Stroke Syndromes

Stroke syndromes ‘This comprehensive work will provide its owner with a ready source of reference for a multitude of questions that might arise in the evaluation and localization of individual stroke patients’ (European Neurology) ‘A detailed compilation of descriptions that puts into one place a wealth of information on the clinical observations that can be collected into meaningful stroke syndromes’ (Vascular Medicine) ‘An excellent sourcebook for anyone interested in stroke’ (Neuroradiology) The first edition of Stroke Syndromes was widely welcomed as a new and authoritative reference in the assessment and diagnosis of stroke. This revised and updated edition remains the definitive guide to patterns and syndromes in stroke. A comprehensive survey of all types of neurological, neurophysiological and other clinical dysfunction due to stroke, the book is organized to make pattern recognition easier. It contains descriptions of clinical problems encountered in stroke patients and their differential diagnosis, and will enable clinicians to differentiate between possible locations on the basis of symptoms and signs. A companion volume Uncommon Causes of Stroke completes this highly authoritative reference work, which clinicians in neurology will find essential to the understanding and diagnosis of stroke. Julien Bogousslavsky is Professor and Chair in the University Department of Neurology, and Professor of Cerebrovascular Diseases, University of Lausanne, Switzerland. He was Cofounder of the European Stroke Conference and of the journal Cerebrovascular Diseases. Louis R. Caplan is Professor of Neurology at Harvard Medical School and Chief of the Stroke Service, Beth Israel Deaconess Medical Center, Boston. He is Vice-President of the American Neurological Association.

Stroke syndromes Second edition

Edited by

Julien Bogousslavsky University of Lausanne, Switzerland

and

Louis R. Caplan Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA

                                                     The Pitt Building, Trumpington Street, Cambridge, United Kingdom    The Edinburgh Building, Cambridge CB2 2RU, UK 40 West 20th Street, New York, NY 10011-4211, USA 10 Stamford Road, Oakleigh, VIC 3166, Australia Ruiz de Alarcón 13, 28014 Madrid, Spain Dock House, The Waterfront, Cape Town 8001, South Africa http://www. cambridge.org © Cambridge University Press, 1995, 2001 This book is in copyright. Subject to statutory exception and to the provisions of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published 1995 Reprinted 1996, 1998 Second edition 2001 Printed in the United Kingdom at the University Press, Cambridge Typeface Utopia 8.5/12pt.

System QuarkXPress™ [  ]

A catalogue record for this book is available from the British Library Library of Congress Cataloguing in Publication data Stroke syndromes / edited by Julien Bogousslavsky, Louis Caplan – 2nd ed. p.

cm.

Includes bibliographical references and index. ISBN 0 521 77142 0 (hb) 1. Cerebrovascular disease – Diagnosis. 2. Diagnosis, Differential. 3. Symptoms. I. Bogousslavsky, Julien. II. Caplan, Louis R. [DNLM: 1. Cerebrovascular Accident – diagnosis. 2. Syndrome. WL 355 S9213735 2000] RC388.5 .S8567 616.8⬘1–dc21

2000 00-058499

ISBN 0 521 77142 0 hardback ISBN 0 521 80258 X boxed set (with Uncommon causes of stroke)

Every effort has been made in preparing this book to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Nevertheless, the authors, editors and publisher can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publisher therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.

To Lucie Belime-Laugier and Carl and Bess Caplan. Who have passed on but remain as an eternal inspiration.

To our patients. They have taught us much about stroke, dealing with adversity, courage, and the meaning of health, life, and death. We shall always be in their debt.  

Contents

List of contributors Preface

page x xvii

PA RT I CL I N I C A L M A N I F E S TAT I O N S 11

Stroke onset and courses Haruko Yamamoto, Masayasu Matsumoto, Kazuo Hashikawa and Masatsugu Hori

3

12

Clinical types of transient ischemic attacks Graeme J. Hankey

8

13

Hemiparesis and other types of motor weakness 22 Teresa Pinho e Melo and Julien Bogousslavsky

14

Sensory abnormality Jong Sung Kim

34

15

Cerebellar ataxia Dagmar Timmann and Hans Christoph Diener

48

16

Headache: stroke symptoms and signs Conrado J. Estol

60

17

Eye movement abnormalities Charles Pierrot-Deseilligny

76

18

Cerebral visual dysfunction Jason J.S. Barton and Louis R. Caplan

87

19

Visual symptoms (eye) Shirley H. Wray

111

10

Vestibular syndromes and vertigo Marianne Dieterich and Thomas Brandt

129

11

Auditory disorders in stroke Robert A. Levine and Rudolf Häusler

144

12

Abnormal movements Joseph Ghika and Julien Bogousslavsky

162

vii

viii

Contents

13

Seizures and stroke Anne L. Abbott, Christopher F. Bladin and Geoffrey A. Donnan

14

Disturbances of consciousness and sleep– wake functions Claudio Bassetti

182

PA RT I I VA S C U L A R TO P O G R A PH I C SYNDROMES 29

Arterial territories of human brain Laurent Tatu, Thierry Moulin, Julien Bogousslavsky and Henri Duvernoy

375

30

Superficial middle cerebral artery syndromes Jean-Philippe Neau and Julien Bogousslavsky

405

31

Lenticulostriate arteries Patrick Pullicino

428

32

Anterior cerebral artery John C.M. Brust, Tohru Sawada and Seiji Kazui

439

33

Anterior choroidal artery territory infarcts Philippe Vuadens and Julien Bogousslavsky

451

34

Thalamic infarcts and hemorrhages Alain Barth, Julien Bogousslavsky and Louis R. Caplan

461

35

Caudate infarcts and hemorrhages Chin-Sang Chung, Hye-Seung Lee and Louis R. Caplan

469

192

15

Aphasia and stroke Andrew Kertesz

211

16

Agitation and delirium John C.M. Brust and Louis R. Caplan

222

17

Frontal lobe stroke syndromes Paul J. Eslinger and Raymond K. Reichwein

232

18

Memory loss José M. Ferro and Isabel P. Martins

242

19

Neurobehavioural aspects of deep hemisphere stroke José M. Ferro

252

20

Right hemisphere syndromes Stephanie Clarke

264

21

Poststroke dementia Didier Leys and Florence Pasquier

273

36

Posterior cerebral artery Claudia J. Chaves and Louis R. Caplan

479

22

Disorders of mood behaviour Florence Ghika-Schmid and Julien Bogousslavsky

285

37

Large and panhemispheric infarcts Stefan Schwarz, Stefan Schwab and Werner Hacke

490

23

Agnosias, apraxias and callosal disconnection syndromes Patrik Vuilleumier

38 302

Multiple, multilevel and bihemispheric infarcts Emre Kumral

Muscle, peripheral nerve and autonomic changes Thierry Kuntzer and Bernard Waeber

323

24

25

Dysarthria Paola Santalucia and Edward Feldmann

334

26

Dysphagia and aspiration syndromes Mark J. Alberts and Jennifer Horner-Catt

341

27

Respiratory dysfunction François Vingerhoets and Julien Bogousslavsky

353

28

Clinical aspects and correlates of stroke recovery 363 Marta Altieri, Vittorio Di Piero, Edoardo Vicenzini and Gian Luigi Lenzi

499

39

Midbrain infarcts Marc Hommel and Gérard Besson

512

40

Pontine infarcts and hemorrhages Chin-Sang Chung and Louis R. Caplan

520

41

Medullary infarcts and hemorrhages Bo Norrving

534

42

Cerebellar stroke syndromes Pierre Amarenco

540

43

Extended infarcts in the posterior circulation (brainstem/cerebellum) Barbara E. Tettenborn

557

44

Border zone infarcts E. Bernd Ringelstein and Florian Stögbauer

564

45

Classical lacunar syndromes John M. Bamford

583

Contents

46

Putaminal hemorrhages Kazuo Minematsu and Takenori Yamaguchi

590

47

Lobar hemorrhages Carlos S. Kase

599

48

Intraventricular hemorrhages Peter C. Gates

612

49

Subarachnoid hemorrhage syndromes Jan van Gijn and Gabriel J.E. Rinkel

618

50

Brain venous thrombosis syndromes Caroline Arquizan, Jean-François Meder and Jean-Louis Mas

626

Carotid occlusion syndromes François Nicoli and Julien Bogousslavsky

651

51

52

Cervical artery dissection syndromes Tobias Brandt, Erdem Orberk and Werner Hacke

53

Syndromes related to large artery thromboembolism within the vertebrobasilar system Louis R. Caplan

54

Spinal stroke syndromes Matthias Sturzenegger

Index

660

667 691

705

ix

Contributors

Anne L. Abbott (née Harris) Neurology Department Repatriation Campus Austin and Repatriation Medical Centre Locked Bag 1 Heidelberg West Victoria 3081 Australia Mark J. Alberts Division of Neurology Department of Medicine, PO Box 2900 Duke University Medical Center Durham, NC 27710 USA Marta Altieri Università degli studi di Roma Department of Neurological Science V Cattedra di Clinica Neurologica V. le dell’Università, 30 00185 Rome Italy Pierre Amarenco Neurology Services Saint-Antoine Hospital Rue du Fbg St-Antoine 184 F-75571 Paris France Caroline Arquizan Neurology Services Sainte Anne Hospital 1 Rue Cabanis 75674 Paris Cedex 14 France

x

Contributors

John M. Bamford St James’s University Hospital Beckett Street Leeds LS9 7TF UK

Tobias Brandt Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany

Alain Barth Inselspital Neurological Clinic and Poliklinik 3010 Berne Switzerland

John C.M. Brust Department of Neurology Harlem Hospital Center 506 Lenix Avenue New York, NY 10037 USA

Jason J.S. Barton Beth Israel Deaconess Medical Center East Campus 330 Brooklyn Avenue Boston, MA 02215 USA Claudio Bassetti Inselspital Hospital of L’lle Neurological Clinic and Poliklinik CH 3010 Bern-Schweiz Switzerland Gérard Besson Central University Hospital of Grenoble Department of Clinical and Biological Neurosciences Neurological Services BP 217X 38043 Grenoble Cedex 9 France

Louis R. Caplan Beth Israel Deaconess Medical Center East Campus 330 Brooklyn Avenue Boston, MA 01125 USA Claudia J. Chaves Beth Israel Deaconess Medical Center East Campus 330 Brooklyn Avenue Boston, MA 01125 USA Chin-Sang Chung Department of Neurology Samsung Medical Center Sungkyunkwan University School of Medicine 50 ILWON-dong Kangnam-ku Seoul, South Korea 135–710

Christopher F. Bladin Neurology Department Box Hill Hospital Nelson Road Box Hill, Victoria 3128 Australia

Stephanie Clarke Division of Neuropsychology CHUV-Nestle CH-1011 Lausanne Switzerland

Julien Bogousslavsky Department of Neurology University of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland

Hans C. Diener Neurological Clinic University Clinic Essen Hufelandstr. 55 D-45122 Essen Germany

Thomas Brandt Department of Neurology Klinikum Grosshadern Ludwig Maximilians University Munich Marchioninistr. 15 D-81377 Munich 70 Germany

Marianne Dieterich Department of Neurology Klinikum Grosshadern Ludwig Maximilians University Munich Marchioninistr. 15 D-81377 Munich 70 Germany

xi

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Contributors

Geoffrey A. Donnan Department of Neurology and Neurosciences Neurosciences Building Repatriation Campus Austin and Repatriation Medical Centre Locked Bag 1 Heidelberg West Victoria 3081 Australia Henri Duvernoy Anatomy Laboratory Central University Hospital Jean Minjoz Hospital 25030 Besancon France Paul J. Eslinger Hershey Medical Center 500 University Drive Hershey, PA 17033 USA Conrado J. Estol Centre for Neurological Treatment and Rehabilitation Pacheco de Melo 1860 Buenos Aires 1128 Argentina Edward Feldmann Department of Clinical Neurosciences Brown University School of Medicine 110 Lockwood Street 324 Providence, RI 02903 USA José M. Ferro University of Lisbon Faculty of Medicine Av. Prof. Egas Moniz 1699 Lisbon Codex Portugal Peter C. Gates Department of Neuroscience Greelong Hospital Geelong Victoria 3220 Australia

Joseph Ghika Department of Neurology University of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland Florence Ghika-Schmid Department of Neurology University of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland Werner Hacke Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany Graeme J. Hankey Royal Perth Hospital Neurology Box X2213 GPO Perth 6847 Western Australia Kazuo Hashikawa Division of Strokology Department of Internal Medicine and Therapeutics (A8) Osaka University Graduate School of Medicine 2-2, Yamadaoko, Suita Osaka 565-0871 Japan Rudolf Häusler Department of ENT Department of Otorhinolaryngology Head and Neck and Cranio-MaxilloFacial Surgery University Hospital of Berne University of Berne 3010 Berne Switzerland

Contributors

Marc Hommel Central University Hospital of Grenoble Department of Clinical and Biological Neurosciences Neurological Services BP 217X 38043 Grenoble Cedex 9 France Masatsugu Hori Division of Strokology Department of Internal Medicine and Therapeutics (A8) Osaka University Graduate School of Medicine 2-2, Yamadaoko, Suita Osaka 565-0871 Japan Jennifer Horner-Catt Department of Speech and Language Therapy University of Canterbury Private Bag 4800 Christchurch New Zealand Carlos S. Kase Department of Neurology Boston University School of Medicine 715 Albany Street Robinson Building 605 Boston, MA 02118-2526 USA Seiji Kazui National Cardiovascular Center Fujishirodai 5-7-1, Suita Osaka 565-8565 Japan Andrew Kertesz St Jospeh’s Health Centre Department of Clinical Neurological Sciences University of Western Ontario 268 Grosvenor Street London, Ontario Canada NA 4V2

Jong Sung Kim Department of Neurology Asan Medical Center Song-Pa PO Box 145 Seoul 138-600 South Korea Emre Kumral Stroke and Neuropsychology Unit Department of Neurology School of Medicine Ege University Bornova Izmir 35100 Turkey Thierry Kuntzer Service de Neurologie CHUV BH 07/306 CH-1011 Lausanne Switzerland Hye-Seung Lee Department of Neurology Samsung Medical Center Sungkyunkwan University School of Medicine 50 ILWON-dong Kangnam-ku Seoul South Korea 135-710 Gian Luigi Lenzi Department of Neurological Sciences University of Rome La Sapienza Via Cavour, 325 00184 Rome Italy Robert A. Levine Eaton Laboratory of Auditory Physiology Massachusetts Eye and Ear Infirmary Harvard University Boston, MA USA Didier Leys Neurology Services Salengro Hospital Rue Oscar Lambret 59037 Lille France

xiii

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Contributors

Isabel P. Martins Department of Neurology Santa Maria Hospital Av. Prof. Egas Moniz P-1699 Lisbon Portugal

François Nicoli Neurology Services Pr. JL Gastaut Sainte Marguerite Hospital F-13009 Marseilles France

Jean-Louis Mas Neurology Services Centre Raymond Garcin-1 CHSA Sainte Anne Hospital 1 Rue Cabanis 75674 Paris Cedex 14 France

Bo Norrving Department of Neurology University Hospital S-22185 Lund Sweden

Masayasu Matsumoto Division of Strokology Department of Internal Medicine and Therapeutics (A8) Osaka University Graduate School of Medicine 2-2, Yamadaoko, Suita Osaka 565-0871 Japan Jean-François Meder Radiology Services Centre Raymond Garcin-CHSA Sainte Anne Hospital 1 Rue Cabanis 75674 Paris Cedex 14 France Kazuo Minematsu Cerebrovascular Division Department of Medicine National Cardiovascular Center Fujishirodai 5-7-1, Suita Osaka 565-8565 Japan Thierry Moulin Neurology Services Central University Hospital Jean Minjoz Hospital 25030 Besancon France Jean-Philippe Neau Clinical Neurology Services Jean Bernard Hospital BP 577 86021 Poitiers France

Erdem Orberk Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany Florence Pasquier University of Lille Lille France Vittorio Di Piero Università degli studi di Roma Department of Neurological Science V Cattedra di Clinica Neurologica V. le dell’Università, 30 00185 Rome Italy Charles Pierrott-Deseilligny Clinique Paul Castaigne Clinic Neurology Services Hospitals Group Pitié-Salpêtrière 47–83 Boulevard de l’Hôpital 75651 Paris Cedex 13 France Teresa Pinho e Melo University of Lisbon Neurology Clinic Santa Maria Hospital Av. Prof Egas Moniz P-1699 Lisbon Portugal Patrick Pullicino Department of Neurology Buffalo General Hospital 100 High Street Buffalo, NY 14203 USA

Contributors

Raymond K. Reichwein Section of Neurology H037 Hershey Medical Center 500 University Drive Hershey, PA 17033 USA E. Bernd Ringelstein Neurology Clinic Westfälische Wilhelms-University Münster Albert Schweitzer Str. 33 D-48129 Münster Germany Gabriel J.E. Rinkel University Department of Neurology University Medical Centre Box 85500 3508 GA Utrecht The Netherlands Paolo Santalucia Department of Clinical Neurosciences Brown University School of Medicine 110 Lockwood Street 324 Providence, RI 02903 USA Tohru Sawada National Cardiovascular Center Fujishirodai 5-7-1, Suita Osaka 565-8565 Japan Stefan Schwab Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany Stefan Schwarz Neurological Clinic Im Neuenheimer Feld 400 69120 Heidelberg Germany Florian Stögbauer Neurology Clinic Westfälische Wilhelms-University Münster Albert Schweitzer Str. 33 D-48129 Münster Germany

Matthias Sturzenegger Inselspital Neurological Clinic and Policlinic 3010 Berne Switzerland Laurent Tatu Neurology Services Central University Hospital Jean Minjoz Hospital 25030 Besancon France Barbara E. Tettenborn Kantonsspital St Gallen CH-9007 St Gallen Switzerland Dagmar Timmann Neurological Clinic Universitätsklinikum Essen Hufelandstr. 55 D-45122 Essen Germany Jan van Gijn Department of Neurology University Medical Centre PO Box 85500 3508 GA Utrecht The Netherlands Edoardo Vicenzini Università degli studi di Roma Department of Neurological Science V Cattedra di Clinica Neurologica V. le dell’Università, 30 00185 Rome Italy François Vingerhoets Department of Neurology, University of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland Philippe Vuadens Department of Neurology Unversity of Lausanne CHUV BH 13 CH-1011 Lausanne Switzerland

xv

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Contributors

Patrik Vuilleumier University of Davis Neurology Department 127 VA Medical Center Building E 150 Muir Road Martinez, CA 94553 USA

Takenori Yamaguchi Cerebrovascular Division Department of Medicine National Cardiovascular Center Fujishirodai 5-7-1, Suita Osaka 656-8565 Japan

Bernard Waeber Division of Clinical Pathophysiology CHUV BH 19/640 CH-1011 Lausanne Switzerland

Haruko Yamamoto Pharmaceuticals and Medical Devices Evaluation Center National Institute for Health Services MHW 3-8-21 Toranomon Minato-ku Tokyo 105-8409 Japan

Shirley H. Wray Harvard Medical School Department of Neurology Director, Unit for Neurovisual Disorders Massachusetts General Hospital Boston, MA 02114 USA

Preface

The success of Stroke syndromes over the 5 years elapsed since its publication is the reason for this second edition. Indeed, numerous comments made to us by colleagues, from trainees to international experts, have confirmed to us the interest and importance of a book deeply rooted in the clinical practice with stroke patients – especially in the era of starwars medicine aiming to help examination of these patients and facilitate diagnosis of their condition. The best compliment to medical teachers is when their work is liked by students and junior residents. However, we thought that there was room for improvement, and we have tried to reshape Stroke syndromes, so that some omissions have been filled, and so that it is still more userfriendly. Besides, we have divided the initial book into two volumes, the first focusing on syndromes and their brain and vascular correlates, the second on the particular vascular etiologic syndromes which formed Part III of the first edition. However, the book, still meant as a guide, remains what it was, ‘a bound source and store of patterns and syndromes for non-experts in stroke to refer to when they encounter an unfamiliar pattern’, of three different types: ii(i) patterns of symptoms and signs; i(ii) lesion patterns found in patients with infarcts and hemorrhages in various loci and various vascular territories; (iii) patterns and syndromes that occur in unusual conditions that are known to cause stroke but that are not encountered very often. We thank all authors who have agreed to adapt, rewrite and modify their initial chapters, as well as the numerous new contributors. Five years ago, we were grateful for the availability of fax machines, allowing rapid Lausanne–Boston communications, while now we are grateful for the availability of email; we also wrote that, for stroke management, ‘the window of opportunity is short, probably less than

xvii

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Preface

24 hours, while we know today that it is below 6 hours in most instances. Many other advances have been achieved. With this in mind, we hope that this completely updated and rewritten edition will continue to be of help in the care of patients with stroke. Julien Bogousslavsky, Lausanne Louis R. Caplan, Boston

Part I.i

Clinical manifestations

1

Stroke onset and courses Haruko Yamamoto, Masayasu Matsumoto, Kazuo Hashikawa and Masatsugu Hori Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Japan

Introduction The onset and early natural course of stroke gives critical information about the stroke mechanism (Caplan, 1993). For example, the deficit which is maximal at onset and not associated with headache is most compatible with an embolic mechanism, while a stuttering onset with improvement followed by worsening in the deficit would be against cerebral hemorrhage, but most compatible with a thrombotic process. The gradual development of a progressive focal deficit, accompanied by gradually developing symptoms of increased intracranial pressure, may suggest cerebral hemorrhage (Caplan, 1993). Despite the clinical importance of understanding the time course, there have not been many stroke databanks referring to it. In the Harvard Cooperative Stroke Registry, speed of onset was classified into four subtypes, and recorded for each type of stroke (Mohr et al., 1978). A similar classification of speed of onset has been used in the Lausanne Stroke Registry (Bogousslavsky et al., 1988). Table 1.1 shows the speed of onset for each subtype of stroke reported in these two registries. One may see the similarity of speed of onset in each subtype of stroke between the data from the two stroke registries, despite the different criteria to identify stroke subtype.

Onset and time course in early phase of stroke Ischemic stroke Anterior circulation damage Jones and Millikan (1976) reported the temporal profile of 179 patients with acute carotid ischemic stroke. In their study, 39% of patients had sudden onset and no change in the neurological deficit during the first 7 days after the

onset, while 35% of the patients showed improvement, 22% showed progression or remission and relapse of deficit, and 4% experienced later worsening of neurological deficit after a stable profile of at least 2 days. According to them, if hemiplegia develops within 3 hours of the onset and persists for 36 hours, there is more than a 90% chance that the patient will have a permanent incapacitating motor deficit. They also said that the combination of hemiplegia and any decrease in consciousness on admission predicted poor prognosis. However, they did not refer to the cause of stroke. Both the Harvard Cooperative Stroke Registry and the Lausanne Stroke Registry showed that sudden onset was observed most frequently in embolic infarction, followed by atherosclerotic infarction and lacunar infarction (see Table 1.1). There are reports which analyse speed of onset among infarction in a certain cerebral artery territory. In a report of 27 patients with anterior cerebral artery (ACA) infarction, 74% of them had sudden onset and the rest of them had smooth progressive onset over a few hours to 3 weeks (Bogousslavsky & Regli, 1990). The dominance of sudden onset may be related to the frequent embolic phenomenon from the internal carotid artery (ICA) or from the heart observed in 63% of the patients, although a study from Japan which evaluated angiographic abnormalities in 17 patients with solitary infarction in ACA territory revealed atherothrombosis as the cause of infarction in 59% (Kazui et al., 1993). Another paper from the Lausanne Stroke Registry mentioned large infarction in the middle cerebral artery (MCA) territory (Heinsius et al., 1998). According to this report, 73% of patients with large infarcts in MCA territory (infarction exceeding any one of the three main portions of MCA, that is, anterior superficial, posterior superficial, or deep white matter portion) had sudden onset of stroke. However, 40% of patients with infarction due to ICA dissection had

3

4

H. Yamamoto et al.

Table 1.1. Time course of onset for each type of stroke Speed of onset

Sudden

Stepwise or stutteringa

Smooth or graduala

Fluctuations

Atherosclerosis

HCSR LSR

40 66

34 27

13 —

13 7

Cardiac embolism

HCSR LSR

79 82

11 13

5 —

5 5

Lacune

HCSR LSR

38 54

32 40

20 —

10 6

Cerebral hemorrhage

HCSR LSR

34 44

3 52

63 —

0 4

Notes: Data are percentage of row. HCSR: Harvard Cooperative Stroke Registry, LSR: Lausanne Stroke Registry. a In LSR, only one subtype ‘progressive onset’ was applied for the two subtypes of ‘stepwise onset’ and ‘smooth onset’ in HCSR. Sources: Mohr et al. (1978); Bogousslavsky et al. (1988).

progressive onset, which was a significantly higher frequency compared with patients without dissection. Patients with ICA occlusion also showed higher frequency of progressive (34%) onset compared to patients without occlusion. Another paper from the Lausanne Stroke Registry about multiple infarction in the anterior circulation showed that 37 of 40 patients had sudden onset (Bogousslavsky et al., 1996). They reported various presumed causes of infarction, including major stenosis of ipsilateral ICA, cardiogenic embolism, granulomatous angitis, and ICA dissection. The above mentioned may suggest a tendency of sudden onset for infarction with embolic cause and of gradual or progressive onset for infarction with vascular occlusive lesion. Yamawaki et al. (1998) studied retrospectively 523 consecutive patients with thrombotic infarction who were admitted in a stroke care unit within 7 days after onset, and showed that progressive neurological deterioration occurred in 18% of patients, which was more frequent in atherothrombotic infarction located in the corona radiata or pons compared with lacunar infarction. Yamamoto et al. also revealed the significantly higher frequency of progressive neurological deterioration in patients with large artery atherosclerosis compared to those with lacunar infarction (Yamamoto et al., 1998). Watershed infarction occurs in the border zones between two main artery territories after severe hypotension. It may also occur under the existence of severe occlusive lesion in major arteries including ICA and MCA. A study from the Lausanne Stroke Registry about unilateral watershed infarction in the anterior circulation reported that the onset was usually immediately complete (65%),

progressed briefly (31%), or fluctuated over 24 hours (4%) in 51 patients (Bogousslavsky & Regli, 1986). More interestingly, 29% of the patients had preceding ipsilateral transient ischemic attacks (TIAs).

Posterior circulation damage Non-sudden onset or progressive neurological deterioration has been found more frequently among infarction in posterior circulation than that in anterior circulation. Jones et al. (1980) reported 20 (54%) of 37 patients with posterior circulation infarction had non-sudden onset, while only 48 (27%) of 179 patients with anterior circulation infarction had non-sudden onset. They observed that it took a long time (up to 96 hours), for stabilization of the clinical symptoms in patients with posterior circulation infarction. A similar result was reported by another study (Patrik et al., 1980). In their paper, 56.4% of patients with posterior circulation infarction had progressing or fluctuating onset. One of their patients had progressive ataxia over 7 days. They also observed progressive neurologic impairment after the original deficit had been stabilized for 24 hours in a few patients. The stable interval time was up to 7 days. They warned that instability and late exacerbation after the stable interval time could be expected for 7 days after onset. Vuilleumier et al. (1995) studied 28 patients with infarction in the lower brainstem. In their paper, 46% of the patients had stepwise neurological deterioration during up to 14 days after the onset. Before the onset, 46% of all patients experienced one or several warning TIAs, which were imbalance and/or vertigo. A report of 45 patients with basilar artery embolism

Stroke onset and courses

found that most of them had sudden onset (41 patients, 91%), and 15 of them had complete loss of consciousness (Schwarz et al., 1997). However, four patients had slowly progressive onset despite proven embolic etiology. Stroke in posterior circulation is rather rare territory, but Neau and Bogousslavsky (1996) reported posterior choroidal artery territory infarction. According to them, ten patients, which was 1.5% of 740 patients with posterior circulation infarction, had ischemic lesion in the posterior choroidal artery territory. None of the patients had TIA prior to their infarcts. Stroke was stabilized within a few minutes in nine of ten patients, and progressed over half an hour in one patient. Small artery disease was the most common presumed cause of infarction.

Hemorrhagic stroke Neurological deterioration may be often observed in patients with cerebral hemorrhage. In a study from the Lausanne Stroke Registry, the rate of progressive deficit after onset was similar between cerebral infarction and cerebral hemorrhage, and in both was significantly higher than the rate of progressive deficit in cardiogenic cerebral embolism (Yamamoto et al., 1998). A study of 204 patients with intracerebral hemorrhage, who underwent an initial CT scan within 48 hours and a repeat CT within 120 hours of the onset, reported that enlargement of hematoma was common in the hyperacute stage but seemed extremely rare after 24 hours of onset. Clinical deterioration was observed significantly more frequently in the patient group with hematoma enlargement than that without (the odds ratio; 11.7, 95% confidence intervals; 5.0–27.8) (Kazui et al., 1996). A similar result was reported by another study of 103 patients with cerebral hemorrhage (Brott et al., 1997).

Progressive stroke Deterioration of neurological symptoms in the acute phase after the onset is not rare in patients with ischemic or hemorrhagic stroke. It has attracted clinicians’ attention for more than 40 years (Millikan & Siekert, 1955a,b), and called various terms, such as progressive stroke, stroke-inprogression, or stroke-in-evolution. However, the definition of ‘progressive stroke’ has never been generally accepted. Some reports used certain stroke scales, others chose clinical definition (Gautier, 1985). Trials for revealing risk factors, which may predict progressive stroke, have also reached to variable and controversial results. A report investigated predictors of progressive stroke in each stroke

subtype group, and revealed that different risk factors were related to progressive stroke in different subtype groups, that is, infarction in posterior circulation territory and reduced level of consciousness for large-artery atherosclerosis, while at age younger than 65, hypertension, lack of preceding TIA, reduced level of consciousness, and infarction not in superficial anterior circulation for lacunar infarction (Yamamoto et al., 1998). Another report evaluated only patients with supratentorial lacunar infarction in the internal capsule or the corona radiata, and found that diabetes mellitus and severity of motor deficit on admission were related independently to neurological deterioration (Nakamura et al., 1999). At this point, however, it remains difficult to predict progressive stroke from clinical factors alone. There have been studies trying to reveal mechanisms involved in progressive stroke. Thrombus propagation, narrowing of arterial stenosis, development of brain edema, etc. have been suggested as causes. One study showed sequential changes of angiographic findings, including arterial stenosis or thrombus displacement in patients who had progressive stroke (Irino et al., 1983), while other studies suggested that insufficient blood supply caused by poor collateral circulation development might commonly contribute (Fisher & Garcia, 1996; Toni, et al., 1995). Recently, delayed neuronal death, mediated by the accumulation of glutamate and other excitatory amino acids in extracellular spaces, was suggested to play a role in experimental focal ischemia (Asplund, 1993). A recent study of 128 patients with ischemic hemispheric stroke found that concentrations of glutamate in plasma and cerebrospinal fluid (CSF) within the first 24 hours from stroke onset were significantly higher in patients presented with progressive stroke than in those with stable stroke (Castillo et al., 1997). This study also revealed that a plasma glutamate concentration of more than 200 ␮mol/l and a CSF glutamate concentration of more than 8.2 ␮mol/l were independently and significantly associated with progression of neurological deficit, and both of them were good predictors of progression (positive predictive value; 97% for plasma, 94.3% for CSF). This study also found that high body temperature at admission was an independent risk factor for progression within the first 48 hours of ischemic hemispheric stroke. However, it is open for future research whether these findings could explain progression of neurological deficit of other subgroups of stroke, including lacunar infarction and cerebral hemorrhage. Progressive stroke is always a sign of poor outcome in any subtypes of stroke, and early prediction and effective therapy would be mandatory.

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H. Yamamoto et al.

Early spontaneous improvement In acute phase of stroke, not only deterioration but also amelioration of neurological deficit may be observed, although it would never occur in cerebral hemorrhage. In particular, this may be found in cases of cardiogenic brain embolism, usually within minutes to hours, in the form of abrupt onset of a major hemispheric syndrome followed by dramatic improvement or complete disappearance of the symptoms. Mohr et al. (1986) called this phenomenon ‘a spectacular shrinking deficit’. They assumed the mechanism to be rapid migration of an embolus from a large artery of the carotid system to its distal branches, and emphasized the phenomenon as a sign of cardiogenic embolism. A study of 118 patients with an initial major hemispheric syndrome found that 14 (12%) of them had spectacular shrinking deficit, and all but one were compatible for cardiogenic brain embolism (Minematsu et al., 1992). According to this study, recovery began from 15 minutes to 24 hours after stroke onset, and earlier onset of recovery, which means shorter duration of a major hemispheric syndrome, was significantly related to better outcome. Patients with recovery tended to be young, and had significantly fewer risk factors. The study also revealed more distal occlusion of intracerebral arteries in patients with recovery compared to those without recovery, suggesting distal migration of embolus. Another recent study investigated cerebral blood flow in acute phase of ischemic stroke with single-photon emission computed tomography (SPECT) (Barber et al., 1998). In this study, repeated SPECT images revealed that early reperfusion observed between the first SPECT scan (9.2 hours after onset of stroke) and the second SPECT scan (44.3 hours after onset of stroke) was associated with better outcome and smaller final infarct size, while non-nutritional or luxury reperfusion was not associated with either an improved or an adverse outcome. It may explain the difficulty of the timing of thrombolysis for tissue salvage. Toni et al. (1998) also suggested the existence of individual time frames for tissue recovery in their study of spontaneous improvement after ischemic stroke with serial transcranial Doppler ultrasonography. These studies agreed with the point that spontaneous neurological improvement in the acute phase may usually lead to better outcome.

Transient ischemic attack Reports of the frequency with which TIA patients suffer cerebral infarction range from 2% to 62%. When assessed

retrospectively, the range is from 9% to 74%. About 36% have infarction within the month and 50% within 12 months of onset of TIAs. It is estimated that about onethird of those who suffer recurrent TIAs continue to have attacks without developing permanent disability; another third eventually have cerebral infarction, and in the remainder the attacks stop spontaneously. So, TIA could be a clinical course before stroke. Five-year mortality rates in TIA patients average about 20% to 25%. However, the majority of causes of death are secondary to myocardial rather than to cerebral infarction. Prognosis of TIA depends on its etiology and concomitant diseases. In younger populations, etiologies such as valvular and congenital heart disease and hypotension are major contributors to TIA, while in the elderly, hypertension and atherosclerosis are major contributors to risk in the course and prognosis is poorest. In a report of 1093 patients admitted with TIA, repetitive attacks (three or more attacks in 24 hours) in the presumed subcortical region occurred in 50 patients (4.5% of all TIAs). The episodes were usually clustered in a relatively brief interval, for example, five episodes in 3 hours, and the maximum number of events was 13. However, in 33 patients with the repetitive attacks who underwent angiographic study or duplex ultrasound of ICA, only three patients had significant stenotic change in ICA. The attacks were resistant to various forms of therapies, including hemodilution with plasma expanders, anticoagulation with intravenous heparin, and antithrombotic medication with aspirin. Twenty-one patients (42%) developed a fixed neurological deficit, although most of them presented typical lacunar syndrome (Donnan et al., 1993). A study of 47 patients with repetitive TIAs presenting acutely with repetitive symptoms indicative of anterior circulation ischemia reported that 55% of all patients were found to have anatomically significant disease. In particular, 85% of the patients with signs or symptoms suggestive of cortical ischemia, amaurosis fugax, or both had ‘positive’ angiogram (75% or more carotid stenosis, less than 75% carotid stenosis associated with ulceration, or 75% or more middle cerebral stenosis) (Rothrock et al., 1988).

Conclusion Type of onset and early clinical course may contain rich information about pathophysiology of stroke. Understanding the stroke dynamics would be necessary for active treatment in the acute phase, including thrombolysis.

Stroke onset and courses

iReferencesi Asplund, K. (1993). Deterioration of acute stroke. In Thrombolytic Therapy in Acute Ischemic Stroke II, ed. G. J.del Zoppo, E. Mori & W. Hacke, pp. 119–28. Berlin: Springer-Verlag. Barber, P.A., Davis, S.M., Infeld, B. et al. (1998). Spontaneous reperfusion after ischemic stroke is associated with improved outcome. Stroke, 29, 2522–8. Bogousslavsky, J. & Regli, F. (1986). Unilateral watershed cerebral infarcts. Neurology, 36, 373–7. Bogousslavsky, J. & Regli, F. (1990). Anterior cerebral artery territory infarction in the Lausanne Stroke Registry. Clinical and etiologic patterns. Archives of Neurolology, 47, 144–50. Bogousslavsky, J., van Melle, G., & Regli, F. (1988). The Lausanne Stroke Registry: analysis of 1000 consecutive patients with first stroke. Stroke, 19, 1083–92. Bogousslavsky, J., Bernasconi, A., & Kumral, E. (1996). Acute multiple infarction involving the anterior circulation. Archives of Neurology, 53, 50–7. Brott, T., Broderick, J., Kothari, R. et al. (1997). Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke, 28, 1–5. Caplan, L.R. (1993). Stroke. A Clinical Approach, 2nd edn. Stoneham, MA: Butterworth-Heinemann. Castillo, J., Davalos, A., & Noya, M. (1997). Progression of ischaemic stroke and excitotoxic aminoacids. Lancet, 349, 79–83. Donnan, G.A., O’Malley, R.N., Quang, L., Hurley, S., & Bladin, P.F. (1993). The capsular warning syndrome: pathogenesis and clinical features. Neurology, 43, 957–62. Fisher, M. & Garcia, J.H. (1996). Evolving stroke and the ischemic penumbra. Neurology, 47, 884–8. Gautier, J.C. (1985). Stroke-in-progression. Stroke, 16, 729–33. Heinsius, T., Bogousslavsky, J., & van Melle, G. (1998). Large infarcts in the middle cerebral artery territory. Etiology and outcome patterns. Neurology, 50, 341–50. Irino, T., Watanabe, M., Nishide, M., Gotoh, M., & Tsuchiya, T. (1983). Angiographical analysis of acute cerebral infarction followed by ‘cascade’-like deterioration of minor neurological deficits: what is progressing stroke? Stroke, 14, 363–8. Jones, H.R. & Millikan, C.H. (1976). Temporal profile of acute cerebral infarction in the distribution of the internal carotid artery. Stroke, 7, 64–71. Jones, H.R., Millikan, C.H., & Sandok, B.A. (1980). Temporal profile (clinical course) of acute vertebrobasilar system cerebral infarction. Stroke, 11, 173–7. Kazui, S., Sawada, T., Naritomi, H., Kuriyama, Y., & Yamaguchi, T. (1993). Angiographic evaluation of brain infarction limited to the anterior cerebral artery territory. Stroke, 24, 549–53. Kazui, S., Naritomi, H., Yamamoto, H., Sawada, T., & Yamaguchi, T. (1996). Enlargement of spontaneous intracerebral hemorrhage. Incidence and time course. Stroke, 27, 1783–7.

Millikan, C.H., & Siekert, R.G. (1955a). Studies in cerebrovascular disease, I: the syndrome of intermittent insufficiency of the basilar arterial system. Proceedings of Staff Meetings Mayo Clinic, 30, 61–8. Millikan, C.H. & Siekert, R.G. (1955b). Studies in cerebrovascular disease, IV: the syndrome of intermittent insufficiency of the carotid arterial system. Proceedings of Staff Meetings Mayo Clinic, 30, 186–91. Minematsu, K., Yamaguchi, T., & Omae, T. (1992). ‘Spectacular shrinking deficit’: rapid recovery from a major hemispheric syndrome by migration of an embolus. Neurology, 42, 157–62. Mohr, J.P. & Barnett, H.J.M. (1986). Classification of ischemic strokes. In Stroke: Pathophysiology, Diagnosis, and Management, ed. H.J.M. Barnett, B. M.Stein, J.P. Mohr, & F.M.Yatsu, vol 1, pp. 281–91. New York: Churchill Livingston. Mohr, J.P., Caplan, L.R., Melski, J.W. et al. (1978). The Harvard Cooperative Stroke Registry: a prospective registry. Neurology, 28, 754–62. Nakamura, K., Saku, Y., Ibayashi, S., & Fujishima, M. (1999). Progressive motor deficits in lacunar infarction. Neurology, 52, 29–33. Neau, J-P. & Bogousslavsky, J. (1996). The syndrome of posterior choroidal artery territory infarction. Annals in Neurology, 39, 779–88. Patrick, B.K., Ramirez-Lassepas, M., & Snyder, B.D. (1980). Temporal profile of vertebrobasilar territory infarction. Prognostic implications. Stroke, 11, 643–8. Rothrock, J.F., Lyden, P.D., Yee, J., & Wiederholt, W.C. (1988). ‘Crescendo’ transient ischemic attacks: clinical and angiographic correlations. Neurology, 38, 198–201. Schwarz, S., Egelhof, T., Schwab, S., & Hacke, W. (1997). Basilar artery embolism. Clinical syndrome and neuroradiologic patterns in patients without permanent occlusion of the basilar artery. Neurology, 49, 1346–52. Toni, D., Fiorelli, M., Gentile, M. et al. (1995). Progressing neurological deficit secondary to acute ischemic stroke: a study on predictability, pathogenesis and prognosis. Archives of Neurology, 52, 670–5. Toni, D., Fiorelli, M., Zanette, E.M. et al. (1998). Early spontaneous improvement and deterioration of ischemic stroke patients. A serial study with transcranial Doppler ultrasonography. Stroke, 29, 1144–8. Vuilleumier, P., Bogousslavsky, J., & Regli, F. (1995). Infarction of the lower brainstem. Clinical, aetiological and MRI-topographical correlations. Brain, 118, 1013–25. Yamamoto, H., Bogousslavsky, J., & van Melle, G. (1998). Different predictors of neurological worsening in different causes of stroke. Archives of Neurology, 55, 481–6. Yamawaki, T., Yanagimoto, S., Kinugawa H., & Naritomi, H. (1998). Subtype and location in progressing stroke. Cerebrovascular Disease, 8(4), 40 (Abstract).

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Clinical types of transient ischemic attacks Graeme J. Hankey Department of Neurology, Royal Perth Hospital and University of Western Australia

Definition of transient ischemic attacks (TIAs) A transient ischemic attack of the brain or eye (TIA) is a clinical syndrome characterized by an acute loss of focal brain or monocular function with symptoms lasting less than 24 hours and which is thought to be due to inadequate cerebral or ocular blood supply as a result of low blood flow (hypotension), arterial thrombosis or embolism associated with disease of the arteries, heart or blood (Hankey & Warlow, 1994). Focal symptoms are those which allow clinicoanatomical correlation (Table 2.1), whereas non-focal symptoms are not anatomically localizing and are therefore not usually TIAs (Table 2.2). The distinction between focal and non-focal neurological symptoms has a grey area, however; sensory and motor disturbances in a pseudo-radicular pattern (such as a wrist drop or tingling in two or three fingers) probably reflect focal neurological dysfunction (Youl et al., 1991; Bassetti et al., 1993; Kim, 1996); so may cognitive changes but these can be difficult to characterize and quantify and are usually not considered as focal neurological symptoms. The symptoms of TIAs are usually ‘negative’ in quality, representing a loss of function (e.g. loss of sensation, power, vision, etc.). If different parts of the body (e.g. face, upper limb and lower limb) are affected, the symptoms usually start at the same time and do not intensify, spread or ‘march’; i.e. they are maximal at onset. The symptoms usually resolve slowly, but completely, within about 15 to 60 minutes (Pessin et al., 1977; Bogousslavsky et al., 1986; Levy, 1988; Werdelin & Juhler, 1988; Dennis, 1988). Sometimes, however, they last longer – by definition not more than 24 hours. Episodes of transient monocular blindness (amaurosis fugax (AFx)) tend to be briefer, lasting less than 5 minutes in most cases, than

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transient ischemic attacks of the brain (Hankey & Warlow, 1994). The difference in duration of attacks may have several explanations, all of which are speculative. Following symptomatic recovery, a few physical signs such as reflex asymmetry or an extensor plantar response, which are not important functionally and are therefore not noticed by the patient, may be elicited in about 5% of patients (Hankey et al., 1991), depending on when the patient is examined after the resolution of symptoms, on the thoroughness of the examination, and on the competence of the examiner. Cranial computerized tomography (CT) or magnetic resonance imaging (MRI) may also reveal evidence of infarction in an area of the brain relevant to the transient symptoms (Dennis et al., 1990; Hankey & Warlow, 1994); the proportion of TIA/ischemic stroke patients with an appropriate infarct on CT scanning gradually rises with the duration of symptoms, from 10% with attacks under 30 minutes, to 40% with symptoms lasting 1–6 weeks (Koudstaal et al., 1992). The only factor which distinguishes a TIA from a mild ischemic stroke is the duration of the symptoms of focal neurological dysfunction (i.e. less or more than 24 hours). Otherwise, patients with TIA and mild ischemic stroke are qualitatively the same; they are of similar age and sex, have a similar prevalence of coexistent vascular risk factors (and probably therefore pathogenesis), share the same longterm prognosis for serious vascular events, and describe qualitatively similar clinical symptoms (Koudstaal et al., 1992).

Clinical symptoms and types of TIAs The symptoms of loss of function of a particular part of the brain or eye due to regional ischemia are determined by the site of ischemia (and therefore the site of the arterial

Clinical types of transient ischemic attacks

Table 2.1. Focal neurological and ocular symptoms

Table 2.2. Non-focal neurological symptoms

Motor symptoms Weakness or clumsiness of one side of the body, in whole or in part Simultaneous bilateral weaknessa Difficulty swallowinga

Generalized weakness and/or sensory disturbance Faintness and/or imbalance Altered consciousness or fainting, in isolation or with impaired vision in both eyes Incontinence of urine or feces Confusion or memory disturbance A spinning sensationa Difficulty swallowinga Slurred speecha Double visiona Loss of balancea

Speech/language disturbances Difficulty understanding or expressing spoken language Difficulty reading or writing Slurred speecha Difficulty calculating Sensory symptoms Somatosensory Altered feeling on one side of the body, in whole or in part Visual Loss of vision in one eye, in whole or in part Loss of vision in the left or the right half of the visual field Bilateral blindness Double visiona Vestibular A spinning sensationa Note: a In isolation these symptoms do not necessarily indicate transient focal cerebral ischemia.

occlusion), the degree of ischemia, the duration of ischemia (which depends on the capacity of the collateral blood supply to perfuse the ischemic area and the rate at which the occluded vessel is recanalized), the activities in which the patient is engaged at the time of the ischemic event, the patient’s recall of the event and ability to communicate it, and the quality of interrogation by the clinician. Therefore, the clinical manifestations of focal brain or eye ischemia, or clinical ‘types’ of TIA, are variable (Table 2.3). As many hours of wakefulness are spent in an alert state with eyes open, a keen sensorium, an upright posture, and often speaking or reading, it is not surprising that most of the symptoms that TIA patients experience are a loss of motor, somatosensory, visual or speech function. Other, more transient activities, such as swallowing and calculation, are less frequently reported as being affected. Presumably TIAs, like strokes, occur during sleep and the patient is unaware of them and there are no sequelae other than perhaps CT scan evidence of infarction if a scan is done for some other reason months or years later. Although TIAs often occur only once, they may recur, and recur frequently up to several times a day (Dennis,

Note: a If these symptoms occur in combination, or with focal neurological symptoms, they may indicate a transient focal cerebral ischemia.

1988; Hankey et al., 1991, 1992). Recurrent TIAs may sometimes be remarkably stereotyped or they may be quite different in terms of the ‘type’ of attack (i.e. the nature of the symptoms). As the Oxfordshire Community Stroke Project (OCSP) is one of the few large community-based prospective studies of TIA and the clinical types of TIA, I will describe the data from the OCSP in some detail, and supplement it with data from other well-studied hospital-referred cohorts (Pessin et al., 1977; Bogousslavsky et al., 1986). In the OCSP, 184 TIA patients reported 201 clinical ‘types’ of attacks; 168 patients (91%) presented with one clinical ‘type’ of attack, 15 patients (8%) experienced more than one ‘type’ of attack and one patient described three separate ‘types’ of attack, although sometimes these appeared to involve the same arterial territory (Table 2.3) (Dennis, 1988).

Motor symptoms Motor symptoms are the most common symptoms described by TIA patients; in the OCSP they were experienced in 101 of the 184 patients (54%), and were a feature in 109 of the 201 (54%) clinical ‘types’ of attack (Dennis, 1988). ‘Weakness’ was by far the most common motor symptom, followed by ‘heaviness’ and ‘clumsiness’. In most series, motor symptoms are reported to be associated with sensory symptoms of some sort; pure motor symptoms are present in only about 15–25% of patients (Pessin et al., 1977; Bogousslavsky et al., 1986; Dennis, 1988). However, it is unwise to be dogmatic about the presence or absence of sensory symptoms because often a weak limb is described by the patient as ‘numb’ or ‘dead’

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and this is often interpreted by the doctor as a combination of motor and sensory symptoms.

focal neurological (usually cranial nerve) dysfunction may represent a TIA; this was the case for eight TIA patients (4%) in the OCSP (Table 2.3) (Dennis, 1988).

Weakness on one side of the body In the OCSP, motor symptoms (i.e. weakness) involved the left side of the body in 51 patients (28%), the right side in 42 patients (23%) and were both sides in eight patients (4%) (Dennis, 1988). Among the 93 patients with unilateral motor symptoms, weakness involved the face and upper and lower limb in 8%, the face and upper limb in 36%, the upper and lower limb (hemiparesis) in 26%, and either the face, upper limb or lower limb only (monoparesis) in 30%. Similar findings were reported by Bogousslavsky et al. (1986). Unilateral facial weakness is probably under-reported in TIAs because many patients do not realize they have had facial weakness unless they have seen themselves in the mirror, or unless the attack has been witnessed by an observer. If there is a clear history of dysarthria, in the absence of symptoms of cerebellar or bulbar dysfunction, it is reasonable to suspect facial weakness because facial weakness may cause dysarthria (if the patient attempts to speak). Having established that facial weakness was present, it can be even more difficult to determine which side of the face was weak. This is because the interpretation and recall of the patient and any witnesses may have been affected by anxiety and panic during the attack. Alternatively, the patient and witnesses may have suffered from left–right confusion or misinterpreted which side of the ‘twisted’ face was weak and which side was contracting. So, the side of the face which is reported to have been weak is very unreliable and cannot be assumed to have been ipsilateral to the limb weakness, unless there was also sensory loss (as well as motor loss) on one side of the face. Transient weakness of only one lower limb usually indicates a disturbance in the parasagittal region of the contralateral cerebral cortex due to ischemia in the anterior cerebral artery territory or the boundary zone between the anterior and middle cerebral artery territories. The latter is more likely if the upper extremity is also somewhat weak and if the symptoms have been precipitated or aggravated by standing or walking. These patients usually have underlying carotid occlusive disease (Yanagihara et al., 1988).

Weakness on both sides of the body Although generalized weakness is a non-focal neurological symptom, the sudden onset of clearcut bilateral weakness (quadriparesis, paraparesis, bilateral facial, and face and contralateral hand weakness) together with symptoms of

Unsteadiness Unsteadiness is a fairly common symptom in TIA patients (12% of the OCSP cohort) but, unless associated with clearly focal symptoms, it can be difficult to decide whether the patient simply means weakness, incoordination or both.

Difficulty swallowing Although dysphagia is a common feature of acute stroke, it is uncommonly reported by TIA patients. In the OCSP only one patient described dysphagia during a TIA, the attack occurring during a meal. The rarity of this symptom in a TIA is not surprising; although we are continually swallowing saliva, it is usually performed subconsciously and any transient deficit is likely to pass unnoticed. Difficulty in swallowing food is far more likely to be noticed but as we do not spend much of the day eating, a TIA is unlikely to coincide with such activity.

Movement disorders Episodic movement disorders are rare manifestations of transient cerebral ischemia and include paroxysmal dyskinesia (Margolin & Marsden, 1982; Stark, 1985; Hess et al., 1991) and orthostatic ‘limb-shaking’ spells (see below) (Yanagihara et al., 1985; Baquis et al., 1985).

Speech disturbances Patients with TIA may complain of transient speech disturbances due to an articulatory and/or a language disturbance. If the patient describes slurred speech, as if drunk, and if the ability to understand and express spoken and written language was preserved, the diagnosis is dysarthria, which is usually due to facial weakness or incoordination of the respiratory, bulbar or facial muscles. If the main difficulty was that of understanding or producing sentences, with words in their proper place, the diagnosis is dysphasia, which is usually due to dominant frontotemporo-parietal ischemia. If speech production was so severely affected that the patient was mute, it may be extremely difficult to ascertain retrospectively whether a language deficit was present, unless there was an associated disturbance of comprehension, reading or writing (not due to weakness) or the examiner has tested language function during the attack. The type of speech disturbance during the phase of recovery may be a helpful clue. Dysphasia and dysarthria may coexist. In the OCSP, dysarthria was the most common form of

Clinical types of transient ischemic attacks

speech disorder, occurring simultaneously with other focal neurological symptoms in 43 patients (23%) (Dennis, 1988). Dysarthria occurring in isolation, without any other symptoms, is not considered to be a TIA. Dysphasia was present in 34 patients (18%), a few of whom also described slurred speech. No patient described transient problems with reading, writing or calculation as part of the TIA; these deficits possibly occurred but were not recognized as the patient needs to be engaged in the relevant activities at the time of the TIA to notice any deficit and be asked about them later by a more than usually inquisitive clinician!

Sensory symptoms Somatosensory symptoms Somatosensory symptoms, when present, are usually described by the patient as a numbness, tingling or dead sensation and very rarely as pain. The anatomical distribution of somatosensory symptoms is usually unilateral affecting the face, arm and/or leg, as it is for motor symptoms (Table 2.3). In the OCSP, 64 patients (35%) described somatosensory symptoms, usually in the form of ‘numbness’. Associated motor symptoms were present in 53 patients. Only 11 patients (6%) had purely somatosensory symptoms. Bogousslavsky et al. (1986) reported pure somatosensory TIAs as the most common single type of carotid TIA (27%), at least in patients who underwent angiography, with another 45% having sensory symptoms combined with motor, visual or speech disturbances. Pessin et al. (1977) found pure sensory symptoms in 15% and combined motor and sensory symptoms in another 58% of patients with carotid TIAs. However, it can be very difficult to interpret transient isolated sensory symptoms involving a part of one extremity or only one side of the face during a single attack because they may be a manifestation of other disorders such as an entrapment mononeuropathy (e.g. median neuropathy at the wrist), multiple sclerosis, hyperventilation and even hysteria. This difficulty probably accounts for some of the variation in both the diagnosis of TIA among different observers and the prevalence of sensory symptoms among different TIA cohorts.

‘Neglect’ Visual–spatial–perceptual dysfunction, sometimes manifesting as ‘neglect’ of one side of the body or extrapersonal space, can occur in patients with ischemia of the contralateral non-dominant cerebral hemisphere. It is probably the corollary to dysphasia, which may occur during ischemia in the dominant cerebral hemisphere subserving language function. Unlike dysphasia, however, visual–spatial–per-

ceptual dysfunction is a difficult symptom to recognize, particularly when it is transient and associated with other more striking neurological deficits, such as hemiparesis. In the OCSP, only two patients had symptoms other than weakness or numbness that indicated ischemia of the nondominant hemisphere (Dennis, 1988). For example, one man complained that, during the TIA, his left arm was twisted up in the sheets and this was his explanation of why he was unable to use it. His wife and the attending general practitioner were certain that he had quite severe weakness of the left side of which he was unaware. This lack of awareness may have been due to ‘neglect’ of his left side. It is possible that some of the patients who are described as being confused during the attack actually have nondominant hemisphere ischemia (causing dressing apraxia, etc.) or alternatively, dominant hemisphere ischemia (causing dysphasia) and that other coexisting focal neurological symptoms are not recalled or reported; although these can be found in most stroke patients with confusional states.

Visual symptoms Visual symptoms associated with transient cerebral and retinal ischemia are generally of three types: obscuration or loss of vision in one eye, in both eyes, or double vision. Positive visual effects such as shimmering and visual hallucinations are usually binocular and associated with migraine. In the OCSP (Dennis, 1988), 60 patients (33%) experienced visual symptoms during their TIA, most commonly monocular blindness (AFx).

Loss of vision in one eye: transient monocular blindness (amaurosis fugax) Amaurosis fugax (meaning literally ‘fleeting blindness’) is a term used to describe the abrupt onset, over seconds, of loss of vision (greyish haze or black) in one eye due to transient ischemia in the territory of supply of the ophthalmic or central retinal artery. Typically, the symptoms arise spontaneously, without provocation, and recover rapidly after several seconds to a few (usually less than 5) minutes. Uncommonly the visual loss lasts for several hours before full recovery occurs. The visual deficit is usually complete immediately but it may appear as if a curtain or shade has progressively obscured vision over a few seconds. The ‘curtain’ usually comes down from above but sometimes it comes up from below. The loss of vision may be complete or partial and usually involves the entire visual field. Occasionally, however, it is restricted to either the upper or lower half of the visual field and, even less frequently, to the peripheral nasal and/or

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Table 2.3. Clinical features in a cohort of 184 community TIA patients % of 184

95% confidence interval

Type of attack ‘Single ‘type’ of attack’ ‘More than one ‘type’ of attack’

91 9

87 to 95 5 to 13

Vascular territory Carotid TIA eye (amaurosis fugax) TIA brain TIA brain and eye Vertebrobasilar Uncertain (hemiphenomena) More than one vascular territory

80 17 62 1 13 7 1

74 to 86 12 to 22 55 to 69 0 to 3 8 to 18 3 to 11 0 to 3

Motor symptoms Weakness/heaviness/clumsiness unilateral left side of body right side of body bilateral quadriparesis paraparesis facea and contralateral arm ‘Unsteadiness’ Dysphagia Limb shaking

54 51 28 23 4 1 2 1 12 1 1

47 to 61 43 to 57 22 to 34 17 to 29 1 to 7 0 to 3 0 to 4 0 to 3 7 to 1 0 to 3 0 to 3

Speech disturbances Dysarthria (with other focal symptoms) Dysphasia ‘Dyslexia, Dysgraphia, Dyscalculia’

40 23 18 0

33 to 47 17 to 29 12 to 24 0 to 3

Somatosensory symptoms isolated associated with motor symptoms ‘Neglect’

35 6 29 1

28 to 42 3 to 9 22 to 36 0 to 3

Visual symptoms Monocular blindness Hemianopia (isolated) Bilateral blindness (with other focal symptoms) Double vision (with other focal symptoms) Blurred vision in both eyes (with other focal symptoms)

33 18 5 1 5 4

26 to 40 12 to 24 2 to 8 0 to 3 2 to 8 1 to 7

Vestibular symptoms Vertigo (with other focal symptoms)

5

2 to 8

Loss of consciousness

1

0 to 3

Note: a Patients have difficulty detecting facial weakness; they usually only note dysarthria and a witness is usually required to describe facial weakness. Source: From Dennis (1988).

Clinical types of transient ischemic attacks

temporal field. Patchy and sectorial loss may also occur but presumably is less likely to be noticed by the patient (Bogousslavsky et al., 1986). Occasionally, young patients describe a series of ‘blobs’ or lacunae throughout the field of vision which may gradually coalesce into a complete loss of visual field; it has been suggested that this pattern of visual loss may correspond to the lobular arrangement of the blood supply in the choriocapillaris and indicate ischemia in the choroid circulation rather than the retinal circulation (O’Sullivan et al., 1992). Flashing lights, shooting stars, scintillations or other positive phenomena in the area of impaired vision can occasionally arise during retinal or optic nerve ischemia (Goodwin et al., 1987), but they are far more commonly encountered during migraine, involving the retina or occipital lobe. Amaurosis fugax (AFx) may not be the only symptom; other symptoms may coexist such as transient sensory symptoms (paraesthesias) over the same side of the face (Ropper, 1985) and contralateral hemiparesis and hemisensory deficit. Amaurosis fugax may recur, usually in a stereotyped fashion, but the area of visual impairment may vary from one episode to the next, depending on which part of the retina is ischemic.

Lone bilateral blindness Sudden, spontaneous and simultaneous blindness in both eyes indicates retinal, chiasmal or occipital lobe dysfunction bilaterally. In the OCSP register of patients with suspected TIA (and without prior stroke), 14 patients had lone bilateral blindness, defined as rapid onset of dimming or loss of vision over all of both visual fields simultaneously, lasting less than 24 hours, without associated symptoms of focal cerebral ischemia, seizures or reduction in consciousness. The age of these patients was close to that of the 184 patients who presented with TIAs, and they had an equally high prevalence of vascular risk factors. During a mean follow-up period of 2.4 years, five of the 14 had a first-ever stroke (only 0.31 expected). In view of their 16 times excess risk of stroke, such patients are now considered, for practical purposes, as TIAs (Dennis et al., 1989b). The differential diagnosis of patients who describe the simultaneous occurrence of binocular blurring, dimming or complete loss of vision depends on the associated symptoms. If the symptoms arise when the patient is feeling faint and experiencing other pre-syncopal symptoms, the likely cause is global cerebral hypoperfusion. If bilateral blindness occurs in isolation, it is probably caused by bilateral posterior cerebral artery ischemia, unless it has been provoked by a photostress such as bright or white light, in which case it is probably bilateral retinal ischemia (see below).

Loss of vision in the left or right half of the visual field Isolated homonymous hemianopia is rare in comparison to other varieties of TIA, although asymptomatic visual field defects, chiefly located in the upper part of the visual field, have been reported in 29% of 17 patients with TIA and 57% of 14 patients with minor stroke (Falke et al., 1991). In the OCSP, nine patients (5%) had isolated sudden onset of hemianopia with no positive visual symptoms (or brainstem symptoms) (Dennis, 1988). Part of the reason for the relatively low frequency of this symptom may be that patients have difficulty recognising and also describing it, particularly if there are other symptoms (such as hemiparesis) which are more readily appreciated and described. Also, it can be difficult to distinguish binocular loss of vision (such as a homonymous hemianopia) from monocular loss of vision; the patient needs to have covered each eye in turn during the symptoms and noted the effect (of objects that were previously seen in the centre of the visual field now appearing to be split in half). Even if the patient has covered each eye in turn during the attack, it may not be possible to be really confident of the distinction because an incongruous homonymous hemianopia does not necessarily split macular vision and may be interpreted by the patient as a loss of vision in one eye only. Similarly, if patients have only one functioning eye, it is almost impossible to distinguish a homonymous hemianopia from visual loss caused by ischemia in the good eye unless symptoms of posterior (or middle) cerebral artery ischemia coexist. It is therefore important to recognize that neurological conditions, such as migraine, that affect postchiasmal pathways and cause homonymous visual field defects are not infrequently described (erroneously) by the patient as monocular.

Visual loss in bright or white light In 1979, Furlan et al. reported the phenomenon of unilateral loss of vision (causing things to appear bleached like a photographic negative) in five patients when exposed to bright sunlight. All patients had decreased retinal artery pressure on the symptomatic side and high-grade stenosis or occlusion of the ipsilateral internal carotid artery (ICA). Attenuation of the visual evoked response immediately after exposure to bright light was subsequently demonstrated in four such patients but not in controls (Donnan et al., 1982). A similar phenomenon of unilateral loss of vision induced by white light is also recognized in patients with ipsilateral carotid occlusive disease (Sempere et al., 1992). Light exposure may also induce episodic bilateral visual impairment in patients with high-grade stenosis or occlusion of both internal carotid arteries (Wiebers et al., 1989). The visual symptoms consist of blurring, dimming or scotomata in both eyes (and never a shade or blind effect). The

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symptoms persist for as long as the patient is exposed to bright light and for seconds to hours after the exposure. Other clues to the presence of anterior circulation disease may be the presence of venous-stasis retinopathy. Sunglasses may be an effective treatment. The diagnosis of episodic bilateral visual impairment associated with light exposure in patients with bilateral carotid occlusive disease needs to be differentiated from that caused by bilateral occipital lobe ischemia in vertebrobasilar system disease; bilateral blindness from occipital lobe ischemia is usually more rapid in onset and not related to light exposure (see above) (Dennis et al., 1989b). Visual loss in bright or white light is considered to represent macular dysfunction as a result of retinal ischemia from reduced choroidal (choriocapillaris) blood flow causing a delay in the regeneration of visual pigments in the retinal pigment epithelial layer. Other possible causes of loss of vision by photostress include macular disease due to chorioretinitis or retinal pigmentary degeneration (Glaser et al., 1977).

Diplopia Transient diplopia alone is a relatively non-specific symptom that may or may not be an indication of a brainstem ischemic event. However, the occurrence of transient diplopia in association with other symptoms of brainstem or cerebellar dysfunction, such as unilateral or bilateral motor or sensory disturbances, vertigo, ataxia or dysarthria, usually signifies a vertebrobasilar circulation TIA. In the OCSP, nine TIA patients (5%) suffered double vision with other brainstem symptoms (Dennis, 1988).

Vestibular symptoms Vertigo Episodic vertigo is a well-recognized symptom of vertebrobasilar ischemia when it occurs together with other symptoms of ischemic brainstem dysfunction, such as diplopia or bilateral sensorimotor symptoms. In the OCSP, ten patients (5%) gave a convincing history of vertigo (a sensation of rotational movement or spinning) associated with other symptoms of focal neurological (brainstem) dysfunction (Dennis, 1988). Vertigo in isolation is generally not considered a focal neurological symptom and therefore is not classified as a TIA. Although it may be due to selective ischemia of the vestibular nerve or the superior vestibular labyrinth in the inner ear (Grad & Baloh, 1989; Baloh, 1992; Oas & Baloh, 1992, Gomez et al., 1996), this is all but impossible to tell in practice. If such attacks do exist, they are vastly outnumbered by disorders of the peripheral vestibular apparatus

(e.g. benign positional vertigo) and even more by episodes of non-rotatory dizziness such as orthostatic hypotension or hyperventilation. So, unless associated with other concurrent brainstem symptoms, vertigo should not be classified as a TIA, and this applies even more strongly to non-rotatory dizziness.

Associated symptoms Headache Headache at the onset of a TIA is not uncommon but is generally not severe. The site of the headache associated with TIA is usually ipsilateral to the site of cerebral or ocular ischemia, at least in carotid territory TIAs, and is often above the eye in patients with AFx who experience headache. A prospective study of 3126 patients with acute cerebral or retinal ischemia revealed that headache occurred in 16% of all patients with TIA of the brain, 16% of those with TIA of the eye (AFx), 18% of those with reversible ischemic neurological deficits and in 19% of patients with minor stroke (Koudstaal et al., 1991). The headache was mostly continuous and not throbbing. The occurrence of headache was not related to the mode of onset, mode of disappearance, or duration of the attack. However, patients with evidence of cortical ischemia or vertebrobasilar circulation ischemia had headache more often than patients with lacunar syndromes. These findings concur with the lower frequency of headache reported in series of patients with only carotid territory TIAs, e.g. 4% (Bogousslavksy et al., 1986). Some other studies have noted a higher frequency of headache in TIA patients, e.g. 36% (Portenoy et al., 1984), 30% (Loeb et al., 1985), but have not mentioned the possibility that some of these patients may have been migraine sufferers (and misdiagnosed as TIA) and have not stated the distinguishing diagnostic criteria. The cause of the headache associated with TIA is unknown. Edmeads (1979, 1983) has suggested that the headache in cerebral ischemia may be due to the release of vasoactive substances, such as serotonin and prostaglandins, from platelets activated by cortical cerebral ischemia. Castillo et al. (1995) propose that the ischemic penumbra may cause a state of cortical hyperexcitability that is responsible for the cortical release of amino acid neurotransmitters and the induction of headache by altering pain perception mechanisms. Another possibility is dilatation of collateral arterial pathways causing headache. Some of the headaches are probably due to muscle tension.

Symptoms of panic and anxiety The sudden loss of limb, speech or eye function is a frightening experience which often evokes considerable anxiety

Clinical types of transient ischemic attacks

Table 2.4. Where is the TIA? Arterial Territory Symptom

Carotid

Dysphasia Monocular visual loss Unilateral weaknessa Unilateral sensory disturbancea Dysarthriab Homonymous hemianopia Unsteadiness/Ataxiab Dysphagiab Diplopiab Vertigob Bilateral simultaneous visual loss Bilateral simultaneous weakness Bilateral simultaneous sensory disturbance Crossed sensory/motor loss

⫹ ⫹

Either

Vertebrobasilar

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹

Notes: a Usually regarded as carotid distribution. b Not necessarily if isolated symptom, only if associated with ⱖ 1 other on list.

and panic in patients and carers, particularly in the first, if not later attacks. Patients may consequently hyperventilate and in turn develop sensory symptoms, such as peripheral paraesthesias and pre-syncopal symptoms. It is important to meticulously distinguish the primary (TIA) and secondary (panic/anxiety) symptoms under these circumstances.

Brief loss of consciousness Loss of consciousness is seldom recognised as a symptom of focal brain ischemia and therefore does not usually indicate a TIA unless accompanied before or after by clearcut focal neurological symptoms. When loss of consciousness does occur, it seems to be associated with ischemia of the deep diencephalic and mesencephalic structures superimposed on widespread bihemispheric ischemia as a result of either bilateral carotid (Yanagihara et al., 1989) or vertebrobasilar occlusive disease.

Neurovascular relevance of clinical types of TIAs The clinical symptoms of TIAs (i.e. the ‘types’ of attacks) not only help to establish the diagnosis of a TIA but also to identify the neuroanatomical and neurovascular site of the ischemia.

Carotid and vertebrobasilar territory TIAs were originally described as distinct clinical syndromes by Millikan and Siekert (1955a,b). It has since been established from community studies that about 80% of TIAs involve the carotid artery territory (63% cerebral, 17% ocular), and the remainder are either vertebrobasilar or the vascular distribution is uncertain (Table 2.3) (Dennis et al., 1989a).

Carotid territory TIAs (Table 2.4) Carotid distribution TIAs can be subclassified as either monocular or hemispheric; rarely the eye and ipsilateral hemisphere are affected simultaneously (Pessin et al., 1977). The only symptoms that almost definitely indicate carotid territory ischemia are TMB (AFx) and dysphasia.

Transient monocular blindness Unless a patient with transient visual disturbance alternately covers and uncovers each eye during the event, it can be difficult to ascertain afterwards whether vision was obscured or lost in one eye only, or in one half of the visual field. The distinction is important because monocular ischemic events are generally due to ischemia of the retina and/or optic nerve (as a result of carotid, central retinal artery or posterior ciliary artery ischemia) whereas homonymous hemianopic events usually indicate dysfunction of the contralateral optic tracts, optic radiations or calcarine

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cortex which are supplied by the middle (carotid territory) and posterior (vertebrobasilar territory) cerebral arteries; predominantly the latter, at least in most patients.

Dysphasia Similarly, it is necessary to make a clear distinction between dysarthria (a pure speech disorder due to difficulty with articulation) and dysphasia (a language disorder). The former is a relatively non-localizing symptom and may be seen with ischemia in the anterior or posterior circulation. Dysphasia indicates a disturbance of the dominant cerebral hemisphere (almost invariably the left hemisphere in right-handed individuals and the right hemisphere in more than 50% of left-handed individuals), as a rule from anterior circulation (carotid) ischemia. However, it is identifiable only if the patient actually tried to speak during the TIA.

Hemiphenomena The most common symptoms in patients presenting with what have been considered as carotid TIAs are contralateral limb weakness and/or sensory disturbance. Symptoms of unilateral motor and/or sensory dysfunction (involving some or all parts of the face, upper and lower limbs), homonymous hemianopia or dysarthria occurring in isolation may indicate ischemia anywhere along the pathways of the contralateral corticospinal and/or ascending sensory tracts, optic radiation or corticobulbar tracts, respectively. As these pathways share both carotid and vertebrobasilar arterial supply at different sites along their course, it is not possible to tell whether the ischemia was in the carotid or vertebrobasilar arterial territory unless other unequivocally localising symptoms were also present, e.g dysphasia (carotid) or diplopia (vertebrobasilar). These episodes of isolated unilateral motor and/or sensory dysfunction may be classified as ‘hemiphenomena’ due to contralateral brain ischemia. Although these symptoms, particularly unilateral weakness and/or sensory loss, are probably due to carotid territory ischemia most of the time (because carotid ischemic events are more common than vertebrobasilar events), it is impossible to be sure.

Vertebrobasilar TIAs Vertebrobasilar territory ischemia may cause any of a whole constellation of symptoms as outlined in Table 2.4 (Caplan, 1985). These occur simultaneously, in combination with one another. The most common symptoms are vertigo, visual disturbance (reduced vision bilaterally or double vision) and unilateral, crossed or bilateral weak-

ness and/or sensory loss involving any combination of the limbs and face. If some of these symptoms occur in isolation, such as diplopia or vertigo then the attack may have been a TIA but other causes must be considered, e.g. vestibular disease. For example, if the patient describes true vertigo, the presence of associated auditory symptoms, e.g. tinnitus, hearing loss, usually indicates peripheral labyrinthine dysfunction whereas the simultaneous presence of symptoms of brainstem dysfunction, e.g. diplopia, usually indicates a central brainstem disturbance. Impairment or loss of consciousness is very unusual in TIA and usually suggests a non-focal neurological disorder such as a generalized seizure or systemic or metabolic disturbance (see above). In adolescence, transient bilateral loss of vision is usually benign and does not share the same prognosis as other forms of TIA. Prosopagnosia (inability to recognize familar faces or their photographs despite being able to identify the persons by their voice or clothing) has been reported as a TIA on one occasion, due to presumed ischemia of the inferomedial occipitotemporal cortex bilaterally (Marti-Vilalta et al., 1981). Symptoms compatible with vertebrobasilar ischemia (such as transient bilateral motor, sensory or visual impairment) have been reported in patients with unilateral or bilateral carotid occlusive disease (Bogousslavsky & Regli, 1985; Yanagihara et al., 1989; Sloan & Haley, 1990). Subtle alterations in perfusion pressure in patients with severe hemodynamic lesions of both internal carotid arteries may provoke simultaneous bilateral border zone ischemia and a syndrome of bilateral motor and/or sensory symptoms with facial sparing, gait disturbances, or bilateral visual phenomena, but no intrinsic brainstem symptoms. In rare cases, the occurrence of diplopia might reflect parietooccipital dysfunction due to posterior border zone (middle cerebral artery/posterior cerebral artery) ischemia as opposed to intrinsic brainstem ischemia (Bogousslavsky & Regli, 1985).

Etiological relevance of clinical types of TIAs A TIA is a symptom of one or more of any number of underlying pathological processes. Not only is it important to accurately elicit and interpret the patient’s symptoms, so that the diagnosis of TIA and its likely vascular territory can be established, but it is also important to know which symptoms or types of TIAs, if any, help predict the underlying cause of the TIA. After all, it is not the symptoms which usually need to be treated (as they are transient anyway), but the cause of the TIA, to reduce the risk of stroke and other serious vascular events.

Clinical types of transient ischemic attacks

Clinical history Very few studies of TIA patients have correlated TIA symptoms (e.g. nature of symptoms, duration and number of attacks, etc.) with underlying pathology. Bogousslavsky et al. (1986) attempted to identify clinical predictors of cardiac and arterial lesions in 205 patients with carotid TIA but the number of patients in each subgroup analysis was really too small to reach any definitive conclusions other than the negative observation that very few clinical characteristics of TIAs give a clue to the underlying cause. Nevertheless, there are a few distinct TIA syndromes which probably do have some pathogenic significance, such as ‘lacunar’ TIAs, ‘cortical’ TIAs, and ‘low flow’ TIAs.

‘Lacunar’ and ‘cortical’ TIAs A theoretical analogy with lacunar and cortical stroke syndromes Several stroke syndromes are recognized, which carry pathogenic, prognostic and potential therapeutic implications. Ischemic lacunar stroke syndromes, which account for about 25% of all ischemic strokes are usually caused by thrombosis complicating microatheroma or lipohyalinosis of a single small perforating artery (Fisher, 1969; Bamford et al., 1987; Bamford & Warlow, 1988; Boiten et al., 1996; Gan et al., 1997). Ischemic cortical stroke syndromes in the carotid artery distribution are usually caused by occlusion of the main stem or branches of the anterior (ACA) or, much more often, the middle cerebral artery (MCA) in patients who either have a cardiac source of embolus or atherothrombosis of the ipsilateral extracranial carotid artery giving rise to artery-to-artery embolism and/or hemodynamic compromise (Kase, 1988; World Health Organization Task Force, 1989; Lodder et al., 1990; Bamford et al., 1991). Whilst a qualitative difference (in arterial pathology) seems to exist between ischemic ‘lacunar’ strokes (small vessel disease) and ischemic ‘cortical’ strokes (large vessel or cardiac disease), the difference between ischemic stroke and transient ischemic attack (TIA) is only quantitative being based arbitrarily on the duration of the patient’s symptoms up to or beyond 24 hours; there appears to be no major difference in the age, sex, prevalence of coexistent vascular diseases and risk factors, nor prognosis of patients with TIA and mild ischemic stroke (Dennis et al., 1989c). It is therefore plausible that qualitative differences in arterial disease and pathophysiology are shared by TIAs as well as ischemic strokes, and that these may be more relevant for management and prognosis than the quantitative differences by which TIAs and strokes are conventionally separated.

How can ‘lacunar’ TIAs be recognized? In patients with radiological or pathological evidence of lacunar infarction, the clinical history and physical signs at the time of maximal neurological deficit are usually one of four distinct clinical syndromes: (a) a pure motor syndrome: unilateral weakness of the face and upper limb, upper and lower limbs, or face and upper and lower limbs; (b) a pure sensory syndrome: a unilateral sensory disturbance in distributions similar to those of the pure motor syndrome; (c) a sensorimotor syndrome: a unilateral motor and sensory disturbance again in distributions similar to those of the pure motor syndrome; and (d) an ataxic hemiparesis; all occurring without cortical involvement (e.g. dysphasia, visual spatial perceptual disturbance) (Bamford et al., 1987). Although clinical–radiological–pathological correlation is rarely possible for TIA patients, it may often be possible to distinguish ‘lacunar’ and ‘cortical’ TIAs by means of the same clinical criteria as used for lacunar infarction (obtained from the clinical history); i.e. if a fully conscious right-handed patient experiences transient right-sided facial and limb symptoms and also attempts to speak during the TIA, it should be possible to infer whether the TIA involved the cortical branches of the MCA (‘cortical’ TIA) or the penetrating lenticulostriate branches (‘lacunar’ TIA) because in the former the speech may be dysphasic and in the latter it may be normal or dysarthric (Hankey & Warlow, 1991). Even if the patient does not attempt to speak, or if speech is normal, or if the patient has left sided weakness, it may still be possible to diagnose ‘cortical’ dysfunction if the motor and/or sensory disturbance involved only one body area (face or upper limb or lower limb) or two body areas incompletely, since permanent deficits of these types are usually due to ‘cortical’ rather than ‘lacunar’ strokes (Kase, 1988; Boiten & Lodder, 1991). However, if the patient does not attempt to speak and the weakness involves all of the face and upper limb, upper and lower limb, or face and upper limb and lower limb, it is impossible to tell whether the ischemic event was lacunar or cortical (Hankey & Warlow, 1991). The interobserver agreement for the diagnosis of a ‘lacunar’ TIA can be very good; in one study four neurologists interviewed 36 patients (referred for TIA) in alternating pairs and the chance-corrected agreement rate (kappa statistic) was 0.88 (Landi et al., 1992).

Are ‘lacunar’ TIAs of clinical relevance? Several studies have shown that the vast majority of ‘lacunar’ TIAs (and lacunar ischemic strokes), when they can be recognized as such, occur in patients with little ICA disease in the neck (Harrison et al., 1986; Rothrock et al.,

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1988; Hankey & Warlow, 1991; Kappelle et al., 1991). In contrast, most ‘cortical’ TIAs (and ischemic strokes) in the carotid territory arise in patients with significant stenosis of the origin of the symptomatic ICA or an embolic source in the heart. If these results can be interpreted in pathogenic terms, it would seem reasonable to postulate that, in patients without an obvious cardiac embolic source, the majority of ‘lacunar’ TIAs arise from small vessel disease (lipohyalinosis or microatheroma) and that most ‘cortical’ TIAs are due to significant disease (usually atheroma) at the origin of the ICA. However, this clinical distinction is not always possible (it requires right-handed patients with left carotid TIAs who attempt to speak), nor is it robust, because (a) cardiac, large vessel and small vessel disease may coexist in the same patient (Bogousslavsky et al., 1986), (b) cardiac sources of emboli may be missed by clinical evaluation and echocardiography, particularly in the older age groups, (c) ‘lacunar’ syndromes may also occur with (i) brainstem ischemia outside the carotid artery territory (Stiller et al., 1982), (ii) intracerebral hemorrhage (Bamford et al., 1987; Mori et al., 1985), (iii) cortical ischemia due to occlusion of the extracranial ICA (as in one of our cases) (Aleksic & George, 1973) or the MCA (Adams et al., 1983) or (iv) subcortical ischemia due to cardiac emboli (Santamaria et al., 1983), and (d) some small deep infarcts, like those seen in the majority of lacunar syndromes, may give rise to restricted neurological deficits suggestive of cortical involvement (Huang & Broe, 1984).

‘Low flow’ TIAs It is often difficult to be certain about the exact pathophysiological mechanism of a TIA but most TIAs are probably caused by artery-to-artery or cardiogenic embolism and, less often, by acute arterial thrombosis or low flow. Attacks that are due to low flow almost always occur in the setting of a severely stenosed or occluded artery in the neck which makes the patient susceptible to a small drop in blood pressure, perhaps because autoregulation is impaired or cerebral perfusion is exhausted; a sudden fall in systemic blood pressure in people with a normal arterial tree causes non-focal neurological symptoms such as faintness, imbalance, bilateral visual blurring and loss of consciousness (Russell, 1988). The evidence favouring low flow is sometimes circumstantial, usually when a precipitating event is recognized, such as a clinically or electrophysiologically obvious cardiac arrhythmia, exercising, chewing (increasing blood flow from the common carotid artery up the external carotid, thereby reducing the fraction going up the ICA), extending the neck, eating a heavy meal, having a

hot bath (Raymond et al., 1980), sitting or standing up quickly; and medications that lower blood pressure (Purvin & Dunn, 1981). The nature of ‘low flow’ TIAs may be atypical. They may not arise abruptly but instead over several seconds to minutes. Also, they may consist of monocular or binocular visual blurring, dimming, fragmentation or bleaching, often only in bright or white light (Furlan et al., 1979; Wiebers et al., 1989; Sempere et al., 1992). Other types of ‘low flow’ TIAs include lower limb weakness (Yanagihara et al., 1988), and irregular shaking of the arm or leg contralateral to cerebral ischemia (Yanagihara et al., 1985; Baquis et al., 1985; Tatemichi et al., 1990). Patients with severe carotid occlusive disease have been observed to experience brief, repetitive, involuntary, coarse, irregular, wavering, trembling or jerking movements of the contralateral arm and/or leg, resembling simple partial motor seizures. They are usually provoked by postural change (from lying to sitting or standing up) or by hyperextension of the neck. They may be alleviated promptly by sitting or lying down. Electroencephalography reveals no epileptiform activity at rest, during sleep or during the involuntary movements. Perfusion insufficiency has been demonstrated by xenon133 inhalation (Tatemichi et al., 1990) and, in some cases, the attacks have ceased following carotid endarterectomy (Baquis et al., 1985; Stark, 1985).

Cardioembolic TIAs With the aid of a stethoscope and modern non-invasive imaging, it is becoming easier to identify, in the individual patient, one or more of the large variety of heart diseases that may be a potential source of cardiogenic embolism. The real difficulty, however, is not in identifying a potential source of cardiogenic embolism but in deciding whether an identified potential embolic source is actually the source. The rather imprecise mainstay of the diagnosis of cardioembolic TIA continues to be the presence of a potential cardioembolic source in the absence of cerebrovascular or hematological disease in a patient with non-lacunar TIAs (Hart, 1992). The following features favour embolism from the heart as a cause of the TIA: (a) Cortical TIAs (lacunar TIAs and infarcts are uncommonly embolic in origin) (b) TIAs in more than one arterial territory (c) Ischemic episodes in organs other than the brain (d) Calcific emboli visible in the retina (from calcified mitral or aortic valves) (e) A probable source of embolism in the heart is present. (f) No other likely cause of TIA identified, e.g. absence of other manifestations of atherosclerosis (such as angina,

Clinical types of transient ischemic attacks

peripheral vascular disease, cervical bruit or duplex carotid ultrasound evidence of carotid stenosis) and risk factors (such as hypertension). (g) Patient younger than 50 years of age.

Conclusions The clinical types of TIA of the brain are generally the same as the clinical types of ischemic stroke. There is no qualitative difference between a mild ischemic stroke and a TIA in its clinical manifestations, etiology or prognosis. The only difference between TIA and ischemic stroke is quantitative and even this is arbitrary, enshrined in the temporal distinction of symptoms lasting more or less than 24 hours. So, anything which causes an ischemic stroke may, if less severe or less prolonged, cause a TIA while anything which causes a TIA may, if more severe or more prolonged, cause an ischemic stroke. It is not so certain, however, whether the clinical types of TIA of the eye are the same as the clinical types of ischemic stroke of the eye (retinal infarction). It has never been answered whether there is a similar small vessel disease which affects the blood supply to the retina and optic nerve, causing ‘lacunar’ syndromes of the eye equivalent to lacunar syndromes of the brain. It is clear that a high proportion of patients with ischemic amaurosis fugax, retinal infarction, and acute ischemic optic neuropathy do not have any detectable and likely proximal source of embolism (or low flow) in the heart or in the arterial blood supply to the eye, and perhaps it is these patients who have symptomatic small vessel disease like patients with lacunar infarcts in the brain.

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Furlan, A.J., Whisnant, J.P., & Kearns, T.P. (1979). Unilateral visual loss in bright light: an unusual symptom of carotid artery occlusive disease. Archives of Neurology, 36, 675–6. Gan, R., Sacco, R.L., Kargman, D.E., Roberts, J.K., Boden-Albala, B., & Gu, Q. (1997).Testing the validity of the lacunar hypothesis: The Northern Manhattan Stroke Study experience. Neurology, 48, 1204–11. Glaser, J.S., Savino, P.J., Sumers, K.D., McDonald, S.A., & Knighton, R.W. (1977). The photostress recovery test in the clinical assessment of visual function. American Journal of Ophthalmology, 83, 255–60. Gomez, C.R., Cruz-Flores, S., Malkoff, M.D., Sauer, C.M., & Burch, C.M. (1996). Isolated vertigo as a manifestation of vertebrobasilar ischemia. Neurology, 47, 94–7. Goodwin, J.A., Gorelick, P.B., & Helgason, C.M. (1987). Symptoms of amaurosis fugax in atherosclerotic carotid artery disease. Neurology, 37, 829–32. Grad, A. & Baloh, R.W. (1989). Vertigo of vascular origin. Clinical and electronystagmographic features in 84 cases. Archives of Neurology, 46, 281–4. Hankey, G.J. & Warlow, C.P. (1991). Lacunar transient ischemic attacks: a clinically useful concept? Lancet, 337, 335–8. Hankey, G.J. & Warlow, C.P. (1994). Transient Ischaemic Attacks of the Brain and Eye. London: W.B. Saunders/Balliere Tindall. Hankey, G.J., Slattery, J.M., & Warlow, C.P. (1991). The prognosis of hospital-referred transient ischemic attacks. Journal of Neurology, Neurosurgery and Psychiatry, 54, 793–802. Hankey, G.J., Slattery, J.M., & Warlow, C.P. (1992). Transient ischemic attacks: which patients are at high (and low) risk of serious vascular events? Journal of Neurology, Neurosurgery and Psychiatry, 55, 640–52. Harrison, M.J.G., Iansek, R., & Marshall, J. (1986). Clinical identification of TIAs due to carotid stenosis. Stroke, 17, 391–2. Hart, R.G. (1992). Cardiogenic embolism to the brain. Lancet, 339, 589–94. Hess, D.C., Nichols, F.T., Sethi, K.D., & Adams, R.J. (1991). Transient cerebral ischemia masquerading as paroxysmal dyskinesia. Cerebrovascular Diseases, 1, 54–7. Huang, C.Y. & Broe, G. (1984). Isolated facial palsy: a new lacunar syndrome. Journal of Neurology, Neurosurgery and Psychiatry, 47, 84–6. Kappelle, L.J., van Latum, J.C., Koudstaal, P.J., & van Gijn, J. for the Dutch TIA study group (1991). Transient ischemic attacks and small vessel disease. Lancet, 337, 339–41. Kase, C.S. (1988). Middle cerebral artery syndromes. In Handbook of Clinical Neurology, ed. P.J. Vinken, G.W. Bruyn, H.L. Klawans & J.F. Toole, pp. 353–70. Amsterdam: Elsevier. Kim, J.S. (1996). Restricted nonacral sensory syndrome. Stroke, 27, 988–90. Koudstaal, P.J., van Gijn, J., & Kappelle, L.J. for the Dutch TIA Study Group (1991). Headache in transient or permanent cerebral ischemia. Stroke, 22, 754–9. Koudstaal, P.J., van Gijn, J., Frenken, C.W.G.M. et al. for the Dutch Transient Ischaemic Attack Group. (1992). TIA, RIND, minor

stroke: a continuum, or different subgroups? Journal of Neurology, Neurosurgery and Psychiatry, 55, 95–7. Landi, G., Candelise, L., Cella, E., & Pinardi, G. (1992). Interobserver reliability of the diagnosis of lacunar transient ischemic attack. Cerebrovascular Diseases, 2, 297–300. Levy, D.E. (1988). How transient are transient ischemic attacks? Neurology, 38, 674–7. Lodder, J., Bamford, J.M., Sandercock, P.A.G., Jones, L.N., & Warlow, C.P. (1990). Risk factors amongst subgroups of cerebral infarction in the Oxfordshire Community Stroke Project: are hypertension or cardiac embolism likely causes of lacunar infarction? Stroke, 21, 375–81. Loeb, C., Gandolfo, C., & Dall’Agata, D. (1985). Headache in transient ischemic attacks (TIA). Cephalalgia, Suppl 2, 17–19. Margolin, D.I. & Marsden, C.D. (1982). Episodic dyskinesias and transient cerebral ischemia. Neurology, 32, 1379–80. Marti-Vilalta, J.L., Dalmau, J. & Santalo, M. (1981). Prosopagnosia, a transient ischemic attack. Stroke, 12, 702. Millikan, C.H. & Siekert, R.G. (1955a). Studies in cerebrovascular disease. I. The syndrome of intermittent insufficiency of the basilar arterial system. Proceedings of Staff Meetings Mayo Clinic, 30, 61–8. Millikan, C.H. & Siekert, R.G. (1955b). Studies in cerebrovascular disease. IV. The syndrome of intermittent insufficiency of the carotid arterial system. Proceedings of Staff Meetings Mayo Clinic, 30, 186–91. Mori, E., Tabuchi, M., & Yamadori, A. (1985). Lacunar syndrome due to intracerebral haemorrhage. Stroke, 16, 454–9. Oas, J.G. & Baloh, R.W. (1992). Vertigo and the anterior inferior cerebellar artery syndrome. Neurology, 42, 2274–9. O’Sullivan, F., Rossor, M., & Elston, J.S. (1992). Amaurosis fugax in young people. British Journal of Ophthalmology, 76, 660–2. Pessin, M.S., Duncan, G.W., Mohr, J.P., & Poskanzer, D.C. (1977). Clinical and angiographic features of carotid transient ischemic attacks. New England Journal of Medicine, 296, 358–62. Portenoy, R.K., Abissi, C.J., Lipton, R.B. et al. (1984). Headache in cerebrovascular disease. Stroke, 15, 1009–12. Purvin, V.A. & Dunn, D.W. (1981). Nitrate-induced transient ischemic attacks. Southern Medical Journal, 74, 1130–1. Raymond, L.A., Sacks, J.G., Choromokos, E., & Khodadad, G. (1980). Short posterior ciliary artery insufficiency with hyperthermia (Uhthoff’s symptom). American Journal of Ophthalmology, 90, 619–23. Ropper, A.H. (1985). Transient ipsilateral paraesthesias (TIPS) with transient monocular blindness. Archives of Neurology, 42, 295–6. Rothrock, J.F., Lyden, P.D., Yee, J., & Wiederholt, W.C. (1988). ‘Crescendo’ transient ischemic attacks: clinical and angiographic correlation. Neurology, 38, 198–201. Russell, R.W.R. (1988). Cause and treatment of insufficiency in the cerebral circulation. Clinical Neurology and Neurosurgery, 90, 19–24. Santamaria, J., Graus, F., Rubio, F., Arbizu, T., & Peres, J. (1983). Cerebral infarction of the basal ganglia due to embolism from the heart. Stroke, 14, 911–14.

Clinical types of transient ischemic attacks

Sempere, A.P., Duarte, J., Coria, F., & Claveria, L.E. (1992). Loss of vision by the colour white: a sign of carotid occlusive disease. Stroke, 23, 1179. Sloan, M.A. & Haley, E.C. (1990). The syndrome of bilateral hemispheric border zone ischemia. Stroke, 21, 1668–73. Stark, S.R. (1985). Transient dyskinesia and cerebral ischemia (letter). Neurology, 35, 445. Stiller, J., Shanzer, S., & Yang, W. (1982). Brainstem lesions with pure motor hemiparesis. Computed tomographic demonstration. Archives of Neurology, 39, 660–1. Tatemichi, T.K., Young, W.L., Prohovnik, I., Gitelman, D.R., Correll, J.W., & Mohr, J.P. (1990). Perfusion insufficiency in limb-shaking transient ischemic attacks. Stroke, 21, 341–7. Werdelin, L. & Juhler, M. (1988). The course of transient ischemic attacks. Neurology, 38, 677–80. Wiebers, D.O., Swanson, J.W., Cascino, T.L., & Whisnant, J.P. (1989). Bilateral loss of vision in bright light. Stroke, 20, 554–8.

World Health Organization Task Force on Stroke and Other Cerebrovascular Disorders: Stroke (1989). Recommendations on stroke prevention, diagnosis and therapy. Stroke, 20, 1407–31. Yanagihara, T., Piepgras, D.G., & Klass, D.W. (1985). Repetitive involuntary movements associated with episodic cerebral ischemia. Annals of Neurology, 18, 244–50. Yanagihara, T., Sundt, T.M., & Piepgras, D.G. (1988). Weakness of the lower extremity in carotid occlusive disease. Archives in Neurology, 45, 297–301. Yanagihara, T., Klass, D.W., Piepgras, D.G., & Houser, O.W. (1989). Brief loss of consciousness in bilateral carotid occlusive disease. Archives in Neurology, 46, 858–61. Youl, B.D., Adams, R.W. & Lance, J.W. (1991).Parietal sensory loss simulating a peripheral lesion, documented by somatosensory evoked potentials. Neurology, 41, 152–4.

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3

Hemiparesis and other types of motor weakness Teresa Pinho e Melo1 and Julien Bogousslavsky2 Department of Neurology, University of Lisbon, Portugal and 2Department of Neurology, University of Lausanne, Switzerland

1

Introduction Motor weakness, isolated or in association with other symptoms or signs, is the commonest problem of stroke patients. In epidemiological stroke studies, motor deficit (paresis/paralysis) is found in 80–90% of all patients (Herman et al., 1982; Bogousslavsky et al., 1988; Libman et al., 1992). There have been attempts to explain this fact using a variety of distinct arguments: (i) motor weakness is easily recorded by the patient, family, or physician; (ii) it can be caused by a stroke anywhere along the corticospinal pathways, from the cerebral cortex to the spinal cord; (iii) the most frequent types of stroke (lacunar, cardioembolic) have a ‘predilection’ for anatomic motor centres or tracts. Motor-weakness profiles and associated abnormalities can be helpful in predicting stroke subtypes (localization, cause) in the acute phase, which is essential for etiologic diagnostic strategies, for treatment, and for prognosis in individual patients. Motor weakness is also a major element in the rating scales for clinical stroke, because it is important for daily living activities, it is not difficult to evaluate, and its assessment has shown a good interobserver reliability.

Anatomic considerations The motor cortex is not confined to the large motor cells of Betz in the fifth layer of the precentral gyrus (primary motor cortex), as formulated at the turn of the century. Experimental studies in monkeys have indicated that only 60% of the corticospinal fibres arise from the primary motor cortex and the premotor and supplementary motor areas. The remaining fibres arise mainly from the postcentral gyrus and parietal cortex. The consensus is that in

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humans, approximately 60% of the corticospinal axons arise from the primary motor cortex, and the remainder from the premotor area, supplementary area, and the parietal lobe. According to the classic view, the primary motor cortex contains a somatotopic representation of body parts (homunculus) (Schott, 1993), the face being in the most inferior part of the precentral gyrus on the lateral surface of the hemisphere, and the leg in the paracentral lobule on the medial surface of the cerebral hemisphere. The particular parts of the body capable of the most delicate movements have the largest cortical representations. However, recent investigations support the notion of multiple representations of different body parts within the primary motor cortex (Strick & Preston, 1978). The corticospinal fibres converge within the corona radiata and pass downward through the internal capsule, crus cerebri, pons, and medulla. At the junction of the medulla and spinal cord, some 75–90% of the fibres cross the midline, and three separate corticospinal tracts are formed (crossed lateral or pyramidal, anterior or ventral, and uncrossed lateral). The positioning of the corticospinal tract in the internal capsule has evoked conflicting opinions. The largely accepted conclusions reached by Charcot (1883) and Dejérine (1901) that fibres occupy the anterior half of the posterior limb of the internal capsule are in apparent contradiction to the observations of fibres’ degeneration in patients with amyotrophic lateral sclerosis (Hirayama et al., 1962) as well as the findings from stereotaxic stimulation studies (Guiot et al., 1959) and from case reports of patients with isolated internal-capsule infarct (Englander et al., 1975). Such data indicate that in the internal capsule the corticospinal tract lies within a compact bundle in the third quarter of the posterior limb. This controversy probably arose because the corticospinal tract does not maintain a fixed position in the internal capsule. In 1980, Elliott

Hemiparesis and other types of motor weakness

Ross concluded that the pyramidal tract enters the rostral capsule in the anterior half of the posterior limb and progressively shifts into the posterior half of the posterior limb in the more caudal horizontal section. In progressively caudal horizontal sections, the anterior limb attenuates, and at the lower thalamic level the internal capsule has only a posterior limb. In the traditional view, the somatotopic motor representation is as a homunculus, with the head and eye in its anterior limb, the mouth and larynx/pharynx in the genu, the upper extremities in the anterior part of the posterior limb, and the lower extremities in the posterior part of the posterior limb (Dejérine, 1901). Although this somatotopic organization is suggested by clinicotopographic correlations in many cases, in others (Mohr et al., 1982) the pattern of hemiparesis is not exactly like a homunculus. Magnetic-resonance imaging (MRI) and use of the concept that the corticospinal tract assumes an oblique direction within the posterior limb of the internal capsule will help to solve this problem in the future. Although lesion sites other than the corticospinal tract have been reported to produce motor weakness (Critchley, 1930; Fisher, 1979; Donnan et al., 1982; Caplan et al., 1990; Boiten & Lodder, 1991a), the main cause is damage to the primary crossed corticospinal tract. Other lesions probably result in motor deficit by affecting indirect pathways that do not run in the pyramidal tract.

Hemiparesis When one is assessing a stroke patient with motor weakness, one of the first questions to be asked is whether or not the weakness is isolated. When analysed independently of other symptoms or signs, motor weakness is found in some 80–90% of all patients with stroke (Herman et al., 1982; Bogousslavsky et al., 1988; Libman et al., 1992). Hemiparesis with uniform weakness of the hand, foot, shoulder, and hip is the most frequent (at least two-thirds of cases) motor-deficit profile (Herman et al., 1982; Mohr et al., 1984). Monoplegia is found in about 19% of all stroke patients, and paraplegia in 1%, and in 2% of stroke patients three or four limbs are involved (Herman et al., 1982). It must be emphasized that inability to perform movements correctly can result not only from hemiparesis but also from neuropsychological dysfunction. Patients with motor neglect have a lack of initiative in moving the contralateral limbs, despite preserved muscular strength, and patients with motor impersistence are unable to maintain a voluntary action such as keeping arms or legs outstretched. Apraxia is another cause of inability to perform

correctly learned skilled movements in the absence of weakness. An abnormality in reaching a goal under visual control (visuomotor ataxia) may more rarely be confounded with hemiparesis. On the other hand some patients with acute hemiplegia are unaware of their weakness (anosognosia). To avoid erroneous diagnosis, highlevel cortical functions must be carefully tested. Hemiparesis with uniform weakness of the arm and leg does not predict the severity of the stroke, but when that is accompanied by trunk weakness or hemisensory deficit, it usually indicates a large lesion. Faciobrachial paresis is, in the majority of the patients, due to middle cerebral artery superficial infarcts (Freitas et al., 2000). Monoplegia is usually associated with small infarcts of the cortex or centrum ovale (Bogousslavsky & Regli, 1992). Distal predominance of the hemiparesis is usually related to cortical involvement, and only rarely (1 of 52 patients from the NINDS) to stroke confined to the putamen or internal capsule (Mohr et al., 1984).This has been thought to reflect the density of the body-parts representation over the hemispheral surface. Schneider and Gautier (1994) studied the infarct topography that caused leg-predominant weakness in 63 patients with acute stroke. Lesions restricted to the rear portion of the medial part of the precentral gyrus caused a contralateral, predominantly distal, severe leg weakness, with little improvement. Lesions involving the medial part of the premotor cortex, the supplementary motor area and the rear portion of the medial part of the precentral gyrus caused a contralateral distally predominant hemiparesis with leg plegia, and recovery was much better for the arm than for the leg. Lesions affecting the medial part of the premotor cortex, the supplementary motor area but sparing the precentral gyrus caused a contralateral proximal hemiparesis predominating on the leg, with good recovery for leg and arm. Some authors tried to find differences, in terms of frequency, severity, or profile of the hemiparesis, between right- and left-sided lesions, but in the majority of such studies no significant differences have been found (Herman et al., 1982; Mohr et al., 1984, 1993). Recently Freitas et al. (2000) found a higher frequency of left hemispheric infarcts in patients with motor deficit sparing the leg. In patients with acute spinal vascular lesions, the paralysis of voluntary movements typically is associated with flaccidity and abolishment of spinal reflexes (spinal shock) that after a few days will give way to a state of spasticity (hypertonus and heightened stretch reflexes). However, in patients with brain lesions, that sequence of changes is not a rule: Limb spasticity may develop in the acute phase, and

23

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T. Pinho e Melo and J. Bogousslavsky

limb flaccidity may be associated with retained reflexes; not rarely, tonus and/or reflexes will remain normal or will even be increased. Patients with massive brain hemorrhages and infarcts may present at onset with spastic limbs (bilateral or contralateral to the hemispheric lesion). This spasticity is not persistent and usually implies abnormal extensor responses of the arm and leg, termed decerebrate rigidity. Mohr et al. (1993) studied the infarct topography and hemiparesis profiles in 183 patients with infarction at the middle cerebral artery convexity. In this stroke subtype, they found a good correlation between infarct size and the severity of weakness, whether estimated by overall motor function on one side or by arm or hand function alone, but their attempts to correlate a specific syndrome with a specific brain location were frustrating. However, Foix and Lévy (1927), using autopsy findings in individual cases, described the characteristics of hemiplegia from different infarct topographies of the middle cerebral arteries. Infarction involving the whole territory of the middle cerebral artery produced a severe controlateral hemiplegia. But two patterns of hemiplegia in relation to the infarct extension were possible when only the deep territory was concerned: (i) a ‘massive hemiplegia’, similar to that found when the infarct involved both the superficial and deep territories, affecting the leg and the arm rendering the patient unable to walk, and usually lacking secondary spasticity (flask hemiplegia), and (ii) a ‘moderate hemiplegia’ involving the leg and the arm proportionally, although in some cases the arm seemed more affected than the leg and developed marked contracture. The syndrome of hemiplegia caused by an infarct of the entire surface territory of the middle cerebral artery was characterized by brachial predominance of hemiplegia, not rarely involving mainly distal movements. Some authors have found a possible correlation between specific movements and cerebral–lesion localization. Freund and Hummelsheim (1985) studied 11 patients, each with hemiparesis of proximal muscles and a lesion involving the premotor cortex but not the primary motor cortex. They found a stereotyped syndrome, with the paresis affecting mainly those shoulder muscles that abduct and elevate the arm, and affecting all hip muscles to similar extents, the arm being functionally more affected than the leg. The associated lesions, diagnosed by computed tomography (CT), were border-zone infarcts between the anterior and the middle cerebral arteries. Those authors suggested that the different pattern of involvement of shoulder and hip muscles might be related to a particular role of the human premotor cortex in the act of reaching. Yasuo et al. (1993) reported a 78-year-old man

with a small cortical infarct over the left central sulcus presenting at the time of hospital discharge with isolated mild weakness of his contralateral thumb. Thumb flexion was affected to a greater degree than other thumb movements, suggesting that an arrangement of intracortical efferent zones similar to that found in monkeys (Asanuma & Rosén, 1972) also exists in humans. Motor weakness was present in all but 1 of the 27 patients, each with an infarct in the anterior cerebral artery territory, studied by Bogousslavsky and Regli (1990a). In the majority of those patients the hemiparesis predominated in the lower limb, including three patients with crural monoparesis. Only two patients had isolated motor deficit, involving the arm and leg in one patient and only the leg in the other. Kubis et al. (1999) reported a higher percentage of patients with isolated motor deficit (10 from the 16 patients studied), that involved the arm and leg (with leg predominance) in six patients, the arm and face in one patient and only the leg in three patients. Hemiparesis predominating in the lower limb is seen mainly in large infarcts in the anterior cerebral artery territory, being associated with involvement of the parasagittal precentral area. When the infarct spares the precentral region and involves the more anterior premotor region or extends deeply towards the internal capsule, the motor deficit may involve either face/arm/leg or face/arm, usually predominating in the upper limb. Recently, Chamorro et al. (1997) suggested that the faciobrachial paresis is not caused by corticospinal tract weakness, but by motor neglect caused by damage of medial premotor areas or its connections. Infarcts of the posterior cerebral artery cause a spectrum of manifestations (hemianopia, abnormal visual perception, neuropsychological signs and symptoms), but usually without weakness. However, hemiparesis can sometimes occur, resulting from infarction of the cerebral peduncle (peduncular perforators and anterior circumflex arteries) (Hommel et al., 1990). In cerebellar infarcts a motor deficit suggests brainstem lesion or compression of motor fibres by a mass effect due to edema (Kanis et al., 1994). In pontine infarcts motor weakness depends on the topography of the lesion. Ventromedial pontine infarcts, usually large infarcts, cause severe faciobrachiocrural hemiparesis with ataxia and dysarthria, while ventrolateral pontine infarcts, usually small infarcts, cause mild motor dysfunction corresponding to lacunar syndromes (Bassetti et al., 1996). Kim et al. (1995a) compared rostral, middle and caudal pontine ventromedial infarcts and found that large lesions involving the caudal or middle pons correlated with severe hemiparesis, whereas lesions of similar size located

Hemiparesis and other types of motor weakness

in the rostral pons tended to have minimal or no limb weakness. Pontine hemiparesis is usually more marked in the upper than lower limb and in distal than proximal parts of the limbs. A mild facial palsy, much more commonly homolateral to the motor deficit, is often present, and can be attributed to the damage of supranuclear fibers at the ventrotegmental junction of the upper middle pons. Hemiparesis is the hallmark of medial medullary infarct, a rare localization for posterior circulation strokes. The motor deficit is usually contralateral, more pronounced in the upper extremity and in the distal portion of the limbs. Hemiparesis can occasionally be isolated (pure motor stroke). Other patterns of motor deficit can be observed: tetraparesis caused by bilateral pyramid infarct, ipsilateral hemiparesis caused by infarct below the pyramidal decussation, crural predominance in more ventral infarcts and rarely weakness can be minimal or absent. In about one half of patients ipsilateral lingual palsy is associated with the contralateral hemiparesis. In the absence of lingual palsy signs of involvement of structures close to the pyramids such as lemniscal hyposthesia, mild decrease in pain sensation, nystagmus and mental changes are helpful for the clinical diagnosis of medial medullary infarct (Bassetti et al., 1997; Kim et al., 1995b).

Faciobrachial paresis A considerable number of patients develop stroke without involvement of the lower limb. This pattern of paresis is highly suggestive of damage to the motor cortex, due to involvement of the superficial branches of the middle cerebral artery, but it is often seen in lesions involving the complete territory of the middle cerebral artery, the complete territory of the lenticulostriate arteries or the territory of the lateral lenticulostriate arteries. More rarely it was reported after anterior cerebral artery or brainstem infarcts. Even if we considered only ‘pure faciobrachial paresis’ it is frequently caused by a cortical infarct. The majority of the 895 patients with paresis sparing the leg (73% faciobrachial, 21% brachial and 6% facial) studied by Freitas et al. (2000) had a superficial infarct, restricted to the superficial branches of the middle cerebral artery in half of the patients. Even when only patients with pure motor weakness were considered, the most common site of the lesions was still the superficial middle cerebral artery territory. Studies performed in patients with middle cerebral artery infarcts showed that faciobrachial paresis accounts for about three-quarters of all types of motor deficit after anterior middle cerebral artery infarcts, and for about two-

thirds after posterior middle cerebral artery infarcts (Bogousslavsky et al., 1989). Large-artery disease and cardioembolism are the main causes of strokes sparing the lower limb, while the frequency of strokes due to small-artery disease is low (Freitas et al., 2000).

Pure motor hemiparesis Pure motor hemiparesis (PMH) was reported by Fisher and Curry (1965) as an acute pure motor stroke involving face, arm, and leg on one side, in the absence of sensory deficit, homonymous hemianopia, aphasia, agnosia, or apraxia. They found that it resulted from a small infarct in the internal capsule or in the basis pontis, most often due to occlusion of one of the small penetrating vessels (i.e. a ‘lacune’). However, at the beginning of this century, Pierre Marie (1901) and J. Ferrand (1902) had first stressed the link between isolated sudden hemiparesis and lacunes. In his essay on hemiplegia in old age, Ferrand reported on 88 patients with lacunes in whom the typical picture was a ‘sudden, partial incomplete and often transient hemiparesis not rarely accompanied by dysarthria’. Nowadays, PMH is considered the most common lacunar syndrome (Mohr et al., 1978; Nelson et al., 1980; Donnan et al., 1982; Bamford et al., 1987; Arboix et al., 1990; Sohn et al., 1990; Norrving & Staaf, 1991; Gan et al., 1997), but the original restrictive definition has been broadened by some authors to include cases with little or no facial involvement and other types of nonproportional hemiparesis (Rascol et al., 1982; Bamford et al., 1987; Kappelle et al., 1988; Orgogozo & Bogousslavsky, 1989; Arboix et al., 1990). Dysarthia may be present (Fisher, 1979) and it is probably due in the majority of patients to facio-oral weakness. The presence of dysarthria in patients with isolated hemiparesis does not influence the determination of stroke type and localization (Melo et al., 1992a). As the majority of the studies on isolated hemiparesis were performed in selected populations with so-called lacunar stroke, the incidence of this syndrome among stroke patients in general is not well defined. In the Lausanne Stroke Registry (Melo et al., 1992a) and in the Norrving & Staaf (1991) series, all patients with unilateral motor weakness, partial or complete, were included. About 14% of all patients who had suffered a first stroke had isolated unilateral hemiparesis or hemiplegia, with face/arm/leg involvement in half of them. In the Oxfordshire Community Stroke Project (Bamford et al., 1987) and in the Harvard Cooperative Stroke Registry (Mohr et al., 1978), the incidence of isolated hemiparesis

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T. Pinho e Melo and J. Bogousslavsky

Table 3.1. PMH stroke series Strokea

Reference Fisher & Curry

Weakness

Percentage

Imaging/

No lesion

Deep

Superficial

Number of

distribution

of all

autopsy

visible

infarct

infarct

Hemorrhage

Brain-stem

cases

(%)

strokes

(no. of cases)

(%)

(%)

(%)

(%)

infarct (%)

50

FULb

—

AUc (9)

—

67

—

—

33

14

?

—

Brain scan (11)

82

—

18

—

—

25

FUL

3

Brain scan (18)

67

—

33

—

—

?

—

CT (29)

31

34

24

10

(1965) Chokroverty & Rubino (1975) Richter et al. (1977) Weisberg (1979) Pullicino

29 18

d

d

d

—

?

—

CT (18)

—

61

39

—

—

26

FUL

8e

CT (26)

38

42

19

—

—

30

FUL (53);

—

CT (30)

3

83

—

7

7

14

CT (123)

43

41

13

2

—

14

CT (255)

20

47

25

4

4

(1994) Nelson et al. (1980) Rascol et al. (1982)

FU (43); L (3)

Norrving &

199

Staaf (1991)

FUL (67); FU (8); UL (21); F, U, L (4)

Melo et al.

255

(1992a)

FUL (50); FU (29); UL (9); U (10); F, L (2)

Notes: a

Patients with imaging autopsy.

b

F, face; U, Upper limb; L, lower limb.

c

AU, autopsy

d

Only patients with infarct on CT.

e

312 patients with stroke and CT.

f

Only patients with presumed lacunar stroke (n ⫽ 180).

was lower, around 9%, probably because patients with monoparesis were excluded. Some studies have attempted to clarify how the distribution of weakness in PMH correlates with stroke type, topography, and potential cause (Norrving & Staaf, 1991; Chamorro et al.,1991; Melo et al., 1992a; Gan et al., 1997). When face, arm, and leg weakness are considered in any possible combination, a significant number of patients will be found to have a cortical or brainstem infarction or a hemorrhage, whereas less than half of patients will be found to have a deep infarct (Table 3.1 and 3.2). Rarely non-

vascular occasional causes of PMH have been reported: nocardial abscess (Weintraub & Glaser, 1970), cerebral metastases (Chokroverty & Rubino, 1975; Weisberg, 1979), subdural hematoma, and demyelinating disease (Weisberg, 1979). These rare cases may now be easily detected by imaging techniques. In all PMH series studied, face/arm/leg involvement was the most common type of weakness distribution (50–70%), and isolated leg or face weakness was rare. The percentages of face/arm, arm/leg, and isolated arm weakness varied with inclusion criteria. When all stroke patients were

Hemiparesis and other types of motor weakness

Table 3.2. Distribution of weakness related to stroke type and localization Stroke type

Distribution of weaknessa FUL (%) FU (%) UL (%) U (%) L (%) F (%)

No lesion visible (n⫽51)

Deep infarct (n⫽121)

Superficial infarct (n⫽65)

(18b (35.3) (15 (29.4) ( 7 (14) (10b (20) (1 (2) (0

(89c (73.6) (19c (15.7) (9 (7.4) (2c (1.7) (1 (0.8) (1 (0.8)

( 6 (9.2) (39 (60) (5 (7.7) (12 (18.5) ( 2 (3.1) (1 (1.5)

Hemorrhage (n⫽9) (7 (77.8) (0 (1 (11.1) (1 (11.1) (0 (0

Brainstem infarct (n⫽9) (8 (88.9) (1 (11.1) (0 (0 (0 (0 (0

Total (n⫽255) 128 (50.2) 74 (29) 22 (8.6) 25 (9.8) 4 (1.6) 2 (0.8)

Notes: a F, face; U, upper limb; L, lower limb. b The percentage among patients without visible lesions differed significantly (P⬍0.05) from that among patients with ischemic infarcts seen on CT c The percentage among patients with deep infarcts differed significantly (P⬍0.05) from that among other patients with other lesions seen on CT. Source: Lausanne Stroke Registry.

included, face/arm was the second more frequent type of distribution (29–43%) (Rascol et al., 1982; Melo et al., 1992a), but when only patients with a presumed lacunar stroke were studied, a higher percentage of arm/leg distribution was found (Donnan et al., 1982; Arboix et al., 1990; Norrving & Staaf, 1991), because patients with face/arm motor-weakness distributions more frequently have cortical infarct. Traditionally, brachiocrural hemiparesis, with facial sparing, was suggestive of a medullary lacune involving the corticospinal tract within the pyramid (Fisher & Curry, 1965; Ropper et al., 1979; Bogousslavsky et al., 1986). Melo et al. (1992a) suggest that an arm/leg weakness distribution in hypertensive patients is highly suggestive of a deep infarct. This fact may be explained by the rostro-caudal displacement of the pyramidal tract in the internal capsule. In rostral sections, face and limb fibers are less close to each other. A cortical infarct may produce an isolated (usually nonproportional) hemiparesis. However, this is not common, because of the proximity of the motor and sensory cortices. Table 3.3 correlates weakness distribution profiles with superficial infarct localization in Lausanne Stroke Registry patients with isolated motor deficit (Melo et al., 1992a).

About half of the patients with face/arm or isolated arm weakness had a superficial infarct, which was in the anterior superficial middle cerebral artery territory in the majority of cases. Isolated motor deficits in any possible combination were the clinical manifestation in about half of the patients having infarcts of the middle cerebral artery pial territory, affecting the anterior superior division in the majority of cases (69%) (Bogousslavsky et al., 1989). Moreover, when PMH involving face, arm, and leg is considered, infarcts in the posterior inferior division of the middle cerebral artery are never responsible. We studied which variables would give good predictions of the presence of a deep infarct in patients with PMH (Melo et al., 1992a). We concluded that patients with proportional face/arm/leg involvement and hypertension had a 90% probability of deep infarct, whereas patients either with a face/arm/leg distribution but no hypertension or with an arm/leg distribution and hypertension had each a 70% probability of deep infarct; when weakness distribution other than face/arm/leg or arm/leg was present, such probability fell to 38% for patients with hypertension, and to 18% for patients without hypertension. Recently, Gan et al. (1997) determined for the PMH syndrome a positive predictive value of 79% for detecting radiological lacunes.

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Table 3.3. Superficial infarct topography correlated with distribution of weakness Topography of superficial infarcts

Distribution of weaknessa

Anterior superficial MCAb (n⫽53)

Posterior superficial MCA (n⫽2)

ACAc (n⫽5)

Watershed (n⫽5)

FUL FU UL U L F

5 36 1 10 0 1

0 2 0 0 0 0

0 0 4 0 1 0

1 1 0 2 1 0

Notes: a F, face; U, upper limb; L, lower limb. b MCA, middle cerebral artery. c ACA, anterior cerebral artery.

However they did not find change in this value when only the proportional face/arm/leg involvement was considered. Toni et al. (1994) aver that PMH are poorly predictive of lacunar stroke when patients are evaluated within 12 hours of the event. Some of their patients, during hospitalization, present further clinical changes, developing cortical signs and symptoms. When the potential mechanism of infarct is considered and not only the infarct size and location, a non-lacunar mechanism is found in about onethird of the patients with PMH (Melo et al., 1992a; Gan et al., 1997). In our study the remaining deep infarcts were mainly large deep infarcts (striatocapsular, anterior choroidal artery territory, thalamic, junctional) most frequently due to embolism (heart-to-heart or artery-to-artery) or hypoperfusion. In those large deep infarcts, despite maximal ischemia in the depth of the hemisphere, there was also compromise of the cortical blood supply, resulting in clinical ‘cortical’ features. Thus, the frequency of patients presenting with isolated motor deficit as manifestations of large deep infarct is rather low, varying between zero and 17% (Ghika et al., 1989; Bogousslavsky & Regli, 1992). Kittner et al. (1992) studied the features of the neurological examinations as they related to a cardiac embolic stroke mechanism and concluded that ‘hemiparesis’ that included both arm and leg without sensory or ‘cortical’ deficits had a strong inverse association with a cardiac source of embolism. For a significant number of patients with isolated motor deficits, CT will reveal no appropriate lesions (Weisberg,

1979; Melo et al., 1992a). A very small deep infarct may be the cause in such cases, but some studies suggest that patients in whom CT shows no lesions and patients with deep infarcts revealed by CT have different characteristics (Melo et al., 1992a). Patients in whom CT does not reveal appropriate lesion less often have a proportional distribution of weakness, whereas brachial monoparesis may be more frequent. Also, hypertension and diabetes, which are the most important vascular risk factors for lacunar infarcts, are less frequent in patients in whom CT shows no appropriate lesions. Nighoghossian et al. (1993) studied with MRI a small series of patients with PMH and repeatedly negative CT and found a pontine paramedian infarct in all these patients. They suggest that the combination of dysarthria and a history of previous transient gait abnormality or vertigo may favour a pontine location. Transient episodes of PMH have been said to constitute a capsular warning syndrome by Donnan et al. (1993). This form of transient ischemic attack (TIA) may be due to a hemodynamic phenomenon, with diseased single small penetrating vessels, that subsequently leads to early capsular infarction in a high proportion of cases (42%). In conclusion, isolated hemiparesis or hemiplegia is a common manifestation of stroke and can be due to lesions at various locations, with different mechanisms. The pattern of distribution of motor weaknesses seems to be best predictor of stroke type, topography, and cause.

