaneous buccolingualfacial dyskinesia in the elderly. Acta NeurolScand 1977;56:256-62. deMari M, De Blasi R, Lamberti Petal. Unilateral pallidal lesion after acute disulfiram intoxication: a clinical and magnetic resonance imaging study. Mov Disorders 1993; 8:247-9. Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol 1995; 38:571-9. Denckla MB, Bemporad JR, MacKay MC. Tics following methylphenidate administration: a report of 20 cases. JAMA 1976; 235:1349-51. Dennis MS, Byrne EJ, Hopkinson EN et al. Neuropsychiatric systemic lupus erythematosis in elderly people: a case series. J Neurol Neurosurg Psychiatry 1992; 55:1157-61. Deshmukh DK, Joshi VS, Agarwal MR. Rabbit syndrome-a rare complication of long-term neuroleptic medication. BrJ Psychiatry 1990; 157:293. Deuschl G, Koester B, Luecking CH et al. Diagnostic and pathophysiological aspects of psychogenic tremor. Movement Disord 1998; 13:294-302. Dewey RB, Jankovic J. Hemiballism-hemichorea. Clinical and pharmacologic findings in 21 patients. Arch Neurol 1989; 46:862-7. Dickoff DJ, Raps M, Yahr MD. Striatal syndrome following hyponatremia and its rapid correction: a manifestation of extrapontine myelinolysis confirmed by magnetic resonance imaging. Arch Neurol 1988;45:112-14. Dierssen G, Gioini GG. Cooper IS. Participation of ipsilateral hemisphere lesions in the pathology of hemichoreaand hemiballism./Veuro/ogy 1961; 11:894-8. Digre KB. Opsoclonus in adults- report of three cases and review of the literature. Arch Neurol 1986; 43:1165-75. DiMascio A, Bernardo DL, Greenblatt DJ et al. A controlled trial of amantadine in drug-induced extrapyramidal disorders. Arch Gen Psychiatry 1976; 33:599-602. Donaldson IM, Espiner EA. Disseminated lupus erythematosus presenting as chorea gravidarum. Arch Neurol 1971; 25:240-4. Donlon PT. The therapeutic use of diazepam for akathisia. Psychosomatics 1973; 14:222-5.

Abnormal movements 123 Pooling EC, Adams RD. Pathologic anatomy or posthemiplegic athetosis. Brain 1975; 98:29-48. DoolingEC,SchoeneWC, Richardson EP. Halervorden-Spatzsyndrome. Arch Neurol 1974; 30:70-83. Drake RE, Ehrlich J. Suicide attempts associated with akathisia. Am J Psychiatry 1985; 142:499-501. Dufresne RL, Wagner RL Antipsychotic-withdrawal akathisia versus antipsychotic-induced akathisia: further evidence for the existence of tardive akathisia. J Clin Psychiatry 1988; 49:435-8. Duvoisin RC,YahrMD. Encephalitis and parkinsonism. Arch Neurol 1965; 12:227-39. Eberstein S, Adler LA, Angrist B. Nefazodone and akathisia. Biol Psychiatry 1996; 40:798-9. Engel J, Ludwig Bl, Fetell M. Prolonged partial complex status epilepticus: EEG and behavioral observations. Neurology 1978; 28:863-9. Erenberg G, Cruse RP, Rothner AD. Gilles de la Tourette's syndrome: effects of stimulant drugs. Neurology 1985;35:1346-8. Ernst NH, Steur J. Increase of parkinsonian disability after fluoxetine medication. Neurology 1993; 43:211-13. Extein I. Methylphenidate-induced Choreoathetosis./4m 7 Psychiatry 1978; 135:252-3. Federlein J, Postert Th, Allgeier A etal. Remitting parkinsonism as a symptom of multiple sclerosis and the associated magnetic resonance imaging findings. Mov Disorders 1997; 12:1090-1. FeighnerJP, Boyer WF, Tyler Dietal. Adverse consequences of fluoxetine-MAOl combination therapy../ Clin Psychiatry 1990; 51:222-5. FeinbergTE, CianciCD, Morrow JS et al. Diagnostic tests for choreoacanthocytosis. Neurology 1991; 41:1000-6. Fenelon G, Houeto J-L Unilateral parkinsonism following a large infarct in the territory of the lenticulostriate arteries. Mov Disorders 1997; 12:1086-90. Fermaglich J, Streib E, Auth T. Chorea associated with systemic lupus erythematosus. Arch Neurol 1973; 28:276-7. Feve AP, Fenelon G, Wallays C et al. Axial motor disturbances after hypoxic lesions of the globus pallidus. Mov Disord 1993; 8:321-6. Fidler SM, O'Rourke RA, Buchsbaum HW. Choreoathetosis as a manifestation of thyrotoxicosis. Neurology 1971; 21:55-7. Fink JK, Hedera P, Mathay JG et al. Paroxysmal dystonic Choreoathetosis linked to chromosome 2q: clinical analysis and proposed pathophysiology. Neurology 1997; 49:177-83. Finlayson MH, Superville B. Distribution of cerebral lesions in acquired hepatocerebral degeneration. Brain 1981; 104:79-95. Fishbeck KH, Layzer RB. Paroxysmal Choreoathetosis associated with thyrotoxicosis. Ann Neurol 1979; 6:453-4. Flaherty JA, Lahmeyer HW. Larnyngeal-pharyngeal dystonia as a possible cause of asphyxia with haloperidol treatment. Am J Psychiatry 1978; 135:1414-15. Fleishman SB, Lavin MR, Sattler M etal. Antiemetic-induced akathisia in cancer patients receiving chemotherapy. Am] Psychiatry 1994; 151:763-5. Forchetti CM, Katsamakis G, Garron DC. Autoimmune thyroiditis and a rapidly progressive dementia: global hypoperfusion on SPECT scanning suggests a possible mechanism. Neurology 1997; 49:623-6. Friedman A, Sienkiewicz J. Psychotic complications of long-term levodopa treatment of Parkinson's disease. Acta NeurolScand 1991; 84:111-13. Gallo BV, Shulman LM, Weiner WJ et al. HIV encephalitis presenting with severe generalized chorea. Neurol 1996; 46:1163-5. Gambardella A, Valentino P, Annesi G et al. Hyperekplexia in a patient with a brainstem vascular anomaly. Acta Neurol Scand 1999; 99:255-9. Gamboa ET, Issacs G, Harter DH. Chorea associated with oral contraceptive therapy. Arch Neurol 1971; 25:112-14. Garrett PJ, Mulcahey D, Carmody M etal. Aluminium encephalopathy: clinical and immunologic features. QJ Med 1988; 69:775-83.

