Stroke Practical Management

THIRD EDITION

C. Warlow J. van Gijn M. Dennis J. Wardlaw J. Bamford G. Hankey P. Sandercock G. Rinkel P. Langhorne C. Sudlow P. Rothwell

Stroke Practical Management

THIRD EDITION Dedication To our many colleagues, young and old, with whom we have shared the care of so many stroke patients, and with whom we have discussed so many interesting ideas.

Acknowledgement The authors of this book are particularly grateful to Joanna Warldlaw, who has drawn much of the line artwork throughout the three editions. Stroke Practical Management

THIRD EDITION

C. Warlow J. van Gijn M. Dennis J. Wardlaw J. Bamford G. Hankey P. Sandercock G. Rinkel P. Langhorne C. Sudlow P. Rothwell © 2007 C. Warlow, J. van Gijn, M. Dennis, J. Wardlaw, J. Bamford, G. Hankey, P. Sandercock, G. Rinkel, P. Langhorne, C. Sudlow, P. Rothwell

Published by Blackwell Publishing Blackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia

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First edition published 1996 Second edition published 2001 Third edition published 2008

1 2008

Library of Congress Cataloging-in-Publication Data

Stroke : practical management / C. Warlow . . . [et al.]. – 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-2766-0 (hardcover : alk. paper) 1. Cerebrovascular disease. 2. Cerebrovascular disease – Treatment. I. Warlow, Charles, 1934- [DNLM: 1. Cerebrovascular Accident – therapy. 2. Intracranial Hemorrhages – therapy. 3. Ischemic Attack, Transient – therapy. WL 355 S9208 2007]

RC388.5.S847 2007 616.8’1 – dc22 2007022955 ISBN: 978-1-4051-2766-0

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Contributors, vi Acknowledgements, vii Abbreviations, viii 1 Introduction, 1 2 Development of knowledge about cerebrovascular disease, 7 3 Is it a vascular event and where is the lesion?, 35 4 Which arterial territory is involved?, 131 5 What pathological type of stroke is it, cerebral ischaemic or haemorrhage?, 181 6 What caused this transient or persisting ischaemic event?, 259 7 Unusual causes of ischaemic stroke and transient ischaemic attack, 353 8 What caused this intracerebral haemorrhage?, 411 9 What caused this subarachnoid haemorrhage?, 457 10 A practical approach to the management of stroke and transient ischaemic attack patients, 503 11 What are this person’s problems? A problem-based approach to the general management of stroke, 537 12 Specific treatments for acute ischaemic stroke, 635 13 Specific treatment of intracerebral haemorrhage, 703 14 Specific treatment of aneurismal subarachnoid haemorrhage, 719 15 Specific interventions to prevent intracranial haemorrhage, 767 16 Preventing recurrent stroke and other serious vascular events, 789 17 The organization of stroke services, 903 18 Reducing the impact of stroke and improving the public health, 953 Index, 980 Colour plates are found facing p.550

v Contributors

Charles Warlow University of Edinburgh, Western General Hospital, Edinburgh, UK

Jan van Gijn Utrecht University, Utrecht, the Netherlands

Martin Dennis University of Edinburgh, Western General Hospital, Edinburgh, UK

Joanna Wardlaw University of Edinburgh, Western General Hospital, Edinburgh, UK

John Bamford St James’ University Hospital, Leeds, West Yorkshire, UK

Graeme Hankey Royal Perth Hospital, Stroke Unit, Perth WA, Australia

Peter Sandercock University of Edinburgh, Western General Hospital, Edinburgh, UK

Gabriel Rinkel Utrecht University, Utrecht, the Netherlands

Peter Langhorne Academic Section of Geriatric Medicine, Royal Infirmary, Glasgow, UK

Cathie Sudlow University of Edinburgh, Western General Hospital, Edinburgh, UK

Peter Rothwell Department of Clinical Neurology, Radcliffe Infirmary, Oxford, UK

vi Acknowledgements

We have had invaluable help and advice from many Also, thank you to our teachers and colleagues from people in the preparation of this third edition. So thank whom we have learned so many worthwhile things over you all, including: the years:

Sheena Borthwick Henry Barnett Judi Clarke Lou Caplan Carl Counsell David Chadwick Ann Deary Iain Chalmers Alice Emmott Rory Collins Hazel Fraser Hans van Crevel Paut Greebe Richard Doll Gord Gubitz Geoff Donnan Ingrid Kane Stuart Douglas Sarah Keir Shah Ebrahim Alistair Lammie Rob Edis Lynn Legg Barbara Farrell Richard Lindley C. Miller Fisher Mike McDowell Chris Foote Michael Mackie John Fry Ian Marshall Mike Gent Nick Morgan Sonny Gubbay Ross Naylor Michael Harrison Sarah Pendlebury Jim Heron David Perry Steff Lewis Rustam Al-Shahi Salman Bryan Matthews Cameron Sellers Richard Peto Mark Smith Alex Pollock Ian Starkey Geoffrey Rose Stuart Taylor David Sackett Brenda Thomas Robin Sellar Theo vanVroonhoven David Shepherd Nic Weir Jim Slattery Rien Vermeulen Ted Stewart-Wynne Derick Wade Eelco Wijdicks

vii Abbreviations

We don’t care much for abbreviations. They are not liter- ATP Adenosine triphosphate ate (Oliver Twist was not abbreviated to OT each time ATT Antithrombotic Trialists’ Collaboration Dickens mentioned his name!), they don’t look good on AVF Arteriovenous fistula the printed page, and they make things more difficult to AVM Arteriovenous malformation read and understand, particularly for non-experts. But BA Basilar artery they do save space and so we have to use them a bit. BIH Benign intracranial hypertension However, we will avoid them as far as we can in tables, BMI Body mass index figures and the practice points. We will try to define any BP Blood pressure abbreviations the first time they are used in each chap- C Celsius ter, or even in each section if they are not very familiar. CAA Cerebral amyloid angiopathy But, if we fail to be comprehensible, then here is a rather CADASIL Cerebral autosomal dominant arteriopathy long list to refer to. with subcortical infarcts and leukoencephalopathy ACA Anterior cerebral artery CAST Chinese Acute Stroke Trial ACE Angiotensin converting enzyme CAVATAS Carotid and Vertebral Artery Transluminal AChA Anterior choroidal artery Angioplasty Study ACoA Anterior communicating artery CBF Cerebral blood flow ACST Asymptomatic Carotid Surgery Trial CBFV Cerebral blood flow velocity ADC Apparent diffusion coefficient CBV Cerebral blood volume ADH Antidiuretic hormone CCA Common carotid artery ADL Activities of daily living CEA Carotid endarterectomy ADP Adenosine diphosphate CHD Coronary heart disease ADPKD Autosomal dominant polycystic kidney CI Confidence interval disease CK Creatine kinase

AF Atrial fibrillation CMRO2 Cerebral metabolic rate of oxygen AFx Amaurosis fugax CMRglu Cerebral metabolic rate of glucose AH Ataxic hemiparesis CNS Central nervous system AICA Anterior inferior cerebellar artery CPP Cerebral perfusion pressure AIDS Acquired immune deficiency syndrome CPSP Central post-stroke pain AMI Acute myocardial infarction CSF Cerebrospinal fluid ANCA Antineutrophil cytoplasmic antibody CT Computed tomography ANF Antinuclear factor CTA Computed tomographic angiography APS Antiphospholipid syndrome CVR Cerebrovascular resistance APT Antiplatelet Trialists’ Collaboration DBP Diastolic blood pressure APTT Activated partial thromboplastin time DCHS Dysarthria clumsy-hand syndrome ARAS Ascending reticular activating system DIC Disseminated intravascular coagulation ARD Absolute risk difference DNA Deoxyribose nucleic acid ASA Atrial septal aneurysm DSA Digital subtraction angiography ASD Atrial septal defect DSM Diagnostic and statistical manual of mental ATIII Antithrombin III disorders viii Abbreviations ix