Isolated monoparesis Isolated monoparesis following cerebral infarction is rare. It was found in only 1.7% of patients in the Lausanne Stroke Registry (Melo et al., 1992a) and in 1.2% of patients in the series reported by Norrving and Staaf (1991). The majority of such patients have brachial monoparesis; crural monoparesis is almost never present (0.2% of all strokes). Fisher (1982) stated that ‘monoplegia is never due to occlusion of a penetrating branch’. However, Bennett and Campbell (1885) had reported an isolated paresis of the upper limb in an 80-year-old man who at autopsy was found to have had a small infarct immediately posterior to the genu of the internal capsule; however, transient facial involvement had been present initially. Subsequently, others have found small deep infarcts revealed by CT to be the causes of isolated brachial weakness and crural weakness in single patients. Recent representative studies have shown that isolated monoparesis can be the clinical presentation in up to 4% of patients with lacunar infarcts (Arboix et al., 1990; Norrving & Staaf, 1991). This does not

Hemiparesis and other types of motor weakness

contradict the fact that the lesion underlying isolated monoparesis is usually localized in the cortex or centrum semiovale. In the study by Arboix et al. (1990), none of the eight patients with isolated monoparesis had positive CT findings (each patient had at least two CT scans), and only 1 of those patients studied with MRI had a lacune in the internal capsule. Such findings are in accord with those from the Lausanne Stroke Registry (Melo et al., 1992a), in which CT revealed no lesions in 40% of patients with isolated brachial monoparesis. That finding may have been due to the fact that some small cortical infarcts will not be revealed by CT. Melo et al. (1992a) and Boiten and Lodder (1991b) support the rule that a brachial monoparesis is usually due to a small infarct involving the cortex and adjacent subcortex in the territory of the middle cerebral artery. Moreover, among 380 (selected from 1303 patients in the Lausanne Stroke Registry) in whom CT revealed infarcts in the middle cerebral artery pial territory, 13% had a brachial monoparesis. Schneider and Gautier (1994) studied nine patients with crural monoparesis. Three patients had a cortical infarct, one a lacune of the posterior limb of the internal capsule, one a brainstem infarct and two a thalamic hematoma.

Isolated facial paresis Isolated facial paresis of the upper motor neuron type without involvement of the extremities is a rare manifestation of stroke. It has no strong localizing value (Melo et al., 1992a). In a series of 227 patients with lacunar infarcts, there were six patients with motor deficits involving only the face (Arboix et al., 1990). In four of those patients, CT revealed appropriate infarcts, involving the genu of the internal capsule in three patients and the pons in one patient. Donnan et al. (1982) emphasized a capsular-corona radiata localization. Several patients with supranuclear facial palsy and pontine vascular lesion confirmed by CT or MRI have been reported (Hopf et al., 1990). One of the two patients with isolated facial paresis included in the Lausanne Stroke Registry (Table 3.3) had an infarct in the anterior superior middle cerebral artery territory. Figure 3.1 shows a CT scan from a 60-year-old man who developed an acute isolated supranuclear facial palsy caused by an infarct in the genu and anterior limb of the internal capsule. Bogousslavsky and Regli (1990b) reported a ‘capsular genu syndrome’ characterized by contralateral facial and lingual weakness, with dysarthria and mild limb involvement limited to hand weakness.

Fig. 3.1. Infarction localized to the genu and anterior limb of internal capsule in a 60-year-old man with actue isolated supranuclear facial palsy.

Patients described as having isolated facial paresis generally shared dysarthria. The existence of pure supranuclear facial paresis without dysarthria or pure dysarthria remains unconvincing. Kim (1994) suggests that pure dysarthria or isolated facial paresis syndrome be considered as an extreme continuum of dysarthria–facial paresis syndrome, usually associated with small strokes in the corona radiata, basal ganglia/internal capsule or pons.

Hemiparesis and other associated signs Hemiparesis and lacunar syndromes Though not specific, a few neurological syndromes are associated with small infarcts in the territory of the deep perforating branches. PMH is most commonly the result of infarction in the internal capsule. When hemiparesis is associated with homolateral ataxia (i.e. ataxic hemiparesis) the infarct, in the majority of patients, will be located in the pons, corona radiata, or internal capsule (Fisher, 1978). If sensory loss (proprioception, pain) is found with the same distribution as motor weakness (sensorimotor stroke) (Mohr et al., 1977) the infarct usually will be in the internal capsule. Some cases of sensorimotor stroke may represent infarcts in the anterior choroidal artery territory, although

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additional deficits are usually present. Hemiparesis with homolateral hemiataxia and sensory abnormalities (hypesthetic ataxic hemiparesis) is usually caused by a small thalamic infarct, a capsulothalamic infarct, or, more rarely, an infarct in the anterior choroidal artery territory (Helgason & Wilbur,1990; Melo et al., 1992b).

hemiparesis (Weber syndrome). A lower-pontine infarct may produce a unilateral abducens or facial palsy combined with a contralateral hemiparesis (Millard–Gubler syndrome). Hemiparesis due to pontine infarct can also be associated with a ‘one-and-a-half syndrome’, a lateral-gaze palsy associated with internuclear ophthalmoplegia (see Chapter 5).

Hemiparesis with neuropsychological dysfunction In the Tilburg population-based stroke registry (Herman et al., 1982), 62% of 474 patients had combined motor and speech deficit (dysphasia or dysarthria). Such patients had more severe weaknesses than did those with isolated hemiparesis. Speech disturbances have been traditionally linked to hemiparesis caused by a cortical lesion in the dominant hemisphere. But hemiparesis and dysphasia can also occur in patients with deep infarcts in the dominant hemisphere. Lenticulostriate and anterior choroidal artery territories are usually involved. In its typical form, the anterior choroidal artery syndrome features the triad of hemiplegia, hemianesthesia, and homonymous hemianopia, but incomplete forms of the syndrome are more frequent, and PMH may be present in a considerable number of cases (Mohr et al., 1991). In the presence of thalamic infarct (tuberothalamic territory), hemiparesis is rarely associated with a specific speech disturbance. In these patients, hemiparesis is usually mild. Caudate infarct or hemorrhages can cause all types of weakness distribution and severity. Motor signs are usually temporary, being associated with cognitive and behavioural abnormalities (abulia, agitation, hyperactivity, neglect, language abnormalities). The exact mechanism of this motor deficit is unknown, although disruption of frontopontine fibres or corticospinal projections have been suggested (Caplan et al., 1990).

Hemiparesis with eye-movement disorders Conjugate-gaze palsy is one of the most common eyemovement abnormalities in patients with acute stroke. The eyes may be deviated to one side, either to the side of a hemispheral lesion or to the opposite side of a pons lesion, with gaze paresis towards the opposite side. This gaze palsy is almost invariably accompanied by hemiparesis. Abnormal ocular movements in association with motor hemiparesis may be caused by a brainstem vascular lesion involving specific oculomotor centers located near the corticospinal tract. An infarct in the cerebral peduncle usually produces an ipsilateral ophthalmoplegia due to involvement of the third-nerve intraaxial fibres and a contralateral

Bilateral weakness Weakness affecting both sides of the body is not common following a stroke (Herman et al., 1982). It may be caused by spinal-cord, bilateral hemispheric, or brainstem infarcts. A spinal-cord infarct may produce a paraparesis or a quadriparesis, depending on the level of infarct (see Chapter 34). Paralysis of extremities and the lower cranial musculature, with sparing of consciousness (the locked-in syndrome), results from bilateral corticobulbar and cortico-spinal-tract lesions, usually caused by basilar artery occlusion. Simultaneous bilateral infarctions in the anterior cerebral artery territory can occur in relation to the anatomic variants of the junction between the anterior cerebral artery and the anterior communicating artery. Paraplegia combined with akinetic mutism, incontinence, and bilateral grasp is the classic picture produced by this type of infarct. The acute onset of bilateral motor signs, especially with sparing of facial function, can be caused by bilateral border-zone infarctions. Bilateral anterior watershed infarcts (between the anterior cerebral artery and middle cerebral artery territories) limited to the cortex may produce a picture of bibrachial paralysis (man-in-thebarrel), because the junction of the anterior cerebral artery and middle cerebral artery territories is at the level of the arm-shoulder representation on the motor strip. A variant with triplegia has been reported (Fisher & McQuillen, 1981), but the face is usually spared, because the border zone rarely extends laterally over the convexity. Headache, seizures, and bilateral weakness predominating in the legs are suggestive of sagittal sinus thrombosis.

Pseudo-bulbar features Lower cranial nerve palsy induced by supranuclear lesions (corticobulbar and corticopontine pathway) in relation to multiple recurrent strokes was named by Lépine (1877) as ‘pseudo-bulbar palsy’. These patients present a striking incongruity between the loss of voluntary movements of

Hemiparesis and other types of motor weakness

Fig. 3.2. CT scan showing bilateral opercular lesions in a 46-yearold man presenting with Foix–Chavany–Marie syndrome.

muscles innervated by the motor nuclei of the lower pons and medulla (inability to swallow, phonate, articulate, move the tongue, forcefully close the eyes, etc.) and the preservation of reflexive pontomedullary activities (yawning, coughing, throat clearing, spasmodic laughing or crying). Thurel (1929) divided pseudo-bulbar palsy into three forms: the cortical form, characterized by a faciopharyngoglossomasticatory diplegia with automatic voluntary dissociation; the striatal form, having the same features, but also with pyramidal signs, emotional lability, and intellectual impairment; and the pontine form, with faciopharyngoglossomasticatory diplegia associated with emotional lability, pyramidal signs and sometimes cerebellar signs, but a lack of dementia. Some of these features can appear in isolation, without any other manifestation of pseudobulbar palsy. One of the most commonly reported isolated features is spasmodic laughing and crying: inappropriate laughing and crying unrelated to surrounding circumstances or stimulation, with no corresponding emotional feeling.

Although in many patients pseudobulbar palsy results from bilateral and multiple recurrent strokes, acute pseudobulbar palsy has been reported. Besson et al. (1991) studied 13 patients with pseudobulbar palsy of acute onset either with or without prior stroke. They concluded that it may be associated with infarcts or hemorrhages involving the frontal opercular region or the corticonuclear pathways in both cerebral hemispheres, but sparing the corticospinal pathways. The acute onset may be due to acute damage to corticonuclear fibres on one side when contralateral corticonuclear fibres have previously interrupted, with little or no symptom. Helgason et al. (1988) reported eight patients with acute pseudobulbar palsy caused by consecutive bilateral anterior choroidal artery territory. Acute pseudobulbar palsy has also been reported in patients with pontine infarction (Bassetti et al., 1996; Kim et al., 1995a). Foix–Chavany–Marie syndrome is a rare type of pseudobulbar palsy usually associated with cerebrovascular disease (Foix et al., 1926). This syndrome is characterized by anarthria and bilateral central voluntary paresis of lower cranial nerves, with preserved involuntary and emotional innervation. In the majority of patients this syndrome is caused by bilateral opercular lesions (Fig. 3.2), being considered as the cortical or opercular type of pseudobulbar palsy. In contrast to the non-cortical suprabulbar palsy, in the cortical type, the onset is most often acute. Paralysed muscles remain hypotonic, patients are completely unable to talk and swallow, and pathological laughter or crying and emotional lability are less common.

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Kim, J.S. (1994). Pure dysarthria, isolated facial paresis, or dysarthria-facial paresis syndrome. Stroke, 25,1994–8. Kim, J.S., Lee, J.H., Im, J.H., & Lee, M.C. (1995a). Syndromes of pontine base information. A clinical-radiological correlation study. Stroke, 26, 950–5. Kim, J.S., Kim, H.G., & Chung, C.S. (1995b). Medial medullary syndrome. Report of 18 new patients and a review of the literature. Stroke, 26, 1548–52. Kittner, S.J., Sharkness, C.M., Sloan, M.A. et al. (1992). Infarcts with a cardiac source embolism in the NINDS Stroke Data Bank: neurologic examination. Neurology, 42, 299–302. Kubis, N., Guichard, J.-P. & Woimant, F. (1999). Isolated anterior cerebral artery infarcts: a series of 16 patients. Cerebrovascular Diseases, 9, 185–7. Lépine, R. (1877). Note sur la paralysie glosso-labièe cérébrale à forme pseudo-bulbaire. Revue Mens Medicin Chirurgie, 1, 909–22. Libman, R.B., Sacco, R.L., Shi, T., Tatemichi, T.K., & Mohr, J.P. (1992). Neurologic improvement in pure motor hemiparesis: implications for clinical trials. Neurology, 42, 1713–16. Marie, P. (1901). Des foyers lacunaires de désintégration et de différents autres états cavitaires du cerveau. Revue De Medicine (Paris), 21, 281–98. Melo, T.P., Bogousslavsky, J., van Melle, G., & Regli, F. (1992a). Pure motor stroke: a reappraisal. Neurology, 42, 789–98. Melo, T.P., Bogousslavsky, J., Moulin, T., Nader, J., & Regli, F. (1992b). Thalamic ataxia. Journal of Neurology, 239, 331–7. Mohr, J.P, Kase, C.S., Meckler, R.J., & Fisher, C.M. (1977). Sensorimotor stroke due to thalamocapsular ischemia. Archives of Neurology, 34, 739–41. Mohr, J.P, Caplan, L.R., Melski, J.W. et al. (1978). The Harvard Cooperative Stroke Registry: a prospective registry. Neurology, 28, 754–62. Mohr, J.P, Kase, C.S., Wolf, P.A. et al. (1982). Lacunes in the NINCDS Pilot Stroke Data Bank. Annals of Neurology, 1, 84. Mohr, J.P., Rubinstein, L.V., Edelstein, S.Z. et al. (1984). Hemiparesis profiles in acute stroke: the NINCDS Stroke Data Bank. Annals of Neurology, 1, 156. Mohr, J.P, Steinke, W., Timsit, S.G., Sacco, R.L., & Tatemichi, T.K. (1991). The anterior choroidal artery does not supply the corona radiata and lateral ventricular wall. Stroke, 22, 1502–7. Mohr, J.P, Foulkes, M.A., Polis, A.T. et al. (1993). Infarct topography and hemiparesis profiles with cerebral convexity infarction: the Stroke Data Bank. Journal of Neurology, Neurosurgery and Psychiatry, 56, 344–51. Nelson, R.F., Pullicino, P., Kendall, B.E., & Marshall, J. (1980).

Computed tomography in patients presenting lacunar syndromes. Stroke, 11, 256–61. Nighoghossian, N., Ryvlin, P., Trouillas, P., Laharottte, J.C., & Froment, J.C. (1993). Pontine versus capsular pure motor hemiparesis. Neurology, 43, 2197–201. Norrving, B. & Staaf, G. (1991). Pure motor stroke from presumed lacunar infarct. Incidence, risk factors and initial clinical course. Cerebrovascular Disease, 1, 203–9. Orgogozo, J. M. & Bogousslavsky, J. (1989). Lacunar syndromes. In the Handbook of Clinical Neurology, vol. 54, ed. P.J. Vinken, G.W. Bruyn & H.L. Klawans, pp. 235–69. Amsterdam: Elsevier. Pullicino, P. (1994). Bilateral distal upper limb amyotrophy and watershed infarcts from vertebral dissection. Stroke, 25, 1870–2. Rascol, A., Clanet, M., Manelfe, C., Guiraud, B., & Bonafe, A. (1982). Pure motor hemiplegia: CT study of 30 cases. Stroke, 13, 11–17. Richter, R.W., Brust, J.C.M., Bruun, B., & Shafer, S.Q. (1977). Frequency and course of pure motor hemiparesis: a clinical study. Stroke, 18, 58–60. Ropper, A.L., Fisher, C.M., & Kleinman, G.M. (1979). Pyramidal infarction in the medulla: a cause of pure motor hemiplegia sparing the face. Neurology, 29, 91–5. Ross, E.D. (1980). Localization of the pyramidal tract in the internal capsule by whole brain dissection. Neurology, 30, 59–64. Schneider, R. & Gautier J-C. (1994). Leg weakness due to stroke. Site of lesions, weakness patterns and causes. Brain, 117, 347–54. Schott, G.D. (1993). Penfield’s homunculus: a note on cerebral cartography. Journal of Neurology, Neurosurgery and Psychiatry, 56, 329–33. Sohn, Y.H., Lee, B.J., Sunwoo, I.N., Kim, K.W., & Suh, J.H. (1990). Effect of capsular infarct size on clinical presentation of stroke. Stroke, 21, 1258–61. Strick, P.L. & Preston, J.B. (1978). Multiple representation in the primate motor coetex. Brain Research, 154, 366–70. Thurel, R. (1929). Les pseudobulbaires: etude clinique et anatomopathologique. Paris Thesis. Toni, D., Del Luca, R., Fiorelli, M. et al. (1994). Pure motor hemiparesis and sensorimotor stroke. Accuracy of very early clinical diagnosis of lacunar strokes. Stroke, 25, 92–6. Weintraub, M.E. & Glaser, G.H. (1970). Nocardial brain abcess and pure motor hemiplegia. New York State Journal of Medicine, 70, 2717–21. Weisberg, L.A. (1979). Computed tomography and pure motor hemiparesis. Neurology, 29, 490–5. Yasuo, T., Terao, Y., Hayashi, H., Kanda, T., & Tanabe, H. (1993). Discrete cortical infarction with prominent impairment of thumb flexion. Stroke, 24, 2118–20.

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Sensory abnormality Jong Sung Kim Asan Medical Center, Seoul, South Korea

Functional anatomy of somatosensory system Functional anatomy of the sensory system is briefly discussed here. For further details, readers are referred to previous literature (Woolsey, 1958; Martin & Jessell, 1991; Parent, 1996; Kim, 1998a). There are two functionally and anatomically distinct sensory pathways, the medial lemniscal system and the spinothalamic system (Fig. 4.1). The medial lemniscal system subserves proprioception, vibration, tactile discrimination, and some touch sensations. These fibres ascend at the posterior column of the spinal cord up to the caudal medulla where they synapse on the dorsal column nuclei neurons (nuclei of Goll and Burdach). They then decussate as the internal arcuate fibres and ascend through the opposite medial lemniscus, which is located at the medial portion of the medulla oblongata. The spinothalamic system fibres are responsible for pain and temperature sensations. The peripheral fibres, after entering the dorsal root entry zone, ascend a few segments at Lissauer’s tract and then synapse at the dorsal horn. From there, some fibres ascend ipsilaterally, but the majority of the fibres cross the midline in the white commissure and ascend toward the medulla. In the brainstem, the spinothalamic tract is located at the dorso-lateral tegmentum. Some of the spinothalamic fibres are also projected to reticular formations. The facial (trigeminal) sensations are conveyed to the brainstem through the trigeminal nerves which enter the lateral pons. The fibres carrying touch and tactile discrimination synapse at the principal trigeminal nucleus located in the lateral pons. The secondary fibres (quintothalamic fibres) cross the midline and ascend to the thalamus. The fibres subserving pain and thermal sensations do not synapse at the principal sensory nucleus. Instead, just after entering the pons, they run down as descending trigeminal

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tracts and synapse at the trigeminal nuclei that form a long vertical structure extending far down to the second cervical cord. After the synapse, the fibres decussate and then ascend as the secondary ascending trigeminal tract toward the thalamus. Sensory tracts of both systems as well as fibres carrying trigeminal sensations are converged into the thalamus, the principal sensory relay station of the brain. The sensory relay nucleus ventralis posterolateralis (VPL) receives somatic sensation from the limbs and the trunk, and the ventralis posteromedialis (VPM) receives sensory inputs from the face and oral area. In these nuclei, the sensory homunculi for the acral body parts (lip, fingers and toes) are disproportionately large (Fig. 4.2). While the medial lemniscal tracts terminate mainly in the VP nuclei, spinothalamic fibres synapse in more diffuse areas including the posterior nuclei and the intralaminar nuclei as well. From the thalamus, the impulses involved in sensation reach localized areas of the cortex through the thalamocortical projection in the posterior limb of the internal capsule/corona radiata. The primary function of the sensory cortex is to discriminate sensation: appreciation and recognition of spatial relations, appreciation of similarity and differences of external objects, precise localization of the point touched, and identification of objects (stereognosis). The cortical area subserving general somatic sensation (superficial and deep) is located in the postcentral gyrus, Broadman’s area 3,1, and 2 (somatosensory area I, SI) where the various regions of the body are represented somatotopically. Again, the cortical areas representing the mouth, face, hands (especially the thumb and index finger), and toes are disproportionately large (Fig. 4.1). There are observations that the somesthetic cortical area is not limited to the postcentral gyrus (Nii et al., 1996). Electrical stimulation or the occurrence of small

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pathologic lesions in the precentral gyrus or posterior parietal area often produces sensory symptoms (Penfield & Boldrey, 1937). Nevertheless, the sensory threshold is lower in the post-central gyrus compared to other regions (Corkin & Milner, 1970). The somatosensory area II (SII) has been shown to be located in the parietal opercular region, and seems to be unrelated to discriminative sensory function (Roland, 1987). According to animal experiments, sensory cortices have reciprocal connections through the corpus callosum such that SI neurons send fibres to both the contralateral SI and SII while SII area restricts most of its projections to the opposite SII. The post-central gyrus representing the symmetrical axis of the body has ample interhemispheric connections while distal limb-representing regions lack the connections (Jones, 1967; Whitsel et al., 1969).

Sensory dysfunction after stroke Sensory dysfunction tends to be less carefully examined than motor or speech abnormalities in the evaluation of stroke patients (Bowsher, 1993; Carey, 1995). Yet, it must be realized that somatosensory abnormality is present in at least half of the patients suffering from strokes (Carey, 1995). Moreover, if meticulously tested, sensory abnormalities are actually much more frequent. Examinations with the use of tools for quantitative thermal detection (Samuelsson et al., 1994) or discriminative sensations (Kim & Choi-Kwon, 1996) have shown that most of the patients with a clinically defined ‘pure motor stroke’ have concomitant sensory abnormalities. In addition to the high frequency of abnormalities, there are other reasons why a proper understanding of the sensory system dysfunction is important. First, because each pattern of sensory abnormalities differs according to the location of a stroke, a careful sensory examination helps us localize the lesion in stroke patients. In turn, this attempt of clinical–anatomical correlation would allow us to understand the functional neuroanatomy, which frequently has been studied only through animal experiments. Secondly, sensory abnormalities after a stroke often lead the patients to suffer central post-stroke pain (CPSP), involuntary movements (Sharp et al., 1994; Hallett, 1995; Ghika & Bogousslavksy, 1997) including alien hand syndrome (Ay et al., 1998), and abnormal motor execution (Ghika et al., 1998) associated with poor rehabilitation outcome (Stern et al., 1971; Reding & Potes, 1988; Chester & McLaren, 1989; Zeman & Yiannikas, 1989). Therefore, a better understanding of sensory system dysfunction may

Fig. 4.1. A schematic diagram of sensory tracts and sensory homunculus in the parietal cortex. Solid lines represent spinothalamic tract and dotted lines represent medial lemniscal fibers. 1: Lissauer’s tract, 2: fasciculus cuneatus, 3: fasciculus gracilis, 4: posterior column, 5: spinothalamic tract, 6: spinal nucleus of trigeminal nerve, 7: nucleus gracilis, 8: spinal tract of trigeminal nerve, 9: principal trigeminal nucleus, 10: medial lemniscus, 11: thalamus, 12: thalamo-parietal projection, 13: sensory cortex (From Kim, 1998, with permission.)

Dorsal

Medial

VPM

VPL

Fig. 4.2. Schematic somatotopic body representation in the ventral posterior nucleus of thalamus in primates. (Modified from Kim, 1998, with permission.)

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allow us to develop ways to prevent or alleviate pain or other disabling sequelae in stroke victims in the future.

Medial lemniscus leg trunk

arm Corticospinal tract Ascending trigeminal thalamic tract

Medullary stroke In the medulla oblongata, the fibres of the two different sensory systems are widely separated: the medial lemniscus is located medially and the spinothalamic tract, laterally. These tracts are separately involved by medial medullary infarction (MMI) and lateral medullary infarction (LMI), respectively. The descending trigeminal fibres/nuclei are located in the dorsal area while ascending secondary trigeminal tracts are situated ventro-medially (Fig. 4.3). In patients with LMI, sensory abnormalities are fairly common and remain as the most important sequela (Peterman & Siekert, 1960). In the acute stage, they occur in the contralateral body/limbs in approximately 85% and in the face in 58–68% (Sacco et al., 1993; Kim et al., 1997). It has been traditionally taught that sensations in the ipsilateral trigeminal and contralateral body/limbs are typically affected in these patients. However, a recent study (Kim et al., 1997) showed that this ‘classical’ sensory pattern occurred only in one fourth of the LMI patients, who had lesions located dorso-laterally. Other sensory patterns occurring in a similar frequency include the contralateral– trigeminal pattern, the bilateral trigeminal pattern and the sensory pattern limited to body/limbs sparing the face, each of them correlating with a ventrally located lesion, a large lesion encompassing both the posterolateral and ventromedial area, and a small lateral-superficial lesion, respectively (Figs. 4.3, 4.4). In addition, a small portion of the patients with posteriorly located lesions have sensory symptoms limited to the ipsilateral face sparing the body and limbs (Nakamura et al., 1996), while some do not have sensory symptoms/signs at all (Kim et al., 1997). However, because trigeminal sensory symptoms on the side contralateral to the lesion tend to improve rapidly, the classical, ipsilateral trigeminal–contralateral body/limb pattern is the one most commonly found in patients with chronic LMI. In the body/limbs, approximately 30% of LMI patients exhibit sensory gradient or sensory level (pseudospinal type) (Kim et al., 1997). This probably is related to an anatomical arrangement of spinothalamic sensory fibres where fibres from the sacral, leg, trunk, and arm areas are located from the most outer to inner areas (Matsumoto et al., 1988) (Fig. 4.3). Thus, small lesions preferentially involving the superficial area may show a sensory level or have sensory symptoms greater in the leg than in the arm

D

sacral leg trunk arm

Spinothalamic tract

B C Descending trigeminal tract

A

A+B

B+C

A+B+C

B

A

D

Fig. 4.3. Upper: Anatomical structures of medulla. Lower: Various patterns of sensory dysfunction caused by medullary infarction. Lightly dotted area ⫽ decreased spinothalamic sensation, heavily dotted area ⫽ decreased lemniscal sensation.

(Fig. 4.4(c)). The trigeminal sensory abnormalities are also diverse in their manifestation, presenting with onion skin pattern (Kim et al., 1997), divisional pattern (Currier et al., 1961) or a complex mixture of the two. It seems that the perioral area tends to be spared or less severely involved in patients with contralateral–trigeminal pattern (Kim et al., 1997). Although a selective loss of the spinothalamic sensation is a rule, vibration sensation is occasionally involved as well in the hypalgic body/limbs, due probably to the fact that some of vibratory sensations are carried through the lateral column (Calne & Pallis, 1966). On rare occasions, patients with the most caudal lesion have lemniscal sensory deficits on the side ipsilateral to the lesion (Kim et al., 1995a; Brochier et al., 1999). Involvement of the ascending or decussating dorsal column sensory tracts by the lower-most lesion may explain this phenomenon. Finally, some patients with LMI show dissociated spinothalamic sensory dysfunction, i.e. severe deficit of pinprick sensation with mild impairment of temperature sensation or vice versa (Head & Holmes, 1911; Dejerine, 1914). A recent report (Kim, 1998b) showed that small, ventrally located lesions tend to produce a greater deficit of the pinprick than temperature sensations. This observation

Sensory abnormality

(a )

(b)

(c )

Fig. 4.4. T2-weighted magnetic resonance imaging shows infarcts involving (a) dorso-lateral, (b) ventromedial ⫹ dorso-lateral, and (c) lateral–superficial areas of the lateral medulla, producing sensory impairment in the ipsilateral trigeminal–contralateral body/limbs, bilateral trigeminal–contralateral body/limbs, and in the area of contralateral body/limbs below T10 level, respectively.

agrees with an alleged topography of the spinothalamic tract in the spinal cord: fibres carrying the pain sensation are located more ventrally than those subserving temperature sensations (Friehs et al., 1995). A dissociation of warm and cold sensory impairment was also described (Kutner & Kramer, 1907), but awaits further pathological or radiological examination. In patients with MMI, sensory abnormality is the second most frequent symptom followed by muscle weakness, which is characterized by the presence of paresthesias and a selective loss of the lemniscal sensation (Fig. 4.3). However, the degree of impairment between vibration and joint position senses may differ among individual patients (Kim et al., 1995b) reflecting the previous notion that the anatomical pathways for the two sensory modalities are not strictly bound (Ross, 1991). In addition, spinothalamic sensations are occasionally impaired in these patients, which could result from an involvement of either the adjacent spinothalamic tract or the medullary reticular formation (Kim et al., 1995b; Bassetti et al., 1997). Although sensory symptoms most often occur on the side contralateral to the lesion, infarcts occurring in the lower-most area below the crossing lemniscal (internal arcuate) fibres may produce ipsilateral sensory deficits (Vuilleumier et al., 1995; Kim et al., 1995b). In patients with MMI, the face is usually, but not always spared, due probably to an involvement of the adjacent ascending trigeminal tract (Kim et al., 1995b; Kinoshita et al., 1998). The trigeminal sensory symptoms are usually transient and mild as compared to those in the body/limbs. Some MMI patients present with restricted sensory symptoms in the legs or show pseudospinal sensory changes (Kim et al., 1998a). This pattern is explained by an anatomical arrangement that sensory fibres from the leg, trunk and arm are arranged from a ventral to dorsal direction in the medullary medial lemnis-

cal tracts (Brodal, 1981) (Fig. 4.3). Thus, a small ventrally located infarct may produce sensory symptoms restricted to the leg.

Pontine stroke Pontine tegmental strokes affecting the sensory tracts frequently produce sensory symptoms. Lesions concomitantly involving the pyramidal tract in the ventral area would produce sensori-motor deficit while those extending far-dorsally may produce ocular motor dysfunction due to an involvement of the abducens nerve nucleus and related structures. In the pontine tegmentum, the ascending trigeminal tract, the medial lemniscus and the spinothalamic tract are located adjacently in a medial to lateral direction (Fig. 4.5(a)). Small dorsal pontine infarcts (Hommel et al., 1989; Iwasaki et al., 1989; Helgason & Wilbur, 1991; Shintani et al., 1994; Kim & Bae, 1997) or hemorrhages (Araga et al., 1987; Deleu et al., 1992; Kim & Jo, 1992; Kim & Bae, 1997) selectively involving the sensory tract produce a pure or predominant hemisensory deficit without other neurological dysfunctions (Fig. 4.5(b)). Although both the spinothalamic and lemniscal sensations may be simultaneously involved, lemniscal sensations are usually more severely affected in these patients (Kim & Bae, 1997; Shintani, 1998) probably because small infarcts or hemorrhages tend to occur in the paramedian area (Kim et al., 1994a) where the medial lemniscus is located. Occasionally, the patients exhibit hemi-paresthesias without objectively detectable sensory deficits. In the pontine medial lemniscal tract, the sensory projections from the arm, trunk and leg are arranged from a medial to lateral direction. Therefore, a medially located lesion may produce preferential involvement of the face

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(a )

corticospinal tract

ascending trigeminal tract arm medial lemniscus

trunk abducens nucleus

leg spinothalamic tract

aqueduct

(b)

Fig. 4.5. (a) Anatomical structures of pons. (b) T1-weighted MRI shows a pontine hemorrhage selectively involving the medial lemniscus that produces pure sensory stroke.

and arm, thus causing cheiro-oral syndrome whereas laterally located lesions produce leg-dominant sensory symptoms (Kim & Bae, 1997). The most medially located lesions sometimes produce bilateral facial or perioral sensory symptoms due probably to concomitant involvement of the trigemino-thalamic fibres bilaterally (Matsumoto et al., 1989; Kim & Bae 1997). Bilateral cheirooral syndrome also occurs most often, though not exclusively, in paramedian pontine strokes (Chen et al., 1997). In addition, sensory symptoms of cheiro-oral-pedal (Yasuda et al., 1992; Kim 1994), oro-crural (Combarros et al., 1996) or cheiro-retroauricular distribution (Ferro & Pierre, 1998) have been reported to be caused by small pontine strokes. As compared to the patients with thalamic lesions, those with a pontine pure sensory stroke more often exhibit dizziness/gait ataxia, predominant lemniscal sensory involvement, and bilateral perioral involvement (Kim & Bae, 1997). Impairment of the smooth pursuit system eval-

uated by electro-oculography may additionally differentiate pontine from thalamic pure sensory strokes (Johkura et al., 1998). Trigeminal sensory deficit is often observed in patients with infarcts affecting the lateral pons or the middle cerebellar peduncle (anterior inferior cerebellar artery territory) usually accompanied by other symptoms such as hearing difficulty, ataxia and vertigo. Isolated trigeminal sensory symptoms without other neurological deficits may occur in patients with small strokes affecting the trigeminal fascicles or nucleus at the lateral pons (Holzman et al., 1987; Berlit, 1989; Kim et al., 1994b). In some patients, trigeminal sensory symptoms are restricted to the intraoral area. This may be explained by an alleged functional anatomy in which at the most rostral part of the trigeminal tract/nucleus represents sensory fibres from the intraoral area (Graham et al., 1988). Isolated involvement of the taste sensation (Sunada et al., 1995) or facial pains indistin-

Sensory abnormality

(a )

crus cerebri substantia nigra ascending trigeminal tract medial lemniscus red nucleus spinothalamic tract oculomotor nucleus aqueduct

(b)

Fig. 4.6. (a) Anatomical structures of midbrain. (b) T2-weighted MRI shows an infarct in the dorso-lateral area producing pure sensory stroke. The infarct was probably caused by an artery-to-artery embolism from a tightly stenosed basilar artery.

guishable from idiopathic trigeminal neuralgia (Balestrino & Leandri, 1997; Kim et al., 1998b) has also been reported to be caused by small pontine strokes.

Mesencephalic stroke In the midbrain, sensory tracts are located dorso-laterally in which the medial lemniscal fibres are situated medioventrally, and the spinothalamic tracts, dorso-laterally (Fig. 4.6(a)). A pure mesencephalic stroke most commonly presents with the third nerve palsy associated with hemiparesis and/or hemiataxia (Kim et al., 1993; Bogousslavsky et al., 1994). Hemisensory symptoms, if present, are usually not prominent. Mesencephalic pure hemisensory syndrome is extremely rare, and caused by small infarcts or hemorrhages affecting the dorso-lateral area (Tuttle & Reinmuth, 1984; Azouvi et al., 1989; Alvarezc-Sabin et al., 1991; Sabin et al., 1991; Kim & Bae, 1997) (Fig. 4.6(b)). The

patients may present with paresthesias only (Tuttle & Reinmuth, 1984) or selective spinothalamic sensory dysfunction (Azouvi et al., 1989). Symptoms restricted to cheiro-oral (Ono & Inoue, 1985; Kim, 1994) or trigeminal areas (Kim & Kang, 1992; Kim, 1993) were also described, which usually were accompanied by the third or fourth nerve palsy.

Thalamic stroke Strokes involving the VP nucleus of the thalamus produce hemisensory symptoms. Concomitant involvement of the adjacent pyramidal tract would induce a sensory-motor stroke, and additional involvement of the cerebellar– thalamic fibres at the ventral–lateral nucleus may produce the so-called 'hypesthetic ataxic hemiparesis’ syndrome. A small lateral thalamic stroke selectively involving the VP nucleus is the most common etiology of pure sensory

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stroke (Fisher, 1982; Kim, 1992). Although both the spinothalamic and lemniscal sensations are usually impaired simultaneously (Kim, 1992; Shintani, 1998), small lesions may produce paresthesias only or a selective impairment of lemniscal (Sacco et al., 1987; Kim, 1992) or spinothalamic sensations (Landi et al., 1984; Kim, 1992; Paciaroni & Bogousslavsky, 1998). The sensory topography includes half of the face, arm, trunk and leg in more than 50% of the cases (Paciaroni & Bogousslavksy, 1998). In some patients, however, initial hemisensory disturbances are gradually restricted to the most vulnerable areas: the perioral area, the hand, and less frequently, the foot. Occasionally, sensory symptoms are restricted to these acral body parts from the onset (Kim, 1994), the most frequent form being cheiro-oral syndrome (Valzelli, 1987; Ten Holter & Tijssen, 1988; Awada 1989; Kawadami et al., 1989; Combarros et al., 1991, Kim & Lee, 1994; Kim, 1994). (Fig. 4.7) Cheiro-oral-pedal or cheiropedal syndrome has also been observed, but much less frequently (Yasuda et al., 1993; Kim, 1994). Occasionally, the thumb and index finger are preferentially or selectively involved (Combarros et al., 1991; Kim, 1994). This restricted acral sensory syndrome is best explained by the anatomical proximity of sensory fibres from acral body parts (Fig. 4.2). For example, the thumb and index fingerrepresentation areas are located in the most medial portion of the VPL and are adjacent to the lip area of VPM in the thalamus of primates (Kaas et al., 1984). In addition, at least two other hypotheses explain the increased vulnerability of the acral body parts. First, distal body parts have disproportionately large representation areas in the human sensory system. Secondly, unlike the sensory fibres subserving the trunk and proximal limbs, neurons representing distal body parts lack interhemispheric connections (Whitsel et al., 1969). In patients with a hemisensory deficit, intraoral regions (gum, hard palate, tongue) are occasionally involved. A loss of taste sensation is uncommon. The author has found that six of 35 patients with thalamic cheiro-oral syndrome had definite hemiageusia. Interestingly, one of them experienced frequent episodes of vivid recollections of the past (Kim, 1997). On rare occasions, sensory symptoms restricted to the proximal limbs and trunk, with the sparing of the face and distal limbs are observed (Kim, 1996a), which may be attributed to selective involvement of the dorsal part of the VPL to which sensations from the proximal body parts are projected (Kaas et al., 1984). Thalamic pure sensory syndrome usually indicates a lacunar syndrome (Fisher, 1978; Gan et al., 1997) caused by an occlusion of a small penetrating branch. However, other etiologies such as atherothrombosis of the proximal poste-

Fig. 4.7. T2-weighted MRI shows a left thalamic infarct producing paresthesias at the contralateral perioral area and the hand (cheiro-oral syndrome).

rior cerebral artery, cardiogenic embolism, or a hypertensive intracerebral hemorrhage may also produce pure sensory syndrome (Paciaroni & Bogousslavsky, 1998) or even restricted acral sensory syndromes (Kim, 1994).

Subcortical stroke Although motor symptoms are usually dominant in patients with subcortical strokes, small (Kim, 1991, 1992, 1994) or even relatively large lesions (Kim, 1999a) primarily affecting the thalamocortical sensory radiation can produce pure or predominant sensory symptoms (Fig. 4.8). The latter lesions appear to produce sensory changes greater in the leg than in the arm. Although subcortical strokes may cause sensory deficits of both modalities (Shintani, 1998), predominant spinothalamic (Kim, 1992) or lemniscal sensory impairment (Groothuis et al., 1977) has been observed. Some patients with very small lesions present with sensory symptoms restricted to cheiro-oral

Sensory abnormality

(Omae et al., 1992; Isono et al., 1993; Kim 1994), cheirooral-pedal (Yasuda et al., 1994; Kim, 1994) or cheiro-pedal (Derouesné et al., 1984; Kim, 1994) distribution suggesting that an identical pattern of sensory topography as in the VP nucleus of the thalamus exists in the thalamic-cortical sensory radiation.

Cortical stroke In the cerebral cortex, lemniscal sensory fibres are abundantly terminated in the parietal cortex (SI), whereas a significant portion of the ascending spinothalamic fibres terminate in the reticular activating system without reaching the cortex. Strokes involving the cerebral cortex characteristically produce an impairment of discriminative sensations that require cortical participation, including loss of position sense, elevation of two-point discrimination threshold, difficulties in localizing touch and pain stimuli (topagnosia), failure to recognize letters or numbers drawn on the skin (graphesthesia), and failure to appreciate texture, size or shape of objects by palpation (astereognosis) despite relatively preserved protopathic (pain, thermal, vibration) sensations. This ‘parietal cortical sensory syndrome’ was described long ago (Verger, 1900; Dejerine & Mouzon, 1914), and is usually accompanied by other neurological deficits such as hemiparesis, hemianopia, aphasia or hemineglect. In clinical practice, however, decreased protopathic sensation is usually present to some extent. Although discriminitive sensory dysfunction is generally detected in the body/limbs contralateral to the lesion, sensory modalities such as point localization, stereognosis (Corkin & Milner, 1970; Kim & Choi-Kwon, 1996), or texture discrimination (Carmon & Benton, 1969) are occasionally impaired on the ipsilateral side as well. In some patients, however, protopathic sensations are heavily affected, just as in cases of thalamic strokes (pseudothalamic syndrome) (Roussy & Foix, 1910). Unlike the patients with thalamic stroke, however, concomitant cortical symptoms such as aphasia, anosognosia, or acalculia are usually present (Fig. 4.9). The protopathic sensory impairment may be related to an involvement of the secondary somatosensory area (SII) (see functional anatomy) or thalamic-SII sensory connection. A patient with an infarct located at the inner bank of the parietal operculum was reported to produce a pure spinothalamic sensory deficit without involvement of proprioceptive and other discriminative sensations (Horiuchi et al., 1996). Occasionally, patients who apparently have preserved primitive sensations do not adequately respond to noxious stimuli (Berthier et al., 1988). This so called ‘asymbolia for

Fig. 4.8. T2-weighted MRI shows a right putaminal hemorrhage producing pure sensory stroke due probably to selective involvement of the thalamic–cortical sensory radiation.

pain’ may be a disconnection syndrome secondary to an interruption between the SII area and the limbic system. The cortical hemisensory symptoms are observed not only after strokes occurring in the SI or SII area, but also after frontal or posterior parietal lesions, confirming that the sensory cortex is not necessarily limited to the post-central gyrus (see functional anatomy). Since the somatotopic representation of body parts is widely spread in the sensory cortex, small cortical lesions occasionally produce sensory symptoms restricted to a distal arm, leg or even to a few finger tips, which may lead inexperienced physicians to make a wrong diagnosis of a root or peripheral nerve disease (Youl et al., 1991; Bassetti et al., 1993; Kim 1994). Sensory abnormalities restricted to the cheiro-oral area (Bogousslavsky et al., 1991) or to proximal body parts with sparing of the distal limbs (Kim, 1999b) are also observed.

Bilateral sensory abnormalities Sensory symptoms almost always occur on the side contralateral to a unilateral stroke. However, they may occur bilaterally under the following conditions. ii(i) Bilateral trigeminal sensory involvement is observed in patients with a large lateral medullary infarct (Fig. 4.3). An infarct situated at the most caudal lateral medulla may produce ipsilateral lemniscal sensory symptoms in addition to contralateral hemihypalgia (see medullary stroke). i(ii) Bilateral perioral or facial sensory symptoms, reported in the pre-MRI era (Caplan & Gorelick, 1983), are now found to occur most often after paramedian pontine strokes (see pontine stroke). Less frequently, however, this phenomenon is also seen in patients

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presents with repeated attacks of tingling sensation (Fisher, 1965, 1982). Pure cortical sensory transient attacks followed by a cortical stroke were reported (Kim, 1992). I have observed patients with hemisensory symptoms lasting less than 24 hours, most of whom were found to have small thalamic infarcts on MRI. One of them had negative MRI findings but had a high-grade stenosis at the proximal part of the posterior cerebral artery. This seems to be ‘sensory transient ischemic attack’ homologous to the so-called ‘capsular warning syndrome’ associated with middle cerebral artery stenosis (Donnan, 1993). Repeated attacks of bilateral perioral or tongue paresthesias with or without involvement of the body/limbs suggest the presence of basilar artery stenosis.

Post-stroke sensory sequelae Out of diverse post-stroke sensory squelae, the following two deserve special attention.

Central post-stroke pain (CPSP)

Fig. 4.9. CT scan shows a left parietal hemorrhage producing conduction aphasia and hemisensory deficits of all modalities.

with supratentorial lesions (Kim, 1996b). This observation agrees with the previous reports that electrical stimulations on the cortical or thalamic areas produced sensory symptoms in the perioral/tongue area bilaterally in about 6–8% of the responses (Tasker et al., 1976; Picard & Olivier, 1983). An anatomical explanation for this phenomenon could be a relatively dominant uncrossed dorsal trigeminothalamic tract in these patients (Nieuwenhuys et al., 1988). (iii) Some modalities of discriminative sensation are impaired bilaterally (see cortical stroke). (iv) As discussed below, some patients with CPSP have delayed-onset sensory symptoms on the side ipsilateral to the lesion (Kim, 1998c).

Sensory transient ischemic attack Sensory symptoms often accompany motor deficits in patients with transient ischemic attack. A pure sensory transient ischemic attack is uncommon and usually

One of the most troublesome sequelae of patients with sensory deficit is a gradual development of uncomfortable, distressful, sometimes painful paresthesias (Dejerine & Roussy, 1906). Once thought as a typical sequela of thalamic strokes (thalamic syndrome of Dejerine & Roussy), it is now recognized that strokes occurring anywhere in the sensory tract can produce similar symptoms (Schmahmann & Leifer, 1992; Leijon et al., 1989; MacGowan et al., 1997; Bowsher et al., 1998). The incidence of CPSP has been reported to be 2–8% (Bowsher, 1993; Andersen et al., 1995). The symptoms are variably described as burning, aching, squeezing, pricking, cold, lacerating, etc. (Leijon et al., 1989; Bowsher, 1993), and are frequently aggravated by a cold environment, psychological stress, heat or fatigue (Bowsher, 1996). They often have a delayed onset and always develop within the area of initial sensory impairment (Bowsher, 1996). The symptoms may be restricted to certain body parts such as distal limbs, and prominent involvement of the anterior chest region may mimic the symptoms of myocardial ischemia (Gorson et al., 1996). Spinothalamic, particularly temperature sensory abnormalities are frequently associated with CPSP (Tasker et al., 1991; Vestergaard et al., 1995; Bowsher 1996), but patients with medial leminiscal sensory deficit (Shintani, 1998) or without objective sensory deficit may also suffer severe CPSP (Tasker et al., 1991). Dysesthesia and allodynia are commonly present (Leijon et al., 1989; Jensen & Lenz, 1995). The pathogenesis of CPSP remains unknown, but a development of hyper-excitation in damaged sensory

Sensory abnormality

pathways, damage to central inhibitory pathways or a combination of the two has been suggested as plausible mechanisms (Schott, 1995). Tasker (1982) proposed that deafferentiation of the spinothalamic system renders a normally non-excitable spinoreticulothalamic system responsive to stimulation, which in turn induces denervation hypersensitivity. When the sensory sequelae of LMI and MMI patients were compared, it was found that CPSP due to LMI more often had a delayed onset, was more often described as 'burning or cold’, and aggravated more often by a cold environment as compared to that caused by MMI (Kim & Choi-Kwon, 1999). These observations suggest the CPSP may occur from both the spinothalamic and medial lemniscal tract injuries, but with different pathogenic mechanisms. The CPSP may be aggravated by another stroke occurring on the opposite side (Kim, 1999c) or alleviated at least temporarily by an ipsilateral subcortical stroke (Soria & Fine, 1991), suggesting that CPSP may be functionally modified by other structures including those at the opposite hemisphere. Finally, some patients with CPSP may develop delayed-onset sensory symptoms on the side ipsilateral to the lesion (Kim, 1998c). This phenomenon may be explained by a development of hyperexcitation of the clinically insignificant ipsilateral sensory pathway in patients developing CPSP. Canavero (1996) also described a patient with bilateral CPSP caused by a unilateral subparietal cavernous angioma. The CPSP is most often treated by adrenergically active antidepressants (amitriptyline) or certain antiepileptics, but the effect is frequently insufficient (Bowsher, 1995). Recently, Canavero and Bonicalzi (1998) postulated that CPSP is caused by unbalanced glutamate/GABA neurotransmission in the central nervous system with a relative hypofunction of the GABAergic inhibitory system. A combination of drugs modulating this derangement may be of benefit for these patients. Subthreshold electrical stimulation of the motor cortex (Tsubokawa et al., 1993) or destructive surgery on the thalamo-cortical radiation (Talairach et al., 1960) has so far shown limited success.

Sensory deficit-related motor dysfunction Patients with a loss of somatosensory function often have considerable difficulties in executing manual tasks especially complex movements requiring coordination among several joints. This 'pseudoparesis’ phenomenon, observed long ago by Mott and Sherrington (1895) in their monkey experiments, has been recently analysed in human patients (Rothwell et al., 1982; Jeannerod et al., 1984; Pause et al., 1989; Ghika et al., 1998), and is considered to be a consequence of the loss of sensory feedback in the sensory–motor circuitry of the central nervous system.

Post-stroke discriminative sensory disturbances, which were found to be very common if meticulously tested (Kim & Choi-Kwon, 1996), seem at least in part to be responsible for the clumsiness of the patients. Several studies have provided evidence that sensory training is of help in the improvement of motor execution in these patients (Carey et al., 1993; Yekutiel & Guttmann, 1993). In addition, severe sensory loss may result in patients’ motor incoordination (sensory ataxia) (Critchley, 1953) or various involuntary movements. While stretching the arms devoid of position sense, the patient’s fingers and hands may wander or drift especially when the eyes are closed. Sometimes, almost continuous purposeless movements are seen in the fingers (pseudoathetosis) (Sharp et al., 1994; Ghika & Bogousslavsky, 1997). There also has been accumulating evidence that dystonic posture is related to sensory input failure (Hallett, 1995; Ghika et al., 1998). A recent study (Bara-Jimenez et al., 1998) showed that in the primary somatosensory cortex, the area representing D1 in relation to D5 was reorganized in patients with hand dystonia, suggesting that abnormal plasticity in the sensory cortex is involved in the pathogenesis of involuntary movements. According to the author’s observation, post-stroke (mostly thalamic) delayed-onset involuntary movements (chorea, dystonia, ataxic tremor) are closely related to successful recovery of paralysed limbs along with persistently impaired proprioceptive sensory and cerebellar functions. Thus, these mysterious movement disorders may at least in part be related to abnormally organized motor circuitry due to unbalanced recoveries among the motor, cerebellar and sensory systems.

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Cerebellar ataxia Dagmar Timmann and Hans Christoph Diener Department of Neurology, University of Essen, Germany

Introduction Definitions The term ‘ataxia’ (Greek, a- (⫽negative article)⫹taxi (⫽order), ‘lack of order’) is commonly used synonymously with incoordination (Dow & Moruzzi, 1958; Gilman et al., 1981; Timmann & Diener, 1998). Ataxia is the most important sign of cerebellar disease. Cerebellar ataxia is defined as lack of accuracy or coordination of movement which is not due to paresis, alteration in tone, loss of postural sense or the presence of involuntary movements (DeJong, 1979). Cerebellar ataxia relates to motor dysfunctions of the limbs, trunk, eyes, and bulbar musculature. Ataxia of gait refers to incoordination of walking, which might be so severe that the patient cannot walk (abasia). Postural ataxia refers to ataxia of stance and sitting and includes truncal ataxia. The patient may be unable to sit or stand without support (astasia). Limb ataxia refers to incoordination of limb movements and ataxia of speech to cerebellar dysarthia. Cerebellar disease results in postural and limb tremor. There may be a rhythmic tremor of the body that can evolve into a severe titubation. Limb tremor occurs as a kinetic and to a lesser extent static tremor. Kinetic tremor occurs as an oscillatory movement when the subject initiates a movement of the limb or during the course of moving the limb. The tremor becomes more prominent as the moving limb approaches a target (intention tremor). Powerful, but brief involuntary movements at the beginning of the movement are due to intention myoclonus, not tremor, and occur in diseases involving the dentate nucleus or the superior cerebellar peduncle.

Neurological findings in cerebellar disease Patients with cerebellar disorders walk with a wide-based, staggering gait, making it seem as if they were intoxicated

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by alcohol. A tendency to fall or deviate to one side suggests a unilateral cerebellar lesion on the same side. The stance is usually on a broad base with the feet several inches apart. In the mildest form patients have difficulty standing with their feet together, in tandem position or on one foot. The Romberg sign might be present or absent in cerebellar disorders depending on the lesion site (Gilman et al., 1981; Dichgans & Diener, 1985; Timmann & Diener, 1998). Several aspects of limb ataxia might be observed using the finger-to-nose and the heel-to-shin-test. Initiation of movement is delayed. Movement may be decomposed in time into its constituent parts (decomposition of movement). The movement path of the limb is erratic and jerky and the nose is rarely touched at once (dysmetria). Subjects more frequently overshoot the target (hypermetria) and rarely stop the movement too soon (hypometria). In cerebellar subjects rapid alternating movements are irregular (dysdiadochokinesis) and slow (bradydiadochokinesis). Kinetic tremor occurs as an oscillatory movement that becomes more prominent as the moving limb approaches a target (intention tremor). Signs of cerebellar dysarthria include a slurred, monotonous and irregular speech with increased variability of pitch and loudness and articulatory impreciseness. The speech tempo is slow. A variety of eye movement abnormalities are seen in cerebellar disease. Gaze-evoked nystagmus is a common finding. Downbeat nystagmus, upbeat nystagmus, and sustained horizontal nystagmus may also be present. Other frequent abnormalities are impairment of smooth pursuit and saccadic (ocular dysmetria) eye movements, inability to suppress the vestibular ocular reflex by fixation and abnormalities of optokinetic nystagmus. Hypotonia, hyporeflexia and asthenia were described as typical symptoms of acute, traumatic cerebellar lesion by Holmes (1939).

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Vermis Intermediate zone Hemisphere

Associated neurological findings The presence of characteristic accompanying neurological symptoms may help to localize the lesion within the territory of one of the cerebellar arteries or the cerebellar pathways. Diplopia, facial numbness, facial droop, vertigo or hearing loss resulting from associated cranial neuropathies (III, IV, V, VI, VII, VIII), Horner’s syndrome and dysautonomia associated with ataxia suggest a disorder in the brainstem. A slight loss of muscular power and increased fatigability of muscles may occur with acute cerebellar disorders. However, paresis associated with increased muscular tone, hyperreflexia and extensor plantar reflexes (Babinski sign) suggest an additional involvement of upper motor neurons (corticospinal or pyramidal syndrome). Pure cerebellar lesions do not cause disturbances in sensation. Hemianesthesia involving one side of the face, arm, and leg suggests an additional lesion of the sensory tracts (i.e. spinothalamic and medial lemniscal tracts) or contralateral parietal lobe. On the contrary, frontal lobe disorders might cause cerebellar-like symptoms with walking difficulties and clumsiness. However, frontal lobe lesions are commonly associated with impairment of cognitive function and changes in personality. Patients have urinary incontinence.

Anatomy of the cerebellar system

Anterior lobe

Primary fissure

Corpus cerebelli

Flocculonodular Flocculus lobe

Nodulus

Anterior lobe (vermis) Primary fissure Posterior lobe (vermis) Nodulus ‘Vestibulocerebellum’ ‘Spinocerebellum’ ‘Cerebrocerebellum’ Fig. 5.1. Main cerebellar subdivisions. Top, a schematic drawing of the partly unfolded cerebellum. Bottom, drawing shows how the unfolding was performed. The dots indicate roughly the cerebellar terminal regions of the main afferent contingents from the spinal cord, from the vestibular apparatus, and from the cerebral cortex via the pontine nuclei. (With permission from Brodal, P. (1998). Fig. 14.2, p. 395.)

Cerebellar subdivisions The cerebellum is located behind and below the cerebral hemispheres, overlying the brainstem. Several classifications have been used to subdivide the cerebellum based on anatomic, phylogenetic, and functional findings (Brodal, 1998). Anatomically, the cerebellum is subdivided into three major components: the flocculonodular, anterior and posterior lobes, the latter two forming the corpus cerebelli (Fig. 5.1; top, left side). The three lobes are subdivided into several lobules. In the past the lobules carried individual names which have been replaced by Larsell’s numbering system, which consists of Roman numerals in the vermis and the prefix H in the hemispheres. The terms archicerebellum, paleocerebellum and neocerebellum originate from phylogenetic and embryological studies. The terms vestibulo-, spino-, cerebrocerebellum originate from termination sides of cerebellar afferent projections. These subdivisions match well with the subdivisions based on phylogenetic studies. The flocculonodular

lobe (⬵archicerebellum) has been named vestibulocerebellum because of heavily projecting vestibular afferents; the vermis and paravermal parts of the cerebellar hemispheres (⬵paleocerebellum) were called spinocerebellum because of their spinal afferents and the cerebellar hemispheres (⬵neocerebellum) cerebrocerebellum (syn. pontocerebellum) based on their corticopontine input (Fig. 5.1; top, right side). On the basis of the efferent projections from the cerebellar cortex to the cerebellar nuclei, Jansen & Brodal (1940) and later Chambers & Sprague (1955a,b) suggested a subdivision into three longitudinal (⫽sagittal) zones: a medial zone (⫽vermis) projecting to the fastigial nucleus, an

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intermediate (⫽paravermal part of cerebellar hemisphere) zone projecting to the interposed nuclei and a lateral (⫽ lateral part of cerebellar hemisphere) zone projecting to the dentate nucleus (Fig. 5.1; top, right side). Later studies showed that the longitudinal subdivision was more detailed (Voogd, 1969; Hawkes et al., 1992).

Cerebellar pathways The cerebellum is connected with the brainstem by afferent and efferent fibres passing through three pairs of tracts, called the inferior, middle and superior cerebellar peduncle (or restiform body, brachium pontis and brachium conjunctivum). The middle cerebellar peduncle contains only afferent fibres. In the inferior peduncle most fibres are afferent, whereas in the superior cerebellar peduncle most fibres are efferent. The cerebellar cortex receives afferent input from most parts of the peripheral (proprioceptive, cutaneous, vestibular and visual) and central nervous system (Bloedel & Courville, 1982). From the trunk and legs, the dorsal and ventral spinocerebellar tract enter the cerebellum through the ipsilateral inferior and contralateral superior cerebellar peduncle, respectively. From the arms and neck, the cuneo- and rostral spinocerebellar tracts enter the cerebellum through the inferior and superior cerebellar peduncles. Many afferent pathways have additional relay stations (pontine nuclei, inferior olives) before they enter the cerebellum. From the inferior olive, climbing fibres enter the cerebellum through the contralateral inferior cerebellar peduncle. The pontine nuclei represent the most important relay for corticocerebellar pathways. Corticopontine projections enter the cerebellum mainly through the contralateral middle cerebellar peduncle. The cerebellar nuclei are the principal source of cerebellar efferent fibres. Efferent cerebellar pathways descend to the brainstem and spinal cord and ascend to the cerebral cortex. Efferents from the flocculonodular lobe project mainly to the vestibular nuclei in the brainstem directly and indirectly via the fastigial nuclei. Efferents from the globose and emboliform nuclei (i.e. from the interposed nucleus) form the major cerebellar projection to the contralateral nucleus ruber (cerebellorubral tract). The main efferent output from the red nucleus projects to the spinal cord on the contralateral side (rubrospinal tract). Most fibres from the dentate nuclei end in the contralateral thalamus. The main projection from the thalamus goes to motor and premotor cortices via the internal capsule (Fig. 5.2). Because the ascending fibres from the cerebellum to the nucleus ruber and the motor cortex and the descending fibres from the nucleus ruber and cerebral cortex to the

Fig. 5.2. The main connections of the dentate and interposed nuclei. Note that the ascending connections to the cerebral cortex from the dentate nucleus are synaptically interrupted in the thalamus (cerebrocerebellum). Both the spinal cord (via the red nucleus) and the cerebral cortex (via the thalamus) can be influenced by the interposed nucleus (intermediate zone). (With permission from Brodal, P. (1998). Based on Fig. 14.7, p. 400 and Fig. 14.9, p. 402.)

spinal cord are crossed, the cerebellar hemisphere exerts its influence on the body half of the same side. Therefore, in unilateral cerebellar lesions symptoms of limb ataxia occur ipsilaterally.

Afferent connections from the cerebral cortex The vast majority of the afferents to the pontine nuclei arise in the cerebral cortex and form the corticopontine tract. The corticopontine tract is uncrossed whereas most of the pontocerebellar fibres cross; thus the cerebral cortex of one side acts mainly on the cerebellar hemisphere of the opposite side. A large portion of the corticopontine fibres arise in the primary motor and sensory cortex (MI and SI). There are, however, substantial contributions also from the SMA and PMA and from areas 5 and 7 of the posterior parietal cortex. The pontine nuclei also receive afferents from the visual cortex and from parts of the hypothalamus and limbic structures (Middleton & Strick, 1994; Brodal, 1998).

Cerebellar ataxia

(a )

(b)

Fig. 5.3. Diagrammatic drawing of a section (a) through the right internal capsule; and (b) through the mesencephalon, indicating the position of the cerebropontine (a, b), pyramidal (a, b) and thalamocortical tracts (b). (Based on (a) Abb. 252, p. 235 from Benninghoff, A. & Goerttler, K. (1979); and (b) Fig. 4.2, p. 186 from Brodal, A. (1981) modified from Foerster (1936), Springer-Verlag Berlin, with permission.)

The corticopontine tract runs in the internal capsule and in the crus cerebri. The frontopontine tract (Arnold’s bundle) is localized in the anterior limb of the internal capsule, the parietopontine tract in the posterior limb, the occipitopontine tract in the retrolenticular portion of the posterior limb, and the temporopontine tract (Türk’s bundle) in the sublenticular portion of the posterior limb of the internal capsule. The frontopontine tract is in close

neighbourhood to the corticobulbar tract located in the genu of the internal capsule and the corticospinal tract located in the anterior part of the posterior limb (Fig. 5.3(a)). The internal capsule turns rostrally into the corona radiata and caudally into the crus cerebri. In the crus cerebri, the frontopontine tract is localized medially and the temporopontine tract laterally of the corticospinal

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Fig. 5.4. Schematic drawing of the afferent and efferent pathways through the brainstem. Note the close vicinity of the corticopontine tracts and the corticospinal tract in the upper base of the pons. (With permission from Benninghoff, A. & Goerttler, K. (1979). Abb. 208, p. 183.)

tract (Fig. 5.3(b)). The smaller parieto- and occipitopontine tracts are found medially of the temporopontine tract. The corticopontine tract remains in close relationship to the corticospinal and corticobulbar tract on their way through the mesencephalon and the base of the pons (Fig. 5.4).

Efferent connections to the cerebral cortex The fibres from the dentate nucleus leave the cerebellum through the superior cerebellar peduncle. They cross the midline in the mesencephalon, and some fibres end in the nucleus ruber of the opposite side. Most fibres continue rostrally, however, to end in the thalamus, primarily in the ventrolateral nucleus (VL). Some also reach the ventroanterior nucleus (VA). Thalamic fibres from the VL and VA nucleus run through the superior thalamic peduncle in the posterior limb of the internal capsule to the precentral region (MI, SMA and PMA). In the internal capsule, the corticospinal tract lies in close vicinity of the thalamic fibres (Figs. 5.2 and 5.3). The sensory tracts do not travel closely to the cerebellar fibres until they reach the thalamus. The spinothalamic tract and the medial lemniscus, however, do travel in close

proximitity to the superior cerebellar peduncle in the superior lateral pons, and, when affected, a crossed hemisensory ataxic syndrome results. The sensory tracts synapse in the ventroposterolateral nucleus (VLP) of the thalamus and run through the superior thalamic peduncle to the postcentral region. Therefore, sensory and cerebellocortical fibres are in close proximity in the thalamus and the posterior limb of the internal capsule (Fig. 5.5).

Vascular supply of the cerebellum The vascular supply of the cerebellum is provided by three arteries, the posterior inferior cerebellar artery (PICA), the anterior inferior cerebellar artery (AICA), and the superior cerebellar artery (SCA). In brief, branches of the PICA supply the inferior aspect of the cerebellar hemispheres extending up to the primary fissure, the cortex of the inferior vermis, the deep cerebellar nuclei as well as the inferior cerebellar peduncle and the lateral medulla oblongata. Branches of the AICA supply the flocculus and adjacent lobules of the inferior and anterior cerebellum, the inferior and middle cerebellar peduncles as well as the nuclei of the

Cerebellar ataxia

Fig. 5.5. Diagram of a three-dimensional reconstruction of the right human thalamus seen from the dorsolateral aspect. Abbreviations for thalamic nuclei: A: anterior; CM: centromedian; Int. Lam.: intralaminar; LD and LP: lateralis dorsalis and posterior; LG: lateral geniculate body; LM: medial geniculate body; MD: dorsomedial; MI: midline; P: pulvinar; R: reticular; VA: ventralis anterior; VL: ventralis lateralis; VPL and VPM: ventralis posterior lateralis and medialis. (With permission from Brodal, A. (1981). Fig. 2.14, p. 95.)

VII–IX and XII cranial nerves in the brainstem and the inner ear (⫽the internal auditory artery and the labyrinthine artery). The superior cerebellar artery (SCA) supplies the superior parts of the cerebellar hemispheres, major parts of the vermis, all deep cerebellar nuclei and all cerebellar peduncles as well as the pons (Barth et al., 1993; Chaves et al., 1994). All cerebellar arteries supply cerebellar as well as brainstem structures. Therefore, vascular disorders frequently damage the cerebellum and brainstem together (for further details and diagrammatic drawings, see Part II Chapter 42 Cerebellar stroke syndromes).

Cerebellar syndromes Cerebellar syndromes are commonly classified based on the three major functional subdivisions of the cerebellum (Dow & Moruzzi, 1958; Dichgans & Diener, 1985). In brief, lesions of the lower vermis (so-called flocculonodular syndrome) cause postural ataxia of head and trunk during sitting, standing, and walking. Patients frequently fall even during sitting. There is no incoordination of the limbs when the patient is lying in bed. Postural sway is omnidirectional and contains frequency components of < 1 Hz. In patients with such lesions, severe postural sway is present with eyes open and is essentially unchanged with eyes closed. Fine coordinated movements of the limbs are relatively preserved. Damage to the anterior lobe (⫽spino- or paleocerebel-

lum) results in ataxia of stance and gait. Patients with this disorder develop a severe disturbance of standing and walking with relatively preserved fine coordinated movements of the upper limbs. Lesions of the spinocerebellar part of the anterior lobe lead to anteroposterior body sway with a frequency of about 3 Hz. Visual stabilization of posture is preserved and the tremor is provoked by eye closure. Diseases of the cerebellar hemisphere (⫽cerebro- or neocerebellum) are correlated with severe disturbances of limb movements including hypotonia in acute lesions, asynergia, dysdiadochokinesis, and, if the dentate nucleus is involved, kinetic tremor. Past pointing and deviation of gait to the affected side are associated symptoms. Symmetrical involvement of both hemispheres and vermis produces bilateral limb ataxia and ataxia of stance and gait. Dysarthria and oculomotor disturbances are also frequently present. The paramedian regions of the superior cerebellar hemispheres are most relevant for the development of cerebellar dysarthria (Ackermann et al., 1992). Left hemispheric cerebellar lesions appear to be more frequently associated with cerebellar dysarthria than right hemispheric lesions (Lechtenberg & Gilman, 1978). Three principal syndromes of specific cerebellar oculomotor disorders have been identified: the syndrome of the dorsal vermis and underlying fastigial vermis, the syndrome of the flocculus and paraflocculus, and the syndrome of the nodulus. Lesions of the dorsal vermis and fastigial nucleus cause saccadic dysmetria and mild deficits of smooth pursuit. Lesions of the nodulus are accompanied by prolongation of vestibular responses and periodic alternating nystagmus, which is a spontaneous horizontal nystagmus that changes direction every few minutes. Lesions of the flocculus and paraflocculus cause impaired smooth pursuit, gaze-evoked, rebound and downbeat nystagmus, impaired optokinetic nystagmus, and disability to adjust the gain of the VOR (Lewis & Zee, 1993).

Vascular syndromes resulting in ataxia Vascular lesions of the cerebellum itself and of the corticoponto-cerebellar and dentato-thalamic pathways might result in ataxia.

Stroke of the cerebellum The vascular supply of the three functional subdivisions of the cerebellum does not match the territory of any of the

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three cerebellar arteries. Therefore, vascular syndromes in the distribution of one of the cerebellar arteries present as combinations of the cerebellar syndromes described above. Infarction in the territory of any of the three cerebellar arteries results in limb and gait ataxia (Toghi et al., 1993; Kase, 1994). Dysarthria is a characteristic finding in SCA distribution infarcts, whereas vertigo is particularly common in infarcts in the PICA and AICA territories (Kase et al., 1993; Kase, 1994; Erdemoglu & Duman, 1998). AICA territory infarcts almost always include the lateropontine area and are frequently predominated by brainstem signs. The dorsal medullary territory of the PICA and the dorsal mesencephalic territory of the SCA are less frequently involved than assumed previously (Barth et al., 1993). Motor weakness in the setting of cerebellar infarction allows one to suspect multiple cerebellar infarctions (Canaple & Bogousslavsky, 1999). During the first stage after a cerebellar stroke goaldirected movements are hypermetric, due to a delayed onset of the antagonist activity. Both the intensities of the agonist and antagonist are depressed. As a result, patients initially complain of weakness. Recovery of dysmetria following a stroke has been demonstrated to take place in four phases, which can be explained in terms of a differential recovery of agonist and antagonist activities (Manto et al., 1995). Abnormal reprogramming of the EMG pattern may result in the shifting from severe hypermetria to severe hypometria (Manto et al., 1998).

Posterior inferior cerebellar artery (PICA) In instances of combined cerebellar and medullary infarction in the PICA territory, the patient has the features of Wallenberg’s lateral medullary syndrome: ipsilateral limb ataxia and gait imbalance is accompanied by vertigo, nystagmus, occipitocervical headache and ipsilateral facial pain, dysphonia and dysphagia, ipsilateral facial loss of pain and temperature sensation, Horner’s syndrome, palatal weakness, and by thermanalgesia of the limbs and trunk. Ipsilateral lateropulsion may be present. All these features can be present in full and can occur in various combinations. Brainstem involvement, however, is rare (Amarenco et al., 1990; Kase et al., 1993; Chaves et al., 1994). Cerebellar infarcts in the PICA territory that spare the dorsolateral medulla present with occipitocervical headache ipsilateral to the infarct, along with acute vertigo, nausea and vomiting, nystagmus, ipsilateral limb ataxia, and gait ataxia (Barth et al., 1993; Kase et al., 1993; Kase, 1994; Chaves et al., 1994). Initial hoarseness has been described, but no dysarthric deficits (Ackermann et al.,

1992). Isolated vertigo and gait imbalance without other manifestations may be present, which resembles the presentation of labyrinthitis (Duncan et al., 1975). In labyrinthitis, however, the direction of nystagmus is independent of the direction of gaze, whereas in PICA infarction gazeevoked nystagmus is primarily direction changing.

Superior cerebellar artery (SCA) A unilateral isolated full SCA infarct, including the pontine territory, is rare. It results in ipsilateral limb ataxia, Horner’s syndrome, choreiform involuntary movements, contralateral thermoanalgesia and fourth nerve palsy (Kase, 1994; Amarenco & Hauw 1990a). The majority of SCA infarcts affect only fractions of the territory. A common presentation is acute onset of gait imbalance and ipsilateral limb ataxia that is sometimes associated with headache, vertigo, nausea and vomiting (Kase et al., 1985; Kase, 1994; Barth et al., 1993; Amarenco et al., 1991; Terao et al., 1996; Erdemoglu & Duman, 1998). Axial lateropulsion occurs. Vertigo, however, is less common than in PICA- and AICA-distribution infarcts. The relatively lower frequency of vertigo in SCA cases has been related to the comparatively less vestibular connections of those portions of the cerebellum supplied by the SCA, in contrast to the rich connections of the flocculonodular lobe supplied by the PICA and AICA (Kase et al., 1993). Horizontal nystagmus is present in at least 50% of patients. Dysarthria is a prominent feature (Ackermann et al., 1992). Limb ataxia appears to be more prominent in SCA cases as compared to PICA distribution infarcts (Chaves et al., 1994; Toghi et al., 1993). SCA infarcts are often accompanied by other infarcts in the territory of branches of the rostral basilar artery. Symptoms of rostral brainstem and occipital involvement may overshadow signs of cerebellar involvement (Amarenco & Hauw, 1990a,b; Canaple & Bogousslavsky, 1999).

Anterior inferior cerebellar artery (AICA) In PICA and SCA territory infarcts, the clinical signs are dominated by cerebellar infarction, while in AICA territory pontocerebellar infarcts, brainstem signs predominate (Amarenco & Hauw, 1990b; Amarenco et al., 1993). An almost complete syndrome is observed in most cases. The classic syndrome of AICA occlusion involves vertigo, tinnitus, ipsilateral hearing loss, dysarthria, peripheral facial palsy, Horner’s syndrome, multimodal facial hypaethesia, and ipsilateral limb ataxia accompanied by contralateral thermanalgesia of the limbs and trunk. Partial AICA can be confused with Wallenberg’s syndrome. The prominence of the auditory involvement and peripheral facial

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palsy point to a clinical diagnosis of AICA. Partial AICA syndromes rarely can present with pure vertigo (mimicking labyrinthitis) or isolated ipsilateral ataxia (Amarenco et al., 1993; Kase, 1994; Roquer et al., 1998).

Stroke of the pons, thalamus and internal capsule: ‘Ataxic hemiparesis’ Vascular lesions in the course of the cortico-ponto-cerebellar and dentato-thalamic pathways may result in ataxia, primarily of the limbs. Because of the close vicinity of the cerebellar pathways and the corticospinal tracts in the base of the pons, crus cerebri and internal capsule, hemiataxia is frequently associated with homolateral pyramidal signs (Figs. 5.3, 5.4). The vascular syndrome of ‘ataxic hemiparesis’ (i.e. hemiparesis or pyramidal signs and ipsilateral incoordination without sensory loss) was first named by Fisher in 1978. Fisher also coined the terms ‘homolateral ataxia and crural paresis’ (i.e. weakness of the lower limb and Babinski sign associated with ipsilateral ataxia) and ‘dysarthria-clumsy hand syndrome’ to identify separate stroke syndromes (Fisher & Cole, 1965; Fisher, 1967). De Smet (1991) proposed that ‘ataxic hemiparesis’ results from a lesion involving, simultaneously, both the cortico-spinal and cortico-ponto-cerebello-dentatorubro-thalamo-cortical tracts, anywhere between the subcortical and inferior pontine level (Fig. 5.2). He regarded ‘dysarthria-clumsy hand syndrome’ and ‘homolateral ataxia and crural paresis’ as two clinical variants of one and the same syndrome: ‘ataxic hemiparesis’. Although Glass et al. (1990) proposed that the lack of dysarthria, prominent hemiparesis and frequent sensory symptoms and signs in ‘ataxic hemiparesis’ serve to distinguish the ‘ataxic hemiparesis’ and ‘dysarthria-clumsy hand syndrome’, to date, most authors agree that the latter is a variant of the ‘ataxic hemiparesis’, at least at the pontine level (Fisher, 1982; De Smet, 1991; Kim et al., 1995; Bassetti et al., 1996; Gorman et al., 1998). Bogousslavsky et al. (1992), however, provided evidence that ‘homolateral ataxia and crural paresis’ is merely found in superficial anterior cerebral artery infarction. The anatomic and pathophysiological specificity of ataxic hemiparesis had been questioned by Landau in 1988. Landau argued that all patients with hemiparesis are clumsy, and that there ‘are no data to support the concept of a special measurable quality of clumsiness that identifies cerebellar anatomic correlation’. However, previous kinematic and electromyographic studies in patients with ataxic hemiparesis following a stroke of the corona radiata or pons showed disorders that are known to be

characteristic of patients with cerebellar lesions (Wild & Dichgans, 1993; Bartholome et al., 1996). Ataxic hemiparesis has been found to be highly predictive of a lacunar lesion (Chamorro et al., 1991; Gan et al., 1997; Gorman et al., 1998). The syndrome, however, does not seem to predict the lesion locus. Rather, in ataxic hemiparesis infarcts are scattered throughout the motor pathway. The most common lesion sites are the posterior limb of the internal capsule (23–39%) and pons (19–31%). Other lesion sites are the thalamus (11–13%), the anterior part of the corona radiata (13–31%) and the basal ganglia (8–14%) (Boiten & Lodder, 1990; Chamorro et al., 1991; Moulin et al., 1995; Gan et al., 1997). Although the most common lesion in all studies was a small deep infarct (ca. 50%), cerebral hemorrhage and superficial infarcts in the cerebellum (SCA territory) and frontal cortex (A. cerebri anterior territory) have also been shown to cause ataxic hemiparesis in a small percentage of cases (Moulin et al., 1995; Gorman et al., 1998). The clinical features of ataxic hemiparesis with different locations are almost identical. Ataxia nearly always involves the arm and leg with equal intensity. Minor associated signs are common, e.g. paraesthesiae with thalamic infarction, and dysarthria, nystagmus and gait ataxia with a pontine infarct (Huang & Lui, 1984; Moulin et al., 1995; Gorman et al., 1998). The origin of limb ataxia in ataxic hemiparesis remains debated. Some investigators believe that the syndrome of ataxic hemiparesis is due to simultaneous involvement of corticospinal and dentato-rubro-thalamocortico-pontocerebellar pathways, whereas blood flow studies suggest an ipsilateral cerebellar diaschisis (Giroud et al., 1994; Bassetti et al., 1996). Crossed cerebellar diaschisis is a condition in which cerebellar hypoperfusion and hypometabolism is ascribed to functional deactivation of the contralateral cerebellar hemisphere from the cerebral cortex (e.g. motor and premotor areas) or from subcortical areas (e.g. thalamus, pons) (Tanaka et al., 1992; Fazekas et al., 1993; Infeld et al., 1995; Lim et al., 1998; Rousseaux & Steinling, 1999; de Reuck et al., 1999). Interruption of the cerebro-ponto-cerebellar (anterograde) and dentato-thalamic pathway (retrograde) is thought to be the most likely mechanism of this remote transneuronal metabolic depression (Fig. 5.2) (Tien & Ashdown, 1992; Fazekas et al., 1993; Ishihara et al., 1999). It is, however, unclear whether crossed cerebellar diaschisis is merely an epiphenomenon, as its clinical significance remains unkown. The majority of PET and SPECT studies found no association of cerebellar hypoperfusion to clinical signs and symptoms. Most patients did

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not present with cerebellar signs (Piero di et al., 1990; Tien & Ashdown, 1992; Fazekas et al., 1993; Tanaka et al., 1992; Infeld et al., 1995; Kim et al., 1997). As remote consequences are not correlated with clinical deficits, ataxia in ataxic hemiparesis appears to be directly related to the local consequences of the lesion (Kim et al., 1997).

Eye movement disorders, sensory disturbances, and cranial nerve dysfunction (V–VII) suggest additional tegmental pontine infarction. Occassionally, bilateral infarcts can be limited to the ventral pons, presenting with ataxic tetraparesis, almost isolated para- and tetraplegia or locked-in syndrome (Withiam-Leitch & Pullicino, 1995; Bassetti et al., 1996).

Internal capsule The posterior limb of the contralateral internal capsule is a common lesion site in ataxic hemiparesis, sometimes extending toward the corona radiata region and lateral thalamus (Moulin et al., 1995; Helgason & Wilbur, 1990). In these cases, the frontopontine and temporoparietopontine bundles are not involved, because they course in the anterior limb and retro- or sublenticular portion of the internal capsule, respectively (Fig. 5.3). It has been suggested that the cerebellar dysfunction is related to destruction of corticopontine fibres from the precentral cortex or connecting fibres between the ventrolateral nucleus of the thalamus and the precentral region (i.e. superior thalamic tract) (Bogousslavsky et al., 1992). Saitoh et al. (1987) studied ataxia and the readiness potential in four cases of ataxic hemiparesis resulting from a small infarct in the posterior limb of the internal capsule. On the basis of normal readiness potentials the dentatothalamo-cortical system, secondary to interruption of the thalamic radiation at the internal capsule, did not appear to be significantly involved. Therefore, Saitoh et al. concluded that the ataxia appeared to be the result of involvement of the corticopontine tract originating from the precentral region (areas 4 and 6) at this level. Ataxic hemiparesis is frequently accompanied by hemisensory signs because the sensory tracts course within the superior thalamic tract in the posterior limb of the internal capsule (Fig. 5.3; Helgason & Wilbur, 1990).

Pons Bassetti et al. (1996) delineated three main syndromes of isolated infarcts of the pons (ventral, tegmental and bilateral). Ventral lesions interrupt the corticospinal, corticobulbar and corticopontine fibres to various extents (Fig. 5.4). In ventral pontine infarcts, pontine hemiparesis is often accompanied by homolateral (to the motor deficit) facial palsy and brachiocrural ataxia as well as dysarthria. Smaller infarctions in the anterolateral territory are associated with a mild motor dysfunction corresponding to the lacunar syndromes ‘ataxic hemiparesis’ and ‘dysarthriaclumsy hand syndrome’ (Bogousslavsky et al., 1986; Glass et al., 1990; Kim et al., 1995), which can be considered variants of one syndrome (Kim et al., 1995; Bassetti et al., 1996).

Thalamus Hemiataxia is a common occurrence in thalamic infarction involving the ventrolateral part of the thalamus usually from involvement of the thalamogeniculate territory (Bogousslavsky et al., 1984, 1988; Melo et al., 1992). Hemiataxia as a manifestation of thalamic infarction rarely occurs in isolation, being associated with ipsilateral hemiparesis (ataxic hemiparesis), pain and hemiparesis (painful ataxic hemiparesis), ipsilateral sensory disturbance (hemiataxia–hypaesthesia) and ipsilateral sensory disturbance and hemiparesis (hypaesthetic ataxic hemiparesis). These four syndromes might be explained by variations in blood supply to the capsulothalamic region (Moulin et al., 1995). Accompanying sensory signs are frequent in thalamic hemiataxia because of the close neighbourhood of the sensory (i.e. VPL) and cerebellar (i.e. VL (and VA)) thalamic nuclei in the ventral thalamic group (Fig. 5.5). The occurrence of pain has localizing value. Pain is not present in pontine, mesencephalic or capsular ataxic hemiparesis (Bogousslavsky et al., 1984). In contrast to the ascending dentato-thalamic and sensory pathways the corticospinal tract is not part of the thalamus. Corticospinal signs in thalamic ataxic hemiparesis are probably due to ischemia or edema compressing the adjacent corticospinal tract or associated infarction of the adjacent internal capsule, as the thalamogeniculate branches sometimes contribute to the innermost part of the posterior limb of the internal capsule (Moulin et al., 1995; Helgason & Wilbur, 1990). It has been proposed that, if hemiparesis is mild and transient in ataxic hemiparesis, it suggests a thalamic lesion site (Solomon et al., 1994). Infarction or hemorrhage in the thalamus can produce striking problems in balance. Stength, sensation and coordination are normal; however, patients cannot stand without falling. It has been called thalamic astasia, but similar pictures are seen after midbrain and putaminal lesions (Masdeu & Gorelick, 1988).

Subcortical white-matter lesions Abnormalities of gait are common in subcortical arteriosclerotic encephalopathy (SAE) (Thompson & Marsden,

Cerebellar ataxia

1987; Elble et al., 1996). The gait pattern in SAE shows similarities to that of some patients with hydrocephalus, frontal lobe lesions, and ‘senile’ disorders of gait (Bronstein et al., 1996). Thompson and Marsden (1987) evaluated the disordered gaits of 12 patients suspected to have SAE because of typical low-density periventricular cerebral white matter changes on CT scans. The gait disorder was termed parkinsonian-ataxia since it had elements of both parkinsonism and cerebellar ataxia. Patients stood on a wide base, were slightly ataxic, and took slow and shuffling ‘parkinsonian’ steps. Patients show relatively preserved function of the upper limb, lively facial expression and less flexed posture, which has led to the use of ‘lower body parkinsonism’ (syn. marche petits pas, arteriosclerotic parkinsonism) (Nutt et al., 1993). Frequently associated signs are cognitive impairment and urinary incontinence. Gait initiation failure may remain the sole symptom for many years (isolated gait initiation failure, syn. Petren’s gait). On the other hand, the clinical picture may be dominated by impairment of balance (e.g. truncal ataxia) severe enough to prevent standing and walking (frontal disequilibrium) (Elble et al., 1996; Yamonouchi & Nagura, 1997; van Zagten et al., 1998). Thompson and Marsden (1987) proposed that periventricular low density on CT might indicate significantly damaged afferent and efferent interconnections of the leg areas of the motor and supplementary motor areas of the cerebral cortex with the cerebellum and basal ganglia.

Cortical stroke Bogousslavsky et al. (1992) reported five patients with superficial anterior cerebral artery infarction in the paracentral area, who developed a hemiparesis which was predominant in the leg and with homolateral ataxia in the arm. This syndrome of ‘homolateral ataxia and crural paresis’ had been ascribed to lacunar infarction (Fisher & Cole, 1965). Involvement of the corticopontine fibres at their origin, together with damage to the lower limb motor strip or underlying white matter, appears to have been the cause of the clinical syndrome. It has been suggested that homolateral ataxia and crural hemiparesis is not a lacunar syndrome, and that it should not be considered to be merely a variant of ataxic hemiparesis (Bogousslavsky et al., 1992; Moulin et al., 1995).

Concluding remarks Limb ataxia and ataxia of gait are common in SCA, PICA and AICA territory infarctions. Dysarthria is a characteristic

symptom of stroke in the SCA distribution. Vertigo as presenting sign is most common in PICA and AICA territory infarcts. Concomitant brainstem infarction is the rule in stroke in the AICA distribution, but not in the SCA or PICA territory. ‘Ataxic hemiparesis’ occurs most commonly in lacunar lesions of the internal capsule and basis of the pons. Accompanying sensory signs and pain suggest a lesion site in the thalamus and dysarthria in the pons. The ‘dysarthria-clumsy hand syndrome’ is a variant of ‘ataxic hemiparesis’, at least at the pontine level. ‘Homolateral ataxia and crural paresis’ is the result of superficial anterior cerebral artery infarction. Gait disorders in subcortical ateriosclerotic encephalopathy show parkinsonian and ataxic features.

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Headache: stroke symptoms and signs Conrado J. Estol Centre for Neurological Treatment and Rehabilitation, Buenos Aires, Argentina

A riddle wrapped in a mystery inside an enigma. Winston Churchill

Introduction The stroke–migraine interaction is one of the most fascinating and intriguing among neurological diseases. It appears obvious; however, it remains unravelled. The coexistence of headache and stroke encompasses a large spectrum of possibilities including stroke caused by migraine headache, migraine developing after a stroke and non-migraine headache occurring in relation to stroke. Headache occurs in approximately 200 000 of the 550 000 patients who have a stroke annually in the US (Vestergaard et al., 1993). Although not frequent, the bidirectional association between migraine and stroke is well known and important to recognize for diagnostic, treatment and prognostic reasons. Despite recent and significant advances in understanding of the pathophysiology linking both processes, the exact mechanisms relating migraine and stroke have not been fully elucidated. When referring to migraine, we should think of a complex syndrome with many characteristics among which headache is the most prominent and is almost invariably – but not always – present. Migraine and stroke can result in focal sequelae and both share headache as a frequent symptom. All the potential scenarios in the headache–stroke relationship include: (i) patients with history of migraine who at one point in their lives develop a stroke (temporally unrelated to migraine); (ii) patients with migraine who develop brain infarction during a typical migraine attack; (iii) patients who develop migraine immediately after a stroke; (iv) patients who develop migraine some time after having a stroke; (v) patients with migraine as a manifestation of vascular disease (thrombosis, vascular malformation) without the occurrence of a stroke; (vi) patients in whom migraine disappears after stroke occurrence; (vii) patients with non-migrainous headache only present at

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the time of a stroke; (viii) patients with non-migrainous headache following a stroke. I will analyse the most frequent and significant of these manifestations.

Definitions The different categories developed by the Classification Committee of the International Headache Society (IHS) cover most combinations of different headaches in relation to cerebrovascular disease (Headache Classification Committee of the International Headache Society, 1988). The classification includes headache type (migraine, cluster, tension), specific cerebrovascular event (thromboembolic, intracranial hematoma, venous thrombosis), and whether headache occurs de novo after cerebrovascular disease or if pre-existing headache worsened as a result of the vascular episode. For example, a patient who develops headache after a vascular event (group 6), proven ischemic (group 6.1), with a thromboembolic mechanism (group 6.1.2) and migraine as the resulting headache syndrome (group 6.1.2.1.) can be specifically classified by each of these parameters. The classification adds a time limit of 2 weeks to accept the headache as a result of the cerebrovascular event. To establish the diagnosis of ‘migrainous stroke’ (i.e. stroke caused by migraine), the IHS criteria requires a prior diagnosis of migraine with aura and excludes patients that have migraine without aura. The higher frequency of stroke in patients with this migraine type, suggests that aura may be secondary to mechanisms that predispose to ischemic cerebrovascular disease. However, ischemia may also occur, although less frequently, in patients with migraine without aura, supporting that underlying mechanisms common to different migraine types, or genetic

Headache: stroke symptoms and signs

Table 6.1. Classification of migraine related Stroke I

Coexisting migraine and stroke

II

Cerebrovascular disease with clinical features of migraine IIa: Established (symptomatic migraine): AVM, old infarct, etc. IIb: New onset (migraine mimic): arterial dissection, thrombosis, embolism, etc.

III

Migraine induced stroke IIIa: Without risk factors IIIb: With risk factors: oral contraceptives, smoking, etc.

IV

Uncertain: mitral valve prolapse, antiphospholipid antibodies, etc.

Source: Modified from Welch (1994).

factors as yet unidentified, may be responsible for stroke predisposition in different migraine patients. This situation probably reflects limitations in the present IHS classification more than constituting a strong argument against causality between migraine without aura and stroke. Thus, according to IHS criteria, if a stroke occurs during an attack of migraine without aura, the etiology of stroke should be considered as ‘uncertain’. The IHS definition of Migrainous Infarction requires that: (i) the present attack is typical of previous attacks, but neurological deficits are not completely reversible within 7 days and/or neuroimaging demonstrates ischemic infarction in a relevant area; (ii) the patient has fulfilled criteria for migraine with aura; (iii) other causes of infarction are ruled out by appropriate investigations. Welch proposed inclusion, in this third point, of the possibility that stroke risk factors could be present, to allow classification of patients with potential contributing factors such as smoking, use of birth control pills, and others, as ‘migrainous stroke’ (Welch,1994). These criteria for migrainous infarction do not accurately define: (i) cerebral infarction of other cause coexisting with migraine, and (ii) brain infarction of other cause presenting with symptoms resembling migraine (Table 6.1). In summary, and according to the IHS criteria, the different possible scenarios in the migraine–stroke interaction are as follows. ii(i) Young patients who have a stroke during a migraine attack. To be ‘accepted’ as a migrainous stroke, the deficit should be identical to the symptoms that occur during previous auras. However, if stroke occurs during an attack of migraine without aura or the deficit is different from the usual aura, according to the IHS classification, the event is not accepted as a ‘migrainous stroke’.

i(ii) Young patients with migraine who develop a stroke remote from a migraine attack. The chances that migraine could play an etiologic role are significant, especially in patients without any other coexisting stroke risk factors. It remains to be clarified if migraine is a contributing risk factor among all others, to precipitate a stroke even in the absence of a migraine attack. (iii) Older patients with migraine who have a stroke during a migraine attack. In these patients, there is probably a contributing role of coexisting vascular risk factors. However, it has not been demonstrated that stroke in these patients is more frequent than in younger migraine patients without the associated vascular risk factors. (iv) Older patients with migraine who have a stroke remote from a migraine attack. It is difficult to prove causality in this subgroup of patients, especially if they have multiple coexisting stroke risk factors.

Pathophysiology of headache in migraine and stroke The mechanisms of migraine can be summarized as hemodynamic changes preceded by causal neuronal alterations (Olesen et al., 1981; Skyhoj-Olsen et al., 1987; Olesen, 1992). A spreading wave of neuronal depression, similar to that described by Leno, correlates with a spreading wave of blood flow depression which may reach ischemic thresholds (Woods et al., 1994). Persistently decreased blood flow beyond a reversible ischemic window, hypercoagulation secondary to altered coagulation factors, increased platelet aggregation, excessive vasoconstriction related to serotonin or other vasoactive substances, are among the mechanisms that participate in the occurrence of an ischemic infarction.

The trigemino-vascular system and serotonin The trigemino-vascular system is a relatively recent model that integrates the different participating pathways in the genesis of headache. (Olesen, 1987; Welch, 1987; Humphrey et al., 1990; Moskowitz, 1984, 1991). There is strong evidence linking serotonin (5-hydroxytryptamine, 5-HT) with the headache process. During a headache attack plasma serotonin decreases and its metabolite, 5hydroxy-indolacetic acid increases in urine. Stimulation of serotonin 1 a–d receptors by triptans and ergotamine mediate headache improvement.

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Integration of cortical and trigeminal phenomena How are all the above phenomena integrated? The trigeminal spinal tract and nucleus receive afferent branches that innervate vessels in the anterior (carotid artery) and posterior (basilar artery) circulations – visceral afferents – and from the skin in the face, head and occipital region – somatic afferents. Dural and pial arteries have a dense innervation in contrast with subcortical vessels which have poor afferent projections. A variety of stimuli which include the spreading cortical depression, altered potassium concentrations and neurochemical changes in the monoamine brainstem systems, trigger the trigeminal tract and nucleus. Once activated, the trigeminal reflex delivers substance P and other substances to the involved vessels initiating an inflammatory response in the area sorrounding the affected vessel (sterile inflammation).

Vascular alterations and ischemia Severe vasospasm has been well documented with TCD studies revealing high velocities and pulsatility indexes during a migraine attack (Thie et al.,1988). Angiography has also shown, or caused, significant vasospasm in migrainous patients. Angiographic evidence of arterial reopening after severe vasospasm and apparent arterial occlusion, support this hypothesis (Caplan, 1991).

Ischemia The trigemino-vascular system explains the vasodilation occurring in headache, the unilaterality of pain, the role of vasoactive peptides and the pattern of referred vascular pain. Pain sensitive vessels include the intracranial internal carotid artery, middle cerebral artery (MCA), and origin of the anterior cerebral artery (ACA) in the anterior circulation and the top of the basilar artery (including superior cerebellar arteries), and the vertebral arteries (including the postero-inferior cerebellar artery) in the posterior circulation. In the case of ischemia, direct stimulation of the vessel’s wall or sorrounding nociceptors by the vascular occluding process (embolus, atherosclerotic plaque) or cortical neuronal depolarization secondary to the ischemia, may initiate activity of the trigemino-vascular system. Serotonin may also play a role in stroke if ischemia alters the synthesis, metabolism, molecule or receptors of this neurotransmitter (Moskowitz et al.,1989).

Hemorrhage In hemorrhages, blood accumulation may cause pain through increased intracranial pressure or by direct or indirect traction of the meninges and its vessels. Clinico-

pathological observations have failed to show that blood in the CSF or surface of the brain relates to pain. A richer innervation by the trigemino-vascular system of vessels in the posterior circulation may explain why posterior fossa hematomas are more frequently associated with headaches.

Migrainous stroke What is the incidence of migraine-related stroke? In different studies, the incidence of stroke in patients younger than 50 years is up to 25 per 100 000 (Leno et al., 1993). Studies from Portugal and the US have reported migraine as the cause of ischemic stroke in approximately 25% of these young patients. This percentage becomes less significant (3% in the Oxfordshire Community Stroke Project) when stroke patients of all ages are considered (Ferro et al.,1995; Broderick & Swanson, 1987). The incidence of stroke attributed to migraine is close to 17 per 100 000. This figure is not limited to migrainous infarction as defined by the IHS but rather includes all scenarios of the migraine-stroke interrelation. In a more strict definition, among the general population, the annual incidence rate of migrainous stroke (i.e. excluding migrainous patients who suffer a stroke unrelated to a migraine attack) was 3 per 100 000 in the Oxfordshire study and 2 per 100 000 in Rochester (Minnesota). Part of the variation in results can be attributed to whether associated stroke risk factors are considered in the population studied or not (Henrich et al., 1986; Broderick & Swanson,1987). If these rates could be extrapolated to all populations, there will be approximately 150 000 migraine-related strokes worldwide annually. To put these numbers in context, other data should be considered. Most epidemiologic studies on headache and stroke have important limitations, the most relevant being lack of controls, no evaluation of associated vascular risk factors in some, no strict definition of migraine related stroke, and most important, incomplete diagnostic evaluations due to technologic limitations inherent to the time of the studies. The latter probably has resulted in attributing to migraine the stroke in patients with cardiogenic or aortic embolic foci, hypercoagulable states, intracranial dissections and other pathologies strongly dependent on recently developed technology for their diagnosis. Also, the percentage of strokes attributed to migraine is strongly dependent on age since older patients have a greater incidence of atherosclerosis and other etiologies than younger patients.

Headache: stroke symptoms and signs

Is migraine a stroke risk factor? Carolei et al. performed a case control study of 308 patients under 44 years of age with history of TIA or stroke with 600 controls matched by age and sex (Carolei et al., 1996). A history of migraine was significantly more common in the TIA/stroke patients. A history of migraine with aura was more frequent in the stroke compared to the TIA patients. Migraine was the most significant risk factor for stroke in women under 35 years of age. In men and patients older than 35, the usual vascular risk factors accounted for most of the risk. The authors concluded that aggressive control of vascular risk factors and smoking cessation are specially important in young women with migraine with aura. Although with some methodologic limitations, this recent study and a few others suggest that migraine is an independent risk factor for stroke in young patients (Collaborative Group for the Study of Stroke in Young Women, 1975; Henrich & Horowitz, 1989; Tzourio et al., 1993, 1995; Merikangas et al., 1997). In different analyses the increased risk ranges from two to fourfold, in most the risk was associated only with migraine with aura, and the age range at greater risk was under 45. The presence of vascular risk factors in migraine patients is not different from the incidence in non-migraineurs suggesting other underlying mechanism to explain their greater stroke risk (Launer et al., 1999). One study among physicians in the US showed a doubled risk of stroke in those with migraine, after adjusting for all confounding variables, compared to those with non-migrainous headaches (Buring et al., 1995). Tzourio et al., to confirm whether or not headache was more common in women under 45 who had ischemic strokes, interviewed regarding headache history 53 women admitted to three neurological centers with neuroimaging confirmed ischemic stroke and a control group (rheumatologic and surgical disease). Results showed that migraine was significantly more common in patients with stroke (67%) than in controls (27%) even after correcting for birth control pill and tobacco use (Tzourio et al., 1994). Other factors that support migraine as a stroke risk factor include a higher stroke recurrence rate in migraine patients with aura and a very unusual occurrence of arterial lesions in migrainous stroke patients compared to patients without migraine (Rothrock et al., 1993; Bogousslavsky et al., 1988). Alterations in platelets, mitral valve prolapse, smoking, birth control pills, age greater than 35, gender (women) and the migraine with aura type, have all been proposed as factors that predict greater risk of a cerebrovascular event in migraine patients. To evaluate the potential causative value of these variables, Rothrock et al. studied 310 consecutive migraine patients and 30 patients with migrainous stroke

(Rothrock et al., 1993).There were no statistically significant differences in mean age at migraine onset, gender (most patients being women), family history of migraine, smoking, use of estrogen-containing medications, mitral valve prolapse, and hypertension between the stroke and non-stroke groups. Migraine with aura was significantly more common in the stroke group although aura type was not different between the groups. A history of stroke was more frequent in the migrainous stroke group. Interestingly, in this group prior strokes were also probably migraine related, whereas in the non-stroke migraine group, previous strokes had non-migrainous identified etiologies (cardiac embolism, arterial dissection, amphetamine use, ICH). The authors emphasized the significant frequency of stroke recurrence detected and the fact that, despite obtaining studies to exclude patent foramen ovale and antiphospholipid antibodies, they could not detect a variable predictive of recurrence. History of stroke is per se a risk factor for a new stroke; thus patients with migraine and a prior stroke do have an added risk for a new ischemic event. Broderick and Swanson in the Rochester study, reported a 1% annual stroke recurrence in patients with a mean follow-up of 7 years (Broderick & Swanson, 1987). This rate is significantly lower than the 9% reported by Rothrock, although the difference could be attributed to the fact that almost a third of the patients in Rothrock’s group had prior cerebrovascular events (Rothrock et al., 1993). To assess the relation of migraine and stroke, one hospitalbased study evaluated 291 women between 20 and 44 years who had recently suffered an ischemic or hemorrhagic stroke (Chang et al., 1999). Each patient had a matched control. Data from a headache questionnaire revealed that a history of migraine was present in 25% of the patients with stroke vs. 13% of the controls. The risk detected was only for ischemic stroke and affected equally patients with migraine with or without aura. Birth control pill use, smoking and history of hypertension all significantly increased the risk for migrainous stroke. Since this was part of a study on contraceptive use and cardiovascular disease, data revealed that, although low dose (<50 ␮g) estrogen did not increase the stroke risk in women without migraine, it significantly increased the odds ratio in women with migraine. A family history of migraine was a risk factor for both ischemic and hemorrhagic stroke. Almost half of all strokes occurred during a migraine attack.

What is the mechanism of stroke during a migraine attack? No single cause has been proven as the mechanism of migrainous stroke. Considering the high prevalence of

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migraine and the low rate of migrainous stroke it may be that permanent ischemia may only occur when a number of variables coexist during an attack. Endothelial changes, platelet aggregation abnormalities, decreased blood flow, fibrin microemboli, and antiphospholipid antibodies have all been considered as potential contributors to ischemia (Buring et al., 1995; Carolei et al., 1996; Woods et al., 1994).

Should migraine without aura be excluded as a potential cause for stroke? The classification of the IHS excludes patients with migraine without aura to define cases of migraine-related stroke (Welch,1994). However, there is no data that has proven a different pathophysiologic mechanism for migraine with or without aura. Moreover, since the classification was published, TCD, MRA, spiral CT, transesophageal echo and hypercoagulable batteries have been added as a routine part of the stroke diagnostic armamentarium. Reliably excluding non-migrainous etiologies would further support that migraine without aura could be the cause of a stroke occurring during an attack of this migraine type.

Neuroimaging The presence of hyperintensities on MRI contributes to the evidence of significant flow phenomena during migraine episodes. Different studies have shown these changes on MRI in 5.5% up to 40% of patients with migraine (Osborn et al.,1991; Fazekas et al., 1992; Ferbert et al., 1991). Neuroimaging findings are more common in patients with migraine with aura, complicated migraine and those with more frequent attacks.

Headache and stroke Although it is intuitive to think that the more severe the vascular (ischemic or hemorrhagic) episode, the worse the headache, representativeness in most series is limited by the fact that the most severe stroke patients either die without recovery or survive with sequelae (aphasia, right hemisphere syndrome) that do not allow for a valid interrogation about headache. However, it is clear that headache is more frequent and severe in both subarachnoid and parenchymal hemorrhagic stroke compared to ischemic events. When headache occurs in the peri-stroke period, pain is most frequently non-specific, although a typical migraine (with or without aura) headache may occur in 25% of

patients (Jorgensen et al., 1994). The occurrence of headache after stroke, whether migraine or non-specific, is more frequent in patients with previous history of migraine.

The chicken and the egg: migraine-induced stroke or stroke-induced migraine? In a recent review, Olesen et al. (1993) reported a series of patients to conclude that ischemia-induced migraine is more frequent than migraine-induced ischemia. The authors reported three patients with frequent migraine attacks attributed to ischemia from carotid artery severe stenosis/occlusion. Another four patients had a stroke after a first migraine attack in the context of severe atherosclerosis, vascular risk factors, advanced age and no family history of migraine. Three additional patients had known severe migraine with aura and the occurrence of neurological deficits during a typical attack (migrainous infarction). In five patients, the relation between migraine and stroke could not be ‘clearly determined’ and for this reason the cases were ‘not further discussed’. Based on the seven patients in the first two groups, the authors concluded that ischemia-induced migraine may be more frequent than migraine-induced infarction. However, the conclusions in Olesen’s study may be limited not only by the small number of patients analysed but also because the first three patients had a clear history of migraine/headache and carotid disease was caused by dissection in two and probably in the third. These cases do not represent typical cases of occlusive carotid artery disease, but rather are strongly suggestive of migraine as a primary phenomenon. Olesen’s study is valuable to open further the possibilities of this potentially bidirectional migraine–stroke relationship.

Migraine secondary to cerebrovascular disease: symptomatic migraine Vascular disease with or without associated stroke (dissections, thrombotic occlusions) can result in migraine headache. However, an arterio-venous malformation (AVM) is the only vascular alteration that often results in recurrent migraine-like attacks for months or years. Dural AVMs may also manifest with migraine-type headaches. Less frequently, other vascular abnormalities such as aneurysms and dolichoectatic arteries, manifest clinically with migraine-like headaches. Since migraine episodes secondary to a vascular malformation can be indistinguishable from typical migraine, evaluation with neuroimaging should be individually decided. In some cases, clinical sus-

Headache: stroke symptoms and signs

picion derived from atypical features (migraine onset after 40 years, irregular pattern of headache occurrence, lack of family history, pain limited to a particular region, etc.) or unusual response to treatment, will lead to the diagnosis of the underlying structural pathology. Most non-invasive neuroimaging techniques such as MRI, MRA and more recently some special CT techniques, can reliably define the presence of an AVM.

ingly, report frequencies of headache that in some studies are close to those of large vessel disease. This paradox may be explained by reversible and more limited deficits which allow headache recognition and more reliable report by such patients.

Ischemic stroke Transient ischemic attacks

Migraine aura without headache (migraine equivalents): a common pathway with cerebral ischemia? A recent report of the Framingham data revealed that migrainous equivalents (especially visual phenomena) are a common occurrence after age 50 without an associated headache (Wijman et al., 1998). Twenty-six of 2110 subjects, most older than 50 years of age, developed migrainous visual symptoms during follow-up over 18 years. In the majority, spells were stereotyped not associated with headache and, in some, there were other associated neurological symptoms such as aphasia, diplopia, numbness and paresthesia. The cumulative stroke incidence in this group was similar to that of patients without a history of cerebrovascular disease or migrainous visual symptoms. The authors concluded that migrainous visual phenomena without headache after age 50 is a relatively common and benign condition that does not require invasive testing or specific treatment.

Headache characteristics in subtypes of cerebrovascular disease The analysis of many different studies on the characteristics of headaches provides data to help predict the type of cerebrovascular disease according to headache patterns. However, most studies have design limitations including retrospective analysis of data, use of different headache classifications, poor stroke etiology categorization, grouping different types of hemorrhagic stroke, exclusion of stroke subtypes, limited follow-up, not reporting pertinent associated signs such as vomiting, and not reporting differences by sex. Moreover, large hemispheric, brainstem, cerebellar and some subcortical infarctions are associated with changes in mental status, cognitive abnormalities and concern about severe deficits that limit the reliability of headache report by patients, unless this is a major symptom. In most studies 25 to 40% of patients are unable to respond. A counterpart of this situation is represented by TIA and lacunar stroke patients that, surpris-

Headaches have been reported in up to 44% of TIA patients, although no prognostic differences have been documented between patients with TIA presenting with or without headaches (Grindal & Toole, 1974; Edmeads, 1979; Portenoy et al., 1984; Medina et al., 1975). One study reported that half of all patients with TIA developed a throbbing headache. The fact that transient monocular blindness is not associated with headache suggests that parenchymal involvement may be a condition for pain to occur. Headache occurs more frequently in vertebrobasilar versus carotid artery circulation TIAs (Grindal & Toole, 1974; Loeb et al., 1985). This is probably due to a richer trigeminal innervation of posterior circulation vessels. Differentiation of an aura episode from a TIA may be impossible on clinical grounds if headache does not follow the aura. However, the history of similar preceding episodes and the occurrence of associated headache in migraine patients facilitate this distinction.

Embolic arterial disease When emboli affect distal vessels, vascular syndromes are usually not associated with pain. However, emboli to the origin of the MCA, and top of the carotid and basilar arteries frequently have associated pain.

Thrombotic arterial disease The Northern Manhattan Stroke Study analysed headache incidence in a subgroup of 551 patients with greater than 60% stenosis of the carotid or vertebral arteries confirmed with Duplex (Elkind et al., 1998). Severe headache ocurred in 18% of the patients. Symptomatic large artery disease was found in 21% of the patients with headache vs. 11% of the patients without headache. Even after adjusting for migraine history, symptomatic large artery disease was independently associated with headache, thus becoming an important consideration for therapy selection while evaluations are in progress. Carotid artery occlusions may be associated with headache when dilation of collateral vessels occurs. The Harvard Cooperative Stroke Registry reported headaches up to one year after the ischemic event in 10% of patients (Mohr et al., 1978). One study found that 71 (28%) of 250 patients had headache during an acute

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ischemic hemispheric stroke. In a logistic regression analysis, after correction for different variables, diffuse headache was the main predictor (98% positive predictive value) of stroke progression (Castillo et al., 1998).

Hemorrhagic stroke Subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) is a devastating disease that affects approximately 30 000 people per year in the US (5% of all strokes), causing death in 50% within the first month and leaving 50% of the survivors with significant neurological sequelae. The equation of ‘the worst headache in life’ and SAH has been strongly emphasized, however, only 50% of patients with SAH report the occurrence of a severe headache and migraine patients not uncommonly have attacks with the ‘worst headache’ of their life. In one prospective study, 25% of patients with sudden onset, severe headache were found to have SAH (Linn et al., 1994). It is the suddenness, more so than intensity that is typical of SAH. Patients with SAH can describe exactly what they were doing at the time of headache onset whereas the pain in migraine patients builds up over a few minutes to a couple of hours. Pain is also maximal at onset in SAH and if patients have had preceding headaches (sentinel headache) they are usually no more than one to three events as opposed to migraine patients that have a history of multiple previous episodes. However, migraine patients may also have SAH thus presenting a diagnostic problem when their headache is different from the usual. The physician should be alert to any red flags and proceed with a SAH diagnostic evaluation in migraine patients if considered necessary. Transcranial Doppler becomes an invaluable tool in patients with a questionable headache history, since it reliably and rapidly identifies increased velocities consistent with vasospasm. The following example is representative: a 53-year-old man developed difficulty with language comprehension and had slight clumsiness of his right arm. He had vascular risk factors and had suffered a syncopal episode 2 weeks prior to admission attributed to a vasovagal mechanism. A CT showed a left temporal subcortical infarct, and duplex of neck vessels and an echocardiogram were normal. Transcranial Doppler, which we perform on most patients at admission to define the intracranial circulation, revealed a significantly increased left MCA mean blood flow velocity (226 cm/s). Since this velocity is indicative of vasospasm, catheter angiography was obtained and showed a right anterior cerebral artery aneurysm with bilateral MCA vasospasm. The presence of vasospasm

confirmed rupture of the aneurysm despite the absence of headache and subarachnoid blood on CT. This patient represents an example of an atypical presentation of SAH (Fig. 6.1). In an attempt to identify clinical predictors of headache related to aneurysmal, non-aneurysmal or thunderclap headache, Linn et al. prospectively analysed with CT and LP 102 patients with a normal neurological examination, referred to the emergency room due to sudden onset headache. (Linn et al., 1998). Aneurysmal subarachnoid bleeding was diagnosed in 41% of the patients, non-aneurysmal SAH in 23% and benign thunderclap headache in 36%. Diplopia and seizures occurred in five patients in the SAH group, but no clinical manifestation predicted the headache type. No significant differences were noted among groups regarding headache history. Although not confirmed in Linn’s study, loss of consciousness preceding, during or after headache, occurs in one-third of patients and should prompt high suspicion of SAH. The mechanism of loss of consciousness could be a transient, but significant, increase in intracranial pressure at the time of aneurysmal leakage (sentinel bleed). A history of a sentinel headache within 3 weeks of aneurysm rupture is present in half of SAH patients. The diagnosis is less challenging when neurologic focal deficits, a third nerve palsy, meningismus (a late sign), preretinal hemorrhages, low back pain and seizures, occur in association with a typical headache in patients with SAH (Vermeulen & van Gijn, 1990). The only valid diagnostic rule of thumb is to have a low threshold to consider the possibility of SAH in the differential diagnosis of headache. CT is a more sensitive technique than MRI (because deoxyhemoglobin in blood is acutely isointense – non-visible – on MRI) in the first few days with a progressively decreasing sensitivity after that time (Kase & Estol, 1996). A lumbar puncture should be done not earlier than 4 to 6 hours after the presumed hemorrhagic event to allow pigment release from erythrocytes. If both studies are negative, SAH is unlikely but tests should be repeated if suspicion is high. If SAH is present, four vessel angiography with multiple views should be obtained to rule out the presence of multiple aneurysms seen in up to 25% of patients. When a properly performed angiogram is negative, it is not necessary to repeat it if the patient had a strictly defined perimesencephalic hemorrhage (benign condition with blood exclusively localized anterior to the midbrain). In any other cases, angiography should be repeated after a week, and then one or two more times weekly if the study is repeatedly negative (Kaim et al., 1996).

Headache: stroke symptoms and signs

Fig. 6.1. 53-year-old man with history of slight right arm weakness, difficulty with language comprehension and a recent syncopal episode. A transcranial Doppler on admission showed increased velocities consistent with vasospasm. Mean blood flow velocity in the L MCA was 202 cm/s and in the R MCA 104 cm/s.

Thunderclap headache The differential diagnosis between ‘thunderclap’ (benign) and hemorrhagic headache is a frequent emergency room dilemma. Although, as mentioned above, great emphasis has been placed in getting a history of the ‘worst headache’ of the patient’s life, intensity is not a reliable predictor of SAH. In the majority of cases, SAH is more sudden than thunderclap and other headaches. Duration is also a reliable clinical marker since pain shorter than 5 to 10 minutes is unlikely to be secondary to hemorrhage. Headache which increases with head movement is a variant of ‘exertional headache’ and represents a non-specific clinical

parameter. Effort or exertional headache is more common in men with a mean age of 55 and occurs in relation to physical efforts. Unfortunately, none of these characteristics clearly differentiates SAH from exertional headache. Then, how are the limits of the evaluation decided? In SAH a CT and LP could be negative, especially if the headache is caused by an intramural (i.e. without extravascular blood dissemination) sentinel hemorrhage. In this case, if the affected patient had the headache during a sexual relationship (coital cephalalgia), lasting 2–4 minutes, with a history of previous episodes, it may be prudent to avoid further steps. However, if the headache is persistent in a

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Table 6.2. Characteristics of headache in cerebrovascular disease and in migraine SAH

ICH

Ischemia

Migraine

Headache Onset Intensity

Most patients Sudden Severe

Duration Location

Hours Diffuse

Nausea/vomit

At onset

One-third of patients Acute to subacute Variable (could be severe) Hours to months Ischemia location (could be diffuse) Unusual

Most patients Subacute Variable (could be severe) Minutes to hours Unilateral (could be bilateral) Frequent

Prior HA (sentinel HA) Associat. neuro find.

Very frequent Variable

Half of all patients Acute to subacute Variable (could be severe) Hours to months ICH location (could be diffuse) Variable (more with posterior fossa ICH) Variable Present

Uncommon Present

Always Unusual

person without any prior episodes of headache, an MRA and Transcranial Doppler can be of help. If results are contradictory or suspicious, or if the headache persists despite ‘normal’ results, conventional angiography should be considered.

Intracerebral hemorrhage Headaches have been reported in up to 60% of patients at onset of ICH and in 7% during the weeks preceding the hemorrhage. One study reported an incidence of headache in 57% of 289 patients with ICH (Melo et al., 1996). On multiple regression analysis, the independent predictors of headache at ICH onset were location (cerebellar and lobar), female gender, meningeal signs and transtentorial herniation. Surprisingly, although hematoma volume (>10 ml) related more frequently to headache, it was not an independent predictor. Ferro et al. interviewed 90 survivors of ICH and found that 27% never had headaches, 43% had ongoing headaches at the time of ICH, 11% developed headaches after ICH and in 19% headaches dissapeared after ICH (Ferro et al., 1998). In the latter group, improvement was attributed to discontinuation of alcohol intake as a precipitant of previous migraines. New onset headaches were attributed to depression after stroke and manifested as the tension-type group. As is the case in the general epidemiology of migraine, headaches were more frequent in women. Most headaches (pre-existing and new onset) began after a headache free interval of weeks to months and headache frequency and intensity were less severe than non-ICH headaches. It is important to recognize the high frequency and characteristics of headache occurring late after an ICH to avoid the risks and high costs of extensive cerebrovascular eval-

uations. Considering that ICH recurrence approximates 10%, if headaches are sudden, unusually severe or atypical compared to their usual pattern, the suspicion and evaluation to rule out a new event is warranted. The location of pain relates to hemorrhage topography and duration is more prolonged compared to ischemic disease (Arboix et al., 1994). Melo et al. reported that patients with posterior fossa hemorrhages referred their pain to the occipital region. They postulated that irritation of pain sensitive structures such as the tentorium and occipital roots, explain this location of pain. On the other hand, for occipital hematomas, Ropper et al reported pain more commonly localized to the ipsilateral eye (Ropper & Davies, 1980).

Summary of headache characteristics in cerebrovascular disease (Table 6.2) Most studies have not reported a greater frequency of stroke-related headache in women compared to men (Portenoy et al., 1984). Headache is recognized in approximately one-third of patients with stroke and is most frequent in ICH followed by ischemic infarcts, TIA and lacunar infarctions. Headache is most severe in hemorrhagic stroke (Gorelick et al., 1986). There is no significant correlation between infarct size and headache severity (Vestergaard et al., 1993). A severe headache at onset associated with vomiting has been predictive of SAH (Gorelick et al., 1986). Lack of onset headache, sentinel headache or associated vomiting are predictive of ischemic stroke. A history of throbbing headache is predictive of developing headache during a stroke. A headache preceding the cerebrovascular event (sentinel headache) has been a common occurrence in most studies reported in up to 60% of

Headache: stroke symptoms and signs

patients. In some studies, incidence of sentinel headaches has been greater for thromboembolic disease and ICH than for embolic disease and SAH (Mohr et al., 1978; Fisher, 1968). However, others have reported sentinel headache most frequently in SAH (Gorelick, 1986). One study which excluded SAH, showed that 25% of patients had peri-stroke (from 3 days prior to 3 days after) headache (Vestergaard et al., 1993). Duration of headache may range from a few hours to weeks or months after the stroke and some patients develop a chronic headache. In general, headaches are more frequent in posterior circulation than anterior circulation disease. The location of the pain is, in general, a reliable indicator of pathology topography: pain in the forehead or eyes is secondary to internal carotid artery disease, in the temple suggests MCA involvement, the external corner of the eye and eyebrow is related to posterior cerebral artery (PCA) disease, the vertex with the basilar artery and the neck, mastoid and occiput with the vertebral arteries. Because midline structures such as the ACA and superior sagittal sinus receive bilateral trigeminal innervation, their involvement causes diffuse pain. At times, headache does not follow the previous rules and can be contralateral to the arterial pathology or diffuse with focal arterial pathology. Headache is most common with PCA disease, followed by basilar artery, ICA and MCA involvement (Fisher, 1968; Mohr et al., 1978; Edmeads, 1979). Pain is most unusual with ACA disease. The most common headache (IHS criteria) in one study was tensiontype headache although migraine was significantly more common in vertebrobasilar strokes (Vestergaard, 1993).

Special vascular disease scenarios Vertebrobasilar migraine A greater than coincidental relationship between migraine and posterior circulation ischemia should not be unexpected since most aura – visual (occipital lobes), sensory (thalamus), vestibular (brainstem or temporal), and confusional (hippocampic) – reflect transient dysfunction in the vertebrobasilar vascular territory. What leads to a permanent deficit, for example, in a patient who has suffered recurrent episodes of hemianopsia over the years, or to migraine after ischemia occurs, is as yet unknown. The coincidence of migraine and stroke – especially in the posterior circulation – suggests a shared basic mechanism. Bickerstaff coined the term ‘basilar artery migraine’ which he described as a benign condition affecting women more frequently and manifesting with different combinations of transient posterior circulation territory dysfunction.