124 Signs, symptoms and syndromes Garruto RM, Gajdusek DC, Chen KM. Amyotrophic lateral sclerosis and parkinsonism-dementia among Filipino immigrants to Guam. Ann Neurol 1981; 10:341-50. Garvey MJ, Tollefson GD. Occurrence of myoclonus in patients treated with cyclic antidepressants. Arch Gen Psychiatry 1987; 44:269-72. Gautier-Smith PC, Prankerd TAJ. Polycythemia vera and chorea. Acta NeurolScand 1967; 43:357-64. Gelenberg AJ, Jefferson JW. Lithium tremor.) Clin Psychiatry 1995; 56:283-7. Gelenberg AJ, Mandel MR. Catatonic reactions to high-potency neuroleptic drugs. Arch Gen Psychiatry 1977; 34:947-50. Ghika J, Bogousslavsky J. Spinal pseudoathetosis: a rare, forgotten syndrome, with a review of old and recent descriptions. Neurology 1997; 49:432-7. Ghika-Schmid F, Ghika J, Regli F et al. Hashimoto's myoclonicencephalopathy: an underdiagnosed treatable condition? Mov Disord 1996; 11:555-67. Gibb WRG, Lees AJ. The clinical phenomenon of akathisia.y Neurol Neurosurg Psychiatry 1986; 49:861-6. Giladi N, Burke RE, Kostic V et al. Hemiparkinsonism-hemiatrophy syndrome: clinical and neuroradiological features. Neurology 1990; 40:1731-4. Giladi N, McMahon D, Przedborski S et al. Motor blocks in Parkinson's disease. Neurology 1992;

42:333-9. Gilbert GJ. Brueghel syndrome: its distinction from Meige syndrome. Neurology 1996; 46:1767-9. Gimenez-Roldan S, Martin M. Startle epilepsy complicating Down syndrome during adulthood. Ann Neurol 1980; 7:78-80. Gjessing LR. A review of periodic catatonia. Biol Psychiatry 1974; 8:23-5. Glantz R, Weiner WJ, Goetz CG etal. Drug-induced asterixis in Parkinson's disease. Neurology 1982;