DVT Deep venous thrombosis (in the legs or MAOI Monoamine oxidase inhibitor pelvis) MAST-I Multicentre Acute Stroke Trial – Italy DWI Diffusion weighted (MR) imaging MCA Middle cerebral artery EACA Epsilon-aminocaproic acid MCTT Mean cerebral transit time EADL Extended activities of daily living MES Microembolic signals EAFT European Atrial Fibrillation Trial MI Myocardial infarction ECA External carotid artery MLF Medial longitudinal fasciculus ECASS European Cooperative Acute Stroke Study MLP Mitral leaflet prolapse ECG Electrocardiogram MMSE Mini mental state examination EC-IC Extracranial-intracranial MR Magnetic resonance ECST European Carotid Surgery Trial MRA Magnetic resonance angiography EEG Electroencephalogram MRC Medical Research Council EMG Electromyography MRI Magnetic resonance imaging ESR Erythrocyte sedimentation rate MRS Magnetic resonance spectroscopy FDA Food and Drug Administration MRV Magnetic resonance venogram FIM Functional independence measure MTT Mean transit time FLAIR Fluid attenuated inversion recovery NAA N-acetylaspartate FMD Fibromuscular dysplasia NASCET North American Symptomatic Carotid fMRI Functional magnetic resonance imaging Endarterectomy Trial FMZ Flumazenil NELH National Electronic Library for Health GCS Glasgow Coma Scale NG Nasogastric GEF Glucose extraction fraction NIHSS National Institute of Health Stroke Score GKI Glucose, potassium and insulin NINDS National Institute of Neurological Disorders HACP Homolateral ataxia and crural paresis and Stroke Hg Mercury NNT Number-needed-to-treat HITS High intensity transient signals NO Nitric oxide HIV Human immunodeficiency virus OCSP Oxfordshire Community Stroke Project HMPAO Hexamethylpropyleneamine oxime OEF Oxygen extraction fraction HTI Haemorrhagic transformation of an infarct OHS Oxford Handicap Scale HU Hounsfield units OR Odds ratio IAA Internal auditory artery PACI Partial anterior circulation infarction

IAA Intra arterial angiography PaCO2 Arterial partial pressure of carbon dioxide ICA Internal carotid artery PaO2 Arterial partial pressure of oxygen ICH Intracerebral haemorrhage PACS Partial anterior circulation syndrome ICIDH International classification of impairments, PCA Posterior cerebral artery disabilities and handicaps PChA Posterior choroidal artery ICP Intracranial pressure PCoA Posterior communicating artery ICVT Intracranial venous thrombosis PCV Packed cell volume IADSA Intra-arterial digital subtraction PE Pulmonary embolism angiography PEG Percutaneous endoscopic gastrostomy INR International normalized ratio PET Positron emission tomography IST International Stroke Trial PFO Patent foramen ovale IVDSA Intravenous digital subtraction angiography PICA Posterior inferior cerebellar artery IVM Intracranial vascular malformation PMS Pure motor stroke kPa Kilopascals PNH Paroxysmal nocturnal haemoglobinuria L Litre POCI Posterior circulation infarction LACI Lacunar infarction POCS Posterior circulation syndrome LACS Lacunar syndrome PD Proton density LGN Lateral geniculate nucleus PSE Present state examination LP Lumbar puncture PSS Pure sensory stroke LSA Lenticulostriate artery PT Prothrombin time M Molar PTA Percutaneous transluminal angioplasty MAC Mitral annulus calcification PVD Peripheral vascular disease x Abbreviations

PWI Perfusion weighted (MR) imaging SLE Systemic lupus erythematosus QALYs Quality adjusted life years SMS Sensorimotor stroke RAH Recurrent artery of Heubner SPAF Stroke prevention in atrial fibrillation (trial) RCT Randomized controlled trial SPECT Single photon emission computed RIND Reversible ischaemic neurological deficit tomography RNA Ribonucleic acid SVD Small vessel disease ROR Relative odds reduction TACI Total anterior circulation infarction RR Relative risk TACS Total anterior circulation syndrome RRR Relative risk reduction TCD Transcranial Doppler rt-PA Recombinant tissue plasminogen activator TEA Tranexamic acid SADS Schedule for affective disorders and TENS Transcutaneous electrical nerve stimulation schizophrenia TGA Transient global amnesia SAH Subarachnoid haemorrhage TIA Transient ischaemic attack SBP Systolic blood pressure TMB Transient monocular blindness SCA Superior cerebellar artery TOAST Trial of ORG 10172 in Acute Stroke Therapy SD Standard deviation TTP Thrombotic thrombocytopenic purpura SEPIVAC Studio epidemiologico sulla incidenza delle TTP Time to peak vasculopathie acute cerebrali US Ultrasound SF36 Short form 36 VA Vertebral artery SIADH Syndrome of inappropriate secretion of VB Vertebrobasilar antidiuretic hormone WHO World Health Organization SK Streptokinase WFNS World Federation of Neurological Surgeons 1 Introduction

1.1 Introduction to the first edition 1 1.2 Introduction to the second edition 3 1.3 Introduction to the third edition 4

and the rest represent just the tools to solve the problems 1.1 Introduction to the first edition – so they are used when they are needed, and not dis- cussed in isolation. For example, to prevent strokes one needs to know how frequent they are (epidemiology), what types of stroke there are (pathology), what causes 1.1.1 Aims and scope of the book them (aetiology) and what evidence there is to support We, the authors of this book, regard ourselves as prac- therapeutic intervention (randomized controlled trials). tising – and practical – doctors who look after stroke Clinicians mostly operate on a need-to-know basis, and patients in very routine day-to-day practice. The book so when a problem arises they need the information to is for people like us: neurologists, geriatricians, stroke solve it at that moment, from inside their head, from a physicians, radiologists and general internal physicians. colleague – and we hope from a book like this. But it is not just for doctors. It is also for nurses, ther- apists, managers and anyone else who wants practical 1.1.2 General principles guidance about all and any of the problems to do with stroke – from aetiology to organization of services, from To solve a problem one obviously needs relevant inform- prevention to occupational therapy, and from any facet ation. Clinicians, and others, should not be making deci- of cure to any facet of care. In other words, it is for any- sions based on whim, dogma or the last case, although one who has to deal with stroke in clinical practice. It is most do, at least some of the time – ourselves included. It not a book for armchair theoreticians, who usually have is better to search out the reliable information based on no sense of proportion as well as difficulty in seeing the some reasonable criterion for what is meant by reliable, wood from the trees. Or, maybe, it is particularly for get it into a sensible order, review it and make a summary them so that they can be led back into the real world. that can be used at the bedside. If one does not have The book takes what is known as a problem-orientated the time to do this – and who does for every problem? – approach. The problems posed by stroke patients are then one has to search out someone else’s systematic discussed in the sort of order that they are likely to pre- review. Or find the answer in this book. Good clinicians sent themselves. Is it a stroke? What sort of stroke is have always done all this intuitively, although recently it? What caused it? What can be done about it? How can the process has been blessed with the title of ‘evidence- the patient and carer be supported in the short term and based medicine’, and now even ‘evidence-based patient- long term? How can any recurrence be prevented? How focused medicine’! In this book we have used the can stroke services be better organized? Unlike traditional evidence-based approach, at least where it is possible to textbooks, which linger on dusty shelves, there are no do so. Therefore, where a systematic review of a risk ‘-ology’ chapters. Aetiology, epidemiology, pathology factor or a treatment is available we have cited it, and not just emphasized single studies done by us or our friends and with results to suit our prejudices. But so often there is no good evidence or even any evidence at all avail- Stroke: practical management, 3rd edition. C. Warlow, J. van Gijn, M. Dennis, J. Wardlaw, J. Bamford, G. Hankey, P. Sandercock, able, and certainly no systematic reviews. What to do G. Rinkel, P. Langhorne, C. Sudlow and P. Rothwell. Published then? Certainly not what most doctors are trained to do: 2008 Blackwell Publishing. ISBN 978-1-4051-2766-0. ‘Never be wrong, and if you are, never admit it!’ If we do