Caplan reported his findings in nine patients with vertebrobasilar ischemia concluding that: (i) permanent ischemic lesions were not uncommon in the posterior circulation territory of patients with migraine, which questions the ‘benign’ evolution postulated by Bickerstaff, (ii) the spectrum of subjects affected included both sexes and all ages, (iii) migraine may begin after stroke (in two of Caplan’s patients), (iv) ischemia may be transient, permanent, recurrent and affect different territories and (v) arterial occlusions may be temporary (Caplan, 1991). Brainstem symptoms vary from minor, brief episodes, to severe dysfunction. One report described a patient suffering migraine with aura and recurrent episodes of encephalopathy during childhood (Corbin et al., 1991). During at least one of the attacks, the patient was unresponsive to painful stimuli with extensor plantar responses.

Arterial dissections Irrespective of the specific vessel affected or the location (extracranial, intracranial, posterior or anterior circulation), vascular dissections are the classic example of arterial pathology associated with severe headache. In patients with history of migraine with aura, the cerebrovascular episode could be erroneously attributed to a migrainous stroke if the appropriate evaluation (Duplex, Transcranial Doppler, MRA, and catheter angiography) is not completed. The pain in dissections could have a double origin: one secondary to the accumulation of blood in the dissected arterial wall and another from the distention of perivascular structures once the dissecting hematoma expands, deforming the arterial anatomy. Although the pain mechanism is not clear, it may be mediated by the fifth, ninth and tenth cranial nerves. When the affected artery is the internal carotid extracranially, the pain is mostly located in the neck, although it usually radiates to the temple and ipsilateral hemiface. When a dissection affects the vertebral artery, the pain is localized to the ipsilateral mastoid bone and it radiates to the occiput. An intracranial carotid artery dissection – a more unusual occurrence – causes diffuse hemicraneal pain. When branches of the MCA beyond the M1 segment are affected, the occurrence of pain is rare. Pain improves as dissection resolves over a period of 3 to 6 months. Horner’s syndrome is the most frequently associated sign, seen in 50% of cases at onset, and helps diagnose carotid artery dissection. In one study, the next most common symptom of carotid artery dissection was transient monocular blindness (Biousse et al., 1998).

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Since the vertebral artery is the second most common dissection site, patients with a new onset migrainous headache should be tested for equilibrium and face and hemibody sensation to rule out a Wallenberg syndrome. Recently, German investigators have found a relation between infections, abnormal collagen structure and the occurrence of dissections (Grau et al., 1998). Other causes to keep in the differential diagnosis during the diagnostic evaluation of patients with familiar or recurrent dissections include: Marfan syndrome, Ehlers–Danlos syndrome, cystic medial degeneration, fibromuscular dysplasia and syphilitic arteritis. We treat dissections using anticoagulation with the rationale of preventing thrombus propagation and dislodgement through a ruptured intima into the vessel’s lumen. Carotid artery endarterectomy and angioplasty can be associated with benign headaches that begin within hours to a few weeks after the procedure. They may be severe and non-specific or resemble different types of migraine. After carotid endarterectomy the physician should be alert to more severe headaches with associated focal neurological findings or seizures which are indicative of artery thrombosis, dissection or the hyper-perfusion syndrome with leuko-encephalopathy (Lopez-Valdes et al., 1997). These scenarios require specific treatments and management in the intensive care unit.

Venous disease When a diffuse, severe headache occurs associated with convulsions in a young woman taking contraceptive pills, the diagnosis of saggital sinus thrombosis (SST) is likely (Ameri & Bousser, 1992). Recent studies using newer imaging data, have shown a greater incidence than previously suspected of cerebral venous disease manifested by partial SST and venous branch occlusions. It is likely that minimal venous occlusions are frequent but never reach diagnosis because systemic fibrinolysis dissolves the clot before it propagates to cause more significant symptomatology. In the brain, a venous system that bifurcates in closed angles and has no valves in a thromboplastin rich environment, probably predisposes to the occurrence of thrombosis. The most limited occlusions can have a clinical course with little or no headache, making diagnosis difficult. Different situations that predispose to venous thrombosis include use of birth control pills, post partum state, certain drug treatments (-asparaginase, interleukin, etc.), dehydration, air travel, infections, trauma, inflammatory diseases (lupus, Behcet, ulcerative colitis, etc.), clotting factor pathology and other hematological diseases.

Headache is present in 70–80% of patients with venous thrombosis. Onset can be acute within hours of the precipitating event or could take a subacute course spanning over weeks or months. Papilledema, focal motor deficits and changes in mental status are observed in a third of patients. Due to increased intracranial pressure, nausea and vomiting are common. Other findings reflect the etiology of thrombosis (infection, hematological disease, etc.). MRI with phase contrast usually depicts the thrombosed sinus although at times angiography may be necessary (Dormont et al., 1994). Brain imaging reveals ischemic parasagittal areas, in an atypical location for arterial disease, commonly bilateral and associated with a significant hemorrhagic component. Recent randomized studies have shown an improved clinical course and greater recovery in patients treated with anticoagulation (Einhäupl et al., 1991; de Bruijn et al., 1999). This benefit from anticoagulation held equally significant in patients with a hemorrhagic component. Thrombolytics are a consideration in patients that do not respond to anticoagulation. With these treatments, mortality has decreased from 80% to less than 30%.

Antiphospholipid antibodies (APA) Knowledge accumulated in the last decade shows that low titre APA (anticardiolipin antibodies and lupus anticoagulant) are present in up to 12% of the general population and that increased anticardiolipin antibodies are an independent stroke risk factor present in approximately 10% of first stroke patients. Although studies have failed to detect a relation between APA and migraine, based on the high prevalence of both conditions in the young population and role as a stroke risk factor, it seems reasonable to test selected patients with migraine for the presence of these antibodies. Patients with migraine and APA should be advised to avoid hormonal treatments, stop smoking and control other vascular risk factors. Whether this subgroup of migraine–APA is at a higher stroke risk remains to be determined. The precise mechanism of how APA causes thrombosis is unknown but cardioembolic sources (noninfectious vegetations, MVP, endocarditis), associated coagulopathy and endotheliopathy have been proposed. All these mechanisms have also been proposed as potential mechanisms of migrainous infarction (the WARSS, APASS, PICSS and HAS study groups, 1997; The Antiphospholipid Antibodies in Stroke Study Group, 1993).

Mitral valve prolapse (MVP) MVP can be detected in 5% of the general population, but it has been reported in up to 30% of migraineurs. Other

Headache: stroke symptoms and signs

coexistent valvular and cardiac anomalies (redundant leaflets, patent foramen ovale) and hypercoagulable factors (Protein C, antiphospholipid antibodies, platelet adhesiveness alterations) may predispose this population to a greater stroke risk.

other neurological deficits. Pain usually disappears within 2 to 3 days of steroid therapy. Takayasu’s disease (another giant cell arteritis) and other angeitis (periarteritis nodosa, granulomatous arteritis) may have a clinical course with an associated non-specific headache.

Patent foramen ovale (PFO)

Small vessel disease

Anzola et al. (1999) prospectively evaluated a group of patients with migraine with aura (n⫽113), without aura (n ⫽53) and non-migraine controls (n⫽25) to detect the presence of PFO using Transcranial Doppler (TCD) with IV agitated saline. The presence of PFO was significantly more frequent in migraine with aura patients (48% prevalence) compared to migraine without aura (23% prevalence) and controls (20% prevalence). The authors postulate that paradoxical microembolic phenomena in the vertebrobasilar circulation may explain the focal neurological events present in migraine with aura patients. Due to its larger availability, transesophageal echocardiography (TEE) is a good alternative to TCD for PFO detection. Moreover, TEE may reveal embolic sources such as atrial septal aneurysms and aortic arch plaques not detectable with TCD. Future studies should be completed to evaluate further this provocative finding.

Giant cell arteritis Temporal arteritis (TA) – one type of giant cell arteritis – should be considered in the differential diagnosis of all patients older than 55 years with new onset headache. Occurrence of TA in younger patients is very unusual. Headache is present in the majority of patients and is frequently severe. The headache may have migraine features and is usually localized to one or both temples but may be diffuse. Associated systemic and neurological findings such as fever, weight loss, anemia, arthralgia, polymialgia, tender and irregular temporal arteries, and jaw weakness or claudication facilitate the diagnosis but are infrequently found. Visual loss occurs secondary to posterior ciliary or central retinal artery involvement, although the occipital artery and intracranial vessels may be affected as well. The erythrocyte sedimentation rate may reach high values (greater than 60 mm/h) but TA may also occur with normal or only slightly elevated sedimentation rate. The diagnosis is confirmed with biopsy of the temporal artery. Doppler techniques may guide the surgeon to the most affected arterial segment. However, diagnosis should be based more on clinical suspicion than on the presence of a full clinical syndrome or confirmatory laboratory findings. Long-term, high dose corticosteroid treatment should be initiated promptly to avoid irreversible visual loss and

Cadasil Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is a nonatherosclerotic, non-amyloid, microangiopathy that affects young people with recurrent infarctions that lead to pseudobulbar palsy and dementia (Bousser & TournierLasserve, 1994). Genetic linkage analysis has mapped the disease locus to chromosome 19 (same chromosome as hemiplegic migraine). Average age of onset is 45 to 50 years and death occurs at an average of 60 years with most patients being demented by that time. Other characteristic clinical features of these patients include neuropsychiatric manifestations, mostly depression and at times mania. Headache is frequently present. The headache manifests as migraine with aura and at times has associated confusion and fever as reported in ‘basilar migraine’. On neuroimaging, all patients (including asymptomatic subjects) show different degrees of periventricular leukoencephalopathy that frequently extends to the centrum semiovale. Chabriat et al. (1995), the authors that reported the original families in whom CADASIL was described, also reported a group of patients with migraine and white matter abnormalities on MRI mapped to the CADASIL locus but without the characteristic recurrent ischemic events. Inheritance of headache in this family followed an autosomal dominant pattern, headache attacks lasted from 2 hours to 2 days, intensity was severe, the pain was usually unilateral, pulsatile in quality, frequently associated with nausea, vomiting and sono-photo phobia and almost always preceded by neurological aura (visual field deficits and paresthesias the most common). Diffuse white matter disease secondary to microangiopathy is frequently observed in the MRIs of elderly symptomatic or asymptomatic people, who do not have any type of headache associated to this condition. Lacunar infarctions also commonly occur without associated headache. Headache in CADASIL is likely part of the genetic disorder and not related to the small vessel alterations per se.

Lacunar disease Different studies have found a wide fluctuation in headache incidence from 3% to 17% of patients with small vessel (lacunar) disease (Mohr et al., 1978; Fisher, 1968,

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Portenoy et al., 1984; Koudstaal et al., 1991). The pain in these cases probably reflects remote hemodynamic or neuronal effects rather than a deep, local origin related to the occluded penetrator vessel. A relatively smaller number of pain-sensitive structures explains that deep hypertensive hemorrhages in the territory of these penetrator vessels also have a much lower headache incidence than their cortical counterparts.

Treatment General measures Independent of migraine type, it has been shown that patients with a prior migrainous stroke are at increased risk of recurrence (Rothrock et al., 1993). In this group of patients, prevention of a new episode is crucial. In patients receiving hormones, estrogens should be discontinued or, if this is not possible, pills with the lowest concentration of estrogen should be used. Vascular risk factors should be aggressively sought and treated. Patients who take antimigraine drugs with vasoconstrictive (ergotamine, triptans) effects should be advised to discontinue and avoid them. Non-steroidal anti-inflammatories should be used as therapy to avoid headaches. Young women with migraine and depression may have a higher stroke risk due to serotonergic-mediated vasoconstriction. Until further data is available, serotonin reuptake inhibitors and abortive medication with vasoconstrictive effects should be avoided in these patients (Singhal et al., 1999). Patients with migraine and preceding episodes of visual field defects, have also shown a higher risk of stroke in the symptomatic PCA territory. Modification of risk factors should be undertaken and preventive medication indicated in those patients with continuing episodes. Although no studies have addressed the issue of primary stroke prevention in migraine patients, the use of aspirin (300 to 500 mg QD) seems intuitively reasonable based on its analgesic and platelet anti-aggregant effect. The indication is especially appropriate for patients with aura in general, auras with significant deficits such as hemianopsia, hemiparesis or language dysfunction, for patients with mitral valve prolapse or other valvular abnormalities and for those with antiphospholipid antibodies. With the rationale of preventing embolization, now supported by the microembolization documented in patients with PFO, anticoagulation has been used in migraine patients (Fragoso, 1997). Medication is not frequently necessary to treat the head-

ache at the time of a stroke. If needed, codeine or antiinflammatory agents are usually effective.

Preventive therapy If episodes occur more than two or three times per month and in patients who have less frequent attacks of migraine with aura, preventive therapy should be considered. Beta blockers, amytriptiline, valproic acid and verapamil are good first-line options decided according to the patient’s individual characteristics. Amytriptiline should be ideally started with a 5 mg bedtime dose and increased slowly to an average 50 mg single dose. This drug should be used with caution – or avoided – in patients with significant cardiac conduction defects. Calcium channel blockers may be especially effective in patients with aura. Young patients with hypertension benefit most from beta-blockers. The elderly hypertensive population that commonly has lower renin, plasma volume and cardiac output with a higher peripheral resistence, benefit more from calcium channel blockers as a ‘double’ antihypertensive and migraine prophylaxis therapy. Only some calcium channel blockers (mostly verapamil) have significant anti-migraine efficacy and, in general, they are less effective than other first line preventive medications (beta-blockers, antidepressants, etc.). Nifedipine, diltiazem, and flunarizine in our experience have modest effect and may cause sideeffects. In elderly patients without hypertension who take other medications with hypotensive properties (levodopa, antidepressants) anti-hypertensive drugs should be used with caution and strict control of orthostatic symptoms. Valproic acid is a good alternative for these patients. Late onset headaches after an ischemic event may not respond to the usual preventive therapies and management may become difficult. Preventive medications should be preferably avoided or used with caution in patients with a recent stroke.

Conclusions (i) A clear interrelationship exists between migraine and cerebral ischemia. The basic mechanism common to both processes encompasses neuronal and chemical changes but is as yet incompletely understood. (ii) Although no definite epidemiologic data is available, there is class III evidence that migraine secondary to ischemia is at least equally frequent (or may even be more common) than migrainous stroke (stroke secondary to migraine). (iii) Migraine is an independent stroke risk factor.

Headache: stroke symptoms and signs

(iv)

(v) (vi)

(vii)

(viii)

(ix) (x)

(xi)

Patients with migraine with aura have a higher risk of ischemic stroke than age-matched people without migraine or with migraine without aura. Thus, strict control of vascular risk factors is especially important in this group. A higher incidence of patent foramen ovale in migraine with aura patients suggests that cardiac microemboli affecting the vertebrobasilar circulation may participate in the migrainous mechanisms of these patients. Non-migrainous headache is also frequent in ischemic and hemorrhagic stroke. Different studies have not defined patterns of headache predictive of specific types of ischemic cerebrovascular disease. Apparently typical attacks of migraine with aura should be considered the potential manifestation of ischemia in patients with first attacks at an advanced age, family history of stroke, and general vascular risk factors. Duplex of neck vessels, transcranial Doppler and MRI/MRA should safely and accurately rule out a significant vascular lesion. Headache is not always typical or present in SAH patients contributing to a significant under-recognition of this disease. Suddenness and maximal intensity at onset are the most predictive features of SAH headache. Patients who develop migraine after stroke should be treated (if justified by frequency of attacks) with preventive medication. Preventive treatment is underused and may be especially appropriate for migraine with aura patients. Daily aspirin should be considered in this patient population.

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Eye movement abnormalities Charles Pierrot-Deseilligny Paul Castaigne Clinic, Pitié-Salpêtrière, Paris, France

Introduction Eye movement commands originate in diverse cerebral hemispheric areas (for saccades and smooth pursuit) or in labyrinths (for the vestibular ocular reflex). They are carried out in the brainstem by the immediate premotor structures and the motor nuclei. Conjugate lateral eye movements are largely organized in the pons, and vertical eye movements and convergence in the midbrain. In the first part of this chapter, we will see the main types of eye movement paralysis resulting from brainstem lesions, and the related physiopathology. Such types of abnormalities are easily detected at bedside by studying three main types of eye movements: saccades, i.e. rapid eye movements made towards a visual target (such as the finger of the examiner); smooth pursuit, elicited by a small visual target moving slowly in front of the subject’s eyes; the vestibular ocular reflex (VOR), tested using the oculocephalic movement, by moving passively the subject’s head. In the second part of this chapter, eye movement disturbances due to cerebellar and cerebral hemispheric lesions, resulting in relatively more subtle syndromes, will be reviewed.

BRAINSTEM

Lateral eye movements Final common pathway The final common pathway of conjugate lateral eye movements begins in the abducens nucleus, which contains: (i) the motor neurones projecting onto the ipsilateral lateral rectus; and (ii) the internuclear neurones, which decussate at the level of the abducens nucleus, run through the medial longitudinal fasciculus (MLF) and project onto the

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medial rectus motor neurones in the contralateral oculomotor nucleus (Fig. 7.1) (for review, see Pierrot-Deseilligny, 1990 and Leigh & Zee, 1999). Lesions affecting the abducens nerve rootlets in the lower basis pontis result in complete paralysis of abduction in the ipsilateral eye, with marked esotropia (Fig. 7.1, syndrome 1). Ipsilateral peripheral facial paralysis, due to damage to the adjacent facial nerve fibres, and contralateral hemiparesis sparing the face, resulting from damage to the adjacent pyramidal tract, are often associated. Lesions affecting the MLF, between the abducens nucleus and the oculomotor nucleus, result in internuclear ophthalmoplegia (INO), which includes: (i) paralysis of adduction in the ipsilateral eye for all conjugate eye movements, usually with preservation of convergence (Fig. 7.1, syndrome 2); (ii) nystagmus in the contralateral eye when this eye is in abduction. INO is often bilateral, as both MLFs are near each other in the dorsal tegmentum (Fig. 7.1, syndrome 2⫹2⬘). The pathophysiology of the nystagmus remains unclear. An adaptive mechanism involving quick phases could partly account for such nystagmus (Zee et al., 1987). Vertical nystagmus is also common in INO, resulting from damage to the vestibulo-oculomotor pathways passing through the MLF (Ranalli & Sharpe, 1988). A skew deviation (vertical tropia relatively constant whatever the gaze direction) may also be observed in INO, due to damage to the central otolithic pathways (Brandt & Dieterich, 1993). After an abducens nucleus lesion, there is paralysis of all ipsilateral eye movements (Pierrot-Deseilligny & Goasguen, 1984) (Fig. 7.1, syndrome 3). Convergence is preserved. As the fibres of the facial nerve are in the immediate vicinity, there is also usually an ipsilateral peripheral facial paralysis. Return saccades from the contralateral position to the midline persist, because phasic inhibition of the contralateral abducens nucleus is still present. This inhibition is under the control of the

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ipsilateral paramedian pontine reticular formation (PPRF) and the inhibitory burst neurones (IBN), both located in the vicinity of the abducens nucleus (Figs. 7.2 and 7.3). In a lesion affecting both the abducens nucleus and the ipsilateral MLF, a ‘one-and-a-half’ syndrome is realized (Fisher, 1967; Pierrot-Deseilligny et al., 1981b) (Fig. 7.1, syndrome 4). This syndrome includes complete paralysis of lateral conjugate eye movements in one direction (abducens nucleus lesion) and INO in the other direction (MLF lesion). Consequently, the eye ipsilateral to the lesion remains immobile during all lateral eye movements, whereas the other eye can only abduct. Abduction nystagmus also exists in the latter. Both eyes can converge and move vertically. Variants of this syndrome exist when the PPRF is damaged, either in addition to, or instead of, the abducens nucleus (see below).

Premotor structures The premotor structure of lateral saccades, i.e. the final common pathway of these saccades (including quick phases of nystagmus) or the generator of horizontal saccadic pulse, is the PPRF (for review, see Leigh & Zee, 1999). This structure is located on each side of the midline in the central paramedian part of the tegmentum, extending from the pontomedullary junction to the pontopeduncular junction (Fig. 7.2). Each PPRF contains excitatory burst neurones (EBN), active just prior to, and during, all types of ipsilateral saccades. The EBN and IBN receive tonic inhibition (ceasing just prior to, and during, saccades) from the omnipause neurones (OPN) (see Fig. 7.3) located close to the midline, between the rootlets of the abducens nerves (Büttner-Ennever et al., 1988). The OPN are involved in saccade triggering, for horizontal gaze but probably also for vertical gaze (see below). The premotor structure of lateral slow eye movements is the medial vestibular nucleus (MVN). This is well established for the VOR, but probably also true for smooth pursuit (for review, see Leigh & Zee, 1999 and PierrotDeseilligny & Gaymard, 1992). The MVN contains excitatory vestibular neurones, projecting onto the contralateral abducens nucleus (Fig. 7.1). The nucleus prepositus hypoglossi (NPH) is another important immediately premotor structure, involved in horizontal eye position. This nucleus is located medially to the vestibular nucleus, below the abducens nucleus (Fig. 7.2). The NPH both receives afferents from, and projects to, the PPRF, the vestibular nuclei and the abducens nuclei (Belknap & McCrea, 1988). Probably in combination with the MVN (Cannon & Robinson, 1987), the NPH appears to be the integrator of lateral eye movements. It could control the ‘step’ necessary to maintain a lateral eccentric position

Fig. 7.1. Clinical characteristics and physiological interpretation of horizontal ocular motor syndromes. 1: basis pontis syndrome; 2: internuclear ophthalmoplegia; 2 ⫹ 2: bilateral internuclear ophthalmoplegia; 3: abducens nucleus syndrome; 4: ‘one-and-ahalf’ syndrome; 5: caudal PPRF syndrome; 6: oculomotor nucleus and paramedian midbrain syndrome; III: oculomotor nucleus; VI: abducens nucleus; VIII: vestibular nerve; A: suprareticular tracts of saccades; B: corticopontine tract of smooth pursuit; C: cerebellum (flocculus and vermis); EBN: excitatory burst neurone; EVN: excitatory vestibular neurone; IN: internuclear neurone; IVN: inhibitory vestibular neurone; L: left; LR: lateral rectus muscle; M: midline; MLF: medial longitudinal fasciculus; MN: motor neurone; MR: medial rectus muscle; MVN: medial vestibular nucleus; P: smooth pursuit; PPRF: paramedian pontine reticular formation; R: right; S: saccade; V: vestibular eye movement; ?: the organization of smooth pursuit circuitry within the cerebellum is still unclear.

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Fig. 7.2. Sagittal view of the brainstem. C: cerebellum; Da: nucleus of Darkschewitsch; INB: inhibitory burst neurone area; iC: interstitial nucleus of Cajal; MLF: medial longitudinal fasciculus; MRF: mesencephalic reticular formation; NPH: nucleus prepositus hypoglossi; NRTP: nucleus reticularis tegmenti pontis; PC: posterior commissure; PN: pontine nuclei; PPRF: paramedian pontine reticular formation; riMLF: rostral interstitial nucleus of the medial longitudinal fasciculus; RN: red nucleus; SC: superior colliculus; Th: thalamus; V: fourth ventricle; VN: vestibular nucleus; III: oculomotor nucleus; IV: trochlear nucleus; VI: abducens nucleus.

obtained after a saccade, and could also be involved in lateral smooth pursuit control. Lesions affecting the premotor structures concern essentially the PPRF, since, in human pathology, no cases of lesions limited to the vestibular nucleus or the NPH have been reported. Lesions affecting both these structures have been reported in the monkey, and resulted in severe impairment of fixation and slow eye movements (Cannon & Robinson, 1987). However, human lesions may involve the region of the MVN in Wallenberg’s syndrome, resulting in disturbances of the VOR and in ipsilateral or contra-

Fig. 7.3. Supranuclear circuitry of horizontal saccades. C: cerebellum (vermis); EBN: excitatory burst neurone; F: fastigial nuclei; FEF: frontal eye field; IBN: inhibitory burst neurone; NRTP: nucleus reticularis tegmenti pontis; P: omnipause neurones; PB: predorsal bundle; PPC: posterior cortex; PPRF: paramedian pontine reticular formation; PT: pyramidal tract; SC: superior colliculus; VI: abducens nucleus.

lateral or bilateral or multidirectional nystagmus (Vuilleumier et al., 1995; Leigh & Zee, 1999). A unilateral PPRF lesion in man results in an absence of all ipsilateral saccades, including quick phases of nystagmus (Fig. 7.1, syndrome 5). Both eyes remain on the midline in attempted ipsilateral saccades, or, when they are in a position contralateral to the lesion, return to the midline very slowly (Pierrot-Deseilligny et al., 1982a). The absence of ipsilateral saccades between the contralateral position and the midline is explained by damage to the pathway controlling phasic inhibition (Fig. 7.3). The VOR ipsilateral to the lesion is preserved after a PPRF lesion (Pierrot-Deseilligny et al., 1982a) – as is also, on occasion, ipsilateral smooth pursuit (Kommerell et al., 1987; Pierrot-Deseilligny et al., 1989) – since the pathways involved in these slow eye movements do not pass through the PPRF. If the lesion affects the caudal part of the PPRF, a sixth nerve palsy is associated (Fig. 7.1, syndrome 5), since the abducens nerve

Eye movement abnormalities

rootlets pass through this part of the PPRF (Fig. 7.2). In the case of a bilateral PPRF lesion, there is a total loss of horizontal saccades, and, at times, a slight slowing of vertical saccades (Pierrot-Deseilligny et al., 1984; Hanson et al., 1986). The latter results from damage to the OPN, which are located between the PPRFs. The OPN could control, during saccade triggering, both the PPRFs and the premotor midbrain reticular formations involved in vertical saccades, i.e. the rostral interstitial nucleus of the medial longitudinal fasciculus (Kaneko, 1989, 1997).

Afferents of the premotor structures The afferents of the premotor structures are multiple. Two suprareticular structures appear to be crucial for saccade triggering: the superior colliculus and the frontal eye field (FEF). The PPRF receives afferents from the contralateral superior colliculus, via the predorsal bundle (located in the paramedian dorsal tegmentum), and from the contralateral frontal eye field, via a tract following the pyramidal tract (Fig. 7.3). The former decussates at the level of the superior colliculus (Meynert decussation), whereas the latter decussates in the upper pons. The superior colliculus, located in the upper part of the brain stem, is an important relay for saccades between the cortical areas and the premotor reticular formations. Furthermore, the premotor reticular formations receive vermian afferents (via the fastigial nuclei) involved in saccade calibration see Leigh & Zee, 1999). Before the cerebellar relays, such a pathway could include a brain stem relay, the nucleus reticularis tegmenti pontis (NRTP). This nucleus, located in the paramedian ventral tegmentum, at the mid-pons level, receives cortical and collicular afferents (Figs. 7.2 and 7.3). The MVN receives afferents from the ipsilateral labyrinth, via the vestibular nerve, but also from the opposite vestibular nucleus, via the vestibular commissure. These pathways are involved during the VOR. The pathways involved in smooth pursuit come from the cerebellum, in particular the ipsilateral flocculus (see Leigh & Zee, 1999) (Figs. 7.1 and 7.5). Before the cerebellar relay, smooth pursuit circuitry includes pontocerebellar and corticopontine neurones. The latter probably originate in the medial superior temporal visual area, pass through the posterior limb of the internal capsule and the ventral part of the upper brain stem (in a region which is not yet well known) and project to the dorsolateral pontine nuclei (DLPN), located in the mid-pons. The DLPN neurones project to the contralateral flocculus and also to the vermis. This circuitry, therefore, includes a double decussation (Figs. 7.1 and 7.5), first at the mid-pons level (pontocerebellar neurone) and secondly in the lower pons (vestibulo-abducens neurone). As the

flocculovestibular neurone is inhibitory, and given that a unilateral lesion up to the floccular level results in ipsilateral smooth pursuit impairment, there is probably another inhibitory neurone, within (interneurone) (Fig. 7.1) or before the flocculus. Lesions may involve the afferents of the premotor structures of saccades and smooth pursuit. A unilateral superior colliculus lesion results in impairment of contralateral reflexive visually-guided saccades (increased latency and decreased accuracy), with preservation of saccades to command and smooth pursuit (Pierrot-Deseilligny et al., 1991a). A lesion affecting the region of the DLPN results in ipsilateral smooth pursuit impairment and contralateral hemiparesis (Thiers et al., 1991; Gaymard et al., 1993). The ipsilateral impairment is, therefore, explained by the existence of a double decussation of smooth pursuit circuitry below the DLPN (see Fig. 7.5). A lesion affecting the paramedian part of the midbrain, including the medial part of the pyramidal tract, results in: contralateral hemiparesis; contralateral paresis of intentional saccades (since the lesion is located above the single decussation of the frontoreticular pathway of saccades); ipsilateral impairment of smooth pursuit (since the lesion is located above the double decussation of smooth pursuit circuitry); and often ipsilateral oculomotor paralysis, due to damage to the third nerve rootlets and nucleus (Zackon & Sharpe 1984; Pierrot-Deseilligny, 1988) (Fig. 7.1, syndrome 6).

Vertical eye movements Final common pathway The final common pathway of vertical eye movements is formed by the oculomotor and trochlear nuclei. The motor neurones of the trochlear nerve decussate in the brainstem, as do those innervating the superior rectus muscle, before passing through the contralateral oculomotor nucleus and rootlets. Lesions affecting the oculomotor rootlets result in ipsilateral oculomotor paralysis. Such paralysis may be isolated (Bogousslavsky et al., 1994; Kiazek et al., 1994; Schwartz et al., 1995) or, more often, combined with contralateral hemiparesis (Weber’s syndrome) or contralateral ataxia (Claude’s syndrome), when the lesion also affects either the pyramidal tract or, a little posteriorly, the red nucleus, respectively (for review, see Bogousslavsky, 1989). When a lesion affects the oculomotor nucleus, there is more or less complete oculomotor paralysis in the ipsilateral eye and isolated paralysis of the superior rectus muscle in the contralateral eye (Pierrot-Deseilligny et al.,

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1981a; Pierrot-Deseilligny, 1990) (Fig. 7.4, syndrome 1). The latter, due to the decussation of the motor neurones of the superior rectus muscle, is combined with a hypotropia of the contralateral eye, resulting from a tonic imbalance with the spared inferior rectus muscle. A lesion in the brainstem may also affect the trochlear nerve nucleus or rootlets (Guy et al., 1989).

Premotor structures and brainstem afferents

Fig. 7.4. Clinical characteristics and physiological interpretation of vertical ocular motor syndromes. 1: oculomotor nucleus syndrome; 2 ⫹ 2: downward saccade paralysis; 3: upward saccade paralysis; 4: monocular elevation paralysis; 5 ⫹ 5: supranuclear upgaze and downgaze paralysis; BC: brachium conjunctivum; D: down; iC: interstitial nucleus of Cajal; IR: inferior rectus muscle; llb: long-lead burst neurone; M: midline; mlb: medium-lead burst neurone; MLF: medial longitudinal fasciculus; NPC: nuclei of the posterior commissure; P: smooth pursuit; PC: posterior commissure; riMLF: rostral interstitial nucleus of the medial longitudinal fasciculus; S: saccade; SR: superior rectus muscle; U: up; V: vestibular eye movement; V: vestibular nucleus; III: oculomotor nucleus (the trochlear nucleus is not shown); ?: a vertical internuclear neurone in the iC is hypothetical; the role of the NPC in upward saccade control and the projections of these nuclei are not yet well defined; the role of damage to the llb in downward saccade paralysis is still uncertain.

The premotor structure of vertical saccades, i.e. the final common pathway of these saccades or the generator of the vertical saccade pulse, is the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), located at the level of the upper pole of the red nucleus (Büttner-Ennever & Büttner, 1988; Horn & Büttner-Ennever, 1998) (Fig. 7.2). This nucleus contains the immediately premotor excitatory neurones (medium-lead burst neurones) involved in upward and downward saccades, both types of neurones being intermingled, perhaps in the mediodorsal part of the nucleus (Nakao et al., 1990) (Fig. 7.4). The axons of these two types of neurones could follow a similar route, through the rostral part of the MLF, before projecting ipsilaterally to the nucleus of Cajal, ipsilaterally to the inferior rectus subdivision of the oculomotor nucleus (downward saccade neurones) or bilaterally to the superior rectus subdivision of this nucleus (upward saccade neurones) (Moschovakis et al., 1991a,b). The riMLF also contains long-lead burst neurones involved in downward saccades, located in its mediocaudal part and probably projecting to the mediumlead burst neurones (Nakao et al., 1990) (Fig. 7.4). The equivalent neurones for upward saccades could be located either in the lateral part of the riMLF (Nakao et al., 1990) or in the nuclei of the posterior commissure (NPC) (Moschovakis et al., 1991a) (Fig. 7.4). The NPC neurones, which receive afferents from the frontal eye field (FEF) and the superior colliculus (Büttner-Ennever & Büttner, 1988), decussate through the posterior commissure and could project to the contralateral riMLF (Moschovakis et al., 1991a). These various findings should be considered when interpreting the different types of vertical gaze paralysis observed in human pathology (see below). The vestibular nuclei (medial, lateral, superior nuclei and y-group) constitute the final common pathway of vertical slow eye movements. They contain excitatory and inhibitory neurones projecting (contralaterally and ipsilaterally, respectively) to the motor nuclei of the midbrain, through the MLF and the brachium conjunctivum (Fig. 7.4). The latter could be involved during vertical smooth pursuit (Chubb & Fuchs, 1982; Pierrot-Deseilligny et al., 1989). The nucleus of Cajal is another premotor structure,

Eye movement abnormalities

involved in vertical eye position. It is located between the riMLF and the oculomotor nucleus (Fig. 7.2). It is the integrator of vertical eye movements (i.e. the equivalent for these movements of the NPH for lateral eye movements) (Fukushima et al., 1990), and also an important premotor relay for vertical smooth pursuit. The nucleus of Cajal receives ipsilateral afferents from the riMLF and vestibular nuclei, and projects to the contralateral oculomotor and trochlear nuclei through the posterior commissure (Büttner-Ennever & Büttner, 1988) (Fig. 7.4). The nucleus of Cajal may also contain vertical internuclear neurones, to distribute equally to the opposite oculomotor and trochlear nuclei the different supranuclear inputs (for both downward saccades and vertical slow eye movements) arriving unilaterally in the oculomotor and trochlear nuclei. Clinical syndromes with vertical eye movement paralysis, which may be identified at the bedside, essentially result from different lesions affecting the riMLF region. Bilateral lesions located medially and rostrally to the upper pole of the red nucleus result in downward saccade paralysis, with preservation of the downward VOR and, at times, of downward smooth pursuit (Pierrot-Deseilligny et al., 1982b, 1989) (Fig. 7.4, syndrome 2). These lesions are usually due to a bilateral infarction in the territory of the posterior thalamo-subthalamic paramedian artery, but may also result from a tumour (Büttner-Ennever et al., 1989). A portion of the riMLF, perhaps located between the centre of the nucleus and its medial part, could be damaged by such lesions. As the somas of the medium-lead burst neurones involved in upward and downward saccades appear to be intermingled in the medial part of the riMLF and the axons of these two types of neurones seem to follow very similar routes towards the oculomotor nuclei (see above), lesions affecting this part of the nucleus or its efferents cannot account for downward gaze paralysis alone. On the other hand, such paralysis could result from bilateral damage to the long-lead burst neurones involved in downward saccades, located in the mediocaudal part of the riMLF. Bilateral damage is required for downward saccade paralysis probably because the riMLF efferent involved in downward saccades includes both a direct projection onto the ipsilateral oculomotor and trochlear nuclei and an indirect projection onto the contralateral nuclei, perhaps with a relay in the nucleus of Cajal (Fig. 7.4). A unilateral lesion affecting the posterior commissure or the pretectal region immediately adjacent to this commissure results in upward saccade paralysis with preservation of the upward VOR (Pierrot-Deseilligny et al., 1982b; Ranalli et al., 1988) (Fig. 7.4, syndrome 3). This suggests that fibres involved in upward saccades decussate through the PC. Upward saccade paralysis could result from

damage to the NPC and/or their efferents, decussating through the posterior commissure and perhaps projecting onto the contralateral riMLF (i.e. onto the medium-lead burst neurones involved in upward saccades) (see above). It should be noted that the NPC do receive afferents from the two suprareticular structures important for saccade triggering: the FEF and the superior colliculus. A unilateral lesion affecting the tegmentum above the oculomotor nucleus may result in ‘monocular elevation paralysis’, ipsilateral or contralateral to the lesion (Jampel & Fells, 1968; Lessell, 1975; Bogousslavsky et al., 1983; Viader et al., 1984; Thömke & Hopf, 1992) (Fig. 7.4, syndrome 4). The Bell phenomenon is preserved in these cases, suggesting supranuclear impairment. Such a lesion could affect the supranuclear fibres projecting onto the oculomotor subdivisions controlling the two muscles involved in upward gaze. The dorsal midbrain syndrome – which includes damage to the posterior commissure and, therefore, upward gaze paralysis – may also involve other adjacent structures, resulting in various signs (Leigh & Zee, 1999): lid retraction (Collier’s sign), disturbances of vergence eye movements, convergence spasm (with pseudo-abducens palsy), convergence–retraction nystagmus, skew deviation and pupillary abnormalities (light–near dissociation). A vertical ‘one-and-a-half’ syndrome has also been reported, combining either upward gaze paralysis with monocular downward gaze paralysis (Bogousslavsky & Regli, 1984), or downward gaze paralysis with monocular upward gaze paralysis (Deleu et al., 1989). In this case, damage could also be immediately prenuclear. Large lesions affecting the region of the riMLF on both sides result in paralysis of upward and downward saccades with preservation of the vertical VOR (Büttner-Ennever et al., 1982; Pierrot-Deseilligny et al., 1982b) (Fig. 7.4, syndrome 5). Thus, all the cells of the riMLFs or all the efferent tracts are damaged. Other lesions affecting brainstem premotor structures involved in the control of vertical gaze result in various ocular motor syndromes: a unilateral lesion of the riMLF could result only in a contralateral beating torsional nystagmus (Helmchen et al., 1996), or in a more marked deficit affecting the vertical gaze (Bogousslavsky et al., 1990); unilateral lesions to the nucleus of Cajal could result in a see–saw nystagmus (comprising intorsion and elevation of one eye, with synchronous extorsion and depression of the other) (Halmagyi et al., 1994); bilateral isolated lesions of the nucleus of Cajal are not common in humans but result in vertical gaze paralysis with relative preservation of saccades in monkeys (Helmchen et al., 1998); bilateral medial pontine lesions may also affect vertical gaze, in particular saccade velocity, probably because of damage to the OPNs,

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which are also involved in vertical saccade triggering (Hanson et al., 1986; Toyoda et al., 1992; Leigh & Zee, 1999); larger bilateral pontine lesions, existing usually in unconscious patients, result in ocular bobbing (rapid intermittent downward movement followed by a slower return to the central position) or reverse ocular bobbing (upward deviation), with sometimes a slow centrifugal movement preceding a rapid return movement to the midline (‘inverse’ and ‘converse’ bobbing, respectively) (see Leigh & Zee, 1999); vertical nystagmus (in particular, upwards) is also common in bilateral INO because of damage to the vestibulo-oculomotor pathways (see above); lesions affecting the region of the nucleus intercalatus, located medially in the lower brainstem, result in upbeat nystagmus (Janssen et al., 1998); a skew deviation may be observed in INO (see above) and Wallenberg’s syndrome, due to damage to central otolithic pathways (Dieterich & Brandt, 1992; Vuilleumier et al., 1995).

S U P R A R E T I C U L A R S T RU C T U R E S Outside the brainstem, a number of suprareticular structures, located in the cerebellum and the cerebral hemispheres, control eye movements. Damage to these structures results in saccade and/or smooth pursuit disturbances usually much more subtle than those due to brainstem lesions.

metria, typically hypometria if the vermis alone is involved; and hypermetria if the fastigial nuclei are damaged (Selhorst et al., 1976; Büttner & Straube, 1995; Leigh & Zee, 1999).

Smooth pursuit The cerebellum is crucial for smooth pursuit since this eye movement no longer exists after total cerebellectomy in the monkey (Westheimer & Blair, 1974). The dorsal vermis (lobules VI and VII) and the floccular lobe are involved in the cerebellar control of smooth pursuit (Zee et al., 1981; Keller, 1988; Büttner, 1989) (Fig. 7.5). Vermian and floccular cells discharge during both smooth pursuit and VOR suppression. Alteration of smooth pursuit is observed in patients with a dorsal vermian infarction (Vahedi et al., 1995). The inability to maintain an eccentric eye position, commonly observed in cerebellar lesions, is probably due to a dysfunction of the brainstem neural integrator, which receives floccular afferents. The resulting abnormality is termed gaze-evoked nystagmus. Such a nystagmus and ipsilateral smooth pursuit impairment are observed after a unilateral floccular lesion (Straube et al., 1997). The ipsilateral impairment of smooth pursuit after a floccular lesion, thus similar to that observed after a supra-cerebellar lesion despite a first decussation of the circuitry at the upper pontine level, is explained by the fact that the flocculovestibular tract is ipsilateral and inhibitory (Fig. 7.5).

Cerebral hemispheres Cerebellum The cerebellum is involved in saccade calibration and is a crucial relay for smooth pursuit.

Saccades The cortex of the dorsal vermis (lobules VI and VII), the fastigial nuclei on which the dorsal vermis projects, and some parts of the cerebellar hemispheres are involved in saccades (Mano et al., 1991). The dorsal vermis receives afferents from the cerebral hemispheres, mainly via the NRTP (Fig. 7.3) and has a number of connections (via the fastigial nuclei) with brainstem premotor structures controlling saccades. Saccade dysmetria (hypo- or hypermetria) observed after cerebellectomy suggests that the cerebellum is involved in saccade calibration. The cerebellum also exerts long-term adaptive control of saccade accuracy, allowing compensation of modifications caused by various pathological (stroke, intra-orbital lesions) or physiological (ageing) factors (Leigh & Zee, 1999). Lesions of the dorsal vermis and fastigial nuclei cause saccadic dys-

Saccades and pursuit eye movements are controlled by different cortical areas. Each hemisphere appears to control eye movements in both lateral directions. Consequently, ocular motor impairment resulting from unilateral hemispheral damage can be ascertained only by eye movement recordings.

Saccades Two main cortical areas trigger saccades (for review, see Pierrot-Deseilligny et al. 1997) (Fig. 7.3). The FEF, located in the posterior portion of the middle frontal gyrus and the adjacent motor area (Fox et al., 1985), more particularly at the intersection between the precentral sulcus and the superior frontal sulcus (Paus, 1996), controls intentional saccades. The posterior parietal cortex (PPC), located in humans in the intraparietal sulcus bordering the angular gyrus (Müri et al., 1996), could be mainly involved in the triggering of reflexive saccades (made to suddenly appearing visual targets) (Pierrot-Deseilligny et al., 1991a).

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Therefore, two parallel pathways are involved in saccade triggering. The first originates in the FEF and projects directly to the premotor reticular formations of the brain stem (PPRF and riMLF) (Fig. 7.3). The second originates in the PPC and includes a relay in the superior colliculus before reaching the same reticular formations. It seems that saccades can no longer be triggered after bilateral lesions either affecting both the superior colliculus and the FEF in the monkey (Schiller et al., 1980), or affecting both the PPC and the FEF in man (Pierrot-Deseilligny et al., 1988). As saccade deficits are much less severe after bilateral lesions affecting either of these two pathways, each of them could partially replace the other when necessary. The FEF also projects to the superior colliculus, both directly and through the basal ganglia, the caudate nucleus and the substantia nigra, pars reticulata. These different parallel pathways explain how unilateral cerebral hemispheric lesions result in subtle saccade deficits, involving mainly intentional saccades after a FEF lesion and mainly reflexive saccades after a PPC lesion, with principally increase in saccade latency (PierrotDeseilligny et al., 1997). However, frontal or parietal acute unilateral damage to the cerebral hemisphere may result in ocular conjugate deviation, ipsilateral to the lesion, lasting several hours a day (Tijssen, 1990). During this period, contralateral saccades, as well as smooth pursuit and even at times the VOR, may be performed with some difficulty (because of a tonic imbalance), but do in fact persist. Patients with unilateral cerebral lesions may not have ocular deviation when their eyes are open, but only on forced lid closure. Such deviation is much more often contralateral than ipsilateral to the lesion (Sullivan et al., 1991). The causes of these different forms of ocular deviation observed after unilateral cerebral damage are not yet well understood. Bilateral PPC lesions result in Balint’s syndrome, which includes optic ataxia, peripheral visual inattention and severe deficits of smooth pursuit and reflexive visually guided saccades, whereas intentional saccades persist (Pierrot-Deseilligny et al., 1986). Bilateral lesions affecting both the PPC and the FEF result in acquired ocular motor apraxia, in which the triggering of all saccades (except vestibular quick phases) is severely impaired (PierrotDeseilligny et al., 1988). A typical patient with such a syndrome has a great fixity of gaze, and saccades are rarely observed, only after head movements.

Pursuit eye movements Posterior parietal lesions impair smooth pursuit, predominantly in the ipsilateral direction (Morrow & Sharpe,

Fig. 7.5. Circuitry of horizontal smooth pursuit. DLPN: dorsolateral pontine nuclei; DMPN: dorsomedial pontine nuclei; F: flocculus; FEF: frontal eye field; FN: fastigial nuclei; LGN: lateral geniculate nucleus; M: midline; MST: medial superior temporal area; MT: middle temporal area; MVN: medial vestibular nucleus; NPH: nucleus prepositus hypoglossi; OVA: occipital visual areas; PAN: periabducens nuclei; PPC: posterior parietal cortex; V: vermis; VI: abducens nucleus; 1 and 2: first and second decussation of the circuitry. White neurone: excitatory neurone; black neurone: inhibitory neurone; neurone with dotted line: hypothetical neurone or pathway.

1990). Anatomical and electrophysiological data have clarified how and where the smooth pursuit signal is processed (Fig. 7.5). In the monkey, the middle temporal visual area (MT) is especially sensitive to visual target motion. Area MT sends this motion signal to the ipsilateral and contralateral medial superior temporal visual areas (MST).

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Cells in areas MST respond to visual targets moving towards the ipsilateral side (for review, see Leigh & Zee, 1999). In humans, these two areas could lie adjacent to each other at the parietotemporo-occipital junction (areas 19, 37 and 39 of Brodmann). A unilateral lesion limited to area MT results in contralateral bilateral impairment of smooth pursuit initiation when the target is in the contralateral visual field (Thurston et al., 1988). A unilateral lesion affecting area MST results in a decrease in smooth pursuit gain, bilaterally but more markedly in the movement directed ipsilaterally to the lesion (Thurston et al., 1988). Lastly, lesions affecting the FEF also result in a decrease in ipsilateral smooth pursuit gain (Morrow & Sharpe, 1990; Rivaud et al., 1994). All these cerebral areas project ipsilaterally to the pons (Fig. 7.5), mainly to the DLPN (see above). Therefore, lesions of the posterior limb of the internal capsule also results in ipsilateral smooth pursuit deficit (Pierrot-Deseilligny & Gaymard, 1992).

iReferencesi Belknap, D.B. & McCrea, R.A. (1988). Anatomical connections of the prepositus and abducens nuclei in the squirrel monkey. Journal of Comparative Neurology, 268, 13–28. Bogousslavsky, J. (1989). Syndromes oculomoteurs résultant de lesions mésencéphaliques chez l’homme. Reviews in Neurology, 145, 546–59. Bogousslavsky, J. & Regli, F. (1984). Upgaze palsy and monocular paresis of downward gaze from ipsilateral thalamo-mesencephalic infarction: a vertical one-and-a-half syndrome. Journal of Neurology, 231, 43–5. Bogousslavsky, J., Regli, F., Ghika, J., & Hungerbühler, J.P. (1983). Internuclear ophthalmoplegia, prenuclear paresis of contralateral superior rectus, and bilateral ptosis. Journal of Neurology, 230, 197–203. Bogousslavsky, J., Miklossy, J., Regli, F., & Janzer, R. (1990). Vertical gaze palsy and selective unilateral infarction of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). Journal of Neurology, Neurosurgery and Psychiatry, 53, 67–71. Bogousslavsky, J., Maeder, P., Rogli, F., & Meuli, R. (1994). Pure midbrain infarction: clinical syndromes, MRI and etiologic patterns. Neurology, 44, 2032–40. Brandt, T. & Dieterich, M. (1993). Skew deviation with ocular torsion: a vestibular sign of topographic value. Annals of Neurology, 33, 528–34. Büttner, U. (1989). The role of the cerebellum in smooth pursuit eye movements and optokinetic nystagmus in primates. Reviews of Neurology, 145, 560–6. Büttner, U. & Straube, A. (1995). The effect of cerebellar midline lesions on eye movements. Neuro-ophthalmology, 15, 75–82. Büttner-Ennever, J.A. & Büttner, U. (1988). The reticular formation.

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Pierrot-Deseilligny, C. (1990). Motor and premotor structures involved in eye movements. In Neurological Organization of Ocular Movement, ed. R.B. Daroff & A. Neetend, pp. 259–83. Amsterdam: Kügler-Ghedini. Pierrot-Deseilligny, C. & Gaymard, B. (1992). Smooth pursuit disorders. In Ocular Motor Disorders of the Brain Stem. Baillère’s Clinical Neurology, ed. T. Brandt & U. Büttner, Vol. 1 Issue 2, pp. 435–54. London. Pierrot-Deseilligny, C. & Goasguen, J. (1984). Isolated abducens nucleus damage due to histocytosis X. Electro-oculographic analysis and physiological deductions. Brain, 107, 1019–32. Pierrot-Deseilligny, C., Schaison, M., Bousser, M.G., & Brunet, P. (1981a). Syndrome nucléaire du nerf moteur oculaire commun: à propos de deux observations cliniques. Revue Neurologique (Paris), 137, 217–22. Pierrot-Deseilligny, C., Chain, F., Serdaru, M. et al. (1981b). The ‘one-and-a-half’ syndrome: electro-oculographic analyses of five cases with deduction about the physiologic mechanisms of lateral gaze. Brain, 104, 665–99. Pierrot-Deseilligny, C., Chain, F., & Lhermitte, F. (1982a). Syndrome de la formation réticulaire pontique: précisions physiopathologiques sur les anomalies des mouvements oculaires volontaires. Revue Neurologique (Paris), 138, 517–32. Pierrot-Deseilligny, C., Chain, F., Gray, F. et al. (1982b). Parinaud’s syndrome: electro-oculographic and anatomical analysis of six vascular cases with deductions about vertical gaze organization in the premotor structures. Brain, 105, 667–96. Pierrot-Deseilligny, C., Goasguen, J., Chain, F., & Lapresle, J. (1984). Pontine metastasis with dissociated bilateral horizontal gaze paralysis. Journal of Neurology, Neurosurgery and Psychiatry, 47, 159–64. Pierrot-Deseilligny, C., Gray, F., & Brunet, P. (1986). Infarcts of both inferior parietal lobules with impairment of visually guided eye movements, peripheral visual inattention and optic ataxia. Brain, 109, 81–97. Pierrot-Deseilligny, C., Gautier, J.C., & Loron, P. (1988). Acquired ocular motor apraxia due to bilateral fronto-parietal infarcts. Annals of Neurology, 23, 199–202. Pierrot-Deseilligny, C., Rivaud, S., Samson, Y., & Cambon, H. (1989). Some instructive cases concerning the circuitry of ocular smooth pursuit in the brainstem. Neuro-ophthalmology, 9, 31–42. Pierrot-Deseilligny, C., Rosa, A., Masmoudi, K., & Rivaud, S. (1991a). Saccade deficits after a unilateral lesion affecting the superior colliculus. Journal of Neurology, Neurosurgery and Psychiatry, 54, 1106–9. Pierrot-Deseilligny, C., Rivaud, S., Gaymard, B., & Agid, Y. (1991b). Cortical control of reflexive visually-guided saccades. Brain, 114, 1473–85. Pierrot-Deseilligny, C., Gaymard, B., Müri, R., & Rivaud, S. (1997). Cerebral ocular motor signs. Journal of Neurology, 244, 65–70. Ranalli, P.J. & Sharpe, J.A. (1988). Vertical vestibulo-ocular reflex, smooth pursuit and eye-head tracking dysfunction in internuclear ophthalmoplegia. Brain, 111, 1299–317. Ranalli, P.J., Sharpe, J.A., & Fletcher, W.A. (1988). Palsy of upward

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Cerebral visual dysfunction Jason J.S. Barton1 and Louis R. Caplan2 Departments of Neurology and 2Ophthalmology Beth Israel Deaconess Medical Center, Boston, USA

1

Anatomy, physiology and blood supply Axons of the retinal ganglion cells project through the optic nerves, chiasm and tracts. Each optic tract carries visual information from the contralateral hemifield of both eyes, projecting mainly to the lateral geniculate nucleus. Smaller projections subserving the pupillary light reflex exit just prior to the termination of the tract, heading to the pretectal nuclei, and there are minor projections to hypothalamic circadian nuclei and brainstem ocular motor structures. The tract lies ventral to the brain, coursing just dorsal to the hippocampus. The fibres from the two eyes are not well aligned initially, but the correspondence improves gradually along the course of the tract. The retinotopic map also becomes tilted, so that the macula is represented dorsally, superior quadrant laterally, and inferior quadrant medially (Hoyt & Luis, 1963). The optic tract is supplied by branches of the anterior choroidal artery, which originates from the supraclinoid segment of the internal carotid artery. The anterior choroidal artery courses posterolaterally, at first inferior and lateral to the optic tract, and later on its medial side, giving penetrating branches to the optic tract and to the lateral geniculate nucleus. The lateral geniculate nucleus contains the terminations of the optic tract fibres and the neurons which give rise to the optic radiations. It is not merely a relay nucleus, but receives inputs from visual cortex (Sillito & Murphy, 1988) and brainstem (Harting et al., 1991) that modulate its information transfer. It is a subnucleus in the ventro-posterolateral thalamus. Neighbouring subnuclei are the medial geniculate nucleus ventromedially, the ventral posterior nucleus dorsomedially, and the pulvinar dorsally. The acoustic radiations pass dorsomedially on their way to auditory cortex. The hippocampus and parahippocampal gyrus lie ventral to it, across the ambient cistern and the inferior horn of the lateral ventricle. The lateral geniculate

nucleus is a triangle with six layers. The ventral two layers are the magnocellular layers, the remaining four are the parvocellular component; these differ in the type of retinal ganglion cells providing input and the visual information relayed (Schiller et al., 1990). Fibres from the ipsilateral eye end in layers 2, 3, and 5, and those from the contralateral eye in layers 1, 4, and 6. The retinotopic pattern is similar to that of the distal optic tract. The macula is represented in a dorsal wedge including the hilum and the far periphery is ventral. The inferior visual quadrant is in the medial horn and superior visual quadrant in the lateral horn. The lateral geniculate nucleus has a dual blood supply. The lateral choroidal artery, a branch of the posterior cerebral artery, arising from its ambient segment after the posterior cerebral artery has circled the cerebral peduncle, supplies the hilum and dorsal crest in the midzone (Frisén et al., 1978), and the anterior choroidal artery, a branch of the internal carotid artery, enters inferolaterally and supplies the medial and lateral horns (Frisén, 1979; Helgason et al., 1986). The optic radiations (geniculocalcarine tract) arise from the dorsolateral surface of the lateral geniculate nucleus and project to primary visual cortex in the calcarine fissure. The fibres are initially a compact bundle in the posterior internal capsule. Then, fibres for the superior quadrant first project slightly anterolaterally, coursing dorsal to the temporal horn of the lateral ventricle as Meyer’s loop. As they project posteriorly, they join the fibres from the inferior quadrant, which had projected through inferior parietal white matter, and together stream through the occipitotemporal region to terminate in the calcarine fissure. The origins of the geniculocalcarine tracts in the retrolenticular part of the internal capsule are supplied by the anterior choroidal artery. The temporal and parietal portions of the optic radiation are supplied by branches of the inferior division of the middle cerebral artery. The

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Fig. 8.1. Retinotopic representation of the visual hemifield in striate cortex. Views of medial occipital surface. (a) The horizontal meridian is buried in the depths of the calcarine fissure, and the upper and lower vertical meridians are represented at the inferior and superior boundaries of striate cortex respectively. (b) the eccentricity marches anteriorly from central (foveal) at the occipital pole on the left to the far periphery near the parieto-occipital sulcus, just behind the splenium. Note that about half of all striate cortex is devoted to the central 10 degrees of vision – this concentration on central vision is referred to as ‘cortical magnification’. (From Horton & Hoyt, 1991, with permission.)

distal portions of the radiations in the occipitotemporal lobe are supplied by the posterior cerebral artery. The striate cortex – also known as Brodmann area 17, primary visual cortex, V1, and calcarine cortex – is the entry point for most visual information reaching the cerebral cortex. Striate cortex is located in the upper and lower banks of the calcarine fissure, and can vary between individuals: the parieto-occipital fissure is a reliable anterior boundary, but the posterior limit is more variable, extending from the medial occipital surface over the first one or two centimetres of the posterior surface of the occipital lobe. Striate cortex has a systematic retinotopic map of the contralateral visual field (Fig. 8.1): conclusions from early data from war trauma (Inouye, 1909; Holmes & Lister, 1916; Holmes, 1945) have been corroborated by more recent studies of strokes using magnetic-resonance imaging (Horton & Hoyt, 1991). Central (foveal) vision is located at the posterior occipital pole. These neurons have the most detailed spatial resolution and the smallest receptive fields, and hence the highest number of neurons per degree of visual field. This continues a trend through the visual system, to devote more resources to central vision than peripheral vision: in the striate cortex, over half the area is devoted to the central 10 degrees of vision (Horton & Hoyt, 1991; McFadzean et al., 1994). The far peripheral field is anterior, on the medial occipital surface near the junction of the calcarine and parieto-occipital fissures, with the most anterior part representing the monocular temporal crescent, which is the small rim of vision that lies beyond the limits of the nasal field of the other eye. Most striate cortex lies buried in the depths of the calcarine fissure, with the superior bank representing the inferior visual quadrant and the inferior bank the superior quadrant. There are a large variety of cells in different layers of striate cortex, with selectivities to a wide range of visual dimensions, including orientation, stereodisparity, colour opponency, and some rudimentary forms, among others.

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Fig. 8.2. Visual cortical areas in the macaque. The left diagram (a) shows the lateral surface of the macaque brain, and the middle (b) shows the cortex unfolded, with areas normally hidden in sulci marked by dashed lines. The right diagram (c) shows a simplified version of the projections and hierarchical position of the different visual cortical areas, with areas belonging to the ventral (what) stream on the left and areas of the dorsal (where) stream on the right. (Modified from Felleman & Van Essen, 1991.)

The striate cortex is supplied mainly by the posterior cerebral artery. A parieto-occipital branch supplies the superior calcarine bank and a posterior temporal branch supplies its inferior bank. The occipital pole lies in a watershed between a calcarine branch of the posterior cerebral artery and the middle cerebral artery: cortical and vascular variation between individuals means that foveal vision may be supplied by either artery (Smith & Richardson, 1966). Up to striate cortex, the visual pathway has been primarily a serial relay with clear retinotopic arrangements. Beyond striate cortex, the projections to ‘extra-striate visual cortex’ proliferate in a complex web of parallel projections, back-projections, and interconnections among a large number of specialized cortical modules – over 40 have been identified in the monkey (Felleman & Van Essen, 1991). There is an approximate hierarchy, with early visual areas such as V2, V3, V3A in a peristriate zone surrounding the primary visual area, which receive direct inputs from V1. These regions have zones with differentiated responses to form, colour, depth, and motion (Livingstone & Hubel, 1988). Beyond early visual areas, the extrastriate system has an approximate segregation between a ventral and dorsal system (Ungerleider & Mishkin, 1982) (Fig. 8.2). The ventral or temporal system is sometimes considered spe-

cialized for object recognition (‘what’). It consists of area V4 and the various subregions of inferotemporal cortex in monkeys, which in humans likely occupy ventral parts of Brodmann areas 18 and 19 and the medial occipitotemporal region. The ventral stream is supplied by the posterior cerebral artery. Lesions of the medial occipitotemporal regions can cause dyschromatopsia and a variety of visual agnosias, including prosopagnosia and alexia. The dorsal or parietal system is sometimes considered specialized for spatial aspects of vision (‘where’). It consists of areas V5 (middle temporal or MT), V5a (medial superior temporal), and regions in the posterior parietal cortex. Many of these areas have selective responses to motion, stereodisparity, and spatial attention. Most elements of the dorsal stream lie in the watershed between the middle and posterior or anterior cerebral arteries. Lesions of the cuneus and posterior parietal lobe cause visual–spatial problems, including impaired motion perception, spatial disorientation, and defects in attention. Deficits in visual imagery can parallel this spatial and object dissociation in visual dysfunction also (Levine et al., 1985). The ‘where’ versus ‘what’ dichotomy, though conceptually useful, is clearly an oversimplification, and there are many interactive processes that involve both streams. Also, in humans, many vascular lesions do not correspond

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precisely to the anatomic dichotomy, and the resulting pattern of dysfunction may represent a mixture of dorsal and ventral impairments, which vary between patients.

Visual-field defects Patients may or may not be aware of homonymous visual defects. Those who are may also confuse hemifield loss with monocular loss, believing, for example, that left hemianopia is visual loss in the left eye. Asking patients what they notice with each eye covered in turn may help clarify their visual deficit. The visual fields can be tested at the patient’s bedside by confrontation. Adequate lighting and a non-distracting background behind the examiner are helpful. Each eye is tested separately. As the subject fixates on the examiner’s nose, a quick series of targets of increasing subtlety can be used to probe the four quadrants. First, the examiner holds both hands up, palms facing the patient, in the lower quadrants, and the patient is asked if they can see both hands, and if so, whether the two hands are equally clear. This is then repeated in the upper quadrants. Next, one or two fingers are shown briefly, and the patient is asked to count the fingers seen, in one quadrant at a time, or in two quadrants to test for extinction. Finger motion, or smaller items such as pins with white or red heads can be used next. If at any point a deficit is identified in a quadrant, that target should then be moved towards the more normal areas of visual field and the subject is asked to state exactly when the target improves in appearance. A sudden improvement at the vertical meridian, as the target crosses from one hemifield into the other, is pathognomonic of chiasmal or retrochiasmal defects. Retrochiasmal defects will be homonymous, meaning that they affect the same hemifield. The area of hemifield impairment may be the same in the two eyes (congruous) or different (incongruous). Congruity tends to increase as one passes posteriorly through the retino-geniculocalcarine relay. Lesions anywhere along the retrochiasmal pathway can cause complete contralateral hemianopia. Partial hemianopia is more interesting, since the pattern of defect can localize the lesion. With partial optic tract lesions, the area of contralateral hemifield visual loss is often incongruous between the two eyes (Savino et al., 1978; Newman & Miller, 1983). Because the lesion also interrupts visual input to the pupillary light reflex, there is frequently an associated relative afferent pupillary defect, typically in the eye with the temporal field loss (Bell & Thompson, 1978; Newman & Miller, 1983), since the temporal hemifield has more input to the light reflex than the nasal hemifield. Wernicke’s hemianopic

pupil, in which light shone on the hemiretina corresponding to the hemianopia elicits a much reduced light reflex (Pertuiset et al., 1962), is difficult to demonstrate at the bedside, because of the large intraocular light scatter with most penlights (Savino et al., 1978). With time, the axonal damage with tract lesions will be reflected in partial optic atrophy. Optic tract infarction is rare, and a compressive lesion should first be suspected, particularly if optic atrophy is already evident. lnfarction of the lateral geniculate nucleus in the territory supplied by the posterior choroidal artery causes a sectoranopia. (Fig. 8.3). This is a wedge-shaped defect straddling the horizontal meridian and pointing towards fixation (Frisén et al., 1978). Geniculate infarction in the territory of the anterior choroidal artery produces the mirror-image: sector defects adjacent to the vertical meridian and sparing the zone around the horizontal meridian (Frisén, 1979; Helgason et al., 1986; Luco et al., 1992). Partial optic atrophy will also develop a few months after geniculate infarction, but the pupillary light reflexes are normal, since the fibres subserving this reflex leave the optic tract prior to its termination in the lateral geniculate nucleus. Complete hemianopia from optic radiation infarction can occur with large middle cerebral artery ischemia, in which case there are invariably other signs of major dysfunction, such as hemiparesis, hemisensory loss, and aphasia with left-sided lesions. Complete hemianopia with minimal other neurologic signs is unusual but can occur with anterior choroidal artery infarction of the radiations in the retrolenticular internal capsule, or with posterior cerebral artery infarction of the distal radiations in the occipital lobe, sometimes with associated striate damage. More commonly, ischemia of the optic radiations causes partial hemifield defects, with a milder degree of incongruity than optic tract hemifield defects. Superior quadrantanopia occurs with lesions of the temporal optic radiations in Meyer’s loop and inferior quadrantanopia results from damage to the parietal optic radiation. These quadrantic defects usually abut the vertical meridian and extend a variable amount towards the intact quadrant on the same side, seldom aligning on the horizontal meridian (Jacobson, 1997). Damage to the middle zone of the radiations can cause a sectoranopia that mimics posterior choroidal artery infarction of the lateral geniculate nucleus (Carter et al., 1985) (Fig. 8.4). Infarction of striate cortex occurs with posterior cerebral artery ischemia. In about half of patients the field defect is an isolated finding, but amnesia, prosopagnosia, and color perception defects can also occur (Pessin et al., 1987). A syndrome of agitated delirium and hemianopia may be

Cerebral visual dysfunction

seen with lesions extending to the parahippocampus and hippocampus (Medina et al., 1977). Striate infarctions cause homonymous hemifield defects that are highly congruent. When the hemianopia is complete and involves the macula (Fig. 8.5), the responsible lesion usually damages the optic radiations subcortically also. Striate infarction not uncommonly causes partial field defects, though. If the posterior occipital pole is spared, as may occur after posterior cerebral artery infarction in a patient whose pole is supplied by the middle cerebral artery, a macula-sparing hemianopia results (McAuley & Russell, 1979; Gray et al., 1997). Sparing of this central 5 degree zone is pathognomonic of striate infarction (Fig. 8.6). Similarly, sparing of the monocular temporal crescent, the most anterior portion of striate cortex, is seen only with striate lesions (Benton et al., 1980; Ceccaldi et al., 1993) (Fig. 8.8). The converse, a monocular temporal crescentic scotoma, can occur with a retrosplenial lesion (Chavis et al., 1997), but is hard to detect and likely rare. Partial lesions in the superior–inferior dimension can also occur, with infarction of the lower bank of the calcarine fissure causing superior quadrantanopia and infarction of the upper bank causing inferior quadrantanopia. As with radiation lesions, the horizontal boundary of these defects is variable (Fig. 8.6). Overall, a quadrantic defect is more likely to represent striate damage than radiation damage (Jacobson, 1997). Striate quadrantanopia is more frequently an isolated sign, sometimes associated with other visual dysfunction such as alexia or hemiachromatopsia, whereas optic radiation quadrantanopia usually occurs together with hemiparesis, dysphasia, or amnestic problems (Jacobson, 1997). Small lesions can cause homonymous scotomas. Small occipital pole infarcts can cause hemimacular scotomas (Gray et al., 1997), and more anterior lesions cause peripheral scotomas (Fig. 8.7). These can be missed on routine imaging (McAuley & Russell, 1979) unless coronal MR images are obtained. Bilateral ischemic lesions are unusual, except at the striate cortex or distal optic radiations, because of the shared origin of the two posterior cerebral arteries. These cause bilateral hemianopic defects (Fig. 8.8). Bilateral, large lesions cause complete cerebral blindness (Symonds & MacKenzie, 1957; Aldrich et al., 1987), distinguished from bilateral ocular disease by the normal fundus and normal pupillary light responses. Incomplete bilateral hemianopia can be distinguished from bilateral ocular disease by the congruity of the visual loss and usually a step defect along the vertical meridian which reveals the hemifield nature of the loss (Symonds & McKenzie, 1957). Cerebral blindness is permanent in 25% (Symonds & McKenzie, 1957) and residual visual field defects are

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Fig. 8.3. Visual field defects from lesions at various locations in the geniculo-calcarine pathway. A Posterior choroidal artery infarction of the LGN creates a sectoranopia; A⬘ anterior choroidal artery infarction of the LGN creates the inverse field defect; B mildly incongruous inferior quadrantic defect from parietal optic radiation infarct (inferior division of middle cerebral artery); C mildly incongruous superior quadrantic defect from temporal optic radiation infarct (parietal branches of middle cerebral artery); D missing monocular temporal crescent from small infarct of the most anterior portion of striate cortex; E congruous hemianopia with sparing of monocular temporal crescent on the left and sparing of the macula, indicating infarct of mid-zone of striate cortex, sparing both retro-splenial portion and occipital pole; F small mid-periphery congruous and homonymous scotoma from focal lesion of midzone of striate cortex. (Illustrated by Laurel Cook-Lhowe.)

common in the remainder. Bioccipital lucencies on CT scans carry a poor prognosis for visual recovery, but the presence of abnormal visual evoked potentials does not correlate with severity or outcome (Aldrich et al., 1987). As many as 10% of patients with cerebral blindness deny their visual difficulties and claim that they can see (Anton’s syndrome) (Symonds & McKenzie, 1957; Aldrich et al., 1987). Denial of blindness is likely to be only specific for cerebral blindness if there is no associated encephalopathy or dementia, since similar denial has been reported in

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Fig. 8.4. Sectoranopia. Visual defect in a young man with a hemorrhage affecting the mid-portion of his optic radiation (Reprinted from Neuro-ophthalmology, ed. J.S. Glaser, with permission).

patients with ocular diseases and such concurrent cognitive deficits (Geschwind, 1965). On the other hand, some patients with cerebral blindness or hemianopia are said to possess some remnant visual ability in their blind areas, of which they are not aware, a phenomenon called ‘blindsight’ (Stoerig & Cowey, 1997). This can be demonstrated by having subjects point or look towards a visual target in the blind field, or make ‘forced-choice’ guesses about qualities of the object in the blind field, such as its direction of movement or colour. Subjects with blindsight do better than chance in their blind hemifield, though not usually as well as in their seeing hemifield. Sometimes it can also be shown that stimuli in the blind field influence responses to stimuli in the seeing hemifield (Rafal et al., 1990). It has been hypothesized that blindsight represents the function of remaining inputs to either the superior colliculus or extra-striate cortex (Weiskrantz, 1990), which may receive input from the colliculus via the pulvinar, or direct projections from the lateral geniculate nucleus that bypass striate cortex (Cowey & Stoerig, 1991). Blindsight is of extensive research interest: practically, though, it requires careful controls for light scatter (Campion et al., 1983; Barton & Sharpe, 1997), hence is difficult to show with certainty at the bedside, and has yet to be proved to be of practical value to the subjects who possess it.

Hemi-neglect Patients with hemineglect ignore or fail to attend to stimuli on the side of space contralateral to their lesion. Neglect can be multimodal, in that all stimuli whether auditory, tactile or visual are ignored, though sometimes dissociations between sensory modalities are reported. Often, there is an intentional component as well, in that patients fail to explore a side of space, whether with eye movements or hand responses. Visual neglect represents a complex combination of inattention within different frames of reference. Neglect may occur for the contralateral side of space with respect to the patient’s body. It may occur retinotopically, for the contralateral hemifield, even if the eyes are pointed ipsilaterally, towards the ‘normal’ hemispace. It may also be ‘object-centred’, in that it affects the contralateral side of visual objects, no matter which visual field or side of space the objects are in. This complex interaction is best seen in their reading behaviour, ‘neglect dyslexia’ (Behrmann et al., 1990), in which patients – generally with right-sided lesions – may fail to read words on the left side of the page, and also make omission or substitution errors for the left side of words. Furthermore, as they read further down the page the point at which they start to read on each line may progressively shift rightward. Testing for such hemi-inattention and differentiating it

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from hemianopia can sometimes be difficult, especially since a combination of hemianopia and hemineglect is not uncommon. One can start by asking patients what they see in pictures, in the room, or looking out of a window. Patients with neglect will not report people or objects on the neglected side. Their reading can be tested as above. If the examiner observes their eye movements during a visual scanning task, they will not often look towards the contralateral side. In contrast, patients with hemianopia, particularly those with chronic field defects and who are aware of their field loss, compensate by using lots of eye movements to search the space on the side of their hemianopia, and, in fact, devote more time to their blind side than their good side (Behrmann et al., 1997; Barton et al., 1998). Formal testing for visual neglect starts with observations on performance during confrontational examination of visual fields. Both neglect patients and hemianopia patients may fail to respond to stimuli on the contralateral side. However, neglect stems from a gradient of inattention (Bisiach & Vallar, 1990; Behrmann et al., 1997) rather than the sharp demarcation at the vertical meridian so typical of hemifield visual loss: hence when repeatedly moving a stimulus towards the intact side, the points at which neglect patients declare they see the stimulus are not aligned at the meridian, vary from trial to trial, and vary with the intensity of stimulation and distraction. Several easy bedside tests for neglect exist. When asked to mark the

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Fig. 8.5. Near complete right congruous homonymous hemianopia, not sparing the macula (a), from large left posterior cerebral artery infarction (b). Patient also had alexia without agraphia.

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Fig. 8.6. Left congruous inferior quadrantanopia plus, with sparing of the macula (a), from infarction of the upper bank of the right striate cortex (b), sparing the occipital pole. (Reprinted from Neuro-ophthalmology, ed. J.S. Glaser, with permission.)

midpoint of a line (line bisection), such patients place the mark too far towards the side ipsilateral to the lesion, whereas patients with hemianopia place the mark slightly towards their blind contralateral side (Barton et al., 1998; Barton & Black, 1998). If confronted with a paper covered

with small lines and asked to cross all of them out, they will fail to find the ones on the contralateral side of the page (Albert, 1973). If asked to draw a clock or flower, they may omit contralateral details (Fig. 8.9(a)). Perhaps the most sensitive test is object cancellation (Weintraub & Mesulam, 1987), in which subjects search a page cluttered with symbols for one specific type to circle: many more will be missed on the contralateral side (Fig. 8.9(b)). All studies have found that right cerebral lesions are much more likely to cause neglect than are left-sided lesions (Albert, 1973; Weintraub & Mesulam, 1987). Neglect usually occurs in patients with large right cerebral lesions involving the temporal and parietal lobes, supplied by the posterior cerebral artery, or parietal and frontal lobe structures, supplied by the middle cerebral artery. Parietal lobe neglect is usually attributed to failure to attend to stimuli in contralateral space, and frontal lobe neglect is attributed to a lack of motor exploratory behavior towards contralateral space (Liu et al., 1992). Neglect can also be found in patients with lesions of the upper brainstem that decrease the reticular-activating-system stimulation of the ipsilateral cerebral hemisphere (Mesulam, 1981), or lesions of the thalamus or basal ganglia. In patients with posterior cerebral artery-territory infarction, neglect is usually limited to visual stimuli, but thalamic, frontal, and anterior parietal lobe lesions usually cause multimodality neglect, including visual, auditory, and somatosensory stimuli. Hemianopia and inattention are two distinct, different

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phenomena that often coexist. Infarction or hemorrhage restricted to the occipital lobe will cause hemianopia without neglect. Lesions in the temporal, parietal, and frontal lobes will cause visual neglect without hemianopia if the optic radiations are spared. When lesions involve the striate cortex or the optic radiations as well as the parietal or temporal lobes, both hemianopia and neglect are usually present. Concerning other signs, patients with lesions of the inferior parietal and superior temporal lobes usually fail to blink to a threat from the contralateral hemifield and have impaired smooth pursuit eye movements for stimuli moving towards the side of the lesion (Morrow & Sharpe, 1993; Barton et al., 1996). Frontal and parietal lesions often have associated hemi-sensory loss or hemiparesis. In patients with other visual, motor or sensory defects, neglect may appear a secondary issue, yet it often becomes the major obstacle in the rehabilitation of such stroke patients. Fortunately, many but not all cases of neglect show spontaneous improvement over time.

Abnormal ‘positive’ visual perceptions and distortions Visual hallucinations are reports by individuals of seeing something that other observers do not see. They are frequent accompaniments of patients with altered mental status, from dementia (Lerner et al., 1994), confusional

states or delirium, psychosis, sleep deprivation, or drug intoxication or withdrawal – notoriously alcohol withdrawal (Platz et al., 1995), hallucinogenic street drugs, and dopaminergic agonists (Zoldan et al., 1995). In patients with normal mental state, the three major cerebral causes are migraine, focal visual seizures (Fig. 8.10), and ‘release hallucinations’ related to visual deprivation. Photopsias can also be considered types of visual hallucination: these are transient unformed images of sparks, flashes, lights, blobs, or spots, and are related to diseases of the retina, ocular media, and optic nerves, and hence frequently monocular (Lessell, 1975). Release hallucinations (Charles Bonnet syndrome) are restricted to regions of the visual field with homonymous visual loss. These may occur with bilateral ocular disease or hemianopia from cerebral lesions, and up to half of such patients may have hallucinations (Lepore, 1990; Teunisse et al., 1996). The hallucinations vary widely in content, from simple blurs of colour, streaks and patterns (Kölmel, 1984) to detailed images of people and animals (Lance, 1976). Unlike the case with visual seizures, the visual content has no localizing value – in contrast to the field defect – and may even change over time (Weinberger & Grant, 1940). The variability of their content is often another distinction from the stereotyped nature of repeated visual seizures. Release hallucinations usually start days or weeks after the visual loss, and may stop after a few days or persist indefinitely (Lance, 1976; Teunisse

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Fig. 8.8. Bilateral striate infarction causing left upper quadrantanopia plus, and right inferior quadrantanopia. Strokes occurred simultaneously during or after cardiac surgery. Note sparing of the monocular temporal crescent in the right inferior quadrant, highly suggestive of a striate lesion.

et al., 1996). They can be intermittent or continuous. The origins of release hallucinations are probably analogous to the explanations of phantom limb phenomena after amputation, in that the brain has an inherent tendency to generate spontaneous patterns of neural impulses in the absence of sensory input (Schultz & Melzack, 1991). Treatment is rarely required, as most patients are aware that the hallucinations are not real and the content is seldom threatening: reassurance that they are not crazy is often sufficient (Teunisse et al., 1996). Decreasing social isolation may help (Cole, 1992). A less common stroke-related phenomenon is peduncular hallucinosis (van Bogaert, 1927; Lhermitte, 1922). These are complex, detailed hallucinations with varying content, sometimes continuous, sometimes episodic, sometimes accompanied by tactile or auditory hallucinations also (Caplan, 1980; McKee et al., 1990). Patients may or may not have insight into the unreality of their visions. These hallucinations need not be associated with visual field defects, but are invariably accompanied by inversion of the sleep–wake cycle (L’Hermitte, 1922; Noda et al., 1993). Lesions of the cerebral peduncles or paramedian thalamus are seen on imaging (Feinberg & Rapcsak, 1989). The hallucinations may stem from damage to either the reticular activating system (Feinberg & Rapcsak, 1989) or the substantia nigra pars reticulata (McKee et al., 1990), which

may play a role in REM sleep regulation. Vertebrobasilar infarction causing a ‘top of the basilar’ syndrome is the most common cause of this rare problem (Caplan, 1980). Hallucinations can persist indefinitely (McKee et al., 1990), though episodes may become shorter (Noda et al., 1993) or disappear (Feinberg & Rapcsak, 1989). Visual perseverations are the persistence, recurrence or duplication of a real percept, and can take several forms, which may coexist in a given patient (Kinsbourne & Warrington, 1963). All of these are rare phenomena. Palinopsia is visual perseveration in time, in that a recent image either persists after the object disappears, much like an abnormally prolonged afterimage, or else recurs after an interval of minutes or even weeks (Kinsbourne & Warrington, 1963). The palinoptic image can occupy any region of the visual field, and sometimes recurs in a contextually specific manner, in that a previously seen face reappears in the place of other people’s faces, for example (Critchley, 1951; Meadows & Munro, 1977). Almost all patients with palinopsia have visual hemifield defects, in either upper or lower quadrants, or both (Meadows & Munro, 1977), and some have other spatial illusions or complex visual deficits (Critchley, 1951). The localizing value of palinopsia is not clear. The differential includes intoxication with hallucinogenic drugs (including newer antidepressant medications such

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Fig. 8.9. Left hemineglect in a woman with an extensive right fronto-parietal infarction. (a) When asked to copy a flower, she omits left-sided petals. (b) When asked to circle all the bells in a random array, she misses 2 on the right side and 12 on the left.

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allesthesia in which visual images are projected from the ipsilateral side into contralateral space. Visual distortions alter the sizes and shapes of objects, a complaint familiar to readers of Alice in Wonderland. Again, these are rare. Micropsia is the illusion that objects are smaller than they are. Sometimes this occurs only in the contralateral hemifield – hemimicropsia (Cohen et al., 1994). Lateral or medial occipito-temporal lesions have been reported. The differential includes psychiatric disease, migraine (Abe et al., 1989), and, if monocular, macular edema. Macropsia, the illusion that objects are larger than they are, is even more unusual, but has occurred with occipital infarcts (Ardile et al., 1987). Metamorphopsias are illusions of object distortion. These are far more common with macular disease than with cerebral disease. They have occurred with medial temporooccipital infarction (Imai et al., 1995).

Abnormalities of complex visual perception

Fig. 8.10. Small occipital hemorrhage (arrow) in a man with endocarditis and ictal visual hallucinations, repeated waves of pink or grey hues lasting 10 minutes, triggered by sudden changes in ambient illumination.

as trazadone), psychosis, and non-ketotic hyperglycemia. Palinopsia from stroke can be a transient phase in the progression or resolution of a visual field defect (Bender et al., 1968), but can also persist for years (Kinsbourne & Warrington, 1963; Swash, 1979; Cummings et al., 1982). Anti-convulsants may help some patients (Swash, 1979). Cerebral polyopia, the perseveration of a visual image in space, is less frequent than palinopsia. Unlike diplopia from strabismus, the duplicated image is still seen when one eye is closed. Unlike the monocular diplopia from refractive problems like cataracts, cerebral polyopia is seen with either eye viewing alone and is not eliminated by viewing through a pinhole. The number of images reported can range to over a hundred (Lopez et al., 1993). As with palinopsia, visual field defects are common, and this symptom is often a transient phase in their recovery (Bender, 1945). The localization value is again obscure. Other even rarer perseverative phenomena include illusory visual spread, in which the surface texture or colour of an object exceeds its borders (Critchley, 1951), and visual

Once beyond the striate cortex, lesions create very different effects compared with the findings with lesions of the retino-geniculo-calcarine relay. Visual processing and hence its defects become less specific for the region of visual field affected and more specific for the type of visual information involved. There are also interactions with memory processes and other sensory modalities, as well as effects upon motor responses, particularly eye movements. It must be stressed, though, that in general higher cortical visual dysfunction is diagnosed with the caveat that other cognitive functions are relatively spared or, at least, if affected cannot account for the impaired responses observed. Aphasia and dementia in patients with vascular disease are particular problems in this regard. Furthermore, higher visual dysfunction can only be diagnosed if there is enough sparing of the geniculo-calcarine relay to permit vision that should have been sufficient for the visual task provided. Failure to consider unrelated cognitive and ‘low-level’ visual dysfunctions can lead to misleading conclusions about the nature of complex visual perception in patients – the confusing literature on Bálint’s syndrome is a prominent example (Rizzo, 1993).

Unilateral posterior cerebral hemisphere lesions Unilateral dorsal pathway lesions Functional imaging shows a region sensitive to visual motion in the lateral occipitotemporal cortex. Unilateral

Cerebral visual dysfunction

another way to test for constructional apraxia. Patients with posterior right cerebral hemisphere or thalamic lesions are often impaired on these tasks. Their drawings omit portions of the left sides of figures, have abnormal angles, sizes, and proportions, and fail to improve when copying instead of drawing from memory (Paterson & Zangwill, 1944; Piercy et al. 1960). Large right posterior cerebral artery-territory infarcts, right inferior-division middle cerebral artery infarcts, and deep right occipital and temporo-parietal hematomas are most often responsible (Hier et al. 1983), and there is often left visual hemineglect as well. Some patients with left cerebral and thalamic vascular lesions also show a constructional apraxia of a less severe degree: they draw simple diagrams with normal sizes, angles, and proportions, and their drawings are much improved when they copy figures.

Unilateral ventral pathway lesions

Fig. 8.11. Right lateral occipito-temporal infarction (short arrow) associated with asymptomatic impaired motion perception revealed by psychophysical testing. Impaired smooth pursuit of targets moving to the right was also present, but may have been due more to damage to descending fibres in the posterior internal capsule (long arrow).

lesions of this area (Fig. 8.11) cause hemiakinetopsia, in which there are deficits in motion perception limited to the contralateral hemifield (Plant et al., 1993; Greenlee & Smith, 1997), sometimes with more subtle and partial dysfunction in the central visual field also (Vaina, 1989; Regan et al., 1992; Barton et al., 1995). A right-sided bias was found in one study only (Vaina, 1989). These defects are never symptomatic, and generally are detected only with special psychophysical tests. Impaired smooth pursuit eye movements of targets moving towards the side of the lesion may be the only clinical sign that can be demonstrated, but in the chronic state this abnormality may depend more upon white matter than cortical damage (Fig. 8.11), and is independent of defects in motion perception (Barton et al., 1996). Constructional apraxia is the inability to form figures (arranging, building, drawing, copying), despite sufficient visual perceptual and motor functions judged needed to perform such tasks. This is tested by asking patients to draw figures, such as a clock, bicycle, or house, and to copy complex figures. Making or copying constructions using matches, tongue blades, building blocks, or Koh’s blocks is

Visual agnosia is difficulty in recognizing visual objects despite the preservation of ‘elementary’ sensory functions (Farah, 1990). It is the hallmark deficit of ventral pathway lesions. Lissauer (1890) made the original distinction between two types of visual agnosia. In apperceptive agnosia, complex aspects of visual processing are impaired, causing poor formation of the percept of the object and hence the trouble with recognition. In associative agnosia, a correctly formed percept is poorly matched with stored knowledge based on past visual experience (Caplan & Hedley-White, 1974), as in Teuber’s (1968) famous definition of agnosia as percepts stripped of their meanings. Both groups are unable to name or recognize the character and function of objects seen, but most will readily do so if they can experience the object by hearing, touch, or someone else’s description of the properties of the object (e.g. feeling a cat, hearing a cat meow, or describing a small household pet that likes milk). Combined tactile and visual agnosia can occur, though, probably indicating more anterior extension in the left temporal lobe (Feinberg et al., 1986). The distinction between apperceptive and associative agnosia classically rests upon the patient’s ability to copy drawings, match objects with one another, and trace outlines of drawn objects they cannot recognize. Some visual agnosic patients are able to recognize objects after tracing them with their fingers (Landis et al., 1982). Laboratory studies augment these bedside observations with tests of contrast sensitivity, lightness, shape, and orientation perception (Campion & Latto, 1985; Milner & Heywood, 1989; Milner et al., 1991). Visual agnosia must also be distinguished carefully from visual anomia. In contrast to visual agnosia, patients with visual anomia do recognize the nature and function of the

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visual object. In contrast to anomic aphasia, they can name the object if they hear or touch it. Severe apperceptive agnosia, affecting all classes of objects, is rare and likely requires bilateral occipital injury, often occurring as a residual defect after partial recovery from cerebral blindness (Sparr et al., 1991). The classic cause is carbon monoxide poisoning (Adler, 1950; Benson & Greenberg, 1969; Campion & Latto, 1985; Milner & Heywood, 1989), though it has also been reported after bilateral occipital infarction (Riddoch & Humphreys, 1987). The utility of the apperceptive/associative dichotomy in more restricted forms of visual agnosia – such as pure alexia and prosopagnosia – is more questionable (Farah, 1990). Certainly the distinction is not an all-ornone affair: rather, patients vary on the degree to which impaired visual memory versus perception underlies their disorder. In addition to the apperceptive/associative distinction, visual agnosias range from a generalized agnosia affecting most, if not all, categories of objects, to agnosia selective for certain classes, the most prominent exemplars of which are words (alexia) and faces (prosopagnosia). Selective agnosia is typical of unilateral lesions, whereas generalized agnosia often requires bilateral lesions. Hemiachromatopsia, the loss of colour perception in the contralateral hemifield, may be seen with either left or right-sided lesions of the lingual and fusiform gyri (Albert et al., 1975; Damasio et al., 1980; Kölmel, 1988; Paulson et al., 1994). It is usually asymptomatic and hence likely under-recognized; any patient with an upper quadrantanopia should be tested for colour perception in the remaining contralateral hemifield.

Left-sided ventral lesions Alexia without agraphia (‘pure alexia’ or ‘word blindness’) is the loss of previously fluent reading skill despite preserved ability to write, speak, and comprehend spoken language (Dejerine, 1892). The spectrum ranges from ‘global alexia’ (Binder & Mohr, 1992), in which patients cannot read even single numbers, letters or symbols, to ‘letter-byletter reading’, or ‘spelling dyslexia’ (Black & Behrmann, 1994), a less severe deficit of slowed reading with occasional errors, whose hallmark is a correlation of reading time required with the length of a word (Bub et al., 1989; Coslett et al., 1993). Pure alexia has been explained as a ‘disconnection’ of the left angular gyrus from its visual inputs (Dejerine, 1892; Geschwind, 1965). The left-sided lesion often causes a complete right hemianopia and intercepts information from the right visual cortex in the splenium or callosal fibres (Damasio & Damasio, 1983) (Fig. 8.12). Pure alexia without hemianopia, though rarer, may

occur if the lesion causes a disconnection in the white matter underlying the angular gyrus (Henderson et al., 1985; Iragui et al., 1991). Others argue that pure alexia in some cases is a type of visual agnosia from damage of the medial temporo-occipital regions (Warrington & Shallice, 1980; Rentschler et al., 1994). Besides hemianopia, patients often have colour anomia (Geschwind & Fusillo, 1966; Damasio & Damasio, 1983), anomia for visual objects and photographs, defects of verbal memory, and agnosia for other visual objects (Damasio & Damasio, 1983). A disconnection optic ataxia may occur, in which the right hand has difficulty reaching for objects in the left visual field (Damasio & Damasio, 1983). It must be stressed that reading is a complex performance involving vision, form perception, attention and scanning eye movements, and can be impaired for any of these reasons. Hence patients with impaired fixation or inaccurate saccades from biparietal lesions (Holmes, 1918a; Pierrot-Deseilligny et al., 1986; Husain & Stein, 1988) have trouble reading. Patients with hemineglect will have neglect dyslexia, missing the left side of the page and making errors on the left side of words (Behrmann et al., 1990). Patients with left macula-involving hemianopia, having reached the end of one line, have trouble returning to the beginning of the next, which lies in their blind field (Zihl, 1995). Marking their place with an L-shaped ruler helps. Right macular-splitting hemianopia is even more disabling, because the normal process of reading tends to take in substantial information from areas just forward (rightward) of each fixation. These patients must make more small saccades and longer fixations, creeping slowly along each line (Zihl, 1995; Trauzettel-Klosinski & Brendler, 1998). Pure alexia must also be differentiated from other highlevel reading problems too. These generally stem from linguistic rather than visual dysfunction, and are not ventral pathway visual deficits. Alexia with agraphia is the combination of impaired reading and writing with preserved oral language functions. This is caused by infarcts or hemorrhages involving the left angular gyrus (territory of the lower division of the left middle cerebral artery) or white matter, undercutting this region of the inferior parietal lobe (posterior cerebral artery territory) (Dejerine, 1892; Geschwind, 1965; Benson & Geschwind, 1969). These patients cannot read, write, or spell: an acquired illiteracy. It may be accompanied by other elements of Gerstmann’s syndrome. Literal alexia may occur with left frontal infarcts causing Broca’s aphasia. Patients with this deficit have better comprehension of spoken language than written language (Benson et al., 1971; Benson, 1977). They may have more trouble reading individual letters than whole

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(a )

(b)

Fig. 8.12. (a) Dejerine’s diagram of the lesion in pure alexia (without agraphia), interrupting callosal fibres from the right visual cortex as well as damaging the left striate cortex (striped cortical ribbon noted as c). (b) Left lateral occipital-temporal infarction (arrow) associated with pure alexia and right hemianopia.

words (‘letter blindness’). Central dyslexias (Black & Behrmann, 1994) involve problems with accessing word stores or phonological rules: hence some defects are specific to pronouncing words with irregular spelling (i.e. yacht) and others have trouble using language rules to pronounce a nonsense word (i.e. glaster). Reading aloud and for comprehension can be tested with magazines and newspapers, with attention to speed and the performance with long vs. short words. Premorbid intellect must be taken into account. Oral language must be examined to exclude aphasia and writing tested to dictation or spontaneously, not by a signature. Colour anomia is another visual–verbal disconnection symptom (Geschwind & Fusillo, 1966), which only occurs in patients with pure alexia and right hemianopia from lesions of the splenium or adjacent white matter. Despite their naming problems, these patients can perform colour matching or sorting tasks well, in contrast to patients with achromatopsia. They also have normal colour imagery, in that they can describe the usual colours of familiar objects and can colour line drawings of objects with the appropriate colours.

Right-sided ventral lesions Prosopagnosia is the inability to recognize previously familiar faces. Patients usually complain of the social handicap: they cannot recognize individuals except by their voice or idiosyncratic visual features, such as a peculiar hairstyle, glasses, gait, or unusual clothing. They have trouble especially when encountering people out of context (i.e. seeing a teacher at the supermarket). The defect may be so severe that they cannot recognize their family or their own face in a mirror. The specificity of the defect for faces varies among patients: in some, the recognition defect extends to other objects such as individual animals, cars, buildings, food, flowers, coins, handwriting, or personal items of clothing (Damasio et al., 1982), in others the deficit appears more restricted to faces (Bruyer et al., 1983; Farah et al., 1995). Many patients can distinguish sex, estimate age, and recognize expressions from faces (Tranel et al., 1988; Bruyer et al., 1983; Sergent & Poncet, 1990) but some cannot (Campbell et al., 1990). Patients also differ in their ability to match photographs of unknown people, when the views differ in lighting or profile. The performance on such matching tests, as well as

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the ability to perceive age, sex and expression, have been used as an index of face perception, to divide prosopagnosia into apperceptive and associative forms (de Renzi et al., 1991). There are also interesting demonstrations of preserved ‘covert’ knowledge of faces in some, but not all, prosopagnosic patients. Famous faces differ from unfamiliar faces in the eye scanning patterns (Rizzo et al., 1987), galvanic skin responses (Tranel & Damasio, 1985), and P300 evoked potentials (Renault et al., 1989) of some prosopagnosic patients. Some patients even have unconscious access to semantic information about faces, in that their performance on a variety of indirect tasks is influenced by the correct name or occupation belonging to a famous face that they cannot openly recognize (Bauer & Verfaellie, 1988; Sergent & Poncet, 1990; de Haan et al, 1987). Prosopagnosia is caused by lesions in the lingual and fusiform gyri, (Meadows, 1974a; Damasio et al., 1982), occasionally in more anterior temporal cortex (Evans et al., 1995). The most common cause is posterior cerebral artery infarction (Fig. 8.13). Controversy still surrounds the issue of whether prosopagnosia requires bilateral ventral lesions, as claimed in earlier reviews of autopsy data (Meadows, 1974a; Damasio et al., 1982). Neuropsychological data supports a role for both hemispheres in face perception, though the right side is likely dominant. Nevertheless, more recent neuroimaging reports (Landis et al., 1986a; Michel et al., 1989; Takahashi et al., 1995) have documented cases with apparently unilateral right-sided lesions. How bilateral and unilateral cases differ is still not clear. Damasio et al. (1990) hypothesize that unilateral right occipitotemporal lesions may damage the structures needed for perceiving faces, causing an apperceptive prosopagnosia, whereas bilateral anterior temporal lesions may impair the memory for faces, causing an associative prosopagnosia. Prosopagnosia is frequently, but not always, associated with achromatopsia, topographagnosia, and hemifield visual defects. Bilateral upper quadrantanopia is common among those with bilateral temporal lesions and left hemianopia is frequent in those with right-sided lesions (Landis et al., 1986a, Takahashi et al., 1995). Various degrees of visual or verbal memory loss are often found too (Bruyer et al., 1983). Testing for prosopagnosia involves assessing the recognition of faces that should be familiar to them: if images of public figures are used, the likelihood of their familiarity to the patient based on the patient’s interests, education and age needs to be considered. Care should be taken that recognition does not stem from distinctive features (Jimmy Durant’s nose) or props (Winston Churchill’s cigar) that bypass face perception. Face perception, or more correctly recognition of unfamiliar faces, can be

Fig. 8.13. Right medial occipitotemporal infarction associated with left homonymous hemianopia, prosopagnosia and topographagnosia, but no achromatopsia. Note small medial occipital lesion on the left side as well (arrow): whether this also contributes to his prosopagnosia is unclear.

tested with the Benton Face Recognition Test by a neuropsychologist. Topographagnosia (‘disorientation for place’, or ‘environmental agnosia’) is the inability to recognize familiar surroundings (Landis et al., 1986b). These individuals cannot revisualize directions nor describe the relationships of objects in their own rooms or houses or on a standard structure like a baseball or football field. They commonly get lost in their own home or neighbourhood. Some eventually learn to use effortful compensatory strategies, like memorizing the number of turns, doors, or houses on the way to some destination, or peculiar local features like a mailbox or water fountain, reminiscent of the way some prosopagnosic patients rely on distinctive facial features to recognize some people. Most patients have right medial temporo-occipital lesions, but bilateral lesions and right occipito-parietal lesions have been reported also. Prosopagnosia is a frequent companion to this disorder. Disorientation to place, bizarre reports of locale, and daydreaming are also prevalent in patients with rostral brainstem infarcts (Caplan, 1980). A possible related phenomenon is reduplicative paramnesia (Benson & Gardner, 1976). Patients who are other-

Cerebral visual dysfunction

wise alert may duplicate their current location, acknowledging that they are in the hospital but that it is a branch in a distant country. One of our patients in a downtown Boston hospital claimed that he had been in his suburban home during the preceding week of tests, although in reality he had been hospitalized the entire time. He commented that it was very convenient that they had erected the hospital around his home so that he could easily walk back and forth. Reduplicative paramnesia also bears some relation to other misidentification syndromes, such as the Capgras illusion, where patients insist that the familiar person before them is an impostor. Visual amnesia is a modality-specific abnormality of learning and memory. In humans and animals the rightside structures in the Papez circuit (mamillary bodies, medial thalamic nuclei, mamillothalamic tracts, fornices, hippocampi) are specialized for visual-spatial memories, and left-side structures are specialized for languagerelated functions. Patients with right posteromedial thalamic hemorrhages and infarcts have been found to have amnesia especially for visual materials. Selective visual memory deficits can also be found in patients with right or bilateral temporal lobe infarcts (Ross, 1980). Visual hypoemotionality describes reduced affective responses to visual stimuli (Bauer, 1982; Habib, 1986). Flowers, landscapes, and erotic pictures are perceived normally, but no longer elicit the accustomed, expected responses, whereas music, words, and touch do elicit the appropriate, customary affective responses. The reported patients have had right or bilateral temporo-occipital lesions, often with coexistent prosopagnosia.

Bilateral cerebral lesions Bilateral lesions in the posterior portions of the cerebral hemispheres, including the occipital lobes, the posterior temporal lobes, and the inferior posterior parietal lobes, are surprisingly common. The most frequent causes are emboli of the top of the basilar artery and the posterior cerebral arteries (Symonds & MacKenzie, 1957; Caplan, 1980), sequential infarction due to in situ occlusive disease and embolism, sequential intracerebral hematomas, as found in patients with amyloid angiopathy, and borderzone infarctions between the middle cerebral artery and posterior cerebral artery territories. Bilateral embolic infarction affects the medial occipitotemporal regions, whereas border-zone infarction tends to involve lateral occipitotemporal and posterior parietal regions. The very different visual functions subserved by the ventral (temporal) pathway and the dorsal (parietal) pathway make the

deficits of these two different pathologies strikingly different. However, patients are individual entities, and any given person may have a mixture of ventral and dorsal stream deficits, depending upon the extent of their strokes. Also, such strokes often involve the optic radiations or striate cortex, causing ‘low-level’ visual loss as well. Indeed, the likelihood of detecting complex visual deficits depends upon the amount of visual field spared by damage to elements of the geniculo-calcarine relay.

Bilateral ventral (temporal) pathway lesions Cerebral achromatopsia is the loss of colour perception following bilateral cerebral injury (Zeki, 1990). These patients complain bitterly of their impairment, noting that everything appears in shades of grey, the world looks less bright, or has a dirty grey tinge (Meadows, 1974b; Rizzo et al., 1993; Damasio et al., 1980). Rarely, they may complain of a coloured tint to the world (Critchley, 1965). Topographagnosia, prosopagnosia, and upper quadrantic field defects are common accompaniments. Achromatopsic patients have trouble distinguishing colour hue (i.e. blue v. green) and saturation (i.e. red v. pink) but tend to do better along the third dimension of colour space, brightness (Victor et al., 1989; Rizzo et al., 1993). Hue perception can be tested with colour matching or sorting tests, such as the D-15 panel or Farnsworth–Munsell 100-hue test. These patients do poorly across the board, without much selectivity for any particular colour (Rizzo et al., 1993). Despite this severe defect, at least some patients can see the pseudoisochromatic numbers in the Ishihara or AO-14 plates, particularly if viewed from a greater distance (Heywood et al., 1991). This implies that such patients can see boundaries defined by colours even if they cannot name the colours or sort them correctly. This spared colour ability is thought to reflect surviving colour opponent processes in the intact striate cortex (Victor et al., 1989; Heywood et al., 1996). Achromatopsia is due to bilateral lesions of the lingual and fusiform gyri (Damasio et al., 1980; Heywood et al., 1991; Rizzo et al., 1993), of which posterior cerebral artery infarctions are the most common cause. Achromatopsia should be distinguished from the colour anomia that accompanies pure alexia with left-sided lesions. While patients with either defect may not be able to name colours, those with colour anomia can match and sort colours. Also, some patients with milder achromatopsia may be able to name colours approximately, although their discrimination of more subtle colour differences is impaired. Patients with achromatopsia may or may not have preserved colour imagery (Levine et al., 1985; Bartolomeo et al., 1997), so this does not necessarily help.

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As discussed above, some forms of prosopagnosia are associated with bilateral occipitotemporal lesions (Damasio et al., 1982). Bilateral occipital lesions can also cause a severe apperceptive generalized visual agnosia (Riddoch & Humphreys, 1987), and more anterior lesions may cause a generalized associative agnosia, affecting faces, words and other stimuli.

Bilateral dorsal (parietal) pathway lesions Bálint’s syndrome is the classic human dorsal pathway syndrome (Bálint, 1909; Hécaen & de Ajuriaguerra, 1954; Husain & Stein, 1988), though controversy over its validity as a single entity exists (Rizzo, 1993). The three features of Bálint’s syndrome are said to be simultanagnosia, optic ataxia, and apraxia of gaze. As with the ventral pathway syndrome above, these elements are not tightly associated, but can occur independently (Hécaen & de Ajuriaguerra, 1954), suggesting that there is no single mechanism that underlies all elements of the triad. Bálint’s syndrome is typically associated with bilateral angular gyrus lesions (Fig. 8.14), and hence can be associated with other parietal signs such as hemineglect, aphasia or Gerstmann’s syndrome (Benton, 1992). However, similar signs have been found with bifrontal and pulvinar lesions (Ogren et al., 1984), as well as more posterior and inferior occipital regions (Rizzo & Hurtig, 1987; Rizzo & Robin, 1990). Simultanagnosia is the inability to see and interpret an entire visual scene, despite the preserved perception of individual items in that scene (Wolpert, 1924). Thus patients report ‘piecemeal’ vision, with scenes sometimes resembling a jigsaw puzzle with missing pieces. They often report trouble understanding the meaning of pictures. Testing has revealed in simultanagnosia a difficulty with sustaining visuospatial attention over a large array of stimuli; objects often disappear and reappear despite normal visual fixation (Rizzo & Hurtig, 1987; Rizzo & Robin, 1990). At the bedside, simultanagnosia is tested by having a patient freely scan a complex picture with objects in all quadrants, such as the Cookie Theft Picture (Goodglass & Kaplan, 1983), and describe what they see. Omissions should take into account careful prior testing for hemineglect and visual field defects: extensive and patchy holes in peripheral vision can mimic simultanagnosia (Luria, 1959). Optic ataxia refers to poor hand coordination under visual control. Classically, patients should be able to touch parts of their own bodies or point to auditory targets with their eyes shut. However, parietal cortex is a multimodal region, and some patients have trouble reaching for any type of target, visual or otherwise (Holmes & Horrax, 1919).

Fig. 8.14. Sequential bilateral parietal white matter infarctions associated with Bálint’s syndrome.

Holmes (1918a) considered this part of a larger ‘visual disorientation’ disorder, in which judging spatial distance and location is impaired. Such patients have trouble counting objects, walking around obstacles, touching objects with the hands, and looking at stationary or moving objects (Holmes, 1918a; Luria, 1959). To assess optic ataxia, the visual fields must again be assessed first, to ensure that the patient can see the targets. Easily seen tokens are placed at different locations within arm’s reach, and the patient asked to touch or grasp the target. The problem tends to be worse for the hand and hemi-space contralateral to the lesion. The patient is then asked to touch parts of their own bodies. Optic ataxia is differentiated from cerebellar dysmetria by its relative selectivity for visual targets and the lack of intention tremor or dysdiadochokinesia. Apraxia of gaze is a nebulous term that encompasses several different types of saccadic dysfunction in Bálint’s syndrome. ‘Psychic paralysis of gaze’ (Hécaen & de Ajuriaguerra, 1954), or ‘acquired ocular motor apraxia’ (Cogan, 1965) is difficulty in initiating saccades to visual targets on command, though patients may easily make spontaneous scanning saccades or reflex saccades to suddenly appearing stimuli. With ‘spasm of fixation’, patients have trouble tearing their eyes away from a fixated object to saccade to another, doing much better if the first object

Cerebral visual dysfunction

disappears when the second appears (Holmes, 1930; Johnston et al., 1992). Last, when patients can make saccades, their accuracy may be grossly impaired, and the eyes wander in search of the target (Holmes, 1918a; Luria et al., 1962). Because patients cannot direct their fovea to objects appropriately, this renders impossible detailed visual tasks that involve such scanning, such as reading. Impaired saccadic accuracy has been described with bilateral damage to the inferior parietal lobules (PierrotDeseilligny et al., 1986). Acquired ocular motor apraxia is tested clinically by having the subject make saccades to targets on command, and contrasting this with their reflexive saccades to objects or people that suddenly appear or move in the room. Saccadic inaccuracy can be observed with the same simple targets, with care that targets are not placed in known blind regions of the visual field. Cerebral akinetopsia is a rare, relatively recently described condition whose hallmark is impaired motion perception (Zeki, 1991). Only two patients have been well studied. Both had bilateral lesions of lateral occipitotemporal cortex, affecting both cortex and white matter (Zihl et al., 1991; Vaina et al., 1990; Vaina, 1994), consistent with functional imaging reports of a human cortical ‘motion area’ in this region (Tootell et al., 1995; Barton et al., 1996). At least one of the patients had symptoms in her daily life, complaining that objects jumped from place to place instead of moving smoothly (Zihl et al., 1991). On formal laboratory testing, these patients see simple motion of objects relatively well, but fail when small amounts of random motion are added (Baker et al., 1991; Rizzo et al., 1995). Unfortunately, there are no easily available bedside tests for this type of dysfunction. In addition to this more complicated ‘integrative’ motion deficit, they have other problems with spatial and stereoscopic depth perception (Vaina, 1994; Rizzo et al., 1995). Astereopsis is the loss of stereoscopic depth perception. One of the important clues to distance from the observer is the disparity between the retinal images of the object in the two eyes. Patients may complain that the world looks flat and that they cannot tell the depth of objects, and they may misreach for objects in depth but not direction. Yet there are many other clues besides stereopsis to distance, which can be seen with one eye alone, such as relative differences in object size and intensity (which artists exploit), and differences in object motion as the observer’s head moves (motion parallax). It may be that some of these functions are also impaired in these patients, particularly motion parallax. Astereopsis occurs in patients with bilateral occipito-parietal lesions (Holmes & Horrax, 1919; Rizzo & Damasio, 1985). Milder deficits occur with unilateral lesions. Other visuospatial dysfunction may be associated.

Stereotests, which are cards viewed with different polarized or coloured glasses worn by the two eyes, are required to measure deficient stereopsis (Patterson & Fox, 1984): most eye clinics have examples of these at hand.

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9

Visual symptoms (eye) Shirley H. Wray Harvard Medical School, Massachusetts General Hospital, Boston, USA

Transient monocular blindness Temporary loss of vision in one eye, termed transient monocular blindness (TMB), is the most important visual symptom of arteriosclerotic vascular disease, arteritis and states of altered coagulability, and thrombocytosis. In most patients, the visual disturbance during each individual attack of TMB is stereotypic. It may recur over a period of months or over a much briefer span of hours, days, or weeks. A meticulous history of the attack and duration of the visual disturbance will permit classification of the TMB occurrence into one of four types. Type I is due to transient retinal ischemia, type II to retinal vascular insufficiency and type III to vasospasm. Type IV occurs in association with antiphospholipid antibodies but includes cases of unknown etiology (Table 9.1 (Wray, 1988; Burde, 1989)).

TMB type I TMB type I is characterized by a sudden, brief attack of partial or complete dimming or obscuration of vision, lasting seconds to minutes, followed by total recovery. Partial impairment is described as a greyout, or as an ascending or descending curtain or a blind moving sideways across the eye. Occasionally, the patient will describe moving tracks of light. Ipsilateral headache is rare (Wilson et al., 1979). Fisher (1952) drew attention to the association of TMB of this brevity with contralateral hemiplegia. Episodic attacks of fleeting blindness occur as arteriosclerotic plaques progressively narrow the lumen of the ipsilateral internal carotid artery (ICA), leading to periodic reduction in blood flow, reduced pressure in the ophthalmic artery, transient ocular ischemia, or vascular insufficiency. Often, cholesterol crystals or plugs of platelets will detach from an ulcerating plaque in the vessel wall and embolize to distal branches of the carotid and ophthalmic

artery, the central retinal artery (CRA) and/or the posterior ciliary arteries, without causing permanent visual loss. For this reason, TMB is regarded as one variety of carotid artery transient ischemic attack (TIA) and like other TIAs, TMB should be recognized as a warning of an impending stroke. Crescendo TMB occurs in patients with high-grade carotid stenosis or impending CRA occlusion and physical examination of the blood vessels of the head, neck and eyes is key to the detection of signs that can localize the lesion to the ICA.

Clinical signs Retinal emboli A cholesterol embolus is virtually diagnostic of localized ICA disease when a typical ipsilateral carotid bruit is present, when aortic or cardiac disease is absent, and when there is no exogenous source of emboli, as, for example, intravenous drug use, (talc and microcrystalline cellulose), severe trauma, or injection (air) (Table 9.2) Cholesterol emboli (Hollenhorst plaques) appear in the branches of the CRA as bright or shiny bodies whose diameter seems to exceed the intraluminal diameter of the arteriole (Hollenhorst, 1960, 1961). These emboli tend to lodge at arterial bifurcations. They may be invisible except on ocular compression or by varying the incidence angle of the ophthalmoscope light. They may be permanent or quite transient, moving on to the next bifurcation or disappearing before the next examiner can verify them. Cholesterol emboli also produce focal opacification in an arteriole in which they become impacted (Wilson et al., 1979). In an eye with a history of transient visual loss but without visible retinal emboli this sign suggests that an embolus may have been present at one time. The presence of a cholesterol embolus is a poor prognostic sign: 93% of such patients have vascular disease at presentation; 15%

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Table 9.1. Types of TMBa Parameter

Type I

Type II

Type III

Type IV

Onset Visual field

Abrupt All or partial

Less rapid All or partial

Visual loss

May black out completely

Abrupt Resembles Type I, II or III May alternate between eyes

Length

Seconds or minutes Complete No Retinal ischemia, embolus, arteritis

Loss of contrast vision, photopsia, sunlightprovoked Minutes or hours

Abrupt All or progressive contraction May spare fixation, photopsia, scintillating sparkles Minutes Usually complete Often Vasospasm, migraine

Complete No APS, idiopathic

Recovery Pain Mechanism

Complete Rare Retinal hypoperfusion, Carotid occlusive disease

Any length

APS Antiphospholipid antibody syndrome Notes: a Based on 850 personal cases (Wray, 1988) Source: Adapted from Burde (1989), with permission.

Table 9.2. Sources of emboli Type

Patient age

Cardiac valves Rheumatic disease Lupus Acute or subacute endocarditis Floppy mitral valve

Platelet/Calciuma Platelet Marasmic Platelet

Any age Young women Damaged heart Any age; mostly women

Chamber Myxoma Mural thrombus

Myxoma Platelet/clot

Older adult

Carotid artery Ulcerated plaque Stenosis Fibromuscular dysplasia

Platelet/cholesterol ester Platelet Platelet

Young women

Other Amniotic Long bone fractures Chronic i.v. drug users Disseminated intravascular coagulopathya

Debris?a Fata Talca ??

Young women Any age Any age ??

Antiphospholipid antibody(s)

??

Young adult

Note: a Produces retinal infarction; no amaurosis fugax. Source: Adapted from Burde (1989), with permission.

Older adult

Visual symptoms (eye)

Table 9.3. Funduscopic signs in TMB, pupil dilated • • • • • • • •

Normal disc and fundus Retinal emboli BRAO ⫾ visible embolus Retinal infarct (cystoid body) ⫾ hemorrhage Venous stasis retinopathy Asymmetric hypertensive retinopathy A low diastolic ophthalmic artery pressure Ischemic disc swelling

die within the first year, and 55% within 7 years. The cause of death is usually heart disease, 6:1 compared with stroke (Savino et al., 1977). Pale white platelet plugs can also be seen transiently within retinal arteries (Fisher, 1959). In a hypertensive patient, the caliber of the retinal arteries on the side of an ICA stenosis may be reduced and show fewer hypertensive changes than the retinal vessels of the opposite eye. Focal cotton-wool spots (cystoid bodies), in the absence of hypertensive retinopathy, are due to embolic microinfarction and may be seen when no emboli are visible (Table 9.3).

Retinal artery pressure Retinal arterial pressure drops when there is an acute hemodynamically significant lesion in the ipsilateral ICA or ophthalmic artery. Measurements can be by several techniques: by direct use of a hand-held ophthalmodynamometer (ODM) to measure flow in the ophthalmic artery (Toole, 1963); by oculoplethysmography, in which a sensing device is placed on the cornea and measures systolic ophthalmic artery pressure (Gee et al., 1976); by the relative time of arrival of the ocular pulse (Kartchner & McRae, 1977) and by transcranial Doppler ultrasound to measure flow velocities in the ophthalmic artery. Ophthalmodynamometry has the great advantage of being portable and easy to perform. External pressure is applied to the eyeball by the footplate of the dynamometer and is gradually increased while the examiner views the retinal arteries with the ophthalmoscope (Toole, 1963; Ackerman, 1979). When the external pressure applied exceeds the ophthalmic artery diastolic pressure, the arteries on the optic disk will visibly pulsate. When additional pressure is applied to the globe, the systolic arterial pressure will be exceeded, and the arteries will blanch and stop pulsating. The pressures are read from the dynamometer, and the external pressures needed to overcome diastolic and systolic pressures in the two eyes are compared. The ODM

reading will vary with intraocular pressure and the patient’s systemic blood pressure.

Bruit The typical carotid bruit is a high-pitched, long, very focal sound heard loudest over the carotid bifurcation. When a bruit at the bifurcation is also audible over the ipsilateral eye, the neurologist can be confident that the bruit is of ICA origin and that the artery is patent. An ipsilateral ocular bruit alone may indicate stenosis of the intracavernous segment of the ICA. When flow in the ICA is severely diminished no bruit may be audible. A bruit can also arise from the proximal external carotid artery (ECA) in which case it usually radiates towards the jaw and can be diminished by pressure on ECA branches (Reed & Toole, 1981).

Facial pulses Pulsations palpable at the angular, brow, and cheek (ABC) regions may be present when the ICA is occluded or severely stenosed and ECA collaterals feed into the orbit (Fisher, 1970; Caplan, 1973). Embolization from the stump of the occluded ICA is believed to be the mechanism causing TMB in these cases. Absence of the temporal artery pulse, with or without tenderness over the vessel on one or both sides, is indicative of giant-cell arteritis in the elderly patient, until proved otherwise.

Anisocoria Anisocoria, with normal pupil reflexes, is an important sign of ICA dissection. Meiosis and partial ptosis in the ipsilateral eye indicate an oculosympathetic palsy, Horner’s syndrome. Horner’s syndrome results from damage to the autonomic nerve fibres in the ICA sheath in the neck. Facial sweating is preserved, because sympathetic innervation of sweat glands travels along the ECA. Horner’s syndrome is especially common in patients with ICA dissections.

Differential diagnoses Giant-cell arteritis TMB may be the presenting symptom of giant-cell arteritis affecting elderly men and women. This inflammatory disorder typically involves branches of the ECA, especially the superficial temporal and occipital arteries, causing headache, scalp tenderness, claudication of the jaw during chewing, and tenderness over the affected temporal artery. In this systemic disease, TMB usually heralds an ocular stroke. Blindness is a result of an occlusion of the CRA or occlusion of the posterior ciliary arteries, leading to infarction of the optic nerve head. This type of ocular stroke is called anterior ischemic optic neuropathy. Because arte-

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riosclerosis of the carotid arteries in the neck and giant-cell arteritis can coexist in elderly patients, every patient over 55 years of age with TMB should have an immediate measurement of the erythrocyte sedimentation rate (ESR). Characteristic laboratory findings, in addition to a high ESR, include a normochromic or slight hypochromic anemia and increased fibrinogen and alkaline phosphatase levels. If the ESR is elevated, or if the ESR is normal and the fibrinogen level is elevated, treatment with highdosage prednisone must be started pending a temporal artery biopsy – the diagnostic procedure of choice.

Carotid artery dissection The presenting symptom of ICA dissection is pain (Ojemann et al., 1972; Fisher et al., 1978). Ipsilateral neck pain, headache, pain in the face or retro-orbital pain may occur. After a latent interval the patient may have a TIA, such as transient hemiparesis or TMB (Pozzali et al., 1989). TIAs are due to emboli off the top of the dissection into the middle cerebral and/or ophthalmic arteries. TIAs tend to occur more frequently following carotid dissection than in arteriosclerotic ischemia (Ojemann et al., 1972). TMB in some patients with ICA dissection is described as visual scintillations and bright sparkles, very reminiscent of migraine (Caplan, 1993) and migraine may in fact be misdiagnosed if headache is also present. Neck tenderness and bruit are inconstant features, and less common symptoms are pulsatile tinnitus and hypoglossal palsy.

Diffuse disseminated atheroembolism Diffuse disseminated atheroembolism is a rare condition closely related to atherosclerosis (Castleman & McNeely, 1967). Cholesterol-rich atheromatous emboli break off from unusually fragile plaques in the aorta and its major branches and occlude arteries in the brain, retina, kidney, bowel and other organs (Darsee, 1979; Goulet & Mackay, 1963; Coppeto et al., 1984). The diagnosis of diffuse atheroembolism deserves serious consideration in all patients in middle or late life with headache, stroke, TMB, elevated ESR, hypertension, or cholesterol emboli in the retina. Early diagnosis is important because arteriography (Ramirez et al., 1978), endarterectomy, and anticoagulation (Beal et al., 1981) seem to increase the risk for serious, even fatal, embolization in these patients.

Antiphospholipid antibodies The antiphospholipid antibodies (APA) are a group of immunoglobulins, including the lupus anticoagulant (LA) and the anticardiolipin antibody (aCL). These antibodies are found in 1–2% of the general population and in up to 50% of patients with SLE. Patients who are antiphospho-

lipid antibody-positive, without clinical SLE, but with a history of any or all of certain clinical events (recurrent venous or less frequent arterial thromboses in potentially any vascular bed, recurrent spontaneous abortion, thrombocytopenia, and cardiac valvular abnormalities) have a primary antiphospholipid antibody syndrome (Levine & Welch, 1987; Asherson et al., 1989; Coull et al., 1992). In one study of 6 patients, (4 women and 2 men) under the age of 34 yr with episodic TMB, high titres of antiphospholipid antibodies were found (Digre et al., 1989). Patient 1, a 23-year-old woman 20 weeks into her first pregnancy, reported a monocular total visual loss from the bottom up or the top down lasting approximately 2 minutes. She had 20–30 episodes of visual loss over 2 months. Patient 2, a 31-year-old woman in the postpartum period, reported episodic unilateral altitudinal visual loss occurring three to four times in one or other eye every day, each episode lasting 1–5 minutes. Patient 3, a 25-year-old woman with a history of spontaneous abortions, had constriction of the visual field of the right eye at least 20 times each day. At other times, she also had a unilateral central migrating scotoma lasting seconds to minutes at least 20 times each day. Splinter hemorrhages of the nail beds were present in four of the six patients. None had evidence of endocarditis. Some also had neurological symptoms, such as spells of vertigo and diplopia, headache, or an episode of ataxia. Treatment with antiplatelet agents, or anticoagulants, or both, led to significant reduction in the frequency of TMB attacks in five of the patients, but no single therapeutic agent was completely effective. A causal role for antiphospholipid antibodies in thrombogenesis has not been established, despite considerable investigation, but it seems likely, given the increased rate of thrombosis in patients with these antibodies. For this reason, antiphospholipid antibody syndrome (APS) must be a diagnostic consideration in any young patient with arterial or venous occlusive disease with TMB or TIA.