32:553-5. GlassJP, JankovicJ, Borit A. Hemiballism and metastatic brain tumor. Neurology 1984; 34:204-7. Goldings AS, Stewart RM. Organic lead encephalopathy: behavioral change and movement disorder following gasoline inhalation. J Clin Psychiatry 1982; 43:70-2. Gomez EA, Comstock BS, Rosario A. Organic versus functional etiology in catatonia: case report. J Clin Psychiatry 1982; 43:200-1. Good Ml. Catatonia-like symptomatology and withdrawal dyskinesia./Amy Psyc/)/ofry1976; 133:1454-6. Goodman L. Alzheimer's disease: a clinico-pathologic analysis of twenty-three cases with a theory on pathogenesis.y Nerv Ment Dis 1953; 118:97-130. Gordin R. A case of unilateral torsion-dystonia: a clinico-histological study. J Nerv Ment Dis 1939; 90:344-357. Goto S, Kunitoku N.Suyama N et al. Posteroventral pallidotomy in a patient with parkinsonism caused by hypoxic encehpalopathy. Neurology 1997; 49:707-10. Graham JM, Grunewald RA, SagarHJ. Hallucinosis in idiopathic Parkinson's disease. J Neurol Neurosurg

Psychiatry 1997; 63:434-0. Green PM. Chorea induced by oral contraceptives. Neurology 1980; 30:1131-2. GrinkerRR. Parkinsonism following carbon monoxide poisoning. J Nerv Ment Dis 1926; 64:18-28. Guggenheim MA, Couch JR, Weinberg W. Motor dysfunction as a permanent complication of methanol ingestion: presentation of a case with a beneficial response to levodopa treatment. Arch Neurol 1971; 24:550-4. Halstead SM, Barnes TRE, Speller JC. Akathisia: prevalence and associated dysphoria in an in-patient population with chronic schizophrenia. BrJ Psychiatry 1994; 164:177-83. Hansotia P, Cleeland CS, Chun RWM. Juvenile Huntington's chorea. Neurology 1968; 18:217-24. Hardie RJ, Lees AJ. Neuroleptic-induced Parkinson's syndrome: clinical features and results of treatment with levodopa. J Neurol Neurosurg Psychiatry 1988; 51:850-4. Hardie RJ, Pullon HWH, Harding AEetal. Neuroacanthocytosis: a clinical, haematological and pathological study of 19 cases. Brain 1991; 114:13-^49.

Abnormal movements 125 Harsch HH. Neurologyoleptic malignant syndrome: physiological and laboratory findings in a series of nine cases. J Clin Psychiatry 1987; 48:328-33. Harvey PKP, Davis JN. Traumatic encephalopathy in a young boxer. Lancet 1974; 2:928-9. Harwood G, Hierons R, Fletcher NA et al. Lessons from a remarkable family with dopa-responsive dystonia.y Neurol Neurosurg Psychiatry 1994; 57:460-3. Heathfield KWG. Huntington's chorea. Brain 1967; 90:203-32. Heckman JG, Lang CJG, Druschky D etal. Chorea resulting from paraneoplastic encephalitis. Mov Disord

1997; 12:464-6. Heilman KH. Orthostatic tremor. Arch Neurol 1984; 41:880-1. Hely MA, Reid WGJ, Halliday GM et al. Diffuse Lewy body disease: clinical features in nine cases without coexistent Alzheimer's disease. J Neurol Neurosurg Psychiatry 1996; 60:531-8. Hershon HI, Kennedy PF, McGuire RJ. Persistence of extrapyramidal disorders and psychiatric relapse after withdrawal of long-term phenothiazine therapy. Br J Psychiatry 1972; 120:41-50. Hirano A, Arumugasamy N, Zimmerman HM. Amyotrophic lateral sclerosis: a comparison of Guam and classical cases. Arch Neurol 1967; 16:357-63. Hodskins MB, Yakovlev PI. Anatomico-clinical observations on myoclonus in epileptics and on related symptom complexes. Am} Psychiatry 1930; 87:827^8. Hoehn MM, Cherington M. Spinal myoclonus. Neurology 1977; 27:942. Hoogstraten MC, LakkeJ.ZwartsMJ. Bilateral ballism:a rare syndrome. Review of the literature and presentation of a case.) Neurol 1986; 233:25-9. Hori A, Hirose G, Kataoka S etal. Delayed postanoxic encephalopathy after strangulation: serial neuroradiological and neurochemical studies. Arch Neurol 1991; 48:871-4. Howard R, Ford R. From the jumping Frenchmen of Maine to post-traumatic stress disorder: the startle response in neuropsychiatry. Psychol Med1992; 22:695-707. Howard RS, Lees AJ. Encephalitis lethargica: a report of four recent cases. Brain 1987; 110:19-33. Huang C-C, Chu N-S, Lu C-S et al. Chronic manganese intoxication. Arch Neurol 1989; 46:1104-6. HuangC-C, Lu C-S, Chu N-Setal. Progression after chronic manganese exposure. Neurology 1993;