1 2 Chapter 1 Introduction

not know something, we will say so. But, like other and the second draft was sent round to everyone for clinicians, we may have to make decisions even when we comments in an attempt to improve the clarity, remove do not know what to do, and when nobody else does duplication, fill in gaps and expunge as much remaining either. One cannot always adopt the policy of ‘if you neurodogma, neurofantasy and neuroastrology as poss- don’t know what to do, don’t do it’. Throughout the ible. Our final discussion was held at the Bordeaux stroke book we will try to indicate where there is no evidence, meeting in 1995, and the drinks that time were more or feeble evidence, and describe what we do and will con- in relief and celebration that the end was in sight. Home tinue to do until better evidence becomes available; after we all went to update the manuscript and make final all, it is these murky areas of practice that need to be improvements before handing over the whole lot to the flagged up as requiring further research. Moreover, in publisher in January 1996. clinical practice, all of us ask respected colleagues for This process may well have taken longer than a con- advice, not because they may know something that we ventional multiauthor book in which all the sections are do not but because we want to know what they would written in isolation. But it was surely more fun, and do in a difficult situation. hopefully the result will provide a uniform and coherent view of the subject. It is, we hope, a ‘how to do it’ book, or at least a ‘how we do it’ book. 1.1.3 Methods We were all taught to look at the ‘methods’ section of a 1.1.4 Using the book scientific paper before anything else. If the methods are no good, then there is no point in wasting time This is not a stroke encyclopaedia. Many very much and reading further. In passing, we do regard it as more comprehensive books and monographs are avail- most peculiar that some medical journals still print the able now, or soon will be. Nor is this really a book to be methods section in smaller letters than the rest of the read from cover to cover. Rather, it is a book that we paper. Therefore, before anyone reads further, perhaps would like to be used on stroke units and in clinics to we should describe the methods we have adopted. help illuminate stroke management at various different It is now impossible for any single person to write a stages, both at the level of the individual patient and comprehensive book about stroke that has the feel of for patients in general. So we would like it to be kept having been written by someone with hands-on experi- handy and referred to when a problem crops up: how ence of the whole subject. The range of problems is far should swallowing difficulties be identified and man- too wide. Therefore, the sort of stroke book that we as aged? Should an angiogram be done? Is raised plasma practitioners want – and we hope others do too – has to fibrinogen a cause of stroke? How many beds should a be written by a group of people. Rather than putting stroke unit have? And so on. If a question is not addressed together a huge multiauthor book, we thought it would at all, then we would like to know about it so that it can be better and more informative, for ourselves as well be dealt with in the next edition, if there is to be one, as readers, to write a book together that would take a which will clearly depend on sales, the publisher, and particular approach (evidence-based, if you will) and end enough congenial European stroke conferences to keep up with a coherent message. After all, we have all worked us going. together over many years, our views on stroke are more It should be fairly easy to find one’s way around the convergent than divergent, and so it should not be too book from the chapter headings and the contents list terribly difficult to write a book together. at the beginning of each chapter. If that fails, then Like many things in medicine, and in life, this book the index will do instead. We have used a lot of cross- started over a few drinks to provide the initial momen- referencing to guide the reader from any starting point tum to get going, on the occasion of a stroke conference and so avoid constant reference to the index. in Geneva in 1993. At that time, we decided that the As mentioned earlier, we have tried to be as selective book was to be comprehensive (but not to the extent of as possible with the referencing. On the one hand, we citing every known reference), that all areas of stroke want to allow readers access to the relevant literature, must be covered, and who was going to start writing but on the other hand we do not want the text to be which section. A few months later, the first drafts were overwhelmed by references – particularly by references then commented on in writing and in detail by all the to unsound work. To be selective, we have tried to cite authors before we got back together for a general dis- recent evidence-based systematic reviews and classic cussion – again over a few drinks, but on this occasion at papers describing important work. Other references can the Stockholm stroke conference in 1994. Momentum probably mostly be found by those who want to dig deeper restored, we went home to improve what we had written, in the reference lists of the references we have cited. 1.2 Introduction to the second edition 3

Finally, we have liberally scattered what some would genuinely been able to write material together; one call practice points and other maxims throughout the author does a first draft, sends it as an attachment across book. These we are all prepared to sign up to, at least in the world in seconds, the other author appends ideas early 1996. Of course, as more evidence becomes avail- and e-mails the whole attachment back to the first able, some of these practice points will become out of author, copying to other authors for comments perhaps, date. and so on until it is perfect. Of course, we still do not all agree about absolutely everything all of the time. After all, we want readers to have a feel for the rough and 1.1.5 Why a stroke book now? ragged growing edge of stroke research, where there is Stroke has been somewhat of a Cinderella area of bound to be disagreement. If we all knew what to do for medicine, at least with respect to the other two of the stroke patients there would be no need for randomized three most common fatal disorders in the developed controlled trials to help us do better – an unrealistic world – coronary heart disease and cancer. But times are scenario if ever there was one. So where there is uncer- gradually changing, particularly in the last decade when tainty, and where we disagree, we have tried to make stroke has been moving up the political agenda, when that plain. But, on the whole, we are all still prepared to research has been expanding perhaps in the slipstream sign up to the practice points. of coronary heart disease research, when treatments In this second edition, we have been able to correct to prevent, if not treat, stroke have become available the surprising number of minor typographical errors and when the pharmaceutical industry has taken more and hope not to have introduced any more, get all the notice. It seems that there is so much information about X-rays the right way up, improve on some of the figures, stroke that many practitioners are beginning to be over- remove some duplication, reorder a few sections, put whelmed. Therefore, now is a good time to try to capture in some more subheadings to guide the readers, make all this information, digest it and then write down a the section on acute ischaemic stroke more directive, practical approach to stroke management based on the improve the index, and generally tidy the whole thing best available evidence and research. This is our excuse up. It should now be easier to keep track of intracranial for putting together what we know and what we do not venous thrombosis and, in response to criticism, we know, what we do and why we do it. have extended the section on leukoaraiosis, even though it is not strictly either a cause or a consequence of stroke. We have also introduced citations to what we have called ‘floating references’ – in other words, published work that is constantly being changed and updated as 1.2 Introduction to the second edition new information becomes available. An obvious ex- ample is the Cochrane Library, which is updated every 3 months and available on CD-ROM and through the Whether we enjoyed our annual ‘stroke book’ dinners at Internet. There are no page numbers, and the year of the European stroke conferences too much to abandon publication is always the present one. We have therefore them, or whether we thought there really was a lot of cited such ‘floating references’ as being in the present updating to do, we found ourselves working on this sec- year, 2000. But we know that this book will not be read ond edition four short years after the first. It has certainly much until the year 2001 and subsequent years, when helped to have been so much encouraged by the many readers will have to look at the contemporary Cochrane people who seemed to like the book, and find it useful. Library, not the one published in 2000. The same applies We have kept to the same format, authors, and prin- to the new British Medical Journal series called ‘Clinical ciples outlined above in the introduction to the first Evidence’ which is being updated every 6 months, and edition. The first step was for all of us to read the whole to any websites that may be updated at varying intervals book again and collect together any new comments and and are still very much worth directing readers towards. criticisms for each of the other authors. We then rewrote Rather to our surprise, there is a lot of new information our respective sections and circulated them to all the to get across on stroke. Compared with 4 years ago, the other authors for their further comments (and they were concept of organized stroke services staffed by experts in not shy in giving them). We prepared our final words in stroke care has taken root and has allowed the increas- early 2000. ingly rapid assessment of patients with ‘brain attacks’.

A huge technical advance since writing the first edi- It is no longer good enough to sit around waiting 24 ·h tion has been the widespread availability of e-mail and or more to see if a patient is going to have a transient

the use of the Internet. Even more than before, we have ischaemic attack or a stroke, and then another 24 ·h for a 4 Chapter 1 Introduction

computed tomography brain scan to exclude intracere- wanted to ensure our succession, we have recruited four bral haemorrhage. These days we have to assess and scan new and younger authors, all of whom have worked stroke patients as soon as they arrive in hospital, perhaps closely with us over many years, and whose help we give thrombolysis to a few, and enter many more into acknowledged in the earlier editions – Gabriel Rinkel, clinical trials, start aspirin in ischaemic stroke, and get Peter Langhorne, Cathie Sudlow and Peter Rothwell. But, the multidisciplinary team involved – and all of this well even with their help, the rewriting has had to compete