Other non-arteriosclerotic vasculopathies The following non-arteriosclerotic vasculopathies may also give rise to TMB: fibromuscular hyperplasia, granulomatous angiitis, congophilic angiopathy, systemic lupus erythematosus (SLE), Behcet’s syndrome, and moya– moya disease. These rare angiopathies affect small-calibre arteries and collectively must be considered in any patient with a TIA.

Hematological conditions States of altered coagulability and thrombocytosis, such as altered viscosity of the red cells in sickle-cell disease and altered blood viscosity in polycythemia, are associated

Visual symptoms (eye)

with TIAs. TMB associated with antiphospholipid antibodies is discussed in a later section.

TMB type II TMB type II occurs in patients who have extensive extracranial occlusive arterial disease involving both the ipsilateral ICA and ECA due to retinal vascular insufficiency. The visual disturbance differs from that of type I TMB. Typically the attack is less rapid in onset (over 5 min) and longer in duration (minutes to hours), and recovery is gradual (Table 9.1). Visual acuity is not altered significantly during the episode, but contrast acuity is. Bright objects appear brighter, dark objects become more difficult to see, and the edges of bright objects can appear to flicker. When the bright, dazzling sensation is marked, the overall effect is one of overexposure, and the patient may have difficulty reading because of the dazzle of white paper. When sight becomes fragmented and patchy, patients describe the appearance as a photographic negative. Occasionally, they note a transient closing-in of the peripheral vision or a dull pain over the eye. Symptoms of generalized cerebral ischemia (faintness, fatigue, impaired concentration) often coexist, but are mild compared with the visual symptoms. Conditions that provoke attacks of type II TMB are systemic hypotension, venous hypertension and extracerebral steal. The attacks occur on stooping or straining, when venous pressure rises, on standing or during exercise, and on exposure to bright lights or warm surroundings (Furlan et al., 1979; Ross Russell & Page, 1983). This pattern suggests a temporary failure of retinal homeostasis. In the unique case of a man with type II TMB provoked by facial heating with a hair dryer, the mechanism of the visual loss was believed to be diversion of blood to a dilated ECA facial vascular bed, resulting in temporary ocular oligemia on the affected side (Ross Russell & Page, 1983).

Clinical signs Venous stasis retinopathy Type II’s unusual visual symptoms are retinal in origin, and a low retinal arterial pressure is always present. Compensatory retinal venous changes occur, and venous stasis retinopathy develops, indicating that reduction in flow in the ophthalmic artery is severe and longstanding. The early signs of venous stasis retinopathy are microaneurysms, multiple small blot-like intraretinal hemorrhages in the mid-periphery, segmental narrowing and dilation of the veins, spontaneous pulsation of retinal arteries on the disc and ischemic disc swelling (Kearns & Hollenhorst, 1963) (Table 9.4). The fundus appearance resembles dia-

Table 9.4. Funduscopic signs of venous stasis retinopathy Early signs Microaneurysms Dot and blot intraretinal and nerve fibre layer hemorrhages Reduced retinal artery pressure Severe ischemia Dilation and darkening of retinal veins Mild swelling of the optic disc Retinal clouding Spontaneous pulsation retinal arteries on the disc End-stage Ocular ischemic syndrome

betic retinopathy, but is easily distinguished from diabetes by being unilateral. Venous stasis retinopathy occurs ipsilateral to ICA occlusion in 20% of patients. Fundus photographs and a timed fundus fluorescein angiogram, i.e. intravenous use of fluorescein (sodium fluorescein 5%), to study the retinal microcirculation are indicated in most patients to document the severity of impaired retinal perfusion and vascular insufficiency. ECA/ICA transcranial bypass surgery may be helpful when the ECA is not significantly narrowed (Kearns et al., 1979; Edwards et al., 1980).

Ocular ischemic syndrome When the ECA is also stenotic or occluded, signs of anterior-segment ischemia appear; rubeosis of the iris, sluggish reaction of the pupil to light due to ischemia of the iris sphincter or neovascular proliferation on the iris surface, and secondary neovascular glaucoma (Mills, 1989). Ischemic pain, unrelated to glaucoma, is a prominent feature. Pain is felt as a constant ache over the orbit, upper face and temple and is aggravated when the patient is in an upright position (Edwards et al., 1980; Campo & Aaberg, 1983). Ischemic uveitis, present in 18% of eyes with the ocular ischemic syndrome, is typically unresponsive to steroid medication, and posterior synechiae can result. Spontaneous hyphema may also occur, and cataract can be a late complication. At this stage, transcranial bypass is no longer a therapeutic option.

TMB type III Type III is rare. It is due to vasoconstriction (Table 9.1). Temporary vasospasm offers a plausible explanation for TMB in migraineurs, but ocular migraine can be diagnosed only when constriction of the retinal vessels is visualized funduscopically during an attack (Bruno et al., 1990). It may be suspected when all other causes of TMB are

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excluded and examination of the eye yields normal findings. The following is a description of a type III attack in one of our patients with suspected ocular migraine: At the onset, floating bright white lines were present, descending slowly from the top of the visual field over several seconds to involve the entire field. The lines slightly shimmered, but neither pulsed nor flashed on and off. When the lines reached the bottom of the field, the pattern changed to a persistent grey-white, speckled pattern that impaired vision. The patient said this pattern resembled the background design of the Ishihara plates, after being shown the test plate 12, and also mentioned that it resembled the interference pattern on a television screen. At the time, however, believing that her vision was impaired because the eyelid was shut, the patient inspected her eyes in the mirror. No accompanying symptoms occurred – in particular, no eye or head pain. The episode cleared abruptly in seconds, and within 15 min of the onset, and was said to be like ‘a lid lifting off my vision’. Sight returned to normal. Repeated stereotypic attacks occurred twice a day for 9 d, in spite of heparin treatment. A carotid angiogram, ESR, and other investigations showed no abnormality. The patient had a family history of migraine but was not known to have migraines herself.

The clinical profiles of 11 patients with vasospastic TMB are shown in Table 9.5 (Bruno et al., 1990; Burger et al., 1991). Six cases are taken from the literature (Walsh & Hoyt, 1969; Newman et al., 1974; Kline & Kelly, 1980; Ellenberger & Epstein, 1986; Schwartz et al., 1986; Appleton et al., 1988) and 5 new cases are reported. Two patients were teenagers, and three were middle-aged (48–49 years of age). This age distribution is consistent with the previous suggestion that non-embolic transient visual symptoms are not restricted to the young and the healthy (Fisher, 1980). Eight of these patients had 1–12 brief (less than 5 minute) episodes of TMB per day. Nine of the patients had a diffuse or constricting loss of visual field. One 78-year-old woman had an episode of monocular visual loss after she was asked to bend over and stand up. The subsequent ophthalmoscopic examination showed blanching of the CRA, which lasted 3 minutes before suddenly clearing. Fundus photographs taken at the end of the attack showed dilatation of the arteries, but persistent and segmental narrowing of the veins (Burger et al., 1991). The diagnosis in that case was giant-cell arteritis, confirmed by a temporal artery biopsy. Visual loss after bending or exercising has been reported previously (Tomsak & Jergens, 1987; Imes & Hoyt, 1989).

Clinical signs Retinal artery vasospasm In other patients in whom the fundus has been observed during an attack of TMB due to vasospasm, retinal artery and venous narrowing, retinal edema, venous dilatation

and delayed fluorescein filling of retinal vessels have been noted (Burger et al., 1991; Kline & Kelly, 1980; Troost, 1976). Vasospasm initially affects the retinal arteries and then the veins and is relieved first in the arterial bed and subsequently in the venous circulation. Infarction results if retinal ischemia is severe (Wolter & Burchfield, 1971). In rare migrainous patients, vasospastic TMB is complicated by CRA occlusion (Katz, 1986), anterior ischemic optic neuropathy or retinal infarction (Tippin et al., 1989). Vasospastic TMB has also been reported in patients with giant-cell arteritis (Burger et al., 1991), periarteritis nodosa (Newman et al., 1974) and eosinophilic vasculitis (Schwartz et al., 1986).

TMB type IV Cases of TMB type IV include young people with episodic TMB resembling the visual obscurations of type I, except in respect to the duration of the attack, which frequently is too long (30–60 min) or too short (seconds only) (Table 9.1). Occasionally the visual abnormality resembles the temporary loss of contrast vision typical of type II or the photopsias and scintillations of vasospastic type III. In a number of studies (Fisher, 1959; Eadie et al., 1968; Marshall & Meadows, 1968; Carroll, 1970; Corbett, 1983;The Amaurosis Fugax Study Group, 1990) and in our own experience (Wray, 1988; The Amaurosis Fugax Study Group, 1990), no cause has been found to explain recurrent TMB in young adults. One 5-year study of 12 ‘idiopathic’ patients documented benign outcomes for these patients (Eadie et al., 1968), and many investigators regard TMB in healthy children and young adults as benign events (Appleton et al., 1988; Tomsak & Jergens, 1987; Eadie et al., 1968; Carroll, 1970; Longfellow et al., 1962). Others consider TMB in this group of patients as a possible variant of acephalgic migraine (Tomsak & Jergens, 1987; Carroll, 1970; Corbett, 1983).

Clinical signs Antiphospholipid antibodies have been discussed in an earlier section.

Acute monocular blindness Sudden monocular blindness is the major symptom of an ocular stroke causing permanent visual loss. The ocular strokes to be discussed are (i) central retinal artery (CRA) occlusion, (ii) ophthalmic artery (OA) occlusion (iii) branch retinal artery (BRA) occlusion and (iv) ischemic optic neuropathy (ION), which is the result of infarction of the optic nerve.

Table 9.5. Clinical profiles of patients with vasospastic TMB Episode Study

Patient’s age/sex

Pattern of visual

Ellenberger & Epstein (1986) Walsh & Hoyt (1969) Newman et al. (1974) Kline & Kelly (1980) Schwartz et al (1986) Appleton et al. (1988) Present study Present study Present study Present study Present study

? 17/M 48/M 48/M 49/M 19/F 59/M 59/M 65/F 78/F 78/f

? Diffuse Constricting Constricting Diffuse Miscellaneous Constricting Diffuse Diffuse Diffuse Diffuse

Notes: Classified according to the system of Bruno et al. (1990). Photographic documentation of the episode. Source: Adapted from Burger et al. (1991).

a

lossa

Duration

Frequency

Associated condition

5 min Seconds to minutes 5 min 1–2 min 20 min 5–10 min 90 s 1–2 min 15–20 min 3 min 30 s

? 1 in 3 mo 3–12 per day 5 in 5 d 10 in 4 d 1 in 6 wk 30 per day 8 in 24 hr 12 in 11 mo 5 in 4 d 15 in 5 d

? — Periarteritis nodosa Cluster headaches Eosinophilic vasculitis — — — Episodic headaches Temporal arteritis Temporal arteritis

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Central retinal artery occlusion CRA occlusion can occur at any age and is characterized by apoplectic loss of vision. Eye pain is atypical, but when present, it suggests involvement of the ophthalmic artery. TMB may precede the occlusion, and attacks of TMB may increase in frequency over 12–24 h before blindness occurs (i.e., crescendo TMB). The principal causes of CRA occlusion are (i) embolic obstruction, (ii) occlusion in situ, due to thrombosis or hemorrhage into a plaque, (iii) inflammatory arteritis (e.g. giant-cell arteritis)(Cullen, 1963), thromboangiitis obliterans (Gresser, 1932), and polyarteritis nodosa, with involvement of the choroidal and retinal arteries (Goldsmith, 1946), (iv) angiospasm, (e.g. Raynaud’s disease) (Anderson & Gray, 1937) or migraine (Katz, 1986), and (v) arterial occlusion that occurs hydrostatically, with either (a) the high intraocular pressure of glaucoma, (b) the low retinal blood flow of carotid stenosis or the aortic arch syndrome, or (c) severe hypotension. The pathogenesis of a CRA occlusion may be evident if the examination shows a retinal embolus (Table 9.3) hypertension, atrial fibrillation and/or disease of other arteries, notably the ophthalmic, temporal or ipsilateral ICA. Most CRA occlusions occur in the region of the lamina cribrosa, regardless of the cause (Hayreh, 1971). In young patients under the age of 40, retinal arterial occlusions are less likely to be caused by ipsilateral carotid artery stenosis and more likely by cardiac embolism from rheumatic valvular disease, bacterial endocarditis or cardiac myxoma (Cogan & Wray, 1975; Appen et al., 1975) (Table 9.2; Burde, 1989), or to a hypercoagulable state, or vasospasm (Greven et al., 1995). In older patients,TMB type I or II suggests an embolic cause or giant-cell arteritis. The source of the embolus may be cardiac (Zimmerman, 1965) or intra-arterial from atheromatous ulceration of the aorta, ipsilateral ICA dissection, or from the stump of a thrombosed ICA. Trauma is also an important cause. Compression of the globe may be self-inflicted in circumstances involving heavy alcohol use with or without drug consumption followed by stupor (Jayam et al., 1974). Iatrogenic CRA occlusion has been reported in patients undergoing surgery where prolonged pressure to the orbit has occurred inadvertently in association with a period of hypotension during anesthesia (Givner & Jaffe, 1950; Hollenhorst et al., 1954) or as a complication of patient positioning for spinal surgery (Wolfe et al., 1992).

Clinical signs Amaurotic pupil An amaurotic pupil (i.e. absent constriction to light on direct illumination, intact consensual light response, and

intact near response) is present when the eye is completely blind. An afferent pupil defect (i.e. impaired direct-light response) is present if some vision is preserved, even hand motion vision.

Cherry-red spot at the macula Ophthalmoscopy is not often performed within the first hour after a CRA occlusion, and retinal signs are dependent on the time that the fundus is examined. Initial signs are few (i.e. segmentation of the blood column, boxcar segmentation with slow ‘streaming’ of flow in the retinal veins, a normal optic disc and no hemorrhages or exudates). Total obstruction posterior to the laminae cribrosa should be suspected when the retinal arteries on the disc start to pulsate with gentle digital pressure on the globe, indicating a very low retinal diastolic pressure. After an hour or more, the characteristic diagnostic fundus changes are seen. The ischemic retina takes on a white ground-glass appearance, and the normal red colour of the choroid showing through at the fovea accentuates the central cherry-red spot at the macula. Within days of the acute event, the retinal opacification, the cherry-red spot and the nerve fibre layer striations disappear, and optic atrophy of the optic disc of the primary type develops.

Intraocular pressure When the signs of CRA occlusion are secondary to an ophthalmic artery occlusion, the intraocular pressure in the eye is low.

Retinal emboli TMB as a premonitory symptom of CRA occlusion suggests an embolic cause or giant-cell arteritis. The cause is verified when a retinal embolus is visible in a branch artery. However, even in patients with embolic CRA occlusion, an embolus may not be seen initially, because emboli frequently impact behind the inelastic lamina cribrosa. For patients under the age of 40 years the sources of retinal emboli include cardiac disease (particularly rheumatic valvular disease, bacterial endocarditis, and cardiac myxoma) (Cogan & Wray, 1975) and ipsilateral ICA dissection. Over the age of 40 years the sources of emboli include cardiac disease, atheroma of the aorta and diffuse atheromatous embolism, ipsilateral ICA atheromatous disease, and ICA dissection. Calcific emboli can be dislodged by surgical manipulation of calcified heart valves. A cardiac source of embolism accounts for 29 of 103 (28%) patients with CRA occlusion in one series (Wilson et al., 1979). The reported incidences of ICA disease in CRA occlusion have varied, Wilson et al. (1979) found that 12 of 18 patients had carotid

Visual symptoms (eye)

irregularities or stenosis seen on arteriography. Merchut et al. (1988) grouped CRA and BRA occlusions together and noted that 29 of 34 (85%) patients had abnormal ICAs seen on arteriography, of which 12 had occlusion or severe stenosis, and 17 had plaques, ulcers or stenosis of less than 60%. The presence of cholesterol emboli in the fundus increases the likelihood of significant ipsilateral ICA disease. Chawluk et al. (1988) studied patients with CRA occlusion using B-mode ultrasound and integrated pulsed-Doppler ultrasound. Among 17 patients studied, 24% had ICA occlusion, and 36% had occlusive or ulcerated lesions.

Cardiovascular signs The most important additional signs to look for are absence of a temporal artery pulse and/or tenderness over the vessel on palpation. An occlusion of the CRA may be the only symptom of giant-cell arteritis in 5–10% of elderly patients, and the risk for blindness in the fellow eye is extremely high. Physical examination of the vascular system must also focus on angular, brow, and cheek pulses, (Fisher, 1970; Caplan, 1973) auscultation of the head, neck, and eye, and examination for hypertension, atrial fibrillation, and/or peripheral vascular disease.

Ophthalmic artery occlusion Ophthalmic artery (OA) occlusion mimics a CRA occlusion clinically and produces opacification of the infarcted retina. The typical cherry-red spot may be absent or extremely indistinct due to co-existing infarction of the choroid (Burde et al., 1982; Brown et al., 1986; Duker & Brown, 1988). Visual loss is typically severe and permanent with most eyes having no light perception or only bare perception of light (Rafuse et al., 1997). There may be associated eye pain and pupillary dilation from concurrent ischemia to the ciliary ganglion or iris sphincter. The eye may show hypotonous. The retinal vessels are markedly constricted and the optic disc may or may not be swollen. Over time, most patients develop a characteristic fundus appearance characterized by optic atrophy, arterial attenuation and diffuse pigmentary changes. The pathogenesis of OA occlusion is much the same as those of ICA occlusion. The artery may be occluded by a thrombus originating in the artery itself, by a thrombus propagated from an occluded ICA, by an embolus from a distant site, most often the heart, (Rafuse et al., 1997), the common carotid artery or the extracranial portion of the ICA or by an extrinsic process that compresses the vessel (e.g. tumour or aneurysm).

Antiphospholipid antibodies CRA occlusion has been shown to be associated with elevated levels of antiphospholipid antibodies (APA) (Asherson et al., 1989; Englert et al., 1984; Glueck et al., 1985; Shalev et al., 1985; Jonas et al., 1986; The Antiphospholipid Antibodies in Stroke Study Group, 1993). Englert et al.’s case (Englert et al., 1984) was a 36-year-old woman with Degos’ disease, myelopathy, CRA occlusion and bilateral choroidal infarcts. Her partial thromboplastin time (PTT) was normal, but an elevated aCL was demonstrated by radioimmunoassay. Glueck, et al. described a 42-year-old woman with circulating LA and retinal artery thrombosis. Another example is a patient with a CRA occlusion and Sneddon’s disease, a disorder characterized by livedo reticularis, neurologic abnormalities including stroke and labile hypertension. In this case, tests showed a slightly prolonged PTT and elevated aCL (Jonas et al., 1986). Among patients with SLE, persistently positive tests for APA especially LA and aCL characterize a subset of patients with thrombotic tendency (Asherson et al., 1989). In particular, the presence of aCL has been found to be an independent risk factor for ischemic stroke especially among young patients (The Antiphospholipid Antibodies in Stroke Study Group, 1993), and an association between TMB and elevated levels of APA, especially aCL, has been suggested (for review, see Donders et al., 1998).

Clinical signs When only the proximal portion of the OA is occluded, there may be no ocular symptoms or signs because collateral channels from branches of the ECA usually provide sufficient blood to the orbital and ocular vessels normally supplied by the OA. When the occlusion is more extensive, severe visual loss and typical ophthalmoscopic signs are present. Rarely in isolated cases of OA occlusion visual acuity recovers from light perception to 20/30 or from counting fingers at 6 inches to 20/50 with the restoration of retinal and choroidal blood flow (Duker & Brown, 1988). Fundus fluorescein angiography is diagnostic in CRA occlusion or OA occlusion provided that a timed transit is obtained within hours or days of the event, a wide angle lens is used on the fundus camera and the optic disk is photographed in the centre of the picture. In isolated acute CRA occlusion, the choroidal circulation of the eye is normal and there is delay in filling of the branches of the CRA. In OA occlusion there is delayed filling in both the choroidal and the CRA circulation.

Treatment A CRA or OA occlusion requires emergency treatment. The therapeutic goal is to restore circulation to the retina as soon as possible, by abruptly lowering the intraocular

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Table 9.6. Clinical summary of thrombolytic therapy Patient No./ Age (y)/Sexa

Pretreatment visual acuity

Time to therapyb

Thrombolytic agent

Adjunctive therapy

Post-treatment visual acuity

1/56/M 2/74/M 3/61/M

Hand motion Light perception Hand motion

5.5 4.0 2.75

Anistreplase Tissue plasminogen activator Tissue plasminogen activator

Intravenous heparin sodium aspirin 20/60+ Intravenous heparin, warfarin sodium 20/400 Intravenous heparin, warfarin 20/25

Notes: a M, Male; F, female. b Time to initiation of thrombolytic therapy in hours. Source: Data from Mames et al. (1995).

pressure. In eyes that have been blind for less than 24 hours (Stone et al., 1977), the following steps should be taken: place the patient flat, give digital massage to the globe, have the patient rebreath into a paper bag, and give diamox (500 mg) intravenously or mannitol intravenously to reduce intraocular pressure. The patient should then be referred to an ophthalmologist for anterior paracentesis, a procedure that will reduce the intraocular pressure even lower. Prednisone (80 mg daily) is needed immediately for patients suspected of having giant-cell arteritis or in cases of CRA occlusion complicating migraine. Heparin is useful in the treatment of impending CRA occlusion when a patient presents with crescendo TMB or an occlusion of the ophthalmic artery. Unfortunately, however, both medical and surgical approaches have been disappointing (Brown, 1994; Mames et al., for the CRAO Study Group; Mangat, 1995; Atebara et al., 1995). Other medical therapies proposed include sublingual nitroglycerine, oral warfarin sodium, (coumadin) calcium channel blocking agents, vasodilators, antiplatelet agents, intravenous heparin, urokinase or tissue plasminogen activator (TPA), and intra-arterial urokinase or TPA. Schmidt et al. (1992) reported 5 of 14 patients with CRA occlusion had improvement of visual acuity, visual field, or both, following intra-arterial urokinase infusion. In a further five patients, no improvement occurred with this therapy. In these five patients, visual acuity was impaired preoperatively for more than 7 hours. Systemic thrombolytic agents were used in a pilot study involving three consecutive patients with acute CRA occlusion (Mames et al., for the CRAO Study Group, 1995). The selection of the thrombolytic agent, TPA or anistreplase, was at the discretion of the internist. Patients were treated in the hospital emergency department with cardiovascular monitoring. Intravenous heparin sodium and oral coumadin were given as adjuvant therapy after thrombolytic infusion. All three patients noted subjective improvement

within several hours of treatment. The best achieved visual acuity was recorded within 96 h of therapy (Table 9.6; Mames et al., for the CRAO Study Group, 1995). Nevertheless, while the results of these pilot studies are encouraging, it is imperative that the efficacy of thrombolytic therapy in CRA and OA occlusion be tested in a prospective, randomized, clinical trial against conventional modes of therapy.

Differential diagnosis The differential diagnosis of acute persistent blindness includes a number of ophthalmic emergencies; ION (both anterior and posterior ION) due to infarction of the optic nerve, acute central retinal vein occlusion (which is characterized by hemorrhagic retinopathy), detachment of the macula, acute closed-angle glaucoma, sudden vitreous or macula hemorrhage, and factitious visual loss. In the latter condition, the eye claimed to be blind will have a normal brisk pupil response to direct light.

Branch retinal artery occlusion BRA occlusion is due to impaction of an embolus at an arterial bifurcation in a branch of the CRA. The presenting symptom is sudden and permanent loss of a sector of the visual field, with retinal infarction corresponding to the vascular territory of the arteriole blocked. TMB may precede CRA or a BRA occlusion (Table 9.7).

Clinical signs Retinal embolus The ophthalmoscopic appearance of a retinal embolus can provide specific information about the embolic material and its possible source. The commonest emboli are cholesterol, platelet-fibrin and calcific emboli. Less common varieties include tumor emboli from cardiac myxoma and metastatic neoplasms, fat emboli from fractures of long

Visual symptoms (eye)

Table 9.7. Preceding vascular events in occlusion of branch and central retinal arteriesa

Table 9.8. Clinical findings in occlusion of branch and central retinal arteriesa

Retinal artery occlusion

Preceding event

Branchb n⫽68

Centralc n⫽35

Amaurosis fugax Transient cerebral ischemia Stroke Ischemic heart disease Claudication

12 (18) 8 (12) 2 (3) 15 (22) 5 (7)

4 (11) 1 (3) 4 (11) 2 (6) 2 (6)

Notes: a Based on data in Wilson et al., 1979. b 43 male, 25 female patients; mean age 55. c 23 male, 12 female patients; mean age 36. Numbers in parentheses are percentages.

bones, septic emboli, talc emboli and miscellaneous emboli of deposited drugs, silicone or air that occur after injections in the region of the face or scalp (Table 9.2). Cholesterol emboli (Hollenhorst plaques) were discussed in an earlier section. Bruno et al, suggest that these emboli are a marker of systemic arteriosclerosis associated with hypertension, cigarette smoking and bilateral carotid artery disease, and that asymptomatic retinal cholesterol embolism is an independent risk factor for stroke (Bruno et al., 1992, 1995) (Table 9.8). Calcific emboli are characteristically matt-white, nonscintillating, and somewhat wider than the blood column. They may be dislodged by the surgical manipulation of calcified heart valves at the time of valvulotomy or occur spontaneously from rheumatic valvular vegetations and from other disorders of the heart and great vessels that predispose to the formation of calcium (D’Cruz et al., 1977; Guthrie & Fairgrieve, 1963; DiBono & Warlow, 1979; Stefensson et al., 1985). Unlike Hollenhorst plaques and platelet-fibrin emboli calcific emboli tend to lodge permanently in the blood vessels occasionally resulting in the development of collateral vessels forming shunts around the embolic blockage. Patients with these emboli are at significant risk for stroke, heart attack and death (Howard & Ross Russell, 1987). Circulating microemboli that pass through the retina, so called migrant pale emboli, are composed of platelets and associated with thrombocytosis. Emboli that occur after myocardial infarction fall into the category of fibrin plugs. They are especially frequent in patients who have neurological complications after open heart surgery. From the description of Fisher (1959) and

Retinal artery occlusion

Clinical finding

Branch n⫽68

Central n⫽35

Hypertension Carotid bruits Visible retinal embolus Cardiac valvular abnormality

17 (25) 12 (18) 46 (68) 23 (34)

20 (57) 5 (14) 4 (11) 6 (17)

Note: a Based on data in Wilson et al. (1979). Numbers in brackets are percentages.

Ross Russell (1961) platelet-fibrin emboli appear as dull, grey–white plugs that resemble a long white worm slowly passing through the retinal arteries. They become temporarily impacted at bifurcations and then pass on gradually fragmenting and resolve over time.

Treatment The treatment of a patient with BRA occlusion is similar to that for an acute CRA occlusion. Anterior paracentesis and/or medication to lower intraocular pressure are the most common therapeutic approaches. Anticoagulation is advisable in patients with atrial fibrillation. In many instances, however, the BRA occlusion results from lipid, cholesterol or calcific emboli which fail to resolve with anticoagulant therapy. Nevertheless, a patient with a visible retinal embolus, even though having no visual loss, should be investigated urgently because of the risk of a stroke. Arrhythmias are the most common cause of cardiac-related embolic retinal vascular disease, and they may be the most common cause of all emboli to the brain. Abnormal heart rhythms most likely to produce emboli are chronic atrial fibrillation (AF), paroxysmal AF and the abnormal rhythms that develop in patients with disturbances of cardiac conduction. In patients with calcific retinal emboli, the investigative evaluation should focus on the heart valves (Table 9.8). Two-dimensional echocardiogram studies may reveal thickened, calcified valve leaflets or a tight calcified annulus. Transesophageal echocardiography may facilitate cardiac evaluation of patients with suboptimal transthoracic scans such as patients with obesity or emphysema. Compared with transthoracic echocardiography, a transesophageal study is more sensitive for detection of prosthetic valve dysfunction, atrial thrombus and

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other masses, atrial septal defects (especially of the sinus venous type), aortic plaques, aortic dissection and infective endocarditis. To exclude ipsilateral ICA disease as a source of emboli, urgent investigations should include oculopneumoplethysmography, carotid ultrasonography and Doppler studies, and neuroimaging screening with an MRA of the head and neck and/or CT angiography of the neck and brain and when indicated, stroke profile MRI studies including diffusion and perfusion weighted images.

Ischemic optic neuropathy Ischemic optic neuropathy (ION) is the term used for all presumed ischemic causes of optic neuropathy. ION is the commonest cause of sudden persistent visual loss in patients past middle age. There is no significant sex predilection and the average age ranges from 57–65 years with a peak range of 60–69 years (Boghen & Glaser, 1975; The Ischemic Optic Neuropathy Decompression Trial Research Group, 1995). The ophthalmic artery provides the blood supply to the optic nerve by means of two or more posterior ciliary arteries (PCAs), and hypoperfusion of these end arteries is thought to be the commonest mechanism causing infarction of the optic nerve (Onda et al., 1995). The critical region of damage is the prelamina, lamina and immediate retrolaminal portion of the optic nerve. Lessell (1999) suggests that the border zone that determines the site of infarction is between the lamina cribrosa and the centripetal branches of the pial vessels in the retrobulbar segment. Structural and mechanical factors may also render the optic disc more susceptible to vascular damage. The best documented anatomical correlation is with cup–disc ratios. The discs at risk (Burde, 1993) have small cup–disc ratios (Beck et al., 1984) and cross sectional areas (Mansour et al., 1988) which imply that the optic nerve fibres are crowded within the scleral canal. This crowding is probably a contributing factor in the pathogenesis of non-arteritic anterior ischemic optic neuropathy (Doro & Lessell, 1985). The term anterior ischemic optic neuropathy (AION) indicates visible optic disc pathology, swelling of the disc and peripapillary hemorrhages. The term posterior ischemic optic neuropathy (PION) indicates infarction of the retrobulbar or intracranial optic nerve and no disk swelling or other funduscopic signs acutely. AION is far more common than PION, accounting for 90% of cases of ION. The three principal causes of ION are (i) non-arteritic (median age 56 year) occlusive disease, in which the risk factors are diabetes in young patients and hypertension in

older patients, (ii) an arteritic variety due to giant-cell arteritis (median age 74 years), and (iii) embolic obstruction of the PCAs as a complication of cardiac surgery or ipsilateral ICA disease. The clinical characteristics, natural history and management of patients with non-arteritic and arteritic ION are, however, significantly different.

Non-arteritic ischemic optic neuropathy Non-arteritic ION may occur in patients with carotid artery disease as the initial manifestation of an ICA occlusion (Mori et al., 1983). Rarely patients with ICA disease have the simultaneous occurrence of cerebral infarction and ipsilateral ION. This combination is called the opticocerebral syndrome (Bogousslavsky et al., 1987). Three patients described by Bogousslavsky (1987) had AION and cerebral signs. Other patients reported had ICA occlusion or severe stenosis, acute hemispheric stroke and simultaneous monocular blindness caused by PION in the ipsilateral eye (Newman, 1998). Carotid dissections that include the intracranial ICA can also cause this syndrome. No patient gained improvement in vision in the affected eye and all patients developed optic atrophy. The pathogenesis of AION in the setting of disease of the ipsilateral ICA is multifactorial. In some cases, optic nerve infarction results from reduced blood flow secondary to severe ICA stenosis or occlusion, poor collateral blood supply, and local changes in the pial circulation of the optic nerve. In other cases, AION or PION may be due to embolism to the PCAs, pial vessels, or both (Lieberman et al., 1978; Portnoy et al., 1989). In the majority of patients, however, non-arteritic AION is a disease of small vessels and not directly related to carotid artery disease but, rather reflects shared risk factors, such as hypertension, diabetes mellitus or cigarette smoking (Rizzo & Lessell, 1991; Repka et al., 1983; Guyer et al., 1985; Moro et al., 1989; Chung et al., 1994). Non-arteritic AION patients with both hypertension and diabetes have an increased risk of cerebrovascular disease. Furthermore, patients with hypertension, diabetes, cardiovascular disease and cerebrovascular disease have an increased prevalence of subcortical and periventricular white matter lesions on brain MRI, a marker for small vessel (microangiopathic) cerebrovascular disease. Perioperative non-arteritic AION is also the result of multiple factors and occurs in patients who have had various surgical interventions. The two most important factors in conjunction with surgery are hypotension and blood loss (for review, see Williams et al., 1995). Severe anemia alone probably does not cause AION, but even a short episode of hypotension in an already anemic patient may predispose to AION-induced visual loss (Brown et al.,

Visual symptoms (eye)

1994). Williams et al. (1995) emphasized that, because a low hematocrit in the presence of other factors may predispose more surgical patients to visual loss, the current low-level of hemoglobin at which blood transfusion is deemed to be indicated (7–8 g/dl) may not be as safe as previously supposed, especially in patients who become hypotensive. Absolute threshold values for transfusions should, therefore, not be followed when there exists a high risk of operative or postoperative hypovolemia and hypotension. Loss of vision after severe spontaneous hemorrhage is usually bilateral, but it may be unilateral or affect both eyes asymmetrically. The severity ranges from mild or transient blurred vision in one eye to irreversible total blindness in both eyes. The visual loss often occurs at the time of hemorrhage but it may, in rare instances, be delayed beyond 10 days. Most patients are debilitated and over 40 yrs of age. Many have intercurrent systemic illnesses but they do not necessarily have risk factors for arteriosclerosis. Visual loss typically follows repeated hemorrhage although visual loss can occur after a single massive bleed (Kamei et al., 1990). Ophthalmoscopy shows the characteristic changes of AION but the discs can appear normal initially when infarction of the optic nerve(s) occurs in the midorbital portion (Johnson et al., 1987). About 50% of patients who lose vision after an acute bleed have some recovery of vision, but only 10 to 15% recover completely.

Arteritic ischemic optic neuropathy In giant-cell arteritic AION or PION constitutional symptoms of arteritis may be absent and acute visual loss is the herald symptom. The stroke to the optic nerve is caused by inflammatory occlusion of the short posterior ciliary arteries, a process that may also produce sectorial areas of choroidal ischemia. In some cases of arteritic AION constitutional symptoms of giant-cell arteritis are insidious. They include fatigue, anorexia, weight loss and alterations in mental status including depression and memory impairment. Severe persistent headache is present in 40 to 90% of patients with or without tenderness over the temporal arteries or scalp, intermittent claudication of the masseters, and facial swelling. Systemic manifestations include respiratory tract symptoms, myocardial infarction and gastrointerstinal complications due to generalized vasculitis. Acute visual loss is usually unilateral but it may be bilateral and simultaneous, or the second eye may be affected days, weeks or even months after the first eye, particularly if high-dose steroid treatment is not begun immediately or is stopped while the disease is still active. Episodes of TMB may precede persistent visual loss caused by AION, and

occasionally TMB may be induced by exertion or changes in posture. The appearance of the ischemic optic disk in giant-cell arteritis resembles that of nonarteritic AION. Giant-cell arteritis causing PION must always be suspected in acutely blind, elderly patients with a normal appearing optic disc in the affected eye. Infarction of the nerve in these cases may even affect the intracranial portion and in most cases of giant-cell arteritis-associated PION, histopathologic examination reveals inflammatory occlusion of the ophthalmic artery as well as the short posterior ciliary arteries (Hayreh & Podhajsky, 1979). The Westergren method is used to determine the ESR in suspected giant-cell associated INO. The patient age divided by 2 determines the maximum normal ESR for men and the age plus 10 divided by 2 determines the maximum normal ESR for women. It is noteworthy, however, that between 8 and 22% of patients with clinical symptoms consistent with giant-cell arteritis and a positive temporal artery biopsy have an ESR within the normal range.

Clinical signs Visual acuity The loss of vision in ION is usually painless; although some patients (approximately 8%) report discomfort behind and around the eye at the time of visual loss (Rizzo & Lessell, 1991). Visual acuity (VA) data for the initial loss of vision indicates that 31–52% of patients have a VA better than 20/64, whereas 35–54% have a VA worse than 20/200 (Boghen & Glaser, 1975; The Ischemic Neuropathy Decompression Trial Research Group, 1995; Rizzo & Lessell, 1991; Repka et al., 1983). Rarely, visual acuity may drop progressively over 1–7 days. Almost all patients with ION have diminished color perception in the affected eye and a field defect. Altitudinal field defects comprise the most common pattern of visual field loss in 58–80% of cases (Boghen & Glaser, 1975; Rizzo & Lessell, 1991; Repka et al., 1983; Hayreh & Podhajsky, 1979; Ellenberger et al., 1973). Progression of visual loss occurs in some cases (approximately 28%) from 1 to 30 days from onset, with the majority stabilizing in less than 9 days. The best natural history data of ION comes from the IONDT group. The most unexpected and encouraging finding was the high rate of spontaneous improvement of visual acuity observed in the untreated randomized group. At the 6-month evaluation, approximately 43% of patients in this group improved by three or more lines from their baseline evaluation.

Afferent pupil The affected eye has an afferent pupil defect.

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Ischemic papillitis In acute AION, the optic disc is swollen with the swelling being either diffuse (75% patients) or focal (25% patients (The Ischemic Optic Neuropathy Decompression Trial Research Group, 1995)). When diffuse, the swollen disc may simulate the appearance of papilledema. The disc may be pale or hyperemic. Single or multiple flame-shaped hemorrhages are present in the peripapillary region and a few soft exudates. As disc edema begins to subside, optic atrophy develops, and in arteritic AION the optic disc may show increasing cupping mimicking that of glaucoma. AION may also be associated with other signs of ocular ischemia, choroidal infarction, retinal emboli, or iris or anterior chamber neovascularization. AION with iris neovascularization, in the absence of diabetic retinopathy, is a marker for ipsilateral carotid artery occlusive disease. Some patients may develop disc swelling from nonarteritic AION before they have visual symptoms and lose vision up to 2 weeks later. In acute PION due to ischemia of the retrobulbar or intracranial optic nerve (both arteritic and non-arteritic) (Bogden & Glaser, 1975; Hayreh, 1981; Cullen & Duvall, 1983; Isayama et al., 1983; Rizzo & Lessell, 1987; Sawle & Sarkies, 1987; Shimo-Oku & Miyazaki, 1984; Perlman et al., 1994), the optic disc has initially a normal appearance funduscopically. Optic disc pallor subsequently develops, usually within 4–6 weeks. PION is therefore distinguishable from AION by signs of optic nerve dysfunction unassociated with acute ischemic optic disc swelling or retinal hemorrhages.

Treatment High-dosage steroids Temporal artery biopsy must be obtained to confirm the diagnosis of giant-cell arteritis, but it should not delay the initiation of high-dosage steroid treatment. 1 gm/per day of intravenous methylprednisolone or prednisone in a dose of 1–1.5 mg/kg/day should be given until the ESR drops. Prednisone should then be slowly tapered to maintenance doses of 10–15 mg alternate days for 6 months to 1 year. Temporal artery biopsies are likely to remain positive even after 14 days of steroid therapy. In non-arteritic AION or PION high-dosage steroids are of questionable value, and only used by a few physicians when the second eye becomes involved. Numerous other drugs have, however, been tried including anticoagulants, retrobulbar injection of vasodilators, intravenous noradrenaline, and thrombolytic agents. Johnson et al. (1996) reported a combination of levodopa and carbidopa (sinemet) prompted visual recovery in patients with nonarteritic AION of more than 6 months duration. These results have not been confirmed.

Hemodilution has also been described as improving visual function in longstanding non-arteritic AION (Haas et al., 1994) and in AION of less than two weeks duration when combined with pentoxifylline (Wolf et al., 1993). Further verification of this potentially beneficial treatment is required.

Decompression of the optic nerve Direct surgical intervention by optic nerve sheath decompression has been shown in a multicenter randomized trial, to be ineffective and possibly visually harmful (The Ischemic Optic Neuropathy Decompression Trial Research Group, 1995). This surgical procedure is no longer used in the US.

Conclusions In this chapter, the visual symptom of temporary loss of vision in one eye has been reviewed. It has to be emphasized, however, that only a meticulous history of the attack and the duration of the visual episode can permit the physician to classify TMB into one of four types. Immediate investigation of the patient must follow, because TMB is a warning of an impending stroke of the brain or eye. Physical examination of the vascular system and the eye must focus on the following: ii(i) Blood pressure, at rest and standing, heart rate, and cardiac rhythm. i(ii) Palpation of the temporal arteries, and ABC pulses of the face. (iii) Auscultation of the heart, neck, head, and eyes. (iv) A dilated funduscopic examination. i(v) Immediate blood tests: complete blood count, prothrombin time, partial thromboplastin time, platelet count, Westergren ESR, and fibrinogen level. Subsequent studies should include tests for fasting blood sugar, cholesterol, triglyceride and blood lipids, and, when indicated, antiphospholipid antibodies, protein C, protein S and antithrombin III. Non-invasive investigations should utilize: ii(i) A battery of non-invasive carotid artery tests to give information about the presence of a hemodynamic lesion (Doppler ultrasound and oculoplethysmography), and image the artery (B-mode ultrasound). B-mode scans and Doppler colour-flow imaging studies of the carotid origin can help define the nature of plaques, the presence of ulceration, and the dynamics of flow. i(ii) Magnetic resonance angiography (MRA) of the head

Visual symptoms (eye)

and neck and/or CT angiogram of the neck and brain and, when indicated, stroke profile MRI studies including diffusion and perfusion-weighted images. (iii) Cardiac evaluation: two-dimensional transthoracic and transesophageal echocardiogram and Holter monitor. Invasive investigations required in selected patients are: ii(i) A temporal artery biopsy i(ii) A carotid arteriogram if MRA and ultrasound are inadequate to show the lesion and the patient is a candidate for carotid endarterectomy or if an ICA dissection is detected or suspected on a head and neck MRI/MRA. (iii) A timed fundus fluorescein angiogram. We have also discussed in this chapter the clinical presentation and emergency management of ocular strokes due to CRA, OA, or BRA occlusion or due to ischemic optic neuropathy, AION or PION. Because of our growing population of elderly citizens, we must remain alert to symptoms that may herald stroke and direct our attention to reducing and eliminating the identified risk factors.

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10

Vestibular syndromes and vertigo Marianne Dieterich and Thomas Brandt Ludwig Maximilians University, Munich, Germany

Introduction Vertigo is an unpleasant distortion of static gravitational orientation or an erroneous perception of motion of either the sufferer or the environment. It is not a well-defined disease entity, but rather the outcome of many pathological processes causing a mismatch between the visual, vestibular, and somatosensory systems, all of which subserve both static and dynamic spatial orientation. Physiological and clinical vestibular vertigo syndromes are commonly characterized by a combination of phenomena involving perceptual, ocular motor, postural and vegetative manifestations: vertigo, nystagmus, ataxia and nausea (Brandt & Daroff, 1980). The vertigo itself results from a disturbance of cortical spatial orientation, while nystagmus and ocular deviations are secondary to a direction-specific imbalance in the vestibulo-ocular reflex. Postural imbalance and vestibular ataxia are caused by inappropriate or abnormal inactivation of vestibulospinal pathways. Unpleasant vegetative effects, such as nausea and vomiting, are related to clinical activation of the medullary vomiting centre (Brandt, 1991b). Most of the central vestibular syndromes and some of the peripheral vestibular syndromes may have a vascular etiology (Baloh, 1992; Brandt & Dieterich, 1994a). Ischemia can be responsible for a wide range of vestibular syndromes; most of the central and some of the peripheral vestibular syndromes are listed in Table 10.1. Ischemia will sometimes produce a combination of central and peripheral symptoms, as in anterior inferior cerebellar artery (AICA) infarctions, the territory of which encompasses the labyrinth, pontine, and cerebellar structures (Atkinson, 1949). In migraine and in vertebrobasilar ischemia, it may not be possible to determine whether the vertigo is a symptom of a peripheral or a central vestibu-

lar syndrome. The course and prognosis of the vertigo syndrome are variable. The vertigo itself, which is usually abrupt in onset and frequently transient in ischemic attacks, must be differentiated from the episodic vertigo commonly seen in other conditions, such as Menière’s disease, basilar migraine, vestibular paroxysmia, and vestibular epilepsy. The extreme manifestation of central vascular vertigo is either sudden, incapacitating, severe rotational vertigo or bilateral loss of vestibular function, with intolerance of head motion causing oscillopsia and postural imbalance. Some infarctions cause specific syndromes, such as ipsiversive lateropulsion and ocular tilt reaction (OTR) in lateral medullary infarctions (Wallenberg's syndrome) or contraversive OTR in paramedian thalamic infarctions extending to the interstitial nucleus of Cajal (INC). Hemorrhages, inflammations, or acute space-occupying lesions are, however, other principal causes of the same syndromes. Often, vascular abnormalities are considered only in patients who present with positional nystagmus/vertigo without any corresponding lesions indicated by CT or MRI investigations (Brandt, 1991b). Two interesting vascular pathomechanisms should be mentioned, even though their diagnosis could not be confirmed in the patients affected: neurovascular cross-compression (disabling positional vertigo (Moller et al., 1986) or vestibular paroxysmia (Brandt & Dieterich, 1994a)) and the hyperviscosity syndrome, with venous obstruction of labyrinthine blood flow (Andrews et al., 1988). Decompression sickness is a rare vascular vertigo syndrome (Head, 1984), and labyrinthine hemorrhage can cause perilymph fistulas or delayed endolymphatic hydrops. In the case of perilymph fistulas, provocation of symptoms by various situations helps to establish the diagnosis (Brandt, 1991b).

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Table 10.1. Mechanisms and sites of vascular vertigo Mechanism

Syndrome

Site

Migraine

Basilar migraine

Pontomedullary brainstem

Benign paroxysmal vertigo of childhood Benign recurrent vertigo

Vestibulocerebellum Labyrinth

Vestibular or hearing loss (infarction of AICA or internal auditory artery)

Labyrinth, vestibular nerve

Pseudo ‘vestibular neuritis’ (lacunar or PICA infarct)

Vestibular nerve root or vestibular nuclei

Ocular tilt reaction

Pontomesencephalic (contraversive) Pontomedullary (ipsiversive) Vermis (contraversive)

Lateropulsion (Wallenberg’s syndrome)

Dorsolateral medulla (ipsiversive)

Downbeat nystagmus/vertigo

Commissure of vestibular nuclei or bilateral flocculus

Upbeat nystagmus/vertigo

Pontomesencephalic junction or caudal medulla

Positional downbeat nystagmus

Nodulus?

Thalamic astasia

Posterolateral thalamus

Central positional vertigo

Vestibular nuclei, vestibulocerebellar loop

Neurovascular cross-compression

Vestibular paroxysmia (disabling positional vertigo)

Vestibular nerve

Vascular polyneuropathy

Diabetic vestibular loss

Vestibular nerve, labyrinth?

Hyperviscosity with venous obstruction

Hyperviscosity syndrome with episodic vertigo

Labyrinth

Miscellaneous (secondary signs)

Decompression sickness labyrinthine hemorrhage, perilymph fistula or hydrops, vascular fistula signs

Labyrinth

Infarction/hemorrhage

Strokes affecting peripheral and central vestibular disorders Episodic vertigo and ocular motor abnormalities are common early symptoms of reduced vertebrobasilar blood flow due to the steep pressure gradient from the aorta to the terminal pontine arteries. These long, circumferential arteries provide a highly vulnerable blood supply for the vestibular nuclei (Williams & Wilson, 1962). Symptoms are induced when the head is maximally rotated and/or extended while standing, and they terminate abruptly when the head is returned to a normal upright position. However, they may not only indicate a transient vertebrobasilar ischemia caused by a functional compression of the

vertebral artery (particularly in elderly patients with atheromas, cervical spondylosis or osteophytes that narrow the transverse foramina) but also a neurovascular cross-compression of the eighth nerve. Therefore, we shall restrict the presentation of vascular vestibular syndromes to clearly defined strokes of the labyrinth, the vertebrobasilar and the middle cerebral artery territories. These vascular territories supply the peripheral and central vestibular pathways and integration centers. Vestibular pathways run from the eighth nerve and the vestibular nuclei along the medial longitudinal fasciculus to the oculomotor nuclei and the supranuclear integration centers in the rostral midbrain. From there, they reach several vestibular cortex areas through thalamic projec-

Vestibular syndromes and vertigo

Table 10.2. Classification of some central vestibular syndromes of the brainstem tegmentum according to the three major planes of action of the VOR: yaw, pitch, and rolla Disorders of the VOR in the horizontal (yaw) plane

Horizontal nystagmus: pseudovestibular neuritis (partial AICA/ PICA infarctions; multiple sclerosis plaques)

Disorders of the VOR in the sagittal (pitch) plane

Vertical nystagmus: downbeat nystagmus, upbeat nystagmus

Disorders of the VOR in the frontal (roll) plane

OTR and its components

Note: a Syndromes in roll can include complete OTR or its single components, such as skew deviation, ocular torsion, lateral falls, and SVV tilt. Syndromes in yaw include spontaneous horizontal nystagmus, rotational vertigo, postural imbalance, and lateral falls. Syndromes in pitch include upbeat/downbeat nystagmus, pitch tilt of subjective vertical and fore–aft postural instability.

tions. Most central ischemic vertigo syndromes are secondary to paramedian or lateral tegmental infratentorial lesions. Supratentorial vestibular syndromes are less frequent, and only those of the thalamus and the vestibular cortex are relevant to the present discussion. In the following, we attempt to correlate circumscribed unilateral infarctions of the brainstem, the thalamus, and the temporoparietal cortex with the clinical syndromes and the particular vestibular structures involved. Such a scheme of extended vestibular pathways, with different lesion sites causing characteristic vestibular syndromes, is required for topographic diagnosis. Each pathway that mediates the vestibulo-ocular reflex (VOR) in one of the three major planes of action must run a separate course in order to become individually lesioned (Leigh & Brandt, 1993; Brandt & Dieterich, 1995). A classification has been proposed for central vestibular disorders of the brainstem (Tables 10.2 and 10.3) attributing vestibular syndromes such as downbeat nystagmus, pseudo-vestibular neuritis and OTR to lesional tone imbalances in one of the three major planes of action of the VOR (Brandt, 1991b; Brandt & Dieterich, 1995). This hypothetical classification is based on clinical experience and on animal studies showing that a given syndrome can be elicited by distinct and separate lesions of the pathways at different brainstem levels. Pathways that mediate the VOR in one of the three major planes run separate courses and can become lesioned individually or in combination. Our approach to vestibular syndromes in stroke is based on defined vascular territo-

ries and evaluation of lesional malfunction relative to the perceptional, ocular motor, and postural effects in yaw, pitch, and roll planes.

Anterior inferior cerebellar artery and internal auditory artery The anterior inferior cerebellar artery (AICA) supplies not only the anterolateral pons, the middle cerebellar peduncle and the flocculus but also the inner ear (Atkinson, 1949; Kim et al., 1990). Thus, ischemia of the peripheral labyrinthine receptors, the eighth nerve, the vestibular nucleus, or the vestibulocerebellum could cause vertigo. The clinical spectrum includes brainstem and cerebellar signs and symptoms (Amarenco, 1991), but labyrinthine infarction was also demonstrated histopathologically (Hinojosa & Kohut, 1990). Oas and Baloh (1992) described two patients with clinical features of AICA infarctions who had recurrent attacks of rotatory vertigo. The vertigo initially appeared as an isolated symptom months prior to the brain infarction and recurred at the time of the infarction, accompanied by unilateral hearing loss, tinnitus, facial numbness, and hemiataxia. Unilateral auditory and vestibular dysfunction on the affected side were documented by auditometry and caloric irrigation. Therefore, those authors reasoned that the vertigo attacks preceding the infarction resulted from transient ischemia of the inner ear or the vestibular nerve (Fig. 10.1). Nevertheless, a definitive clinical classification is not possible in individual patients with a labyrinthine, vestibular nerve, or vestibular nucleus lesion responsible for vertigo in AICA infarctions. In patients with both vertigo and hearing loss (which supports labyrinthine or eighthnerve ischemia), a combination of peripheral and central vestibular dysfunction is possible. However, recurrent isolated episodes of vertigo without neurological signs and symptoms are an uncommon manifestation of vertebrobasilar ischemia (Estol et al., 1996). Furthermore, it has been repeatedly demonstrated that small demyelinating plaques (Brandt et al., 1986) or lacunar infarctions (Hopf, 1987) at the root entry zone and/or the vestibular nuclei can mimic vestibular neuritis, in that rotational vertigo and spontaneous nystagmus are combined with abolition of caloric responses on the affected side. These manifestations are combined with masseter paresis, as evidenced by the masseter reflex (Hopf, 1987) or by ocular motor abnormalities such as those of saccadic pursuit (Brandt et al., 1986). If transient ischemic attacks with vertigo, nystagmus, and ataxia occur secondary to vertebral artery compression

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Table 10.3. Vestibular dysfunction in VOR planes

Locus

Roll (unilateral lesions)

Yaw (unilateral lesions)

Pitch (bilateral lesions)

Cortex

Contraversive SVV tilt

?

?

Thalamus Posterolateral Paramedian

Ipsiversive/contraversive SVV tilt Contraversive OTR

? ?

? ?

Mesencephalon

Contraversive OTR

Pons

Ipsiversive/contraversive OTR

Pontomedullary

Ipsiversive OTR

Medulla

Ipsiversive OTR

Upbeat nystagmus

Pseudo-vestibular neuritis

Upbeat nystagmus

Flocculus bilateral Vermis/dentate nucleus

Downbeat nystagmus

Downbeat nystagmus Contraversive OTR

with rotational head motion, this is termed as a syndrome of rotational vertebral artery occlusion (Yang et al., 1985). Vertebral arteries are susceptible to mechanical compression with head rotation, because of muscular and tendinous insertions, osteophytes, and other degenerative changes of cervical spondylosis. When the artery passes through the foramina transversaria of the cervical vertebrae at C2–C6, the patients may be symptomatic on right or left head rotation (Kuether et al., 1997). The correct site of occlusion of the vertebral artery can be demonstrated only by dynamic angiography during stepwise head rotation. It most often occurs at C2 level.

Vertebral artery and posterior inferior cerebellar artery A typical syndrome of occlusions of the vertebral artery or the arteries arising from the vertebral artery (to course through the lateral medullary fossa to supply the lateral medulla), and in rare cases affecting the posterior inferior cerebellar artery (PICA) or posterior spinal arteries, is Wallenberg's syndrome, a lateral medullary infarction that mostly includes the medial, and sometimes the superior, vestibular nucleus. A unilateral ischemic lesion of the medial (or superior) vestibular nucleus usually results in a vestibular tone imbalance in the roll plane. Signs and symptoms of vestibular dysfunction in the roll plane can be detected on the basis of deviations from normal function. In the normal position in the roll plane, the graviceptive input from the otoliths and semicircular canals aligns the subjective visual vertical (SVV) with gravitational vertical and adjusts axes of the eyes and the head

? Pseudo-vestibular neuritis

?

horizontally. A vestibular tone imbalance due to a lesion should result in a syndrome consisting of a perceptual tilt (SVV tilt), head and body tilt, vertical misalignment of the visual axes (skew deviation), and ocular torsion. The OTR comprises several of these features: the synkinesis of head tilt, skew deviation, and ocular torsion (Westheimer & Blair, 1975) associated with a perceived tilt of the vertical (Brandt & Dieterich, 1987). There is convincing evidence that all these signs and symptoms reflect vestibular dysfunction in the roll plane. They may be found in combination or as single components, with varying sensitivity at all brainstem levels. A systematic study of 111 patients with acute unilateral brainstem infarctions revealed that pathological tilts of SVV (94%) and ocular torsion (83%) were the most sensitive signs. Skew deviation was found in one-third of these patients, and a complete OTR in one-fifth. Clinical evaluation of vestibular function in roll therefore includes psychophysical adjustments of SVV, determination of the vertical divergence of the visual axes by use of prisms, and determination of ocular torsion by means of fundus photographs; for methods, see Dieterich and Brandt (1993a). All of the 36 patients with Wallenberg's syndrome we tested exhibited significant tilt of the internal representation of the gravity vector, as indicated by deviation of SVV ipsiversive to the lesion. About one-third of these patients had a complete OTR (Fig. 10.2) (Dieterich & Brandt, 1992); these were the same patients exhibiting the most severe body lateropulsion. OTR in Wallenberg's syndrome is ipsiversive (i.e. ipsilateral ear and eye undermost). Quantitative measures of postural sway by means of posturography demonstrate an increased diagonal sway from right forward to left backward for right-sided lesions and

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(a )

(c )

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(b)

Fig. 10.1. Three zones of AICA supply. Zone 1 is supplied by the recurrent penetrating arteries (RPA) of AICA, zone 2 by the internal auditory artery, and zone 3 by the terminal cerebellar branches of AICA. (a) Rostral pons at the level of the facial and abducens nuclei (vertical dotted line represents the mid-sagittal line). Zone 1A and zone 1B represent the arterial supply to areas supplied by a premeatal and postmeatal RPA. Often a single RPA, originating from the premeatal or postmeatal AICA, supplies all of zone 1. The cross-hatched area represents the root entry zone of the facial and vestibulocochlear nerves. (b) Zone 2 represents the arterial supply to the inner ear (modified from Schuknecht, 1974). (c) Cerebellum, anterior view. Zone 3 represents the arterial supply from the terminal cerebellar branches of AICA. (ASC ⫽ anterior semicircular canal, AVA ⫽ anterior vestibular artery, CCA ⫽ common cochlear artery, HSC ⫽ horizontal semicircular canal, IAA ⫽ internal auditory artery, MCP ⫽ middle cerebellar peduncle, PSC ⫽ posterior semicircular canal, V ⫽ spinal trigeminal tract and nucleus, VI ⫽ abducens nucleus, VII ⫽ facial nerve, VIII ⫽ vestibulocochlear nerve). Adapted from Oas & Baloh, 1992, with permission.

from left forward to right backward for left-sided lesions. Body lateropulsion is correlated with SVV tilt (i.e. the more pronounced the lateropulsion, the greater the SVV tilt). We hypothesize that deviation of SVV, lateropulsion of the body, skew deviation, and ocular torsion of the eyes are the perceptual, postural, and ocular motor consequences of a common lesion of the vestibular pathways that subserve VOR in the roll plane (Dieterich & Brandt, 1993a, c). Most patients have disconjugate ocular torsion, usually of the eye ipsilateral to the brainstem lesion, which suggests involvement of posterior semicircular canal pathways (Fig. 10.2). If anterior and posterior semicircular canal pathways are affected, the OTR in Wallenberg's syndrome is manifest as binocular ocular torsion. In rare cases with monocular incyclotropia of the uppermost eye, involvement of anterior semicircular canal pathways can only be assumed. Where is the most probable site of the lesion of graviceptive pathways in roll in Wallenberg's syndrome? Projection of ischemic lesions demonstrated by CT and MRI onto the appropriate sections of a stereotaxic brainstem atlas (Olszewski & Baxter, 1982) allows identification of the medial (and/or superior ?) vestibular nucleus as the critical vestibular structure (Fig. 10.3). The medial and/or superior vestibular nuclei were included in the ischemic areas in the cases of Wallenberg's syndrome with OTR. The blood supply to these structures originates from the PICA, from

the branches of the vertebral artery, or from the branches of the AICA. Our studies on the OTR, lateropulsion, and SVV tilts were concerned with static effects of vestibular dysfunction in roll, which persist for days to weeks, during which time they gradually and spontaneously subside. Additional dynamic signs and symptoms consisting of lateral rotational vertigo and torsional nystagmus occur in the acute stage of infarction (Morrow & Sharpe, 1988; Lopez et al., 1992). Fast phases of rotational nystagmus are contraversive, whereas the slow phases correspond in direction to the static deviation. The combination of static and dynamic effects is not surprising if one considers the functional corroboration of vertical semicircular canals and otolithic input based on neuronal convergence at the second-order vestibular nuclei neurons (Angelaki et al., 1993). We have left out, to a great degree, consideration of the cerebellum in this vestibular chapter. It seems likely that ischemic lesions of the vestibular vermis structures (uvula, nodulus), the flocculus, the fastigial nucleus, the dentate nucleus, and the the middle cerebellar peduncle can cause vertigo or related vestibular syndromes, whereas this is unlikely in infarctions of the cerebellar hemispheres only. From animal experiments it is known that the cerebellar nodulus and uvula receive visual and vestibular (otolith and semicircular canal) information via the climbing fiber

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(a )

(b)

Fig. 10.2. (a) Patient with a right lateral medullary infarction (Wallenberg’s syndrome) presenting with a OTR to the right. OTR consists of ipsiversive head tilt of 20° (bottom), skew deviation of 4° (middle) and ocular torsion of the undermost eye of about 20° (excyclotropia; counterclockwise from the viewpoint of the observer; top), whereas the uppermost eye shows a normal position in roll (5° excyclotropia). (b) Hypothetical explanation of OTR due to lesions of the vertical semicircular canal pathways. Schematic drawing of the three-neuron vestibuloocular reflex arc between the posterior semicircular canal and the extraocular eye muscles. An excitatory ascending pathway is linked from the posterior semicircular canal to the ipsilateral superior oblique and the contralateral inferior rectus muscle; an inhibitory ascending pathway is linked to the ipsilateral inferior oblique and the contralateral superior rectus muscles (Graf et al., 1983; Graf & Ezure, 1986). A lesion of these pathways causes excyclotropia of the ipsilateral and hypertropia of the contralateral eye (AC, PC, HC ⫽ anterior, posterior and horizontal semicircular canal; MLF ⫽ medial longitudinal fasciculus; OS and OI ⫽ superior oblique and inferior oblique muscles; RS and RI ⫽ superior and inferior rectus muscles; III ⫽ oculomotor nucleus; IV ⫽ trochlear nucleus; VIII ⫽ vestibular nucleus).

pathways, especially from the dorso-medial cell column and the beta nucleus of the inferior olive and the vestibular nuclei (Takeda & Maekava, 1989; Barmack, 1996). In two patients with acute cerebellar lesions (one hemorrhage, one PICA infarction) – in which an affection of the nodulus was discussed – contraversive partial OTR with ocular torsion of both eyes but without head tilt was reported (Mossman & Halmagyi, 1997). We saw more than 15 patients with complete or incomplete OTR presenting with acute PICA infarctions or hemorrhages of the vermis, particularly of the uvula (Fig. 10.4), or with cavernoma of the

dentate nucleus and the middle cerebellar peduncle (Fig. 10.5). In contrast to lesions of the pontomedullary brainstem, which always induce an ipsiversive tilt of the signs in the roll plane, tilts in vermal and dentate nucleus lesions were all contraversive due to a loss of cerebellar inhibition of otolith neurons in the ipsilateral vestibular nucleus (resulting in an increase of tonic resting activity). Moreover, it was reported that experimental nodulus lesions in cats cause positional downbeat nystagmus (Fernandez et al., 1960; Fernandez & Fredrickson, 1964), which was less convincingly confirmed in patients by

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Kattah et al. (1984) and Sakata et al. (1987). Furthermore, it is our own experience that severe central positional vertigo is usually induced by lesions located dorsolateral to the fourth ventricle. The differentiation between brainstem and cerebellar lesions is impossible in most clinical cases of infarctions, because the major infratentorial arteries supply both brainstem and cerebellum.

Basilar artery and paramedian pontine and mesencephalic arteries

Fig. 10.3. Unilateral pontomedullary infarctions causing vestibular dysfunction in the roll plane presenting either as ocular tilt reaction or its components; head tilt, skew deviation, ocular torsion and tilt of subjective visual vertical. Schematic representation of two transverse sections (XVI, XXIV) of the stereotaxic brainstem atlas of Olszewski and Baxter (1982) with typical lesioned areas in four patients with unilateral medullary and pontine infarctions as taken from MRI scans and projected onto the appropriate transverse section. In the lateral medullary infarctions (Wallenberg’s syndrome; bottom) – within the territories of the vertebral arteries, the PICA or posterior spinal arteries – vestibular dysfunction with ipsiversive tilts results from involvement of the medial vestibular nucleus (VIIIm). In pontine infarctions, vestibular dysfunction in roll results either from involvement of the superior vestibular nucleus (VIIIs) or the MLF within the territories of the AICA or paramedian arteries from the basilar artery, respectively (top). Occlusions of the AICA may involve the superior vestibular nucleus and cause ipsiversive OTR, whereas MLF lesions cause contraversive OTR.

Unilateral ischemic lesions of the pontomesencephalic vestibular pathways, which run along the MLF, predominantly cause vestibular tone imbalance in the roll plane, which is demonstrated by the frequency of SVV tilts, skew torsion, and OTR in affected patients. The direction of the perceptual, ocular motor, and head tilt may be helpful for determining the level as well as the side of the brainstem lesion. All tilts are ipsiversive (i.e. ipsilateral eye undermost) with caudal pontomedullary lesions and contraversive (contralateral eye undermost) with rostral pontomesencephalic lesions. These directionspecific findings of vestibular dysfunction in roll can be explained by unilateral lesions of a ‘graviceptive’ pathway that crosses the midline at the upper pontine level (Figs. 10.6; 10.7; Brandt & Dieterich, 1993, 1994b), running along the MLF and reaching the INC, a well-known integration center for eye-head coordination in roll (Anderson, 1981; Fukushima, 1987). If the level of the brainstem damage is known from the clinical syndrome, an SVV tilt, OTR, or skew torsion will indicate the side more severely affected. If, on the other hand, the side of the damage is clear from the clinical syndrome, the level of the brainstem damage will be indicated by the tilt direction of these signs (i.e. caudal with ipsiversive tilt and rostral with contraversive tilt). Thus, the diagnostic topographic value of a static vestibular dysfunction in roll is similar to that of cranial nerve lesions, but is more sensitive. One of the most striking findings, previously unreported, was that all of our patients with skew deviations also had ocular torsion (OT) toward the undermost eye. The direction-specific coincidence of skew and OT is helpful for clinical differentiation between supranuclear (mesencephalic) skew and nuclear or fascicular oculomotor or trochlear palsies. A unilateral oculomotor or trochlear palsy causes OT of the paretic eye only, whereas mesencephalic skew can be identified most often by a binocular, conjugated OT. Even in patients with bilateral third- or fourth-nerve palsies, a skew can be differentiated by the

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Fig. 10.4. Unilateral cerebellar lesion causing contraversive OTR. Schematic representation of two transverse sections (106, 107) of the human brainstem and cerebellum atlas of Duvernoy (1995) with typical lesioned areas (right) as taken from MRI scans (left) and projected onto the appropriate section. The patient (SK49M) presented with incomplete OTR to the right (body and head tilt to the right of 15°, minimal alternating skew deviation of 1° at lateral gaze, bilateral ocular torsion with excyclotropia of 0° of the left and 12° of the right eye, tilts of SVV of 10–16° to the right) which resulted from a small medial PICA infarction affecting the left tonsil (22) and uvula (16) of the cerebellar vermis. (12 ⫽ facial nerve, 13 ⫽ vestibulocochlear nerve, 16 ⫽ uvula, 19 ⫽ inferior semilunar lobule, 20 ⫽ superior semilunar lobule, 21 ⫽ flocculus, 22 ⫽ tonsil, 23 ⫽ pyramid of vermis, 24 ⫽ tuber of vermis).

Fig. 10.5. Schematic representation of a transverse section (112) of the human brainstem and cerebellum atlas of Duvernoy (1995) with a lesioned area of a patient (LA25F) presenting with a ‘pseudo-vestibular neuritis’ and incomplete contraversive OTR to the right (strong rotational vertigo, spontaneous horizontal–rotatory nystagmus to the left of 38°/s, caloric hyporesponsiveness of the right ear, ocular torsion with an incyclotropia of 2.5° of the left eye and excyclotropia of 13° of the right eye, tilts of SVV of 8° to the right). The syndrome was caused by a small hemorrhage in a cavernoma lateral to the fourth ventricle affecting the left middle cerebellar peduncle (10) and the left dentate nucleus (18). (10 ⫽ middle cerebellar peduncle, 11 ⫽ trigeminal nerve, 14 ⫽ simple lobule, 15 ⫽ declive, 16 ⫽ uvula, 17 ⫽ nodulus, 18 ⫽ dentate nucleus, 19 ⫽ inferior semilunar lobule, 20 ⫽ superior semilunar lobule).

(d )

(d )

(c )

(c )

(b) (b)

(a ) (a )

Fig. 10.6. Typical lesioned areas in four patients with unilateral pontomedullary infarctions showing ocular skew torsion sign to the left (left eye undermost). Ischemic areas were taken from MRI scans and projected onto the appropriate transverse sections of the stereotaxic brainstem atlas of Olszewski and Baxter (1982). In medullary lesions involving the medial and superior vestibular nuclei (VIIIm in sections XIV and XVI, VIIIs in section XXIV) skew torsion sign was ipsiversive (a), (b), (c). Ocular skew torsion sign was contraversive if the medial longitudinal fasciculus (Flom in section XXIV) was involved with the vestibular nuclei spared (d); same section as in (c). Opposite directions of ocular skew torsion sign in same-sided lesions at pontine level (c), (d) indicate crossing of graviceptive pathways mediating eye position in roll plane. In (c) ipsilateral pathways were affected; in (d) contralateral pathways were affected.

Fig. 10.7. Ischemic areas in four patients with right pontine and mesencephalic infarctions causing contraversive ocular skew torsion sign to the left. Lesions indicated either involvement of the medial longitudinal fasciculus (F lo m in sections XXVIII, XXX, XXXVI) at different pontomesencephalic levels (a), (b), (c) or the rostral midbrain tegmentum including the interstitial nucleus of Cajal (iC in section XXXVIII) (d). The latter seems to be the most rostral brainstem structure to elicit the ocular skew torsion sign.

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Downbeat nystagmus in the primary gaze position, especially in lateral gaze, is often accompanied by oscillopsia and postural instability, with increased fore–aft body sway. Upbeat nystagmus – the directional pendant of downbeat nystagmus – can be induced by two separate and distinct brainstem lesions, located either at the pontomedullary junction near the perihypoglossal nucleus or at the pontomesencephalic junction (Fisher et al., 1983). Transitions between upbeat and downbeat nystagmus are possible, depending on the level of brainstem ischemia. Pontomesencephalic brainstem lesions, whether unilateral or bilateral, may therefore cause a vestibular tone imbalance in roll or pitch, but not in yaw (Brandt & Dieterich, 1995). A tone imbalance in the yaw plane indicates pontomedullary lesions near the root entry zone of the eighth nerve or the vestibular nuclei. Fig. 10.8. Schematic drawing of circumscribed brainstem lesions causing vestibular syndromes in the three major planes of action of the VOR, yaw, pitch and roll. Vestibular syndromes in yaw plane are caused only by unilateral ponto-medullary lesions including the vestibular nuclei (VN) and the root entry zone of the vestibular nerve. Vestibular syndromes in pitch plane are either caused by midline lesions of the ponto-medullary or ponto-mesencephalic junction or bilateral dysfunction of the flocculus. Vestibular syndromes in roll are caused by unilateral graviceptive pathway lesions, e.g. the medial longitudinal fasciculus (MLF), from the vestibular nuclei to the interstitial nucleus of Cajal (INC). These pathways cross at pontine level.

direction of OT, which is disconjugate in the peripheral nerve palsies (i.e. bilaterally excyclotropic in bilateral trochlear palsies and bilaterally incyclotropic in bilateral oculomotor palsies). Therefore, determination of skew and OT (by fundus photographs) can be recommended for routine neuro-ophthalmological investigation in suspected brainstem dysfunction (Dieterich & Brandt, 1993b). Furthermore, a reliable differentiation between dysfunction in the roll plane in central brainstem lesions and OT and SVV tilt caused by extraocular eye muscle paresis is possible, because the latter are not associated with SVV tilts under binocular viewing conditions. A vestibular tone imbalance in the pitch plane typically results from bilateral paramedian lesions (Table 10.3, Fig 10.8) of the vestibular pathways (e.g. basilar artery thrombosis). A tone imbalance in the pitch plane can cause a downbeating nystagmus if the lesion is located at the level of the vestibular nuclei, affecting commissural fibers at the floor of the fourth ventricle (Baloh & Spooner, 1981).

Thalamic infarctions Unilateral thalamic infarctions may cause contralateral falling, astasia (Masdeu & Gorelick, 1988), or contralateral OTR (Halmagyi et al., 1990). SVV, OT, skew deviation, and lateral head tilt were measured in 35 patients with acute thalamic infarctions (14 paramedian, 17 posterolateral, 4 polar) (Dieterich & Brandt, 1993c) and in five patients with mesodiencephalic hemorrhages, in order to determine their differential tonic effects on vestibular function in the roll plane. Eight of 14 patients with paramedian infarctions had complete OTR with contraversive head tilt, skew deviation, OT, and SVV tilt. Projections of infarcted areas in CT scans or MR images onto appropriate transverse sections of cytoarchitectonic atlases clearly showed that OTR was due to concurrent ischemia of the rostral midbrain tegmentum, including the INC (Fig. 10.9). The blood supplies to the two regions may have a common origin in the paramedian thalamic and paramedian mesencephalic arteries. Thus, OTR is not thalamic, and INC (and the rostral interstitial nucleus of the MLF) is obviously the most rostral brainstem structure that mediates eye–head coordination in roll. Eleven of 17 patients with posterolateral infarctions exhibited moderate but significant SVV tilts, which could either be ipsiversive or contraversive (Fig. 10.10). In those cases, thalamic subnuclei (Vim, Vce, Dc) were involved, which are known from animal experiments to convey vestibular and somatosensory information to the cortex. Infarctions were more ventromedial in the remaining cases without SVV tilts. Polar infarctions did not affect vestibular

Vestibular syndromes and vertigo

function in roll. Even if thalamic infarction includes the vestibular subnuclei, it does not result in ocular motor signs such as spontaneous nystagmus or skew deviation.

Cortical infarctions

Fig. 10.9. Collective presentation of lesions taken from MRIs and projected onto the appropriate transverse thalamic and midbrain sections of a stereotaxic thalamus atlas (Van Buren & Borke 1972); 9.7 mm and 0.9 mm above the anterior commissure–posterior commissure [AC–PC] line) (top and middle) and midbrain atlas (Olszewski & Baxter, 1982; plate XXXVIII) (bottom). The AC–PC interval is 25 mm. In the seven ischemic patients with complete contraversive OTR, the infarction involves the rostral midbrain tegmentum in the region of the interstitial nucleus of Cajal (iC ⫽ INC) and the adjacent area of the rostral interstitial nucleus of the MLF. (EW ⫽ Edinger–Westphal nucleus; IIIpr ⫽ nucleus oculomotorius principalis; Icp ⫽ nucleus intracapsularis).

Several distinct and separate areas of the parietal and temporal cortex have been identified in animal studies as receiving vestibular afferents, such as area 2v at the tip of the intraparietal sulcus (Fredrickson et al., 1966; Schwarz & Fredrickson, 1971; Büttner & Buettner, 1978), area 3aV (neck, trunk, and vestibular region of area 3a) in the central sulcus (Ödkvist et al., 1974), the parieto-insular vestibular cortex (PIVC) at the posterior end of the insula (Grüsser et al., 1982, 1990a,b), and area 7 in the inferior parietal lobule (Faugier-Grimaud and Ventre, 1989) (Fig. 10.11). Our knowledge about vestibular cortex function in humans is less precise, derived mainly from stimulation experiments reported anecdotally in the older literature. It is not always possible to extrapolate from monkey species to human cortex, as Anderson and Gnadt (1989) have demonstrated for Brodmann’s area 7 in rhesus monkey and humans. Area 2v corresponds best to the vestibular cortex, as described by Foerster in 1936. PIVC corresponds best to a region from which Penfield and Jasper (1954) were able to induce vestibular sensations by electrical stimulation with a depth electrode within the Sylvian fissure, medial to the primary acoustic cortex. This region was found to be activated during caloric vestibular stimulation as assessed by focal increase of cortical blood flow (Friberg et al., 1985; Bottini et al., 1994), and during electrical vestibular stimulation, as assessed by functional MRI (Bucher et al., 1998). What is the clinical significance of the vestibular cortex? Vertigo has long been recognized as a manifestation of epileptic seizures (Foerster, 1936; Penfield & Jasper, 1954; Schneider et al., 1968). This vertigo is secondary to unilateral focal discharges from the vestibular cortex, whereas functional deficits of this area, such as those caused by infarctions of the medial cerebral artery, do not typically manifest with vertigo. In our study, a reliable test was required for determination of the functional deficit of vestibular cortex lesions in patients with acute ischemic stroke. SVV was chosen as one mode of testing vestibular function, because it provides a sensitive and direction-specific means for measurement of unilateral peripheral (Friedmann, 1971; Curthoys et al., 1991) and central (Dieterich & Brandt, 1993a) vestibular dysfunctions. We systematically investigated 71 patients with infarctions of the middle, posterior and anterior cerebral artery

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Fig. 10.10. Collective presentation of infarcted areas taken from MRI scans and projected onto the appropriate transverse sections (9.7 mm and 0.9 mm above AC–PC line) of the atlas of Duvernoy (1991) in nine patients with posterolateral infarctions that caused either ipsiversive (i; n ⫽ 6) or contraversive (c; n ⫽ 3) tilts of SVV. The overlap area involves the thalamic nuclei Vce, Dc, Vim, Vci, and less frequently Voe, independent of the direction of induced tilt of internal representation of gravity. Black areas represent six overlaps; hatched areas represent five overlaps on the left and three on the right side.

Fig. 10.11. Schematic representation of a monkey brain with the experimentally established areas that receive vestibular input: area 2v at the anterior part of the intraparietal sulcus, area 3aV in the central sulcus, post arcuate area 6, multisensory area 7 a, b at the inferior parietal cortex, and area PIVC, the parieto-insular vestibular cortex, deep in the posterior end of the insula. The visual temporal sylvian area (VTS) at the posterior end of PIVC receives mainly visual input and only minor vestibular input. (c ⫽ central sulcus, ip ⫽ intraparietal sulcus, 1 ⫽ lateral Sylvian sulcus, ts ⫽ superior temporal sulcus).

Vestibular syndromes and vertigo

Fig. 10.12. Collective presentation of infarcted areas taken from MRI scans and projected onto the appropriate transverse sections of the atlas of Duvernoy (1991) in seven patients with clearly demarcated infarctions of the MCA which caused significant contraversive tilts of perceived vertical. Overlapping areas of infarctions (seven of seven in black) in the section ⫹16 mm above the AC–PC line are centred at the posterior part of the insula, involving the long insular gyrus with the adjacent short insular gyrus, the transverse temporal gyrus and the superior temporal gyrus. This area could represent the human homologue of the PIVC in monkey (see Fig. 10.10).

for their visual ability to adjust a test line to vertical. Skew deviation and OT were also evaluated in order to complete perceptual and ocular motor testing of vestibular function in the roll plane. Infarcted areas shown on CT and MRI were projected onto corresponding transverse sections of the atlas of Duvernoy (1991) to identify the critical structures involved. The aim of the study was to address the following three questions: Are there (one or several) distinct supratentorial areas, a lesion of which causes a directionspecific tilt of the SVV? Is it possible to relate these areas to known vestibular structures as identified in animal experiments? Are pathological tilts of the SVV in supratentorial lesions associated with skew deviation and ocular torsion toward the perceptual tilt? Seventy-one patients with unilateral supratentorial infarctions were evaluated with respect to static vestibular function in the roll plane, including determinations of the SVV, skew deviation, and OT. Infarctions in the territories of the posterior and anterior cerebral arteries did not affect static vestibular function in roll. Twenty-three of 52 patients with infarctions in the middle cerebral artery (MCA) territory showed significant, mostly contraversive, pathological SVV tilts. The overlapping area of these infarctions centered on the posterior insula, probably homologous to the PIVC in the monkey (Fig. 10.12). Although

electrophysiological and cytoarchitectonic data in animals demonstrate several multisensory areas, rather than a single primary vestibular cortex, the PIVC seems to represent the integration centre of the multisensory vestibular cortex areas within the parietal lobe. This is in agreement with recent functional imaging data in humans during caloric and galvanic vestibular stimulation (Bucher et al., 1998; Dieterich & Brandt, 2000).

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Grüsser, O.J., Pause, M. & Schreiter, U. (1990a). Localization and responses of neurons in the parieto-insular vestibular cortex of awake monkeys (Macaca fascicularis). Journal of Physiology, 430, 537–57. Grüsser, O.J., Pause, M. & Schreiter, U. (1990b). Vestibular neurons in the parieto-insular cortex of monkeys (Macaca fascicularis): visual and neck receptor responses. Journal of Physiology, 430, 559–83. Halmagyi, G.M., Brandt, Th. Dieterich, M., Curthoys, I.S., Stark, R.J. & Hoyt, W.F. (1990). Tonic contraversive ocular tilt reaction due to unilateral meso-diencephalic lesion. Neurology, 40, 1503–9. Head, P.W. (1984). Vertigo and barotrauma. In Vertigo, ed. M.R. Dix & J.D. Hood, pp. 199–215. Chichester, New York: John Wiley. Hinojosa, R. & Kohut, R.I. (1990). Clinical diagnosis of anterior inferior cerebellar thrombosis: autopsy and temporal bone histopathology study. Annals of Otology Rhinology and Laryngology, 90, 261–71. Hopf, H.C. (1987). Vertigo and masseter paresis. A new local brainstem syndrome probably of vascular origin. Journal of Neurology, 235, 42–5. Kattah, J.C., Kolsky, M.P. & Luessenhof, A.J. (1984). Positional vertigo and cerebellar vermis. Neurology, 34, 527–9. Kim, H.N., Kim, Y.H., Park, I.Y., Kim, G.R. & Chung, I.H. (1990). Variability of the surgical anatomy of the neurovascular complex of the cerebellopontine angle. Annals of Otology Rhinology and Laryngology, 90, 288–96. Kuether, T.A., Nesbit, G.M., Clark, W.M. & Barnwell, S.L. (1997). Rotational vertebral artery occlusion: a mechanism of vertebrobasilar insufficiency. Neurosurgery, 41, 427–33. Leigh, R.J. & Brandt, Th. (1993). A reevaluation of the vestibuloocular reflex: new ideas of its purpose, properties, neural substrate, and disorders. Neurology, 43, 1288–95. Lopez, L., Bronstein, A.M., Gresty, M.A., Rudge, P., Du Boulay, E.P.G.H. (1992). Torsional nystagmus: A neuro-otological and MRI study of 35 cases. Brain, 115, 1107–24. Masdeu, J.C. & Gorelick, P.B. (1988). Thalamic astasia: inability to stand after unilateral thalamic lesions. Annals of Neurology, 23, 596–603. Moller, M.B., Moller, A.R., Jannetta, P.J. & Sekhar, L. (1986). Diagnosis and surgical treatment of disabling positional vertigo. Journal of Neurosurgery, 64, 21–8.

Morrow, M.J. & Sharpe, J.A. (1988). Torsional nystagmus in the lateral medullary syndrome. Annals of Neurology, 24, 390–8. Mossman, S. & Halmagyi, G.M. (1997). Partial ocular tilt reaction due to unilateral cerebellar lesion. Neurology, 49, 51–4. Oas, J.G. & Baloh, R.W. (1992). Vertigo and the anterior inferior cerebellar artery syndrome. Neurology, 42, 2274–9. Ödkvist, L.M., Schwarz, D.W.F., Fredrickson, J.M. & Hassler, R. (1974). Projection of the vestibular nerve to the area 3a arm field in the squirrel monkey (Saimiri sciureus). Experimental Brain Research, 21, 97–105. Olszewski, I. & Baxter, D. (1982). Cytoarchitecture of the Human Brain-stem. Basel, Switzerland: Karger. Penfield, W. & Jasper, H. (1954). Epilepsy and the Functional Anatomy of the Human Brain. Boston: Little Brown. Sakata, E., Ohtsu, K., Shimura, H. & Sakai, S. (1987). Positional nystagmus of benign paroxysmal type (BPPV) due to cerebellar vermis lesions. Pseudo-BPPV. Auris-Nasus-Larynx (Tokyo), 14, 17–21. Schneider, R.C., Calhoun, H.D. & Crosby, E.C. (1968). Vertigo and rotational movement in cortical and subcortical lesions. Journal of Neurological Science, 6, 493–516. Schuknecht, H.F. (1974). Pathology of the Ear. Cambridge: Harvard University Press Schwarz, D.W.F. & Fredrickson, J.M. (1971). Rhesus monkey vestibular cortex: a bimodal primary projection field. Science, 172, 280–1. Takeda, T. & Maekava, K. (1989). Olivary branching projections to the flocculus, nodulus, and uvula in rabbit. II. Retrograde double labeling with fluorescent dyes. Experimental Brain Research, 76, 232–3. Van Buren, J.M. & Borke, R.C. (1972). Variations and Connections of the Human Thalamus. 2.Variations of the Human Diencephalon. Berlin: Springer. Westheimer, G. & Blair, S.M. (1975). The ocular tilt reaction – a brain-stem oculomotor routine. Investigative Ophthalmology, 14, 833–9. Williams, D. & Wilson, T.G. (1962). The diagnosis of the major and minor syndromes of basilar insufficiency. Brain, 85, 741–77. Yang, P.J., Latack, J.T., Gabrielson, T.O., Knake, J.E., Gebarsk, S.S. & Chandler, W.F. (1985). Rotational vertebral artery occlusion at C1–C2. American Journal of Neuroradiology, 6, 98–100.

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Auditory disorders in stroke Robert A. Levine1 and Rudolf Häusler2 1 2

Massachusetts Eye and Ear Infirmary, Harvard University, Boston, USA Department of ENT, Head and Neck Surgery, Inselspital, University of Bern, Switzerland

The auditory and vestibular systems share the same end organ and cranial nerve, yet vestibular signs and symptoms are common with stroke, whereas hearing disturbances are much less frequent. Several reasons would appear to account for this striking dissimilarity. One is that the auditory pathway is less ubiquitous than the vestibular pathways (Nieuwenhuys et al., 1988). The likelihood that a stroke involves the auditory pathway is, therefore, less on this basis alone. A second difference, to our knowledge not previously reported, is that the auditory pathway is often spared by the most common strokes. This is because major parts of the auditory pathways, such as the cochlear nucleus, the inferior colliculus and the medial geniculate body have multiple sources of blood supply (Duvernoy, 1978). A third well-recognized factor is the redundancy of the central auditory system and its strong bilateral representation above the level of the cochlear nuclei (Webster, 1992). Consequently, rostral to the cochlear nuclei, gross deficits in hearing, such as measured by standard pure-tone audiometry and speech discrimination only occur if lesions are bilateral. Furthermore, widespread bilateral lesions of the auditory system typically render the patient unable to respond or are incompatible with life. In contrast, language disorders are more frequent because language is usually unilaterally represented in the cortex. Certainly, cerebral stroke often includes the auditory system, resulting in various types of auditory disorders, but most hemispheral lesions produce subtle hearing dysfunctions that can only be detected with sophisticated psychoacoustical and electrophysiological testing. The purpose of this chapter is to provide an overview of the auditory system and its blood supply and to review how auditory processing can be affected by stroke. Psychoacoustic and electrophysiological test procedures for identifying lesions in the central auditory system are

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described. The literature of hearing disorders due to stroke is reviewed and illustrative cases are presented.

The auditory system and its blood supply Fig. 11.1 is a schematic representation of the afferent central auditory system. Sound passes through the external and middle ear to reach the inner ear, where sensory transduction occurs. The inner ear performs a frequency decomposition of the auditory signal so that the auditory nerve fibres innervating the inner hair cells are frequency selective. Type I auditory nerve fibres, which comprise 95% of all nerve fibres, are excited by inner hair cells. At low or moderate stimulus levels, the approximately 32 000 auditory nerve fibres are tonotopically organized within the cochlear nerve, and this tonotopic organization is a fundamental organizational property throughout the classically described auditory neurological pathway. Those from the base of the cochlea are preferentially responsive to highfrequency components of a sound. The further away a nerve fibre is from the base of the cochlea, the lower the frequency of preferential sensitivity (‘best frequency’). Nerve fibres or cell bodies with similar best frequencies are adjacent, and a systematic distribution of best frequencies is found within any nucleus or fibre tract as well as the auditory cortex. The internal auditory artery is the exclusive arterial supply to the inner ear (Axelsson, 1974; Kim et al., 1990), and in 80% of people, is a branch of the anterior inferior cerebellar artery (AICA). It sometimes emerges directly from the basilar artery, and in about 2–3% of cases it is a branch of the posterior inferior cerebellar artery (PICA). In the internal auditory canal, the auditory nerve also receives collaterals from arteries supplying the dura mater and petrous bone. In the cerebellopontine angle and in the root entry zone, a network of anastamosing vessels

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2 1

3

6 4 8

7 5

10 9 11 12 14 13 15

16 17 18 19

22

20

21 23

24

Fig. 11.1. Schematic depiction of the ascending central auditory system. 1. Planum temporale. 2. Transverse temporal gyrus. 3. Auditory radiations. 4, 5, 6. Medial geniculate body; dorsal, ventral, and medial divisions, respectively. 7. Brachium of inferior colliculus. 8. Superior colliculus. 9. Inferior colliculus, lateral zone. 10. Commissure of the inferior colliculus. 11. Central nucleus of inferior colliculus. 12, 13. Nuclei of lateral lemniscus, dorsal and ventral, respectively. 14. Commissure of Probst. 15. Lateral lemniscus. 16, 17, 18, 19. Superior olivary complex with periolivary, medial, lateral, and trapezoid body nuclei respectively. 20. Trapezoid body. 21. Auditory nerve. 22, 23. Cochlear nuclei, ventral and dorsal, respectively. (From Nieuwenhuys et al., 1988, with permission © Springer–Verlag.)

from the AICA, PICA, and vertebral arteries (e.g. the inferior lateral pontine artery and lateral medullary artery) provide the nerve’s blood supply (Kim et al., 1990; Mazzoni, 1972). The auditory nerve enters the lateral brainstem at the pontomedullary junction. Every type I nerve fibre terminates by splitting into two branches, one for each of the two divisions of the cochlear nucleus: the dorsal cochlear nucleus located dorsolaterally to the restiform body and the ventral cochlear nucleus located ventrolateral to the restiform body. The outputs from the dorsal cochlear nucleus project through the dorsal acoustic stria to the contralateral inferior colliculus; whereas, the ventral cochlear nucleus has multiple projections via the intermediate and ventral acoustic striae, both ipsilaterally and contralaterally, including the opposite cochlear nucleus, the superior olivary complex bilaterally, both lateral lemnisci and the inferior colliculi. The richness of connections of the ventral cochlear nucleus suggests that many auditory functions are processed there. Behavioural studies in experimental animals have thus far found difficulties only with vertical sound localization with lesions of the dorsal cochlear nucleus (Sutherland et al., 1998). The cochlear nuclei receive a rich blood supply from multiple sources including branches of AICA and PICA (Oas & Baloh, 1992). The trapezoid body and superior olivary complex are rostral and medial to the cochlear nuclei in the tegmentum of the lower third of the pons just dorsal to the base of the pons. The superior olivary complex is involved in binaural processing and is composed of several nuclei, the most prominent of which is the medial superior olive (MSO). The MSO receives inputs from both ventral cochlear nuclei and is sensitive to differences in the timing of sounds at the two ears. As the lowest part of the auditory system to receive major inputs from the two sides, the superior olivary complex is also involved in an initial assessment of the intensity differences of the sounds being received from the two sides (Furst et al., 2000). Penetrating branches of the basilar artery or anterior inferior cerebellar artery provide this region’s blood supply (Duvernoy, 1978). Outputs of the superior olivary complex project both ipsilaterally and contralaterally. Some project to the inferior colliculus through the lateral lemnisci while others terminate in one of the nuclei of the lateral lemniscus. The lateral lemnisci extend from the lateral and rostral trapezoid body in the midpons to the inferior colliculi of the tectum of the midbrain. Virtually all ascending and descending auditory tracts synapse in the inferior colliculus. The commissure of the inferior colliculi connects the two inferior colliculi across the quadrigeminal plate, while

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the commissure of Probst connects the dorsal nucleus of the lateral lemniscus to the opposite inferior colliculus. The blood supply of this region is from penetrating branches of the basilar, for the caudal lateral lemniscus and more rostrally from branches of both the superior cerebellar artery and posterior cerebral artery (Duvernoy, 1978). The brachium of the inferior colliculus is a pathway carrying fibres between the inferior colliculus and the ipsilateral medial geniculate body, located in the metathalamus, the caudal subpial portion of the thalamus. This region receives its blood supply through the thalamo-geniculate and posterior choroidal arteries. The auditory radiations pass either through the posterior limb of the internal capsule or sublenticularly to reach the auditory cortex of the temporal lobe (Percheron, 1973). The primary auditory cortex occupies the region of Heschl’s gyrus of the superior temporal lobe. For different individuals, there are likely to be variations in its exact location. Surrounding the primary auditory cortex area are the association cortices extending medially nearly to the insula, posteriorly to the parietal operculum, and anteriorly nearly to the orbitofrontal cortex (Galaburda & Friedrich, 1980; Pandya, 1995). Branches of the middle cerebral artery supply this part of the temporal lobe. Interhemispheric fibres connecting the right and left auditory cortices pass through the posterior corpus callosum, whose blood supply is via the pericallosal artery, a branch of the anterior cerebral artery (Damasio & Damasio, 1979). Paralleling the afferent auditory pathway at all levels is a descending auditory pathway extending from the cortex to the cochlea. These two systems interact at multiple levels (Brodal & Osen, 1981).

Auditory complaints and hearing evaluation Auditory complaints (Table 11.1) It is a common experience that stroke patients seldom complain about hearing. In the vast majority of cases, hearing disorders – even when they are present – are subtle, involving tinnitus, auditory hallucinations, or loss of auditory sensitivity. Patients rarely complain about difficulties with sound localization. In many cases, hearing complaints are overshadowed by more prominent complaints involving other neurological systems; therefore, every patient should be directly questioned for each of the above auditory symptoms. When explicit auditory complaints occur, they may be of diagnostic value. Unilateral

or bilateral deafness may suggest AICA or basilar artery ischemia (Applebaum & Ferguson, 1975; Huang et al., 1993). Hearing deficits are also noted in extensive bilateral lesions of the ascending pathways and in bilateral temporal lobe lesions (Graham et al., 1980; Jerger et al., 1972). Often, hearing loss becomes clinically evident only after sequential infarctions involving both sides have occurred. While hearing loss or tinnitus can be the first symptom of stroke or appear with a latency up to several days, they are rarely symptoms of a transient ischemic attack. Auditory hallucinations have been noted in brainstem (Cambier et al., 1987; Murata et al., 1994) and cortical lesions (Berrios, 1990). Probably the most frequent auditory symptom spontaneously reported by stroke patients is tinnitus. It occurs ipsilaterally with brainstem lesions caudal to the trapezoid body and bilaterally with higher-level lesions. Hyperacusis may occur with midbrain ischemia. Sometimes gross central auditory disorders in stroke are initially mistaken for acute psychosis, aphasia, or peripheral deafness (Case Report 3).

Standard pure tone audiometry and speech discrimination In patients with stroke, hearing evaluation is often restricted to procedures that can be done at the patient’s bedside. When there is suspicion of a hearing problem following a stroke, pure-tone audiometry and speech discrimination tests should be performed, together with the regular otologic examination. One has to bear in mind that, in addition to the neurological event, a peripheral hearing or otologic problem could have been pre-existing. Sometimes unilateral or bilateral hearing impairment or total deafness can result from AICA or basilar ischemia (Huang et al., 1993; Kitamura & Berreby, 1983). A major increase in pure-tone thresholds and a deterioration of speech discrimination scores also can occur in bilateral subcortical and cortical temporal lobe lesions (Case Report 2).

Psychoacoustic methods for the evaluation of central auditory function (Table 11.2) Auditory dysfunction resulting from stroke syndromes varies with the location and extent of auditory pathway infarction. Even if pure tone audiometry and speech discrimination are normal, abnormalities may be present (i) for other types of functions requiring binaural fusion, such as sound localization, or (ii) for more difficult monaural pure-tone or speech tests, such as recognizing distorted

Auditory disorders in stroke

Table 11.1. Auditory symptoms reported in strokes Symptom

Location of ischemia

Hearing loss – Unilateral

Ipsilateral

Cochlea Auditory nerve Cochlear nucleus Acoustic striae

Hearing loss – Bilateral

Bilateral

Cochleae Auditory nerves Cochlear nuclei Acoustic striae Superior olivary complexes Lateral lemnisci Inferior colliculi Brachia of inferior colliculus Medial geniculate bodies Auditory radiations Primary auditory cortices and/or subcortical white matter

Tinnitus – Unilateral

Ipsilateral

Cochlea Auditory nerve Cochlea nucleus Acoustic striae

Tinnitus – Bilateral

Bilateral

Cochleae Auditory nerves Cochlear nuclei Acoustic striae Inferior colliculus (transient)

Unilateral Hallucinations

Pontine tegmentum Midbrain (‘peduncular’) Non-dominant temporal lobe (musical)

Hyperacusis

Unilateral inferior colliculus

stimuli or understanding speech in noise, or (iii) for tests involving competing stimuli to the two ears.

Sound localization and binaural sound lateralization tests Sound localization is based upon (i) differences in the sounds that arrive at the two ears, so called interaural differences, (e.g. differences in the time of arrival or in the intensity of a sound at the two ears) or (ii) upon monaural cues (e.g. the spectral filtering of a sound due to the auricle). Interaural differences or binaural cues are mainly used for left/right localization, while monaural cues are used for vertical and back/front localization. For interaural time or interaural intensity differences, tests under head phones can (i) measure the smallest such difference that a subject can detect reliably (‘just noticeable difference’ or

JND) and (ii) assess a subject’s ability to lateralize (Furst et al., 1995). Patients with brainstem lesions often have highly pathological results in these binaural tests (Furst et al., 2000; Häusler et al., 1983; Häusler & Levine, 1980). Patients with cochlear hearing losses or with unilateral or bilateral cortical lesions usually perform normally. Free-field tests using speakers can also assess sound localization (Häusler et al., 1983). Patients with cortical lesions can have impaired sound localization for the sound field contralateral to the lesion and also with sound localization in the vertical plane (Bocca et al., 1954; Häusler et al., 1983; Pinek et al., 1989; Poirier et al., 1994).

Masking level difference An important binaural function is the detection of one sound in the presence of competing sounds (‘the cock-

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Table 11.2. Psychoacoustic tests of central auditory function Name

Description

I. Tests of brainstem processing (binaural evaluation of fusion) Lateralization of sounds Sounds with interaural time or intensity differences (König, 1964; Häusler & Levine, 1980; Häusler et al., 1983; Furst et al. 1995) Masking level difference (Release from masking). (Hirsch, 1948; Olsen & Noffsinger, 1976)

Speech or pure tone in phase at the two ears plus noise out of phase at the two ears

Binaural fusion (Matzker, 1959)

Low-pass filtered words to one ear and high-pass filtered words presented to the other ear

Alternating speech (Vox alternans) (Hennebert, 1955)

Continuous monaural speech switched from ear to ear every 300 milliseconds

II. Tests of cortical processing (a) Stimulus distortion (monaural evaluation of redundancy) Speech in noise Speech together with background noise at various signal-to(Morales-Garcia & Poole, 1972; Olsen et al., 1975) noise ratios and levels Accelerated speech (Bocca & Calearo, 1963; Beasley et al., 1972)

Time-compressed speech

Retarded speech (Tato & Quiros, 1960)

Time-expanded speech

Filtered speech (Bocca et al., 1954; Willeford, 1987)

Low-pass filtered speech

(b) Competing stimuli (evaluation of ear extinction or hemispheric dominance) Dichotic Listening Test (Vox simultanea) Different stimuli simultaneously at the two ears (consonants, (Feldman, 1960; Kimura, 1961; Fifer & Jerger, 1983; vowels, digits, words, sentences, music etc.) Bergmann et al., 1987; Willeford, 1987)

tail party effect’). The masking level difference, which is measured under headphones, can assess this function by comparing the threshold of a tone presented binaurally in the presence of identical noise at the two ears under two conditions: (a) with the tone in phase at the two ears and (b) out of phase at the two ears. In normal subjects, there is a major improvement in threshold for the out of phase condition. Masking level difference can be abnormal for brainstem lesions (Levine et al., 1994).

Other fusion tests Evaluation of fusion ability can also be tested by presenting non-redundant complementary auditory information to the two ears, e.g. (a) by presenting low-pass filtered words to one ear and the same high-pass filtered words simultaneously to the other ear or (b) by switching a monaural sentence between the two ears every 300 milliseconds. Normal patients are able to fuse the auditory

signals from the two ears and understand the content of the auditory stimulus. This binaural fusion ability is impaired in brainstem lesions and seems to be closely related to the ability to lateralize sounds with interaural differences in time and intensity (König, 1968; Blauert, 1997).

Distorted stimuli Listening tasks with distorted stimuli such as accelerated (Bocca et al., 1954), retarded or decelerated (Tato & Quiros, 1960), and filtered (Matzker, 1959) speech are often poorly performed in patients with temporal lobe lesions, even when pure-tone audiometry and speech discrimination ability are normal. Time-compressed speech recognition has also been reported to be impaired for the ear contralateral to an inferior colliculus lesion, whereas the ability to recognize tone order is preserved (Durrant et al., 1994). Also, speech discrimination in noise typically is impaired

Auditory disorders in stroke

in patients with cortical lesions (Morales-Garcia & Poole, 1972; Olsen et al., 1975).

Competing stimuli Dichotic listening tests consist of simultaneously delivering different stimuli, such as words, sentences or musical stimuli, to the two ears (Feldmann, 1960; Kimura, 1961; König, 1968). Dichotic stimulation creates a perceptual conflict between the two ears. In normal subjects, this test can reveal the dominant hemisphere. In patients with stroke, unilateral lesions of the auditory radiations or cortex typically produce contralateral ear extinction in dichotic testing (Eustache et al., 1990). However, lesions of the dominant hemisphere can sometimes disconnect the auditory areas of the two hemispheres, and thereby produce an ipsilateral, so-called ‘paradoxical’, ear extinction (Damasio & Damasio, 1979).

Extensive psychophysical evaluation of central hearing function Specialized laboratories perform in-depth psychophysical analysis of impairments of pitch, duration or rhythm perception, and more complex percepts such as phonemes, musical and environmental sounds (Keith, 1994). Higher level auditory processing including lexical, semantic and syntactic capacities or even aesthetic features, can also be studied. Deficits in performance have been correlated with specific regions of infarctions (Eustache et al., 1994; Praamstra et al., 1991; Peretz, 1985).

Electrophysiological evaluation of central auditory function Acoustically evoked potentials and electroacoustic tests such as stapedial muscle reflex measurements and otoacoustic emissions provide an objective measure of central auditory function. These electrophysiologic measurements are especially informative when used in association with psychoacoustic test procedures.

responses (BAERs) consist of up to seven waves occurring within 10 milliseconds of the click stimuli (Jewett et al., 1970). Waves I, III and V are the most reliable. These waves reflect mainly neuronal activity in the auditory nerve (wave I), the spherical cell projection from the ventral cochlear nucleus to the superior olivary complex (wave III), and the contralateral lateral lemniscus or inferior colliculus (wave V) (Durrant et al., 1994; Levine et al., 1993b; Melcher & Kiang, 1996). BAERs can distinguish between pathologies of the middle and the inner ear, the auditory nerve, as well as brainstem lesions. Waves may be absent due to nonresponsive or desynchronized neurons. It is interesting to note that a close relationship exists between these electrophysiological measurements and psychoacoustic functions that require precise neuronal timing. For instance, the synchronization and latencies of the BAER waves are closely related to the ability to discriminate interaural time differences, suggesting that acoustic timing information is contained in the precise latencies of the brainstem potentials (Häusler & Levine, 1980). Middle latency responses (MLR) are recorded with a latency of between 10 and 50 milliseconds (Geisler et al., 1958). In part, they are generated by the auditory cortex. Long latency cortical responses (LLR) occur between 50 and 500 milliseconds following the stimulus and are mainly generated in the auditory cortex. MLR and cortical responses are abolished when the cortical or subcortical auditory areas are damaged bilaterally, giving rise to the clinical picture of central deafness. In unilateral or partial bilateral lesions, they usually remain normal. Special stimulus paradigms permit the recording of ‘endogenous’ long latency responses, which appear to relate to specific higher auditory processing. Attention to acoustic stimuli can be evaluated by the ‘cognitive potential’ (P-300) occurring at a latency of about 300 milliseconds after the stimulus (Sutton et al., 1965). P-300 is very sensitive to diffuse ischemia even when there is no overt cognitive decline (Jacobson et al., 1997).

Stapedius reflex measurements Auditory evoked potentials Electrical brain activity elicited by acoustical stimuli, the so-called auditory evoked potentials (AEP), can be measured with electrodes placed on the surface of the head (Kiang, 1961). AEPs consist of a series of waves that are classified into early, middle and late responses according to their latency after the acoustic stimulus. They are generated by subpopulations of neurons that respond synchronously to the acoustic stimulus. Early potentials, also called brainstem auditory evoked

With electroacoustic impedance measurements, stapedius muscle contractions can be readily detected in response to ipsilateral or contralateral sound. Thus, within minutes, objective information about the functional state of the middle ear, the inner ear, the auditory nerve, the facial nerve, and the central auditory pathways in the lower brainstem can be obtained. Ipsilateral and contralateral measurements can distinguish between right, left and mid-line lesions involving the lower brainstem (Hayes & Jerger, 1981).

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Otoacoustic emissions A microphone within the external auditory canal can detect acoustic output from the cochlea in response to either transient or continuous sounds. These ‘evoked otoacoustic emissions’ can be modulated by sounds presented to the opposite ear via the auditory efferent system of the caudal pons including the olivocochlear bundle, which reaches the cochlea via the vestibular nerve. Contralateral modulation of otoacoustic emissions can be abolished by brainstem lesions (Probst & Harris, 1997).

Stroke syndromes involving the auditory pathways (Table 11.3) Auditory symptoms in brainstem strokes The auditory symptoms associated with brainstem stroke include hearing loss, phantom auditory perceptions (tinnitus/hallucinations), and hyperacusis. These may be associated with widespread ischemia due to vertebrobasilar occlusive disease or large hemorrhage or with focal disease due to penetrating artery occlusion or small hemorrhage. Hyperacusis, which means increased sensitivity to sounds, is always bilateral, but hearing loss or tinnitus can be either bilateral or unilateral. Because the trapezoid body is a major auditory decussation, ischemia at or rostral to the trapezoid body generally will result in non-lateralized symptoms, whereas symptoms related to more caudal ischemia, due to lesions of the acoustic striae, cochlear nucleus, auditory nerve, or cochlea, will be strictly localized to the ipsilateral ear. Hyperacusis is the least common of the auditory complaints; it has been reported for a patient with a bilateral tectal midbrain hemorrhage (Sand et al., 1986) and transiently in a case with a stroke presumably involving the medial caudal pontine tegmentum including the trapezoid body (Cambier et al., 1987). By contrast, ‘in lower brainstem ischemia due to vertebro-basilar disease and in other processes as well, assorted auditory hallucinations of a minor nature are not rare (Fisher & Tapia, 1987)’. Phantom auditory perceptions that have been associated with brainstem ischemia have been described as either tinnitus or auditory hallucinations. Aside from when they are musical, the distinction between tinnitus and hallucinations would appear to be largely semantic, since the ‘hallucinations’ have been described in terms similar to those used to describe the tinnitus resulting from ear or auditory nerve disease such as ‘buzzing bees’, ‘organ notes’, ‘seashell’, ‘bells chiming’, ‘grinding noises’, or ‘roaring’ (Cascino & Adams, 1986; Fisher & Tapia, 1987). A few cases of musical

hallucinations, occasionally with verbal hallucinations, have been reported with brainstem stroke (Cambier et al., 1987; Lanska et al., 1987; Murata et al., 1994). All were transient, and most involved the caudal pontine tegmentum unilaterally with ischemia or hemorrhage. One case has been clinically localized to the region of the inferior colliculus (Cambier et al., 1987). Peduncular hallucinations can occur with midbrain strokes, but they are predominantly visual with an occasional minor auditory component, such as seeing people who are ‘whispering’ (Cambier et al., 1987; Kolmel, 1991).

Large vessel occlusion Tinnitus and hearing loss can occur with vertebro-basilar disease. Sudden onset of unilateral or bilateral deafness usually accompanied by dizziness or vertigo can be a sign of basilar artery occlusive disease. However, transient ischemic attacks involving auditory symptoms with hearing loss or tinnitus would appear not to occur, rather hearing loss is followed by other symptoms within a week (Huang et al., 1993; Oas & Baloh, 1992). Bilateral sudden hearing loss with vertigo and tinnitus has a poor prognosis, whereas without vertigo, especially if the hearing loss is mild, the prognosis is more favorable (Huang et al., 1993). Sudden unilateral hearing loss with vertigo frequently occurs with anterior inferior cerebellar artery occlusion proximal to the internal auditory artery. Incomplete hearing loss or hearing loss without vertigo is probably not due to internal auditory artery occlusion (Huang et al., 1993; Oas & Baloh, 1992). Posterior inferior cerebellar artery ischemia generally does not produce any auditory symptoms because PICA generally does not perfuse any of the auditory pathway (Fisher & Tapia, 1987). The ‘classical’ case of superior cerebellar artery occlusion includes the description that ‘on the other side [there was] deafness (Mills, 1912)’. However, no subsequent reports have described deafness from strokes involving the superior cerebellar artery. In fact, despite lateral lemniscus or inferior colliculus infarction in more than half the reported cases of superior cerebellar artery occlusion, no auditory complaints have been described (Amarenco & Hauw, 1990). Similarly, posterior cerebral artery ischemia can involve the brachium of the inferior colliculus or medial geniculate body, but auditory symptoms have not been reported (Tatemichi et al., 1992).

Hemorrhage Sudden unilateral deafness and intense vertigo can be signs of an intralabyrinthine hemorrhage. These can occur in the setting of a bleeding diathesis such as leukemia (Paparella et al., 1973).

Table 11.3. Hearing abnormalities that may occur as related to level of auditory system involvement in stroke Speech Location

Evoked

Stapedius

Otoacoustic

Audiogram

discrimination

Psychoacoustic testing

potentials

reflex

emissions

Hearing loss (I)

Elevated

Impaired (I, ⫹/⫺)

Distortion tests impaired (I)

Absent (I)

Absent (I)

Absent (I)

Tinnitus (I, ⫹/⫺)

Thresholds (I)

Reported symptoms

Unilateral Cochlea Auditory nerve Cochlear nucleus Superior olivary complex

Hearing loss (I)

Elevated

Tinnitus (I, ⫹/⫺)

Thresholds (I)

Hearing loss (I)

Elevated

Tinnitus (I, ⫹/⫺)

Thresholds (I)

Hearing loss (I)

Elevated

Tinnitus (I, transient)

Thresholds (I, ⫹/⫺)

Fusion & dichotic (⫹/⫺) Impaired (I) Impaired (I) Impaired (I, ⫹/⫺)

Present (C)

Distortion tests impaired (I)

I normal (⫹/⫺)

Absent (I)

Present (I)

Fusion & dichotic impaired

III, V abnormal (I)

Present (C)

Present (C)

Distortion tests impaired (I)

I normal

Absent (I)

Present (I)

Fusion & dichotic impaired

III, V abnormal (I)

Present (C)

Present (C)

Fusion

I normal;

Impaired (⫹/⫺) Present (I)

impaired

III, V abnormal (I)

Fusion

V abnormal

Normal (I)

Normal (I)

impaired

bilaterally

Absent (C)

Abnormal (C)

Fusion

V abnormal (C)

Normal

Normal

V abnormal (C)

Normal

Normal

BAERs normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Abnormal (C)

Hallucinations (⫹/⫺) Trapezoid body Lateral lemniscus

None None

Normal Normal

Normal Normal

impaired Inferior colliculus

Tinnitus (⫹/⫺)

Normal

Normal

Hyperacusis (⫹/⫺) Brachium of IC and

None

Fusion impaired

Normal

Normal

medial geniculate body Auditory radiations and auditory cortex

MLR abnormal Difficulties in

Fusion normal

BAERs normal

adverse listening

Normal

Normal (⫹/⫺)

Dichotic & distortion tests

MLR abnormal

conditions

abnormal (C)

LLR abnormal

Normal or

Dichotic

BAERs normal

Unable

impaired

MLR abnormal

Hallucinations (⫹/⫺) Intrahemispheric connections

Speech, music

Normal

or environmental sound (⫹/⫺)

LLR abnormal

Bilateral Lateral lemniscus and

Deaf

inferior colliculus

Elevated

Unable

Thresholds

Bilaterally

Unable

I, III normal; V abnormal MLR abnormal LLR abnormal

Brachium of IC,

Deaf

medial geniculate body and

Elevated

Unable

Unable

Thresholds

MLR abnormal

primary auditory cortex Interhemispheric connections

BAERs normal LLR abnormal

Difficulties in

Normal

adverse listening conditions

Notes: I ⫽ ipsilateral. C ⫽ contralateral. ⫹/⫺ ⫽ sometimes.

Normal

Dichotic

BAERs normal

impaired

MLR normal LLR normal

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Smaller brainstem hemorrhages, in which alertness is maintained, may be associated with hearing loss, hallucinations (usually musical) and tinnitus (Obach & Obach, 1996). Those involving the caudal pons can have hearing impairment and hallucinations that can be either unilateral or bilateral (Cascino & Adams, 1986; Lanska et al., 1987). The hallucinations are usually lateralized only when the hearing loss is unilateral. Sound localization is frequently impaired (Cambier et al., 1987; Lanska et al., 1987). Typically, the auditory symptoms are transient. Wave V of the BAERs is always abnormal and sometimes wave III is abnormal on the side with the hearing loss (Lanska et al., 1987). The contralaterally evoked stapedial reflexes are abnormal (Egan et al., 1995). While no detailed analyses of hemorrhage location and auditory findings have been reported, studies with other types of lesions and animal studies suggest that the more lateral lesions are associated with unilateral hearing loss and affect wave III from involvement of the superior olivary complex and/or the auditory striae. Some patients with midbrain hemorrhages involving the tectum report either bilateral tinnitus or bilateral hyperacusis, even with unilateral tectal involvement. The tinnitus has always been reported as transient and the hyperacusis persistent (Link et al., 1993; Sand et al., 1986). Right posteromedial thalamic hemorrhages have been associated with transient left auditory neglect (Motomura et al., 1986).

Small vessel occlusion Internal auditory artery The arterial blood supply to the inner ear is provided by a single vessel, the internal auditory artery arising from AICA in most cases (Kim et al., 1990; Mazzoni, 1972). Experimental transitory occlusion of the internal auditory artery produces complete cessation of auditory function within minutes (Levine et al., 1993a) and irreversible degeneration of the cochlea. The apical cochlear region is particularly vulnerable (reflected as low frequency loss) and the vestibular end organ is somewhat more resistant (Perlman et al., 1959; Schuknecht, 1993). While bilateral sudden deafness with vestibular symptoms often is a sign of vertebrobasilar occlusive disease (Huang et al., 1993), unilateral sudden deafness as an isolated neurological event is rarely due to internal auditory artery or vertebrobasilar occlusion. Most patients with sudden deafness are young or middle-aged and have no risk factors for vascular disease. Pathologic inner ear studies of unilateral sudden deafness typically show alterations similar to those seen after viral infections, such as mumps or measles, with atrophy of the sensory organ and

without vascular occlusion (Schuknecht et al., 1973). Only isolated pathological reports of sudden deafness have identified a vascular occlusion of the internal auditory artery (Kitamura & Berreby, 1983). Unilateral sudden deafness can be produced by vascular lesions in association with systemic vascular disease, such as leukemia (Schuknecht et al., 1965), Buerger’s disease with thromboangitiis obliterans (Kirikae et al., 1962), macroglobulinemia (Ruben et al., 1969), or fat emboli and hypercoagulation (Jaffe, 1970). Sudden deafness has also been reported as a presumably embolic phenomenon following cardiac and abdominal surgery (Guillemin et al., 1988).

Penetrating branches Penetrating branch artery disease results in small limited subcortical infarcts. Auditory complaints in general are infrequently reported for these strokes. One reason appears to be the richness of collateral blood supply to the regions of the auditory nerves, cochlear nuclei, inferior colliculi, brachia of the inferior colliculus, and medial geniculate bodies. Consequently, single small vessel occlusions generally spare these regions (Bassetti et al., 1996). We are not aware of any well-established cases with small vessel occlusion affecting the cochlear nucleus. One case has been studied pathologically with a lateral medullary infarct extending into the lower pons in the region ‘just medial to the 7th nerve nucleus and lateral to the position of the 6th nerve nucleus which actually lay slightly rostral to the superior border of the infarct (Fisher & Tapia, 1987)’. This patient, who survived only 2 days, presented with intermittent roaring and impaired hearing of the ipsilateral ear. This description suggests the infarct involved the ventral acoustic striae and/or the superior olivary complex. Infarcts of the pons involving the trapezoid body or lateral lemniscus have not been reported to be associated with auditory complaints (Bassetti et al., 1996) or abnormal audiometry (Aharonson et al., 1998), yet tests of sound lateralization are abnormal (see Case Report 1). Patients with infarcts involving the trapezoid body tend to hear all sounds towards the middle (‘centre-biased’), while patients with infarcts involving the lateral lemniscus tend to hear all sounds toward the sides (‘side-biased’) (Furst et al., 2000). While isolated ischemic infarcts of the midbrain have not been reported to involve the inferior colliculus (Bogousslavsky et al., 1994), one case of unilateral necrosis of the right inferior colliculus has been described in a woman with an arteriovenous malformation that had bled

Auditory disorders in stroke

and subsequently was irradiated. She complained of difficulty using the telephone with her contralateral ear. A battery of hearing tests were normal including pure tone thresholds and speech discrimination. All testing of her ipsilateral ear was normal. Wave V of her BAERs was abnormal for contralateral ear stimulation (Durrant et al., 1994). Another case of small traumatic hemorrhage to the right inferior colliculus has recently been reported. Wave V was similarly abnormal. Suppression of the perception of echoes (‘the precedence effect’) was degraded and freefield sound localization was abnormal for the contralateral sound field only (Litovsky et al., 2000). The brachium of the inferior colliculus has been involved by small infarcts, but no auditory symptoms have been reported (Tatemichi et al., 1992). We have not found reports of small infarcts involving the medial geniculate body.

Auditory syndromes in hemispherical strokes Syndromes of elementary central auditory disorders such as cortical deafness (Lichtheim, 1885), pure word deafness (Kussmaul, 1877a,b), auditory agnosia for environmental sounds (Freud, 1953) and amusia (Steinhals, 1871) have been recognized for more than a century on the basis of clinical observations and post mortem studies. More systematic evaluation of central auditory dysfunction became possible in the middle of the twentieth century when electroacoustic equipment became available (Jerger, 1960a,b). In the 1970s, electrophysiological tests were introduced in the clinic, especially the technique of auditory evoked potentials, which allowed one to distinguish a peripheral from a central auditory disorder and also provided some localization of the lesion. CT scanning became available about the same time and allowed anatomical localization of lesions. This was followed a decade later by MRI scanning, which has provided very precise central nervous system anatomy. Presently, newer imaging techniques such as PET and functional MRI confer precise functional and anatomical insights into central auditory processing in normal and pathologic states (Melcher et al., 1999; Zatorre et al., 1992).

Cortical deafness Cortical deafness is a rare condition occurring with bilateral temporal lobe lesions (Wernicke & Friedländer, 1883) or with bilateral subcortical lesions interrupting the ascending auditory pathways (Musiek & Lee, 1998). In cortical deafness, patients appear deaf, though some reflex responses such as turning toward a sudden loud sound

may be preserved. With time, some auditory capacities may re-emerge. Other patients remain permanently deaf (see Case Report 2). LLR are abolished in cortical deafness. MLR are usually also abolished or impaired. BAERs and acoustic reflexes are preserved.