43:1479-83. Huang C-C, Chu N-S, Lu C-S et al. Cock gait in manganese intoxication. Mov Disorders 1997; 12:807-8. Hughes AJ, Daniel SE, Blankson S et al. A clinicopathologic study of 100 cases of Parkinson's disease. Arch Neurol 1993; 50:140-8. Hyman NM, Dennis PD, Sinclair KG. Tremor due to sodium valproate. Neurology 1979; 29:1172-80. Ishii N, Nishihara Y. Pellagra among chronic alcoholics: clinical and pathological study of 20 necropsy cases. J Neurol Neurosurg Psychiatry 1981; 44:209-15. Jacobs MB. Diltiazem and akathisia. Ann Intern Med 1983; 99:794-5. Jaffe N. Catalonia and hepatic dysfunction. Dis Nerv Syst 1967; 28:606-8. Jain S, Padma MV, Puri A et al. Juvenile myoclonic epilepsy: disease expression among Indian families. Ada Neurol Scand 1998; 97:1-7. Jankovic J, Ashizawa T. Tourettism associated with Huntington's disease. Mov Disord 1995; 10:103-5. Jankovic J, Fahn S. Physiologic and pathologic tremors. Ann Int Med 1980; 93:460-5. Jankovic J, Kirkpatrick JB, Blomquist KA et al. Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism. Neurology 1985; 35:227-34. Jankovic J, Caskey TC, Stout T et al. Lesch-Nyhan sydnrome: a study of motor behavior and cerebrospinal fluid neuretransmitters. Ann Neurol 1988; 23:466-9. Jankovic J, Leder S, Warner D etal. Cervical dystonia: clinical findings and associated movement disorders. Neurology 1991; 41:1088-91. Jarman PR, Davis MB, Hodgson SV etal. Paroxysmal dystonic choreoathetosis: genetic linkage studies in a British family. Brain 1997; 120:2125-30. Jarman PR, Bhatia KP, Davie C et al. Paroxysmal dystonic choreoathetosis: clinical features and investigation of pathophysiology in a large family. Mov Disord 2000; 15:648-57.

126 Signs, symptoms and syndromes Jimenez-Jimenez FJ,Tejeiro J, Martinez-Junquera G et al. Parkinson ism exacerbated by paroxetine.

Neurology 1994; 44:2406. Johnson J. Stupor: review of 25 cases. Acta Psychiatr Scand 1984; 70:370-7. Johnson WG, Fahn S. Treatment of vascular hemiballism and hemichorea. Neurology 1977; 27:634-6. Johnson WG, Schwartz G, Barbeau A. Studies of dystonia musculorum deformans. Arch Neurol ^62', 7:301-13. Jones HR, Hedley-Whyte T. Idiopathic hemochromatosis (IHC): dementia and ataxia as presenting signs.

Neurology 1983; 33:1479-83. Jungmann E, SchofflingC. Akathisia and metodopramide. Lancet 1982; 2:221. Kane J, Rifkin A, Quitkin F et al. Extrapyramidal side-effects with lithium treatment. Am J Psychiatry 1978; 135:851-3. Karp Bl, Laureno R. Pontine and extrapontine myelinolysis: a neurologic disorder following rapid correction of hyponatremia. Medicine 1993; 72:359-73. KaseCS, Maulsby GO, dejuan E et al. Hemichorea-hemiballismand lacunar infarction in the basal ganglia. Neurology 1981; 31:452-5. Keane JR, Young JA. Blepharospasm with bilateral basal ganglia infarction. Arch Neurol 1985; 42:1206-8. Keepers GA, Clappison VJ, Casey DE. Initial anticholinergic prophylaxis for neuroleptic-induced extrapyramidal syndromes. Arch Gen Psychiatry 1983; 40:1113-17. Kelwala S, Pomara N, Stanley M etal. Lithium-associated accentuation of extrapyramidal symptoms in individuals with Alzheimer's disease. J Clin Psychiatry 1984; 45:342-4. Kerbeshian J, Burd L, Pettit R. A possible post-streptococcal movement disorder with chorea and tics. Dev Med Child Neurol 1990; 32:642-4. Kertesz A. Paroxysmal kinesigenic choreoathetosis: an entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. Neurology 1967; 17:680-90. Keschner M, Sloane P. Encephalitic, idiopathic and arteriosclerotic parkinsonism: a clinicopathologic study. Arch Neurol Psychiatry 1931; 25:1011-41. Kidron D, Melamed E. Forms of dystonia in patients with Parkinson's disease. Neurology 1987;