within 24 ·h of symptom onset. Through the Cochrane with all the far less interesting things which we have to Library, which was in its infancy when the first edition do these days to satisfy managers, regulatory authorities was published, there is now easy, regularly updated elec- and others keen to track and measure our every move. tronic access to systematic reviews of most of the acute And maybe there is less imperative to write books like interventions and secondary prevention strategies for this which are out of date in at least some ways even stroke, although the evidence base for rehabilitation before they are published. But then searching the Internet techniques is lagging behind. Catheter angiography is for ‘stroke’ does not come up with a coherent account of giving way to non-invasive imaging. Magnetic reson- the whole subject of managing stroke patients using the ance techniques are racing ahead of the evidence as to best available evidence, which is what this book is all how they should be used in routine clinical practice. For about. So, with the help and encouragement of Blackwell better or worse, coiling cerebral aneurysms is replacing Publishing, here is the third edition of ‘the book’ at clipping. The pharmaceutical industry is still tenaciously last. hanging on to the hope of ‘neuroprotection’ in acute We have written the book as before with most of the ischaemic stroke, despite numerous disappointments. authors commenting on most of the chapters before all Hyperhomocysteinaemia and infections are the pres- the chapters were finally written in the form you can ently fashionable risk factors for ischaemic stroke, and read them in now. Again, you will have to guess who they may or may not stand the test of time. So, in this wrote what because we can all lay claim to most of the second edition, we have tried to capture all these advances book in some sense or another. There has been a slight – and retreats – and set them in the context of an up-to- change in the arrangement of the chapters, but loyal date understanding of the pathophysiology of stroke readers of the earlier editions will not find this too and the best available evidence of how to manage it. Of upsetting – they will still find what they want in more course, it is an impossible task, because something new is or less its familiar place, and as ever we hope the index always just around the corner. But then ‘breakthroughs’ has been improved. The practice points we all sign up to in medicine take time to mature – maybe years until the and our day-to-day practice should reflect them. The evidence becomes unassailable and is gradually accepted uncertainties we all share – they will be gradually resolved by front-line clinicians. And then we can all sit back as more research is done, and more uncertainties will doing what we believe to be ‘the right thing’ for a few then be revealed. The biggest change in this edition is more years until the next ‘breakthrough’ changes our succumbing to the space saving offered by a numbered view of the world yet again. reference system, and a change in the colour scheme We hope that the ideas and recommendations in this from a pastel green to various shades of purple. book will be sufficient 99% of the time – at least for the As with the second edition, much has changed and next 4 years, when we will have to see about a third there has been more updating than we originally anti- edition. cipated – what we know about stroke has moved on. Neuroprotection is even less likely to be an effective treatment for ischaemic stroke than it was in the 1990s, we still argue about thrombolysis, clopidogrel cannot very often be recommended, carotid stenting has still 1.3 Introduction to the third edition to prove its worth, routine evacuation of intracerebral haemorrhage is definitely not a good idea, and hormone replacement therapy far from protecting against vascular Six years have gone quickly by since the second edition, disease actually seems to increase the risk. But on the much has happened in stroke research and practice in positive side, much has improved in brain and vessel the meantime, and two of the authors are on the edge of imaging, it is now clear how much blood pressure lower- retirement – so it is time for this third edition of what we ing has to offer in secondary stroke prevention, and fondly refer to as ‘the book’. Maybe because the original cholesterol lowering too. Carotid surgery can now be authors were feeling tired, or increasingly unable to targeted on the few who really need it, not recommended cover in depth all we wanted to, or perhaps because we for the greater number who may or may not need it. 1.3 Introduction to the third edition 5

Coiling has more or less replaced clipping of intracranial crowded and competitive field than it was when some of aneurysms, an astonishing change in practice brought us started in the 1970s. about by a large trial energetically led by an interven- Will there be a fourth edition? We don’t know; this tional neuroradiologist and neurosurgeon. And it is not will be in the hands of the remaining authors as Charles just acute stroke that needs urgent attention nowadays, Warlow and Jan van Gijn dwindle into retirement of a transient ischaemic attacks must be assessed and man- sort, or at least a life that will not require the relentless aged very quickly to minimize the early high risk of battle to keep up with all the stroke literature, critique stroke. Stroke services continue to improve all over the it, absorb anything that is worthwhile, and then put it world, stroke has moved up the political agenda as we into the context of active clinical practice. No one can have managed to wrench it out of the rubric of ‘cardio- write well about stroke unless they can connect research vascular’ disease which always emphasized the cardiac with their own active clinical practice – we are not, we rather than the cerebral, and more and more people are hope, armchair theoreticians; we try to practise what we involved in stroke research, which is now a much more preach.

Development of knowledge 2 about cerebrovascular disease

2.1 Ideas change slowly 7 2.2 The anatomy of the brain and its blood supply 8 2.3 What happens in ‘apoplexy’? 10 2.4 Cerebral infarction (ischaemic stroke) 14 2.5 Thrombosis and embolism 16 2.6 Transient ischaemic attacks 17 2.7 Intracerebral haemorrhage 20 2.8 Subarachnoid haemorrhage 21 2.9 Treatment and its pitfalls 25 2.10 Epilogue 28

‘Our knowledge of disorders of the cerebral circulation the term ‘cerebral thrombosis’ up to the 1970s exem- and its manifestations is deficient in all aspects’ was plifies how deficient our understanding was even at that the opening sentence of the chapter on cerebrovascular time.2 Embolic occlusion, now known to result more diseases in Oppenheim’s textbook of neurology at the often from arterial lesions than from the heart, can be beginning of the 20th century.1 More than 90 years later detected in an early phase by non-invasive angiographic this still holds true, despite the considerable advances techniques or inferred by means of perfusion imaging, that have been made. In fact, the main reason for but so often the source of the clot is still elusive. We Oppenheim’s lament, the limitations of pathological have also learned to distinguish many causes of cerebral anatomy, is to some extent still valid. True, our methods infarction other than atherothrombosis, such as arterial of observation nowadays are no longer confined to dissection, mitochondrial cytopathies and moyamoya the dead, as they were then. They have been greatly syndrome, but the precise pathogenesis of these condi- expanded, first by angiography, then by brain imaging tions is still poorly understood. and measurement of cerebral blood flow and meta- So it is with humility, rather than in triumph, that we bolism, and most recently by non-invasive methods look back on the past. In each era the problems of stroke of vascular imaging such as ultrasound and magnetic have been approached by the best minds, with the best resonance angiography. Yet, our observations are still tools available. Of course many ideas in the past were mostly anatomical, and after the event. It is only in rare wrong, and so presumably are many of our own. Even instances that are we able to reconstruct the dynamics though we are firm believers in evidence-based medicine, of a stroke. At least in haemorrhagic stroke, brain com- some – perhaps many or even most – of our own notions puted tomography (CT) or magnetic resonance imaging will not survive the test of time. Our knowledge may (MRI) in the acute phase gives an approximate indica- have vastly increased in the recent past but it is still a tion of where a blood vessel has ruptured (though not mere island in an ocean of ignorance. why exactly there and then) and how far the extra- vasated blood has invaded the brain parenchyma or the subarachnoid space. With ischaemic stroke, the growth of our understanding has been slower. The ubiquity of 2.1 Ideas change slowly

Stroke: practical management, 3rd edition. C. Warlow, J. van Gijn, M. Dennis, J. Wardlaw, J. Bamford, G. Hankey, P. Sandercock, G. Rinkel, P. Langhorne, C. Sudlow and P. Rothwell. Published The history of medicine, like that of kings and queens 2008 Blackwell Publishing. ISBN 978-1-4051-2766-0. in world history, is usually described by a string of dates

7 8 Chapter 2 Development of knowledge about cerebrovascular disease

and names, by which we leapfrog from one discovery to the background of contemporary knowledge, can often another. The interval between such identifiable advances be inferred from textbooks, particularly if written by full- is measured in centuries when we describe the art of time clinicians rather than by research-minded neuro- medicine at the beginning of civilization, but in mere logists. Therefore we shall occasionally quote old textbooks years where our present times are chronicled. This leads to illustrate the development of thinking about stroke. to the impression that we are witnessing a dazzling A reverse problem is that a new discovery or even a explosion of knowledge. Some qualification of this view new fashion may be interpreted beyond its proper limits is needed, however. First of all, any generation of mankind and linger on as a distorted idea for decades. Take the dis-

takes a myopic view of history in that the importance covery of vitamin B1 deficiency as the cause of a tropical of recent developments is overestimated. The Swedish polyneuropathy almost a century ago; the notion that a Academy of Sciences therefore often waits for years, some- neurological condition, considered untreatable almost times even decades, before awarding Nobel prizes, until by definition, could be cured by a simple nutritional scientific discoveries have withstood the test of time. supplement made such an impact on the medical com- When exceptions were made for the prize in medicine, munity that even in some industrialized countries