Hemianacusia Unilateral cortical temporal strokes produce subtle hearing dysfunction. Pure-tone thresholds and speech discrimination remain largely preserved; dysfunction becomes apparent in tests with distorted and dichotic stimuli. Unilateral cortical lesions produce contralateral ear extinction. Sound localization is impaired in the sound field contralateral to the impaired temporal lobe and also in the vertical plane (Häusler et al., 1983). There exist, in addition, differences between right and left lesions. Eustache et al. (1990) observed, in a patient with a left temporoparietal ischemic lesion, difficulties in understanding verbal stimuli and in identifying melodies in addition to right ear extinction to dichotic testing. Another patient with right internal capsule and frontal lesions had great difficulty discriminating environmental sounds and melodies. He also had left ear extinction with dichotic testing, but intact naming and identification. Robin et al. (1990) describe a series of patients with unilateral temporal lobe infarcts. Those with left temporal infarcts had normal spectral performance but impaired temporal discrimination, and those with right temporal infarcts had normal temporal discrimination but impaired spectral performance. BAERs, MLR and LLR are generally preserved in unilateral cortical lesions.

Auditory agnosia In its most general sense, auditory agnosia refers to impaired perception restricted to certain classes of sounds. For example, word (or verbal) deafness, the most striking type of auditory agnosia, is the incapacity to recognize speech sounds. Pure word deafness (i.e. word deafness without other features of aphasia) is rare. Patients rely on lip-reading and writing for communication. Tonal audiometry is usually preserved, but speech discrimination is abolished. BAERs, MLR, and LLR are preserved. An example of pure word deafness is presented in Case Report 3. Word deafness mostly occurs from bilateral temporal lesions interrupting the connections from the two primary auditory cortices to Wernicke’s area. Occasionally, pure word deafness is produced by a posterior unilateral temporal lobe lesion, when the lesion isolates Wernicke’s area from bilateral primary auditory cortex input (Kanter et al., 1986; Praamstra et al., 1991). Phonagnosia describes the inability

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(a)

(c)

(b)

(d)

Fig. 11.2. Sound lateralization centre-biased with trapezoid body stroke. Imaging, electrophysiological and behavioral studies from an audiometrically normal 80-year-old man, one year following a pontine penetrating branch infarct. He had no auditory complaints, yet his ability to lateralize sounds was markedly impaired. (a) Axial and sagittal T2-weighted MRI sections through the mid-pons, showing the infarct (outlined by open arrowheads). (b) Location of the infarct vis-à-vis the auditory pathway. Schematic coronal projection of the pontine auditory pathway with region of infarct (left trapezoid body) shaded. (c) Right and left BAERs normal. Monaural 65 dB SL alternating polarity clicks; nasion–inion recordings. (d) Position of sound as indicated by patient’s selection of one of the nine possible locations (y-axis) vs. the nine presented interaural level differences for low-frequency narrow-band noise (x-axis) for 56 trials. Each small dot represents a trial. Unlike normal subjects whose responses fall on or near the diagonal (shaded region), this patient’s responses (solid circles) were highly abnormal; he always indicated that sounds were perceived at or near the center (Furst et al., 2000).

to identify a speaker by his/her voice. Amusia refers to a disorder of music perception, such as impaired ability to recognize melodies. Well-documented amusia with preserved perception of tone, pitch and intensity is only exceptionally reported. More often, amusia is associated with other types of auditory agnosia. Amusia is commonly associated with right temporal lesions, but left-sided impairments also may

produce musical perception disorders, in particular, in professional musicians, especially melody and written music identification. There are reports of professional musicians who, following a left-sided hemispherical stroke with Wernicke’s aphasia, retained their pre-morbid musical capacities (Peretz, 1985; Eustache et al., 1994). Finally, sometimes the term auditory agnosia is used to refer to an

Auditory disorders in stroke

impaired ability to hear various types of environmental sounds (Eustache et al., 1994). Such agnosia usually results from non-dominant or bilateral temporal lobe damage.

C A S E R E P O RTS Case report 1 Impaired sound lateralization in a patient with a lower pontine lacunar infarct involving the trapezoid body; all sounds were heard toward the middle (‘centre bias’). An 80-year-old man presented with sudden onset of vertigo and vomiting. On examination, he was found to have a left gaze palsy, dysphagia, dysarthria, and a right hemiplegia that included only the lower face. He had no auditory complaints, and his bedside hearing evaluation was unremarkable. An MRI scan revealed a pontine infarct. A year later, he was evaluated with a battery of hearing tests and a repeat MRI scan (Fig. 11.2). Despite an age appropriate audiogram and normal BAERs, all fusion tests were abnormal for the three stimuli used (clicks, low-pass noise, and high-pass noise) and for interaural time or level disparities. Just noticeable differences were highly abnormal, and regardless of the size or type of interaural disparity, the patient indicated that everything sounded as though it were coming from or near the center of his head. Unlike normal subjects, nothing was heard coming from the far right or left. When mapped onto an atlas of the auditory pathway, his infarct was localized to the left trapezoid body (Aharonson et al., 1998; Furst et al., 2000). Case report 2 Cortical deafness in a patient with traumatic bilateral internal capsule hemorrhages A 20-year-old man was referred for cochlear implants because of bilateral deafness following a motorcycle accident two years earlier. He was initially comatose and CT showed hemorrhagic lesions involving both internal capsules (Fig. 11.3). After several weeks of coma, he awoke quadriparetic, cognitively impaired, and totally deaf. However, he occasionally turned his head towards a sudden loud sound. He used lip-reading for communication. He was able to read and write. Speech was dysarthric, but comprehensible. Pure tone audiometry and speech discrimination measurements confirmed total deafness (Fig. 11.4). Normal tympanograms and stapedial reflexes suggested, however, that the middle and inner ear, and the auditory nerve were intact. A normally functioning inner ear and auditory nerve were also confirmed by evoked responses with normal auditory nerve potentials (N-1 of the

Fig. 11.3. Axial CT scan sections of a patient (male, 20 years; case report 2) with cortical deafness showing a hyper dense lesion at the level of both internal capsules due to traumatic hemorrhages. Psychoacoustical and electrophysiological test results of this patient are shown in Fig. 11.4.

electrocochleogram) with a threshold estimate of 10 dB nHL bilaterally. BAERs showed normal Waves I–III, but an abnormal complex IV–V, suggesting functioning auditory pathways in the lower brainstem and a lesion in the midbrain. Late cortical responses were abolished. Based on these findings, it was concluded that the patient had cortical deafness due to bilateral interruption of the ascending auditory pathway associated with hemorrhagic lesions of both internal capsules. Cochlear implantation was not performed. Case Report 3 ‘Pure’ word deafness in a patient with bilateral temporal lobe infarctions A 64-year-old woman with a history of several minor strokes was admitted to psychiatry because of the onset of sudden agitation and failure to respond to speech despite hearing and responding to other sounds appropriately. She was able to write spontaneously and

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Fig. 11.4. Psychoacoustical and electrophysiological hearing evaluation of a patient (male, 20 years; case report 2) with cortical deafness following traumatic bilateral capsula interna hemorrhages. The pure-tone audiogram shows bilateral, complete deafness. The tympanogram as well as the stapedial reflex thresholds are normal and there is a normal auditory nerve potential on electrocochleography (ECochG) on both sides, suggesting a normally functioning middle ear and normally functioning cochlea and auditory nerves. BAERs have normal waves I–III, but an abnormal complex IV–V on both sides, suggesting normal functioning auditory pathways in the lower brain stem and a lesion in the mid-brain and the diencephalon. Late cortical responses are abolished. Based on these findings, it was concluded that the patient had cortical deafness due to bilateral interruption of the ascending auditory pathways, compatible with the hemorrhagic lesions of the internal capsulas, as observed on the CT scan shown in Fig. 11.3.

Auditory disorders in stroke

Fig. 11.5. Results of hearing tests and AEP recordings of a 64-year-old woman (case report 3) presenting pure word deafness due to sequential bilateral temporal lobe infarctions. Despite nearly normal pure tone thresholds, speech discrimination is 0% in both ears. BAERs and late cortical responses are normal, suggesting a functioning inner ear and functioning ascending auditory pathways, up to the auditory cortex. CT scan section of the same patient is shown in Fig. 11.6.

read with comprehension. Speech was fluent but accompanied by a moderate phonemic paraphasia. Repetition of words and writing to dictation could not be done. She used lip-reading for communication. The result of the hearing tests performed and the AEP recordings are shown in Fig. 11.5. Despite nearly normal pure tone thresholds, speech discrimination was 0% in both ears. Normal stapedial reflexes, BAERs and cortical AEPs,

suggested a functioning inner ear and functioning ascending auditory pathway up to the auditory cortex. Cognitive evoked potentials (P-300) for each ear were abnormal. A CT scan showed extensive hypo dense lesions in both temporal lobes (Fig. 11.6). It was concluded that the patient had an auditory agnosia for speech (⫽pure word deafness) due to her bilateral temporal lobe infarcts.

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iAcknowledgmentsi We would like to express our gratitude for secretarial help to E. Clamann and B. Norris. We acknowledge the help of Norris in making Fig. 11.2. We thank Drs Furst, Aharonson, Pratt and Korczyn for providing the clinical details of Case Report 1.

iReferencesi

Fig. 11.6. Axial CT scan section of a 64-year-old woman (case report 3) suffering pure word deafness due to sequential, bilateral temporal lobe infarctions. The CT scan shows extensive hypo dense lesions in both temporal lobes. Auditory test results and AEP recordings of the same patient are shown in Fig. 11.5.

Conclusions The auditory symptoms and findings for unilateral and bilateral strokes involving different levels of the auditory pathway are summarized in the Tables 11.1 and 11.3. These tables are based on cases reported in the literature and our personal observations. The entries in these tables, however, must be considered provisional as more and more systematic observations of the neurology of hearing expand our knowledge.

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Abnormal movements Joseph Ghika and Julien Bogousslavsky Department of Neurology, University of Lausanne, Switzerland

Introduction Acute, paroxysmal, recurrent, transient, permanent, or delayed movement disorders have been occasionally reported in the acute phase of stroke as well as after a delay up to months or years. Almost any type of hyperkinetic or hypokinetic movement disorder has been reported, most commonly as hemi- or focal dyskinesia. Only isolated case reports or very small series can be found in the literature, and few epidemiologic studies (D’Olhaberriague et al., 1995; Ghika-Schmid et al., 1997) have been performed in order to estimate the prevalence of movement disorders in cerebrovascular disease. However, what is clear in all studies, is the demonstration that any kind of dyskinesia can be found in lesions at any level of the motor frontosubcortical circuits of Alexander et al. (1986), including the sensorimotor cortex, caudate, putamen, pallidum, subthalamic nuclei, thalamus and brainstem and interconnecting pathways (for review, see Bhatia & Marsden, 1994).

Hypokinetic movement disorders Parkinsonism associated with small vessel disease (‘vascular parkinsonism’) Parkinsonism of vascular origin is a controversial entity. Only 2% of patients with cerebral infarcts may have a parkinsonian syndrome (De Reuck et al., 1980; Struck et al., 1990; Takeuchi et al. 1992). Hypertension is found in 22% of patients with parkinsonism (Marttila & Rinne, 1976, 1977). The association of ‘arteriosclerosis’ and parkinsonism has been studied, but does not seem to be significant (Eadie & Sutherland, 1964; Escourolle et al., 1970; Marttila & Rinne, 1976; Schneider et al., 1977; Kim et al., 1981; Horner et al., 1997; Homann & Ott, 1997). Critchley (1929) introduced

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the concept of ‘arteriosclerotic parkinsonism’, characterized by clinical and pathologic criteria, but his definition of this ‘disorder of the pallidal system’ with ‘general rigidity of non-pyramidal type, weakness and slowness of movement’ is somewhat different from what is accepted in the definition of the parkinsonian syndrome (requiring at least two items of bradykinesia, tremor, rigidity and loss of balance or postural responses). In the 1960s and 1970s, the concept of vascular parkinsonism was discarded (for review, see Schwab & England 1968; Parkes et al., 1974). However it is well recognized (since CT and MRI are available), that diffuse lesions of the hemispheric white and/or grey matter, lacunar states, senile or hypertensive leukoencephalopathy, or multiple infarcts can present with bradykinesia, akinesia, mixed features of rigidity and spasticity, loss of balance or gait disorder, which can be easily confused with a parkinsonian syndrome. As pointed out by Critchley (1929), ‘incomplete forms are more common’, and generalized rigidity (‘arteriosclerotic rigidity’ of Foerster 1909), pure akinesia or bradykinesia can be found. The ‘syndrome strié du vieillard’ of Lhermitte (1922), or ‘arteriosclerotic pseudoparkinsonism’ (Critchley, 1981) has also been widely reported by others (see Critchley, 1929 for summary) (Foerster, 1909; Hughes et al., 1954; Schwab & England, 1968; Parkes et al., 1974; Fahn, 1977; De Reuck et al., 1980; Koller et al., 1983; Tolosa & Santamaria, 1984; Kinkel et al., 1985; Friedman et al., 1986; Steingart et al., 1987; Thompson & Marsden, 1987, Dubinsky & Jankovic, 1987; Fitzgerald & Jankovic, 1989; Murrow et al., 1990; Chang et al., 1992; Tison et al., 1993; Bhatia & Marsden, 1994; Inzelberg et al., 1994; Zijlmans et al., 1994, 1995, Scott & Jankovic, 1996, Yamanouchi & Nagura, 1997; van Zagten et al., 1998), but the limit between this entity and ill-defined ‘senile gait disorders’ or ‘lower body parkinsonism’ still remains to be delimited (Fitzgerald & Jankovic, 1989; Achiron et al., 1993; Atchison

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et al., 1993; Nutt et al., 1993). Strategic infarcts or hemorrhage in the mesencephalon can lead to true vascular parkinsonism (Inoue et al., 1997). The parkinsonism reported in association with cerebrovascular lesions correspond to a clinical entity, which is different from the parkinsonian syndrome of degenerative origin. Generally the symptoms tend to be generalized and not lateralized initially, with ictal, slowly progressive, stepwise or insidious onset or progression. Pseudobulbar signs (‘pseudobulbar parkinsonism’ or ‘progressive pyramido-pallidal degeneration’ of Lhermitte (1921), brisk reflexes, Babinski signs, sphincter incontinence and dementia are commonly associated, but ataxia is less frequent. Tremor is characteristically absent (‘sine agitatione’) unless the patient has essential tremor (Critchley, 1929, 1981), but has been reported (Holmes, 1904). The rigidity is generally ‘sticky’ or ‘lead pipe type’ with no cogwheel, characteristically variable in degree (with paratonia or gegenhalten), and the topographic distribution of the hypertonia is more suggestive of spastic antigravity muscles than in parkinsonism. Bradykinesia, akinesia, and hypokinesia are typically found. Micrography has also been reported but, when performing rapid alternating movements, frequent synkineses or mirror movements are common. Hypophonic, dysarthric, monotonous, monosyllabic or elliptic speech may be present, and sometimes frank mutism. Features of bulbar speech can be found. A ‘mask facies with an expression of bewilderment, elevated eyebrows, retracted lids and gaping mouth, accounting for a mixture of spastic and extrapyramidal face’ (Critchley, 1929) has been reported, but sebaceous secretion is generally absent. The ‘marche à petits pas’ or Petren gait (Petren, 1901, 1902) can sometimes be confused with parkinsonian gait; however, stooped posture and excessive flexion of hip and knee are usually absent, both arms are frequently held rigidly away from the sides, with variable loss of armswing. Associated movement occurs at the shoulder joint, and en-bloc turn is present, the steps being exceptionally short (‘one toe advances in front of the other’) and the feet are not lifted from the ground, but festination and propulsion generally do not occur, and the base is not massively increased. Apraxia and magnetism of the feet to the ground can be found. Tandem gait is generally impossible. Retropulsion can be massive. The overall extrapyramidal syndrome predominates in the lower body (‘lower body parkinsonism’, Fitzgerald & Jankovic, 1989) and in the proximal segments of the limbs, usually symmetrically. Dubinsky and Jankovic, (1987) and Winitaker and Jankovic (1994) described a syndrome resembling progressive supranuclear palsy in a patient with a multiinfarct state. A history of hypertension and/or diabetes is present in

Fig. 12.1. Parkinsonism and gait disorders. Synopsis of reported lesions.

most patients and the CT or MRI images clearly show multiple small deep infarcts and white matter changes. Some dilatation of the ventricles and cerebral atrophy are often observed. Convincing cases of sudden parkinsonian syndrome of vascular etiology with bilateral basal ganglia ischemic lesions include patients with bilateral thalamic infarcts (Denny-Brown, 1962; De Reuck et al., 1980; Tolosa & Santamaria, 1984), bilateral putaminal infarcts (Lhermitte & Cornil, 1921; Lhermitte, 1922; Friedman et al., 1986; Tolosa & Santamaria, 1984), bilateral caudate infarcts (Tolosa & Santamaria, 1984; Hughes et al., 1954). In any event, while the clinical picture of atypical parkinsonian syndromes in a patient with multiple vascular lesions on CT and MRI does exist, the diagnosis of vascular parkinsonism is essentially made by exclusion, and the final diagnosis can only be made on pathological examination (Fig. 12.1). Few pathological studies show ischemic involvement of the substantia nigra in status cribrosus, multilacunar state, hypertensive or senile leukoencephalopathy, but the striatum is generally involved (Escourolle et al., 1970; De Reuck et al., 1980). Denny-Brown (1962) reported vascular lesions in the putamen in one-third of patients with ‘diffuse microangiopathic disease’. In other studies, however, there were Lewy bodies in the substantia nigra of patients with cerebrovascular disease and parkinsonism, showing difficulty in separating both entities without pathological studies (Escourolle et al., 1970). The absence of response to antiparkinsonian medication relates to postsynaptic damage with involvement of striato-pallidal structures, making it difficult to differentiate this condition from multiple system atrophy.

Senile gait disorders Higher level gait disorders (Sudarsky & Ronthal, 1983; Thompson & Marsden, 1987, Nutt et al., 1993; Thajeb, 1993) can be found in patients with generalized small vessel disease.

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‘Subcortical disequilibrium’ is characterized by disequilibrium with absent or inefficient postural responses with hyperextension of axial muscles with retropulsion, but stepping is possible. Astasia-abasia, thalamic astasia (Masdeu & Gorelick, 1988) or tottering are synonymous for this type of gait disorder, which can be acute or insidious with lesions in basal ganglia, thalamus, and midbrain. ‘Frontal disequilibrium’ or trunk or gait apraxia, frontal apraxia of Bruns, or astasia–abasia is defined by disequilibrium, inappropriate or counterproductive postural and locomotor synergies, inability to stand, to sit, or to rise from a chair, with severe retropulsion, and crossing of the legs. These patients cannot walk and step or turn. Bilateral corticospinal signs, corticobulbar and frontal syndromes as well as incontinence are frequently associated. In ‘isolated gait ignition failure’ (Atchison et al., 1993) or gait apraxia, magnetic gait, slipping clutch gait, lower body parkinsonism (Fitzgerald & Jankovic 1989), trepidant abasia, Petren’s gait (1901, 1902), or isolated progressive freezing (Atchison et al., 1993) the steps are short, shuffling is present, with hesitation in starting and turning, variable freezing and variable base. Once this difficulty in starting to walk has been overcome, the gait is almost normal, with normal posture, stride base, stride length and armswing, until the need to turn or the meeting with an obstacle. Isolated freezing, start hesitation or turn hesitation can be found. ‘Frontal gait disorder’ or marche à petits pas, magnetic gait apraxia, lower body parkinsonism is characterized by variable base, hesitation in starting, turning, short steps with shuffling and disequilibrium. Apraxia of sitting can be isolated. Cautious gait (elderly gait or senile gait) is defined by shortened stride, with slowing, mild disequilibrium, difficulty in balancing on one foot, normal or wide base, en bloc turn but no hesitation, shuffling or freezing. The stance phase is longer, with short swing phase, increased number of steps and antero-posterior swinging, preserved rhythm but loss of postural responses. Mixed peripheral and central nervous system disorders are frequently found. Posture, standing from a sitting position, equilibrium, postural reflexes, and protective reactions are normal. On MRI, multiple white matter lesions are usually present (Atchison et al., 1993).

in parietal (Ghika et al., 1998) and less often in frontal or striatal strokes (Saposnik et al., 1998), the patient maintaining for minutes postures passively produced by the examiner or actively performed, even though these are uncomfortable. Hemihypokinesia is also found in right hemispheric strokes (Heilman & Valenstein, 1972; Watson et al., 1981; Laplane & Degos, 1983; Coslett & Heilman, 1989; Von Giesen et al., 1994) as part of motor hemineglect, but can be found in basal ganglia strokes (Damasio et al., 1980; Von Giesen et al., 1994), including the thalamus (Laplane et al., 1986, Verret & Lapresle, 1986), and catatonia in biparietal infarcts (Howard & Low-Beer, 1989). Isolated micrographia has been described in a lenticular hematoma (Martinez-Vila et al., 1988). Athymormia, loss of self autoactivation, apathy, abulia and other akinetic syndromes like akinetic mutism can be found in association with generally bilateral basal ganglia infarcts, hemorrhage or deep venous thrombosis (Laplane et al., 1982, 1984, 1988; Richfield et al., 1987; Habib & Poncet, 1988; Habib et al., 1991; Croisile et al., 1989; Haley et al., 1989; Caplan et al., 1990; Desi et al., 1990; Laplane, 1990; Laplane & Dubois, 1998; De Smet et al., 1990; Macucci et al., 1991; Lehembre & Graux, 1992; Tei et al., 1993; Baron, 1994; Bhatia & Marsden,1994; Milandre et al., 1995, Piccirilli et al., 1995; Tatemichi et al., 1995; Mega & Cohenour, 1997) thalamic (Lhermitte et al., 1963; Ogata et al., 1966; Kuriyama et al., 1997, Szirmai et al., 1977; Tomimoto et al., 1984; Tanaka et al., 1986; Bogousslavsky et al., 1991), unior bilateral capsular genu infarcts (Terao et al., 1991; Hara et al., 1992; Tatemichi et al., 1993; Yamanaka et al., 1996), midbrain infarcts or hemorrhage (Cravioto et al., 1960; Kemper & Romanul, 1967; Segawa, 1970; Castaigne et al., 1981; Price et al., 1983; Tomimoto et al., 1984; Hochman et al., 1985; Robles et al. 1995; de Oliveira-Souza et al., 1995; Von Domburg et al., 1996) or bilateral cingulate (Faris, 1969; Freeman, 1971; Buge et al., 1975; Laplane et al., 1981; Habib & Poncet, 1988; Gugliotta et al., 1989; Borggreve et al., 1994; Miyashi et al., 1995), basal forebrain (Okawa et al., 1980) or frontal strokes (Gautier et al., 1983; Calvanio et al., 1993).

Asymmetric catalepsy, motor neglect and hypokinesia and other akinetic syndromes (abulia, athymormia, akinetic mutism, catatonia)

Hemichorea-hemiballism

Asymmetric cataleptic posturing, more prominent in the left side, was found in a patient with a large fronto-parietal infarct (Saver et al., 1993) and can be frequently observed

Hyperkinetic movement disorders

Acute hemichorea-hemiballism Hemichorea-hemiballism is certainly the most frequently reported movement disorder in acute stroke. Hemiballism is defined as a severe, involuntary, very fast, arrhythmic, explosive, large amplitude excursion of the

Abnormal movements

limb at proximal joints, with an element of rotation in the movement, possibly present at rest, but increased by any attempt to move. Patients may attempt to fixate the affected limb with the uninvolved side, and can be exhausted by these explosive motions, especially if they have chronic cardiac failure. The movements generally predominate in one limb and may be strictly unilateral. They disappear during sleep. Hemichorea is characterized by unilateral rapid involuntary motion with flexion and extension, rotation or crossing, which may involve all body parts, but predominantly distally, with fluent distal-to-proximal or proximalto-distal march. There may be some grimacing of the face, tongue protrusion and vocalization. Patients frequently use the involuntary movement in a semi-purposeful manner as if they were hiding them, or hold the moving limb with the good one. Kase et al. (1981) proposed the name of hemichorea-hemiballism. As a mixture of both, the motion has a flinging character, increased on stress. Some degree of dystonia (persistent postures in overflexion, overextension or torsion), and athetosis (inability to maintain fixed postures with slow snake-like motions) can be added. Cases with associated cortico-spinal, sensory, ataxic or neuropsychological or even psychiatric features (like mania) have been reported (Kulisevsky et al., 1993b). The syndrome of hemichorea-hemiballism is generally transient, lasting a few days, less commonly weeks (Hyland & Forman, 1957; Reimer & Knüppel, 1963) but rarely it is persistent (Lang, 1985) or recurring (Goldblatt et al., 1974). It responds generally well to neuroleptics (Klawans et al., 1976). Classically, acute hemichorea and its variants is found after an acute small deep infarct or hemorrhage in the contralateral subthalamic nucleus (Martin, 1927, 1957; Schwartz & Burrows, 1960; Barraquer-Bordas & PeresSerra, 1965; Melamed et al., 1978; Calzetti et al., 1980; Lang, 1985; Cecotti et al., 1986; Maruyama et al., 1992; Bhatia & Marsden, 1994; Bhatia et al., 1994; Lee & Marsden, 1994), sometimes ipsilaterally (Borgohain et al., 1995; Crozier et al., 1996), but any location in the motor frontosubcortical circuit of Alexander et al., (1986), i.e from the caudate to putamen, pallidum (Freund & Vogt, 1912; Martin, 1927; Austregesilo & Galotti, 1924, Davison & Godhart, 1940; Papez et al., 1942; Meyers et al., 1950; Hyland & Forman, 1957, Martin, 1957; Sandyk, 1960; Reimer & Knüppel, 1963; Avenarius et al., 1964; Gioino et al., 1966; Antin et al., 1967; Goldblatt et al., 1974; Lobos-Antunes et al., 1974; Johnson & Fahn, 1977; Calzetti et al., 1980; Kase et al., 1981; Folstein et al., 1981; Lodder & Baard, 1981; Fisher, 1982; Margolin & Marsden, 1982; Becker & Lal, 1983; Saris, 1983; Jones &

Fig. 12.2. Hemichorea–hemiballism. Synopsis of reported lesions.

Baker, 1985; Tabaton et al., 1985; Buruma & Lakke, 1986; Biller et al., 1986; Tognetti & Donati, 1986; Mas et al., 1987; Sethi et al., 1987; Srinivas et al., 1987; Tamaoka et al., 1987; Kawamura et al., 1988; Mempel, 1988; Dewey & Jankovic, 1989; Lopez-Arlandis et al., 1989; Altafullah et al., 1990; Destée et al., 1990; Defebvre et al., 1990; Friedman & Ambler, 1990; Lownie & Gilbert, 1990; Sethi & Patel, 1990; Ghika et al., 1991; Rumi et al., 1992; Bhatia & Marsden, 1994; Bhatia et al., 1994; Borgohain et al., 1995; Deldovici et al., 1995; Lin et al., 1995; D’Olhaberriague et al., 1995; Patel et al., 1995; Takamatsu et al., 1995; Cava et al., 1996; Scott & Jankovic 1996; Ghika-Schmid et al., 1997; Vila & Chamorro, 1997; Dragasevic et al., 1998; Karsidag et al., 1998; Shan et al., 1998), but also in the thalamus (Martin, 1957; Hyland & Forman, 1957; Graff-Radford et al., 1985; Verret & Lapresle, 1986; Bogousslavsky et al., 1988a,b; Camac et al., 1990; Maruyama et al., 1992; Nijssen & Tijssen, 1992; Kulisevsky et al., 1993; Milandre et al., 1993; Lee & Marsden, 1994; Moroo et al., 1994, D’Olhaberriague et al., 1995; GhikaSchmid et al., 1997; Lee et al., 1998) and pathways interconnecting these nuclei, including corona radiata (Barinagarrementeria et al., 1989) also in the frontal lobe (Martin, 1957; Papez et al., 1942) (Fig. 12.2). Cases with primary hemorrhage or hemorrhagic infarcts in the same loci are less frequent than ischemic strokes (Melamed et al., 1978; Lodder & Baard, 1981; Giroud & Dumas, 1988; Jones & Baker, 1985; Cecotti et al., 1986; Srinivas et al., 1987; Giroud & Dumas, 1988; Altafullah et al., 1990; Waragi et al., 1992; Maruyama et al., 1992; Lee & Marsden, 1994; Cava et al., 1996; Ghika-Schmid et al., 1997). Exceptionally, an angioma can be discovered (Avenarius et al., 1964; LobosAntunes et al., 1974; Tamaoka et al., 1987). Transient or paroxysmal hemiballism has been considered as a vertebro-basilar TIA by a few authors (Gänshirt et al., 1978; Margolin & Marsden, 1982) and a case of transient hemiballismus associated with subclavian steal syndrome has been reported (Calzetti et al., 1980). Paroxysmal

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complex dyskinesias have been described in latero-posterior thalamic infarcts (Camac et al., 1990; Nijssen & Tijssen, 1992). Paraballism, bi- or diballism or generalized choreoballism has been reported in patients with bilateral deep hemorrhage (Hoogstratten et al., 1977; Lodder & Baard, 1981), and bilateral deep infarcts (Tabaton et al., 1985; Sethi et al., 1987). One patient presented a clinical picture suggestive of Huntington’s disease (Folstein et al., 1981). On postmortem examination, he had multiple small infarcts in the caudate, putamen and internal capsule. Monoballism confined to one limb has been reported (Davison & Goodhart, 1940; Hyland & Forman, 1957).

Delayed hemichorea Delayed posthemiplegic hemichorea is a rare entity. It has been reported years after a stroke involving the basal ganglia (Dooling & Adams, 1975). It may be considered in patients with transient hemichorea.

Athetosis and pseudoathetosis Athetosis is rarely found in association with stroke. Delayed syndromes after perinatal anoxia are well recognized (Dooling & Adams, 1975). Pseudoathetosis can be found in association with lesions in the parietal lobe, thalamus, brainstem or spinal cord causing severe proprioceptive deficits (Sharp et al., 1994; Waragi et al., 1992; Ghika et al., 1995, 1998).

Dystonia Acute dystonia Dystonia is defined as a persistent inappropriate posture at rest or on action, in overflexion, overextension or rotation by prolonged cocontraction of antagonist muscles or simply tonic contraction of focal muscles (dystonic posture), sometimes associated with various movements (dystonic movements) such as tremor like jerky motion (dystonic tremor) or athetotic snake-like movements (athetotic dystonia or athetosis), or muscle jerks (dystonic myoclonus). Acute hemidystonia has been reported in association with an acute stroke. On CT, MRI, or pathology, large parietal or frontal infarcts or generalized hemiatrophy of perinatal origin have been reported (Marsden et al., 1985). Small infarcts or hematomas have also been found in the motor fronto-subcortical circuit including the caudate and lenticular nuclei (pallidum and putamen) (Lopez Aydillo & Sanz Ibanez, 1956; Burke et al., 1980; Brisson et al., 1981; Grimes et al., 1982; Traub & Ridley, 1982; Demierre & Rondot, 1983; Russo, 1983; Burton et al., 1984; Marsden et

al., 1985; Giroud & Dumas, 1988; Picard et al., 1989; Bhatia & Marsden, 1994; D’Olhaberriague et al., 1995), but preferentially in the putamen (Lopez Aydillo & Sanz Ibanaz, 1956; Oppenheimer, 1967, Zeman & Whitlock, 1968; Burton et al., 1984; Marsden et al., 1985; Merchut & Brumlik, 1986; Berkovic et al., 1987; Fross et al., 1987; Lopez-Arlandis et al., 1989; Midgard et al., 1989; Picard et al., 1989; Choi et al., 1993; Ferraz & Andrade, 1992; Inagaki et al., 1992; Molho & Factor, 1993; Bhatia & Marsden, 1994; Casas-Parera et al., 1994; Girlanda et al., 1997). Lesions in posterior and lateral thalamic nuclei have also been reported (Garcin, 1955; Grimes et al., 1982; Solomon et al., 1982; Gordon & Lendon, 1985; Marsden et al., 1985; Milandre et al., 1993; Lee & Marsden, 1994; Bhatia & Marsden ,1994; Ghika et al., 1994; D’Olhaberriague et al., 1995; Gille et al., 1996; Ghika-Schmid et al., 1997; Motoi et al., 1997; Karsidag et al., 1998; Ghika et al., 1998) as well as in the parietal and frontal cortex (Ferbert et al., 1990; Ghika-Schmid et al., 1997; Ghika et al., 1998) and brainstem (Day et al., 1986; Kulisevky et al., 1993a). Focal hand or foot dystonia has been found in patients with lacunar infarctions in the lenticular or caudate nuclei (Sterling, 1929; Lopez Aydillo & Sans Ibanaz, 1956; Brisson et al., 1981; Traub & Ridley, 1982; Lovis & Russo, 1983; Russo, 1983; Obeso et al., 1984; Pettigrew & Jankovic, 1985; Quinn et al., 1985; Nakashima et al., 1989; Yoshimura et al., 1992; Bhatia & Marsden, 1994; Scott & Jankovic, 1996; Thajeb, 1996; Ghika-Schmid et al., 1997; Rousseaux et al., 1998) or in the thalamus (the ‘thalamic hand or ‘signe de la main creuse’) (Garcin, 1955; Marsden et al., 1985; Karsidag et al., 1998; Ghika-Schmid et al., 1997) and in superficial parietal lobe infarcts (Critchley, 1953; Ferbert et al., 1990; Ghika-Schmid et al., 1997; Ghika et al., 1998). One patient with focal facial and lingual dystonia was reported by Zeman & Whitlock (1968), another one with cephalic dystonia (Meige syndrome) has also been reported in association with a brainstem infarct (Day et al., 1986) and jaw dystonia has been found together with basilar artery thrombosis (Nishi et al., 1985). Two patients with cervical dystonia of acute onset with lacunar infarcts in the basal ganglia were also recently described (Molho & Factor, 1993). Keane & Young (1985) reported a blepharospasm in bilateral basal ganglia infarctions and Powers (1985) reported a patient with a unilateral diencephalic infarction and another one in a thalamo-mesencephalic stroke (Kulisevsky et al., 1993). Generalized dystonia after a stroke is reported, with or without concomitant choreoathetosis (Sterling, 1929; Lopez Aydillo & Sanz Ibanez, 1956; Zeman & Whitlock, 1968). Painful repetitive tonic spasms, described as ‘sudden,

Abnormal movements

vigorous muscle spasm, preceded or accompanied by pain in the same limb’, ‘usually unilateral’, affecting the arm more often than the leg although they may simulatenously be affected, and facial grimacing, lasting a few seconds to minutes, have been reported in patients with putaminal infarcts from various etiologies (lupus erythematosus, anticardiolipin, other vasculitis) (Merchut & Brumlik, 1986). The spasms can be spontaneous or triggered by various stimuli (anxiety, hyperventilation, physical activity or sensory stimuli). Various generalized ‘tetanic postures’ of the limb can be found during the spasm. Progressive dystonia has also been reported after putaminal infarcts (Berkovic et al., 1987) and internal cerebral vein thrombosis (Solomon et al., 1982) ‘Virtual dystonia’, i.e ‘mental dystonia’ has been reported in association with a posterior ventrolateral infarct (de Oliveira et al., 1996). Paroxysmal kinesigenic dystonia has been described in a medullary infarct (Riley, 1996) and action-induced rythmic dystonia in a thalamic stroke (Sunohara et al., 1984).

Delayed hemidystonia Posthemiplegic hemidystonia may develop months or years after hemiplegia of vascular origin (Hammond, 1871; Solomon et al., 1970; Dooling & Adams, 1975; Quaglieri et al., 1977; Nardocci et al., 1996) in association with putamino-caudate infarcts on CT (Grimes et al., 1982; Burke et al., 1980; Burton et al., 1984; Traub & Ridley, 1982; Obeso et al., 1984; Marsden et al., 1985; Picard et al., 1989; Choi et al., 1993) and on MRI (Burton et al., 1984), less frequently with capsulo-thalamic lesions (Marsden et al., 1985; Ghika et al., 1995; Ghika-Schmid et al., 1997; Fig. 12.3).

Tremor

Fig. 12.3. Hemidystonia. Synopsis of reported lesions.

1988a,b; Caplan et al., 1990, 1998; Kim, 1992; Ferbert & Gernig, 1993; Lee et al., 1993; Mano et al., 1993; Milandre et al., 1993; Mossuto-Agatiello et al., 1993; Bhatia & Mardsen, 1994; Lee & Marsden, 1994; Ménégaux et al., 1994; Moroo et al., 1994; Ghika et al., 1994; Miwa et al., 1996; Scott & Jankovic, 1996; Ghika-Schmid et al., 1997; Krauss et al., 1997; Smits-Engelsman & van Galen, 1997; Karsidag et al., 1998; Soler et al., 1998). Subthalamic infarcts can also be accompanied by an acute resting and action tremor (Chiray et al., 1923; Ferbert et al., 1990). Rarely lesions of caudate or striatum are reported (Andrews et al., 1990; Kim, 1992; Dethy et al., 1993), frontal, parietal strokes (Ferbert et al., 1990; Dove et al., 1994; Kim & Lee, 1994; Ghika et al., 1998) or cerebellar strokes are reported (Lovis et al., 1996). Most cases are children, or adults, with stroke, in whom tremor develops during the acute phase or within weeks (Quaglieri et al.,1977) or years (Burke et al., 1980) after the ischemic lesion. In some instances, a stroke can cure an essential or parkinsonian tremor (Kim et al., 1996) (Fig. 12.4).

Acute tremor

Delayed tremor

Tremor is exceptionally reported as an acute event in strokes. Benedikt’s syndrome (1889) associating a resting and action tremor of 3–4 Hz to a contralateral corticospinal deficit is rarely seen in small mesencephalic infarcts or hemorrhage (Chiray et al., 1923; Lunsford, 1988; Berkovic & Bladin, 1984; de Recondo et al., 1993; Mossuto-Agatiello et al., 1993; Nakamura et al., 1993; Defer et al., 1994; Lee & Marsden, 1994; Bhatia & Marsden, 1994; Lynch et al., 1994). Pontine strokes with tremor are exceptional (Shepherd et al., 1997). An acute resting tremor is reported in a patient with a lacunar infarction at the border between the thalamus and the internal capsule (Lee et al., 1993) or lateral or posterior thalamus (Holmes, 1904; Sigwald & Monnier, 1936; Lapresle & Haguenau, 1973; Burke et al., 1980; GraffRadford et al., 1985; Ohye et al., 1985; Bogousslavsky et al.,

Progressive tremor, chorea and dystonia 7 years after stroke has been reported by Burke et al. (1980) in a boy. Intention, action, and postural tremor were found in a boy with venous sinus thrombosis with bilateral thalamic involvement (Solomon et al., 1982). Delayed tremor years after a stroke in posterior thalamic nuclei are reported (Kim, 1992; Ferbert & Gerwig, 1993; D’Olhaberriague et al., 1995; Volkmann et al., 1998), but also in patients with lesions of the cerebellar outflow tracts in the brainstem (Chiray et al., 1923; Burke et al., 1980; Berkovic & Bladin, 1984; de Recondo et al., 1993; Mossuto-Agatiello et al., 1993; Nakamura et al., 1993; Defer et al., 1994; Lee & Marsden, 1994; Miwa et al., 1996; Scott & Jankovic, 1996). We found delayed tremor, with choreo-athetotic and ballistic features, months after a stroke involving three

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Fig. 12.4. Asterixis. Synopsis of reported lesions.

patients with posterior thalamic infarcts in the territory of the posterior choroidal artery (Kim, 1992; Moroo et al., 1994; Ghika et al., 1994; Ghika-Schmid et al., 1997), thalamogeniculate artery (Holmes, 1904; Sigwald & Monnier, 1936; Graff-Radford et al., 1985; Caplan et al., 1988; Bogousslavsky et al., 1988a,b; Ferbert & Gerwig, 1993; Scott & Jankovic, 1996; Ghika-Schmid et al., 1997; Karsidag et al., 1998) but exceptionally in the territory of the anterior choroidal artery (Bogousslavsky et al., 1988a,b) or in giant cell arteritis (Caselli et al., 1988), but also rarely in cortical frontal or parietal strokes (Ferbert et al., 1990; Dove et al., 1994; Kim & Lee., 1994; Ghika et al., 1998) or cerebellar infarcts (Louis et al., 1996).

Asterixis Bilateral asterixis is usually found in association with diffuse encephalopathy (metabolic, toxic, infectious). Clinically, asterixis is a failure to sustain muscle contraction in postures, and electrophysiological studies show a negative myoclonus (paroxysmal brief (less than 200 ms) loss of muscular activity in muscles of the upper, lower extremity, axial muscles or tongue. Unilateral asterixis has been reported with contralateral lesions involving any possible structure involved in motion (fronto-parietal cortex, basal ganglia, cerebellum, thalamus, brainstem, but not yet in the spinal cord)(Conn, 1960; Tarsy, 1977; Tarsy et al., 1977; Degos et al., 1979; Morrey et al., 1979; Aguglia et al., 1990), and exceptionally in ipsilateral brainstem lesion (Peterson & Peterson, 1987) (Fig. 12.5). Sensory, motor, ataxic, eye movement, or neuropsychological disturbances can be associated. Ischemic or hemorrhagic lesions have been found on CT, MRI or pathology, involving the parietal lobe (Leavitt & Tyler, 1964; Degos et al., 1979; Feldmeyer et al., 1984; Ghika et al., 1998), in the territory of the lenticulostriate artery from MCA (head of caudate, lenticular nuclei, internal capsule) (Massey et al., 1979; Yagnik & Dhopesh, 1981; Trejo et al., 1986; Mizutani et al., 1990).

Thalamic ischemic or hemorrhagic lesions (posterior cerebral artery territory) can cause acute unilateral asterixis (Young et al., 1976; Massey, 1979; Morrey et al., 1979; Donat, 1980; Yagnik & Dhopesh, 1981; Feldmeyer et al., 1984; Shuttleworth & Drake, 1987; Bogousslavky et al., 1988a,b; Mizutani et al., 1990; Trouillas et al., 1990; Milandre et al., 1993; Bhatia & Marsden, 1994; Still et al., 1994; Ghika-Schmid et al., 1997). The lesions involved the paramedian nuclei (Donat, 1980), the lateral nuclei (thalamogeniculate territory) (Mizutani et al.,1990), the anterior (polar artery territory) or posterior nuclei (Trouillas et al.,1990), the mesothalamic region (Tarsy et al., 1977; Bril et al., 1979; Lee & Marsden, 1994) or both thalami (Rondot et al., 1983). Bril et al., 1979 and Tarsy, 1977 reported patients with unilateral acute asterixis in association with midbrain infarct, but no topographic correlate was described. In the posterior fossa, cases with mesencephalic (Tarsy et al., 1977; Bril et al., 1979; Fingerote et al., 1990) pontine or bulbar strokes have been reported (Kudo et al.,1985; Peterson & Peterson, 1987; Aguglia et al., 1990; Tarao et al., 1994; Shepherd et al., 1997) or in the cerebellum (Pullicino et al., 1990). Multiple bilateral hemispheric and cerebellar lesions are also described (Tarsy, 1977; Shuttleworth & Drake, 1987.

Myoclonus Myoclonus is exceptionally seen in patients with strokes, outside of clonic seizures. Generalized myoclonus has never been reported. The anoxic action myoclonus of Lance & Adams (1963) has been reported in association with multiple lacunar lesions in the basal ganglia. Intention and action myoclonus was found in a patient with a thalamic angioma (Avanzani et al., 1977). Focal reflex myoclonus has been reported by Sutton & Meyer (1974) in a patient with a superficial sylvian stroke involving the frontoparietal lobes and later by others (Bartolomei et al., 1995). It was a hemimyoclonus, mixed rhythmic and arrhythmic, both at rest and increased on action and reflex stimuli, disappearing during sleep. Segmental myoclonus have been reported in association with basilar lesions (De Mattos et al., 1992; Ghika-Schmid et al., 1997), midbrain or pontine strokes (Shibasaki et al., 1988; Palmer et al., 1991), basal ganglia (Scott & Jankovic, 1996) or cerebellar infarcts (Sutton & Meyer, 1974) and spinal cord ischemia (Fujimoto et al., 1989; Polo & Jabbari, 1994). Palatal myoclonus is generally found in association with pontine or bulbar strokes (Koeppen et al., 1980; Westmoreland et al., 1983; Overlacq et al., 1987; Iwadate et al., 1988; Itoh & Sakata, 1989; Kalshnikova & Lavrova, 1989; Diehl & Wilmes, 1990; Dubinsky et al., 1991; Chang et al., 1993). Intractable

Abnormal movements

Fig. 12.5. Tremor. Synopsis of reported lesions.

hiccup has similar topography (Al Deeb et al., 1991). Myorrhythmia have also been found in thalamic strokes (Lee & Marsden, 1994).

Transient, paroxysmal, episodic, orthostatic dyskinesia, ‘limb shaking’ Paroxysmal, episodic or transient dyskinesia can be symptoms of transient cerebral ischemia in the territory of the internal carotid artery (ICA) or the vertebrobasilar system. Repetitive stereotyped, often complex involuntary limb movements have been reported in the literature as carotid TIA. The movements are described as rhythmic or arrhythmic, uncontrollable, transient, lasting a few seconds to minutes, and are elicited by sitting, standing or stress, rarely kinesigenic (Loiseau, 1969) or progressive (Solomon et al.,1982). Orthostatic ‘limb shaking’ spells have been described, with involuntary, uncontrollable shaking, coarse irregular wavering, flapping, circling, flailing-type lateral excursions, drawing up or trembling of the upper and/or lower extremity on one hemibody or bilaterally, sometimes with pseudojaskonian march, sometimes difficult to be distinguished from epileptic seizures (Fisher, 1962; Loiseau, 1969; Pessin et al., 1977; Margolin & Marsden, 1982; Ross Russell & Page, 1983; Baquis et al., 1985; Yanagihara et al., 1985; Gordon & Lendon, 1985; Stark, 1985; Prick & Korten, 1988; Lopez Arlandis et al., 1989; Michel et al., 1989; Tatemichi et al., 1990; Hess et al., 1991; Milandre et al., 1993). Flexion and pronation of the wrist, movements of the hand behind the neck, transient hemichoreo-athetoid, writhing, snake-like, gyratory or hemiballic movements lasting a few minutes have also been reported without neuroimaging by Margolin & Marsden (1982), in association with severe uni- or bilateral carotid stenosis, or basilar artery stenosis or occlusion (Stark, 1985; Prick & Korten, 1988), and in children with moya-moya disease (Suzuki & Kodama, 1983) and verteb-

robasilar thrombosis (Gordon & Lendon, 1985). Transient weakness and transient sensory, visual, or aphasic symptoms can coexist with these movements. Painful tonic spasms (Merchut & Brumlik, 1986) or transient abnormal movements in patients with thalamic infarcts (Milandre et al., 1993) can be of difficult differential diagnosis. EEG performed during the paroxysmal movements showed slow waves without paroxysms, and cerebral blood flow studies demonstrated transient hypoperfusion in contralateral fronto-parietal regions (Yanagihara et al., 1985; Baquis et al., 1985; Michel et al., 1989). Paroxysmal complex dyskinesias with elements of dystonia, ballism, chorea, jerks and stereotypies have been described in a postero-lateral thalamic infarct (Camac et al., 1990), another patient presented with a paroxysmal stimulus-sensitive complex dyskinesia (Nijssen & Tijssen, 1992).

Stereotypies Complex stereotypies have been found in a patient with an infarct in the territory of the lenticulostriate arteries on the right side (Maranganore et al., 1991), bilateral thalamocapsular infarcts (Combarros et al., 1990), parietal strokes (Ghika et al., 1998), and Wallesch et al. (1983) reported stereotypies of speech in patients with aphasic strokes.

Mirror movements Mirror movements have been described in strokes and recently studied (Nelles et al., 1998).

Hyperplexia Hyperplexia exacerbated by the occlusion of posterior thalamic arteries has been described (Farriello et al., 1983).

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Akathisia, maniform agitation, compulsive motor behaviours Akathisia per se has not been reported in association with stroke, except in one case of unilateral akathisia in a posterior thalamic infarct (Ghika et al., 1995). Cases of agitation or agitated confusional state have also been reported in association with various locations (Robinson et al., 1984; Starkstein et al., 1987, 1988, 1991; Pardo et al., 1993) especially subthalamic infarcts (Bogousslavsky et al., 1988a,b; Bhatia & Marsden, 1994; Trillet et al., 1995) but also caudate hemorrhagic and ischemic strokes (Cambier et al., 1979; Stein et al., 1984; Weisberg, 1984; Fernandez-Pardal et al., 1985; Pozzoli et al., 1987; Krishnan & Figiel, 1989; Mendez et al., 1989; Wang, 1991; Milhaud et al., 1994), mesencephalic and substantia nigra (Lauterbach & Barreira, 1989), thalamic (Lauterbach et al., 1994; Lauterbach, 1996), right hemispheric (Cummings & Mendez, 1984; Migliorelli et al., 1993) or multiple lacunar strokes (Danel et al., 1991, 1992; Fujikawa et al., 1996). Hypergraphia (Yamadori et al., 1986), graphomania (Williams et al., 1988), logorrhea (Trillet et al., 1995), compulsive grasping or manipulation (Castaigne et al., 1970; Mori & Yamadori, 1982; Lhermitte, 1983; Strub, 1989; Eslinger et al., 1991; Sandson et al., 1991) or obsessive-compulsive behaviours have been described in basal ganglia (Berthier et al., 1996; Laplane et al., 1989, Laplane, 1994; Tonkonogy & Barreira, 1989; Weilber et al., 1989), thalamic (Guard et al., 1986; Eslinger et al., 1991; Sandson et al., 1991), subthalamic (Trillet et al., 1990), temporo-parietal (Bogousslavsky et al., 1995) and cingulate (Paunovic, 1984) strokes.

Hyperkinesia contralateral to hemiplegia We reported a series of patients with hemiplegic strokes who presented various types of hyperkinetic motor behaviors contralateral to the motor deficits (Ghika et al., 1995), including compulsive grasp reaction reported in frontal strokes (Castaigne et al., 1970), but also generalized non goal-directed hypermotility and stereotypias.

the Dejerine–Roussy syndrome (1906). Very complex dyskinesia with dystonia, avoidance and withdrawal behaviors, hypertonia (poikilotonia), persistence of awkward postures (hemicatalepsy, levitation), akinesia, multiple apraxias, ataxia, and sensorimotor deficits is found in the parietal lobe motor syndrome (Critchley 1953; Ghika et al., 1998), but also in temporo-parietal (Ferbert et al., 1990), basal ganglia (Williams et al., 1988) and fronto-cingulate strokes (also see maniform agitation, compulsive motor behaviours and athymormic states above).

Modification of previous movement disorders by strokes Strategic strokes can be a treatment for essential tremor contralaterally to a thalamic (Gioino et al., 1966; Kim et al., 1996; Urushitani et al., 1997) or subthalamic lesion (Struck et al., 1990).

Conclusions In conclusion, acute hypo- or hyperkinetic syndromes can occur in patients with acute strokes at any level of the motor fronto-subcortical circuit of Alexander. The majority of them are hemichorea and hemiballism, but acute unilateral asterixis, dystonia, or less frequently myoclonus, tremor, stereotypy or complex motor behaviours including akinetic states, can be found. Most of them are transient and are not specific for any vascular topopraphy or anatomical structure, but the majority of them are caused by a lesion in the basal ganglia or thalamus. Exceptional complex recurring acute movement disorders like ‘limb shaking’ can be found in transient ischemic attacks and are important to recognize early. Delayed or recurring hyperkinetic syndromes can be found months or years after a stroke. Parkinsonism-like syndromes in association with diffuse small artery disease are common, usually not asymmetrical, and resistant to treatment.

Complex hyperkinesias

iReferencesi

The most complex hyperkinesia associated with stroke is found in association with posterio-lateral thalamic strokes, mostly posterior choroidal or thalamogeniculate. A mixture of rubral tremor, chorea, pseudoathetosis, myoclonus, dystonia and ataxia is regularly found, which has been called the ‘jerky dystonic unsteady hand syndrome’ by our group (Ghika et al., 1995; Ferroir et al., 1992). When associated with a painful syndrome, this is well known as

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Seizures and stroke Anne L. Abbott, Christopher F. Bladin and Geoffrey A. Donnan National Stroke Research Institute, Austin, Heidelberg, Victoria, Australia

Introduction Historical references for stroke as a cause of seizures date back to Greco-Roman times when Hippocrates in 400  described epilepsy as a disease of the brain due to natural rather than supernatural causes. Hippocrates described older persons with paralysis following seizures consistent with seizures occurring at the onset of stroke. However, it was not until 1864 that Hughling Jackson clearly documented stroke as a cause of epilepsy. Jackson noted that ‘it is not uncommon to find when a patient has recovered or is recovering from hemiplegia, the result of embolism of the middle cerebral artery, or of some branch of this vessel, that he is attacked by convulsions beginning in some part of the paralysed region’. (Taylor, 1958). Since these times it has become clear that stroke is an important cause of seizures and epilepsy, particularly in the older age group. There are, however, some important questions still to be answered.

Post stroke seizures – comparison of cerebral infarction with hemorrhage Timing and frequency of seizures Reports on the frequency of seizures at the onset of, and following, stroke vary quite widely because of differing stroke patient populations, sample sizes studied, followup periods, definitions used for stroke and seizures, use of investigations such as computerized tomography (CT) and types of statistical analysis. In most studies to date the follow-up period was less than a few weeks, so the documentation of later onset or recurring seizures is limited. Studies of early and late onset poststroke seizures where patients with prestroke seizures, were largely excluded and CT was used in the diagnosis of cerebral ischemia or hem-

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orrhage in 90% or more of patients, are summarized in Table 13.1. Early seizures are usually defined as those occurring within 2 weeks of stroke onset. They are reported in anywhere from 1.0–5.5% of patients with recent stroke, more commonly after intracerebral hemorrhage than infarction. When intracerebral hemorrhage alone has been studied, seizures have been reported in 5–25% of patients (Table 13.2). The Seizures After Stroke Study (Stroke Research Unit, University of Toronto) was a prospective, international multicentre study examining the frequency and outcome of seizures in consecutive stroke patients (SAS Study, Bladin et al., 1998). In this study there were 1897 eligible patients followed for a mean of 9 months with an overall frequency of seizures of 9%. Seizures were significantly more common after intracerebral hemorrhage (10.6%) compared to cerebral infarction (8.6%). Most often, seizures occur at the onset or within the first few days of stroke due to infarction or bleeding. The risk of new seizures then falls progressively and is then very low beyond 2 years (Gupta et al., 1988; Faught et al., 1989; Lanceman et al., 1993; Bladin et al., 1996). Most seizures associated with stroke are single (Gupta et al., 1988; Kilpatrick et al., 1990; Giroud et al., 1994). As mentioned earlier, the frequency of recurrent otherwise unprovoked seizures (epilepsy) after stroke has rarely been quantified because of limited patient follow-up in most studies. In the SAS Study, although the incidence of early seizures was common, epilepsy developed in 3% of the stroke population overall. Even though the risk of an individual developing epilepsy after stroke is small, because stroke is such a common affliction in the older population, especially beyond 60 years, it is the leading cause of epilepsy in this age group. Cerebrovascular disease (infarction or hemorrhage) accounts for 14% to 54% of diagnosed cases of epilepsy in

Seizures and stroke

183

Table 13.1. Frequency of early and late seizures following cerebral infarction or hemorrhage in CT scan confirmed cases

Study

Kilpatrick et al., 1990(1)a,b

Davlos et al., 1992(2)a,b

Lanceman et al., 1993(1)

Giroud et al., 1994(2)a

Lo et al., 1994(1)a

Arboix et al., 1997(2)a

Reith et al., 1997(3)

Bladin et al., 1998(4)

Total patients

1000

1000

219

1640

1200

1220

1195

1897

Number of infarcts haemorrhages

601 65

662 156

183 36

1213 129

696 384

1012 208

900 75

— —

Follow-up

7 months (mean, early seizures only)

not stated

11.5 month (mean)

none

none

not stated

not stated

9

Threshold; early vs. late seizures (days)

14

2

30

15

14

2

14

14

Early seizures (%) all patients infarction hemorrhage

4.4 6.5 15.4

5 5.4 8.3

5.4 3.8 14

5.4 7 16

2.5 2.3 2.8

2.4 2 4.3

4.2 3 8

— — 8

Late seizures (%) all patients infarction hemorrhage

— — —

— — —

4.5 3 11

— — —

— — —

— — —

— — —

— — —

Notes: 1⫽hospital stroke patients, 2⫽stroke registry/database, 3⫽hospital/community database, 4⫽multicentre hospital stroke patients. a includes patients with TIA and/or subarachnoid haemorrhage and/or unclassified stroke types. b includes underlying causes of hemorrhage such as arteriovenous malformation, coagulation disorders.

Table 13.2. Frequency of seizures after intracerebral haemorrhagea

Number of patients Follow-up duration (months) Total seizures (%) Threshold of early vs. late seizures (days) Early seizures (%) Late seizures (%) Frequency of total seizures according to hemorrhage location (%); • Lobar/cortical • Thalamic • Basal ganglia. • Massived

Berger et al., 1988b

Faught et al., 1989c

Sung & Chu, 1989b

Weisberg et al., 1991b

112 2 (median) 17 — 17 —

123 55 (mean) 25 30 19 6

1402 20-22 (mean) 5 14 3 2

222 12 15 3 12 3

26 — — —

54 0 17 5

32 2 2 —

30 4 3 —

Notes: all studies were CT supported, largely descriptive, with only two ( Berger et al. and Faught et al. ) having limited univariate analysis with delineation of risk factors for seizures. b study includes patients with underlying causes such as neoplasm, aneurysm, mycotic aneurysm, anticoagulant complication, arteriovenous malformations and angioma. c includes patients with seizures before cerebral haemorrhage. d massive haematoma defined as ⬎ 50ml/s. a

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Table 13.3. Etiology of epilepsy in the elderly Etiology (%) Author

Year

N

Stroke

Tumour

Trauma

Metabolic

Drug/Alcohol

Otherb

Unknown

Roberts et al.c Guptad Dam et al.c Luhdorf et al.d Sundaramc Forsgrena,d,e Sander et al.a,d Sung and Chuc Loiseau et al.a,d Cohen & Scheuerd Hauser et al.a,d Ettinger & Shinnarc

1982 1983 1985 1986a 1989 1990 1990 1990a 1990 1991 1992 1993

81 78 221 151 67 239 196 342 284 123 214 80

44 50 14 32 22 41 49 39 47 25 32 54

12 0 16 14 24 10 11 11 9 18 3 8

6 4 4 4 6 5 — 21 3 0 3 —

6 2 — 2 7 — — 7 18 0 0 16

0 — 25 10 — — — — 3 — — —

15 12 3 13 7 7 — 10 7 7 12 14

16 28 38 25 34 37 38 12 13 50 50 8

Notes: N =number of elderly patients (⭓60 years). a subjects are subsets of larger population studies. b includes CNS infection, dementia, degenerative diseases, mixed conditions. c hospital-based study. d community-based study. e includes only non-provoked seizures; occurring without an identifiable causative metabolic or acute structural abnormality.

older patients according to the most recent studies (Table 13.3). Although a cause for epilepsy is more frequently found in older compared to younger people, up to about a third of cases are idiopathic (Luhdorf et al., 1986a; Loiseau et al., 1990; Sander et al., 1990). In addition, epilepsy in the elderly is a common medical problem with a high age-specific incidence (Forsgren, 1990; Tallis et al., 1991; Hauser, 1992). Tallis et al. (1991) in a large primary care computerized database encompassing over 300 000 patients in the United Kingdom, noted a bimodal distribution in the annual incidence of new seizures according to age. There was a peak incidence of 100/100 000 at approximately 5 years of age and a progressive rise from an incidence of 76/100 000 at 60 years. The incidence continued to rise with each decade to a figure of 159/100 000 for those aged over 80 years. A similar trend in the age-specific incidence of epilepsy was seen in the community-based study in Rochester Minnesota by Hauser (1992).

Types of seizures Partial seizures predominate after cerebral infarction and haemorrhage (Faught et al., 1989; Sung & Chu, 1989; Sung

& Chu 1990b; Kilpatrick et al., 1990; Lo et al., 1994; Giroud et al., 1994; Bladin et al., 1998). Partial seizures are usually simple motor in type, sometimes secondarily generalizing. Tonic-clonic seizures are also common but it is probable that, in many, the focal onset is unwitnessed or not appreciated. Complex partial seizures occur relatively rarely after stroke. Status epilepticus has been reported in up to 13% of stroke patients with seizures (Sung & Chu 1990b; Kilpatrick et al., 1990; Lo et al., 1994; Bladin et al., 1998). Status epilepticus can be a presenting feature of cerebral infarction or hemorrhage, or occur later. Seizure activity is often focal motor involving the hemiparetic limbs or may be tonicclonic in nature (Berger et al., 1988; Faught et al., 1989; Sung & Chen, 1989; Kilpatrick et al., 1990). Lobar hemorrhages are more commonly associated with status epilepticus than other types of intracerebral hemorrhage (Sung & Chen, 1989). Cerebrovascular disease is a common cause of status epilepticus in older patients. In addition, the mortality of status epilepticus increases with advancing age beyond 60 years and duration of seizures (DeLorenzo et al., 1992), hence the importance of early treatment. Important causes of status epilepticus after stroke are anticonvulsant

Seizures and stroke

withdrawal and non-compliance (Lowenstein & Alldredge, 1993).

Risk factors for post-stroke seizures Stroke location The most consistent risk factor for seizures at the onset or following cerebral infarction or hemorrhage is cortical involvement in pathological (Richardson & Dodge, 1954) and clinical studies (Olsen et al., 1987; Berger et al., 1988; Faught et al., 1989; Kilpatrick et al., 1990; Davlos et al., 1992; Lanceman et al., 1993; Lo et al., 1994; Arboix et al., 1997; Bladin et al., 1998). The anterior hemispheres and carotid arterial territory are sites of brain infarction with a higher risk of seizures (Lo et al., 1994; So et al., 1996; Burn et al., 1997). In the SAS study (Bladin et al., 1998), cerebral infarcts producing seizures were typically in the frontoparietal lobe in the region of the motor strip and extending down to the insula. With respect to intracerebral hemorrhage, lobar hemorrhages carry a higher risk of seizures compared to those located subcortically (Table 13.2). Deep cerebral and brain stem infarcts and infratentorial hemorrhages have not commonly been associated with seizures (Kilpatrick et al., 1990).

Stroke type The greater risk of seizures following intracerebral hemorrhage compared to infarction has been noted. Seizure risk does not appear to increase with amount of ventricular or cisternal blood nor the presence of hydrocephalus or shift of intracranial structures (Berger et al., 1988; Bladin et al., 1996). Hemorrhagic infarction did not confer a higher risk of seizures in the SAS study (Bladin et al., 1998). Subcortical infarctions are less commonly associated with seizures than cortical. Seizures have been noted in up to 3% of patients following lacunar infarcts (Kilpatrick et al., 1990; Giroud et al., 1994; Arboix et al., 1997; Bladin et al., 1998). However, some have proposed that lacunar infarcts are a marker of more widespread vascular disease rather than being directly responsible for stroke-related seizures (Roberts et al., 1988). Seizures have been noted in 23% of patients with striatocapsular infarction (Giroud & Dumas, 1995). It is possible that CT underestimates the number of patients with cortical ischemia in this form of subcortical stroke. A more sensitive indicator may be single photon emission tomography (SPECT), positron emission tomography (PET) or magnetic resonance imaging (MRI) (Olsen et al., 1986; Perani et al., 1987; Reith et al., 1997). The mecha-

nisms by which over lying cortical tissue can be functionally deranged in subcortical infarction and therefore involved in seizure production is discussed elsewhere (Olsen et al., 1986; Donnan et al., 1991). Less than 2% of patients with transient ischemic attacks experience seizures (Kilpatrick et al., 1990; Giroud et al., 1994). Patients suffering subarachnoid hemorrhage have 8 to 17% risk of seizures (Giroud et al., 1994; Kilpatrick et al., 1990) and these usually occur early, or with rebleeding.

Stroke size Larger strokes, especially cerebral infarctions, have been associated with an increased risk of seizures (Davlos et al., 1992; Lanceman et al., 1993; Arboix et al., 1997; Bladin et al., 1998). However, patients with small lobar hemorrhages, because of their cortical location, experience seizures more often than patients with larger bleeds located elsewhere (Berger et al., 1988; Faught et al., 1989; Weisberg et al., 1991; Bladin et al., 1996).

Presumed stroke mechanism; embolic vs. thrombotic Some studies have reported a presumed embolic cause of stroke more often than thrombotic among patients with seizures after stroke (Richardson & Dodge, 1954; Mohr et al., 1978; Giroud et al., 1994). Others have not found this association (Black et al., 1983; Kilpatrick et al., 1990; Davlos et al., 1992; Bladin et al., 1998). One must consider the limitations of diagnosing a cause of stroke in individual patients because of non-specific clinical syndromes, limitations of investigations and identification of several coincident predisposing factors (Ramirez-Lassepas et al., 1987; Lodder et al., 1994; Madden et al., 1995).

Underlying pathology Patients with intracerebral hemorrhage due to an underlying cause such as blood dyscrasia, tumour, arteriovenous malformations or aneurysm are more likely to have early and recurrent seizures than patients with spontaneous or hypertensive bleeds (Kilpatrick et al., 1990; Weisberg et al., 1991; Davlos et al., 1992). Lobar hemorrhages occur in the subcortical white matter of the cerebral lobes and are more often associated with seizures than deeper hemorrhages because of frequent cortical involvement. In addition, lobar hemorrhages are more frequently associated with underling causes of bleeding apart from hypertension (Kase et al., 1982; Kilpatrick et al., 1990).

Clinical features Reported clinical predictors for seizures after ischemic stroke are stroke severity, acute agitated confusional state,

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altered consciousness and persisting paresis (Olsen et al., 1986; Arboix et al., 1997; Reith et al., 1997). In the SAS Study, patient age, sex, hemisphere affected and vascular risk factors did not influence seizures following stroke (Bladin et al., 1996).

ring that is epileptogenic. The temporal occurrence of poststroke seizures, clinical features and proposed pathogenesis shares similarities with brain trauma associated seizures (Jennett, 1979; Willmore, 1993).

Morbidity and mortality Risk factors for poststroke epilepsy The issue of epilepsy following stroke has been poorly studied, mainly because of lack of long-term patient follow-up. Most patients suffering seizures within the first few weeks of a stroke do not have recurrent seizures, but have a higher risk than the age-matched population. Those with late onset seizures are possibly at higher risk (up to three-fold) for epilepsy than those with early-onset seizures (Louis & McDowell, 1967; Lesser et al., 1985; Faught et al., 1989; Sung & Chu, 1989, 1990b; Hornig et al., 1990; Weisberg et al., 1991). Cortical lesions increase the risk of epilepsy after cerebral infarction or hemorrhage (Olsen et al., 1987). With respect to intracerebral hemorrhage, lobar hemorrhage (Sung & Chu, 1989) and an identified structural cause (Weisberg et al., 1991) increase the risk of epilepsy.

Pathogenesis Little is known about the mechanism of seizures associated with stroke. As discussed earlier, it appears that cortical involvement is important in both infarction and haemorrhage. Because of the different frequency of seizures associated with cerebral hemorrhage compared to infarction, seizure pathogenesis is likely to be different. Some authors have raised the possibility that extravasated red cells and particularly the iron they contain may be responsible for the development over time of a chronic epileptic focus (Chusid & Kopeloff, 1962, Willmore et al., 1978; Lesser et al., 1985). Because most patients who experience early seizures after cerebral infarction or hemorrhage do not suffer recurrences, the pathogenesis of the two phenomena is likely to be different (Lesser et al., 1985). Acutely, seizures may occur due to transient metabolic alterations that may be seizure inducing. The size of the ischemic penumbra, for instance, may be influential, although this hypothesis needs to be formally tested. Bladin et al. (1996) detected a threefold greater blood flow defect in stroke patients with seizures compared to those without using CT and SPECT technology possibly indicative of a larger ischaemic penumbra. As acute metabolic derangements are reversed, seizures cease. Epilepsy, on the other hand, may occur when the stroke results in later structural change or scar-

Some authors have noted higher in-hospital mortality for patients with early seizures following cerebral infarction or hemorrhage (Arboix et al., 1997) but not others (Black et al., 1983; Davlos et al., 1992; Kilpatrick et al., 1990; Reith et al., 1997). In the SAS Study seizures were identified as an independent risk factor for death following cerebral infarction but not cerebral hemorrhage (Bladin et al., 1998). Predictors of a poor prognosis after stroke are the size of the lesion, initial stroke severity and a reduced level of consciousness (Davlos et al., 1992, Reith et al., 1997). There has been a reported lower mortality and better functional outcome for lobar compared to deeper hemorrhages because of their superficial nature (Kase et al., 1982).

Differential diagnosis The differentiation of seizures, and particularly ischemic stroke, can be difficult for several reasons (Godfrey et al., 1982). First, seizures can mimic stroke because of postictal worsening of preseizure neurological deficits. Fine in 1967 described posthemiplegic epilepsy in stroke patients. According to Fine, ‘after each convulsive seizure the hemiplegia was greatly deepened and could well be diagnosed as a fresh cerebral thrombus . . . or embolus’. Exacerbation of pre-existing neurological deficits postseizure can last more than a week or several months (Bogousslavsky et al., 1992; Hankey, 1993). Such an exacerbation is more likely after a prolonged seizure and a longer partial seizure before generalization, indicating the importance of prompt seizure control. Critical in the diagnosis is the history of the seizure preceding the exacerbation, previous stereotyped episodes which have recovered, absence of evidence of a further cerebral insult with brain imaging and the response to anticonvulsants. Secondly, seizures and strokes can also mimic each other because both can present with confusion. Ictal or postictal confusion can be prolonged for days (Ellis & Lee, 1978). Seizures and strokes can both be misdiagnosed as other disorders, commonly other confusional states or syncope, which can only be diagnosed clinically (Norris, 1982). Norris found in his study of 821 consecutive patients admitted to an acute stroke unit, that the initial diagnosis of stroke proved incorrect in 108 (13%). Misdiagnosis was most often due to inadequate clinical assessment. Norris

Seizures and stroke

concluded that ‘although CT and other neurological investigations are useful aids in the diagnosis of stroke, they remain a supplement to, and not a substitute for, correct clinical evaluation’. In addition, there are reports suggesting that focal seizures may resemble TIAs. These have been termed ‘inhibitory seizures’ and were first described by Gordon Holmes in 1927. Subtle postictal neurological deficits following these could mimic an ischemic stroke (Lee & Lerner, 1990). These are uncommon and noted by transient, focal loss of neurological function sometimes with coincident EEG changes and response to anticonvulsants. Various etiologies have been reported, including cerebral ischemia.

Role of the EEG EEG changes after stroke are not specific, but when present tend to be focal (Gupta et al., 1988; Faught et al., 1989; Lo et al., 1994; Arboix et al., 1997). With cerebral ischemia most commonly there is slowing, loss of normal background activity and reduction in overall amplitude (Faught, 1993). Other findings include periodic lateralizing epileptiform discharges (PLEDS), sharp activity and frontal intermittent delta activity (FIRDA). These changes can resolve within months of cerebral infarction or persist for years. The presence of PLEDS, however, usually indicates recent infarction. PLEDS have been particularly associated with watershed ischemia (Chatrian et al., 1964), see Fig. 13.1. After intracerebral hemorrhage, slowing is commonly focal but can be diffuse in the presence of coma or multifocal in the presence of vasospasm. The EEG is not reliable in predicting type, timing or recurrence of seizures after stroke and should not be used as the sole basis for prophylactic anticonvulsant therapy (Holmes, 1980; Luhdorf et al., 1986b; Bladin et al., 1996, 1998). In addition, there are considerable logistic difficulties in obtaining an EEG in ill patients with acute stroke.

Management There is little information on the impact of anticonvulsant medication or surgical intervention with respect to the risk of seizures associated with stroke. Fortunately, most stroke patients experiencing seizures within the first few weeks of stroke will not have another. Conversely, because of a higher likelihood of recurrence, to commence anticonvulsants after a second seizure would be appropriate in most cases. Some (Kilpatrick et al., 1990) but not all (Louis & McDowell, 1967) authors have reported that early seizures after stroke are easily controlled. A first prolonged seizure

or status epilepticus needs urgent therapy. A trial of anticonvulsant withdrawal if a patient has been seizure free for more than 2 or 3 years and is healthy enough to survive a recurrent seizure is reasonable. One must weigh up the risks of anticonvulsant therapy in the individual patient, especially as many will be elderly and particularly susceptible to adverse drug reactions and drug interactions (Reynolds 1975; Patsalos & Duncan, 1993; Scheuer & Cohen, 1993; Rambeck et al., 1996; Spina et al., 1996). Equally, the elderly are particularly vulnerable to injuries sustained from seizures (Grisso et al., 1991). In recent years a number of new anticonvulsants have been introduced. These include lamotrigine, vigabatrin, topiramate, gabapentin and tiagabine (Dichter & Brodie, 1996; Sander, 1996). As yet, these have not been evaluated specifically in the therapy of epilepsy related to cerebrovascular disease. However, they have the theoretical advantage of fewer adverse reactions and have demonstrated efficacy in other clinical situations.

Seizures preceding stroke Barolin (1982) coined the term ‘vascular precursor epilepsy’ for seizures preceding stroke. He described 69 cases in their neurology unit. Of these patients, 36 and 33, respectively, had focal and generalized seizures. Most of the patients with focal seizures experienced definite stroke of the relevant hemisphere within a year. He felt that such focal seizures were just as important a sign of impending stroke as transient ischemic attacks and an opportunity for prophylactic therapy. Cocito et al. (1982) reported that seizures (especially focal) may be the sole manifestation of subtotal or total internal carotid occlusion, and recommended a cerebrovascular assessment and risk factor management for patients with otherwise unexplained seizures. The basis for seizures preceding stroke symptoms for months or many years may be otherwise silent cerebrovascular infarction. Dodge et al. (1954) described three cases of focal epilepsy due to otherwise silent cortical infarction subsequently demonstrated at autopsy. Asymptomatic cerebral infarction detected on CT scan of patients presenting with their first or recurrent stroke are not uncommon and become more so with increasing age over 50 years (Jorgensen et al., 1994). Most of such infarcts are small and subcortical. It has been proposed that these infarcts are easier to see than small cortical ones that can be difficult to distinguish from atrophy. Hence, small subcortical infarcts may be a marker for vascular disease elsewhere and not directly responsible for seizures.

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Fp2-F8

7 nuV

F8-T4

7 uV

T4-T6

7 uV

T6-O2

7 uV

Fp1-F7

7 uV

F7-T3

7 uV

T3-T5

7 uV

T5-O1

7 uV

PG-PG

A.L. Abbott, C.F. Bladin and G.A. Donnan

– – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – – – — – – – – –— – – –

Fig. 13.1. Sample of an EEG showing PLEDS (periodic lateralizing epileptiform discharges) in the left temporal electrodes in a patient with cerebral ischemia. PLEDS is sometimes seen with focal cerebral pathology, especially watershed infarction demonstrated in the computerized tomogram (CT scan). In this case the infarction is bilateral and extensive, particularly in the left cerebral hemisphere.

Seizures and stroke

Further evidence for the epileptogenic potential for silent cerebral infarcts came from a study by Shinton et al. (1987) who showed an increased frequency of preceding epilepsy in first stroke patients compared to age, sex and race matched controls. In addition, patients with late onset unexplained epilepsy may have a higher prevalence of silent ischemic lesions on CT brain compared to age and sex matched controls (Roberts et al., 1988). The mechanism of silent ischemia and associated seizures may relate to internal carotid artery stenosis or occlusion and associated embolism, or hypoperfusion (Cocito et al., 1982). Regardless of the mechanism, unexplained seizures in an older population should be considered a marker for possible underlying cerebrovascular disease and appropriate investigations instigated.

Conclusions Seizures following stroke are common and occur in about 9% of patients overall, especially in the first few weeks. Seizures are more common after cerebral hemorrhage than infarction. The risk of epilepsy following stroke for the individual is low, about 3%, yet still higher than the age-matched population. Because stroke is common in older age groups, poststroke seizures and epilepsy are important community health issues. While little is known about the pathogenesis of seizures and epilepsy after stroke, it is clear that cortical location is a risk factor after both cerebral infarction and hemorrhage. Lesion size is such a predictor only after cerebral infarction. Underlying structural lesions increase the risk of seizures and epilepsy after intracerebral hemorrhage. A better understanding of the role of anticonvulsant therapy in the management and prophylaxis of poststroke seizures and epilepsy is required to provide guidelines for management. Currently, there is little clinical experience with the newer anticonvulsants in this setting, but an extrapolation of available data from studies in epilepsy would suggest that they are likely to be of use in the future.

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Shinton, R.A., Zezulka, A.V., Gill, J.S. & Beevers, D.G. (1987). The frequency of epilepsy preceding stroke. Lancet, i, 11–12. So, E.L., Annegers, J.F., Hauser, W.A. et al. (1996). Population based study of seizure disorders after cerebral infarction. Neurology, 46, 350–5. Spina, E., Pisani, F. & Perucca, E. (1996). Clinically significant pharnacokinetic drug interactions with carbamazepine. Clinical Pharmacokinetics, 31, 198–214. Sundaram, M.B.M.(1989). Etiology and pattern of seizures in the elderly. Neuroepidemiology, 8, 234–8. Sung, C.Y. & Chu, N.S. (1989). Epileptic seizures in intracerebral haemorrhage. Journal of Neurology, Neurosurgery and Psychiatry, 52, 1273–6. Sung, C.Y. & Chu, N. (1990a). Epileptic seizures in elderly people: aetiology and seizure type. Age and Aging, 19, 25–30.

Sung, C.Y. & Chu, N.S. (1990b). Epileptic seizures in thrombotic stroke. Journal of Neurology, 237, 166–70. Tallis, R., Gillian, H., Craig, I. & Dean, A. (1991). How common are epileptic seizures in old age? Age and Aging, 20, 442–8. Taylor, J. (ed.) (1958). Selected Writings of John Hughlings Jackson; edited for the quarantors of Brain. Vol 1. Epilepsy and Epileptiform Convulsions. New York: Basic Books Inc. Weisberg, L.A., Shamsnia, M. & Elliott, D. (1991). Seizures caused by nontraumatic parenchymal brain haemorrhages. Neurology, 41, 1197–9. Willmore, L.J., Sypert, G.W. & Munson, J.B. (1978). Recurrent seizures induced by cortical iron injection: a model for post-traumatic epilepsy. Annals of Neurology, 4, 329–36. Willmore, L.J. (1993) Post-traumatic seizures. Neurologic Clinics, 1, 823–33.

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Disturbances of consciousness and sleep–wake functions Claudio Bassetti Neurology Department, University Hospital, Bern, Switzerland

Introduction Quantitative and qualitative alterations of consciousness are frequently observed in stroke patients, rarely in the absence of major sensorimotor deficits (‘inobvious stroke’; Dunne et al. 1986). Disorders of wakefulness and delirium (acute confusional state), often in combination, are the most common disorders of consciousness in patients with acute stroke. In prospective studies, decreased levels of wakefulness – ranging from somnolence (hypersomnia) to coma – can be observed in 15–25% of patients (Bassetti, 2000; Bogousslavsky et al., 1988b; Melo et al., 1992), and acute confusional states are seen in up to 48% of patients (Gustafson et al., 1991). Less often, stroke causes coma-like states (akinetic mutism, locked-in syndrome), vegetative state, or other sleep–wake disturbances. Analysis of disturbances of consciousness and sleep–wake functions in stroke patients is of clinical interest. First, the presence of an altered consciousness may suggest topography or etiology of stroke. A severe impairment of wakefulness favours the presence of large hemispheric or (bilateral) brainstem strokes, whereas an acute confusional state is suggestive of a supratentorial stroke. In addition, a decreased level of consciousness is relatively common in patients with intracerebral hemorrhage (Bogousslavsky et al., 1988a), cardioembolic stroke (Kittner et al.,1990), and intracranial dissections (Bassetti et al., 1994a), being conversely rare in those with lacunar strokes. Secondly, patients with altered consciousness require different monitoring and therapeutical strategies. Early detection and prompt surgical treatment of patients with decreased levels of consciousness due to cerebellar stroke and large hemispheric stroke was shown, for example, to improve prognosis (Hornig et al., 1994; Mathew et al., 1995; Schwab et al., 1998). Thirdly, level of consciousness (as estimated, for example, by the Glasgow

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Coma Score) is among the best predictors of outcome in ischemic as well as hemorrhagic stroke (Broderick et al., 1993; Bushnell et al., 1999; Hénon et al., 1995; Lampl et al., 1995; Steiner et al., 1997; Tuhrim et al.,1988). The shortterm case fatality goes from 80% in comatose, to 60% in stuporous, and 40% in somnolent patients (Asplund & Britton, 1989; Melo et al., 1992). Finally, recent observations have shown that the prevalence of sleep disturbances is high not only in patients with brainstem strokes but also in hemispheric stroke patients (Bassetti et al.,1996a; Bassetti et al., 1997a,b; Markand & Dyken, 1976). Studies of sleep disorders in stroke patients not only could provide new insights into the mechanisms of sleep–wake regulation, but also may suggest new approaches to treatment (e.g. control of sleep apnea), and improve stroke outcome.

Physiology of consciousness and sleep–wake functions Consciousness can be defined as the ability to relate both to self and to environment (Cobb, 1957). From a pragmatic viewpoint, consciousness has been differentiated into its partial aspects of wakefulness (arousal, alertness, vigilance) and awareness. Awareness involves both a subjective experience (‘consciousness as such’) and the sum of higher cognitive and emotional functions (contents of consciousness).

Wakefulness (arousal systems) Wakefulness corresponds to the cortical ‘tone’ necessary to run the cognitive apparatus and depends on the integration of the ARAS (ascending reticular activating system) with the descending (cortico-reticular) pathways that modulate its function. The ARAS is viewed today as a functional system

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Fig. 14.1. The ascending reticular activating system (ARAS) in the upper pons and midbrain projecting diffusely to the cortex through synaptic relays in the midline (intralaminar, IL) and dorsomedial thalamic nuclei (thalamic route), and in the basal forebrain (BF, extrathalamic route). BG, basal ganglia, DM, dorsomedial nucleus of the thalamus (Drawing by C. Langenegger, AUM, University Hospital, Bern, Switzerland.)

in the upper brainstem and paramedian diencephalon (Fig. 14.1), which is organized in morphologically and biochemically distinct subgroups of neurons (Berlucchi, 1997; Jouvet, 1996; McCormick & Bal, 1997; Moruzzi & Magoun, 1949; Steriade, 1996). These bilateral, mainly adrenergic, cholinergic, and dopaminergic neuronal networks project diffusely to the cortex through synaptic relays in the midline (intralaminar) and dorsomedial thalamic nuclei (thalamic route) and in the basal forebrain (extrathalamic route) leading to a non-specific activation of the hemispheres (‘tonic arousal’) necessary for the awake or aroused state (Jones, 1994). Descending projecting neurons from the posterior hypothalamus (subthalamus) to brainstem, medulla, and spinal cord are necessary for the motor expression of this activated state (Chammas et al., 1999). Single reticulo-cortical as well as cortico-reticular neuronal systems, such as Nauta’s forebrain–midbrain circuit modulate the activity of the ARAS and, while regulating the level of cortical activation, subserve the capacity to focus and sustain attention to specific tasks and stimuli (‘phasic arousal’) (Contreras et al., 1996; Villablanca & Salinas-

Zeballos, 1972). An adequate tonic and phasic arousal of associative cortical regions is a requisite for a normal state of consciousness.

Awareness Awareness requires sufficient arousal and attention, and corresponds to the experience (‘consciousness as such’) and the sum of higher cognitive and emotional functions (contents of consciousness). Directing and maintaining attention to a specific task depends upon the function of the prefrontal cortex of the right hemisphere and its descending connection to the thalamus. These pathways allow selective gating of external inputs and consequently the choice between environmentally driven and internally driven behaviour. The ‘aroused and attentive’ brain is finally enabled by multiple partially segregated corticosubcortical circuits to perform such higher cognitive functions as memory, thinking and language. Awareness has been suggested to arise from the simultaneous activation (‘binding’) of these brain areas over a few milliseconds, a

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synchronization which, in turn, may depend on intrinsic oscillatory properties of thalamo-cortico-thalamic networks (Bogen, 1997; Munk et al., 1996; Paré & Llinas, 1995).

Sleep–wake cycle Modulation of the state of wakefulness and the appearance of a normal sleep–wake cycle depend on a complex reciprocal interaction between the wakefulness-maintaining systems of the ARAS (and its inputs) and sleep-promoting systems localized in the brainstem, anterior hypothalamus and basal preoptic area (Jones, 1994; Steriade, 1992). Sleep onset is accompanied by a decreased activity of the ARAS and an increased firing rate of ‘sleep neurons’ in basal forebrain and anterior hypothalamus. As a result, the transfer of sensory information at the level of the thalamic relay nuclei is diminished and thalamocortical neurons become hyperpolarized. Sleep spindles and slow wave sleep (1–4 Hz delta rhythms), the electrophysiological hallmarks of NREM sleep, arise from the interaction of increasingly hyperpolarized thalamocortical neurons with neuronal oscillators in the reticular thalamic nucleus (pacemaker of sleep spindles) and cerebral cortex (pacemaker of ⬍1 Hz rhythms) (Amzica & Steriade, 1998). The generators of the different REM sleep phenomena (EEG activation, muscle atonia, rapid eye movements) are located in the mediolateral tegmentum of the ponto-mesencephalic junction (Siegel, 1994). There is increasing support for the hypothesis that mental, motor (behavioural), autonomic, and EEG arousal may depend upon the action of different ascending and descending neuronal systems (Chammas et al., 1999; Holstege, 1992; Koella,1986). This diversity may explain how different focal brain lesions may lead to such ‘dissociated states’ as normal mental wakefulness with insufficient motor arousal (akinetic mutism) (Cairns et al., 1941), hyperkinesia with mutism (Inbody & Jankovic, 1986), behavioral coma with normal EEG (alpha-coma EEG) (Loeb & Poggio, 1953), alert state with severely disturbed EEG (Cravioto et al., 1960), intrusion of REM motor atonia (cataplexy) or dreaming (peduncular hallucinosis) in the awake state (Lhermitte, 1922).

Disturbances of consciousness and sleep–wake functions Disorders of wakefulness In clinical practice, wakefulness and awareness are often affected together but the profile of involvement of arousal,

and of cognitive, motor, and vegetative functions may differ depending on the topography, nature, and time course of the underlying lesion. Disorders of wakefulness can be differentiated clinically depending on the intensity of stimulation needed to arouse the patient in: (i) hypervigilance (hyperalertness, hyperarousal), (ii) normal arousal, (iii) hypersomnia (drowsiness, somnolence, sleepiness) (iv) sopor (stupor), and (v) coma. In patients with large cortico-subcortical hemispheric strokes, disorders of wakefulness are the first symptom of developing brain edema due to vertical (transtentorial herniation) or horizontal (midline shift of the pineal gland) displacement of the brain with disruption of the upper brainstem (McNealy & Plum, 1962; Plum & Posner, 1980; Ropper, 1986; Ropper & King, 1984). Disturbances of wakefulness are accompanied by the clinical features of ‘uncal’ and ‘central’ syndromes (Plum & Posner, 1980), which typically precedes a critical rise in the intracranial pressure (Franck, 1995; Schwab et al., 1996). Pupil enlargement contralateral to hemiparesis is characteristic of ‘uncal syndrome’ (herniation of the medial temporal lobe into the space between the edge of the tentorium and the midbrain). The other pupil may subsequently present a diminished light reaction and a reduction or increase in size (Ropper, 1990). The ‘central syndrome’ (downward displacement of the upper brainstem through the tentorium) is characterized by initially bilaterally small and reactive pupils, which later may be in midposition and become areactive (Plum & Posner, 1980). In both syndromes decreased wakefulness and pupillary abnormalities are accompanied by paratonia and Babinski‘s sign contralateral to hemiparesis and periodic (Cheyne–Stokes) breathing (Broderick et al., 1993; Ropper & Shafran, 1984). In deep (subcortical) hemispheric strokes sparing the thalamus dearousal is usually mild and transient, probably because of the widespread distribution of ARAS projections at this level. The occasional observation of significant hypersomnia following anterior caudate and other deep hemispheric stroke suggests that subcortical centres may play a more important role in sleep–wake functions than usually considered (Braun et al., 1997; Villablanca et al., 1976). The rare occurrence of hypersomnia following corticosubcortical hemispheric strokes without mass effect supports the hypothesis of a role of the cerebral cortex in sleep–wake functions (Bassetti, 2000;Villablanca & Marcus, 1972). A few positron emission tomography studies suggested that hypersomnia may be related in these patients to a reduced metabolism of the contralateral hemisphere (‘transhemispheric diaschisis’) (Lenzi et al., 1982).

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In patients with brainstem stroke, disorders of wakefulness are due to direct disruption of the ARAS (Cairns, 1952; Plum & Posner, 1980). The most severe and persisting disturbances of wakefulness are seen in patients with thalamic, subthalamic, midbrain and upper pontine strokes, where fibres of the ARAS are bundled and can be severely affected by a single lesion. Mental arousal seems to be affected more by medial lesions, whereas involvement of lateral portions of the ARAS may impair preferentially motor arousal (Castaigne & Escourolle, 1967; Passouant et al., 1967). In paramedian thalamic lesions (even without subthalamic extension) the initial clinical picture may be similar to disturbance of consciousness of midbrain origin but recovery is usually better, probably because of the existence of an extrathalamic route of cerebral activation (Jones, 1994). The core of the lesion in these patients involves the dorsomedial nucleus (particularly its magnocellular part) and intralaminar (midline) nuclei (Bassetti et al., 1996b; Castaigne et al., 1981). Patients with lower pontine and medullary strokes have usually no, or only a limited, effect on arousal (Bassetti et al., 1997c; Toyoda et al., 1996). Insomnia, sleep deprivation, seizures, drugs, and systemic complications (fever, infections, metabolic disturbances) may contribute to decreased arousal in all patients with stroke. Genetic factors may play a role in determining the variable clinical effects of similar brain lesions in different patients (Bassetti, 2000).

Hypersomnia (drowsiness, somnolence, sleepiness) Hypersomnia can be defined on clinical grounds as an exaggerated sleep propensity with excessive daytime sleepiness, increased daytime napping or prolonged nighttime sleep. Patients are drowsy or appear asleep, show little interest in the environment, may be difficult to arouse or to stay awake once awakened. Verbal stimuli are usually sufficient to elicit speech and appropriate motor behaviour. Hypersomnia can appear after an initial period of sopor or coma, less commonly of hypervigilance with insomnia. Hypersomnia is often associated with inattention, decreased motor activity, reduced speech production, and flattening of mood. As a direct effect of brain damage poststroke hypersomnia may arise from decreased wakefulness (somnolence, ‘passive’ hypersomnia, or dearousal), enhanced sleep mechanisms (sleepiness or ‘active hypersomnia’), or both (Davison & Demuth, 1946a,b; Passouant et al., 1967). Both somnolence and sleepiness are characterized by a reduced latency to sleep. The somnolent patient usually presents – in addition to a disturbed state of consciousness – other neurological or neuropsychological deficits.

Conversely, the sleepy patient has usually – once aroused – a normal neurological examination. In clinical practice, somnolence and sleepiness may, however, be difficult to separate, evolve to each other or even coexist. ‘Passive’ hypersomnia is due to damage of the ARAS (see above). ‘Active’ hypersomnia with increased production of sleep can be induced in the cat by small, bilateral lesions of the periaqueductal gray and reticular formation at the ponto-mesencephalic junction (Petitjean et al., 1975; Sastre et al., 1996). In patients with poststroke hypersomnia, an increased sleep production has been documented by EEG criteria in only a few patients with thalamic, mesencephalic and pontine stroke (Arpa et al., 1995; Bassetti et al., 1996b; Bastuji et al., 1994). In large cortico-subcortical hemispheric strokes hypersomnia is accompanied by an ipsilateral (to the lesion) gaze palsy or preference and head deviation, contralateral severe sensori-motor hemisyndrome, visual field deficits, and variable neuropsychological deficits (Hacke et al., 1996). Hypersomnia, which is usually only transient, can be seen also in the absence of significant brain edema (see also above) in anterior more than posterior strokes, and in left more than right hemispheric strokes (Albert et al., 1976; Glosser et al., 1999). In a prospective study of 47 patients, Albert et al. found for example an impairment of arousal in 57% of patients with left hemispheric strokes and in only 25% of those with similarly extensive right hemispheric lesions (Albert et al., 1976). This as well as other similar observations supports the hypothesis of a left hemispheric dominance for wakefulness (Ahern, 1995; Glosser et al., 1999). In patients with frontal (particularly cingulate) stroke akinetic mutism may be misinterpreted as hypersomnia (Buge et al., 1975).

Castaigne and Escourolle reported a 66-year-old patient with bilateral anterior cerebral artery stroke and severe hypersomnia persisting over a few months (Castaigne & Escourolle, 1967). We recently observed a 40-year-old patient with left cortico-subcortical, partial middle-cerebral artery stroke in whom profound hypersomnia was present for the first 4–5 days after stroke despite the absence of both mass effect on brain-MRI and medical complications (Fig. 14.2).

Hypersomnia can occasionally complicate also deep (subcortical) hemispheric strokes involving uni- or bilaterally the caudate nucleus, putamen, globus pallidum, or capsula interna. In such cases apathy, athymormia, and

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Fig. 14.2. Brain MRI (axial T2-images) of a 40-year-old woman with left cortico-subcortical middle-cerebral artery stroke. During the first 4–5 days after stroke the patient appears asleep during 12–13 hours per day, is depressed, and has crying spells. Hypersomnia (somnolence) resolves within 1 week (see also text). (Courtesy of Professor G. Schroth, Division of Neuroradiology, University Hospital, Bern, Switzerland.)

akinetic mutism (see below) are also commonly seen. Caplan et al. reported, for example, abulia in 10 of 18 patients with acute caudate stroke, occasionally alternating with periods of confused hyperactivity with restlessness, insomnia and hallucinations (Caplan et al.,1990).

In a 68-year-old woman with left paraventricular striatocapsular stroke and mild sensorimotor deficits, a profound inversion of sleep–wake cycle were first noted. Two weeks later daytime hypersomnia had almost recovered, while nighttime insomnia with estimated 2–3 hours of sleep per night was still present. Sleep–wake functions finally normalized 4 weeks after stroke onset.

Unilateral and particularly bilateral (‘en ailes de papillon’) paramedian thalamic strokes in the territory of the anterior thalamic–subthalamic (or thalamoperforating) arteries present typically with the triad hypersomnia, supranuclear vertical gaze defects and confabulatory (Korsakow-like) amnesia (the so-called ‘paramedian dien-

cephalic syndrome’ (Meissner et al., 1987)). Hypersomnia, which was found in a review of the literature in 15 of 40 cases of paramedian thalamic stroke, appears typically after an initial short-lasting coma, less commonly after an agitated delirium (Gentilini et al., 1987). In patients with bilateral thalamic strokes, hypersomnolent behaviour may be present for ⬎20 hours per day and mimic physiologic sleep with normal postures, regular quiet breathing and rapid arousability (Bassetti et al., 1996a). In patients with a unilatreal stroke extending to the midbrain, however, hypersomnia may persists for weeks or even months (Bassetti et al., 1996a; Freund, 1913). Hypersomnia may correspond in other patients to a preparatory behaviour for sleep rather then ‘true sleep’ (Catsman-Berrevoets & Harskamp, 1988). During this socalled ‘pre-sleep behaviour’, the patients yawn, stretch, close their eyes, curl up and assume a normal sleeping posture while complaining of a constant urge to sleep. When stimulated or given explicit tasks to perform, these patients are, however, able to control their behaviour. In patients with unilateral paramedian thalamic stroke, hypersomnia is usally mild and transient. Additional symptoms of paramedian thalamic strokes include dysarthria, gait instability, skew deviation, Horner’s syndrome, hypogeusia, hyposmia, incontinence. Breathing is usually unaffected. Some patients also present a ‘frontal lobe syndrome’ with anosognosia, hyperphagia (and weight gain), hypersexuality, ‘utilization behaviour’, and altered mood (Bassetti et al., 1996a; Eslinger et al., 1991; Gentilini et al., 1987; Guberman & Stuss, 1983). Flat or depressed mood is frequently observed. Less commonly, patients present with insomnia, hallucinatory confusional state, logorrhea, euphoria with childish behavior, and motor restlessness with compulsive-like activity (Bogousslavsky et al., 1988a; Feinberg & Rapcsack, 1989; Fukatsu et al., 1997; Walther, 1945). Hypersomnia after thalamic stroke can persist for several months or years or evolve to apathy and dementia (Castaigne et al., 1966; Gentilini et al., 1987; Schuster, 1937).

A 60-year-old patient with bilateral paramedian thalamic stroke presented with abrupt coma followed by sleep behaviour over 19 hours per day, complete vertical gaze palsy, ‘frontal’ behaviour, moderate amnesia, hyperphagia and hypersexuality (Fig. 14.3). One week after stroke onset the patient is ‘asleep’ by actigraphic criteria over 80% of the time. At 8 months the patient still sleeps 12 hours per day. Methylphenidate (20 mg per day) and mazindol (4 mg per day) do not improve hypersomnia. Because of attentional and mnestic deficits,

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of a frequent common arterial supply through the socalled thalamo-perforating pedicle of Foix and Hillemand, upper mesencephalic strokes can extend to paramedian thalamic structures and give rise to a variety of possible clinical pictures. Isolated mesencephalic or thalamo-mesencephalic strokes are less common than strokes involving simultaneously midbrain, superior cerebellum and occipital cortex – (so-called top of the basilar syndrome (see also ‘Stuper and coma’, p. 198; Caplan, 1980). The severity of hypersomnia is variable and even in a single patient fluctuations between coma, hypersomnia and akinetic mutism are observed (Brage et al., 1961). Mesencephalic hypersomnia is characteristically associated with hypnagogic hallucinations (so-called peduncular hallucinations, see also ‘Hallucinations and altered dreaming, p. 202). III nerve palsy, a vertical gaze impairment and (less commonly), contralateral sensory and – occasionally – motor deficits (tremor, hemiparesis or ataxia).

Fig. 14.3. Brain MRI (coronal T2-images) of a 60-year-old man with bilateral paramedian thalamic stroke of cardiac origin presenting with initial coma evolving to severe hypersomnia (sleep-like behaviour over 19 hours per day) with severe upgaze palsy and amnesia. At 8 months the patient still reports sleeping 12 hours per day (see also text). (Courtesy of Professor G. Schroth, Division of Neuroradiology, University Hospital, Bern, Switzerland.)

the patient has to retire from work. Two years after stroke onset, hypersomnia has clinically improved to 9–11 hours sleep per day (Bassetti et al., 1996a).

Hypersomnia is also very characteristic of tegmental mesencephalic strokes due either to occlusion of the posterior thalamic–subthalamic (superior mesencephalic) arteries or to occlusion of the inferior mesencephalic arteries. The presence of a bilateral lesion is usually required but mild and transient hypersomnia is occasionally observed also in unilateral lesions (Claude & Loyez, 1912). Because

Façon et al. (1958) described a 78-year-old patient with bilateral tegmental mesencephalic infarct due to basilar thrombosis presenting with a bilateral III nerve palsy including ptosis, bilateral Babinski’s sign, hallucinations and severe hypersomnia. The latter was accompanied by an inversion of the sleep–wake cycle with nocturnal agitation and it persisted unchanged until his death 3 years later. A 54-year-old patient with right paramedian tegmental mesencephalic stroke of cardiac origin (coronarography) presented with peduncular hallucinosis, transient hypersomnia, skew deviation, amnesia, and vertical-oneand-a-half syndrome (Fig. 14.4). The patient reported the vision over several minutes of a group of dwarf-like figures, accompanied by tigers, and headed by a small girl in bright-orange dress.

Upper tegmental pontine stroke is suggested by the association of hypersomnia with ipsilateral IV nerve palsy, nystagmus, internuclear ophthalmoplegia, irregular breathing, and contralateral (or bilateral) sensory and motor deficits. Compared to thalamic and midbrain lesions, rostral pontine strokes lead more commonly to coma (see below) than to hypersomnia or akinetic mutism

Van Bogaert (1926) reported a 47-year-old patient with right tegmental ponto-mesencephalic stroke presenting with right IV and VII nerve palsy, facial myoclonus, right hemiparesis, severe, imperative (narcolepsy-like)

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Fig. 14.4. Brain MRI (axial T2-images) of a 54-year-old man with right paramedian tegmental mesencephalic stroke of cardiac origin presenting with transient hypersomnia, peduncular hallucinosis, skew deviation, amnesia, and vertical one-and-ahalf syndrome (see also text). (Courtesy of Dr A. Uske, Division of Neuroradiology, University Hospital, Lausanne, Switzerland.)

hypersomnia, and increased dreaming persisting until death five months later. Arpa recently reported a 44-year-old man with a right lateral-tegmental pontine hematoma and severe hypersomnia, in whom long-term EEG-monitoring showed, during the first 3 months after stroke, increased amounts of sleep ranging from 11 to 15 hours per day (Arpa et al.,1995).

In lower tegmental pontine and medullary strokes, a mild hypersomnia is occasionally observed (Bassetti et al., 1997a,b; Davison & Demuth, 1946a,b; Rousseaux et al., 1993).

Stupor (sopor) and coma Stupor and coma correspond to more advanced stages of impaired arousal. In stupor patients usually appear to be asleep and awaken only when stimulated with a loud voice

or vigorous shaking. They may be agitated or combative at such times but they do not communicate in a meaningful way apart from monosyllabic sounds, groans, and simple behaviors. They return to a sleep-like state as soon as stimulation ceases. Coma refers to a sleep-like state of unarousability in which consciousness is completely absent. Comatose patients keep their eyes closed even after painful stimuli, are not capable of any comprehensible verbal response, do not obey commands, and do not localize painful stimuli, although they may make posturing and reflexive responses. The percentage of patients in coma ranges from 5–18% in ischemic stroke to 31–55% in intracerebral hemorrhage (ICH) (Melo et al.,1992). In patients with hemispheric strokes, stupor and coma develop progressively over time with the clinical features of ‘central’ or (less commonly) ‘uncal’ syndromes (Plum & Posner, 1980; Ropper & Shafran, 1984), see also above). Stupor and coma are associated with a horizontal pineal displacement of greater than 4–8 mm which is usually maximal 4–5 days after stroke onset (Franck, 1995; Pullicino et al., 1999; Ropper, 1986). In patients with intracerebral hemorrhages, disturbances of wakefulness can have an abrupt onset, particularly in patients with basal ganglia hematomas. In hematomas ⬎55 cm3 coma was found in 14 of 17 patients (Kase & Caplan, 1994). In brainstem strokes coma may appear abruptly as a consequence of bilateral thalamic, midbrain or upper pons lesions (Cairns, 1952). Sudden disturbances of wakefulness, with delirium, hemi-tetraparesis, ataxia, gaze palsy, pupillary abormalities, and cortical blindness are typical features of the ‘top of basilar’ syndrome related to embolism of the rostral part of the basilar artery (Caplan, 1980; Mehler,1988, 1989). In most cases, some spontaneous fragmentation of the embolus occurs leaving multiple infarcts involving the paramedian thalamus (80% of cases), occipital lobes (46%), cerebellum (44%), midbrain (29%), and pons (18%) (Schwarz et al., 1997). As a consequence of spontaneous recanalization, over 40% of patients with ‘top of the basilar syndrome’ have a good outcome with no or only minor deficits (Schwarz et al., 1997). Sudden coma as well as coma of progressive onset are typical features also of basilar artery occlusion. Coma was found at hospital admission, for example, in 26 out of 85 consecutive patients with angiographic proven basilar artery occlusion (Ferbert et al., 1990). In these patients, particularly when the pathogenesis is local atherothrombosis, mortality exceeds 80%. After thrombolytic treatment, survival may be achieved in up to 50% of patients (Brandt et al., 1996; Ferbert et al., 1990; Kubik & Adams, 1946). Disturbances of wakefulness reaching from somnolence to coma, occa-

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sionally associated with hyperthermia, increased sweating and tachycardia, are seen also in patients with isolated ventro-tegmental infarcts of the pons or pontine hemorrhage (Bassetti et al., 1996b; Wijdicks & St. Louis, 1997). Finally, in patients with cerebellar infarcts and hemorrhages, coma can appear within a wide range of time (minutes up to 10 days), typically between day 3 and 4, after onset of symptoms due to compression of the brainstem, from upward or downward herniation (Cuneo et al., 1979; Hornig et al., 1994). Coma is rarely a permanent state, probably because of redundancy of activating systems, and most patients either die or regain identifiable sleep–wake cycles after a few days or weeks. Mortality of stroke patients in stupor and coma, particularly when requiring mechanical ventilation, is as high as 80% (Bushnell et al., 1999; Melo et al., 1992; Wijdicks & Scott, 1996). Coma persisting over more than a few days or weeks is rare and usually associated with bilateral pontine and mesencephalic strokes (Chase et al., 1968; Ingvar & Sourander, 1970; Obrador et al., 1975).

Hypervigilance (hyperarousal) Although decreased arousal is most often encountered in organic brain disorders, the opposite occasionally is observed. Hypervigilance may be caused by an increase in activity of systems maintaining wakefulness or by impairment of sleep promoting mechanisms as can occur with lesions of the anterior hypothalamus, thalamus or brainstem. Hypervigilance, insomnia (see ‘Insomnia’), inversion of sleep–wake cycle and delirium often coexist in the same patient (Girard et al., 1962; Van Bogaert, 1926).

Syncope Syncope is defined as a short and transient loss of consciousness with loss of postural control. Syncope is rarely caused by TIA or stroke (Davidson et al., 1991; Kapoor, 1983). Among a series of 551 patients with acute cerebrovascular disorders, syncope was observed in 6% of those who had suffered stroke and in less than 1% of those with TIAs (Bousser et al., 1981), more often in the carotid than in the vertebrobasilar territory. About half of all cases were attributed to seizures, and the rest to brainstem ischemia (with impairment of the ARAS) or to bihemispheric dysfunction related to diaschisis.

Coma-like conditions Patients in coma after stroke usually have a simultaneous involvement of ARAS and motor pathways. However, due to the anatomic segregation of the two systems in the ventral and tegmental portions of the brainstem respec-

tively, there is no close correlation between impairment of consciousness and motor dysfunction (Cairns, 1952). Occasionally, even a dissociated involvement of the two systems is possible with, at the one extreme patients with preserved ARAS but tetraplegia (locked-in syndrome and its variants) and, at the other extreme, patients with preserved motor control but disrupted ARAS (akinetic mutism).

Akinetic mutism The term akinetic mutism was coined by Cairns to describe a patient with an epidermoid cyst of the third ventricle, who was mute and immobile, but followed with her eyes the observer as well as moving objects and who could be brought by repetitive stimulation to ‘whisper few monosyllables’ and ‘slow feeble voluntary movements’, in the absence of ‘gross alterations of sensory–motor mechanisms operating at a more peripheral level’ (Cairns et al., 1941). Akinetic mutism (a.m.) represents an extreme form of abulia (abulia major) due to disruption of reticulothalamo-frontal and extrathalamic reticulo-frontal afferents. Two forms of a.m. have been identified. The first variety of a.m. has been described in patients with bilateral occlusion of the anterior cerebral arteries (Fig. 14.5) and hemorrhages (with vasospasm) from anterior communicating aneurysms. In a literature review of patients with bilateral infarctions in the territory of the anterior cerebral artery, a.m. was found in seven of eight cases (Minagar & David, 1999). Damage to the cingulate gyri seems to be crucial but alone not sufficient for the appearance of a.m. (Buge et al., 1975; Plum & Posner, 1980). Additional features of this ‘fronto-diencephalic’ variety of a.m. are urinary incontinence, normal wakefulness, grasping and bifrontal or generalized EEG-slowing, with lack of desynchronization following external stimuli. The second variety of a.m. has been observed in paramedian thalamic and thalamomesencephalic strokes and is characterized by the association of akinetic mutism with disturbances of vertical eye movements and hypersomnia (Lhermitte et al., 1963; Segarra, 1970). Occasionally, the discrepancy between hetero- and autoactivation can be extreme, with normal (or almost normal) behaviour of the patients under the influence of exogenous stimulation. This particular form of abulia or a.m. has been observed in bilateral deep lesions of the frontal white matter or of the basal ganglia (especially of the globus pallidum) and has been called athymormia (loss of psychic self-activation or ‘pure psychic akinesia’) (Bogousslavsky et al., 1991; Laplane, 1990; Laplane et al., 1984). Finally, a lesser degree of abulia (abulia minor) has been described also in bilateral caudate

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1979; Patterson & Grabois, 1986). Recovery is possible not only in incomplete LiS but also in patients with complete LiS and persistence of tetraparesis for months (McCusker et al., 1982; Yang et al., 1989). Bilateral, simultaneous deep hemispheric strokes (usually involving the capsula interna) can cause a clinical picture similar to akinetic mutism and LiS, for which different terms have been used in the literature (Chia, 1984; De Smet et al., 1990; Ferbert & Thron, 1992; Nicolai & Lazzarino, 1993). Because of the direct disruption of cortico-spinal and cortico-bulbar pathways and because of the normality of horizontal eye movements it should rather be called anarthric tetraparesis.

Disorders of awareness* *Most related clinical syndromes are presented in other chapters of this book (in particular ‘Agitation and delirium’ by A. Yamadori)

The spectrum of disorders of awareness is wide and includes relatively isolated dysfunctions of such specific functions as memory or language, or more diffuse disturbances of mental activities as occur with delirium, dementia or the vegetative state.

Delirium (acute confusional state) Fig. 14.5. Brain CT of a 24-year-old woman with bilateral strokes in the territory of the Heubner’s arteries due to spontaneous intracranial dissection of the anterior system presenting with akinetic mutism. (With permission from Bassetti et al., 1994a,b.)

stroke, thalamic infarcts in the territory of the polar artery and infratentorial stroke (Fisher, 1983).

Locked-in syndrome The term locked-in syndrome (LiS) was coined in 1966 by Plum and Posner for a condition first described by Alexander Dumas with the figure of the Count of Villefort in his book ‘Le comte de Monte-Cristo’ (Plum & Posner, 1980). The criteria of classical LiS are paralysis of all cranial nerves except vertical eye movements, tetraplegia and preserved consciousness. A differentiation between transient and chronic form as well as between incomplete, classical and total locked-in syndrome (LiS) has been proposed (Bassetti et al., 1994a,b; Bauer et al., 1979). LiS is classically due to bilateral pontine infarction (Fig. 14.6), related to basilar thrombosis, bilateral occlusion of paramedian arteries and vertebral artery dissection (Fisher, 1977; RaeGrant et al., 1989). Occasionally, LiS can be due to bilateral midbrain stroke (Karp & Hurtig, 1974; Meienberg et al.,

Delirium is characterized by reduced ability to maintain attention; disturbance of immediate memory; and disorganized, slowed, and impoverished thinking (Lipowski, 1990; Taylor & Lewis, 1993). Disorientation, altered shortterm and long-term memory, illusions, and hallucinations are frequently but not invariably present. Although delirium usually is accompanied by decreased arousal and psychomotor slowing, occasionally it may be characterized by hypervigilance and enhanced psychomotor activity. Occasionally, there is a ‘dreamy’ or ‘twilight’ state associated with partial loss of contact with the outer world. The severity of delirium typically waxes and wanes, occasionally from minute to minute, and may be interrupted by relatively lucid moments. Exacerbation of delirium in the night hours is typical and is called ‘sundowning’. Associated nighttime insomnia (Fisher, 1983), and daytime hypersomnia are common (Bassetti et al., 1996a). Stroke of any topography may lead to delirium (Bassetti & Regli, 1994; Fisher, 1983; Gustafson et al., 1991), although tegmental mesencephalic (Mehler, 1989), and paramedian thalamic (Bogousslavsky et al., 1988a), basal ganglia (Bhatia & Marsden, 1994; Caplan et al., 1990), right frontotemporal (Mori & Yamadori, 1987), and occipital strokes (Devinski et al., 1988) have been more commonly implicated with this disturbance of consciousness.

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Other disorders of sleep Due to the widespread anatomo-physiological organization of wakefulness, NREM sleep and REM sleep, other disorders of sleep–wake functions – in addition to the already mentioned hypersomnia – can be found in patients with both supra- as well as infratentorial stroke ranging from severe insomnia and other clinically relevant disturbances to subclinical polysomnographic findings.

Insomnia

Fig. 14.6. Brain MRI (sagittal T1-images) of a 36-year-old man with bilateral ventral pontine infarction due to basilar thrombosis presenting with a ‘locked-in syndrome’. (With permission from Bassetti et al., 1994a,b.)

Vegetative state This syndrome is defined as an awake-but-unaware condition with preservation of vital vegetative functions and absence of all cognitive functions (Jennett & Plum, 1972; The Multi-Society Task Force, 1994a,b). Spontaneous eye opening, yawns, chewing, grimacing, and other reflex motor actions occur along with spontaneous respiration. The lack of awareness and cognition is apparent in the inability of such patients to respond in a learned manner to external stimuli and the absence of sustained, reproducible, purposeful, or voluntary responses to stimulation. The reduction in cognitive and metabolic activity is usually associated with extensive damage to cortex and subcortical structures with relative sparing of brainstem structures; preserved brainstem function accounts for the persistence of autonomic functions and sleep–wake cycle. Less commonly, PVS can follow more or less selective damage of paramedian thalamic structures, emphasizing the key role of these structures in cognitive processes (Kinney et al., 1994). The vegetative syndrome has no topographic specificity and can follow different types of brain injury (head trauma, diffuse cerebral hypoxia, stroke or diffuse encephalopathies) (Jennett & Plum, 1972). In non-traumatic cases, persistence for over 1 month carries a very poor prognosis, provided that the diagnosis is accurate (Childs et al., 1993).

Insomnia is a frequent, usually non-specific, and often multifactorial complication of acute stroke. Insomnia may predispose to such quantitative and qualitative disturbances of consciousness as delirium and hypersomnia (see above), and may slow poststroke functional recovery. Recurrent arousals, sleep discontinuity and sleep deprivation can result from pre-existing disorders (e.g. congestive heart failure, chronic pulmonary disease). Seizures, sleepdisordered breathing (see ‘Sleep disordered breathing’, p. 202); drugs, infections and fever, inactivity, environmental disturbances (e.g. noise, medical controls and tests, light) and emotional stress are other stroke-related factors predisposing to insomnia. Insomnia as a direct consequence of brain damage (agrypnia) is less common in stroke patients but may occur, often in association with inversion of the sleep–wake cycle and depressive symptoms (Garrel et al., 1966; Girard et al., 1962; Rondot et al., 1986; Van Bogaert, 1926). The occasional observation of patients with rapid transition from insomnia to hypersomnia emphasizes the dual influence of such brain areas as thalamus, basal forebrain and ponto-mesencephalic junction in sleep–wake regulation (Bogousslavsky et al., 1988a; Fisher, 1983; Hösli, 1962; Jones, 1994).

Van Bogaert reported a patient with thalamohypothalamic stroke, who presented an almost complete insomnia over more than 2 months (Van Bogaert, 1926) . Freemon reported a patient with a ‘locked-in’ syndrome following brainstem infarction of the basis pontis bilaterally, left pontine tegmentum and pontine and mesencephalic raphae nuclei who presented with severe polygraphically confirmed insomnia, which was almost complete for at least 1 month (Freemon et al., 1974). Stroke patients occasionally have an inversion of the sleep–wake rhythm, which is usually characterized by insomnia with agitation during the night and by hypersomnolence during the day.

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Sleep disordered breathing* *see also chapter on ‘Respiratory dysfunction’ by F. Vingeroets

The presence of breathing disturbances in stroke patients has been linked in several studies with a poorer outcome (Dyken et al., 1996; Good et al., 1996; North & Jennett, 1974; Rout et al., 1971). Breathing disturbances are more common during sleep than during wakefulness (Bassetti et al., 1997b; Lee et al., 1974; North & Jennett, 1974). Several studies have shown that sleep disordered breathing (SDB) can be found in over 50% of patients with acute TIA or stroke (Bassetti & Aldrich, 1999; Bassetti et al., 1996a; Dyken et al., 1996). Specific types of poststroke breathing disorders have limited topographic specificity (Bassetti et al., 1997a; Lee et al., 1974, 1976). Supratentorial stroke is, however, often associated with Cheyne–Stokes breathing, whereas central hyperventilation, central apnea, apneustic breathing, and ataxic breathing usually indicate the presence of infratentorial stroke. Finally, OSA is found in both supra- and infratentorial strokes.

Obstructive sleep apnea (OSA) This is the most common type of SDB in patients with acute cerebrovascular disorders. Although patients at risk for cerebrovascular disease frequently have OSA before they experience a stroke, in some patients OSA appears to have been aggravated (e.g. by sleep disruption, Cheyne–Stokes breathing) or even caused ‘de novo’ (e.g. medullary infarction, severe pharyngeal palsy) by acute brain ischemia. OSA can influence the course of cerebrovascular diseases in different ways. Chronically, recurrent nocturnal respiratory events and hypoxemia (Fig. 14.7) may lead to hypertension, heart disease, increased platelet aggregation, decreased fibrinolysis, and increased atherogenesis (Bassetti & Aldrich, 1999). Acutely, hypopneas and apneas may lead to brady- and tachyarrhythmias, hypotension, decreased cardiac output, increased intracranial pressure, decreased cerebral blood flow, and eventually brain ischemia (Bonsignore et al., 1994; Diomedi et al., 1998; Fischer et al., 1992; Leslie et al., 1999; Netzer et al., 1998).

Cheyne-Stokes breathing (CSB) This is well known in bihemispheric stroke, heart failure, somnolence, and brain edema with increased intracranial pressure (Brown & Plum, 1961; Heyman et al., 1958). Recent studies have shown, however, that CSB is also frequent in awake patients without cardiac disease who have had a unilateral hemispheric or infratentorial stroke (Bassetti et al., 1997a,b; Hudgel et al., 1993; Nachtmann et al., 1995). Finally, CSB and OSA may occur in the same

patient and exacerbate each other (Nachtmann et al., 1995; North & Jennett, 1974). Strokes in the frontal cortex, basal ganglia or capsula interna may cause respiratory apraxia, with impairment of voluntary modulation of breathing amplitude and frequency, leaving patients unable to take a deep breath or hold the breath (Plum, 1970). Volitional breathing can be impaired also by brainstem strokes involving corticobulbar and corticospinal pathways at pontine and medullary levels (Munschauer et al., 1991; Plum, 1970). Sustained respiratory rates above 25–30/minute in the absence of hypoxemia (neurogenic hyperventilation) were originally described in six comatose patients with ventro-tegmental pontine strokes (Plum & Swanson, 1959), but were subsequently attributed to stimulation of lung and chest wall afferent reflexes due to pulmonary congestion (Plum & Posner, 1980). Inspiratory breath holding (apneustic breathing), originally described in two patients with bilateral ventro-tegmental infratrigeminal pontine stroke (Plum & Alvord, 1964), is rare and usually secondary to basilar artery occlusion. Erratic variations in breathing frequency and amplitude (ataxic or Biot’s breathing), and failure of automatic breathing (central sleep apnea or Ondine’s curse), usually imply a lateral, often bilateral medullary stroke (Bogousslavsky et al., 1990; Levin & Margolis, 1977). Damage to the medullary reticular formation and nucleus ambiguus may be sufficient to cause a loss of automatic breathing, while a lesion that also includes the nucleus tractus solitarius is necessary to cause failure of both automatic and voluntary respiration (Bogousslavsky et al., 1990).

Hallucinations and altered dreaming Patients with tegmental mesencephalic strokes (Fig. 14.4) and, less commonly, with paramedian thalamic strokes, may experience vivid dream-like hallucinations that are complex, colourful, full of motion, and typically occur in the evening and at sleep onset, Lhermitte’s peduncular hallucinosis (Feinberg & Rapcsack, 1989; Garrel et al., 1966; Howlett et al., 1994; Lhermitte, 1922; Van Bogaert, 1924). The original patient described by Lhermitte had, in addition to the complex visual hallucinations, an inversion of the sleep–wake cycle with nocturnal insomnia and daytime hypersomnia (Lhermitte, 1922). Peduncular hallucinosis may represent a release of REM sleep mentation (Mahowald & Schenck, 1992), can be associated with insomnia and usually resolves spontaneously.