37:1009-11. Kim CH, Perlstein MA. Encephalitis with catatonic schizophrenic symptoms. Ill Med J 1970; 138:503-7. Kimber TE, Thompson PD. Symptomatic hyperekplexia occurring as a result of pontine infarction. Mov Disord 1997; 12:815-16. Kirby GH, Davis TK. Psychiatric aspects of epidemic encephalitis. Arch Neurol Psychiatry 1921; 5:491-51. Kiriakakis V, Bhatia K, Quinn NP et al. The natural history of tardive dystonia: a long-term follow-up study of 107 cases. Brain 1998; 121:2053-66. Kirubakaren V, Mayfield D, Rengachary S. Dyskinesia and psychosis in a patient following baclofen withdrawal. Am j Psychiatry 1984; 141:692-3. Klatka LA, Louis ED, Schiffer RB. Psychiatric features in diffuse Lewy body disease: a clinicopathologic study using Alzheimer's disease and Parkinson's disease comparison groups. Neurology 1996;

47:1148-52. Klawans HL, Goetz CG, Bergen D. Levodopa-induced myoclonus. Arch Neurol 1975; 32:331-4. Klawans HL, Moses H, Nausieda PA etal. Treatment and prognosis of hemiballism. N Eng J Med 1976; 295:1348-50. Klawans HL, Lipton M, Simon L. Calcification of the basal ganglia as a cause of levodopa-resistant parkinsonism. Neurology 1976; 26:221-5. Klawans HL, Barr A. Prevalence of spontaneous lingual-facial-buccal dyskinesias in the elderly. Neurology 1981; 31:558-9. Klawans HL, Glantz R, Tanner CM etal. Primary writing tremor: a selective action tremor. Neurology

1982a; 32:203-6.

Abnormal movements 127 Klawans HL, Stein RW, Tanner CM etal. A pure parkinsonian syndrome following acute carbon monoxide intoxication. Arch Neurol 1982b; 39:302-4. Kobari M, Nogawa S, Sugimoto Y et al. Familial idiopathic brain calcification with autosomal dominant inheritance. Neurology 1997; 48:645-9. Koehler J, Jakumeit U. Subacute sclerosing panencephalitis presenting as Leonhard's speech-prompt catatonia. Br J Psychiatry-1976; 129:29-31. Koller WC. Edentulous orodyskinesia. Neurology 1983; 13:97-9. Koller WC, Cochran JW, Klawans HL. Calcification of the basal ganglia: computerized tomography and clinical correlation. Neurology 1979; 29:328-33. KollerWC, Lang A, Vetere-Overfield Bet al. Psychogenic tremors. Neurology 1989; 39:1094-9. KooikerJC,SumiSM. Movement disorder as a manifestation of diphenylhydantoin intoxication. Neurology 1974; 24:68-71. Koskiniemi M, DonnerM, Majuri \\etal. Progressive myoclonus epilepsy: a clinical and histopathological study. Acta NeurolScand 1974; 50:307-32. KoukoulisA, HerrerdJS, Gomez-AlonsoJ. Blepharospasm induced by t\unarazme.J Neurol Neurosurg Psychiatry 1997; 63:412-13. Kraepelin E. Dementia praecoxandparaphrenia, 1919, translated by Barclay RM, Robert E. Hungtington, NY: Krieger Publishing, 1971. Kraepelin E. Psychiatry. A textbook for students and physicians, 6th edn, 1899, translated by Metoui H, Ayed S. Canton, MA: Science History Publications, 1990. Kramer PL, Mineta M, Klein Cetal. Rapid-onset dystonia-parkinsonism: linkage to chromosome 19q13. Ann Neurol 1999; 46:176-82. KraussJK, SeegerWJankovicJ. Cervical dystonia with tumors of the posterior fossa. Mov Disord 1997; 12:443-7. Kristensen 0, Sindrup EH. Psychomotor epilepsy and psychosis. III. Social and psychological correlates. Acta Neurol Scand 1979; 59:1-9. Kronfol Z, Greden JF, Zis AP. Imipramine-induced tremor: effects of a beta-adrenergic blocking agent, y Clin Psychiatry 1983; 44:225-6. Kulisevsky J, Berthier ML, Pujol J. Hemiballismus and secondary mania following right thalamic infarction. Neurology 1993; 43:1422-4. Kulisevsky J, Asuncion A, Berthier ML. Bipolar disorder and unilateral parkinsonismaftera brainstem infarction. Mov Disord 1995; 10:799-802. Kushner MJ. Chorea and cimetidine. Ann Intern Med 1982; 96:126. Kutcher SP, Williamson P, MacKenzie S et al. Successful clonazepam treatment of neuroleptic-induced akathisia in older adolescents and young adults, y Clin Psychopharmacon989; 9:403-6. Lance JW. Familial paroxysmal dystonicchoreoathetosisand its differentiation from related syndromes. Ann Neurol 1977; 2:285-93. Lancman ME, Asconape MJ, PenryJK. Choreiform movements associated with the use of valproateMrd? Neurol 194; 51:702^. LangAE. Persistent hemiballismuswith lesions outside the subthalamic nucleus. Can] Neurol Sci 1985; 12:125-8. Lang AE. Withdrawal akathisia: case reports and a proposed classification of chronic akathisia. Mov Disord 1994; 9:188-92. LangAE, Johnson K. Akathisia in idiopathic Parkinson's disease./Stewro/ogy 1987; 37:477-81. LangstonJW, Ballard P, TetrudJWeto/. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983; 249:979-80. Lanham JG, Brown MM, Hughes GRV. Cerebral systemic lupus erythematosus presenting with catatonia. Postgrad MedJ 1985; 61:329-30. Laplane D, Attal N, Sauron B etal. Lesions of basal ganglia due to disulfiram neurotoxicity. J Neurol Neurosurg Psychiatry 1992; 55:925-9.