the early accolades were not always borne out: Wagner- vitamin B1 is still widely used as a panacea for almost any Jauregg’s malaria treatment for neurosyphilis (1927) is neurological symptom. no longer regarded as a landmark, while Moniz’s prize So broadly speaking there are two kinds of medical his- (1949) for prefrontal leucotomy no longer seems justi- tory, that of the cutting edge of research and that of the fied; at least he also introduced contrast angiography of medical profession as a whole. The landmarks are easy to the brain, although this procedure may again not survive identify only with the hindsight of present knowledge. beyond the end of this century. We can only hope that In reality, new ideas often only gradually dawned on the introduction of X-ray CT by Hounsfield (Nobel prize consecutive scientists, instead of the popular notion of a for medicine in 1979) will be judged equally momentous blinding flash of inspiration occurring in a single indi- by future generations as by ourselves. vidual. For this reason, accounts of the history of stroke Another important caveat if one looks back on progress are not always identical.9,10 Also many important pri- in medicine is that most discoveries gain ground only mary sources are not easy to interpret – not only because slowly. Even if new insights were quickly accepted by they were written in Latin, but also because ‘new obser- peer scientists, which was often not the case, it could still vations’ have sometimes been identified only by later be decades before these had trickled down to the rank historians, in retrospect, while the authors at the time and file of medical practitioners. The mention of a cer- attached no importance to them.11 tain date for a discovery may create the false impression that this change in medical thinking occurred almost overnight, like the introduction of the single European currency. In most instances, this was far from the truth. An apt example is the extremely slow rate at which the 2.2 The anatomy of the brain and its blood concept of lacunar infarction became accepted by the supply medical community, despite its potentially profound implications in terms of pathophysiology, treatment and prognosis. The first pathological descriptions date From at least the time of Hippocrates (460–370 BC), the from around 1840,3,4 but it took the clinicopathological brain was credited with intelligence and thought, and correlations of C. Miller Fisher (Fig. 2.7) in the 1960s before also with movements of the opposite side of the body, the neurological community and its textbooks started to through observation of unilateral convulsions after take any notice.5–7 And it was not until new techniques head wounds on the contralateral side.12 Yet, stroke, or for brain imaging in the 1980s provided instantaneous ‘apoplexy’ (Greek for ‘being struck down’), was defined clinicoanatomical correlations that no practising neuro- as a sudden but mostly general, rather than focal, dis- logist could avoid knowing about lacunar infarcts – some order of the brain. The pathogenesis was explained 150 years after the first description! It is best to become according to the humoral theory, which assumed a reconciled to the idea that a slow rate of diffusion of new delicate balance between the four humours: blood, knowledge is unavoidable. The problem is one of all phlegm, black bile and yellow bile. Anatomy played times. Franciscus Biumi, one of the early pathologists, almost no part in these explanations. Apoplexy was lamented in 1765: ‘Sed difficile est adultis novas opiniones often attributed to accumulation of black bile in the inserere, evellere insitas’ (But it is difficult to insert new arteries of the brain, obstructing the passage of animated opinions in adults and to remove rooted ones).8 How spirits from the ventricles.13 Galenus of Pergamon (131– slowly new ideas were accepted and acted upon, against 201), a prolific writer and animal experimenter whose 2.2 The anatomy of the brain and its blood supply 9 views dominated medicine up to the 17th century,14 dis- the forms of nature. As a consequence, many non- tinguished ‘karos’ from ‘apoplexy’, in that respiration neurological disease conditions with sudden onset must was unaffected in the former condition.15 Leading have been misclassified as ‘apoplexy’. Islamic physicians like Avicenna (980–1037) tried to In 1543 Andries van Wesele (1514–1564), the great reconcile Galenic tenets with the Aristotelian view of the Renaissance anatomist who Latinized his name to heart as the seat of the mind.16 In Western Europe, Andreas Vesalius, produced the first accurate drawings of mostly deprived of Greek learning until the fall of the brain in his famous book De humani corporis fabrica Constantinople in 1453 prompted the Renaissance,17 libri septem, with the help of the draughtsman Johan these Arabic texts were translated into Latin before those Stephaan van Calcar and the printer Oporinus in Basle.19 of Galen and Hippocrates.18 All these theories had no It was the same year in which Copernicus published anatomical counterpart; dissection of the human body De revolutionibus, proclaiming the sun and not the earth was precluded by its divine connotations. Any illustra- as the centre of the universe.20 Vesalius largely ignored tions of the human brain that are known before the the blood vessels of the brain, although he retracted 16th century are crude and schematic representations an earlier drawing (Fig. 2.1) depicting a ‘rete mirabile’, a of Galenic theories, rather than attempts at copying network of blood vessels at the base of the brain that

Fig. 2.1 Plate depicting the blood vessels, from Vesalius’s Tabulae Anatomicae Sex, of 1538.21 This shows the carotid arteries ending up in a network (b) at the base of the brain; the structures marked (a) represent the choroid plexus in the lateral ventricles. The network of blood vessels (rete mirabile) is found in oxen; Galen had assumed it was found also in the human brain, a belief perpetuated throughout the Dark and Middle Ages, up to the early Renaissance. Leonardo da Vinci had also drawn a (human?) brain with a ‘rete mirabile’ at its base.22 Vesalius retracted the existence of a network in his atlas of 1543. 10 Chapter 2 Development of knowledge about cerebrovascular disease

Galen had found in pigs and oxen and that had been extrapolated to the human brain ever since.21,22 Before him, Berengario da Carpi had also denied the existence of the rete.23 Vesalius was vehemently attacked by tradi- tionally minded contemporaries as an iconoclast of Galenic dogmas. Nevertheless, initially, he did not go as far as outright opposition to the central Galenic tenet that blood could pass through the septum between the right and left ventricle of the heart, allowing the mixture of blood and air and the elimination of ‘soot’. Instead, he praised the creator for having made the openings so small that nobody could detect them, another striking example of how the power of theory may mislead even the most inquisitive minds. Only later, in the 1555 edition of his De humani corporis fabrica, did he firmly state that the interventricular septum was tightly closed. The decisive blow to the humoral theory came in 1628, through the description of the circulation by William Harvey (1578–1657);24 it need no longer surprise us that it took many decades before these views were widely accepted. Harvey’s work formed the foundation for the recognition of the role of blood vessels in the patho- genesis of stroke. Thomas Willis (1641–1675) is remembered not so Fig. 2.2 Illustration of the base of the brain from Willis’s 26 much for having coined the term ‘neurology’, or for his Cerebri Anatome (1664), showing the interconnections iatrochemical theories, a modernized version of humoral between the right and left carotid systems, and also between these two and the posterior circulation (drawing by medicine, or for his part in the successful resuscitation of Christopher Wren). Ann Green after judicial hanging,25 as he is for his work on the anatomy of the brain, first published in 1664,26 Arteries, both the Carotid and the Vertebral, within the especially for his description of the vascular interconnec- Skull, were become bony and impervious, and did shut tions at the base of the brain (Fig. 2.2).27 Before him, forth the blood from that side, notwithstanding the Fallopius, Casserio, Vesling and Wepfer had all observed sick person was not troubled with the astonishing at least part of the circle,28–31 in the case of Casserio and Disease. Vesling even with an illustration.32 But undisputedly, it was Willis who grasped the functional implications of It seems that the idea of infusing coloured liquids these anastomoses in a passage illustrating his profici- into blood vessels, practised from 1659 onwards and ency in performing necropsies as well as postmortem later perfected by Frederik Ruysch (1638–1731) and in experiments (from a posthumous translation):33 the next century by John Hunter (1728–1793),34,35 had come from Christopher Wren (1632–1723).25 Wren also We have elsewhere shewed, that the Cephalick Arteries, made the etchings for Willis’s book (he is now mainly viz. the Carotides, and the Vertebrals, do so commun- remembered as the architect of St Paul’s Cathedral and icate with one another, and all of them in different many other churches built after the great fire of London places, are so ingraffed one in another mutually, that in 1666). if it happen, that many of them should be stopped or pressed together at once, yet the blood being admitted to the Head, by the passage of one Artery only, either the Carotid or the Vertebral, it would presently pass thorow all those parts exterior and interior: which 2.3 What happens in ‘apoplexy’? indeed we have sufficiently proved by an experiment, for that Ink being squirted in the trunk of one Vessel, quickly filled all the sanguiferous passages, and every Willis’s ‘astonishing Disease’, apoplexy, had of old intuit- where stained the Brain it self. I once opened the ively been attributed to some ill-defined obstruction, dead Carcase of one wasted away, in which the right whether from want of ‘animal spirits’ via the nerves in 2.3 What happens in ‘apoplexy’? 11 the tradition of Greek medicine, or, after Harvey’s time, of blood and, on the other, extravasation of blood into by deprivation of blood flow. Yet, it should be remem- the substance of the brain or the ventricular cavities. His bered that the notion of an intrinsic ‘nervous energy’ interpretation was, however, that blockage of arteries only slowly lost ground. Even the great 18th-century as well as extravasation of blood impeded the transmis- physician Boerhaave, though clearly recognizing the sion of ‘spiritus animalis’ to the brain.11 Accordingly, he role of blood vessels and the heart in the development regarded apoplexy as a process of global stunning of the of apoplexy, invoked obstruction of the cerebrospinal brain, while the focal nature of the disease largely escaped fluid.36 In Table 2.1 we have provided a schematic repres- him. The four cases of haemorrhage Wepfer described entation of the development of ideas about apoplexy were massive, at the base of the brain or deep in the through the ages, together with its relationship to arterial parenchyma. In cases with obvious hemiplegia, incident- lesions. That Willis had found ‘bony’ and ‘impervious’ ally a term dating back to the Byzantine physician Paulus arteries in patients who actually had not died from Aegineta (625–690),38 Wepfer suspected dysfunction of a stroke was probably the reason that he was not out- the ipsilateral rather than the contralateral side. He also spoken on the pathogenesis of apoplexy. His contempor- observed patients who had recovered from apoplectic aries, Wepfer (1620–1695) in Schaffhausen, and Bayle attacks, and noted that those most liable to apoplexy (1622–1709) in Toulouse, only tentatively associated were ‘the obese, those whose face and hands are livid, apoplexy with ‘corpora fibrosa’,31 or with calcification of and those whose pulse is constantly unequal’. cerebral arteries.37 That the paralysis was on the opposite side of the Wepfer (Fig. 2.3) not only recognized arterial lesions, apoplectic lesion was clearly predicted by Domenico but he also prompted one of the great advances in the Mistichelli (1675–1715) from Pisa on the basis of his knowledge about stroke by distinguishing between, on observation of the decussation of the pyramids (Fig. 2.4).39 the one hand, arterial obstruction preventing the influx A landmark in the recognition of the anatomical sub- strate of stroke – and of many other diseases – was the work of Morgagni (1682–1771), professor of medicine and subsequently of pathological anatomy in Padua. In 1761 Morgagni published an impressive series of clinico- pathological observations collected over a lifetime (he