Disturbances of consciousness and sleep–wake functions 203

Fig. 14.7. Polysomnographic study of a 51-year-old man performed 2 days after a severe middle cerebral artery stroke. There is a severe sleep-disordered breathing (apnea–hypopnea index ⫽ 48) consisting of mainly mixed and obstructive apneas with severe oxygen desaturations (minimal SaO2 ⫽ 33%). The figure shows an apneic event during light NREM sleep of a duration of almost 90 seconds with accompanying SaO2-desaturation to 54.5%.

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Similar hallucinatory phenomena can be seen also in patients with delirium and right temporal and occipital stroke (Milandre et al., 1994; Mori & Yamadori, 1987). The Charles Bonnet syndrome generally involves less complex visual hallucinations that also occur in the setting of diminished arousal (Lepore, 1990; Teunisse et al., 1996). These hallucinations represent ‘release phenomena’ of strokes that involve visual loss and may be limited to a hemianopic field (Martin et al., 1992; Vaphiades et al., 1996). Cessation or reduction of dreaming occurs in the Charcot–Wilbrand syndrome and is occasionally limited to alteration of the visual component of the dream (as in the original patient described by Charcot) (Charcot, 1883; Gloning & Sternbach, 1953; Grünstein, 1924; Solms, 1997; Wilbrand, 1887). This syndrome can occur in patients with parieto-occipital, occipital or deep frontal strokes and the lesions are often bilateral (Bischof et al., 1998; Murri et al., 1984; Solms, 1997). Patients frequently, but not invariably, show deficient revisualization (referred to as visual irreminiscence), topographical amnesia, and prosopagnosia (Murri et al., 1985). A 73-year-old woman with a bilateral medial occipital lobe and left posteroventral thalamic infarction presented with left homonymous hemianopsia, right quadrantanopsia, achromatopsia, mild left hemiparesis, and bilateral crural ataxia. Detailed neuropsychological examination revealed only reading difficulties related to visual field deficits. The patient reported frequent dreaming (several times/week) before stroke. After stroke the patient denied any dream experience for the first 3 months after stroke. On polysomnography REM sleep characteristics were normal and even after four awakenings from REM sleep the patient denied any dream experience (Bischof et al., 1998). The syndrome of dream-reality confusion and recurrent nightmares may occur as a consequence of focal seizures secondary to stroke, particularly in the course of rightsided temporal lesions (Boller et al., 1975; Solms, 1997). Increased frequency or vividness of dreaming may occur after thalamic and occipital stroke (Gloning & Sternbach, 1953; Grünstein, 1924).

Sleep EEG changes Sleep EEG changes have been reported more often in brainstem strokes but are common also in hemispheric stroke. Changes in sleep architecture are due to brain damage but also other such non-cerebral factors as sys-

temic complications of stroke (e.g. fever, infections, breathing disturbances, depression/anxiety), drug treatment, and environmental causes.

Brainstem strokes These can cause selective loss of REM-sleep or a decrease of all, REM- and NREM-sleep as well as total sleep time (Autret et al., 1988; Freemon et al., 1974; Markand & Dyken, 1976; Tamura et al., 1983). In paramedian thalamic strokes reduction of sleep spindles and NREM-sleep stage 2 correlates with clinical severity of hypersomnia (Bassetti et al., 1996c).

Hemispheric strokes These can be accompanied by a decrease of sleep spindles, NREM-sleep and REM-sleep, which have been correlated with stroke extension and clinical outcome (Bassetti & Aldrich, 1999; Giubilei et al., 1992; Hachinski et al., 1978; Körner et al., 1986).

Others Occasionally, brainstem strokes can disrupt specific components of REM-sleep. REM-sleep behaviour disorder, with potentially injurious ‘acting out’ of dreams due to loss of REM-sleep atonia, has been reported in patients with small (lacunar) strokes in the dorsal ponto-mesencephalic tegmentum (Culebras & Moore, 1989). A reduction of physiologic sleep myoclonus during NREM-sleep was described in the hemiplegic limbs of a stroke patient (Dagnino et al., 1969). Periodic leg movements in sleep can increase or decrease after unilateral hemispheric stroke and may persist after spinal stroke (Dyken & Rodnitzky, 1992; Yokota et al., 1991). Whereas circadian hypersomnia is common following stroke (see above), paroxysmal hypersomnia (narcolepsy) is extremely rare. The best-documented case has been observed in an HLA-DR2-negative patient with multiple pons lesion following respiratory arrest (Rivera et al., 1986). A Kleine–Levine-like syndrome characterized by hypersomnia and megaphagia has been reported once in association with brain infarction in an elderly hypertensive woman with multiple lacunar strokes (Drake, 1987).

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15

Aphasia and stroke Andrew Kertesz St Joseph’s Health Centre, London, Ontario, Canada

Introduction The regular recurrence of aphasic syndromes, especially with strokes, has formed the basis of the cortical localizationist models and has provided clinicians a solid foundation for diagnosis and prognosis. Approximately 25% of stroke patients have significant aphasia (Leske, 1981), making this a common neurological and rehabilitation issue. Broca (1861) established the importance of the left hemisphere in language. Meynert (1867/1868) is credited with the motor sensory dichotomy of cortical function and also with recognizing the accompanying anteroposterior anatomical distinction. Wernicke (1874), subsequently, extended the description of aphasic syndromes including comprehension deficit, on the basis of this motor–sensory dichotomy. Upon these foundations, a number of aphasic syndromes have been described subsequently. The taxonomy of these syndromes has been much debated, but in Table 15.1 the most commonly accepted classification and terminology are summarized. The issue of specialized language cortex, functionally unique and anatomically localizable, similar to the primary motor or visual cortex, has become an important question for research. The existence of such a language cortex is supported by the large number of persisting aphasic patients and the anatomical and physiological evidence for networks for language output and comprehension. The characteristics of such networks can be summarized as: (i) a function is represented at multiple sites, therefore lesions from multiple sites can produce a similar deficit, (ii) each area may belong to several overlapping networks, therefore a lesion in a single area often produces multiple deficits, and (iii) severe and lasting deficit of function occurs when all or most structural components of a network are involved.

Broca’s aphasia, expressive aphasia, motor aphasias Articulated language This is an example of complex cognitive function subserved by a neural network. Speech output is an easily available, clinically and scientifically much studied function. It is elaborated differently whether it is in response to questions (responsive speech), spontaneous (internally generated) expression of ideas, descriptive speech, or repetition. Spoken language incorporates many subfunctions, which have been categorized by linguists as articulation, fluency, prosody, phonological processing, lexical retrieval, syntax, and pragmatics, etc. Nevertheless, all or most of the functional components tend to be involved to some extent in the clinical syndrome of Broca’s aphasia which can be reliably defined by standardized test scores (Kertesz, 1979) or by careful clinical description. Many identifiable, even dissociable central processes, such as agrammatism or dysprosody contribute to the syndrome, but these do not have nearly as reliable localization as the syndrome as a whole. Articulation and language output are affected in other syndromes as well and these will be discussed further.

Broca’s aphasia This is defined as effortful speech output with hesitations, pauses, word-finding difficulty, phonemic errors (verbal apraxia) consisting of substitutions, deletions, transpositions and anticipations, occasional semantic errors, and agrammatism, but relatively preserved comprehension (Goodglass & Kaplan, 1972).

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Table 15.1. Major aphasic stroke syndromes

Broca’s aphasia – expressive aphasia Pure motor aphasia – aphemia Transcortical motor aphasia Global aphasia Wernicke’s aphasia – sensory aphasia Pure word deafness – cortical deafness Transcortical sensory aphasia Anomic aphasia Conduction aphasia Isolation or mixed transcortical aphasia

Output

Comprehension

Repetition

Naming

Other feature

– – – – ⫹ ⫹ ⫹ ⫹ ⫹ –

⫹ ⫹ ⫹ – – – – ⫹ ⫹ –

– – ⫹ – – – ⫹ ⫹ – ⫹

– ⫾ ⫾ – – – ⫾ – ⫹ –

agrammatic better writing not paraphasic mute or stereotypy paraphasic better reading semantic jargon only naming deficit mainly repetition deficit only repetition spared

Agrammatism This is characterized by short utterances, omission of small grammatical words such as article, preposition, auxiliary verbs, and inflexions. Nouns or single words substantive utterances predominate and the verb is often deleted. Speech becomes telegraphic suggesting to some that it represents an ‘economy of effort’ (Pick, 1913). Agrammatism has different manifestations in different languages (Goodglass, 1997). Lesions producing Broca’s aphasia have been described from Broca’s area, which is the ‘foot’ of the inferior frontal convolution or F3, although they often extend beyond this to involve the rolandic operculum, anterior insula, subcortical (capsulostriatal) area, and periventricular or centrum semiovale lesion (Moutier, 1908; Henschen, 1922; Kertesz et al., 1979; Levine & Sweet, 1983). Involvement of only Broca’s area is usually followed by good recovery (Mohr, 1976). The variation in lesion size and location is related to the extent of anterior middle cerebral artery occlusion. The overlap of acute aphasic lesions, based on our study, is summarized in Fig. 15.1 (Kertesz et al., 1979). Broca’s aphasia which persists is associated with large lesions including not only Broca’s area (posterior third of F3 and the frontal operculum), but also the inferior parietal and often the subcortical regions (Kertesz, 1988; Kertesz et al., 1979; Mohr, 1976). Persistent non-fluency has been associated with lesions extending to the rolandic cortical region and underlying white matter in previous studies (Lecours & Lhermitte, 1976; Levine & Sweet, 1983). The involvement of the central white matter was also important for the fluency deficit in the head-injured population of Russell and Espir (1961) and Ludlow et al. (1986), and in stroke (Naeser et al., 1989). The centrum semiovale or periventricular white matter, which is involved in persistent

cases of global or Broca’s aphasia, often includes the pyramidal tract, thalamocortical somatosensory projections, striatocortical connections, callosal radiations, the subcallosal fasciculus (Muratoff, 1893), thalamocortical projections from the dorsomedial and ventrolateral nuclei (Yakovlev & Locke, 1961), and the occipitofrontal fasciculus (Dejerine & Dejerine-Klumpke, 1895). The overlap of lesions with persisting aphasic syndromes is summarized in Fig. 15.2. Lesion location was evaluated in Broca’s aphasics, who were divided at the median for poor and good recovery. The structures with significant involvement (more than 50%) were the inferior frontal gyrus, especially the pars opercularis and triangularis, and the insula in both groups. The difference between the persisting cases of Broca’s aphasics and those who show good recovery was most prominent in the involvement of the precentral, postcentral, and supramarginal gyri in cases of poor recovery. The subcortical regions showed significant differences in the involvement of the putamen and the caudate, which was twice as frequent in the persistent cases (Kertesz, 1988). Outcome measures had a high negative correlation with lesion size throughout. Naming was an interesting exception, indicating possibly a ceiling effect combined with the relative persistence of even moderate naming deficit. All of these patients were treated with a variable amount of language therapy; many of them for the duration of the study. Some of them participated in a formal study of language therapy (Shewan & Kertesz, 1984). There are several patterns by which a vascular lesion could produce Broca’s aphasia. The most common pattern involves the frontal opercular and central cortex, and the anterior insula, with or without significant subcortical involvement. These patients often recover quite well, with the exception of those who had cortical, central, insular, and

Aphasia and stroke

Fig. 15.1. The overlap of lesions in acute aphasic syndromes. (Reprinted with permission from Kertesz et al., 1979.)

subcortical involvement. There is, however, a certain amount of variability in how the components of the network are affected producing different degrees of recovery.

Global aphasia This is defined by the loss of speech output, as well as comprehension, usually associated with destruction of both the anterior and posterior language areas (Kertesz & Phipps, 1977). Large middle cerebral artery stroke, occasionally hemorrhage, is the usual etiology. However, in patients who are initially global, Wernicke’s area may be spared. These patients tend to recover towards Broca’s aphasia. Even ‘Broca’s area’ cortex may not be destroyed, although it is usually disconnected from the rest of the language cortex by white matter involvement (Naeser et al., 1989). Occasionally, mostly white matter lesions can produce persistent global aphasia. There are also case reports of patients with initial global aphasia without hemiplegia, who recover dramatically when they have posterior–frontal and posterior temporal regions but sparing of the central structures (Van Horn & Hawes, 1982; Ferro, 1983). The classification of severely non-fluent aphasics influences the results of localization and recovery studies. For instance, in the Boston Diagnostic Aphasia Examination (BDAE) (Goodglass & Kaplan, 1972), a large group of what others would classify as severe Broca’s aphasics may be labelled, at times, as ‘mixed anterior aphasics’. In the clas-

sification system of Aachen Aphasia Test (AAT) (Huber et al., 1983), many global aphasics would be reclassified as Broca’s aphasics in other clinics. Some of these problems in taxonomy have been systematically studied in the comparison of aphasia batteries and how their scoring systems affect classification (Ferro & Kertesz, 1987). Global and Broca’s aphasias, as defined by our taxonomy and methods of measurements, have similar spontaneous language characteristics. In our previous taxonomic studies (Kertesz & Phipps, 1977), these were the two closest groups in the nearest neighbour-network analysis. The major difference between the two groups is in the extent of comprehension deficit. Since comprehension often recovers well, there are a great number of patients who change from global to Broca’s aphasia during recovery (Syndromenwandeln) (Leischner, 1976).

Pure motor aphasia Also called cortical motor aphasia aphemia, or verbal apraxia, this has been associated with Broca’s area anterior subcortical, inferior rolandic, and insular cortical lesions. Verbal apraxia is frequently used by speech pathologists to denote hesitation, stuttering, dysprosody, ritual consonant substitution, deletions, repetition, transposition and anticipation (Darley et al., 1975) that can occur as part of non-fluent or Broca’s aphasia, or occasionally alone. All forms of speech output are affected, including repetition, in contrast with transcortical motor aphasia.

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Fig. 15.2. The overlap of persisting aphasic lesions. (Reprinted with permission from Kertesz et al., 1979.)

Transcortical motor aphasia This is characterized by poor spontaneous speech but good repetition and comprehension. There is a variable naming deficit and the writing output is also poor. The localization of lesions is characteristically in the mesial frontal region or the supplementary speech area in the dominant hemisphere (Goldstein, 1948; Kornyey, 1975; Rubens, 1975; Chusid et al., 1954; Arseni & Botez, 1961). These are often caused by an anterior cerebral artery stroke. The importance of the supplementary motor areas on the left was recognized by Penfield and Roberts (1959), who renamed it the ‘supplementary speech area’ because of the frequent speech arrest which was found during stimulation of this region. Cytoarchitecturally, the supplementary motor cortex appears to represent a paralimbic extension of the limbic cortex (Sanides, 1970). This suggests a link between the limbic system and initiation of the motor mechanisms of speech. The lack of speech initiation is often considered a part of a general hypokinetic syndrome associated with frontal lobe lesions. The term ‘adynamic aphasia’ has also been used to describe this behaviour since Arnold Pick and Kleist. Recovery is usually excellent and these patients are only seen in acute units as a rule. A similar, but progressive nonfluent aphasia is recognized increasingly as part of clinical Pick’s disease (Kertesz et al., 1994), but the temporal characteristic of this syndrome is the opposite from stroke-induced aphasia.

The onset is insidious and deterioration instead of improvement takes place with time.

Wernicke’s aphasia, sensory aphasia Language comprehension This is a complex process involving analysis of acoustic and phonological properties of input, as well as a recognition of syntactic and lexical elements (Liebermann et al., 1967). This rapid parallel processing of input and matching it to linguistic precepts is an analytical left hemisphere function. The most likely candidate to perform this is the auditory association cortex, localized to the superior temporal gyrus region and the planum temporale located behind Heschl’s gyrus.

Wernicke’s aphasia This is characterized by fluent, paraphasic speech with impaired comprehension, repetition, and naming. Syntax and morphology are relatively preserved, but the substantive words are often substituted by semantic or phonological paraphasias. At times, a large number of paraphasias, almost all nouns, distort the speech output to the extent it sounds like jargon. At times this is produced under pressure in great quantities and the patients are not aware of

Aphasia and stroke

their disability (anosognosia for language impairment). Reading and writing are similarly affected. The taxonomic boundaries of Wernicke’s aphasia can be defined with language scores, although this may be considered arbitrary (Kertesz, 1982).

‘Pure word deafness’ This is used when the patient complains of not understanding speech, but hearing, reading, and speech output remain undisturbed. One type is called word form deafness (Kohn & Friedman, 1986). These patients often ‘mishear’ phonologically similar words, and they cannot tell words from non-words (lexical decision). The other type is ‘word meaning deafness’ where patients can perform lexical decision tasks but cannot access semantics (Franklin et al., 1994). Auditory agnosia for non-verbal sounds and amusia is often associated, although these symptoms may be seen with right-sided lesions without the verbal component. In cortical deafness, which is the result of bilateral temporal lesions, the patient appears clinically deaf with preserved primary hearing, but impaired central auditory processes (Kertesz, 1983).

Neologistic jargon Neologistic jargon output is distinctive and occurs in severe Wernicke’s aphasia, associated with lesions of both the superior temporal and inferior parietal regions (Kertesz & Benson, 1970). The superior posterior temporal branch of the middle cerebral artery is usually involved. Wernicke’s aphasia with semantic jargon is correlated with lesions which are somewhat smaller, inferior and more temporal than those with neologisms or phonemic paraphasia (Kertesz, 1983). Other CT studies indicated that patients with semantic substitutions have lesions posterior to those with phonemic paraphasia (Cappa et al., 1981). Wernicke postulated that the auditory association area plays a monitoring role in language output (presaging modern concepts of feedback and parallel processing), and its damage results in paraphasic, faulty speech.

Conduction aphasia This is distinguished by poor repetition with relatively fluent, but paraphasic, speech and good comprehension. The term was originated by Wernicke (1874) on the basis of the theory that conduction of sensory impulses to motor patterns is impaired. However, it was Lichtheim (1885) who specified the disturbance of repetition as a feature of conduction aphasia. Others have observed the close asso-

ciation of conduction aphasia and claimed it is part of a spectrum. Goldstein (1948) considered it ‘central aphasia’ and many others subsequently accepted it as a separate form. Some conduction aphasics struggle a great deal to approximate target phonemes (conduites d’approche) and some investigators consider conduction aphasia a form of expressive aphasia such as Luria, who called these patients ‘afferent motor aphasics’. The patients are aware of their mistakes and their efforts are considered corrective. The repetition deficit in conduction aphasia has been viewed as a disturbance in short-term verbal memory (Warrington & Shallice, 1969) or as an ordering deficiency (Tzortis & Albert, 1974). The more fluent varieties can be distinguished on taxonomic studies (Kertesz & Phipps, 1977) and their lesions are also more posterior. More recently some patients have been renamed ‘deep dysphasia’ as they had difficulty accessing meaning through phonology, lexicalized nonwords and produced semantic paraphasias (Katz & Goodglass, 1990).

Transcortical sensory aphasia This is characterized by fluent, semantic jargon, poor comprehension and good repetition. These patients usually have far more posterior lesions, usually in the watershed area between the middle cerebral and posterior cerebral circulation (Kertesz et al., 1982), although at times thalamic lesions are described with ‘transcortical sensory’ features. Recovery is usually rapid unless the syndrome evolves from a more severe lesion initially producing Wernicke’s aphasia.

Isolation syndrome, or mixed transcortical aphasia This has features of both motor and sensory transcortical aphasia, and tends to have a poor prognosis with nonfluency persisting and not all comprehension returning, depending on the etiology. It is called isolation syndrome because the lesions tend to surround the middle cerebral artery territory, often in watershed areas, isolating the language areas (Goldstein, 1948). It occurs relatively uncommonly and the recovery patterns have not been described extensively. In our experience, persisting cases occur with strokes and with post-traumatic lesions.

Anomic aphasia This is the mildest form of aphasic syndrome, characterized by fluent output, good comprehension, and only naming and word finding difficulty. Word finding or word access, the retrieval of lexical items (often tested by

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naming), is a fundamental process in language, and anomia is a feature of most aphasic syndromes. Various types of anomia however have been distinguished, and certain differences in brain damage associated with these types have been described (Benson, 1979). Anterior and central lesions are more likely to produce lexical retrieval deficit without a loss of semantic representation. Posterior temporoparietal lesions often produce naming difficulty which is associated with some comprehension deficit for the same lexical item or a loss of meaning of words, even though they may be used in a correct grammatical sentence. Head (1926) called these cases ‘semantic aphasia’. The study of lexical access and semantic processing is a major scientific and clinical topic. Recent advances in this field include the study of modality-specific fields (verbal vs. visual) and the category specificity of recognition and retrieval of lexical items. Lexical retrieval is thought to be dependent on a widely distributed cortical network (Berndt & Mitchum, 1997). Lesion studies and functional activation have suggested the role of left temporoparietal and temporo-occipital cortex and functional activation and have added the frontal lobe as having a role in semantic processing (Petersen et al., 1990). Considering the complex nature of semantic association, narrowly restricted localization of this function is not likely. This is already evidenced from the wide distribution of lesions resulting in anomia or anomic aphasia. Patients who only have anomic aphasia de novo usually recover well. Mild word finding and naming difficulty are very common in acute stroke. They can be seen transiently with subcortical, anterior cortical and posterior cortical lesions. Rapid recovery is the rule even before these patients are transferred to rehabilitation.

Subcortical stroke aphasias The role of subcortical structures in language is not fully understood. Marie (1906; 1926) proposed a role of subcortical structures in language early on, some of these have been recently duplicated. Motor impairments often dominate the deficit in lesions of the basal ganglia. This is ranging from dysarthria and hypophonia (which has been known to occur commonly after thalamotomies) to severe global aphasia. Anomic aphasia is often observed, presenting as a disturbance of word retrieval and rather hesitant speech (Mazzocchi & Vignolo,1979; Alexander & Loverme, 1980). The often preserved repetition is called a ‘transcortical feature’ (Selby, 1967; Cappa & Vignolo, 1979). Bell (1968) considered the deficit to be similar to the aphasias of the frontal regions. Lesions in the putamen and the anterior internal capsule produces slow, anomic, dysarthric

speech and with posterior extension comprehension is also impaired with paraphasic speech and jargon (Barat et al., 1981; Naeser et al., 1982; Damasio et al., 1982). Isolated lesions of the caudate or putamen are rare, but both have been described as causing transient speech deficits (Hier et al., 1977). Damasio et al. (1982) found that infarcts in the anterior limb of the internal capsule and in the striatum caused aphasia, while non-aphasics had more lateral or caudal lesions. Naeser et al. (1982) divided nine patients with capsuloputaminal lesions into three syndromes related to lesion site. Patients with lesions extending into anterior–superior paraventricular white matter had good comprehension and grammatical, but slow, dysarthric speech. Posterior extension across the temporal isthmus resulted in fluent speech with poor comprehension. Patients with both anterior-superior and posterior extension had global aphasia. Alexander et al. (1987) presented a more detailed model. Only minor language disorders were seen with lesions confined to striatum and internal capsule, and it was postulated that subcortical aphasia is due to disruption of intra-hemispheric white matter pathways. Thalamic lesions produce fluctuating jargon aphasia alternating with relatively non-fluent speech (Mohr et al., 1975). Although subcortical lesions are often said to produce atypical syndromes (Damasio et al., 1982) when an attempt is made to compare the scores of patients with subcortical lesions with equivalent sized cortical lesions, the differences are not significant (Kertesz, 1984; Basso et al., 1987; Kirk & Kertesz, 1994). Distant cortical hypometabolism or diaschisis are considered possible reasons for the deficit, in addition to whatever intrinsic coordinating or processing may take place in the basal ganglia (Metter et al., 1981; Perani et al., 1987; Baron et al., 1986).

Alexia and agraphia Disturbance of reading and writing may occur in isolation with distinct cortical localization, but also in various combinations with aphasia. Written language functions are also subserved by networks and therefore more than one lesion site will account for the same syndrome. Dejerine (1892) made the classical distinction between pure alexia with left occipital lesions which usually involve the splenium or its radiation, and alexia with agraphia which are associated with parietal, at times specifically angular gyrus, lesions on the left side. Dejerine’s description of the lesion in pure alexia was the prime model for the disconnection theories postulating the existence of white matter lesions disconnecting various cortical language processors (Geschwind, 1965). The recent linguistic distinction of

Aphasia and stroke

deep and surface dyslexia (deep and surface refers to linguistic, not anatomical structures), based on error analysis of the reading of non-words and orthographically irregular words, are partially correlated with anatomical differences (Ellis, 1984). Deep dyslexia seems related to large perisylvian infarcts and corresponds to what other authors describe as aphasic alexia (or the third alexia) (Benson, 1979). Surface dyslexia or reading without comprehension is seen with temporal damage mainly (Bub & Kertesz, 1982). Other varieties of lesions disconnecting primary visual input from the angular gyrus were termed ‘preangular’ or ‘subangular’ alexias by Greenblatt (1983). Agraphia is associated with parietal lobe lesions on the dominant side but agraphia is common with any lesion producing aphasia, although dissociations have also been observed (Bub & Kertesz, 1982). Frontal lobe lesions can produce agraphia, although the existence of Exner’s centre in the second frontal convolution in front of the hand area of the precentral gyrus has not been generally supported. Recent studies showed a considerable amount of agraphia with purely subcortical lesions, which is somewhat different from agraphia due to cortical lesions because it seems mostly the graphomotor aspects rather than grammatical and semantic aspects are involved (Kertesz, 1984). This type of agraphia used to be designated as apraxic agraphia. Ideographic (Kanji) and syllabic (Kana) writing in Japanese have been reported to be dissociated with different lesion localization, suggesting different neuronal processing. Kanji processing is semantic and context dependent. Kana, on the other hand, can be read aloud without semantic processing. Iwata (1984) suggested semantic processing takes place through inferior occipitotemporal connections, because lesions in this area interfere with Kanji selectively (Kawahata et al., 1988; Kawamura et al., 1987). Dorsal connections through the angular gyrus are involved in Kana (or phonological) processing, similar to Indo-European languages. Pure agraphia for Kanji has also been reported with subcortical damage under-cutting the left inferior temporal gyrus (Mochizuki & Ohtomo, 1988).

Recovery of aphasic stroke syndromes Clinicians have recognized aphasic stroke syndromes are not stable and recovery takes place to a considerable extent. Wernicke (1886) postulated much of the recovery from aphasic symptoms is affected by right hemisphere compensation. Von Monakow (1914) stated, ‘the temporary nature is one of the most important characteristics of aphasia’. He based his diaschisis theory on observations

with aphasics and on the analogy of spinal shock, well established by physiologists. Diaschisis means acute brain damage deprives the surrounding, functionally connected areas of a trophic influence causing a severe deficit initially. As the surrounding areas recover by acquiring reinervation from somewhere else or become active after adapting to the state of partial denervation, in either way, recovery takes place. There are certain structural limitations of recovery, allowing compensation to take place only in certain areas, such as the adjacent cortex, contralateral homologous cortex or hierarchically connected structure, such as the subcortical ganglia (Lashley, 1938; Bucy, 1934). The principle of contralateral homologous cortical substitution was based on large left hemisphere lesions with relatively good recovery where there was very little left hemisphere remaining to take over. More recently, CAT scan studies made the same point (Cummings et al., 1979; Landis et al., 1980). In addition, in some patients who became aphasic with a single left hemisphere stroke but recovered, a second, right hemisphere stroke produced a language deficit again (Nielsen, 1946; Levine & Mohr, 1979; Cambier et al., 1983). These cases, however, may have represented bilateral language organization to begin with, rather than a commonly operating mechanism of functional transfer to the contralateral hemispheres. The idea of compensation through right hemisphere function, even after partial left hemisphere damage, was also supported by studies of effects of sodium amytal given to aphasics who had recovered (Kinsbourne, 1971; Czopf, 1972). These studies indicated that, even though the aphasic disturbance occurred from a left hemisphere lesion, it was the right hemispheric injection which increased the language disturbance, implying the right hemisphere compensated for the previous deficit produced by the left-sided lesion. The variation in recovery, which cannot entirely be explained by the extent and location of lesions, has been postulated to relate to differences in language laterality, handedness, age, and gender. Subirana’s (1969), Gloning et al’s (1969), and Geschwind’s (1974) suggestion that left handers and right handers, with a family history of left handedness, recover better from aphasia because of more bilateral language distribution, is based on anecdotal evidence. Recent studies of anatomical asymmetry on CT scans, inspired by the demonstration of commonly larger planum temporale on the left by Geschwind and Levitsky (1968), have correlated better outcome with atypical or less asymmetry (Pieniadz et al., 1983). This is also based on the idea that this pattern may be associated with more right hemisphere language. We have studied the factor of anatomical asymmetry on CT, as measured by occipital width,

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frontal width, and protuberance (petalia) and could not confirm atypical asymmetry played a role in recovery in any of the aphasic groups (Kertesz, 1988). It could be that anatomical asymmetries relate more to handedness variables rather than language distribution, as suggested by some of our studies in normals (Kertesz et al., 1992); therefore, we are not seeing an effect on language recovery. It has been suggested woman have more bilaterally distributed language (McGlone, 1980). However, when we looked at sex differences in recovery, we found none and no evidence to support better right hemisphere substitution by women (Kertesz, 1988). We did not find a sex difference in the anterior–posterior distribution of language impairment either (Kertesz & Benke, 1989). Cerebral blood flow (CBF) and positron emission tomography (PET) studies of cerebral metabolism provide methodologies which add functional information to structural or lesion studies of recovery. Recent studies of CBF with xenon 133 have also revealed a right-hemisphere hypometabolism in aphasic strokes, the extent of which has correlated with recovery to a modest degree (Knopman et al., 1984). PET studies of cerebral metabolism have shown a great deal of hypometabolism surrounding, but also remote from, cerebral infarcts thus suggesting not only surrounding areas but also homologous areas in the contralateral hemisphere play a role in compensation (Metter et al., 1981). However, one CBF study showed no significant change, while clinical recovery occurred in severe aphasics (Demeurisse et al., 1983). Patients who improved more, showed more blood flow in the left hemisphere. This appears to be the consequence of the size of the lesion, which correlates with the CBF changes. Another CBF study showed better than 60% hemispheric flow in patients with good recovery (Nagata et al., 1986). More recent studies of PET activation suggested right hemisphere, as well as ipsilateral, compensation (Weiller et al., 1992).

Functional activation of language More recent functional activation confirms the importance of the posterior temporal area in auditory perception of language, and the central and premotor cortex in articulation, in addition to some newly emphasized components to the language network, such as the mesial frontal and lateral frontal areas in word retrieval and semantic association (Petersen et al., 1990). The anterior cingulate gyrus appeared part of an anterior attentional system indicated by its activation while monitoring lists of words for semantic category (Petersen et al., 1990). Some of the con-

tinuing work with PET and O15 and recent efforts on magnetic resonance functional activation promises to shed further light on these issues (Weiller et al., 1992; Binder & Rao, 1994; Chertkow & Murtha, 1997). Functional activation is complementary to the clinical study of aphasic stroke syndromes.

Conclusions The size and location of lesions, time-from-onset, etiology and initial severity, are complex, interdependent factors in clinical symptomatology and the recovery of language loss. Other biological factors, such as age, education, handedness, and sex play a less significant role when an adult stroke population is followed. Lesion size is undoubtedly a significant factor in the extent of recovery and can be easily determined by CT or MRI scanning. An exception to the negative correlation between language recovery and lesion size is comprehension. In some patients, even with large lesions, the amount of comprehension recovery is considerable; while patients with small lesions demonstrate a relatively small degree of recovery. One of the unresolved issues remains whether ipsilateral connected adjacent, or distant, even contralateral, cortex plays a major role in compensation. The answer is probably both, but our studies of lesion location and recovery in Broca’s and Wernicke’s aphasia suggest ipsilateral connected structures play the major role in restoration of function after damage. These are structures which are likely to be used normally in the language network, although for somewhat different functions at different times. The functional participation by these structures implies neuroplasticity rather than a built-in redundancy when recovery from damage occurs. The cytoarchitectonic similarity and anatomical contiguity make adjacent structures prime candidates for substitution. The language network of the left hemisphere is capable of a considerable degree of compensation, producing various clinical patterns of deficit, but its complete destruction results in permanent loss in the majority of individuals. Functional activation and cortical stimulation provides convergent evidence of such networks, as well as bilateral activation and integration in language function. The addition of cognitive neuropsychology and functional neuroimaging to the clinical knowledge of aphasic syndromes has deepened our understanding of language organization in the brain. In clinical practice, the value of clinical symptoms and aphasic syndromes in predicting localization of stroke lesions and prognosis remains undiminished.

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Agitation and delirium John C.M. Brust1 and Louis R. Caplan2 1 2

Department of Neurology, Harlem Hospital Center, New York, USA Beth Israel Deaconess Medical Center, Boston, USA

Introduction, definition of terms, and frequency of the problem The fundamental feature of delirium is disordered attention. Delirious patients cannot focus and sustain attention on one stimulus among multiple stimuli, and cannot shift attention at will. Table 16.1 lists diagnostic criteria for delirium from the American Psychiatric Association. If delirious patients are attentive enough to allow testing, abnormalities of thinking, perception, and memory will usually be found. The abnormalities may include disorientation to time and place, impaired immediate, recent, and remote memory, dysnomia, agraphia, and visual-spatial dysfunction. Much of the difficulty with perceptual function and speech output relates to the inability to sustain attention to the task at hand. Illusions, hallucinations, and delusions may also be prominent. Sleep–wake patterns are usually abnormal with reduced wakefulness during the day and reduced, often fragmented sleep at night. Autonomic hyperactivity produces flushing, mydriasis, sweating, tachycardia, and labile blood pressures. Delirious patients may quickly shift from hyperactivity to reduced activity. During the day lethargy and even catatonic behaviour may predominate, shifting at night to agitation, shouting, and aggressive behaviour. The terms delirium, confused, agitation, and confusional state are used variously by different neurologists and psychiatrists. The criteria cited in Table 16.1 incorporate several very different elements including acuteness of onset, altered thought and concentration, level of consciousness, and cause. Confusion is defined by Adams et al. (1997) as: denoting the patient’s incapacity to think with customary speed, clarity, and coherence. Its most conspicuous attributes are an

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inner sense of bewilderment, impaired attention and concentration, an inability to properly register immediate events and to recall them later, and a dimunition of all mental activity including the normally constant inner ideation . . . Reduced perceptiveness with visual and auditory illusions and even hallucinations and paranoid delusions are variable features.

Confusion in their terminology is an essential component of delirium. Adams et al. (1997) use the term delirium to denote a special type of confusional state. ‘Delirium is marked by a prominent disorder of perception, terrifying hallucinations and vivid dreams, a kaleidoscopic array of strange and absurd fantasies and delusions, inability to sleep, a tendency to convulse, and intense emotional reactions.’ Lipowski (1990) defined the acute confusional state as: an organic mental syndrome featuring global cognitive impairment, attentional abnormalities, a reduced level of consciousness, increased or decreased psychomotor activity, and a disordered wake–sleep cycle.

Some authors, including Victor et al. (1997) reserve the term delirium to describe an overactive state of heightened alertness that includes agitation, frenzied excitement and trembling, while other physicians and authors, including many psychiatrists, include both hypoactive and hyperactive behavior with confusion within the spectrum of delirium. Many simply reserve the term delirium to describe behavioural and cognitive states that closely resemble the most familiar form of delirium – delirium tremens that develops in alcoholics during withdrawal. Delirium and confusional state are thus terms that are used variably and these terms are difficult to apply practically. The word confused is used in common parlance to mean mixed up. Confusion refers to altered thinking ability. It is not a technical term. Since the terms delirium

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Table 16.1. Diagnostic criteria for delirium (American Psychiatric Association (1987) A. Reduced ability to maintain attention to external stimuli (e.g. questions must be repeated because attention wanders) and to appropriately shift attention to new external stimli (e.g. perseverates with the answer to a previous question) B. Disorganized thinking as indicated by rambling, irrelevant, or incoherent speech C. At least two of the following: 1. reduced level of consciousness (e.g. difficulty in keeping awake during examination) C. 2. perceptual disturbances (misinterpretations, illusions, or hallucinations) C. 3. disturbances of sleep–wake cycle, with insomnia or sleepiness during the day C. 4. increased or decreased psychomotor activity C. 5. disorientation to time, place, or person C. 6. memory impairment (e.g. inability to learn new material, such as the names of several unrelated objects after 5 min, or to remember past events, such as the current episode of illness) D. Clinical features developing over a short period of time (usually hours to days) and tending to fluctuate over the course of a day E. Either 1 or 2 below C. 1. evidence from the history, physical examination, or laboratory tests of a specific organic factor (or factors) judged to be etiologically related to the disturbance C. 2. in the absence of such evidence, an etiologic organic factor can be presumed if the disturbance cannot be accounted for by any nonorganic mental disorder (e.g. manic episode accounting for agitation and sleep C. 2. disturbance)

and confusional state are used so variously and include so many disparate features, their use sometimes only serves to confuse physicians. Preferable is to describe in simple direct English: (i) the acuteness or chronicity of the disorder, (ii) the level and amount of activity, (iii) the nature of the altered thinking, and (iv) the cause. It is well understood and appreciated that individuals who are sleepy or stuporous cannot pay attention or concentrate normally and cannot think as clearly as those who are wide awake and alert. For that reason, we believe it serves little purpose to apply the term delirium to individuals who have decreased alertness. In this chapter we will limit the discussion to hyperactive behavioural states in which thinking and concentration are abnormal. In our opinion it is best to consider etiology as a separate

issue and not to incorporate it into the definition of the clinical state. Diffuse brain dysfunction characterized by altered level of consciousness, poor ability to concentrate, and altered cognitive functions when caused by potentially reversible biochemical and physiological changes is usually referred to as encephalopathy. When the behavioral abnormality relates to endogenous usually biochemical abnormalities in various internal organs, the term metabolic encephalopathy is used, while dysfunction due to exogenous factors such as drugs and toxic substance exposure is usually called toxic encephalopathy. Since this book is concerned mostly with the neuroanatomy and neurophysiology of various neurological stroke-related symptoms and signs, we will emphasize hyperactive states with accompanying confusion associated with focal strokes and will not discuss the encephalopathies herein. Delirium is common. Agitation or delirium occur at one time or another in one-third to one-half of hospitalized elderly patients and after surgery in 10–15% of general surgery patients ages 65 and older (Lipowski, 1983). Delirium is associated with a variety of medical illnesses including pneumonia, urinary tract infection, sepsis, meningitis, dehydration, electrolyte imbalance, congestive heart failure, uremia, liver failure, head injury, and postictal states. It is often associated with drugs such as anticholinergic agents, cocaine, amphetamines, hallucinogens, etc., and may occur after withdrawal from benzodiazepines, alcohol, or barbiturates. The presence of delirium carries a poor prognosis, especially in the elderly. In one study, onethird of 4000 patients admitted to a hospital with delirium died within 1 month (Bedford, 1959). Increased mortality and morbidity are likely due to the seriousness of the underlying disease and the difficulty in caring adequately for very agitated patients who often cannot co-operate with treatments.

Neuroanatomical substrate of hyperactivity and agitation Delirium may occur after an acute stroke. Often unappreciated, however, is that delirium may be the predominant or even the only readily observable neurological abnormality and yet may indicate focal brain damage rather than a general toxic or metabolic abnormality. In a retrospective study of 661 stroke patients admitted to a hospital in Perth, Australia, 19 (3%) patients presented with ‘delirium, an organic delusional state, the acute onset of dementia, or mania, mimicking psychiatric illness’; computed tomography (CT) or autopsy showed focal lesions in all of these

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patients (Dunne et al., 1986). Among nine patients with ‘acute delirium’ all had right cerebral hemisphere infarcts (perisylvian in 3, temporal 2, frontal 1, parietal 1, frontotemporal 1, and temporoparietal 1). A prospective study of 145 consecutive stroke patients found delirium, either at admission or within 1 week of admission, in 69 patients (48%) (Gustafson et al., 1991). In this study, delirium affected 56 of 113 (50%) patients with brain infarcts, 6 of 21 (29%) patients with TIAs, and 7 of 8 (88%) patients who had brain hemorrhages. Delirium was more common in patients with left-sided brain lesions (38/65, 58%) than in patients with right-sided lesions (18/47, 38%). Independent predictors of the likelihood of delirium were: severe weakness, previous episodes of delirium, old age, and treatment with anticholinergic drugs. Delirium was also associated with complications of stroke such as myocardial infarction, pulmonary embolism, deep vein thrombosis, urinary retention, and urinary tract infection. In a later report, the same authors found that delirium correlated with elevated blood levels of cortisol, both before and after receiving dexamethasone (Gustafson et al., 1993). In a study that addressed the association of delirium and structural lesions, 36 of 60 hospitalized patients with ‘acute confusional state’ had focal brain lesions (Mullally et al., 1982a). Nineteen of these patients had ‘minor or absent elementary signs’. In that and other reports, confusion and delirium were associated with infarction involving the territories of the anterior, middle, or posterior cerebral arteries (de Reuck et al., 1982). Miller Fisher (1983) reviewed his experience with two behavioural states that seemed to be polar opposites: abulia and agitated behaviour. Abulic patients had decreased activity. They were often apathetic and lacked initiative and exploratory behaviour. They were slow to respond and their responses were brief and unsustained. In contrast were patients who were hyperactive and agitated. These individuals were often restless, excited and hyperalert, and had an increased amount of speech (logorrhea) and activity (Fisher, 1983). The brain lesions in patients with abulia, when localizable, were located in the upper mesencephalic tegmentum, substantia nigra, medial thalami, striatum, and frontal lobes. Many of the lesions involved or interupted projecting fibres to the frontal lobes. In contrast, when hyperactive agitated patients had focal brain lesions, the location was most often in the posterior portions of the cerebral hemispheres in the temporal, occipital and inferior parietal lobes. Many of the agitated patients had infarcts or inflammatory lesions that involved limbic cortex.

Posterior circulation territory strokes Top-of-the basilar artery embolism and posterior cerebral artery territory (PCA) strokes Embolism to the rostral basilar artery causes infarction in the paramedian midbrain and thalamus and/or in the temporo-occipital lobe territory of the posterior cerebral arteries (PCAs) (Caplan, 1980). Agitation lasted 2 months and was followed by ‘severe dementia’ in a middle-aged woman who had bilateral infarction of the hippocampal formation and the fusiform and lingual gyri (Glees & Griffith, 1952). Horenstein et al. (1962) reported nine patients who had hyperactive agitated behaviour and sudden onset visual loss. They described the behaviour of their patients as ‘restlessness, agitation, forced crying out, and extreme distractability’. These patients were very talkative and their conversations tended to flow freely from one topic to another without any external interference. All had infarcts in the unilateral or bilateral territory supplied by the PCAs. The infarcts most often involved the fusiform and lingual gyri (Horenstein et al., 1962). Later, Medina et al. (1974) described the clinical and pathological findings in a 78-year-old man who had the sudden onset of an agitated, excited state. This man was described as previously quiet and stable, despite a prior stroke that caused a transient left hemiparesis and left hemisensory loss, and a persistent left hemianopia. His niece found him suddenly agitated. He cursed and became violent, striking her. On admission to the hospital he was extremely agitated, perspired profusely and screamed, tried to bite individuals, and spat. He was also blind and had poor memory. This man remained agitated and shouted most responses to queries until his death about five months after his stroke. Necropsy showed an old infarct in the territory of the inferior division of the right middle cerebral artery involving the superior temporal gyrus and the inferior parietal lobe. The left PCA territory was also infarcted including the entire lingual gyrus and portions of the adjacent fusiform, parahippocampal, and calcarine gyri (Medina et al., 1974). The left hippocampus, the mamillary bodies, and portions of the left thalamus were also involved including the pulvinar. Reviewing nine of their own patients and 49 patients gleened from other reports, Symonds and MacKenzie (1957) noted ‘confusion at the onset’ in half of patients who had acute infarct with visual loss in the bilateral territories of the PCAs. One of the patients reviewed by Symonds and MacKenzie (1957) had paranoid behaviour associated with bilateral PCA territory infarction. Other patients had either hallucinations, or denial of blindness, but none was

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described as frankly delirious (Symonds & MacKenzie (1957). Caplan (1980, 1996, 2000) reviewed reports of patients who developed an agitated delirious state caused by embolism to the rostral basilar artery and its PCA branches. Necropsy and neuroimaging of these patients showed bilateral infarcts invariably involving occipital and temporal lobe cortex below the calcarine sulcus including the lingual and fusiform gyri. Bilateral visual field defects and memory loss usually accompanied the agitated, hyperactive state. Some patients had visual defects that predominantly affected the superior quadrants. Some also had infarcts in the rostral brainstem and superior cerebellar artery territory of the cerebellum; however, no patient with an isolated rostral brainstem infarct had an agitated hyperactive state. The patients with bilateral rostral brainstem tegmental infarcts were, in contrast, sleepy and had reduced activity. Infarction of the PCA territory on the lower bank of the calcarine sulcus was always present in delirious patients with posterior circulation brain embolism (Caplan 1980, 1996, 2000). A hyperactive agitated state also occasionally develops after vertebral artery angiography (Caplan, 1996). During or after dye contrast angiography, these patients become hyperactive and restless, have markedly reduced vision, and poor memory. The agitation, confusion, and other neurological signs usually remit within several hours. In most patients angiography is normal and the patients have received a large amout of iodinated contrast material. This syndrome is most probably caused by a reaction to the contrast material in the bilateral territories of the PCAs. Other reports describe patients with unilateral lesions in the territory of one PCA. Devinsky et al. (1988) reported the clinical and imaging abnormalities in four patients with left PCA territory infarcts who had an agitated confusional state, and reviewed prior reports of confusional states in patients with unilateral PCA terrritory infarcts. All four patients had lesions of the left occipital and posteromedial temporal lobes. Three had infarcts in the distribution of the left PCA that were most likely explained by cardiogenic embolism. One patient most likely had dural sinus and cortical venous thrombosis with left posteromedial temporal lobe and occipital lobe infarction. Three of the patients had agitated states sometimes alternating with lethargy. One had the sudden onset of ‘confusion, agitated disorientation, and aggressive behavior’, shouting curses and threats and throwing objects at the wall. He was ‘distractable and shifted the focus of his attention to virtually any novel stimulus’ (Devinsky et al., 1988). Another agitated patient had speech described as ‘fluent but tangen-

tial with difficulty finding words’. In some patients the agitated confusional state was transient. Devinsky and colleagues reviewed prior reports of patients with unilateral PCA territory infarction who had acute confusional states. Eighteen of the 19 patients (95%) described in ten different reports had left PCA territory infarcts while only one had a right PCA territory infarct. Fisher (1983) also commented that, when an agitated delirium developed in patients with unilateral PCA territory infarct the lesion was usually in the dominant left cerebral hemisphere.

Thalamic strokes Graff-Radford et al. (1984) described altered cognitive functioning in five patients with unilateral thalamic infarcts involving in four patients, the dorsomedial, anterior, ventrolateral, ventral anterior, and midline nuclei, and in one, the central median and the parafascicular, dorsomedial, and ventral posterior nuclei. Each had abnormalities of memory, visual-spatial perception, intellect, and personality. Patients with left-sided lesions had transcortical aphasia. One patient had delusions but none was frankly delirious. Santamaria et al. (1984) described five patients with anteromedial small thalamic hemorrhages who showed ‘lack of initiative and spontaneous movements, loss of insight, placidity, and impaired attention, orientation, and anterograde memory’. One also showed prominent ‘agitation, loquacity, easy laughing, and social disinhibition’. Four were incontinent. All five patients had minimal focal neurological signs. Bogousslavsky et al. (1988) reported a woman with ‘a disinhibition syndrome affecting speech (with logorrhea, delirium, jokes, laughs, inappropriate comments, extraordinary confabulations)’. This patient had an infarct in the right thalamus involving the dorsomedial nucleus, the intralaminar nuclei, and the medial portion of the ventral lateral nucleus. In contrast to her disinhibited speech, there was little motor or behavioural spontaneity (Bogousslavsky et al., 1988). In this patient, single photon emission computed tomography (SPECT) showed hypoperfusion of the overlying cerebral cortex especially frontally. The authors posited that the patient’s findings might have represented a disconnection of the dorsomedial thalamic nucleus from the frontal lobe and limbic system (Bogousslavsky et al., 1988).

Brainstem strokes Arseni and Danaila (1977) described hyperactive behaviour and increased amount of speech in relation to pontine brainstem disease. A patient with a basilar artery aneurysm and a clinical deficit localizable to the pons and upper

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brainstem showed logorrhea and hyperactivity. Speech flowed without stimulation from one idea and topic to another without interuption. They emphasized that logorrhea and hyperactivity did not always occur together. Among their 13 patients, six had both logorrhea and hyperactivity while one patient had logorrhea without hyperactivity and six other patients were hyperkinetic but mute. A patient reported by Pessin et al. (1989) had a dolichoectatic basilar artery and an infarct in the territory of a penetrating pontine artery branch and suddenly became loquacious and had persistent logorrhea after she developed a hemiparesis caused by her pontine infarct. Logorrhea and hyperactivity are frequent components of agitation and delirium. None of the reported patients with brainstem lesions was frankly delirious.

Infarcts in the territory of the middle cerebral arteries (MCA) Boudin et al. (1963) described ten patients who had the sudden onset of confusion with agitated behaviour. Two of the patients died and necropsy showed right temporal lobe infarcts. In the other patients clinical and EEG abnormalities suggested that the vascular lesions involved the right temporal lobe. Juillet and colleagues (1964) reported four patients who had visual abnormalities and confusion often with agitation. In two of these patients the clinical and EEG abnormalities suggested right temporal lobe infarction. Mesulam et al. (1976) reported three patients who had acute confusion with agitation related to infarction in the territory of the right MCA. The abnormal behaviour in these patients began abruptly, with extreme distractability, incoherent streams of thought, restlessness, agitation, and hyperactive behaviour. In one patient an early generation CT scan showed a lesion in the inferior right frontal lobe, although this patient had no motor or sensory signs. In the other two patients a radionuclide scan showed lesions in the right temporal and inferior parietal lobes. Angiography in one patient showed an occlusion of the right angular artery branch of the MCA but was normal in the patient with the CT-documented frontal lobe infarct. These patients all had emboli to the right MCA. Although the authors posited that right parietal lobe infarction was the likely explanation for the agitated state, the localization of the ischemic lesions in their patients was imprecise. Guard et al. (1979) reported ten patients with right temporal lobe lesions who had inattention, disorientation, agitation, and impaired cognitive functioning. Four had visual hallucinations, and one was initially thought to have a manic-depressive illness. Only 6/10 had left-sided neuro-

logical signs. Mullally et al. (1982b) reported three patients with left hemiparesis secondary to MCA territory infarction who had ‘failure to maintain a coherent stream of thought or action with inattention and distractabiltiy’. A year later, left hemiparesis had cleared, but all three patients remained ‘confused’. Levine and Finkelstein (1982) described ‘delayed psychosis’ in eight right-handed patients with acute right temporo-parietal lesions. Four had embolic infarcts, three had subcortical hemorrhages, and one had a contusion. Mental symptoms began abruptly 1 month to 11 years after the initial brain damage and lasted days to months, recurring in two patients. All patients had formed auditory and visual hallucinations; insight into the reality of the hallucinations varied, as did coexisting abnormalities of orientation, memory, cognition, and affect. Each patient had paranoid delusions and agitation, and some had fluctuating inattentiveness, perseveration, incoherent thinking, screaming, or aggressive violent behaviour. Focal signs were slight. No patient had prior psychiatric illness or drug abuse. Seven of the eight patients had seizures, often focal. The psychotic symptoms did not resemble the seizure manifestations and were too long-lasting to be postictal. Seizures and mental symptoms were considered parallel rather than causal manifestations of ‘an unstable pathophysiological state’ (Levine & Finkelstein, 1982). Price and Mesulam (1985) reported five right-handed patients with inattention, agitation, hallucinations, and paranoid delusions following probable infarction of the right parietal, frontal, or temporal lobes. Schmidley and Messing (1984) reviewed the clinical and imaging findings in 46 patients who had infarction in the territory of the right MCA. Two patients presented with agitation and confusion. Each had left hemianopia and minor left limb motor signs. CT scans in one of these patients were normal, and in another, showed an enhancing right temporal–parietal infarct. Angiography in the agitated patient who had a normal CT showed delayed filling of the temporal and inferior parietal branches of the inferior division of the right MCA. The other 44 patients had more severe motor and sensory signs indicating that their infarcts were more anterior, deeper, or both. A clinico-pathological conference in Paris concerned a 68-year-old man who had the sudden onset of abnormal behaviour. (Awada et al.,1984). He was agitated, could not attend to tasks, and spoke incessantly and incoherently. There was left hemianopia but no motor, sensory, or reflex abnormalities. CT showed an infarct that involved the right inferior parietal and temporal lobes in the territory of the inferior division of the right MCA. In another report, Dunne et al. (1986) considered seizures the most likely

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cause of intermittent altered behaviour that appeared weeks to months after left lobar cerebral hemorrhages (temporal, frontal, occipito-parietal) in three patients. Two patients had delusions and hallucinations and one had a ‘manic delirium’. Caplan et al. (1986) searched the Stroke Data Bank registry and their own patient files for patients with acute strokes that involved the inferior division of the right MCA. All ten patients reported had left visual field abnormalities. Motor abnormaliites were slight and transient. Three had severe agitated delirium at onset. One patient moaned continuously and repeatedly removed all treatment lines, tubes, and catheters despite four-limb restraints. He became less restless after 12 hours, but continued to call out random names and spoke incoherently, and his conversation incessantly flitted from one topic to another. His wife said that he had told her that people entered his room through the windows and so he often hid under the covers to avoid them. Four other patients were restless and had difficulty concentrating for neurologic testing. The restless agitated patients had abnormal drawing and copying. The anatomical localization of infarcts was plotted in the five agitated, restless patients vs. the five other patients who were not agitated. Figs. 16.1 and 16.2 show this reconstruction. The agitated patients all had right temporal lobe infarcts. The authors concluded that infarction of the right temporal lobe was the likely explanation for the agitation that sometimes accompanies right MCA territory infarcts. Mori and Yamadori (1987) studied 41 patients with right MCA territory infarcts, among whom 25 had acute confusion and six had acute agitated delirium characterized by extreme agitation, irritability, vivid hallucinations, delusions, insomnia, and signs of autonomic nervous system overactivity. The six patients with agitation had infarcts in the distribution of the inferior division of the right MCA, involving the territories of middle and posterior temporal artery branches in five of the six patients. Mori and Yamadori (1987) attributed confusion to right frontal and basal ganglionic dysfunction and agitated delirium to temporal lobe infarction. They posited a limbic–sensory disconnection as the mechanism of the agitated state. Agitation, anger, and paranoia are sometimes noted in patients with Wernicke’s aphasia, who most often have embolic occlusions of the inferior branch of the left MCA causing temporal lobe infarction. Patients with aphasia, who are irascible and show anger, usually have Wernicke type aphasia (Fisher, 1970). These behavioural changes are most likely explained by dysfunction of structures that lie medial to the convexal temporal lobe infarcts that cause the aphasia. The reports cited provide conclusive data that infarcts

involving the right temporal lobe in the territories of temporal artery branches of the right MCA are an important cause of an agitated hyperactive state associated with logorrhea. Possibly relevant is that logorrhea is also a feature in patients with left temporal lobe infarcts and Wernicke’s aphasia and excessive loquaciousness may be a characteristic of temporal lobe dysfunction involving either hemisphere and may be present without aphasia.

Anterior cerebral artery territory, frontal and caudate strokes Medial frontal lobe lesions Infarction in the territory of the anterior cerebral arteries (ACAs), especially when bilateral, can cause a variety of behavioural abnormalities, most often abulia (decreased spontaneous behavior and speech with apparent emotional apathy). (Fisher, 1983; Brust, 1998). The relative contribution to abulia, or less often to agitation and delirium, of damage to the cingulate gyrus, supplementary motor area, orbitofrontal cortex and other limbic structures is uncertain. Hyland (1933) reported a patient who had thrombosis of an azygous type ACA and developed a left hemiparesis accompanied by hypersexuality and incessant talking. Amyes and Nielsen (1955) reported eight patients who had lesions involving the cingulate gyri; seven lesions were vascular and one patient had multiple sclerosis. Three of these patients had agitation, hyperactivity, and psychosis. One patient with an aneurysm and bilateral paramedian frontal and orbitofrontal infarcts had severe agitation that alternated with abulia. Agitation and screaming also alternated with akinetic mutism in a patient with bilateral ACA territory infarcts reported by Faris (1969). Starkstein et al. (1988) reported 12 patients with maniclike behaviour after brain lesions clustered in and near limbic areas with strong frontal lobe projections. After reviewing reports of similar patients, the authors posited that dysfunction of the orbito-frontal region might underlie the production of the somatic and mood abnormalities found in patients with mania. Starkstein et al. (1990) later described a second group of eight patients with mania after brain injuries. All were elated and had pressured speech and grandiose delusions. Seven were hyperactive and had insomnia and flights of ideas; five were irritable and six were hypersexual. All of the lesions involved the right cerebral hemisphere. One patient had an infarct involving the head of the caudate, medial temporal gyrus, and basotemporal and dorsolateral

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Fig. 16.1 and 16.2. Five CT scans from patients without agitation (Fig. 16.1) and 5 CT scans from patients with agitation (Fig. 16.2) were analysed. In patients without agitation (Fig. 16.1) the lesions tended to extend mostly into the inferior parietal lobe, sparing the temporal lobe. In agitated patients (Fig. 16.2) the lesions tended to extend into the temporal lobe. Solid black shading indicates involvement of the

frontal regions. Another had an infarct involving the head of the caudate, amygdala, hippocampus, and basotemporal cortex. Another patient developed an infarct after embolization of a right basotemporal vascular malformation. One had a right temporal lobe hemorrhage. Another had bilateral orbitofrontal contusions. Brain scans in three patients showed subcortical lesions including: a contusion that involved the white matter of the anterior frontal lobe, an infarct of the ventromedial caudate head and adjacent anterior limb of the internal capsule, and a larger infarct of the caudate nucleus and anterior limb. PET scans in the three patients with subcortical lesions showed abnormal metabolism in the right lateral basotemporal regions. Bakchine et al. (1989) reported a manic-like state in a patient with bilateral orbitofrontal and right temporoparietal lobe contusions. This patient had a reduced amount of spontaneous behavior when left alone but became manic when stimulated. She had reduced sleep time and frequent outbursts of anger. When spoken to, she became

logorrheic and constantly switched conversation from one topic to another. She was easily distracted and often told jokes with a sexual content. Agitation, hypersexuality, aggressiveness, and anger are often noted in patients with brain injuries that involve the orbitofrontal regions, although additional basotemporal contusions often cannot be excluded by the neuroimaging tests performed. Lesions of the orbitofrontal cortex do cause distractability, overactivity and motor disinhibition. A so-called ‘inhibitory control of interference’ is lost in patients with orbito-frontal lesions (Stuss et al., 1982). The patients seem unable to ignore even trivial stimuli and cannot maintain attention to tasks and ideas if there are any alternative external stimuli.

Caudate nucleus infarcts and hemorrhages Stein et al. (1984), describing patients with caudate nucleus hemorrhages, noted restlessness, agitation,

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area in 80% of patients, diagonal striped shading indicates involvement in 60% of patients, and cross-hatched shading indicates involvement in 40% of patients. (From Caplan et al. (1986) with permission.)

memory dysfunction and confusion. These hemorrhages often dissected into the anterior horn of the lateral ventricle causing blood to spill into the subarachnoid space. Restlessness, irritability, and agitation are well-recognized features in patients with subarachnoid hemorrhages and meningitis but the mechanism is unknown. Meningeal irritation and increased intracranial pressure are possible factors. Mendez et al. (1989) reported neurobehavioural abnormalities in 12 patients with caudate nucleus infarcts, 11 unilateral and one bilateral. Five patients had ‘affective symptoms with psychotic features’. One of these was extremely anxious and had difficulty sleeping and had feelings of panic. She was suspicious and paranoid and heard voices that commented on ‘activities in the atmosphere’. During examination she was very restless and ‘fidgety’. Patients with agitation and psychotic features had lesions that involved mostly the ventromedial portion of the caudate nucleus. Three other patients were disinhibited,

inappropriate and impulsive. One such patient was unkempt, distractable, loquacious, unconcerned, and sexually disinhibited. These three patients had larger lesions that included most of the head of the caudate nucleus and spread to adjacent structures. Mendez et al. (1989) pointed to the similarities of the behavioural and cognitive abnormalities found in their patients with those associated with Huntington’s chorea, another disorder known to involve the caudate nucleus. They pointed out that the ventromedial caudate (the ‘limbic striatum’; Nauta,1986; Nauta & Domesick, 1984) was topographically connected to orbitofrontal cortex. Caplan et al. (1990) reported 18 patients with caudate infarcts, which often extended into the adjacent anterior limb of the internal capsule and the anterior portion of the putamen. The cause was most likely occlusion of lenticulostriate arterial branches of the proximal MCA or recurrent artery of Heubner branches of the ACA. Transient or persistent restlessness and hyperactivity were present in

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seven patients, three of whom had left caudate infarcts and four had right-sided lesions. In these patients apathy and abulia often alternated with hyperactivity. Two patients with right-sided infarcts had severe hyperactivity, talked and moved incessantly, and often called out loudly. Reviewing the anatomical connections of the caudate nucleus (Alexander et al., 1986; Nauta, 1986; Nauta & Domesick, 1984) the authors noted that lateral orbitofrontal cortex (Brodman area 10) projects to the ventromedial portion of the caudate nucleus and that this portion of the caudate also receives input from temporal lobe visual and auditory association cortex. The anterior cingulate cortex (Brodman area 24), the hippocampi, the amygdala, and enterorhinal and perirhinal cortex project to the ventral striatum (nucleus accumbens, septal nuclei, olfactory tubercle, and ventromedial caudate nucleus). The caudate nuclei also have reciprocal connections with the internal segment of the globus pallidus, the rostromedial substantia nigra and the ventral anterior and dorsomedial thalamic nuclei (Caplan et al., 1990; Alexander et al. 1986; Nauta, 1986; Nauta & Domesick, 1984). To our knowledge, however, an agitated state has not been described in patients with lesions limited to the globus pallidus or putamen.

Concluding remarks Hyperactive agitated states can develop after focal brain lesions. Some but not all patients have additional features including logorrhea, press of ideas with rapid flitting from one idea to another, distractability, insomnia, shouting, aggressive sometimes violent behaviour, disinhibition, hypersexuality, hallucinations, delusions, and paranoia. The full syndrome is most apparent in patients with right temporal lobe infarcts that include the hippocampus, amygdala, entorhinal and perirhinal cortex and their underlying white matter. Patients with bilateral lesions involving the fusiform and lingual gyri have a similar agitated delirium, as do some patients with predominantly left fusiform and lingual gyri infarcts. Lesions of the ventromedial caudate nucleus and its underlying white matter can also produce a similar syndrome perhaps more often when the lesions are on the right. Less often, orbitofrontal lesions produce similar findings. Common to these lesions is involvement of structures that relate closely to the limbic cortex of the temporal lobes and the orbitofrontal regions. The right baso-temporal lobe and its connections with the right ventral limbic striatum and the left lingual and fusiform gyri are preferred sites for lesions that cause an overactive, restless, talkative

state. Occasional brainstem lesions also can produce logorrhea and hyperactivity but usually without an accompanying confusional state.

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Mendez, M.F., Adams, N.L. & Lewandowski, K.S. (1989). Neurobehavioral changes associated with caudate lesions. Neurology, 39, 349–54. Medina, J.L., Rubino, F.A. & Ross, E. (1974). Agitated delirium caused by infarctions of the hippocampal formation and fusiform and lingual gyri: a case report. Neurology, 24, 1181–3. Mesulam, M., Waxman, S., Geschwind, N. & Sabin, T. (1976). Acute confusional states with right middle cerebral artery infarctions. Journal of Neurology, Neurosurgery and Psychiatry, 39, 84–9. Mori, E. & Yamadori, A. (1987). Acute confusional state and agitated delirium. Occurrence after infarction in the right middle cerebral artery territory. Archives of Neurology, 44, 1139–43. Mullally, W., Huff, K., Ronthal, M. & Geschwind, N. (1982a). Frequency of acute confusional states with lesions of the right hemisphere. Annals of Neurology, 12, 113 (Abstract). Mullally, W., Huff, K., Ronthal, M. & Geschwind, N. (1982b). Chronic confusional state with right middle cerebral artery occlusion Neurology, 32, A96 (Abstract). Nauta, H.J.W. (1986). The relationship of the basal ganglia to the limbic system. In Handbook of Clinical Neurology: Vol 5, Extrapyramidal Disorders, ed. P.J. Vinken, G.W. Bruyn & H.L. Klawans, pp. 19–31. Amsterdam: Elsevier Science. Nauta, W.J.H. & Domesick, V.B. (1984). Afferent and efferent relationships of the basal ganglia. In Functions of the Basal Ganglia. Ciba Foundation Symposium 107, pp. 3–29. London: Pitman. Pessin, M.S., Chimowitz, M.I., Levine, S.R. et al. (1989). Stroke in patients with fusiform vertebrobasilar aneurysms. Neurology, 39, 16–21. Price, B.H. & Mesulam, M. (1985) Psychiatric manifestations of right hemisphere infarctions. Journal of Nervous and Mental Disease, 173, 610–14. Santamaria, J., Blesa, R. & Tolosa, E. (1984). Confusional syndrome in thalamic stroke. Neurology, 34, 1618. Schmidley, J. & Messing, R. (1984). Agitated confusional states in patients with right hemispheral infarctions. Stroke, 15, 883–5. Starkstein, S.E., Boston, J.D. & Robinson, R.G. (1988). Mechanisms of mania after brain injury: 12 case reports and review of the literature. Journal of Nervous and Mental Disease, 176, 87–100. Starkstein, S.E., Mayberg, H.S., Berthier, M.L. et al. (1990). Mania after brain injury: neuroradiological and metabolic findings. Annals of Neurology, 27, 652–9. Stein, R.W., Kase, C.S., Hier, D.B. et al. (1984). Caudate hemorrhage. Neurology, 34, 1549–54. Stuss, D.T., Kaplan, E.F., Benson, D.F., Weir, W.S., Chiulli, S. & Sarazin, F.F. (1982). Evidence for the involvement of the orbitofrontal cortex in memory function – an interference effect. Journal of Comparative Physiology, 96, 913–25. Symonds, C. & Mackenzie, I. (1957). Bilateral loss of vision from cerebral infarction. Brain, 80, 415–55.

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Frontal lobe stroke syndromes Paul J. Eslinger1 and Raymond K. Reichwein2 1

Department of Medicine and 2Behavioral Science Penn State University College of Medicine, PA, USA

Introduction Stroke is one of the most common neurological problems faced by neurologists and internists. Frontal lobe strokes produce wide variations of symptoms and outcome, which can be challenging even to experienced clinicians. Presentations range from profound akinesia and mutism to subtle changes in emotional processing and personality. Because of its large size, its dependence on both anterior and middle cerebral arteries, and its mediation of many processes underlying human adaptation, the frontal lobe is a particularly important cerebral region to understand. This chapter addresses both organizational and clinical aspects of the frontal lobe, particularly those signs, symptoms and cerebrovascular lesion patterns that clinicians are likely to encounter. Stroke management has changed dramatically over the past few years, particularly with the FDA approval of intravenous t-PA. The new acute stroke motto is ‘stroke is a brain attack and time is brain’. There are multiple acute stroke therapies, including intravenous/intra-arterial thrombolysis and various neuroprotective agents on the horizon, and these therapies may have a significant impact on subsequent stroke outcomes. There are currently no studies that specifically address functional outcomes after acute stroke with frontal lobe involvement. As frontal stroke syndromes can be quite devastating to the patient and family, we hope future studies will better address these syndromes and whether hyperacute stroke interventions alter their outcome.

Anatomical and organizational features of the frontal lobe Perhaps the most fundamental feature of the frontal lobe is its division into primary motor, premotor and prefrontal

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cortical areas. This is based on cytoarchitecture as well as functional distinctions, and is evident on lateral and mesial surfaces of the frontal lobe. In developing a comprehensive clinical-anatomical classification model for the frontal lobe, we and others have identified four major regions: lateral, mesial and ventral frontal cortices and the deep white matter. Table 17.1 provides a summary of these regions with reference to prominent anatomical landmarks, cytoarchitectonic characteristics (according to the schema of Brodmann, 1909), and their functional affiliation with diverse brain systems. Historical descriptions have emphasized important roles for the frontal lobe in motor strength, certain reflexes, autonomic processing, olfaction, personality and social–emotional behaviour (e.g. Harlow, 1848, 1868; Moniz, 1936; Freeman & Watts, 1942; Sachs & Brendler, 1946; Brickner, 1936; Hebb & Penfield, 1940; for historical review, see also Benton, 1991). Recent formulations have emphasized additional processes often subsumed under the rubrics of executive functions and self-regulation of cognition, emotion and behaviour (e.g. Tranel et al., 1994; Grafman, 1995; Damasio & Anderson, 1993; Eslinger, 1996). To accomplish such diverse and complex neural processes, the frontal lobes must be in a position to receive and evaluate ongoing information about the organism and the environment through afferent projections, as well as access prior experiences and expectancies in order to devise and pursue adaptive goals and actions. The latter also implies that the frontal lobes must be able to influence efferent systems such as cognitive, emotional, autonomic–visceral, endocrine and motor structures for implementation and modification of responses. The following summarizes several organizational aspects of these afferent–efferent systems: • Physiological frameworks in the frontal lobe are evident for both neocortical processing (e.g. temporary memory

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Table 17.1. Anatomical features of specialized frontal lobe regions

Regions Lateral frontal region Primary motor and premotor cortices Dorsolateral prefrontal cortex

Mesial frontal region Superior mesial

Inferior mesial Ventral frontal region Basal forebrain

Orbital

Deep white matter

Prominent anatomical landmarks

Brodmann’s cytoarchitectonic areas

Central sulcus/precentral gyrus Broca’s area (left) Frontal pole Frontal Gyri Inferior Middle Superior

4, 6 (lateral), 44, 45 8, 9, 10, 11, 43, 46, 47

Motor Premotor Prefrontal

Central sulcus/precentral gyrus Supplementary motor area Anterior cingulate gyrus Subcallosal gyrus Mesial gyrus rectus

4 (mesial), 6 (mesial) 24

Motor Premotor Limbic Paralimbic Prefrontal

Septal nuclei Precommissural fornix Nucleus accumbens Substantia innominata Diagonal band of Broca Gyrus rectus Olfactory tracts Orbital gyri Medial Middle Lateral Periventricular (rostral, lateral, inferior, superior to frontal horns)

representations, long-term knowledge storage, associative mechanisms for decision-making) and limbic system processing (e.g. learning and emotions). • Prefrontal cortex is interconnected with other cortical regions subserving visual, auditory, somatosensory and multimodal perceptual processing in temporal, parietal and occipital lobes. This is reflected in multiple projection pathways to and from prefrontal cortex, conveying details about environmental events and stimuli in relation to knowledge, language, spatial and other cognitive systems. • Prefrontal cortex is interconnected with limbic and paralimbic system structures including amygdala, hippocampus, dorsomedial nucleus of the thalamus, temoral polar cortex, insula and anterior cingulate gyrus. These struc-

25, 32, 14, 12

Neural systems

Limbic

10, 11, 13, 14, 47

Paralimbic Prefrontal

Frontal–striatal Frontal–thalamic Frontal–limbic Frontal–cortical pathways

tures are implicated in memory, emotion, and visceral–autonomic functions and have strong projections particularly to the orbital frontal region. Thus, there is convergence of cognitive, emotional and visceral–autonomic streams of processing in the frontal lobe. • Cortical and subcortical structures mediating somatic, visceral, autonomic and hormonal regulation are interconnected with prefrontal cortices, along with pathways to motor system structures of the basal ganglia, thalamus and primary motor cortex. Thus, multiple effector systems are influenced by the prefrontal cortex. • The frontal lobe is interconnected with key subcortical structures to form parallel networks that subserve adaptive behaviour. Damage to these subcortical structures (including portions of the basal ganglia and thalamus)

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can produce frontal-type impairments such as disinhibition, perseveration, loss of initiation, etc. (e.g. Cummings, 1993; Bogousslavsky, 1994). Hence, frontal–subcortical networks are an important extension to frontal lobe models. Recent examples of procedures that produce frontal lobe activation in functional brain imaging studies of normal volunteers include tasks of simple and complex finger movements (Rao et al., 1993), verbal associative fluency (Paulesu et al., 1997), memory retrieval (Tulving et al., 1994), deductive reasoning (Goel et al., 1998), interpretation of figurative aspects of language (Bottini et al., 1994), working memory (Ungerleider et al., 1998; McCarthy et al., 1994; Jonides et al., 1993), planning (Owen et al., 1996), and language/semantic processing (Binder, 1997; Spitzer et al., 1998).

as a general rule, the anterior cerebral artery supplies the mesial aspects of the frontal lobes and the middle cerebral artery supplies the lateral aspects. From available literature and clinical cases of frontal lobe stroke, it is possible to identify specialized regions which have distinctive clinical–behavioural characteristics. We classify these into seven general profiles, modelled after the anatomical regions described in Table 17.1. However, it must be realized that stroke may cause diverse combinations of these syndromes depending upon its size and location. Brief description of each syndrome follows (see Table 17.2 for summary of prominent impairments associated with damage to each region).

Lateral frontal syndromes Primary motor and premotor cortices

Clinical presentations and correlates of frontal lobe stroke Given the unique and complex characteristics of frontal lobe anatomy and organization, it is perhaps not surprising that diagnosis and management of frontal lobe stroke encompasses a broad range of signs and symptoms. These include motor, reflex, autonomic regulation, multiple cognitive domains, emotion, personality and social behaviour. The cognitive, emotional and behavioural domains of frontal lobe syndromes can be particularly challenging. It is often in a patient’s real-life management of temporary, changing circumstances, their planful achievement of long-term goals, and their handling of diverse social– emotional interactions that impairments related to prefrontal damage will be revealed most clearly and consistently. These deficiencies can include disorganization, loss of initiative, motivation and emotional expressions of face, voice and gesture, hypomania, depression, irritability, euphoria, disinhibition and impulsivity, perseveration, cognitive rigidity, obsessive behaviours, apathy, poor memory, loss of insight, empathy and social discourse processing. Some of these impairments seem almost opposite in nature (e.g. loss of initiative and disinhibition), yet these contrasts speak to an overarching principle of frontal lobe processing, namely the regulation of behaviour. Thus, frontal lobe stroke may cause release of complex behaviour–emotional processes, loss of such mechanisms or erratic regulation of such mechanisms. The frontal lobe is irrigated by branches of both the anterior and middle cerebral arteries. There are different nomenclatures describing such branches (see Damasio, 1983 for comparison and common vascular anatomy), but

Stroke involving the lateral primary motor and premotor cortices (area 4 and 6 lateral) typically involves rostral branches of the middle cerebral artery. These regions are involved in motor activation, planning and programmed execution of movement in coordination with sensory– perceptual systems. Weakness and loss of skilled movements of the contralateral face, oral masculature and upper extremity (apraxia) result from stroke in these areas. There is often more deficit in distal than proximal aspects of the contralateral extremity, with rigidity and abnormal muscle tone possible. Bilateral or contralateral motor impersistence can occur with right-sided stroke. An example is inability of the patient to maintain eye closure for 10 seconds. Input from the prefrontal cortex, basal ganglia and thalamus provides important information to these areas about perceptual processing and decision-making choices that activate and inhibit diverse motor responses. Involvement of the lateral premotor region (areas 6, 44, 45) can cause oral and limb apraxia, dysarthria and nonfluent aphasia with prominent disturbance in the initiation and fluency of speech. Smaller lesions have been associated with less severe speech and apraxic disturbances, often with good recovery (e.g. Damasio, 1992; Bogousslavsky, 1994). Larger lesions involving Broca’s area, underlying white matter of the frontal operculum and lower motor strip may lead to the severe syndrome of Broca’s aphasia with non-fluent, telegraphic speech, short verbal responses, paraphasic errors, repetition deficit, and impairments of reading, writing and naming. Oral apraxia is often present but functional levels of language comprehension may be preserved. Contralateral lower facial and distal upper extremity weakness may be present as well. Loss of emotional intonation of speech (aprosodia) can occur with left or right frontal opercular stroke.

Frontal lobe stroke syndromes

Table 17.2. Prominent impairments associated with damage to specific frontal lobe regions Region Lateral frontal region Primary motor and premotor cortices

Dorsolateral prefrontal cortices

Mesial frontal region Superior mesial cortices

Inferior mesial cortices

Ventral frontal region Basal forebrain

Orbital cortices

Deep white matter region

Clinical impairments

Hemiparesis Dysarthria Aprosodia Disorganized thinking and behaviour Perseveration Poor planning Impulsive responding Stimulus-boundedness Poor self-regulation Right left hemispatial neglect poor spatial cognition

Apraxia (oral and limb kinetic) Motor impersistence Non-fluent aphasia (left) Impaired working memory Cognitive rigidity Intentional disorders Inattention Lack of empathy Conjugate eye deviation Left transcortical motor aphasia

Akinesia/bradykinesia Apathy Apraxia Grasp reflex Intentional disorders Disinhibition Utilization behaviour Altered self-regulation

Mutism Loss of motivation Alien hand Altered self-regulation Callosal disconnection signs Lack of motivation Altered emotional processing

Amnesia Reduced motivation

Confabulations Delusions (e.g. Capgras syndrome, reduplicative paramnesia) Impulsive actions Reduced empathy Altered self-regulation

Personality change Poor social judgment Lack of goal-directed behaviour Environmental dependency Personality change Reduced emotions

Dorsolateral prefrontal cortices The dorsolateral prefrontal region contains the so-called ‘frontal eye fields’ and also mediates diverse cognitive operations often referred to as ‘executive functions’. The frontal eye fields (Brodmann’s area 8) regulate voluntary eye movements. Damage to this area results in conjugate eye deviation to the side of the lesion. This deviation is transient, usually resolving within several days. Executive functions are processes often invoked when conceptualizing goal-directed achievements that require planning, organization, timely responding, working memory, coordination of attentional abilities, implementing plans and intentions, problem-solving, and cognitive aspects of relating to and understanding others (empathy). Damage from stroke is devastating when it is bilateral (usually from two separate strokes), which fortunately is

Poor empathy Irritability

rare, and single left or right dorsolateral strokes are much more common (see Fig. 17.1 for an example). The ‘executive function’ capacities of these regions often respect general hemispheric biases. That is, left dorsolateral damage rostral or deep to Broca’s area can lead to transcortical motor aphasia and other less disabling impairments of verbal fluency, verbal working memory and verbal cognition. Transcortical motor aphasia is characterized as a non-fluent or semi-fluent aphasia causing difficulties particularly in the initiation and fluency of speech and to a lesser extent in comprehension, reading, writing and naming, but with preserved repetition. Poststroke depression is more common after damage to left prefrontal cortex and may interfere with recovery if not treated (Robinson, 1997). In contrast, right dorsolateral damage can disrupt visuospatial processing and cognitive organization,

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Fig. 17.1. CT scan demonstrating hemorrhagic infarct with edema and mass effect in the left dorsolateral frontal region. This patient presented with disorganization, difficulties in effective verbal communication, reduced problem-solving and mild right hemiparesis.

causing left hemispatial neglect, spatial planning and spatial working memory impairments, constructional apraxia and emotional indifference.

Mesial frontal syndromes Superior mesial frontal cortex Unilateral or bilateral stroke occurring in the territory of the anterior cerebral artery can damage extensive portions of the mesial frontal lobe. Stroke in the more distal, superior branches affects the mesial extension of the primary motor cortex (area 4), the premotor cortex (area 6: supplementary motor area) and the anterior cingulate gyrus. The posterior surface of the superior mesial frontal lobe contains the motor representation for the trunk and lower extremities. Effects of stroke can include lower extremity weakness and Babinski sign, with sensory loss occurring when the lesion extends to the postcentral gyrus (Bogousslavsky & Regli, 1990). Damage to the supplementary motor area and anterior cingulate gyrus leads to loss of behavioural initiation, ranging far beyond speech to many aspects of intentional, goal-directed behaviour such as dressing, preparing food, and completing other everyday tasks (see Fig. 17.2, for example of superior mesial frontal

stroke). Such damage disconnects the superior mesial frontal cortices from the basal ganglia, primary motor cortex, pons and limbic system. Clinically, such patients are described as akinetic and mute, the severity and duration depending upon the unilateral or bilateral extension of the lesion. This alteration of self-regulation extends to virtually all domains of behaviour, whether participating in social interactions, answering the telephone, initiating self-care or responding to other environmental stimulants. Brief responses may occur and be entirely appropriate, but there is a failure to maintain such responsiveness and to initiate spontaneous behaviour. Cases of bilateral superior mesial damage have a much more difficult course of recovery, with frequent lower extremity weakness, urinary urgency and incontinence and profound loss of motivation, emotional expression and emotional experience. Treatment with a dopamine agonist agent such as bromocriptine may hasten recovery (Eslinger et al., 1995). Patients with unilateral lesions recover more quickly and completely, with some greater involvement of speech and language behaviour (i.e. transcortical motor aphasia) after left-sided damage. Unilateral lesions may cause forced grasping/groping in the contralateral hand, abulia (i.e. diminution of spontaneous behaviour and reported emo-

Frontal lobe stroke syndromes

Fig. 17.2. T2 MRI scan showing right superior mesial frontal lobe ischemic stroke. Note the lesion location in the upper left image, disconnecting fibres crossing in the anterior corpus callosum.

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Fig. 17.3. T1 MRI scan in sagittal plane showing bilateral inferior mesial frontal lobe ischemic lesions from rupture and surgical repair of pericallosal artery and anterior communicating artery aneurysms. Reduced emotional expression, lack of motivation, personality change and decreased memory retrieval were residual consequences.

tional experience, often described as lowered motivation and personality change) as well as callosal-related abnormalities such as left upper extremity ideomotor apraxia, agraphia and tactile anomia.

Inferior mesial frontal cortex Inferior mesial frontal stroke can occur as isolated infarcts or as complications from rupture and surgical repair of anterior communicating proximal artery aneurysms (e.g. Bogousslavsky & Regli, 1990; Eslinger & Damasio, 1984). An example of infarction related to aneurysm rupture is shown in Fig. 17.3. Motivatonal, personality and memory changes are frequently observed but without the more profound akinesia, mutism and transcortical aphasia associated with damage to superior mesial frontal areas. There is reduced emotional expression in face and voice, and less emotional intensity with family members. This region has strong connections with the limbic system and autonomic effector structures, and has been implicated in bipolar disorder and primary familial depression (e.g. Drevets et al., 1997). Deficits in memory occur, particularly retrieval and efficiency of learning, but recognition memory and general orientation can be intact. Lapses in contextual memory and guidance of behaviour may lead to utilization behaviour and the environmental dependency syndrome such as

a patient reporting to a job not held in several years after encountering an old work uniform in the wardrobe (e.g. Lhermitte, 1983; Eslinger & Damasio, 1984).

Ventral frontal syndromes Basal Forebrain Almost all cases of basal forebrain damage arise from rupture and surgical repair of anterior communicating artery (ACoA) aneurysms, although rare cases have occurred of non-aneurysm stroke close to this region. There is a spectrum of cerebrovascular complications from ACoA aneurysms, and Fig. 17.4 shows one example. The basal forebrain encompasses several subcortical nuclear and pathway structures that are heavily interconnected with the amygdala, hippocampus and ventral striatum. Memory impairment, confabulations, delusions such as Capgras syndrome and reduplicative paramnesia and motivational changes can occur. Larger vascular lesions can extend to nearby medial and orbital frontal cortex as well as to basal ganglia, which complicates recovery and often leads to disability.

Orbital frontal cortex This region is most known for its association with prominent personality and social behaviour changes without

Frontal lobe stroke syndromes

Fig. 17.4. CT scan demonstrating extensive mesial orbital frontal ischemic lesion as a consequence of rupture and surgical repair of anterior communicating artery aneurysm.

primary neurologic signs or cognitive impairments. More recently, the orbital frontal cortex has been linked to emotional processing, empathy, contingency-based learning, and autonomic processing related to anticipation of the future consequences of one’s actions (e.g. Grafman et al., 1986; Rolls, 1999; Bechara et al., 1996; Eslinger, 1998). Stroke that is isolated to this cortical region is rare except as a complication of rupture and repair of anterior communicating artery aneurysms, when memory impairment will accompany personality and behavioural changes. Damage can lead to impulsive actions, disinhibition and poor social judgment despite lack of change in general intelligence, memory, perception, and language. Interpersonal behaviours and judgment are also affected by reductions in empathy that impair perception and appreciation of the situational and emotional experiences of others, most particularly family members.

Deep white-matter pathways Infarctions of the middle cerebral artery or the deep penetrating vessels of the anterior cerebral and anterior communicating arteries can affect the deep white-matter pathways of the frontal lobe. White-matter adjacent to the

frontal horns is a high traffic area for frontal–subcortical (e.g. frontal–striatal; frontal–thalamic; frontal–amygdala) and frontal–cortical (e.g. orbital–dorsolateral frontal; uncinate fasciculus) pathways that have behavioural, cognitive and emotional significance (e.g. Cummings, 1993). Disconnection of cortical areas by white matter lesion can lead to marked alterations in neural networks subserving complex emotional processes. For example, a 49-year-old man had a right middle cerebral artery territory infarct affecting the deep white matter of the frontal lobe with extension to the temporal lobe and insula. His cognitive and neurologic impairments (i.e. mild left-sided weakness, coldness of left upper extremity) were minimal and recovered quickly. However, his family reported marked disturbance of his emotional processing, with indifference to usual family dynamics and interactions, reduced sensitivity to their concerns and loss of emotional expression in face and voice. They interpreted this change as lack of interest and insensitivity, since he now spoke his mind without the grace, patience and humour he usually expressed. Treatment with Prozac and then low dose amitriptyline (50 mg qhs) led to improvement in emotional responsiveness and reduction of cold sensations in the left upper extremity. Despite this improvement, the patient

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continued to report few emotional experiences which did not concern him, and therapy was focused on addressing altered family dynamics.

of social comportment and empathic relationship with others. These subtle, and not so subtle, consequences of frontal lobe damage require long-term management by family and health providers.

Recovery and outcome Although few studies have systematically analysed the short- and long-term outcome of patients with frontal lobe stroke, it is clear that there is a substantial role for health providers in managing and supporting such recovery. Variables influencing recovery include the location and extent of the cerebral damage, associated cognitive, motor and emotional impairments, treatment services and supportive care. Since impairments can range from physical limitations to speech, cognitive, social and emotional changes, an interdisciplinary approach is often needed, encompassing neurological, neuropsychological and everyday functional abilities of patients. While hemiplegia, aphasia and memory impairments can often be recognized and addressed through current neurorehabilitation modalities, motivational, emotional, executive and interpersonal changes are more difficult to evaluate and remediate. Some pharmacologic interventions appear promising, such as dopamine agonists, low-dose stimulants and selective serotonin reuptake inhibitors for motivational, attentional and emotional impairments. In addition, environmental modifications, behaviour management and cognitive self-management training can be helpful approaches to long-term deficits that require in-home management by patients and family members (see Eslinger, 1996 for a summary of these approaches). More studies are needed to advance neurorehabilitation approaches.

Conclusions The sequelae of frontal lobe stroke can be evident and limited or enigmatic and life-changing for patients and their families. Early diagnosis with appreciation for both the obvious and subtle levels of poststroke impairment is a key step in fostering a multidisciplinary approach to patients’ recovery of function. Some frontal lobe syndromes may be particularly difficult for families, coworkers and others to understand since a patient’s general intelligence may appear normal. However, their lack of initiation, judgment and foresight may significantly limit their independence and productivity on a daily basis. Although depression is a recognizable emotional change after frontal lobe stroke, other changes may include a loss

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Moniz, E. (1936). Prefrontal leucotomy in the treatment of mental disorders. American Journal of Psychiatry, 93, 1379–85. Owen, A.M., Doyon, J., Petrides, M. & Evans, A.C. (1996). Planning and spatial working memory: a positron emission tomography study in humans. European Journal of Neuroscience, 8, 353–64. Paulesu, E., Goldaire, B., Scifo, P. et al. (1997). Functional heterogeneity of left inferior frontal cortex as revealed by fMRI. Neuroreport, 8, 2011–17. Rao, S.M., Binder, J.R., Bandettini, B.S. et al. (1993). Functional magnetic resonance imaging of complex human movements. Neurology, 43, 2311–18. Robinson, R.G. (1997). Neuropsychiatric consequences of stroke. Annual Review of Medicine, 48, 217–29. Rolls, E.T. (1999). The functions of the orbitofrontal cortex. Neurocase, 5, 301–12. Sachs, E. & Brendler, S.J. (1946). The orbital gyri. Brain, 72, 227–40. Spitzer, M., Kischka, U., Guckel, F. et al. (1998). Functional magnetic resonance imaging of category-specific cortical activation: evidence for semantic maps. Cognitive Brain Research, 6, 309–19. Tranel, D., Anderson, S.W. & Benton, A. (1994). Development of the concept of ‘executive function’ and its relationship to the frontal lobes. In Handbook of Neuropsychology, Vol. 9, ed. F. Boller & J. Grafman, pp. 125–48. Amsterdam: Elsevier Science BV. Tulving, E., Kapur, S., Craik, F.I.M. et al. (1994). Hemisphere encoding/retrieval asymmetry in episodic memory; positron emission tomography findings. Proceedings of the National Academy of Sciences, USA, 91, 2016–20. Ungerleider, L.G., Courtney, S.M. & Haxbry, J.V. (1998). A neural system for human visual working memory. Proceedings of the National Academy of Sciences, USA, 95, 883–90.

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Memory loss José M. Ferro and Isabel P. Martins University of Lisbon Faculty of Medicine, Portugal

Classification of memory

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Memory is the persistence of information in the central nervous system. It is not a unitary function, it comprises independent systems and processes that can dissociate from each other (Tulving, 1991). Three major cognitive processes are involved in memory: registration (or encoding, during which information is translated into a code to be stored), retention (or storage) and retrieval (when the information is searched and recalled). Memory can be impaired at any of these three steps, but it may be difficult to differentiate between them. A registration disorder should produce mainly an anterograde amnesia, since facts already stored should not be so much affected. However, it may also include a limited period of retrograde amnesia, involving recent memories still undergoing a process of consolidation (Squire et al., 1992). A retrieval or a storage impairment, on the contrary, will produce both a retrograde, and an anterograde, amnesia. While a storage disorder is irreversible, a retrieval impairment may recover and is identified by an improved performance in memory tests with cueing recall (vs. free recall) and in recognition tasks (when compared to recall tasks) (Ellis & Young, 1997). According to Tulving (1995), memory systems may be divided into five main categories: semantic, episodic, primary, procedural and perceptual representation systems. A major distinction is made between declarative (or explicit) and procedural (or implicit, non-declarative) memory (Table 18.1). Declarative memory is the type of memory one is aware of. It is directly acessible to conscious recollection and may be subdivided into semantic memory (our general knowledge of facts, concepts, and meanings) and episodic memory (consisting mainly in autobiographic events framed by a specific spatio-temporal context). In amnesia,

episodic memory (specially for recent episodes) is much more impaired than semantic memory. Both semantic and episodic memories are forms of longterm memory. They can be evaluated by the ability to learn new information, such as lists of unrelated words, pairs of words, stories, visual material, etc. The tests consist of recalling that information after a variable delay, during which another task is performed to prevent rehearsal. The subject is requested to reproduce the information either spontaneously (free recall), with some type of facilitation (cued recall), or by recognition. Autobiographic memory requires a safe source to check the information, someone that knows an individual’s life well. Primary memory, also called short-term, immediate and working memory, is a system that stores data for short periods of time, or holds several pieces of information ‘on line’, while some other type of mental task is being performed (mental arithmetic, reasoning, problem solving, complex sentence analysis, for example). This system is conceptualized as consisting of a central executive (an attentional control system) and two slave systems, one visual (the visuospatial sketch pad) and one verbal (the phonological loop) (Baddeley, 1999). It is usually evaluated by the serial recall of digits or words lists (or by the reproduction of visually presented material) immediately after its presentation. This type of memory is fully intact in human amnesia (Baddeley & Warrington, 1970; Cave & Squire, 1992). Procedural memory and perceptual representation systems are implicit forms of memory and underlie certain abilities like learning of motor and cognitive skills (skilled perceptuo-motor tasks and reading, for instance), simple conditioning and associative learning. They also include perceptual priming, which is a facilitation of perception, or identification, of a stimuli after a first encounter with it. These systems are relatively preserved in amnesics. They are difficult to study because there are no standardized

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Table 18.1. Major categories of human learning and memory System

Other terms

Subsystems

Retrieval

Evaluation tests

Procedural

Non-declarative

Implicit

Pursuit rotor Mazes Jigsaw puzzles

PRS

Priming

Implicit

Figure recognition Word-stem completion

Semantic

Generic Factual Knowledge Working Short-term Personal Autobiographical

Visuo-motor skills Cognitive skills Simple conditioning Simple associate learning Structural description Visual word form Auditory word form Spatial Relational

Implicit

Visual–spatial sketch pad Phonological loop

Explicit

Factual knowlegde Vocabulary Pairs, list of words Digit span Word span Personal history

Primary Episodic

Explicit

Note: Adapted from Tulving (1995). PRS = perceptual representation systems.

a

tests for those abilities. The most commonly used tasks consist of word stem completion (evaluating the effect of a previous exposure to a list of words on their use upon word completion), recognition of fragmented words, sentence puzzle solutions and perceptuo-motor tasks.

The functional anatomy of memory The anatomical structures underlying declarative memory are multiple. Episodic memory depends upon the ‘bottleneck structures’ where the information is processed before long-term storage. These structures can be divided into three major anatomical systems: the Papez circuit (hippocampal formation, parahippocampus, ento and perirhinal cortex, cingulate gyrus, fornix, nucleus anterior thalami, mammillothalamic tracts and mammillary bodies), the basolateral limbic circuit (comprising the dorso-medial thalamic nucleus, the subcallosal area and the amygdala), and the basal forebrain, which includes the septum, the diagonal band, and the nucleus basalis of Meynert. The basal forebrain is important for promoting the impact and memorability of novel and motivationally relevant events. The medial septal nucleus and the diagonal band provide the major cholinergic input of the hippocampus. The cerebral cortex receives dense cholinergic input from the nucleus of Meynert, through a medial and a lateral pathway (Selden et al., 1998). The retrieval of old episodic information also depends on other structures, namely the lateral temporo-polar and inferior prefrontal regions. On

the other hand, storage of episodic and semantic memories depends upon different areas of the associative cerebral cortex. Imaging activation studies (Cabeza & Nyberg, 1997) have shown that there are hemispheric asymmetries in those processes. While the left dorsolateral prefrontal region predominates in episodic memory encoding (possibly due to its semantic processing), the right prefrontal cortex (together with other regions) predominates in declarative memory retrieval. The specific role of the right frontal region consists of supporting or guiding the retrieval process rather than actually recovering stored information. This right/left difference has been conceptualized as an hemispheric encoding/retrieval asymmetry (HERA model) (Tulving, 1995; Desgranges et al., 1998). Working memory depends mostly upon the frontal (Brodman areas 6 and 44 for the phonological loop) and the parietal cortices. In what concerns implicit memory, its neural correlates are different from those of the explicit system. While the basal ganglia and the cerebellum play a role in learning motor skills and classical conditioning, PET studies have consistently shown an activation of the right posterior neocortex in perceptual priming (Markowitsh, 1995; Squire et al., 1992).

Arterial blood supply The arterial blood supply of anatomical structures involved in memory comes (Fig. 18.1) from different sources (Lazorthes, 1961; Krayenbühl & Yasargil, 1972;

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Fornix

NA

NA – anterior nuclei NDM – dorsomedial nuclei MTC – mammillothalamic tract

NDM Thalamus MTC

Basal forebrain

Mammillary body

HIPPOCAMPUS PARA HIPPOCAMPAL GYRUS

Posterior choroidal artery

Anterior cerebral artery

Anterior choroidal artery Posterior cerebral artery

Anterior communicating artery Posterior communicating artery

Fig. 18.1. Schematic representation of the anatomical structures involved in declarative memory and their blood supply.

Ghika et al., 1990). The anterior hippocampus and adjacent cortex are supplied by the anterior choroidal artery. Its posterior part, adjacent cortex and the parahippocampus gyrus belong to the territory of the anterior and posterior temporal arteries, which are branches of the posterior cerebral artery. The fornix is supplied by the anterior cerebral artery, the posterior communicating artery and by a branch from the posterior choroidal artery to the crura fornicis. The mammillary bodies are supplied by the posterior communicating and posterior cerebral arteries. The anterior nuclei of the thalamus and part of the mammillothalamic tract receive blood from the polar (tubero-thalamic) artery, which is a branch of the posterior communicating artery. The left and right polar arteries can have a common origin. The dorsomedial thalamus receives its blood supply from the thalamo-subthalamic (or thalamoperforating) arteries, that are branches of the P1 segment of the posterior cerebral artery. The left and right thalamoperforating arteries can also have a common origin. The basal forebrain has its blood supply from perforating branches of the anterior cerebral and anterior communicating arteries.

severe in 52%. It was the only neuropsychological abnormality in 6%. Patients with memory impairment were older and more likely to have left-sided lesions than those without. Memory deficits were not correlated with the intensity of depressive symptoms (Madureira et al, 1999). In some cases this memory impairment may be due to the cumulative effects of stroke and preclinical Alzheimer’s disease or to unrecognized pre-existing dementia (Hénon et al., 1997). In patients with vascular dementia, memory is less severely impaired in early stages than in Alzheimer’s disease. Vascular dementia patients have poorer verbal fluency, but better free recall, fewer intrusion errors and better recognition than Alzheimer’s disease (Pasquier & Leys, 1997) patients, indicating subcortical–frontal dysfunction as opposed to medial temporal in Alzheimer’s disease (Lafosse et al., 1997).

Specific vascular syndromes Medial temporal infarcts

Memory impairment following stroke Mild memory complaints are frequent in stroke survivors. Neuropsychological testing 3 months after stroke revealed impairment in memory tests in 20% of stroke survivors. This disturbance was mild in 38%, moderate in 10% and

About 25% of posterior cerebral artery (PCA) territory infarcts, present with severe memory defects (Brandt et al., 1995), in particular, when there is mesial temporal involvement. Hippocampal damage alone seems not to be sufficient to produce lasting amnesia. Additional damage to the ento- and perirhinal cortex, collateral isthmus or parahip-

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Fig. 18.2. Two cases of bilateral simultaneous mesial temporal infarcts producing permanent severe amnesia.

pocampal gyrus is deemed necessary (Von Cramon et al., 1988). Recent research indicates that damage to the hippocampus and its projections results in deficits in recall of episodic information, while damage to other regions, such as the rhinal cortex, disrupts recognition based on familiarity judgments (Aggleton & Saunders, 1997). The memory defect can follow unilateral or bilateral infarcts (Victor et al., 1961), but is more frequent after left-sided (Benson et al., 1974) or bilateral temporal damage. Left-sided infarcts usually cause predominantly verbal amnesia, often in combination with pure colour and object agnosia or anomia (Geschwind & Fusillo, 1966; Caplan & HedleyWhite, 1974), while right-sided ones can disturb visuospatial memory, as well as memory for faces or locations. Not infrequently, unilateral infarcts located on the left mesial temporal lobe can produce a global (verbal and visuospatial) memory defect (Ott & Saver, 1993). Visual amnesia, i.e. a modality-specific, visual learning defect was also reported after bilateral lesions (Ross, 1980). Medial temporal amnesia is a declarative memory defect, disturbing especially episodic memory. It produces mainly anterograde amnesia. The encoding and consolidation of new facts, events, names and concepts is defective, while retrieval of previously learned data is adequate. Working

and procedural memory are not affected. Most patients are aware of the defect. Confabulations are infrequent, unless there is coincidental medial thalamic damage, that hypothetically causes a fronto-cingular deafferentation (Servan et al., 1994). There are few studies on the recovery of memory defects after PCA infarcts. Recovery can be almost complete or fair, if the lesion is unilateral, but the prognosis is ominous when damage is bilateral (Fig. 18.2). Memory loss can then be very severe and permanent, leading to dependency in everyday life. Bilateral PCA infarcts are one of the mechanisms of ‘focal’ or ‘strategic infarct’ forms of vascular dementia (Román et al., 1993).

Thalamic infarcts and hemorrhages Anterior and dorsomedial thalamic infarcts (Graff-Radford et al., 1985; Bogousslavsky et al., 1988) (Fig. 18.3) and anterolateral, large medial and posteromedial hematomas (Kawahara et al., 1986) can disturb a wide range of neuropsychological functions (arousal, attention, motivation, initiative and executive functions), and produce severe memory deficits. Because blood supply to both anterior nuclei can derive from a single vessel, simultaneous bilateral infarcts can occur.The same applies to the dorsomedial

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Fig. 18.3. Polar (right) and medio dorsal (left) infarcts causing transient memory defects.

nuclei (Castaigne et al., 1981). When thalamic infarcts are bilateral, they also tend to be larger (in each hemisphere) than unilateral infarcts. Defects in verbal memory were also reported as a sequela of deep venous thrombosis with thalamic venous infarct (Haley et al., 1989; Peru & Fabbro, 1997; Rousseaux et al., 1998). After anterior (polar) infarcts, amnesia is found in combination with abulia, decreased expression of emotions, language disturbances or neglect (Bogousslavsky et al., 1986), but a case of pure amnesia has also been described (Clarke et al., 1994). After mediodorsal infarcts, memory defects are combined with drowsiness, abulia, flattened emotions and vertical gaze disturbances (Castaigne et al., 1966, 1981; Guberman & Stuss, 1983). Amnesia becomes specially apparent when vigilance improves. It is disputable which of the two locations, anterior or dorsomedial, produces the more severe and long-lasting amnesia. For some authors (Clarke et al., 1994), amnesia is more severe and stable after polar infarcts. This is due to damage to the mammillothalamic tract of the anterior nuclei and its projections to the posterior medial frontal lobe. After mediodorsal infarcts memory impairment is transient, unless the lesion extends rostrally enough to include the mammillothalamic tract, the ventral portion of the lamina

medullaris interna (Von Cramon et al., 1985) or the inferior thalamic peduncle, that includes axons of the ventroamydgalofugal pathway (Graff-Radford et al., 1990). In the experience of others (Caplan, 1996), memory defects are more severe and persistent after dorsomedial than after polar infarcts. The memory defect produced by thalamic lesions includes verbal (Mori et al., 1986) or both verbal and visual memory, for left-sided infarcts, and only visual memory, for right-sided lesions (Speedie & Heilman, 1983). However, both right (Rousseaux et al., 1991) and left (Von Cramon et al., 1985) unilateral thalamic lesions with global amnesia have been described. Unilateral amnesic stroke has been reported more often in association with left hemispheric lesions (Ott & Saver, 1993; Pepin & Auray-Pepin, 1993). Graff-Radford et al. (1990) attribute this dense amnesia to simultaneous damage to the mamillothalamic pathway and the inferior thalamic peduncle. In thalamic amnesia, the memory defect affects predominantly episodic declarative memory, i.e. the acquisition and recall of new facts and events. These patients have severe anterograde and moderate and partly reversible retrograde amnesia. As in other forms of diencephalic amnesia, there seems to be a dual pathology, affecting the

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encoding of new memories, as well as the retrieval of both new and old memories. There is no evidence of rapid decay or forgetting. Thalamic amnestic patients have preserved motor learning and implicit memory, with intact priming (Malamut et al., 1992). Some patients are aware of the defect but others are not. The memory defect is not secondary to the other behavioural abnormalities, as it can be demonstrated in single tasks requiring immediate recall. Performance of patients with dorsomedial infarcts in memory tasks is characterized by severe distractibility (Mennemeier et al., 1992). They can show a ‘scalloping’ effect, with alternating good–bad performance and the best performance on the first attempts, suggesting that motivation and attention influence performance (Stuss et al., 1988). After unilateral infarcts, memory disturbances usually show considerable recovery, but occasionally the defect persists. Sala et al. (1997) reported a case with persistent global amnesia caused by a unilateral right thalamic stroke, but displaying bilateral mesial frontal hypometabolism in PET. After tuberothalamic infarction, inactivity, depression and memory disturbances remain the dominant residual symptoms, often preventing return to work (Kotila et al., 1994). Patients with bilateral lesions have a more severe and long-lasting memory defect. Bilateral paramedian thalamic infarcts are another form of ‘strategic’ infarct vascular dementia (Román et al., 1993).

Strokes in other locations (caudate, capsular genu, retrosplenial cortex fornix) Caudate infarcts and hemorrhages can produce several cognitive and behavioural deficits (Caplan et al., 1990; Mendez et al., 1989). Formal neuropsychological testing reveals impaired problem-solving ability, decreased attentional capacity and moderate impairment on memory tasks due to difficulty in recall even with cues, but with normal recognition. However, in caudate lesions, abulia and ‘frontal-lobe like’ abnormalities predominate over memory troubles (Kumral et al., 1999). Confusion and memory loss can also result from infarction of the inferior genu of the internal capsule (Tatemichi et al., 1992). This syndrome features fluctuating alertness, inattention, memory loss, apathy, abulia, psychomotor retardation and severe memory loss. This strategic infarct location interrupts the inferior and anterior thalamic peduncles, and causes deactivation of the ipsilateral frontal cortex. The majority of these defects improve during follow-up, and the patients are left with minor residual cognitive and moderate memory troubles, that in

general do not interfere with previous lifestyle (Madureira & Ferro, 1999). Valenstein et al. (1987) reported a case of retrograde and anterograde amnesia, following hemorrhage from an arteriovenous malformation situated near the splenium of the corpus callosum, damaging the retrosplenial cortex and a pathway linking the subiculum to the anterior thalamus. Brion et al. (1969) described a Korsakoff syndrome (amnesia and confabulation) in association with a pathologically verified infarct of both columns of the fornix.

Intraventricular hemorrhage Many of the structures (fornix, medial thalamus, mammillary bodies, mammillothalamic tract) subserving episodic memory are situated in close anatomical relation to the third ventricle. It is therefore not suprising that memory is frequently disturbed after primary intraventricular hemorrhage. In this rare form of spontaneous intracerebral hemorrhage, intraventricular bleeding is confined to the ventricles and is not secondary to the rupture into the ventricles of a neighbouring intraparenchymatous hematoma. In the acute phase, non-comatose patients often display a general cognitive dysfunction with fluctuating attention, orientation and concentration, with slow improvement over weeks or months. Mild memory problems remain in about one-third of the survivors (MartíFábregas et al., 1999), formal neuropsychological testing revealing a learning defect more striking for novel words or associations (Darby et al., 1988).

Subarachnoid hemorrhage Despite progress in the management of subarachnoid haemorrhage (SAH), anterior communicating artery (ACoA) aneurysmal rupture is often complicated by a range of neuropsychological disturbances including amnesia, personality changes, confabulation, abulia and jocosity (Lindqvist & Norlen, 1966; Alexander & Freedman, 1984; Damásio et al., 1985; DeLuca & Diamond, 1995). Less often, memory troubles can follow posterior communicating artery aneurysmal rupture. These defects are specially prevalent in the acute/subacute stage. Although complete or considerable recovery occurs in the majority of the patients, some are left with permanent memory deficits. Amnesia is due to mediobasal frontal damage, secondary to ACoA aneurysmal rupture or the severing of ACoA perforators during surgery. The relevant structures involved include the anterior cingulate, the subcallosal area and basal forebrain, including the septal and Meynert nuclei and the diagonal band (Alexander & Freedman, 1984;

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Damásio et al., 1985). Hydrocephalus, intraventricular and subarachnoid bleeding do not play a relevant role in the pathogenesis of amnesia. Du Cros and Lhermitte (1984) found a link between resection of the gyrus rectus and the deterioration of mnestic capacities. Confabulations are attributed to dual frontal and basal forebrain damage (DeLuca & Cicerone, 1991). The amnestic syndrome of AcoA rupture is characterized by severe anterograde deficit, mild (weeks or months) retrograde loss and normal implicit memory (Bondi et al., 1993). Immediate recall is relatively intact while delayed recall is significantly compromised. Recognition is mildly impaired and later returns to normal. ACoA patients show impairment in their ability to tag episodic information with the appropriate spatiotemporal markers. Their memory defect is susceptible to proactive and retroactive interferences (Damásio et al., 1985; DeLuca, 1992; DeLuca & Diamond, 1995; Rousseaux et al., 1998a,b). In the acute/subacute stage patients are unaware of their memory defects, but awareness is retained in the chronic stage.

Reduplicative paramnesia Reduplicative paramnesia (Pick, 1903), also labelled disorientation for place or spatial delirium, is a bizarre disturbance where a patient believes he/she is in a different place from the actual one, even in the face of compelling counter evidence (Benson et al., 1976). While in the hospital ward, patients claim they are in another hospital they knew before, or even at home, that has been transformed in a hospital or in a section of the hospital. When faced with the evidence that the walls, furniture and people around are different from those at home, they reply with plausible answers like ‘Changes have been made without my permission’ or ‘These people are visiting me’. This delirious belief, or false conviction of familiarity, is in some patients associated with delirium, visuospatial defects and neglect, but is not fully explained by these disturbances. The majority of cases of reduplicative paramnesia have lesions involving the right hemisphere (Murai et al., 1997), with variable localization: parietal-occipital (Fisher, 1982), frontal (Kapur et al., 1988) or subcortical (De La Sayette et al., 1995).

Transient global amnesia Transient global amnesia (TGA) is a episodic dysfunction of the central nervous system during which there is a sudden loss of declarative memory for recent events

without other neuropsychological or neurological symptoms. The etiology of TGA is not yet clear: migrainous disorder, transient arterial hemodynamic disturbance or brief venous ischemia caused by Valsalva manoeuvre in prone individuals (Lewis, 1998). TGA is often precipitated by exertion, emotion or exposition to cold or warm temperatures (Melo et al., 1992). It usually lasts for some hours. During the episode patients display a very typical defect: profound anterograde amnesia, retrograde amnesia extending back for weeks or months, altered categorial fluency, preserved lexical–semantic and procedural memory and priming (Eustache et al., 1997). Metamemory is also spared, explaining patients’ anxious reaction, the characteristic repetitive questioning and adaptive behaviour to the defect. Patients with TGA are more likely to have hypertension and migraine than communitary controls but less likely to have diabetes, hyperlipidemia and also atrial fibrillation than TIA patients (Melo et al., 1992; Lauria et al., 1998). CT, routine MR, extracranial and transcranial Doppler are usually uninformative. During TGA, EEG and transcranial Doppler are also normal (Melo, 1995). Recent PET studies during TGA demonstrated patchy CBF-CMRO2 uncoupling compatible with a migraine-like phenomenon (Eustache et al., 1999). Strupp et al. (1998) were able to demonstrate left or bilateral hippocampal increased signal on diffusion-weighted MRI in seven of ten patients with TGA, interpreted as cellular edema. About 10% of the patients experience a second episode of TGA. The risk of stroke or dementia is not increased in TGA, and long-term antiplatelet treatment is not necessary. TGA should not be confused with amnestic TIAs or infarcts during which the memory loss is always accompanied by other neurological symptoms or an appropriate infarct is demonstrated by CT/MR. It should also be distinguished from post-traumatic amnesia and from ictal or postictal eplipeptic transient amnesic episodes, that are briefer (minutes), stereotyped and with multiple recurrences at short intervals (Hodges & Warlow, 1990; Melo et al., 1994).

Treatment There are, at present, no effective pharmacological treatments for amnesic disturbances of vascular cause. Whether some antidepressants would facilitate recovery, while diazepan and haloperidol would be detrimental, as suggested in animal studies (Goldstein, 1998), remains to be tested in clinical studies. Methylphenidate was reported to be of benefit in a single trial (Tiberti et al., 1998). Drugs with anticholinergic effects are better avoided. Cholinergic

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agents can conceivably be useful, but no trials have yet been completed in stroke patients. Several behavioural memory retraining programmes are available at memory clinics, but their long-term ecological efficacy remains to be proved.

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Neurobehavioural aspects of deep hemisphere stroke José M. Ferro University of Lisbon Faculty of Medicine, Portugal

Introduction The discussion of the role of subcortical structures in language and other higher nervous functions begins with the famous polemic opposing Dejerine (a corticalist) to Pierre Marie, who described several anatomico-clinical cases of subcortical strokes causing aphasia, and claimed that damage to an area including the insula and external capsule was crucial to the production of anarthria. However, during the next decades, few authors attributed any role to the thalamus or to other subcortical structures in relation to symbolic and cognitive behaviour. Since the widespread use of modern neuroimaging techniques, it has become evident that aphasia and other ‘cortical’ syndromes can result from lesions limited to subcortical structures. Both single-photon-emission computed tomography (SPECT) and positron-emission tomography (PET) have shown that subcortical strokes are accompanied by important abnormalities of cortical metabolism and perfusion. Magnetic resonance (MR) can demonstrate cortical lesions that were not apparent on CT. These facts raise the question as to whether neurobehavioural disturbances seen after subcortical strokes are due to subcortical damage per se or are related to functional cortical inactivation (diaschisis), to cortical hypoperfusion or to subtle concomitant cortical lesions.

Subcortical aphasia–striatocapsular aphasia Damasio et al. (1982) and Naeser et al. (1982) described the first patients with subcortical aphasia correlated with CT. Transcortical motor aphasia produced by small ischemic lesions of the basal ganglia, was first described by Wallesch et al. (1983). All of those authors stressed the difficulty of classifying subcortical aphasia in terms of the classic corti-

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cal aphasia syndromes (Table 19.1). Damasio et al. (1982) summarized the distinguishing features of subcortical aphasia: dysarthria independent of the degree of fluency, often accompanied by dysprosody, and rapid recovery, preceding that of motor disturbances. Subcortical infarcts producing aphasia involve the anterior limb of the internal capsule, the head of the caudate nucleus, and the anterosuperior part of the putamen. Lesions located in more posterior aspects of the internal capsule, corona radiata and striatum usually cause dysarthria only. Naeser et al. (1982) identified three capsuloputaminal aphasia syndromes, depending on the extension of the lesion into the white matter: (i) patients with anterosuperior extensions of white-matter lesion had a grammatical, slow, dysarthric speech and good comprehension, similar to what is seen in Broca’ s aphasia, except that they had more grammatical speech and longer phrase lengths; (ii) those with posterior white-matter extension to the auditory radiations and temporal isthmus showed a fluent type of speech; (iii) subjects with both anterosuperior and posterior extensions were global aphasics. Alexander et al. (1987), on the basis of a few positive cases, further detailed that classification, trying to design a neuroanatomic model for specific components of subcortical aphasia: small lesions of the striatum and lateral anterior limb of the internal capsule would cause aphasia or only mild word-finding deficits, whereas lesions extending beyond that territory would cause various speech and language disorders in predictable relationships to the extent of the lesion in the white-matter pathways. Auditory comprehension deficits would result from damage to the geniculotemporal pathway in the temporal isthmus and to the auditory callosal fibres in the posterior periventricular white-matter (PVWM). If the external, extreme capsules or the arcuate fasciculus were involved, repetition deficits and phonemic paraphasia would occur. Motor speech deficits could be due to ante-

Neurobehavioural aspects of deep hemisphere stroke

Table 19.1. Proposed distinctive features of subcortical aphasia Study

Features

Alexander and La Verme Hypophonia; mumbling (1980) Difficulty in initiating, and reduced spontaneous speech Fluent unhesitant responses ‘Extended’ jargon Relative preservation of repetition and praxis Similar to transcortical aphasia Damasio et al. Atypical (1982) Dysarthria and dysprosody independent of the degree of fluency Gestural praxis intact Rapid recovery Naeser et al. Atypical (1982) More grammatical speech and longer phrase length Brunner et al. Broca’s aphasia with transcortical fea(1982) tures Substantial improvement Wallesch et al. Dramatic increase in fluency in the (1983) first days Better preserved written than auditory language comprehension Puel et al. (1984) ‘Dissident’, subtranscortical aphasia Voice and articulation impairment Reduction of spontaneous speech ‘Bizarre’ verbal paraphasias; verbal incoherence Normal repetition ability Dissociation between anomia in spontaneous speech and good confrontation naming Kennedy and Murdoch Impaired divergent semantic behaviour (1993) Semantic paraphasias Atypical dysarthria Slow dysarthria Weiller et al. (1993) No distinct pattern of language disturbance Mega and Alexander Core profile: impairment in generative (1994) language ability and lexical selection anomia

rior and superior PVWM or genu of the internal capsule damage. Decreased speech output would be caused by anterosuperior PVWM lesions, isolating Broca’s area from supplementary motor area, and by damage to the deep anterior frontal white matter, interrupting pertinent anterior callosal pathways.

Fig. 19.1. CT templates of acute (first month) striatocapsular infarctions presenting as global aphasia (top), Broca’s aphasia (middle), and transcortical motor aphasia (bottom).

Series that included non-selected patients who had subcortical strokes, such as Puel et al. (1984) and Colombo et al. (1989) and a comprehensive review by Nadeau and Crosson (1997) found no correlation between site of lesion, type or intensity of language disturbance, failing to confirm the anatomoclinical subtypes proposed by Naeser and Alexander. Lesions of the same subcortical structures yield different neurolinguistic impairments, and comparable linguistic patterns are observed with lesions in different deep areas (Fig. 19.1). More recent reports, such as those of Weiller et al. (1993) and Mega and Alexander (1994) did not confirm the specific features of language impairment associated with damage to individual subcortical centres or tracts. Aphasia syndromes did not differ in the amount of involvement of the putamen, pallidum, caudate and different white-matter tracts. Following a striatocapsular infarction, there is a rather similar coherent aphasia profile, with impaired executive and generative

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Fig. 19.2. Hypertensive hemorrhage involving the left medial thalamus, producing transient fluent aphasia (semantic jargon) and verbal memory defect (right). Recurrent right thalamic hemorrhage 1 year later, resulting in abulia and severe dementia (left).

language functions, accompanied by a lexical selection anomia. The generative language defect features abnormal performance on verbal fluency tasks, simplified sentence structure generation with increased latencies, perseverations, echolachia, bizarre or loose content, despite almost normal fluency and syntax in conversation and responsive language. Naming and word retrieval are reduced. Semantic paraphasias are frequent while phonemic paraphasias are rare. Repetition, oral reading and word comprehension are normal (Mega & Alexander, 1994). The severity of aphasia depends on the size of the infarct. Small infarcts may present only dysarthria, hypophonia or delayed speech initiation. The prognosis of striatocapsular aphasia is favourable with usually rapid and complete recovery in about two-thirds of the cases (Démonet et al., 1991).