128 Signs, symptoms and syndromes LapresleJ. Palatal myoclonus. Adv Neurol 1986; 43:265-73. Leavitt S, Tyler H. Studies in asterixis. Arch Neurol 1964; 10:360-8. Lederman RJ, Henry CE. Progressive dialysis encephalopathy. Ann Neurol 1978; 4:199-204. Lee B-C, Hwang S-H, Chang GY. Hemiballismus-hemichorea in older diabetic women: a clinical syndrome with MRI correlation. Neurology 1999; 52:646-8. Lee Bl, Lesser RP, PippengerCEefo/. Familial paroxysmal hypnogenicdystonia. Neurology 1985; 35:1357-60. Lee MS, Rinne JO, Ceballos-Baumann A etal. Dystonia after head trauma. Neurology 1994; 44:1374-8. Lee MS, Kim YD, Lyoo CH. Oculogyric crises as an initial manifestation of Wilson's disease. Neurology 1999; 52:1714-15. Lees AJ, Robertson M, Trimble MR etal. A clinical study of Gilles de la Tourette syndrome in the United Kingdom. J Neurol Neurosurg Psychiatry 1984; 47:1-8. Lehericy S, Vidailhet M, Dormont D et al. Striatopallidal and thalamic dystonia: a magnetic resonance imaging anatamoclinical study. Arch Neurol 1996; 53:241-50. Lenton RJ, Cofti M, Smith RG. Hemiballismus treated with sodium valproate. BMJ1981; 283:17-18. Lesch M, Nyhan WL. A familial disorder of uric acid metabolism and central nervous system function. 4my/W«/1964; 36:561-70. Lewis I, Johnson IM. Chorea: an unusual manifestation of cerebral metastases. Neurology 1968; 18:948-52. Lim J, Yagnik P, Schrader P etal. Ictal catatonia as a manifestation of nonconvulsive status epilepticus. J Neurol Neurosurg Psychiatry 1986; 49:833-6. Lin J-J, Chang M-K. Hemiballism-hemichorea and non-ketotic hyperglycemia.y Neurol Neurosurg Psychiatry 1994; 57:748-50. Lipinski JF, Zubenko GS, Cohen BM etal. Propranolol in the treatment of neuroleptic induced akathisia. Am J Psychiatry 1984; 141:412-15. Lipinski JF, Mallya A, Zimmerman P etal. Fluoxetine-induced akathisia: clinical and theoretical implications../Clin Psychiatry 1989; 50:339-42. LippmannS, MoskovitzR, O'Tuama L. Tricyclic-induced myoclonus. Am] Psychiatry 1977; 134:90-1. Little BW, Brown PW, Rodgers-Johnson Petal. Familial myoclonic dementia masquerading as Creutzfeldt-Jakob disease. Ann Neurol 1986; 20:231. Little JT, JankovicJ. Tardive myoclonus: a case report. /WovD/so/Y/1987; 2:307-11. Litvan I, MangoneCA, McKeeAeffl/. Natural history of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) and clinical predictors of survival: a clinicopathologic study. J Neurol Neurosurg Psychiatry 1996; 61:615-20. Litvan I, Goetz CG, Jankovic J et al. What is the accuracy of the clinical diagnosis of multiple system atrophy? A clinicopathologic study. Arch Neurol 1997a; 54:937^44. Litvan I, Agid Y, Goetz C etal. Accuracy of the clinical diagnosis of corticobasal degeneration: a clinicopathologic study. Neurology 1997b; 48:119-25. Lodder J, Baard WC. Paraballism caused by bilateral hemorrhagic infarction in basal ganglia. Neurology 1981; 31:484-6. Logsdail SJ, Toone BK. Postictal psychoses: a clinical and phenomenological description. BrJ Psychiatry