Fig. 2.4 Illustration from Mistichelli’s book on apoplexy (1709) in which he shows the decussation of the pyramids and also Fig. 2.3 Johann Jakob Wepfer (1620–1695). the outward rotation of the leg on the paralysed side.39 12 Chapter 2 Development of knowledge about cerebrovascular disease St Matthew Erlkönig Historical events 0 Birth of Jesus Christ 1642 Rembrandt paints Night Watch 1682 Peter I ascends Russian throne 1707 Union between England and Scotland 1729 Bach writes Passion 1776 US Declaration of Independence 1815 Battle of Waterloo; Schubert writes Observations on arterial lesions ‘Corpora fibrosa’ Calcifications (1677) ‘Bony, impervious arteries’ (1684) Narrowing due to cartilaginous change (1735) Hardening of arteries associated with haemorrhage? (1795) Ossification of cerebral arteries (1820) 37 33 42 Medical scientist Wepfer (1658) Bayle (Toulouse) (1622–1709) Willis (Oxford) (1621–1675) Boerhaave Baillie (London) (1761–1823) Rostan Non-haemorrhagic ‘Serous apoplexy’, extravasation of serum? (1761) ‘Ramollissement’ (1820): – softening more frequent than haemorrhage – condition not inflammatory? Haemorrhagic Sudden loss of consciousness, as a result brain disease Sudden loss of consciousness, as a result brain disease Extravasation of blood in brain tissue (1658) Paralysis is unilateral, and crossed with respect to lesion (1709) ‘Stoppage of the spirits’ ‘Sanguineous apoplexy’ (1761) 15 13 31 39 36 40 57 Development of ideas about ‘apoplexy’ and its relationship with arterial lesions. Medical scientist Ideas about ‘apoplexy’ Hippocrates (Kos) (460–370 BC) Galenus (Pergamum and Rome) (131–201) Wepfer (Schaffhausen) (1620–1695) Mistichelli (Pisa) (1675–1715) Boerhaave (Leiden) (1668–1738) Morgagni (Padua) (1682–1771) Rostan (Paris) (1790–1866) Table 2.1 2.3 What happens in ‘apoplexy’? 13 The Le 1829 Stephenson builds the railway engine called ‘The Rocket’ 1837 Queen Victoria ascends the throne of British Empire 1848 Year of revolutions; Louis Napoleon elected president of France 1859 Darwin publishes Origin of Species 1863 Manet paints Déjeuner sur l’herbe 1869 Opening of the Suez Canal 1871 Stanley meets Livingstone at Ujiji 1877 Bell invents telephone, Edison the phonograph 1895 Röntgen discovers X-rays in Würzburg 1907 Ehrlich introduces arsphenamine as treatment for syphilis ‘Arteriosclerosis’ (1829) Due to ossification of arteries? Arteriosclerosis leads to thrombosis; thrombi may be torn off and lodge distally (‘embolism’) (1856) End-arteries most vulnerable; paradoxical embolism Thrombosis at the carotid bifurcation may cause secondary embolization to brain (1905) 67 70 Lobstein (Strasbourg) (1777–1835) Abercrombie Virchow Cohnheim Chiari (Prague) (1851–1916) Cerebral softening is definitely inflammatory in nature (1824) Cerebral softening analogous to gangrene of limb? (1836) Cerebral softening caused by obliteration of arteries? (one possible causes; 1838) ‘Encephalomalacia’ (1844): – white, or serous (congestion) – red (inflammatory) – yellow (frequent; unexplained) Cerebral softening caused by capillary congestion, secondary to ‘irritation’ (1842) ‘Yellow softening’ of the brain is secondary to arterial obliteration; any inflammation is secondary (1856) ‘Infarction’ (stuffing) is haemorrhagic by definition, as opposed to ischaemic necrosis (1872) 58 60 62 219 63 66 68 Lallemand (Montpelier) (1790–1853) Abercrombie (Edinburgh) (1780–1844) Carswell (London) (1793–1857) Rokitansky (Vienna) (1804–1878) Cruveilhier (Paris) (1791–1874) Virchow (Berlin) (1821–1902) Cohnheim (Berlin) (1839–1884) 14 Chapter 2 Development of knowledge about cerebrovascular disease