Thalamic aphasia Aphasia can also follow thalamic hemorrhages or infarcts of the dominant hemisphere. The first reports of thalamic hemorrhages causing aphasia stressed the decreased voice

volume, anomia, perseveration, and semantic paraphasia. Mohr et al. (1975) called attention to the fluctuating performances of such patients, who, when rendered fully alert, appeared to have virtually intact language functions, but would quickly lapse into a state of unwonted logorreic paraphasia. Some authors have talked of ‘quasi-aphasia’ or ‘aphasia delirium’ to stress that those language disturbances appeared to be related to loss of activation of some neurolinguistic functions, such as the logical control of speech and semantics. Cappa and Vignolo (1979) emphasized the transcortical features of aphasia following left thalamic hemorrhages: reduced spontaneous speech, semantic paraphasia, preserved repetition ability and partly defective auditory verbal comprehension. In summary, deficits in thalamic aphasia can tentatively be grouped into four clusters: extrapyramidal (hypophonia), lexical access (anomia, semantic paraphasia), vigilance (fluctuating performance) and comprehension defects. Posterior hematomas including the pulvinar and dorsal nuclei, are those most commonly associated with aphasia, because this is the only region of the thalamus connected with cortical language areas (Fig. 19.2.) Obviously, tha-

Neurobehavioural aspects of deep hemisphere stroke

Fig. 19.3. Mild language disturbance (scarce, poorly monitored output, anomia, semantic paraphasia) caused by an anterior thalamic infarction.

lamic infarcts offer a better source than hemorrhages to study the linguistic relevance of the different thalamic divisions. Aphasia is produced mainly by tuberothalamic infarctions, followed by paramedian and posterior choroidal infarctions (Graff-Radford et al., 1985; Bogousslavsky et al., 1988b). Reported language defects in anterior infarctions (Fig. 19.3) include aspontaneity, diminished content of speech, paraphasias, decreased generation of words, anomia, and defects of spelling, comprehension, reading and writing. Repetition ability is usually preserved. Stuss et al. (1988) described the language disturbances in several patients with paramedian thalamic infarcts: poor initiation of speech, with a general poverty of output, occasionally contaminated by confabulation and lack of monitoring of output, fluctuation and variability in performance, relatively intact repetition and comprehension abilities, a deficit in word-list generation, and naming problems, characterized more by perceptive errors, nonaphasic misnaming, intrusions, persevations and confabulation than by phonemic or semantic paraphasias (Fig. 19.4). It appears that, in most cases, the deficit is mainly one of lack of initiative of speech and disruption of speech by memory and arousal disturbances, probably due to damage to the frontal lobe-inferior thalamic peduncle–nucleus reticularis–centre median system, preventing selective focal engagement of specific cortical networks, via enhancement of selective focal thalamo-cortical transmission (Nadeau & Crosson, 1997). However, not all

Fig. 19.4. Medial thalamic infarction after aneurysm surgery: transcortical sensory aphasia and verbal incoherence.

authors agree with these linguistic–topographic correlations. Some support the thesis that there are no specific thalamic nuclei subserving specific elements of speech. Puel et al. (1984) stressed that anatomic studies do not allow thorough correlations between linguistic disturbances and distinct intrathalamic systems, but they mentioned that anterior lesions tended to produce more aspontaneity, and posterior ones more verbal incoherence. A few investigators made systematic comparisons between striatocapsular and thalamic aphasias. Alexander and La Verme (1980) found no definite difference between aphasia after hemorrhages in the putamen and in the thalamus. Wallesch et al. (1983) distinguished between patients with left basal ganglia lesions, who performed worse in tests of articulation, syntax and lexical function, and patients with left thalamic lesions, who showed impairments in speech fluency and in the Token test. In a comprehensive review of 103 patients with thalamic aphasia described in the literature up to 1990, Démonet et al. (1992) found only seven patients with classic aphasia (6%),of whom 10% had phonemic disorders and 26% had

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comprehension deficits, which contrast with the findings among those with subcortical non-thalamic lesions: 36 patients with classic aphasia, of whom 60% had phonemic disturbances and 67% had comprehension disorders. They stressed, however, that more than half of their own patients with subcortical aphasias showed some common characteristics: reduction of spontaneous speech, semantic paraphasias and persevations, relative sparing of auditory comprehension and intact word repetition. For this type of aphasia they proposed the term ‘subtranscortical aphasia’.

defects, patients with verbal spontaneity had normal cerebral perfusion, and those with pure lexical incoherence had only subcortical perfusion defects. Patients with aphasia following subcortical stroke had longer duration of middle cerebral artery occlusion, poor leptomeningeal collaterals (Weiller et al., 1993) and often have associated cortical lesions not seen on CT scan. In some series aphasia and other cortical defects were only seen in the subgroups with associated cortical lesions (Godefroy et al., 1992, 1994).

Cortical dysfunction in subcortical aphasia

Agraphia

Shortly after the ‘rediscovery’ of subcortical aphasia in CT, regional cerebral blood flow (rCBF) and PET studies showed low-flow areas and extensive zones of mild hypometabolism in the cortex overlying those deep lesions (Perani et al., 1987). Cortical low flow was confined to occluded territories, such as occlusion or stenosis of the middle cerebral artery (MCA) causing both a striatocapsular infarction and frontotemporal hypoperfusion. Although the presence of cortical hypoperfusion is in agreement with the clinical findings in acute scans, disagreement can be found in the case of late scans. Puel and associates (1992) demonstrated the importance of ‘regional’ diaschisis, as they found a relationship between left sylvian hypoperfusion and repetition impairment, as well as a relationship among mild temporoparietal hypometabolism, phonemic paraphasia, and comprehension disorders (Vallar et al., 1992). Metter et al. (1988) used pathway analysis of CT findings, glucose metabolism measured by PET, and language data to determine whether subcortical lesions produced aphasia by a direct or indirect (via cortex) effect. They concluded that, for fluency, subcortical structural damage had direct and indirect (through the frontal lobe) effects, whereas for comprehension subcortical damage had no direct effect and a slight indirect effect (through the temporal lobe). Similar results were obtained in a PET study of performance on the Token Test, revealing that basal ganglia metabolism did not contribute significantly to performance on that comprehension test. Thalamic strokes induce a significant decrease in overall cortical metabolism on both sides, more so ipsilaterally. In the fluent type of thalamic aphasia, reduced cortical flow was demonstrated in parietotemporal areas. Frontal hypoperfusion correlates with fluency, while insular, lenticular, and posterior depressions correlate with comprehension, naming, and paraphasia. Puel and co-workers (Puel et al., 1992) showed that whereas ‘subtranscortical’ or ‘dissident’ aphasias featured subcortical and cortical perfusion

Kertesz (1992) found that the severity of writing disturbance was similar in patients with subcortical and cortical lesions of the same size. As in cortical lesions, the severity of the writing defects was correlated with impairments in oral language and reading. All types of writing errors were observed. The agraphia appeared more severe in patients with putaminal infarcts, with a dissociation between spontaneous writing and writing on dictation. Agraphia tended to persist and sometimes was present even as a patient recovered from aphasia, thus producing a ‘chronic’ pure agraphia. In some of these cases, ‘subcortical’ agraphia is related to frontal cortical diaschisis. The alternative hypothesis is that the basal ganglia integrate semantic, lexical, phonological and graphemic information with motor control, being a key station for the graphomotor pathway. The error pattern, mainly orthographic and graphomotor (illegibility, errors in the shape and characteristics of letters) supports that hypothesis.

Apraxia Some of the early descriptions of apraxia linked apraxia to lesion of white-matter tracts, disconnecting relevant cortical areas. Examples are verbomotor facial apraxia due to damage to the arcuate fasciculus or the extreme capsule, disconnecting Wernicke’s area from the left premotor areas, and left-hand (or leg) sympathetic apraxia, resulting from interruption of the callosal fibres linking both premotor areas. Internal border-zone infarcts (between the territories of the MCA and the anterior cerebral artery (ACA) territories) can produce this type of apraxia. Lenticulostriate infarcts disturb the development of strategies involved in motor procedural learning. In contrast, apraxia arising from pure deep hemorrhages or infarcts is infrequent and in many of the reported cases the deep parietal and occipitofrontal fibers (in the central and parietal white-

Neurobehavioural aspects of deep hemisphere stroke

Fig. 19.5. Infarctions involving the posterior limb of the right internal capsule without (right) and with severe neglect and visuospatial disturbances (left).

matter), or frontostriatal connections were also involved. Pramstaller and Marsden (1996) analysed 82 cases (the majority due to stroke) of such ‘deep’ apraxias reported in the literature. They concluded that lesions confined to the basal ganglia rarely cause apraxia. Apraxia was most commonly seen when there was additional involvement of capsular, periventricular or peristriatal white-matter. Periventricular white-matter lesions also caused apraxia. The vast majority of ‘deep’ apraxia lesions were located in the left hemisphere. The most common type of deep apraxia was bilateral ideomotor apraxia, or of the left hand, if there was a right hemiparesis. Bucofacial and ideative apraxia were very rare. Thalamic lesions can also cause apraxia, even if there is no apparent involvement of the white-matter. Visuomotor apraxia, apparently due to interruption of the most caudal fibres of the internal capsule, was reported after a thalamic haemorrhage (Classen et al., 1995).

Neglect Shortly after the introduction of CT in clinical practice it became apparent that subcortical strokes could produce neglect. Several thalamic nuclei (Watson et al., 1981), the striatum, the anterior and posterior limbs of the internal capsule were recognized as sites at which damage could cause sensory extinction, motor extinction, hemispatial

inattention, lack of intention to explore the contralateral space, mental representational neglect, and anosognosia. The majority of those lesions were located in the right hemisphere, indicating that, like cortical regions, right subcortical structures are dominant for hemispatial attention and intention. Probably because of their larger size, pressure effects, and more extensive cortical diaschisis, neglect produced by deep hemorrhages is usually more frequent, severe and long lasting than that caused by ischemic lesions. Attempts to correlate the presence, type and severity of neglect with the involvement of specific deep vascular territories or specific subcortical structures have been relatively deceiving. Apart from its absence in single-perforator disease and its frequent association with posterior or medial thalamic infarcts, no other consistent correlation emerged (Fig. 19.5). Infarcts of the medial and lateral deep perforators of the MCA and ACA cause neglect in about one-third of patients (Ferro et al., 1987). Neglect is usually mild and transient. Infarcts of the territory of the anterior choroidal artery that involve the posterior limb of the internal capsule can cause severe neglect, displaying both intentional and attentional features, and associated with cortical diaschisis (Bogousslavsky et al., 1988a) related to damage to non-specific thalamic projections and to pulvinar–parietal disconnection. Also, no particular association was found between subcortical lesion location and neglect characteristics or components. All its features can be

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Fig. 19.6. SPECT showing frontal hypoperfusion in a patient with hypertensive right striatal intracerebral hemorrhage, without neglect.

demonstrated after subcortical lesions (Ferro et al., 1987), including some, that in theoretical models are considered as ‘cortical’, such as spatial representation and imagery. The strong interconnections among the different subcortical structures and the lack of correspondence between anatomic boundaries and deep vascular territories (which comprise more than one anatomic structure, but only a part of each) may help to explain these findings. Perfusion and metabolic investigations have demonstrated that, with a few exceptions, the presence of neglect is associated with cortical metabolic/perfusion depression, recovery from which parallels improvement in the area of neglect (Vallar et al., 1988). This explains why cortical and subcortical neglect are phenomenologically similar. Some regional differences in diaschisis can, however, be found. Medial thalamic lesions cause bilateral cortical depression. Posterior infarcts mostly depress the visual cortex and inferior limbic cortex, whereas posterolateral sensory thalamic strokes without neuropsychological deficits do not cause cortical hypometabolism (Baron et al., 1992). Striatal lesions causing localized frontal diaschisis are not

associated with neglect (Fig. 19.6), but if they cause parietal depression, the neglect disturbance will arise (Demeurisse et al., 1997). This helps to explain why apparently similar lesions can show surprisingly different neurobehavioural counterparts, varying from severe neglect to an errorless performance in an extensive neglect-testing battery. Individual variation in the degree of hemispheric dominance for hemispatial attention may also contribute to that variability.

Amnesia and abulia Behavioural and cognitive abnormalities are usually prominent following caudate, medial and anterior thalamic lesions. Following caudate infarcts (Caplan et al., 1990) and hemorrhages (Mendez et al., 1989) several types of neurobehavioural changes have been described. Acutely, patients appear confused and disoriented or, in rare cases, mute. Abulia is the most frequent behavioural change followed by ‘psychic akinesia’ and frontal system abnormal-

Neurobehavioural aspects of deep hemisphere stroke

ities (Kumral et al., 1999). Patients lack spontaneous verbal and motor initiative, and tend to speak or act only when prompted. They display increased latency in response to stimuli, and their responses are slow, although correct. They have difficulty in sustaining attention and persisting with a task. Less often, patients are restless and hyperactive or alternate periods of apathy and agitation. Formal neuropsychological testing will reveal impaired problem-solving ability, decreased attentional capacity, and moderate impairment on memory tasks, because of difficulty in recall, even with cues, but with normal recognition. These behavioral deficits tend to persist and seriously limit the ability of these patients to return to work or to their premorbid social lives. Some patients with unilateral or bilateral caudate lesions are left with permanent cognitive impairment. A significant number of patients with caudate infarction deteriorate in their intellectual function between 1 and 2 years after stroke. This phenomenon could be mediated through disruption of cortical projections to the caudate (Bokura & Robinson, 1997). Anterior and medial thalamic lesions cause a wide range of neuropsychological defects involving memory, arousal, attention, motivation, initiation and executive functions. In anterior infarcts, amnesia is combined with abulia, language disturbances or neglect. In mediodorsal infarcts, drowsiness and abulia are combined with memory defects and vertical gaze disturbances. Isolated infarcts of the dorsal intralaminar nuclei cause problems with attention, concentration, executive disturbances and memory retrieval (Van Der Werf et al., 1999). Some of these patients, especially those with bilateral paramedian infarcts (Fig. 19.2), can be labelled as demented (Katz et al., 1987). Bilateral paramedian thalamic infarcts cause a significant diffuse metabolic decrease in the whole cortex. Dementia is uncommon after unilateral infarcts, in which memory disturbances usually show considerable recovery. The memory defect impairs both verbal memory and visual memory for left-side infarcts, but only visual memory in right-side infarcts. Patients with bilateral lesions will have more severe and long-lasting defects. These patients are hypersomnolent and abulic and appear confused. They confabulate and can show reduplicative paramnesia. The memory defect affects predominantly explicit declarative memory (i.e. the acquisition and recall of new facts and events). These patients have severe anterograde amnesia and mild and transient retrograde amnesia. Thalamic amnestic patients have preserved abilities for motor learning and implicit memory, with intact priming (unconscious registration from one task to another) (Malamut et al., 1992). Remote memory can be more affected if the lesion extends outside the dorsomedial nuclei. The

memory defect is not secondary to the other behavioural abnormalities, as it can be demonstrated in single tasks requiring immediate recall. These patients can show a ‘scalloping’ effect, with alternating good-bad performances and the best performance on the first attempt, suggesting that motivation and attention influence performance (Stuss et al., 1988). Severe memory defect in those thalamic infarcts is related to simultaneous damage to the mamillo-thalamic tract and the ventroamygdalofugal pathway. Infarction of the inferior genu of the internal capsule (Tatemichi et al., 1992) can produce a syndrome featuring fluctuating alertness, inattention, memory loss, apathy, abulia and psychomotor retardation. This strategic infarct location can interrupt the inferior and anterior thalamic peduncles and causes deactivation of the ipsilateral inferior and medial frontal cortex, as shown by CBF studies. Unilateral or bilateral internal capsule genu infarctions sparing the inferior thalamic peduncle produce abulia without memory disturbance (Yamanaka et al. 1996). Considerable improvement of the neuropsychological defects occurs in the months following inferior capsular genu infarction (Madureira et al., 1999).

Depression and behavioural changes As in cases of cortical lesions, patients with right subcortical strokes usually display the indifference reaction. Some studies have found that depression is more severe in left anterior subcortical lesions than in posterior or righthemisphere subcortical sites (Starkstein et al., 1987). The spontaneous recovery rate from depression appears higher for subcortical lesions than for cortical lesions. The most depressed subjects have lesions of the head of the caudate nucleus and the anterior limb of the internal capsule. These rostral basal ganglia lesions interrupt frontocaudate connections and the biogenic amine pathways. Lesions of the caudate nucleus, particularly if bilateral, can cause abulia or, less often, agitation, with disinhibition, inappropriate and impulsive behaviour, and rarely, major affective disturbances with hallucinations. Thalamic lesions, either left or right, do not, in general, cause significant depression (Starkstein et al., 1988). However, other behavioural changes can be observed, depending on intrathalamic infarct location. Personality changes, abulia, apathia, or more rarely, euphoria or mania, are consistent findings following medial or anterior thalamic damage. A peculiar case of stereotyped, compulsive tendency to assume a sleeping behaviour was reported after bilateral anterior paramedian thalamic infarcts. Euphoria has been related to the disruption of

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dorsomedian thalamic nuclei–orbitofrontal pathways, and apathy has been the result of injury to the anterior thalamic–cingulate pathways. The rarity of depression following thalamic infarcts may be due to hypoarousal or to sparing of the ascending biogenic amine pathways that run ventral to the thalamic nuclei. Other frequent findings in patients with subcortical lesions, particularly in left or bilateral lesions, are uncontrollable fits of laugher or crying, many times devoid of emotional content and precipitated by minor affective or even neutral events. This has variously been labelled pathological or forced crying, emotional lability, emotional expression incontinence, or emotionalism. Half of the patients with bilateral capsular infarcts display emotionalism, probably because efferent fibers mediating emotional impulses to the bulbar cranial nerves do not travel in the posterior limb of the internal capsule, but rather through its anterior limb or through the thalamus. Several recent investigations established an association between subcortical vascular disease, depression, associated cognitive impairment and response to antidepressants. Silent infarcts, small basal ganglia lesions and white-matter hyperintensities on MR were found in different studies to be independently associated with geriatric depression (Fujikawa et al., 1993; Salloway et al., 1996; Steffens et al., 1999). Depressed patients with moderateto-severe deep white-matter hyperintensities had worse neuropsychological functioning (memory, language, executive functions) than depressed patients without such lesions or than normal elderly controls (Kramer-Ginsberg et al., 1999). Furthermore, confluent subcortical hyperintensities and multiple basal ganglia lesions are predictors of a poor response to antidepressants (Simpson et al., 1998).

Subcortical vascular dementia In pathological studies of vascular dementia, subcortical lesions have been found in 60–80% of patients. Subcortical vascular lesions that can cause dementia include multiple lacunes, strategic infarcts located in functionally crucial areas such as the anterior and medial thalamus, the inferior capsular genu and white-matter lesions, shown by CT as leuko-araiosis or by MR as confluent areas of increased T2 signal. Subjects with neuropathological criteria for Alzheimer disease are also more likely to have poor cognitive function and dementia if they had concomitant subcortical lacunar infarcts or deep white-matter changes (Snowdon et al., 1997).

The impact on cognition is different following a single large subcortical infarct, a single lacunar infarct or multiples lacunes. Cognitive impairment is also influenced by other variables such as age, education, the extent of whitematter changes and to a lesser degree by the severity of cortical and subcortical atrophy. In the stroke databank cohort (Tatemichi et al., 1990) the clinical diagnosis of dementia was made in 11% of patients with striatocapsular infarcts and 14% of those with thalamic infarcts, these figures being lower than those for cortical sites. Patients with single supratentorial lacunar infarcts may have a decreased capacity for mental effort (van Zandvoort et al., 1998). However, disabling cognitive impairment is uncommon and dementia very rare following a single lacunar infarct (Guerreiro et al., 1994). Loeb et al. (1992) followed, for an average of 4 years, 108 patients with CT-demonstrated lacunar infarction and found that 23% developed dementia. Dementia was more common in those with new vascular events or with evidence of cerebral atrophy, but was not associated with leuko-araiosis or frontal location of the lacunes. Dementia is more frequent after multiple lacunar strokes. Demented and cognitively impaired patients with multiple lacunar strokes had more extensive white-matter changes (Fukuda et al., 1990; van Swieten et al., 1996), and larger ventricles (Corbett et al., 1994) than those who are cognitively intact. Patients with multiple lacunar infarcts perform less well than normal controls on several neuropsychological measures (language, visuospatial function, memory, executive functions, motor programming, set/shifting, response inhibition) (Babikian et al., 1990; Wolfe et al., 1990). They are more often rated apathetic. About one-quarter might meet the criteria for the clinical diagnosis of dementia (Wolfe et al., 1990). Demented patients with multiple subcortical infarcts have more abnormalities of the motor aspects of speech (pitch, melody, articulation, rate) than Alzheimer’s patients. These abnormalities are related to lesions involving subcortical structures (Wallesch et al., 1983). Subcortical white matter changes are more frequent in older people, subjects with vascular risk factors or silent infarcts and in patients with subcortical strokes. The spectrum of their clinical manifestations ranges from totally assymptomatic subjects, to subtle cognitive and behavioural changes, gait disorders, depression, cognitive decline and dementia (Steingart et al., 1987; van Swieten et al., 1991; Schmidt et al., 1991; Breteler et al., 1994). It is difficult to disentangle the role of white-matter changes and of subcortical infarcts, because they are often associated and share several risk factors (van Swieten et al., 1996). There is a threshold effect (Boone et al., 1992) and a relationship

Neurobehavioural aspects of deep hemisphere stroke

between the intensities of white matter changes and cognitive decline (Longstreth et al., 1996). The most affected cognitive domains are attention and concentration, speed of mental processes (Junqué et al., 1990), executive functions and to a less degree verbal and visual memory (van Gijn, 1998; Leys et al., 1999)

Conclusions Several methodological flaws of many studies on the neuropsychological consequences of subcortical stroke are now evident: patients with hemorrhages should be analysed separately from those with infarcts, unselected series of patients should be evaluated and time post onset should be controlled. Hemorrhages compress overlying cortex and produce a large area of cortical diaschisis. The role of cortical hypoperfusion, due to possible occlusion of the internal carotid or middle cerebral artery must be considered. Focal cortical atrophy on MR, indicating coexistence of cortical damage should be looked for in late scans. In conclusion, the pathophysiology of neuropsychological symptoms/syndromes after subcortical vascular lesions can have several explanations: ii(i) Indirect effect on the cortex by pressure or diaschisis. i(ii) Cortical ischemia related to proximal vascular occlusion. (iii) Direct damage of centres and pathways integrating distributed networks subserving declarative memory, working memory, attention, mood and initiative. Disturbance of these functions can have an indirect effect on other cognitive ‘cortical’ process, such as language or praxis. Complex cognitive and behavioural functions are supported by large-scale, distributed neural networks that have multiple interconnections both ‘horizontal’, composed by connected cortical zones, and ‘vertical’, including cortical neurons, their efferent thalamic fibers, and the neostriatal regions that receive their projections (Alexander et al., 1990). These networks are ordered (Vallar et al., 1992), meaning that the relative weights of the cortical and subcortical components vary from one network to another. This ordered, multiple-network approach explains why (i) lesions in different cortical and subcortical sites cause similar specific cognitive deficits, (ii) recovery takes place, unless the whole loop (or, in same instances, its upper-hierarchy component) is damaged, (iii) cortical and subcortical syndromes can be distinguished on the basis of various combinations of loops disturbed by strokes of different localizations.

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Right hemisphere syndromes Stephanie Clarke Division of Neuropsychology, CHUV-Nestle, Lausanne, Switzerland

Delimiting the field Right hemisphere lesions are often associated with a number of specific syndromes, such as left hemineglect, topographical disorientation, anosognosia, visual agnosias and visuo-spatial deficits. Unlike the left hemisphere syndromes of aphasia and apraxia, none of the right hemisphere syndromes possesses a simple and clinically relevant model derived from human observations. The rare models that we have and that are gaining importance in rehabilitation, concern visual agnosias, visuo-spatial deficits or hemineglect and rely on experimental data from non-human primates. Clinical observations and experimental studies of the past 30 years show that the field of right hemisphere syndromes is far more complex than originally believed (Table 20.1). Although some of the syndromes have been repeatedly reported following right unilateral lesions, other syndromes can occur after right or left unilateral lesions, but do so more often after right than left lesions. For other syndromes the right hemispheric lesion is necessary, but not sufficient; these syndromes occur invariably after bilateral lesions, but never after unilateral left lesions. This chapter concentrates on syndromes for which right hemispheric involvement is necessary or which have been classically associated with right hemisphere damage.

Hemineglect Hemineglect is characterized by lack or decrease of attention to stimuli and events on the left-hand side of the patient following a right hemispheric lesion. In extreme cases, patients do not react when they are spoken to from the left side, do not eat food on the left half of their plate, do not shave or make up the left half of their face or read the left side of their newspaper. Hemineglect can affect,

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sometimes to a varying degree, visual, auditory, somatosensory and motor modalities (Barbieri & De Renzi, 1989). Formal testing of hemineglect consists of tests that require cancelling of items on a sheet of paper, copying or drawing of objects, dichotic listening or simultaneous tactile stimulation.

A modular deficit Experimental studies in patients with unilateral neglect suggest that perceptual processing may be intact up to the level of semantic classification, and that neglect only acts at the level of selection for action and access to awareness, e.g. preattentive vision is still able to parse the scene, to segregate figure from ground, group objects, and to define their primary axis. Several mechanisms are currently evoked as contributing to neglect, including disinhibited orienting to the ipsilesional field, a deranged representation of space, and deficits in disengaging attention, oculomotor corollary discharge, and representation of contralesional movement trajectories (for review, see Rafal, 1994). In some cases, hemineglect does not only affect perception but also mental imagery. Bisiach and Luzzatti (1978) described the case of a patient whose hemineglect affected mental images of well known Milanese landmarks. An intriguing aspect of hemineglect was described recently by Ramachandran et al. (1997) as mirror agnosia. Patients with right hemisphere stroke and left visual field neglect were shown objects that were on their left via a vertical parasagittal mirror. They confirmed seeing the object, and they understood the principle of the mirror, but remained unable to use this information to explore the left hemispace. A series of recent reports suggested that hemineglect is a modular deficit. Left visuo-spatial neglect can affect differently near and far space; selective deficits for one or the

Right hemisphere syndromes

Table 20.1. Right hemisphere syndromes

RHD necessary and sufficient Attention Awareness

Hemineglect

Vision

Topographical disorientation Apperceptive visual agnosia (⫽ deficient perceptual categorization) Prosopagnosia Supernumerary limbs

Body scheme

RHD necessary but probably not sufficient

Capgras delusion

Unilateral lesion sufficient, more often right than left

Anosognosia Acute confusional state Reduplicative paramnesia Palinopsia Astereopsis Optic ataxia

Asomatognosia

Note: RHD ⫽ right hemisphere damage.

other aspect and double dissociations were reported (Cowey et al., 1994; Beschin & Robertson, 1997; Guariglia & Antonucci, 1992). Furthermore, neglect can affect differently visual perception and visual imagery; selective deficits for extrapersonal space, but not for visual images (Anderson, 1993) and a double dissociation between vision and visual imagery (Coslett, 1997; Guariglio et al., 1993) were described. Stimuli that are correctly perceived in a type of task may be neglected in another; Marshall and Halligan (1995) described a case of a patient who perceived correctly global forms of figures that were composed of small elements, but on cancellation task this patient crossed only the right half of the small elements.

1984). The lesions in the latter locations were often associated with infarctions in the area of the right anterior choroidal artery (Bogousslavsky et al., 1988; de la Sayette et al., 1995; Masson et al., 1983). Several cases of left hemineglect following subcortical lesions were investigated by SPECT, demonstrating cortical hypoperfusion (Bogousslavsky et al., 1988; Perani et al., 1987; Weiller et al., 1993). Although left spatial hemineglect is most often discussed in terms of unilateral right lesions, most cases that are referred for clinical evaluation or for research projects on neglect may have bilateral lesions, as suggested by a recent study (Weintraub et al., 1996).

Anatomoclinical correlations

Models

Anatomoclinical correlations in cases of left-sided neglect stressed the critical role of right hemispheric lesions (Brain, 1941; McFie et al., 1950). Studies on series of neglect patients helped to identify the involved structures. The most commonly used technique was the so-called overlap of lesions. This technique lead to the identification of the most common lesion site in left visuo-spatial hemineglect, namely the inferior parietal lobule (Vallar & Perani, 1986; Fig. 20.1). However visual neglect can occur also in right frontal lesions (Heilman & Valenstein, 1972) and in these cases the most often damaged structure was the dorsal aspect of the inferior frontal gyrus and the immediate underlying white-matter (Husain & Kennard, 1996; Fig. 20.1). Hemineglect was also described in association with subcortical lesions and in particular in cases of thalamic (Watson & Heilman, 1979; Watson et al., 1981), basal ganglia (Damasio et al., 1980; Healton et al., 1982; Hier et al., 1977) or internal capsula lesions (Ferro & Kertesz,

Several theories and models of neglect proposed interpretations of the laterality bias. Kinsbourne proposed the existence of attentional gradients within hemispace (for updated review, see Kinsbourne, 1994). Mesulam (1981) proposed different roles for each hemisphere in spatial attention. Other models, more influenced by data from non-human primates, stressed the role of spontaneous eye movements in orienting attention (Gainotti, 1994). Anatomoclinical correlations identified several key structures for hemineglect. Heilman and Valenstein (1972) proposed that two subcortical loops were involved in different aspects of hemineglect: one loop was concerned with spatial perception and involved the temporoparieto-occipital junction, posterior cingulate cortex and posterolateral, dorsomedian and lateral geniculate nuclei of the thalamus; the second loop was concerned with movement and involved the premotor cortex, anterior cingulate cortex, basal ganglia and the centromedian,

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Fig. 20.1. Cortical regions identified by anatomoclinical correlations as playing a major role in hemispatial neglect.

ventroanterior and ventrolateral thalamic nuclei. Mesulam (1981, 1990) proposed a model with three components, perceptual, motor and motivational, which depended on the parietal, frontal and cingulate cortex, respectively. The models of Heilman and Mesulam were inspired by connectivity studies in non-human primates, but this approach remains unsatisfactory for a clearly lateralized function. Furthermore, recent tracing studies suggested that human cortical connectivity differs significantly from that of nonhuman primates (Di Virgilio & Clarke, 1997; Fig. 20.2).

Recovery and rehabilitation The presence of hemineglect beyond the acute stage is associated with poor outcome in terms of independence (Denes et al., 1982; Stone et al., 1992) and considerable effort is therefore devoted to its rehabilitation. The classical approaches are very pragmatic, such as verbalization and establishment of left orienting strategies. Although this approach can be adopted successfully for the trained situation, patients fail usually to generalize in other settings (Weinberg et al., 1977). Other approaches try to increase the attentional load on the left side by auditory (Robertson & Cashman, 1991), visual (Butler et al., 1990), vestibular (Cappa et al., 1987; Karnath, 1995; Rubens, 1985; Vallar & Perani, 1986), somatosensory (Karnath, 1995) or motor stimulations (Robertson & North, 1992).

Topographical disorientation Topographical recognition, orientation and memory Patients with predominantly or exclusively right hemisphere lesions were reported to suffer from topographical

disorientation (Brain, 1941; Clarke et al., 1993; Habib & Sirigu, 1987; Landis et al., 1986a; Paterson & Zangwill, 1945; Whitty & Newcombe, 1973). The disorientation can affect previously known places or can cause serious difficulties in learning to orient in previously unknown surroundings. The disorientation was reported both in relatively small spaces, mostly hospital wards, and in large spaces such as towns or complex buildings. Since Brain’s report (1941), two different aspects contributing to correct topographical orientation are distinguished. One aspect is recognition of spaces and/or their constituents; in several studies, this was explicitly reported to be impaired (Hécaen et al., 1980; Paterson & Zangwill, 1945). In several cases, lack of recognition was accompanied by a loss of familiarity in previously known (and familiar) surroundings (Landis et al., 1986a). The second aspect is the actual spatial orientation, whose impairment does not seem to occur in complete isolation, since difficulties in recognition, even if sometimes transitory, are usually reported. However, different types of navigation appear to be involved in spatial orientation and can be disrupted independently by brain lesions (for review, see, e.g. Farrell, 1996).

Right and left hemisphere strategies Topographical disorientation associated with unilateral right hemispheric lesions is characterized by the inability to use two- and three-dimensional information. For such patients the use of maps does not improve performance. We had the opportunity to investigate a patient with this type of deficit and found that the strategies that were successful relied all on a linear, speech-related approach (Clarke et al., 1993). Identification of buildings was based on verbal description and not visuo-spatial impression. Plans of buildings were analysed in a detail-by-detail fashion, without any two-dimensional understanding. Orientation in large buildings and in towns was only possible if a route could be decomposed into a linear sequence of landmarks. Similarly, orientation on maps was often based on a route-simulating strategy (‘How would I get there?’). The anatomical particularities of this patient’s lesion (lesion of the posterior part of the right thalamus and the right optic radiation; destruction of the posterior half of the corpus callosum) made it clear that the compensatory strategies were sustained uniquely by the left hemisphere.

Visual agnosias Visual agnosia denotes impaired recognition of visually presented material in a patient with normal or almost

Right hemisphere syndromes

Fig. 20.2. Recent studies of human cortical connectivity suggest major differences with non-human primates. Thus, human visual cortex of the right hemispheres has a very wide array of monosynaptic heterotopic interhemispheric connections (A, D, E) as well as homotopic connections (B, C). This means that visual information can be relayed very rapidly, and by several possible routes, to key centres in the left hemisphere, such as the speech areas. No such widely heterotopic interhemispheric connections have been described in non-human primates (From Di Virgilio & Clarke, 1997; Clarke, 1998, with permission).

normal visual acuity; auditory and tactile recognition is normally spared. The term visual agnosia was introduced in 1891 by Sigmund Freud and it stresses the role of internally represented knowledge in visual perception.

Types of visual agnosias Deficits of visual recognition following hemispheric lesions can take several forms (Fig. 20.3). Historically, the first form to be described was associative visual agnosia (Lissauer, 1890). In this condition the patient, who is unable to recognize objects, discriminates shapes perfectly well and is able, e.g. to copy drawings (Rubens & Benson, 1971). This type of visual agnosia is often associated with alexia and occurs most often in cases of bilateral inferior occipito-temporal lesions. Shape perception is severely

impaired in apperceptive visual agnosia; the patient is unable to copy drawings and reports seeing shapes of objects very poorly (Goldstein & Gelb, 1918; Landis et al., 1982; Fig. 20.3). The lesions associated with this severe type of apperceptive visual agnosia are usually disseminated and most likely bilateral as in carbon monoxide poisoning.

Deficits in perceptual categorization Two types of visual agnosias were described in association with unilateral right hemispheric lesions. One of them is characterized by deficits in perceptual categorization and is sometimes referred to as apperceptive visual agnosia (Warrington & Taylor, 1973). Patients with this type of relatively light visual agnosia perceive shapes normally when objects are presented in familiar views. Their difficulties

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Inability to recognize object by vision Visual agnosias

Inability to copy drawings Normal copy

Apperceptive visual agnosia

Normal perception of superposed figures and unfamiliar views

Inability to perceive superposed figures and to deal with unfamiliar views

Associative visual agnosia

Deficient perceptual categorization = Apperceptive visual agnosia

Fig. 20.3. Differential diagnosis of visual recognition deficits. Note that the term ‘apperceptive visual agnosia’ is used in the literature for two very different conditions.

become apparent when objects are hidden behind lines, e.g. in the classical visual discrimination task of Poppelreuter or when objects are presented in unfamiliar views. Lesions that are associated with deficient perceptual categorization are usually within the right hemisphere and more often than not centred on the parietal lobe (Warrington & Taylor, 1973).

Capgras delusion Capgras delusion denotes a peculiar syndrome in which a patient believes that familiar persons have been replaced by impersonating doubles. This syndrome was first described in psychiatric patients, but was also found in conditions suggesting right hemispheric damage (Alexander et al., 1979).

Prosopagnosia The other type of visual agnosia that was reported to occur after purely right hemispheric lesions is prosopagnosia. Prosopagnosia denotes the inability to recognize previously known faces, whereas voice recognition remains normal and allows the patients to compensate their deficit in everyday life. Testing for prosopagnosia involves use of photographs of faces of famous people (actors, politicians). A patient with prosopagnosia is typically unable to recognise the person on the photograph, although he can give fairly precise biographical details verbally. Furthermore, most prosopagnosic patients describe correctly the face on the photograph, its expression, the age of the person and the gender. The difficulty recognizing individuals can involve other categories, such as animals, plants, cars, buildings, handwriting and landscapes (e.g. Assal et al., 1984; Clarke et al., 1997). Although in most published cases of prosopagnosia the underlying lesion was bilateral, several well-documented cases show convincingly that a unilateral right lesion is sufficient (for discussion see De Renzi et al., 1994; Landis et al., 1986b, 1988; Fig. 20.4).

Models The disturbances of visual recognition associated with right hemispheric damage, namely deficits in visual categorization, prosopagnosia and Capgras delusion, were proposed to result from disruption of different aspects of visual processing. Work on non-human primates (Mishkin et al., 1983) and observations in patients with focal lesions (for review, see, e. g. Grüsser & Landis, 1991) suggested that visual information is processed at the cortical level along two distinct pathways (Fig. 20.5). Both pathways originate in the primary visual cortex; one pathway is directed towards the inferior part of the temporal lobe and is involved in recognition, but the other pathway is directed towards the parietal lobe and is involved in visuo-spatial functions. In the human, damage to the ventral pathway in the right hemisphere is often accompanied by prosopagnosia, whereas damage to the dorsal pathway by deficits in visual categorization and visuo-spatial functions. It has been recently proposed that damage to a particular aspect of the dorsal pathway, namely its link to the limbic system, plays a role in Capgras delusion (Ellis & de Pauw, 1994).

Right hemisphere syndromes

Fig. 20.4. Cortical regions identified by anatomoclinical correlations as playing a major role in prosopagnosia.

Body scheme alterations Fig. 20.5. Visual processing pathways in the right hemisphere.

Supernumerary limbs The occurrence of supernumerary phantom limbs was described in association with unilateral right hemispheric lesions. A patient with left sensory–motor hemisyndrome and neglect had a vivid impression of having a third arm (Halligan et al., 1993); the lesion was within the right basal ganglia. Another case, with six arms, was described after an infarction in the territory of the right middle cerebral artery (Sellal et al., 1996).

In studies of consecutive patients with unilateral hemispheric lesions, anosognosia was noted more often following right than left lesions, but it did occur after isolated unilateral left lesions (Starkstein et al., 1992; Stone et al., 1993). Lesions associated with anosognosia include temporoparietal junction, pre- and postcentral gyri, thalamus, basal ganglia and the internal capsula (Levine et al., 1991; Starkstein et al., 1992; Ellis & Small, 1997).

Hyperattention syndromes An exaggerated attention to the left side of the body was developed by three patients with stroke in the territory of the right anterior parietal artery (Bogousslavsky et al., 1995). One patient was reported to respond to the stimulations that were administered not to him but to the patient in the next bed (Bogousslavsky & Regli, 1988).

Anosognosia The term anosognosia was introduced in 1914 by Anton and Babinski to denote lack of interest and concern for deficits relative to the left hemispace. Typically a patient may deny left hemiplegia or left hemianopia. There appears to be no causal link with hemineglect, since anosognosia was reported in cases without hemineglect (Bisiach et al., 1986).

Acute confusional state The acute confusional state denotes a syndrome of limited duration that is characterized by temporo-spatial disorientation, distractibility, attentional deficits and often agitation. In a number of cases auditory and/or visual hallucinations have been described. Acute confusional state occurs often, but not exclusively, in cases of right hemisphere damage. The most frequently observed pathology are middle cerebral artery infarctions (Mesulam et al., 1976; Schmidley et al., 1984). Reduplicative paramnesia denotes delusional reduplication of places and people. It has been most often observed in post-traumatic encephalopathies, but also in cases with unilateral right lesions (Patterson & Mack, 1985; Kapur et al., 1988).

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21

Poststroke dementia Didier Leys and Florence Pasquier University of Lille, France

The association of stroke and dementia is frequent and can be seen either in the diagnostic work-up of patients attending a memory clinic, or during the follow-up of stroke patients. The terms ‘vascular dementia’ (VaD), and ‘poststroke dementia’ (PSD) are respectively used for these two different clinical situations. The term PSD includes any type of dementia occurring after a stroke, irrespective of its presumed cause (Pasquier & Leys, 1997). VaD is a dementia syndrome likely to be due to stroke lesions (Chui et al., 1992; Roman et al., 1993). VaD accounts only for a part of PSD (Tatemichi et al., 1994a, b; Pasquier & Leys, 1997) and may occur without any obvious clinical history of stroke. VaD is the second most common cause of dementia, as it accounts for 10 to 50% of the cases, depending on the geographic location, population and criteria used (Rocca et al., 1991; Hebert & Brayne, 1995). Strokes lead to a high risk of cognitive impairment and dementia (Tatemichi et al., 1992; Tatemichi et al., 1994). As vascular causes of cognitive impairment are common, and perhaps preventable, patients could benefit from therapy, early detection and accurate diagnosis of vascular cognitive impairment and VaD is a challenge (Bowler & Hachinski, 1995).

Epidemiology of poststroke dementia Descriptive epidemiology Prevalence Depending upon the composition of cohorts, prevalence rates of PSD vary between 13.6% (Censori et al., 1996) and 31.8% (Pohjasvaara et al., 1997) at 3 months. A study reported a prevalence rate of 32.0% after 5 years (Bornstein et al., 1996). The prevalence of dementia is higher in stroke survivors than in matched controls (Censori et al., 1996;

Pohjasvaara et al., 1997). However, a systematic evaluation of pre-existing dementia in stroke patients revealed that 16% of stroke patients aged 40 years or more had preexisting dementia (Hénon et al., 1997). Therefore, pre-existing dementia may account for some dementia recognized after stroke. Medial temporal lobe atrophy, associated with an increased risk of AD (Jobst et al., 1992), is more frequent in stroke patients who have pre-existing dementia (Hénon et al., 1998), leading to the hypothesis that most prestroke dementia are due to AD (Hénon et al., 1998).

Incidence One-fourth of stroke patients develop new-onset dementia 1 year after stroke (Andersen et al., 1996). The relative risk of new-onset dementia within 4 years is 5.5 (Tatemichi et al., 1994b). So far, there is only a single population-based study on the incidence of dementia in patients with stroke (Kokmen et al., 1996): this study was conducted over an observational period of 25 years. The cumulative incidence of PSD increased from 7% at year 1 to 48% at year 25; using a standardized mortality ratio, the relative risk of dementia was 8.8 one year after stroke and decreased to 2.0 at the end of follow-up (Kokmen et al., 1996), the incidence of AD being doubled in stroke patients (Kokmen et al., 1996). One-third of patients developing PSD already had some degree of pre-existing cognitive decline (Pohjasvaara et al., 1997).

Risk factors Stroke features associated with an increased risk of PSD are the lacunar origin and the left side of the lesion (Tatemichi et al., 1993). A major left hemisphere syndrome is also a significant and independent predictor of PSD (Tatemichi et al., 1993; Censori et al., 1996; Pohjasvaara et al., 1997).

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The volume of functional tissue loss is also important because it also includes the effect of deafferented cortex (Mielke et al., 1992). Increasing age (Tatemichi et al., 1993; Gorelick, 1997), non white race, low education (Tatemichi et al., 1993; Gorelick, 1997), diabetes mellitus, cortical atrophy (Tatemichi et al., 1990; Loeb et al., 1992; Kinkel et al. 1985) and comorbid disorders leading to hypoxemia, such as seizures, cardiac arrhythmia or pneumonia (Moroney et al., 1996), are associated with a higher risk of PSD, but not cigarette smoking (Tatemichi et al., 1993).

Influence of PSD on stroke outcome A significant reduction in survival rates has been reported in stroke patients with PSD (Tatemichi et al., 1994a): the cumulative proportion of survivors at 5 years is 39% for stroke patients with dementia and 75% for non-demented stroke patients (Tatemichi et al., 1994a). Dementia diagnosed 3 months after stroke is associated with an increased risk of stroke recurrence (Moroney et al., 1997b). A possible explanation is that dementia may be a surrogate marker for multiple vascular risk factors that may increase the risk of recurrence (Moroney et al., 1997b). However, less intensive management of stroke patients with cognitive impairment, and their lack of compliance, may also contribute to the increased risk of recurrence (Moroney et al., 1997b).

Diagnosis of PSD The cornerstones in the evaluation of a patient with suspected dementia after a stroke are traditional clinical skills to perform detailed clinical and neurological history and examination, including the interview of an informant. Assessment of social functions, activities of daily living, as well as psychiatric and behavioural symptoms are parts of the basic evaluation.

Mental status examination The bedside mental status examination includes the Mini Mental State Examination (Folstein et al., 1975), which has limitations as it emphasizes language, does not include timed elements and recognition portion of the memory tests, is insensitive to mild deficits, and is influenced by education and age. Other screening instruments for VaD include a 4 to 10 word memory test with delayed recall, cube drawing test for copy, verbal fluency test (number of animals named in 1 minute), Luria's alternating hand sequence or finger rings and letter cancellation test

(Roman et al., 1993). Usually, a more detailed neuropsychological assessment is necessary, which should cover the main cognitive domains including memory functions (short- and long-term memory), abstract thinking, judgement, aphasia, apraxia, agnosia, orientation, attention, executive functions, and speed of information processing (Erkinjuntti et al., 1997; Pohjasvaara et al., 1998).

Brain imaging Brain imaging should be performed at the initial diagnostic work-up. MRI is better than CT scan, because of its higher sensitivity and ability to demonstrate medial temporal lobe and basal forebrain areas. Depending on the criteria of VaD used, focal brain infarcts are found in 70 to 100% and more extensive white matter lesions in 70 to 100% of cases (Erkinjuntti et al., 1987; Roman et al., 1993; Erkinjuntti, 1996).

Diagnostic criteria for VaD The most widely used criteria for VaD are the DSM-IV (American Psychiatric Association, 1994), the ICD-10 (World Health Organization, 1993), the ADDTC (Chui et al., 1992), and the NINDS–AIREN criteria (Roman et al., 1993). The two key elements implemented in the clinical criteria for VaD are (i) the definition of dementia (Erkinjuntti et al., 1997), and (ii) the definition of the vascular disorder (Erkinjuntti, 1994; Wetterling et al., 1994; Wetterling et al., 1996). All the clinical criteria used are consensus criteria, which are neither derived from prospective communitybased studies on vascular factors affecting the cognition, nor based on detailed natural histories (Chui et al., 1992; Roman et al., 1993; Rockwood et al., 1994; Rockwood et al., 1994; Erkinjuntti, 1994; Erkinjuntti, 1997). All the cited criteria are based on the ischemic infarct concept and designed to have high specificity, although they have been poorly implemented and validated (Rockwood et al., 1994; Erkinjuntti, 1997). Variations in defining the dementia syndrome (Pohjasvaara et al., 1997; Erkinjuntti et al., 1997), and the vascular cause (Skoog et al., 1993; Wetterling et al., 1996), has led to a critical consequence: different definitions give different point prevalence estimates, identify different groups of subjects, and further identify different types and distribution of lesions. The DSM-IV definition requires focal neurological signs and symptoms or laboratory evidence of focal neurological damage clinically judged to be related to the disturbance (American Psychiatric Association, 1994). The course is

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specified by sudden cognitive and functional losses. Brain imaging requirements are not detailed. The DSM-IV definition for VaD is reasonably broad and lack detailed clinical and radiological guidelines. The ICD-10 criteria require unequal distribution of cognitive deficits, focal signs as evidence of focal brain damage, and significant cerebrovascular disease judged to be etiologically related to the dementia (World Health Organization, 1993). The criteria do not detail brain imaging requirements. The ICD-10 criteria specify altogether six subtypes of VaD. The ICD-10 criteria for VaD has been shown to be highly selective and only a subset of those fulfilling the general criteria for ICD-10 VaD can be classified into defined subtypes (Wetterling et al., 1994; Wetterling et al., 1996). The shortcoming of these criteria include lack of detailed guidelines, e.g. unequal cognitive deficits and neuroimaging, lack of etiological cues, and heterogeneity (Wetterling et al., 1994; Wetterling et al., 1996). The ADDTC criteria are exclusively criteria for ischemic VaD (IVD) (Chui et al., 1992). They require (i) evidence of two or more ischemic strokes by history, neurologic signs or neuroimaging studies (CT or T1-weighted MRI), or (ii) in case of a single stroke a clearly documented temporal relationship (not specified in detail), and always a neuroradiological evidence of at least one infarct outside the cerebellum. Ischemic white matter changes on CT or MRI do not qualify as brain imaging evidence of probable IVD, but may support a diagnosis of possible IVD. The criteria list features supporting the diagnosis, as well as a list of features casting doubt on a diagnosis of probable IVD. The NINDS–AIREN research criteria for VaD (Roman et al., 1993) include dementia syndrome, cerebrovascular disease and a relationship between dementia and cerebrovascular disorders. Cerebrovascular disease is defined by the presence of focal neurological sins and detailed brain imaging evidence of ischemic changes in the brain. A relationship between dementia and cerebrovascular disorder is based on the onset of dementia within 3 months following a recognized stroke, or on abrupt deterioration in cognitive functions or fluctuating, stepwise progression of cognitive deficits. The criteria include a list of features consistent with the diagnosis, as well as a list of features that make the diagnosis uncertain or unlikely. Also different levels of certainty of the clinical diagnosis (probable, possible, definite) are included. The NINDS–AIREN criteria recognize heterogeneity (Erkinjuntti, 1994) of the syndrome and variability of the clinical course in VaD, highlight detection of ischemic lesions and a relationship between lesion and cognition, as well as stroke and dementia onset. The inter-rater reliability of the NINDS–AIREN

criteria has been shown to be moderate to substantial (kappa 0.46 to 0.72) (Lopez et al., 1994). The current criteria for VaD are not interchangeable; they identify different numbers and cluster of patients labelled as VaD. The DSM-IV criteria are less restrictive compared to the ICD-10, the ADDTC and the NINDS–AIREN criteria (Wetterling et al., 1996; Verhey et al., 1996). The clinical criteria for VaD of older origin (DSM-IV and ICD-10) do not specify brain imaging requirements for the diagnosis in detail. The ADDTC requires one CT or T1 MRI infarct outside cerebellum, but white-matter lesions do not qualify for support of probable IVD. The NINDS–AIREN criteria require multiple infarcts (more than one cortico-subcortical or lacunar) or extensive white-matter lesions (CT or T1 MRI), but accept also a clinically ‘strategic’ single infarct as an evidence of ‘relevant cerebrovascular disease’. As evaluated neuropathologically, the ADDTC criteria seem to be more sensitive and the NINDS–AIREN criteria more specific, but neither are perfect (Gold et al., 1997). In a neuropathological series sensitivity of the NINDS–AIREN criteria was 58% and specificity 80% (Gold et al., 1997). The criteria successfully excluded AD in 91% of cases, and the proportion of combined cases misclassified as probable VaD was 29% (Gold et al., 1997). Compared to the ADDTC criteria, the NINDS–AIREN criteria were more specific and they better excluded combined cases (54% vs. 29%) (Gold et al., 1997).

Clinical patterns of dementia in stroke patients Cognitive syndrome The cognitive syndrome of VaD is characterized by (i) memory deficit, (ii) dysexecutive syndrome, (iii) slowed information processing, and (iv) mood and personality changes. These features are especially typical for cases with subcortical lesions. The patients with cortical lesions have in addition often a combination of different cortical neuropsychological syndromes (Mahler & Cummings, 1991). The memory deficit in VaD is often less severe than in AD, and consists impaired recall, relative intact recognition and better benefit from cues (Desmond et al., 1999). The dysexecutive syndrome in VaD includes impairment in goal formulation, initiation, planning, organising, sequencing, executing, set-sifting and set- maintenance, as well as in abstracting (Mahler & Cummings, 1991; Cummings, 1994; Desmond et al., 1999). The dysexecutive syndrome in VaD relates to lesions affecting the prefrontal subcortical circuit including prefrontal cortex, caudate,

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pallidum, thalamus, and the thalamo-cortical circuit (capsular genu, anterior capsule, anterior centrum semiovale, and anterior corona radiata) (Cummings, 1993). Relatively preserved personality and insight in mild and moderate cases of VaD is typical. Features that make the diagnosis of VaD disease uncertain or unlikely include early onset and progressive worsening of memory deficit or some other cognitive cortical deficit in the absence of corresponding focal lesions on brain imaging (Roman et al., 1993).

Associated neurological findings Frequent clinical neurological findings indicating focal brain lesion early in the course of VaD disease include: mild motor or sensory deficits, decreased coordination, brisk tendon reflexes, Babinski's sign, field cut, bulbar signs including dysarthria and dysphagia, extrapyramidal signs (mainly rigidity and akinesia), gait disorder (hemiplegic, apractic–atactic or small-stepped), unsteadiness and unprovoked falls, as well as urinary frequency and urgency (Babikian & Ropper, 1987; Roman, 1987; Erkinjuntti, 1987; Roman et al., 1993; Ishii et al., 1986). On the other hand, features that make the diagnosis of VaD uncertain or unlikely include absence of focal neurological signs, other than cognitive disturbance (Roman et al., 1993). In cortical VaD typical clinical features are sensorimotor changes and abrupt onset of cognitive impairment and aphasia, and in subcortical VaD disease pure motor hemiparesis, bulbar signs and dysarthria (Erkinjuntti, 1987).

Behavioural and psychological symptoms of dementia Depression, anxiety, emotional lability and incontinence, and other psychiatric symptoms are frequent in VaD (Roman, 1987). Depression, ablulia, emotional incontinence and psychomotor retardation are frequent in subcortical VaD (Mahler & Cummings, 1991; Cummings, 1994).

Ischemic scores Cardinal features of VaD disease are incorporated to the Hachinski Ischemic Score (Hachinski et al., 1975). In a recent neuropathological series stepwise deterioration (OR 6.0), fluctuating course OR 7.6), history of hypertension (OR 4.3), history of stroke (OR 4.3) and focal neurological symptoms (OR 4.4) differentiated patients with definite VaD from those with definite AD (Moroney et al.,

1997a). Nocturnal confusion and depression had no discriminating value. However, the ischemic score was unable to differentiate the ADv from VaD.

Heterogeneity of VaD Classification of VaD may be based according to (i) the underlying vascular pathology, (ii) the type of brain lesions, (iii) the location of brain lesions, (iv) the clinical syndrome. The subtypes of VaD included in current classifications are the cortical VaD (or multi-infarct dementia), the subcortical VaD (or the small vessel dementia), and the strategic infarct dementia (Erkinjuntti, 1987; Roman et al., 1993; Cummings, 1994; Brun, 1994; Wallin & Blennow, 1994; Loeb & Meyer, 1996; Konno et al., 1997). Many classifications also include hypoperfusion dementia (Sulkava & Erkinjuntti, 1987; Roman et al., 1993; Cummings, 1994; Brun, 1994). Further classifications include hemorrhagic dementia, hereditary VaD, and combined AD with cerebrovascular disease. The current clinical criteria for VaD differ in their classification of VaD into subtypes. None of them include detailed criteria for their subtypes. The DSM-IV (American Psychiatric Association, 1994) do not specify subtypes. The ICD-10 (World Health Organization, 1993) include six subtypes with rather superficial clinical descriptions (acute onset, multi-infarct, subcortical, mixed cortical and subcortical, other, and unspecified). The criteria are selective as only a subset of those fulfilling the general criteria for ICD-10 VaD can be classified into defined subtypes (Wetterling et al., 1994, 1996). The ADDTC (Chui et al., 1992) criteria do not specify detailed subtypes, but highlight that classification of ischemic VaD for research purposes should specify features of the infarcts that may differentiate of the disorder, such as location (cortical, white matter, periventricular, basal ganglia, thalamus), size (volume), distribution (large, small, or microvessel), severity (chronic ishemia versus infarction), etiology (embolism, aherosclerosis, arteriosclerosis, cerebral amyloid angiopathy, hypoperfusion). The NINDS–AIREN criteria (Roman et al., 1993) include without detailed description cortical VaD, subcortical VaD, Binswanger’s disease, and thalamic dementia.

Cortical VaD Cortical VaD relates to large-vessel disease, cardiac embolic events and also hypoperfusion. It shows predominantly cortical and cortico-subcortical arterial territorial

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and distal field (watershed) infarcts. Typical clinical features are lateralized sensorimotor changes and abrupt onset of cognitive impairment and aphasia (Erkinjuntti, 1987). In addition, some combination of different cortical neuropsychological syndromes has been suggested to be present in cortical VaD (Mahler & Cummings, 1991). This group shows heterogeneity in regards to the etiologies, vascular mechanisms, changes in the brain, as well as clinical manifestations.

Strategic infarct VaD Focal, often small, ischemic lesions involving specific sites critical for higher cortical functions have been classified separately. This group shows most heterogeneity. Isolated brain infarcts or hemorrhages may lead to dementia. In such cases, dementia is due to the location of the lesion, rather than the volume of brain loss. Each of the following cortical locations has been associated with neuropsychological impairment leading to dementia: left angular gyrus infarcts (Benson et al., 1982); right hemisphere angular gyrus infarcts; inferomesial temporal infarcts (Ott & Saver, 1993; Caplan et al., 1974); and mesial frontal infarcts (Alexander & Freeman, 1984; Damasio et al., 1987; Sawada & Kasui, 1995). Isolated subcortical vascular lesions consist of lacunar infarcts, deep territorial infarcts and deep hemorrhages, disrupting specific subcortical–cortical functional loops crucial for the maintenance of cognitive status (Baron et al., 1992). Dementia has been reported in thalamic (Graff-Radford et al., 1990; Barth et al., 1995), left-sided capsular genu (Tatemichi et al., 1992; Tatemichi, 1995; Pullicino & Benedict, 1996), and caudate nuclei infarcts (Bhatia & Marsden, 1994; Caplan et al., 1990; Mendez et al., 1990; Wenchiang & Caplan, 1995).

Subcortical VaD The currently proposed subtypes of VaD incorporate a variable combination of the given categories reflecting heterogeneity. The subcortical VaD incorporate small vessel disease as primary vascular etiology, lacunar infarcts and white matter lesions as primary types of brain lesions, and subcortical location as the primary location of lesions. The ischemic lesions in VaD affect especially the prefrontal subcortical circuit including prefrontal cortex, caudate, pallidum, thalamus, and the thalamo-cortical circuit (genu or anterior limb of the internal capsule, anterior centrum semiovale, and anterior corona radiata) (Cummings, 1993). Accordingly, the subcortical syndrome is the primary clinical manifestation. Dementia is not always

present in patients with a lacunar state. Lacunar infarcts appear as small miliary softenings, mostly located in the putamen, thalamus or pons (Marie, 1901), or in the deep white matter (De Reuck et al., 1980). They are small (5 to 15 mm) cavitations filled by a fine network of astrocytic processes, macrophages and siderophages, surrounded by fibrillary and protoplasmic astrocytes and sometimes also by hemosiderin pigments. They are the consequence of the occlusion of one single, deep perforating artery (Fisher, 1965). Multiple lacunes, in association with diffuse white matter changes, have been reported as the anatomical substrate of progressive cognitive decline in some patients who were clinically diagnosed as having AD, in the absence of a history of stroke and of a stepwise course of dementia (Pantoni et al., 1996). In demented with similarly progressive decline and absence of clinical strokes, diffuse whitematter changes without lacunes were neuropathologically described (Englund et al., 1989). These cases were however clinically diagnosed as VaD. Such arteriopathies are usually due to chronic arterial hypertension (Fisher, 1965, 1969). Small-vessel disease is the consequence of the occlusion of one single, deep perforating artery, caused by segmental fibrinoid degeneration with lipohyalinosis (Fisher, 1965, 1969; Olsson et al., 1996). Many perforating branches have multiple stenosis and poststenotic dilatations, suggesting that some hemodynamic events might also play a role, rather than local thrombosis (De Reuck & Van der Eecken, 1976). Stroke patients with lacunes are more likely to have white matter changes (Hijdra et al., 1990; Leys et al., 1992) and to develop dementia (Tatemichi et al., 1993) than patients with other stroke subtypes. Traditionally, VaD has been characterized by a relative abrupt onset (days to weeks), a stepwise deterioration (some recovery after worsening), and fluctuating course, e.g. difference between days of cognitive functions. This is seen in patients with repeated lesions affecting cortical and cortico-subcortical brain structures. In patients with subcortical VaD, however, the onset of cognitive symptoms is relatively insidious and course more slowly progressive (Roman, 1987; Erkinjuntti, 1987; Babikian & Ropper, 1987; Chui et al., 1992; Roman et al., 1993; Skoog, 1997). The mean duration of any VaD is around 5 years (Hebert & Brayne, 1995), and their survival is less than for the general population or AD (Skoog et al., 1993; Mölsä et al., 1995). Detailed studies on the natural history of subcortical VaD are lacking, and little is known or can be predicted about the rate and pattern of cognitive decline, and prognosis in subcortical VaD (Chui & Gonthier, 1999). The cognitive syndrome of subcortical VaD is characterized by:

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• a dysexecutive syndrome including impairment in goal formulation, initiation, planning, organizing, sequencing, executing, set-sifting and set-maintenance, as well as in abstracting (Mahler & Cummings, 1991; Cummings, 1994; Desmond et al., 1999). • mild memory deficits consisting of impaired recall, relative intact recognition, less severe forgetting, and better benefit from cues than in AD (Desmond et al., 1999). • behavioural changes including depression, personality change, emotional lability and incontinence, as well as inertia, emotional bluntness and psychomotor retardation (Roman et al., 1993; Mahler & Cummings, 1991; Cummings, 1994). The clinical neurological findings especially early in the course of subcortical VaD include episodes of mild upper motor neuron signs (drift, reflex assymetry, incoordination), gait disorder (apractic–atactic or small-stepped), imbalance and falls, urinary frequency and incontinence, dysarthria, dysphagia, extrapyramidal signs (hypokinesia, rigidity) (Ishii et al., 1986; Roman, 1987; Erkinjuntti, 1987; Babikian & Ropper, 1987; Roman et al., 1993). However, often these focal neurological signs are subtle only (Skoog, 1997).

Brain lesions associated with poststroke dementia Multiple large vascular lesions The occurrence of dementia depends mainly on the total volume of infarcts and hemorrhages (Tomlinson et al., 1970; Erkinjuntti et al., 1988; del Ser et al., 1990), and the number and location of the lesions (De Reuck et al., 1981). It has also been suggested that it may depend on the presence and volume of perifocal ischemic damage (Brun & Englund, 1997). There is no clear cutoff point on the volume of infarction resulting in dementia.

Strategic vascular lesions of the brain Each of the following cortical locations has been associated with neuropsychological impairment leading to dementia: left angular gyrus infarcts (Benson et al., 1982), right hemisphere angular gyrus infarcts, inferomesial temporal infarcts (Ott & Saver, 1993), and mesial frontal infarcts (Alexander & Freeman, 1984; Damasio et al., 1987; Sawada & Kasui, 1995). Dementia has been reported in infarcts of the following subcortical areas: thalamic (GraffRadford et al., 1990; Barth et al., 1995), left capsular genu (Pullicino & Benedict, 1996), and caudate nuclei (Bhatia &

Marsden, 1994; Mendez et al., 1990; Wenchiang & Caplan, 1995). ‘Strategic’ locations have been described in single cases or in small series (Benson et al., 1982; Alexander & Freeman, 1984); however, in case reports with first generations of computed tomographic (CT) scans, another vascular lesion of the brain cannot be excluded and may interfere with the neuropsychological profile (Godefroy et al., 1994). Moreover, in elderly patients without follow-up after stroke, the contribution of Alzheimer lesions to the neuropsychological profile cannot be excluded (Pasquier & Leys, 1997; Snowdon et al., 1997; Pasquier et al., 1998). The concept of strategic stroke should, therefore, be revisited with modern imaging techniques and a longer follow-up.

Multiple lacunar infarcts with leukoencephalopathy Small deep infarcts in the basal ganglia, centrum semiovale or brainstem, are often associated with leukoencephalopathy. Dementia is not always present in patients with a lacunar state. In 1894, Otto Binswanger described a condition characterized by dementia, recurrent strokes and white-matter changes at autopsy (Binswanger, 1894). Binswanger’s disease may be considered in patients with pathological evidence of the underlying vasculopathy, lacunes and leukoencephalopathy. Pathological examination of cases of Binswanger’s disease show diffuse or patchy rarefaction of myelin predominating in the periventricular and occipital regions of the centrum semiovale and associated with gliosis and spongiosis (De Reuck et al., 1980). The U fibres, internal capsules, and cerebral cortex are usually spared (Babikian & Ropper, 1987). White-matter changes are associated with multiple lacunes in the white-matter and basal ganglia (Babikian & Ropper, 1987). Binswanger’s encephalopathy may represent the end-stage pathology of lacunar state (De Reuck et al., 1980; Roman, 1987; Fredriksson et al., 1992; Leys et al., 1992; Pantoni & Garcia, 1995). However, the existence of Binswanger’s disease as a specific type of VaD remains controversial (Pantoni & Garcia, 1995). Dementia may occur after several strokes, when patients have dysarthria, dysphagia, ‘marche à petits pas’, incontinence, spasmodic laughing or crying, and parkinsonism. In other cases, multiple brain infarcts are recognized on brain imaging, in patients with dementia and no clear clinical evidence of stroke. Multiple lacunes in association with diffuse cerebral white-matter changes have been reported as the anatomical substrate of progressive cognitive decline in some patients who were clinically diagnosed as having AD, in the absence of a history of stroke and a stepwise course of dementia (Pantoni et al., 1996).

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Most cases of multiple lacunar infarcts with leukoencephalopathy are due to lipohyalinosis of the deep perforating arteries, which is the consequence of chronic arterial hypertension (Fisher, 1965, 1969). However, other causes may be associated with a higher risk of dementia in stroke patients. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant arteriopathy due to NOTCH 3 gene mutations (Joutel et al., 1996) on chromosome 19 (Tournier-Lasserve et al., 1993). Usually, lacunar infarcts occur between 40 and 50 years of age, and dementia occurs in one-third of patients with lacunes, and is almost always present before death (Chabriat et al., 1997). Mild cognitive impairment, of subcortical type, is probably present years before occurrence of dementia (Taillia et al., 1998), but dementia occurs in a stepwise fashion in a setting of several strokes, and is rarely progressive (Ruchoux et al., 1995). MRI is always abnormal in symptomatic subjects: it shows confluent hyperintensities in the white-matter and lacunar infarcts (Chabriat et al., 1998). Other rare arteriolopathies leading to multiple lacunar infarcts and dementia have been recognized. Their origin remains unknown, but genetic studies might help to classify them in the future: non-CADASIL Binswanger-like syndromes without arterial hypertension (Loizou et al., 1982; Berthier et al., 1992; Estes et al., 1991) autosomal recessive leukoencephalopathy with alopecia and lumbago (Fukutake & Hirayama, 1995), and cerebroretinal vasculopathy (Grand et al., 1988). Other hereditary vascular conditions unlinked to NOTCH 3 gene mutations and responsible for cerebral infarcts leading to dementia have also been identified (Jen et al., 1997).

Can VaD occur without detected infarcts? One-third to one-half of patients with pathologic evidence of VaD lack a history of clinically recognized stroke (Yoshitake et al., 1995; Moroney et al., 1997a). The question remains whether chronic ischemia plays an important role in VaD. Unilateral or bilateral occlusion of carotid arteries is the most common cause of hemodynamic VaD (Tatemichi et al., 1995). The role of hemodynamic factors and hypoxemia in the pathogenesis of post-stroke dementia has already been mentioned (Moroney et al., 1996). Several authors have found no evidence of chronic ischemic states in VaD, studied by means of positron emission tomography (PET) (Frackowiak et al., 1981; Brown et al., 1991). However, presence of arterial border zones in the deep white-matter and the high susceptibility of oligodendroglial cells to ischemia, along with the findings of widespread, histopathologically verified non-

infarct damage in patients with VaD, suggest that chronic ischemic leukoencephalopathies leading to VaD exist (Englund et al., 1989). Chronic ischemia without infarction in the carotid territory might be an exceptional cause of dementia, attributed to a ‘misery perfusion’ with positron emission tomography studies (Baron et al., 1981). This type of dementia might be reversible after correcting correction of the hemodynamic deficit. In a documented case, extra-intracranial arterial bypass surgery apparently improved the patient's cognitive status (Baron et al., 1981). Hemodynamic VaD is probably under-recognized, although a potential for surgical treatment in certain patients might exist (Tatemichi et al., 1995). Brun and Englund (1986) have suggested the term ‘incomplete white-matter infarction’, including rarefaction of the deep white matter, diffuse partial loss of myelin sheets, axons and oligodendroglial cells and mild astrocytic and macrophagic reactions in association with a central stenosing small-vessel disorder (Brun & Englund, 1986). It correlates to the frequent finding of white matter changes on CT and MRI scans in elderly patients (Brun & Englund, 1986; Englund et al., 1988; Janota et al., 1989). The brain damage may be more severe, and affect several of the most sensitive structures of the brain, leading to laminar necrosis of the neocortex, hippocampal degeneration, Purkinje cell loss of the cerebellar cortex and deep cerebral white matter demyelination. It is difficult to detect such lesions on macroscopic examination, and histological sections using specific staining techniques are usually necessary. Brun (1994) has also described Aa rare cortical–subcortical dementia syndrome caused by due to a hypertensive and atherosclerotic angiopathy of intracerebral and leptomeningeal vessels and leading to small infarcts located in the white matter, the basal ganglia and the brainstem, as well as in the cortex (Brun, 1994). They may represent a mixture of large- and small-vessel diseases rather than an isolated entity (Erkinjuntti, 1987; Mas et al., 1993).

Other factors contributing to dementia in stroke patients Role of white-matter changes in poststroke dementia White-matter changes are independent predictors of PSD (Tatemichi et al., 1994a, b). In first-ever lacunar infarctions, mortality, stroke recurrence, risks of dementia and of dependence are higher in presence of white-matter changes (Inzitari et al., 1995). White-matter changes may

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be associated with subtle cognitive (Skoog et al., 1996) and behavioural (Tarvonen-Schröder et al., 1996) changes. The functions which are the most sensitive to white-matter changes are memory, attention, and frontal lobe functions (Breteler et al., 1994; DeCarli et al., 1995). White-matter changes probably contribute to the cognitive decline in PSD (Pasquier & Leys, 1997).

Role of Alzheimer pathology in poststroke dementia Alzheimer and vascular lesions of the brain are frequently associated at autopsy (Jellinger et al., 1990; Victoroff et al., 1995). The links between PSD and AD are probably closer than expected (Pasquier & Leys, 1997). Shared risk factors of the two clinical entities may be responsible for their cooccurrence. Besides advancing age, one of them might be the ␧4 allele of the apolipoprotein E (APOE) gene (Frisoni et al., 1994; Saunders & Roses, 1993). The APOE ␧4 allele is a genetic risk factor for dementia with stroke, including VaD and AD with cerebrovascular disease. It may imply shared genetic susceptibility to dementia associated with stroke and AD. AD patients have some degree of vascular changes, including cerebral amyloid angiopathy (Yamada et al., 1987), which may lead to cerebral hemorrhages (Ellis et al., 1996; Lucas et al., 1992) or infarcts (Ellis et al., 1996; Premkumar et al., 1996), cerebral microvascular degeneration (and non-specific fibrohyaline thickening of the wall of the small perforating intracerebral arteries (Brun & Englund, 1986; Rezek et al., 1987; Leys et al., 1991; Erkinjuntti et al., 1996)), which may cause lacunes (Fisher, 1969), white-matter changes (Rezek et al., 1987; Hijdra et al., 1990; Leys et al., 1992; Erkinjuntti et al., 1996), or both. More recently, an increased intima-media thickness in the common carotid artery, which is associated with an increased risk of stroke in the community (Bots et al., 1996), has been found with a higher frequency in AD patients (Hofman et al., 1997). This concurs with the finding that aortic arteriosclerosis is common in autopsy verified AD subjects compared to age-matched controls (Kalaria, 1997).

The multifactorial origin of poststroke dementia From a clinical point of view, dementia is probably due to stroke alone in the following circumstances: (i) in young stroke patients who become demented after one or several strokes; (ii) when the clinician has a high level of certainty

that the cognitive functioning of the patient was normal before stroke, impaired immediately after and does not worsen over time or even slightly improve; (iii) when the lesions are located in strategic areas; and (iv) when a specific vascular condition known to cause dementia is proven by pathological data or a specific marker. Many cases of dementia occurring in stroke patients are probably the consequence of the cumulative effect of the cerebrovascular lesions, Alzheimer pathology, and whitematter changes. Even when these changes do not lead to dementia by themselves, their cumulative effect may reach the threshold of lesions required to produce dementia (Pasquier & Leys, 1997). When stroke, white-matter changes, or both, occur in a patient with asymptomatic Alzheimer pathology, the period of preclinical AD may be shortened (Pasquier & Leys, 1997). In the nun study, among 61 patients who met neuropathological criteria for AD, those with brain infarcts had poorer cognitive functions and a higher prevalence of dementia than those without infarcts, while among 41 patients who did not meet neuropathological criteria for AD, brain infarcts were only weakly associated with poor cognitive functions and dementia (Snowdon et al., 1997). Stroke lesions may play an important role in determining the presence and severity of the clinical symptoms of AD (Snowdon et al., 1997). In patients included in the dementia substudy of SYSTEUR, a beneficial effect of antihypertensive therapy on the risk of cognitive decline and of AD has been shown (Forette et al., 1998): treatment of 1000 patients aged 60 years or more, over a 5-year period, prevents 19 cases of dementia, including AD. This effect may be the consequence of the reduced incidence of infarcts by lowering of blood pressure, leading to a prevention of the anticipation of the clinical expression of AD (Leys & Pasquier, 1999).

Stroke prevention in patients with poststroke dementia Patients with dementia after stroke are significantly less frequently treated with aspirin or warfarin than nondemented patients (Moroney et al., 1998). However, trials of secondary prevention of stroke usually exclude patients with obvious dementia. As a consequence, optimal methods for the secondary prevention of stroke in patients with dementia remains speculative. Anticoagulation is not recommended in dementia, and carotid endarterectomy is thought to be associated with increased risk of the therapeutic procedure. However, this has never been evaluated. Therefore, stroke prevention trials should include dementia as a secondary end-point.

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22

Disorders of mood behaviour Florence Ghika-Schmid and Julien Bogousslavsky Department of Neurology, University of Lausanne, Switzerland

Introduction Although recognized as early as 1924 by Bleuler, depression and, more generally, mood disorders following cerebral lesions have only been studied systematically in the last 20 years. Initial studies of emotional disorders in brain injuries included patients with various lesions such as surgical incision, traumatic closed head injuries, penetrating head injury and stroke making it difficult to determine the location of the lesion. Some more recent stroke studies suggest a critical role of the anterior left hemisphere in depression, but other authors deny causal contribution of lesion location to depression. The predominant role of the right hemisphere in secondary mania is well recognized, but a consensus is still lacking and further studies are needed to determine the clinico-topographic correlation of disorders, such as apathy, anxiety, catastrophe reaction and pathological laughing and crying sometimes encountered after stroke. These affective disorders are important to consider in stroke patients, since they may negatively influence neurological recovery and may be responsive to treatment. Specific emotional behaviours, such as disinhibition, denial, indifference, overt sadness and aggressiveness, often occur during the very first days following stroke. They might be overlooked if not searched for systematically with appropriately designed scales. Some of these early behaviours, such as denial, may be related to the late development of depression and anxiety. Prospective studies of mood changes during and immediately after stroke have not been performed yet. Such studies on large samples of patients may permit the delineation of which of these acute emotional behavioural changes are markers for the delayed development of emotional disturbances (GhikaSchmid & Bogousslavsky, 1997).

Some stroke subtypes, such as cardioembolic stroke, may have a specific pattern of early emotional behaviour. Stroke occurrence itself may be related to a different individual vulnerability to stress, as in carotid artery disease. In stroke, early disregard of the symptoms by the patient or his relatives, may delay consultation and compromise acute management with new developing techniques, such as thrombolysis (Grotta & Bratina, 1995). Even after improvement some patients with denial may require much persuasion to enrol in stroke prevention therapy or be reluctant to accept rehabilitation. However, in spite of this important impact on management, little is known about the subjective experience of acute stroke patients. The current data of the acute Lausanne Emotion in Acute Stroke Study (LEASS) (Ghika-Schmid & Bogousslavsky, 1997; Ghika-Schmid et al., 1999) showed that early emotional behaviour can be quantified in acute stroke. Further analyses on a larger sample of patients may allow us to delineate which are the best markers of ulterior development of depression or anxiety and to perform detailed clinico-topographical correlation.

Depression Diagnosis The standardized diagnostic criteria of the DSM IV for mood disorders are appropriate for stroke, since poststroke depression has a similar symptomatic profile to primary depression (Starkstein & Robinson, 1989; Starkstein, 1998). Adapted depression rating scales, such as the Hamilton scale for depression, can be useful tools, with the cut-off score for poststroke depression being suggested as 13 (Andersen et al., 1994c). Other scales have been

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developed, more directly aiming at the evaluation of poststroke depression (Gainotti et al., 1997a). However, these different scales include features such as anxiety and catastrophe reaction, which may be specific clinical syndromes (see below). Special attention should be paid to autonomic disturbances, such as abnormal sleep patterns, decreased appetite and libido, vegetative anxious signs and subjective anergia (Ghika-Schmid & Bogousslavsky, 1997). No definite relationship has been established between severity of neurological impairment and presence of depressive features (Herrmann et al., 1995), but the negative influence of depression on neurological recovery is well recognized (Starkstein et al., 1990; Parikh et al., 1990; Morris et al., 1992).

Prevalence and risk factors The prevalence of depression in the acute phase of stroke is about 40% (20% major depression, 20% minor depression) (Starkstein et al., 1990; Starkstein, 1998), whereas estimates made in the chronic phases range between 18% and 54% (Astrom et al., 1993; Sinyor et al., 1986; Burvill et al., 1995a). The period of maximal prevalence and the evolution varies in the different studies; poststroke depression might be especially frequent in the acute phase of stroke, but can also occur 1 to 2 years after stroke and if left untreated, may last for up to 1 year (House et al., 1991; Starkstein et al., 1990; Starkstein, 1998; Astrom et al., 1993; Burvill et al., 1995a). Among risk factors for the development of poststroke depression, pre-existing cerebral atrophy has been suggested, but remains controversial (Herrmann et al., 1995, Starkstein et al., 1988; Astrom, 1996). An increased frequency of personal or familial history of psychiatric disorders was found in patients with poststroke depression, suggesting a personal or genetic predisposition (Starkstein et al., 1990, Starkstein, 1998; Andersen et al., 1995). Intellectual impairment might also explain some of the variation in mood scales (Andersen et al., 1995). These various risk factors may be differentially implicated in the development of depression a certain period of time after the stroke (Astrom et al., 1993).

Lesion location The left frontal anterior region, both the dorso-lateral prefrontal cortex and subcortical region, was found to be important for depression in left hemisphere (LH)damaged patients (Starkstein et al., 1990; Starkstein, 1998; Astrom et al., 1993). The severity of depression may be associated with lesion proximity to the frontal pole in the

LH, in cortical or subcortical location (Starkstein et al., 1900; Starkstein, 1998). Among patients with right hemisphere (RH) stroke, who developed depression, a positive association with a posterior lesion was found (Starkstein et al., 1990; Starkstein, 1998). However, although an association was found between major depressive disorder and left lentiform nucleus, no significant difference between depression scores in LH and RH lesions, or a correlation between the severity of depression and the anterior location or volume of the lesion, was seen in 47 patients during acute stroke (Herrmann et al., 1995). Moreover, severity of depression is not always proportional to the distance of the lesion from the frontal pole suggesting a more complex nature of association (Sinyor et al., 1986). Thus, an association between left-sided lesions and depression and right-sided lesions and hypomania is not a constant finding (House et al., 1990). Some authors even suggest that lesion location may not be a prime etiological factor for poststroke depression (Andersen et al., 1995; Burvill et al., 1996; Gainotti et al., 1997b). In the Lausanne Emotion in Acute Stroke Study (Ghika-Schmid et al., 1996, 1999), the use of previously developed precise templates of the vascular territories may shed some new light on this issue. On the other hand, electrophysiological evidence for a crucial role of left frontal activation of ‘positive affects’ (Davidson et al., 1987) and rapid-rate transcranial magnetic stimulation, showing a lateralized control of mood, following prefrontal cortex stimulation in normal volunteers (Pasqual-Leone et al., 1996), argue for the ‘localizing’ thesis. The hypothetical mechanisms considered by those authors supporting the role of lesion location are based on the observation of a higher incidence of familial psychiatric disorders in patients with right posterior lesion, which might suggest differential vulnerability to depression for right and left lesions (Starkstein et al., 1990). PET studies showed a possible compensatory upregulation of 5-HT2 (serotonin) receptors in the RH after stroke, which is not seen after left-sided lesions (Mayberg et al., 1988). Animal studies also showed a lateralized biochemical response to ischemia, suggesting asymmetry in the human biological response to injury, which supports these views (Starkstein et al., 1990). However, the findings of temporolimbic hypoperfusion in patients with depression and subcortical stroke suggests that alternative mechanisms should be considered (Grasso et al., 1994). Various mechanisms have been suggested to link depression and coronary heart disease, such as changes in lipid metabolism, in catecholamine-corticoid and serotonergic modulations, and altered sympathetic arousal in patients

Disorders of mood behaviour

with depression leading to arrhythmia (WassertheilSmoller et al., 1996). Identical physiopathological mechanisms might be present in patients with poststroke depression. In a similar way poststroke depression may be related to a higher secondary occurrence of hypertension (Jonas et al., 1997).

Double-blind placebo-controlled nortriptyline, trazodone serotonin reuptake inhibitors citalopram, fluoxetine

Treatment

Open studies methylphenidate imipramine mianserine moclobemide

Nortriptyline, trazodone and serotonin reuptake inhibitors (Lipsey et al., 1984; Reding et al., 1986; Andersen et al., 1994a; Dam et al., 1996) were shown to be effective in randomized placebo controlled studies of poststroke depression. Because of the high frequency of their contraindication and adverse effects (orthostatic hypotension, atrioventricular block), tricyclic antidepressants are not the first choice in cerebrovascular patients (Gustafson et al., 1995). Serotonin reuptake inhibitors may be the best choice (Reding et al., 1986; Andersen et al., 1994); however, adverse reactions, such as fluoxetine-induced mania, can occur in patients with poststroke depression (Berthier & Kulisevsky, 1993). Open trials have suggested the potential benefit of psychostimulants (methylphenidate), but further controlled studies are required to reach a conclusion (Gustafson et al., 1995). Imipramine and mianserine have been effective in trials and imipramine probably has a combined action on the noradrenergic and especially the serotononergic systems (Gustafson et al., 1995). The potential benefit of electroconvulsive therapy warrants confirmation (Gustafson et al., 1995, Currier et al., 1992). Treatment against spasticity, psychological assistance and social support should not be neglected (Angeleri et al., 1993).

Main studied treatments of poststroke depression (Fig. 22.1)

Fear and anxiety Historically, the word fear derived from the Old English word faer, which meant peril or calamity. The word anxiety originated from the Latin word anxius, which means troubled in mind, solicitous or uneasy. Fear is an emotional state involving physiological arousal (e.g. increased heart rate), verbal reports of distress (e.g. apprehension, worry), overt behaviour (e.g. avoidance) and cognitive disruption (e.g. hyperawareness about possible threat cues in the environment), typically triggered by specific object or situations. It is a fundamental emotion, present across ages,

Fig. 22.1. Main studied treatments of poststroke depression.

cultures, ethnic groups and species. Its functions are often described as an alarm system activating the organism in response to threat (McNeil et al., 1994).

Diagnosis of poststroke anxiety Restricted criteria from the DSM-III-R have been proposed to diagnose anxiety in stroke patients, but duration of symptoms was not included, as we wished to use the criteria for assessment immediately after stroke (Castillo et al., 1993). Anxiety involves the same emotional state as fear, but with a lesser mobilization for physical action. It is characterized by feelings of distress and worry, maladaptative shifts in attention due to off-target thinking, and the perception that aversive events are occurring in an unpredictable and uncontrollable manner. It is associated with more cognitive symptoms, and less visceral activation. Cues for its manifestation are more diffuse and changeable relative to fear (McNeil et al., 1994).

Prevalence and risk factors Anxiety is the second most prevalent mood disorder following stroke, being found in 3.5% to 24% of patients (Castillo et al., 1993; Starkstein et al., 1990; Starkstein et al., 1988b; Astrom, 1996; Burvill et al., 1995a,b). It is frequently associated with depression (Astrom, 1996). A personal history of alcohol abuse may be a significant association (Castillo et al., 1993), as well as cerebral atrophy (Astrom, 1996). According to a recent study, a combination of anxiety and depression is more frequent after left cortical stroke, whereas anxiety without depression is mainly seen following RH lesion (Castillo et al., 1993). Comorbidity with depression may impair the prognosis of depression (Astrom, 1996). One study suggested it

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may be more frequent after right hemisphere stroke (Astrom et al., 1993).

Relationship to stroke The occurrence of fear or anxiety in reaction to a stressful challenge is determined in part by the social context in which they occur and the social status of the individual, such as whether he is dominant or subordinate (Lazarus 1966; McEwen, 1996). The effect of potential stress evoking situations on the nervous system is influenced by genetic predisposition, biological development, sex and learned experience (McEwen, 1996). An unknown stress source induces physiological arousal. Known threatening may induce high-cost response such as aggression, or, if no response is available, displaced aggression, helplessness, or hopelessness, with altered physiological responses (McEwen, 1996). Alcohol and substance abuse as well as risk-taking behaviours are other coping alternatives (Sher, 1987; McEwen, 1996). The central nucleus of the amygdala is an important neural control centre for fear and conditioned fear (Aggleton, 1992). It projects to cardiovascular, facial, autonomic, respiratory and neuroendocrine control centers in the brain that affect cardiovascular, gastrointestinal and adrenocortical activity, facial expression, social interaction and cause arousal (McEwen, 1996). The hippocampus also plays an important role in controlling the secretion of adrenal steroids and in processing spatial temporal aspects of a changing environment, and maybe auditory processing of fear (Eichenbaum & Otto, 1992; GhikaSchmid & Bogousslavsky, 1997; McEwen, 1996). Stroke incidence may be related to a different individual vulnerability to mental stress, as shown in patients with carotid artery disease (Barnett et al., 1997). Cardiovascular reactivity can be assessed by measuring hemodynamic changes during a frustrating cognitive task such as the Stroop Colour Word Interference Task. In 136 untreated subjects followed for 2 years, a greater change in systolic blood pressure during the task was a strong predictor of the rate of progression of carotid arteriosclerosis measured with Doppler ultrasound (Barnett et al., 1997). In the clinical setting, patients with high blood pressure in a doctor’s office may be at similar risk. In animals, exposure to social stress and competition for dominance is associated with coronary atherosclerosis (Spence, 1996). Individual and cultural variability in the appraisal of emotion certainly plays an important role in these phenomena and would deserve further studies. When faced with the same situation, different people often respond

with different emotions. This general statement may be painfully self-evident, but appraisal theories go beyond the general statement to specify the differences (Ellsworth, 1991). For example, a person who characteristically sees his misfortunes as caused by bad luck may be more prone to depression, while one who attributes these to other people’s malice may be more prone to aggression (Roseman, 1984). Among the Utku Eskimos, feelings of anger are strongly condemned (Briggs, 1970), but in certain Arab Groups, a man’s failure to respond with anger is seen as dishonourable (Abu-Lughod, 1986). It is clear that much of atherosclerosis is genetic, the candidate gene extending from lipoprotein lipase to angiotensin receptor gene for example (Spence, 1996). In that sense, the study of vascular reactivity can be a new tool for investigating the genetics of atherosclerosis. Moreover, a significantly higher incidence of stroke was found in men reporting a higher level of stress (Harmsen et al., 1990). Life settings such as grief, mourning, loss of status or self-esteem, threat of injury, involve a response of overwhelming excitation or giving up and may be associated with neurovegetative responses, that may lead to lethal cardiac events particularly in individuals with pre-existing cardiovascular disease (Engel, 1971). Similar phenomena may be important in cerebrovascular disease, as well as certain at-risk personality features including behavioural pattern to assure satisfaction of self-set goals, difficulty in the control of anger and object-related style characterized by assumption of personal responsibility for gratification of needs. The systematic study of the personality characteristics of 32 men who had ischemic stroke occurring within a period of sustained emotional disturbance showed that some features appeared with unexpected frequency (Adler et al., 1971). These included: (i) a pressure to keep busy; (ii) a self-image of an active, hard worker; (iii) high standards and a pronounced sense of responsibility; (iv) a sense of urgency, time pressure and a need to fulfil goals and (v) a sense of determination and strong will (Adler et al., 1971). Twenty-eight of these 32 patients reported they were concerned with controlling the expression of their anger aroused mostly by a feeling of not being able to control their environment or their own bodies, which frustrated their attempts to fulfil self-set goals (Adler et al., 1971). In that group of patients, the onset of stroke at the moment of an intense peak of emotion was unusual, occurring only twice (Adler et al., 1971). These findings of psychological characteristics of stroke patients were very similar to what is reported for coronary patients, such as angina pectoris occurring in a ‘keen and ambitious man, the indicator of whose engines is always set at full speed

Disorders of mood behaviour

ahead’ (Adler et al., 1971). The main drawback of this study is its retrospective nature, leading to possible distortion by the interviewer. In a meta-analysis of the relation between psychological factors and coronary heart disease, reliable associations were found for ‘Type A behaviour’, referring to a person who is involved in an aggressive and incessant struggle to achieve more and more in less and less time, for anger, hostility, aggression, but also for depression and anxiety (Booth-Kewley & Friedman, 1987). This suggests that coronary proneness may not be the expected hurried impatient workaholic, but, instead, one person with one or more negative emotion. Other studies have emphasized the importance of hostility, especially an antagonistic interactional style, rather than the whole set of behaviours associated with type A behaviour, as a risk factor for coronary heart disease (Dembroski et al., 1989). A new experimental approach in applying the appraisal theories of emotions may prove useful in better characterizing the individual balance between fear, anger and anxiety in such a setting as well as in stroke (Ellsworth, 1991, Scherer, 1984). A relationship may exist between fear and anxiety, and anger. These three emotional states are common responses to stressful situations and are often difficult to distinguish because all involve unpleasant feelings and physiological arousal. Some evidence suggests that anxiety and fear can be differentiated from anger according to feelings along the dominance–submissiveness continuum. People who are angry may feel in control of events, while people who are anxious or fearful may feel out of control or vulnerable. Physiologically, fear and anxiety have been associated with increased skin conductance and respiratory rate, while anger has been involved in increased diastolic blood pressure (McNeil et al., 1994). Repeated and successful practice of courageous behaviour leads to a decrease in verbal reports of fear and physiological responsivity, which can lead to a state of fearlessness (McNeil et al., 1994). Stress could also affect metabolic control of diabetes, by changes in compliance behaviour and neurohumoral axis, but the findings supporting these hypotheses remain contradictory (Barglow et al., 1984). Thus the relative importance of personality features and emotional reaction, both in cardiovascular and in cerebrovascular diseases, remains debated. Precise prospective data on the emotional profile of patients with acute stroke may allow a better understanding of their characteristics and the implications. Preliminary data from the Lausanne Emotion in Acute Stroke Study (Ghika-Schmid et al., 1990) suggest that patients with acute cardioembolic stroke may have a specific pattern of early emotional disturbances. Among 85

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Anger (acute) Random etiology Cardioembolic Depression (3rd month)

0%

5%

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Fig. 22.2. Early anger reaction and delayed depression in cardioembolic vs. non-cardioembolic stroke.

patients, 23 (13 men, 10 women, age 66 ⫾ 17 years) had cardioembolic sources, 15 had stroke in the MCA territory and 8 in the posterior circulation (10 right, 13 left). They presented acute emotional reactions of disinhibition (12), denial (6), indifference (7), overt sadness (6), aggressiveness (5). On questioning, 6 patients expressed fear, 5 anger, 14 joy and 8 sadness. In the third month, 12 (52%) patients were: anxious (4), anxio-depressive (3), or depressed (5). Compared to 55 patients with stroke of random etiology, they expressed more anger during the acute phase, 21% vs. 12% and displayed more depression at 3 months, 21% vs. 5% (Fig. 22.2). No other between-group difference was observed. These data suggest that, during the acute period, patients with cardioembolic stroke express anger more often than the overall stroke population. This may be related to specific personality features, such as difficulty in the control of anger. This may suggest that such a behavioural pattern indicates a risk for cardioembolic events. In the third month, patients with cardioembolic stroke had a higher incidence of depressive, but not anxious, manifestations. Thus the expression of poststroke affective disorders may be different in relation to different stroke etiologies. This may be due to pre-existing personality features favouring a peculiar stroke mechanism, such as cardiac embolism.

Pseudodepressive manifestations Abulia The clinical characterization of apathy, or abulia, has been debated in the literature, and includes features such as flat affect, short and delayed answers, hypophonia, reduced

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motor responses, fixed gazed and blank face, perseverations and lack of awareness of condition (Fisher, 1995). Clinical scales, which can be useful diagnostic and followup tools, have been developed (Starkstein, 1998). Abulia is related to the disruption, at various anatomical sites, of fronto-subcortical pathways, such as anterior cingulate and capsular lesion (Starkstein et al., 1993a; Fisher, 1995). Apathy was reported as more frequent following stroke in the posterior arm of the internal capsule in the LH, probably because anterior cerebral artery stroke with cingulate involvement is rare (Starkstein et al., 1993a). Major depression is significantly more frequent in patients with apathy (Starkstein et al., 1993a), but should be distinguished from it (Marin et al., 1993). Poststroke apathy may be significantly associated with age and more severe impairment in activities of daily living (ADL) and cognitive functions (Starkstein, 1998), and with frontal and anterior temporal reduction in cerebral blood flow measured by 133 Xe inhalation. The therapeutic potential of agents such as bromocriptine or methylphenidate has been suggested (Watanabe et al., 1995; Muller & Von Cramon, 1994).

(Robinson et al., 1993), although this point remains controversial (Andersen et al., 1995). A corresponding lesion location is not clear (Robinson et al., 1993; Derex et al., 1997), although bilateral pontine lesions have been emphasized (Andersen et al., 1994a). Unilateral lesion, especially if subcortical, might be sufficient. Pathological laughing and crying is often delayed (Berthier et al., 1996), suggesting a mechanism similar to delayed onset movement disorders. Symptomatic improvement has been reported with serotonin reuptake agents and tricyclics (Robinson et al., 1993; Andersen et al., 1994a), being consistent with the hypothesis of stroke-induced partial involvement of the serotoninergic raphe nuclei in the brainstem or their ascending projection to the brain hemispheres (Derex et al., 1997; Andersen et al., 1994a). Emotionalism is a term preferred by some authors, defined as an increase in frequency of crying and laughing, without warning and outside normal control (Tig et al., 1998). Its presence was reported in 20–25% of patients 6 months after stroke (Tig et al., 1998). Emotional lability may follow stroke mainly if the anterior regions of both cerebral hemispheres are involved (Morris et al., 1993b).

Loss of psychic self-activation Apathetic, aspontaneous, indifferent behaviour, with loss of motor and affective drive and reversible when patients are repeatedly stimulated by another person, can be seen in toxic bilateral subcortical lesions involving the pallidum or putamen and in bithalamic infarct (Laplane, 1990; Bogousslavsky et al., 1991). Occasionally, loss of psychic self activation following bilateral thalamic infarct of venous origin may be accompanied by obsessive-compulsive behaviours (OCB) (Bogousslavsky, 1993; J. Bogousslavsky, personal observation), similar to the effects seen following bilateral basal ganglia involvement due to encephalitis, anoxia, disulfiram, carbon monoxide intoxication or trauma (Ali-Cherif et al., 1984; Laplane, 1994). OCB may be due to dysfunction of the fronto-striato-pallido frontal circuit (Laplane, 1994), and the occurrence of identical symptoms after bilateral thalamic stroke suggests an additional thalamic connection to this circuit. Patients with OCB have a low affective resonance to their symptoms and loss of projection of themselves into the future, different from the depressive state, but sometimes associated with it (Laplane, 1994).

Pathological laughing and crying This is characteristically unrelated to the patient’s inner emotional state. It can occur independently of depression

Catastrophe reactions First recognized by Babinski in 1914, catastrophe reactions were defined by Goldstein (1939) as an inability to cope when confronted with the deficit, with short-lasting sudden bursts of tears, refusal and irritation. They were initially reported predominantly in patients with left hemispheric lesions (Gainotti, 1972). However, recent studies have failed to demonstrate significant hemispheric involvement differences, but rather suggest a preferential basal ganglia involvement (Starkstein et al., 1993b). They may be associated with a positive personal and familial history of psychiatric disorder, increased frequency of major depression, and lower scores of daily living activity (Starkstein et al., 1993b).

Mania Mania, characterized by signs, such as inflated self-esteem or grandiosity, decreased need for sleep, distractibility, flight of ideas and excessive involvement in pleasurable activities with potential painful consequences (DSM-IV), is a rare occurrence following stroke. Starkstein (Starkstein et al., 1987) found the prevalence of manic patients among a consecutive series of more than 300 patients with acute stroke to be 1%. In manic syndromes following cerebral

Disorders of mood behaviour

injury, lesions were located mainly in the RH and involved the thalamus (Bogousslavsky et al., 1998a,b; Starkstein et al., 1988b; Cummings & Mendez, 1984), right temporal lobe (Starkstein et al., 1988b), head of the caudate (Starkstein et al., 1990b) or, bilaterally, the frontal cortex (Starkstein et al., 1988a,b,c). As for major depression, silent cerebral infarcts may play a role in the occurrence of lateonset mania (Fujikawa et al., 1995). Hypometabolism involving the right inferior temporal lobe was seen in a PET study of two patients with lesions of the right head of the caudate (Starkstein et al., 1990b), leading to the hypothesis of a direct or indirect role (diaschisis) of the right inferior temporal lobe in secondary mania. In primary mania, decreased blood flow to the right temporal lobe has also been found (Migliorelli et al., 1993). Poststroke mania has been reported in patients previously free of psychiatric conditions, but with a family history of psychiatric disease (Starkstein et al., 1987; Robinson et al., 1988). In a patient with previous recurrent episodes of mania, a dramatic change in symptoms, with the appearance of persisting hyperthymia has been reported following a right thalamic infarct (Vuilleumier et al., 1998). A dual mechanism of depression and mania, the former being associated with left anterior lesions and the second with RH lesions, may be related to a differential neuromodulation by serotoninergic agents and a differential adaptive mechanism of S2 receptors in both hemispheres (Starkstein et al., 1990). The influence of a positive family history of psychiatric disorders in right-sided damaged patients with secondary mood disorders suggests a genetic predisposition in this population (Robinson et al., 1988). Lithium may be effective for treating patients with secondary mania, but data from published studies show that, in this population, the associated adverse effects often limit its usefulness (Evans et al., 1995). Anticonvulsants appear to offer an effective alternative, for example, valproate has been shown an effective and well-tolerated treatment in open trials in patients with secondary mania (Evans et al., 1995). Controlled clinical trials are necessary to confirm the efficacy and tolerability of mood-stabilizing anticonvulsants in the treatment of secondary mania.

Aggressive burst Bursts of anger may occur following stroke accompanied by behaviours ranging from shouting to violence (Paradiso et al., 1996). These behaviours seem to occur preferentially in patients with higher Hamilton scores and greater cognitive impairment (Paradiso et al., 1996). They are more frequent following LH stroke (Paradiso et al., 1996).

Poststroke psychosis Hallucinations or paranoid delusions occur more often in older patients, with a positive personal and family history of psychosis in 50% of cases (Starkstein, 1998). The ventricular to brain ratio in these patients is often decreased, suggesting subcortical atrophy (Starkstein, 1998). The stroke can be parieto-temporal, occipital, frontal or subcortical in the RH, or pontine (Starkstein, 1998; Kim et al., 1995).

Subjective experience and nosognosia Even after patients improve, some may require much persuasion to enrol in follow-up and stroke prevention therapy. Moreover, patients with denial of hemiplegia are often reluctant to accept rehabilitation, sometimes to the point of refusing to use a cane to walk (Prigatano & Schacter, 1991; Ullman et al., 1960). However, in spite of this important impact on management, little is known about the subjective experience of stroke patients. In his detailed self-observation of motor hemiplegia, dysarthria and modification of handwriting following infarction in the right internal capsule and surroundings, Brodal (1973) mentioned his ‘incontinence of emotional expression’ and his ‘painful awareness of no longer being what he used to be’. Although a couple of historical stroke patients, such as Auguste Forel, have pointed to the potential importance of patient’s self-evaluation, studies of subjective experience in stroke remained exceptional (Ullman et al., 1960; Ullman & Gruen, 1961; Alajouanine & Lhermitte, 1964). Systematic prospective studies are required to evaluate the influence of subjective experience, especially in the acute phase of stroke, when this aspect may be overlooked. Since the initial descriptions, the terms anosognosia and denial have been used interchangeably, although some authors have preferred denial, to emphasize that the notion is wider than the initially recognized anosognosia for hemiplegia or hemianopia (Prigatano & Schacter, 1991). Denial is the product of an interaction, in which the observer interprets the patient’s behaviour. The type of interview can influence the degree of denial (Prigatano & Schacter, 1991). Some authors have proposed scales aimed at quantifying the severity of anosognosia (Prigatano & Schacter, 1991). On the other hand, the various entities often lumped together in the terms denial or anosognosia should be separated from each other. In order to differentiate between the patient’s own appreciation of his/her condition and observed behaviour, the terms anosognosia/anosodiaphoria can be reserved for the patients’

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25

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Fig. 22.3. Observation made among 53 stroke patients. Anosognosia may also develop after left-sided lesions. Anosodiaphoria was even more frequent following left strokes (Ghika-Schmid et al., 1999).

display euphoria and indifference towards their symptoms (anosodiaphoria and anosognosia). Gainotti suggested that depression in patients with RH lesions, may be underdiagnosed due to a tendency to denial and failure to express affects (Gainotti, 1989). However, no significant difference was found in depression scores between patients with anosognosia for hemiplegia (common with right parieto-temporal or basal ganglia involvement) and patients who were nosognosic, suggesting that anosognosic patients do not deny depression (Starkstein et al., 1990a). Thus, anosognosia, neglect and major depression may coexist. A longitudinal case study suggested that they are independent phenomena (Starkstein et al., 1990a). The coexistence of anosognosia and depression challenges the psychological theory of depression (Gainotti, 1989; Ramasubbu, 1994).

Behavioural reactions of denial own assessment of their deficits during questioning, while denial reactions can be used to describe activities observed by an external examiner, such as attempts to stand in spite of hemiplegia. In addition, subjective experience, defined as the patients’ own appreciation, of their affective state (happiness, sadness, anger or fear), should be emphasized. In a recent study assessing subjective experience in acute stroke to correlate it with stroke features, acute emotional behaviour, and impact on medical care seeking, we studied all patients with acute first-ever stroke. During the first 4 days, we rated subjective experience (happiness, sadness, irascibility, fear), mood (Hamilton) and behavioural reactions using a specifically designed scale. Fifty-three patients (30 men, 23 women, 60 ⫾ 19 years) completed 3month follow-up. Strokes were in the anterior (32/53) or posterior circulation (21/53) (17 right, 33 left, 3 bilateral). Seventeen (32%) patients failed to seek medical care spontaneously (Ghika-Schmid et al., 1999).

Anosognosia and anosodiaphoria Anosognosia has been shown to be frequent in right-sided lesions, but may also develop after left-sided lesions (Fig. 22.3). Anosodiaphoria was even reported to be more frequent following left strokes (Ghika-Schmid et al., 1999). The lack of recognition of the deficit was manifested in various functions, such as hemianopia, dysarthria, aphasia or sensory loss (Prigatano & Schacter, 1991). Babinski (1914) noted that patients with RH lesions may

Acute behavioural signs of denial were independent of anosognosia. They were not related to the side of the lesion, but were significantly more frequent in patients with deep lesions on either side. This confirms a clear distinction between the behavioural manifestations of denial and nosognosia. It suggests that these two aspects may also be independent in terms of their neuroanatomic substrate, since nosognosia, but not behavioural signs of denial, related to the side of the lesion. This may imply a dissociation between behavioural display and insight of physical impairment. Thus, the behavioural signs of denial and nosognosia should be distinguished in further studies; their confusion may have accounted for some of the discrepancies in the literature (Ullman & Gruen, 1961). Denial reactions were inversely correlated to subjective experience of fear. The possibility of a relationship between anxiety, fear and denial has been raised, but has remained ambiguous (Ullman et al., 1960). In Ullman’s widow patient, the rejection of denial (realizing that her paralysed arm was not her dead husband’s) decreased her fear. In contrast, in another patient, initial feelings of fright were relieved by the identification of the arm upon her breast (her arm) as that of her husband (Ullman et al., 1960). The presence of denial may be related to a reduction of the patient’s experience of fear (Ghika-Schmid et al., 1999). An impact of denial on the patient’s outcome, as shown by a worsening record of employment, has been reported in follow-up studies of patients with head injury (Prigatano & Schacter, 1991). The presence of an acute denial reaction may be correlated with delayed occurrence of depression and anxiety (Ghika-Schmid et al., 1999).

Disorders of mood behaviour

Subjective experience For all other emotions than fear (joy, sadness and anger), the patients’ subjective experience was not related to the behaviour displayed during the acute phase of stroke (Ghika-Schmid et al., 1999). Such an independence of nosognosia from the emotional reactions supports a similar dissociation observed over time in a prospective longitudinal single case study (Starkstein et al., 1990). The coexistence of anosognosia and depression challenges the psychological theory of depression (Ramasubbu, 1994). This seems to confirm the hypothesis that a decreased experience of fear may relate to the manifestation of denial, which is sometimes interpreted as a defence mechanism. Fear may be mediated by a different neuronal network, accounting for the dissociation we observed between subjective experience of fear (which related to behaviour of denial) and the independent subjective experience of other emotions in regard to the observed behavioural response. Impaired recognition of fear in emotional faces has been noted in patients with selective bilateral damage to the amygdala (Adolphs et al., 1994; Calder et al., 1996), whereas the hippocampus and adjacent whitematter may play a crucial role in the vocal perception of fear (Ghika-Schmid, 1997), see Fig. 22.3. This suggests that there may be multiple emotion systems for different aspects of emotion (Adolphs et al., 1994; Damasio, 1994). Abnormal fear reactions may be related to affective disorders such as anxiety and stress (Le Doux, 1996).

Recall of the acute event A third of the patients could only partially recall or did not recall at all the acute event (Ghika-Schmid et al., 1999). These results are consistent with a study on patients showing dramatic recovery following thrombolysis (Grotta & Bratina, 1995). This impaired recall of the acute phase certainly adds to the difficulties encountered in trying to motivate patients to enroll in regular follow-up.

Medical-care seeking Patients with preserved nosognosia did spontaneously better at seeking medical attention on their own initiative than those with anosognosia, suggesting that a lack of insight may indeed be the cause of the failure to consult. The presence of subjective experience was related with appropriate care-seeking. Its impairment may contribute, as for anosognosia, to increase delay in consultation. In conclusion, patients with acute behavioural denial

reactions may have a decreased frequency of subjective experience of fear. Preserved subjective experience of fear relates with appropriate care-seeking and its impairment may contribute, as for anosognosia, to increase delay in consultation. All other emotional reactions seem to be dissociated from the patients’ subjective experience, suggesting that emotional behaviour should be distinguished from the subjective emotional experience, which may be closer to affective disorders. This distinction, which was not made previously (Ullman & Gruen, 1961), should be confirmed in further studies.

Mood disorders and cognition in acute brain lesions On rare occasions, the relationship between mood disorders and cognitive impairment has been studied in stroke (Downhill & Robinson, 1994; Iacoboni et al., 1995; BollaWilson et al., 1989). Studies based on the Mini-Mental State Examination are not sufficient, since this test mainly depends on language abilities and left hemispheric function and does not allow a proper estimation of cognitive function due to RH lesion. A study using a complete neuropsychological battery of tests has shown impaired orientation, language and visuo-perceptive and executive functions in LH damaged depressed patients, while no significant correlation between depression and a specific cognitive defect was found in RH patients (Bolla-Wilson et al., 1989). Poststroke depression might contribute to cognitive impairment in the late phase after stroke (Iacoboni et al., 1995). Further studies would be needed to confirm these findings and to demonstrate a possible improvement of cognitive symptoms following treatment. Moreover, the possibility of a positive adrenergic effect on neurological signs and cognition following physical therapy has been suggested (Feeney, 1997). As diagnosis of depression among patients with aphasia is difficult, these patients have been excluded from most studies of poststroke depression. Patients with non-fluent aphasia may show a higher frequency of depression than patients with fluent aphasia, but this may be related to the sharing of a lesion location (left frontal) between non-fluent aphasia and depression (Starkstein et al., 1990; Starkstein, 1998). Cognitive functions and mood may be related to each other and share common neuronal networks and neurotransmitter systems. However, the way in which these different brain functions interact and their relationship to the possible occurrence and clinical features of poststroke

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mood disorder are far from understood and require further investigation.

Mood and emotional perception and expression Emotional aptitudes in patients with stroke and their relationship to mood disorder and cognition have rarely been studied (Starkstein et al., 1994). Emotional aprosody may not necessarily be associated with poststroke depression (Starkstein et al., 1994). One limitation of this study (Starkstein et al., 1994) was the exclusion of patients with comprehension disorder, which may explain the finding of an association between aprosody and right hemisphere lesion; this observation therefore needs to be confirmed. A relationship between memory dysfunction and emotional perception is suggested by studies on the role of the amygdala in acquiring and storing long-term associative memory to link sensory information and affective significance (Ono et al., 1995). The role of the lateral nucleus of the amygdala in fear is recognized in animals (Le Doux, 1996). Recognition of fear in emotional faces may be mediated by the amygdala (Adolphs et al., 1994; Calder et al., 1996). Animal studies suggest that the emotional functions of the amygdala and hippocampus may be relayed through amygdalo-hippocampal interconnections (Aggleton, 1986). Recent observations suggest that the amygdala may process emotional aspects of events (Starter & Markowitsch, 1985). These studies on the role of the amygdala in fear challenge the septohippocampal theories of fear and anxiety (Gray, 1987). On detailed testing of the recognition of facial and vocal expression of emotion (Ekman & Friesen, 1971; Pittam & Scherer, 1993) an impairment of the vocal perception of fear, but not that of other emotions, such as joy, sadness and anger was found in a patient with bihippocampal hemorrhage (GhikaSchmid et al., 1997b). Such selective impairment of fear perception was not present in the recognition of facial expression of emotion. Thus, emotional perception varies according to the different aspects of emotions and the different modality of presentation (faces vs. voices). Evidence about the origin and universality of the production of particular facial expressions (Ekman & Friesen, 1971) initially led to the claim of the existence of a ‘specialized perceptual system tuned to the peculiar movements that signal them’ (Etcoff & Magee, 1992). However, the possibility of a distinct processing of emotion according to the modality of perception should be considered, consistent with the idea that there may be multiple emotion systems

for different aspects of emotion (Adolphs et al., 1994; Damasio, 1994). The hippocampus and adjacent whitematter may play a critical role in the recognition of fear in vocal expression, possibly dissociated from that of other emotions (Ghika-Schmid et al., 1997b). A critical role of the right hemisphere in acquired deficit of emotional expression and comprehension (prosody, emotional faces and lexical emotional expression) has been suggested by numerous studies (Heilman et al., 1975; Ross & Mesulam, 1979; Ross, 1981; De Kosky et al., 1980; Borod et al., 1992; Ahern et al., 1991), but remains controversial (Stone et al., 1996). Other authors emphasized the role of basal ganglia (Cancelliere & Kertesz, 1990). A relative superiority of the visuo-spatial (70) vs. verbal (54) IQ on the Weschler memory scale, observed in a patient with bihippocampal hemorrhage and impaired recognition of fear in vocal expression was not suggestive of a predominant right-side dysfunction (Ghika-Schmid et al., 1997b). Data from tachistoscopic presentation of emotional faces in the right and left hemisphere also challenge the view that the right hemisphere is uniquely involved in all emotional behaviour (Davidson et al., 1987). In Klüver–Bucy syndrome (kBS – first described in rhesus monkeys following bilateral temporal lobectomy, with tendency to examine all objects orally, loss of anger and fear responses and increased sexual activity) an interesting feature has been called ‘psychic blindness’. In the human, psychic blindness may be characterized by an inability to differentiate strangers from friends. It may be associated with sensory agnosia. Cummings and Duchen (1981) suggested that sensory agnosia results from disruption of the temporal neocortex or its connections, and that the other components of the syndrome (hyperorality, hypersexuality) are caused by disturbances of the amygdala functions. Loss of recognition of persons has been reported following lesions in the anterior temporal region and in the limbic structures of the mesial temporal region (Corkin, 1984; Damasio, 1989). Patient HM was unable to learn the identity of the face he had come into contact with since he sustained bilateral ablation of entorhinal cortex and hippocampus (Corkin, 1984). Another patient with bilateral mesial limbic system structures and bilateral higherorder neocortical damage was unable to recognize the identity of the people she met, not only in the visual modality, but also with the help of vocal or sensory clues (Damasio, 1985). These findings support the critical role of the anterior temporal lobe in the formation of binding codes, which allow the reconstruction and retrieval of unique memories (Damasio, 1989). The rare occurrence of complete KBS after a lesion restricted to the left temporo-

Disorders of mood behaviour

mesial region (see Fig. 22.4), may suggest that some aspects of facial recognition such as a sense of familiarity may require the integrity of the left temporal-mesial region. This may represent a distinct network from the one involved with the recognition of facial expression, which may relate more specifically with the function of the right fusiform gyrus.

Prognostic impact of mood disorders Mortality is more frequent in stroke patients with initial depression (70%) than without (40%), even when signs of depression were no longer present at the time of death (Morris et al., 1993a). The suicide rate remains low; when present, its risk factors are insomnia and cognitive impairment (Kishi et al., 1996). The evolution may be dependent on stroke location and a better prognosis of depression was found following stroke in the posterior circulation (Starkstein et al., 1988). The presence of negative affective signs an aspect responding to treatment may lengthen hospital stay, (Galynker et al., 1997). Depression is associated with an increased risk of low responses on Activities of Daily Living (ADL) (Paolucci et al., 1998). Anxiety significantly reduces outcome of ADL and social functioning (Astrom et al., 1993), especially in interaction with depression (Shimoda & Robinson, 1998). The etiopathogeny of these findings may relate to observations that agents which block catecholamines in the central nervous system seem to delay recovery. The description and assessment of emotional and related behavioural changes in acute stroke is very poorly known, although they may be associated with specific prognostic correlates. The potential role of very acute, or ‘during stroke’, behavioural changes as markers for the ulterior development of mood disorder is the subject of an ongoing study (the Lausanne Emotion in Acute Stroke Study; Ghika-Schmid et al., 1996, 1999). Emotional reactions can be already present during the very first days following acute stroke and include a wide range of reactions, which include: overt sadness, passivity, aggressiveness, indifference, disinhibition, denial, adaptation and abnormal sleep or feeding pattern. These reactions can be quantified using a specifically designed scale, the Behavioural Index Form validated for its inter-examiner fidelity (see Fig. 22.4), and may be predictors of the later development of depression (Ghika-Schmid et al., 1997a, 1999). In a prospective study on 53 patients with strokes in the anterior (32) or posterior circulation (21) (17 right, 33 left, 3 bilateral), analysis suggests that acute behavioural

EMOTIONAL BEHAVIOUR INDEX A – overt sadness cries looks sad complains shouts whines B – passivity gives up isolated C – aggression tensed agitated angry rebellious oppositional aggressive revolted D – indifference indifferent neglected apathetic E – disinhibition jokes disinhibited laughs impatient F – denial minimized denial of all symptoms partial denial G – adaptation smiles socializes quiet makes sensible demands pudic interested looks serious sensitive to what happens helpful active collaboration expressive clean, self-attentive obeys H – abnormal sleep/feeding

Fig. 22.4. Emotional behaviour index.

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signs of denial may be regarded as markers of delayed poststroke depression and anxiety (Ghika-Schmid et al., 1999).

Conclusions Studies in patients with focal acute brain lesion, suggest that the left frontal anterior region, both dorso-lateral prefrontal cortex and white-matter, may be strategically important for depression (Bogousslavsky, 1993; Starkstein et al., 1990; Starkstein, 1998; Astrom et al., 1993). These findings could not always be replicated (Bogousslavsky, 1993; House et al., 1990), and some authors even deny any causal contribution of lesion location to depression (Burvill et al., 1996; Gainotti et al., 1997b). In secondary mania, lesion location was mainly in the right hemisphere (Bogousslavsky et al., 1998a; Starkstein, 1998; Cummings & Mendez, 1984), but a consensus is still lacking concerning a possible clinico-topographical correlation of disorders, such as apathy, anxiety, catastrophe reaction and pathological laughing and crying, sometimes encountered after stroke. Important methodological problems and difficulties in comparing the data certainly account for some of the discrepancies found in the literature. Psychiatric diagnosis has not always been made using standardized criteria (DSM-III-R or DSM-IV). The prevalence and correlation of mood disorders may change over time, and studies considering only the acute or chronic phase might not be accurate (Starkstein, 1998). The psychiatric assessment of aphasic patients remains problematic, although these patients may be evaluated through their behavioural changes, such as sleep and food intake (Ross & Rush, 1981). Their exclusion from studies may induce a bias. Studies including patients with previous stroke or multiple lesions may introduce confusing variables in trying to correlate clinical and topographic information (Starkstein et al., 1990; Starkstein, 1998). Also, the classification of stroke subtype and localization has been variable and often simplistic, leading to much difficulty in repeating studies. Further studies using precise templates of vascular involvement in large series of patients are still needed to clarify these points. The systematic study of mood change during and immediately after stroke, as assessed in the on-going Lausanne Emotion in Acute Stroke Study (Ghika-Schmid et al., 1996, 1999), remains poor. However, early thymic alterations may be useful markers of the late functional prognosis. Appropriately designed scales, such as the Behavioural Index Form, make it possible to quantify early emotional reactions (GhikaSchmid et al., 1996, 1999). Systematic studies on large

samples of patients may allow the delineation of acute emotional behaviour, which may be markers for the delayed occurrence of emotional disturbances. Studies in animals suggest that stress-induced biological modification of the hippocampal and hypothalmic responsiveness to glutamate may play a critical functional role (Bartanusz et al., 1995). In humans, a selective reduction in a serotonin metabolite (5HIAA) was found in the CSF of depressed, but not non-depressed, poststroke patients, supporting the hypothesis of a serotoninergic mechanism in poststroke depression (Bryer et al., 1992). Studies on the overall stroke population showed a higher level of glutamate and glycine in the plasma and CSF of patients with large cerebral infarcts, cortical infarcts and severe neurological deficit, supporting the concept of the excitotoxic activity of glycine and glutamate in these patients (Castillo et al., 1996). These findings suggest that neuroexcitatory amino acids may not only be a useful parameter to monitor the severity of stroke, but that measurement of other metabolites such as serotonin metabolites, might allow more selective measures of the differential biological response in patients prone to develop poststroke mood disorders. Further systematic studies, with careful monitoring of stroke and measurement of monoamine metabolites and neuroexcitatory amino acids, may give a better understanding of the biological mechanism underlining poststroke emotional disturbances. In conclusion, although most stroke studies on mood disorder agree on the critical role of the anterior LH in depression and the predominant role of the RH in manic syndromes, controversy exists concerning the exact clinical characterization of poststroke mood disorders in relation to the site of the lesion. Further studies are needed to determine the clinico-topographic correlation and to define predictors of handicap in connection with the different patterns of emotional behaviour.

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Agnosias, apraxias and callosal disconnection syndromes Patrik Vuilleumier Department of Neurology, University of California, Davis, USA

Introduction and definitions Lesions in primary sensory or motor cortices and pathways disrupt cerebral input or output functions, producing anesthesia, blindness, deafness, or paralysis. Most other brain areas are concerned with higher level processes that organize sensory input into meaningful perception and motor output into goal-directed action. Specialized streams of processing deal separately with different kind of information for different purposes (Fig. 23.1). For instance, visual cortical areas are divided into two major pathways: a ventral stream along occipito-temporal areas extracts object properties such as shapes or colour, allowing recognition and long-term memory of visual stimuli; whereas a dorsal stream along occipito-parietal areas encodes the spatial location, orientation, and motion of objects, subserving a variety of visuospatial capacities and visuomotor coordination. Besides, in right-handed subjects, the left hemisphere is usually dominant for linguistic and semantic functions, while the right hemisphere is dominant for spatial, attentional, and emotional behaviour. Focal damage to secondary and associative cortices, or to their connections in the white-matter and corpus callosum, cause specific behavioural and cognitive disorders, which have useful diagnostic value (Table 23.1), and often represent a major burden for patients and their relatives. Agnosias are disorders in the recognition of objects not due to an impairment of elementary sensory processes, memory, language, and other general intellectual functions, and can be specific for a modality (vision, audition, touch) and a class of stimuli (e.g. objects, faces, or words). Visual agnosias follow damage to ventral visual areas, whereas spatial and visuomotor disorders follow damage to dorsal areas. Apraxias are disturbances in skilled and purposeful movements not due to elementary motor, sensory, or extrapyramidal dysfunction, and can involve

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one or more effectors (limb, orofacial, or eye movements). In some cases, elementary sensory or motor defects may coexist with agnosia or apraxia but in themselves cannot account for the disorder. Callosal disconnection syndromes reflect impaired transmission of information from one hemisphere to the other, so that lateralized cortical functions fail to interact with operations carried out in the contralateral side. Disconnection can also occur between cortical areas within one hemisphere and contribute to agnosia, apraxia, as well as other cognitive disorders. This chapter focuses on clinical and anatomical correlates of these disorders. The underlying neurocognitive mechanisms are only briefly discussed.