1988; 152:246-52. Lombroso CT. Lamotrigene-induced tourettism. Neurology 1999; 52:1191^. Lou J-S, JankovicJ. Essential tremor: clinical correlates in 350 patients. Neurology 1991; 41:234-8. Louis ED, Lynch T, Kaufmann Petal. Diagnostic guidelines in central nervous system Whipple's disease. Ann Neurol 1996; 40:561-8. Louis ED, Klatka LA, Liu Yet al. Comparison of extra pyramidal features in 31 pathologically confirmed cases of diffuse Lewy body disease and 34 pathologically confirmed cases of Parkinson's disease.

Neurology 1997; 48:376-80.

Abnormal movements 129 Lugaresi E, Cirignotta F. Hypnogenic paroxysmal dystonia: epileptic seizure or a newsyndrome? sleep 1981; 4:129-38. Lugaresi E, Cirignotta F, Montagna P. Nocturnal paroxysmal dystonia. J Neurol Neurosurg Psychiatry 1986;49:375-80. Lundh H, Tunving K. An extra pyramidal choreiform syndrome caused by amphetamine addiction. J Neurol Neurosurg Psychiatry 1981; 44:728-30. Mac DS, Pardo MP. Systemic lupus erythematosus and catatonia: a case report.y Clin Psychiatry 1983; 44:155-6. McKeith IG, Fairbairn AF, Perry RH etal. The clinical diagnosis and misdiagnosis of senile dementia of Lewy body type (SDLT). BrJ Psychiatry 1994a; 165:324-32. McKeith IG, Fairbairn AF, Bothwell RAetal. An evaluation of the predictive validity and inter-rater reliability of clinical diagnostic criteria for senile dementia of Lewy body type. Neurology 1994b; 44:872-7. McLean DR, Jacobs H, MielkeBW. Methanol poisoning: a clinical and pathological study. Ann Neurol 1980;8:161-7. MaherER, Lees AJ. The clinical features and natural history of Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 1986; 36:1005-8. Maher J, Choudri S, Halliday W et al. AIDS dementia complex with generalized myoclonus. Mov Disord

1997;12:593-7. Mahloudji M, Pikielny R. Hereditary essential myoclonus. Brain 1967; 90:669-74. Malamud N, Hirano A, Kurland LT. Pathoanatomic changes in amyotrophic lateral sclerosis on Guam. Neurology 1961; 5:401-14. Mann SC, Caroff SN, Bleir HRetal, Lethal catatonia. Am J Psychiatry 1986; 143:1374-81. MarderK, Ming-XinT, Cote letal. The frequency and associated risk factors for dementia in patients with Parkinson's disease. Arch Neurol 1995; 52:695-701. Margolin D, HammerstadJ, Orwoll Eetal. Intracranial calcification in hyperparathyroidismassociated with gait apraxia and parkinsonism. Neurology 1980; 30:1005-7. Marsden CD, Harrison MJG. Idiopathic torsion dystonia (dystonia musculorum deformans): a review of forty-two patients. Brain 1974; 97:793-810. Marti-MassoJF, Poza JJ. Cinnarizine-induced parkinsonism: ten years later. MovD/sord 1998; 13:453-6. Martin JP. Hemichorea (hemiballismus) without lesions in the corpus luysii. Brain 1957; 80:1-10. Martin JP, Alcock NS. Hemichorea associated with a lesion of the corpus luysii. Brain 1934; 57:504-16. Martin WE, Loewenson RB, Resch fietal. Parkinson's disease: clinical analysis of 100 patients. Neurology 1973; 23:783-90. Martinelli P, Gabellini AS, Gulli MRetal. Different clinical features of essential tremor: a 200-patient study. Acta Neurol Scand 1987; 75:106-11. Martinez-Cage JM, Marsden CD. Hemi-dystonia secondary to localized basal ganglia tumors, y Neurol Neurosurg Psychiatry 1984; 47:704-9. MartlandHS. Punch drunk.y/\A?7/Wed>4ssoc1928; 91:1103-7. Marttila RJ, Rinne UK. Dementia in Parkinson's disease./4cta Neurol Scand ^76; 54:431-41. Mathews WB. Familial calcification of the basal ganglia with response to parathormone.y Neurol Neurosurg Psychiatry 1957; 20:172-7. Matsuo H, Kamakura K, Saito M etal. Familial paroxysmal dystonic choreoathetosis. Clinical findings in a large Japanese family and genetic linkage to chromosome 2q. Arch Neurol 1999; 56:721-6. Mayeux R, Stern Y, Rosenstein R etal. An estimate of the prevalence of dementia in idiopathic Parkinson's disease. Arch A/euro/1988; 45:260-2. Mayeux R, Denaro J, Hemenegildo N et al. A population-based investigation of Parkinson's disease with and without dementia: relationship to age and gender. Arch Neurol 1992; 49:492-7. Medori R, Montagna P, Tritschler HJ etal. Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178. Neurology 1992; 42:669-70.