was 79 at the time of publication), in which he firmly recovery, ingravescent apoplexy with partial recovery put an end to the era of systemic (humoral) theories of and relapse, and paraplexic apoplexy with paralysis).49 disease and replaced them by an organ-based approach, There are several reasons why the brain lesion in what though he did not include even a single illustration; we now call cerebral infarction was not identified until characteristically, the title of the book was ‘De sedibus the middle of the 19th century. First, it was impossible to et causis morborum...’ (about the sites and causes of recognize ischaemic softening in patients who had usu- disease).40 Morgagni not only confirmed the notion of ally died not long after their stroke. Fixation methods crossed paralysis but also firmly divided apoplexy into were not available until the end of the 18th century; ‘sanguineous apoplexy’ and ‘serous apoplexy’ (and a third Vicq d’Azyr, Marie Antoinette’s physician, was the form which was neither serous nor sanguineous). A first to use alcohol as a tissue fixative,50 while formal- decade later, Portal (1742–1832) rightly emphasized dehyde fixation was not employed until a century later.51 that it was impossible to distinguish between these Second, it is probable that many patients diagnosed as two forms during life.41 However, it would be a mistake having died from apoplexy in fact had suffered from to assume that ‘serous’ (non-haemorrhagic) apoplexy other conditions. If in our time the diagnosis is wrong in was recognized at that time as being the result of 20–30% of patients referred with a presumed stroke,52–54 impaired blood flow, let alone of mechanical obstruction the diagnostic accuracy was presumably no better in of blood vessels. Some even linked the arterial hardening centuries past. with brain haemorrhages and not with the serous apo- plexies.42 Although we quoted 17th-century scientists such as Bayle and Wepfer in that they associated some non-haemorrhagic cases of apoplexy with obstruction of blood flow, in the 18th century medical opinion swayed 2.4 Cerebral infarction (ischaemic stroke) towards ‘vascular congestion’, a kind of pre-haemorrhagic state. That explanation was propounded not only by Morgagni40 but also by many of his contemporaries and After Morgagni’s seminal book the organ-based approach followers.41,43,44 John Cheyne (1777–1836) pointed out to medicine quickly spread from Italy to other countries. that autopsy in patients who had survived a ‘stroke of In France, the first proponents were surgeons. After apoplexy’ for a considerable time might show a cavity the French revolution the strict distinction between filled with rusty serum that stained the adjacent brain medicine and surgery disappeared, driven by the reorgan- tissue, but he may have been describing a residual lesion ization of hospital care (no longer managed by the after cerebral haemorrhage rather than infarction.45 church but by the state) and by the need to train a large The anatomical, organ-based approach exemplified number of new doctors, for military as well as civilian by Morgagni reflected the Italian practice, in which the duties (‘peu lire, beaucoup voir, beaucoup faire’).55,56 It separation between physicians and surgeons was much was Leon Rostan (1790–1866; Fig. 2.5), a physician at less strict than in northern Europe with its more theo- the Salpêtrière in Paris, who clearly recognized softening retical framework of medicine. The protagonists of the of the brain as a separate lesion, distinct from haemor- Northern school of thinking were Herman Boerhaave rhage, although the pathogenesis still escaped him. He (1668–1738) in Leiden and later William Cullen (1710– published his findings in an unillustrated monograph, 1790) in Edinburgh, the most influential clinical teachers the first edition of which appeared in 1820.57 The lesions of their time. They established a nosological classifica- were most commonly found in the corpus striatum, tion that was based much more on holistic theory, in thalamus or centrum semiovale, but they also occurred terms of a disturbed system, than on actual observations in the cerebral cortex, brainstem and cerebellum. Old at the level of the organ, at least with 20th-century hind- cases showed a yellowish-green discoloration, whereas sight.46 Probably our own time will be branded as the if the patients had died soon after the event the colour era of exaggerated reductionism! In the intellectual of the lesion was chestnut or reddish. The softening tradition of the Dutch-Scottish school, purely clinical might be so extreme as to lead to the formation of a cyst. classifications of apoplexy were proposed in the early In other patients it was difficult to detect any change 19th century by Serres (with and without paralysis),47 in firmness or in colour. Rostan distinguished softening by Abercrombie (primary apoplexy, with deprivation of the brain from ‘apoplexy’, a term he no longer used of sense and motion, and sometimes with convulsions, for stroke in general, but which he regarded as being a second type beginning with headache, and a third synonymous with haemorrhagic stroke. He supposed type with loss of power on one side of the body and of that softening of the brain was more common than brain speech, often with recovery),48 and by Hope and Bennett haemorrhage, although some haemorrhages were second- (transient apoplexy, primary apoplexy with death or slow ary to softening. The clinical manifestations were thought 2.4 Cerebral infarction (ischaemic stroke) 15

seemed for a long time the most logical ‘paradigm’ to fall back on to explain liquefaction of brain tissue.59 The first inkling of a relationship between arterial disease and ‘ramollissement’, as many English writers continued to call brain softening in deference to Rostan, was voiced by Abercrombie, in a later edition of his text- book.60 He drew an analogy with gangrene, caused by ‘failure of circulation’, this in turn being secondary to ‘ossification of arteries’. The role of arterial obstruction as a primary cause of softening of the brain was confirmed by others,61,62 but the theory of inflammation continued to be defended by a few adherents.63,64 Some were aware that apoplexy could be caused by ‘cerebral anaemia’ (as opposed to congestion), not only through loss of blood but also by a reduced vascular pressure, particularly in the case of heart disease.44 Other missing links in the understanding of cerebral infarction were clarified by Rokitansky (1804–1878) in Vienna and by Virchow (1821–1902) in Berlin. Rokitansky divided cerebral softening (which he termed encephalomalacia) into three varieties: red (haem- orrhagic) softening, inflammatory in nature; white softening (synonymous with ‘serous apoplexy’) caused by congestion and oedema; and, the most common vari- ety, yellow softening, of which the pathogenesis was unknown.219 Virchow (Fig. 2.6) revolutionized medical thinking about vascular disease by firmly putting the

Fig. 2.5 Léon Rostan (1790–1866). to occur in two stages: first ‘fugitive’ disturbances in the use of a limb, in speech or in visual or auditory percep- tion, sooner or later followed by hemiplegia and coma, in a slowly progressive fashion. Although Rostan recognized ‘ossification’ of the cerebral arteries, he did not associate these lesions with cerebral softening via obstruction of the arterial system. At any rate he doubted the prevailing opinion that the primary lesion was some kind of inflammatory response. After all, there was redness and swelling (rubor, tumor), if not warmth and pain (calor, dolor), to complete the cardinal signs of inflammation delineated by Celsus in the first century AD. Rostan’s contemporary Lallemand (1790– 1853) was much more outspoken and had little doubt that inflammation was at the root of cerebral softening.58 Readers trained in the 21st century may find this difficult to understand but they should be aware that ‘inflamma- tion’ was a rather common explanation for disease from the middle of the 18th century until some hundred years later.46 Just as in our time some poorly understood medical conditions are often interpreted in terms of auto- Fig. 2.6 Rudolph Virchow (1821–1902) teaching at a immune disease, perhaps erroneously, inflammation postmortem in the Charité Hospital in Berlin. 16 Chapter 2 Development of knowledge about cerebrovascular disease