Agnosias Visual agnosias Distinct capacities are mediated by the ventral visual pathways of the two hemispheres. Schematically, left-side processes are specialized for representing numerous local parts, critical for word recognition and reading; right-side processes are specialized for representing global configurations, critical for face recognition (Farah, 1990). Both of these capacities participate in the processing of other common objects. Depending on hemispheric side and topography, a lesion will impair visual recognition for different classes of stimuli unequally, and result in a specific combination of deficits (e.g. agnosia for faces but not words, with or without agnosia for objects, after a rightside lesion). Ischemic or hemorrhagic strokes in the distribution of the posterior cerebral arteries (PCA) are the most common causes of visual agnosia (Fig. 23.2). Transient agnosia can occur during migraine, or vasospam after vertebral angiography.

Agnosia, apraxia and disconnection

Shape and object agnosia Patients with visual agnosia fail to identify visually presented objects or pictures of objects (i.e. name, point to, describe, or pantomine their use). Knowledge about objects and recognition through other modalities are intact. Some patients may complain that their vision is ‘foggy’ or behave as if blind, but others deny their difficulties. Visual field defects are usually associated, typically in the upper quadrants, and careful ophthalmologic examination must exclude an impairment of elementary perception (e.g. acuity, brightness and contrast discrimination) in the spared fields. As first proposed by Lissauer (1890), it is useful to distinguish between apperceptive and associative agnosia, although the distinction may be both theoretically and clinically blurred (Grüsser & Landis, 1991) .

Apperceptive agnosia This is a failure to integrate elementary visual features into coherent shapes. Even though visual acuity can be normal, patients cannot match pairs of similar objects or shapes, and fail to copy drawings. They have particular difficulties in extracting forms from fragmented, incomplete, or overlapping figures (Fig. 23.3(a)–(c)). Judgments of length, size, orientation, or surface texture may be also impaired. These patients have large and bilateral strokes in the territory of the posterior cerebral arteries (occipital and parietooccipital branches), involving secondary visual areas in the lateral and inferomedial occipital lobes. This often occurs after a second stroke in a patient who has suffered a previous unilateral posterior stroke in the other hemisphere. Occlusion of the basilar artery (top of the basilar) and anoxia after cardiac arrest are also common causes. Many cases follow recovery from cortical blindness. CT scan occasionally fails to demonstrate extensive focal damage in patients with diffuse cortical laminar necrosis, or after carbon monoxide intoxication.

Associative agnosia This is a failure to retrieve the precise identity of objects, while the perception of shape and other constituents is relatively unimpaired. Patients can match pairs of similar objects or drawings, and copy them in a slavish manner, but remain unable to figure out what it is (Fig. 23.3(d )). As Teuber (1968) put it, the visual percept ‘has somehow been stripped of its meaning’. Some patients may be able to match different views of the same object, but matching two exemplars that are visually dissimilar or different objects from the same category is not possible. Recognition difficulties may occasionally be restricted to certain categories, e.g. worse for living things (fruits, animals) than for manufactured artifacts (tools, furniture). The lesions typically

Right hemisphere

S1 where V1

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Left hemisphere

when

why

A1 who

S1 how A1 what

which Fig. 23.1. Schematic illustration of specialized cortical streams that process specific attributes of sensory information in the right and left hemispheres. The occipital and inferior–medial temporal lobes subserve the recognition of visual stimuli (who it is, e.g. face agnosia; or what it is, e.g., object agnosia). The lateral and superior temporal lobe subserves auditory recognition (who, e.g. voices; what, e.g. object sounds and spoken words). The parietal lobes are involved in spatial perception and action onto stimuli (where it is, e.g. visual spatial agnosia for localization, orientation, or motion; how to use it, e.g. ideomotor apraxia). The frontal lobes are involved in higher cognitive and strategic processes, such as organizing and monitoring information and actions (when, e.g. confabulation and dyschronology; why, e.g. reasoning and self-attribution of actions). Finally, limbic structures, including the hippocampus, subserve the formation of episodic memories for unique entities and events (which). V1 ⫽ primary visual sensory cortex; A1 ⫽ primary auditory sensory cortex; S1 ⫽ primary somatosensory cortex.

involve the inferior and medial temporo-occipital areas in ventral visual pathways, in particular the fusiform and lingual gyri, vascularized by posterior temporal and anterior occipital branches from the posterior cerebral arteries. The fusiform and lateral aspects of the inferotemporal cortex appear critical, since bilateral destruction of the lingual gyri does not to cause a major recognition deficit but impairs colour perception and/or learning. Damage is most often bilateral, but unilateral cases have been reported, more often with left than right-side damage. Left-side cases are accompanied by pure alexia, while right-side cases are associated with prosopagnosia; it is considered to be exceptional, if not impossible, that agnosia for objects occurs without agnosia for words or faces. Agnosia after multifocal infarcts in the posterior circulation has been reported in patients with MELAS.

Optic aphasia This should be distinguished from associative agnosia, although some authors considered the distinction to be one of degree rather than kind. It is a modality-specific anomia: patients cannot name visually presented objects (often producing circumlocutions or gross semantic errors) but can recognize them, e.g. describe or pantomine

V1

Table 23.1. Summary of typical lesion sites in agnosia, apraxia, and callosal syndromes Lesion Vascular territory

Left-hemisphere

Right-hemisphere

Bilateral

Corpus callosum

PCA -leptomeningeal

R-hemianopia/ superior quadranopia Pure alexia

L-hemianopia/superior quadranopia

Cortical blindness

L-hemialexia

Prosopagnosia (apperceptive, associative)

Apperceptive object/shape agnosia Associative object agnosia

L-hemianomia (object/colour)

Associative object agnosia Optic aphasia R-hemiachromatopsia Colour anomia Colour agnosia Ventral simultanagnosia

L-hemiachromatopsia

-deep

Opticosensory alien hand (Ideomotor apraxia)

Topographical agnosia (perceptual, spatial, mnesic) Opticosensory alien hand (Constructional apraxia)

MCA -leptomeningeal (superior division)

Subangular alexia

Visual spatial agnosias

Finger agnosia/ Gerstmann syndrome

Agnosia for noncanonical views

(inferior division)

(Neglect dyslexia) R cortical astereognosia R tactile agnosia (R palpatory apraxia) Ideomotor apraxia Orofacial apraxia Associative–semantic auditory agnosia (Arrhythmia) Pure word deafness

-deep

Ideomotor apraxia Paradoxical L ear suppression (dichotic) Bilateral tactile anomia/ tactile aphasia

Agnosia for orientation Neglect dyslexia L cortical astereognosia L tactile agnosia (L palpatory apraxia) Constructional apraxia Dressing apraxia Apperceptive–acoustic auditory agnosia Amusia (amelodia) Receptive aprosodia Phonagnosia (Constructional apraxia)

Bilateral crossed optic ataxia

Central achromatopsia

Opticosensory alien hand? Dorsal simultanagnosia (Balint)

Akinetopsia

Cortical deafness Complete auditory agnosia and amusia Pure word deafness

Bilateral tactile alexia (Pure word deafness) ACA -callosomarginal/ frontopolar -pericallosal

R-hand grasping

L-hand grasping

R palpatory apraxia

L palpatory apraxia

Gait apraxia

Frontal alien hand

Callosal alien hand Impaired crossed touch localization Impaired bimanual coordination Impaired crossed replication of hand/finger postures Impaired crossed tactile matching L-hand non-ownership (‘alien hand sign’) Unilateral L tactile anomia Unilateral L tactile alexia L-hand tactile extinction (dichaptic) L ear suppression (dichotic) Unilateral L ideomotor apraxia Unilateral L agraphia (apraxic or aphasic) Unilateral R constructional apraxia

Notes: ACA, MCA, PCA = anterior / middle / posterior cerebral arteries; L = left: R = right; parentheses indicate deficits that are uncommon, and question marks indicate deficits that have been only rarely described.

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Fig. 23.2. Anatomical correlates of visual agnosias.

their use. Oral language is preserved, including naming through other modalities (although tactile naming is sometimes altered in the acute stage). Anomia for colour and alexia are usually associated (De Renzi et al., 1987). Whether precise and complete semantic knowledge can be accessed from all seen objects is still unknown, but patients with optic aphasia usually interact with objects in their

everyday surrounding much better than agnosic patients do. This rare disorder results from a disconnection between some form of visual semantic knowledge and verbal lexical knowledge. The lesion always involves the territory of the left PCA and encroaches upon interhemispheric callosal fibres in the splenium or the paracallosal white-matter. As a right hemianopia is usually present, all visual information

Agnosia, apraxia and disconnection

(a )

(e )

(b) (f )

(c )

(g )

(h )

(d )

(i ) Fig. 23.3. Examples of stimuli used to test for visual agnosia. Apperceptive agnosia impairs the extraction of shapes from fragmented contours, overlapping figures, or crossed-out masked stimuli ((a), (b), (c)). Associative agnosia impairs the semantic identification of objects whose shapes are correctly perceived and can even be copied (d ). Visual spatial disorders entail various difficulties in judging the spatial location (e) or orientation ( f ) of visual stimuli; patients fail to recognize objects seen in noncanonical orientation (g), or recognize objects but fail to judge their orientation (h). In dorsal simultanagnosia, only one object is perceived at a time but apperceptive mechanisms extracting and grouping their shape constituents are preserved (i ): although the patients detects only one of two or three unconnected shapes (either one of the round shapes or the bar, but not the two or three of them; left-side panel), he sees accurately all shapes when connected in a single object (asymmetrical eye glasses; right-side panel).

must be processed by the right hemisphere before transiting to the left hemisphere language areas. Preservation of dorsal visual pathways in apperceptive or associative agnosia may allow a better recognition of objects that move, as well as appropriate grasping (e.g. correct shaping of the hand and fingers) for unrecognized objects. Similarly, it has been suggested that the preserved evocation of sensorimotor representations in dorsal parietal areas might explain why some patients with agnosia or optic aphasia are better in recognizing and naming drawings that depict actions rather than static objects, or manual tools rather than other object categories.

selective loss in the ability to recognize faces, including previously known faces (relatives, celebrities) or newly seen faces (physician, hospital staff). Recognition of people using other cues (voice, gait, dressing) and knowledge about their identity or biography is intact. As for object agnosia, this takes two clinical forms (De Renzi et al., 1991).

Face agnosia

Associative prosopagnosia

Faces constitute special visual stimuli whose recognition relies on dedicated neural mechanisms. Prosopagnosia is a

This results either from a loss or a disconnection of stored representations of known faces (‘face recognition units’);

Apperceptive prosopagnosia This results from a deficit in the structural encoding of facial traits; patients are unable to discriminate between two different individuals or match two different pictures of the same individual, known or not.

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patients can match pairs of identical faces but fail to identify who the person is, provide any information about him/her, or even tell if he/she’s familiar or not. New faces cannot be learned. Recognition difficulties may be specific to faces or sometimes extend to other visual categories that are made of many perceptually similar exemplars, like flowers, dogs, glasses, famous buildings, or car makes. Stockfarmer patients unable to recognize their cows have been reported. Reading is normal in pure cases, but identification of familiar (or own) handwritings may be impaired. Achromatopsia or left hemianopia are often associated. Prosopagnosia is always caused by a lesion in the territory of the PCA. While the medial fusiform gyrus in both hemispheres is specifically involved in processing faces, unilateral damage to the right inferior temporo-occipital cortex appears both necessary and sufficient to cause prosopagnosia, particularly in the acute stage (De Renzi et al., 1994). According to some authors, bilateral damage might be more common in long-lasting cases (Damasio et al., 1982). In apperceptive prosopagnosia, the lesion is usually large and extends to the inferolateral temporo-occipital convexity; in associative prosopagnosia, the lesion is centered on the medial temporo-occipital region and tends to include the inferior longitudinal fasciculus. Many prosopagnosics are still able to discriminate gender, age, facial expression, and direction of gaze. Conversely, impaired recognition of expressions (prosopoaffective agnosia) follows damage to the temporal lobe, amygdala, thalamus, or orbitofrontal cortex. Impaired recognition of gaze direction may occur with lesions in the lateral temporal lobe, close to the posterior superior sulcus, or the amygdala. Misidentification syndromes comprise a group of delusional disorders initially described in psychiatric cases, but often associated with organic brain damage. Patients with Capgras syndrome believe that a familiar person is replaced by a disguised impostor, whereas patients with Frégoli syndrome believe that a known person disguises himself as others. Recognition of known faces is preserved, but subjective familiarity is altered, and memory and matching abilities for unfamiliar faces may be impaired. Unilateral right or bilateral temporal damage, as well as bifrontal lesions and diffuse cerebral atrophy have been implicated. A visuolimbic disconnection in the presence of intact ventral occipitotemporal pathways is postulated, whereby recognition of identity is preserved but not familiarity. Another unusual disorder with false familiarity for unknown faces without misidentification or delusion (face paragnosia) has been observed in a patient with a left temporo-occipital venous stroke (inferior anastomotic vein thrombosis).

Pure alexia Reading can be selectively lost due to impaired recognition of written words in the absence of other language disturbance, and in particular without writing disorder (alexia without agraphia, or pure word blindness). Although different subtypes may exist, there is no clear classification. Typically, patients can name individual letters, and read words letter by letter, being eventually able to utter a word correctly after spelling it (aloud or covertly). Hence, word-length rather than word-class (e.g. abstract vs. concrete, or regular vs. irregular) strongly affects error rate and reading time. A few visual errors in identyfing single letters (G → C, h → b) sometimes occur. Discriminating real words from non-word letter-strings is usually impaired. Reading is normal for words that are spelled orally by the examiner, or tactually written on their hand, indicating that lexical ‘word-form’ representations are preserved but not activated by visual inputs. Reading may be variably spared for arabic numbers (1998), iconic symbols ($, %, ideographic Kanji characters in Japanese), familiar acronyms (USA), or familiar proper names (people, cities), probably because these stimuli are still recognized as a whole through other ‘global’ perceptual processes. Inability to read a written text may contrast with the correct identification of a known person’s handwriting. Pure alexia is practically always caused by a lesion in the territory of the left PCA. While the lateral part of both fusiform gyri appears crucial for processing letter-strings, a lesion involving the left inferomedial temporo-occipital region together with the (ventroposterior) splenium of the corpus callosum is the most common (Damasio & Damasio, 1983) . Thus, pure alexia is usually accompanied by right hemianopia (or superior quadranopia), colour anomia, and/or optic aphasia. However, the minimal critical area of damage involves the paraventricular whitematter around the left occipital horn, including fibres from the inferior forceps major of the corpus callosum but sparing the splenium (Fig. 23.2). Visual fields can be intact if the left optic radiations are spared. In either case, such lesions disconnect the right occipital lobe from the left hemisphere, or interrupt both inter- as well as intrahemispheric transfer of visual inputs to word-form representations in more anterior temporo-occipital regions and to the angular gyrus of the left hemisphere (Benito-León et al., 1997; Verstichel & Cambier, 1997). An involvement of more anterior and dorsal parts of the splenium seems necessary to produce associated optic aphasia. Colour anomia is usually absent if the posterior temporo-occipital cortex is spared. Rarely, when there is no visual field defect, the lesion responsible for pure alexia may involve the left subangular

Agnosia, apraxia and disconnection

region in the posterior sylvian territory, undercutting association fibers in the vertical occipital fasciculus (Fig. 23.2). Some elements of Gerstmann syndrome may be then present (e.g. finger agnosia, right–left confusion). Damage to the left angular gyrus itself causes a different disorder, alexia with agraphia, that is, a defect of written language rather than visual recognition.

Neglect dyslexia This is a distinct disorder, common with left hemispatial neglect after right parietal damage, but also seen in isolation after unilateral right or left hemisphere lesions. It is characterized by omissions of the first left-side letters (in right hemisphere cases) or last right-sided letters (in left hemisphere cases) in the reading of words, which is typically worse for nonwords than real letter-strings. It reflects a disorder of visual attention rather than a problem of recognition or language.

lexical codes and object semantic representations, or from impaired mental imagery. Anatomical correlates are unclear, but lesions usually involve the inferior, more than the mesial, temporo-occipital cortex in the left hemisphere (Grüsser & Landis, 1991).

Colour anomia This is less uncommon, and consists of a selective inability to name seen colours that is not due to impaired colour perception. It is usually accompanied by optic aphasia or pure alexia, but can dissociate from them. It correlates with damage to the posterior mesial occipitotemporal region of the left hemisphere, centred on the lingual and posterior parahippocampal gyri, underneath the splenium of the corpus callosum. This results in a right hemianopia by concomitant damage to the optic radiations (or a right upper quadranopia plus a lower hemiachromatopsia) and prevents the transfer of all visual colour information to the left hemisphere’s language areas (Damasio & Damasio, 1983).

Colour agnosia Several disturbances of colour perception and colour recognition must be distinguished. Any of these can be associated with one of the above recognition disorders.

Central achromatopsia This is a selective loss in the perception of colours (colour blindness), affecting one quadrant, one hemifield, or both hemifields. Objects and shapes are recognized but perceived in shades of grey. Congenital (inherited) colour blindness should be ruled out. The lesion must involve areas specialized in colour processing in the posterior part of the lingual gyrus and collateral sulcus, in either hemisphere. Other perceptual defects also occur in the absence of complete achromatopsia, in particular in colour constancy (the ability to identify the same colour under different illuminations).

Colour agnosia This means a loss in the knowledge about colours that are associated with objects, while perception and discrimination of colours are preserved. This is manifest in visual, verbal, or visuoverbal association tasks (e.g. matching appropriate colours to line drawings of objects, indicating verbally the colour of common objects, or listing objects that have a given colour). Colour categorization may be impaired (e.g. sorting hues into groups of ‘related colours’) despite intact hue discrimination. Knowledge of abstract conceptual associations to colours (e.g. red–anger, green–youth) should be also tested. Naming of seen colours may be normal. Colour agnosia is a rare condition, resulting either from a disconnection between colour

Visual spatial disorders Various disorders of spatial perception are associated with damage to the dorsal visual pathways. Most of them are much less well characterized than ventral visual agnosias, both in neuropsychological and anatomical terms.

Simultanagnosia Dorsal (or competitive) simultanagnosia This is a rare condition that results from bilateral damage to the posterior parietal lobes and/or superior occipital lobes. In the former case, it is associated with optic ataxia (an inability to reach for, or point to, visual targets) and gaze apraxia (‘psychic paralysis of gaze’, an inability to direct voluntary eye movements to visual targets), this triad constituting Balint’s syndrome. Visual disorientation (inability to localize objects in space) is also a prominent feature. As the term coined by Wolpert (1924) suggests, the patient with simultanagnosia is unable to see more than one object at a time. He behaves like a blind person and often complains that objects disappear, or that he loses sight of them. Yet, acuity is normal and visual fields may be intact. He recognizes objects, pictures, or faces (unlike in visual agnosia), although in a piecemeal fashion. If two objects are shown, whatever their position, he perceives only one and fails to reach for it. Objects’ size does not matter. Perception of spatial relationships and depth is virtually abolished. The patient may detect only one of several overlapping figures (Fig. 23.3(b)), and remain unaware of others. Which visual stimuli reach awareness can be modulated by grouping factors, so that although only one of

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two unconnected shapes is perceived, the two same shapes are perceived if they form a single connected object (Fig. 23.3(i )). Likewise, real or familiar words can be read or spelled aloud, whereas non-word letter-strings yield greater difficulty because their letters cannot be grouped in a single known entity. The patient may also miscombine features from an unseen object to another that is reported (e.g. perceive a blue X when there is a red X and a blue O). Simultanagnosia is regarded as a bilateral disorder of spatial attention, that is, a form of bilateral neglect or extinction. Attention and fixation become locked on a single object, unable to shift to others in the field so as to afford conscious perception, and direct arm or eye movements to them. Lesions always involve the posterior and superior angular region, including the posterior intraparietal sulcus, and extending into the precuneus in the superior occipital lobe, in both hemispheres. A common cause is cardiac arrest or bypass cardiac surgery with severe hypotension, producing watershed infarction between the posterior and middle cerebral arteries. Sequential embolic infarcts in the distribution of the posterior parietal and angular branches of the middle cerebral artery (MCA) may have the same result. Acute Balint’s syndrome also occurs with venous thrombosis (posterior superior longitudinal sinus), MELAS, or reversible posterior leukoencephalopathy associated with eclampsia, malign hypertension, immunosuppressive therapies, or AIDS.

Ventral (or integrative) simultanagnosia This is even rarer, associated with left inferior temporooccipital damage and pure alexia. Patients perceive more than one object in their visual field but have difficulties in identifying and integrating multiple components into a meaningful whole. Hence words are spelled letter by letter, and pictures are described in a piecemal fashion (e.g. reporting wheels, pedals, and a face, without seeing the whole scene of a man standing beside his bike). There is no disturbance in reaching, gazing, or walking around obstacles.

Topographical (or environmental) agnosia An inability to recognize familiar places and find one’s way, not due to impaired general memory, visual loss, or neglect, may take several different forms: a perceptual type where previously familiar buildings and landmarks are not identified; a mnesic type where known places and layouts are not recognized; and a spatial type where familiar buildings and places are recognized but their location and relationship in space are not retained (Grüsser & Landis, 1991). Most often, lesions involve, respectively, the medial

temporo-occipital lobe and the parahippocampal gyrus in the right hemisphere (perceptual and mnesic type, often associated with prosopagnosia); the right posterior cingulate cortex (mnesic type); the right retrosplenial region and medial posterior parietal lobe (spatial type) (Takahashi et al., 1997). A particular form of transient topographical amnesia has been described, often in middle-aged women, somehow similar to transient global amnesia but with preserved recall; a vascular etiology is debated (Stracciari et al., 1994).

Visuospatial agnosia A heterogeneous collection of disturbances involves the perception of spatial location, orientation, layout, or size. These are assessed by tasks such as judging the relative positions of objects in space (e.g. single or multiple dots on cards), discriminating the relative orientation of straight lines, or mental rotation tasks (Fig. 23.3(e)–(h)). All correlate with right parieto-occipital damage (Fig. 23.4).

Agnosia for non-canonical views This is a failure to recognize objects presented under unsual viewpoints, though recognition is normal under a prototypical view. This might reflect a deficit in a perceptual categorization stage deriving a viewer-dependent representation of objects’ shapes, carried out in the right posterior hemisphere before being available for semantic identification in the left hemisphere. Hence, this is observed after right temporoparietal lesions or callosal disconnection by splenial damage (Grüsser & Landis, 1991).

Agnosia for object orientation This is a failure to recognize the correct orientation of known objects, with a striking inability to discriminate upright oriented objects from rotated, upside-down inverted, or mirror-inverted ones. Drawings are copied accurately but similarly rotated. Recognition of objects themselves is normal, whichever their orientation. This might result from mechanisms in ventral visual areas subserving viewer-independent recognition of objects without coding orientation information. Accordingly, such disorders occur after right inferior parietal and frontal strokes (Turnbull et al., 1996).

Akinetopsia Patients with selective motion blindness perceive only static stimuli, and fail to perceive visual motion; their vision is thus a succession of stroboscopic images. Complete loss of motion perception is exceptional, and follows bilateral damage to a motion-specific area in the

Agnosia, apraxia and disconnection

Fig. 23.4. Anatomical correlates of visual spatial disorders.

parieto-temporo-occipital fossa, just anterior to the lateral occipital gyrus. This has been reported after venous thrombosis of the occipital superior cerebral veins, or bilateral sequential hemorrhages in the parieto-temporo-occipital junction. Effects from unilateral damage are unclear, but a partial ipsidirectional impairment may occur.

Finger agnosia and Gerstmann syndrome This complex syndrome includes: (i) finger agnosia, (ii) right-left disorientation, (iii) acalculia, and (iv) agraphia. Finger agnosia refers to an inability to identify, name, individuate, or designate the individual fingers of both hands (and toes) not due to sensorimotor loss or aphasia. The presence of the four symptoms with concomittant absence of other disorder strongly correlates with lesions in, or adjacent to, the left angular gyrus. But each symptom may occur independently, or the four symptoms may occur together with other deficits such as aphasia, apraxia, or spatial disorders, in cases with various lesions elsewhere (e.g. left frontal, left thalamic, right parietal). In pure Gerstmann syndrome, a deficit in the mental manipulation of internal spatial representations (e.g. relative position of body parts) might underlie both finger agnosia and right–left confusion, and perhaps acalculia as well (Mayer et al., 1999).

Auditory agnosias As for vision, lesions may impair auditory recognition at different stages of processing and affect specific classes of sounds (objects, spoken words, voices, music) in isolation or combination, depending on the hemispheric side and site of damage. Schematically, the left hemisphere is specialized for analysing speech and other sequentially organized sounds, and attributes semantic meaning; the right hemisphere is better for non-verbal sound patterns and fine discriminations, and attributes emotional value. Auditory agnosia is rare. It is diagnosed in the absence of significant hearing loss as measured by standard audiometry. Tape-recorded material is required for a precise assessment of auditory capacities, but bedside testing may use common objects (e.g. crumpling paper, shaking a bunch of keys) or a walkman. The primary auditory cortex (Heschl’s gyrus) must be relatively spared at least on one side, with lesions variably involving the auditory association areas in the superior temporal gyrus and/or their connections from Heschl’s gyrus. Most often, damage is bilateral and results from sequential strokes in the sylvian territory (Fig. 23.5). An occlusion in the distribution of the inferior leptomeningeal division of the MCA (supplying

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Fig. 23.5. Anatomical correlates of auditory agnosias.

the temporal cortex and adjacent white-matter) or the deep perforating lenticulostriate branches (supplying the auditory radiations in the rentrolenticular part of the internal capsule) can both be seen. Subcortical hemorrhages in the posterior capsulo-lenticular region are also possible. Auditory agnosia sometimes follows an acute stage of cortical deafness, in which the function of the primary auditory cortex and/or its afferents in the auditory radiations are compromised on both sides. In the case of lefthemisphere damage, impaired auditory recognition of nonverbal sounds is most often accompanied by some degree of receptive aphasia.

Amusia

Sound agnosia

Pure word deafness

Impaired identification of non-verbal environmental sounds (telephone ringing, animals scream, car engine, etc.) is shown by naming or matching pictures to sounds. There are two types of deficit (Schnider et al., 1994). Patients with the apperceptive–acoustic type have difficulty in discriminating between pairs of meaningless sounds and make predominantly acoustic errors in identifying meaningul sounds (e.g. a cat meowing mistaken for ‘a crying baby’). This occurs with unilateral right temporal damage. Patients with the associative–semantic type perform normally in discrimination tasks, but make recognition errors with semantically related sound sources (e.g. plane takeoff mistaken for ‘a train’). This occurs with unilateral left temporal damage, usually associated with language and other associative-semantic disturbances (e.g. word–picture or picture–picture matching tasks).

This refers to a selective auditory agnosia for speech (auditory verbal agnosia) without other language disturbance. The patient fails to understand spoken words but can read, speak, and write relatively normally. He/she can often discriminate speech from other sounds but complains that it sounds muffled or foreign. Occasionally, he/she may be anosognosic and develop paranoid psychotic disturbances. Discrimination of phonemes is severely impaired. Typically, this follows recovery from a severe Wernicke’s aphasia. It is caused by a disconnection of Wernicke’s area, in the left posterior superior temporal gyrus, from all auditory inputs coming from both left and right primary auditory cortices. Two loci of damage are possible: (i) bilateral cortical and subcortical lesions involving the superior temporal gyrus in both hemispheres, but sparing Heschl’s gyrus; (ii) a single lesion in the dominant temporal lobe

Perception of music is impaired in most patients with auditory sound agnosia, but a disproportionate difficulty in recognizing melodies is referred to as sensory (or receptive) amusia. Involvement of the right or left superior temporal gyrus disrupts, respectively, the discrimination of melody contour and pitch (amelodia) or the discrimination of interval duration and rhythmic temporal grouping (arrhythmia). Individual differences in musical expertise and gender affect the degree of lateralization. Expressive amusia, or inability to sing, is not necessarily associated with receptive amusia.

Agnosia, apraxia and disconnection

Fig. 23.6. Anatomical correlates of tactile recognition disorders. Each can occur in either hemisphere, hence affect only the contralateral hand, except for tactile anomia which can be bilateral after unilateral left hemisphere damage.

involving the primary auditory cortex and/or the ipsilateral auditory radiations from the medial geniculate nucleus, together with callosal fibres from controlateral auditory areas.

Paralinguistic agnosia Receptive aprosodia (affective auditory agnosia) is a difficulty in understanding affective tone in people’s speech. Phonagnosia is a difficulty in identifying voices from known people. In both cases, there is no defect in understanding linguistic speech content. These disorders follow right hemisphere damage, in particular in the temporoparietal region homologous to Wernicke’s area.

Tactile agnosias Tactile recognition of objects can be disrupted in the absence of elementary sensory loss (e.g. touch, temperature, pain, vibration) and impaired manipulation. Astereognosia is common, resulting from impaired discrimination of haptic properties of objects (simple forms, size, texture, weight), and may be considered as an apperceptive disorder of tactile recognition. Deficits in twopoint discrimination and agraphesthesia are usually present. True tactile agnosia has been very rarely reported and studied. The diagnosis implies a specific failure to identify objects and complex shapes with preserved perception of haptic properties, metric length, and spatial localization, and may be considered as an associative dis-

order of tactile recognition. Such patients can eventually draw or match tactually the objects that are placed in their hand (out of sight). Tactile recognition disorders occur in the hand contralateral to a brain lesion on either side, but bilateral impairment has been often observed after extensive right hemisphere damage (i.e. left-hand anesthesia or astereognosia with right-hand tactile agnosia) for unclear reasons. Right or left hemisphere lesions might produce more frequently an apperceptive or associative disorder, respectively, as in audition and vision. These disorders are associated with strokes in the superficial territory of the MCA (anterior or posterior parietal branches), but uncommonly accompanied by conduction aphasia or ideomotor apraxia unlike elementary (‘pseudothalamic’) sensory defects (Fig. 23.6). As for the visual system, there might be two streams of somatosensory processing from the primary sensory cortex on, including a ventrolateral pathway concerned with shape and object identification and learning, and a dorsomedial pathway concerned with sensorimotor and spatial integration (Caselli, 1993). Prominent astereognosia and agraphesthesia typically follow lesions close to the hand area of the somatosensory cortex, in the middle postcentral gyrus, although complex sensory loss after subcortical or brainstem lemniscal lesions sometimes produces similar defects. Tactile agnosia implicates the ventrolateral somatosensory association areas, which extend from the parietal operculum, posterior insula, and retroinsular cortex, to the anterior and inferior parietal lobe. On the other hand, the

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Table 23.2. Examples of gestures to test ideomotor and orofacial apraxia Meaningless Meaningful transitive

Meaningful intransitive

Unimanual:

Bimanual:

Ideomotor apraxiaa Use a scissor Use a saw Use a hammer Use a screwdriver Comb one’s hair Brush teeth Eat with a spoon Drink with a glass Open a bottle Open a door with a key Cut bread Write with a pencil

Wave good-bye Hitchhike Military salute Come here Go away Silence, hush Scold, threaten Thumb one’s nose OK, all going well Be quiet Someone is crazy Cross oneself

Hand under chin Hand’s back on ear Fist on head Hand on shoulder Thumb to little finger

Double ring with fingers L- and R-hand’s back next to another L- and R-hand fingers next to another L-hand forefinger to R-hand middle finger Butterfly-shaped crossed hands

Orofacial apraxiab Blow out a match Suck on a straw Smoke a cigarette Kiss Lick one’s lip

Whistle Yawn Frown Wink Wrinkle forehead

Open mouth Stick out tongue Puff out cheeks Click tongue “Pa-ta-ka”

Notes: a Ideomotor apraxia may be also tested for the lower limbs with appropriate gestures (e.g. pedalling, shooting, stubbing a cigarette out, etc.). b Orofacial apraxia may be also tested for respiratory movements (e.g. sniff, cough, pant as if exhausted, clear throat as if embarassed, breathe in and out deeply, etc.).

dorsomedial somatosensory areas, including the superior parietal lobe and medially situated supplementary sensory area, are related to atypical loss of tactile recognition and localization with an impairment of skilful manipulative movements (palpatory apraxia); these areas are partly vascularized by the anterior cerebral artery (ACA).

Tactile anomia (or tactile aphasia) This must be distinguished from the preceding disorders, representing a modality-specific inability to name objects presented by touch, although these are correctly recognized (as shown by normal use, matching, or association abilities). A similar deficit has been reported selectively involving letter tactile reading (pure somesthetic alexia). These exceptional disorders are associated with subcortical lesions in the left inferior parietal lobe, placed so as to produce a somatosensory–verbal disconnection. Unilateral left tactile anomia is usually due to callosal disconnection (see below).

Apraxias Ideomotor apraxia Patients with ideomotor apraxia fail to execute purposeful, skilled or learned movements without this being due to elementary sensorimotor, extrapyramidal, or other cognitive disturbances. The disorder affects both the limbs contralateral and ipsilateral to a unilateral lesion which practically always involves the left hemisphere (in righthanded subjects). In patients with a right hemiparesis, it is best seen in the left hand (ipsilateral ‘sympathetic apraxia’). If possible, both sides of the body must be tested separately for pantomimes of meaningful transitive (pretending objects use), meaningful intransitive (symbolic signs), and meaningless, gestures (Table 23.2). Pantomimes should be examined on verbal command and imitation, as well as in response to visual, tactual, and visual–tactual presentation of objects. Apraxic errors include substitutions (e.g. hammering instead of

Agnosia, apraxia and disconnection

Fig. 23.7. Anatomical correlates and mechanisms of ideomotor apraxias; m1 ⫽ primary motor cortex; pm ⫽ premotor cortex and supplementary motor area; slf ⫽ superior longitudinal (arcuate) fasciculus; sof ⫽ superior occipito-frontal fasciculus; smg/apa ⫽ supramarginal gyrus and anterior parietal area; wa ⫽ Wernicke’s area.

combing), perseverations, incorrect spatial posturing of the limb, incorrect temporal sequencing, or body part used as an object (e.g. hammering with a clenched fist). Specific anatomical correlates for the different subtypes of gestures or errors are still imprecise, however. Both meaningful and nonsense movements are poorly performed after lefthemisphere damage with little improvement to imitation, but habitual actions like actual object use and intransitive gestures are often better than transitive and novel gestures. On the contrary, right hemisphere damage may sometimes impair the production of intransitive gestures and imitation of novel meaningless gestures, as well as actions in naturalistic settings (e.g. meal), probably because of spatial and attentional difficulties (Rothi & Heilman, 1997). Since Liepmann (1900), it has been assumed that the (left) hemisphere opposite to the preferred (right) hand is dominant for the organization of skilled motor activities (Rothi & Heilman, 1997). The parietal cortex holds action patterns (‘movement formula’ or ‘visuokinesthetic engrams’) that represent specific spatiotemporal parameters of skilled

movements, and areas in the left supramarginal gyrus appear particularly crucial for the selection and temporal sequencing of these patterns. Goal-directed gestures require these action patterns to be activated (e.g. by visual or auditory–verbal inputs) in left parietal areas and then transmitted to supplementary motor and premotor areas, which in turn control the primary motor cortex both ipsilaterally and (through callosal connections) contralaterally (Fig. 23.7). Ideomotor apraxia is therefore usually accompanied by aphasia of varying type, but the two disorders can dissociate. Broca’s and conduction aphasics may have more severe apraxia than Wernicke’s aphasics, even though their comprehension is much better. However, some righthanded subjects have bilateral representations of movement patterns, and show no apraxia after large unilateral lesions, while exceptional cases may have a right hemisphere dominance and show ‘crossed ideomotor apraxia’ after right-side damage. Left-handed subjects are more likely to have action patterns represented in their right

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hemisphere (independently of language functions) and may demonstrate apraxia after a right-side lesion with or without aphasia. Ideomotor apraxia follows a variety of lesions in the dominant hemisphere (Fig. 23.7). It is common after cortico-subcortical strokes in the superficial MCA territory, particularly with involvement of frontal branches (associated with Broca’s aphasia or aphemia and hemiparesis) or anterior parietal branches (associated with conduction aphasia and hemisensory loss). It is also common after deep lesions in the paraventricular or peristriatal whitematter, involving the superior longitudinal (arcuate) fasciculus (coursing adjacent to the insular and lenticular region) and/or the superior occipito-frontal fasciculus (adjacent and superior to the body of the lateral ventricle). Such lesions produce a disconnection of posterior language areas and visual associative areas of the parietal lobe from anterior premotor areas (Alexander et al., 1992). Ideomotor apraxia is rarely, if ever, caused by lesions confined to the basal ganglia (putamen, caudate, or globus pallidus), but a few cases were reported after thalamic hemorrhage or infarct in the distribution of the polar artery (involving the ventral anterior, ventral lateral, and reticular nuclei) or the posterior choroidal artery (involving the pulvinar), together with mild language disturbances (Pramstaller & Marsden, 1996). It has been suggested that apraxic patients with parietal lesions fail to recognize gestures performed by the examiner (‘pantomime agnosia’) due to the loss of stored action patterns, whereas apraxic patients with frontal or subcortical lesions show intact recognition of correct gestures.

Apraxic agraphia This is characterized by a specific impairment in writing with preseved sensorimotor function, spelling, and typing, most often associated with but dissociable from ideomotor apraxia; it follows parietal lesions superior to the angular gyrus or lesions in the middle frontal gyrus, superior to Broca’s area (Exner’s area).

without ideomotor apraxia, is caused by contralateral damage to the anterior bank of the intraparietal sulcus.

Ideational apraxia This is uncommon and ill-defined, characterized by impaired knowledge of object use (‘conceptual apraxia’ or ‘agnosia of usage’) or impaired execution of correct steps in familiar actions (e.g. put a letter in an envelope to send, prepare a cup of tea). This has been reported, respectively, after focal lesions in the left temporoparietal region, or bifrontal damage and confusional states.

Orofacial apraxia Orofacial apraxia This is an impairment in skilled purposive execution of bucco-lingual and facial movements. As for limb apraxia, testing should assess meaningful, transitive and nontransitive, and meaningless movements involving the lips, tongue, face, or eyelids (Table 23.2). Automatic–voluntary dissociation is common (e.g. failing to mimic a kiss but succeeding when the hand is brought close to the mouth). Ideomotor limb and orofacial apraxia occur together in only a third of cases. Orofacial apraxia is typically associated with nonfluent aphasia and almost constant in Broca’s aphasics, but dissociations have been reported. Lesions involve the frontal and central opercular cortex, the anterior insula, or the anterior paraventricular whitematter (Alexander et al., 1992). Orofacial apraxia must be distinguished from Foix–Chavany–Marie syndrome due to bilateral anterior opercular damage, where all voluntary orofacial movements are impaired but automatic movements are preserved.

Speech apraxia This is a distinct linguistic disorder, similar to anarthria, in which the articulation and sequencing of phonemes is impaired.

Constructional apraxia Melokinetic apraxia This is a unilateral difficulty in making fine finger movements (e.g. pick up a coin, buttoning up a shirt), often disregarded as a ‘true’ apraxia and probably related to impaired sequencing of elementary motor segments. It may be seen with lesions in the supplementary motor and somatosensory areas, premotor cortex, basal ganglia, or superior parietal lobe (afferent kinesthetic apraxia, associated with sensory disturbances and pseudodystonic– ataxic components). A selective defect in the adjustement of hand and fingers posture during object grasping, with or

An inability to execute or copy simple drawings (cube, clock, house), or to arrange elements (blocks or sticks) in an appropriate spatial relationship, is a very sensitive sign of brain damage but relatively non-specific. It implicates a number of basic skills, including visual and spatial perception, visuomotor integration and coordination, motor manual skills, and monitoring responses. Therefore, it can result from a variety of lesions, and often indicates coexistent general intellectual deterioration. However, when present as a prominent disturbance, constructional apraxia strongly correlates with damage to

Agnosia, apraxia and disconnection

the right hemisphere, in particular in the superior and posterior parietal lobe (Villa et al., 1986). It also occurs with right-side subcortical and thalamic damage (anterior nuclei supplied by the polar artery). Deficits in visuospatial perception or hemispatial neglect can be associated but are not sufficient to account for the constructive disorder. Typically, drawings show a lack of global structure, piecemeal approach, or rotated orientation, and do not improve with a model or landmarks. Constructional apraxia is also found in patients with left parietal damage and aphasia, usually correlated more with visuoperceptive difficulties than ideomotor apraxia, but present in all reported cases with apraxic agraphia. Typically, drawings show a preserved global structure but are oversimplified, and often better with a model or landmarks. Finally, constructional performance may be impaired after frontal lesions due to defective planning, but typically improve to normal when sequential steps are provided by a model.

Other apraxic disorders Dressing apraxia This is an inability to dress not due to sensorimotor loss or impaired recognition of garments, usually related to neglect, visuospatial, or visuomotor disorders.

Gait apraxia This is a difficulty to initiate and maintain the automatic sequences of walking, seen with diffuse damage to frontal white-matter and corticostriatal connections, common in vascular dementia.

Callosal disconnection syndromes Callosal fibres connect homologous cortical areas, allowing interhemispheric transfer of information, as well as integrative and reciprocal inhibitory influences that determine coherent behaviour. Callosal disconnection signs result from an interruption of these fibres by damage either directly to the corpus callosum, or to the paracallosal white matter. As noted in previous sections, a loss of interhemispheric transfer plays a critical role in several agnosic and apraxic disorders after lateralized hemispheric lesions that compromise callosal fibers (e.g. pure alexia, optic aphasia, color anomia, pure word deafness, ideomotor apraxia). Strokes involving the corpus callosum are not uncommon, but the large majority are associated with extracallosal lesions in the distribution of the ACA or the PCA. Only rarely, damage is confined to the corpus callosum due to embolic occlusion of the pericallosal and/or callosomarginal branches of the ACA, or the splenial branches of the PCA.

Callosal damage is common after a ruptured aneurysm of the anterior communicating artery (secondary vasospasm), or bleeding from an arteriovenous malformation fed by pericallosal or splenial arteries. Small, multiple, lacunar infarcts limited to the corpus callosum or associated with hemispheric subcortical lacunes have been described, attributed to small vessel disease (Giroud & Dumas, 1995). Callosal infarction without injury to the adjacent hemispheres has been observed with bilateral occlusion of the internal carotid arteries (Kumral et al., 1995). More commonly, interhemispheric fibres may be undercut by watershed infarction in the deep white-matter between the anterior and sylvian circulation. Chronic hypoperfusion from severe carotid stenosis or occlusion also results in a progressive atrophy of white-matter fibers in the corpus callosum, the neuropsychological consequences of which are still unknown. Also, acute presentation with disconnection signs due to callosal necrosis and demyelinisation is encountered in Miarchafava–Bignami disease.

Posterior disconnection and ‘split-brain’ syndromes Each hemisphere has specialized processing capacities, and controls only contralateral sensory inputs (visual, tactile, etc.) and contralateral distal limb movements. The left hemisphere has a well-known dominance for linguistic functions, and usually for motor praxis as well. The right hemisphere possesses only a moderate capacity for the comprehension of auditory and visual verbal material, and practically no capacity to produce oral or written language, but is dominant for a number of visuospatial and visuocontructive abilities. Clinical callosal signs reflect the lack of communication between areas in the right hemisphere that can see, hear, touch, or move the left hand, and areas in the left hemisphere that can speak or write. Signs that can be assessed at the bedside will be described below, but some deficits may require special procedures to be demonstrated, such as rapid (tachistoscopic) presentation to each visual hemifield. Most disconnection deficits follow lesions of the posterior half of the corpus callosum, i.e. the trunk (vascularized by the ACA) and the splenium (vascularized by the PCA). Various combinations are found depending on the extent and location of damage (Fig. 23.8), although precise anatomical-clinical correlations remain incompletely settled. Individual differences in cerebral lateralization may exist in both right- and left-handed subjects, and modulate the occurence of these deficits.

Splenial split signs Loss of interhemispheric visual transfer follows spenial lesions. Left visual hemianomia, an inability to name or

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Fig. 23.8. Anatomical correlates of callosal disconnection syndromes.

verbally describe stimuli presented in the left hemifield (pictures, colours, faces), correlates with the most posterior and dorsal damage. Normal perception of stimuli by the right hemisphere can be demonstrated by the ability to point to a corresponding picture, match a tactually presented object, or draw them with the left hand (but not with the right). Left hemialexia, an inability to read words in the left visual field with normal reading in the right field, correlates with more ventroposterior damage; the ability to copy letters with the left hand may be preserved. Matching of pairs of stimuli presented across hemifields is always impaired. Bilateral crossed visuomotor ataxia refers to an inability to reach for objects in the left visual hemifield with the right arm, which is controlled by the opposite hemisphere, and vice versa. When left occipital damage and right hemianopia are associated to splenial damage (PCA

infarction), the presentation is that of pure alexia, optic aphasia, and/or colour anomia.

Posterior trunk split signs Loss of auditory transfer correlates with damage to the posterior trunk or isthmus. It is demonstrated by an extinction of auditory-verbal stimuli presented to the left ear in dichotic listening (left ear suppression), even though ipsilateral auditory pathways can mediate normal reception of left-sided material in the absence of right-sided competitors. Note that paradoxical left ear extinction occurs with unilateral lesions in the deep white-matter of the left hemisphere, which interrupt fibers crossing the callosum; bilateral ideomotor apraxia and right hemisensory defect are then often associated. Loss of tactile transfer follows damage to the posterior

Agnosia, apraxia and disconnection

half of the trunk and causes unilateral left tactile anomia, an inability to name objects palpated with the left hand (blindfolded). The right hemisphere can none the less recognize the objects, as shown by correct manipulation, pointing, or matching abilities. In unilateral left tactile alexia, naming of letters drawn upon skin is impaired, but perception of the letter shapes is preserved in same/different judgements on successive stimulations (unlike in agraphesthesia). Touched left-hand fingers can be moved but not named. Tactual extinction of objects held in the left hand may arise with bilateral simultaneous palpation, suggesting a role of attentional factors. Loss of somatosensory transfer also disrupts crossed tactile matching of objects, crossed replication of hand or finger posture, and crossed point localization (fingers tips) in both directions (right-toleft, and vice versa). A failure to recognize one’s own hand (vs. the examiner’s) when held by the other hand (with eyes closed or behind one’s back) was termed alien hand sign (not to confound with the alien hand syndrome described below) by Brion and Jedynak (1975).

Left unilateral agraphia This is an inability to write orthographically correct words with the left hand, and may result from different disconnection defects. In unilateral left aphasic agraphia, individual letters are well formed but incorrect. Writing with anagram block letters and typing are similarly impaired, suggesting impaired transfer of linguistic spelling information from the left to the right hemisphere (i.e. probably disconnecting the two angular gyri). Lesions involve the isthmus and anterior splenium. In unilateral left apraxic agraphia, letters are replaced by illegible scrawls. Writing with anagram block letters and typing are preserved, suggesting impaired transfer of graphomotor patterns but not spelling information (i.e. probably disconnecting superior parietal areas). Lesions are more anterior, in the posterior end of the trunk. Unilateral apraxic agraphia and left ideomotor apraxia may occur independently.

damage to the genu (unilateral ‘disassociation apraxia’). Unilateral ideational-conceptual apraxia of the left hand may or may not be associated.

Unilateral constructional apraxia Unilateral constructional apraxia of the right hand is also observed with posterior trunk damage, reflecting a disconnection of the left motor cortex from visuospatial competences of the right hemisphere. Drawing, copying, or stick construction are possible only with the left hand. Finally, a loss of sensorimotor transfer disrupts bimanual coordination (e.g. synchronous or alternating tapping, clapping hands, bimanual tasks) and voluntary control of the left hand. The latter disturbances are described below.

Anterior disconnection and ‘alien hand’ (AH) syndromes The function of the anterior half of the corpus callosum is still unknown, but presumably involves organizing coherent motor contol, decision making, and strategic memory retrieval processes. Usually, damage to the anterior trunk and genu produces no apparent clinical sign. In some cases, problems in response initiation and left ‘dissociation apraxia’ were attributed to genu lesions. Gait disorders with wide base, shuffling, and astasia–abasia have been reported following acute infarction limited to the anterior callosum (Giroud & Dumas, 1995; Kumral et al., 1995), but could result from associated bifrontal dysfunction or diaschisis. Albeit rare, the alien-hand syndrome(s) constitute(s) the most common disturbance ascribed to anterior callosal lesions. The term refers to a variety of abnormal motor behavior and action of one’s hand dissociated from conscious volition, not due to an extrapyramidal movement disorder. There is a considerable confusion about the terminology, symptomatology, and anatomy of this syndrome. It seems that the following distinctions should be made (Feinberg et al., 1992).

Left unilateral ideomotor apraxia This usually follows a lesion centered on the mid-posterior callosal trunk, anterior to those producing left agraphia, which disconnects the right motor cortex from language and praxic networks of the left hemisphere. It is typically associated with a right crural paresis after ACA infarction. Left limb apraxia is most severe to verbal command, and does not improve to imitation after callosal trunk damage (except in patients with bilateral representation of motor action patterns). A severe inability to produce left hand movement on verbal command (including writing and typing) with normal performance on imitation may follow

Motor AH syndromes ‘Pure’ callosal AH syndrome occurs with focal damage to the midtrunk (especially its ventral part), just anterior to that associated with unilateral ideomotor apraxia (Geschwind et al., 1995; Tanaka et al., 1996). Hence, the latter was present in most reported cases. There is no extracallosal damage and no elementary sensorimotor loss. The characteristic features best correspond to those of a ‘wayward hand’: (i) The left hand makes unintended movements during actions performed with the right hand; these can be antagonistic to the right (intermanual conflict, e.g.

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unfolding a letter put in an envelope by the right hand), irrelevant but non-antagonistic (e.g. slapping on the table while drawing with the right), or mirror-symmetric (e.g. reaching simultaneously for the same target and colliding with the right). (ii) The left hand does not make the intended movements; this can be a failure to initiate a willed action (e.g. trying hard to grasp a given object), a failure to interrupt a current action (e.g. letting go of an object held in the hand), or another movement being executed instead, inconsistent with verbally stated purposes (e.g. drawing circles instead of a line). The combination of intermanual conflict and inconsistencies with overt intentions has been referred to as diagonistic dyspraxia. The left (non-dominant) hand is seemingly always involved. Abnormal movements of the left leg and whole-body have been occasionally described. Typically, the patient is aware of and concerned by his problems, verbally commenting and reproving the abnormal hand’s behavior, and often talking to it so as to guide it. There is a loss of intentional motor control and separate programming of the left limb. Spontaneous actions appear semi-purposeful, targeted towards objects, and triggered by the evocation of a motor action schema (perhaps generated in both parietal areas), especially when a volitional act is intended with the right hand. The lateral motor cortex on each side is under dual control from posterior parietal areas (providing external environmental cues to action) and the supplementary motor area (SMA) in the medial frontal lobe (providing internal sources of selection to action), and transcallosal inhibitory influences (possibly between SMAs) may be required to select and coordinate the appropriate limb movements so as to execute coherent actions. Alien hand behaviour might reflect a loss of transcallosal inhibition of superior parietal areas and/or premotor areas in the non-dominant (right) hemisphere, normally exerted by homologous regions in the opposite (left) hemisphere which is dominant for motor activities. The right-side premotor–motor system controlling the left hand, deprived of contralateral signals from the dominant side due to interhemispheric disconnection, might then function in an autonomous responsive mode, alien to the patient’s will. The disorder is usually transient and recovers after a few months, but ill-defined complaints about left hand use may persist for years. ‘Frontal’ AH syndrome occurs with larger lesions that encompass the anterior callosum as well as the medial frontal lobe, on one or both sides (Goldberg et al., 1981). It is best characterized as an ‘anarchic hand’ with (i) forced grasping of objects, (ii) impulsive reaching and groping movements towards objects in near sight, and (iii) occasional compulsory manipulation of tools, i.e. unilateral

involuntary handling and utilization of objects within reach. This abnormal motor behavior manifests as reflexive, stereotyped, and often perseverative movements triggered by nearby stimuli through vision or touch, with little evidence of purpose or adequacy towards the target objects. The alien hand’s action cannot be refrained by will, but restraining manoeuvres using the opposite hand are common. Although this has been more often reported in the right (dominant) hand, either hand can be affected contralaterally to the damaged hemisphere, and bilateral cases have been reported after bilateral lesions. Paradoxically, unilateral limb motor neglect (hemiakinesia) may coexist, in particular in the acute stage and after right hemisphere damage. This might initially suppress the alien hand disorder which becomes apparent only later when hypokinesia is decreasing, and explains the rarer occurence in the left (non-dominant) hand. Usually the frontal alien hand slowly abates during the 6–12 months postonset, but recovery depends on the size of extracallosal brain damage. Leg weakness, transcortical aphasia, mutism, apathia, and incontinence are other common associated symptoms indicating medial frontal dysfunction. The frontal alien hand syndrome probably results from a unilateral release of elementary, reflexive exploratory motor behavior. The relative role of callosal disconnection and medial frontal lesions is unclear. Grasping correlates with lesions relatively confined to the contralateral SMA for some investigators and involvement of the anterior cingulate gyrus for others, whereas groping and compulsive manipulation of tools both have been found to be associated with extensive lesions of the anterior cingulate gyrus adjoining the callosal genu (De Renzi & Barbieri, 1992; Hashimoto & Tanaka, 1998). Patients with damage confined to the corpus callosum do not exhibit grasping or groping. However, alien hand seems not to occur after medial frontal damage without coexisting anterior callosal damage. Destruction of medial premotor areas (SMA) combined with anterior callosal disconnection might release the primary motor cortex simultaneously from ipsilateral and contralateral inhibitory control, resulting in an abnormal externally driven activation of manual exploration and prehension motor patterns. Possibly, a mixed ‘frontocallosal’ AH syndrome may occur with more extensive lesions in the ACA territory. Rarely, involuntary grasping and alien hand phenomena have been also observed after subcortical lesions involving the striatum and anterior limb of the internal capsule without cortical or callosal damage, suggesting a participation of these structures in the control of voluntary actions, consistent with their connections with medial premotor areas (Pageot et al., 1997).

Agnosia, apraxia and disconnection

Sensory alien hand syndromes Unintentional and uncontrollable movements of the upper limb opposite to a unilateral brain lesion occur in patients who show a complex combination of disturbances in proprioceptive sensation (sensory ataxia) and visuomotor coordination (optic ataxia), constituting an ‘opticosensory’ alien hand syndrome. This was reported after large posterior infarcts or hemorrhages involving the right thalamus (ventroposterolateral and ventrolateral nuclei) and subthalamic region, and/or the posterior parietal lobes (Levine & Rinn, 1986; Ventura et al., 1995). Callosal damage (splenium) may be associated with infarction in the territory of the PCA but does not seem obligatory, as it was absent in a few cases with isolated thalamic or parietal lesion. Spontaneous motor activities are non-goaloriented but often self-directed, and include scratching, hitting, choking, as well as drifting, catatonia, synkinesis, and exaggerated automatisms. These movements are subjectively perceived by the patient as autonomous and out of control, commonly attributed to someone else’s action. Feeling of foreigness or non-ownership of the affected limb (asomatognosia), hemispatial neglect, or anosognosia are associated. There is no grasping or groping. A dystonic or myoclonic component has been described with thalamic–subthalamic injury.

iAckowledgementsi Illustration work realized thanks to S. Schwartz. Supported by grant 81–GE-50080 from the Swiss National Science Foundation.

iReferencesi Alexander, M.P., Baker, E., Naeser, M.A., Kaplan, E. & Palumbo, C. (1992). Neuropsychological and neuroanatomical dimensions of ideomotor apraxia. Brain, 115, 87–107. Benito-León, J., Sánchez-Suárez, C. & Díaz-Guzmán, J. (1997). Pure alexia could not be a disconnection syndrome. Neurology, 49, 305–6. Brion, S. & Jedynak, C.P. (1975). Les Troubles du Transfert Interhimisphirique. Paris: Masson. Caselli, R.J. (1993). Ventrolateral and dorsomedial somatosensory association cortex damage produces distinct somesthetic syndromes in humans. Neurology, 43, 762–71. Damasio, A.R. & Damasio, H. (1983). The anatomic basis of pure alexia. Neurology, 33, 1573–83. Damasio. A.R., Damasio, H. & Van Hoesen, G.W. (1982).

Prosopagnosia: anatomic basis and behavioral mechanisms. Neurology, 32, 331–41. De Renzi, E., & Barbieri, C. (1992). The incidence of the grasp reflex following hemispheric lesion and its relation to frontal damage. Brain, 115, 293–313. De Renzi, E., Faglioni, P., Grossi, D. & Nicelli, P. (1991). Associative and apperceptive forms of prosopagnosia. Cortex, 27, 213–21. De Renzi, E., Perani, D., Carlesimo, G.A., Silveri, M.C. & Fazio, F. (1994). Prosopagnosia can be associated with damage confined to the right hemisphere – An MRI and PET study and a review of the literature. Neuropsychologia, 32, 893–902. De Renzi, E., Zambolin, A. & Crisi, G. (1987). The pattern of neuropsychological impairment associated with left posterior cerebral artery infarcts. Brain, 110, 1099–116. Farah, M.J. (1990). Visual Agnosias: Disorders of Object Recognition and What They Tell Us About Normal Vision. Cambridge: MIT Press. Feinberg, T.E., Schindler, R.J., Gilson Flanagan, N. & Haber, L.D. (1992). Two alien hand syndromes. Neurology, 42, 19–24. Geschwind, D.H., Iacoboni, M., Mega, M.S., Zaidel, D.W., Cloughesy, T. & Zaidel, E. (1995). Alien hand syndrome: interhemispheric motor disconnection due to a lesion in the midbody of the corpus callosum. Neurology, 45, 802–8. Giroud, M. & Dumas, R. (1995). Clinical and topographical range of callosal infarction: a clinical and radiological correlation study. Journal of Neurology, Neurosurgery, and Psychiatry, 59, 238–42. Goldberg, G., Mayer, N.H. & Toglia, J.U. (1981). Medial frontal cortex infarction and the alien hand sign. Archives of Neurology, 38, 683–6. Grüsser, O.J. & Landis, T. (1991). Visual Agnosia and Other Disturbances of Visual Perception and Cognition, Vol. 12, ed. J. R. Cronly-Dillon. London: MacMillan. Hashimoto, R. & Tanaka, Y. (1998). Contribution of the supplementary motor area and anterior cingulate gyrus to pathological grasping phenomena. European Neurology, 40(3), 151–8. Kumral, E., Kocaer, T., Sagduyu, A. et al. (1995). Infarctus calleux après occlusion bilatérale des artères carotides internes avec syndrome d’héminégligence et astasie–abasie. Revue Neurologique, 151, 202–5. Levine, D.N. & Rinn, W.E. (1986). Opticosensory ataxia and alien hand syndrome after posterior cerebral artery territory infarction. Journal of Neurology, Neurosurgery and Psychiatry, 36, 1094–7. Liepmann, H. (1900). Das Krankheitsbild der Apraxie. Monatsschrift für Psychiatrie und Neurologie, 8, 15–44. Lissauer, H. (1890). Ein Fall von Seelenblindheit nebst einem Beitrage zur Theorie derselben. Archiv Psychiatrie und Nervenkrankenheiten, 21, 222–70. Mayer, E., Martory, M.D., Pegna, A.J., Landis, T., Delavelle, J. & Annoni, J.M. (1999). A pure Gerstmann syndrome. Brain, 122, 1107–20. Pageot, N., Nighoghossian, N., Derex, L., Bascoulergue, Y. & Trouillas, P. (1997). Activité motrice involontaire ou ‘alien hand syndrome’ à l’issue d’une lésion ischémique respectant le cortex frontal médian. Revue Neurologique, 153, 339–43.

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Pramstaller, P.P. & Marsden, C.D. (1996). The basal ganglia and apraxia. Brain, 119, 319–38. Rothi, L.J.G. & Heilman, K.M. (1997). Apraxia: The Neuropsychology of Action. Hove, UK: Psychology Press. Schnider, A., Benson, D.F., Alexander, D.L. & Schnider-Klaus, A. (1994). Non-verbal environmental sound recognition after unilateral hemispheric stroke. Brain, 117, 281–7. Stracciari, A., Lorusso, S. & Pazzaglia, P. (1994). Transient topographical amnesia. Journal of Neurology, Neurosurgery, and Psychiatry, 57, 1423–5. Takahashi, N., Kawamura, M., Shiota, J., Kasahata, N. & Hirayama, K. (1997). Pure topographic disorientation due to right retrosplenial lesion. Neurology, 49, 464–9. Tanaka, Y., Yoshida, A., Kawahata, N., Hashimoto, R. & Obayashi, T. (1996). Diagonistic dyspraxia: clinical characteristics, responsible lesion and possible underlying mechanism. Brain, 119, 859–73. Teuber, H.L. (1968). Alteration of perception and memory in man.

In Analysis of Behavioural Change, ed. L. Weiskrantz. New York: Harper and Row. Turnbull, O.H., Beschin, N. & Della Salla, S. (1996). Agnosia for object recognition: implication for theories of object recognition. Neuropsychologia, 35, 153–63. Ventura, M.G., Goldman, S. & Hildebrand, J. (1995). Alien hand syndrome without a corpus callosum lesion. Journal of Neurology, Neurosurgery and Psychiatry, 58, 735–7. Verstichel, P. & Cambier, J. (1997). Letter-by-letter alexia after left hemispheral lesion without hemianopsia nor callosal involvement: 2 cases. Revue Neurologique, 153, 561–8. Villa, G., Gainotti,G. & De Bonis, C. (1986). Constructive disabilities in focal brain-damaged patients: influence of hemispheric side, locus of lesion and coexistent mental deterioration. Neuropsychologia, 24, 497–510. Wolpert, I. (1924). Die Simultanagnosie-Stvrung der Gesamtauffassung. Zeitschrift für Gesamte Neurologische und Psychiatrie, 93, 397–415.

24

Muscle, peripheral nerve and autonomic changes Thierry Kuntzer1 and Bernard Waeber2 Service de Neurologie and Division of Clinical Pathophysiology, Lausanne, Switzerland

1

Introduction This chapter discusses the diseases of muscle and peripheral nerve that are associated with cerebrovascular events. The peripheral nervous system, defined anatomically by neural structures enveloped by a Schwann cell plasma membrane, includes cranial nerves III to XII, the spinal roots, the nerve trunks, the dorsal roots, the autonomic centers, ganglia and their nerves. Involvement of muscle or peripheral nerve or autonomic system associated with cerebrovascular events, designated herein as multiple neurological complications (MNCs), may occur with varying frequency and pattern and may be seen as primary or secondary (Table 24.1). Early diagnosis of primary MNCs can give valuable information about a patient’s causal disease, a vasculitis, for example, cardiomyopathy or mitochondrial changes in both muscles and central nervous system (CNS) cells. Secondary MNCs may induce increased mortality and morbidity rates of stroke. The large variety of presentations of these disorders means that the MNCs represent a potentially frequent problem in neurologic practice. The full characterization of MNCs, however, needs investigations, including radiological, immunological, biochemical and genetic analyses, as well as electrophysiologic and autonomic function tests coupled with muscle or nerve biopsies.

Primary changes Primary MNCs can result from vascular and cardiogenic embolisms, dissection of large vessels, primary and secondary vasculitis and mitochondrial cytopathies (Table 24.1). Prognosis will be determined by, and therapy tailored to, each specific cause.

Vascular and cardiogenic embolism Simultaneous or delayed involvement of the neuromuscular system and the CNS in embolism has received little attention except in infective endocarditis (IE) where neuropathy is known to be a possible initial complication of the disease. The signs and symptoms are extremely variable owing to the diversity of the etiologic agents and of the various organs involved (Francioli, 1997). Patients may have fever or be afebrile, may or may not have evidence of pre-existing heart disease, may have a very acute or rather chronic course. Fever with a murmur is the most frequent clinical presentation. More than one-half of patients will have some degree of congestive heart failure. Distant complications such as major emboli, lumbar pain, or rupture of a mycotic aneurysm may be the first presenting manifestations of IE. The reported overall incidence of CNS complications of IE varies between 20% and 40%. Stroke is the most common presentation and accounts for one-half to two-thirds of the neurologic manifestations. The majority of these cases are due to cerebral emboli with infarction, but some are also due to intracerebral hemorrhage. Meningitis, either septic or aseptic, decreased level of consciousness, seizures, headache, psychiatric abnormalities, spinal cord involvement, in relation to ischemic lesions or secondary to extramedullary compression by metastatic abscesses can be observed. Peripheral nerve and muscle involvement, as a result of embolism may account for cases of mononeuropathy or localized pain (Pamphlett & Walsh, 1989). The nerves and muscles may be involved as an ischemic monomelic neuropathy, that refers to an infarction of the distal-extremity nerve tissues in which the extent of the abnormality varies with the location of occlusion (Wilbourn & Levin, 1993), or as a cholesterol emboli neuropathy that may resemble polyarteritis nodosa

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Table 24.1. Primary and secondary neuromuscular and autonomic changes seen in multiple neurological complications with stroke as the main clinical presentation Frequency

Type of neuromuscular changes

Remark

Primary changes, where neuromuscular or autonomic, and CNS may be simultaneously involved Vascular and cardiogenic embolisms (infective endocarditis, High Cranial neuropathies, Peripheral See Table 24.2 Ischemic monomelic neuropathy, cholesterol emboli neuropathies, muscular embolisms neuropathy, myocardial involvement in neuromuscular disorders) Dissection of carotid and vertebral arteries

Rare

Horner’s syndrome, cranial neuropathies, cervical radiculopathies and spinal cord ischemia

See Chap. 51

Primary and secondary vasculitis

Rare

Peripheral neuropathies and myopathies

See Table 24.2

Mitochondrial encephalomyopathies

Rare

Myopathies, myalgia, cardiac conduction abnormalities

See Chap. 44 (Uncommon Causes)

Secondary changes, as a consequence of a cerebrovascular event Cardiovascular dysfunctions High

Dysautonomia

Muscle atrophy contralateral to cerebral lesions

High

Muscle changes

Peripheral nerve compression

Rare

Peripheral neuropathies

Reflex sympathetic dystrophy

Rare

Sympathetic dysfunction

Disorders of micturition, faecal continence and sexual changes

High

Somatic and autonomic dysfunction

Sweating disorders and temperature dysregulation Others: dysregulation of respiration, hiccup

Rare Rare

Autonomic dysfunction

(Bendixen et al., 1992). The clinical presentation is remarkably stereotyped. Persistent deep, burning pain is the most prominent symptom. Sensory and motor deficits are found, with a distal to proximal gradient of change. The causes of vascular and cardiogenic embolisms are the same as those usually observed with embolism to the brain, but involvement of the heart in neuromuscular disorders is often overlooked. Cardiac involvement may be subclinical or present as a life-threatening manifestation early or late in the natural history of the underlying disorder (Swash & Schwartz, 1996) (Table 24.2). In some neuromuscular disorders, e.g. Becker X-linked muscular dystrophy, myocardial involvement is unrelated to the severity or duration of skeletal muscle weakness and may even precede the onset of skeletal muscle weakness. In myotonic dystrophy, two-thirds of patients show ECG abnormalities, but only one-quarter have cardiac symptoms. In acute, acquired disorders, e.g. in Guillain–Barré syndrome and in acute polymyositis, cardiac complications may be simultaneous with neuromuscular disorder.

See Chap. 51 (Uncommon Causes)

In recent years, molecular genetics has brought completely new insights into the understanding of the pathogenesis of cardiomyopathies and congenital arrhythmias.

Familial hypertrophic cardiomyopathies (FHC) These are genetically heterogeneous and all the known diseases encode sarcomeric proteins (Bonne et al. 1998) (Table 24.2). There is also a striking allelic heterogeneity, and more than 100 mutations have been found so far. The recent development of animal models have allowed a better understanding of the pathophysiological mechanisms associated with FHC. The mutation leads to a poison polypeptide that would be incorporated into the sarcomere. This would alter the sarcomeric function that would result first, in an altered cardiac function, and then secondly, in the alteration of the sarcomeric and myocyte structure. Some mutations induce functional impairment and support the pathogenesis hypothesis of an hypocontractile state followed by compensatory hypertrophy. Other mutations induce cardiac hyperfunction and

Muscle, peripheral nerve and autonomic changes

Table 24.2. Myocardial involvement in neuromuscular disorders Cardiac involvementa

Mode of inheritance

Gene location

Symbol

Gene product

Limb-girdle dominant Limb-girdle recessive

+++ +++ + + + +

XR XR AD AD AD AR

Desmin-related myopathy Steinert myotonic MD Myotonic MD type 2

++ ++ ++

AD AD AD

Xp21.2 Xq28 4q35 ? 5q, 1q, 3p 15q, 2p 13q, 17q 4q, 5q 11q22 19q13 3q

DMD EMD FSHD FSHD2 LGMD1A-C LGMD2A, 2B LGMD2C, 2D LGMD2E, 2F DRM DM DM2

Dystrophin Emerin ? ? ?, ?, caveolin-3 calpain 3, dysferlin ␥, ␣ sarcoglycan ␤, ␦- sarcoglycan ␣␤-crystallin Myotonin-kinase ?

Hereditary cardiomyopathies +++

AD

14q11

FHC1

+++ +++

AD AD

1q32 11p11

FHC2 FHC3

+++ +++

AD AD

15q22 12q23

FHC4 MYL2

+++

AD

3p21

MYL3

+++ +++

AD AD

19q12 15q14

TNNI3 ACTC

cardiac myosin heavy-chain ␣ or ␤ cardiac troponin T cardiac myosin binding protein C ␣-tropomyosin regulatory myosin light chain Essential myosin light chain Cardiac troponin I Cardiac actin

+++

AD

2q35

DES

Desmin

++

AD

17q13

SCN4A

+++

AD

3p21

LQT3

+++ +++

AD AD

7q35 11p15

LQT2 KVLQT1

Sodium channel ␣-subunit Sodium channel ␣-subunit Potassium channel Cardiac potassium channel

Inherited polyneuropathies Friedreich ataxia Familial amyloid neuropathy

++ +

AR AD

9cen-q21 18q11

FA PALB

Acquired neuromuscular disorders

Guillain–Barré syndrome, diphtheria, diabetic neuropathy, alcoholic neuropathy. Inflammatory, endocrine, drug-induced myopathies, infections and infestations

Muscular dystrophies Duchenne/Becker Emery-Dreifuss Facio-scapulo-humeral

Idiopathic dilated cardiomyopathy Desmin-related cardioskeletal myopathy Ion channel muscle diseases Hyperkalemic periodic paralyses Long QT syndromes

Frataxin Transthyretrin

Note: a +++: frequent, ++: rare, +: extremely rare. The nosology and molecular genetics of the neuromuscular diseases is changing rapidly, and the current classification will inevitably require frequent updating. The journal Neuromuscular Disorders (Pergamon Press) provides regular information on genetic aspects.

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determine a hypercontractile state that would directly induce cardiac hypertrophy. The diagnosis of FHC is usually based on ECG and echocardiography (Maron et al., 1998; Bonne et al., 1998). Mutations in another sarcomeric gene, cardiac actin, cause dilated cardiomyopathy in humans. This raises the important issue of whether hypertrophic and dilated cardiomyopathies are inherently independent diseases or whether dilatation is part of the FHC spectrum. The identification of the genetic origin of congenital arrhythmias has enhanced our understanding of these hereditary diseases, as has been the case for the long QT syndromes (LQTS), the Jervell and Lange Nielsen (JLNS) and the Romano–Ward (RWS) syndromes (Maron et al., 1998) (Table 24.2). These syndromes, characterized by prolongation of the QTc interval on the ECG and syncopes or sudden death triggered by stress, are differentiated by their modes of transmission, recessive or dominant, and by the presence or absence of deafness. The discovery of genetic origin of the hereditary arrhythmias will open new perspectives for the management of patients by providing basis for new criteria and novel therapeutics.

Dissection of internal carotid artery and vertebral artery Dissection should be considered whenever a stroke is associated with a notable headache or neck pain or is complicated by Horner’s syndrome or a cranial nerve palsy. The existence of ischemic cranial nerve syndromes has been well demonstrated (Lapresle & Lasjaunias, 1986).Three systems play a role in the vascularization of cranial nerves: the inferolateral trunk (IIIrd, IVth, VIth and V1), most often arising from the internal carotid artery, the middle meningeal system (V2,V3, and VIIth), and the ascending pharyngeal system (IXth to XIIth), both derived from the external carotid artery. Peripheral cranial nerve palsy and Horner’s syndrome caused by internal carotid dissection is rarely observed (see Chap. 51). Palsies of the IXth to XIIth nerves are more frequently found, probably as the result of the compression by an enlarging artery due to mural hematoma. The IIIrd, IVth and Vth (facial pain) nerves are seldom affected by ischemia. Only about one-third of the patients culled from the literature showed concomitant cerebral involvement. Carotid dissection might have been underestimated as a cause of isolated lower cranial nerve palsies (some of the reported Vernet, Villaret, Collet Sicard syndromes) before the advent of magnetic resonance imaging (MRI). The extracranial vertebral artery is the second most common location for a cervicocephalic dissection.

Headache and ischemic stroke are the most frequent symptoms. Vertebral artery dissection can lead to ischemia to the spinal cord or spinal brainstem and cranial nerves (see Chap. 52). On the other hand, tiny pontine lesions can cause isolated (nuclear) neuropathies without other neurologic deficits. These well-placed small pontine infarctions are increasingly reported thanks to their confirmation by MRI, with involvement of the VIth, VIIth and VIIIth nerves (see Chap. 39 and 40).

Vasculitis There have been several proposals for the classification of vasculitis (Ferro, 1998), but all have limitations because of the frequent overlap between different syndromes. In 1994 the Chapel Hill International Consensus Conference proposed names and definitions for selected categories of vasculitis (Jennette & Falk, 1997); however, no diagnostic criteria were suggested. Vasculitis is usually considered as primary and secondary (Table 24.3). Involvement of the peripheral nerves, muscles and CNS occurs with varying frequency and pattern among vasculitis, and therefore the clinical presentation of ‘neurologic’ vasculitis is variable, with CNS symptoms and signs (headaches, meningeal signs, encephalopathy, psychiatric syndromes, dementia, cranial nerve palsies, seizures, strokes), alone or in combination with painful neuropathy and myopathy, multiorgan involvement (purpura, nephritis, arthralgia, abdominal pain), and non-specific systemic symptoms with fever, anorexia and weight loss. Neurological symptoms and stroke may be the inaugural manifestations of vasculitis or may complicate the clinical course of a previously diagnosed case . Vasculitis is a rare cause of stroke, even in the young age groups. Therefore, routine screening of stroke patients for vasculitis is not cost effective (see Chap. 1–3, 7–8, Uncommon Causes for specific entities). If the diagnosis is suspected, a comprehensive medical history and physical examination, appropriate laboratory tests and other ancillary procedures must be performed to assess organ damage. This requires the knowledgeable integration of clinical and laboratory data, both positive and negative. Laboratory assessment for ANCA (cytoplasmic and perinuclear), antinuclear antibodies (ds-DNA, anti-SM, anti-RNP, anti-Ssa/Ro, anti-SSb/La, anticentromere, anti-Scl-70, anti-nRNP, anti-Jo-1, anti-PM-Sd), complement, cryoglobulins, fecal blood, antibodies to hepatitis B and C, rheumatoid factor, azotemia, hematuria, and proteinuria is useful. Either ANCA specificity may occur in a patient with any type of ANCA-associated small-vessel vasculitis; however,

Muscle, peripheral nerve and autonomic changes

Table 24.3. Classification of vasculitis CNS involvementa

Neuro-muscular involvementa

Primary large vessel vasculitis Giant cell arteritis

+++

+++

Primary angiitis of the CNS

+++

Takayasu’s disease

++

Associated autoantibody

Anti-endothelial

Remark

Granulomatous inflammation of the aorta and its branches.

Primary medium-sized-vessel vasculitis Polyarteritis nodosa

++

+++

Hepatitis B

Kawasaki disease

++

Primary small-vessel vasculitis Churg–Strauss syndrome

++

+++

c-ANCA

Asthma and eosinophilia

Wegener’s granulomatosis

++

+++

c-ANCA

Necrotizing glomerulonephritis is common

Microscopic polyangiitis

++

++

c-ANCA

Necrotizing glomerulonephritis and pulmonary capillaritis are common

Henoch–Schönlein purpura

+

Essential cryoglobulinaemia vasculitis

++

Coronary arteries are often involved. Usually occurs in children

Typically involves skin, gut, and glomeruli and is associated with arthralgia ++

Rheumatoid factor Hepatitis C

Cutaneous leukocytoclastic angiitis

Isolated cutaneous angeiitis without systemic vasculitis

Secondary vasculitis Lupus vasculitis

++

+++

ANA, ds-DNA, anti-SM

Rheumatoid vasculitis

++

+++

Rheumatoid factor

Sjögren’s vasculitis

+++

+++

Anti-SSA/Ro

Hypocomplementemic urticarial vasculitis Behcet’s disease

++

+

Goodpasture’s syndrome Serum-sickness vasculitis

+

+

Drug-induced immune-complex vasculitis

++

++

Infection-induced immune-complex

+

+

Note: a +++: frequent, ++: rare, +: extremely rare.

Skin and glomeruli are often involved

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most patients with Wegener’s granulomatosis have cytoplasmic ANCA, whereas most patients with microscopic polyangiitis or Churg–Strauss syndrome have perinuclear ANCA. It is very important to realize that approximately 10% of patients with typical Wegener’s granulomatosis or microscopic polyangiitis have negative assays for ANCA; thus, ANCA negativity does not completely rule out these diseases (Jennette & Falk, 1997; Ferro, 1998). The addition of serologic tests for ANCA to the diagnostic armamentarium provided a positive marker for certain types of pauci-immune small-vessel vasculitis. Testing for ANCA, along with other immunopathologic markers such as vascular IgA deposits and serum cryoglobulins, facilitates the diagnostic categorization of small-vessel vasculitis. Chest and sinus radiographs and computed tomographic scans may reveal occult respiratory tract disease. Nerve conduction studies can document peripheral neuropathy. Evidence of conditions that are known to cause vasculitis, such as drug hypersensitivity, infection, rheumatoid arthritis, systemic lupus erythematosus, cancer, and inflammatory bowel disease, should be sought. Pathological examination of involved tissue, such as skin, muscle, nerve, lung, or kidney, may document small-vessel vasculitis. Immunohistologic evaluation may yield more specific information, such as the presence of IgA-dominant vascular immune deposits indicative of Henoch-Schonlein purpura, or IgM and IgG immune complexes that are consistent with cryoglobulinemic vasculitis. Normal MRI almost excludes intracranial vasculitis (Ferro, 1998). There are, however, no pathognomonic MRI findings in vasculitis. Single or multiple territorial infarcts and hemorrhages and non-specific T2 hyperintense lesions involving the cortex, the basal ganglia and the white-matter can be seen. These lesions are less numerous and periventricular changes are milder than in multiple sclerosis. The angiographic aspects characteristic of vasculitis include multiple arterial occlusions (in particular of the small vessels over the convexity) and segmental stenosis of intracranial vessels, sometimes separated by dilatations (‘sausage’ appearance), avascular areas and intracranial aneurysms. A normal arteriogram does not exclude vasculitis, because vessels under 100–200 ␮m cannot be visualized by this method.

tion with methamphetamine, and other sympathomimetic drugs, heroine, crack and cocaine (see Chap. 17, Uncommon Causes, for specific entities). A careful investigation should be done to rule out endocarditis and angiography should be performed in hemorrhagic strokes to rule out an aneurysm or arteriovenous malformation.

Drug-induced vasculitis

Secondary changes

Although the mechanisms are disputed, there is no doubt that drug abuse increases the incidence of ischemic and hemorrhagic cerebral events, atraumatic multiple neuropathy and rhabdomyolysis. The risk is not confined to any one variety of drug or to a particular route of administration. The condition has been particularly noted in associa-

Other vasculitis A necroziting vasculitis may occur in patients with herpes zoster or neurosyphilis, acquired immunodeficiency syndrome, either directly or due to nonvasculitic etiologies with focal signs of encephalitis (see Chap. 3, Uncommon Causes). It is noteworthy that other meningovascular diseases may induce cerebrovascular events as well as peripheral neuropathies, such as listeriosis (Uldry et al., 1993) and Lyme disease (Kuntzer et al., 1991).

Mitochondrial encephalomyopathies Mutations in mitochondrial DNA (mtDNA) are associated with a number of diseases, in which clinical symptoms reflect a primary defect in tissues with high oxidative demand (Poulton, 1998). In these tissues, such as in muscle, there is a massive proliferation of mitochondria, which clump together in abnormal muscle cells. As the disease progresses, these can be stained to give a characteristic ‘ragged red’ appearance, which may not be evident in the early stage. Immunohistological staining may show decreased cytochrome oxidase (cox) activity. Although primarily affecting muscle, these disorders may also have profound effects on brain, eyes, heart, endocrine organs, liver, kidney, pancreas and blood. In general, single partial deletions of mtDNA are found in isolated patients, in contrast to point mutations in mtDNA, which are usually found to be associated with familial disease. In MELAS patients (see Chap. 44, Uncommon Causes), strokes have been explained by the proliferation of abnormal mitochondria in the smooth muscle and endothelial cells of the small arteries, arterioles of the brain and the pia matter. Other symptoms have to be explained by a combination of abnormal cellular metabolism and capillary angiopathy or cardiogenic emboli due to an associated cardiomyopathy.

Cardiovascular dysfunction Neuroanatomy of cardiovascular regulation The CNS plays a key role in the regulation of autonomic functions. The brainstem, the pons and the hypothalamus

Muscle, peripheral nerve and autonomic changes

are the main levels contributing to the neural control of cardiovascular homeostasis. At each of these brain levels are located integrative sites that are interconnected by afferent and efferent pathways (Lowey & McKellar, 1980). Any lesion involving this complex network may provoke cardiovascular disturbances.

sion. The natural tendency of blood pressure is to decline within a few days in hospital, down to around 170/100 mmHg. Ten days following the acute event, blood pressure is expected to be still elevated in no more than one-third of the patients with poststroke hypertension.

Neurally induced cardiac damage Arterial hypertension in response to acute elevation in intracranial pressure An acute rise in intracranial pressure, for instance, following subarachnoid hemorrhage, may cause severe hypertension with an accompanying bradycardia and occasionally apnea. This life-threatening condition, known as Cushing response, is due to a distorsion of the stretchsensitive area under the floor of the fourth ventricule (Magnus et al., 1977). The distorting force renders the brain stem ischemic, eliciting a marked sympathetic discharge. It is generally associated with a fatal outcome unless the raised intracranial pressure can be effectively lowered.

Blood pressure course in patients with acute stroke Blood pressure is abnormally elevated in approximately 70 to 80% of patients admitted to the hospital for acute stroke (Talman, 1985; Powers, 1993). Several mechanisms might be responsible for this phenomenon. They include an activation of sympathetic nerve activity secondary to the brain damage, an impaired autoregulatory vasodilatation and decreased perfusion in the ischemic border zone of the cerebral lesion. Pre-existing hypertension is a strong predictor of elevated blood pressure on admission. The patients with increased blood pressure after stroke are at higher risk of early mortality, but the severity of hypertension on admission and that of the clinical outcome are not related. Lesions involving the nucleus of solitary tract typically have hypertension and an enhanced blood pressure lability. Yet, in most cases, the occurrence of hypertension after stroke does not allow attribution of the elevation of blood pressure to a welldefined localization of the brain damage. In patients with ischemic stroke, worsening of neurological deficits might occur if blood pressure is lowered too drastically during the first few days after the event. This is mainly because cerebral autoregulation is impaired during the early phase of stroke. Cerebral blood flow could therefore become unsufficient if blood pressure is lowered below a critical level. Blood pressure achieves often very high levels immediately following intracerebral hemorrhage. Restoring blood pressure to previous levels is appealing in this condition to avoid early rebleeding but, as with acute ischemic stroke, it is recommended to lower blood pressure cautiously only in patients with extreme hyperten-

Electrocardiographic (ECG) changes consistent with myocardial ischemia or necrosis are commonly seen after stroke, even in the absence of established coronary heart disease (Talman, 1985; Valeriano & Elson, 1993). Abnormalities on ECG can be found in 60 to 70% of patients with intracerebral hemorrhage and 15 to 40% of cases with ischemic stroke. Increased activity of cardiac enzymes, indicating cardio-myocytolysis, is also frequently seen after stroke. ECG changes in patients with acute cerebrovascular events are associated with an increased mortality even in the absence of coronary lesion. The ECG and enzyme changes may revert partially or totally to normal. They are thought to be the consequence of focal myocardial necrosis. Another frequent complication of stroke is cardiac arrhythmia, with an estimated incidence of more than 75%. Most rhythm problems are benign but the risk of developing severe ventricular arrhythmia is increased about fourfold after stroke, representing a major cause of sudden death. Rhythm disturbances should therefore be treated aggressively when required. Of note is that the QT interval is frequently prolonged in stroke patients. This repolarization abnormality is often associated with potentially malignant polymorphic ventricular tachycardia such as the ‘torsades de pointes’. ECG abnormalities, as well as myocardial cell necrosis encountered after stroke are due most likely to a centrally mediated increase in sympathetic nerve activity. The diffuse, focal areas of myocardial necrosis are similar to those observed in patients with pheochromocytoma and very high catecholamine concentrations in the circulation. Parasympathetic overactiviy may, however, prevail in some patients, accounting for the occurence of sinus node suppression or atrio-ventricular blocks.

Neurogenic pulmonary edema A protein-rich alveolar pulmonary edema can develop rapidly in patients with intracranial hypertension or subarachnoid hemorrhage (Simon, 1993). Theoretically, a massive and sudden systemic hypertension may increase left atrial pressure and, by this way, pulmonary capillary hydrostatic pressure, to a point that pulmonary edema occurs. Neurogenic pulmonary edema can, however, occur even if blood pressure is normal, showing that the

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hemodynamic response to systemic hypertension is not the causal factor. Sympathetic overactivity is probably an important factor. Thus, sympathetic stimulation increases pulmonary capillary permeability to proteins and might cause, by contracting the capacitive system, a shift of blood to the pulmonary circulation.

Hypotension Strokes may occasionally produce hypotension. The lesions responsible for the fall in blood pressure are located principally in the rostral, ventrolateral medulla (Talman, 1985).

Muscle atrophy contralateral to cerebral lesions We have attempted to demonstrate that muscle atrophy .. may be seen in hemiplegia .., and that this atrophy is more frequent than previously thought (E. Brissaud, 1879).

Hemiplegic atrophy in humans is a long-established observation made as early as 1850 by Romberg and then by Charcot (for review, see Brissaud, 1879). Lesions in the cerebral hemisphere interrupting descending projections to the brainstem and spinal motoneurons are associated with a variety of structural changes in the spinal cord and muscles. These changes have been seen in both small cortical lesions, lacunes, and large lesions of the hemispheres. Histologic studies of hemiplegic muscles have shown type II muscle fibre atrophy and increased complexity of endplates, suggestive of collateral sprouting. In some instances, type I fibre hypertrophy was also seen (for review, see Brown & Snow, 1990; Brown, 1984). Atrophy of muscles contralateral to cerebral lesions or pyramidal tract sections is also well documented in primates. The appearance of denervation supersensitivity in hemiparetic muscles, i.e. fibrillation potentials seen in electromyographic studies, was described by Goldkamp and then by several other authors (for review, see Brown & Snow, 1990); they suggest that ‘transsynaptic degeneration’ of motor neurons may explain the development of fibrillation and contribute to the development of atrophy. The afferent axons’ influence on the postsynaptic cell is due partly to transmitter-mediated mechanisms and partly to trophic ones that may modulate voltage-dependent ion channels or regulate gene expression (for review, see Clarke & Clarke, 1996). Physiologically, up to 50% losses of functioning spinal motor units were observed on the weakened side within 2 months of the cerebrovascular event (McComas, 1995). Fibrillation potentials are accompanied by reduced maximum motor-response size and are seen as early as the

second and third week and may last many weeks thereafter. Reports vary as to the frequency of this denervation activity, but it was found in the hemiplegic muscles in as much as two-thirds of the patients in one study (Brown & Snow, 1990). The denervation activity is most common in more distal muscles (for review, see Brown & Snow, 1990; Brown, 1984). In one single-fibre EMG study, it was demonstrated that increased jitter may persist over years (Chang, 1998). The distribution of the fibrillation and the normal conduction studies suggest that trauma of peripheral nerves is not a causal factor. The possibility that descending motor pathways other than the corticospinal tract might also exert a trophic influence on spinal motoneurons is suggested by the severe losses of motor units, which may occur after transection of the spinal cord (for review, see McComas, 1995). Since cord transection in animals is often not followed by histological evidence of motoneuron loss, it is likely that, in humans, the motoneurons are still present, albeit in a dysfunctional state. The changes observed in human muscles might also be secondary to inactivation of motoneurons and disuse. Close correlation between the number of motor units and the time, size and location of the cerebrovascular events is needed to evaluate the influence of hemidenervation on the outcome of these patients.

Peripheral nerve compression Moderate to severe paresis of contralateral muscles as the result of an acute cerebrovascular event may induce trauma to various components of the peripheral nerves. External pressure is probably the cause of ulnar and peroneal neuropathies in certain bedridden patients. Neither the reason why the patient is confined to bed, nor the severity of his illness, are essential factors (Mumenthaler & Schliak, 1991). Bedridden patients who develop these neuropathies exhibit often a constellation of weight loss, underlying polyneuropathy and pressure on hard hospital mattresses or bed railings. In patients without underlying factors it is not known whether a neuropathy may develop acutely or later in the course of the weakness. We have estimated the relative proportion of denervated nerve fibres, surviving but blocked fibres and fibres affected by conduction slowing alone, by quantifying the axon loss and conduction blocks in both peroneal and ulnar nerves in 20 weakened sides with the unaffected limb as control. We have found reduced conduction velocity in 5% of the cases with no conduction blocking within the 15 days following the onset of the cerebrovascular event (T. Kuntzer, unpublished data). Management designed to unload the ulnar

Muscle, peripheral nerve and autonomic changes

and peroneal nerves is thus important to avoid multiple and repeated pressures on these nerves that may induce later muscle atrophy.

Reflex sympathetic dystrophy Reflex sympathetic dystrophy (RSD) is a progressive illness characterized by pain, edema, autonomic dyfunction, movement disorder and trophic changes. The illness evolves in stages and there is no consensus for its diagnosis. In any stage of RSD, the symptom complex may be dissociated: the autonomic dysfunction may be minimal while the patient suffers great pain. Conversely, patients may have severe livedo reticularis and circulating abnormalities of muscle and skin with little pain and no movement abnormality. RSD in patients with cerebrovascular events is well recognized but its prevalence is not known. In these patients, the RSD symptoms may be difficult to recognize early as patients may be unable to express or localize pain, underlying the role of early proximal and distal movings of the involved extremity. Sensitization of neurons in the central nociceptive pathway has been proposed as a key element in pathophysiologic mechanisms of this disorder (Schott, 1998).

Disorders of micturition, fecal continence and sexual changes Normal bladder function requires the integrated activity of the somatic and autonomic pathways that extend from the frontal lobes and the pons to the sacral spinal cord (Kuntzer, 1998). The neural control of micturition in humans is essentially similar to what is established in cats and other animals (Fowler, 1998). The symptoms and findings in neurological impairment of urinary bladder function depend more on the site of the lesion than on the specific disease. Cerebral disorders can affect bladder function by causing loss of control over the transition between filling and voiding states. This leads to loss of inhibition and facilitation of the detrusor reflex, resulting in urgency, incontinence, hesitancy, or more rarely, retention because of a failure of voluntary initiation of the voiding reflex. After studying patients with cerebral lesions, it was deduced that the cortical loci controlling micturition are in the superomedial part of the frontal lobes in the region of the anterior cingulate and superior frontal gyri. Also important are white-matter tracts that run to and from the genu of the corpus callosum. In stroke syndromes, incontinence is said to be common, but transient in about half of

the patients. Incontinence can be a continuing problem for about 15% of the patients at 1 year poststroke stage and is associated with a poor outcome with severe functional loss. The incontinence with incomplete emptying of the bladder is also related to other factors rather than directly to the brain damage, such as inability to walk, speech disorders, and mental changes. The pontine or brainstem micturition centre lies in the dorsal tegmentum of the pons, and abnormalities affecting this area give rise to disorders of voiding usually with other neurological deficits, but occasionally a lesion can be sufficiently dorsal and discrete to produce predominantly a defect of bladder function. An internuclear ophthalmoplegia is a frequent additional sign, due to the proximity of the median longitudinal fasciculus. Any spinal cord lesion involving the lateral columns bilaterally, such as trauma, multiple sclerosis, transverse myelitis, vitamin B12 deficiency, cervical spondylotic myelopathy, tethered cord syndrome will also result in urinary disturbance. Here, the bladder is more or less isolated from the pontine micturition centre, and the coordination of the voiding act itself, as well as its inhibition, initiation, and completion, is impaired, and the normal coordinated relaxation of the sphincter that precedes and accompanies a detrusor contraction is lost, so that the disorder of ‘detrusor–sphincter dyssynergia’ occurs. Retention alone is uncommon, except in the early phase of spinal shock. Thus in a chronic spinal lesion, abnormal voiding is common, accompanied by detrusor hyperreflexia, with urgency and frequency, difficulty of voluntary initiation or interrupted stream and incomplete emptying. Because of the relative levels at which the innervation of the lower limbs and the bladder arise, it is unusual to have a lesion between the pons and the sacral part of the cord giving rise to a neurogenic bladder that does not also produce other neurological signs in the lower limbs. A possible exception might be expected from a conus or cauda equina lesion affecting only S2–S4. It is clear that the human has the ability of responding to the conscious sensation of rectal filling by retaining fecal matter, and defecation is initiated as a voluntary act. Its cortical representation is mapped but the higher-level processes concerned with suppression and initiation of reflex and voluntary defecation in human are unknown (Swash & Henry, 1991). The descending pathways through brainstem and spinal cord are thought to be closely related to those subserving micturition. Control of defecation or continence is lost in diffuse lesions of the brain, especially those associated with frontal or bifrontal dysfunction. Fecal incontinence needs symptomatic management to prevent fecal impaction with overflow and to maintain

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adequate stool consistency. Cerebrovascular events are generally followed by some important alterations in sexual life, concerning both behavior and the subject’s feeling about sexuality. Clinical features, as well as the side of hemispheric lesion, do not seem to play a crucial role (Boldrini et al. 1991).

Sweating disorders and temperature regulation Asymmetric sweating has been reported to be a common phenomenon after both brain and pontine vascular lesions, reflecting sympathetic hyperfunction on the paretic side of the body (Korpelainen et al., 1995). This asymmetry seems to be a long-lasting consequence of autonomic failure occuring in the majority of patients with hemispheral brain infarction. Hyperhydrosis correlates with the severity of paresis and may be significant in estimating recovery of the patients. Interruption of a descending sympathoinhibitory system might cause excessive sweating. Unilateral sweating dysfunction in patients with Horner’s syndrome is discussed elsewhere. Bilateral lesions in the hypothalamus or its pathways seem necessary to produce thermic dysregulation, both hyper- and hypothermia as seen in patients with pontine hemorrhages. Failure of the homeostatic mechanisms that generate and conserve heat, and lesions of the pyretic or antipyretic areas are known in animals but not in humans (Andersen & Moser, 1995).

iReferencesi Andersen, P. & Moser, E.I. (1995). Brain temperature and hippocampal function. Hippocampus, 5, 491–8. Bendixen, B.H., Younger, D.S., Hair, L.S. et al. (1992). Cholesterol emboli neuropathy. Neurology, 42, 428–30. Boldrini, P., Basaglia, N. & Calanca, M.C. (1991). Sexual changes in hemiparetic patients. Archives of Physical Medicine and Rehabilitation, 72, 202–7. Bonne, G., Carrier, L., Richard, P., Hainque, B. & Schwartz, K. (1998). Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circulation Research, 83, 580–93. Brissaud, E. (1879). De l’atrophie musculaire dans l’hémiplégie. Revue mensuelle de Médecine et Chirurgie, 3, 616–25. Brown, W.F. (1984). Electromyography and disorders of the central nervous system. In The Physiological and Technical Basis of Electromyography, pp. 459–89. Boston: Butterworth. Brown, W.F. & Snow, R. (1990). Denervation in hemiplegic muscles. Stroke, 21, 1700–4. Chang, C.W. (1998). Evident trans-synaptic degeneration of motor

neurons after stroke: a study of neuromuscular jitter by axonal microstimulation. Electroencephalography and Clinical Neurophysiology, 109, 199–202. Clarke, P.G. & Clarke, S. (1996). Nineteenth century research on naturally occurring cell death and related phenomena. Anatomy and Embryology, 193, 81–99. Ferro, J.M. (1998). Vasculitis of the central nervous system. Journal of Neurology, 245, 766–76. Fowler, C.J. (1998). Brain activation during micturition. Brain, 121, 2031–2. Francioli, P. (1997). Complications of infective endocarditis. In Infections of the Central Nervous System, eds. W.M. Scheld, R.J. Whitley & D.T. Durack, pp. 523–53. Philadelphia: LippincottRaven. Jennette, J.C. & Falk, R.J. (1997). Small-vessel vasculitis. New England Journal of Medicine, 337, 1512–13. Korpelainen, J.T., Sotaniemi, K.A. & Myllyla, V.V. (1995). Asymmetrical skin temperature in ischemic stroke. Stroke, 26, 1543–7. Kuntzer, T. (1998). Neuro-urological and anal sphincter dysfunction. In Textbook of Neurology, ed. J. Bogousslavsky & M. Fisher, pp. 277–86. Boston: Butterworth–Heinemann. Kuntzer, T., Bogousslavsky, J., Miklossy, J., Steck, A.J., Janzer R. & Regli, F. (1991). Borrelia rhombencephalomyelopathy. Archives of Neurology, 48, 832–6. Lapresle, J. & Lasjaunias, P. (1986). Cranial nerve ischemic arterial syndromes. Brain, 109, 207–15. Lowey, A.D. & Mckellar, S. (1980). The neuroanatomical basis of central cardiovascular control. Federation Proceedings, 39, 2495–503. McComas, A.J. (1995). Motor unit estimation: anxieties and achievements. Muscle and Nerve, 18, 369–79. Magnus, O., Koster, M. & Van der Drift, J.H.A. (1977). Cerebral mechanisms and neurogenic hypertension in man, with special reference to baroreceptor control. Progress in Brain Research, 47, 199–218. Maron, B.J., Moller, J.H., Seidman, C.E. et al. (1998). Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases: hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. A statement for healthcare professionals from the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association. Circulation, 98, 1460–71. Mumenthaler, M. & Schliak, H. (1991). Peripheral Nerve Lesions, Stuttgart: Thieme Verlag. Pamphlett, R. & Walsh, J. (1989). Infective endocarditis with inflammatory lesions in the peripheral nervous system. Acta Neuropathologica, 78, 101–4. Poulton, J. (1998). Mitochondrial myopathies and related disorders. In Neuromuscular Disorders: Clinical and Molecular Genetics, ed. A.E.H. Emery, pp. 203–16. Chichester: John Wiley. Powers, W.J. (1993). Acute hypertension after stroke: the scientific basis for treatment decisions. Neurology, 43, 461–7. Schott, G.D. (1998). Interrupting the sympathetic outflow in cau-

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salgia and reflex sympathetic dystrophy. British Medical Journal, 316, 792–3. Simon, R.P. (1993). Neurogenic pulmonary edema. Neurocardiology, 11, 309–23. Swash, M. & Henry, M. (1991). The colon and anal sphincters. In Clinical Neurology, ed. M. Swash & J. Oxburg, pp. 614–23. London: Churchill Livingstone. Swash, M. & Schwartz, M.S. (1996). Cardiac involvement in neuromuscular disease. In Handbook of Muscle Disease, ed. R.J.M. Lane, pp. 655–62. New York: Marcel Dekker.

Talman, W.T. (1985). Cardiovascular regulation and lesions of the central nervous system. Annals of Neurology, 18, 1–12. Uldry, P.A. Kuntzer, T., Bogousslavsky, J. et al. (1993). Early symptoms and outcome of Listeria monocytogenes rhombencephalitis: 14 adult cases. Journal of Neurology, 240, 235–42. Valeriano, J. & Elson, J. (1993). Electrocardiographic changes in central nervous system disease. Neurocardiology, 11, 257–72. Wilbourn, A.J. & Levin, K.H. (1993). Ischemic neuropathy. In Clinical Electromyography, ed. W.F. Brown & C.F. Bolton, pp. 369–90. London, Ontario: Butterworth–Heinemann.

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Dysarthria Paola Santalucia and Edward Feldmann Brown University School of Medicine, Rhode Island Hospital, Providence, USA

Introduction Dysarthria is a pure motor disorder of speech, occurring in 24–29% of patients with cerebral ischemia (Arboix et al., 1990; Melo et al., 1992). It is characterized by dysfunction of the structures implicated in the control, initiation and coordination of speech output: lips, tongue, jaw, and palate, which are innervated by the facial, glossopharyngeal, vagal, and hypoglossal nerves. The dysarthric patient exhibits intact cortical language mechanisms and comprehension, is able to understand perfectly what he hears and has no difficulty in reading and writing, although his speech is inarticulate and may be unintelligible. Lesions that cause dysarthria may occur in one of several locations along the neuraxis (Schiff et al., 1983; Yorkston et al., 1988). The upper and/or lower motor neuron may be involved as well as the extrapyramidal system from the basal ganglia to the cerebellum. Each region may receive blood supply from more than one artery. The examination of the patient with dysarthria is used to identify the specific type of abnormality. It is conducted by listening to the patient’s speech during ordinary conversation, after testwords, or in the attempt of rapid repetition of lingual, labial, and guttural consonants. The clinical features of the dysarthria and the associated neurological findings identify the responsible lesion. Dysarthria has also been described as an isolated symptom (Ozaki et al., 1986; Caplan et al., 1990); in such circumstances the responsible lesion is suggested by the characteristics of the dysarthria itself and by imaging studies. Defects in articulation may be subdivided into several types: upper motor neuron or spastic (pseudobulbar), lower motor neuron (neuromuscular), cerebellar–ataxic, hypo- and hyperkinetic. This chapter reviews the clinical features of dysarthria resulting from stroke and its associated neurologic signs. The classification and features of

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the different types of dysarthria, along with their associated neurological signs, are listed in Tables 25.1–25.6. These tables were developed by analysing 38 features of speech and voice for each subclass of dysarthria, and have been adapted from Darley et al. (1969a). According to the authors, dysarthria comprises a group of speech disorders resulting from disturbances in muscular control. Because there has been damage to the central or peripheral nervous system, some degree of weakness, slowness, incoordination, or altered muscle tone characterizes the activity of the speech mechanism. The muscles involved in respiration and phonation (sound production at the laryngeal level) may also be affected. Prosody (musical or melodic characteristics of speech including stress and intonation pattern) may also be disrupted (Darley et al., 1969a). A description of these features is provided in Table 25.7. The characteristics of each type of dysarthria are listed in rank order, with the most prominent feature listed first. Although any individual feature may occur in more than one class of dysarthria, Darley and colleagues identified clusters of speech abnormalities that conform to the presumed disorder of neuromuscular physiology seen with each subclass of dysarthria. These clusters of speech dysfunction provide each dysarthria subclass with unique clinical features (Darley et al., 1969b).

Upper motor neuron lesions The corticospinal fibres originate from the motor cortex (area 4), the supplementary motor area (area 6), and part of the parietal lobe (areas 1, 3, 5, and 7). They converge in the corona radiata and descend through the posterior limb of the internal capsule, crus cerebri, basis pontis, and medulla oblongata. Within the corticospinal tract the fibres are somatotopically arranged. However, overlapping

Dysarthria

may occur. Fibres to the cranial nerve nuclei are located more anteriorly near the genu, followed by the cervical, thoracic, lumbar and sacral segments located successively more dorsally. In the brainstem, the corticospinal tract is accompanied by the corticobulbar tracts, which are distributed to the motor nuclei of the cranial nerves, ipsilaterally and contralaterally. As the corticospinal and corticobulbar fibres have a similar origin and the motor nuclei of the brainstem are the homologues of the motor nuclei of the spinal cord, the term upper motor neuron may be applied to both of these systems. Ischemic lesions of the upper motor neuron system may be unilateral or bilateral, cortical or subcortical. Cortical strokes that produce dysarthria may involve the territory of the anterior and middle cerebral arteries (Ropper, 1987). Subcortical dysarthria may be seen following strokes occurring in the territory of anterior, middle or posterior cerebral arteries, as these vessels nourish the corticopontine and corticobulbar fibres in their subcortical locations (Bogousslavsky & Regli, 1990; Sohn et al., 1990; Ichicawa & Yasutumi, 1991). The dysarthria produced by lesions of the upper motor neuron, whether cortical or subcortical, has been classified as spastic dysarthria. Lesions that involve both corticobulbar tracts result in a syndrome known as spastic bulbar (pseudobulbar) palsy. Since the bulbar muscles on each side are innervated by both motor cortices, there may be no impairment in speech or swallowing following a unilateral corticobulbar lesion. The patient may have had a clinically silent vascular lesion in the past, affecting the corticobulbar fibres on one side; should another stroke then occur, involving the other corticobulbar tract, the patient immediately becomes dysphagic, dysphonic and anarthric or dysarthric, often with paresis of the tongue and facial muscles (Adams & Victor, 1993). Unilateral upper motor neuron lesions may cause supranuclear dysarthria, with or without swallowing difficulty and lower facial paresis, without significant motor weakness. This is usually transient. Considerable improvement occurs in 6 weeks to 6 months. Bilateral strokes involving the pyramidal tract may produce supranuclear palsy without significant motor weakness; this is usually a permanent deficit, although the patient may experience some improvement (Darley et al., 1969b). In individual case reports of patients with dysarthria due to supratentorial strokes, the lesions were located in or near the anterior limb, (Ozaki et al, 1986; Ichikawa et al., 1991), the genu (Ozaki et al. 1986; Bogousslavsky & Regli 1990; Ichikawa et al., 1991), the posterior limb of the internal capsule (Decroix et al., 1986; Combarros et al., 1992), corona radiata and lower motor cortex (Tonkonogy & Goodglass,

1981; Ichikawa et al., 1991). However, even when the site of the lesion is obvious from imaging studies, it may not be possible to reach a definitive conclusion concerning the involvement or sparing of individual corticospinal or corticobulbar fibre subpopulations due to the close proximity of the fibre tracts (Urban et al., 1997). Various headings, such as isolated facial palsy, pure or isolated dysarthria (Ozaki et al., 1986; Ichikawa et al., 1991), and ‘capsular genu syndrome’ (Bogousslavsky & Regli, 1990) have been used to describe these case reports. In a series of 13 patients, all complaining of dysarthria, most of them had a combination of dysarthria and facial paresis, due to corticolingual and corticofacial tract involvement, given the proximity of the two tracts during their entire course from the motor cortex to the brainstem. The degree of dysarthria was usually mild or moderate and none of them had unintelligible speech. The facial paresis was also mild and transient, likely to be unnoticed by conventional neurological testing, especially when the patients were not examined early enough. Therefore, the authors concluded that pure dysarthria and isolated facial paresis syndrome, if they exist, were quite rare. Pure dysarthria and isolated facial paresis syndrome may be considered the two extremes of this syndrome, which is attributed to small unilateral strokes involving the corticobulbar tract but sparing the corticospinal fibres in the regions of the corona radiata, basal ganglia–internal capsule and subcortical–cortical motor regions (Kim, 1994). Bogousslavsky et al. reported six patients with acute stroke limited to the genu of the internal capsule. The constant feature was the combination of contralateral faciolingual paresis with dysarthria. The authors assumed, therefore, that the location of the corticopontine and corticobulbar fibres within the internal capsule can be considered quite constant and that faciolingual paresis, whether or not associated with masseter, palatal, pharyngeal, laryngeal, or hand weakness, is highly suggestive of stroke limited to the genu of the contralateral internal capsule (Bogousslavsky & Regli, 1990). Damasio et al. investigated the anatomo-clinical correlation in six cases of atypical aphasia and five cases of speech disturbance without aphasia. In all but two cases there were lesions consistently involving three structures: (i) the anterior limb of the internal capsule, (ii) the head of the caudate nucleus, (iii) the putamen. They concluded: (i) right-handed patients with left-sided lesions that involve the anterior limb of the internal capsule, the head of the caudate, and the putamen had aphasia, right hemiparesis, and often dysarthria and dysprosody; (ii) a right-handed patient with a lesion that failed to involve the previously mentioned areas but did compromise more posterior

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Table 25.1. Features of spastic (upper motor neuron) dysarthria listed in order of importance, and associated neurological signs Speech features Imprecise consonants Monopitch Reduced stress Harsh voice Monoloudness Low pitch Slow rate Hypernasality Strained voice Short phrases Associated signs Spasticity Hyper-reflexia Babinski signs Tongue, face, hand weakness Gaze preferences Hemianopia Aphasia Neglect Hemiparesis Source: Adapted from Darley et al. (1969a).

aspects of the internal capsule, corona radiata, caudate nucleus, and putamen had dysarthria and right hemiparesis but no aphasia; (iii) right-handed patients with righthemisphere lesions, involving the anterior limb of the internal capsule, head of the caudate, and putamen had dysarthia and left hemiparesis but not aphasia. (Damasio et al., 1982). The association of dysarthria with either contralateral hemiparesis or brachial monoparesis has been described in a series of 49 patients with acute paramedian pontine infarcts in the territory of the paramedian branches of the basilar artery. Regardless of the topographic distribution of the lesions within the pons (paramedian basal, paramedian basal–tegmental or paramedian tegmental), the most frequent motor abnormality was dysarthria (Kataoka et al., 1997). A stereotyped combination of dysarthia and clumsiness of one hand, the dysarthria-clumsy hand syndrome, has been described by Fisher in a series of 20 patients (Fisher, 1967). Usually no prodromal symptoms precede the rapid onset of neurologic deficit. The clinical picture consists of dysarthria, central weakness of one side of the face and

tongue, dysphagia, clumsiness and mild weakness of the ipsilateral hand (Wanger et al., 1979). The features of dysarthria produced by supranuclear lesions are shown in Table 25.1. The speech is slow and labored, the word articulation is imprecise, especially with complicated groups of consonants. The voice quality is harsh and strangled, the voice pitch is low and monotonous. These features can be attributed to the reduced range, speed, and force of movement and hypertonus typical of upper motor neuron disorders (Darley et al, 1969a). Cortical and subcortical dysarthria can be differentiated by their associated neurological findings. Dysarthria following cortical strokes may be associated with aphasia, gaze preference or neglect. Features shared by dysarthria due to cortical and subcortical strokes include facial, tongue, or hand weakness, hemiparesis, hyperreflexia, spasticity, hemianopia, and Babinski sign. These findings may occur as a result of a lesion in either the left or the right hemisphere.

Lower motor neuron lesions Lower motor neuron dysarthria can result from lesions of the motor nuclei of the cranial nerves VII, IX, X, and XII, following ischemia in the vascular territory of the vertebrobasilar system and its branches (Adams & Victor, 1993). The seventh cranial or facial nerve is mainly a motor nerve supplying all the muscles concerned with facial expression. The ninth cranial or glossopharyngeal nerve has a somatic efferent component that contributes to the motor innervation of the striated musculature of the pharynx, mainly of the stylopharyngeus, which elevates the pharynx. The tenth cranial or vagus nerve has two important branches: the pharyngeal branch, which innervates the muscles of the palate and pharynx, and the laryngeal branch, which innervates the muscles of the larynx. It also conveys sensory information from the pharyngeal and laryngeal mucosa. The twelfth cranial or hypoglossal nerve is a pure motor nerve which supplies the musculature of the tongue. The dysarthria associated with lower motor neuron lesions has been classified as flaccid dysarthria (Table 25.2). It is a neuromuscular disorder due to weakness of the articulatory muscles. The most prominent feature is the nasality of the speech. Inhalation and exhalation are audible, giving speech a breathy quality. Air wastage produces short phrases. The articulation of vowels and consonants is imprecise, the lingual and labial consonants are not pronounced at all. Associated neurological signs are face, tongue, palatal weakness, wasting and fasciculations

Dysarthria

Table 25.2. Features of flaccid (lower motor neuron) dysarthria listed in order of importance, and associated neurological signs

Table 25.3. Features of combined spastic and flaccid dysarthria listed in order of importance, and associated neurological signs

Speech features Hypernasality Imprecise consonants Breathy voice Monopitch

Speech features Imprecise consonants Hypernasality Harsh voice Slow rate Monopitch Short phrases Distorted vowels Low pitch Monoloudness Excess and equal stress Prolonged intervals

Associated signs Face, tongue, palatal weakness Fasciculations Dysphagia Dysphonia Atrophy of the tongue Limb weakness, sensory loss Ataxia Extraocular movement abnormalities Source: Adapted from Darley et al. (1969a).

of the tongue, dysphonia, and dysphagia (Darley et al., 1969a; Adams & Victor, 1993). Other brainstem and long tract signs may also occur, due to the involvement of other brainstem structures. These signs include upper motor limb weakness and sensory loss, as well as extraocular movement abnormalities and cerebellar dysfunctions.

Combined upper and lower motor neuron lesions Ischemic lesions in the vertebrobasilar territory can result in both, upper and lower motor neuron involvement. In such instances the dysarthria has been classified as mixed, carrying the features of the spastic and flaccid types. Table 25.3 shows how mixed dysarthria not only combines the features of upper and lower motor neuron lesions, but also creates a unique pattern of motor speech dysfunction. The voice quality is harsh, the voice pitch is low and monotonous as in upper motor neuron disease, the speech is hypernasal; vowel and consonant articulation is imprecise as in lower motor neuron lesions. Overall the speech is poorly intelligible. Voice quality, articulation, prosody and the respiration are markedly altered, making it difficult for the patient to produce even short phrases. The associated neurological signs of mixed dysarthria include those discussed in the section on flaccid dysarthria, as the responsible lesions occur within the vertebrobasilar arterial territory.

Associated signs Tongue, face, hand weakness Atrophy Spasticity Hyporeflexia Hemianopia Fasciculations Dysphagia Dysphonia Extraocular abnormalities Source: Adapted from Darley et al. (1969a).

Cerebellar lesions Ataxic dysarthria is the result of lesions occurring in the territory of the superior cerebellar and posterior inferior cerebellar arteries. The paravermal zone of the rostral cerebellum (lobulus simplex and semilunaris superior), corresponding to the territory of the medial branch of the superior cerebellar artery, has been identified as the most frequently involved in cerebellar dysarthria. Therefore, dysarthria has been described as a characteristic sign of rostral cerebellar involvement, as vertigo is for caudal cerebellar involvement (Lechtenberg & Gilman, 1978). In some other reports, dysarthria has been observed in patients with small infarcts of the anterior part of the rostral cerebellum, the territory of the lateral branch of the superior cerebellar artery, and not the paravermal zone (Amarenco et al., 1991). The precise anatomic location of the lesions associated with cerebellar dysarthria is still controversial. The speech disorder related to cerebellar lesions may take one of two forms, it can be either a slow, slurring

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Table 25.4. Features of ataxic (cerebellar) dysarthria listed in order of importance, and associated neurological signs Speech features Imprecise consonants Excess and equal stress Irregular articulatory breaks Distorted vowels Harsh voice Associated signs Dysdiadochokinesia Dysmetria Nystagmus Hypotonia Gait or truncal ataxia Source: Adapted from Darley et al. (1969a).

Table 25.5. Features of hypokinetic (parkinsonian type) dysarthria listed in order of importance, and associated neurological signs Speech features Monopitch Reduced stress Monoloudness Imprecise consonants Inappropriate silence Short rushes Harsh voice Breathy voice Associated signs Resting tremor Masked face Paucity of movement

dysarthria, or a scanning, ataxic dysarthria, so called because the words are broken up into syllables (Table 25.4). Scanning dysarthria is uniquely cerebellar, the principal abnormalities being slowness of speech, slurring, monotony, and unnatural separation of the syllables of words (scanning). The coordination of speech and of respiration is disordered. There may not be enough breath to express certain words or syllables, and others are expressed with greater force than intended (explosive speech) (Adams & Victor, 1993). Speech proceeds at an artificial, measured pace. An alteration in the prosody places undue stress on words and syllables that usually are unstressed. The neuromuscular basis for this pattern of dysarthria is believed to include inaccurate direction and rhythm of movement, slow movement, ataxia, and flaccidity (Darley et al., 1969a). Neurological deficits associated with the dysarthria of cerebellar stroke include dysdiadochokinesia, dysmetria, nystagmus, hypotonia and gait or truncal ataxia (Adams & Victor, 1993).

Source: Adapted from Darley et al. (1969a).

Extrapyramidal lesions

Dysarthria resulting from a lesion in one of these structures is classified as either hypokinetic (Table 25.5) or hyperkinetic (Table 25.6) (Darley et al, 1969a; Espir & Rose, 1985). In hypokinetic dysarthria the voice is low pitched and monotonous. Loudness variation, from the explosive utterance of words to the point where speech is almost inaudible, is characteristic. Speech is short and rushed, with unclear articulation, followed by periods of inappropriate silence. The underlying neuromuscular dysfunction includes reduced range of individual and repetitive movements and weakness of movements (Darley et al., 1969a). An example of hypokinetic dysarthria is the speech distur-

Dysarthria can follow ischemic lesions of the extrapyramidal system occurring in the vascular territories of the deep penetrating branches of the anterior and middle cerebral arteries. The deep penetrator from the anterior cerebral artery is the medial striate artery, also known as Heubner’s artery. The penetrators from the middle cerebral artery are the lenticulostriate arteries. The grey nuclei of the extrapyramidal system, caudate nucleus, putamen, and globus pallidum, are believed to be the sites of lesions producing dysarthria (Adams & Victor, 1993).

Table 25.6. Features of hyperkinetic (choreic or dystonictype) dysarthria listed in order of importance, and associated neurological signs Speech features Imprecise consonants Distorted vowels Harsh voice Irregular articulatory breaks Strained voice Monopitch Monoloudness Associated signs Choreic: random, unsustained irregular movements Dystonic: distorted posturing of the head, neck, trunk, or proximal limbs Source: Adapted from Darley et al. (1969a).

Dysarthria

Table 25.7. Features of speech dysfunction seen in dysarthria Dimension

Description

Imprecise consonants

Consonants lack clarity and sharpness Monotone voice lacking inflectional changes Reduction of proper emphasis pattern Monotone of loudness Level of voice sound is low Speed of speech is low Excessively nasal-sounding voice Sounds pronounced with great effort Phrases shortened, as though speaker is out of breath Weak, continuous, breathy voice Nasal emission of air stream Excess stress on parts of speech that are not usually stressed Nonsystematic breakdown of articulation Vowels sound are distorted throughout their duration Rough, raspy voice Silent intervals occur inappropriately Short rushes of speech separated by pauses Rate alternates from fast to slow

Monopitch Reduced stress Monoloudness Low pitch Slow rate Hypernasality Strained voice Short phrases Breathy voice Nasal emission Excess and equal stress Irregular articulatory breaks Distorted vowels Harsh voice Inappropriate silence Short rushes Variable rate

Source: Adapted from Darley et al. (1969a).

bance found in Parkinson’s disease. The associated neurological findings are tremor, masked facies, and paucity of movements. In hyperkinetic dysarthria, speech is loud, poorly coordinated with respiration, and interrupted by anticipations and/or involuntary bodily and facial movements. This results in unpredictable voice halting, with disintegration of articulation and prosody (Table 25.7). There is excessive variation of loudness resulting from an altered breathing cycle. The neuromuscular basis includes inaccurate, unsustained, and irregular rhythm of movement, slowness of movement, reduced force of movement and sustained or spasmodic hypertonus (Darley et al., 1969a). The random, unsustained and irregular movements of chorea or the distorted posturing of the head, neck, trunk and proximal limbs of dystonia are the neurological findings associated with hyperkinetic dysarthria.

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Dysphagia and aspiration syndromes Mark J. Alberts1 and Jennifer Horner-Catt2 1 Department of Medicine, Duke University Medical Center, Durham NC, USA and 2Department of Speech and Language Therapy, University of Canterbury, Christchurch, New Zealand

Introduction Dysphagia (abnormal swallowing causing dysfunction) and aspiration (passage of material below the level of the true vocal folds) are being