130 Signs, symptoms and syndromes Melamed E. Early-morning dystonia, a late effect of long-term levodopa therapy in Parkinson's disease. Arch Neurol 1979; 36:308-10. Melamed E, Korn-Lubetzk I, Reches hetal. Hemiballismus: detection of focal hemorrhage in subthalamic nucleus by CT scan. Ann Neurol 1978; 4:582. Menza MA, Cocchiola J, Golbe LI. Psychiatric symptoms in progressive supranuclear palsy. Psychosomatic* 1995; 36:550-4. MicheelsLJ. Catatonic syndrome in a case of subdural hematoma. J Nerv Ment Dis 1953; 117:123-9. Micheli M.Cersosimo MG, Scorticati MCetal. Myoclonus secondary to albuterol (salbutamol) instillation. Neurology2000; 54:2022-3. Miller DD, Sharafuddin MJA, Kathol RG. A case of clozapine-induced neuroleptic malignant syndrome.

J Clin Psychiatry 1991; 52:99-101. Misra PC, Hay GG. Encephalitis presenting as acute schizophrenia. Br MedJ 1971; 1:532-3. Mitchell E, Mathews KL Gilles de la Tourette's disorder associated with pemoline. Am J Psychiatry 1980; 137:1618-19. Moersch FP, KernohanJW. Hemiballismus: a clinicopathologic study. Arch Neurol Psychiatry 1939; 41:365-72. Mones RJ, Elizan TS, Siegel GJ. Analysis of L-dopa induced dyskinesias in 51 patients with parkinsonism. J Neurol Neurosurg Psychiatry 1971; 34:668-73. Morrison JR. Catalonia. Retarded and excited types. Arch Gen Psychiatry 1973; 28:515-16. Mount LA, RebackS. Familial paroxysmal choreoathetosis: preliminary report an hitherto undescribed clinical syndrome. Arch Neurol Psychiatry 1940; 44:841-7. Mulder DW, Parrott M, Thaler M. Sequelae of western equine encephalitis. Neurology 1951; 1:318-27. Muller-Vahl KR, Kolbe H, Dengler R. Transient severe parkinsonism after acute organophosphate poisoning.) Neurol Neurosurg Psychiatry 1999; 66:253-4. Munchau A, Valente EM, Shahidi GA et al. A new family with paroxysmal exercise induced dystonia and migraine: a clinical and genetic study. J Neurol Neurosurg Psychiatry 2000; 68:609-14. MurrowRW, SchweigerGD, KepesJJefo/. Parkinsonism due to a basal ganglia lacunar state: clinicopathologic correlation. Neurology 1990; 40:897-900. Nath AJankovicJ, PetigrewLC. Movement disorders and AIDS. Neurology 1987; 37:37-^1. Nausieda PA, Koller WC, Klawans [Metal. Phenytoin and choreic movements. N EnglJMed 1978; 298:1093^1. Nausieda PA, Koller WC, Weiner WJ et al. Chorea induced by oral contraceptives. Neurology 1979;

29:1605-9. Nausieda PA, Grossman BJ, Koller\NCetal. Sydenham chorea: an update. Neurology 1980a; 30:331^. Nausieda PA, Weiner WJ, Klawans HL Dystonic foot response of parkinsonism. Arch A/e

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