emphasis on changes in the vessel wall rather than in illustration of how slowly ideas change). Sources of blood; Schiller called it the victory of ‘solidism’ over embolism in the extracranial arteries were hardly con- ‘humoralism’.9 Virchow also firmly established that sidered until the 1960s, at least in teaching. By the same thrombosis of arteries was caused not by inflammation token, the term ‘cerebral thrombosis’ remained firmly but by fatty metamorphosis of the vessel wall, even if he entrenched in clinical thinking as being more or less had to found his own journal before his papers could be synonymous with cerebral infarction without associated published.65,66 To describe the changes in the arterial heart disease, the implication being that in these cases wall Virchow revived the term ‘arteriosclerosis’, first used the site of the atheromatous occlusion was in the by Lobstein.67 Virchow’s disciple Julius Cohnheim intracranial vessels. For example, this is what the sixth coined the culinary term ‘infarction’ (from the Latin edition of Brain’s Diseases of the Nervous System says on verb infarcire, ‘to stuff into’), but strictly reserved it for the subject in 1968: haemorrhagic necrosis (‘stuffing’, by seeping of blood Progressive occlusion of cerebral blood vessels impairs into ischaemic tissue, through damaged walls of capillar- the circulation in the regions they supply. The effects ies) as opposed to ischaemic necrosis.68 of this depend upon the size and situation of the vessel, and the rate of onset of the occlusion particularly in relation to the collateral circulation. Actual obstruc- tion of an artery by atheroma, with or without sub- sequent thrombosis, causes softening of the region of 2.5 Thrombosis and embolism the brain supplied by the vessel.2 That the notion of ‘local thrombosis’ persisted for such Virchow observed thrombosis as the result of athero- a long time must have been because of its appealing sclerosis, and also embolism, in patients with gangrene simplicity, not by lack of observations to the contrary. As of the lower limbs caused by clots from the heart. The long ago as 1905, Chiari drew attention to the frequency term ‘embolism’ was newly coined by him, at least in of atherosclerosis in the region of the carotid bifurca- medical parlance. He extrapolated these events to the tion and suggested that embolization of atheromatous cause of cerebral softening: material might be a cause of cerebral softening,70 and not much later Hunt described the relationship between Here there is either no essential change in the vessel carotid occlusion and stroke.71 The much later general wall and its surroundings, or this is ostensibly second- acceptance of extracranial atherosclerosis as an import- ary. I feel perfectly justified in claiming that these clots ant cause of cerebral ischaemia was prompted by two never originated in the local circulation but that they further developments. The first was the attention gener- are torn off at a distance and carried along in the blood ated by Fisher’s studies, in which he re-emphasized the stream as far as they can go.65 role of atherosclerosis at the carotid bifurcation, at least The relationship between vegetations on the heart in white patients.72 He clinically correlated these lesions valves and stroke had in fact been suggested a century not only with contralateral hemiplegia but also with earlier by Boerhaave’s pupil Gerard van Swieten, per- attacks of monocular blindness in the ipsilateral eye.73 sonal physician to the Austrian empress Maria Theresa The second development was imaging. Cerebral angio- and founder of the Viennese school of medicine: graphy by direct puncture of the carotid artery had been introduced by Moniz in 1927,74,75 but imaging of the It has been established by many observations that carotid bifurcation in patients with stroke became com- these polyps occasionally attach themselves as excres- mon only after the advent of catheter angiography,76 cences to the columnae carneae of the heart, and per- and later of ultrasound techniques. Now it is modern CT haps then separate from it and are propelled, along or MR angiography that often shows abnormalities with the blood, into the pulmonary artery or the aorta, of the internal carotid artery near its origin, at least in and its branches . . . were they thrown into the carotid patients with transient or permanent deficits in the ter- or vertebral arteries, could disturb – or if they com- ritory of the main trunk of the middle cerebral artery or pletely blocked all approach of arterial blood to the one of its branches. The earlier patients are investigated, brain – utterly abolish the functions of the brain.69 the greater the chance of detecting the site where the For more than a century after Virchow’s accurate embolus has become impacted in the cerebral arterial pathological descriptions of arterial occlusions, the tree. The therapeutic implications of identifying lesions term ‘cerebral embolism’ was almost synonymous with in the carotid artery in symptomatic patients became embolism from the heart (parenthetically, it still is, clear through the two large randomized controlled in many contemporary textbooks and papers – another trials of carotid endarterectomy in the 1980s and 1990s, 2.6 Transient ischaemic attacks 17 which showed overall benefit from the operation for The subject is Jean Paul Grandjean de Fouchy, writing in severe degrees of stenosis.77 1783, at the age of 76 years:84 In 25–30% of patients with temporary or permanent Toward the end of dinner, I felt a little increase of pain occlusion of large intracranial vessels no source of above the left eye and in that very instant I became embolism can be found in the neck or in the heart.78,79 unable to pronounce the words that I wanted. I heard Pathological observations suggesting that the aorta may what was said, and I thought of what I ought to reply, harbour atherosclerotic lesions80 have been confirmed in but I spoke other words than those which would a large autopsy series and by transoesophageal echocar- express my thoughts, or if I began them I did not com- diography during life.81,82 Of course, there is more to plete them, and I substituted other words for them. ischaemic stroke than embolism from large vessels, but I had nevertheless all movements as freely as usual... the history of small vessel disease and non-atheromatous I saw all objects clearly, I heard distinctly what was causes of ischaemia is rather more recent. being said; and the organs of thought were, it seemed Before concluding the sections on cerebral infarction, to me, in a natural state. This sort of paroxysm lasted thrombosis and embolism, we should like briefly to draw almost a minute. attention to the term ‘cerebrovascular accident’, which enjoyed some undeserved popularity in the middle half Once it had become established, in the middle of the of the last century. The problem was that sometimes the 19th century, that cerebral softening was not caused by term was used as a synonym for cerebral infarction, at an inflammatory process but by occlusion of cerebral other times to denote stroke in general. In this day and arteries, temporary episodes of ischaemia were recognized age the term is a highly specific sign of woolly thinking. increasingly often in the next few decades.1,85–89 In the We can do no better than quote Schiller:9 course of time, three main theories have been invoked to explain the pathophysiology of TIAs, at least in relation That rather blurry and pompous piece of nomenclature to atherosclerosis: the vasospasm theory, the haemo- must have issued from the well-meant tendency to dynamic theory and the thromboembolic theory.83 soften the blow to patients and their relatives, also from a desire to replace ‘stroke’, a pithy term that may sound unscientific and lacking gentility. ‘Cerebrovascular 2.6.1 The vasospasm theory accident (CVA)’ can be traced to the early 1930s – Arterial spasm as a cause of gangrene of the extremities between 1932, to be exact, when it was still absent from was described by Raynaud (1834–1881) in his doctoral the 15th edition of Dorland’s Medical Dictionary, and thesis of 1862.90 Others extrapolated his theory of the following edition of 1936 where it first appeared. vasospasm to the cerebral circulation.91,92 Russel, writing The occasional medical student or junior doctor who in 1909 about a 50-year-old farmer who had suffered still takes refuge in the term ‘CVA’ in an attempt to cover three attacks of tingling and numbness in the right arm up ignorance about the precise type of cerebrovascular and the right side of the face, dismissed thrombosis event in a given patient (while avoiding sharing the term (‘Thrombus, once formed, does not break up and dis- ‘stroke’ with the laity) should either find out or come appear in some mysterious way’) and instead invoked a clean about not knowing. phenomenon of ‘local syncope’, analogous to Raynaud’s disease or some cases of migraine: ‘There must be some vessel constriction, local in site, varying in degree and in extent, coming and going, intermittent’.92 Even the great Osler mounted the bandwagon of the vasospastic 2.6 Transient ischaemic attacks theory to explain transient attacks of aphasia and para- lysis: ‘We have plenty of evidence that arteries may pass into a state of spasm with obliteration of the lumen and It is difficult to trace the first descriptions of what we loss of function in the parts supplied’.89 Vasospasm now call transient ischaemic attacks (TIAs) of the brain remained the most popular theory to explain TIAs in the or eye, because symptoms representing focal deficits first half of the 20th century and provided the rationale were not clearly distinguished from non-specific symp- for so-called cerebral vasodilators. Up to the 1980s toms of a more global nature such as fainting or these useless drugs were still widely prescribed in some headache.83 Wepfer recorded that he had seen patients European countries, not only for TIAs but for ‘senility’ in who recovered from hemiplegia in one day or less.31 An general; in France they were the third most commonly 18th-century account has been retrieved in the patient’s prescribed medication in 1982.93 own words, not muddled by medical interpretation, In the front line of medicine, however, the vasospastic which makes it as lucid as it would have been today. theory went into decline soon after World War II, firstly 18 Chapter 2 Development of knowledge about cerebrovascular disease

because the cerebral arteries are among the least reactive That the haemodynamic theory does not apply to most in the body,94,95 and secondly because more plaus- patients with TIAs is not to say that the exceptional ible theories emerged (see below). Only under strictly patient cannot suffer from ‘misery perfusion’.104 In the defined conditions can vasospasm be a causal factor in presence of multiple occlusions or stenoses of the extra- the pathogenesis of cerebral ischaemia, that is, after sub- cranial arteries, the haemodynamic reserve may be so arachnoid haemorrhage or in association with migraine, poor that minor changes in systolic blood pressure can- and even in these conditions its role is contentious. Never- not be compensated for. Such triggering events include theless, vasospasm has resurfaced as a possible cause of a change from a sitting to a standing position, turning episodes of transient monocular blindness that are fre- the head, heating of the face or looking into bright quent and stereotyped and have no altitudinal distribu- light.105–107 Perhaps for this small group of patients tion,96 or even of transient motor or sensory deficits not extracranial-intracranial bypass surgery has something related to migraine.97 Such events must be extremely rare. to offer after all, despite the negative results of the ran- domized trial in a large but relatively unselected group of patients with occlusion of the internal carotid or 2.6.2 The haemodynamic theory middle cerebral artery.108 The notion of ‘low flow’ without acute vessel obstruction as a cause of cerebral ischaemia should perhaps be 2.6.3 The thromboembolic theory attributed to Ramsay Hunt, who drew an analogy between the symptoms of carotid stenosis or occlusion and the In the 1950s C. Miller Fisher (Fig. 2.7) not only gave symptoms of intermittent claudication in patients with new impetus to some older observations about the severe peripheral arterial disease.71 But, it was especially relationship between stroke and atheromatous lesions of after 1951, when Denny-Brown suggested that TIAs might be caused by ‘episodic insufficiency in the circle of Willis’,95 that interest in the haemodynamic aspects of TIAs was fully aroused. Indeed, it was mainly the surgical community for which the concept of ‘cerebral inter- mittent claudication’ continued to have great appeal, despite the incongruity of the relatively constant blood flow to the brain and the large fluctuations in flow that occur in the legs, depending on their level of activity. Clinical studies failed to support the notion of haemo- dynamic failure. After artificial lowering of the blood pressure by means of hexamethonium and postural tilting, in 35 patients who had either experienced TIAs or who had known carotid artery disease, only one of the patients developed symptoms of focal cerebral ischaemia before a syncopal attack which signified global rather than focal ischaemia of the brain.98 Similarly, cerebral ischaemia with naturally occurring attacks of hypoten- sion, such as cardiac arrhythmias, is almost always syn- copal and not focal in nature,99 and cardiac arrhythmias do not occur more often in patients with TIAs than in controls.100 Once the first successful carotid reconstruc- tion had been reported,101 the intuitive belief in the haemodynamic theory led to an ever-increasing number of carotid endarterectomies being performed (indeed, often called ‘carotid disobstruction’) in patients with and even without TIAs, despite the absence of any formal proof of efficacy. These developments caused under- standable concern in the neurological community.102,103 Fortunately the controversy prompted well-designed clinical trials, which have served to define to a large extent the role of this operation.77 Fig. 2.7 C. Miller Fisher (1913–).